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Evaluation of the direct and indirect effects of bazedoxifene/conjugated estrogens on sleep disturbance using mediation modeling

Pinkerton, JoAnn V. MD1; Bushmakin, Andrew G. MS2; Racketa, Jill MS3; Cappelleri, Joseph C. PhD, MPH2; Chines, Arkadi A. MD3; Mirkin, Sebastian MD3

doi: 10.1097/GME.0b013e31829f05d1
Original Articles

Objective: Mediation modeling was used to evaluate the direct effects of bazedoxifene (BZA)/conjugated estrogens (CE) on sleep, compared with its indirect effects via improvements in hot flushes, in postmenopausal women enrolled in the SMART (Selective estrogens, Menopause, And Response to Therapy)-2 and SMART-5 trials.

Methods: Statistical mediation modeling estimated the direct effects of BZA/CE on sleep disturbance (Medical Outcomes Study sleep scale) and its indirect effects via hot flush improvement (item 1 of the Menopause-Specific Quality of Life questionnaire). In SMART-2, a total of 318 women with moderate to severe vasomotor symptoms (VMS) received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo; in SMART-5, a total of 1,843 women seeking menopausal symptom treatment received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, CE 0.45 mg/medroxyprogesterone acetate 1.5 mg, BZA 20 mg, or placebo. The SMART-5 sleep substudy enrolled 459 women with bothersome VMS and sleep disturbances.

Results: In SMART-2, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg had a primarily direct effect on sleep in symptomatic women (64% and 66%, respectively; P < 0.001). Conversely, in the overall SMART-5 population, effects were primarily indirect (82% and 75% for BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg, respectively; P < 0.01), suggesting that sleep improvement was largely mediated via hot flush improvements. In a subpopulation of SMART-5 (participants with bothersome VMS), BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg affected sleep disturbance directly (82% and 76%, respectively; P < 0.0001).

Conclusions: BZA/CE improves sleep in postmenopausal women with moderate to severe and milder VMS. This study suggests that improvements occur directly in women with moderate to severe VMS and indirectly in less symptomatic women.

From the 1Division of Midlife Health, Department of Obstetrics and Gynecology, University of Virginia Health System, Charlottesville, VA; 2Pfizer Inc, Groton, CT; and 3Pfizer Inc, Collegeville, PA.

Received March 7, 2013; revised and accepted May 31, 2013.

J.R. and A.A.C. are no longer affiliated with Pfizer Inc.

All authors had access to study data, were involved in all aspects of manuscript writing and editing, and provided final approval.

Funding/support: This study was sponsored by Pfizer Inc. SMART (Selective estrogens, Menopause, And Response to Therapy)-2 and SMART-5 studies were sponsored by Wyeth Research, which was acquired by Pfizer in October 2009. Medical writing support for this manuscript was providedby Katie Gersh, PhD (MedErgy), and funded by Pfizer.

Financial disclosure/conflicts of interest: In the past 12 months, J.V.P. has served as a consultant (fees to the University of Virginia) to Pfizer Inc, Noven Pharmaceuticals, Shionogi, and DepoMed; has received grants/research support (fees to the University of Virginia) from DepoMed, Bionova, and Endoceutics; and has received travel funds from Pfizer Inc, Noven Pharmaceuticals, Shionogi, and DepoMed. A.G.B., J.C.C., and S.M. are employees of Pfizer Inc. J.R. and A.A.C. are former employees of Pfizer Inc.

Address correspondence to: JoAnn V. Pinkerton, MD, Box 801104, University of Virginia Health System, Charlottesville, VA 22908. E-mail: jvp9u@virginia.edu

© 2014 by The North American Menopause Society.