New MsFLASH Results Add Another Choice in Hot Flash Therapy

Kate Johnson

October 14, 2013

DALLAS — The antidepressant venlafaxine (Effexor XR, Pfizer) is just as effective as estradiol for combating hot flashes, according to first results from the MsFLASH 3 (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) trial.

The findings for venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), put another option on the table for the treatment of vasomotor symptoms. They also build on the first MsFLASH study (JAMA. 2011;305:267-274), which evaluated the efficacy of the serotonin-reuptake inhibitor (SSRI) escitalopram (Lexapro, Forest Laboratories).

"What the MsFLASH results show is that escitalopram, venlafaxine, and 17-beta estradiol have approximately the same effects on hot flash frequency and bother," said principal investigator Andrea LaCroix, PhD, professor of epidemiology in the Department of Family and Preventive Medicine and director of the Center of Excellence in Women's Health at the University of California, San Diego.

The study results were presented here at the North American Menopause Society 2013 Annual Meeting by Hadine Joffe, MD, director of research development in the women's mental health division, Department of Psychiatry, Brigham and Women's Hospital, Boston.

The recommendation of the US Food and Drug Administration is for "estrogen at the lowest dose possible for the shortest amount of time, but the real paradigm shift is that all of these medicines are comparable, so women have a choice. When they say the only thing that relieves hot flashes is estrogen, it's simply not true," said Dr. LaCroix.

These results add new information to help clinicians and patients in decision-making. "It's the first head-to-head study of estrogen vs an SNRI," explained Martha Hickey, MD, director of the Women's Gynaecology Research Centre and professor of obstetrics and gynecology at the University of Melbourne in Australia.

"In our clinical practice, this really helps us to inform and advise women about effective treatments," she told Medscape Medical News.

The double-blind randomized placebo-controlled MsFLASH 3 trial compared 8 weeks of low-dose oral 17-beta-estradiol 0.5 mg/day (n = 97), extended-release venlafaxine 75 mg/day (n = 96), and placebo (n = 146) for the treatment of vasomotor symptoms.

The average age of the study participants was 54 years. Daily diaries were used to assess the frequency of vasomotor symptoms, and hot flash bother, severity, and interference were measured with the Hot Flash Related Daily Interference Scale (HFRDIS).

The frequency of vasomotor symptoms was lower in women treated with venlafaxine (P = .005) and estradiol (P < .001), Dr. Joffe reported.

After 8 weeks of treatment, there was a mean of 4.5 hot flashes in the estradiol group (a 53% reduction), 3.9 in the venlafaxine group (a 48% reduction), and 2.2 in the placebo group (a 29% reduction).

Secondary end points were lower with estradiol and venlafaxine than with placebo.

Table. Improvement in Secondary End Points With Treatment

Daily Vasomotor Symptoms P Value for Venlafaxine vs Placebo P Value for Estradiol vs Placebo
Severity .02 .02
Bother .07 .01
Interference .03 <.001


A pooled analysis of all 3 MsFLASH studies showed that clinical improvement in the frequency of vasomotor symptoms, defined as a 50% or greater improvement over baseline, was "very, very similar" for all medication groups, at 54% for escitalopram, 48% for estradiol, and 49% for venlafaxine.

The pattern was similar for bother.

Behavioral interventions, evaluated in the second MsFLASH trial, showed no statistical improvement with yoga (Menopause. Published online September 16, 2013), exercise (Menopause. Published online August 12, 2013), or omega-3 supplements (Menopause. Published online August 26, 2013), Dr. LaCroix noted.

For clinicians and women, the decision between estradiol, venlafaxine, and escitalopram will come down to the finer details of their individual effects on other measures, such as sleep and sexual function, Dr. Hickey said.

"The 2 nonhormonal treatments — escitalopram and venlafaxine — have different profiles of risks and benefits, not for hot flushes but for other associated symptoms," she told Medscape Medical News. This means that the management of individual women can be personalized to "what other symptoms she has, apart from hot flashes."

There are other things that influence decision-making, Dr. LaCroix pointed out. "Estrogen is associated with blood clots and strokes, and the 2 nonhormonals are not. If a woman has a uterus and has to take progestin, she can take estrogen for a few years, but will then have an increased risk of breast cancer."

In a separate plenary session at the meeting, psychiatrist Lee Cohen, MD, an MsFLASH investigator and director of the Center for Women's Health at Harvard University in Boston, went further. Treatments for vasomotor symptoms "may need to be used in a somewhat chronic fashion over time, even if symptoms wax and wane, and that may shift the risk/benefit decision," he said.

"Tolerable treatments that can be used over substantial time without risk of harm are very, very important. We have very good data supporting the safety of SSRIs and SNRIs. From a safety point of view, those of us who prescribe these medications over the long haul are particularly comfortable," Dr. Cohen said.

The MsFLASH study was supported by the National Institutes of Health. The MsFLASH investigators and Dr. Hickey have disclosed no relevant financial relationships.

North American Menopause Society (NAMS) 2013 Annual Meeting. Presented October 11, 2013.


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