Background In observational studies, lower homocysteine levelsare associated with lower rates of coronary heart disease andstroke. Folic acid and vitamins B6 and B12 lower homocysteinelevels. We assessed whether supplementation reduced the riskof major cardiovascular events in patients with vascular disease.
Methods We randomly assigned 5522 patients 55 years of age orolder who had vascular disease or diabetes to daily treatmenteither with the combination of 2.5 mg of folic acid, 50 mg ofvitamin B6, and 1 mg of vitamin B12 or with placebo for an averageof five years. The primary outcome was a composite of deathfrom cardiovascular causes, myocardial infarction, and stroke.
Results Mean plasma homocysteine levels decreased by 2.4 µmolper liter (0.3 mg per liter) in the active-treatment group andincreased by 0.8 µmol per liter (0.1 mg per liter) inthe placebo group. Primary outcome events occurred in 519 patients(18.8 percent) assigned to active therapy and 547 (19.8 percent)assigned to placebo (relative risk, 0.95; 95 percent confidenceinterval, 0.84 to 1.07; P=0.41). As compared with placebo, activetreatment did not significantly decrease the risk of death fromcardiovascular causes (relative risk, 0.96; 95 percent confidenceinterval, 0.81 to 1.13), myocardial infarction (relative risk,0.98; 95 percent confidence interval, 0.85 to 1.14), or anyof the secondary outcomes. Fewer patients assigned to activetreatment than to placebo had a stroke (relative risk, 0.75;95 percent confidence interval, 0.59 to 0.97). More patientsin the active-treatment group were hospitalized for unstableangina (relative risk, 1.24; 95 percent confidence interval,1.04 to 1.49).
Conclusions Supplements combining folic acid and vitamins B6and B12 did not reduce the risk of major cardiovascular eventsin patients with vascular disease. (ClinicalTrials.gov number,NCT00106886
[ClinicalTrials.gov]
; Current Controlled Trials number, ISRCTN14017017
[controlled-trials.com]
.)
Numerous studies suggest that homocysteine may be a modifiablerisk factor for cardiovascular disease. In experimental studies,homocysteine causes oxidative stress, damages endothelium, andenhances thrombogenicity.1,2,3 In general, epidemiologic studiesshow an independent and graded association between homocysteinelevels and cardiovascular risk.4,5,6,7,8 The observational datasuggest that even mild-to-moderate elevations in homocysteineincrease cardiovascular risk; this observation is important,because such increases are common and can easily be correctedwith safe and inexpensive therapy. Folic acid is the most importantdietary determinant of homocysteine; daily supplementation with0.5 to 5.0 mg typically lowers plasma homocysteine levels byabout 25 percent. Vitamin B12 supplementation of at least 0.4mg daily further lowers levels by about 7 percent, and vitaminB6 supplements may be particularly important in lowering homocysteineafter methionine loading.9,10
We report the results of the Heart Outcomes Prevention Evaluation(HOPE) 2 study, a large, prospective, randomized clinical trialdesigned to determine whether prolonged administration of folicacid combined with vitamins B6 and B12 reduces the risk of majorvascular events in persons at high cardiovascular risk.
Methods
Study Design
HOPE-2 was a randomized, double-blind, placebo-controlled trialevaluating whether therapy with homocysteine-lowering B vitaminsreduces the risk of major vascular events in a high-risk population.The trial design has been described previously.11 The studywas coordinated by the Population Health Research Instituteat McMaster University in Hamilton, Ontario, and sponsored bythe Canadian Institutes of Health Research. Study drug and matchingplacebo were provided by Jamieson Laboratories, Canada. Thestudy sponsors were not involved in the design, execution, analysis,or reporting of the trial results. An independent data and safetymonitoring board monitored the safety of the participants andthe overall quality and scientific integrity of the study. Thestudy was approved by the ethics review boards of all participatinginstitutions, and all patients provided written informed consent.
Study Population
Men and women 55 years of age or older who had a history ofvascular disease (coronary, cerebrovascular, or peripheral vascular)or diabetes and additional risk factors for atherosclerosiswere enrolled, irrespective of their homocysteine levels, fromcountries with mandatory folate fortification of food (Canadaand the United States) and countries without mandatory folatefortification (Brazil, western Europe, and Slovakia). Patientswho were taking vitamin supplements containing more than 0.2mg of folic acid per day were excluded. Detailed eligibilitycriteria have been published previously11 and are provided inthe Supplementary Appendix (available with the full text ofthis article at www.nejm.org).
Study Intervention
Patients were randomly assigned to receive a combined pill containing2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitaminB12 (active treatment) or matching placebo daily. The studyused central telephone randomization. The randomization codewas generated with the use of a fixed block size of four, stratifiedaccording to center. All study investigators, personnel, andparticipants were unaware of the randomization procedure andthe treatment assignments.
Follow-up and Laboratory Evaluation
After randomization, patients were evaluated every six monthsto determine their adherence to treatment (by interview andpill count) and identify adverse events and clinical outcomes.Blood samples were collected at randomization, at two years,and at the end of the study in a randomly selected subgroupof patients after an overnight fast, with proportional representationfrom countries with folate fortification of food and countrieswithout folate fortification and with expected significant differencesin dietary habits.
Plasma levels of folate (Roche chemiluminescence method, RocheDiagnostics), vitamin B6 (Chromsystems kit, Instruments andChemicals), and vitamin B12 (Immulite 2000 Analyzer, DiagnosticProducts) were measured at randomization and at two years. Totalplasma homocysteine levels were measured (Abbott IMX immunofluorescencemethod, Abbott) at randomization, at two years, and at the endof the study (average, five years).
Trial Outcomes
The primary study outcome was the composite of death from cardiovascularcauses, myocardial infarction, and stroke. Secondary outcomeswere total ischemic events (defined as the composite of deathfrom cardiovascular causes, myocardial infarction, stroke, hospitalizationfor unstable angina, and revascularization), death from anycause, hospitalization for unstable angina, hospitalizationfor congestive heart failure, revascularization, the incidenceof cancer, and death from cancer. Other outcomes included transientischemic attacks, venous thromboembolic events, and fractures.All primary and secondary outcomes were centrally adjudicated.
Deaths classified as due to cardiovascular causes were unexpecteddeaths presumed to be due to ischemic cardiovascular diseaseand occurring within 24 hours after the onset of symptoms withoutclinical or postmortem evidence of another cause, deaths frommyocardial infarction or stroke within 7 days after the event,deaths associated with cardiovascular interventions within 30days after cardiovascular surgery or within 7 days after percutaneousinterventions, and deaths from congestive heart failure, arrhythmia,pulmonary embolism, or ruptured aortic aneurysm. Deaths fromuncertain causes were presumed to be due to cardiovascular causes.
Myocardial infarction was diagnosed when two of the followingthree criteria were met: typical symptoms, increased cardiac-enzymelevels, and diagnostic electrocardiographic changes.12 Strokewas defined as a focal neurologic deficit lasting more than24 hours. Computed tomography or magnetic resonance imagingwas recommended to identify the type of stroke (ischemic orhemorrhagic). When these tools were not available, the strokewas classified as of uncertain type. Cancers (except basal-cellskin cancer) were diagnosed on the basis of pathological (orcytologic) findings or, when pathological data were not available,on the basis of clinical summaries, results of imaging, levelsof serum markers, and other diagnostic procedures. Cancers wereclassified according to the International Classification ofDiseases, 9th Revision.
Statistical Analysis
The study was designed to enroll 5000 patients and to averagefive years of follow-up to allow the detection of a proportionalreduction in the risk of the primary outcome of 17 to 20 percent,with a statistical power of 80 percent and 90 percent, respectively,given an annual event rate of 4 percent in the placebo groupand a two-tailed value of 0.05. This enrollment target wasalso estimated to provide over 80 percent power to detect a15 percent reduction in the risk of total ischemic events.
All analyses were performed according to the intention to treatand included all randomized patients. Survival curves were estimatedaccording to the Kaplan–Meier procedure and were comparedbetween treatment groups with the log-rank test. Prespecifiedsubgroup analyses involving Cox models were used to evaluateoutcomes in patients from regions with folate fortificationof food and regions without folate fortification, accordingto the baseline plasma homocysteine level and the baseline serumcreatinine level. Additional exploratory subgroup analyses wereconducted to evaluate the consistency of the study results.
Results
Characteristics of the Patients
Between January and December 2000, 5522 patients were recruitedat 145 centers in 13 countries: 3982 (72.1 percent) were fromcountries with folate fortification of food, and 1540 (27.9percent) were from countries without folate fortification. Ofthese patients, 2758 were randomly assigned to active treatmentwith folic acid and vitamins B6 and B12 and 2764 were assignedto placebo. Baseline characteristics are shown in Table 1 andwere generally well balanced between the study groups.
Table 1. Baseline Characteristics of the Patients.
Adherence, Adverse Events, and Follow-up
Among those assigned to the active-treatment group, 95.5 percentwere still taking the study drug at one year, 94.0 percent weredoing so at two years, 92.5 percent at three years, 91.4 percentat four years, and 90.8 percent at five years. The respectivefigures for the placebo group were 96.0 percent, 93.4 percent,92.3 percent, 89.9 percent, and 88.5 percent. Use of open-labelfolic acid supplements ranged from 2.3 to 4.5 percent in theactive-treatment group and from 2.2 to 5.5 percent in the placebogroup. There were no serious adverse events related to studytreatment. The most common reasons for permanently or temporarilydiscontinuing treatment at any time were the patient's decision(11.1 percent in the active-treatment group, vs. 12.6 percentin the placebo group), physician's advice (1.6 percent vs. 2.0percent), hospitalization (1.0 percent vs. 0.8 percent), andgeneral malaise (1.0 percent vs. 0.7 percent).
Follow-up averaged five years. A total of 37 patients, 21 inthe active-treatment group and 16 in the placebo group, didnot complete the study (21 declined to continue, and 16 werelost to follow-up). The vital status of 99.3 percent of patientswas ascertained at the end of the study. All patients who declinedto continue the study or were lost to follow-up completed atleast two clinic visits and were included in the final analysis,with data censored at the time of the last follow-up visit.
Effects of Supplementation on Vitamin and Homocysteine Levels
Plasma vitamin levels and homocysteine levels for the subgroupof patients in whom they were measured are shown in Figure 1.At randomization, there were no significant differences betweenthe two groups in plasma levels of folate (27.6 nmol per liter[12.2 ng per milliliter] in the active-treatment group and 27.1nmol per liter [12.0 ng per milliliter] in the placebo group),vitamin B6 (pyridoxal) (61.9 nmol per liter [10.3 ng per milliliter]and 58.1 nmol per liter [9.7 ng per milliliter], respectively),or vitamin B12 (322.2 pmol per liter [436.6 pg per milliliter]and 314.5 pmol per liter [426.1 pg per milliliter], respectively).Mean total plasma homocysteine levels were also similar in bothgroups (12.2 µmol per liter [1.6 mg per liter] in both).As expected, there were regional differences, with lower folateand higher homocysteine levels in patients from regions thatdid not require folate fortification of food than in patientsfrom regions that required folate fortification.
Figure 1. Mean (+SD) Plasma Levels of Total Homocysteine, Folate, Vitamin B6, and Vitamin B12.
Total plasma homocysteine levels were measured in 1644 patients in the active-treatment group and 1661 patients in the placebo group at baseline; in 581 and 588, respectively, at two years; and in 533 and 531, respectively, at five years (the end of the study). Folate and vitamin B levels were measured in 571 patients in the active-treatment group and in 575 patients in the placebo group at baseline and in 572 and 573, respectively, at two years. To convert values for homocysteine to milligrams per liter, divide by 7.396. To convert values for folate to nanograms per milliliter, divide by 2.266. To convert values for vitamin B6 to nanograms per milliliter, divide by 5.982. To convert values for vitamin B12 to picograms per milliliter, divide by 0.7378.
Values obtained two years after randomization showed that plasmafolate and vitamin B12 levels had approximately doubled andvitamin B6 levels had approximately quadrupled in the active-treatmentgroup, with no significant changes in the placebo group (Figure 1).In the active-treatment group, the mean homocysteine level haddecreased to 9.9 µmol per liter (1.3 mg per liter) attwo years (a decrease of 2.2 µmol per liter [0.3 mg perliter] from baseline) and to 9.7 µmol per liter (1.3 mgper liter) at the end of the study (a decrease of 2.4 µmolper liter [0.3 mg per liter] from baseline). In the placebogroup, the mean homocysteine level had increased to 13.2 µmolper liter (1.8 mg per liter) at two years (an increase of 1.1µmol per liter [0.1 mg per liter] from baseline) and to12.9 µmol per liter (1.7 mg per liter) at the end of thestudy (an increase of 0.8 µmol per liter [0.1 mg per liter]from baseline) (Figure 1). As a result, there was a differenceof 3.3 µmol per liter (0.4 mg per liter) in the changefrom baseline in homocysteine levels between the treatment groupsat two years and a difference of 3.2 µmol per liter (0.4mg per liter) at the end of the study. These differences weregreater in the regions that did not require folate fortification(3.7 µmol per liter [0.5 mg per liter] at two years and4.1 µmol per liter [0.6 mg per liter] at the end of thestudy) than in regions that required folate fortification (3.2µmol per liter at two years and 2.9 µmol per liter[0.4 mg per liter] at the end of the study).
Primary Outcomes and Deaths from Any Cause
In the active-treatment group, 519 patients (18.8 percent) diedof cardiovascular causes or had a myocardial infarction or stroke,as compared with 547 patients (19.8 percent) in the placebogroup (relative risk, 0.95; 95 percent confidence interval,0.84 to 1.07; P=0.41) (Figure 2 and Table 2). When each of thecomponents of the primary composite outcome was analyzed separately,there were no significant differences between the groups inthe rates of death from cardiovascular causes or myocardialinfarction (Table 2 and the Supplementary Appendix). Fewer patientsin the active-treatment group than in the placebo group hada stroke (111 [4.0 percent] vs. 147 [5.3 percent]; relativerisk, 0.75; 95 percent confidence interval, 0.59 to 0.97; P=0.03).The risk of death from any cause was similar in the active-treatmentgroup and the placebo group (relative risk, 0.99 with activetreatment; 95 percent confidence interval, 0.88 to 1.13; P=0.94).
Figure 2. Kaplan–Meier Estimates of the Proportion of Patients with the Composite Primary Outcome of Death from Cardiovascular Causes, Myocardial Infarction, or Stroke.
The relative risk of the composite primary outcome in the active-treatment group, as compared with the placebo group, was 0.95 (95 percent confidence interval, 0.84 to 1.07; P=0.41 by the log-rank test).
Among the prespecified cardiovascular secondary outcomes, totalischemic events occurred in 900 (32.6 percent) patients in theactive-treatment group and in 890 patients (32.2 percent) inthe placebo group (relative risk, 1.03; 95 percent confidenceinterval, 0.94 to 1.13; P=0.57) (Table 2). A total of 268 patients(9.7 percent) in the active-treatment group were hospitalizedfor unstable angina, as compared with 219 (7.9 percent) in theplacebo group (relative risk, 1.24; 95 percent confidence interval,1.04 to 1.49; P=0.02). There were no significant differencesbetween the treatment groups in hospitalization for heart failureand revascularization.
There were no significant differences in incident cancers anddeaths from cancer. There were also no significant differencesin the rates of transient ischemic attack, venous thromboembolism,or fracture.
Subgroup Analysis
There were no significant treatment benefits with respect tothe primary outcome in any of the prespecified or exploratorysubgroups evaluated (Figure 3). Of particular interest was thetreatment effect among patients with high baseline levels ofhomocysteine. In the top third of the baseline homocysteinedistribution (homocysteine 12.7 µmol per liter [1.7 mgper liter]), 23.9 percent of the patients in the active-treatmentgroup and 24.0 percent of the patients in the placebo grouphad a primary-outcome event. Primary event rates also did notdiffer significantly between the treatment groups among patientsin the upper fifth of the baseline homocysteine distribution(19.7 µmol per liter [2.7 mg per liter]).
Figure 3. Effect of Folic Acid and Vitamins B6 and B12 on the Primary Outcome in Prespecified and Exploratory Subgroups.
There was no beneficial treatment effect in any of the subgroups evaluated. The size of each symbol is proportional to the number of patients in each subgroup. To convert values for homocysteine to milligrams per liter, divide by 7.396. To convert the value for creatinine to micromoles per liter, multiply by 88.4. To convert the value for cholesterol to millimoles per liter, multiply by 0.02586.
We further explored the effect of treatment on stroke. Moststrokes (185, or 71.7 percent) were ischemic, 19 (7.4 percent)were hemorrhagic, 48 (18.6 percent) were classified as of uncertaintype, and 6 (2.3 percent) were classified as occurring aftersurgery or an invasive cardiovascular intervention. Ischemicstroke occurred in 81 patients (2.9 percent) in the active-treatmentgroup and 104 (3.8 percent) in the placebo group (relative risk,0.78; 95 percent confidence interval, 0.58 to 1.04; P=0.10).There were no significant differences in the rates of hemorrhagicstroke. Fewer patients in the active-treatment group than inthe placebo group had a nonfatal stroke (84 vs. 117; relativerisk, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.02).The incidence of fatal stroke was low and not significantlydifferent between the treatment groups. The apparent effectof treatment on stroke did not differ significantly betweenregions with mandatory folate fortification of food and regionswithout mandatory folate fortification and between patientswith higher as compared with lower baseline total homocysteinelevels (upper vs. middle or lower third of the baseline homocysteinedistribution).
The baseline homocysteine level (as a continuous measure) wasa predictor of cardiovascular events in analyses adjusted forage, sex, and treatment assignment. Hazard ratios for theseanalyses were 1.03 for the primary outcome (95 percent confidenceinterval, 1.02 to 1.04), 1.04 for death from cardiovascularcauses (95 percent confidence interval, 1.02 to 1.05), 1.02for myocardial infarction (95 percent confidence interval, 1.01to 1.04), and 1.03 for stroke (95 percent confidence interval,1.02 to 1.05).
Discussion
In our study, daily administration of the combination of folicacid, vitamin B6, and vitamin B12 lowered homocysteine levelssignificantly but did not reduce the incidence of the primaryoutcome — the composite of death from cardiovascular causes,myocardial infarction, and stroke — during a mean follow-upperiod of five years. In subgroup analysis, there was no heterogeneityof treatment effects among patients from regions with mandatoryfortification of food with folate and regions without mandatoryfolate fortification and among patients with higher as comparedwith lower baseline homocysteine levels.
Our findings are consistent with those of the Norwegian Vitamin(NORVIT) trial, reported elsewhere in this issue of the Journal.13The NORVIT trial evaluated 3749 patients with recent myocardialinfarction from Norway, a country without folate fortificationof food, and found no significant beneficial effect of combinedtreatment with folic acid and vitamin B12, with or without vitaminB6, in spite of adequate homocysteine lowering. Similarly, therewas no treatment benefit in the Vitamin Intervention for StrokePrevention (VISP) study14 and in a smaller trial conducted in593 patients with stable coronary heart disease in the Netherlands.15
On the basis of epidemiologic studies conducted before our studywas initiated, many of which were retrospective, our trial wasadequately powered to allow the detection of a proportionalreduction in the risk of the primary outcome of 17 to 20 percent.More recent prospective observational studies and a meta-analysisof these studies found the magnitude of the association betweenhomocysteine and cardiovascular risk to be lower. After adjustmentfor known cardiovascular risk factors and regression dilutionbias, a 25 percent decrease in the homocysteine level (about3 µmol per liter [0.4 mg per liter]) was associated withan 11 percent decrease in the risk of coronary heart diseaseand a 19 percent decrease in the risk of stroke.8 Our findingscannot definitively exclude the possibility that B vitamin supplementshave a very small beneficial effect on coronary heart disease,of a magnitude similar to these more recent estimates of thestrength of the epidemiologic association (for example, a reductionin risk of 10 percent or less). However, this appears unlikely,considering the consistency of our findings across various coronaryheart disease outcomes and subgroups, the lack of effect oftreatment on total ischemic events — for which the trialwas well powered to detect even a 13 percent reduction in risk— and the concordant findings of the NORVIT and VISP trials.The apparent increase in the rate of unstable angina in theactive-treatment group is inconsistent with the neutral findingsfor all other coronary heart disease outcomes evaluated andmay be related to the difficulty in establishing this diagnosisand to the play of chance.
With regard to the risk of stroke, we observed an absolute reductionof 1.3 percentage points and a relative reduction of 24 percentamong patients assigned to the active-treatment group. However,these results must be interpreted with caution. The number ofstrokes in our study was much lower than the number of coronaryevents, the confidence intervals around the estimated risk reductionare wide, and the results are not adjusted for the multiplicityof outcomes compared. Also, we found no effect of treatmenton transient ischemic attacks. From a biologic perspective,a treatment benefit restricted to stroke would be difficultto explain. Furthermore, the two other large trials of homocysteine-loweringvitamins that have been completed did not show a beneficialeffect of treatment on stroke.13,14 Therefore, we believe thatthe apparent beneficial effect of B vitamin supplements on strokein our trial may represent either an overestimate of the realeffect or a spurious result due to the play of chance. Ongoingtrials and a meta-analysis of all homocysteine-lowering trials16should be able to clarify this issue.
The discordance between the epidemiology of homocysteine andthe results of the clinical trials completed to date is similarto that noted for antioxidant vitamins17 and estrogen18 andmay be related to inherent limitations of observational studies.Indeed, homocysteine levels are related to renal dysfunction,smoking, elevated blood pressure, and other cardiovascular riskfactors and are higher in people with atherosclerosis than inthose without.4 Therefore, homocysteine could be a marker, butnot a cause, of vascular disease, and the epidemiologic datacould be the result of residual confounding that cannot be fullyadjusted for, of reverse causality, or of both. Our findingsmay also relate to exposure to folate-fortified food in over70 percent of the study patients. This exposure probably reducedthe number of patients with substantially increased homocysteinelevels, the subgroup that might be most likely to benefit fromB vitamin supplementation. Several large trials are furtherexploring these questions.16
In conclusion, combined daily administration of 2.5 mg of folicacid, 50 mg of vitamin B6, and 1 mg of vitamin B12 for fiveyears had no beneficial effects on major vascular events ina high-risk population with vascular disease. Our results donot support the use of folic acid and B vitamin supplementsas a preventive treatment.
No potential conflict of interest relevant to this article wasreported.
Supported by a Canadian Institutes of Health Research Grant(MT-15418) and in-kind contributions by Jamieson Laboratories,Canada.
* The HOPE-2 investigators are listed in the Appendix.
Source Information
The Writing Group (Eva Lonn, M.D., and Salim Yusuf, D.Phil., M.B., B.S., Population Health Research Institute, McMaster University, and the Department of Medicine, Division of Cardiology, Hamilton Health Sciences, Hamilton, Ont.; Malcolm J. Arnold, M.D., Department of Medicine, Division of Cardiology, University of Western Ontario, London; Patrick Sheridan, M.Sc., Janice Pogue, M.Sc., and Mary Micks, C.T.R.C., Population Health Research Institute, McMaster University, Hamilton, Ont.; Matthew J. McQueen, M.D., Ph.D., Pathology and Molecular Medicine, McMaster University, Hamilton, Ont.; Jeffrey Probstfield, M.D., University of Washington School of Medicine, Seattle; George Fodor, M.D., Ph.D., University of Ottawa Heart Institute, Ottawa; Claes Held, M.D., Ph.D., Department of Cardiology, Karolinska University Hospital, Stockholm; and Jacques Genest, Jr., M.D., Division of Cardiology, McGill University Health Center and Royal Victoria Hospital, Montreal) assumes responsibility for the overall content and integrity of the manuscript. This article was published at www.nejm.org on March 12, 2006.
Address reprint requests to Dr. Lonn at the Population Health Research Institute, Hamilton General Hospital, 237 Barton St. East, Hamilton, ON L8L 2X2, Canada, or at lonnem{at}mcmaster.ca.
References
Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042-1050. [Free Full Text]
Harker LA, Harlan JM, Ross R. Effect of sulfinpyrazone on homocysteineinduced endothelial injury and arteriosclerosis in baboons. Circ Res 1983;53:731-739. [Free Full Text]
Harker LA, Slichter SJ, Scott CR, Ross R. Homocysteinemia: vascular injury and arterial thrombosis. N Engl J Med 1974;291:537-543. [Web of Science][Medline]
Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999;131:363-375. [Free Full Text]
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-1057. [Free Full Text]
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-1202. [Free Full Text]
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023-2031. [Free Full Text]
The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-2022. [Free Full Text]
Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005;82:806-812. [Free Full Text]
Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-182. [Free Full Text]
Lonn E, Held C, Arnol JM, et al. 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. Can J Cardiol 2006;22:47-53. [Web of Science][Medline]
Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined -- a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-969. [Erratum, J Am Coll Cardiol 2001;37:973.] [Free Full Text]
Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-1588. [Free Full Text]
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575. [Free Full Text]
Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: effects on clinical outcomes. J Am Coll Cardiol 2003;41:2105-2113. [Free Full Text]
B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 2006;151:282-287. [CrossRef][Web of Science][Medline]
Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003;361:2017-2023. [Erratum, Lancet 2004;363:662.] [CrossRef][Web of Science][Medline]
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613. [Free Full Text]
Appendix
The following persons participated in the HOPE-2 Study: WritingGroup: — E. Lonn, S. Yusuf, M.J.O. Arnold, P. Sheridan,M.J. McQueen, J. Pogue, J. Probstfield, G. Fodor, C. Held, M.Micks, J. Genest, Jr.; Steering Committee — E. Lonn (chairand principal investigator), S. Yusuf (cochair), J. Genest,Jr. (coprincipal investigator); M.J.O. 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; Events Adjudication Committee— M.J.O. Arnold (chair), A. Arnold, P. Auger, A. Avezum,I. Bata, V. Bernstein, M. Bourassa, G. Dagenais, M. Fisher,G. Fodor, J. Grover, C. Held, R. Hoeschen, J. Mann, J. Mathew,D. Meldrum, C. Pilon, R. Roccaforte, C. Ross, R. Starra, B.Sussex, K. Teo; Substudies and Publication-Policy Committee— J. Probstfield (chair), R. Davies, E. Lonn, M. McQueen,J. Ostergren, S. Yusuf; Data and Safety Monitoring Board —D. Sackett (chair), R. Collins, E. Davis, C. Furberg, C. Hennekens,B. Pitt, W. Taylor; Senior Study Statistician — J. Pogue;Junior Study Statistician — P. Sheridan; Study Coordination— A. Avezum, J. Bosch, B. Cracknell, M. Fuentes, E. Lonn,C. MacKay, M. McQueen, M. Micks, L. Piegas, J. Pogue, L. Richardson,J. Riley, L. Sardo, P. Sheridan, M. Villamarin, W. West, S.Yuki Miyakoshi, S. Yusuf; Principal Investigators and Coinvestigators— Austria: M. Grisold, W. Klein; Belgium: G. Heyndrickx,Brazil: E. Alexandre, C. Amodeo, D. Araújo, D. Armaganijan,H. Barbato, M. Bertolami, L.C. Bodanese, F. Borelli, C.O.I.Brasil, A. Carvalho, S.M. Carvalhaes, A. Chaves, J.M. Esteves,M.Z. Fichino, B. Garbelini, N. Ghorayeb, G. Greque, C.P. Jaeger,F. Malheiros, V. Mozetic, F.S. Neto, O. Passarelli, A.C. Silva,P. Smith, A.G. Sousa, L.F. Tanajura, J. Tavares, M.N. de Villalon,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, M. Crowther, B. Cujec, G. D'Amours, R.A.Davies, R.F. Davies, K.G. 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, 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,I.M. Hramiak, J. Imrie, A. Irving, C.O. Jenkins, D. Johnstone,C. Joyce, N. Kandalaft, S. Kassam, A. Kenshole, H. Kim, J. Kornder,W.J. 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, L.B. Mitchell,A. Montgomery, T. Muzyka, S. Nawaz, D. O'Keefe, G. Ong, S. Pallie,A. Panju, M.A. 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. Hämäläinen;Germany: S. Cilaci, B. Friederichs, A. Gordalla, R. Hampel,A. Knauerhase, J. Mann, J. Maus, B. Mayinger, S. Miedlich, K.Miehle, S. Mühldorfer, H.P. Nast, R. Paschke, B. Prehn,R. Riel, V. Tirneci; the Netherlands: L.G. van Doorn; SlovakRepublic: M. Kotrec, V. Krpciar, J. Lietava; Spain: X. Albert,R. Masiá, A. Karoni, I. Garcia Polo, C. Suárez;Sweden: M. Bennermo, H. Björkman, U.-B. Ericsson, C. Held,P. Katzman, U. Rosenqvist, K.A. Svensson; Switzerland: P. Gerber,T. Moccetti, E. Safwan, G. Spinas; United States: 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,R. Mack, D. Parikh, G. Pierpont, R.K. Primm, J. Probstfield,A. Rashkow, P. Reiter, R. Rough, K. Schwartz, V. Sridharan,A. Suryaprasad, A. Susmano, W. Wickemeyer, R. Zolty.
Homocysteine, B Vitamins, and Cardiovascular Disease
de Craen A. J.M., Stott D. J., Westendorp R. G.J., Khare A., Lopez M., Gogtay J., Quinlivan E. P., Gregory J. F. III, Refsum H., Smith A. D., Wang X., Demirtas H., Xu X., Tomlinson D. R., Lang D., Lewis M. J., Lonn E., the HOPE-2 Investigators , Bønaa K. H., Tverdal A., Ueland P. M.
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N Engl J Med 2006;
355:205-211, Jul 13, 2006.
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[Abstract][Full Text]
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[Abstract][Full Text]
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[Full Text]
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[Abstract][Full Text]
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[Abstract][Full Text]
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(2008). Methionine-Loading Rapidly Impairs Endothelial Function, by Mechanisms Independent of Endothelin-1: Evidence for an Association of Fasting Total Homocysteine with Plasma Endothelin-1 Levels. J. Am. Coll. Nutr.
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[Abstract][Full Text]
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299: 2086-2087
[Full Text]
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167: 954-961
[Abstract][Full Text]
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[Full Text]
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(2008). Vitamin B12 and health. cfp
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[Abstract][Full Text]
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87: 517-533
[Abstract][Full Text]
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[Abstract][Full Text]
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23: 1069-1071
[Full Text]
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138: 551-555
[Abstract][Full Text]
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(2008). Vitamin status in morbidly obese patients: a cross-sectional study. Am. J. Clin. Nutr.
87: 362-369
[Abstract][Full Text]
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27: 127-136
[Abstract][Full Text]
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117: 503-511
[Abstract][Full Text]
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86: 1581-1585
[Abstract][Full Text]
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22: 3377-3380
[Full Text]
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92: 1703-1706
[Abstract][Full Text]
Getz, G. S., Reardon, C. A.
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27: 2499-2506
[Abstract][Full Text]
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86: 1405-1413
[Abstract][Full Text]
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86: 1563S-1568S
[Abstract][Full Text]
Lazzerini, P.E., Capecchi, P.L., Selvi, E., Lorenzini, S., Bisogno, S., Galeazzi, M., Laghi Pasini, F.
(2007). Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases?. Lupus
16: 852-862
[Abstract]
Ray, J.G., Lonn, E., Yi, Q., Rathe, A., Sheridan, P., Kearon, C., on behalf of the HOPE-2 investigators,
(2007). Venous thromboembolism in association with features of the metabolic syndrome. QJM
100: 679-684
[Abstract][Full Text]
Weikert, C., Dierkes, J., Hoffmann, K., Berger, K., Drogan, D., Klipstein-Grobusch, K., Spranger, J., Mohlig, M., Luley, C., Boeing, H.
(2007). B Vitamin Plasma Levels and the Risk of Ischemic Stroke and Transient Ischemic Attack in a German Cohort. Stroke
38: 2912-2918
[Abstract][Full Text]
Sawka, A. M., Ray, J. G., Yi, Q., Josse, R. G., Lonn, E.
(2007). Randomized Clinical Trial of Homocysteine Level Lowering Therapy and Fractures. Arch Intern Med
167: 2136-2139
[Full Text]
Martinez-Berriotxoa, A., Ruiz-Irastorza, G., Egurbide, M.-V., Garmendia, M., Gabriel Erdozain, J., Villar, I., Aguirre, C.
(2007). Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus. Lupus
16: 810-816
[Abstract]
Carluccio, M. A., Ancora, M. A., Massaro, M., Carluccio, M., Scoditti, E., Distante, A., Storelli, C., De Caterina, R.
(2007). Homocysteine induces VCAM-1 gene expression through NF-{kappa}B and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants. Am. J. Physiol. Heart Circ. Physiol.
293: H2344-H2354
[Abstract][Full Text]
Ferreira, G. A., Navarro, T. P., Telles, R. W., Andrade, L. E. C., Sato, E. I.
(2007). Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology (Oxford)
46: 1560-1565
[Abstract][Full Text]
Jamison, R. L., Hartigan, P., Kaufman, J. S., Goldfarb, D. S., Warren, S. R., Guarino, P. D., Gaziano, J. M., For the Veterans Affairs Site Investigators,
(2007). Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease: A Randomized Controlled Trial. JAMA
298: 1163-1170
[Abstract][Full Text]
Baigent, C., Clarke, R.
(2007). B Vitamins for the Prevention of Vascular Disease: Insufficient Evidence to Justify Treatment. JAMA
298: 1212-1214
[Full Text]
de Bree, A., van Mierlo, L. A, Draijer, R.
(2007). Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am. J. Clin. Nutr.
86: 610-617
[Abstract][Full Text]
Hron, G., Lombardi, R., Eichinger, S., Lecchi, A., Kyrle, P. A., Cattaneo, M.
(2007). Low vitamin B6 levels and the risk of recurrent venous thromboembolism. haematol
92: 1250-1253
[Abstract][Full Text]
Chertow, G. M., Pupim, L. B., Block, G. A., Correa-Rotter, R., Drueke, T. B., Floege, J., Goodman, W. G., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Albizem, M., Olson, K., Klassen, P., Parfrey, P.
(2007). Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overview. CJASN
2: 898-905
[Abstract][Full Text]
van den Donk, M., Pellis, L., Crott, J. W., van Engeland, M., Friederich, P., Nagengast, F. M., van Bergeijk, J. D., de Boer, S. Y., Mason, J. B., Kok, F. J., Keijer, J., Kampman, E.
(2007). Folic Acid and Vitamin B-12 Supplementation Does Not Favorably Influence Uracil Incorporation and Promoter Methylation in Rectal Mucosa DNA of Subjects with Previous Colorectal Adenomas. J. Nutr.
137: 2114-2120
[Abstract][Full Text]
Ludvigsson, J F, de Faire, U, Ekbom, A, Montgomery, S M
(2007). Vascular disease in a population-based cohort of individuals hospitalised with coeliac disease. Heart
93: 1111-1115
[Abstract][Full Text]
Anderson, J. L., Adams, C. D., Antman, E. M., Bridges, C. R., Califf, R. M., Casey, D. E. Jr, Chavey, W. E. II, Fesmire, F. M., Hochman, J. S., Levin, T. N., Lincoff, A. M., Peterson, E. D., Theroux, P., Wenger, N. K., Wright, R. S., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Krumholz, H. M., Kushner, F. G., Lytle, B. W., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2007). ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol
50: e1-e157
[Full Text]
Anderson, J. L., Adams, C. D., Antman, E. M., Bridges, C. R., Califf, R. M., Casey, D. E. Jr, Chavey, W. E. II, Fesmire, F. M., Hochman, J. S., Levin, T. N., Lincoff, A. M., Peterson, E. D., Theroux, P., Wenger, N. K., Wright, R. S., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Krumholz, H. M., Kushner, F. G., Lytle, B. W., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2007). ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol
50: 652-726
[Full Text]
A correction has been published: N Engl J Med 2006;355(7):746.
value of 0.05. This enrollment target was also estimated to provide over 80 percent power to detect a 15 percent reduction in the risk of total ischemic events. 
12.7 µmol per liter [1.7 mg per liter]), 23.9 percent of the patients in the active-treatment group and 24.0 percent of the patients in the placebo group had a primary-outcome event. Primary event rates also did not differ significantly between the treatment groups among patients in the upper fifth of the baseline homocysteine distribution (
T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023-2031. 
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