April 13, 2004

Chicago, IL - Final results of the Women's Health Initiative estrogen-only trial confirm that the risks of treatment outweigh the benefits seen among women who have had a previous hysterectomy. The results were broadly similar to those seen with the WHI estrogen-plus-progestin trial in postmenopausal women without hysterectomynamely, benefits in reduction of bone fracture offset by an increase in stroke and venous thromboembolic (VTE) events. However, unlike the combined trial, there was no increase seen in breast cancer and no increase in coronary heart disease (CHD), although there was no protection against it, either.The WHI estrogen-alone results are published this week in the April 14, 2004 issue of the Journal of the American Medical Association[1]. Final results of the combined trial were first published in the July 9, 2002 issue of JAMA, after that arm of the trial was also stopped early[2].

"These findings reinforce the recommendation that estrogen-alone therapy should not be used for the prevention of chronic disease," said Dr Barbara Alving, director of the WHI and acting director of the National Heart, Lung, and Blood Institute (NHLBI), which sponsored both trials. "NIH continues to advise women to follow current FDA guidance, which says that hormone therapy should be used to treat menopausal symptoms at the smallest effective dose for the shortest period of time," Alving told a press conference this morning.

Dr Marian Limacher (University of Florida, Gainesville), a cardiologist and principal investigator on both trials, pointed out there are other very effective therapies for prevention of heart disease and stroke. "These are things that women should be focusing on, not the complex hormones that have many different effects and clearly do not prevent heart disease."

Significant excess of stroke

The WHI estrogen-alone trial randomized 10739 women with a prior hysterectomy to 0.625 mg of estrogen (Premarin®, Wyeth) or placebo. It was stopped in February 2004 when an excess of stroke was noted in the data to November 30, 2003, in the context of no benefit on cardiovascular outcomes. Women in the trial had been followed for an average of 6.8 years. Findings in the new publication include events to February 29, 2004 and show a significant excess of 12 cases of stroke with estrogen (44 cases in those on estrogen alone vs 32 in those on placebo) and an excess of six cases of venous thrombosis (21 cases vs 15), including a trend to more pulmonary embolism (PE) in treated women. There was no significant difference in the risk of coronary heart disease (CHD), with five fewer cases in treated women (49 vs 54), although, similar to other trials of estrogen, there was a slight excess with estrogen early after treatment began that subsided over time. No significant difference was seen for colorectal cancer, total cancer, or breast cancer, unlike the increased risk seen in the combined trial. There were actually seven fewer cases of breast cancer among estrogen-treated women (26 vs 33 in the placebo group), although this difference was not statistically significant. "A possible reduction in breast-cancer risk requires further investigation," the investigators write.

The sole significant benefit for estrogen over placebo was in bone fractures, with six fewer cases of hip fracture seen in treated women (11 vs 17 in the placebo group).

WHI Estrogen Alone trial: Major clinical outcomes for estrogen vs placebo

End points (# of cases)

Hazard ratio

95% CI

CHD (376)

0.91 0.75 - 1.12

Breast cancer (218)

0.77 0.59 - 1.01

Stroke (276)

1.39 1.10 - 1.77

PE (85)

1.34 0.87 - 2.06

Colorectal cancer (119)

1.08 0.75 - 1.55

Hip fracture (102)

0.61 0.41 - 0.91

Total CVD (811)

1.12 1.01 - 1.24

Total cancer (372)

0.93 0.81 - 1.07

Total fractures (503)

0.70 0.63 - 0.79

Total mortality (291)

1.04 0.88 - 1.22

Global index*

1.01 0.91 - 1.12

*Global index of risks and benefits, summarizing overall effects of treatment

Women in the estrogen-only trial also participated in the WHI Memory Study (WHIMS). In its advisory for physicians announcing termination of the trial, NHLBI notes that preliminary data indicate a trend toward increased probable dementia and/or mild cognitive impairment in women receiving estrogen. A similar finding on dementia was also seen in the combined trial[3,4].

Do things look better?

In an editorial accompanying the publication[5], Drs Stephen B Hulley and Deborah Grady (University of California, San Francisco) give some "provisional" clinical implications of data from the two WHI trials.

For treatment of menopausal symptoms, they write, "things do look better for estrogen alone than for estrogen plus progestin. However, estrogen alone does have adverse effects, and it remains prudent to keep the dose low and the duration of treatment short." For the prevention of chronic disease, the absence of benefit for estrogen alone and the evidence of harm for estrogen plus progestin means neither therapy should be used for this purpose, they add."Although it is possible that other forms or doses of hormones could be more beneficial, this must be demonstrated in disease-end-point trials before any hormone regimen can be recommended for disease prevention," Hulley and Grady conclude. "Fortunately, there are other good approaches to preventing CHD and fractures for which trials have found benefits to outweigh harms."


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