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WHI Estrogen-Plus-Progestin Trial: 3 Years Later

Increased risk for adverse cardiovascular outcomes and invasive breast cancer — and reduced risk for fractures and colorectal cancer — did not persist after women discontinued HT.

In the summer of 2002, the Women’s Health Initiative (WHI) randomized trial of estrogen plus progestin was stopped after the WHI writing group concluded that the results showed more risk than benefit: An increased risk for venous thromboembolism and modestly increased risks for stroke, cardiovascular disease (CVD), coronary heart disease (CHD), and invasive breast cancer outweighed the reduced risks for fractures and colorectal cancer. In this latest update, WHI investigators report on outcomes 3 years after study medication (estrogen-plus-progestin hormone therapy or placebo) was halted.

In contrast to findings at the time study medication was discontinued, no increased risk for thrombosis, CHD, or stroke was observed during the subsequent 3 years in women who had received HT; furthermore, neither a statistically significant increased risk for invasive breast cancer nor reduced risk for fractures or colorectal malignancies was seen. The global risk index for the entire 8 years of follow-up (hazard ratio, 1.12; 95% confidence interval, 1.03–1.21), elevated at the time the trial was stopped, was noted to be 1.11 (95% CI, 0.99–1.27) during the post-discontinuation years of observation. The all-cause death rate was higher during the post-discontinuation follow-up than during the overall follow-up, although this difference was not statistically significant (HR, 1.15; 95% CI, 0.95–1.39 and HR, 1.04; 95% CI, 0.91–1.18, respectively). Three years after randomized trial discontinuation, the risk for diagnosis of any cancer was modestly higher than during the active trial in those women who had been assigned to HT versus those who received placebo (HR, 1.24; 95% CI, 1.04–1.48). The authors noted that the increased cancer incidence in women previously assigned to HT seemed to reflect a higher risk for diagnosis of cancers other than those prespecified as outcomes (in particular, lung malignancies).

Comment: The observation that increased risks for adverse cardiovascular outcomes or invasive breast cancer and prevention of fractures and colorectal cancer all did not persist after women discontinued HT represents a notable take-home message from this follow-up analysis of WHI participants. Recent WHI reports have suggested that HT, particularly estrogen-only therapy, might be associated with a lower risk for CHD in recently menopausal women and menopausal women in their 50s (Journal Watch Women’s Health May 3 2007 and Jun 21 2007). Accordingly, we await with interest the age-specific follow-up analyses of both the estrogen-plus-progestin and the estrogen-alone WHI clinical trials focusing on cardiovascular outcomes. At the same time, the overall increase in risk for malignancies calls for continued surveillance after estrogen-plus-progestin HT is stopped.

— Andrew M. Kaunitz, MD

Published in Journal Watch Women's Health March 4, 2008

Citation(s):

Heiss G et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008 Mar 5; 299:1036.

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