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 after myocardial infarction


ACP J Club. 2006 Jul-Aug;145:3. doi:10.7326/ACPJC-2006-145-1-003

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

Clinical Impact Ratings

GIM/FP/GP: 7 stars

Cardiology: 6 stars

Source Citation

Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354:1578-88. [PubMed ID: 16531614]



In patients with acute myocardial infarction (MI), does lowering plasma homocysteine levels with folic acid plus vitamin B12 or vitamin B6 reduce risk for major vascular events?


Design: Randomized, 2 × 2 factorial design, placebo-controlled trial (Norwegian Vitamin [NORVIT] trial).

Allocation: Concealed.*

Blinding: Blinded (clinicians, patients, data collectors, and outcome assessors).*

Follow-up period: 2.0 to 3.5 years (median 3.3 y).

Setting: 35 hospitals in Norway.

Patients: 3749 patients 30 to 85 years of age (mean age 63 y, 74% men) with acute MI in the previous 7 days. Exclusion criteria included life expectancy < 4 years.

Intervention: A combined capsule with 0.8 mg folic acid, 40 mg vitamin B6, and 0.4 mg vitamin B12 (n = 937); 0.8 mg folic acid and 0.4 mg vitamin B12 (n = 935); 40 mg vitamin B6 (n = 934); or placebo (n = 943), taken once daily. The 2 folic acid groups received a loading dose of 5 mg folic acid daily for 2 weeks.

Outcomes: A composite endpoint of MI, stroke, or sudden death from coronary heart disease. Secondary outcomes included MI, stroke, hospitalization for unstable angina, coronary revascularization, and death from any cause.

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

Main results

Mean baseline homocysteine levels were 12.9 to 13.3 µmol/L (1.7 to 1.8 mg/L). Mean homocysteine level at 2 years decreased by 3.4 to 3.7 µmol/L (0.5 mg/L) in the 2 folic acid groups and increased by 0.4 to 0.5 µmol/L (0.1 mg/L) in the 2 groups without folic acid. Groups did not differ for any clinical outcome (Table).


In patients with myocardial infarction, lowering plasma homocysteine levels with folic acid and vitamin B12, with or without vitamin B6, did not reduce risk for the composite endpoint of myocardial infarction, stroke, or death from coronary heart disease. The use of vitamin B6, with or without folic acid and vitamin B12, also did not reduce risk.

*See Glossary.

Sources of funding: Norwegian Research Council; Council on Health and Rehabilitation; Norwegian Council on Cardiovascular Disease; Northern Norway Regional Health Authority; Norwegian Red Cross; Foundation to Promote Research into Functional Vitamin B12Deficiency; private donation. Study drugs provided by Alpharma.

For correspondence: Dr. K.H. Bønaa, University of Tromsø, Tromsø, Norway. E-mail

Table. Folic acid plus vitamin B12 and vitamin B6, separately and in combination, to prevent vascular events after myocardial infarction†

Outcomes RRR/RRI (95% CI)
Folic acid/B12 vs no folic acid/B12 B6 vs no B6 Folic acid/B12/B6 vs placebo
Composite endpoint‡ RRI: 8% (−7 to 25) RRI: 14% (−2 to 32) RRI: 22% (0 to 50)
Myocardial infarction RRI: 6% (−9 to 24) RRI: 17% (0 to 37) RRI: 23% (−1 to 52)
Stroke RRI: 2% (−32 to 51) RRR: 19% (−20 to 46) RRR: 17% (−47 to 53)
Death from any cause RRI: 2% (−17 to 26) RRI: 19% (−4 to 46) RRI: 21% (−9 to 61)
Unstable angina RRI: 6% (−11 to 27) RRR: 12% (−5 to 26) RRR: 7% (−19 to 27)
Coronary artery bypass surgery RRR: 10% (−5 to 24) RRR: 1% (−17 to 16) RRR: 11% (−13 to 29)
Percutaneous coronary intervention RRR: 8% (−3 to 18) RRR: 6% (−5 to 17) RRR: 14% (−2 to 28)

†Abbreviations defined in Glossary; RRR, RRI, and CI calculated from data in article. All comparisons were not significant.
‡Myocardial infarction, stroke, or death from coronary heart disease.


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—and 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
Greater Los Angeles VA Healthcare System
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]