on February 19, 2009
Published online before print February 19, 2009, doi: 10.1161/STROKEAHA.108.529503
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Submitted on June 21, 2008
From Division of Neurology (G.S.), Departments of Medicine, and Health Policy Management and Evaluation, St. Michael's Hospital, University of Toronto, Toronto, Ontario; Departments of Medicine, Obstetrics, and Gynecology (G.S., J.G.R.), and Health Policy Management and Evaluation, St. Michael's Hospital, University of Toronto, Toronto, Ontario; Population Health Research Institute (P.S.), Hamilton General Hospital, McMaster University, Hamilton, Ontario; Department of Pathology and Molecular Medicine and Population Health Research Institute (M.M.), Hamilton General Hospital, McMaster University, Hamilton, Ontario; Population Health Research Institute (E.L.), Hamilton General Hospital, McMaster University, and the Department of Medicine, Division of Cardiology, Hamilton Health Sciences, Hamilton, Ontario. * To whom correspondence should be addressed. E-mail: saposnikg{at}smh.toronto.on.ca.
Background and Purpose—Elevated total homocysteine is associated with a higher risk of cerebrovascular disease. It is not known whether lowering homocysteine impacts on stroke risk, both in terms of severity and ischemic vs hemorrhagic stroke subtypes. Our aim was to determine whether vitamin therapy reduces the risk of ischemic and hemorrhagic stroke, as well as stroke-related disability. Methods—We analyzed stroke outcomes among participants of the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial that randomized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or matching placebo, for 5 years. Results—Among 5522 participants, stroke occurred in 258 (4.7%) individuals during a mean of 5 years of follow-up. The geometric mean homocysteine concentration decreased by 2.2 µmol/L in the vitamin therapy group and increased by 0.80 µmol/L in the placebo group. The incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group (hazard ratio [HR], 0.75; 95% CI, 0.59–0.97). Vitamin therapy also reduced the risk of nonfatal stroke (HR, 0.72; 95% CI, 0.54–0.95) but did not impact on neurological deficit at 24 hours (P=0.45) or functional dependence at discharge or at 7 days (OR, 0.95; 95% CI, 0.57–1.56). In subgroup analysis, patients aged younger than 69 years, from regions without folic acid food fortification, with higher baseline cholesterol and homocysteine levels, and those not receiving antiplatelet or lipid-lowering drugs at enrollment had a larger treatment benefit. Conclusions—Lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke, but not stroke severity or disability.
Revised on August 13, 2008
Accepted on August 26, 2008
Homocysteine-Lowering Therapy and Stroke Risk, Severity, and Disability. Additional Findings From the HOPE 2 Trial
Gustavo Saposnik MD, MSc, FAHA*;
Key words: cardiovascular disease • folate • folic acid • homocysteine • primary stroke • randomized clinical trial • secondary stroke • stroke prevention • vitamin B12
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