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Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

BMJ 2012; 345 doi: (Published 09 October 2012) Cite this as: BMJ 2012;345:e6409

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Re: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

Hormone replacement therapy (HRT) in post-menopausal women is the topic of heated debate; central to the controversy is whether the direction of effect of HRT on cardiovascular disease is dependent on time of initiation of therapy relative to age or onset of menopause. The results of the trial by Schierbeck and colleagues initially promise to fuel the discourse, however, the limitations of this trial in the context of existing evidence should temper opinions.

It is important to recognize that few cardiovascular events occurred in this trial despite the 10 years of follow-up, with only 49 participants in total experiencing a primary endpoint event, five of which were myocardial infarctions. For comparison, there were 335 coronary events in the landmark Women’s Health Initiative (WHI) study, including 64 in the subgroup of women 50 to 59 years of age.1 Thus, adding the events of this trial to those of the WHI study is unlikely to have a significantly impact on the existing estimate of effect of HRT in women in this age range.

Even considering this trial in isolation, the results warrant caution. As described in the article, the trial was truncated 10 years prior to the planned follow-up duration, which increases the risk of false positive findings, especially with so few events. Indeed, the relative risk reduction of approximately 50% for the primary outcome is striking and unusual for single interventions in cardiology, and is likely an overestimation, if a benefit does exist. These results could also be influenced by - or be entirely a consequence of - detection bias introduced by the trial’s open-label design, as this trial largely took place when HRT was widely believed to reduce cardiovascular events prior to the reporting of the Heart and Estrogen/Progestin Replacement Study (HERS).2 This explanation is made more likely by the fact that stroke rates were also numerically lower in the HRT group in this trial (hazards ratio 0.77), contrary to the clear increased risk of stroke with HRT independent of age or years since menopause in the double-blind WHI study.3

1. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-34.
2. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.
3. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-77.

Competing interests: No competing interests

22 October 2012
Ricky D Turgeon
Pharmacy Resident
Kelvin Lou
Lower Mainland Pharmacy Services
899 W 12th Ave Vancouver BC V5Z 1M9