Confessions of a Quackbuster

This blog deals with healthcare consumer protection, and is therefore about quackery, healthfraud, chiropractic, and other forms of so-Called "Alternative" Medicine (sCAM).

Wednesday, July 13, 2005

Vitamin E May Not Prevent Heart Disease or Cancer in Healthy Women

Vitamin E May Not Prevent Heart Disease or Cancer in Healthy Women CME
News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP


To earn CME credit, read the news brief along with the CME information that follows and answer the test questions.

Release Date: July 6, 2005; Valid for credit through July 6, 2006

Credits Available

Physicians - up to 0.25 AMA PRA Category 1 continuing physician education credits

July 6, 2005 — Supplements of vitamin E are associated with a 24% significant reduction in cardiovascular death but no overall benefit in primary prevention of cardiovascular disease (CVD) and cancer, according to the results of the randomized Women's Health Study (WHS) published in the July 6 issue of JAMA. The authors found no reason to recommend these supplements to women.

"Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer," write I-Min Lee, MBBS, ScD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. "Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons."

In a 2x2 factorial design, 39,876 apparently healthy U.S. women of at least age 45 years were randomized to receive vitamin E (600 IU of natural-source vitamin E on alternate days) or placebo and aspirin or placebo. The study took place between 1992 and 2004, and the average duration of follow-up was 10.1 years. The primary outcome measure was a composite endpoint of first major cardiovascular event (nonfatal myocardial infarction [MI], nonfatal stroke, or cardiovascular death) and total invasive cancer.

During follow-up, 482 major cardiovascular events occurred in the vitamin E group and 517 in the placebo group (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82 - 1.05; P = .26). Vitamin E did not significantly affect the incidences of MI (RR, 1.01; 95% CI, 0.82 - 1.23; P = .96), stroke (RR, 0.98; 95% CI, 0.82 - 1.17; P = .82), or ischemic or hemorrhagic stroke. However, vitamin E was associated with a significant 24% reduction in cardiovascular death (RR, 0.76; 95% CI, 0.59 - 0.98; P = .03).

Vitamin E supplements had no significant effect on the incidences of total cancer (1,437 cases in the vitamin E group and 1,428 in the placebo group; RR, 1.01; 95% CI, 0.94 - 1.08; P = .87) or of breast (RR, 1.00; 95% CI, 0.90 - 1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83 - 1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77 - 1.31; P = .99). Cancer deaths were not significantly different between groups, and vitamin E had no significant effect on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93 - 1.16; P = .53).

"The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women," the authors write. "These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women."

Factors that might explain the lack of overall benefit of vitamin E on cardiovascular events could include insufficient dose or duration, use of a natural source of vitamin E, declining compliance over time, possible adverse interactions of antioxidants with simvastatin and niacin treatment, and the possibility that γ-tocopherol may be the relevant compound for CVD prevention.

"At present, in the primary prevention of CVD and cancer, therapeutic lifestyle changes including a healthy diet and control of major risk factors remain important clinical and public health strategies," the authors conclude.

The National Heart, Lung, and Blood Institute and the National Cancer Institute supported this study. Bayer Healthcare provided aspirin and aspirin placebo and has financial arrangements with four of the authors, two of whom also report financial arrangements with McNeil.

In an accompanying editorial, Rita F. Redberg, MD, MSc, from the University of California, San Francisco, discusses the crucial role of preventive medicine and how optimal strategies may differ in men and women.

"Perhaps the most important outcome of the WHS reports will be greater recognition that it is time to concentrate on teaching nutrition, promoting regular physical activity, and strongly encouraging smoking cessation and particularly increasing outreach to women of racial and ethnic minorities," Dr. Redberg writes. "Although vitamin E is not a successful primary prevention strategy for women, one should not make the mistake of concluding that it will not turn out to be beneficial for men. The WHS highlights the importance of recognizing biological differences between the sexes in cardiovascular research by providing valuable sex-specific data on primary prevention."

Dr. Redberg reports no financial disclosures.

JAMA. 2005;294:56-65, 107-109

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

* Describe evidence suggesting that vitamin E supplementation may reduce the risk of CVD and cancer.

* Compare long-term outcomes for women treated with vitamin E vs outcomes for those receiving placebo.

Clinical Context

As a potent antioxidant, vitamin E has been hypothesized to reduce the risks of both CVD and cancer. Epidemiologic studies have demonstrated a reduced risk of atherogenesis associated with vitamin E, and population studies have suggested that higher plasma levels of vitamin E can reduce the risk of death from ischemic heart disease. Individuals who choose to increase vitamin E intake have been demonstrated to have reduced rates of CVD and cancer.

These findings regarding the benefits of vitamin E have not necessarily been borne out in randomized, controlled trials, which offer a better means to measure the effects of vitamin E. Still, the question remains as to whether these randomized studies were of sufficient duration to detect a difference in cardiovascular and cancer outcomes.

To address this issue, the WHS investigators examined outcomes in a cohort of women taking a relatively high dose of vitamin E for an average of 10 years.

Study Highlights

* Women eligible to participate in WHS were health care professionals who were at least age 45 years and were generally healthy, with no history of CVD or cancer.

* Participants were randomized to receive either 100 mg of aspirin every other day, 600 IU of vitamin E every other day, or matching placebo in a 2X2 factorial design. Results for the vitamin E vs placebo groups are presented in the current article.

* The primary study endpoints included a composite of the first major cardiovascular event (MI, nonfatal stroke, or cardiovascular death) and total invasive cancer. These results were obtained primarily by patient self-report and were cross-checked in the medical record. Overall mortality was also monitored, as were adverse events related to study therapy.

* The mean duration of follow-up was 10.1 years. Compliance with study therapy was judged to be more than 70% at 10 years.

* 39,876 women were randomized into the trial. Baseline characteristics were similar between groups. Rates of smoking were 13% in the vitamin E and placebo cohorts. Slightly more than half of study subjects had a BMI < 25 kg/m2, and approximately one quarter of women had hypertension and hyperlipidemia. However, diabetes was rare in the cohort.

* A total of 999 cardiovascular events were reported during the trial. For the composite outcome, vitamin E was associated with a nonsignificant 7% reduction in events. Vitamin E also had no significant effect on total rates of MI or stroke when each of these outcomes was examined individually. However, study subjects receiving vitamin E were 24% less likely to die from CVD, a significant difference attributable in large part to a reduction in sudden deaths and other CVD deaths besides MI and stroke.

* Vitamin E appeared to have a stronger effect in reducing the risk of cardiovascular death as the study progressed from years 6 to 10. Noncompliance did not appear to alter the study's main findings, nor did randomization to receive aspirin or placebo.

* Patients with probable increased oxidative stress (i.e., those with hyperlipidemia and hypertension) were no more likely to benefit from vitamin E therapy in terms of cardiovascular outcomes.

* On multivariate analysis of cardiovascular outcomes, only being older than age 65 years was associated with a better outcome for vitamin E. Women in this age group experienced a significant 26% reduction in major cardiovascular events and a 49% reduction in the risk of cardiovascular death.

* 2,865 women developed invasive cancer during the trial. There was no difference between the placebo and vitamin E groups in terms of the overall risk of invasive cancer or the risk of individual cancers.

* 636 women in the vitamin E group died during the study period, compared with 615 women in the placebo group, a nonsignificant difference.

* Rates of major bleeding, gastrointestinal symptoms, and fatigue were similar between the vitamin E and placebo groups. Rates of epistaxis were slightly higher with vitamin E supplementation.

Pearls for Practice

* The hypothesis of the benefit of vitamin E for CVD and cancer is grounded in epidemiologic data, population-based studies, and cohort trials involving individuals who chose to increase intake of vitamin E.

* In long-term follow-up of a cohort of middle-aged women, vitamin E was no more effective than placebo in preventing cardiovascular events, invasive cancer, or death. Rates of adverse events were similar between placebo and vitamin E groups.