Trials That Matter: Should We Routinely Measure Homocysteine Levels and Treat Mild Hyperhomocysteinemia?

Several observational studies involving healthy populations in the 1990s showed positive associations between elevated homocysteine level and increased risk for ischemic heart disease and stroke (1). Several small trials conducted in western populations in the early and mid-1990s suggested that daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 mol/l to 8-9 mol/l) (2). In 1998, the U.S. Food and Drug Administration mandated fortification of enriched cereal grain flour products with 140 g of folic acid per 100 g of flour (3). The prevalence of folate deficiency and hyperhomocysteinemia fell sharply (4). A population cohort study that assessed the impact of folic acid fortification found a decrease in stroke deaths in the year after fortification (5). Several large secondary prevention trials in patients with vascular disease began. One of the first trials, the Vitamin Intervention for Stroke Prevention (VISP) trial, found that a moderate reduction of total homocysteine level after nondisabling cerebral infarction had no statistically significant effect on vascular outcomes during 2 years of follow-up (6). The trial was designed with the expectation of lowering homocysteine levels by 5 mol/L, but a lower than expected average baseline homocysteine level permitted only a 2-mol decrease in plasma homocysteine. Two larger, double-blind, placebo-controlled trials with longer follow-up followed: the Heart Outcomes Prevention Evaluation (HOPE) 2 (7) and the Norwegian Vitamin (NORVIT) Trial (8). What Did These Landmark Trials Show? The HOPE 2 trial involved 5522 adults with vascular (coronary, cerebrovascular, or peripheral) disease or diabetes and additional risk factors (7). Most were older (average age, 69 years) men (71%) from countries with folate fortification of food (72%). Few (11%) smoked. Many took several cardiovascular therapies, such as aspirin (80%), -blockers (47%), lipid-lowering agents (60%), or angiotensin-converting enzyme inhibitors (66%), and 12% took multivitamins. Patients were randomly assigned to daily treatment with either the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B6 or placebo. Adherence to assigned therapy was high: Ninety-one percent of patients were taking the study treatment at 5 years, and only 2% to 5% took open-label folic acid supplements. Ninety-nine percent of participants completed follow-up. No serious drug-related adverse events were reported. Mean plasma homocysteine levels decreased from about 12 mol/L to 9.7 mol/L in the active therapy group and increased to 12.9 mol/L in the placebo group. Over an average follow-up of 5 years, about 20% of the patients in each group either died of cardiovascular causes or had a stroke or myocardial infarction. Fewer active-treatment patients had a stroke (relative risk, 0.75 [95% CI, 0.59 to 0.97]), but more were hospitalized for unstable angina (relative risk, 1.24 [CI, 1.04 to 1.49]). Preplanned analyses showed no statistically significant benefits for the primary composite outcome of death from cardiovascular causes, myocardial infarction, and stroke in several subgroups, including patients with high baseline levels of homocysteine. The NORVIT Trial included 3749 persons from Norway (a country without folate fortification) with recent myocardial infarction (8). Most were older (average age, 63 years) men (74%). Many were smokers (48%) and took cardiovascular-related therapies, such as aspirin (88%), -blockers (91%), statins (81%), and angiotensin-converting enzyme inhibitors (31%). About one third took vitamin supplements. Patients were randomly assigned, in a 22 factorial design, to 1 of 4 daily therapies: 0.8 mg of folic acid, 0.4 mg of vitamin B12, and 40 mg of vitamin B6; 0.8 mg of folic acid and 0.4 mg of vitamin B12; 40 mg of vitamin B6; or placebo. Eleven percent stopped taking the study medication during the trial. No serious adverse effects were reported. Twenty patients had incomplete follow-up data on nonfatal cardiovascular events. Over an average follow-up of 3 years, mean plasma homocysteine levels decreased from about 13 mol/L to between 9.5 mol/L and 9.8 mol/L in groups that were given folic acid and did not change in the groups that took vitamin B6 alone or placebo. Groups given folic acid and vitamin B12 had no statistically significant reductions in the composite primary outcome of myocardial infarction, stroke, and sudden death or in total mortality compared with groups not given folic acid and vitamin B12. Compared with the placebo group, the group given folic acid, vitamin B12, and vitamin B6 had an increased risk for the composite primary outcome (rate ratio, 1.22 [CI, 1.00 to 1.50]) and for myocardial infarction (rate ratio, 1.23 [CI, 0.99 to 1.52]). How Do the Trials Advance Knowledge? The findings are sobering. They dampen enthusiasm for the homocysteine hypothesis that postulates a causal relationship between hyperhomocysteinemia and atherosclerosis. Before casting aside that hypothesis, however, one should examine the context and limitations of the trials. Several factors could explain an apparent null effect of homocysteine-lowering therapy on cardiovascular outcomes. First, therapy may not have reduced homocysteine levels relative to baseline levels or to control group levels enough to see a salutary effect on clinical outcomes. Baseline mean total homocysteine concentrations were about 12 mol/L to 13 mol/L in the trials, and treatments reduced concentrations by about 15% to 20% (2.3 mol/L to 3.5 mol/L). Theoretically, more marked lowering of homocysteine in groups with higher baseline levels might benefit some patients. Second, even the large HOPE 2 trial may have included too few patients to exclude possible small proportional reductions of about 15% in either the composite outcome or myocardial infarction, and no trials included enough patients to exclude possible large proportional reductions of about 40% in stroke. Third, hyperhomocysteinemia might cause cardiovascular disease, but therapy aimed at lowering homocysteine levels might have independent and deleterious effects that offset potential benefits. The unexpected finding of increased rates of cardiovascular events among patients receiving combined vitamin B treatment in the NORVIT Trial suggests this possibility. Also, as pointed out in an editorial accompanying that trial, folic acid might adversely affect either atherosclerotic plaque formation or homocysteine metabolism (9). Fourth, hyperhomocysteinemia may mark increased risk for cardiovascular disease but may not cause it. What Should Clinicians Do? Many physicians already follow the recommendations set out by the American Heart Association in 1999, in which population-wide screening for blood homocysteine is not recommended until (or unless) controlled clinical trials show that modifying homocysteine levels reduces cardiovascular disease risk (10). Although several major trials are still ongoing, current best evidence shows that supplements combining folic acid and vitamin B do not reduce overall cardiovascular disease risk by large amounts in patients with vascular disease and homocysteine levels of about 12 mol/L to 13 mol/L. In 2006, we find that folate deficiency and hyperhomocysteinemia decreased markedly after mandated folic acid fortification of food products, and we have no proven beneficial therapy that targets homocysteine levels that are prevalent in the U.S. population. Ergo, clinicians need not routinely measure homocysteine levels nor routinely treat mild hyperhomocysteinemia with folic acid or vitamin B supplementation.