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‘Complex and combined’ initiatives split into different levels and implemented through multidisciplinary integrated approaches. Overall, the quality of communication and congruous duration of clinical meetings between health care professionals (doctors and nurses) and patients represent the key elements that condition compliance. Myocardial revascularization Indications for coronary angiogram and coronary angioplasty Coronary angiography is an invasive technique allowing a direct assessment of the coronary tree. In this context, the radial approach reduces haemorrhagic complications and allows earlier patient mobilization than the femoral approach. The application of coronary angiography and coronary angioplasty (PCI) should be guided by angina symptoms. The diagnosis of angina is a ‘clinical’ diagnosis. As indicated in European guidelines,3 it is important to stress that the diagnosis of angina must be primarily clinical, consisting of thorough medical history collection, in order to evaluate symptoms in their full complexity. The distinction between stable and instable angina is not always well defined in the real world. There is often a diagnostic delay (>1 month), which can lead to a completely different approach to patient management, by changing the diagnosis from unstable angina to stable angina. In these cases of angina of (relatively) recent onset, a coronary angiogram could be considered as the first investigation.

The distinction between stable and instable angina is not always well defined in the real world. There is often a diagnostic delay (>1 month), which can lead to a completely different approach to patient management, by changing the diagnosis from unstable angina to stable angina. In these cases of angina of (relatively) recent onset, a coronary angiogram could be considered as the first investigation. The assessment of coronary anatomy has an essential role in prognostic stratification. According to European guidelines, PCI should be guided by coronary anatomy and a 50% stenosis on the left anterior descending artery should be treated, even in patients with atherosclerosis or silent ischaemia (Class I guideline).3 A recent sub-analysis of the COURAGE trial154 showed that the anatomical situation assessed by angiogram and EF are predictors of events rather than the size of inducible ischaemia. This said, high-risk patients were excluded from the COURAGE study.155

Revised by: Roberto Caporale, Marco Malvezzi Caracciolo, Giovanna Geraci, Alfredo Marchese, Roberto Pedretti, and Guerrino Zuin Consensus Document Aproval Faculty in appendix Definitions and clinical profiles For a clear definition of chronic ischaemic cardiopathy (CIC), the most correct approach is to identify the groups of patient suffering from the condition (Figure 1).1Figure 1 The complex interrelationships between the various components of chronic ischaemic cardiomyopathy. Among these we can undoubtedly include those who have had prior cardiovascular events, patients who have already undergone percutaneous coronary intervention (PCI) or surgical coronary artery bypass grafting (CABG), and also those patients in whom, despite having no history of acute myocardial infarction (AMI), there are findings of necrosis on the electrocardiogram (ECG) or of localized akinesia on the ECG. The condition of post-AMI stability is currently defined after 1 year, as established by the EuroHeart Survey.2 The same interval applies to all patients who have suffered acute ischaemic events. It is, however, a far more complex issue to consider other subsets, i.e. those of the patients who do not belong to the previous groups and have angina symptoms, evidence of ischaemia at baseline or after an induction test or a coronary angiogram or computed tomography (CT) angiogram finding of coronary stenosis.

The condition of post-AMI stability is currently defined after 1 year, as established by the EuroHeart Survey.2 The same interval applies to all patients who have suffered acute ischaemic events. It is, however, a far more complex issue to consider other subsets, i.e. those of the patients who do not belong to the previous groups and have angina symptoms, evidence of ischaemia at baseline or after an induction test or a coronary angiogram or computed tomography (CT) angiogram finding of coronary stenosis. The most recent European guidelines3 concerning CIC include both the known and the suspected form of the condition and therefore characterize different groups of patients: those who are symptomatic for angina or equivalents; those who are asymptomatic but are known to have coronary disease, occlusive or otherwise; and those who report for the first-time symptoms that they have been experiencing for several months (Table 1). Table 1 Operative definition of chronic ischaemic cardiopathy Symptomatic patients with stable angina (or equivalents). Patients who are asymptomatic but have clinical or instrumental evidence of prior myocardial infarction or acute coronary syndrome (for over a year). Patients who are asymptomatic but have a confirmed diagnosis of occlusive coronary disease (e.g. patients who have already had percutaneous coronary intervention or coronary artery bypass grafting or with coronary angiogram findings of significant stenosis or evidence of ischaemia on the induction tests).

Patients who are asymptomatic but have clinical or instrumental evidence of prior myocardial infarction or acute coronary syndrome (for over a year). Patients who are asymptomatic but have a confirmed diagnosis of occlusive coronary disease (e.g. patients who have already had percutaneous coronary intervention or coronary artery bypass grafting or with coronary angiogram findings of significant stenosis or evidence of ischaemia on the induction tests). Clinical overview Angina is one of the main clinical presentations of CIC. The diagnosis of angina is purely clinical and is based on a number of characteristics, such as quality, duration, site, and the precipitating and triggering factors. The various types are: Exertional; Varying (transient alteration in blood supply due to coronary vasospasm or platelet aggregation, in the absence or presence of atherosclerotic plaques); and Cardiac syndrome X (with anatomically normal coronary arteries, caused by a microcirculation disorder, with a good long-term prognosis). The definition of stable angina uses exclusion criteria (i.e. without the characteristics of unstable angina: onset at rest, appearance <1–2 months previously or with a worsening evolution). Clinical epidemiology and natural history Although the survival of patients with CIC is rapidly improving, this condition is the first cause of death due to cardiovascular disease in both men and women, in whom it is responsible for 27% of deaths.4

The definition of stable angina uses exclusion criteria (i.e. without the characteristics of unstable angina: onset at rest, appearance <1–2 months previously or with a worsening evolution). Clinical epidemiology and natural history Although the survival of patients with CIC is rapidly improving, this condition is the first cause of death due to cardiovascular disease in both men and women, in whom it is responsible for 27% of deaths.4 An epidemiological description of CIC is difficult for a number of reasons: The data obtained from various randomized controlled trials often do not reflect the real-life patient population. Because of the multi-form nature of stable angina, prevalence and incidence vary according to the diagnostic criteria used. For epidemiological purposes, in order to identify and stage angina symptoms, it is possible to use dedicated questionnaires such as the Rose Angina Questionnaire. There are various other questionnaires or assessment scales that are useful above all for quantifying the severity and incidence of symptoms on patients’ quality of life. These include: the angina classification devised by the Canadian Cardiovascular Society (CCSA), which is similar to the New York Heart Association (NYHA) classification for decompensated heart failure5; the Multidimensional Seattle Angina Questionnaire (SAQ); the HeartQoL; and the ANMCO Cardiotest6 (Table 2). Table 2 The ANMCO cardiotest

There are various other questionnaires or assessment scales that are useful above all for quantifying the severity and incidence of symptoms on patients’ quality of life. These include: the angina classification devised by the Canadian Cardiovascular Society (CCSA), which is similar to the New York Heart Association (NYHA) classification for decompensated heart failure5; the Multidimensional Seattle Angina Questionnaire (SAQ); the HeartQoL; and the ANMCO Cardiotest6 (Table 2). Table 2 The ANMCO cardiotest Incidence In Italy, the annual incidence of hospitalization for myocardial infarction (MI) is estimated to be approximately 100 000 cases. The number of isolated CABG procedures carried out in heart surgery units has dropped over time, and the number of PCI procedures has consequently progressively increased. The data available suggest an annual incidence of angina pectoris of 1% in Western male populations aged 45–65 years, with a slightly higher incidence among women.4,7 The incidence of stable angina increases progressively with age.7 However, in men, there is a peak around 55–65 years of age.8 Prevalence It is estimated that prevalence in Western countries is 30 000–40 000 cases per million inhabitants.9 In Italy, we can use the data of the Osservatorio Epidemiologico Cardiovascolare [Cardiovascular, Epidemiology Database (OEC)] and, more recently, those of the OEC/Health Examination Survey, according to which, 30 000 patients per million inhabitants have stable angina, with a higher prevalence among women and on the increase in both sexes.10

data of the Osservatorio Epidemiologico Cardiovascolare [Cardiovascular, Epidemiology Database (OEC)] and, more recently, those of the OEC/Health Examination Survey, according to which, 30 000 patients per million inhabitants have stable angina, with a higher prevalence among women and on the increase in both sexes.10 It is estimated, in any case, that in Italy there are approximately 5 000 000 patients with coronary disease, of whom 1 500 000 with stable angina. Prognosis and related variables Patients who survive acute coronary syndrome (ACS) or AMI remain at risk of events. In one sub-analysis of the GRACE Registry, total mortality 5 years after ACS was 19.8%, whereas the incidence of new AMIs, stroke, and revascularization procedures was 9.3, 7.7, and 17%, respectively.11 The real-life data2,7 are slightly more pessimistic, as shown by the Primary Prevention Study.12 Instrumental diagnosis Laboratory diagnostics Laboratory diagnostics is useful for determining a possible cause of ischaemia, in order to evaluate cardiovascular risk and for prognostic stratification, by means of the evaluation of: haemoglobin and white blood cell levels13,14; creatininaemia and estimated glomerular filtration rate using the Cockroft–Gault or Modification of Diet in Renal Disease formula15; glycaemia and glycated haemoglobin (HbA1c)16,17. total cholesterolaemia, HDL, LDL, and triglyceride levels are essential for the assessment of cardiovascular risk, the indication for anti-dyslipidaemia treatment, and for assessing the results obtained with treatment18,19;

creatininaemia and estimated glomerular filtration rate using the Cockroft–Gault or Modification of Diet in Renal Disease formula15; glycaemia and glycated haemoglobin (HbA1c)16,17. total cholesterolaemia, HDL, LDL, and triglyceride levels are essential for the assessment of cardiovascular risk, the indication for anti-dyslipidaemia treatment, and for assessing the results obtained with treatment18,19; myocardial necrosis marker (troponin, preferably with high sensitivity) in the event of a destabilization of the clinical situation; and assessment of the thyroid hormones free triiodothyronine, free thyroxine, and thyroid stimulating hormone. Instrumental diagnostics for the purpose of prognostic stratification Patients with recent acute coronary syndrome The prognostic stratification of patients with stable angina must take into account the presence or absence of a recent acute episode. Early risk assessment is essential. The variables with a documented prognostic value after an ACS have differing weights: the conventional risk factors have a poorer long-term predictive capacity than the left ventricular damage parameters.20 The prognostic indicators after ACS are left ventricular dysfunction, decompensated heart failure (DHF) and, to a lesser extent, the determinants of thrombotic risk.21

an ACS have differing weights: the conventional risk factors have a poorer long-term predictive capacity than the left ventricular damage parameters.20 The prognostic indicators after ACS are left ventricular dysfunction, decompensated heart failure (DHF) and, to a lesser extent, the determinants of thrombotic risk.21 Patients with an ejection fraction (EF) of <40% and patients with an EF of between 40% and 45%, but with an associated remodelling predictor (either mild mitral insufficiency, restrictive diastolic filling, high asynergy score, or non-dilated ventricle), represent a high-risk subgroup. In the follow-up, it is therefore important to guarantee serial echocardiographic monitoring. The prognostic importance of the DHF that develops during hospitalization for AMI is well known.22,23 It is therefore important to achieve a diagnosis of DHF, which is often underestimated, before the patient is discharged for ACS, as shown by the BLITZ-4 study. DHF developing after an ACS is also associated with an unfavourable prognosis.24 In a younger population, the incidence of CHF 1 year after discharge was lower (12.2%); however, the development of DHF was associated with an increase in mortality at 1 year that was four times that of those patients who did not develop it. The indicators of DHF are max Killip class, echocardiographic EF, predictors of remodelling, use of loop diuretics, and, lastly, brain natriuretic peptide level variation.

er, the development of DHF was associated with an increase in mortality at 1 year that was four times that of those patients who did not develop it. The indicators of DHF are max Killip class, echocardiographic EF, predictors of remodelling, use of loop diuretics, and, lastly, brain natriuretic peptide level variation. As far as thrombotic risk is concerned, elements such as initial clinical presentation, the ECG tracing, and biomarkers are strongly predictive of recurrent ischaemic events. In addition, old age, co-morbidities including diabetes mellitus, renal insufficiency, prior stroke/transient ischaemic attack (TIA), peripheral or carotid arterial disease, prior AMI are associated with an increased risk of recurrent ischaemic events.25–27 Scores such as GRACE and TIMI28,29 are certainly of help. For patients undergoing a coronary angiogram, certain angiographic parameters can also be used, such as the number of coronary arteries affected by significant stenosis or incomplete revascularization, which increase the risk of recurrence. There are also other scores based on angiographic parameters, such as the SYNTAX,30 Clinical SYNTAX, SYNTAX II, and ACUITY-PCI scores.31,32 These thromboembolic risk assessment parameters must be included in the patient’s discharge papers so that he/she can be referred to a diversified secondary prevention programme (Table 3). Table 3 Variables to be considered for patient stratification with recent acute coronary syndrome

X II, and ACUITY-PCI scores.31,32 These thromboembolic risk assessment parameters must be included in the patient’s discharge papers so that he/she can be referred to a diversified secondary prevention programme (Table 3). Table 3 Variables to be considered for patient stratification with recent acute coronary syndrome Predictors of mortality High Killip class Ejection fraction <40% Ejection fraction ≥40 to < 45% with (i) Restrictive diastolic filling pattern (ii) Mitral insufficiency (iii) High WMSI and no ventricular dilation Significant BNP alteration Use of loop diuretics Predictors of recurrence of ischaemia Peripheral arterial disease or prior stroke/TIA History of angina or prior myocardial infarction Diabetes mellitus Multi-vessel coronary disease Incomplete revascularisation Non-revascularized patients BNP, brain natriuretic peptide; TIA, transient ischaemic attack; WMSI, wall motion score index. Patients without recent acute coronary syndrome or coronary index event Clinical assessment, followed by non-invasive instrumental diagnostics that make it possible to evaluate ventricular function and response to stress tests and the severity of the coronary disease, through to invasive imaging, represent the key elements for the stratification of cardiovascular risk.33

ronary index event Clinical assessment, followed by non-invasive instrumental diagnostics that make it possible to evaluate ventricular function and response to stress tests and the severity of the coronary disease, through to invasive imaging, represent the key elements for the stratification of cardiovascular risk.33 Risk stratification by clinical assessment The patient’s history and physical examination provide prognostic information of great importance regarding the risk factors that are known to be predictive of an unfavourable outcome.33 Other important factors include renal dysfunction, peripheral arterial disease, prior MI, decompensated heart failure, and the severity of angina (Table 4). Table 4 The Euro Heart Survey prognostic score (Daly) Score sheet to calculate risk score for patients presenting with stable angina Risk factor Score contribution Individual score Co-morbidity No 0 Yes 86 Diabetes No 0 Yes 57 Angina score Class I 0 Class II 54 Class III 91 Duration of symptoms ≥6 months 0 <6 months 80 Abnormal ventricular function No 0 Yes 114 ST depression or T wave inversion on resting electrocardiogram No 0 Yes 34 Total = In this phase, the presence of ECG alterations at rest, such as evidence of prior MI, left branch bundle block, left anterior hemiblock, left ventricular hypertrophy, second- and third-degree atrioventricular block, or atrial fibrillation, identifies those patients at a higher risk.

Score sheet to calculate risk score for patients presenting with stable angina Risk factor Score contribution Individual score Co-morbidity No 0 Yes 86 Diabetes No 0 Yes 57 Angina score Class I 0 Class II 54 Class III 91 Duration of symptoms ≥6 months 0 <6 months 80 Abnormal ventricular function No 0 Yes 114 ST depression or T wave inversion on resting electrocardiogram No 0 Yes 34 Total = In this phase, the presence of ECG alterations at rest, such as evidence of prior MI, left branch bundle block, left anterior hemiblock, left ventricular hypertrophy, second- and third-degree atrioventricular block, or atrial fibrillation, identifies those patients at a higher risk. Risk stratification by ventricular function assessment Left ventricular function is the most important predictive factor of long-term survival. The data of the CASS study34 showed that 12-year survival in patients with EF >50, between 35–49%, and <35% was 73, 54, and 21% (P < 0.0001), respectively. The presence of diastolic dysfunction identifies those patients with the worst prognosis in both the early and the later phases.35 Special attention must be dedicated to hypertensive and diabetic patients, in whom the ECG makes it possible to identify the presence of hypertrophy and systolic and diastolic left ventricular dysfunction. Asymptomatic ventricular dysfunction is not rare36 and consequently a resting echocardiogram is recommended for all patients suspected of having stable angina.

ensive and diabetic patients, in whom the ECG makes it possible to identify the presence of hypertrophy and systolic and diastolic left ventricular dysfunction. Asymptomatic ventricular dysfunction is not rare36 and consequently a resting echocardiogram is recommended for all patients suspected of having stable angina. Risk stratification by stress testing The prognostic information that can be obtained through ischaemia induction tests, combined if necessary with imaging techniques, regards not merely the demonstration of ischaemia but also the evaluation of the ischaemic threshold, the extent and the severity of the ischaemia, and functional capacity. In order to predict future events, induction tests must be completed with a clinical assessment. More specifically, symptomatic patients with suspected or confirmed coronary disease should have an induction test for prognostic stratification and the results should constitute the basis for therapeutic decision making for those patients who are candidates for revascularization.

completed with a clinical assessment. More specifically, symptomatic patients with suspected or confirmed coronary disease should have an induction test for prognostic stratification and the results should constitute the basis for therapeutic decision making for those patients who are candidates for revascularization. Exercise electrocardiogram The contribution of the exercise ECG in the risk stratification of symptomatic patients with confirmed or suspected coronary disease has been extensively demonstrated. For example, the prognosis of patients with a normal exercise ECG and low clinical risk for severe coronary disease is excellent.37 The exercise test parameters of greatest prognostic value are exercise capacity, blood pressure (BP)response, and the finding of stress-induced ischaemia. One important prognostic indicator is work capacity, which can be measured according to the maximum duration of the exercise, maximum metabolic equivalent level achieved, maximum load expressed in watts, maximum heart rate, and the pressure rate product (heart rate × BP). Indeed, in patients with known coronary disease, 5-year survival is greater in those with greater stress tolerance.38 The Duke treadmill score is the most commonly used score for the exercise test, as its prognostic value has been extensively proven.39 Stress echocardiography The stress echocardiogram (both physical, which is always recommended due to the greater information it offers, and pharmacological) is effective for the stratification of the risk of future cardiovascular events.40,41

The Duke treadmill score is the most commonly used score for the exercise test, as its prognostic value has been extensively proven.39 Stress echocardiography The stress echocardiogram (both physical, which is always recommended due to the greater information it offers, and pharmacological) is effective for the stratification of the risk of future cardiovascular events.40,41 Stress myocardial perfusion scintigraphy It has been demonstrated that a normal scintigraphy study is highly predictive of a favourable prognosis, with an incidence of death and MI at 1 year of <1%.42 Conversely, the presence of extensive perfusion defects is an unfavourable factor. Patients with reversible stress-induced perfusion defects >10% of the whole myocardium are at high risk and should have a coronary angiogram as soon as possible.43 The prognostic value of the stress test combined with imaging techniques is greater than that of pharmacologically induced stress tests as it provides information on symptoms and exercise tolerance. Stress cardiac magnetic resonance Single studies have shown that there is an independent association between the absence of ischaemia on dobutamine cardiac magnetic resonance and the absence of events during follow-up (up to 3 years).44 Similar data have also been obtained with adenosine.45

Stress myocardial perfusion scintigraphy It has been demonstrated that a normal scintigraphy study is highly predictive of a favourable prognosis, with an incidence of death and MI at 1 year of <1%.42 Conversely, the presence of extensive perfusion defects is an unfavourable factor. Patients with reversible stress-induced perfusion defects >10% of the whole myocardium are at high risk and should have a coronary angiogram as soon as possible.43 The prognostic value of the stress test combined with imaging techniques is greater than that of pharmacologically induced stress tests as it provides information on symptoms and exercise tolerance. Stress cardiac magnetic resonance Single studies have shown that there is an independent association between the absence of ischaemia on dobutamine cardiac magnetic resonance and the absence of events during follow-up (up to 3 years).44 Similar data have also been obtained with adenosine.45 Risk stratification by coronary anatomy assessment Computed tomography coronary angiography Prospective studies have established the independent prognostic value of CT coronary angiogram, due to both the presence and the extent of coronary lesions and the presence of non-occlusive atherosclerotic plaques. Its negative predictive power is especially important.46 However, international recommendations suggest performing an additional pre-coronary angiogram ischaemia test for patients at high risk on the basis of the CT angiogram but with uncertain symptoms, which gives this technique an ambiguous role.47

Risk stratification by coronary anatomy assessment Computed tomography coronary angiography Prospective studies have established the independent prognostic value of CT coronary angiogram, due to both the presence and the extent of coronary lesions and the presence of non-occlusive atherosclerotic plaques. Its negative predictive power is especially important.46 However, international recommendations suggest performing an additional pre-coronary angiogram ischaemia test for patients at high risk on the basis of the CT angiogram but with uncertain symptoms, which gives this technique an ambiguous role.47 Follow-up and the timing of check-ups The follow-up strategies in patients with stable angina are often inadequate. While low-risk patients are often subject to unnecessary assessments, high-risk patients have a lower probability of accessing appropriate checks.48,49 For the first year after ACS, where the programme should be individualized and clearly defined in the discharge extract, guidance is provided in a recent inter-society consensus.21 Another multidisciplinary document has also been produced for patients who recently underwent PCI, which identifies three strategies with decreasing levels of follow-up intensity. For further details and for the three different flow charts, reference should be made to the document in question.

nter-society consensus.21 Another multidisciplinary document has also been produced for patients who recently underwent PCI, which identifies three strategies with decreasing levels of follow-up intensity. For further details and for the three different flow charts, reference should be made to the document in question. In patients with stable angina and no recent index event, follow-up should focus primarily on secondary prevention, patients’ functional status and on symptoms. In this context, the main player is the general practitioner who should monitor treatment compliance, risk factor correction, and the appearance of new symptoms. On the basis of clinical elements, the cardiologist should establish the most suitable clinical and/or instrumental workup, a specialist consultation with an ECG and routine blood chemistry tests are often sufficient for identifying patients at low risk or at high risk for whom there is an indication for a coronary angiogram without other preliminary investigations, thereby identifying those patients at intermediate risk in whom further instrumental investigations are justified.3,50 For clinically stable patients with no recent acute event, a cardiologist consultation with ECG and blood chemistry tests once a year are adequate. After an efficacious elective PCI, the first check-up should take place after ∼3 months and thereafter, in the absence of new clinical events, within 1 year. A recent document published by the ANMCO Prevention Area provided guidance on the timing of instrumental investigations.51

In patients with stable angina and no recent index event, follow-up should focus primarily on secondary prevention, patients’ functional status and on symptoms. In this context, the main player is the general practitioner who should monitor treatment compliance, risk factor correction, and the appearance of new symptoms. On the basis of clinical elements, the cardiologist should establish the most suitable clinical and/or instrumental workup, a specialist consultation with an ECG and routine blood chemistry tests are often sufficient for identifying patients at low risk or at high risk for whom there is an indication for a coronary angiogram without other preliminary investigations, thereby identifying those patients at intermediate risk in whom further instrumental investigations are justified.3,50 For clinically stable patients with no recent acute event, a cardiologist consultation with ECG and blood chemistry tests once a year are adequate. After an efficacious elective PCI, the first check-up should take place after ∼3 months and thereafter, in the absence of new clinical events, within 1 year. A recent document published by the ANMCO Prevention Area provided guidance on the timing of instrumental investigations.51 For resting echocardiograms, after the first 6 months from the AMI, where it is useful to monitor the ventricular function and remodelling, its repetition (especially at annual intervals) is of no use in stable patients.52

A recent document published by the ANMCO Prevention Area provided guidance on the timing of instrumental investigations.51 For resting echocardiograms, after the first 6 months from the AMI, where it is useful to monitor the ventricular function and remodelling, its repetition (especially at annual intervals) is of no use in stable patients.52 Repeating the routine stress test (<2 years from the previous test) is not indicated unless there are changes in the symptoms experienced. After revascularization, in asymptomatic patients, there is no indication to repeat the ischaemia induction test before 2 years in the case of PCI and sooner than 5 years in the case of CABG, except when revascularization is incomplete or new symptoms appear.53 This applies for both stress ECGs and ischaemia induction tests using imaging techniques. On the other hand, in the presence of suspected ischaemic symptoms, the CT angiogram can be used to confirm graft patency.54 Lifestyle and pharmacological therapy Smoking Smoking is a strong independent risk factor in patients with ischaemic cardiopathy. To resume smoking doubles the risk of having another event at 1 year, whereas stopping smoking leads to a reduction in the risk that is greater than any pharmacological intervention.55–58

On the other hand, in the presence of suspected ischaemic symptoms, the CT angiogram can be used to confirm graft patency.54 Lifestyle and pharmacological therapy Smoking Smoking is a strong independent risk factor in patients with ischaemic cardiopathy. To resume smoking doubles the risk of having another event at 1 year, whereas stopping smoking leads to a reduction in the risk that is greater than any pharmacological intervention.55–58 Tobacco dependency is a chronic, relapsing condition. Given these characteristics, smoking addiction requires constant treatment, through counselling, support, and pharmacological therapy.59–61 The use of medicinal products can be effective, especially in the presence of frequent and violent withdrawal symptoms and those most commonly used are varenicline, bupropion, and nicotine. At the current time, treatment with varenicline is that which has yielded the greatest success. In literature, cutting back on the number of cigarettes has not been associated with a clear reduction in effects. It is therefore fundamental that smoking be evaluated systematically and objectively using the Fagenstrom test. Counselling should be introduced while the patient is still in hospital and continued at each outpatient clinic appointment. The family environment should also be stimulated to create a smoking-free home.

Tobacco dependency is a chronic, relapsing condition. Given these characteristics, smoking addiction requires constant treatment, through counselling, support, and pharmacological therapy.59–61 The use of medicinal products can be effective, especially in the presence of frequent and violent withdrawal symptoms and those most commonly used are varenicline, bupropion, and nicotine. At the current time, treatment with varenicline is that which has yielded the greatest success. In literature, cutting back on the number of cigarettes has not been associated with a clear reduction in effects. It is therefore fundamental that smoking be evaluated systematically and objectively using the Fagenstrom test. Counselling should be introduced while the patient is still in hospital and continued at each outpatient clinic appointment. The family environment should also be stimulated to create a smoking-free home. For patients with high-grade addictions and those who experience frequent relapses, predefined, privileged programmes should be implemented in intensive secondary prevention clinics, ambulatory rehabilitation centres, or in dedicated anti-smoking centres (Table 5). Table 5 Suggestions to improve smoking cessation Diet A correct diet modulates a number of cardiovascular risk factors, thereby playing a crucial role in the prevention of ischaemic relapses. In patients with cardiovascular conditions, the protective effect of the ‘Mediterranean diet’ has been known for some time now.

For patients with high-grade addictions and those who experience frequent relapses, predefined, privileged programmes should be implemented in intensive secondary prevention clinics, ambulatory rehabilitation centres, or in dedicated anti-smoking centres (Table 5). Table 5 Suggestions to improve smoking cessation Diet A correct diet modulates a number of cardiovascular risk factors, thereby playing a crucial role in the prevention of ischaemic relapses. In patients with cardiovascular conditions, the protective effect of the ‘Mediterranean diet’ has been known for some time now. On the basis of the cornerstones of the ESC guidelines, in accordance with the results of GISSI-Prevenzione study, the following guidelines can be considered (Table 6): •saturated fatty acids should constitute <10% of the total daily calorie intake; •unsaturated fatty acids should constitute no more than 1% of the total daily calorie intake; • <5 g of salt a day; • 200 g of fruit a day; • 200 g of vegetables a day; •increase fish consumption; and •the consumption of alcoholic beverages, preferably red wine, should be limited to two glasses a day (20 g/day) for men and one glass a day (10 g) for women. Table 6 An organic approach to change the lifestyle Diet plays an important role in chronic ischaemic cardiomyopathy, as it interferes positively with all the main risk factors, such as diabetes, hypertension, and dyslipidaemia. All patients and their families must be informed of the need to follow a correct diet. Information must be provided using simple and straight-forward language.

Diet plays an important role in chronic ischaemic cardiomyopathy, as it interferes positively with all the main risk factors, such as diabetes, hypertension, and dyslipidaemia. All patients and their families must be informed of the need to follow a correct diet. Information must be provided using simple and straight-forward language. Exercise We now have a great amount of evidence supporting the prescription of regular ‘moderate’ exercise, not merely for the prevention of ischaemic heart disease1 but also as part of a treatment programme after MI, angioplasty, and CABG.3,62–64 Clinical studies have provided irrefutable evidence on exercise’s capacity to improve physical performance and reduce cardiovascular and all-cause morbidity and mortality.65,66 The guidelines of all European and American scientific societies therefore include exercise (Class 1A) as one of the cornerstones of secondary prevention,3,67 recommending between 30 and 60 min of aerobic exercise several times a week, even better once a day. In patients who recently had ACS, aerobic exercise should be recommended at an early phase as part of a structured rehabilitative cardiology programme.

(Class 1A) as one of the cornerstones of secondary prevention,3,67 recommending between 30 and 60 min of aerobic exercise several times a week, even better once a day. In patients who recently had ACS, aerobic exercise should be recommended at an early phase as part of a structured rehabilitative cardiology programme. Physical exercise has direct and indirect effects on the cardiovascular system.68–70 The indirect benefits include a reduction in risk factors, including reduction in stress. The direct benefits include a reduction in heart rate and BP and an increase in cardiac contractility. An increase in coronary blood flow has also been reported. The reduction in resting heart rate is perhaps the most obvious effect of regular physical exercise. The increase in cardiac contractility reduces the dimensions of the ventricles, by reducing wall tension, thereby promoting the perfusion of critical areas of the myocardium. Diabetes Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with a significant increase in cardiovascular risk,71–73 as well as a worse prognosis in patients with CIC,74 which therefore exposes diabetics to a risk that is similar to that of patients with prior AMI.75 There is no certain information available regarding the effects of close glycaemic monitoring on the prevention of macrovascular complications. To this end, the Action to Control CArdiovascular Risk in Diabetes (ACCORD) study observed a slight increase in mortality in the arm receiving intensive treatment.76

Diabetes Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with a significant increase in cardiovascular risk,71–73 as well as a worse prognosis in patients with CIC,74 which therefore exposes diabetics to a risk that is similar to that of patients with prior AMI.75 There is no certain information available regarding the effects of close glycaemic monitoring on the prevention of macrovascular complications. To this end, the Action to Control CArdiovascular Risk in Diabetes (ACCORD) study observed a slight increase in mortality in the arm receiving intensive treatment.76 There is, however, a clear positive effect of intensive glycaemia treatment on cardiovascular complications in young diabetic patients, in the absence of chronic vascular alterations secondary to poor glycaemic control.77 However, the greater effects of cardiovascular prevention occur when intensive glycaemic control is combined with an effective control of the other risk factors.78 The medicinal products that act on glycaemia can be broken down into three classes: medicinal products that increase blood insulin levels: insulin, fast and slow insulin analogues, sulfonylureas, mitiglinides, glucagon-like peptide-1 analogues and DipePtyl Peptidase-4 inhibitors; medicinal products that increase insulin sensitivity (metformin and pioglitazone); and glucose absorption inhibitors that work on an intestinal level (acarbose) and on a renal tubule level [sodium glucose co-transporter-2 (SGLT-2) inhibitors].

The medicinal products that act on glycaemia can be broken down into three classes: medicinal products that increase blood insulin levels: insulin, fast and slow insulin analogues, sulfonylureas, mitiglinides, glucagon-like peptide-1 analogues and DipePtyl Peptidase-4 inhibitors; medicinal products that increase insulin sensitivity (metformin and pioglitazone); and glucose absorption inhibitors that work on an intestinal level (acarbose) and on a renal tubule level [sodium glucose co-transporter-2 (SGLT-2) inhibitors]. However, none of the glycaemia-lowering agents have been seen to significantly reduce cardiovascular risk,79 with the exception of metformin in overweight subjects.80 Only recently, empagliflozin, an SLGT-2 inhibitor used in diabetic patients at high cardiovascular risk, was seen to reduce the rates of cardiovascular mortality and non-fatal infarction and stroke, when added to standard therapy.81 Moreover, although close glycaemia monitoring (HbA1c <6.5–7%) is preferable in young subjects with a short history of diabetes, it can be harmful in elderly patients. One aspect of crucial importance would appear to be the treatment of hypercholesterolaemia, with the aim of reaching the target for high-risk patients with an LDL cholesterol value below 70 mg/dL.

ng (HbA1c <6.5–7%) is preferable in young subjects with a short history of diabetes, it can be harmful in elderly patients. One aspect of crucial importance would appear to be the treatment of hypercholesterolaemia, with the aim of reaching the target for high-risk patients with an LDL cholesterol value below 70 mg/dL. Arterial hypertension Arterial hypertension in Italy is still the second cause of reduced life expectancy. However, the recent ESH/ESC guidelines recommend a target pressure of <140/90 mmHg for all patients, regardless of the risk level,82 therefore including those with CIC. The criticism of the above is based on the following assumptions: it has been proved that the relationship between BP and cardiovascular events is linear and continuous without thresholds for values <115/70 mmHg83; various studies show a reduction in cardiovascular events in the intensive treatment strategy (BP <130 mmHg) compared with the conservative strategy (BP <140 mmHg) without any paradox effect of increase in risk at the lowest systolic BP values achieved. The optimal BP level in hypertensive patients with cardiovascular events is controversial, especially given the presumed reduction in survival for a significant drop in arterial BP, the so-called J-curve phenomenon, which appears to be important in the elderly people84; however, this remains a subject for debate.85,86

Arterial hypertension Arterial hypertension in Italy is still the second cause of reduced life expectancy. However, the recent ESH/ESC guidelines recommend a target pressure of <140/90 mmHg for all patients, regardless of the risk level,82 therefore including those with CIC. The criticism of the above is based on the following assumptions: it has been proved that the relationship between BP and cardiovascular events is linear and continuous without thresholds for values <115/70 mmHg83; various studies show a reduction in cardiovascular events in the intensive treatment strategy (BP <130 mmHg) compared with the conservative strategy (BP <140 mmHg) without any paradox effect of increase in risk at the lowest systolic BP values achieved. The optimal BP level in hypertensive patients with cardiovascular events is controversial, especially given the presumed reduction in survival for a significant drop in arterial BP, the so-called J-curve phenomenon, which appears to be important in the elderly people84; however, this remains a subject for debate.85,86 Of the trials designed specifically to evaluate the benefit of intensive BP monitoring (<130 mmHg) in patients with a history of coronary events, the results were positive for the EUROPA87 and CAMELOT88 studies, but negative in the PREVENT, ACTION, and PEACE studies.89–91

The optimal BP level in hypertensive patients with cardiovascular events is controversial, especially given the presumed reduction in survival for a significant drop in arterial BP, the so-called J-curve phenomenon, which appears to be important in the elderly people84; however, this remains a subject for debate.85,86 Of the trials designed specifically to evaluate the benefit of intensive BP monitoring (<130 mmHg) in patients with a history of coronary events, the results were positive for the EUROPA87 and CAMELOT88 studies, but negative in the PREVENT, ACTION, and PEACE studies.89–91 In this context, the recent article of Vidal-Petiot et al.92 published by Lancet puts in evidence that it seems to exist a clear J-curve both for systolic and, more importantly, for diastolic BP. These data suggest that in patients with stable coronary artery disease (CAD) and hypertension, a very intensive treatment likely to determinate systolic BP values <120 mmHg and diastolic BP values <70 mmHg were associated with adverse cardiovascular outcomes, also with an increase in mortality. These observations support the idea that the relationship between a reduction in BP and mortality only interests certain subgroups, and actually, only has a prognostic weight for elderly patients.84,93

In this context, the recent article of Vidal-Petiot et al.92 published by Lancet puts in evidence that it seems to exist a clear J-curve both for systolic and, more importantly, for diastolic BP. These data suggest that in patients with stable coronary artery disease (CAD) and hypertension, a very intensive treatment likely to determinate systolic BP values <120 mmHg and diastolic BP values <70 mmHg were associated with adverse cardiovascular outcomes, also with an increase in mortality. These observations support the idea that the relationship between a reduction in BP and mortality only interests certain subgroups, and actually, only has a prognostic weight for elderly patients.84,93 In addition, in one meta-analysis of 147 trials, the weight of pharmacological treatment was evident in both primary and secondary prevention, regardless of the clinical or epidemiological settings.94 On the basis of a series of experiences, a recent joint American Heart Association/American College of Cardiology/American Society of Hypertension95 consensus document states that (i) a lower systolic BP is associated with a lower risk of stroke; (ii) the achievement of diastolic BP values between 70 and 79 mmHg would seem to be safe; (iii) a target BP <130/80 mmHg may be appropriate in certain subjects with CIC, prior AMI, stroke or TIA, or ischaemic equivalents, such as carotid atherosclerosis, peripheral arterial disease or abdominal aortic aneurysm (Class IIB, evidence level B). The recent (Systolic Blood Pressure Intervention Trial (SPRINT) study96 further supports this evidence (Table 7).21Table 7 Subgroups of patients in secondary prevention schemes (prior cardiovascular event) for whom it would appear reasonable to set lower blood pressure targets (<130 mmHg) than the usual standard (<140 mmHg) (more intensive therapeutic regimen)

ention Trial (SPRINT) study96 further supports this evidence (Table 7).21Table 7 Subgroups of patients in secondary prevention schemes (prior cardiovascular event) for whom it would appear reasonable to set lower blood pressure targets (<130 mmHg) than the usual standard (<140 mmHg) (more intensive therapeutic regimen) Clinical condition Target/(mean BP achieved) Outcome Main (level of) evidence Reference Prior stroke or TIA (5665 patients) (143 vs. 149 mmHg) Recurrence of cerebrovascular events Incidence of non-fatal stroke reduced by 29%, absolute benefit of 29 events per 1000 subjects/3 years PATS Collaborating Group. Chin Med J (Engl) 1995; 108: 710–717. Prior stroke or TIA (6106 patientst) (132 vs. 141 mmHg) Recurrence of cerebrovascular events Reduced incidence of stroke (−28%) and major vascular events (−26%) PROGRESS Collaborative Group. Lancet 2001;358:1033–1041. High-risk non-diabetic hypertensive patients (1111), >55 years of age with uncontrolled arterial blood pressure (SBP >150 mmHg) despite therapy + additional risk factor. <130 vs. <140 mmHg Prevalence of LV hypertrophy on the ECG at 2 years Reduction in the prevalence of LV hypertrophy. Cardio-Sis Study Group. Lancet 2009;374:525–533. Parallel reduction in the composite secondary endpoint of CV events and all-cause mortality. Chronic ischaemic cardiomyopathy (subgroup with cardiovascular events vs. subgroup without prior cardiovascular events) <130 vs. <140 mmHg Reduction in the composite secondary endpoint of CV events and all-cause mortality. The drop in BP < 130 mmHg did not cause any increase in cardiovascular events (no J-curve effect) Cardio-Sis Study Group. Hypertension. 2014;63:475–482. Chronic ischaemic cardiomyopathy (13 655 subjects): 64% with prior AMI

s. <140 mmHg Reduction in the composite secondary endpoint of CV events and all-cause mortality. The drop in BP < 130 mmHg did not cause any increase in cardiovascular events (no J-curve effect) Cardio-Sis Study Group. Hypertension. 2014;63:475–482. Chronic ischaemic cardiomyopathy (13 655 subjects): 64% with prior AMI 61% with coronary disease, 55% prior revascularization Normal LVEF (126 vs. 133 mmHg) Total mortality, non-fatal AMI, instable angina, non-resuscitated cardiac arrest 20% reduction in the RR of the composite endpoint The European Trial on reduction of cardiac events with perindopril in stable coronary artery disease Investigators. Lancet 2003;362:782–788. Subjects at high cardiovascular risk (20% with prior CV event) <120 vs. <140 mmHg AMI, ACS, stroke, cardiac insufficiency or death by cardiovascular causes Reduction (−25%) in the composite endpoint, and reduction (−27%) in total mortality The SPRINT Research Group. N Engl J Med 2015;373:2103–2116. Chronic ischaemic cardiomyopathy: Prior AMI Prior stroke or TIA Ischaemic cardiomyopathy equivalents: carotid atherosclerosis peripheral arterial disease abdominal aortic aneurysm <130 mmHg Class IIa; evidence level: B A Scientific Statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension Journal of the American College of Cardiology, 2015;65: 1998–2038 TIA, transient ischaemic attack; BP, blood pressure; SBP, systolic blood pressure; LV, left ventricle; CV, cardiovascular; ECG, electrocardiogram, AMI, acute myocardial infarction; RR, relative risk, ACS, acute coronary syndrome.

Society of Hypertension Journal of the American College of Cardiology, 2015;65: 1998–2038 TIA, transient ischaemic attack; BP, blood pressure; SBP, systolic blood pressure; LV, left ventricle; CV, cardiovascular; ECG, electrocardiogram, AMI, acute myocardial infarction; RR, relative risk, ACS, acute coronary syndrome. Dyslipidaemia The role of LDL cholesterol (C-LDL), as both a marker of cardiovascular risk and a therapeutic target, is well known. Statins were seen to be capable of significantly reducing C-LDL with an absolutely favourable risk–benefit assessment,97–100 lowering mortality and the recurrence of ischaemic events, data that are confirmed by registry studies101 and meta-analyses102,103; however, the higher the basic risk and the levels of C-LDL, the greater the benefit of treatment. For these reasons, the C-LDL target recommended by European guidelines for patients with CIC is 70 mg/dL, or, should this not be possible, a reduction of at least 50%.1,5,104 Statins should be prescribed at the recommended maximum dose or, in any case, the maximum tolerable dose in order to meet the target.104 The use of statins and ezetimibe, the advantages of which were shown by the IMPROVE-IT study105 and implemented by AIFA [Italian Medicines Agency] in its circular no.13 must be considered if the statins are not tolerated or if the target is not achieved.104

se, the maximum tolerable dose in order to meet the target.104 The use of statins and ezetimibe, the advantages of which were shown by the IMPROVE-IT study105 and implemented by AIFA [Italian Medicines Agency] in its circular no.13 must be considered if the statins are not tolerated or if the target is not achieved.104 The very recent American guidelines, on the other hand, have criticized the benefit of achieving specific targets for C-LDL.106 This strategy has been strongly disputed.107 Indeed, treatment compliance is significantly greater in patients with a strategy addressing a specific target.108 A more extensive consideration of the approach to patients with dyslipidaemia after acute coronary syndrome and on the emerging role of PCSK9 inhibitors is dealt with in the ANMCO documents currently being published, which should be consulted. Therefore, from now on, physicians must be aware of the importance of achieving and maintaining the recommended lipid targets.109 Non-HDL cholesterol would also appear to have a prognostic importance110 and its recommended target value is 100 mg/dL in patients with CIC. In the recent ANMCO/GICR/GISE consensus document,21 the Panel agreed that the C-LDL and HDL targets of 70 mg/dL and 100 mg/dL, respectively, remain a fundamental objective to be met and maintained in secondary prevention schemes. On the other hand, no specific target is currently indicated for triglycerides.1,104

Non-HDL cholesterol would also appear to have a prognostic importance110 and its recommended target value is 100 mg/dL in patients with CIC. In the recent ANMCO/GICR/GISE consensus document,21 the Panel agreed that the C-LDL and HDL targets of 70 mg/dL and 100 mg/dL, respectively, remain a fundamental objective to be met and maintained in secondary prevention schemes. On the other hand, no specific target is currently indicated for triglycerides.1,104 Anti-thrombotic therapy Anti-platelet therapy Anti-platelet therapy in patients with CIC has the aim of preventing the risk of ischaemic events, spontaneous or secondary to revascularisation and stenting procedures. However, it is important to achieve a careful balance between thrombotic and haemorrhagic risk.111 Acetylsalicylic acid (ASA) remains the anti-platelet agent of election in chronic treatment. Monotherapy with ASA at the optimal dose of 75–150 mg/day has been seen to reduce mortality, the incidence of MI, and stroke in patients with CIC, and therefore, it should be initiated and continued indefinitely as soon as the diagnosis has been established.112 In case of allergy or intolerance, ASA should be replaced by clopidogrel at a dose of 75 mg/dL.113

of 75–150 mg/day has been seen to reduce mortality, the incidence of MI, and stroke in patients with CIC, and therefore, it should be initiated and continued indefinitely as soon as the diagnosis has been established.112 In case of allergy or intolerance, ASA should be replaced by clopidogrel at a dose of 75 mg/dL.113 In patients with CIC undergoing coronary angioplasty and stenting, there is an indication for dual anti-platelet therapy (DAT) with ASA and clopidogrel. In patients who are not on treatment with ASA, in the case of coronary angioplasty, it is appropriate to administer a loading dose of 150-300 mg by mouth or 80-150 mg i.v. prior to the procedure, followed by maintenance doses of 75-100 mg a day.114 Despite the absence of definitive evidence, in clinical practice, pre-PCI treatment with Clopidogrel is common, at least in patients with non-high haemorrhagic risk. In the case of pre-treatment, a loading dose of 300 mg should be administered at least six hours before the procedure or 600 mg at least two hours beforehand.115 In patients with CIC, it is recommended that DAT be continued for 1 month after procedures with bare metal stents and for 6 months after those involving drug-eluting stents. For new-generation drug-eluting stents, it is possible to contemplate a reduction on the duration of DAT to <6 months in the presence of significant haemorrhagic risk (or in the case of clinically relevant bleeds). It is, in any case, considered reasonable to not suspend DAT earlier than 3 months, except in the case of severe bleeding.116,117

eluting stents, it is possible to contemplate a reduction on the duration of DAT to <6 months in the presence of significant haemorrhagic risk (or in the case of clinically relevant bleeds). It is, in any case, considered reasonable to not suspend DAT earlier than 3 months, except in the case of severe bleeding.116,117 It would appear reasonable to continue DAT for longer than 6 months, e.g.12 months or even longer, in patients at a high-risk of thrombosis and low risk of haemorrhage118: in the case of multiple stents, stents on the proximal left anterior descending artery or left main coronary artery and in the presence of diabetes or a history of AMI. DAP for 30 months reduces intra-stent thrombosis and MI with an increase in moderate bleeds and consequently should only be considered for patients with a low risk of haemorrhage but a high risk of ischaemia. A score is available in order to identify those who may benefit from this strategy: http://www.daptstudy.org/. In the presence of ASA allergy or intolerance and the need for double-platelet therapy, it is possible to consider the empirical use of another cyclo-oxygenase inhibitor (COX-1), indobufen, at a dose of 200 mg/b.i.d., combined with clopidogrel. For patients with CIC not undergoing coronary angioplasty or stenting, there is no indication for DAT. There are few data available on the use of prasugrel and ticagrelor in patients with CIC and it must take into account the aforesaid balance between thrombotic and haemorrhagic risk.119

In the presence of ASA allergy or intolerance and the need for double-platelet therapy, it is possible to consider the empirical use of another cyclo-oxygenase inhibitor (COX-1), indobufen, at a dose of 200 mg/b.i.d., combined with clopidogrel. For patients with CIC not undergoing coronary angioplasty or stenting, there is no indication for DAT. There are few data available on the use of prasugrel and ticagrelor in patients with CIC and it must take into account the aforesaid balance between thrombotic and haemorrhagic risk.119 The only study available at the current time is the PEGASUS study,120 which showed that both doses of ticagrelor reduce the rate of cardiovascular mortality, MI, and stroke, but with a higher number of TIMI major bleeds among patients treated with ticagrelor than with placebo (P < 0.001 for both doses vs. placebo). Therefore, for long-term treatment, the lower dose presents equal advantages and better tolerance. The data of a sub-analysis of the PEGASUS study show that,121 in patients with a high thrombotic risk, it may be appropriate to continue treatment with ticagrelor after the first year or, in any case, to recommence within 30 days of suspension, whereas recommencing it after more than 1 year increases bleeds but does not produce any benefit. The efficacy and safety profiles of ticagrelor were also seen to be similar in both sexes.121

The data of a sub-analysis of the PEGASUS study show that,121 in patients with a high thrombotic risk, it may be appropriate to continue treatment with ticagrelor after the first year or, in any case, to recommence within 30 days of suspension, whereas recommencing it after more than 1 year increases bleeds but does not produce any benefit. The efficacy and safety profiles of ticagrelor were also seen to be similar in both sexes.121 Lastly, the data regarding treatment with ticagrelor in patients with kidney disease are extremely interesting.122 In the PEGASUS study, the relative reduction in the risk of ischaemic events with ticagrelor was seen to be similar for all estimated glomerular filtration rate (eGFR) categories. The relative risk of TIMI major bleeding was also seen to be similar, whereas TIMI minor bleeding increased with a worsening in renal function (P-trend = 0.007). Therefore, patients with severe but non-end-stage renal dysfunction (dialysed patients were excluded from the study) benefited from a greater reduction in absolute risk for ischaemic events with an increase in risk for TIMI major bleeding similar to that of patients with normal eGFR.

n renal function (P-trend = 0.007). Therefore, patients with severe but non-end-stage renal dysfunction (dialysed patients were excluded from the study) benefited from a greater reduction in absolute risk for ischaemic events with an increase in risk for TIMI major bleeding similar to that of patients with normal eGFR. Another novel aspect of anti-thrombotic therapy is constituted by vorapaxar (an antagonist of the protease-activated receptor PAR-1 for thrombin), a compound that was tested in the TRAP 2P-TIMI50 study,123 with a reduction in ischaemic events but an increase in moderate or severe bleeds and, in addition, a significant increase in intracranial haemorrhages and TRACER,124 where the use of vorapaxar was associated with a reduction in the same composite endpoint if used in combination with clopidogrel and as monotherapy. In short, the above data show that in patients at a high risk of thrombosis, a high risk of ischaemic events persists even in the first few years of what we call CIC. This risk can be reduced using the new forms of anti-thrombotic therapy or by prolonging therapies already used with success in the previous clinical phase, i.e. in the year after an acute coronary syndrome. The use of long-term anti-platelet therapies that are more potent that ASA monotherapy, in patients with CIC nevertheless exposes them to an increase in haemorrhagic complications, which must always be taken into careful consideration when choosing treatment options and regularly reassessed in the follow-up period.

me. The use of long-term anti-platelet therapies that are more potent that ASA monotherapy, in patients with CIC nevertheless exposes them to an increase in haemorrhagic complications, which must always be taken into careful consideration when choosing treatment options and regularly reassessed in the follow-up period. Anti-ischaemic therapy The ESC guidelines for the pharmacological treatment of angina and myocardial ischaemia recommend, as first-line therapy, the use of short-acting nitrates (taken via the sublingual route) in order to control symptoms (Class I Level B) and the use of beta-blockers and/or calcium channel blockers in order to control heart rate and symptoms (Class I Level A). As second-line therapy, it is recommended to combine long-acting nitrates (long-acting transdermal or oral products) or ivabradine or nicorandil or ranolazine, depending on heart rate, BP, and the respective tolerance of the various medicinal products (Class IIa Level B). It is also indicated, in the case of necessity for co-morbidity or intolerance, to use a second-line therapy as first-line in certain patients (Class I Level C) and to also use beta-blockers in asymptomatic patients, provided they have a large inducible ischaemia area (>10%; Class IIa Level C). In patients with vasospastic angina, it is recommended to use calcium channel blockers or nitrates and to avoid beta-blockers (Class IIa Level B).

It is also indicated, in the case of necessity for co-morbidity or intolerance, to use a second-line therapy as first-line in certain patients (Class I Level C) and to also use beta-blockers in asymptomatic patients, provided they have a large inducible ischaemia area (>10%; Class IIa Level C). In patients with vasospastic angina, it is recommended to use calcium channel blockers or nitrates and to avoid beta-blockers (Class IIa Level B). Beta-blockers Recent data provided by registries, such as the REACH125 and the Kaiser Permanente Northern California registries,126 do not show a lower risk of cardiovascular events, using beta-blockers in stable CAD. In particular, in the REACH, authors concluded that the use of beta-blockers is not protective in reducing mortality both in patients with prior MI and in whom with known CAD without MI, with a reduction, on the other hand, of the rate of recurrent MI and angina. Andersson et al.126 observed a lower rate of cardiac events, and also a reduction in mortality, associated with the use of beta-blockers, only in the setting of patients with a prior AMI. For these controversial data, beta-blockers are not indicated for the reduction of cardiac events by ESC guideline of stable CAD of 20133 but only for control of symptoms. Nevertheless, beta-blockers remain a cornerstone for the treatment of this condition in clinical practice and are indicated for reducing events in the presence of decompensated heart failure or post-infarction left ventricular dysfunction with EF <40%.127

ideline of stable CAD of 20133 but only for control of symptoms. Nevertheless, beta-blockers remain a cornerstone for the treatment of this condition in clinical practice and are indicated for reducing events in the presence of decompensated heart failure or post-infarction left ventricular dysfunction with EF <40%.127 Calcium channel blockers The rationale recommended by the ESC for calcium channel blockers lies, for amlodipine, in the demonstration of efficacy on the tolerance to use in combination with beta-blockers obtained in the CASIS study128 and for verapamil on the results of the APSIS study129 in which an equivalence was observed between metoprolol and verapamil in terms of mortality and non-fatal cardiovascular events. Therefore, given the absence of recent evidence, the ESC’s recommendations should be considered for a use of verapamil in the replacement of beta-blockers, when they are contraindicated or not tolerated, and for amlodipine in combination with beta-blockers. Nitrates The ESC guidelines on CIC affirm that routine use of long-lasting nitrates must be critically reassessed in all patients, given the tolerance and the ever-increasing evidence concerning the relationship between long-lasting nitrates and endothelial dysfunction.

Therefore, given the absence of recent evidence, the ESC’s recommendations should be considered for a use of verapamil in the replacement of beta-blockers, when they are contraindicated or not tolerated, and for amlodipine in combination with beta-blockers. Nitrates The ESC guidelines on CIC affirm that routine use of long-lasting nitrates must be critically reassessed in all patients, given the tolerance and the ever-increasing evidence concerning the relationship between long-lasting nitrates and endothelial dysfunction. Therefore, long-lasting nitrates have lost evidence in symptom prophylaxis (IIB), whereas short-acting nitrates remain the choice of election (IB guideline). However, in Italy, about 70% of general practitioners prescribe long-acting nitrates as the treatment of election, which is far higher than the value for Europe, where 44% of prescriptions regard prescriptions for new anti-angina products (ivabradine and ranolazine). Ivabradine The use of ivabradine in patients with stable ischaemic cardiomyopathy was trialled in different studies with positive results. In particular, Borer et al.130 tested the drug vs. placebo, while Tardif et al.131 in the INITIATIVE trial and Ruzyllo et al.132 compared ivabradine with atenolol and amlodipine, respectively, showing a non-inferiority profile in terms of efficacy and safety.

thy was trialled in different studies with positive results. In particular, Borer et al.130 tested the drug vs. placebo, while Tardif et al.131 in the INITIATIVE trial and Ruzyllo et al.132 compared ivabradine with atenolol and amlodipine, respectively, showing a non-inferiority profile in terms of efficacy and safety. In the SIGNIFY study133 conducted in patients with CIC without decompensated heart failure, with an EF >40% and high a heart rate >70 b.p.m., the sinus rhythm with the addition of ivabradine in comparison with standard therapy did not improve outcomes. However, Tendera et al.134 observed a consistent improvement in self-reported quality of life parameters related to angina pectoris, in particular with a reduction of symptoms frequency and of disease perception. Furthermore, the failure of this study can be partially explained by an excessive decreasing of heart rate, related to the high-dose regime of ivabradine and concomitant use of verapamil and diltiazem. According to these observations, the association of ivabradine with verapamil and diltiazem is contraindicated for the synergic effect in reducing the heart rate. These data do not influence the results obtained previously in populations with stable ischaemic cardiomyopathy and decompensated heart failure or left ventricular dysfunction.

In the SIGNIFY study133 conducted in patients with CIC without decompensated heart failure, with an EF >40% and high a heart rate >70 b.p.m., the sinus rhythm with the addition of ivabradine in comparison with standard therapy did not improve outcomes. However, Tendera et al.134 observed a consistent improvement in self-reported quality of life parameters related to angina pectoris, in particular with a reduction of symptoms frequency and of disease perception. Furthermore, the failure of this study can be partially explained by an excessive decreasing of heart rate, related to the high-dose regime of ivabradine and concomitant use of verapamil and diltiazem. According to these observations, the association of ivabradine with verapamil and diltiazem is contraindicated for the synergic effect in reducing the heart rate. These data do not influence the results obtained previously in populations with stable ischaemic cardiomyopathy and decompensated heart failure or left ventricular dysfunction. Indeed, in the BEAUTIFUL135 study, in the predefined subgroup of patients with heart rates ≥70 b.p.m., treatment with ivabradine reduced the secondary endpoints: hospitalization for fatal and non-fatal MI and myocardial revascularisation. Furthermore, in the subgroup with a heart rate >70 b.p.m. and limiting angina, the same medicinal product also reduced the primary endpoint.136

of patients with heart rates ≥70 b.p.m., treatment with ivabradine reduced the secondary endpoints: hospitalization for fatal and non-fatal MI and myocardial revascularisation. Furthermore, in the subgroup with a heart rate >70 b.p.m. and limiting angina, the same medicinal product also reduced the primary endpoint.136 The SHIFT study137 found that for 67.5% of patients with CIC and decompensated heart failure, the medicinal product caused a reduction in the primary composite endpoint of cardiovascular mortality or hospitalization for a worsening in decompensated heart failure, due primarily to the reduction in hospitalization for a worsening in decompensated heart failure.138 Lastly, in the ASSOCIATE study,139 ivabradine combined with atenolol was seen to significantly prolong the duration of exercise compared with the placebo. Ultimately, the use of ivabradine should be considered, in combination with beta-blockers, for patients with CIC and decompensated heart failure or left ventricular dysfunction, or as the treatment of election in the case of a contraindication to beta blockers. Ranolazine Recently, the RIVER-PCI study,140 a trial with a number of limitations and without the statistical power to show a reduction in angina symptoms, conducted on patients with chronic angina and incomplete revascularization gave conflicting results by showing an improvement in the frequency of evident angina at 6 months in diabetics treated with ranolazine and in the more symptomatic patients; however, in both cases the advantage disappeared at 12 months.

symptoms, conducted on patients with chronic angina and incomplete revascularization gave conflicting results by showing an improvement in the frequency of evident angina at 6 months in diabetics treated with ranolazine and in the more symptomatic patients; however, in both cases the advantage disappeared at 12 months. Previously, in the MERLIN-TIMI 36 study, ranolazine was seen to reduce recurrent ischaemia after non-ST segment elevation MI,141 though without the effects on the composite primary endpoint of cardiovascular mortality, MI, and recurrent ischaemia. Among the previous studies on the influence of ranolazine on tolerance to exercise, the CARISA study showed that ranolazine in combination with beta-blockers, diltiazem, or amlodipine142 compared with placebo obtained a 24% increase in the duration of exercise without prolonging the time of ST-segment depression onset. To conclude, the use of ranolazine in chronic ischaemic cardiomyopathy should be considered in combination with beta-blockers and/or calcium channel blockers, especially in patients with severe angina and in diabetics,143 or as the treatment of election in patients with contraindications to the use of beta-blockers, taking caution in patients with NYHA Class III–IV decompensated heart failure. Conclusions In patients with chronic ischaemic cardiomyopathy, anti-ischaemic pharmacological therapy must envisage (Figures 2–4): Figure 2 Patient with angina who is not controlled by beta-blocker. HR, heart rate; LA, long-acting; SR, sinus rhythm; LV, left ventricle.

To conclude, the use of ranolazine in chronic ischaemic cardiomyopathy should be considered in combination with beta-blockers and/or calcium channel blockers, especially in patients with severe angina and in diabetics,143 or as the treatment of election in patients with contraindications to the use of beta-blockers, taking caution in patients with NYHA Class III–IV decompensated heart failure. Conclusions In patients with chronic ischaemic cardiomyopathy, anti-ischaemic pharmacological therapy must envisage (Figures 2–4): Figure 2 Patient with angina who is not controlled by beta-blocker. HR, heart rate; LA, long-acting; SR, sinus rhythm; LV, left ventricle. Figure 3 Patient with angina and contraindications to use of beta-blockers. HR, heart rate; LA, long acting; SR, sinus rhythm; LV, left ventricle. Figure 4 Algorithm for optimal management of symptomatic treatment of patients with stable chronic ischaemic cardiomyopathy. HR, heart rate; LA, long-acting; SR, sinus rhythm; LV, left ventricle. extensive beta-blocker use; a critical review of long-acting nitrates and calcium channel blockers; the use of ranolazine to control symptoms; and the use of ivabradine in patients with decompensated heart failure or left ventricular dysfunction, both as second-line therapy and, sometimes, as first-line treatment.

Figure 4 Algorithm for optimal management of symptomatic treatment of patients with stable chronic ischaemic cardiomyopathy. HR, heart rate; LA, long-acting; SR, sinus rhythm; LV, left ventricle. extensive beta-blocker use; a critical review of long-acting nitrates and calcium channel blockers; the use of ranolazine to control symptoms; and the use of ivabradine in patients with decompensated heart failure or left ventricular dysfunction, both as second-line therapy and, sometimes, as first-line treatment. Treatment compliance Prescriptive inertia and therapeutic compliance There is widespread underuse of the pharmacological treatments recommended in the guidelines for the treatment of CIC.144–146 This results in failure to achieve therapeutic objectives and stems from a combination of organizational factors and patient behaviour.144–146 The clinical management of the main risk factors would, in any case, appear to be inadequate in current clinical practice, partly due to physicians’ clinical and therapeutic inertia, characterized by147: failure to prescribe the recommended treatments; prescription of reduced, potentially inadequate doses; and the absence of adequate intervention and effective treatment adjustments. All of this constitutes a key aspect in cardiovascular prevention, by representing an ‘additional hidden risk factor’.148 Patients are considered to be ‘treatment compliant’ when they take 80% of the medication prescribed, ‘partially compliant’ if they take between 20% and 70%, and ‘non-compliant’ if they take <20%.

the absence of adequate intervention and effective treatment adjustments. All of this constitutes a key aspect in cardiovascular prevention, by representing an ‘additional hidden risk factor’.148 Patients are considered to be ‘treatment compliant’ when they take 80% of the medication prescribed, ‘partially compliant’ if they take between 20% and 70%, and ‘non-compliant’ if they take <20%. Dimensions of the phenomenon Non-compliance is thought to involve 50–60% of patients in primary cardiovascular prevention schemes and 30–40% of those in secondary prevention schemes.148,149 Studies conducted in the USA and Canada suggest that lipid-lowering treatment with statins is interrupted in 30–40% of cases within just 6 months of first prescription.150 Similar data have also been recorded in Italy.151 In clinical studies, the interruption of treatment or intermittent use are determined by a number of factors, which can be divided into 5 categories (Table 8). Table 8 Non-compliant factors associated with therapeutic prescriptions Patient related Related to clinical condition Therapy related Health service related Related to socio-economic system Old age Female Cognitive, sight or hearing deficits Depression • Chronic illness • Frequent administration • Poor prescribing physician authoritativeness Poor academic record No spouse Low income Need to contribute to medical expenses

Patient related Related to clinical condition Therapy related Health service related Related to socio-economic system Old age Female Cognitive, sight or hearing deficits Depression • Chronic illness • Frequent administration • Poor prescribing physician authoritativeness Poor academic record No spouse Low income Need to contribute to medical expenses • Multiple co-morbidities • High number of medicinal products • Inadequacy of information on the condition and medicinal products • Efficacy cannot be assessed • Uncertainty as to the duration of treatment • Side effects • Limited time dedicated to the patient • Follow-up frequency Clinical assessment The evaluation of treatment compliance is usually performed in a direct talk with the patient. This assessment is highly subjective and involves a possible 20–30% overestimate of the real use of medicinal products.148,152 On the contrary, however, problems of non-compliance can be better identified using questionnaires (example in Table 9). Table 9 Morisky Medication Adherence Scale Morisky scale Have you ever forgotten to take your medication? Are you occasionally a bit careless about taking your medication? When you feel better, do you ever interrupt your therapy? When you feel worse, do you ever interrupt your therapy? Each positive response has a score of 0, and each negative response a score of 1. Patients with scores of 0–2 are considered non-compliant, those with scores of 3–4 are considered compliant. Adapted from Morisky et al.154

When you feel better, do you ever interrupt your therapy? When you feel worse, do you ever interrupt your therapy? Each positive response has a score of 0, and each negative response a score of 1. Patients with scores of 0–2 are considered non-compliant, those with scores of 3–4 are considered compliant. Adapted from Morisky et al.154 Intervention to improve compliance Intervention to improve compliance can be broken down into four types153 (Table 10): Table 10 Intervention intended to improve compliance with prescriptions Changes to therapeutic prescriptions Training initiatives Behavioural intervention Complex intervention Reduction in the number of doses Transdermal administration Adapt treatment regimen to patient s lifestyle Facilitate access to medication stocks Audiovisual material Information sheets Telephone contacts Mailing Short motivational counselling Frequent check-ups after the beginning of therapy Use of reminder aids (calendars, diaries, pillboxes, and alarms) Scheduled residual pill counts Home visits • Combination of two or more initiatives belonging to the other categories Intervention regarding prescription, with simplification and modification of drug posology and doses. Patient awareness schemes. Initiatives aimed at changing patients’ individual behaviour. ‘Complex and combined’ initiatives split into different levels and implemented through multidisciplinary integrated approaches. Overall, the quality of communication and congruous duration of clinical meetings between health care professionals (doctors and nurses) and patients represent the key elements that condition compliance.

ents with atherosclerosis or silent ischaemia (Class I guideline).3 A recent sub-analysis of the COURAGE trial154 showed that the anatomical situation assessed by angiogram and EF are predictors of events rather than the size of inducible ischaemia. This said, high-risk patients were excluded from the COURAGE study.155 The pretest probability mentioned in European guidelines3 before proceeding with a coronary angiogram, has certain obvious limits: In accordance with this definition, only male subjects aged >70 years, with typical angina, should be candidates for a coronary angiogram, without having first performed induction tests. In all other cases, a preventive demonstration of ischaemia is indicated. In this model, the only determinants indicated by European guidelines are age, gender, and the typicality of symptoms.2 These data that dictate pretest probability originate from databases that were not created ad hoc for this diagnostic doubt and they do not always contemplate the presence of clinical risk factors, which undoubtedly increase pretest probability. The evidence concerning coronary CT as a surrogate for the invasive approach are not univocal and, in addition, no gains in terms of costs were seen in the PROMISE study, which compared coronary CT with functional stress tests in subjects with suspected stable angina.156,157

The pretest probability mentioned in European guidelines3 before proceeding with a coronary angiogram, has certain obvious limits: In accordance with this definition, only male subjects aged >70 years, with typical angina, should be candidates for a coronary angiogram, without having first performed induction tests. In all other cases, a preventive demonstration of ischaemia is indicated. In this model, the only determinants indicated by European guidelines are age, gender, and the typicality of symptoms.2 These data that dictate pretest probability originate from databases that were not created ad hoc for this diagnostic doubt and they do not always contemplate the presence of clinical risk factors, which undoubtedly increase pretest probability. The evidence concerning coronary CT as a surrogate for the invasive approach are not univocal and, in addition, no gains in terms of costs were seen in the PROMISE study, which compared coronary CT with functional stress tests in subjects with suspected stable angina.156,157 Nowadays, no coronary angiographic assessment can be considered from a merely anatomical standpoint, but also from a functional one, with an assessment of the fractional flow reserve (FFR).The FFR assessment is an invasive technique that allows the identification of coronary lesions that are functionally significant, despite being angiographically intermediate. European guidelines3 recommend (Class I) the use of FFR in all cases in which there is an indication for a coronary angiogram without any evidence of ischaemia in the non-invasive tests. Method validation refers to the FAME 1 and 2 trials.158,159 Despite the significant critical elements of the above trials, a number of studies have effectively confirmed the validity of the method.

ases in which there is an indication for a coronary angiogram without any evidence of ischaemia in the non-invasive tests. Method validation refers to the FAME 1 and 2 trials.158,159 Despite the significant critical elements of the above trials, a number of studies have effectively confirmed the validity of the method. A recent meta-analysis of Johnson showed that a FFR-guided strategy reduces the indication for PCI by 50%, despite significantly reducing both adverse events and angina symptoms.160 The reliability of FFR has also been seen in left main coronary artery lesions, intra-stent restenosis, CABG, residual stenosis in patients with acute coronary syndrome, and in patients with multi-vessel coronary disease.161–165 At the current time, the procedural risks associated with coronary angiograms and coronary angioplasties are extremely low. One recent American registry (2008–10) reported a cumulative incidence of vascular complications associated with elective diagnostic and interventional procedures performed via a femoral access of 0.8%.166 Furthermore, in one dedicated study,167 the radial approach was shown to reduce the incidence of bleeding and vascular complications compared with the femoral approach, especially for major bleeds, by 73%.

tions associated with elective diagnostic and interventional procedures performed via a femoral access of 0.8%.166 Furthermore, in one dedicated study,167 the radial approach was shown to reduce the incidence of bleeding and vascular complications compared with the femoral approach, especially for major bleeds, by 73%. The COURAGE study does not reflect the real-world setting and enrolled patients known to have coronary disease. In the COURAGE study,155 PCI is not associated with a reduction in the risk of death, MI, or other major cardiovascular events compared with optimized medical therapy. However, the trial population was not representative of the real world, as randomization was only performed after patients considered to be at a high risk on the basis of their angiogram findings had been excluded from the study. The main objective of PCI in stable angina could be (even just) that of providing relief from angina symptoms, by improving the quality of life, despite having a neutral effect on survival. Angina symptoms and silent ischaemia are important prognostic factors in stable coronary disease, especially if they occur at low loads.168,169 In this context, the use of coronary angiography and, even, of PCI could have a merely symptomatic purpose. Although it would not seem to affect mortality, PCI makes it possible to treat ischaemia, improve the quality of life and exercise capacity, and improve prognosis in patients already on optimum medical therapy.171–174 This was demonstrated by the RITA-2 and COURAGE trials.174,175

ould have a merely symptomatic purpose. Although it would not seem to affect mortality, PCI makes it possible to treat ischaemia, improve the quality of life and exercise capacity, and improve prognosis in patients already on optimum medical therapy.171–174 This was demonstrated by the RITA-2 and COURAGE trials.174,175 On the basis of these considerations, in accordance with the document issued by GISE,50 the panel of experts agrees in affirming that: in patients with typical angina and multiple cardiovascular risk factors, the first approach can be coronary angiography (Figure 5). Patients with typical angina but at intermediate risk and those with atypical symptoms at high or intermediate risk should have an imaging procedure before proceeding with a coronary angiogram; Figure 5 Indications for coronary angiogram in patients with typical angina (coronary artery disease). PCI could be indicated in patients with single-vessel coronary disease with critical stenosis and angina with or without evidence of inducible ischaemia (Figures 5 and 6); Figure 6 Indications for coronary angiogram in patients with atypical symptoms. PCI could be indicated in patients with single-vessel coronary disease with intermediate stenosis and evidence of inducible ischaemia (Figure 7); Figure 7 Indications for coronary angioplasty (percutaneous coronary intervention) fractional flow reserve. The white boxes contain the recommendations in agreement with European guidelines; the grey boxes contain the consensus recommendations.

with intermediate stenosis and evidence of inducible ischaemia (Figure 7); Figure 7 Indications for coronary angioplasty (percutaneous coronary intervention) fractional flow reserve. The white boxes contain the recommendations in agreement with European guidelines; the grey boxes contain the consensus recommendations. In patients with single- or multi-vessel coronary disease with intermediate stenosis in the absence of inducible ischaemia, PCI is indicated if FFR is < 0.80. Coronary artery bypass grafting Introduction The aspects that influence the decision-making process in CIC with an indication for CABG are: benefits expected from the revascularization procedure; site, extent, and complexity of the coronary lesions, which can be evaluated by SYNTAX score and derivatives that are rarely used in clinical practice; the extent of the ischaemic area, left ventricular function, in association with CAD and heart valve disease or with other structural defects; type of patient, bearing in mind that the risk scores such as the logistic EuroSCORE and STS may overestimate or underestimate the effective risk; characteristics of the heart surgery facility; technical elements such as: (i) the use of the double mammary technique, (ii) on-pump bypass vs. off-pump bypass, (iii) complete revascularisation, and (iv) duration of extracorporeal circulation; and pre-procedural discussion with the patient to establish his/her wishes.

type of patient, bearing in mind that the risk scores such as the logistic EuroSCORE and STS may overestimate or underestimate the effective risk; characteristics of the heart surgery facility; technical elements such as: (i) the use of the double mammary technique, (ii) on-pump bypass vs. off-pump bypass, (iii) complete revascularisation, and (iv) duration of extracorporeal circulation; and pre-procedural discussion with the patient to establish his/her wishes. This information, together with the waiting time before the procedure, the mean post-operative hospitalization time and the need for rehabilitation, should be given to the patient in a clear and detailed manner. Expected benefit of revascularization obtained by coronary artery bypass grafting The aim of coronary artery revascularization is to improve both symptoms and prognosis. The persistence of angina symptoms, despite optimum medical therapy, concerns about 50% of patients and worsens the quality of life. Prognosis is related to the severity of the coronary disease, in terms of the number and the type of vessels involved, the extent of the ischaemic area (>10% of the left ventricle), and ventricular function. These elements represent a strong indication for coronary revascularization110 (Table 11). Table 11 Indications for revascularisation in patients with stable angina or silent ischaemia

f the number and the type of vessels involved, the extent of the ischaemic area (>10% of the left ventricle), and ventricular function. These elements represent a strong indication for coronary revascularization110 (Table 11). Table 11 Indications for revascularisation in patients with stable angina or silent ischaemia Classa Levelb More than 50% stenosis of left main coronary arteryc I A More than 50% stenosi of the proximal left anteriori descending artery I A Two- or three-vessel coronary artery disease with left ventriucular EF < 40% I B Substantiated myocardial ischaemia >10% of the left ventricle I B Stenosis >50% of only patent vesselc I C CAD, coronary artery disease; EF, ejection fraction. Adapted from Windecker et al.111 a Recommendation class. b Evidence class. c With substantiated ischaemia or fractional flow reserve prognostic reasons ≤0.80, if stenosis <90%. Site and size of the coronary lesions The anatomical indication for CABG is related to three aspects: lesions on the left main coronary artery (LMCA), lesions on the proximal left anterior descending artery (LAD), and the size and complexity of coronary diseases with a high SYNTAX score.

c With substantiated ischaemia or fractional flow reserve prognostic reasons ≤0.80, if stenosis <90%. Site and size of the coronary lesions The anatomical indication for CABG is related to three aspects: lesions on the left main coronary artery (LMCA), lesions on the proximal left anterior descending artery (LAD), and the size and complexity of coronary diseases with a high SYNTAX score. The most recent relevant European guidelines identify those patients with an indication for CABG. The superiority of CABG over medical therapy, in large, complex lesions, is based on the results of a meta-analysis of the most important randomized clinical trials,176 which showed a clear reduction in mortality at 5, 7, and 10 years in patients treated with CABG vs. medical therapy, which is more evident in patients with LMCA disease and three-vessel coronary disease. The study that had the greatest impact on the type of revascularization is the SYNTAX Trial, which confirmed the superiority of CABG vs. PCI in terms of the need for revascularization; however, the two strategies are equivalent with regard to mortality, stroke, and infarction. New-generation stents [everolimus-eluting stents (EES)] were studied in the BEST trial, which reconfirmed the superiority of CABG vs. PCI with EES in patients with multi-vessel disease with complex lesions.177 Table 12 shows the indications for CABG according to the ESC 2014 guidelines in Class I evidence Levels A and B.110Table 12 Indications for coronary artery bypass grafting

The study that had the greatest impact on the type of revascularization is the SYNTAX Trial, which confirmed the superiority of CABG vs. PCI in terms of the need for revascularization; however, the two strategies are equivalent with regard to mortality, stroke, and infarction. New-generation stents [everolimus-eluting stents (EES)] were studied in the BEST trial, which reconfirmed the superiority of CABG vs. PCI with EES in patients with multi-vessel disease with complex lesions.177 Table 12 shows the indications for CABG according to the ESC 2014 guidelines in Class I evidence Levels A and B.110Table 12 Indications for coronary artery bypass grafting Classa Levelb Left main coronary artery stenosis SYNTAX score >32 I B Left main coronary artery stenosis with SYNTAX score 23–32 I B Three-vessel coronary disease with SYNTAX score 23–32 I A Three-vessel coronary disease with SYNTAX score >32 I A Three-vessel coronary disease in diabetics I A Adapted from Windecker et al.111 a Recommendation class. b Evidence class. The extent of the ischaemic area, left ventricular function, association of CAD with heart valve disease or with other structural heart defects Myocardial perfusion scintigraphy is the gold standard for evaluating the extent of the ischaemic area in patients with CIC; coronary revascularization is recommended if the ischaemic area is >10%.154 In clinical practice, the stress echocardiogram is the most commonly used imaging test.

The extent of the ischaemic area, left ventricular function, association of CAD with heart valve disease or with other structural heart defects Myocardial perfusion scintigraphy is the gold standard for evaluating the extent of the ischaemic area in patients with CIC; coronary revascularization is recommended if the ischaemic area is >10%.154 In clinical practice, the stress echocardiogram is the most commonly used imaging test. Left ventricular dysfunction with EF <35% is a known mortality risk factor; indeed, two studies have confirmed the advantage of revascularization in these patients.178 The concomitance of heart valve disease associated with critical stable coronary disease is an indication for combined surgery. Patient and SCORES Although even the most recent scores (Logistical EuroSCORE II and STS score) are ineffective for global patient assessment, they are certainly useful for communications between the various members of the heart team and the scientific community. Characteristics of the heart surgery facility and relations with the heart surgeon The relationship between the cardiologist and heart surgeon is of paramount importance to the management of patients with chronic ischaemic cardiomyopathy and indications for revascularization; in this context, the heart team must be functional to the institution in which it works and tailored to suit patient needs. The heart team is also responsible for establishing: prognostic stratification and clinical classification; the technical aspects of the procedure; and

Characteristics of the heart surgery facility and relations with the heart surgeon The relationship between the cardiologist and heart surgeon is of paramount importance to the management of patients with chronic ischaemic cardiomyopathy and indications for revascularization; in this context, the heart team must be functional to the institution in which it works and tailored to suit patient needs. The heart team is also responsible for establishing: prognostic stratification and clinical classification; the technical aspects of the procedure; and the waiting time, which should be no more than 2 weeks in the presence of angina with a CCS of three, left main CAD or equivalent, three-vessel coronary disease or depressed left ventricular function; After this procedure and once the patient’s consent has been obtained, the patient can be put on the waiting list for CABG. Myocardial revascularization vs. medical therapy Myocardial revascularization must not be intended as an alternative to optimal medical therapy (OMT), rather, when indicated, as an essential part of the overall treatment of a patient with CIC, with the aim of further improving prognosis and/or symptoms. The indication for revascularization in order to improve the prognosis of the individual patient must be based on coronary anatomy, left ventricular function, and the size of the ischaemic area. As far as symptoms are concerned, no solid data are available to support or refute revascularization with a view to prognostic improvement. Coronary anatomy

The indication for revascularization in order to improve the prognosis of the individual patient must be based on coronary anatomy, left ventricular function, and the size of the ischaemic area. As far as symptoms are concerned, no solid data are available to support or refute revascularization with a view to prognostic improvement. Coronary anatomy More than 50% stenosis of the left main coronary artery: in studies comparing medical therapy and CABG,179,180 the prognostic benefit of revascularization was so evident as to make this anatomical condition an absolute indication for revascularization. Multi-vessel disease: the evidence obtained by studies comparing CABG and medical therapy176,181–183 have shown an improvement in the survival of revascularized patients only in the presence of three-vessel disease or two-vessel disease involving the proximal left anterior descending artery. The most recent study, the MASS II study, confirmed the prognostic benefit of revascularization, in particular with CABG.184 The recommendation of European guidelines for revascularization of patients with two or three-vessel disease with reduced left ventricular function or decompensation is of Class IA.110 Stenosis of the proximal left anterior descending artery: the presence of critical stenosis in the proximal portion of the left anterior descending artery is prognostically unfavourable; however, there are few studies in this setting. The European guidelines based on the data available,176,184–186 nevertheless, provide a IA recommendation for revascularization in this patient subgroup.110

of critical stenosis in the proximal portion of the left anterior descending artery is prognostically unfavourable; however, there are few studies in this setting. The European guidelines based on the data available,176,184–186 nevertheless, provide a IA recommendation for revascularization in this patient subgroup.110 Left ventricular function The presence of a left ventricular dysfunction, in particular an EF of between 35% and 49%, when associated with three-vessel disease pinpoints those patients who could benefit from myocardial revascularization,176,182–184 as shown in the recent STICH trial.179 Size of the ischaemic area In the presence of an ischaemic area >10% of the area of the left ventricle revascularization improves prognosis,43,154,187,188 and this also applies for patients with silent ischaemia,187 as revealed by the COURAGE study.154 In the European guidelines, revascularization has Class IB recommendation.110 Last patent vessel but with >50% stenosis: even in the absence of evidence, this anatomical context would appear to have such a high risk as to a warrant Class IC indication.110 As far as an improvement in symptoms is concerned, for those patients who continue to experience symptoms even in the presence of OMT, revascularization with CABG or PCI is able to improve quality of life.176,189 In the European guidelines, revascularization has Class IA recommendation.110

Last patent vessel but with >50% stenosis: even in the absence of evidence, this anatomical context would appear to have such a high risk as to a warrant Class IC indication.110 As far as an improvement in symptoms is concerned, for those patients who continue to experience symptoms even in the presence of OMT, revascularization with CABG or PCI is able to improve quality of life.176,189 In the European guidelines, revascularization has Class IA recommendation.110 Table 13 lists the indications for revascularization for patients with CIC, taken from the 2013 and 2014 European guidelines.3,110Table 13 Indications for revascularization in patients with stable ischaemic cardiomyopathy Classa Levelb Indications to improve prognosis More than 50% stenosis of left main coronary artery I A More than 50% stenosis of the proximal left anteriordescending artery I A Two- and three-vessel coronary disease with LV dysfunction or decompensated heart failure I A Last patent vessel with >50% stenosis I C Substantiated large area of ischaemia (>10% of LV) I B Indications for improving symptoms that are refractory to optimal medical therapy Each >50% symptom-related stenosis DCH, decompensated heart failure; LV, left ventricle. Adapted from Montalescot et al.3 and Windecker et al.111 a Recommendation class. b Evidence class. c With fractional flow reserve of 0.80.

Last patent vessel with >50% stenosis I C Substantiated large area of ischaemia (>10% of LV) I B Indications for improving symptoms that are refractory to optimal medical therapy Each >50% symptom-related stenosis DCH, decompensated heart failure; LV, left ventricle. Adapted from Montalescot et al.3 and Windecker et al.111 a Recommendation class. b Evidence class. c With fractional flow reserve of 0.80. Coronary angioplasty vs. coronary artery bypass grafting The optimal revascularization strategy in patients with chronic ischaemic cardiomyopathy that does not respond to medical therapy or with a significantly sized area of ischaemia was, for many years, considered to be that of surgery. However, the arrival of coronary angioplasty (especially after the advent of drug-eluting stents) has cast doubt on this concept.

patients with chronic ischaemic cardiomyopathy that does not respond to medical therapy or with a significantly sized area of ischaemia was, for many years, considered to be that of surgery. However, the arrival of coronary angioplasty (especially after the advent of drug-eluting stents) has cast doubt on this concept. The studies The two most recent studies comparing the two revascularization strategies, the SYNTAX and the FREEDOM studies, redefined the evidence in this sense and deserve a special mention: in the SYNTAX study.190,191 for which the primary endpoint was death, infarction, stroke, or need for another revascularization procedures, a particular benefit in favour of CABG would seem to emerge in patients with three-vessel coronary disease, in whom a significant reduction in mortality, infarction, and the need for revascularization without an increase in strokes was seen. Another score has been defined that if high or intermediate identifies those patients who benefit most from CABG, unlike a score lower than 23, in which the two revascularization techniques would appear to be equivalent. Conversely, in patients with left main coronary artery stenosis not associated with three-vessel coronary disease, surgical reduction did not reduce either mortality or infarctions, but only the need for revascularization. Two meta-analyses, one of which was published in the JACC and the other in Circulation Journal came to different conclusions.192,193

ain coronary artery stenosis not associated with three-vessel coronary disease, surgical reduction did not reduce either mortality or infarctions, but only the need for revascularization. Two meta-analyses, one of which was published in the JACC and the other in Circulation Journal came to different conclusions.192,193 in the FREEDOM study, the results at 5 years showed a significant reduction in the primary endpoint in patients treated with CABG. Again in this study, patients treated with BPAC had a significant excess of stroke. The registry studies Registry data, however, tell a different tale. A study conducted on patients with multi-vessel coronary disease treated with CABG or PCI with second-generation drug EES was recently published.194 At about 3 years, there was no difference in mortality, but a significant increase, in the patients treated with PCI, of the risk of infarction and the need for new revascularization counterbalanced by the significant reduction in the risk of stroke in patients treated with PCI.

tion drug EES was recently published.194 At about 3 years, there was no difference in mortality, but a significant increase, in the patients treated with PCI, of the risk of infarction and the need for new revascularization counterbalanced by the significant reduction in the risk of stroke in patients treated with PCI. The guidelines On the basis of the SYNTAX study, the ESC guidelines on myocardial revascularization in patients with CIC narrowed the indications for PCI and widened the recommendations for CABG, by assigning a stronger indication for CABG in patients with three-vessel disease, in patients with two-vessel coronary disease involving the proximal left anterior descending artery and in those cases with stenosis of the left main coronary artery in whom the SYNTAX score is > 22. The only patients for whom there is a preferential indication for PCI are those with single- and two-vessel coronary disease without the involvement of the proximal left anterior descending artery.110 It should be noted that the CABG vs. PCI with second-generation stents registry was published after the ESC guidelines. To conclude, the tendency, in recent years, towards a reduction in PCIs and an increase in CABG could change direction with a more widespread adoption of second generation stents, thanks also to ongoing trials, such as the ISCHEMIA study and studies using modern drug-eluting stents.

The guidelines On the basis of the SYNTAX study, the ESC guidelines on myocardial revascularization in patients with CIC narrowed the indications for PCI and widened the recommendations for CABG, by assigning a stronger indication for CABG in patients with three-vessel disease, in patients with two-vessel coronary disease involving the proximal left anterior descending artery and in those cases with stenosis of the left main coronary artery in whom the SYNTAX score is > 22. The only patients for whom there is a preferential indication for PCI are those with single- and two-vessel coronary disease without the involvement of the proximal left anterior descending artery.110 It should be noted that the CABG vs. PCI with second-generation stents registry was published after the ESC guidelines. To conclude, the tendency, in recent years, towards a reduction in PCIs and an increase in CABG could change direction with a more widespread adoption of second generation stents, thanks also to ongoing trials, such as the ISCHEMIA study and studies using modern drug-eluting stents. Special populations Elderly patients The number of elderly patients with ischaemic cardiomyopathy is undergoing a constant increase.8 Coronary disease in the elderly requires special attention, given the tendency to be more aggressive and widespread.

To conclude, the tendency, in recent years, towards a reduction in PCIs and an increase in CABG could change direction with a more widespread adoption of second generation stents, thanks also to ongoing trials, such as the ISCHEMIA study and studies using modern drug-eluting stents. Special populations Elderly patients The number of elderly patients with ischaemic cardiomyopathy is undergoing a constant increase.8 Coronary disease in the elderly requires special attention, given the tendency to be more aggressive and widespread. Most of the cardiovascular risk factors are also present in old age.1 Moreover, pharmacological and non-pharmacological treatments must take into account aspects concerning treatment compliance and persistence, especially in patients taking many different drugs, the co-morbidities that are most common in the elderly and, lastly, the exclusion of this group of patients from trials.3 Lifestyle correction remains important, and individualized strategies would be preferable. Dyslipidaemia requires compliance with the same targets as for young patients and the use of statins must be recommended. Once again with regard to BP monitoring, the benefits identified in young subjects are also expected in the elderly population. However, although the most recent guidelines recommend maintaining a maximum BP of <140 mmHg and a minimum of <90 mmHg in all hypertensive patients, there is no specific evidence for the elderly, for whom the only value provided is a maximum BP of <160 mmHg The guidelines recommend annual flu vaccination in elderly patients with CIC.195

Once again with regard to BP monitoring, the benefits identified in young subjects are also expected in the elderly population. However, although the most recent guidelines recommend maintaining a maximum BP of <140 mmHg and a minimum of <90 mmHg in all hypertensive patients, there is no specific evidence for the elderly, for whom the only value provided is a maximum BP of <160 mmHg The guidelines recommend annual flu vaccination in elderly patients with CIC.195 As far as anti-platelet therapy is concerned, current recommendations suggest a similar use to that of the younger population with greater attention dedicated to the gastric damage caused by aspirin and the greater risk of bleeding. With regard to anti-ischaemic therapy in the elderly people, treatment is similar to that of younger patients with the difference that the likelihood of adverse events is greater, in the same way as there is a higher risk of both haemorrhagic and renal complications, due to the need for invasive procedures. When choosing the revascularization strategy, PCI is often preferable to CABG. In this sense, the TIME study196 provides evidence as to how interventional therapy can improve symptoms and quality of life compared with medical therapy. Lastly, ranolazine and ivabradine have been seen to be safe and efficacious in the elderly at the recommended doses, provided they are used with caution in subjects with severe kidney disease.

With regard to anti-ischaemic therapy in the elderly people, treatment is similar to that of younger patients with the difference that the likelihood of adverse events is greater, in the same way as there is a higher risk of both haemorrhagic and renal complications, due to the need for invasive procedures. When choosing the revascularization strategy, PCI is often preferable to CABG. In this sense, the TIME study196 provides evidence as to how interventional therapy can improve symptoms and quality of life compared with medical therapy. Lastly, ranolazine and ivabradine have been seen to be safe and efficacious in the elderly at the recommended doses, provided they are used with caution in subjects with severe kidney disease. Women The female population presents a delay of between 10 and 20 years compared with the male population in the clinical onset of coronary disease.197 There is evidence that women present greater hypercoagulability, more extensive endothelial dysfunction and smaller vessels, a situation that is further influenced by hormonal and genetic factors. We must also reconsider the opinion that female coronary disease is anatomically less severe than in males, as shown by the WISE study.198 Women are characterized by a higher intrahospital complication rate during acute coronary syndrome and invasive procedures.8,199,200 In addition, treatment compliance is poorer and the incidence of depression higher, with a consequent worsening in prognosis.

Women The female population presents a delay of between 10 and 20 years compared with the male population in the clinical onset of coronary disease.197 There is evidence that women present greater hypercoagulability, more extensive endothelial dysfunction and smaller vessels, a situation that is further influenced by hormonal and genetic factors. We must also reconsider the opinion that female coronary disease is anatomically less severe than in males, as shown by the WISE study.198 Women are characterized by a higher intrahospital complication rate during acute coronary syndrome and invasive procedures.8,199,200 In addition, treatment compliance is poorer and the incidence of depression higher, with a consequent worsening in prognosis. There has been a great deal of debate on the possibility that hormone replacement therapy might improve the prognosis of chronic ischaemic cardiomyopathy in women. The results of the PEPI201 and HERS studies are not conclusive.202 Diabetic patients Diabetic patients are a high-risk population, with poorer prognosis.

Women are characterized by a higher intrahospital complication rate during acute coronary syndrome and invasive procedures.8,199,200 In addition, treatment compliance is poorer and the incidence of depression higher, with a consequent worsening in prognosis. There has been a great deal of debate on the possibility that hormone replacement therapy might improve the prognosis of chronic ischaemic cardiomyopathy in women. The results of the PEPI201 and HERS studies are not conclusive.202 Diabetic patients Diabetic patients are a high-risk population, with poorer prognosis. As far as revascularization strategies are concerned, the BARI Trial203 compared CABG and PCI with OMT vs. OMT alone, without yielding evidence as to the superiority of either of the two strategies. In addition, in this study, no significant details were observed between glycaemia-lowering medication based on insulin-sensitizing drugs and insulin therapy. As regards the comparison between CABG and PCI in diabetic patients, almost all studies indicate surgical revascularization as being superior, but with an increase in the incidence of non-fatal stroke.190,204–208 As regards PCI, the use of drug-eluting stents vs. bare metal stents reduces the risk of restenosis208 without modifying cardiovascular mortality and all-cause mortality.209

s, almost all studies indicate surgical revascularization as being superior, but with an increase in the incidence of non-fatal stroke.190,204–208 As regards PCI, the use of drug-eluting stents vs. bare metal stents reduces the risk of restenosis208 without modifying cardiovascular mortality and all-cause mortality.209 Patients with chronic kidney disease Chronic kidney disease (CKD) is one of the most common important co-morbidities and one that often poses complex implications in terms of management. CKD is present in ∼20% of patients with CIC. The latter condition is, in turn, very common among nephropathic patients.1,3 The unfavourable prognostic role of CKD is proportionate to the reduction in GFR, with a higher risk to be attributed to those with a GFR of <15 mL/min/1.73 m2 or who are on dialysis.210 Subjects with CKD also present multiple risk factors that promote particularly aggressive and accelerated atherosclerosis. Vascular calcification is particularly common in the advanced stages of CKD. Statin therapy improves outcome in patients with Stages 2 and 3 CKD and slows down disease progression. In these patients, caution is required when using iodinated contrast medium and when adapting posology to a reduction in glomerular filtration rate for those medicinal products that are excreted primarily via the kidneys. Generally speaking, the treatments to be used in subjects with CKD and CIC are the same as in the remaining population. Given the aggressiveness of atherosclerosis in these patients, risk factor treatment must be intensive.

In these patients, caution is required when using iodinated contrast medium and when adapting posology to a reduction in glomerular filtration rate for those medicinal products that are excreted primarily via the kidneys. Generally speaking, the treatments to be used in subjects with CKD and CIC are the same as in the remaining population. Given the aggressiveness of atherosclerosis in these patients, risk factor treatment must be intensive. It is necessary to choose statins with the least possible renal excretion in the most advanced forms of CKD, and the simvastatin–ezitimibe combination has been seen to be both efficacious and safe.211 As far as ranolazine is concerned, FDA recommends regular GFR monitoring in subjects with moderate/severe CKD. The data concerning revascularization treatment would appear to be controversial. In general, CABG entails higher periprocedural mortality, a higher probability of starting dialysis in patients with CKD but also a better long-term outcome than treatment with angioplasty.212,213

As far as ranolazine is concerned, FDA recommends regular GFR monitoring in subjects with moderate/severe CKD. The data concerning revascularization treatment would appear to be controversial. In general, CABG entails higher periprocedural mortality, a higher probability of starting dialysis in patients with CKD but also a better long-term outcome than treatment with angioplasty.212,213 Patients with chronic lung disease CIC and chronic lung disease are two conditions that are often associated, in part because they share two extremely important risk factors (age and smoking). In addition, the presence of chronic lung disease is included in all the main patient stratification scores for ischaemic cardiomyopathy (EuroSCORE, SYNTAX, and STS). The data in our possession suggest that the causes of death in patients with chronic lung disease are very often cardiovascular.214 In addition, the cardiovascular morbidity in patients with COPD is very high, as shown by the Lung Health Study.215 In this study, a relationship was observed between pulmonary function and risk of cardiovascular death. After all, COPD is known to be an independent risk factor in patients with CIC, leading to a worse prognosis in patients with acute MI treated with both PCI and CABG.216 Restrictive pulmonary disease in particular would appear to be that with the worst prognosis. However, the same study showed that patients with even severe COPD should not be denied the possibility of surgical revascularization.

, leading to a worse prognosis in patients with acute MI treated with both PCI and CABG.216 Restrictive pulmonary disease in particular would appear to be that with the worst prognosis. However, the same study showed that patients with even severe COPD should not be denied the possibility of surgical revascularization. As far as chronic therapy is concerned, the evidence available currently on cardioselective beta-blockers, which used to be contraindicated, actually improve survival in patients with COPD and ischaemic cardiomyopathy.216 Similar results were obtained with renin–angiotensin system inhibitors217 and statins218 that, in addition to reducing mortality, have also been seen to slow down the deterioration in pulmonary function.

, which used to be contraindicated, actually improve survival in patients with COPD and ischaemic cardiomyopathy.216 Similar results were obtained with renin–angiotensin system inhibitors217 and statins218 that, in addition to reducing mortality, have also been seen to slow down the deterioration in pulmonary function. Consensus Document Approval Faculty Alunni Gianfranco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Audo Andrea, Azzarito Michele, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Bonvicini Marco, Cacciavillani Luisa, Calculli Giacinto, Caldarola Pasquale, Capecchi Alessandro, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Cassin Matteo, Casu Gavino, Cemin Roberto, Chiarandà Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Ciccone Marco Matteo, Cicini Maria Paola, Clerico Aldo, D’Agostino Carlo, De Luca Leonardo, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Di Tano Giuseppe, Egidy Assenza Gabriele, Egman Sabrina, Enea Iolanda, Francese Giuseppina Maura, Gabrielli Domenico, Giardina Achille, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Ledda Antonietta, Lucà Fabiana, Macera Francesca, Marini Marco, Mascia Franco, Masson Serge, Maurea Nicola, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Mininni Nicola, Molon Giulio, Moreo Antonella, Moretti Luciano, Mortara Andrea, Murrone Adriano, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Oreglia Jacopo, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Procaccini Vincenza, Pugliese Francesco Rocco, Pulignano Giovanni, Radini Donatella, Rao Carmelo Massimiliano, Rasetti Gerardo, Roncon Loris, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Scherillo Marino, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Themistoclakis Sakis, Uguccioni Massimo, Urbinati Stefano, Vatrano Marco, Vianello Gabriele, and Vinci Eugenio.

Gerardo, Roncon Loris, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Scherillo Marino, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Themistoclakis Sakis, Uguccioni Massimo, Urbinati Stefano, Vatrano Marco, Vianello Gabriele, and Vinci Eugenio. Conflict of interest: none declared.

Revised by: Antonio Francesco Amico, Roberto Antonicelli, Francesco Sisto Consensus Document Approval Faculty in appendix Introduction Definition of telemedicine Telemedicine is defined as a mode of delivering health care services, through the use of innovative technologies, in particular the Information and Communication Technologies, in situations where the health professional and the patient or two professionals are not in the same place. Telemedicine involves the secure transmission of information and medical data in the form of text, sound, images or other modalities for the prevention, diagnosis, treatment and subsequent patient follow-up.1 The telemedicine services should be therefore considered as a true diagnostic/therapeutic health service. Utility of telemedicine Telemedicine can be used in different contexts and by different operators: general practitioners, hospital specialists, any health care worker, including non-physicians, and patients may benefit from the use of telemedicine in several aspects (better management, simplification of procedures, reduction in transfer). Telemedicine transmission may include texts (medical records, personal data), images (electrocardiograms, ambulatory electrocardiograms, telemetric monitoring, radiological exams, ultrasound), audio recordings, videos. Telemedicine and cardiovascular disease The most important areas of application of telemedicine in the field of cardiology are: early (pre-hospital) diagnosis of acute myocardial infarction (AMI) with electrocardiogram transmission remote control of device (pacemakers, defibrillators)

Utility of telemedicine Telemedicine can be used in different contexts and by different operators: general practitioners, hospital specialists, any health care worker, including non-physicians, and patients may benefit from the use of telemedicine in several aspects (better management, simplification of procedures, reduction in transfer). Telemedicine transmission may include texts (medical records, personal data), images (electrocardiograms, ambulatory electrocardiograms, telemetric monitoring, radiological exams, ultrasound), audio recordings, videos. Telemedicine and cardiovascular disease The most important areas of application of telemedicine in the field of cardiology are: early (pre-hospital) diagnosis of acute myocardial infarction (AMI) with electrocardiogram transmission remote control of device (pacemakers, defibrillators) monitoring of patients with chronic heart failure monitoring of patients arrhythmias transmission of echo images to a III level centre for a ‘second opinion’

Telemedicine and cardiovascular disease The most important areas of application of telemedicine in the field of cardiology are: early (pre-hospital) diagnosis of acute myocardial infarction (AMI) with electrocardiogram transmission remote control of device (pacemakers, defibrillators) monitoring of patients with chronic heart failure monitoring of patients arrhythmias transmission of echo images to a III level centre for a ‘second opinion’ ST-elevation acute myocardial infarction (STEMI) network activation for primary percutaneous coronary intervention (PCI) is recommended by guidelines and should be as fast as possible; most regions in Italy have therefore implemented efficient STEMI networks over the past 15 years. Pre-hospital electrocardiogram and diagnosis is one of the most efficient solutions to reduce time of treatment. Current technologies allow now for electrocardiogram transmission in a very short time and with a very high quality to dispatch centres, arranging the best reperfusion strategy.2 Similarly, remote control and monitoring of ICDs has progressively improved over the last years, and this has allowed a significant reduction in clinical visits and hospital access, and faster recognition of device failure or arrhythmic complications. Home monitoring of heart failure patients seems to have positive effects by reducing hospital admissions; remote monitoring of simple parameters (blood pressure, heart rate, body weight) can anticipate an occurring destabilization of the patient with heart failure, and, when followed by changes in drug therapy, reducing re-hospitalizations.3,4

failure patients seems to have positive effects by reducing hospital admissions; remote monitoring of simple parameters (blood pressure, heart rate, body weight) can anticipate an occurring destabilization of the patient with heart failure, and, when followed by changes in drug therapy, reducing re-hospitalizations.3,4 Remote monitoring of heart failure patients with ICDs/CRT-Ds significantly reduce long-term mortality in a real-world clinical condition, 2.1% vs. 11.5% 1-year mortality (P < 0.0001), also maintained during a 3-year follow-up (4.9% vs. 22.3%, P < 0.0001).5 In other studies, the use of healthcare resources was significantly reduced by remote telemedicine monitoring as a result of a marked reduction of in-office visits without compromising patient safety.6 Transmission of data and images between different centres has become routine in radiology, but also very common in cardiology, in particular for ‘second opinion’ consultation. Tele-echocardiography may guide treatment, reduce long and potentially risky transports, and triage transports to destination centres with the most appropriate cardiac capabilities.7 In case of neonantes with suspected congenital heart disease, transfer to the regional unit was avoided in 72% of patients thanks to remote second opinion consultation with tele-echocardiography.8 More and more fields in cardiology are interested by progress in telemedicine.

the most appropriate cardiac capabilities.7 In case of neonantes with suspected congenital heart disease, transfer to the regional unit was avoided in 72% of patients thanks to remote second opinion consultation with tele-echocardiography.8 More and more fields in cardiology are interested by progress in telemedicine. Telemedicine in cardiovascular emergencies: acute myocardial infarction and acute coronary syndrome ST-elevation acute myocardial infarction The guidelines of the European Society of Cardiology (ESC) on the treatment of STEMI recommend primary angioplasty (pPCI) as the preferred treatment strategy when performed in due time. The maximum benefit is obtained when the reperfusion is achieved in the first 3 h of symptom onset. The delay due to the health care system can be reduced if there is a network between spoke hospitals by which the patient is promptly transferred to a hub centre for pPCI, an efficient transfer service by ambulances, if the cathlab can be activated by ‘en route’ ambulance. Therefore, early diagnosis of STEMI, which is possible with pre-hospital 12-lead electrocardiogram, can greatly reduce the time of treatment, by-passing any delay through the emergency department. The time indicated by the guidelines as optimal for pPCI from first medical contact is 90 min (acceptable a 120-min delay). ST-elevation acute myocardial infarction networks A network for the efficient treatment of STEMI should be characterized by: a clear definition of the geographic areas covered by the service;

Telemedicine in cardiovascular emergencies: acute myocardial infarction and acute coronary syndrome ST-elevation acute myocardial infarction The guidelines of the European Society of Cardiology (ESC) on the treatment of STEMI recommend primary angioplasty (pPCI) as the preferred treatment strategy when performed in due time. The maximum benefit is obtained when the reperfusion is achieved in the first 3 h of symptom onset. The delay due to the health care system can be reduced if there is a network between spoke hospitals by which the patient is promptly transferred to a hub centre for pPCI, an efficient transfer service by ambulances, if the cathlab can be activated by ‘en route’ ambulance. Therefore, early diagnosis of STEMI, which is possible with pre-hospital 12-lead electrocardiogram, can greatly reduce the time of treatment, by-passing any delay through the emergency department. The time indicated by the guidelines as optimal for pPCI from first medical contact is 90 min (acceptable a 120-min delay). ST-elevation acute myocardial infarction networks A network for the efficient treatment of STEMI should be characterized by: a clear definition of the geographic areas covered by the service; protocols for the transport, by ambulance or helicopter, equipped with 12-lead electrocardiogram, remote transmission of the electrocardiogram, defibrillator and at least one health care (doctor or nurse) expert in advanced life support; possibility to transfer the patient for pPCI with a transfer time <60 min cathlab activation while the patient is en route

protocols for the transport, by ambulance or helicopter, equipped with 12-lead electrocardiogram, remote transmission of the electrocardiogram, defibrillator and at least one health care (doctor or nurse) expert in advanced life support; possibility to transfer the patient for pPCI with a transfer time <60 min cathlab activation while the patient is en route availability of the cathlab staff within 20 min of calling patient’s direct transport directly to cathlab by-passing the emergency department in case of access in a hospital without pPCI capability, electrocardiogram within 10’and, in case of confirmed diagnosis of STEMI, transfer to hub for pPCI within 30’, if the travel time is less than 60’, otherwise fibrinolysis. The hub-spoke organizational model for the management of STEMI reduces the delay to treatment and increases the rates of patients who receive reperfusion treatment within benchmark time. In any STEMI network, each time interval should be monitored to enable actions aimed at performance improvement and delay reductions. The public decision-maker involvement is essential for the optimization of resources and to resolve conflicts in management (automated, paramedic, emergency physician, or interventional cardiologist interpretation of the electrocardiograms Hub cathlabs position through the country).

The hub-spoke organizational model for the management of STEMI reduces the delay to treatment and increases the rates of patients who receive reperfusion treatment within benchmark time. In any STEMI network, each time interval should be monitored to enable actions aimed at performance improvement and delay reductions. The public decision-maker involvement is essential for the optimization of resources and to resolve conflicts in management (automated, paramedic, emergency physician, or interventional cardiologist interpretation of the electrocardiograms Hub cathlabs position through the country). Non-ST-evaluation acute myocardial infarction and unstable angina The ESC 2015 guidelines for the management of patients with NSTE–acute coronary syndrome (ACS)9 recommend in patients with chest pain: The execution of 12-lead electrocardiogram within 10 min of first medical contact and its interpretation. Therefore, even if the network for NSTEMI management is not, with some exceptions, time-dependent, pre-hospital electrocardiogram is however required: the STEMI network can be used also for patients with NSTE–ACS. Only cases with very high-risk criteria (haemodynamic instability or shock, refractory angina to medical therapy, cardiac arrest or life-threatening arrhythmias, acute heart failure, mechanical complications of infarction, transient ST changes, especially if ST-elevation) should be referred to the hub centre where angioplasty should be performed within 120 min.

emodynamic instability or shock, refractory angina to medical therapy, cardiac arrest or life-threatening arrhythmias, acute heart failure, mechanical complications of infarction, transient ST changes, especially if ST-elevation) should be referred to the hub centre where angioplasty should be performed within 120 min. In other cases, which are the majority, there is time to decide which is the best treatment, as it must also take account the ischaemic risk of bleeding and comorbidities. In any case, the patient should be admitted to a cardiology ward, as close as possible (not necessarily the hub centre), to where electrocardiogram monitoring is possible (in the cardiology care unit (CCU) or just telemetry depending on the clinical severity). If, by evaluating the risk/benefit ratio, it is considered appropriate to perform a revascularization, this should be done within 24 h, even transferring the patient to the hub centre for the PCI, and returning at the centre spoke after the procedure, if not complicated. Telemedicine in arrhythmic emergencies The applications of telemedicine have been classified into three categories in relation to the place where the service is carried out: pre-hospital, in-hospital, and post-hospital. In all these areas it is possible to identify potential uses of telemedicine in the management of arrhythmias.

ne in arrhythmic emergencies The applications of telemedicine have been classified into three categories in relation to the place where the service is carried out: pre-hospital, in-hospital, and post-hospital. In all these areas it is possible to identify potential uses of telemedicine in the management of arrhythmias. Pre-hospital Pre-hospital electrocardiogram directly interpreted or transmitted for telediagnosis may be extremely useful for the management of severe arrhythmias, allowing for immediate intervention or patient’s admission in the most appropriate structure. Several studies have demonstrated the feasibility of using a 12-lead electrocardiogram in pre-hospital setting.10–13 Good quality diagnostic electrocardiograms are transmitted with a success rate of 85%.14 In-hospital In-hospital telecardiology is often used for electrocardiogram sharing between different departments or between peripheral hospitals to central hospitals.15–17 The diagnostic quality of the images sent and received through the use of telemedicine has proved to be very high. Post-hospital The post-hospital management of patients with arrhythmias can be articulated in two points: the teleconsultation between general practitioners and specialists, the use of telemedicine in chronic cardiovascular disease. General practitioners can access via telemedicine specialist tele-diagnosis of a 12-lead electrocardiogram, concurring in real time the best treatment for the patient.

rticulated in two points: the teleconsultation between general practitioners and specialists, the use of telemedicine in chronic cardiovascular disease. General practitioners can access via telemedicine specialist tele-diagnosis of a 12-lead electrocardiogram, concurring in real time the best treatment for the patient. Remote monitoring of implantable cardiac devices has proven to be extremely important in the diagnosis of atrial fibrillation, particularly silent. In patients with defibrillators capable of remote monitoring (TRUST trial), the recognition of atrial fibrillation occurred with 34.5 days in advance18; in another population of pacemakers with daily monitoring (COMPAS trial), the incidence of hospitalizations for atrial arrhythmias and stroke proved by 7.3% in the control group and 2.4% in the remote monitoring group with an incidence of stroke of 3.3% and 0.8%, respectively.19 On the other hand, in case of episodes of tachycardia and ventricular fibrillation with or without shock delivery, remote monitoring of ICD allows a ready assessment of appropriateness and effectiveness of the therapy delivered. It is therefore possible, with an individualized management of the event, avoiding unplanned and unnecessary emergency room or clinic access.

dia and ventricular fibrillation with or without shock delivery, remote monitoring of ICD allows a ready assessment of appropriateness and effectiveness of the therapy delivered. It is therefore possible, with an individualized management of the event, avoiding unplanned and unnecessary emergency room or clinic access. Telemedicine for the reduction of time to treatment: supporting evidence First studies on the pre-hospital electrocardiogram transmission from ambulances, aimed at the activation of cathlab for primary angioplasty in AMI, now back in the late 90’s.20–21(Table 1) Data from non-randomized studies show that patients with AMI and pre-hospital telemedicine diagnosis are treated in a shorter time than patients whose diagnosis is performed in the hospital, either in case of direct access to a hub centre or to a spoke centre22 (median 41 mins less, in the 81st s). The transmission of a pre-hospital 12-lead electrocardiogram directly to the cardiologist by mobile phone is able to reduce the door-to-balloon time of about an hour [34 vs. 97 min (median)].23 This diagnostic approach is associated with a time between first medical contact and angioplasty of 74 min (median) in contrast to 127 with traditional approach without telemedicine. Table 1 Reduction of time to treatment of acute myocardial infarction thanks to pre-hospital electrocardiogram by telemedicine

edian)].23 This diagnostic approach is associated with a time between first medical contact and angioplasty of 74 min (median) in contrast to 127 with traditional approach without telemedicine. Table 1 Reduction of time to treatment of acute myocardial infarction thanks to pre-hospital electrocardiogram by telemedicine Study (authors) N (telemedicine vs. controls) Time interval Differences Relative reduction Terkelsen & al. 21 vs. 85 vs. 55a Call-to-balloon 87 vs. 168 min −48% Sejersten & al. 146 vs. 89 Door-to-balloon 34 vs. 97 min −65% Call-to-balloon 74 vs. 127 min −42% Sorensen & al. 460 vs. 83 vs. 216a Call-to-balloon 92 vs. 153 min −40% Brunetti & al. 123 vs. 174 ECG to balloon 41 vs. 94 min −56% Optimal time perfusion rate 85% vs. 35% +143% 69% vs. 29% in rural areas +138 Pedersen & al. 616 vs. 821 Door-to-balloon 83 vs. 103 min −19% 61% vs. 36% +69% Chan & al. 167 vs. 427 Optimal time perfusion rate 80% vs. 9% +789% Zanini & al. 136 vs. 263 Total time to balloon 148 vs. 262 min −43% Sanchez-Ross & al. 92 vs. 50 Door-to-balloon 63 vs. 119 min −47% PCI, percutaneous coronary intervention. a Triage by telemedicine and direct transfer for PCI vs. triage with telemedicine without direct transfer vs. traditional triage without telemedicine.

Study (authors) N (telemedicine vs. controls) Time interval Differences Relative reduction Terkelsen & al. 21 vs. 85 vs. 55a Call-to-balloon 87 vs. 168 min −48% Sejersten & al. 146 vs. 89 Door-to-balloon 34 vs. 97 min −65% Call-to-balloon 74 vs. 127 min −42% Sorensen & al. 460 vs. 83 vs. 216a Call-to-balloon 92 vs. 153 min −40% Brunetti & al. 123 vs. 174 ECG to balloon 41 vs. 94 min −56% Optimal time perfusion rate 85% vs. 35% +143% 69% vs. 29% in rural areas +138 Pedersen & al. 616 vs. 821 Door-to-balloon 83 vs. 103 min −19% 61% vs. 36% +69% Chan & al. 167 vs. 427 Optimal time perfusion rate 80% vs. 9% +789% Zanini & al. 136 vs. 263 Total time to balloon 148 vs. 262 min −43% Sanchez-Ross & al. 92 vs. 50 Door-to-balloon 63 vs. 119 min −47% PCI, percutaneous coronary intervention. a Triage by telemedicine and direct transfer for PCI vs. triage with telemedicine without direct transfer vs. traditional triage without telemedicine. The diagnosis by pre-hospital electrocardiogram and direct transfer to cathlab enable patients with STEMI who live far from a hub centre performing primary PCI and or in rural areas to be treated with an angioplasty within times comparable to that of patients who live in close proximity to a centre with primary angioplasty. In 750 patients with STEMI enrolled in a Danish registry, subjects with pre-hospital diagnosis by telemedicine in rural areas and direct access in cathlab had a treatment time of 92 min (median) compared with 153 subjects without pre-hospital diagnosis: those from rural areas, despite traveling longer distances [further 30 km (median)], had treatment times only 9 min longer than those from urban areas.24

agnosis by telemedicine in rural areas and direct access in cathlab had a treatment time of 92 min (median) compared with 153 subjects without pre-hospital diagnosis: those from rural areas, despite traveling longer distances [further 30 km (median)], had treatment times only 9 min longer than those from urban areas.24 In an Italian registry on over 27 000 patients screened with pre-hospital electrocardiogram by telemedicine, almost 50% of patients with STEMI received a diagnosis within 30 min of symptom onset.25 More recent data from the Apulia emergency medical service (EMS) (1-1-8) registry on pPCI for STEMI show times from pre-hospital electrocardiogram to primary angioplasty of 41 min (mean) vs. 1 h and 34 min in subjects not triaged by telemedicine, with a relative time to treatment reduction of 56%: the relative reduction is 49% even in areas distant from cathlabs.26 Thanks to the pre-hospital diagnosis by telemedicine the rates of subjects with time from diagnosis to treatment <1 h rose from 29% to 69% in ‘remote’ areas (+138%) and from 35% to 85% in the whole population observed (+143%). In another Danish registry on almost 1500 patients with STEMI, patients with pre-hospital triage by telemedicine were characterized by door-to-balloon times of 83 min (median) compared with 103 of the ‘controls’: the times <90’ were achieved in 61% of subjects in the telemedicine group vs. 36% of others.27 With transfer distances likely to be greater, in British Columbia, pre-hospital triage by telemedicine has been able to increase the percentage of patients with door-to-balloon <90 min from 9% to 80%.28 Data from the US National Register on STEMI (more than 50 000 patients) show door-to-balloon times of 94 min in case of pre-hospital triage against 110 of ‘control’.29

ritish Columbia, pre-hospital triage by telemedicine has been able to increase the percentage of patients with door-to-balloon <90 min from 9% to 80%.28 Data from the US National Register on STEMI (more than 50 000 patients) show door-to-balloon times of 94 min in case of pre-hospital triage against 110 of ‘control’.29 Immediate screening with pre-hospital electrocardiogram can reduce the false negative rate in cases of STEMI with atypical presentation.30 From a clinical point of view, moreover, the early assessment and pre-hospital triage of patients with STEMI using telemedicine reduce the time door-to-balloon, the infarct size, impaired ejection fraction and subsequent duration of hospitalization.31 The pre-hospital triage by telemedicine is in fact able to impact significantly also on the endpoint mortality. A dramatic 60% reduction of early and late mortality associated with the use of pre-hospital electrocardiogram by telemedicine was observed in registries on AMI28; pre-hospital triage is thus an independent predictor of survival at 1 year (hazard ratio: 0.37). Even a modest increase in the rate of subjects with call-to-balloon <90 min (28% vs. 21%) was associated in a large population of almost 290 000 patients with a significant reduction in 30-day mortality (7.4% vs. 8.2%) of patients with acute coronary syndrome (STEMI and NSTEMI).32

rvival at 1 year (hazard ratio: 0.37). Even a modest increase in the rate of subjects with call-to-balloon <90 min (28% vs. 21%) was associated in a large population of almost 290 000 patients with a significant reduction in 30-day mortality (7.4% vs. 8.2%) of patients with acute coronary syndrome (STEMI and NSTEMI).32 Even data from meta-analyses show a 0.65 relative risk of intra hospital mortality for AMI in the case of pre-hospital diagnosis by telemedicine compared with standard treatment.33 Data from a recent meta-analysis of 14 randomized trials of approximately 4400 patients with STEMI show that pre-hospital triage and direct transfer are associated with a reduction in 30-day mortality of 42%.34 The use of pre-hospital electrocardiogram by telemedicine in a network for the treatment of STEMI has been already implemented in different areas of Italy35–37 and in the world,38,39 with optimal results. In an Italian provincial network for the treatment of STEMI, treatment times were significantly reduced in the group using telemedicine diagnosis compared with controls 148 ± 81 min vs. 262 ± 112.37 Reducing the time of treatment seems to significantly affect the prognosis, especially in patients with increased risk of complications and more unstable medical conditions, cardiogenic shock,40 more comorbidities,41 more severe Killip class.36

telemedicine diagnosis compared with controls 148 ± 81 min vs. 262 ± 112.37 Reducing the time of treatment seems to significantly affect the prognosis, especially in patients with increased risk of complications and more unstable medical conditions, cardiogenic shock,40 more comorbidities,41 more severe Killip class.36 Telemedicine and cardiovascular emergency networks in Italy Several networks for cardiovascular emergencies with telemedicine support, mainly based on 12-lead pre-hospital electrocardiogram, have been implemented so far in Italy. The Italian Ministry of Health and the Superior Council of Health set in 2010 a working group for telemedicine in order to have a shared governance model and harmonized models of implementation.42 The working group followed prior experiences43 and aimed to build a map of the networks to facilitate the exchange of best practices and organizational models. Each model in the system is described in its general characteristics, the type of service, the scope, and the state of the project, the technology used and the geographical area. The telemedicine projects for cardiovascular emergency, reported on the www.onecare.cup2000.it site are reported in Table 2. The projects, mainly based on four types of organizational models, are shown in Figure 1. All telemedicine emergency models are characterized by a spoke, sending an electrocardiogram, the EMS (in Italy 1-1-8) and a hub receiving the electrocardiograms (a cardiology ward/CCU or 118 dispatch centre). In one case, the hub is represented by a dedicated telemedicine centre with cardiologists experienced in interpreting pre-hospital electrocardiograms other than a cardiology ward/CCU.

n electrocardiogram, the EMS (in Italy 1-1-8) and a hub receiving the electrocardiograms (a cardiology ward/CCU or 118 dispatch centre). In one case, the hub is represented by a dedicated telemedicine centre with cardiologists experienced in interpreting pre-hospital electrocardiograms other than a cardiology ward/CCU. Figure 1 Model of telemedicine network for cardiovascular emergency report on website www.onecare.2000cup.it (1 November 2015). Table 2 Telemedicine experience on cardiovascular emergency reported on the national Ministry of Health website www.onecare.cup2000.it (1 November 2015) Region Project Area Descrizione Connectivity Tools Basilicata TELESAL Region Satellite communication technologies to improve or enable telemedicine applications and services Satellite Rete cardiologica SCA Region Avoid unnecessary hospitalization, enable early pharmacologic treatment of acute myocardial infarction, primary angioplasty, thrombolysis, prevention of heart failure GSM Lifepak 12 Medtronic Campania Sistema di Telecardiologia in emergenza City of Benevento Activation of telediagnosis for patients with suspected AMI, triaged at emergency department and mobile stations; the goal is to record a pre-hospital standard electrocardiogram (12-lead) immediately, transmitted to a telemedicine hub, with the aims of an early diagnosis, a timely treatment, and a fast transfer Telephone line Monitor ECG/defibrillator UMTS/GPRS

Campania Sistema di Telecardiologia in emergenza City of Benevento Activation of telediagnosis for patients with suspected AMI, triaged at emergency department and mobile stations; the goal is to record a pre-hospital standard electrocardiogram (12-lead) immediately, transmitted to a telemedicine hub, with the aims of an early diagnosis, a timely treatment, and a fast transfer Telephone line Monitor ECG/defibrillator UMTS/GPRS Progetto per la diagnosi, trattamento precoce e trasporto assistito presso strutture specializzate del paziente con patologie cardiovascolari acute ai fini della riduzione della mortalità preospedaliera City of Avellino EMS electrocardiogram sent to Ariano Irpino CCU. Telephone line Emilia Romagna Trasmissione telematica di ECG verso l'Unità Terapia Intensiva Coronarica dell'Azienda Ospedaliera di Reggio Emilia City of Reggio Emilia The telemedicine hub located in the Azienda Ospedaliera Arcispedale Santa Maria Nuova enable the on-duty 24/7 cardiologist to confirm the diagnosis of STEMI eligible for primary PCI. UMTS/GPRS Lifepak 12 Gestione Emergenza Extra-Intraospedaliera City of Forli’-Cesena Condirmation of STEMI diagnosis UMTS/GPRS Piemonte S.C. Servizio emergenza sanitaria territoriale 118 Provincia di Alessandria Region Since 2011 transmission of 12-lead ECG and clinical data from EMS ambulance to dispatch centre and from this to cathlab for primary PCI UMTS/GPRS Mobimed Ortivus

Gestione Emergenza Extra-Intraospedaliera City of Forli’-Cesena Condirmation of STEMI diagnosis UMTS/GPRS Piemonte S.C. Servizio emergenza sanitaria territoriale 118 Provincia di Alessandria Region Since 2011 transmission of 12-lead ECG and clinical data from EMS ambulance to dispatch centre and from this to cathlab for primary PCI UMTS/GPRS Mobimed Ortivus Puglia La Telecardiologia per il 118 nella Regione Puglia Region Pre-hospital 12-lead electrocardiogram to a single telemedicine hub with dedicated cardiologists active 24/7 for pre-hospital diagnosis of cardiovascular emergency, STEMI and cathlab alert for primary PCI Telephone line CardioVox P12 UMTS/GPRS Sicilia Telecardio SEA Project City of Trapani, Egadi Island, Pantelleria Pre-hospital diagnosis of STEMI and arrhythmias Electrocardiograph, blood pressure, and saturation data transmission Toscana Telelettura ECG in emergenza territoriale da parte della centrale 118 District of Florence Pre-hospital ECG (nurses) transmitted and diagnosed by cardiologist in CCU Broadband

Sicilia Telecardio SEA Project City of Trapani, Egadi Island, Pantelleria Pre-hospital diagnosis of STEMI and arrhythmias Electrocardiograph, blood pressure, and saturation data transmission Toscana Telelettura ECG in emergenza territoriale da parte della centrale 118 District of Florence Pre-hospital ECG (nurses) transmitted and diagnosed by cardiologist in CCU Broadband Percorso diagnostico terapeutico dell’Infarto Miocardico Acuto City of Massa Carrara UMTS/GPRS STEMI: trattamento dolore toracico acuto non traumatico City of Lucca ECG transmission to EMS dispatch centre and CCU of Versilia Hospital Telephone line UMTS/GPRS 118 Cuore City of Empoli Telephone transmission to CCU of ECG UMTS/GPRS Progetto pilota di teleconsulto su mezzo mobile City of Prato TelediagnosisTeleconsultation Satellite Electrocadiograph and Videocamera Gestione telematica delle emergenze coronariche per l'attuazione preospedaliera della Trombolisi Sistemica PIstoia Pre-hospital ECG transmission to CCU and pre-hospital fibrinolysis. UMTS/GPRS Collegamento Auto Medica 118-Centrale Operativa Siena Teleconsultation between EMS dispatch centre and ambulances UMTS/GPRS broadband Defibrillator/monitor, multichannel router, PC. Bluetooth Rilevazione e refertazione di ECG nel Carcere di Sollicciano Prison of Sollicciano Remote electrocardiogram transmission and interpretation GSM electrocardiograph, blue tooth and laptop. Data are transmitted to Torregalli Hospital as PDF and after to a hub in Florence

Collegamento Auto Medica 118-Centrale Operativa Siena Teleconsultation between EMS dispatch centre and ambulances UMTS/GPRS broadband Defibrillator/monitor, multichannel router, PC. Bluetooth Rilevazione e refertazione di ECG nel Carcere di Sollicciano Prison of Sollicciano Remote electrocardiogram transmission and interpretation GSM electrocardiograph, blue tooth and laptop. Data are transmitted to Torregalli Hospital as PDF and after to a hub in Florence Umbria Trattamento Ottimale della Sindrome Coronarica Acuta (TOSCA) Part of Umbria Teleconsultation between EMS ambulances and CCU of Perugia UMTS/GPRS Valle d’Aosta Partout Sanita’ - E-refuge Region Video conference and data-transmission from Alpine shelters for teleconsultation (EMS, CCU) UMTS/GPRSBluetooth Partout sanita’—video/telepresenza Region Video conference for EMS UTMS/GPRS STEMI Region Network for online read of ECGs Defibrillator/monitor, electrocardiograph, blood oxygen PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; EMS, emergency medical service; CCU, cardiology care unit. The Piedmont regional model is the most complex: the electrocardiogram of a suspected STEMI is transmitted by the 118 ambulance crew to a dispatch centre, where, in case of suspected STEMI, it is forwarded to the closest CCU, which decides for cathlab activation.44

Valle d’Aosta Partout Sanita’ - E-refuge Region Video conference and data-transmission from Alpine shelters for teleconsultation (EMS, CCU) UMTS/GPRSBluetooth Partout sanita’—video/telepresenza Region Video conference for EMS UTMS/GPRS STEMI Region Network for online read of ECGs Defibrillator/monitor, electrocardiograph, blood oxygen PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; EMS, emergency medical service; CCU, cardiology care unit. The Piedmont regional model is the most complex: the electrocardiogram of a suspected STEMI is transmitted by the 118 ambulance crew to a dispatch centre, where, in case of suspected STEMI, it is forwarded to the closest CCU, which decides for cathlab activation.44 The Apulian regional telemedicine model instead provides 12-lead electrocardiogram transmitted by EMS ambulances to a telemedicine dispatch centre operated by experienced cardiologists in electrocardiography, which return the correct diagnosis, leaving the EMS responsible for direct transfer for pPCI. In local networks of territories covered by a single cathlab 24/7, as for example in the nearby of Massa Carrara, the model is much simpler and consists of the direct transmission of 12-lead electrocardiogram to the only CCU/cathlab hub covering the area that, after diagnosis, receives the patient with STEMI (Figure 1).

In local networks of territories covered by a single cathlab 24/7, as for example in the nearby of Massa Carrara, the model is much simpler and consists of the direct transmission of 12-lead electrocardiogram to the only CCU/cathlab hub covering the area that, after diagnosis, receives the patient with STEMI (Figure 1). Two surveys conducted respectively in 2006–2008 and 2012–2013, with the support of the Italian Interventional Cardiology Society GISE and Stent-for-Life initiative, took a snapshot of current management of STEMI in Italy45–47 (Figures 2 and 3). Figure 2 Pre-hospital 12-lead electrocardiogram 12 (IMAWeb 1 survey 2006–2009). Figure 3 Reperfusion strategies in Italy according to IMAWeb 1 2006–2009 (left) and 2012–2013 (right) survey. Professional profiles and organizational models Devices for electrocardiogram transmission In recent years, the concept of network as groups of professionals who work in a coordinated manner, to ensure equitable provision of effective, ‘high-quality’ services48 has been progressively implemented in health systems, becoming an organizational model able to provide effective solutions for the optimal management of the complex patient and to enhance the action of interdisciplinary professionals.49,50

ed manner, to ensure equitable provision of effective, ‘high-quality’ services48 has been progressively implemented in health systems, becoming an organizational model able to provide effective solutions for the optimal management of the complex patient and to enhance the action of interdisciplinary professionals.49,50 For these reasons, the network model, which integrates emergency EMS with hospitals with different levels of care, represents the standard of care even more for the treatment of acute time-dependent disease, by ensuring equal access to procedures and using diagnostic and therapeutic strategies shared and modulated on both the patient’s risk profile and on the structural and logistical resources available. This document therefore aims to describe a telemedicine-system-model that pursues and achieves the objectives of the network model, with the most advanced and innovative organizational models. In spite of a large implementation of networks for STEMI, there are still a number of problems that require improvement actions in terms of ‘maintenance’ of the network, standardization, and facilitation of clinical pathways. Despite the implementation of information systems with fast connectivity, there are still existing problems that mainly consist of: still suboptimal implementation of the fast track paths (EMS-cathlab); improvable timing between first medical contact and cathlab admission; delays in the time to balloon of patients with STEMI accessing the network through spoke centres.

This document therefore aims to describe a telemedicine-system-model that pursues and achieves the objectives of the network model, with the most advanced and innovative organizational models. In spite of a large implementation of networks for STEMI, there are still a number of problems that require improvement actions in terms of ‘maintenance’ of the network, standardization, and facilitation of clinical pathways. Despite the implementation of information systems with fast connectivity, there are still existing problems that mainly consist of: still suboptimal implementation of the fast track paths (EMS-cathlab); improvable timing between first medical contact and cathlab admission; delays in the time to balloon of patients with STEMI accessing the network through spoke centres. It should be considered that the network could and should be extended also to other time-dependent diseases such as NSTE–ACS, acute aortic syndromes, cardiac arrest and severe acute heart failure. New frontier of telemedicine applied to networks for cardiovascular emergencies also intends to pursue the following objectives: to identify and implement clinical and organizational requirements essential to guarantee the quality of care provided by the network, also with regards to accreditation; to define the parameters for the monitoring and the improvement of the network performance; to optimize the diagnostic and therapeutic pathways for the cardiovascular patient, encouraging the early diagnosis with the use of digital systems for remote transmission of electrocardiogram and tele-consultation with hub centres;

to define the parameters for the monitoring and the improvement of the network performance; to optimize the diagnostic and therapeutic pathways for the cardiovascular patient, encouraging the early diagnosis with the use of digital systems for remote transmission of electrocardiogram and tele-consultation with hub centres; to rationalize the use of resources by avoiding duplication of services and ensuring respect for the principles of inclusiveness and distinctive vocations of the hub centres; to encourage the development and maintenance of ‘clinical competence’ based on minimal activity requirements in terms of volume per operator and per hospital as defined by international benchmarks; to promote a network system of governance, which integrates each hospital involved in the network; to extend the network activities to other urgent cardiovascular diseases such as NSTE–ACS, acute aortic syndromes, cardiac arrest and acute heart failure. Organizational models State of the art and advanced application in telemedicine Acute myocardial infarction with ST-segment elevation Clinical, instrumental, and organizational recommendations direct transfer to the hub by direct EMS activation correct treatment even before hospital admission by remote transmission of pre-hospital 12-lead electrocardiogram, preferably with digital devices, to a dispatch centre where the electrocardiogram diagnosis can be confirmed by skilled operators (Tables 3 and 4). Table 3 Management, administration, and system service modules

ct treatment even before hospital admission by remote transmission of pre-hospital 12-lead electrocardiogram, preferably with digital devices, to a dispatch centre where the electrocardiogram diagnosis can be confirmed by skilled operators (Tables 3 and 4). Table 3 Management, administration, and system service modules Log and security Module including all the application security functions such as authentication and user profiling, and the users' tracing and access logs function Requirements Authorization system through user profiling and definition of distinct privileges for profile Configuration and encodings Module collecting all the management functions of the encoding tables and registers necessary for the application system Reporting Drawing, execution, and publication of the reports (both standard and custom) component used by the process modules of the application system Table 4 Process’ modules

guration and encodings Module collecting all the management functions of the encoding tables and registers necessary for the application system Reporting Drawing, execution, and publication of the reports (both standard and custom) component used by the process modules of the application system Table 4 Process’ modules Process manager (process workflow) It is the module of coordination and cooperation of the other modules, which implements the process workflow by addressing the reporting and patient transport requests according to dispatch centres’ resources. It also includes the applicative cooperation layer with external systems. Availability of an appropriate application designed to determine the most suitable dispatch centre Re-addressing function of reporting requests, with activation of the alert system, in the case of transmission of the application to the competent dispatch centre error Ability to interface with external systems via standard HL7 protocol Intervention management in emergency cardiology The module containing the functions dedicated to the health emergency personnel. It allows the collection of all data required for the subsequent assessment, including the instrumental data through two components of managing and interfacing electrocardiograph and defibrillator; it links data to the EMS ID code Requirements Ability to acquire ECG and EMS ID Code wirelessly transmitted by electrocardiographs/ defibrillators monitor Repository of data and reports Data and documents collected or produced during the process management module. It allows the storage, classification, research, and publication of data and documents, using competence and profiling criteria, previously configured, to regulate the access by users Requirements Storage capacity, and online management of at least 1 000 000 ECG in high definition on at least 12 leads ECG and report display and print function on the client systems of the dispatch centres Digital archiving of the report and ECG Ability to store more ECG (with related reports) relating to the same emergency event (the same EMS ID code) Ability to search in archives the ECG and the related reports according to the EMS ID code Reporting and analysis dashboard Framework in which functions and components dedicated to the analysis of clinical data and the production of the report digitally signed document are accessible. It manages the work lists of the dispatch centre and transmits the alarm signal.

related reports according to the EMS ID code Reporting and analysis dashboard Framework in which functions and components dedicated to the analysis of clinical data and the production of the report digitally signed document are accessible. It manages the work lists of the dispatch centre and transmits the alarm signal. It uses of components dedicated to ECG analysis, the signature, reporting Requirements Possibility of reporting from multiple stations simultaneously Ability to process adult ECG Ability to process paediatric ECG Availability of an alarm system alerting the dispatch centre responsible for the ECG deactivation of the alert system after request processing by the competent dispatch central; ability to generate the report with date and time of request receipt tracking Capacity of digital or electronic report signature Management of reports’ state: ‘Waiting for processing’; ‘in process’ or ‘processing completed’ Output data format DICOM, XML, PDF All modules must comply with the following requirements Requirements Web-based architecture: application access via the web, through the major market browsers Online download for accessory applications for the remote computer's configuration Clinical decision support system After acquisition and of medical history, patient’s vital and instrumental data, DSS suggests activities, therapeutic pathways and information in accordance with approved protocols and literature validated at international level, both for the operator of the emergency network and for the reporting cardiologist, early diagnosing cases of STEMI/NSTEMI. STEMI, ST-elevation myocardial infarction; NSTEMI, non-STEMI; DSS, decision support system; EMS, emergency medical service.

with approved protocols and literature validated at international level, both for the operator of the emergency network and for the reporting cardiologist, early diagnosing cases of STEMI/NSTEMI. STEMI, ST-elevation myocardial infarction; NSTEMI, non-STEMI; DSS, decision support system; EMS, emergency medical service. direct access to the cathlab possibly with fast-tracks by-passing emergency room or CCU; pre-hospital treatment, pharmacological and non-pharmacological, for EMS crews operating in remote areas far from the cathlab; correct and timely diagnosis of STEMI in emergency room by seriate 12-lead electrocardiogram monitoring and automatic electronic sharing of diagnosis and treatment with the CCU cardiologist; immediate transfer to cathlab for STEMI patients directly accessing the network through spoke emergency rooms; preferentially hospitalization in cardiology wards; inter-hospital transfers in the most homogeneous ways throughout any region network; appropriate drug prescription at discharge; follow-up after discharge.

correct and timely diagnosis of STEMI in emergency room by seriate 12-lead electrocardiogram monitoring and automatic electronic sharing of diagnosis and treatment with the CCU cardiologist; immediate transfer to cathlab for STEMI patients directly accessing the network through spoke emergency rooms; preferentially hospitalization in cardiology wards; inter-hospital transfers in the most homogeneous ways throughout any region network; appropriate drug prescription at discharge; follow-up after discharge. Electrocardiogram and pre-hospital diagnosis of acute myocardial infarction The EMS should be staffed with personnel able to perform a 12-lead electrocardiogram. The telematic destination of en-route electrocardiogram should be always known in advance, according to the different clinical and electrocardiogram settings (STEMI, NSTEMI, cardiac arrest, tachy-arrhythmias, brady-arrhythmias) and capabilities of network facilities (Cardiology wards, CCU, cathlab). The electrocardiogram tele-transmission and the availability of clinical data and medical history collected on site allow the cardiologist in the dispatch centre to confirm the diagnosis, in agreement with EMS ambulance staff.23,36,51–54 In case of uncertain diagnosis but with reasonable suspicion of STEMI or equivalent syndrome (typical pain without persistent ST-segment elevation or atypical pain and ST borderline anomalies), direct transfer for coronary angiography should be organized.

the diagnosis, in agreement with EMS ambulance staff.23,36,51–54 In case of uncertain diagnosis but with reasonable suspicion of STEMI or equivalent syndrome (typical pain without persistent ST-segment elevation or atypical pain and ST borderline anomalies), direct transfer for coronary angiography should be organized. Referral centres and direct referral paths Any network protocols must clearly identify the referral cathlab where EMS ambulance should transfer subjects with suspected ACS. The same protocol should be followed for patients with STEMI accessing the network through emergency rooms or spoke hospitals. Agreement protocols between EMS, spoke and hub hospitals must include times, means and staff required for each step in the management of the patient. A telemedicine system is capable of tracking each phase of the process. Emergency room Direct presentation to the nearest emergency department is another modality to access the STEMI network. In a telemedicine model-system EMS automatically provides for a rapid transfer to cathlab (Figure 4 and Table 5). Figure 4 Organizational telemedicine model for cardiovascular emergency. Table 5 Telecardiology and urgent care centres of the hub-and-spoke Telecardiology operating protocols and necessary skills for the network Fast-track protocols which provide a diagnostic ECG within 10 min after presentation of patients with suspected STEMI Avoid unnecessary additional diagnostic tests to not delay the reperfusion treatment Instant Activation STEMI patient transport to the cathlab with primary transport by EMS

Telecardiology operating protocols and necessary skills for the network Fast-track protocols which provide a diagnostic ECG within 10 min after presentation of patients with suspected STEMI Avoid unnecessary additional diagnostic tests to not delay the reperfusion treatment Instant Activation STEMI patient transport to the cathlab with primary transport by EMS STEMI, ST-elevation myocardial infarction; EMS, emergency medical service. Cathlab The cathlab (Table 6) represents a crucial point in the diagnostic evaluation and treatment because it is there that primary angioplasty is performed (Table 4). The hub cathlab must provide a 24/7 availability, have adequate instruments and staffing in accordance with the regional accreditation criteria and the recommendations of the national consensus documents,55 and access to telemedicine systems by accredited profile credentials. The cathlab team should be automatically alerted by the telemedicine system soon as the diagnosis of STEMI is made. Table 6 The telemedicine and the haemodynamic laboratories of hub centres Instrumentation, operating characteristics and skills required for the telemedicine network (credentials according to accreditated security protocols) 24/7 activity guaranteed by the availability of medical, nursing and technical staff Expertise of operators: at least 75 coronary angioplasties per year Habitual use of radial access.

Instrumentation, operating characteristics and skills required for the telemedicine network (credentials according to accreditated security protocols) 24/7 activity guaranteed by the availability of medical, nursing and technical staff Expertise of operators: at least 75 coronary angioplasties per year Habitual use of radial access. The parameters specified as a standard of activity are monitored through indicators derived from administrative or clinical databases. The analysis of such parameters could be further useful for regional health care planning as representative of the quality of care. Cardiology care units The CCU of the hub centres have to manage patients with STEMI after treatment with primary angioplasty, awaiting the activation of the cathlab, as well as those for which PCI reperfusion is not feasible (late arrival, patient refusal, contraindications to anticoagulant and antiplatelet therapy, lack of arterial access, etc.). Acute myocardial infarction without ST segment elevation, and unstable angina Clinical and organizational recommendations The telemedicine system-model should monitor and ensure preferentially, but by automatic protocol, hospitalization in a cardiology ward; provide the patient with ACS and moderate risk of ischaemic events performing a coronary angiogram within 72 h of presentation at the hospital; ensure the patient with ACS and high risk of ischaemic events performing a coronary angiogram within 24 h of presentation at the hospital; facilitate and promote transfers between hospitals;

provide the patient with ACS and moderate risk of ischaemic events performing a coronary angiogram within 72 h of presentation at the hospital; ensure the patient with ACS and high risk of ischaemic events performing a coronary angiogram within 24 h of presentation at the hospital; facilitate and promote transfers between hospitals; Indicators and measurable standard with an advanced telemedicine system The following list represents the set of indicators and reference standards that will serve as a reference for performance evaluations of health facilities and the planning of any audits and corrective actions. The telemedicine system model records and automatically analyses the indicators. STEMI Reperfused/STEMI patients Primary angioplasty/thrombolysis Primary angioplasty <120’ Primary angioplasty/patients in patients with cardiogenic shock Timing of diagnosis and treatment (early pain/ECG/reperfusion) Access by EMS/patients presenting to the emergency room False positives sent from EMS to cathlab False negatives sent from EMS in emergency department Inpatients (CCU/ICU/other) Length of stay In-hospital mortality Mortality at 30 days NSTEMI–ACS Number and standardized rate of hospitalization per 100 000 inhabitants Patients treated with angioplasty within 3 days out of the total of NSTE–ACS patients (>70%) Patients admitted to the spoke and never sent to hub (<25%) Patients admitted to spoke, re-sent to a spoke (post-acute) after passing through a hub (>95%) Patients admitted to the cardiology department (>90%) Length of stay in the CCU and full hospitalization (2 days and 7 days) Proper drafting of the discharge letter (>90%)

Patients treated with angioplasty within 3 days out of the total of NSTE–ACS patients (>70%) Patients admitted to the spoke and never sent to hub (<25%) Patients admitted to spoke, re-sent to a spoke (post-acute) after passing through a hub (>95%) Patients admitted to the cardiology department (>90%) Length of stay in the CCU and full hospitalization (2 days and 7 days) Proper drafting of the discharge letter (>90%) Clinical and prognostic assessment with indications for life-style changes Planned outpatient controls Drug therapy Drug prescription at discharge In-hospital mortality/cardiology ward (<8% and <4%, respectively) Mortality at 30 days Security management The security module typically contains a diffuse pattern identified by the triple A, which is the size AAA—authentication, authorization, and accounting. Signal transmission requirements All electrocardiograms should follow the guidelines for the electrocardiogram standardization56 and comply with bandwidth of at least 0.05 up to 150 Hz.

Security management The security module typically contains a diffuse pattern identified by the triple A, which is the size AAA—authentication, authorization, and accounting. Signal transmission requirements All electrocardiograms should follow the guidelines for the electrocardiogram standardization56 and comply with bandwidth of at least 0.05 up to 150 Hz. Training The telemedicine for cardiovascular emergency requires skills that are often not part of the know-how of the clinical cardiologist. Different training required for tele-diagnosis of electrocardiogram depends crucially on to who this task should pertain. 2010 ILCOR guidelines stated the possibility for lay people adequately trained to access electrocardiogram tele-recording systems.57 In this specific situation, in the presence of lay or non-medical individuals, the training must be focused on the execution of a maximally standardized recording, with positions of the peripheral and precordial electrodes on anatomical landmarks and simple devices. Many of the devices available also allow an automatic interpretation in line with the existing conventions with good specificity.58 It appears however inadvisable to encourage the use of the only automatic interpretation of the electrocardiogram, unless in the absolute impossibility of obtaining an expert-opinion, even at a distance.

ices available also allow an automatic interpretation in line with the existing conventions with good specificity.58 It appears however inadvisable to encourage the use of the only automatic interpretation of the electrocardiogram, unless in the absolute impossibility of obtaining an expert-opinion, even at a distance. Lay personnel training should comply to teaching methods issued by scientific societies (ILCOR, ANMCO, ESC, ERC, AHA), should include theoretical sessions, showing opportunities and criticalities (privacy and consent to the procedure), and at least a practical training session, supervised by expert trainers. Local protocols should be developed on specific territorial needs. The nursing staff should be trained, not indeed in electrocardiogram recording, which is part of the usual nurse skills, but in the management of patients in the absence of direct medical care. The nursing staff can be given simple and interpretive information, as widely standardized in ACLS training methodologies of the American Heart Association ALS or ERC. Effective models for distance education via e-learning allowing the goals required with a minimum occupation of time have been therefore developed, also to reduce cost of education.49

The nursing staff should be trained, not indeed in electrocardiogram recording, which is part of the usual nurse skills, but in the management of patients in the absence of direct medical care. The nursing staff can be given simple and interpretive information, as widely standardized in ACLS training methodologies of the American Heart Association ALS or ERC. Effective models for distance education via e-learning allowing the goals required with a minimum occupation of time have been therefore developed, also to reduce cost of education.49 Regulatory issues The regulatory assessment regarding telemedicine and emergency network needs to be addressed separately since the two aspects have a completely different regulatory framework. In fact, while for telemedicine there is a National legislation which regulates principal aspects, emergency networks are normed by national guidelines and several regional deliberations. The State-Regions agreement of 20 February 2014 regulates the matter and aims to harmonize purposes and applications of telemedicine models, as a prerequisite to interoperability of services. The memorandum of understanding enounces principles and requirements for accreditation and operability of telemedicine centres.42 The document refers to classical aspects of the patient’s informed consent and the processing of personal data. However, the use of telemedicine in cardiology is mainly focused on patients in imminent risk of death and, therefore, the obtaining of consent is a marginal issue. Much more important aspects, instead, from a regulatory perspective, are represented by the responsibility for diagnosis or therapeutic approach, the problems related to the malfunctioning of the computer system, the confidentiality of information.

of death and, therefore, the obtaining of consent is a marginal issue. Much more important aspects, instead, from a regulatory perspective, are represented by the responsibility for diagnosis or therapeutic approach, the problems related to the malfunctioning of the computer system, the confidentiality of information. Professional liability in telemedicine Telemedicine revolutionized the classic relationship between doctor and patient and introduced more actors and more places: from this point of view, then the professional responsibility does not fall only on the physician interpreting the remote electrocardiogram, but also on the operator recording the electrocardiogram. From this point of view, then the profiles of professional liability cover not only the inadequate professional training in the use of the devices but also the inadequate supervisory action on the presence of device and system malfunctions that are not reported. There are therefore two further types of negligent attitude: ‘Culpa in Vigilando’ that is the fault of those who omit a necessary control action, and ‘Culpa in Eligendo’, that is the fault of those who do not properly follow the operating procedures. Then there are the responsibilities attributed to the manufacturer of the health equipment used and the responsibilities attributed to those who are using the equipment with lack of maintenance or incorrect use thereof. In general, the physician who interprets the electrocardiogram or the images is responsible for the error related to the interpretation of the data, while the sender is responsible for an erroneous or misleading transmission. It’s important to note, however, that if the physician who interprets is aware of impaired quality of the data, he is also responsible for any mistake, regardless of the quality of the transmission. If the delay in the transmission of data, or alteration of the data transferred confer an injury to the patient, in the context of a network management, levels of responsibility should be determined. In this respect, it is necessary to identify a Director of telemedicine service, who is responsible both for the selection of medical staff and the control of its employees. Obviously, the Director can’t be informed of any act that is done by the team and therefore, as established by the Supreme Court, the Clerk’s responsibility is not unlimited. (Cassaz. Civ., 16 May 2000, n. 6318).

icine service, who is responsible both for the selection of medical staff and the control of its employees. Obviously, the Director can’t be informed of any act that is done by the team and therefore, as established by the Supreme Court, the Clerk’s responsibility is not unlimited. (Cassaz. Civ., 16 May 2000, n. 6318). Moreover, as telemedicine implies a relationship not only between patient and physician but also with another provider (doctor or nurse) who, from a distance, records an electrocardiogram, it is mandatory to refer to the principle of ‘reliance on’, whereby each operator is required to monitor the work of colleagues being remedied for errors, regardless of role. In the present case, therefore, during the transmission of an electrocardiogram, all actors involved are required to assess the possibility of error on the part of colleagues, regardless of the role they play. Procedures and guidelines Internal procedures are required to adapt international guidelines to local networks and technological resources. It’s important that internal procedures clearly identify proper individual roles (who should do it), the skills of each team member (who does what) and the correct mode of execution (how it should be done), in order to avoid gaps in protocol indications or conflicting activities. Internal protocols complying to international guidelines improve patient safety and also prevent unpleasant legal consequences.

ould do it), the skills of each team member (who does what) and the correct mode of execution (how it should be done), in order to avoid gaps in protocol indications or conflicting activities. Internal protocols complying to international guidelines improve patient safety and also prevent unpleasant legal consequences. Privacy in telemedicine The obligation to respect the privacy pertains to telemedicine in the same way as any other field in medicine, with some variants. The legislation refers to the 31 December 1996, n. 675 act (Protection of persons and other subjects regarding the processing of personal data) and subsequent amendments and additions and the Legislative Decree 30 June 2003, n. 196 (Code on the protection of personal data) articles 75–94 referring to ‘Privacy in healthcare’. In telemedicine, protection of data electronically managed and of databases containing personal health data should be carefully pursued (Table 7) Table 7 Regulatory aspects telemedicine Appropriate training (training and retraining) in the use of computer systems for all personnel involved Suitable organization through protocols and guidelines, with specific definition of levels of responsibility Periodic verification of the quality of the instrumentation Verification of quality of data transmitted and received Verification of the ‘skill’ of those who interpret the data received Cost/effectiveness analysis in the choice of activation procedures Assessment of the effectiveness of methods for the protection of personal and sensitive data, also because of possible studies and research

Verification of quality of data transmitted and received Verification of the ‘skill’ of those who interpret the data received Cost/effectiveness analysis in the choice of activation procedures Assessment of the effectiveness of methods for the protection of personal and sensitive data, also because of possible studies and research National law for emergency networks and regional statements In the field of networks for emergency, the latest regulations issued by the Ministry of Health is represented by the 2 April 2015 Decree No. 70 entitled ‘Regulation defining the quality, structural technological and quantitative standards for hospital care’ published in the Official Gazette of 24 September 2015. The regulation in Section 8 defines the characteristics of the ‘Network for Emergency Cardiovascular Care’ indicating the network and the current standard of care for STEMI. The document also provides explicitly the possibility of support by telemedicine for STEMI networks. Besides national statements, regions, with diverse levels of complexity and state of progress, have produced regional resolutions that regulate in detail the formation, characteristics and areas of responsibility of networks for emergency in cardiology. Model frequently used in emergency telecardiology service with the required functionality in a modern information system for the management of a telecardiology service (Figure 4).

Besides national statements, regions, with diverse levels of complexity and state of progress, have produced regional resolutions that regulate in detail the formation, characteristics and areas of responsibility of networks for emergency in cardiology. Model frequently used in emergency telecardiology service with the required functionality in a modern information system for the management of a telecardiology service (Figure 4). The staff of the Network acquires the personal and clinical data of the patient and manages medical devices (portable electrocardiograph/defibrillator) in order to allow cardiologists in the telemedicine central interpretation of electrocardiogram and diagnose. EMS dispatch centre directs the staff. A single regional central for EMS and telecardiology service providing the application of services to all actors and mediate communications between them. The identification of cases handled is generally based on the unique code assigned by the EMS. Inside the telecardiology service, appears important in perspective the innovative function of a clinical decision support system (CDSS) both in phase of emergency intervention and in the evaluation phase. The CDSS, through instruments of guidance and management of the workflow, might help the Territorial Network staff to reduce errors and to codify the outcome of an event as quickly as possible.

ive function of a clinical decision support system (CDSS) both in phase of emergency intervention and in the evaluation phase. The CDSS, through instruments of guidance and management of the workflow, might help the Territorial Network staff to reduce errors and to codify the outcome of an event as quickly as possible. Consensus Document Approval Faculty Abrignani Maurizio Giuseppe, Alunni Gianfranco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Cacciavillani Luisa, Calculli Giacinto, Capecchi Alessandro, Caporale Roberto, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Casolo Giancarlo, Cassin Matteo, Casu Gavino, Cemin Roberto, Chiarandà Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Clerico Aldo, Colivicchi Furio, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Di Lenarda Andrea, Di Tano Giuseppe, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Ferraiuolo Giuseppe, Francese Giuseppina Maura, Geraci Giovanna, Giardina Achille, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Ledda Antonietta, Lucà Fabiana, Lukic Vjerica, Macera Francesca, Marini Marco, Maseri Attilio, Masson Serge, Maurea Nicola, Mennuni Mauro, Menozzi Alberto, Mininni Nicola, Moreo Antonella, Moretti Luciano, Mortara Andrea, Mureddu Gian Francesco, Murrone Adriano, Musumeci Giuseppe, Nardi Federico, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Pulignano Giovanni, Radini Donatella, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scherillo Marino, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

natella, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scherillo Marino, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino. Conflict of interest: none declared.

Revised by: Pasquale Caldarola, Maria Frigerio, Domenico Gabrielli, Fabrizio Oliva, Vittorio Palmieri, Giovanni Pulignano, Stefano Urbinati Consensus Document Approval Faculty in Appendix Table of contents Introduction Background The network for integrated heart failure care Function of the network Construction of the network Network architecture Patient’s pathway within the network Organization of the services Communication systems Professional skills and training Network management The heart failure management protocol Heart failure outpatient clinics Conclusions References Introduction Efficiency and sustainability of health-care systems are based on the ability of professionals to tailor patient care in the context of scientific evidence, making a rational and appropriate use of resources. The epidemiological scenario of Western countries, marked by ageing of the population and rising multimorbidity and chronicity, mandates a shift from the ‘acute care model’ to the ‘chronic care model’ where patients suffering from chronic diseases are effectively managed outside the hospital with the goal of improving their quality of life and ensure their empowerment through education and knowledge of the disease.

ultimorbidity and chronicity, mandates a shift from the ‘acute care model’ to the ‘chronic care model’ where patients suffering from chronic diseases are effectively managed outside the hospital with the goal of improving their quality of life and ensure their empowerment through education and knowledge of the disease. The purpose of this document is to outline the characteristics of a national care network for heart failure (HF) patients. The document describes requirements and responsibilities of the different points of contact with the patient, and procedures for recording and sharing processes of diagnosis, treatment and care. Contents are intended to harmonize with the novel hospital standards set by DM 70 02/04/2015 and the National Plan for Chronicity in the Healthcare Agreement 2014-2015. This document originates from hospital cardiology, the largest share in this medical branch, in order to improve the standards for specialist care, but turns back to it with the understanding that HF management goes beyond the hospital setting. The document acknowledges the need to integrate cardiology in multidisciplinary cooperation with the scientific societies of all other professionals active in the care of HF patients, in the community, in hospitals and in specialist training.

t with the understanding that HF management goes beyond the hospital setting. The document acknowledges the need to integrate cardiology in multidisciplinary cooperation with the scientific societies of all other professionals active in the care of HF patients, in the community, in hospitals and in specialist training. The creation of regional networks based on a nationally shared address is proposed here as the main road to integrate cardiology specialist approach to multidisciplinary and multi-professional settings in order to take care of HF patients at different stages of the disease in an appropriate and cost-effective manner. A health services ‘Network’ is the integration of diagnostic, therapeutic and care activities provided by different professionals and different organizations, in the hospital and in the community, that cooperate to achieve a shared mission. As other forms of health services network, the HF Network is characterized by the presence of elements (‘nodes’), with reciprocal uni-or bi-directional connections, that are governed according to clear predefined rules and agreements and share common objectives. The objectives of the HF network are the improvement of patients’ quality of life, the decrease of hospital admissions and the containment of health-care costs. Therefore, this document is open to dialogue with government bodies and health services administrations, as well as with organizations and health professionals, and patients, public opinion, and society in the broadest sense.

quality of life, the decrease of hospital admissions and the containment of health-care costs. Therefore, this document is open to dialogue with government bodies and health services administrations, as well as with organizations and health professionals, and patients, public opinion, and society in the broadest sense. Background Chronic HF (CHF) is a leading cause of mortality, morbidity, and resource consumption in Western countries.1–4 The natural history of CHF is characterized by clinical exacerbations interspersed with periods of clinical stability, leading to progressive deterioration of functional capacity and quality of life. The role of cardiologist for high-quality care of CHF patients has been well documented in the literature: specialist input is associated with improved survival and reduced readmissions rates, in particular when shared multidisciplinary care pathways are activated.5–8 Dedicated HF clinics may allow prompt intervention through earlier detection of impending destabilization to reinstate euvolaemia and thus reduce the readmission rate. Disease management programmes of the late 90s focused on hospital-based multidisciplinary HF outpatient clinics (HFOCs), staffed by cardiologists and dedicated nurses. However, the diverse structure of European and North American health-care systems, differences in enrolled populations, program components, and professional competences, the inadequate definition of the comparative standard of care and the negative results of many recent trials have cast doubt on program effectiveness and their potential additional costs.9

pean and North American health-care systems, differences in enrolled populations, program components, and professional competences, the inadequate definition of the comparative standard of care and the negative results of many recent trials have cast doubt on program effectiveness and their potential additional costs.9 Although during the last decade standards for HFOCs have been defined and the need for careful evaluation of the quality of care they offer has been stressed,10–12 few studies have assessed the services offered and the characteristics of patients attending these clinics.13 Overall, patients followed-up at HF outpatients clinics seems to be ‘cream-skimmed’ with respect to the typical patient discharged after an acute HF episode: they are younger age, less often female, with fewer comorbidities; many are stable and paucisymptomatic and could be trusted to primary care physicians. The wide variability among clinics as concerns the proportion of new patients recruited, the frequency of follow-up visits, diagnostic test orders, and availability of telemonitoring tools, appears vastly unrelated to clinical characteristics. Hence homogeneous and standardized care pathways are sorely needed, as well as greater population turn-over, in order to take care of new patients and/or of those who can most benefit from specialist care.

ostic test orders, and availability of telemonitoring tools, appears vastly unrelated to clinical characteristics. Hence homogeneous and standardized care pathways are sorely needed, as well as greater population turn-over, in order to take care of new patients and/or of those who can most benefit from specialist care. During the last two decades, the Italian Association of Hospital Cardiologists (ANMCO) has pioneered the growth and integration into a pragmatic research network of HFOCs, through observational studies and standardized data collection using a common software in a database where over 22 000 patients had been recruited up to 2015. The subgroup enrolled in the IN-HF outcome registry branch is representative of the most recent Italian cardiology practice,14 and underscores how CHF patients are highly selected with respect to contemporary acute HF patients admitted to Cardiology or Medicine wards14,15 (Table1). Table 1 Characteristics of patients with acute HF hospitalized in cardiology or medicine wards and CHF patients followed-up in outpatient clinics

iology practice,14 and underscores how CHF patients are highly selected with respect to contemporary acute HF patients admitted to Cardiology or Medicine wards14,15 (Table1). Table 1 Characteristics of patients with acute HF hospitalized in cardiology or medicine wards and CHF patients followed-up in outpatient clinics Acute HF Chronic HF INHF outcome (n = 1855) CONFINEa (n = 1411) INHF outcome (n = 3755) Age years 72 ± 12 79 ± 10 69 ± 12 Proportion female 40% 52% 24% Body mass index 28 ± 5 27 ± 5 27 ± 4 Obesity (BMI > 30 kg/m2) 29% 22% 22% Hypertension 58% 63% 43% Chronic kidney dysfunction 32% 44% 21% COPD 30% 27% 21% Diabetes 40% 32% 30% Anaemia 39% 40% 20I Ischaemic aetiology 42% 44% 46% Atrial fibrillation 8% 43% 30% LV ejection fraction% 38 ± 14 43 ± 12 38 ± 11 Pressione sistolica mmHg 134 ± 33 141 ± 27 126 ± 19 Sodium < 136 mEq/l 19% 28% 9% Creatinine mg/dl 1.2 [1.0–1.6] 1.5 ± 0.9 1.2 [1.0–1.5] In-hospital mortality 6.4% 4.4% 5.9%b Length of stay 12 ± 10 14 ± 10 — Beta blockers 65%b 31%b 79% ACE inhibitors/ARB 78%b 79%b 90% Aldosterone antagonists 59%b 32%b 38% ACE, angiotensin converting enzyme; ADHF, acute decompensated heart failure; ARB, angiotensin receptor blockers; BMI, body mass index; COPD, chronic obstructive pulmonary disease; HF, heart failure; INHF, Italian Network on Heart Failure; LV, left ventricular. aMedicine wards. bOne-year post-discharge.

Acute HF Chronic HF INHF outcome (n = 1855) CONFINEa (n = 1411) INHF outcome (n = 3755) Age years 72 ± 12 79 ± 10 69 ± 12 Proportion female 40% 52% 24% Body mass index 28 ± 5 27 ± 5 27 ± 4 Obesity (BMI > 30 kg/m2) 29% 22% 22% Hypertension 58% 63% 43% Chronic kidney dysfunction 32% 44% 21% COPD 30% 27% 21% Diabetes 40% 32% 30% Anaemia 39% 40% 20I Ischaemic aetiology 42% 44% 46% Atrial fibrillation 8% 43% 30% LV ejection fraction% 38 ± 14 43 ± 12 38 ± 11 Pressione sistolica mmHg 134 ± 33 141 ± 27 126 ± 19 Sodium < 136 mEq/l 19% 28% 9% Creatinine mg/dl 1.2 [1.0–1.6] 1.5 ± 0.9 1.2 [1.0–1.5] In-hospital mortality 6.4% 4.4% 5.9%b Length of stay 12 ± 10 14 ± 10 — Beta blockers 65%b 31%b 79% ACE inhibitors/ARB 78%b 79%b 90% Aldosterone antagonists 59%b 32%b 38% ACE, angiotensin converting enzyme; ADHF, acute decompensated heart failure; ARB, angiotensin receptor blockers; BMI, body mass index; COPD, chronic obstructive pulmonary disease; HF, heart failure; INHF, Italian Network on Heart Failure; LV, left ventricular. aMedicine wards. bOne-year post-discharge. The mismatch between real-world epidemiology and the current role of HF outpatient clinic management fuels the controversy around the effectiveness of HFOCs in targeting heath care needs and their added value in care networks.16,17 The open challenge is the field validation of tailored, cost-effective models, that should spread from community care across to intensive tertiary care referral programs, with variable options for telemonitoring, teleconsulting, and patient education. HFOCs should strive for more efficient care pathways by maintaining an appropriate mix between entry of new patients to be assessed or re-evaluated at critical epochs of their disease history, and personalized follow-up controls for patients with advanced unstable disease. We need an efficient organization of care in a HF network to serve with specialist input a wide population of patients, while interfacing cardiologists in a systematic and flexible style with different health-care professionals. In this way, we will be able to adapt care pathways to emerging epidemiological needs and pursue quality of care and appropriate allocation of finite resources.

th specialist input a wide population of patients, while interfacing cardiologists in a systematic and flexible style with different health-care professionals. In this way, we will be able to adapt care pathways to emerging epidemiological needs and pursue quality of care and appropriate allocation of finite resources. The network for integrated heart failure care Functions of the network The network of heart failure centres fulfils the following functions To ensure a clinical care pathway aimed to achieve continuity of care, timeliness of response and flexibility in identifying the appropriate care setting. To integrate in-hospital and outpatient cardiologist care with the activities of general practitioners, of other specialists and health and social workers, according to shared pathways with predefined roles and responsibilities of the different actors. Care pathways should identify the most appropriate care in relation to the stage of disease, the severity and the absolute and relative weight of the disease in determining life expectancy and quality of life. To define and apply tools useful to evaluate and improve the quality of care, by assessing indicators of outcome, process and response to patients’ preferences and needs. To promote continuous training of all professionals involved in the network. Construction of the network

To integrate in-hospital and outpatient cardiologist care with the activities of general practitioners, of other specialists and health and social workers, according to shared pathways with predefined roles and responsibilities of the different actors. Care pathways should identify the most appropriate care in relation to the stage of disease, the severity and the absolute and relative weight of the disease in determining life expectancy and quality of life. To define and apply tools useful to evaluate and improve the quality of care, by assessing indicators of outcome, process and response to patients’ preferences and needs. To promote continuous training of all professionals involved in the network. Construction of the network Recommendation 1—Define the essential nodes of the network, which should be made available to every patient, in relation to his/her individual characteristics and needs. The nodes are represented by (i) primary care; (ii) out-of-hospital cardiology centres for the care of chronic diseases and HF; (iii) hospital cardiology centres; and (iv) medical-surgical centre with Heart Transplantation and/or Mechanical Circulatory Support Programs. Recommendation 2—Define catchment areas according to geographical location, population characteristics, availability and quantity of resources that may influence the organization of the offer.

Recommendation 1—Define the essential nodes of the network, which should be made available to every patient, in relation to his/her individual characteristics and needs. The nodes are represented by (i) primary care; (ii) out-of-hospital cardiology centres for the care of chronic diseases and HF; (iii) hospital cardiology centres; and (iv) medical-surgical centre with Heart Transplantation and/or Mechanical Circulatory Support Programs. Recommendation 2—Define catchment areas according to geographical location, population characteristics, availability and quantity of resources that may influence the organization of the offer. Recommendation 3—Analyse, within each area, the characteristics of services in terms of specialist care provided in and out of the hospital, as well as the organization of primary care. This analysis should define the mode of interaction between general practitioners and the ‘proximity cardiology’, i.e. the cardiology unit with direct access from the community when appropriate. Recommendation 4—Identify, within each area, one or more hospitals with ultra-specialistic skills and resources, in order to deal with the diagnostic process and care of complex cases and patients with advanced HF. This ‘reference Cardiology’ should represent the interface for centres with a heart replacement program. Recommendation 5—Identify on a national level, the medical-surgical centres with heart replacement programs. For their limited number, the referral area of centres with heart replacement program will necessarily have expanded borders overcrossing areas.

Recommendation 4—Identify, within each area, one or more hospitals with ultra-specialistic skills and resources, in order to deal with the diagnostic process and care of complex cases and patients with advanced HF. This ‘reference Cardiology’ should represent the interface for centres with a heart replacement program. Recommendation 5—Identify on a national level, the medical-surgical centres with heart replacement programs. For their limited number, the referral area of centres with heart replacement program will necessarily have expanded borders overcrossing areas. Recommendation 6—Identify and involve centres for rehabilitative care, residential or home palliative care, psychiatric and social services, long-term care as well as other medical specialties. Recommendation 7—The organizational structure and methods of formal government of the HF network must be defined by all the actors/managers of clinical pathways. Regulatory and control functions pertain to the regional health authorities and strategic directions of health-care providers.

Recommendation 6—Identify and involve centres for rehabilitative care, residential or home palliative care, psychiatric and social services, long-term care as well as other medical specialties. Recommendation 7—The organizational structure and methods of formal government of the HF network must be defined by all the actors/managers of clinical pathways. Regulatory and control functions pertain to the regional health authorities and strategic directions of health-care providers. Network architecture In the HF network, the ‘proximity’(secondary referral centres/district hospital) and ‘reference’ (tertiary referral) centres, as well as the heart replacement program, represent the range of HF specialist cardiology care. The connections between the various nodes over different levels of complexity are necessarily bidirectional hence the HF network architecture is polycentric. Of note, the HF network is intrinsically more complex than the network for acute coronary syndromes, since it has to take care of both acute and chronic phases, throughout the entire spectrum of the clinical history from the diagnosis to the terminal stages of the disease. Furthermore, the HF network must deal with diverse clinical profiles, from the young patient, in whom heart disease is the main prognostic determinant, to the frail elderly with multiple chronic comorbidities, in whom HF may not represent the strongest predictor of mortality and poor-quality of life.

es of the disease. Furthermore, the HF network must deal with diverse clinical profiles, from the young patient, in whom heart disease is the main prognostic determinant, to the frail elderly with multiple chronic comorbidities, in whom HF may not represent the strongest predictor of mortality and poor-quality of life. Within the network, the distribution and type of HF centres will vary according to regional characteristics and geographical distribution of health-care facilities. Care pathways will be identified for inpatients and outpatients depending on such distribution. Patients’ journey within the network The stages of a patient's journey in the HF network can be summarized as follows Entry into the path. This step corresponds to the first diagnosis of HF. Diagnostic classification and initial therapy setup are crucial for the eventual clinical course. In accordance with the recommendations outlined in European and North American Guidelines, a cardiologist should assess all patients with suspected or new diagnosis of HF, even if they are admitted to non-cardiology units or managed in primary care.

nd initial therapy setup are crucial for the eventual clinical course. In accordance with the recommendations outlined in European and North American Guidelines, a cardiologist should assess all patients with suspected or new diagnosis of HF, even if they are admitted to non-cardiology units or managed in primary care. Follow-up setting. Once diagnostic procedures have been completed, the appropriate therapy has been started and educational interventions aimed at patient empowerment delivered, an outpatient follow-up plan must be drafted. Follow-up should be conducted, in most cases, in synergy with community care and general practitioners. Shared clinical documentation is essential for optimizing this synergy. Finally, according to the individual diagnostic-therapeutic plan, the patient’s guideline-based personalized pathway is drawn up, shared and approved by the different actors of the network. This plan defines timing of scheduled visits as well as the reasons and modalities for unscheduled ones.

optimizing this synergy. Finally, according to the individual diagnostic-therapeutic plan, the patient’s guideline-based personalized pathway is drawn up, shared and approved by the different actors of the network. This plan defines timing of scheduled visits as well as the reasons and modalities for unscheduled ones. Switching between HF centres. Within the network, the patient will be entrusted to different types of HF centres or to primary care practitioners, in relation to improvement/stability achieved or to clinical worsening or for supervening frailty. In order to facilitate a coordinated and unified management, a single HF centre, in synergy with the general practitioner, should take care of the patient. Within the HF network, community care will be promoted as much as possible, with the support of hospital cardiology. Innovative ways of cooperating could include teleconsulting or onsite cardiology consultations at primary care group practices, besides direct contact with the patient and his/her general practitioner through telemedicine or remote monitoring services. Stable collaborations among HF centres of different types or with different range of skills are also encouraged in relation to specific issues such as: (i) arrhythmias and implantation and/or monitoring of electrical devices; (ii) haemodynamic and interventional procedures, (iii) HF surgery, (iv) renal replacement therapy, and (v) mechanical circulation support. Referral indications based on patients’ profiles and centre facilities are described in Figure1.

Switching between HF centres. Within the network, the patient will be entrusted to different types of HF centres or to primary care practitioners, in relation to improvement/stability achieved or to clinical worsening or for supervening frailty. In order to facilitate a coordinated and unified management, a single HF centre, in synergy with the general practitioner, should take care of the patient. Within the HF network, community care will be promoted as much as possible, with the support of hospital cardiology. Innovative ways of cooperating could include teleconsulting or onsite cardiology consultations at primary care group practices, besides direct contact with the patient and his/her general practitioner through telemedicine or remote monitoring services. Stable collaborations among HF centres of different types or with different range of skills are also encouraged in relation to specific issues such as: (i) arrhythmias and implantation and/or monitoring of electrical devices; (ii) haemodynamic and interventional procedures, (iii) HF surgery, (iv) renal replacement therapy, and (v) mechanical circulation support. Referral indications based on patients’ profiles and centre facilities are described in Figure1. Figure 1 Care referral pathways within the HF network based on patients’ clinical profiles. Stable patients at low-to-moderate risk of cardiovascular events, as well as frail elderly subjects with multiple comorbidities, should be managed in the community (green circle), with a focus on clinical monitoring and patient education. Patients with acute exacerbations or de novo gradual—onset symptoms should be referred to the geographically nearest (proximity) cardiology using shared protocols based on validated biomarkers. Proximity cardiology units (yellow circles) should admit to hospital patients with acute HF syndromes or outpatients from the community to perform appropriate diagnostic tests, to start or optimize drug therapy and to draft a tailored follow-up plan. Proximity cardiology units should share with network hubs the follow-up care of patients with advanced HF who are candidates to or have received heart transplantation or mechanical circulatory support. Network hubs, based on geographic location, are tertiary referral cardiology units (red circles) that should offer advanced treatment options to unstable patients at high risk of events. All network nodes should entertain close relationships with palliative network nodes for shared care of end-stage HF patients. CRT, cardiac resynchronization therapy; HF, heart failure; HTx, heart transplantation; ICD, implantable cardioverter defibrillator; LVAD, left ventricular assist device; Tx, transplantation.

s. All network nodes should entertain close relationships with palliative network nodes for shared care of end-stage HF patients. CRT, cardiac resynchronization therapy; HF, heart failure; HTx, heart transplantation; ICD, implantable cardioverter defibrillator; LVAD, left ventricular assist device; Tx, transplantation. Organisation of services Communication systems Communication is a crucial element in the network. Effective communication strategies foresee: online registration of ongoing activities, planned and carried out on the patient, in an electronic medical record which should be accessible by all operators involved, according to predefined arrangements to ensure security and privacy; exchange of clinical data and care protocols; and identification of a mandatory minimum data set, which allows to share information necessary for patient management, according to the postulate: ‘a shared patient, a single shared registration system’. The main objectives, therefore, should be to ensure that all technological supports (toll-free numbers, e-mail, access to databases, access to records, the medical records, the medical reports, the discharge letters, etc.) useful to favour communication between health professionals are made available; coordinate the use of patient data in aggregate form to evaluate and improve the quality and performance of care, as well as for research purposes, at least on the regional level; and

The main objectives, therefore, should be to ensure that all technological supports (toll-free numbers, e-mail, access to databases, access to records, the medical records, the medical reports, the discharge letters, etc.) useful to favour communication between health professionals are made available; coordinate the use of patient data in aggregate form to evaluate and improve the quality and performance of care, as well as for research purposes, at least on the regional level; and make telematic services accessible to all stakeholders who may become involved, even if only occasionally or for a limited period, in the management of patients with HF, including hospital, emergency services, primary care offices, district, home care services, hospices. Professional skills and training It is the responsibility of the authority for health services organization to ensure that the HF network makes use of competent and trained staff. If there are no such professionals in the area, appropriate plans for staff training should be implemented before starting HF centre activity. Moreover, continuous education processes should be in place to ensure up-to-date competence. Essential skills of the HF network staff include the ability to relation themselves with patients and care-givers, to work in teams, to recognize diagnostic markers of suspect HF, the indicators of clinical worsening and warning signs. If these skills are not present the staff should be adequately trained.

Professional skills and training It is the responsibility of the authority for health services organization to ensure that the HF network makes use of competent and trained staff. If there are no such professionals in the area, appropriate plans for staff training should be implemented before starting HF centre activity. Moreover, continuous education processes should be in place to ensure up-to-date competence. Essential skills of the HF network staff include the ability to relation themselves with patients and care-givers, to work in teams, to recognize diagnostic markers of suspect HF, the indicators of clinical worsening and warning signs. If these skills are not present the staff should be adequately trained. Network management The management rules of the HF network should be concerted by chiefs of the HF centres, with the coordination of regional health service authorities, and the involvement of all stakeholders. The tasks of HF network governance will be to promote the definition and implementation of diagnostic and therapeutic plans;

ment The management rules of the HF network should be concerted by chiefs of the HF centres, with the coordination of regional health service authorities, and the involvement of all stakeholders. The tasks of HF network governance will be to promote the definition and implementation of diagnostic and therapeutic plans; plan and carry out the reorganization of the functions of hospital and community care in the HF network, and their coordination using minimum structural criteria for dedicated staff, structure type, and control of staff competence. Tasks, responsibilities, resources, methods of communication and patient file sharing should be defined, as well as patient referral criteria across nodes. Furthermore, methods of data collection and analysis to evaluate performance, and commissioning for provision of information flows for clinical audit should be identified; define indicators of structure, process and outcome, perceived quality of care and resource use, and activate monitoring by means of clinical audits; monitor systematically all components of the network and of the care pathway, with particular attention to the critical issues that may arise in the implementation phase; and promote training, cultural development, shared objectives, and communication among all professionals involved, with mutual support and consultation, exchange of diagnostic and therapeutic protocols, interactive discussion of clinical problems, shared management of complex cases, training events, production of teaching and educational material.

l development, shared objectives, and communication among all professionals involved, with mutual support and consultation, exchange of diagnostic and therapeutic protocols, interactive discussion of clinical problems, shared management of complex cases, training events, production of teaching and educational material. The heart failure management protocol Regional health service authorities in cooperation with representatives of HF Centres and of the other organizations involved in the network, should prepare a protocol for diagnosis, treatment, rehabilitation, the main operational tool of networking which details the most appropriate steps in the delivery of care to HF patients Although they may differ locally in content and degree of detail, these protocols should generally contain the following points, in accordance with guidelines recommendations: Process for HF diagnosis and aetiological research. Treatment planning and optimization. Identification of precipitating factors for acute exacerbations and/or HF progression. Evaluation of risk factors and comorbidities. Risk stratification. The use of risk scores designed to assess the severity of the disease and to estimate the probability of adverse events during follow-up is recommended to enable more intensive care for high-risk patients. Since there is no single perfect model, the score validated in populations most similar to each patient's individual characteristics should be chosen.

ssess the severity of the disease and to estimate the probability of adverse events during follow-up is recommended to enable more intensive care for high-risk patients. Since there is no single perfect model, the score validated in populations most similar to each patient's individual characteristics should be chosen. Indications for hospital admission. Clear criteria for hospital admission and in-hospital pathways with regard to the destination ward are essential to optimize care processes and set out diagnostic procedures appropriate to each patient’s clinical profile, in particular for the frail disabled elderly. The following points should be defined: In-hospital treatment according to the clinical profile and therapeutic perspectives. Follow-up and transitional post-discharge home care. Criteria for discharge and contents of the discharge summary. Contents of the outpatient clinical report. Criteria for cardiac rehabilitation. Criteria for the activation of home care. Criteria for the activation of palliative care. Criteria for interventional/surgical therapies. Indication, conduction and reporting of the most common diagnostic tests. Contents of the educational program. Indications for counselling. Criteria for the intervention of social services. Use of telemedicine and/or remote monitoring tools.

Criteria for the activation of palliative care. Criteria for interventional/surgical therapies. Indication, conduction and reporting of the most common diagnostic tests. Contents of the educational program. Indications for counselling. Criteria for the intervention of social services. Use of telemedicine and/or remote monitoring tools. The heart failure outpatient clinic In order to harmonize patients’ pathways within the HF network and ensure transparent provision of care services, it is essential to define the tasks of health-care professionals working in outpatient HF clinics (Table2), the standards for medical record documentation, performance measures for organization structure, process of care and outcomes, and clinical competence of staff (Table3). An overview of the desirable characteristics of HFOCs in the network is presented in Table4. Table 2 Recommended activities of HF outpatient clinics Activity domains Key procedures Functional evaluation Assess NYHA class at each visit Perform 6-min walking test at baseline and according to clinical course Perform cardiopulmonary test in advanced HF patients and heart transplant candidates Quality of life Assess using validated questionnaires eneric (e.g. SF36, euroQOL). pecific (e.g. Minnesota Living with Heart Failure, Kansas City Cardiomyopathy) Revision and optimization of medical therapy Prepare a standardized scheme of instructions for all prescribed drugs (indications, common side effects, drug interactions) Register in the clinical record any therapeutic changes and confirm the patient has been properly instructed

pecific (e.g. Minnesota Living with Heart Failure, Kansas City Cardiomyopathy) Revision and optimization of medical therapy Prepare a standardized scheme of instructions for all prescribed drugs (indications, common side effects, drug interactions) Register in the clinical record any therapeutic changes and confirm the patient has been properly instructed Check all medicines taken by the patient, including OTC drugs and supplements Check drug intolerances/allergies in order to reassess any stopped or uninitiated treatment Verify adherence to prescribed treatment and investigate causes of poor compliance Establish a procedure to systematically identify eligible patients who do not receive appropriate medications. Revision and optimization of therapy with devices Establish a procedure to adequately identify patients eligible for device therapy (exclusion of reversible causes of heart failure, appropriate drug titration, careful evaluation of estimated life expectancy) Communication with electrophysiologists for conflicting indications Training in device management in order to detect device malfunction or need for reprogramming; Documentation in the medical record of any variation in device parameters Discussion with the patients of the benefit/risk of electrical therapies Nutritional evaluation Restriction of sodium and fluid intake to decrease fluid retention and minimize diuretic dose Cooperation with a dietician Sequential recording of weight and body mass index Personalized dietary guidelines according to co-morbidity (e.g. diabetes, obesity, dyslipidaemia, renal failure)

Discussion with the patients of the benefit/risk of electrical therapies Nutritional evaluation Restriction of sodium and fluid intake to decrease fluid retention and minimize diuretic dose Cooperation with a dietician Sequential recording of weight and body mass index Personalized dietary guidelines according to co-morbidity (e.g. diabetes, obesity, dyslipidaemia, renal failure) Prevention of cardiac cachexia caused by reduced synthesis and/or absorption of nutrients for liver and intestinal congestion Follow-up schedule Guarantee scheduled or urgent visits Assure early follow-up after discharge from an ADHF admission. Contact high-risk patients within 72 h after discharge from an ADHF admission. Schedule follow-up visits according to needs Plan close follow-up, till proper education of the patient and family and clinical stability have been achieved Schedule monitoring of biochemical or instrumental parameters according to therapy and clinical course Communication Set up an open and sensitive communication system to allow patients to express their needs and desires Explain potential complications related to the course of the disease and the available treatment options. Investigate potential defects in patient understanding of their clinical status Take into account the discrepancies between individual life expectancy and the estimates of validated scores Advance directives Investigate the perceptions of patients and family members about disease progression and the choices to be made in the most advanced stages

Investigate potential defects in patient understanding of their clinical status Take into account the discrepancies between individual life expectancy and the estimates of validated scores Advance directives Investigate the perceptions of patients and family members about disease progression and the choices to be made in the most advanced stages Indicate in the clinical record patient’s wishes with respect to cardiopulmonary resuscitation, the possible deactivation of the defibrillator, invasive or surgical procedures, hospitalization Record options in the plan of care and advance directives Continuous staff training Specific training for nurses (elements of pathophysiology, pharmacology, self-management approach to care, psychosocial issues, quality of life, and palliative care) Specific training for outpatient clinics taking care patients with advanced HF and candidates to heart replacement therapy Promotion of clinical audit Quality assessment Equipment and personnel adequate for appropriate patient management Implementation of a continuous monitoring system of indicators within the HF outpatient clinic network Electronic sharing of medical records to facilitate audit procedures ADHF, acute decompensated heart failure; HF, heart failure; NYHA, New York Heart Association; OTC, over the counter. Table 3 Clinical competencies of medical staff in HFOCs (A) Community-based HFOCs Knowledge of: the pathophysiology, differential diagnosis, stages, and natural history of HF the typical history and physical examination findings, and their limitations, in the evaluation of HF syndromes

ADHF, acute decompensated heart failure; HF, heart failure; NYHA, New York Heart Association; OTC, over the counter. Table 3 Clinical competencies of medical staff in HFOCs (A) Community-based HFOCs Knowledge of: the pathophysiology, differential diagnosis, stages, and natural history of HF the typical history and physical examination findings, and their limitations, in the evaluation of HF syndromes the indications, contraindications, and clinical pharmacology of drugs used for HF treatment, including adverse effects the appropriate pharmacological or non-pharmacological treatment for the prevention of HF in patients with either presymptomatic (stage B) or overt (stage C) HF the effects and interactions of HF with other organ systems (kidney, nutritional, metabolic) and in the setting of other systemic disease the management of cardiac arrhythmias in HF patients, as well as the indications and risks of ICD, CRT and arrhythmia ablation Skills: to evaluate and manage patients with new-onset and chronic HF to use history and physical examination findings to accurately assess volume status and perfusion in HF patients to recognize and manage comorbidities in HF patients to recognize, manage, and seek appropriate consultation for depression or undue anxiety in HF patients as part of their overall care to interpret imaging results in the evaluation of HF patients to identify appropriate candidates for palliative care and hospice Activities Identify and address financial, cultural, and social barriers to diagnostic and treatment recommendations

to recognize, manage, and seek appropriate consultation for depression or undue anxiety in HF patients as part of their overall care to interpret imaging results in the evaluation of HF patients to identify appropriate candidates for palliative care and hospice Activities Identify and address financial, cultural, and social barriers to diagnostic and treatment recommendations Utilize an interdisciplinary, coordinated, team approach for patient management, including care transitions and palliative care Utilize appropriate care settings and teams for various levels and stages of HF Incorporate risk/benefit analysis and cost considerations in diagnostic and treatment decisions Effective management of end-of-life issues, including family meetings across the spectrum of patients with HF Communicate with and educate patients and families across a broad range of cultural, ethnic, and socioeconomic backgrounds Engage in shared-decision making with patients, including options for diagnosis and treatment (B) Hospital-based HFOCs. In addition to (A) Skills: to evaluate and manage patients with new-onset, chronic, and acute decompensated HF to appropriately obtain and incorporate data from the history, laboratory studies, and imaging modalities in evaluation and management of HF patients to select and implement appropriate arrhythmia management, including utilization of ICD, CRT, and ablation of arrhythmias in patients with HFof all aetiologies and severity to manage HF patients with complex contributing comorbidities to manage refractory HF with temporary MCS

to appropriately obtain and incorporate data from the history, laboratory studies, and imaging modalities in evaluation and management of HF patients to select and implement appropriate arrhythmia management, including utilization of ICD, CRT, and ablation of arrhythmias in patients with HFof all aetiologies and severity to manage HF patients with complex contributing comorbidities to manage refractory HF with temporary MCS use of invasive and non-invasive methods of mechanical ventilation use of continuous renal replacement therapy (SCUF/CVVH/CVVHD/CVVHDF) Activities Effectively utilize an interdisciplinary approach to monitor HF outpatients to maintain stability and avoid preventable hospitalization (C) Advanced care HFOCs and HRT programs. In addition to (B) Knowledge of: the management and diagnostic strategies for populations with HF not due to ischaemic heart disease, including infiltrative and restrictive cardiomyopathies, inherited cardiomyopathies, and those associated with pregnancy and chemotherapy the management strategies for highly specialized populations with HF, including those associated with congenital heart disease and chronic pulmonary disease the indications, contraindications, and clinical pharmacology for intravenous, vasoactive, and inotropic drugs used for cardiovascular support in advanced/refractory HF the indications for referral for HRT the types of and indications for MCS the indications and clinical rationale for the pharmacological management of patients implanted with MCS

the indications, contraindications, and clinical pharmacology for intravenous, vasoactive, and inotropic drugs used for cardiovascular support in advanced/refractory HF the indications for referral for HRT the types of and indications for MCS the indications and clinical rationale for the pharmacological management of patients implanted with MCS the clinical pharmacology and use of immunosuppressive medications and other interventions in heart transplant patients in the treatment of acute rejection (physicians working in heart transplant programs only) Skills: to evaluate and manage patients with severe HF despite treatment to perform invasive haemodynamic monitoring to incorporate results of haemodynamic measurements and monitoring to make appropriate management decisions in complex or advanced HF patients of all aetiologies and severity or in patients with MCS to interpret and incorporate results of cardiopulmonary exercise testing into management of HF patients, including physical activity and exercise recommendations to manage patients with advanced HF and complex arrhythmias, including patients with MCS, in conjunction with clinical cardiac electrophysiologists to appropriately utilize initial screening studies to determine patient eligibility for HRT of individuals cared for at non-transplant/non-ventricular assist device facilities, in collaboration with individuals working in HRT programs to evaluate, order all appropriate testing, and determine the appropriateness of a patient for cardiac transplant or MCS (physicians working in HRT programs only)

to appropriately utilize initial screening studies to determine patient eligibility for HRT of individuals cared for at non-transplant/non-ventricular assist device facilities, in collaboration with individuals working in HRT programs to evaluate, order all appropriate testing, and determine the appropriateness of a patient for cardiac transplant or MCS (physicians working in HRT programs only) to evaluate and manage heart transplant/MCS recipients (physicians working in HRT programs only) to identify and manage patients who require transition from hospital to home or to a care facility while on infusion of inotropic or vasoactive agents to identify and manage patients who require transition from hospital to home or to a care facility after heart transplant or permanent MCS (physicians working in HRT programs only) Others Identify the financial, social, and emotional barriers to successful outcomes after surgery Clearly and objectively discuss the therapies available for advanced HF, including palliative care, transplant, or MCS Effectively lead and communicate with the interdisciplinary team involved in heart transplant and MCS (physicians working in HRT programs only) Based on the ACC 2015 Core Cardiovascular Training Statement (COCATS 4)18. CRT, cardiac resynchronization therapy; HF, heart failure; HFOCs, heart failure outpatient clinics; HRT, heart replacement therapy; ICD, implantable cardioverter defibrillator; MSD, mechanical circulatory support; SCUF, slow continuous ultrafiltration. Table 4 Structure and organization of HFOCs

Based on the ACC 2015 Core Cardiovascular Training Statement (COCATS 4)18. CRT, cardiac resynchronization therapy; HF, heart failure; HFOCs, heart failure outpatient clinics; HRT, heart replacement therapy; ICD, implantable cardioverter defibrillator; MSD, mechanical circulatory support; SCUF, slow continuous ultrafiltration. Table 4 Structure and organization of HFOCs Clinic (A) Community based (B) Hospital based (C) Advanced care and HRTa programs Location Community: Primary care territorial unit, health home, functional territorial aggregation, primary care association General cardiology outpatients’ clinic Hospital: Non-cardiology units (internal medicine, geriatrics, emergency medicine) Hospitals with emergency services only Intermediate long-term care units Cardiac rehabilitation units Hospitals with cardiology units: Cardiology inpatient unit and/orCICU and/orCardiac catheterization laboratory either on site or in a functionally linked centre and/orEP Laboratory either on site or in a functionally linked centre Hospitals with a cardiology division: cardiology inpatient unit CICU on site cardiac catheterization laboratory open 24 h/day, 7 days/week, with expertise in performing EBM on site EP Laboratory cardiac surgery unit Integrated Cardiac-Surgical HF program Patient profile Patients with stable chronic HFb who have concluded the risk stratification process OR do not need additional diagnostic/therapeutic procedures or these are ongoing in collaboration with hospital-based clinics Patients with newly diagnosed HF who need risk stratification investigation of the aetiology of HF Patients with recent decompensation

Patient profile Patients with stable chronic HFb who have concluded the risk stratification process OR do not need additional diagnostic/therapeutic procedures or these are ongoing in collaboration with hospital-based clinics Patients with newly diagnosed HF who need risk stratification investigation of the aetiology of HF Patients with recent decompensation Patients needing interventional diagnostic or therapeutic procedures Patients at high risk of decompensation (severe exercise intolerance and/or severe cardiac dysfunction) Patients who are taken care of in (B), but need diagnostic and/or therapeutic procedures only available in (C). Patients needing cardiac surgery Patients with advanced HFc HRT programs: as above, but dedicated primarily to: patients with advanced HF who are potential candidates for HRT heart transplant/MCSD recipients Requirements Compliance with regional accreditation standards for outpatient clinics Compliance with regional accreditation standards for outpatient specialist clinics. Outpatient clinic dedicated to HF patients Day-hospital and/or Day-service and/or intensive hospital-based outpatient care Either on site or functionally linked EP laboratory with expertise in both ablation and pacing, including cardiac resynchronization therapy Either on site or functionally linked cardiac catheterization laboratory In addition to (B): multidisciplinary team led by HF cardiologists, cardiac surgeons and HF specialist nurses, and including additional health-care professionals as needed the multidisciplinary team is responsible for integration across the HF care continuum

Either on site or functionally linked cardiac catheterization laboratory In addition to (B): multidisciplinary team led by HF cardiologists, cardiac surgeons and HF specialist nurses, and including additional health-care professionals as needed the multidisciplinary team is responsible for integration across the HF care continuum Heart transplant/MCSD programs: compliance with current legislation about heart transplant and MCSD centres active MCSD program (heart transplant programs) on site availability of the facilities and competencies necessary for the diagnosis and treatment of the potential complications of HRT Equipment and facilities Sphygmomanometer Electrocardiograph Pulse oximeter Scales Defibrillator (desirable) Cardiac ultrasound scanner: optional but desirable, as it allows objective documentation of cardiac dysfunction and, thus, the diagnosis of HF In addition to (A): cardiac ultrasound scanner defibrillator dressing and phlebotomy tray On site or in a functionally linked centre Holter monitoring cardiopulmonary exercise testing advanced cardiac imaging equipment for the interrogation of implantable devices remote device monitoring program As in (B) but all the facilities and equipment must be available on site, and in addition: telemetry equipment, allowing also oxygen saturation monitoring by pulse oximeter and non-invasive blood pressure monitoring nuclear cardiology MCSD programs: equipment for MCSD monitoring Minimal volume of activity Time slots and/or days dedicated to HF patients At least 2 days/week dedicated to HF patients Fast track (within 72 h) for unstable patients

As in (B) but all the facilities and equipment must be available on site, and in addition: telemetry equipment, allowing also oxygen saturation monitoring by pulse oximeter and non-invasive blood pressure monitoring nuclear cardiology MCSD programs: equipment for MCSD monitoring Minimal volume of activity Time slots and/or days dedicated to HF patients At least 2 days/week dedicated to HF patients Fast track (within 72 h) for unstable patients Nurse-led telephone follow-up for unstable patients In addition to (B): at least 3 days/week dedicated to HF patients HRT programs: telephone consulting 24 h/day, 7 days/week specialist assistance for emergencies in the hospital 24 h/day, 7 days/week Staff At least one physician with expertise in HF At least one nurse At least one HF cardiologist At least one HF specialist nurse responsible for care integration across the HF spectrum The involvement, in a multidisciplinary team, of additional medical (internists, geriatricians, nephrologists, etc.) and non-medical (psychologists, nutritionists, dietitians, physiotherapists) professionals is desirable At least three HF cardiologists HF specialist nurses Cardiac surgeons with expertise in the surgical treatment of HF Multidisciplinary team MCSD programs: nurses and cardiac surgeons with expertise in the management of MCSD recipientsd; this is desirable for all Advanced care clinics, so that they can participate in the follow-up of MCSD recipients Heart transplant programs: nurses with expertise in the management of heart transplant recipients

Multidisciplinary team MCSD programs: nurses and cardiac surgeons with expertise in the management of MCSD recipientsd; this is desirable for all Advanced care clinics, so that they can participate in the follow-up of MCSD recipients Heart transplant programs: nurses with expertise in the management of heart transplant recipients Services Referral of patients newly diagnosed with HF to hospital clinics, if the aetiology is unclear Implementation of guideline-directed medical therapy, assessment of clinical stability and referral to hospital-based clinics where appropriate Support to institutions or home care services for frail patients Integration with palliative care services In addition to (A): timely consultation for confirmation of HF diagnosis, risk stratification, implementation of guideline-directed therapy, referral to advanced care clinics/HRT programs when appropriate referral of stable patients at low-risk of events to community-based clinics, according to predefined protocols support to institutions/home-care services for frail/end-stage patients by means of telemonitoring development of collaborative clinical pathways with the ER, and internal medicine and cardiology units, that describe appropriateness criteria for admission to the CICU, transfer to a regular floor/intermediate care unit, referral to palliative care services, admission of low-risk patients to the ER observation unit with subsequent follow-up in the HF clinic patient self-care education, including the preparation of educational material for patients and care givers

support to institutions/home-care services for frail/end-stage patients by means of telemonitoring development of collaborative clinical pathways with the ER, and internal medicine and cardiology units, that describe appropriateness criteria for admission to the CICU, transfer to a regular floor/intermediate care unit, referral to palliative care services, admission of low-risk patients to the ER observation unit with subsequent follow-up in the HF clinic patient self-care education, including the preparation of educational material for patients and care givers continuous education of health-care professional working in the hospital and in the community In addition to (B): referral of stable patients at low risk for hospitalization to Community-based clinics, according to defined protocols referral of potential candidates for HRT to HRT programs follow-up of MCSD recipients HRT programs: assessment of patient eligibility for heart transplant or MCSD Heart transplant programs: management of patients on the transplant waiting list and of transplant recipients MCSD programs: continuous education of MCSD recipients and community health-care professional involved in the care of these patients evaluation of the quality of life before and after MCSD implant by means of validated questionnaires

Heart transplant programs: management of patients on the transplant waiting list and of transplant recipients MCSD programs: continuous education of MCSD recipients and community health-care professional involved in the care of these patients evaluation of the quality of life before and after MCSD implant by means of validated questionnaires CICU, cardiac intensive care unit; CVVH, continuous vene-venous hemofiltration; CVVHD, continuous vene-venous hemodialysis; CVVHDF, continuous vene-venous hemodiafiltration; EP, electrophysiology; HF, heart failure; HRT, heart replacement therapy; EBM, endomyocardial biopsy; MCSD, mechanical circulatory support devices. aHRT: heart transplant, implant of durable mechanical circulatory support devices. bStable chronic HF is defined as: • stable symptoms on oral therapy for at least 15 days; • stable dose of diuretics for at least 15 days; • no signs of congestion (peripheral oedema, rales, jugular veins distension); • no symptomatic hypotension. cIn accordance with the 2007 position statement from the Heart Failure Association of the European Society of Cardiology19, Advanced HF is defined as: • NYHA functional class III-IV symptoms; • episodes of fluid retention and/or of reduced cardiac output at rest; • objective evidence of severe cardiac dysfunction; • severe impairment of functional capacity; • history of ≥ 1 HF hospitalisation in the past 6 months; • presence of all the previous features despite attempts to optimize therapy, including CRT, when indicated. dSee Table 3 for detailed staff competencies required.

• episodes of fluid retention and/or of reduced cardiac output at rest; • objective evidence of severe cardiac dysfunction; • severe impairment of functional capacity; • history of ≥ 1 HF hospitalisation in the past 6 months; • presence of all the previous features despite attempts to optimize therapy, including CRT, when indicated. dSee Table 3 for detailed staff competencies required. Activities The activity of medical staff should include medical visit, assessment of HF-related symptoms and definition of New York Heart Association (NYHA) class, detection of signs related to central and peripheral congestion, evaluation of laboratory data and comorbidities, revision and optimization of pharmacological and non-pharmacological therapy, scheduled laboratory assessment and functional evaluations (e.g. 6-min walking test, cardiopulmonary test), drafting a personalized plan for patient’s care. Nurse staff should participate to patient’s care by performing multidimensional evaluation and cooperating in patients’ monitoring (e.g. phone follow-up or remote monitoring by implanted cardioverter defibrillator or home sensors), by assessing therapeutic adherence, by empowering patients and relatives with a personalized counselling in order to promote self-management. Documentation HF outpatient clinics should record data and information that reflect the adopted protocols and allow clinical management of cases, development of research programs, evaluation, and supervision of clinical activities. Each HF outpatient clinic should have a registry of patients attending the clinic and activities performed

Documentation HF outpatient clinics should record data and information that reflect the adopted protocols and allow clinical management of cases, development of research programs, evaluation, and supervision of clinical activities. Each HF outpatient clinic should have a registry of patients attending the clinic and activities performed individual patient records should include: consent to personal data collection; the diagnostic process followed; risk stratification by validated scores; the care plan; the assessment of the efficacy of the adopted treatment; the frequency of scheduled visits; copy of clinical reports transmitted to general practitioners, where information about the patient’s diagnostic and therapeutic plan are detailed. Protocols HF outpatient clinic should have in place procedures and operating instructions aimed to ensure the quality of services declared; allow an adequate interaction with primary care and other outpatient clinics within the HF network; and standardize the collection of data useful to monitor the indicators for audits and to assess patient-perceived quality. Quality of care indicators Organization-oriented indicators Time from referral to patient’s first visit at the clinic. Proportion of patients with clinical reports to primary care physicians. Continuous medical education credits earned by the team. Compilation of a patient satisfaction questionnaire. Patient-level indicators HF aetiology. NYHA class or other functional parameter. Signs and symptoms of congestion, vital signs, results of laboratory tests. Patient education, including self-care education.

Proportion of patients with clinical reports to primary care physicians. Continuous medical education credits earned by the team. Compilation of a patient satisfaction questionnaire. Patient-level indicators HF aetiology. NYHA class or other functional parameter. Signs and symptoms of congestion, vital signs, results of laboratory tests. Patient education, including self-care education. Quantitative evaluation of left ventricular ejection fraction (LVEF). If reduced LVEF and no contraindications: ACE inhibitor/angiotensin receptor antagonist prescribed AND target dose achieved. beta-blocker prescribed AND target dose achieved. mineralocorticoid receptor antagonist prescribed AND target dose achieved. If comorbid atrial fibrillation and no contraindications: Oral anticoagulant therapy. For eligible patients: Cardioverter defibrillator implantation. cardiac resynchronization therapy. Outcome indicators Number of all—cause, cardiovascular, and HF readmissions at 1, 3, and 12 months. Mortality rate at 1 year. Quality of life. Conclusions Heart failure is a complex disease that generates an enormous burden to health-care systems. Ageing increasing multimorbidity and an expanding array of costly advanced-technology therapeutic options further impact on the challenges of caring for these patients. The shift from acute to chronic care mandates a proactive role of health-care professionals in building efficient network system and chaperone HF patients through them.

multimorbidity and an expanding array of costly advanced-technology therapeutic options further impact on the challenges of caring for these patients. The shift from acute to chronic care mandates a proactive role of health-care professionals in building efficient network system and chaperone HF patients through them. This guidance document details roles and interactions among cardiologists, so as to best exploit the added value of specialist input in the care of HF patients and is expected to promote a more efficient and effective organization of HF.

multimorbidity and an expanding array of costly advanced-technology therapeutic options further impact on the challenges of caring for these patients. The shift from acute to chronic care mandates a proactive role of health-care professionals in building efficient network system and chaperone HF patients through them. This guidance document details roles and interactions among cardiologists, so as to best exploit the added value of specialist input in the care of HF patients and is expected to promote a more efficient and effective organization of HF. Consensus Document Approval Faculty Abrignani Maurizio Giuseppe, Amico Antonio Francesco, Amodeo Vincenzo, Angeli Fabio, Audo Andrea, Azzarito Michele, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Bonvicini Marco, Cacciavillani Luisa, Calculli Giacinto, Canzone Giuseppe, Capecchi Alessandro, Caporale Roberto, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Casolo Giancarlo, Cassin Matteo, Casu Gavino, Cemin Roberto, Chiarandà Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Ciccone Marco Matteo, Cicini Maria Paola, Clerico Aldo, Colivicchi Furio, Comoglio Francesca Maria, D’Agostino Carlo, De Luca Leonardo, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Egidy Assenza Gabriele, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Francese Giuseppina Maura, Geraci Giovanna, Giardina Achille, Greco Cesare, Gregorio Giovanni, Khoury Georgette, Ledda Antonietta, Lucà Fabiana, Macera Francesca, Mascia Franco, Masson Serge, Maurea Nicola, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Menozzi Alberto, Mininni Nicola, Molon Giulio, Moreo Antonella, Moretti Luciano, Mureddu Gian Francesco, Murrone Adriano, Musumeci Giuseppe, Nardi Federico, Nicolosi Gian Luigi, Oreglia Jacopo, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pino Paolo Giuseppe, Pirelli Salvatore, Procaccini Vincenza, Pugliese Francesco Rocco, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Scherillo Marino, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Themistoclakis Sakis, Uguccioni Massimo, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

ini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Scherillo Marino, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Themistoclakis Sakis, Uguccioni Massimo, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino. Conflict of interest: none declared.

Document Revisors: Roberto Caporale, Giuseppe Patti, Roberta Rossini, Pasquale Caldarola, Giovanna Geraci, and Serafina Valente Consensus Document Approval Faculty in appendix Introduction Practicing physicians may need systematic evidence-based guidance to facilitate decision making in delivering clinical care. One approach for the provision of such guidance is the use of clinical pathways as implementation tools. Clinical pathways represent structured intervention plans containing essential steps in the care of patients with specific clinical problems. They are usually developed by translating evidence-based guidelines into stepped care protocols for application in clinical practice. In accordance with such a concept, the main aim of this document is to provide clear, practical, and evidence-based indications for an effective management of antithrombotic therapy (anticoagulant and antiplatelet therapy) in the ever changing clinical scenario of acute coronary syndromes (ACSs). All therapeutic options outlined in this document are consistent with the recommendations of the European Society of Cardiology guidelines1,2 and are carefully considered for both indications and contraindications of each specific drug (Table 1). However, in order to overcome increasing clinical challenges and implement effective therapeutic interventions, this document identifies all potential specific care pathway for ACS patients and accordingly proposes individualized therapeutic options. In particular, as shown in Figure 1, the following care pathways have been preliminary identified:

increasing clinical challenges and implement effective therapeutic interventions, this document identifies all potential specific care pathway for ACS patients and accordingly proposes individualized therapeutic options. In particular, as shown in Figure 1, the following care pathways have been preliminary identified: Figure 1 Patient care pathways proposed in the consensus paper. CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention. Table 1 Indications, contraindications, and precautions in using main antithrombotic drugs in ACSs Drug Mode of action Indications Contraindications Precautions Clopidogrel Irreversible inhibitor of the platelet P2Y12 receptor for ADP (with ASA): NSTE-ACS STEMI treated with thrombolysis Acute hepatic impairment Active pathological bleeding Ischaemic stroke ≤ 7 days Glucose/galactose intolerance/malabsorption Withhold treatment ≥ 5 days before elective surgery Renal impairment Moderate hepatic impairment PPIs other than pantoprazole Prasugrel Irreversible inhibitor of the platelet P2Y12 receptor for ADP (With ASA): NSTE-ACS STEMI Both treated with PCI Medical history of TIA/stroke Acute hepatic impairment (Child-Pugh Grade C) Active pathological bleeding Glucose/galactose intolerance/malabsorption Patients ≥ 75 years –> 5 mg once daily maintenance dose Patients < 60 kg –> 5 mg once daily maintenance dose Mild-to-moderate hepatic impairment Renal impairment Withhold treatment ≥ 7 days before elective surgery Concomitant warfarin/NSAID Ticagrelor Reversible inhibitor of the platelet P2Y12 receptor for ADP (With ASA): NSTE-ACS STEMI managed with: -medical treatment -PCI -CABG

Patients ≥ 75 years –> 5 mg once daily maintenance dose Patients < 60 kg –> 5 mg once daily maintenance dose Mild-to-moderate hepatic impairment Renal impairment Withhold treatment ≥ 7 days before elective surgery Concomitant warfarin/NSAID Ticagrelor Reversible inhibitor of the platelet P2Y12 receptor for ADP (With ASA): NSTE-ACS STEMI managed with: -medical treatment -PCI -CABG Moderate-to-acute hepatic impairment Haemorrhagic stroke at any time Active pathological bleeding Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir) or strong CYP3A4 inducers (rifampicin, dexamethasone, phenytoin, carbamazepin, phenobarbital) uric Acid nephropathy Predisposition to bleeding NSAID, OAT, fibrinolytic agents ≤ 24 h Digoxin P-gp inhibitors (verapamil, quinidine, cyclosporine) Withhold ≥ 5 days before CABG High risk of bradycardic events (SAND, AVB II-III, syncope) Asthma/COPD Hyperuricaemia Abciximab Inhibitor of platelet glycoprotein IIb/IIIa receptors (With UFH and ASA) PCI PCI in unstable angina Ongoing haemorrhage Cerebrovascular accident ≤ 2 years. Trauma or major cranial/spine surgery ≤ 2 months Intracranial disease Bleeding diathesis, thrombocytopaenia, vasculitis, hypertensive retinopathy Acute hepatic impairment Dialysis Tirofiban Inhibitor of platelet glycoprotein IIb/IIIa receptors NSTE-ACS Stroke ≤ 30 days or intracerebral haemorrhage at any time Intracranial disease Clinically relevant bleeding ≤ 30 days Malignant hypertension Trauma/major surgery ≤ 6 weeks Platelet count < 100 000/mm3 Coagulation or platelet function disorders Acute hepatic impairment

Tirofiban Inhibitor of platelet glycoprotein IIb/IIIa receptors NSTE-ACS Stroke ≤ 30 days or intracerebral haemorrhage at any time Intracranial disease Clinically relevant bleeding ≤ 30 days Malignant hypertension Trauma/major surgery ≤ 6 weeks Platelet count < 100 000/mm3 Coagulation or platelet function disorders Acute hepatic impairment Eptifibatide Inhibitor of platelet glycoprotein IIb/IIIa receptors (With UFH and ASA) NSTE-ACS Clinically significant hepatic impairment Acute renal impairment (eCrCl < 30 mL/min) Active bleeding ≤ 30 days Stroke ≤ 30 days or intracerebral Haemorrhage at any time Intracranial diseases Acute trauma/major surgery ≤ 6 weeks Bleeding diathesis, platelet count < 100 000/mm3, altered coagulation SBP > 200/DBP > 110 mmHg despite hypertension therapy Women Elderly Low body weight Upstream administration UFH Indirect thrombin inhibitor Prophylaxis/therapy of venous and arterial thromboembolic disease Ongoing haemorrhagic events Propensity for haemorrhagic manifestations Concomitant ASA Enoxaparin Indirect FXa and thrombin inhibitor NSTEMI STEMI Haemostasis disorders organic lesions at risk of bleeding Intracerebral haemorrhage at any time Acute infective endocarditis (except with mechanical prostheses) Ticlopidine, salicylates, NSAID, antiplatelet agents Recent ischaemic stroke, peptic ulcer, uncontrolled hypertension, retinopathy, recent neurological/ophthalmic surgery Mild-to-moderate renal impairment Dose reduction with acute renal impairment Low body weight Fondaparinux Indirect FXa inhibitor NSTEMI, except with PCI < 120 min STEMI treated with fibrinolysis or without reperfusion therapy eCrCl < 20 mL/min ongoing haemorrhage

Recent ischaemic stroke, peptic ulcer, uncontrolled hypertension, retinopathy, recent neurological/ophthalmic surgery Mild-to-moderate renal impairment Dose reduction with acute renal impairment Low body weight Fondaparinux Indirect FXa inhibitor NSTEMI, except with PCI < 120 min STEMI treated with fibrinolysis or without reperfusion therapy eCrCl < 20 mL/min ongoing haemorrhage acute bacterial endocarditis Acute hepatic impairment Bivalirudin Direct thrombin inhibitor (With ASA and clopidogrel) STEMI treated with primary PCI NSTE-ACS with urgent/immediate PCI PCI eGFR < 30 mL/min/1.73 m2 active bleeding Haemostasis disorders Acute uncontrolled hypertension Subacute bacterial endocarditis eGFR 30-50 mL/min/1.73 m2 Elderly ADP, adenosine diphosphate; ASA, acetylsalicylic acid; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; PPI, proton pump inhibitor; PCI, percutaneous coronary intervention; TIA, transient ischaemic attack; NSAID, non-steroidal anti-inflammatory drug; OAT, oral anticoagulant therapy; CABG, coronary artery bypass grafting; SAND, sinoatrial node disease; AVB, atrioventricular block; COPD, chronic obstructive pulmonary disease; UFH, unfractionated heparin; SBP, systolic blood pressure; DBP, diastolic blood pressure; eCrCl, estimated creatinine clearance; eGFR, estimated glomerular filtration rate. Pathway 1: pre-hospital management of ACS; Pathway 2: initially conservative management of ACS; Pathway 3: management with immediate referral for coronary angiography;

ADP, adenosine diphosphate; ASA, acetylsalicylic acid; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; PPI, proton pump inhibitor; PCI, percutaneous coronary intervention; TIA, transient ischaemic attack; NSAID, non-steroidal anti-inflammatory drug; OAT, oral anticoagulant therapy; CABG, coronary artery bypass grafting; SAND, sinoatrial node disease; AVB, atrioventricular block; COPD, chronic obstructive pulmonary disease; UFH, unfractionated heparin; SBP, systolic blood pressure; DBP, diastolic blood pressure; eCrCl, estimated creatinine clearance; eGFR, estimated glomerular filtration rate. Pathway 1: pre-hospital management of ACS; Pathway 2: initially conservative management of ACS; Pathway 3: management with immediate referral for coronary angiography; Pathway 4: management with referral for coronary angiography after an initially conservative treatment; Pathway 5: management in case of percutaneous coronary intervention (PCI); Pathway 6: management in case of surgical myocardial revascularization procedure; and Pathway 7: management with definite conservative treatment after coronary angiography. Pathway 1: pre-hospital treatment of ACS A pre-hospital pharmacological treatment is extremely important in ACS patients and becomes crucial in patients with confirmed diagnosis of ST-segment elevation myocardial infarction (STEMI), particularly within the framework of a well-organized emergency medical network.3 This pathway will therefore focus on the use of antithrombotic drugs for the pre-hospital management of STEMI patients.

tients and becomes crucial in patients with confirmed diagnosis of ST-segment elevation myocardial infarction (STEMI), particularly within the framework of a well-organized emergency medical network.3 This pathway will therefore focus on the use of antithrombotic drugs for the pre-hospital management of STEMI patients. Antithrombotic drugs, in association with coronary revascularization, are used in the management of STEMI to enhance myocardial reperfusion before a percutaneous coronary intervention (PCI) or to achieve an appropriate active drug level at the time of the mechanical reperfusion. The combination of PCI with early pharmacological reperfusion therapy for reducing the total ischaemic time and minimizing the detrimental effects of delayed revascularization has long been considered a fascinating pathophysiological approach and a useful practical solution to extend the benefits of primary PCI (pPCI) to the majority of STEMI patients.4 Recent randomized trials have shown that pre-hospital fibrinolysis in specific care settings and STEMI patient categories can be a reasonable therapeutic alternative to pPCI.5 On the other hand, certain drugs—based on their route of administration and relatively reduced bioavailability—are administered to reduce recurrent ischaemic events as soon as an STEMI diagnosis is confirmed. These drugs have no immediate effect on reperfusion, but when initiated early, they significantly reduce the incidence of recurrent ischaemic events compared with delayed administration.

relatively reduced bioavailability—are administered to reduce recurrent ischaemic events as soon as an STEMI diagnosis is confirmed. These drugs have no immediate effect on reperfusion, but when initiated early, they significantly reduce the incidence of recurrent ischaemic events compared with delayed administration. Antiplatelet agents To date, no trial has compared the timing of aspirin (ASA) administration with outcome in STEMI patients. However, the guidelines recommend the earliest possible administration of ASA at an initial dose of 150–325 mg.1

relatively reduced bioavailability—are administered to reduce recurrent ischaemic events as soon as an STEMI diagnosis is confirmed. These drugs have no immediate effect on reperfusion, but when initiated early, they significantly reduce the incidence of recurrent ischaemic events compared with delayed administration. Antiplatelet agents To date, no trial has compared the timing of aspirin (ASA) administration with outcome in STEMI patients. However, the guidelines recommend the earliest possible administration of ASA at an initial dose of 150–325 mg.1 With regard to P2Y12 inhibitors, the latest guidelines on myocardial revascularization recommend the administration of a P2Y12 inhibitor upon first medical contact (Class 1 recommendation, level of evidence B). For many years, international guidelines have also recommended the pre-hospital administration of clopidogrel with a Class 1 recommendation, level of evidence C (consensus of expert opinion).1 No randomized clinical trials have been conducted on the upstream vs. downstream use of clopidogrel in STEMI patients. Indeed, the documented benefits of pre-treatment with clopidogrel in other patient groups with ACS have been applied tout court to STEMI patients. Data supporting the early use of clopidogrel are available from a meta-analysis6 of clinical studies that evaluated the association of 300 mg clopidogrel administered at a median time of about 2 h prior to pPCI with a decreased rate of mortality and reinfarction. Retrospective data from large registries or posthoc analyses of randomized clinical trials showed a beneficial effect of upstream treatment with 300 mg clopidogrel in STEMI patients on the composite endpoint of ischaemia and mortality.7 In a recent retrospective study,8 the administration of clopidogrel in the emergency department was associated with an improved long-term clinical outcome compared with the administration in the catheterization laboratory. Similarly, a posthoc analysis of the randomized HORIZONS-AMI trial suggested that upstream administration of a 600 mg loading dose of clopidogrel would boost such beneficial effect with no further increase in the rate of major bleeding.9 Of note, a 600 mg clopidogrel load has been associated with reduction of the infarct size when compared with 300 mg dose in patients undergoing pPCI and therefore the higher regimen merits recommendation in this setting.10

ogrel would boost such beneficial effect with no further increase in the rate of major bleeding.9 Of note, a 600 mg clopidogrel load has been associated with reduction of the infarct size when compared with 300 mg dose in patients undergoing pPCI and therefore the higher regimen merits recommendation in this setting.10 The recent European guidelines indicate the new platelet P2Y12 receptor inhibitors as first-choice drugs in the management of STEMI patients,1 as they provide for improved long-term clinical outcomes. However, a late antiplatelet effect seems to be associated also with this oral antiplatelet drug class. Thus, it is a reasonable assumption that upstream administration may result in improved beneficial clinical effect in terms of reduction of early, recurrent ischaemic events.

for improved long-term clinical outcomes. However, a late antiplatelet effect seems to be associated also with this oral antiplatelet drug class. Thus, it is a reasonable assumption that upstream administration may result in improved beneficial clinical effect in terms of reduction of early, recurrent ischaemic events. In the TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38) trial randomization to 60 mg prasugrel vs. 300 mg clopidogrel before assessment of the coronary tree was allowed in STEMI patients who presented within 12 h of symptom onset, if pPCI was intended.11 Overall, in the STEMI cohort of the TRITON-TIMI 38 trial (n = 3534), an average time from symptom onset to drug administration of 228 min and an average time from symptom onset to pPCI of 252 min were registered; only 31% of these patients could benefit from prasugrel treatment before coronary angiography evaluation.12 Although there are no published data available on the patient population randomized to early treatment, it is assumed that the same clear benefits of prasugrel vs. clopidogrel observed in STEMI patients, with regard to the primary composite endpoint (death, myocardial infarction, and stroke) and stent thrombosis without associated increase in major bleeding, apply to that patient population too. On the other hand, there are no data from randomized clinical data comparing the efficacy and safety of pre-hospital treatment strategy with prasugrel vs. in-hospital prasugrel treatment of STEMI patients. The multinational, multicentre, prospective, MULTIPRAC (MULTInational non-interventional study of patients with ST-segment elevation myocardial infarction treated with PRimary Angioplasty and Concomitant use of upstream antiplatelet therapy with prasugrel or clopidogrel) registry was conducted to gain insights into the use patterns and outcomes of pre-hospital initiation of oral antiplatelet agents on top of ASA with prasugrel or clopidogrel.13 In this study, 2053 STEMI patients were enrolled. Pre-hospital use of prasugrel increased from 12.5% to 67.1% at study end. The major adverse cardiac events (MACE) rate was 1.6% in prasugrel-treated patients vs. 2.3% in clopidogrel-treated patients [adjusted odds ratio (OR) 0.749, 95% confidence interval (CI) [0.285–1.968]].13 Non-coronary artery bypass graft (non-CABG) bleeding occurred in 4.1% of prasugrel-treated patients vs.

study end. The major adverse cardiac events (MACE) rate was 1.6% in prasugrel-treated patients vs. 2.3% in clopidogrel-treated patients [adjusted odds ratio (OR) 0.749, 95% confidence interval (CI) [0.285–1.968]].13 Non-coronary artery bypass graft (non-CABG) bleeding occurred in 4.1% of prasugrel-treated patients vs. 6.1% of clopidogrel-treated patients (adjusted OR 0.686 [0.349–1.349]). Pre-percutaneous coronary intervention TIMI flow 2–3 was seen in 38.7% treated with prasugrel vs. 35.6% with clopidogrel (adjusted OR 1.170 [0.863–1.585]). Post-PCI ST-segment resolution ≥50%, was 71.6% with prasugrel vs. 65.0% with clopidogrel (adjusted OR 1.543 [1.138–2.093], P = 0.0052).13

d OR 0.686 [0.349–1.349]). Pre-percutaneous coronary intervention TIMI flow 2–3 was seen in 38.7% treated with prasugrel vs. 35.6% with clopidogrel (adjusted OR 1.170 [0.863–1.585]). Post-PCI ST-segment resolution ≥50%, was 71.6% with prasugrel vs. 65.0% with clopidogrel (adjusted OR 1.543 [1.138–2.093], P = 0.0052).13 Although there was no pre-hospital randomization to 180 mg ticagrelor vs. 300 mg or 600 mg clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial, the first dose of the study drug was administered as early as possible after patient recruitment and always before admission to the catheterization laboratory, with a median time of 25 min from first dose administration of the drug to PCI, for both treatment arms.14 Therefore, the clinical beneficial outcomes observed in the ticagrelor arm vs. clopidogrel can be reasonably extended to the subgroup of over 7000 STEMI patients randomized in the PLATO trial.14 The recent ATLANTIC (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery) study was the first randomized trial to compare the efficacy and safety of the pre-hospital administration of dual antiplatelet therapy (DAPT) with ticagrelor vs. in-hospital ticagrelor treatment.15 Approximately 1800 STEMI patients <6 h from symptom onset undergoing pPCI were randomized in this study. Although there was no difference in the primary outcome measures (i.e. a mechanical rather than clinical endpoints: achievement of TIMI flow 3 at initial angiography or ST-segment elevation resolution ≥70% at pre-PCI electrocardiogram) among the two treatment groups, the study provided further data on pre-hospital treatment with ticagrelor in STEMI patients,15 particularly showing that pre-treatment with ticagrelor is not associated with increased haemorrhagic risk (according to all applied definitions). It also showed that the drug significantly reduced (1.2% vs. 0.2%; P = 0.02) acute stent thrombosis (secondary endpoint of the study).15

with ticagrelor in STEMI patients,15 particularly showing that pre-treatment with ticagrelor is not associated with increased haemorrhagic risk (according to all applied definitions). It also showed that the drug significantly reduced (1.2% vs. 0.2%; P = 0.02) acute stent thrombosis (secondary endpoint of the study).15 The use of glycoprotein IIb/IIIa inhibitors (GPIs), particularly abciximab, in STEMI patients was associated with a reduction in the relative mortality risk and of composite endpoints of ischaemic events without increasing major bleeding episodes.16 However, the pre-hospital use of GPIs in STEMI, particularly when associated with high clopidogrel doses,17 is controversial; although the ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up)18 trial supports pre-hospital administration of abciximab, the recent large, randomized FINESSE trial (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events)19 did not show any significantly improved clinical outcomes with a routine, early administration of GPIs. Conversely, the angiographic evaluation in the EUROTRANSFER Registry documented an improved incidence of TIMI flow 2 and 3 in the STEMI patients group treated with upstream abciximab, particularly in early onset patients20; this study also indicated improvement in long-term survival with abciximab pre-treatment, particularly in STEMI patients with early onset and low risk.21 Another GPI, tirofiban, when administered in the pre-hospital setting as double bolus in association with 600 mg clopidogrel, ASA, and heparin showed beneficial effects in terms of an average reduction of the ST-segment 1 h after pPCI compared with placebo in the ON-TIME 2 randomized trial (Ongoing Tirofiban In Myocardial infarction Evaluation 2).22 In a recent pre-specified angiography analysis of the ON-TIME 2 trial, the incidence of TIMI flow 2 and 3 and the reduction of intracoronary thrombus burden at initial coronary angiography were significantly higher in the group randomized to pre-hospital tirofiban compared with placebo.23

al infarction Evaluation 2).22 In a recent pre-specified angiography analysis of the ON-TIME 2 trial, the incidence of TIMI flow 2 and 3 and the reduction of intracoronary thrombus burden at initial coronary angiography were significantly higher in the group randomized to pre-hospital tirofiban compared with placebo.23 Anticoagulants Current STEMI guidelines recommend the use of unfractionated heparin (UFH) with an intravenous bolus of 100 U/kg (to downgrade to 60 U/kg when associated with GPIs) in patients scheduled for pPCI,1 although there are no data from comparative trials of UFH vs. placebo to support such recommendation.

al infarction Evaluation 2).22 In a recent pre-specified angiography analysis of the ON-TIME 2 trial, the incidence of TIMI flow 2 and 3 and the reduction of intracoronary thrombus burden at initial coronary angiography were significantly higher in the group randomized to pre-hospital tirofiban compared with placebo.23 Anticoagulants Current STEMI guidelines recommend the use of unfractionated heparin (UFH) with an intravenous bolus of 100 U/kg (to downgrade to 60 U/kg when associated with GPIs) in patients scheduled for pPCI,1 although there are no data from comparative trials of UFH vs. placebo to support such recommendation. Low-molecular-weight heparins (LMWHs) present less biological variability compared with UFH and seem to offer a better clinical efficacy in STEMI patients when administered intravenously.24,25 In the recent ATOLL (Acute STEMI Treated with primary angioplasty and intravenous enoxaparin Or UFH to Lower ischaemic and bleeding events at short and Long-term follow-up) trial, ∼900 STEMI patients treated with pPCI were randomized—over 70% in a pre-hospital setting—to receive an intravenous bolus of enoxaparin (0.5 mg/kg) or UFH.26 In the study, enoxaparin was not superior to UFH in reducing the primary composite endpoint (death, complication of myocardial infarction, procedural failure, and major bleeding). However, enoxaparin was associated with a significant reduction in the secondary endpoint (a composite of death, recurrent ACS, or urgent revascularization) and a significant reduction in individual endpoints, including mortality, major haemorrhage, and urgent revascularization.26

ocedural failure, and major bleeding). However, enoxaparin was associated with a significant reduction in the secondary endpoint (a composite of death, recurrent ACS, or urgent revascularization) and a significant reduction in individual endpoints, including mortality, major haemorrhage, and urgent revascularization.26 There are no studies specifically designed to assess the efficacy of the pre-hospital administration of fondaparinux, an activated factor X inhibitor. In the OASIS-6 (Organisation to Assess Strategies in Ischaemic Syndromes) trial,27 the impact of fondaparinux on mortality and reinfarction was assessed in over 12 000 STEMI patients, stratified in two groups based on their eligibility to receive UFH treatment. Fondaparinux was associated with a significant reduction in the incidence of the primary endpoint compared with UFH/placebo (9.7% vs. 11.2%; P = 0.008).27 Regarding the treatment, fondaparinux proved to be superior to placebo/UFH in patients who received thrombolysis (mainly streptokinase) or conservative treatment, whereas it proved to be inferior to UFH in pPCI patients.27

in the incidence of the primary endpoint compared with UFH/placebo (9.7% vs. 11.2%; P = 0.008).27 Regarding the treatment, fondaparinux proved to be superior to placebo/UFH in patients who received thrombolysis (mainly streptokinase) or conservative treatment, whereas it proved to be inferior to UFH in pPCI patients.27 The efficacy of bivalirudin in STEMI patients was assessed in the HORIZONS AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial28; the treatment with this direct thrombin inhibitor resulted in better net clinical outcomes (including reduction in mortality and bleeding) compared with UFH in association with the GPIs (see Pathway 6). The EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) study29 recently evaluated the efficacy of a pre-hospital administration of a prolonged bivalirudin infusion (initiated 50 min prior to pPCI and continued for at least 4 h thereafter) in comparison with the use of heparin and routine or bailout GPIs (∼70% of the cases) in ∼2200 patients with STEMI undergoing pPCI. The results showed that bivalirudin was superior at 30 days in the composite endpoint of death and major bleeding not associated with CABG (8.4% vs. 5.1%, P = 0.03), mainly due to a decrease in the rates of major bleeding events (6.1% vs. 2.7%, P < 0.001).29 Conversely, bivalirudin showed a significant increase in the frequency of stent thrombosis (1.6% vs. 0.5%, P < 0.02) compared with the usual heparin regimen. Moreover, a recent aggregated data analysis of the HORIZONS-AMI and EUROMAX trials also confirmed a net benefit with bivalirudin in STEMI management with a documented significant increase in stent thrombosis vs. a combination of UFH and GPIs.30 The incidence of acute thrombosis is apparently not reduced by the upstream use of the newer oral antiplatelet agents (employed in about 50% of the cases). However, the prolongation of the bivalirudin infusion (1.75 mg/kg/h) seems to be associated with a lower incidence of this alarming complication.31 These data are yet to be confirmed through large randomized clinical trials.

by the upstream use of the newer oral antiplatelet agents (employed in about 50% of the cases). However, the prolongation of the bivalirudin infusion (1.75 mg/kg/h) seems to be associated with a lower incidence of this alarming complication.31 These data are yet to be confirmed through large randomized clinical trials. Of note, in a recent meta-analysis on overall 22 controlled randomized trials and 22 434 patients undergoing pPCI use of LMWH plus GPI provided the best protection from adverse events compared with UFH, fondaparinux, and bivalirudin, apparently without increase in bleeding complications; among the single-drug strategies, a similar degree of prevention from ischaemic events was found with UFH, fondaparinux, and bivalirudin; the latter, however, was associated with a 42% relative reduction in the risk of major bleeding vs. UFH alone.32 Executive summary

Of note, in a recent meta-analysis on overall 22 controlled randomized trials and 22 434 patients undergoing pPCI use of LMWH plus GPI provided the best protection from adverse events compared with UFH, fondaparinux, and bivalirudin, apparently without increase in bleeding complications; among the single-drug strategies, a similar degree of prevention from ischaemic events was found with UFH, fondaparinux, and bivalirudin; the latter, however, was associated with a 42% relative reduction in the risk of major bleeding vs. UFH alone.32 Executive summary In patients with a confirmed diagnosis of ACS (particularly STEMI) admitted in a structured and efficient network of emergency transport, it is reasonable to start antithrombotic therapies (DAPT + an anticoagulant agent) in the pre-hospital setting. The bleeding risk beside the ischaemic risk should be carefully evaluated in all patients with ACS. Pre-hospital thrombolysis is a valid alternative to pPCI in patients with a confirmed diagnosis of STEMI in whom pPCI cannot be performed within 1 h, a short time interval between symptom onset and diagnosis (<3 h), as long as followed by PCI at least 3 h after successful thrombolysis. In patients treated with pre-hospital thrombolysis, it is recommended the use of clopidogrel (300 mg loading dose (LD)) and enoxaparin (30 mg intravenous bolus, followed by 1 mg/kg subcutaneous injection every 12 h in patients <75 years or only 0.75 mg/kg subcutaneous injection every 12 h in patients ≥75 years), with fondaparinux or UFH as second choice. In patients scheduled for pPCI: It is recommended to use enoxaparin (preferentially intravenous route 0.5 mg/kg) or UFH (bolus 5000 UI ev) or bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h infusion);

0.75 mg/kg subcutaneous injection every 12 h in patients ≥75 years), with fondaparinux or UFH as second choice. In patients scheduled for pPCI: It is recommended to use enoxaparin (preferentially intravenous route 0.5 mg/kg) or UFH (bolus 5000 UI ev) or bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h infusion); It is recommended to use novel oral antiplatelet agents (prasugrel 60 mg LD or ticagrelor 180 mg LD); in case of very high bleeding risk, contraindications to or unavailability of novel oral antiplatelet agents it is reasonable to use clopidogrel (600 mg LD); and upstream use of GPI is reasonable for STEMI patients at high ischaemic risk and short time interval between symptom onset and diagnosis.

It is recommended to use novel oral antiplatelet agents (prasugrel 60 mg LD or ticagrelor 180 mg LD); in case of very high bleeding risk, contraindications to or unavailability of novel oral antiplatelet agents it is reasonable to use clopidogrel (600 mg LD); and upstream use of GPI is reasonable for STEMI patients at high ischaemic risk and short time interval between symptom onset and diagnosis. Pathway 2: conservative treatment (unknown coronary anatomy) International registries showed that about 30–50% of patients presented with ACS diagnosis are essentially subjected to conservative medical management.33–37 Recent data from the Italian EYESHOT Registry (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalised in iTalian cardiac care units) showed that about 42% of the study patients with confirmed non-ST-elevation ACS diagnosis did not receive revascularization at the time of admission.38 The risk associated with this patient group is believed to be too high to allow them to undergo angiography and possible revascularization. However, these patients have a much higher rate of in-hospital and long-term mortality.33–38 Besides a higher risk profile and lack of revascularization, this patient group does not apparently receive an optimal pharmacological treatment, as lower administration of antithrombotic drugs compared with guideline recommendations has been observed.33–38 These findings may at least in part explain the high frequency of long-term fatal events.

le and lack of revascularization, this patient group does not apparently receive an optimal pharmacological treatment, as lower administration of antithrombotic drugs compared with guideline recommendations has been observed.33–38 These findings may at least in part explain the high frequency of long-term fatal events. Antiplatelet agents The use of ASA represents the basis for antiplatelet therapy in ACSs. ASA administration is based on the results of almost 30-year-old studies in patients with unstable angina. In this clinical setting, ASA significantly reduced recurrent infarction and mortality rates compared with placebo.39–41 Over the last decades, several studies focused on the association of ASA with thienopyridines in the acute and long-term treatment of ACS patients.

-year-old studies in patients with unstable angina. In this clinical setting, ASA significantly reduced recurrent infarction and mortality rates compared with placebo.39–41 Over the last decades, several studies focused on the association of ASA with thienopyridines in the acute and long-term treatment of ACS patients. Ticlopidine was the first thienopyridine associated with ASA. This molecule was subsequently replaced with clopidogrel due to its higher bioavailability, easier use, and reduced incidence of adverse events incidence (mainly neutropenia, rush, and diarrhoea). ACS treatment with clopidogrel was validated in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial, which was specifically designed to evaluate a conservative approach, and included primarily centres in which there was no routine policy of early use of angiography and revascularization.42 The CURE trial randomized over 12 500 patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) to receive clopidogrel (a 300 mg loading dose, followed by a 75 mg maintenance dose) or placebo in addition to ASA for up to 12 months. The incidence of both primary study endpoints (death from cardiovascular causes, myocardial infarction, or stroke and death from cardiovascular causes, myocardial infarction, stroke, or refractory ischaemia) was significantly reduced with clopidogrel administration, even though there was a significant increase of non-fatal major bleeding complications.42

endpoints (death from cardiovascular causes, myocardial infarction, or stroke and death from cardiovascular causes, myocardial infarction, stroke, or refractory ischaemia) was significantly reduced with clopidogrel administration, even though there was a significant increase of non-fatal major bleeding complications.42 Regarding the use of new inhibitors of the platelet P2Y12 receptor in the conservative strategy, relevant data on ticagrelor are available from a pre-specified analysis of the PLATO trial,43 which assessed patients (28% of the total study population) who were first initiated to a conservative management (although about 25% of this population later received percutaneous or surgical revascularization). In this analysis, the incidence of the primary endpoint (cardiovascular death, myocardial infarction, and stroke) was lower with ticagrelor than with clopidogrel (12.0% vs. 14.3%; HR: 0.85, 95% CI: 0.73–1.00; P = 0.04), and overall mortality was also reduced (6.1% vs. 8.2%; HR: 0.75, 95% CI: 0.61–0.93; P = 0.01).43

n). In this analysis, the incidence of the primary endpoint (cardiovascular death, myocardial infarction, and stroke) was lower with ticagrelor than with clopidogrel (12.0% vs. 14.3%; HR: 0.85, 95% CI: 0.73–1.00; P = 0.04), and overall mortality was also reduced (6.1% vs. 8.2%; HR: 0.75, 95% CI: 0.61–0.93; P = 0.01).43 There are available data on the efficacy and safety of prasugrel in the conservative treatment from the recent TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial.44 In this study, prasugrel was not associated with any beneficial effect in comparison with clopidogrel: at 30 months, the primary endpoint of death from cardiovascular causes, myocardial infarction, or stroke occurred in 13.9% of the prasugrel patient group and in 16.0% of the clopidogrel cohort (HR: 0.91; 95% CI: 0.79–1.05; P = 0.21). The study provided a particularly interesting efficacy outcome: a posthoc analysis on the drug effect showed similar occurrence of ischaemic events on the two arms within the first 12 months of the study and a trend towards a superiority of prasugrel in the following time frame up to 30 months: 0.99 (0.84–1.16) vs. 0.72 (0.54–0.97) (P = 0.07).44 Such potential long-term effect was identified in previous analyses on ACS patients treated conservatively45–47; this has, however, not yet been explained and may be the objective of further studies or trials with longer follow-up phases. With regard to safety in TRILOGY, major bleeding (according to TIMI criteria) in the two study groups occurred with similar frequency among patients aged <75 years: 2.1% with prasugrel vs. 1.5% with clopidogrel (HR: 1.31, 95% CI: 0.81–2.11, P = 0.27). Conversely, the rates of major or minor bleeding were higher in the prasugrel group: 3.3% vs. 2.1% (HR: 1.54; 95% CI: 1.06–2.23; P = 0.02).44 Considering the posthoc nature of the above-mentioned TRILOGY analysis on the long-term outcome, the results should be cautiously interpreted, as confirmed by the fact that, according to the product information sheet, the use of prasugrel is contraindicated in ACS patients receiving a conservative strategy.

= 0.02).44 Considering the posthoc nature of the above-mentioned TRILOGY analysis on the long-term outcome, the results should be cautiously interpreted, as confirmed by the fact that, according to the product information sheet, the use of prasugrel is contraindicated in ACS patients receiving a conservative strategy. Anticoagulants UFH and LMWHs have been the most frequently used anticoagulants in the clinical practice for many decades. Among these, enoxaparin is certainly the most widely studied agent in randomized clinical trials.48,49 The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) and TIMI 11B (Thrombolysis in Myocardial Infarction 11B) trials were performed in a period when conservative treatment was predominant; they were the first studies that compared UFH with enoxaparin in ACS: both trials showed a significant reduction of the primary composite endpoint of death and myocardial infarction in patients treated with LMWHs, without increase in major bleeding complications.50–52 The subsequent trials were conducted in a setting of more invasive strategies and with a more frequent usage of combined platelet aggregation inhibitors, including the A to Z (Aggrastat to Zocor)53 and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) trials.54 However, these studies showed no significant reduction of the composite endpoint of death and myocardial infarction in the enoxaparin arm and revealed a trend towards increased bleeding events; however, in both investigations, a reduction of ischaemic adverse events was observed in ACS patients naive to antithrombotic treatment prior to randomization (∼25% of recruited patients). For the first time, this result highlighted the importance of keeping different anticoagulants during hospitalization separate instead of combining them. A subsequent meta-analysis also including the ACUTE II (Antithrombotic Combination Using Tirofiban and Enoxaparin II) and INTERACT (Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment) trials confirmed the superiority of enoxaparin compared with UFH in terms of death and infarction at 30 days (10.1% vs. 11.0%; OR: 0.91; 95% CI: 0.83–0.99) in ∼22 000 patients with ACS, particularly in those who did not receive antithrombotic treatment prior to randomization (8.0% vs. 9.4%; OR: 0.81; 95% CI: 0.70–0.94), without any increase in major bleeding risk.48

ompared with UFH in terms of death and infarction at 30 days (10.1% vs. 11.0%; OR: 0.91; 95% CI: 0.83–0.99) in ∼22 000 patients with ACS, particularly in those who did not receive antithrombotic treatment prior to randomization (8.0% vs. 9.4%; OR: 0.81; 95% CI: 0.70–0.94), without any increase in major bleeding risk.48 Fondaparinux proved its non-inferiority compared with enoxaparin with respect to the primary efficacy endpoint (death, myocardial infarction, or refractory ischaemia) at 9 days (5.8% vs. 5.7%) in the OASIS-5 clinical trial.55 In this study, over 20 000 NSTE-ACS patients were randomized to receive either fondaparinux, at a dose of 2.5 mg once daily for 8 days by subcutaneous injection, or enoxaparin (1 mg/kg body weight twice daily by subcutaneous injection, with a dose reduction to 1 mg/kg once daily in cases of severe renal impairment) for 2–8 days. The incidence of major bleeding at 9 days was markedly lower with fondaparinux compared with enoxaparin (2.2% vs. 4.1%; HR: 0.52; P < 0.001) and was constant throughout the study and consistent among all the analysed subgroups. At the same time, a significant reduction in mortality with fondaparinux compared with LMWHs was observed at 30 days (2.9% vs. 3.5%; HR: 0.83; P = 0.02) and 6 months (5.8% vs. 6.5%; HR: 0.89; P = 0.05).55 A similar safety and efficacy beneficial outcome compared with treatment with heparin was also observed in STEMI patients undergoing pharmacological treatment from the OASIS-6 trial.56,57 Executive summary

Fondaparinux proved its non-inferiority compared with enoxaparin with respect to the primary efficacy endpoint (death, myocardial infarction, or refractory ischaemia) at 9 days (5.8% vs. 5.7%) in the OASIS-5 clinical trial.55 In this study, over 20 000 NSTE-ACS patients were randomized to receive either fondaparinux, at a dose of 2.5 mg once daily for 8 days by subcutaneous injection, or enoxaparin (1 mg/kg body weight twice daily by subcutaneous injection, with a dose reduction to 1 mg/kg once daily in cases of severe renal impairment) for 2–8 days. The incidence of major bleeding at 9 days was markedly lower with fondaparinux compared with enoxaparin (2.2% vs. 4.1%; HR: 0.52; P < 0.001) and was constant throughout the study and consistent among all the analysed subgroups. At the same time, a significant reduction in mortality with fondaparinux compared with LMWHs was observed at 30 days (2.9% vs. 3.5%; HR: 0.83; P = 0.02) and 6 months (5.8% vs. 6.5%; HR: 0.89; P = 0.05).55 A similar safety and efficacy beneficial outcome compared with treatment with heparin was also observed in STEMI patients undergoing pharmacological treatment from the OASIS-6 trial.56,57 Executive summary Antiplatelet agents [A] STEMI -ASA as soon as possible at a LD of 150–325 mg, followed by 75–100 mg/day. -Ticagrelor (LD of 180 mg, followed by 90 mg × 2/day). -In case of thrombolysis, very high bleeding risk, contraindications to or unavailability of ticagrelor:clopidogrel (LD of 300 mg, followed by 75 mg/day). [B] NSTEMI -ASA as soon as possible at a LD of 150–325 mg, followed by 75–100 mg/day.

Antiplatelet agents [A] STEMI -ASA as soon as possible at a LD of 150–325 mg, followed by 75–100 mg/day. -Ticagrelor (LD of 180 mg, followed by 90 mg × 2/day). -In case of thrombolysis, very high bleeding risk, contraindications to or unavailability of ticagrelor:clopidogrel (LD of 300 mg, followed by 75 mg/day). [B] NSTEMI -ASA as soon as possible at a LD of 150–325 mg, followed by 75–100 mg/day. -Ticagrelor (LD of 180 mg, followed by 90 mg × 2/day. -In case of very high bleeding risk, contraindications to or unavailability of ticagrelor, it is reasonable to use clopidogrel (LD of 300 mg, followed by 75 mg/day). Anticoagulant agents [A] STEMI -Enoxaparin: 30 mg intravenous, followed by 1 mg/kg × 2/day subcutaneously (max 100 mg for the first 2 doses). In patients ≥75 years: no bolus, 0.75 mg/kg × 2/day subcutaneously (max 75 mg for the first 2 doses). [B] NSTEMI -It is recommended to use fondaparinux (2.5 mg/day subcutaneously). -In case of contraindications to or unavailability of fondaparinux, it is reasonable to use enoxaparin (1 mg/kg × 2/day subcutaneously). -Anticoagulation should be maintained up to hospital discharge. -Crossover of heparins (UFH and LMWH) is not recommended.

[B] NSTEMI -It is recommended to use fondaparinux (2.5 mg/day subcutaneously). -In case of contraindications to or unavailability of fondaparinux, it is reasonable to use enoxaparin (1 mg/kg × 2/day subcutaneously). -Anticoagulation should be maintained up to hospital discharge. -Crossover of heparins (UFH and LMWH) is not recommended. Pathways 3 and 4: patient referral for coronary angiography Over the last decades, the percentage of ACS patients referred for coronary angiography markedly increased.58–60 In Italy, the frequency of coronary angiography in ACS patients apparently depends more on the availability of a catheterization laboratory in the hospital of admission rather than on the patient’s ischaemic risk profile.38 In addition to this difference in strategic approach, which clearly differs according to the various hospital facilities, the time between diagnosis and invasive treatment initiation also varies considerably depending on the availability of a catheterization laboratory. In this context, therefore, an adequate antithrombotic pre-treatment and the selection of the appropriate pharmaceutical product become increasingly important in order to reduce the incidence of recurrent ischaemic events.

nitiation also varies considerably depending on the availability of a catheterization laboratory. In this context, therefore, an adequate antithrombotic pre-treatment and the selection of the appropriate pharmaceutical product become increasingly important in order to reduce the incidence of recurrent ischaemic events. Antiplatelet agents The risk/benefit profile of an early administration of a loading dose of thienopyridine is still debated (whereas early administration of ASA is generally approved, regardless of the strategy adopted initially). Based on the results of the EYESHOT Registry, which evidenced an 8-day median time between hospital admission and bypass intervention (when it was needed)—compatible with the programmed discontinuation of any P2Y12 receptor inhibitors38—the potential bleeding risk associated with pre-treatment in patients referred for CABG after coronary angiography appears unsupported.

evidenced an 8-day median time between hospital admission and bypass intervention (when it was needed)—compatible with the programmed discontinuation of any P2Y12 receptor inhibitors38—the potential bleeding risk associated with pre-treatment in patients referred for CABG after coronary angiography appears unsupported. With regard to pre-treatment with oral antiplatelet agents in STEMI patients, reference should be made to the paragraph on pre-hospital management in Pathway 1. In the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, clopidogrel was associated with a clinical benefit in NSTE-ACS patients with a >6 h interval between diagnosis and coronary angiography.61 However, a meta-analysis of the PCI-CURE (PCI-Clopidogrel in Unstable angina to prevent Recurrent Events), CREDO, and PCI-CLARITY (PCI-Clopidogrel as Adjunctive Reperfusion Therapy) trials showed that clopidogrel pre-treatment was beneficial compared with the administration of the loading dose in the catheterization laboratory in terms of both infarction prior to PCI and mortality and infarction following PCI.62 Another meta-analysis of six randomized clinical trials and nine observational studies on close to 38 000 patients with ACS or stable chronic angina recently showed that clopidogrel pre-treatment has a beneficial effect on major cardiac events (9.8% vs. 12.3%; OR: 0.77; 95% CI: 0.66–0.89; P < 0.001), although no effects on overall mortality was observed.63

d clinical trials and nine observational studies on close to 38 000 patients with ACS or stable chronic angina recently showed that clopidogrel pre-treatment has a beneficial effect on major cardiac events (9.8% vs. 12.3%; OR: 0.77; 95% CI: 0.66–0.89; P < 0.001), although no effects on overall mortality was observed.63 The PLATO trial was not a study aimed to evaluate upstream vs. downstream initiation of antiplatelet therapy in patients with ACS; it explored the benefit of ticagrelor compared with clopidogrel pre-treatment as patients were treated before coronary assessment and independently from the adopted strategy.64 This trial showed the superiority of ticagrelor when compared with clopidogrel in reducing clinical adverse events (death, myocardial infarction, or stroke) at 1 year (HR: 0.84; 95% CI: 0.77–0.92; P < 0.001), associated with a significant reduction in mortality (4.5%, vs. 5.9%; P < 0.001), also probably due to the pleiotropic effects related to the similarities with the adenosine mechanism.65 These beneficial effects were also particularly evident in patients with impairment of renal function (estimated glomerular filtration rate from 30 to 60 mL/min)66; treatment with ticagrelor was not associated with increased rates of overall major bleeding events (1.5% vs. 1.3%; P = 0.22), but higher incidence of non-CABG–related major bleeding (4.5% vs. 3.8%; P = 0.03) and intracranial fatal bleeding, even if the occurrence of such complication was very rare in both arms (0.1% vs. 0.01%).64 In addition, ticagrelor is not a prodrug and does not require metabolic conversion before activating: it is therefore an elective drug to achieve a faster platelet inhibition compared with other oral antiplatelet agents, as showed in recent studies on pharmacodynamics.67

n was very rare in both arms (0.1% vs. 0.01%).64 In addition, ticagrelor is not a prodrug and does not require metabolic conversion before activating: it is therefore an elective drug to achieve a faster platelet inhibition compared with other oral antiplatelet agents, as showed in recent studies on pharmacodynamics.67 The ACCOAST (A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pre-treatment At the Time of Diagnosis in Patients with Non-ST-Elevation Myocardial Infarction) trial evaluated the possible benefit of prasugrel pre-treatment in NSTEMI patients who were scheduled to undergo coronary angiography and possible PCI; it compared two different loading doses of prasugrel: a 30 mg loading dose of prasugrel at the time of diagnosis and an additional 30 mg dose at the time of PCI (pre-treatment group) vs. a 60 mg loading dose at the time of angiography.68 The incidence of the primary endpoint, a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or GPI bailout through Day 7, did not differ significantly between the two groups (HR with pre-treatment: 1.02; 95% CI: 0.84–1.25; P = 0.81).68 Conversely, the rate of TIMI major bleeding episodes, whether related or non-related to CABG, was significantly increased through Day 7 in the pre-treatment group (HR: 1.90; 95% CI: 1.19–3.02; P = 0.006), which led to the early interruption of the trial.68 A following meta-analysis, which included ACCOAST and studies on clopidogrel, further confirmed the increased risk of bleeding with no apparent improved ischaemic outcomes.69

increased through Day 7 in the pre-treatment group (HR: 1.90; 95% CI: 1.19–3.02; P = 0.006), which led to the early interruption of the trial.68 A following meta-analysis, which included ACCOAST and studies on clopidogrel, further confirmed the increased risk of bleeding with no apparent improved ischaemic outcomes.69 Against this background, GPIs or the novel antiplatelet agents with intravenous administration (e.g. cangrelor70) can be useful to achieve a rapid and an effective platelet inhibition in ACS patients with high ischaemic risk and allow to wait for the initiation of oral thienopyridine treatment until the coronary tree has been assessed. Recently, the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared with or on top of PRasugrel given at loading dOse) study demonstrated that a standard dose of intravenous bolus-only tirofiban achieves a higher and earlier platelet aggregation inhibition compared with an oral 60 mg loading dose of prasugrel by 6 h.71

P = 0.025), registering, however, a significant 4.5-fold increase in major bleeding vs. clopidogrel (13% vs. 3%; P < 0.001).118 Therefore, the indicated practical approach in case of early prasugrel treatment in patients then scheduled for CABG is comparable to clopidogrel (drug-free period of 5–7 days before surgery). In the PLATO trial, about 2000 patients underwent CABG post-randomization. Based on the study protocol, the study drug was withheld for 5 days in the clopidogrel group and for 24 to 72 h in the ticagrelor group.64 Overall, approximately 1200 patients underwent CABG within 7 days after interruption of the study drug. In the PLATO CABG sub-study, ticagrelor showed a better outcome in the primary ischaemic endpoint, which was consistent with the overall results of the trial, without difference in the rates of CABG-related bleeding events. However, the treatment with ticagrelor instead of clopidogrel resulted in lower total mortality (4.7% vs. 9.7%; HR: 0.49; 95% CI: 0.32–0.77; P < 0.01) and cardiovascular mortality (4.1% vs 7.9%; HR: 0.52; 95% CI: 0.32–0.85; P < 0.01).119 This impressive mortality decline is likely to be due to the drug’s favourable pharmacokinetics and on/off effect, which in this setting resulted in a drastic decrease in major bleeding and perioperative infections compared with clopidogrel.120

n patients with ST-segment elevation myocardial infarction compared with or on top of PRasugrel given at loading dOse) study demonstrated that a standard dose of intravenous bolus-only tirofiban achieves a higher and earlier platelet aggregation inhibition compared with an oral 60 mg loading dose of prasugrel by 6 h.71 Various studies have evaluated the effects of GPIs in early treatment of ACS patients scheduled for coronary angiography. However, this treatment approach was associated with the administration of clopidogrel or other novel P2Y12 receptor inhibitors72 in only a few of these trials. A meta-analysis on ∼30 000 NSTE-ACS patients treated with a conservative approach or undergoing PCI showed a 9% reduction of the relative risk of death and non-fatal myocardial infarction with the use of GPIs when compared with placebo.73 This beneficial effect was associated to PCI performance, whereas no reduction in the death or infarction rates was observed in patients who received only medical therapy. Recent clinical trials assessed whether benefits from GPI treatment could be increased with pre-treatment instead of usage in the catheterization laboratory. The ACUITY Timing (Acute Catheterization and Urgent Intervention Triage strategY) trial evaluated deferred treatment (during PCI only) vs. upstream administration of a GPI in 9207 ACS patients pre-treated with thienopyridine in 64% of the cases.74 Deferred vs. upstream therapy was identified with a lower incidence of non-CABG–related major bleeding episodes at 30 days (4.9% vs. 6.1%; RR: 0.80; 95% CI: 0.67–0.95; P = 0.009), without any difference in the ischaemic adverse event rates (7.9% vs. 7.1%; RR: 1.12; 95% CI: 0.97–1.29; P = 0.13). In the EARLY-ACS (The Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial, 9500 ACS patients who were assigned to an invasive strategy were randomized to early vs. delayed treatment with eptifibatide75; the primary endpoint (a composite of death, myocardial infarction, urgent revascularization, or the occurrence of a thrombotic complication during PCI at 96 h) was similar between two groups (9.3% vs. 10.0%; OR: 0.92; 95% CI: 0.80–1.06; P = 0.23), without significant interaction among the various tested subgroups, including diabetic or troponin-positive patients. Conversely, major bleeding rate was higher in patients receiving early treatment with eptifibatide (2.6% vs.

96 h) was similar between two groups (9.3% vs. 10.0%; OR: 0.92; 95% CI: 0.80–1.06; P = 0.23), without significant interaction among the various tested subgroups, including diabetic or troponin-positive patients. Conversely, major bleeding rate was higher in patients receiving early treatment with eptifibatide (2.6% vs. 1.8%; OR: 1.42; 95% CI: 1.97–1.89; P = 0.015).75 Following these studies, the upstream use of GPIs decreased drastically, especially in the era of the newer P2Y12 antagonists, and GPI treatment is now only applied within the catheterization laboratory based on the coronary angiography results (e.g. in the presence of intracoronary thrombi or based on the extent of the coronary artery disease) and after a careful evaluation of the haemorrhage risk for each patient. The guidelines suggest considering upstream treatment with GPIs in the presence of a large ischaemic area in high-risk patients.1,2 Anticoagulants As in the initially conservative treatment, UFH and LMWHs represent the most commonly used anticoagulants also in patients diagnosed with ACS and scheduled for coronary angiography. The EXTRACT-TIMI 25 trial investigated patients diagnosed with STEMI treated with successful thrombolysis followed by PCI: the study showed the superiority of enoxaparin vs. UFH in reducing the incidence of major adverse events at 30 days in patients treated with TNK-tPA and clopidogrel, although a higher rate of minor and major bleeding events was observed.76

ients diagnosed with STEMI treated with successful thrombolysis followed by PCI: the study showed the superiority of enoxaparin vs. UFH in reducing the incidence of major adverse events at 30 days in patients treated with TNK-tPA and clopidogrel, although a higher rate of minor and major bleeding events was observed.76 International guidelines strongly recommend consistency with the initially selected antithrombotic treatment and the avoidance of any crossover,1,2 as switches in the heparin treatment are associated with increased occurrence of fatal adverse events and short- and long-term major bleeding episodes.77,78

ients diagnosed with STEMI treated with successful thrombolysis followed by PCI: the study showed the superiority of enoxaparin vs. UFH in reducing the incidence of major adverse events at 30 days in patients treated with TNK-tPA and clopidogrel, although a higher rate of minor and major bleeding events was observed.76 International guidelines strongly recommend consistency with the initially selected antithrombotic treatment and the avoidance of any crossover,1,2 as switches in the heparin treatment are associated with increased occurrence of fatal adverse events and short- and long-term major bleeding episodes.77,78 When treatment with fondaparinux is initially selected, it should be noted that this drug had been previously associated with higher incidence of catheter thrombosis in the OASIS-5 trial (see Pathway 2) when coronary angiography and subsequent PCI were performed.55 This problem was basically resolved by adding a UFH dose in the catheterization setting. In the FUTURA/OASIS-8 (Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes) trial, the addition of a standard dose of UFH (85 mg/kg or 60 mg/kg with concomitant use of GPIs) resulted in the decrease of catheter thrombosis rate to 0.1%79 (see Pathway 4, paragraph on PCI). On the other hand, if switching of anticoagulant treatment from UFH/LMWH therapy to bivalirudin in the catheterization laboratory setting (and related timing) is considered, such approach is apparently safe and still maintains the efficacy level of bivalirudin in terms of net clinical benefit at 30 days and 2 years.80,81

ascular mortality (4.1% vs 7.9%; HR: 0.52; 95% CI: 0.32–0.85; P < 0.01).119 This impressive mortality decline is likely to be due to the drug’s favourable pharmacokinetics and on/off effect, which in this setting resulted in a drastic decrease in major bleeding and perioperative infections compared with clopidogrel.120 Due to their reduced plasma half-life, GPIs can be relatively safely interrupted shortly before surgery: eptifibatide and tirofiban have a short half-life of approximately 2 h; abciximab has an even shorter plasma half-life (10 min), but dissociates slowly from the platelet so that full recovery of platelet aggregation responses takes ∼48 h after the infusion has been terminated. Patients undergoing urgent CABG surgery while receiving oral antiplatelet agents or GPI IIb/IIIa receptors require appropriate measures to ensure adequate haemostasis, such as platelet transfusion,1,2 to begin with. In any event, antiplatelet therapy should be resumed 24 h after the resolution of the major bleeding event. Anticoagulants As for PCI, the use of UFH has become widespread in CABG procedures. Treatment can be continued until a few hours before CABG, it is easily manageable in the perioperative time frame and is not associated with significant bleeding. LMWHs can also be conveniently administered up to 12 h before surgical revascularization with no associated major bleeding.121–123 Executive summary

the other hand, if switching of anticoagulant treatment from UFH/LMWH therapy to bivalirudin in the catheterization laboratory setting (and related timing) is considered, such approach is apparently safe and still maintains the efficacy level of bivalirudin in terms of net clinical benefit at 30 days and 2 years.80,81 Executive summary Antiplatelet agents [A] STEMI -ASA as soon as possible at an LD of 150–325 mg, followed by 75–100 mg/day. -Prasugrel (LD of 60 mg, followed by 10 mg/day, in patients clopidogrel naive, younger than 75 years, with a body weight >60 kg and without a history of cerebrovascular events) or ticagrelor (LD 180 mg, followed by 90 mg × 2/day) as soon as possible. -In case of very high bleeding risk, contraindications to or unavailability of the newer oral antiplatelet agents, it is reasonable to use clopidogrel (LD of 600 mg, followed by 75 mg/day). -In case of thrombolysis, it is reasonable to continue with a clopidogrel maintenance dose of 75 mg/day. -Consider upstream GPI in patients at very high thrombotic risk, long time to PCI, and short time interval between symptom onset and diagnosis. [B] NSTEMI -ASA as soon as possible at an LD of 150–325 mg, followed by 75–100 mg/day. -Ticagrelor (LD of 180 mg, followed by 90 mg × 2/day), especially if time to coronary angiography is supposed to be longer than 24 h. -In case of very high bleeding risk, contraindications to or unavailability of ticagrelor, it is reasonable to use clopidogrel (LD of 300 mg, followed by 75 mg/day).

[B] NSTEMI -ASA as soon as possible at an LD of 150–325 mg, followed by 75–100 mg/day. -Ticagrelor (LD of 180 mg, followed by 90 mg × 2/day), especially if time to coronary angiography is supposed to be longer than 24 h. -In case of very high bleeding risk, contraindications to or unavailability of ticagrelor, it is reasonable to use clopidogrel (LD of 300 mg, followed by 75 mg/day). -In patients promptly addressed to an invasive strategy pre-treatment with DAPT has not been adequately investigated. Anticoagulant agents [A] STEMI -It is recommended to use enoxaparin (preferentially intravenouis route 0.5 mg/kg) or UFH with an intravenous bolus of 70–100 U/kg (50–70 U/kg in case of concomitant GPI use). -In patients treated with thrombolysis, it is recommended to use enoxaparin (see Pathway 1). [B] NSTEMI -If an anticoagulant agent (enoxaparin, UFH, or fondaparinux) has been previously initiated, it is recommended to be continued, without any replacement. -If no anticoagulant agent has been previously initiated, the use of fondaparinux (2.5 mg/day subcutaneously) is recommended. -In case of contraindications to or unavailability of fondaparinux, it is reasonable to use enoxaparin (1 mg/kg × 2/day). If patients do not receive any type of revascularization, anticoagulation should be maintained up to hospital discharge. Crossover of heparins (UFH and LMWH) is not recommended.

-If no anticoagulant agent has been previously initiated, the use of fondaparinux (2.5 mg/day subcutaneously) is recommended. -In case of contraindications to or unavailability of fondaparinux, it is reasonable to use enoxaparin (1 mg/kg × 2/day). If patients do not receive any type of revascularization, anticoagulation should be maintained up to hospital discharge. Crossover of heparins (UFH and LMWH) is not recommended. Pathway 5: percutaneous coronary revascularization (percutaneous coronary intervention) Percutaneous coronary intervention is the most widely used revascularization procedure in the framework of ACSs, which led to a net improvement in the prognosis of these patients.82,83 Based on the assumption that ACS patients already present a high thrombin generation level and a substantial platelet aggregation activity, and that PCI with intracoronary stent implantation is per se associated with thrombotic activation, achieving a maximum antithrombotic effect is crucial. Over the past years, several randomized clinical trials have focused on peri-procedural antithrombotic therapy, a topic that requires a constant update of international guidelines on ACSs.

acoronary stent implantation is per se associated with thrombotic activation, achieving a maximum antithrombotic effect is crucial. Over the past years, several randomized clinical trials have focused on peri-procedural antithrombotic therapy, a topic that requires a constant update of international guidelines on ACSs. Antiplatelet agents The CURRENT OASIS-7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) trial was specifically aimed at investigating the optimal clopidogrel and aspirin doses for ACS patients undergoing PCI within 72 h from admission.84 Results indicated that a double dose of clopidogrel (600 mg loading dose, followed by 150 mg once daily for 1 week) could achieve a faster and stronger effect compared with a routine dose (300 mg loading dose, followed by 75 mg once daily), resulting in a more significant clinical benefit. The study, carried out in 597 coronary care units in 39 countries, included 25 000 patients, 17 000 of which underwent PCI. Among these, a significant 15% reduction of the primary endpoint (cardiovascular death, myocardial infarction, and stroke) was observed in the group treated with the clopidogrel double dose.84 Such reduction mainly concerned the infarction rate with a 22% decrease. In addition, a 42% reduction in the risk of stent thrombosis was registered. The double dose of the drug did not result in increased brain or fatal haemorrhages, but overall major bleeding was significantly increased. The study also showed no difference between low (75–100 mg once daily) and high dosage (300–325 mg once daily) of ASA in terms of both efficacy and safety.84

bosis was registered. The double dose of the drug did not result in increased brain or fatal haemorrhages, but overall major bleeding was significantly increased. The study also showed no difference between low (75–100 mg once daily) and high dosage (300–325 mg once daily) of ASA in terms of both efficacy and safety.84 Data from the PLATO trial are based on the patient population for whom an invasive strategy was planned (PLATO INVASIVE). In the study, however, there are no specific data on the patient group undergoing PCI.85 At randomization, an invasive strategy was planned for 72% of the ACS patients enrolled. The primary endpoint occurred in 9% of the ticagrelor patient group vs. 10.7% of the clopidogrel group (HR: 0.84; 95% CI: 0.75–0.94; P = 0.0025), and no difference was observed between the two treatment groups in the rates of total major and severe bleedings at 1 year follow-up.85 The PEGASUS TIMI-54 trial (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) recently also opened to long-term treatment in specific patient populations.86 The trial randomized 21 162 high-risk patients with previous infarction (83% of whom had already undergone PCI) to receive ticagrelor (90 or 60 mg) vs. placebo on top of low-dose ASA for a median duration of 33 months. Both dosages of ticagrelor significantly reduced the incidence of the primary endpoint (cardiovascular death, myocardial infarction, and stroke) compared with placebo (HR of 90 mg ticagrelor vs. placebo: 0.85; 95% CI: 0.75–0.96; P = 0.008; HR of 60 mg ticagrelor vs. placebo: 0.84; 95% CI: 0.74–0.95; P = 0.004). Both ticagrelor dosages increased the rate of major TIMI bleeding episodes (2.60% at 90 mg and 2.30% at 60 mg) compared with placebo (1.1%; P < 0.001 for each ticagrelor vs. placebo dose). However, the risk of intracranial haemorrhages and fatal bleedings was comparable between ticagrelor and placebo.86

95; P = 0.004). Both ticagrelor dosages increased the rate of major TIMI bleeding episodes (2.60% at 90 mg and 2.30% at 60 mg) compared with placebo (1.1%; P < 0.001 for each ticagrelor vs. placebo dose). However, the risk of intracranial haemorrhages and fatal bleedings was comparable between ticagrelor and placebo.86 Efficacy data with prasugrel in patients who underwent PCI are available from the TRITON TIMI 38 trial.87 In the study, 13 608 patients with moderate-to-high-risk ACS with scheduled PCI were randomized to receive clopidogrel (300 mg loading dose, followed by 75 mg once daily) or prasugrel (60 mg loading dose, followed by 10 mg once daily) in the catheterization laboratory following coronary angiography (with the exception of the STEMI population,21 for whom randomization before assessment of the coronary tree was allowed).87 Patients under chronic clopidogrel treatment, with bleeding diatheses or presenting any other features of high risk of bleeding, were not eligible to participate in the study. The primary endpoint was death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. The primary efficacy endpoint occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (HR: 0.81; 95% CI: 0.73–0.90; P < 0.001). The primary endpoint outcomes were mostly characterized by a 24% reduction in the prasugrel group in the rates of myocardial infarction.87 The benefit tended to be greater among the patient subgroup with diabetes, with a 30% reduction of the primary endpoint (HR: 0.70; 95% CI: 0.58–0.85) and a statistically significant interaction with respect to the reduction of myocardial infarction rate.87 It should be noted that a marked reduction in the stent thrombosis rate was registered in the TRITON-TIMI 38 trial in the patients randomized to receive prasugrel: possible or probable thrombosis (as per the Academic Research Consortium definition) was reduced by 52% (1.1% vs. 2.4%; P < 0.001), while the documented thrombosis rate (by coronary angiography or autopsy) decreased by 58% (0.9% vs. 2.0%; P < 0.001). Data were consistent among patients who received conventional or medicated stents.88 With regard to safety, the rate of TIMI major bleeding episodes not CABG-related was higher in the prasugrel treatment group (2.4% vs. 1.8%; HR: 1.32; 95% CI: 1.03–1.68; P = 0.03), with an increase in the rate of life-threatening and—although infrequent—fatal bleeding events.

eceived conventional or medicated stents.88 With regard to safety, the rate of TIMI major bleeding episodes not CABG-related was higher in the prasugrel treatment group (2.4% vs. 1.8%; HR: 1.32; 95% CI: 1.03–1.68; P = 0.03), with an increase in the rate of life-threatening and—although infrequent—fatal bleeding events. A multivariate analysis showed that the highest risk of major bleeding was registered among patients with 75 years of age or older, patients weighing <60 kg (relative contraindication for the use of prasugrel) and patients who had a history of cerebrovascular events (absolute contraindication for the use of prasugrel).87 In the other patients, the higher prasugrel efficacy was not associated with any increase of bleeding events. Despite biological evidence89 and the availability of recently published data from observational studies showing the relative safety of switching from clopidogrel to prasugrel in patients undergoing PCI,90–92 further data from larger studies are needed to investigate the risk/benefit profile of such therapeutic strategy.

Despite biological evidence89 and the availability of recently published data from observational studies showing the relative safety of switching from clopidogrel to prasugrel in patients undergoing PCI,90–92 further data from larger studies are needed to investigate the risk/benefit profile of such therapeutic strategy. The efficacy of cangrelor (an intravenous adenosine diphosphate (ADP)-receptor antagonist) during PCI performance was mostly assessed in patients with stable coronary artery diseases and in the CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial: in the study population, which included over 11 000 stable and unstable patients naive to oral antiplatelet therapy, cangrelor significantly reduced the incidence of the primary endpoint, a composite of death, myocardial infarction, stent thrombosis, and revascularization, at 48 h compared with placebo (4.7% vs. 5.9%; P = 0.005), and reduced the rate of stent thrombosis at 48 h (0.8% vs. 1.4%; P = 0.01), with no increase in severe bleeding rate at 48 h (0.16% vs. 0.11%; P = 0.44).93,94

primary endpoint, a composite of death, myocardial infarction, stent thrombosis, and revascularization, at 48 h compared with placebo (4.7% vs. 5.9%; P = 0.005), and reduced the rate of stent thrombosis at 48 h (0.8% vs. 1.4%; P = 0.01), with no increase in severe bleeding rate at 48 h (0.16% vs. 0.11%; P = 0.44).93,94 Vorapaxar is an orally active selective inhibitor of the platelet thrombin receptor PAR-1. The TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial enrolled 12 944 NSTE-ACS patients randomized to vorapaxar 40 mg loading and 2.5 mg daily maintenance or placebo in addition to ASA and clopidogrel. After a median follow-up of 502 days, the primary endpoint of cardiovascular death, myocardial infarction, stroke, recurrent ischaemia, and urgent revascularization did not differ significantly among the groups [vorapaxar 18.5% vs. placebo 19.9%; HR 0.92 (95% CI 0.85–1.01), P = 0.07], while severe bleeding events were more frequent in the study drug group [vorapaxar 7.2% vs. placebo 5.2%; HR 1.35 (95% CI 1.16–1.58), P < 0.001], with a marked increase in intracranial haemorrhage [HR 3.39 (95% CI 1.78–6.45), P < 0.001].95 In the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial, including 26 449 patients with prior myocardial infarction, stroke, or peripheral vascular disease, randomization to vorapaxar was associated with a modest reduction in cardiovascular death, myocardial infarction, and stroke over 3 years [vorapaxar 9.3% vs. placebo 10.5%; HR 0.87 (95% CI 0.80–0.94), P < 0.001].96 Administration of the study drug was associated with an increase in intracranial haemorrhage, and the absolute increase in TIMI clinically significant bleeds [vorapaxar 15.8% vs. placebo 11.1%; HR 1.46 (95% CI 1.36–1.57), P < 0.001] was greater than the absolute reduction in ischaemic events. In the subgroup of 17 779 patients with prior myocardial infarction, rates of the primary endpoint over 3 years were 8.1% in the vorapaxar group vs. 9.7% in the placebo group [HR 0.80 (95% CI 0.72–0.89), P < 0.0001]. TIMI clinically significant bleeding occurred in 15.1% and 10.4% of patients, respectively [HR 1.49 (95% CI 1.36–1.63), P < 0.0001].96

nts with prior myocardial infarction, rates of the primary endpoint over 3 years were 8.1% in the vorapaxar group vs. 9.7% in the placebo group [HR 0.80 (95% CI 0.72–0.89), P < 0.0001]. TIMI clinically significant bleeding occurred in 15.1% and 10.4% of patients, respectively [HR 1.49 (95% CI 1.36–1.63), P < 0.0001].96 Notably, around 5–8% of ACS patients undergoing PCI have an indication for long-term oral anticoagulation therapy (OAC) with vitamin K antagonists or novel OAC (NOAC) due to various conditions such as atrial fibrillation, mechanical heart valves, or venous thromboembolism. In the peri-procedural phase, it should be considered to perform coronary angiography on OAC, because interruption of OAC and bridging with parenteral anticoagulants may lead to an increase in both thromboembolic episodes and bleeds.1 Regarding long-term antithrombotic treatment, evidence to guide the management of ACS patients undergoing PCI and requiring long-term OAC is limited. Duration of triple therapy, defined as the combination of ASA, clopidogrel, and OAC, should be as limited as possible, depending on careful assessment of both thromboembolic and bleeding risks.1

thrombotic treatment, evidence to guide the management of ACS patients undergoing PCI and requiring long-term OAC is limited. Duration of triple therapy, defined as the combination of ASA, clopidogrel, and OAC, should be as limited as possible, depending on careful assessment of both thromboembolic and bleeding risks.1 Anticoagulants The use of UFH during PCI is restricted because of the unpredictability of its anticoagulant effects, the narrow therapeutic windows it provides, and the related need for close monitoring.97 Despite those restrictions and the lack of supporting, randomized, placebo-controlled clinical trials of relevance, the use of anticoagulants during urgent or primary elective PCI has always focused on the application of UFH, based on personal experiences and empirical data. Currently, enoxaparin is the most scientifically supported LMWH in the PCI setting. It offers a predictable anticoagulation effect and no required anticoagulation monitoring.98,99 The drug can be subcutaneously or intravenously administered to achieve immediate anticoagulation. A recent meta-analysis of 23 trials, including approximately 31 000 patients with stable coronary artery disease, non-ST-elevation ACSs, and STEMI undergoing PCI, demonstrated the clinical benefits of enoxaparin vs. UFH with regard to reduction in mortality (relative risk: 0.66; 95% CI: 0.57–0.76; P < 0.001), the composite endpoint of death or myocardial infarction (0.68, 0.57–0.81; P < 0.001), complications of myocardial infarction (0.75, 0.6–0.85; P < 0.001) and major bleeding episodes (0.80, 0.68–0.95; P = 0.009).7

oxaparin vs. UFH with regard to reduction in mortality (relative risk: 0.66; 95% CI: 0.57–0.76; P < 0.001), the composite endpoint of death or myocardial infarction (0.68, 0.57–0.81; P < 0.001), complications of myocardial infarction (0.75, 0.6–0.85; P < 0.001) and major bleeding episodes (0.80, 0.68–0.95; P = 0.009).7 Bivalirudin apparently overcomes the limits of conventional anticoagulation agents, and thanks to its high efficacy and reduced plasma half-life, appeared to be an ideal drug for patients referred for PCI.100 The ACUITY trial101 enrolled over 13 800 moderate-to-high-risk patients with non-ST-elevation ACSs. The subjects were randomized to receive UFH or enoxaparin plus a GPI, bivalirudin plus a GPI, or bivalirudin alone and underwent coronary angiography with eventual PCI within 72 h after randomization; the study tested the hypothesis that bivalirudin would be non-inferior compared with the standard treatment with UFH + GPI. In the study, bivalirudin alone reduced the rates of major bleeding (48%) and the net clinical outcome endpoint (14%).101 In the recent ISAR REACT 4 trial, over 1700 patients with non-ST-segment elevation myocardial infarction were assigned to receive abciximab plus UFH or bivalirudin.102 This study’s specific objective was to assess the superiority of bivalirudin compared with the UFH + abciximab group in reducing the composite endpoint of death, recurrent myocardial infarction, target vessel revascularization, or major bleeding within 30 days. The primary endpoint occurred in 10.9% of the patients randomized to abciximab and in 11.0% of the bivalirudin group (relative risk with abciximab: 0.99; 95% CI: 0.74–1.32; P = 0.94). Major bleeding occurred in 4.6% of the patients in the abciximab group, compared with 2.6% in the bivalirudin group (relative risk: 1.84; 95% CI: 1.10–3.07; P = 0.02).102 As stated above, the HORIZONS-AMI trial tested bivalirudin in STEMI patients.10 Anticoagulation with bivalirudin compared with heparin plus GPIs consistently reduced the rate of major bleeding (4.9% vs. 8.3%; P < 0.001) and resulted in a reduced 30-day rate of net adverse clinical events, defined as major bleeding, mortality, urgent revascularization, myocardial infarction, and stroke (9.2% vs. 12.1%; P = 0.005). Interestingly, patients randomized to bivalirudin also showed reduced rates of death from all causes (2.1% vs. 3.1%; P = 0.047) and death from cardiac causes (1.8% vs.

adverse clinical events, defined as major bleeding, mortality, urgent revascularization, myocardial infarction, and stroke (9.2% vs. 12.1%; P = 0.005). Interestingly, patients randomized to bivalirudin also showed reduced rates of death from all causes (2.1% vs. 3.1%; P = 0.047) and death from cardiac causes (1.8% vs. 2.9%; P = 0.03).10 In a landmark analysis at 3 years, which excluded 30-day adverse events, bivalirudin was still associated with a significantly reduced cardiac mortality compared with the population treated with UFH + GPI (1.1% vs. 2.2%; P = 0.01), even excluding patients with a history of major bleeding (3.8% vs. 2.6%; P = 0.048).103 Recent randomized clinical trials questioned the efficacy of bivalirudin in STEMI patients compared with UFH alone (without systemic use of GPIs). The multicentre, randomized BRAVE-4 (The Bavarian Reperfusion Alternatives Evaluation 4) trial, which was prematurely stopped due to issues with patient enrolment, randomized 548 STEMI patients (compared with a planned population of 1240 patients) to prasugrel plus bivalirudin regimen vs. treatment with clopidogrel plus UFH.104 At 30 days, the primary composite endpoint of death, myocardial infarction, urgent revascularization, stent thrombosis, stroke, or bleeding was comparable in the two treatment groups (15.6% vs. 14.5%; P = 0.68) and neither the composite of ischaemic complications nor bleeding presented major differences; results were consistent across the pre-specified subgroups of patients.104 The HEAT PPCI (Unfractionated heparin vs bivalirudin in primary percutaneous coronary intervention) trial enrolled ∼1800 STEMI patients from a single centre and randomized them to bivalirudin or UFH (GPIs were used in a little over 15% of the patient population).105 The incidence of the primary efficacy outcome, a composite of mortality, cerebrovascular accident, myocardial infarction, or urgent revascularization at 30 days, was lower in the UFH group (5.7% vs. 8.7%; P = 0.01), and no difference was observed in the rate of major bleeding events between the two groups (3.5% vs. 3.1%; P = 0.59). A significantly higher rate of stent thrombosis was registered in the bivalirudin group (3.4% vs.

nfarction, or urgent revascularization at 30 days, was lower in the UFH group (5.7% vs. 8.7%; P = 0.01), and no difference was observed in the rate of major bleeding events between the two groups (3.5% vs. 3.1%; P = 0.59). A significantly higher rate of stent thrombosis was registered in the bivalirudin group (3.4% vs. 0.9%; P = 0.001).105 Finally, in the recent MATRIX (Minimising Adverse haemorrhagic events by TRansradial access site and systemic Implementation of angioX) trial,106 which enrolled 6800 ACS patients undergoing invasive management, bivalirudin failed to significantly reduce the 30-day risk of MACE or net adverse clinical events, a co-primary endpoint including MACE and major bleeding, when compared with patients who received UFH. Treatment with bivalirudin did significantly reduce all-cause mortality, including a statistically significant 30% relative reduction in the risk of cardiovascular death and a 32% reduction in the risk of cardiac death (even if not powered for both endpoints). In addition, the use of bivalirudin did result in a significant reduction in non-access site bleeding, bleeding requiring a blood transfusion, fatal bleeding, and other bleeding measures.106

on in the risk of cardiovascular death and a 32% reduction in the risk of cardiac death (even if not powered for both endpoints). In addition, the use of bivalirudin did result in a significant reduction in non-access site bleeding, bleeding requiring a blood transfusion, fatal bleeding, and other bleeding measures.106 In the OASIS-5 (see Pathway 2) trial, fondaparinux was associated with a higher rate of catheter thrombosis when used in combination with invasive procedures compared with enoxaparin.55 This led to an amendment during the trial: the introduction of UFH in case of PCI prevented this dangerous thrombotic event.107 The subsequent FUTURA/OASIS-8 trial.79 was designed and conducted to assess the correct dose of UFH to be added to fondaparinux in case of PCI in high-risk ACS patients. The study randomly compared two different UFH dose regimens in addition to fondaparinux in 2000 patients undergoing PCI within 72 h: a low (50 U/kg, regardless of concomitant use of GPIs) or standard dose (85 U/kg and 60 U/kg in association with GPIs). Incidence of minor or major bleeding, or major vascular complications up to 48 h after PCI was similar in both dose regimens (OR: 0.80; 95% CI: 0.54–1.19; P = 0.27), with a lower rate of minor bleeding events in the low-dose group (OR: 0.40; 95% CI: 0.16–0.97; P = 0.04).79 For the clinical secondary outcome, defined as a composite of major bleeding at 48 h and death, myocardial infarction, or target vessel revascularization within Day 30, the rates in the UFH low dose arm lower (OR: 1.51; 95% CI: 1.00–2.28; P = 0.05) than in the standard dose group.79

.40; 95% CI: 0.16–0.97; P = 0.04).79 For the clinical secondary outcome, defined as a composite of major bleeding at 48 h and death, myocardial infarction, or target vessel revascularization within Day 30, the rates in the UFH low dose arm lower (OR: 1.51; 95% CI: 1.00–2.28; P = 0.05) than in the standard dose group.79 Regarding long-term anticoagulation therapy, it is worth to quote the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin with or without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI 51) study that compared rivaroxaban 2.5 mg or 5 mg twice daily with placebo in 15 526 patients following ACS, on top of ASA and clopidogrel.108 At a mean follow-up of 13 months, the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke was 10.7% with placebo, 9.1% with rivaroxaban 2.5 mg [HR 0.84 (95% CI 0.72–0.97), P =0.02] and 8.8% with rivaroxaban 5 mg [HR 0.85 (95% CI 0.73–0.98), P = 0.03], with no interaction by ACS subtype. Rates of definite, probable, or possible stent thrombosis were 2.2% and 2.3% with 2.5 and 5 mg rivaroxaban, respectively, vs. 2.9% with placebo (P = 0.02 and P = 0.04, respectively).108 Rates of cardiovascular death were significantly lower only in the rivaroxaban 2.5 mg arm compared with placebo [2.7% vs. 4.1%; HR 0.66 (95% CI 0.51–0.86), P = 0.002]. On the other hand, intracranial haemorrhage rates were 0.4% with 2.5 mg and 0.7% with 5 mg rivaroxaban vs. 0.2% with placebo [HR 2.83 (95% CI 1.02–7.86), P= 0.04 for 2.5 mg; HR 3.74 (95% CI 1.39–10.07), P = 0.005 for 5 mg].108 Therefore, the use of rivaroxaban 2.5 mg twice daily, while not recommended in patients treated with ticagrelor or prasugrel, might be considered in combination with ASA and clopidogrel for ACS patients who have high ischaemic and low bleeding risks. It is contraindicated in patients with a prior history of ischaemic stroke/transient ischaemic attack and its use is cautioned in patients >75 years of age or <60 kg body weight.

or or prasugrel, might be considered in combination with ASA and clopidogrel for ACS patients who have high ischaemic and low bleeding risks. It is contraindicated in patients with a prior history of ischaemic stroke/transient ischaemic attack and its use is cautioned in patients >75 years of age or <60 kg body weight. Executive summary Antiplatelet agents The duration of triple therapy (ASA, clopidogrel, and OAC), when needed, should be as limited as possible, depending on the clinical setting as well as the thromboembolic (CHA2DS2-VASc score) and bleeding risks (6 months in case of HAS-BLED 0-2 and 1 month for HAS-BLED ≥3). In the absence of safety and efficacy data, the use of prasugrel or ticagrelor as part of triple therapy should be avoided. P2Y12 inhibitor administration in addition to ASA beyond 1 year should be considered in selected post-myocardial infarction patients, after careful assessment of both ischaemic and bleeding risks [A] STEMIIn patients treated with thrombolysis before PCI: -continue ASA (75–100 mg/day) and clopidogrel (75 mg/day). In patients treated with pPCI: -continue ASA (75–100 mg/day) and the P2Y12 receptor antagonist previously selected (Pathway 4); -in patients on treatment with clopidogrel (for unavailability of the newer P2Y12 receptor antagonists), a switch to ticagrelor (LD 180 mg, followed by 90 mg × 2/day) is possible and a switch to prasugrel (LD 60 mg followed by 10 mg/day) appears reasonable (if not contraindicated and in the absence of very high bleeding risk); and

on treatment with clopidogrel (for unavailability of the newer P2Y12 receptor antagonists), a switch to ticagrelor (LD 180 mg, followed by 90 mg × 2/day) is possible and a switch to prasugrel (LD 60 mg followed by 10 mg/day) appears reasonable (if not contraindicated and in the absence of very high bleeding risk); and -consider in cath use of GPI in case of high thrombotic burden, bailout or for patients at very high thrombotic risk but without features of high bleeding risk. [B] NSTEMI -Continue ASA (75–100 mg/day) and the P2Y12 receptor antagonist previously selected (Pathway 4). -In patients on treatment with clopidogrel (for unavailability of novel P2Y12 receptor antagonists), a switch to ticagrelor (LD 180 mg followed by 90 mg × 2/day) is possible and a switch to prasugrel (LD 60 mg, followed by 10 mg/day) appears reasonable (if no very high bleeding risk or contraindications exist). -In patients not receiving any P2Y12 inhibitor before PCI (naive), it is recommended to use prasugrel (LD 60 mg, followed by 10 mg/day, with the exception of those older than 75 years, with a body weight <60 kg, and a history of cerebrovascular events) or ticagrelor (LD 180 mg, followed by 90 mg × 2/day) or, in case of very high bleeding risk or contraindications to or unavailability of the newer P2Y12 inhibitors, clopidogrel (LD 600 mg, followed by 75 mg/day). -Consider the use of GPI in bailout or for patients at very high thrombotic risk but without features of high bleeding risk or with high thrombotic burden.

-In patients not receiving any P2Y12 inhibitor before PCI (naive), it is recommended to use prasugrel (LD 60 mg, followed by 10 mg/day, with the exception of those older than 75 years, with a body weight <60 kg, and a history of cerebrovascular events) or ticagrelor (LD 180 mg, followed by 90 mg × 2/day) or, in case of very high bleeding risk or contraindications to or unavailability of the newer P2Y12 inhibitors, clopidogrel (LD 600 mg, followed by 75 mg/day). -Consider the use of GPI in bailout or for patients at very high thrombotic risk but without features of high bleeding risk or with high thrombotic burden. -In patients not receiving any P2Y12 inhibitor before PCI (naive), the use of cangrelor may be considered. Anticoagulant agents [A] STEMI -In patients on treatment with UFH, the use of bivalirudin (at least 30 min after the last UFH dose) is indicated. -In patients not receiving any anticoagulant agents at the time of PCI, the use of bivalirudin (especially in those at high bleeding risk) is indicated. [B] NSTEMI -In patients on treatment with fondaparinux, it is recommended to administer UFH (at least 50 U/kg) at the time of PCI. -In patients on treatment with subcutaneous enoxaparin, it is recommended to administer enoxaparin intravenously (0.3 mg/kg) at the time of PCI. -In patients on treatment with UFH, bivalirudin may be used (at least 30 min after the last UFH dose). -In patients not receiving any anticoagulant agents at the time of PCI, the use of bivalirudin (especially in those at high ischaemic and bleeding risk) is indicated.

-In patients on treatment with subcutaneous enoxaparin, it is recommended to administer enoxaparin intravenously (0.3 mg/kg) at the time of PCI. -In patients on treatment with UFH, bivalirudin may be used (at least 30 min after the last UFH dose). -In patients not receiving any anticoagulant agents at the time of PCI, the use of bivalirudin (especially in those at high ischaemic and bleeding risk) is indicated. -Crossover of heparins (UFH and LMWH) is not recommended.

-In patients on treatment with UFH, bivalirudin may be used (at least 30 min after the last UFH dose). -In patients not receiving any anticoagulant agents at the time of PCI, the use of bivalirudin (especially in those at high ischaemic and bleeding risk) is indicated. -Crossover of heparins (UFH and LMWH) is not recommended. Pathway 6: surgical myocardial revascularization (coronary artery bypass graft) Today’s therapeutic and strategic choices are still influenced by the fear that ACS patients could present a coronary artery disease of such significant extent and severity as to require CABG. This fear led to under-treatment in early ACS stages in the attempt to avoid surgical revascularization, a procedure that is becoming increasingly rarer, particularly in an emergency setting, due to advanced cardiac interventional technology and the increased experience of operators.109 Moreover, recent surgical technologies, such as the off-pump surgery and emerging new methods for blood salvage and platelet transfusion markedly reduced the risk of major bleeding in ACS patients managed with single or dual antiplatelet therapy.110 The upstream antithrombotic treatment was gradually abandoned in consequence of this technological progress, as well as of recently designed studies, combined with a decreased time of diagnosis and coronary angiography in centres equipped with 24-h operational catheterization laboratories, which resulted in a worrisome increased risk of antithrombotic under-treatment in ACS patients.

onsequence of this technological progress, as well as of recently designed studies, combined with a decreased time of diagnosis and coronary angiography in centres equipped with 24-h operational catheterization laboratories, which resulted in a worrisome increased risk of antithrombotic under-treatment in ACS patients. Antiplatelet agents Several studies showed that perioperative use of ASA and clopidogrel is associated with a higher risk of bleeding, transfusion, and reoperation for bleeding.111–115 In a study carried out in 14 centres on 350 patients undergoing CABG, a three-fold increase in the risk of reoperation for bleeding was observed in patients who received clopidogrel within 5 days from surgery.116 This is consistent with the data from a sub-analysis of the CURE trial117 and led to the recommendation that treatment with clopidogrel in patients scheduled for CABG should be withheld 5–7 days before surgery.

of reoperation for bleeding was observed in patients who received clopidogrel within 5 days from surgery.116 This is consistent with the data from a sub-analysis of the CURE trial117 and led to the recommendation that treatment with clopidogrel in patients scheduled for CABG should be withheld 5–7 days before surgery. There are relatively few data on clopidogrel safety in CABG patients, as the only available information can be inferred from the TRITON-TIMI 38 trial population, a study basically designed to include patients with scheduled PCI, where only 1% of the enrolled population underwent surgical revascularization.87 In this small patient subgroup, prasugrel was associated with reduced all-cause mortality (adjusted odds ratio: 0.26; P = 0.025), registering, however, a significant 4.5-fold increase in major bleeding vs. clopidogrel (13% vs. 3%; P < 0.001).118 Therefore, the indicated practical approach in case of early prasugrel treatment in patients then scheduled for CABG is comparable to clopidogrel (drug-free period of 5–7 days before surgery).

Anticoagulants As for PCI, the use of UFH has become widespread in CABG procedures. Treatment can be continued until a few hours before CABG, it is easily manageable in the perioperative time frame and is not associated with significant bleeding. LMWHs can also be conveniently administered up to 12 h before surgical revascularization with no associated major bleeding.121–123 Executive summary Antiplatelet agents In all ACS patients (STEMI and NSTEMI): -Postponing surgery at least for 5 days after cessation of ticagrelor or clopidogrel, and 7 days for prasugrel, if clinically feasible and unless the patient is at high risk of ischaemic events. -DAPT should be considered to be (re)started after CABG surgery as soon as considered safe and continued up to 12 months. -Ticagrelor in addition to ASA has been shown to have an optimal safety/efficiacy profile in ACS patients undergoing CABG. Anticoagulant agents In all ACS patients (STEMI and NSTEMI): It is reasonable to continue the anticoagulant agent (UFH, enoxaparin, and fondaparinux) until few hours before surgery (UFH: 6 h; enoxaparin: 12 h; fondaparinux: 24 h).

-Ticagrelor in addition to ASA has been shown to have an optimal safety/efficiacy profile in ACS patients undergoing CABG. Anticoagulant agents In all ACS patients (STEMI and NSTEMI): It is reasonable to continue the anticoagulant agent (UFH, enoxaparin, and fondaparinux) until few hours before surgery (UFH: 6 h; enoxaparin: 12 h; fondaparinux: 24 h). Pathway 7: conservative treatment (after coronary angiography evaluation) This patient subgroup presents similarities with the patient category described in Pathway 2 (initially conservative treatment). The difference between the two groups is that in Pathway 2 coronary angiography is seldom performed because of the estimated high clinical risk, whereas conservative treatment for this patient subgroup is selected in view of the high anatomical/procedural risk or because there is minimal/no evidence of coronary disease at the angiography evaluation. A further difference with patients receiving an initially conservative treatment lies in the fact that knowledge of the coronary anatomy leads to a more aggressive use of pharmacological treatment.124 However, this population still presents a high risk of long-term events compared with patients benefiting from revascularization procedures. An analysis of the EARLY-ACS trial showed that patients with greater extent of coronary disease (patients with three-vessel coronary disease and critical involvement of the left main) treated with a conservative strategy present a significantly higher risk of both short-term and long-term mortality compared with patients with the same extent of coronary disease who have undergone some kind of revascularization.36

(patients with three-vessel coronary disease and critical involvement of the left main) treated with a conservative strategy present a significantly higher risk of both short-term and long-term mortality compared with patients with the same extent of coronary disease who have undergone some kind of revascularization.36 Antiplatelet agents What was described in Pathway 2 with regard to antiplatelet agents also applies to antiplatelet therapy within this pathway: clopidogrel and ticagrelor are beneficial in a conservative setting even after coronary angiography, performed in 35% of the patients enrolled in the CURE trial42 and in 42% of the PLATO patients undergoing conservative treatment.43 The PLATO study also confirmed the superiority of ticagrelor compared with clopidogrel in the population that was treated conservatively. ESC guidelines recommend the use of ticagrelor, and only when ticagrelor is unavailable or contraindicated of clopidogrel. Treatment with prasugrel is covered in the TRILOGY-ACS trial44; it should be noted that although there was no beneficial outcome in the overall population associated with acute-phase and long-term treatment with prasugrel compared with clopidogrel, a reduction of the primary long-term endpoint was registered in the prasugrel group within the 3000 patients treated with a conservative approach after coronary angiography (10.7% vs. 14.9%; HR: 0.77; 95% CI: 0.61–0.98; P = 0.031). This was observed even though the P value for interaction between the patients who underwent coronary angiography and those who did not was not significant (P = 0.08).44 However, it should be noted that, as mentioned above, this is a posthoc analysis of a study that failed to meet its primary endpoint.

.98; P = 0.031). This was observed even though the P value for interaction between the patients who underwent coronary angiography and those who did not was not significant (P = 0.08).44 However, it should be noted that, as mentioned above, this is a posthoc analysis of a study that failed to meet its primary endpoint. Anticoagulants Recommendations on the use of anticoagulant agents are also similar to those described in Pathway 2. As recommended in the guidelines, anticoagulation treatment should be selected based on the assessment of the ischaemic and haemorrhagic risk profile of each ACS patient and after an evaluation of the efficacy/risk profile of the selected agent (Class 1A recommendation).1,2 In the setting of a conservative treatment, the guidelines also recommend the use of an anticoagulant agent throughout hospitalization (Class 1A recommendation) and discourage the crossing over from one heparin to another.1,2 Executive summary Antiplatelet agents In all ACS patients (STEMI and NSTEMI): -It is recommended to use ASA at a dose of 75–100 mg/day. -Even in patients initially treated with clopidogrel, it is recommended to use ticagrelor (LD of 180 mg, followed by 90 mg ×2/day) for at least 1 year, in those patients without very high bleeding risk and contraindications. Anticoagulant agents In all ACS patients (STEMI and NSTEMI): -Anticoagulation should be maintained up to hospital discharge. -Crossover of heparins (UFH and LMWH) is not recommended.

-Even in patients initially treated with clopidogrel, it is recommended to use ticagrelor (LD of 180 mg, followed by 90 mg ×2/day) for at least 1 year, in those patients without very high bleeding risk and contraindications. Anticoagulant agents In all ACS patients (STEMI and NSTEMI): -Anticoagulation should be maintained up to hospital discharge. -Crossover of heparins (UFH and LMWH) is not recommended. Consensus Document Approval Faculty Abrignani Maurizio Giuseppe, Alunni Gianfranco, Amico Antonio Francesco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Audo Andrea, Azzarito Michele, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Bonvicini Marco, Cacciavillani Luisa, Calculli Giacinto, Canzone Giuseppe, Capecchi Alessandro, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Casolo Giancarlo, Cassin Matteo, Casu Gavino, Cemin Roberto, Chiarandà Giacomo, Chiarella Francesco, Chiatto Mario, Ciccone Marco Matteo, Cicini Maria Paola, Clerico Aldo, Comoglio Francesca Maria, D'Agostino Carlo, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Di Lenarda Andrea, Di Tano Giuseppe, Egidy Assenza Gabriele, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Francese Giuseppina Maura, Gabrielli Domenico, Giardina Achille, Greco Cesare, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Ledda Antonietta, Lucà Fabiana, Macera Francesca, Marini Marco, Mascia Franco, Masson Serge, Maurea Nicola, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Menozzi Alberto, Mininni Nicola, Molon Giulio, Moreo Antonella, Moretti Luciano, Mortara Andrea, Mureddu Gian Francesco, Murrone Adriano, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Oreglia Jacopo, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Procaccini Vincenza, Pulignano Giovanni, Radini Donatella, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Themistoclakis Sakis, Uguccioni Massimo, Urbinati Stefano, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, and Zuin Guerrino

Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Themistoclakis Sakis, Uguccioni Massimo, Urbinati Stefano, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, and Zuin Guerrino Conflict of Interest: L.D.L. reports personal fees from Abbott Vascular, Astra Zeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Daiichi Sankyo, Pharmevo, Menarini and The Medicines Company, outside the submitted work. G.M. reports personal fees from Abbott Vascular, Astra Zeneca, Daiichi Sankyo, Menarini, MSD, St. Jude Medical and The Medicine Company, outside the submitted work. The other authors have no conflicts of interest to declare.

Revised by: Pasquale Caldarola, Giacomo Chiarandà, Mario Chiatto, Mauro Mennuni, Marino Scherillo, Massimo Uguccioni Consensus Document Approval Faculty in Appendix Introduction Statins are drugs registered for the treatment of hypercholesterolaemia. The clinical effect of these drugs is mainly linked to a reduction of the plasmatic level of total cholesterol and of the low-density lipoprotein (LDL) fraction which has a central role in the genesis of atherosclerotic cardiovascular disease. A reduction in plasmatic lipid levels is obtained by inhibition of hepatic3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme in cholesterol biosynthesis. Depletion of hepatic intracellular cholesterol triggers an increase in the expression of surface receptors for plasmatic LDL-cholesterol (LDL-C) which facilitates its removal from the plasma. The result is a reduction in the plasmatic cholesterol level due to reduced synthesis and increased catabolism.1

l biosynthesis. Depletion of hepatic intracellular cholesterol triggers an increase in the expression of surface receptors for plasmatic LDL-cholesterol (LDL-C) which facilitates its removal from the plasma. The result is a reduction in the plasmatic cholesterol level due to reduced synthesis and increased catabolism.1 There are differences among statins in terms of pharmacokinetics, metabolism, excretion route, and efficacy in decreasing plasmatic cholesterol. Simvastatin and lovastatin are both given as prodrugs, whereas other statins are taken in the active form. Pravastatin and rosuvastatin are hydrophilic compounds, but other statins are lipophilic. Lipophilic compounds are metabolized in more hydrophilic compounds as the latter are better able to be eliminated via urinary excretion. Instead, hydrophilic statins are eliminated without being metabolized, thus resulting in less inter-drugs interactions. Excluding pravastatin and rosuvastatin, all the other statins are metabolized in the liver by the isoenzymes of cytochrome P450 (Table 1). Table 1 Clinical pharmacokinetics of the statins

y excretion. Instead, hydrophilic statins are eliminated without being metabolized, thus resulting in less inter-drugs interactions. Excluding pravastatin and rosuvastatin, all the other statins are metabolized in the liver by the isoenzymes of cytochrome P450 (Table 1). Table 1 Clinical pharmacokinetics of the statins Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Sinvastatin Dose, mg 10–80 40–80 20–40 20–40 5-40 10–40 LDL-c reduction, % 30–55 25–35 25–35 25–35 35–60 25–40 Optimal time of administration Any time Evening With meals Evening Any time Evening Absorption 30% 98% 30% 40% 50% 70% Solubility Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic Lipophilic Primary metabolic pathway-cytochromes CYP3A4 CYP2C9 CYP3A4 CYP3A4-minimal CYP2C9-minimal CYP3A4 Metabolites Active Inactive Active Mainly inactive No Active Renalexcretion 2% 6% 30% 60% 10% 15% Hepaticexcretion 90% 90% 70% 40% 90% 85% LDL-C, low-density lipoprotein-cholesterol.

philic Hydrophilic Hydrophilic Lipophilic Primary metabolic pathway-cytochromes CYP3A4 CYP2C9 CYP3A4 CYP3A4-minimal CYP2C9-minimal CYP3A4 Metabolites Active Inactive Active Mainly inactive No Active Renalexcretion 2% 6% 30% 60% 10% 15% Hepaticexcretion 90% 90% 70% 40% 90% 85% LDL-C, low-density lipoprotein-cholesterol. The introduction of these drugs in clinical practice has radically changed management of patients with high cardiovascular risk, both in primary and secondary prevention. In all clinical studies conducted in the last 25 years, the reduction of cholesterolaemia values obtained by statins has always been linked with a significant reduction in atherosclerotic cardiovascular morbidity.1,2 The clinical effect of statins seems independent of the molecule used, being instead completely ascribable to the statin’s efficacy in reducing LDL-C levels.1,2 Meta-analysis shows that each 1 mmol/L (40mg/dL) LDL-C reduction, regardless of the statin used, reduces the relative risk of ischemic cardiac events by 25%, the relative risk of all-cause mortality by 10%, and the ictus risk by 17%.1,2 Being a relative risk reduction, the clinical benefit of statin therapy is independent of single patient characteristics. The probability of adverse cardiovascular events decreases proportionally to the initial risk profile, therefore the higher the initial cardiovascular risk, the more considerable the benefit.

7%.1,2 Being a relative risk reduction, the clinical benefit of statin therapy is independent of single patient characteristics. The probability of adverse cardiovascular events decreases proportionally to the initial risk profile, therefore the higher the initial cardiovascular risk, the more considerable the benefit. Scientific evidence shows a progressive increase in both prescription and pharmaceutical expense for statins in western countries. In Italy, for example, the statin consumption in 2014 reached a defined daily dose of 66 per 1000 inhabitants per day, which reflects an approximately 4% increase in consumption as compared to the previous year.3 Data analysis of pharmaceutical expense covered by public insurance shows that statins have an overall cost of 646 million euros for the Italian National Health Service (SSN) with a total cost of about 11 euros per person per year.3 This cost is quite high considering the lack of patent protection on almost all of these drugs. On the whole, statins account for 3.2% of total SSN pharmaceutical costs.3

ins have an overall cost of 646 million euros for the Italian National Health Service (SSN) with a total cost of about 11 euros per person per year.3 This cost is quite high considering the lack of patent protection on almost all of these drugs. On the whole, statins account for 3.2% of total SSN pharmaceutical costs.3 Safety and tolerability of statin therapy Statins have proven to be safe in the great majority of patients who use them. However, like all drugs, they are not completely without adverse reactions and side effects. The onset of these negative events is the main reason for insufficient adherence to statin treatment and for the resulting failure to meet therapeutic targets. Statin side effects are linked to four main risk factors.4–6Statin dose: as for all drugs, side effects depend on the dose used and have been observed especially during the so-called ‘intensive treatment’, when high doses of lipophilic statins are used (atorvastatin and simvastatin). Exogenous factors: alcohol consumption and excessive physical activity may cause myalgia and an increase in muscle enzyme levels during statin treatment.

Safety and tolerability of statin therapy Statins have proven to be safe in the great majority of patients who use them. However, like all drugs, they are not completely without adverse reactions and side effects. The onset of these negative events is the main reason for insufficient adherence to statin treatment and for the resulting failure to meet therapeutic targets. Statin side effects are linked to four main risk factors.4–6Statin dose: as for all drugs, side effects depend on the dose used and have been observed especially during the so-called ‘intensive treatment’, when high doses of lipophilic statins are used (atorvastatin and simvastatin). Exogenous factors: alcohol consumption and excessive physical activity may cause myalgia and an increase in muscle enzyme levels during statin treatment. Endogenous factors: advanced age, female gender, and low body weight are all conditions that can predispose patients to statin side effects, especially in cases of systemic disease (renal and hepatic dysfunctions, untreated hypothyroidism) and congenital metabolic muscle disease (McArdle disease, carnitinepalmitoyl transferase II deficiency). A complete list of endogenous and exogenous factors associated with statin side effects is reported in Table 2. Table 2 Exogenous and endogenous risk factors for statin side effects

ctions, untreated hypothyroidism) and congenital metabolic muscle disease (McArdle disease, carnitinepalmitoyl transferase II deficiency). A complete list of endogenous and exogenous factors associated with statin side effects is reported in Table 2. Table 2 Exogenous and endogenous risk factors for statin side effects Risk factors Anthropometric Advanced age Female sex Small body weight Asian ethnicity Concomitant disease Acute infections Hypothyroidism Chronic kidney disease Liver cirrhosis Biliary tree obstruction Hepatitis C virus infection Vitamin D deficiency Medical history Previous evidence of CK elevation History of muscle pain Neuromuscular disease History of statin adverse reactions Other factors Drug addiction Alcohol abuse Strenuous exercise Grapefruit juice consumption CK, creatine kinase. Drug interaction: 58% of the most severe side effects are linked to an interaction with concomitant drugs and occur mostly in cases where statins metabolised by cytochrome P450 were used. Therefore, concomitant use of drugs known to interact with statins has to be carefully evaluated. Table 3 reports the list of interacting drugs. Table 3 Main drug–statin interactions

cts are linked to an interaction with concomitant drugs and occur mostly in cases where statins metabolised by cytochrome P450 were used. Therefore, concomitant use of drugs known to interact with statins has to be carefully evaluated. Table 3 reports the list of interacting drugs. Table 3 Main drug–statin interactions Drugs Statin to use or to avoid Fibrates (fenofibrate) Treatment with statins is possible but it is necessary to check CK level because of the myopathy risk Cyclosporine Statin use not recommended Antifungals (azoles) Statin use not recommended Macrolide antibiotics Statin use not recommended Proteaseinhibitors Therapy is possible with pravastatin Amiodarone Use of simvastatin and lovastatin not recommended Dronedarone Use of simvastatin and lovastatin not recommended Non-dihydropyridine calcium channel blockers Use of simvastatin not recommended Ranolazine Use of simvastatin not recommended CK, creatine kinase. Muscle-related adverse effects The most prevalent side effects associated with statin treatment are musculoskeletal complaints referred to in scientific literature as statin-associated muscle symptoms (SAMS). Muscle pain can be persistent and symmetrical, typically involving proximal limb muscles and often associated with weakness and stiffness.4,7,8 Myalgia usually occurs at the beginning of statin treatment (within the first 4 weeks to 6 months of statin exposure), has a widely variable intensity, and, in the majority of cases, occurs without an increased plasmatic level of cytolysis muscle markers, such as creatine kinase (CK).4,7,8

weakness and stiffness.4,7,8 Myalgia usually occurs at the beginning of statin treatment (within the first 4 weeks to 6 months of statin exposure), has a widely variable intensity, and, in the majority of cases, occurs without an increased plasmatic level of cytolysis muscle markers, such as creatine kinase (CK).4,7,8 A mild increase in CK levels can also be observed in the absence of myalgia. In rare cases ‘myopathy or myositis’ (the presence of myalgia with a CK elevation typically 10-fold higher than the normal upper limit of normal) or ‘rhabdomyolysis’ (muscle symptoms associated with a CK level >10 000 U/L or 40-fold higher than the normal upper limit, myoglobinuria, and acute renal failure) can occur.4,7,8 Overall diagnosis of statin muscle injury can be challenging in clinical practice. To overcome these difficulties, several criteria for defining myopathy induced by statins have been proposed. The recent European Atherosclerosis Society Consensus Panel4 avoiding the use of the term ‘intolerance’, suggests classifying SAMS based on symptoms and the increase of the CK plasmatic level. Based on these criteria several distinct cases can be identified (Table 4). Table 4 Definitions of statin-associated muscle symptoms according to the European Atherosclerosis Society EAS Consensus Panel

se of the term ‘intolerance’, suggests classifying SAMS based on symptoms and the increase of the CK plasmatic level. Based on these criteria several distinct cases can be identified (Table 4). Table 4 Definitions of statin-associated muscle symptoms according to the European Atherosclerosis Society EAS Consensus Panel Symptoms Biomarkers Comment Muscle pain, weakness, cramps Normal CK Usually named ‘myalgia’—causal relationship with statin treatment not always certain or obvious. Detailed clinical assessment is advisable. Muscle pain, weakness, cramps CK>ULN <4× ULN Muscle symptoms associated with modest CK increase are often ascribable to physical activity. A detailed clinical study (thyroid function check) and cardiovascular risk reassessment are advisable. Statin discontinuation may be indicated. Muscle pain, weakness, cramps CK > 4 <10× ULN Condition associated with higher risk of clinically significant muscle problems. Statin discontinuation is appropriate. Muscle pain, weakness, cramps CK > 10× ULN Indicated as ‘myositis’ or ‘myopathy’ by international regulatory agencies. It has an incidence of about 1 per 10 000 per year. Intense proximal muscle pain associated with loss of strength. It is often associated with underlying muscle disease. Statin discontinuation is necessary. Muscle pain, weakness, cramps CK > 40× ULN Referred to as rhabdomyolysis if associated with impairment of kidney function and/or myoglobinuria Absent CK >ULN < 4× ULN CK elevation found incidentally during statin treatment. Useful to assess thyroid function and the possibility of an exercise-related CK elevation. Absent CK > 4× ULN Unclear clinical significance. Repeated checks of CK value end accurate clinical evaluation are necessary. CK, creatine kinase; ULN, upper limit of the normal range.

found incidentally during statin treatment. Useful to assess thyroid function and the possibility of an exercise-related CK elevation. Absent CK > 4× ULN Unclear clinical significance. Repeated checks of CK value end accurate clinical evaluation are necessary. CK, creatine kinase; ULN, upper limit of the normal range. Over the last 25 years, clinical trials have reported a SAMS incidence of approximately 13% in both patients who received statins and in those who received a placebo9 (Table 5). Rhabdomyolysis has seldom been observed, with a rate of 0.03% in patients treated with statins and of 0.02% in patient treated with placebo. Withdrawal of treatment due to muscle problems has been reported in about 0.5% of participants, with a rate of 0.49% in patients treated with statins and of 0.47% in patients treated with a placebo. However, it must be highlighted that in the majority of clinical trials, SAMS are not systematically evaluated and there is a lack of a standard definition for myalgia and myopathy. Furthermore, CK values during treatment are often not adequately collected and reported.9Table 5 Incidence of muscle problems associated with statins in clinical studies9 Variables Statin group (%) Placebo group (%) P-value Any muscle problems 12.7 12.3 0.06 CK > 5× ULN 0.3 0.1 0.11 CK > 10× ULN 0.2 0.1 0.28 Rhabdomyolysis 0.03 0.02 0.48 Treatment discontinuation because of muscle symptoms 0.49 0.46 0.75 CK, creatine kinase; ULN, upper limit of the normal range.

Over the last 25 years, clinical trials have reported a SAMS incidence of approximately 13% in both patients who received statins and in those who received a placebo9 (Table 5). Rhabdomyolysis has seldom been observed, with a rate of 0.03% in patients treated with statins and of 0.02% in patient treated with placebo. Withdrawal of treatment due to muscle problems has been reported in about 0.5% of participants, with a rate of 0.49% in patients treated with statins and of 0.47% in patients treated with a placebo. However, it must be highlighted that in the majority of clinical trials, SAMS are not systematically evaluated and there is a lack of a standard definition for myalgia and myopathy. Furthermore, CK values during treatment are often not adequately collected and reported.9Table 5 Incidence of muscle problems associated with statins in clinical studies9 Variables Statin group (%) Placebo group (%) P-value Any muscle problems 12.7 12.3 0.06 CK > 5× ULN 0.3 0.1 0.11 CK > 10× ULN 0.2 0.1 0.28 Rhabdomyolysis 0.03 0.02 0.48 Treatment discontinuation because of muscle symptoms 0.49 0.46 0.75 CK, creatine kinase; ULN, upper limit of the normal range. Data gathered from the real world depicts a different scenario than that reported in clinical trial. Based on observational studies, it has been estimated that 25–30% of patients starting statin treatment develop SAMS during follow-up.10,11 These adverse events lead to treatment discontinuation in the majority of cases.10 In patients who had significant complaints or considerable CK elevation, the treatment is often withdrawn permanently.10,11 However, the majority of patients who suspend statin therapy because of SAMS eventually restart the treatment with a different statin without developing further complications.10,11 Discrepancy between real world and clinical trial data might be explained, at least in part, by patient selection criteria in clinical trials which often excludes subjects with a concomitant disease potentially predisposing them to statin adverse events. However, rhabdomyolysis incidence in the real world is very low, similar to the 0.01% incidence found in clinical trial.12

ght be explained, at least in part, by patient selection criteria in clinical trials which often excludes subjects with a concomitant disease potentially predisposing them to statin adverse events. However, rhabdomyolysis incidence in the real world is very low, similar to the 0.01% incidence found in clinical trial.12 In closing, several clinical conditions can be associated with muscle problems and biochemical abnormalities similar to those typical of statin myopathy (Table 2). Among these conditions are advanced age, severe chronic renal disease, untreated hypothyroidism, vitamin D deficiency and neuromuscular disease.4–6 Furthermore, unfavourable interaction with several drugs may also be relevant in clinical practice, increasing plasmatic concentration of statins and the risk of adverse reactions4–6 (Table 3). Abnormalities in hepatic function Asymptomatic alteration in hepatic function tests (transaminases elevation >3 higher than the normal upper limit) has been found in 0.5–2% of patients treated with statins.13 These abnormalities are more common in patients who take higher statin doses and usually occur within the first 4–12 weeks of treatment.14 In most cases, hepatic abnormalities are ascribable to adverse drug–drug interactions rather than to statin toxicity.14 In clinical practice, detection of a hepatic alteration almost unavoidably leads to statin discontinuation.15

who take higher statin doses and usually occur within the first 4–12 weeks of treatment.14 In most cases, hepatic abnormalities are ascribable to adverse drug–drug interactions rather than to statin toxicity.14 In clinical practice, detection of a hepatic alteration almost unavoidably leads to statin discontinuation.15 Other adverse reactions and side effects Although SAMS and asymptomatic alterations in hepatic function are the most frequent adverse events during statin treatment, other side effects can be observed with a much lower frequency5 (Table 6). Table 6 Possible side effects associated with statin treatment Organ/system Side effects Respiratory system Risk of interstitial lung disease increased by about 0.01% Risk of upper respiratory tract infection increased by 1% Nervous system Headache increased by 2–17% Dizziness increased by 1–4% Asthenia increased by 1–4% Endocrine Increase of the relative risk of diabetes mellitus. One extra case every 255 patients after four years of treatment Eye Possible increase of cataract risk Gastrointestinal tract Constipation risk increased by 1–5% Dyspepsia risk increased by 1–5%

by 2–17% Dizziness increased by 1–4% Asthenia increased by 1–4% Endocrine Increase of the relative risk of diabetes mellitus. One extra case every 255 patients after four years of treatment Eye Possible increase of cataract risk Gastrointestinal tract Constipation risk increased by 1–5% Dyspepsia risk increased by 1–5% How to define statin intolerance in clinical practice During statin treatment, the occurrence of the adverse events previously described might require a dosage change (lowering the dose or reducing the dosage frequency) or treatment discontinuation, either temporarily or permanently. In clinical practice, the term ‘statin intolerance’ (SI) refers to the occurrence of clinically significant side effects or adverse reactions that cause treatment discontinuation. To date, a consensus on a standardized definition of SI does not exist in Italy. This void has very relevant clinical and normative implications, one of which being the employment of new non-statins cholesterol-lowering agents (PCSK-9 inhibitors) which would potentially be useful in case of SI. In general, SI can be defined as a condition in which unacceptable patient symptoms or biochemical parameter alterations occur during statin treatment which suggests a significant clinical risk. Both symptoms and biohumoral abnormalities should be reversible and conclusively linked to statin treatment. The occurrence of these events can lead to therapy discontinuation.16 In the majority of cases, SI is characterized by disabling symptoms perceived as unacceptable by patients which leads to the discontinuation of treatment. Cases in which SI is related to the occurrence of asymptomatic alterations in laboratory parameters are less frequent. Nevertheless, in a non-negligible percentage of cases statins are withdrawn by a physician because of an overstated perception of clinical risk associated with the treatment, even when relevant clinical complications are absent.15–17 The correct identification of an actual condition of SI is particularly important in order to avoid unnecessary treatment discontinuation. Statin withdrawal can expose at-risk patients to adverse cardiovascular events.15–17

l risk associated with the treatment, even when relevant clinical complications are absent.15–17 The correct identification of an actual condition of SI is particularly important in order to avoid unnecessary treatment discontinuation. Statin withdrawal can expose at-risk patients to adverse cardiovascular events.15–17 The international definitions In recent years, several scientific and professional associations have aimed to establish a more concrete definition of the clinical condition termed SI. Various definitions have been proposed for this complex phenomenon.16–19 Of particular interest is the work published on the SI issue by the Canadian Working Group Consensus Conference on Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance in 2013.18 The Canadian working group proposes defining SI as a clinical syndrome characterized by: Inability to use statins for reduction of LDL-C and cardiovascular risk because of symptoms or biomarker abnormalities that are temporally linked to starting or increasing dose of treatment. Correlation between symptoms or laboratory alterations and statins can be confirmed by treatment withdrawal and rechallenge. SI can be either ‘complete’ (intolerance to any statin at any dose) or ‘partial’ (intolerance to some statins at some doses). Symptoms or laboratory alterations not ascribable to modifiable clinical conditions (such as concomitant disease, drug interactions).

The international definitions In recent years, several scientific and professional associations have aimed to establish a more concrete definition of the clinical condition termed SI. Various definitions have been proposed for this complex phenomenon.16–19 Of particular interest is the work published on the SI issue by the Canadian Working Group Consensus Conference on Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance in 2013.18 The Canadian working group proposes defining SI as a clinical syndrome characterized by: Inability to use statins for reduction of LDL-C and cardiovascular risk because of symptoms or biomarker abnormalities that are temporally linked to starting or increasing dose of treatment. Correlation between symptoms or laboratory alterations and statins can be confirmed by treatment withdrawal and rechallenge. SI can be either ‘complete’ (intolerance to any statin at any dose) or ‘partial’ (intolerance to some statins at some doses). Symptoms or laboratory alterations not ascribable to modifiable clinical conditions (such as concomitant disease, drug interactions). In 2014, the National Lipid Association (NLA) of the USA also presented a document on SI,19 which proposes identifying SI in light of all symptoms, signs and laboratory abnormalities attributed by the patient or by the physician to statin therapy. Symptoms are perceived by the patient as disabling when they interfere with normal daily activities, leading to a discontinuation or reduction of the treatment dose. In some cases, the decision to discontinue or reduce the treatment dose can be made by a physician due to the occurrence of asymptomatic laboratory abnormalities (increase of CK or transaminases values) suggesting a significant risk of adverse events. The NLA highlights the need for assessing each individual case in depth, taking into account every aspect of physician–patient communication, and supporting a patient-centred approach. The NLA discourages the discontinuation of treatment for a symptomatological framework which is not actually ascribable to a possible statin toxicity. Furthermore, the NLA proposes a pragmatic and actionable definition:Statin intolerance is a clinical syndrome characterized by the inability to tolerate at least 2 statins: one statin at the lowest starting daily dose AND another statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal lab determinations, which are temporally related to statin treatment and reversible upon statin discontinuation, but reproducible by re-challenge with other known determinants being excluded (such as hypothyroidism, interacting drugs, concurrent illnesses, significant changes in physical activity or exercise, and underlying muscle disease). Specifically, the lowest starting statin daily dose is defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, and pitavastatin 2 mg.

ng drugs, concurrent illnesses, significant changes in physical activity or exercise, and underlying muscle disease). Specifically, the lowest starting statin daily dose is defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, and pitavastatin 2 mg. Operational summary for clinical practice In many cases, there may be difficulties in making an accurate diagnosis of SI. A simplified approach focusing on the identification and characterization of this condition can be very useful in clinical management of these cases. A diagnosis of SI should be considered in the presence of muscle symptom characteristics, the occurrence of CK and/or transaminase elevation, and their temporal association with statin use, discontinuation, and rechallenge. We propose the following definitions: ‘Muscle statin intolerance’: the patient complains of clinically relevant muscle symptoms, with or without significant CK increase, which disappear when the treatment is withdrawn and recur after the rechallenge; ‘Hepatic statin intolerance’: the patient has a significant transaminase elevation of (>3 fold higher the normal upper limit) that disappears when statins are withdrawn and recurs after the rechallenge; ‘Complete statin intolerance’: the adverse reactions occur with all statins at any dose; ‘Partial statin intolerance’: the patient can tolerate a reduced dose of any statin.

‘Hepatic statin intolerance’: the patient has a significant transaminase elevation of (>3 fold higher the normal upper limit) that disappears when statins are withdrawn and recurs after the rechallenge; ‘Complete statin intolerance’: the adverse reactions occur with all statins at any dose; ‘Partial statin intolerance’: the patient can tolerate a reduced dose of any statin. Diagnostic–therapeutic pathway in patients with muscle statin intolerance In the event that a patient complains of muscle symptoms during statin treatment, it is necessary to first of all check the CK levels (Figure 1). In general, it is always advisable to assess CK values before starting treatment with any statin. Figure 1 Diagnostic–therapeutic pathway in the patient with muscle statin intolerance. CK, creatine kinase; ULN, upper limit of the normal range.

Diagnostic–therapeutic pathway in patients with muscle statin intolerance In the event that a patient complains of muscle symptoms during statin treatment, it is necessary to first of all check the CK levels (Figure 1). In general, it is always advisable to assess CK values before starting treatment with any statin. Figure 1 Diagnostic–therapeutic pathway in the patient with muscle statin intolerance. CK, creatine kinase; ULN, upper limit of the normal range. If high CK levels are found (CK values in the rhabdomyolysis range) it is necessary to withhold drug intake, carefully monitor renal function, and, if need be, to arrange hospitalization. When CK values are >4 times higher than the normal upper limit, it is recommended to stop the drug and evaluate the presence of factors that increase myopathy/myalgia risk.1 More specifically, it is necessary to exclude the presence of hypothyroidism, rheumatic polymyalgia, osteo-articular disease, or recent intense physical activity. If there are not secondary causes, a rechallenge, using the same statin previously used or a different one based on the pharmacokinetic characteristics, is encouraged. In the event that muscle symptoms recur (regardless of whether or not they are associated with CK increase), the presence of an SI can be considered confirmed.

e are not secondary causes, a rechallenge, using the same statin previously used or a different one based on the pharmacokinetic characteristics, is encouraged. In the event that muscle symptoms recur (regardless of whether or not they are associated with CK increase), the presence of an SI can be considered confirmed. The management of patients with ‘confirmed SI’ should contemplate: a further attempt at prescribing another statin, different from that/those initially used (hydrophilic vs lipophilic molecules) and/or with different metabolism (CYP3A4 o CYP2C9), starting with a minimum dosage then increasing the dose until the optimal dose is achieved; prescription of a low statin dose combined with ezetimibe (intestinal cholesterol absorption inhibitor); prescription of statins with longer half-life (atorvastatin and rosuvastatin) administered on alternate days or every 2 days at low/minimum dosages; ezetimibe prescription as monotherapy or combined with nutraceuticals, based on the target of LDL-c reduction. The sequence of these interventions must take into account the relative efficacy of single options. Indeed, using ezetimibe or nutraceutical allows only a modest LDL-c reduction when compared to statin treatment. In conclusion, an additional possibility is offered by the new non-statin lipid lowering agents, particularly the PCSK9 protein inhibitors. However, to date the cost of these drugs (alirocumab and evolocumab) is not covered by the SSN in Italy.

cal allows only a modest LDL-c reduction when compared to statin treatment. In conclusion, an additional possibility is offered by the new non-statin lipid lowering agents, particularly the PCSK9 protein inhibitors. However, to date the cost of these drugs (alirocumab and evolocumab) is not covered by the SSN in Italy. Diagnostic–therapeutic pathway in patients with hepatic statin intolerance It should be take into account that an increase of transaminases values <3 times the normal upper limit is not a contraindication to statin therapy (Figure 2). Several patients with diabetes, metabolic syndrome, or obesity have transaminases values fluctuating around 1–3 times the normal upper limit values20 because of a non-alcoholic steatohepatitis. In the case that an increase >3 times the normal value occurs during statin treatment, it is recommended to discontinue the drug. There is not a consensus on when the best time is to recheck transaminases values. In some clinical trials with statins, hepatic function tests were rechecked after 2–3 weeks, and in 70% of these cases the values had normalized. Some authors suggest repeating the tests after 6 weeks.21 Figure 2 Diagnostic–therapeutic pathway in the patient with hepatic statin intolerance. ULN, upper limit of the normal range.

Diagnostic–therapeutic pathway in patients with hepatic statin intolerance It should be take into account that an increase of transaminases values <3 times the normal upper limit is not a contraindication to statin therapy (Figure 2). Several patients with diabetes, metabolic syndrome, or obesity have transaminases values fluctuating around 1–3 times the normal upper limit values20 because of a non-alcoholic steatohepatitis. In the case that an increase >3 times the normal value occurs during statin treatment, it is recommended to discontinue the drug. There is not a consensus on when the best time is to recheck transaminases values. In some clinical trials with statins, hepatic function tests were rechecked after 2–3 weeks, and in 70% of these cases the values had normalized. Some authors suggest repeating the tests after 6 weeks.21 Figure 2 Diagnostic–therapeutic pathway in the patient with hepatic statin intolerance. ULN, upper limit of the normal range. After verifying the absence of other factors which could be responsible for transaminase increases, a rechallenge should be considered in which the new intake of a statin is prescribed (either the same previously used, or a different one based on pharmacokinetic characteristics). If a transaminase increase reoccurs, different options should be contemplated. Since a greater incidence of hepatic abnormalities occurs when higher statin doses are used, it may be more appropriate to prescribe low doses or non-daily dosing regimens. Transaminase levels should be checked monthly during the first 3–4 months, and then every 3 months thereafter. In addition, the use of statins not metabolized in the liver (rosuvastatin or pravastatin) or non-statin compounds may also be considered.

more appropriate to prescribe low doses or non-daily dosing regimens. Transaminase levels should be checked monthly during the first 3–4 months, and then every 3 months thereafter. In addition, the use of statins not metabolized in the liver (rosuvastatin or pravastatin) or non-statin compounds may also be considered. Conclusions Currently, statins remain a mainstay of hypercholesterolaemia treatment and it is not ethical to deny this therapy to patients with high or very-high cardiovascular risk (like those with diabetes or documented cardiovascular disease). On the other hand, the use of this ‘lifesaving’ treatment in cases of SI opposes the basic therapeutic principle of not causing damage (primum non nocere). Therefore, it is fundamental to implement unanimous and unambiguous procedures which can guarantee the continuation of an optimal lipid-lowering treatment complying with patient safety needs. The diagnostic–therapeutic pathways proposed in this document represent a summary of the current knowledges and of the best available clinical procedures. In conclusion, it is necessary to point out that the diagnostic–therapeutic pathway of each individual patient with SI must be completely and accurately documented. In particular, the rechallenge procedure must be sufficiently verified and each therapeutic change duly recorded. These precautions can safeguard the maximum appropriateness and ensure transparency in public health care resource allotment, especially in light of the high cost of prospective new non-statin drugs.

ented. In particular, the rechallenge procedure must be sufficiently verified and each therapeutic change duly recorded. These precautions can safeguard the maximum appropriateness and ensure transparency in public health care resource allotment, especially in light of the high cost of prospective new non-statin drugs. Consensus Approval Faculty Alunni Gianfranco, Amico Antonio Francesco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Audo Andrea, Azzarito Michele, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni, Amedeo, Bonvicini Marco, Cacciavillani Luisa, Calculli Giacinto, Capecchi Alessandro, Caporale Roberto, Caretta Giorgio, Carmina, Maria Gabriella, Casazza Franco, Casolo Giancarlo, Cassin, Matteo, Casu Gavino, Cemin Roberto, Chiarella Francesco, Cibinel, Gian Alfonso, Ciccone Marco Matteo, Cicini Maria Paola, Clerico Aldo, D’Agostino Carlo, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Di Lenarda, Andrea, Di Tano Giuseppe, Egidy Assenza Gabriele, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Favilli Silvia, Ferraiuolo Giuseppe, Francese Giuseppina Maura, Gabrielli Domenico, Geraci Giovanna, Giardina Achille, Greco Cesare, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Ledda Antonietta, Lucà, Fabiana, Lukic Vjerica, Macera Francesca, Marini Marco, Masson, Serge, Maurea Nicola, Mazzanti Marco, Menotti Alberto, Menozzi, Alberto, Mininni Nicola, Moreo Antonella, Moretti Luciano, Mortara Andrea, Mureddu Gian Francesco, Murrone Adriano, Musumeci Giuseppe, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Procaccini Vincenza, Pugliese Francesco Rocco, Pulignano Giovanni, Radini, Donatella, Rao Carmelo Massimiliano, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Urbinati Stefano, Valente Serafina, Vatrano, Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

ini, Donatella, Rao Carmelo Massimiliano, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Urbinati Stefano, Valente Serafina, Vatrano, Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino. Conflict of interest: none declared.

Document Revisors: Sandro Barni, Iolanda Enea, Stefania Gori, Chiara Lestuzzi, Stefano Oliva, Carmine Pinto, Sonia Tosoni. Consensus Document Approval Faculty in Appendix Introduction Cardiovascular (CV) disease and cancer are the cause of about two-thirds of all deaths worldwide.1 Due to the progressive aging of the population the eventuality that a same individual may be affected by both, CV and cancer, is not uncommon.2The association, indeed, is not casual, cancer and heart diseases may share the same risk factors,3 and such chance is amplified by cardiovascular complication of oncologic therapy that can lead to premature morbidity and death of cancer survivors.4 The above considerations have led to the development of a new branch of clinical cardiology: the cardio-oncology,5 a discipline based on the collaboration among cardiologists, oncologists and other medical specialists in order to find solutions for the prevention, monitoring, diagnosis and treatment of heart damage before, during and after antitumour treatments (Figure 1). In this Executive Summary we point out the major key points in order to achieve the most effective cancer treatment, while minimizing the risk of cardiac toxicity.

n order to find solutions for the prevention, monitoring, diagnosis and treatment of heart damage before, during and after antitumour treatments (Figure 1). In this Executive Summary we point out the major key points in order to achieve the most effective cancer treatment, while minimizing the risk of cardiac toxicity. Figure 1 The collaborative model in cardio-oncology. The realization of a management strategy to effectively treat cancer and minimize the risk of cardiac damage provides for close multidisciplinary collaboration between the different actors involved in patient management. The cooperation is particularly necessary in the presence of a patient with a structural heart disease or a high CV risk and with potentially cardiotoxic care plan.

cer and minimize the risk of cardiac damage provides for close multidisciplinary collaboration between the different actors involved in patient management. The cooperation is particularly necessary in the presence of a patient with a structural heart disease or a high CV risk and with potentially cardiotoxic care plan. The assessment of the cardiovascular risk Many oncologic drugs have cardiotoxic effects4 (Table 1) often exacerbated by the presence of a pre-existing heart disease (clinical or subclinical) or by the presence of traditional CV risk factors.4 The estimation of CV risk profile of patients (Table 2) is valuable in cardio-oncology and should be integrated with data related to tumour treatment, in order to improve the choice on the most appropriate chemotherapy protocol and on the best cardio-protective therapy as well as to perform the most appropriate monitoring measures to schedule the follow-up. The CV risk factors should be treated with appropriate primary and secondary prevention measures according with the most recent guidelines on cardiovascular prevention of the European Society of Cardiology (ESC).6Table 1 Antineoplastic agents and their cardiotoxic effect6

monitoring measures to schedule the follow-up. The CV risk factors should be treated with appropriate primary and secondary prevention measures according with the most recent guidelines on cardiovascular prevention of the European Society of Cardiology (ESC).6Table 1 Antineoplastic agents and their cardiotoxic effect6 Class Indication* Incidence Drug Arrhythmias QT elongation Systolic dysfunction Hypertension Myocardial ischaemia Thrombo- embolism Anthracyclines Daunorubicin Leukemia  ++/ +++ ✓ + — — — Adriamicin Breast, Lymphomas, Sarcomas +/ ++ ✓  ++/ +++ — — ✓ Liposomial adriamicin Lymphomas, Sarcomas + ✓ — +/ ++/ +++ Epirubicin Breast, Stomach — ✓ +/ ++ — — ✓ Idarubicin Leukemia  ++/ +++ ✓  ++/ +++ — — ✓ Mitoxantrone Leukemia  ++/ +++ ✓  ++/ +++  ++  ++ — Alkylating agents Cisplatino Bladder, HNC, Lung, Ovary ✓ ✓ ✓ ✓ ✓  ++ Cyclophosphamide Hemat. Breast — — ✓ — — + Ifosfamide Cervix Sarcomas ✓ —  +++ — — + Antimicrotubules agents Docetaxel Breast Lung +/ ++ ✓  ++  ++  ++ ✓ Nab-Paclitaxel Breast Pancreas +/ ++ ✓ — — — + Paclitaxel Breast Lung  ++ ✓ + — + — Antimetabolites Capecitabine Colon-Rectum Breast ✓ ✓ ✓ —  ++ +/ ++ 5-Fluorouracil Gastrointestinal ✓ ✓ + —  ++/ +++ ✓ Hormone therapy Abiraterone Prostate  ++ —  ++  ++/ +++  ++ — Anastrozole Breast — — —  ++/ +++  ++  ++ Exemestane Breast — — —  ++ + Letrozole Breast — — —  ++  ++/ +++  ++ Tamoxifen Breast — ✓ —  ++/ +++  ++  ++ Target therapy with monoclonal antibody Bevacizumab Colon-Rectum Breast  ++ ✓ +/ ++  ++/ +++ +/ ++  ++/ +++ Brentuximab Lymphomas — — — — +  ++ Cetuximab Colon-Rectum HNC  ++ — ✓  ++ ✓ +/ ++ Ipilimumab Melanoma — — — — — — Panitumumab Colon-Rectum ✓ — —  ++  ++ + Pertuzumab Breast — —  ++ — — — Rituximab Hemat.

++  ++ Target therapy with monoclonal antibody Bevacizumab Colon-Rectum Breast  ++ ✓ +/ ++  ++/ +++ +/ ++  ++/ +++ Brentuximab Lymphomas — — — — +  ++ Cetuximab Colon-Rectum HNC  ++ — ✓  ++ ✓ +/ ++ Ipilimumab Melanoma — — — — — — Panitumumab Colon-Rectum ✓ — —  ++  ++ + Pertuzumab Breast — —  ++ — — — Rituximab Hemat. ✓ — —  ++  ++  ++/ +++ Trastuzumab Breast Stomach  ++ —  ++/ +++  ++ — +/ ++ Target therapy with small molecules Bortezomib Multiple myeloma + — +/ ++ + + + Dasatinib (TKI) Leukemia  ++/ +++ +/ ++  ++  ++  ++ +/ ++ Erlotinib (TKI) Lung ✓ — — —  ++  ++ Gefitinib (TKI) Lung ✓ ✓ — — +/ ++ ✓ Imatinib (TKI) CMC — — +/ ++ —  +++ + Lapatinib (TKI) Breast ✓  +++  ++ — — — Nilotinib (TKI) CMC  ++  ++  ++  ++ ✓ + Pazopanib (TKI) RCC — — +  +++ +/ ++  ++ Sorafenib (TKI) RCC, HCC + ✓ +  +++  ++  ++ Sunitinib (TKI) GIST, RCC + +  ++/ +++  +++  ++ +/ ++ Vemurafenib (TKI) Melanoma  ++ ✓ +  ++  ++  ++ Miscellanea Everolimus RCC — —  ++  ++ — + Lenalidomide Multiple myeloma +/ ++ +  ++  ++  ++  ++/ +++ Temsirolimus RCC — ✓ —  ++  +++  ++ *, Selected examples on the frequency of use of the drug; +++, >10%; ++, 1–10%; +, <1% or rare; ✓, observed but the precise incidence has not been well established; —, complication not reported; CML, chronic myeloid leukemia; GIST, gastrointestinal stromal tumour; HCC, hepatocellular carcinoma; Emat., haematological; HF, heart failure; HNC, cancer of the head and neck; RCC, carcinoma of the kidney; TKI, tyrosine kinase inhibitor. Table 2 Patient-related risk factors for cardiotoxicity

✓ — —  ++  ++  ++/ +++ Trastuzumab Breast Stomach  ++ —  ++/ +++  ++ — +/ ++ Target therapy with small molecules Bortezomib Multiple myeloma + — +/ ++ + + + Dasatinib (TKI) Leukemia  ++/ +++ +/ ++  ++  ++  ++ +/ ++ Erlotinib (TKI) Lung ✓ — — —  ++  ++ Gefitinib (TKI) Lung ✓ ✓ — — +/ ++ ✓ Imatinib (TKI) CMC — — +/ ++ —  +++ + Lapatinib (TKI) Breast ✓  +++  ++ — — — Nilotinib (TKI) CMC  ++  ++  ++  ++ ✓ + Pazopanib (TKI) RCC — — +  +++ +/ ++  ++ Sorafenib (TKI) RCC, HCC + ✓ +  +++  ++  ++ Sunitinib (TKI) GIST, RCC + +  ++/ +++  +++  ++ +/ ++ Vemurafenib (TKI) Melanoma  ++ ✓ +  ++  ++  ++ Miscellanea Everolimus RCC — —  ++  ++ — + Lenalidomide Multiple myeloma +/ ++ +  ++  ++  ++  ++/ +++ Temsirolimus RCC — ✓ —  ++  +++  ++ *, Selected examples on the frequency of use of the drug; +++, >10%; ++, 1–10%; +, <1% or rare; ✓, observed but the precise incidence has not been well established; —, complication not reported; CML, chronic myeloid leukemia; GIST, gastrointestinal stromal tumour; HCC, hepatocellular carcinoma; Emat., haematological; HF, heart failure; HNC, cancer of the head and neck; RCC, carcinoma of the kidney; TKI, tyrosine kinase inhibitor. Table 2 Patient-related risk factors for cardiotoxicity What to look What to evaluate How to treat Known heart disease Present/absenta Implement primary/secondary prevention measures provided for by the Guidelines Prior exposure to cardiotoxic chemotherapy and/or mediastinal radiotherapy Present/absentb In case of exposure in asymptomatic patient evaluate the cardiovascular status (ventricular function, silent ischaemia, valves disease) Smoke Pack/yearc Quit Alcohol consumption Daily Units Abstention o moderate use (1–4 U/die) Physical activity Weekly hours Encourage mild to moderate aerobic activity (at least 3–5 h/week) Blood pressure High blood pressure search ventricular hypertrophy Give priority to drugs with proven cardioprotective action (ace-i/ARBs, beta-blockers) Obesity Calculate body mass index weight reduction with the Mediterranean diet High blood sugar Post-prandial glycaemia (2 h) or glycated haemoglobin and blood glucose ≤ 125 mg/dL but> 100 mg/dL Implement dietary program and exercise when carbohydrate intolerance, encourage the use of metformin in the case of type II diabetes Abdominal circumferenced Establish whether there is metabolic syndrome Implement dietary program and exercise, treatment of dyslipidaemia and high blood pressure Lipid profile Total cholesterol, HDL cholesterol, triglycerides Implement dietary program and exercise, statins Renal functione Creatinine, eGFR Low-protein, low-salt diet, treat high blood pressure and dyslipidaemia aDefine the type, severity and clinical stability in relation to the oncology care program.

od pressure Lipid profile Total cholesterol, HDL cholesterol, triglycerides Implement dietary program and exercise, statins Renal functione Creatinine, eGFR Low-protein, low-salt diet, treat high blood pressure and dyslipidaemia aDefine the type, severity and clinical stability in relation to the oncology care program. b‘Life span’ threshold of high-risk: prior anthracyclines exposure (adriamycin 250–300 mg/m2 epirubicin 600–800 mg/m); radiation exposure (35–50 Gy). In the case of radiation define whether he was involved the left hemithorax. cIs obtained by multiplying the number of cigarette packs (20 cigarettes) smoked per day by the number of years of smoking. d>102 cm men; >90 cm in women. eRenal dysfunction = eGFR <60 ml/min.

b‘Life span’ threshold of high-risk: prior anthracyclines exposure (adriamycin 250–300 mg/m2 epirubicin 600–800 mg/m); radiation exposure (35–50 Gy). In the case of radiation define whether he was involved the left hemithorax. cIs obtained by multiplying the number of cigarette packs (20 cigarettes) smoked per day by the number of years of smoking. d>102 cm men; >90 cm in women. eRenal dysfunction = eGFR <60 ml/min. Heart failure Heart failure (HF) is a very common complication of antineoplastic treatments and may occur with several classes of anticancer drugs7–9 (Table 1). Table 3 shows the risk factors for anthracyclines cardiotoxicity that may lead also to late onset cardiomyopathy.10,11 Other conventional chemotherapies, cyclophosphamide, cisplatin, ifosfamide, and taxanes (paclitaxel and docetaxel), can rarely induce left ventricular dysfunction (LVD) and HF. Immunotherapies and targeted therapies (Table 1) can, also, cause LVD and HF. Moreover, concomitant use of anthracyclines with trastuzumab, a monoclonal antibody directed against the receptor HER2/ErbB2, especially in cancer patients with high CV risk, may lead to severe cardiotoxicity effects.7–9,12,13 Nevertheless, trastuzumab-related cardiomyopathy is not dependent on cumulative dose and is considered to be reversible upon treatment discontinuation and proper therapy.9 The cardiotoxicity risk of other anti-HER2/ErbB2 targeted agents (lapatinib, pertuzumab, and trastuzumab-emtansine) appears to be similar to that of trastuzumab.9Table 3 Risk factors of anthracyclines cardiotoxicity

n cumulative dose and is considered to be reversible upon treatment discontinuation and proper therapy.9 The cardiotoxicity risk of other anti-HER2/ErbB2 targeted agents (lapatinib, pertuzumab, and trastuzumab-emtansine) appears to be similar to that of trastuzumab.9Table 3 Risk factors of anthracyclines cardiotoxicity Risk factor Cumulative dose (life-span) Total cumulative dose (Adriamycin> 450 mg/m2; epirubicin> 900 mg/m2) markedly increases the risk in the long-term cardiotoxicity Duration of follow-up The risk increases with prolonged survival for doses>250 mg/m2 Rate of administration The risk of acute cardiotoxicity is lower withslow rate of infusion Individual dose Single high doses increase the risk of late onset toxicity Type of anthracycline The liposomal anthracyclines are less cardiotoxicity Radiotherapy Prior or concomitant administration (>30 Gy) increases the risk of cardiotoxicity Complementary chemotherapy Trastuzumab, bevacizumab, paclitaxel, alkylating agents (cyclophosphamide, ifosfamide, melphalan), bleomycin, vincristine, paclitaxel, docetaxel Pre-existing cardiovascular risk factors Hypertension, ischaemic heart disease, valvular heart disease, previous cardiotoxic treatments Comorbidity Diabetes mellitus, chronic obstructive pulmonary disease, renal dysfunction, liver failure, obesity, dysthyroidism, electrolyte disorders, sepsis Age Young and old are at greatest risk Sex Women are at greater risk than men Additional factors Trisomy 21 and African American race are at greater risk

eatments Comorbidity Diabetes mellitus, chronic obstructive pulmonary disease, renal dysfunction, liver failure, obesity, dysthyroidism, electrolyte disorders, sepsis Age Young and old are at greatest risk Sex Women are at greater risk than men Additional factors Trisomy 21 and African American race are at greater risk Vascular endothelial growth factor (VEGF) inhibitors can cause reversible or irreversible cardiac side effects: arterial hypertension is the most frequent, with potential LVD and HF.

eatments Comorbidity Diabetes mellitus, chronic obstructive pulmonary disease, renal dysfunction, liver failure, obesity, dysthyroidism, electrolyte disorders, sepsis Age Young and old are at greatest risk Sex Women are at greater risk than men Additional factors Trisomy 21 and African American race are at greater risk Vascular endothelial growth factor (VEGF) inhibitors can cause reversible or irreversible cardiac side effects: arterial hypertension is the most frequent, with potential LVD and HF. Management Cardiotoxic cardiomyopathy is difficult to treat and has a relatively poor prognosis if not promptly diagnosed.14 Among the imaging techniques, a predominant role is played by echocardiography, a non-invasive, repeatable, available and relatively inexpensive technique.9 The ejection fraction (EF) is the echocardiographic parameter most frequently used to monitor heart health. Significant declines of EF often may occur at a later time with irreversible cardiac damage. One of the aims of clinical research is to find the best technique able to identify the early cardiac damage before it produces alterations of the common ventricular contractility indexes, and then before the cardiac damage becomes irreversible (Table 4). In the recent years, Global Longitudinal Strain (GLS) technique, assessed using automated speckle-tracking echocardiography (STE), has emerged for detecting and quantifying LVD. A drop of 10% from baseline is very largely abnormal and may represent subclinical dysfunction in order to consider cardioprotection also in patients without the classic criteria of cardiotoxicity (LVEF < 50%).It has been largely demonstrated that this technique is very promising to monitor the effects of cardioprotection. Table 4 Summary table of the instrumental parameters used to identify the damage from chemotherapy

to consider cardioprotection also in patients without the classic criteria of cardiotoxicity (LVEF < 50%).It has been largely demonstrated that this technique is very promising to monitor the effects of cardioprotection. Table 4 Summary table of the instrumental parameters used to identify the damage from chemotherapy Method used Parameter Diagnostic values for cardiotoxicity Limits Echocardiography Ejection fraction (EF) * Decrease>5% with EF < 55% if symptomatic patient for heart failure (HF) * Image quality (better with ultrasound contrast agent) * Decrease>10% with EF < 55% if asymptomatic patient * Dependence on the haemodynamic state * Intra- and inter-operator variability (better with 3D-echo) * Late and irreversible alterations Dobutamine stress-echo EF Fractional shortening (FS) * Reduction of EF and/or FS during pharmacological stress * Consistent results but from small and not confirmed studies Doppler Echocardiography Diastolic parameters: isovolumetric relaxation time (IVRT), deceleration time (DT), E, e’, E/A ratio, * Diastolic dysfunction (↑ IVRT and DT, ↓ E, e' and E/A ratio) * Discordant data on the predictive power of future dysfunction * Not recommended for monitoring Tissue Doppler Imaging (TDI) Mitral annulus velocity (s') septal and lateral * Reduction below 15 cm/sec (septal) and 20 cm/sec (lateral) * Discordant data between different studies * Frequent reduction ofs' in pts with prior chemotherapy, without development of HF Two-dimensional Speckle Tracking echocardiography Global longitudinal strain * Reduction of > 15% from baseline within days after chemotherapy seems to predict future decline in EF * Need for dedicated software * Results still to be confirmed on a large scale Cardiac magnetic resonance (CMR), dynamic sequences without contrast LV and RV volumes and EF * Improved accuracy and reproducibility in identifying drops in EF * Costs * Availability on the territory CMR, delayed sequences after contrast agent (gadolinium) Early (oedema) and late (fibrosis) enhancement * Intramyocardial oedema seen during therapy with trastuzumab and ↓ FE * Results regarding prognostic significance of oedema and fibrosis to be confirmed on a large scale * Fibrosis is associated with poor prognosis

CMR, delayed sequences after contrast agent (gadolinium) Early (oedema) and late (fibrosis) enhancement * Intramyocardial oedema seen during therapy with trastuzumab and ↓ FE * Results regarding prognostic significance of oedema and fibrosis to be confirmed on a large scale * Fibrosis is associated with poor prognosis Biomarkers (Table 5), also, may be used as ‘red flags’ to encourage a close clinical and instrumental monitoring and treatment. The same biomarker assay may be used for continued screening throughout the treatment pathway and substantial increases during follow-up may anticipate asymptomatic LVD in high CV risk patient treated with potentially cardiotoxic chemotherapy. Nevertheless at present the evidence to establish the interpretation of subtle variation is insufficient and their role as exclusive method for routinely surveillance of cardiac damage is not clearly ascertained. Table 5 Biomarkers and risk stratification

risk patient treated with potentially cardiotoxic chemotherapy. Nevertheless at present the evidence to establish the interpretation of subtle variation is insufficient and their role as exclusive method for routinely surveillance of cardiac damage is not clearly ascertained. Table 5 Biomarkers and risk stratification Marker type Population studied Findings and observations TnT, TnI, hsTnT Anthracyclines: baseline measurement, at the end of the infusion, and one month after chemotherapy * High predictive value (mostly negative) in the high-dose anthracyclines * Maybe poor prognostic factor in medium and low doses TnT, TnI, hsTnT Trastuzumab for metastatic breast cancer: baseline survey, 2 and 4 months after starting treatment * It seems to anticipate about 2 months the development of systolic dysfunction * Increased positive predictive value when combined with declining global longitudinal strain * Results to be confirmed in larger studies BPN, Nt-proBNP Anthracyclines (breast cancer): before and after treatment * A > 36% increase from baseline seems to correlate with LV systolic dysfunction * Mixed results in different studies BNP, Nt-proBNP Trastuzumab * Few studies, mixed results

g global longitudinal strain * Results to be confirmed in larger studies BPN, Nt-proBNP Anthracyclines (breast cancer): before and after treatment * A > 36% increase from baseline seems to correlate with LV systolic dysfunction * Mixed results in different studies BNP, Nt-proBNP Trastuzumab * Few studies, mixed results Strategies for reducing cardiotoxicity In the absence of definite treatments that can reverse the anthracyclines-related myocardial damage, it is important to identify new treatment strategies that prevent or minimize the potential cardiotoxic side effects (Table 6), especially in high risk patients (Table 3) that require a strict control of traditional CV risk factor. Table 6 Strategies to control the risk of cardiotoxicity

ines-related myocardial damage, it is important to identify new treatment strategies that prevent or minimize the potential cardiotoxic side effects (Table 6), especially in high risk patients (Table 3) that require a strict control of traditional CV risk factor. Table 6 Strategies to control the risk of cardiotoxicity Type of strategy Advantages Only retrospective studies Weekly infusions (instead of three times a week) Lower blood peaks, observed incidence of heart failure 0.8% (vs. 2.9% with traditional scheme) Only retrospective studies Prolonged infusion (>6 h) instead of rapid bolus Lower blood peaks, reduced incidence of heart failure Need for central venous access, with increase of costs, preparation time and care, risk of infection Epirubicin Better tolerance compared with doxorubicin. Higher costs of doxorubicin Liposomal anthracyclines (pegylated or non-pegylated) Lower volume of distribution, with greater concentration on the neoplastic tissue * Not available studies directly comparing with free doxorubicin. less cardiotoxicity Iron chelating agents (dexrazoxane) Protective effect on acute cardiotoxicity * Not available data on the protective effect of late toxicity Currently only indicated for patients with metastatic breast cancer previously treated with high doses of anthracyclines * Equivocal increase of seconds in the long run tumours Ischaemic heart disease Radiation therapy as well as many cancer drugs can induce myocardial ischaemia4,7,9 (Tables 1and7). Table 7 Chemotherapy associated with ischaemia (Modified by 14)

Type of strategy Advantages Only retrospective studies Weekly infusions (instead of three times a week) Lower blood peaks, observed incidence of heart failure 0.8% (vs. 2.9% with traditional scheme) Only retrospective studies Prolonged infusion (>6 h) instead of rapid bolus Lower blood peaks, reduced incidence of heart failure Need for central venous access, with increase of costs, preparation time and care, risk of infection Epirubicin Better tolerance compared with doxorubicin. Higher costs of doxorubicin Liposomal anthracyclines (pegylated or non-pegylated) Lower volume of distribution, with greater concentration on the neoplastic tissue * Not available studies directly comparing with free doxorubicin. less cardiotoxicity Iron chelating agents (dexrazoxane) Protective effect on acute cardiotoxicity * Not available data on the protective effect of late toxicity Currently only indicated for patients with metastatic breast cancer previously treated with high doses of anthracyclines * Equivocal increase of seconds in the long run tumours Ischaemic heart disease Radiation therapy as well as many cancer drugs can induce myocardial ischaemia4,7,9 (Tables 1and7). Table 7 Chemotherapy associated with ischaemia (Modified by 14) Drug Incidence 5-Fluorouracil 1–68% Capecitabine 3–9% Paclitaxel <1–5% Sunitinib/Sorafenib 2.3% Erlotinib 2.3% Bevacizumab 0.6–1.7% Axitinib 1–2% Pazopanib 2% Ponatinib 3–20%

Ischaemic heart disease Radiation therapy as well as many cancer drugs can induce myocardial ischaemia4,7,9 (Tables 1and7). Table 7 Chemotherapy associated with ischaemia (Modified by 14) Drug Incidence 5-Fluorouracil 1–68% Capecitabine 3–9% Paclitaxel <1–5% Sunitinib/Sorafenib 2.3% Erlotinib 2.3% Bevacizumab 0.6–1.7% Axitinib 1–2% Pazopanib 2% Ponatinib 3–20% Fluoropyrimidine and capecitabine Asymptomatic ST-segment changes on ECG represents the most frequent cardiotoxic manifestation (55%). Chest pain with or without ST-segment changes is the common clinical complaint (45%) and evolution in acute coronary syndrome may occur. Patients should be closely monitored for myocardial ischaemia using regular ECG. The symptoms usually occur within the first 72 h of 5-fluorouracil (5-FU) infusion and in the first 6 days of initiation in the case of oral administration of capecitabine.15 Occasionally, 5-FU and Capecitabine toxicity appear as acute heart failure and Tako-tsubo syndrome with LVD, in such case ventricular arrhythmias and sudden death may occur. Ischaemic heart disease can also be a complication of antiangiogenic agents: bevacizumab and tyrosine kinase inhibitors (sunitinib, sorafenib, ponatinib, axitinib, pazopanib, regorafenib).9 Coronary artery disease may be a late complication of high radiation doses to mediastinum.

arrhythmias and sudden death may occur. Ischaemic heart disease can also be a complication of antiangiogenic agents: bevacizumab and tyrosine kinase inhibitors (sunitinib, sorafenib, ponatinib, axitinib, pazopanib, regorafenib).9 Coronary artery disease may be a late complication of high radiation doses to mediastinum. Management In the case of fluoropyrimidine toxicity, chemotherapy should be stopped and patients hospitalized in coronary intensive care if acute coronary syndrome is suspected. The administration of non-dihydropyridine calcium channel blockers (verapamil or diltiazem) and nitrates may be indicated for the frequent occurrence of coronary spasm. If there is an absolute indication on drug rechallenge, the treatment should be performed with half dose and the patients monitored closely. The association of calcium channel blockers therapy may be useful.

l blockers (verapamil or diltiazem) and nitrates may be indicated for the frequent occurrence of coronary spasm. If there is an absolute indication on drug rechallenge, the treatment should be performed with half dose and the patients monitored closely. The association of calcium channel blockers therapy may be useful. Arrhythmias In cancer patients Heart Rhythm Disturbances (HRD) may be the result of multiple risk factors. Metabolic disorders, electrolyte disturbances, medications (e.g. antihistamines, antiemetic, anti-infective, psychotropic drugs) can affect the appearance of cardiac arrhythmias. Nevertheless, HRD are more frequent with some chemotherapies (Tables 1and8). A 12-lead ECG should be recorded and the QT interval, corrected for heart rate with Bazett’s or Fridericia’s formula, should be obtained in all patients at baseline. Treatment should be interrupted or alternative regimens considered if the QTc is >500 ms, QTc prolongation is >60 ms or arrhythmias are present. Factors as hypokalaemia, hypomagnesiemia, extreme bradycardia, and QT-prolonging drugs should be minimized inpatients treated with potential QT-prolonging chemotherapy (Figure 2). Figure 2 Algorithm for the evaluation and management in the course of chemotherapy with potential effect on the QT. Table 8 Arrhythmias and related mechanisms of action induced by chemotherapy drugs

Arrhythmias In cancer patients Heart Rhythm Disturbances (HRD) may be the result of multiple risk factors. Metabolic disorders, electrolyte disturbances, medications (e.g. antihistamines, antiemetic, anti-infective, psychotropic drugs) can affect the appearance of cardiac arrhythmias. Nevertheless, HRD are more frequent with some chemotherapies (Tables 1and8). A 12-lead ECG should be recorded and the QT interval, corrected for heart rate with Bazett’s or Fridericia’s formula, should be obtained in all patients at baseline. Treatment should be interrupted or alternative regimens considered if the QTc is >500 ms, QTc prolongation is >60 ms or arrhythmias are present. Factors as hypokalaemia, hypomagnesiemia, extreme bradycardia, and QT-prolonging drugs should be minimized inpatients treated with potential QT-prolonging chemotherapy (Figure 2). Figure 2 Algorithm for the evaluation and management in the course of chemotherapy with potential effect on the QT. Table 8 Arrhythmias and related mechanisms of action induced by chemotherapy drugs Aritmia Farmaco Meccanismo d’azione Bradycardia Paclitaxel Interference with His-Purkinje system Talidomide Hyper-reactivity to Cremophor EL (with release of histamine) Vaso-vagal stimulation ↓TNFα and inhibition of the neurons of the nucleus of the vagus Hyperactivity of the parasympathetic system Hypothyroidism QT prolongation Arsenic trioxide Block of the potassium channels Tyrosine kinase inhibitors Calcium overload (due to oxidative stress) Dasatinib Apoptosis Lapatinib Fragmentation of DNA Nilotinib Block of the potassium channels (encoded by the HERG gene) Sunitinib Vandetanib Pazopanib Vemurafenib Vorinostat Anthracyclines Ventricular fibrillation Capecitabine Coronary artery spasmKounis Syndrome

se inhibitors Calcium overload (due to oxidative stress) Dasatinib Apoptosis Lapatinib Fragmentation of DNA Nilotinib Block of the potassium channels (encoded by the HERG gene) Sunitinib Vandetanib Pazopanib Vemurafenib Vorinostat Anthracyclines Ventricular fibrillation Capecitabine Coronary artery spasmKounis Syndrome Arterial hypertension Hypertension is a frequent co-morbidity in patients with cancer and may be worsened or newly induced by steroids o non-steroid anti inflammatory drugs frequently used in oncology. Antiangiogenetic agents (Table 1) can induce hypertension and degenerate to related heart complications (i.e. heart failure, myocardial ischaemia). ACE inhibitors or ARBs, beta-blockers and dihydropyridine calcium channel blockers are the antihypertensive drugs of choice. Non-dihydropyridine calcium channel blockers should preferably be avoided due to drug interactions.

nsion and degenerate to related heart complications (i.e. heart failure, myocardial ischaemia). ACE inhibitors or ARBs, beta-blockers and dihydropyridine calcium channel blockers are the antihypertensive drugs of choice. Non-dihydropyridine calcium channel blockers should preferably be avoided due to drug interactions. Thrombo-embolic disease Thrombo-embolism often complicates the course of cancer and recognizes different aetiological moments (Table 9). The arterial thrombotic events (ETA) in cancer can occur in case of treatment with anti-angiogenic drugs, cisplatin, VEGF inhibitors, and hormonal therapies. Ischaemia/myocardial infarction is the most common clinical manifestation. The pro-thrombotic state may facilitate embolic events secondary to atrial fibrillation. The most frequent thrombo-embolic complications in cancer patients are venous thrombo-embolism (VTE) with deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE is the second cause of death in cancer patients. It may affect up to 20% of hospitalized patients and is frequently undiagnosed. A four weeks antithrombotic therapy with low molecular weight heparin (LMWH) is currently recommended for VTE prophylaxis by consensus guidelines.9 In the case of major surgery, systematic prophylaxis for VTE in outpatient admitted for chemotherapy is not recommended and the decision should be individualized. In stable patients LMWH given over a period of 3–6 months is the first choice for TVE therapy in cancer patients. At the moment we do not have enough data to support the use of fondaparinux or new oral anticoagulants (NOAC) for the initial treatment of acute VTE in patients with cancer. We are waiting the results of Hokusai VTE-cancer to know if edoxaban is similar to dalteparin in preventing recurrence of acute VTE following and initial index in cancer subjects.15 Different NOACs may differ because of potential drug interactions and sensitivity to renal or hepatic dysfunction. The use of vitamin K antagonists (VKA) in cancer patients is complicated; difficulties in maintaining a therapeutic International Normalised Ratio (INR) occur due to a variety of reasons such as drug interactions, unpredictable bioavailability, vomiting, malnutrition or diarrhea, poor compliance for repeated laboratory tests. Table 9 Risk factors and biomarkers associated with thrombosis in cancer

ulties in maintaining a therapeutic International Normalised Ratio (INR) occur due to a variety of reasons such as drug interactions, unpredictable bioavailability, vomiting, malnutrition or diarrhea, poor compliance for repeated laboratory tests. Table 9 Risk factors and biomarkers associated with thrombosis in cancer Cancer-related factors Treatment-related factors Patient-related factors Biomarkers Primary site of Tumour (pancreas, brain, stomach, kidney, lung, lymphoma, myeloma) Advanced Stage (metastatic) Histology (>adenocarcinoma) Initial period after diagnosis (3–6 months) Major Surgery (abdomen, pelvis) Chemotherapy Antioangiogenetic Agents (Lenalidomide, Talidomide, Bevacizumab) Hormone Therapy erythropoiesis-stimulating factors (ESA), transfusion; central venous catheters (CVC); duration of surgery > 30’, radiotherapy (RT) Old Age Gender (Female > Male) African ethnicity Comorbidities (infections, renal dysfunction, pulmonary disease, atherosclerotic disease) Inherited prothrombotic Mutations Obesity History of thombo-embolic disease Poor performance status (PPS) Platelet Count ≥ 350000, White Blood Cells count> 11000 Haemoglobin (Hb) <10 g/dL high levels of D-dimer, high level of soluble P-selectin, high level of C-reactive protein Surveillance in the follow-up Cancer patients follow-up is critical for the prevention and treatment of possible late cardiovascular complications (Table 10). Table 10 Suggested follow-up and treatment after cancer therapy

Platelet Count ≥ 350000, White Blood Cells count> 11000 Haemoglobin (Hb) <10 g/dL high levels of D-dimer, high level of soluble P-selectin, high level of C-reactive protein Surveillance in the follow-up Cancer patients follow-up is critical for the prevention and treatment of possible late cardiovascular complications (Table 10). Table 10 Suggested follow-up and treatment after cancer therapy Treatment performed Exams programmed Associated risk factors Anthracyclines, Echocardiogram particularly if: At 6–12 month of follow-up, after completion of chemotherapy Hypertension Female Age <15 years or > 60 years Dose (Doxorubicin> 240 mg/mq; Epirubicin >360 mg/mq) Every 1–5 years, depending on the risk profile Dyslipidaemia Diabetes mellitus Obesity Sedentary Smoke Target therapy ± Taxanes Yearly for 5 years after the conclusion of therapy. Thereafter every 5 years Alcohol consumption Hormone therapy Clinical follow-up Kidney failure Radiation therapy to the chest/mediastinal Echocardiography at 6–12 month of follow-up, then every 1–5 years depending on risk profile if involved the left hemithorax and/or total radiation in the cardiac Exercise test after 5 years and then every 3–5 years. area ≥ 30Gy Consider Stress-Echocardiography or coronary CT scan Radiation therapy to the head/neck Carotid artery Echo-Doppler after 3–5 years Ultrasound thyroid and periodic evaluation of thyroid hormones (FT3, FT4, TSH)

horax and/or total radiation in the cardiac Exercise test after 5 years and then every 3–5 years. area ≥ 30Gy Consider Stress-Echocardiography or coronary CT scan Radiation therapy to the head/neck Carotid artery Echo-Doppler after 3–5 years Ultrasound thyroid and periodic evaluation of thyroid hormones (FT3, FT4, TSH) Cancer patients should be aware on the possible cardiovascular risk factors, overall subjects treated with anthracyclines or mediastinal radiotherapy. At 10 years it is mandatory to perform stress test or CT coronary angiography16 (Figure 3). Moreover, patients should be encouraged to a healthy lifestyle. A careful surveillance is often necessary for the patients in long-term hormonal therapy. Tamoxifen may increase the risk of thrombo-embolic complications and aromatase inhibitors have been linked to increased risk of heart disease The same applies to patients treated with androgen deprivation therapy (ADT) for prostate cancer which are prone to metabolic syndrome, diabetes, accelerated atherosclerosis, and cardiovascular events. Figure 3 Algorithm of patient management during and after radiation.

Cancer patients should be aware on the possible cardiovascular risk factors, overall subjects treated with anthracyclines or mediastinal radiotherapy. At 10 years it is mandatory to perform stress test or CT coronary angiography16 (Figure 3). Moreover, patients should be encouraged to a healthy lifestyle. A careful surveillance is often necessary for the patients in long-term hormonal therapy. Tamoxifen may increase the risk of thrombo-embolic complications and aromatase inhibitors have been linked to increased risk of heart disease The same applies to patients treated with androgen deprivation therapy (ADT) for prostate cancer which are prone to metabolic syndrome, diabetes, accelerated atherosclerosis, and cardiovascular events. Figure 3 Algorithm of patient management during and after radiation. Consensus Document Approval Faculty Alunni Gianfranco, Amico Antonio Francesco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Battistoni Ilaria, Bianca Innocenzo, Bongarzoni Amedeo, Cacciavillani Luisa, Calculli Giacinto, Caldarola Pasquale, Capecchi Alessandro, Caporale Roberto, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Casolo Giancarlo, CassinMatteo, Casu Gavino, Cemin Roberto, Chiaranda Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Clerico Aldo, Colivicchi Furio, De Luca Giovanni, De Maria Renata, Di Fusco StefaniaAngela, Di Tano Giuseppe, Egman Sabrina, Fattirolli Francesco, Ferraiuolo Giuseppe, Francese Giuseppina Maura, Gabrielli Domenico, Geraci Giovanna, Giardina Achille, Gregorio Giovanni, IacovielloMassimo, Khoury Georgette, Ledda Antonietta, Luca Fabiana, LukicVjerica, Marini Marco, Maseri Attilio, Masson Serge, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Menozzi Alberto, Mininni Nicola, Moreo Antonella, Moretti Luciano, Mortara Andrea, Murrone Adriano, Musumeci Giuseppe, Nardi Federico, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Parato Vito Maurizio, Patane Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, RossiniRoberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, SauroRosario, Scherillo Marino, Severi Silva, Sicuro Marco, Sisto Francesco, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

miliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, RossiniRoberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, SauroRosario, Scherillo Marino, Severi Silva, Sicuro Marco, Sisto Francesco, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino. Conflict of interest: none declared.

Revised by Antonio Francesco Amico. Matteo Cassin, Emilio Di Lorenzo, Luciano Moretti, Alessandro Parolari, Emanuela Pccaluga, Paolo Rubartelli Consensus Document Approval Faculty in appendix Introduction The great efficacy in the treatment of acute coronary syndromes (ACS) and coronary disease in general, can be attributed to the diffusion of myocardial revascularization by both percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG), and to the availability of antithrombotic drugs that effectively reduce ischaemic complications. It is a widespread practice to administer antiplatelet and/or anticoagulant therapy before performing coronary angiography (a strategy known as ‘pre-treatment’) in order to prevent ischaemic events before a revascularization procedure and to reduce peri-procedural infarction in case of PCI. Pre-treatment may however, expose the patient to haemorrhagic complications without providing any benefit in case of low ischaemic risk, or require its rapid discontinuation in case of surgical revascularization. Pre-treatment may furthermore provide very different theoretical benefits according to the patient's clinical conditions, as they could be greater in acute syndromes, where the instability of the atherosclerotic plaque and thrombosis prevail.

, or require its rapid discontinuation in case of surgical revascularization. Pre-treatment may furthermore provide very different theoretical benefits according to the patient's clinical conditions, as they could be greater in acute syndromes, where the instability of the atherosclerotic plaque and thrombosis prevail. The choice of the drugs to be administered before invasive intervention is made more complex since the last European Society of Cardiology (ESC) guidelines on non ST-segment elevation (NSTE) ACS1 state that patients with ischaemia-induced troponin elevation, who are defined as being at high risk, should be referred for a coronary angiography within 24 h; something that actually occurs in a minority of patients. This consensus document, which was drawn up by experts from the leading Italian societies of cardiology, aims to provide an instrument to guide the choice of treatments as well-suited as possible to the clinical condition of patients candidates to myocardial revascularization. Suggested options are summarized in tables reported at the end of every chapter. The weight of the recommendations is shown on a coloured scale: the recommended treatment appears in green; the optional treatment for which a favourable opinion prevails appears in yellow; a treatment that is possible, but only in selected cases is in orange whereas contraindicated treatments are in the red column.

r. The weight of the recommendations is shown on a coloured scale: the recommended treatment appears in green; the optional treatment for which a favourable opinion prevails appears in yellow; a treatment that is possible, but only in selected cases is in orange whereas contraindicated treatments are in the red column. ST-segment elevation acute coronary syndrome Antiplatelet drugs Oral antiplatelet agents Pre-treatment with aspirin is recommended in all ST-segment elevation acute coronary syndrome (STE ACS) patients’ candidates for PCI, but no specific data are available in the literature.2 In patients with STE ACS, angioplasty is usually performed within a few hours or minutes, making difficult to effectively inhibit platelets hyperactivity by oral agents, given their metabolism and bioavailability. Pre-treatment with clopidogrel in the patient subgroup of the CLARITY-TIMI 28 study3 undergoing PCI reduced the incidence of major adverse cardiovascular events (MACE) without a significant increase in bleeding.4 However, PCI was performed hours after thrombolysis. Successively, two studies on primary PCI did not reveal any significant benefit from pre-treatment.5,6 Lastly, the ACTION meta-analysis showed a significant reduction in MACE with clopidogrel pre-treatment without increase in major bleeds.7

ant increase in bleeding.4 However, PCI was performed hours after thrombolysis. Successively, two studies on primary PCI did not reveal any significant benefit from pre-treatment.5,6 Lastly, the ACTION meta-analysis showed a significant reduction in MACE with clopidogrel pre-treatment without increase in major bleeds.7 The superiority of prasugrel and ticagrelor compared with clopidogrel in reducing MACE in ACS patients was demonstrated by both TRITON TIMI-388 and PLATO studies.9 The new antiplatelet drugs were more effective than clopidogrel even in the STE ACS subgroup10,11; however, very few data are available on pre-treatment and in patients undergoing primary PCI. The only randomized trial on pre-hospital treatment with a P2Y12 inhibitor is the ATLANTIC study,12 in which no difference was observed in pre- and post-PCI reperfusion markers by ticagrelor pre-treatment, compared with its cath lab administration; the mean time difference between the two strategies was a mere 31 min. Pre-treatment with ticagrelor did not reduce MACE, but without an increased risk of bleeding. Despite the lack of evidence from randomized trials, early administration of a P2Y12 inhibitor, preferably prasugrel or ticagrelor, would seem advisable, even in the ambulance if allowed by local organization, especially if the patient transport time exceeds 30 min. The administration of clopidogrel must be reserved for cases in which prasugrel and ticagrelor are contraindicated or not available.2

2Y12 inhibitor, preferably prasugrel or ticagrelor, would seem advisable, even in the ambulance if allowed by local organization, especially if the patient transport time exceeds 30 min. The administration of clopidogrel must be reserved for cases in which prasugrel and ticagrelor are contraindicated or not available.2 Glycoprotein IIb/IIIa inhibitors Glycoprotein IIb/IIIa inhibitors (GPI) have been used in STE ACS to obtain an effective anti-platelet action during angioplasty. A meta-regression performed by De Luca G. et al.13 showed a significant relationship between the patient risk profile and the reduction in mortality in patients pre-treated with GPI. However, many of the studies included were conducted without systematic use of GPI. In patients pre-treated with clopidogrel, the HORIZONS-AMI trial14 showed the superiority of pre-treatment with bivalirudin over unfractionated heparin combined with abciximab. In patients pre-treated with a loading dose of clopidogrel, the BRAVE-3 study15 did not show any advantage from the administration of abciximab on the amount of myocardial necrosis. These data suggest that routine up-stream use of a GPI does not yield benefits in terms of outcome, whilst increasing the risk of bleeding,16 and is therefore generally not indicated. It may be considered in patients with a high thrombotic risk and low haemorrhagic risk, for whom PCI is delayed due to longer transfer time.12,17

a suggest that routine up-stream use of a GPI does not yield benefits in terms of outcome, whilst increasing the risk of bleeding,16 and is therefore generally not indicated. It may be considered in patients with a high thrombotic risk and low haemorrhagic risk, for whom PCI is delayed due to longer transfer time.12,17 Anticoagulants Although there are no specific data on the up-stream administration of unfractioned heparin (UFH) in patients with STE ACS scheduled for primary PCI, its use would appear to be reasonable.2 Enoxaparin is a potential option; however, in the ATOLL study18 it doesn’t demonstrate to be superior to UFH in reducing ischaemic and haemorrhagic events. Bivalirudin would appear to be preferable in patients at high haemorrhagic risk, for its efficacy similar to UFH associated with GPI but with a lower incidence of bleeding; its use was associated with a reduction in total and cardiovascular mortality, but increased the incidence of intra-stent thrombosis.19,20 It should be pointed out that bivalirudin favourable results have not always been confirmed.21,22

efficacy similar to UFH associated with GPI but with a lower incidence of bleeding; its use was associated with a reduction in total and cardiovascular mortality, but increased the incidence of intra-stent thrombosis.19,20 It should be pointed out that bivalirudin favourable results have not always been confirmed.21,22 It is not therefore possible to pinpoint the best anticoagulant treatment, but the choice should be taken depending on the characteristics of the individual patient. In cases of low haemorrhagic risk and low thrombotic burden, UFH or enoxaparin are reasonable options. In those patients treated with a combination of UFH and GPI, which guarantees excellent antithrombotic efficacy but increases haemorrhagic risk, it is fundamental not to overdose heparin and to privilege radial access. Bivalirudin, on the other hand, should be preferred in patients with a higher haemorrhagic risk or in those with delayed presentation, in whom GPI are less effective. Anticoagulant therapy should be discontinued after PCI, except in patients in whom it has a specific indication or for the prophylaxis of venous thromboembolism. There are no randomized studies available on parenteral anticoagulant therapy in patients on oral anticoagulant therapy (OAT) to be treated with primary PCI, only expert opinions.23,24 Regardless of whether the patient is on treatment with a vitamin K antagonist or with a new oral anticoagulant (NOA), it is nevertheless required to administer an additional dose of i.v. anticoagulant, like reduced-dose UFH or bivalirudin, which has a lower bleeding risk.

ed with primary PCI, only expert opinions.23,24 Regardless of whether the patient is on treatment with a vitamin K antagonist or with a new oral anticoagulant (NOA), it is nevertheless required to administer an additional dose of i.v. anticoagulant, like reduced-dose UFH or bivalirudin, which has a lower bleeding risk. Anti-ischaemic drugs Beta-blockers Beta-blockers have shown to reduce mortality in the acute phase of STE ACS in the pre-thrombolytic age25,26; however, the evidence of a benefit in primary PCI treated patients is inconsistent. Early use of high doses is associated with increased mortality,27 particularly in patients at risk of developing cardiogenic shock.28 Calcium channel-blockers Verapamil and diltiazem own an efficacy similar to that of beta-blockers in reducing heart rate and symptoms; however, in the acute phases of STE ACS they could be potentially harmful and should therefore not be used.29 Nitrates Routine administration of nitrates in STE ACS is generally not recommended2; their usefulness has been however, acknowledged in patients with hypertension or heart failure. Statins In patients with STE ACS high-dose statins should be administered early and continued in the long term, with a target low density lipoprotein cholesterol level (C-LDL) below 70 mg/dL.2 This treatment is recommended regardless of reperfusion therapy.

Nitrates Routine administration of nitrates in STE ACS is generally not recommended2; their usefulness has been however, acknowledged in patients with hypertension or heart failure. Statins In patients with STE ACS high-dose statins should be administered early and continued in the long term, with a target low density lipoprotein cholesterol level (C-LDL) below 70 mg/dL.2 This treatment is recommended regardless of reperfusion therapy. Statins could have ‘pleiotropic effects’ on vessel walls, with anti-inflammatory, antioxidant, and antithrombotic properties that could improve endothelial function and stabilize the atherosclerotic disease.30 They have been used in primary PCI in an attempt to reduce the extent of myocardial damage and favour optimal reperfusion.31–35 High doses of high efficacy statins (atorvastatin 80 mg and rosuvastatin 40 mg), administered immediately before primary PCI could improve both epicardial (TIMI flow and TIMI frame count) and myocardial reperfusion (TIMI myocardial perfusion grade or myocardial blush grade), and could reduce the incidence of no-reflow and the levels of myocardial damage markers. Studies on this topic are too small to demonstrate a definite effect of pre-treatment; however, given the lack of significant side effects in the acute phase, it would seem appropriate to suggest their early administration.

Statins could have ‘pleiotropic effects’ on vessel walls, with anti-inflammatory, antioxidant, and antithrombotic properties that could improve endothelial function and stabilize the atherosclerotic disease.30 They have been used in primary PCI in an attempt to reduce the extent of myocardial damage and favour optimal reperfusion.31–35 High doses of high efficacy statins (atorvastatin 80 mg and rosuvastatin 40 mg), administered immediately before primary PCI could improve both epicardial (TIMI flow and TIMI frame count) and myocardial reperfusion (TIMI myocardial perfusion grade or myocardial blush grade), and could reduce the incidence of no-reflow and the levels of myocardial damage markers. Studies on this topic are too small to demonstrate a definite effect of pre-treatment; however, given the lack of significant side effects in the acute phase, it would seem appropriate to suggest their early administration. In Italy statin prescription is ruled by circular no. 13 issued by the Italian Medicines Agency (AIFA),36 which identifies high-dose atorvastatin (≥40 mg/day) as the first treatment option in patients with ACS and/or undergoing myocardial revascularization. Suggested treatment options for STE ACS patients are summarized in Table 1. Table 1 ST-segment elevation acute coronary syndromes pre-treatment UFH, unfractioned heparin; ASA, acute coronary syndromes; PCI, percutaneous coronary intervention. aAs an alternative to UFH. bAfter or as an alternative to UFH. cIn addition to ASA. dIn patients at low bleeding risk and at high ischaemic risk to be transferred to a PCI centre.

Suggested treatment options for STE ACS patients are summarized in Table 1. Table 1 ST-segment elevation acute coronary syndromes pre-treatment UFH, unfractioned heparin; ASA, acute coronary syndromes; PCI, percutaneous coronary intervention. aAs an alternative to UFH. bAfter or as an alternative to UFH. cIn addition to ASA. dIn patients at low bleeding risk and at high ischaemic risk to be transferred to a PCI centre. eAs an alternative to i.v. ASA. fAs an alternative to oral ASA. Non ST-segment elevation acute coronary syndrome Antiplatelet drugs Oral antiplatelet agents The ESC 2011 guidelines on NSTE ACS37 recommended the administration of aspirin and P2Y12 inhibitors ‘as soon as possible’, whereas the 2015 edition suggests that this treatment should be administered timely from the time of diagnosis, without however providing specific indications about when, and recommending haemorrhagic risk stratification.1 Invasive strategy should be adopted: immediately (within 2 h of diagnosis) for patients with haemodynamic or electric instability, or another very high risk criterion; early (with 24 h of diagnosis) in patients with at least one high risk criterion, including troponin elevation; electively (within 72 h of diagnosis) in patients with at least one intermediate ischaemic risk criterion.

immediately (within 2 h of diagnosis) for patients with haemodynamic or electric instability, or another very high risk criterion; early (with 24 h of diagnosis) in patients with at least one high risk criterion, including troponin elevation; electively (within 72 h of diagnosis) in patients with at least one intermediate ischaemic risk criterion. Aspirin Aspirin has demonstrated to be effective in patients with unstable angina38; the incidence of myocardial infarction or death was reduced in four trials in the pre-PCI era.39–42 A meta-analysis of these studies showed a significant reduction at 2 years in the MACE rate.43 However, there are no specific data available on the administration before an invasive strategy. Clopidogrel The pre-treatment strategy comes from the results of the PCI-CURE trial,44 in which a 30% reduction in the primary endpoint of death, infarction or stroke was seen in patients pre-treated with clopidogrel; however, this sub-group represents only about 20% of the whole CURE trial population, and the average time interval between pre-treatment and PCI was 10 days, which is far longer than nowadays.

hich a 30% reduction in the primary endpoint of death, infarction or stroke was seen in patients pre-treated with clopidogrel; however, this sub-group represents only about 20% of the whole CURE trial population, and the average time interval between pre-treatment and PCI was 10 days, which is far longer than nowadays. Prasugrel The only randomized trial on pre-treatment with a P2Y12 inhibitor in patients with NSTE ACS is the ACCOAST study,45 in which patients intended for an invasive approach were randomized to receive pre-treatment with an oral loading dose of 30 mg of prasugrel followed by a further oral 30 mg load at the time of PCI, or the administration of 60 mg of prasugrel in the cath lab. The mean duration of pre-treatment was 4.3 h. At 7 days no reduction was observed in the occurrence of the primary endpoint, while major bleeds where significantly increased in the pre-treatment arm. Pre-treatment with prasugrel in patients with NSTE ACS is therefore not recommended.1 Ticagrelor In the NSTE ACS patient subgroup of the PLATO study, the primary composite efficacy endpoint was significantly reduced by ticagrelor compared with clopidogrel;46 however, results in patients actually pre-treated are not available.

Prasugrel The only randomized trial on pre-treatment with a P2Y12 inhibitor in patients with NSTE ACS is the ACCOAST study,45 in which patients intended for an invasive approach were randomized to receive pre-treatment with an oral loading dose of 30 mg of prasugrel followed by a further oral 30 mg load at the time of PCI, or the administration of 60 mg of prasugrel in the cath lab. The mean duration of pre-treatment was 4.3 h. At 7 days no reduction was observed in the occurrence of the primary endpoint, while major bleeds where significantly increased in the pre-treatment arm. Pre-treatment with prasugrel in patients with NSTE ACS is therefore not recommended.1 Ticagrelor In the NSTE ACS patient subgroup of the PLATO study, the primary composite efficacy endpoint was significantly reduced by ticagrelor compared with clopidogrel;46 however, results in patients actually pre-treated are not available. Intravenous antiplatelet agents Cangrelor Cangrelor is a direct reversible inhibitor of P2Y12 receptor, that has been compared with clopidogrel in patients undergoing PCI,47–49 most of whom affected by ACS. A meta-analysis of these trials showed that the infusion of cangrelor reduced the relative risk of the composite endpoint (peri-procedural death, myocardial infarction, ischaemia-guided revascularization and intra-stent thrombosis), determining also an increase in minor and major bleeds, but not in the need for transfusions.50

nalysis of these trials showed that the infusion of cangrelor reduced the relative risk of the composite endpoint (peri-procedural death, myocardial infarction, ischaemia-guided revascularization and intra-stent thrombosis), determining also an increase in minor and major bleeds, but not in the need for transfusions.50 European Society of Cardiology guidelines suggest considering pre-treatment with cangrelor in patients who are not treated with a P2Y12 inhibitor.1 Cangrelor, which has been approved by the European Medicines Agency, is currently not available in Italy. Glycoprotein IIb/IIIa inhibitors Up-stream use of GPI in patients with NSTE ACS has been studied in two trials. In the ACUITY,51 the deferred GPI administration strategy compared with the up-stream use led to a significant reduction at 30 days in major bleedings not related to CABG, without any difference in the primary efficacy endpoint. The EARLY-ACS study52 did not reveal any significant reduction in the primary endpoint occurrence in the arm pre-treated with eptifibatide compared with the optional use arm, but showed a significant increase in major bleeds. Lastly, a meta-analysis indicated that GPI pre-treatment did not reduce mortality or myocardial infarction recurrence at 30 days, with a significant increase in major bleeds.53 Thus pre-treatment with GPI inhibitors is not recommended.1

pared with the optional use arm, but showed a significant increase in major bleeds. Lastly, a meta-analysis indicated that GPI pre-treatment did not reduce mortality or myocardial infarction recurrence at 30 days, with a significant increase in major bleeds.53 Thus pre-treatment with GPI inhibitors is not recommended.1 Proposed ‘decision-making’ scheme for pre-treatment with a P2Y12 inhibitor We propose a decision-making scheme for pre-treatment in NSTE ACS patients based on the ESC stratification of the ischaemic risk,1 on the timing of the coronary angiography and on the haemorrhagic risk, assessed by the CRUSADE score,54 choosing a cut-off value of 50 that identifies patients at high risk of major bleeds. Time to invasive strategy is longer than recommended in a significant amount of patients in Italy,55 in Europe56,57 and in the USA.58 Sometime this deferral could be related to associated clinical conditions that recommend stabilization or a more thorough diagnosis before performing coronary angiography; in the majority of cases, however, the delay stems from the need to transfer the patient in hospitals with cath labs.

Europe56,57 and in the USA.58 Sometime this deferral could be related to associated clinical conditions that recommend stabilization or a more thorough diagnosis before performing coronary angiography; in the majority of cases, however, the delay stems from the need to transfer the patient in hospitals with cath labs. Patients at very high ischaemic risk In case of invasive intervention within 2 h, the oral load of P2Y12 inhibitor will be ineffective at the time of the procedure, and it would therefore appear to be preferable to use GPI if needed, given also their faster resolution of the effect in case of need of a surgical treatment. However, pre-treatment with ticagrelor or prasugrel is not excluded, mainly when the ischaemic risk is far greater than the haemorrhagic risk and the likelihood of surgery is not high. Patients at high or moderate ischaemic risk In case of very high haemorrhagic risk, identified by a CRUSADE score ≥ 50, pre-treatment is usually not recommended (red box), and only if the time to the coronary angiography is longer can pre-treatment be considered in selected cases (orange box) (Figure 1). Figure 1 Pre-treatment with P2Y12 inhibitors in non ST-segment elevation acute coronary syndromes at moderate/high risk. In case of a CRUSADE score <50 pre-treatment is not mandatory but however allowed (yellow box) if coronary angiography will be performed within the recommended time; if the angiography is delayed, pre-treatment with P2Y12 inhibitors would appear to be appropriate (green box).

Figure 1 Pre-treatment with P2Y12 inhibitors in non ST-segment elevation acute coronary syndromes at moderate/high risk. In case of a CRUSADE score <50 pre-treatment is not mandatory but however allowed (yellow box) if coronary angiography will be performed within the recommended time; if the angiography is delayed, pre-treatment with P2Y12 inhibitors would appear to be appropriate (green box). Patients at low ischaemic risk In patients with NSTE ACS at low ischaemic risk pre-treatment with P2Y12 inhibitors is not recommended.1 Anticoagulants The anticoagulant of choice in NSTE ACS should be fondaparinux, due to its more favourable efficacy and safety profile compared with UFH and enoxaparin.1,59,60 In patients pre-treated with fondaparinux an additional bolus of standard-dose UFH must be administered at the time of PCI. Enoxaparin and UFH are recommended when fondaparinux is not available.13 There are no conclusive data regarding the superiority of one drug over the other.61 In a meta-analysis of over 30 000 patients, enoxaparin compared with UFH determined a slight decrease in the composite endpoint of death and myocardial infarction at 30 days without differences in terms of major bleeds.62 In patients pre-treated with enoxaparin is strongly recommended to avoid to switch to UFH, unfortunately frequently done,55 due to a higher risk of ischaemic and haemorrhagic complications.63 UFH is particularly indicated in patients with severe renal insufficiency.

days without differences in terms of major bleeds.62 In patients pre-treated with enoxaparin is strongly recommended to avoid to switch to UFH, unfortunately frequently done,55 due to a higher risk of ischaemic and haemorrhagic complications.63 UFH is particularly indicated in patients with severe renal insufficiency. In the ACUITY study64 bivalirudin was non-inferior to UFH in the reduction of ischaemic events, reducing also major bleeds, but it has to be administered only at the time of the PCI. The usefulness of continuing its infusion after PCI in order to reduce the risk of intra-stent thrombosis was recently questioned.22 Anticoagulation should be discontinued after PCI, except in those patients in whom it has a specific indication. In patients with NSTE ACS candidates to coronary angiography while on chronic OAT with vitamin K inhibitors or NOA there are still no consistent data. OAT can be stopped and replaced by UFH or enoxaparin, or could be continued at reduced dosages, in order to reduce the risk of both thromboembolic and haemorrhagic events. It is not necessary to administer UFH during PCI if the INR value is greater than 2.5, whereas in case of NOA treatment, administration of an additional intravenous bolus of UFH is recommended.1,23,24 Anti-ischaemic drugs Beta-blockers The administration of beta-blockers in NSTE ACS patients demonstrated to reduce in-hospital mortality, except that in patients at risk of cardiogenic shock or with unknown left ventricular function.65

In patients with NSTE ACS candidates to coronary angiography while on chronic OAT with vitamin K inhibitors or NOA there are still no consistent data. OAT can be stopped and replaced by UFH or enoxaparin, or could be continued at reduced dosages, in order to reduce the risk of both thromboembolic and haemorrhagic events. It is not necessary to administer UFH during PCI if the INR value is greater than 2.5, whereas in case of NOA treatment, administration of an additional intravenous bolus of UFH is recommended.1,23,24 Anti-ischaemic drugs Beta-blockers The administration of beta-blockers in NSTE ACS patients demonstrated to reduce in-hospital mortality, except that in patients at risk of cardiogenic shock or with unknown left ventricular function.65 Calcium channel-blockers Diltiazem and verapamil are possible alternatives in case of contraindications to the use of beta-blockers. They can be used to control angina or in case of vasospasm.1 Nitrates Nitrates are highly effective in reducing angina and are particularly suitable in patients with incomplete blood pressure control. Their usefulness remains limited to symptom control.1 Statins The evidences in favour of pre-treatment with high doses of statins in case of PCI in patients with NSTE ACS were summarized in a meta-analysis66 that shows how the administration of atorvastatin 80 mg or rosuvastatin 40 mg before PCI is associated with a reduction in the incidence and amount of post-procedural necrosis, as expressed by lower myocardial damage markers levels, and of short-term MACE.

in patients with NSTE ACS were summarized in a meta-analysis66 that shows how the administration of atorvastatin 80 mg or rosuvastatin 40 mg before PCI is associated with a reduction in the incidence and amount of post-procedural necrosis, as expressed by lower myocardial damage markers levels, and of short-term MACE. Reloading is also advisable in patients who are already treated with statins.67 Suggested treatment options for NSTE ACS patients are summarized in Tables 2and3. Table 2 Non ST-segment elevation acute coronary syndromes pre-treatment: very high risk UFH, unfractioned heparin; ASA, acute coronary syndromes. Table 3 Non ST-segment elevation acute coronary syndromes pre-treatment: moderate/high risk UFH, unfractioned heparin; ASA, acute coronary syndromes. aIn addition to ASA. bSee risk/time schedule. cPt. with severe kidney disease. dIn patient with heparin induced thrombocytopenia. Patients with stable ischaemic heart disease Antiplatelet drugs Aspirin pre-treatment is recommended in all PCI candidates, also if there are no specific data available.68 In the lack of studies, ESC guidelines suggest a loading dose of clopidogrel before PCI when coronary anatomy is known, recommending its administration at least 2 h before the procedure;68 guidelines take also into consideration a loading dose of clopidogrel in patients with a high likelihood of coronary stenosis to revascularize.38,68,69 In patients who are already on treatment with clopidogrel, reloading with 600 mg can be considered once angioplasty is planned.

ion at least 2 h before the procedure;68 guidelines take also into consideration a loading dose of clopidogrel in patients with a high likelihood of coronary stenosis to revascularize.38,68,69 In patients who are already on treatment with clopidogrel, reloading with 600 mg can be considered once angioplasty is planned. There are no data available on the use of ticagrelor and prasugrel in non-ACS patients, so their administration is not recommended. Use of GPI should be reserved as rescue therapy in case of intra-procedural thrombotic complications.70 Anticoagulants In patients with stable ischaemic heart disease the aim of anticoagulant therapy is to reduce the risk of peri-procedural thrombotic complications, and it should therefore only be administered at the time of PCI. UFH remains the standard of care.71 Enoxaparin can be used as alternative to UFH.72 Bivalirudin should be reserved for patients at very high bleeding risk.73 In stable patients on OAT it is reasonable to continue administration of vitamin K inhibitors, adding a reduced dose of UFH only in case of radial approach. The great handling of NOAs makes it easy to temporarily stop treatment.23,24,74 Anti-ischaemic drugs In general, there is no specific need of anti-ischaemic treatment before a revascularization procedure, if not those suited to the patient's specific clinical condition. Statins Statins are recommended with the aim of keeping C-LDL levels below 70 mg/dL.68 Pre-procedural administration in stable patients is thought to be effective to prevent contrast-induced kidney disease.75

Anti-ischaemic drugs In general, there is no specific need of anti-ischaemic treatment before a revascularization procedure, if not those suited to the patient's specific clinical condition. Statins Statins are recommended with the aim of keeping C-LDL levels below 70 mg/dL.68 Pre-procedural administration in stable patients is thought to be effective to prevent contrast-induced kidney disease.75 A recent meta-analysis76 showed that pre-treatment with high doses of high-efficacy statin is associated with a reduction in the risk of peri-procedural myocardial necrosis, and a reduction in short-term MACE. It would therefore appear advisable to administer an oral loading dose of 80 mg of atorvastatin or 20–40 mg of rosuvastatin before elective percutaneous revascularization procedure. Reloading is appropriate in patients already on therapy with another statin.77 Suggested treatment options for stable ischaemic heart disease patients are summarized in Table 4. Table 4 Stable ischaemic heart disease pre-treatment UFH, unfractioned heparin; ASA, acute coronary syndromes; PCI, percutaneous coronary intervention. aIn addition to ASA in case of scheduled PCI for known anatomy or high likelihood of PCI. Patients candidates to coronary artery bypass grafting Most patients who are candidates to CABG are on treatment with antiplatelet, anticoagulant, beta-blocker and statin therapy, whose pre-operative administration must be managed in order to maintain their cardio-protective effects, but avoiding to increase bleeding or hypotension.

dates to coronary artery bypass grafting Most patients who are candidates to CABG are on treatment with antiplatelet, anticoagulant, beta-blocker and statin therapy, whose pre-operative administration must be managed in order to maintain their cardio-protective effects, but avoiding to increase bleeding or hypotension. Antiplatelet drugs Antiplatelet drugs improve short- and long-term outcomes even in patients undergoing CABG;78,79 bleeding is however a serious and common complication80,81 that implies an additional risk of further adverse events.82–84 Pre-operative discontinuation of aspirin is considered to be risky in patients with ACS or with coronary stents,85 and it should only be considered in case of a very high risk of bleeding or in patients who refuse transfusions, stopping treatment three days before the procedure.86,87 In patients with stable coronary disease, the benefits of continuing therapy with aspirin up to the day of the procedure are less well defined. It was highlighted a slight increase in the risk of bleeding without improving the early graft patency rate.88 The ATACAS trial89 did not reveal any differences in major bleeds with the pre-operative use of aspirin, nor a reduction in thrombotic events or in mortality, possibly due to the low risk of the population studied. Prasugrel compared with clopidogrel significantly increases post-operative bleedings, including fatal ones; however, after discontinuation of the drug, post-operative mortality was lower than for patients treated with clopidogrel.90

In patients with stable coronary disease, the benefits of continuing therapy with aspirin up to the day of the procedure are less well defined. It was highlighted a slight increase in the risk of bleeding without improving the early graft patency rate.88 The ATACAS trial89 did not reveal any differences in major bleeds with the pre-operative use of aspirin, nor a reduction in thrombotic events or in mortality, possibly due to the low risk of the population studied. Prasugrel compared with clopidogrel significantly increases post-operative bleedings, including fatal ones; however, after discontinuation of the drug, post-operative mortality was lower than for patients treated with clopidogrel.90 Ticagrelor demonstrated peri-operative bleeding risk similar to clopidogrel,91 but mortality in patients treated 3–5 days after the last administered dose was significantly lower.92 Ticagrelor has a reversible binding with platelets, and may remain in circulation for a long time, inhibiting also transfused platelets.93 A specific antidote is currently being developed.94 It may be appropriate to monitor platelet inhibition with dedicated tests, in order to limit the antiplatelet discontinuation period to 1–2 days.95,96 These are the ESC guidelines suggestions:37,68in case of high or very high risk of haemorrhage: aspirin should be maintained for the entire surgical period; clopidogrel and ticagrelor should be discontinued 5 days before the procedure; prasugrel should be discontinued 7 days before;

It may be appropriate to monitor platelet inhibition with dedicated tests, in order to limit the antiplatelet discontinuation period to 1–2 days.95,96 These are the ESC guidelines suggestions:37,68in case of high or very high risk of haemorrhage: aspirin should be maintained for the entire surgical period; clopidogrel and ticagrelor should be discontinued 5 days before the procedure; prasugrel should be discontinued 7 days before; in case of high or very high thrombotic risk (clinical and/or anatomical): aspirin should be maintained for the entire surgical period; in emergency, discontinuing the P2Y12 inhibitor is not recommended and all possible measures must be taken to reduce the risk of bleeding; in case of urgent surgery, consider to perform the procedure after 1-2 days of discontinuation. In case of very high both thrombotic and ischaemic risk, ‘bridging’ strategies with short half-life intravenous anti-platelet drugs were evaluated: discontinuation of clopidogrel 5 days before the procedure and administration of tirofiban or eptifibatide i.v. up to 4 h before;97 discontinuation of thienopyridine (99% clopidogrel) 48 h before the procedure and administration of intravenous cangrelor up to 1–6 h before.98 Replacing double antiplatelet therapy with heparin is not recommended. A P2Y12 inhibitor should be administered as soon as possible after the procedure, as it improves graft patency and outcome at 30 days.99,100

discontinuation of thienopyridine (99% clopidogrel) 48 h before the procedure and administration of intravenous cangrelor up to 1–6 h before.98 Replacing double antiplatelet therapy with heparin is not recommended. A P2Y12 inhibitor should be administered as soon as possible after the procedure, as it improves graft patency and outcome at 30 days.99,100 Anticoagulants In patients treated with vitamin K inhibitors, normal INR values must be restored before an elective procedure. The use of low molecular weight heparin as a therapeutic bridge may increase the risk of peri-procedural bleeding.100 In case of emergency/urgency, vitamin K and/or transfusions of fresh plasma or prothrombin complex concentrates may be administered.101 If a NOA is used, it should be discontinued 48–96 h before a scheduled procedure, taking into account the patient's kidney function and the drug used,102 without bridging with heparin.74,100,103 Laboratory tests to measure NOA effects have not yet been validated, as the relationship between the value of the measured parameter and the risk of bleeding is not known.102 In case of urgent heart surgery, it would seem preferable to wait until the NOAs are no longer effective. In case of emergency procedures, activated prothrombin complexes may be used.104 Specific inhibitors have so far been studied on a very limited number of patients. Idarucizumab is an antibody fragment that in a few minutes overrides the effect of dabigatran,105 whereas Andexanet inhibits the effect of anti-Xa NOA.106

In case of urgent heart surgery, it would seem preferable to wait until the NOAs are no longer effective. In case of emergency procedures, activated prothrombin complexes may be used.104 Specific inhibitors have so far been studied on a very limited number of patients. Idarucizumab is an antibody fragment that in a few minutes overrides the effect of dabigatran,105 whereas Andexanet inhibits the effect of anti-Xa NOA.106 The administration of NOAs should not be restarted earlier than 48–72 h after the procedure, and there are no data available on use at reduced dosages. Beta-blockers The enthusiasm on the use of these drugs was curbed by the results of a meta-analysis,107 by the results of a Texas Heart Surgery Society database,108 and by a retrospective analysis of the data of over 500 000 patients without recent myocardial infarction109: pre-operative use did not lead to a mortality reduction, while slightly increased the incidence of atrial fibrillation; the underlying mechanism is possibly related to hypotension. Statins Statins reduce the development of venous graft disease110; pleiotropic effects are associated with a reduction in adverse clinical events and to cardiovascular protection.111,112 Despite these premises, a review113 on pre-operative treatment indicated as the only result a reduction in the incidence of post-operative atrial fibrillation and consequently of the duration of hospitalization. There were no significant effects on mortality, stroke, peri-operative infarction or kidney disease.

Statins Statins reduce the development of venous graft disease110; pleiotropic effects are associated with a reduction in adverse clinical events and to cardiovascular protection.111,112 Despite these premises, a review113 on pre-operative treatment indicated as the only result a reduction in the incidence of post-operative atrial fibrillation and consequently of the duration of hospitalization. There were no significant effects on mortality, stroke, peri-operative infarction or kidney disease. Conclusions The antithrombotic drugs administration before coronary angiography in patients with coronary disease on the one hand may make it possible to bring forward optimal therapy but on the other it may expose to risk of bleeding that, particularly in patients with ACS, can weigh heavily on prognosis, even more so than the theoretical benefit of pre-treatment. In NSTE ACS patients in particular, we suggest a ‘selective pre-treatment’ with P2Y12 inhibitors, guided by a careful assessment of both ischaemic and haemorrhagic risk, whilst also taking into consideration the actual time delay before the coronary angiography. Many of the issues regarding this topic could be solved by early access to coronary angiography, particularly in patients at greatest risk of events.

In NSTE ACS patients in particular, we suggest a ‘selective pre-treatment’ with P2Y12 inhibitors, guided by a careful assessment of both ischaemic and haemorrhagic risk, whilst also taking into consideration the actual time delay before the coronary angiography. Many of the issues regarding this topic could be solved by early access to coronary angiography, particularly in patients at greatest risk of events. Consensus Document Approval Faculty Abrignani Maurizio Giuseppe, Alunni Gianfranco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Audo Andrea, Azzarito Michele, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Bonvicini Marco, Cacciavillani Luisa, Calculli Giancarlo Giacinto, Caldarola Pasquale, Capecchi Alessandro, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Casu Gavino, Cemin Roberto, Chiarandà Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Ciccone Marco Matteo, Cicini Maria Paola, Clerico Aldo, D'Agostino Carlo, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Di Lenarda Andrea, Di Tano Giuseppe, Egidy Assenza Gabriele, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Favilli Silvia, Ferraiuolo Giuseppe, Francese Giuseppina Maura, Gabrielli Domenico, Giardina Achille, Greco Cesare, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Lucà Fabiana, Lukic Vjerica, Macera Francesca, Marini Marco, Masson Serge, Maurea Nicola, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Mininni Nicola, Moreo Antonella, Mortara Andrea, Mureddu Gian Francesco, Murrone Adriano, Nardi Federico, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Procaccini Vincenza, Pugliese Francesco Rocco, Pulignano Giovanni, Radini Donatella, Rao Carmelo Massimiliano, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

iliano, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino. Conflict of Interest: Dr. Roberto Caporale reports honoraria for consulting from Lilly and Boehringer Ingelheim. Dr. Alberto Menozzi reports honoraria for lectures and consulting from Astra-Zeneca, Abbott Vascular, Bayer, Correvio, Daiichi-Sankyo, Medtronic, MSD, The Medicines Company. Giuseppe Musumeci reports honoraria for lectures from Daiichi Sankyo, Astra Zeneca, Menarini, Servier and Abbott Vascular. Prof. Giuseppe Tarantini reports honoraria for lectures from Boston Scientific, St. Jude Medical, Philips Volcano, Medtronic and Abbott Vascular.

Revised by Piero Maglia, Gennaro Santoro Consensus Document Approval Faculty in appendix Table of contents Introduction Stroke and thromboembolic risk layering: risk of haemorrhage associated to oral anticoagulant treatment Current antithrombotic treatment recommendations Specific clinical situations associated to high risk of haemorrhage Anatomy of the left atrial appendage Surgical closure (occlusion) of the left atrial appendage Results Echocardiogram assessment Indications for surgical occlusion of the left atrial appendage Requirements for staff and Centres Percutaneous occlusion of the left atrial appendage Left atrial appendage occlusion devices currently available Devices currently under development Cost-effectiveness studies Indications for left atrial appendage occlusion Screening of patients who are possible candidates for left atrial appendage occlusion Echocardiogram assessment and echocardiogram anatomy of the left atrial appendage ‘Step by step’ procedure Choice of anaesthesia Choice of vascular access Transseptal puncture Intraprocedural antithrombotic therapy Insertion of the deployment system into the left atrium Choice of device Preparation of the system and device Implantation of the device Deployment of the device Management of antithrombotic therapy after the procedure Recommended organisational and operating standards General requirements Staff training and preparation Requirements for the centre and operating room Procedural recommendations and minimum skill levels Requirements for the facility and staff Management of complications Pericardial effusion and cardiac tamponade Gaseous embolism Embolization of the device Conclusions Acknowledgments Annex References

Recommended organisational and operating standards General requirements Staff training and preparation Requirements for the centre and operating room Procedural recommendations and minimum skill levels Requirements for the facility and staff Management of complications Pericardial effusion and cardiac tamponade Gaseous embolism Embolization of the device Conclusions Acknowledgments Annex References Introduction Non-valvular atrial fibrillation (AF) is the most common form of cardiac arrhythmia and its incidence and prevalence are constantly increasing1 due to the ageing of the population and the higher survival rates of patients with conditions such as ischaemic cardiopathy, valve defects, congenital heart defects, and cardiac insufficiency. The estimated prevalence in the general population is about 2% and increases with age.1 The lifetime risk of onset of AF is 25% in men and women with age > 40 with heart defects, while for those without heart defects the risk is about 15%.2,3 A diagnosis of AF features in about 3–6% of hospitalizations for acute heart conditions,3 especially coronary heart diseases and congestive cardiac insufficiency. In the general population, arterial hypertension is the most common condition associated with AF.3,4 Moreover, AF is a common post-operative complication, especially after cardiothoracic surgery.3,4 However, there are also isolated forms of AF, diagnosed mainly by exclusion once concomitant cardiac diseases have been ruled out.

neral population, arterial hypertension is the most common condition associated with AF.3,4 Moreover, AF is a common post-operative complication, especially after cardiothoracic surgery.3,4 However, there are also isolated forms of AF, diagnosed mainly by exclusion once concomitant cardiac diseases have been ruled out. Most patients are asymptomatic and AF is an occasional occurrence. In some patients, it may occur with minor symptoms (palpitations) while in others the first onset may be a complication of AF such as ischaemic stroke. The presence of AF is an independent risk factor for increased mortality and morbidity, and is a cause of stroke and/or thromboembolism, congestive cardiac insufficiency, and seriously reduced quality of life, with a consequent increase in health-care costs.3,4 The risk of stroke in patients with non-valvular AF is ∼5% per year and at least 15–20% of all ischaemic strokes are associated with AF.5 AF is also an independent risk factor for the recurrence of stroke6 and is associated with higher mortality and morbidity than stroke not correlated to AF, underlining the need for more effective stroke prevention in these patients.5,6 AF, subdivided into ‘valvular’ (patients with mechanical valve prostheses or mitral stenosis) and ‘non valvular’, is classified in four different categories depending on the mode of presentation and duration of the arrhythmia: paroxystic AF (ends spontaneously or after therapy within 7 days after onset), persistent AF (lasts more than 7 days), persistent or long-standing AF (continues for more than 1 year), and

AF, subdivided into ‘valvular’ (patients with mechanical valve prostheses or mitral stenosis) and ‘non valvular’, is classified in four different categories depending on the mode of presentation and duration of the arrhythmia: paroxystic AF (ends spontaneously or after therapy within 7 days after onset), persistent AF (lasts more than 7 days), persistent or long-standing AF (continues for more than 1 year), and permanent AF (continual, and the patient and physician have decided together against attempts at cardioversion and maintenance of the sinus rhythm). The risk of stroke is basically the same for all four types of AF.4 Stroke and thromboembolic risk layering: risk of haemorrhage associated to oral anticoagulant treatment The presence of AF is an independent risk factor for ischaemic stroke and thromboembolic events, significantly increases mortality and morbidity and can cause serious disabilities, as well as longer hospitalization. The treatment of choice for the prevention of ischaemic stroke is oral anticoagulant therapy (OAT) with warfarin or, in the case of non-valvular AF, with the new oral anticoagulants (NOACs). In the case of non-valvular AF, warfarin has been shown to reduce the risk of stroke by about 62%, but it increases the risk of haemorrhage in percentages which vary from 1.2% to 3.4% per year.7 NOACs have proved equally effective with a lower risk of cerebral haemorrhage.4

AF, with the new oral anticoagulants (NOACs). In the case of non-valvular AF, warfarin has been shown to reduce the risk of stroke by about 62%, but it increases the risk of haemorrhage in percentages which vary from 1.2% to 3.4% per year.7 NOACs have proved equally effective with a lower risk of cerebral haemorrhage.4 In about 90% of non-valvular AF patients, the thrombi form in the left atrial appendage (LAA);8 however, it is fundamental to bear in mind that, even in AF patients, ischaemic stroke can be correlated to other factors, such as hypercoagulability or atherosclerosis of the ascending aorta and carotids. Basically, the management of AF can be summed up in two main steps: identification and treatment of predisposing factors and concomitant pathologies and assessment of the thromboembolic risk and haemorrhagic risk for choice of the best therapeutic strategy. In AF patients, risk layering is crucial. In fact, in spite of the plentiful, universally accepted evidence of the benefits of OAT in reducing the risk of ischaemic stroke, many studies have revealed that this therapy is underused, especially in high-risk patients.8,9 A large number of stroke risk layering methods have been produced on the basis of risk factors identified in the control arms of clinical studies on warfarin, cohort studies and consent documents. These methods vary in complexity and the number of risk factors assessed, but they have almost all divided AF patients, by convention, into low, moderate and high risk.4,10

ve been produced on the basis of risk factors identified in the control arms of clinical studies on warfarin, cohort studies and consent documents. These methods vary in complexity and the number of risk factors assessed, but they have almost all divided AF patients, by convention, into low, moderate and high risk.4,10 CHA2DS2-VASc10 is the thromboembolic risk assessment score recommended by the European Society of Cardiology (ESC), the American Heart Association (AHA) and the American College of Cardiology (ACC), which considers gender, vascular diseases, cardiac insufficiency, hypertension, age (divided into two classes), diabetes and ischaemic stroke as risk factors. The HAS-BLED score is the most widely used for the layering of haemorrhage risk.11 HAS-BLED has been compared with the HEMORR2HAGES method and with ATRIA and, although, like the others, it has shown only a moderate ability to predict the risk of bleeding, it has proved the most effective in significantly predicting the risk of intracranial haemorrhage, and is also the simplest.12 A HAS-BLED score ≥ 3 identifies patients with high risk of haemorrhage but is not a criterion for exclusion from OAT. Tables 1 and 2 summarize the risk factors assessed in CHA2DS2-VASc and HAS-BLED with the relative scores. Table 1 CHA2DS2-VASc score and incidence of stroke

The HAS-BLED score is the most widely used for the layering of haemorrhage risk.11 HAS-BLED has been compared with the HEMORR2HAGES method and with ATRIA and, although, like the others, it has shown only a moderate ability to predict the risk of bleeding, it has proved the most effective in significantly predicting the risk of intracranial haemorrhage, and is also the simplest.12 A HAS-BLED score ≥ 3 identifies patients with high risk of haemorrhage but is not a criterion for exclusion from OAT. Tables 1 and 2 summarize the risk factors assessed in CHA2DS2-VASc and HAS-BLED with the relative scores. Table 1 CHA2DS2-VASc score and incidence of stroke Risk factors for stroke and thromboembolism in non-valvular AF ‘Major’ risk factors ‘Significant’ risk factors Previous stroke, TIA or systemic embolism Cardiac insufficiency or moderate or severe systolic dysfunction (EF < 40%) Age > 75 years Arterial hypertension, diabetes mellitus, female gender, age 65–74 years, peripheral vascular disease Risk factors included in the CHA2DS2-VASc score Risk factors Score Cardiac insufficiency/ systolic dysfunction 1 Arterial hypertension 1 Age 65–74 years. 1 Age > 75 years 2 Diabetes mellitus 1 Stroke/TIA/thromboembolism 2 Peripheral vascular disease 1 Female gender 1 EF, ejection fraction; TIA, transient ischaemic attack. Table 2 HAS-BLED score Letter Clinical characteristics Score H Hypertension 1 A Impaired kidney or liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Old age (>65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 INR, international normalized ratio.

Risk factors for stroke and thromboembolism in non-valvular AF ‘Major’ risk factors ‘Significant’ risk factors Previous stroke, TIA or systemic embolism Cardiac insufficiency or moderate or severe systolic dysfunction (EF < 40%) Age > 75 years Arterial hypertension, diabetes mellitus, female gender, age 65–74 years, peripheral vascular disease Risk factors included in the CHA2DS2-VASc score Risk factors Score Cardiac insufficiency/ systolic dysfunction 1 Arterial hypertension 1 Age 65–74 years. 1 Age > 75 years 2 Diabetes mellitus 1 Stroke/TIA/thromboembolism 2 Peripheral vascular disease 1 Female gender 1 EF, ejection fraction; TIA, transient ischaemic attack. Table 2 HAS-BLED score Letter Clinical characteristics Score H Hypertension 1 A Impaired kidney or liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Old age (>65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 INR, international normalized ratio. The final decision on the type of antithrombotic treatment in AF patients must therefore balance the degree of reduction of the risk of thromboembolism against the minimization of serious haemorrhagic complications (in other words intracranial haemorrhage) associated with these therapies.

Letter Clinical characteristics Score H Hypertension 1 A Impaired kidney or liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Old age (>65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 INR, international normalized ratio. The final decision on the type of antithrombotic treatment in AF patients must therefore balance the degree of reduction of the risk of thromboembolism against the minimization of serious haemorrhagic complications (in other words intracranial haemorrhage) associated with these therapies. Current antithrombotic treatment recommendations An analysis of the net clinical benefit (balancing the reduction of ischaemic and haemorrhagic events) of vitamin K antagonists was conducted on a large population of AF patients in the real world (n = 130 000) using the CHA2DS2-VASc and HAS-BLED scores. This study revealed a net benefit for anticoagulant therapy in patients with CHA2DS2-VASc ≥2. The effect was neutral in patients with CHA2DS2-VASc =1, while there was no net benefit in patients with CHA2DS2-VASc =0. Moreover, this study further confirmed the absence of benefits from aspirin alone in any risk layer.13,14

his study revealed a net benefit for anticoagulant therapy in patients with CHA2DS2-VASc ≥2. The effect was neutral in patients with CHA2DS2-VASc =1, while there was no net benefit in patients with CHA2DS2-VASc =0. Moreover, this study further confirmed the absence of benefits from aspirin alone in any risk layer.13,14 The most recent guidelines (2014) on the treatment of AF are those of the AHA/ACC,15 which suggest, in AF patients with CHA2DS2-VASc ≥2, the use of warfarin with class I and level of evidence A and of NOACs with class I and level of evidence B, while the 2012 ESC guidelines16 recommend class I with level of evidence A for both warfarin and NOACs in the same patients. In patients with CHA2DS2-VASc =1, the US guidelines basically advise against antithrombotic therapy (IIb, C), while the European ones are more in favour (IIa, A). All guidelines advise against any anticoagulant therapy in patients with CHA2DS2-VASc =0. Warfarin or NOACs are definitely the most widely used therapy with the highest level of evidence in the prevention of AF-related thromboembolism. NOACs, in particular, have been shown to be as effective as warfarin [in patients with international normalized ratio (INR) on target], and are associated with a lower risk of haemorrhagic events.17

finitely the most widely used therapy with the highest level of evidence in the prevention of AF-related thromboembolism. NOACs, in particular, have been shown to be as effective as warfarin [in patients with international normalized ratio (INR) on target], and are associated with a lower risk of haemorrhagic events.17 Although OAT with warfarin has been shown to significantly reduce the incidence of AF-related stroke, a high percentage of patients with AF (∼40%) do not receive appropriate prophylactic therapy.18,19 Moreover, about 20% of patients have contraindications for OAT and a further 30–40% of patients receiving OAT are unable to maintain a TTR of ≥65%, meaning that the risk of inefficacy of the therapy is high. Furthermore, a considerable proportion of patients suspend anticoagulant treatment within 1 year.20 In addition, although NOACs are more manageable and apparently safer than warfarin, they are still associated with a risk of haemorrhagic events (1.6–3.6% haemorrhagic events/year). Moreover, in the trials which tested these new drugs, between 20% and 35% of patients were forced to suspend administration due to the onset of side effects, and a high risk of bleeding was one of the exclusion criteria in all trials.

ll associated with a risk of haemorrhagic events (1.6–3.6% haemorrhagic events/year). Moreover, in the trials which tested these new drugs, between 20% and 35% of patients were forced to suspend administration due to the onset of side effects, and a high risk of bleeding was one of the exclusion criteria in all trials. Specific clinical situations associated to high risk of haemorrhage The decision with regards to any antithrombotic treatment must necessarily involve an assessment of the risk of stroke as against the risk of major bleeding, especially cerebral haemorrhage, which is the most dangerous complication, associated with a high rate of mortality and disability.21 However, the risk of cerebral haemorrhage in AF patients receiving OAT with vitamin K antagonists is currently quite low, between 0.1% and 0.6%. The percentage of intracranial haemorrhages increases for INR values around 3.5–4.0, while there is no difference in haemorrhage risk in patients with INR between 2.0 and 3.0 compared to those with lower INR.21 In the general population of AF patients, there are some categories with particularly high risk of haemorrhage, specifically: elderly patients: it is known that the prevalence of AF is dramatically higher in patients with age > 75 years and that in these patients the risk of thromboembolism and haemorrhage is often much higher than in younger patients; patients with a history of major bleeding episodes, especially intracranial;

In the general population of AF patients, there are some categories with particularly high risk of haemorrhage, specifically: elderly patients: it is known that the prevalence of AF is dramatically higher in patients with age > 75 years and that in these patients the risk of thromboembolism and haemorrhage is often much higher than in younger patients; patients with a history of major bleeding episodes, especially intracranial; patients with gastrointestinal diseases (liver diseases, angiodysplasias) or with peptic ulcer, a condition which is a significant problem for the use of NOACs, which are associated with a higher number of gastrointestinal haemorrhages than warfarin16–18; patients with chronic renal failure, who account for about 3% of AF patients; in 90% of cases, this population of patients with kidney disease has a CHA2DS2-VASc >2 and has a HAS-BLED ≥ 3 in 40% of cases.16–18 Moreover, there is no concrete proof on the efficacy-safety ratio of anticoagulants in patients undergoing dialysis or with glomerular filtration rate <30 mL/min.22 In dialysis patients, the risk of ischaemic stroke is higher than that of the general population, even in the absence of AF,23 as is the risk of haemorrhage.24 Moreover, in haemodialysis patients an association has been suggested between the use of warfarin and an increase in vascular calcification25–27; patients with coagulation disorders;

patients with chronic renal failure, who account for about 3% of AF patients; in 90% of cases, this population of patients with kidney disease has a CHA2DS2-VASc >2 and has a HAS-BLED ≥ 3 in 40% of cases.16–18 Moreover, there is no concrete proof on the efficacy-safety ratio of anticoagulants in patients undergoing dialysis or with glomerular filtration rate <30 mL/min.22 In dialysis patients, the risk of ischaemic stroke is higher than that of the general population, even in the absence of AF,23 as is the risk of haemorrhage.24 Moreover, in haemodialysis patients an association has been suggested between the use of warfarin and an increase in vascular calcification25–27; patients with coagulation disorders; patients with acute coronary diseases who have received stent implants and require prolonged dual antiplatelet therapy (DAPT). AF may, for example, occur in 5–10% of patients with acute coronary syndrome and is associated with a significant increase in mortality.20 In view of the fact that the vast majority of patients with acute coronary syndrome undergo coronary angioplasty with stent implant, the population of patients requiring DAPT + anticoagulant therapy (triple therapy) is presumably very large. It is known and also logical that the combination of antiplatelet agents with anticoagulants increases the risk of bleeding in the case of both warfarin and NOACs. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, the risk of major bleeding increased by 2.8% to 4.8% per year when antiplatelet agents were added to warfarin and from 2.6% to 4.4%/year with dabigatran 150 mg18; and

s increases the risk of bleeding in the case of both warfarin and NOACs. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, the risk of major bleeding increased by 2.8% to 4.8% per year when antiplatelet agents were added to warfarin and from 2.6% to 4.4%/year with dabigatran 150 mg18; and patients with mental disabilities or at risk of frequent falls. All these categories represent a large segment of patients for whom randomized trials fail to provide clear evidence with regard to the best therapeutic strategy. Anatomy of the left atrial appendage The LAA is an embryonic remnant of the primordial left atrium, a small offshoot opening off the side wall of the atrium, with variable, elongated, trabecular, often multi-lobed shape. The appendage’s orifice on the atrial cavity is oval in form and is located between the left upper pulmonary vein, from which it is separated by the fibrous ligament of Marshall, and the mitral valve. On the outside the LAA extends antero-laterally parallel with the left atrioventricular sulcus, just above the proximal part of the circumflex artery. On the inside, the distal part is trabecular, with the distinctive uneven surface of the endocardium, while the proximal end has a smooth surface. It varies in length (16–51 mm), volume (0.7–19.2 mL) and orifice diameter (5–40 mm).28

e left atrioventricular sulcus, just above the proximal part of the circumflex artery. On the inside, the distal part is trabecular, with the distinctive uneven surface of the endocardium, while the proximal end has a smooth surface. It varies in length (16–51 mm), volume (0.7–19.2 mL) and orifice diameter (5–40 mm).28 The LAA consists of a main body onto which one or more lobes may be attached and its variable in both shape and size. The study performed by Di Biase et al.,29 using computed tomography and magnetic resonance, gathered information about the morphology of the LAA and also correlated the various forms with risk of ischaemic stroke/transient ischaemic attack (TIA). Four main forms emerged: Cactus (30%), Chicken Wing (48%), Windsock (19%), and Cauliflower (3%). The correlation with thromboembolic events revealed a diverse, significant (P < 0.001) distribution, of 12, 4, 10, and 18%, respectively, in patients with Cactus, Chicken Wing, Windsock, and Cauliflower morphology. The Chicken Wing morphology showed a significantly lower prevalence of events compared with the other morphologies; in particular, patients with Cactus morphology showed a risk of cerebral ischaemic events 4 times higher, those with Windsock morphology 4.5 times higher and those with Cauliflower morphology 8 times higher than patients with Chicken Wing morphology.

ntly lower prevalence of events compared with the other morphologies; in particular, patients with Cactus morphology showed a risk of cerebral ischaemic events 4 times higher, those with Windsock morphology 4.5 times higher and those with Cauliflower morphology 8 times higher than patients with Chicken Wing morphology. Surgical closure (occlusion) of the left atrial appendage Surgical closure of the LAA has been proposed since the ’40s as prophylaxis for thromboembolism in patients with mitral valve disease.30–32 Even then, the observation that in this condition about 50% of thrombi were located in the LAA pointed to its occlusion as prophylaxis for the risk of stroke.33 During the same period, Belcher and Somerville32 noted that after mitral surgery LAA thrombosis occurred in 64% of patients who experienced embolic events. In the ’80s, further to the findings of a review of the mitral commissurotomy procedure, Halseth et al.34 suggested that surgical occlusion was only indicated in cases of large-sized LAA. In modern times, LAA amputation has been reintroduced as an integral part of the surgical procedure for AF ablation, initially proposed by Cox35 in the ’90s and still performed with various technologies.

Surgical closure (occlusion) of the left atrial appendage Surgical closure of the LAA has been proposed since the ’40s as prophylaxis for thromboembolism in patients with mitral valve disease.30–32 Even then, the observation that in this condition about 50% of thrombi were located in the LAA pointed to its occlusion as prophylaxis for the risk of stroke.33 During the same period, Belcher and Somerville32 noted that after mitral surgery LAA thrombosis occurred in 64% of patients who experienced embolic events. In the ’80s, further to the findings of a review of the mitral commissurotomy procedure, Halseth et al.34 suggested that surgical occlusion was only indicated in cases of large-sized LAA. In modern times, LAA amputation has been reintroduced as an integral part of the surgical procedure for AF ablation, initially proposed by Cox35 in the ’90s and still performed with various technologies. The history of the surgical treatment of the LAA originated in 1949, when Madden31 performed a complete amputation of the LAA on 2 patients with rheumatic mitral disease. An analysis of the literature only reveals 7 studies with detailed assessments (Table 3).36–43 These 7 studies recruited a total of 3653 patients with an LAA occlusion group (LAAO) (1716 patients) compared to a non LAAO group (1937 patients). In three works,37,39,42 the main operation was mitral valve surgery, in one39 it was coronary surgery and in the other three40,41,43 there was a mix of aortocoronary bypass and valve procedures. Four studies used surgical sutures for the LAAO37,38,41,42 while in two the LAA was amputated with a Stapler.38,43Table 3 Studies in the literature which assessed surgical treatment of the left atrial appendage

coronary surgery and in the other three40,41,43 there was a mix of aortocoronary bypass and valve procedures. Four studies used surgical sutures for the LAAO37,38,41,42 while in two the LAA was amputated with a Stapler.38,43Table 3 Studies in the literature which assessed surgical treatment of the left atrial appendage Author Period Type of study Number of LAA Number of non-LAA LAA occlusion method Lee et al.39 1999–2011 Propensity-score matched 119 119 LAA amputation during crio-Maze Whitlock et al.43 2009–2010 Miscellaneous 26 25 Amputation and stapler Kim et al.40 2001–2010 Propensity-score matched 631 631 Amputation or closure of LAA Zapolanski et al.41 2005–2012 Observational 808 969 Double ligature with suture Nagpal et al.37 2007 RCT 22 21 Amputation, suture Healey et al.38 2001–2002 RCT 52 25 Suture or stapler Garcia-Fernandez et al.42 1996–2001 Observational 58 147 Ligature of LAA with endocardial suture LAA, left atrial appendage; RCT, randomized controlled trial. Results The incidence of stroke was significantly reduced in patients who underwent LAAO. Mortality was significantly lower in the LAAO group. No significant differences were identified between the two groups with regards to periprocedural bleeding requiring reoperation.

Author Period Type of study Number of LAA Number of non-LAA LAA occlusion method Lee et al.39 1999–2011 Propensity-score matched 119 119 LAA amputation during crio-Maze Whitlock et al.43 2009–2010 Miscellaneous 26 25 Amputation and stapler Kim et al.40 2001–2010 Propensity-score matched 631 631 Amputation or closure of LAA Zapolanski et al.41 2005–2012 Observational 808 969 Double ligature with suture Nagpal et al.37 2007 RCT 22 21 Amputation, suture Healey et al.38 2001–2002 RCT 52 25 Suture or stapler Garcia-Fernandez et al.42 1996–2001 Observational 58 147 Ligature of LAA with endocardial suture LAA, left atrial appendage; RCT, randomized controlled trial. Results The incidence of stroke was significantly reduced in patients who underwent LAAO. Mortality was significantly lower in the LAAO group. No significant differences were identified between the two groups with regards to periprocedural bleeding requiring reoperation. The Left Atrial Appendage Occlusion Study (LAAOS)38 is the first randomized trial to assess the feasibility, safety, and efficacy of LAAO during elective coronary surgery using surgical sutures or automatic staplers. The study, conducted in Germany during 2001–2002, considers 52 patients who underwent LAAO vs. 25 non-LAAO patients. Occlusion was found to be effective in 66% of patients and it was even more so when the surgeon performed a complete amputation of the LAA rather than simply suturing it; the studies analysed reveal the uncertainty concerning the efficacy of surgical suturing in LAAO.

tients who underwent LAAO vs. 25 non-LAAO patients. Occlusion was found to be effective in 66% of patients and it was even more so when the surgeon performed a complete amputation of the LAA rather than simply suturing it; the studies analysed reveal the uncertainty concerning the efficacy of surgical suturing in LAAO. Echocardiogram assessment Imaging plays a fundamental role in both the pre- and the intraprocedural phase, and in the follow-up.44 The LAA can occasionally be viewed by transthoracic echocardiography, but the transoesophageal method (TEE), sometimes with three-dimensional assessment, is always necessary. TEE plays a fundamental role in the pre-procedural assessment, to confirm that the LAA is free from thrombi; any thrombi must be carefully considered to ensure that the procedure is safe and free from complications. It also allows the acquisition of additional information concerning the size, shape and position of the LAA. At the end of the surgical procedure, TEE is fundamental for defining the positioning of the device and the achievement of LAAO, by checking for any leaks. During follow-up, TEE is the most accurate assessment method for the description of any leaks or thrombosis.

ion concerning the size, shape and position of the LAA. At the end of the surgical procedure, TEE is fundamental for defining the positioning of the device and the achievement of LAAO, by checking for any leaks. During follow-up, TEE is the most accurate assessment method for the description of any leaks or thrombosis. TEE is the gold standard for confirming the failure of LAAO; in this case the patient continues to be exposed to the risk of thromboembolism, with an increased risk of stroke.45,46 In fact, incomplete occlusion of the LAA has been reported in up to over 50% of cases, with thrombi recorded in up to more than 25% of these patients.46 Furthermore, thromboembolic events have been reported in up to 22% of these cases.47 A variety of surgical techniques are currently used in LAAO: surgical removal, surgical suture, and more recently the application of specific devices (Tiger Paw and Atriclip). Surgical removal of the LAA generally involves tangential clamping as close as possible to the orifice. It is then removed and the orifice is sealed with a double surgical suture. Since the LAA is an extremely fragile structure, this technique may lead to tearing at its orifice, with bleeding and difficulties in achieving haemostasis. This technique is therefore not widely used, although in the literature no increase in morbidity arising from the surgical operation is described.38

rgical suture. Since the LAA is an extremely fragile structure, this technique may lead to tearing at its orifice, with bleeding and difficulties in achieving haemostasis. This technique is therefore not widely used, although in the literature no increase in morbidity arising from the surgical operation is described.38 Occlusion of the LAA by means of surgical suture is currently the most commonly used technique. Especially during mitral valve surgery, it is a simple, quick procedure with no complications. The surgical suture can be created with a tobacco-pouch shape around the orifice, or by means of two seams at its point of origin. During the last few years, the data in the literature indicate that the use of dedicated devices has been introduced. The devices currently available remain epicardial and therefore are not fitted into the cavity, and they potentially have a low incidence of thrombosis, infections and embolization.43

s point of origin. During the last few years, the data in the literature indicate that the use of dedicated devices has been introduced. The devices currently available remain epicardial and therefore are not fitted into the cavity, and they potentially have a low incidence of thrombosis, infections and embolization.43 The Tiger Paw System II (Maquet Cardiovascular, Mahwah, NJ, USA) is currently not available on the market because of a suspicion that it may apply traction to the atrial tissues. The Atriclip LAA Occlusion System device (Atricure, Inc, West Chester, OH, USA) allows easy, safe LAAO. It has been approved by the Food and Drug Administration since 2009 and consists of a convenient handle with the device at one end; the latter comprises a self-clamping clip consisting of two parallel crossbars in titanium with etinol, with a polyester cladding; during the operation the system can be positioned several times prior to deployment, and it comes in different sizes for selection in relation to the dimensions of the orifice of the LAA. It is a simple, safe procedure with minimal complications and allows complete occlusion of the LAA. It is an epicardial and therefore not an intracavitary device, usable for all the various shapes and sizes of LAA, and it allows anatomical and electric LAAO with short procedural times. This device is currently used in a large number of patients who undergo mini-invasive surgery or mini-invasive surgical treatment for AF.

s an epicardial and therefore not an intracavitary device, usable for all the various shapes and sizes of LAA, and it allows anatomical and electric LAAO with short procedural times. This device is currently used in a large number of patients who undergo mini-invasive surgery or mini-invasive surgical treatment for AF. Indications for surgical occlusion of the left atrial appendage The ESC guidelines maintain that there is no conclusive evidence concerning the efficacy of LAAO or the best techniques for its performance and provide a recommendation of IIB, evidence level C, only for patients who are to undergo cardiac surgery.17 Nor have the recent AHA/ACC guidelines16 on the management of AF arrived at a clear consensus on this procedure, and they confirm this recommendation with the same level of evidence. The panel agrees with these recommendations and maintains that every candidate must be discussed by the Heart Team. Potential candidates may be: patients with high thromboembolic risk with permanent, persistent or paroxystic AF undergoing concomitant cardiac surgery, possibly in association with surgical ablation of the AF and patients with high-thromboembolic risk undergoing mini-invasive surgery (mini-thoracotomy) or a sternotomy surgical procedure for AF.

The panel agrees with these recommendations and maintains that every candidate must be discussed by the Heart Team. Potential candidates may be: patients with high thromboembolic risk with permanent, persistent or paroxystic AF undergoing concomitant cardiac surgery, possibly in association with surgical ablation of the AF and patients with high-thromboembolic risk undergoing mini-invasive surgery (mini-thoracotomy) or a sternotomy surgical procedure for AF. Requirements for staff and centres In-depth knowledge of cardiac anatomy, especially of the left atrium, the LAA, and the surrounding structures, is essential for staff performing LAAO. Staff must have in-depth knowledge of the anatomical variables of the LAA in terms of size, angles and mobility. The procedure’s success and safety depend to a large extent on the knowledge and experience of every member of the team, including the echocardiographer.

g structures, is essential for staff performing LAAO. Staff must have in-depth knowledge of the anatomical variables of the LAA in terms of size, angles and mobility. The procedure’s success and safety depend to a large extent on the knowledge and experience of every member of the team, including the echocardiographer. Specific, properly organized training is necessary for every staff member, including the echocardiographer. The training must include basic principles and study of the characteristics of the device and the procedure. It must comprise a short course on anatomy, clinical procedures and device implantation techniques and the analysis of critical factors such as patient and device selection and the possible complications and their prevention and management, as well as a practical part and the use of simulators on virtual cases. The nurses and technicians on the team must also receive training. During the first few procedures, a surgeon with documented experience in use of the device must be present.44 Percutaneous occlusion of the left atrial appendage Left atrial appendage occlusion devices currently available There are currently four endocardial devices with CE marking available for percutaneous occlusion of the LAA: the Watchman (Boston Scientific, Maple Grove, MN, USA), the Amplatzer Cardiac Plug and Amulet (St. Jude Medical, Minneapolis, MN, USA), the WaveCrest (Coherex Medical, Salt Lake City, UT, USA) and the Lariat (SentreHEART, Inc., Palo Alto, CA, USA), which has a combined endocardial/epicardial percutaneous access.

e LAA: the Watchman (Boston Scientific, Maple Grove, MN, USA), the Amplatzer Cardiac Plug and Amulet (St. Jude Medical, Minneapolis, MN, USA), the WaveCrest (Coherex Medical, Salt Lake City, UT, USA) and the Lariat (SentreHEART, Inc., Palo Alto, CA, USA), which has a combined endocardial/epicardial percutaneous access. The Watchman is a self-expandable device with a basket-like structure in nitinol clad with a polyethylene membrane covering the exposed surface in the left atrium; it has hooks around its external perimeter which anchor it to the walls of the LAA. The device is available in various sizes (21, 24, 27, 30, and 33 mm) and is deployed with the aid of a delivery catheter of 14 Fr which may have one or two bends at its distal end for easier approach to the LAA. The device’s length is equal to its diameter (Figure 1). Figure 1 Watchman Device (Boston Scientific).

The Watchman is a self-expandable device with a basket-like structure in nitinol clad with a polyethylene membrane covering the exposed surface in the left atrium; it has hooks around its external perimeter which anchor it to the walls of the LAA. The device is available in various sizes (21, 24, 27, 30, and 33 mm) and is deployed with the aid of a delivery catheter of 14 Fr which may have one or two bends at its distal end for easier approach to the LAA. The device’s length is equal to its diameter (Figure 1). Figure 1 Watchman Device (Boston Scientific). As of today, clinical studies conducted with the Watchman medical device have included more than 2400 patients with more than 6000 patient years of follow-up. The most important clinical studies supporting the efficacy and safety of this device are the Watchman Left Atrial System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF)48–50 and Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL)51 randomized studies. In the PROTECT AF randomized study, Holmes et al.48 compared implantation of the Watchman with conventional pharmacological treatment with warfarin in 707 patients with non-valvular AF and CHADS2 score ≥ 1. The device was successfully implanted in 90.9% of the patients who underwent the procedure and the administration of warfarin was stopped in 87% of them 45 days later. The primary endpoint for efficacy was defined as the composite of stroke, cardiovascular or unexplained death, and systemic embolism. The rate of events recorded for effectiveness was 3.0 per 100 patient years in the Watchman group compared to 4.9 per 100 patient years in the warfarin group; this 38% reduction is equivalent to a non-inferiority of the Watchman in relation to warfarin. However, ischaemic stroke was more frequent in the group treated with the Watchman than in the control group due to five pre-procedural events linked to gaseous embolism. Excluding these events, the incidence of ischaemic stroke was not substantially different between the two groups (1.3%/year in the successfully implanted group compared to 1.6%/year in the control group). The primary endpoint for safety, on the other hand, was defined as a composite of major bleeding and complications correlated to the procedure. The rate of these adverse events was 7.4 per 100 patient years in the Watchman group compared to 4.4 per 100 patient years in the warfarin group.

6%/year in the control group). The primary endpoint for safety, on the other hand, was defined as a composite of major bleeding and complications correlated to the procedure. The rate of these adverse events was 7.4 per 100 patient years in the Watchman group compared to 4.4 per 100 patient years in the warfarin group. The complications which occurred in the patients treated with the Watchman were: cardiac tamponade (5%), major haemorrhages (3.5%), pericardial effusions (1.7%), periprocedural stroke (1%) mainly arising from gaseous embolism, embolization of the device (0.6%), which in most cases (67%) made surgical removal necessary, and the induction of arrhythmias (0.2%). In total, 2.2% of attempts to implant the device led to cardiac surgery to deal with complications correlated to it. Most of these events occurred in the periprocedural period (55% of adverse events relate to the day of implantation) and pericardial effusion was the most common event (7.1% of the first 3 patients at each centre and 4.4% of subsequent patients); none of these events caused permanent disability or death. In fact, it should be emphasized that the adverse events correlated to the procedure decreased as the staff’s experience grew. In particular, pericardial effusions, which accounted for about 50% of adverse events recorded in the PROTECT AF study, decreased significantly in the subsequent CAP registry as the operators’ experience increased (5 vs. 2.2%, P = 0.019), as did periprocedural strokes (0.9 vs. 0%; P = 0.039).48,49

ff’s experience grew. In particular, pericardial effusions, which accounted for about 50% of adverse events recorded in the PROTECT AF study, decreased significantly in the subsequent CAP registry as the operators’ experience increased (5 vs. 2.2%, P = 0.019), as did periprocedural strokes (0.9 vs. 0%; P = 0.039).48,49 The PREVAIL study enrolled 407 patients with the aim of comparing the Watchman device with warfarin patients with AF at high risk of thromboembolism (average CHADS2 score of 2.6) and eligible for long-term therapy with warfarin. The implantation success rate was 95.1%, a higher value than reported in the previous PROTECT AF randomized study (90.9%). In this study, LAAO with the Watchman proved to be not inferior to warfarin in the prevention of ischaemic stroke or peripheral embolism 1 week after the procedure. Although statistical non-inferiority was not achieved for the total efficacy of the procedure, including periprocedural events, it should be kept in mind that the incidence of these events was low and similar in the two arms of the study.

prevention of ischaemic stroke or peripheral embolism 1 week after the procedure. Although statistical non-inferiority was not achieved for the total efficacy of the procedure, including periprocedural events, it should be kept in mind that the incidence of these events was low and similar in the two arms of the study. With regards to adverse events correlated to the procedure (within 7 days), an event was reported in 2.2% of implanted patients. Major complications correlated to the device or the procedure within 7 days of implantation occurred in 4.4% of patients compared to the 8.7% of the PROTECT AF study, meaning a 49% reduction. Pericardial effusion occurred in 1.9% of patients compared to 4.0% in PROTECT AF, and thus with a reduction of 52%. It is important to underline that the results of the PREVAIL study revealed very low-complication rates amongst both clinicians who were performing their first implantations and more skilled clinicians. The data relating to the use of this device in patients with contraindications for OAT are rather limited. Specifically, in the ASAP study52 LAAO was performed in 150 patients: the rate of cerebral ischaemic events observed was 2.3%/year, meaning a risk reduction calculated as 77% in a population of patients with an expected rate of events per year of 7.3%.

vice in patients with contraindications for OAT are rather limited. Specifically, in the ASAP study52 LAAO was performed in 150 patients: the rate of cerebral ischaemic events observed was 2.3%/year, meaning a risk reduction calculated as 77% in a population of patients with an expected rate of events per year of 7.3%. A meta-study including 2406 patients recruited to PROTECT AF, PREVAIL, and the respective registries has recently been published.53 Compared to warfarin therapy, percutaneous occlusion of the LAA was associated with a significant reduction of haemorrhagic stroke [0.15 vs. 0.96 events/100 patient years, hazard ratio (HR) 0.22, P = 0.004], cardiovascular or undefined mortality (1.1 vs. 2.3 events/patient year, HR 0.48, P = 0.006) and non-procedural bleeding (6 vs. 11.3 events/100 patient years, HR 0.51, P = 0.006).53 The Amplatzer Cardiac Plug (ACP) is a self-expanding nitinol device, clad completely in polyester, in three parts: a nitinol cylinder, called the lobe, at the tip, used to anchor the device inside the LAA, a larger disc below it which covers and blocks the orifice of the LAA, and a very short wire in the middle connecting the lobe and disc (Figure 2). Figure 2 Amplatzer Cardiac Plug (St. Jude Medical).

The Amplatzer Cardiac Plug (ACP) is a self-expanding nitinol device, clad completely in polyester, in three parts: a nitinol cylinder, called the lobe, at the tip, used to anchor the device inside the LAA, a larger disc below it which covers and blocks the orifice of the LAA, and a very short wire in the middle connecting the lobe and disc (Figure 2). Figure 2 Amplatzer Cardiac Plug (St. Jude Medical). There are anchor hooks around the edge of the lobe. The lobe sizes available are 16, 18, 20, 22, 24, 26, 28, and 30 mm, while the disc is 4 mm larger for the sizes from 16 to 22 m and 6 mm larger for the 24 to 30 mm sizes. The lobe’s length is much less than its diameter, making it preferable for particularly shallow LAAs. The only data available for the ACP are provided by feasibility reports covering only small patient populations. A retrospective registry study on a population of 137 patients in which an attempt at occluding the LAA with ACP was performed54 show that the procedure was successful in 96% of cases; major intraprocedural complications were observed in 7% of cases (3 ictus, 2 device embolizations, and 5 cardiac tamponades). The percentage rose if minor complications, including four negligible pericardial effusions and transient myocardial ischaemia caused by gaseous embolism, were also considered. In another study conducted on 20 patients, the ACP was successfully implanted in 95% of cases with 2 periprocedural complications (one transient myocardial ischaemia caused by gaseous embolism and one oesophageal lesion due to the TEE). In this study, no adverse events such as stroke or death were observed during a follow-up of 12.7 ± 3.1 months, compared to a theoretical risk of ischaemic events of 5.3%.55

ses with 2 periprocedural complications (one transient myocardial ischaemia caused by gaseous embolism and one oesophageal lesion due to the TEE). In this study, no adverse events such as stroke or death were observed during a follow-up of 12.7 ± 3.1 months, compared to a theoretical risk of ischaemic events of 5.3%.55 The first Italian registry study, including a population of 134 patients with high-cardioembolic risk (average CHA2DS2-VASc 4.3 ± 1.3) with contraindication to the administration of anticoagulant therapy) was published in 2014. The authors report a high-procedural success rate (95.5%) and a low rate of major complications (2.2%). In the follow-up, a reduction in cerebral ischaemic events of 85.5% compared to the risk predicted by the scores was described.56 Recently, Tzikas et al.57 published the data of a multicentric registry study which describes, on a total of 1047 patients, a procedural success rate of 97.3%, and an incidence of procedural complications of 5%, with a 59% reduction in embolic events and a 60% decrease in haemorrhagic events calculated in relation to the CHA2DS2-VASc and HAS-BLED scores. Another registry study, performed on the Iberian Peninsula, collected the data of 167 patients with contraindication for OAT and indicated a procedural success rate of 94.6% with an incidence of procedure-related complications of 5.38%. The incidence of embolic events was lower than that predicted by the CHA2DS2-VASc score (2.4 vs. 8.3%), and the incidence of haemorrhagic events was also below the prediction provided by the HAS-BLED score (3.1 vs. 6.6%).58

procedural success rate of 94.6% with an incidence of procedure-related complications of 5.38%. The incidence of embolic events was lower than that predicted by the CHA2DS2-VASc score (2.4 vs. 8.3%), and the incidence of haemorrhagic events was also below the prediction provided by the HAS-BLED score (3.1 vs. 6.6%).58 The latest version of this device is the Amulet, which has the same three-part structure as the ACP but a wider range of sizes (16, 18, 20, 22, 25, 28, 31, and 34 mm), allowing the treatment of a wider spectrum of anatomies, a longer lobe with more anchor hooks, a longer central wire and a screw fitting for the disc, which has been retracted to create a uniform surface (Figure 3). Figure 3 Amulet Device (St. Jude Medical). The WaveCrest, not currently available on the market, is a self-expanding device in nitinol with a polytetrafluoroethylene coating on the surface which remains exposed in the left atrium; it has anchor hooks around its circumference, which engage with the walls of the left atrium appendage. This device is designed to be positioned close to the orifice of the left atrium appendage, with no need to penetrate deep down with the deployment system (Figure 4). Figure 4 WaveCrest Device (Coherex Medical). At present, data from feasibility and safety trials59 are available, but there are no major clinical studies. The Lariat, not currently available in Italy, is an occlusion system with a combined approach consisting of three components: a balloon, a guide wire with magnetic tip and a loop suture wire which will be closed on the orifice of the LAA (Figure 5).

At present, data from feasibility and safety trials59 are available, but there are no major clinical studies. The Lariat, not currently available in Italy, is an occlusion system with a combined approach consisting of three components: a balloon, a guide wire with magnetic tip and a loop suture wire which will be closed on the orifice of the LAA (Figure 5). Figure 5 Lariat (SentreHEART) system with its three components. The system requires the collimation of two magnets at the tips of the first two components (used with percutaneous and epicardial approach), which form a single body that serves as guide for the third component, the lariat, positioned with epicardial approach to occlude the orifice of the LAA. The benefit of this procedure is that once it has been performed nothing prosthetic is left inside the left atrium, and therefore no anticoagulant or antiplatelet therapy is required. However, the only studies performed on this device so far are feasibility studies on small populations of patients. The results of a study on LAAO on 89 patients using this device revealed that the LAA was completely occluded in 91% of cases with 3 acute complications (2 during pericardial access and 1 during transseptal catheterization). After the procedure 2 cases of pericarditis, 1 delayed pericardial effusion, 2 sudden deaths from undetermined causes, and 2 strokes considered not to be of cardioembolic origin were observed.60

y occluded in 91% of cases with 3 acute complications (2 during pericardial access and 1 during transseptal catheterization). After the procedure 2 cases of pericarditis, 1 delayed pericardial effusion, 2 sudden deaths from undetermined causes, and 2 strokes considered not to be of cardioembolic origin were observed.60 Devices currently under development The Watchman FLX device, (Boston Scientific) a development on the Watchman device already described, will apparently soon be available. It differs from the previous version in shorter length, the presence of a fluoroscopic marker on the distal tip, the possibility of recapture and redeployment, a larger range of sizes (20, 24, 27, 31, and 35 mm) allowing treatment of a wider range of anatomies, a larger number of perimeter anchors arranged in two rows and retraction of the device's screw connection, to create a flat surface on the atrial side (Figure 6). Figure 6 Watchman FLX Device (Boston Scientific). The Transcatheter Patch (Custom Medical Devices, Athens, Greece) is a device consisting of a polyurethane patch with an adhesive band at the distal end which is carried into the LAA by a balloon; the proximal side of the patch is tightened with a loop, and is then released once the balloon has been deflated and the insertion catheter has been withdrawn (Figure 7). Figure 7 Lariat (SentreHEART) system with its three components. This device is currently undergoing clinical assessment.

The Transcatheter Patch (Custom Medical Devices, Athens, Greece) is a device consisting of a polyurethane patch with an adhesive band at the distal end which is carried into the LAA by a balloon; the proximal side of the patch is tightened with a loop, and is then released once the balloon has been deflated and the insertion catheter has been withdrawn (Figure 7). Figure 7 Lariat (SentreHEART) system with its three components. This device is currently undergoing clinical assessment. Lifetech (LambreTM, Lifetech Scientific Corp., Shenzhen, China) is a self-expanding nitinol device consisting of three parts: a disc and an umbrella, connected by a very short central component. This device is undergoing preclinical assessment. Cost-effectiveness studies A number of cost-effectiveness studies have been performed in different social and health-care contexts. An analysis of the German health system, which compared costs and outcomes in terms of mortality of the LAAO procedure compared to warfarin and dabigatran, reveals long-term medical and financial benefits in favour of LAAO. In fact, after 8 years LAAO is less expensive than dabigatran (€15,061 vs. €16,184) and at 10 years it only costs 10% more than warfarin (€16,736 vs. €15,168). The assumption is therefore that LAAO may be financially beneficial for the health system over the long term.61

edical and financial benefits in favour of LAAO. In fact, after 8 years LAAO is less expensive than dabigatran (€15,061 vs. €16,184) and at 10 years it only costs 10% more than warfarin (€16,736 vs. €15,168). The assumption is therefore that LAAO may be financially beneficial for the health system over the long term.61 Another study, based on costs and the years of quality-adjusted life (QALY) gained by percutaneous occlusion of the LAA compared to warfarin and dabigatran therapy, reveals that the cost per QALY of medical therapy is $46 560, while for this device this value is $41 565 over a lifetime period.62 From the point of view of the Italian National Health Service, the comparison between LAAO and treatment with a single antiplatelet drug or no drug in patients with contraindications for OAT is in favour of occlusion of the LAA with a benefit which comes into effect at 3 years, due to the increase in the cost of stroke-related disability in patients treated with antiplatelet medication.63 A comparison between the costs of treatment with the Watchman and with the NOAC drugs by the United Kingdom Department of Health also found in favour of LAAO in patients with high risk of embolism with contraindications for OAT: an investigation of the cost of 10 patients reveals that the cost of the device (€49 300) is recouped within 3 years, considering that the cost per annum of the untreated patients would amount to €14 600 (1 stroke prevented per year for every 10 patients).64

ts with high risk of embolism with contraindications for OAT: an investigation of the cost of 10 patients reveals that the cost of the device (€49 300) is recouped within 3 years, considering that the cost per annum of the untreated patients would amount to €14 600 (1 stroke prevented per year for every 10 patients).64 The cost-effectiveness studies therefore reveal the potential benefit of LAAO compared to anticoagulant therapy in the long term. This benefit apparently also occurs in the short-medium term for populations with high risk of embolism and haemorrhage. Indications for left atrial appendage occlusion According to the current indications for percutaneous LAAO, which reflect the ESC guidelines,17 the procedure is indicated (recommendation class IIb, level of evidence B) in patients with non-valvular AF with high-thromboembolic risk (CHA2DS2-VASc score ≥ 2) with long-term contraindication for OAT (e.g. history of intracranial bleeding, life-threatening bleeding, coagulation diseases). The recent EHRA/EAPCI44 consensus suggests that the spectrum of patients who could benefit from this technique should be extended (Table 4). Moreover, this therapy could also be considered in the following clinical situations: Table 4 Left atrial appendage occlusion: possible clinical situations As an alternative to OAT in patients intolerant of OAT Patients with high risk of stroke and high risk of haemorrhage Patients with thromboembolic events during OAT in the therapeutic range or during treatment with NOACs (when no other origin of the bleeding can be identified)

The recent EHRA/EAPCI44 consensus suggests that the spectrum of patients who could benefit from this technique should be extended (Table 4). Moreover, this therapy could also be considered in the following clinical situations: Table 4 Left atrial appendage occlusion: possible clinical situations As an alternative to OAT in patients intolerant of OAT Patients with high risk of stroke and high risk of haemorrhage Patients with thromboembolic events during OAT in the therapeutic range or during treatment with NOACs (when no other origin of the bleeding can be identified) Patients who can be treated with oral anticoagulants but may have indication for left atrial appendage occlusion NOACs, new oral anticoagulants; OAT, oral anticoagulant therapy. patients with non-valvular AF with high-thromboembolic risk and high-haemorrhagic risk (HAS-BLED ≥ 3); patients requiring triple antithrombotic therapy indefinitely; patients with tumours with increased risk of haemorrhage, underestimated by the HAS-BLED score; patients in whom OAT is ineffective in providing protection against cerebral ischaemic events probably correlated to thromboembolisms originating from the LAA; patients with kidney failure or undergoing dialysis, bearing in mind that all NOACs are contraindicated with creatinine clearance < 15 mL/min and that in these patients warfarin could increase tissue calcification and the degree of atherosclerosis; patients with major bleeding of the urogenital or gastrointestinal system, or any other districts, such as the ocular area;

patients with kidney failure or undergoing dialysis, bearing in mind that all NOACs are contraindicated with creatinine clearance < 15 mL/min and that in these patients warfarin could increase tissue calcification and the degree of atherosclerosis; patients with major bleeding of the urogenital or gastrointestinal system, or any other districts, such as the ocular area; frail patients (the very old, dementia, neurodegenerative diseases, malnutrition, etc.); patients with difficulty in managing oral therapies (e.g. mental illnesses, vision impairment); and patients who, after being suitably informed about the OAT/NOACs therapy, refuse it and demand a ‘definitive’ therapy. In this context, it should be underlined that the Watchman has had approval by the US regulatory authority as a valid alternative to warfarin in patients who refuse or prefer not to take OAT. The decision must therefore be made in the context of the doctor–patient relationship, after appropriate information about all the benefits and drawbacks related to the percutaneous LAAO procedure or the alternative OAT/NOACs therapies (Figure 8). It should however be underlined that at present there is no evidence on this question and additional clinical studies are required to assess the usefulness of LAAO in these clinical situations before the indications for this type of treatment are extended to the aforesaid groups of patients. Figure 8 Algorithm for stroke prevention in patients with atrial fibrillation. CRF, chronic renal failure; NOACs, new oral anticoagulants, OAT, oral anticoagulant therapy. Adapted from Meier et al.44

The decision must therefore be made in the context of the doctor–patient relationship, after appropriate information about all the benefits and drawbacks related to the percutaneous LAAO procedure or the alternative OAT/NOACs therapies (Figure 8). It should however be underlined that at present there is no evidence on this question and additional clinical studies are required to assess the usefulness of LAAO in these clinical situations before the indications for this type of treatment are extended to the aforesaid groups of patients. Figure 8 Algorithm for stroke prevention in patients with atrial fibrillation. CRF, chronic renal failure; NOACs, new oral anticoagulants, OAT, oral anticoagulant therapy. Adapted from Meier et al.44 Screening of patients who are possible candidates for left atrial appendage occlusion Screening must be carried out in the context of discussion and choice of a strategy in agreement with the patient, giving due consideration to personal preferences and health expectations65 and avoiding superfluous tests or investigations. Screening must aim to establish the individual risk/benefit profile and in particular the ratio between embolic and haemorrhagic risk and its progression over time, and include the anatomical characteristics of the LAA in order to allow planning of the most important procedural aspects.

Screening of patients who are possible candidates for left atrial appendage occlusion Screening must be carried out in the context of discussion and choice of a strategy in agreement with the patient, giving due consideration to personal preferences and health expectations65 and avoiding superfluous tests or investigations. Screening must aim to establish the individual risk/benefit profile and in particular the ratio between embolic and haemorrhagic risk and its progression over time, and include the anatomical characteristics of the LAA in order to allow planning of the most important procedural aspects. As has been shown to be the case in cardiac surgery, with large benefits for outcomes,66 screening must be disciplinary and preferably use local protocols which clearly identify the role of each player within the team, and ensure strong interaction between its members and the patient.67 Assessment of the patient’s preferences and health and quality of life factors must include clear, appropriate methods for their formal expression.68 Table 5 summarizes the main factors to be considered in this phase of the diagnostic and therapeutic process. From the anatomical point of view, in-depth echocardiogram examination is required. An anatomical assessment of the LAA with computed tomography or magnetic resonance can be useful if echocardiography is not definitive. Table 5 Screening factors Thromboembolic risk score Haemorrhage risk score Age Patient’s preference and health expectations Diagnosis of diabetes mellitus Arterial pressure assessment Kidney function assessment

Table 5 summarizes the main factors to be considered in this phase of the diagnostic and therapeutic process. From the anatomical point of view, in-depth echocardiogram examination is required. An anatomical assessment of the LAA with computed tomography or magnetic resonance can be useful if echocardiography is not definitive. Table 5 Screening factors Thromboembolic risk score Haemorrhage risk score Age Patient’s preference and health expectations Diagnosis of diabetes mellitus Arterial pressure assessment Kidney function assessment Cardiac function assessment, NYHA class Carotid and/or aortic vascular assessment Liver and gastrointestinal diseases (angiodysplasia, peptic ulcer) Assessment of coagulative factor and haemorrhagic diathesis Assessment of contraindications for coagulants Assessment of multi-drug interaction Assessment of therapeutic compliance and frailty Assessment of psychiatric diseases (dementia, alcoholism) Colour-Doppler transthoracic echocardiogram Colour-Doppler transoesophageal echocardiogram Cardiac angio-CT or angio-MR CT, computed tomography; MR, magnetic resonance; NYHA, New York Heart Association. Echocardiogram assessment and echocardiogram anatomy of the left atrial appendage TEE is the method of choice for the anatomical and functional assessment of the LAA. Three-dimensional echocardiography may be useful although not essential for a correct assessment.

CT, computed tomography; MR, magnetic resonance; NYHA, New York Heart Association. Echocardiogram assessment and echocardiogram anatomy of the left atrial appendage TEE is the method of choice for the anatomical and functional assessment of the LAA. Three-dimensional echocardiography may be useful although not essential for a correct assessment. When assessing thrombotic risk, it is important to consider both anatomical and functional aspects in order to assign a specific LAA-related risk within the overall cardiac and systemic thrombotic risk. As already described, the LAA often has several lobes and its contractility is the main determinant of its blood outflow.69 In the context of AF, it has been shown that a LAA outflow rate > 40 cm/s is correlated, after cardioversion of the arrhythmia, with a reduction in spontaneous echo contrast.70 A high level of spontaneous echo contrast correlates with endo-LAA flow rates < 40 cm/s and the formation of sludge in the LAA (a pre-thrombotic condition).

t of AF, it has been shown that a LAA outflow rate > 40 cm/s is correlated, after cardioversion of the arrhythmia, with a reduction in spontaneous echo contrast.70 A high level of spontaneous echo contrast correlates with endo-LAA flow rates < 40 cm/s and the formation of sludge in the LAA (a pre-thrombotic condition). The main data on the linear average measurements relating to this anatomical structure are derived from autopsy investigations, which have also revealed a correlation with age and gender. More recently, a study of LAA volumes has been conducted using multilayer computer tomography, reaching the conclusion that there are no gender-related differences although there are differences linked to age-band (larger at 60–70 years than at 40–59 years).71,72 TEE allows calculation of the main planimetric parameters (transverse and longitudinal dimensions and area) which allow correct planning of the occlusion procedure (Table 6). Table 6 Main echocardiographic parameters to be obtained Dimensions of LAA and atrium Shape of LAA Flow rates within LAA Relations with mitral isthmus and annulus Presence/absence of structural defects of the atrium (patent foramen ovale, interatrial septum aneurysm, atrial or LAA thrombosis, spontaneous echo contrast) Left ventricle functions and dimensions Mitral valve function Presence/absence of pericardial effusion LAA, left atrial appendage.

Flow rates within LAA Relations with mitral isthmus and annulus Presence/absence of structural defects of the atrium (patent foramen ovale, interatrial septum aneurysm, atrial or LAA thrombosis, spontaneous echo contrast) Left ventricle functions and dimensions Mitral valve function Presence/absence of pericardial effusion LAA, left atrial appendage. ‘Step by step’ procedure There are now a large number of publications which offer a detailed description of the LAAO procedure.45 Below, we list some suggestions to be considered useful for standardising the procedure as far as possible, in order to render outcomes reproducible and reduce complications.

LAA, left atrial appendage. ‘Step by step’ procedure There are now a large number of publications which offer a detailed description of the LAAO procedure.45 Below, we list some suggestions to be considered useful for standardising the procedure as far as possible, in order to render outcomes reproducible and reduce complications. Choice of anaesthesia Although the procedure can be performed both under general anaesthesia and in analgosedation, the former option appears to be advisable. On the one hand, the need for transoesophageal monitoring requires prolonged collaboration from patients, who often have difficulty in tolerating the presence of the oesophageal probe. On the other hand, general anaesthesia allows the patient's complete immobility to be guaranteed, preventing small, involuntary movements which may increase the risk of mechanical complications, especially during the transseptal puncture or during manipulation of the deployment system inside the LAA. Although the possibility of performing the procedure under local anaesthetic with intracardiac echocardiographic guidance is intriguing, sufficient data are not available for this approach to be recommended. In fact, although transseptal puncture under intracardiac echocardiography is feasible, it currently appears difficult to establish the size of the device and assess its positioning without the use of TEE.

c echocardiographic guidance is intriguing, sufficient data are not available for this approach to be recommended. In fact, although transseptal puncture under intracardiac echocardiography is feasible, it currently appears difficult to establish the size of the device and assess its positioning without the use of TEE. Choice of vascular access The access of choice is the right femoral vein, which simplifies the manipulation of the materials and gives more safer transseptal puncture; the literature describes performance of the procedure through a puncture in the left femoral vein,73 but this access should only be used in patients where the right access is impracticable (severely twisted vessel, previous vascular access, large arteriovenous fistula, etc.). Here again, in-depth knowledge of the materials and specific experience in the management of the possible vascular complications are important.

but this access should only be used in patients where the right access is impracticable (severely twisted vessel, previous vascular access, large arteriovenous fistula, etc.). Here again, in-depth knowledge of the materials and specific experience in the management of the possible vascular complications are important. Transseptal puncture This is one of the most delicate phases of the procedure. Although for a skilled electrophysiologist or haemodynamics specialist performance of the transseptal puncture with fluoroscopic monitoring only (with or without aids such as a coronary catheter) is not a specific problem, the use of echocardiographic guidance for the puncture is strongly recommended in order to obtain a better angle of approach to the LAA. A puncture low down to the rear exposes the LAA with the ideal angle for existing deployment systems (Figure 9). Passage of the interatrial septum through the patency of the foramen ovale offers an angle which is less than ideal, which may render the subsequent procedure more problematical and less safe. Figure 9 View of the fossa ovalis and the preferred points for the puncture for LAA occlusion. ACP, Amplatzer Cardiac Plug; AF, atrial fibrillation; Ao, aorta; LA, left atrium; LAA, left atrial appendage; LV, left ventricle; RA, right atrium; RV, right ventricle.

Transseptal puncture This is one of the most delicate phases of the procedure. Although for a skilled electrophysiologist or haemodynamics specialist performance of the transseptal puncture with fluoroscopic monitoring only (with or without aids such as a coronary catheter) is not a specific problem, the use of echocardiographic guidance for the puncture is strongly recommended in order to obtain a better angle of approach to the LAA. A puncture low down to the rear exposes the LAA with the ideal angle for existing deployment systems (Figure 9). Passage of the interatrial septum through the patency of the foramen ovale offers an angle which is less than ideal, which may render the subsequent procedure more problematical and less safe. Figure 9 View of the fossa ovalis and the preferred points for the puncture for LAA occlusion. ACP, Amplatzer Cardiac Plug; AF, atrial fibrillation; Ao, aorta; LA, left atrium; LAA, left atrial appendage; LV, left ventricle; RA, right atrium; RV, right ventricle. Intraprocedural antithrombotic therapy Although the literature describes cases of LAAO performed during therapy with warfarin in the therapeutic range, in order to minimize the risks all anticoagulant therapy should have been suspended at least 48 h prior to the procedure, and the INR value should be < 2. Once the transseptal puncture has been performed, antithrombotic therapy must be administered: non fractionated heparin (dosage 70–100 U/kg to obtain an activated coagulation time of 250–300 s) is the first choice. In our opinion, the dwell time in the left atrium should be minimized in order to reduce the risk of embolism. In the event that the TEE reveals thrombosis on the deployment system, we advise manual aspiration of the thrombus through the catheter, associated with the administration of heparin; if this strategy fails, the procedure should be interrupted.

he left atrium should be minimized in order to reduce the risk of embolism. In the event that the TEE reveals thrombosis on the deployment system, we advise manual aspiration of the thrombus through the catheter, associated with the administration of heparin; if this strategy fails, the procedure should be interrupted. Insertion of the deployment system into the left atrium There are two possible approaches: the deployment system delivery catheter is exchanged over a stiff guidewire which is placed in the left upper pulmonary vein and then manoeuvred, containing a pigtail catheter through which the angiography of the LAA will also be performed. If this approach is chosen when using the ACP-Amulet system, a longer pigtail catheter (125 cm) will be needed. It should be emphasized that with this procedure the system can be manoeuvred with greater safety and the risk of iatrogenic damage when the delivery catheter is moved into the LAA is reduced and the alternative method is to use the pigtail for the angiography and then exchange it for the deployment system delivery catheter on a rigid guide positioned in the LAA (this ‘saves’ one exchange but increases the risks of tearing of the wall of the LAA).

Insertion of the deployment system into the left atrium There are two possible approaches: the deployment system delivery catheter is exchanged over a stiff guidewire which is placed in the left upper pulmonary vein and then manoeuvred, containing a pigtail catheter through which the angiography of the LAA will also be performed. If this approach is chosen when using the ACP-Amulet system, a longer pigtail catheter (125 cm) will be needed. It should be emphasized that with this procedure the system can be manoeuvred with greater safety and the risk of iatrogenic damage when the delivery catheter is moved into the LAA is reduced and the alternative method is to use the pigtail for the angiography and then exchange it for the deployment system delivery catheter on a rigid guide positioned in the LAA (this ‘saves’ one exchange but increases the risks of tearing of the wall of the LAA). Choice of device A number of devices have been developed and placed on the market. However, in clinical practice the devices currently available are the Watchman (Boston Scientific) and the New Amulet (St. Jude). The Lariat device is used for combined endocardial-epicardial ligature of the LAA and will not be discussed here. The scientific findings supporting the use of the devices were discussed in the previous section; here, we will simply detail the devices’ specific technical features. It should be underlined that both the devices available on the market are completely repositionable and recapturable in the event of imperfect deployment or if the chosen size is not suitable.

se of the devices were discussed in the previous section; here, we will simply detail the devices’ specific technical features. It should be underlined that both the devices available on the market are completely repositionable and recapturable in the event of imperfect deployment or if the chosen size is not suitable. The Watchman device is inserted by means of a preformed deployment system (single or double bend) of 14 Fr. For optimal sealing, it is recommended that the device chosen should be oversized by 10–20% (it is available in sizes from 21 to 33 mm). A higher device oversizing percentage appears to offer better leak reduction but could be more risky. The new generation of the device, which will probably be on the market from 2016, will provide better sealing even without oversizing, thanks to an increase in the number of anchor hooks and a shallower profile. For the current generation of the device, the depth of the LAA must be similar to the diameter to allow safe deployment. In the Panel’s experience this characteristic, which is apparently the device’s biggest drawback, has never prevented safe implantation, probably because several studies74 have shown that as AF persists, LAA increase in size, generally with the same rate of expansion in their diameter and depth. However, if in doubt it is important to use the radiopaque markers provided on the deployment system which easily reveal the minimum device deployment depth.

n, probably because several studies74 have shown that as AF persists, LAA increase in size, generally with the same rate of expansion in their diameter and depth. However, if in doubt it is important to use the radiopaque markers provided on the deployment system which easily reveal the minimum device deployment depth. The New Amulet occlusion device (the evolution of the Amplatzer ACP system, now more or less replaced on the market by the New Amulet) has an unusual structure which enables it to adapt to virtually any LAA morphology. This device is able to occlude all LAAs between 11 and 31 mm and is inserted in a deployment system with 9–14 Fr delivery catheters (depending on the size of the device). It should be remembered that while the delivery catheters of the ACP were available in diameters 9, 10, and 13 Fr, those of the Amulet are in sizes 12 or 14 Fr. Preparation of the system and device After the device and size have been chosen, the implantation system and device must be prepared. Experience has shown that through flushing of the catheter and device is essential to minimize the risk of air embolization during implantation.

The New Amulet occlusion device (the evolution of the Amplatzer ACP system, now more or less replaced on the market by the New Amulet) has an unusual structure which enables it to adapt to virtually any LAA morphology. This device is able to occlude all LAAs between 11 and 31 mm and is inserted in a deployment system with 9–14 Fr delivery catheters (depending on the size of the device). It should be remembered that while the delivery catheters of the ACP were available in diameters 9, 10, and 13 Fr, those of the Amulet are in sizes 12 or 14 Fr. Preparation of the system and device After the device and size have been chosen, the implantation system and device must be prepared. Experience has shown that through flushing of the catheter and device is essential to minimize the risk of air embolization during implantation. Implantation of the device Once the deployment system is in an appropriate positon, it is withdrawn, enabling the device to open. In this phase, small movements are sometimes required to adjust the device’s positon, turning, pushing, or pulling to correct the angle of access to the LAA, which is not always optimal in spite of careful planning of the transseptal puncture. Once the device is open, a combined check is performed by angiography (the electrical projections are the right cranial and right caudal arteries) and echocardiography, to check stability (shape and compression) and efficacy (presence of leaks). This is followed by a tug test on the deployment wire.

ansseptal puncture. Once the device is open, a combined check is performed by angiography (the electrical projections are the right cranial and right caudal arteries) and echocardiography, to check stability (shape and compression) and efficacy (presence of leaks). This is followed by a tug test on the deployment wire. Deployment of the device Once the result is considered satisfactory, the device can be deployed by turning the deployment wire anticlockwise. At the end of the procedure, an additional echocardiographic check is required to ensure that the device is correctly positioned and that there are no pericardial effusions (which may occur at any phase of the implantation process). The system is then removed and local haemostasis is performed (manual compression or figure-of-8 suture). The decision as to whether to administer protamine sulphate will depend on the assessment of its clinical utility as appropriate to the individual patient. Management of antithrombotic therapy after the procedure After the procedure, antithrombotic therapy is recommended to prevent the formation of thrombi on the device until its complete endothelialization. The current management protocol is the outcome of the PROTECT AF,48 PREVAIL,51 and ASAP52 studies based on the Watchman device and experience gained from use of the Amplatzer PFO Occluder device.

tithrombotic therapy is recommended to prevent the formation of thrombi on the device until its complete endothelialization. The current management protocol is the outcome of the PROTECT AF,48 PREVAIL,51 and ASAP52 studies based on the Watchman device and experience gained from use of the Amplatzer PFO Occluder device. For the Watchman device, the antithrombotic protocol of the PROTECT AF trial involved the suspension of warfarin 45 days after the procedure and its replacement with dual antiplatelet therapy if the TEE revealed the absence of thrombi or a residual leak < 5 mm; the second antiplatelet medication was suspended after 6 months if the follow-up TEE did not show significant periprosthetic leaks around the device. The PREVAIL trial and the ASAP study revealed the feasibility of DAPT as an alternative to therapy with warfarin after implantation of the Watchman device. Observational studies assessed DAPT for 1 month after implantation of the ACP device and single antiplatelet therapy for the next 3–6 months, in accordance with the antithrombotic therapy protocol acquired from experience with the Amplatzer PFO Occluder.75 In all these various therapeutic approaches, single antiplatelet therapy is indicated quoad vitam.

Observational studies assessed DAPT for 1 month after implantation of the ACP device and single antiplatelet therapy for the next 3–6 months, in accordance with the antithrombotic therapy protocol acquired from experience with the Amplatzer PFO Occluder.75 In all these various therapeutic approaches, single antiplatelet therapy is indicated quoad vitam. DAPT with aspirin and clopidogrel can be suggested with the execution of TEE at 3 months or even earlier in the event of significant post-procedural leaks (≥5 mm). If there are no complications of any kind, the second antiplatelet therapy could be suspended after this period and an echocardiogram (by the transoesophageal approach) repeated after about 1 year. However, widely varying protocols are found in the records of the largest centres for patients with high and very high risk of haemorrhage, with the use of low molecular weight heparin therapy for a period ranging from a few days to some weeks, the use of a single antiplatelet therapy or, in specific cases, no antithrombotic therapy. The incomplete occlusion of the LAA is another topic open to discussion. In theory, this could create pockets, which would be a potential source of cardioembolism. However, small residual leaks (<5 mm) are considered irrelevant and may close spontaneously; their presence has not been shown to imply an increased risk of thromboembolism compared to patients with complete LAAO76 although their clinical significance requires assessment in large randomized prospective studies with longer term follow-up.

dual leaks (<5 mm) are considered irrelevant and may close spontaneously; their presence has not been shown to imply an increased risk of thromboembolism compared to patients with complete LAAO76 although their clinical significance requires assessment in large randomized prospective studies with longer term follow-up. Recommended organisational and operating standards The expansion of the LAAO procedure within interventionist cardiology has led both national77 and international48,67 scientific societies to put forward recommendations and propose operating standards for the centres intending to adopt it. Some requirements should be considered essential; those listed below are the requirements to be considered fundamental for centres and staff.

rdiology has led both national77 and international48,67 scientific societies to put forward recommendations and propose operating standards for the centres intending to adopt it. Some requirements should be considered essential; those listed below are the requirements to be considered fundamental for centres and staff. General requirements Within the hospital, the LAAO procedure should include joint decision-making within the Heart Team, including the interventionist cardiologist (haemodynamic specialist or electrophysiologist), the clinical cardiologist, the echocardiographer, the anaesthetist, and the cardiac surgeon, to ensure optimal coordination of the procedure. Since patient selection is the first fundamental step, other specialists (neurologists, nephrologists, internists, geriatrists, and haematologists) may be involved in indicating LAAO as the most appropriate antithrombotic strategy for a given patient. Therefore, the formation of a multidisciplinary team should be a prerequisite for the choice of the ideal candidate, the success of the procedure and post-procedural management. The presence/availability of a cardiac surgery unit on site is considered as a requirement in the North American Heart Society document67 and is also recommended by the recent EHRA/EAPCI guidelines44 which consider access to a cardiac surgery theatre within 60 min. adequate. The joint document issued by the Società Italiana di Cardiologia Interventistica/Associazione Italiana di Aritmologia e Cardiostimolazione (GISE/AIAC) requires the presence of a cardiac surgery unit on-site.77

the recent EHRA/EAPCI guidelines44 which consider access to a cardiac surgery theatre within 60 min. adequate. The joint document issued by the Società Italiana di Cardiologia Interventistica/Associazione Italiana di Aritmologia e Cardiostimolazione (GISE/AIAC) requires the presence of a cardiac surgery unit on-site.77 Staff training and preparation Interventionist cardiologists or electrophysiologists intending to perform the LAAO procedure must have in-depth knowledge of the anatomy of the heart, and of the morphological characteristics of the atrium and the LAA in particular. All scientific societies underline the need for the professional performing the procedure to have specific expertise in transseptal puncture and how to perform it in relation to implementation of LAAO devices. With regards to the transseptal puncture, the position of the national and international electrophysiology societies [AIAC/Heart Rhythm Society (HRS)] is that the professional should have performed at least 50 transseptal punctures and be skilled in manoeuvring catheters/inserters in the left atrium. The professional must be familiar not only with the anatomical position of the LAA and how to reach it but also the relationships between this structure and the surrounding anatomical formations. He or she must also have sufficient experience in the interpretation of radiological images (from angiography, tomography and magnetic resonance) and echocardiogram images of the LAA to obtain all the information needed for the correct choice of device. In particular, the scientific societies emphasize the need for consultation between the professional performing the procedure and the echocardiographer, a key factor for success.

omography and magnetic resonance) and echocardiogram images of the LAA to obtain all the information needed for the correct choice of device. In particular, the scientific societies emphasize the need for consultation between the professional performing the procedure and the echocardiographer, a key factor for success. Professional performing the procedure must also have experience in pericardial puncture (or at least an interventionist cardiologist with this technical skill must be present) in order to deal with the eventuality of pericardial tamponade during manoeuvres in the left atrium or positioning of the device in the LAA. Training of the first professional in the skills needed to perform the procedure is the fundamental first step in becoming autonomous. Training is provided by a proctor who is able to supply the trainee with explanations of all the phases of the procedure for successful LAAO. In detail, the recommendations of all the various scientific societies agree that every professional must attend theoretical lessons together with technical support through familiarization with the procedure and the instruments required, involving virtual sessions using simulators and/or practical sessions, in animal laboratories where possible.

ons of all the various scientific societies agree that every professional must attend theoretical lessons together with technical support through familiarization with the procedure and the instruments required, involving virtual sessions using simulators and/or practical sessions, in animal laboratories where possible. It is advisable for those who are learning the procedure to attend implantation operations in order to learn the various steps with precision. The proctor must be present at the first implantation performed in every centre. Although there is no minimum number required to allow a professional to acquire complete independence, it is reasonable to assume that at least 15 implants must be performed in each centre before a satisfactory degree of autonomy and independence is gained. One key factor for the achievement of procedural success, strongly recommended in the documents of the various scientific societies, is the creation of a well-organized operating team including the echocardiographer, the anaesthetist, and the nursing staff, who must also be familiar with the characteristics of the various devices and have proven experience in interventionist cardiology/electrophysiology procedures.

the various scientific societies, is the creation of a well-organized operating team including the echocardiographer, the anaesthetist, and the nursing staff, who must also be familiar with the characteristics of the various devices and have proven experience in interventionist cardiology/electrophysiology procedures. Requirements for the centre and operating room Since most procedures are performed under general anaesthetic, the operating room must have the instrumentation required for anaesthesiology and have sufficient physical space not only for the anaesthetist but also for the echocardiographer, who plays a fundamental role in the procedure. The international scientific societies require the operating room staff, including nursing and technical staff, to have experience in interventionist procedures and be able to understand every step of the procedure, such as, for example, how to respond quickly to emergencies. Staff's familiarity with the materials used is an additional factor in facilitating all steps of the procedure. Although not specifically recommended by the various scientific societies, it would be preferable for the nursing members of the team also to be involved in the technical training, attending LAAO sessions performed by the proctor and getting to know the materials by means of virtual sessions. All operating room staff involved in the procedure must have a clearly defined role to play, in order to prevent overlaps during the procedure and delays in responding to emergencies.

Staff's familiarity with the materials used is an additional factor in facilitating all steps of the procedure. Although not specifically recommended by the various scientific societies, it would be preferable for the nursing members of the team also to be involved in the technical training, attending LAAO sessions performed by the proctor and getting to know the materials by means of virtual sessions. All operating room staff involved in the procedure must have a clearly defined role to play, in order to prevent overlaps during the procedure and delays in responding to emergencies. Procedural recommendations and minimum skill levels In view of the large number of procedures already performed and the potential additional increase in the near future, it appears appropriate for the national and scientific societies to draw up a position which can act as a consensus guideline. Therefore, on the one hand, the existing literature has been combined to extract indications for the selection and preparation of patients for the procedure. On the other hand, considering the opinions of staff skilled in the procedure, it appears useful to analyse the most purely technical aspects of percutaneous LAAO in order to standardize the various steps of the method, increasing its success in acute cases and reducing complications.

ion of patients for the procedure. On the other hand, considering the opinions of staff skilled in the procedure, it appears useful to analyse the most purely technical aspects of percutaneous LAAO in order to standardize the various steps of the method, increasing its success in acute cases and reducing complications. Requirements for the facility and staff As already stated, percutaneous LAAO is a procedure which requires a multidisciplinary approach and can be performed either by an electrophysiologist or by a haemodynamic specialist: professionals from both these disciplines can combine their specific skills. However, the general opinion is that this procedure is technically complex and is a considerable challenge within interventionist-structural cardiology, due to the large number of skills required (transseptal puncture, navigation in left atrium and LAA, use of contrast medium, catheters and specific materials) (Figure 10). Figure 10 Complexity ratio between the procedures used in interventionist cardiology. ASD, atrial septal defect; PFO, patent foramen ovale; TAVI, transcatheter aortic valve implantation.

Requirements for the facility and staff As already stated, percutaneous LAAO is a procedure which requires a multidisciplinary approach and can be performed either by an electrophysiologist or by a haemodynamic specialist: professionals from both these disciplines can combine their specific skills. However, the general opinion is that this procedure is technically complex and is a considerable challenge within interventionist-structural cardiology, due to the large number of skills required (transseptal puncture, navigation in left atrium and LAA, use of contrast medium, catheters and specific materials) (Figure 10). Figure 10 Complexity ratio between the procedures used in interventionist cardiology. ASD, atrial septal defect; PFO, patent foramen ovale; TAVI, transcatheter aortic valve implantation. Therefore, this working group believes that a facility wishing to start a percutaneous LAAO programme must have a multidisciplinary team allowing optimal assessment of the patient for the procedure. Particular attention will be focused on cardiac imaging techniques, in order to assess feasibility and plan the procedure most effectively: the presence of a specialist echocardiographer, both to monitor the positioning of the device and to recognize acute complications, is fundamental (Table 7). Table 7. Intraprocedural complications which can be identified by echocardiography. 1. Pericardial effusion 2. Cardiac tamponade 3. Embolization of the device 4. Thrombosis on the catheter 5. Tearing of the left atrial appendage 6. Damage to nearby structures: 7. During transseptal puncture

Therefore, this working group believes that a facility wishing to start a percutaneous LAAO programme must have a multidisciplinary team allowing optimal assessment of the patient for the procedure. Particular attention will be focused on cardiac imaging techniques, in order to assess feasibility and plan the procedure most effectively: the presence of a specialist echocardiographer, both to monitor the positioning of the device and to recognize acute complications, is fundamental (Table 7). Table 7. Intraprocedural complications which can be identified by echocardiography. 1. Pericardial effusion 2. Cardiac tamponade 3. Embolization of the device 4. Thrombosis on the catheter 5. Tearing of the left atrial appendage 6. Damage to nearby structures: 7. During transseptal puncture 8. During manipulation or deployment of the device 9. Interference with the mitral valve, the circumflex artery or the left upper pulmonary vein Although it is not a sine qua non, radiological imaging plays a major role: high definition multidetector computed tomography and cardiac magnetic resonance are able to identify any thrombotic formations and study the anatomy of the LAA most effectively.78 However, it must be underlined that these techniques are not the ideal support during the procedure, although they are useful, especially during the initial phases.

ctor computed tomography and cardiac magnetic resonance are able to identify any thrombotic formations and study the anatomy of the LAA most effectively.78 However, it must be underlined that these techniques are not the ideal support during the procedure, although they are useful, especially during the initial phases. It thus appears advisable to perform the entire procedure under the guidance of echocardiography and fluoroscopy, as already emphasized in the PROTECT AF study. In all cases, according to the data in the literature and the experience of many professionals, it does not seem to be more risky than other interventionist procedures such as transcatheter ablation of AF, with which it shares the risk of mechanical complications (cardiac tamponade and damage to the structures adjoining the left atrium). It is important to point out that the incidence of what is to all effects the most serious complication, cardiac tamponade, has fallen over the years as operators’ experience has increased and the technical characteristics of devices have improved: the rate has decreased from the about 5% of PROTECT AF48 to a minimum of 0.8–1.3% in the latest ‘real world’ registry studies.51,58 Analysing the data available to us from the PROTECT AF48 and PREVAIL51 studies, which together total 1271 patients, we find 40 (3.1%) pericardial effusions; the two studies report that 10 (0.8%) of these were surgically drained within 7 days after deployment of the device. If we compare the data of the two studies, PROTECT AF and PREVAIL, there is a significant reduction in surgically drained pericardial effusions (P = 0.027), with a fall from 1.6% to 0.4%.

dial effusions; the two studies report that 10 (0.8%) of these were surgically drained within 7 days after deployment of the device. If we compare the data of the two studies, PROTECT AF and PREVAIL, there is a significant reduction in surgically drained pericardial effusions (P = 0.027), with a fall from 1.6% to 0.4%. Considering the complexity of the procedure and the potential complications, with current knowledge and the data now available, the need for a cardiac surgery team on-site has been the subject of debate, as reflected by the different positons taken in the international documents. Although the majority of the Panel believed that the presence of a cardiac surgery team on-site was not an indispensable requirement and that access to a cardiac surgery room within 60 min. was sufficient a unanimous position on this point was not achieved, even after lengthy discussion. One essential prerequisite (relevant for both interventionist cardiologists and electrophysiologists) is skill in pericardiocentesis.79 Management of complications Pericardial effusion and cardiac tamponade Pericardial effusion, in all its clinical forms (from asymptomatic effusion to cardiac tamponade) is one of the most serious complications of the percutaneous LAAO procedure. The risk factors include the transseptal puncture, the manipulation of rigid structures like the delivery catheters and the devices themselves inside the left atrium, and the intrinsic fragility of the atrial wall.80

sion to cardiac tamponade) is one of the most serious complications of the percutaneous LAAO procedure. The risk factors include the transseptal puncture, the manipulation of rigid structures like the delivery catheters and the devices themselves inside the left atrium, and the intrinsic fragility of the atrial wall.80 In the PROTECT AF study, conducted on the Watchman device, the incidence of pericardial effusion within 7 days of implantation was 4.4%, with pericardiocentesis required in 3.3% of patients.48 It should be underlined that this complication was observed more frequently at the start of the learning curve. In the registry of the PAC system, which contains the results achieved by skilled staff, the rate of pericardial effusion fell to 2.2%74 and the same values were also reported in the subsequent PREVAIL trial.51 The recent study performed by Tzikas et al.57 on the results achieved with the ACP device in more than 20 European and Canadian centres revealed a rate of pericardial effusion requiring drainage of 1.2%. In a multicentric study analysing the data on the use of the Lariat device, Price et al.81 report an incidence of pericardial effusion requiring drainage of 10.4%. The procedural strategies to reduce the incidence of pericardial effusion include: performance of the device implantation procedure under TEE guidance and pressure monitoring to ensure safe transseptal puncture in the correct position; use of a pigtail catheter inside the access sheath or a loop wire in the LAA to facilitate safe, trauma-free movement inside it;

The procedural strategies to reduce the incidence of pericardial effusion include: performance of the device implantation procedure under TEE guidance and pressure monitoring to ensure safe transseptal puncture in the correct position; use of a pigtail catheter inside the access sheath or a loop wire in the LAA to facilitate safe, trauma-free movement inside it; the use of slow, careful movements during manipulation of the catheter and occlusion device inside the left atrium; and performance of the tug test after implantation of the device under echocardiographic and fluoroscopic guidance, with injection of small amounts of contrast medium. With regards to the therapeutic management of pericardial effusion, in the case of cardiac tamponade with hypotension a swift, aggressive approach is required, with pericardiocentesis and suspension of anticoagulation therapy. Early diagnosis of a pericardial effusion by means of TEE/intracardiac echography can often prevent the onset of cardiac tamponade, leading to serious deterioration of the haemodynamic condition. Pericardiocentesis can be performed by means of a subxiphoid or subcostal transcutaneous puncture with echocardiographic guidance, or through a small cutaneous incision of about 3–5 cm underneath the xiphoid appendix (subxiphoid window), which allows the pericardial cavity to be accessed directly through its incision, followed by insertion of a pericardial drain.

of a subxiphoid or subcostal transcutaneous puncture with echocardiographic guidance, or through a small cutaneous incision of about 3–5 cm underneath the xiphoid appendix (subxiphoid window), which allows the pericardial cavity to be accessed directly through its incision, followed by insertion of a pericardial drain. In the event of recurrent tamponade or perforation of the left atrial wall, conventional surgery is required to review the pericardial cavity, suturing the breach in the atrial wall in an off-pump, beating heart procedure (if possible). If the lesion requires luxation of the heart for better surgical exposure, and tolerance of this procedure is poor, extracorporeal circulation may be necessary. In selected cases, a thoracoscopic approach may initially be indicated, with fitting of an epicardial device (e.g. AtriClip) to close the breach in the LAA, if the lesion does not involve its orifice. This technique has not yet been described in the literature, and where it is not indicated the thoracoscopic approach can be transformed into minithoracotomy, which allows easier control of the anatomical structures and control of the haemostasis.

close the breach in the LAA, if the lesion does not involve its orifice. This technique has not yet been described in the literature, and where it is not indicated the thoracoscopic approach can be transformed into minithoracotomy, which allows easier control of the anatomical structures and control of the haemostasis. Although most cases of pericardial effusion occur early, subacute forms and delayed effusions are still described in the literature after the implantation of percutaneous LAAO devices. Therefore, monitoring of heart rate and arterial pressure are recommended for at least 48 h after implantation of the device, with performance of a transthoracic echocardiogram before discharge to ensure that no pericardial effusion has occurred and that the device is correctly positioned. Subacute effusions may be due to rubbing or irritation caused by the device’s anchors against the wall of the atrium, in which lesions may eventually occur in view of its thinness. In these cases, if the pericardial effusion is of significant extent or produces instrumental signs of haemodynamic impairment, pericardiocentesis, or in some cases conventional surgical exploration, must be performed. Delayed, haemodynamically insignificant effusions can probably be ascribed to post-procedural inflammation. They are normally treated with non-steroid anti-inflammatories such as aspirin, ibuprofen and diclofenac, or more rarely with steroid therapy.

Although most cases of pericardial effusion occur early, subacute forms and delayed effusions are still described in the literature after the implantation of percutaneous LAAO devices. Therefore, monitoring of heart rate and arterial pressure are recommended for at least 48 h after implantation of the device, with performance of a transthoracic echocardiogram before discharge to ensure that no pericardial effusion has occurred and that the device is correctly positioned. Subacute effusions may be due to rubbing or irritation caused by the device’s anchors against the wall of the atrium, in which lesions may eventually occur in view of its thinness. In these cases, if the pericardial effusion is of significant extent or produces instrumental signs of haemodynamic impairment, pericardiocentesis, or in some cases conventional surgical exploration, must be performed. Delayed, haemodynamically insignificant effusions can probably be ascribed to post-procedural inflammation. They are normally treated with non-steroid anti-inflammatories such as aspirin, ibuprofen and diclofenac, or more rarely with steroid therapy. Gaseous embolism Gaseous embolism is often a clinically silent event, although in rare cases it may cause TIA, acute coronary ischaemia, hypotension and/or cardiac arrest.48 Gaseous embolisms may reach the left atrium due to an accidental injection of air or may be the consequence of gas bubbles generated by a gradient between atmospheric and intracardiac pressure due to a deep intake of breath.82

n rare cases it may cause TIA, acute coronary ischaemia, hypotension and/or cardiac arrest.48 Gaseous embolisms may reach the left atrium due to an accidental injection of air or may be the consequence of gas bubbles generated by a gradient between atmospheric and intracardiac pressure due to a deep intake of breath.82 Most of the management of gaseous embolisms consists of support. Hyperbaric oxygen has shown clinical benefits in 80% of cases of cerebral gaseous embolism, although no controlled studies have yet been performed. Gaseous embolism in the coronary circulation most often becomes evident in the right coronary due to the anatomical position of its orifice, and is often resolved within a few minutes. However, it may generate an ST depression, hypotension and ventricular arrhythmias, through to cardiogenic shock. Aspiration of the air with a specific device or the injection of contrast medium into the coronary artery may be useful in these cases. Embolization of the device The implantation procedure may be complicated by immediate or delayed formation of embolisms around the perimeter of the device itself. The careful selection of patients with favourable LAA morphology and use of the appropriate size of device are crucial for preventing this complication. Conversely, negative predictors are: large LAA orifice size, use of undersized devices, short LAA, and unusual anatomical variants.

Embolization of the device The implantation procedure may be complicated by immediate or delayed formation of embolisms around the perimeter of the device itself. The careful selection of patients with favourable LAA morphology and use of the appropriate size of device are crucial for preventing this complication. Conversely, negative predictors are: large LAA orifice size, use of undersized devices, short LAA, and unusual anatomical variants. Embolized devices in the left atrium or left ventricle can be captured and then driven forwards towards the mitral and aortic valves by means of endocatheters, allowing them to be recovered in the descending aorta. The recovery of devices from inside the heart itself is difficult and dangerous, while recovery in the aorta with a loop or bioptome catheter is a safer, more reproducible method. In the rare cases of the embolization of larger-sized devices in the direction of the iliac-femoral axis, recovery through open surgery is necessary.

ery of devices from inside the heart itself is difficult and dangerous, while recovery in the aorta with a loop or bioptome catheter is a safer, more reproducible method. In the rare cases of the embolization of larger-sized devices in the direction of the iliac-femoral axis, recovery through open surgery is necessary. Conclusions OAT is the strategy of first choice for the prevention of thromboembolic events in AF patients with medium/high risk (CHA2DS2-VASc ≥1). However, many of these patients are difficult to treat, especially due to bleeding, a dangerous adverse event related to the therapy, which limits or contraindicates its use. The observation that most thrombi are generated by the LAA has led to the consideration of its surgical or percutaneous occlusion as an alternative; during the last few years, the Watchman percutaneous occlusion device has proved to be not inferior to anticoagulant therapy for the prevention of thromboembolic events, with the added benefit of a lower rate of haemorrhagic events; other, new devices have recently been introduced or are under development.

alternative; during the last few years, the Watchman percutaneous occlusion device has proved to be not inferior to anticoagulant therapy for the prevention of thromboembolic events, with the added benefit of a lower rate of haemorrhagic events; other, new devices have recently been introduced or are under development. The procedure for the percutaneous occlusion of the LAA requires considerable technical skill and theoretical knowledge, as well as suitable training under the supervision of expert colleagues. Anyone wishing to perform it will require the cooperation of skilled echocardiographers, familiar with the transoesophageal technique, to obtain the support of suitable imaging; he or she must also be capable of managing any complications, meaning, in particular, experience in the execution of pericardiocentesis, since cardiac tamponade is the most common and most dangerous complication. The presence of a cardiac surgery unit on-site does not appear to be indispensable although it is reasonable to ensure access to a cardiac surgery room within 60 min. if necessary. At present, the main indication for LAAO is the relative or absolute contraindication of anticoagulant therapy in patients with AF. These indications derive from observational or registry studies made comparing devices with the use of warfarin. Fur the future, the indication for LAAO in association with the AF ablation procedure AF83–85 and MitraClip implantation, and the data obtained from comparison with the NOACs, remain to be assessed.

with AF. These indications derive from observational or registry studies made comparing devices with the use of warfarin. Fur the future, the indication for LAAO in association with the AF ablation procedure AF83–85 and MitraClip implantation, and the data obtained from comparison with the NOACs, remain to be assessed. Large populations of very high-risk patients have still not been studied, including those who are unable to take any type of anticoagulant or antiplatelet therapy, in order to establish the impact of these factors on the prevention of complications and mortality. Acknowledgments The authors wish to thank Dr. Pierluigi Merella (Cardiologia, Ospedale San Francesco, Nuoro) and Dr. Simonetta Genovesi (Dipartimento di Medicina e Chirurgia, Università degli Studi Milano-Bicocca, Clinica Nefrologica, A.O. San Gerardo, Monza) for their useful comments during drafting of the document. Conflict of interest: none declared.

Acknowledgments The authors wish to thank Dr. Pierluigi Merella (Cardiologia, Ospedale San Francesco, Nuoro) and Dr. Simonetta Genovesi (Dipartimento di Medicina e Chirurgia, Università degli Studi Milano-Bicocca, Clinica Nefrologica, A.O. San Gerardo, Monza) for their useful comments during drafting of the document. Conflict of interest: none declared. Annex Consensus Document Approval Faculty Abrignani Maurizio Giuseppe, Alunni Gianfranco, Amico Antonio Francesco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Azzarito Michele, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Bonvicini Marco, Cacciavillani Luisa, Calculli Giacinto, Caldarola Pasquale, Capecchi Alessandro, Caporale Roberto, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Cassin Matteo, Cemin Roberto, Chiarandà Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Ciccone Marco Matteo, Cicini Maria Paola, Clerico Aldo, Colivicchi Furio, D’Agostino Carlo, De Luca Leonardo, De Luca Giovanni, De Maria Renata, Del Sindaco Donatella, Di Fusco Stefania Angela, Di Lenarda Andrea, Di Tano Giuseppe, Egidy Assenza Gabriele, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Francese Giuseppina Maura, Gabrielli Domenico, Geraci Giovanna, Giardina Achille, Greco Cesare, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Ledda Antonietta, Lucà Fabiana, Macera Francesca, Marini Marco, Mascia Franco, Masson Serge, Maurea Nicola, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Menozzi Alberto, Mininni Nicola, Moreo Antonella, Moretti Luciano, Mortara Andrea, Mureddu Gian Francesco, Murrone Adriano, Nardi Federico, Navazio Alessandro, Nicolosi Pier Luigi, Oliva Fabrizio, Parato Vito Maurizio, Parrini Iris, Patanè Leonardo, Pini Daniela, Pino Paolo Giuseppe, Pirelli Salvatore, Procaccini Vincenza, Pugliese Francesco Rocco, Pulignano Giovanni, Radini Donatella, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scalvini Simonetta, Scherillo Marino, Severi Silva, Sicuro Marco, Silvestri Paolo, Sisto Francesco, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

Revised by Roberto Antonicelli, Roberto Caporale, Donatella del Sindaco. Silvio Klugmann, Gennaro Santoro Consensus Document Approval Faculty in appendix Introduction Aortic stenosis (AS) is one of the most common acquired valvular abnormalities in developed countries, with an increasing prevalence due to the ageing population.1–3 The prognosis of AS is relatively benign in the absence of symptoms; however, an incidence of sudden death between 1% and 3% must be taken into account. The onset of symptoms coincides with a dramatic reduction in life expectancy, with a median survival of 2–3 years in patients with angina or syncope and only 1–2 years in symptomatic patients with heart failure.3,4 Surgical aortic valve replacement (SAVR) remains the gold standard of care;5 however, at least 40% of potential patients are not candidate because of the prohibitive nature of their co-morbidities and consequent perioperative risk.6,7 Consistent with the epidemiological changes, in clinical practice, about three-quarters of patients with isolated SAVR receive a bioprosthesis.8 Advanced age alone cannot be considered an obstacle to surgery, but medical options are limited. Elderly patients who do not receive a SAVR have a higher risk of mortality compared with those treated surgically.9 Isolated SAVR can be performed in octogenarians with low post-operative mortality10 and result in significant improvement in quality of life (QOL), symptoms, and functional capacity.11 In addition, cost-effectiveness analyses have shown that SAVR is convenient also for very elderly patients.12

hose treated surgically.9 Isolated SAVR can be performed in octogenarians with low post-operative mortality10 and result in significant improvement in quality of life (QOL), symptoms, and functional capacity.11 In addition, cost-effectiveness analyses have shown that SAVR is convenient also for very elderly patients.12 In the last years, transcatheter aortic valve implantation (TAVI) has emerged as a less invasive treatment strategy in high-risk patients, allowing the treatment of more complex, elderly patients, with severe symptomatic AS, previously considered ineligible for surgery.13–15 However, even today, a considerable percentage of these patients die or do not present a significant improvement in dyspnoea, fatigue, and functional impairment. This observation has raised a lively discussion on the need to identify and recognize the boundaries of indications for surgical and interventional procedures and, consequently, identify a possible futility in some patients.16 The decision-making process in this population is difficult because of co-morbidity, disability, frailty, and reduced life expectancy, and these factors, as well as traditional ones, should be considered in risk stratification. It is likely that TAVI will be used in an increasing number of AS patients, but its exact role alongside surgery will need to be defined in a judicious and evidence-based manner. The assessment by a multidisciplinary team is therefore essential to predict possible benefits and allow to make complex decisions with a clear communication to the patient. The decision that surgical treatment or with TAVI is useless/futile should include alternative routes to optimize the patient’s health state and to consider options for assistance to the terminal stages.17

ential to predict possible benefits and allow to make complex decisions with a clear communication to the patient. The decision that surgical treatment or with TAVI is useless/futile should include alternative routes to optimize the patient’s health state and to consider options for assistance to the terminal stages.17 Heterogeneity and complexity The peculiar feature of the elderly patient can be summarized in two words: phenotypic heterogeneity and complexity. In these two dimensions describe the effects of cardiovascular ageing, heart disease, lifestyle, and socio-environmental factors and three different entities: co-morbidity, disability, and frailty (Figure 1).18 Complexity considers not only the sum of all coexisting diseases and geriatric conditions but also their mutual interactions. From a conceptual point of view, therefore, the elderly person is in himself/herself a complex patient. Figure 1 Frailty, co-morbidity and disability. Modified from Afilalo et al.18 BADL: basic activities of daily living; IADL: instrumental ADL.

Heterogeneity and complexity The peculiar feature of the elderly patient can be summarized in two words: phenotypic heterogeneity and complexity. In these two dimensions describe the effects of cardiovascular ageing, heart disease, lifestyle, and socio-environmental factors and three different entities: co-morbidity, disability, and frailty (Figure 1).18 Complexity considers not only the sum of all coexisting diseases and geriatric conditions but also their mutual interactions. From a conceptual point of view, therefore, the elderly person is in himself/herself a complex patient. Figure 1 Frailty, co-morbidity and disability. Modified from Afilalo et al.18 BADL: basic activities of daily living; IADL: instrumental ADL. An accurate pre-operative/pre-procedural risk stratification in the elderly person should identify those who benefit from the intervention, exclude those who have a prohibitive risk, and identify those who need more intensive care in the post-operative period. In this sense, the ideal tool for risk stratification in the elderly person waiting for cardiac surgery should be reliable and targeted at easily obtainable variables. Any tool should be tested in a real-world ageing population with different degrees of frailty or disability, pointing out that the two concepts are interdependent but not synonymous. Pre-operative evaluation in the elderly patient should collect information on physical functional status, cognitive function, and non-cardiac co-morbidities of prognostic importance.19

g population with different degrees of frailty or disability, pointing out that the two concepts are interdependent but not synonymous. Pre-operative evaluation in the elderly patient should collect information on physical functional status, cognitive function, and non-cardiac co-morbidities of prognostic importance.19 Co-morbidity is defined as the simultaneous presence of two or more diseases in the same patient, an event that increases with age.20 About 16% of patients >65 years have co-morbidity with two or more diseases, a percentage that increases to 35% in octogenarians.21 At this age, chronic co-morbidities are associated with a higher risk of death, rehospitalization, disability, and reduced QOL beyond those related to individual disorders. Co-morbidity plays a central role in the implementation of evidence-based medicine in clinical geriatrics, because trials have often excluded older subjects with co-morbidities, raising questions about the transferability of the results obtained in the geriatric populations.22 Co-morbidity also becomes crucial in influencing the diagnostic–therapeutic process, because the onset of symptoms can be different from the usual and makes the interpretation of symptoms and signs of the index disease more difficult.

ons about the transferability of the results obtained in the geriatric populations.22 Co-morbidity also becomes crucial in influencing the diagnostic–therapeutic process, because the onset of symptoms can be different from the usual and makes the interpretation of symptoms and signs of the index disease more difficult. The elderly candidate to heart surgery is, regardless of his death risk, susceptible to frequent serious complications. These often result in a cascade of negative events that converge to lose autonomy in carrying out the activities of daily living, leading to significant health-care costs and decreased QOL. This phenotype of reduced homeostatic physiological reserves and greater vulnerability to stressful events is described as frailty.23 The complex pathophysiological substrate of frailty is described in Figure 2.24 Frailty has been defined ‘a condition or syndrome that results from a multi-systemic reduction in homeostatic reserve, to the extent that the physiological systems are close to the threshold of symptomatic clinical failure. Consequently the frail person is at increased risk of disability and death for a minimum external stress’.25 The concept of frailty (although the two conditions are frequently overlapping) is not synonymous of disability nor is equivalent to the concept of co-morbidity (Figure 1). Figure 2 Pathophysiology of fragility. Modified fromWalston et al.24

The elderly candidate to heart surgery is, regardless of his death risk, susceptible to frequent serious complications. These often result in a cascade of negative events that converge to lose autonomy in carrying out the activities of daily living, leading to significant health-care costs and decreased QOL. This phenotype of reduced homeostatic physiological reserves and greater vulnerability to stressful events is described as frailty.23 The complex pathophysiological substrate of frailty is described in Figure 2.24 Frailty has been defined ‘a condition or syndrome that results from a multi-systemic reduction in homeostatic reserve, to the extent that the physiological systems are close to the threshold of symptomatic clinical failure. Consequently the frail person is at increased risk of disability and death for a minimum external stress’.25 The concept of frailty (although the two conditions are frequently overlapping) is not synonymous of disability nor is equivalent to the concept of co-morbidity (Figure 1). Figure 2 Pathophysiology of fragility. Modified fromWalston et al.24 Given this definition, there are basically two conceptual models of frailty: the ‘frailty phenotype’26 and the ‘clinical frailty phenotype’.27 The first substantially recognizes a set of five domains such as unintentional weight loss, muscle strength measured by handgrip, self-reported fatigue, gait speed, and self-reported physical activity.26 The second model is based on a ‘deficit accumulation model of frailty’ and has been built from a list multiple items, both functional and clinical, exploring the physical, cognitive, and independence in activities of daily living, with a final score ranging from 0 to 7 for increasing frailty.27 Both models have been tested in the stratification of the elderly patient’s surgical risk but also showing some of the limitations related to the complexity of their clinical routine implementation.

gnitive, and independence in activities of daily living, with a final score ranging from 0 to 7 for increasing frailty.27 Both models have been tested in the stratification of the elderly patient’s surgical risk but also showing some of the limitations related to the complexity of their clinical routine implementation. The negative impact of frailty on prognosis of cardiovascular diseases has been demonstrated in a wide range of conditions, including stable cardiovascular disease,28 heart failure,29 ischaemic heart disease and acute coronary syndromes,30 cardiac surgery,31,32 and TAVI.33,34 Disability is defined by the level of dependence in performing basic and instrumental activities of daily living, i.e. basic activities of daily living (BADL)35 and instrumental activities of daily living (IADL).36 In the recent US TAVI guidelines,16 a specific section—Frailty and futulity versus Utility—was included, demonstrating that when deciding a therapeutic intervention in elderly subjects, the assessment of frailty and the risk of disability is a key variable for deciding the effectiveness and utility of the intervention itself.

recent US TAVI guidelines,16 a specific section—Frailty and futulity versus Utility—was included, demonstrating that when deciding a therapeutic intervention in elderly subjects, the assessment of frailty and the risk of disability is a key variable for deciding the effectiveness and utility of the intervention itself. Outcomes of surgical and interventional procedures in the elderly persons Results of surgical aortic valve replacement Overall, the outcomes of surgery for severe AS are excellent in patients with moderate-to-low surgical risk. A meta-analysis of 48 observational studies in 13 216 patients >80 years, undergoing isolated aortic valve surgery10 showed an immediate post-operative mortality of 6.7% (5.8% for patients treated from 2000 to 2006 and 7.5% in patients treated from 1982 to 1999). The post-operative stroke rate was 2.4%, dialysis of 2.6%, and pacemaker implant 4.6%. The 1-, 3-, 5-, and 10-year mortality rates after isolated SAVR were approximately 12.4%, 21.3%, 34.7% and 70.3%, respectively. These data confirm that advanced age, as the only risk factor, cannot be considered a contraindication to conventional isolated SAVR. In the Society of Thoracic Surgeons (STS) database, mortality at 30 days after isolated SAVR over 80 years was 3.7% in low-risk patients but rose to 10% and 17%, respectively, in patients with STS score ≥5 and ≥10.37 Octogenarians also report improvements in symptoms and ventricular function.38

ventional isolated SAVR. In the Society of Thoracic Surgeons (STS) database, mortality at 30 days after isolated SAVR over 80 years was 3.7% in low-risk patients but rose to 10% and 17%, respectively, in patients with STS score ≥5 and ≥10.37 Octogenarians also report improvements in symptoms and ventricular function.38 Results of transcatheter aortic valve implantation in patients at high or prohibitive risk On the basis of two main randomized trials and various observational studies, recent guidelines2 indicate TAVI as an option of choice in patients deemed inoperable because a prohibitive risk (with results far superior to medical therapy alone) and a reasonable alternative to SAVR in those at high risk (Table 1).13–15,39–47Table 1 Risk assessment combining STS risk estimate, frailty, major organ system dysfunction, and procedure-specific impediments4

in patients deemed inoperable because a prohibitive risk (with results far superior to medical therapy alone) and a reasonable alternative to SAVR in those at high risk (Table 1).13–15,39–47Table 1 Risk assessment combining STS risk estimate, frailty, major organ system dysfunction, and procedure-specific impediments4 Low risk (must meet all criteria in this column) Intermediate risk (any 1 criterion in this column) High risk (any 1 criterion in this column) Prohibitive risk (any 1 criterion in this column) STS PROMa <4% AND 4–8% OR >8% OR Predicted risk with surgery of death or major morbidity (all-cause) >50% at 1 year OR Frailtyb None AND 1 Indice (lieve) OR ≥2 Indices (moderate-severe) OR Major organ system compromise not to be improved postoperativelyc None AND 1 Organ system OR No more than 2 organ system OR ≥3 Organ system OR Procedurespecific impedimentd None Possible Possible Severe aUse of the STS PROM to predict risk in a given institution with reasonable reliability is appropriate only if institutional outcomes are within 1 standard deviation of STS average observed/expected ratio for the procedure in question. bSeven frailty indices: Katz activities of daily living (independence in feeding, bathing, dressing, transferring, toileting, and urinary continence) and independence in ambulation (no walking aid or assist required or 5 m walk in < 6 s). Other scoring systems can be applied to calculate no, mild-, or moderate-to-severe frailty.

ilty indices: Katz activities of daily living (independence in feeding, bathing, dressing, transferring, toileting, and urinary continence) and independence in ambulation (no walking aid or assist required or 5 m walk in < 6 s). Other scoring systems can be applied to calculate no, mild-, or moderate-to-severe frailty. cExamples of major organ system compromise: Cardiac—severe LV systolic or diastolic dysfunction or RV dysfunction, fixed pulmonary hypertension; CKD Stage 3 or worse; pulmonary dysfunction with FEV1 <50% or DLCO2 <50% of predicted; CNS dysfunction (dementia, Alzheimer’s disease, Parkinson’s disease, CVA with persistent physical limitation); GI dysfunction—Crohn’s disease, ulcerative colitis, nutritional impairment, or serum albumin <3.0; cancer—active malignancy; and liver—any history of cirrhosis, variceal bleeding, or elevated INR in the absence of VKA therapy. dExamples include tracheostomy present, heavily calcified ascending aorta, chest malformation, arterial coronary graft adherent to posterior chest wall, and radiation damage. CKD, chronic kidney disease; CNS, central nervous system; CVA, stroke; DLCO2, diffusion capacity for carbon dioxide; FEV1, forced expiratory volume in 1 s; GI, gastrointestinal; INR, international normalized ratio; LV, left ventricular; PROM, predicted risk of mortality; RV, right ventricular; STS, Society of Thoracic Surgeons; and VKA, vitamin K antagonist.

l nervous system; CVA, stroke; DLCO2, diffusion capacity for carbon dioxide; FEV1, forced expiratory volume in 1 s; GI, gastrointestinal; INR, international normalized ratio; LV, left ventricular; PROM, predicted risk of mortality; RV, right ventricular; STS, Society of Thoracic Surgeons; and VKA, vitamin K antagonist. In the PARTNER trial (Cohort A), which included patients with high operative risk,44 patients undergoing SAVR had a higher incidence of bleeding and a lower incidence of vascular complications, compared with those undergoing TAVI at 5 years. The percentage of residual aortic moderate and severe insufficiency was 14% in patients undergoing TAVI and 1% of patients undergoing SAVR (P <0.0001) and, if moderate and severe, correlated with an increase in mortality. The data of Registries confirm those of trials. In the GARY (Germany Aortic Valve Registry)48 hospital mortality was 5.2% and serious complications occurred in 5% in patients undergoing TAVI from 2011 to 2013. In the FRANCE TAVI Registry, enrolling 6827 patients undergoing TAVI in 2013 and 2014, the hospital mortality was 5.9%, the incidence of major bleeding was 9.3%, stroke 2.2%, need for pacemaker 15%, and severe aortic insufficiency 1.2%.49 The Italian OBSERVANT study analysed propensity-matched patients undergoing TAVI or SAVR. The mean logistic EuroSCORE 1 was 10.2 in SAVR group and 9.5 in the TAVI group. No significant differences were recorded in mortality (13.6% and 13.8%), MACE rate (17.6% vs. 18.2%), and in hospitalizations for cardiac causes.50

49 The Italian OBSERVANT study analysed propensity-matched patients undergoing TAVI or SAVR. The mean logistic EuroSCORE 1 was 10.2 in SAVR group and 9.5 in the TAVI group. No significant differences were recorded in mortality (13.6% and 13.8%), MACE rate (17.6% vs. 18.2%), and in hospitalizations for cardiac causes.50 The recent STS–TVT Registry confirms that typical TAVI patients are highly symptomatic, frail elderly with multiple co-morbidities, a high STS predicted risk of mortality (STS PROM) score, advanced functional class, and a poor health status. From 2012 to 2014, in-hospital mortality decreased from 5.3% to 4.4%, vascular complications from 5.6% to 4.2%, while stroke rates remained stable at 2.2%.51 In this Registry, ∼16% of patients were aged >90 years. Although 30-day and 1-year mortality rates were statistically higher compared with younger patients, the absolute and relative differences were clinically modest. TAVI also improved QOL to the same degree in nonagenarians as in younger patients.52 Results of transcatheter aortic valve implantation in low-intermediate risk patients NOTION study randomized low-risk patients >70 years to SAVR or TAVI (STS score 2.9% vs. 3.1%.53 At 1 year, the primary endpoint (death, stroke, or myocardial infarction) showed no significant differences. Patients undergoing surgery had a better functional outcome and those who underwent TAVI had a significantly higher incidence of moderate or severe peri- or intraprosthetic regurgitation (15.7% vs, 0.9%, P <0.001).53

year, the primary endpoint (death, stroke, or myocardial infarction) showed no significant differences. Patients undergoing surgery had a better functional outcome and those who underwent TAVI had a significantly higher incidence of moderate or severe peri- or intraprosthetic regurgitation (15.7% vs, 0.9%, P <0.001).53 In PARTNER 2 study,54 patients at intermediate risk (mean STS score 5.8%, mean age 81.6 years) randomized to TAVI with self-expandable SAPIEN XT prosthesis and SAVR. There was no significant difference in the primary endpoint of death from any cause or disabling stroke at 2 years between the two groups. Another randomized trial, SURTAVI, designed to evaluate the safety and efficacy of TAVI in intermediate surgical risk patients, will evaluate 2500 patients with STS score between 4 and 10. The primary endpoint is composed of mortality and disabling stroke at 24 months. Patients will be followed for 5 years (www.clinicaltrials.gov). Procedural complications of transcatheter aortic valve implantation Mortality is strongly conditioned by periprocedural complications, represented by stroke (1–5%), pacemaker implantation (7–40%), and vascular complications (up to 20%).55–57 The improvement of the femoral approach techniques has resulted in a reduction in major bleeding.56 In a recent meta-analysis57 of randomized trials and observational studies, the incidence of stroke was 2.9%, regardless the prosthesis used. That effect was not, however, different than in patients treated with SAVR.47

The improvement of the femoral approach techniques has resulted in a reduction in major bleeding.56 In a recent meta-analysis57 of randomized trials and observational studies, the incidence of stroke was 2.9%, regardless the prosthesis used. That effect was not, however, different than in patients treated with SAVR.47 The main Achilles heel of TAVI compared with SAVR is represented by periprosthetic leak, that, if moderate to severe, is one of the major predictors of mortality.14,39,57–59 Numerous studies have shown that, for this complication, results are in favour of surgery.59 In the recent PARTNER 2, the incidence and severity of paravalvular regurgitation after TAVI were more frequent compared with SAVR, and TAVI patients with moderate-to-severe paravalvular regurgitation at 30 days had a higher mortality at 2 years than those without or with mild regurgitation.53 Proper sizing of the annulus, a better understanding of the procedure and optimization of the immediate result, may lead to a gradual reduction in incidence of this complication. In the subgroup of inoperable, symptomatic patients at excessive risk for TAVI, valvuloplasty balloon can be a procedure of choice or bridge for further treatment.60 In this context, valvuloplasty could also be used to verify whether the patient’s frailty is related to valvular disease or not.

The main Achilles heel of TAVI compared with SAVR is represented by periprosthetic leak, that, if moderate to severe, is one of the major predictors of mortality.14,39,57–59 Numerous studies have shown that, for this complication, results are in favour of surgery.59 In the recent PARTNER 2, the incidence and severity of paravalvular regurgitation after TAVI were more frequent compared with SAVR, and TAVI patients with moderate-to-severe paravalvular regurgitation at 30 days had a higher mortality at 2 years than those without or with mild regurgitation.53 Proper sizing of the annulus, a better understanding of the procedure and optimization of the immediate result, may lead to a gradual reduction in incidence of this complication. In the subgroup of inoperable, symptomatic patients at excessive risk for TAVI, valvuloplasty balloon can be a procedure of choice or bridge for further treatment.60 In this context, valvuloplasty could also be used to verify whether the patient’s frailty is related to valvular disease or not. Clinical risk assessment Clinical and imaging parameters Risk stratification has assumed a key role in patient selection and recent guidelines from the European Society of Cardiology have stressed the importance of a multidisciplinary ‘Heart Team’ approach to help determine this risk.42 Appropriate selection is critical for the success of aortic procedures and must take into consideration several clinical and anatomical factors, also in asymptomatic patients, in which treatment remains controversial.61–64 Even patients with mild-to-moderate asymptomatic AS have an excess of mortality and cardiovascular events than the general population.65 Many parameters have been shown to have an important role in predicting adverse events and therefore considered useful for the prognostic stratification.

educed area (AS with low flow and low gradient). In doubtful cases, low-dose dobutamine stress and anatomical evaluation using planimetric transoesophageal echocardiography (TEE) (preferably with three-dimensional reconstruction) can help differentiate a true AS by a pseudo-stenosis and to assess contractile reserve.85 The evaluation of the anatomic suitability for revalving procedure includes the study of the vascular iliofemoral axis accessibility and of the aortic valve. Multilayer CT is the method of choice for assessing the size of the vessel, inner diameter, tortuosity, degree and extent of calcification, presence of high risk of dissection of complex plaques. This information is required to express an opinion on the possibility of introducing and advancing the guides and catheters and to assess the risk of any vascular complications. In the case of apical access, TTE verify the absence of apical aneurysm with thrombosis that represents a contraindication to this approach.

t remains controversial.61–64 Even patients with mild-to-moderate asymptomatic AS have an excess of mortality and cardiovascular events than the general population.65 Many parameters have been shown to have an important role in predicting adverse events and therefore considered useful for the prognostic stratification. The echocardiographic parameters include speed of the transvalvular jet,65 average and maximum transvalvular gradients, changes of these parameters over time,66 degree of valve calcification, left ventricular hypertrophy, and excess mass compared with the predicted values (inappropriate mass)67 and increased left atrial systolic force. Main clinical parameters include coexistence of coronary artery disease, advanced age,66 diabetes mellitus,67 increased body mass index,68 worse functional capacity, cigarette smoking, and high arterial blood pressure.4 Finally, biological parameters include increased serum levels of brain-type natriuretic peptide measured at baseline conditions and/or C-reactive protein.4,69 A system to further improve the prognostic stratification of AS patients may also consist in the use of indexes alternative to the classical method of the equation of continuity, such as energy loss index,70 stroke work loss,71 and valvuloarterial impedance.72 A correct stratification must also include a quantification of aortic valve calcifications.

prognostic stratification of AS patients may also consist in the use of indexes alternative to the classical method of the equation of continuity, such as energy loss index,70 stroke work loss,71 and valvuloarterial impedance.72 A correct stratification must also include a quantification of aortic valve calcifications. The assessment of systolic function and left ventricle (LV) geometry plays an important role in stratifying a patient’s prognosis. Ejection fraction remains normal for a long time even in the presence of a high chronic pressure overload, while myocardial contractility is reduced significantly.73–75 A reduced midwall shortening has been associated with the onset of symptoms and a worse prognosis.76 The use of recent technologies such as speckle tracking enables to analyse the reduced longitudinal myocardial deformation that identify the AS patients with the greatest risk to transit from the compensatory phase to the pathological remodelling77 and worst prognosis after valve replacement.78 In addition to subclinical deterioration of systolic function parameters, also the changes in LV geometry and hypertrophy are able prognosticators of poor outcome. The presence of an LV mass in excess with respect to the aforementioned theoretical values in the individual patient (inappropriate mass) identifies a subgroup of subjects at higher risk compared with subjects having the same degree of AS but appropriate LV mass.73 An intrinsic myocardial dysfunction in the presence of preserved ejection fraction and severe low flow/low gradient is of clinical and prognostic significance.77–79

atient (inappropriate mass) identifies a subgroup of subjects at higher risk compared with subjects having the same degree of AS but appropriate LV mass.73 An intrinsic myocardial dysfunction in the presence of preserved ejection fraction and severe low flow/low gradient is of clinical and prognostic significance.77–79 Clinical and echocardiographic prognostic scores A useful method for more accurate risk stratification in patients with AS is based on multiparametric scores.69,80,81 Monin et al.69 first proposed a score based on three variables: female sex, the maximum speed of the transvalvular aortic jet, and baseline BNP. The SEAS score,80 validated in mild-to-moderate AS, is based on seven parameters: age, sex, smoking, heart rate, serum bilirubin, serum levels of C-reactive protein, and LV mass. The ‘CAIMAN–ECHO score’,81 validated in moderate-to-severe AS, is based on three echocardiographic parameters: aortic valve calcium score assessed with conventional transthoracic echocardiography (TTE), maximum speed of transvalvular aortic flow, and inappropriate mass, measured as the ratio of measured and predicted mass. Role of imaging in patient selection before transcatheter aortic valve implantation or surgical aortic valve replacement

Clinical and echocardiographic prognostic scores A useful method for more accurate risk stratification in patients with AS is based on multiparametric scores.69,80,81 Monin et al.69 first proposed a score based on three variables: female sex, the maximum speed of the transvalvular aortic jet, and baseline BNP. The SEAS score,80 validated in mild-to-moderate AS, is based on seven parameters: age, sex, smoking, heart rate, serum bilirubin, serum levels of C-reactive protein, and LV mass. The ‘CAIMAN–ECHO score’,81 validated in moderate-to-severe AS, is based on three echocardiographic parameters: aortic valve calcium score assessed with conventional transthoracic echocardiography (TTE), maximum speed of transvalvular aortic flow, and inappropriate mass, measured as the ratio of measured and predicted mass. Role of imaging in patient selection before transcatheter aortic valve implantation or surgical aortic valve replacement Multimodality imaging plays an essential role in patient selection and procedural planning, performance, and follow-up. In each of these steps, optimal imaging can help to enhance successful outcome. Non-invasive imaging methods used for the selection of patients for TAVI are echocardiography,82 computed tomography (CT), and, less frequently, nuclear magnetic resonance.16,61 There is variability in the preferred imaging protocols in individual institutions, as a result of institutional and individual experience and equipment, and patient characteristics. The aim of the imaging is to: (i) confirm the severity of aortic stenosis; (ii) evaluate the anatomical suitability of revalving procedure and vascular accesses; and (iii) evaluate associated cardiovascular diseases.

ons, as a result of institutional and individual experience and equipment, and patient characteristics. The aim of the imaging is to: (i) confirm the severity of aortic stenosis; (ii) evaluate the anatomical suitability of revalving procedure and vascular accesses; and (iii) evaluate associated cardiovascular diseases. Baseline TTE is usually adequate to confirm severity based on ACC/AHA/ESC criteria.61,83,84 A rigorous methodology that takes into account the possible technical difficulties and sources of error is however necessary. In the elderly people, the frequent coexistence of LV dysfunction can cause a discrepancy between low gradients and reduced area (AS with low flow and low gradient). In doubtful cases, low-dose dobutamine stress and anatomical evaluation using planimetric transoesophageal echocardiography (TEE) (preferably with three-dimensional reconstruction) can help differentiate a true AS by a pseudo-stenosis and to assess contractile reserve.85

. This information is required to express an opinion on the possibility of introducing and advancing the guides and catheters and to assess the risk of any vascular complications. In the case of apical access, TTE verify the absence of apical aneurysm with thrombosis that represents a contraindication to this approach. The anatomy of aortic cusps must have certain characteristics that make it suitable for the proper anchoring of the bioprosthesis.84 The bicuspid valve86 is a relative contraindication to TAVI for the risk of spontaneous aortic dissection or of an incorrect opening of the bioprosthesis due to the elliptical orifice. A mildly calcified aortic valve is also a contraindication to TAVI.87 CT is the method of choice for the study of quantification and distribution of calcifications. Particular attention should be paid in the study of asymmetric distribution that could prevent perfect adhesion of the bioprosthesis and increase the risk of compressing the coronary ostia. The TTE and even more TEE can be used for the study of the number of cusps, their mobility, thickness, and calcification. The aortic rings are four (virtual basal ring, ventricular–arterial ring, crown-like ring, sino-tubular ring).88 The correct aortic valve size ring is crucial to choose the size of the prosthesis89 and prevent complications related to an inadequate size prosthesis implant. The measurement of virtual basal ring, corresponding to the implant of the cusps (nadir) is used for the implantation of the bioprosthesis, rather than the ventricular–arterial ring (located more distally within the aortic root). Multi-slice CT is the method currently considered as the gold standard. The extent of the area of the virtual basal ring, rather than the diameters or the perimeter, is used in many centres to choose the size of the prosthesis.90 Three-dimensional TEE, by multiplanar reconstruction of the rings, is a reliable alternative to CT.91 An outflow tract deformed by the hypertrophied septum similar to that of hypertrophic cardiomyopathy is a contraindication to TAVI.

ters or the perimeter, is used in many centres to choose the size of the prosthesis.90 Three-dimensional TEE, by multiplanar reconstruction of the rings, is a reliable alternative to CT.91 An outflow tract deformed by the hypertrophied septum similar to that of hypertrophic cardiomyopathy is a contraindication to TAVI. Aortic valve calcifications extending to the outflow tract are associated with a high risk of breaking the ring in case of a balloon-expandable bioprosthesis implant.92 The sigmoid septum, with a very acute angle between outflow and aortic vessel, can make the implantation of a self-expandable bioprosthesis and therefore prefer implantation of a balloon-expandable bioprosthesis difficult.93 A suitable distance between the aortic ring and coronary ostia is required, because compression of calcific aortic valve, during implantation of a balloon-expandable bioprosthesis can occlude the coronary ostium. The distance of the coronary ostia does not affect the self-expandable type. Computed tomography is the method of choice for this measure.94 A dilated ascending aorta is a relative contraindication to the system of self-expandable bioprosthesis, because the upper portion is positioned in the ascending aorta to direct the flow from the valve. Computed tomography and TTE or TEE provide equivalent information.

Aortic valve calcifications extending to the outflow tract are associated with a high risk of breaking the ring in case of a balloon-expandable bioprosthesis implant.92 The sigmoid septum, with a very acute angle between outflow and aortic vessel, can make the implantation of a self-expandable bioprosthesis and therefore prefer implantation of a balloon-expandable bioprosthesis difficult.93 A suitable distance between the aortic ring and coronary ostia is required, because compression of calcific aortic valve, during implantation of a balloon-expandable bioprosthesis can occlude the coronary ostium. The distance of the coronary ostia does not affect the self-expandable type. Computed tomography is the method of choice for this measure.94 A dilated ascending aorta is a relative contraindication to the system of self-expandable bioprosthesis, because the upper portion is positioned in the ascending aorta to direct the flow from the valve. Computed tomography and TTE or TEE provide equivalent information. Left ventricular dysfunction is not a contraindication to TAVI also in view of the improvement observed in many patients undergoing this procedure. The TTE is the method of choice for evaluation of left ventricular function. Mitral regurgitation may be secondary to LV dysfunction or annulus dilation due to atriomegalia/atrial fibrillation, or recognize an organic cause, most frequently the annulus calcification and more rarely a myxoid degeneration or fibroelastica deficiency. The TTE/TEE are the methods of choice for the anatomical and functional assessment of mitral regurgitation.95,96Severe pulmonary hypertension and right ventricular dysfunction represent a contraindication for TAVI. The TTE/TEE are the methods of choice for the study of this associated pathology.

broelastica deficiency. The TTE/TEE are the methods of choice for the anatomical and functional assessment of mitral regurgitation.95,96Severe pulmonary hypertension and right ventricular dysfunction represent a contraindication for TAVI. The TTE/TEE are the methods of choice for the study of this associated pathology. Conventional and new pre-procedural risk scores Surgical risk stratification requires objective and reliable methods. Of the many risk scores published over the years, those most frequently used for the estimation of short-term mortality risk in adult cardiac surgery are basically three: the EuroSCORE II (online calculator http://www.euroscore.org/calc.html),97 the STS score (online calculator http://riskcalc.sts.org/stswebriskcalc/#/calculate version 2.81),98 and the ACEF score.99 While the EuroSCORE II and ACEF are models applicable for the estimation of the risk of both coronary artery bypass surgery to valvular procedures or combined interventions, STS score offer separate models for isolated valve surgery98 or in combination with myocardial revascularization. The use of these risk scores is recommended by the European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS)42 and the American Heart Association/American College of Cardiology (AHA/ACC)2 guidelines.

dels for isolated valve surgery98 or in combination with myocardial revascularization. The use of these risk scores is recommended by the European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS)42 and the American Heart Association/American College of Cardiology (AHA/ACC)2 guidelines. The EuroSCORE was developed over 15 years ago, mainly in candidates for bypass coronary artery, while only one-third of patients were candidate for valve surgery.100 Considering the year of publication, the EuroSCORE I is defined ‘out of date’ by the authors and should not be used in favour of the updated version, the EuroSCORE II in which some new variables have been introduced while others have been modified.97 The STS risk score, unlike the EuroSCORE, was developed to identify the risk of death or perioperative complications, taking into consideration the specific type of intervention, coronary surgery, mitral, aortic, or combined.

roSCORE II in which some new variables have been introduced while others have been modified.97 The STS risk score, unlike the EuroSCORE, was developed to identify the risk of death or perioperative complications, taking into consideration the specific type of intervention, coronary surgery, mitral, aortic, or combined. The main features of a risk score are the power of discrimination—the ability to differentiate between low- and high-risk patients101—and calibration—the ratio between observed and predicted mortality. Table 2 shows the characteristics of EuroSCORE, EuroSCORE II and STS score. A difference between these scores is that the calculation algorithms for EuroSCORE (I and II) and ACEF score are freely available but not periodically updated to the progressive change of patient’s clinical characteristics, while the algorithms of the STS risk scores are not freely available, but are regularly updated on the basis of the STS database. In SAVR, the performance of these algorithms is satisfactory for predicting the risk of category (high or low risk), with areas under the receiver-operating characteristics (ROC) curve ranging between 0.7 (fair discrimination) and 0.8 (good discrimination), even in octogenarians.102–105 These models tend to show more performance problems in calibration, in particular in the assessment of patients usually defined as ‘high’ and ‘very high’ risk.103 In high-risk patients, EuroSCORE, EuroSCORE II, and ACEF overestimate mortality, while STS score tends to underestimate the risk. With regard to the medium- and long-term mortality, these scores show little satisfactory performances both in discrimination (AUC between 0.6 and 0.7) and in calibration.106,107Table 2 Comparison of EuroSCORE, EuroSCORE II, and STS score (modified from Nashef et al.97 and O’Brien et al.98)

s to underestimate the risk. With regard to the medium- and long-term mortality, these scores show little satisfactory performances both in discrimination (AUC between 0.6 and 0.7) and in calibration.106,107Table 2 Comparison of EuroSCORE, EuroSCORE II, and STS score (modified from Nashef et al.97 and O’Brien et al.98) EuroSCORE EuroSCORE II STS score Outcome In-hospital mortality 30-day Mortality Mortalitày and post-operative complications Surgery Mainly CABG Not specific Specific for surgery High risk threshold >20% >7% >10% Discrimination: ability to differentiate between low and high-risk patients (assessed using the ‘under the ROC curve area’ or the c-index) AUC for valvular surgery = 0.72; AUC = 0.81 AUC Acceptable Acceptable For lone valvular surgery = 0.80 For valvular surgery + CABG = 0.75 Acceptable Calibration: report predicted/observed mortality Greatly overestimated mortality in all categories of risk, especially in the high-risk group: suboptimal. Documented calibration loss in time because of the update to EuroSCORE II I Low-risk group calibration: good Low-risk group calibration: good Overestimated mortality in high-risk group: suboptimal Underestimated mortality in high-risk group: suboptimal Discrimination in TAVI Not acceptable Not acceptable Not acceptable Calibration in TAVI Not acceptable Not acceptable Not acceptable TAVI, transcatheter aortic valve implantation.

-risk group calibration: good Overestimated mortality in high-risk group: suboptimal Underestimated mortality in high-risk group: suboptimal Discrimination in TAVI Not acceptable Not acceptable Not acceptable Calibration in TAVI Not acceptable Not acceptable Not acceptable TAVI, transcatheter aortic valve implantation. Several studies have recently addressed the issue of the applicability of these risk scores to TAVI candidates. Overall, the acceptable discrimination allows to estimate with good approximation risk category, but poor calibration performance prevents from using these scores to estimate the individual operative mortality, especially in the high-risk category.108 In several studies, an average area under the curve around 0.6–0.7 was observed,104,109 a lower performance that could be obtained with surgery. EuroSCORE II and STS score performance was assessed in a meta-analysis of patients undergoing SAVR or TAVI. In the SAVR group, the difference between observed and expected mortality was not statistically significant with EuroSCORE II, while for the STS score the relationship was closer to 1. On the contrary, both the EuroSCORE II and the STS score have underestimated the risk of death in patients undergoing TAVI, confirming problems with calibration of these scores in this procedure.110

mortality was not statistically significant with EuroSCORE II, while for the STS score the relationship was closer to 1. On the contrary, both the EuroSCORE II and the STS score have underestimated the risk of death in patients undergoing TAVI, confirming problems with calibration of these scores in this procedure.110 The proportion of patients considered at high surgical risk on the basis of a single score (EuroSCORE II >7%, logistic EuroSCORE >20% and STS score >10%) and the correlation between scores were assessed in patients considered at high surgical risk based on a multiparameter stratification and candidates for TAVI. About half of the patients did not reach the value of high-risk threshold on the basis of the only score. The correlation between logistic EuroSCORE, EuroSCORE II, and STS was modest.111 A recent analysis of the PARTNER trial suggests that performances for prediction of mortality with STS score and the logistic EurSCORE are even less satisfactory (AUCs ≤0.6) for both SAVR and TAVI in very elderly patients.112 In summary, traditional risk scores seem to be inadequate as the only way to identify older patients with severe symptomatic AS at high risk and candidates for TAVI. There is a need to develop and validate specific score for this population. An Italian multicentre study enrolling patients undergoing TAVI identified a previous stroke, creatinine clearance, and pulmonary hypertension as independent predictors of death at 1 year and calculated a score that showed a better performance than the STS score.113

In summary, traditional risk scores seem to be inadequate as the only way to identify older patients with severe symptomatic AS at high risk and candidates for TAVI. There is a need to develop and validate specific score for this population. An Italian multicentre study enrolling patients undergoing TAVI identified a previous stroke, creatinine clearance, and pulmonary hypertension as independent predictors of death at 1 year and calculated a score that showed a better performance than the STS score.113 The TAVI2 score has been developed in a study of patients thought to be at high or prohibitive surgical risk.114 Variables independently associated with mortality at 1 year include: porcelain aorta, anaemia, low ejection fraction, recent myocardial infarction, male gender, mean aortic gradient >70 mmHg, age >85 years, creatinine clearance <30 mL/min. For each variable, a score was assigned and the sum identified the predicted risk of death at 1 year. The TAVI2 score showed improved power of discrimination and calibration compared with logistic EuroSCORE, EuroSCORE II, and the STS score.114 The OBSERVANT study (Efficacy And Effectiveness of AVR-TAVI Procedures For the Treatment Of Symptomatic Severe Aortic Stenosis) has proposed another 30 days death risk score in patients undergoing TAVI.115 Seven independent variables related to the risk of death at 30 days were identified and integrated into a risk score.

OBSERVANT study (Efficacy And Effectiveness of AVR-TAVI Procedures For the Treatment Of Symptomatic Severe Aortic Stenosis) has proposed another 30 days death risk score in patients undergoing TAVI.115 Seven independent variables related to the risk of death at 30 days were identified and integrated into a risk score. Multidimensional assessment In recent years, the availability of new techniques has extended to an older and frail population effective AS treatments, however, currently used risk scores do not seem to be adequate in these patients.34,116–119 Therefore, it seems necessary to include other variables—i.e. co-morbidities and geriatric conditions—to improve risk stratification and compare the results of the procedures. Functional status is a multidimensional variable and also includes the ability of an individual to carry out daily activities within all functional domains. An overall assessment of functional status often requires multiple validated instruments, but on the other hand, a too complex battery may be little applicable and useful in clinical settings. The major open issues are the uncertainty of an operational definition of ‘frailty’ and what measurement tools to validate and use. However, there is no doubt that cardiac risk assessment of elderly people with heart disease should be performed, taking into account two fundamental points: (i) the instrument is valid, reproducible, and easy to use and (ii) is able to further stratify perioperative risk.

nd what measurement tools to validate and use. However, there is no doubt that cardiac risk assessment of elderly people with heart disease should be performed, taking into account two fundamental points: (i) the instrument is valid, reproducible, and easy to use and (ii) is able to further stratify perioperative risk. The European Valve Academic Research Consortium (VARC)120 described the importance of measuring clinical benefits such as functional status, but acknowledged the uncertainty that accompanied the choice of various measuring instruments and the overall lack of standardization.121 The Canadian Cardiovascular Society has also encouraged the use of an ‘objective assessment of function and neuro-cognitive Frailty’ to evaluate candidates for TAVI.122 Without providing an operational definition, the American Heart Association (AHA) recommended to include a functional assessment in the selection of elderly TAVI candidates.16

lar Society has also encouraged the use of an ‘objective assessment of function and neuro-cognitive Frailty’ to evaluate candidates for TAVI.122 Without providing an operational definition, the American Heart Association (AHA) recommended to include a functional assessment in the selection of elderly TAVI candidates.16 Different tools have been proposed to identify frailty.26,123,124 The frailtyindex26,123 includes five easily detectable characteristics: muscle strength (handgrip), gait speed, weight loss, exhaustion, and level of activity. The subject that has no deficiency in any item is considered ‘robust’, ‘pre–frail’ if it has a deficit in one or two, ‘frail’ if it is positive in three or more of the items.26 The predictive value of frailty is independent of co-morbidities and clinical disability. The identification of frailty in the elderly people should not be made only for prognosis but should lead to ‘pre-rehabilitation’ interventions125 that have proven effective in the prevention of functional decline and mortality. It is still debated whether disability and cognitive impairment should be considered frailty domains or just modulating factors that catalyse the transition from frailty to manifest disability.126

Different tools have been proposed to identify frailty.26,123,124 The frailtyindex26,123 includes five easily detectable characteristics: muscle strength (handgrip), gait speed, weight loss, exhaustion, and level of activity. The subject that has no deficiency in any item is considered ‘robust’, ‘pre–frail’ if it has a deficit in one or two, ‘frail’ if it is positive in three or more of the items.26 The predictive value of frailty is independent of co-morbidities and clinical disability. The identification of frailty in the elderly people should not be made only for prognosis but should lead to ‘pre-rehabilitation’ interventions125 that have proven effective in the prevention of functional decline and mortality. It is still debated whether disability and cognitive impairment should be considered frailty domains or just modulating factors that catalyse the transition from frailty to manifest disability.126 The clinical evaluation of frailty as accumulation of deficits requires the evaluation of up to 70 symptoms, signs, morbidities, disability, and frailty, and for this reason, a simplified version was developed.127 However, disability, generally defined as difficulty or dependency in ADL or IADL, should be distinguished from frailty. Disability is more accurately conceptualized as a negative outcome associated with frailty or as an entirely separate entity. The International Academy Nutrition and Aging Frailty Task Force128 prefers the functional approach, stating that co-morbidity and disability must be separated from frailty.

uished from frailty. Disability is more accurately conceptualized as a negative outcome associated with frailty or as an entirely separate entity. The International Academy Nutrition and Aging Frailty Task Force128 prefers the functional approach, stating that co-morbidity and disability must be separated from frailty. A simple means for identification of frailty is the Short Physical Performance Battery (SPPB), which consists of three items129: reduced gait speed, weakness in standing up from a chair, and reduced balance in three positions. A score from 0 to 4 is assigned to each item, where a total score >5 of 12 indicates the presence of frailty. The SPPB predicts the risk of disability and death in the elderly general population130 and with heart failure.131 As an alternative to these composite scores, individual variables such as gait speed on 4–5 m distance and handgrip force have been proposed as a single valid, simple, and reliable marker of frailty.132,133 Several instruments and measures to assess the various components of functional status, QOL, disability, cognitive impairment, and various measures of frailty have been considered in pre-operative evaluation before TAVI.116–118 In PARTNER study,134 TAVI resulted in significant improvement in NYHA Class and QOL, without reporting results on disability.

Several instruments and measures to assess the various components of functional status, QOL, disability, cognitive impairment, and various measures of frailty have been considered in pre-operative evaluation before TAVI.116–118 In PARTNER study,134 TAVI resulted in significant improvement in NYHA Class and QOL, without reporting results on disability. Another study reported that elderly patients undergoing TAVI were significantly more likely to develop clinically significant cognitive decline than those who underwent SAVR, but it is difficult to determine whether the results can be attributed to old age, reduced level of education, co-morbidity, or to the different treatment.135 Therefore, recent studies have focused their interest on the concept of frailty and its importance in risk stratification before SAVR or TAVI. Afilalo et al.31 have shown in elderly patients undergoing coronary and valvular surgery that a low gait speed on 5 m identified a subpopulation at high-risk mortality and morbidity. The speed of <0.83 m/s was chosen as the optimal threshold based on ROC curves. Importantly, gait speed had an incremental value when combined with the STS score in predicting incidence of mortality/morbidity. There was tendency towards interaction for female patients and those undergoing SAVR, both of which had a much higher relative risk in the presence of frailty.

threshold based on ROC curves. Importantly, gait speed had an incremental value when combined with the STS score in predicting incidence of mortality/morbidity. There was tendency towards interaction for female patients and those undergoing SAVR, both of which had a much higher relative risk in the presence of frailty. Lee et al.136 and Sündermann et al.137,138 have demonstrated that pre-operative frailty is associated with post-operative 30-day and long-term mortality. These two studies differed in frailty scales used and in the results. Lee et al.,136 defined frailty as a dependency in walking, disability in ADLs, or dementia, a definition that includes more a concept of disability than frailty. Sündermann et al.137,138 defined frailty as an aggregate of 35 criteria reporting a prevalence of 50%. In another study, Afilalo et al.32 observed a prevalence of 46% and 20% of frailty, using respectively, gait speed and Fried index, and a 5% prevalence of ADL disability; the measurement of gait speed alone was superior to the other scales in predicting outcomes.

Lee et al.136 and Sündermann et al.137,138 have demonstrated that pre-operative frailty is associated with post-operative 30-day and long-term mortality. These two studies differed in frailty scales used and in the results. Lee et al.,136 defined frailty as a dependency in walking, disability in ADLs, or dementia, a definition that includes more a concept of disability than frailty. Sündermann et al.137,138 defined frailty as an aggregate of 35 criteria reporting a prevalence of 50%. In another study, Afilalo et al.32 observed a prevalence of 46% and 20% of frailty, using respectively, gait speed and Fried index, and a 5% prevalence of ADL disability; the measurement of gait speed alone was superior to the other scales in predicting outcomes. Some studies have been conducted specifically on patients undergoing TAVI. Ewe et al.140 found that one-third of patients undergoing TAVI were frail according to Fried index and that frailty was among the most powerful predictors of death, myocardial infarction, stroke, or heart failure at 9 months. Frailty was not a significant predictor of outcome if defined only according to subjective judgement of the physician in the study by Rodés-Cabau et al. 39 Green et al.33 observed that frailty was predictive of 1-year mortality, but not at 30 days. There was a trend towards increased risk for major bleeding, vascular complications, and length of stay in frail patients. A gait speed of 0.50 m/s was selected as the optimal threshold, slower than the 0.65–0.85 m/s reported in other settings. The authors observed that >80% of their patients would be considered frail if they had used the traditional cut-off values. Only 19%–35% of patients were able to complete the gait speed test. This significant percentage of non-walkers, larger than usually reported for other cohorts, may reflect the heavy burden of morbidity and disability in patients undergoing TAVI. The impossibility to complete gait speed test was an indicator of advanced frailty or ADL disability.

re able to complete the gait speed test. This significant percentage of non-walkers, larger than usually reported for other cohorts, may reflect the heavy burden of morbidity and disability in patients undergoing TAVI. The impossibility to complete gait speed test was an indicator of advanced frailty or ADL disability. In another study,34,139 where the vast majority of patients were able to complete the timed-up-and-go (TUG) test (which requires getting up from a chair and walk 3 m), 61% were able to do it in faster than 20 s. The frailty composite index used included TUG test, limitation of mobility, BADL and IADL disability, cognitive impairment, and nutritional assessment. Frailty was predictive of a three- to four-fold increase of functional decline in BADL at 6 months and higher incidence of cardiac and cerebral adverse events at 1 year. A trend for frailty and mortality was observed, which was stronger at 30 days compared with 1 year, although the number of events was small. In all these studies, the overall approach to the evaluation of frailty aimed at predicting morbidity and mortality following TAVI involved the use of multidimensional assessment tools, including cognitive function, gait, nutritional status, and activities of daily living.34,139

In another study,34,139 where the vast majority of patients were able to complete the timed-up-and-go (TUG) test (which requires getting up from a chair and walk 3 m), 61% were able to do it in faster than 20 s. The frailty composite index used included TUG test, limitation of mobility, BADL and IADL disability, cognitive impairment, and nutritional assessment. Frailty was predictive of a three- to four-fold increase of functional decline in BADL at 6 months and higher incidence of cardiac and cerebral adverse events at 1 year. A trend for frailty and mortality was observed, which was stronger at 30 days compared with 1 year, although the number of events was small. In all these studies, the overall approach to the evaluation of frailty aimed at predicting morbidity and mortality following TAVI involved the use of multidimensional assessment tools, including cognitive function, gait, nutritional status, and activities of daily living.34,139 The presence of disability is uncommon in the cardiac surgery population, partly because disabled patients are less likely to be considered for surgery. Therefore, the scales of disability for basic ADL are relatively insensitive to screen elderly patients in this context. Higher level disability scales such as the Nagi Scale145 are more sensitive and better predict outcomes. An interaction between frailty and disability was still observed, with the prognostic weight of frailty which decreases progressively in patients with more advanced stages of disability.32

patients in this context. Higher level disability scales such as the Nagi Scale145 are more sensitive and better predict outcomes. An interaction between frailty and disability was still observed, with the prognostic weight of frailty which decreases progressively in patients with more advanced stages of disability.32 An attempt to combine clinical risk scores and geriatric evaluation is reported in recent guidelines,16 where frailty indices proposed include gait speed and disability indicators such as those that contribute to the ADL score (Table 1). Frailty is summarily stratified as follows: not frail (able to carry out all ADL and to walk 5 m in <6 s), pre-frail (unable to perform one ADL or to walk 5 m >6 s), and moderately–severely frail (unable to perform >2 ADL). In addition to this risk classification, it would be appropriate to defer any kind of intervention in patients with reduced life expectancy. In summary, it is not yet clear whether the standard of frailty assessment tools (frailty index) or surrogate measures, such as single physical performance test (gait speed, SPPB, and handgrip) are sufficiently valid if used alone, or if these measures should be combined with disability (inability to walk, low albumin, and ADL disability), a cognitive and nutritional screening or psychoemotional state to better discriminate the risk.126

such as single physical performance test (gait speed, SPPB, and handgrip) are sufficiently valid if used alone, or if these measures should be combined with disability (inability to walk, low albumin, and ADL disability), a cognitive and nutritional screening or psychoemotional state to better discriminate the risk.126 In clinical practice, the feasibility of variables and speed of execution are fundamental as much as the reliability of the instruments themselves. Future studies should aim to develop more reliable and reproducible ways to identify frailty and validate its use to estimate risk and expected benefits. Recent studies incorporate measures of frailty such as CoreValve,53 and Partner II.118 FRAILTY-AVR (NCT01845207) compared different frailty instruments to determine which is more predictive in high-risk patients with AS undergoing TAVI and SAVR.142 A European register (European CGA-TAVI registry) has been scheduled for the same purpose.143

orate measures of frailty such as CoreValve,53 and Partner II.118 FRAILTY-AVR (NCT01845207) compared different frailty instruments to determine which is more predictive in high-risk patients with AS undergoing TAVI and SAVR.142 A European register (European CGA-TAVI registry) has been scheduled for the same purpose.143 Gait speed over 5 m has been added to the STS database. In this database, patients undergoing TAVI were classified in very slow walkers (<0.5 m/s), slow walkers (0.5–0.83 m/s), and normal walkers (>0.83 m/s), and 30-day all-cause mortality rates were 8.4%, 6.6%, and 5,4%, respectively (P <0.001). Each decrease of 0.2 m/s speed corresponded to an increase of 11% in 30-day mortality. Very slow walkers had 35% higher 30-day mortality compared with normal, longer hospital admissions and were less likely to be discharged home.144 Pending further results, it is reasonable to apply a decision algorithm based on an initial screening carried out with a gait speed test, followed by a more thorough multidimensional assessment in patients with indicative results of Frailty (Figure 3).147 Figure 3 Decision-making algorithm for the initial screening of the frailty and the selection of elderly patients with SA. Modified from Lilamand et al.151

Gait speed over 5 m has been added to the STS database. In this database, patients undergoing TAVI were classified in very slow walkers (<0.5 m/s), slow walkers (0.5–0.83 m/s), and normal walkers (>0.83 m/s), and 30-day all-cause mortality rates were 8.4%, 6.6%, and 5,4%, respectively (P <0.001). Each decrease of 0.2 m/s speed corresponded to an increase of 11% in 30-day mortality. Very slow walkers had 35% higher 30-day mortality compared with normal, longer hospital admissions and were less likely to be discharged home.144 Pending further results, it is reasonable to apply a decision algorithm based on an initial screening carried out with a gait speed test, followed by a more thorough multidimensional assessment in patients with indicative results of Frailty (Figure 3).147 Figure 3 Decision-making algorithm for the initial screening of the frailty and the selection of elderly patients with SA. Modified from Lilamand et al.151 Conclusions TAVI enables the treatment of very elderly patients with severe AS considered ineligible for surgery and with an acceptable life expectancy,42 with good results in terms of survival and symptoms. However, many patients still develop complications and die or show no improvement in QOL at follow-up. These issues raise important questions on the need to identify and recognize the possible futility of treatments in some patients approaching the final stages of life, where the clinical condition is too advanced and in which even a technically successful procedure is useless and does not improve health outcomes. Thus, in the decision-making process, it is important to determine: (i) whether and how much frailty affects the risk of the procedures; (ii) whether the QOL and the individual survival are influenced by aortic valve disease alone or from other factors; (iii) whether a geriatric specialist intervention to evaluate and correct co-morbid diseases, frailty, and disabilities can further improve outcomes.

how much frailty affects the risk of the procedures; (ii) whether the QOL and the individual survival are influenced by aortic valve disease alone or from other factors; (iii) whether a geriatric specialist intervention to evaluate and correct co-morbid diseases, frailty, and disabilities can further improve outcomes. Although futility may be invoked to justify the refusal to treat an individual patient, the threshold for the definition of futility itself is still not clear. In inoperable patients, therefore, a clear definition of the conditions that may adversely affect survival and QOL, despite the procedural success is essential to ensure that this therapy is properly used in patients who can benefit or not. These patients should receive targeted medical and palliative care.148 As TAVI patients are usually very elderly, with high risk score, advanced functional class, and frailty,144,51 to assess the expected benefit of TAVI, a number of variables should be considered in addition to the traditional risk scores. The evaluation of patient’s complexity can provide a valuable prognostic contribution and assist cardiologists and cardiac surgeons in the definition of the optimal treatment in the individual patient.17 Moreover, complexity therefore is not a sufficient reason to refuse a certain treatment but rather a means to choose a personalized and more patient-centred care.

vide a valuable prognostic contribution and assist cardiologists and cardiac surgeons in the definition of the optimal treatment in the individual patient.17 Moreover, complexity therefore is not a sufficient reason to refuse a certain treatment but rather a means to choose a personalized and more patient-centred care. At present time, the evaluation of the operative risk is carried out using standard indices that have not been calibrated to intercept all the risk factors of very elderly patients and do not estimate frailty with specific parameters. An attempt is reported in the recent guidelines,2 where a combination of frailty (reduced gait speed), disability indicators, and cognitive deficit are proposed. Probably the combination of traditional risk scores such as EuroSCORE II and STS score with indices of frailty and co-morbidity could better refine the assessment of the operative risk in SAVR, while specific risk scores should be used in TAVI.

ced gait speed), disability indicators, and cognitive deficit are proposed. Probably the combination of traditional risk scores such as EuroSCORE II and STS score with indices of frailty and co-morbidity could better refine the assessment of the operative risk in SAVR, while specific risk scores should be used in TAVI. Moreover, because frailty is a physiological phenotype and may be reversible in some cases, it is premature to consider this a permanent feature of the patient. To the extent that AS may contribute to the decline in functional status, SAVR or TAVI may reduce or cancel the amount of frailty which depends on it. In this case, frailty can be a marker to identify the benefit of treatment. Conversely, if the individual is frail due to the decline of multiple organ systems, frailty may be a risk marker. Pre-operative optimization through a multidisciplinary approach with a Heart Team can counteract the multiple damage that can potentially aggravate the reduced physiological reserves characteristic of frailty (Figure 4). Figure 4 Algorithm decision by the multidisciplinary team of patients undergoing TAVI. Modified fromLindman et al.17

Moreover, because frailty is a physiological phenotype and may be reversible in some cases, it is premature to consider this a permanent feature of the patient. To the extent that AS may contribute to the decline in functional status, SAVR or TAVI may reduce or cancel the amount of frailty which depends on it. In this case, frailty can be a marker to identify the benefit of treatment. Conversely, if the individual is frail due to the decline of multiple organ systems, frailty may be a risk marker. Pre-operative optimization through a multidisciplinary approach with a Heart Team can counteract the multiple damage that can potentially aggravate the reduced physiological reserves characteristic of frailty (Figure 4). Figure 4 Algorithm decision by the multidisciplinary team of patients undergoing TAVI. Modified fromLindman et al.17 Finally, ensuring the best appropriateness and cost-effectiveness of care in times of economic restraints is vital for modern health systems.149 Technological progresses in new implants and techniques could lead to a reduction in costs and procedural complications, while the systematic application of a standardized multidimensional assessment150 (Table 3) should improve outcomes. Table 3 Pre-procedure screening recommendations. Modified from ref.150

systems.149 Technological progresses in new implants and techniques could lead to a reduction in costs and procedural complications, while the systematic application of a standardized multidimensional assessment150 (Table 3) should improve outcomes. Table 3 Pre-procedure screening recommendations. Modified from ref.150 Laboratory indices Full blood count, serum urea, creatinine and electrolytes, C-reactive protein, serum transaminases, serum albumin, coagulation profile, blood culture, sputum culture, mid-stream urine, glycosylated haemoglobin, human immunodeficiency virus, and hepatitis serology Physical indices Height, weight, and body mass index Clinical data to calculate logistic EuroSCORE or STS score Detailed clinical history, examination and current medication list, 12-lead electrocardiography, echocardiography (transthoracic/transoesophageal), coronary angiography, peripheral vascular screening (contrast angiography/multidetector computed tomography), pulmonary function testing, and right heart catheterization Clinical parameters of co-morbid conditions Pulmonary function tests, carotid, and vertebral and abdominal ultrasonography Frailty and cognitive functiona Grip strength, graded exercise testing, walk test, physical activity level, and mini-mental score Confirmation of aortic stenosis severity and assessment of associated pathology Echocardiography (transthoracic/transesophageal), exercise stress testing, and stress echocardiography Procedural planning Multidetector computed tomography/transoesophageal echocardiography

t, physical activity level, and mini-mental score Confirmation of aortic stenosis severity and assessment of associated pathology Echocardiography (transthoracic/transesophageal), exercise stress testing, and stress echocardiography Procedural planning Multidetector computed tomography/transoesophageal echocardiography Aortic annulus: dimensions (minimal, maximal, and mean diameter; area; perimeter) and severity/distribution of calcification Other: Height of coronary arteries, sinus of valsalva dimensions, ascending aorta dimensions Iliofemoral vessels: minimal luminal diameter, tortuosity, calcium distribution Aorta: aortic plaque distribution, descending aortic tortuosity, proximal ascending aortic diameter STS, Society of Thoracic Surgeons. aFried frailty index.

Aortic annulus: dimensions (minimal, maximal, and mean diameter; area; perimeter) and severity/distribution of calcification Other: Height of coronary arteries, sinus of valsalva dimensions, ascending aorta dimensions Iliofemoral vessels: minimal luminal diameter, tortuosity, calcium distribution Aorta: aortic plaque distribution, descending aortic tortuosity, proximal ascending aortic diameter STS, Society of Thoracic Surgeons. aFried frailty index. Consensus Document Approval Faculty Abrignani Maurizio Giuseppe, Alunni Gianfranco, Amico Antonio Francesco, Amodeo Vincenzo, Angeli Fabio, Aspromonte Nadia, Battistoni Ilaria, Bianca Innocenzo, Bisceglia Irma, Bongarzoni Amedeo, Cacciavillani Luisa, Calculli Giacinto, Caldarola Pasquale, Capecchi Alessandro, Caretta Giorgio, Carmina Maria Gabriella, Casazza Franco, Casolo Giancarlo, Cassin Matteo, Casu Gavino, Cemin Roberto, Chiarandaà Giacomo, Chiarella Francesco, Chiatto Mario, Cibinel Gian Alfonso, Clerico Aldo, Colivicchi Furio, De Luca Giovanni, De Maria Renata, Di Fusco Stefania Angela, Di Lenarda Andrea, Di Tano Giuseppe, Egman Sabrina, Enea Iolanda, Fattirolli Francesco, Ferraiuolo Giuseppe, Francese Giuseppina Maura, Gabrielli Domenico, Geraci Giovanna, Giardina Achille, Gregorio Giovanni, Iacoviello Massimo, Khoury Georgette, Ledda Antonietta, Luca Fabiana, Lukic Vjerica, Macera Francesca, Marini Marco, Maseri Attilio, Masson Serge, Maurea Nicola, Mazzanti Marco, Mennuni Mauro, Menotti Alberto, Menozzi Alberto, Mininni Nicola, Moreo Antonella, Moretti Luciano, Mortara Andrea, Mureddu Gian Francesco, Nardi Federico, Navazio Alessandro, Nicolosi Gian Luigi, Oliva Fabrizio, Parato Vito Maurizio, Parrini Iris, Pini Daniela, Pirelli Salvatore, Radini Donatella, Rao Carmelo Massimiliano, Rasetti Gerardo, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scherillo Marino, Severi Silva, Sicuro Marco, Sisto Francesco, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino.

rardo, Riccio Carmine, Roncon Loris, Rossini Roberta, Ruggieri Maria Pia, Rugolotto Matteo, Sanna Fabiola, Sauro Rosario, Scherillo Marino, Severi Silva, Sicuro Marco, Sisto Francesco, Tarantini Luigi, Uguccioni Massimo, Urbinati Stefano, Valente Serafina, Vatrano Marco, Vianello Gabriele, Vinci Eugenio, Zuin Guerrino. Conflict of interest: none declared.

Revised by: Mario Chiatto, Maria Frigerio, Aldo Pietro Maggioni, and Mario Plebani Consensus Document Approval Faculty in Appendix Heart failure (HF) is a complex syndrome involving neurohumoral and inflammatory changes of different cell types including cardiac myocytes, fibroblasts, endothelial, and vascular smooth muscle cells. A consequence of the complex pathophysiological substrate of HF is the ever increasing number of circulating molecules (i.e. biomarkers) found/discovered to be altered in patients with HF. Many molecules have been labelled as circulating ‘biomarkers’ in HF. The present document aims at helping the clinician in (i) appropriately using available biomarkers, and (ii) approaching new biomarkers through the literature with a critical attitude. Of all biomarkers reported to provide original information in diagnosis, prognosis, or management of HF, only cardiac troponins I or T and natriuretic peptides are cardio-specific. This explains why the largest body of evidence supporting their clinical use has been collected on these two families of biomarkers. Background The consensus document for Italian clinical cardiologists has been published very recently, where the evidence on the use of troponins and natriuretic peptides in HF are reported in several sections.1

Heart failure (HF) is a complex syndrome involving neurohumoral and inflammatory changes of different cell types including cardiac myocytes, fibroblasts, endothelial, and vascular smooth muscle cells. A consequence of the complex pathophysiological substrate of HF is the ever increasing number of circulating molecules (i.e. biomarkers) found/discovered to be altered in patients with HF. Many molecules have been labelled as circulating ‘biomarkers’ in HF. The present document aims at helping the clinician in (i) appropriately using available biomarkers, and (ii) approaching new biomarkers through the literature with a critical attitude. Of all biomarkers reported to provide original information in diagnosis, prognosis, or management of HF, only cardiac troponins I or T and natriuretic peptides are cardio-specific. This explains why the largest body of evidence supporting their clinical use has been collected on these two families of biomarkers. Background The consensus document for Italian clinical cardiologists has been published very recently, where the evidence on the use of troponins and natriuretic peptides in HF are reported in several sections.1 The present document does not aim at comprehensively reviewing all established and candidate laboratory biomarkers in HF. Other types of biomarkers, such as imaging or genetic biomarkers, will not be discussed in detail, but will be evaluated in comparison with laboratory biomarkers. Unless otherwise specified, ‘biomarkers’ will be used for ‘circulating biomarkers’ or ‘laboratory biomarkers’ throughout the present document.

markers in HF. Other types of biomarkers, such as imaging or genetic biomarkers, will not be discussed in detail, but will be evaluated in comparison with laboratory biomarkers. Unless otherwise specified, ‘biomarkers’ will be used for ‘circulating biomarkers’ or ‘laboratory biomarkers’ throughout the present document. Objectives Aims of the present review are To summarize the evidence supporting the clinical use of cardiac specific biomarkers, the main issue being how to make a good use of these validated markers in specific clinical/ambulatory settings. To provide the interested clinician with concise, essential information on the so-called ‘new biomarkers’ in order to help them in a critical use of the literature. Premises Before dealing with individual biomarkers, grouped by ‘reasonable’ categories, a general agreement on the following two methodological issues should be reached: Assays of the biomarkers; Sample size of studies to assess clinical performance of biomarkers. Analytical issues The contribution of the laboratory to the clinical management of HF by the biomarkers, represents one of the most important breakthroughs of the last decades. Standardization and validation of diagnostic methods, combined with a close link between the laboratory and the clinic improves the confidence of the cardiologist in the use and in a correct interpretation of analytical results on circulating biomarkers.

ents one of the most important breakthroughs of the last decades. Standardization and validation of diagnostic methods, combined with a close link between the laboratory and the clinic improves the confidence of the cardiologist in the use and in a correct interpretation of analytical results on circulating biomarkers. Cardiovascular biomarkers are usually measured with non-competitive immunometric assays in clinical laboratory practice.2 Analytical performance of biomarker laboratory tests has progressively improved in the last 20 years. In particular, the last generation of immunometric assays using automated platforms is able to measure circulating levels of biomarkers [such as B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), cTnI, and cTnT] with a limit of detection (LoD) of few ng/L (from 1 ng/L to 5 ng/L), a limit of quantification (LoQ) ≤ 10 CV% in the range of 5–15 ng/L, and a turn round time (TAT) of less than 30 min.2 These very good analytical performances allowed the use of these biomarkers as favourite methods even in the emergency department. Despite this remarkable increase in analytical performances, these immunoassays still suffer significant systematic differences between the biomarkers values measured by commercially available laboratory tests, especially for BNP2,3 and cTnI4 methods. Accordingly, clinicians should take great care in comparing results obtained by laboratories using different methods.

rformances, these immunoassays still suffer significant systematic differences between the biomarkers values measured by commercially available laboratory tests, especially for BNP2,3 and cTnI4 methods. Accordingly, clinicians should take great care in comparing results obtained by laboratories using different methods. More difficulties are to be expected from point-of-care testing (POCT), whose reliability is, at the present time, not always adequately optimized and evaluated.5 As far as the POCT methods for cardiac troponins are concerned, it is important to consider that the commercial methods so far available, do not satisfy the analytical quality specifications recommended by the international guidelines.6–8 The POCT methods usually measure the recommended upper limit of normal with an error > 20% CV and so they should be used for rule-in and rule-out of myocardial infarction only where (or when) the more sensitive immunoassay methods using automated platforms are not available.8 As far as the POCT methods for the measurement of natriuretic peptides are concerned, these assays are often used in both emergency departments and primary care, although their analytical sensitivity and reproducibility is lower than that of immunoassay methods using automated platforms.9–11

atforms are not available.8 As far as the POCT methods for the measurement of natriuretic peptides are concerned, these assays are often used in both emergency departments and primary care, although their analytical sensitivity and reproducibility is lower than that of immunoassay methods using automated platforms.9–11 Sample size It is common belief that sample size calculations, in order to minimize the risk of false-negative results, are the matter of clinical trials testing drugs. This is definitely wrong, since the same risk is inherent in studies assessing predictive value or associations of risk factors, such as biomarkers. Without an adequate power, say above 60%, the risk of a false negative result is too high to reject the null hypothesis. The same is true for positive results obtained in small samples, too susceptible of bias and play of chance to be translated into clinical practice. An authoritative example of power calculation is provided by an analysis of Framingham on renin. Given the lack of a significant association of renin with cardiovascular risk, the statistical power to detect modest effects was assessed. At an alpha of 0.05, the power was at least 80% for each outcome (hard cardiovascular disease and all-cause mortality), in the full sample and in the hypertensive sub-sample, for the true HR of 1.25 per SD of log-renin.12

on of renin with cardiovascular risk, the statistical power to detect modest effects was assessed. At an alpha of 0.05, the power was at least 80% for each outcome (hard cardiovascular disease and all-cause mortality), in the full sample and in the hypertensive sub-sample, for the true HR of 1.25 per SD of log-renin.12 The data reported in Table 1, considering different combinations of hazard ratios and power, provide an idea on the number of patients needed for a reliable assessment of association between biomarkers and risk. Table 1 Number of patients to be enrolled in studies testing prognostic value of biomarkers. Different calculations are presented according to power (type II error) and impact on outcomes expressed as hazard ratio (HR) of above vs below the median level of the biomarker HR Sample size Power 1.2 4240 80% 1.4 1192 80% 1.6 580 80% 1.2 3334 70% 1.4 937 70% 1.6 457 70% HR, hazard ratio.

The data reported in Table 1, considering different combinations of hazard ratios and power, provide an idea on the number of patients needed for a reliable assessment of association between biomarkers and risk. Table 1 Number of patients to be enrolled in studies testing prognostic value of biomarkers. Different calculations are presented according to power (type II error) and impact on outcomes expressed as hazard ratio (HR) of above vs below the median level of the biomarker HR Sample size Power 1.2 4240 80% 1.4 1192 80% 1.6 580 80% 1.2 3334 70% 1.4 937 70% 1.6 457 70% HR, hazard ratio. Myocardial stress and function laboratory biomarkers Pathophysiological and clinical interpretation HF is considered the fatal finishing line of all cardiovascular disorders. HF is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intra-cardiac pressures at rest or during stress.13 Positive history and some physical signs (such as orthopnoea, rales, third heart sound, or jugular vein distension) share a good diagnostic specificity, but also a poor sensitivity in diagnosing acute congestive HF (Table 2).13,14 Therefore, the diagnosis of both acute and chronic HF is based on the clinical judgment including a combination of history, physical examination, and appropriate investigations, as recommended by all international guidelines.15–19Table 2 Accuracy of history and physical findings in diagnosing acute congestive heart failure (modified from references 13 and 14)

d chronic HF is based on the clinical judgment including a combination of history, physical examination, and appropriate investigations, as recommended by all international guidelines.15–19Table 2 Accuracy of history and physical findings in diagnosing acute congestive heart failure (modified from references 13 and 14) Variable Sensitivity Specificity Accuracy History of HF 62 94 80 Dyspnea 56 53 54 Orthopnoea 47 88 72 Rales 56 80 70 Third heart sound 20 90 66 Jugular vein distension 39 94 72 Oedema 67 68 68 HR, heart failure. The pathophysiological interpretation of plasma BNP/NT-proBNP variations may be difficult in some clinical settings. The cardiac endocrine function has a pivotal role in the regulation of body fluids, electrolytes, and haemodynamics.20 The cardiac peptide hormones, ANP and BNP, share diuretic, natriuretic, vasodilating, and anti-hypertrophic activities.20 A continuous and intense information exchange flows from the endocrine heart system to nervous and immunological systems and to other organs, including kidney, endocrine glands, liver, adipose tissue, immune-competent cells, and vice versa. This close link between cardiac natriuretic peptide system and counter-regulatory systems with sodium-retentive, vasoconstrictive and hypertrophic activities (including renin-angiotensin-aldosterone system, endothelins, catecholamines, arginine-vasopressine system, and pro-inflammatory cytokines) may explain the increase in circulating levels of BNP/NT-proBNP in patients with some extra-cardiac diseases.20

with sodium-retentive, vasoconstrictive and hypertrophic activities (including renin-angiotensin-aldosterone system, endothelins, catecholamines, arginine-vasopressine system, and pro-inflammatory cytokines) may explain the increase in circulating levels of BNP/NT-proBNP in patients with some extra-cardiac diseases.20 A deficiency in biological action of circulating cardiac natriuretic peptide hormones may contribute to explain the altered electrolyte and fluid balance occurring in chronic HF: a phenomenon, defined as the ‘endocrine paradox’ of HF.20 Patients with congestive HF show signs of fluid retention and vasoconstriction, despite the extremely high circulating BNP levels, measured by immunoassay methods at present time commercially available.1,20 Indeed, a blunted natriuretic response after pharmacological doses of ANP and BNP has been observed in experimental models and in patients with chronic HF, suggesting a resistance to the biological effects of natriuretic peptides.20 An explanation of the paradox of high circulating levels of the hormone, but low plasma natriuretic activity may be the large cross-reactivity of proBNP on the immunoassay methods considered specific for BNP.1,21 This cross-reaction produces a great overestimation of the measured levels of BNP, because proBNP is the predominant peptide form present in plasma of patients with severe HF.1,20 Another cause of resistance to biological action of natriuretic peptides is that proBNP is able to bind to the natriuretic peptide receptors, but it stimulates the receptor with lower potency than the active hormones, ANP and BNP, and so it produces a decrease in natriuretic activity by displacing the more biologically active peptide hormones from the receptors.22

on of natriuretic peptides is that proBNP is able to bind to the natriuretic peptide receptors, but it stimulates the receptor with lower potency than the active hormones, ANP and BNP, and so it produces a decrease in natriuretic activity by displacing the more biologically active peptide hormones from the receptors.22 Another important clinical issue in the interpretation of measurements of natriuretic peptides in HF is that circulating BNP and NT-proBNP levels mirror the effectiveness of the treatment of acute or chronic HF, with lowering of levels over time associated with better clinical outcomes.23–26 Use of BNP/NT-proBNP in clinical diagnosis of acute and chronic heart failure All the most recent national and international guidelines13,16–20 recommend the natriuretic peptides, and in particular the peptides related to the B-type cardiac peptide hormone (such as BNP and NT-proBNP), as the first line biomarkers for the diagnosis of both acute and chronic HF. In particular, the 2013 ACCF/AHA guidelines recommend the BNP and NT-proBNP measurement for the diagnosis or exclusion of HF in patients with chronic or acute decompensated HF (with the maximum degree of class of recommendation I and level of evidence A).16 The clinical contribution to the diagnosis of BNP/NT-proBNP assay is particularly significant when the etiology of dyspnoea is unclear. Moreover, the 2013 ACCF/AHA guidelines recommend the measurement of natriuretic peptides with the maximum degree of evidence (class I and level A) also for the prognosis of HF patient.16

e clinical contribution to the diagnosis of BNP/NT-proBNP assay is particularly significant when the etiology of dyspnoea is unclear. Moreover, the 2013 ACCF/AHA guidelines recommend the measurement of natriuretic peptides with the maximum degree of evidence (class I and level A) also for the prognosis of HF patient.16 Usually there are no differences in the diagnostic use of BNP and NT-proBNP immunoassays.1 However, two recent studies from the PARADIGM-HF (prospective comparison of angiotensin II receptor blocker neprilysin inhibitor (ARNI) with angiotensin-converting-enzyme inhibitor (ACEI) to determine impact on global mortality and morbidity in heart failure (HF)] trial27,28 reported conflicting results between BNP and NT-proBNP levels. PARADIGM-HF study evaluated the clinical effects of a new drug (denominated LCZ696 or ENTRESTO), including a combination of sacubitril, a neprilysin (NEP) inhibitor, and valsartan, an angiotensin II receptor blocker. The mechanism of of action of this drug is complex, combining the effect of the angiotensin II receptor blocker and that of the neprilysin inhibitor. The enzyme neprilysin causes degradation not only of natriuretic peptides but also of a variety of components affecting the mechanisms of action for several other circulating hormones, including adrenomedullin, bradykinins, angiotensin I, endothelin-1, and substance P.29 The rationale for the use of a drug containing a neprilysin inhibitor in HF patients is that this proteolytic enzyme can degrade the biologically active natriuretic peptides (ANP, BNP, and CNP).29 For this reason, a drug, containing a substance inhibiting natriuretic peptide degradation (such as LCZ696), may increase the circulating levels of the biologically active natriuretic hormones and, by doing so, may improve the clinical conditions of HF patients by increasing diuresis and natriuresis and reducing cardiac stress.29 PARADIGM-HF study found that plasma BNP levels were higher during treatment with LCZ696 than with enalapril, but, on the contrary, circulating levels of NT-proBNP and cardiac troponin T (cTnT) were lower during treatment with LCZ696 than with enalapril in the first week of treatment.27 Authors explained these conflicting results obtained in the PARADIGM-HF study by considering the combined action of LCZ696 drug. Indeed, BNP (but not NT-proBNP) is a substrate for neprilysin29,30; as a result, the increase in BNP levels should reflect the inhibiting action of the drug on the enzyme neprilysin.

tment.27 Authors explained these conflicting results obtained in the PARADIGM-HF study by considering the combined action of LCZ696 drug. Indeed, BNP (but not NT-proBNP) is a substrate for neprilysin29,30; as a result, the increase in BNP levels should reflect the inhibiting action of the drug on the enzyme neprilysin. On the contrary, the decrease in NT-proBNP levels may reflect the beneficial effects of the drug on myocardial function and vascular haemodynamics, especially by inhibiting the renin-angiotensin-aldosterone system activity.29,30 Indeed, the reduction of cardiac stress during LCZ696 treatment should reduce the production and secretion of natriuretic peptides from cardiomyocytes (and so a fall of the circulating levels of NT-proBNP, too).1 In conclusion, clinicians should accurately consider the clinical setting in order to correctly interpret the variations of natriuretic peptides measured by commercially available laboratory methods. In particular, clinicians should distinguish the increase in BNP levels, due to the inhibiting effect of LCZ696 from those due to deterioration of clinical conditions.

sider the clinical setting in order to correctly interpret the variations of natriuretic peptides measured by commercially available laboratory methods. In particular, clinicians should distinguish the increase in BNP levels, due to the inhibiting effect of LCZ696 from those due to deterioration of clinical conditions. Several studies, including also several meta-analyses,31–37 demonstrated the clinical relevance of BNP/NT-proBNP assay in patients with both acute and chronic HF in different clinical settings (including emergency department and primary care). The measurement of BNP and NT-proBNP is useful in supporting clinical judgment for the diagnosis or exclusion of HF in the setting of chronic ambulatory HF or acute decompensated HF (with the maximum degree of class of recommendation I and level of evidence A).16 Indeed, all international guidelines, starting from the first years of this century, state that lower values of BNP or NT-proBNP actually exclude the presence of HF, while higher values have reasonably high positive predictive value to diagnose HF.13,16–19,38–41 Therefore, BNP/NT-proBNP assay is recommended for ruling-out HF, but not to establish the diagnosis.13 Although some international guidelines13,17–19 suggest some cut-off values of BNP assay for the ruling-out or ruling-in HF, these values are only indicative, because there are large systematic between BNP immunoassay methods.2,3 On the contrary, the cut-off values reported by international guidelines for NT-proBNP assay are more reliable, because only one manufacturer distributes the standard and materials for all immunoassay methods, commercially available in Europe for NT-proBNP measurement.2,3

systematic between BNP immunoassay methods.2,3 On the contrary, the cut-off values reported by international guidelines for NT-proBNP assay are more reliable, because only one manufacturer distributes the standard and materials for all immunoassay methods, commercially available in Europe for NT-proBNP measurement.2,3 BNP/NT-proBNP assay can be also useful for detection of early phases of HF (phase A or B),16,40 when patients are still asymptomatic or pauci symptomatic (functional NYHA classes I and II).42 BNP/NT-proBNP assay cannot differentiate the type of cardiac dysfunction (systolic vs. diastolic); however, the BNP/NT-proBNP levels found in HF patients with preserved left ventricular ejection fraction usually are lower than those of HF patients with reduced left ventricular ejection fraction.13,36 As recommended by national and international guidelines,13,16–19,38–41 the clinical information obtained from electrocardiographic and echocardiographic examination and from the BNP/NTproBNP assay are not equivalent, but they contribute independently to the HF diagnosis and to the definition of the patient's clinical status. At present time, with the exception of cardiac natriuretic peptides, no other cardiovascular biomarkers are recommended by international guidelines for the diagnosis of both acute and chronic HF with the maximum degree of class of recommendation and level of evidence.13,16–19 Synthesis of evidences

BNP/NT-proBNP assay can be also useful for detection of early phases of HF (phase A or B),16,40 when patients are still asymptomatic or pauci symptomatic (functional NYHA classes I and II).42 BNP/NT-proBNP assay cannot differentiate the type of cardiac dysfunction (systolic vs. diastolic); however, the BNP/NT-proBNP levels found in HF patients with preserved left ventricular ejection fraction usually are lower than those of HF patients with reduced left ventricular ejection fraction.13,36 As recommended by national and international guidelines,13,16–19,38–41 the clinical information obtained from electrocardiographic and echocardiographic examination and from the BNP/NTproBNP assay are not equivalent, but they contribute independently to the HF diagnosis and to the definition of the patient's clinical status. At present time, with the exception of cardiac natriuretic peptides, no other cardiovascular biomarkers are recommended by international guidelines for the diagnosis of both acute and chronic HF with the maximum degree of class of recommendation and level of evidence.13,16–19 Synthesis of evidences The measurement of cardiac natriuretic peptides is recommended for the diagnosis of HF in patients with dyspnoea by national and international guidelines since year 2005.

At present time, with the exception of cardiac natriuretic peptides, no other cardiovascular biomarkers are recommended by international guidelines for the diagnosis of both acute and chronic HF with the maximum degree of class of recommendation and level of evidence.13,16–19 Synthesis of evidences The measurement of cardiac natriuretic peptides is recommended for the diagnosis of HF in patients with dyspnoea by national and international guidelines since year 2005. Due to the high degree of clinical sensitivity and negative predictive value, the measurement of cardiac natriuretic peptides is useful for excluding the diagnosis of HF, especially using method-specific reference limits and taking into account sex and age of the patient as well as the presence of obesity and kidney failure. The measurement of cardiac natriuretic peptides cannot differentiate the type of cardiac dysfunction (systolic vs. diastolic). The clinical information obtained from echocardiographic examination and from BNP/NT-proBNP assay is not equivalent, but they contribute independently to the HF diagnosis and to the definition of the patient's clinical status.

The measurement of cardiac natriuretic peptides cannot differentiate the type of cardiac dysfunction (systolic vs. diastolic). The clinical information obtained from echocardiographic examination and from BNP/NT-proBNP assay is not equivalent, but they contribute independently to the HF diagnosis and to the definition of the patient's clinical status. Clinical use of cardiac natriuretic peptides as prognostic biomarkers in heart failure patients More than 1000 published studies, including several meta-analyses,43–56 evaluated the prognostic accuracy of natriuretic peptides (in particular BNP and NT-proBNP) in patients with acute or chronic HF. Plasma BNP and NT-proBNP levels usually decrease during treatment of chronic HF, correlating with improved clinical outcomes, including mortality, hospital stay and/or readmission rate.15,24,25,41,43–47,48,51–54,56–60 According to these experimental and clinical evidences, measurement of natriuretic peptides is recommended with the maximum score (class I and level A) for prognosis in both ambulatory and acute HF patient by the 2013 AACF/AHA guidelines for the management of HF.16 Synthesis of evidences Cardiac natriuretic peptides measurement is recommended for risk stratification in all patients with acute and chronic HF. The short- and long-term risk of death and of cardiovascular events increases gradually with the increase of biomarker values, even for BNP and NT-proBNP levels within the normal range.

Synthesis of evidences Cardiac natriuretic peptides measurement is recommended for risk stratification in all patients with acute and chronic HF. The short- and long-term risk of death and of cardiovascular events increases gradually with the increase of biomarker values, even for BNP and NT-proBNP levels within the normal range. The prognostic information provided by the cardiac natriuretic peptides is independent of that provided by other known cardiovascular risk factors and is associated additively with that of cardiac troponins and cardiac fibrosis markers, such as galectin-3 and sST2 protein.

The short- and long-term risk of death and of cardiovascular events increases gradually with the increase of biomarker values, even for BNP and NT-proBNP levels within the normal range. The prognostic information provided by the cardiac natriuretic peptides is independent of that provided by other known cardiovascular risk factors and is associated additively with that of cardiac troponins and cardiac fibrosis markers, such as galectin-3 and sST2 protein. Use of cardiac natriuretic peptides in clinical management of HF patients There is an increasing consensus about the use of natriuretic peptide-guided HF management.26 Several clinical trials and meta-analyses23–25,43–56,58–60 demonstrated that either baseline level of BNP and NT-proBNP or its decrease after treatment hold a powerful prognostic value in HF patients. In particular, the decrease in peptide natriuretic levels during treatment is associated with clinical improvement, whereas unchanged or increased levels are associated with disease progression and worse prognosis.23–26 The rationale for the use of BNP-guided treatment is that the variation in plasma peptide concentrations before and after a period of standard therapy is able to distinguish ‘responders’ with a better prognosis (i.e. a decrease > 30% in peptide levels after therapy), from ‘non-responders’ patients with a more severe prognosis (i.e. not decrease or even increase in peptide levels after therapy), who probably need both a re-evaluation of clinical status and a re-assessment of treatment.16,26,45 Moreover, it is important to note that the rationale for the use of natriuretic peptide-guided HF management is based also on the assumption that laboratory tests are able to accurately assess the true status of the cardiac endocrine function.2,20

-evaluation of clinical status and a re-assessment of treatment.16,26,45 Moreover, it is important to note that the rationale for the use of natriuretic peptide-guided HF management is based also on the assumption that laboratory tests are able to accurately assess the true status of the cardiac endocrine function.2,20 Despite this large number of experimental and clinical evidences found in the literature,23–25,43–56,58–60 the international guidelines still report an interlocutory judgement about the natriuretic peptide-guided HF management. It should be recognized that evidence is not based on a single, well designed, adequately sized phase III trial. The ESC 2016 guidelines13 provide only some general recommendations about the usefulness of the natriuretic peptides as a guide-to therapy. In particular, it is recommended to begin treatment with valsartan-sacubitril only in patients with high levels of natriuretic peptides. The 2013 ACCF/AHA guidelines16 recommended that the dosage of BNP or NT-proBNP to optimize the therapy should be limited to euvolaemic patients and in the context of a well-structured program of management of chronic HF (class of evidence: IIa, level of evidence: B). As for acute HF, the effectiveness of therapy guided by natriuretic peptides has low levels of recommendation and evidence (class of evidence: class IIb, level of evidence: C type).16 The NICE guidelines19 summarize the evidence in the literature and concluded that the use of natriuretic peptides to guide treatment in chronic HF may lead to potential reduction in mortality in some subgroups, although the overall usefulness in all HF patients remains uncertain.

lass IIb, level of evidence: C type).16 The NICE guidelines19 summarize the evidence in the literature and concluded that the use of natriuretic peptides to guide treatment in chronic HF may lead to potential reduction in mortality in some subgroups, although the overall usefulness in all HF patients remains uncertain. Synthesis of evidences Patients who respond to treatment with a significant decrease in circulating levels of BNP or NT-proBNP have a better prognosis, particularly with regard to the decrease of mortality and/or major cardiovascular events. BNP/NT-proBNP guided therapy significantly reduces mortality in patients younger than 75 years while hospitalization is reduced for all ages and for all causes of hospitalization. In light of the current scientific evidence, it is appropriate to measure the BNP/NT-proBNP levels in patients hospitalized for acute HF at least at the admission and before the discharge to assess the patient's response to therapy. A reduction in levels greater than 30% should be considered significant. There is no evidence in the literature regarding the serial evaluation of BNP/NT-proBNP during hospitalization (except for the admission and discharge)

In light of the current scientific evidence, it is appropriate to measure the BNP/NT-proBNP levels in patients hospitalized for acute HF at least at the admission and before the discharge to assess the patient's response to therapy. A reduction in levels greater than 30% should be considered significant. There is no evidence in the literature regarding the serial evaluation of BNP/NT-proBNP during hospitalization (except for the admission and discharge) Laboratory biomarkers of myocardial injury Pathophysiological and clinical interpretation of myocardial release of troponin in heart failure patients Cardiac troponin I (cTnI) and cTnT are the most widely used biomarkers of myocardial injury in clinical research and in patients with acute coronary syndromes.1,2 More recently, the availability of highly sensitive assays has markedly increased the analytical sensitivity, thus allowing to monitor also the majority of patients with stable chronic HF, whose concentrations of troponins were often below the LoD of earlier generation assays.61–64 cTnI and cTnT are essentially equivalent as markers of cardiac injury in HF patients. In virtually all HF patients, highly sensitive methods can measure circulating cTnI and cTnT levels above their respective limits of detection. In particular, patients with HF, aged 70 years or more, often have circulating concentrations of cTnI and cTnT assayed with high sensitivity methods above the decision limit (99th percentile in a reference population of apparently healthy individuals).61–64

nI and cTnT levels above their respective limits of detection. In particular, patients with HF, aged 70 years or more, often have circulating concentrations of cTnI and cTnT assayed with high sensitivity methods above the decision limit (99th percentile in a reference population of apparently healthy individuals).61–64 From an analytical point of view, some important issues should be discussed in detail, regarding the analytical sensitivity and specificity of laboratory tests at present employed for cTnI and cTnT measurement. First, it is important to accurately define the analytical specifications characterizing the highly sensitive methods.66,67 One should define methods with high sensitivity only the immunoassays that measure the 99th percentile of the distribution of proteins cTnI and cTnT in the reference population (99th ULN) with an error (expressed as coefficient of variation, CV) equal to or lower than 10%,66,67 as required by all the most international guidelines, including the Third Universal Definition of Myocardial Infarction.6 The methods showing an intermediate imprecision (10–20%) should be considered clinically usable (but not highly sensitive methods).6–8,66,67 The reference population on which the 99th URL value is calculated should consist of at least 300 apparently healthy subjects of both genders with a broad age distribution (usually from 18 to 70 years).7,66,67 It is important to note that highly sensitive immunoassay methods should also measure the levels of cTnI and cTnT in the majority (i.e. >50%) of apparently healthy adults, who compose the reference population. In particular, the most sensitive, commercially available in Europe, cTnI method is able to measure troponin levels above the detection limit in the great majority (>95%) of healthy subjects,66,67 also including neonates, children, and adolescents.68,69 Second, as far as the cardio-specificity of cardiac troponin immunoassay methods is concerned, recent studies suggested that the cTnT may be re-expressed in skeletal myocytes of patients with a wide spectrum of neuromuscular diseases in the absence of clinical and cTnI evidence of myocardial injury.70–75 Although cTnT and cTnI are both absent in healthy adult skeletal muscle, cTnT (but not cTnI) is present in foetal skeletal muscle.