Leo Plouffe

Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.

OBJECTIVE: To examine the effect of raloxifene on major adverse events that occur with postmenopausal estrogen therapy or tamoxifen. METHODS: The Multiple Outcomes of Raloxifene Evaluation, a multicenter, randomized, double-blind trial, enrolled 7,705 postmenopausal women with osteoporosis. Women were randomly assigned to raloxifene 60 mg/d or 120 mg/d or placebo. Outcomes included venous thromboembolism, cataracts, gallbladder disease, and endometrial hyperplasia or cancer. RESULTS: During a mean follow-up of 3.3 years, raloxifene was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1; 95% confidence interval [CI] 1.2–3.8). The excess event rate was 1.8 per 1,000 woman-years (95% CI −0.5–4.1), and the number needed to treat to cause 1 event was 170 (95% CI 100–582) over 3.3 years. Risk in the raloxifene group was higher than in the placebo group for the first 2 years, but decreased to about the same rate as in the placebo group thereafter. Raloxifene did not increase risk for cataracts (RR 0.9; 95% CI 0.8–1.1), gallbladder disease (RR 1.0; 95% CI 0.7–1.3), endometrial hyperplasia (RR 1.3; 95% CI 0.4–5.1), or endometrial cancer (RR 0.9; 95% CI 0.3–2.7). CONCLUSION: Raloxifene was associated with an increased risk for venous thromboembolism, but there was no increased risk for cataracts, gallbladder disease, endometrial hyperplasia, or endometrial cancer. LEVEL OF EVIDENCE: I

Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60.

Objective To assess the uterine effects of 3 years of therapy with raloxifene in healthy, postmenopausal women under age 60. Methods Integrated data from two identically designed, randomized, double-masked, placebo-controlled clinical trials were analyzed. Nine hundred sixty-nine healthy women with uteri (ages 45 through 60, 2 to 8 years postmenopausal) were assigned randomly to raloxifene 30, 60, or 150 mg per day, or an identical placebo for 3 years. Endometrial thickness was evaluated with transvaginal ultrasonography every 6 months for 2 years and again after 3 years. Further uterine evaluation, including endometrial sampling if necessary, was initiated for vaginal bleeding or findings of endometrial thickness greater than 5 mm. Results Endometrial thickness was unchanged by raloxifene and not significantly different from placebo at any time. One hundred seventy-two women had at least one episode of endometrial thickness greater than 5 mm or vaginal bleeding distributed equally among all groups. A total of 102 (10.5%) women underwent endometrial sampling at least once: 15 (1.5%) for vaginal bleeding, 78 (8.0%) for endometrial thickness greater than 5 mm, and nine (0.9%) for other reasons. There were no significant treatment differences in the proportion of women sampled, in the clinical findings, or in the histologic diagnoses. Conclusion Raloxifene given to healthy postmenopausal women at doses from 30 to 150 mg per day does not stimulate uterine growth and does not cause vaginal bleeding, spotting, or discharge through 3 years of therapy. Thus, any bleeding during therapy should be deemed unexpected and prompt a clinical evaluation.

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years.

ObjectiveRaloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DesignThe current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturers database for the lumbar spine and the National Health and Nutrition Examination Surveys 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. ResultsCompared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: −10.9%, P < 0.001; bone-specific alkaline phosphatase: −7.2%, P = 0.042; urinary C-telopeptide: −11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (−5.5%; P < 0.001) and low-density lipoprotein cholesterol (−8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P ≥ 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. ConclusionsFive years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.

Raloxifene effect on frequency of surgery for pelvic floor relaxation.

OBJECTIVE To assess the effects of raloxifene therapy on the frequency of surgery for pelvic floor relaxation in postmenopausal women. METHODS This analysis used safety data through 3 years of treatment from three double‐masked, placebo‐controlled, randomized trials of raloxifene, which included 6926 postmenopausal women with uteri at entry. Studies 1 and 2 enrolled 969 nonosteoporotic, postmenopausal women who were assigned to 30, 60, or 150 mg per day raloxifene or placebo. Study 3 enrolled 5957 osteoporotic, postmenopausal women randomized to raloxifene 60 or 120 mg per day or placebo. Indications for any reported pelvic operations were identified, including procedures performed for pelvic organ prolapse or urinary incontinence. RESULTS A total of 34 (1.51%) women in the placebo group and 35 (0.75%) raloxifene‐treated women underwent surgical procedures for pelvic floor relaxation. The odds ratio (and 95% confidence interval) for pelvic floor repair in women assigned to raloxifene was 0.50 (0.31, 0.81). Thus, raloxifene therapy was associated with a significantly reduced risk for pelvic floor surgery (P < .005). CONCLUSION Raloxifene does not increase pelvic floor relaxation. An apparent protective effect on pelvic floor function warrants further investigation.

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.

Etiologic factors of recurrent abortion and subsequent reproductive performance of couples: Have we made any progress in the past 10 years?

OBJECTIVES We hypothesize that the diagnostic yield and pregnancy outcomes of patients with recurrent abortion have improved over the past 10 years. STUDY DESIGN The study was performed in an academic medical center. Diagnoses and outcomes for group A, a published series of 100 patients investigated for recurrent abortion in the section between 1968 and 1977, was compared with those for group B, the 131 patients seen between 1987 and 1991. A standardized protocol was followed, enhanced by new techniques and autoimmune investigations in the latter group. Results were compiled retrospectively. Descriptive statistics and chi 2 analysis were used. RESULTS No cause could be found in 37% of patients in group A compared with 24% of couples in group B (p less than 0.05). No clear difference could be shown in the subsequent outcomes of pregnancies. CONCLUSIONS Our ability to establish a cause of recurrent abortion has improved slightly over the past 15 years. The gain is not yet reflected in successful pregnancy rates. Multicenter trials are indicated.

Effect of raloxifene on the response to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal atrophy

OBJECTIVE To study the effect of raloxifene on the response to conjugated estrogen cream or nonhormonal moisturizer in postmenopausal women with preexisting signs of vaginal atrophy. METHODS Postmenopausal women with preexisting and untreated vaginal atrophy were enrolled in this parallel, placebo-controlled, randomized study. A total of 187 women were randomized to four treatment groups: daily oral raloxifene (60 mg per day) or a placebo in a double-blind manner plus one application of conjugated estrogen cream (0.5 g) or one applicator full of nonhormonal moisturizer, open label. The conjugated estrogen cream or non-hormonal moisturizer was applied daily for the first 2 weeks, and then twice weekly thereafter for 3 months. Efficacy of treatment regimens on signs and symptoms of vaginal atrophy was evaluated by monitoring objective and subjective parameters. RESULTS Signs and symptoms of vaginal atrophy improved in all four treatment groups. Raloxifene did not diminish the magnitude of improvement when administered with either vaginal preparation. Conjugated estrogen cream produced a statistically greater improvement in signs (P < .05) but not in individual symptoms or overall satisfaction relative to nonhormonal moisturizer. CONCLUSION Postmenopausal women with evidence of preexisting vaginal atrophy may use either low-dose conjugated estrogen cream or nonhormonal moisturizer to treat the atrophy concurrently with raloxifene (60 mg per day).

Comparison of Fracture, Cardiovascular Event, and Breast Cancer Rates at 3 Years in Postmenopausal Women with Osteoporosis

Objectives: To compare event rates for osteoporotic fractures, cardiovascular events, and breast cancer in postmenopausal women with osteoporosis.

Transition from estrogen-progestin to raloxifene in postmenopausal women: effect on vasomotor symptoms.

OBJECTIVE: To compare vasomotor symptoms after transition from estrogen–progestin therapy to raloxifene 60 mg/d with and without a placebo washout. METHODS: Postmenopausal women currently taking continuous combined estrogen–progestin therapy (conjugated equine estrogen, 0.625 mg/medroxyprogesterone acetate, 2.5 or 5 mg) daily for 5 or more months were enrolled. Women were randomized to 1 of 4 blinded regimens: 1) 12 weeks estrogen–progestin; 2) 12 weeks placebo; 3) 4 weeks placebo, then 8 weeks raloxifene; or 4) 12 weeks raloxifene. For the final 36 weeks, all subjects received raloxifene. Vasomotor symptoms were assessed by patient diaries. RESULTS: A total of 266 women (mean age 57.5) were enrolled. Mean hot flush frequency at baseline was approximately 1 per week in the entire population, with 16% of women reporting hot flushes. Mean frequency and severity of hot flushes during the first 12 weeks of the study were statistically greater in the 3 groups transitioned off estrogen–progestin (range of hot flushes per week: 4 weeks, 11–12; 8 weeks, 18–24; 12 weeks, 13–16), as compared with those continuing estrogen–progestin, with no difference between these 3 groups (P ≥ .1). Approximately 50–70% of these women reported hot flushes, generally rated as mild to moderate by participants, after estrogen–progestin discontinuation. CONCLUSION: A large proportion of women discontinuing estrogen–progestin experience hot flushes. Raloxifene does not appear to increase the frequency or severity of vasomotor symptoms in women discontinuing estrogen–progestin more than that observed with placebo treatment after estrogen–progestin discontinuation. Transition from estrogen–progestin to raloxifene with no washout period therefore may be acceptable. LEVEL OF EVIDENCE: I

Diagnostic and treatment results from a southeastern academic center-based premenstrual syndrome clinic: The first year

OBJECTIVES We attempted to ascertain the following: (1) the yield of a structured workup in a premenstrual syndrome clinic coordinated by a university-based gynecology department in the southeast, (2) referral patterns and care provided before consultation, and (3) therapeutic outcomes. STUDY DESIGN The first 100 women seen prospectively entered a uniform diagnostic and treatment protocol. Data analysis was performed with analysis of variance and confidence interval for a population proportion. RESULTS Thirty-eight women (95% confidence interval 28% to 48%) had premenstrual syndrome, 24 had premenstrual magnification syndrome (95% confidence interval 16% to 32%), 13 had an affective or other psychiatric disorder (95% confidence interval 6% to 20%). Only 44% of women previously given a diagnosis of premenstrual syndrome were found to have premenstrual syndrome. Overall, 84% of women with premenstrual syndrome and premenstrual magnification syndrome responded to treatment. CONCLUSIONS Too many women are still given the diagnosis of premenstrual syndrome without appropriate prospective documentation. Premenstrual magnification represents an important diagnostic category. Therapeutic responses to present treatments are encouraging.