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Executive Summary

PREMARIN PLUS PROGESTIN MAY HAVE SUPERIOR EFFECT ON CARDIOVASCULAR RISK factors than estrogen replacement therapy alone in postmenopausal women, according to a cross-sectional analysis of the Atherosclerosis Risk in Communities study published in the April 15 issue of The New England Journal of Medicine. "The use of estrogen [Wyeth-Ayerst's Premarin] combined with progestin appears to be associated with a better profile than the use of estrogen alone," study authors Azmi Nabulsi et al. concluded. The study found that postmenopausal women receiving conjugated estrogens alone or estrogen with progestin had higher high-density lipoprotein and lower low-density lipoprotein levels compared to nonusers. However, only estrogen therapy alone had the undesirable effect of raising triglycerides, coagulation Factor VII and protein C levels, the authors noted. Nabulsi et al. estimated that the benefit of hormone therapy translates into a 42% reduction in the risk of coronary heart disease as compared to those postmenopausal women not on hormone therapy. "Women using estrogen with progestin would have an even greater estimated benefit," the authors said. An Office of Technology Assessment report released in May 1992 on "The Menopause, Hormone Therapy, and Women's Health" found that most physicians prescribe combination estrogen/progestin therapy in women with intact uteruses to prevent estrogen-induced endometrial cancers ("The Pink Sheet" June 1, 1992, p. 11). That report maintained that it was uncertain how progestins affect the apparent cardiovascular benefit of estrogens. The NEJM study analyzed data from 4,958 postmenopausal women from the 15,800-subject cohort of the Atherosclerosis Risk in Communities study from four different U.S. regions. About 63% of the women had never used hormone replacement therapy. Of the 21% who were currently using hormone therapy, 83% were taking conjugated estrogens (Premarin) alone and 17% were using estrogen plus medroxyprogesterone acetate (Upjohn's Provera). Women using estrogen alone or estrogen plus medroxyprogesterone had statistically significantly lower mean levels of LDL than non-users: 125 mg/dl and 127 mg/dl compared to 141 mg/dl. The mean levels of HDL were raised by estrogen alone and estrogen with progestin, to 67 mg/dl and 66 mg/dl, compared to 58 mg/dl for no hormone therapy. Estrogen therapy alone raised mean total triglyceride levels compared to no hormone therapy from 120-123 mg/dl to 141 mg/dl. The mean triglyceride level for women using estrogen plus progestin was 131 mg/dl. While the study results suggest that progestin does not diminish the effects of estrogen on cardiovascular risk factors, and in fact may enhance them, the study authors and other physicians emphasized that the results must be confirmed by a randomized trial. "Although the study offers some reassuring evidence that the negative effect of progestins may be less than initially feared, it would be premature to conclude that women taking combined estrogen and progestin have an even lower risk of coronary disease than those taking estrogen alone," Kathryn Martin, MD, and Mason Freeman, MD, Massachusetts General Hospital stated in an accompanying editorial. Martin and Freeman noted that prospective trials such as the National Institute of Health's 15-year Women's Health Initiative study, which will enroll up to 25,000 women, may more definitively answer such questions. Wyeth-Ayerst is providing 100 mil. tablets of Premarin and its not yet approved estrogen-progestin combination Premarin MPA for the study. W-A is planning to file an NDA for Premarin MPA in the next few months. Another study, the National Heart Lung & Blood Institute's Postmenopausal Estrogen/Progestin Interventions (PEPI) trial in 875 women, should yield results by mid-to-late 1994. Wyeth-Ayerst began its own double-blind, placebo-controlled study in January called the Heart and Estrogen-Progestin Replacement study (HERS), which will enroll about 2,300 women and cost $40 mil. The end points of the five-and-a-half year study will be heart attack and cardiac death.

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