Supplemental Vitamin E May Increase Heart Failure Risk
March 15, 2005
Laurie Barclay, MD, Medscape

Supplemental vitamin E does not reduce the risk of cancer of major cardiovascular events but does increase the risk of heart failure, according to the results of the Heart Outcomes Prevention Evaluation — The Ongoing Outcomes (HOPE-TOO) trial, an extension of the randomized Heart Outcomes Prevention Evaluation (HOPE) trial, published in the March 16 issue of JAMA.

"Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events," write Eva Lonn, MD, MSc, from McMaster University in Hamilton, Ontario, Canada, and colleagues. "Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration."

The initial double-blind HOPE trial, conducted between Dec. 21, 1993, and April 15, 1999, enrolled patients at least 55 years old with vascular disease or diabetes mellitus. The trial was extended (HOPE-TOO) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9,541 patients, 174 centers enrolling 7,030 patients participated in the HOPE-TOO trial. Of these 7,030 patients, 916 (13.0%) had died by the beginning of the extension, 1,382 (19.66%) refused to participate, 3,994 (56.81%) continued to take the study intervention (natural source vitamin E, 400 IU, daily or matching placebo), and 738 (10.5%) agreed to passive follow-up. Median duration of follow-up was seven years.

Primary outcome measures were cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction [MI], stroke, and cardiovascular death), and secondary outcome measures were heart failure, unstable angina, and revascularizations.

The primary analysis revealed no significant differences between groups for all HOPE patients. Cancer incidence was 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 =.30) For cancer deaths, incidence was 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24), and for major cardiovascular events, incidence was 1,022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34).

Risk of heart failure was higher in the vitamin E group (RR, 1.13; 95% CI, 1.01-1.26; P = .03), as was hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). For patients enrolled at the centers participating in HOPE-TOO, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but rates of heart failure and hospitalizations for heart failure were higher in the vitamin E group.

Limitations of this study include reported cancers not adjudicated in the initial HOPE trial, and possible bias related to not all eligible centers and patients continuing in the study extension. The authors note that the adverse effect of vitamin E was unexpected and unconfirmed by other trials, but that their data were internally consistent. They therefore recommend a meta-analysis of heart failure events in all completed large vitamin E trials.

"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," the authors write. "In conjunction with its lack of efficacy, the potential for harm suggested by our findings strongly supports the view that vitamin E supplements should not be used in patients with vascular disease or diabetes mellitus.... Our findings emphasize the need to thoroughly evaluate all vitamins, other natural products, and complementary medicines in appropriately designed trials before they are widely used for presumed health benefits."

The Medical Research Council of Canada, Hoechst-Marion Roussel, AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association and Negma, and the Heart and Stroke Foundation of Ontario funded the HOPE trial. Aventis, King Pharmaceuticals, and the Natural Source Vitamin E Association funded the HOPE trial extension (HOPE-TOO). One author reports various financial arrangements with the British Heart Foundation, U.K. Medical Research of Canada, Ontario Heart and Stroke Foundation, AstraZeneca, Aventis, Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Monarch, Merck Sharpe & Dohme, Natural Source Vitamin E Association, Roche, Abbott, Bayer, Boehringer Mannheim, Genentech, Knoll, Menarini, Novartis, Organon, Pfizer, Pharmacia, Sanofi, Schering, and Servier.

In an accompanying editorial, B. Greg Brown, MD, PhD, from the University of Washington School of Medicine, and John Crowley, PhD, from the University of Washington School of Public Health and Community Medicine in Seattle, also emphasize the importance of controlled clinical trials for testing important hypotheses derived from biological mechanisms or from epidemiologic observations.

"The hopes for vitamin E alone or in combination with vitamin C and beta carotene have been diminished by a compelling body of clinical trial evidence, and by certain adverse effects with plausible biological explanation," Drs. Brown and Crowley write. "These hopes are now confined to modest expectations for specific disorders and there are concerns about adverse effects. While there is solid evidence linking oxidative processes to human disease (as well as to normal biological function), the details of these processes and of proposed therapeutic or preventive interventions appear to need considerable rethinking."

Journal of the American Medical Association, 2005;293:1338-1347, 1387-1390