To the Editor: The randomised controlled trial associated with the Women’s Health Initiative (WHI) found that long-term hormone replacement therapy (HRT) with combined oestrogen–progestin causes net harm.1 Both the article by Baber and colleagues on HRT2 and a previous editorial by Patel and colleagues3 imply that the method used to calculate the confidence intervals in the WHI report is questionable. Baber et al suggest that “a trial such as this, with multiple endpoints, should use adjusted rather than nominal confidence intervals to test individual endpoints for significance”.2 It is important that this issue is clarified.

In the WHI report in JAMA, Table 2 shows both nominal and adjusted confidence intervals for the primary and secondary outcomes.1 Nominal confidence intervals are appropriate for the preselected primary outcomes of the trial — breast cancer, coronary heart disease and the composite global-index score.4 Confidence intervals adjusted for multiple comparisons are possibly appropriate for the multiple secondary endpoints in the study, but are not advocated by all statisticians.5 In any case, the decision of Baber and colleagues to concentrate on adjusted confidence intervals for the preselected primary outcomes is not valid.4

The purpose of confidence intervals is to assess the effects of random variation or chance. It is not sensible to suggest that the extra harm that occurred in the combined HRT arm of the WHI study could be due to chance. Moreover, 42% of women in the HRT group stopped taking the drug, and 11% of women in the placebo group started taking it.1 Therefore, the reported findings of the intention-to-treat analysis underestimated the true harm to individual women taking long-term HRT. Also, if duration of treatment is important (as appears the case with breast cancer risk), and because compliance decreased over time, 5-year results underestimated longer-term treatment harm.4

The aim of the WHI trial was to assess whether long-term HRT is a useful preventive intervention for postmenopausal women. It did not assess the short-term use of HRT to relieve severe hot flushes. As Sackett points out, curative and preventive medicine are absolutely and fundamentally different in their obligations and implied promises to the individuals whose lives they hope to modify.6 As a long-term preventive intervention, HRT causes more harm than good. Although the absolute risks were small, millions of women were prescribed this treatment worldwide, causing harm to thousands. Billions of dollars were spent on an ineffective preventive intervention.6 The thousands of Australian women who stopped taking HRT on learning the results of the WHI trial made a sensible decision.

In reply: We acknowledge that not all statisticians agree on the place of adjusted confidence intervals. However, we and others1,2 believe they represent a conservative choice for secondary endpoints in a study with multiple endpoints, such as the WHI trial.

Results of recent randomised controlled trials of hormone replacement therapy (HRT) and cardiovascular disease certainly support the notion that HRT confers no protection. However, any real harm of HRT must be questionable in light of the rapid review by Beral and colleagues, which, also using nominal confidence intervals, showed no change in relative risk for HRT users.3

We are surprised that, having emphasised the importance of nominal confidence intervals for primary endpoints, Coory did not mention that the breast cancer risk in the WHI report was not statistically significant using either nominal or adjusted CIs, or that the global index used was a non-validated instrument designed for and used only in the WHI study.4 Intention-to-treat analysis is used to avoid overestimates of both harm and benefit. While drop-in and drop-out rates (equal in both arms) may have led to underestimates of harm from HRT, they may also have led to underestimates of benefit, with no net change to risk–benefit assessment.

The aim of the WHI trial was to assess the benefit or otherwise of long-term HRT on disease processes in otherwise healthy women. There seems little doubt that in the group of older, overweight, somewhat hypertensive, women enrolled in this trial the use of HRT was not beneficial.

The aim of our article was to assess the case for and against HRT use.5 In reaching our conclusions, we drew on a broad range of published data, including, but not confined to, the WHI data. Our conclusions make it clear that we believe the use of HRT is primarily for short-term relief of symptoms during the menopause transition. However, we sought to defend the right of a small number of women to choose to continue HRT for long-term improvement of quality of life and symptom relief after appropriate, balanced, individualised counselling about the risks and benefits of such a decision.

We do not agree with Coory’s final comment. The thousands of Australian women who stopped taking HRT on learning the results of the WHI trial did so in fear and ignorance in an environment where their physicians were unable to offer balanced counsel — hardly a formula for good medicine.