A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder

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1 european urology 54 (2008) available at journal homepage: Review Neuro-urology A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder Giacomo Novara a, Antonio Galfano b, Silvia Secco b, Carolina D Elia b, Stefano Cavalleri b, Vincenzo Ficarra b, Walter Artibani b, * a I.R.C.C.S. Istituto Oncologico Veneto (I.O.V.), Padova, Italy b Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Italy Article info Article history: Accepted June 25, 2008 Published online ahead of print on July 9, 2008 Keywords: Overactive bladder Urgency frequency syndrome Detrusor overactivity Muscarinic receptor antagonist Darifenacin Emepronium Fesoterodine Oxybutynin Propantheline Propiverine Solifenacin Tolterodine Trospium Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Context: Anticholinergic drugs are commonly used in patients with overactive bladder (OAB) who do not achieve symptom relief and quality of life improvement with conservative management. Several drugs, with different doses, formulations, and routes of administration are currently available, making the choice quite difficult. Objective: To evaluate efficacy and safety of different doses, formulations, and route of administration of the available anticholinergic drugs. Evidence acquisition: A systematic review of the literature was performed in August 2007 using Medline, Embase, and Web of Science. Efficacy (micturitions, volume voided per micturition, urgency urinary incontinence episodes, incontinence episodes ) and safety (mainly, adverse events and withdrawal rates) end points were evaluated in the randomized control trials (RCTs) assessing the role of anticholinergic drugs in non-neurogenic OAB. Meta-analysis of RCTs was conducted using the Review Manager software 4.2 (Cochrane Collaboration). Evidence synthesis: Our systematic search identified 50 RCTs and three pooled analyses. Tolterodine immediate release (IR) had a more favorable profile of adverse events than oxybutynin IR. Regarding different dosages of IR formulations, dose escalation might yield some limited improvements in the efficacy but at the cost of significant increase in the rate of adverse events. In the comparisons between IR and extended-release (ER) formulations, the latter showed some advantages, both in terms of efficacy and safety. With regard to the route of administration, use if a transdermal route of administration does not provide significant advantage over an oral one. Conclusion: Many of the available RCTs have good methodological quality. ER formulations should be preferred to the IR ones. With regard to IR formulations, dose escalation might yield some improvements in the efficacy with significant increase in the AE. More clinical studies are needed to indicate which of the drugs should be used as first-, second-, or third-line treatment. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV Floor, Via Giustiniani 2, 35128, Padua, Italy. Tel ; Fax: address: walter.artibani@unipd.it (W. Artibani) /$ see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 54 (2008) Fig. 1 Flow-chart of meta-analysis. RCTs, randomized control trials, OAB, overactive bladder. 1. Introduction Overactive bladder (OAB) is a highly prevalent condition [1,2] with enormous related costs per year [3,4]. First-line treatments for OAB include lifestyle modifications, behavioral therapy, pelvic floor muscle training, and bladder training. Antimuscarinic drugs are the first-line drug therapy, while other therapeutic options, such as botulinum toxin injection, neuromodulation, or surgical interventions are used in a smaller percentage of patients who are non-responders to drug therapies [5,6]. Several antimuscarinic drugs are on the market, including oxybutynin, tolterodine, propiverine, trospium, the recently released solifenacin and darifenacin, and fesoterodine, which was the last one to receive the European Medicines Evaluation Agency (EMEA) marketing authorization in Moreover, some drugs such as oxybutynin, tolterodine, propiverine, or trospium are available both in immediate-release (IR) and extended-release (ER) formulations, while oxybutynin is also available in a sustained-delivery patch for transdermal administration [7]. Two meta-analyses evaluated the efficacy of the anticholinergic drugs in comparison to placebo, showing that the use of these drugs results in statistically significant improvements in symptoms and quality of life [8,9]. To date, however, the clinical data available on the active comparisons of different drugs, formulations, and routes of administration are more limited. Specifically, a Cochrane meta-analysis based on a systematic review performed in January 2002 demonstrated that tolterodine was as effective as, but better tolerated than, oxybutynin; moreover, ER formulations of oxybutynin and/or tolterodine were shown to cause a lower risk of dry mouth compared to the IR formulations. Comparing head-to-head the ER formulations, xerostomia was less common in those patients receiving tolterodine [10]. Inamore recent meta-analysis which mainly focused on placebo-controlled trials, Chapple et al reported some data on the trials of drugs which provided active drug controls. Solifenacin was shown to be more effective than tolterodine IR in terms of reduction of both urgency episodes and number of micturitions, while oxybutynin ER was shown to be more effective than tolterodine ER, in terms of reduction of incontinence episodes. Finally, oxybutynin IR 15 mg once daily, solifenacin 5 mg once daily, and solifenacin 10 mg once daily were more effective than tolterodine IR in increasing the volume voided per micturitions [8]. The purpose of the present systematic review and meta-analysis was to evaluate all the clinical data derived from randomized controlled trials in order to assess the efficacy and safety of different doses, formulations, and routes of administration of the currently available anticholinergic drugs, as well as head-to-head comparisons of different drugs. 2. Methods The systematic review of the literature was performed in August 2007 using the Medical Literature Analysis and

3 Table 1 Efficacy data from the randomized control trials (RCTs) comparing different doses and formulations of oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine 742 Reference Dose (no. of cases) Treatment duration Jadad score in daytime micturitions in nighttime micturitions in micturitions in volume voided per micturitions (ml) in urgency episodes in UUI episodes in incontinence episodes in pads used Oxybutynin Nilsson et al 1997 [13] Oxy IR 5 mg bid (17) 8 wk 1 NR NR 2.8 (24%) NR NR NR NR NR Oxy ER 10 mg qd (16) 2.6 (23%) Versi et al 2000 [14] Oxy IR different doses (115) variable 3 NR NR NR NR NR 0.6 (76%) 0.7 (75%) NR Oxy ER different doses (111) 0.4 (83%) 0.5 (81%) Barkin et al 2004 [15] Oxy IR different doses (41) 6 wk 3 NR NR 2.4 (22%) +40 (18%) 1.3 (41%) NR 2.41 (73%) 0.5 (21%) Oxy ER different doses (53) 1.8 (16%) +25 (14%) 1.0 (30%) 1.81 (54%) 0.6 (26%) Corcos et al 2005 [16] Oxy ER 5 mg qd (77) 4 wk 3 NR NR 0.8 (7%) (8%) 1.8 (37%) NR NR NR Oxy ER 10 mg qd (77) 1.1 (11%) (10%) 1.5 (34%) Oxy ER 15 mg qd (83) 1.5 (14%) (21%) 2.0 (46%) Propiverine Junemann et al 2006 [17] Propi IR 15 mg bid (395) 4 wk 1 NR NR 3.69 (29%) ml (32.6%) 2.03 (33%) NR 2.21 (67%) NR Propi ER 30 mg qd (391) 3.63 (28%) ml (27.9%) 2.58 (40%) 2.47 (73%) Tolterodine Jonas et al 1997 [18] Tolt IR 1 mg bid (99) 4 wk 3 NR NR 1.4 (12%) +20 ml* NR NR 1.1* NR Tolt IR 2 mg bid (99) 1.7 (15%) +20 ml* 1.6* Rentzhog et al 1998 [19] Tolt IR 0.5 mg bid (21) 2 wk 1 NR NR 1.0 (10%) +15%* NR NR 0.7 (35%) 10%* Tolt IR 1 mg bid (16) 1.1 (10%) +25%* 0.6 (37%) 10%* Tolt IR 2 mg bid (14) 2.5 (20%) +30%* 0.8 (46%) 29%* Tolt IR 4 mg bid (16) 2.0 (20%) +30%* 1.6 (60%) 40%* Millard et al 1999 [20] Tolt IR 1 mg bid (123) 12 wk 1 NR NR 2.3 (20%) +27 (18%) NR 1.7 (44%) NR NR Tolt IR 2 mg bid (129) 2.3 (20%) +36 (23%) 1.7 (47%) Jacquetin et al 2001 [21] Tolt IR 1 mg bid (97) 4 wk 1 NR NR 1.4 (13%) +20 (13%) NR 1.1 (41%) NR NR Tolt IR 2 mg bid (103) 1.4 (13%) +19 (12%) 1.3 (41%) Malone-Lee et al 2001 [22] Tolt IR 1 mg bid (61) 4 wk 3 NR NR 0.7 (6%) +9 (6%) NR 0.3 (13%) NR NR Tolt IR 2 mg bid (73) 0.7 (6%) +16 (11%) 0.7 (25%) Van Kerrebroeck et al 2001 [23] Tolt IR 2 mg bid (514) 12 wk 3 NR NR 1.7 (15%) +29 (21%) NR NR 1.51 (46%) 0.5 (36%) Tolt ER 4 mg qd (507) 1.8 (16%) +34 (24%) 1.68 (53%) 0.5 (36%) Swift et al 2003 [24] Tolt IR 2 mg bid (408) 12 wk 3 NR NR 1.7 (15%) +32 (24%) NR NR 1.44 (44%) 0.5 (33%) Tolt ER 4 mg qd (417) 1.9 (17%) (27%) 1.68 (53%) 0.6 (37%) european urology 54 (2008) Solifenacin Cardozo et al 2004 [25] Soli 5 mg qd (286) 12 wk 2 NR 0.56 (25.3%) 2.37 (20%) * 2.84 (25%) 1.3 (63%) 1.63 (61%) NR Soli 10 mg qd (290) 0.71 (38.5%) 2.81 (22%) * 2.90 (30%) 1.2 (57%) 1.57 (52%) Chapple et al 2004 [26] Soli 5 mg qd (264) 12 wk 2 NR NR 2.19 (17%) (25%) 2.85 (52%) 1.41 (65%) 1.42 (59%) NR Soli 10 mg qd (261) 2.61 (20%) (29%) 3.07 (55%) 1.36 (63%) 1.45 (47%) Chapple et al 2006** [27] Soli 5 mg qd (552) 12 wk NA NR 0.6* 2.3* +32.3* 2.9* NR 1.5* NR Soli 10 mg qd (1158) 0.6* 2.7* +42.5* 3.4* 1.8* Darifenacin Chapple et al 2005** [28] Dari 7.5 mg qd (337) 12 wk NA NR NR 1.6 (17%) +15 (10%) 2.0 (29%) NR 4.0 (77%) NR Dari 15 mg qd (334) 1.9 (17%) +27 (17%) 2.3 (29%) 4.8 (79%) Foote et al 2005** [29] Dari 7.5 mg qd (97) 12 wk NA NR NR 1.8 (18%) +14 (10%) 2.1 (26%) NR 1.6 (67%) NR Dari 15 mg qd (110) 1.8 (17%) +27 (18%) 2.4 (26%) 1.5 (76%) Zinner et al 2005 [30] Dari 15 mg qd (58) 2 wk 2 NR NR 1.14 (12%) NR 1.27 (16%) NR 1.44 (92%) NR Dari 30 mg qd (58) 1.62 (18%) 1.63 (21%) 1.74 (138%) Hill et al 2006 [31] Dari 7.5 mg qd (108) 12 wk 3 NR NR 1.7 (17%) +17 (10%) 1.8 (29%) NR 1.15 (69%) NR Dari 15 mg qd (107) 1.9 (18%) +24 (16%) 2.3 (27%) 1.48 (76%) Dari 30 mg qd (115) 2.2 (21%) +44 (26%) 3.0 (33%) 1.62 (77%)

4 european urology 54 (2008) Table 1 (Continued ) in pads used in incontinence episodes in UUI episodes in urgency episodes in volume voided per micturitions (ml) in micturitions in nighttime micturitions in daytime micturitions Jadad score Reference Dose (no. of cases) Treatment duration Fesoterodine Nitti et al 2005 [32] Feso 4 mg qd (44) 8 wk 2 NR NR 0.996* * NR NR NR NR Feso 8 mg qd (47) 1.815* * Feso 12 mg (39) 1.784* * Chapple et al 2007 [33] Feso 4 mg qd (272) 12 wk (14%) 0.39 (29%) 1.76 (17%) (17%) 1.88 (18%) 1.95 (80%) NR NR Feso 8 mg qd (288) 1.48 (17%) 0.39 (23%) 1.88 (19%) (22%) 2.36 (19%) 2.22 (87%) Nitti et al 2007 [34] Feso 4 mg (283) 12 wk (10%) 0.58 (26%) 1.61 (12%) (11%) 1.91 (15%) 1.65 (42%) NR NR Feso 8 mg (279) 1.54 (15%) 0.55 (29%) 2.09 (17%) (21%) 2.3 (20%) 2.28 (59%) *Baseline values not provided in the published manuscript; **pooled analysis of RCTs; NR: not reported; NA, not applicable; qd, once daily; bid, twice daily. Retrieval System Online (U.S. National Library of Medicine s life science database; MEDLINE), the Excerpta Medica database (EMBASE), and Thomson-Reuters Web of Science. The MED- LINE search employed a complex search strategy, including both MeSH (Medical Subject Heading) and free text protocols. Specifically, the MeSH search was conducted by combining the following terms retrieved from the MeSH browser provided by MEDLINE: urinary bladder, overactive and cholinergic antagonists. Multiple free-text searches were performed applying singularly the following terms through all the fields of the records: overactive bladder, detrusor overactivity, bladder overactivity, urgency frequency syndrome, darifenacin, emepronium, fesoterodine, oxybutynin, propantheline, propiverine, solifenacin, tolterodine, and trospium. Subsequently, the searches were pooled and limited to randomized controlled trials (RCTs). No temporal limits were used. Searches on EMBASE and Web of Science used only the free-text protocol, with the same key words. Subsequently, the queries were pooled without applying any limits. In addition, other significant studies cited in the reference lists of the selected papers were considered. Three of the authors individually reviewed all the abstracts of the retrieved studies in order to select the papers that were relevant to the review topic. Specifically, all the full-test studies including data of efficacy (changes in daytime micturitions in 24 h, nighttime micturitions in 24 h, micturitions in 24 h, volume voided per micturitions, urgency, episodes in 24 h, urge urinary incontinence [UUI] episodes in 24 h, incontinence episodes in 24 h, pads used, quality of life scores) and complications (overall rates of adverse events, withdrawals due to adverse events, dry mouth rate, moderate-to-severe or severe dry mouth rate, constipation, acute urinary retention, vision abnormality, headache, etc) of anticholinergic drugs comparing different drugs, formulations, doses, and routes of administration were considered. Data were extracted separately and independently by two of the authors and were cross-checked. Moreover, the web site of the Food and Drug Administration ( was searched for RCTs concerning the same drugs. The quality of all the retrieved RCTs was assessed using the Jadad score [11]. All the identified RCTs were included in the meta-analysis, regardless of the quality score. Meta-analysis was conducted using the Review Manager software version 4.2 (The Cochrane Collaboration, Oxford, UK). Specifically, statistical heterogeneity was tested using the chi-square test. A p value <0.10 was used to indicate heterogeneity. In case of lack of heterogeneity, fixed-effects models were used for the meta-analyses. Random-effects models were used in case of heterogeneity. The results were expressed as weighted means and standard deviations for continuous outcomes and relative risk for dichotomous variables. Only the RCTs presenting data in this format were included in the meta-analysis. All the authors whose studies presented the data in a format not suitable for the metaanalysis were contacted and asked for the missing figures, but only three authors provided useful data. The presence of publication bias was evaluated using a funnel plot [12].

5 Table 2 Safety data from the randomized control trials (RCTs) comparing different doses and formulations of emepropium, oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine 744 Reference Dosage (no. of cases) Treatment duration Jadad Adverse score events rate Withdrawals due to adverse events Dry Moderate to Constipation AUR Vision Headache mouth severe or severe dry mouth abnormality Oxybutynin Nilsson 1997 [13] Oxy IR 5 mg bid (17) 8 wk 1 100% 0 82% NR NR NR 12% 41% Oxy ER 10 mg qd (16) 87% 0 69% 25% 44% Anderson 1999 [35] Oxy IR 5 mg different doses (52) variable 3 94% NR 87% 46% 31% NR 17% NR Oxy ER different doses (53) 87% 68% 25% 30% 28% Birns et al 2000 [36] Oxy IR 5 mg tid (67) 4 wk 3 67% NR 17% NR NR NR 4% 4% Oxy ER 10 mg qd (63) 55% 23% 6% 0 Versi et al 2000 [14] Oxy IR different doses (115) variable 3 NR NR 59% 45% NR NR NR NR Oxy ER different doses (111) 48% 39% Barkin et al 2004 [15] Oxy IR different doses (60) 6 wk 3 NR 13% 72% 45% 10% NR 15% 22% Oxy ER different doses (65) 9% 68% 38% 8% 3% 12% Corcos et al 2005 [16] Oxy ER 5 mg qd (77) 4 wk 3 NR 4% 56% 3% 5% 3% 1% NR Oxy ER 10 mg qd (77) 14% 68% 14% 4% 10% 1% Oxy ER 15 mg qd (83) 14% 70% 5% 5% 7% 1% Propiverine Abrams et al 2006 [37] Propi IR 15 mg tid (42) 2 wk 3 81% NR 52% NR 24% NR 33% 7% Propi ER 20 mg qd (38) 79% 34% 16% 24% 3% Junemann et al 2006 [17] Propi IR 15 mg bid (395) 4 wk 1 38% 4% 23% NR 4% NR 3.8% 2% Propi ER 30 mg qd (391) 34% 3% 22% 3% 4.6% 1% Tolterodine Jonas 1997 [18] Tolt IR 1 mg bid (99) 4 wk 3 31% 4% 8% NR 2% NR 3% 3% Tolt IR 2 mg bid (99) 32% 3% 10% 3% 5% 3% Rentzhog 1998 [19] Tolt IR 0.5 mg bid (21) 2 wk 1 38% 5% 9% 0 5% 0 0 NR Tolt IR 1 mg bid (16) 37% 0 12% 0 19% 0 19% Tolt IR 2 mg bid (14) 50% 0 36% 0 7% 0 7% Tolt IR 4 mg bid (16) 75% 6% 56% 6% 12% 6% 6% Millard 1999 [20] Tolt IR 1 mg bid (123) 12 wk 1 74% 2% 24% NR NR NR 2% NR Tolt IR 2 mg bid (129) 73% 6% 39% 6% Jacquetin et al 2001 [21] Tolt IR 1 mg bid (97) 4 wk 1 40% 3% 21% NR 4% NR NR 3% Tolt IR 2 mg bid (103) 53% 2% 34% 2% 3% Malone-Lee et al 2001 [22] Tolt IR 1 mg bid (61) 4 wk 3 NR 7% 49% NR 8% 0 0 8% Tolt IR 2 mg bid (73) 10% 66% 0 0 4% 10% Van Kerrebroeck et al 2001 [23] Tolt IR 2 mg bid (512) 12 wk 3 NR 5% 30% NR 7% NR NR 4% Tolt ER 4 mg qd (505) 5% 23% 6% 6% Swift et al 2003 [24] Tolt IR 2 mg bid (408) 12 wk 3 NR 5% 31% 3% 7% NR 1% 4% Tolt ER 4 mg qd (417) 5% 23% 2% 6% 1% 7% european urology 54 (2008) Solifenacin Cardozo et al 2004 [25] Soli 5 mg qd (299) 12 wk 3 NR 2% 8% 2% 4% NR 4% NR Soli 10 mg qd (307) 4% 23% 5% 9% 6%

6 Table 2 (Continued ) Reference Dosage (no. of cases) Treatment duration Jadad Adverse score events rate Withdrawals due to adverse events Dry Moderate to Constipation AUR Vision Headache mouth severe or severe dry mouth abnormality Chapple et al 2004 [26] Soli 5 mg qd (279) 12 wk 3 NR 3% 14% NR 7% NR 4% NR Soli 10 mg qd (268) 3% 21% 8% 6% Chapple et al 2006* [27] Soli 5 mg qd (552) 12 wk 3 91% 3% 11% 0.2% 5% NR 4% NR Soli 10 mg qd (1158) 87% 7% 28% 1% 13% 5% Darifenacin Chapple et al 2005* [28] Dari 7.5 mg qd (337) 12 wk NA 54% 1% 20% NR 15% NR NR 4% Dari 15 mg qd (334) 66% 5% 35% 21% 5% Foote et al 2005* [29] Dari 7.5 mg qd (97) 12 wk NA 54% 1% 21% NR 19% NR NR 0 Dari 15 mg qd (110) 69% 9% 31% 24% 0 Zinner et al 2005 [30] Dari 15 mg qd (76) 2 wk 2 NR 0 13% NR 10% NR 0 NR Dari 30 mg qd (76) 1% 34% 21% 0 Hill et al 2006 [31] Dari 7.5 mg qd (108) 12 wk 3 57% 0 23% NR 16% NR 2% 6% Dari 15 mg qd (107) 68% 2% 40% 25% 0 6% Dari 30 mg qd (115) 80% 4% 59% 59% 3% 6% Fesoterodine Nitti et al 2005 [32] Feso 4 mg qd (43) 8 wk 2 NR 2% 37% 14% NR NR NR NR Feso 8 mg qd (47) 4% 43% 21% Feso 12 mg (38) 13% 63% 13% Chapple et al 2007 [33] Feso 4 mg (272) 12 wk 3 50% 3% 22% NR 3% 0.3% 2% 4% Feso 8 mg (282) 58% 5% 34% 4% 1% 4% 2% Nitti et al 2008 [34] Feso 4 mg (283) 12 wk 3 61% 6% 16% NR 5% 1% 0.7% 4% Feso 8 mg (279) 69% 9 36% 8% 2% 3% 3% * Pooled analysis of RCTs; NA, not applicable; qd, once daily; bid, twice daily; tid, three times daily; NR, not reported. european urology 54 (2008)

7 746 european urology 54 (2008) Results 984 records were retrieved by searching MEDLINE: 910 records were retrieved from EMBASE, and 669 records were retrieved from Web of Science. The studies evaluating lower urinary tract storage symptoms in patients with bladder-outlet obstructions, papers evaluating neurogenic OAB or OAB in children, phase I studies, post-hoc analyses of RCTs, and duplicate publications were excluded. We finally identified 50 RCTs and three pooled analyses of RCTs for inclusion in this review (Fig. 1) Comparisons of different doses and formulations of the same drug Tables 1 and 2 summarize the efficacy and safety data from the available RCTs comparing different doses and formulations of oxybutynin, tolterodine, propiverine, trospium, darifenacin, solifenacin, and fesoterodine Oxybutynin A single study, published as congress abstract only and really outdated, evaluated the efficacy and safety of oxybutynin IR 2.5 mg, taken three times a day or as needed [38]. Five RCTs compared IR and ER formulations [13 15,35,36], while two further studies compared different doses of the ER formulation [16,39]. Meta-analysis of efficacy between oxybutynin IR and oxybutynin ER was not possible because the only two RCT reporting data in the proper format [15,16] were not suitable for cumulative evaluation of any clinical significance. With regard to adverse events, the occurrence of any adverse event (odds ratio [OR]: 1.9; 95% confidence interval [CI], ; Fig. 2 Forest plots of adverse events after immediate release (IR) and extended release (ER) oxybutynin. (A) Occurrence of any adverse event; (B) dry mouth; (C) moderate-to-severe or severe dry mouth. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.

8 european urology 54 (2008) Table 3 Meta-analysis of adverse events with oxybutynin immediate release (IR) and oxybutynin extended release (ER) Oxybutynin IR vs oxybutynin ER RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Difference favors Any adverse event Oxybutynin ER Withdrawals due to adverse events None Dry mouth Oxybutynin ER Moderate-to-severe or severe dry mouth Oxybutynin ER Headache None Constipation None Vision abnormality None RCT, randomized control trial; IR, immediate release; ER, extended release; OR, odds ratio; CI, confidence interval. p = 0.04), dry mouth (OR: 1.45; 95% CI, ; p = 0.04), and moderate-to-severe or severe dry mouth (OR: 1.49; 95 CI, ; p = 0.04) were significantly more common with oxybutynin IR (Fig. 2). On the other hand, withdrawals due to adverse events, headache, constipation, and vision abnormality were similar for the two formulations of oxybutynin (Table 3) Tolterodine Eight RCTs compared different doses and formulations of tolterodine. Specifically, four studies compared two different dosages of tolterodine IR 1 mg twice daily vs tolterodine IR 2 mg twice daily [18,20 22], while a further study evaluated four different dosages (0.5 mg twice daily vs 1 mg twice daily vs 2 mg twice daily vs 4 mg twice daily) [19]. Two RCTs compared tolterodine IR 2 mg twice daily and tolterodine ER 4 mg once daily [23,24], while a single study compared two dosages of tolterodine ER [39]. With regard to efficacy analysis, four papers presented the data in a format unsuitable for meta-analysis [18,19,22,39]. Comparing the tolterodine IR 1 mg and tolterodine IR 2 mg doses, micturitions (weighted mean difference [WMD], 0.11; 95% CI, ; p = 0.70), volume voided per micturition (WMD, 8.68; 95% CI, ; p = 0.09), and UUI episodes (WMD, 0.06; 95% CI, ; p = 0.81) were similar for both doses. With regard to adverse events, only dry mouth was significantly more frequent in those patients taking tolterodine IR 2 mg (OR: 0.52; 95% CI, ; p < ). Regarding the comparison of tolterodine IR and tolterodine ER formulations, patients randomized to tolterodine ER formulation experienced a lower number of micturitions (WMD, 0.34; 95% CI, ; p = 0.03) and a higher volume voided per micturition (WMD, 9.12; 95% CI, ; p = ), but a similar number of incontinence episodes and pad use per day (Table 4). Evaluating Table 4 Meta-analysis of randomized control trials (RCTs) comparing tolterodine immediate release (IR) and tolterodine extended release (ER) Tolterodine IR vs tolterodine ER RCT (no.) Participants (no.) WMD 95% CI, WMD Test for overall effect ( p value) Difference favors Micturitions Tolterodine ER Volume voided per micturition Tolterodine ER Incontinence episodes None Pad use None Adverse events RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Difference favors Withdrawals due to None adverse events Dry mouth Tolterodine ER Headache Tolterodine IR Constipation None IR, immediate release; ER, extended release; UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.

9 748 european urology 54 (2008) Fig. 3 Forest plots of efficacy and safety after tolterodine immediate release (IR) and tolterodine extended release (ER). (A) Micturitions ; (B) volume voided per micturition; (C) dry mouth; (D) headache. OAB, overactive bladder; N, number of patients in the study arm; SD, standard deviation; WMD, weighted-mean difference; CI, confidence interval. the adverse events with the use of the two formulations of tolterodine, patients treated with tolterodine ER formulations had a significantly lower rate of dry mouth (OR: 1.39; 95% CI, ; p = 0.002) but a higher rate of headache (OR: 0.53; 95% CI, ; p = 0.004). Withdrawals due to adverse events and constipation were similarly prevalent in both cases (Table 4; Fig. 3) Propiverine A single study evaluated the efficacy of 21-d treatment with different doses of propiverine IR Fig. 4 Forest plots of adverse events after different dosages of darifenacin (Dari). Darifenacin 7.5 mg versus darifenacin 15 mg: (A) Occurrence of any adverse event; (B) withdrawals due to adverse events; (C) dry mouth; (D) constipation. Darifenacin 15 mg versus darifenacin 30 mg: (E) dry mouth; (F) constipation. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.

10 european urology 54 (2008)

11 750 european urology 54 (2008) Table 5 Meta-analysis of adverse events with immediate-release (IR) and extended-release (ER) formulations of propiverine Propiverine IR vs propiverine ER RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Difference favors Any adverse event None Dry mouth None Headache None Constipation None Vision abnormality None RCT, randomized control trial; OR, odds ratio; CI, confidence interval. (15 mg twice daily vs 30 mg twice daily vs 45 mg three times daily vs 60 mg four times daily), showing that propiverine IR 15 mg twice daily and 30 mg twice daily were the doses with the most favorable ratio of efficacy in micturition frequency to tolerability [40]. Two studies compared propiverine hydrochloride IR and propiverine hydrochloride ER formulations [17,37]. Meta-analysis was possible only for complication rates, in spite of the different dosages of propiverine IR of in the two studies. The two formulations of propiverine showed similar rates of adverse events, dry mouth, constipation, headache, and vision abnormality (Table 5) Solifenacin Four RCTs evaluated the efficacy of different doses of solifenacin [25,26,41,42]. The two studies by Gittelman et al [41,42] were not included in Tables 1 and 2 because it was not possible to obtain the data in an extended form. Three pooled analyses of these four RCTs sharing similar designs were published [27,43,44]. The largest analysis, which also included the patients without UUI, evaluated 2848 patients out of 3032 randomized patients: 552 patients received solifenacin 5 mg, 1158 patients received solifenacin 10 mg, and 1138 patients received placebo [27]. Both doses of solifenacin were significantly more efficacious than placebo. Indeed, comparing the two dosages, solifenacin 10 mg was significantly better only in terms of the percentage of patients having a 50% reduction in incontinence episodes ( p = 0.006). However, withdrawals due to adverse events ( p = ), dry mouth ( p < ), and constipation ( p < ) were significantly more common among the patients treated by solifenacin 10 mg [27] Darifenacin Our systematic search identified two RCTs evaluating the efficacy of darifenacin at different doses [30,31] and two pooled analyses of RCTs [28,29], which, however, failed to clearly report the included trials. The larger studies evaluated 337 patients randomized to receive darifenacin 7.5 mg and 334 patients who received darifenacin 15 mg. The analysis identified significant dose response effects for change in weekly incontinence episodes [28]. The study from Foote et al [29] was a subgroup analysis of the patients aged 65 yr in Chapple et al [28] and was not evaluated in our analyses. Meta-analysis of efficacy between the different doses of darifenacin was not possible because all the studies reported the data in a format that was not suitable for the evaluation. With regard to adverse events, darifenacin 7.5 mg was followed by significantly lower rates of adverse events (OR: 0.62; 95% CI, ; p = ), withdrawals due to adverse events (OR: 0.30; 95% CI, ; p = 0.02), dry mouth (OR: 0.46; 95% CI, ; p < ), and constipation (OR: 0.62; 95% CI, ; p = 0.006), compared with darifenacin 15 mg. Similarly, comparing darifenacin 15 mg and darifenacin 30 mg, darifenacin 15 mg was followed by significantly lower rates of dry mouth (OR: 0.40; 95% CI, ; p < ) and constipation (OR: 0.27; 95% CI, ; p < ; Table 6; Fig. 4) Fesoterodine Three RCTs compared different doses of fesoterodine, the most recently released anticholinergic drug [32 34]. With regard to efficacy analysis, the three papers presented the data in a format unsuitable for meta-analysis. Regarding adverse events, adverse event rate (OR: 0.68; 95% CI, ; p = 0.002), dry mouth (OR: 0.46; 95% CI, ; p < ) and vision abnormality (OR: 0.38; 95% CI, ; p = 0.02) were more common in those patients receiving fesoterodine 8 mg (Table 7) Comparisons of different drugs Tables 8 and 9 summarize the efficacy and safety data from the available RCTs comparing different drugs.

12 european urology 54 (2008) Table 6 Meta-analysis of adverse events with different doses of darifenacin RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Difference in favor Darifenacin 7.5 mg vs darifenacin 15 mg Any adverse event Darifenacin 7.5 mg Withdrawal due to adverse event Darifenacin 7.5 mg Dry mouth < Darifenacin 7.5 mg Headache None Constipation Darifenacin 7.5 mg Darifenacin 15 mg vs darifenacin 30 mg Withdrawal due to adverse event None Dry mouth < Darifenacin 15 mg Constipation < Darifenacin 15 mg RCT, randomized control trial; OR, odds ratio; CI, confidence interval; NR, not reported. Table 7 Meta-analysis of adverse events with different doses of fesoterodine Fesoterodine 4 mg vs fesoterodine 8 mg RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Difference in favor of Any adverse event Fersoterodine 4 mg Withdrawal due to adverse event None Dry mouth < Fersoterodine 4 mg Constipation None Headache None Vision abnormality Fersoterodine 4 mg Acute urinary retention None RCT, randomized control trial; OR, odds ratio; CI: confidence interval Oxybutynin versus tolterodine Twelve RCTs compared efficacy and safety of oxybutynin and tolterodine [45 54,62,63]. Specifically, eight of these studies compared the IR formulations of the two drugs (oxybutynin 5 mg two or three times daily vs tolterodine 2 mg twice daily) [45 47,49,50,53,62,63]. With regard to the comparisons of the IR formulations, only four RCTs provided the data in a format suitable for meta-analysis of the efficacy data [47,49,50,53]. Micturitions, volume voided per micturition, UUI episodes, and incontinence episodes were overlapping for the IR formulations of the two drugs. Regarding adverse events, occurrence of any adverse event (OR: 2.30; 95% CI, ; p ), withdrawal due to adverse events (OR: 1.82; 95% CI, ; p = ), dry mouth of any grade (OR: 3.98; 95% CI, ; p ), and moderate-to-severe or severe dry mouth (OR: 7.21; 95% CI, ; p ) were significantly more common in those patients receiving oxybutynin IR (Table 10 and Fig. 5). A single trial compared oxybutynin ER to tolterodine IR [48]. After a 12-wk treatment, oxybutynin ER was shown to be more efficacious than tolterodine IR in terms of reduction in urgency incontinence episodes ( p = 0.03), total incontinence episodes ( p = 0.02), and micturitions ( p < ), while all the evaluated adverse events (overall number, dry mouth, constipation, blurred vision, headache) were overlapping in the two arms [48]. Two further RCTs compared oxybutynin IR and tolterodine ER [52,54]. The larger study, which enrolled 608 patients with OAB, showed similar efficacy for both drugs in terms of reductions in the number of incontinence episodes per week and micturitions per day, but patients taking oxybutynin IR more frequently experienced dry mouth, severe dry mouth, and eye disorders [52]. Similar figures were provided in the RCT from Homma et al [54]. The format used in these two studies to report efficacy data was unsuitable for meta-analysis. With regard to adverse events, dry mouth (OR: 2.44; 95% CI, ; p < ) and severe dry mouth (OR: 16.87; 95% CI, ; p = ) were significantly more common with the IR formulation of oxybutynin. Finally, a single study compared the formulations of oxybutynin ER and tolterodine ER [51]. After a 12-wk treatment, the average number of weekly UUI episodes, which was the primary end point of the study, was overlapping between the two arms, as

13 Table 8 Efficacy data from the randomized control trials (RCTs) comparing different drugs 752 Reference Dose (no. of cases) Treatment duration Jadad score in daytime micturitions in nighttime micturitions in micturitions in VV per micturitions (ml) in urgency episodes in UUI episodes in incontinence episodes Mean change in pads used Oxybutynin vs tolterodine Van Kerrebroeck 1997 [45] Oxy IR 5 mg tid (120) 12 wk 1 NR NR 2.7 * +54 * NR NR NR NR Tolt IR 2 mg bid (120) 2.1 * +35 * Abrams et al 1998 [46] Oxy IR 5 mg tid (118) 12 wk 3 NR NR 2.3 (19%) +47 (31%) NR NR 1.7 (71%) NR Tolt IR 2 mg bid (118) 2.7 (21%) +38 (27%) 1.3 (47%) Drutz et al 1999 [47] Oxy IR 5 mg tid (112) 12 wk 3 NR NR 2.0 (17%) +50 (33%) NR NR 1.7 (50%) NR Tolt IR 2 mg bid (109) 2.0 (17%) + 34 (22%) 1.7 (46%) Appell et al 2001 [48] Oxy ER 10 mg qd(185) 12 wk 3 NR NR 3.5 (27%) NR NR 2.78 (76%) 3.07 (75%) NR Tolt IR 2 mg bid(193) 2.8 (22%) 2.32 (68%) 2.52 (65%) Malone Lee et al 2001 [49] Oxy IR 5 mg bid (188) 10 wk 3 NR NR 1.7 (15%) +34 (23%) NR 1.8 (62%) NR 0.9 (32%) Tolt IR 2mg bid (190) 1.7 (15%) +33 (22%) 1.3 (54%) 1.1 (35%) Lee et al 2002 [50] Oxy IR 5 mg bid (116) 8 wk 3 NR NR 1.8 (15%) NR NR NR 1.4 (67%) NR Tolt IR 2 mg bid (112) 2.6 (20%) 2.2 (76%) Diokno et al 2003 [51] Oxy ER 10 mg qd (391) 12 wk 3 NR NR 3.75 (28%) NR NR 3.82 (72%) 4.5 (73%) NR Tolt ER 4 mg qd (399) 3.42 (25%) 3.42 (65%) 4.2 (69%) Homma et al 2003 [52] Oxy IR 3 mg tid (246) 12 wk 3 NR NR 2.0 (18%) (18%) NR NR NR 0 Tolt ER 4 mg qd (240) 2.1 (17%) (14%) 0 Giannitsas et al 2004 [53] Oxy IR 5 mg tid (107) 6+6 wk 3 NR NR 0.8 (9%) (22%) NR NR NR NR (crossover) Tolt IR 2 mg bid (107) 0.9 (10%) (21%) Homma et al 2004 [54] Oxy IR 3 mg tid (122) 12 wk 3 NR NR 19.1%* +22 * NR NR 87% * NR Tolt ER 4 mg qd (114) 17.9%* * 86% * Oxybutynin vs propiverine Madersbacher et al 1999 [55] Oxy IR 5 mg bid (121) 4 wk 2 NR NR 1.6 (13%) NR 3 (24%) NR NR NR Propi 15 mg tid (126) 1.9 (18%) 3.1 (33%) Oxybutynin vs trospium Halaska et al 2003 [56] Oxy IR 5 mg bid (90) 52 wk 3 NR NR 4.2 (34%) NR 3.6 (33%) NR NR NR Trospium 20 mg bid (267) 3.5 (31%) 3.5 (34%) Oxybutynin vs darifenacin Zinner et al 2005 [30] Oxy IR 5 mg tid (58) 2 wk 3 NR NR 1.23 (13%) NR 1.1 (13%) NR 1.65 (122%) NR Dari 15 mg qd (58) 1.14 (12%) 1.27 (16%) 1.44 (92%) Dari 30 mg qd (58) 1.62 (18%) 1.63 (21%) 1.74 (138%) european urology 54 (2008) Tolterodine vs trospium Junemann et al 2000 [57] Tolt IR 2 mg bid (60) 3 wk 1 NR NR 2.6* NR NR NR NR NR Trospium IR 20 mg bid (57) 3.4* Tolterodine vs propiverine Junemann et al 2005 [58] Tolt IR 2 mg bid (101) 4 wk 2 NR NR 3.07* * 3.04* NR 0.91* 0.43* Propi 15 mg bid (100) 2.75* * 3.26* 1.2* 0.65* Tolterodine vs solifenacin Chapple et al 2004 [26] Tolt IR 2 mg bid (250) 12 wk 3 NR NR 1.88 (15%) (20%) 2.05 (38%) 0.91 (58%) 1.14 (59%) NR Soli 5 mg qd (264) 2.19 (17%) (25%) %) 1.41 (65%) 1.42 (59%) Soli 10 mg qd (261) 2.61 (20%) (29%) 3.07 (55%) 1.36 (63%) 1.45 (47%) Chapple et al 2005 [59] Tolt ER 4 mg qd (599) 12 wk 3 NR 0.63 (33%) 2.24 (19%) +31 (21%) 2.42 (41%) 0.83 (39%) 1.11 (43%) 1.19 (41%) Soli 5/10 mg qd (578) 0.71 (35%) 2.45 (21%) +38 (26%) 2.85 (47%) 1.42 (61%) 1.6 (58%) 1.72 (53%) Chapple et al 2007 [60] Tolt ER 4 mg qd (599) 4 wk 3 NR 0.44 (23%) 1.47 (13%) (17%) 1.67 (29%) 0.91 (43%) 0.90 (42%) 0.80 (27%) Soli 5 mg qd (578) 0.51 (23%) 1.71 (14%) (19%) 1.98 (33%) 1.22 (53%) 1.30 (53%) 1.21 (37%) Tolterodine vs fesoterodine

14 european urology 54 (2008) Table 8 (Continued ) Mean change in pads used in incontinence episodes in UUI episodes in urgency episodes in VV per micturitions (ml) in micturitions in nighttime micturitions in daytime micturitions Jadad score Reference Dose (no. of cases) Treatment duration Chapple et al 2007 [33] Tolt ER 4 mg qd (290) 12 wk (14%) 0.4 (25%) 1.73 (14%) (15%) 2.03 (16%) 1.74 (70%) NR NR Feso 4 mg qd (272) 1.37 (14%) 0.39 (29%) 1.76 (17%) (17%) 1.88 (18%) 1.95 (80%) Feso 8 mg (288) 1.48 (17%) 0.39 (23%) 1.88 (19%) (22%) 2.36 (19%) 2.22 (87%) VV, voided volume; UUI, urge urinary incontinence; QD, once daily; BID, twice daily; TID, three times daily; NR, not reported. well as the number of incontinence episodes of any type. Indeed, patients taking oxybutynin ER had a greater decrease in the mean weekly micturition frequency compared with tolterodine ER participants ( p = 0.003). Regarding adverse events, the occurrence of dry mouth was significantly less common in the patients randomized to tolterodine ER ( p = 0.02), although in most of the cases it was of mild degree [51] Oxybutynin versus propantheline Two studies compared oxybutynin IR 5 mg three times daily and propantheline 15 mg three times daily [61,64]. The larger study evaluated 154 patients, 63 patiented receiving the oxybutynin dosage and 54 patients receiving the propantheline dosage. The propantheline arm showed a higher mean grade of improvements in visual analogue scale, counterbalanced by higher rate of adverse events in the oxybutynin arm [61]. The data from the two studies were unsuitable for meta-analysis Oxybutynin versus propiverine Two studies compared oxybutynin with propiverine [55,65]. In the larger study, the two drugs were similarly effective in terms of both bladder diary variables and urodynamic parameters, although dry mouth and severe dry mouth were less frequent in the propiverine arm [55] Oxybutynin versus trospium A single trial compared efficacy and safety of oxybutynin IR 5 mg twice daily and trospium IR 20 mg twice daily [56]. This study is of particular clinical relevance because the treatments were continued for 52 wk. This study showed similar efficacy for the two drugs in terms of both bladder diary variables such as mean change in micturitions and in the number of of urgency episodes, and in terms of urodynamic parameters, such as change in maximum cystometric capacity and change in volume at first contraction. The occurrence of any adverse event ( p = 0.045) and dryness of the mouth ( p = 0.021) were significantly less common in those patients receiving trospium [56] Oxybutynin versus darifenacin Zinner et al evaluated the efficacy of oxybutynin IR and darifenacin in a four-way crossover study [30]. With regard to efficacy, darifenacin 15 mg once daily was comparable to oxybutynin in terms of the improvement in OAB symptoms, with both drugs similarly reducing the number of incontinence episodes per week and the number of micturitions and urgency episodes per day after a 2-wk treat-

15 Table 9 Safety data from the randomized control trials (RCTs) comparing different drugs 754 Reference Dose (no. of cases) Treatment duration Jadad score Adverse events rate Withdrawal due to adverse events Dry mouth Moderate-to-severe or severe dry mouth Headache Constipation AUR Vision abnormality Oxybutynin vs propantheline Thuroff et al 1991 [61] Oxy IR 5 mg tid (63) 4 wk 1 63% 3% 48% 27% 1% 3% NR 3% Propantheline 15 mg tid (54) 44% 5% 31% 18% 5% 0 4% Oxybutynin vs tolterodine Van Kerrebroeck et al 1997 [45] Oxy IR 5 mg tid (120) 12 wk 1 93% 21% 78% 23% NR NR NR NR Tolt IR 2 mg bid (120) 63% 11% 38% 3% Abrams et al 1998 [46] Oxy IR 5 mg tid (118) 12 wk 3 97% 17% 86% NR NR NR NR NR Tolt IR 2 mg bid (118) 89% 8% 50% Drutz et al 1999 [47] Oxy IR 5 mg tid (112) 12 wk 3 90% 21% 69% 44% 10% NR NR NR Tolt IR 2 mg bid (109) 78% 6% 30% 9% 15% Appell et al 2001 [48] Oxy ER 10 mg qd (185) 12 wk 3 NR 8% 28% NR 8% 7% 3% 2% Tolt IR 2 mg bid (193) 8% 33% 9% 6% 3% 1% Malone-Lee et al 2001 [49] Oxy IR 5 mg bid (188) 10 wk 3 81% 15% 61% 15% 10% 6% NR 5% Tolt IR 2mg bid (190) 69% 12% 37% 4% 11% 8% 5% Lee et al 2002 [50] Oxy IR 5 mg bid (116) 8 wk 3 NR 16% 63% 28% 5%. NR NR NR Tolt IR 2 mg bid (112) 10% 35% 9% 4% Leung et al 2002 [62] Oxy IR5 mg bid (53) 10 wk 3 49% 15% NR NR NR NR NR NR Tolt IR 2 mg bid (53) 60% 17% Diokno et al 2003 [51] Oxy ER 10 mg qd (391) 12 wk 3 NR 5% 30% 7% 6% 6% NR NR Tolt ER 4 mg qd (399) 5% 22% 5% 6% 8% Homma et al 2003 [52] Oxy IR 3 mg tid (244) 12 wk 3 NR 17% 54% 8% 4% 6% 3% 3% Tolt ER 4 mg qd (239) 5% 33% 0.4% 4% 7% 0.4% 1% Homma et al 2004 [54] Oxy IR 3 mg tid (122) 12 wk 3 NR NR 61% 3% NR NR NR NR Tolt ER 4 mg qd (114) 37% 0 Altan-Yacioglu et al 2005 [63] Oxy IR 5 mg tid (24) 4 wk 2 NR NR 83% 83% NR NR NR 58% Tolt IR 2 mg bid (28) 50% 28% 43% Oxybutynin vs propiverine Madersbacher et al 1999 [55] Oxy IR 5 mg bid (145) 4 wk 2 72% NR NR NR NR NR NR 18% Propi 15 mg tid (149) 64% 27% Abrams et al 2006 [37] Oxy IR 5 mg tid (41) 2 wk 3 93% NR 83% NR 15% 10% NR 22% Propi 15 mg tid (42) 81% 52% 7% 24% 33% Propi 20 mg qd (38) 79% 34% 0 16% 24% Oxybutynin vs trospium Halaska et al 2003 [56] Oxy IR 5 mg bid (90) 52 wk 3 77% 7% 50% NR 9% NR NR 6% Trospium 20 mg bid (267) 68% 4% 33% 4% 3% european urology 54 (2008) Oxybutynin vs darifenacin Zinner et al 2005 [30] Oxy IR 5 mg tid (76) 2 wk 3 NR 5% 36% NR NR 8% NR 3% Dari 15 mg qd (76) 0 13% 10% 0 Dari 30 mg qd (76) 1% 34% 21% 0 Tolterodine vs trospium Junemann et al 2000 [37] Trospium IR 20 mg bid (76) 3 wk 1 34% NR 29% NR NR NR NR NR Tolt IR 2 mg bid (77) 32% 27% Tolterodine vs propiverine Junemann et al 2005 [58] Tolt IR 2 mg bid (101) 4 wk 2 43% 6% 19% NR NR NR NR 7% Propi 15 mg bid (100) 42% 6% 20% 9% Tolterodine vs solifenacin Chapple et al 2004 [26] Tolterodine IR 2 mg bid (263) 12 wk 3 NR 2% 19% NR NR 3% NR 1% Soli 5 mg qd (279) 3% 14% 7% 4% Soli 10 mg qd (268) 3% 22% 8% 6%

16 european urology 54 (2008) Table 9 (Continued ) Headache Constipation AUR Vision abnormality Moderate-to-severe or severe dry mouth Dry mouth Withdrawal due to adverse events Adverse events rate Jadad score Reference Dose (no. of cases) Treatment duration Chapple et al 2005 [59] Tolt ER 4 mg qd (599) 12 wk 3 NR 3% 24% 1% NR 2% NR 2% Soli 5/10 mg qd (578) 3% 30% 2% 6% 1% Chapple et al 2007 [60] Tolt ER 4 mg qd (607) 4 wk 3 3% 3% 15% NR NR 1% NR NR Soli 5 mg qd (593) 3% 3% 18% 3% Tolterodine vs fesoterodine Chapple et al 2007 [33] Tolt ER 4 mg qd (290) 12 wk 3 50% 3% 17% NR 5% 3% 0 0.3% Feso 4 mg qd (272) 50% 3% 22% 4% 3% 0.3% 2.2% Feso 8 mg qd (282) 58% 5% 34% 2% 4% 1% 4% NR, not reported; qd, once daily; bid, twice daily; tid, three times daily. ment. Concerning adverse events, dry mouth was significantly more common in the oxybutynin arm than in the darifenacin 15 mg arm ( p < 0.05), while overlapping rates occurred between the oxybutynin 30 mg and darifenacin 30 mg arms. On the other hand, constipation was significantly more frequent in those patients treated by darifenacin 30 mg, but it occurred in similar percentages in the oxybutynin 15 mg arm and the darifenacin 15 mg arm [30] Tolterodine versus trospium A single RCT, published as congressional abstract, compared tolterodine IR 2 mg twice daily and trospium IR 20 mg twice daily. The study showed similar efficacy and similar adverse event rates for the two drugs [57]. The lack of a publication in a peer-reviewed journal does not permit the evaluation of the power of the statistical analysis for the comparisons between tolterodine and trospium Tolterodine versus propiverine A single study compared tolterodine IR 2 mg bid and propiverine 15 mg bid [58]. The study showed similar efficacy for the two drugs in terms of both bladder diary variables such as mean change in micturitions, number of UUI episodes, and number of incontinence episodes and in terms of urodynamic parameters, such as change in maximum cystometric capacity and change in volume at first contraction. Similarly, the number of adverse events was comparable in both treatment groups [58] Tolterodine versus solifenacin Two studies reported data on the comparisons between solifenacin and tolterodine [26,59,60]. The first study, designed for the registration of solifenacin, compared solifenacin 5-mg and solifenacin 10-mg to tolterodine IR 2 mg twice daily or placebo [26]. However, the most interesting data came from the STAR study, whose primary end point tested the non-inferiority of solifenacin compared to tolterodine ER [59]. Solifenacin 5 mg and solifenacin10 mg were not inferior to tolterodine ER with regard to change from baseline in the following ways: mean number of micturitions ( p = for noninferiority), reduction in number of urgency episodes per day ( p < 0.05), urge incontinence episodes per day ( p < 0.01), incontinence episodes per day ( p < 0.01), and pad usage ( p < 0.002). Dry mouth ( p = 0.02) and constipation ( p = 0.002) were significantly more common in the solifenacin arm, although they were mainly of mild or moderate severity [59]. A secondary analysis of the same trial was recently published, limiting all the evaluation

17 756 european urology 54 (2008) Table 10 Meta-analysis of randomized control trials (RCTs) comparing immediate-release (IR) formulations of oxybutynin and tolterodine Oxybutynin IR vs tolterodine IR RCT (no.) Participants (no.) WMD 95% CI, WMD Test for overall effect ( p value) Difference in favor Micturitions None Volume voided per micturition None Urgency urinary incontinence None episodes Incontinence episodes None Adverse events RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Adverse events < Tolterodine IR Withdrawals due to Tolterodine IR adverse events Dry mouth < Tolterodine IR Moderate to severe or < Tolterodine IR severe dry mouth Headache None Constipation None Vision abnormality None UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio. during the first 4 wk of active treatment before solifenacin dose escalation, showed similar efficacy for solifenacin 5 mg and tolterodine ER with regard to reduction in number of micturitions and most of the secondary end points [60]. In the two RCTS comparing solifenacin and tolterodine [26,59] the format used to report efficacy data was unsuitable for meta-analysis. With regard to adverse events, the meta-analysis, although impaired by the use of different doses of solifenacin and different formulations of tolterodine, suggests that only constipation (OR: 2.78; 95% CI, ; p < ) was more common in the solifenacin arm (Table 11) Tolterodine versus fesoterodine A single RCT compared fesoterodine to tolterodine [33]. The trial was designed to compare the fesoterodine 4 mg and fesoterodine 8 mg to placebo and included an active control arm in which the patients were treated with tolterodine ER 4 mg. Fesoterodine 8 mg outperformed tolterodine 4 mg with regard to the median change from baseline in number of UUI episodes ( p < 0.05) and volume voided per micturition ( p < 0.05), while similar efficacy was shown for fesoterodine 4 mg and tolterodine 4 mg. Fesoterodine 4 mg and tolterodine ER 4 mg had overlapping statistics with regard to complications and adverse events, while fesoterodine 8 mg was followed by significantly higher rates of dry mouth ( p < ) and dry eye ( p = 0.02), compared with tolterodine 4 mg [33] Comparison of different routes of administration Tables 12 and 13 summarize the efficacy and safety data from the available RCTs comparing different routes of administration of anticholinergic drugs. Two RCTs compared the oral and transdermal routes of administration of oxybutynin [64,65]. Table 11 Meta-analysis of randomized control trials (RCTs) comparing solifenacin and tolterodine Solifenacin 5 mg and solifenacin 10 mg vs tolterodine ER RCT Participants OR 95% CI, OR Test for overall effect ( p value) Difference in favor Withdrawals due to adverse events None Dry mouth None Constipation < Tolterodine ER Vision abnormality None CI, confidence interval; OR, odds ratio.

18 european urology 54 (2008) Table 12 Efficacy data from the randomized control trials (RCTs) comparing oral and transdermal formulations of anticholinergic drugs Reference Dosage (no. of cases) Treatment duration Jadad score in micturitions in VV per micturitions (ml) in incontinence episodes Davila et al 2001 [64] Oxy IR 2.5 mg bid or tid (38) 4 wk 3 NR NR 0.8 (23%) Oxy TDS twice a week (38) 0.4 (17%) Dmochowski et al 2003 [65] Tolt ER 4 mg qd (123) 12 wk (18%) +29 (19%) 3.2 (64%) Oxy TDS 3.9 mg qd (121) 1.9 (15%) +32 (19%) 2.9 (62%) VV, voided volume; NR, not reported; qd: once daily; bid: twice daily; tid: three times daily. Placebo transdermal system was used in those patients taking oral anticholinergic drugs. Table 13 Safety data from the randomized control trials (RCTs) comparing oral and transdermal formulations of anticholinergic drugs Reference Dosage (no. of cases) Treatment duration Jadad score Systemic adverse event rate Localized application site reaction * Withdrawal due to adverse events Dry mouth (%) Constipation AUR Vision abnormality Davila et al 2001 [64] Oxy IR 2.5 mg bid or tid (38) 4 wk 3 NR 23% NR 82% 50% 34% 24% Oxy TDS twice a week (38) 38% 39% 21% 24% 18% Dmochowski et al 2003 [65] Tolt ER 4 mg qd (123) 12 wk 3 24% 5.7% 2% 7% 6% NR NR Oxy TDS 3.9 mg qd (121) 19% 26% 11% 4% 3% AUR, acute urinary retention; NR, not reported; qd, once daily; bid, twice daily; tid, three timse daily. * Placebo transdermal system was used in those patients taking oral anticholinergic drugs. Specifically, Davila et al compared the efficacy and safety of oxybutynin IR at different doses administered orally or transdermally [65], while Dmochowski et al evaluated transdermal oxybutynin 3.9 mg once daily and tolterodine ER 4 mg once daily [65]. Meta-analysis of efficacy showed similar reduction in the number of incontinence episodes (WMD: 0.05; 95% CI, ; p = 0.88). Dry mouth (OR: 3.67; 95% CI, ; p = ) and constipation (OR: 2.78; 95% CI, ; p = 0.01) were significantly more common in those patients taking the drug orally, while localized application side effects (OR: 0.26; 95% CI, ; p < ) and withdrawal due to adverse events (OR: 0.14; 95% CI, ; p = 0.01) were significantly more frequent in those patients receiving active transdermal formulations (Table 14; Fig. 6) Publication bias Funnel plots of the studies used in this metaanalysis were generated for all of the evaluated comparisons. Only four studies [15,21,45,62] lay outside the 95% CI with an even distribution around the vertical, suggesting little evidence of publication bias (plots not shown). 4. Discussion Due to the large number of drugs available on the market, the selection of the most appropriate one for every single patient might be quite a complex task. The choice of the first drug to be used, the selection of the most appropriate dosage, formulation, and route of administration, the criteria for selection of a Table 14 Meta-analysis of adverse events with oral and transdermal formulations of anticholinergic drugs Oral oxybutynin vs transdermal oxybutynin RCT (no.) Participants (no.) OR 95% CI, OR Test for overall effect ( p value) Difference favors Systemic adverse event None Localized application site reactions < Oral Withdrawals due to adverse events Oral Dry mouth Transdermal Constipation Transdermal Vision abnormality None RCT, randomized control trials; OR, odds ratio; CI, confidence interval.

19 758 european urology 54 (2008) Fig. 5 Forest plots of adverse events after oxybutynin immediate release (IR) or tolterodine IR. (A) Occurrence of any adverse event; (B) withdrawals due to adverse events; (C) dry mouth of any severity; (D) moderate to severe or severe dry mouth. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.

20 european urology 54 (2008) Fig. 6 Forest plots of adverse events after oral and transdermal formulations of anticholinergic drugs. (A) Localized application site reactions; (B) withdrawal due to adverse events; (C) dry mouth of any severity; (D) constipation. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval. second anticholinergic drug in case of insufficient efficacy or intolerable adverse events, and, finally, costs are some of the most important issues that should be evaluated. The data from our systematic review and metaanalyses showed that tolterodine IR had a more favorable profile of adverse events than oxybutynin IR, while the ER formulations of the two drugs had similar efficacy and safety profiles. In all the comparisons among IR and ER formulations, the latter showed some advantages, either in terms of efficacy (tolterodine IR vs oxybutynin ER; tolterodine IR vs tolterodine ER) or safety (oxybutynin IR vs oxybutynin ER; oxybutynin IR vs tolterodine ER; oxybutynin IR vs darifenacin). With regard to solifenacin, a single RCT demonstrated the non-