A randomized placebo-controlled trial of the effects of HRT on dementia and cognitive function in post-menopausal women.

Lead Research Organisation: King's College London
Department Name: Unlisted

Abstract

Two years ago the Medical Research Council funded a large study of the effects of Hormone Replacement Therapy (HRT). HRT is already extensively prescribed to British women around the time of the menopause, to counter the unpleasant symptoms, such as flushing. In many cases HRT is only being prescribed more long term, because of evidence that it may reduce the risk of heart disease and stroke, and also prevent fractures. However, long term use of HRT may be associated with small increases in the risk for breast cancer, and the overall risks and benefits of therapy are unclear. The WISDOM trial, administered through the MRC General Practice Research Framework, seeks to answer these questions. WISDOM will involve 18,000 British women in 450 practices being randomly allocated to treatment with one of two types of active hormone replacement therapy, or a placebo (a mocked up tablet with no active ingredient). The testament will continue for 10 years and the women will be followed for up to 20 years to determine how they fare. The first results from the trial are expected in 2009.

Now, an extension of the WISDOM trial, WISDOM-COG, will test whether hormone replacement therapy may delay or prevent the onset of dementia and Alzheimer‘s disease, or slow down age-related changes in memory and concentration. Dementia is a degenerative brain disease, involving a progressive loss of memory and other intellectual functions to the point of loss of independence. These conditions, highlighted recently by the plight of famous sufferers such as ex-president Ronald Reegan, are very common, affecting as many as one in three of those who live into their eighties. Despite recent advances in our understanding of the basic disease process, there is no cure, and recently development drug treatments offer only very limited improvements for some of the patients. The suggestion then, from two studies in the USA, that HRT may halve the risk of developing dementia offers considerable hope fothe future. However, the American studies simply found that women who happened to be taking HRT were less likely to go on to develop dementia than those not taking HRT. However there were other important differences between these two groups which could have confused the comparison. Only a properly conducted trial, such as the MRC‘s WISDOM study, which allocates women randomly to active treatment or a placebo tablet can hope to settle the important question of whether HRT really can help to prevent dementia.

Technical Summary

The effects of hormone replacement therapy on post-menopausal women are to be tested in an MRC-funded randomised placebo-controlled double blind trial (WISDOM). IN the UK, over 18,000 women will be randomised to HRT or placebo, for a median 10 years of treatment. WISDOM endpoints currently include mortality and morbidity from cardiovascular and cerebrovascular disease, osteoporotic fractures and breast cancer. Evidence from animal experiments and from observational epidemiology suggests that HRT may also delay or prevent the onset of dementia, and reduce cognitive decline. We propose a cost-efficient extension to the WISDOM protocol, (WISDOM-COG), enabling change in cognitive function and dementia to be included as outcomes.

The dementia sub-study aims to identify dementia onsets occurring over the full 11 years of the WISDOM trial; an estimated 424 new cases among 12,688 women randomised to PORT or placebo. Dementia diagnosis involves three stages. All subjects will be screened every two years by MRC GPRF nurses in 450 practices. 12 specially trained regional nurse co-ordinators will administer a detailed cognitive, functional and clinical assessment to those screening positive as possible cases. Final diagnosis will be by an expert consensus panel. The principal outcome is onset of dementia (ICD-10 criteria). The secondary outcome is onset of Alzheimer‘s disease. This component of the trial has over 80% power to detect a 20% reduction (or greater) in dementia incidence.

The cognitive sub-study investigates the impact of HRT on cognitive decline over five years after randomisation, in a consecutive sample of 2,240 women recruited in a subset of 65 practices. The baseline cognitive assessment, two weeks before commencing randomised treatment, will be repeated in years 2 and 5. Tests will be administered by GPRF clinic nurses after training. The cognitive test battery focuses on memory and related functions (language, attention, speed of information processg). The battery is well tolerated and can be completed in one hour.

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