Daily B vitamin supplementation is no more effective than is placebo for reducing the incidence of major vascular events in patients who have had a recent stroke or transient ischemic attack, according to findings from the Vitamins to Prevent Stroke (VITATOPS) trial.
Among 8,164 patients enrolled in the multicenter, parallel, double-blind trial, major vascular events (nonfatal stroke, nonfatal myocardial infarction, or death from any vascular cause) occurred in 15% of patients randomized to B vitamin supplementation and in 17% randomized to placebo after a median follow-up period of 3.4 years. This translated into a nonsignificant relative risk of 0.91, Dr. Graeme J. Hankey of Royal Perth (Australia) Hospital and his colleagues from the VITATOPS Trial Study Group reported.
When each type of vascular event was analyzed separately, B vitamin supplementation was not associated with a significant reduction in the relative risk for nonfatal or fatal stroke, nonfatal or fatal MI, or death from any cause. However, there was a slight, but statistically significant, reduction in the risk of death from vascular causes (relative risk, 0.86).
Dr. Hankey and his associates wrote that the findings suggest that B vitamins, while safe in poststroke and post-TIA patients, should not be recommended to prevent recurrent stroke (Lancet Neurology 2010 Aug. 4 [doi:10.1016/S1474-4422(10)70187-3]).
Study participants were enrolled between Nov. 19, 1998, and Dec. 31, 2008, within 7 months of experiencing stroke or TIA and were randomized to receive placebo or 2 mg of folic acid, 25 mg of vitamin B6, and 0.5 mg of vitamin B12 daily in addition to usual medical care.
No unexpected adverse events occurred during follow-up, and no significant differences were seen between the treatment and placebo groups in regard to common adverse events, the investigators noted.
Although prior cross-sectional and observational epidemiological studies have suggested that raised plasma concentrations of total homocysteine are associated with increased risk for major vascular events, and that B vitamin supplementation can lower total homocysteine—as it did in this study—this did not translate to a reduced incidence of subsequent vascular events in the study, they said.
Fasting blood tests performed at the end of follow-up in 1,164 patients showed that the B vitamin group had 3.8 micromol/L lower homocysteine than in the placebo group (10.5 vs. 14.3 micromol/L). An analysis of a subset of 925 patients with fasting blood levels of homocysteine available from baseline and follow-up indicated that each 1.0-micromol/L decrease in total homocysteine was associated with only a nonstatistically significant 2% reduction in risk of the primary outcome.
The study is limited by incomplete adherence to trial drugs and by incomplete follow-up, as well as by a relatively short duration of follow-up, the investigators said.
To control for random error, the researchers added their data to those from other randomized controlled trials of homocysteine-lowering therapy in patients with or without preexisting cardiovascular disease. This “updated meta-analysis” also showed that B vitamins are not significantly more effective than placebo for reducing the risk of the composite outcome of stroke, myocardial infarction, or vascular death (RR, 0.99).
In a subgroup analysis, B vitamins were shown to possibly reduce the risk of stroke, myocardial infarction, or vascular death in patients with symptomatic small vessel disease of the brain causing lacunar infarction or intracerebral hemorrhage—a reduction that has also been suggested by other investigators who have reported that homocysteine is a risk factor for cerebral small vessel disease, they noted.
Dr. Hankey and some other authors of the study reported receiving payments and honoraria for various duties from companies that manufacture stroke therapies, including Johnson and Johnson, Sanofi-Aventis, and Schering Plough, Boehringer Ingelheim, and Pfizer.
The study was funded by the Australia National Health and Medical Research Council, the U.K. Medical Research Council, the Singapore Biomedical Research Council, the Singapore National Medical Research Council, the Australia National Heart Foundation, the Royal Perth Hospital Medical Research Foundation, and the Health Department of Western Australia.
My Take
Don't Give Up on B Vitamins Yet
The VITATOPS trial indicated that there is still weak evidence for a small relative risk reduction in fatal or nonfatal stroke with B vitamin supplementation. This is one reason why B vitamins might still be potentially worthwhile in stroke and TIA patients. A much larger global trial would be needed to confirm or refute such moderate effects.
Indeed, there are numerous examples of treatments that required an accumulation of data from large, sufficiently powered trials along with meta-analyses of the data from those trials before the benefits of the treatments were appreciated. Examples include antiplatelet treatment with aspirin, cholesterol reduction with drugs, and tamoxifen for breast cancer.