Level 1: Likely reliable evidence

The Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM) was a randomized trial of 5,692 postmenopausal women aged 50-69 years (mean age 63 years) who were randomized to HRT vs. placebo (BMJ. 2007;335:239). Inclusion criteria included women who demonstrated ≥80% compliance during a 12-week run-in period. Women with a uterus were randomized to combination HRT (Prempro) vs. placebo daily; women without a uterus and unwilling to take placebo were randomized to Prempro vs. estrogen alone (Premarin) 0.625 mg orally daily; women without a uterus and willing to take placebo were randomized to Prempro vs. Premarin vs. placebo daily. Oral medroxyprogesterone acetate 5 mg (Premique) was given daily to women with a uterus and within three years of their last period, women aged 50-53 years, and older women with unacceptable breakthrough bleeding. Median follow-up was one year due to early closure of the trial. Major cardiovascular disease (CVD) was defined as unstable angina requiring hospitalization, MI (fatal or nonfatal), or sudden coronary death.

In an analysis of 4,385 women, combination therapy (compared with placebo) was associated with a significantly increased risk of major CVD (0.32% vs. 0, NNH 312) and venous thromboembolism (1% vs. 0.14%, NNH 116). But the therapy was also associated with decreased risk of osteoporotic fractures (1.8% vs. 2.6%, NNT 125). There were no significant differences in rates of cerebrovascular disease, cancer, or death.

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Comparing combination therapy vs. estrogen alone, there were no significant differences in major CVD, venous thromboembolism, cancer, osteoporotic fracture, or death in analysis of 1,641 women. Some women taking combination HRT were counted in both this analysis and in the analysis compared with placebo.

Of 11 women who had major cardiovascular events, nine were older than 64 years and had other cardiovascular risk factors.