MEDICATIONS: HEALTH RISKS OUTWEIGH BENEFITS FOR COMBINED ESTROGEN PLUS PROGESTIN CLINICAL TRIAL STOPPED EARLY IN MAJOR STUDY

July 16, 2002 — Researchers have stopped the estrogen plus progestin portion of the Women's Health Initiative, a clinical trial designed to assess the major health benefits and risks of the most commonly used hormone preparation in the United States on healthy menopausal women, after overall health risks were found to exceed the health benefits, according to an article published in the July 17 issue of The Journal of the American Medical Association (JAMA). The study is posted on the JAMA Web site (www.jama.com).

Jacques E. Rossouw, M.D., of the National Heart, Lung and Blood Institute in Bethesda, MD, and colleagues from the Women's Health Initiative (WHI), report that the trial was stopped because of apparent increased risks in invasive breast cancer, as well as coronary heart disease, stroke and pulmonary embolisms in study participants. There were some benefits of estrogen plus progestin noted during the study, including fewer cases of hip fractures and colorectal cancers, but the overall health risks outweighed the benefits.

The estrogen plus progestin part of the WHI is a randomized controlled primary prevention trial that was planned to last for 8.5 years. It was stopped on May 31, 2002 after a mean of 5.2 years of follow-up because of the health safety concerns. The study enrolled 16,608 postmenopausal women aged 50 -79 years with an intact uterus at baseline who participated in the clinical trial at 40 clinical centers in the United States. In this study, the combined estrogen and progestin was provided in one daily tablet (conjugated equine estrogen [CEE], 0.625 mg/d, and medroxyprogesterone acetate [MPA], 2.5 mg/d). A matching placebo was provided to the control group. "A parallel trial of CEE (estrogen) only in women who have had a hysterectomy is being continued, and the planned end of this trial if March 2005, by which time the average follow-up with be about 8.5 years," the authors write.

Study Results

"The rate of women experiencing coronary heart disease (CHD) events was increased by 29 percent for women taking estrogen plus progestin relative to the placebo," the authors note. The researchers report that strokes rates were 41 percent higher in women receiving estrogen plus progestin, and the participants had double the rates of venous thromboembolism (blood clots), invasive breast cancer rates increased by 26 percent, and total cardiovascular disease was increased by 22 percent in the estrogen-plus-progestin group. The benefits included a 37 percent reduction in colorectal cancer rates, hip fracture rates reduced by one-third and total fractures reduced by 24 percent.

"The trial results indicate that treatment for up to 5.2 years is not beneficial overall and that there is early harm for CHD, continuing harm for stroke and VTE (blood clots), and increasing harm for breast cancer with increasing duration of treatment," the authors write. "The risk-benefit profile is not consistent with the requirements for a viable intervention for the primary prevention of chronic diseases."

The researchers note that this trial did not address the short-term risks and benefits of hormones given for the treatment of menopausal symptoms.

"Results from WHI indicate that the combined postmenopausal hormones CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, should not be initiated or continued for the primary prevention of CHD. In addition, the substantial risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis," the authors conclude.

Editor's Note: The National Heart, Lung and Blood Institute funds the WHI program. Wyeth-Ayerst Research provided the study medication (active and placebo).

Editorial: Stop Prescribing Estrogen plus Progestin for Prevention

In an accompanying editorial, Suzanne W. Fletcher, M.D., M. Sc., and Graham A. Colditz, M.D. Dr.P.H., of the Harvard Medical School, note that the results from the WHI study are surprising, but add to the growing body of medical literature on the effects of combination estrogen/progestin.

"Approximately 38 percent of postmenopausal women in the United States use hormone replacement therapy," according to background information the authors provide. "In 2000, 46 million prescriptions were written for Premarin (conjugated estrogens), making it the second most frequently prescribed medication in the United States and accounting for more than $1 billion in sales, and 22.3 million prescriptions were written for Prempro (conjugated estrogens plus medroxyprogesterone acetate). While U.S. Food and Drug Administration-approved indications for hormone therapy include relief of menopausal symptoms and prevention of osteoporosis, long-term use has been in vogue to prevent a range of chronic conditions, especially heart disease," the authors add.

"The absolute risk of harm to an individual woman is very small. As the authors (Rossouw et al) point out, the increased risk of estrogen/progestin combinations means that in 10,000 women, there will be 7 more coronary heart disease events, 8 more breast cancers, 8 more strokes, and 8 more pulmonary emboli, but 6 fewer colorectal cancers and 5 fewer hip fractures. Nevertheless, when counting all events over the 5.2 years of the trial, the excess number of events in the active drug group was 100 per 10,000 (or 1 in 100 women). This is still a small risk, but it demonstrates that risks from the drug add up over time."

"The whole purpose of healthy women taking long-term estrogen/progestin therapy is to preserve health and prevent disease," the authors write. "The results of this study provide strong evidence that the opposite is happening for important aspects of women's health, even if the absolute risk is low. Given these results, we recommend that clinicians stop prescribing this combination for long-term use."