Long-term follow-up of WHI indicates menopausal hormone therapy not helpful for chronic disease prevention

Hormone therapy after menopause is not effective for chronic disease prevention, according to a new analysis of long-term follow-up data from the Women's Health Initiative (WHI).

Researchers presented an overview of findings from 2 WHI trials of hormone therapy with extended postintervention follow-up. In the trials, women who had an intact uterus received conjugated equine estrogen (CEE), 0.625 mg/d, plus medroxyprogesterone acetate (MPA), 2.5 mg/d, or placebo. Women who had had a hysterectomy received CEE alone at the same dosage or placebo. The intervention phase of the CEE plus MPA trial was 5.6 years, while the intervention phase of the CEE-only trial lasted 7.2 years; there were 13 years of cumulative follow-up until Sept. 30, 2010. In the current analysis, the primary efficacy outcome was coronary heart disease (CHD) and the primary safety outcome was invasive breast cancer. In addition, a global index of monitored clinical events included time to first event for CHD, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture and death from all other causes, plus endometrial cancer in the CEE plus MPA group. The study was published in the Oct. 2 Journal of the American Medical Association.

Overall, 27,347 postmenopausal women 50 to 79 years of age were enrolled in the study at 40 U.S. centers. A total of 8,506 women received CEE plus MPA and 8,102 received placebo, while 5,310 women received CEE alone and 5,429 received placebo. For the CEE plus MPA intervention, 196 CHD cases occurred in the CEE plus MPA group and 159 occurred in the placebo group (hazard ratio [HR], 1.18; 95% CI, 0.95 to 1.45); the numbers of breast cancer cases were 206 and 155, respectively (HR, 1.24; 95% CI, 1.01 to 1.53). Patients in the intervention group also had increased risk for stroke, pulmonary embolism, dementia (if ≥65 years of age), gallbladder disease and urinary incontinence but decreased risk for hip fractures, diabetes and vasomotor symptoms. Most risks and benefits dissipated during cumulative postintervention follow-up with the exception of risk for breast cancer, which remained elevated in the intervention group (434 cases vs. 323 cases; HR, 1.28; 95% CI, 1.11 to 1.48).

The CEE-only intervention yielded more balanced risk and benefits. Two hundred four CHD cases and 104 invasive breast cancer cases occurred in the intervention group versus 222 cases and 135 cases in the placebo group; the HR for CHD was 0.94 (95% CI, 0.78 to 1.14), while the HR for invasive breast cancer was 0.79 (95% CI, 0.61 to 1.02). A cumulative total of 168 breast cancer cases was diagnosed in the CEE-only group versus 216 in the placebo group (HR, 0.79; 95% CI, 0.61 to 1.02). Other outcomes in the CEE-only intervention were similar to those seen in the CEE plus MPA intervention.

Neither of the interventions appeared to affect all-cause mortality. Women 50 to 59 years of age had more favorable outcomes with CEE only for all-cause mortality, myocardial infarction and the global index. The range of absolute risks of adverse events with CEE plus MPA as measured by the global index per 10,000 women annually was 12 excess cases in women age 50 to 59 and 51 excess cases in women age 70 to 79. Outcomes related to quality of life were mixed for both interventions. Younger women age 50 to 54 years in the CEE plus MPA and CEE-only groups who were having hot flashes, night sweats or both at study enrollment (n=979) reported substantial improvement in symptoms at 1 year, while among the entire cohort, women taking either study regimen had less sleep disturbance but more breast tenderness than those taking placebo. Those taking CEE plus MPA were also less likely than those taking placebo to report joint pain.

The authors noted that because the WHI trials each examined only 1 hormone dose, type and route of administration, the results may not be generalizable to other hormone preparations, and that 20% of surviving study participants did not give consent for extended follow-up, among other limitations. However, they concluded, the current WHI findings don't support the use of either intervention for chronic disease prevention. They noted that the risks of CEE plus MPA outweighed the benefits for women of all studied ages, that younger women with hysterectomy had a more favorable risk-to-benefit ratio with CEE alone, and that increased stroke and venous thrombosis risk persisted with both regimens.

“Even though hormone therapy is a reasonable option for the management of moderate to severe menopausal symptoms among generally healthy women during early menopause, the risks associated with hormone therapy, in conjunction with the multiple testing limitations attending subgroup analyses, preclude a recommendation in support of its use for disease prevention even among younger women,” the authors wrote. “Current findings also suggest caution when considering hormone therapy treatment in older age groups, even in the presence of persistent vasomotor symptoms, given the high risk of CHD and other outcomes associated with hormone therapy use in this setting.”