Routine Vitamin Supplementation To Prevent Cardiovascular Disease: A Summary of the Evidence for the U.S. Preventive Services Task Force

Approximately 60 million persons in the United States have some form of cardiovascular disease (CVD), and in 1996, CVD accounted for 41.4% of all deaths in the United States (1). While hypertension, diabetes, dyslipidemia, and smoking are leading risk factors, nutritional status plays a substantial role in the development of atherosclerotic CVD. Antioxidant nutrients, including vitamin C, vitamin E, and beta-carotene, are thought to play a role in atherosclerosis (25). Some experts believe that mild to moderate deficiencies of these vitamins, although not severe enough to cause classic deficiency diseases, may be involved in the development of CVD (3, 4, 6). Therefore, it is thought that antioxidant supplementation may help reduce the incidence or progression of atherosclerotic CVD. The biological basis of antioxidant use to prevent atherosclerotic heart disease is based largely on the oxidative modification hypothesis of atherosclerosis (6). According to this hypothesis, lipid peroxidation or oxidative modification of low-density lipoprotein is the initiator of atherosclerosis. Antioxidants capable of inhibiting lipid peroxidation should support primary and secondary prevention and consequently reduce cardiovascular events, including myocardial infarction. This evidence review was conducted for the U.S. Preventive Services Task Force (USPSTF) to serve as the foundation for its recommendations on vitamin supplementation for disease prevention. This article addresses a key question posed by the Task Force: Does supplementation with vitamin A, vitamin C, vitamin E, beta-carotene, or a multivitamin reduce cardiovascular death, all-cause mortality, or cardiovascular events in the general adult population of the United States and in a population with evidence of atherosclerotic heart disease? Methods Literature Search and Study Selection Search Strategy We searched the Cochrane Controlled Trials Registry and MEDLINE for relevant papers published in English from 1966 to September 2001, using Medical Subject Headings and keywords for the individual nutrients (vitamin A, vitamin C, vitamin E, beta-carotene, folic acid) and for multivitamin and antioxidant supplements, combined with terms for CVD, coronary artery disease, myocardial infarction, and related risk factors (blood pressure, hypertension, hyperlipidemia, homocysteine). We examined reference lists of review articles (615) and asked experts for additional references. Finally, we searched MEDLINE using the acronyms or full titles of the major trials and cohort studies to identify additional publications. Study Selection The scope of this review was developed with input from the USPSTF. We included reports of randomized trials and prospective cohort studies from U.S. and European populations that assessed use of vitamin supplements and reported incidence of or death from cardiovascular events. We included only studies that measured intake of vitamins from supplements, not from foods; most supplements provide single or limited nutrient combinations, whereas dietary sources are nutritionally complex and complicate data interpretation. Only cohorts that reported specifically on vitamin supplement use with risk ratios independent of dietary intake were included. Both primary and secondary prevention trials were considered but were analyzed separately. Studies conducted in specific populations that were not widely generalizable, such as a cohort with end-stage renal disease, were excluded. Only cohort studies rated as being of good to fair quality, according to predetermined criteria from a system developed by the current USPSTF (16), were included. Studies were excluded if they contained no original data, were not relevant (for example, addressed vitamin deficiency disease), did not report data on the specified outcomes, or took place in an acute care setting. Casecontrol studies were excluded because of retrospective data collection. Two reviewers read titles and abstracts of 2758 identified articles and selected 306 as possibly relevant. Full-text articles of these citations were retrieved for further review. Of these, 38 articles, representing 10 cohort studies and 20 randomized, controlled trials (RCTs), were selected for inclusion in evidence tables. An additional 25 articles were included for background and context. Data Abstraction, Validity Assessment, and Synthesis We abstracted the following descriptive information: population, setting, sample size, supplement (dose, formulation, and frequency), control group intervention, length of follow-up, follow-up rate, confounding factors, factors controlled for in analyses, method of ascertaining adherence, adherence rate, and adverse effects. We recorded data on the following outcomes: cardiovascular events, myocardial infarction, restenosis, change in angina, cardiovascular mortality, and all-cause mortality. Study quality was assessed by using the standards of the current USPSTF (16). For RCTs, we summarized study quality using the Jadad score, which rates trials on a scale of 1 to 5 on the basis of adequacy of randomization method, blinding, and other criteria (17). Data abstraction and quality assessment were conducted independently by at least two reviewers. Disagreements were resolved by consensus or by a third reviewer. Finally, we summarized the strength, level, and quality of the overall evidence tables for the effectiveness of each of the vitamin supplements in preventing CVD. Included Studies We included 11 reports from 10 prospective cohort studies (1828), 12 reports from 10 randomized trials of primary prevention of CVD (2940), and 15 reports from 12 randomized trials of secondary prevention of CVD (4155). The principal epidemiologic cohort studies (Table 1) included the Nurses' Health Study (87 245 female nurses followed for >10 years) (18, 19), the Health Professionals' Follow-up Study (39 910 male health professionals followed for 4 years) (20), the Iowa Women's Health Study (34 486 Iowa women followed for 7 years) (21), and a cohort of 83 639 male physicians invited to participate in the Physicians' Health Study (27). Other studies include the Established Populations for Epidemiologic Studies of the Elderly (11 178 men and women >65 years of age) (23); the first National Health and Nutrition Examination Survey (NHANES I) (22), which followed a similar number of participants; and a study of more than 1 million people recruited for a mortality study by the American Cancer Society (25). These studies were all rated as good or fair using the USPSTF rating scale (16). Most had follow-up rates above 90% after 4 or more years, used well-defined outcomes, and adjusted for relevant confounders. Table 1. Cohort Studies of the Association between Vitamin Supplement Use and Cardiovascular Disease Risk The RCTs of primary prevention (Table 2) principally comprised large factorial trials, including an antioxidant supplement with a co-intervention (angiotensin-converting enzyme inhibitor, aspirin, or lipid-lowering agent) examining CVD incidence or mortality. Of these nine trials, only four had the primary objective of preventing CVD: the Heart Outcomes Prevention Evaluation (HOPE) (35), the Women's Health Study (30), the Primary Prevention Project (36), and the Heart Protection Study (40). The others were designed to test whether antioxidants would prevent cancer or reduce progression of age-related eye disease; cardiovascular events were analyzed as a secondary end point. With one exception (36), all primary prevention trials were double-blind and placebo controlled. Table 2. Randomized, Controlled Trials of Vitamin Supplementation for Primary Prevention of Cardiovascular Disease Among secondary prevention trials, 10 of 12 examined the effects of vitamin supplementation in patients enrolled on the basis of preexisting CVD (Table 3). Two studies analyzed subgroups with previous coronary disease (4144). In addition, two major trials analyzed primary and secondary prevention together (35, 40). Jadad scores for these studies ranged from 3 to 5 on the 5-point scale, indicating fair to good quality. Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Agency staff and Task Force members participated in the initial design of the study and also reviewed interim analyses and the final manuscript. Results Vitamin A One good-quality cohort study evaluated the effect of vitamin A supplementation on incident coronary death (21). Participants in the highest quartile of vitamin A use did not have a lower risk for coronary death than those in the lowest quartile. There are no data from clinical trials on the effect of vitamin A supplements on atherosclerotic CVD. Vitamin C In three of four cohort studies, vitamin C supplementation was not associated with coronary heart disease mortality (2123) or all-cause mortality (23). In two studies in older samples (21, 23), vitamin C use did not protect against coronary disease or all-cause mortality after adjustment for relevant confounders (23). Similarly, vitamin C had no impact on cardiovascular or coronary heart disease mortality (27). However, in a good-quality follow-up study of NHANES I (22), regular use of a vitamin C supplement reduced the standardized mortality ratio for cardiovascular mortality by 48% and for all-cause mortality by 26%. In a cohort analysis of a secondary prevention trial of cholesterol reduction or coronary stenosis, vitamin C use ( 250 mg/d) had no appreciable effect on progression of stenosis (28). Table 3. Randomized, Controlled Trials of Vitamin Supplementation for Secondary Prevention of Cardiovascular Disease Table 3Continued No randomized clinical trial of primary prevention has evaluated the effect of supplementation with vitamin C alone on CVD outcomes. One small, poorly controlled trial of secondary prevention with vitamin C suggested a red