Vitamin E and beta carotene supplementation in high risk for stroke: a subgroup analysis of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.

CONTEXT: High serum or dietary levels of vitamin E and beta carotene appear to be associated with lower risk of stroke, but studies regarding their supplementation have not supported their use in stroke prevention. OBJECTIVE: To determine if vitamin E (dl-alpha tocopherol) and beta carotene supplementations could be used in prevention of stroke in men at high risk for hemorrhagic or ischemic events. DESIGN: Population-based, randomized, double-blind, placebo-controlled, 2 x 2 factorial design trial (the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study), conducted from April 1985 through April 30, 1993, with median follow-up of 6 years. INTERVENTIONS: Alpha tocopherol, 50 mg; beta carotene, 20 mg; both; or placebo. PARTICIPANTS: From the total male population aged 50 through 69 years in southwestern Finland (n = 290,406), 29,133 male smokers were randomized to 1 of 4 treatment regimens. We excluded 614 men because of previous stroke at baseline, leaving 28, 519. MAIN OUTCOME MEASURES: Incident and fatal subarachnoid and intracerebral hemorrhage, cerebral infarction, and unspecified stroke. RESULTS: Stroke occurred in a total of 1057 men: 85 had subarachnoid and 112 had intracerebral hemorrhage, 807 had cerebral infarction, and 53 had unspecified stroke. Within 90 days from onset, 160 men died of stroke. Vitamin E supplementation increased the risk of subarachnoid hemorrhage (relative risk [RR], 2.45; 95% confidence interval [CI], 1.08-5.55) and decreased risk of cerebral infarction (RR, 0.70; 95% CI, 0.55-0.89) in hypertensive men but had no effect among normotensive men. Furthermore, it decreased the risk of cerebral infarction, without elevating the risk of subarachnoid hemorrhage, among hypertensive men with concurrent diabetes (RR, 0.33; 95% CI, 0.14-0.78). Beta carotene supplementation appeared to increase the risk of intracerebral hemorrhage and modestly decrease that of cerebral infarction among men with greater alcohol consumption. CONCLUSION: Vitamin E supplementation may prevent ischemic stroke in high-risk hypertensive patients, but further studies are needed. Arch Neurol. 2000;57:1503-1509

Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers.

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 alpha-tocopherol and beta-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 alpha-tocopherol, 20 mg beta-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). alpha-Tocopherol supplementation increased the risk of subarachnoid hemorrhage 50% (95% CI -3% to 132%, P=0.07) but decreased that of cerebral infarction 14% (95% CI -25% to -1%, P=0.03), whereas beta-carotene supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to 136%, P=0.01). alpha-Tocopherol supplementation also increased the risk of fatal subarachnoid hemorrhage 181% (95% CI 37% to 479%, P=0.01). The overall net effects of either supplementation on the incidence and mortality from total stroke were nonsignificant. alpha-Tocopherol supplementation increases the risk of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be due to the antiplatelet actions of alpha-tocopherol. beta-Carotene supplementation increases the risk of intracerebral hemorrhage, but no obvious mechanism is available.

Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants.

BACKGROUND AND PURPOSE: Blood pressure is an important risk factor for stroke, but the roles of serum total and HDL cholesterol, alpha-tocopherol, and beta-carotene are poorly established. We studied these factors in relation to stroke subtypes. METHODS: Male smokers (n=28 519) 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 alpha-tocopherol and beta-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 > or = 160 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 > or = 7.0 mmol/L. The risks of subarachnoid hemorrhage and cerebral infarction were lowered with serum HDL cholesterol levels > or = 0.85 mmol/L. Pretrial high serum alpha-tocopherol decreased the risk of intracerebral hemorrhage by half and cerebral infarction by one third, whereas high serum beta-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. The performance of antioxidants needs confirmation from clinical trials.

Alcohol consumption and stroke incidence in male smokers.

BACKGROUND: Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available. METHODS AND RESULTS: We studied the risk of stroke in 26 556 male cigarette smokers 50 to 69 years of age without history of stroke. The men were categorized as nondrinkers, light (60 g/d) drinkers. A total of 960 men suffered from incident stroke: 83 with subarachnoid and 95 with intracerebral hemorrhage, 733 with cerebral infarction, and 49 with unspecified stroke. The adjusted relative risk of subarachnoid hemorrhage was 1.0 in light drinkers, 1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with nondrinkers. The respective relative risks of intracerebral hemorrhage were 0.8, 0.6, and 1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood pressure attenuated the effect of alcohol consumption in all subtypes of stroke, whereas HDL cholesterol strengthened the effect of alcohol in subarachnoid hemorrhage and cerebral infarction but attenuated the effect in intracerebral hemorrhage. CONCLUSIONS: 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.

Validation of stroke diagnosis in the National Hospital Discharge Register and the Register of Causes of Death in Finland.

The validity of stroke diagnosis in the National Hospital Discharge Register and the Register of Causes of Death was examined among 546 middle-aged men in Finland. The subjects were cases of cerebrovascular diseases of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and identified by record linkage to the registers. In all, 375 events with cerebrovascular disease as hospital discharge diagnosis and 218 events with cerebrovascular disease as the underlying cause of death were reviewed using specific criteria modified from the classifications of the National Survey of Stroke and the WHO MONICA Study. For hospital stroke diagnoses, there was agreement on diagnosis for all strokes in 90%, for subarachnoid hemorrhage in 79%, intracerebral hemorrhage in 82%, and cerebral infarction in 90%. The respective agreement rates for stroke as the underlying cause of death were 97%, 95%, 91%, and 92%. The data were insufficient for review in 1% and 3% of the stroke events, respectively. Age, observation year and trial supplementation with alphatocopherol or beta-carotene had no effect on validity. In conclusion, the validity of stroke diagnosis was good in registers of hospital diagnoses and causes of death justifying their use for endpoint assessment in epidemiological studies.