Efficacy and Adverse Events of Antimuscarinics for Treating Overactive Bladder: Network Meta-analyses

Transcription

1 EUROPEAN UROLOGY 62 (2012) available at journal homepage: Platinum Priority Review Neuro-urology Editorial by Jean-Nicolas Cornu on pp of this issue Efficacy and Adverse Events of Antimuscarinics for Treating Overactive Bladder: Network Meta-analyses Nora Buser a,y, Sandra Ivic b,y, Thomas M. Kessler c, Alfons G.H. Kessels d,z, Lucas M. Bachmann b, * a Horten Center, University of Zurich, Switzerland; b Medignition Inc., Research Consultants, Zug, Switzerland; c Neuro-Urology, Spinal Cord Injury Centre, Balgrist University Hospital, Zürich, Switzerland; d Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, The Netherlands Article info Article history: Accepted August 28, 2012 Published online ahead of print on September 6, 2012 Keywords: Overactive bladder Antimuscarinics Efficacy Adverse events Abstract Context: Millions of people worldwide experience overactive bladder (OAB), and antimuscarinics are the pharmacologic treatment of choice. Several conventional metaanalyses have been published, but they fail to quantify efficacy and adverse events across drugs, dosages, formulations, and pharmaceutical forms. Objective: To perform two network meta-analyses summarizing the efficacy and adverse events of antimuscarinics in the treatment of OAB. Evidence acquisition: Medline and Scopus searches, previous systematic reviews, conference abstracts, book chapters, and the reference lists of relevant articles were searched. Trialists were contacted. Eligible studies were randomized trials that compared at least one antimuscarinic for treating OAB with placebo or with another antimuscarinic, and that reported efficacy and/or adverse event outcomes. Efficacy was assessed for six outcomes (perception of cure or improvement, urgency episodes per 24 h, leakage episodes per 24 h, urgency incontinence episodes per 24 h, micturitions per 24 h, and nocturia episodes per 24 h). Adverse events were assessed in seven categories according to the Common Terminology Criteria for Adverse Events. Across all outcomes, a summary efficacy and an adverse event score were computed. Two authors independently extracted data. Evidence synthesis: For the comparison of the efficacy, 76 trials enrolling patients were included; for adverse events, 90 trials enrolling patients were included. In the subset of studies reporting on treatments and dosages as used in clinical practice, 40 /d trospium chloride, 100 /g per day oxybutynin topical gel, and 4 /d fesoterodine had the best efficacy, while higher dosages of orally administered oxybutynin and propiverine had the least favorable relationship of efficacy and adverse events. Conclusions: This is the first study allowing trade-offs between efficacy and adverse events of various drugs and dosages in the treatment of patients with OAB. Differences among the various antimuscarinics call for careful, patient-centered management in which regimen changes should be considered. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. y These authors contributed equally. z Responsible statistician. * Corresponding author. Medignition Inc., Poststrasse 15, 6300 Zug, Switzerland. Tel ; Fax: address: bachmann@medignition.ch (L.M. Bachmann) /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 EUROPEAN UROLOGY 62 (2012) Introduction Overactive bladder (OAB) is a widespread chronic illness that affects the lives of millions of people worldwide at all ages but is more common in the elderly, with a prevalence of up to 31% in women and 42% in men >75 yr [1]. OAB has a major impact on quality of life; it affects emotional, social, sexual, occupational, and physical aspects of daily life [2 4] and is associated with a greater risk of falls and injuries, including fractures [5], which may even lead to death. Besides the debilitating manifestations for patients, OAB also imposes a substantial economic burden, as direct annual costs are comparable to those of other chronic diseases such as dementia and diabetes mellitus [6]. Among several nonsurgical interventions, antimuscarinics are the pharmacologic treatment of choice for OAB. Various conventional systematic reviews [7 14] have assessed the efficacy of eight currently available antimuscarinics (darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride). However, despite applying up-to-date systematic review methods, these conventional meta-analyses fell short in quantifying and comparing the efficacy and adverse events across different drugs, dosages, formulations, and routes of administration, because these summaries did not use all available information on reported comparisons. This shortfall is a major impediment when examining the tradeoffs in a decision-analytic context. Recently, new meta-analytic methods network metaanalysis have become available that allow complete assessments across different drugs [15 19]. Because the selection of a specific drug should be based on a careful assessment of its efficacy and related adverse events, a complete examination and careful benchmarking of all available drugs, formulations, and dosages is the first step in rational decision-analytic reasoning. However, for the efficacy assessment, such an analysis is not available yet. Until recently, such an analysis was also lacking for adverse events. In 2011, Kessler and colleagues published the first network meta-analysis summarizing the most common adverse events of various antimuscarinics, dosages, and formulations [20]. The authors concluded that based on adverse events, most currently used antimuscarinics would qualify for the initial treatment of OAB. Since publication of that paper, various new study reports have been published. A new drug formulation [21] and a new OAB drug [22] also have become available. In this paper, we describe a network meta-analysis summarizing data from all randomized comparative clinical trials assessing the efficacy of all currently used antimuscarinics for the most salient and commonly reported outcomes, and we present the results of an update of the existing network analysis on adverse events of Kessler et al. [20]. We provide efficacy and adverse events charts for all assessed medications and dosages, allowing straightforward benchmarking of antimuscarinics for treating OAB in clinical practice. 2. Evidence acquisition The systematic reviews were done according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement [23] Search strategy Efficacy data To identify randomized controlled trials of antimuscarinics compared with placebo and head-to-head comparative trials without a placebo arm, we started with the recent Cochrane Review by Nabi et al. [13] and three recent metaanalyses by Chapple et al. [7], Novara et al. [14], and Madhuvrata et al. [12]. Secondarily, an update search from June 2005 until April 2012 was done. The Medline search employed a search algorithm, including combinations of the two MeSH terms urinary bladder, overactive and muscarinic antagonists, as well as various associated free text terms. Searches were repeated in Scopus, entering the same search terms. In addition, other relevant studies cited in the reference lists of the selected papers were considered. We also searched reference lists and conference abstracts by hand, checked relevant reviews and book chapters, and contacted manufacturers and trialists. Searches were limited to published randomized controlled trials. The search was conducted without restriction on language. The search strategies are available on request. To be included, studies had to be randomized controlled trials comparing at least one antimuscarinic for treating OAB with placebo or with another antimuscarinic. Crossover trials and studies that were described only in an abstract were not included Adverse events data A literature search update from January 2008 to April 2012 was done to identify randomized controlled clinical studies of antimuscarinics compared with placebo or head-to-head comparisons. Electronic searches were performed in Medline using combinations of the MeSH terms muscarinic antagonists, urinary bladder, and overactive, as well as associated free text terms. Scopus was searched using the key words antimuscarinic* AND overactive AND bladder. In addition, we searched reference lists and conference abstracts by hand, checked relevant reviews and book chapters, and contacted manufacturers and trialists. The search strategy is available in the Appendix Selection criteria All currently used antimuscarinics were considered. Trials with intravesical antimuscarinic administration, drugs with less direct antimuscarinic effects (such as smooth muscle relaxants, flavoxate hydrochloride, calcium channel blockers, potassium channel openers, b-adrenoceptor agonists, a-adrenoceptor antagonists, prostaglandin synthetase inhibitors, and tricyclic antidepressants), and drugs no longer used in clinical practice were excluded. In the case of multiple publications on the same patients, the most complete report was chosen for each trial. We extracted

3 1042 EUROPEAN UROLOGY 62 (2012) data in duplicate (N.B., S.I.), and a third reviewer (L.M.B.) resolved any discrepancies if the other two reviewers disagreed. We contacted authors of eligible trials that reported insufficient data and asked them for additional information. Dichotomous data were abstracted into 2 2 tables. For continuous data, summary estimates per group (means, changes in means) with measures of variability (standard deviation [SD], 95% confidence interval [CI]), as available, were extracted. The efficacy network meta-analysis was limited to six outcome measures (perception of cure or improvement, urgency episodes per 24 h, leakage episodes per 24 h, urgency incontinence episodes per 24 h, micturitions per 24 h, and nocturia episodes per 24 h), as only these measures provided enough information to perform the network meta-analysis. Within these outcomes, we summarized different formulations and routes of administration. Antimuscarinics were categorized, based on the daily dose used, into the following groups: 4, 8, or 12 /d fesoterodine; 0.2 /d imidafenacin; 2.5, 5, 7.5, 9, 10, 15, or 20 /d oxybutynin immediate release (IR); 5, 10, 15, 20, or 30 /d oxybutynin extended release (ER); 1.3, 2.6, or 3.9 /d oxybutynin transdermal system (TDS); 100 /g per day oxybutynin topical gel; 20, 30, or 45 /d propiverine IR; 30 /d propiverine ER; 2.5, 5, 10, or 20 /d solifenacin; 1, 2, 4, or 8 /d tolterodine IR; 4 /d tolterodine ER; or 40, 60, or 90 /d trospium chloride. For the adverse events network meta-analysis, we applied the same method described previously [20]. Adverse events were classified according to the Common Terminology Criteria for Adverse Events v.3.0 [24] into seven categories (gastrointestinal, ocular/visual, urinary tract related, neurologic, cardiac, respiratory tract related, and dermatologic adverse events) and then graded using a visual analogue scale (0 = minimum severity and 10 = maximum severity) based on the consensus of experts [20]. Summarizing different formulations and routes of administration, antimuscarinics were categorized based on the daily dose used into the following groups: 3.75, 7.5, 15, or 30 /d darifenacin; 4, 8, or 12 /d fesoterodine; 0.2 /d imidafenacin; 5, 7.5, 9, 10, 15, or 20 /d oxybutynin; 1.3, 2.6, or 3.9 /d oxybutynin TDS; 100 /g per day oxybutynin topical gel; 20, 30, or 45 /d propiverine; 2.5, 5, 10, or 20 /d solifenacin; 1, 2, 4, or 8 /d tolterodine; or 40 or 60 /d trospium chloride (a dosage of 45 /d was considered 40 /d) Statistical analysis Efficacy analysis Whenever possible, we used results from intention-to-treat analysis. For continuous outcomes, we imputed missing SDs of mean changes for each treatment using the largest SD reported in the set of included studies for this outcome. This procedure was necessary in 32 cases. For each participant, we simulated the outcome by sampling from a normal distribution with the mean and SD of the outcome in a specific treatment arm as described in the study report. Because of chance, the mean and SD parameters could be different from the original values. These differences were corrected by a simple linear transformation. For all the treatment arms, such a data set was generated that led to the same likelihood function as that from the original data. To that new data set, a linear regression model was fitted. Drug and dosage, creating a unique code for each treatment, were entered as covariates. To preserve randomization within each trial, we included an indicator variate for each study. This variate adjusted for all differences in risk profiles and study setup among trials. In a second analysis, only treatments applied in standard clinical practice were considered (ie, 7.5 and 15 /d darifenacin; 4 and 8 /d fesoterodine; 0.2 /d imidafenacin; 10, 15, and 20 /d oxybutynin; 3.9 /d oxybutynin TDS; 100 /g per day oxybutynin topical gel; 30 and 45 /d propiverine; 5 and 10 /d solifenacin; 4 /d tolterodine; and 40 and 60 /d trospium chloride). For dichotomous outcomes, a logistic regression analysis was performed with drug and dosage as covariates (creating a unique code for each treatment) and applying a similar concept as Berlin et al. [15] and Hasselblad [16]. The event outcome for each single treatment arm was used as the dependent variable. To preserve randomization within each trial, we again also included an indicator variate for each study. From this regression model, we estimated the odds ratio and 95% CIs between placebo and all other treatment options Adverse events analysis We applied the method of adverse events analysis described before [20]: For each of the seven adverse event categories and each of the treatment arms, the number of adverse events was weighted according to the expert consensus, added up, and then divided by the total number of patients in the corresponding treatment arm. Thus, the weighted adverse events per patient in each of the trials given a specific treatment and dosage were determined. The total score of adverse events was calculated by adding up these estimates of the seven adverse event categories. For the sum of adverse event outcomes, a linear regression analysis was performed with drug and dosage as covariates [15,16]. The analysis was weighted with the total number of patients in each treatment arm as a substitute for the inverse of the variance. Again, the analysis was repeated for the subset of treatments as used in clinical practice Trade-off analysis We interviewed five experts of neurologic urology and asked them to rank order the assessed outcomes according to clinical relevance and found a consensus. The relevance was ranked as follows: (1) urgency episodes per 24 h (most important), (2) urgency incontinence episodes per 24 h, (3) leakage episodes per 24 h, (4) micturitions per 24 h, (5) perception of cure or improvement, and (6) nocturia episodes per 24 h (least important). In other words, the weight for urgency episodes per 24 h would be 1, the weight for urgency incontinence episodes per 24 h would

4 Table 1 Characteristics of trials assessing efficacy of antimuscarinics included in the network meta-analysis First author Year Patients, no. Females, % Age, yr, mean Treatment duration, wk Placebo Darifenacin, Fesoterodine, Oxybutynin, Propiverine, Solifenacin, Tolterodine, Trospium chloride, Imidafenacin, Abrams IR 5 3 IR 2 2 Anderson ER 5, 10,15, 20, 25, 30 1 ;IR5 1 4 Appell ER 10 1 IR 2 2 Barkin ER 15 1,IR5 3 Birns ER 10 1,IR5 2 Burgio IR 2.5, 5 3 Cardozo IR 20 2 Cardozo , 10 1 Cardozo , 10 1 Cartwright TDS Chapple , 8 1 ER 4 1 Chapple , 10 1 ER 4 1 Chapple ER 7.5, 15 1 Chapple (a) , 5, 10, 20 1 IR 2 2 Chapple (b) , 10 1 IR 2 2 Choo , 10 1 IR 2 2 Chu Corcos ER 5, 10, 15 1 Diokno ER 10 1 ER 4 1 Dmochowski TDS ER 4 1 Dmochowski TDS 1.3, 2.6, 3.9 Dmochowski ER 60 1 Dmochowski , 8 1 Dorschner IR 15 3 Dorschner IR 15 3 Drutz IR 5 3 IR 2 2 Frenkl ER 4 1 Goode IR Haab ER 3.75, 7.5, 15 1 Halaska IR 5 2 IR 20 2 Herschorn ER 4 1 Herschorn , 8 1 ER 4 1 Hill ER 7.5, 15, 30 1 Homma IR 3 3 ER 4 1 Homma IR Jacquetin IR 1, 2 2 Jonas IR 1, 23 Jünemann IR 15 2 IR 2 2 Jünemann IR 15 2, ER 30 1 Kaplan ER 4 1 Kaplan , 8 1 ER 4 1 Karram Khullar ER 4 1 Lee IR 5 2 IR 2 2 EUROPEAN UROLOGY 62 (2012)

5 Table 1 (Continued ) First author Year Patients, no. Females, % Age, yr, mean Treatment duration, wk Placebo Darifenacin, Fesoterodine, Oxybutynin, Propiverine, Solifenacin, Tolterodine, Trospium chloride, Imidafenacin, 1044 Lee IR 20 1 Leung IR 5 2 IR 2 2 Madersbacher IR 2, 5 2 IR 15 3 Malone-Lee IR 1, 2 2 Malone-Lee IR 2.5, 5 2 IR 2 2 Malone-Lee ER 4 1 Millard IR 1, 2 2 Nitti , 8 1 Nitti , 8, 12 1 Rackley ER 4 1 Rentzhog IR 0.5, 1, 2, 4 2 Robinson NA 6 + ER 4 1 Rogers ER 4 1 Rudy IR 20 2 Staskin ER 60 1 Staskin Topical gel 1 Steers ER Stöhrer IR 15 3 Stöhrer IR 5 3 IR 15 3 Swift ER 4 1,IR2 2 Szonyi IR Van Kerrebroeck IR 0.5, 1, 2, 4 2 Van Kerrebroeck ER 4 1,IR2 2 Vardy , 10 1 Versi ER/IR 5, 10, 15, 20 1 Wang NA Yamaguchi IR , 10 1 Za tura IR 5 3 Zellner IR 2.5, 5 3 IR 15, 30 3 Zinner ER 4 1 Zinner IR 20 2 Zinner ER 15 1 EUROPEAN UROLOGY 62 (2012) IR = immediate release; ER = extended release; TDS = transdermal system; NA = not available. 1 Once daily. 2 Twice daily. 3 Three times daily. 4 Four times daily.

6 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 62 (2012) (a) Included Eligibility Screening Iden fica on Records iden fied through database searching (n = 731) Records a er duplicates removed (n = 828) Records screened (n = 828) Full-text ar cles assessed for eligibility (n = 262) Studies included in quan ta ve synthesis (n = 76) Addi onal records iden fied through other sources (n = 111) Records excluded (n = 566) Full-text ar cles excluded, with reasons (n = 186) (b) Included Eligibility Screening Iden fica on Records iden fied through database searching (n = 492) Records a er duplicates removed (n = 541) Records screened (n = 541) Full-text ar cles assessed for eligibility (n = 130) Studies included in quan ta ve synthesis (n = 21)* Addi onal records iden fied through other sources (n = 49) Records excluded (n = 411) Full-text ar cles excluded, with reasons (n = 109) Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-analysis (a) flow diagram of efficacy studies and (b) flow diagram of adverse events studies. For analysis we included 69 studies from the previous study, resulting in a total number of 90 trials. * = from update.

7 1046 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 62 (2012) Treatment, Fesoterodine 12 Solifenacin 20 Oxybutynin IR 7.5 Solifenacin 10 Oxybutynin IR 15 Propiverine IR 45 Oxybutynin IR 10 Trospium chloride 90 Fesoterodine 8 Trospium chloride 40 Solifenacin 5 Propiverine IR 20 Tolterodine IR 8 Tolterodine ER 4 Trospium chloride 60 Tolterodine IR 4 Oxybutynintopical gel Tolterodine IR 2 Fesoterodine 4 Propiverine IR 30 Oxybutynin TDS 3.9 Propiverine ER 30 Imidafenacin 0.2 Oxybutynin ER 15 Solifenacin 2.5 Oxybutynin ER 5 Tolterodine IR 1 Oxybutynin ER 10 Oxybutynin TDS 1.3 Oxybutynin TDS 2.6 Oxybutynin IR ( 3.15 to 0.03); p = ( 3.24 to 0.13); p = ( 4.06 to 1.26); p = ( 1.32 to 0.87); p < ( 1.78 to 0.31); p = ( 1.82 to 0.28); p = ( 1.60 to 0.40); p = ( 1.78 to 0.05); p = ( 1.15 to 0.66); p < ( 1.34 to 0.38); p < ( 1.20 to 0.51); p < ( 1.26 to 0.39); p < ( 2.83 to 1.17); p = ( 0.94 to 0.58); p < ( 1.29 to 0.24); p = ( 1.05 to 0.46); p < ( 1.33 to 0.07); p = ( 1.45 to 0.08); p = ( 1.09 to 0.19); p = ( 1.24 to 0.11); p = ( 1.24 to 0.12); p = ( 1.27 to 0.22); p = ( 1.22 to 0.20); p = ( 1.71 to 0.69); p = ( 1.84 to 1.33); p = ( 1.66 to 1.20); p = ( 2.07 to 1.75); p = ( 0.69 to 0.39); p = ( 1.09 to 0.93); p = ( 1.09 to 0.92); p = ( 0.28 to 3.88); p = Reduction in micturition per 24 h compared with placebo Mean. 95% confidence interval. Fig. 2 Reductions of micturitions per 24 h compared with placebo (red line), including patients. IR = immediate release; ER = extended release; TDS = transdermal system. be 0.5 (1/2), and so on. For each outcome and per treatment, the efficacy was standardized with the mean of all reported outcomes. Treatments without efficacy data for an outcome [(Fig._3)TD$FIG] were set at 1. Each of the standardized efficacy parameters was multiplied by the inverse of the relevance ranking and summarized per treatment, thus generating an efficacy Treatment, Solifenacin 10 Oxybutynin ER 10 Propiverine ER 30 Solifenacin 5 Propiverine IR 45 Oxybutynin IR 15 Oxybutynin TDS 3.9 Solifenacin 2.5 Propiverine IR 30 Propiverine IR 20 Trospium chloride 40 Solifenacin 20 Tolterodine ER 4 Tolterodine IR 8 Tolterodine IR 4 Oxybutynin ER 15 Oxybutynin ER 30 Tolterodine IR 2 Oxybutynin TDS 1.3 Oxybutynin IR 20 Oxybutynin TDS 2.6 Tolterodine IR 1 Oxybutynin IR ( 0.90 to 0.51); p < ( 1.10 to 0.30); p = ( 1.20 to 0.17); p = ( 0.98 to 0.36); p < ( 1.34 to 0.15); p = ( 1.01 to 0.02); p = ( 0.97 to 0.06); p = ( 1.56 to 0.65); p = ( 0.90 to 0.04); p = ( 0.84 to 0.03); p = ( 0.94 to 0.14); p = ( 1.55 to 0.80); p = ( 0.55 to 0.17); p < ( 1.65 to 1.15); p = ( 0.34 to 0.08); p = ( 1.44 to 1.31); p = ( 1.52 to 1.38); p = ( 0.72 to 0.63); p = ( 0.75 to 0.67); p = ( 0.77 to 0.86); p = ( 0.49 to 0.92); p = ( 1.04 to 1.64); p = ( 0.65 to 2.00); p = Reduction in leakage episodes per 24 h compared with placebo Mean. 95% confidence interval. Fig. 3 Reductions of leakage episodes per 24 h compared with placebo (red line), assessed in patients. IR = immediate release; ER = extended release; TDS = transdermal system.

8 [(Fig._4)TD$FIG] EUROPEAN UROLOGY 62 (2012) Treatment, Oxybutynin IR 7.5 Trospium chloride 40 Propiverine IR 45 Fesoterodine 8 Solifenacin 10 Solifenacin 5 Solifenacin 20 Propiverine ER 30 Oxybutynin TDS 3.9 Oxybutynin IR 10 Propiverine IR 20 Fesoterodine 4 Oxybutynin IR 15 Tolterodine ER 4 Imidafenacin 2 Tolterodine IR 4 Propiverine IR 30 Oxybutynin ER 15 Oxybutynin ER 5 Solifenacin ( 3.97 to 0.57); p = ( 1.86 to 0.87); p < ( 2.37 to 0.35); p = ( 1.51 to 1.08); p < ( 1.49 to 1.07); p < ( 1.41 to 0.81); p < ( 2.55 to 0.34); p = ( 1.67 to 0.39); p = ( 2.73 to 0.69); p = ( 1.76 to 0.19); p = ( 1.34 to 0.54); p < ( 1.28 to 0.50); p < ( 2.77 to 1.17); p = ( 0.96 to 0.58); p < ( 1.29 to 0.06); p = ( 0.96 to 0.07); p = ( 1.10 to 0.07); p = ( 1.69 to 0.69); p = ( 1.51 to 0.91); p = ( 1.29 to 1.42); p = Reduction in urgency episodes per 24 h compared with placebo Mean. 95% confidence interval. Fig. 4 Reductions of urgency episodes per 24 h compared with placebo (red line), assessed in patients. IR = immediate release; ER = extended release; TDS = transdermal system. parameter across all outcomes. This efficacy parameter was plotted against adverse events from the network metaanalysis. This analysis was limited to treatments applied in standard clinical practice. Analyses were performed with Stata SE v (Stata- Corp LP, College Station, TX, USA). [(Fig._5)TD$FIG] 3. Evidence synthesis 3.1. Efficacy outcomes In total, 76 studies, including a total of patients, were available for analysis [21,22,25 96]. The study selection Treatment, Oxybutynin IR 20 Oxybutynin ER 20 Fesoterodine 12 Solifenacin 10 Oxybutynin IR 10 Trospium chloride 60 Solifenacin 5 Fesoterodine 8 Propiverine IR 20 Oxybutynin ER 10 Oxybutynin topical gel Imidafenacin 2 Fesoterodine 4 Trospium chloride 40 Tolterodine ER 4 Tolterodine IR 2 Tolterodine IR 4 Oxybutynin TDS ( 3.11 to 1.38); p < ( 3.35 to 1.05); p < ( 1.95 to 0.24); p = ( 1.01 to 0.56); p < ( 1.60 to 0.08); p = ( 1.01 to 0.33); p < ( 0.96 to 0.34); p < ( 0.76 to 0.41); p < ( 0.89 to 0.19); p = ( 0.92 to 0.15); p = ( 0.91 to 0.09); p = ( 0.98 to 0.01); p = ( 0.75 to 0.09); p = ( 0.91 to 0.11); p = ( 0.50 to 0.19); p < ( 1.15 to 0.60); p = ( 0.65 to 0.13); p = ( 1.41 to 0.93); p = Reduction in urgency incontinence episodes per 24 h compared with placebo Mean. 95% confidence interval. Fig. 5 Reductions of urgency incontinence episodes per 24 h compared with placebo (red line), assessed in patients. IR = immediate release; ER = extended release; TDS = transdermal system.

9 1048 [(Fig._6)TD$FIG] EUROPEAN UROLOGY 62 (2012) Treatment, Propiverine IR 45 Fesoterodine 8 Trospium chloride 40 Oxybutynin IR 5 Oxybutynin IR 10 Oxybutynin IR 15 Tolterodine IR 4 Propiverine IR 20 Fesoterodine 4 Oxybutynin IR 9 Tolterodine ER 4 Tolterodine IR (2.73 to 6.67); p < (2.42 to 5.03); p < (2.21 to 5.40); p < (0.93 to 9.52); p = (1.60 to 3.72); p < (0.98 to 5.81); p = (1.48 to 3.77); p < (1.18 to 4.14); p = (1.53 to 3.07); p < (1.36 to 2.91); p < (1.62 to 2.40); p < (0.65 to 1.98); p = Perception of cure or improvement compared with placebo (odds ratio 95% CI) Mean. 95% confidence interval. Fig. 6 Perception of cure or improvement compared with placebo (red line), assessed in 5245 patients. Results are shown as odds ratios and 95% confidence intervals (CIs). IR = immediate release; ER = extended release. procedure is described in Figure 1, and a study description is provided in Table 1. The networks are provided in the online appendix (Supplementary Fig. 1 6). Reductions of micturitions were assessed for 31 different drugs and formulations in patients. Reductions of leakage episodes were assessed in 23 treatment modalities in patients. Reductions of urgency episodes were assessed for 20 drugs and dosages in patients. The corresponding numbers [(Fig._7)TD$FIG] for reductions of urgency incontinence episodes (18 treatments), perception of cure or improvement (12 treatments), and reductions of nocturia episodes (10 treatments) were , 5245, and patients, respectively. Figures 2 7 provide forest plots describing each treatment and dosage assessed against placebo for each outcome assessed. Drugs and dosages were rank ordered according to extent of efficacy. Treatment, Trospium chloride 40 Solifenacin 10 Fesoterodine 8 Fesoterodine 4 Propiverine IR 20 Oxybutynin TDS 3.9 Solifenacin 5 Oxybutynin topical gel Tolterodine ER 4 Tolterodine IR ( 0.39 to 0.08); p = ( 0.25 to 0.08); p < ( 0.23 to 0.05); p = ( 0.27 to 0.00); p = ( 0.28 to 0.03); p = ( 0.63 to 0.41); p = ( 0.23 to 0.03); p = ( 0.28 to 0.08); p = ( 0.17 to 0.01); p = ( 0.35 to 0.27); p = Reduction in nocturia episodes per 24 h compared with placebo Mean. 95% confidence interval. Fig. 7 Reductions of nocturia episodes per 24 h compared with placebo (red line), assessed in patients. IR = immediate release; ER = extended release; TDS = transdermal system.

10 Table 2 Details of studies on adverse events First author Year Patients, no. Females, % Age, yr, mean Treatment duration, wk Placebo Darifenacin, Fesoterodine, Oxybutynin, Propiverine, Solifenacin, Tolterodine, Trospium chloride, Imidafenacin, Bono * NA NA IR 5 3 Murray * NA NA 4 + IR 5 3 Riva * IR 5 3 Zorzitto * IR 5 2 Moore * IR 3 3 Takayasu NA NA 2 + IR 20 1 Tapp * IR 5 4 Stöhrer IR 20 2 Thüroff IR 5 3 Wehnert * NA NA 3 + IR 5 3 IR 15 3 Szonyi IR Abrams NA NA 2 + IR 0.5, 1, 2, 4 2 Jonas IR 1, 2 2 Abrams IR 5 3 IR 2 2 Alloussi IR 20 2 Burgio IR Rentzhog IR 0.5, 1, 2, 4 2 Van Kerrebroeck IR 0.5, 1, 2, 4 2 Drutz IR 5 3 IR 2 2 Madersbacher IR 5 2 IR 15 3 Millard IR 1, 2 2 Stöhrer IR 15 3 Cardozo IR 20 2 Dorschner IR 15 3 Jünemann NA NA 3 + IR 2 2 IR 20 2 Serrano Brambila * IR 5 3 Jacquetin IR 1, 2 2 Malone-Lee IR 1, 2 2 Ulshofer IR 15 3 Van Kerrebroeck IR 2 2,ER4 1 Dmochowski TDS 1.3, 2.6, Zinner ER ER 4 1 Dmochowski TDS ER 4 1 Homma IR 3 3 ER 4 1 Cardozo , 10 1 Chapple , 10 1 IR 2 2 Chapple , 5, 10, 20 1 IR 2 2 Haab , 7.5, 15 1 Khullar ER 4 1 Zinner IR 20 2 Abrams ER 4 1 Abrams ER 4 1 Cardozo Nitti NA NA 8 + 4, 8, 12 1 Romanzi NA NA IR 2 2 Zinner * , 30 1 IR 5 3 Abrams IR 2 2 Abrams * 77 NA 2 + IR 5 3 IR 20 1,15 3 Hill , 15, 30 1 EUROPEAN UROLOGY 62 (2012)

11 Table 2 (Continued ) First author Year Patients, no. Females, % Age, yr, mean Treatment duration, wk Placebo Darifenacin, Fesoterodine, Oxybutynin, Propiverine, Solifenacin, Tolterodine, Trospium chloride, Imidafenacin, 1050 Jünemann IR 15 2,ER30 1 Kaplan ER 4 1 Rackley ER 4 1 Rudy IR 20 2 Zinner Chapple , 8 1 ER 4 1 Chapple , 15 1 Yamaguchi IR , 10 1 Nitti , 8 1 Staskin ER 60 1 Abrams * 77 NA 2 + IR 5 3 IR 20 1,IR15 3 Cardozo , 10 1 Cartwright TDS Choo , 10 1 IR 2 2 Chu IR Dmochowski ER 60 1 Dmochowski , 8 1 Frenkl ER 4 1 Herschorn ER 4 1 Herschorn , 8 1 ER 4 1 Herschorn IR Homma IR Kaplan , 8 1 ER 4 1 Karram Lee IR 20 1 Malone-Lee ER 4 1 Nitti , 8, 12 1 Rogers ER 4 1 Staskin Topical gel 1 Vardy , 10 1 Zellner IR 2.5, 5 3 IR 15, 30 3 Mazur IR Van Kerrebroeck NA NA 12 IR 5 3 IR 2 2 Appell ER 10 1 IR 2 2 Malone-Lee IR 5 2 IR 2 2 Lee IR 5 2 IR 2 2 Diokno ER 10 1 ER 4 1 Halaska IR 5 2 IR 20 2 Giannitsas * IR 5 3 IR 2 2 Altan-Yaycioglu IR 5 3 IR 2 2 Jünemann IR 15 2 IR 2 2 Corcos ER 5, 10, 15 1 Chapple ER 4 1 EUROPEAN UROLOGY 62 (2012) IR = immediate release; ER = extended release; TDS = transdermal system; NA = not available. 1 Once daily. 2 Twice daily. 3 Three times daily. 4 Four times daily. * Crossover design.

12 [(Fig._8)TD$FIG] EUROPEAN UROLOGY 62 (2012) Treatment, Oxybutynin ER 5 Propiverine IR 15 Oxybutynin IR 5 Oxybutynin topical gel Oxybutynin TDS 1.3 Tolterodine IR 2 Oxybutynin TDS 2.6 Solifenacin 5 Tolterodine ER 4 oxybutynin ER 15 Imidafenacin 0.2 Trospium chloride 60 Trospium chloride 40 Fesoterodine 4 Darifenacin 7.5 Tolterodine IR 4 Oxybutynin TDS 3.9 Oxybutynin ER 10 Propiverine IR 20 Propiverine ER 30 Fesoterodine 8 Solifenacin 10 Propiverine IR 30 Darifenacin 15 Oxybutynin IR 10 Propiverine IR 45 Trospium chloride 90 Oxybutynin IR 9 Propiverine IR 60 Oxybutynin IR 15 Fesoterodine 12 Oxybutynin IR Global adverse events compared with placebo Mean. 95% confidence interval. Fig. 8 Adverse event profiles (from 90 trials) of different antimuscarinic treatments and dosages compared with placebo (reference line through 0). For each of the seven adverse event categories, the weighted adverse events per patient in each of the trials given a specific treatment and dosage were determined. The total score (x-axis) was calculated by adding up estimates of the seven adverse event categories. IR = immediate release; ER = extended release; TDS = transdermal system Adverse events outcomes Our searches identified 21 additional papers since publications of the previous study [21,22,32,34,40,41, 45,47,50,54,55,63,64,67,71,74,78,88,93,97,98]. Fortheselection process, see Figure 1. We added those papers to 69 trials from the previous network meta-analysis [25,27, 31,33,37,39,42 44,46,48,49,52,53,56 62,65,66,69,70,72, 73,75,76,80,82,85 87,91,94 97,99 126]. In total, patients were available for analysis (Table 2). Further details regarding participants average age, proportion of female participants, total number of participants per arm assessed, treatments, and dosages can be seen in Table Total adverse event profiles The first analysis, covering all assessed treatments, examined adverse events of 32 different treatments against placebo. Various drugs, formulations, and dosages were similar to placebo: 5 /d oxybutynin ER, 15 /d propiverine IR, 5 /d oxybutynin IR, oxybutynin topical gel, and 1.3 /d oxybutynin TDS ranked among the top five. On the other end of the ranking, the five treatments with worst adverse event profiles were 20 /d oxybutynin IR, followed by 12 /d fesoterodine, 15 /d oxybutynin IR, 60 /d propiverine IR, and 9 /d oxybutynin IR. The full ranking is available in Figure Adverse event profiles for treatments and dosages applied in clinical practice The analysis of adverse event profiles for treatments and dosages applied in clinical practice included 21 treatments. The top five treatments were 100 /g per day oxybutynin topical gel, followed by 5 /d solifenacin, 4 /d tolterodine ER, 15 /d oxybutynin ER, and 0.2 /d imidafenacin. On the other end of the ranking, the five treatments with the worst adverse event profiles were 20 /d oxybutynin IR, followed by 15 /d oxybutynin IR, 45 /d propiverine IR, 10 /d oxybutynin IR, and 15 /d darifenacin. The full ranking is available on Figure Adverse events per treatment Table 3 shows how often a specific adverse event was investigated for each treatment. For example, gastrointestinal adverse events of 7.5 darifenacin were investigated in two studies. Gastrointestinal adverse events were

13 1052 [(Fig._9)TD$FIG] EUROPEAN UROLOGY 62 (2012) Treatment, Oxybutynin topical gel Solifenacin 5 Tolterodine ER 4 Oxybutynin ER 15 Imidafenacin 0.2 Trospium chloride 60 Trospium chloride 40 Fesoterodine 4 Darifenacin 7.5 Tolterodine IR 4 Oxybutynin TDS 3.9 Oxybutynin ER 10 Propiverine ER 30 Fesoterodine 8 Solifenacin 10 Propiverine IR 30 Darifenacin 15 Oxybutynin IR 10 Propiverine IR 45 Oxybutynin IR 15 Oxybutynin IR Global adverse events compared with placebo Mean. 95% confidence interval. Fig. 9 Adverse event profiles of the difference between adverse events of the placebo and the dosages applied in standard clinical practice. For each of the seven adverse event categories, the weighted adverse events per patient in each of the trials given a specific treatment and dosage were determined. The total score (x-axis) was calculated by adding up estimates of the seven adverse event categories. IR = immediate release; ER = extended release; TDS = transdermal system. most commonly explored and reported, followed by neurologic, ocular, and renal/genitourethral adverse events. Cardiologic adverse events were least commonly reported Trade-off between efficacy and adverse events In summary, Figure 10 shows the relationship between efficacy and adverse events for clinically meaningful dosages. Treatments left of the trade-off line have a positive efficacy/adverse events relationship. The length of the orthogonal distance from the trade-off line determinestherating.thetopthreemedicationswere 40 /d trospium chloride, 100 /g per day oxybutynin topical gel, and 4 /d fesoterodine. The right side of the trade-off line shows drugs with a less favorable efficacy/ adverse events relationship. Higher dosages of orally administered oxybutynin and propiverine are found on that side Discussion Main findings To our knowledge, this study is the first one providing a direct comparison of various treatments, formulations, and dosages in the efficacy assessment of important clinical outcomes, as well as a profile of adverse events, based on an analysis involving almost patients with OAB. On review, the results are scattered, and no treatment stands out in all assessed outcomes. In general, the efficacy of antimuscarinics is at best moderate. For the treatment of leakage or nocturia episodes, none of the examined agents showed satisfactory effects. In terms of adverse events, currently prescribed antimuscarinics seem to be an equivalent first choice to start the treatment of OAB, except for higher oral oxybutynin and propiverine dosages, which may have more unfavorable adverse event profiles. In an exploratory trade-off analysis, 40 /d trospium chloride, 100 /g per day oxybutynin topical gel, and 4 /d fesoterodine had the best relationship of efficacy and adverse events (Fig. 10) Findings in the context of existing studies Because of differences in the analysis and presentation of the results, we could not easily compare our findings with those of previous reviews. Various reports showed that there is no relevant difference among the various treatments [8,12,21]. Only our more comprehensive approach, which allowed consideration of all the available data, revealed that some agents performed better than others. In contrast to the findings of Novara et al. [14], our results showed no consistent pattern regarding the superiority of

14 Table 3 Exploration of a specific adverse event per treatment Medication Dosage, Dermatology/skin, no. Cardiac, no. Gastrointestinal, no. Neurology, no. Ocular/visual, no. Pulmonary/upper respiratory, no. Renal/genitourethral, no. Placebo Darifenacin Darifenacin Fesoterodine Fesoterodine Fesoterodine Imidafenacin Oxybutynin ER Oxybutynin ER Oxybutynin ER Oxybutynin IR Oxybutynin IR Oxybutynin IR Oxybutynin IR Oxybutynin IR Oxybutynin TDS Oxybutynin TDS Oxybutynin TDS Oxybutynin Topical gel Propiverine IR Propiverine IR Propiverine IR Propiverine IR Propiverine IR Propiverine ER Trospium chloride IR Trospium chloride IR Trospium chloride IR Trospium chloride ER Tolterodine IR Tolterodine IR Tolterodine IR Tolterodine IR Tolterodine ER Solifenacin Solifenacin Solifenacin IR = immediate release; ER = extended release; TDS = transdermal system. 1 Once daily. 2 Twice daily. 3 Three times daily. 4 Four times daily. EUROPEAN UROLOGY 62 (2012)

15 1054 [(Fig._10)TD$FIG] EUROPEAN UROLOGY 62 (2012) Fig. 10 Trade-off between efficacy and adverse events of clinically relevant dosages of antimuscarinics. IR = immediate release; ER = extended release; TDS = transdermal system. ER compared with IR formulations (Table 2). For the sake of completeness, we included treatments that are uncommonly found in clinical practice. In line with previous reports, some findings remain implausible or incompletely understood. It appears to be counterintuitive that low dosages attain higher efficacy than higher dosages of the same treatment. Our update of the Kessler et al. paper [20], combining those data with data of 21 recent trials and doubling the number of patients assessed, confirmed the Kessler et al. findings, with some exceptions. First, a new formulation of oxybutynin, oxybutynin topical gel, overtook the lead from 5 /d solifenacin (Fig. 9). Oxybutynin topical gel has been examined only once in a trial, which enrolled approximately 800 patients [21]. Further studies still need to confirm this favorable profile. Tolterodine at a dosage of 4 /d asserted its position on rank 3. A new drug, imidafenacin, reached rank 5. On the other end of the ranking, all stayed the same: 20 and 15 /d oxybutynin IR, 45 /d propiverine IR, and 10 /d oxybutynin remain at the bottom of the league. In the trade-off analysis, 40 trospium chloride showed the most favorable profile. Although this finding reflects the available evidence, the result contradicts clinical observation. Arguably, the studies examining 40 trospium chloride included a higher number of patients with neurogenic detrusor overactivity. Also, the higher dose of trospium chloride (60 ) was clearly less effective and had fewer adverse events, which seems counterintuitive Strengths and limitations The methods applied in this paper allow steps beyond conventional reviews. The approach incorporates all available information from clinical trials while fully maintaining randomization. A direct comparison of various treatments and a rank ordering are readily available. Finally, the combination of efficacy and adverse events provides the evidence base for formal decision-analytic models. The major limitation of this study lies in the reporting quality of some studies. For example, despite contacting corresponding authors, precision estimates (SDs and CIs) remained missing for some papers, which forced us to impute some value to use the data. For missing SDs of continuous efficacy outcomes, we decided to use the highest SD reported within a specific outcome domain, resulting in a more conservative estimation of treatment effects. For the efficacy analysis, we excluded papers with a crossover design, because they did not report withinsubject correlations. In the adverse events assessment, 11 studies used a crossover design. In this case, we considered these studies for analysis, because our assessment of adverse events was an update of the Kessler et al. paper [20], which included crossover studies. Including crossover studies is not unproblematic. Dependent on the withinsubject correlation, the variance of the within-subject comparison of the adverse event score will be lower than the between-subject comparison [127]. As the weights are inversely proportional to the variance, this characteristic would mean that the weights of the crossover studies should be increased. We performed a sensitivity analysis increasing the weights of studies with a crossover design with a factor 2, showing only minimal differences compared with the presented results. For the adverse events analysis, the within-study variance of the adverse event scores was not available, so a customary network analysis investigating heterogeneity was not possible. In fact, we assumed

16 EUROPEAN UROLOGY 62 (2012) heterogeneity by allowing the outcome parameter to have a variance comprising both the between-study and the within-study variance. Given that our data represent averaged adverse event profiles of the antimuscarinics, it is unclear how predictive the mean values are for an individual patient. Almost all studies published are fixed-dose trials, and we excluded the few studies that did not clearly specify the dose regarding adverse events. This limitation is important, since in clinical practice the dose of a drug is often titrated, and flexibledose studies tend to report fewer adverse events. None of the trials reported whether or how many patients had two or more adverse events. Therefore, we had to assume that the occurrence of an adverse event was independent of the presence of another adverse event, although this situation might be more complex in clinical reality. Policy and completeness for adverse event reporting differed among the trials. The impact of this variability on the results is impossible to determine, but underreporting of adverse events, particularly in earlier trials, is possible. Our grading of adverse events was based on experts opinion. Arguably, patients opinion may be completely different. Actually, a previous study by our group showed that patients and physicians values and preferences can differ substantially [128]. However, as the decision for a specific antimuscarinic treatment is usually made by the physician, we believe that our approach is rational. Finally, some treatments were investigated only once and thus provided only a point estimate of effect, because no variance value could be computed Implications for practice This analysis aimed at displaying the available evidence in the most complete way, which included some dosages that are uncommonly used in practice. For example, in the case of oxybutynin IR, the generally used dosages are / d. In this analysis, the very uncommon dosage of 7.5 /d, which was assessed for only a limited number of outcomes, appeared to be better than standard dosages. In addition, fesoterodine is typically commercialized as 4 and 8 /d but not as 12 /d, but precisely this dosage scored second best. Some treatment options are not available in all countries. An oxybutynin ER dosage of 20 /d, for instance, is not available in Switzerland. Another treatment ranked among the top five is 10 /d solifenacin. In clinical practice, however, the physician would start with 5 /d and titrate up to 10 /d in the case of an insufficient effect. From the clinical viewpoint, the forest plots (Figs. 2 9) and the trade-off chart (Fig. 10) provide the most useful information. Clinicians can obtain a quick overview of treatment efficacy for each outcome or see a benchmark in respect to adverse events. The trade-off chart allows an examination of the relationship between efficacy and adverse events of various drugs and dosages. Based on these charts, clinicians may consider exchanging an unsatisfactory treatment with another treatment that scores higher. However, we would like to urge caution. Some of the drugs displayed in Figure 10 have not been assessed very often. It is possible that further examinations will reveal lower efficacy and higher adverse event rates in these cases. In terms of implications for practice, an important issue remains the same. While antimuscarinics are generally seen to be well accepted, nonadherence to medication is a big issue [129]. Kelleher et al. showed that up to 40% of patients in the community setting discontinue antimuscarinic treatment because of adverse events [130]. Based on the adverse events assessment, various treatments are equivalent. Given the clear disadvantages of higher dosages of oxybutynin and propiverine, these treatments should not be used or should be replaced, if possible Implications for research We believe that our method provides a useful and complete overview of the evidence for the benefits and downsides of various medications prescribed in a particular clinical area. To us, the method is of most value for researchers commissioned to provide comprehensive summaries and decision-analytic models to guide decisions of health authorities. From a decision-making point of view, there are new opportunities that could be explored. When attributing costs of treatments and adverse events, our findings could result in a straightforward economic analysis. Our simple trade-off concept could be expanded by including study size or methodological aspects. Our findings should be updated once new evidence on the efficacy and adverse events of less examined drugs becomes available. 4. Conclusions This is the first study allowing direct comparisons among various drugs and dosages in the treatment of patients with OAB. The combination of efficacy with adverse event profiles from these network meta-analyses contributes to the creation of a rational decision-analytic model outlining the optimal therapeutic strategy in OAB. Differences among the various antimuscarinics call for careful, patientcentered management in which regimen changes should be considered. Author contributions: Lucas M. Bachmann had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bachmann, Kessler, Kessels. Acquisition of data: Buser, Ivic. Analysis and interpretation of data: Bachmann, Kessler, Kessels. Drafting of the manuscript: Bachmann, Buser, Ivic. Critical revision of the manuscript for important intellectual content: Bachmann, Buser, Ivic, Kessels, Kessler. Statistical analysis: Kessels, Bachmann. Obtaining funding: Bachmann. Administrative, technical, or material support: Buser, Ivic. Supervision: Bachmann. Other (specify): None. Financial disclosures: Lucas M. Bachmann certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding,

17 1056 EUROPEAN UROLOGY 62 (2012) consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: This study was supported by an unrestricted grant of Watson Pharmaceuticals, Inc. Appendix A. Example of Search String to Identify Relevant Articles in Medline and Scopus About Adverse Events of Antimuscarinics Medline (PubMed interface) search Muscarinic Antagonists [Mesh] AND Urinary Bladder, Overactive [Mesh] AND ( humans [MeSH Terms] AND 2007/04/01 [PDat]: 2012/03/29 [PDat]) Scopus search (TITLE-ABS-KEY(antimuscarinic* AND overactive AND bladder) AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal OR mult OR ceng OR CHEM OR comp OR eart OR ener OR engi OR envi OR mate OR math OR phys) AND PUBYEAR > 2007) AND (randomized OR randomised) AND (LIMIT-TO(DOCTYPE, ar )) AND (LIMIT-TO(SUBJAREA, MEDI ) OR LIMIT-TO(SUBJAREA, PHAR ) OR LIMIT- TO(SUBJAREA, MULT )) Appendix B. Supplementary data Supplementary data associated with this article can be found, in the online version, at j.eururo References [1] Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. 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