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


Therapeutics

Vitamin E was associated with a decreased risk for angina pectoris

ACP J Club. 1996 July-Aug;125:14. doi:10.7326/ACPJC-1996-125-1-014


Source Citation

Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA. 1996 Mar 6; 275:693-8.


Abstract

Objective

To determine whether vitamin E (α-tocopherol), β-carotene, or both reduce the risk for developing angina pectoris in men who were considered initially free of coronary heart disease (CHD).

Design

Randomized, double-blind, placebo-controlled trial with mean follow-up of 4.7 years (Alpha Tocopherol Beta-Carotene [ATBC] Study).

Setting

14 study centers in southern and western Finland.

Patients

22 269 men aged 50 to 69 years (median age 57 y) who smoked ≥ 5 cigarettes/d and did not have a history of angina pectoris or CHD. Exclusion criteria were malignancy, chronic renal insufficiency, liver cirrhosis, alcoholism, anticoagulant therapy, other serious illnesses, and use of supplements that contained vitamin E, vitamin A, or β-carotene. Follow-up was 73%.

Intervention

Randomization was based on a 2 — 2 factorial design. 5570 men were allocated to vitamin E, 50 mg/d; 5602 men were allocated to β-carotene, 20 mg/d; 5548 men were allocated to both; and 5549 men were allocated to neither (placebo).

Main outcome measures

Typical angina (pain, discomfort, heaviness, or pressure in the chest on exertion that was relieved by rest within 10 minutes and situated at the upper or lower sternum area or on the left side of the chest and in the left arm); atypical chest pain; and report of typical angina on 2 of 3 consecutive questionnaires. The treatment-specific incidence of angina was calculated using the Kaplan-Meier method; Cox proportional hazards regression was used to calculate the relative risk (RR) for angina.

Main results

1983 new cases of typical angina occurred during follow-up. The data showed that the 2 supplements did not interact. Vitamin E compared with no vitamin E led to a decrease in the risk for angina (RR 0.91, 95% CI 0.83 to 0.99). The incidence of angina per 1000 patient-years was 19.6 for the vitamin E group and 21.5 for those who did not receive vitamin E. {This means that 517 patients would need to be treated with vitamin E (compared with no vitamin E) for a mean of 4.7 years to prevent 1 additional case of angina.}* β-carotene was not associated with a change in the risk for angina (RR 1.06, CI 0.97 to 1.16). Adjustment for multiple risk factors and analysis of the alternate end points did not substantially alter the risk for angina.

Conclusions

Men with no known CHD who took vitamin E had a small decrease in the risk for angina pectoris. β-carotene was not associated with a change in the risk for angina pectoris.

Source of funding: National Cancer Institute.

For article reprint: Dr. J.M. Rapola, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland.

*Numbers calculated from data in article.


Commentary

Vitamin E reduced the risk for cardiovascular events in coronary atherosclerosis

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.