In the 3 years after the Women's Health Initiative clinical trial was halted early, risks and benefits related to hormone therapy changed rapidly in those who stopped taking the medication, according to WHI investigators.
Despite these alterations, the overall assessment of health risks and benefits associated with combined HT (conjugated equine estrogens plus medroxyprogesterone acetate) “continues to be weighted toward risk,” said Dr. Gerardo Heiss of the University of North Carolina, Chapel Hill, and his WHIassociates.
But representatives of Wyeth Pharmaceuticals, manufacturer of Prempro, the combination HT product used in the study, said during a company-sponsored teleconference that the study does not reflect the current, lower HT dosages doctors recommend for typical HT users, who are younger, newly menopausal women.
Dr. Gary Stiles, executive vice president and chief medical officer for Wyeth, said the findings were an “ad hoc analysis without providing the full context.” He noted that today's patients were “more than a decade” younger than the WHI participants, who had a mean age of 63 years at baseline. The company encourages doctors to provide lower dosages of HT drugs for the shortest time possible, he added.
The portion of the WHI trial that dealt with combined hormone therapy (HT) was stopped in 2002 at a mean of 5.6 years of follow-up because an interim analysis showed the therapy increased the risk of invasive breast cancer and failed to yield any overall health benefit. Analysis of the results accumulated to that date showed those who took HT (0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate daily) for menopausal symptoms also had higher risks of cardiovascular disease, coronary heart disease, stroke, and venous thromboembolism, along with lower risks of fracture and of colorectal cancer, compared with those not on HT.
Most of the subjects were followed through the planned 8-year duration of the WHI. Results are now available on 15,730 of these women for a further 2.4 years of follow-up after discontinuation. (See box.)
The increased risk of cardiovascular disease-related events noted in the interim analysis did not persist after stopping HT, and the risk of deep vein thrombosis and pulmonary embolism also “disappeared.”
But the risk of all malignancies increased, probably due to a rise in the rate of cancers other than breast and colorectal, primarily lung cancers.
The increased risk of breast cancer noted at the interim analysis did not persist after discontinuing HT, but neither did the decreased risk of colorectal cancer.
HT's protective effect against fractures also dissipated after discontinuation. Women who had taken and then stopped HT showed the same risk of hip, vertebral, and other fractures as did those who had taken placebo.
During the intervention phase of the WHI, all-cause mortality was virtually identical between subjects taking HT and those taking placebo. But in the postintervention phase, mortality was 15% higher in women who had taken and then discontinued HT.
Although this difference did not reach statistical significance because of the small number of deaths, it suggests that all-cause mortality increased after HT, the researchers said (JAMA 2008;299:1036–45).
Associate editor Lorinda Bullock contributed to this article.
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