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Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial
Abstract
BACKGROUND
Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial – the Heart Outcomes Prevention Evaluation (HOPE)-2 study – is being conducted to evaluate this therapy in patients at high risk for CV events.
OBJECTIVES
To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke.
METHODS
A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005.
RESULTS
The patients’ baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention.
Résumé
HISTORIQUE
D’après les études épidémiologiques, une élévation bénigne à modérée de la concentration d’homocystéine plasmatique s’associe à une augmentation du risque de maladie cardiovasculaire (CV) athérothrombotique. Une thérapie simple, peu coûteuse et non toxique à l’acide folique et aux vitamines B6 et B12 réduit les taux d’homocystéine plasmatique d’environ 25 % à 30 % et peut limiter le nombre d’événements CV. Par conséquent, un vaste essai aléatoire clinique, l’étude HOPE-2 sur l’évaluation de la prévention des issues cardiaques, est en cours pour évaluer cette thérapie chez les patients très vulnérables à un événement CV.
OBJECTIFS
Évaluer si une thérapie à long terme à l’acide folique et aux vitamines B6 et B12 réduit le risque de graves événements CV dans la population très vulnérable. La principale issue de l’étude est le composite de décès causés par un événement CV, un infarctus du myocarde ou un accident vasculaire cérébral.
MÉTHODOLOGIE
Au total, 5 522 patients de 55 ans ou plus déjà atteints d’une maladie CV ou de diabète, présentant des facteurs de risque supplémentaires et provenant de 145 centres répartis dans 13 pays ont été divisés aléatoirement entre un placebo et une thérapie associative quotidienne de 2,5 mg d’acide folique, de 50 mg de vitamine B6 et de 1 mg de vitamine B12. Le suivi durera une moyenne de cinq ans et se terminera à la fin de 2005.
RÉSULTATS
Les caractéristiques des patients en début d’étude ont confirmé leur état de forte vulnérabilité. Les taux d’homocystéine de départ variaient selon les pays et les régions. HOPE-2 est l’un des plus vastes essais sur l’administration de folate et de vitamine B6 et B12. Il devrait contribuer considérablement à évaluer le rôle de la diminution de l’homocystéine dans la prévention des événements CV.
STUDY RATIONALE
Homocysteine is a sulfur-containing amino acid produced during catabolism of the essential amino acid methionine. Severe hyperhomocysteinemia can be caused by a number of rare inborn errors of metabolism, affecting several distinct enzymatic pathways. These distinct genetic conditions share as common features extreme elevations of plasma homocysteine associated with homocystinuria and premature atherothrombotic disease with typical histopathological features of endothelial injury, vascular smooth muscle cell proliferation, progressive arterial stenosis and hemostatic changes consistent with a prothrombotic state (1–3). The typical premature vascular disease associated with these conditions, irrespective of the specific site of the metabolic genetic abnormality, suggests that homocysteine is responsible for the vascular damage. Over 30 years ago, these observations led McCully and Wilson (4) to propose the ‘homocysteine theory of atherosclerosis’. While the genetic inborn errors of metabolism associated with severe hyperhomocysteinemia are extremely rare, they provide an in vivo human ‘model’ for vascular injury associated with high homocysteine concentrations. Experimental studies, which show that homocysteine can increase oxidative stress, cause direct endothelial injury and enhance thrombogenicity, also support a potential role for homocysteine in atherothrombosis (5–7).
A large number of epidemiological observational studies have suggested that mild to moderate elevations in homocysteine concentrations may also be associated with increased risk of atherothrombotic vascular disease (8–10). Such modest elevations in homocysteine levels are caused by one or a combination of genetic, physiological, pathological and nutritional factors (10). Of particular interest among these factors are nutritional deficiencies in vitamin cofactors required for homocysteine metabolism (folic acid, vitamins B6 and B12), which are prevalent and account for most cases of mild and moderate hyperhomocysteinemia.
Several lines of evidence provided by observational studies support the hypothesis of a causal link between hyperhomocysteinemia and cardiovascular (CV) disease. Thus, a fairly common genetic polymorphism, the C677T polymorphism of the MTHFR gene, which causes impaired folate metabolism resulting in high homocysteine levels, has been associated with increased risk of coronary artery disease (CAD) and stroke (11,12). Cross-sectional and case-control studies have suggested an association between plasma homocysteine levels and the anatomical extent of carotid, coronary and aortic atherosclerosis, and a meta-analysis of such studies found a strong, independent and graded association between homocysteine and the risk of CV disease (9,10). Prospective observational studies and a meta-analysis of these studies also support, in general, an association between increased homocysteine levels and the risk of ischemic heart disease and stroke, although the association in these investigations is less consistent and appears to be of lesser magnitude than that estimated in retrospective studies (13).
Folic acid is the most important dietary determinant of homocysteine, and dietary supplementation with folic acid 0.5 mg to 5 mg daily typically lowers plasma homocysteine concentrations by approximately 25% (14). Vitamin B12 supplementation further lowers homocysteine levels by approximately 3% to 10%, and vitamin B6 supplements may be particularly important in lowering homocysteine levels post-methionine loading (14).
Therefore, in the late 1990s, several large-scale, randomized trials in high-risk populations (defined as populations with pre-existing CAD, stroke or renal disease) were initiated to test the hypothesis that homocysteine lowering with folic acid and B vitamins could reduce the risk of recurrent CV events. The design of these trials has recently been reviewed (15).
The Heart Outcomes Prevention Evaluation (HOPE)-2 study is one of the largest studies initiated to test this hypothesis. It is also one of the best powered studies to detect a treatment effect, based on the high baseline risk of the study participants, the large sample size and the long duration of follow-up.
STUDY DESIGN
Overview
The HOPE-2 study is a randomized, multicentre, international, double-blind, placebo-controlled trial evaluating whether therapy with homocysteine-lowering folic acid and vitamins B6 and B12 reduces the risk of major vascular events in a high- risk population with vascular disease. The trial design is based on several methodological principles. First, study participants were selected based on their high risk of CV events, independent of baseline homocysteine levels. Thus, middle-aged and elderly patients with prior vascular events or diabetes with additional risk factors were enrolled, without cut-offs for baseline homocysteine levels. These eligibility criteria increased feasibility of the study and considered the continuous, graded relationship between hyperhomocysteinemia and CV risk demonstrated in epidemiological studies. Second, wide eligibility criteria were used, reflecting the pathophysiological and epidemiological data, which suggest that atherosclerosis is a diffuse process, affecting different arterial territories, and that hyperhomocysteinemia may be a significant risk factor for atherothrombotic disease in all vascular territories; furthermore, the wide eligibility criteria ensure generalizability of the study results to a broad range of high-risk individuals. Third, the study design is simple, and the trial was conducted at low cost.
These features enable the evaluation of an important clinical question in a large, clinical trial without financial support from the pharmacological industry.
Patient eligibility criteria
The study was designed to enroll a broad range of patients with stable, high-risk vascular disease, including CAD, cerebrovascular disease and peripheral arterial disease. Patients with diabetes and additional risk factors were also eligible for the study, based on previous data suggesting that middle-aged and elderly patients with type II diabetes are at high risk of vascular events (16). There were few exclusion criteria, including current use of vitamin supplements with a high content of folic acid and vitamins B6 and B12, and the presence of other illnesses or conditions expected to limit compliance and/or impact on patients’ ability to complete the study. The eligibility criteria are listed in Table 1.
TABLE 1
Patient eligibility criteria for the Heart Outcomes Prevention Evaluation (HOPE)-2 trial
| Inclusion criteria | |
| • Women and men 55 years of age and older with any of the following: | |
| Coronary artery disease | Previous myocardial infarction (>1 month ago) |
| Stable or unstable angina with documented multivessel coronary artery disease (by angiography or stress test) | |
| Previous multivessel percutaneous coronary intervention (>1 month before informed consent) | |
| Multivessel coronary artery bypass graft surgery >4 years ago or with recurrence of angina | |
| Multivessel coronary artery disease documented on coronary angiography (>50% stenosis in ≥2 arteries) | |
| Peripheral arterial disease | Previous limb bypass surgery or percutaneous transluminal angioplasty |
| Intermittent claudication with ankle/arm blood pressure ratio ≤0.80 on at least one side | |
| Significant peripheral artery stenosis (>50%) documented by angiography | |
| Previous ischemic limb or foot amputation | |
| Cerebrovascular disease | Previous stroke (>1 month before informed consent) |
| Previous endarterectomy | |
| Diabetes mellitus with at least one additional risk factor | Hypertension (blood pressure >160 mmHg systolic or >90 mmHg diastolic or on treatment) |
| Total cholesterol >5.2 mmol/L | |
| High density lipoprotein cholesterol <0.9 mmol/L | |
| Current cigarette smoking | |
| Known microalbuminuria | |
| Evidence of atherothrombotic vascular disease | |
| • Provision of informed consent | |
Exclusion criteria
| |
Study intervention
After confirming eligibility for the trial, patients were randomly assigned to receive folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg in one combined pill, or to placebo. The study used central randomization via a computerized, voice-activated telephone call (accessible 24 h a day) to the project office in Hamilton, Ontario. The randomization code was generated using a fixed block size of four, stratified by centre. The information about block size and whether it was random or fixed was kept confidential from all study investigators. The randomization sequence was concealed, and all study investigators, study personnel and participants were blinded to treatment allocation. The active vitamin and placebo pill formulations were manufactured (NutriCorp International, Canada) to be indistinguishable by size, colour, taste and dissolution in water.
Follow-up and study outcomes
Following randomization, patients were evaluated at six monthly intervals. Follow-up visits were aimed at documenting and enhancing adherence and at evaluating study outcomes. The study used simple data collection forms, which were faxed to the project office via toll-free lines and read into a database suited for quality control assessments and statistical analyses, using optical character recognition (DataFax software, Clinical DataFax Systems, Canada). Follow-up will extend for an average of five years. During follow-up, event status is reviewed and recorded by the site investigator at each visit. All primary and secondary outcome events and all hospitalizations are reported to the project office. All primary and secondary outcomes are centrally adjudicated by an Events Adjudication Committee using all available supporting source documentation. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke. Secondary outcomes are total major ischemic events (including CV death, myocardial infarction, stroke, hospitalizations for unstable angina and revascularization procedures), hospitalizations for unstable angina, hospitalizations for congestive heart failure, revascularization procedures, total mortality and the composite of incident cancers and cancer deaths. The study design and outcomes are shown in Figure 1.
A number of substudies will evaluate additional end points and biological mechanisms and are summarized in Table 2.
TABLE 2
Summary of substudies
| Substudy | Objectives |
|---|---|
| Homocysteine Lowering and Atherosclerosis Reduction Trial (HART) | To evaluate the effects of the study intervention on atherosclerosis progression, evaluated by quantitative carotid ultrasonography |
| Status of Mental Examination (SOME) | To evaluate effects of the study intervention on cognitive function |
| Dietary Micronutrient Evaluation Substudy | To evaluate micronutrient intake in the Heart Outcomes Prevention Evaluation (HOPE)-2 study regions with and without folate food fortification policies and to study potential interactions between dietary micronutrient intake and the effects of the study intervention |
| Homocysteine Lowering Therapy and Venous Thromboembolism | To evaluate effects of the study intervention on deep vein thrombosis and pulmonary embolism |
| Homocysteine Lowering Therapy and Fractures | To evaluate the effects of the study intervention on vertebral and nonvertebral fractures |
| Studies of Novel Biochemical Risk Factors and Markers | Collection of baseline and follow-up blood samples for analysis of novel cardiovascular risk factors and markers |
Sample size and statistical analysis
The study was designed to enroll 5000 participants to allow the detection of a 17% to 20% proportional reduction in risk for the primary outcome with 80% and 90% power, respectively, estimating an annual placebo event rate of 4% for the primary outcome, an average follow-up of five years and allowing a two-tailed alpha value of 0.05. For the secondary end point of total ischemic events (comprising death from CV causes, myocardial infarction, stroke, hospitalizations for unstable angina and revascularization procedures) for an estimated yearly placebo event rate of 6%, the study was designed to have over 90% power to detect a 15% proportional reduction in risk.
All analyses will be by intention to treat and will include all randomized patients. Survival curves will be estimated using the Kaplan-Meier procedure and will be compared between treatments using the log rank test. Prespecified subgroup analyses using Cox models are planned to evaluate outcomes in patients from regions with folate food fortification policies (Canada and United States) and those without (Brazil, western Europe and Slovakia) by using baseline plasma homocysteine concentration (using baseline homocysteine concentration as a continuous variable and evaluating its interaction with the treatment effect, and by tertiles of baseline homocysteine concentration) and by baseline serum creatinine concentration (above/below median). Additional exploratory subgroup analyses will be conducted to test the consistency of the study results in patient subsets defined by age, sex, presence or absence of hypertension, diabetes, history of CAD, cerebrovascular or peripheral arterial disease and geographical region (North America, Brazil, western Europe and Slovakia). All analyses will be considered statistically significant if the two-tailed P value is less than 0.05.
Study organization
HOPE-2 is a multicentre, international study. The trial is coordinated and monitored by the Population Health Research Institute at McMaster University (Hamilton, Ontario). A Steering Committee, with representation from national leaders, oversees the conduct of the trial and takes overall responsibility. Central adjudication of primary and secondary outcome events is conducted by an Events Adjudication Committee, and a Substudies and Publications Committee oversees the conduct of substudies, additional analyses and publications. The study is sponsored by the Canadian Institutes of Health Research, and in-kind contributions are provided by Jamieson Laboratories (Canada). The study sponsors are not involved in the study design and have no influence on the execution of the study, the analyses and the reporting of the trial results. An independent Data Safety and Monitoring Board consisting of scientists with content and methodological expertise meets yearly and is monitoring the trial for safety of the study participants and overall quality and scientific integrity of the study.
Ethics and patient confidentiality
The study protocol is in accordance with the Helsinki declaration and has been approved by the ethics review boards of all participating institutions. All patients have given informed, written consent. The confidentiality of all patients receives maximal protection both at the local centres and at the project office.
TRIAL PROGRESS AND BASELINE CHARACTERISTICS
Between January 2000 and December 2000, a total of 5522 patients were recruited from 145 centres, including community hospitals and practices and tertiary academic centres in 13 countries. Three thousand five hundred sixty-eight patients were recruited in Canada, 414 in the United States, 265 in Brazil, 426 in nine western European countries and 849 in Slovakia. Follow-up will be completed by the end of 2005. Baseline characteristics are shown in Table 3 and reveal that the study patients are middle-aged and elderly with vascular disease and a high prevalence of CV risk factors. Use of cardiac and vascular protective drugs at baseline was relatively high, and many patients underwent revascularization procedures before enrollment in the study. Measured risk factors were relatively well controlled, although most patients were overweight.
TABLE 3
Baseline characteristics of the Heart Outcomes Prevention Evaluation (HOPE)-2 study participants (n=5522)
| Age, years (mean ± SD) | 68.9±7.0 |
| Female sex, n (%) | 1558 (28.2) |
| Vascular disease by history, n (%) | |
| Coronary artery disease | 4600 (83.3) |
| Myocardial infarction | 2999 (54.3) |
| Stable angina | 3288 (59.5) |
| Unstable angina | 1439 (26.1) |
| Coronary artery bypass graft surgery | 1501 (27.2) |
| Percutaneous coronary intervention | 1111 (20.1) |
| Stroke/transient ischemic attack | 684 (12.4) |
| Intermittent claudication | 133 (2.4) |
| Peripheral artery surgery or percutaneous transluminal angioplasty | 276 (5.0) |
| Carotid endarterectomy | 146 (2.6) |
| Risk factors by history, n (%) | |
| Hypertension | 3039 (55.0) |
| Diabetes mellitus | 2209 (40.0) |
| Elevated total cholesterol | 2639 (47.8) |
| Low HDL cholesterol | 886 (16.0) |
| Current smoking | 633 (11.5) |
| Medication use, n (%) | |
| Acetylsalicylic acid or antiplatelets | 4372 (79.2) |
| Beta-blockers | 2564 (46.4) |
| Lipid-lowering drugs | 3317 (60.1) |
| Angiotensin-converting enzyme inhibitors (history) | 3645 (66.0) |
| Angiotensin receptor blockers | 255 (4.6) |
| Calcium channel blockers | 2057 (37.3) |
| Diuretics | 1452 (26.3) |
| Oral hypoglycemic agents | 1300 (23.5) |
| Insulin | 767 (13.9) |
| Hormone replacement therapy | 267 (17.1% of women) |
| Multivitamins | 638 (11.6) |
| Physical examination, mean ± SD | |
| Heart rate, beats/min | 68.9±11.4 |
| Systolic blood pressure, mmHg | 138.9±22.6 |
| Diastolic blood pressure, mmHg | 77.4±11.8 |
| Body mass index, kg/m2 | 29.6±18.9 |
| Waist-to-hip ratio | 0.9±0.2 |
| Laboratory results*, mean ± SD | |
| Total cholesterol, mmol/L | 4.8±1.0 |
| Low density lipoprotein-cholesterol, mmol/L | 2.7±0.8 |
| HDL-cholesterol, mmol/L | 1.2±0.3 |
| Triglycerides, mmol/L | 2.0±1.3 |
| Plasma glucose, mmol/L | 7.1±3.1 |
| Creatinine, μmol/L | 91.6±27.7 |
| hs-CRP†, mg/L | 4.1±7.2‡ |
Baseline homocysteine levels were measured in 3289 patients (60% of the entire study population), with proportional representation from countries with and without folate food fortification policies, and with expected significant differences in dietary patterns. The mean plasma homocysteine concentration was 12.2 μmol/L and there were large regional variations, with the highest levels in Slovakia (Table 4).
TABLE 4
Baseline plasma homocysteine concentration in Heart Outcomes Prevention Evaluation (HOPE)-2 study participants*
| Region | Mean ± SD | Median | Interquartile range |
|---|---|---|---|
| Canada (n=2443) | 11.80±4.59 | 11.00 | 9.1–11.3 |
| United States (n=279) | 11.72±5.21 | 10.70 | 9.0–12.8 |
| Spain (n=62) | 12.83±3.74 | 11.85 | 10.2–15.2 |
| Sweden (n=124) | 13.29±4.30 | 12.50 | 10.3–15.6 |
| Austria (n=6) | 12.02±1.76 | 11.65 | 11.4–13.8 |
| Denmark (n=30) | 13.46±6.73 | 12.45 | 9.2–15.7 |
| Switzerland (n=26) | 12.55±5.84 | 11.25 | 9.8–13.7 |
| Slovakia (n=319) | 14.54±6.55 | 13.30 | 10.6–16.4 |
| Overall (n=3289)† | 12.16±4.94 | 11.20 | 9.3–13.8 |
DISCUSSION
HOPE-2 is one of the largest prospective, randomized trials evaluating the effects of homocysteine lowering using folic acid and vitamins B6 and B12 on major CV events. To date, several studies in restenosis and stable CAD have reported inconsistent and conflicting results (17–19). However, these studies were not adequately powered to conclusively evaluate the role of homocysteine lowering in the prevention of CV events. In addition, two larger studies (20, 21) failed to demonstrate benefits. The Vitamin Intervention for Stroke Prevention (VISP) trial (20) evaluated 3680 patients with recent nondisabling stroke and reported that moderate homocysteine lowering had no effect on vascular outcomes during two years of follow-up. The Norwegian Vitamin Trial (NORVIT) (21) found no benefits in 3749 patients with recent acute myocardial infarction treated with folic acid and vitamin B6 for 3.5 years. However, these trials were also not sufficiently powered to fully exclude a beneficial treatment effect.
The HOPE-2 trial, expected to report its findings by early 2006, will have a larger sample size and be of longer duration than any of the other trials evaluating the value of homocysteine lowering to date. Additional large trials are ongoing (Table 5). The HOPE-2 trial exceeded original recruitment targets and succeeded in enrolling patients at high risk for vascular events, as evidenced by their baseline characteristics. Follow-up, extending for an average of five years, will be completed by the end of 2005, and adherence and data quality are high. Several important substudies will evaluate effects of therapy on atherosclerosis progression, venous thromboembolism, cognitive function and fractures, and will examine dietary patterns and novel CV risk factors and markers. Thus, the trial is expected to make a major contribution to the evaluation of the homocysteine theory of atherosclerosis. However, the trial encountered several challenges. First, the association between homocysteine and the risk of CV events may be of lesser magnitude than estimated at the time of the study design. Older, often retrospective epidemiological studies have suggested that reducing plasma homocysteine concentrations by approximately 25% would result in an approximate 25% to 30% reduction in the risk of major CV events (9). A more recent meta-analysis of prospective observational epidemiological studies suggests that a 25% lowering in homocysteine levels is associated with only an approximate 11% lower risk of CV events and an 18% lower risk of stroke (13).
TABLE 5
Major homocysteine-lowering trials
| Homocysteine-lowering regimen (daily doses in mg)
| |||||||
|---|---|---|---|---|---|---|---|
| Trial | Population studied | Prior disease | n (actual or projected) | Duration of follow-up (years) | Folic acid | Vitamin B12 | Vitamin B6 |
| CHAOS-2* | UF | CAD | 1880 | 2 | 5.0 | – | – |
| WENBIT | UF | CAD | 3000 | 3 | 0.8 | 0.4 | 40 |
| NORVIT† | UF | CAD | 3749 | 3 | 0.8 | 0.4 | 40 |
| SEARCH | UF | CAD | 12,064 | 7 | 2.0 | 1.0 | – |
| WACS | F | CAD | 5442 | 7.4 | 2.5 | 1.0 | 50 |
| VITATOPS | UF | Stroke | 8000 | 3 | 2.0 | 0.5 | 25 |
| VISP† | F | Stroke | 3680 | 2 | 2.5 | 0.4 | 25 |
| SU.FOL.OM3 | UF | CAD/stroke | 3000 | 5 | 0.5 | 0.02 | 3 |
| HOPE-2 | F/UF | CAD/stroke/PAD | 5522 | 5 | 2.5 | 1.0 | 50 |
| FAVORIT | F | Renal | 4000 | 5 | 2.5 | 0.4 | 20 |
| HOST | F | Renal | 2056 | 5 | 40.0 | 0.5 | 100 |
Second, the increasing use of effective CV protective drugs and revascularization procedures may result in lower CV event rates, as was the case in several recent clinical trials in CAD patients (22,23).
Third, it has been suggested that folate food fortification policies, introduced in the United States in January 1998 and in Canada in November 1998, may have a higher than originally anticipated effect on baseline plasma folate and homocysteine concentrations, and that additional B vitamin supplementation may result in a lower than expected homocysteine lowering (24,25).
These issues have been carefully examined. Blinded interim analyses reviewed by the Steering Committee in March 2005 revealed that CV event rates are high and similar to the original projections. The CV event rates in the HOPE-2 study are higher than in other recent trials in patients with CAD, likely reflecting the enrollment of many elderly patients (mean age 68.8 years) with advanced atherosclerosis. Measurement of baseline and two-year plasma homocysteine levels in 1143 randomly selected study patients from fortified and nonfortified regions revealed relatively high baseline homocysteine levels (average 12.2 μmol/L) and adequate homocysteine lowering of approximately 25%, as projected. Finally, the study enrolled approximately 10% more study patients than originally planned. Thus, the study remains 80% powered to detect proportional reductions in risk of approximately 15% or higher for the primary composite endpoint and of 12% or higher for the secondary endpoint, defined as total major ischemic CV events. Moreover, recent in vitro and in vivo data suggest that folic acid improves nitric oxide bioavailability and may exert vascular benefits, independent of its homocysteine-lowering effect (26–28). In addition, the Steering Committee decided to join the prospective meta-analysis of the large ongoing trials of homocysteine-lowering. This meta-analysis is expected to include data from over 50,000 patients with CAD, stroke and renal disease, and will have high power to detect treatment effects of at least 10% on specific outcomes (ie, major coronary events, stroke and major vascular events) (15). Even such ‘modest’ benefits could have substantial public health implications.
CONCLUSIONS
Homocysteine has been proposed as a treatable risk factor for atherosclerosis. However, the hypothesized beneficial effects of homocysteine lowering with folic acid and vitamins B6 and B12 on CV morbidity and mortality remain unproven. HOPE-2 is a large, Canadian-led and sponsored clinical trial, soon to be completed, and will significantly contribute to the evaluation of the role of homocysteine lowering in the prevention of CV events.
APPENDIX
Writing Group: E Lonn, C Held, JMO Arnold, J Probstfield, M McQueen, M Micks, J Pogue, P Sheridan, J Bosch, J Genest, S Yusuf.
Steering Committee: E Lonn (Chair and Principal Investigator), S Yusuf (Co-Chair), J Genest Jr (Co-Principal Investigator); JMO Arnold, A Avezum, J Bosch, J Choy, G Dagenais, R Davies, M Fisher, G Fodor, T Hamalainen, G Heyndrickx, R Hoeschen, W Klein, R Kuritzky, J Mann, M McQueen, M Micks, B Mitchell, J Ostergren, L Piegas, J Pogue, J Probstfield, P Sleight, G Spinas, B Sussex, K Teo, L Title, R Tsuyuki.
Event Adjudication Committee: JMO Arnold (Chair), A Avezum, A Arnold, P Auger, I Bata, V Bernstein, M Bourassa, G Dagenais, G Fodor, R Hoeschen, D Meldrum, C Pilon, C Ross, R Starra, B Sussex, K Teo, J Mann, R Roccaforte, C Held, M Fisher, J Grover, J Mathew.
Substudies/Publication Policy Committee: J Probstfield (Chair), R Davies, E Lonn, M McQueen, J Pogue, S Yusuf.
Data and Safety Monitoring Board: D Sackett (Chair), W Taylor, R Collins, B Pitt, C Furberg, E Davis, C Hennekens.
Study Statisticians: J Pogue (Senior statistician), P Sheridan (Junior statistician).
Study Coordination: A Avezum, J Bosch, B Cracknell, M Fuentes, E Lonn, C MacKay, M McQueen, M Micks, J Pogue, L Richardson, J Riley, L Sardo, P Sheridan, A Stranaghan, M Villamarin, W West, S Yuki Miyakoshi, S Yusuf.
Site Principal Investigators and Co-Investigators by Country: Austria: M Grisold, W Klein; Belgium: G Heyndrickx; Brazil: E Alexander, C Amodeo, D Araujo, D Armaganijan, H Barbatto, M Bertolami, LC Bodanese, F Borelli, C Brasil, A Carvalho, A Chaves, J Esteves, M Fichino, B Garbelini, N Ghorayeb, G Greque, SM Grespan Carvalhaes, F Malheiros, V Mozetic, M Nakamura de Villalon, F Neto, C Ogawa, O Passarelli, C Jaeger, A Seixas Silva, P Smith, AG Sousa, LF Tanajura, J Tavares, H Zatz; Canada: G Abraham, N Aris-Jilwan, M Arnold, T Ashton, P Auger, M Baird, T Baitz, I Bata, A Belanger, V Bernstein, R Bessoudo, W Bishop, P Bogaty, M Boulianne, R Brossoit, W Cameron, J Campeau, S Carrier, N Chan, Y Chan, J-L Chiasson, J Choy, J Cox, M Crowther, B Cujec, G D’Amours, RA Davies, RF Davies, KG Dawson, F Delage, G DeRose, P DeYoung, D Dion, R Dong, J Douketis, M Drobac, J Dufton, R Dupuis, A Edwards, L Finkelstein, T Forbes, R Fowlis, J Frohlich, J Fulop, R Geddis, P Gervais, S Ghosh, JP Giannoccaro, P Giannoccaro, R Giroux, P Gladstone, A Glanz, E Goode, D Gossard, G Gosselin, G Goulet, P Greenwood, F Grondin, N Habib, J Halle, K Harris, J Heath, M Heule, L Higginson, B Hoeschen, R Houlden, IM Hramiak, J Imrie, A Irving, CO Jenkins, C Joyce, N Kandalaft, S Kassam, A Kenshole, H Kim, J Kornder, WJ Kostuk, G Kumar, R Kuritzky, G Kuruvilla, K Kwok, Z Lakhani, A Lamy, C Lauzon, M LeBlanc, H Lee, M Lee, B Lent, R Lesoway, R Loisel, E Lonn, P Ma, T Machel, K MacLellan, D MacRitchie, S Majumdar, D Massel, T Mathew, P Mehta, D Meldrum, A Miller, F Miller, J Misterski, LB Mitchell, A Montgomery, T Muzyka, S Nawaz, D O’Keefe, G Ong, S Pallie, A Panju, MA Patel, A Pearce, P Pflugfelder, C Pilon, P Plourde, C Poirier, P Polasek, G Pruneau, S Rabkin, M Ravalia, T Rebane, J Ricci, C Riel, M Ruel, D Saulnier, D Savard, M Sayeed, A Selby, F Sestier, W Sheridan, G Sherman, M Shirley, G Simkus, N Singh, R Smith, R Southern, D Spence, R Starra, D Steeves, L Sternberg, R St-Hilaire, J Stone, H Sullivan, H Sullivan, M Sullivan, B Sussex, J Swan, T Talibi, P Tan, P Tanser, D Taylor, K Teo, G Thomasse, L Title, W Tymchak, T Vakani, S Vederah, R Vexler, K Wagner, M Walker, A Weeks, S Wetmore, G Wisenberg, M Wolfe, K Woo, B Zinman; Denmark: H Juhl; Finland: T Hamalainen; Germany: S Cilaci, B Friederichs, A Gordalla, R Hampel, A Knauerhase, J Mann, J Maus, B Mayinger, S Miedlich, K Miehle, S Muehldorfer, HP Nast, R Paschke, B Prehn, R Riel, V Tirneci; Netherlands: LG van Doorn; Slovakia: M Kotrec, V Krpciar, J Lietava; Spain: X Albert, R Masiá, A Karoni, I Garcia Polo, C Suárez; Sweden: M Bennermo, H Bjorkman, L Ekholm, U-B Ericsson, C Held, T Jonasson, P Katzman, L Ljungdahl, U Rosenqvist, KA Svensson, P Weber; Switzerland: P Gerber, T Moccetti, E Safwan, G Spinas; USA: J Abrams, S Advani, A Basu, S Berger, G Cohen, K Danisa, M Davidson, A Dimova, C Forchetti, L Gage, J Geohas, J Gorham, S Graham, S Gupta, V Hart, B Hoogwerf, L Horwitz, R Kohn, E Lader, G Lorch, R Mack, J Nemanich, D Parikh, G Pierpont, RK Primm, J Probstfield, A Rashkow, P Reiter, R Rough, K Schwartz, V Sridharan, A Suryaprasad, A Susmano, R Utley, W Wickemeyer, R Zolty.
Footnotes
FUNDING: This study is sponsored by the Canadian Institutes of Health Research (grant MT-15418) and by in-kind contributions provided by Jamieson Laboratories, Canada.