We thank Dr. Mikkola for his response to our commentary, but we do not agree with his interpretation of the WHI reports or our conclusions. As we originally stated, the WHI trial of estrogen-only therapy (ET) and EPT provides an opportunity to observe outcomes in the largest randomized controlled trial of HT in healthy postmenopausal women. Our commentary was based on the most recent, 13-year follow-up of the WHI trials,1 and we are confident in the accuracy of our presentation of the results.
As the debate apparently focuses on the safety of stopping HT, we wish to reiterate, for those who may not be familiar with the data, that, in the ET trial, all-cause mortality declined (although not significantly) after stopping ET, as summarized here:
| HR (95% CI) |
Intervention phase | 1.03 (0.88–1.21) |
Postintervention phase (after stopping study medication) | 0.96 (0.84–1.10) |
Cumulative 13 years of follow-up | 0.99 (0.90–1.10) |
Similarly, in the EPT trial, as the following findings indicate, stopping HT did not increase all-cause mortality:
| HR (95% CI) |
Intervention phase | 0.97 (0.81–1.16) |
Postintervention phase (afterstopping study medication) | 1.01 (0.91–1.11) |
Cumulative 13 years of follow-up | 0.99 (0.91–1.08) |
Again, these findings from the largest randomized trial of HT in healthy postmenopausal women are adequate for us to conclude that stopping HT does not elevate risk of mortality. Among all women participating in the WHI HT trials, HRs for coronary heart disease, pulmonary embolism, stroke, and cardiovascular disease mortality likewise were lower (better) after stopping treatment than during the intervention phase. The results for these outcomes in younger women followed similar patterns but, due to smaller numbers of events, could not be tested formally for differences in time trends.
Moreover, the data Dr. Mikkola cites from analyses conducted 3 years postcessation2 reflected a borderline increased risk of cancer mortality that emerged in the EPT trial after stopping treatment. This clearly was related to the prolonged effects of EPT on breast cancer and other cancers, given the known latency period for cancer, and was not observed in the ET trial postcessation. The risk elevation in the EPT trial became attenuated with longer follow-up and, as of 13 years, the HRs for cancer mortality were 1.07 (0.93–1.23) in the EPT trial and 0.95 (0.81–1.13) in the ET trial.
It is interesting that Dr. Mikkola now inculcates his interpretation of his findings3 with those from secondary prevention trials such as the Heart and Estrogen/progestin Replacement Study and the Women’s Estrogen for Stroke Trial, neither of which was included as corroborative evidence in the discussion section of his originally published manuscript, and neither of which is considered applicable to healthy postmenopausal women taking HT for treatment of menopausal symptoms. Based on these findings, we do not recommend that clinicians counsel women that stopping HT increases their risk of cardiovascular or overall mortality. Thank you for the opportunity to clarify the evidence and our position.
References
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.
- Heiss G, Wallace R, Anderson GL, et al; WHI investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036–1045.
