Zalmai Hakimi

Persistence and Adherence with Mirabegron versus Antimuscarinic Agents in Patients with Overactive Bladder: A Retrospective Observational Study in UK Clinical Practice

BACKGROUNDnPersistence with antimuscarinic therapy in overactive bladder (OAB) is poor, but may be different for mirabegron, a β3-adrenoceptor agonist with a different adverse event profile.nnnOBJECTIVEnTo compare persistence and adherence with mirabegron versus tolterodine extended release (ER) and other antimuscarinics in routine clinical practice over a 12-mo period.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective, longitudinal, observational study of anonymised data from the UK Clinical Practice Research Datalink GOLD database. Eligibility: age ≥18 yr, ≥1 prescription for target OAB drug (between May 1, 2013 and June 29, 2014), and 12-mo continuous enrolment before and after the index prescription date.nnnINTERVENTIONSnMirabegron, darifenacin, fesoterodine, flavoxate, oxybutynin ER or immediate-release (IR), propiverine, solifenacin, tolterodine ER or IR, and trospium chloride.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe primary endpoint was persistence (time to discontinuation). Secondary endpoints included 12-mo persistence rates and adherence (assessed using medication possession ratio, MPR). Cox proportional-hazards regression models and logistic regression models adjusted for potential confounding factors were used to compare cohorts. Analyses were repeated after 1:1 matching.nnnRESULTS AND LIMITATIONSnThe study population included 21996 eligible patients. In the unmatched analysis, the median time-to-discontinuation was significantly longer for mirabegron (169 d, interquartile range [IQR] 41-not reached) compared to tolterodine ER (56 d, IQR 28-254; adjusted hazard ratio [HR] 1.55, 95% confidence interval 1.41-1.71; p<0.0001) and other antimuscarinics (range 30-78 d; adjusted HR range 1.24-2.26, p<0.0001 for all comparisons). The 12-mo persistence rates and MPR were also significantly greater with mirabegron than with all the antimuscarinics. Limitations include the retrospective design, use of prescription records to estimate outcomes, and inability to capture reasons for discontinuation.nnnCONCLUSIONSnPersistence and adherence were statistically significantly greater with mirabegron than with tolterodine ER and other antimuscarinics prescribed for OAB in the UK.nnnPATIENT SUMMARYnThis study assessed persistence and adherence (or compliance) with medications prescribed for OAB in a large UK population. We found that patients prescribed mirabegron remained on treatment for longer and showed greater adherence than those prescribed traditional antimuscarinics.

Mirabegron as Add-On Treatment to Solifenacin in Patients with Incontinent Overactive Bladder and an Inadequate Response to Solifenacin Monotherapy.

PURPOSEnWe investigated improvements in overactive bladder and patient reported outcomes in patients with overactive bladder and refractory incontinence treated with mirabegron 50 mg plus solifenacin 5 mg vs solifenacin 5 or 10xa0mg.nnnMATERIALS AND METHODSnPatients with overactive bladder who were incontinent despite 4 weeks of single-blind daily solifenacin 5 mg were randomized 1:1:1 to a double-blind daily combination of mirabegron 50 mg/solifenacin 5 mg, or solifenacin 5 or 10 mg for 12 weeks. The mirabegron dose was increased from 25 to 50 mg after week 4. Symptom bother, health related quality of life and patient perception of bladder condition were assessed by OAB-q (Overactive Bladder Questionnaire) and the PPBC (Patient Perception of Bladder Condition) questionnaire, respectively. Responder rates were based on a 50% reduction in daily incontinence, zero incontinence episodes and fewer than 8xa0micturitions per 24xa0hours with minimal important differences in OAB-q and PPBC.nnnRESULTSnOverall 2,174 patients with a median age of 59 years were randomized, including 727 to the combination, 728 to solifenacin 5 mg and 719 to solifenacin 10 mg. Symptom bother, total health related quality of life and its subscales (coping, concern and social), and PPBC were significantly improved with combination vs solifenacin monotherapy (p <0.05). The odds of achieving clinically meaningful improvements in incontinence, micturition frequency, symptom bother, health related quality of life and PPBC were significantly higher for combination than solifenacin monotherapy. The odds of becoming continent was 47% and 28% higher for combination vs solifenacin 5 andxa010 mg (OR 1.47, 95% CI 1.17-1.84, pxa0= 0.001 and OR 1.28; 95% CI 1.02-1.61, p = 0.033, respectively).nnnCONCLUSIONSnSignificantly more patients on the combination achieved clinically meaningful improvements inxa0incontinence and micturition frequency. Improvements were accompanied by similar improvements in PPBC, symptom bother and health related quality of life.

Total urgency and frequency score as a measure of urgency and frequency in overactive bladder and storage lower urinary tract symptoms.

The term lower urinary tract symptoms (LUTS) encompasses a range of urinary symptoms, including storage symptoms (e.g. overactive bladder [OAB]) as well as voiding and post‐micturition symptoms. Although treatment of male LUTS tends to focus on voiding symptoms, patients typically find storage symptoms the most bothersome. The core storage symptom is urgency, which drives the other main storage symptoms of increased daytime frequency, nocturia and incontinence. Although several validated questionnaires have been widely used to study urgency, few measure the two important storage parameters, urgency and frequency, in a single assessment. The total urgency and frequency score (TUFS) is a new validated tool that captures both variables and is derived from the Patient Perception of Intensity of Urgency Scale, which has been validated in patients with OAB and LUTS. The TUFS was first validated in OAB in the phase IIa BLOSSOM study, which was designed to assess the efficacy and safety of mirabegron, a β3‐adrenoceptor agonist, in 260 patients. The responsiveness of the TUFS to treatment has been confirmed in a further three large‐scale randomized controlled trials of solifenacin in patients with OAB or LUTS. Changes in TUFS from baseline to end of treatment were consistent with changes in micturition diary variables in all four studies. Furthermore, the TUFS was significantly correlated with several health‐related quality‐of‐life variables in the phase III NEPTUNE study. Thus, the TUFS appears to be useful for assessing improvements in major storage symptoms (urgency and frequency) in clinical trials.

Qualitative Exploration of the Patient Experience of Underactive Bladder

BACKGROUNDnUnderactive bladder (UAB) is considered the symptom complex associated with the urodynamic diagnosis of detrusor underactivity.nnnOBJECTIVEnThe aim of this research was to investigate the patient reported experience of the symptoms, signs, and impact of UAB. This research is also part of the initial qualitative phase for the development of a new patient reported outcome measure for the assessment of UAB.nnnDESIGN, SETTING, AND PARTICIPANTSnQualitative methods were used to understand the experience of UAB from a patient perspective, in a purposive sample of male (n=29) and female (n=15) patients aged 27-88 yr (mean: 64 yr), diagnosed with a primary diagnosis of detrusor underactivity, with or without coexisting urological conditions. Semistructured interviews were conducted in Bristol, UK.nnnRESULTSnMale and female patients reported a variety of lower urinary tract symptoms and associated impact on quality of life. Storage symptoms of nocturia, increased daytime frequency, and urgency, and the voiding symptoms of slow stream, hesitancy, and straining were reported by over half of the patients. A sensation of incomplete emptying and postmicturition dribble were also frequently described. Most had a post void residual >30ml (n=34, 77%, median: 199ml) with many reporting urinary tract infections, a history of self-catheterisation, and some experiencing occasional acute retention episodes. These symptoms and signs can have a broad impact on quality of life including having to plan their daily activities around the location of toilets, disruption to sleep, social life, and associated effect on family and friends.nnnCONCLUSIONSnKnowledge of the lived experience of UAB obtained in the current study will be used for the development of a new patient reported outcome measure and help inform the current working definition of UAB.nnnPATIENT SUMMARYnThe symptoms, signs, and impact on quality of life of underactive bladder are described by patients with the condition.

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

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.

Responder and health-related quality of life analyses in men with lower urinary tract symptoms treated with a fixed-dose combination of solifenacin and tamsulosin oral- controlled absorption system: results from the NEPTUNE study

To evaluate the effect of a fixed‐dose combination (FDC) of solifenacin and an oral‐controlled absorption system (OCAS™) formulation of tamsulosin (TOCAS) on health‐related quality of life (HRQoL) in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH).

Efficacy and Tolerability of Mirabegron Compared with Antimuscarinic Monotherapy or Combination Therapies for Overactive Bladder: A Systematic Review and Network Meta-analysis

BACKGROUNDnMirabegron is an established treatment alternative to antimuscarinic therapy for patients with overactive bladder (OAB), as shown by efficacy and tolerability data from phase III trials.nnnOBJECTIVEnTo assess efficacy and tolerability of mirabegron 50mg versus antimuscarinic monotherapies and combination therapies.nnnDESIGN, SETTING, AND PARTICIPANTSnSystematic literature review and network meta-analysis of randomised controlled trials (2000-2017) assessing eligible treatments for OAB.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnEfficacy assessments included micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence. Tolerability assessments included dry mouth, constipation, blurred vision, and hypertension.nnnRESULTS AND LIMITATIONSnA total of 64 studies (n=46 666) were included in the network meta-analysis. Mirabegron 50mg was significantly more efficacious than placebo for all efficacy endpoints. Comparable overall efficacy was observed for mirabegron 50mg versus most active treatments, but solifenacin 10mg monotherapy and solifenacin 5mg plus mirabegron 25 or 50mg in combination were more efficacious for some/all outcomes. Mirabegron 50mg was significantly better tolerated regarding dry mouth, constipation, and urinary retention than 21/22, 9/20, and 7/10 active comparators, respectively; similar overall tolerability was observed between mirabegron 50mg and all treatments (including placebo) for the remaining endpoints. Limitations of the study included between-trial variations in the definition of certain endpoints and heterogeneity of the available data (eg, number of studies and patients assessed) for comparator treatments across different endpoints.nnnCONCLUSIONSnThe relief of key OAB symptoms produced by mirabegron 50mg is significantly better than placebo, and similar to a range of common antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects such as dry mouth. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg appears to provide an efficacy benefit compared with mirabegron 50mg, with the expected side effects of individual antimuscarinics.nnnPATIENT SUMMARYnThis study assessed the efficacy and tolerability of different drug treatments for OAB. Mirabegron 50mg was as effective as antimuscarinic therapy, with fewer common, bothersome side effects such as dry mouth, constipation, and urinary retention. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg was more effective than mirabegron 50mg alone, but with more anticholinergic side effects.

Economic Impact of Mirabegron Versus Antimuscarinics for the Treatment of Overactive Bladder in the UK

PurposeOur objective was to estimate the economic outcomes of using mirabegron versus antimuscarinics in the treatment of patients with overactive bladder (OAB) from a societal perspective in the UK.Materials and MethodsA Markov model was developed using Microsoft Excel®. The time horizon and cycle length are 12 and 1 months, respectively; and the hypothetical cohort size 100 patients. Antimuscarinic comparators are fesoterodine, oxybutynin extended release (ER) and immediate release (IR), solifenacin, tolterodine ER/IR, trospium ER/IR, darifenacin and flavoxate. Model inputs included real-world treatment patterns data, healthcare resource use (e.g. clinic visits) and direct and indirect costs (e.g. drug acquisition and productivity loss). Model outputs included patient disposition, healthcare resource use, drug acquisition costs and other treatment-related costs over a 1-year time horizon. A one-way sensitivity analysis was performed to determine the key drivers of the model.ResultsIn a hypothetical cohort of 100 patients, total annual costs per patient were lower with mirabegron than with all antimuscarinics (£1270.84 vs. 1321.71–1607.48). Healthcare resource use was lower with mirabegron than with all antimuscarinics (115 vs. 119–123 general practitioner visits; 173 vs. 178–185 specialist visits and 0.0042 vs. 0.0050–0.0060 surgical operations) and fewer work hours were lost (4017 vs. 5114–6990 [all per 100 patients]). Sensitivity analysis showed the model was sensitive to persistence and switching rates, although the impact on the overall results was minimal.ConclusionsIn the UK, using mirabegron to treat OAB may improve persistence and lead to reductions in switching treatment, healthcare resource utilization, productivity costs, and overall treatment costs versus antimuscarinics.

Mirabegron as Add-on Treatment to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Solifenacin Monotherapy: Responder Analyses and Patient-Reported Outcomes from the BESIDE study

PURPOSEnWe investigated improvements in overactive bladder and patient reported outcomes in patients with overactive bladder and refractory incontinence treated with mirabegron 50 mg plus solifenacin 5 mg vs solifenacin 5 or 10xa0mg.nnnMATERIALS AND METHODSnPatients with overactive bladder who were incontinent despite 4 weeks of single-blind daily solifenacin 5 mg were randomized 1:1:1 to a double-blind daily combination of mirabegron 50 mg/solifenacin 5 mg, or solifenacin 5 or 10 mg for 12 weeks. The mirabegron dose was increased from 25 to 50 mg after week 4. Symptom bother, health related quality of life and patient perception of bladder condition were assessed by OAB-q (Overactive Bladder Questionnaire) and the PPBC (Patient Perception of Bladder Condition) questionnaire, respectively. Responder rates were based on a 50% reduction in daily incontinence, zero incontinence episodes and fewer than 8xa0micturitions per 24xa0hours with minimal important differences in OAB-q and PPBC.nnnRESULTSnOverall 2,174 patients with a median age of 59 years were randomized, including 727 to the combination, 728 to solifenacin 5 mg and 719 to solifenacin 10 mg. Symptom bother, total health related quality of life and its subscales (coping, concern and social), and PPBC were significantly improved with combination vs solifenacin monotherapy (p <0.05). The odds of achieving clinically meaningful improvements in incontinence, micturition frequency, symptom bother, health related quality of life and PPBC were significantly higher for combination than solifenacin monotherapy. The odds of becoming continent was 47% and 28% higher for combination vs solifenacin 5 andxa010 mg (OR 1.47, 95% CI 1.17-1.84, pxa0= 0.001 and OR 1.28; 95% CI 1.02-1.61, p = 0.033, respectively).nnnCONCLUSIONSnSignificantly more patients on the combination achieved clinically meaningful improvements inxa0incontinence and micturition frequency. Improvements were accompanied by similar improvements in PPBC, symptom bother and health related quality of life.

Patient and physician preferences for oral pharmacotherapy for overactive bladder: two discrete choice experiments.

Abstract Objective We examined patient and treating physician (general practitioners, urologists, and [uro]gynecologists) preferences for oral pharmacotherapy (antimuscarinics and beta-3 adrenoceptor agonists) for overactive bladder to gain a deeper understanding of which attributes drive their treatment decision-making and to quantify to what extent. Research design and methods Two separate discrete choice experiments were developed and validated using the input of patients and physicians. The patient experiment contained the following attributes: micturition frequency, incontinence, nocturia, urgency, dry mouth, constipation, increased heart rate, and increased blood pressure. The physician experiment contained two additional attributes: coping and atrial fibrillation. Both were fielded in five European countries. To allow for preference heterogeneity, utility functions were estimated using a mixed multinomial logit model. Results A total of 442 patient and 318 physician responses were analyzed. Patients ranked the attributes based on their largest potential impact on treatment value as follows: incontinence, nocturia, risk of an increased heart rate, urgency, frequency, risk of increased blood pressure, risk of constipation, and risk of dry mouth; and physicians as follows: incontinence, urgency, nocturia, frequency, risk of dry mouth, coping, risk of increased heart rate, risk of increased blood pressure, risk of atrial fibrillation, and risk of constipation. Conclusion and limitations In their valuations, physicians put more emphasis on increasing benefits, whereas patients put more emphasis on limiting risks of side effects. Another contrast that emerged was that patients’ valuations of side effects were found to be fairly insensitive to the presented risk levels (with the exception of risk of dry mouth), whereas physicians’ evaluated all side effects in a risk-level dependent manner. The obtained utility functions can be used to predict whether, to what extent, and for which reasons patients and physicians would choose one oral pharmacotherapy over another, as well as to advance shared decision-making.