Clinical Studies
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:
| Event† | Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI‡) | Placebo n = 8102 | CE/MPA n = 8506 |
|---|---|---|---|
| |||
| Absolute Risk per 10,000 Person-years | |||
| CHD events | 1.29 (1.02–1.63) | 30 | 37 |
| Non-fatal MI | 1.32 (1.02–1.72) | 23 | 30 |
| CHD death | 1.18 (0.70–1.97) | 6 | 7 |
| Invasive breast cancer§ | 1.26 (1.00–1.59) | 30 | 38 |
| Stroke | 1.41 (1.07–1.85) | 21 | 29 |
| Pulmonary embolism | 2.13 (1.39–3.25) | 8 | 16 |
| Colorectal cancer | 0.63 (0.43–0.92) | 16 | 10 |
| Endometrial cancer | 0.83 (0.47–1.47) | 6 | 5 |
| Hip fracture | 0.66 (0.45–0.98) | 15 | 10 |
| Death due to causes other than the events above | 0.92 (0.74–1.14) | 40 | 37 |
| Global Index† | 1.15 (1.03–1.28) | 151 | 170 |
| Deep vein thrombosis¶ | 2.07 (1.49–2.87) | 13 | 26 |
| Vertebral fractures¶ | 0.66 (0.44–0.98) | 15 | 9 |
| Other osteoporotic fractures¶ | 0.77 (0.69–0.86) | 170 | 131 |
For those outcomes included in the "global index," absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See Boxed Warning, WARNINGS, and PRECAUTIONS.)
Women's Health Initiative Memory Study
The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See Boxed Warning and WARNINGS, Dementia.)