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Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial

Elizabeth Barrett-Connor, MD; Deborah Grady, MD; Andreas Sashegyi, PhD; Pamela W. Anderson, MD; David A. Cox, PhD; Krzysztof Hoszowski, MD; Pentti Rautaharju, MD; Kristine D. Harper, MD; for the MORE Investigators

JAMA. 2002;287:847-857.

Context  Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown.

Objective  To determine the effect of raloxifene on cardiovascular events in osteoporotic postmenopausal women.

Design  Secondary analysis of data from the Multiple Outcomes of Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted between November 1994 and September 1999.

Setting  Outpatient and community settings at 180 sites in 25 countries.

Participants  A total of 7705 osteoporotic postmenopausal women (mean age, 67 years).

Intervention  Patients were randomly assigned to receive raloxifene, 60 mg/d (n = 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years.

Main Outcome Measures  Cardiovascular events, including coronary events (myocardial infarction, unstable angina, or coronary ischemia) and cerebrovascular events (stroke or transient ischemic attack), collected as safety end points and subsequently adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study entry was determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure.

Results  In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately. Among the subset of 1035 women with increased cardiovascular risk at baseline, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P = .94), or among women at increased cardiovascular risk (P = .86) or with evidence of established coronary heart disease (P = .60).

Conclusions  Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. Before raloxifene is used for prevention of cardiovascular events, these findings require confirmation in trials with evaluation of cardiovascular outcomes as the primary objective.

Author Affiliations: Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla (Dr Barrett-Connor); Department of Epidemiology and Biostatistics, University of California, San Francisco (Dr Grady); Lilly Research Laboratories, Indianapolis, Ind (Drs Sashegyi, Anderson, Cox, and Harper); Medical Center, Railway Hospital, Warsaw, Poland (Dr Hoszowski); and Department of Public Health Services, Wake Forest University, Winston-Salem, NC (Dr Rautaharju).

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