Abstract & Commentary
The homocysteine (HC) hypothesis has been popularized for a long time since the recognition 35 years ago that elevated HC appears to be associated with vascular disease. A number of case-controlled and retrospective studies, as well as meta-analyses, have confirmed a relationship of elevated HC with stroke and coronary artery disease (CAD), although not all reports have been concordant. A relatively harmless and inexpensive therapy, folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12), lowers HC and has been theorized to decrease the vascular risk associated with elevated HC levels. A recent positive angioplasty trial has provoked further interest within the cardiovascular community. The Vitamin Intervention and Stroke Prevention (VISP) investigators sought to determine whether 2 different doses of folic acid, as well as vitamins B6 and B12, given to individuals following a stroke would reduce subsequent recurrent stroke and CAD outcomes. This multicenter trial enrolled 3700 individuals who had had a stroke no sooner than 72 hours prior to randomization. Subjects were carefully selected by a variety of diagnostic parameters, and all had an unequivocal CVA unrelated to hemorrhagic or embolic events.
Patients were randomized to the high- or low-dose vitamin group with stratification by trial center location, sex, and age. In regard to multivitamins, the high-dose formulation contained 2.5 mg folic acid, compared to 20 mg in the low-dose group. The amounts of pyridoxine and cobalamin were also different in the high-dose and low-dose groups. Patients were followed with "the best available surgical and medical management to prevent current stroke," including daily aspirin. Participants were contacted every 3 months; the study duration was 2 years. In addition to physical and laboratory exams, all patients were given a stroke-symptoms questionnaire. Subsequent cerebral events were evaluated by blinded neurologists, as well as by the questionnaire. Head CT or MRI were obtained in all patients at 2 years and whenever a subject had a suspected cerebral event during the study. CAD data were collected using standard clinical criteria, including nonfatal CAD and death. It was assumed that there would be an 8% probability of recurrent stroke at year 1 and 4% by year 2. The primary end point was a diagnosis of recurrent stroke. Multiple statistical analyses were carried out. During the trial period, there was a small decrease in the HC levels required for study eligibility due to the decline in HC levels in the United States and Canada populations due to folate fortification of the US grain supply. Recruitment took place between 1997 and 2001. The study was terminated early due to an analysis that determined that no difference in event rates between the 2 doses could be found even if the study was continued. HC eligibility cut points for entry were > 8.5 µmol/L for women and > 9.5 for men; three-quarters of screened subjects were eligible. Of all eligible patients, 75-80% were randomized to 1 of 2 HC doses. Current smokers, diabetics, and individuals with a history of chest pain had a somewhat higher likelihood of developing recurrent stroke irrespective of HC levels and dose assignment. Compliance with medication was good.
At the end of the trial, there were an equivalent number of strokes in each group. Mean follow-up was approximately 20 months, and complete data collection was more than 90%. Initial values of HC were identical in 2 groups at 13.4 µmo/L. Both groups experienced a decline in HC levels over the study period, greater in the high-dose vitamin cohort by 2.0 µmo/L at 1 month and 2.3 µmo/L at 2 years. Vitamin B12 levels were substantially greater in the high-dose group and barely changed in the low-dose group. Using an intention-to-treat analysis, the primary end point of recurrent stroke was 8.1% in the low-dose HC group vs 8.4% in the high-dose cohort. Fatal or disabling ischemic strokes were comparable. CAD events were low dose 6.7%, and high dose 6.3% (P = NS), with a slightly lower incidence of CAD events of 0.5% by study completion in the high-dose cohort (NS). Using a combined end point of ischemic stroke, CAD events, and death, there was a 17.2% event rate in the low-dose group vs 16.27% in the high-dose group (NS). In the highest tertile of HC levels at baseline (> 14 µmo/L), high-dose therapy was associated with a decreased risk of stroke, CAD events, and death by approximately 10% (NS). In both treatment groups, there were "persistent and greater associations between baseline total HC and outcomes, significant for stroke at the low dose (P = .02) but NS for the high-dose group" for CAD events P = . 001 for low dose and P = .002 for high dose, with comparable findings for death. Thus, higher HC levels were consistently associated with a greater frequency of vascular events. Although the primary end point was not reached, Toole and associates conclude that the study does support a relationship between HC and vascular disease. They offer multiple explanations for the negative results, including inadequate sample size, a short follow-up period, and most importantly, the advent of folate fortification of US grains that occurred simultaneously with the trial initiation, beginning in 1996 and mandated in 1998, which "profoundly reduced the prevalence of low folate and high total HC levels." Thus, the difference in HC levels between the groups actually narrowed over the treatment period. They suggest that food folate fortification may have reduced the cardiovascular risk of high HC. They also question whether HC may represent a marker and not a cause for vascular disease. Toole et al stress that their data are comparable to other trials indicating that baseline total HC is an independent predictor of vascular outcomes. They call for further trials to explore the relationship between HC and vascular disease, as well as longer trials.
An accompanying editorial by Hanley,1 in the same issue of JAMA, laments the fact that preventive measures for recurrence of ischemic stroke in general are not carried out consistently and do not mirror the more prevalent aggressive approaches to CAD patients. He notes that the stroke rate in the VISP trial was lower than anticipated (only 8% over 2 years). Hanley suggests that HC may have differing effects on coronary vs cerebral arteries (without any data). He also calls for further research and better ways to stratify individuals with recurrent stroke (Toole JF, et al. JAMA. 2004;291:565-575).
Comment by Jonathan Abrams, MD
This trial, as well as other data in the literature, is clearly supportive that homocysteine is related to vascular events, with higher HC levels being linearly related to adverse outcomes. However, this study, with a reasonable dose differential between the low and high multivitamin cocktails, does not support the concept that lowering HC will decrease vascular events, be they cerebrovascular or coronary. The HC gradient and clinical outcomes between the 2 cohorts might have been significant if the high-dose cohort was compared to placebo folate, which would have resulted in a greater HC differential between the cohorts. Data from a recent HC supplement study in CAD patients do not support the routine use of folate with B vitamins for the prevention of CAD. It is clear that preventive measures for first or recurrent stroke, including cigarette cessation, hypertension control, and aggressive lipid therapy, are not commonly used. Thus, far more benefit would be gained by conventional interventions as opposed to adding folate and multivitamins. Along with the demise of the antioxidant vitamins C, E, and beta-carotene, perhaps folate replacement should be rendered to the junk heap of vitamin therapy. While the final word on homocysteine is not in, and current literature clearly supports a linear relationship between HC and vascular events, this trial offers little to suggest a breakthrough. Perhaps one of the ongoing HC trials will yet make me eat my vitamins!
Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.
1. Hanley DF. JAMA. 2004;291:621-622.