Steven Watts

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.

Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction.

OBJECTIVES To compare the safety and efficacy of the daily erectogenic therapy, tadalafil, on lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS) in men with or without comorbid erectile dysfunction (ED). METHODS Following a 4-week placebo run-in period, men with moderate-to-severe BPH-LUTS were randomized to placebo or tadalafil 2.5, 5, 10, or 20 mg once daily for 12 weeks. International Prostate Symptom Scores (IPSS), IPSS quality of life, and BPH Impact Index were measured every 4 weeks. Safety was mainly assessed via spontaneous reports of adverse events. Data from men with (n=716) or without (n=340) ED at baseline were compared in posthoc analyses. RESULTS Men with ED were older and had more frequent hypertension, hyperlipidemia, coronary artery disease, and diabetes at baseline compared with men without ED. After 12 weeks, changes in IPSS in men with ED (least squares mean change from baseline, placebo: -2.4; tadalafil 2.5, 5, 10, 20 mg: -4.3, -4.8, -5.3, -5.6) and without ED (-2.4, -3.2, -5.3, -5.1, -4.5) were not significantly different (subgroup/interaction P values: .352/.644). Similar effects were observed for IPSS quality of life (with ED: -0.6, -0.9, -0.9, -1.0, -1.1; without ED: -0.6, -0.7, -0.9, -0.8, -0.8; 0.090/0.773) and BPH Impact Index (with ED: -0.7, -0.9, -1.3, -1.3, -1.4; without ED: -1.0, -0.7, -1.3, -1.3, -1.2; 0.753/0.852). Tadalafil was generally well tolerated, and men with or without ED had similar tolerability profiles. CONCLUSIONS Changes in BPH-LUTS after 12 weeks of treatment with placebo or various doses of once daily tadalafil were similar in men with or without comorbid ED.

Tadalafil Once Daily Improves Ejaculatory Function, Erectile Function, and Sexual Satisfaction in Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia and Erectile Dysfunction: Results from a Randomized, Placebo- and Tamsulosin-Controlled, 12-Week Double-Blind Study

INTRODUCTION Tadalafil, a long-acting phosphodiesterase type 5 inhibitor, is approved for treating signs and symptoms of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED); tamsulosin, an alpha-blocker, is approved for treating signs and symptoms of BPH. AIM To determine the effects of tadalafil or tamsulosin on sexual function, including ejaculation and orgasm, satisfaction, and erectile function, in sexually active men with ED and lower urinary tract symptoms suggestive of BPH (LUTS/BPH). METHODS A randomized, double-blind, placebo-controlled study of tadalafil 5 mg once daily for 12 weeks in men with LUTS/BPH; tamsulosin 0.4 mg once daily was an active control. MAIN OUTCOME MEASURES The International Index of Erectile Function (IIEF) questionnaire was administered at baseline and 4, 8, and 12 weeks. Analysis of orgasm and ejaculation was post hoc based on the IIEF-Orgasmic Function (OF) domain (IIEF-Q9 [ejaculatory frequency] and Q10 [orgasmic frequency]). Other measures included IIEF-Intercourse Satisfaction (IS), Overall Satisfaction (OS), and Erectile Function (EF) domains. Changes from baseline to 12 weeks (or last observation) vs. placebo were analyzed using analysis of covariance. Higher IIEF scores indicate better functioning. RESULTS Of 511 study participants, 310 (60.7%) had ED and were sexually active. The IIEF-OF increased significantly through 12 weeks with tadalafil vs. placebo (P = 0.048), as did IIEF-Q9 (P = 0.045) but not IIEF-Q10 (P = 0.100). Compared with placebo, IIEF-OF, Q9, and Q10 decreased significantly with tamsulosin (all P < 0.05). The IIEF-IS and OS increased significantly at end point with tadalafil (both P < 0.001); for tamsulosin, change was not significant for IS, while OS decreased significantly (P = 0.009). The IIEF-EF domain increased significantly vs. placebo with tadalafil (P < 0.001) but not tamsulosin (P = 0.699). CONCLUSIONS Tadalafil 5 mg once daily significantly improved ejaculation and orgasm, intercourse and overall satisfaction, and erectile function. Men receiving tamsulosin 0.4 mg once daily experienced a decrease in both ejaculatory/orgasmic frequency and overall satisfaction vs. placebo, with no significant effect on erectile function.

Efficacy and safety of tadalafil once daily : considerations for the practical application of a daily dosing option

ABSTRACT Objective: To provide clinically relevant information on tadalafil 2.5 or 5 mg once daily for the treatment of erectile dysfunction (ED), by reviewing safety and efficacy study findings. Findings from an integrated analysis of trials of tadalafil 10 and 20 mg as needed are presented to provide context for the daily dosing regime. Research design and methods: Of the three studies that included approved once-daily doses, two were conducted in the general ED population and one in a diabetic ED population. An integrated analysis was performed using 12-week efficacy and safety data from the studies conducted in the general ED population. Results: In the general ED population, the 12-week mean International Index of Erectile Function (IIEF) erectile function (EF) domain scores increased by 6.2 to an endpoint score of 19.2 and by 8.6 to 21.9 for 2.5 and 5 mg doses, respectively, versus an increase of 1.3 to 14.9 for placebo (p < 0.01). Mean successful intercourse attempts (SEP3) were 50% and 62% for tadalafil 2.5 and 5 mg once daily, respectively, versus 33% for placebo (p < 0.01). These findings were consistent with those for tadalafil as needed. In 1- and 2-year open label extensions of tadalafil 5 mg once daily, efficacy was maintained. In the diabetic ED population, 12-week mean IIEF EF scores increased by 4.8 to 18.3 and 4.5 to 17.2 with tadalafil 2.5 and 5 mg, respectively, versus an increase of 1.3 to 14.7 for placebo (p < 0.01). Mean successful intercourse attempts were more than 40% for each tadalafil dose, versus 28% for placebo (p < 0.01). The profile of treatment-emergent adverse events with tadalafil once daily was similar to that previously reported with as-needed treatment; the most common adverse events with tadalafil (dyspepsia, nasopharyngitis, headaches) were reported in ≤4% of participants. Conclusions: Findings from the three published studies support a favorable risk–benefit balance for tadalafil 2.5 or 5 mg once daily. Although no direct comparison studies were performed (no head-to-head trials), efficacy and safety findings were consistent with those with tadalafil as needed.

Efficacy and Safety of Tadalafil 5 mg Once Daily for Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Subgroup Analyses of Pooled Data From 4 Multinational, Randomized, Placebo-controlled Clinical Studies

OBJECTIVE To assess the efficacy and safety of tadalafil, a phosphodiesterase 5 (PDE5) inhibitor efficacious for erectile dysfunction and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), in population subgroups, using pooled data from 4 international, randomized, placebo-controlled studies in men with LUTS/BPH. METHODS The safety database included 1500 men randomized to tadalafil 5 mg once daily or placebo for 12 weeks. Changes in total International Prostate Symptom Score (IPSS), IPSS-quality of life index, and BPH impact index were examined overall, and changes in IPSS or adverse events (AEs) were examined across subgroups of interest. Treatment-group differences were assessed using analysis of covariance. RESULTS Results of pooled data confirmed that tadalafil (N = 752) resulted in significant improvements from baseline vs placebo (N = 746) in IPSS (mean difference -2.3; P <.001), and also in BPH impact index and IPSS-quality of life index (both P <.001). Subgroup analyses demonstrated that IPSS improvements were significant regardless of baseline LUTS severity (IPSS <20/≥20), age (≤65/>65 years), recent previous use of α-blockers or PDE5 inhibitors, total testosterone level (<300/≥300 ng/dL), or prostate-specific antigen predicted prostate volume (<40/≥40 mL). [corrected] Rates of treatment emergent AEs were comparable between subgroups of baseline age (≤65/>65 years), previous PDE5 inhibitor use, and the presence or absence of pre-existing diabetes, hypertension, or cardiovascular disease (including hypertension), but somewhat higher for recent previous α-blocker use. CONCLUSION In these pooled data analyses, tadalafil 5 mg improved LUTS/BPH across subgroups of age, LUTS severity, testosterone levels, and prostate volume. Rates of AEs were similar across the subgroups assessed.

Direct Effects of Tadalafil on Lower Urinary Tract Symptoms versus Indirect Effects Mediated through Erectile Dysfunction Symptom Improvement: Integrated Data Analyses from 4 Placebo Controlled Clinical Studies

PURPOSE Tadalafil has regulatory approval for the treatment of men with signs/symptoms of benign prostatic hyperplasia with and without erectile dysfunction. We assessed whether the effects of treatment with tadalafil for lower urinary tract symptoms/benign prostatic hyperplasia are independent of improvements in erectile dysfunction. MATERIALS AND METHODS Four separate analyses used integrated data from 4 randomized, double-blind, placebo controlled studies in men with lower urinary tract symptoms/benign prostatic hyperplasia with and without erectile dysfunction to test whether total I-PSS (International Prostate Symptom Score) improvement was due to improvement in IIEF-EF (International Index of Erectile Function-Erectile Function domain score). Unidirectional and bidirectional path analysis models determined direct and indirect treatment effects mediated by improvements in lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction symptoms. RESULTS A total of 1,496 men, of whom 77% had erectile dysfunction, received at least 1 dose of tadalafil 5 mg once daily or placebo. The placebo adjusted treatment effect for men with erectile dysfunction was represented by a mean decrease of -2.3 (p <0.0001) in total I-PSS vs -2.2 (p = 0.0007) for men without erectile dysfunction. The correlation between change from baseline in total I-PSS and IIEF-EF was weak (r(2) = 0.08, p <0.0001). The unidirectional path analysis model suggested that the total treatment effect on total I-PSS score improvement (2.25) was derived from a direct treatment effect of 1.57 (70%, p <0.001) and an indirect treatment effect of 0.67 (30% via IIEF-EF improvement, p <0.001). Bidirectional path analysis showed that total I-PSS improvement was largely attributed to direct (92.5%, p <0.001) vs indirect (7.5%, p = 0.32) treatment effects via IIEF-EF improvement. CONCLUSIONS Regardless of the analytical approach, self-reported erectile dysfunction status did not appreciably influence tadalafil treatment response in men with lower urinary tract symptoms/benign prostatic hyperplasia, supporting the dual action of tadalafil on lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction.

Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo‐controlled studies

Disorders of ejaculation and orgasm are common, even in men with only mild erectile dysfunction (ED). Treatment with the phosphodiesterase type‐5 inhibitor tadalafil was associated with improvements in ejaculatory and orgasmic function. Patients with residual ejaculatory or orgasmic dysfunction experience reduced sexual satisfaction. These findings need to be corroborated in further clinical trials involving men without ED.

Factors associated with ejaculatory and orgasmic dysfunction in men with erectile dysfunction: analysis of clinical trials involving the phosphodiesterase type 5 inhibitor tadalafil.

Study Type – Prognosis (cohort series)

Likelihood of Tadalafil-associated Adverse Events in Integrated Multiclinical Trial Database: Classification Tree Analysis in Men With Erectile Dysfunction

OBJECTIVES To identify the patient demographic factors, comorbidities, and concomitant medications associated with a change in the likelihood of tadalafil-associated adverse events (AEs) in men with erectile dysfunction. METHODS Pooled safety data were analyzed from 3488 tadalafil-treated men who participated in 21 placebo-controlled clinical trials of tadalafil taken as needed or once daily. Three categories of tadalafil-associated AEs were defined: vasodilatory (headache, flushing, nasal congestion, nasopharyngitis, and dizziness); musculoskeletal (back pain and myalgia); and gastrointestinal (dyspepsia). A classification and regression tree analysis was used to determine the patient characteristics most likely to be associated with a change in the likelihood of these types of AEs. RESULTS Of the 3488 tadalafil-treated patients, 973 (27.9%) had any vasodilatory, musculoskeletal, and/or gastrointestinal tadalafil-associated AE. The patient characteristics associated with a change in the likelihood of any tadalafil-associated AE were diabetes, geographic region, and age. The patient characteristics associated with a change in the likelihood of a vasodilatory tadalafil-associated AE included antihypertensive medication use, geographic region, and height, with several additional splits occurring along these primary and secondary nodes. No patient characteristics associated with a change in the likelihood of musculoskeletal or gastrointestinal AEs were identified owing to the limitation of a relatively low incidence of these types of AEs. CONCLUSIONS The findings from classification and regression tree analyses could help physicians to better understand some of the associations between patient characteristics and the tolerability of phosphodiesterase type 5 inhibitors and could contribute to improved patient outcomes, satisfaction, treatment seeking, and treatment persistence.