The Editors, BMJ

Re: Effect of hormone replacement therapy on cardiovascular events in recently menopausal women: randomized trial

The Danish Osteoporosis Prevention Study (DOPS) report on the cardiovascular effects of menopausal hormone therapy (MHT) in younger women raises several concerns about the robustness of the findings [1]. The open label design with no placebo control represents a key limitation; the trial could not control for placebo effect (which can be expected to occur in both active and placebo groups), and knowledge of active treatment assignment could have led to differential health choices, physician visits, hospitalizations, and outcomes reporting and ascertainment.

A second issue is whether the composite outcome of mortality, myocardial infarction, and heart failure was pre-specified. There is no mention of this “primary outcome” in the design paper of the Danish Osteoporosis Prevention Study (DOPS), which specifically notes lack of statistical power over the planned 20-year follow up to evaluate “side effects” such as breast cancer and coronary heart disease (angina and myocardial infarction) and does not mention total or cardiovascular mortality, heart failure, stroke, or venous thromboembolism [2]. We find heart failure to be a curious choice for inclusion since we are not aware of an effect of MHT on this clinical outcome.

A third concern is that the control group event rates for myocardial infarction are unusually low. The annualized rate of 0.08% is less than one-half of that predicted from Women’s Health initiative data in 50-59 year old women [3]. Also, the 4 cases recorded over 10 years appears to be inconsistent with the 14 strokes and 7 heart failure cases; in total there were 25 cases of cardiovascular disease while the total count for cardiovascular death is 18. The apparent lack of proportionality for these outcomes may simply reflect the uncertainties introduced by low numbers, but it also suggests an unusually high case-fatality rate from myocardial infarction, stroke, and heart failure in this cohort.

Since four-fifths of DOPS participants had an intact uterus, the most appropriate comparison is with the Women’s Health Initiative (WHI) trial of estrogen plus progestin E+P) which included 4978 women aged 50-59 years, with ~28,000 person-years of follow up, compared to the 1006 women aged 45-58 years in DOPS, with ~10,000 person-years of follow up [3]. The age range in the WHI subgroup is similar to (but not identical) to the 45-58 years in the DOPS; in DOPS all participants were within 7 months of menopause while in WHI 74% of women below age 60 were within 10 years of menopause onset.. Even with larger numbers of outcomes than DOPS, the WHI trial lacked adequate power in this younger subgroup, yet point estimates suggested that E+P might increase the risk of stroke, breast cancer, and venous thromboembolism compared to placebo, although it might decrease total mortality risk. Hazard ratios for myocardial infarction In WHI were above 1.0 for women 50-59 and only slightly below 1.0 for women <10 years since menopause onset. Hence, only the DOPS findings for total mortality are consistent with the much larger randomized placebo-controlled WHI E+P trial. Finally, combining results from the DOPS E+P and E-alone intervention arms is inappropriate, especially for outcomes such as breast cancer, for which WHI intervention effects were widely divergent.

In conclusion, the DOPS did not have sufficient power to address issues relating to safety of MHT. This is a problem of small numbers for any specific outcome, and also for the composite outcome. Now the published findings add further questions about the study design and interpretation of the study results.

Sincerely,

Jacques E. Rossouw, JoAnn E. Manson, Andrew M. Kaunitz, Marcia L. Stefanick

References
[1] Schierbeck LL, Reynmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Randomised trial. BMJ 2012 Oct 10; 345:e6409. (http://dx.doi.org/10.1136/bmj.e6409)

[2] Mosekilde L, Hermann AP, Beck-Nielsen H, Charles P, Nielsen SP, Sorensen OH. The Danish Osteoporosis prevention study (DOPS): project design and inclusion of 2000 normal perimenopausal women. Maturitas 1999;31:207-219

[3] Rossouw JE, Prentice RL, Manson JE, Wu LL, Barad D, Barnabei VM, et al. Post menopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-1477.

Competing interests: None declared