14 September, 2015

The aim of a recently published study by Guthrie and colleagues was to describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women [1]. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health (FLASH) network tested several interventions for menopausal vasomotor symptoms in three randomized clinical trials. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10–20 mg escitalopram per day, non-aerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17β-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8–12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and the corresponding control group adjusted for baseline characteristics. The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% CI -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements. These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes.

Comment

I picked this pooled analysis of three trials not only because of its results (each study was previously reported separately), but to demonstrate again the gap between the information you get from the Abstract and that derived from the full manuscript. Furthermore, the notes brought in the Discussion highlight essential key points that may change the perception of the study conclusions as per the Abstract. Here are some issues to remember while evaluating the data: (1) the methodology of all studies was identical, which makes the comparisons more reliable; (2) women had mean 7.6–9.8 vasomotor symptoms (VMS) per day at baseline; (3) to minimize the placebo response, women whose VMS frequency decreased more than 50% over the 3-week screening period were excluded; (4) the highest mean reduction in VMS from baseline to week 8 was 3.2 per day, around 30% improvement in daily frequency relative to the placebo group; (5) vasomotor symptom bother reduction was minimal.

The conclusions presented in the Abstract were: 'These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes.' Thus, whoever reads the Abstract would probably remember that all three therapies, one thought to have serious adverse effects (E2), and two 'safer' medications have similar beneficial outcomes and therefore the choice of what to prescribe for VMS might be subliminally biased. But, in fact, the issue of dosage of estrogen is not fully discussed, as the estradiol arm that was tested could be considered as low- to very low-dose (0.5 mg) in terms of the effect on VMS. The investigators do address this point by explaining that 'The FDA recommends use of the lowest dose possible.' My reservation would be that the proof of the pudding is in the eating, and any given therapy should seek to achieve maximal effectiveness. If low-dose E2 led only to 30% improvement, with minimal subjective bother reduction of VMS, I would say that the treatment missed its goals and should be changed. In fact, the investigators admit that "E2 efficacy is dose-dependent for both 17β-E2 and conjugated equine E2', but this sentence appears at the end of the Discussion and might be overlooked during a quick reading of the full text.

Thus, if the aim of the current pooled analysis was according to the authors to 'facilitate translation of the results for clinicians and symptomatic women', I think they should also add to the Abstract that symptomatic women who seek relief from bothering VMS should use higher doses of estrogen as needed, since this therapy is the most effective among the spectrum of potential medications and non-pharmacological interventions, and has a good safety profile during the first 10 years of menopause.

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

Reference

1. Guthrie KA, LaCroix AZ, Ensrud KE, et al. Pooled analysis of six pharmacologic and nonpharmacologic interventions for vasomotor symptoms. Obstet Gynecol 2015;126:413-22 http://www.ncbi.nlm.nih.gov/pubmed/26241433