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Comparative efficacy and safety of estradiol transdermal preparations for the treatment of vasomotor symptoms in postmenopausal women: an indirect comparison meta-analysis

Derzko, Christine MD, FRCSC; Sergerie, Martin PhD, DESS; Siliman, Gaye MSc; Alberton, Mark MSc; Thorlund, Kristian PhD, MSc

doi: 10.1097/GME.0000000000000552
Original Articles
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Objective: Divigel and Estrogel are estradiol gels for the treatment of postmenopausal women with moderate to severe vasomotor symptoms. They differ with respect to several factors including estradiol concentration and surface application, and cannot be compared solely on the basis of their estradiol dose. No randomized clinical trials have compared them head to head, but both have been compared with placebo. Therefore, the objective of this study was to conduct a systematic review and network meta-analysis of the two estradiol gels.

Methods: We performed a comprehensive systematic literature review. One publication reporting on one Divigel trial, three publications reporting on two Estrogel trials, and five publications reporting on other estradiol transdermal preparations were identified. Efficacy outcomes were change from baseline in daily hot flush frequency and change from baseline in daily hot flush severity. Safety outcomes were frequency of treatment-related adverse events (AEs) and frequency of treatment-emergent AEs leading to discontinuation. Bayesian indirect treatment comparison meta-analysis of trial-level data was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research, Academy of Managed Care Pharmacy, National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Questionnaire. All outcomes were compared with respect to doses of the considered preparations.

Results: For hot flush frequency, Divigel 0.25 mg was similar to Divigel 0.5 mg and to Estrogel 0.75 mg, and was statistically significantly superior to Estrogel 1.5 mg. The largest effect was observed with Divigel 1.0 mg (mean difference of 3.91 hot flushes/wk vs placebo), and was statistically significantly superior to all other interventions. The 1.5 mg Estrogel dose was associated with the smallest estimate of efficacy. For hot flush severity, Divigel 0.25 mg was similar to the efficacy of Divigel 0.5 mg, and for 0.25 mg and 0.5 mg of other estradiol gels, but was statistically inferior to Divigel 1.0 mg, Estrogel 0.75 mg, Estrogel 1.5 mg, and the 1.0 and 1.5 mg doses of all other estradiol gels. The estimated efficacy of Divigel 0.5 mg was similar to that of Estrogel 0.75 mg, Estrogel 1.5 mg, and the 0.25 and 0.5 mg doses of other transdermal estradiol preparations. Risks of treatment-related AEs for Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel 1.5 mg were similar and all were of a slightly higher risk than placebo. Among these, Divigel 1.0 mg, Estrogel 1.5 mg, and other gels 0.5 mg were statistically significantly less safe than placebo. However, for treatment-emergent AEs leading to discontinuation, none of the gels were associated with statistically significantly higher relative risks compared with placebo. In this study, statistically significant refers to the 95% credible intervals used in the Bayesian Network Analysis.

Conclusions: Using network meta-analysis for indirect treatment comparison, we have shown that the efficacy of Divigel 0.25 mg, as measured by reduced hot flush frequency and severity, was similar to that of Divigel 0.5 mg and of Estrogel 0.75 and 1.5 mg. Overall, our analysis showed that Divigel 1.0 mg provided the best efficacy profile, but that this treatment was also associated with a higher risk of AEs. The network meta-analysis also showed that treatment with Estrogel 1.5 mg was associated with the smallest estimate of reduction in frequency of hot flushes.

1Department of Obstetrics & Gynecology and Division of Endocrinology, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Ontario

2Teva Canada Innovation, Montreal, Quebec

3Redwood Outcomes Inc, Vancouver, British Columbia

4Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.

Address correspondence to: Kristian Thorlund, PhD, MSc, 302-1505 West 2nd Ave, V6H 3Y4 Vancouver, BC, Canada. E-mail: kthorlund@redwoodoutcomes.com

Received 2 April, 2015

Revised 25 August, 2015

Accepted 25 August, 2015

The decision to publish this article was solely the responsibility of the authors. All statements, opinions, and content presented in the published article are those of the authors and do not represent the opinions of Teva. Teva provided a medical accuracy review of the article.

Funding/support: This study was supported by the Medical Affairs Department at Teva Canada Innovation.

Financial disclosure/conflicts of interest: C.D. has previously received research grants, consultant fees, or speaker honoraria from Abbott, Amgen, Bayer, Boehringer, Eli Lilly, Merck/Organon, Novartis, Novo Nordisk, Ortho, Proctor Gamble, Servier, Teva, Watsan/Actavis, and Wyeth. M.S. is an employee of Teva Canada Innovation. G.S., M.A., and K.T. are employees of Redwood Outcomes Inc, a health economics and outcomes research firm that provides services to pharmaceutical companies and biotech.

© 2016 by The North American Menopause Society.