The Heart and Estrogen/progestin Replacement Study (HERS)

Abstract

The heart and estrogen/progestin replacement study (HERS) was a randomized, double-blind, placebo-controlled clinical trial supported by Wyeth–Ayerst for $40 million [1]. The objective of the trial was to determine whether daily treatment with 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate would reduce coronary heart disease events in women with preexisting coronary disease. A total of 2763 women (average age 66.7 years) were enrolled in 20 US clinical centers and randomized to treatment and placebo beginning in February, 1993, and ending in July, 1998. Overall, there were 172 myocardial infarctions and coronary deaths in the hormone group and 176 in the placebo group, obviously no overall difference. However, over time, differences were recorded (Table 1). Thus, there was an increase in events in the first year (mostly in the first 4 months), and after 2 years of treatment, the appearance of a beneficial impact (although the annual relative risks did not achieve statistical significance, the test for the trend was significant). The authors attribute the increasing beneficial impact noted with increasing duration of treatment to a favorable effect on lipids, an 11% decrease in LDL-cholesterol and a 10% increase in HDL-cholesterol after 1 year, compared with the levels in the placebo group. In addition, a number of overall observations were recorded (Table 2). The increased risk of venous thromboembolism reported in observational studies was confirmed (although these women were a high risk group for this problem). The increased risk of gall bladder disease did not reach statistical significance. There were no differences in the incidences of breast cancer, endometrial cancer, other cancers and fractures (however, the size and duration of the study did not allow meaningful conclusions in these categories). The authors concluded that combined estrogen–progestin therapy does not reduce the risk of coronary events in postmenopausal women with pre-existing coronary disease. The results of the HERS trial are surprising in view of the overwhelming evidence from observational studies that postmenopausal hormone therapy prevents coronary heart disease. The authors offer two possible explanations for the difference between the HERS trial and previous observational studies. First, they point out the common and favorite criticism of the observational studies: selection bias, specifically that healthier women choose to use postmenopausal hormone therapy and, therefore, develop less coronary heart disease. Indeed, women who choose to use hormone therapy have been reported to have a better cardiovascular risk profile compared to nonusers [2]. This question has been addressed by the Lipid Research Clinics study, the Leisure World Study, and the Nurses Health Study [3–5]. These epidemiologists have concluded that their evidence strongly indicates that, in women receiving estro-