Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: A randomized clinical trial

Hadine Joffe, Katherine A. Guthrie, Andrea Z. LaCroix, Susan D. Reed, Kristine E. Ensrud, JoAnn E. Manson, Katherine M. Newton, Ellen W. Freeman, Garnet L. Anderson, Joseph C. Larson, Julie Hunt, Jan Shifren, Kathryn M. Rexrode, Bette Caan, Barbara Sternfeld, Janet Carpenter, Lee Cohen

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

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 (0.5mg/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 outcomewas 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

Original languageEnglish
Pages (from-to)1058-1066
Number of pages9
JournalJAMA Internal Medicine
Volume174
Issue number7
DOIs
StatePublished - 2014

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Estradiol
Randomized Controlled Trials
Placebos
Therapeutics
Estrogens
Hot Flashes
Serotonin and Noradrenaline Reuptake Inhibitors
Venlafaxine Hydrochloride
Sweat
Menopause
Clinical Trials
Health

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms : A randomized clinical trial. / Joffe, Hadine; Guthrie, Katherine A.; LaCroix, Andrea Z.; Reed, Susan D.; Ensrud, Kristine E.; Manson, JoAnn E.; Newton, Katherine M.; Freeman, Ellen W.; Anderson, Garnet L.; Larson, Joseph C.; Hunt, Julie; Shifren, Jan; Rexrode, Kathryn M.; Caan, Bette; Sternfeld, Barbara; Carpenter, Janet; Cohen, Lee.

In: JAMA Internal Medicine, Vol. 174, No. 7, 2014, p. 1058-1066.

Research output: Contribution to journalArticle

Joffe, H, Guthrie, KA, LaCroix, AZ, Reed, SD, Ensrud, KE, Manson, JE, Newton, KM, Freeman, EW, Anderson, GL, Larson, JC, Hunt, J, Shifren, J, Rexrode, KM, Caan, B, Sternfeld, B, Carpenter, J & Cohen, L 2014, 'Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: A randomized clinical trial', JAMA Internal Medicine, vol. 174, no. 7, pp. 1058-1066. https://doi.org/10.1001/jamainternmed.2014.1891
Joffe, Hadine ; Guthrie, Katherine A. ; LaCroix, Andrea Z. ; Reed, Susan D. ; Ensrud, Kristine E. ; Manson, JoAnn E. ; Newton, Katherine M. ; Freeman, Ellen W. ; Anderson, Garnet L. ; Larson, Joseph C. ; Hunt, Julie ; Shifren, Jan ; Rexrode, Kathryn M. ; Caan, Bette ; Sternfeld, Barbara ; Carpenter, Janet ; Cohen, Lee. / Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms : A randomized clinical trial. In: JAMA Internal Medicine. 2014 ; Vol. 174, No. 7. pp. 1058-1066.
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abstract = "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 (0.5mg/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 outcomewas 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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TY - JOUR

T1 - Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms

T2 - A randomized clinical trial

AU - Joffe, Hadine

AU - Guthrie, Katherine A.

AU - LaCroix, Andrea Z.

AU - Reed, Susan D.

AU - Ensrud, Kristine E.

AU - Manson, JoAnn E.

AU - Newton, Katherine M.

AU - Freeman, Ellen W.

AU - Anderson, Garnet L.

AU - Larson, Joseph C.

AU - Hunt, Julie

AU - Shifren, Jan

AU - Rexrode, Kathryn M.

AU - Caan, Bette

AU - Sternfeld, Barbara

AU - Carpenter, Janet

AU - Cohen, Lee

PY - 2014

Y1 - 2014

N2 - 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 (0.5mg/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 outcomewas 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

AB - 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 (0.5mg/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 outcomewas 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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