A Retrospective Database Analysis to Investigate Treatment Patterns and Health Care Resource Utilisation in Patients who CYCLe AntiMuscarinics in ENgland (CYCLAMEN).

BACKGROUND: Patients with overactive bladder may cycle through different antimuscarinic medications even though there is limited evidence to support this approach. OBJECTIVE: To describe treatment patterns and the associated health care resource utilisation (HCRU) according to antimuscarinic cycling groups. DESIGN, SETTING, AND PARTICIPANTS: The CYCLe AntiMuscarinics in ENgland (CYCLAMEN) study was a retrospective observational investigation that used primary care records from the Clinical Practice Research Datalink GOLD database linked to Hospital Episode Statistics secondary care data. Eligible patients (≥18 yr) were prescribed their first antimuscarinic between January 2014 and December 2017. Patients were categorised into groups prescribed one, two, or three or more (groups 1-3) consecutive unique antimuscarinics over 18 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The HCRU rate and costs were calculated for the period of continuous antimuscarinic therapy (first antimuscarinic treatment episode) and the 18-mo follow-up period. Treatment sequence patterns were displayed using sunburst plots and Kaplan-Meier analysis was used to assess time on treatment. RESULTS AND LIMITATIONS: Overall, 35 369 patients were included, of whom 31 760 (89.8%) received one antimuscarinic (group 1), 3182 (9.0%) received two (group 2), and 427 (1.2%) received three or more (group 3). The most common initial antimuscarinics were solifenacin (13 628 patients, 42.9%) in group 1, and oxybutynin in group 2 (1267 patients, 39.8%) and group 3 (200 patients, 46.8%). The median duration of the first antimuscarinic treatment episode was 57 d and <20% of patients were receiving any antimuscarinic after 18 mo. The number of primary care visits and mean costs increased across groups. The reasons for cycling could not be identified in this study. CONCLUSIONS: Approximately 10% of patients underwent sequential cycling with two or more antimuscarinics. Furthermore, as the majority discontinued treatment within 18 mo, there is a need to improve the management of these patients in the clinical care setting. PATIENT SUMMARY: We investigated treatment patterns and health care use for patients with overactive bladder who were prescribed at least one antimuscarinic drug (AMD), which are drugs that reduce some of the impulses passing from the bladder to the brain. Around 10% of patients accessing primary health care in England received more than one sequential AMD. Most patients discontinued treatment, which may indicate inadequate management of their condition. Prescription of a higher number of AMDs was associated with higher health care costs.

Treatment Patterns in Men Prescribed Benign Prostatic Obstruction or Overactive Bladder Medications in Canada: A Retrospective Population-based Study.

OBJECTIVE: To characterize first therapeutic change and healthcare resource utilization in older men initiating an overactive bladder (OAB) or benign prostatic obstruction (BPO) medication. METHODS: A retrospective cohort study using health administrative data from ICES in Ontario, Canada (from April 01, 2010 to December 31, 2018) was conducted in men aged ≥66 years with ≥1 OAB (ß3 agonist, antimuscarinic) or BPO (α-blocker, 5-α-reductase inhibitor) prescription and ≥1-year postindex data (index=first observed dispensation). EXCLUSIONS: prescriptions for these drugs ≤1 year preindex, a related procedure ≤5 years. Patients were grouped by condition based on index prescription. Treatment changes in relation to OAB and BPO were characterized by type. Costs and healthcare resource utilization pre- and post-index were compared. RESULTS: Age, geographic region, and income were similar between groups. The most common initial treatments were antimuscarinics (78.1%) in the OAB group and alpha-blockers (86.4%) in the BPO group. The OAB group was more likely to experience a therapeutic change and had a shorter time to first change in therapy (78 [30,231] vs 104 [30,350] days) and higher mean healthcare costs both pre- ($12,354 vs $11,497) and postindex ($14,423 vs $12,852). The most common first therapeutic change in both groups was discontinuing treatment (OAB: 75.6%; BPO: 69.9%). CONCLUSION: Men initiating OAB medications changed therapy sooner than those initiating BPO medications. Most discontinued first-line therapy without initiating further treatment, suggesting unmet need in this population.

Treatment Sequence After Initiating Biologic Therapy for Patients With Rheumatoid Arthritis in Korea: A Nationwide Retrospective Cohort Study.

Objective: To evaluate treatment patterns and healthcare resource utilization (HCRU) after initiating biologic disease-modifying antirheumatic drugs (bDMARDs) in Korean patients with rheumatoid arthritis (RA). Methods: Patients newly diagnosed with RA in 2014 were identified and followed up on using the Korean National Health Insurance Database until 2018. The initial line of therapy (LOT) or LOT1 included patients treated with conventional DMARDs (cDMARD). Patients who started a bDMARD were assigned to LOT2 bDMARD. Those who moved from a bDMARD to a Janus kinase inhibitor were assigned to LOT3. Analyzed outcomes were treatment patterns and HCRU in LOT2 bDMARD. Results: The most prescribed initial bDMARD was a tumor necrosis factor inhibitor. Seventy-five percent of patients had changes in treatment after starting a bDMARD, such as addition/removal or switch of a DMARD, and transition to LOT3. For the first and second changes in LOT2 bDMARD, adding a cDMARD to a bDMARD was more common than switching to another bDMARD (7.98% vs. 2.93% for the first change, and 17.10% vs. 6.51% for the second change). Tocilizumab was the most common bDMARD that was switched to. Forty-eight percent of patients had at least one hospitalization after initiating bDMARDs. Of these patients, 64.3% were admitted due to RA-related reasons. Conclusion: This real-world study provides information on treatment characteristics of RA patients in Korea after starting a bDMARD. In contrary to guidelines, cDMARD addition was more often than bDMARD switches in daily clinical practice.

Clinical factors for predicting cardiovascular risk, need for renal replacement therapy, and mortality in patients with non-dialysis-dependent stage 3-5 chronic kidney disease from the Salford Kidney Study.

BACKGROUND: Established cardiovascular risk assessment tools lack chronic kidney disease-specific clinical factors and may underestimate cardiovascular risk in non-dialysis-dependent chronic kidney disease (CKD) patients. METHODS: A retrospective analysis of a cohort of patients with stage 3-5 non-dialysis-dependent chronic kidney disease in the Salford Kidney Study (UK, 2002-2016) was performed. Multivariable Cox regression models with backward selection and repeated measures joint models were used to evaluate clinical risk factors associated with cardiovascular events (individual and composite cardiovascular major adverse cardiovascular events), mortality (all-cause and cardiovascular-specific), and need for renal replacement therapy. Models were established using 70% of the cohort and validated on the remaining 30%. Hazard ratios ([95% CIs]) were reported. RESULTS: Among 2192 patients, mean follow-up was 5.6 years. Cardiovascular major adverse cardiovascular events occurred in 422 (19.3%) patients; predictors included prior history of diabetes (1.39 [1.13-1.71]; P = 0.002) and serum albumin reduction of 5 g/L (1.20 [1.05-1.36]; P = 0.006). All-cause mortality occurred in 740 (33.4%) patients, median time to death was 3.8 years; predictors included reduction of estimated glomerular filtration of 5 mL/min/1.73 m2 (1.05 [1.01-1.08]; P = 0.011) and increase of phosphate of 0.1 mmol/L (1.04 [1.01-1.08]; P = 0.021), whereas a 10 g/L hemoglobin increase was protective (0.90 [0.85-0.95]; P < 0.001). In 394 (18.0%) patients who received renal replacement therapy, median time to event was 2.3 years; predictors included halving of estimated glomerular filtration rate (3.40 [2.65-4.35]; P < 0.001) and antihypertensive use (1.23 [1.12-1.34]; P < 0.001). Increasing age, albumin reduction, and prior history of diabetes or cardiovascular disease were risk factors for all outcomes except renal replacement therapy. CONCLUSIONS: Several chronic kidney disease-specific cardiovascular risk factors were associated with increased mortality and cardiovascular event risk in patients with non-dialysis-dependent chronic kidney disease.

Epidemiology and treatment patterns of UK women diagnosed with vasomotor symptoms: Findings from the Clinical Practice Research Datalink GOLD database.

OBJECTIVES: To describe the epidemiology and treatment of vasomotor symptoms (VMS) in the UK. STUDY DESIGN: Retrospective study that used electronic medical records from UK primary care centers. MAIN OUTCOME MEASURES: The prevalence and incidence of moderate-to-severe VMS, the proportion treated, persistence with initial treatment, treatment patterns, and menopausal hormone therapy (HT) experience were investigated over the study period (Jan. 2009-Dec. 2018). The study population comprised women aged 40-65 years registered at general practitioner clinics. For incident cases, the uptake of pharmacological non-hormonal or hormonal treatment was recorded, which included experience of HT. RESULTS: Over the 10-year study period, 1,481,646 women were included from the database, among whom there were 313,031 prevalent and 90,434 incident cases of VMS. Annual prevalence and incidence rates were stable over time, with a weighted average of 21.1 % and 15.3 per 1000 person-years, respectively (results varied across age groups). Among women who were incident VMS cases, 32.4 % (29,275) were initially prescribed non-hormonal treatments for a median of 3.9 months, 49.4 % (44,700) were prescribed hormonal treatments for 4.0 months, and 18.2 % (16,459) had no treatment. Approximately one-third of treated women switched between non-hormonal and hormonal treatments. The HT experience results showed that 52.7 % (47,639) of women were HT-eligible, 13.1 % (11,872) were HT-contraindicated (they may or may not have received HT), and 34.2 % (30,923) did not receive HT. CONCLUSIONS: Variations in prescribed treatment patterns suggest that education may be needed for clinicians and women regarding the potential pharmacological options for treating VMS in the UK.

Vasomotor symptoms, sleep problems, and depressive symptoms in community-dwelling Japanese women.

AIM: To assess prevalence and characteristics of vasomotor symptoms in community-dwelling Japanese women. METHODS: These were cross-sectional analyses using data from the National Institute for Longevity Sciences-Longitudinal Study of Aging. The main outcome measures were prevalence and severity of hot flashes and sweating. Associations between hot flashes/sweating (slight, moderate, or severe vs none) and sleep problems were explored using logistic regression, with and without adjustment for age, daily physical activity, and number of urinations/night. Associations between hot flashes/sweating and sleep problems, depressive symptoms, and dietary variables were explored in logistic regression models or general linear models. RESULTS: A total of 1152 women between 40 and 91 years of age were enrolled. Hot flashes were reported by 24.5% of participants; with prevalence and severity highest in those 50-54 years or 2-5 years postmenopause. Sleep problems were reported 15 percentage points more frequently by women who reported hot flashes than by those without hot flashes. Adjusted odds ratios [95% CI] for difficulty in falling asleep and difficulty in sleeping through were 2.09 [1.565-2.796] and 2.07 [1.549-2.763]), respectively. Also, hot flashes were associated with higher risk of depressive symptoms (adjusted odds ratio [95% CI]: 2.99 [2.07-4.32]) and lower life satisfaction, self-esteem, and self-rated health status. A similar pattern was observed in women with and without sweating. No associations were found between hot flashes and dietary factors. CONCLUSIONS: Clear associations were found between hot flashes and sleeping problems, even after adjusting for potential confounding factors. Women who reported hot flashes also reported worse mental and physical health than those who did not report hot flashes.

Increased Healthcare Resource Utilization and Direct and Indirect Costs in Patients with Depression and Comorbid Overactive Bladder: Evidence From a Retrospective, Matched Case-Control Cohort Analysis.

INTRODUCTION: This study sought to compare healthcare resource utilization (HCRU), costs, and workplace productivity among patients with depression, with and without overactive bladder (OAB). METHODS: This retrospective, case-control cohort analysis compares HCRU, costs, and workplace productivity among propensity score matched patients with depression and OAB (case cohort) and patients with depression without OAB (control cohort). Patients were aged 18 years or older, insured/on Medicare, and had diagnosed depression and an antidepressant medication claim pre index. First OAB-related event was index for cases; controls were assigned a proxy (study period 12 months). Comparisons of HCRU and costs and regression models assessed the relationship between OAB and costs. For the workplace productivity subset analyses cases and controls were balanced on baseline covariates for the short-term disability analyses but as they were unbalanced for the absentee analyses, multivariate regression analyses were used for this subset. RESULTS: The study criteria were met by 39,085 cases and 308,736 controls, from which, 37,997 patients were successfully matched 1:1 (mean age 55 years; 81% female). Most depression-related HCRU measures were similar across cohorts; however, outpatient visits, ER visits, and number of unique depression medications were significantly higher (all p < 0.05) among cases. Cases also had 13% higher total depression-related costs (p < 0.0001). Total mean (standard deviation [SD]) depression-related costs were $1796 ($4235) for cases versus $1597 ($3863) for controls (p < 0.0001). For workplace productivity (absentee data: cases [n = 686], controls [n = 642]; short-term disability data: cases [n = 4395], controls [n = 4433]) absentee outcomes were similar across cohorts. However, a higher percentage of cases used short-term disability benefits compared to controls (21.3% versus 16.9%; p < 0.0001) and cases experienced more case days (11.0 versus 8.6 mean days) and received higher mean payments than controls ($1226 versus $1033; p < 0.0001) in this subset. CONCLUSIONS: OAB was associated with 13% higher depression-related costs and 4.4% more cases used short-term disability benefits.

The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652 in First-in-Human and Ascending Multiple Oral Dose Studies in Healthy Subjects.

INTRODUCTION: Inhibitors of fatty acid amide hydrolase (FAAH) increase the levels of endocannabinoids and have shown analgesic and anti-inflammatory activity in animal models. ASP3652 is a peripherally acting FAAH inhibitor in development for the treatment of chronic bladder and pelvic pain disorders. Here we describe the safety, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of ASP3652 administered in healthy non-elderly and elderly male and female volunteers. METHODS: Study 1 was a combined single-ascending dose and food-effect study in which ASP3652 was given as single doses (1-600 mg) or matching placebo in healthy subjects. Study 2 was a multiple ascending dose study in which ASP3652 or matching placebo was administered in multiple oral doses (10-300 mg bid and 600 mg qd for 14 days) to healthy subjects. In both studies, the levels of ASP3652, FAAH, endocannabinoids (eCBs) and safety were evaluated. RESULTS: ASP3652 was readily absorbed to reach Cmax at 1 h after a single dose. Steady state was reached within 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 increased in a slightly more than dose-proportional manner after a single dose of ASP3652 at 30-600 mg. There was some accumulation (15-38%) based on Cmax and AUC12h upon multiple doses. Cmax was 47% lower in combination with food. There was no significant effect of gender or age on the pharmacokinetics of ASP3652. FAAH activity was inhibited in a dose-dependent manner in all dose groups after single and multiple doses of ASP3652, paralleled by an increase in plasma levels of anandamide (AEA). The incidence of adverse events following multiple doses was similar across all treatment groups including the placebo group. CONCLUSIONS: Single and multiple doses of ASP3652 were safe and well tolerated and increased endogenous cannabinoid plasma levels.

Safety and Efficacy of Mirabegron: Analysis of a Large Integrated Clinical Trial Database of Patients with Overactive Bladder Receiving Mirabegron, Antimuscarinics, or Placebo.

BACKGROUND: Mirabegron, a ß3-adrenoreceptor agonist, is an alternative drug to antimuscarinics for overactive bladder (OAB) symptoms. OBJECTIVE: To summarise safety and efficacy reporting of mirabegron treatment for OAB symptoms. DESIGN, SETTING, AND PARTICIPANTS: Pooled data analysed from 10 phase 2-4, double-blind, 12-wk mirabegron monotherapy studies in adults with OAB who had received one or more doses of study drug. INTERVENTION: Mirabegron: 25 and 50mg; antimuscarinics: solifenacin (2.5, 5, and 10mg) and tolterodine extended release (4mg). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline OAB-related characteristics, intrinsic and extrinsic factors, and analyses by age (<65 vs ≥65yr and <75 vs ≥75yr) and sex were assessed. Solifenacin 2.5 and 10mg groups were not included in the efficacy analyses (small patient numbers). Safety was evaluated using the proportion of treatment-emergent adverse events. Efficacy variables were derived from bladder diaries (baseline and week 12). RESULTS AND LIMITATIONS: Baseline hypertension and diabetes were more frequent across treatment groups in the older versus younger age groups and in men versus women. Within sexes, frequencies were similar between treatment groups. Some differences were observed in baseline characteristics, including type of incontinence and medical history between sexes. No previously unreported safety concerns were identified. Improvements in efficacy (mean number of incontinence episodes/24h, micturitions/24h, urgency episodes/24h, volume voided/micturition, and nocturia episodes) versus placebo were observed in all treatment groups. Significant treatment-by-subgroup interactions included change from baseline in the mean number of incontinence episodes/24h by age (<65 vs ≥65yr), nocturia by age (<65 vs ≥65yr and <75 vs ≥75yr), and urgency episodes by previous OAB medication. CONCLUSIONS: Data from this integrated database of 10 mirabegron studies reaffirm the safety and efficacy profiles of mirabegron, solifenacin, and tolterodine in adults of different age groups and sexes. PATIENT SUMMARY: Overactive bladder is a complex of symptoms including a compelling desire to pass urine that leads to increased frequency, which may lead to a degree of incontinence if you do not reach the toilet in time and may wake you from sleep. We pooled data from 10 different studies of mirabegron in patients with overactive bladder symptoms, and looked at the effect in the total number of patients who received the treatment, as well as in different age groups and between men and women. No new safety concerns were identified, and mirabegron improved the symptoms of overactive bladder.

Efficacy and Safety of Combination Pharmacotherapy for Patients with Overactive Bladder: A Rapid Evidence Assessment.

CONTEXT: Oral pharmacotherapy consisting of antimuscarinics, ß3-adrenoreceptor agonists, or combinations of these agents forms the mainstay of overactive bladder (OAB) management. OBJECTIVE: To evaluate the efficacy and safety of combination therapy in patients with OAB. EVIDENCE ACQUISITION: A literature search was conducted in June 2018 using Embase, MEDLINE, and Cochrane databases via Ovid and relevant congress abstracts. Studies reporting the efficacy/safety of two antimuscarinics or a ß3-adrenoreceptor agonist plus an antimuscarinic were included. EVIDENCE SYNTHESIS: Publications reported on clinical efficacy, safety, and health-related quality of life (HRQoL) for mirabegron (M) plus solifenacin (S) from three 12-wk randomised controlled trials (RCTs)-SYMPHONY, SYNERGY, and BESIDE-and a 12-mo RCT, SYNERGY II. SYMPHONY reported statistically significant improvements in clinical symptoms and HRQoL with combination therapy versus solifenacin 5 mg (S5) and placebo. In SYNERGY, there were consistent improvements in urinary incontinence (UI) episodes/24 h and micturitions/24 h (coprimary endpoints), and in secondary efficacy parameters with mirabegron 25 mg (M25) + S5 and mirabegron 50 mg (M50) + S5 versus respective monotherapies. In patients with an inadequate response to S5 monotherapy (BESIDE), greater improvements in UI (primary endpoint) were noted for M50 + S5 versus S5 (p = 0.001). Combination therapy was noninferior to solifenacin 10 mg (S10) for reduction in UI and superior to S10 for improvement in micturition frequency (p < 0.001), and resulted in greater improvements from baseline in OAB-5 Dimension scores versus S5 and S10 (p < 0.01). In SYNERGY II, clinically meaningful and sustained improvements in clinical outcomes were observed for M50 + S5 versus M50 or S5. Combination therapy was well tolerated in all four trials. The incidence of adverse events (AEs) was similar across groups, and there were no notable differences in the incidence of specific AEs. Positive efficacy outcomes were observed in five studies of dual antimuscarinic therapy (trospium + solifenacin). CONCLUSIONS: Mirabegron plus solifenacin provides effective, well-tolerated treatment for patients with OAB. Limited data for dual antimuscarinic therapy suggest a benefit in patients with moderate-to-severe symptoms. PATIENT SUMMARY: Overactive bladder (OAB) is treated with medicines called antimuscarinics, such as solifenacin, propiverine, or trospium, or another ß-adrenoreceptor agonist medicine called mirabegron, which works in a different way. We looked at published scientific studies of patients with OAB treated with mirabegron plus solifenacin together, or with two antimuscarinics. We found that mirabegron plus solifenacin can help reduce symptoms and improve quality of life. Patients tolerate this treatment well, with few patients experiencing side effects.

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

AIMS: SYNERGY II was a 12-month phase III trial in patients with overactive bladder (OAB) symptoms that investigated the safety and efficacy of the combination of mirabegron and solifenacin in comparison with each monotherapy. This analysis evaluated the trial findings using four age subgroups (<65, ≥65, <75, and ≥75 years). METHODS: Eligible patients were ≥18 years with symptoms of "wet" OAB (urinary frequency and urgency with incontinence) for ≥3 months. Patients were randomized to receive once-daily solifenacin succinate and mirabegron (5 mg/50 mg; combination), solifenacin succinate, or mirabegron (4:1:1). Safety evaluations: treatment-emergent adverse events (TEAEs), vital signs, and electrocardiogram, post-void residual volume, and laboratory assessments. Primary efficacy variables: change from baseline to end of treatment in number of incontinence episodes/24 h and micturitions/24 h. RESULTS: Of 1794 patients (full analysis set), 614 (34.2%) and 168 (9.4%) were ≥65 and ≥75 years old, respectively. Overall, 856 (47.2%) patients experienced ≥1 TEAE. Higher TEAE incidences were typically observed for the combination versus both monotherapies (eg, constipation) and in the older versus younger age groups (eg, urinary tract infection). Increases in mean pulse rate from baseline of >1 bpm were noted in the combination and mirabegron younger age groups only. No clinically significant findings were observed in the other safety parameters. The efficacy variables improved with all treatments and the greatest improvements were typically observed with combination therapy. CONCLUSIONS: Mirabegron and solifenacin combination therapy was a well-tolerated and effective treatment for patients with OAB symptoms irrespective of their age.

Long-term Safety and Efficacy of Mirabegron and Solifenacin in Combination Compared with Monotherapy in Patients with Overactive Bladder: A Randomised, Multicentre Phase 3 Study (SYNERGY II).

BACKGROUND: The long-term potential of solifenacin and mirabegron combination treatment for patients with overactive bladder (OAB) has not been previously assessed. OBJECTIVES: To evaluate the safety and efficacy of solifenacin succinate 5mg plus mirabegron 50mg tablets (combination treatment) versus solifenacin or mirabegron monotherapy in patients with OAB over 12 mo. DESIGN, SETTING, AND PARTICIPANTS: Randomised, double-blind, multicentre, phase 3 trial (SYNERGY II) of patients with "wet" OAB symptoms (urinary frequency and urgency with incontinence) for ≥3 mo. The study was conducted from March 2014 to September 2016; with 1829 patients randomised. The full analysis set was comprised of 1794 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was safety, measured as treatment-emergent adverse events (TEAEs). Efficacy was measured as the change from baseline to the end of treatment in the mean number of incontinence episodes/24h and micturitions/24h. RESULTS AND LIMITATIONS: The median age was 60 yr (range 19-86 yr) and 1434 patients (80%) were female. Overall, 856 patients (47%) experienced ≥1 TEAE. TEAE frequency was slightly higher in the combination group (596 patients, 49%; mirabegron 126 patients, 41%; solifenacin 134 patients, 44%). Serious TEAEs were reported by 67 patients (3.7%); one was considered possibly treatment-related (mirabegron group, atrial fibrillation). Dry mouth was the most common TEAE (combination 74 patients, 6.1%; solifenacin 18 patients, 5.9%; mirabegron 12 patients, 3.9%). Combination therapy was statistically superior to mirabegron and solifenacin for the number of incontinence episodes (vs mirabegron: adjusted mean difference [AMD] -0.5, 95% confidence interval [CI] -0.7 to -0.2, p<0.001; vs solifenacin: AMD -0.1, 95% CI -0.4 to 0.1, p=0.002) and micturitions (vs mirabegron: AMD -0.5, 95% CI -0.8 to -0.2, p<0.001; vs solifenacin: AMD -0.4, 95% CI -0.7 to -0.1, p=0.004). CONCLUSIONS: Mirabegron and solifenacin combination treatment for OAB symptoms was well tolerated over 12 mo and led to efficacy improvements over each monotherapy. This innovative combination is a treatment option that could become widely used in the clinic. PATIENT SUMMARY: This study looked at the safety and efficacy of a combination of solifenacin succinate 5mg plus mirabegron 50mg tablets over 12 mo in patients with the overactive bladder (OAB) symptoms of increased urination frequency, heightened urgency to urinate, and unintentional passing of urine. We compared this treatment with solifenacin succinate 5mg or mirabegron 50mg alone, and found that the combination treatment was well tolerated by patients and led to greater improvements in symptoms. This novel combination could be an improved treatment option in the clinical setting for patients with OAB. This study is registered at ClinicalTrials.gov as NCT02045862.

Cardiovascular Safety of the ß3 -Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial.

There have been concerns that treatment of overactive bladder with ß3 -adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a ß3 -adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double-blind, parallel-group, placebo and active-controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12-week double-blind treatment period. A total of 3398 patients were included in the study. Mean changes from baseline to the end of therapy in ECG parameters were similar across treatment groups, although there was an increase in heart rate of 1 beat/minute in the mirabegron treatment groups. There were no clinically meaningful differences in change from baseline in QTcF between monotherapies and placebo and between monotherapies and combination therapy. There were very few major CV events: 1 of 853 (0.1%) with a nonfatal myocardial infarction in the combination 5 + 25 mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5 + 50 mg group, and no events in the other groups. This CV safety analysis of the combination of mirabegron and solifenacin showed rates of CV events comparable with those for monotherapy treatments based on assessments of vital signs, electrocardiograms, and adjudicated CV events.

A strategy utilizing ambulatory monitoring and home and clinic blood pressure measurements to optimize the safety evaluation of noncardiovascular drugs with potential for hemodynamic effects: a report from the SYNERGY trial.

OBJECTIVE: The aim of this study was to perform a blood pressure (BP) safety evaluation in patients with an overactive bladder receiving solifenacin (an antimuscarinic agent), mirabegron (a ß3-adrenoceptor agonist), or both compared with placebo in the SYNERGY trial. PATIENTS AND METHODS: Patients were randomized to receive solifenacin 5 mg+mirabegron 50 mg (combination 5+50 mg); solifenacin 5 mg+mirabegron 25 mg (combination 5+25 mg); solifenacin 5 mg; mirabegron 50 mg; mirabegron 25 mg; or placebo for a double-blind 12-week treatment period. Systolic BP, diastolic BP, and heart rate were measured by ambulatory BP monitoring, and in the clinic or home. RESULTS: A total of 715 patients were analyzed in an ambulatory BP monitoring substudy. At the end of treatment, ambulatory BP monitoring measurements showed no consistent increases from baseline in the mean 24-h systolic BP or diastolic BP for combination versus monotherapy groups or for monotherapy groups versus placebo. Analysis of 1-h BP averages during the 6 h range that included the Tmax values of both study drugs showed no significant BP effects. Shift analysis (switch between different normotension/hypertension stages) did not show differences among the active and placebo groups, nor did outlier analysis of major BP changes differ between placebo and active treatment. Similarly, there were no significant signals in the 24-h heart rate. Office and home measurements were consistent with ambulatory BP monitoring findings. CONCLUSIONS: A paradigm of ambulatory BP monitoring analysis designed to test BP safety of noncardiovascular drugs showed that solifenacin plus mirabegron combination therapy during 12 weeks produced no meaningful changes in BP or heart rate.

Patient-reported outcomes from SYNERGY, a randomized, double-blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients.

AIMS: To evaluate patient-reported outcomes (PROs) of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo in patients with overactive bladder (OAB) from the SYNERGY trial. METHODS: Following a 4-week placebo run-in, period patients (≥18 years) with OAB were randomized 2:2:1:1:1:1 to receive solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg + mirabegron 50 mg, (combination 5 + 50 mg), solifenacin 5 mg, mirabegron 25 mg, mirabegron 50 mg or placebo for 12 weeks, followed by a 2-week washout period. At each visit, PROs related to quality of life, symptom bother, and treatment satisfaction were assessed, including OAB-q Symptom Bother score, health-related quality of life (HRQOL) Total score, treatment satisfaction-visual analogue scale (TS-VAS), and patient perception of bladder condition (PPBC) questionnaires. RESULTS: Overall, 3527 patients were randomized into the study, with 3494 receiving double-blind treatment. At end of treatment (EoT), both combination groups showed greater improvements in OAB-q Symptom Bother score compared with the monotherapy groups (nominal P < 0.001). Statistically significant improvements in HRQOL Total scores were observed in the combination groups versus monotherapy groups (P ≤ 0.002). For both combination groups, the OAB-q Symptom Bother score responder rates at EoT were statistically significantly higher versus mirabegron monotherapy (P < 0.05). The mean adjusted changes from baseline to EoT for PPBC were greater in the combination groups compared with monotherapy groups. CONCLUSIONS: PROs showed that combination therapy provided clear improvements and an additive effect for many HRQOL parameters, including OAB-q Symptom Bother score, HRQOL Total score, and PPBC.

Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study).

OBJECTIVE: To evaluate the potential of solifenacin 5 mg combined with mirabegron 25 or 50 mg to deliver superior efficacy compared with monotherapy, with acceptable tolerability, in the general overactive bladder (OAB) population with urinary incontinence (UI). PATIENTS AND METHODS: After a 4-week placebo run-in, patients aged ≥18 years with wet OAB (urgency, urinary frequency and UI) for ≥3 months who recorded on average ≥8 micturitions/24 h, ≥1 urgency episode/24 h, and ≥3 UI episodes over the 7-day micturition diary, were eligible for randomisation to double-blind treatment [2:2:1:1:1:1 ratio, solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25 group); solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50 group); solifenacin 5 mg; mirabegron 25 mg; mirabegron 50 mg; or placebo for 12 weeks], and 2-weeks' single-blind, placebo run-out. Co-primary efficacy variables were change from baseline to end of treatment (EoT) in the mean number of UI episodes/24 h and micturitions/24 h, assessed using a 7-day electronic micturition diary. Secondary efficacy variables included change from baseline to EoT in the mean volume voided/micturition, change from baseline at weeks 4, 8, 12 and EoT in mean number of UI episodes/24 h, micturitions/24 h, urgency episodes/24 h, urgency UI (UUI) episodes/24 h and nocturia episodes/24 h; the percentage of patients (responders) achieving zero UI episodes/24 h at EoT in the last 7 days prior to each visit, micturition frequency normalisation (<8 episodes/24 h) at weeks 4, 8, 12 and EoT; and the number of UUI episodes and nocturia episodes in the 7-day diary. Safety assessments included incidence and frequency of treatment-emergent adverse events (TEAEs), post-void residual (PVR) urine volume, and changes from baseline in laboratory parameters. RESULTS: Whilst the combined S5 + M50 group was superior to solifenacin 5 mg for UI, with a mean (standard error) adjusted difference of -0.20 (0.12) UI episodes/24 h (95% confidence interval -0.44, 0.04, P = 0.033), there was no statistical superiority vs mirabegron 50 mg [-0.23 (0.12) UI episodes/24 h; P = 0.052]. In secondary analyses, all active treatment groups had greater improvements in UI episodes/24 h vs placebo, with effect sizes for the combined therapy groups (combined S5 + M25 group: -0.70 episodes/24 h; combined S5 + M50 group: -0.65 episodes/24 h) that were substantially higher than those obtained with monotherapy (range -0.37 episodes/24 h for mirabegron 25 mg to -0.45 episodes/24 h for solifenacin 5 mg). For micturitions/24 h, adjusted change from baseline to EoT was greater in the combined therapy groups vs monotherapies (combined S5 + M50 group, nominal P values 0.006 and <0.001 vs solifenacin 5 mg and mirabegron 50 mg, respectively; combined S5 + M25 group, nominal P values 0.040 and 0.001 vs solifenacin 5 mg and mirabegron 25 mg, respectively). All active treatment groups had greater improvements in the mean numbers of micturitions/24 h vs placebo, with effect sizes for the combined therapy groups (combined S5 + M25 group: -0.85 micturitions/24 h; combined S5 + M50 group: -0.95 micturitions/24 h) higher than with mirabegron monotherapy (25 mg: -0.36; 50 mg: -0.39 micturitions/24 h) and solifenacin 5 mg (-0.56 micturitions/24 h). The combined S5 + M50 group was statistically significantly superior to both monotherapies at EoT for UUI episodes, urgency episodes and nocturia, with effect sizes that appeared to be additive. The combined S5 + M25 group was statistically significantly superior to mirabegron 25 mg for the same variables, except for nocturia. In responder analyses at the EoT, odds ratios in favour of both combined therapies vs monotherapies were shown for the proportion of patients with zero UI episodes and those achieving micturition frequency normalisation. There was a slightly increased frequency of TEAEs in the combined therapy groups vs monotherapies and placebo. Most of the TEAEs were mild or moderate in severity. Events indicative of urinary retention were reported slightly more frequently in the combined therapy groups vs monotherapy and placebo. PVR volume was slightly increased in the combined therapy groups vs solifenacin 5 mg, mirabegron monotherapy, and placebo groups. There were slightly higher frequencies of dry mouth, constipation, and dyspepsia in the combined therapy groups vs monotherapies. There were no concerns regarding electrocardiograms and laboratory data. CONCLUSION: In the largest OAB study to date, combined therapy with solifenacin 5 mg + mirabegron 25 mg and solifenacin 5 mg + mirabegron 50 mg provided consistent improvements in efficacy compared with the respective monotherapies across most of the outcome parameters, with effect sizes generally consistent with an additive effect. Although the combined S5 + M50 group did not achieve a statistically significant effect vs mirabegron 50 mg in the primary analysis of one of the co-primary endpoints (change from baseline in mean number of UI episodes/24 h), it approached statistical significance (P = 0.052), and the nominal P values for the other co-primary endpoint (micturitions/24 h) were <0.05. Most effects of combined therapy vs monotherapy were observable by week 4. The clinical relevance of the improvements seen with combined therapy for several objective OAB outcome measures was also supported by the improvements of combined therapy vs monotherapy in the responder analyses.

Cardiovascular safety in refractory incontinent patients with overactive bladder receiving add-on mirabegron therapy to solifenacin (BESIDE).

AIMS/OBJECTIVES: In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and ß3 -adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation. METHODS: OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV-related treatment-emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters. RESULTS: The frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], -0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (-0.93 mm Hg [0.38], -0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (-1.28 mm Hg [0.38], -0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds). CONCLUSION: The comparable frequency of CV-related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined.