Both low-dose and micro-dose 17β-oestradiol reduced hot flushes

ED FROM Bachmann GA, Schaefers M, Uddin A, et al. Lowest effective transdermal 17b-estradiol dose for relief of hot flushes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2007;110:771–9. Correspondence to: Dr G A Bachmann, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA; gloria.bachmann@umdnj.edu Source of funding: Schering c Clinical impact ratings: Gynaecology 6/7; GP/FP/Primary care 5/7 Low-dose or micro-dose transdermal hormone therapy v placebo for hot flushes in postmenopausal women* Outcomes at 12 weeks Low-dose Micro-dose Placebo Low-dose v placebo Micro-dose v placebo Difference in mean change p value Difference in mean change p value Mean change in hot flush frequency/wk 252 238 226 26 ,0.001 13 ,0.001 Mean change in hot flush severity score{ 21.19 20.81 20.35 0.84 ,0.001 0.46 ,0.001 RBI (95% CI) NNT (CI) RBI (CI) NNT (CI) >75% reduction in hot flush frequency 63% 41% 24% 160% (90 to 264) 3 (2 to 4) 70% (20 to 145) 6 (4 to 17) >90% reduction in hot flush frequency 48% 35% 14% 230% (113 to 421) 4 (3 to 5) 143% (53 to 291) 5 (4 to 10) *Abbreviations defined in glossary. Difference in mean change, RBI, NNT, and CI calculated from data in article. Low-dose = 0.023 mg/d 17b-oestradiol + 0.0075 mg/d levonorgestrel; micro-dose = 0.014 mg/d 17b-oestradiol. {Severity score = 2 for moderate and 3 for severe (baseline mean score 2.5). C O M M EN TA R Y I n the wake of caution following the Women’s Health Initiative trials, many postmenopausal women are looking for alternatives to traditional hormone therapy for relief of vasomotor symptoms. Healthcare providers are seeking evidence of effectiveness, usually evaluated by a composite score of frequency and severity of hot flushes. For researchers and journals, the important result is often whether the reduction in the mean hot flush score attains statistical significance. However, such an outcome may not be clinically meaningful. Bachmann et al addressed this concern in a post hoc analysis that used 75% and 90% reductions in hot flush frequency as patient-important benchmarks. This trial also adds to knowledge about the wide variation among women in responsiveness to interventions for vasomotor symptoms. Based on the results, a clinician could conclude that 5 patients out of 12 would have at least a 75% reduction in vasomotor symptoms using micro-dose E2 (2 patients responding to the hormone and 3 patients responding to the placebo effect). Further, most responders could be identified after 4 weeks of therapy. The authors speculated that non-responders at the micro-dose level will respond to a higher E2 dose, but this hypothesis was not part of their study design. They recommended a customised approach to therapy, beginning with micro-dose, then increasing the dose for non-responders. One criticism of the trial is that it did not compare 2 doses of E2, but rather micro-dose E2 alone with low-dose E2 plus progestogen. The authors offered evidence that levonorgestrel added to E2 has no effect on hot flushes, but opposing evidence also exists. They claimed that 0.014 mg/day is the lowest effective dose but did not test a lower dose. Previous studies showed a decrease in placebo effect beyond 12 weeks; the relatively short duration of the current study prevented confirmation of this finding. Potential adverse effects not addressed in this study include endometrial hyperplasia and cancer, and venous thromboembolism. Bachmann et al reported the mean number of vaginal bleeding/spotting days, rather than the percentage of women with bleeding. The latter outcome is important because vaginal bleeding should be investigated in all postmenopausal women taking oestrogen, and clinicians need to know the risk of this side effect before recommending the therapy. Jeff Andrews, MD Vanderbilt University Medical Center Nashville, Tennessee, USA 1. Shulman LP, Yankov V, Uhl K. Menopause 2002;9: 195–207. 2. Hickey M, Davis SR, Sturdee DW. Lancet 2005;366: 409–21. Therapeutics EBM April 2008 Vol 13 No 2 43