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Introduction Observational studies show a strong, positive, and dose-related association between serum concentrations of homocysteine and the risk of stroke, which is independent of other vascular risk factors and biologically plausible.1,2 Homocysteine can be lowered by a mean of 25% (95% CI 23–28) with folic acid supplementation.3 A meta-analysis of eight randomised, placebo-controlled trials of folic acid supplementation in 37 485 patients4 showed that, despite yielding an average 25% reduction in homocysteine, folic acid had no significant effect on the rate of first stroke (rate ratio 0·96, 95% CI 0·87–1·06) over a median follow-up of 5 years. However, the role of homocysteine-lowering in stroke prevention might be complex.5 A meta-analysis of 237 genetic epidemiological studies,6 in which homocysteine and the presence of the methylene tetrahydrofolate reductase C677T polymorphism in 60 000 individuals were correlated with 20 885 subsequent stroke events, suggested that established or increasing dietary folate intake in the countries where the trials were undertaken might have modified the effect of lowering homocysteine on risk of stroke.6

methylene tetrahydrofolate reductase C677T polymorphism in 60 000 individuals were correlated with 20 885 subsequent stroke events, suggested that established or increasing dietary folate intake in the countries where the trials were undertaken might have modified the effect of lowering homocysteine on risk of stroke.6 Antiplatelet therapy might also modify the effect of lowering homocysteine on the risk of stroke and ischaemic heart disease events.7–9 An exploratory analysis of trials of lowering homocysteine7 suggested an interaction between antiplatelet therapy and the effect of lowering homocysteine on risk of ischaemic heart disease events: in the five trials with the lowest prevalence of antiplatelet therapy (mean 60%, usually aspirin), the relative risk was 0·93 (95% CI 0·84–1·05) and in the five trials with the highest prevalence (mean 91%) the relative risk was 1·09 (1·00–1·19), p for interaction=0·037. In another analysis of trials of the effects of lowering homocysteine on the risk of stroke events,8 the effect was greater in the four trials that enrolled patients with renal disease and oesophageal dysplasia (who were not likely to be taking antiplatelet therapy) compared with the trials that enrolled patients with previous vascular disease. The Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial9 subsequently reported a non-significant trend towards a greater effect of folic acid-based vitamin B supplementation, compared with placebo, in reducing stroke in patients with known cardiovascular disease who were not taking antiplatelet therapy at enrolment compared with patients who were (p for interaction=0·25). The biological plausibility of these findings is supported by the recognised potential for antiplatelet therapy to modify any antithrombotic or other antiatherogenic effects of lowering homocysteine.10–13

ase who were not taking antiplatelet therapy at enrolment compared with patients who were (p for interaction=0·25). The biological plausibility of these findings is supported by the recognised potential for antiplatelet therapy to modify any antithrombotic or other antiatherogenic effects of lowering homocysteine.10–13 These analyses prompted us to undertake a post-hoc subanalysis of the vitamins to prevent stroke (VITATOPS) trial. We aimed to explore the hypothesis that there is an interaction between antiplatelet therapy and the effect of folic acid-based vitamin B supplementation on major vascular events in the VITATOPS trial population of patients with previous stroke or transient ischaemic attack.14 Methods Participants The methods and primary results of the VITATOPS trial have been reported.14 Briefly, the VITATOPS trial was a randomised, double-blind, parallel, placebo-controlled trial in which 8164 patients were recruited from 123 centres in 20 countries of four continents, and randomly assigned to take one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, 500 μg vitamin B12). Patients were eligible for inclusion if they had a stroke (ischaemic or haemorrhagic) or transient ischaemic attack (eye or brain) within the past 7 months. Patients were excluded if they were taking folic acid, vitamin B6, vitamin B12, or a folate antagonist (eg, methotrexate), if they were pregnant or were women of childbearing potential, or if they had a restricted life expectancy (eg, because of ill health).

Methods Participants The methods and primary results of the VITATOPS trial have been reported.14 Briefly, the VITATOPS trial was a randomised, double-blind, parallel, placebo-controlled trial in which 8164 patients were recruited from 123 centres in 20 countries of four continents, and randomly assigned to take one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, 500 μg vitamin B12). Patients were eligible for inclusion if they had a stroke (ischaemic or haemorrhagic) or transient ischaemic attack (eye or brain) within the past 7 months. Patients were excluded if they were taking folic acid, vitamin B6, vitamin B12, or a folate antagonist (eg, methotrexate), if they were pregnant or were women of childbearing potential, or if they had a restricted life expectancy (eg, because of ill health). At enrolment, participants were asked if they were taking antiplatelet drugs (eg, aspirin, clopidogrel, dipyridamole). The trial received ethical approval from national (India, New Zealand, and the UK) and local research ethics committees and all patients provided written informed consent before enrolment.

Patients were excluded if they were taking folic acid, vitamin B6, vitamin B12, or a folate antagonist (eg, methotrexate), if they were pregnant or were women of childbearing potential, or if they had a restricted life expectancy (eg, because of ill health). At enrolment, participants were asked if they were taking antiplatelet drugs (eg, aspirin, clopidogrel, dipyridamole). The trial received ethical approval from national (India, New Zealand, and the UK) and local research ethics committees and all patients provided written informed consent before enrolment. Procedures Patients were randomly assigned (1:1) to receive either B vitamins or matching placebo by means of a central 24 h telephone service or an interactive website in which random permuted blocks were stratified by hospital. Treatment groups were masked from patients and investigators. Randomisation was not stratified in accordance with the presence or absence of antiplatelet therapy. The primary outcome was the composite of any stroke, myocardial infarction, or death from vascular causes.

andom permuted blocks were stratified by hospital. Treatment groups were masked from patients and investigators. Randomisation was not stratified in accordance with the presence or absence of antiplatelet therapy. The primary outcome was the composite of any stroke, myocardial infarction, or death from vascular causes. Statistical analysis We tabulated baseline characteristics and laboratory data in accordance with the presence or absence of antiplatelet therapy at baseline and in accordance with the assigned treatment groups, and expressed them as proportions for categorical variables and means for continuous variables. We compared categorical variables in each group with the χ2 test, and continuous variables with the t test. We calculated event rates as the number of events during the follow-up period divided by the total number of patients that entered randomisation. We constructed Kaplan-Meier curves to show the cumulative effects of B vitamins compared with placebo on the primary outcome in participants who were and were not taking antiplatelet therapy at baseline.

Statistical analysis We tabulated baseline characteristics and laboratory data in accordance with the presence or absence of antiplatelet therapy at baseline and in accordance with the assigned treatment groups, and expressed them as proportions for categorical variables and means for continuous variables. We compared categorical variables in each group with the χ2 test, and continuous variables with the t test. We calculated event rates as the number of events during the follow-up period divided by the total number of patients that entered randomisation. We constructed Kaplan-Meier curves to show the cumulative effects of B vitamins compared with placebo on the primary outcome in participants who were and were not taking antiplatelet therapy at baseline. We assessed the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome by means of Cox proportional hazards regression before and after adjusting for imbalances in important baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline, and in participants assigned B vitamins or placebo. We also assessed the consistency of the interaction effect in different subgroups of patients, and in different secondary outcome events including ischaemic stroke, haemorrhagic stroke, myocardial infarction, and death from vascular causes.

platelet drugs at baseline, and in participants assigned B vitamins or placebo. We also assessed the consistency of the interaction effect in different subgroups of patients, and in different secondary outcome events including ischaemic stroke, haemorrhagic stroke, myocardial infarction, and death from vascular causes. We adjusted for certain variables in our models: age, sex, ethnic origin, pathological and causal subtypes of stroke and transient ischaemic attack, stroke severity as measured by the Oxford handicap score, smoking, treated and untreated hypercholesterolaemia, and history of stroke, myocardial infarction, ischaemic heart disease, peripheral arterial disease, atrial fibrillation, and diabetes. We compared the mean serum concentrations of homocysteine and vitamin B12 and mean red-cell concentration of folate, which were measured at both baseline and follow-up in the same individual, with a paired t test. We calculated the difference between baseline and follow-up measures, and tested the interaction effect between antiplatelet use at baseline and treatment allocation with a linear regression model. We used two-sided significance tests throughout and we deemed a two-sided p value of less than 0·05 to be significant. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444.

We compared the mean serum concentrations of homocysteine and vitamin B12 and mean red-cell concentration of folate, which were measured at both baseline and follow-up in the same individual, with a paired t test. We calculated the difference between baseline and follow-up measures, and tested the interaction effect between antiplatelet use at baseline and treatment allocation with a linear regression model. We used two-sided significance tests throughout and we deemed a two-sided p value of less than 0·05 to be significant. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444. Role of the funding source The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, the writing of the report, or in the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Results At baseline, 6609 patients (81%) were in receipt of antiplatelet therapy, 1463 (18%) were not, and in 92 (1%) antiplatelet therapy status was not known. The composite primary outcome of stroke, myocardial infarction, or death from vascular causes was recorded in 616 patients (15%) assigned to receive B vitamins and 678 (17%) assigned to receive placebo (risk ratio 0·91, 95% CI 0·82 to 1·00, p=0·05; absolute risk reduction 1·56%, 95% CI −0·01 to 3·16).14

was not known. The composite primary outcome of stroke, myocardial infarction, or death from vascular causes was recorded in 616 patients (15%) assigned to receive B vitamins and 678 (17%) assigned to receive placebo (risk ratio 0·91, 95% CI 0·82 to 1·00, p=0·05; absolute risk reduction 1·56%, 95% CI −0·01 to 3·16).14 Compared with patients receiving antiplatelet therapy, patients who were not receiving antiplatelet therapy at baseline were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation (table 1). They were less likely to be smokers and to have a history of peripheral vascular disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a revascularisation procedure. Of patients who were or were not receiving antiplatelet therapy at baseline, baseline characteristics were evenly distributed between patients assigned to receive either B vitamins or placebo (table 2). Baseline antiplatelet therapy was an independent significant predictor of a lower rate of subsequent stroke, myocardial infarction, or death from vascular causes in all patients who entered randomisation (hazard ratio [HR] 0·66, 95% CI 0·55–0·81).

Compared with patients receiving antiplatelet therapy, patients who were not receiving antiplatelet therapy at baseline were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation (table 1). They were less likely to be smokers and to have a history of peripheral vascular disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a revascularisation procedure. Of patients who were or were not receiving antiplatelet therapy at baseline, baseline characteristics were evenly distributed between patients assigned to receive either B vitamins or placebo (table 2). Baseline antiplatelet therapy was an independent significant predictor of a lower rate of subsequent stroke, myocardial infarction, or death from vascular causes in all patients who entered randomisation (hazard ratio [HR] 0·66, 95% CI 0·55–0·81). Of the 6609 participants in receipt of antiplatelet drugs at baseline, the primary outcome was recorded in roughly 15% of participants assigned to receive B vitamins or placebo (table 3). By contrast, of the 1463 participants who were not in receipt of antiplatelet drugs at baseline, the primary outcome was recorded in slightly more participants in the placebo group (table 3). After adjusting for the effects of imbalance in baseline variables, the HR for the primary outcome for patients assigned B vitamins versus placebo was greater for participants taking antiplatelet therapy than for those who were not (table 3).

me was recorded in slightly more participants in the placebo group (table 3). After adjusting for the effects of imbalance in baseline variables, the HR for the primary outcome for patients assigned B vitamins versus placebo was greater for participants taking antiplatelet therapy than for those who were not (table 3). The figure shows Kaplan-Meier curves of the cumulative probability of the primary outcome event in patients who were and were not taking antiplatelet at the time of randomisation into the VITATOPS trial. In table 3 we also show the results for the individual components of the primary outcome. The overall results for the primary outcome were consistent for stroke and for vascular death, but not for myocardial infarction. In table 4 we show a significant interaction between antiplatelet use at baseline and the effect of B vitamins on recurrent ischaemic stroke after adjustment for baseline factors. The trend was similar, but not significant, for recurrent haemorrhagic stroke. In table 5 we show that of all the listed subgroups, with the exception of participants with cardioembolic ischaemic stroke, the HR for the effect of B vitamins compared with placebo on the primary outcome was lower in patients who were not in receipt of antiplatelet therapy at baseline than in patients who were, but many of the comparisons were not statistically significant.

the exception of participants with cardioembolic ischaemic stroke, the HR for the effect of B vitamins compared with placebo on the primary outcome was lower in patients who were not in receipt of antiplatelet therapy at baseline than in patients who were, but many of the comparisons were not statistically significant. In table 6 we show that supplementation with B vitamins significantly lowered total homocysteine and increased red cell folate concentration during follow-up in patients who were and were not in receipt of antiplatelet therapy at baseline. Supplementation with B vitamins also significantly increased serum vitamin B12 concentration during follow-up in patients in receipt of antiplatelet therapy at baseline, but the effect was not significant for patients not receiving antiplatelet therapy at baseline. The effects of supplementation with B vitamins on lowering total homocysteine and increasing red-cell folate and vitamin B12 concentration were not significantly different between patients who were and were not in receipt of antiplatelet therapy at baseline. The p for interaction between antiplatelet therapy at baseline and trial treatment was 0·2501 for total homocysteine, 0·8996 for red cell folate, and 0·6591 for vitamin B12.

vitamin B12 concentration were not significantly different between patients who were and were not in receipt of antiplatelet therapy at baseline. The p for interaction between antiplatelet therapy at baseline and trial treatment was 0·2501 for total homocysteine, 0·8996 for red cell folate, and 0·6591 for vitamin B12. After excluding patients with a qualifying diagnosis of haemorrhagic stroke, the interaction between B vitamins and antiplatelet therapy was not significant (adjusted p=0·1159), but the adjusted HR for B vitamins versus placebo on the primary outcome in participants not in receipt of antiplatelet therapy at baseline was still lower (HR 0·75, 95% CI 0·54–1·03) than in participants who were in receipt of therapy (0·98, 0·86–1·12). We also did a matched paired analysis, and a similar pattern was evident. Discussion The principal result of the VITATOPS trial was that daily administration of B vitamins to patients with recent stroke or transient ischaemic attack for a median of 3·4 years had no significant effect, compared with placebo, on the overall incidence of major vascular events. However, our post-hoc subanalysis supports hypotheses from previous independent trials of lowering total homocysteine on both ischaemic heart disease and stroke outcome events that antiplatelet therapy, which was taken by most patients, might have modified any favourable effect of folic acid supplementation on major vascular events (panel).7,9

analysis supports hypotheses from previous independent trials of lowering total homocysteine on both ischaemic heart disease and stroke outcome events that antiplatelet therapy, which was taken by most patients, might have modified any favourable effect of folic acid supplementation on major vascular events (panel).7,9 The VITATOPS trial had several strengths: systematic bias in treatment allocation was minimised by the randomisation process; observer bias in the assessment of vascular outcomes was minimised by the masking of treatment allocation from assessors, clinicians, and patients; and random error was reduced by the reasonably large number of outcome events. The strengths of our analysis are that it was based on a pre-existing hypothesis (that antiplatelet therapy might interact with the effect of B vitamins on vascular risk), the hypothesis is plausible, the interaction between B-vitamin supplementation and only one subgroup was assessed (antiplatelet use at baseline or not; table 3), the primary trial outcome was the main outcome studied, the distribution of important prognostic factors was reasonably, although not perfectly, balanced between treatment groups within each subgroup (table 2), the analysis was based on appropriate statistical tests of subgroup-treatment effect interaction, all subgroup analyses that were undertaken have been reported, and the results have been interpreted cautiously on the premise that subgroup analyses are intrinsically limited.15

ment groups within each subgroup (table 2), the analysis was based on appropriate statistical tests of subgroup-treatment effect interaction, all subgroup analyses that were undertaken have been reported, and the results have been interpreted cautiously on the premise that subgroup analyses are intrinsically limited.15 Potential limitations are that, because this substudy was not a primary aim or prespecified analysis of the VITATOPS trial, the type of antiplatelet therapy taken (eg, aspirin, clopidogrel, aspirin combined with dipyridamole) was not recorded, and there was a significant imbalance in baseline characteristics of participants in receipt of antiplatelet therapy compared with participants who were not (table 1), and a mild imbalance in baseline characteristics in participants assigned to receive B vitamins versus placebo (table 2). The more favourable recorded effect of B vitamins in participants not in receipt of antiplatelet therapy might have been confounded by the reason they were not in receipt of the therapy—ie, B vitamins might have been more effective in patients of east Asian origin or patients with cardioembolic ischaemic stroke or intracerebral haemorrhage (who tend not be given antiplatelet drugs). However, we adjusted for the effects of this imbalance on the rates of each vascular outcome in our Cox multiple regression analysis. Through our Cox analysis we identified that, after adjusting for these effects, the use of antiplatelet therapy at baseline was a significant, independent predictor of the incidence of major vascular events (p<0·0001) and that there was a significant interaction between antiplatelet therapy and treatment with B vitamins on the primary outcome (adjusted p for interaction=0·0204), stroke (adjusted p for interaction=0·0134), and death from vascular causes (adjusted p for interaction=0·0225). We acknowledge the possibility of residual imbalance in other, unmeasured, prognostic factors at baseline, for which we could not adjust our analysis, and that such residual confounding after adjusting for imbalances in measured prognostic factors (eg, haemorrhagic stroke, cardioembolic ischaemic stroke) could affect our results. We also acknowledge that our findings might represent not an interaction of B-vitamin supplementation with antiplatelet therapy but a significant effect of lowering homocysteine by B-vitamin supplementation in patients with haemorrhagic stroke or cardioembolic ischaemic stroke.

chaemic stroke) could affect our results. We also acknowledge that our findings might represent not an interaction of B-vitamin supplementation with antiplatelet therapy but a significant effect of lowering homocysteine by B-vitamin supplementation in patients with haemorrhagic stroke or cardioembolic ischaemic stroke. If our findings are valid, the mechanisms by which raised homocysteine might impair vascular function in the absence of antiplatelet therapy remain to be ascertained. Laboratory investigations suggest several potential mechanisms, including impairment of endothelial function, oxidation of low-density lipids, increased monocyte adhesion to the blood vessel wall, increased lipid uptake and retention, activation of inflammatory pathways, stimulatory effects on smooth-muscle-cell proliferation, and prothrombotic tendency mediated by activation of coagulation factors and platelet dysfunction.11–13 If antiplatelet therapy really does modify the effects of lowering homocysteine on vascular outcomes, this might be mediated by direct effects of antiplatelet drugs on platelet activation and thrombus formation, or indirect effects of antiplatelet drugs, such as aspirin, in reducing vasoconstrictor tone, vascular smooth-muscle-cell proliferation, and release of inflammatory cytokines, oxygen radicals, and growth factors.10

might be mediated by direct effects of antiplatelet drugs on platelet activation and thrombus formation, or indirect effects of antiplatelet drugs, such as aspirin, in reducing vasoconstrictor tone, vascular smooth-muscle-cell proliferation, and release of inflammatory cytokines, oxygen radicals, and growth factors.10 In conclusion, our findings of a significant interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome, in our exploratory analysis of an independent group of patients with previous stroke or transient ischaemic attack, support the hypothesis generated from other studies that antiplatelet therapy might modify any potential benefits of lowering homocysteine with folic-acid supplementation in the secondary prevention of major vascular events. Rather than antiplatelet therapy negating all of the effects of lowering homocysteine, it is also possible that lowering homocysteine might have a small benefit independent of antiplatelet therapy and a larger benefit in the absence of additional prophylactic antiplatelet therapy.

y prevention of major vascular events. Rather than antiplatelet therapy negating all of the effects of lowering homocysteine, it is also possible that lowering homocysteine might have a small benefit independent of antiplatelet therapy and a larger benefit in the absence of additional prophylactic antiplatelet therapy. The external validity of our findings can be assessed more reliably by means of a meta-analysis of the relevant data from all individual patients enrolled in trials of B vitamins to prevent both stroke and ischaemic heart disease events. If validated, the implications of the findings for clinicians are that B vitamins might have a role in the prevention of vascular events in individuals at high risk but who have an allergy to, intolerance of, or lack of indication for antiplatelet therapy, such as those who are also at risk of bleeding events (eg, haemorrhagic stroke). Supplementary Material Supplementary appendix Acknowledgments The VITATOPS trial was funded by the National Health and Medical Research Council of Australia, the UK Medical Research Council, the Biomedical Research Council of Singapore, the National Medical Research Council of Singapore, the National Heart Foundation of Australia, the Royal Perth Hospital Medical Research Foundation, and the Health Department of Western Australia. Blackmores, Australia, supplied the B vitamin and matching placebo tablets.

the Biomedical Research Council of Singapore, the National Medical Research Council of Singapore, the National Heart Foundation of Australia, the Royal Perth Hospital Medical Research Foundation, and the Health Department of Western Australia. Blackmores, Australia, supplied the B vitamin and matching placebo tablets. Contributors GJH initiated the analysis for this substudy and wrote the first and final drafts of the report. QY did all the analyses. JWE, KRL, CC, DX, JCN, UKR, WU, SR, JG, and RS contributed to each draft of the report. All authors were members of the International Steering Committee of the VITATOPS trial. Conflicts of interest We declare that we have no conflicts of interest. Figure Kaplan-Meier curves of the cumulative probability of the primary outcome event Cumulative probability of stroke, myocardial infarction, or death from vascular causes in patients with previous stroke or transient ischaemic attack who were (A) or were not (B) in receipt of antiplatelet therapy at the time of randomisation into the VITATOPS trial. Table 1 Baseline characteristics

Figure Kaplan-Meier curves of the cumulative probability of the primary outcome event Cumulative probability of stroke, myocardial infarction, or death from vascular causes in patients with previous stroke or transient ischaemic attack who were (A) or were not (B) in receipt of antiplatelet therapy at the time of randomisation into the VITATOPS trial. Table 1 Baseline characteristics Antiplatelet treatment (N=6609) No antiplatelet treatment (N=1463) p value Age (years) 62·9 (12·3) 61·1 (13·2) <0·0001 Men 4227 (64·0%) 922 (63·0%) 0·4910 Women 2380 (36·0%) 541 (37·0%) .. Ethnic origin White 2755 (43·2%) 511 (36·3%) <0·0001 East Asian 1455 (22·8%) 445 (31·6%) .. South Asian 1733 (27·2%) 316 (22·4%) .. Other 435 (6·8%) 136 (9·7%) .. Oxfordshire classification of stroke subtype Total anterior circulation syndrome 132 (2·0%) 60 (4·1%) <0·0001 Partial anterior circulation syndrome 3512 (53·7%) 780 (53·9%) .. Lacunar syndrome 2516 (38·5%) 511 (35·3%) .. Posterior circulation syndrome 382 (5·8%) 95 (6·6%) .. Pathological subtype of stroke Transient ischaemic attack 1250 (18·9%) 146 (10·0%) <0·0001 Ischaemic stroke 5117 (77·5%) 574 (39·3%) .. Intracerebral haemorrhage 82 (1·2%) 654 (44·8%) .. Subarachnoid haemorrhage 10 (0·2%) 56 (3·8%) .. Retinal infarction 16 (0·2%) 2 (0·1%) .. Unknown or uncertain pathology 126 (1·9%) 29 (2·0%) .. Causal subtype of stroke Large artery disease 2788 (42·5%) 227 (15·6%) <0·0001 Small artery disease 2555 (38·9%) 203 (14·0%) .. Embolism from the heart 190 (2·9%) 209 (14·4%) .. Uncertain or unknown 911 (13·9%) 97 (6·7%) .. Haemorrhagic event 118 (1·8%) 718 (49·4%) .. Oxford handicap score 2 or less (independent) 5136 (79·0%) 902 (63·2%) <0·0001 3 or greater (dependent) 1366 (21·0%) 525 (36·8%) ..

mall artery disease 2555 (38·9%) 203 (14·0%) .. Embolism from the heart 190 (2·9%) 209 (14·4%) .. Uncertain or unknown 911 (13·9%) 97 (6·7%) .. Haemorrhagic event 118 (1·8%) 718 (49·4%) .. Oxford handicap score 2 or less (independent) 5136 (79·0%) 902 (63·2%) <0·0001 3 or greater (dependent) 1366 (21·0%) 525 (36·8%) .. Medical history Stroke 1041 (15·8%) 233 (16·1%) 0·7732 Myocardial infarction 501 (7·6%) 95 (6·6%) 0·1797 Peripheral arterial disease 321 (4·9%) 44 (3·0%) 0·0024 Revascularisation procedure of brain, heart, or limbs 482 (7·3%) 82 (5·6%) 0·0219 Hypertension* 4634 (70·3%) 1081 (74·7%) 0·0009 Treated hypertension event 3631 (55·3%) 783 (54·2%) 0·4516 Smoking 3337 (50·7%) 671 (46·4%) 0·0033 Present smoker or at time of event 1615 (24·6%) 288 (19·9%) 0·0001 Hypercholesterolaemia† 2315 (35·2%) 330 (22·9%) <0·0001 Treated hypercholesterolaemia event 2001 (30·6%) 266 (18·6%) <0·0001 Diabetes mellitus 1641 (24·9%) 254 (17·5%) <0·0001 Atrial fibrillation 333 (5·1%) 313 (21·6%) <0·0001 Ischaemic heart disease 1126 (17·6%) 197 (14·1%) 0·0014 History of depression 451 (7·6%) 92 (7·0%) 0·4947 Alcohol intake (standard drinks [10 g alcohol] per day) 0·8 (2·5) 0·9 (2·5) 0·1888 Data are mean (SD) or n (%). * History of hypertension or treated hypertension at randomisation. † History of hypercholesterolaemia (>6·5 mmol/L) or treated hypercholesterolaemia at randomisation. Table 2 Baseline characteristics by treatment allocation

Medical history Stroke 1041 (15·8%) 233 (16·1%) 0·7732 Myocardial infarction 501 (7·6%) 95 (6·6%) 0·1797 Peripheral arterial disease 321 (4·9%) 44 (3·0%) 0·0024 Revascularisation procedure of brain, heart, or limbs 482 (7·3%) 82 (5·6%) 0·0219 Hypertension* 4634 (70·3%) 1081 (74·7%) 0·0009 Treated hypertension event 3631 (55·3%) 783 (54·2%) 0·4516 Smoking 3337 (50·7%) 671 (46·4%) 0·0033 Present smoker or at time of event 1615 (24·6%) 288 (19·9%) 0·0001 Hypercholesterolaemia† 2315 (35·2%) 330 (22·9%) <0·0001 Treated hypercholesterolaemia event 2001 (30·6%) 266 (18·6%) <0·0001 Diabetes mellitus 1641 (24·9%) 254 (17·5%) <0·0001 Atrial fibrillation 333 (5·1%) 313 (21·6%) <0·0001 Ischaemic heart disease 1126 (17·6%) 197 (14·1%) 0·0014 History of depression 451 (7·6%) 92 (7·0%) 0·4947 Alcohol intake (standard drinks [10 g alcohol] per day) 0·8 (2·5) 0·9 (2·5) 0·1888 Data are mean (SD) or n (%). * History of hypertension or treated hypertension at randomisation. † History of hypercholesterolaemia (>6·5 mmol/L) or treated hypercholesterolaemia at randomisation. Table 2 Baseline characteristics by treatment allocation Antiplatelet treatment (N=6609) No antiplatelet treatment (N=1463) Placebo group (n=3303) B-vitamins group (n=3306) Placebo group (n=729) B-vitamins group (n=734) Age (years) 63·0 (12·2) 62·8 (12·4) 61·3 (13·0) 61·0 (13·3) Men 2097 (63·5%) 2130 (64·4%) 475 (65·2%) 447 (60·9%) Women 1205 (36·5%) 1175 (35·6%) 254 (34·8%) 287 (39·1%) Ethnic origin White 1378 (43·3%) 1377 (43·1%) 257 (36·5%) 254 (36·1%) East Asian 732 (23·0%) 723 (22·6%) 217 (30·8%) 228 (32·4%) South Asian 857 (26·9%) 876 (27·4%) 159 (22·6%) 157 (22·3%) Other 215 (6·8%) 220 (6·9%) 71 (10·1%) 65 (9·2%) Oxfordshire classification of stroke subtype Total anterior circulation syndrome 71 (2·2%) 61 (1·9%) 31 (4·3%) 29 (4·0%) Partial anterior circulation syndrome 1758 (53·8%) 1754 (53·6%) 390 (54·1%) 390 (53·8%) Lacunar syndrome 1256 (38·4%) 1260 (38·5%) 253 (35·1%) 258 (35·6%) Posterior circulation syndrome 184 (5·6%) 198 (6·0%) 47 (6·5%) 48 (6·6%) Pathological subtype of stroke Transient ischaemic attack 634 (19·2%) 616 (18·7%) 80 (11·0%) 66 (9·0%) Ischaemic stroke 2560 (77·6%) 2557 (77·4%) 278 (38·2%) 296 (40·4%) Intracerebral haemorrhage 37 (1·1%) 45 (1·4%) 317 (43·5%) 337 (46·0%) Subarachnoid haemorrhage 4 (0·1%) 6 (0·2%) 30 (4·1%) 26 (3·5%) Retinal infarction 9 (0·3%) 7 (0·2%) 2 (0·3%) 0 (0%) Unknown or uncertain pathology 55 (1·7%) 71 (2·2%) 21 (2·9%) 8 (1·1%) Causal subtype of stroke Large artery disease 1405 (42·9%) 1383 (42·1%) 118 (16·3%) 109 (15·0%) Small artery disease 1281 (39·1%) 1274 (38·8%) 104 (14·3%) 99 (13·6%) Embolism from the heart 88 (2·7%) 102 (3·1%) 97 (13·4%) 112 (15·4%) Uncertain or unknown 453 (13·8%) 458 (13·9%) 54 (7·4%) 43 (5·9%) Haemorrhagic event 50 (1·5%) 68 (2·1%) 353 (48·6%) 365 (50·1%) Oxford handicap score 2 or less (independent) 2556 (78·7%) 2580 (79·2%) 461 (64·8%) 441 (61·6%) 3 or greater (dependent) 690 (21·3%) 676 (20·8%) 250 (35·2%) 275 (38·4%) Medical history Stroke 528 (16·0%) 513 (15·6%) 126 (17·5%) 107 (14·8%) Myocardial infarction 255 (7·8%) 246 (7·5%) 45 (6·3%) 50 (6·9%) Peripheral arterial disease 163 (5·0%) 158 (4·8%) 25 (3·5%) 19 (2·6%) Revascularisation procedure of brain, heart, or limbs 248 (7·5%) 234 (7·1%) 44 (6·0%) 38 (5·2%) Hypertension* 2330 (70

ical history Stroke 528 (16·0%) 513 (15·6%) 126 (17·5%) 107 (14·8%) Myocardial infarction 255 (7·8%) 246 (7·5%) 45 (6·3%) 50 (6·9%) Peripheral arterial disease 163 (5·0%) 158 (4·8%) 25 (3·5%) 19 (2·6%) Revascularisation procedure of brain, heart, or limbs 248 (7·5%) 234 (7·1%) 44 (6·0%) 38 (5·2%) Hypertension* 2330 (70 ·7%) 2304 (69·9%) 534 (74·0%) 547 (75·4%) Treated hypertension event 1812 (55·2%) 1819 (55·4%) 390 (54·2%) 393 (54·2%) Smoking 1669 (50·7%) 1668 (50·6%) 332 (45·9%) 339 (46·9%) Present smoker or at time of event 806 (24·6%) 809 (24·6%) 138 (19·1%) 150 (20·7%) Hypercholesterolaemia† 1157 (35·1%) 1158 (35·2%) 161 (22·4%) 169 (23·4%) Treated hypercholesterolaemia event 987 (30·2%) 1014 (31·0%) 135 (19·0%) 131 (18·2%) Diabetes mellitus 823 (25·0%) 818 (24·8%) 121 (16·7%) 133 (18·3%) Atrial fibrillation 165 (5·0%) 168 (5·1%) 152 (21·1%) 161 (22·2%) Ischaemic heart disease 573 (18·0%) 553 (17·3%) 96 (13·7%) 101 (14·5%) History of depression 218 (7·3%) 233 (7·8%) 52 (8·0%) 40 (6·1%) Alcohol intake (standard drinks [10 g alcohol] per day) 0·9 (2·7) 0·8 (2·2) 0·8 (2·2) 1·0 (2·8) Data are mean (SD) or n (%). * History of hypertension or treated hypertension at randomisation. † History of hypercholesterolaemia (>6·5 mmol/L) or treated hypercholesterolaemia at randomisation. Table 3 Interaction between B-vitamin supplementation and antiplatelet therapy at baseline on each major vascular outcome

·7%) 2304 (69·9%) 534 (74·0%) 547 (75·4%) Treated hypertension event 1812 (55·2%) 1819 (55·4%) 390 (54·2%) 393 (54·2%) Smoking 1669 (50·7%) 1668 (50·6%) 332 (45·9%) 339 (46·9%) Present smoker or at time of event 806 (24·6%) 809 (24·6%) 138 (19·1%) 150 (20·7%) Hypercholesterolaemia† 1157 (35·1%) 1158 (35·2%) 161 (22·4%) 169 (23·4%) Treated hypercholesterolaemia event 987 (30·2%) 1014 (31·0%) 135 (19·0%) 131 (18·2%) Diabetes mellitus 823 (25·0%) 818 (24·8%) 121 (16·7%) 133 (18·3%) Atrial fibrillation 165 (5·0%) 168 (5·1%) 152 (21·1%) 161 (22·2%) Ischaemic heart disease 573 (18·0%) 553 (17·3%) 96 (13·7%) 101 (14·5%) History of depression 218 (7·3%) 233 (7·8%) 52 (8·0%) 40 (6·1%) Alcohol intake (standard drinks [10 g alcohol] per day) 0·9 (2·7) 0·8 (2·2) 0·8 (2·2) 1·0 (2·8) Data are mean (SD) or n (%). * History of hypertension or treated hypertension at randomisation. † History of hypercholesterolaemia (>6·5 mmol/L) or treated hypercholesterolaemia at randomisation. Table 3 Interaction between B-vitamin supplementation and antiplatelet therapy at baseline on each major vascular outcome B-vitamins group Placebo group Hazard ratio (95% CI) p for interaction Adjusted hazard ratio (95% CI)* Adjusted p for interaction* Total n (%) Total n (%) Stroke, myocardial infarction, or vascular death Antiplatelet use 3306 488 (14·8%) 3303 519 (15·7%) 0·94 (0·83–1·07) 0·0980 0·98 (0·86–1·11) 0·0204 No antiplatelet use 734 123 (16·8%) 729 153 (21·0%) 0·76 (0·60–0·96) 0·71 (0·55–0·90) Stroke Antiplatelet use 3306 293 (8·9%) 3303 297 (9·0%) 0·99 (0·84–1·17) 0·0452 1·03 (0·87–1·22) 0·0134 No antiplatelet use 734 65 (8·9%) 729 89 (12·2%) 0·69 (0·50–0·95) 0·65 (0·46–0·91) Vascular death Antiplatelet use 3306 254 (7·7%) 3303 278 (8·4%) 0·92 (0·78–1·10) 0·0838 0·96 (0·81–1·16) 0·0225 No antiplatelet use 734 70 (9·5%) 729 97 (13·3%) 0·68 (0·50–0·93) 0·63 (0·46–0·88) Myocardial infarction Antiplatelet use 3306 98 (3·0%) 3303 95 (2·9%) 1·04 (0·78–1·37) 0·6630 0·97 (0·72–1·31) 0·9588 No antiplatelet use 734 18 (2·5%) 729 19 (2·6%) 0·90 (0·47–1·72) 0·89 (0·45–1·79) Stroke or vascular death Antiplatelet use 3306 453 (13·7%) 3303 476 (14·4%) 0·96 (0·84–1·09) 0·0553 0·99 (0·87–1·14) 0·0072 No antiplatelet use 734 113 (15·4%) 729 145 (19·9%) 0·74 (0·57–0·94) 0·68 (0·52–0·88) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack.

145 (19·9%) 0·74 (0·57–0·94) 0·68 (0·52–0·88) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack. Table 4 Interaction between B-vitamin supplementation and antiplatelet therapy at baseline on recurrent stroke subtypes

145 (19·9%) 0·74 (0·57–0·94) 0·68 (0·52–0·88) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack. Table 4 Interaction between B-vitamin supplementation and antiplatelet therapy at baseline on recurrent stroke subtypes B-vitamins group Placebo group Hazard ratio (95% CI) p for interaction Adjusted hazard ratio (95% CI)* Adjusted p for interaction* Total n (%) Total n (%) All patients† Recurrent stroke (ischaemic; first ever or recurrent) Antiplatelet use 3306 212 (6·4%) 3303 187 (5·7%) 1·14 (0·94–1·39) 0·1154 1·16 (0·94–1·43) 0·0392 No antiplatelet use 734 36 (4·9%) 729 44 (6·0%) 0·78 (0·50–1·21) 0·69 (0·44–1·11) Recurrent stroke (haemorrhagic; first ever or recurrent) Antiplatelet use 3306 26 (0·8%) 3303 24 (0·7%) 1·09 (0·63–1·90) 0·0866 1·10 (0·61–1·97) 0·0757 No antiplatelet use 734 15 (2·0%) 729 27 (3·7%) 0·52 (0·28–0·99) 0·48 (0·24–0·94) Patients with only non-haemorrhagic stroke or transient ischaemic attack‡ Recurrent stroke (ischaemic; first ever or recurrent) Antiplatelet use 3255 211 (6·5%) 3262 187 (5·7%) 1·14 (0·93–1·38) 0·3208 1·16 (0·94–1·43) 0·1193 No antiplatelet use 371 29 (7·8%) 382 33 (8·6%) 0·88 (0·53–1·44) 0·75 (0·44–1·29) Recurrent stroke (haemorrhagic; first ever or recurrent) Antiplatelet use 3255 25 (0·7%) 3262 24 (0·7%) 1·05 (0·60–1·84) 0·5815 1·06 (0·59–1·93) 0·6016 No antiplatelet use 371 7 (1·9%) 382 9 (2·4%) 0·76 (0·28–2·05) 0·69 (0·233–2·04) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack.

2 9 (2·4%) 0·76 (0·28–2·05) 0·69 (0·233–2·04) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack. † Qualifying event was ischaemic or haemorrhagic stroke or transient ischaemic attack. ‡ Qualifying event was only ischaemic stroke or transient ischaemic attack. Table 5 Interaction between B-vitamin supplementation and antiplatelet therapy at baseline on the primary outcome stratified by baseline characteristics

2 9 (2·4%) 0·76 (0·28–2·05) 0·69 (0·233–2·04) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack. † Qualifying event was ischaemic or haemorrhagic stroke or transient ischaemic attack. ‡ Qualifying event was only ischaemic stroke or transient ischaemic attack. Table 5 Interaction between B-vitamin supplementation and antiplatelet therapy at baseline on the primary outcome stratified by baseline characteristics B-vitamins group Placebo group Hazard ratio (95% CI) p for interaction Adjusted p for interaction* Total n (%) Total n (%) Age <60 years Antiplatelet use 1237 122 (9·9%) 1208 135 (11·2%) 0·89 (0·70–1·13) 0·4957 0·3521 No antiplatelet use 325 34 (10·5%) 319 43 (13·5%) 0·75 (0·48–1·17) Age between 60–69 years Antiplatelet use 960 123 (12·8%) 995 139 (14·0%) 0·90 (0·72–1·17) 0·6991 0·4442 No antiplatelet use 206 43 (16·5%) 200 38 (19·0%) 0·83 (0·52–1·32) Age >69 years Antiplatelet use 1109 243 (21·9%) 1100 245 (22·3%) 1·00 (0·84–1·20) 0·1018 0·0379 No antiplatelet use 203 55 (27·1%) 210 72 (34·3%) 0·73 (0·51–1·03) Transient ischaemic attack Antiplatelet use 616 63 (10·2%) 634 83 (13·1%) 0·79 (0·57–1·09) 0·2669 0·3513 No antiplatelet use 66 6 (9·1%) 80 17 (21·3%) 0·48 (0·19–1·22) Ischaemic stroke Antiplatelet use 2557 405 (15·8%) 2560 416 (16·3%) 0·98 (0·85–1·12) 0·5673 0·2114 No antiplatelet use 296 75 (25·3%) 278 73 (26·3%) 0·90 (0·65–1·24) Non-haemorrhagic stroke or transient ischaemic attack Antiplatelet use 3255 481 (14·8%) 3262 512 (15·7%) 0·94 (0·83–1·07) 0·5907 0·1159 No antiplatelet use 371 82 (22·10%) 382 93 (24·4%) 0·87 (0·65–1·17) Intracerebral haemorrhage Antiplatelet use 45 6 (13·3%) 37 7 (18·9%) 0·72 (0·24–2·14) 0·5842 0·8060 No antiplatelet use 337 39 (11·6%) 317 57 (18·0%) 0·58 (0·39–0·88) Subarachnoid haemorrhage Antiplatelet use 6 1 (16·7%) 4 0 (0·0%) .. .. ..

5907 0·1159 No antiplatelet use 371 82 (22·10%) 382 93 (24·4%) 0·87 (0·65–1·17) Intracerebral haemorrhage Antiplatelet use 45 6 (13·3%) 37 7 (18·9%) 0·72 (0·24–2·14) 0·5842 0·8060 No antiplatelet use 337 39 (11·6%) 317 57 (18·0%) 0·58 (0·39–0·88) Subarachnoid haemorrhage Antiplatelet use 6 1 (16·7%) 4 0 (0·0%) .. .. .. No antiplatelet use 26 2 (7·7%) 30 3 (10·0%) 0·80 (0·13–4·80) Large artery disease Antiplatelet use 1383 255 (18·4%) 1405 232 (16·5%) 1·13 (0·95–1·35) 0·2104 0·0438 No antiplatelet use 109 24 (22·0%) 118 31 (26·3%) 0·81 (0·47–1·37) Small artery disease Antiplatelet use 1274 167 (13·1%) 1281 206 (16·1%) 0·80 (0·65–0·98) 0·5589 0·8683 No antiplatelet use 99 23 (23·3%) 104 33 (31·7%) 0·67 (0·39–1·14) Embolism from the heart Antiplatelet use 102 22 (21·6%) 88 27 (30·7%) 0·64 (0·37–1·13) 0·1576 0·8186 No antiplatelet use 112 27 (24·1%) 97 21 (21·7%) 1·14 (0·64–2·01) Smoking Antiplatelet use 1668 279 (16·7%) 1669 275 (16·5%) 1·03 (0·87–1·22) 0·0633 0·0553 No antiplatelet use 339 61 (18·0%) 332 81 (24·4%) 0·73 (0·52–1·02) No smoking Antiplatelet use 1626 206 (12·7%) 1623 242 (14·9%) 0·84 (0·70–1·01) 0·7663 0·1333 No antiplatelet use 384 61 (15·9%) 391 71 (18·2%) 0·80 (0·57–1·13) Diabetes Antiplatelet use 818 147 (18·0%) 823 153 (18·6%) 1·00 (0·79–1·25) 0·0555 0·0205 No antiplatelet use 133 32 (24·1%) 121 43 (35·5%) 0·61 (0·39–0·97) No diabetes Antiplatelet use 2480 339 (13·7%) 2471 364 (14·7%) 0·93 (0·80–1·08) 0·3179 0·1520 No antiplatelet use 593 89 (15·0%) 602 109 (18·1%) 0·80 (0·60–1·06) High cholesterol (≥6·5 mmol/L) Antiplatelet use 1158 170 (14·7%) 1157 184 (15·9%) 0·92 (0·75–1·14) 0·3346 0·2473 No antiplatelet use 169 29 (17·2%) 161 36 (22·4%) 0·72 (0·44–1·18) Normal cholesterol (<6·5 mmol/L) Antiplatelet use 1496 214 (14·3%) 1463 209 (14·3%) 1·03 (0·85–1·25) 0·0265 0·0069 No antiplatelet use 354 51 (14·4%) 377 75 (19·9%) 0·66 (0·46–0·94) Treated high cholesterol Antiplatelet use 1014 144 (14·2%) 987 160 (16·2%) 0·88 (0·70–1·10) 0·1825 0·2762 No antiplatelet use 131 22 (16·8%) 135 25 (25·2%) 0·60 (0·35–1·03) Untreated high cholesterol Antiplatelet use 2261 339 (15·0%) 2283 356 (15·6%) 0·97 (0·84–1·13) 0·2154 0·0234 No antiplatelet use 589 97 (16·5%) 577 114 (19·8%) 0·81 (0·62–1·07) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack.

9 97 (16·5%) 577 114 (19·8%) 0·81 (0·62–1·07) * Adjusted for age, sex, ethnic origin, history of stroke, myocardial infarction, hypertension, ischaemic heart disease, peripheral arterial disease, diabetes, cholesterol, smoking status, Oxford handicap score, pathology, and cause of stroke and transient ischaemic attack. Table 6 Homocysteine, red cell folate, and vitamin B12 concentrations at baseline and during follow-up Antiplatelet treatment No antiplatelet treatment Baseline Follow-up Difference (95% CI); p value* Baseline Follow-up Difference (95% CI); p value* Homocysteine (μmol/L) B-vitamins group 13·7 (6·6) 10·5 (4·4) −3·18 (−2·66 to −3·70); p<0·0001 12·4 (4·3) 9·9 (2·6) −2·46 (−1·46 to −3·46); p<0·0001 Placebo group 13·4 (4·9) 14·4 (5·8) 0·94 (0·40 to 1·47); p=0·0006 13·3 (5·8) 13·8 (5·1) 0·56 (−0·50 to 1·63); p=0·2937 Red cell folate (nmol/L) B-vitamins group 971·6 (464·6) 2297·9 (789·4) 1326·2 (1195·8 to 1456·6); p<0·0001 906·8 (432·7) 2090·9 (752·3) 1184·1 (951·1 to 1417·2); p<0·0001 Placebo group 867·0 (445·3) 1156·5 (686·0) 289·5 (186·9 to 392·1); p<0·0001 990·7 (515·9) 1112·9 (628·7) 122·2 (−109·2 to 353·5); p=0·2901 Vitamin B12 (pmol/L) B-vitamins group 312·3 (139·3) 367·5 (195·6) 55·1 (21·3 to 89·0); p=0·0016 368·6 (192·4) 396·9 (239·4) 28·4 (−67·0 to 123·7); p=0·5494 Placebo group 311·9 (127·5) 205·7 (132·2) −106·2 (−79·7 to −132·8); p<0·0001 342·7 (127·5) 186·4 (90·7) −156·3 (−109·8 to −202·8); p<0·0001 Data are mean (SD) unless otherwise stated.

) B-vitamins group 312·3 (139·3) 367·5 (195·6) 55·1 (21·3 to 89·0); p=0·0016 368·6 (192·4) 396·9 (239·4) 28·4 (−67·0 to 123·7); p=0·5494 Placebo group 311·9 (127·5) 205·7 (132·2) −106·2 (−79·7 to −132·8); p<0·0001 342·7 (127·5) 186·4 (90·7) −156·3 (−109·8 to −202·8); p<0·0001 Data are mean (SD) unless otherwise stated. * Comparison between baseline and during the follow-up was undertaken with a paired t test. Some of the follow-up measures were taken during follow-up (eg, at the regular follow-up assessments every 6 months) and some at the end of follow-up. Panel Research in context Systematic review We searched PubMed with the terms “homocysteine”, “folic acid”, “vitamins”, “antiplatelet”, “aspirin”, “clopidogrel”, “dipyridamole”, “cilostazol”, “stroke”, “ischaemic heart disease”, “major vascular events”, “interaction”, “randomised trial”, and “clinical trial” for reports of an interaction between antiplatelet therapy and treatments that lower homocysteine in the prevention of stroke and other major vascular events. We searched for work published before March, 2012. The quality of evidence we required was a randomised, controlled trial or meta-analysis of such trials. We identified the Heart Outcomes Prevention Evaluation 2 trial9 and the meta-analysis of randomised trials of lowering total homocysteine on risk of ischaemic heart disease events7 as directly relevant, and a further meta-analysis8 as indirectly relevant. Interpretation

We searched PubMed with the terms “homocysteine”, “folic acid”, “vitamins”, “antiplatelet”, “aspirin”, “clopidogrel”, “dipyridamole”, “cilostazol”, “stroke”, “ischaemic heart disease”, “major vascular events”, “interaction”, “randomised trial”, and “clinical trial” for reports of an interaction between antiplatelet therapy and treatments that lower homocysteine in the prevention of stroke and other major vascular events. We searched for work published before March, 2012. The quality of evidence we required was a randomised, controlled trial or meta-analysis of such trials. We identified the Heart Outcomes Prevention Evaluation 2 trial9 and the meta-analysis of randomised trials of lowering total homocysteine on risk of ischaemic heart disease events7 as directly relevant, and a further meta-analysis8 as indirectly relevant. Interpretation The results of our exploratory analyses of the VITATOPS trial support previous hypotheses that antiplatelet therapy, which was taken by most patients, might modify any favourable effect of folic acid supplementation on major vascular events.7,9 If our finding are validated in independent studies, B vitamins might have a role in the prevention of vascular events in high-risk individuals with an allergy, intolerance, or lack of indication for antiplatelet therapy, such as those with haemorrhagic stroke.