Major Finding: Both venlafaxine and clonidine reduced the frequency and severity of hot flashes by approximately 45%, compared with placebo.
Data Source: A prospective, randomized, double-blind, multicenter clinical trial comparing 12 weeks of venlafaxine, clonidine, or placebo for control of hot flashes in 102 Dutch women with breast cancer.
Disclosures: No financial conflicts of interest were reported.
Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a randomized, placebo-controlled trial.
Effective treatments for hot flashes may improve these patients' ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.
The selective serotonin reuptake inhibitor venlafaxine (Effexor) and the antihypertensive clonidine “both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted” until now, they noted.
In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg of venlafaxine (41 patients), 0.1 mg of clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.
The study participants completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. In addition, they recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.
A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of the study participants discontinued because of noncompliance, which “had some effect on the observed differences between treatments in this study.”
Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1–4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo, according to Dr. Boekhout and her colleagues.
Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1–4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.
Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12.
“A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine,” Dr. Boekhout and her co-investigators said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).
It is “advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired.”
A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said that they wished to continue the study treatment at the end of the trial.
Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression.
Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to permit adequate assessment of these adverse effects, according to the researchers.
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Small Numbers Mar Findings
The main weakness of this study was that “the patient numbers were too small to reliably identify suspected differences between the two active study arms,” said Dr. Charles L. Loprinzi, Dr. Debra L. Barton, and Dr. Rui Qin.
The unbalanced randomization scheme and the unequal dropout rates, which likely were due to perceived toxicities, meant that only 35 patients were available for analysis in the venlafaxine group, 28 in the clonidine group, and 17 in the placebo group. To detect a10% difference between the two active drugs, 156 subjects would have been needed per study arm, and to detect a 5% difference, 620 would have been needed.
“With the currently reported sample size … the power of detecting a 10% difference is only 29%,” they noted.
For clinicians, they added, available data suggest that multiple nonestrogenic options are available for treating hot flashes. “Our suggestion is that these nonhormonal options be tried in the order in which they are listed (an antidepressant, then an antiseizure medication, then clonidine), unless there are contraindications to particular drugs in individual patients,” they wrote.