In the 3 years after the Women's Health Initiative clinical trial was halted early, risks and benefits related to hormone therapy changed rapidly among the subjects who stopped taking the medication, investigators with the long-term trial reported in JAMA.
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 associates in the Women's Health Initiative (WHI) study (JAMA 2008;299:1036–45).
But according to representatives of Wyeth Pharmaceuticals who spoke during a company-sponsored March 4 press teleconference, the study does not reflect the current, much lower HT dosages doctors are recommending for typical HT users, who are younger, newly menopausal women. Wyeth manufactures Prempro, the combination HT product used in the WHI study.
“This isn't how we practice today; we've decreased dosages; we are using the lowest effective dose,” said Dr. Hugh S. Taylor, an associate chief for research at the Center for Research in Reproductive Biology at Yale University, New Haven, Conn.
Dr. Gary Stiles, executive vice president and chief medical officer for Wyeth Pharmaceuticals, said the company continues to encourage doctors to provide lower dosages of HT drugs for the shortest time possible.
Describing the findings as an “ad hoc analysis without providing the full context,” Dr. Stiles said today's patients, in comparison to those in the study, were “more than a decade” younger than the study participants, who had a mean age of 63 years at baseline.
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 that women 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 women who did not take HT.
Most of the subjects continued to be 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 the HT intervention was stopped (see bar chart).
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,” the investigators said.
In contrast, the risk of all malignancies increased. This was attributed to a rise in the rate of cancers other than breast and colorectal malignancies, primarily lung cancers.
The increased risk of breast cancer noted at the interim analysis did not persist after discontinuing HT. But at the same time, the decreased risk of colorectal cancer also did not persist after discontinuing HT.
HT's protective effect against fractures also dissipated after the treatment was discontinued. Women who had taken and then stopped HT showed the same risk of hip, vertebral, and other osteoporotic fractures as did women who had taken placebo.
In reference to the risks and benefits reported in the study, Dr. Taylor said the differences between the HT and placebo groups were not statistically significant. He added that the study did not show “important” age breakdown information nor did it distinguish the difference between the effects of combination HT and estrogen-only therapies.
During the intervention phase of the WHI, all-cause mortality was virtually identical between subjects taking HT and those taking placebo. In contrast, during the postintervention phase, mortality was 15% higher among women who had taken and then discontinued HT. Although this difference did not reach statistical significance because of the small number of deaths in the study, it suggests that all-cause mortality did increase after HT, the researchers said.
Overall, the findings show that the risks of HT continue to outweigh benefits. “The global index of risk versus benefit remained essentially unchanged in the postintervention period, maintaining a nominally significant overall 12% increase from baseline” through extended follow-up in the women who had taken HT, Dr. Heiss and his associates said.
The results also indicate that maintaining clinical vigilance for malignancies, particularly lung cancer, is warranted in women who have taken HT, they added.
Dr. Taylor disclosed that he receives honoraria for speaking engagements but was not compensated for speaking at Wyeth's teleconference.