Vitamin E supplementation and cardiovascular events in high risk patients
Title: Vitamin E supplementation and cardiovascular events in high risk patients
Authors: The Heart Outcomes Prevention Evaluation Study Investigators
Reference: N Engl J Med 2000;342:254-60.
Reviewer: Joaquin Barnoya
Problem addressed: Oxidative modification of low-density lipoprotein is an important step in the development and progression of atherosclerosis in experimental studies, and antioxidants such as vitamin E have been shown to slow atherosclerosis. Observational studies have indicated that persons who consume more than 100 IU of vitamin E a day for more than two years have lower rates of coronary events and lower rates of progression of coronary artery lesions. Results from four randomized controlled trials of the relation between vitamin E and coronary heart disease are conflicting.
Study design: The authors evaluated a high dose (400 IU per day) of vitamin E from natural resources, in a large, five-year, prospective study of patients at high risk for cardiovascular events. After nearly 4.5 years of follow-up, the collection of data on cardiovascular disease was stopped in April 1999 on the basis of a finding by the independent data and safety monitoring board that the trial had conclusively demonstrated the benefits of ramipril and lack of effect of vitamin E on cardiovascular events.
Methods: The Heart Outcomes Prevention Evaluation (HOPE) Study is a double-blind, randomized trial with a two-by-two factorial design, conducted to evaluate the effects of ramipril and vitamin E in 9541 patients at high risk for cardiovascular events. Eligible patients at high risk were randomly assigned to receive either 400 IU of vitamin E from natural resources or an equivalent placebo daily for 4 to 6 years (mean, 4.5) and in addition to receive either 10 mg of Ramipril or a placebo daily. Patients were evaluated every six months for a variety of outcomes. The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. Secondary and other outcomes were death from any cause; unstable angina; hospitalization for heart failure with clinical and radiologic signs of congestion; revascularization or limb amputation; the development of overt nephropathy or the need for dialysis or laser therapy among patients with diabetes; and the development of heart failure or new or worsening angina regardless of the need for hospitalization.
Results: Patients characteristics were similar among the vitamin E and the placebo group. The percentages of patients that were taking vitamin E in the vitamin E and the placebo group, respectively, were 94.2% and 1% at one year, 93.3% and 1.7% at two years, 91.3% and 2% at three years, 90.2% and 2.7% at four years, and 89.2% and 3.4% at the final visit. A total of 772 of the 4761 patients who were assigned to receive vitamin E (16.2%) and 739 of the 4780 who were assigned to placebo (15.5%) had a primary cardiovascular event (RR 1.05; 95 CI 0.95 to 1.16; P=0.33).
There were no significant differences between the groups in the numbers of deaths from cardiovascular causes (RR 1.05), myocardial infarction (RR 1.02), deaths from coronary heart disease (RR 1.06), or strokes (RR 1.17). Vitamin E had no significant effect on the primary outcome either among patients receiving Ramipril (RR 1.08) or among patients who were not receiving Ramipril (RR 1.05).
There were no differences between patients assigned to vitamin E and those assigned to placebo in the number of hospitalizations for unstable angina (RR 1.04), hospitalizations for heart failure (RR 1.12), or revascularizations or limb amputations (RR 1.09). There were no significant differences in the number of patients with angina of new onset (RR 1.15) or microvascular complications of diabetes (RR 1.06). A combined analysis of the proportion of patients who had any primary or secondary event found a nonsignificantly higher rate among those assigned to vitamin E (RR 1.05, 95% CI 0.98 to 1.13, P=0.14).
There was no significant difference in the incidence of the primary outcome among patients with diabetes (RR 1.04) or among smokers (RR 1.02).
There was no significant difference between groups in the incidence of adverse effects or in the number of patients who stopped taking the study medication.
Discussion: In this study, vitamin E did not reduce the incidence of cardiovascular events, as compared with the incidence among patients assigned to placebo, during a follow-up period of four to six years. Given the large number of events and the consistent lack of difference in all secondary cardiovascular outcomes, it is very unlikely that vitamin E had any clinically worthwhile beneficial effect on cardiovascular disease during four or five years of treatment.
Results have been reported from four randomized trial of the effects of vitamin E on cardiovascular events. In a Chinese study, 29,584 adults free of cardiovascular disease were randomly assigned to receive daily vitamin E (30 mg), beta carotene, and selenium supplements or to receive placebo. During the 5.2 years of follow-up, there was a 9% decrease in deaths from any cause without any significant reduction in cardiovascular events. The second trial was the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study, that involved male smokers who were 50 to 69 years of age. Daily treatement with 50 mg of vitamin E for five to eight years had no effect on the risk of death from coronary heart disease. A reduction in the risk of nonfatal myocardial infarction was documented among men assigned to vitamin E only, but not among those receiving the combination of vitamin E and beta carotene, in comparison with those receiving placebo only. In this trial, vitamin E had no effect on coronary heart disease. The Cambridge Heart Antioxidant Study randomly assigned 2002 patients with coronary atherosclerosis to receive either vitamin E or placebo. The majority of patients received 400 IU of vitamin E per day. After a median follow-up of 1.4 years, a large reduction in the number of patients with nonfatal myocardial infarction was observed, but there was no difference in deaths due to cardiovascular causes. In this trial, the number of events was small and there were imbalances in several base-line characteristics. Furthermore, the very large reduction in nonfatal myocardial infarction within a relatively short time (median, 1.4 years) is inconsistent with the results of other interventions, such as lipid lowering agents. It is therefore likely that the results from this trial my have been due to chance.
Combining all the trials of vitamin E indicates that such treatment has little effect on the risk of death or cardiovascular events, at least over a four-to-six-year period. Steinberg has hypothesized that unlike agents that lower cholesterol or blood pressure, antioxidants my have to be used for more than five years to have a demonstrable benefit, since the primary mechanism of these agents may be the prevention of new lesions.
Although the moderate duration of vitamin E supplementation and the characteristics of the population may explain the finding of a lack of benefit of vitamin E, another reason may be our use of vitamin E alone, without other antioxidants. It is possible that vitamin E supplementation requires these cofactors to have a beneficial effect.
In conclusion, 400 IU of vitamin E administered daily for four to six years had no beneficial effects on cardiovascular outcomes in a high-risk population of patients who were 55 years of age or older.
Comments: At present the weight of evidence does not justify prescription of vitamin E to either halt the development or slow the progression of cardiovascular disease. Indeed both theoretical and experimental data support the thesis that Oxidative damage to the cell plays a role in the pathogenesis of cardiovascular disease as well as various cancers. The antioxidant properties of vitamin E in a dose of 400 iu, however, does not exert a salutary clinical effect when administered over a period of five years. The organism may require a host of cofactors, as provided by the consumption of fruits and vegetables, for the antioxidant properties of vitamin E to induce a beneficial effect.