Update on Vitamin Supplements for the Prevention of Coronary Disease and Stroke

Author: Kevin A. Pearce, Bryan Yeager
Date: Sept 15, 2000

Dietary antioxidants and folic acid may play a role in the pathophysiology of coronary disease and stroke. We review patient-oriented evidence on the effectiveness of supplementation with antioxidants and/or folic acid in the prevention of myocardial infarction and stroke. Observational data suggest cardiovascular benefit of vitamin E supplementation, but results of controlled clinical trials are inconsistent regarding the effect on nonfatal myocardial infarction. Moreover, studies have not shown a protective effect of vitamin E against fatal myocardial infarction and have not addressed stroke. For vitamin C and folic acid supplementation, observational data are inconsistent and controlled clinical trials are lacking. Thus, the available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of myocardial infarction or stroke. The evidence argues against the use of beta carotene supplements for this purpose. The costs and risks associated with these supplements are low, however, and physicians may choose to recommend vitamin E, folate and/or vitamin C supplementation pending conclusive evidence from clinical trials. (Am Fam Physician 2000;62:1359-66.)

Because dietary antioxidants and folic acid (folate) may play a part in the pathophysiology of coronary disease and stroke, interest in the role of vitamin supplements in preventing these diseases is high. This article reviews the evidence from patient-oriented studies to provide information to help physicians decide whether to recommend supplements of antioxidants and/or folate in the prevention of coronary disease and stroke.

Biological Plausibility

Oxidized low-density lipoprotein (LDL) cholesterol attracts and interacts with monocytes, macrophages and platelets to promote atherogenesis in the vascular lining. It also causes endothelial necrosis and interferes with vasorelaxation. Unlike beta carotene, vitamins E and C inhibit LDL oxidation in vitro. Vitamin E reduces monocyte adhesion to endothelium, inhibits platelet activation in vitro and inhibits atherosclerosis in rodents; in humans, angiographic and ultrasonographic studies suggest that vitamin E also inhibits the progression of atherosclerosis.(1)

Homocysteine is an amino acid product of normal protein metabolism. Folate, vitamin B12 and vitamin B6 are all involved in the metabolism of homocysteine. Deficiencies of one or more of these vitamins can lead to hyperhomocysteinemia.(2,3) Homocysteinuria is a rare, congenital enzyme deficiency that results in high serum and urine levels of homocysteine, and persons with this disorder have premature vascular disease and usually die of myocardial infarction (MI), stroke or pulmonary embolus.(2)

Homocysteine, at five to 10 times the normal concentrations, directly damages endothelium, promotes proliferation of vascular smooth muscle cells, exhibits procoagulant activity and increases collagen synthesis.(4) Results of clinical studies reveal that folate and vitamin B12 supplements lower serum homocysteine levels, with mixed results from vitamin B6 supplementation.(2,5) Of these three B vitamins, folate has been studied the most and clearly shows the most powerful effect.(2-5)

Observational Studies

ANTIOXIDANT VITAMINS

Prospective observational studies (Table 1)(6-14) have addressed whether the intake of vitamin C, vitamin E or beta carotene affects cardiovascular risk after adjustment for known major cardiovascular risk factors. Some studies combined dietary and supplemental intakes, while others attempted to separate these sources. Taken together, the results of these studies do not support any conclusions about potential differential effects by vitamin source.

Seven studies(6-12) examined the association of vitamin E intake (from diet and/or supplement sources) with coronary disease. The results of all of these studies except two(10,12) reported a reduction in coronary events associated with higher vitamin E intakes. The only vitamin E study that included stroke6 reported a statistically insignificant trend favoring its use.

Eight studies(7-14) examined the association of vitamin C intake with the incidence of coronary disease. Results were inconsistent between genders and among cohorts, and two of these studies failed to control for vitamin E use.(13,14) The results of one study(14) that investigated stroke revealed an apparent protective effect of vitamin C.

Five prospective cohort studies(7-10,12) examined associations between coronary disease and beta carotene intake. Results of three studies(8-10) revealed no evidence of a protective effect. In the other two studies,(7,12) a protective association was observed only among smokers and ex-smokers.

HOMOCYSTEINE AND FOLATE

Multiple cross-sectional and case-control studies linking plasma homocysteine levels with coronary disease and stroke have been published. The only prospective data come from nested case-control studies involving small subsamples within large cohort studies. Two recent systematic reviews(15,16) have summarized this literature. The first review(15) included 15 studies on coronary disease (involving 5,617 persons) and nine studies addressing stroke (involving 2,547 persons) in a meta-analysis. In all but two of the studies included in this analysis, coronary and stroke risks were higher in persons with higher homocysteine levels. The second review(16) summarized pertinent studies published since the first review. Results of all but five of the 26 studies in this review revealed a positive relationship between plasma homocysteine and coronary disease and/or stroke.

Since the time of these reviews, results of three more prospective studies have been published.(17-19) Among all 12 of the prospective studies now reported, five(17,18,20-22) failed to demonstrate that plasma homocysteine levels were a risk factor for coronary disease or stroke. This lack of consistency among prospective studies makes a causal relationship questionable.

If hyperhomocysteinemia causes cardiovascular disease, then folate supplementation should help prevent it. As yet, there are no reports that link folate intake directly with coronary disease or stroke, but results of interventional studies of folate supplementation have consistently shown a reduction in homocysteine levels, with a plateau effect at a dosage of about 1 mg per day.(5,15)

SUMMARY OF OBSERVATIONAL STUDIES

The prospective observational evidence is fairly consistent for a protective effect of vitamin E against coronary disease. Evidence about the effect of vitamin E on the risk of stroke is sparse. The evidence linking vitamin C to cardiovascular disease is inconsistent, and a protective effect of beta carotene has been observed only among those who smoke. These studies all addressed primary prevention, and absolute risk reductions appear modest at best.

Based on our calculations, if the observed protective effect of vitamin E is real, 170 to 250 persons would need to take vitamin E supplements (or have high dietary vitamin E intake) for 10 years to prevent one MI or stroke. Observational evidence linking homocysteine with cardiovascular disease is less consistent among prospective studies than in cross-sectional or retrospective analyses.

Controlled Clinical Trials

Observational studies cannot prove or disprove a protective effect because they cannot avoid the real possibility that intake of these vitamins is only a marker for other factors or behaviors that are the true modulators of heart attack and stroke. In the case of antioxidant vitamins and cardiovascular disease, results of seven controlled clinical trials have been reported (Table 2).(23-30) Results from controlled clinical trials on the effects of folate supplements in the prevention of MI or stroke have yet to be published.

Neutral or negative effects were reported in all four primary prevention trials.(23,25-27) However, only two of these included vitamin E and at doses that were only about one half of that associated with reduced cardiovascular risk in observational studies. In the Alpha Tocopherol Beta Carotene Cancer Prevention Trial(23) (ATBC), neither vitamin E (50 IU per day) nor beta carotene (20 mg per day) had a significant effect on the risk of a first MI or stroke. In the Beta Carotene and Retinol Efficacy Trial,(26) the combination of 30 mg per day of beta carotene plus 25,000 IU per day of vitamin A increased the risk of death from all causes, with a marginally significant increase in the risk of cardiovascular death.

TABLE 1Observational Studies of Antioxidant VitaminsStudy DesignNurse's Health(6) 87,245 women; follow-up for 8 years Vitamin E [greater than or equal] 100 IU per dayHealth Professionals(7) 39,910 men; follow-up for 4 years Vitamin E [greater than or equal] 100 IU per day Beta carotene [greater than or equal] 14,000 IU per day Vitamin C up to 1,100 mg per dayIowa Women(8) 34,486 women; follow-up for 7 years Vitamin E [greater than or equal] 10 IU per day Beta carotene [greater than or equal] 13,000 IU per day Vitamin C [greater than or equal] 196 mg per dayFinnish cohort(9) 5,133 men/women; follow-up for 14 years Vitamin E [greater than or equal] 5 IU per day Vitamin C [greater than] 90 mg per day Beta caroteneNational Health and 11,348 men/women; follow-upNutrition Examination for 10 yearsSurvey (NHANES)(13) Vitamin C [greater than or equal] 50 mg per dayGale, et al.(14) 730 elderly men/women; follow-up for 20 years Vitamin C [greater than or equal] 45 mg per dayEstablished Populations 11,178 elderly men/women;for Epidemiologic follow-up for 6 yearsStudies of the Elderly Vitamin E supplement use(EPESE)(11)[*] Vitamin C supplement useScottish Heart Health 11,629 men/women; follow-upStudy(10)[] for 8 years Vitamin E Vitamin C Beta caroteneThe Rotterdam Study(12)[] 4,802 men/women; follow-up for 4 years Vitamin E Vitamin C Beta caroteneDesign Outcomes (95% confidence interval)87,245 women; follow-up Endpoints: MI or strokefor 8 yearsVitamin E [greater than or equal] 100 IU per day RR: 0.57 (range: 0.41 to 0.78)39,910 men; follow-up for 4 years Endpoints: MI or coronary revascularizationVitamin E [greater than or equal] 100 IU per day RR: 0.63 (range: 0.47 to 0.84)Beta carotene [greater than or equal] 14,000 IU per day RR: 0.30 (range: 0.11 to 0.72)Vitamin C up to 1,100 mg per day No effect34,486 women; follow-up Endpoint: fatal MIfor 7 yearsVitamin E [greater than or equal] 10 IU per day RR: 0.38 (range: 0.18 to 0.80)Beta carotene [greater than or equal] 13,000 IU per day No effectVitamin C [greater than or equal] 196 mg per day No effect5,133 men/women; Endpoint: fatal MIfollow-up for 14 yearsVitamin E [greater than or equal] 5 IU per day RR: 0.35 (range: 0.14 to 0.88)Vitamin C [greater than]90 mg per day RR: 0.49 (range: 0.32 to 0.98)Beta carotene No effect11,348 men/women; follow-up Endpoint: cardiovascular deathfor 10 yearsVitamin C [greater than or equal] 50 mg per day Men--RR: 0.58 (range: 0.53 to 0.82) Women--RR: 0.75 (range: 0 .55 to 0.99)730 elderly men/women; follow-up Endpoints: fatal stroke or MIfor 20 yearsVitamin C [greater than or equal] 45 mg per day RR: 0.50 (range: 0.30 to 0.80), stroke only11,178 elderly men/women; Endpoint: fatal MIfollow-up for 6 yearsVitamin E supplement use RR: 0.53 (range: 0.34 to 0.84)Vitamin C supplement use No effect11,629 men/women; follow-up Endpoints: MI or coronaryfor 8 years revascularizationVitamin E No significant effectVitamin C No significant effectBeta carotene No significant effect4,802 men/women; follow-up for MI4 yearsVitamin E No effectVitamin C No effectBeta carotene RR: 0.55 (range: 0.34 to 0.83)Design Comments87,245 women; follow-up Trend towards stroke preventionfor 8 yearsVitamin E [greater than or equal] 100 IU per day39,910 men; follow-up for 4 yearsVitamin E [greater than or equal] 100 IU per dayBeta carotene [greater than or equal] 14,000 IU per day Beta carotene benefit in smokers onlyVitamin C up to 1,100 mg per day34,486 women; follow-upfor 7 yearsVitamin E [greater than or equal] 10 IU per day Supplement use rare in this cohortBeta carotene [greater than or equal] 13,000 IU per dayVitamin C [greater than or equal] 196 mg per day5,133 men/women; Supplement use rare in thisfollow-up for 14 years cohortVitamin E [greater than or equal] 5 IU per day Benefit among women onlyVitamin C [greater than]90 mg per dayBeta carotene11,348 men/women; follow-up Vitamin E intake unaccountedfor 10 years forVitamin C [greater than or equal] 50 mg per day730 elderly men/women; follow-up Vitamin E intake unaccountedfor 20 years forVitamin C [greater than or equal] 45 mg per day Fatal MI--no effect11,178 elderly men/women;follow-up for 6 yearsVitamin E supplement use RR: 0.53 (range: 0.34 to 0.84)Vitamin C supplement use No effect11,629 men/women; follow-upfor 8 yearsVitamin EVitamin C Trend toward protectionBeta carotene Trend toward protection4,802 men/women; follow-up for4 yearsVitamin EVitamin CBeta carotene Beta carotene benefit in smokers onlyMI = myocardial infarction; RR = relative risk.[*]--Milligram doses of vitamins E and C in supplements not reported.[]--Vitamin doses adjusted for dietary energy intakes--dosesin mg per day units not reported.Information from references 6 through 14.TABLE 2Placebo-Controlled Clinical Trials of Antioxidant VitaminsStudy Study populationAlpha Tocopherol Beta 29,133 male smokers;Carotene Cancer follow-up for 6 yearsPreventionTrial (ATBC)(23)[*](24)[] Same as abovePhysician's Health(25)[*] 22,071 men; follow-up for 12 yearsBeta Carotene and 18,314 men/women;Retinol Efficacy Trial follow-up for 4 years(CARET)(26)[*]Chinese Ca 29,584 men/women;Prevention(27)[*] follow-up for 5 years Same as aboveCambridge Heart 2,002 men/women withAntioxidant Study CHD; follow-up for(CHAOS)(28)[] 1.5 yearsHeart Outcomes 9,541 men/women withPrevention Evaluation CVD; follow-up for(HOPE)(29)[] 4.5 yearsGISSI-Prevenzione(30)[] 11,324 men/women secondary prevention after recent MI; follow-up for 3.5 yearsStudy population Treatment29,133 male smokers; Vitamin E, 50 IU per dayfollow-up for 6 yearsSame as above Beta carotene, 20 mg per day22,071 men; follow-up Beta carotene, 50 mg everyfor 12 years other day18,314 men/women; Beta carotene, 30 mg per dayfollow-up for 4 years plus vitamin A, 25,000 IU per day29,584 men/women; Vitamin E, 30 IU per day,follow-up for 5 years plus beta carotene, 15 mg per daySame as above Vitamin C, 120 mg per day2,002 men/women with Vitamin E, 400 to 800 IU perCHD; follow-up for day1.5 years9,541 men/women with Vitamin E, 400 IU per dayCVD; follow-up for4.5 years11,324 men/women Vitamin E, 300 mg per day[]secondary preventionafter recent MI;follow-up for 3.5 yearsStudy population Endpoint(s)29,133 male smokers; MI or strokefollow-up for 6 yearsSame as above MI or stroke22,071 men; follow-up MI or strokefor 12 years18,314 men/women; Death--any cause;follow-up for 4 years cardiovascular death29,584 men/women; Cardiovascular deathfollow-up for 5 yearsSame as above Cardiovascular death2,002 men/women with Fatal or nonfatal MICHD; follow-up for1.5 years9,541 men/women with MI, stroke orCVD; follow-up for cardiovascular death4.5 years11,324 men/women MI, stroke orsecondary prevention cardiovascular deathafter recent MI;follow-up for 3.5 years Outcomes (95%Study population confidence interval)29,133 male smokers; No effect for primaryfollow-up for 6 years prevention RR: 0.62 (range: 0.41 to 0.96) for nonfatal MI if past history of MISame as above No significant effect22,071 men; follow-up No effectfor 12 years18,314 men/women; Marginal increases infollow-up for 4 years risk for both outcomes29,584 men/women; No significant effectfollow-up for 5 yearsSame as above No effect2,002 men/women with RR: 0.27 (0.11 to 0.47),CHD; follow-up for (nonfatal MI only)1.5 years9,541 men/women with No effect on any ofCVD; follow-up for these three outcomes4.5 years11,324 men/women No effect on any ofsecondary prevention these three outcomesafter recent MI;follow-up for 3.5 yearsStudy population Comments29,133 male smokers; Vitamin E dose lower thanfollow-up for 6 years observed as protective in most observational studiesSame as above Trend toward increased risk22,071 men; follow-up --for 12 years18,314 men/women; --follow-up for 4 years29,584 men/women; Vitamin E dose low; trendfollow-up for 5 years toward fatal stroke protectionSame as above --2,002 men/women with No effect on fatal MICHD; follow-up for1.5 years9,541 men/women with --CVD; follow-up for4.5 years11,324 men/women Also studied n-3secondary prevention polyunsaturated fattyafter recent MI; acids, which werefollow-up for 3.5 years protectiveMI = myocardial infarction; RR = relative risk;CHD = coronary heart disease; CVD = cardiovascular disease.[*]--Primary prevention trials.[]--Secondary prevention trials.[]--Vitamin E dosage equivalent: 1 mg = 1.26 IU.Information from references 23 through 30.

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