Browse the corpus

In the heart, L-type calcium channels (LTCCs) are essential in determining the electric and mechanical properties of cardiac muscle.1 In adult ventricular myocytes, LTCCs are predominantly located in the transverse tubules (T-tubules),2 where they form dyadic complexes with calcium-sensing and -release units, the ryanodine receptors (RyR2s) on the opposing junctional sarcoplasmic reticulum membrane (SR). A well-developed network of ventricular T-tubules ensures that the electric impulse is conducted into the cell interior, where Ca2+ influx can trigger the opening of RyR2 and subsequent release of SR Ca2+ stores. Atrial myocytes are believed to lack an elaborate T-tubule network3–5 and their Ca2+ signaling is substantially different from that in ventricular myocytes.6–8 Lack of a regular T-tubular system has been thought to affect the distribution of LTCCs and give rise to the unique Ca2+ signaling in atrial myocytes.6,9,10 Clinical Perspective on p 2384

In the heart, L-type calcium channels (LTCCs) are essential in determining the electric and mechanical properties of cardiac muscle.1 In adult ventricular myocytes, LTCCs are predominantly located in the transverse tubules (T-tubules),2 where they form dyadic complexes with calcium-sensing and -release units, the ryanodine receptors (RyR2s) on the opposing junctional sarcoplasmic reticulum membrane (SR). A well-developed network of ventricular T-tubules ensures that the electric impulse is conducted into the cell interior, where Ca2+ influx can trigger the opening of RyR2 and subsequent release of SR Ca2+ stores. Atrial myocytes are believed to lack an elaborate T-tubule network3–5 and their Ca2+ signaling is substantially different from that in ventricular myocytes.6–8 Lack of a regular T-tubular system has been thought to affect the distribution of LTCCs and give rise to the unique Ca2+ signaling in atrial myocytes.6,9,10 Clinical Perspective on p 2384 A number of important LTCC subpopulations have been identified in ventricular myocytes that associate with unique macromolecular signaling complexes and scaffolding proteins, which enables the modulation of Ca2+ signaling.11 Although the main population of LTCCs is localized to dyadic junctions, extradyadic channels are also associated with the surface membrane.12,13 Caveolin-3 (Cav3)–rich signaling microdomains are found to harbor specific LTCCs that may play an important role in modulation of Ca2+ signaling, particularly in cells lacking organized T-tubules such as atrial5,14–16 and neonatal17 myocytes. However, until recently, it was difficult to test this hypothesis because of the lack of appropriate experimental approaches.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a vasoconstrictive, proliferative, thrombotic phenotype, leading to increased pulmonary artery pressure and pulmonary vascular resistance, and eventually to right ventricular failure.1 In addition to pulmonary vascular remodeling, the pathophysiology of PAH includes in situ thrombosis of the small pulmonary arteries.2–4 The World Symposium on Pulmonary Hypertension group I category includes several types of PAH with similar pathological changes.5–7 It is unclear whether thrombotic vascular lesions are an integral part of the pulmonary vascular pathology or are simply an epiphenomenon. In support of the former hypothesis are abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system observed in patients with idiopathic PAH (IPAH).8 However, these abnormalities have not been described in other forms of group I PAH, including PAH associated with systemic sclerosis (SSc-PAH). Editorial see p 2360 Clinical Perspective on p 2411 Based on these pathological considerations suggesting a prothrombotic milieu of the diseased pulmonary vasculature, 8 observational studies (2 prospective and 6 retrospective) have evaluated the effect of chronic anticoagulation on outcome in patients with IPAH; 6 of these studies reported positive outcomes.9–16 Most of these observational studies were published more than a decade ago, before the introduction of many current PAH therapies. However, despite the limitations of the available evidence, current treatment algorithms recommend warfarin in patients with IPAH.17 Data regarding anticoagulation in patients with associated forms of PAH such as SSc-PAH are even scarcer; however, such a strategy has been extrapolated from IPAH studies and current treatment algorithms recommend warfarin in these patients, based mostly on consensus opinion.17 Expert opinions on the benefit of warfarin in SSc-PAH and IPAH patients vary widely in regard to the effectiveness of treatment.18

e found to harbor specific LTCCs that may play an important role in modulation of Ca2+ signaling, particularly in cells lacking organized T-tubules such as atrial5,14–16 and neonatal17 myocytes. However, until recently, it was difficult to test this hypothesis because of the lack of appropriate experimental approaches. The spatial compartmentation of Ca2+-signaling complexes was first assessed by immunofluorescence microscopy,18 but imaging does not provide information on the functionality of channel proteins within a subcellular domain. Recent methodological advances have made it possible to image the topography of a live cardiomyocyte and study the clustering of functional ion channels within specific microdomains.2 Here, we used a super-resolution scanning patch-clamp technique to study the distribution of functional LTCCs in different structural microdomains of the sarcolemma of rat and human atrial myocytes. We provide direct evidence for 2 distinct subpopulations of atrial LTCCs: one localized in the T-tubules and another linked to caveolae structures. Our findings demonstrate that LTCCs, which are located in caveolae, critically contribute to atrial Ca2+ signaling, particularly in cardiomyocytes lacking an organized T-tubule network. These different LTCC subpopulations may underlie the regional heterogeneity of Ca2+ signaling and susceptibility to spontaneous Ca2+ release events in the atrial. Using a rat model of heart failure (HF), we highlight the relevance of the concept of microdomain-specific remodeling of LTCCs: a disruption in the delicate balance of dynamic interactions between dyadic LTCCs and their cellular microenvironment can alter Ca2+ signaling and lead to pathological changes in cellular physiology.

rat model of heart failure (HF), we highlight the relevance of the concept of microdomain-specific remodeling of LTCCs: a disruption in the delicate balance of dynamic interactions between dyadic LTCCs and their cellular microenvironment can alter Ca2+ signaling and lead to pathological changes in cellular physiology. Materials and Methods Detailed methods are provided in the online-only Data Supplement Methods. All studies complied with the United Kingdom Home Office regulation governing the care and use of laboratory animals and with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996). Myocyte Isolation, T-Tubule Characterization, and Animal Models Single atrial myocytes were isolated separately from both left (LA) and right (RA) atrial of control and 16-week post–myocardial infarction rats (online-only Data Supplement Table I). The subcellular T-tubule system was visualized by confocal imaging of Di-8-ANEPPS–stained cells. Surface topography was characterized by scanning ion conductance microscopy which uses a glass nanopipette as a sensitive probe.19

f control and 16-week post–myocardial infarction rats (online-only Data Supplement Table I). The subcellular T-tubule system was visualized by confocal imaging of Di-8-ANEPPS–stained cells. Surface topography was characterized by scanning ion conductance microscopy which uses a glass nanopipette as a sensitive probe.19 Super-resolution Scanning Patch-Clamp With Pipette Clipping Modification After generating a topographical image of the cell surface by scanning ion conductance microscopy, the tip diameter of the pipette was widened by clipping19 to increase the area of attachment. The pipette was then lowered to a specific location until it touched the membrane, and a high-resistance seal was established. Recordings were then performed in a cell-attached mode. Controlled widening of the scanning nanopipette tip is described in detail in the online-only Data Supplement Methods. Macroscopic calcium currents were recorded by using the whole-cell patch-clamp technique.20 Optical Mapping and Data Analysis Optical mapping of cells loaded with the Ca2+-sensitive fluorescent dye Fluo-4 AM via a complementary metal-oxide semiconductor camera ULTIMA-L (SciMedia, USA Ltd, Costa Mesa, CA) was used to monitor localized changes in [Ca2+]i.

Super-resolution Scanning Patch-Clamp With Pipette Clipping Modification After generating a topographical image of the cell surface by scanning ion conductance microscopy, the tip diameter of the pipette was widened by clipping19 to increase the area of attachment. The pipette was then lowered to a specific location until it touched the membrane, and a high-resistance seal was established. Recordings were then performed in a cell-attached mode. Controlled widening of the scanning nanopipette tip is described in detail in the online-only Data Supplement Methods. Macroscopic calcium currents were recorded by using the whole-cell patch-clamp technique.20 Optical Mapping and Data Analysis Optical mapping of cells loaded with the Ca2+-sensitive fluorescent dye Fluo-4 AM via a complementary metal-oxide semiconductor camera ULTIMA-L (SciMedia, USA Ltd, Costa Mesa, CA) was used to monitor localized changes in [Ca2+]i. Statistical Analysis All graphs and statistical analysis were performed by using either GraphPad prism 5 or Origin version 6.1. The average values were calculated throughout all cells studied within the groups and then compared between the groups. Normality was tested using the Kolmogorov-Smirnov test. In cases where data failed the normality test, the nonparametric Mann-Whitney test was used instead of the unpaired Student t test, and the nonparametric Kruskal-Wallis test was used instead of analysis of variance. Statistical differences were assessed with analysis of variance, Student t test, Mann-Whitney test, Kruskal-Wallis test, χ2, and Fisher exact test as appropriate. All data are expressed as mean±standard error of the mean. A value of P<0.05 was considered statistically significant.

used instead of analysis of variance. Statistical differences were assessed with analysis of variance, Student t test, Mann-Whitney test, Kruskal-Wallis test, χ2, and Fisher exact test as appropriate. All data are expressed as mean±standard error of the mean. A value of P<0.05 was considered statistically significant. Results In Situ T-Tubule Imaging in Isolated Rat Atrial Preparations To characterize the atrial T-tubular network, we performed in situ T-tubule imaging on intact rat atrial using whole-mount fluorescence labeling with glycophilic lectin wheat germ agglutinin. We found significant region-dependent heterogeneity in T-tubule structure throughout the atrial. Although the LA myocardium predominantly consisted of cardiomyocytes with T-tubules (Figure 1A, Right), in the RA, we observed 3 groups of cardiomyocytes: cells (1) with organized T-tubules, (2) with disorganized T-tubules, and (3) with absent T-tubules (Figure 1A, Left).

ty in T-tubule structure throughout the atrial. Although the LA myocardium predominantly consisted of cardiomyocytes with T-tubules (Figure 1A, Right), in the RA, we observed 3 groups of cardiomyocytes: cells (1) with organized T-tubules, (2) with disorganized T-tubules, and (3) with absent T-tubules (Figure 1A, Left). Figure 1. Spatial heterogeneity of the atrial T-tubular system: in situ and in vitro measurements. A, In situ confocal imaging of T-tubules (TTs) in intact rat atrial preparation stained with wheat germ agglutinin. In the middle, the schematic outlines of the isolated rat atrial preparation showing the main anatomic features. The enlarged images from the endocardium of the right (RAA) and left (LAA) atrial appendages demonstrate typical atrial myocytes with organized TTs (white arrows), disorganized TTs (red arrows), or mixture of both types. AVN indicates atrioventricular node; CT, crista terminalis; IAS, interatrial septum; IVC, inferior vena cava; SAN, sinoatrial node; SVC, superior vena cava; and TRAB, trabeculae. B, Di-8-ANEPPS membrane staining showing a TT network in ventricular myocytes and in atrial myocytes with organized, disorganized, and absent TTs. Below the confocal images, enlarged areas of 40×5 µm are shown that were binarized and used in TT density and regularity measurements. For structured atrial myocytes, 3D reconstructions of the TTs obtained from confocal stack images are shown (see also online-only Data Supplement Movies I and II). C, Representative distribution of power of the predominant frequency retrieved from 2D Fourier transformation of confocal images (B insets). D, Average width of cells with different TT structure isolated from left ventricle (LV, n=45 cells from 3 rats) and LA and RA (n=29/2, 26/35, and 22/38 cells from 6 rats for organized, disorganized, and absent TTs for cells from LA/RA, respectively). * P<0.001 versus atrial myocytes; ** P<0.001 versus other cell groups within the atrium by unpaired Student t test. E, Correlation between surface structure and cell size. Optical images and topography scans (zoomed areas) of a ventricular myocyte and atrial myocytes with various degrees of organization of surface structures are shown. TTs, crests, and nonstructured areas are indicated by arrows. Note that the cell shown in the right-most panel does not possess any organized surface structures.

images and topography scans (zoomed areas) of a ventricular myocyte and atrial myocytes with various degrees of organization of surface structures are shown. TTs, crests, and nonstructured areas are indicated by arrows. Note that the cell shown in the right-most panel does not possess any organized surface structures. Subcellular T-Tubule System in Rat Atrial Cardiomyocytes Confocal imaging of Di-8-ANEPPS–stained cardiomyocytes isolated separately from the LA and RA revealed that, although about one-third of cells do not have T-tubules (≈39% in RA; 34% in LA), other cardiomyocytes possess a T-tubular network of some sort. We also found cells with organized T-tubular networks similar to those found in ventricular myocytes, and those with disorganized T-tubules (Figure 1B). The majority of atrial myocytes with organized T-tubules were isolated from the LA (≈40% versus 2% in LA versus RA). Conversely myocytes isolated from the RA were more likely to have disorganized T-tubule network (26% versus 59% in LA versus RA) (online-only Data Supplement Figure I). In ventricular rat myocytes, T-tubules are distributed regularly at ≈2-µm intervals, as demonstrated by Fourier transform of binarized images of T-tubules (Figure 1C). In contrast, the atrial T-tubular network is less dense and less regular than in ventricular myocytes. Atrial myocytes with organized T-tubules showed a smaller, but still distinct peak in the Fourier transform plot (3.1±0.6 AU versus 11.3±0.9 AU in atrial (n=31 cells from 4 rats) versus ventricular myocytes (n=45 cells from 3 rats), P<0.001). On the other hand, atrial cells with disorganized or absent T-tubules (both in LA and RA) did not show a dominant peak on the Fourier transform plot (Figure 1C). Organization of the atrial T-tubular network correlates with cell width: cells showing organized T-tubular networks were larger than cells with disorganized or absent T-tubules (Figure 1D and online-only Data Supplement Figure II).

th in LA and RA) did not show a dominant peak on the Fourier transform plot (Figure 1C). Organization of the atrial T-tubular network correlates with cell width: cells showing organized T-tubular networks were larger than cells with disorganized or absent T-tubules (Figure 1D and online-only Data Supplement Figure II). Surface Structures in Rat Atrial Myocytes Our previous scanning ion conductance microscopy imaging of rat ventricular myocytes21 has clearly showed the surface topography to be structured with T-tubule openings arranged along Z-grooves and the domed crests located in between them. To characterize cardiomyocyte topography, we have introduced the Z-groove index21: a ratio of the observed Z-groove length to the total extrapolated Z-groove length (as if they were present throughout the entire surface). We applied this analysis to characterize topography of atrial myocytes. We found that the larger an atrial myocyte, the more regular its surface topography. This is consistent with the more organized T-tubule network noted in these larger myocytes. Atrial myocytes with organized surface structures and apparent T-tubule openings, similar to those seen in ventricular myocytes, were wider than those with patchy nonstructured areas on their surface, which in turn were wider than atrial myocytes that entirely lacked surface structures (Figure 1E). Similarly, the Z-groove index was significantly higher in LA versus RA myocytes (0.66±0.03 versus 0.50±0.03 in LA versus RA, respectively, P<0.001), confirming the presence of more structured myocytes in the LA.

surface, which in turn were wider than atrial myocytes that entirely lacked surface structures (Figure 1E). Similarly, the Z-groove index was significantly higher in LA versus RA myocytes (0.66±0.03 versus 0.50±0.03 in LA versus RA, respectively, P<0.001), confirming the presence of more structured myocytes in the LA. Rat Atrial Myocyte Ca2+ Signaling Atrial myocytes differ strikingly from ventricular myocytes in shape, magnitude, and kinetics of subcellular Ca2+ transients and in the dynamic of spontaneous Ca2+ release events, as well.4,6 These differences were hypothesized to be largely attributed to the distinct structure of atrial T-tubules and to altered distribution of LTCCs and their coupling to RyR, as well.10 Optical mapping of spontaneous Ca2+ activity revealed that atrial myocytes have different Ca2+ cycling than ventricular myocytes. Among all spontaneous Ca2+ release events, Ca2+ waves propagating throughout the entire cell (Figure 2A) were distinguished from nonpropagating Ca2+ release events (Figure 2B). Although we did not distinguish Ca2+ sparks from Ca2+ puffs,22,23 we observed 2 groups of nonpropagating Ca2+ events: one with a smaller amplitude (23±1% of the amplitude of the corresponding paced Ca2+ transients, 60% of all nonpropagating Ca2+ events) and another with a higher amplitude (60±4% of the paced Ca2+ transient amplitude, 40% of all nonpropagating Ca2+ events), which could be attributed to Ca2+ puffs and Ca2+ sparks, respectively.22 In comparison with ventricular myocytes, atrial cells showed a significantly higher frequency of nonpropagating Ca2+ release events following a period of high-frequency stimulation (Figures 2C and 2D and online-only Data Supplement Figure III).

), which could be attributed to Ca2+ puffs and Ca2+ sparks, respectively.22 In comparison with ventricular myocytes, atrial cells showed a significantly higher frequency of nonpropagating Ca2+ release events following a period of high-frequency stimulation (Figures 2C and 2D and online-only Data Supplement Figure III). Figure 2. Spontaneous Ca2+ release events. Spontaneous Ca2+ activity was measured in isolated ventricular (A) and atrial (B) myocytes. Cells were electrically paced at 4 Hz for 1 minute to enhance sarcoplasmic reticulum Ca2+ loading. Ca2+ sparks and waves were quantified during a 8- to 16-s rest period after cessation of pacing. On the left, optical traces indicating changes in [Ca2+]i during measurements are shown from 3 different areas (1–3) from the selected cardiomyocytes. On the right, Ca2+ transient propagation color contour maps are presented for a spontaneous Ca2+ wave recorded from the ventricular myocyte (A) and 3 Ca2+ sparks obtained from the atrial myocyte (B). Near the maps, the corresponding color time scales for propagation time are shown. C, Average frequency of spontaneous Ca2+ sparks and waves measured in ventricular (n=126 from 8 rats) and atrial (n=357 from 9 rats) myocytes. *** P<0.001 by Mann-Whitney test. D, Percentage of atrial (n=126) and ventricular myocytes (n=357) with spontaneous Ca2+ release events. ** P<0.01 by unpaired Student t test. E, Average cell width for atrial myocytes with and without spontaneous Ca2+ release events (n=117 cells from 7 rats). *** P<0.001 by Mann-Whitney test. F, Average frequency of spontaneous Ca2+ sparks and waves measured separately in right (RA, n=156 from 4 rats) and left (LA, n=201 from 4 rats) atrial myocytes. * P<0.05 by Mann-Whitney test. G, Percentage of RA (n=156) and LA myocytes (n=201) with spontaneous Ca2+ events. H, Correlation between cell width and frequency of spontaneous Ca2+ events for atrial myocytes together with a correlation coefficient. CM indicates cardiomyocyte; LA, left atrium; and RA, right atrium.

tes. * P<0.05 by Mann-Whitney test. G, Percentage of RA (n=156) and LA myocytes (n=201) with spontaneous Ca2+ events. H, Correlation between cell width and frequency of spontaneous Ca2+ events for atrial myocytes together with a correlation coefficient. CM indicates cardiomyocyte; LA, left atrium; and RA, right atrium. We found that wider rat atrial myocytes exhibited a significantly higher number of spontaneous Ca2+ release events (Figure 2E). No spontaneous Ca2+ release events were observed in cells thinner than 11.0±0.4 µm (P=0.002 versus cells with events, Figure 2E). In addition, nonpropagating Ca2+ release events were observed in atrial myocytes 13.2±0.6 µm wide, whereas propagating Ca2+ waves were found in cells ≥14.9±1.1 µm wide (data not shown). Cardiomyocytes isolated from the LA demonstrated a higher number of Ca2+ release events than RA myocytes (Figures 2F and 2G). In atrial myocytes that exhibited spontaneous Ca2+ release events, the number of events was found to be proportional to cell width, as shown in Figure 2H. Spatial Localization of Functional LTCCs In adult rat ventricular myocytes, functional LTCCs are predominantly localized in the T-tubules.2 Here, we applied the same super-resolution scanning patch-clamp method2 (Figures 3A through 3C) and found that, in contrast to ventricular myocytes, in rat atrial cells LTCCs were recorded with similar frequency from T-tubules (T-LTCC), crests (C-LTCC), and nonstructured areas (Figure 3D).

localized in the T-tubules.2 Here, we applied the same super-resolution scanning patch-clamp method2 (Figures 3A through 3C) and found that, in contrast to ventricular myocytes, in rat atrial cells LTCCs were recorded with similar frequency from T-tubules (T-LTCC), crests (C-LTCC), and nonstructured areas (Figure 3D). Figure 3. Single LTCC activity recorded from T-tubule, crest, and nonstructured areas in rat atrial myocytes. Typical 10×10 µm topographical scans of cardiomyocytes showing locations where a pipette was placed after clipping and a giga-seal was obtained over a T-tubule (A), a crest (B), and a nonstructured flat area (C) of the sarcolemma. On the right, corresponding representative current traces of single LTCC activity at the given voltages using a pipette of 25 Ω resistance. D, Percentage of occurrence of the LTCC current from the T-tubules (TT; 78 successful patches), crests (63 successful patches), and nonstructured areas (NStr; 26 successful patches). E, Current-voltage relationship of single LTCC activity recorded from the T-tubules, crest, and NStr areas . n=6 to 16 channels for T-tubules, n=8 to 12 channels for crests, and n=5 channels for nonstructured areas. * P<0.05 and ** P<0.01 versus C-LTCCs by analysis of variance. F, Top, LTCC openings evoked by voltage jumps to –26.7mV and using 90 mM Ba2+ as the charge carrier. The dashed lines indicate substates and fully open levels. Bottom, The LTCC amplitude histogram of single-channel openings to different substate levels measured as shown on the panel above. C-LTCC indicates crest L-type calcium channel; and LTCC, L-type calcium channel.

6.7mV and using 90 mM Ba2+ as the charge carrier. The dashed lines indicate substates and fully open levels. Bottom, The LTCC amplitude histogram of single-channel openings to different substate levels measured as shown on the panel above. C-LTCC indicates crest L-type calcium channel; and LTCC, L-type calcium channel. Although no difference in LTCC open probability was found in different locations (P[open] at –6.7mV: 0.060±0.006 for T-LTCCs versus 0.067±0.013 for C-LTCCs, not significant [NS]; and versus 0.053±0.006 in nonstructured area, NS), T-LTCCs possessed ≈40% higher amplitude at negative voltages in comparison with the other 2 groups of channels (Figure 3E). Like many other types of channels, LTCCs show multiple subconductance levels in addition to the largest and the main open state of the channel.24,25 Examples of these substates are given in Figure 3F, Top, and online-only Data Supplement Figure IV. As summarized in Figure 3F, Bottom, C-LTCCs exhibited low-amplitude subconductance states more frequently than T-LTCCs: open probability of low-amplitude subconductance states was 0.027±0.005 and 0.005±0.002 for C-LTCCs (n=4) and T-LTCCs (n=5), respectively, P<0.01.

e 3F, Top, and online-only Data Supplement Figure IV. As summarized in Figure 3F, Bottom, C-LTCCs exhibited low-amplitude subconductance states more frequently than T-LTCCs: open probability of low-amplitude subconductance states was 0.027±0.005 and 0.005±0.002 for C-LTCCs (n=4) and T-LTCCs (n=5), respectively, P<0.01. In addition, we explored microdomain-specific distribution of functional LTCCs in several human RA samples (Figure 4A). On average, human atrial myocytes had a Z-groove index of 0.57±0.02 (n=27), which is similar to that measured in rat RA. Similar to rat, human LTCCs were recorded with similar frequency from T-tubules and crest (Figure 4B). We did not observe any difference in the voltage-current characteristics between the areas (Figure 4C). However, in contrast to rat, human T-LTCCs had significantly higher open probability than C-LTCCs: P(open) at –6.7mV: 0.03±0.002 for T-LTCCs versus 0.017±0.001 for C-LTCCs, P<0.001.

m T-tubules and crest (Figure 4B). We did not observe any difference in the voltage-current characteristics between the areas (Figure 4C). However, in contrast to rat, human T-LTCCs had significantly higher open probability than C-LTCCs: P(open) at –6.7mV: 0.03±0.002 for T-LTCCs versus 0.017±0.001 for C-LTCCs, P<0.001. Figure 4. Microdomain distribution of functional LTCCs in human right atrial myocytes. A, Left, Typical 10×10 µm topographical scan of the human right atrial myocyte isolated from a patient with sinus rhythm. T-tubule and crest areas are indicated by arrows. Z-grooves are shown by the dotted lines when present. Right, Representative current traces of single LTCC activity recorded at –6.7mV using a pipette of 25 Ω resistance. B, Percentage of occurrence of functional LTCC current from the T-tubules and crest areas of human atrial myocytes. Above the columns is the number of patches with the active current out of the total number of patches for each location. C, Current-voltage relationship of single LTCC current activity recorded from the T-tubules and from the crests. LTCC indicates L-type calcium channel.

bules and crest areas of human atrial myocytes. Above the columns is the number of patches with the active current out of the total number of patches for each location. C, Current-voltage relationship of single LTCC current activity recorded from the T-tubules and from the crests. LTCC indicates L-type calcium channel. Caveolae as a Source of Extradyadic LTCCs It has been demonstrated in ventricular myocytes that some LTCCs could be housed in caveolae.12,13 We hypothesized that atrial extratubular LTCCs recorded from the crests and nonstructured areas might be localized to caveolae. To address this hypothesis, we used 2 different approaches to disrupt caveolae: treatment with methyl-β-cyclodextrin (MβCD) and direct LTCC inhibition in Cav3-containig membranes using a specific peptide inhibitor Rem.

l extratubular LTCCs recorded from the crests and nonstructured areas might be localized to caveolae. To address this hypothesis, we used 2 different approaches to disrupt caveolae: treatment with methyl-β-cyclodextrin (MβCD) and direct LTCC inhibition in Cav3-containig membranes using a specific peptide inhibitor Rem. Incubation of atrial myocytes with 10 mM MβCD for 30 minutes at room temperature17,26 resulted in ≈60% depletion of caveolae (Figure 5A), with no changes in cell topography and T-tubule density (online-only Data Supplement Figure V). While MβCD did not affect LTCCs occurrence in the T-tubules (28% versus 28%, before and after MβCD, NS), it completely abolished the occurrence of extratubular LTCCs (30.1% versus 0% before and after MβCD, respectively) (Figures 5B and 5C), suggesting a crucial role of caveolae for spatial compartmentation of LTCCs in atrial myocytes. No changes in either the open probability or the current-voltage relationship of T-LTCCs were observed after MβCD (online-only Data Supplement Figure VI). Associated with LTCC removal from the crest, MβCD significantly decreased the whole-cell calcium current (ICa,L) density by ≈30% (Figure 5D) without affecting cell capacitance (73.9±14.6 pF for control [n=9] versus 72.6±5.8 pF for MβCD [n=13] groups, NS). In contrast, in ventricular myocytes, no changes in either cell capacitance (136.9±8.1 pF for control versus 112.1±9.5 pF for MβCD groups, n=10/group, P=0.062) or ICa,L was observed after MβCD treatment (online-only Data Supplement Figure VII).

9±14.6 pF for control [n=9] versus 72.6±5.8 pF for MβCD [n=13] groups, NS). In contrast, in ventricular myocytes, no changes in either cell capacitance (136.9±8.1 pF for control versus 112.1±9.5 pF for MβCD groups, n=10/group, P=0.062) or ICa,L was observed after MβCD treatment (online-only Data Supplement Figure VII). Figure 5. Cholesterol depletion removes caveolae, abolishes the occurrence of extratubular LTCCs decreasing whole-cell ICa,L and suppressing spontaneous Ca2+ sparks. A, Ultrastructural changes in rat atrial myocytes after methyl-β-cyclodextrin incubation. Electron micrographs of representative control (Left) and 10 mM methyl-β-cyclodextrin (MβCD)–treated rat atrial (Right) myocytes are shown. Caveolae are marked by arrowheads. Right, Caveolae per micrometer in the cellular membrane before and after MβCD treatment (n=16 for control and n=10 for MβCD group, n=3 rats per group). *** P<0.001 by unpaired Student t test. B, Typical 10×10 µm topographical scans of control (Left) and MβCD-treated (Right) rat atrial myocytes. Below are single-channel recordings obtained from the T-tubule (TT) and the crest of sarcolemma (Crest). C, Percentage of LTCC current occurrence in the T-tubules and crests. ** P<0.01 for Crest MβCD LTCC versus other groups, by Fisher exact test. D, Whole-cell ICa,L density (n=9 for control and n=12 for MβCD groups) before and after MβCD treatment. * P<0.05 by unpaired Student t test. E, Along with changes in ICa,L, MβCD significantly suppressed the occurrence of spontaneous Ca2+ sparks. *** P<0.001 by Mann-Whitney test. The proportion of cells with spontaneous Ca2+ events (F) and Ca2+ spark amplitude (G) were also decreased following the treatment. Ca2+ spark amplitude was calculated as a percentage from the amplitude of electrically induced Ca2+ transient measured during 4-Hz pacing. n=82 cells from 12 rats and n=99 cells from 7 rats for control and MβCD groups, respectively. * P<0.05, ** P<0.01 by unpaired Student t test. LTCC indicates L-type calcium channel.

Ca2+ spark amplitude was calculated as a percentage from the amplitude of electrically induced Ca2+ transient measured during 4-Hz pacing. n=82 cells from 12 rats and n=99 cells from 7 rats for control and MβCD groups, respectively. * P<0.05, ** P<0.01 by unpaired Student t test. LTCC indicates L-type calcium channel. Ignition of Ca2+ Sparks Through Caveolae Along with changes in LTCC distribution, MβCD significantly suppressed the occurrence of spontaneous Ca2+ release events in rat atrial myocytes (online-only Data Supplement Figure VIII). MβCD treatment significantly decreased the number of spontaneous Ca2+ sparks, but not waves (Figure 5E) and reduced the number of cells featuring spontaneous Ca2+ release events (Figure 5F). Moreover, removing caveolae via MβCD treatment also reduced the amplitude of Ca2+ sparks in atrial myocytes (Figure 5G), as has been previously demonstrated in neonatal ventricular myocytes and arterial smooth muscle cells.17

ure 5E) and reduced the number of cells featuring spontaneous Ca2+ release events (Figure 5F). Moreover, removing caveolae via MβCD treatment also reduced the amplitude of Ca2+ sparks in atrial myocytes (Figure 5G), as has been previously demonstrated in neonatal ventricular myocytes and arterial smooth muscle cells.17 Caveolae-Targeted LTCC Antagonist Eliminates Occurrence of Extradyadic LTCC Current To confirm that extratubular LTCCs are localized to Cav3-associated caveolae structures, rather than lipid rafts, we used a Cav3-targeted LTCC-blocking agent, Rem peptide.12 The caveolae-targeted LTCC blocker (Rem1-265-Cav) was generated by molecular modification of Rem, a member of the RGK GTPase family that is known to potently inhibit LTCCs.27 Makarewich et al12 have demonstrated that in rat ventricular myocytes Rem1-265-Cav localizes to plasma membrane specifically within caveolin-containing lipid rafts, rather than lipid rafts in general, and does not displace molecules normally found in caveolae.

GK GTPase family that is known to potently inhibit LTCCs.27 Makarewich et al12 have demonstrated that in rat ventricular myocytes Rem1-265-Cav localizes to plasma membrane specifically within caveolin-containing lipid rafts, rather than lipid rafts in general, and does not displace molecules normally found in caveolae. With 60% to 65% infection efficiency, expressing Rem in rat atrial myocytes resulted in a significant decrease in the occurrence of the single LTCC on the crest area of sarcolemma (Figure 6A) without affecting LTCC biophysical properties (Figure 6B). Similarly, Rem1-265-Cav decreased spontaneous Ca2+ release events in infected cells (Figure 6C). Truncation of the membrane-docking domain in the Rem1-265-Cav peptide (Rem1-265) resulted in the inability of Rem to affect the occurrence of the single LTCC current on the crest and to change spontaneous Ca2+ events (Figure 6). No changes in the single channel open probability were observed.

nfected cells (Figure 6C). Truncation of the membrane-docking domain in the Rem1-265-Cav peptide (Rem1-265) resulted in the inability of Rem to affect the occurrence of the single LTCC current on the crest and to change spontaneous Ca2+ events (Figure 6). No changes in the single channel open probability were observed. Figure 6. A caveolae-targeted LTCC antagonist decreases the occurrence of single LTCC current on the crest area of the sarcolemma and reduces spontaneous Ca2+ events. Percentage of occurrence (A) and current-voltage relationship (B) of the single LTCC current from the crest area of uninfected (48 hours of culturing without a virus; 12 channels in 32 patches), Rem1-265-infected (8 channels in 21 patches), and Rem1-265-Cav-infected (48 hours after infection; 5 channels in 28 patches) atrial myocytes. C, Average data for Ca2+ sparks and waves measured in uninfected (n=67 cells from 5 rats), Rem1-265-infected (n=50 cells from 4 rats), and Rem1-265-Cav–infected (n=35 cells from 5 rats) atrial myocytes measured 48 hours after infection. *** P<0.001 versus uninfected, # P<0.05 versus Rem1-256 by Kruskal-Wallis test. D, Percentage of atrial myocytes with spontaneous Ca2+ events in 3 groups of cells studied. * P<0.05 versus both groups by Kruskal-Wallis test. LTCC indicates L-type calcium channel.

rats) atrial myocytes measured 48 hours after infection. *** P<0.001 versus uninfected, # P<0.05 versus Rem1-256 by Kruskal-Wallis test. D, Percentage of atrial myocytes with spontaneous Ca2+ events in 3 groups of cells studied. * P<0.05 versus both groups by Kruskal-Wallis test. LTCC indicates L-type calcium channel. HF Model and Structural Changes in the Atrial To study disease-associated atrial remodeling, we used the 16 weeks of post–myocardial infarction rat model of HF.28 This model recapitulates many features of chronic HF in patients including adverse remodeling of the organ, characterized by left ventricle dilatation, reduced ejection fraction, and raised filling pressures (online-only Data Supplement Table I). Atrial cellular hypertrophy was noted with an increase in planar width (Figure 7A). Figure 7. Structural remodeling of atrial myocytes in heart failure (HF) rats. Average cell width (A), composition (in percent) of populations of myocytes (B), and T-tubule system density (C) in cells with different T-tubule (TT) structure isolated from control and HF left (LA) and right (RA) atrial, n=77/75 control cells for LA/RA (29/26/22 and 2/35/38 cells for organized/disorganized/absent TT in LA and RA, respectively) versus n=65/43 HF cells for LA/RA (9/19/37 and 0/10/33 cells for organized/disorganized/absent TT in LA and RA, respectively) for LA/RA control versus HF rats). * P<0.05, ** P<0.01, *** P<0.001 versus control by unpaired Student t test or Mann-Whitney test as appropriate.

organized/absent TT in LA and RA, respectively) versus n=65/43 HF cells for LA/RA (9/19/37 and 0/10/33 cells for organized/disorganized/absent TT in LA and RA, respectively) for LA/RA control versus HF rats). * P<0.05, ** P<0.01, *** P<0.001 versus control by unpaired Student t test or Mann-Whitney test as appropriate. Similar to control, in HF we also observed 3 groups of cardiomyocytes, although cells with organized T-tubules were found exclusively in the LA (Figure 7B). Despite cell hypertrophy, HF led to a profound degradation of the T-tubule system in all groups of cells, decreasing the proportion of structured myocytes and reducing the T-tubule density in both LA and RA (Figure 7C). Similarly, HF resulted in the loss of surface structures and a reduction in Z-groove index (0.57±0.01 versus 0.45±0.02 in control versus HF, P<0.001).

radation of the T-tubule system in all groups of cells, decreasing the proportion of structured myocytes and reducing the T-tubule density in both LA and RA (Figure 7C). Similarly, HF resulted in the loss of surface structures and a reduction in Z-groove index (0.57±0.01 versus 0.45±0.02 in control versus HF, P<0.001). Functional Atrial Remodeling in HF Along with the degradation of the atrial T-tubular system, HF also caused altered Ca2+ cycling. We found a ≈30% increase in spontaneous Ca2+ spark frequency and a 3-fold increase in wave frequency (Figure 8A and 8B). The average amplitude of nonpropagated Ca2+ events was increased, perhaps suggesting a greater proportion of high-amplitude events (Ca2+ events), as opposed to low-amplitude events (Ca2+ puffs) (23/77 versus 60/40 for Ca2+ puffs/sparks in HF versus control, respectively). In addition, failing atrial myocytes were associated with slower and wider Ca2+ waves (Figure 8D and online-only Data Supplement Figure IX), which may result from T-tubule degradation and increase time required for dyad-to-dyad Ca2+ propagation.

77 versus 60/40 for Ca2+ puffs/sparks in HF versus control, respectively). In addition, failing atrial myocytes were associated with slower and wider Ca2+ waves (Figure 8D and online-only Data Supplement Figure IX), which may result from T-tubule degradation and increase time required for dyad-to-dyad Ca2+ propagation. Figure 8. Microdomain-specific remodeling of single LTCCs in HF. A, Spontaneous Ca2+ activity measured in isolated control (Left) and HF (Right) rat atrial myocytes. Optical traces indicating changes in [Ca2+]i are shown from 3 different areas (1–3) from the selected cardiomyocytes. Below the traces, Ca2+ transient propagation color contour maps are presented for selected events. Near the maps, the corresponding color time scales for propagation time are shown. B, Average frequency of spontaneous Ca2+ sparks and waves measured in control (n=116 cells from 5 rats) and HF (n=119 cells from 4 rats) atrial myocytes. *** P<0.001 by Mann-Whitney test. C, Maximal amplitude of sparks (in percent from a paced Ca2+ transient, %CaTA). ** P<0.01 by Mann-Whitney test. D, Maximal length activated by a spark (ΔLmax, pixels). *** P<0.001 by unpaired Student t test. E, Current-voltage relationship of single LTCC activity recorded from the T-tubules (TT) and crest in control and HF rat atrial myocytes. F, LTCC amplitude histogram of single-channel openings to different substate levels calculated for T-LTCC in control and HF. CaTA indicates calcium transient amplitude; LTCC, L-type calcium channel; and T-LTCC, T-tubule L-type calcium channel.

ded from the T-tubules (TT) and crest in control and HF rat atrial myocytes. F, LTCC amplitude histogram of single-channel openings to different substate levels calculated for T-LTCC in control and HF. CaTA indicates calcium transient amplitude; LTCC, L-type calcium channel; and T-LTCC, T-tubule L-type calcium channel. Microdomain-Specific Remodeling of Atrial LTCCs in HF When characterized by the super-resolution scanning patch clamp, LTCCs in HF cells demonstrate the same equal distribution between T-tubules and crests as observed in control cells (34.3% and 30.5% versus 28% and 30.1% for T-LTCCs and C-LTCCs in HF versus control, respectively, NS). This corresponds with the similar caveolae density in HF and control myocytes (3.7±0.5 caveolae/µm in control versus 4.6±0.4 caveolae/µm in HF, P=0.167). Although we did not observe any significant changes in open probability for T-LTCCs and C-LTCCs in HF, we found that T-LTCCs had ≈25% smaller amplitude in HF in comparison with control T-LTCCs (Figure 8E). No changes in C-LTCC amplitude were revealed in HF. The decrease in T-LTCC amplitude in HF was associated with a change in the accessibility of the channel subconductance states (Figure 8F). In HF, the occupancy of low-amplitude substates becomes more accessible than high-amplitude substates in comparison with control (0.018±0.006 and 0.006±0.002 versus 0.006±0.002 and 0.075±0.005 for low- and high-amplitude subconductance states in HF versus control, respectively).

annel subconductance states (Figure 8F). In HF, the occupancy of low-amplitude substates becomes more accessible than high-amplitude substates in comparison with control (0.018±0.006 and 0.006±0.002 versus 0.006±0.002 and 0.075±0.005 for low- and high-amplitude subconductance states in HF versus control, respectively). Discussion Functional Anatomy of Atrial Myocardium Atrial myocytes have long been perceived as having no or very few T-tubules.3,10,29 However, recent experimental evidence demonstrates that atrial myocytes from certain species, such as sheep,30 cows, horses, humans,5 and even rodents4,10,15 do possess an organized T-tubule network. In general, atrial T-tubules are sparse and less regular when compared with those in ventricular myocytes as assessed both in situ31 and in vitro.10 Our observations of T-tubules in rat atrial myocytes are consistent with those previously observed using electron microscopy32,33 and fluorescent membrane labeling.4,16 In the present study, we found significant heterogeneity of T-tubule organization between LA and RA, which might correlate with the arrangement of pectinate muscle bundles within the atrial appendages. It has been reported in rabbit atrial that myocytes isolated from the crista terminalis were significantly larger than those from the pectinate muscles, whereas the shape (the ratio of the length to the width) was found to be similar in the 2 types of cells.34

t of pectinate muscle bundles within the atrial appendages. It has been reported in rabbit atrial that myocytes isolated from the crista terminalis were significantly larger than those from the pectinate muscles, whereas the shape (the ratio of the length to the width) was found to be similar in the 2 types of cells.34 Anatomic heterogeneity of the T-tubular system within the atrial has been proposed to underlie heterogeneous calcium current measured within the right atrium, in addition to different expression of LTCCs. In healthy dogs, Ca2+ influx through LTCCs was found to be largest in crista terminalis cells, intermediate in cells from the appendage and pectinate muscles, and smallest in atrioventricular ring cells.35 In contrast, in rabbit right atrial myocytes isolated from different areas, whole-cell clamp recordings showed no definite variation in the density of the voltage-dependent LTCCs.34 Frisk and colleagues16 used both isolated atrial cells and tissue to demonstrate that in pig and rat atrial there was a high variability in the distribution of T-tubules and ICa,L among cells, with a steep dependence of ICa,L on atrial myocyte capacitance and T-tubule density. The authors observed more T-tubules in the epicardium than in the endocardium, which may contribute to the synchronization of contraction across the atrial wall. Thus, anatomic heterogeneity of the T-tubule network and ICa,L may explain complex features of atrial electric and mechanical activity including highly anisotropic physiological activation patterns,36 action potential duration distribution,37 and contractile function. In addition, disease-associated loss of T-tubules found in HF30 and atrial fibrillation38 may have an impact on calcium cycling and promotes the development of triggers of arrhythmia. One might hypothesize that distinct anatomic regions within the atrial will differentially respond on the stress and thus promote the propagation of arrhythmia triggers at specific locations aroused from superposition of areas of significant T-tubular degradation with those of profound molecular remodeling.39 The mechanisms that result in the development of such trigger “hot spots” require special investigation and will be the focus of our follow-up studies.

ion of arrhythmia triggers at specific locations aroused from superposition of areas of significant T-tubular degradation with those of profound molecular remodeling.39 The mechanisms that result in the development of such trigger “hot spots” require special investigation and will be the focus of our follow-up studies. Role of Caveolae Structures in Atrial Ca2+ Signaling It has been proposed that, because of the lack of a regular T-tubule system in atrial myocytes, differential spatial distribution of LTCCs with regard to their coupling to RyR2s may underlie a unique atrial myocyte Ca2+-signaling process.9,40 In the present study, we uncovered for the first time the distinct distribution of functional atrial LTCCs in the sarcolemma where they appear at a similar frequency both in the T-tubules and the crests, in contrast to ventricular myocytes where LTCCs were primarily clustered in the T-tubules.2 We demonstrated the importance of the extradyadic channels, which are predominantly located in caveolae, in the regulation of Ca2+ signaling, particularly in cardiomyocytes lacking an organized T-tubule network. The function of LTCCs localized in caveolae remains open to question. It has been proposed that some LTCCs housed in Cav3-rich microdomains, could play an important role in the modulation of Ca2+ signaling. Indeed, local spontaneous Ca2+ release events are plentiful and, in contrast to ventricular myocytes, seem to be normally present in healthy atrial.6,41

olae remains open to question. It has been proposed that some LTCCs housed in Cav3-rich microdomains, could play an important role in the modulation of Ca2+ signaling. Indeed, local spontaneous Ca2+ release events are plentiful and, in contrast to ventricular myocytes, seem to be normally present in healthy atrial.6,41 Walden and colleagues demonstrated important differences in Ca2+-handling mechanisms between ventricular and atrial myocytes: atrial myocytes were found to have a more robust and abundant Ca2+ uptake mechanism and a higher SR Ca2+ content than ventricular myocytes.7 Higher SR Ca2+ content in atrial myocytes has been proposed to lead to Ca2+ overload and thus increase the sensitivity of RyR2s to cytosolic [Ca2+]i.9 This means that 1 Ca2+ spark is more likely to trigger another Ca2+ spark in atrial myocytes but remains a rare event in normal ventricular myocytes. Therefore, the benefit of the elevated SR Ca2+ content is that it should improve the synchrony of the atrial [Ca2+]i transients when T-tubules are disorganized or absent. The downside is that in atria the elevated SR Ca2+ content and enhanced [Ca2+]SR lead to the increased sensitivity of the Ca2+-induced Ca2+ release process. For thin cells, or thick cells with organized T-tubules, the Ca2+ signal propagation is likely to be relatively stable. However, larger myocytes with disorganized T-tubules may have an increased propensity toward subcellular Ca2+ alternans and thus appear to be more prone to Ca2+ sparks as demonstrated in our study (Figure 2). Uncontrolled [Ca2+]i elevations, as occurs with Ca2+ alternans,42 will activate the Na/Ca exchanger and thereby generate Na/Ca exchanger current (INCX) between action potentials with subsequent induction of delayed afterdepolarizations. Thus, the high SR Ca2+ content in atrial myocytes may be proarrhythmic. Such arrhythmogenic tendencies are unmasked in HF as cells undergo hypertrophy and the T-tubule system degrades (Figures 7 and 8). Slower and wider Ca2+ waves observed in failing cells in the present study would lead to prolonged depolarization time required for Na/Ca exchanger activation and thus they are more likely to result in the formation of delayed afterdepolarizations observed in failing atrial.43,44 Along with elevated diastolic [Ca2+]i and SR Ca2+ overload, observed in HF, it would result in the formation of foci of triggered ectopic activity located within areas of significant T-tubular degradation.

s they are more likely to result in the formation of delayed afterdepolarizations observed in failing atrial.43,44 Along with elevated diastolic [Ca2+]i and SR Ca2+ overload, observed in HF, it would result in the formation of foci of triggered ectopic activity located within areas of significant T-tubular degradation. Unique Atrial Myocyte Ca2+ Signaling It is possible that the mechanism behind the localized spontaneous Ca2+ release events in atrial differs from that in ventricles. In rat ventricular myocytes, 85% of all Ca2+ sparks evoked by electric stimulation occur within 0.5 µm of a T-tubule,45 and formamide-induced detubulation significantly reduces Ca2+ sparks in rat ventricular myocytes,14 suggesting an important role for T-tubules in Ca2+ spark initiation. Despite the broad distribution of RyRs in atrial myocytes principally along the Z-lines, most Ca2+ sparks occur within 1 µm of the sarcolemma.4,8 In contrast to ventricular myocytes, where the close (≈12 nm) proximity of RyRs and LTCCs in dyadic junctions of T-tubules facilitates Ca2+ release from the SR,46 atrial myocytes have an additional, functionally separated nonjunctional Ca2+ release site in the central SR not associated with T-tubules.8,41 Based on immunochemical experiments, these 2 kinds of atrial Ca2+ release sites were proposed to differ in their probability of initiating a Ca2+ spark, with some being designated as eager sites, whereas others normally fail to spark.8,40 As demonstrated by Woo et al41 in rat atrial myocytes, although the frequency of spontaneous unitary Ca2+ sparks was significantly higher in the dyads, the compound sparks, that is, localized Ca2+ release composed of several unitary events occurring synchronously and occupying >2 sarcomeres, appeared more prevalent in nonjunctional sites. These findings support the idea that the retarded dissipation of unitary nonjunctional focal Ca2+releases may facilitate the activation of neighboring release sites, leading to recruitment of a larger number of unitary that which in turn improves synchronicity of the atrial [Ca2+]i transients despite their less organized T-tubule network.9

t the idea that the retarded dissipation of unitary nonjunctional focal Ca2+releases may facilitate the activation of neighboring release sites, leading to recruitment of a larger number of unitary that which in turn improves synchronicity of the atrial [Ca2+]i transients despite their less organized T-tubule network.9 Nonjunctional Ca2+ events might be attributed to inositol-1,4,5-trisphosphate (IP3) dependent activation of nonjunctional RyRs.22 Recently, Horn et al47 have shown that IP3 can effectively modulate RyR openings and Ca2+ spark probability. Direct interaction between Cav3 and IP3-associated Gq-protein–coupled receptor-signaling pathway has been demonstrated in canine ventricular myocytes48 which can link IP3-dependent nonjunctional Ca2+ events to caveolae and explain a significant decrease in occurrence of spontaneous Ca2+ sparks observed in atrial myocytes treated with MβCD (Figures 5E through 5G). Interestingly, a similar reduction in Ca2+ sparks via direct inhibition of caveolae-housed LTCCs by Rem protein (Figure 6) highlights the importance of these channels in the initiation of Ca2+ sparks. Alternatively, it is possible that MβCD- or Rem1-265-Cav–induced reduction in the whole-cell ICa,L decreases the steady-state SR Ca2+ load and thus suppresses the occurrence of spontaneous Ca2+ transients observed in our experiments.

igure 6) highlights the importance of these channels in the initiation of Ca2+ sparks. Alternatively, it is possible that MβCD- or Rem1-265-Cav–induced reduction in the whole-cell ICa,L decreases the steady-state SR Ca2+ load and thus suppresses the occurrence of spontaneous Ca2+ transients observed in our experiments. Microdomain-Specific Remodeling of Atrial LTCCs in HF Decrease in atrial ICa,L in HF has been shown in both animal models49 and patients with congestive HF.50 Taking into account the T-tubule degradation, one would expect a reduction of the number of functional channels to be mainly responsible for the reduction in ICa,L. However, as we demonstrated in the present study, an additional mechanism responsible for the reduction in ICa,L in failing atrial might be represented by the reduction in the amplitude of T-LTCCs. Despite the decreased ICa,L, an increase in SR Ca2+ load (caffeine-induced [Ca2+]i release) has been observed in failing atrial.44,49 In addition to the increased SR Ca2+ loading, a significant reduction in calsequestrin expression has been found in failing atrial,44 and this has been linked to increase in SR Ca2+ leak and atrial arrhythmogenesis, perhaps as a result of decreased SR Ca2+ buffering.39 Both SR Ca2+ leak and elevated diastolic [Ca2+]i may affect T-LTCC current, causing a reduction in amplitude, either through Ca2+-dependent inactivation or phosphorylation (Figures 8E and 8F). Therefore, a disruption in the delicate balance of dynamic interactions between dyadic LTCCs and their microenvironment may alter Ca2+ signaling and can lead to pathological changes in cellular physiology. This extends beyond the classical concept of electric remodeling, stressing that alterations of spatial compartmentation of ion channels and receptors are responsible for pathology, in addition to classically appreciated changes in protein expression and posttranslational modifications.

changes in cellular physiology. This extends beyond the classical concept of electric remodeling, stressing that alterations of spatial compartmentation of ion channels and receptors are responsible for pathology, in addition to classically appreciated changes in protein expression and posttranslational modifications. Limitations In the present study, we used MβCD to disrupt caveolae structures that might have some potential side effects on cellular electrophysiology. However, it is the only available approach to physically destroy caveolae at the moment and it is widely used by many groups, without significant effects on T-tubule structure.13,17,26 Accordingly, in our study, after 30 minutes treatment with 10 mM MβCD, no changes in cell topography and T-tubule density were found (online-only Data Supplement Figure V). In addition, MβCD treatment did not affect T-LTCC biophysical properties: neither T-LTCC occurrence nor their open probability and current-voltage characteristics were altered. Moreover, similar results on LTCC distribution and Ca2+ activity were obtained with use of a specific Cav3-targeted LTCC-blocking agent, Rem peptide,12 suggesting no direct effect of MβCD on LTCC. Therefore, the influence on the use of MβCD in this study should be limited, if there is any, and will not affect the result and the deducting conclusion regarding the LTCC distribution and functioning.

with use of a specific Cav3-targeted LTCC-blocking agent, Rem peptide,12 suggesting no direct effect of MβCD on LTCC. Therefore, the influence on the use of MβCD in this study should be limited, if there is any, and will not affect the result and the deducting conclusion regarding the LTCC distribution and functioning. Acknowledgments We thank Peter O’Gara for cardiomyocyte isolation, and Andrei Buzuk for his help with data processing. We are grateful for the generous help provided by Dr Rogers, Electron Microscopy Unit, Royal Brompton Hospital, London, SW3 6NP. Sources of Funding This work was primarily supported by Wellcome Trust WT090594 and British Heart Foundation 12/18/30088 to Dr Gorelik. Disclosures None. Supplementary Material * Drs Glukhov and Balycheva contributed equally. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.018131/-/DC1.

Sources of Funding This work was primarily supported by Wellcome Trust WT090594 and British Heart Foundation 12/18/30088 to Dr Gorelik. Disclosures None. Supplementary Material * Drs Glukhov and Balycheva contributed equally. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.018131/-/DC1. CLINICAL PERSPECTIVE Heart failure is one of the most important causes of arrhythmogenic atrial remodeling. The overall risk of atrial arrhythmias increases almost 6-fold when heart failure is present. Despite these troubling statistics, the mechanisms of atrial remodeling in the settings of heart failure are still poorly understood. In this study, we introduced a novel concept of electrophysiological atrial remodeling resulting from changes in the subcellular compartmentation of calcium-signaling complexes, accompanied by a disruption of cellular structure. We provide direct evidence for 2 distinct subpopulations of functional L-type calcium channels in rat and human atrial myocytes: one localized in the T-tubules and another linked to caveolae structures. Such spatial compartmentation is believed to impact calcium channel function and regulation, which is evident from their distinct role in the control of sarcoplasmic reticulum calcium release in atrial versus ventricular myocytes. We demonstrate a heart failure–dependent and microdomain-specific remodeling of biophysical properties of calcium channels, resulting from a disruption of the delicately balanced dynamic interactions between the channels and their cellular microenvironment. Importantly, this may alter autonomic modulation of channels’ functioning dramatically affecting the excitation-contraction processes and underlying pathophysiology of atrial remodeling. Our findings extend beyond the classical concept of electric remodeling in heart failure and add a new dimension to cardiovascular disease, besides well-acknowledged changes in protein expression and their posttranslational modifications. We anticipate that our assay will be a development platform for more sophisticated therapeutic approaches for atrial-remodeling treatments based on the subcellular distribution of their targets.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a vasoconstrictive, proliferative, thrombotic phenotype, leading to increased pulmonary artery pressure and pulmonary vascular resistance, and eventually to right ventricular failure.1 In addition to pulmonary vascular remodeling, the pathophysiology of PAH includes in situ thrombosis of the small pulmonary arteries.2–4 The World Symposium on Pulmonary Hypertension group I category includes several types of PAH with similar pathological changes.5–7 It is unclear whether thrombotic vascular lesions are an integral part of the pulmonary vascular pathology or are simply an epiphenomenon. In support of the former hypothesis are abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system observed in patients with idiopathic PAH (IPAH).8 However, these abnormalities have not been described in other forms of group I PAH, including PAH associated with systemic sclerosis (SSc-PAH). Editorial see p 2360 Clinical Perspective on p 2411

re even scarcer; however, such a strategy has been extrapolated from IPAH studies and current treatment algorithms recommend warfarin in these patients, based mostly on consensus opinion.17 Expert opinions on the benefit of warfarin in SSc-PAH and IPAH patients vary widely in regard to the effectiveness of treatment.18 Recently, the retrospective analysis from the European database Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) examined survival in patients with IPAH and SSc-PAH who received anticoagulation in comparison with patients who did not receive anticoagulation.15 In this analysis, survival improved in IPAH patients who received anticoagulation; however, anticoagulation was not associated with a survival benefit in patients with SSc-PAH.15 These observations are of particular concern because chronic anticoagulation can be associated with major fatal bleeding.19 Specifically, SSc-PAH patients with arteriovenous malformations of the gastrointestinal tract are at increased risk of serious bleeding.20 Last, all but 1 of the aforementioned studies were conducted before the availability of PAH-specific therapies,7 some of which have an antiplatelet effect and may alter the thrombotic profile of the pulmonary blood and vasculature. Therefore, in an era when multiple effective PAH therapies are available, the role of anticoagulation in the treatment of PAH is even more uncertain.

before the availability of PAH-specific therapies,7 some of which have an antiplatelet effect and may alter the thrombotic profile of the pulmonary blood and vasculature. Therefore, in an era when multiple effective PAH therapies are available, the role of anticoagulation in the treatment of PAH is even more uncertain. In an effort to reconcile the variable results and the limitations of previous studies, we used the large, multicenter, observational, US-based, longitudinal registry of patients with group I PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), to assess the association between chronic anticoagulation use with warfarin and outcomes in contemporary patients with IPAH and SSc-PAH.

large, multicenter, observational, US-based, longitudinal registry of patients with group I PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), to assess the association between chronic anticoagulation use with warfarin and outcomes in contemporary patients with IPAH and SSc-PAH. Methods REVEAL Registry The design and baseline characteristics of patients enrolled in the REVEAL Registry have been described previously.21 In brief, the REVEAL Registry is a multicenter (55 sites, university-affiliated and community hospitals), observational, US-based study designed to provide information about demographics, disease course, and management of 3515 consecutively enrolled patients with newly or previously diagnosed group I PAH. The study was conducted in accordance with the amended Declaration of Helsinki and the protocol was reviewed by the institutional review board of each participating center with written informed consent obtained from all patients.21 Patients were followed for at least 5 years from the time of enrollment. Diagnosis was confirmed by right heart catheterization within 3 months before enrollment for newly diagnosed and >3 months before enrollment for previously diagnosed patients. PAH was defined as a mean pulmonary artery pressure >25 mm Hg at rest or >30 mm Hg with exercise, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤18 mm Hg, and pulmonary vascular resistance ≥240 dyn·sec·cm–5. The IPAH group included only patients with IPAH and did not include patients with heritable or anorexigen-induced PAH. SSc-PAH included patients with both limited and diffuse SSc-PAH.

nary capillary wedge pressure or left ventricular end-diastolic pressure ≤18 mm Hg, and pulmonary vascular resistance ≥240 dyn·sec·cm–5. The IPAH group included only patients with IPAH and did not include patients with heritable or anorexigen-induced PAH. SSc-PAH included patients with both limited and diffuse SSc-PAH. Data were collected at the time of enrollment, followed by quarterly updates including information from any clinic visits or other patient contact in the previous 90 days. Exact dates of PAH-specific medications were collected throughout the study, whereas concomitant medications such as warfarin were identified at quarterly updates.

cted at the time of enrollment, followed by quarterly updates including information from any clinic visits or other patient contact in the previous 90 days. Exact dates of PAH-specific medications were collected throughout the study, whereas concomitant medications such as warfarin were identified at quarterly updates. Patients Who Initiated Warfarin On-Study and Patients Never on Warfarin The patient cohort for this analysis was enrolled from 2006 to 2009. We identified 4 groups based on etiologic cohort and warfarin initiation. A nested design was used to match patients who initiated warfarin after REVEAL Registry enrollment to patients never on warfarin within each etiologic cohort (IPAH and SSc-PAH). These new warfarin users and patients never on warfarin were matched by a 1:1 ratio with the same enrollment center and exact etiology. Patients were also matched by diagnosis status (newly or previously diagnosed) at study enrollment and were followed on a quarterly basis. To adjust for warfarin discontinuation, a separate analogous time-varying covariate Cox proportional hazards model including all warfarin data within each etiologic cohort was performed as a sensitivity analysis. This model accounts for warfarin starts and stops at each quarter of data collection and includes all warfarin data until the last available quarter. To avoid immortal time bias,22 the time at risk was defined as the initiation of warfarin or at the matching quarterly update so that all survival follow-up was prospective (online-only Data Supplement Figure I). Thus, patients were excluded if they were already on warfarin at enrollment in both the matching-designed analysis and the sensitivity analysis.

me at risk was defined as the initiation of warfarin or at the matching quarterly update so that all survival follow-up was prospective (online-only Data Supplement Figure I). Thus, patients were excluded if they were already on warfarin at enrollment in both the matching-designed analysis and the sensitivity analysis. Statistical Analysis All statistical comparisons were made between patients receiving and not receiving warfarin within etiology. Categorical data were presented as percentages and were analyzed using the χ2 or Fisher exact test where appropriate. Continuous data are summarized as mean±standard deviation or percentiles and were analyzed using the Student t test or Wilcoxon 2-sample rank sum test. Kaplan-Meier curves and estimates of survival were presented from the initiation of warfarin or the matching quarter to 36 months. Matching does not address potential confounding associated with differences in PAH severity. Therefore, univariable comparisons based on Kaplan-Meier curves and the log-rank test were supplemented with multivariable Cox proportional hazards models adjusting for differences in the risk profile. Risk adjustment to account for selection bias23 was conducted based on the REVEAL Registry prognostic equation24 at the quarterly update corresponding to warfarin initiation and match.

d the log-rank test were supplemented with multivariable Cox proportional hazards models adjusting for differences in the risk profile. Risk adjustment to account for selection bias23 was conducted based on the REVEAL Registry prognostic equation24 at the quarterly update corresponding to warfarin initiation and match. In addition to the main analysis, a multivariable Cox proportional hazards model including all warfarin data within each etiologic cohort was performed as a sensitivity analysis within both the IPAH and SSc-PAH subgroups. Warfarin use was modeled as time-interval time-varying covariates. In 2 different models, (1) past use (any on-study warfarin use) or (2) current use (any on-study warfarin use within the previous year) was compared with all patients who had no on-study warfarin use or patients who had no on-study warfarin use within the past year, respectively, as the main predictors in each model. PAH severity at baseline (study enrollment) was also accounted for after adjusting the models for diagnosis status, PAH medications, and risk profile at baseline. Survival was based on all-cause mortality, with patients censored only for loss to follow-up or at the close of study in December 2012. A P value of <0.05 was considered statistically significant.

ent) was also accounted for after adjusting the models for diagnosis status, PAH medications, and risk profile at baseline. Survival was based on all-cause mortality, with patients censored only for loss to follow-up or at the close of study in December 2012. A P value of <0.05 was considered statistically significant. Results Patient Characteristics A total of 2197 IPAH and SSc-PAH patients were enrolled in the REVEAL Registry: 1645 IPAH patients and 552 SSc-PAH patients. In this registry, 922 IPAH patients and 194 SSc-PAH patients started warfarin before or at enrollment. Of these, 163 IPAH patients and 55 SSc-PAH patients started warfarin after enrollment (postbaseline) and were included in the sensitivity analysis (Figure 1). Based on the matching criteria, we identified 144 IPAH and 43 SSc-PAH patients who initiated warfarin after enrollment (Figure 1) and were matched to 144 IPAH and 43 SSc-PAH patients, respectively, who were never on warfarin. These patients were included in the main analysis. Most patients were previously diagnosed with PAH at the time of enrollment into the REVEAL Registry. Table 1 describes the demographics and clinical characteristics of the 4 groups of PAH patients. With the exception of New York Heart Association (NYHA)/World Health Organization (WHO) functional class III/IV status and brain natriuretic peptide levels in the warfarin groups, characteristics were similar between the 2 pairs of groups. Notably, the REVEAL Risk Score was higher in the SSc-PAH warfarin cohort. Overall, the REVEAL Registry cohort was 72.4% white and 77.6% female. In the current analysis, no sex- or ethnicity-specific effects were observed. However, because of the small representation of some subgroups in this study, it is difficult to interpret whether these effects are truly absent.

SSc-PAH warfarin cohort. Overall, the REVEAL Registry cohort was 72.4% white and 77.6% female. In the current analysis, no sex- or ethnicity-specific effects were observed. However, because of the small representation of some subgroups in this study, it is difficult to interpret whether these effects are truly absent. Table 1. Patient Characteristics Figure 1. Study design. IPAH indicates idiopathic pulmonary arterial hypertension; and SSc-PAH, pulmonary arterial hypertension associated with systemic sclerosis.

SSc-PAH warfarin cohort. Overall, the REVEAL Registry cohort was 72.4% white and 77.6% female. In the current analysis, no sex- or ethnicity-specific effects were observed. However, because of the small representation of some subgroups in this study, it is difficult to interpret whether these effects are truly absent. Table 1. Patient Characteristics Figure 1. Study design. IPAH indicates idiopathic pulmonary arterial hypertension; and SSc-PAH, pulmonary arterial hypertension associated with systemic sclerosis. Comorbid conditions were similar between the 2 sets of groups, including a low prevalence of thromboembolism (Table 2). PAH-specific medications are listed in Table 3. More patients in the warfarin groups received parenteral prostacyclins; (46.4% versus 15.1% for IPAH patients who started warfarin and never on warfarin, respectively, and 34.1% versus 14.6% SSc-PAH patients who started warfarin and never on warfarin, respectively). Moreover, patients in the warfarin groups received combination PAH-specific therapies more frequently (50.0% versus 40.2% for IPAH patients who started warfarin and never on warfarin, respectively, and 55.9% versus 25.6% SSc-PAH patients who started warfarin and never on warfarin, respectively). The mean international normalized ratio (INR) was 1.9 for IPAH and 2.0 for SSc-PAH patients (Table 4). In both IPAH and SSc-PAH warfarin-treated groups, the mean time on warfarin was 1 year. Time on warfarin ranged from 3 months to 42 months. Nearly two-thirds of patients discontinued warfarin before the last assessment (65.3% and 62.8% for IPAH and SSc-PAH, respectively) (Table 4).

d 2.0 for SSc-PAH patients (Table 4). In both IPAH and SSc-PAH warfarin-treated groups, the mean time on warfarin was 1 year. Time on warfarin ranged from 3 months to 42 months. Nearly two-thirds of patients discontinued warfarin before the last assessment (65.3% and 62.8% for IPAH and SSc-PAH, respectively) (Table 4). Table 2. Patient Comorbidities Table 3. PAH Medications at Baseline Table 4. Warfarin Use Survival Analysis Survival was assessed over the duration of the study. In IPAH patients, warfarin treatment was not significantly associated with survival at the end of the study in either the unadjusted Cox proportional hazards model (hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.86–2.32; P=0.17) or the adjusted (HR, 1.37; 95% CI, 0.84–2.25; P=0.21) analysis for risk factors (Figure 2). In SSc-PAH patients, the unadjusted survival analysis showed that warfarin use was associated with significantly lower survival compared with matched controls (HR, 2.03; 95% CI, 1.09–3.79; P=0.03). However, when adjusted for the REVEAL Risk Score, there was no statistical difference between the 2 groups (HR, 1.60; 95% CI, 0.84–3.06; P=0.15) (Figure 3). Figure 2. Kaplan-Meier estimates of survival at 36 months for IPAH patients. CI indicates confidence interval; and IPAH, idiopathic pulmonary arterial hypertension. *IPAH risk score at quarterly update corresponding to warfarin start.

Survival Analysis Survival was assessed over the duration of the study. In IPAH patients, warfarin treatment was not significantly associated with survival at the end of the study in either the unadjusted Cox proportional hazards model (hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.86–2.32; P=0.17) or the adjusted (HR, 1.37; 95% CI, 0.84–2.25; P=0.21) analysis for risk factors (Figure 2). In SSc-PAH patients, the unadjusted survival analysis showed that warfarin use was associated with significantly lower survival compared with matched controls (HR, 2.03; 95% CI, 1.09–3.79; P=0.03). However, when adjusted for the REVEAL Risk Score, there was no statistical difference between the 2 groups (HR, 1.60; 95% CI, 0.84–3.06; P=0.15) (Figure 3). Figure 2. Kaplan-Meier estimates of survival at 36 months for IPAH patients. CI indicates confidence interval; and IPAH, idiopathic pulmonary arterial hypertension. *IPAH risk score at quarterly update corresponding to warfarin start. Figure 3. Kaplan-Meier estimates of survival at 36 months for SSc-PAH patients. CI indicates confidence interval; and SSc-PAH, pulmonary arterial hypertension associated with systemic sclerosis. *IPAH risk score at quarterly update corresponding to warfarin start.

Figure 2. Kaplan-Meier estimates of survival at 36 months for IPAH patients. CI indicates confidence interval; and IPAH, idiopathic pulmonary arterial hypertension. *IPAH risk score at quarterly update corresponding to warfarin start. Figure 3. Kaplan-Meier estimates of survival at 36 months for SSc-PAH patients. CI indicates confidence interval; and SSc-PAH, pulmonary arterial hypertension associated with systemic sclerosis. *IPAH risk score at quarterly update corresponding to warfarin start. Matching analysis design results in the loss of information for unmatched patients and does not account for the time of warfarin discontinuation. Because there was a high warfarin discontinuation rate in the REVEAL Registry, a time-varying covariate model of the longitudinal effect of warfarin use was used to overcome this limitation. This model accounts for warfarin starts and stops and was used as a sensitivity analysis (online-only Data Supplement Table I). After adjusting for diagnosis status, PAH medication, and REVEAL Risk Score in the sensitivity analysis, the model affirmed the results in the main analysis in the IPAH cohort: there was no survival advantage in IPAH patients who were current (HR, 0.96; 95% CI 0.66–1.39, P=0.82) or past warfarin users (HR, 0.84; 95% CI, 0.59–1.20, P=0.34) in comparison with IPAH patients who had no on-study warfarin use within the past year or who had no on-study warfarin use, respectively (online-only Data Supplement Table I). On the contrary, SSc-PAH patients receiving warfarin within the previous year (HR, 1.57; 95% CI, 1.04–2.36; P=0.031) or at any time postbaseline (HR, 1.49; 95% CI, 1.01–2.20; P=0.046) had a poorer survival outcome than patients who had no on-study warfarin use within the past year or who had no on-study warfarin use, respectively, even after adjusting for diagnosis status, PAH medication, and REVEAL Risk Score (online-only Data Supplement Table I).

postbaseline (HR, 1.49; 95% CI, 1.01–2.20; P=0.046) had a poorer survival outcome than patients who had no on-study warfarin use within the past year or who had no on-study warfarin use, respectively, even after adjusting for diagnosis status, PAH medication, and REVEAL Risk Score (online-only Data Supplement Table I). Causes of death are presented in Table 5. The majority of deaths were attributed to worsening of PAH. Table 5. Reasons for Death

postbaseline (HR, 1.49; 95% CI, 1.01–2.20; P=0.046) had a poorer survival outcome than patients who had no on-study warfarin use within the past year or who had no on-study warfarin use, respectively, even after adjusting for diagnosis status, PAH medication, and REVEAL Risk Score (online-only Data Supplement Table I). Causes of death are presented in Table 5. The majority of deaths were attributed to worsening of PAH. Table 5. Reasons for Death Discussion Our study shows no significant survival advantage in IPAH patients treated with warfarin in comparison with matched controls never treated with warfarin. This is further supported by the sensitivity analysis, which shows no survival advantage after adjustment for diagnosis status, PAH medication, and REVEAL Risk Score. Although SSc-PAH patients treated with warfarin had decreased survival in comparison with matched controls in the unadjusted analysis, SSc-PAH patients receiving warfarin were inherently sicker; no survival difference associated with warfarin therapy was present with adjustment for disease severity. After accounting for the high warfarin discontinuation rate in our study, the sensitivity analysis confirmed the observation of increased SSc-PAH patient mortality even after adjusting for disease severity at enrollment. Thus, analyses of the REVEAL Registry data provided no conclusive evidence to support the use of warfarin to reduce mortality in PAH patients. These data are in concordance with a Bayesian analysis of observational data from a longitudinal cohort of patients with SSc-PAH or IPAH, which demonstrated a low probability of a survival benefit with warfarin.25 In this Bayesian analysis, patients with SSc-PAH and IPAH who received warfarin were also determined to be sicker than patients not receiving warfarin, similar to COMPERA15 and to our REVEAL Registry population.25 In other disease states such as atrial fibrillation, warfarin has been shown to be effective in reducing the risk of morbid events (including stroke and systemic thromboembolism),26 with a recommended INR generally between 2.0 and 3.0.26,27 Importantly, the presumed goal of anticoagulant therapy in PAH is prevention of mortality, with a target INR of 1.5 to 2.5.

llation, warfarin has been shown to be effective in reducing the risk of morbid events (including stroke and systemic thromboembolism),26 with a recommended INR generally between 2.0 and 3.0.26,27 Importantly, the presumed goal of anticoagulant therapy in PAH is prevention of mortality, with a target INR of 1.5 to 2.5. The INR values for the patient population in the REVEAL Registry were within the American Heart Association recommended range for PAH28 and were below the levels of anticoagulation recommended for other conditions.26,27 Therefore, the risk of bleeding was likely minimized, because bleeding risk for patients treated with warfarin increases with increasing INR, particularly above a level of 4.29 Indeed, we did not detect an increased risk of death from bleeding, although morbid events were not specifically collected to detect adverse events related to warfarin use. Surprisingly, adherence to warfarin therapy in this cohort was poor in both cohorts. During the 3-year study, mean warfarin exposure was 1 year with a high discontinuation rate for both IPAH and SSc-PAH patients, suggesting a particularly poor tolerance to anticoagulation in PAH patients enrolled in the REVEAL Registry, a registry that represents current practice for treatment of PAH in the United States.

ing the 3-year study, mean warfarin exposure was 1 year with a high discontinuation rate for both IPAH and SSc-PAH patients, suggesting a particularly poor tolerance to anticoagulation in PAH patients enrolled in the REVEAL Registry, a registry that represents current practice for treatment of PAH in the United States. The current analysis is specifically designed to include new warfarin starts and excludes previously anticoagulated patients. This design is deliberate; to address the issue of immortal time bias,22 we focus on new warfarin starts and, hence, evaluate the possibility of anticoagulation-attributable survival. In contrast, the COMPERA analysis included patients who were anticoagulated (mostly with warfarin) at the time of enrollment, and thus did not account for immortal time bias. Importantly, COMPERA showed a positive correlation between anticoagulation and survival in IPAH patients only.15 Of note, both the REVEAL Registry and COMPERA revealed no positive association between anticoagulation and survival in SSc-PAH patients. This major difference in study design and immortal time bias might explain the discrepant results between the REVEAL Registry and the COMPERA-derived analyses in IPAH patients. The extent of this immortal time bias depends on the length of time occurring between diagnosis and initiation of warfarin (ie, immortal time) and whether this immortal time was misclassified or excluded. Immortal time refers to the period of time patients had to survive to initiate warfarin and be included in the warfarin cohort rather than the nonwarfarin cohort. For example, survival estimates may be biased in favor of the warfarin group if a lengthy period of prewarfarin survival is instead attributed to longer survival for warfarin patients (online-only Data Supplement Figure I). On the other hand, if patients typically initiate warfarin quickly after diagnosis, immortal time bias would be minimal and unlikely to fully explain the differences between the REVEAL Registry and COMPERA results.15 As such, immortal time bias could not definitively be excluded in COMPERA.

y Data Supplement Figure I). On the other hand, if patients typically initiate warfarin quickly after diagnosis, immortal time bias would be minimal and unlikely to fully explain the differences between the REVEAL Registry and COMPERA results.15 As such, immortal time bias could not definitively be excluded in COMPERA. Other potential explanations for the discrepancy in results may include differences in patient characteristics between the 2 registries. The COMPERA cohort included more males than females and the patients were older. Moreover, the older age of patients in COMPERA is an important difference; patients 65 years or older had poorer survival despite having less severe (presumably advantageous) hemodynamic impairment.30 In addition, the use of prostacyclins in PAH care differs greatly between Germany, France, and the United States. In France and the United States, parenteral prostacyclins are initiated routinely—and early—as long-term therapy for patients presenting with NYHA/WHO functional class III/IV PAH. In contrast, in Germany, parental prostacyclin therapy is reserved mainly as a rescue therapy for hospitalized patients who are then discharged on oral therapies. Similarly, differences exist in PAH anticoagulation practices between the United States and Europe. In Europe, the target INR for PAH anticoagulation is 2.0 to 3.06 and temporary interruptions are usually bridged with heparin or analogues. In contrast, the US PAH centers target an INR of 1.5 to 2.5 for PAH patients28 with no bridging for temporary interruptions. Of note, INR levels were not reported in COMPERA, but are reported in the REVEAL Registry.

nticoagulation is 2.0 to 3.06 and temporary interruptions are usually bridged with heparin or analogues. In contrast, the US PAH centers target an INR of 1.5 to 2.5 for PAH patients28 with no bridging for temporary interruptions. Of note, INR levels were not reported in COMPERA, but are reported in the REVEAL Registry. Limitations of our study include the inherent limitations of observational registry-derived data and the retrospective nature of the report.31 Additionally, a high discontinuation rate of warfarin was observed, consistent with practice patterns in US PAH centers and suggestive of poor tolerance of anticoagulation in PAH patients. We attempted to account for this high rate of discontinuation by using a time-varying covariate model as a sensitivity analysis. Although both the matched and sensitivity analyses were adjusted for disease severity as captured by the REVEAL Risk Score, the anticoagulation arm was characterized by parameters consistent with disease severity. For example, a greater proportion of patients on anticoagulation received PAH parenteral and combination therapy, and had higher brain natriuretic peptide and NYHA/WHO functional class, which may well reflect that sicker PAH patients were more likely to be anticoagulated at baseline. The REVEAL Risk Score encompasses PAH risk factors including demographic data, comorbidities, NYHA/WHO group I subgroup, NYHA/WHO functional class, vital signs, 6-minute walk distance, and brain natriuretic peptide along with echocardiographic, pulmonary function testing, and hemodynamic risk factors, in a risk score prognostic model.32 Although it is evident that the REVEAL Risk Score captures most, if not all, known prognostic risk factors in PAH, the possibility of an unknown possible factor cannot be excluded. Furthermore, the REVEAL Risk Score has been validated in both incident and prevalent patients and has been cross-validated using the French registry database.33 Although a predictive score combining right ventricular function and right atrial function indices for predicting outcome has been validated in PAH patients, this score was not shown to be statistically different from the REVEAL Risk Score.34 Because no other general risk scores have been evaluated or validated in PAH, the use of the REVEAL Risk Score is currently the best tool that accounts for differences in disease severity.

ng outcome has been validated in PAH patients, this score was not shown to be statistically different from the REVEAL Risk Score.34 Because no other general risk scores have been evaluated or validated in PAH, the use of the REVEAL Risk Score is currently the best tool that accounts for differences in disease severity. Our study is novel in that it consists of a rigorous analysis of a large database with inclusion of new starts on warfarin, exclusion of immortal time bias, as well as adjustment for disease severity as measured by the REVEAL PAH-specific Risk Scores. This study also reports on the length of anticoagulant therapy and on the level of anticoagulation measured by INR during warfarin use, all of which contribute to the strength and accuracy of the results. In addition, statistical modeling was done to address the limitations as well as to validate the matching analysis, by performing a time-varying covariate model as an analogous sensitivity analysis. In conclusion, in IPAH patients in the REVEAL Registry, there is insufficient evidence to conclude that the initiation of warfarin is associated with improved survival. Furthermore, similar results were observed in SSc-PAH patients. Our findings differ from COMPERA in regard to IPAH patients but are concordant with COMPERA and other studies with regard to the use of anticoagulation in SSc-PAH patients. Further studies are required to resolve this ongoing controversy.

mproved survival. Furthermore, similar results were observed in SSc-PAH patients. Our findings differ from COMPERA in regard to IPAH patients but are concordant with COMPERA and other studies with regard to the use of anticoagulation in SSc-PAH patients. Further studies are required to resolve this ongoing controversy. Acknowledgments Medical writing and editorial assistance was provided by Terri Schochet, PhD, of AlphaBioCom, LLC, King of Prussia, PA. The authors thank Simona Neumann, PhD, of Actelion Pharmaceuticals US, Inc., for final draft-writing support. Sources of Funding Actelion Pharmaceuticals US, Inc., is the sponsor of the REVEAL Registry and provided funding and support for the analysis presented.

Acknowledgments Medical writing and editorial assistance was provided by Terri Schochet, PhD, of AlphaBioCom, LLC, King of Prussia, PA. The authors thank Simona Neumann, PhD, of Actelion Pharmaceuticals US, Inc., for final draft-writing support. Sources of Funding Actelion Pharmaceuticals US, Inc., is the sponsor of the REVEAL Registry and provided funding and support for the analysis presented. Disclosures Dr Preston has served as a consultant for Actelion Pharmaceuticals, Bayer, Gilead, and United Therapeutics; and has received research support from Actelion Pharmaceuticals, AIRES, Bayer, Gilead, and United Therapeutics. Dr Roberts has no conflicts of interest to report. At the time the research was conducted, D. Miller was an employee of ICON Clinical Research the biostatistics CRO for the REVEAL Registry. G. Sen is an employee of ICON Clinical Research the biostatistics CRO for the REVEAL Registry. Dr Selej holds stock or stock options in and is an employee of Actelion Pharmaceuticals. At the time of writing, W. Benton held stock options in and was an employee of Actelion Pharmaceuticals. Dr Hill has served as a consultant for Actelion Pharmaceuticals, Bayer, and Gilead; has received research grants from Actelion Pharmaceuticals, Bayer, Gilead, Ikaria, Reata, and United Therapeutics; and serves on the Data and Safety Monitoring Board for the BEAT study sponsored by Lung LLC. Dr Farber has received research grants from Gilead and United Therapeutics; consulting fees from Gilead, Actelion Pharmaceuticals, United Therapeutics, Bayer, and Ikaria; and has served on a speaker’s bureau or given presentations on behalf of Actelion Pharmaceuticals, Gilead, and Bayer.

AT study sponsored by Lung LLC. Dr Farber has received research grants from Gilead and United Therapeutics; consulting fees from Gilead, Actelion Pharmaceuticals, United Therapeutics, Bayer, and Ikaria; and has served on a speaker’s bureau or given presentations on behalf of Actelion Pharmaceuticals, Gilead, and Bayer. Supplementary Material The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.018435/-/DC1.

AT study sponsored by Lung LLC. Dr Farber has received research grants from Gilead and United Therapeutics; consulting fees from Gilead, Actelion Pharmaceuticals, United Therapeutics, Bayer, and Ikaria; and has served on a speaker’s bureau or given presentations on behalf of Actelion Pharmaceuticals, Gilead, and Bayer. Supplementary Material The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.018435/-/DC1. CLINICAL PERSPECTIVE Long-term warfarin anticoagulation is recommended for patients with idiopathic pulmonary arterial hypertension and in patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). In this analysis of data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Registry, we found that treatment with warfarin conferred no survival benefit in patients with idiopathic pulmonary arterial hypertension or with SSc-PAH in comparison with matched controls. Importantly, SSc-PAH patients receiving warfarin had increased mortality in comparison with warfarin-naïve patients. Combined with a recent analysis of idiopathic pulmonary arterial hypertension and SSc-PAH patients exposed to warfarin from the European registry Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), our observations suggest that warfarin therapy should not be recommended or instituted in patients with SSc-PAH. However, in patients with idiopathic pulmonary arterial hypertension, a definitive recommendation is not as clear, because, in contrast to our findings, a survival benefit was observed in these patients from the COMPERA registry. As such, until there is a robust trial prospectively examining this cohort—which is unlikely—clinical judgment and the risk of untoward events should be the critical factors underlying the decision to initiate warfarin therapy.

The risk of recurrence of venous thromboembolism (VTE) persists for many years after anticoagulant treatment is withdrawn1 and is particularly high among patients with unprovoked VTE.2 About 20% of patients have a recurrence within 2 years after discontinuation of treatment with a vitamin K antagonist (VKA).3–6 Extending the treatment with VKA reduces the risk of recurrence but increases the risk of bleeding, as well as the inconvenience and costs of laboratory monitoring and dose adjustments.7,8 The effects of the newer non-VKA oral anticoagulants for therapy of acute VTE events9–12 and for extended treatment to avoid recurrences13,14 have recently been investigated by a number of clinical trials that, as a whole, showed an efficacy noninferior to VKA and rates of bleeding in general inferior to VKA, especially for extended treatment. Editorial see p 1856 Clinical Perspective on p 1897

The risk of recurrence of venous thromboembolism (VTE) persists for many years after anticoagulant treatment is withdrawn1 and is particularly high among patients with unprovoked VTE.2 About 20% of patients have a recurrence within 2 years after discontinuation of treatment with a vitamin K antagonist (VKA).3–6 Extending the treatment with VKA reduces the risk of recurrence but increases the risk of bleeding, as well as the inconvenience and costs of laboratory monitoring and dose adjustments.7,8 The effects of the newer non-VKA oral anticoagulants for therapy of acute VTE events9–12 and for extended treatment to avoid recurrences13,14 have recently been investigated by a number of clinical trials that, as a whole, showed an efficacy noninferior to VKA and rates of bleeding in general inferior to VKA, especially for extended treatment. Editorial see p 1856 Clinical Perspective on p 1897 Sulodexide is a natural glycosaminoglycan with antithrombotic and profibrinolytic activities15 that can be administered orally or parenterally and affects the normal hemostasis to a lower extent than heparin with a very low risk of bleeding. Several clinical studies proved that prolonged sulodexide administration was associated with no or negligible risk of bleeding,16–18 as also highlighted in a recent review.19 Sulodexide exerts its actions through complexation with antithrombin and heparin cofactor II and the attending inhibition of some factors of the coagulation cascade.20–22 It also exerts favorable effects on endothelial dysfunction, release of cytokines and chemokines, and metalloprotease-9 secretion from white blood cells.23,24

e exerts its actions through complexation with antithrombin and heparin cofactor II and the attending inhibition of some factors of the coagulation cascade.20–22 It also exerts favorable effects on endothelial dysfunction, release of cytokines and chemokines, and metalloprotease-9 secretion from white blood cells.23,24 The pharmacological and clinical profiles suggest that oral sulodexide may have a role in the prevention of recurrent VTE when classic anticoagulation is discontinued. Indeed, recent clinical studies proved a positive effect of oral sulodexide administration in reducing the risk of recurrence compared with either anticoagulation with acenocoumarol25 or standard of care after withdrawal of VKA treatment.18 The aim of this randomized, double-blind, controlled trial (Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis [SURVET]) was to verify the efficacy and safety of sulodexide in the prevention of recurrent VTE after the end of the VKA treatment in patients with a first-ever unprovoked VTE.

treatment.18 The aim of this randomized, double-blind, controlled trial (Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis [SURVET]) was to verify the efficacy and safety of sulodexide in the prevention of recurrent VTE after the end of the VKA treatment in patients with a first-ever unprovoked VTE. Methods Patients We recruited patients of ≥18 years of age with a documented first-ever unprovoked proximal deep vein thrombosis or pulmonary embolism treated with VKA for 3 to 12 months. VTE was considered unprovoked when it occurred in the absence of any known risk factor for this event. We excluded patients with persistent pulmonary hypertension after pulmonary embolism, those with solid neoplasm or blood disease, those with anti-phospholipid antibody syndrome or antithrombin congenital deficit, patients with New York Heart Association class III to IV cardiorespiratory failure, and patients with known hypersensitivity to glycosaminoglycans. Fertile women were enrolled if not lactating if their pregnancy test at screening was negative and they were willing to use contraception (except oral contraceptives) throughout the study period. Each subject was enrolled only after having issued the written informed consent to participate to the study.

osaminoglycans. Fertile women were enrolled if not lactating if their pregnancy test at screening was negative and they were willing to use contraception (except oral contraceptives) throughout the study period. Each subject was enrolled only after having issued the written informed consent to participate to the study. Study Design and Intervention SURVET was a multicenter, multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. Eligible patients were allocated to treatment for 2 years with oral sulodexide (2×250–lipasemic unit capsules twice daily) or matching placebo in a 1:1 ratio based on a computer-generated randomization list in blocks of 4 produced by an independent operating unit. This same unit also packaged drug and matching placebo in identical-looking treatment units, 1 for each randomized patient, identified exclusively by the randomization number. Patients, recruiting physicians, physicians or pharmacists delivering the treatments units, physicians or technicians assessing the outcome, and Steering Committee members were blinded to the intervention and to the block size until the end of the statistical analysis. Each sequentially numbered treatment unit was accompanied by an opaque, sealed envelope that allowed unblinding of the individual patient treatment in case of need. Randomization occurred within 1 to 12 weeks after VKAs had been withdrawn, with the patient assigned to the treatment unit with the lowest number available at the relevant study center.

A central principle in cardiovascular disease (CVD) management is that the first lifetime diagnosis signals the failure of primary prevention and the need to initiate secondary prevention of recurrent or related CVD events. The decades-long emphasis given to prevention of myocardial infarction (MI) and stroke is reflected in remarkable declines – ≈33% over the past decade – in their incidence in developed countries.1 Incidence rates for chronic CVD presentations such as angina or heart failure, although less studied, do not appear to have similarly declined.1–3 Consequently, the spectrum of initial presentations of CVD in contemporary practice is likely to have changed in comparison with the latter part of the last century. Cohort studies that report only fatal end points (final presentations),4 may have less relevance to informing the success of primary prevention than those which investigate initial presentations. Within studies that incorporate nonfatal events, acute MI and stroke have been more commonly investigated than other chronic presentations.5–7 Large-scale contemporary studies that evaluate the first lifetime diagnosis in women and men across a wide range of acute and chronic CVDs including both fatal and nonfatal presentations can provide additional insight into the understanding of CVDs. Editorial see p 1303 Clinical Perspective on p 1328

atment unit was accompanied by an opaque, sealed envelope that allowed unblinding of the individual patient treatment in case of need. Randomization occurred within 1 to 12 weeks after VKAs had been withdrawn, with the patient assigned to the treatment unit with the lowest number available at the relevant study center. Outcome Measures The central adjudication committee members who were unaware of the group assignments and who reviewed all the patients’ raw data assessed all suspected study outcome events. The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis objectively confirmed by compression ultrasonography26 and nonfatal or fatal pulmonary embolism objectively confirmed by computed tomography or lung scanning. Secondary efficacy outcomes included distal or superficial vein thrombosis and nonfatal or fatal myocardial infarction, stroke, or acute ischemia of the lower limbs. The principal safety outcome was major or clinically relevant nonmajor bleeding. An overt bleeding event was defined as major if fatal, if it occurred in a critical location, or if it required a transfusion of ≥2 U whole blood or red cells. Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, interruption of the study drug, or discomfort or impairment of activities of daily life.27

whole blood or red cells. Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, interruption of the study drug, or discomfort or impairment of activities of daily life.27 Surveillance and Follow-Up The investigators, according to the study protocol, recommended to each participant the use of a class II elastic stocking after the diagnosis of proximal deep vein thrombosis. Their use was to be continued for 2 years. The investigators renewed this recommendation at each periodic visit. Patients were re-examined at the relevant clinical center every 3 months for 24 months after randomization. Patients were instructed to report to the study center if they had symptoms suggestive of VTE, other circulatory events, or bleeding complications for objective evaluation. Each patient was contacted by telephone every month between examinations. In case of symptoms suggesting that an end point occurred, the patient was invited to the center of reference for an unplanned interview. Symptoms and signs suggestive of adverse events (AEs) were also recorded. At month 24, we contacted by telephone all patients who prematurely interrupted or left the study without formally withdrawing consent so that we could monitor whether symptoms or signs suggestive of a vascular event had occurred.

nned interview. Symptoms and signs suggestive of adverse events (AEs) were also recorded. At month 24, we contacted by telephone all patients who prematurely interrupted or left the study without formally withdrawing consent so that we could monitor whether symptoms or signs suggestive of a vascular event had occurred. Study Oversight The members of the Steering Committee designed the study, registered in the EU Clinical Trials Register with the EudraCT number 2009-016923-77 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=SURVET). Independent contract research organizations monitored the study and collected and maintained the data. The Department of Pharmaceutical Sciences of the University of Milan (Milan, Italy) analyzed the data. Each study center initiated the trial only after the local Ethics Committee or Institutional Review Board had approved the protocol. The study was performed in accordance with the protocol, with the Declaration of Helsinki, with Good Clinical Practice, and with local regulations.

Milan (Milan, Italy) analyzed the data. Each study center initiated the trial only after the local Ethics Committee or Institutional Review Board had approved the protocol. The study was performed in accordance with the protocol, with the Declaration of Helsinki, with Good Clinical Practice, and with local regulations. The Steering Committee had final responsibility for verification and analyses of the data, wrote the manuscript, and vouches for the accuracy and completeness of the reported data. All authors contributed to the interpretation of the results, approved the final version of the manuscript, and made the decision to submit the manuscript for publication. The study was supported by Alfa Wassermann SpA (Via Ragazzi del 99, 5-Bologna, Italy), which supplied its commercially available capsules of sulodexide and manufactured the matching placebo. A separate, independent contract organization prepared the randomization list and the treatment units. Alfa Wassermann funded the study but played no role in the design of the study, in data collection or analysis, or in manuscript preparation. Statistical Analysis Assuming an incidence of recurrent VTE with standard care of ≈17.5% in 2 years3–7 and hypothesizing a 50% relative reduction by adding sulodexide,18 we determined that a total of 620 patients (≈310 per group) had 90% power to show superiority of sulodexide over placebo at a 2-sided level of α=0.05.

Statistical Analysis Assuming an incidence of recurrent VTE with standard care of ≈17.5% in 2 years3–7 and hypothesizing a 50% relative reduction by adding sulodexide,18 we determined that a total of 620 patients (≈310 per group) had 90% power to show superiority of sulodexide over placebo at a 2-sided level of α=0.05. The primary efficacy analysis, which considered all outcome events occurring from randomization to the end of treatment, was performed according to the intention-to-treat (ITT) principle and included all patients who had been randomized (except 2 blinded administrative exclusions). Hazard ratios, 95% confidence intervals (CIs), and P values were calculated with the Cox proportional hazards models and SPSS statistical software, version 17.0, with treatment as the only covariate. A Cox proportional hazards model analysis was also performed with adjustment for age (in decades), sex, type of index event (pulmonary embolism or deep vein thrombosis), country, dichotomized (<6/≥6 months) exposure to VKA, and dichotomized (<1/≥1 month) delay between the end of VKA treatment and randomization. An “all failures” efficacy analysis was performed in which all patients for whom no information on health status at 24 months was available were considered as having had an event (failure), the proportions of failures were compared by the Fisher exact probability test, and the incidence risk ratio and 95% CI were estimated with “epiR”28 in R.29 The outcome for patients lost to follow-up was also estimated by assigning the outcome of the nearest neighbor estimated by propensity score, computed from the same predictors as for the Cox regression except treatment. An additional sensitivity analysis was performed on the per-protocol population that included all patients of the ITT population who had the 24-month evaluation, had taken at least 75% of the planned study medication, and were exempt of major protocol violations as indicated by the study Steering Committee in a blind review. The safety analysis included all randomized patients.

protocol population that included all patients of the ITT population who had the 24-month evaluation, had taken at least 75% of the planned study medication, and were exempt of major protocol violations as indicated by the study Steering Committee in a blind review. The safety analysis included all randomized patients. Results Patients and Study Treatment Between September 2010 and May 2012, 629 patients were screened in 43 centers in 7 European countries. The follow-up was closed on May 2014. Twelve patients were screening failures; 617 were included in the safety population. Two patients were excluded from efficacy analysis because of administrative reasons: 1 was the sole individual recruited in 1 of the planned countries, and 1 entered twice in the trial at 2 different sites, and the first entry was excluded from efficacy analysis. A total of 308 patients received placebo and 307 received sulodexide for a median duration of 23.9 months. The blinded review by the study Steering Committee included 521 patients in the per-protocol analysis (Figure 1). The study drug was discontinued prematurely in 28 patients given sulodexide (9.1%) and in 29 patients given placebo (9.4%; Figure 1). There were no significant differences between groups in baseline characteristics of the patients (Table 1), except for exposure to VKA (slightly more sulodexide patients in the <6-month category; P=0.044). Table 1. Demographic and Clinical Characteristics of the Patients According to Study Group Figure 1. Enrollment and randomization. VTE indicates venous thromboembolism.

Results Patients and Study Treatment Between September 2010 and May 2012, 629 patients were screened in 43 centers in 7 European countries. The follow-up was closed on May 2014. Twelve patients were screening failures; 617 were included in the safety population. Two patients were excluded from efficacy analysis because of administrative reasons: 1 was the sole individual recruited in 1 of the planned countries, and 1 entered twice in the trial at 2 different sites, and the first entry was excluded from efficacy analysis. A total of 308 patients received placebo and 307 received sulodexide for a median duration of 23.9 months. The blinded review by the study Steering Committee included 521 patients in the per-protocol analysis (Figure 1). The study drug was discontinued prematurely in 28 patients given sulodexide (9.1%) and in 29 patients given placebo (9.4%; Figure 1). There were no significant differences between groups in baseline characteristics of the patients (Table 1), except for exposure to VKA (slightly more sulodexide patients in the <6-month category; P=0.044). Table 1. Demographic and Clinical Characteristics of the Patients According to Study Group Figure 1. Enrollment and randomization. VTE indicates venous thromboembolism. Recurrent VTE Recurrence of VTE occurred in 45 patients as a result of proximal deep vein thrombosis in 36 patients and pulmonary embolism in 9 patients (fatal in 1 patient).

Table 1. Demographic and Clinical Characteristics of the Patients According to Study Group Figure 1. Enrollment and randomization. VTE indicates venous thromboembolism. Recurrent VTE Recurrence of VTE occurred in 45 patients as a result of proximal deep vein thrombosis in 36 patients and pulmonary embolism in 9 patients (fatal in 1 patient). The primary outcome, recurrence of VTE, occurred in 15 of the 307 patients who received sulodexide (4.9%; 95% CI, 2.9–8.1) compared with 30 of the 308 patients who received placebo (9.7%; 95% CI:, 6.8–13.7; hazard ratio, 0.49; 95% CI, 0.27–0.92; P=0.02; Figure 2A). Figure 2. Risk of recurrence of venous thromboembolism in patients randomly assigned to sulodexide or placebo. A, Cumulative risk of recurrent venous thromboembolism. B, Results of an analysis of risk after adjustment for age, sex, index event (pulmonary embolism, or deep vein thrombosis), duration of anticoagulant therapy, and time from completion of anticoagulation therapy to randomization.

assigned to sulodexide or placebo. A, Cumulative risk of recurrent venous thromboembolism. B, Results of an analysis of risk after adjustment for age, sex, index event (pulmonary embolism, or deep vein thrombosis), duration of anticoagulant therapy, and time from completion of anticoagulation therapy to randomization. The analysis adjusted for age, sex, index event (pulmonary embolism or deep vein thrombosis), country, duration of exposure to VKA, and delay between the end of VKA treatment and randomization confirmed that sulodexide treatment reduced the risk of recurrence (adjusted hazard ratio, 0.45; 95% CI, 0.24–0.84; P=0.01; Figure 2B). Independent risk factors for recurrent VTE included age (hazard ratio, 1.33 per decade; 95% CI, 1.06–1.65; P=0.01) and male sex (hazard ratio, 2.45; 95% CI, 1.25–4.78; P=0.01). No association was found between recurrent VTE and length of exposure to VKA (hazard ratio, 0.79; 95% CI, 0.41–1.53; P=0.48), delay between the end of VKA treatment and randomization (hazard ratio, 0.71; 95% CI, 0.37–1.36; P=0.71), country (P=0.09), or index event (hazard ratio, 1.67; 95% CI, 0.63–4.44; P=0.30).

0.01). No association was found between recurrent VTE and length of exposure to VKA (hazard ratio, 0.79; 95% CI, 0.41–1.53; P=0.48), delay between the end of VKA treatment and randomization (hazard ratio, 0.71; 95% CI, 0.37–1.36; P=0.71), country (P=0.09), or index event (hazard ratio, 1.67; 95% CI, 0.63–4.44; P=0.30). Under the “all failures” assumption, the proportion of failures among control subjects was 48 of 308 or 15.6% (95% CI, 11.7–20.1) and that among treated patients was 26 of 307 or 8.5% (95% CI, 5.6–12.2; P=0.009, Fisher test). The incidence risk ratio of failure among treated patients was 0.54 (95% CI, 0.35–0.85) versus control subjects. The results of the logistic analysis adjusted for the same confounders indicated for the Cox analysis are reported in the text and in Table I in the online-only Data Supplement. Applying the nearest-neighbor outcome to the 29 patients lost to follow-up using the propensity score yielded a proportion of events of 30 of 308 (9.7%) among control subjects and 16 of 307 (5.2%) among treated subjects (P=0.045, Fisher test; incidence risk ratio, 0.54; 95% CI, 0.30–0.96).

Under the “all failures” assumption, the proportion of failures among control subjects was 48 of 308 or 15.6% (95% CI, 11.7–20.1) and that among treated patients was 26 of 307 or 8.5% (95% CI, 5.6–12.2; P=0.009, Fisher test). The incidence risk ratio of failure among treated patients was 0.54 (95% CI, 0.35–0.85) versus control subjects. The results of the logistic analysis adjusted for the same confounders indicated for the Cox analysis are reported in the text and in Table I in the online-only Data Supplement. Applying the nearest-neighbor outcome to the 29 patients lost to follow-up using the propensity score yielded a proportion of events of 30 of 308 (9.7%) among control subjects and 16 of 307 (5.2%) among treated subjects (P=0.045, Fisher test; incidence risk ratio, 0.54; 95% CI, 0.30–0.96). In the per-protocol population, VTE recurred in 14 of the 263 patients who received sulodexide compared with 30 of the 258 patients who received placebo (hazard ratio, 0.45; 95% CI, 0.24–0.85; P=0.014). In addition, the results of the adjusted Cox analysis in the per-protocol population did not differ appreciably from those in the ITT population (data reported in the online-only Data Supplement). The different procedures used to estimate the outcome in the ITT population resulted in a number needed to treat ranging 15 to 24, with variable width of the CI. The number needed to treat estimated from the adjusted Cox regression was 24 (95% CI, 16–98; details given in the online-only Data Supplement).

a Supplement). The different procedures used to estimate the outcome in the ITT population resulted in a number needed to treat ranging 15 to 24, with variable width of the CI. The number needed to treat estimated from the adjusted Cox regression was 24 (95% CI, 16–98; details given in the online-only Data Supplement). We also performed an unplanned subgroup analysis of recurrence rates by major potentially prognostic subgroups that failed to indicate subgroups more or less likely to respond to treatment (details in the text and Figure I in the online-only Data Supplement). Hemorrhagic Complications There were no episodes of major bleeding. Clinically relevant, nonmajor bleeding occurred in 2 patients who received sulodexide (occasional nose bleeding in 1 patient, and 2 episodes of bleeding after evacuation in the other) and in 2 patients who received placebo (occasional events of rectal bleeding in 1 patient, and a dysfunctional uterine bleeding in the other). The hazard ratio for clinically relevant bleeding was 0.97 (95% CI, 0.14–6.88; P=0.98).

nal nose bleeding in 1 patient, and 2 episodes of bleeding after evacuation in the other) and in 2 patients who received placebo (occasional events of rectal bleeding in 1 patient, and a dysfunctional uterine bleeding in the other). The hazard ratio for clinically relevant bleeding was 0.97 (95% CI, 0.14–6.88; P=0.98). Secondary End Points Individually, none of the protocol-defined secondary end points was frequent enough to warrant a separate analysis (details in the online-only Data Supplement). The total incidence of primary plus secondary vascular events was 43 of 308 (14.0%; 95% CI, 10.3–18.3) among control subjects and 22 of 307 (7.2%; 95% CI, 4.5–10.6) among treated subjects (P=0.008, Fisher test; Table 2). Death occurred in 1 patient in the sulodexide group (as a result of stroke) and 3 patients in the placebo group (1 as a result of lower-limb ischemia, and 2 resulting from acute coronary syndrome). Table 2. Number of Outcome Events According to Study Group

Secondary End Points Individually, none of the protocol-defined secondary end points was frequent enough to warrant a separate analysis (details in the online-only Data Supplement). The total incidence of primary plus secondary vascular events was 43 of 308 (14.0%; 95% CI, 10.3–18.3) among control subjects and 22 of 307 (7.2%; 95% CI, 4.5–10.6) among treated subjects (P=0.008, Fisher test; Table 2). Death occurred in 1 patient in the sulodexide group (as a result of stroke) and 3 patients in the placebo group (1 as a result of lower-limb ischemia, and 2 resulting from acute coronary syndrome). Table 2. Number of Outcome Events According to Study Group Safety End Points We analyzed the AEs in the safety data set. The 309 control and 308 treated patients reported 397 and 368 treatment-emergent AEs, respectively. There was no significant difference in the number of patients with at least 1 AE (52.4% of control versus 48.7% of treated subjects), at least 1 serious AE (11.0% versus 8.1%), at least 1 AE causing discontinuation (13.6% versus 9.1%), at least 1 AE resulting in death (1.3% versus 0.3%), and at least 1 not definitely unrelated AE (12.9% versus 16.6%). The most frequent (>1% of patients) AEs, regardless of the potential correlation with treatment, are reported in Table II in the online-only Data Supplement. Discussion This study aimed at assessing whether a standard oral treatment with sulodexide after an anticoagulant regimen could, in addition to compression therapy, decrease the risk of recurrent deep vein thrombosis or pulmonary embolism over a period of 2 years.

Safety End Points We analyzed the AEs in the safety data set. The 309 control and 308 treated patients reported 397 and 368 treatment-emergent AEs, respectively. There was no significant difference in the number of patients with at least 1 AE (52.4% of control versus 48.7% of treated subjects), at least 1 serious AE (11.0% versus 8.1%), at least 1 AE causing discontinuation (13.6% versus 9.1%), at least 1 AE resulting in death (1.3% versus 0.3%), and at least 1 not definitely unrelated AE (12.9% versus 16.6%). The most frequent (>1% of patients) AEs, regardless of the potential correlation with treatment, are reported in Table II in the online-only Data Supplement. Discussion This study aimed at assessing whether a standard oral treatment with sulodexide after an anticoagulant regimen could, in addition to compression therapy, decrease the risk of recurrent deep vein thrombosis or pulmonary embolism over a period of 2 years. The hazard ratio of qualifying events with sulodexide was 0.45 (95% CI, 0.24–0.84; P=0.01) after adjustment for age, sex, type of index event, country, exposure to VKA, and delay between the end of VKA treatment and randomization. Similar results were seen in the per-protocol population, in the “all failures” approach to the ITT population, and in the sensitivity analysis by propensity score in the ITT population. The generalizability of these results appears sufficiently supported. The study included patients from different European countries with different healthcare systems without showing statistically significant heterogeneity.

The hazard ratio of qualifying events with sulodexide was 0.45 (95% CI, 0.24–0.84; P=0.01) after adjustment for age, sex, type of index event, country, exposure to VKA, and delay between the end of VKA treatment and randomization. Similar results were seen in the per-protocol population, in the “all failures” approach to the ITT population, and in the sensitivity analysis by propensity score in the ITT population. The generalizability of these results appears sufficiently supported. The study included patients from different European countries with different healthcare systems without showing statistically significant heterogeneity. The results of the SURVET study were similar to those of the trials performed with aspirin, the Warfarin and Aspirin (WARFASA) trial30 and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trial,31 which were published while the SURVET study was underway. The pooled ASPIRE-WARFASA hazard ratio for VTE was 0.68 (95% CI, 0.51–0.90)31; the unadjusted hazard ratio in SURVET was 0.49 (95% CI, 0.27–0.92). The pooled ASPIRE-WARFASA hazard ratio for major vascular events was 0.66 (95% CI, 0.51–0.86) and that in SURVET was 0.50 (95% CI, 0.30–0.83). Finally, the ASPIRE-WARFASA pooled hazard ratio for clinically relevant bleeding was 1.47 (95% CI, 0.70–3.08) and that in SURVET was 0.97 (95% CI: 0.14–6.88). The studies performed with the newer direct anticoagulants, similarly published while the SURVET study was in progress, reported high efficacy compared with placebo for preventing recurrence (1.7% versus 8.8% with apixaban, 0.4% versus 5.6% with dabigatran, and 1.3% versus 7.1% with rivaroxaban) at the expense of increased major or clinically relevant nonmajor bleeding (3.2% versus 2.3%, 5.3% versus 1.8%, and 6.0% versus 1.2%, respectively).10,13,14

efficacy compared with placebo for preventing recurrence (1.7% versus 8.8% with apixaban, 0.4% versus 5.6% with dabigatran, and 1.3% versus 7.1% with rivaroxaban) at the expense of increased major or clinically relevant nonmajor bleeding (3.2% versus 2.3%, 5.3% versus 1.8%, and 6.0% versus 1.2%, respectively).10,13,14 Our study, however, has some limitations. The total incidence of qualifying events was less than expected but similar to that of other trials.32,33 A better preventive approach during the period immediately after the index events and perhaps more frequent application of compressive therapy in the studied population could have contributed to decrease this incidence that, however, under the “all failures” assumption was close to the one anticipated in the sample size calculation. The smaller incidence of primary end point therefore appears unlikely to have biased the estimate of the effect size.

ve therapy in the studied population could have contributed to decrease this incidence that, however, under the “all failures” assumption was close to the one anticipated in the sample size calculation. The smaller incidence of primary end point therefore appears unlikely to have biased the estimate of the effect size. The proportion of patients entered in the study with major protocol violations was larger than expected. These violations included cases at lesser (longer anticoagulant treatment or short interval from anticoagulant withdrawal to randomization) and at higher (shorter or no anticoagulant treatment or long untreated interval before randomization) risk. None of these factors significantly affected the risk of recurrence in the multivariable analysis. Furthermore, the results in the per-protocol population were similar to those in the ITT population. There is therefore no evidence that the potential bias associated with protocol violations may have affected the estimate of the effect to an appreciable extent.

ted the risk of recurrence in the multivariable analysis. Furthermore, the results in the per-protocol population were similar to those in the ITT population. There is therefore no evidence that the potential bias associated with protocol violations may have affected the estimate of the effect to an appreciable extent. The proportion of patients prematurely interrupting the study without having reached the end point was also higher than expected yet limited for a 2-year study (5% total; 18 of 308 among control subjects and 11 of 307 among treated subjects). We performed a number of sensitivity analyses to monitor whether, and in which direction, this could have affected the assessment of the effect size. Applying constant risks ranging from 0 (“all successes” case) to 1 (“all failures” case) to the patients lost to follow-up yielded risk ratios from 0.50 (95% CI, 0.28–0.91; P=0.029) to 0.54 (95% CI, 0.35–0.85; P=0.009). Assigning instead the outcomes at random resulted in 228 possible combinations, with a median value of P=0.016. Not statistically significant results could occur only if the risk ratio of having the event among those randomized to treatment and lost to follow-up versus those randomized to control and lost to follow-up was ≥1.5. It was considered clinically improbable that patients extracted from a group who, when monitored, had a risk ratio of 0.49 (15 of 296 versus 30 of 290) could exhibit a risk ratio of ≥1.5 when not monitored. Finally, we performed a number of sensitivity analyses applying the nearest-neighbor outcome to the patients lost to follow-up using the propensity score, which was considered essentially independent from any assumption and more clinically reliable (more details are given in the online-only Data Supplement). These analyses yielded risk ratios between 0.44 (95% CI, 0.22–0.86; P=0.014) and 0.54 (95% CI, 0.30–0.96; P=0.045). The combination of the results of the survival analysis, those under the “all failures” assumption, those estimated by sensitivity analyses (in particular by propensity score), and those estimated per protocol, all comparable to each other, suggests that the subjects who left the study prematurely were a random subset of the total population and that the estimates of the effect size were sufficiently accurate for all practical purposes.

ensitivity analyses (in particular by propensity score), and those estimated per protocol, all comparable to each other, suggests that the subjects who left the study prematurely were a random subset of the total population and that the estimates of the effect size were sufficiently accurate for all practical purposes. The proportion of patients with pulmonary embolism as the index event was low (7.6%). The results of this study should therefore be considered poorly applicable to this specific subpopulation. Safety was favorable without unexpected AEs, likely in correlation with the treatment and clinically irrelevant risks of bleeding despite the 2-year continued treatment. It should be noted, however, that the absence of serious bleeding could be a chance finding because this study was underpowered to detect events occurring with very small frequency. Conclusions Treatment with oral sulodexide at 500 lipasemic units twice daily for 2 years along with compression therapy decreased the incidence of recurrences of thromboembolic events without detectable risks for the patient safety. Future investigations should examine whether a similar effect can be obtained after treatment of the index event with non-VKA oral anticoagulants; whether there is a summation of effects with aspirin; whether prevention of recurrence could equally be performed with sulodexide, antiplatelets, or extended anticoagulation; and whether specific subgroups are more or less likely to benefit from sulodexide or other treatments.

ex event with non-VKA oral anticoagulants; whether there is a summation of effects with aspirin; whether prevention of recurrence could equally be performed with sulodexide, antiplatelets, or extended anticoagulation; and whether specific subgroups are more or less likely to benefit from sulodexide or other treatments. Acknowledgments We are indebted to all the patients who agreed to participate in this study and to all clinical centers (listed in the online-only Data Supplement) that contributed to recruiting the patients. Study Committee: The SURVET study was monitored by a Steering Committee of 3 experts: Drs Andreozzi, Davì, and Palareti. The same committee, having full blinded access to all the data, acted also as Adjudication Committee to define the occurrence of events and the attribution of individual subjects to the analysis populations, after which the database was frozen. The same committee monitored the statistical analysis, which was performed blinded by the study statistician (Dr Bignamini) on the frozen database. Sources of Funding The study was financed by Alfa Wassermann, manufacturer of sulodexide. Disclosures Dr Andreozzi received consultancy fees or lecture grants from Mediolanum Farmaceutici, Alfa Wassermann, and Laboratorios Elmor. Drs Bignamini and Davì received consultancy fees from Bayer Healthcare and Alfa Wassermann. Dr Palareti received consultancy fees from Alfa Wassermann and Daiichi-Sankyo, as well as lecture fees from Werfen Group and Stago. Dr Sokurenko received lecture grants from Alfa Wassermann and Sanofi. The other authors report no conflicts.

i and Davì received consultancy fees from Bayer Healthcare and Alfa Wassermann. Dr Palareti received consultancy fees from Alfa Wassermann and Daiichi-Sankyo, as well as lecture fees from Werfen Group and Stago. Dr Sokurenko received lecture grants from Alfa Wassermann and Sanofi. The other authors report no conflicts. Supplementary Material Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. * A complete list of the SURVET Study Investigators can be found in the online-only Data Supplement. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.016930/-/DC1.

Supplementary Material Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. * A complete list of the SURVET Study Investigators can be found in the online-only Data Supplement. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.016930/-/DC1. CLINICAL PERSPECTIVE Patients with unprovoked venous thromboembolism are at high risk for recurrence after discontinuation of treatment with vitamin K antagonists (VKAs). Extending treatment with VKAs reduces the recurrence risk but increases the bleeding risk. In clinical practice, VKAs are generally discontinued when the perceived risk of bleeding outweighs the risk of recurrence. Drugs with low or no bleeding risk and less aggressive antithrombotic activity may represent adequate alternatives to continue anticoagulation with VKAs, or patients should be left to only physical management (elastic stockings) in cases of doubt. Rates of bleeding in general inferior to VKAs and efficacy not inferior to VKAs have been shown by the newer non-VKAs. However, compared with placebo, the extended anticoagulation with dabigatran, rivaroxaban, or apixaban, although reducing the risk of venous thromboembolism recurrence, carried a higher risk of major or clinically relevant nonmajor bleeding. The pooled data of the Warfarin and Aspirin (WARFASA) and Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed a significant risk reduction of venous thromboembolism recurrence, although at a lower extent than with the new non-VKAs, but still a worse result than placebo in terms of the occurrence of clinically relevant bleeding. In the 2 years of treatment in the Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) study, venous thromboembolism recurred in 15 of 307 patients on sulodexide and 30 of 308 on placebo (hazard ratio, 0.49; 95% confidence interval, 0.27–0.92; P=0.02). There were no differences in major or clinically relevant nonmajor bleeding between the sulodexide and placebo groups. Sulodexide appears to be an important treatment option when extended anticoagulation is potentially useful but associated with unwanted bleeding risk.

The prognosis of immunoglobulin light-chain (AL or primary systemic) and transthyretin (ATTR) amyloidosis is substantially influenced by the presence and severity of cardiac involvement, which then governs therapeutic strategies.1,2 Although blood biomarkers are useful guides for risk stratification,3 they are not specific for cardiac involvement, and current strategies do not ascertain all patients at risk. Mortality, despite treatment progress, remains high.4–7 Over the last decade, new chemotherapy regimens and stem cell transplantation have been associated with improved survival in patients with AL amyloidosis, but the prognosis remains poor in those with cardiac involvement, which also contributes substantially to treatment-related morbidity and mortality. There remains a large unmet need for improved noninvasive criteria to stratify risk in selecting optimal therapy while avoiding serious toxicities. Editorial see p 1525 Clinical Perspective on p 1579

The prognosis of immunoglobulin light-chain (AL or primary systemic) and transthyretin (ATTR) amyloidosis is substantially influenced by the presence and severity of cardiac involvement, which then governs therapeutic strategies.1,2 Although blood biomarkers are useful guides for risk stratification,3 they are not specific for cardiac involvement, and current strategies do not ascertain all patients at risk. Mortality, despite treatment progress, remains high.4–7 Over the last decade, new chemotherapy regimens and stem cell transplantation have been associated with improved survival in patients with AL amyloidosis, but the prognosis remains poor in those with cardiac involvement, which also contributes substantially to treatment-related morbidity and mortality. There remains a large unmet need for improved noninvasive criteria to stratify risk in selecting optimal therapy while avoiding serious toxicities. Editorial see p 1525 Clinical Perspective on p 1579 Cardiac amyloid deposition represents a key process in amyloid pathophysiology.8,9 Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) identifies myocardial infiltration: after the administration of contrast, CMR shows a characteristic pattern of global subendocardial LGE coupled with abnormal myocardial and blood-pool gadolinium kinetics.10,11 However, despite excellent diagnostic accuracy for the presence of amyloid, conflicting results have been reported for the prognostic impact on AL amyloidosis, and no studies have been published in ATTR amyloidosis.12–19 Newer techniques, particularly phase-sensitive inversion recovery (PSIR), an LGE image reconstruction technique that is less sensitive to operator choice of null point and renders signal intensity truly T1 weighted, may better reflect extent of cardiac involvement20 and thereby improve risk stratification.

idosis.12–19 Newer techniques, particularly phase-sensitive inversion recovery (PSIR), an LGE image reconstruction technique that is less sensitive to operator choice of null point and renders signal intensity truly T1 weighted, may better reflect extent of cardiac involvement20 and thereby improve risk stratification. We report here a prospective CMR study conducted in amyloidosis in which we investigated the prognostic value of LGE in 250 consecutive CMR-eligible subjects. The aims of the study were to assess the LGE patterns and the benefit of new more robust approaches (PSIR), the correlation with the cardiac amyloid burden, and the prognostic impact of LGE in both AL and ATTR cardiac amyloidosis.

ich we investigated the prognostic value of LGE in 250 consecutive CMR-eligible subjects. The aims of the study were to assess the LGE patterns and the benefit of new more robust approaches (PSIR), the correlation with the cardiac amyloid burden, and the prognostic impact of LGE in both AL and ATTR cardiac amyloidosis. Methods Amyloidosis Patients Subjects were prospectively recruited at the National Amyloidosis Center, Royal Free Hospital, London, UK, from 2010 to 2014 (Figure I in the online-only Data Supplement). Outcome (dead/alive) was ascertained from death certificates. A total of 250 patients were categorized into 3 groups. The first group included 119 subjects with biopsy-proven systemic AL amyloid (77 male, 65%; age, 62±10 years), with biopsies from the myocardium (n=7, 6%) or other tissues (n=112, 94%). The second group comprised 122 consecutive, consenting patients with ATTR amyloidosis (101 male, 83%; age, 71±11years). Sixty-nine percent (n=84) had histological proof of ATTR amyloidosis by Congo red and immunohistochemical staining of myocardial (n=35, 29%) or other (n=49, 40%) tissues. The presence of cardiac amyloid was defined by the presence of ATTR amyloid in a myocardial biopsy or positive technetium-labeled bone scintigraphy using 3,3-diphosphono-1,2-propanodicarboxylicacid (DPD scintigraphy). All subjects underwent sequencing of exons 2, 3, and 4 of the TTR gene. The third group was made up of 9 subjects with amyloidogenic TTR gene mutations (3 male, 33%; age, 47±6 years) defined as individuals with no evidence of clinical disease (no cardiac uptake on DPD scintigraphy and normal echocardiography, CMR, N-terminal pro-brain natriuretic peptide [NT-proBNP], and troponin T).

gene. The third group was made up of 9 subjects with amyloidogenic TTR gene mutations (3 male, 33%; age, 47±6 years) defined as individuals with no evidence of clinical disease (no cardiac uptake on DPD scintigraphy and normal echocardiography, CMR, N-terminal pro-brain natriuretic peptide [NT-proBNP], and troponin T). Exclusion Criteria We excluded all patients with contraindications to CMR: glomerular filtration rate <30 mL/min and CMR-incompatible devices. All ethics were approved by the University College London/University College London Hospital Joint Committees on the Ethics of Human Research Committee, and all participants provided written informed consent. CMR Image Acquisition All subjects underwent standard CMR on a 1.5-T clinical scanner (Avanto, Siemens Healthcare, Erlangen, Germany). Within a standard clinical scan (pilots, transverse white- and black-blood images, cines images to assess volumes and mass), LGE imaging was acquired with magnitude-only inversion recovery (MAG-IR) and PSIR sequence reconstructions in 43% of patients.

-T clinical scanner (Avanto, Siemens Healthcare, Erlangen, Germany). Within a standard clinical scan (pilots, transverse white- and black-blood images, cines images to assess volumes and mass), LGE imaging was acquired with magnitude-only inversion recovery (MAG-IR) and PSIR sequence reconstructions in 43% of patients. T1 measurement was performed with the use of the shortened modified look-locker inversion recovery sequence (ShMOLLI)21 with regions of interest drawn in the 4-chamber view at the level of the basal and mid inferoseptum (2 segments, large region of interest).22 After a bolus of gadoterate meglumine (0.1 mmol/kg, gadolinium-DOTA, Dotarem, Guerbet S.A. France) and standard LGE imaging (standard fast low-angle shot inversion recovery or balanced steady state free precession sequence with MAG-IR and PSIR reconstruction), the patient was removed from the scanner. The extracellular volume (ECV) measurement approach used equilibrium CMR with a primed infusion: At 15 minutes after bolus, an infusion at a rate of 0.0011 mmol·kg−1·min−1 contrast (equivalent to 0.1 mmol/kg over 90 minutes) was given. Between 45 and 80 minutes after bolus, the patient was returned to the scanner with the infusion continuing, and the T1 measurement was repeated using the same parameters of the precontrast ShMOLLI sequence.

an infusion at a rate of 0.0011 mmol·kg−1·min−1 contrast (equivalent to 0.1 mmol/kg over 90 minutes) was given. Between 45 and 80 minutes after bolus, the patient was returned to the scanner with the infusion continuing, and the T1 measurement was repeated using the same parameters of the precontrast ShMOLLI sequence. CMR LGE Interpretation During interpretation, before our adoption of PSIR for all amyloidosis patients, because myocardial nulling can be difficult in the presence of amyloid, any confusion with MAG-IR images was resolved by selecting the images that most matched the postcontrast T1 maps, with “bright” LGE expected to correlate with areas with the lowest postcontrast T1 (ie, the highest gadolinium concentration, the highest interstitial expansion). The LGE pattern was classified by 2 different observers (M.F. and S.P.) into 3 groups according to the degree of transmurality: group 1, no LGE; group 2, subendocardial LGE (when there was global subendocardial involvement but no transmural LGE); and group 3, transmural LGE (when the LGE was extending transmurally; Figure 1). Thus, a patient with basal transmural LGE but apical subendocardial LGE would be classified as transmural LGE. Figure 1. Characteristic phase-sensitive inversion recovery late gadolinium enhancement (LGE) patterns in 3 patients with immunoglobulin light-chain amyloidosis (AL) and 3 patients with transthyretin amyloidosis (ATTR). Left, No LGE; middle, subendocardial LGE; right, transmural LGE.

The LGE pattern was classified by 2 different observers (M.F. and S.P.) into 3 groups according to the degree of transmurality: group 1, no LGE; group 2, subendocardial LGE (when there was global subendocardial involvement but no transmural LGE); and group 3, transmural LGE (when the LGE was extending transmurally; Figure 1). Thus, a patient with basal transmural LGE but apical subendocardial LGE would be classified as transmural LGE. Figure 1. Characteristic phase-sensitive inversion recovery late gadolinium enhancement (LGE) patterns in 3 patients with immunoglobulin light-chain amyloidosis (AL) and 3 patients with transthyretin amyloidosis (ATTR). Left, No LGE; middle, subendocardial LGE; right, transmural LGE. CMR PSIR Versus MAG-IR A sample of 100 images (50 PSIR, 50 MAG-IR reconstruction) was analyzed for concordance or discordance with the postcontrast T1 maps that were used as the truth standard (Figure 2). We considered that nulled tissue should be the tissue with the least contrast (longest T1 on the postcontrast T1 map). This means that a normal subject should have nulled myocardium; a high-infiltration amyloid patient should have bright myocardium (transmural) and nulled blood, with the possibility of intermediate blood and myocardium nulling concurrently (typically with “bright” endocardium). This is discussed further in the figure legends and Discussion.

al subject should have nulled myocardium; a high-infiltration amyloid patient should have bright myocardium (transmural) and nulled blood, with the possibility of intermediate blood and myocardium nulling concurrently (typically with “bright” endocardium). This is discussed further in the figure legends and Discussion. Figure 2. Characteristic cardiovascular magnetic resonance scans. Late gadolinium enhancement (LGE) with magnitude reconstruction (left); LGE with phase-sensitive inversion recovery reconstruction (PSIR; middle); and postcontrast shortened modified look-locker inversion recovery sequence (ShMOLLI) T1 maps (right). On PSIR, there is 100% concordance between myocardial T1 and LGE: first, areas of low T1 (darkest blue) and focal areas of LGE; second, where myocardial T1 is lower than blood T1, global LGE is demonstrated; and third, where myocardial T1 is higher than blood T1, no LGE is demonstrated. On magnitude-only inversion recovery (MAG) images, discordance is present in all 4 of these cases: mid myocardial rather than subendocardial (A), apical rather than basal (B), transmural LGE rather than normal (C), and normal rather than transmural (D).

ere myocardial T1 is higher than blood T1, no LGE is demonstrated. On magnitude-only inversion recovery (MAG) images, discordance is present in all 4 of these cases: mid myocardial rather than subendocardial (A), apical rather than basal (B), transmural LGE rather than normal (C), and normal rather than transmural (D). Statistical Analysis Statistical analysis was performed with IBM SPSS Statistics version 19 (IBM, Somers, NY) and the R programming language (http://www.r-project.org/). All continuous variables were normally distributed (Shapiro-Wilk) except for NT-proBNP and troponin T, which were therefore ln-transformed for bivariate testing. These are presented as mean±SD, and nontransformed NT-proBNP is presented as median and quartiles 1 through 3. Comparisons between groups were performed by 2-way ANOVA with post hoc Bonferroni correction. The χ2 test or Fisher exact test was used to compare discrete data as appropriate. Correlations between parameters were assessed with the Pearson r or Spearman ρ. To assess the agreement of the assignment of the LGE pattern by 2 different observers, the intraclass correlation coefficient was calculated. Statistical significance was defined as P<0.05.

was used to compare discrete data as appropriate. Correlations between parameters were assessed with the Pearson r or Spearman ρ. To assess the agreement of the assignment of the LGE pattern by 2 different observers, the intraclass correlation coefficient was calculated. Statistical significance was defined as P<0.05. Survival was evaluated with Cox proportional hazards regression analysis, providing estimated hazard ratios with 95% confidence intervals and Kaplan–Meier curves. Variables selected a priori for clinical relevance and first explored with univariate Cox regression were entered into the multivariable models. Multivariable models evaluated the independent predictive value of LGE above other clinically and statistically significant covariates. The Harrell C statistic was calculated for the different models.

ri for clinical relevance and first explored with univariate Cox regression were entered into the multivariable models. Multivariable models evaluated the independent predictive value of LGE above other clinically and statistically significant covariates. The Harrell C statistic was calculated for the different models. Results Study Population The details of the 250 subjects are shown in Table 1. At the time of scanning, the AL amyloidosis cohort had 46 new untreated (to date) patients, 21 patients undergoing second- or third-line therapy, and 52 stable patients (complete or very good response, 80%; stable partial response, 20%). UK first-line therapy at the time of this study was typically cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, bortezomib, and dexamethasone. Relapse therapy was typically cyclophosphamide, bortezomib, and dexamethasone or a lenalidomide-containing regimen. The TTR mutations were as follows: V122I, n=23; T60A, n=13; V30M, n=10; E54G, n=2; S77Y, n=2; E89K, n=2; and D38Y, G47V, E89K, I84S, I107F, and L12P, n=1 each. Of the 9 asymptomatic individuals with TTR mutations, 5 had TTR V30M, 3 had T60A, and 1 had S77Y. Table 1. Main Clinical Characteristics and Echocardiographic and ECG Findings in Patients With AL and ATTR Amyloidosis According to the LGE Pattern

Results Study Population The details of the 250 subjects are shown in Table 1. At the time of scanning, the AL amyloidosis cohort had 46 new untreated (to date) patients, 21 patients undergoing second- or third-line therapy, and 52 stable patients (complete or very good response, 80%; stable partial response, 20%). UK first-line therapy at the time of this study was typically cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, bortezomib, and dexamethasone. Relapse therapy was typically cyclophosphamide, bortezomib, and dexamethasone or a lenalidomide-containing regimen. The TTR mutations were as follows: V122I, n=23; T60A, n=13; V30M, n=10; E54G, n=2; S77Y, n=2; E89K, n=2; and D38Y, G47V, E89K, I84S, I107F, and L12P, n=1 each. Of the 9 asymptomatic individuals with TTR mutations, 5 had TTR V30M, 3 had T60A, and 1 had S77Y. Table 1. Main Clinical Characteristics and Echocardiographic and ECG Findings in Patients With AL and ATTR Amyloidosis According to the LGE Pattern MAG-IR Versus PSIR MAG-IR LGE and T1 maps were discordant in 57% (in which the operator was selecting the inversion time according to his/her best judgment), meaning that operator TI selection was mainly incorrect. Ten patients with MAG-IR only had no LGE images that matched the T1 mapping for classification (implying that the operator systematically kept the TI incorrect for the whole scan). All patients with PSIR LGE had diagnostic images. PSIR LGE and T1 maps were never (0%) discordant (Figures 2 and 3). MAG-IR could be incorrect in 3 ways: inappropriately nulling global LGE (Figure 2D), particularly the highest ECV cases; getting the incorrect distribution (especially making LGE apical rather than basal; Figure 2A and 2B); or creating transmural LGE where there should be global nulling (and the ECV was low; Figure 2C). With PSIR, the longest T1 tissue after windowing is always nulled.

LGE (Figure 2D), particularly the highest ECV cases; getting the incorrect distribution (especially making LGE apical rather than basal; Figure 2A and 2B); or creating transmural LGE where there should be global nulling (and the ECV was low; Figure 2C). With PSIR, the longest T1 tissue after windowing is always nulled. Figure 3. Two patients (top and bottom) with magnitude-only inversion recovery (MAG) and phase-sensitive inversion recovery reconstruction (PSIR) late gadolinium enhancement (LGE) reconstruction images (left). In both patients, the MAG and PSIR are discordant with opposite LGE patterns. Only one can be correct. The tissue to null is the one with the slowest T1 recovery (ie, the least gadolinium). Right, Signal intensity curves as the TI varies for MAG and PSIR. How the operator sets the TI matters in MAG imaging but not in PSIR. The operator set the TI for both patients at X, nulling the wrong tissue. The image would have been correct only if the operator had set the TI greater than Y. With PSIR, the TI could have been set anywhere, and the tissue with the least gadolinium has lower signal and will be nulled after windowing.

g but not in PSIR. The operator set the TI for both patients at X, nulling the wrong tissue. The image would have been correct only if the operator had set the TI greater than Y. With PSIR, the TI could have been set anywhere, and the tissue with the least gadolinium has lower signal and will be nulled after windowing. LGE Pattern and Correlation With ECV Three patterns of LGE are observed: no LGE, subendocardial LGE, and transmural LGE (Figure 1). There was good agreement in the assignment of these patterns between 2 observers (intraclass correlation coefficient, 0.97; 95% confidence interval, 0.97–098). All patterns were present in AL and ATTR cardiac amyloidosis (Figure 1) but to different extents, with subendocardial LGE being more prevalent in AL (39% in AL versus 24% in ATTR; P<0.05) and transmural LGE more prevalent in ATTR (27% in AL versus 63%; P<0.0001; Figure 4). Figure 4. Late gadolinium enhancement (LGE) pattern correlation with amyloid burden. Top, Histograms showing the prevalence of the different LGE patterns in patients with immunoglobulin light-chain amyloidosis (AL) and patients with transthyretin amyloidosis (ATTR). Bottom, Correlation with the amyloid burden measured as extracellular volume (ECV) in AL and ATTR patients. Bonferroni adjustment was applied. CI indicates confidence interval.

of the different LGE patterns in patients with immunoglobulin light-chain amyloidosis (AL) and patients with transthyretin amyloidosis (ATTR). Bottom, Correlation with the amyloid burden measured as extracellular volume (ECV) in AL and ATTR patients. Bonferroni adjustment was applied. CI indicates confidence interval. Increasing LGE (none, subendocardial, transmural) was associated with increasing ECV (AL: 0.31±0.04, 0.47±0.06, and 0.58±0.07; ATTR: 0.29±0.04, 0.50±0.05, and 0.60±0.05; P<0.0001 for both; Figure 4). In ATTR, this correlated also with DPD grade (P<0.0001). Apparent transitions are evident, with subendocardial LGE appearing at an ECV of 0.40 to 0.43 for AL and 0.39 to 0.40 for ATTR and transmural at an ECV of 0.48 to 0.55 for AL and 0.47 to 0.59 for ATTR. However, 39% of the patients with no LGE had ECV elevation compared with normal range (ECV elevation between 0.32 and 0.40). Of the patients with no LGE and increased ECV, 4 patients had mutant ATTR (and DPD was grade 1 in 3 patients and grade 0 in 1 patient), and 17 patients had AL amyloidosis.

0.47 to 0.59 for ATTR. However, 39% of the patients with no LGE had ECV elevation compared with normal range (ECV elevation between 0.32 and 0.40). Of the patients with no LGE and increased ECV, 4 patients had mutant ATTR (and DPD was grade 1 in 3 patients and grade 0 in 1 patient), and 17 patients had AL amyloidosis. Increasing LGE (none, subendocardial, transmural) was associated in both AL and ATTR with lower systolic blood pressure, ECG changes (prolonged PR interval, prolonged QRS in ATTR), increased NT-proBNP, structural and functional changes (increased LV mass, increased end-systolic volume, decreased stroke volume, decreased ejection fraction, left atrial dilatation), increasingly abnormal tissue characterization (elevated native T1 and ECV; Table 2), and more severe echocardiographic diastolic dysfunction. In ATTR, increasing LGE was also associated with decreased functional capacity (6-minute walking test). Table 2. CMR Findings in Patients With AL and ATTR Amyloidosis According to the LGE Pattern LGE Pattern and Prognosis At follow-up (mean, 24±13 months), 67 of 250 patients (27%) had died. Transmural LGE was a significant predictor of mortality in the overall population (hazard ratio, 5.4; 95% confidence interval, 2.1–13.7; P<0.0001; Figure 5). Figure 5. Kaplan–Meier curves for late gadolinium enhancement (LGE) patterns in all patients (top), patients with immunoglobulin light-chain amyloidosis (AL; bottom left), and patients with transthyretin amyloidosis (ATTR; bottom right).

LGE Pattern and Prognosis At follow-up (mean, 24±13 months), 67 of 250 patients (27%) had died. Transmural LGE was a significant predictor of mortality in the overall population (hazard ratio, 5.4; 95% confidence interval, 2.1–13.7; P<0.0001; Figure 5). Figure 5. Kaplan–Meier curves for late gadolinium enhancement (LGE) patterns in all patients (top), patients with immunoglobulin light-chain amyloidosis (AL; bottom left), and patients with transthyretin amyloidosis (ATTR; bottom right). The survival curves indicates that there is an ≈92% chance of survival at 24 months in patients with a no LGE (92% in AL, 94% in ATTR) compared with 81% for patients with subendocardial LGE (81% in AL, 81% in ATTR) and 61% with transmural LGE (45% in AL, 65% in ATTR). The median survival in patients with transmural LGE was 17 months in AL and 38 months in ATTR. Transmural LGE was significantly associated with mortality (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P<0.05) in multivariable Cox models that included NT-proBNP, ejection fraction, stroke volume indexed, E/E′, and left ventricular mass indexed (Troponin results were not available in all patients). NT-ProBNP and stroke volume indexed also remained independently predictive (Table 3). Harrell C statistics for this model was 0.72. Table 3. Univariate and Multivariate Analyses of Risk of Death in the Overall Population

The survival curves indicates that there is an ≈92% chance of survival at 24 months in patients with a no LGE (92% in AL, 94% in ATTR) compared with 81% for patients with subendocardial LGE (81% in AL, 81% in ATTR) and 61% with transmural LGE (45% in AL, 65% in ATTR). The median survival in patients with transmural LGE was 17 months in AL and 38 months in ATTR. Transmural LGE was significantly associated with mortality (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P<0.05) in multivariable Cox models that included NT-proBNP, ejection fraction, stroke volume indexed, E/E′, and left ventricular mass indexed (Troponin results were not available in all patients). NT-ProBNP and stroke volume indexed also remained independently predictive (Table 3). Harrell C statistics for this model was 0.72. Table 3. Univariate and Multivariate Analyses of Risk of Death in the Overall Population The Harrell C statistics of a comparable pre-CMR model including demographics, systolic and diastolic function parameters, and biomarkers (age, ejection fraction, E/E′, NT-ProBNP, interventricular septal wall thickness) was 0.67.

The survival curves indicates that there is an ≈92% chance of survival at 24 months in patients with a no LGE (92% in AL, 94% in ATTR) compared with 81% for patients with subendocardial LGE (81% in AL, 81% in ATTR) and 61% with transmural LGE (45% in AL, 65% in ATTR). The median survival in patients with transmural LGE was 17 months in AL and 38 months in ATTR. Transmural LGE was significantly associated with mortality (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P<0.05) in multivariable Cox models that included NT-proBNP, ejection fraction, stroke volume indexed, E/E′, and left ventricular mass indexed (Troponin results were not available in all patients). NT-ProBNP and stroke volume indexed also remained independently predictive (Table 3). Harrell C statistics for this model was 0.72. Table 3. Univariate and Multivariate Analyses of Risk of Death in the Overall Population The Harrell C statistics of a comparable pre-CMR model including demographics, systolic and diastolic function parameters, and biomarkers (age, ejection fraction, E/E′, NT-ProBNP, interventricular septal wall thickness) was 0.67. Discussion Cardiac infiltration is the chief driver of prognosis in systemic amyloidosis, and stratification of patients is essential for prognosis and optimal management, including selection of patients to receive aggressive higher-risk therapies and to minimize cardiac toxicities. Echocardiography, once the gold standard cardiac investigation in amyloidosis, has limited sensitivity and specificity, and risk stratification currently places great emphasis on blood biomarkers. However, these strategies do not identify all amyloidosis patients at risk, and the findings of studies evaluating cardiac involvement by CMR have been conflicting.4–7,19 Recently, considerable interest has emerged in using LGE to improve the risk stratification model,12–19 but studies in AL cardiac amyloidosis have been few, mostly small, and retrospective; have used nonstandardized LGE approaches; and have produced inconsistent results.10,12,13,15,16,19 No studies have been published in ATTR amyloidosis.

le interest has emerged in using LGE to improve the risk stratification model,12–19 but studies in AL cardiac amyloidosis have been few, mostly small, and retrospective; have used nonstandardized LGE approaches; and have produced inconsistent results.10,12,13,15,16,19 No studies have been published in ATTR amyloidosis. In the present study, the largest CMR study in amyloidosis to date, we showed that misleading results using the MAG-IR LGE technique were likely to account for the conflicting finding that have previously been published. By convention, areas with the most contrast should be displayed as bright on LGE imaging (ie, shortest T1 on T1 maps). For amyloidosis, myocardium can contain more gadolinium than blood. Under those circumstances, myocardium should appear globally bright (transmural LGE). It is a property of MAG imaging that the signal is highly dependent and nonlinear with a user-defined choice of the TI (time to null; Figure 2), and images can be “inverted” with the wrong TI choice. When all of the myocardium is abnormal (seen frequently in cardiac amyloidosis), the abnormal myocardium could be wrongly nulled because the MAG-IR relies on “nulling” what is perceived to be normal myocardium. This limitation was quantified in our study by comparison with a true standard of postcontrast T1. More important, this problem does not occur with the PSIR approach. PSIR substantially removes the issue of operator-selected inversion time and completely removes the potential for a “mirror image.” On a PSIR reconstruction when windowed by the operator, the tissue with the longest T1 (least gadolinium, ie, blood or myocardium) after windowing is always nulled. The practical results include the following: first, if myocardium is globally nulled by PSIR and the ECV is less than blood and <0.4 to 0.43, any amyloid present (detectable by an ECV >0.32) is not extensive. Second, above this value, LGE areas appear particularly in the subendocardium. PSIR LGE areas are the areas of most amyloid deposition in the heart. Third, above an ECV of 0.47 to 0.59, when blood has less gadolinium than myocardium and blood is nulled (myocardium appears uniformly bright), heterogeneity is present but is swamped by all the myocardium becoming bright.

larly in the subendocardium. PSIR LGE areas are the areas of most amyloid deposition in the heart. Third, above an ECV of 0.47 to 0.59, when blood has less gadolinium than myocardium and blood is nulled (myocardium appears uniformly bright), heterogeneity is present but is swamped by all the myocardium becoming bright. Examples of MAG-IR errors are shown in Figure 2: mid myocardial rather than subendocardial (Figure 2A), apical rather than basal (Figure 2B), transmural LGE rather than normal (Figure 2C), and normal rather than transmural (Figure 2D).20,23 Accordingly, we believe that PSIR should be universally adopted for amyloid LGE imaging, particularly because PSIR-LGE is easily available from all scanner manufacturers (whereas T1 mapping is not yet).

basal (Figure 2B), transmural LGE rather than normal (Figure 2C), and normal rather than transmural (Figure 2D).20,23 Accordingly, we believe that PSIR should be universally adopted for amyloid LGE imaging, particularly because PSIR-LGE is easily available from all scanner manufacturers (whereas T1 mapping is not yet). With PSIR, 3 patterns were relatively easy to determine, and the frequently described LGE pattern of patchy LGE was not evident with PSIR (many of these on PSIR appeared to have transmural LGE). A key insight is that amyloid cardiac involvement is not dichotomous but a continuum from no LGE to subendocardial to transmural tracking increasing ECV (Figure 6).24,25 Transmural LGE appears to be the pattern that carries the most adverse prognosis. It is an important marker of all-cause mortality after adjustment for other relevant disease variables and regardless of treatment status (indeed regardless of whether patients are presenting at diagnosis or years into the disease process). Indeed, in ATTR, the majority of the deaths are in patients with transmural LGE (no LGE, subendocardial LGE, and transmural TGE: 1, 6, and 24 deaths, respectively). Figure 6. Hypothesized cardiac amyloid progression across time. When amyloid starts to accumulate, 3 steps can be identified: (1) no evidence of late gadolinium enhancement (LGE) but an increase in native T1 and extracellular volume (ECV), (2) a further increase in T1 and ECV and the appearance of subendocardial LGE; and (3) a further increase in native T1 and ECV and progression to transmural LGE.

ts to accumulate, 3 steps can be identified: (1) no evidence of late gadolinium enhancement (LGE) but an increase in native T1 and extracellular volume (ECV), (2) a further increase in T1 and ECV and the appearance of subendocardial LGE; and (3) a further increase in native T1 and ECV and progression to transmural LGE. Within this spectrum, the degree of involvement is important, with transmural LGE defining the high-risk group. The prevalence of patients in the different stages of disease progression (Figure 6) is different in AL and ATTR. Thirty-nine percent of the patients with no LGE had ECVs in the range of 0.32 to 0.4, particularly patients with AL amyloidosis. It is expected that ATTR patients must pass through this phase, but it is not clinically recognized. Early cardiac involvement in AL is detected through cardiac screening of AL patients presenting with extracardiac disease. The majority of ATTR patients (wild-type ATTR and mutant ATTR associated with the variant V122I) present with heart failure symptoms that appear only when advanced (LGE, mostly transmural, is invariably present). This has potential treatment implications. Currently, patients with subendocardial LGE may be classified as having cardiac involvement and denied therapies that are known to improve long-term survival but are contraindicated in cardiac involvement such as stem cell transplantations (AL), some chemotherapy regimens (AL), and liver transplantations (ATTR). More data are needed, and consideration of cardiac involvement as a continuum should provide insights into the impact of different degrees of cardiac infiltration, possibly resulting in changes in the current therapeutic approach. Within the transmural pattern, the median survival is significantly different in the 2 amyloid types: 17 months for AL and 38 months for ATTR.

volvement as a continuum should provide insights into the impact of different degrees of cardiac infiltration, possibly resulting in changes in the current therapeutic approach. Within the transmural pattern, the median survival is significantly different in the 2 amyloid types: 17 months for AL and 38 months for ATTR. These findings support the concept that cardiac amyloid is not a disease of solely infiltration but may have superimposed toxicity (AL more than ATTR) or that the rate of accumulation is myotoxic, a contributor to different prognoses or AL and ATTR despite ATTR having higher degrees of left ventricular hypertrophy, cardiac dysfunction, and amyloid burden.26 T1 mapping techniques provide new insights into this, being able to follow the disease at 3 different levels, that is, infiltration (amyloid burden, ECV), edema (native T1), and myocyte response (intracellular volume), and providing new prognostic markers.27 These new biomarkers may aid diagnosis and risk stratifications and act as surrogate end points in clinical trials. However, the current limited availability and the technical challenges related to sequence- and vendor-specific differences limit the role of T1 mapping in routine clinical practice. The common use of the LGE technique in all clinical CMR scans and the availability of PSIR reconstruction on all different vendor platforms make LGE a robust and reliable approach for routine risk stratification of patients with cardiac amyloidosis.

differences limit the role of T1 mapping in routine clinical practice. The common use of the LGE technique in all clinical CMR scans and the availability of PSIR reconstruction on all different vendor platforms make LGE a robust and reliable approach for routine risk stratification of patients with cardiac amyloidosis. Limitations of the study are that patients were at different treatment stages, with treatment reflecting current UK practice. Cardiac biopsy was present in only a minority of patients, but this cohort of patients was fully characterized with all other clinical investigative techniques currently available, including DPD scanning. This composite diagnostic pathway is known to provide high diagnostic accuracy. The causes of death are not known because patients die locally and the National Amyloidosis center receives only notification of death, not the cause of death. Although this study highlights the prognostic role of transmural LGE for risk stratification of patients with cardiac amyloidosis, further studies are needed to assess the direct correlation between patterns of LGE and treatment-related mortality.

osis center receives only notification of death, not the cause of death. Although this study highlights the prognostic role of transmural LGE for risk stratification of patients with cardiac amyloidosis, further studies are needed to assess the direct correlation between patterns of LGE and treatment-related mortality. Sources of Funding Dr Fontana is supported by a Clinical Research Training Fellowships from the British Heart Foundation (FS/12/56/29723). A. Abdel-Gadir is supported by the Rosetrees Trust. T.A. Treibel is supported by the National Institute for Health Research (DRF-2013-06-102). Dr Moon is supported by the Higher Education Funding Council for England. Dr Bucciarelli-Ducci is supported by the Bristol NIHR Biomedical Research Unit. This work was undertaken at the University College London Hospital and University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. Disclosures None. Supplementary Material The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.016567/-/DC1.

Sources of Funding Dr Fontana is supported by a Clinical Research Training Fellowships from the British Heart Foundation (FS/12/56/29723). A. Abdel-Gadir is supported by the Rosetrees Trust. T.A. Treibel is supported by the National Institute for Health Research (DRF-2013-06-102). Dr Moon is supported by the Higher Education Funding Council for England. Dr Bucciarelli-Ducci is supported by the Bristol NIHR Biomedical Research Unit. This work was undertaken at the University College London Hospital and University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. Disclosures None. Supplementary Material The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.016567/-/DC1. CLINICAL PERSPECTIVE Cardiac infiltration is the chief driver of prognosis in systemic amyloidosis. Its assessment aids in the selection of patients to receive (or not) aggressive chemotherapy, stem cell therapy, and newer therapies. Currently, stratification uses blood biomarkers and echocardiography, but echocardiography has limited sensitivity and specificity, particularly in apparently early disease and when confounders (such as hypertension) are present. Cardiovascular magnetic resonance shows promise with the late gadolinium enhancement (LGE) technique to visualize infiltration, but the technique has always been difficult in cardiac amyloidosis because of difficult nulling, with both early and advanced disease being potentially misclassified. Here, using T1 mapping as a truth standard (bright myocardium should have the most contrast present), we show in 250 patients with both immunoglobulin light chain and transthyretin amyloidosis that a new but widely available LGE technique, phase-sensitive inversion recovery, completely solves the nulling problems in amyloidosis. With the use of phase-sensitive inversion recovery, the longest T1 tissue after windowing is always nulled. Three LGE patterns are present in cardiac amyloidosis: no LGE, subendocardial LGE, and transmural TGE. The transmural LGE pattern is associated with the highest infiltration and carries the most adverse prognosis. It is a marker of all-cause mortality, even after adjustment for other relevant disease variables. These results suggest that cardiac infiltration is a continuum with the degree of involvement being measurable and important, with transmural LGE defining the high-risk group and the subendocardial LGE group being a potential key group to focus on for therapy.

A central principle in cardiovascular disease (CVD) management is that the first lifetime diagnosis signals the failure of primary prevention and the need to initiate secondary prevention of recurrent or related CVD events. The decades-long emphasis given to prevention of myocardial infarction (MI) and stroke is reflected in remarkable declines – ≈33% over the past decade – in their incidence in developed countries.1 Incidence rates for chronic CVD presentations such as angina or heart failure, although less studied, do not appear to have similarly declined.1–3 Consequently, the spectrum of initial presentations of CVD in contemporary practice is likely to have changed in comparison with the latter part of the last century. Cohort studies that report only fatal end points (final presentations),4 may have less relevance to informing the success of primary prevention than those which investigate initial presentations. Within studies that incorporate nonfatal events, acute MI and stroke have been more commonly investigated than other chronic presentations.5–7 Large-scale contemporary studies that evaluate the first lifetime diagnosis in women and men across a wide range of acute and chronic CVDs including both fatal and nonfatal presentations can provide additional insight into the understanding of CVDs. Editorial see p 1303 Clinical Perspective on p 1328 Fundamental unanswered questions about initial CVD presentation arise. First, what is the relative frequency of different CVDs as they affect women and men in contemporary practice? Second, is male sex an equally strong risk factor common to all CVDs, or does the association differ across a range of diseases?

Clinical Perspective on p 1328 Fundamental unanswered questions about initial CVD presentation arise. First, what is the relative frequency of different CVDs as they affect women and men in contemporary practice? Second, is male sex an equally strong risk factor common to all CVDs, or does the association differ across a range of diseases? The lack of large, contemporary, population-based cohorts with detailed clinical follow-up spanning hospital and ambulatory care has hindered the study of the initial presentation of a wide range of acute and chronic CVDs. It has been suggested that electronic health record (EHR) data might be meaningfully reused8 to create mega-cohorts for such research.9 We studied a contemporary, population-based cohort based on linked EHRs across primary, secondary, disease registry, and death records10–13 to address these 2 questions. We investigated a wide range of acquired symptomatic CVDs that are recognized to have differing pathogenic mechanisms.

ega-cohorts for such research.9 We studied a contemporary, population-based cohort based on linked EHRs across primary, secondary, disease registry, and death records10–13 to address these 2 questions. We investigated a wide range of acquired symptomatic CVDs that are recognized to have differing pathogenic mechanisms. Methods Data Sources Anonymized patients were selected from the Cardiovascular Research Using LInked Bespoke Studies and Electronic Records (CALIBER) program, described14 and validated10–13,15 elsewhere. Patients were linked across 4 clinical data sources: the Clinical Practice Research Database (CPRD), the Myocardial Ischemia National Audit Project registry, Hospital Episodes Statistics, and the national death registry from the Office for National Statistics. CPRD provides primary care data on anthropometric measurements, laboratory tests, medical history, clinical diagnoses, prescriptions, medical procedures, and health behaviors, coded using the Read clinical coding scheme. Patients registered in practices submitting linkable data to CPRD, covering ≈4% of the English population, have been found to be representative of the English population in terms of age, sex, and ethnicity.16,17 Myocardial Ischemia National Audit Project is a national registry of patients admitted to the hospital with acute coronary syndromes. Hospital Episodes Statistics provides information on diagnoses and medical procedures related to all elective and emergency hospital admissions across all National Health Service hospitals in England.

hemia National Audit Project is a national registry of patients admitted to the hospital with acute coronary syndromes. Hospital Episodes Statistics provides information on diagnoses and medical procedures related to all elective and emergency hospital admissions across all National Health Service hospitals in England. Study Population We studied 1 937 360 patients from 225 general practices across England registered between January 1997 and March 2010. We required that at study entry patients were aged ≥30 years, were free of diagnosed CVD, and had been followed up for at least 1 year. We used the entire medical history available on each patient to confirm they were free of diagnosed CVD. The look-back period ranged from 20 years to the minimum of 1 year, which previous research has indicated is a sufficient period to ensure accurate assessment of initial disease presentations.18 We used an open cohort design, so patients effectively entered the study when they met the inclusion criteria. Patients were censored on the earliest date from among: the date of first CVD presentation, date of death from other causes, date leaving the practice, or date of last practice data collection. (See Figure I in the online-only Data Supplement for study flow diagram.)

ered the study when they met the inclusion criteria. Patients were censored on the earliest date from among: the date of first CVD presentation, date of death from other causes, date leaving the practice, or date of last practice data collection. (See Figure I in the online-only Data Supplement for study flow diagram.) Risk Factors The exposures of interest were sex and baseline age, analyzed as 10-year age groups between 30 and 80. A priori confounders were baseline age as a continuous variable (in analyses estimating associations with sex), smoking status, body mass index, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes mellitus, socioeconomic status (based on area deprivation measure), use of statins, use of blood pressure medication, and, in women only, use of oral contraceptives or hormone replacement therapy. The baseline value for these confounders was taken as the most recent measurement as recorded during consultations in primary care (CPRD) up to 1 year before study entry. (Detailed definitions are in online-only Data Supplement Methods I.)

, and, in women only, use of oral contraceptives or hormone replacement therapy. The baseline value for these confounders was taken as the most recent measurement as recorded during consultations in primary care (CPRD) up to 1 year before study entry. (Detailed definitions are in online-only Data Supplement Methods I.) End Points Primary end points were defined as the first recorded diagnosis of the 12 most common symptomatic manifestations of CVD, irrespective of underlying disease mechanism, arising from pathology in the head, heart, abdomen, or legs. The first diagnosis could occur in primary care, secondary care, or at death. We studied the following CVDs: stable angina, unstable angina, nonfatal MI, unheralded coronary death (UCD), heart failure, a composite of cardiac arrest, ventricular arrhythmia, and sudden cardiac death (SCD), transient ischemic attack, ischemic stroke, subarachnoid hemorrhage (SAH), intracerebral hemorrhage, abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD), composite CVD, and other deaths. In secondary analysis, we examined associations in a subset of nonfatal MIs that were classified into ST-segment–elevation MI and non–ST-segment–elevation MI. Coronary heart disease (CHD) and stroke that were not otherwise specified (NOS) were also studied. We classified as fatal events where a death record exists for the same calendar date. (Overview of codes and data sources used to define cardiovascular end points available in online-only Data Supplement Methods II.)

MI. Coronary heart disease (CHD) and stroke that were not otherwise specified (NOS) were also studied. We classified as fatal events where a death record exists for the same calendar date. (Overview of codes and data sources used to define cardiovascular end points available in online-only Data Supplement Methods II.) Statistical Analysis Hazard ratios (HRs) were estimated for the disease-specific Cox proportional-hazards models with length of follow-up as the timescale, stratified by practice, with women as the reference category, and included interactions between age (linear and quadratic term) and sex. Where we estimated the HR for baseline age, we additionally stratified by sex, to allow the baseline hazard to vary. The proportional hazard assumption was tested using Schoenfield residuals, with no significant effects found. In the main analyses, we estimated the association of each end point with age groups, the age-adjusted association with sex across all subjects, and by age group in a model with sex interactions. Assuming mutual independence between initial presentations, we assessed heterogeneity in the reported associations based on τ2, an estimate of the between-group variance of the log hazard ratio, and a way of summarizing the variability in effect sizes across all the end points in a single statistic.19

sex interactions. Assuming mutual independence between initial presentations, we assessed heterogeneity in the reported associations based on τ2, an estimate of the between-group variance of the log hazard ratio, and a way of summarizing the variability in effect sizes across all the end points in a single statistic.19 In secondary analysis, we examined whether associations with sex change after adjusting for smoking status, body mass index, diabetes mellitus, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and social deprivation, or additionally for baseline use of blood pressure–lowering medications (diazides, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers), statins, oral contraceptives and hormone replacement therapy. Missing covariate data were handled by multiple imputation. (Methods used for multiple imputation are described in online-only Data Supplement Methods III). In sensitivity analyses we studied associations between sex and CVDs (1) ignoring primary care diagnoses and (2) restricting end points to fatal events. In a post hoc analysis, we assessed the discrimination of age- and sex-adjusted models for each of the 12 end points by calculating the separate concordance index (C-index) for each.20 Approval was granted by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency and the Myocardial Ischemia National Audit Project Academic Group. We registered the protocol at clinicaltrials.gov (NCT01164371).

In a post hoc analysis, we assessed the discrimination of age- and sex-adjusted models for each of the 12 end points by calculating the separate concordance index (C-index) for each.20 Approval was granted by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency and the Myocardial Ischemia National Audit Project Academic Group. We registered the protocol at clinicaltrials.gov (NCT01164371). Results Baseline characteristics of the cohort are shown in the Table. The cohort was young at baseline, as would be expected from a population free from CVD, and 90% were white. Both systolic and diastolic blood pressure increased with age, as did the proportion on blood pressure–lowering medication, with more women than men treated at all ages. More men than women were current or ex-smokers, the proportion of current smokers declining at >60 years of age. Rates of statin prescription were low, but were higher in men than in women at all ages. Table. Baseline Characteristics in Men and Women by 10-Year Age Groups

Results Baseline characteristics of the cohort are shown in the Table. The cohort was young at baseline, as would be expected from a population free from CVD, and 90% were white. Both systolic and diastolic blood pressure increased with age, as did the proportion on blood pressure–lowering medication, with more women than men treated at all ages. More men than women were current or ex-smokers, the proportion of current smokers declining at >60 years of age. Rates of statin prescription were low, but were higher in men than in women at all ages. Table. Baseline Characteristics in Men and Women by 10-Year Age Groups Initial CVD Presentations Over a 6-year median follow-up (interquartile range, 2–10), 114 859 initial CVD presentations were observed (52.3% in men), among which nonfatal MI, UCD, and ischemic or NOS stroke together accounted for 32.5%. The proportion of events varied by sex and age group (Figure 1; Table I in the online-only Data Supplement). The most frequent initial CVD presentation for men was nonfatal MI, which accounted for 27.9% of events in the 30 to 39 age group and more than double the proportion in women in the same age group (11.2%). This proportion declined in men as age increased, becoming similar to that in women in the >80 age group. In contrast, stable angina and unstable angina accounted for similar proportions of initial presentations in both men and women and declined with age. Although evident in younger age groups, heart failure and ischemic stroke as an initial presentation started to increase in both sexes at age 60 to form the 2 most common initial presentations at age >80.

able angina accounted for similar proportions of initial presentations in both men and women and declined with age. Although evident in younger age groups, heart failure and ischemic stroke as an initial presentation started to increase in both sexes at age 60 to form the 2 most common initial presentations at age >80. Figure 1. Age and sex distribution of 60 155 events in men and 54 704 in women representing the initial presentation of a wide range of CVDs. CHD indicates coronary heart disease; CVD, cardiovascular disease; NOS, not otherwise specified; and SCD, sudden cardiac death. Associations With Age The strength and shape of the association of CVDs with age varied from predominantly linear (in angina and nonfatal MI) to strongly quadratic (UCD, stroke, AAA), and from weak (SAH, unstable angina, and cardiac arrest/SCD) to very strong (heart failure and AAA. (See Figure II in the online-only Data Supplement.)

th Age The strength and shape of the association of CVDs with age varied from predominantly linear (in angina and nonfatal MI) to strongly quadratic (UCD, stroke, AAA), and from weak (SAH, unstable angina, and cardiac arrest/SCD) to very strong (heart failure and AAA. (See Figure II in the online-only Data Supplement.) Associations With Sex SAH was less common in men (HR men versus women, 0.69; 95% confidence interval [CI], 0.59–0.79); other CVDs were positively associated with male sex but with considerable heterogeneity (τ2=0.196; Figure 2). Specifically, the age-adjusted HR (all P<0.001) was <1.5 for transient ischemic attack, intracerebral hemorrhage, and unstable angina, 1.5 to 2.0 for stable angina, ischemic stroke, PAD, heart failure, and cardiac arrest/SCD, and 3.6 to 5.0 for AAA, MI, and UCD. The age-adjusted HR for men versus women was 4.14 (95% CI, 3.72–4.60) in ST-segment–elevation MI and 3.18 (95% CI, 2.86–3.52) in non–ST-segment–elevation MI. These associations changed little after adjustment for conventional CVD risk factors and baseline medications, with the exception of intracerebral hemorrhage, where the association reduced to null (Figure III in the online-only Data Supplement). Figure 2. Hazard ratios of men in comparison with women for initial presentation of 12 different cardiovascular diseases among a population of 1.93 million adults. CHD indicates coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; NOS, not otherwise specified; and SCD, sudden cardiac death.

rd ratios of men in comparison with women for initial presentation of 12 different cardiovascular diseases among a population of 1.93 million adults. CHD indicates coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; NOS, not otherwise specified; and SCD, sudden cardiac death. Associations between sex and initial CVD presentation were differentially modified by age (Figure 3). The largest differences in HRs for men versus women were observed in the younger (coronary end points) and middle (ischemic stroke, PAD, AAA) age groups. Most dramatically, men <60 years old had an >4-fold higher risk of MI or UCD than similarly aged women. In all cases, associations with male sex diminished with age. Figure 3. Hazard ratios for men in comparison with women for initial presentation of 12 cardiovascular diseases by baseline age group among a population of 1.93 million adults. CHD indicates coronary heart disease; CI, confidence interval; HR, hazard ratio; NOS, not otherwise specified; and SCD, sudden cardiac death. Sensitivity Analyses The pattern and magnitude of associations with sex were similar in multiply-adjusted analyses to analyses adjusted for age alone (see Figure III in the online-only Data Supplement). Stable angina and PAD were the only initial presentations where the association with male sex differed when the EHRs used were restricted to secondary care and mortality (Figure IV in the online-only Data Supplement).

usted analyses to analyses adjusted for age alone (see Figure III in the online-only Data Supplement). Stable angina and PAD were the only initial presentations where the association with male sex differed when the EHRs used were restricted to secondary care and mortality (Figure IV in the online-only Data Supplement). Discrimination of Age- and Sex-Adjusted Models for Different CVDs Using disease-specific age and sex coefficients in risk prediction models resulted in markedly different discrimination performance (Figure V in the online-only Data Supplement), with C-indices ranging from very low for SAH (0.57; 95% CI, 0.55–0.59) to relatively high for AAA (0.86; 95% CI, 0.85–0.88) in comparison with a conventional composite CVD model with C-index of 0.73 (95% CI, 0.72–0.73). Discussion Objectives Addressed, Summary of Main Findings By linking EHRs from multiple sources we curated a cohort of nearly 2 million patients with >100 000 nonfatal and fatal CVD end points of 12 different types. We found that the majority of CVD first presentations are not MI or ischemic stroke but rather heart failure, angina, transient ischemic attack, and PAD. In our contemporary population-based cohort, we find that 51.3% of men and 41.2% of women experienced some form of CVD during their lifetime, with heart failure and stroke (primarily ischemic and NOS) becoming more common as the initial presentations in both men and women in later life. The variable associations of sex and age with different CVDs have important consequences for risk prediction.

.2% of women experienced some form of CVD during their lifetime, with heart failure and stroke (primarily ischemic and NOS) becoming more common as the initial presentations in both men and women in later life. The variable associations of sex and age with different CVDs have important consequences for risk prediction. Importance of Studying First Manifestations of CVD We compared the relative frequency of 12 of the most common CVDs affecting atherothrombotic processes in the coronary, cerebral, and peripheral circulations, aneurysms in the cerebral and peripheral circulations, and disorder of myocardial function and cardiac arrhythmia. This family of diseases is clinically relevant, because having one is strongly associated with the subsequent development of another and should initiate a range of secondary preventive interventions.21 Despite the insights to be gained from considering the first presentation among these diseases together, this first-lifetime-presentation approach has rarely been reported in the literature22 and has tended to exclude major diseases such as heart failure, been restricted to small cohorts, or reported in men only.23–27

Despite the insights to be gained from considering the first presentation among these diseases together, this first-lifetime-presentation approach has rarely been reported in the literature22 and has tended to exclude major diseases such as heart failure, been restricted to small cohorts, or reported in men only.23–27 Innovative Role of Large-Scale Health Record Linkages Through the use of linked EHRs, we were able to capture diseases first presenting in primary care and were not confined to hospitalized cases. Our cohort is population based, with >99% of the English population estimated to be registered with a family physician,28 unlike other recent large cohort studies, such as UK Biobank, with response rates <10%.29 The size of cohort— nearly 2 million people— possible with this EHR platform allows us to include serious but less commonly diagnosed events such as AAA and SAH, and to have sufficient events in women to study sex differences reliably. We were able to follow up actual events in a clinically meaningful 5-year time frame, similar to the time horizon of randomized, controlled trials. More broadly, we demonstrate the potential of linked EHR cohorts to complement bespoke, investigator-led cohorts. The UK Biobank,30 the Research Program for Genes Environment and Health in Kaiser,31 and precision medicine initiatives32 all place a major emphasis on specific disease types and follow-up through health records. Such large EHR cohorts further hold out the promise of lower cost to research funders for data collection, the intrinsic clinical relevance of real-world data, the opportunities to study diseases with higher specificity given the cohort sizes possible, and the prospect for researchers and clinicians to work across the boundaries that currently impede the translation of new discoveries into public health benefit.33

llection, the intrinsic clinical relevance of real-world data, the opportunities to study diseases with higher specificity given the cohort sizes possible, and the prospect for researchers and clinicians to work across the boundaries that currently impede the translation of new discoveries into public health benefit.33 We expect the pattern of the age and sex associations we found with the CVD outcomes to apply to the broader UK population and other European populations free from symptomatic CVD. Our patients were drawn from >200 practices representative of the English population. Indeed, a recent article investigating similar questions in a smaller investigator-led Dutch cohort found broadly similar associations, albeit with fewer end points.22 Different cohorts, especially those with more people from differing ethnic groups or differing baseline risk profiles, may well present different associations.

a recent article investigating similar questions in a smaller investigator-led Dutch cohort found broadly similar associations, albeit with fewer end points.22 Different cohorts, especially those with more people from differing ethnic groups or differing baseline risk profiles, may well present different associations. Validity of Risk Factor and Disease Measurements in EHRs Although a principal strength of this study is the ability to resolve a wide range of CVDs in a large-scale cohort, the principal limitation is the possibility of errors in the individual EHR data sources.34,35 However, evidence for the validity of our risk factor and disease end points comes from several sources. First, in this population, using identical phenotypic definitions for these same 12 diseases, we have replicated anticipated risk factor – disease associations with systolic and diastolic blood pressure,11 type 2 diabetes mellitus,15 smoking,10 and socioeconomic deprivation.12 These findings support the prospective prognostic validity of both the risk factor and the disease measurements. Second, a recent systematic review of studies validating diagnoses in CPRD found a median positive predictive value of 88% across a wide range of diagnoses,7 whereas a separate systematic review found the accuracy of discharge coding in Hospital Episodes Statistics to be 83%.35 Third, the associations we found when considering events from all data sources (Figure V in the online-only Data Supplement) were consistent with those when excluding nonfatal cases or those from primary care. The doctors and coders responsible, and the information on which these diagnoses are based, differ for each data source (primary care, hospital, and death); it was reassuring that the associations were broadly similar. Finally, we13 and others36 have demonstrated the validity of using linked data for end point follow-up.

e doctors and coders responsible, and the information on which these diagnoses are based, differ for each data source (primary care, hospital, and death); it was reassuring that the associations were broadly similar. Finally, we13 and others36 have demonstrated the validity of using linked data for end point follow-up. Male Sex as a Risk Factor for Different CVDs We demonstrate that male sex does not have a common underlying association on the incidence of different CVDs. Rather, the strength of this association is highly variable, ranging from protective for SAH; minor for transient ischemic attack, intracerebral hemorrhage, and unstable angina; moderate for stable angina, ischemic stroke, PAD, heart failure, and cardiac arrest/SCD; and strong for AAA, MI, and UCD. Additionally, we found that these associations change with age, with sex differences in proportion of initial presentation of MI and coronary death reducing with age, and with heart failure and stroke (ischemic and NOS) emerging as the most common initial presentations in both sexes. These findings suggest that stratifying patients into low-=, intermediate-, and high-risk groups based on their total and disease-specific risks,37 accompanied by the establishment of new cost-effective treatment thresholds,38 could improve risk management, particularly for diseases such as heart failure and stroke that affect high proportions of women but are undermanaged based on current clinical risk assessment.39

ed on their total and disease-specific risks,37 accompanied by the establishment of new cost-effective treatment thresholds,38 could improve risk management, particularly for diseases such as heart failure and stroke that affect high proportions of women but are undermanaged based on current clinical risk assessment.39 Clinical Implications and Risk Prediction Current risk algorithms in common use focus on CHD40 and CVD,41 as does the new American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk,42 yet we show that chronic disease, such as heart failure and PAD, account for a substantial proportion of initial CVD presentations in contemporary practice. These diseases are associated with marked increased risk of subsequent events and death, yet have been excluded from many risk prediction algorithms. Given the recent decline in the incidence of acute events of MI and stroke, our findings raise the question of whether risk algorithms should take account of the current burden of CVDs and, in efforts to personalize cardiovascular risk, whether there is a need for risk algorithms tailored to account for specific diseases. For clinical use the latter would only have a role if decisions on prevention strategies were altered by using a more specific than a more generic risk prediction tool. Our post hoc analysis of the discrimination performance of risk prediction models using disease-specific age and sex coefficients supports the importance of having more tailored risk algorithms.

a role if decisions on prevention strategies were altered by using a more specific than a more generic risk prediction tool. Our post hoc analysis of the discrimination performance of risk prediction models using disease-specific age and sex coefficients supports the importance of having more tailored risk algorithms. A more nuanced application of age and sex in the clinical setting that takes account of their heterogeneous associations with different CVDs is provided by the following example: A 69-year-old woman with untreated hypertension has a 20% 10-year general risk of CVD, fulfilling guideline criteria for primary prevention. With heart failure her most likely initial CVD presentation within that 10-year time frame (see Figure 1), a tailored blood pressure–lowering regime that excludes calcium antagonists would optimize CVD prevention because these drugs are relatively less effective at reducing risk of heart failure.43 At earlier ages, where CHD is the more common initial presentation, the choice of blood pressure–lowering medication is likely to make little difference to outcomes. This is just 1 example of the way in which understanding of the heterogeneity of risks associated with specific end points could lead to more personalized risk modification.

ere CHD is the more common initial presentation, the choice of blood pressure–lowering medication is likely to make little difference to outcomes. This is just 1 example of the way in which understanding of the heterogeneity of risks associated with specific end points could lead to more personalized risk modification. We also provide further evidence of the need to protect women against CVD with the same vigor as for men. The current strategy of evaluating and treating short-term risk of total CVD has the consequence that almost all men aged >70 should be on treatment, irrespective of their CVD risk factors. However, a wider group of people with high risk of specific CVDs could be targeted and treated earlier by increasing the sensitivity (by extending the time horizon to lifetime, as suggested by the Joint British Societies latest recommendations44) and specificity (by using more specific diagnoses) of risk predictions. Given that the majority of initial CVD presentations in our cohort were nonfatal (84% in men and 80% in women), such opportunities for earlier intervention via refinement of prediction tools should not be missed.

Societies latest recommendations44) and specificity (by using more specific diagnoses) of risk predictions. Given that the majority of initial CVD presentations in our cohort were nonfatal (84% in men and 80% in women), such opportunities for earlier intervention via refinement of prediction tools should not be missed. Furthermore, our findings have potentially important consequences for the accuracy of models used to predict CVD risk in clinical practice. We found large differences in the associations of different CVDs with age (from very weak with SAH to very strong with UCD, heart failure, stroke, and AAA) and male sex (from negative with SAH to very strong with AAA, nonfatal MI, and UCD). So far, most efforts to improve the prediction of CVD have focused on refining current models with new predictors. Although there are several models for specific CVDs (eg, heart failure,45 stroke46), current guidelines recommend assessment of total CVD risk to simplify clinical decision making.21 Here we show that this one-size-fits-all approach reduces the ability to discriminate between individuals with high and low risk of specific CVDs.

there are several models for specific CVDs (eg, heart failure,45 stroke46), current guidelines recommend assessment of total CVD risk to simplify clinical decision making.21 Here we show that this one-size-fits-all approach reduces the ability to discriminate between individuals with high and low risk of specific CVDs. Implications for Research Our findings suggest that future research on the primary prevention of CVDs should take account of current patterns of disease presentation and redress the imbalance of previous literature that has focused extensively on heart attack and stroke. Our findings have implications for the design and interpretation of observational studies, randomized trials, and meta-analyses investigating the primary prevention of CVDs. Because the fundamental risk factors of age and sex have such heterogeneous associations with different CVDs, and most studies are only sufficiently powered to examine CVD aggregates, it is important to account for the relative proportion of each disease in the composite end point in meta-analysis. Despite an extensive literature on the underlying biological and behavioral pathways by which sex may influence aggregates of CVD and CHD, there is a lack of mechanism studies that investigate why sex has such heterogeneous associations on different CVDs.

ion of each disease in the composite end point in meta-analysis. Despite an extensive literature on the underlying biological and behavioral pathways by which sex may influence aggregates of CVD and CHD, there is a lack of mechanism studies that investigate why sex has such heterogeneous associations on different CVDs. Limitations Our study has important limitations. First, we were not able to resolve some disease subtypes, eg, systolic versus diastolic heart failure or ruptured versus nonruptured cases of AAA. We did find that the association of MI with male sex was more marked for ST-segment–elevation MI than non–ST-segment–elevation MI, suggesting an even greater degree of heterogeneity may be unmasked by investigating more specific diagnoses. Second, we did not evaluate common CVDs that are commonly asymptomatic such as atrial fibrillation. Third, EHRs contain limited covariates for explaining the heterogeneity in sex differences that we report. Fourth, there were 2 less well-specified diagnoses (CHD NOS and stroke NOS) which we were unable to resolve further, but which we included to ensure all potential initial presentations were taken into account. Stroke NOS is likely to be largely ischemic stroke, based on proportion of strokes that are ischemic1 and the behavior of this end point in modeling, indicating that we may have overestimated the association of ischemic stroke with male sex. We believe CHD NOS is a mixture of stable and unstable angina given the associations in this article and others, but are unable to substantiate this.

of strokes that are ischemic1 and the behavior of this end point in modeling, indicating that we may have overestimated the association of ischemic stroke with male sex. We believe CHD NOS is a mixture of stable and unstable angina given the associations in this article and others, but are unable to substantiate this. Conclusion In an era of modern primary prevention, CVDs commonly first present with heart failure, transient ischemic attack, stable angina, and PAD – diseases that have seldom been the focus of primary prevention studies. Predicting CVD risk should take account a wide range of CVDs, and the different association each has with age and sex, as well.

primary prevention, CVDs commonly first present with heart failure, transient ischemic attack, stable angina, and PAD – diseases that have seldom been the focus of primary prevention studies. Predicting CVD risk should take account a wide range of CVDs, and the different association each has with age and sex, as well. Sources of Funding This study was supported by the National Institute for Health Research (RP-PG-0407-10314), Wellcome Trust (WT 086091/Z/08/Z), and the Farr Institute of Health Informatics Research, funded by The Medical Research Council (K006584/1), in partnership with Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office (Scottish Government Health Directorates), and the Wellcome Trust. Dr George was funded by a National Institute for Health Research Doctoral Fellowship (DRF-2009-02-50). Dr Shah is supported by a Clinical Research Training Fellowship from the Wellcome Trust (0938/30/Z/10/Z). Dr Smeeth is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science. Dr Timmis acknowledges support of St Bartholomew’s and the London Cardiovascular Biomedical Research Unit, funded by the National Institute for Health Research. This article presents independent research funded in part by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors declare that the funding sources had no role in the conduct, analysis, interpretation and writing of this manuscript.

his article presents independent research funded in part by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors declare that the funding sources had no role in the conduct, analysis, interpretation and writing of this manuscript. Disclosures None. Supplementary Material Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz * Drs George and Rapsomaniki are joint first authors. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.114.013797/-/DC1.

Supplementary Material Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz * Drs George and Rapsomaniki are joint first authors. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.114.013797/-/DC1. CLINICAL PERSPECTIVES The first lifetime presentation of cardiovascular disease in men and women in the 21st century is not currently well understood, with contemporary studies of sufficient size and clinical resolution to distinguish the most common cardiovascular diseases (CVDs) lacking. Traditional cohort studies have, to date, commonly focused on incident heart attack and stroke, but it is well recognized that both have been rapidly declining in incidence. Understanding how CVDs first present is important for developing primary prevention strategies that protect against specific phenotypes and against the wider cascade of other CVDs that often follow. Electronic health records based on usual clinical practice in unselected, contemporary populations provide an important opportunity to assess how CVD first presents in women and men across a wide range of 12 different diseases affecting the head, heart, abdominal, and peripheral circulations. In a study of 1.9 million adults, 114 859 people experienced an incident cardiovascular diagnosis, the majority (66%) of which were neither myocardial infarction nor ischemic stroke. Sex has differing associations with different CVDs, with implications for risk prediction and management strategies. Chronic disease, such as heart failure and peripheral arterial disease, account for a substantial proportion of initial lifetime CVD presentations, yet are been excluded from many risk prediction algorithms. Given the recent decline in the incidence of acute events, our findings emphasize the relevance of risk algorithms that take account of the current burden of CVDs.

Congenital, acquired (licorice ingestion), or age-related deficiency in the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) promotes low-renin hypertension, hypokalemia, and sodium retention attributable to unregulated activation of the mineralocorticoid receptor (MR) by endogenous cortisol (corticosterone in rodents).1 Reduced 11βHSD2 activity causes a spectrum of disease: genetic ablation of the enzyme causes the life-threatening syndrome of Apparent Mineralocorticoid Excess (AME; OMIM +218030), diagnosed in early childhood2; reduced activity causes hypertension in adults,3 and loss-of-function variants in HSD11B2 are associated with increased blood pressure per se or with salt sensitivity of blood pressure.4,5 Editorial, see p 1335 Clinical Perspective on p 1370 AME presents with sodium retention6 and, in common with monogenic Liddle syndrome,7 can be resolved by renal transplantation.8 This suggests that high blood pressure follows the kidney,9 at least in these spectral disorders. This renal-centric view of hypertension is supported by our studies in Hsd11b2 null mice, which are hypertensive on a basal salt intake;10 renal sodium excretion is reduced, and sodium transport pathways in the aldosterone-sensitive distal nephron are inappropriately activated.11,12 Similarly, Hsd11b2 heterozygote null mice, which have normal basal blood pressure, cannot efficiently excrete a sodium load and are salt sensitive.13,14

a basal salt intake;10 renal sodium excretion is reduced, and sodium transport pathways in the aldosterone-sensitive distal nephron are inappropriately activated.11,12 Similarly, Hsd11b2 heterozygote null mice, which have normal basal blood pressure, cannot efficiently excrete a sodium load and are salt sensitive.13,14 11βHSD2 is also normally expressed in the brain, but the contribution of central pathways to hypertension in AME and other hypertensive states is poorly understood and often overlooked. Studies in humans suggest that 11βHSD2 in the brain may contribute to abnormal sodium homeostasis: increased salt appetite has been reported in AME15 and loss-of-function variants positively associate with sodium intake in the general population.16 Moreover, the sympathetic nervous system is activated in Hsd11b2 null mice, contributing importantly to the maintenance of hypertension in these animals.11

m homeostasis: increased salt appetite has been reported in AME15 and loss-of-function variants positively associate with sodium intake in the general population.16 Moreover, the sympathetic nervous system is activated in Hsd11b2 null mice, contributing importantly to the maintenance of hypertension in these animals.11 11βHSD2 has a widespread central expression during fetal development and modulates glucocorticoid programming of adult behavior and cognitive function.17 Fetal 11βHSD2 expression is progressively silenced from midgestation, and, in adulthood, 11βHSD2 is restricted to subpopulations of neurons in brain areas influencing blood pressure and, less certainly, salt appetite.17–19 In the adult mouse, Hsd11b2 is only expressed in the nucleus of the solitary tract (NTS).20 However, defining the role of 11βHSD2 in these NTS neurons of the adult brain has been challenging. Overstimulation of these neurons by intracerebrovascular infusion of aldosterone21 or 11βHSD2 inhibitors22 increases blood pressure. Such studies are informative but lack precision; conventional gene targeting induces a complex and unstable phenotype with deranged systemic electrolyte and hormonal status.11 We therefore recently used a Cre-Lox strategy to conditionally delete Hsd11b2 in the mouse central nervous system. At embryonic day 12.5, the peak of gestational 11βHSD2 expression in the brain, mRNA abundance was reduced by 96% in the knockout mice.23 This programmed depressive behavior and cognitive impairment in adulthood.23 Renal 11βHSD2 expression was not affected by conditional brain targeting, and, in adults, basal blood pressure and sodium excretion were normal.23 In the current study, we show that central deletion of Hsd11b2 causes an innate salt appetite, leading to a sustained increase in blood pressure without systemic sodium retention. Hypertension was associated with an exaggerated pressor response to α-adrenoreceptor activation and an attenuated baroreflex.

were normal.23 In the current study, we show that central deletion of Hsd11b2 causes an innate salt appetite, leading to a sustained increase in blood pressure without systemic sodium retention. Hypertension was associated with an exaggerated pressor response to α-adrenoreceptor activation and an attenuated baroreflex. Methods Generation of Experimental Mice Hsd11b2f/f mice were generated on a C57BL6 background (Artemis Pharmaceuticals, Cologne, Germany) by inserting LoxP sites into introns 1 and 5. These mice were bred with transgenic mice expressing Cre recombinase under the control of a rat nestin promoter/enhancer (B6.Cg-Tg(Nes-cre)1Kln/J; Jackson Laboratory, Bar Harbor, ME), as we described.23 This generated Nestin-Cre.Hsd11b2fl/fl offspring (Hsd11b2 Brain Knockout; Hsd11b2.BKO) and Hsd11b2fl/fl littermate controls. All experiments were performed blinded to genotype and in accordance with the United Kingdom Home Office Animals (Scientific Procedures) Act, following ethical review by the University. Measurement of 11βHSD2 Expression and Activity mRNA abundance for Hsd11b2 in whole kidney and in isolated NTS was assessed by quantitative polymerase chain reaction and quantified by using the second derivative maximum method.24 11βHSD2 expression in the aldosterone-sensitive distal nephron was confirmed by immunohistochemistry, and 11βHSD2 enzyme activity was measured as the conversion of [3H]corticosterone to [3H]dehydrocorticosterone, quantified by thin-layer chromatography.

on and quantified by using the second derivative maximum method.24 11βHSD2 expression in the aldosterone-sensitive distal nephron was confirmed by immunohistochemistry, and 11βHSD2 enzyme activity was measured as the conversion of [3H]corticosterone to [3H]dehydrocorticosterone, quantified by thin-layer chromatography. Blood Pressure Measurement Radiotelemetry devices (model TA-11PAC-10, Data Systems International, St Paul, MN) were inserted into Hsd11b2.BKO (n=6) and control mice (n=6) under ketamine-medetomidine anesthesia. After a week of postoperative recovery, data were collected over a 5-minute period every 20 minutes at an acquisition rate of 2 kHz. Mice were housed under controlled temperature (21±1°C) and humidity (50±10%) with a fixed 12-hour light:dark cycle (lights on 7 am local time). Each animal underwent the following protocols. Ad Libitum Salt Intake Blood pressure was recorded over a 7-day baseline period during which mice were able to drink from 2 bottles containing deionized water. This experiment was repeated in an independent cohort of nontelemetered mice, and the data sets were merged to give Hsd11b2.BKO (n=12) and control (n=9). Water intake was ≈4 mL/24 h and was not different between groups. After 7 days, 1 water bottle was replaced with a 1.5% NaCl bottle for a 21-day period. Bottle position was alternated every 24 hours to negate side preference. Throughout this experiment, both groups of mice had a similar food intake.

and control (n=9). Water intake was ≈4 mL/24 h and was not different between groups. After 7 days, 1 water bottle was replaced with a 1.5% NaCl bottle for a 21-day period. Bottle position was alternated every 24 hours to negate side preference. Throughout this experiment, both groups of mice had a similar food intake. Fixed Salt Intake Mice were fed a diet in which sodium was incorporated as a powdered chow mixed with gelatin. During baseline, the diet contained ≈0.1% sodium by weight, which was then increased to ≈1% sodium for a 7-day period. The amount of the gel consumed per day was predetermined to ensure that mice ate the entire block, clamping sodium intake across genotypes during the experimental phase. Mice had access to deionized drinking water throughout this experiment, and blood pressure was recorded by radiotelemetry. Dexamethasone Once blood pressure had reached steady state under matched sodium feeding, dexamethasone (DEX) was administered via the drinking water (1 μg/mL in 0.1% ethanol) and plasma corticosterone measured at 7 pm was reduced in both genotypes (Hsd11b2.BKO=186±38 versus 31±5 nmol/L after DEX; Control=205±18 basal versus 43±8 nmol/L after DEX). Salt-Taste Threshold In a cohort of control (n=4) and Hsd11b2.BKO (n=4) mice, taste threshold was assessed by offering a first drinking bottle containing deionized water and a second containing either a saline solution (0.25%–3%) or quinine (1%). Each measurement was made over 48 hours.

Dexamethasone Once blood pressure had reached steady state under matched sodium feeding, dexamethasone (DEX) was administered via the drinking water (1 μg/mL in 0.1% ethanol) and plasma corticosterone measured at 7 pm was reduced in both genotypes (Hsd11b2.BKO=186±38 versus 31±5 nmol/L after DEX; Control=205±18 basal versus 43±8 nmol/L after DEX). Salt-Taste Threshold In a cohort of control (n=4) and Hsd11b2.BKO (n=4) mice, taste threshold was assessed by offering a first drinking bottle containing deionized water and a second containing either a saline solution (0.25%–3%) or quinine (1%). Each measurement was made over 48 hours. Mineralocorticoid Receptor Antagonism Intake of 1.5% saline was determined in a separate group of Hsd11b2.BKO mice (n=8), before (baseline) and after MR antagonism with spironolactone; measurements were also made in a group (n=3) of control mice. Spironolactone was distributed 1:4 w:w in an elastomer matrix (Silastic MDX4-4210, Dow Corning) and pellets cured overnight at 37°C. After ad libitum salt preference had been measured, pellets were implanted subcutaneously under isoflurane anesthesia. Each pellet contained ≈30 mg of the drug, designed to achieve a plasma concentration of canrenone (the active metabolite of spironolactone) of ≈75 nmol/L.25

orning) and pellets cured overnight at 37°C. After ad libitum salt preference had been measured, pellets were implanted subcutaneously under isoflurane anesthesia. Each pellet contained ≈30 mg of the drug, designed to achieve a plasma concentration of canrenone (the active metabolite of spironolactone) of ≈75 nmol/L.25 Sodium Balance in Conscious Mice Mice (n=6 of each genotype) were housed in individual metabolism cages for measurement of sodium and potassium excretion, first on basal sodium diet (0.1% sodium), then 1% sodium diet. Urinary sodium and potassium concentration was measured by flame photometry; plasma sodium and potassium were measured by ion-selective electrode (AVI 9180 Electrolyte analyzer, Roche UK). Aldosterone26 and corticosterone27 concentration in urine was measured by enzyme-linked immunosorbent assay.

, then 1% sodium diet. Urinary sodium and potassium concentration was measured by flame photometry; plasma sodium and potassium were measured by ion-selective electrode (AVI 9180 Electrolyte analyzer, Roche UK). Aldosterone26 and corticosterone27 concentration in urine was measured by enzyme-linked immunosorbent assay. Baroreceptor Reflex The integrated baroreceptor reflex was assessed pharmacologically in anesthetized mice (thiobutabarbital; 120 mg/kg IP) maintained on either 0.1% sodium diet or 1% sodium diet for 7 days before the experiment. A cannula was inserted into the jugular vein and a tracheostomy was performed. A cannula filled with heparin-saline was placed in the carotid artery. The cannula was made from a ≈5-mm length of p10 Portex tubing inserted into a ≈50-mm length of p50 tubing. The undampened pulse wave was recorded continuously at 1 kHz using a Capto pressure transducer connected to a Powerlab (AD Instruments, Oxford, UK). After postsurgical equilibration, sodium nitroprusside (30, 60, and 120 μg/kg) and phenylephrine (10, 20, and 40 μg/kg) were injected intravenously in random order, to induce acute decreases and acute increases in blood pressure, respectively. For each injection, the change in heart rate at the peak change in systolic blood pressure (SBP) was recorded and Δheart rate/ΔSBP was used as an index of baroreceptor gain.

(10, 20, and 40 μg/kg) were injected intravenously in random order, to induce acute decreases and acute increases in blood pressure, respectively. For each injection, the change in heart rate at the peak change in systolic blood pressure (SBP) was recorded and Δheart rate/ΔSBP was used as an index of baroreceptor gain. Statistics Data are presented as mean±standard error, as medians with interquartile range, or as linear regression with 95% confidence interval, as appropriate. Statistical comparisons (Graphpad Prism 6, La Jolla, CA) were made by using 2-way analysis of variance (ANOVA) with repeated measures, Mann-Whitney U or t tests, as stated in the figure legends. For 2-way ANOVA, we assessed the main effects of the genotype and treatment and the interaction between the 2. When used, planned or post hoc comparisons were made by using Holm-Sidak test to correct for multiple comparisons. The family P value was fixed at 0.05, and the number of comparisons is indicated in the figure legends. The diurnal variation in SBP and heart rate was characterized by cosinor analysis,28 calculating by sine function least-squares regression, mesor, amplitude, and acrophase for each mouse; these values were then used to calculate the group mean comparison between genotypes by the Welch t test. The goodness-of-fit model was confirmed in all cases by the significance of the F statistic using the zero-amplitude test (P<0.01 or less).

least-squares regression, mesor, amplitude, and acrophase for each mouse; these values were then used to calculate the group mean comparison between genotypes by the Welch t test. The goodness-of-fit model was confirmed in all cases by the significance of the F statistic using the zero-amplitude test (P<0.01 or less). Results Baseline Parameters The expression of Hsd11b2 mRNA in the NTS of adult Hsd11b2.BKO mice was reduced by >90% in comparison with controls (Figure I in the online-only Data Supplement). Expression and localization of renal 11βHSD2 in adult Hsd11b2.BKO mice was not different from control animals (Figure II in the online-only Data Supplement). Under baseline conditions SBP, diastolic blood pressure (DBP), and heart rate were similar in Hsd11b2.BKO mice and controls (Figure III in the online-only Data Supplement; Table I in the online-only Data Supplement); the acrophase of the diurnal variation for SBP and heart rate corresponded to 3 am local time in both groups of animals. Food/water intake, plasma electrolytes, hematocrit, and corticosteroids were not different between genotypes (Table II in the online-only Data Supplement). These data contrast with observations in animals with global Hsd11b2 deletion,10,11 which are hypertensive and hyperkalemic and have a suppressed renin-angiotensin-aldosterone system under conditions of basal sodium intake.

ticosteroids were not different between genotypes (Table II in the online-only Data Supplement). These data contrast with observations in animals with global Hsd11b2 deletion,10,11 which are hypertensive and hyperkalemic and have a suppressed renin-angiotensin-aldosterone system under conditions of basal sodium intake. Salt-Sensitive Hypertension in Hsd11b2.BKO Mice When offered 1.5% NaCl solution to drink, Hsd11b2.BKO mice became hypertensive, average 24-hour SBP increasing by 20 to 30 mm Hg over a 2-week period (Figure 1A); blood pressure was not changed in control mice during ad libitum access to saline. In Hsd11b2.BKO mice, blood pressure returned to baseline when the saline-drinking option was withdrawn (Figure 1A).

Hsd11b2.BKO mice became hypertensive, average 24-hour SBP increasing by 20 to 30 mm Hg over a 2-week period (Figure 1A); blood pressure was not changed in control mice during ad libitum access to saline. In Hsd11b2.BKO mice, blood pressure returned to baseline when the saline-drinking option was withdrawn (Figure 1A). Figure 1. Salt sensitivity in Hsd11b2.BKO mice. Blood pressure was measured in conscious, unrestrained Hsd11b2.BKO (n=6; filled squares) and control mice (n=6; open circles) using radiotelemetry. All mice had access to 2 drinking bottles for the entire experiment; from day 8 to 29, 1 bottle contained 1.5% NaCl; at other times, both bottles contained water. A, 24-hour average systolic blood pressure. Data are mean±SEM. Two-way ANOVA reported a significant effect of genotype (P<0.0001), of treatment (P=0.013), and of the interaction between the main effects (P=0.0021). Mesor, amplitude, and acrophase were calculated by cosinor analysis (Figure I and Table II in the online-only Data Supplement) of nonaveraged data obtained over consecutive days indicated by the boxes. Systolic blood pressure (B) and diastolic blood pressure (C) measured every 20 minutes over a 24-hour period. The black line indicates subjective night (7 pm to 7 am local time). Data are group mean±SEM, generated by averaging each mouse over 5 consecutive days of recording. Mesor, amplitude, and acrophase were calculated by cosinor analysis (Table II in the online-only Data Supplement). ANOVA indicates analysis of variance; and SEM, standard error of the mean.

night (7 pm to 7 am local time). Data are group mean±SEM, generated by averaging each mouse over 5 consecutive days of recording. Mesor, amplitude, and acrophase were calculated by cosinor analysis (Table II in the online-only Data Supplement). ANOVA indicates analysis of variance; and SEM, standard error of the mean. Cosinor analysis was performed on data acquired over 4 consecutive days (periods indicated in Figure 1A) during both basal and saline periods. High salt intake caused a significant increase in mesor SBP in Hsd11b2.BKO mice but not in controls (Figure IVA in the online-only Data Supplement; Table I in the online-only Data Supplement). The amplitude of the diurnal SBP variation was also significantly higher in Hsd11b2.BKO mice than in controls (Figure IVB in the online-only Data Supplement; Table I in the online-only Data Supplement), whereas acrophase was not affected by sodium intake. Both SBP (Figure 1B) and DBP (Figure 1C) were significantly elevated during the dark phase of the day/night cycle in Hsd11b2.BKO mice, but this salt sensitivity was not associated with a genotypic difference in the heart rate over the 24-hour cycle (Figure V in the online-only Data Supplement; Table I in the online-only Data Supplement).

) and DBP (Figure 1C) were significantly elevated during the dark phase of the day/night cycle in Hsd11b2.BKO mice, but this salt sensitivity was not associated with a genotypic difference in the heart rate over the 24-hour cycle (Figure V in the online-only Data Supplement; Table I in the online-only Data Supplement). Salt Appetite and Hypertension Both Hsd11b2.BKO and control mice had a daily deionized water intake of ≈4 mL. When presented with the option, Hsd11b2.BKO mice spontaneously drank ≈8 mL/24 h of 1.5% NaCl while maintaining their deionized water intake (Figure 2A). Hsd11b2.BKO mice had salt preference, saline accounting for >60% of total fluid intake. Control mice also drank from the saline bottle but displayed a modest salt aversion, with saline accounting for <40% of total intake. Thus, daily sodium intake increased significantly in both genotypes, but the average intake over the experiment was ≈3 times higher in the Hsd11b2.BKO mice than in controls (Hsd11b2.BKO=3154±352 μmol/24 h; Control=982±129 μmol/24 h; P<0.001).

ayed a modest salt aversion, with saline accounting for <40% of total intake. Thus, daily sodium intake increased significantly in both genotypes, but the average intake over the experiment was ≈3 times higher in the Hsd11b2.BKO mice than in controls (Hsd11b2.BKO=3154±352 μmol/24 h; Control=982±129 μmol/24 h; P<0.001). Figure 2. Salt-appetite in Hsd11b2.BKO mice. A, Water and 1.5% saline intake per 24 hours in Hsd11b2.BKO (gray bars; n=12) and controls (open bars; n=9) mice. Individual data and group mean±SEM are shown. Two-way ANOVA indicates a significant effect of genotype (P=0.002) and interaction between genotype and drinking behavior (P=0.002). Two post hoc comparisons were made, P values as indicated. ***P<0.001. B, Preference testing for 0.25% to 3% saline and quinine versus water in Hsd11b2.BKO (gray bars; n=4) and controls (open bars; n=4) mice. The dashed line indicates no preference, and values below this line indicate aversion. Individual data and group mean±SEM are shown. Two-way ANOVA reported a significant effect of genotype (P<0.0001). Six multiple comparisons were made and P values are as indicated. **P<0.01, *P<0.05. C, 1.5% saline intake in Hsd11b2.BKO (n=8) and control mice before (open bars) and after systemic spironolactone treatment (hashed bars). Group mean±SEM are shown. D, Effect of spironolactone (filled squares) on basal salt intake (open squares) in Hsd11b2.BKO mice in comparison with 1-tailed paired t test. ANOVA indicates analysis of variance; SEM, standard error of the mean; and SPIRO, spironolactone.

ter systemic spironolactone treatment (hashed bars). Group mean±SEM are shown. D, Effect of spironolactone (filled squares) on basal salt intake (open squares) in Hsd11b2.BKO mice in comparison with 1-tailed paired t test. ANOVA indicates analysis of variance; SEM, standard error of the mean; and SPIRO, spironolactone. We were not able to detect a lower threshold for salt preference, Hsd11b2.BKO mice maintained a higher saline-to-water intake at all but the highest concentration (3% NaCl) tested (Figure 2B). This abnormality was not a generalized taste phenomenon, because Hsd11b2.BKO mice retained an aversion for quinine (Figure 2B). Systemic administration of the MR antagonist, spironolactone, did not affect saline intake in the 3 control mice (Figure 2C) but reduced saline drinking in all 8 Hsd11b2.BKO mice tested (Figure 2D). On average, spironolactone reduced saline intake to 69±5% of predrug values (P=0.0006, 1-sample t test). Nevertheless, saline intake remained higher in Hsd11b2.BKO mice than in controls during spironolactone treatment. Spironolactone did not affect water consumption in either group of mice.

BKO mice tested (Figure 2D). On average, spironolactone reduced saline intake to 69±5% of predrug values (P=0.0006, 1-sample t test). Nevertheless, saline intake remained higher in Hsd11b2.BKO mice than in controls during spironolactone treatment. Spironolactone did not affect water consumption in either group of mice. To resolve whether increased salt intake in Hsd11b2.BKO mice was causal or permissive for the hypertensive phenotype, the 2 groups of mice were fed an equivalent amount of sodium-rich gel-diet. The average sodium intake was 4619±121 μmol/24 h in Hsd11b2.BKO mice and 4790±215 μmol/24 h in controls (n=6 per group. P=0.452). High sodium feeding significantly increased SBP (Figure 3A and 3B) and DBP (Figure 3C) in Hsd11b2.BKO mice. The amplitude of the 24-hour SBP rhythm was also significantly increased (P=0.006; Table I in the online-only Data Supplement). Heart rate was not different between genotypes, but high salt intake reduced the amplitude of the 24-hour rhythm significantly in Hsd11b2.BKO mice (P=0.044; Table I in the online-only Data Supplement).

tude of the 24-hour SBP rhythm was also significantly increased (P=0.006; Table I in the online-only Data Supplement). Heart rate was not different between genotypes, but high salt intake reduced the amplitude of the 24-hour rhythm significantly in Hsd11b2.BKO mice (P=0.044; Table I in the online-only Data Supplement). Figure 3. Radiotelemetry data from conscious unrestrained mice on fixed sodium intake. A, Systolic blood pressure measured every 20 minutes over a 24-hour period in Hsd11b2.BKO mice (n=6; filled squares) and controls (n=6; open circles). Data are group mean±SEM, generated by averaging each mouse over 5 consecutive days of recording. Mesor, amplitude, and acrophase were calculated by cosinor analysis (Figure I and Table II in the online-only Data Supplement) of nonaveraged data obtained over consecutive days indicated by the box. The black line indicates subjective night (7 pm to 7 am local time). Twenty-four–hour averaged systolic (B) and 24-hour averaged diastolic (C) blood pressure in Hsd11b2.BKO mice (filled squares) and controls (open circles) before and during a period of equivalent high-sodium feeding. Data are mean±SEM. For SBP ANOVA reported a significant effect of diet (P<0.0001) but not genotype (P=0.079); for DBP, there were significant differences for diet (P<0.0001), genotype (P=0.013), and the interaction between these main effects (P<0.0001). ANOVA indicates analysis of variance; DBP, diastolic blood pressure; SBP, systolic blood pressure; and SEM, standard error of the mean.

t (P<0.0001) but not genotype (P=0.079); for DBP, there were significant differences for diet (P<0.0001), genotype (P=0.013), and the interaction between these main effects (P<0.0001). ANOVA indicates analysis of variance; DBP, diastolic blood pressure; SBP, systolic blood pressure; and SEM, standard error of the mean. Blood pressure in control mice was not affected by high salt intake, indicating that the C57BL6/J background strain was not intrinsically salt sensitive. This salt resistance in the control animals means that the salt-sensitive hypertension of Hsd11b2.BKO mice cannot just reflect increased salt appetite. The data suggest that central homeostatic response to salt intake becomes abnormal following deletion of 11βHSD2 in the brain. This does not reflect abnormalities in systemic corticosteroid production: aldosterone and corticosterone excretion were similar in both genotypes under high-salt conditions (Table II in the online-only Data Supplement). Effect of Oral Dexamethasone Deficiency of 11βHSD2 allows MR to be activated by endogenous glucocorticoid. DEX suppression of the hypothalamo-pituitary-adrenal axis, which markedly reduces cortisol levels, can be used to treat patients with AME. DEX suppressed corticosterone (the endogenous glucocorticoid in rodents) in both Hsd11b2.BKO mice and controls, and, after 5 days of treatment, the genotypic difference in mean blood pressure was no longer apparent (Figure 4A). However, unequivocal interpretation of these data is challenging, because, as expected, DEX increased SBP (Figure 4B) and DBP (Figure 4C) in control mice.

n rodents) in both Hsd11b2.BKO mice and controls, and, after 5 days of treatment, the genotypic difference in mean blood pressure was no longer apparent (Figure 4A). However, unequivocal interpretation of these data is challenging, because, as expected, DEX increased SBP (Figure 4B) and DBP (Figure 4C) in control mice. Figure 4. Effect of dexamethasone on blood pressure. A, Mean arterial blood pressure averaged over the final 5 days of the high sodium and high sodium with dexamethasone periods in Hsd11b2.BKO mice (n=6; filled squares) and controls (n=6; open squares). Individual mice are shown along with the group mean±SEM. Two-way ANOVA reported a significant effect of genotype (P=0.015) but not of treatment (P=0.542); the interaction between main effects was significant (P=0.044). Two comparisons were made, between genotypes before and after DEX treatment. **P<0.01 by Holm-Sidak post test. Twenty-four–hour average systolic (B) and 24-hour average diastolic (C) blood pressure in Hsd11b2.BKO mice and controls over the course of the experiment. Data are mean±SE. For both SBP and DBP, 2-way ANOVA reported a significant effect of dexamethasone (P<0.0001) and genotype (P<0.0001) and a significant interaction between the main effects (P<0.0001). ANOVA indicates analysis of variance; DBP, diastolic blood pressure; DEX, dexamethasone; SBP, systolic blood pressure; SE, standard error; and SEM, standard error of the mean.

rted a significant effect of dexamethasone (P<0.0001) and genotype (P<0.0001) and a significant interaction between the main effects (P<0.0001). ANOVA indicates analysis of variance; DBP, diastolic blood pressure; DEX, dexamethasone; SBP, systolic blood pressure; SE, standard error; and SEM, standard error of the mean. Hypertension Is Not Caused by Sodium Retention The effect of increased salt intake on renal sodium excretion was assessed in a separate cohort of mice (n=6 for each genotype), fed first the basal salt diet (0.1% sodium) diet, followed by the high-salt (1% sodium) diet. Basal sodium intake averaged 420±15 μmol/24 h in Hsd11b2.BKO mice and 397±20 μmol/24 h in controls: urinary sodium excretion was not different between genotypes (Figure VIA in the online-only Data Supplement). During the high-salt phase, average sodium intake again increased 10-fold in both control (4810±177 μmol/24 h) and Hsd11b2.BKO (4335±240 μmol/24 h) mice and was not significantly different between the 2 groups (P=0.143; unpaired t test). Urinary sodium excretion was significantly higher in Hsd11b2.BKO mice than in controls during this period (Figure VIA in the online-only Data Supplement), suggesting that hypertension was not attributable to renal sodium retention.

ice and was not significantly different between the 2 groups (P=0.143; unpaired t test). Urinary sodium excretion was significantly higher in Hsd11b2.BKO mice than in controls during this period (Figure VIA in the online-only Data Supplement), suggesting that hypertension was not attributable to renal sodium retention. Basal urine flow rate was slightly higher in Hsd11b2.BKO mice than in controls, and the diuresis prompted by high-sodium feeding was significantly greater in Hsd11b2.BKO mice (Figure VIB in the online-only Data Supplement). Dietary sodium feeding was not associated with marked changes in hematocrit in either genotype (Table II in the online-only Data Supplement). Overall, these data indicate that hypertension was not caused by absolute plasma volume expansion following sodium retention. The high-sodium diet induced hypokalemia in Hsd11b2.BKO mice (Table II in the online-only Data Supplement). This did not reflect a change in dietary potassium intake, which was consistent throughout the study and not different between genotype. Given the exaggerated salt-induced diuresis in Hsd11b2.BKO mice, we anticipated that urinary potassium losses would account for potassium depletion. Although urinary potassium excretion was indeed higher in Hsd11b2.BKO than in controls, this difference was observed under both dietary regimens and not increased during the high-sodium feeding (Figure VIC in the online-only Data Supplement).

icipated that urinary potassium losses would account for potassium depletion. Although urinary potassium excretion was indeed higher in Hsd11b2.BKO than in controls, this difference was observed under both dietary regimens and not increased during the high-sodium feeding (Figure VIC in the online-only Data Supplement). Enhanced Pressor Effect of Phenylephrine and Impaired Baroreflex Gain in Hsd11b2.BKO Mice The salt-sensitive hypertension in Hsd11b2.BKO mice was not associated with a compensatory fall in heart rate, but the amplitude of the 24-hour cycle of heart rate was significantly reduced, suggesting impaired autonomic cardiac control. The NTS is an important site of baroreflex integration, and we therefore assessed directly the bradycardic response to an acutely applied pressor stimulus. In Hsd11b2.BKO mice maintained on a 0.1% salt diet, the pressor response to phenylephrine was significantly enhanced (Figure 5A), and the bradycardic baroreflex gain was significantly attenuated (Figure 5B). Reflex tachycardia response to sodium nitroprusside was similar in both genotypes (Figure 5C), as was the net fall in SBP. Overall, Hsd11b2.BKO mice displayed an asymmetrical attenuation of the baroreceptor reflex curve (Figure 5D; P<0.0001). Similar results were obtained in a separate cohort of Hsd11b2.BKO mice and controls maintained on a 1% sodium diet for 7 days (Figure VII in the online-only Data Supplement). There was no significant effect of increased dietary salt intake on baroreflex function in control mice. Hsd11b2.BKO mice displayed and impaired bradycardic baroreflex gain. This defect was not exaggerated by dietary salt loading.

aintained on a 1% sodium diet for 7 days (Figure VII in the online-only Data Supplement). There was no significant effect of increased dietary salt intake on baroreflex function in control mice. Hsd11b2.BKO mice displayed and impaired bradycardic baroreflex gain. This defect was not exaggerated by dietary salt loading. Figure 5. Baroreceptor reflex function. The baroreflex was measured pharmacologically in anesthetized Hsd11b2.BKO mice (filled squares; n=10 mice/63 responses) and controls (open circles; n=9 mice; 71 responses) mice. A, The mean change in systolic blood pressure (ΔSBP) in response to intravenous injection of phenylephrine. Two-way ANOVA reported a significant effect of dose (P<0.0001) and genotype (P=0.0002). Planned comparisons were made comparing each dose between genotypes. *P<0.05. The baroreflex gain during intravenous injection of phenylephrine (B) and during intravenous injection of sodium nitroprusside (C); individual data points are shown and the median compared by Mann-Whitney test, with P values as indicated. D, The baroreflex curve showing individual data points for the change in heart rate (ΔHR) in response to induced changes in systolic blood pressure (ΔSBP). There was a significant difference (P<0.0001) between genotypes by Linear regression analysis. ANOVA indicates analysis of variance; and PE, phenylephrine.

dicated. D, The baroreflex curve showing individual data points for the change in heart rate (ΔHR) in response to induced changes in systolic blood pressure (ΔSBP). There was a significant difference (P<0.0001) between genotypes by Linear regression analysis. ANOVA indicates analysis of variance; and PE, phenylephrine. Discussion Reduced 11βHSD2 activity causes a spectrum of hypertension-associated disease. Its most severe form, AME, can be rescued by renal transplantation,8,29 suggesting that high blood pressure follows the kidney.9 However, 11βHSD2 is also expressed in the brain,17 restricted to a subset of neurons in the NTS in the adult mouse.20 We used a Cre-Lox strategy to conditionally delete Hsd11b2 in the brain, reducing expression in the NTS by >90%. We found that 11βHSD2 in the brain normally exerts significant influence over sodium homeostasis and blood pressure control, independent of renal function. We identified 3 important phenotypes in Hsd11b2.BKO mice: (1) an innate salt appetite, blocked by MR antagonism; (2) salt sensitivity of blood pressure, independent of salt appetite and sodium retention; and (3) an exaggerated pressor response to α-adrenoreceptor activation and an impaired reflex bradycardia.

function. We identified 3 important phenotypes in Hsd11b2.BKO mice: (1) an innate salt appetite, blocked by MR antagonism; (2) salt sensitivity of blood pressure, independent of salt appetite and sodium retention; and (3) an exaggerated pressor response to α-adrenoreceptor activation and an impaired reflex bradycardia. Central Deletion of 11βHSD2 and Salt Appetite Negative salt balance evokes an instinctive salt-seeking behavior. The central pathways for this physiological response are not fully elucidated, but 11βHSD2-expressing neurons in the NTS are selectively activated by sodium depletion and rapidly inactivated when salt appetite is satiated.18 Hsd11b2.BKO mice had a strong salt appetite in the absence of sodium/volume depletion or systemic aldosterone excess. This underscores the concept that local corticosteroid levels in the brain influence the physiological control of sodium homeostasis. Genetic defects in central MR signaling would act synergistically with those in the distal nephron to amplify hypertension.

nce of sodium/volume depletion or systemic aldosterone excess. This underscores the concept that local corticosteroid levels in the brain influence the physiological control of sodium homeostasis. Genetic defects in central MR signaling would act synergistically with those in the distal nephron to amplify hypertension. Systemic administration of an MR antagonist was an effective treatment but did not completely abolish salt appetite in Hsd11b2.BKO mice. Spironolactone is a competitive antagonist of MR and, although our method of delivery achieves high plasma concentrations of the active metabolite, canrenone,25 the levels reaching the NTS may be lower.30 Nevertheless, similar dosing regimens provide neuroprotection after cerebral ischemia in mice,31 and oral administration of low-dose spironolactone decreases sympathetic drive and improves baroreflex function in rats with heart failure.32 This suggests that central MR can be effectively blocked by systemic spironolactone, and the incomplete rescue of salt appetite in the current study may suggest that additional pathways contribute in the Hsd11b2.BKO mice. Central angiotensin II promotes thirst and, to a lesser extent, sodium appetite, particularly in response to sodium depletion or hypovolemia.33 Because water intake was not different between genotypes, we discount a major role for angiotensin II in the salt appetite of the Hsd11b2.BKO mice.33 In epithelia, MR and the glucocorticoid receptor may interact to regulate aldosterone-induced transport proteins such as ENaC.34,35 Indeed, we found that the salt sensitivity of the Hsd11b2 heterozygote mouse could be blocked by glucocorticoid receptor antagonists.13 Whether glucocorticoid receptor contributes to salt sensitivity in Hsd11b2.BKO mice is not known. Although glucocorticoids are not directly natriorexigenic, they potentiate the salt appetite induced by mineralocorticoids by increasing MR expression in the brain.36

ld be blocked by glucocorticoid receptor antagonists.13 Whether glucocorticoid receptor contributes to salt sensitivity in Hsd11b2.BKO mice is not known. Although glucocorticoids are not directly natriorexigenic, they potentiate the salt appetite induced by mineralocorticoids by increasing MR expression in the brain.36 Central Deletion of 11βHSD2 and Salt-Sensitive Blood Pressure An important observation in our study was the salt-resistant blood pressure of the control mice. Thus, with the enzymatic barrier protecting MR intact, blood pressure is not affected by large (3-fold) increases in sodium intake; if the barrier is broken this same sodium load induces a rapid and sustained hypertension. The influence of 11βHSD2-positive neurons in the NTS therefore extends beyond the regulation of salt appetite by normally preventing large fluctuations in dietary salt intake from exerting corresponding changes to blood pressure. Unlike humans,6 in mice10 or rats37 with global 11βHSD2 deficiency, deletion in the brain alone is not sufficient to change basal blood pressure, and the additional insult of a sustained high sodium intake is required for hypertension. The nature of this interaction is not yet defined. High salt intake was necessary but not sufficient for the hypertensive response, a situation analogous to the pressor effect of intracerebrovascular aldosterone infusion, which is sensitized by, but not exclusively dependent on, sodium intake.38

uired for hypertension. The nature of this interaction is not yet defined. High salt intake was necessary but not sufficient for the hypertensive response, a situation analogous to the pressor effect of intracerebrovascular aldosterone infusion, which is sensitized by, but not exclusively dependent on, sodium intake.38 What activates MR to induce salt sensitivity? Aldosterone synthase is expressed in rat brain,39 and aldosterone is synthesized centrally.40 However, this is not the case in mouse and human brains,41,42 and salt sensitivity in Hsd11b2.BKO mice is unlikely to reflect central aldosterone excess. Corticosterone and the neurosteroid precursor deoxycorticosterone are plausible alternatives. Indeed, oral DEX attenuated the blood pressure differential between genotypes. However, it is difficult to interpret these data because DEX did not actually reduce blood pressure in Hsd11b2.BKO mice. Instead, DEX increased blood pressure in control animals but not in Hsd11b2.BKO mice. It is likely that the peripheral pressor effects of excess DEX offset the reversal of central salt sensitivity, making the overall benefit for blood pressure in Hsd11b2.BKO mice modest.

ually reduce blood pressure in Hsd11b2.BKO mice. Instead, DEX increased blood pressure in control animals but not in Hsd11b2.BKO mice. It is likely that the peripheral pressor effects of excess DEX offset the reversal of central salt sensitivity, making the overall benefit for blood pressure in Hsd11b2.BKO mice modest. Central Deletion of 11βHSD2 and Peripheral Blood Pressure Control Salt sensitivity was not associated with sodium retention; urinary sodium excretion was higher in Hsd11b2.BKO mice than in controls during the dietary salt challenge. The regulation of blood pressure by aldosterone-target neurons in the NTS appears independent of kidney function, suggesting that MR-dependent hypertension may have a substantial neurogenic component.22,43 In other salt-sensitive models, increased central sympathetic drive and increased peripheral resistance sustain hypertension.44–46 The salt-induced increase in DBP and heightened pressor responsiveness to α-adrenoreceptor agonism in Hsd11b2.BKO mice are consistent with this hypothesis. Similarly, salt-induced hypokalemia in the absence of potassium wasting may suggest redistribution of potassium into the intracellular compartment following sympathetic activation.47 An impaired baroreflex would release tonic inhibition of sympathetic nerve activity, increasing sympathetic drive to the peripheral vasculature. In Hsd11b2.BKO mice, the impairment was asymmetrical, and the ability to buffer a pressor response was compromised. Similar observations are found in healthy humans following systemic aldosterone infusion48 and in patients with mild congestive heart failure,49 and contribute to increased cardiovascular risk in these patients.50

2.BKO mice, the impairment was asymmetrical, and the ability to buffer a pressor response was compromised. Similar observations are found in healthy humans following systemic aldosterone infusion48 and in patients with mild congestive heart failure,49 and contribute to increased cardiovascular risk in these patients.50 Summary and Perspectives Our study demonstrates a unifying link between activation of MR in the NTS, salt appetite, and blood pressure control. In the absence of a physiological stimulus to consume salt, this arc is maladaptive and causes salt-sensitive hypertension. These same molecular pathways regulate renal salt reabsorption. Thus, global mutations in key genes will give a double hit for hypertension by increasing the behavioral drive to consume sodium and impairing the ability of the kidney to excrete this salt. Given that global sodium intake is habitually high, this integrated framework of sodium homeostasis is highly relevant and suggests that MR antagonists could be used to improve compliance to dietary sodium restriction in the treatment of cardiovascular disease. Sources of Funding Drs Evans and Ivy were funded by British Heart Foundation 4-year PhD studentships (FS/07/063/24075; FS/11/78/29328). Dr Christensen was funded by the Lundbeck Foundation (R152-2013–14574). Dr McNairn was funded by the Medical Research Council Doctoral Training Award to The University. The authors acknowledge support from The British Heart Foundation Center of Research Excellence Award (RE/08/001), Kidney Research UK (IN11/2011), and The Wellcome Trust (WT079009).

he Lundbeck Foundation (R152-2013–14574). Dr McNairn was funded by the Medical Research Council Doctoral Training Award to The University. The authors acknowledge support from The British Heart Foundation Center of Research Excellence Award (RE/08/001), Kidney Research UK (IN11/2011), and The Wellcome Trust (WT079009). Disclosures None. Supplementary Material The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.019341/-/DC1.

he Lundbeck Foundation (R152-2013–14574). Dr McNairn was funded by the Medical Research Council Doctoral Training Award to The University. The authors acknowledge support from The British Heart Foundation Center of Research Excellence Award (RE/08/001), Kidney Research UK (IN11/2011), and The Wellcome Trust (WT079009). Disclosures None. Supplementary Material The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.019341/-/DC1. CLINICAL PERSPECTIVE For the majority of people in industrialized societies, dietary salt intake habitually exceeds the recommended upper tolerable limit. This sustained high salt intake is associated with hypertension and with increased risk of cardiovascular disease. Reducing sodium intake may be beneficial for a large number of people, particularly those with hypertension or heart failure. However, compliance to restricted salt intake is poor, which may in part reflect enhanced salt appetite. The central pathways controlling salt intake are incompletely defined, but it is known that certain neurons in the brain stem are activated by salt depletion. We genetically modified mice, removing a gene in the brain stem to amplify local aldosterone signaling. Basal blood pressure and systemic electrolyte and hormonal status were not affected by this genetic modification. However, ad libitum salt intake increased 3-fold and this caused hypertension. We were able to partially block salt appetite with the mineralocorticoid antagonist spironolactone. This study demonstrates an important role for brain stem pathways in the control of sodium homeostasis and blood pressure. Mineralocorticoid antagonists could help improve compliance to restricted salt regimens during the management of cardiovascular disease.

Because women remain underrepresented in clinical trials,1,2 there exists uncertainty regarding the relative benefit and risk of established and novel antiplatelet therapies in women for the management of cardiovascular disease. In particular, concerns have been raised that the relative risk of thrombosis and bleeding in response to antiplatelet therapy may differ between men and women,3–6 and this may therefore influence the net clinical benefit of further intensification of antiplatelet therapy for individual patients. Clinical Perspective on p 255 Cangrelor is a potent intravenous inhibitor of the P2Y12 receptor that has a rapid onset and a half-life of 3 to 6 minutes, with offset of pharmacodynamic effect within 1 hour.7 Cangrelor’s pharmacological profile is consistent regardless of sex, age, or renal or hepatic function.8,9 In patients scheduled to undergo elective or urgent percutaneous coronary intervention (PCI), cangrelor reduced the incidence of cardiac ischemic events and stent thrombosis (ST) as compared to clopidogrel without a significant increase in bleeding. Since thrombotic and bleeding complications at the time of PCI remain a major concern, we examined the relative efficacy and safety of cangrelor in women versus men in a prespecified analysis of the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) PHOENIX trial.10

eding. Since thrombotic and bleeding complications at the time of PCI remain a major concern, we examined the relative efficacy and safety of cangrelor in women versus men in a prespecified analysis of the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) PHOENIX trial.10 Methods Patient Population and Study Treatment The design and results of the CHAMPION PHOENIX trial have been previously reported.10,11 In brief, CHAMPION PHOENIX was a double-blind, double-dummy trial that enrolled 11 145 patients undergoing urgent or elective PCI and randomized them before PCI to either cangrelor (iv bolus then infusion) or clopidogrel (300 mg or 600 mg loading dose) on a background of guideline-recommended therapy. At the end of the infusion, patients were administered either 600 mg of clopidogrel (cangrelor arm) or matching placebo (clopidogrel arm). Aspirin (75 mg to 325 mg) was to be administered in all patients, in addition to a maintenance dose of clopidogrel during the first 48 hours. The choice of periprocedural anticoagulant was left to the discretion of the treating physician. The use of a glycoprotein IIb/IIIa inhibitor was allowed only as rescue therapy during PCI.

5 mg to 325 mg) was to be administered in all patients, in addition to a maintenance dose of clopidogrel during the first 48 hours. The choice of periprocedural anticoagulant was left to the discretion of the treating physician. The use of a glycoprotein IIb/IIIa inhibitor was allowed only as rescue therapy during PCI. Patients were considered eligible for enrollment if they were ≥18 years of age and required PCI for treatment of stable angina or an acute coronary syndrome. Relevant exclusion criteria included administration of a P2Y12 inhibitor or abciximab in the past 7 days or the use of eptifibatide, tirofiban, or fibrinolytic in the 12 hours before randomization. Patients were also excluded if they were perceived to be at increased risk of bleeding, including ischemic stroke in last year or previous hemorrhagic stroke, intracranial aneurysm or arteriovenous malformation, recent (<1 month) trauma or major surgery, those currently receiving warfarin or with signs of active bleeding. The study protocol was reviewed and approved by institutional review committees and all subjects gave informed consent prior to participation.

Patients were considered eligible for enrollment if they were ≥18 years of age and required PCI for treatment of stable angina or an acute coronary syndrome. Relevant exclusion criteria included administration of a P2Y12 inhibitor or abciximab in the past 7 days or the use of eptifibatide, tirofiban, or fibrinolytic in the 12 hours before randomization. Patients were also excluded if they were perceived to be at increased risk of bleeding, including ischemic stroke in last year or previous hemorrhagic stroke, intracranial aneurysm or arteriovenous malformation, recent (<1 month) trauma or major surgery, those currently receiving warfarin or with signs of active bleeding. The study protocol was reviewed and approved by institutional review committees and all subjects gave informed consent prior to participation. End Points The primary efficacy end point was the composite of death from any cause, myocardial infarction (MI), ischemia-driven revascularization, or ST at 48 hours after randomization. The key secondary end point was ST at 48 hours which included definite ST according to the Academic Research Consortium definition and intraprocedural ST.10,12 As a secondary analysis, efficacy outcomes were collected through 30 days. Safety outcomes were only collected through 48 hours because off-treatment bleeding events that occurred outside of the first 2 days would not be anticipated to be study drug-related based on the rapid pharmacokinetics of cangrelor.

ral ST.10,12 As a secondary analysis, efficacy outcomes were collected through 30 days. Safety outcomes were only collected through 48 hours because off-treatment bleeding events that occurred outside of the first 2 days would not be anticipated to be study drug-related based on the rapid pharmacokinetics of cangrelor. The key safety end point was severe bleeding not related to coronary artery bypass graft according to the GUSTO classification system.13 Other bleeding definitions were also applied including the Thrombolysis in Myocardial Infarction (TIMI)14 and Acute Catheterization and Urgent Intervention Triage strategY (ACUITY)15 bleeding classifications. All deaths, cardiac ischemic events, and STs were independently adjudicated by a clinical events committee. Bleeding end points were not adjudicated, but were captured by the site.

The key safety end point was severe bleeding not related to coronary artery bypass graft according to the GUSTO classification system.13 Other bleeding definitions were also applied including the Thrombolysis in Myocardial Infarction (TIMI)14 and Acute Catheterization and Urgent Intervention Triage strategY (ACUITY)15 bleeding classifications. All deaths, cardiac ischemic events, and STs were independently adjudicated by a clinical events committee. Bleeding end points were not adjudicated, but were captured by the site. Statistical Analysis Baseline characteristics were compared using t-tests for continuous variables and χ2 or Fisher exact tests for categorical variables. Primary efficacy analyses were conducted in the modified intention-to-treat population comprising those patients who underwent PCI and received study drug. Safety analyses were conducted in the safety population that included all patients who underwent randomization and received ≥1 dose of the study drug according to the actual treatment received. End points are reported as incidence rates at 48 hours. Difference between treatment groups was tested using the Pearson χ2 statistic as well as odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Analyses were adjusted for any imbalances (P<0.10) in baseline characteristics between randomized treatment arms when stratified by patient sex. Because the female subgroup was relatively underpowered in comparison with the male subgroup, potential confounders identified in the male subgroup were also included as covariates in the female-only models, including previous MI, history of heart failure, peripheral arterial disease, previous coronary artery bypass graft, or abnormal cardiac biomarkers. To assess the homogeneity of the crude odds ratios in the sex subgroup analyses, a Breslow-Day statistic was used. A multivariable model was created to examine independent predictors of the primary efficacy outcome and GUSTO severe or moderate bleeding; a complete list of covariates is included in the online-only Data Supplement. Nominal P values are reported, and no adjustment was made for the comparison of multiple outcomes; all tests were 2-sided with a P value <0.05 considered to be significant. Analyses were performed using SAS version 9.3 (Cary, NC).

e bleeding; a complete list of covariates is included in the online-only Data Supplement. Nominal P values are reported, and no adjustment was made for the comparison of multiple outcomes; all tests were 2-sided with a P value <0.05 considered to be significant. Analyses were performed using SAS version 9.3 (Cary, NC). Results Of 11 145 patients enrolled in the CHAMPION PHOENIX trial, 3051 subjects (28%) were female. Women were more likely than men to be older and have a history of diabetes mellitus, hypertension, hyperlipidemia, previous stroke or transient ischemic attack, and were more likely to be enrolled in the United States in comparison with other regions (Table 1). Women were more likely than men to be enrolled with a qualifying event of stable angina or non–ST-segment–elevation myocardial infarction whereas men were more frequently enrolled with ST-segment–elevation myocardial infarction. Women tended to have a lower weight, and were less likely to be smokers or have a previous history of MI or coronary revascularization. Women had a lower baseline hemoglobin and hematocrit than men (Table 1). The choice of clopidogrel loading dose and the use of unfractionated heparin and bivalirudin were similar for both sexes, but men were more likely to be administered aspirin. The median duration of PCI was longer in men than women, but the choice of access site (femoral versus radial) was similar for both sexes (Table 1). Table 1. Baseline Characteristics in the CHAMPION PHOENIX Trial Stratified by Patient Sex

Results Of 11 145 patients enrolled in the CHAMPION PHOENIX trial, 3051 subjects (28%) were female. Women were more likely than men to be older and have a history of diabetes mellitus, hypertension, hyperlipidemia, previous stroke or transient ischemic attack, and were more likely to be enrolled in the United States in comparison with other regions (Table 1). Women were more likely than men to be enrolled with a qualifying event of stable angina or non–ST-segment–elevation myocardial infarction whereas men were more frequently enrolled with ST-segment–elevation myocardial infarction. Women tended to have a lower weight, and were less likely to be smokers or have a previous history of MI or coronary revascularization. Women had a lower baseline hemoglobin and hematocrit than men (Table 1). The choice of clopidogrel loading dose and the use of unfractionated heparin and bivalirudin were similar for both sexes, but men were more likely to be administered aspirin. The median duration of PCI was longer in men than women, but the choice of access site (femoral versus radial) was similar for both sexes (Table 1). Table 1. Baseline Characteristics in the CHAMPION PHOENIX Trial Stratified by Patient Sex After multivariable adjustment, female sex was independently associated with increased odds of the primary efficacy outcome (OR, 1.31; 95% CI, 1.03–1.67) and GUSTO moderate or severe (non–coronary artery bypass graft–related) bleeding (OR, 2.70; 95% CI, 1.19–6.13).

Table 1. Baseline Characteristics in the CHAMPION PHOENIX Trial Stratified by Patient Sex After multivariable adjustment, female sex was independently associated with increased odds of the primary efficacy outcome (OR, 1.31; 95% CI, 1.03–1.67) and GUSTO moderate or severe (non–coronary artery bypass graft–related) bleeding (OR, 2.70; 95% CI, 1.19–6.13). Efficacy Outcomes With Cangrelor In women, cangrelor reduced the odds of the primary end point by 35% (adjusted OR, 0.65; 95% CI, 0.48–0.89; P=0.01; Figure and Table 2) and reduced the odds of ST by 61% (adjusted OR, 0.39; 95% CI, 0.20–0.77; P=0.01) as compared with clopidogrel. In male patients, cangrelor was associated with a 14% reduction in the odds of the primary end point (adjusted OR, 0.86; 95% CI, 0.70–1.05; P=0.14; P interaction=0.23; Figure and Table 2) and a 16% reduction in the odds of ST (adjusted OR, 0.84; 95% CI, 0.53–1.33; P=0.44; P interaction=0.11). Table 2. Efficacy and Net Clinical Benefit of Cangrelor Versus Clopidogrel Stratified by Sex at 48 Hours Figure. The Kaplan–Meier incidence of the primary end point of death, MI, ischemia-driving revascularization or stent thrombosis at 48 hours in women (A) and men (B) in the CHAMPION-PHOENIX trial. The interaction between sex and randomized treatment assignment was not significant (P interaction=0.23). CI indicates confidence interval; HR, hazard ratio; and MI, myocardial infarction.

ath, MI, ischemia-driving revascularization or stent thrombosis at 48 hours in women (A) and men (B) in the CHAMPION-PHOENIX trial. The interaction between sex and randomized treatment assignment was not significant (P interaction=0.23). CI indicates confidence interval; HR, hazard ratio; and MI, myocardial infarction. The efficacy of cangrelor in women toward reducing the primary end point appeared to be primarily driven by the aforementioned reduction in ST, in addition to a 38% reduction in the odds of MI (adjusted OR, 0.62; 95% CI, 0.44–0.89; P=0.01) and a 56% reduction in the odds of ischemia-driven revascularization (adjusted OR, 0.44; 95% CI, 0.18–1.08; P=0.07; Table 2). In men, cangrelor was associated with a 12% lower odds of MI (adjusted OR, 0.88; 95% CI, 0.70–1.11; P=0.28; P interaction=0.15) and a more neutral effect on the odds of ischemia-driven revascularization (adjusted OR, 1.04; 95% CI, 0.56–1.90; P=0.91; P interaction=0.18; Table 2). Directionally consistent results were observed when the efficacy of cangrelor by patient sex was examined at 30 days (Table I in the online-only Data Supplement).

The efficacy of cangrelor in women toward reducing the primary end point appeared to be primarily driven by the aforementioned reduction in ST, in addition to a 38% reduction in the odds of MI (adjusted OR, 0.62; 95% CI, 0.44–0.89; P=0.01) and a 56% reduction in the odds of ischemia-driven revascularization (adjusted OR, 0.44; 95% CI, 0.18–1.08; P=0.07; Table 2). In men, cangrelor was associated with a 12% lower odds of MI (adjusted OR, 0.88; 95% CI, 0.70–1.11; P=0.28; P interaction=0.15) and a more neutral effect on the odds of ischemia-driven revascularization (adjusted OR, 1.04; 95% CI, 0.56–1.90; P=0.91; P interaction=0.18; Table 2). Directionally consistent results were observed when the efficacy of cangrelor by patient sex was examined at 30 days (Table I in the online-only Data Supplement). Safety Outcomes With Cangrelor In both women and men, cangrelor did not increase the odds of the primary safety end point, GUSTO severe or life-threatening bleeding, as compared with clopidogrel (0.3% versus 0.2%, P=0.30; 0.1% versus 0.1%, P=0.41, respectively; P interaction=0.88). However, cangrelor increased the odds of GUSTO moderate bleeding in women when compared with clopidogrel (0.9% versus 0.3%, P=0.02; Table 3). In contrast, an excess in GUSTO moderate bleeding was not observed in male patients treated with cangrelor as compared to clopidogrel (0.2% versus 0.2%, P=0.68; P interaction=0.04). The increase in GUSTO moderate bleeding in women was explained by a higher incidence of blood transfusions in cangrelor-treated women (1.1% versus 0.3%, P=0.01), as compared with those treated with clopidogrel. Cangrelor did not increase the odds of blood transfusions in men (0.2% versus 0.3%, P=0.56; P interaction=0.03). Intracranial hemorrhage was infrequent in both men and women and not significantly increased with use of cangrelor in either sex (Table 3). There were no confirmed fatal bleeding events. Additional bleeding end points are shown in Table 3.

dds of blood transfusions in men (0.2% versus 0.3%, P=0.56; P interaction=0.03). Intracranial hemorrhage was infrequent in both men and women and not significantly increased with use of cangrelor in either sex (Table 3). There were no confirmed fatal bleeding events. Additional bleeding end points are shown in Table 3. Table 3. Safety End Points Stratified by Sex in Safety Population Net Clinical Benefit The net clinical benefit (composite of the primary efficacy and safety end points) favored cangrelor as compared with clopidogrel in both women (adjusted OR, 0.68; 95% CI, 0.50–0.92; P=0.01) and in men (adjusted OR, 0.87; 95% CI, 0.71–1.06; P=0.17; P interaction=0.26). Consistent results were observed with cangrelor when moderate bleeding was included in the net benefit outcome (primary end point or GUSTO moderate or severe bleeding) in both women (adjusted OR, 0.78; 95% CI, 0.58–1.04; P=0.09) and men (adjusted OR, 0.86; 95% CI, 0.70–1.05; P=0.14; P interaction=0.73; Table 2).

0.26). Consistent results were observed with cangrelor when moderate bleeding was included in the net benefit outcome (primary end point or GUSTO moderate or severe bleeding) in both women (adjusted OR, 0.78; 95% CI, 0.58–1.04; P=0.09) and men (adjusted OR, 0.86; 95% CI, 0.70–1.05; P=0.14; P interaction=0.73; Table 2). Discussion In the current prespecified subgroup analysis of the CHAMPION PHOENIX trial, cangrelor demonstrated a consistent reduction in the odds of major adverse cardiovascular events (MACE) and ST in both male and female patients. In particular, cangrelor reduced the odds of the primary end point by 32% and the odds of ST by 61% in female subjects as compared with those treated with clopidogrel. By comparison, cangrelor was associated with a 15% reduction in the odds of MACE and a 16% reduction in the odds of ST in male subjects without evidence of heterogeneity by sex. Although some previous reports have demonstrated sex-based differences in response to some antiplatelet therapies,3–5,16 the observed benefit with cangrelor was consistent in female and male patients.

on in the odds of MACE and a 16% reduction in the odds of ST in male subjects without evidence of heterogeneity by sex. Although some previous reports have demonstrated sex-based differences in response to some antiplatelet therapies,3–5,16 the observed benefit with cangrelor was consistent in female and male patients. Although it remains unclear whether true biological differences exist at the level of the platelet, several previous studies have demonstrated that women have higher baseline platelet reactivity as compared with men.17–19 Therefore, a strategy of platelet inhibition for the prevention of cardiovascular events could offer particular appeal in women. Although aspirin has a comparable pharmacodynamic response in both women and men, women have higher on-treatment platelet reactivity on aspirin owing to their higher platelet reactivity levels at baseline.18 For clopidogrel, some reports have suggested that its pharmacodynamic response in women may be attenuated thereby leading to a higher proportion of clopidogrel hyporesponders.20,21 These observations have contributed to a greater need to adequately evaluate novel antiplatelet therapies in both women and men. In a meta-analysis of trials for aspirin use in the primary prevention of cardiovascular disease, aspirin reduced cardiovascular events in both women and men, but the benefit of aspirin in women was primarily toward stroke reduction, whereas aspirin reduced the risk of MI in men.5 In the Antithrombotic Trialists’ Collaboration, the clinical benefit of aspirin in women was diminished when compared with men when primary and secondary prevention studies were combined, but this difference was no longer significant once adjusted for multiple comparisons.22 Subsequently, in a meta-analysis of randomized trials that studied clopidogrel, clopidogrel had comparable efficacy toward MACE reduction in both women and men, but the benefit of clopidogrel in women was driven primarily by a reduction in MI, whereas men had a more robust reduction in the risk of MI, stroke, and all-cause mortality.23 A meta-analysis of trials of glycoprotein IIb/IIIa inhibitors uncovered a significant interaction in efficacy between men and women with a potential signal toward harm in female patients.

driven primarily by a reduction in MI, whereas men had a more robust reduction in the risk of MI, stroke, and all-cause mortality.23 A meta-analysis of trials of glycoprotein IIb/IIIa inhibitors uncovered a significant interaction in efficacy between men and women with a potential signal toward harm in female patients. However, when the female population was restricted to those with elevated troponin levels, there appeared to be a more consistent benefit regardless of sex.3 Notably in the current analysis, cangrelor demonstrated marked efficacy in women during the periprocedural period even though the majority of patients were enrolled with stable angina and had normal baseline cardiac biomarkers.

elevated troponin levels, there appeared to be a more consistent benefit regardless of sex.3 Notably in the current analysis, cangrelor demonstrated marked efficacy in women during the periprocedural period even though the majority of patients were enrolled with stable angina and had normal baseline cardiac biomarkers. In the current analysis, although severe and life-threatening bleeds were similar regardless of treatment arm, we observed an increase in the risk of GUSTO moderate bleeding with cangrelor in women (0.9% versus 0.3%) that was not seen in male patients (0.2% versus 0.2%; P interaction=0.04). However, it is relevant that the definition of a GUSTO moderate bleeding event includes any bleeding that requires transfusion (without hemodynamic compromise). Because the decision to transfuse is often based on the patient’s hemoglobin concentration, it is notable that women had a lower baseline hemoglobin concentration than men at study entry. Therefore, it is plausible that this baseline difference between sexes may have contributed to a higher frequency of blood transfusions in female patients. To that end, the odds of bleeding with cangrelor were more comparable in both women and men when alternate bleeding definitions were applied. Nonetheless, women overall had a higher incidence of bleeding than men regardless of therapy, as has been noted in prior PCI analyses,24 and a nonsignificant trend was observed across alternate bleeding definitions toward more bleeding in cangrelor-treated women than those treated with clopidogrel. One cannot exclude that higher age, a lower body mass index, and other comorbidities in women may have explained the observed bleeding signal. Importantly, the net clinical benefit that considered both efficacy and bleeding (including GUSTO severe or moderate bleeding events) continued to favor cangrelor in both women and men because of the marked reduction in MACE in female patients treated with cangrelor.

men may have explained the observed bleeding signal. Importantly, the net clinical benefit that considered both efficacy and bleeding (including GUSTO severe or moderate bleeding events) continued to favor cangrelor in both women and men because of the marked reduction in MACE in female patients treated with cangrelor. Limitations of the current analysis include the fact that tests for heterogeneity are conservative and the trial was not powered to examine outcomes within individual subgroups. Exploration within patient subgroups may increase the risk of a false-positive finding and should therefore be considered exploratory. As well, randomization was not stratified on the basis of patient sex and therefore we cannot exclude that unmeasured confounders may have differed across randomized treatment arms in either women or men. However, very few imbalances were observed between randomized treatment arms when stratified by sex because of the large size of the trial and all analyses were adjusted for potential confounders. Although the GUSTO moderate bleeding definition is based on criteria that may have been influenced by the patient’s baseline hemoglobin, multiple bleeding definitions were included in the current analysis.

stratified by sex because of the large size of the trial and all analyses were adjusted for potential confounders. Although the GUSTO moderate bleeding definition is based on criteria that may have been influenced by the patient’s baseline hemoglobin, multiple bleeding definitions were included in the current analysis. Because CHAMPION PHOENIX enrolled patients with either stable angina (58.1% of patients enrolled) or acute coronary syndrome, the trial did not compare the efficacy or safety of cangrelor to prasugrel or ticagrelor, which are now endorsed preferentially over clopidogrel in appropriate patients in the setting of acute coronary syndrome.25–27 These therapies are not currently recommended in the setting of elective PCI and were therefore not studied in the current trial. The current substudy is underpowered to examine whether efficacy and safety were comparable in women or men within the acute coronary syndrome or stable angina subgroups. In summary, the current findings provide important reassurance that the efficacy and net clinical benefit of cangrelor at the time of PCI is maintained in female patients, a population historically understudied in cardiology trials. Efforts should continue to identify patient characteristics that may help to find those individuals who will derive the greatest net clinical benefit from novel antiplatelet therapies.

benefit of cangrelor at the time of PCI is maintained in female patients, a population historically understudied in cardiology trials. Efforts should continue to identify patient characteristics that may help to find those individuals who will derive the greatest net clinical benefit from novel antiplatelet therapies. Acknowledgments We thank Steven E. Elkin, MS and Debra Bernstein, PhD of The Medicines Company for their statistical support, along with Yuyin Liu, MS and Lanyu Lei, MS of the Harvard Clinical Research Institute for their independent verification of the analyses. Harvard Clinical Research Institute received funding from The Medicines Company for these analyses. Sources of Funding The CHAMPION PHOENIX trial was funded by The Medicines Company.

Acknowledgments We thank Steven E. Elkin, MS and Debra Bernstein, PhD of The Medicines Company for their statistical support, along with Yuyin Liu, MS and Lanyu Lei, MS of the Harvard Clinical Research Institute for their independent verification of the analyses. Harvard Clinical Research Institute received funding from The Medicines Company for these analyses. Sources of Funding The CHAMPION PHOENIX trial was funded by The Medicines Company. Disclosures Dr O’Donoghue has received research grants from Merck, GlaxoSmithKline, Eisai, and AstraZeneca. Dr White has received research grants from Sanofi, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Schering Plow, Merck Sharpe & Dohme AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Pharma Development, and Bristol-Myers Squibb and has served on the Advisory Boards of Merck Sharpe & Dohme, Roche, and Regado Biosciences. Dr Gibson has received funding from or has been a consultant for Angel Medical Corporation, AstraZeneca, Atrium Medical Systems, Baxter Healthcare, Bayer, Cardiovascular Research Foundation, Consensus Medical Communications, CSL Behring, Cytori Therapeutics, Daiichi Sankyo, Eli Lilly, Exeter Group, Genentech, GlaxoSmithKline, Ikaria, Janssen Pharmaceuticals, Johnson & Johnson, Lantheus Medical Imaging, Merck, Ortho-McNeil, Portola Pharmaceuticals, Roche Diagnostics, Sanofi, StealthPeptides, St. Jude Medical, The Medicines Company, UpToDate in Cardiovascular Medicine Volcano Corp, and Walk Vascular. Dr Hamm has received honoraria from Abbott, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Merck Sharpe & Dohme, Bristol-Myers Squibb, BRAHMS, Daiichi Sankyo, Essex, GlaxoSmithKline, Medtronic, Lilly, Sanofi, Correvio, Pfizer, Roche, The Medicines Company, Boston Scientific, and Gilead. Dr Mahaffey’s financial disclosures prior to August 1, 2013, can be viewed at https://www.dcri.org/about-us/conflict-of-interest/Mahaffey-COI_2011-2013.pdf; disclosures after August 1, 2013, can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Dr Price has received consulting honoraria from AstraZeneca, Merck, Terumo, Spectranetics, The Medicines Company, Medtronic, St. Jude Medical, and Boston Scientific and speaker honoraria from AstraZeneca. Dr Steg has received personal fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, Novartis, Otsuka, Pfizer, Roche, Sanofi, Servier, The Medicines Company, and Vivus.

and Boston Scientific and speaker honoraria from AstraZeneca. Dr Steg has received personal fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, Novartis, Otsuka, Pfizer, Roche, Sanofi, Servier, The Medicines Company, and Vivus. Dr Stone has been a consultant for Abbott Vascular, Boston Scientific, Bristol-Myers Squibb–Sanofi partnership, Eli Lilly, Daiichi Sankyo, AstraZeneca, and The Medicines Company. Dr Harrington has received research grants from AstraZeneca, Bristol-Myers Squibb, Sanofi, The Medicines Company, Eli Lilly, Daiichi Sankyo, GlaxoSmithKline, Johnson & Johnson, Portola, Merck, and Regado and has been a consultant for Sanofi, Bristol-Myers Squibb, Merck, Johnson & Johnson, and Gilead. Drs Prats, Deliargyris, and Liu are employees of The Medicines Company. Dr Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company (including for his role as Co-Chair of CHAMPION PHOENIX); Site Co-Investigator: Biotronik, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. The other authors report no conflicts.

oratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company (including for his role as Co-Chair of CHAMPION PHOENIX); Site Co-Investigator: Biotronik, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. The other authors report no conflicts. Supplementary Material Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Guest Editor for this article was Gilles Montalescot, MD, PhD. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.017300/-/DC1. * A full list of investigators can be found in Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303-1313.

S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303-1313. CLINICAL PERSPECTIVE Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed. The CHAMPION PHOENIX trial randomized 11 145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. Overall the efficacy of cangrelor was similar in men and women with an observed trend toward greater benefit in women. The odds of severe bleeding with cangrelor were similar in men and women; however, cangrelor increased the odds of moderate bleeding in women but not in men (P interaction=0.045). In part, this might be explained by lower baseline hemoglobin concentration thereby contributing to a higher frequency of blood transfusions in women. Overall, the net clinical benefit favored cangrelor over clopidogrel in both women and men undergoing percutaneous coronary intervention.

Cangrelor is a reversible, intravenous adenosine diphosphate receptor antagonist and has a rapid onset and offset of its antiplatelet effects. Cangrelor has been approved for use in patients undergoing percutaneous coronary intervention (PCI) not pretreated with a P2Y12 inhibitor on the basis of the results of the CHAMPION PHOENIX trial (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition).1 The CHAMPION PHOENIX trial compared cangrelor with clopidogrel in patients undergoing PCI and found that cangrelor reduced the composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis by 22%.1 The definition of MI used in the trial was based on the second universal definition of MI, and the protocol mandated the collection of blood samples to test for biomarkers of myonecrosis after the initial PCI.2 A core laboratory also reviewed all angiograms from the index PCI to determine whether there was evidence of angiographic complications during the procedure, including intraprocedural stent thrombosis (IPST).3

rotocol mandated the collection of blood samples to test for biomarkers of myonecrosis after the initial PCI.2 A core laboratory also reviewed all angiograms from the index PCI to determine whether there was evidence of angiographic complications during the procedure, including intraprocedural stent thrombosis (IPST).3 Some have questioned whether MIs and IPST detected through these standardized efforts represent clinically meaningful events. In this analysis, we sought to determine whether changes in the definition of MI or stent thrombosis would have affected the overall primary end point of the trial. Additionally, we aimed to evaluate the effects of cangrelor on MIs of different sizes and types. Finally, we sought to better understand the impact of the different definitions on the incidence of MI and the prognosis of patients who have an MI. METHODS Study Population and Design CHAMPION PHOENIX was a double-blind, placebo-controlled trial that randomized 11 145 patients who were undergoing PCI to either intravenous cangrelor or clopidogrel. The full inclusion and exclusion criteria and protocol of the trial have been reported previously.1,4 In brief, patients were eligible for the trial if they had not been treated previously with platelet inhibitors and were undergoing PCI for ST-segment–elevation MI, non–ST-segment–elevation acute coronary syndrome, or stable angina.

sion and exclusion criteria and protocol of the trial have been reported previously.1,4 In brief, patients were eligible for the trial if they had not been treated previously with platelet inhibitors and were undergoing PCI for ST-segment–elevation MI, non–ST-segment–elevation acute coronary syndrome, or stable angina. Patients were randomized to receive either cangrelor followed by clopidogrel after the infusion of cangrelor was complete or clopidogrel as soon as possible after randomization. Patients randomized to cangrelor received an infusion of cangrelor (30 μg/kg followed by an infusion of 4 μg/kg per minute) and placebo capsules. Cangrelor was continued for at least 2 hours or for the duration of the procedure (if the procedure lasted >2 hours) and was followed by clopidogrel 600 mg after the infusion of the intravenous study drug. Patients randomized to clopidogrel received either 600 or 300 mg clopidogrel as determined by clinician preference. Randomization was stratified by intended loading dose of clopidogrel (600 versus 300 mg) and normal or abnormal status at baseline (status based on cardiac biomarkers, changes in the ECG, and symptoms). Biomarkers of myonecrosis (creatinine kinase-MB fraction [CK-MB]; Siemens ADVIA Centaur 2-site sandwich immunoassay) were to be measured every 6 hours and analyzed by a core laboratory (Quest Diagnostics).

and normal or abnormal status at baseline (status based on cardiac biomarkers, changes in the ECG, and symptoms). Biomarkers of myonecrosis (creatinine kinase-MB fraction [CK-MB]; Siemens ADVIA Centaur 2-site sandwich immunoassay) were to be measured every 6 hours and analyzed by a core laboratory (Quest Diagnostics). End Points A Clinical Events Committee that was independent, was unaware of the treatment assignments, and was based at the Duke Clinical Research Institute adjudicated all components of the primary and secondary efficacy end points. The primary efficacy end point was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours. The definition of MI used in the adjudication of the primary efficacy end point was based on the second Universal Definition of MI and was the most contemporary definition available at the time in which the trial was designed (Table 1).2 Table 1. Definitions of PCI-Related (Type 4a) MI

End Points A Clinical Events Committee that was independent, was unaware of the treatment assignments, and was based at the Duke Clinical Research Institute adjudicated all components of the primary and secondary efficacy end points. The primary efficacy end point was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours. The definition of MI used in the adjudication of the primary efficacy end point was based on the second Universal Definition of MI and was the most contemporary definition available at the time in which the trial was designed (Table 1).2 Table 1. Definitions of PCI-Related (Type 4a) MI To determine whether patients had a periprocedural MI within 48 hours of randomization, the Clinical Events Committee classified patients on the basis of their cardiac biomarker status at baseline. Patients were considered to be normal at baseline if they were undergoing PCI for stable angina, had baseline levels of cardiac biomarkers below the 99th percentile, and had no new ECG changes or symptoms consistent with acute coronary syndrome within the prior 6 hours. Additionally, patients were considered to be normal at baseline if they were classified as undergoing PCI for a non–ST-segment–elevation acute coronary syndrome but had 2 biomarker samples ≥6 hours apart that were below the 99th percentile, no new ECG changes, and no ongoing acute coronary syndrome symptoms or symptoms within 6 hours before the sample. In these patients who had no evidence of MI at baseline, MI was considered to have occurred if there was an elevation in CK-MB that was ≥3 times the upper limit of normal (ULN).

e below the 99th percentile, no new ECG changes, and no ongoing acute coronary syndrome symptoms or symptoms within 6 hours before the sample. In these patients who had no evidence of MI at baseline, MI was considered to have occurred if there was an elevation in CK-MB that was ≥3 times the upper limit of normal (ULN). All other patients in the trial were considered to be having an MI at the time of PCI and were further categorized on the basis of whether biomarkers were decreasing and returned to normal, were decreasing but remaining abnormal, were increasing, or had an unknown baseline. Those patients in whom baseline biomarkers were decreasing and were beneath the ULN were considered to have a reinfarction if there was an elevation in CK-MB that was ≥3 times the ULN. Patients with biomarkers that were decreasing at baseline but remained above the ULN were considered to have a reinfarction if they had an angiographic complication, ischemic symptoms, or new ECG changes (new ST-segment elevation/depression >0.1mV in at least 2 contiguous leads; new left bundle-branch block; new Q wave [> 0.03 seconds]) in conjunction with a re-elevation of CK-MB that was ≥3 times the ULN and ≥ 50% higher than the nadir. Patients in whom biomarkers were increasing at baseline (including patients with only 1 elevated biomarker sample at baseline or 2 biomarkers values collected <6 hours apart that prevented the adequate assessment of the biomarker trajectory) had to have both angiographic evidence consistent with a periprocedural event (sustained acute vessel closure, new Thrombolysis in Myocardial Infarction grade 0/1 flow, evidence of distal embolization, side-branch closure off a vessel ≥2 mm in diameter, dissection, thrombus, or no reflow) and ischemic ECG changes in addition to a re-elevation of CK-MB that was ≥3 times the ULN and ≥50% from baseline. Patients determined to have a ST-segment–elevation MI at baseline (including those patients with normal baseline cardiac markers who are confirmed by the Clinical Events Committee to have a baseline ST-segment–elevation MI ECG) were not reviewed for potential type 4a MI.

hat was ≥3 times the ULN and ≥50% from baseline. Patients determined to have a ST-segment–elevation MI at baseline (including those patients with normal baseline cardiac markers who are confirmed by the Clinical Events Committee to have a baseline ST-segment–elevation MI ECG) were not reviewed for potential type 4a MI. The Society of Coronary Angiography and Intervention (SCAI) subsequently proposed a new definition for periprocedural MI.5 In this analysis, we retrospectively applied the SCAI criteria to those events adjudicated as an MI during the trial. In patients with normal cardiac biomarkers at baseline, patients had to have an elevation of CK-MB to ≥10 times the ULN. Patients who had normal biomarkers at baseline but developed new pathological Q waves in ≥2 contiguous leads or left bundle-branch block were considered to have an MI if they have a CK-MB elevation ≥5 times the ULN. Patients with cardiac biomarkers that were either stable or falling at baseline required a new elevation from the previous nadir level by an absolute increment of ≥10 times the ULN of CK-MB. Patients with biomarkers that were rising at baseline required a further increase in cardiac biomarkers (CK-MB ≥10 times the ULN) beyond the last level. In the population of patients with rising biomarkers, the SCAI definition also requires signs consistent with a clinically relevant MI (ie, new onset or worsening heart failure or sustained hypotension). These specific events were not prospectively collected in the trial. Instead, for this analysis, we required patients with biomarkers that were rising at baseline to have either new ischemic ECG changes or angiographic evidence consistent with a clinically relevant MI.

worsening heart failure or sustained hypotension). These specific events were not prospectively collected in the trial. Instead, for this analysis, we required patients with biomarkers that were rising at baseline to have either new ischemic ECG changes or angiographic evidence consistent with a clinically relevant MI. The predefined definition of stent thrombosis used in the original analysis of CHAMPION PHOENIX included both definite stent thrombosis (as defined by the Academic Research Consortium [ARC]) and IPST (angiographically confirmed new or worsening thrombus related to the placement of the coronary stent).6,7 The first sensitivity analysis excluded IPST and was the composite of death, MI, ischemia-driven revascularization, or ARC definite stent thrombosis at 48 hours after randomization. Additional sensitivity analysis also excluded IPST and used revised MI definitions based on SCAI’s proposed clinically relevant threshold for an MI (death, MI [SCAI definition for peri-procedural events], ischemia-driven revascularization, or ARC definite stent thrombosis) and a definition of MI that required a postprocedural CK-MB elevation of ≥10 times the ULN (death, MI [CK-MB ≥10 times the ULN], ischemia-driven revascularization, or ARC definite stent thrombosis) at 48 hours after randomization.

-procedural events], ischemia-driven revascularization, or ARC definite stent thrombosis) and a definition of MI that required a postprocedural CK-MB elevation of ≥10 times the ULN (death, MI [CK-MB ≥10 times the ULN], ischemia-driven revascularization, or ARC definite stent thrombosis) at 48 hours after randomization. An academic executive committee and The Medicines Company designed the trial. The Medicines Company funded the trial. At the conclusion of the trial, the database was transferred to the Harvard Clinical Research Institute, which had full access to the data and validated the analyses included in this article. The Institutional Review Board or Ethics Committee for each participating institution reviewed and approved the trial. All patients provided written informed consent. Statistical Analysis This analysis used the modified intention to treat population of patients who underwent PCI and were treated with study drug (n=10 942). The association between MI type and the primary efficacy end point was examined with a logistic regression model that controlled for potential confounders (treatment, patient status, age [≥65 years], history of congestive heart failure, diabetes mellitus, prior MI, country [United States/Non–United States], PCI duration). The effects of cangrelor compared with clopidogrel on MI were determined with a logistic regression model that was stratified by intended loading dose of clopidogrel (600 versus 300 mg) and patient status at baseline (normal/abnormal).

Statistical Analysis This analysis used the modified intention to treat population of patients who underwent PCI and were treated with study drug (n=10 942). The association between MI type and the primary efficacy end point was examined with a logistic regression model that controlled for potential confounders (treatment, patient status, age [≥65 years], history of congestive heart failure, diabetes mellitus, prior MI, country [United States/Non–United States], PCI duration). The effects of cangrelor compared with clopidogrel on MI were determined with a logistic regression model that was stratified by intended loading dose of clopidogrel (600 versus 300 mg) and patient status at baseline (normal/abnormal). A 2-sided significance level of 0.05 was used, and there were no corrections for multiple comparisons because of the exploratory nature of this analysis. Event curves were developed from 48-hour Kaplan-Meier estimates. Analyses were performed with SAS software version 9.3 (SAS Institute, Cary, NC).

The effects of cangrelor compared with clopidogrel on MI were determined with a logistic regression model that was stratified by intended loading dose of clopidogrel (600 versus 300 mg) and patient status at baseline (normal/abnormal). A 2-sided significance level of 0.05 was used, and there were no corrections for multiple comparisons because of the exploratory nature of this analysis. Event curves were developed from 48-hour Kaplan-Meier estimates. Analyses were performed with SAS software version 9.3 (SAS Institute, Cary, NC). RESULTS The primary efficacy end point as originally defined in the CHAMPION PHOENIX trial was the composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours. In this sensitivity analysis in which IPST was not included as part of the stent thrombosis events considered in the composite end point, cangrelor reduced death, MI, ischemia-driven revascularization, or ARC definite stent thrombosis at 48 hours (4.2% versus 5.2%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.67–0.95; P=0.01; Figure 1). When different definitions of MI were used in the primary efficacy end point, the results of the trial were consistent with previously reported results. Treatment with cangrelor reduced the composite end point of death, MI (using SCAI definition for periprocedural MI), ischemia-driven revascularization, or ARC definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51–0.92; P=0.01) and the composite end point of death, MI (peak CK-MB ≥10 times the ULN), ischemia-driven revascularization, or ARC definite stent thrombosis (1.4% versus 2.0%; OR, 0.69; 95% CI, 0.51–0.92; P=0.01; Figure 2).

iven revascularization, or ARC definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51–0.92; P=0.01) and the composite end point of death, MI (peak CK-MB ≥10 times the ULN), ischemia-driven revascularization, or ARC definite stent thrombosis (1.4% versus 2.0%; OR, 0.69; 95% CI, 0.51–0.92; P=0.01; Figure 2). Figure 1. Protocol-defined and sensitivity analyses of primary efficacy end points at 48 hours using different definitions of myocardial infarction (MI).ARC indicates Academic Research Consortium; CI, confidence interval; CK-MB, creatinine kinase-MB; IDR, ischemia-driven revascularization; OR, odds ratio; SCAI, Society of Coronary Angiography and Intervention; ST, stent thrombosis; and ULN, upper limit of normal. Figure 2. Sensitivity analyses evaluating outcomes at 48 hours of cangrelor compared with clopidogrel using different definitions of myocardial infarction (MI).Time to first occurrence of (A) death, MI (Society of Coronary Angiography and Intervention [SCAI] definition), ischemia-driven revascularization (IDR), and Academic Research Consortium (ARC) definite stent thrombosis (ST) and (B) death, MI (creatinine kinase-MG [CK-MB] ≥10 times the upper limit of normal [ULN]), IDR, and ARC definite stent thrombosis. OR indicates odds ratio.

ary Angiography and Intervention [SCAI] definition), ischemia-driven revascularization (IDR), and Academic Research Consortium (ARC) definite stent thrombosis (ST) and (B) death, MI (creatinine kinase-MG [CK-MB] ≥10 times the upper limit of normal [ULN]), IDR, and ARC definite stent thrombosis. OR indicates odds ratio. Treatment with cangrelor reduced the incidence of MI at 48 hours (3.8% versus 4.7%; OR, 0.80; 95% confidence interval [CI], 0.67–0.97; P=0.02). Of the 462 patients with MI that occurred in CHAMPION PHOENIX (4.2%), the majority were considered type 4a (related to PCI; n=433, 93.7%) and occurred in patients with baseline biomarkers that were normal (Table I in the online-only Data Supplement). Treatment with cangrelor reduced the incidence of type 4a MI compared with clopidogrel (3.5% versus 4.4%; OR, 0.80; 95% CI, 0.66–0.98; P=0.03; Table 2). When the SCAI definition of periprocedural MI was used for potential ischemic events that occurred during the trial, there were fewer overall events (n=134). Treatment with cangrelor also reduced the incidence of MI using the SCAI criteria for periprocedural events (1.0% versus 1.5%; OR, 0.65; 95% CI, 0.46–0.92; P=0.01). In patients with baseline biomarkers that were normal, cangrelor reduced the incidence of MIs with symptoms and CK-MB ≥5 times the ULN (0.4% versus 0.7%; OR, 0.54; 95% CI, 0.32–0.91; P=0.02). Similarly, cangrelor reduced MIs with a peak CK-MB ≥10 times the ULN (0.9% versus 1.4%; OR, 0.64; 95% CI, 0.45–0.91; P=0.01) and those MI with peak CK-MB ≥10 times the ULN, symptoms, or ECG changes (1.5% versus 2.4%; OR, 0.63; 95% CI, 0.48–0.84; P=0.001). There was no heterogeneity in the effects of cangrelor on MI based on index diagnosis (Table II in the online-only Data Supplement). The distribution of peak biomarkers in patients treated with cangrelor and clopidogrel is shown in Figure I in the online-only Data Supplement.

.4%; OR, 0.63; 95% CI, 0.48–0.84; P=0.001). There was no heterogeneity in the effects of cangrelor on MI based on index diagnosis (Table II in the online-only Data Supplement). The distribution of peak biomarkers in patients treated with cangrelor and clopidogrel is shown in Figure I in the online-only Data Supplement. Table 2. Effect of Cangrelor on MI at 48 Hours Patients randomized in CHAMPION PHOENIX who had an MI as defined with the definition in the original protocol that was based on the second universal definition of MI were at increased risk of death at 30 days even after adjustment for potential confounders (adjusted OR, 4.60; 95% CI, 2.49–8.51; P<0.001; Figure 3). MI also was associated with increased risk of death at 30 days when using the SCAI definition (adjusted OR, 8.85; 95% CI, 4.29–18.25; P<0.001) and when considering only MI that resulted in a peak CK-MB ≥10 times the ULN (adjusted OR, 9.20; 95% CI, 4.45–18.99; P<0.001). Figure 3. Association between the types of myocardial infarction (MI) using various definitions and the risk of death at 30 days.CHF indicates coronary heart failure; CI, confidence interval; CK-MB, creatinine kinase-MB; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; SCAI, Society of Coronary Angiography and Intervention; and ULN, upper limit of normal.

ing various definitions and the risk of death at 30 days.CHF indicates coronary heart failure; CI, confidence interval; CK-MB, creatinine kinase-MB; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; SCAI, Society of Coronary Angiography and Intervention; and ULN, upper limit of normal. DISCUSSION In this sensitivity analysis of the CHAMPION PHOENIX trial, we found that treatment with cangrelor reduced the incidence of death, MI, ischemia-driven revascularization, or stent thrombosis regardless of the definition of MI or stent thrombosis. The consistency of the results across a variety of different definitions supports the efficacy of cangrelor in patients undergoing PCI. Furthermore, cangrelor reduced MIs of different sizes, but particularly those MIs associated with high levels of biomarkers and MIs that were associated with signs or symptoms of ischemia. We also found that the occurrence of an MI, regardless of type, remains associated with significant odds of death in the 30 days after the event. Thus, the benefits of cangrelor in reducing periprocedural MI remain clinically important in the current era.

and MIs that were associated with signs or symptoms of ischemia. We also found that the occurrence of an MI, regardless of type, remains associated with significant odds of death in the 30 days after the event. Thus, the benefits of cangrelor in reducing periprocedural MI remain clinically important in the current era. Because the majority of ischemic events that occurred during the first 48 hours of CHAMPION PHOENIX were type 4a MIs related to PCI, these data highlight the need for adequate and effective antithrombotic therapies.8 Current guidelines recommend that patients undergoing PCI be treated with oral antiplatelet therapies before or immediately after the procedure.9–11 The oral P2Y12 inhibitors currently used in practice have a delayed onset of action and do not result in antiplatelet effects for ≈60 to 120 minutes.12,13 The delay in the onset of antiplatelet effect is a particular problem in patients such as those treated with ad hoc PCI after elective coronary angiography or in patients undergoing PCI for acute coronary syndrome in whom little antiplatelet effect may be present during the actual PCI. Furthermore, some medications such as those used during moderate sedation may delay the onset of antiplatelet effects.14

as those treated with ad hoc PCI after elective coronary angiography or in patients undergoing PCI for acute coronary syndrome in whom little antiplatelet effect may be present during the actual PCI. Furthermore, some medications such as those used during moderate sedation may delay the onset of antiplatelet effects.14 Intravenous glycoprotein IIb/IIIa inhibitors are available and can be used in patients undergoing PCI who are not pretreated with an oral P2Y12 inhibitor.15 However, prior studies showed that the majority of benefit from glycoprotein IIb/IIIa inhibitors occurred in patients with elevated cardiac biomarkers, yet the EARLY-ACS trial (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) and ACUITY trial (Acute Catheterization and Urgent Intervention Triage Strategy) showed that the routine use of these agents in these populations increased the risk of bleeding without significant improvements in clinical outcomes.16,17 As a result, the use of glycoprotein IIb/IIIa inhibitors has declined, and some current guidelines do not endorse routine use.9 Because cangrelor is an intravenous formulation that has high bioavailability and is a highly effective platelet inhibitor, it is likely that much of the benefit with regard to the reduction of MI seen in this study reflects an antiplatelet effect that is more potent and occurs more quickly than the effects of clopidogrel.18 Prior studies have shown that more intensive antiplatelet therapy can reduce ischemic events in patients undergoing PCI.10,11,19 These findings from CHAMPION PHOENIX build on prior studies and show that drugs with greater bioavailability and a faster onset of action can reduce ischemic events even compared with effective antiplatelet therapies.20–23

ore intensive antiplatelet therapy can reduce ischemic events in patients undergoing PCI.10,11,19 These findings from CHAMPION PHOENIX build on prior studies and show that drugs with greater bioavailability and a faster onset of action can reduce ischemic events even compared with effective antiplatelet therapies.20–23 Some have questioned whether MIs, particularly those events with low elevations in cardiac biomarkers that may not have been previously detected, are clinically relevant in the contemporary era.24,25 We found that patients with an MI after randomization had a risk of death that was between 4- and 13-fold greater than that for patients who had no event. The clear association between MI and death, which was present for all definitions of MI evaluated in these analyses, provides evidence that therapies designed to reduce MIs are likely important in the treatment of patients undergoing PCI.

that was between 4- and 13-fold greater than that for patients who had no event. The clear association between MI and death, which was present for all definitions of MI evaluated in these analyses, provides evidence that therapies designed to reduce MIs are likely important in the treatment of patients undergoing PCI. Numerous definitions of MI have been proposed for use in clinical trials2,5,26; however, the optimal definition remains unclear.7,27 Furthermore, differences in the definitions change the incidence of periprocedural MI as noted by the fact that only 31% of the type 4a MIs as defined by the second universal definition met the SCAI criteria. The second universal definition of MI noted that it was difficult to define MI in patients with elevated biomarkers at baseline. These guidelines suggested including criteria that incorporate features supportive of ischemia (eg, imaging, ECG). In CHAMPION PHOENIX, patients with elevated biomarkers required evidence of symptoms, angiographic evidence consistent with a periprocedural event, or ischemic ECG changes, in addition to further elevations in biomarkers, to be considered as having a type 4a MI. In patients who had no evidence of MI at baseline, MI was considered to have occurred if there was an elevation in CK-MB that was ≥3 times the ULN regardless of whether symptoms were present. The third universal definition now requires that patients have signs or symptoms of myocardial ischemia regardless of baseline biomarkers. In addition, the third universal definition proposes a >5-fold rise above the 99th percentile for the upper reference limit for patients with normal biomarkers at baseline to meet the MI definition.26

definition now requires that patients have signs or symptoms of myocardial ischemia regardless of baseline biomarkers. In addition, the third universal definition proposes a >5-fold rise above the 99th percentile for the upper reference limit for patients with normal biomarkers at baseline to meet the MI definition.26 The SCAI definition differs in some important ways from the universal definition. Patients with normal cardiac biomarkers at baseline had to have an elevation of CK-MB to ≥10 times the ULN or cardiac troponin (I or T) to ≥70 times the ULN to meet the definition of MI. Although this definition identified fewer events in CHAMPION PHOENIX, the events identified were clinically meaningful and were associated with increased risk of death at 30 days even when controlling for the extent of coronary artery disease.

cardiac troponin (I or T) to ≥70 times the ULN to meet the definition of MI. Although this definition identified fewer events in CHAMPION PHOENIX, the events identified were clinically meaningful and were associated with increased risk of death at 30 days even when controlling for the extent of coronary artery disease. These data should be considered in light of some limitations. First, these analyses are post hoc analyses that were not prespecified. As a result, they represent sensitivity analyses that supplement the findings from the predefined, primary results of the trial. Accordingly, the MI definition based on the SCAI criteria was not prospectively adjudicated and was obtained retrospectively. This trial assessed MI using the universal definition that was available at that time the trial was designed and did not use the third universal definition that is now available. In addition, CK-MB was systematically collected in the CHAMPION PHOENIX trial, whereas the second and third universal definitions of MI prefer cardiac troponin. Bleeding was investigator reported and was not adjudicated, although post hoc adjudication did not qualitatively change the safety profile.23 Finally, CHAMPION PHOENIX was not powered for this specific component of the primary end point or to assess the effects of cangrelor on specific types of MI.

er cardiac troponin. Bleeding was investigator reported and was not adjudicated, although post hoc adjudication did not qualitatively change the safety profile.23 Finally, CHAMPION PHOENIX was not powered for this specific component of the primary end point or to assess the effects of cangrelor on specific types of MI. CONCLUSIONS MI, as defined with a variety of different classifications, continues to be an important event in the contemporary era that significantly increases the risk of death at 30 days. Although there are multiple proposed definitions of MI and these different definitions result in changes in the incidence of MI, there were no qualitative differences in the effects of cangrelor with the use of various definitions. As a result, cangrelor was effective in reducing ischemic events in patients undergoing PCI in CHAMPION PHOENIX regardless of the definition of MI tested in this study. ACKNOWLEDGMENTS We would like to thank Steven E. Elkin, MS, and Debra Bernstein, PhD, of The Medicines Company for their statistical support, along with Yuyin Liu, MS, and Lanyu Lei, MS, of the Harvard Clinical Research Institute for their independent verification of the analyses. Harvard Clinical Research Institute received funding from The Medicines Company for these analyses. SOURCE OF FUNDING The CHAMPION PHOENIX trial was funded by The Medicines Company. DISCLOSURES Dr Cavender reports consulting fees from AstraZeneca and Merck.

ACKNOWLEDGMENTS We would like to thank Steven E. Elkin, MS, and Debra Bernstein, PhD, of The Medicines Company for their statistical support, along with Yuyin Liu, MS, and Lanyu Lei, MS, of the Harvard Clinical Research Institute for their independent verification of the analyses. Harvard Clinical Research Institute received funding from The Medicines Company for these analyses. SOURCE OF FUNDING The CHAMPION PHOENIX trial was funded by The Medicines Company. DISCLOSURES Dr Cavender reports consulting fees from AstraZeneca and Merck. Dr Bhatt has served on the Advisory Board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the Board of Directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; as chair for the American Heart Association Quality Oversight Committee; and on the Data Monitoring Committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute. Dr Bhatt has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); other funding from Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (vice-chair), VA CART Research and Publications Committee (chair); research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company (including for serving as co-chair of CHAMPION PHOENIX); and royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). Dr Bhatt was a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; was a trustee for the American College of Cardiology; and performed unfunded research for FlowCo, PLx Pharma, Takeda.

); and royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). Dr Bhatt was a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; was a trustee for the American College of Cardiology; and performed unfunded research for FlowCo, PLx Pharma, Takeda. Dr Stone reports no relevant disclosures. Dr White reports honoraria from AstraZeneca and research funding from Sanofi-Aventis, Eli Lilly, National Health Institute, Glaxo Smith Kline, Merck Sharpe & Dohme, and AstraZeneca. Dr Steg has received a research grant (to INSERM U1148) from Sanofi and Servier; has received speaking or consulting fees from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, Regeneron, Roche, Sanofi, Servier, The Medicines Company; and owns stock in Aterovax. Dr Gibson has received honoraria from The Medicines Company. Dr Hamm has received honoraria from AstraZeneca, Sanofi Aventis, and Lilly, as well as research funding from Astra Zeneca and The Medicines Company. Dr Price reports honoraria from AstraZeneca, Merck & Co, Accriva Diagnostics, and The Medicines Company. Dr Leonardi has served on the Advisory Board for The Medicines Company, Eli Lilly, and Merck. Drs Prats and Deliargyris are employed by The Medicines Company.

Dr Hamm has received honoraria from AstraZeneca, Sanofi Aventis, and Lilly, as well as research funding from Astra Zeneca and The Medicines Company. Dr Price reports honoraria from AstraZeneca, Merck & Co, Accriva Diagnostics, and The Medicines Company. Dr Leonardi has served on the Advisory Board for The Medicines Company, Eli Lilly, and Merck. Drs Prats and Deliargyris are employed by The Medicines Company. Dr Mahaffey has received honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cubist, Eli Lilly, Epson, Forest, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Merck, Mt. Sinai, Myokardia, Omthera, Portola, Purdue Pharma, Spring Publishing, Vindico, and WebMD, as well as research funding from Daiichi, Johnson & Johnson, Medtronic, St. Jude, and Tenax. Dr Harrington has served on the Advisory Board for Evidint, Regado, and Scanadu; has received honoraria from Amgen, Daiichi-Lilly, Gilead Sciences, Gilead Sciences Inc, Janssen R&D, Medtronic, Merck, Novartis Corporation, The Medicines Company, Vida Health, Vox Media, and WebMD; has received other funding from the American Heart Association; has received research funding from AstraZeneca, BMS, CSL Behring, GSK, Merck, Portola, Sanofi-Aventis, and The Medicines Company; and has ownership interest in Element Science and MyoKardia. Supplementary Material * For the full list, please see Bhatt et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;134:723–733. Sources of Funding, see page 731 Guest Editor for this article was Eric R. Bates, MD.

Dr Harrington has served on the Advisory Board for Evidint, Regado, and Scanadu; has received honoraria from Amgen, Daiichi-Lilly, Gilead Sciences, Gilead Sciences Inc, Janssen R&D, Medtronic, Merck, Novartis Corporation, The Medicines Company, Vida Health, Vox Media, and WebMD; has received other funding from the American Heart Association; has received research funding from AstraZeneca, BMS, CSL Behring, GSK, Merck, Portola, Sanofi-Aventis, and The Medicines Company; and has ownership interest in Element Science and MyoKardia. Supplementary Material * For the full list, please see Bhatt et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;134:723–733. Sources of Funding, see page 731 Guest Editor for this article was Eric R. Bates, MD. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.020829/-/DC1. Circulation is available at http://circ.ahajournals.org. Clinical Perspective What Is New? Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not previously treated with a P2Y12 inhibitor. 4.2% of patients had a myocardial infarction (MI) as defined by the second universal definition within 48 hours after undergoing percutaneous coronary intervention.

Clinical Perspective What Is New? Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not previously treated with a P2Y12 inhibitor. 4.2% of patients had a myocardial infarction (MI) as defined by the second universal definition within 48 hours after undergoing percutaneous coronary intervention. Cangrelor reduced MIs regardless of whether the MI was defined with the second universal or Society of Coronary Angiography and Intervention definition or when MIs were restricted to only those with large biomarker elevations and either symptoms or ECG changes. What Are the Clinical Implications? Changes in the definition of MI used in the primary end point did not affect the overall findings from the CHAMPION PHOENIX trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Some have questioned whether MI remains an important clinical event in the current era; however, we found that patients who had an MI, regardless of the definition, were at increased risk of death at 30 days. These findings demonstrate the importance of therapies that reduce ischemic events in patients undergoing percutaneous coronary intervention and provide further evidence for the clinical utility of cangrelor when used in patients undergoing percutaneous coronary intervention.

1. Introduction 1.1. Methodology and Evidence Review The recommendations listed in this guideline are, whenever possible, evidence based. An initial extensive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline, was conducted from January through September 2015. Key search words included but were not limited to the following: acute limb ischemia, angioplasty, ankle-brachial index, anticoagulation, antiplatelet therapy, atypical leg symptoms, blood pressure lowering/hypertension, bypass graft/bypass grafting/surgical bypass, cilostazol, claudication/intermittent claudication, critical limb ischemia/severe limb ischemia, diabetes, diagnostic testing, endovascular therapy, exercise rehabilitation/exercise therapy/exercise training/supervised exercise, lower extremity/foot wound/ulcer, peripheral artery disease/peripheral arterial disease/peripheral vascular disease/lower extremity arterial disease, smoking/smoking cessation, statin, stenting, and vascular surgery. Additional relevant studies published through September 2016, during the guideline writing process, were also considered by the writing committee, and added to the evidence tables when appropriate. The final evidence tables included in the Online Data Supplement summarize the evidence utilized by the writing committee to formulate recommendations. Additionally, the writing committee reviewed documents related to lower extremity peripheral artery disease (PAD) previously published by the ACC and AHA.9,10 References selected and published in this document are representative and not all-inclusive.

ence utilized by the writing committee to formulate recommendations. Additionally, the writing committee reviewed documents related to lower extremity peripheral artery disease (PAD) previously published by the ACC and AHA.9,10 References selected and published in this document are representative and not all-inclusive. As stated in the Preamble, the ACC/AHA guideline methodology provides for commissioning an independent ERC to address systematic review questions (PI-COTS format) to inform recommendations developed by the writing committee. All other guideline recommendations (not based on the systematic review questions) were also subjected to an extensive evidence review process. For this guideline, the writing committee in conjunction with the Task Force and ERC Chair identified the following systematic review questions: 1) Is antiplatelet therapy beneficial for prevention of cardiovascular events in the patient with symptomatic or asymptomatic lower extremity PAD? 2) What is the effect of revascularization, compared with optimal medical therapy and exercise training, on functional outcome and quality of life (QoL) among patients with claudication? Each question has been the subject of recently published, systematic evidence reviews.11–13 The quality of these evidence reviews was appraised by the ACC/AHA methodologist and a vendor contracted to support this process (Doctor Evidence [Santa Monica, CA]). Few substantive randomized or nonrandomized studies had been published after the end date of the literature searches used for the existing evidence reviews, so the ERC concluded that no additional systematic review was necessary to address either of these critical questions.

rocess (Doctor Evidence [Santa Monica, CA]). Few substantive randomized or nonrandomized studies had been published after the end date of the literature searches used for the existing evidence reviews, so the ERC concluded that no additional systematic review was necessary to address either of these critical questions. A third systematic review question was then identified: 3) Is one revascularization strategy (endovascular or surgical) associated with improved cardiovascular and limb-related outcomes in patients with critical limb ischemia (CLI)? This question had also been the subject of a high-quality systematic review that synthesized evidence from observational data and an RCT14; additional RCTs addressing this question are ongoing.15–17 The writing committee and the Task Force decided to expand the survey to include more relevant randomized and observational studies. Based on evaluation of this additional evidence the ERC decided that further systematic review was not needed to inform the writing committee on this question. Hence, the ERC and writing committee concluded that available systematic reviews could be used to inform the development of recommendations addressing each of the 3 systematic review questions specified above. The members of the Task Force and writing committee thank the members of the ERC that began this process and their willingness to participate in this volunteer effort. They include Aruna Pradhan, MD, MPH (ERC Chair); Natalie Evans, MD; Peter Henke, MD; Dharam J. Kumbhani, MD, SM, FACC; and Tamar Polonsky, MD.

ed above. The members of the Task Force and writing committee thank the members of the ERC that began this process and their willingness to participate in this volunteer effort. They include Aruna Pradhan, MD, MPH (ERC Chair); Natalie Evans, MD; Peter Henke, MD; Dharam J. Kumbhani, MD, SM, FACC; and Tamar Polonsky, MD. 1.2. Organization of the Writing Committee The writing committee consisted of clinicians, including noninvasive and interventional cardiologists, exercise physiologists, internists, interventional radiologists, vascular nurses, vascular medicine specialists, and vascular surgeons, as well as clinical researchers in the field of vascular disease, a nurse (in the role of patient representative), and members with experience in epidemiology and/or health services research. The writing committee included representatives from the ACC and AHA, American Association of Cardiovascular and Pulmonary Rehabilitation, Inter-Society Consensus for the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, Society for Vascular Surgery, and Vascular and Endovascular Surgery Society.

r the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, Society for Vascular Surgery, and Vascular and Endovascular Surgery Society. 1.3. Document Review and Approval This document was reviewed by 2 official reviewers nominated by the ACC and AHA; 1 to 2 reviewers each from the American Association of Cardiovascular and Pulmonary Rehabilitation, Inter-Society Consensus for the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, Society for Vascular Surgery, and Vascular and Endovascular Surgery Society; and 16 additional individual content reviewers. Reviewers' RWI information was distributed to the writing committee and is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the ACC and the AHA and endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, Inter-Society Consensus for the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, Society for Vascular Surgery, and Vascular and Endovascular Surgery Society.

r the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, Society for Vascular Surgery, and Vascular and Endovascular Surgery Society. 1.4. Scope of Guideline Lower extremity PAD is a common cardiovascular disease that is estimated to affect approximately 8.5 million Americans above the age of 40 years and is associated with significant morbidity, mortality, and QoL impairment.18 It has been estimated that 202 million people worldwide have PAD.19 The purpose of this document is to provide a contemporary guideline for diagnosis and management of patients with lower extremity PAD. This document supersedes recommendations related to lower extremity PAD in the “ACC/AHA 2005 Guidelines for the Management of Patients With Peripheral Arterial Disease”9 and the “2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease.”10 The scope of this guideline is limited to atherosclerotic disease of the lower extremity arteries (PAD) and includes disease of the aortoiliac, femoropopliteal, and infrapopliteal arterial segments. It does not address nonatherosclerotic causes of lower extremity arterial disease, such as vasculitis, fibromuscular dysplasia, physiological entrapment syndromes, cystic adventitial disease, and other entities. Future guidelines will address aneurysmal disease of the abdominal aorta and lower extremity arteries and diseases of the renal and mesenteric arteries.

s of lower extremity arterial disease, such as vasculitis, fibromuscular dysplasia, physiological entrapment syndromes, cystic adventitial disease, and other entities. Future guidelines will address aneurysmal disease of the abdominal aorta and lower extremity arteries and diseases of the renal and mesenteric arteries. In developing the “2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease,” the writing committee reviewed the evidence to support recommendations in the relevant ACC/AHA guidelines noted in Table 2 and affirms the ongoing validity of the related recommendations, thus obviating the need to repeat existing guideline recommendations in the current guideline. Table 2 also contains a list of other statements that may be of interest to the reader. Table 3 includes definitions for PAD key terms used throughout the guideline. 2. Clinical Assessment for PAD Evaluating the patient for PAD begins with the clinical history, review of symptoms, and physical examination. 2.1. History and Physical Examination: Recommendations Recommendations for History and Physical Examination COR LOE Recommendations I B-NR Patients at increased risk of PAD (Table 4) should undergo a comprehensive medical history and a review of symptoms to assess for exertional leg symptoms, including claudication or other walking impairment, ischemic rest pain, and nonhealing wounds.52–57

Recommendations for History and Physical Examination COR LOE Recommendations I B-NR Patients at increased risk of PAD (Table 4) should undergo a comprehensive medical history and a review of symptoms to assess for exertional leg symptoms, including claudication or other walking impairment, ischemic rest pain, and nonhealing wounds.52–57 See Online Data Supplement 1. The symptoms and signs of PAD are variable. Patients with PAD may experience the classic symptom of claudication or may present with advanced disease, including CLI. Studies have demonstrated that the majority of patients with confirmed PAD do not have typical claudication but have other non–joint-related limb symptoms or are asymptomatic.53,55 Atypical lower extremity symptoms related to PAD may include pain or discomfort that begins at rest but worsens with exertion, pain or discomfort that does not stop an individual from walking, and pain or discomfort that begins with exertion but is not alleviated within 10 minutes of rest.54 Patients with PAD who do not have typical claudication but have other leg symptoms, or who are asymptomatic, have been shown to have functional impairment comparable to patients with claudication.54 Thus, all patients at increased risk of PAD should be asked not only about claudication but also about other exertional non–joint-related limb symptoms and perceived walking impairment.

other leg symptoms, or who are asymptomatic, have been shown to have functional impairment comparable to patients with claudication.54 Thus, all patients at increased risk of PAD should be asked not only about claudication but also about other exertional non–joint-related limb symptoms and perceived walking impairment. I B-NR Patients at increased risk of PAD (Table 4) should undergo vascular examination, including palpation of lower extremity pulses (ie, femoral, popliteal, dorsalis pedis, and posterior tibial), auscultation for femoral bruits, and inspection of the legs and feet.56,58,59

other leg symptoms, or who are asymptomatic, have been shown to have functional impairment comparable to patients with claudication.54 Thus, all patients at increased risk of PAD should be asked not only about claudication but also about other exertional non–joint-related limb symptoms and perceived walking impairment. I B-NR Patients at increased risk of PAD (Table 4) should undergo vascular examination, including palpation of lower extremity pulses (ie, femoral, popliteal, dorsalis pedis, and posterior tibial), auscultation for femoral bruits, and inspection of the legs and feet.56,58,59 See Online Data Supplements. A thorough lower extremity vascular examination and careful inspection of the legs and feet are important components of the clinical assessment for PAD. To perform a thorough examination, legs and feet are examined with lower garments (pants/skirt, shoes, and socks) removed. Examination findings suggestive of PAD are shown in Table 5. Lower extremity pulses should be assessed and rated as follows: 0, absent; 1, diminished; 2, normal; or 3, bounding. Reproducibility of pulse assessment is better for detection of normal versus absent pulse than for normal versus diminished pulse.56 Absence of the dorsalis pedis pulse is less accurate for diagnosis of PAD than is absence of the posterior tibial pulse because the dorsalis pedis pulse can be absent on examination in a significant percentage of healthy patients.56,58 The presence of multiple abnormal physical findings (ie, multiple pulse abnormalities, bruits) increases the likelihood of confirmed PAD.56,58,59 Abnormal physical findings, such as a pulse abnormality, require confirmation with the ankle-brachial index (ABI) to establish the diagnosis of PAD. Similarly, an entirely normal pulse examination and absence of bruits decreases the likelihood of confirmed PAD.56,58 The presence of nonhealing lower extremity wounds may be a sign of CLI. Findings of cool or discolored skin and delayed capillary refill are not reliable for PAD diagnosis.56 To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing (Section 3), generally with the ABI as the initial test.

g lower extremity wounds may be a sign of CLI. Findings of cool or discolored skin and delayed capillary refill are not reliable for PAD diagnosis.56 To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing (Section 3), generally with the ABI as the initial test. I B-NR Patients with PAD should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment.60–62 See Online Data Supplement 1. An inter-arm blood pressure difference of >15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis. Patients with PAD are at increased risk of subclavian artery stenosis.60–62 Measuring blood pressure in both arms identifies the arm with the highest systolic pressure, a requirement for accurate measurement of the ABI.27 Identification of unequal blood pressures in the arms also allows for more accurate measurement of blood pressure in the treatment of hypertension (ie, blood pressure is taken at the arm with higher measurements). Although a difference in arm systolic pressures of >15 to 20 mm Hg suggests subclavian (or innominate) artery stenosis, in the absence of symptoms (eg, arm claudication or symptoms of vertebral artery steal), no further imaging or intervention is warranted. 3. Diagnostic Testing for the Patient with Suspected Lower Extremity PAD (Claudication or CLI) 3.1. Resting ABI for Diagnosing PAD: Recommendations Recommendations for Resting ABI for Diagnosing PAD COR LOE Recommendations

See Online Data Supplement 1. An inter-arm blood pressure difference of >15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis. Patients with PAD are at increased risk of subclavian artery stenosis.60–62 Measuring blood pressure in both arms identifies the arm with the highest systolic pressure, a requirement for accurate measurement of the ABI.27 Identification of unequal blood pressures in the arms also allows for more accurate measurement of blood pressure in the treatment of hypertension (ie, blood pressure is taken at the arm with higher measurements). Although a difference in arm systolic pressures of >15 to 20 mm Hg suggests subclavian (or innominate) artery stenosis, in the absence of symptoms (eg, arm claudication or symptoms of vertebral artery steal), no further imaging or intervention is warranted. 3. Diagnostic Testing for the Patient with Suspected Lower Extremity PAD (Claudication or CLI) 3.1. Resting ABI for Diagnosing PAD: Recommendations Recommendations for Resting ABI for Diagnosing PAD COR LOE Recommendations I B-NR In patients with history or physical examination findings suggestive of PAD (Table 5), the resting ABI, with or without segmental pressures and waveforms, is recommended to establish the diagnosis.64–69

3. Diagnostic Testing for the Patient with Suspected Lower Extremity PAD (Claudication or CLI) 3.1. Resting ABI for Diagnosing PAD: Recommendations Recommendations for Resting ABI for Diagnosing PAD COR LOE Recommendations I B-NR In patients with history or physical examination findings suggestive of PAD (Table 5), the resting ABI, with or without segmental pressures and waveforms, is recommended to establish the diagnosis.64–69 See Online Data Supplement 4. The resting ABI is obtained by measuring systolic blood pressures at the arms (brachial arteries) and ankles (dorsalis pedis and posterior tibial arteries) in the supine position by using a Doppler device. The ABI of each leg is calculated by dividing the higher of the dorsalis pedis or posterior tibial pressure by the higher of the right or left arm blood pressure.27 In patients with a history or physical examination suggestive of PAD, the ABI has good validity as a first-line test in the diagnosis of PAD, as shown by vascular imaging, with sensitivities ranging from 68% to 84% and specificities from 84% to 99%.64–69 Segmental lower extremity blood pressures and Doppler or plethysmographic waveforms (pulse volume recordings) can be used to localize anatomic segments of disease (eg, aortoiliac, femoropopliteal, infrapopliteal).34,70,71 I C-LD Resting ABI results should be reported as abnormal (ABI ≤0.90), borderline (ABI 0.91–0.99), normal (1.00–1.40), or noncompressible (ABI >1.40).27,67–69,72

See Online Data Supplement 4. The resting ABI is obtained by measuring systolic blood pressures at the arms (brachial arteries) and ankles (dorsalis pedis and posterior tibial arteries) in the supine position by using a Doppler device. The ABI of each leg is calculated by dividing the higher of the dorsalis pedis or posterior tibial pressure by the higher of the right or left arm blood pressure.27 In patients with a history or physical examination suggestive of PAD, the ABI has good validity as a first-line test in the diagnosis of PAD, as shown by vascular imaging, with sensitivities ranging from 68% to 84% and specificities from 84% to 99%.64–69 Segmental lower extremity blood pressures and Doppler or plethysmographic waveforms (pulse volume recordings) can be used to localize anatomic segments of disease (eg, aortoiliac, femoropopliteal, infrapopliteal).34,70,71 I C-LD Resting ABI results should be reported as abnormal (ABI ≤0.90), borderline (ABI 0.91–0.99), normal (1.00–1.40), or noncompressible (ABI >1.40).27,67–69,72 See Online Data Supplement 4. Standardized reporting improves communication among healthcare providers. Calculated ABI values should be recorded to 2 decimal places. Patients with ABI ≤0.90 are diagnosed with PAD.67–69 Those with ABI 0.91 to 0.99 may possibly have PAD and should undergo exercise ABI, if the clinical suspicion of PAD is significant (Tables 4 and 5).73,74 Values >1.40 indicate that the arteries were not able to be compressed, which is more common among individuals with diabetes mellitus and/or advanced chronic kidney disease. In the setting of noncompressible ABI values, additional imaging can be used to diagnose PAD if the clinical suspicion is significant (Figures 1 and 2).72 These cutpoints for ABI interpretation have been previously proposed and represent a reasonable standardized categorization.27

nd/or advanced chronic kidney disease. In the setting of noncompressible ABI values, additional imaging can be used to diagnose PAD if the clinical suspicion is significant (Figures 1 and 2).72 These cutpoints for ABI interpretation have been previously proposed and represent a reasonable standardized categorization.27 IIa B-NR In patients at increased risk of PAD (Table 4) but without history or physical examination findings suggestive of PAD (Table 5), measurement of the resting ABI is reasonable.54,55,75–97 See Online Data Supplements 3 and 4. The ABI test is noninvasive, is simple to perform, and has minimal risks, making it suitable for use in asymptomatic individuals. Previous studies have demonstrated a significant prevalence of abnormal resting ABI among asymptomatic patients with risk factors for PAD.55,79,95 A significant body of evidence demonstrates that patients with an abnormal ABI who are asymptomatic have poorer cardiovascular morbidity and mortality outcomes than do patients with normal ABI.79–87 While there is no conclusive evidence that aspirin treatment changes cardiovascular or limb outcomes in this population, in 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes.75–78,96

iovascular morbidity and mortality outcomes than do patients with normal ABI.79–87 While there is no conclusive evidence that aspirin treatment changes cardiovascular or limb outcomes in this population, in 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes.75–78,96 There is also evidence that asymptomatic patients with a low resting ABI have a poorer functional status and a more rapid rate of functional decline than do patients with a normal ABI.54,88–92 Although physical activity has been shown to be associated with improvement in functional status in patients with asymptomatic PAD,93,94 the benefit of resting ABI testing to identify asymptomatic patients who are at increased risk of functional decline and may benefit from structured exercise programs remains to be determined. III: No Benefit B-NR In patients not at increased risk of PAD (Table 4) and without history or physical examination findings suggestive of PAD (Table 5), the ABI is not recommended.95,98

There is also evidence that asymptomatic patients with a low resting ABI have a poorer functional status and a more rapid rate of functional decline than do patients with a normal ABI.54,88–92 Although physical activity has been shown to be associated with improvement in functional status in patients with asymptomatic PAD,93,94 the benefit of resting ABI testing to identify asymptomatic patients who are at increased risk of functional decline and may benefit from structured exercise programs remains to be determined. III: No Benefit B-NR In patients not at increased risk of PAD (Table 4) and without history or physical examination findings suggestive of PAD (Table 5), the ABI is not recommended.95,98 See Online Data Supplement 4. The prevalence of PAD among individuals without risk factors for atherosclerosis and who are <50 years of age is low. Data from population-based cohort studies have demonstrated a low prevalence (approximately 1%) of abnormal resting ABI among individuals <50 years of age.95,98 In the NHANES (National Health and Nutrition Study), approximately 95% of participants with an abnormal resting ABI had at least 1 risk factor for atherosclerosis.95 The yield of ABI testing among younger, asymptomatic individuals without risk factors for atherosclerosis is low, and these patients should not be routinely tested for PAD.95,98 3.2. Physiological Testing: Recommendations Recommendations for Physiological Testing COR LOE Recommendations I B-NR Toe-brachial index (TBI) should be measured to diagnose patients with suspected PAD when the ABI is greater than 1.40.72,99–102

See Online Data Supplement 4. The prevalence of PAD among individuals without risk factors for atherosclerosis and who are <50 years of age is low. Data from population-based cohort studies have demonstrated a low prevalence (approximately 1%) of abnormal resting ABI among individuals <50 years of age.95,98 In the NHANES (National Health and Nutrition Study), approximately 95% of participants with an abnormal resting ABI had at least 1 risk factor for atherosclerosis.95 The yield of ABI testing among younger, asymptomatic individuals without risk factors for atherosclerosis is low, and these patients should not be routinely tested for PAD.95,98 3.2. Physiological Testing: Recommendations Recommendations for Physiological Testing COR LOE Recommendations I B-NR Toe-brachial index (TBI) should be measured to diagnose patients with suspected PAD when the ABI is greater than 1.40.72,99–102 See Online Data Supplement 5. TBI is a noninvasive test that is useful to evaluate for PAD in patents with noncompressible arteries, which cause an artificial elevation of the ABI.99,100,102,103 A TBI ≤0.70 is abnormal and diagnostic of PAD because the digital arteries are rarely noncompressible.99–102,104,105 Patients with longstanding diabetes mellitus72,101 or advanced chronic kidney disease106 have a high incidence of noncompressible arteries. Therefore, TBI assessment allows for the diagnosis of PAD in these patients with noncompressible arteries who have history or physical examination findings suggestive of PAD (Figure 1).

nts with longstanding diabetes mellitus72,101 or advanced chronic kidney disease106 have a high incidence of noncompressible arteries. Therefore, TBI assessment allows for the diagnosis of PAD in these patients with noncompressible arteries who have history or physical examination findings suggestive of PAD (Figure 1). I B-NR Patients with exertional non–joint-related leg symptoms and normal or borderline resting ABI (>0.90 and ≤1.40) should undergo exercise treadmill ABI testing to evaluate for PAD.71,74,107–110 See Online Data Supplement 5. Exercise treadmill ABI testing is important to objectively measure symptom limitations and diagnose PAD.71,74,107–110 It is useful in establishing the diagnosis of lower extremity PAD in the symptomatic patient when resting ABIs are normal or borderline and to differentiate claudication from pseudoclaudication in individuals with exertional leg symptoms. If the post-exercise treadmill ABI is normal, alternative causes of leg pain are considered (Table 6). If a treadmill is not available, the pedal plantarflexion ABI test is a reasonable alternative because the results correlate well with treadmill ABIs (Figure 1).111 IIa B-NR In patients with PAD and an abnormal resting ABI (≤0.90), exercise treadmill ABI testing can be useful to objectively assess functional status.71,74,107–110

See Online Data Supplement 5. Exercise treadmill ABI testing is important to objectively measure symptom limitations and diagnose PAD.71,74,107–110 It is useful in establishing the diagnosis of lower extremity PAD in the symptomatic patient when resting ABIs are normal or borderline and to differentiate claudication from pseudoclaudication in individuals with exertional leg symptoms. If the post-exercise treadmill ABI is normal, alternative causes of leg pain are considered (Table 6). If a treadmill is not available, the pedal plantarflexion ABI test is a reasonable alternative because the results correlate well with treadmill ABIs (Figure 1).111 IIa B-NR In patients with PAD and an abnormal resting ABI (≤0.90), exercise treadmill ABI testing can be useful to objectively assess functional status.71,74,107–110 See Online Data Supplement 5. In patients with PAD, exercise treadmill ABI testing can objectively assess symptoms, measure change in ABI in response to exercise, and assess functional status71,74,107–110 (Figure 1). It can be useful to correlate exertional lower extremity symptoms to a decline in ABI after treadmill exercise. Exercise treadmill ABI testing can document the magnitude of symptom limitation in patients with PAD and provide objective data that can demonstrate the safety of exercise and help to individualize exercise prescriptions in patients with PAD before initiation of a formal program of structured exercise training. Exercise ABI may also be used to objectively measure the functional improvement obtained in response to claudication treatment (eg, structured exercise program or revascularization). Administration of a 6-minute walk test in a corridor is a reasonable alternative to treadmill ABI testing for assessment of functional status.54

e ABI may also be used to objectively measure the functional improvement obtained in response to claudication treatment (eg, structured exercise program or revascularization). Administration of a 6-minute walk test in a corridor is a reasonable alternative to treadmill ABI testing for assessment of functional status.54 IIa B-NR In patients with normal (1.00–1.40) or borderline (0.91–0.99) ABI in the setting of nonhealing wounds or gangrene, it is reasonable to diagnose CLI by using TBI with waveforms, transcutaneous oxygen pressure (TcPO2), or skin perfusion pressure (SPP).112–116

e ABI may also be used to objectively measure the functional improvement obtained in response to claudication treatment (eg, structured exercise program or revascularization). Administration of a 6-minute walk test in a corridor is a reasonable alternative to treadmill ABI testing for assessment of functional status.54 IIa B-NR In patients with normal (1.00–1.40) or borderline (0.91–0.99) ABI in the setting of nonhealing wounds or gangrene, it is reasonable to diagnose CLI by using TBI with waveforms, transcutaneous oxygen pressure (TcPO2), or skin perfusion pressure (SPP).112–116 See Online Data Supplement 5. The toe pressure and TBI may be discordant with the ABI 0.90 to 1.40 in some patients with diabetes mellitus and a nonhealing wound (Figure 2).115,116 A TBI ≤0.70 is considered diagnostic of PAD.101,104,105 Doppler or plethysmographic waveforms taken at the toe supplement the toe pressure and TBI measurement and may be severely dampened in the setting of CLI. The likelihood of wound healing decreases with toe pressure <30 mm Hg.100 Perfusion assessment measures (ie, TBI with waveforms, TcPO2, SPP) are obtained in a warm room to prevent arterial vasoconstriction in response to the cold. TcPO2 measurements are performed with a standardized protocol and are taken at multiple sites.117 Correlation between TBI, TcPO2, and SPP has been reported.113 TcPO2 >30 mm Hg has been used to predict ulcer healing.118 SPP ≥30 to 50 mm Hg is associated with increased likelihood of wound healing.113 If perfusion measures are normal or only mildly impaired, alternative causes of the nonhealing wounds are considered (Table 7). TcPO2 and SPP can be used in angiosome-targeted assessment for revascularization.119

predict ulcer healing.118 SPP ≥30 to 50 mm Hg is associated with increased likelihood of wound healing.113 If perfusion measures are normal or only mildly impaired, alternative causes of the nonhealing wounds are considered (Table 7). TcPO2 and SPP can be used in angiosome-targeted assessment for revascularization.119 IIa B-NR In patients with PAD with an abnormal ABI (≤0.90) or with noncompressible arteries (ABI >1.40 and TBI ≤0.70) in the setting of nonhealing wounds or gangrene, TBI with waveforms, TcPO2, or SPP can be useful to evaluate local perfusion.112–116

predict ulcer healing.118 SPP ≥30 to 50 mm Hg is associated with increased likelihood of wound healing.113 If perfusion measures are normal or only mildly impaired, alternative causes of the nonhealing wounds are considered (Table 7). TcPO2 and SPP can be used in angiosome-targeted assessment for revascularization.119 IIa B-NR In patients with PAD with an abnormal ABI (≤0.90) or with noncompressible arteries (ABI >1.40 and TBI ≤0.70) in the setting of nonhealing wounds or gangrene, TBI with waveforms, TcPO2, or SPP can be useful to evaluate local perfusion.112–116 See Online Data Supplement 5. Perfusion assessment measures (eg, TBI with waveforms, TcPO2, SPP) can be useful when the ABI is only mildly reduced (eg, ABI 0.70–0.90) to determine whether factors other than PAD may be contributing to impaired wound healing (Figure 2). These perfusion assessment measures are obtained in a warm room to prevent arterial vasoconstriction in response to the cold. TcPO2 measurements are performed with a standardized protocol and are taken at multiple sites.117 The likelihood of wound healing decreases with toe pressure <30 mm Hg.100 There is correlation between TBI, TcPO2, and SPP. TcPO2 >30 mm Hg has been used to predict ulcer healing.118 SPP ≥30 to 50 mm Hg is associated with increased likelihood of wound healing.113 TcPO2 and SPP can be used in angiosome-targeted assessment for revascularization.119 Additional perfusion assessment may also be useful for patients with nonhealing wounds or gangrene who have noncompressible arteries (ABI >1.40) but who have a diagnosis of PAD that is based on an abnormal TBI (ABI ≤0.70).

healing.113 TcPO2 and SPP can be used in angiosome-targeted assessment for revascularization.119 Additional perfusion assessment may also be useful for patients with nonhealing wounds or gangrene who have noncompressible arteries (ABI >1.40) but who have a diagnosis of PAD that is based on an abnormal TBI (ABI ≤0.70). 3.3. Imaging for Anatomic Assessment: Recommendations Recommendations for Imaging for Anatomic Assessment COR LOE Recommendations I B-NR Duplex ultrasound, computed tomography angiography (CTA), or magnetic resonance angiography (MRA) of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patients with symptomatic PAD in whom revascularization is considered.118,120–122

Recommendations for Imaging for Anatomic Assessment COR LOE Recommendations I B-NR Duplex ultrasound, computed tomography angiography (CTA), or magnetic resonance angiography (MRA) of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patients with symptomatic PAD in whom revascularization is considered.118,120–122 See Online Data Supplement 6. For symptomatic patients in whom ABI/TBI confirms PAD and in whom revascularization is considered, additional imaging with duplex ultrasonography, CTA, or MRA is useful to develop an individualized treatment plan, including assistance in selection of vascular access sites, identification of significant lesions, and determination of the feasibility of and modality for invasive treatment. All 3 of these noninvasive imaging methods have good sensitivity and specificity as compared with invasive angiography.118,120–122 Renal function does not affect the safety of duplex ultrasonography, although duplex offers lower spatial resolution than CTA and MRA in the setting of arterial calcification. The tomographic data from CTA and MRA afford 3-dimensional reconstruction of the vessels examined. The iodinated contrast used in CTA confers risk of contrast-induced nephropathy and (rarely) severe allergic reaction123,124; CTA uses ionizing radiation. MRA does not use ionizing radiation; however, gadolinium contrast used frequently in MRA studies confers risk of nephrogenic systemic sclerosis for patients with advanced renal dysfunction and is therefore contraindicated in this population.125 The choice of the examination should be determined in an individualized approach to the anatomic assessment for each patient, including risk–benefit assessment of each study type. If these noninvasive tests are nondiagnostic, then invasive angiography may be required to delineate anatomy and plan revascularization.

125 The choice of the examination should be determined in an individualized approach to the anatomic assessment for each patient, including risk–benefit assessment of each study type. If these noninvasive tests are nondiagnostic, then invasive angiography may be required to delineate anatomy and plan revascularization. I C-EO Invasive angiography is useful for patients with CLI in whom revascularization is considered. N/A By definition, CLI results from extensive PAD that limits tissue perfusion. Because timely diagnosis and treatment are essential to preserve tissue viability in CLI, it is often most effective and expeditious to pursue invasive angiography with endovascular revascularization directly, without delay and potential risk of additional noninvasive imaging. IIa C-EO Invasive angiography is reasonable for patients with lifestyle-limiting claudication with an inadequate response to GDMT for whom revascularization is considered.

N/A By definition, CLI results from extensive PAD that limits tissue perfusion. Because timely diagnosis and treatment are essential to preserve tissue viability in CLI, it is often most effective and expeditious to pursue invasive angiography with endovascular revascularization directly, without delay and potential risk of additional noninvasive imaging. IIa C-EO Invasive angiography is reasonable for patients with lifestyle-limiting claudication with an inadequate response to GDMT for whom revascularization is considered. N/A For patients with lifestyle-limiting claudication despite GDMT (including structured exercise therapy) for whom revascularization is being considered, proceeding directly to invasive angiography for anatomic assessment and to determine revascularization strategy is reasonable. In certain clinical settings, noninvasive imaging studies for anatomic assessment (ie, duplex ultrasound, CTA, or MRA) may not be available because of lack of local resources or expertise. In addition, there are clinical scenarios in which noninvasive studies for anatomic assessment may be perceived to confer greater risk to the patient than invasive angiography (eg, patient with advanced chronic kidney disease for whom contrast dose for invasive angiography would be lower than that required for CTA). III: Harm B-R Invasive and noninvasive angiography (ie, CTA, MRA) should not be performed for the anatomic assessment of patients with asymptomatic PAD.123,124,126

N/A For patients with lifestyle-limiting claudication despite GDMT (including structured exercise therapy) for whom revascularization is being considered, proceeding directly to invasive angiography for anatomic assessment and to determine revascularization strategy is reasonable. In certain clinical settings, noninvasive imaging studies for anatomic assessment (ie, duplex ultrasound, CTA, or MRA) may not be available because of lack of local resources or expertise. In addition, there are clinical scenarios in which noninvasive studies for anatomic assessment may be perceived to confer greater risk to the patient than invasive angiography (eg, patient with advanced chronic kidney disease for whom contrast dose for invasive angiography would be lower than that required for CTA). III: Harm B-R Invasive and noninvasive angiography (ie, CTA, MRA) should not be performed for the anatomic assessment of patients with asymptomatic PAD.123,124,126 See Online Data Supplements 6 and 7. Angiography, either noninvasive or invasive, should not be performed for the anatomic assessment of patients with PAD without leg symptoms because delineation of anatomy will not change treatment for this population. This lack of benefit occurs in the setting of risk of contrast-induced nephropathy, patient discomfort, and allergic reactions.123,124,126 This recommendation does not address assessment of lower extremity aneurysmal disease or nonatherosclerotic causes of arterial disease, which is beyond the scope of this document.

. This lack of benefit occurs in the setting of risk of contrast-induced nephropathy, patient discomfort, and allergic reactions.123,124,126 This recommendation does not address assessment of lower extremity aneurysmal disease or nonatherosclerotic causes of arterial disease, which is beyond the scope of this document. 4. Screening for Atherosclerotic Disease in Other Vascular Beds for the Patient with PAD 4.1. Abdominal Aortic Aneurysm: Recommendation Recommendation for Abdominal Aortic Aneurysm COR LOE Recommendation IIa B-NR A screening duplex ultrasound for abdominal aortic aneurysm (AAA) is reasonable in patients with symptomatic PAD.127–129 See Online Data Supplement 8. PAD has been recognized as a risk factor for AAA. In observational studies, the prevalence of AAA (aortic diameter ≥3 cm) was higher in patients with symptomatic PAD than in the general population127,129 and in a population of patients with atherosclerotic risk factors.128 The prevalence of AAA among patients with PAD increased with age, beginning in patients ≥55 years of age, and was highest in patients ≥75 years of age.129 There are no data on AAA screening in patients with asymptomatic PAD. This recommendation refers to screening patients with symptomatic PAD for AAA regardless of patient age, sex, smoking history, or family history of AAA. Recommendations for screening the general population with risk factors for AAA (based on age, sex, smoking history, and family history) have been previously published.9

his recommendation refers to screening patients with symptomatic PAD for AAA regardless of patient age, sex, smoking history, or family history of AAA. Recommendations for screening the general population with risk factors for AAA (based on age, sex, smoking history, and family history) have been previously published.9 4.2. Screening for Asymptomatic Atherosclerosis in Other Arterial Beds (Coronary, Carotid, and Renal Arteries) The prevalence of atherosclerosis in the coronary, carotid, and renal arteries is higher in patients with PAD than in those without pad.128,130–135 However, intensive atherosclerosis risk factor modification in patients with PAD is justified regardless of the presence of disease in other arterial beds. Thus, the only justification for screening for disease in other arterial beds is if revascularization results in a reduced risk of myocardial infarction (MI), stroke, or death, and this has never been shown. Currently, there is no evidence to demonstrate that screening all patients with PAD for asymptomatic atherosclerosis in other arterial beds improves clinical outcome. Intensive treatment of risk factors through GDMT is the principle method for preventing adverse cardiovascular ischemic events from asymptomatic disease in other arterial beds.

evidence to demonstrate that screening all patients with PAD for asymptomatic atherosclerosis in other arterial beds improves clinical outcome. Intensive treatment of risk factors through GDMT is the principle method for preventing adverse cardiovascular ischemic events from asymptomatic disease in other arterial beds. 5. Medical Therapy for the Patient with PAD Patients with PAD should receive a comprehensive program of GDMT, including structured exercise and lifestyle modification, to reduce cardiovascular ischemic events and improve functional status. Smoking cessation is a vital component of care for patients with PAD who continue to smoke. A guideline-based program of pharmacotherapy to reduce cardiovascular ischemic events and limb-related events should be prescribed for each patient with PAD and is customized to individual risk factors, such as whether the patient also has diabetes mellitus. Previous studies have demonstrated that patients with PAD are less likely to receive GDMT than are patients with other forms of cardiovascular disease, including coronary artery disease (CAD).136–138 5.1. Antiplatelet Agents: Recommendations Recommendations for Antiplatelet Agents COR LOE Recommendations I A Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD. 139–142

5. Medical Therapy for the Patient with PAD Patients with PAD should receive a comprehensive program of GDMT, including structured exercise and lifestyle modification, to reduce cardiovascular ischemic events and improve functional status. Smoking cessation is a vital component of care for patients with PAD who continue to smoke. A guideline-based program of pharmacotherapy to reduce cardiovascular ischemic events and limb-related events should be prescribed for each patient with PAD and is customized to individual risk factors, such as whether the patient also has diabetes mellitus. Previous studies have demonstrated that patients with PAD are less likely to receive GDMT than are patients with other forms of cardiovascular disease, including coronary artery disease (CAD).136–138 5.1. Antiplatelet Agents: Recommendations Recommendations for Antiplatelet Agents COR LOE Recommendations I A Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD. 139–142 See Online Data Supplement 13. The effect of antiplatelet therapy on cardiovascular events has been systematically reviewed by the Antithrombotic Trialists' Collaboration.139 Of note, this meta-analysis included studies of antiplatelet agents other than aspirin or clopidogrel. Among patients with symptomatic PAD treated with antiplatelet therapy, there was a 22% odds reduction for cardiovascular events, including MI, stroke, or vascular death.139 Symptomatic patients with lower extremity PAD included both those with claudication and those with prior lower extremity revascularization. The Antithrombotic Trialists' Collaboration meta-analysis also compared the efficacy of different doses of aspirin.139 The proportional reduction in vascular events was 32% with 75 to 150 mg daily, 26% with 160 to 325 mg daily, and 19% with 500 to 1500 mg daily, whereas there was a significantly smaller (13%) reduction in cardiovascular events in patients being treated with <75 mg of aspirin per day.139 CLIPS (Critical Leg Ischaemia Prevention Study) demonstrated a benefit of aspirin (100 mg daily) compared with placebo in preventing vascular events, but the study was too small to derive meaningful conclusions.140 A meta-analysis of trials of aspirin (alone or in combination with dipyridamole) for prevention of cardiovascular events in patients with PAD found a non–statistically significant reduction in the primary endpoint of cardiovascular death, MI, and stroke and a statistically significant reduction in the secondary endpoint of nonfatal stroke with aspirin versus placebo.141 The CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial demonstrated a benefit of clopidogrel as compared with aspirin in cardiovascular risk reduction and bleeding events in a population of patients with symptomatic atherosclerotic vascular disease, including a subgroup of patients with symptomatic PAD.142

dogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial demonstrated a benefit of clopidogrel as compared with aspirin in cardiovascular risk reduction and bleeding events in a population of patients with symptomatic atherosclerotic vascular disease, including a subgroup of patients with symptomatic PAD.142 IIa C-EO In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. See Online Data Supplement 13. Patients with PAD (ie, ABI ≤0.90) who do not have claudication may have leg symptoms atypical for claudication or may be too functionally limited to allow for adequate leg symptom assessment. Patients with PAD without claudication are at increased cardiovascular risk.79 Subgroup analysis in a trial evaluating asymptomatic patients did not show an effect of aspirin in patients with an abnormally low ABI (<0.80 or ≤0.90).76 However, the trial was not powered to analyze subgroups, and the uncertainty of the result does not rule out the possibility that aspirin could provide benefit in such patients, especially in those at increased risk of cardiovascular events. Another trial that included asymptomatic patients was too small to derive meaningful conclusions.140 IIb B-R In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain.75,76

See Online Data Supplement 13. Patients with PAD (ie, ABI ≤0.90) who do not have claudication may have leg symptoms atypical for claudication or may be too functionally limited to allow for adequate leg symptom assessment. Patients with PAD without claudication are at increased cardiovascular risk.79 Subgroup analysis in a trial evaluating asymptomatic patients did not show an effect of aspirin in patients with an abnormally low ABI (<0.80 or ≤0.90).76 However, the trial was not powered to analyze subgroups, and the uncertainty of the result does not rule out the possibility that aspirin could provide benefit in such patients, especially in those at increased risk of cardiovascular events. Another trial that included asymptomatic patients was too small to derive meaningful conclusions.140 IIb B-R In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain.75,76 See Online Data Supplement 13. In asymptomatic patients with an abnormal or borderline ABI, 2 RCTs found that aspirin had no effect in reducing cardiovascular events75,76 and might increase bleeding.76 However, the trials were not powered to examine patients with borderline ABI separately. Given that cardiovascular risk is lower in patients with borderline ABI than in those with abnormal ABI,80 it would be unlikely that aspirin would have a meaningful effect in this subgroup when there was no evidence of an effect in the total trial populations.

powered to examine patients with borderline ABI separately. Given that cardiovascular risk is lower in patients with borderline ABI than in those with abnormal ABI,80 it would be unlikely that aspirin would have a meaningful effect in this subgroup when there was no evidence of an effect in the total trial populations. IIb B-R The effectiveness of dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established.143,144 See Online Data Supplement 13. Based on findings from a subset of patients with PAD in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, DAPT with aspirin plus clopidogrel may be considered for patients with PAD at particularly high risk of cardiovascular ischemic events who are not at high risk of bleeding.143,144 Currently, there are sparse data on newer P2Y12 antagonists for PAD. There is uncertainty about the net benefit of long-term DAPT for patients with PAD—specifically the balance of risks of cardiovascular ischemic events versus major bleeding. Additional clinical trials are needed in the population with PAD. Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD.20 IIb C-LD DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization.145–148

See Online Data Supplement 13. Based on findings from a subset of patients with PAD in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, DAPT with aspirin plus clopidogrel may be considered for patients with PAD at particularly high risk of cardiovascular ischemic events who are not at high risk of bleeding.143,144 Currently, there are sparse data on newer P2Y12 antagonists for PAD. There is uncertainty about the net benefit of long-term DAPT for patients with PAD—specifically the balance of risks of cardiovascular ischemic events versus major bleeding. Additional clinical trials are needed in the population with PAD. Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD.20 IIb C-LD DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization.145–148 See Online Data Supplements 13 and 14. There are sparse data on DAPT after lower extremity revascularization. Still, DAPT is prescribed in up to 55% of patients after endovascular revascularization for CLI.146 One small RCT of aspirin or aspirin plus clopidogrel in patients undergoing endovascular revascularization demonstrated that patients with DAPT had fewer repeat revascularization procedures for clinical symptoms.145 A subsequent small RCT of aspirin plus placebo or aspirin plus clopidogrel in patients after endovascular revascularization also showed a decrease in the need for repeat revascularization at 6 months in patients receiving clopidogrel.147 An RCT of aspirin plus placebo or aspirin plus clopidogrel in patients who underwent below-knee bypass graft showed a decrease in limb-related events only in the prespecified subgroup of patients with prosthetic bypass grafts.148 Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD.20

n RCT of aspirin plus placebo or aspirin plus clopidogrel in patients who underwent below-knee bypass graft showed a decrease in limb-related events only in the prespecified subgroup of patients with prosthetic bypass grafts.148 Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD.20 IIb B-R The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain.149–152 See Online Data Supplement 13. This novel antagonist of protease-activated receptor-1 added to existing antiplatelet therapy reduced the risk of cardiovascular ischemic events in patients with atherosclerosis who were receiving standard therapy in an RCT.150,151 However, it also increased the risk of moderate or severe bleeding. Although the cardiovascular benefit was not demonstrated in the subgroup with symptomatic PAD, there was a reduction in limb-related events with vorapaxar, specifically in acute limb ischemia (ALI) and peripheral revascularization.149,152 More than half of ALI events in the PAD subset were due to thrombosis of lower extremity bypass grafts.149 Unfortunately, the benefit in limb events in patients with PAD was accompanied by an increased risk of bleeding.149,152 Therefore, the overall clinical benefit of vorapaxar in patients with PAD is uncertain. 5.2. Statin Agents: Recommendation Recommendation for Statin Agents COR LOE Recommendation I A Treatment with a statin medication is indicated for all patients with PAD.96,153–157

See Online Data Supplement 13. This novel antagonist of protease-activated receptor-1 added to existing antiplatelet therapy reduced the risk of cardiovascular ischemic events in patients with atherosclerosis who were receiving standard therapy in an RCT.150,151 However, it also increased the risk of moderate or severe bleeding. Although the cardiovascular benefit was not demonstrated in the subgroup with symptomatic PAD, there was a reduction in limb-related events with vorapaxar, specifically in acute limb ischemia (ALI) and peripheral revascularization.149,152 More than half of ALI events in the PAD subset were due to thrombosis of lower extremity bypass grafts.149 Unfortunately, the benefit in limb events in patients with PAD was accompanied by an increased risk of bleeding.149,152 Therefore, the overall clinical benefit of vorapaxar in patients with PAD is uncertain. 5.2. Statin Agents: Recommendation Recommendation for Statin Agents COR LOE Recommendation I A Treatment with a statin medication is indicated for all patients with PAD.96,153–157 See Online Data Supplements 15 and 16. Statin therapy improves both cardiovascular and limb outcomes in patients with PAD.157 In a subgroup of 6748 patients with PAD in the HPS (Heart Protection Study), simvastatin 40 mg daily reduced the rate of first major vascular event by 22% relative to placebo.155

I A Treatment with a statin medication is indicated for all patients with PAD.96,153–157 See Online Data Supplements 15 and 16. Statin therapy improves both cardiovascular and limb outcomes in patients with PAD.157 In a subgroup of 6748 patients with PAD in the HPS (Heart Protection Study), simvastatin 40 mg daily reduced the rate of first major vascular event by 22% relative to placebo.155 In a multinational registry, statin use among patients with PAD reduced 4-year adverse limb-related events (ie, worsening claudication, new CLI, new lower extremity revascularization, new ischemic amputation) compared with no statin.153 Use of simvastatin in the HPS reduced relative risk of peripheral vascular events (including noncoronary revascularization, aneurysm repair, major amputation, or PAD death) compared with placebo.155 In Medicare patients undergoing lower extremity revascularization, 1-year limb salvage rates were improved among those receiving statin medication.154 In a multicenter RCT, use of atorvastatin 80 mg daily improved pain-free walking time and community-based walking at 12 months compared with placebo.156 In 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes.96 Guidelines for dosing of statin medications have been previously published.24 5.3. Antihypertensive Agents: Recommendations Recommendations for Antihypertensive Agents COR LOE Recommendations I A Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death.158–162

In a multinational registry, statin use among patients with PAD reduced 4-year adverse limb-related events (ie, worsening claudication, new CLI, new lower extremity revascularization, new ischemic amputation) compared with no statin.153 Use of simvastatin in the HPS reduced relative risk of peripheral vascular events (including noncoronary revascularization, aneurysm repair, major amputation, or PAD death) compared with placebo.155 In Medicare patients undergoing lower extremity revascularization, 1-year limb salvage rates were improved among those receiving statin medication.154 In a multicenter RCT, use of atorvastatin 80 mg daily improved pain-free walking time and community-based walking at 12 months compared with placebo.156 In 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes.96 Guidelines for dosing of statin medications have been previously published.24 5.3. Antihypertensive Agents: Recommendations Recommendations for Antihypertensive Agents COR LOE Recommendations I A Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death.158–162 See Online Data Supplements 17 and 18. Treatment of elevated blood pressure is indicated to lower the risk of cardiovascular events.162 Target blood pressure and selection of antihypertensive therapy should be consistent with current published guidelines for hypertension management. Concerns have been raised that antihypertensive therapy may reduce limb perfusion. However, multiple studies have demonstrated that blood pressure treatment, including the use of beta blockers, does not worsen claudication symptoms or impair functional status in patients with PAD.163–165 There is no evidence that one class of antihypertensive medication or strategy is superior for blood pressure lowering in PAD.158,166,167 An updated multisocietal guideline on the management of high blood pressure is anticipated in 2017.

sen claudication symptoms or impair functional status in patients with PAD.163–165 There is no evidence that one class of antihypertensive medication or strategy is superior for blood pressure lowering in PAD.158,166,167 An updated multisocietal guideline on the management of high blood pressure is anticipated in 2017. IIa A The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD.161,168,169

sen claudication symptoms or impair functional status in patients with PAD.163–165 There is no evidence that one class of antihypertensive medication or strategy is superior for blood pressure lowering in PAD.158,166,167 An updated multisocietal guideline on the management of high blood pressure is anticipated in 2017. IIa A The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD.161,168,169 See Online Data Supplement 17. The effect of ramipril versus placebo on cardiovascular events was studied in high-risk patients free of heart failure in the HOPE (Heart Outcomes Prevention Evaluation) trial.168,169 Patients were normotensive on average at the time of enrollment. In a subgroup of 4051 patients with PAD, ramipril reduced the risk of MI, stroke, or vascular death by 25%, similar to the efficacy in the entire study population.168,169 The efficacy was similar in patients with PAD with symptomatic disease and asymptomatic low ABI.168 ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) compared telmisartan, ramipril, and combination therapy in patients with cardiovascular disease, including PAD, and/or diabetes mellitus.161 All 3 treatments had similar cardiovascular event rates with higher rates of adverse events (including hypotension, syncope, and renal failure) in the combination-therapy group. The efficacy of telmisartan was similar in the subgroup of 3468 patients with PAD, which supports the use of angiotensin-receptor blockers as an alternative to angiotensin-converting enzyme inhibitors.161 The effect of angiotensin-receptor blockers in asymptomatic PAD has not been studied.

he combination-therapy group. The efficacy of telmisartan was similar in the subgroup of 3468 patients with PAD, which supports the use of angiotensin-receptor blockers as an alternative to angiotensin-converting enzyme inhibitors.161 The effect of angiotensin-receptor blockers in asymptomatic PAD has not been studied. 5.4. Smoking Cessation: Recommendations Recommendations for Smoking Cessation COR LOE Recommendations I A Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit.170–172 See Online Data Supplements 19 and 20. Tobacco use is a strong risk factor for the development and progression of PAD.173,174 Sparse evidence exists with regard to the association of novel tobacco product use, including electronic cigarettes, and PAD.175 Observational studies suggest that smoking cessation is associated with lower rates of cardiovascular ischemic events, limb-related events, bypass graft failure, amputation, and death in patients with PAD.172,176–178 Clinician advice increases quit rates, which supports simple provider-based measures as a component of smoking cessation programs.22,171,179 I A Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (ie, varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program.170,180–182

See Online Data Supplements 19 and 20. Tobacco use is a strong risk factor for the development and progression of PAD.173,174 Sparse evidence exists with regard to the association of novel tobacco product use, including electronic cigarettes, and PAD.175 Observational studies suggest that smoking cessation is associated with lower rates of cardiovascular ischemic events, limb-related events, bypass graft failure, amputation, and death in patients with PAD.172,176–178 Clinician advice increases quit rates, which supports simple provider-based measures as a component of smoking cessation programs.22,171,179 I A Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (ie, varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program.170,180–182 See Online Data Supplements 19 and 20. Coordinated smoking cessation interventions that include nonpharmacological and pharmacological approaches have the greatest efficacy. An RCT of a follow-up program and smoking cessation medications provided to hospitalized patients, including those with PAD, demonstrated a modest increase in quit rates.181 In an RCT of patients with PAD specifically, a comprehensive smoking cessation program combining counseling and pharmacological agents increased the rates of smoking cessation to 21.3%, compared with 6.8% with standard advice.170 Three pharmacological approaches (ie, varenicline, bupropion, and nicotine replacement therapy) used alone or in combination all increase smoking cessation rates.179,180,182 Two meta-analyses of RCTs of smoking cessation medications showed no evidence of increased cardiovascular event rates with nicotine replacement, bupropion, or varenicline.183,184 Sparse data suggest that electronic cigarettes have no benefit on smoking cessation rates.179

ll increase smoking cessation rates.179,180,182 Two meta-analyses of RCTs of smoking cessation medications showed no evidence of increased cardiovascular event rates with nicotine replacement, bupropion, or varenicline.183,184 Sparse data suggest that electronic cigarettes have no benefit on smoking cessation rates.179 I B-NR Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places.185,186 See Online Data Supplement 20. Passive smoke exposure has been associated with the development of PAD.186 Observational studies have shown lower cardiovascular and cerebrovascular event rates in the general population after enactment of smoke-free legislation.185 The effects of avoidance of passive smoke exposure on limb-related events are not known. 5.5. Glycemic Control: Recommendations Recommendations for Glycemic Control COR LOE Recommendations I C-EO Management of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team.

See Online Data Supplement 20. Passive smoke exposure has been associated with the development of PAD.186 Observational studies have shown lower cardiovascular and cerebrovascular event rates in the general population after enactment of smoke-free legislation.185 The effects of avoidance of passive smoke exposure on limb-related events are not known. 5.5. Glycemic Control: Recommendations Recommendations for Glycemic Control COR LOE Recommendations I C-EO Management of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team. N/A Diabetes mellitus is an important risk factor for the development of PAD.187 Furthermore, the presence of diabetes mellitus increases the risk of adverse outcomes among patients with PAD, including progression to CLI, amputation, and death.188,189 A comprehensive care plan for patients with PAD and diabetes mellitus is important and may include diet and weight management, pharmacotherapy for glycemic control and management of other cardiovascular risk factors, and foot care and ulcer prevention.25,190 Guidelines for glycemic control among patients with diabetes mellitus and atherosclerotic vascular disease have been previously published.25,29 Regular follow-up with and communication among the patient's healthcare providers, including vascular specialists and diabetes care providers (eg, primary care physicians, endocrinologists) constitute an important component of care for patients with PAD and diabetes mellitus. IIa B-NR Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes.191,192

N/A Diabetes mellitus is an important risk factor for the development of PAD.187 Furthermore, the presence of diabetes mellitus increases the risk of adverse outcomes among patients with PAD, including progression to CLI, amputation, and death.188,189 A comprehensive care plan for patients with PAD and diabetes mellitus is important and may include diet and weight management, pharmacotherapy for glycemic control and management of other cardiovascular risk factors, and foot care and ulcer prevention.25,190 Guidelines for glycemic control among patients with diabetes mellitus and atherosclerotic vascular disease have been previously published.25,29 Regular follow-up with and communication among the patient's healthcare providers, including vascular specialists and diabetes care providers (eg, primary care physicians, endocrinologists) constitute an important component of care for patients with PAD and diabetes mellitus. IIa B-NR Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes.191,192 See Online Data Supplement 22. In a cohort of 1974 participants with diabetes mellitus from the Strong Heart Study, compared with patients without PAD, patients with PAD and a Hg A1c level <6.5% had lower age-adjusted odds of major amputation compared to patients with PAD and hemoglobin A1c 6.5% to 9.5% and hemoglobin A1c >9.5%.188 Glycemic control is particularly important for patients with PAD and diabetes mellitus who have CLI. Single-center observational studies have demonstrated improved limb-related outcomes, including lower rates of major amputation and improved patency after infrapopliteal intervention, among patients with CLI who have more optimized glycemic control parameters compared with patients with inferior glycemic control.191,192

ingle-center observational studies have demonstrated improved limb-related outcomes, including lower rates of major amputation and improved patency after infrapopliteal intervention, among patients with CLI who have more optimized glycemic control parameters compared with patients with inferior glycemic control.191,192 5.6. Oral Anticoagulation: Recommendations Recommendations for Oral Anticoagulation COR LOE Recommendations IIb B-R The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain.193–195 See Online Data Supplements 23 and 24. Two RCTs evaluating the effectiveness of oral anticoagulation (warfarin) in improving lower extremity bypass patency demonstrated improved patency among the subgroup of patients with autogenous vein bypass grafts.193,194 However, a Cochrane systematic review showed no patency benefit with the use of anticoagulation compared with antiplatelet therapy.195 All RCTs and observational studies evaluating the effect of anticoagulants on bypass patency demonstrated increased bleeding complications associated with anticoagulant use. One RCT evaluating the effectiveness of oral anticoagulation (warfarin) in addition to aspirin in improving lower extremity bypass patency demonstrated improved patency in a subgroup of patients with 6-mm polytetrafluoroethylene (known as PTFE) bypass graft.196 Randomization to anticoagulation plus aspirin was associated with increased risk of death and major hemorrhage versus aspirin alone.

addition to aspirin in improving lower extremity bypass patency demonstrated improved patency in a subgroup of patients with 6-mm polytetrafluoroethylene (known as PTFE) bypass graft.196 Randomization to anticoagulation plus aspirin was associated with increased risk of death and major hemorrhage versus aspirin alone. III: Harm A Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.194,196–198 See Online Data Supplements 23 and 24 RCTs and observational studies have uniformly demonstrated that oral anticoagulation therapy aimed at decreasing major cardiovascular ischemic events provided no benefit and resulted in increased morbidity.194,196–198 In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial of patients with atherosclerotic vascular disease, including PAD, there was no difference in cardiovascular ischemic events among patients randomized to oral anticoagulation and antiplatelet therapy versus antiplatelet therapy alone.198 In addition, there was an increase in bleeding endpoints including life-threatening and intracranial bleeding.198 One RCT demonstrated increased death rate among patients randomized to warfarin plus aspirin versus aspirin alone after lower extremity bypass grafting.196 5.7. Cilostazol: Recommendation Recommendation for Cilostazol COR LOE Recommendation I A Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication.199,200

See Online Data Supplements 23 and 24 RCTs and observational studies have uniformly demonstrated that oral anticoagulation therapy aimed at decreasing major cardiovascular ischemic events provided no benefit and resulted in increased morbidity.194,196–198 In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial of patients with atherosclerotic vascular disease, including PAD, there was no difference in cardiovascular ischemic events among patients randomized to oral anticoagulation and antiplatelet therapy versus antiplatelet therapy alone.198 In addition, there was an increase in bleeding endpoints including life-threatening and intracranial bleeding.198 One RCT demonstrated increased death rate among patients randomized to warfarin plus aspirin versus aspirin alone after lower extremity bypass grafting.196 5.7. Cilostazol: Recommendation Recommendation for Cilostazol COR LOE Recommendation I A Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication.199,200 See Online Data Supplement 25. In a Cochrane review including 15 double-blind RCTs with a total of 3718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in cardiovascular deaths or QoL when compared with placebo.199 In 1 RCT, cilostazol was more effective than pentoxifylline or placebo.200 Side effects include headache, abnormal stool (diarrhea), dizziness, and palpitations. Cilostazol is contraindicated in patients with congestive heart failure.201 In 1 trial, 20% of patients discontinued cilostazol within 3 months.202

lacebo.199 In 1 RCT, cilostazol was more effective than pentoxifylline or placebo.200 Side effects include headache, abnormal stool (diarrhea), dizziness, and palpitations. Cilostazol is contraindicated in patients with congestive heart failure.201 In 1 trial, 20% of patients discontinued cilostazol within 3 months.202 5.8. Pentoxifylline: Recommendation Recommendation for Pentoxifylline COR LOE Recommendation III: No Benefit B-R Pentoxifylline is not effective for treatment of claudication.200,203 See Online Data Supplement 26. In a Cochrane review of 24 studies with 3377 participants, there was large variability in study design and results between individual studies, and therefore the review's effectiveness was unclear.203 Pentoxifylline was shown to be generally well tolerated.203 In a multicenter RCT of pentoxifylline, cilostazol, or placebo for patients with moderate-to-severe claudication, there was no difference between pentoxifylline and placebo in the primary endpoint of maximal walking distance.200 Therefore, pentoxifylline is not recommended as treatment for claudication. 5.9. Chelation Therapy: Recommendation Recommendation for Chelation Therapy COR LOE Recommendation III: No Benefit B-R Chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication.204 See Online Data Supplement 27. In a Cochrane review of 5 studies with 260 participants, chelation therapy showed no significant difference in symptoms (maximal and pain-free walking distance) compared with placebo.204 5.10. Homocysteine Lowering: Recommendation Recommendation for Homocysteine Lowering

III: No Benefit B-R Chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication.204 See Online Data Supplement 27. In a Cochrane review of 5 studies with 260 participants, chelation therapy showed no significant difference in symptoms (maximal and pain-free walking distance) compared with placebo.204 5.10. Homocysteine Lowering: Recommendation Recommendation for Homocysteine Lowering COR LOE Recommendation III: No Benefit B-R B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended.205–207 See Online Data Supplements 28 and 29. Although patients with PAD have been shown to have increased plasma homocysteine levels compared with patients without PAD, there is no evidence that B-complex vitamin supplementation improves clinical outcomes in patients with PAD.207 The HOPE-2 trial randomized 5522 patients with atherosclerotic vascular disease, including symptomatic PAD, or diabetes mellitus with additional risk factors to receive folic acid/vitamin B6/vitamin B12 or placebo.205,206 Despite lowering of homocysteine levels in the vitamin supplementation arm, there was no improvement in the primary endpoint of cardiovascular death, MI, or stroke. 5.11. Influenza Vaccination: Recommendation Recommendation for Influenza Vaccination COR LOE Recommendation I C-EO Patients with PAD should have an annual influenza vaccination.

See Online Data Supplements 28 and 29. Although patients with PAD have been shown to have increased plasma homocysteine levels compared with patients without PAD, there is no evidence that B-complex vitamin supplementation improves clinical outcomes in patients with PAD.207 The HOPE-2 trial randomized 5522 patients with atherosclerotic vascular disease, including symptomatic PAD, or diabetes mellitus with additional risk factors to receive folic acid/vitamin B6/vitamin B12 or placebo.205,206 Despite lowering of homocysteine levels in the vitamin supplementation arm, there was no improvement in the primary endpoint of cardiovascular death, MI, or stroke. 5.11. Influenza Vaccination: Recommendation Recommendation for Influenza Vaccination COR LOE Recommendation I C-EO Patients with PAD should have an annual influenza vaccination. See Online Data Supplements 30 and 31. Observational studies have demonstrated reduced cardiovascular event rates among patients with cardiovascular disease who have received an influenza vaccination.30 Two RCTs that enrolled patients with CAD demonstrated a benefit of an influenza vaccination on the prevention of cardiovascular events, particularly coronary ischemic events.208,209 Although these trials did not specifically enroll participants with PAD, a majority of patients with PAD also have CAD.30 On the basis of this evidence, an annual influenza vaccination is recommended as a component of medical therapy for patients with PAD.

ovascular events, particularly coronary ischemic events.208,209 Although these trials did not specifically enroll participants with PAD, a majority of patients with PAD also have CAD.30 On the basis of this evidence, an annual influenza vaccination is recommended as a component of medical therapy for patients with PAD. 6. Structured Exercise Therapy: Recommendations Structured exercise therapy is an important element of care for the patient with PAD. Components of structured exercise programs for PAD are outlined in Table 8. Recommendations for Structured Exercise Therapy COR LOE Recommendations I A In patients with claudication, a supervised exercise program is recommended to improve functional status and QoL and to reduce leg symptoms.36–38,40–46,48,210,211

6. Structured Exercise Therapy: Recommendations Structured exercise therapy is an important element of care for the patient with PAD. Components of structured exercise programs for PAD are outlined in Table 8. Recommendations for Structured Exercise Therapy COR LOE Recommendations I A In patients with claudication, a supervised exercise program is recommended to improve functional status and QoL and to reduce leg symptoms.36–38,40–46,48,210,211 See Online Data Supplement 32. The data supporting the efficacy of supervised exercise training as an initial treatment for claudication continue to develop and remain convincing, building on many earlier RCTs.40–46,48,210,211 Trials with long-term follow-up from 18 months37,38 to 7 years36 have demonstrated a persistent benefit of supervised exercise in patients with claudication. Data also support a benefit of supervised exercise for patients with symptomatic PAD and diabetes mellitus.212 The risk–benefit ratio for supervised exercise in PAD is favorable, with an excellent safety profile in patients screened for absolute contraindications to exercise such as exercise-limiting cardiovascular disease, amputation or wheelchair confinement, and other major comorbidities that would preclude exercise.36,39,49,213–216 Despite the health benefits associated with supervised exercise in patients with PAD, initiating and maintaining a high level of adherence remain challenging. Frequent contact with patients both when performing exercise in the supervised setting and at home has been somewhat effective in promoting retention.37,38

3–216 Despite the health benefits associated with supervised exercise in patients with PAD, initiating and maintaining a high level of adherence remain challenging. Frequent contact with patients both when performing exercise in the supervised setting and at home has been somewhat effective in promoting retention.37,38 I B-R A supervised exercise program should be discussed as a treatment option for claudication before possible revascularization.36–38 See Online Data Supplement 32. The CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) trial randomized patients with symptomatic aortoiliac PAD and showed comparable benefits for supervised exercise and stent revascularization at 6 and 18 months, with each therapy being superior to optimal medical care.37,38 Overall, the safety profile for supervised exercise was excellent. An RCT that compared 7-year effectiveness of supervised exercise or endovascular revascularization in patients with stable claudication with iliac or femoropopliteal disease found no differences in improved walking and QoL outcomes.36 Although more secondary interventions occurred in the exercise group, the total number of interventions was greater in the endovascular revascularization group. Collectively, these studies provide strong support for offering patients a supervised exercise program for reducing claudication symptoms and for improving functional status and QoL.

interventions occurred in the exercise group, the total number of interventions was greater in the endovascular revascularization group. Collectively, these studies provide strong support for offering patients a supervised exercise program for reducing claudication symptoms and for improving functional status and QoL. A 3-month RCT that compared percutaneous transluminal angioplasty (PTA), supervised exercise, and combined treatment for claudication found that both supervised exercise and PTA improved clinical and QoL outcomes, whereas PTA plus supervised exercise produced greater benefits than either therapy alone.217 The ERASE (Endovascular Revascularization and Supervised Exercise) study randomized participants with claudication to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group.218 Collectively, these studies support the continued provision of supervised exercise to patients with claudication, whether as a monotherapy or combined with revascularization. IIa A In patients with PAD, a structured community- or home-based exercise program with behavioral change techniques can be beneficial to improve walking ability and functional status.49,88,94,213

A 3-month RCT that compared percutaneous transluminal angioplasty (PTA), supervised exercise, and combined treatment for claudication found that both supervised exercise and PTA improved clinical and QoL outcomes, whereas PTA plus supervised exercise produced greater benefits than either therapy alone.217 The ERASE (Endovascular Revascularization and Supervised Exercise) study randomized participants with claudication to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group.218 Collectively, these studies support the continued provision of supervised exercise to patients with claudication, whether as a monotherapy or combined with revascularization. IIa A In patients with PAD, a structured community- or home-based exercise program with behavioral change techniques can be beneficial to improve walking ability and functional status.49,88,94,213 See Online Data Supplement 32. Unstructured community-based or home-based walking programs that consist of providing general recommendations to patients with claudication to simply walk more are not efficacious.50 Studies supporting structured community- or home-based programs for patients with symptomatic PAD (claudication and/or leg symptoms atypical for claudication) are more recent than studies supporting supervised exercise programs, and have provided strong evidence in support of the community- or home-based approach.47,49,51,88,94,213 For example, the GOALS (Group Oriented Arterial Leg Study) trial94 included patients with confirmed PAD with and without claudication (atypical lower extremity symptoms or no symptoms) and showed increases in several parameters of functional status for both of these patient cohort subgroups, versus nonexercising controls, after 6 months,88 with improvement maintained at 12 months.94

4 included patients with confirmed PAD with and without claudication (atypical lower extremity symptoms or no symptoms) and showed increases in several parameters of functional status for both of these patient cohort subgroups, versus nonexercising controls, after 6 months,88 with improvement maintained at 12 months.94 As with supervised exercise programs, despite proven benefit, initiating and maintaining a high level of adherence to community- or home-based exercise programs remains challenging. Studies that have incorporated behavioral change techniques, such as health coaching and activity tracking used in supervised settings, appear to reduce attrition and promote higher levels of adherence, thereby improving functional and QoL outcomes, both short term and long term.49,88,94 IIa A In patients with claudication, alternative strategies of exercise therapy, including upper-body ergometry, cycling, and pain-free or low-intensity walking that avoids moderate-to-maximum claudication while walking, can be beneficial to improve walking ability and functional status.39,215,219,220

As with supervised exercise programs, despite proven benefit, initiating and maintaining a high level of adherence to community- or home-based exercise programs remains challenging. Studies that have incorporated behavioral change techniques, such as health coaching and activity tracking used in supervised settings, appear to reduce attrition and promote higher levels of adherence, thereby improving functional and QoL outcomes, both short term and long term.49,88,94 IIa A In patients with claudication, alternative strategies of exercise therapy, including upper-body ergometry, cycling, and pain-free or low-intensity walking that avoids moderate-to-maximum claudication while walking, can be beneficial to improve walking ability and functional status.39,215,219,220 See Online Data Supplements 32 and 33. Protocols for exercise therapy for PAD traditionally have recommended intermittent walking bouts to moderate or higher pain levels interspersed with short periods of rest. Although these protocols are efficacious, intolerance of pain may lead to poor exercise adherence. An increasing number of studies have shown that modalities of exercise that avoid claudication or walking performed at intensities that are pain free or produce only mild levels of claudication can achieve health benefits comparable to walking at moderate or higher levels of claudication pain.39,41,215,219–221 7. Minimizing Tissue Loss in Patients with PAD: Recommendations Recommendations for Minimizing Tissue Loss in Patients With PAD COR LOE Recommendations

See Online Data Supplements 32 and 33. Protocols for exercise therapy for PAD traditionally have recommended intermittent walking bouts to moderate or higher pain levels interspersed with short periods of rest. Although these protocols are efficacious, intolerance of pain may lead to poor exercise adherence. An increasing number of studies have shown that modalities of exercise that avoid claudication or walking performed at intensities that are pain free or produce only mild levels of claudication can achieve health benefits comparable to walking at moderate or higher levels of claudication pain.39,41,215,219–221 7. Minimizing Tissue Loss in Patients with PAD: Recommendations Recommendations for Minimizing Tissue Loss in Patients With PAD COR LOE Recommendations I C-LD Patients with PAD and diabetes mellitus should be counseled about self–foot examination and healthy foot behaviors.222,223 See Online Data Supplement 34. Some RCTs have suggested that patient education may help reduce the incidence of serious foot ulcers and lower extremity amputations, but the quality of evidence supporting patient education is low.222 Educational efforts generally include teaching patients about healthy foot behaviors (eg, daily inspection of feet, wearing of shoes and socks; avoidance of barefoot walking), the selection of proper footwear, and the importance of seeking medical attention for new foot problems.223 Educational efforts are especially important for patients with PAD who have diabetes mellitus with peripheral neuropathy.

(eg, daily inspection of feet, wearing of shoes and socks; avoidance of barefoot walking), the selection of proper footwear, and the importance of seeking medical attention for new foot problems.223 Educational efforts are especially important for patients with PAD who have diabetes mellitus with peripheral neuropathy. I C-LD In patients with PAD, prompt diagnosis and treatment of foot infection are recommended to avoid amputation.224–228

(eg, daily inspection of feet, wearing of shoes and socks; avoidance of barefoot walking), the selection of proper footwear, and the importance of seeking medical attention for new foot problems.223 Educational efforts are especially important for patients with PAD who have diabetes mellitus with peripheral neuropathy. I C-LD In patients with PAD, prompt diagnosis and treatment of foot infection are recommended to avoid amputation.224–228 See Online Data Supplement 34. Foot infections (infection of any of the structures distal to the malleoli) may include cellulitis, abscess, fasciitis, tenosynovitis, septic joint space infection, and osteomyelitis. Studies have investigated the accuracy of physical findings for identification of infection and determining infection severity and risk of amputation.224–226 Because of the consequences associated with untreated foot infection—especially in the presence of PAD—clinicians should maintain a high index of suspicion.228 It is also recognized that the presence of diabetes mellitus with peripheral neuropathy and PAD may make the presentation of foot infection more subtle than in patients without these problems. Foot infection should be suspected if the patient presents with local pain or tenderness; periwound erythema; periwound edema, induration or fluctuance; pretibial edema; any discharge (especially purulent); foul odor; visible bone or a wound that probes-to-bone; or signs of a systemic inflammatory response (including temperature >38°C or <36°C, heart rate >90/min, respiratory rate >20/min or Paco2 <32 mm Hg, white blood cell count >12 000 or <4000/mcL or >10% immature forms).226 Probe-to-bone test is moderately predictive for osteomyelitis but is not pathognomonic.227

to-bone; or signs of a systemic inflammatory response (including temperature >38°C or <36°C, heart rate >90/min, respiratory rate >20/min or Paco2 <32 mm Hg, white blood cell count >12 000 or <4000/mcL or >10% immature forms).226 Probe-to-bone test is moderately predictive for osteomyelitis but is not pathognomonic.227 IIa C-LD In patients with PAD and signs of foot infection, prompt referral to an interdisciplinary care team (Table 9) can be beneficial.228–230 See Online Data Supplement 34. The EuroDIALE (European Study Group on Diabetes and the Lower Extremity) study demonstrated that the presence of both PAD and foot infection conferred a nearly 3-fold higher risk of leg amputation than either infection or PAD alone.228 The treatment of deep soft-tissue infection typically requires prompt surgical drainage; vascular imaging and expeditious revascularization generally follow. Experienced clinical teams have reported very good outcomes when this is performed in a coordinated and timely fashion.229,230 Previous groups have described various combinations of functions of interdisciplinary care teams (See Online Data Supplement 34a for a complete list of functions). See Section 9.2 for recommendations related to the role of the interdisciplinary care team in wound healing therapies for CLI. IIa C-EO It is reasonable to counsel patients with PAD without diabetes mellitus about self–foot examination and healthy foot behaviors.

See Online Data Supplement 34. The EuroDIALE (European Study Group on Diabetes and the Lower Extremity) study demonstrated that the presence of both PAD and foot infection conferred a nearly 3-fold higher risk of leg amputation than either infection or PAD alone.228 The treatment of deep soft-tissue infection typically requires prompt surgical drainage; vascular imaging and expeditious revascularization generally follow. Experienced clinical teams have reported very good outcomes when this is performed in a coordinated and timely fashion.229,230 Previous groups have described various combinations of functions of interdisciplinary care teams (See Online Data Supplement 34a for a complete list of functions). See Section 9.2 for recommendations related to the role of the interdisciplinary care team in wound healing therapies for CLI. IIa C-EO It is reasonable to counsel patients with PAD without diabetes mellitus about self–foot examination and healthy foot behaviors. N/A Although there are limited data to support patient education about self–foot examination and foot care for patients with diabetes mellitus, there are no data that have evaluated this practice in a population of patients with PAD but without diabetes mellitus. Nonetheless, this is a very low-risk intervention with potential for benefit. Educational efforts generally include teaching patients about healthy foot behaviors (eg, daily inspection of feet; foot care and hygiene, including appropriate toenail cutting strategies; avoidance of barefoot walking), the selection of appropriately fitting shoes, and the importance of seeking medical attention for new foot problems.223

generally include teaching patients about healthy foot behaviors (eg, daily inspection of feet; foot care and hygiene, including appropriate toenail cutting strategies; avoidance of barefoot walking), the selection of appropriately fitting shoes, and the importance of seeking medical attention for new foot problems.223 IIa C-EO Biannual foot examination by a clinician is reasonable for patients with PAD and diabetes mellitus. N/A A history of foot ulcers, foot infections, or amputation identifies patients with a very high (>10%) yearly incidence of recurrent ulcers.231 Examination includes a visual inspection for foot ulcers (full-thickness epithelial defects) and structural (bony) deformities, monofilament testing for sensory neuropathy, and palpation for pedal pulses. 8. Revascularization for Claudication An individualized approach to revascularization for claudication is recommended for each patient to optimize outcome. Revascularization is but one component of care for the patient with claudication, as each patient should have a customized care plan that also includes medical therapy (Section 5), structured exercise therapy (Section 6), and care to minimize tissue loss (Section 7). If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both.

t also includes medical therapy (Section 5), structured exercise therapy (Section 6), and care to minimize tissue loss (Section 7). If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both. Because of the variability of ischemic limb symptoms and impact of these symptoms on functional status and QoL, patients should be selected for revascularization on the basis of severity of their symptoms. Factors to consider include a significant disability as assessed by the patient, adequacy of response to medical and structured exercise therapy, status of comorbid conditions, and a favorable risk–benefit ratio. Patient preferences and goals of care are important considerations in the evaluation for revascularization. The revascularization strategy should have a reasonable likelihood of providing durable relief of symptoms. A general recommendation for revascularization as a treatment option for claudication is provided below followed by specific recommendations for endovascular (Section 8.1.1) and surgical (Section 8.1.2) procedures if a revascularization strategy is undertaken. 8.1. Revascularization for Claudication: Recommendation Recommendation for Revascularization for Claudication COR LOE Recommendation IIa A Revascularization is a reasonable treatment option for the patient with lifestyle-limiting claudication with an inadequate response to GDMT.12,37,38,232,233

Because of the variability of ischemic limb symptoms and impact of these symptoms on functional status and QoL, patients should be selected for revascularization on the basis of severity of their symptoms. Factors to consider include a significant disability as assessed by the patient, adequacy of response to medical and structured exercise therapy, status of comorbid conditions, and a favorable risk–benefit ratio. Patient preferences and goals of care are important considerations in the evaluation for revascularization. The revascularization strategy should have a reasonable likelihood of providing durable relief of symptoms. A general recommendation for revascularization as a treatment option for claudication is provided below followed by specific recommendations for endovascular (Section 8.1.1) and surgical (Section 8.1.2) procedures if a revascularization strategy is undertaken. 8.1. Revascularization for Claudication: Recommendation Recommendation for Revascularization for Claudication COR LOE Recommendation IIa A Revascularization is a reasonable treatment option for the patient with lifestyle-limiting claudication with an inadequate response to GDMT.12,37,38,232,233 See Online Data Supplements 35 and 36. A minority of patients with claudication (estimated at <10% to 15% over 5 years or more) will progress to CLI.234–237 Therefore, the role of revascularization in claudication is improvement in claudication symptoms and functional status, and consequently in QoL, rather than limb salvage. Revascularization is reasonable when the patient who is being treated with GDMT (including structured exercise therapy) presents with persistent lifestyle-limiting claudication.12,37,38,232,233 Lifestyle-limiting claudication is defined by the patient rather than by any test. It includes impairment of activities of daily living and/ or vocational and/or recreational activities due to claudication. There should be clear discussion with the patient about expected risks and benefits of revascularization, as well as discussion of the durability of proposed procedures.

t rather than by any test. It includes impairment of activities of daily living and/ or vocational and/or recreational activities due to claudication. There should be clear discussion with the patient about expected risks and benefits of revascularization, as well as discussion of the durability of proposed procedures. 8.1.1. Endovascular Revascularization for Claudication: Recommendations Endovascular techniques to treat claudication include balloon dilation (angioplasty), stents, and atherectomy. These techniques continue to involve and now include covered stents, drug-eluting stents (DES), cutting balloons, and drug-coated balloons. The technique chosen for endovascular treatment is related to lesion characteristics (eg, anatomic location, lesion length, degree of calcification) and operator experience. Assessment of the appropriateness of specific endovascular techniques for specific lesions for the treatment of claudication is beyond the scope of this document.

osen for endovascular treatment is related to lesion characteristics (eg, anatomic location, lesion length, degree of calcification) and operator experience. Assessment of the appropriateness of specific endovascular techniques for specific lesions for the treatment of claudication is beyond the scope of this document. Revascularization is performed on lesions that are deemed to be hemodynamically significant, and stenoses selected for endovascular treatment should have a reasonable likelihood of limiting perfusion to the distal limb. Stenoses of 50% to 75% diameter by angiography may not be hemodynamically significant, and resting or provoked intravascular pressure measurements may be used to determine whether lesions are significant.238,239 Multiple RCTs have compared endovascular procedures to various combinations of medical treatment with or without supervised or unsupervised exercise programs.12,37,38,217,232,233,240–251 These trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels. Recommendations for Endovascular Revascularization for Claudication COR LOE Recommendations I A Endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease.12,37,38,232,240,242,246

Revascularization is performed on lesions that are deemed to be hemodynamically significant, and stenoses selected for endovascular treatment should have a reasonable likelihood of limiting perfusion to the distal limb. Stenoses of 50% to 75% diameter by angiography may not be hemodynamically significant, and resting or provoked intravascular pressure measurements may be used to determine whether lesions are significant.238,239 Multiple RCTs have compared endovascular procedures to various combinations of medical treatment with or without supervised or unsupervised exercise programs.12,37,38,217,232,233,240–251 These trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels. Recommendations for Endovascular Revascularization for Claudication COR LOE Recommendations I A Endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease.12,37,38,232,240,242,246 See Online Data Supplements 35 and 36. Two separate systematic analyses that included RCTs that enrolled patients with aortoiliac disease reported that endovascular treatment of claudication improved walking parameters and QoL.11,12,233 The CLEVER trial enrolled only patients with aortoiliac disease and compared endovascular therapy to supervised exercise therapy and to medications alone.37,38 At 6-month follow-up, both the endovascular therapy and supervised exercise groups had improved peak walking time compared with medication alone, with a greater improvement in the supervised exercise group.37 By 18 months, there was no significant difference between the endovascular therapy and supervised exercise groups, with a sustained benefit versus medication alone.38 Other RCTs that included patients with aortoiliac disease have shown QoL, as assessed by questionnaires and time to onset of claudication, may be superior with endovascular treatment in combination with a medical and an exercise treatment plan, compared versus medical treatment alone.232,233,246 The ERASE trial randomized patients with claudication and aortoiliac (as well as femoropopliteal) disease to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group.218 The long-term comparative efficacy of endovascular revascularization versus supervised exercise therapy and medical therapy compared to supervised exercise therapy and medical therapy without revascularization for aortoiliac disease is unknown.

th-related QoL, with greater improvements in the combined-therapy group.218 The long-term comparative efficacy of endovascular revascularization versus supervised exercise therapy and medical therapy compared to supervised exercise therapy and medical therapy without revascularization for aortoiliac disease is unknown. IIa B-R Endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease.217,232,243–245,250,251

th-related QoL, with greater improvements in the combined-therapy group.218 The long-term comparative efficacy of endovascular revascularization versus supervised exercise therapy and medical therapy compared to supervised exercise therapy and medical therapy without revascularization for aortoiliac disease is unknown. IIa B-R Endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease.217,232,243–245,250,251 See Online Data Supplement 35. Multiple RCTs have demonstrated short-term efficacy with endovascular treatment of femoropopliteal disease for claudication versus supervised exercise training or medical therapy, with benefit that diminishes by 1 year.217,232,240–246,250,251 Two separate systematic reviews that included RCTs that enrolled patients with femoropopliteal disease, reported that endovascular treatment of claudication improved walking parameters and QoL.11,12,233 The durability of endovascular treatment for claudication is directly related to vessel patency. Long-term patency is greater in the iliac artery than in the femoropopliteal segment. Furthermore, durability is diminished with greater lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poor-quality runoff, diabetes mellitus, chronic kidney disease, renal failure, and smoking.252–255 The choice of endovascular therapy as a revascularization approach for claudication due to femoropopliteal disease therefore should include a discussion of outcomes, addressing the risk of restenosis and repeat intervention, particularly for lesions with poor likelihood of long-term durability.

ure, and smoking.252–255 The choice of endovascular therapy as a revascularization approach for claudication due to femoropopliteal disease therefore should include a discussion of outcomes, addressing the risk of restenosis and repeat intervention, particularly for lesions with poor likelihood of long-term durability. IIb C-LD The usefulness of endovascular procedures as a revascularization option for patients with claudication due to isolated infrapopliteal artery disease is unknown.256–258 See Online Data Supplement 35. Isolated infrapopliteal disease is unlikely to cause claudication. Incidence of in-stent restenosis is high and long-term benefit lacking with bare-metal stenting of the infrapopliteal arteries.256 Studies that have enrolled patients with claudication as well as CLI have demonstrated a benefit of DES versus bare-metal stents or versus drug-coated balloons for revascularization of infrapopliteal lesions.257,258 However, these differences were mainly for patency and restenosis endpoints, and neither of these studies included patient-oriented outcomes, such as walking function or QoL parameters. Additional efficacy data on the use of infrapopliteal drug-coated balloon or DES for the treatment of claudication are likely to be published in the near future. III: Harm B-NR Endovascular procedures should not be performed in patients with PAD solely to prevent progression to CLI.234–237,259–261

See Online Data Supplement 35. Isolated infrapopliteal disease is unlikely to cause claudication. Incidence of in-stent restenosis is high and long-term benefit lacking with bare-metal stenting of the infrapopliteal arteries.256 Studies that have enrolled patients with claudication as well as CLI have demonstrated a benefit of DES versus bare-metal stents or versus drug-coated balloons for revascularization of infrapopliteal lesions.257,258 However, these differences were mainly for patency and restenosis endpoints, and neither of these studies included patient-oriented outcomes, such as walking function or QoL parameters. Additional efficacy data on the use of infrapopliteal drug-coated balloon or DES for the treatment of claudication are likely to be published in the near future. III: Harm B-NR Endovascular procedures should not be performed in patients with PAD solely to prevent progression to CLI.234–237,259–261 See Online Data Supplements 36 and 38. There are no data to support a practice paradigm of performing endovascular procedures on patients with PAD for the purpose of preventing progression of claudication symptoms to CLI. Reported rates of amputation or progression to CLI from prospective cohort studies of patients with claudication are <10% to 15% over 5 years or more, and increased mortality rate associated with claudication is usually the result of cardiovascular events rather than limb-related events.234–237,262 Similarly, there are no data to support revascularization in patients with asymptomatic PAD. Procedural risks include bleeding, renal failure from contrast-induced nephropathy, and the possibility of adverse limb outcomes.259–261 Therefore, the known risks of endovascular procedures outweigh any hypothetical benefit of preventing progression from asymptomatic PAD or claudication to CLI.

with asymptomatic PAD. Procedural risks include bleeding, renal failure from contrast-induced nephropathy, and the possibility of adverse limb outcomes.259–261 Therefore, the known risks of endovascular procedures outweigh any hypothetical benefit of preventing progression from asymptomatic PAD or claudication to CLI. 8.1.2. Surgical Revascularization for Claudication: Recommendations Recommendations for Surgical Revascularization for Claudication COR LOE Recommendations I A When surgical revascularization is performed, bypass to the popliteal artery with autogenous vein is recommended in preference to prosthetic graft material.263–271

with asymptomatic PAD. Procedural risks include bleeding, renal failure from contrast-induced nephropathy, and the possibility of adverse limb outcomes.259–261 Therefore, the known risks of endovascular procedures outweigh any hypothetical benefit of preventing progression from asymptomatic PAD or claudication to CLI. 8.1.2. Surgical Revascularization for Claudication: Recommendations Recommendations for Surgical Revascularization for Claudication COR LOE Recommendations I A When surgical revascularization is performed, bypass to the popliteal artery with autogenous vein is recommended in preference to prosthetic graft material.263–271 See Online Data Supplements 37 and 38. The superficial femoral and proximal popliteal arteries are the most common anatomic sites of stenosis or occlusion among individuals with claudication. Femoral-popliteal bypass is therefore one of the most common surgical procedures for claudication and may be performed under general or regional anesthesia. The type of conduit and site of popliteal artery anastomosis (above versus below knee) are major determinants of outcomes associated with femoral-popliteal bypass. Systematic reviews and meta-analyses have identified a clear and consistent primary patency benefit for autogenous vein versus to prosthetic grafts for popliteal artery bypass.270,271 Prosthetic grafts to the popliteal artery above the knee have reduced patency rates and increased rates of repeat intervention.263,266,269,272 Sparse evidence suggests a long-term patency advantage for Dacron over polytetrafluoroethylene (known as PTFE) graft for above-knee bypass,270 although this finding has not been consistently demonstrated in all RCTs.266,273,274

e knee have reduced patency rates and increased rates of repeat intervention.263,266,269,272 Sparse evidence suggests a long-term patency advantage for Dacron over polytetrafluoroethylene (known as PTFE) graft for above-knee bypass,270 although this finding has not been consistently demonstrated in all RCTs.266,273,274 IIa B-NR Surgical procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication with inadequate response to GDMT, acceptable perioperative risk, and technical factors suggesting advantages over endovascular procedures.232,265,275–277

e knee have reduced patency rates and increased rates of repeat intervention.263,266,269,272 Sparse evidence suggests a long-term patency advantage for Dacron over polytetrafluoroethylene (known as PTFE) graft for above-knee bypass,270 although this finding has not been consistently demonstrated in all RCTs.266,273,274 IIa B-NR Surgical procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication with inadequate response to GDMT, acceptable perioperative risk, and technical factors suggesting advantages over endovascular procedures.232,265,275–277 See Online Data Supplements 37 and 38. Systematic reviews have concluded that surgical procedures are an effective treatment for claudication and have a positive impact on QoL and walking parameters but have identified sparse evidence supporting the effectiveness of surgery compared with other treatments.11,233,278,279 Although symptom and patency outcomes for surgical interventions may be superior versus less invasive endovascular treatments for specific patients, surgical interventions are also associated with greater risk of adverse perioperative events.280–286 Treatment selection should therefore be individualized on the basis of the patient's goals, perioperative risk, and anticipated benefit. Surgical procedures for claudication are usually reserved for individuals who a) do not derive adequate benefit from nonsurgical therapy, b) have arterial anatomy favorable to obtaining a durable result with surgery, and c) have acceptable risk of perioperative adverse events. Acceptable risk is defined by the individual patient and provider on the basis of symptom severity, comorbid conditions, and appropriate GDMT risk evaluation. Guidelines for the evaluation and management of patients undergoing noncardiac surgery, including vascular surgical procedures, have been previously published.21

Acceptable risk is defined by the individual patient and provider on the basis of symptom severity, comorbid conditions, and appropriate GDMT risk evaluation. Guidelines for the evaluation and management of patients undergoing noncardiac surgery, including vascular surgical procedures, have been previously published.21 III: Harm B-R Femoral-tibial artery bypasses with prosthetic graft material should not be used for the treatment of claudication.287–289 See Online Data Supplement 37. Bypasses to the tibial arteries with prosthetic material for treatment of claudication should be avoided because of very high rates of graft failure and amputation.287–289 III: Harm B-NR Surgical procedures should not be performed in patients with PAD solely to prevent progression to CLI.234–237,262 See Online Data Supplements 37 and 38. Claudication does not commonly progress to CLI. Reported rates of amputation or progression to CLI from prospective cohort studies of patients with claudication are <10% to 15% for 5 years or more, and increased mortality rate associated with claudication is usually the result of cardiovascular events rather than limb-related events.234–237,262 Surgical intervention should not be performed primarily to prevent disease progression, given the risk of adverse perioperative events without potential for significant benefit. Similarly, there are no data to support surgical revascularization in patients with asymptomatic PAD to prevent progression to CLI.

34–237,262 Surgical intervention should not be performed primarily to prevent disease progression, given the risk of adverse perioperative events without potential for significant benefit. Similarly, there are no data to support surgical revascularization in patients with asymptomatic PAD to prevent progression to CLI. 9. Management of CLI Patients with CLI are at increased risk of amputation and major cardiovascular ischemic events. Care of the patient with CLI includes evaluation for revascularization and wound healing therapies, with the objective to minimize tissue loss, completely heal wounds, and preserve a functional foot. Medical therapy to prevent cardiovascular ischemic events is also an important component of care for the patient with CLI (Section 5). 9.1. Revascularization for CLI: Recommendations Recommendation for Revascularization for CLI COR LOE Recommendation I B-NR In patients with CLI, revascularization should be performed when possible to minimize tissue loss.290

9. Management of CLI Patients with CLI are at increased risk of amputation and major cardiovascular ischemic events. Care of the patient with CLI includes evaluation for revascularization and wound healing therapies, with the objective to minimize tissue loss, completely heal wounds, and preserve a functional foot. Medical therapy to prevent cardiovascular ischemic events is also an important component of care for the patient with CLI (Section 5). 9.1. Revascularization for CLI: Recommendations Recommendation for Revascularization for CLI COR LOE Recommendation I B-NR In patients with CLI, revascularization should be performed when possible to minimize tissue loss.290 See Online Data Supplement 39. Patients with CLI are at high risk of major cardiovascular ischemic events, as well as nonhealing wounds and major amputation. In a systematic review of 13 studies of patients with CLI who did not receive revascularization, which included patients enrolled in medical and angiogenic therapy trials, there was a 22% all-cause mortality rate and a 22% rate of major amputation at a median follow-up of 12 months.290 The goal of surgical or endovascular revascularization is to provide in-line blood flow to the foot through at least 1 patent artery, which will help decrease ischemic pain and allow healing of any wounds, while preserving a functional limb. Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing.15–17 Revascularization is not warranted in the setting of a nonviable limb.

gh at least 1 patent artery, which will help decrease ischemic pain and allow healing of any wounds, while preserving a functional limb. Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing.15–17 Revascularization is not warranted in the setting of a nonviable limb. I C-EO An evaluation for revascularization options should be performed by an interdisciplinary care team (Table 9) before amputation in the patient with CLI. N/A Patients with CLI should be evaluated by an interdisciplinary care team. Before amputation, evaluation generally includes imaging for assessment of revascularization options (eg, duplex ultrasound, CTA, MRA, or catheter-based angiogram). The objective of this strategy is to minimize tissue loss and preserve a functional limb with revascularization. 9.1.1. Endovascular Revascularization for CLI: Recommendations Recommendations for Endovascular Revascularization for CLI COR LOE Recommendations I B-R Endovascular procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.292,293

N/A Patients with CLI should be evaluated by an interdisciplinary care team. Before amputation, evaluation generally includes imaging for assessment of revascularization options (eg, duplex ultrasound, CTA, MRA, or catheter-based angiogram). The objective of this strategy is to minimize tissue loss and preserve a functional limb with revascularization. 9.1.1. Endovascular Revascularization for CLI: Recommendations Recommendations for Endovascular Revascularization for CLI COR LOE Recommendations I B-R Endovascular procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.292,293 See Online Data Supplement 39. The technique chosen for endovascular treatment of CLI is related to anatomic location of lesions, lesion characteristics, and operator experience. Revascularization is performed on hemodynamically significant stenoses that are likely to be limiting blood flow to the limb. For stenoses of 50% to 75%, where the hemodynamic significance is unclear, intravascular pressure measurements may be used to determine hemodynamic significance.294 The BASIL (Bypass versus Angioplasty in Severe Ischemia of the Leg) RCT demonstrated that endovascular revascularization is an effective option for patients with CLI as compared with open surgery.292,293 The primary endpoint of amputation-free survival was the same in the endovascular and surgical arms. Of note, the endovascular arm used only PTA.292,293 Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing.15–17 Table 10 addresses factors that may prompt an endovascular versus surgical approach to the patient with CLI.

he same in the endovascular and surgical arms. Of note, the endovascular arm used only PTA.292,293 Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing.15–17 Table 10 addresses factors that may prompt an endovascular versus surgical approach to the patient with CLI. IIa C-LD A staged approach to endovascular procedures is reasonable in patients with ischemic rest pain.295,296 N/A For patients with multilevel disease who suffer from ischemic rest pain, in-flow lesions are generally addressed first.295,296 Depending on procedural characteristics, including contrast volume used, radiation exposure, and procedure time, out-flow lesions can be addressed in the same setting or at a later time if symptoms persist. This strategy for ischemic rest pain is distinct from the strategy recommended for CLI in the patient with a nonhealing wound or gangrene. In that scenario, restoration of direct in-line flow to the foot is essential for wound healing. IIa B-R Evaluation of lesion characteristics can be useful in selecting the endovascular approach for CLI.297,298

N/A For patients with multilevel disease who suffer from ischemic rest pain, in-flow lesions are generally addressed first.295,296 Depending on procedural characteristics, including contrast volume used, radiation exposure, and procedure time, out-flow lesions can be addressed in the same setting or at a later time if symptoms persist. This strategy for ischemic rest pain is distinct from the strategy recommended for CLI in the patient with a nonhealing wound or gangrene. In that scenario, restoration of direct in-line flow to the foot is essential for wound healing. IIa B-R Evaluation of lesion characteristics can be useful in selecting the endovascular approach for CLI.297,298 See Online Data Supplement 39. The lesion characteristics to consider include length, anatomic location, and extent of occlusive disease. For example, if an adequate angioplasty result can be achieved with PTA alone for short (<10 cm) stenoses in the femoropopliteal segment, then stent placement is not necessary.297,298 Presence of thrombosis or calcification at the lesion site will also affect the endovascular approach. In general, the advantages of DES and drug-coated balloons over PTA alone or bare-metal stents are more consistent in the femoropopliteal segment than for infrapopliteal interventions.257,258,299–309 However, these differences are mainly for patency, restenosis, and repeat-revascularization endpoints. Most studies were underpowered or did not examine other patient-oriented outcomes, such as amputation or wound healing in CLI. Endovascular techniques continue to evolve rapidly, and there has been limited literature comparing techniques with regard to clinically significant outcomes, such as amputation or wound healing.

st studies were underpowered or did not examine other patient-oriented outcomes, such as amputation or wound healing in CLI. Endovascular techniques continue to evolve rapidly, and there has been limited literature comparing techniques with regard to clinically significant outcomes, such as amputation or wound healing. IIb B-NR Use of angiosome-directed endovascular therapy may be reasonable for patients with CLI and nonhealing wounds or gangrene.310–319

st studies were underpowered or did not examine other patient-oriented outcomes, such as amputation or wound healing in CLI. Endovascular techniques continue to evolve rapidly, and there has been limited literature comparing techniques with regard to clinically significant outcomes, such as amputation or wound healing. IIb B-NR Use of angiosome-directed endovascular therapy may be reasonable for patients with CLI and nonhealing wounds or gangrene.310–319 See Online Data Supplements 39 and 40. During the past decade, the goal of care with regard to endovascular therapy for the treatment of nonhealing wounds due to CLI has been establishment of direct in-line blood flow to the affected limb. The angiosome concept has also been described in the literature in relation to the treatment of nonhealing wounds. Angiosome-directed treatment entails establishing direct blood flow to the infrapopliteal artery directly responsible for perfusing the region of the leg or foot with the nonhealing wound. Multiple retrospective studies and 1 small nonrandomized prospective study assessing the efficacy of this concept have been published.119,310–321 Meta-analyses of these studies found improved wound healing and limb salvage with angiosome-guided therapy but cautioned that the quality of the evidence was low.322,323 Although the angiosome concept is theoretically satisfying, randomized data comparing the establishment of in-line flow versus angiosome-guided therapy have yet to be published. Furthermore, there is no evidence yet to demonstrate the potential benefit of treating additional infrapopliteal arteries once in-line flow has been established in one artery, regardless of angiosome. Important considerations with regard to angiosome-guided therapy include the potential for longer procedural times, more contrast exposure, and more technically complex procedures. The impact of all these factors needs to be weighed against the likelihood of a technically successful procedure providing hypothetical added benefit over the establishment of in-line blood flow.

therapy include the potential for longer procedural times, more contrast exposure, and more technically complex procedures. The impact of all these factors needs to be weighed against the likelihood of a technically successful procedure providing hypothetical added benefit over the establishment of in-line blood flow. 9.1.2. Surgical Revascularization for CLI: Recommendations Recommendations for Surgical Revascularization for CLI COR LOE Recommendations I A When surgery is performed for CLI, bypass to the popliteal or infrapopliteal arteries (ie, tibial, pedal) should be constructed with suitable autogenous vein.263,266,269,272 See Online Data Supplement 37. Many large RCTs have demonstrated that bypasses above the knee should be autogenous vein either reversed or in situ vein.263,266,269,272 There are large single-center trials showing the efficacy of autogenous vein to distal tibial vessels.324,325 In addition, composite sequential femoropopliteal-tibial bypass and bypass to an isolated popliteal arterial segment that has collateral out flow to the foot are both acceptable methods of revascularization and should be considered when no other form of bypass with adequate autogenous conduit is possible.326,327 I C-LD Surgical procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.328–330

See Online Data Supplement 37. Many large RCTs have demonstrated that bypasses above the knee should be autogenous vein either reversed or in situ vein.263,266,269,272 There are large single-center trials showing the efficacy of autogenous vein to distal tibial vessels.324,325 In addition, composite sequential femoropopliteal-tibial bypass and bypass to an isolated popliteal arterial segment that has collateral out flow to the foot are both acceptable methods of revascularization and should be considered when no other form of bypass with adequate autogenous conduit is possible.326,327 I C-LD Surgical procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.328–330 See Online Data Supplement 42. In patients presenting with nonhealing ulcers or gangrene, surgical procedures should be performed to establish in-line blood flow to the foot.328–330 Table 10 addresses factors that may prompt a surgical approach to the patient with CLI. IIa B-NR In patients with CLI for whom endovascular revascularization has failed and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries.331–333

See Online Data Supplement 42. In patients presenting with nonhealing ulcers or gangrene, surgical procedures should be performed to establish in-line blood flow to the foot.328–330 Table 10 addresses factors that may prompt a surgical approach to the patient with CLI. IIa B-NR In patients with CLI for whom endovascular revascularization has failed and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries.331–333 See Online Data Supplement 42. There are studies demonstrating that patients for whom endovascular treatment for CLI has failed can be treated successfully with autogenous vein bypass graft332,333 or prosthetic material.331 Although autogenous vein is the preferred conduit for surgical revascularization, prosthetic conduit is a secondary option for patients with CLI without suitable saphenous vein who require surgical revascularization. IIa C-LD A staged approach to surgical procedures is reasonable in patients with ischemic rest pain.334–336 N/A It is reasonable to perform a staged approach to revascularization in patients with ischemic rest pain with multilevel disease. For example, aortoiliac (inflow) disease may be treated first with endovascular treatment or by surgical reconstruction, depending on lesion characteristics, patient comorbidities, and patient preference.337,338 Combined percutaneous and surgical revascularization may require separate interventions, typically with the most proximal procedure performed first. 9.2. Wound Healing Therapies for CLI: Recommendations

N/A It is reasonable to perform a staged approach to revascularization in patients with ischemic rest pain with multilevel disease. For example, aortoiliac (inflow) disease may be treated first with endovascular treatment or by surgical reconstruction, depending on lesion characteristics, patient comorbidities, and patient preference.337,338 Combined percutaneous and surgical revascularization may require separate interventions, typically with the most proximal procedure performed first. 9.2. Wound Healing Therapies for CLI: Recommendations Recommendations for Wound Healing Therapies for CLI COR LOE Recommendations I B-NR An interdisciplinary care team should evaluate and provide comprehensive care for patients with CLI and tissue loss to achieve complete wound healing and a functional foot.229,339–341

N/A It is reasonable to perform a staged approach to revascularization in patients with ischemic rest pain with multilevel disease. For example, aortoiliac (inflow) disease may be treated first with endovascular treatment or by surgical reconstruction, depending on lesion characteristics, patient comorbidities, and patient preference.337,338 Combined percutaneous and surgical revascularization may require separate interventions, typically with the most proximal procedure performed first. 9.2. Wound Healing Therapies for CLI: Recommendations Recommendations for Wound Healing Therapies for CLI COR LOE Recommendations I B-NR An interdisciplinary care team should evaluate and provide comprehensive care for patients with CLI and tissue loss to achieve complete wound healing and a functional foot.229,339–341 See Online Data Supplement 44. The management of patients with CLI and nonhealing wounds should include coordinated efforts for both revascularization and wound healing, because the risk of limb-threatening infections remains until complete wound healing is achieved. The structure and activities of interdisciplinary care teams for CLI may vary according to several factors, including the local availability of resources. Previous groups have described various combinations of activities of this team, which are in addition to revascularization and include functions such as wound care, infection management, orthotics, and prosthetics (see Online Data Supplement 34a for a complete list of functions). Coordination of these activities and some degree of organized team structure are recommended, as opposed to ad hoc or unstructured referrals among various specialty clinicians not involved in interdisciplinary care.

anagement, orthotics, and prosthetics (see Online Data Supplement 34a for a complete list of functions). Coordination of these activities and some degree of organized team structure are recommended, as opposed to ad hoc or unstructured referrals among various specialty clinicians not involved in interdisciplinary care. Ambulatory patients with PAD and nonhealing foot ulcers should be considered for efforts to prevent amputation. The components of this effort may include revascularization, offloading, treatment of infection, and wound care. The long-term outcome of the limb is excellent when complete wound healing can be achieved.339Revascularization should be coordinated with the efforts of clinicians who manage foot infections, provide offloading, and achieve complete wound healing, either through medical therapy, surgical options, or a combination thereof. Coordinated and timely interdisciplinary care can achieve excellent limb outcomes for patients with PAD and nonhealing foot wounds.229,339–341 I C-LD In patients with CLI, wound care after revascularization should be performed with the goal of complete wound healing.339

Ambulatory patients with PAD and nonhealing foot ulcers should be considered for efforts to prevent amputation. The components of this effort may include revascularization, offloading, treatment of infection, and wound care. The long-term outcome of the limb is excellent when complete wound healing can be achieved.339Revascularization should be coordinated with the efforts of clinicians who manage foot infections, provide offloading, and achieve complete wound healing, either through medical therapy, surgical options, or a combination thereof. Coordinated and timely interdisciplinary care can achieve excellent limb outcomes for patients with PAD and nonhealing foot wounds.229,339–341 I C-LD In patients with CLI, wound care after revascularization should be performed with the goal of complete wound healing.339 See Online Data Supplement 44. A comprehensive plan for treatment of CLI must include a plan for achieving an intact skin surface on a functional foot. One study demonstrated a limb salvage rate of 100% at 3 years in a cohort of patients with CLI who achieved complete wound healing with endovascular revascularization and dedicated wound care.339 Before revascularization, the interdisciplinary care team should devise a plan to achieve the goal of complete wound healing. After successful revascularization, most patients with gangrene of the foot are evaluated for minor amputation with staged/delayed primary closure or surgical reconstruction when feasible.342–344 Negative-pressure wound therapy dressings are helpful to achieve wound healing after revascularization and minor (ie, digit or partial foot) amputation when primary or delayed secondary closure is not feasible.345,346 Spontaneous amputation, or autoamputation, of gangrenous digits should be reserved for palliation in patients without options for revascularization.345,347,348

achieve wound healing after revascularization and minor (ie, digit or partial foot) amputation when primary or delayed secondary closure is not feasible.345,346 Spontaneous amputation, or autoamputation, of gangrenous digits should be reserved for palliation in patients without options for revascularization.345,347,348 Other evidence-based guidelines relevant to those with nonhealing foot wounds following revascularization cover the full spectrum of diabetic foot problems349 or separately consider the management of infection,225,350 offloading,351 and wound care.352 To date, there are no RCTs or high-quality studies that have focused on wound healing adjuncts in limbs with severe PAD (eg, topical cytokine ointments, skin substitutes, cell-based therapies intended to optimize wound healing). IIb B-NR In patients with CLI, intermittent pneumatic compression (arterial pump) devices may be considered to augment wound healing and/or ameliorate severe ischemic rest pain.353 See Online Data Supplement 44. A systematic review of studies that used intermittent pneumatic compression devices specifically designed to augment arterial perfusion of the lower extremities suggests that these may provide modest clinical benefit (specifically, decreased amputation rates and improved QoL) in patients with CLI who were ineligible for revascularization.353 The potential benefit appears to outweigh the low risk associated with the use of these devices. IIb C-LD In patients with CLI, the effectiveness of hyperbaric oxygen therapy for wound healing is unknown.354

See Online Data Supplement 44. A systematic review of studies that used intermittent pneumatic compression devices specifically designed to augment arterial perfusion of the lower extremities suggests that these may provide modest clinical benefit (specifically, decreased amputation rates and improved QoL) in patients with CLI who were ineligible for revascularization.353 The potential benefit appears to outweigh the low risk associated with the use of these devices. IIb C-LD In patients with CLI, the effectiveness of hyperbaric oxygen therapy for wound healing is unknown.354 See Online Data Supplement 44. The literature evaluating the utility of hyperbaric oxygen therapy has focused on patients without severe PAD and has not demonstrated a long-term benefit on wound healing or improving amputation-free survival when compared with sham treatment.355 There are no published studies evaluating the role of hyperbaric oxygen therapy for patients with nonreconstructible PAD. One small RCT that focused on patients with foot ulcers and PAD (ABI <0.80 or TBI <0.70) for whom no revascularization was planned demonstrated a significant decrease in ulcer area at 6 weeks, but no significant differences in ulcer size at 6 months, complete ulcer healing at 6 weeks or 6 months, and major or minor amputations.354 Further research on the utility of hyperbaric oxygen therapy in this context is needed. III: No Benefit B-R Prostanoids are not indicated in patients with CLI.356

See Online Data Supplement 44. The literature evaluating the utility of hyperbaric oxygen therapy has focused on patients without severe PAD and has not demonstrated a long-term benefit on wound healing or improving amputation-free survival when compared with sham treatment.355 There are no published studies evaluating the role of hyperbaric oxygen therapy for patients with nonreconstructible PAD. One small RCT that focused on patients with foot ulcers and PAD (ABI <0.80 or TBI <0.70) for whom no revascularization was planned demonstrated a significant decrease in ulcer area at 6 weeks, but no significant differences in ulcer size at 6 months, complete ulcer healing at 6 weeks or 6 months, and major or minor amputations.354 Further research on the utility of hyperbaric oxygen therapy in this context is needed. III: No Benefit B-R Prostanoids are not indicated in patients with CLI.356 See Online Data Supplement 43. A systematic review and meta-analysis concluded that RCTs have not demonstrated meaningful long-term clinical benefit from the administration of prostanoids to patients with CLI attributable to nonreconstructible PAD.356

III: No Benefit B-R Prostanoids are not indicated in patients with CLI.356 See Online Data Supplement 43. A systematic review and meta-analysis concluded that RCTs have not demonstrated meaningful long-term clinical benefit from the administration of prostanoids to patients with CLI attributable to nonreconstructible PAD.356 10. Management of ALI ALI is one of the most treatable and potentially devastating presentations of PAD. Timely recognition of arterial occlusion as the cause of an ischemic, cold, painful leg is crucial to successful treatment. The writing committee has used a standard definition of ALI in which symptom duration is <2 weeks (Table 3).33,34 Category I refers to viable limbs that are not immediately threatened. Category II refers to threatened limbs. Category IIa limbs are marginally threatened and salvageable, if promptly treated. Category IIb are immediately threatened limbs that require immediate revascularization if salvage is to be accomplished. Category III are irreversibly damaged limbs, in which case resultant major tissue loss or permanent nerve damage is inevitable.34 10.1. Clinical Presentation of ALI: Recommendations Recommendations for Clinical Presentation of ALI COR LOE Recommendations I C-EO Patients with ALI should be emergently evaluated by a clinician with sufficient experience to assess limb viability and implement appropriate therapy.

10. Management of ALI ALI is one of the most treatable and potentially devastating presentations of PAD. Timely recognition of arterial occlusion as the cause of an ischemic, cold, painful leg is crucial to successful treatment. The writing committee has used a standard definition of ALI in which symptom duration is <2 weeks (Table 3).33,34 Category I refers to viable limbs that are not immediately threatened. Category II refers to threatened limbs. Category IIa limbs are marginally threatened and salvageable, if promptly treated. Category IIb are immediately threatened limbs that require immediate revascularization if salvage is to be accomplished. Category III are irreversibly damaged limbs, in which case resultant major tissue loss or permanent nerve damage is inevitable.34 10.1. Clinical Presentation of ALI: Recommendations Recommendations for Clinical Presentation of ALI COR LOE Recommendations I C-EO Patients with ALI should be emergently evaluated by a clinician with sufficient experience to assess limb viability and implement appropriate therapy. N/A Patients with ALI should be rapidly evaluated by a vascular specialist if one is available. Depending on local clinical expertise, the vascular specialist may be a vascular surgeon, interventional radiologist, cardiologist, or a general surgeon with specialized training and experience in treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (including communication about potential patient transfer) needs to occur.

treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (including communication about potential patient transfer) needs to occur. I C-LD In patients with suspected ALI, initial clinical evaluation should rapidly assess limb viability and potential for salvage and does not require imaging.357–361

treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (including communication about potential patient transfer) needs to occur. I C-LD In patients with suspected ALI, initial clinical evaluation should rapidly assess limb viability and potential for salvage and does not require imaging.357–361 See Online Data Supplements 45 and 46. ALI is a medical emergency and must be recognized rapidly. The time constraint is due to the period that skeletal muscle will tolerate ischemia—roughly 4 to 6 hours.362 A rapid assessment of limb viability and ability to restore arterial blood flow should be performed by a clinician able to either complete the revascularization or triage the patient.358 Lower extremity symptoms in ALI can include both pain and loss of function. The longer these symptoms are present, the less likely the possibility of limb salvage.360,361 Clinical assessment must include symptom duration, pain intensity, and motor and sensory deficit severity to distinguish a threatened from a nonviable extremity (Figure 3). The bedside assessment should include arterial and venous examination with a handheld continuous-wave Doppler because of the inaccuracy of pulse palpation.34 The loss of dopplerable arterial signal indicates that the limb is threatened. The absence of both arterial and venous Doppler signal indicates that the limb may be irreversibly damaged (nonsalvageable). Comorbidities should be investigated and managed aggressively, but this must not delay therapy. Even in the setting of rapid and effective revascularization, the 1-year morbidity and mortality rates associated with ALI are high.360,363

Doppler signal indicates that the limb may be irreversibly damaged (nonsalvageable). Comorbidities should be investigated and managed aggressively, but this must not delay therapy. Even in the setting of rapid and effective revascularization, the 1-year morbidity and mortality rates associated with ALI are high.360,363 10.2. Medical Therapy for ALI: Recommendations Recommendation for ALI Medical Therapy COR LOE Recommendation I C-EO In patients with ALI, systemic anticoagulation with heparin should be administered unless contraindicated. N/A Heparin (generally intravenous unfractionated heparin) is given to all patients acutely.35,364 This can stop thrombus propagation and may provide an anti-inflammatory effect that lessens the ischemia. Patients who have received heparin before the onset of ALI and have a decrease in platelet count may have heparin-induced thrombocytopenia.365,366 In this situation, a direct thrombin inhibitor is given, rather than heparin, if heparin-induced thrombocytopenia with thrombosis is suspected. 10.3. Revascularization for ALI: Recommendations Recommendations for Revascularization for ALI COR LOE Recommendations I C-LD In patients with ALI, the revascularization strategy should be determined by local resources and patient factors (eg, etiology and degree of ischemia).367–369

N/A Heparin (generally intravenous unfractionated heparin) is given to all patients acutely.35,364 This can stop thrombus propagation and may provide an anti-inflammatory effect that lessens the ischemia. Patients who have received heparin before the onset of ALI and have a decrease in platelet count may have heparin-induced thrombocytopenia.365,366 In this situation, a direct thrombin inhibitor is given, rather than heparin, if heparin-induced thrombocytopenia with thrombosis is suspected. 10.3. Revascularization for ALI: Recommendations Recommendations for Revascularization for ALI COR LOE Recommendations I C-LD In patients with ALI, the revascularization strategy should be determined by local resources and patient factors (eg, etiology and degree of ischemia).367–369 See Online Data Supplement 47. For marginally or immediately threatened limbs (Category IIa and IIb ALI [Figure 3]), revascularization should be performed emergently (within 6 hours). For viable limbs (Category I ALI [Figure 3]), revascularization should be performed an on urgent basis (within 6–24 hours). The revascularization strategy can range from catheter-directed thrombolysis to surgical thromboembolectomy. Available facilities and clinical expertise are factors that should be considered when determining the revascularization strategy. The technique that will provide the most rapid restoration of arterial flow with the least risk to the patient should be selected. For example, catheter-directed thrombolysis can provide rapid restoration of arterial flow to a viable or marginally threatened limb, particularly in the setting of recent occlusion, thrombosis of synthetic grafts, and stent thrombosis.367 If this is not available locally, surgical options for timely revascularization should be considered, along with the feasibility of timely transfer to a facility with the necessary expertise.

ket value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. * Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Section numbers pertain to those in the full-text guideline. † Significant relationship. ‡ No financial benefit.

nally threatened limb, particularly in the setting of recent occlusion, thrombosis of synthetic grafts, and stent thrombosis.367 If this is not available locally, surgical options for timely revascularization should be considered, along with the feasibility of timely transfer to a facility with the necessary expertise. I A Catheter-based thrombolysis is effective for patients with ALI and a salvageable limb.367–371 See Online Data Supplement 47. Assessment of the comparative effectiveness of catheter-based thrombolysis versus open surgery is complicated by variable definitions of ALI in this literature. Four RCTs comparing catheter-based thrombolysis to surgery,367,369–371 as well as a meta-analysis,368 have demonstrated similar limb salvage rates between the 2 approaches but better survival with catheter-based therapy. The survival advantage of catheter-based therapy may be at least in part attributable to multiple comorbidities found among the population of patients who present with ALI. Increased comorbidities are likely to contribute to increased perioperative risk. Several of the RCTs included patients with relatively chronic ischemia. Acuity and severity are both factors in the decision to consider thrombolysis.367,369–371 I C-LD Amputation should be performed as the first procedure in patients with a nonsalvageable limb.372,373

See Online Data Supplement 47. Assessment of the comparative effectiveness of catheter-based thrombolysis versus open surgery is complicated by variable definitions of ALI in this literature. Four RCTs comparing catheter-based thrombolysis to surgery,367,369–371 as well as a meta-analysis,368 have demonstrated similar limb salvage rates between the 2 approaches but better survival with catheter-based therapy. The survival advantage of catheter-based therapy may be at least in part attributable to multiple comorbidities found among the population of patients who present with ALI. Increased comorbidities are likely to contribute to increased perioperative risk. Several of the RCTs included patients with relatively chronic ischemia. Acuity and severity are both factors in the decision to consider thrombolysis.367,369–371 I C-LD Amputation should be performed as the first procedure in patients with a nonsalvageable limb.372,373 See Online Data Supplement 48. For patients with Category III ALI (Figure 3), amputation should be performed as the index procedure. Prolonged duration of ischemia is the most common factor in patients requiring amputation for treatment of ALI. The risks associated with reconstruction outweigh the potential benefit in a limb that is already insensate or immobile because of prolonged ischemia. Patients who have an insensate and immobile limb in the setting of prolonged ischemia (>6 to 8 hours) are unlikely to have potential for limb salvage.34,362 In addition, in this setting the reperfusion and circulation of ischemic metabolites can result in multiorgan failure and cardiovascular collapse. However, if pain can be controlled and there is no evidence of infection, amputation may be deferred if this meets with the patient's goals.

otential for limb salvage.34,362 In addition, in this setting the reperfusion and circulation of ischemic metabolites can result in multiorgan failure and cardiovascular collapse. However, if pain can be controlled and there is no evidence of infection, amputation may be deferred if this meets with the patient's goals. I C-LD Patients with ALI should be monitored and treated (eg, fasciotomy) for compartment syndrome after revascularization.372,373 See Online Data Supplement 48. The lower extremity muscles reside in compartments, surrounded by fascia and bones. Reperfusion to ischemic muscles can cause cellular edema, resulting in increased compartment pressure. When compartment pressure is >30 mm Hg, there is capillary and venule compression that leads to malperfusion of the muscle; this is compartment syndrome. Fasciotomy is indicated when the compartment pressure increases. Measurement of intracompartment pressure is not always easily accessible. In such cases, evaluation for fasciotomy is prompted by development of increased pain, tense muscle, or nerve injury. Fasciotomy should be considered for patients with Category IIb ischemia for whom the time to revascularization is >4 hours. IIa B-NR In patients with ALI with a salvageable limb, percutaneous mechanical thrombectomy can be useful as adjunctive therapy to thrombolysis.374–378 See Online Data Supplements 49 and 50. Multiple nonrandomized studies have suggested that percutaneous mechanical thrombectomy in combination with pharmacological therapy can be beneficial in the treatment of threatened limbs.374–378

IIa B-NR In patients with ALI with a salvageable limb, percutaneous mechanical thrombectomy can be useful as adjunctive therapy to thrombolysis.374–378 See Online Data Supplements 49 and 50. Multiple nonrandomized studies have suggested that percutaneous mechanical thrombectomy in combination with pharmacological therapy can be beneficial in the treatment of threatened limbs.374–378 IIa C-LD In patients with ALI due to embolism and with a salvageable limb, surgical thromboembolectomy can be effective.379–381 See Online Data Supplements 49 and 50. Patients with arterial embolism and an absent pulse ipsilateral to the ischemic limb can be treated by exposure of an artery in the affected limb and balloon-catheter thromboembolectomy. These patients may benefit from adjunctive intraoperative fibrinolytics. In the event that thromboembolectomy does not restore arterial flow, bypass can be performed.381–383 IIb C-LD The usefulness of ultrasound-accelerated catheter-based thrombolysis for patients with ALI with a salvageable limb is unknown.384–386 See Online Data Supplements 47 and 50. The use of ultrasound-accelerated catheter delivery of thrombolytic agents has been published in case series384 and retrospective analyses.385 However, the single RCT comparing this technique to standard catheter-based thrombolytic therapy failed to demonstrate a difference in outcomes, including bleeding, despite a lower total amount of lytic delivered.386 10.4. Diagnostic Evaluation of the Cause of ALI: Recommendations Recommendations for Diagnostic Evaluation of the Cause of ALI COR LOE Recommendations

See Online Data Supplements 47 and 50. The use of ultrasound-accelerated catheter delivery of thrombolytic agents has been published in case series384 and retrospective analyses.385 However, the single RCT comparing this technique to standard catheter-based thrombolytic therapy failed to demonstrate a difference in outcomes, including bleeding, despite a lower total amount of lytic delivered.386 10.4. Diagnostic Evaluation of the Cause of ALI: Recommendations Recommendations for Diagnostic Evaluation of the Cause of ALI COR LOE Recommendations I C-EO In the patient with ALI, a comprehensive history should be obtained to determine the cause of thrombosis and/or embolization. N/A In addition to identifying a known history of PAD, the history should focus on uncovering clinical evidence of other conditions that can result in ALI through either embolic or thrombotic mechanisms. These conditions include atrial fibrillation, left ventricular thrombus, aortic dissection, trauma, hypercoagulable state, and presence of a limb artery bypass graft. The clinical history should identify the presence or absence of a history of MI, symptoms and signs of left ventricular dysfunction resulting in congestive heart failure, or possible endocarditis. The history should evaluate for possibility of deep vein thrombosis with intracardiac shunt (eg, patent foramen ovale or other that may result in paradoxical arterial embolism), hypercoagulable state, and family history of thrombosis. IIa C-EO In the patient with a history of ALI, testing for a cardiovascular cause of thromboembolism can be useful.

N/A In addition to identifying a known history of PAD, the history should focus on uncovering clinical evidence of other conditions that can result in ALI through either embolic or thrombotic mechanisms. These conditions include atrial fibrillation, left ventricular thrombus, aortic dissection, trauma, hypercoagulable state, and presence of a limb artery bypass graft. The clinical history should identify the presence or absence of a history of MI, symptoms and signs of left ventricular dysfunction resulting in congestive heart failure, or possible endocarditis. The history should evaluate for possibility of deep vein thrombosis with intracardiac shunt (eg, patent foramen ovale or other that may result in paradoxical arterial embolism), hypercoagulable state, and family history of thrombosis. IIa C-EO In the patient with a history of ALI, testing for a cardiovascular cause of thromboembolism can be useful. N/A Treatment of ALI should not be delayed for testing for the underlying cause of the limb ischemia. Delay from symptom onset to revascularization is a major determinant of outcome.360,361 The evaluation of a cardiovascular cause of ALI is most useful in the patient without underlying PAD. Evaluation for cardiovascular cause includes electrocardiogram or additional heart rhythm monitoring to detect atrial fibrillation, electrocardiogram to detect evidence of MI, and echocardiography to further determine whether there is a cardiac etiology for thromboembolism, such as valvular vegetation, left atrial or left ventricular thrombus, or intracardiac shunt.387

ocardiogram or additional heart rhythm monitoring to detect atrial fibrillation, electrocardiogram to detect evidence of MI, and echocardiography to further determine whether there is a cardiac etiology for thromboembolism, such as valvular vegetation, left atrial or left ventricular thrombus, or intracardiac shunt.387 11. Longitudinal Follow-Up: Recommendations PAD is a lifelong chronic medical condition. Ongoing care focuses on cardiovascular risk reduction with medical therapy, optimizing functional status with structured exercise and, when indicated, revascularization. Recommendations for Longitudinal Follow-Up COR LOE Recommendations I C-EO Patients with PAD should be followed up with periodic clinical evaluation, including assessment of cardiovascular risk factors, limb symptoms, and functional status. N/A A comprehensive care plan for patients with PAD includes periodic clinical evaluation by a healthcare provider with experience in the care of vascular patients. Clinical evaluation should include assessment of cardiovascular risk factors, assessment of adherence to medical therapy, and re-evaluation of smoking cessation efforts. Comprehensive lifestyle modification, including heart-healthy nutrition, is encouraged.22 Patients with PAD should also undergo periodic assessment of limb symptoms, functional status, and their ability to participate in vocational and recreational activities. Ongoing participation in a structured exercise program should be facilitated. Foot examination and patient counseling about healthy foot behaviors in PAD are addressed in Section 7.

dergo periodic assessment of limb symptoms, functional status, and their ability to participate in vocational and recreational activities. Ongoing participation in a structured exercise program should be facilitated. Foot examination and patient counseling about healthy foot behaviors in PAD are addressed in Section 7. I C-EO Patients with PAD who have undergone lower extremity revascularization (surgical and/or endovascular) should be followed up with periodic clinical evaluation and ABI measurement. N/A In addition to the clinical evaluation of cardiovascular risk factors, functional status, and adherence to medical therapy and smoking cessation, patients with PAD who have previously undergone lower extremity revascularization (surgical and/or endovascular) require additional ongoing assessment and care. Follow-up visits after revascularization should include reassessment of the patient's limb symptoms and interval change in functional status, as well as participation in a structured exercise program. Pulse examination and ABI are included in the assessment. A change in ABI of 0.15 is considered clinically significant.388 IIa B-R Duplex ultrasound can be beneficial for routine surveillance of infrainguinal, autogenous vein bypass grafts in patients with PAD.389–395

N/A In addition to the clinical evaluation of cardiovascular risk factors, functional status, and adherence to medical therapy and smoking cessation, patients with PAD who have previously undergone lower extremity revascularization (surgical and/or endovascular) require additional ongoing assessment and care. Follow-up visits after revascularization should include reassessment of the patient's limb symptoms and interval change in functional status, as well as participation in a structured exercise program. Pulse examination and ABI are included in the assessment. A change in ABI of 0.15 is considered clinically significant.388 IIa B-R Duplex ultrasound can be beneficial for routine surveillance of infrainguinal, autogenous vein bypass grafts in patients with PAD.389–395 See Online Data Supplements 51 and 52. A general surveillance schedule may be at 4 to 6 weeks, 6 months, and 12 months in the first year and yearly thereafter. It is important that testing frequency is individualized to the patient, type of arterial bypass, and any prior duplex scan findings. Duplex graft surveillance focuses on the identification of high-grade stenosis (eg, peak systolic velocity >300 cm/s and peak systolic velocity ratio across the stenosis >3.5) or impending graft failure (eg, PSV <40 cm/s).392,395 Detection of a graft stenosis prompts the consideration of further revascularization to treat the stenosis and maintain graft patency. Duplex may detect significant stenoses that may not be detected by a decline in ABI.394 Although case series have demonstrated high rates of primary assisted patency with a duplex ultrasound-surveillance strategy, RCTs of duplex surveillance versus clinical surveillance with the ABI have demonstrated mixed results in terms of a benefit on patency and limb outcomes.391,393,396

ected by a decline in ABI.394 Although case series have demonstrated high rates of primary assisted patency with a duplex ultrasound-surveillance strategy, RCTs of duplex surveillance versus clinical surveillance with the ABI have demonstrated mixed results in terms of a benefit on patency and limb outcomes.391,393,396 IIa C-LD Duplex ultrasound is reasonable for routine surveillance after endovascular procedures in patients with PAD.397–399 See Online Data Supplement 52. Studies have developed duplex ultrasound diagnostic criteria for diagnosing restenosis at the site of endovascular revascularization. Diagnostic criteria need to be customized to the location (eg, iliac or superficial femoral artery) and type of intervention (eg, angioplasty, uncovered stent, or covered stent). The optimal timing for surveillance after endovascular procedures is unclear.397–399 There are limited outcome data on routine duplex surveillance versus clinical surveillance plus the ABI after endovascular revascularization.397–399 The value of duplex ultrasound may be greater in cases with higher rates of restenosis, such as after interventions to treat very long lesions or occlusions.400 IIb B-R The effectiveness of duplex ultrasound for routine surveillance of infrainguinal prosthetic bypass grafts in patients with PAD is uncertain.393,401–403

See Online Data Supplement 52. Studies have developed duplex ultrasound diagnostic criteria for diagnosing restenosis at the site of endovascular revascularization. Diagnostic criteria need to be customized to the location (eg, iliac or superficial femoral artery) and type of intervention (eg, angioplasty, uncovered stent, or covered stent). The optimal timing for surveillance after endovascular procedures is unclear.397–399 There are limited outcome data on routine duplex surveillance versus clinical surveillance plus the ABI after endovascular revascularization.397–399 The value of duplex ultrasound may be greater in cases with higher rates of restenosis, such as after interventions to treat very long lesions or occlusions.400 IIb B-R The effectiveness of duplex ultrasound for routine surveillance of infrainguinal prosthetic bypass grafts in patients with PAD is uncertain.393,401–403 See Online Data Supplements 51 and 52. Duplex ultrasound of prosthetic bypass grafts may be used to characterize mid-graft velocity, because low velocities can predict impending graft failure.401–403 Outcome studies of duplex surveillance of prosthetic grafts have not shown consistent benefit.393,401–403 One RCT of duplex versus clinical surveillance with the ABI for femoropopliteal grafts did not show a benefit of duplex on outcome in the subset of patients with prosthetic grafts, though there was a benefit of duplex surveillance for vein bypass grafts.393

rosthetic grafts have not shown consistent benefit.393,401–403 One RCT of duplex versus clinical surveillance with the ABI for femoropopliteal grafts did not show a benefit of duplex on outcome in the subset of patients with prosthetic grafts, though there was a benefit of duplex surveillance for vein bypass grafts.393 12. Evidence Gaps and Future Research Directions In performing the evidence review and in developing the present guidelines, the writing committee identified the following critical evidence gaps and future directions for PAD-related research: Basic science and translational studies to better understand the vascular biology of endovascular therapies and bypass grafting and to develop new methods for preventing restenosis after revascularization. Determination of risk factors for progression from asymptomatic PAD to symptomatic disease, including CLI. RCTs needed to determine the value of using the ABI to identify asymptomatic patients with PAD for therapies to reduce cardiovascular risk (eg, antiplatelet agents, statins, and other therapies). Advancement in PAD diagnostics, such as technologies for simplified yet highly accurate measurement of the ABI and tools for more reliable noninvasive perfusion assessment in CLI. Comparative-effectiveness studies to determine the optimal antiplatelet therapy (drug or drugs and dosage) for prevention of cardiovascular and limb-related events in patients with PAD. Development of additional medical therapies for claudication–an area of unmet medical need with a currently limited research pipeline.404

Comparative-effectiveness studies to determine the optimal antiplatelet therapy (drug or drugs and dosage) for prevention of cardiovascular and limb-related events in patients with PAD. Development of additional medical therapies for claudication–an area of unmet medical need with a currently limited research pipeline.404 Studies to investigate the role of dietary intervention, in addition to statin therapy, to improve outcome and modify the natural history of PAD. Additional research to identify the best community-or home-based exercise programs for patients with PAD to maximize functional status and improve QoL, as well as the role of such exercise programs before or in addition to revascularization. Development and validation of improved clinical classification systems for PAD that incorporate symptoms, anatomic factors, and patient-specific risk factors and can be used to predict clinical outcome and optimize treatment approach. An example of a recently developed classification system is the Society for Vascular Surgery limb classification system, based on wound, ischemia, and foot infection (WIfI), which has been validated in different populations and may permit more meaningful prognosis in patients with CLI.405–409

timize treatment approach. An example of a recently developed classification system is the Society for Vascular Surgery limb classification system, based on wound, ischemia, and foot infection (WIfI), which has been validated in different populations and may permit more meaningful prognosis in patients with CLI.405–409 Comparative- and cost-effectiveness studies of the different endovascular technologies for treatment of claudication and CLI, including drug-coated balloons and DES. Studies should include patient-centered end-points, such as functional parameters, time to wound healing, and QoL, in addition to standard patency-focused outcomes. These studies could then be incorporated into value-based clinical algorithms for approach to revascularization for claudication and CLI. Additional studies to demonstrate the impact of multisocietal registries on clinical outcomes and appropriate use. At present, these include the Vascular Quality Initiative (VQI), the National Cardiovascular Data Registry Peripheral Vascular Intervention Registry™ (PVI Registry™), and the National Radiology Data Registry for Interventional Radiology (NRDR). These registries provide an opportunity to obtain “real-world” data on surgical and endovascular procedures for PAD and to improve quality by providing feedback to participating centers. Future efforts should incorporate these registries into interventional RCTs and postmarketing studies of PAD-related devices.

(NRDR). These registries provide an opportunity to obtain “real-world” data on surgical and endovascular procedures for PAD and to improve quality by providing feedback to participating centers. Future efforts should incorporate these registries into interventional RCTs and postmarketing studies of PAD-related devices. 13. Advocacy Priorities The writing committee identified 3 priorities for multi-societal advocacy initiatives to improve health care for patients with PAD. First, the writing committee supports the availability of the ABI as the initial diagnostic test to establish the diagnosis of PAD in patients with history or physical examination findings suggestive of PAD (Table 5). Although the ABI test is generally reimbursed by third-party payers for patients with classic claudication or lower extremity wounds, payers may not provide reimbursement for the ABI with other findings suggestive of PAD, such as lower extremity pulse abnormalities or femoral bruits. The writing committee affirms the importance of confirming the diagnosis of PAD in such patients to allow for GDMT as delineated in this document. Second, the writing committee supports the vital importance of insuring access to supervised exercise programs for patients with PAD. Although extensive high-quality evidence supports supervised exercise programs to improve functional status and QoL, only a minority of patients with PAD participate in such programs because of lack of reimbursement by third-party payers. Third, the writing committee recognizes the need for incorporation of patient-centered outcomes into the process of regulatory approval of new medical therapies and revascularization technologies. For revascularization technologies, regulatory approval is driven primarily by data on angiographic efficacy (ie, target lesion patency) and safety endpoints. The nature of the functional limitation associated with PAD warrants the incorporation of patient-centered outcomes, such as functional parameters and QoL, into the efficacy outcomes for the approval process.

approval is driven primarily by data on angiographic efficacy (ie, target lesion patency) and safety endpoints. The nature of the functional limitation associated with PAD warrants the incorporation of patient-centered outcomes, such as functional parameters and QoL, into the efficacy outcomes for the approval process. Supplementary Material Evidence Table 1. Nonrandomized Trials, Observational Studies, and/or Registries of History for Clinical Assessment for PAD–Section 2.1. Evidence Table 2. Nonrandomized Trials, Observational Studies, and/or Registries of Physical Examination for Clinical Assessment for PAD–Section 2.1. Evidence Table 3. RCTs of Resting ABI for Diagnosing PAD–Section 3.1. Evidence Table 4. Nonrandomized Trials, Observational Studies, and/or Registries of Resting ABI for Diagnosing PAD–Section 3.1. Evidence Table 5. Nonrandomized Trials, Observational Studies, and/or Registries of Physiological Testing–Section 3.2. Evidence Table 6. Nonrandomized Trials, Observational Studies, and/or Registries of Imaging for Anatomic Assessment (Ultrasound, CTA, MRA, Angiography)–Section 3.3. Evidence Table 7. RCTs of Imaging for Anatomic Assessment (Ultrasound, CTA, MRA, Angiography)–Section 3.3. Evidence Table 8. Nonrandomized Trials, Observational Studies, and/or Registries for Abdominal Aortic Aneurysm–Section 4.1. Evidence Table 9. Nonrandomized Trials, Observational Studies, and/or Registries of Coronary Artery Disease Screening in PAD–Section 4.2. Evidence Table 10. RCTs for CAD Screening in PAD–Section 4.2.

Evidence Table 7. RCTs of Imaging for Anatomic Assessment (Ultrasound, CTA, MRA, Angiography)–Section 3.3. Evidence Table 8. Nonrandomized Trials, Observational Studies, and/or Registries for Abdominal Aortic Aneurysm–Section 4.1. Evidence Table 9. Nonrandomized Trials, Observational Studies, and/or Registries of Coronary Artery Disease Screening in PAD–Section 4.2. Evidence Table 10. RCTs for CAD Screening in PAD–Section 4.2. Evidence Table 11. Nonrandomized Trials, Observational Studies, and/or Registries of Screening in Carotid Artery Disease–Section 4.3. Evidence Table 12. Nonrandomized Trials, Observational Studies, and/or Registries for Renal Artery Disease–Section 4.4. Evidence Table 13. RCTs Evaluating Antiplatelet Agents– Section 5.1. Evidence Table 14. Nonrandomized Trials, Observational Studies, and/or Registries of Antiplatelet Agents–Section 5.2. Evidence Table 15. Randomized Trials Comparing Statin Agents–Section 5.2. Evidence Table 16. Nonrandomized Trials, Observational Studies, and/or Registries of Statin Agents–Section 5.2. Evidence Table 17. RCTs for Antihypertensive Agents– Section 5.3. Evidence Table 18. Nonrandomized Trials, Observational Studies, and/or Registries of Antihypertensive Agents–Section 5.3. Evidence Table 19. RCTs for Smoking Cessation–Section 5.4. Evidence Table 20. Nonrandomized Trials, Observational Studies, and/or Registries of Smoking Cessation–Section 5.4. Evidence Table 21. RCTs Evaluating Glycemic Control in Patients with PAD and Diabetes Mellitus–Section 5.5. Evidence Table 22. Nonrandomized Trials, Observational Studies, and/or Registries of Glycemic Control–Section 5.5.

Evidence Table 20. Nonrandomized Trials, Observational Studies, and/or Registries of Smoking Cessation–Section 5.4. Evidence Table 21. RCTs Evaluating Glycemic Control in Patients with PAD and Diabetes Mellitus–Section 5.5. Evidence Table 22. Nonrandomized Trials, Observational Studies, and/or Registries of Glycemic Control–Section 5.5. Evidence Table 23. RCTs Evaluating Oral Anticoagulation–Section 5.6. Evidence Table 24. Nonrandomized Trials, Observational Studies, and/or Registries of Oral Anticoagulation–Section 5.6. Evidence Table 25. RCTs and Observational Studies of Cilostazol–Section 5.7. Evidence Table 26. Nonrandomized Trials, Observational Studies, and/or Registries of Pentoxifylline–Section 5.8. Evidence Table 27. Systematic Review of Chelation Therapy–Section 5.9. Evidence Table 28. Nonrandomized Trials, Observational Studies, and/or Registries of Homocysteine Lowering Therapy for Lower Extremity PAD in Patients with Diabetes Mellitus–Section 5.10.1. Evidence Table 29. RCTs Comparing Additional Medical Therapies of Homocysteine Lowering Therapy for Lower Extremity PAD–Section 5.10.1. Evidence Table 30. RCTs for Influenza Vaccination–Section 5.10.2. Evidence Table 31. Nonrandomized Trials for Influenza Vaccination–Section 5.10.2. Evidence Table 32. RCTs for Exercise Therapy–Section 6. Evidence Table 33. Nonrandomized Trials, Observational Studies, and/or Registries for Exercise Therapy–Section 6. Evidence Table 34. Nonrandomized Trials and Observational Studies of Minimizing Tissue Loss in Patients with PAD–Section 7.

Evidence Table 31. Nonrandomized Trials for Influenza Vaccination–Section 5.10.2. Evidence Table 32. RCTs for Exercise Therapy–Section 6. Evidence Table 33. Nonrandomized Trials, Observational Studies, and/or Registries for Exercise Therapy–Section 6. Evidence Table 34. Nonrandomized Trials and Observational Studies of Minimizing Tissue Loss in Patients with PAD–Section 7. Data Supplement 34a. Functions of a Multidisciplinary Foot Care / Amputation Prevention Team–Section 7. Evidence Table 35. RCTs Comparing Endovascular Treatment and Endovascular Versus Noninvasive Treatment of Claudication–Section 8.1. Evidence Table 36. Nonrandomized Trials, Observational Studies, and/or Registries of Endovascular and Endovascular Versus Noninvasive Treatment of Claudication–Section 8.1. Evidence Table 37. RCTs Evaluating Surgical Treatment for Claudication–Section 8.1.2. Evidence Table 38. Nonrandomized Trials, Observational Studies, and/or Registries of Surgical Treatment for Claudication–Section 8.1.2. Evidence Table 39. RCTs Comparing Endovascular Revascularization for Chronic CLI–Section 8.2. Evidence Table 40. Nonrandomized Trials, Observational Studies, and/or Registries of Endovascular Revascularization for Chromic CLI–Section 8.2.1. Evidence Table 41. RCTs of Surgical Revascularization for Chronic CLI–Section 8.2. Evidence Table 42. Nonrandomized Trials, Observational Studies, and/or Registries for Surgical Revascularization for Chronic CLI–Section 8.2. Evidence Table 43. RCT Comparing Prostanoids for End-Stage Peripheral Artery Disease–Section 8.2.3.

Evidence Table 40. Nonrandomized Trials, Observational Studies, and/or Registries of Endovascular Revascularization for Chromic CLI–Section 8.2.1. Evidence Table 41. RCTs of Surgical Revascularization for Chronic CLI–Section 8.2. Evidence Table 42. Nonrandomized Trials, Observational Studies, and/or Registries for Surgical Revascularization for Chronic CLI–Section 8.2. Evidence Table 43. RCT Comparing Prostanoids for End-Stage Peripheral Artery Disease–Section 8.2.3. Evidence Table 44. Nonrandomized Trials, Observational Studies, and/or Registries for Would Healing Therapies for CLI–Section 8.2.3. Evidence Table 45. Nonrandomized Trials, Observational Studies, and/or Registries of Acute Limb Ischemia–Section 9.1. Evidence Table 46. Nonrandomized Trials, Observational studies, and/or Registries Comparing Evaluating Noninvasive Testing and Angiography for ALI–Section 9.1. Evidence Table 47. RCTs of Revascularization Strategy for ALI–Section 9.2.2. Evidence Table 48. Nonrandomized Trials, Observational Studies, and/or Registries of Clinical Presentation of ALI–Section 9.2.2. Evidence Table 49. Nonrandomized Trials, Observational Studies, and/or Registries of Diagnostic Evaluation of the Cause of ALI–Section 9.2.2. Evidence Table 50. Nonrandomized Trials, Observational Studies, and/or Registries of Revascularization Strategy for ALI–Section 9.2.2. Evidence Table 51. RCTs for Longitudinal Follow-Up–Section 10. Evidence Table 52. Nonrandomized Trials, Observational Studies, and/or Registries for Longitudinal Follow-Up–Section 10. References.

Evidence Table 50. Nonrandomized Trials, Observational Studies, and/or Registries of Revascularization Strategy for ALI–Section 9.2.2. Evidence Table 51. RCTs for Longitudinal Follow-Up–Section 10. Evidence Table 52. Nonrandomized Trials, Observational Studies, and/or Registries for Longitudinal Follow-Up–Section 10. References. The American Heart Association requests that this document be cited as follows: Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FGR, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RAG, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, Walsh ME. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. ACC/AHA Task Force Members Jonathan L. Halperin, MD, FACC, FAHA, Chair; Glenn N. Levine, MD, FACC, FAHA, Chair-Elect; Sana M. Al-Khatib, MD, MHS,FACC, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA; Ralph G. Brindis, MD, MPH, MACC; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; José Joglar, MD, FACC, FAHA; Susan J. Pressler, PhD, RN, FAHA; Duminda N. Wijeysundera, MD, PhD Presidents and Staff American College of Cardiology: Richard A. Chazal, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer

ACC/AHA Task Force Members Jonathan L. Halperin, MD, FACC, FAHA, Chair; Glenn N. Levine, MD, FACC, FAHA, Chair-Elect; Sana M. Al-Khatib, MD, MHS,FACC, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA; Ralph G. Brindis, MD, MPH, MACC; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; José Joglar, MD, FACC, FAHA; Susan J. Pressler, PhD, RN, FAHA; Duminda N. Wijeysundera, MD, PhD Presidents and Staff American College of Cardiology: Richard A. Chazal, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/American Heart Association: Katherine Sheehan, PhD, Director, Guideline Strategy and Operations Lisa Bradfield, CAE, Director, Guideline Methodology and Policy Abdul R. Abdullah, MD, Associate Science and Medicine Advisor Allison Rabinowitz, MPH, Project Manager, Clinical Practice Guidelines American Heart Association: Steven R. Houser, PhD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations

Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations The Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000471/-/DC2. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org) and the American Heart Association (professional.heart.org). A copy of the document is available at http://professional.heart. org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements and select the “Policies and Development” link. Figure 1 Diagnostic Testing for Suspected PAD Colors correspond to Class of Recommendation in Table 1. ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; GDMT, guideline-directed management and therapy; MRA, magnetic resonance angiography; PAD, peripheral artery disease; and TBI, toe-brachial index.

Suspected PAD Colors correspond to Class of Recommendation in Table 1. ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; GDMT, guideline-directed management and therapy; MRA, magnetic resonance angiography; PAD, peripheral artery disease; and TBI, toe-brachial index. Figure 2 Diagnostic Testing for Suspected CLI Colors correspond to Class of Recommendation in Table 1. *Order based on expert consensus. †TBI with waveforms, if not already performed. ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; MRA, magnetic resonance angiography; TcPO2, transcutaneous oxygen pressure; and TBI, toe-brachial index. Figure 3 Diagnosis and Management of ALI 33,34, Colors correspond to Class of Recommendation in Table 1. ALI indicates acute limb ischemia. Table 1 ACC/AHA Recommendation System: Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) CLASS (STRENGTH) OF RECOMMENDATION CLASS 1 (STRONG) Benefit >>> Risk Suggested phrases for writing recommendations: ■ Is recommended ■ Is indicated/useful/effective/beneficial ■ Should be performed/administered/other ■ Comparative-Effectiveness Phrases†: ○ Treatment/strategy A is recommended/indicated in preference to treatment B ○ Treatment A should be chosen over treatment B CLASS IIa (MODERATE) Benefit >> Risk Suggested phrases for writing recommendations; ■ Is reasonable ■ Can be useful/effective/beneficial

■ Should be performed/administered/other ■ Comparative-Effectiveness Phrases†: ○ Treatment/strategy A is recommended/indicated in preference to treatment B ○ Treatment A should be chosen over treatment B CLASS IIa (MODERATE) Benefit >> Risk Suggested phrases for writing recommendations; ■ Is reasonable ■ Can be useful/effective/beneficial ■ Comparative-Effectiveness Phrases†: ○ Treatment/strategy A is probably recommended/indicated in preference to treatment B ○ It is reasonable to choose treatment A over treatment B CLASS IIb (WEAK) Benefit ≥ Risk Suggested phrases for writing recommendations: ■ May/might be reasonable ■ May/might be considered ■ Usefulness/effectiveness is unknown/unclear/uncertain or not well established CLASS III: No Benefit (MODERATE) (Generally, LOE A or B use only) Benefit = Risk Suggested phrases for writing recommendations: ■ Is not recommended ■ Is not indicated/useful/effective/beneficial ■ Should not be performed/administered/other CLASS III: Harm (STRONG) Risk > Benefit Suggested phrases for writing recommendations: ■ Potentially harmful ■ Causes harm ■ Associated with excess morbidity/mortality ■ Should not be performed/administered/other LEVEL (QUALITY) OF EVIDENCE‡ LEVEL A ■ High-quality evidence‡ from more than 1 RCT ■ Meta-analyses of high-quality RCTs ■ One or more RCTs corroborated by high-quality registry studies LEVEL B-R (Randomized) ■ Moderate-quality evidence‡ from 1 or more RCTs ■ Meta-analyses of moderate-quality RCTs LEVEL B-NR (Nonrandomized) ■ Moderate-quality evidence‡ from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies

■ One or more RCTs corroborated by high-quality registry studies LEVEL B-R (Randomized) ■ Moderate-quality evidence‡ from 1 or more RCTs ■ Meta-analyses of moderate-quality RCTs LEVEL B-NR (Nonrandomized) ■ Moderate-quality evidence‡ from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies ■ Meta-analyses of such studies LEVEL C-LD (Limited Data) ■ Randomized or nonrandomized observational or registry studies with limitations of design or execution ■ Meta-analyses of such studies ■ Physiological or mechanistic studies in human subjects LEVEL C-EO (Expert Opinion) Consensus of expert opinion based on clinical experience COR and LOE are determined independently (any COR may be paired with any LOE), A recommendation with LOE C does not imply that the recommendation is weak. Many important clinical questions addressed in guidelines do not lend themselves to clinical trials. Although RCTs are unavailable, there may be a very dear clinical consensus that a particular test or therapy is useful or effective. * The outcome or result of the intervention should be specified (an improved clinical outcome or increased diagnostic accuracy or incremental prognostic information). † For comparative-effectiveness recommendations (COR I and lla; LOE A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

* The outcome or result of the intervention should be specified (an improved clinical outcome or increased diagnostic accuracy or incremental prognostic information). † For comparative-effectiveness recommendations (COR I and lla; LOE A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. ‡ The method of assessing quality is evolving, including the application of standardized, widely used, and preferably validated evidence grading tools; and for systematic reviews, the incorporation of an Evidence Review Committee. COR indicates Class of Recommendation; EO, expert opinion; LD, limited data; LOE, Level of Evidence; NR, nonrandomized; R, randomized; and RCT randomized controlled trial.

‡ The method of assessing quality is evolving, including the application of standardized, widely used, and preferably validated evidence grading tools; and for systematic reviews, the incorporation of an Evidence Review Committee. COR indicates Class of Recommendation; EO, expert opinion; LD, limited data; LOE, Level of Evidence; NR, nonrandomized; R, randomized; and RCT randomized controlled trial. Table 2 Important Guideline Policy Title Organization Publication Year (Reference) ACC/AHA Guideline policy relevant to the management of lower extremity PAD Duration of dual antiplatelet therapy in patients with coronary artery disease ACC/AHA 201620 Perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery ACC/AHA 201421 Lifestyle management to reduce cardiovascular risk AHA/ACC 201322 Assessment of cardiovascular risk ACC/AHA 201323 Blood cholesterol to reduce atherosclerotic cardiovascular risk in adults ACC/AHA 201324 PAD (lower extremity, renal, mesenteric, and abdominal aortic) ACC/AHA 20059 and 201110 Secondary prevention and risk-reduction therapy for patients with coronary and other atherosclerotic vascular disease AHA/ACC 201125 Other related publications Atherosclerotic occlusive disease of the lower extremities guideline SVS 201526 Measurement and interpretation of the ankle-brachial index AHA 201227 Cardiac disease evaluation and management among kidney and liver transplantation candidates AHA/ACC 201228 Intensive glycemic control and the prevention of cardiovascular events ADA/ACC/AHA 200929 Influenza vaccination as secondary prevention for cardiovascular disease AHA/ACC 200630 Indications for renal arteriography at the time of coronary arteriography AHA/CLCD/CVRI/KCVD 200631 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)* NHLBI 200332 * A revision to the current document is being prepared, with publication expected in 2017. The new title is expected to be “ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Detection, Evaluation, Prevention and Management of High Blood Pressure.”

Treatment of High Blood Pressure (JNC 7)* NHLBI 200332 * A revision to the current document is being prepared, with publication expected in 2017. The new title is expected to be “ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Detection, Evaluation, Prevention and Management of High Blood Pressure.” AAPA indicates American Academy of Physician Assistants; ABC, Association of Black Cardiologists; ACC, American College of Cardiology; ACPM, American College of Preventive Medicine; ADA, American Diabetes Association; AGS, American Geriatrics Society; AHA, American Heart Association; APhA, American Pharmacists Association; ASH, American Society of Hypertension; ASPC, American Society for Preventive Cardiology; CLCD, Council on Clinical Cardiology; CVRI, Council on Cardiovascular Radiology and Intervention; KCVD, Council on the Kidney in Cardiovascular Disease; NHLBI, National Heart, Lung, and Blood Institute; NMA, National Medical Association; PAD, peripheral artery disease; PCNA, Preventive Cardiovascular Nurses Association; and SVS, Society for Vascular Surgery.

RI, Council on Cardiovascular Radiology and Intervention; KCVD, Council on the Kidney in Cardiovascular Disease; NHLBI, National Heart, Lung, and Blood Institute; NMA, National Medical Association; PAD, peripheral artery disease; PCNA, Preventive Cardiovascular Nurses Association; and SVS, Society for Vascular Surgery. Table 3 Definition of PAD Key Terms Term Definition Claudication Fatigue, discomfort, cramping, or pain of vascular origin in the muscles of the lower extremities that is consistently induced by exercise and consistently relieved by rest (within 10 min). Acute limb ischemia (ALI) Acute (<2 wk), severe hypoperfusion of the limb characterized by these features: pain, pallor, pulselessness, poikilothermia (cold), paresthesias, and paralysis. One of these categories of ALI is assigned (Section 10): Viable—Limb is not immediately threatened; no sensory loss; no muscle weakness; audible arterial and venous Doppler. Threatened—Mild-to-moderate sensory or motor loss; inaudible arterial Doppler; audible venous Doppler; may be further divided into IIa (marginally threatened) or IIb (immediately threatened). Irreversible—Major tissue loss or permanent nerve damage inevitable; profound sensory loss, anesthetic; profound muscle weakness or paralysis (rigor); inaudible arterial and venous Doppler.33,34 Tissue loss Type of tissue loss: Minor—nonhealing ulcer, focal gangrene with diffuse pedal ischemia. Major—extending above transmetatarsal level; functional foot no longer salvageable.33

Irreversible—Major tissue loss or permanent nerve damage inevitable; profound sensory loss, anesthetic; profound muscle weakness or paralysis (rigor); inaudible arterial and venous Doppler.33,34 Tissue loss Type of tissue loss: Minor—nonhealing ulcer, focal gangrene with diffuse pedal ischemia. Major—extending above transmetatarsal level; functional foot no longer salvageable.33 Critical limb ischemia (CLI) A condition characterized by chronic (≥2 wk) ischemic rest pain, nonhealing wound/ulcers, or gangrene in 1 or both legs attributable to objectively proven arterial occlusive disease. The diagnosis of CLI is a constellation of both symptoms and signs. Arterial disease can be proved objectively with ABI, TBI, TcPO2, or skin perfusion pressure. Supplementary parameters, such as absolute ankle and toe pressures and pulse volume recordings, may also be used to assess for significant arterial occlusive disease. However, a very low ABI or TBI does not necessarily mean the patient has CLI. The term CLI implies chronicity and is to be distinguished from ALI.35

ure. Supplementary parameters, such as absolute ankle and toe pressures and pulse volume recordings, may also be used to assess for significant arterial occlusive disease. However, a very low ABI or TBI does not necessarily mean the patient has CLI. The term CLI implies chronicity and is to be distinguished from ALI.35 In-line blood flow Direct arterial flow to the foot, excluding collaterals. Functional status Patient's ability to perform normal daily activities required to meet basic needs, fulfill usual roles, and maintain health and well-being. Walking ability is a component of functional status. Nonviable limb Condition of extremity (or portion of extremity) in which loss of motor function, neurological function, and tissue integrity cannot be restored with treatment. Salvageable limb Condition of extremity with potential to secure viability and preserve motor function to the weight-bearing portion of the foot if treated. Structured exercise program Planned program that provides individualized recommendations for type, frequency, intensity, and duration of exercise. Program provides recommendations for exercise progression to assure that the body is consistently challenged to increase exercise intensity and levels as functional status improves over time. There are 2 types of structured exercise program for patients with PAD: Supervised exercise program Structured community- or home-based exercise program

In-line blood flow Direct arterial flow to the foot, excluding collaterals. Functional status Patient's ability to perform normal daily activities required to meet basic needs, fulfill usual roles, and maintain health and well-being. Walking ability is a component of functional status. Nonviable limb Condition of extremity (or portion of extremity) in which loss of motor function, neurological function, and tissue integrity cannot be restored with treatment. Salvageable limb Condition of extremity with potential to secure viability and preserve motor function to the weight-bearing portion of the foot if treated. Structured exercise program Planned program that provides individualized recommendations for type, frequency, intensity, and duration of exercise. Program provides recommendations for exercise progression to assure that the body is consistently challenged to increase exercise intensity and levels as functional status improves over time. There are 2 types of structured exercise program for patients with PAD: Supervised exercise program Structured community- or home-based exercise program Supervised exercise program Structured exercise program that takes place in a hospital or outpatient facility in which intermittent walking exercise is used as the treatment modality. Program can be standalone or can be made available within a cardiac rehabilitation program. Program is directly supervised by qualified healthcare provider(s).

Supervised exercise program Structured exercise program that takes place in a hospital or outpatient facility in which intermittent walking exercise is used as the treatment modality. Program can be standalone or can be made available within a cardiac rehabilitation program. Program is directly supervised by qualified healthcare provider(s). Training is performed for a minimum of 30 to 45 min per session, in sessions performed at least 3 times/wk for a minimum of 12 wk.36–46 Patients may not initially achieve these targets, and a treatment goal is to progress to these levels over time. Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest. Warm-up and cool-down periods precede and follow each session of walking. Structured community- or home-based exercise program Structured exercise program that takes place in the personal setting of the patient rather than in a clinical setting.41,47–51 Program is self-directed with the guidance of healthcare providers who prescribe an exercise regimen similar to that of a supervised program. Patient counseling ensures that patients understand how to begin the program, how to maintain the program, and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching and/or use of activity monitors.

Structured community- or home-based exercise program Structured exercise program that takes place in the personal setting of the patient rather than in a clinical setting.41,47–51 Program is self-directed with the guidance of healthcare providers who prescribe an exercise regimen similar to that of a supervised program. Patient counseling ensures that patients understand how to begin the program, how to maintain the program, and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching and/or use of activity monitors. Emergency versus urgent An emergency procedure is one in which life or limb is threatened if the patient is not in the operating room or interventional suite and/or where there is time for no or very limited clinical evaluation, typically within <6 h. An urgent procedure is one in which there may be time for a limited clinical evaluation, usually when life or limb is threatened if the patient is not in the operating room or interventional suite, typically between 6 and 24 h. Interdisciplinary care team A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care.

ines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care. Interdisciplinary care team members may include: Vascular medical and surgical specialists (ie, vascular medicine, vascular surgery, interventional radiology, interventional cardiology) Nurses Orthopedic surgeons and podiatrists Endocrinologists Internal medicine specialists Infectious disease specialists Radiology and vascular imaging specialists Physical medicine and rehabilitation clinicians Orthotics and prosthetics specialists Social workers Exercise physiologists Physical and occupational therapists Nutritionists/dieticians Cardiovascular ischemic events Acute coronary syndrome (acute MI, unstable angina), stroke, or cardiovascular death. Limb-related events Worsening claudication, new CLI, new lower extremity revascularization, or new ischemic amputation. ABI indicates ankle-brachial index; ALI, acute limb ischemia; CLI, critical limb ischemia; MI, myocardial infarction; PAD, peripheral artery disease; TBI, toe-brachial index; and TcPO2, transcutaneous oxygen pressure.

ts Worsening claudication, new CLI, new lower extremity revascularization, or new ischemic amputation. ABI indicates ankle-brachial index; ALI, acute limb ischemia; CLI, critical limb ischemia; MI, myocardial infarction; PAD, peripheral artery disease; TBI, toe-brachial index; and TcPO2, transcutaneous oxygen pressure. Table 4 Patients at Increased Risk of PAD Age ≥65 y Age 50–64 y, with risk factors for atherosclerosis (eg, diabetes mellitus, history of smoking, hyperlipidemia, hypertension) or family history of PAD63 Age <50 y, with diabetes mellitus and 1 additional risk factor for atherosclerosis Individuals with known atherosclerotic disease in another vascular bed (eg, coronary, carotid, subclavian, renal, mesenteric artery stenosis, or AAA) AAA indicates abdominal aortic aneurysm; PAD, peripheral artery disease. Table 5 History and/or Physical Examination Findings Suggestive of PAD History Claudication Other non–joint-related exertional lower extremity symptoms (not typical of claudication) Impaired walking function Ischemic rest pain Physical Examination Abnormal lower extremity pulse examination Vascular bruit Nonhealing lower extremity wound Lower extremity gangrene Other suggestive lower extremity physical findings (eg, elevation pallor/dependent rubor) PAD indicates peripheral artery disease.

cation) Impaired walking function Ischemic rest pain Physical Examination Abnormal lower extremity pulse examination Vascular bruit Nonhealing lower extremity wound Lower extremity gangrene Other suggestive lower extremity physical findings (eg, elevation pallor/dependent rubor) PAD indicates peripheral artery disease. Table 6 Alternative Diagnoses for Leg Pain or Claudication With Normal Physiological Testing (Not PAD-Related) Condition Location Characteristic Effect of Exercise Effect of Rest Effect of Position Other Characteristics Symptomatic Baker's cyst Behind knee, down calf Swelling, tenderness With exercise Also present at rest None Not intermittent Venous claudication Entire leg, worse in calf Tight, bursting pain After walking Subsides slowly Relief speeded by elevation History of iliofemoral deep vein thrombosis; edema; signs of venous stasis Chronic compartment syndrome Calf muscles Tight, bursting pain After much exercise (jogging) Subsides very slowly Relief with rest Typically heavy muscled athletes Spinal stenosis Often bilateral buttocks, posterior leg Pain and weakness May mimic claudication Variable relief but can take a long time to recover Relief by lumbar spine flexion Worse with standing and extending spine Nerve root compression Radiates down leg Sharp lancinating pain Induced by sitting, standing, or walking Often present at rest Improved by change in position History of back problems; worse with sitting; relief when supine or sitting Hip arthritis Lateral hip, thigh Aching discomfort After variable degree of exercise Not quickly relieved Improved when not weight bearing Symptoms variable; history of degenerative arthritis Foot/ankle arthritis Ankle, foot, arch Aching pain After variable degree of exercise Not quickly relieved May be relieved by not bearing weight Symptoms variable; may be related to activity level or present at rest Modified from Norgren L et al.35

not weight bearing Symptoms variable; history of degenerative arthritis Foot/ankle arthritis Ankle, foot, arch Aching pain After variable degree of exercise Not quickly relieved May be relieved by not bearing weight Symptoms variable; may be related to activity level or present at rest Modified from Norgren L et al.35 PAD indicates peripheral artery disease.

not weight bearing Symptoms variable; history of degenerative arthritis Foot/ankle arthritis Ankle, foot, arch Aching pain After variable degree of exercise Not quickly relieved May be relieved by not bearing weight Symptoms variable; may be related to activity level or present at rest Modified from Norgren L et al.35 PAD indicates peripheral artery disease. Table 7 Alternative Diagnoses for Nonhealing Wounds With Normal Physiological Testing (Not PAD-Related) Condition Location Characteristics and Causes Venous ulcer Distal leg, especially above medial mellolus Develops in regions of skin changes due to chronic venous disease and local venous hypertension Typically wet (ie, wound drainage) rather than dry lesion Distal small arterial occlusion (microangiopathy) Toes, foot, leg Diabetic microangiopathy End-stage renal disease Thromboangiitis obliterans (Buerger's) Sickle cell anemia Vasculitis (eg, Churg-Strauss, Henoch-Schonlein purpura, leukocytoclastic vasculitis, microscopic polyangiitis, polyarteritis nodosa) Scleroderma Cryoagglutination Embolic (eg, cholesterol emboli, thromboemboli, endocarditis) Thrombotic (eg, antiphospholipid antibody syndrome, Sneddon's syndrome, warfarin skin necrosis, disseminated intravascular coagulation, livedoid vasculitis, protein C or S deficiency, prolonged vasospasm) Local injury Toes, foot, leg Trauma Insect or animal bite Burn Medication related Toes, foot, leg Drug reactions (eg, erythema multiforme) Medication direct toxicity (eg, doxorubicin, hydroxyurea, some tyrosine kinase inhibitors) Neuropathic Pressure zones of foot Hyperkeratosis surrounds the ulcer Diabetes mellitus with peripheral neuropathy Peripheral neuropathy without diabetes mellitus Leprosy Autoimmune injury Toes, foot, leg With blisters (eg, pemphigoid, pemphigus, epidermolysis bullosa) Without blisters (eg, dermatomyositis, lupus, scleroderma) Infection Toes, foot, leg Bacterial (eg, pseudomonas, necrotizing streptococcus) Fungal (eg, blastomycosis, Madura foot, chromomycosis) Mycobacterial Parasitic (eg, Chagas, leishmaniasis) Viral (eg, herpes) Malignancy Toes, foot, leg Primary skin malignancy Metastatic malignancy Malignant transformation of ulcer Inflammatory Toes, foot, leg Necrobiosis lipoidica Pyoderma gangrenosum Granuloma annulare PAD indicates peripheral artery disease.

momycosis) Mycobacterial Parasitic (eg, Chagas, leishmaniasis) Viral (eg, herpes) Malignancy Toes, foot, leg Primary skin malignancy Metastatic malignancy Malignant transformation of ulcer Inflammatory Toes, foot, leg Necrobiosis lipoidica Pyoderma gangrenosum Granuloma annulare PAD indicates peripheral artery disease. Table 8 Structured Exercise Programs for PAD: Definitions Supervised exercise program (COR I, LOE A) Program takes place in a hospital or outpatient facility. Program uses intermittent walking exercise as the treatment modality. Program can be standalone or within a cardiac rehabilitation program. Program is directly supervised by qualified healthcare provider(s). Training is performed for a minimum of 30–45 min/session; sessions are performed at least 3 times/wk for a minimum of 12 wk.36–46 Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest. Warm-up and cool-down periods precede and follow each session of walking. Structured community- or home-based exercise program (COR IIa, LOE A) Program takes place in the personal setting of the patient rather than in a clinical setting.41,47–51 Program is self-directed with guidance of healthcare providers. Healthcare providers prescribe an exercise regimen similar to that of a supervised program. Patient counseling ensures understanding of how to begin and maintain the program and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching or use of activity monitors. COR indicates Class of Recommendation; LOE, Level of Evidence; and PAD, peripheral artery disease.

egin and maintain the program and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching or use of activity monitors. COR indicates Class of Recommendation; LOE, Level of Evidence; and PAD, peripheral artery disease. Table 9 Interdisciplinary Care Team for PAD A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care. Interdisciplinary care team members may include: Vascular medical and surgical specialists (ie, vascular medicine, vascular surgery, interventional radiology, interventional cardiology) Nurses Orthopedic surgeons and podiatrists Endocrinologists Internal medicine specialists Infectious disease specialists Radiology and vascular imaging specialists Physical medicine and rehabilitation clinicians Orthotics and prosthetics specialists Social workers Exercise physiologists Physical and occupational therapists Nutritionists/dieticians CLI indicates critical limb ischemia; and PAD, peripheral artery disease.

sease specialists Radiology and vascular imaging specialists Physical medicine and rehabilitation clinicians Orthotics and prosthetics specialists Social workers Exercise physiologists Physical and occupational therapists Nutritionists/dieticians CLI indicates critical limb ischemia; and PAD, peripheral artery disease. Table 10 Therapy for CLI: Findings That Prompt Consideration of Surgical or Endovascular Revascularization Findings That Favor Consideration of Surgical Revascularization Examples Factors associated with technical failure or poor durability with endovascular treatment  Lesion involving common femoral artery, including origin of deep femoral artery Long segment lesion involving the below-knee popliteal and/or infrapopliteal arteries in a patient with suitable single-segment autogenous vein conduit Diffuse multilevel disease that would require endovascular revascularization at multiple anatomic levels Small-diameter target artery proximal to site of stenosis or densely calcified lesion at location of endovascular treatment Endovascular treatment likely to preclude or complicate subsequent achievement of in-line blood flow through surgical revascularization  Single-vessel runoff distal to ankle Findings That Favor Consideration of Endovascular Revascularization Examples The presence of patient comorbidities may place patients at increased risk of perioperative complications from surgical revascularization. In these patients, an endovascular-first approach should be used regardless of anatomy  Patient comorbidities, including coronary ischemia, cardiomyopathy, congestive heart failure, severe lung disease, and chronic kidney disease Patients with rest pain and disease at multiple levels may undergo a staged approach as part of endovascular-first approach  In-flow disease can be addressed first, and out-flow disease can be addressed in a staged manner, when required, if clinical factors or patient safety prevent addressing all diseased segments at one setting Patients without suitable autologous vein for bypass grafts  Some patients have had veins harvested for previous coronary artery bypass surgery and do not have adequate remaining veins for use as conduits. Similarly, patients may not have undergone prior saphenous vein harvest, but available vein is of inadequate diameter CLI indicates critical limb ischemia.

for bypass grafts  Some patients have had veins harvested for previous coronary artery bypass surgery and do not have adequate remaining veins for use as conduits. Similarly, patients may not have undergone prior saphenous vein harvest, but available vein is of inadequate diameter CLI indicates critical limb ischemia. Appendix 1 Author Relationships With Industry and Other Entities (Relevant)—2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease (March 2014) Committee Member Employment Consultant Speakers Bureau Ownership/Partnership /Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Marie D. Gerhard-Herman, Chair Harvard Medical School—Associate Professor None None None None None None None Heather L. Gornik, Vice Chair Cleveland Clinic Foundation, Cardiovascular Medicine—Medical Director, Noninvasive Vascular Laboratory None None Summit Doppler Systems Zin Medical Astra Zeneca Theravasc None None 3.1, 3.2, 5.1–5.3, and 5.6. Coletta Barrett Our Lady of the Lake Regional Medical Center—Vice President None None None None None None None Neal R. Barshes Baylor College of Medicine, Division of Vascular Surgery and Endovascular Therapy Michael E. DeBakey Department of Surgery—Assistant Professor None None None None None None None Matthew A. Corriere University of Michigan—Frankel Professor of Cardiovascular Surgery, Associate Professor of Surgery None None None None None None None Douglas E. Drachman Massachusetts General Hospital—Training Director Abbott Vascular

akey Department of Surgery—Assistant Professor None None None None None None None Matthew A. Corriere University of Michigan—Frankel Professor of Cardiovascular Surgery, Associate Professor of Surgery None None None None None None None Douglas E. Drachman Massachusetts General Hospital—Training Director Abbott Vascular St. Jude Medical None None Atrium Medical Bard Lutonix None None 4, 8.1.1–9.1.2, and 10.2.2. Lee A. Fleisher University of Pennsylvania Health System Department of Anesthesiology and Critical Care—Chair None None None None None None None Francis Gerry R. Fowkes University of Edinburgh—Emeritus Professor of Epidemiology AstraZeneca† Bayer Merck None None None None None 5.1–5.3, 5.6, 5.10, 7, and 9.2. Naomi M. Hamburg Boston University School of Medicine, Cardiovascular Medicine Section—Associate Professor of Medicine None None None None None None None Scott Kinlay VA Boston Healthcare System—Associate Chief, Cardiology Director, Cardiac Catheterization Laboratory & Vascular Medicine None None None Medtronic† The Medicines Company† None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1, and 10.2.2. Robert Lookstein Mount Sinai Medical Center—Chief, Interventional Radiology; Professor of Radiology and Surgery; Vice Chair, Department of Radiology Boston Scientific Medrad Interventional Possis The Medicines Company Cordis‡ None Shockwave (DSMB) None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1, and 10.2.2. Sanjay Misra Mayo Clinic, Division of Vascular and Interventional Radiology—Professor; Department of Radiology— Interventional Radiologist None None None Johnson & Johnson (DSMB)

None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1, and 10.2.2. Robert Lookstein Mount Sinai Medical Center—Chief, Interventional Radiology; Professor of Radiology and Surgery; Vice Chair, Department of Radiology Boston Scientific Medrad Interventional Possis The Medicines Company Cordis‡ None Shockwave (DSMB) None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1, and 10.2.2. Sanjay Misra Mayo Clinic, Division of Vascular and Interventional Radiology—Professor; Department of Radiology— Interventional Radiologist None None None Johnson & Johnson (DSMB) None None 4, 7, 8, and 10.2.2. Leila Mureebe Duke University Medical Center—Associate Professor of Surgery, Division of Vascular Surgery None None None None None None None Jeffrey W. Olin Ichan School of Medicine at Mount Sinai, Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health—Professor of Medicine, Cardiology; Director, Vascular Medicine AstraZeneca Merck Novartis Plurestem None Northwind† AstraZeneca† None None 5.1–5.3, 5.6, 5.10, and 12. Rajan A.G. Patel John Ochsner Heart & Vascular Center, Ochsner Clinical School, University of Queensland School of Medicine— Senior Lecturer None None None None None None None Judith G. Regensteiner University of Colorado, Health Sciences Center, Division of Cardiology—Associate Professor of Medicine None None None None None None None Andres Schanzer University of Massachusetts Medical School—Professor of Surgery and Quantitative Health Sciences; Program Director, Vascular Surgery Residency Cook Medical

gensteiner University of Colorado, Health Sciences Center, Division of Cardiology—Associate Professor of Medicine None None None None None None None Andres Schanzer University of Massachusetts Medical School—Professor of Surgery and Quantitative Health Sciences; Program Director, Vascular Surgery Residency Cook Medical None None None None None 4, 8.1.1, 9.1.1, and 10.2.2. Mehdi H. Shishehbor Cleveland Clinic, Interventional Cardiology and Vascular Medicine— Director, Endovascular Services Boston Scientific‡ Medtronic‡ None None None Atrium Medical AstraZeneca†

gensteiner University of Colorado, Health Sciences Center, Division of Cardiology—Associate Professor of Medicine None None None None None None None Andres Schanzer University of Massachusetts Medical School—Professor of Surgery and Quantitative Health Sciences; Program Director, Vascular Surgery Residency Cook Medical None None None None None 4, 8.1.1, 9.1.1, and 10.2.2. Mehdi H. Shishehbor Cleveland Clinic, Interventional Cardiology and Vascular Medicine— Director, Endovascular Services Boston Scientific‡ Medtronic‡ None None None Atrium Medical AstraZeneca† None 4, 8.1.1– 9.1.2, and 10.2.2. Kerry J. Stewart Johns Hopkins University, School of Medicine; Johns Hopkins Bayview Medical Center— Professor of Medicine; Director, Clinical and Research Exercise Physiology None None None None None None None Diane Treat-Jacobson University of Minnesota, School of Nursing— Professor None None None None None None None M. Eileen Walsh University of Toledo, College of Nursing— Professor None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person's household, has a reasonable potential for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document.

rug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person's household, has a reasonable potential for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document. * Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. † Significant relationship. ‡ No financial benefit. ACC indicates American College of Cardiology; AHA, American Heart Association; DSMB, data safety monitoring board; and VA, Veterans Affairs. Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)—2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease (March 2016) Reviewer Representation Employment Consultant Speakers Bureau Ownership/Partnership /Principal Personal Research Institutional,Organizational, or Other FinancialBenefit Expert Witness Deepak L. Bhatt Official Reviewer—ACC Board of Trustees Brigham and Women's Hospital— Executive Director of Interventional Cardiovascular Programs; Harvard Medical School—Professor of Medicine Elsevier None None Amarin* Amgen* AstraZeneca* Bristol-Myers Squibb* Cardax† Eisai* Ethicon* FlowCo† Forest Laboratories* Ischemix* Mayo Clinic Medtronic* Merck† Pfzer* PLx Pharma† Regado Biosciences† Roche* Sanof-aventis* St. Jude Medical Takeda† The Medicines Company* WebMD* Belvoir Publications (Editor)* Biotronik Boston Scientific Clinical Cardiology(Deputy Editor)† Harvard Clinical Research Institute HMP Communications (Editor)*

Bristol-Myers Squibb* Cardax† Eisai* Ethicon* FlowCo† Forest Laboratories* Ischemix* Mayo Clinic Medtronic* Merck† Pfzer* PLx Pharma† Regado Biosciences† Roche* Sanof-aventis* St. Jude Medical Takeda† The Medicines Company* WebMD* Belvoir Publications (Editor)* Biotronik Boston Scientific Clinical Cardiology(Deputy Editor)† Harvard Clinical Research Institute HMP Communications (Editor)* Duke Clinical Research Institute* Journal of Invasive Cardiology (Editor)* Medscape Cardiology Slack Publications (Editor)* St. Jude Medical VA Healthcare System† None Mark A. Creager Official Reviewer—AHA Dartmouth-Hitchcock Medical Center— Director None None None None AHA (Past President)† None Philip Goodney Official Reviewer—AHA Dartmouth-Hitchcock—Associate Professor of Surgery and The Dartmouth Institute Director None None None NIH* NIH None John S. Ikonomidis Official Reviewer—ACC/ AHA Task Force on Clinical Practice Guidelines Medical University of South Carolina—Chief None None None None None None Amy W. Pollak Official Reviewer—AHA Mayo Clinic—Cardiovascular Medicine Physician None None None None None None Michael D. White Official Reviewer—ACC Board of Governors Catholic Health Initiatives—Chief Academic Officer Anthera Pharmaceuticals† None None AstraZeneca† None None Ehrin J. Armstrong Organizational Reviewer—SVM University of Colorado—Director, Interventional Cardiology Abbott Medtronic Merck Spectranetics

None John S. Ikonomidis Official Reviewer—ACC/ AHA Task Force on Clinical Practice Guidelines Medical University of South Carolina—Chief None None None None None None Amy W. Pollak Official Reviewer—AHA Mayo Clinic—Cardiovascular Medicine Physician None None None None None None Michael D. White Official Reviewer—ACC Board of Governors Catholic Health Initiatives—Chief Academic Officer Anthera Pharmaceuticals† None None AstraZeneca† None None Ehrin J. Armstrong Organizational Reviewer—SVM University of Colorado—Director, Interventional Cardiology Abbott Medtronic Merck Spectranetics None None None None None Bernadette Aulivola Organizational Reviewer—VESS Loyola University medical Center, Stritch School of Medicine—Director, Division of Vascular Surgery and Endovascular Therapy; Associate Professor, Department of Surgery; Program Director, Vascular Surgery Fellowship; Medical Director, Vascular Noninvasive lab None None None None None None Alison Bailey Organizational Reviewer—AACVPR University of Tennessee Chattanooga—Cardiologist None None None CSL Behring AACVPR† ZOLL Medical None Todd Brown Organizational Reviewer—AACVPR University of Alabama at Birmingham—Associate Professor None None None Amgen* Omthera† NIH* None None Kristen Columbia Organizational Reviewer—SVN University of Maryland Baltimore Washington Medical Center, Maryland Vascular Center—Nurse practitioner None None None None None None Michael S. Conte Organizational Reviewer—SVS University of California San Francisco—Professor and Chief Cook Medical Medtronic None None Bard University of California Department of Surgery

None None Kristen Columbia Organizational Reviewer—SVN University of Maryland Baltimore Washington Medical Center, Maryland Vascular Center—Nurse practitioner None None None None None None Michael S. Conte Organizational Reviewer—SVS University of California San Francisco—Professor and Chief Cook Medical Medtronic None None Bard University of California Department of Surgery None Alik Farber Organizational Reviewer—SCVS Boston Medical Center—Chief, Division of Vascular Surgery Bard† None None None None None Robert Feezor Organizational Reviewer—VESS University of Florida—Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy Cook Medical* Medtronic Terumo None None Cook Medical Cook Medical Novate Defendant, peripheral angioplasty, 2015 Dmitriy N. Feldman Organizational Reviewer—SCAI Weill Cornell Medical College, New York Presbyterian Hospital—Associate Professor of Medicine AstraZeneca Abbott Bristol-Myers Squibb† Daiichi-Sankyo Eli Lilly Medtronic Pfizer The Medicines Company None None Biotronic The Medicines Company None Jonathan Golledge Organizational Reviewer—TASC James Cook University—Professor, Department of Surgery, Head of Vascular Biology Unit None None None James Cook University* None None Bruce H. Gray Organizational Reviewer—SCAI Greenville Health System—Director of Clinical Trials, Department of Surgery None Medtronic† None Abbott† W.L. Gore† NCDR† ACC† None William R. Hiatt Organizational Reviewer—TASC Colorado Prevention Center—Professor of Medicine None None None AstraZeneca* Bayer* CSI Kowa Kyushu University Merck Pluristem* ReNeuron CPC Clinical Research* NIH*

None None Bruce H. Gray Organizational Reviewer—SCAI Greenville Health System—Director of Clinical Trials, Department of Surgery None Medtronic† None Abbott† W.L. Gore† NCDR† ACC† None William R. Hiatt Organizational Reviewer—TASC Colorado Prevention Center—Professor of Medicine None None None AstraZeneca* Bayer* CSI Kowa Kyushu University Merck Pluristem* ReNeuron CPC Clinical Research* NIH* None Joseph Mills Organizational Reviewer—SVS Baylor College of Medicine—Professor and Chief, Division of Vascular surgery and Endovascular Therapy None None None None AnGes Bayer Cesca None Mohammad Reza Rajebi Organizational Reviewer—SIR University of Colorado Denver— Assistant Professor None None None None None None Mitchell J. Silver Organizational Reviewer—SVM McConnell Heart Hospital for Critical Limb Care—Director of Vascular Imaging Boston Scientific W.L. Gore Medtronic Bristol-Myers Squibb* Pfzer* Contego Medical* None W.L. Gore Medtronic NIH None Lily Thomson Organizational Reviewer—SVN Hôpital St-Boniface Hospital—Clinical Research Coordinator, Vascular Surgery Nurse, Section of Vascular Surgery, Health Sciences Centre None None None None None None Sana M. Al-Khatib Content Reviewer—ACC/ AHA Task Force on Clinical Practice Guidelines Duke Clinical Research Institute—Associate Professor of Medicine None None None FDA* NHLBI* PCORI* VA (DSMB) HRS (Board of Trustees)† Elsevier* None Herbert Aronow Content Reviewer—ACC Peripheral Vascular Disease Member Section Rhode Island Hospital—Director of Cardiac Catheterization Laboratories None None None Silk Road Medical† Saint Luke's Health System The Medicines Company† Bard NIH PCORI† SVM† W.L. Gore

None Lily Thomson Organizational Reviewer—SVN Hôpital St-Boniface Hospital—Clinical Research Coordinator, Vascular Surgery Nurse, Section of Vascular Surgery, Health Sciences Centre None None None None None None Sana M. Al-Khatib Content Reviewer—ACC/ AHA Task Force on Clinical Practice Guidelines Duke Clinical Research Institute—Associate Professor of Medicine None None None FDA* NHLBI* PCORI* VA (DSMB) HRS (Board of Trustees)† Elsevier* None Herbert Aronow Content Reviewer—ACC Peripheral Vascular Disease Member Section Rhode Island Hospital—Director of Cardiac Catheterization Laboratories None None None Silk Road Medical† Saint Luke's Health System The Medicines Company† Bard NIH PCORI† SVM† W.L. Gore Joshua A. Beckman Content Reviewer Vanderbilt University Medical Center— Director AstraZeneca* Merck* Sanof* None EMX† JanaCare† Bristol-Myers Squibb* Merck* NIH Vascular Interventional Advances Defendant, venous thrombo-embolism, 2015* James C. Blankenship Content Reviewer Geisinger Medical Center—Staff Physician; Director, Cardiac Catheterization Laboratory None None None Abbott† AstraZeneca† Boston Scientific† GlaxoSmithKline† Hamilton Health Sciences† Medinal LTD† Orexigen Therapeutics† St. Jude Medical† Stentys† Takeda Pharmaceuticals† SCAI (Past President)† AMA† None Biykem Bozkurt Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines Michael E. DeBakey VA Medical Center—The Mary and Gordon Cain Chair and Professor of Medicine None None None Novartis

Hamilton Health Sciences† Medinal LTD† Orexigen Therapeutics† St. Jude Medical† Stentys† Takeda Pharmaceuticals† SCAI (Past President)† AMA† None Biykem Bozkurt Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines Michael E. DeBakey VA Medical Center—The Mary and Gordon Cain Chair and Professor of Medicine None None None Novartis None None Joaquin E. Cigarroa Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines Oregon Health and Science University—Clinical Professor of Medicine None None None None ACC/AHA† AHA† ASA† Catheterization and Cardiovascular Intervention† Portland Metro Area AHA(President)† SCAI Quality Interventional Council† NIH None Federico Gentile Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines Centro Medico Diagnostico—Director, Cardiovascular Disease None None None None None None Anuj Gupta Content Reviewer—ACC Peripheral Vascular Disease Member Section University of Maryland—Assistant Professor of Medicine None None None Seimens* Medtronic† Direct Flow Medical† Edwards† None John Jeb Hallett Content Reviewer Medical University of South Carolina—Clinical Professor of Surgery None None None None None None Alan Hirsch Content Reviewer University of Minnesota Medical School—Professor of Medicine, Epidemiology and Community Health, and Director Vascular Medicine Program Merck* Novartis† None None Bayer* Pluristem (PLX-PAD trial-PI)† AstraZeneca (EUCLID trial–PI)† Pluristem* AHA† Tactile Medical*

None John Jeb Hallett Content Reviewer Medical University of South Carolina—Clinical Professor of Surgery None None None None None None Alan Hirsch Content Reviewer University of Minnesota Medical School—Professor of Medicine, Epidemiology and Community Health, and Director Vascular Medicine Program Merck* Novartis† None None Bayer* Pluristem (PLX-PAD trial-PI)† AstraZeneca (EUCLID trial–PI)† Pluristem* AHA† Tactile Medical* None Mark A. Hlatky Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines Stanford University School of Medicine—Professor of Health Research and Policy, Professor of Medicine Acumen* Genentech None None Blue Cross/Blue Shield Center for Effectiveness Evaluation* George Institute HeartFlow* NHLBI Sanofi-aventis ACC (Associate Editor)* None Michael R. Jaff Content Reviewer Newton-Wellesley Hospital; Harvard Medical School— Professor of Medicine AOPA Cardinal Health Covidien† Micell Vascular Therapies None MC10† Janacare† Northwind PQ Bypass Primacea SanoV Valiant Medical Abbott† Boston Scientific† Cordis† IC Sciences Medtronic† Novello CBSET Intersocietal Accreditation Commission SCAI† VIVA Physicians Group*

ACC (Associate Editor)* None Michael R. Jaff Content Reviewer Newton-Wellesley Hospital; Harvard Medical School— Professor of Medicine AOPA Cardinal Health Covidien† Micell Vascular Therapies None MC10† Janacare† Northwind PQ Bypass Primacea SanoV Valiant Medical Abbott† Boston Scientific† Cordis† IC Sciences Medtronic† Novello CBSET Intersocietal Accreditation Commission SCAI† VIVA Physicians Group* None José A. Joglar Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines UT Southwestern Medical Center—Professor of Internal Medicine; Clinical Cardiac Electrophysiology—Fellowship Program Director None None None None None None Glenn N. Levine Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines Baylor College of Medicine—Professor of Medicine; Director, Cardiac Care Unit None None None None None None Khusrow Niazi Content Reviewer—ACC Peripheral Vascular Disease Member Section Emory University Department of Medicine—Associate Professor of Medicine None Medtronic* None Bard Impeto Terumo None Plaintiff, MI resulting in death, 2015* Paul D. Varosy Content Reviewer—Task Force on Performance Measures VA Eastern Colorado Health Care System—Associate Professor None None None VA Health Services Research and Development (PI)* AHA (Guest Editor)† None Christopher J. White Content Reviewer Ochsner Clinical School, University of Queensland—Chairman, Department of Cardiology Neovasc None None AstraZeneca Pharmaceuticals NIH Neovasc Surmodics ACE (Board of Directors)†

Paul D. Varosy Content Reviewer—Task Force on Performance Measures VA Eastern Colorado Health Care System—Associate Professor None None None VA Health Services Research and Development (PI)* AHA (Guest Editor)† None Christopher J. White Content Reviewer Ochsner Clinical School, University of Queensland—Chairman, Department of Cardiology Neovasc None None AstraZeneca Pharmaceuticals NIH Neovasc Surmodics ACE (Board of Directors)† None This table represents all relationships of reviewers with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/ relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. * Significant relationship. † No financial benefit.

None This table represents all relationships of reviewers with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/ relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. * Significant relationship. † No financial benefit. AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; ACC, American College of Cardiology; ACE, Accreditation for Cardiovascular Excellence; AHA, American Heart Association; AMA, American Medical Association; DSMB, data and safety monitoring board; EUCLID, Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease; FDA, US Food and Drug Administration; HRS, Heart Rhythm Society; MI, myocardial infarction; NCDR, National Cardiovascular Data Registry; NIH, National Institutes of Health; NHLBI, National Heart, Lung, and Blood Institute; PCORI, Patient-Centered Outcomes Research Institute; PI, primary investigator; PLX-PAD, placental-derived adherent stromal cell; SCAI, Society for Cardiovascular Angiography and Interventions; SCVS, Society for Clinical Vascular Surgery; SIR, Society of Interventional Radiology; SVM, Society for Vascular Medicine; SVN, Society for Vascular Nursing; SVS, Society for Vascular Surgery; TASC, Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease; VA, Veterans Affairs; VESS, Vascular and Endovascular Surgery Society; and VIVA, Vascular Intervention Advances.

logy; SVM, Society for Vascular Medicine; SVN, Society for Vascular Nursing; SVS, Society for Vascular Surgery; TASC, Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease; VA, Veterans Affairs; VESS, Vascular and Endovascular Surgery Society; and VIVA, Vascular Intervention Advances. Appendix 3 Abbreviations AAA = abdominal aortic aneurysm ABI = ankle-brachial index ALI = acute limb ischemia CAD = coronary artery disease CLI = critical limb ischemia CTA = computed tomography angiography DAPT = dual antiplatelet therapy DES = drug-eluting stent(s) GDMT = guideline-directed management and therapy MI = myocardial infarction MRA = magnetic resonance angiography PAD = peripheral artery disease PTA = percutaneous transluminal angioplasty RCT = randomized controlled trial SPP = skin perfusion pressure TBI = toe-brachial index TcPO2 = transcutaneous oxygen pressure QoL = quality of life

1. Introduction 1.1. Methodology and Evidence Review The recommendations listed in this guideline are, whenever possible, evidence based. An initial extensive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline, was conducted from January through September 2015. Key search words included but were not limited to the following: acute limb ischemia, angioplasty, ankle-brachial index, anticoagulation, antiplatelet therapy, atypical leg symptoms, blood pressure lowering/hypertension, bypass graft/bypass grafting/surgical bypass, cilostazol, claudication/intermittent claudication, critical limb ischemia/severe limb ischemia, diabetes, diagnostic testing, endovascular therapy, exercise rehabilitation/exercise therapy/exercise training/ supervised exercise, lower extremity/foot wound/ulcer, peripheral artery disease/peripheral arterial disease/ peripheral vascular disease/lower extremity arterial disease, smoking/smoking cessation, statin, stenting, and vascular surgery. Additional relevant studies published through September 2016, during the guideline writing process, were also considered by the writing committee, and added to the evidence tables when appropriate. The final evidence tables included in the Online Data Supplement summarize the evidence utilized by the writing committee to formulate recommendations. Additionally, the writing committee reviewed documents related to lower extremity PAD previously published by the ACC and AHA.10,11 References selected and published in this document are representative and not all-inclusive.

pplement summarize the evidence utilized by the writing committee to formulate recommendations. Additionally, the writing committee reviewed documents related to lower extremity PAD previously published by the ACC and AHA.10,11 References selected and published in this document are representative and not all-inclusive. As stated in the Preamble, the ACC/AHA guideline methodology provides for commissioning an independent ERC to address systematic review questions (PICOTS format) to inform recommendations developed by the writing committee. All other guideline recommendations (not based on the systematic review questions) were also subjected to an extensive evidence review process. For this guideline, the writing committee in conjunction with the Task Force and ERC Chair identified the following systematic review questions: 1) Is antiplatelet therapy beneficial for prevention of cardiovascular events in the patient with symptomatic or asymptomatic lower extremity PAD? 2) What is the effect of revascularization, compared with optimal medical therapy and exercise training, on functional outcome and quality of life (QoL) among patients with claudication? Each question has been the subject of recently published, systematic evidence reviews.12–14 The quality of these evidence reviews was appraised by the ACC/AHA methodologist and a vendor contracted to support this process (Doctor Evidence [Santa Monica, CA]). Few substantive randomized or nonrandomized studies had been published after the end date of the literature searches used for the existing evidence reviews, so the ERC concluded that no additional systematic review was necessary to address either of these critical questions.

rocess (Doctor Evidence [Santa Monica, CA]). Few substantive randomized or nonrandomized studies had been published after the end date of the literature searches used for the existing evidence reviews, so the ERC concluded that no additional systematic review was necessary to address either of these critical questions. A third systematic review question was then identified: 3) Is one revascularization strategy (endovascular or surgical) associated with improved cardiovascular and limb-related outcomes in patients with critical limb ischemia (CLI)? This question had also been the subject of a high-quality systematic review that synthesized evidence from observational data and an RCT15; additional RCTs addressing this question are ongoing.16–18 The writing committee and the Task Force decided to expand the survey to include more relevant randomized and observational studies. Based on evaluation of this additional evidence the ERC decided that further systematic review was not needed to inform the writing committee on this question. Hence, the ERC and writing committee concluded that available systematic reviews could be used to inform the development of recommendations addressing each of the 3 systematic review questions specified above. The members of the Task Force and writing committee thank the members of the ERC that began this process and their willingness to participate in this volunteer effort. They include Aruna Pradhan, MD, MPH (ERC Chair); Natalie Evans, MD; Peter Henke, MD; Dharam J. Kumbhani, MD, SM, FACC; and Tamar Polonsky, MD.

r the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, Society for Vascular Surgery, and Vascular and Endovascular Surgery Society. 1.4. Scope of Guideline Lower extremity PAD is a common cardiovascular disease that is estimated to affect approximately 8.5 million Americans above the age of 40 years and is associated with significant morbidity, mortality, and QoL impairment.19 It has been estimated that 202 million people worldwide have PAD.20 The purpose of this document is to provide a contemporary guideline for diagnosis and management of patients with lower extremity PAD. This document supersedes recommendations related to lower extremity PAD in the “ACC/AHA 2005 Guidelines for the Management of Patients With Peripheral Arterial Disease”10 and the “2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease.”11 The scope of this guideline is limited to atherosclerotic disease of the lower extremity arteries (PAD) and includes disease of the aortoiliac, femoropopliteal, and infrapopliteal arterial segments. It does not address nonatherosclerotic causes of lower extremity arterial disease, such as vasculitis, fibromuscular dysplasia, physiological entrapment syndromes, cystic adventitial disease, and other entities. Future guidelines will address aneurysmal disease of the abdominal aorta and lower extremity arteries and diseases of the renal and mesenteric arteries.

s of lower extremity arterial disease, such as vasculitis, fibromuscular dysplasia, physiological entrapment syndromes, cystic adventitial disease, and other entities. Future guidelines will address aneurysmal disease of the abdominal aorta and lower extremity arteries and diseases of the renal and mesenteric arteries. For the purposes of this guideline, key terms associated with PAD are defined in Table 2. 2. Clinical Assessment For Pad Evaluating the patient at increased risk of PAD (Table 3) begins with the clinical history, review of symptoms, and physical examination. The symptoms and signs of PAD are variable. Patients with PAD may experience the classic symptom of claudication or may present with advanced disease, including CLI. Studies have demonstrated that the majority of patients with confirmed PAD do not have typical claudication but have other non-joint-related limb symptoms (atypical leg symptoms) or are asymptomatic.40,41 Patients with PAD who have atypical leg symptoms or no symptoms may have functional impairment comparable to patients with claudication.42 The vascular examination for PAD includes pulse palpation, auscultation for femoral bruits, and inspection of the legs and feet. Lower extremity pulses are assessed and rated as follows: 0, absent; 1, diminished; 2, normal; or 3, bounding. See Table 4 for history and physical examination findings suggestive of PAD. To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing (Section 3), generally with the ankle-brachial index (ABI) as the initial test.

absent; 1, diminished; 2, normal; or 3, bounding. See Table 4 for history and physical examination findings suggestive of PAD. To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing (Section 3), generally with the ankle-brachial index (ABI) as the initial test. Patients with confirmed diagnosis of PAD are at increased risk for subclavian artery stenosis.43–45 An inter-arm blood pressure difference of >15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis. Measuring blood pressure in both arms identifies the arm with the highest systolic pressure, a requirement for accurate measurement of the ABI.46 Identification of unequal blood pressures in the arms also allows for more accurate measurement of blood pressure in the treatment of hypertension (ie, blood pressure is taken at the arm with higher measurements). See Online Data Supplements 1 and 2 for data supporting Section 2. 2.1. History and Physical Examination: Recommendations Recommendations for History and Physical Examination COR LOE Recommendations I B-NR Patients at increased risk of PAD (Table 3) should undergo a comprehensive medical history and a review of symptoms to assess for exertional leg symptoms, including claudication or other walking impairment, ischemic rest pain, and nonhealing wounds.40–42,47–49

Recommendations for History and Physical Examination COR LOE Recommendations I B-NR Patients at increased risk of PAD (Table 3) should undergo a comprehensive medical history and a review of symptoms to assess for exertional leg symptoms, including claudication or other walking impairment, ischemic rest pain, and nonhealing wounds.40–42,47–49 I B-NR Patients at increased risk of PAD (Table 3) should undergo vascular examination, including palpation of lower extremity pulses (ie, femoral, popliteal, dorsalis pedis, and posterior tibial), auscultation for femoral bruits, and inspection of the legs and feet.48,50,51 I B-NR Patients with PAD should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment.43–45

I B-NR Patients at increased risk of PAD (Table 3) should undergo vascular examination, including palpation of lower extremity pulses (ie, femoral, popliteal, dorsalis pedis, and posterior tibial), auscultation for femoral bruits, and inspection of the legs and feet.48,50,51 I B-NR Patients with PAD should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment.43–45 3. Diagnostic Testing For The Patient With Suspected Lower Extremity Pad (Claudication or Cli): Recommendations History or physical examination findings suggestive of PAD need to be confirmed with diagnostic testing. The resting ABI is the initial diagnostic test for PAD and may be the only test required to establish the diagnosis and institute GDMT The resting ABI is a simple, noninvasive test that is obtained by measuring systolic blood pressures at the arms (brachial arteries) and ankles (dorsalis pedis and posterior tibial arteries) in the supine position by using a Doppler device. The ABI of each leg is calculated by dividing the higher of the dorsalis pedis pressure or posterior tibial pressure by the higher of the right or left arm blood pressure.46 Segmental lower extremity blood pressures and Doppler or plethysmographic waveforms (pulse volume recordings) are often performed along with the ABI and can be used to localize anatomic segments of disease (eg, aortoiliac, femoropopliteal, infrapopliteal).22,53,54

y the higher of the right or left arm blood pressure.46 Segmental lower extremity blood pressures and Doppler or plethysmographic waveforms (pulse volume recordings) are often performed along with the ABI and can be used to localize anatomic segments of disease (eg, aortoiliac, femoropopliteal, infrapopliteal).22,53,54 Depending on the clinical presentation (eg, claudication or CLI) and the resting ABI values, additional physiological testing studies may be indicated, including exercise treadmill ABI testing, measurement of the toe-brachial index (TBI), and additional perfusion assessment measures (eg, transcutaneous oxygen pressure [TcPO2], or skin perfusion pressure [SPP]). Exercise treadmill ABI testing is important to objectively measure functional limitations attributable to leg symptoms and is useful in establishing the diagnosis of lower extremity PAD in the symptomatic patient when resting ABIs are normal or borderline.54–59 The TBI is used to establish the diagnosis of PAD in the setting of non-compressible arteries (ABI >1.40) and may also be used to assess perfusion in patients with suspected CLI. Studies for anatomic imaging assessment (duplex ultrasound, computed tomography angiography [CTA], or magnetic resonance angiography [MRA], invasive angiography) are generally reserved for highly symptomatic patients in whom revascularization is being considered. Depending on the modality, these studies may confer procedural risk.

anatomic imaging assessment (duplex ultrasound, computed tomography angiography [CTA], or magnetic resonance angiography [MRA], invasive angiography) are generally reserved for highly symptomatic patients in whom revascularization is being considered. Depending on the modality, these studies may confer procedural risk. See Table 5 for alternative causes of leg pain in the patient with normal ABI and physiological testing; Figure 1 for the algorithm on diagnostic testing for suspected PAD and claudication; Table 6 for alternative causes of nonhealing wounds in patients without PAD; Figure 2 for the algorithm on diagnostic testing for suspected CLI; and Online Data Supplements 3 to 7 for data supporting Section 3. 3.1. Resting ABI for Diagnosing PAD Recommendations for Resting ABI for Diagnosing PAD COR LOE Recommendations I B-NR In patients with history or physical examination findings suggestive of PAD (Table 4), the resting ABI, with or without segmental pressures and waveforms, is recommended to establish the diagnosis.60–65 I C-LD Resting ABI results should be reported as abnormal (ABI ≤0.90), borderline (ABI 0.91–0.99), normal (1.00–1.40), or noncompressible (ABI >1.40).46,63–66 IIa B-NR In patients at increased risk of PAD (Table 3) but without history or physical examination findings suggestive of PAD (Table 4), measurement of the resting ABI is reasonable.41,42,67–89 III: No Benefit B-NR In patients not at increased risk of PAD (Table 3) and without history or physical examination findings suggestive of PAD (Table 4), the ABI is not recommended.87,90 3.2. Physiological Testing

IIa B-NR In patients at increased risk of PAD (Table 3) but without history or physical examination findings suggestive of PAD (Table 4), measurement of the resting ABI is reasonable.41,42,67–89 III: No Benefit B-NR In patients not at increased risk of PAD (Table 3) and without history or physical examination findings suggestive of PAD (Table 4), the ABI is not recommended.87,90 3.2. Physiological Testing Recommendations for Physiological Testing COR LOE Recommendations I B-NR Toe-brachial index (TBI) should be measured to diagnose patients with suspected PAD when the ABI is greater than 1.40.66,91–94 I B-NR Patients with exertional non–joint-related leg symptoms and normal or borderline resting ABI (>0.90 and ≤1.40) should undergo exercise treadmill ABI testing to evaluate for PAD.54–59 IIa B-NR In patients with PAD and an abnormal resting ABI (≤0.90), exercise treadmill ABI testing can be useful to objectively assess functional status.54–59 IIa B-NR In patients with normal (1.00–1.40) or borderline (0.91–0.99) ABI in the setting of nonhealing wounds or gangrene, it is reasonable to diagnose CLI by using TBI with waveforms, TcPO2, or SPP.95–99 IIa B-NR In patients with PAD with an abnormal ABI (≤0.90) or with noncompressible arteries (ABI >1.40 and TBI ≤0.70) in the setting of nonhealing wounds or gangrene, TBI with waveforms, TcPO2, or SPP can be useful to evaluate local perfusion.95–99 3.3. Imaging for Anatomic Assessment Recommendations for Imaging for Anatomic Assessment COR LOE Recommendations

IIa B-NR In patients with PAD with an abnormal ABI (≤0.90) or with noncompressible arteries (ABI >1.40 and TBI ≤0.70) in the setting of nonhealing wounds or gangrene, TBI with waveforms, TcPO2, or SPP can be useful to evaluate local perfusion.95–99 3.3. Imaging for Anatomic Assessment Recommendations for Imaging for Anatomic Assessment COR LOE Recommendations I B-NR Duplex ultrasound, CTA, or MRA of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patients with symptomatic PAD in whom revascularization is considered.100–103 I C-EO Invasive angiography is useful for patients with CLI in whom revascularization is considered. IIa C-EO Invasive angiography is reasonable for patients with lifestyle-limiting claudication with an inadequate response to GDMT for whom revascularization is considered. III: Harm B-R Invasive and noninvasive angiography (ie, CTA, MRA) should not be performed for the anatomic assessment of patients with asymptomatic PAD.104–106 4. Screening For Atherosclerotic Disease In Other Vascular Beds For The Patient With Pad: Recommendations See Online Data Supplement 8 for data supporting Section 4.

III: Harm B-R Invasive and noninvasive angiography (ie, CTA, MRA) should not be performed for the anatomic assessment of patients with asymptomatic PAD.104–106 4. Screening For Atherosclerotic Disease In Other Vascular Beds For The Patient With Pad: Recommendations See Online Data Supplement 8 for data supporting Section 4. 4.1. Abdominal Aortic Aneurysm PAD has been recognized as a risk factor for abdominal aortic aneurysm (AAA). In observational studies, the prevalence of AAA (aortic diameter ≥3 cm) was higher in patients with symptomatic PAD than in the general population107,108 and in a population of patients with atherosclerotic risk factors.109 The prevalence of AAA among patients with PAD increased with age, beginning in patients ≥55 years of age, and was highest in patients ≥75 years of age.107 There are no data on AAA screening in patients with asymptomatic PAD. This section refers to screening patients with symptomatic PAD for AAA. Recommendations for screening the general population with risk factors for AAA (based on age, sex, smoking history, and family history) have been previously published.10 Recommendation for Abdominal Aortic Aneurysm COR LOE Recommendation IIa B-NR A screening duplex ultrasound for AAA is reasonable in patients with symptomatic PAD.107–109

4.1. Abdominal Aortic Aneurysm PAD has been recognized as a risk factor for abdominal aortic aneurysm (AAA). In observational studies, the prevalence of AAA (aortic diameter ≥3 cm) was higher in patients with symptomatic PAD than in the general population107,108 and in a population of patients with atherosclerotic risk factors.109 The prevalence of AAA among patients with PAD increased with age, beginning in patients ≥55 years of age, and was highest in patients ≥75 years of age.107 There are no data on AAA screening in patients with asymptomatic PAD. This section refers to screening patients with symptomatic PAD for AAA. Recommendations for screening the general population with risk factors for AAA (based on age, sex, smoking history, and family history) have been previously published.10 Recommendation for Abdominal Aortic Aneurysm COR LOE Recommendation IIa B-NR A screening duplex ultrasound for AAA is reasonable in patients with symptomatic PAD.107–109 4.2. Screening for Asymptomatic Atherosclerosis in Other Arterial Beds (Coronary, Carotid, and Renal Arteries) The prevalence of atherosclerosis in the coronary, carotid, and renal arteries is higher in patients with PAD than in those without PAD.109–115 However, intensive atherosclerosis risk factor modification in patients with PAD is justified regardless of the presence of disease in other arterial beds. Thus, the only justification for screening for disease in other arterial beds is if revascularization results in a reduced risk of myocardial infarction (MI), stroke, or death, and this has never been shown. Currently, there is no evidence to demonstrate that screening all patients with PAD for asymptomatic atherosclerosis in other arterial beds improves clinical outcome. Intensive treatment of risk factors through GDMT is the principle method for preventing adverse cardiovascular ischemic events from asymptomatic disease in other arterial beds.

evidence to demonstrate that screening all patients with PAD for asymptomatic atherosclerosis in other arterial beds improves clinical outcome. Intensive treatment of risk factors through GDMT is the principle method for preventing adverse cardiovascular ischemic events from asymptomatic disease in other arterial beds. 5. Medical Therapy For The Patient With Pad: Recommendations Patients with PAD should receive a comprehensive program of GDMT, including structured exercise and lifestyle modification, to reduce cardiovascular ischemic events and improve functional status. Smoking cessation is a vital component of care for patients with PAD who continue to smoke. A guideline-based program of pharmacotherapy to reduce cardiovascular ischemic events and limb-related events should be prescribed for each patient with PAD and is customized to individual risk factors, such as whether the patient also has diabetes mellitus. Pharmacotherapy for the patient with PAD includes antiplatelet and statin agents and is customized to additional risk factors, such as whether the patient also has diabetes mellitus or hypertension. Previous studies have demonstrated that patients with PAD are less likely to receive GDMT than patients with other forms of cardiovascular disease, including coronary artery disease.116–118 Cilostazol is an effective medical therapy for treatment of leg symptoms and walking impairment due to claudication.119 However, side effects include headache, diarrhea, dizziness, and palpitations and in 1 trial, 20% of patients discontinued cilostazol within 3 months.120

ase, including coronary artery disease.116–118 Cilostazol is an effective medical therapy for treatment of leg symptoms and walking impairment due to claudication.119 However, side effects include headache, diarrhea, dizziness, and palpitations and in 1 trial, 20% of patients discontinued cilostazol within 3 months.120 See Online Data Supplements 13 to 19 for data supporting Section 5. 5.1. Antiplatelet, Statin, Antihypertensive Agents, and Oral Anticoagulation Recommendations for Antiplatelet, Statin, and Antihypertensive Agents COR LOE Recommendations Antiplatelet Agents I A Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD.121–124 IIa C-EO In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. IIb B-R In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain.67,68 IIb B-R The effectiveness of dual antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established.125,126 IIb C-LD Dual antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization.127–130

IIb B-R The effectiveness of dual antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established.125,126 IIb C-LD Dual antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization.127–130 IIb B-R The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain.131–134 Statin Agents I A Treatment with a statin medication is indicated for all patients with PAD.88,135–139 Antihypertensive Agents I A Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death.140–144 IIa A The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD.143,145,146 Oral Anticoagulation IIb B-R The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain.147–149 III: Harm A Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.148,150–152 5.2. Smoking Cessation Recommendations for Smoking Cessation COR LOE Recommendations I A Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit.153–155

III: Harm A Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.148,150–152 5.2. Smoking Cessation Recommendations for Smoking Cessation COR LOE Recommendations I A Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit.153–155 I A Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (ie, varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program.153,156–158 I B-NR Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places.159,160 5.3. Glycemic Control Recommendations for Glycemic Control COR LOE Recommendations I C-EO Management of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team. IIa B-NR Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes161,162 5.4. Cilostazol, Pentoxifylline, and Chelation Therapy Recommendations for Cilostazol, Pentoxifylline, and Chelation Therapy COR LOE Recommendations I A Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication.119,163 III: No Benefit B-R Pentoxifylline is not effective for treatment of claudication.119,164 III: No Benefit B-R Chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication.165 5.5. Homocysteine Lowering Recommendation for Homocysteine Lowering COR LOE Recommendation

I A Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication.119,163 III: No Benefit B-R Pentoxifylline is not effective for treatment of claudication.119,164 III: No Benefit B-R Chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication.165 5.5. Homocysteine Lowering Recommendation for Homocysteine Lowering COR LOE Recommendation III: No Benefit B-R B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended.166–168 5.6. Infuenza Vaccination Recommendation for Influenza Vaccination COR LOE Recommendation I C-EO Patients with PAD should have an annual influenza vaccination.

III: No Benefit B-R B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended.166–168 5.6. Infuenza Vaccination Recommendation for Influenza Vaccination COR LOE Recommendation I C-EO Patients with PAD should have an annual influenza vaccination. 6. Structured Exercise Therapy: Recommendations Structured exercise therapy is an important element of care for the patient with PAD. Components of structured exercise programs for PAD are outlined in Table 7. The data supporting the efficacy of supervised exercise programs as an initial treatment for claudication continue to develop and remain convincing, building on many earlier RCTs.28–34,36,169,170 Trials with long-term follow-up from 18 months25,26 to 7 years24 have demonstrated a persistent benefit of supervised exercise in patients with claudication. The risk–benefit ratio for supervised exercise in PAD is favorable, with an excellent safety profile in patients screened for absolute contraindications to exercise such as exercise-limiting cardiovascular disease, amputation or wheelchair confinement, and other major comorbidities that would preclude exercise.24,27,37,171–174

–benefit ratio for supervised exercise in PAD is favorable, with an excellent safety profile in patients screened for absolute contraindications to exercise such as exercise-limiting cardiovascular disease, amputation or wheelchair confinement, and other major comorbidities that would preclude exercise.24,27,37,171–174 Studies supporting structured community- or home-based programs for patients with PAD are more recent than studies supporting supervised exercise programs and have provided strong evidence in support of the community- or home-based approach.35,37,39,80,86,171 Unstructured community- or home-based walking programs that consist of providing general recommendations to patients with claudication to simply walk more are not efficacious.38 See Online Data Supplements 32 and 33 for data supporting Section 6. Recommendations for Structured Exercise Therapy COR LOE Recommendations I A In patients with claudication, a supervised exercise program is recommended to improve functional status and QoL and to reduce leg symptoms.24–26,28–34,36,169,170 I B-R A supervised exercise program should be discussed as a treatment option for claudication before possible revascularization.24–26 IIa A In patients with PAD, a structured community-or home-based exercise program with behavioral change techniques can be beneficial to improve walking ability and functional status.37,80,86,171

I B-R A supervised exercise program should be discussed as a treatment option for claudication before possible revascularization.24–26 IIa A In patients with PAD, a structured community-or home-based exercise program with behavioral change techniques can be beneficial to improve walking ability and functional status.37,80,86,171 IIa A In patients with claudication, alternative strategies of exercise therapy, including upper-body ergometry, cycling, and pain-free or low-intensity walking that avoids moderate-to-maximum claudication while walking, can be beneficial to improve walking ability and functional status.27,173,175,176 7. Minimizing Tissue Loss In Patients With Pad: Recommendations Prevention of wounds through patient education, foot examination, and prompt recognition of foot infection is important to minimize tissue loss among patients with PAD. Education includes teaching patients about healthy foot behaviors (eg, daily inspection of feet, wearing of shoes and socks; avoidance of barefoot walking), the selection of proper footwear, and the importance of seeking medical attention for new foot problems.177 Educational efforts are especially important for patients with PAD who have diabetes mellitus with peripheral neuropathy.

(eg, daily inspection of feet, wearing of shoes and socks; avoidance of barefoot walking), the selection of proper footwear, and the importance of seeking medical attention for new foot problems.177 Educational efforts are especially important for patients with PAD who have diabetes mellitus with peripheral neuropathy. Foot infections (infection of any of the structures distal to the malleoli) may include cellulitis, abscess, fasciitis, tenosynovitis, septic joint space infection, and osteomyelitis. Because of the consequences associated with untreated foot infection—especially in the presence of PAD—clinicians should maintain a high index of suspicion.178 Foot infection is suspected if the patient presents with local pain or tenderness; periwound erythema; periwound edema, induration, or fluctuance; pretibial edema; any discharge (especially purulent); foul odor; visible bone or a wound that probes to bone; or signs of a systemic inflammatory response (including temperature >38°C or <36°C, heart rate >90/min, respiratory rate >20/min or Paco2 <32 mm Hg, white blood cell count >12 000 or <4000/mcL or >10% immature forms).179 It is recognized that the presence of diabetes mellitus with peripheral neuropathy and PAD may make the presentation of foot infection more subtle than in patients without these problems. See Online Data Supplement 34 for data supporting Section 7. Recommendations for Minimizing Tissue Loss in Patients With PAD COR LOE Recommendations I C-LD Patients with PAD and diabetes mellitus should be counseled about self–foot examination and healthy foot behaviors.177,180

Foot infections (infection of any of the structures distal to the malleoli) may include cellulitis, abscess, fasciitis, tenosynovitis, septic joint space infection, and osteomyelitis. Because of the consequences associated with untreated foot infection—especially in the presence of PAD—clinicians should maintain a high index of suspicion.178 Foot infection is suspected if the patient presents with local pain or tenderness; periwound erythema; periwound edema, induration, or fluctuance; pretibial edema; any discharge (especially purulent); foul odor; visible bone or a wound that probes to bone; or signs of a systemic inflammatory response (including temperature >38°C or <36°C, heart rate >90/min, respiratory rate >20/min or Paco2 <32 mm Hg, white blood cell count >12 000 or <4000/mcL or >10% immature forms).179 It is recognized that the presence of diabetes mellitus with peripheral neuropathy and PAD may make the presentation of foot infection more subtle than in patients without these problems. See Online Data Supplement 34 for data supporting Section 7. Recommendations for Minimizing Tissue Loss in Patients With PAD COR LOE Recommendations I C-LD Patients with PAD and diabetes mellitus should be counseled about self–foot examination and healthy foot behaviors.177,180 I C-LD In patients with PAD, prompt diagnosis and treatment of foot infection are recommended to avoid amputation.178,179,181–183 IIa C-LD In patients with PAD and signs of foot infection, prompt referral to an interdisciplinary care team (Table 8) can be beneficial.178,184,185

I C-LD Patients with PAD and diabetes mellitus should be counseled about self–foot examination and healthy foot behaviors.177,180 I C-LD In patients with PAD, prompt diagnosis and treatment of foot infection are recommended to avoid amputation.178,179,181–183 IIa C-LD In patients with PAD and signs of foot infection, prompt referral to an interdisciplinary care team (Table 8) can be beneficial.178,184,185 IIa C-EO It is reasonable to counsel patients with PAD without diabetes mellitus about self–foot examination and healthy foot behaviors. IIa C-EO Biannual foot examination by a clinician is reasonable for patients with PAD and diabetes mellitus.

IIa C-LD In patients with PAD and signs of foot infection, prompt referral to an interdisciplinary care team (Table 8) can be beneficial.178,184,185 IIa C-EO It is reasonable to counsel patients with PAD without diabetes mellitus about self–foot examination and healthy foot behaviors. IIa C-EO Biannual foot examination by a clinician is reasonable for patients with PAD and diabetes mellitus. 8. Revascularization For Claudication: Recommendations A minority of patients with claudication (estimated at <10% to 15% over 5 years or more) will progress to CLI.186–189 Therefore, the role of revascularization in claudication is improvement in claudication symptoms and functional status, and consequently in QoL, rather than limb salvage. Revascularization is reasonable when the patient who is being treated with GDMT (including structured exercise therapy) presents with persistent lifestyle-limiting claudication.13,25,26,190,191 Lifestyle-limiting claudication is defined by the patient rather than by any test. It includes impairment of activities of daily living and/or vocational and/or recreational activities due to claudication. An individualized approach to revascularization for claudication is recommended for each patient to optimize outcome. Revascularization is but one component of care for the patient with claudication, inasmuch as each patient should have a customized care plan that also includes medical therapy (Section 5), structured exercise therapy (Section 6), and care to minimize tissue loss (Section 7). If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both.

t also includes medical therapy (Section 5), structured exercise therapy (Section 6), and care to minimize tissue loss (Section 7). If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both. Due to the variability of ischemic limb symptoms and impact of these symptoms on functional status and QoL, patients should be selected for revascularization on the basis of severity of their symptoms. Factors to consider include a significant disability as assessed by the patient, adequacy of response to medical and structured exercise therapy, status of comorbid conditions, and a favorable risk–benefit ratio. Patient preferences and goals of care are important considerations in the evaluation for revascularization. The revascularization strategy should have a reasonable likelihood of providing durable relief of symptoms. There should be clear discussion with the patient about expected risks and benefits of revascularization, as well as discussion of the durability of proposed procedures. A general recommendation for revascularization as a treatment option for claudication is provided below followed by specific recommendations for endovascular (Section 8.1.1) and surgical (Section 8.1.2) procedures if a revascularization strategy is undertaken. See Online Data Supplements 35 to 38 for data supporting Section 8. 8.1. Revascularization for Claudication Recommendation for Revascularization for Claudication COR LOE Recommendation

Due to the variability of ischemic limb symptoms and impact of these symptoms on functional status and QoL, patients should be selected for revascularization on the basis of severity of their symptoms. Factors to consider include a significant disability as assessed by the patient, adequacy of response to medical and structured exercise therapy, status of comorbid conditions, and a favorable risk–benefit ratio. Patient preferences and goals of care are important considerations in the evaluation for revascularization. The revascularization strategy should have a reasonable likelihood of providing durable relief of symptoms. There should be clear discussion with the patient about expected risks and benefits of revascularization, as well as discussion of the durability of proposed procedures. A general recommendation for revascularization as a treatment option for claudication is provided below followed by specific recommendations for endovascular (Section 8.1.1) and surgical (Section 8.1.2) procedures if a revascularization strategy is undertaken. See Online Data Supplements 35 to 38 for data supporting Section 8. 8.1. Revascularization for Claudication Recommendation for Revascularization for Claudication COR LOE Recommendation IIa A Revascularization is a reasonable treatment option for the patient with lifestyle-limiting claudication with an inadequate response to GDMT.13,25,26,190,191

See Online Data Supplements 35 to 38 for data supporting Section 8. 8.1. Revascularization for Claudication Recommendation for Revascularization for Claudication COR LOE Recommendation IIa A Revascularization is a reasonable treatment option for the patient with lifestyle-limiting claudication with an inadequate response to GDMT.13,25,26,190,191 8.1.1. Endovascular Revascularization for Claudication Endovascular techniques to treat claudication include balloon dilation (angioplasty), stents, and atherectomy. These techniques continue to involve and now include covered stents, drug-eluting stents, cutting balloons, and drug-coated balloons. The technique chosen for endovascular treatment is related to lesion characteristics (eg, anatomic location, lesion length, degree of calcification) and operator experience. Assessment of the appropriateness of specific endovascular techniques for specific lesions for the treatment of claudication is beyond the scope of this document.

osen for endovascular treatment is related to lesion characteristics (eg, anatomic location, lesion length, degree of calcification) and operator experience. Assessment of the appropriateness of specific endovascular techniques for specific lesions for the treatment of claudication is beyond the scope of this document. Revascularization is performed on lesions that are deemed to be hemodynamically significant, and stenoses selected for endovascular treatment should have a reasonable likelihood of limiting perfusion to the distal limb. Stenoses of 50% to 75% diameter by angiography may not be hemodynamically significant, and resting or provoked intravascular pressure measurements may be used to determine whether lesions are significant.192,193 Multiple RCTs have compared endovascular procedures to various combinations of medical treatment with or without supervised or unsupervised exercise programs.13,25,26,190,191,194–206 These trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels. Long-term patency is greater in the aortoiliac than in the femoropopliteal segment. Furthermore, for femoropopliteal disease, durability is diminished with greater lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poor-quality runoff, diabetes mellitus, chronic kidney disease, renal failure, and smoking.207–210 Recommendations for Endovascular Revascularization for Claudication COR LOE Recommendations

Revascularization is performed on lesions that are deemed to be hemodynamically significant, and stenoses selected for endovascular treatment should have a reasonable likelihood of limiting perfusion to the distal limb. Stenoses of 50% to 75% diameter by angiography may not be hemodynamically significant, and resting or provoked intravascular pressure measurements may be used to determine whether lesions are significant.192,193 Multiple RCTs have compared endovascular procedures to various combinations of medical treatment with or without supervised or unsupervised exercise programs.13,25,26,190,191,194–206 These trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels. Long-term patency is greater in the aortoiliac than in the femoropopliteal segment. Furthermore, for femoropopliteal disease, durability is diminished with greater lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poor-quality runoff, diabetes mellitus, chronic kidney disease, renal failure, and smoking.207–210 Recommendations for Endovascular Revascularization for Claudication COR LOE Recommendations I A Endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease.13,25,26,190,194,196,201 IIa B-R Endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease.190,197–200,205,206

I A Endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease.13,25,26,190,194,196,201 IIa B-R Endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease.190,197–200,205,206 IIb C-LD The usefulness of endovascular procedures as a revascularization option for patients with claudication due to isolated infrapopliteal artery disease is unknown.211–213 III: Harm B-NR Endovascular procedures should not be performed in patients with PAD solely to prevent progression to CLI.186–189,214–216

IIa B-R Endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease.190,197–200,205,206 IIb C-LD The usefulness of endovascular procedures as a revascularization option for patients with claudication due to isolated infrapopliteal artery disease is unknown.211–213 III: Harm B-NR Endovascular procedures should not be performed in patients with PAD solely to prevent progression to CLI.186–189,214–216 8.1.2. Surgical Revascularization for Claudication Systematic reviews have concluded that surgical procedures are an effective treatment for claudication and have a positive impact on QoL and walking parameters but have identified sparse evidence supporting the effectiveness of surgery compared with other treatments.12,191,217,218 Although symptom and patency outcomes for surgical interventions may be superior to those for less invasive endovascular treatments, surgical interventions are also associated with greater risk of adverse perioperative events219–225 Treatment selection should therefore be individualized on the basis of the patient's goals, perioperative risk, and anticipated benefit. Surgical procedures for claudication are usually reserved for individuals who a) do not derive adequate benefit from nonsurgical therapy, b) have arterial anatomy favorable to obtaining a durable result with surgery, and c) have acceptable risk of perioperative adverse events. Acceptable risk is defined by the individual patient and provider on the basis of symptom severity, comorbid conditions, and appropriate GDMT risk evaluation.

nonsurgical therapy, b) have arterial anatomy favorable to obtaining a durable result with surgery, and c) have acceptable risk of perioperative adverse events. Acceptable risk is defined by the individual patient and provider on the basis of symptom severity, comorbid conditions, and appropriate GDMT risk evaluation. The superficial femoral and proximal popliteal arteries are the most common anatomic sites of stenosis or occlusion among individuals with claudication. Femoral-popliteal bypass is therefore one of the most common surgical procedures for claudication. The type of conduit and site of popliteal artery anastomosis (above versus below knee) are major determinants of outcomes associated with femoral-popliteal bypass. Systematic reviews and meta-analyses have identified a clear and consistent primary patency benefit for autogenous vein versus prosthetic grafts for popliteal artery bypass.226,227 Recommendations for Surgical Revascularization for Claudication COR LOE Recommendations I A When surgical revascularization is performed, bypass to the popliteal artery with autogenous vein is recommended in preference to prosthetic graft material.226–234 IIa B-NR Surgical procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication with inadequate response to GDMT, acceptable perioperative risk, and technical factors suggesting advantages over endovascular procedures.190,230,235–237 III: Harm B-R Femoral-tibial artery bypasses with prosthetic graft material should not be used for the treatment of claudication.238–240

IIa B-NR Surgical procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication with inadequate response to GDMT, acceptable perioperative risk, and technical factors suggesting advantages over endovascular procedures.190,230,235–237 III: Harm B-R Femoral-tibial artery bypasses with prosthetic graft material should not be used for the treatment of claudication.238–240 III: Harm B-NR Surgical procedures should not be performed in patients with PAD solely to prevent progression to CLI.186–189,241 9. Management Of Cli: Recommendations Patients with CLI are at increased risk of amputation and major cardiovascular ischemic events. Care of the patient with CLI includes evaluation for revascularization and wound healing therapies, with the objective to minimize tissue loss, completely heal wounds, and preserve a functional foot. Medical therapy to prevent cardiovascular ischemic events is also an important component of care for the patient with CLI (Section 5). See Online Data Supplements 39 and 40 for data supporting Section 9.

9. Management Of Cli: Recommendations Patients with CLI are at increased risk of amputation and major cardiovascular ischemic events. Care of the patient with CLI includes evaluation for revascularization and wound healing therapies, with the objective to minimize tissue loss, completely heal wounds, and preserve a functional foot. Medical therapy to prevent cardiovascular ischemic events is also an important component of care for the patient with CLI (Section 5). See Online Data Supplements 39 and 40 for data supporting Section 9. 9.1. Revascularization for CLI The goal of surgical or endovascular revascularization in CLI is to provide in-line blood flow to the foot through at least 1 patent artery, which will help decrease ischemic pain and allow healing of any wounds, while preserving a functional limb. The BASIL (Bypass versus Angioplasty in Severe Ischemia of the Leg) RCT242,243 demonstrated that endovascular revascularization is an effective option for patients with CLI as compared with open surgery. The primary endpoint of amputation-free survival was the same in the endovascular and surgical arms. Of note, the endovascular arm used only percutaneous transluminal angioplasty.242,243 Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing.16–18 Table 9 addresses factors that may prompt an endovascular versus surgical approach to the patient with CLI.

urgical arms. Of note, the endovascular arm used only percutaneous transluminal angioplasty.242,243 Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing.16–18 Table 9 addresses factors that may prompt an endovascular versus surgical approach to the patient with CLI. The angiosome concept has been described in the literature and entails establishing direct blood flow to the infrapopliteal artery directly responsible for perfusing the region of the leg or foot with the nonhealing wound. Multiple retrospective studies and 1 small nonrandomized prospective study assessing the efficacy of this concept have been published.245–257 Meta-analyses of these studies found improved wound healing and limb salvage with angiosome-guided therapy but cautioned that the quality of the evidence was low.258,259 Although the angiosome concept is theoretically satisfying, randomized data comparing the establishment of in-line flow versus angiosome-guided therapy have yet to be published. Furthermore, there is no evidence yet to demonstrate the potential benefit of treating additional infrapopliteal arteries once in-line flow has been established in one artery, regardless of angiosome. Recommendation for Revascularizations for CLI COR LOE Recommendation I B-NR In patients with CLI, revascularization should be performed when possible to minimize tissue loss.260 I C-EO An evaluation for revascularization options should be performed by an interdisciplinary care team (Table 8) before amputation in the patient with CLI.

Recommendation for Revascularizations for CLI COR LOE Recommendation I B-NR In patients with CLI, revascularization should be performed when possible to minimize tissue loss.260 I C-EO An evaluation for revascularization options should be performed by an interdisciplinary care team (Table 8) before amputation in the patient with CLI. 9.1.1. Endovascular Revascularization for CLI Recommendations for Endovascular Revascularization for CLI COR LOE Recommendations I B-R Endovascular procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.242,243 IIa C-LD A staged approach to endovascular procedures is reasonable in patients with ischemic rest pain.261,262 IIa B-R Evaluation of lesion characteristics can be useful in selecting the endovascular approach for CLI.263,264 IIb B-NR Use of angiosome-directed endovascular therapy may be reasonable for patients with CLI and nonhealing wounds or gangrene.245,247–249,251–253,255–257 9.1.2. Surgical Revascularization for CLI Recommendations for Surgical Revascularization for CLI COR LOE Recommendations I A When surgery is performed for CLI, bypass to the popliteal or infrapopliteal arteries (ie, tibial, pedal) should be constructed with suitable autogenous vein.228,231,234,265 I C-LD Surgical procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.266–268

COR LOE Recommendations I A When surgery is performed for CLI, bypass to the popliteal or infrapopliteal arteries (ie, tibial, pedal) should be constructed with suitable autogenous vein.228,231,234,265 I C-LD Surgical procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene.266–268 IIa B-NR In patients with CLI for whom endovascular revascularization has failed and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries.269–271 IIa C-LD A staged approach to surgical procedures is reasonable in patients with ischemic rest pain.272–274 9.2. Wound Healing Therapies for CLI A comprehensive plan for treatment of CLI includes a plan to achieve an intact skin surface on a functional foot. The management of patients with CLI and nonhealing wounds includes coordinated efforts for both revascularization and wound healing among members of an interdisciplinary care team (Table 8). The structure and activities of interdisciplinary care teams for CLI may vary according to several factors, including the local availability of resources. Revascularization is coordinated with the efforts of clinicians who manage foot infections, provide offloading, and achieve complete wound healing, either through medical therapy, surgical options, or a combination of these options. See Online Data Supplement 34a for a complete list of functions of the interdisciplinary care team. Recommendations for Wound Healing Therapies for CLI COR LOE Recommendations

9.2. Wound Healing Therapies for CLI A comprehensive plan for treatment of CLI includes a plan to achieve an intact skin surface on a functional foot. The management of patients with CLI and nonhealing wounds includes coordinated efforts for both revascularization and wound healing among members of an interdisciplinary care team (Table 8). The structure and activities of interdisciplinary care teams for CLI may vary according to several factors, including the local availability of resources. Revascularization is coordinated with the efforts of clinicians who manage foot infections, provide offloading, and achieve complete wound healing, either through medical therapy, surgical options, or a combination of these options. See Online Data Supplement 34a for a complete list of functions of the interdisciplinary care team. Recommendations for Wound Healing Therapies for CLI COR LOE Recommendations I B-NR An interdisciplinary care team should evaluate and provide comprehensive care for patients with CLI and tissue loss to achieve complete wound healing and a functional foot.184,275–277 I C-LD In patients with CLI, wound care after revascularization should be performed with the goal of complete wound healing.275 IIb B-NR In patients with CLI, intermittent pneumatic compression (arterial pump) devices may be considered to augment wound healing and/or ameliorate severe ischemic rest pain.278 IIb C-LD In patients with CLI, the effectiveness of hyperbaric oxygen therapy for wound healing is unknown.279 III: No Benefit B-R Prostanoids are not indicated in patients with CLI.280

IIb B-NR In patients with CLI, intermittent pneumatic compression (arterial pump) devices may be considered to augment wound healing and/or ameliorate severe ischemic rest pain.278 IIb C-LD In patients with CLI, the effectiveness of hyperbaric oxygen therapy for wound healing is unknown.279 III: No Benefit B-R Prostanoids are not indicated in patients with CLI.280 10. Management Of Acute Limb Ischemia: Recommendations Acute limb ischemia (ALI) is one of the most treatable and potentially devastating presentations of PAD. Timely recognition of arterial occlusion as the cause of an ischemic, cold, painful leg is crucial to successful treatment. The writing committee has used a standard definition of ALI in which symptom duration is <2 weeks (Table 2).21,22 Category I refers to viable limbs that are not immediately threatened. Category II refers to threatened limbs. Category IIa limbs are marginally threatened and salvageable, if promptly treated. Category IIb are immediately threatened limbs that require immediate revascularization if salvage is to be accomplished. Category III are irreversibly damaged limbs, in which case resultant major tissue loss or permanent nerve damage is inevitable.22

limbs are marginally threatened and salvageable, if promptly treated. Category IIb are immediately threatened limbs that require immediate revascularization if salvage is to be accomplished. Category III are irreversibly damaged limbs, in which case resultant major tissue loss or permanent nerve damage is inevitable.22 Patients with ALI should be rapidly evaluated by a vascular specialist if one is available. Depending on local clinical expertise, the vascular specialist may be a vascular surgeon, interventional radiologist, cardiologist, or a general surgeon with specialized training and experience in treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (eg, with regard to potential patient transfer) needs to occur.

perience in treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (eg, with regard to potential patient transfer) needs to occur. ALI is a medical emergency and must be recognized rapidly. The time constraint is due to the period that skeletal muscle will tolerate ischemia—roughly 4 to 6 hours.281 A rapid assessment of limb viability and ability to restore arterial blood flow should be performed by a clinician able to either complete the revascularization or triage the patient.282 Lower extremity symptoms in ALI can include both pain and loss of function. The longer these symptoms are present, the less likely the possibility of limb salvage.283,284 Clinical assessment must include symptom duration, pain intensity, and motor and sensory deficit severity to distinguish a threatened from a nonviable extremity (Figure 3). The bedside assessment includes arterial and venous examination with a handheld continuous-wave Doppler because of the inaccuracy of pulse palpation.22 The loss of Dopplerable arterial signal indicates that the limb is threatened. The absence of both arterial and venous Doppler signal indicates that the limb may be irreversibly damaged (nonsalvageable). Comorbidities should be investigated and managed aggressively, but this must not delay therapy. Even in the setting of rapid and effective revascularization, the 1-year morbidity and mortality rates ALI are high.283,285

rial and venous Doppler signal indicates that the limb may be irreversibly damaged (nonsalvageable). Comorbidities should be investigated and managed aggressively, but this must not delay therapy. Even in the setting of rapid and effective revascularization, the 1-year morbidity and mortality rates ALI are high.283,285 See Figure 3 for the algorithm on diagnosis and management of ALI and Online Data Supplements 45 to 50 for data supporting Section 10. 10.1. Clinical Presentation of ALI Recommendations for Clinical Presentation of ALI COR LOE Recommendations I C-EO Patients with ALI should be emergently evaluated by a clinician with sufficient experience to assess limb viability and implement appropriate therapy. I C-LD In patients with suspected ALI, initial clinical evaluation should rapidly assess limb viability and potential for salvage and does not require imaging.282–284,286,287 10.2. Medical Therapy for ALI Recommendation for ALI Medical Therapy COR LOE Recommendation I C-EO In patients with ALI, systemic anticoagulation with heparin should be administered unless contraindicated.

I C-LD In patients with suspected ALI, initial clinical evaluation should rapidly assess limb viability and potential for salvage and does not require imaging.282–284,286,287 10.2. Medical Therapy for ALI Recommendation for ALI Medical Therapy COR LOE Recommendation I C-EO In patients with ALI, systemic anticoagulation with heparin should be administered unless contraindicated. 10.3. Revascularization for ALI For marginally or immediately threatened limbs (Category IIa and IIb ALI), revascularization should be performed emergently (within 6 hours). For viable limbs (Category I ALI), revascularization should be performed an on urgent basis (within 6–24 hours). The revascularization strategy can range from catheter-directed thrombolysis to surgical thromboembolectomy. Available facilities and clinical expertise are factors that should be considered when determining the revascularization strategy. The technique that will provide the most rapid restoration of arterial flow with the least risk to the patient should be selected. For example, catheter-directed thrombolysis can provide rapid restoration of arterial flow to a viable or marginally threatened limb, particularly in the setting of recent occlusion, thrombosis of synthetic grafts, and stent thrombosis.288 If this is not available locally, surgical options for timely revascularization should be considered, along with the feasibility of timely transfer to a facility with the necessary expertise.

nally threatened limb, particularly in the setting of recent occlusion, thrombosis of synthetic grafts, and stent thrombosis.288 If this is not available locally, surgical options for timely revascularization should be considered, along with the feasibility of timely transfer to a facility with the necessary expertise. Prolonged duration of ischemia is the most common factor in patients requiring amputation for treatment of ALI. The risks associated with reconstruction outweigh the potential benefit in a limb that is already insensate or immobile because of prolonged ischemia. Patients who have an insensate and immobile limb in the setting of prolonged ischemia (>6 to 8 hours) are unlikely to have potential for limb salvage with revascularization. Recommendations for Revascularization for ALI COR LOE Recommendations I C-LD In patients with ALI, the revascularization strategy should be determined by local resources and patient factors (eg, etiology and degree of ischemia).288–290 I A Catheter-based thrombolysis is effective for patients with ALI and a salvageable limb.288–292 I C-LD Amputation should be performed as the first procedure in patients with a nonsalvageable limb.293,294 I C-LD Patients with ALI should be monitored and treated (eg, fasciotomy) for compartment syndrome after revascularization.293,294 IIa B-NR In patients with ALI with a salvageable limb, percutaneous mechanical thrombectomy can be useful as adjunctive therapy to thrombolysis.295–299 IIa C-LD In patients with ALI due to embolism and with a salvageable limb, surgical thromboembolectomy can be effective.300–302

I C-LD Patients with ALI should be monitored and treated (eg, fasciotomy) for compartment syndrome after revascularization.293,294 IIa B-NR In patients with ALI with a salvageable limb, percutaneous mechanical thrombectomy can be useful as adjunctive therapy to thrombolysis.295–299 IIa C-LD In patients with ALI due to embolism and with a salvageable limb, surgical thromboembolectomy can be effective.300–302 IIb C-LD The usefulness of ultrasound-accelerated catheter-based thrombolysis for patients with ALI with a salvageable limb is unknown.303–305 10.4. Diagnostic Evaluation of the Cause of ALI ALI may be related to underlying PAD (including prior lower extremity bypass graft) or may be related to other conditions that can result in ALI through either thrombotic (eg, hypercoagulable state) or embolic mechanisms. Treatment of ALI should not be delayed for testing for the underlying cause of the limb ischemia because delay from symptom onset to revascularization is a major determinant of outcome.283,284 The evaluation of a cardiovascular (ie, embolic) cause for ALI is most useful in the patient without underlying PAD and can be completed after revascularization. Evaluation for cardiovascular cause includes electrocardiogram or additional heart rhythm monitoring to detect atrial fibrillation, electrocardiogram to detect evidence of MI, and echocardiography to further determine whether there is a cardiac etiology for thromboembolism, such as valvular vegetation, left atrial or left ventricular thrombus, or intracardiac shunt. Recommendations for Diagnostic Evaluation of the Cause of ALI

10.4. Diagnostic Evaluation of the Cause of ALI ALI may be related to underlying PAD (including prior lower extremity bypass graft) or may be related to other conditions that can result in ALI through either thrombotic (eg, hypercoagulable state) or embolic mechanisms. Treatment of ALI should not be delayed for testing for the underlying cause of the limb ischemia because delay from symptom onset to revascularization is a major determinant of outcome.283,284 The evaluation of a cardiovascular (ie, embolic) cause for ALI is most useful in the patient without underlying PAD and can be completed after revascularization. Evaluation for cardiovascular cause includes electrocardiogram or additional heart rhythm monitoring to detect atrial fibrillation, electrocardiogram to detect evidence of MI, and echocardiography to further determine whether there is a cardiac etiology for thromboembolism, such as valvular vegetation, left atrial or left ventricular thrombus, or intracardiac shunt. Recommendations for Diagnostic Evaluation of the Cause of ALI COR LOE Recommendations I C-EO In the patient with ALI, a comprehensive history should be obtained to determine the cause of thrombosis and/or embolization. IIa C-EO In the patient with a history of ALI, testing for a cardiovascular cause of thromboembolism can be useful.

Recommendations for Diagnostic Evaluation of the Cause of ALI COR LOE Recommendations I C-EO In the patient with ALI, a comprehensive history should be obtained to determine the cause of thrombosis and/or embolization. IIa C-EO In the patient with a history of ALI, testing for a cardiovascular cause of thromboembolism can be useful. 11. Longitudinal Follow-Up: Recommendations PAD is a lifelong chronic medical condition. A comprehensive care plan for patients with PAD includes periodic clinical evaluation by a healthcare provider with experience in the care of vascular patients. Ongoing care focuses on cardiovascular risk reduction with medical therapy, optimizing functional status with structured exercise, and, when indicated, revascularization. The care plan is further customized depending on whether the patient has undergone a revascularization procedure. See Online Data Supplements 51 and 52 for data supporting Section 11. Recommendations for Longitudinal Follow-Up COR LOE Recommendations I C-EO Patients with PAD should be followed up with periodic clinical evaluation, including assessment of cardiovascular risk factors, limb symptoms, and functional status. I C-EO Patients with PAD who have undergone lower extremity revascularization (surgical and/or endovascular) should be followed up with periodic clinical evaluation and ABI measurement. IIa B-R Duplex ultrasound can be beneficial for routine surveillance of infrainguinal, autogenous vein bypass grafts in patients with PAD.306–312

I C-EO Patients with PAD who have undergone lower extremity revascularization (surgical and/or endovascular) should be followed up with periodic clinical evaluation and ABI measurement. IIa B-R Duplex ultrasound can be beneficial for routine surveillance of infrainguinal, autogenous vein bypass grafts in patients with PAD.306–312 IIa C-LD Duplex ultrasound is reasonable for routine surveillance after endovascular procedures in patients with PAD.313–315 IIb B-R The effectiveness of duplex ultrasound for routine surveillance of infrainguinal prosthetic bypass grafts in patients with PAD is uncertain.310,316–318 12. Evidence Gaps and Future Research Directions In performing the evidence review and in developing the present guidelines, the writing committee identified the following critical evidence gaps and future directions for PAD-related research: Basic science and translational studies to better understand the vascular biology of endovascular therapies and bypass grafting and to develop new methods for preventing restenosis after revascularization. Determination of risk factors for progression from asymptomatic PAD to symptomatic disease, including CLI. RCTs needed to determine the value of using the ABI to identify asymptomatic patients with PAD for therapies to reduce cardiovascular risk (eg, antiplatelet agents, statins, and other therapies). Advancement in PAD diagnostics, such as technologies for simplified yet highly accurate measurement of the ABI and tools for more reliable noninvasive perfusion assessment in CLI.

RCTs needed to determine the value of using the ABI to identify asymptomatic patients with PAD for therapies to reduce cardiovascular risk (eg, antiplatelet agents, statins, and other therapies). Advancement in PAD diagnostics, such as technologies for simplified yet highly accurate measurement of the ABI and tools for more reliable noninvasive perfusion assessment in CLI. Comparative-effectiveness studies to determine the optimal antiplatelet therapy (drug or drugs and dosage) for prevention of cardiovascular and limb-related events in patients with PAD. Development of additional medical therapies for claudication—an area of unmet medical need with a currently limited research pipeline.319 Studies to investigate the role of dietary intervention, in addition to statin therapy, to improve outcome and modify the natural history of PAD. Additional research to identify the best community-or home-based exercise programs for patients with PAD to maximize functional status and improve QoL, as well as the role of such exercise programs before or in addition to revascularization. Development and validation of improved clinical classification systems for PAD that incorporate symptoms, anatomic factors, and patient-specific risk factors and can be used to predict clinical outcome and optimize treatment approach. An example of a recently developed classification system is the Society for Vascular Surgery limb classification system, based on wound, ischemia, and foot infection (WIfI), which has been validated in different populations and may permit more meaningful prognosis in patients with CLI.320–324

timize treatment approach. An example of a recently developed classification system is the Society for Vascular Surgery limb classification system, based on wound, ischemia, and foot infection (WIfI), which has been validated in different populations and may permit more meaningful prognosis in patients with CLI.320–324 Comparative- and cost-effectiveness studies of the different endovascular technologies for treatment of claudication and CLI, including drug-coated balloons and drug-eluting stents. Studies should include patient-centered endpoints, such as functional parameters, time to wound healing, and QoL, in addition to standard patency-focused outcomes. These studies could then be incorporated into value-based clinical algorithms for approach to revascularization for claudication and CLI. Additional studies to demonstrate the impact of multisocietal registries on clinical outcomes and appropriate use. At present, these include: the Vascular Quality Initiative (VQI), the National Cardiovascular Data Registry Peripheral Vascular Intervention Registry™ (PVI Registry™), and the National Radiology Data Registry for Interventional Radiology (NRDR). These registries provide an opportunity to obtain “real-world” data on surgical and endovascular procedures for PAD and improve quality by providing feedback to participating centers. Future efforts should incorporate these registries into interventional RCTs and post-marketing studies of PAD-related devices.

y (NRDR). These registries provide an opportunity to obtain “real-world” data on surgical and endovascular procedures for PAD and improve quality by providing feedback to participating centers. Future efforts should incorporate these registries into interventional RCTs and post-marketing studies of PAD-related devices. 13. Advocacy Priorities The writing committee identified 3 priorities for multisocietal advocacy initiatives to improve health care for patients with PAD. First, the writing committee supports the availability of the ABI as the initial diagnostic test to establish the diagnosis of PAD in patients with history or physical examination findings suggestive of PAD (Table 4). Although the ABI test is generally reimbursed by third-party payers for patients with classical claudication or lower extremity wounds, payers may not provide reimbursement for the ABI with other findings suggestive of PAD, such as lower extremity pulse abnormalities or femoral bruits. The writing committee affirms the importance of confirming the diagnosis of PAD in such patients to allow for GDMT as delineated in this document. Second, the writing committee supports the vital importance of insuring access to supervised exercise programs for patients with PAD. Although extensive high-quality evidence supports supervised exercise programs to improve functional status and QoL, only a minority of patients with PAD participate in such programs because of lack of reimbursement by third-party payers. Third, the writing committee recognizes the need for incorporation of patient-centered outcomes into the process of regulatory approval of new medical therapies and revascularization technologies. For revascularization technologies, regulatory approval is driven primarily by data on angiographic efficacy (ie, target-lesion patency) and safety endpoints. The nature of the functional limitation associated with PAD warrants the incorporation of patient-centered outcomes, such as functional parameters and QoL, into the efficacy outcomes for the approval process.

approval is driven primarily by data on angiographic efficacy (ie, target-lesion patency) and safety endpoints. The nature of the functional limitation associated with PAD warrants the incorporation of patient-centered outcomes, such as functional parameters and QoL, into the efficacy outcomes for the approval process. Supplementary Material Evidence Table 1. Nonrandomized Trials, Observational Studies, and/or Registries of History for Clinical Assessment for PAD–Section 2.1. Evidence Table 2. Nonrandomized Trials, Observational Studies, and/or Registries of Physical Examination for Clinical Assessment for PAD–Section 2.1. Evidence Table 3. RCTs of Resting ABI for Diagnosing PAD–Section 3.1. Evidence Table 4. Nonrandomized Trials, Observational Studies, and/or Registries of Resting ABI for Diagnosing PAD–Section 3.1. Evidence Table 5. Nonrandomized Trials, Observational Studies, and/or Registries of Physiological Testing–Section 3.2. Evidence Table 6. Nonrandomized Trials, Observational Studies, and/or Registries of Imaging for Anatomic Assessment (Ultrasound, CTA, MRA, Angiography)–Section 3.3. Evidence Table 7. RCTs of Imaging for Anatomic Assessment (Ultrasound, CTA, MRA, Angiography)–Section 3.3. Evidence Table 8. Nonrandomized Trials, Observational Studies, and/or Registries for Abdominal Aortic Aneurysm–Section 4.1. Evidence Table 9. Nonrandomized Trials, Observational Studies, and/or Registries of Coronary Artery Disease Screening in PAD–Section 4.2. Evidence Table 10. RCTs for CAD Screening in PAD–Section 4.2.

Evidence Table 40. Nonrandomized Trials, Observational Studies, and/or Registries of Endovascular Revascularization for Chromic CLI–Section 8.2.1. Evidence Table 41. RCTs of Surgical Revascularization for Chronic CLI–Section 8.2. Evidence Table 42. Nonrandomized Trials, Observational Studies, and/or Registries for Surgical Revascularization for Chronic CLI–Section 8.2. Evidence Table 43. RCT Comparing Prostanoids for End-Stage Peripheral Artery Disease–Section 8.2.3. Evidence Table 44. Nonrandomized Trials, Observational Studies, and/or Registries for Would Healing Therapies for CLI–Section 8.2.3. Evidence Table 45. Nonrandomized Trials, Observational Studies, and/or Registries of Acute Limb Ischemia–Section 9.1. Evidence Table 46. Nonrandomized Trials, Observational studies, and/or Registries Comparing Evaluating Noninvasive Testing and Angiography for ALI–Section 9.1. Evidence Table 47. RCTs of Revascularization Strategy for ALI–Section 9.2.2. Evidence Table 48. Nonrandomized Trials, Observational Studies, and/or Registries of Clinical Presentation of ALI–Section 9.2.2. Evidence Table 49. Nonrandomized Trials, Observational Studies, and/or Registries of Diagnostic Evaluation of the Cause of ALI–Section 9.2.2. Evidence Table 50. Nonrandomized Trials, Observational Studies, and/or Registries of Revascularization Strategy for ALI–Section 9.2.2. Evidence Table 51. RCTs for Longitudinal Follow-Up–Section 10. Evidence Table 52. Nonrandomized Trials, Observational Studies, and/or Registries for Longitudinal Follow-Up–Section 10.

Evidence Table 49. Nonrandomized Trials, Observational Studies, and/or Registries of Diagnostic Evaluation of the Cause of ALI–Section 9.2.2. Evidence Table 50. Nonrandomized Trials, Observational Studies, and/or Registries of Revascularization Strategy for ALI–Section 9.2.2. Evidence Table 51. RCTs for Longitudinal Follow-Up–Section 10. Evidence Table 52. Nonrandomized Trials, Observational Studies, and/or Registries for Longitudinal Follow-Up–Section 10. The American Heart Association requests that this document be cited as follows: Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FGR, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RAG, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, Walsh ME. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Acc/Aha Task Force Members: Jonathan L. Halperin, MD, FACC, FAHA, Chair; Glenn N. Levine, MD, FACC, FAHA, Chair-Elect; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Boz-kurt, MD, PhD, FACC, FAHA; Ralph G. Brindis, MD, MPH, MACC; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; José Joglar, MD, FACC, FAHA; Susan J. Pressler, PhD, RN, FAHA; Duminda N. Wijeysundera, MD, PhD

dis, MD, MPH, MACC; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; José Joglar, MD, FACC, FAHA; Susan J. Pressler, PhD, RN, FAHA; Duminda N. Wijeysundera, MD, PhD Presidents And Staff: American College of Cardiology: Richard A. Chazal, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/American Heart Association: Katherine Sheehan, PhD, Director, Guideline Strategy and Operations Lisa Bradfield, CAE, Director, Guideline Methodology and Policy Abdul R. Abdullah, MD, Associate Science and Medicine Advisor Allison Rabinowitz, MPH, Project Manager, Clinical Practice Guidelines American Heart Association: Steven R. Houser, PhD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations

Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Comilla Sasson, MD, PhD, FACEP, Vice President, Science and Medicine Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations Copies: This document is available on the World Wide Web sites of the American College of Cardiology (//www.acc.org) and the American Heart Association (professional.heart.org). A copy of the document is available at //http://professional.heart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements and select the “Policies and Development” link.

Copies: This document is available on the World Wide Web sites of the American College of Cardiology (//www.acc.org) and the American Heart Association (professional.heart.org). A copy of the document is available at //http://professional.heart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements and select the “Policies and Development” link. Appendix 1 Author Relationships With Industry and Other Entities (Relevant)—2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease (March 2014) Committee Member Employment Consultant Speakers Bureau Ownership/Partnership/Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Marie D. Gerhard-Herman, Chair Harvard Medical School—Associate Professor None None None None None None None Heather L. Gornik, Vice Chair Cleveland Clinic Foundation, Cardiovascular Medicine—Medical Director, Noninvasive Vascular Laboratory None None Summit Doppler Systems Zin Medical AstraZeneca Theravasc

Appendix 1 Author Relationships With Industry and Other Entities (Relevant)—2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease (March 2014) Committee Member Employment Consultant Speakers Bureau Ownership/Partnership/Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Marie D. Gerhard-Herman, Chair Harvard Medical School—Associate Professor None None None None None None None Heather L. Gornik, Vice Chair Cleveland Clinic Foundation, Cardiovascular Medicine—Medical Director, Noninvasive Vascular Laboratory None None Summit Doppler Systems Zin Medical AstraZeneca Theravasc None None 3.1, 3.2, 5.1–5.3, and 5.6. Coletta Barrett Our Lady of the Lake Regional Medical Center—Vice President None None None None None None None Neal R. Barshes Baylor College of Medicine, Division of Vascular Surgery and Endovascular Therapy Michael E. DeBakey Department of Surgery— Assistant Professor None None None None None None None Matthew A. Corriere University of Michigan— Frankel Professor of Cardiovascular Surgery, Associate Professor of Surgery None None None None None None None Douglas E. Drachman Massachusetts General Hospital—Training Director Abbott Vascular St. Jude Medical None None Atrium Medical Bard Lutonix None None 4, 8.1.1– 9.1.2, and 10.2.2. Lee A. Fleisher University of Pennsylvania Health System Department of Anesthesiology and Critical Care—Chair None None None None None None None Francis Gerry R. Fowkes University of Edinburgh— Emeritus Professor of Epidemiology AstraZeneca†

St. Jude Medical None None Atrium Medical Bard Lutonix None None 4, 8.1.1– 9.1.2, and 10.2.2. Lee A. Fleisher University of Pennsylvania Health System Department of Anesthesiology and Critical Care—Chair None None None None None None None Francis Gerry R. Fowkes University of Edinburgh— Emeritus Professor of Epidemiology AstraZeneca† Bayer Merck None None None None None 5.1–5.3, 5.6, 5.10, 7, and 9.2. Naomi M. Hamburg Boston University School of Medicine, Cardiovascular Medicine Section—Associate Professor of Medicine None None None None None None None Scott Kinlay VA Boston Healthcare System—Associate Chief, Cardiology Director, Cardiac Catheterization Laboratory & Vascular Medicine None None None Medtronic† The Medicines Company† None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1 and 10.2.2. Robert Lookstein Mount Sinai Medical Center—Chief, Interventional Radiology; Professor of Radiology and Surgery; Vice Chair, Department of Radiology Boston Scientific Medrad Interventional Possis The Medicines Company None Cordis‡ Shockwave (DSMB) None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1 and 10.2.2. Sanjay Misra Mayo Clinic, Division of Vascular and Interventional Radiology—Professor; Department of Radiology—Interventional Radiologist None None None Johnson & Johnson (DSMB)

None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1 and 10.2.2. Robert Lookstein Mount Sinai Medical Center—Chief, Interventional Radiology; Professor of Radiology and Surgery; Vice Chair, Department of Radiology Boston Scientific Medrad Interventional Possis The Medicines Company None Cordis‡ Shockwave (DSMB) None None 4, 5.6, 8.1.1, 9.1.1, 10.2.1 and 10.2.2. Sanjay Misra Mayo Clinic, Division of Vascular and Interventional Radiology—Professor; Department of Radiology—Interventional Radiologist None None None Johnson & Johnson (DSMB) None None 4, 7, 8, and 10.2.2. Leila Mureebe Duke University Medical Center—Associate Professor of Surgery, Division of Vascular Surgery None None None None None None None Jeffrey W. Olin Ichan School of Medicine at Mount Sinai, Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health— Professor of Medicine, Cardiology; Director, Vascular Medicine AstraZeneca Merck Novartis Plurestem None Northwind† AstraZeneca† None None 5.1–5.3, 5.6, 5.10, and 12. Rajan A. G. Patel John Ochsner Heart & Vascular Center, Ochsner Clinical School, University of Queensland School of Medicine—Senior Lecturer None None None None None None None Judith G. Regensteiner University of Colorado, Health Sciences Center, Division of Cardiology— Associate Professor of Medicine None None None None None None None Andres Schanzer University of Massachusetts Medical School—Professor of Surgery and Quantitative Health Sciences; Program Director, Vascular Surgery Residency Cook Medical

ensteiner University of Colorado, Health Sciences Center, Division of Cardiology— Associate Professor of Medicine None None None None None None None Andres Schanzer University of Massachusetts Medical School—Professor of Surgery and Quantitative Health Sciences; Program Director, Vascular Surgery Residency Cook Medical None None None None None 4, 8.1.1, 9.1.1 and 10.2.2. Mehdi H. Shishehbor Cleveland Clinic, Interventional Cardiology and Vascular Medicine— Director, Endovascular Services BostonScientific‡ Medtronic‡ None None None AtriumMedical AstraZeneca†

ensteiner University of Colorado, Health Sciences Center, Division of Cardiology— Associate Professor of Medicine None None None None None None None Andres Schanzer University of Massachusetts Medical School—Professor of Surgery and Quantitative Health Sciences; Program Director, Vascular Surgery Residency Cook Medical None None None None None 4, 8.1.1, 9.1.1 and 10.2.2. Mehdi H. Shishehbor Cleveland Clinic, Interventional Cardiology and Vascular Medicine— Director, Endovascular Services BostonScientific‡ Medtronic‡ None None None AtriumMedical AstraZeneca† None 4, 8.1.1– 9.1.2, and 10.2.2. Kerry J. Stewart Johns Hopkins University, School of Medicine; Johns Hopkins Bayview Medical Center— Professor of Medicine; Director, Clinical and Research Exercise Physiology None None None None None None None Diane Treat-Jacobson University of Minnesota, School of Nursing— Professor None None None None None None None M. Eileen Walsh University of Toledo, College of Nursing— Professor None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.

ket value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. * Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Section numbers pertain to those in the full-text guideline. † Significant relationship. ‡ No financial benefit. AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; ACC, American College of Cardiology; ACE, Accreditation for Cardiovascular Excellence; AHA, American Heart Association; AMA, American Medical Association; DSMB, data and safety monitoring board; EUCLID, Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease; FDA, US Food and Drug Administration; HRS, Heart Rhythm Society; MI, myocardial infarction; NCDR, National Cardiovascular Data Registry; NIH, National Institutes of Health; NHLBI, National Heart, Lung, and Blood Institute; PCORI, Patient-Centered Outcomes Research Institute; PI, primary investigator; PLX-PAD, placental-derived adherent stromal cell; SCAI, Society for Cardiovascular Angiography and Interventions; SCVS, Society for Clinical Vascular Surgery; SIR, Society of Interventional Radiology; SVM, Society for Vascular Medicine; SVN, Society for Vascular Nursing; SVS, Society for Vascular Surgery; TASC, Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease; VA, Veterans Affairs; VESS, Vascular and Endovascular Surgery Society; and VIVA, Vascular Intervention Advances.

logy; SVM, Society for Vascular Medicine; SVN, Society for Vascular Nursing; SVS, Society for Vascular Surgery; TASC, Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease; VA, Veterans Affairs; VESS, Vascular and Endovascular Surgery Society; and VIVA, Vascular Intervention Advances. Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)—2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease (March 2016) Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Deepak L. Bhatt Official Reviewer—ACC Board of Trustees Brigham and Women's Hospital— Executive Director of Interventional Cardiovascular Programs; Harvard Medical School—Professor of Medicine Elsevier None None Amarin* Amgen* AstraZeneca* Bristol-Myers Squibb* Cardax† Eisai* Ethicon* FlowCo† Forest Laboratories* Ischemix* Mayo Clinic Medtronic* Merck† Pfzer* PLx Pharma† Regado Biosciences† Roche* Sanof-aventis* St. Jude Medical Takeda† The Medicines Company* WebMD* Belvoir Publications (Editor)* Biotronik Boston Scientific Clinical Cardiology (Deputy Editor)† Harvard Clinical Research Institute HMP Communications (Editor)* Duke Clinical Research Institute* Journal of Invasive Cardiology (Editor)* Medscape Cardiology Slack Publications (Editor)* St. Jude Medical VA Healthcare System† None Mark A. Creager Official Reviewer—AHA Dartmouth-Hitchcock Medical Center—Director None None None None AHA (Past President)†

Harvard Clinical Research Institute HMP Communications (Editor)* Duke Clinical Research Institute* Journal of Invasive Cardiology (Editor)* Medscape Cardiology Slack Publications (Editor)* St. Jude Medical VA Healthcare System† None Mark A. Creager Official Reviewer—AHA Dartmouth-Hitchcock Medical Center—Director None None None None AHA (Past President)† None Philip Goodney Official Reviewer—AHA Dartmouth-Hitchcock— Associate Professor of Surgery and The Dartmouth Institute Director None None None NIH* NIH None John S. Ikonomidis Official Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Medical University of South Carolina— Chief None None None None None None Amy W. Pollak Official Reviewer—AHA Mayo Clinic— Cardiovascular Medicine Physician None None None None None None Michael D. White Official Reviewer—ACC Board of Governors Catholic Health Initiatives—Chief Academic Officer Anthera Pharmaceuticals† None None AstraZeneca† None None Ehrin J. Armstrong Organizational Reviewer— SVM University of Colorado—Director, Interventional Cardiology Abbott Medtronic Merck Spectranetics None None None None None Bernadette Aulivola Organizational Reviewer—VESS Loyola University medical Center, Stritch School of Medicine—Director, Division of Vascular Surgery and Endovascular Therapy; Associate Professor, Department of Surgery; Program Director, Vascular Surgery Fellowship; Medical Director, Vascular Noninvasive lab None None None None None None Alison Bailey Organizational Reviewer—AACVPR University of Tennessee Chattanooga— Cardiologist None None None CSL Behring AACVPR† ZOLL Medical

None None None None None Bernadette Aulivola Organizational Reviewer—VESS Loyola University medical Center, Stritch School of Medicine—Director, Division of Vascular Surgery and Endovascular Therapy; Associate Professor, Department of Surgery; Program Director, Vascular Surgery Fellowship; Medical Director, Vascular Noninvasive lab None None None None None None Alison Bailey Organizational Reviewer—AACVPR University of Tennessee Chattanooga— Cardiologist None None None CSL Behring AACVPR† ZOLL Medical None Todd Brown Organizational Reviewer—AACVPR University of Alabama at Birmingham— Associate Professor None None None Amgen* Omthera† NIH* None None Kristen Columbia Organizational Reviewer—SVN University of Maryland Baltimore Washington Medical Center, Maryland Vascular Center— Nurse practitioner None None None None None None Michael S. Conte Organizational Reviewer—SVS University of California San Francisco— Professor and Chief Cook Medical Medtronic None None Bard University of California Department of Surgery None Alik Farber Organizational Reviewer—SCVS Boston Medical Center—Chief, Division of Vascular Surgery Bard† None None None None None Robert Feezor Organizational Reviewer—VESS University of Florida—Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy Cook Medical* Medtronic Terumo None None Cook Medical Cook Medical Novate Defendant, peripheral angioplasty, 2015 Dmitriy N. Feldman Organizational Reviewer—SCAI Weill Cornell Medical College, New York Presbyterian Hospital—Associate Professor of Medicine AstraZeneca Abbott Bristol-Myers Squibb† Daiichi-Sankyo Eli Lilly Medtronic Pfzer

None None None None None Robert Feezor Organizational Reviewer—VESS University of Florida—Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy Cook Medical* Medtronic Terumo None None Cook Medical Cook Medical Novate Defendant, peripheral angioplasty, 2015 Dmitriy N. Feldman Organizational Reviewer—SCAI Weill Cornell Medical College, New York Presbyterian Hospital—Associate Professor of Medicine AstraZeneca Abbott Bristol-Myers Squibb† Daiichi-Sankyo Eli Lilly Medtronic Pfzer The Medicines Company None None Biotronic The Medicines Company None Jonathan Golledge Organizational Reviewer—TASC James Cook University— Professor, Department of Surgery, Head of Vascular Biology Unit None None None James Cook University* None None Bruce H. Gray Organizational Reviewer—SCAI Greenville Health System—Director of Clinical Trials, Department of Surgery None Medtronic† None Abbott† W.L. Gore† NCDR† ACC† None William R. Hiatt Organizational Reviewer—TASC Colorado Prevention Center—Professor of Medicine None None None AstraZeneca* Bayer* CSI Kowa Kyushu University Merck Pluristem* ReNeuron CPC Clinical Research* NIH* None Joseph Mills Organizational Reviewer—SVS Baylor College of Medicine— Professor and Chief, Division of Vascular surgery and Endovascular Therapy None None None None AnGes Bayer Cesca None Mohammad Reza Rajebi Organizational Reviewer—SIR University of Colorado Denver— Assistant Professor None None None None None None Mitchell J. Silver Organizational Reviewer—SVM McConnell Heart Hospital for Critical Limb Care— Director of Vascular Imaging Boston Scientific W.L. Gore Medtronic Bristol-Myers Squibb* Pfzer* Contego Medical*

None Mohammad Reza Rajebi Organizational Reviewer—SIR University of Colorado Denver— Assistant Professor None None None None None None Mitchell J. Silver Organizational Reviewer—SVM McConnell Heart Hospital for Critical Limb Care— Director of Vascular Imaging Boston Scientific W.L. Gore Medtronic Bristol-Myers Squibb* Pfzer* Contego Medical* None W.L. Gore Medtronic NIH None Lily Thomson Organizational Reviewer—SVN Hôpital St-Boniface Hospital—Clinical Research Coordinator, Vascular Surgery Nurse, Section of Vascular Surgery, Health Sciences Centre None None None None None None Sana M. Al-Khatib Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Duke Clinical Research Institute— Associate Professor of Medicine None None None FDA* NHLBI* PCORI* VA (DSMB) HRS (Board of Trustees)† Elsevier* None Herbert Aronow Content Reviewer—ACC Peripheral Vascular Disease Member Section Rhode Island Hospital—Director of Cardiac Catheterization Laboratories None None None Silk Road Medical† Saint Luke's Health System The Medicines Company† Bard NIH PCORI† SVM† W.L. Gore Joshua A. Beckman Content Reviewer Vanderbilt University Medical Center— Director AstraZeneca* Merck* Sanof* None EMX† JanaCare† Bristol-MyersSquibb* Merck* NIH Vascular Interventional Advances Defendant, venous thrombo-embolism, 2015* James C. Blankenship Content Reviewer Geisinger Medical Center—Staff Physician; Director, Cardiac Catheterization Laboratory None None None Abbott† AstraZeneca† Boston Scientific† GlaxoSmithKline† Hamilton Health Sciences† Medinal LTD† Orexigen Therapeutics† St. Jude Medical† Stentys† Takeda Pharmaceuticals† SCAI (PastPresident)† AMA†

Defendant, venous thrombo-embolism, 2015* James C. Blankenship Content Reviewer Geisinger Medical Center—Staff Physician; Director, Cardiac Catheterization Laboratory None None None Abbott† AstraZeneca† Boston Scientific† GlaxoSmithKline† Hamilton Health Sciences† Medinal LTD† Orexigen Therapeutics† St. Jude Medical† Stentys† Takeda Pharmaceuticals† SCAI (PastPresident)† AMA† None Biykem Bozkurt Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Michael E. DeBakey VA Medical Center—The Mary and Gordon Cain Chair and Professor of Medicine None None None Novartis None None Joaquin E. Cigarroa Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Oregon Health and Science University—Clinical Professor of Medicine None None None None ACC/AHA† AHA† ASA† Catheterization and Cardiovascular Intervention† Portland Metro Area AHA(President)† SCAI Quality Interventional Council† NIH None Federico Gentile Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Centro Medico Diagnostico— Director, Cardiovascular Disease None None None None None None Anuj Gupta Content Reviewer—ACC Peripheral Vascular Disease Member Section University of Maryland— Assistant Professor of Medicine None None None Seimens* Medtronic† Direct Flow Medical† Edwards† None John Jeb Hallett Content Reviewer Medical University of South Carolina— Clinical Professor of Surgery None None None None None None Alan Hirsch Content Reviewer University of Minnesota Medical School—Professor of Medicine, Epidemiology and Community Health, and Director Vascular Medicine Program Merck* Novartis† None None Bayer*

None John Jeb Hallett Content Reviewer Medical University of South Carolina— Clinical Professor of Surgery None None None None None None Alan Hirsch Content Reviewer University of Minnesota Medical School—Professor of Medicine, Epidemiology and Community Health, and Director Vascular Medicine Program Merck* Novartis† None None Bayer* Pluristem (PLX-PAD trial–PI)† AstraZeneca (EUCLID trial–PI)† Pluristem* AHA† Tactile Medical* None Mark A. Hlatky Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Stanford University School of Medicine— Professor of Health Research and Policy, Professor of Medicine Acumen* Genentech None None Blue Cross/Blue Shield Center for Effectiveness Evaluation* George Institute HeartFlow* NHLBI Sanofi-aventis ACC (Associate Editor)* None Michael R. Jaff Content Reviewer Newton-Wellesley Hospital; Harvard Medical School— Professor of Medicine AOPA Cardinal Health Covidien† Micell Vascular Therapies None MC10† Janacare† Northwind PQ Bypass Primacea SanoV Valiant Medical Abbott† Boston Scientific† Cordis† IC Sciences Medtronic† Novello CBSET Intersocietal Accreditation Commission SCAI† VIVA Physicians Group*

ACC (Associate Editor)* None Michael R. Jaff Content Reviewer Newton-Wellesley Hospital; Harvard Medical School— Professor of Medicine AOPA Cardinal Health Covidien† Micell Vascular Therapies None MC10† Janacare† Northwind PQ Bypass Primacea SanoV Valiant Medical Abbott† Boston Scientific† Cordis† IC Sciences Medtronic† Novello CBSET Intersocietal Accreditation Commission SCAI† VIVA Physicians Group* None José A. Joglar Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines UT Southwestern Medical Center— Professor of Internal Medicine; Clinical Cardiac Electrophysiology— Fellowship Program Director None None None None None None Glenn N. Levine Content Reviewer— ACC/AHA Task Force on Clinical Practice Guidelines Baylor College of Medicine— Professor of Medicine; Director, Cardiac Care Unit None None None None None None Khusrow Niazi Content Reviewer— ACC Peripheral Vascular Disease Member Section Emory University Department of Medicine— Associate Professor of Medicine None Medtronic* None Bard Impeto Terumo None Plaintiff, MI resulting in death, 2015* Paul D. Varosy Content Reviewer—Task Force on Performance Measures VA Eastern Colorado Health Care System—Associate Professor None None None VA Health Services Research and Development (PI)* AHA (Guest Editor)† None Christopher J. White Content Reviewer Ochsner Clinical School, University of Queensland— Chairman, Department of Cardiology Neovasc None None AstraZeneca Pharmaceuticals NIH Neovasc Surmodics ACE (Board of Directors)†

Paul D. Varosy Content Reviewer—Task Force on Performance Measures VA Eastern Colorado Health Care System—Associate Professor None None None VA Health Services Research and Development (PI)* AHA (Guest Editor)† None Christopher J. White Content Reviewer Ochsner Clinical School, University of Queensland— Chairman, Department of Cardiology Neovasc None None AstraZeneca Pharmaceuticals NIH Neovasc Surmodics ACE (Board of Directors)† None This table represents all relationships of reviewers with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. * Significant relationship. † No financial benefit.

None This table represents all relationships of reviewers with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. * Significant relationship. † No financial benefit. AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; ACC, American College of Cardiology; ACE, Accreditation for Cardiovascular Excellence; AHA, American Heart Association; AMA, American Medical Association; DSMB, data and safety monitoring board; EUCLID, Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease; FDA, US Food and Drug Administration; HRS, Heart Rhythm Society; MI, myocardial infarction; NCDR, National Cardiovascular Data Registry; NIH, National Institutes of Health; NHLBI, National Heart, Lung, and Blood Institute; PCORI, Patient-Centered Outcomes Research Institute; PI, primary investigator; PLX-PAD, placental-derived adherent stromal cell; SCAI, Society for Cardiovascular Angiography and Interventions; SCVS, Society for Clinical Vascular Surgery; SIR, Society of Interventional Radiology; SVM, Society for Vascular Medicine; SVN, Society for Vascular Nursing; SVS, Society for Vascular Surgery; TASC, Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease; VA, Veterans Affairs; VESS, Vascular and Endovascular Surgery Society; and VIVA, Vascular Intervention Advances.

logy; SVM, Society for Vascular Medicine; SVN, Society for Vascular Nursing; SVS, Society for Vascular Surgery; TASC, Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease; VA, Veterans Affairs; VESS, Vascular and Endovascular Surgery Society; and VIVA, Vascular Intervention Advances. Appendix 3 Abbreviations AAA = abdominal aortic aneurysm ABI = ankle-brachial index ALI = acute limb ischemia CLI = critical limb ischemia GDMT = guideline-directed management and therapy MRA = magnetic resonance angiography PAD = peripheral artery disease RCT = randomized controlled trial SPP = skin perfusion pressure TBI = toe-brachial index TcPO2 = transcutaneous oxygen pressure QoL = quality of life Figure 1 Diagnostic Testing for Suspected PAD Colors correspond to Class of Recommendation in Table 1. ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; GDMT, guideline-directed management and therapy; MRA, magnetic resonance angiography; PAD, peripheral artery disease; and TBI, toe-brachial index. Figure 2 Diagnostic Testing for Suspected CLI Colors correspond to Class of Recommendation in Table 1. *Order based on expert consensus. †TBI with waveforms, if not already performed. ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; MRA, magnetic resonance angiography; TcPO2, transcutaneous oxygen pressure; and TBI, toe-brachial index. Figure 3 Diagnosis and Management of ALI 21,22 Colors correspond to Class of Recommendation in Table 1. ALI indicates acute limb ischemia.

Figure 2 Diagnostic Testing for Suspected CLI Colors correspond to Class of Recommendation in Table 1. *Order based on expert consensus. †TBI with waveforms, if not already performed. ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; MRA, magnetic resonance angiography; TcPO2, transcutaneous oxygen pressure; and TBI, toe-brachial index. Figure 3 Diagnosis and Management of ALI 21,22 Colors correspond to Class of Recommendation in Table 1. ALI indicates acute limb ischemia. Table 1 ACC/AHA Recommendation System: Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) CLASS (STRENGTH) OF RECOMMENDATION Class I (strong) Benefit >>> Risk Suggested phrases for writing recommendations: ■ Is recommended ■ Is indicated/useful/effective/beneficial ■ Should be performed/administered/other ■ Comparative-Effectiveness Phrases†: ○ Treatment/strategy A is recommended/indicated in preference to treatment B ○ Treatment A should be chosen over treatment B CLASS IIa (MODERATE) Benefit >> Risk Suggested phrases for writing recommendations; ■ Is reasonable ■ Can be useful/effective/beneficial ■ Comparative-Effectiveness Phrases†: ○ Treatment/strategy A is probably recommended/indicated in preference to treatment B ○ It is reasonable to choose treatment A over treatment B CLASS IIb (WEAK) Benefit ≥ Risk Suggested phrases for writing recommendations: ■ May/might be reasonable ■ May/might be considered

■ Can be useful/effective/beneficial ■ Comparative-Effectiveness Phrases†: ○ Treatment/strategy A is probably recommended/indicated in preference to treatment B ○ It is reasonable to choose treatment A over treatment B CLASS IIb (WEAK) Benefit ≥ Risk Suggested phrases for writing recommendations: ■ May/might be reasonable ■ May/might be considered ■ Usefulness/effectiveness is unknown/unclear/uncertain or not well established CLASS III: No Benefit (MODERATE) (Generally, LOE A or B use only) Benefit = Risk Suggested phrases for writing recommendations: ■ Is not recommended ■ Is not indicated/useful/effective/beneficial ■ Should not be performed/administered/other CLASS III: Harm (STRONG) Risk > Benefit Suggested phrases for writing recommendations: ■ Potentially harmful ■ Causes harm ■ Associated with excess morbidity/mortality ■ Should not be performed/administered/other LEVEL (QUALITY) OF EVIDENCE‡ LEVEL A ■ High-quality evidence‡ from more than 1 RCT ■ Meta-analyses of high-quality RCTs ■ One or more RCTs corroborated by high-quality registry studies LEVEL B-R (Randomized) ■ Moderate-quality evidence‡ from 1 or more RCTs ■ Meta-analyses of moderate-quality RCTs LEVEL B-NR (Nonrandomized) ■ Moderate-quality evidence‡ from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies ■ Meta-analyses of such studies LEVEL C-LD (Limited Data) ■ Randomized or nonrandomized observational or registry studies with limitations of design or execution ■ Meta-analyses of such studies ■ Physiological or mechanistic studies in human subjects LEVEL C-E0 (Expert Opinion)

■ Moderate-quality evidence‡ from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies ■ Meta-analyses of such studies LEVEL C-LD (Limited Data) ■ Randomized or nonrandomized observational or registry studies with limitations of design or execution ■ Meta-analyses of such studies ■ Physiological or mechanistic studies in human subjects LEVEL C-E0 (Expert Opinion) Consensus of expert opinion based on clinical experience COR and LOE are determined independently (any COR may be paired with any LOE). A recommendation with LOE C does not imply that the recommendation is weak. Many important clinical questions addressed in guidelines do not lend themselves to clinical trials. Although RCTs are unavailable, there may be a very dear clinical consensus that a particular test or therapy is useful or effective. * The outcome or result of the intervention should be specified (an improved clinical outcome or increased diagnostic accuracy or incremental prognostic information). † For comparative-effectiveness recommendations (COR 1 and lla; LOE A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. ‡ The method of assessing quality is evolving, including the application of standardized widely used, and preferably validated evidence grading tools; and for systematic reviews, the incorporation of an Evidence Review Committee.

† For comparative-effectiveness recommendations (COR 1 and lla; LOE A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. ‡ The method of assessing quality is evolving, including the application of standardized widely used, and preferably validated evidence grading tools; and for systematic reviews, the incorporation of an Evidence Review Committee. COR indicates Class of Recommendation; EO, expert opinion; LD, limited data; LOE, Level of Evidence; NR, nonrandomized; R, randomized; and RCT randomized controlled trial. Table 2 Definition of PAD Key Terms Term Definition Claudication Fatigue, discomfort, cramping, or pain of vascular origin in the muscles of the lower extremities that is consistently induced by exercise and consistently relieved by rest (within 10 min). Acute limb ischemia (ALI) Acute (<2 wk), severe hypoperfusion of the limb characterized by these features: pain, pallor, pulselessness, poikilothermia (cold), paresthesias, and paralysis. One of these categories of ALI is assigned (Section 10): Viable—Limb is not immediately threatened; no sensory loss; no muscle weakness; audible arterial and venous Doppler. Threatened—Mild-to-moderate sensory or motor loss; inaudible arterial Doppler; audible venous Doppler; may be further divided into IIa (marginally threatened) or IIb (immediately threatened).

Table 2 Definition of PAD Key Terms Term Definition Claudication Fatigue, discomfort, cramping, or pain of vascular origin in the muscles of the lower extremities that is consistently induced by exercise and consistently relieved by rest (within 10 min). Acute limb ischemia (ALI) Acute (<2 wk), severe hypoperfusion of the limb characterized by these features: pain, pallor, pulselessness, poikilothermia (cold), paresthesias, and paralysis. One of these categories of ALI is assigned (Section 10): Viable—Limb is not immediately threatened; no sensory loss; no muscle weakness; audible arterial and venous Doppler. Threatened—Mild-to-moderate sensory or motor loss; inaudible arterial Doppler; audible venous Doppler; may be further divided into IIa (marginally threatened) or IIb (immediately threatened). Irreversible—Major tissue loss or permanent nerve damage inevitable; profound sensory loss, anesthetic; profound muscle weakness or paralysis (rigor); inaudible arterial and venous Doppler.21,22 Tissue loss Type of tissue loss: Minor—nonhealing ulcer, focal gangrene with diffuse pedal ischemia. Major—extending above transmetatarsal level; functional foot no longer salvageable.21

Irreversible—Major tissue loss or permanent nerve damage inevitable; profound sensory loss, anesthetic; profound muscle weakness or paralysis (rigor); inaudible arterial and venous Doppler.21,22 Tissue loss Type of tissue loss: Minor—nonhealing ulcer, focal gangrene with diffuse pedal ischemia. Major—extending above transmetatarsal level; functional foot no longer salvageable.21 Critical limb ischemia (CLI) A condition characterized by chronic (≥2 wk) ischemic rest pain, nonhealing wound/ulcers, or gangrene in 1 or both legs attributable to objectively proven arterial occlusive disease. The diagnosis of CLI is a constellation of both symptoms and signs. Arterial disease can be proved objectively with ABI, TBI, TcPO2, or skin perfusion pressure. Supplementary parameters, such as absolute ankle and toe pressures and pulse volume recordings, may also be used to assess for significant arterial occlusive disease. However, a very low ABI or TBI does not necessarily mean the patient has CLI. The term CLI implies chronicity and is to be distinguished from ALI.23

ure. Supplementary parameters, such as absolute ankle and toe pressures and pulse volume recordings, may also be used to assess for significant arterial occlusive disease. However, a very low ABI or TBI does not necessarily mean the patient has CLI. The term CLI implies chronicity and is to be distinguished from ALI.23 In-line blood flow Direct arterial flow to the foot, excluding collaterals. Functional status Patient's ability to perform normal daily activities required to meet basic needs, fulfill usual roles, and maintain health and well-being. Walking ability is a component of functional status. Nonviable limb Condition of extremity (or portion of extremity) in which loss of motor function, neurological function, and tissue integrity cannot be restored with treatment. Salvageable limb Condition of extremity with potential to secure viability and preserve motor function to the weight-bearing portion of the foot if treated. Structured exercise program Planned program that provides individualized recommendations for type, frequency, intensity, and duration of exercise. Program provides recommendations for exercise progression to assure that the body is consistently challenged to increase exercise intensity and levels as functional status improves over time. There are 2 types of structured exercise program for patients with PAD: Supervised exercise program Structured community- or home-based exercise program

Supervised exercise program Structured exercise program that takes place in a hospital or outpatient facility in which intermittent walking exercise is used as the treatment modality. Program can be standalone or can be made available within a cardiac rehabilitation program. Program is directly supervised by qualified healthcare provider(s). Training is performed for a minimum of 30 to 45 min per session, in sessions performed at least 3 times/wk for a minimum of 12 wk.24–34 Patients may not initially achieve these targets, and a treatment goal is to progress to these levels over time. Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest. Warm-up and cool-down periods precede and follow each session of walking. Structured community- or home-based exercise program Structured exercise program that takes place in the personal setting of the patient rather than in a clinical setting.29,35–39 Program is self-directed with the guidance of healthcare providers who prescribe an exercise regimen similar to that of a supervised program. Patient counseling ensures that patients understand how to begin the program, how to maintain the program, and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching and/or use of activity monitors.

Structured community- or home-based exercise program Structured exercise program that takes place in the personal setting of the patient rather than in a clinical setting.29,35–39 Program is self-directed with the guidance of healthcare providers who prescribe an exercise regimen similar to that of a supervised program. Patient counseling ensures that patients understand how to begin the program, how to maintain the program, and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching and/or use of activity monitors. Emergency versus urgent An emergency procedure is one in which life or limb is threatened if the patient is not in the operating room or interventional suite and/or where there is time for no or very limited clinical evaluation, typically within <6 h. An urgent procedure is one in which there may be time for a limited clinical evaluation, usually when life or limb is threatened if the patient is not in the operating room or interventional suite, typically between 6 and 24 h. Interdisciplinary care team A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care.

ts Worsening claudication, new CLI, new lower extremity revascularization, or new ischemic amputation. ABI indicates ankle-brachial index; ALI, acute limb ischemia; CLI, critical limb ischemia; MI, myocardial infarction; PAD, peripheral artery disease; TBI, toe-brachial index; and TcPO2, transcutaneous oxygen pressure. Table 3 Patients at Increased Risk of PAD Age ≥65 y Age 50–64 y, with risk factors for atherosclerosis (eg, diabetes mellitus, history of smoking, hyperlipidemia, hypertension) or family history of PAD52 Age <50 y, with diabetes mellitus and 1 additional risk factor for atherosclerosis Individuals with known atherosclerotic disease in another vascular bed (eg, coronary, carotid, subclavian, renal, mesenteric artery stenosis, or AAA) AAA indicates abdominal aortic aneurysm; PAD, peripheral artery disease. Table 4 History and/or Physical Examination Findings Suggestive of PAD History Claudication Other non–joint-related exertional lower extremity symptoms (not typical of claudication) Impaired walking function Ischemic rest pain Physical Examination Abnormal lower extremity pulse examination Vascular bruit Nonhealing lower extremity wound Lower extremity gangrene Other suggestive lower extremity physical findings (eg, elevation pallor/dependent rubor) PAD indicates peripheral artery disease.

cation) Impaired walking function Ischemic rest pain Physical Examination Abnormal lower extremity pulse examination Vascular bruit Nonhealing lower extremity wound Lower extremity gangrene Other suggestive lower extremity physical findings (eg, elevation pallor/dependent rubor) PAD indicates peripheral artery disease. Table 5 Alternative Diagnoses for Leg Pain or Claudication With Normal Physiological Testing (Not PAD-Related) Condition Location Characteristic Effect of Exercise Effect of Rest Effect of Position Other Characteristics Symptomatic Baker's cyst Behind knee, down calf Swelling, tenderness With exercise Also present at rest None Not intermittent Venous claudication Entire leg, worse in calf Tight, bursting pain After walking Subsides slowly Relief speeded by elevation History of iliofemoral deep vein thrombosis; edema; signs of venous stasis Chronic compartment syndrome Calf muscles Tight, bursting pain After much exercise (jogging) Subsides very slowly Relief with rest Typically heavy muscled athletes Spinal stenosis Often bilateral buttocks, posterior leg Pain and weakness May mimic claudication Variable relief but can take a long time to recover Relief by lumbar spine flexion Worse with standing and extending spine Nerve root compression Radiates down leg Sharp lancinating pain Induced by sitting, standing, or walking Often present at rest Improved by change in position History of back problems; worse with sitting; relief when supine or sitting Hip arthritis Lateral hip, thigh Aching discomfort After variable degree of exercise Not quickly relieved Improved when not weight bearing Symptoms variable; history of degenerative arthritis Foot/ankle arthritis Ankle, foot, arch Aching pain After variable degree of exercise Not quickly relieved May be relieved by not bearing weight Symptoms variable; may be related to activity level or present at rest Modified from Norgren L et al.23

not weight bearing Symptoms variable; history of degenerative arthritis Foot/ankle arthritis Ankle, foot, arch Aching pain After variable degree of exercise Not quickly relieved May be relieved by not bearing weight Symptoms variable; may be related to activity level or present at rest Modified from Norgren L et al.23 PAD indicates peripheral artery disease.

not weight bearing Symptoms variable; history of degenerative arthritis Foot/ankle arthritis Ankle, foot, arch Aching pain After variable degree of exercise Not quickly relieved May be relieved by not bearing weight Symptoms variable; may be related to activity level or present at rest Modified from Norgren L et al.23 PAD indicates peripheral artery disease. Table 6 Alternative Diagnoses for Nonhealing Wounds With Normal Physiological Testing (Not PAD-Related) Condition Location Characteristics and Causes Venous ulcer Distal leg, especially above medial mellolus Develops in regions of skin changes due to chronic venous disease and local venous hypertension Typically wet (ie, wound drainage) rather than dry lesion Distal small arterial occlusion (microangiopathy) Toes, foot, leg End-stage renal disease Thromboangiitis obliterans (Buerger's) Sickle-cell anemia Vasculitis (eg, Churg-Strauss, Henoch-Schonlein purpura, leukocytoclastic vasculitis, microscopic polyangiitis, polyarteritis nodosa) Scleroderma Cryoagglutination Embolic (eg, cholesterol emboli, thromboemboli, endocarditis) Thrombotic (eg, antiphospholipid antibody syndrome, Sneddon's syndrome, warfarin skin necrosis, disseminated intravascular coagulation, livedoid vasculitis, protein C or S deficiency, prolonged vasospasm) Local injury Toes, foot, leg Trauma Insect or animal bite Burn Medication related Toes, foot, leg Drug reactions (eg, erythema multiforme) Medication direct toxicity (eg, doxorubicin, hydroxyurea, some tyrosine kinase inhibitors) Neuropathic Pressure zones of foot Hyperkeratosis surrounds the ulcer Diabetes mellitus with peripheral neuropathy Peripheral neuropathy without diabetes mellitus Leprosy Autoimmune injury Toes, foot, leg With blisters (eg, pemphigoid, pemphigus, epidermolysis bullosa) Without blisters (eg, dermatomyositis, lupus, scleroderma) Infection Toes, foot, leg Bacterial (eg, pseudomonas, necrotizing streptococcus) Fungal (eg, blastomycosis, Madura foot, chromomycosis) Mycobacterial Parasitic (eg, Chagas, leishmaniasis) Viral (eg, herpes) Malignancy Toes, foot, leg Primary skin malignancy Metastatic malignancy Malignant transformation of ulcer Inflammatory Toes, foot, leg Necrobiosis lipoidica Pyoderma gangrenosum Granuloma annulare PAD indicates peripheral artery disease.

momycosis) Mycobacterial Parasitic (eg, Chagas, leishmaniasis) Viral (eg, herpes) Malignancy Toes, foot, leg Primary skin malignancy Metastatic malignancy Malignant transformation of ulcer Inflammatory Toes, foot, leg Necrobiosis lipoidica Pyoderma gangrenosum Granuloma annulare PAD indicates peripheral artery disease. Table 7 Structured Exercise Programs for PAD: Definitions Supervised exercise program (COR I, LOE A) Program takes place in a hospital or outpatient facility. Program uses intermittent walking exercise as the treatment modality. Program can be standalone or within a cardiac rehabilitation program. Program is directly supervised by qualified healthcare provider(s). Training is performed for a minimum of 30–45 min/session; sessions are performed at least 3 times/wk for a minimum of 12 wk.24–34 Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest. Warm-up and cool-down periods precede and follow each session of walking. Structured community- or home-based exercise program (COR IIa, LOE A) Program takes place in the personal setting of the patient rather than in a clinical setting.29,35–39 Program is self-directed with guidance of healthcare providers. Healthcare providers prescribe an exercise regimen similar to that of a supervised program. Patient counseling ensures understanding of how to begin and maintain the program and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching or use of activity monitors. COR indicates Class of Recommendation; LOE, Level of Evidence; and PAD, peripheral artery disease.

egin and maintain the program and how to progress the difficulty of the walking (by increasing distance or speed). Program may incorporate behavioral change techniques, such as health coaching or use of activity monitors. COR indicates Class of Recommendation; LOE, Level of Evidence; and PAD, peripheral artery disease. Table 8 Interdisciplinary Care Team for PAD A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care. Interdisciplinary care team members may include: Vascular medical and surgical specialists (ie, vascular medicine, vascular surgery, interventional radiology, interventional cardiology) Nurses Orthopedic surgeons and podiatrists Endocrinologists Internal medicine specialists Infectious disease specialists Radiology and vascular imaging specialists Physical medicine and rehabilitation clinicians Orthotics and prosthetics specialists Social workers Exercise physiologists Physical and occupational therapists Nutritionists/dieticians CLI indicates critical limb ischemia; and PAD, peripheral artery disease.

sease specialists Radiology and vascular imaging specialists Physical medicine and rehabilitation clinicians Orthotics and prosthetics specialists Social workers Exercise physiologists Physical and occupational therapists Nutritionists/dieticians CLI indicates critical limb ischemia; and PAD, peripheral artery disease. Table 9 Therapy for CLI: Findings That Prompt Consideration of Surgical or Endovascular Revascularization Findings That Favor Consideration of Surgical Revascularization Examples Factors associated with technical failure or poor durability with endovascular treatment Lesion involving common femoral artery, including origin of deep femoral artery Long segment lesion involving the below-knee popliteal and/or infrapopliteal arteries in a patient with suitable single-segment autogenous vein conduit Diffuse multilevel disease that would require endovascular revascularization at multiple anatomic levels Small-diameter target artery proximal to site of stenosis or densely calcified lesion at location of endovascular treatment Endovascular treatment likely to preclude or complicate subsequent achievement of in-line blood flow through surgical revascularization Single-vessel runoff distal to ankle Findings That Favor Consideration of Endovascular Revascularization Examples The presence of patient comorbidities may place patients at increased risk of perioperative complications from surgical revascularization. In these patients, an endovascular-first approach should be used regardless of anatomy Patient comorbidities, including coronary ischemia, cardiomyopathy, congestive heart failure, severe lung disease, and chronic kidney disease Patients with rest pain and disease at multiple levels may undergo a staged approach as part of endovascular-first approach In-flow disease can be addressed first, and out-flow disease can be addressed in a staged manner, when required, if clinical factors or patient safety prevent addressing all diseased segments at one setting Patients without suitable autologous vein for bypass grafts Some patients have had veins harvested for previous coronary artery bypass surgery and do not have adequate remaining veins for use as conduits. Similarly, patients may not have undergone prior saphenous vein harvest, but available vein is of inadequate diameter CLI indicates critical limb ischemia.

ts with no serious adverse effects of the MRI or contrast medium. Moreover, we have demonstrated its applicability across multiple sites, and we have developed robust computer algorithms and image analysis techniques that enable automated reporting of USPIO enhancement, lending itself to immediate clinical application. In conclusion, in a multicenter prospective observational cohort study, we have demonstrated that USPIO-enhanced MRI predicts the rate of aneurysm expansion and the risk of abdominal aortic aneurysm rupture and repair. Although this study does not provide independent prediction of aneurysm expansion or clinical outcomes in a model incorporating known clinical risk factors, it is the first demonstration of a cellular imaging technique that can predict clinical events in patients with abdominal aortic aneurysm. Whether clinical outcomes can be improved by treatment decisions on the basis of this novel imaging approach remains to be established.

Clinical Perspective What Is New? In this proof-of-concept phase 2 study, we demonstrate for the first time that functional imaging of abdominal aortic aneurysms can predict disease progression and clinical events. Aortic wall inflammation detected by ultrasmall superparamagnetic particles of iron oxide–enhanced magnetic resonance imaging predicts the rate of aneurysm growth and the risk of aneurysm rupture or repair as well as being associated with all-cause and aneurysm-related mortality. What Are the Clinical Implications? Multivariate analysis demonstrated that ultrasmall superparamagnetic particles of iron oxide–enhanced magnetic resonance imaging does not appear to improve risk stratification beyond current predictors of clinical outcome, including ultrasound measures of aneurysm diameter. This technique may be a useful adjunctive imaging approach in those with high-risk or borderline aneurysm sizes or those with larger aneurysms, where the balance of risk and benefit is uncertain. This approach may also have utility in assessing candidate anti-inflammatory therapies targeted at reducing disease progression.

This technique may be a useful adjunctive imaging approach in those with high-risk or borderline aneurysm sizes or those with larger aneurysms, where the balance of risk and benefit is uncertain. This approach may also have utility in assessing candidate anti-inflammatory therapies targeted at reducing disease progression. Abdominal aortic aneurysms have a prevalence of 5% in 65- to 74-year-old men and, when ruptured, are associated with a mortality of ≤90%.1 At a population level, ruptured aortic aneurysms are a major cause of death, being the 13th most common cause of death and accounting for >150 000 deaths in 2013.2 Preemptive elective open surgical or endovascular repair can be life-saving and is considered when the abdominal aortic aneurysm diameter is >55 mm, is rapidly expanding (≥10 mm/year), or causes symptoms.3–5

e a major cause of death, being the 13th most common cause of death and accounting for >150 000 deaths in 2013.2 Preemptive elective open surgical or endovascular repair can be life-saving and is considered when the abdominal aortic aneurysm diameter is >55 mm, is rapidly expanding (≥10 mm/year), or causes symptoms.3–5 Abdominal aortic aneurysms are usually associated with no symptoms and are often identified incidentally or as part of an ultrasound-based screening program. Population screening has been established in some countries and is associated with a halving of the mortality associated with abdominal aortic aneurysms.6,7 However, continued surveillance of aneurysms is challenging because of the nonlinearity and unpredictability of expansion rates,8 although the best current predictor of aneurysm expansion and rupture is the baseline aneurysm diameter.1,9 Furthermore, the pathophysiological mechanisms underlying aneurysm expansion remain uncertain, and the role of cellular inflammation and macrophage infiltration has been debated. Last, ≤20% of ruptured abdominal aortic aneurysms are <55 mm in diameter, and 40% of patients with aneurysm diameters between 70 and 100 mm do not experience aneurysm rupture.10 Therefore, an unmet clinical need exists to identify more reliable methods of identifying those patients at risk of abdominal aortic aneurysm expansion and rupture,11,12 and techniques that assess both the structure and biology of aneurysms hold considerable promise.

70 and 100 mm do not experience aneurysm rupture.10 Therefore, an unmet clinical need exists to identify more reliable methods of identifying those patients at risk of abdominal aortic aneurysm expansion and rupture,11,12 and techniques that assess both the structure and biology of aneurysms hold considerable promise. Ultrasmall superparamagnetic particles of iron oxide (USPIO) constitute a class of magnetic resonance imaging (MRI) contrast agent taken up by tissue-resident macrophages and can be used to identify cellular inflammation within tissues,13,14 including abdominal aortic aneurysms.15,16 In a small pilot study of 29 patients with abdominal aortic aneurysm,15 we have previously demonstrated that USPIO enhancement on MRI is associated with macrophage infiltration of the abdominal aortic aneurysm wall and more rapid rates of abdominal aortic aneurysm expansion. We therefore aimed to validate these preliminary findings in a larger multicenter cohort of patients and determine whether USPIO-enhanced MRI could predict the rate of abdominal aortic aneurysm expansion and subsequent rates of rupture or surgical repair.

all and more rapid rates of abdominal aortic aneurysm expansion. We therefore aimed to validate these preliminary findings in a larger multicenter cohort of patients and determine whether USPIO-enhanced MRI could predict the rate of abdominal aortic aneurysm expansion and subsequent rates of rupture or surgical repair. Methods Study Design The MA3RS study (MRI Using Ultrasound Superparamagnetic Particles of Iron Oxide to Predict Clinical Outcome in Patients Under Surveillance for Abdominal Aortic Aneurysms) was a prospective multicenter observational open-label cohort study of patients under routine ultrasound surveillance for abdominal aortic aneurysm. The research design and protocol has been described previously (ISRCTN.com. Unique identifier: ISRCTN76413758).17 The study was approved by the local research ethics committee (12/ES/0068), and the use of ferumoxytol was given clinical trial authorization by the Medicines and Healthcare products Regulatory Authority of the United Kingdom (EudraCT Number 2012-002488-25).

previously (ISRCTN.com. Unique identifier: ISRCTN76413758).17 The study was approved by the local research ethics committee (12/ES/0068), and the use of ferumoxytol was given clinical trial authorization by the Medicines and Healthcare products Regulatory Authority of the United Kingdom (EudraCT Number 2012-002488-25). Study Population Consecutive patients were recruited from 3 centers in Scotland (Royal Infirmary of Edinburgh, Western Infirmary of Glasgow, and Forth Valley Royal Hospital in Larbert) between November 8, 2012, and December 5, 2014. Inclusion criteria were age >40 years, maximum anteroposterior abdominal aortic aneurysm diameter ≥40 mm by abdominal ultrasound, and under ultrasound surveillance as part of routine clinical care. Exclusion criteria included patients with planned repair of abdominal aortic aneurysm, known inflammatory aneurysm, aneurysm arising from a connective tissue disorder, women of childbearing potential, renal failure (estimated glomerular filtration rate ≤30 mL/min/1.73 m2), and contraindication to MRI or ferumoxytol. All participants gave written informed consent to participate in the study.