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Original Investigation |

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

Hadine Joffe, MD, MSc1,2,3; Katherine A. Guthrie, PhD4; Andrea Z. LaCroix, PhD4; Susan D. Reed, MD, MPH5; Kristine E. Ensrud, MD, MPH6,7; JoAnn E. Manson, MD, DrPH1; Katherine M. Newton, PhD8; Ellen W. Freeman, PhD9,10; Garnet L. Anderson, PhD4; Joseph C. Larson, MS4; Julie Hunt, PhD4; Jan Shifren, MD3; Kathryn M. Rexrode, MD, MPH1; Bette Caan, DrPH11; Barbara Sternfeld, PhD11; Janet S. Carpenter, PhD, RN12; Lee Cohen, MD3
[+] Author Affiliations
1Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
2Department of Psychosocial Oncology and Palliative Care, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
3Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
4MsFLASH Data Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
5Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle
6Division of Epidemiology and Community Health, Department of Medicine, Veterans Affairs Health System, Minneapolis, Minnesota
7Department of Medicine, University of Minnesota, Minneapolis
8Group Health Research Institute, Seattle, Washington
9Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
10Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
11Division of Research, Kaiser Permanente of Northern California, Oakland
12School of Nursing, Indiana University, Indianapolis
JAMA Intern Med. 2014;174(7):1058-1066. doi:10.1001/jamainternmed.2014.1891.
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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  clinicaltrials.gov Identifier: NCT01418209

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Figure 1.
Consolidated Standards of Reporting Trials Diagram

VMS indicates vasomotor symptoms.

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Figure 2.
Frequency of Vasomotor Symptoms (VMS) by Treatment Group

BL indicates baseline.

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