Current issues of ACP Journal Club are published in Annals of Internal Medicine


Lowering homocysteine with folic acid and B vitamins did not prevent vascular events in vascular disease


ACP J Club. 2006 Jul-Aug;145:2. doi:10.7326/ACPJC-2006-145-1-002

Related Content in this Issue
• Companion Abstract and Commentary: Lowering homocysteine with folic acid and B vitamins did not prevent vascular events after myocardial infarction

Clinical Impact Ratings

GIM/FP/GP: 7 stars

Cardiology: 6 stars

Endocrinology: 6 stars

Neurology: 6 stars

Source Citation

Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-77. [PubMed ID: 16531613]



In patients with vascular disease, does lowering plasma homocysteine levels with folic acid and B vitamins reduce risk for major vascular events?


Design: Randomized placebo-controlled trial (Heart Outcomes Prevention Evaluation [HOPE] 2 trial).

Allocation: Concealed.*

Blinding: Blinded {clinicians, patients, data collectors, outcome assessors, and data analysts}†.*

Follow-up period: Mean 5 years.

Setting: 145 centers in 13 countries (Canada, United States, Brazil, western Europe, and Slovakia).

Patients: 5522 patients ≥ 55 years of age (mean age 69 y, 72% men) with a history of coronary artery, cerebrovascular, or peripheral artery disease, or diabetes with ≥ 1 risk factor for atherosclerosis. 54% of patients had a history of myocardial infarction (MI), and 9% had a history of stroke. Patients were eligible regardless of homocysteine levels. Exclusion criteria included planned revascularization and other types of significant cardiovascular disease (CVD).

Intervention: A combined pill with 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 taken once daily (n = 2758), or placebo (n = 2764).

Outcomes: A composite endpoint of MI, stroke, or death from CV causes. Secondary outcomes included total ischemic events (primary outcome components plus hospitalization for unstable angina or revascularization), death from any cause, hospitalization for unstable angina, and revascularization.

Patient follow-up: 99% (intention-to-treat analysis).

Main results

Mean baseline homocysteine level was 12.2 µmol/L (1.6 mg/L). In a randomly selected subgroup of 21% of patients, the mean homocysteine level at 2 years decreased by 2.2 µmol/L (0.3 mg/L) in the intervention group and increased by 1.1 µmol/L (0.1 mg/L) in the placebo group. Groups did not differ for the primary composite endpoint, total ischemic events, or death from any cause (Table). Hospitalization for unstable angina was increased in the intervention group (Table).


In patients with vascular disease, lowering plasma homocysteine levels with folic acid and B vitamins did not reduce risk for the composite endpoint of myocardial infarction, stroke, or death from cardiovascular causes more than placebo.

*See Glossary.

†Information provided by author.

Sources of funding: Canadian Institutes of Health Research. Study drugs provided by Jamieson Laboratories.

For correspondence: Dr. E.M. Lonn, McMaster University, Hamilton, Ontario, Canada. E-mail

Table. Folic acid and vitamins B6 and B12 (intervention) vs placebo to prevent vascular events in vascular disease‡

Outcome Intervention Placebo RRR (95% CI) NNT
Composite endpoint§ 19% 20% 5% (−7 to 16) Not significant
Death from any cause 17% 17% 1% (−13 to 12) Not significant
Total ischemic events 33% 32% 3% (−6 to 13) Not significant
Unstable angina 9.7% 7.9% 24% (4 to 49) 53 (26 to 317)
Revascularization 17% 15% 10% (−4 to 26) Not significant

‡Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from control event rates and relative risks in article.
§Myocardial infarction, stroke, or death from cardiovascular causes.


It's déjà vu all over again. On the basis of a plausible biological rationale, observational studies consistently showing an association between a risk factor and subsequent CVD, and small experimental studies showing an effect of the intervention on surrogate endpoints, it is proposed that a cheap and simple pill can have a dramatic effect on CV outcomes. In this case, the cheap and simple pill is a combination of folic acid and B vitamins. The hypothesis is that taking this pill will reduce plasma levels of homocysteine (which a large body of epidemiologic evidence shows is associated with CV risk) and that this effect will, in turn, reduce CV events.

This compelling rationale has now been tested in 3 related randomized controlled trials. The first trial compared a high-dose combination of folate and B vitamins with a control pill of low doses of the same vitamins in 3680 patients who had recently had a nondisabling stroke and had fasting total homocysteine levels > 25th percentile for stroke patients (1). Despite documented increases in blood levels of folate and vitamin B12, the intervention had no effect on stroke, a composite endpoint of coronary events, or death over a 2-year period.

These disappointing results were reinforced by the findings of the HOPE-2 and NORVIT trials. In HOPE-2, men and women ≥ 55 years of age with CVD, 55% and 40% of whom had hypertension and diabetes, respectively, were randomized to a combination of folate and vitamins B6 and B12 or placebo. Despite an average 22% reduction in plasma homocysteine levels, there was no effect of the intervention on the composite endpoint of CVD death, MI, or stroke. In analyses of each outcome separately, a beneficial effect of the intervention on stroke was observed, but this is unlikely to be a causal association, since such an effect was not observed in either of the other 2 trials. Like the authors of HOPE-2, I believe this finding was an overestimate of the effect or due to chance.

In NORVIT, 3749 patients with recent MI were randomized to placebo, folate and vitamin B12, vitamin B6, or the combination of folate and vitamins B12 and B6. These treatments predictably lowered plasma homocysteine levels by an average of 27%. However, after more than 3 years, not only was there no evidence of a benefit, the combination-vitamin group had a trend toward an increase in the composite endpoint of fatal or nonfatal MI, stroke, or sudden cardiac death.

Proponents point to the lower (but not statistically significant) relative risk seen in HOPE-2 in the countries in which folate fortification of food is not routine and the slight divergence of the Kaplan-Meier curves beyond year 4 as evidence that the folate-homocysteine hypothesis might yet be correct. They claim that what is needed to see an effect is simply more time and folate supplementation in appropriately “folate-deficient” populations. Perhaps, but I doubt it. The plasma total homocysteine level in the whole HOPE-2 sample was at a value (about 12 µmol/L) that has been associated, in observational studies, with increased risk for CVD events. In HOPE-2, lowering this level of homocysteine by about 20% produced no change in CVD outcomes.

These results are distressingly familiar to anyone who has followed the stories about vitamin E and postmenopausal hormone therapy for prevention of CVD. The conclusion, in my opinion, is that in CVD prevention there is simply no substitute for large randomized controlled trials that measure clinical—not surrogate—endpoints. To do otherwise risks chasing rainbows, while putting insufficient effort into ensuring that all eligible patients are receiving therapy proven to save lives.

Paul Shekelle, MD
RAND Corporation
Santa Monica, California, USA


1. 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;291:565-75. [PubMed ID: 14762035]