Comment by Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA.
Source: Lonn E, et al.; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA 2005;293:1338-1347.
Abstract: Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. These researchers sought to evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9,541 patients, 174 centers participated in the HOPE-TOO trial. Of 7,030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1,382 refused participation, 3,994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. Participants were given a daily dose of natural source vitamin E (400 IU) or matching placebo. Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs. 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = 0.30); for cancer deaths, 156 (3.3%) vs. 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = 0.24); and for major cardiovascular events, 1,022 (21.5%) vs. 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = 0.34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = 0.03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = 0.045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. The authors concluded that in patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.
Comment
The rationale for this study is interesting. as the trial investigators point out, oxidative injury has been implicated as a key mechanism, leading to atherosclerotic cardiovascular disease and cancer. For instance, LDL cholesterol is more atherogenic when it is oxidized. Also, oxidative cellular metabolism generates oxygen-free radicals that are thought to damage DNA and other cellular structures, thereby initiating and promoting tumorigenesis. The most active form of vitamin E is a-tocopherol, and it has been shown to possess antioxidant activity in many in vitro model systems. Further, epidemiological studies indicated an inverse link between vitamin E intake from dietary sources and cardiovascular disease and cancer. Thus, it seemed only a small leap of logic to think that exogenously administered vitamin E might be good for those with established cardiovascular disease. Indeed, it has been common practice for cardiologists to recommend its use. Further, observational studies indicated that diets high in fresh fruits and vegetables (that provide a ready source of vitamin E) were associated with a reduced incidence of cancer. The present study was undertaken to see if long-term exogenous administration of vitamin E use would confer reduced cardiovascular disease and cancer in those at high risk for these outcomes. When the initial results yielded null results, the investigators decided to continue the study to see if additional time would yield different results. The final results are presented in the current article.
The study design was an international, multicenter, double-blind, randomized, 2 × 2 factorial trial that evaluated the antihypertensive ramipril vs. placebo and vitamin E vs. placebo alone in 9,541 patients at high risk for cardiovascular events. All patients were at least 55 years old at the start of the trial. The initial observation period was 3-5 years and included almost 5,000 patients in the vitamin E and placebo arms. The continuation phase included more than 3,500 patients in each arm, with a mean follow-up of 7.0 years. Natural vitamin E was given at a dose of 400 IU daily. Mean plasma vitamin E increased from 30 to 49 mmoL/L in the vitamin E group. Compliance was high, and the data were analyzed by intention-to-treat.
The results showed no decrease in fatal or nonfatal cancer. Specifically, there was no reduction in prostate, colorectal, or breast cancer. Vitamin E use also did not reduce myocardial infarction, stroke, cardiovascular death, unstable angina, revascularization, or total mortality. There was an increase in hospitalization for heart failure in the vitamin E group.
Vitamin E long has been touted as a mainstay in the armamentarium for chemoprevention of aging. Even before the results of the Women’s Health Initiative (WHI) cast a shadow on the use of standard hormone therapy regimens, the use of vitamin E had been advocated as a “natural intervention” for the control of menopausal hot flashes. Given the increased patient and physician trepidation concerning HRT that followed the publication of the WHI results, many menopausal women have looked for alternative therapies for the amelioration of hot flashes and found vitamin E. Physicians generally endorse the exogenous intake of vitamin E, thinking that it is certainly safe, even if less effective than HRT for the control of hot flashes. As is typically the case, the less we know about a substance, the safer it appears. Conversely, the more a substance is studied, the less the promise and the more the risk. This caveat appears to hold also for vitamin E supplementation. Multivitamins typically contain about 30 IU, but there are many mega-vitamin preparations that contain doses as high as 800 IU. Interestingly, there are no clinical trial data to suggest that vitamin E is effective in the amelioration of hot flashes, although there is wide-spread belief that its use is helpful in this context.
Taking the aggregate results at face value, how might we reconcile the observational and cellular data with the results of this and similar studies showing no benefit when vitamin E is administered in randomized clinical trials to at-risk populations? One worries about dose. The use of 400 IU led to a modest increase, but we have no way to know if the increase was “too large” or “too small.” Perhaps vitamin E only works as prophylaxis, and this study included older individuals with a high risk for CVD. If the observational studies are right, one would suspect that vitamin E would work when overall health and health behaviors are good, but that it would not help once there was established disease. This might suggest that there are synergistic or additive effects when vitamin E levels are in the right range, but that vitamin E alone cannot reverse health misbehaviors or established disease even when levels are raised.
Observational studies showed that individuals with good diets that led to high circulating vitamin E levels had better cardiovascular health and less cancer. In this context, vitamin E might be a marker for dietary rigor but not the active ingredient in a diet that confers health. Vitamins in food are delivered as part of a “matrix” that contains many other substances in addition to the vitamins that we recognize. Indeed, it is more than a bit presumptuous to think that we can do a better job of conferring nutritional adequacy than exercising dietary discretion.
By now it is clear that randomized, clinical trials evaluating agents intended for chemoprevention of aging raise epistemological concerns and challenge the validity of modern scientific methodologies. In the past, we used the scientific method of altering one variable at a time to identify those key substances whose levels were so critical that their manipulation yielded clear and robust changes in an organism’s physiological or health status. A prime example might be cortisol, a hormone whose range must be “just right” for health. Using binary scientific method, we were able to isolate the effective range of this incredibly critical hormone. But the science of health promotion is less simplistic and does not involve adjusting the level of a single substance. Health is a state and there are many important determinants to maintaining it. Of course, in a health care system that rewards transactions, especially simple transactions like writing a prescription for an easy-to-take product, health promotion continues to be suspect and poorly rewarded. One can only conclude that we will continue to be stymied in our efforts to promote good health unless we can provide reliable information on how to do this while avoiding the hucksterism of mercantile promotions.
Berga SL. Long-term effects of vitamin E on cardiovascular disease and cancer. Altern Ther Women's Health 2005;7(6):45-47.
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