Long-term WHI Results: Mixed Results, Still Controversial

Larry Hand

October 01, 2013

The health risks associated with long-term hormone replacement therapy (HRT) outweigh the benefits, according to an extended follow-up analysis of the Women's Health Initiative (WHI) trials, although HRT may be appropriate for management of menopause symptoms in some women, the researchers write in an article published in the October 1 issue of JAMA.

Outside researchers, however, remain split on the value of the new analysis, with one critic saying politics are driving the report, rather than data.

In the new analysis, JoAnn E. Manson, MD, DrPH, from Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and colleagues constructed a "comprehensive, integrated overview" of original findings of the 2 WHI clinical trials and a cumulative 13 years of follow-up.

The trials involved 27,347 postmenopausal women aged 50 to 79 years enrolled at 40 US centers in 1993. Women with intact uteri received conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA; n = 8506) or placebo (n = 8102). Women who had had hysterectomies received CEE alone (n = 5310) or placebo (n =5429).

The CEE+MPA trial was stopped in July 2002, after a median intervention period of 5.6 years, when investigators detected an increased breast cancer risk and an unfavorable risk-to-benefit ratio in the HRT group. The CEE-alone trial was stopped in February 2004, after a median intervention period of 8.1 years, when researchers discovered an increased stroke incidence that was not offset by lower heart disease risk in the HRT group. Postintervention follow-up continued through September 2010, for a median follow-up of 8.2 years for the CEE+MPA trial and 6.6 years for the CEE-alone trial (cumulative 13.2 years).

The results the researchers report in this extended analysis include:

  • Women in the CEE+MPA group were 80% more likely to develop coronary heart disease (CHD) at year 1 than women receiving placebo (hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.08 - 2.99), whereas HRs for the CEE-alone group did not differ significantly by year. Postintervention results were neutral for both trials.

  • Women in the CEE+MPA group were 24% more likely to develop breast cancer than women in the placebo group (HR, 1.24; 96% CI, 1.10 - 1.53). However, women in the CEE-alone group had a nonsignificant trend for a reduced risk (HR, 0.79; 95% CI, 0.61 - 1.02). The risk remained significant for the CEE+MPA women after intervention and during follow-up, whereas the risk reduction for CEE women became statistically significant during follow-up (HR,0.79; 95% CI, 0.65 - 0.97).

  • Stroke risk increased with both groups during the intervention (HR, 1.37; CEE+MPA, 1.35 CEE). Postintervention stroke risk was neutral in both groups.

  • Women receiving HRT in both trials had significantly lower rates of treated diabetes than women receiving placebo (HR, 0.81; 95% CI, 0.70 - 0.94), although the risk reductions did not carry into postintervention and follow-up.

  • CEE+MPA treatment was associated with "small but statistically significant" improvement in factors including general health, physical functioning, and bodily pain, whereas CEE treatment was associated with "nominally significant adverse effects for social functioning and emotional role."

  • Women 50 to 54 years old experiencing hot flashes, night sweats, or both at enrollment had "substantial reductions in symptoms" when receiving treatment during both trials compared with placebo.

  • Women 70 to 79 years old who had vasomotor symptoms at baseline on treatments in both trials had high risks for CHD compared with women receiving placebo, whereas younger women did not.

Not so Fast…

Wulf H. Utian, MD, PhD, DSc, professor emeritus of reproductive biology at Case Western Reserve University in Cleveland and an obstetrics and gynecology consultant in Beachwood, Ohio, told Medscape Medical News that the WHI researchers are reading their own data incorrectly and not including counter research recently published.

"I continue to have the same disappointment as I see these articles come out," said Dr. Utian, who wrote an article in 2012 calling for an independent panel to study the WHI data. "Instead of it being science, it's become almost like politics. It's 'report what you believe and slant your discussions and your readings of the results toward the conclusion that you want to make,' instead of looking very closely at what the data really and truly said."

The researcher team is "not as frank as it should be," he continued. "[B]ased on their own data, their conclusions are wrong." He thinks the WHI data do show chronic disease benefits when estrogen alone is used. For example, he pointed out results from a table in the study (Figure 5) that showed benefits for estrogen use alone in several categories, mostly for younger women. "You're showing a major impact on chronic disease and you're also showing that it has a beneficial effect on health-related quality of life, and it alleviates symptoms of menopause," he said.

Moreover, he added, the WHI researchers failed to mention other research that shows negative aspects of not using hormone therapy. For example, he points to a study that showed significantly increased risk for hip fracture in women who discontinued hormone therapy and another very recent study, showing an increase in premature mortality in women who avoided hormone therapy.

HRT Needs to Be Individualized

Other specialists, however, find the data more convincing and think the questions have been largely settled. "These findings demonstrate that menopausal hormone therapy has a complex profile of risks and benefits," Elizabeth G. Nabel, MD, also from Brigham and Women's Hospital and Harvard Medical School, writes in an accompanying editorial in JAMA. "Even though short-term use of hormone therapy may be useful for menopausal symptom relief, such as for vasomotor instability, long term use of hormone therapy for chronic disease prevention is not warranted."

Meanwhile, the American Congress of Obstetricians and Gynecologists recently published a position paper online that concludes that hormone or estrogen therapy should be "individualized based on each woman's risk–benefit ratio and clinical presentation."

This research was supported by the by the National Heart, Lung, and Blood Institute and US Department of Health and Human Services. Wyeth-Ayerst donated study drugs. The authors report various financial relationships with Novartis, Amgen, AstraZeneca, Pfizer, Educational Concepts Group, the National Institutes of Health, MedStar Health, Merck, Stanford University, UptoDate Inc, and the Research Foundation for the State University of New York, Buffalo. Dr. Manson and Dr. Nabel have disclosed no relevant financial relationships.

JAMA. 2013;310:1349-1350, 1353-1368. Article full text, Editorial extract

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