Gmail - [ProCOR] Hormone Replacement Therapy in Postmenopausal Women

Gmail - [ProCOR] Hormone Replacement Therapy in Postmenopausal Women



Title: Main Morbidities Recorded in the Women's International Study of Long Duration Oestrogen After Menopause (WISDOM): A Randomised Controlled Trial of Hormone Replacement Therapy in Postmenopausal Women

Authors: MR Vickers, AH MacLennan, B Lawton, D Ford, J Martin, SK Meredith, BL DeStavola, S Rose, A Dowell, HC Wilkes, JH Darbyshire, TW Meade

Reference: BMJ 2007; 335: 239,http://www.bmj.com/cgi/content/abstract/335/7613/239
Reviewer: Robert Goldberg, PhD, ProCor contributing editor

Results of the study below suggest that postmenopausal women starting or restarting hormone replacement therapy are at increased risk for developing coronary heart disease than women not treated with this drug regimen.

Problem addressed: Long-term risks and benefits associated with use of hormone replacement therapy (HRT) in postmenopausal women.

Purpose of study: To assess the long-term benefits as well as risks associated with HRT in a large sample of postmenopausal women recruited from nearly 500 general practices in the UK, Australia and New Zealand.

Location of study: London, England, UK

Study design: RCT

Results: The WISDOM Trial recruited a large number of postmenopausal womenbetween the ages of 50-69 years from a total of 499 general practices in the UK (# of practices = 384), Australia (n=91) and New Zealand (n=24) to the receipt of estrogen only therapy, combined hormone therapy, or to placebo medication. A total of more than 56,000 women were screened for trial entry, 8,980 entered a trial run-in phase, and 5,692 were randomly assigned to the different treatment modalities. Recruitment to the trial began in 1999 and 2000; of the women enrolled in the trial, the vast majority was from the UK.

The trial randomization schema was stratified based on hysterectomy status and intended use of HRT. Women with an intact uterus were randomly assigned to the receipt of either combined estrogen plus progestogen therapy or to placebo. In parallel, women without a uterus or who were unwilling to take placebo therapy were randomly assigned to estrogen therapy, combined estrogen plus progestogen therapy or to placebo treatment.

A number of predefined primary as well as secondary study outcomes were examined in this trial. The primary trial outcomes were the occurrence of a major CHD event (e.g., unstable angina, fatal or nonfatal MI, or SCD), osteoporotic fractures, and breast cancer. The secondary trial outcomes included mortality from breast and other cancers, deaths from all causes, venous thromboembolic disease, cerebrovascular disease and dementia. The mean age of participating women at the time of study enrollment was 63 years, the majority were white, the average BMI was 28 and the primary comparison groups were relatively well balanced on the trial entry characteristics.

Over an average follow-up of approximately one year, women taking combined HRT had markedly increased rates of CVD and venous thromboembolic disease, and a nonsignificant reduction in the risk of developing osteoporatic fractures (31% reduction), as compared to those taking placebo. The incidence rates of cerebrovascular disease, breast cancer and other cancers were not significantly different between the respective comparison groups. The incidence rates of serious adverse events did not significantly differ in either of the randomized comparisons performed.

While there were no significant differences in the incidence rates of CVD events or venous thrombosis between women prescribed estrogen therapy, as compared to those taking estrogen plus progestogen treatment, there were suggestions of an increase in these primary endpoints in women prescribed combination therapy. Twice as many women in the combined therapy versus placebo groups withdrew from the trial while the rates of study withdrawal were similar in the combined versus estrogen therapy groups. This trial was prematurely stopped because of the results of the Women's Health Initiative Study which were published in 2002.

Comments: The results of the WISDOM Trial suggest that postmenopausal women starting or restarting combined estrogen and progestogen therapy are at increased risk for developing CHD than women not treated with this drug regimen. On the other hand, treatment with HRT was associated with a decreased risk of osteoporotic practices and decreased risk of osteoporotic fractures and no apparent impact on the risk of stroke or malignancy. Despite the large number of women included in this study, and rigorous trial design, appropriate caveats need to be placed in interpreting the results of this investigation given the premature discontinuation of this trial, relatively short duration of follow-up, and small number of events accrued at the time of study completion.

Similar to the Women's Health Initiative, the WISDOM trial tested the hypothesis that the use of HRT in elderly asymptomatic postmenopausal women might reduce the risk of developing several major comorbidities including CHD, stroke and cancer and have possible beneficial effects on reducing the risk of osteoporotic fractures.

A considerable amount of adverse publicity and patient concern and confusion has resulted from the results of the Women's Health Initiative trial. The results of the WISDOM trial and the Women's Health Initiative call into question any health benefits that might be accrued from the initiation of HRT in postmenopausal women in their 60s, especially on the occurrence of CVD. Decisions about the use of HRT in peri and postmenopausal women need to be carefully considered by patients and their physicians, together with considerations about quality of life, with benefits and risks carefully weighed in both absolute and relative terms.