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Results from the Cancelled WISDOM Trial
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Cancelled WISDOM clinical trial agrees with WHI results: hormone therapy is associated with an increased risk of cardiovascular events in older postmenopausal women.
Source: Vickers MR, et al. BMJ. 2007;335:239-250.
WISDOM was a multicenter, randomized, placebo-controlled clinical trial of postmenopausal hormone therapy that began recruitment in 1999 in the U.K. and in 2000 in Australia and New Zealand. The trial was prematurely cancelled in 2002 after the initial publication of results in the Women's Health Initiative (WHI). This report summarizes the outcomes in 5,692 women (26% of the target number of 22,300) who started treatment. Treatment arms were similar to those in the WHI: daily combined estrogen-progestin with 0.625 mg conjugated equine estrogens (CEE) and 2.5 or 5.0 mg medroxyprogesterone acetate or estrogen only with 0.625 mg CEE daily. The women taking combined estrogen-progestin had significantly increased rates of cardiac events and venous thrombosis. The numbers were much smaller in the estrogen-only arm, but there was a similar trend. Rates for stroke and breast cancer were no different comparing treatment and placebo groups. All but two of the 11 cardiovascular events in treated women were in participants over age 64 who had one or more recognized cardiovascular risk factors. The authors concluded that the results were similar to those in the WHI, reflecting the impact of starting or restarting hormone therapy in older women.1
The participants in the WISDOM trial were similar to those in WHI with an average age of 62.8 years and a distance from menopause of 15 years. The mean follow-up time was 11.9 months. Of course, the small number of events and the short follow-up time do not allow strong conclusions. However, the cardiovascular results come as no surprise, consistent with the current recognition that only the oldest women in the WHI experienced an increase in cardiovascular clinical events. Even venous thrombosis may be concentrated in women with risk factors for this condition, such as obesity or previous cardiovascular disease.
A trend toward a reduction in fractures in the WISDOM trial was also consistent with the finding in the WHI of a potent preventive effect in a general population of women. The cancer outcomes are not meaningful given the short follow-up; only a small number of women achieved a follow-up of 3 years before cancellation of the trial.
Now we are left with no on-going clinical trials of hormone therapy measuring clinical events. To my knowledge, there are 3 trials in progress measuring the effect of hormone therapy in relatively young postmenopausal women on surrogate cardiovascular markers, mainly ultrasonographic assessment of intima media thickness in carotid arteries. Results from these trials are still several years away from being available. Given the difficulties of funding and compliance, it is unlikely that a long-term clinical trial of hormone therapy in the younger postmenopausal years will be performed in the near future. Nevertheless, the accurate and current appraisal of the WHI data that is finally public knowledge allows us to once again have reason to believe that hormone therapy offers primary prevention against coronary heart disease when treatment is started in the early postmenopausal years. A recent reassessment of the WHI results supports this conclusion, even finding no increase in stroke when women over the age of 60 or those with cardiovascular risk factors were excluded.2 In my view, it is appropriate to return this possible benefit into the decision-making process for women considering hormone therapy for symptom control.
The publicity and responses that followed the first reports from the WHI led to about a 30% to 40% discontinuation rate of hormone therapy among women throughout the world. This raises two serious questions. First, in the coming years will data emerge documenting a rise in coronary heart disease and fractures in this population of women? Second, is restarting hormone therapy in these women associated with an increased risk of cardiovascular events? I believe the answer is "yes" to both of these questions. We now recognize that many of the women who discontinued treatment have returned asking for resumption of therapy. There are no relatively inexpensive markers or tests to assess their current state of atherosclerosis and risk of clinical events. This must be a subjective judgment on the part of the clinician. If a substantial length of time has passed since discontinuation and there is concern now for progression of atherosclerosis and an increase in risk, prior to resuming treatment with a low dose of estrogen, it is worth considering a 3-month period of treatment with statins to stabilize any plaques that have developed.