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J. David Schnatz, M.D.
Director, Lipid Education Service
Saint Francis Hospital and Medical Center
114 Woodland Street, Hartford, CT 06105
Telephone: (860) 714-5555
November 1998
Observational studies on the use of hormone replacement therapy (HRT) have suggested significant risk reduction for post menopausal women with coronary heart disease (CHD) who take Estrogen (1, 2, 3, 4). These studies have led the National Cholesterol Education Program (NCEP) (5) and American College of Physicians (6) to recommend Estrogen replacement therapy in post menopausal women who do not have a personal or family history of breast or uterine cancer. The scientific community recognized that a randomized trial would be necessary to confirm the results of the observational studies, and to lend credibility to the ongoing recommendations. The HERS Trial was established to do this, and the results were published in August of this year (7).
The HERS Trial was conducted in 20 US clinical centers and entered 2763 postmenopausal women with CHD into a randomized, placebo controlled, blinded, secondary prevention trial. The main age of participants was 67 years with a range from 44 to 79 years. Patients were excluded from participating for a variety of reasons, including a CHD event within 6 months, triglyceride greater than 300 mg/dl, Estrogen therapy within 3 months, and a history of deep vein thrombosis or pulmonary embolus. Patients were randomized to 1 tablet daily of placebo or Prempro (0.625 mg of Premarin and 2.5 mg of Medroxy Progesterone Acetate).
To maintain the blindfold approach for the investigators and their coordinating staff, gynecology staff handled complaints of breast discomfort and vaginal bleeding. They did not communicate with the investigators about gynecological symptoms, and they did not contribute to the determination of cardiovascular outcomes. Under pre-specified and limited circumstances, the gynecologist could obtain treatment information. Such unblinding occurred in 30 women in the hormone and 4 in the placebo group.
Follow-up visits to the Center occurred every 4 months for assessment of compliance, medication refills and recording of outcome data. Separate annual physical and laboratory examinations were done by the investigators and the gynecology staff. The average duration of follow-up was 4.1 years.
Over the study interval, 172 women in the hormone group and 176 in the placebo group had a CHD event, consisting of death or non-fatal myocardial infarction. The absence of a difference between the groups was a surprise, contrary to expectations and despite an 11 percent lowering of LDL and 10 percent elevation of HDL in the hormone group compared with placebo (P < 0.001). Within the 4 years of follow-up, comparing hormone to placebo treatment, more CHD events occurred in the hormone group during the first year and less in years 3 and 4. More women in the hormone group had deep vein thrombosis (28 vs 6, P=0.004), pulmonary embolism (11 vs 4, P=0.08), any thomboembolic event (34 vs 12, P=0.002) and gall bladder disease (84 vs 62, P=0.05).
These results highlight the differences between observational and prospective, randomized, controlled clinical trials, designed to answer a specific question. The well known "healthy" user
bias could account for the results seen in the observational studies. Also, early adverse events
often are not detected in observational studies.
A major problem with interpreting this study is its length. Would the favorable trends in lipids have made a difference and would there have been a favorable outcome in the hormone treated group, if the study had gone longer? If so, the issue would then be one of balancing the risks during the first year with the benefits later on. Several studies are in progress that will provide further information, including WELL-HART, a secondary prevention study to be completed in 2000 and the Women's Health Initiative, a primary prevention study to be completed in 2005.
Based on the present data which are the best we have at the moment, the recommendation from the HERS investigators is that "We do not recommend starting this treatment for the purpose of secondary prevention of CHD". Further, they state that "it could be appropriate for women already receiving hormone treatment to continue". It is important to note that this study did not address the issue of primary prevention in women without CHD, nor did it address the use of unopposed Estrogen in women who have had a hysterectomy.
Of particular note is the fact that there are treatments proven to reduce risk that are not being used sufficiently. For example, in a previous report (8) the HERS group demonstrated that only 9.6 percent of women were treated to NCEP goals for CHD, and in the current report (7), they note only 32 percent receiving beta blockers. In these two areas, more aggressive therapy would have reduced risk by proven methods.
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