A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate

Abstract

Objective To compare the uterine effects of 60 mg of raloxifene with a continuous combined hormone replacement therapy, a preparation of 2 mg 17β-oestradiol (E 2) and 1 mg norethisterone acetate for a duration of 12 months. Design A randomised, double-blind trial. Setting Multicentre: Europe, Israel, South Africa. Population Asymptomatic postmenopausal women with risk factors for osteoporosis or cardiovascular disease who had an endometrial thickness of less than 5 mm. One thousand and eight women were randomised for the six month core; of these 420 were invited to continue into a six month extension period. Methods Randomisation to either raloxifene or continuous combined hormone replacement therapy. Patients, recruiters and assessors were blinded to the treatment used. Main outcome measures The frequency of vaginal spotting/bleeding as recorded in a diary, endometrial thickness and uterine volume as measured by transvaginal ultrasonography at baseline and after 6 and 12 months. Results After six months of therapy with raloxifene, the rate of women on raloxifene reporting vaginal bleeding and spotting (6.8%) was similar to the rate in the lead-in phase (8.3%) but increased from 7.0% to 55.1% in the continuous combined hormone replacement therapy group. Raloxifene treatment was not associated with a significant change from baseline to endpoint in mean endometrial thickness ( P = 0.11), whereas continuous combined hormone replacement therapy treatment was associated with an increase in this value of mean (SD) of 1.2 (2.2) mm ( P < 0.001). Compared with raloxifene, mean endometrial thickness for women on continuous combined hormone replacement therapy was significantly increased at endpoint [4.6 (2.1) mm vs 3.5 (1.7) mm; change from baseline P < 0.001]. In the raloxifene group, there was a trend towards a decrease from baseline in uterine volume [from 31.4 (20.3) to 30.3 (16.2) mm; P = 0.37]; in the continuous combined hormone replacement therapy group, there was a significant increase in uterine volume [from 31.3 (16.3) to 54.0 (36.1) mm; P < 0.001], and the difference in the effect of both compounds on change in uterine volume at endpoint reached statistical significance ( P < 0.001). Statistically significant differences between the treatment groups were sustained for all parameters during the extension period. Early discontinuation rates, both overall and due to adverse events, were significantly lower ( P < 0.001) in the raloxifene group after 6 and 12 months. Conclusion Compared with continuous combined hormone replacement therapy, 6 and 12 months of raloxifene treatment do not lead to vaginal bleeding/spotting, are not associated with increased endometrial thickness or uterine volume and result in a significantly lower rate of early treatment discontinuations in asymptomatic women receiving treatment to prevent long term postmenopausal health risks.