Background and Purpose-Blood pressure is an important risk factor for stroke, but the roles of serum total and HDL cholesterol, ␣-tocopherol, and ␤-carotene are poorly established. We studied these factors in relation to stroke subtypes. Methods-Male smokers (nϭ28 519) aged 50 to 69 years without a history of stroke participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a controlled trial to test the effect of ␣-tocopherol and ␤-carotene supplementation on cancer. From 1985 to 1993, a total of 1057 men suffered from primary stroke: 85 had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. Results-Systolic blood pressure Ն160 mm Hg increased the risk of all stroke subtypes 2.5 to 4-fold. Serum total cholesterol was inversely associated with the risk of intracerebral hemorrhage, whereas the risk of cerebral infarction was raised at concentrations Ն7.0 mmol/L. The risks of subarachnoid hemorrhage and cerebral infarction were lowered with serum HDL cholesterol levels Ն0.85 mmol/L. Pretrial high serum ␣-tocopherol decreased the risk of intracerebral hemorrhage by half and cerebral infarction by one third, whereas high serum ␤-carotene doubled the risk of subarachnoid hemorrhage and decreased that of cerebral infarction by one fifth. Conclusions-The risk factor profiles of stroke subtypes differ, reflecting different etiopathology. Because reducing atherosclerotic diseases, including ischemic stroke, by lowering high serum cholesterol is one of the main targets in public health care, further studies are needed to distinguish subjects with risk of hemorrhagic stroke.

Abstract-Observational data suggest that diets rich in fruits and vegetables and with high serum levels of antioxidants are associated with decreased incidence and mortality of stroke. We studied the effects of ␣-tocopherol and ␤-carotene supplementation. The incidence and mortality of stroke were examined in 28 519 male cigarette smokers aged 50 to 69 years without history of stroke who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). The daily supplementation was 50 mg ␣-tocopherol, 20 mg ␤-carotene, both, or placebo. The median follow-up was 6.0 years. A total of 1057 men suffered from incident stroke: 85 men had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. Deaths due to stroke within 3 months numbered 38, 50, 65, and 7, respectively (total 160). ␣-Tocopherol supplementation increased the risk of subarachnoid hemorrhage 50% (95% CI Ϫ3% to 132%, Pϭ0.07) but decreased that of cerebral infarction 14% (95% CI Ϫ25% to Ϫ1%, Pϭ0.03), whereas ␤-carotene supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to 136%, Pϭ0.01). ␣-Tocopherol supplementation also increased the risk of fatal subarachnoid hemorrhage 181% (95% CI 37% to 479%, Pϭ0.01). The overall net effects of either supplementation on the incidence and mortality from total stroke were nonsignificant. ␣-Tocopherol supplementation increases the risk of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be due to the antiplatelet actions of ␣-tocopherol. ␤-Carotene supplementation increases the risk of intracerebral hemorrhage, but no obvious mechanism is available. Key Words: ␣-tocopherol Ⅲ ␤-carotene Ⅲ cerebral infarction Ⅲ intracerebral hemorrhage Ⅲ subarachnoid hemorrhage H igh amounts of fruits and vegetables in the diet 1,2 as well as diets rich in antioxidant vitamins 3 have been associated with decreased incidence of stroke. A similar inverse relation has been observed between serum concentrations of antioxidant vitamins and the risk of fatal stroke. 4,5 These findings suggest that the antioxidants may be effective in the primary prevention of stroke. However, associations shown by observational studies, particularly weak ones, must not be causal, because the elimination of both known and especially unknown confounders is difficult, if not impossible. These limitations are abolished in large controlled trials, such as the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study), 6,7 in which evaluation of the effects of ␣-tocopherol and ␤-carotene on cardiovascular diseases was incorporated into the study protocol. In the present study, we report the effects of these antioxidant vitamins on the incidence and mortality from hemorrhagic and ischemic strokes among the participants of the ATBC Study. MethodsThe ATBC Study was a randomized, double-blind, placebocontrolled, 2ϫ2 factorial design trial primarily testing the hypothesis that ␣-tocopherol and ␤-carotene supplements reduce the incid...

Alcohol consumption may have a distinct dose-response relationship within each stroke subtype-linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction-but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved.