Relation of Consumption of Vitamin E, Vitamin C, and Carotenoids to Risk for Stroke among Men in the United States

Considerable evidence supports the hypothesis that vitamin E reduces the risk for atherosclerosis (1). Vitamin E inhibits the proliferation of smooth-muscle cells in vitro (2) and increases the resistance of low-density lipoprotein to oxidation when it is added to plasma or administered to humans (3, 4). Furthermore, platelets from persons taking vitamin E supplements had markedly reduced adhesiveness to collagen (5). Consistent with these findings, vitamin E intake has been inversely associated with risk for coronary heart disease (6-8) and for peripheral arterial disease (9) and with carotid artery wall thickness (10, 11). Risk for ischemic stroke also increases with atherosclerosis and might therefore be reduced by vitamin E. However, few studies have addressed the relation between vitamin E and risk for ischemic stroke, and those that have been done were small, had little variation in vitamin E intake, or did not distinguish between ischemic and hemorrhagic stroke (12-15). Risk for hemorrhagic stroke is unlikely to be reduced by high doses of vitamin E and could even be increased by the reduced platelet adhesion that these doses cause (5). The most informative previous studiesa large randomized trial in men (16, 17) and a prospective investigation in women (6)supported a modest beneficial effect of vitamin E with respect to ischemic stroke, but the results were not statistically significant. Moreover, in the trial in men (16), this apparent benefit was offset by an increased risk for hemorrhagic stroke. Like vitamin E, vitamin C and carotenoids have antioxidant properties (18, 19) and have been hypothesized to reduce risk for stroke, but epidemiologic evidence to support these hypotheses is limited (14-17, 20-22). Of the carotenoids, we considered -carotene, -carotene, lutein, and lycopene because they are present in relatively large amounts in the diet and have distinct antioxidant properties (23). Our primary hypothesis was that high intake of these antioxidants would reduce risk for ischemic stroke. We report here the associations between intakes of vitamin E, vitamin C, and specific carotenoids and risks for ischemic and hemorrhagic stroke in a large cohort of men in the United States. Methods Study Sample The Health Professionals Follow-up Study began in 1986, when 51 529 health professionals 40 to 75 years of age [24] completed a 131-item food-frequency questionnaire and supplied information about medical history and lifestyle. Follow-up questionnaires were sent every 2 years so that we could update information on potential risk factors, including use of vitamin supplements, and identify newly diagnosed cases of stroke and other diseases. We excluded from analysis 1595 men who did not have 1) a daily caloric intake between 800 and 4200 kcal and 2) fewer than 70 blanks (among 131 listed food items) on the food-frequency questionnaire. We also excluded men with previous myocardial infarction, angina, coronary artery surgery, stroke, transient ischemic attack, peripheral arterial disease, or diabetes. We followed the 43 738 eligible men for incidence of stroke for 8 years. The average response rate for the 2-year follow-up cycles was more than 94%. Nonresponding participants who were not matched to the National Death Index were assumed to be alive. This study was approved by the institutional review board of the Harvard School of Public Health. Assessment of Diet and Other Exposure Variables On the 1986 questionnaire, we asked about 1) the average frequency of intake over the previous year of specified portions of 131 foods and 2) the use of vitamin and mineral supplements. We specifically asked about dose and duration of use of multivitamin, vitamin E, and vitamin C supplements. Nutrient calculations took into account the specific brands of breakfast cereal and multivitamin supplements reported by each participant. We assessed the questionnaire's validity in a random sample of 127 men who completed two 1-week diet records (25); 121 of these men also provided blood samples (26, 27). The correlations between the food-frequency assessments of intake and plasma concentrations were 0.51 for -tocopherol, 0.47 for -carotene and lycopene, 0.35 for -carotene, and 0.40 for lutein. These correlations were similar to those seen between plasma levels of these nutrients and intake of these nutrients as estimated by the two 1-week diet records (25), and they support the validity of the food-frequency questionnaire. Even if dietary measurements were perfect, vitamin intake and plasma levels would not be highly correlated because multiple factors contribute to between-person variations in plasma vitamin levels. The correlation between the food-frequency and diet-record assessments was 0.92 for both vitamin C and vitamin E (25). In 1986, in addition to reporting on diet, participants were asked to report their usual systolic and diastolic blood pressures and whether they had physician-diagnosed hypertension. The validity of these variables has been documented (28). Other potential risk factors for stroke that were assessed at baseline and in the follow-up questionnaire included smoking history, body mass index, history of hypercholesterolemia, physical activity, parental history of myocardial infarction, and alcohol consumption. Events End points were fatal or nonfatal stroke occurring between the return of the baseline questionnaire and 31 January 1994. If a participant reported an incident stroke on a follow-up questionnaire, we asked for permission to review that participant's medical records. Strokes were confirmed if they were characterized by a typical neurologic defect of sudden or rapid onset that lasted at least 24 hours and was attributable to a cerebrovascular event. Strokes caused by infection or neoplasia were excluded. Reviews were conducted by physicians who had no knowledge of participants' risk factor status. Strokes were subclassified, according to the criteria of the National Survey of Stroke, as due to ischemia (embolism or thrombosis), subarachnoid hemorrhage, intracerebral hemorrhage, or an unknown cause (29). If no records could be obtained, a stroke was considered probable if it necessitated hospitalization and was corroborated by additional information provided in a letter or interview. Deaths were initially reported by next-of-kin, coworkers, postal authorities, or the National Death Index. Fatal strokes were confirmed by medical records (84%) or autopsy reports (2%) or were considered probable if medical records or autopsy reports could not be obtained and stroke was listed as the underlying cause of death on the death certificate (14%). Statistical Analysis Participants contributed follow-up time from the return of the 1986 questionnaire to the occurrence of a confirmed stroke or death or 31 January 1994. Men who had nonfatal myocardial infarction or coronary surgery during the follow-up period were retained in the analysis. Intake of vitamin E and other nutrients was energy-adjusted to 2000 kcal/d (30). Relative risks were calculated by dividing the incidence of stroke among men in each quintile of energy-adjusted vitamin E intake at baseline by the incidence of stroke among men in the lowest quintile of intake. Similar calculations were done for the other nutrients. Quintiles were used to avoid assumptions about the shape of the dose-response relation and to provide sufficient power to compare men in the extreme categories of intake. For vitamin E, vitamin C, and -carotene, additional analyses separately considered supplemental and dietary intake. We adjusted relative risks for age (in 5-year categories) (31) and used the Mantel extension test (32) to test for linear trends. To adjust for other risk factors, we used pooled logistic regression with 2-year intervals. Where the probability of an event within an interval is small, this method is equivalent to a Cox proportional-hazards analysis (33). The multivariate models included the following as covariates: calendar time (in 2-year intervals), total energy intake (continuous variable), smoking (current; past; or 1 to 14, 15 to 24, and 25 cigarettes/d), alcohol consumption (<5, 5 to 9, 10 to 14, 15 to 29, or 30 g/d), history of hypertension, history of hypercholesterolemia, parental history of myocardial infarction before 65 years of age, profession, and quintiles of body mass index and physical activity. In these models, we evaluated monotonic trends by using the median value of each category and modeling it as a continuous variable. Analyses were also conducted to update dietary intake and other covariates during follow-up. In these analyses, the incidence of stroke in 1986-1990 was related to vitamin and carotenoid intake reported in 1986, whereas the incidence of stroke in 1990-1994 was related to the average intake reported in 1986 and 1990. Because dietary changes made after the development of intermediate end points, such as coronary heart disease, peripheral arterial disease, transient ischemic attacks, diabetes, and hypercholesterolemia, may confound the associations between diet and disease (34), we repeated the analyses without updating information on diet for men who reached an intermediate end point before completing the 1990 dietary questionnaire. All P values are two-sided. Role of the Funding Source The National Institutes of Health had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results During 323 394 person-years of follow-up, we documented 328 strokes: 210 ischemic, 70 hemorrhagic, and 48 unclassified. Fifty of the 328 strokes were fatal. The distribution of risk factors for stroke differed somewhat by vitamin E, vitamin C, and -carotene intake (Table 1). Men in the top quintiles of vitamin E or vitamin C intakemost of whom used multivitamin or specific vitamin supplementswere less likely to smoke, were more likely to use aspirin, and were more