JAMA Publishes HRT Study
JAMA. 2008;299(9):1036-1045.
Context: The Women’s Health Initiative (WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits.
Objective: To report health outcomes at 3 years (mean 2.4 years of follow-up) after the intervention was stopped.
Design, Setting, and Participants: The intervention phase was a double-blind, placebo-controlled, randomized trial of conjugated equine estrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate (MPA) 2.5 mg daily, in 16 608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15 730 women.
Main Outcome: Measures Semi-annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
Results: The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04-1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91-1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95-1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03-1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention.
Conclusions: The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo.
Trial Registration clinicaltrials.gov Identifier: NCT00000611
Author Affiliations: University of North Carolina, Chapel Hill (Dr Heiss); University of Iowa, Iowa City (Dr Wallace); Fred Hutchinson Cancer Research Center, Seattle, Washington (Drs Anderson, Beresford, LaCroix, Prentice, and Mr Aragaki); University of Texas Health Science Center, San Antonio (Dr Brzyski); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California (Dr Chlebowski); University of Cincinnati, Cincinnati, Ohio (Dr Gass); Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Dr Manson); National Heart, Lung, and Blood Institute, Bethesda, Maryland (Dr Rossouw); and Stanford Prevention Research Center, Stanford, California (Dr Stefanick).
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From: http://womens-health.jwatch.org/cgi/content/full/2008/304/1
WHI Estrogen-Plus-Progestin Trial: 3 Years Later
Increased risk for adverse cardiovascular outcomes and invasive breast cancer — and reduced risk for fractures and colorectal cancer — did not persist after women discontinued HT.
In the summer of 2002, the Women’s Health Initiative (WHI) randomized trial of estrogen plus progestin was stopped after the WHI writing group concluded that the results showed more risk than benefit: An increased risk for venous thromboembolism and modestly increased risks for stroke, cardiovascular disease (CVD), coronary heart disease (CHD), and invasive breast cancer outweighed the reduced risks for fractures and colorectal cancer. In this latest update, WHI investigators report on outcomes 3 years after study medication (estrogen-plus-progestin hormone therapy or placebo) was halted.
In contrast to findings at the time study medication was discontinued, no increased risk for thrombosis, CHD, or stroke was observed during the subsequent 3 years in women who had received HT; furthermore, neither a statistically significant increased risk for invasive breast cancer nor reduced risk for fractures or colorectal malignancies was seen. The global risk index for the entire 8 years of follow-up (hazard ratio, 1.12; 95% confidence interval, 1.03–1.21), elevated at the time the trial was stopped, was noted to be 1.11 (95% CI, 0.99–1.27) during the post-discontinuation years of observation. The all-cause death rate was higher during the post-discontinuation follow-up than during the overall follow-up, although this difference was not statistically significant (HR, 1.15; 95% CI, 0.95–1.39 and HR, 1.04; 95% CI, 0.91–1.18, respectively). Three years after randomized trial discontinuation, the risk for diagnosis of any cancer was modestly higher than during the active trial in those women who had been assigned to HT versus those who received placebo (HR, 1.24; 95% CI, 1.04–1.48). The authors noted that the increased cancer incidence in women previously assigned to HT seemed to reflect a higher risk for diagnosis of cancers other than those prespecified as outcomes (in particular, lung malignancies).
Comment: The observation that increased risks for adverse cardiovascular outcomes or invasive breast cancer and prevention of fractures and colorectal cancer all did not persist after women discontinued HT represents a notable take-home message from this follow-up analysis of WHI participants. Recent WHI reports have suggested that HT, particularly estrogen-only therapy, might be associated with a lower risk for CHD in recently menopausal women and menopausal women in their 50s (Journal Watch Women’s Health May 3 2007 and Jun 21 2007). Accordingly, we await with interest the age-specific follow-up analyses of both the estrogen-plus-progestin and the estrogen-alone WHI clinical trials focusing on cardiovascular outcomes. At the same time, the overall increase in risk for malignancies calls for continued surveillance after estrogen-plus-progestin HT is stopped.
— Andrew M. Kaunitz, MD
Source: From: http://jama.ama-assn.org/cgi/content/short/299/9/1036
Paper Researchers:
Gerardo Heiss, MD; Robert Wallace, MD; Garnet L. Anderson, PhD; Aaron Aragaki, MS; Shirley A. A. Beresford, PhD; Robert Brzyski, MD; Rowan T. Chlebowski, MD; Margery Gass, MD; Andrea LaCroix, PhD; JoAnn E. Manson, MD; Ross L. Prentice, PhD; Jacques Rossouw, MD; Marcia L. Stefanick, PhD; for the WHI Investigators
Published in Journal Watch Women’s Health March 4, 2008
