Re: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial
Schierbeck and colleagues suggest that healthy women treated with hormone replacement therapy (HRT) early after menopause have reduced risk of a composite outcome of mortality, admission to hospital for myocardial infarction, and heart failure (1). In our opinion, the study results should be interpreted with caution.
According to the trial information on clinicaltrials.gov, the primary outcomes were fractures and bone mineral density. Neither the composite outcome nor the individual outcomes are mentioned at all. We contacted Schierbeck and she clarified that the composite outcome had indeed been defined post hoc, before the data analysis, and that no protocol for this analysis had been written. This information has important implications on the interpretation of this study and should have been clearly stated in the published paper. Outcomes defined post-hoc are conventionally considered exploratory and the Schierbeck study should rather be interpreted as an observational study.
Furthermore, the open label design with a “no treatment” group creates important risks of bias. First, awareness of group assignment may affect the behaviour of patients and staff (i.e. performance bias). Second, the outcome ascertainment was not standardised, but is based on coding in the database by individual clinicians. At the time the study was conducted HRT, was thought to have a beneficial effect on cardiovascular disease, which may have influenced choice of diagnostic tests and coding (i.e. detection bias) and differed between treatment arms. Lastly, the trials’ use of envelopes in the randomisation procedure is susceptible to selection bias (2), which could be a reason for the significant imbalance between the groups in regards to age.
The Women’s Health Initiative (WHI) study found that HRT was associated with increased risk of cardiovascular disease and Schierbeck et al. explain their contradictory results with the lower age in their population. This is supported by a subgroup analysis of WHI data that found lower mortality among women less than 60 years old and among women who started HRT less than 10 years after menopause (3). However, another analysis of the same data actually found higher mortality among women initiating estrogen treatment 5 years or less after menopause. (4). The same study also found increased risk of breast cancer among the women initiating combined HRT earlier than 5 years after menopause, a finding that the current study cannot reject due to lack of statistical power. When the benefits and harms of an intervention has to be weighted a study with sufficient power is needed.
Lastly, important conflicts of interest are not disclosed in the paper. According to the Danish Health and Medicines Authority’s public disclosure list at least two additional authors (LS, LK) had undisclosed conflicts with producers of study drugs.
1. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.
2. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
3. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77
4. Prentice RL, Manson JE, Langer RD, Anderson GL, Pettinger M, Jackson RD, et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12-23
Competing interests: No competing interests