Despite mounting evidence concerning the risks of hormone therapy, the NHS authors still believe that it is cardioprotective if initiated in newly menopausal women without atherosclerosis. However, NHS data show that the cardioprotective effect was the same among women in their 50s and 60s (relative risk, 0.71 vs. 0.66) and among women with and without CHD risk factors (1). Grodstein and colleagues' argument hinges on one statistically insignificant subgroup analysis of WHI women within 10 years of menopause (relative risk, 0.89; 65 CHD cases). Of note, subgroup analysis of WHI women 50 to 59 years of age yielded conflicting results: a relative risk of 1.27. Because of the complexities of dating menopause, the subgroup defined by age is probably the more robust estimate of the effect of hormone therapy among newly menopausal women.

The NHS authors have not recognized the importance of unblinded assessment of outcomes. The bias introduced by the lack of concealment of treatment allocation is substantial and has been empirically demonstrated among randomized, controlled trials. Unblinded trials substantially overestimate (41%) treatment effects compared with blinded trials (2). The impact of unblinding within observational studies could potentially be larger given the other potential sources of bias within nonrandomized studies.

The NHS authors dispute the potential impact of excluding silent events, stating that the rate of silent events in their study should mirror the 3% reported in the WHI rather than the 34% range reported in the Framingham Study and many other population-based studies (3). Because risk factors for silent myocardial infarction were similar in the NHS and the Framingham Study, their rates should also be similar. In contrast, silent event rates in population-based studies should not mirror those in randomized, controlled trials, whose protocols were designed to recognize adverse events that might otherwise have gone unnoticed.

Literature on the purported cardioprotective effect of hormones long predates the NHS observation period. In the 1960s, 2 trials were published (4, 5) and a third nationwide collaborative study began, all hoping to extend cardioprotection from women to men (6). In 1985, one explanation offered for discrepant results between the first NHS and the Framingham Study was predicated on the widespread belief that hormone therapy was cardioprotective: "Could the [Framingham Study] data ... be seriously biased by one or several physicians who were unusually alert to possible estrogen effects?" (7).

Is it plausible to believe that hormone therapy prevents CHD in newly menopausal women but induces it in all others? While this issue is not completely resolvable with the data at hand, the argument for such a window rests on one statistically insignificant, discordant subgroup analysis from the WHI and 3 small studies of unopposed estrogen. Unopposed estrogen is markedly different from combined estrogen and progesterone in its effects on the heart. One of these studies (8), involving only 83 women, found an inconsequential 0.0053-mm change in arterial walls; the other studies were in animals (9, 10).

Should the treatment of all women be driven by these data despite the experience of 16 608 women in a well-designed randomized, controlled trial? We believe not and think that clinicians should continue to advise only substantially symptomatic women to take hormone therapy.