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Randomized Controlled Trial
, 174 (7), 1058-66

Low-dose Estradiol and the Serotonin-Norepinephrine Reuptake Inhibitor Venlafaxine for Vasomotor Symptoms: A Randomized Clinical Trial

Randomized Controlled Trial

Low-dose Estradiol and the Serotonin-Norepinephrine Reuptake Inhibitor Venlafaxine for Vasomotor Symptoms: A Randomized Clinical Trial

Hadine Joffe et al. JAMA Intern Med.


Importance: Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.

Objective: To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).

Design, setting, and participants: In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.

Interventions: Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks.

Main outcomes and measures: The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.

Results: Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated.

Conclusions and relevance: Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.

Trial registration: Identifier: NCT01418209.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure. Dr. Joffe currently receives research support from NIH and Cephalon/Teva, and consults for Sunovion and Noven. Dr. Reed reports research support from NIH. Dr. Ensrud reported receiving financial compensation for consultancy for being on the Data Monitoring Committee at Merck Sharpe & Dohme. Dr. Newton reports receiving research support from Otsuka Pharmaceuticals Inc., LTD. Dr. Shifren reports receiving financial compensation from New England Research Institutes for consulting work related to a research study of vulvovaginal atrophy. Dr. Rexrode reports receiving financial compensation from Pfizer advisory board for consultancy. Dr. Rexrode also receives research support from NIH grants, and royalties for being the textbook editor of “Women and Health-Second Edition”. Dr. Cohen reported receiving financial compensation from Noven Pharmaceuticals, PamLab LLC for consultancy work. Additionally, Dr. Cohen receives research support from Astra-Zeneca Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Inc, Forest Laboratories, Inc, GlaxoSmithKline, Ortho-McNeil Janssen, Pfizer Inc, Sunovion Pharmaceuticals Inc, NIH, NIMH, and NIA. Dr. LaCroix reports serving as a consultant to Amgen and Bayer and to receiving research grants from the University of Massachusetts, Center for Outcomes Research and NIH. Dr. Freeman reports receiving research support from Forest Laboratories, Inc., Bionovo, and Xanodyne Pharmaceuticals, Inc. Drs. Anderson, Guthrie, Manson, Larson, Hunt, Caan, Carpenter and Sternfeld did not disclose any financial conflicts. Teva, Noven, Pfizer, and Bayer manufacture estrogen products for the treatment of menopausal symptoms. Pfizer and Teva manufacture venlafaxine. All financial activities were reported to fall outside of this study.


Figure 1
Figure 1
Figure 2
Figure 2
Vasomotor Symptom (VMS) Frequency by Treatment Arm

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