Commentary

The 2 meta-analyses by Humphrey et al and Nelson et al, and much of the medical literature, do not clearly define postmenopausal HRT. Although authors often claim that many observational studies show the benefits of HRT on CAD risk, the data almost completely relate to unopposed oestrogen.¹ Few epidemiological studies have evaluated oestrogen plus progestin administered as continuous combined therapy. A limited number of studies were included in the meta-analyses by Humphrey et al and Nelson et al, and the included studies sometimes failed to specify type of HRT. Studies published in the 1980s and earlier probably refer to unopposed oestrogen therapy.

The lack of specificity in type of HRT is problematic because of the potential for different effects of oestrogen alone and oestrogen plus progestin. It is important to note that the meta-analyses used a common protocol to apply standard criteria for quality² and included only studies of higher quality. For studies assessing CAD outcomes, the authors identified a relation between poorer quality studies and greater protection against CAD.

Changing patterns of use (oestrogen alone replaced by combined oestrogen plus progestin) and indications for use (eg, starting women on treatment before menopause to reduce bone loss) may account, in part, for differences in results. Also, acute effects of combined treatment (eg, the prothrombotic and proinflammatory effects of progestins) may be missed in prospective studies because of lack of attention to early events and follow up.

Data from both epidemiological studies and RCTs of HRT consistently show other thrombotic effects, such as stroke and pulmonary embolus. This argues, at least in part, against a bias related to this pathway in the observational studies. Although socioeconomic status (SES) appears as one other important variable in this analysis, the authors note that the range of cardiovascular risk factors controlled for in observational studies also varied substantially. The authors, however, did not point out that studies that controlled for SES observed similar results before and after such control, which suggests that this is not an explanation for the discrepancy between RCT and observational study results. Is confounding by indication changing over time concurrent with changing patterns of drug combination? Is SES merely a marker for more recent studies that evaluate oestrogen plus progestin? Alternatively, is the timing of exposure in relation to menopause the explanatory factor? Animal studies suggest that oestrogens have beneficial effects in the early stages of atherogenesis, but reduced beneficial effects in the final stages of plaque complications.³

How can drug formulation change over time and most associations observed in epidemiological studies (ie, breast cancer, pulmonary embolus, stroke, colon cancer, cholecystitis, and osteoporotic fracture) be consistent, and yet CAD outcomes diverge? Consistent evidence across the RCTs argues against chance.

The consistency between non-RCTs and RCTs for non-cardiac outcomes is reassuring and supports other evaluations of the contribution of different study designs to evaluation of medical therapies.^4–7 Such studies comparing designs may be limited in power, but on average, well designed observational studies show a similar magnitude of estimated benefits as RCTs. We should not focus solely on study design but must also consider the formulation and timing of use of postmenopausal HRT that is being evaluated.