title: Evaluation of the direct and indirect effects of bazedoxifene/conjugated estrogens on sleep disturbance using mediation modeling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Joann V
authors.initials: JV
authors.lastname: Pinkerton
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bushmakin
authors.forename: Jill
authors.initials: J
authors.lastname: Racketa
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cappelleri
authors.forename: Arkadi A
authors.initials: AA
authors.lastname: Chines
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mirkin
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage*; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D008875:Middle Aged; D015233:Models, Statistical; D010919:Placebos; D017698:Postmenopause; D012893:Sleep Wake Disorders / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D004966:Estrogens, Conjugated (USP); D007211:Indoles; D010919:Placebos; D017258:Medroxyprogesterone Acetate; C447119:bazedoxifene