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HRT suffers another blow

Carl Heneghan
Last edited 26th May 2009
The NEJM publication [1] of Breast Cancer after use of Estrogen plus progestin in postmenopausal women, NEJM 2009 Volume 360:573-587, analyses the effect of the substantial reduction in Hormone replacement therapy (which is estrogen plus progestin also known as HRT) prescriptions that followed the publication of the Women's Health Initiative (WHI) trial in 2002. They analyse temporal trends in breast cancer diagnosis in the WHI cohort following the 5.6 year period after the trial had finished and both initial groups (those on HRT and placebo) both stopped taking HRT. In the original trials first two years, fewer breast-cancer diagnoses occurred in the HRT group than in the placebo group, but the number of breast cancers increased over the ensuing 5.6-year intervention period and decreased after both groups stopped taking the study pills. Initially the incidence of breast cancer was twice as high in HRT group, but this higher incidence decreased by about 2 years, coinciding with the reductions in HRT use. The good news is that within one year of stopping HRT a women’s risk is back to normal. The issues in HRT treatment have unraveled over the last decade. Initially cardioprotective effects of HRT were based on data on lipid levels and a large body of observational studies suggesting approximately a 50% CVD reduction in risk among HRT users. [2,3] Initial comparisons between patients treated and untreated with HRT in observational studies were biased by variables which were not controlled for at the outset. [4] Subsequent randomized controlled trials of HRT [5] confounded the reports of all observational data and most expert opinion, and showed that the positive benefits reported over many years were entirely the result of unrecognised selection bias at the outset. The evidence-based practitioner will recognize that the problem with observational studies is that the initial decision of who receives the treatment is not randomly assigned at the outset and is therefore potentially biased. In terms of assessing causation Austin Bradford Hill in 1965 set out nine detailed criteria for the assessment of causation, [6] which are widely used to determine the strength of an association between a disease and a supposed causative agent. Combining the original WHI trial [5] and this recent NEJM article [1] conclusions, overall health risks exceeded benefits from use of combined HRT. All-cause mortality was not affected during the trial and results indicate that HRT should not be initiated or continued for primary prevention of CHD. The increased risk of breast cancer associated with the use of HRT declined markedly after discontinuation and was unrelated to changes in frequency of mammography.
  1. http://content.nejm.org/cgi/content/short/360/6/573
  2. Stampfer M, Colditz G. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47-63.
  3. Grady D, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-1037.
  4. Stukel TA, et al. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA 2007; 297(3):278-285.
  5. Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288(3):321-333
  6. Hill AB (1965). "The environment and disease: association or causation?" Proceedings of the Royal Society of Medicine 58: 295–300.

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