Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Vitamin E reduced the risk for cardiovascular events in coronary atherosclerosis

ACP J Club. 1996 July-Aug;125:15. doi:10.7326/ACPJC-1996-125-1-015


Source Citation

Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996 Mar 23;347:781-6.


Abstract

Objective

To determine the effectiveness of vitamin E (α-tocopherol) in reducing the risk for myocardial infarction (MI) or cardiovascular death in patients with coronary atherosclerosis.

Design

Double-blind, randomized, placebo-controlled trial with median 510-day follow-up (Cambridge Heart Antioxidant Study [CHAOS]).

Setting

Tertiary care center in England.

Patients

2002 patients (mean age 62 y, 84% men) who had angiographically confirmed coronary atherosclerosis. Patients were excluded if they had previously taken vitamin supplements that contained vitamin E. Follow-up was 98%.

Intervention

Patients were prestratified by sex, blood pressure, age, body mass index, total cholesterol, smoking status, and planned therapy for coronary artery disease, then were randomly assigned to vitamin E, 400 or 800 IU daily (n = 1035), or placebo (n = 967). The first 546 patients assigned to active treatment received vitamin E, 800 IU/d, during the trial; the remaining 489 patients received vitamin E, 400 IU/d. The 2 dosages were not distinguished in the analysis. Compliance was gauged by requests for follow-up medication.

Main outcome measures

Nonfatal MI alone and a combined endpoint of nonfatal MI and cardiovascular death.

Main results

The main analysis was by intention to treat. Treatment with vitamin E led to a lower occurrence of the combined endpoint of nonfatal MI or cardiovascular death compared with placebo (41 events [4%] vs 64 events [7%], P = 0.005). {This absolute risk reduction (ARR) of 3% means that 38 patients would need to be treated (NNT) with vitamin E for a median of 510 days (compared with placebo) to prevent 1 additional major cardiovascular event, 95% CI 21 to 141; the relative risk reduction (RRR) was 40%, CI 13% to 59%.}* Nonfatal MI occurred in 14 patients (1.4%) who received vitamin E compared with 41 patients (4.2%) who received placebo (P = 0.005) {ARR 2.8%, NNT 35, CI 22 to 67; RRR 68%, CI 42% to 82%}*. The vitamin E and placebo groups did not differ for all-cause mortality (3.5% vs 2.7%, P = 0.31).

Conclusion

Vitamin E at doses ≥ 400 IU daily was effective in reducing the risk for nonfatal myocardial infarction in patients with coronary atherosclerosis.

Sources of funding: East Anglia Region; Henkel Corporation; Council for Responsible Nutrition.

For article reprint: Dr. N.G. Stephens, Cardiology Department, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, England, UK. FAX 44-181-869-2588.

*Numbers calculated from data in article.


Commentary

Vitamin E was associated with a decreased risk for angina pectoris

β-carotene and other carotenoids are readily obtainable from many fruits and vegetables, but only small amounts of vitamin E, found mainly in oils, are available from the typical diet. Lipid-soluble antioxidants (e.g., vitamin E and β-carotene) and water-soluble antioxidants (e.g., ascorbic acid and flavonoids) may inhibit the oxidative modification of low-density lipoprotein cholesterol levels and thereby lower the risk for CHD. Antioxidants may also affect CHD risk by other mechanisms (e.g., by decreasing platelet adhesion and aggregation and vascular tone). Because antioxidant vitamin consumption, both from the diet and supplements, may simply be a marker for a generally healthy lifestyle, clinical trials are being done to verify the results of the observational studies that have found an inverse correlation between antioxidant nutrient status and CHD risk.

The 2 abstracted studies represent important contributions to this area of research, with its long history of controversy (1). The study by Rapola and colleagues (ATBC) was a large primary CHD prevention trial with incident angina as the end point, and the study by Stephens and colleagues (CHAOS) was a secondary CHD prevention trial with nonfatal MI and cardiovascular death as end points. In the ATBC study, low-dose vitamin E supplementation (50 mg/d) was associated with a small reduction in angina risk. The dose of vitamin E used in this study, however, may have been too low. Larger doses of vitamin E (≥ 100 IU/d) may be necessary before substantial reductions in CHD risk are seen (2, 3). In the CHAOS trial, higher-dose vitamin E supplementation (400 and 800 IU/d) resulted in a 68% relative risk reduction for nonfatal MI, although no association was found between vitamin E supplementation and risk for cardiovascular death. It is important to note that no increase in side effects was reported among participants taking these larger doses of vitamin E.

In the analysis of data from the ATBC study, β-carotene supplementation (20 mg/d) had no effect on angina risk and, in fact, was previously reported to increase the risk for lung cancer among the study population of middle-aged Finnish men who smoked (4). Recently announced results from the Physicians' Health Study (5) and the Beta Carotene and Retinol Efficacy Trial (CARET) (6) also found no benefit from β-carotene supplementation. Because no convincing data exist that β-carotene supplementation is of benefit (and possibly may be harmful), it is not recommended.

Whether to recommend vitamin E supplementation is more problematic. Observational data suggest that vitamin E lowers CHD risk. Results from the ATBC study and CHAOS concur with these data. The magnitude of the angina risk reduction associated with vitamin E supplementation in the ATBC study was small, however, and vitamin E supplementation did not lower total mortality in either study. Although traditional CHD risk reduction strategies (e.g., smoking cessation, diet, and exercise) remain paramount, physicians will need to respond to their patients when asked about vitamin E supplementation. As with other issues that are clinically uncertain, the potential benefits and risks should be discussed using the available, albeit incomplete, data. Some patients may reasonably make an informed decision to take a vitamin E supplement (100 to 400 IU/d) pending the results of ongoing trials.

Joel A. Simon, MD, MPH
San Francisco Veterans Affairs Medical CenterUniversity of California, San FranciscoSan Francisco, California, USA


References

1. Vitamin E and heart disease [Editorial]. JAMA. 1946;131:746.

2. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444-9.

3. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328:1450-6.

4. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029-35.

5. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long term supplementation with β-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334:1145-9.

6. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of β-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-5.