Risk Persists After HRT Cessation

Heiss G, Wallace R, Anderson GL, et al, for the WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036-1045.

Three years after the termination of the Women's Health Initiative (WHI) trial of hormone replacement therapy (HRT) in postmenopausal women, "the overall assessment of health risks and benefits associated with [HRT] continued to be weighted toward risk," Heiss et al report in JAMA. In light of these findings, "clinical vigilance seems warranted with respect to a sustained higher risk of malignancies."

After the intervention was halted, the investigators conducted a mean 2.4 years of follow-up with 15,730 WHI participants: 8,052 who had received estrogen plus progestin during the trial (the HRT group) and 7,678 who had received placebo. During the intervention phase, women receiving HRT were observed to have an increased risk for cardiovascular events and venous thromboembolism and a reduced risk for total and hip fractures, compared to placebo recipients. During the postintervention interval, these risks and benefits were attenuated, with comparable event rates in both the HRT and placebo groups.

However, the risk for all cancers was 24% higher in the HRT group than in the placebo group during the postintervention phase. All-cause mortality risk, which had been similar between groups during the trial, was 15% higher in the HRT group than in the placebo group during follow-up (although this difference was considered nonsignificant). Furthermore, a global risk index--which included coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes--remained significantly higher for women in the HRT group, with a 12% increase from baseline maintained through follow-up, an indication that risk exceeds benefit.

Considering the "rapid changes in hormone therapy–related risks and benefits" already observed, Heiss et al say ongoing follow-up "will be informative" with regard to "possible delayed effects" of HRT.