23 June, 2014: 

"the importance of the current study lies in the format of head-to-head comparison between estrogen therapy, which is the gold-standard treatment for hot flushes, and the SNRI venlafaxine hydrochloride..."

The aim of a recently published study was to determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS) [1]. In total, 339 perimenopausal and postmenopausal women (42–62 years old, mean age 55 years) with at least two bothersome VMS per day (mean 8.1 per day) were followed for 8 weeks. Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/day) (n =  97), low-dose venlafaxine hydrochloride extended release (75 mg/day) (n =  96), or placebo (n =  146). 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. Treatment satisfaction was highest (70.3%) for estradiol, lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine. Both interventions were well tolerated.

Comment

It has been known already for many years that antidepressants from the family of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may be helpful also in reducing the number and severity of hot flushes. Good-quality studies, such as with desvenlafaxine [2] or paroxetine [3], demonstrated a significant benefit, and the latter product was recently approved for that indication in the USA (see Menopause Live 24 March, 2014). Now research has moved one step ahead and, as noted by the investigators in their article [1], the importance of the current study lies in the format of head-to-head comparison between estrogen therapy, which is the gold-standard treatment for hot flushes, and the SNRI venlafaxine hydrochloride, which is already used off-label as a non-hormonal treatment. The study conclusion was that 'While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.' In other words, venlafaxine is a very good alternative for estrogen in regard to alleviation of VMS. So where is the 'catch'? Is there any 'catch' at all? The study design and data analysis seem quite OK, and the host journal, JAMA, adds to credibility. However, as always, one should read the small details in order to be able to grasp the impact of the study results. Here are some facts to be considered:

1. The study included a rather heterogeneous group of women; some were relatively young or in the menopause transition, whereas others were postmenopausal or older in age. To note, 40% of the participants reported less than six VMS per day, so some women had mild symptomatology, while others had a more frequent and severe course.
2. The subgroup analyses included small numbers of women.
3. Dosage was defined as low-dose estradiol, at 0.5 mg daily, which may not be optimal for treatment of menopausal symptoms in the early phase of menopause. In fact, the reduction in the number of VMS in the estradiol group was around 50% from baseline, compared to about 25% in the placebo group, a figure which is much less than that expected with standard dosages.
4. The follow-up period was only 8 weeks, and thus long-term effects are missing.

Thus two sentences taken from the study may be a little problematic:

1. The Abstract reads 'Some women are unable or unwilling to use estrogen because of associated risks'. This sentence points subconsciously at a risky safety profile of estrogen, on the one hand, and at a relatively good safety profile of venlafaxine on the other hand. In fact, estrogen therapy is associated with a good safety profile in healthy women under age 60, whereas venlafaxine may cause serious adverse events. I don't think that SSRIs or SNRIs should be preferred over estrogen because of safety concerns in the perimenopause or the early phase of menopause.
2. As already quoted above, the article reads 'While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.'

The authors actually refer to estradiol and venlafaxine as equal, first-line therapies for VMS. There was a minor discussion on the implication of the low estradiol dosage prescribed in the study in regard to efficacy, and the potential better outcome of higher estradiol doses. The authors did write that 'Our findings may be specific to the particular dosage of each agent used', and mention a 12-week trial in which 17β-estradiol (0.5 mg/day) reduced VMS by 65.5%, while 17β-estradiol at a higher dosage (1.0 mg/day) reduced VMS by 83.2% [4]. Thus, for women who suffer moderate to severe hot flushes, estrogen should be the therapeutic first choice, and in many clinical set-ups this has a definite clinical relevance while comparing estrogen to SSRIs or SNRIs.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Joffe H, Guthrie KA, LaCroix AZ, et al. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: A randomized clinical trial. JAMA Intern Med 2014 May 26. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/24861828
2. Speroff L, Gass M, Constantine G, Olivier S; Study 315 Investigators. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol 2008;111:77-87
http://www.ncbi.nlm.nih.gov/pubmed/18165395
3. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause 2013;20:1027-35
http://www.ncbi.nlm.nih.gov/pubmed/24045678
4. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17β-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000;95:726-31
http://www.ncbi.nlm.nih.gov/pubmed/10775738