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The Women's Health Initiative Randomized Controlled Trial

The Women's Health Initiative Steering Committee^*

JAMA. 2004;291:1701-1712.

Context  Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.

Objective  To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.

Intervention  Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.

Main Outcome Measures  The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.

Results  In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.

Conclusions  The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

^*Authors/WHI Steering Committee: Garnet L. Anderson, PhD (writing group chair, Fred Hutchinson Cancer Research Center, Seattle, Wash); Marian Limacher, MD (writing group cochair, University of Florida, Gainesville/Jacksonville). Members (in alphabetical order): Annlouise R. Assaf, PhD (Brown University, Providence, RI); Tamsen Bassford, MD (University of Arizona, Tucson/Phoenix); Shirley A. A. Beresford, PhD (Fred Hutchinson Cancer Research Center, Seattle); Henry Black, MD (Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill); Denise Bonds, MD (Wake Forest University School of Medicine, Winston-Salem, NC); Robert Brunner, PhD (University of Nevada, Reno); Robert Brzyski, MD (University of Texas Health Science Center, San Antonio); Bette Caan, DrPH (Kaiser Permanente Division of Research, Oakland, Calif); Rowan Chlebowski, MD (Harbor-UCLA Research and Education Institute, Torrance, Calif); David Curb, MD (University of Hawaii, Honolulu); Margery Gass, MD (University of Cincinnati, Cincinnati, Ohio); Jennifer Hays, PhD (Baylor College of Medicine, Houston, Tex); Gerardo Heiss, MD (University of North Carolina, Chapel Hill); Susan Hendrix, DO (Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich); Barbara V. Howard, PhD (MedStar Research Institute/Howard University, Washington, DC); Judith Hsia, MD (George Washington University Medical Center, Washington, DC); Allan Hubbell, MD (University of California at Irvine, Orange); Rebecca Jackson, MD (The Ohio State University, Columbus); Karen C. Johnson, MD (University of Tennessee, Memphis); Howard Judd, MD (University of California at Los Angeles); Jane Morley Kotchen, MD (Medical College of Wisconsin, Milwaukee); Lewis Kuller, MD (University of Pittsburgh, Pittsburgh, Pa); Andrea Z. LaCroix, PhD (Fred Hutchinson Cancer Research Center, Seattle); Dorothy Lane, MD (State University of New York at Stony Brook); Robert D. Langer, MD (University of California at San Diego, LaJolla/Chula Vista); Norman Lasser, MD (University of Medicine and Dentistry of New Jersey, Newark); Cora E. Lewis, MD (University of Alabama at Birmingham); JoAnn Manson, MD (Brigham and Women's Hospital, Harvard Medical School, Boston, Mass); Karen Margolis, MD (University of Minnesota, Minneapolis); Judith Ockene, PhD (University of Massachusetts/Fallon Clinic, Worcester); Mary Jo O'Sullivan, MD (University of Miami, Miami, Fla); Lawrence Phillips, MD (Emory University, Atlanta, Ga); Ross L. Prentice, PhD (Fred Hutchinson Cancer Research Center, Seattle); Cheryl Ritenbaugh, PhD (Kaiser Permanente Center for Health Research, Portland, Ore); John Robbins, MD (University of California at Davis, Sacramento); Jacques E. Rossouw, MD (National Heart, Lung, and Blood Institute, Bethesda, Md); Gloria Sarto, MD (University of Wisconsin, Madison); Marcia L. Stefanick, PhD (Stanford Prevention Research Center, Stanford University, Stanford, Calif); Linda Van Horn, PhD (Northwestern University, Chicago, Ill); Jean Wactawski-Wende, PhD (University at Buffalo, Buffalo, NY); Robert Wallace, MD (University of Iowa, Iowa City/Davenport); Sylvia Wassertheil-Smoller, PhD (Albert Einstein College of Medicine, Bronx, NY).

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