HRT on trial. (Guest Editorial).

The stunning decision to call an early halt to one of two hormone studies in the Women's Health Initiative unleashed a host of questions about the long-term safety of hormone replacement therapy.

A full 3 years ahead of plan, the WHI safety panel stopped the test of the mostly commonly used combination HRT regimen--0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (MPA) daily--in women with a uterus. The other WHI placebo-controlled HRT trial continues testing the most commonly used estrogen-only regimen--0.625 mg of conjugated equine estrogen--in women who have had a hysterectomy.

Volunteers in clinical trials are asked to take an unidentified treatment, often for a long time--9 years in the WHI. The regimen is not individualized and there are few, if any options for adjusting it. Thus an independent safety panel must closely monitor participants to avoid unnecessary risk and expense if the effort appears likely to be futile. The WHI safety panel monitored six outcomes: coronary disease, stroke, thromboembolic disease, breast cancer, hip fracture, and colorectal cancer.

After more than 5 years of treatment, the rate of invasive breast cancer in the combination HRT group had just exceeded the threshold for action by the safety panel and was trending upwards. Despite a modest trend toward reversal of early HRT-related coronary harm, rates of stroke and thromboembolic disease remained elevated. Meanwhile, there were benefits for hip fracture and colorectal cancer. Considering all six outcomes per 10,000 women per year, there were 41 extra events and 11 cases prevented, a net negative trend of 30. The safety panel concluded that the mix of these outcomes was unlikely to cross over to benefit if the trial continued.

The study question had been answered: There was no overall benefit for the HRT combination rested. Continuation would be futile under preset criteria.

These results do not rule out the possibility that other ...