The Effects of Antimuscarinic Treatments in Overactive Bladder: An Update of a Systematic Review and Meta-Analysis

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1 european urology 54 (2008) available at journal homepage: Review Neuro-urology The Effects of Antimuscarinic Treatments in Overactive Bladder: An Update of a Systematic Review and Meta-Analysis Christopher R. Chapple a, *, Vik Khullar b, Zahava Gabriel c, Dominic Muston c, Caty Ebel Bitoun d, David Weinstein d a Sheffield Teaching Hospital NHS Trust, Royal Hallamshire Hospital, Urology Research, Sheffield, UK b Imperial College, St. Mary s Hospital, London, UK c Heron Evidence Development Ltd., UK d Pfizer, France Article info Article history: Accepted June 11, 2008 Published online ahead of print on June 20, 2008 Keywords: Antimuscarinic Overactive bladder Detrusor overactivity Incontinence Meta-analysis Systematic review Abstract Context: Antimuscarinic agents are currently the first-line pharmacotherapy for overactive bladder. Objectives: A systematic review published in 2005 was updated, including data on a newly licensed antimuscarinic (fesoterodine). The primary aim of this study was to systematically review evidence on the efficacy of licensed administration of antimuscarinic treatments in overactive bladder from randomised controlled trials. Secondary aims were to review evidence on tolerability and safety and health-related quality of life (HRQL). Evidence acquisition: All relevant data sources from randomised controlled trials were searched, and two independent reviewers considered publications for inclusion and extracted relevant data. Meta-analysis was used to pool efficacy, tolerability, safety, and HRQL outcomes by treatment. Efficacy was measured by continent days, mean voided volume, urgency episodes, and micturition frequency. Tolerability and safety were measured by means of adverse event and withdrawal rates. HRQL was measured by various instruments. Evidence synthesis: An additional 1118 references were retrieved with data on 83 studies extracted. Antimuscarinics were found to be more effective than placebo. Tolerability was good; few of the antimuscarinics were found to have significantly higher withdrawal rates in comparison to placebo. No serious adverse event for any product was statistically significant compared to placebo. Dry mouth (mild, moderate, severe) was the most commonly reported adverse event (29.6% on treatment vs 7.9% on placebo), followed by pruritus (15.4% on treatment vs 5.2% on placebo). Improvements were seen in HRQL with treatment by darifenacin, fesoterodine, oxybutynin transdermal delivery system, propiverine extended release (ER), solifenacin, tolterodine ER and immediate release, and trospium. Limitations of the study include restrictions on the types of patients typically included in overactive bladder trials and topics that have not been adequately addressed in the current antimuscarinic literature. Conclusions: Antimuscarinics are efficacious, safe, and well-tolerated treatments that improve HRQL. Profiles of each drug and dosage differ and should be considered in making treatment choices. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Sheffield Teaching Hospital, Glossop Road, Sheffield S10 2JK, United Kingdom. Tel ; Fax: address: c.r.chapple@shef.ac.uk (C.R. Chapple) /$ see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 544 european urology 54 (2008) Introduction 2. Methods Overactive bladder (OAB) refers to the common and bothersome group of storage lower urinary tract symptoms (LUTS). The International Continence Society (ICS) defines OAB syndrome as urgency with or without urge urinary incontinence (UUI), usually with frequency and nocturia [1]. Prevalence rates for OAB are estimated to be approximately 12% in North America and Europe [2]. Both men and women are equally affected by OAB, and the incidence rate increases with age [2]. This condition has a serious impact on individuals as well as on society as a whole [3,4]; to illustrate, the annual cost of OAB has been estimated as to be as high as s3.98 billion in Germany alone [5]. OAB can be managed with bladder and behavioural training, biofeedback, electrical stimulation, pharmacologic treatments, or with a combination of therapies [6]. Antimuscarinic agents are the first-line pharmacotherapy for OAB treatment [7]. A systematic review of the tolerability, safety, and efficacy of licensed antimuscarinic treatments in OAB was published in October 2005 [8]. This review represented an update to that published in 2003 by Herbison et al [9]. Since then, there have been considerable changes to the evidence base. A large number of new trials with existing agents have been published, particularly for solifenacin and darifenacin. Some of these new trials are head-to-head trials, an area identified as a research priority in the 2005 review. Additionally, there are data on a newly developed antimuscarinic, fesoterodine [10]. Fesoterodine is rapidly and extensively hydrolyzed by nonspecific ubiquitous esterases to 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine and is responsible for all of the antimuscarinic activity of fesoterodine [11 13]. Fesoterodine has two active doses, 4 and 8mg [14,15], and clinical studies have shown that plasma concentrations are dose proportional [16]. This meta-analysis was conducted to update the 2005 data. The primary aim of this study was to review all of the evidence on the efficacy of licensed antimuscarinic therapy for OAB available from randomised controlled trials. The efficacy outcomes of interest were the changes in the number of micturitions, urgency and incontinence episodes per day, volume voided per micturition, and both the proportion of patients returning to continence or undergoing global improvements in their storage LUTS. Secondary aims were to review evidence on tolerability, safety, and effects of treatment on health-related quality of life (HRQL) Publication searches The review undertook a comprehensive search of all major literature databases and the abstract books from several major conferences: American Urological Association, ICS, European Association of Urology, International Urogynaecological Association, International Consultation of Incontinence, and Societe Internationale d Urologie. As with the 2005 review, there were no restrictions on the inclusion of publications by language; publications in languages other than English were translated into English. The literature database search for the previous 2005 review was carried out on August 31, 2004, for publications published since 1966 in the MEDLINE, EMBASE, Cochrane Controlled Trials Register, and Cumulative Index to Nursing and Allied Health Literature databases. The literature database search for this review was carried out on October 18, 2007, and included all publications published in 2004 or later in the same databases. Conference proceedings had previously been searched to the end of For the review update, we added evidence from further proceedings of each conference up to October The overlap in date ranges for the searches led to duplication in retrieved publications but was designed to ensure that no evidence was missed Study procedures The same rigorous processes were followed in this review as in the last. This review was conducted and reported according to QUORUM guidelines [17]. A team of reviewers independently determined the eligibility of each publication by applying a set of criteria (Table 1). Two different reviewers considered each publication, and discrepancies were resolved through discussion. Cited references from included trials and reviews of similar trials were also searched. Many studies were reported in more than one publication, and all studies that met the inclusion criteria were included in the review. However, only one extraction dataset per study was compiled from all publications relating to that study, so as to avoid the error of double-counting patients in subsequent analyses. Two independent reviewers extracted study characteristics and placed the baseline and outcomes data, including publications in parallel, into a Microsoft Access database (Microsoft Corporation, Redmond, WA, USA). The methodological quality of publications was assessed as previously reported [8]. A third reviewer checked the resulting extractions and resolved any discrepancies. Safety and tolerability outcome data were extracted from all studies; efficacy outcome data were extracted only from studies reporting that patients and investigators had been blinded to treatment allocation. Table 2 provides a list of outcomes extracted Treatment dosing There were seven drugs included in this review (darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, and trospium), each of which could be delivered

3 european urology 54 (2008) Table 1 Study inclusion and exclusion criteria for the review Criterion Included Excluded Population Age: 18 yr Race: any Gender: male or female Qualifying event/disease/factors: Idiopathic OAB/DO/UI (including UUI) 50% of patients with DO consequent upon neurogenic pathology UUI MUI (urge-predominant incontinence) 50% of patients with BOO/BPH/BPO/benign prostatic enlargement or previous LUTD surgery Any severity of disease at baseline Age: <18 yr Qualifying event/disease/factors: >50% of patients with DO consequent upon neurogenic pathology SUI MUI (stress-predominant incontinence) >50% of patients with BOO/ BPH/BPO/benign prostatic enlargement or previous LUTD surgery Perspective of study Prospective (concurrent) Retrospective (nonconcurrent, Comparative historical) Noncomparative Type of study RCT (Blinded RCTs only for clinical efficacy data, open-label RCTs and blinded RCTs for safety and tolerability data) Crossover trials with a wash-out period between treatments Language All None Trial Length 2wk <2wk* Sample Size Any None Intervention/ treatments Control intervention/ treatments Nonrandomised CCT Open-label follow-up of RCT Cohort Observational Case-control Case study Crossover trials without a wash-out period between treatments Oral and TDS monotherapy with antimuscarinics; UK licensed doses: Oral monotherapy with antimuscarinics: Flavoxate (Urispas 1 ) Darifenacin (Enablex 1 ): all doses Propantheline (Pro-Banthine 1 ) IR (Cystrin 1, Ditropan 1 ): mg bid, tid, 5 mg qid ER (Ditropan XL 1 ): 5 mg od, 10 mg od, 15 mg od, 20 mg od TDS (Kentera 1, Oxytrol 1 ): 3.9 mg od All intravesical antimuscarinic IR (Detrunorm 1 ): 15 mg od, bid, tid, qid formulations ER (Detrunorm XL 1 ): all doses Solifenacin (Vesicare 1 ): all doses Tolterodine IR (Detrusitol SR 1, Detrol 1 ): 1 mg bid, 2 mg bid Tolterodine ER (Detrusitol XL 1, Detrol LA 1, Detrusitol Neo 1, Dereustiol Retard 1 ): 2 mg od, 4 mg od Trospium (Regurin 1 ): 20 mg bid Fesoterodine (Toviaz 1 ): all doses. Combination therapy with one of the included drugs and a nonpharmacological treatment if all the treatment arms receive the same nonpharmacological treatment Placebo or any of the included drugs, including a different formulation of the same drug Included trial outcomes Any None Combination therapy with antimuscarinics, and an a-blocker Combination therapy with one of the included drugs and a nonpharmacological treatment when not all the treatment arms receive the same nonpharmacological treatment Nonpharmacological treatment (bladder training, electronic stimulation, physiotherapy) Usual care No intervention Abbreviations: BOO, bladder outlet obstruction; BPH, benign prostatic hyperplasia; BPO, benign prostatic obstruction; CCT, controlled clinical trial; DO, detrusor overactivity; ER, extended release; IR, immediate release; LA, extended release; LUTD, lower urinary tract disease; MUI, mixed urinary incontinence; OAB, overactive bladder; RCT, randomised controlled trial; SUI, stress urinary incontinence; TDS, transdermal system; UI, urinary incontinence; UUI, urge urinary incontinence; XL, extended release. * Studies in which patients received <2 wk of study treatment were excluded.

4 546 european urology 54 (2008) Table 2 Efficacy, tolerability, safety, and HRQL/PRO outcomes extracted from included studies Efficacy* Tolerability Safety HRQL/PRO Change from baseline in the number of urgency episodes/24 h Change from baseline in the number of incontinence episodes/24 h Change from baseline in the number of pads used per day Change from baseline in the number of daytime incontinence episodes/24 h Number of patients returned to continence at trial end point (recording no incontinence episodes on last voiding diary entry) Change from baseline in the number of nocturnal incontinence episodes/24 h Change from baseline in number of nocturnal awakenings related to overactive bladder/24 h Number of patients achieving normal micturition frequency (7 or8 micturitions/24 h) at trial end point Change from baseline in the volume of urine voided per micturition (ml) Change from baseline in the number of micturitions/24 h Change from baseline in maximum cystometric capacity (ml) Total withdrawals Withdrawals due to adverse events Withdrawals due to death Any adverse event Any serious adverse event Blurred vision, confusion, dizziness, palpitations, tremor, vertigo Constipation, diarrhoea, dry mouth (any severity), dry mouth (mild), dry mouth (moderate), dry mouth (severe), dry mouth (mild/moderate), dry mouth (moderate/severe), dyspepsia, nausea, vomiting Fatigue, headache, insomnia, somnolence, increased sweating, urinary retention, UTI, erythema, pruritus Generic: SF-36, SF-12 Disease-specific: Incontinence Impact Questionnaire (IIQ), KHQ, UDI, OAB-q Number of patients reporting improvement in disease VAS scores of improvement in disease Abbreviations: HRQL, health-related quality of life; KHQ, King s Health Questionnaire; OAB-q, Overactive Bladder Questionnaire; PRO, patientreported outcome; UDI, Urogenital Distress Inventory; UTI, urinary tract infection; VAS, visual analog scale; SF-36, Short-form 36; SF-12, Shortform 12. * Efficacy outcomes were extracted only from studies which reported that patients and investigators had been blinded to treatment allocation. through various formulations at various doses and frequencies. Data from arms of studies in which drug doses delivered to patients fell outside the European licensed range were not extracted (Table 1). Treatments were stratified according to whether the drug formulation was immediate release (IR), for which administration was oral and the dose frequency was generally more than once per day, or extended release (ER), for which administration was oral and the dose frequency was generally once per day. The only exception was in the case of oxybutynin administered via a transdermal system (TDS) patch. Treatments were stratified into categories according to the total daily dose at the start of the study and whether the study allowed flexible dosing Statistical analysis Meta-analysis was conducted where possible to pool results for each outcome of interest and for each combination of treatment by daily dose category and formulation using the meta-analysis command METAN written for Stata v.9 (Stata- Corp LP, College Station, TX, USA) [18]. Dichotomous outcomes were summarised as risk ratios (RR) using the Mantel- Haenszel method; continuous outcomes were summarised as nonstandardised (also known as weighted) mean differences using inverse variance weighting. Fixed rather than random effects models were used because the stratification was judged to largely remove the likelihood of substantial clinical or statistical heterogeneity [19]. As with the previous review, trials with more than two treatment arms were analysed as if they were conducted as trials of each paired treatment comparison. For simplicity, consistency with the previous review [8] and consistency between trials, analyses of such trials were not adjusted for multiple comparisons (using Bonferonni correction methods or similar). 3. Results 3.1. Trial flow This review retrieved 1118 references in addition to the retrieved for the 2005 review. Of the newly retrieved references, 88 publications were included to add to the 123 included from the previous review for a total of 211 publications. There were on average 2.5 publications per included trial. From these publications, data on 83 trials were extracted (Appendix A). Ten trials included for this review were excluded from this meta-analysis; eight were excluded because they contained no data relevant or suitable for meta-analysis [20 27]; one was excluded because the treatment dosing was mixed or unclear [28]; and one was excluded because randomisation was unclear [29]. Fig. 1 is a diagram of the study flow, showing the relationship between studies

5 european urology 54 (2008) Fig. 1 Trial flow. considered now and those considered at the 2005 review Trial characteristics Summaries of the patient and study design characteristics of the included trials are presented in Table 3. Twenty-four trials were published in abstract format only, and 59 trials were published as full publications. Forty-six trials (55%) had placebo arms. There was at least one placebocontrolled trial for all of the included antimuscarinic formulations, apart from the oxybutynin ER formulation. Most trials were parallel-group studies, the remaining ten trials being crossover in design. At least 72 of the trials were double-blind, five did not report blinding clearly, and the remaining six were single-blind or open-label studies. Study lengths ranged from 2 to 52 wk, with 34 trials of 12-wk length. The number of patients in trials ranged from 30 to 1593 patients, with five trials of >1000 patients [14,30 33] and 20 trials with fewer than 100 patients. The mean age of patients included in the trials was 58 yr (range: yr) Efficacy Efficacy results are summarized in Table 4. Greater proportions of patients treated with antimuscarinics than with placebo returned to continence, and these differences were statistically significant. The pooled RR varied between 1.3 and 3.5 across treatments and nominally were strongly statistically significant ( p < 0.01) with the exception of fesoterodine, for which no data were available, and propiverine IR 45 mg/day, for which evidence was available from only one study [34]. There were no statistically significant differences among treatments in meta-analyses of active-controlled trials for this outcome. Active treatments were more effective than placebo in terms of the mean change in the number

6 Table 3 Summary of included trials Trial Treatment arms No. of randomised patients Trial length (weeks) Disease Patient baseline characteristics Proportion of patients with prior therapy (%) Mean number of incontinence episodes per day 548 New trials for this review Abrams mg/day propiverine ER, 45 mg/day propiverine IR, 15 mg/day oxybutynin IR, placebo 77 2 OAB Chapple 2004 (A) 4 and 8 mg/day fesoterodine, placebo OAB Chapple and 8 mg/day fesoterodine, 4 mg/day tolterodine ER, placebo OAB Corcos , 10, and 15 mg/day oxybutynin ER UUI Giannitsas 2004 (A) 4 mg/day tolterodine IR, 15 mg/day oxybutynin IR OAB Herschorn 2007 (A) 4 mg/day tolterodine ER, placebo OAB Hirani 2004 (A) 20 mg/day propiverine ER, 45 mg/day propiverine IR, 77 2 OAB 15 mg/day oxybutynin IR, placebo Homma cm 2,39cm 2, and 52 cm 2 oxybutynin TDS, placebo OAB 3.0 Khullar 2005 (A) 4 mg/day tolterodine ER, placebo OAB Khullar 2007 (A) 4 mg/day tolterodine ER, placebo OAB Lee 2006 (A) 20 mg/day propiverine ER, placebo OAB Madersbacher 2005 (A) 30 and 45 mg/day propiverine IR 464 OAB Minassian mg/day oxybutynin ER, 7.5 mg/day oxybutynin IR OAB Nitti 2006 (A) 4 and 8 mg/day fesoterodine, placebo OAB Olshansky 2006 (A) 4 mg/day tolterodine IR, 15 mg/day darifenacin ER, placebo OAB Rackley mg/day tolterodine ER, placebo OAB 0.7 Robinson mg/day tolterodine ER, placebo OAB 2.6 Rogers 2007 (A) 4 mg/day tolterodine ER, placebo OAB Rovner 2005 (A) 4 and 8 mg/day fesoterodine, placebo UUI Salvatore mg/day oxybutynin ER and IR 96 4 OAB STAR 5 mg/day solifenacin titrated, 4 mg/day tolterodine ER OAB 2.7 SUNRISE (A) 5 mg/day solifenacin, placebo OAB VENUS (A) 5 mg/day solifenacin, placebo OAB Wang mg/day oxybutynin IR, placebo OAB Yamaguchi & 10 mg/day solifenacin, 20 mg/day propiverine ER OAB 2.2 Yaycioglu mg/day tolterodine IR, 15 mg/day oxybutynin IR 52 4 OAB Zinner mg/day oxybutynin IR, 15 mg/day darifenacin ER, placebo 76 2 OAB 2.9 Zinner mg/day darifenacin, placebo OAB 53.7 european urology 54 (2008) Trial from 2005 review, but supplemented by new publication Burgio mg/day oxybutynin IR, placebo MUI Cardozo and 10 mg/day solifenacin, placebo OAB 33.9 Hill and 15 mg/day darifenacin ER, placebo OAB 22.8 Jünemann mg/day tolterodine IR, 30 mg/day propiverine IR OAB Jünemann mg/day propiverine ER & IR, placebo OAB 3.4 OPERA 4 mg/day tolterodine ER, 10 mg/day oxybutynin ER OAB Rudy mg/day trospium, placebo OAB 50.3 Steers mg/day darifenacin ER titrated, placebo OAB 23.8

7 Table 3 (Continued ) Trial Treatment arms No. of randomised patients Trial length (weeks) Disease Patient baseline characteristics Proportion of patients with prior therapy (%) Mean number of incontinence episodes per day Trials from 2005 review with no new publications Abrams mg/day tolterodine IR, 15 mg/day oxybutynin IR, placebo DO (30% post LUT surgery) Abrams 2001 (A) 4 mg/day tolterodine IR, placebo DO/BOO Alloussi mg/day trospium, placebo DO Anderson mg/day oxybutynin IR and ER UUI/MUI Barkin mg/day oxybutynin IR and ER UUI 3.5 Birns mg/day oxybutynin IR and ER DO 100 Brambila mg/day oxybutynin IR, placebo 44 6 Urgency/UUI Cardozo mg/day trospium, placebo DO Chaliha 1998 (A) 40 mg/day trospium, placebo 76 3 DO Chapple & 10 mg/day solifenacin, 4 mg/day tolterodine IR DO 1.7 Chapple 2004b 5 & 10 mg/day solifenacin, 4 mg/day tolterodine IR, placebo OAB Davila mg/day oxybutynin IR titrated, 2.6 mg per fortnight 76 4 UUI oxybutynin TDS titrated Dmochowski mg/day oxybutynin TDS, placebo DO Dmochowski mg/day tolterodine ER, 3.9 mg/day oxybutynin TDS, placebo OAB and UUI/MUI Dorschner mg/day propiverine IR, placebo Urgency/UUI/MUI 0.9 Drutz mg/day tolterodine IR, 15 mg/day oxybutynin IR, placebo DO (UUI) Haab and 15 mg/day darifenacin ER, placebo DO Halaska 1994 (A) 45 mg/day propiverine IR, placebo 93 4 Urgency/UUI Halaska mg/day trospium, 10 mg/day oxybutynin IR DO/UUI Homma mg/day tolterodine ER, 9 mg/day oxybutynin IR, placebo OAB Jacquetin and 4 mg/day tolterodine IR, placebo DO Jonas and 4 mg/day tolterodine IR, placebo DO Jünemann 2000 (A) 40 mg/day trospium, 4 mg/day tolterodine IR, placebo DO Khullar mg/day tolterodine ER, placebo MUI 34 3 Kirschner-Hermans 1997 (A) 10 mg/day oxybutynin IR, placebo 36 3 Incontinence Lee mg/day tolterodine IR, 10 mg/day oxybutynin IR OAB Leung mg/day tolterodine IR, 10 mg/day oxybutynin IR DO Madersbacher mg/day oxybutynin IR, 45 mg/day propiverine IR, placebo Urgency/UUI Malone-Lee and 4 mg/day tolterodine IR, placebo OAB Malone-Lee 2001b 4 mg/day tolterodine IR, 10 mg/day oxybutynin IR OAB Malone-Lee 2002 (A) 4 mg/day tolterodine ER, placebo DO Millard and 4 mg/day tolterodine IR, placebo DO Miller 2002 (A) 7.5 mg/day oxybutynin IR, placebo UUI Moisey mg/day oxybutynin IR, placebo 30 4 DO Moore mg/day oxybutynin IR, placebo 53 Unclear DO Neimark 2002 (A) oxybutynin IR and TDS (dose unreported) 68 6 OAB (basis of diagnosis unclear) OBJECT 10 mg/day oxybutynin ER, 4 mg/day tolterodine ER OAB european urology 54 (2008)

8 550 european urology 54 (2008) Patient baseline characteristics Trial length (weeks) Table 3 (Continued ) Trial Treatment arms No. of randomised patients Mean number of incontinence episodes per day Disease Proportion of patients with prior therapy (%) Rentzhog and 4 mg/day tolterodine IR, placebo 81 2 DO Riva mg/day oxybutynin IR, placebo 30 3 UUI/OAB Szonyi mg/day oxybutynin IR, placebo 60 6 DO Tapp mg/day oxybutynin IR, placebo 37 2 DO Thuroff mg/day oxybutynin IR, placebo UUI Uchida 2002 (A) 5 and 10 mg/day solifenacin, placebo OAB 3.7 Van Kerrebroeck mg/day tolterodine ER and IR, placebo OAB UUI Versi mg/day oxybutynin IR and ER, titrated 226 Titration period + 1 wk Xia mg/day oxybutynin ER, 2 mg/day tolterodine ER OAB 3 Zinner mg/day trospium, placebo OAB (UUI) Abbreviations: (A), trial published in abstract form only; BOO, bladder outlet obstruction; DO, detrusor overactivity; ER, extended release; IR, immediate release; MUI, mixed urinary incontinence; OAB, overactive bladder; OBJECT, Overactive Bladder: Judging Effective Control and Treatment trial; OPERA, Overactive Bladder: Performance of Extended Release Agents trial; STAR, Solifenacin and Tolterodine as an Active comparator in a Randomised trial; SUNRISE, Solifenacin in the treatment of UrgeNcy symptoms of overactive bladder in a RISing dose, randomised, placebo-controlled, doubleblind Efficacy trial; TDS, transdermal system; UUI, urgency urinary incontinence; VENUS, Vesicare Efficacy and safety in patients with Urgency Study. of incontinence episodes per day. Statistically significant results were obtained for interventions involving each licensed drug with the exception of trospium chloride, which was not reported. Pooled differences in mean changes ranged from 0.4 to 1.1 incontinence episodes per day. Tolterodine was not significantly more effective as IR 2 mg/day but was significantly more effective at the higher 4-mg/day dose as ER and IR when compared to placebo. There were no statistically significant differences among active treatments with the exception of fesoterodine 8 mg/day, which the meta-analyses found on the basis of one study [14] to be statistically significantly favourable to tolterodine ER 4 mg/day (mean difference: 0.48; 95% CI, episodes per day; p = 0.03). Active treatments were more effective than placebo in terms of the mean change in the number of micturitions per day. Statistically significant results were obtained for interventions involving each licensed drug, with the exception of trospium chloride, which was not reported. Pooled differences in mean changes ranged from 0.5 to 1.3 episodes per day. There was some evidence from three trials [30,31,35] favouring solifenacin 10 mg/day over tolterodine IR 4 mg/day (difference in mean change: 0.73; 95% CI, micturitions per day; p = 0.01) and from four trials [36 39] favouring solifenacin 10 mg/day over solifenacin 5 mg/day (difference in mean change: 0.30; 95% CI, micturitions per day; p = 0.02). Otherwise, there were no statistically significant differences among active treatments. Fesoterodine, propiverine, solifenacin, and tolterodine were statistically significantly more effective than placebo in terms of the mean change in the number of urgency episodes per day, where reported. The outcomes for oxybutynin and trospium chloride were not suitable for meta-analysis. Pooled differences in mean changes varied between 0.64 and 1.56 episodes per day. There was, again, some evidence favouring solifenacin 10 mg/day over tolterodine IR 4 mg/day (difference in mean change: 1.02; 95% CI, episodes per day; p < 0.01) and propiverine IR 20 mg/day (difference in mean change: 0.48; 95% CI episodes per day; p = 0.03), and evidence favouring solifenacin 5 mg/ day over tolterodine IR 4 mg/day (difference in mean change: 0.80; 95% CI, episodes per day; p = 0.01). Otherwise, there were no statistically significant differences among active treatments. Active treatments were all statistically significantly more effective than placebo in terms of the mean change in the volume voided per micturition (milliliter) where reported for each licensed drug

9 Table 4 Efficacy of antimuscarinics compared to placebo: Results from meta-analyses* Fesoterodine 4 mg/day Fesoterodine 8 mg/day IR mg/ day vs placebo IR 15 mg/ day vs placebo TDS mg/ day vs placebo IR 30 mg/ day vs placebo IR 45 mg/ day vs placebo ER 20 mg/ day vs placebo ER 30 mg/ day vs placebo Solifenacin 5 mg/ day vs placebo Solifenacin 10 mg/day Tolterodine ER 4 mg/day Tolterodine IR 2 mg/day Tolterodine IR 4 mg/day Trospium chloride 40 mg/day Mean change in incontinence episodes/day Mean change in micturitions/ day Mean change in urgency episodes/day Mean change in volume voided per micturition (ml) Patients returned to continence at end point Patients with improvement in disease to 1.52 to 1.23 to 1.05 to 0.92 to 1.02 to 1.06 to 0.42 to 0.56 to 0.67 to p < 0.01 p < 0.01 p < 0.01 p = 0.02 p = 0.01 p < 0.01 p < 0.01 p < 0.01 p = 0.23 p < (1) 434 (1) 312 (2) 612 (2) 578 (1) 1157 (2) 1170 (2) 3095 (5) 605 (3) 2614 (7) to 1.37 to 1.43 to 0.99 to 1.33 to 1.28 to 1.23 to 1.56 to 0.96 to 1.07 to 0.93 to p < 0.01 p < 0.01 p < 0.01 p = 0.02 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < (1) 555 (1) 431 (3) 608 (2) 98 (1) 779 (1) 1803 (2) 1789 (2) 3223 (5) 637 (3) 3121 (7) to 1.83 to 1.44 to 1.57 to 1.88 to 1.37 to 1.16 to p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p = (1) 555 (1) 779 (1) 1786 (2) 1771 (2) 1416 (2) 994 (1) to to to 10.3 to 8.18 to to to to to 6.63 to to p < 0.01 p < 0.01 p < 0.01 p < 0.01 p = 0.13 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < (1) 553 (1) 382 (2) 355 (1) 98 (1) 776 (1) 1799 (2) 1785 (2) 3091 (5) 637 (3) 3120 (7) to to to to to to to to to to 2.86 p < 0.01 p < 0.01 p < 0.01 p = 0.07 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < (1) 355 (1) 597 (1) 76 (1) 578 (1) 593 (1) 557 (1) 553 (1) 357 (1) 821 (2) to 1.11 to 1 to to p = 0.01 p = 0.01 P = 0.05 p = (1) 555 (1) 44 (1) 562 (1) Row 1: effect size (RR for dichotomous outcomes, unstandardised [weighted] mean difference for continuous outcomes). Row 2, 3: 95% CI. Row 4: p value vs a null hypothesis of no difference in effect (RR: 1; mean difference: 0). Row 5: Number of patients (studies) which contributed to meta-analysis. Abbreviations: CI, confidence interval; ER, extended release; IR, immediate release; RR, risk ratio. * Only data suitable for meta-analysis are presented in this table. european urology 54 (2008)

10 552 Table 5 Tolerability of antimuscarinics compared to placebo control: Results from meta-analyses* Darifenacin 7.5 mg/day Darifenacin 7.5 mg/day titrated Darifenacin 15 mg/day Fesoterodine 4 mg/day Fesoterodine 8 mg/day IR 5 mg/day IR mg/day IR 15 mg/day IR 30 mg/day Total withdrawals Withdrawals due to adverse events Total withdrawals Withdrawals due to adverse events Withdrawals due to deaths p = 0.27 p = 0.54 p = 0.88 p = 0.23 p = 0.73 p = 0.36 p = 0.04 p < 0.01 p = (2) 398 (1) 1416 (4) 557 (1) 573 (1) 60 (1) 1054 (5) 751 (5) 597 (1) p = 0.66 p = 0.16 p = 0.07 p = 0.35 p = 0.44 p = 0.64 p = 0.01 p < 0.01 p = (1) 398 (1) 657 (2) 926 (2) 929 (2) 60 (1) 488 (1) 743 (4) 597 (1) IR 45 mg/day ER 20 mg/day ER 30 mg/day Solifenacin 5 mg/day Solifenacin 10 mg/day Tolterodine ER 4 mg/day Tolterodine IR 2 mg/day Tolterodine IR 4 mg/day Trospium chloride 40 mg/day p = 0.41 p = 0.76 p = 0.83 p = 0.15 p = 0.1 p = 0.24 p = 0.44 p = (1) 805 (1) 593 (1) 2710 (4) 2689 (4) 2113 (5) 398 (2) 2261 (6) 832 (2) p = 0.01 p = 0.1 p = 0.44 p = 0.04 p = 0.02 p = 0.77 p = 0.39 p = (1) 593 (1) 3575 (5) 2689 (4) 3777 (5) 851 (5) 3973 (11) 1490 (3) p = 0.5 p = 0.61 p = (1) 1678 (2) 1015 (1) 251 (1) 1324 (2) european urology 54 (2008) Row 1: effect size (risk ratio [RR]). Row 2: 95% CI. Row 3: p value vs a null hypothesis of no difference in effect (RR: 1). Row 4: Number of patients (studies) which contributed to meta-analysis. Abbreviations: ER, extended release; IR, immediate release. * Only data suitable for meta-analysis are presented in this table.

11 european urology 54 (2008) other than trospium chloride, for which this outcome was not reported. Differences in pooled mean changes were ml. was not statistically more effective as IR 45 mg/day based on evidence from data from two trials [40,41] but was statistically more effective in this outcome as ER 20 mg/day based on evidence from one trial [24]. The following statistically significant differences among active treatments were found: solifenacin 10 mg/ day was favoured over tolterodine IR 4 mg/day (14.8; 95% CI, ; p < 0.01); solifenacin 10 mg/day was favoured over solifenacin 5 mg/day (7.3; 95% CI, ; p < 0.01); solifenacin 10 mg/day was favoured over propiverine ER 20 mg/day (7.0; 95% CI, ; p = 0.02); fesoterodine 8 mg/day was favoured over tolterodine ER 4 mg/day (10.0; 95% CI, ; p = 0.03); and oxybutynin IR 15 mg/day was favoured over tolterodine IR 4 mg/day (13.3; 95% CI, ; p < 0.01). Proportions of patients with improvements in their bladder condition (ie, storage symptoms) from two trials were suitable for meta-analysis [14,42]. The proportion of patients was statistically significantly higher for fesoterodine 4 mg/day and 8 mg/ day than for placebo (RR: 1.49; 95% CI, ; p = 0.01; and RR: 1.51; 95% CI, ; p = 0.01, respectively). Results were also reported in this outcome for oxybutynin IR mg/day and tolterodine ER 4 mg/day but were not statistically significant. There were no statistically significant differences among active treatments Tolerability Summaries of the results of the meta-analyses of tolerability outcomes are shown in Table 5. Withdrawals due to any cause were a frequently reported outcome. IR 15 mg/day and oxybutynin IR mg/day were associated with statistically significantly higher risk of withdrawal from trial due to any cause than placebo (RR: 1.33; 95% CI, ; p = 0.04; and RR: 1.72; 95% CI, ; p < 0.01, respectively). Otherwise, no statistically significant differences in proportions of patients who withdrew from trials for any causes were found between placebo and any active treatments (Fig. 2). The following statistically significant differences among active treatments were found: oxybutynin IR mg/day was associated with a significantly greater risk of withdrawal due to any cause than oxybutynin ER 5 mg/day (RR; 2.22; 95% CI, ; p = 0.03); oxybutynin IR mg/day carried a greater risk of withdrawal than tolterodine ER 4 mg/day (RR: 2.22; 95% CI, ; p < 0.01) and tolterodine IR 4 mg/day (RR: 1.41; 95% CI, ; p = 0.04); oxybutynin IR 15 mg/day carried a greater risk of withdrawal than tolterodine IR 4 mg/day (RR: 2.44; 95% CI, ; p < 0.01) and oxybutynin ER 15 mg/day (RR: 1.83; 95% CI, ; p = 0.04). Tolterodine ER 4 mg/day was the only formulation found to be associated with a statistically significantly lower risk than placebo of withdrawal due to an adverse event (RR: 0.71; 95% CI, ; p = 0.02). Four formulations were found to be associated with a statistically significantly higher risk of withdrawal due to adverse events than placebo: oxybutynin IR mg/day (RR: 1.91; 95% CI, ; p = 0.01), oxybutynin IR 15 mg/ day (RR: 1.89; 95% CI, ; p < 0.01), propiverine ER 20 mg/day (RR: 2.39; 95% CI, ; p = 0.01), and solifenacin 10 mg/day (RR: 1.53; 95% CI, ; p = 0.04). Additionally, tolterodine ER 4 mg/day was associated with lower risk of this outcome than oxybutynin TDS 3.9 mg/day (RR: 0.15; 95% CI, ; p = 0.01) and oxybutynin IR 15 mg/day (RR: 0.32; 95% CI, ; p < 0.01); tolterodine IR 4 mg/day was associated with a lower risk than oxybutynin IR 15 mg/day (RR: 0.47; 95% CI, ; p < 0.01); and oxybutynin ER 5 mg/day was associated with a lower risk than oxybutynin ER 15 mg/day (RR: 0.27; 95% CI, ; p = 0.04). There were no other statistically significant differences among active treatments. Withdrawal due to death was infrequently reported, possibly due to the low incidence of mortality relative to other outcomes in OAB patients in trials of this length. No statistically significant differences were reported among treatments (active and placebo) in any of the analyses conducted Safety Summaries of the results of the meta-analyses of safety outcomes are shown in Table 6. Every treatment in the review, with two exceptions, was statistically significantly associated with a greater risk of adverse events than placebo (Fig. 3). The two exceptions were tolterodine IR 2 mg/day (RR: 1.00; 95% CI, ; p = 0.97) and oxybutynin TDS 3.9 mg/day (RR: 1.59; 95% CI, ; p = 0.07). Where statistically significant, the pooled RR for any adverse event in comparison to placebo varied between 1.13 and No treatment was shown to be significantly associated with serious adverse events. In accordance with the data on tolerability, there were favourable results for tolterodine formulations relative to other active treatments. The risk of adverse events was statistically significantly lower with tolterodine IR 2 mg/day than with oxybutynin ER 5 mg/day (RR: 0.59; 95% CI, ; p < 0.01) and

12 554 european urology 54 (2008) Fig. 2 Forest plot of relative risk of all-cause withdrawals versus placebo for each included treatment and dose. lower with tolterodine IR 4 mg/day than with oxybutynin IR 7.5 to 10 mg/day (RR: 0.83; 95% CI, ; p < 0.01) and oxybutynin IR 15 mg/day (RR: 0.86; 95% CI, ; p < 0.01). One trial provided data suggestive of a higher risk of adverse events with fesoterodine 8 mg/day than with fesoterodine 4 mg/day (RR: 1.17; 95% CI, ; p = 0.04) and tolterodine ER 4 mg/day (RR: 1.18; 95% CI, ; p = 0.04). The remaining statistically significant result favoured trospium 40 mg/day over oxybutynin IR mg/day (RR: 0.85; 95% CI, ; p = 0.02). No treatment in the review was statistically significantly associated with a greater risk of serious adverse events than placebo or other active treatment. A study by Jünemann et al [34], however, reported that 26 (3.3%) of 786 patients receiving 30 mg/day propiverine ER and IR in a trial had experienced serious adverse events compared to none of the 202 patients receiving placebo. No data were available for propiverine at other doses from this or other studies. Table 7 ranks the frequency of reporting by patients of specific adverse events in antimuscarinic arms of the trials included in this review. Dry mouth was the most frequently reported adverse event, reported by 29.6% and 7.9% of active treatment and placebo-arm patients, respectively. The next most common adverse event was pruritus (15.4% on treatment vs 5.2% on placebo) [43,44]. In OAB trials, the severity of dry mouth, defined as the subjective assessment of the subject experiencing the adverse event, is a commonly recorded outcome. Dry mouth of any severity (mild, moderate, or severe) was found to be highly statistically significantly more common in all interventions than placebo ( p 0.01). Where significant, the pooled RR varied between 2.15 and It was apparent that the RR generally increased with drug dose for darifenacin, fesoterodine, solifenacin, and toltero-

13 Table 6 Adverse events of antimuscarinics compared to placebo: Results from meta-analyses* Darifenacin 7.5 mg/day Darifenacin 7.5 mg/day titrated Darifenacin 15 mg/day Fesoterodine 4 mg/day Fesoterodine 8 mg/day IR 5 mg/day IR mg/day IR 15 mg/day IR 20 mg/day TDS mg/day Any adverse event Any serious adverse event Dry mouth (any severity) Any adverse event Any serious adverse event Dry mouth (any severity) p < 0.01 p < 0.01 p < 0.01 p = 0.01 p < 0.01 p < 0.01 p < 0.01 p = (2) 395 (1) 1262 (3) 555 (1) 570 (1) 289 (1) 748 (4) 355 (1) p = 0.08 p = 0.43 p = 0.37 p = 0.06 p = (2) 395 (1) 1262 (3) 488 (1) 568 (2) p < 0.01 p = 0.01 p < 0.01 p < 0.01 p < 0.01 p = 0.41 p < 0.01 p < 0.01 p < 0.01 p = (2) 395 (1) 1611 (5) 1010 (3) 1016 (3) 57 (1) 923 (4) 1006 (7) 62 (1) 612 (2) IR 30 mg/day IR 45 mg/day ER 20 mg/day ER 30 mg/day Solifenacin 5 mg/day Solifenacin 10 mg/day Tolterodine ER 4 mg/day Tolterodine IR 2 mg/day Tolterodine IR 4 mg/day Trospium chloride 40 mg/day p < 0.01 p < 0.01 p = 0.04 p < 0.01 p < 0.01 p = 0.02 p < 0.01 p = 0.97 p < 0.01 p < (1) 457 (3) 62 (1) 593 (1) 1230 (3) 488 (2) 2634 (4) 851 (5) 2119 (10) 1409 (4) p = 0.05 p = 0.09 p = 0.53 p = 0.25 p = 0.45 p = (1) 593 (1) 3199 (4) 398 (2) 2335 (6) 517 (2) p < 0.01 p = 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < (1) 164 (2) 867 (2) 593 (1) 3691 (6) 2951 (5) 4129 (6) 838 (5) 4071 (11) 1389 (3) Row 1: effect size (RR). Row 2: 95% CI. Row 3: p value vs a null hypothesis of no difference in effect (RR: 1). Row 4: Number of patients (studies) which contributed to meta-analysis. Abbbreviations: CI, confidence interval; ER, extended release; IR, immediate release; RR, risk ratio. * Only data suitable for meta-analysis are presented in this table. european urology 54 (2008)

14 556 european urology 54 (2008) Fig. 3 Forest plot of relative risk of any- or all-cause adverse event versus placebo for each included treatment and dose. dine, although this trend was not apparent for oxybutynin and propiverine. Mild dry mouth was found to be statistically significantly more common in patients treated with oxybutynin, propiverine, solifenacin, and tolterodine than with placebo. Event rates were not significant for fesoterodine, and no data were available for metaanalysis for darifenacin. The pooled RR varied between 1.91 and The RR for solifenacin 10 mg/day was higher than for solifenacin 5 mg/ day. The risk of this adverse event in patients treated with tolterodine ER 4 mg/day was statistically significantly less than in those treated with oxybutynin 7.5 mg/day IR (RR: 0.76; 95% CI, ; p = 0.05). The following adverse events were reported at statistically significantly higher levels in active treatments than in placebo: blurred vision (oxybutynin IR 15 and 20 mg/day; propiverine 20, 30, and 45 mg/day; solifenacin 10 mg/day; and tolterodine ER 4 mg/day); constipation (darifenacin 7.5 mg/day, with and without titration, and 15 mg/day; propiverine ER 20 mg/day and IR 3 and 4.5 mg/day; solifenacin 5 and 10 mg/day; tolterodine 4 mg/day; and trospium 40 mg/day); erythema (oxybutynin TDS 3.9 mg/day); fatigue (tolterodine ER 4 mg/day); pruritus (oxybutynin TDS 3.9 mg/day); increased sweating (solifenacin 5 mg/day); and urinary retention (oxybutynin IR mg/day). The following adverse events were reported at statistically significantly higher levels in firstnamed active treatments than in second-named active treatments: blurred vision (solifenacin 10 mg/ day vs solifenacin 5 mg/day, solifenacin 10 mg/day vs tolterodine IR 4 mg/day, propiverine IR 45 mg/day vs oxybutynin IR mg/day); constipation (solifenacin 10 mg/day vs propiverine ER 20 mg/day, solifenacin 5 mg/day vs tolterodine ER and IR 4 mg/ day, darifenacin 15 mg/day vs tolterodine IR 4 mg/ day); fatigue (tolterodine ER 4 mg/day vs fesoterodine 4 or 8 mg/day); nausea (oxybutynin IR 15 mg/ day titrated vs oxybutynin ER 15 mg/day titrated; oxybutynin IR mg/day vs propiverine IR

15 european urology 54 (2008) Table 7 Proportion of patients in placebo arms of included trials who experienced adverse events Outcome Patients receiving placebo treatment Patients receiving antimuscarinic treatment Proportion of patients reporting adverse event Number of patients followed up Proportion of patients reporting adverse event Number of patients followed up Any adverse event 39.9% % 9199 Dry mouth (any severity) 7.9% % Dry mouth (mild/moderate) 8.5% % 3006 Dry mouth (mild) 5.7% % 7348 Pruritus 5.2% % 246 Dry mouth (moderate/severe) 2.7% % 3884 Vertigo 16.7% % 24 Constipation 3.9% % Confusion 11.3% % 65 Erythema 2.0% % 246 Dry mouth (moderate) 0.9% % 5967 Headache 4.9% % 9784 Urinary tract infection 3.6% % 4428 Dyspepsia 2.1% % 6477 Blurred vision 2.6% % Diarrhoea 3.1% % 4238 Dizziness 2.5% % 7154 Nausea 3.1% % 7429 Somnolence 1.9% % 3752 Dry mouth (severe) 0.2% % 6300 Any serious adverse event 1.9% % 7391 Sweating increased 0.0% % 109 Vomiting 2.8% % 1462 Insomnia 1.8% % 2605 Fatigue 0.6% % 1929 Urinary retention 0.2% % mg/day); and vomiting (tolterodine ER 4 mg/day vs oxybutynin ER 7.5 to 10 mg/day) Health-related quality of life The importance of HRQL as an outcome in OAB trials is becoming increasingly appreciated. Of the 83 included trials in this review, 37 (44%) reported HRQL findings, and of those, 15 were either new studies added in the update or supplementary information from those studies previously included. Although the HRQL data were limited by inconsistencies among the instruments used and few reported domains, statistically significant differences in HRQL compared to placebo were reported for darifenacin, fesoterodine, oxybutynin TDS, propiverine ER and IR, solifenacin, tolterodine ER and IR, and trospium (Table 8). An update of a separate meta-analysis of the effects of antimuscarinics on HRQL [45] will address this topic in greater detail. 4. Discussion We present here the updated results of the largest systematic review conducted to date on the efficacy, safety, and tolerability of antimuscarinic treatments for OAB. Considerably more evidence is presented in this review than in the previous review published in 2005 [8]. The number of trials extracted increased from 56 to 83, reflecting the sizeable amount of newly published research in this field and the inclusion of the new agent fesoterodine in the review, which received marketing authorisation in April 2007 [10]. Antimuscarinics proved to be efficacious compared to placebo in this update, just as they did in the prior systematic review. The relative efficacy of each antimuscarinic is less clear, although there are some statistically significant results in favour of the higher dosage of propiverine, fesoterodine, and solifenacin over placebo and lower dose antimuscarinics. More data are presented to demonstrate the tolerability of antimuscarinics relative to placebo. As in the previous review, oxybutynin treatment was found to be significantly associated with greater rates of withdrawal. A new aspect which has appeared in this therapeutic area is that of dose flexibility with newer agents; this allows titration towards optimal efficacy versus tolerability. The relative tolerability of each antimuscarinic is less

16 558 european urology 54 (2008) Table 8 Summary of the effects of antimuscarinics on HRQL (all significant differences between antimuscarinics and placebo reported in included trials) Significant impact reported for: Global HRQL Domains Overall HRQL Contilife: Overall HRQL Solifenacin IIQ: Overall HRQL TDS; Tolterodine ER; Trospium ICIQ-SF: Overall score Fesoterodine; Tolterodine ER KHQ: Overall score IR; ER, IR KHQ: General health Solifenacin; OAB-q: Overall HRQL Darifenacin; Tolterodine ER; Solifenacin PISQ: Overall score Tolterodine ER SQOL-F: Overall score Tolterodine ER Daily activities Contilife: Daily activities Solifenacin; Tolterodine IR Physical limitations KHQ: Physical limitations Tolterodine IR, ER; Darifenacin; Solifenacin; Travel IIQ: Travel TDS; Tolterodine ER; Trospium Sleep and energy KHQ: Sleep and energy Tolterodine IR, ER; Solifenacin; OAB-q: Sleep Solifenacin Basle: Tired fresh IR Self-image Contilife: Self-image Solifenacin Emotions Contilife: Emotional consequences Solifenacin OAB-q: Concern Tolterodine ER; Solifenacin KHQ: Emotional problems Tolterodine IR, ER; Solifenacin; HAD: Anxiety Tolterodine ER IIQ: Feelings Trospium Relationships IIQ: Relationships Trospium KHQ: Role limitations Tolterodine IR, ER; Darifenacin; Solifenacin; KHQ: Personal relationships Tolterodine ER; Solifenacin; Sexuality Contilife: Sexuality Solifenacin Social limitations KHQ: Social limitations Tolterodine ER; Solifenacin; Basle: Taciturn talkative IR Basle: Retiring gregarious IR OAB-q: Social interaction Tolterodine ER Coping KHQ: Severity (coping) Tolterodine IR, ER OAB-q: Coping Tolterodine ER; Solifenacin Disease-specific domains Symptom severity KHQ: Symptom severity Tolterodine IR, ER; Darifenacin; Solifenacin; OAB-q: Bother Solifenacin UDI: Irritative symptoms TDS; Tolterodine ER OAB-q: Symptom bother Tolterodine ER Incontinence KHQ: Incontinence impact Tolterodine IR, ER; Darifenacin; Solifenacin; GAQ: Stress score IR UDAAQ: Warning time Darifenacin UDAAQ: Leakage Darifenacin Urgency GAQ: Urge score IR Abbreviations: Basle, Basle Subjective Well-Being Survey; Contilife, Quality of Life Assessment Questionnaire Concerning Urinary Incontinence; ER, extended release; GAQ, Gaudenz Appraisal Questionnaire; HAD, Hospital Anxiety Depression Scale Questionnaire; HRQL, health-related quality of life; ICIQ-SF, International Consultation on Incontinence Questionnaire-Short Form; IIQ, Incontinence Impact Questionnaire; IR, immediate release; KHQ, King s Health Questionnaire; OAB-q, Overactive Bladder Questionnaire; PISQ, Pelvic Organ Prolapse/Urinary Incontinence Questionnaire; SQOL-F, Sexual Quality of Life-Female; UDAAQ, Urinary Daily Activity Assessment Questionnaire; UDI, Urinary Distress Inventory. clear, though there are consistently favourable data available for tolterodine ER 4 mg/day. Antimuscarinics were associated with greater risks of adverse events than placebo, the most common being dry mouth, pruritus, and headache; however, there was no association between treatment with antimuscarinics and risk of serious adverse events, with the possible exception of propiverine ER 30 mg/day [34]. There was a wide range in incidence of dry mouth (range: 4 70%), as might be expected given the variability in study protocols and subject populations. However, the incidence of dry mouth was generally similar for ER antimuscarinics and appeared to increase with higher dosages. Constipation may be the most burdensome and bothersome adverse effect for the majority of those on antimuscarinic treatment. Constipation is common, particularly in elderly patients, and increased risk of constipation with medications is a concern

17 european urology 54 (2008) for HRQL along with the increased financial burden for health care costs in this population [46]. Moreover, there is evidence that constipation can aggravate symptoms of OAB [47]. There appears to be a trend for a lower incidence of constipation as an adverse effect with fesoterodine. Antimuscarinics may cause central nervous system (CNS) adverse events, such as dizziness, somnolence, insomnia, or cognitive effects. Antimuscarinics differ in their propensity to cross the blood brain barrier due to differences in lipophilicity, and thus in the likelihood that they will produce CNS adverse events [48 50]. may be the most likely to cross the blood brain barrier; trospium is least likely. Elderly patients who have cerebrovascular disease or other comorbidities that alter the permeability of the brain blood barrier, reduced muscarinic receptor densities in the brain, age-related changes in drug elimination, or who are taking multiple medications might be at greater risk for CNS adverse events [51]. Despite the systematic search, collation, and presentation of evidence into the efficacy, safety, and tolerability of antimuscarinics in OAB, there are limitations to this study. Many outcomes and many treatments (including placebo) were compared, stratified by dose and mode of administration. This methodology creates a large number of potential comparisons and, although it is mitigated through the unavailability of data for more obscure active treatment comparisons, the strong potential for false-positive results clearly exists. It is therefore worth adopting a cautious approach to the interpretation of p values, particularly for uncommonly reported outcomes in comparisons among active treatments in which few data may have been available. Additionally, we used frequency, incontinence, urgency, and mean voided volume to assess the efficacy of antimuscarinics; these are all commonly used efficacy outcomes in OAB trials. However, a consensus has not yet been reached on the optimal way to measure urgency, which is the hallmark symptom of OAB, and there is variation among patients in the OAB symptoms and the degree of symptom bother that they experience. This study is also limited by restrictions on the types of patients typically included in OAB trials as well as by topics that have not been adequately addressed in the current antimuscarinic literature. For example, most of the studies restrict the study population to patients with limited comorbidities, and there is an evident gap in the literature base concerning the evaluation of elderly patients with significant comorbidity. Moreover, potentially important CNS adverse events, such as memory impairment, have traditionally not been evaluated in antimuscarinic trials; this is an area for future research, particularly in patient populations that may be at increased risk for such effects. Little data are also available on efficacy and tolerability of antimuscarinic agents in treatment-naïve subjects versus subjects previously treated with antimuscarinics. This information is often not reported, and different studies use wash-out periods of varying length. Finally, a systematic review is to some extent reliant on the unbiased selection of outcomes in the reviewed studies [52]. We found that histograms of p values from the meta-analyses were highly skewed, a result suggestive of outcomes that were statistically significant in individual studies being more commonly reported than equally valid but not statistically significant results from those trials. The development of a standard set of outcomes to be included in all OAB studies would alleviate this issue for future research and more pragmatic, direct headto-head comparative studies are highly recommended. A strength of the meta-analytic technique is that it provides an overall perspective of differences between efficacy and safety among individual antimuscarinic drugs using all suitable data and large numbers of trial participants and is therefore less susceptible to the weaknesses of individual studies. Head-to-head trials designed to mirror clinical practice, such as the STAR trial [30], are very useful, but for any individual head-to-head study, it must always be borne in mind that results may be atypical for one agent or influenced by trial design and must always be interpreted in the context of the body of literature. 5. Conclusions This comprehensive systematic review and metaanalysis has evaluated all data currently available on antimuscarinic therapy for OAB. Conclusions derived from such a comparison between antimuscarinics must be interpreted cautiously, taking into account the different inclusion and exclusion criteria, investigative sites, geographical locations, and study durations for individual trials. The ceiling may have been reached for the therapeutic efficacy of antimuscarinics, with the only new innovation being that of dose flexibility with the newer antimuscarinics such as darifenacin, solifenacin, and fesoterodine. Dose flexibility allows for individual titration of therapy to produce a maximum efficacy versus tolerability in individual cases. Certainly the new agents have greater tolerability

18 560 european urology 54 (2008) than drugs such as oxybutinin, and once-a-day formulations of all of the agents seem to be better tolerated by patients and potentially more efficacious in improving OAB symptoms as well as in terms of patient perception of treatment impact. Therapeutic agents with different mechanisms of action are currently being studied, and alternative treatments with improved efficacy and tolerability may eventually be developed. However, the evidence to date suggests that antimuscarinics are efficacious, safe, and well-tolerated treatments for OAB, which improve HRQL, and these agents currently remain the first-line pharmacologic treatment for OAB. Author contributions: Christopher R. Chapple 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: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein. Acquisition of data: Chapple, Muston, Bitoun, Weinstein. Analysis and interpretation of data: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein. Drafting of the manuscript: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein. Critical revision of the manuscript for important intellectual content: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein. Statistical analysis: Gabriel, Muston, Weinstein. Obtaining funding: Chapple. Administrative, technical, or material support: Gabriel, Muston, Bitoun, Weinstein Supervision: Chapple, Gabriel, Muston, Bitoun, Weinstein. Other (specify): None. Financial disclosures: I certify 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, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Chapple is a scientific consultant and researcher with Allergan, Astellas, Novartis, and Pfizer. Khullar is a consultant, investigator, researcher or speaker with Astellas, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Schwartz Pharma. Gabriel and Muston were consultants with Heron Evidence Ltd. at the time this research was conducted. Gabriel, Bitoun, and Weinstein are currently employees of Pfizer. Funding/Support and role of the sponsor: Research grant from Pfizer Ltd for review. 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