Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial.
OBJECTIVE
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 micromol/L in the vitamin therapy group and increased by 0.80 micromol/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.
Saposnik
Gustavo
G
Department of Medicine, Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. saposnikg@smh.toronto.on.ca
Ray
Joel G
JG
Sheridan
Patrick
P
McQueen
Matthew
M
Lonn
Eva
E
D000368:Aged; D004185:Disability Evaluation; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D005500:Follow-Up Studies; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke / Q000453:epidemiology* / Q000503:physiopathology; D014805:Vitamin B 12 / Q000008:administration & dosage; D025101:Vitamin B 6 / Q000008:administration & dosage; D014803:Vitamin B Complex / Q000008:administration & dosage; D014815:Vitamins / Q000008:administration & dosage*
D014815:Vitamins; D006710:Homocysteine; D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12