Femoral Trochanter BMD 0.625 84 0.78 ± 0.13 3.82 ± 0.58 < 0.001 0.45 91 0.76 ± 0.12 3.16 ± 0.56 0.003 0.3 87 0.75 ± 0.10 3.05 ± 0.57 0.005 Placebo 85 0.75 ± 0.12 0.81 ± 0.58 a: Identified by dosage (mg) of Premarin or placebo. Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater than the value shown on the x-axis. Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND PLACEBO GROUPS The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 2. Significant differences between each of the Premarin dosage groups and placebo were found at cycles 6, 13, 19, and 26. Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBO The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium. 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 Premarin (0.625 mg conjugated equine estrogens per day) alone or the use of Prempro (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate 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 Premarin or Prempro on menopausal symptoms. The Premarin-only substudy is continuing and results have not been reported. The Prempro 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 Prempro 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 4 below. TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPRO SUBSTUDY OF WHI a Placebo n = 8102 Prempro n = 8506 Event c Relative Risk Prempro vs Placebo at 5.2 Years (95% CI*) 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 b 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 c 1.15 (1.03-1.28) 151 170 Deep vein thrombosis d 2.07 (1.49-2.87) 13 26 Vertebral fractures d 0.66 (0.44-0.98) 15 9 Other osteoporotic fractures d 0.77 (0.69-0.86) 170 131 a: adapted from JAMA, 2002; 288: 321-333 b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c: a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes d: not included in Global Index * nominal confidence intervals unadjusted for multiple looks and multiple comparisons. For those outcomes included in the "global index," absolute excess risks per 10,000 person-years in the group treated with Prempro were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-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 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) | ||||
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