Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin.
BACKGROUND
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.


METHODS
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.


METHODS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00000611.
Heiss
Gerardo
G
University of North Carolina, School of Public Health, Department of Epidemiology, Chapel Hill, NC 27514-3628, USA. gerardo_heiss@unc.edu
Wallace
Robert
R
Anderson
Garnet L
GL
Aragaki
Aaron
A
Beresford
Shirley A A
SA
Brzyski
Robert
R
Chlebowski
Rowan T
RT
Gass
Margery
M
LaCroix
Andrea
A
Manson
JoAnn E
JE
Prentice
Ross L
RL
Rossouw
Jacques
J
Stefanick
Marcia L
ML
D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage*; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology*; D018570:Risk Assessment
D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate