Medpage: LaCroix A, et al "Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial" JAMA 2011; 305: 1305-1314.

Blogger's Note: also see website for video

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New WHI Estrogen Analysis Shows Lower Breast Ca Risk

By John Gever, Senior Editor, MedPage Today

Published: April 05, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

• Explain that post-intervention follow-up of the WHI Estrogen-Alone Trial showed that both risks and benefits of unopposed estrogen largely disappeared after therapy stopped.
• Note that while the risk of breast cancer remained decreased for the intervention and post-intervention period combined, the decreased risk during the post-intervention period itself was not statistically significant.

In contrast to other studies of unopposed postmenopausal estrogen therapy, long-term follow-up of Women's Health Initiative (WHI) Estrogen-Alone Trial participants showed a persistent reduction in breast cancer risk, researchers said.

But other benefits and risks associated with use of conjugated equine estrogens (CEE) quickly dissipated after the therapy was stopped, according to Andrea Z. LaCroix, PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

"Considering the entire follow-up period, rates of total mortality and the global index of chronic diseases were essentially the same in the conjugated equine estrogen and placebo groups," LaCroix and co-authors wrote in the April 6 issue of the Journal of the American Medical Association.
"Statistically significant age interactions for conjugated equine estrogen use, suggesting greater safety and possible benefit among women in their 50s and potential harm among older women, were observed for coronary heart disease, total MI, colorectal cancer, total mortality, and the global index of chronic diseases," they added.

An editorial in the same issue suggested more caution in interpreting the breast cancer results.


Like its sister WHI trial, which tested combination hormone therapy (CEE plus medroxyprogesterone acetate, MPA) in postmenopausal women, the Estrogen-Alone Trial was stopped early -- after a mean of 7.1 years of follow-up -- because of a clearly higher rate of adverse effects in the active-treatment group.

In this case, the increased risk was for stroke and deep vein thrombosis (DVT). The randomized, placebo-controlled trial, which enrolled nearly 11,000 women with prior hysterectomy 50 to 79 years old, was stopped in 2004. However, 7,645 women agreed to be followed afterward.
LaCroix and colleagues are now reporting the first data from this follow-up phase, representing a mean 10.7 years from baseline.
When the Estrogen-Alone trial was stopped, a hazard ratio of 1.36 for stroke (95% CI 1.08 to 1.71) was seen with CEE relative to placebo and 1.47 for DVT (95% CI 1.06 to 2.06).
There was also a strong trend for increased risk of pulmonary embolism (HR 1.37, 95% CI 0.90 to 2.07).

Rates of invasive breast cancer, however, appeared lower in the CEE group when the trial was halted (HR 0.79, 95% CI 0.61 to 1.02) -- in contrast to the other WHI trial, in which higher rates of breast cancer among participants receiving CEE plus MPA forced a premature end to that study.

Hip fractures were also reduced with treatment in the Estrogen-Alone study when it was ended (HR 0.67, 95% CI 0.46 to 0.96).
But when LaCroix and colleagues analyzed outcomes during the subsequent follow-up period, most of the risks and benefits associated with CEE hormone therapy became insignificant, clinically and/or statistically.

The following are hazard ratios during the Estrogen-Alone post-intervention period:
(Blogger's Note/Reminder <1.0 = benefit; >1.0=risk)

• Stroke: 0.89 (95% CI 0.64 to 1.24)
• DVT: 0.63 (95% CI 0.41 to 0.98)
• Pulmonary embolism: 0.98 (95% CI 0.62 to 1.55)
• All cardiovascular events: 0.93 (95% CI 0.79 to 1.10)
• Invasive breast cancer: 0.75 (95% CI 0.51 to 1.09)
• All cancers: 0.93 (95% CI 0.77 to 1.13)
• Hip fracture: 1.27 (95% CI 0.88 to 1.82)
• All-cause mortality: 1.00 (95% CI 0.84 to 1.18)
• Global index of adverse outcomes: 1.02 (95% CI 0.89 to 1.16)

Although the decrease in breast cancer during the post-intervention period did not reach statistical significance, the overall rate through the entire study period did -- with a hazard ratio of 0.77 (95% CI 0.62 to 0.95).
It was the only outcome for which the treatment group differed relative to controls over the full 10.7 years of data.
LaCroix and colleagues found it especially noteworthy because, they wrote, most other studies of unopposed estrogens have pointed to increased risk of breast cancer "especially in lean women and after long duration of exposure."
They also found an age-related effect in the study, with more benefits and fewer cardiovascular events among women younger than 60.
"Mechanisms underlying the reduced risks of breast cancer in all women, and coronary events in younger but not older women, warrant further study, the researchers concluded.
As a result, they recommended that women should be counseled individually -- with older women warned of the multiple risks associated with unopposed estrogen whereas younger women may indeed benefit from estrogen therapy.

But LaCroix and colleagues noted that median treatment duration in the study was less than six years and the median time that women took more than 80% of the medication was only 3.5 years for both CEE and placebo. "Our results cannot be extrapolated to longer or shorter treatment," they cautioned.

In the accompanying editorial, two physicians at Washington University in St. Louis said the study's main message was that the risks and benefits of unopposed estrogens were mainly confined to the period of active treatment -- that there do not seem to be persistent effects after the therapy stops.
"Short-term use appears safe with rapid decline of risks and benefits after cessation of use," wrote Emily Jungheim, MD, and Graham Colditz, MD, DrPH.
Both were more skeptical of the current study's finding of reduced breast cancer rates with CEE, arguing that the balance of all studies still tips toward elevated risk -- especially in leaner women and those taking unopposed estrogens for long periods.
"This body of evidence has led the International Agency for Research on Cancer to conclude that unopposed estrogen hormone therapy and combination hormone therapy are carcinogenic," Jungheim and Colditz wrote.
"There may still be a role for short-term use of unopposed estrogen for treating some women with menopausal symptoms, but this role may be vanishing," they added.
The editorialists suggested that other treatment strategies and lifestyle adjustments should be discussed with women needing relief from menopause symptoms.

The Women's Health Initiative has been funded by the National Heart, Lung and Blood Institute. Wyeth supplied study medications.
Study authors reported consulting and/or speakers' bureau service for Warner Chilcott, Amgen, Pfizer, AstraZeneca, Novartis, and Merck/Schering-Plough.
The editorialists declared they had no relevant financial interests.

Primary source: Journal of the American Medical Association
Source reference:
LaCroix A, et al "Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial" JAMA 2011; 305: 1305-1314.
Additional source: Journal of the American Medical Association
Source reference:
Jungheim E, et al "Short-term use of unopposed estrogen: a balance of inferred risks and benefits" JAMA 2011; 305: 1354-1355.

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