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

European Urology

Volume 54, issue 4, pages 709-970, October 2008

Reviews

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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 .

Accepted 25 June 2008, Published online 9 July 2008, pages 740 - 764

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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 per 24 h, volume voided per micturition, urgency urinary incontinence episodes per 24 h, incontinence episodes per 24 h) 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.

Take Home Message

Extended-release (ER) formulations might be preferred to immediate-release (IR) formulations. Dose escalation might yield some limited improvements in the efficacy of IR formulations with significant increase in the adverse events. More studies are needed to indicate which of the drugs should be used as first-, second-, or third-line treatment.

Keywords: Overactive bladder, Urgency frequency syndrome, Detrusor overactivity, Muscarinic receptor antagonist, Darifenacin, Emepronium, Fesoterodine, Oxybutynin, Propantheline, Propiverine, Solifenacin, Tolterodine, Trospium.

1. Introduction

Overactive bladder (OAB) is a highly prevalent condition [1], and [2] with enormous related costs per year [3], and [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], and [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 2006. 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], and [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]. In a more 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.

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2. Methods

The systematic review of the literature was performed in August 2007 using the Medical Literature Analysis and 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 MEDLINE 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 per 24 h, 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 (http://www.fda.gov) 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 meta-analysis 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].

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3. 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).

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Fig. 1 Flow-chart of meta-analysis. RCTs, randomized control trials, OAB, overactive bladder.

3.1. Comparisons of different doses and formulations of the same drug

Table 1, and Table 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.

Table 1 Efficacy data from the randomized control trials (RCTs) comparing different doses and formulations of oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine

Reference	Dose (no. of cases)	Treatment duration	Jadad score	Mean change in daytime micturitions per 24 h	Mean change in nighttime micturitions per 24 h	Mean change in micturitions per 24 h	Mean change in volume voided per micturitions (ml)	Mean change in urgency episodes per 24 h	Mean change in UUI episodes per 24 h	Mean change in incontinence episodes per 24 h	Mean change in pads used per 24 h
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
Nilsson et al 1997 [13]	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
Versi et al 2000 [14]	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%)
Barkin et al 2004 [15]	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%)	+17.1 (8%)	−1.8 (37%)	NR	NR	NR
	Oxy ER 10 mg qd (77)					−1.1 (11%)	+20.5 (10%)	−1.5 (34%)
	Oxy ER 15 mg qd (83)					−1.5 (14%)	+44.6 (21%)	−2.0 (46%)

Propiverine
Junemann et al 2006 [17]	Propi IR 15 mg bid (395)	4 wk	1	NR	NR	−3.69 (29%)	+46.5 ml (32.6%)	−2.03 (33%)	NR	−2.21 (67%)	NR
Junemann et al 2006 [17]	Propi ER 30 mg qd (391)					−3.63 (28%)	+40.1 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
Jonas et al 1997 [18]	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
Millard et al 1999 [20]	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
Jacquetin et al 2001 [21]	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
Malone-Lee et al 2001 [22]	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%)
Van Kerrebroeck et al 2001 [23]	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%)
Swift et al 2003 [24]	Tolt ER 4 mg qd (417)					−1.9 (17%)	+37.9 (27%)			−1.68 (53%)	−0.6 (37%)

Solifenacin
Cardozo et al 2004 [25]	Soli 5 mg qd (286)	12 wk	2	NR	−0.56 (25.3%)	−2.37 (20%)	+30.75*	−2.84 (25%)	−1.3 (63%)	−1.63 (61%)	NR
Cardozo et al 2004 [25]	Soli 10 mg qd (290)				−0.71 (38.5%)	−2.81 (22%)	+35.99*	−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%)	+32.9 (25%)	−2.85 (52%)	−1.41 (65%)	−1.42 (59%)	NR
Chapple et al 2004 [26]	Soli 10 mg qd (261)					−2.61 (20%)	+39.2 (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
Chapple et al 2006** [27]	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
Chapple et al 2005** [28]	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
Foote et al 2005** [29]	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
Zinner et al 2005 [30]	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%)

Fesoterodine
Nitti et al 2005 [32]	Feso 4 mg qd (44)	8 wk	2	NR	NR	−0.996*	+27.94*	NR	NR	NR	NR
	Feso 8 mg qd (47)					−1.815*	+58.69*
	Feso 12 mg (39)					−1.784*	+92.34*
Chapple et al 2007 [33]	Feso 4 mg qd (272)	12 wk	≥3	−1.37 (14%)	−0.39 (29%)	−1.76 (17%)	+27.72 (17%)	−1.88 (18%)	−1.95 (80%)	NR	NR
Chapple et al 2007 [33]	Feso 8 mg qd (288)			−1.48 (17%)	−0.39 (23%)	−1.88 (19%)	+33.62 (22%)	−2.36 (19%)	−2.22 (87%)
Nitti et al 2007 [34]	Feso 4 mg (283)	12 wk	≥3	−1.04 (10%)	−0.58 (26%)	−1.61 (12%)	+16.5 (11%)	−1.91 (15%)	−1.65 (42%)	NR	NR
Nitti et al 2007 [34]	Feso 8 mg (279)			−1.54 (15%)	−0.55 (29%)	−2.09 (17%)	+33.6 (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.

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

Reference	Dosage (no. of cases)	Treatment duration	Jadad score	Adverse events rate	Withdrawals due to adverse events	Dry mouth	Moderate to severe or severe dry mouth	Constipation	AUR	Vision abnormality	Headache
Oxybutynin
Nilsson 1997 [13]	Oxy IR 5 mg bid (17)	8 wk	1	100%	0	82%	NR	NR	NR	12%	41%
Nilsson 1997 [13]	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
Anderson 1999 [35]	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%
Birns et al 2000 [36]	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
Versi et al 2000 [14]	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%
Barkin et al 2004 [15]	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%
Abrams et al 2006 [37]	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%
Junemann et al 2006 [17]	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%
Jonas 1997 [18]	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
Millard 1999 [20]	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%
Jacquetin et al 2001 [21]	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%
Malone-Lee et al 2001 [22]	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%
Van Kerrebroeck et al 2001 [23]	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%
Swift et al 2003 [24]	Tolt ER 4 mg qd (417)				5%	23%	2%	6%		1%	7%

Solifenacin
Cardozo et al 2004 [25]	Soli 5 mg qd (299)	12 wk	≥3	NR	2%	8%	2%	4%	NR	4%	NR
Cardozo et al 2004 [25]	Soli 10 mg qd (307)				4%	23%	5%	9%		6%
Chapple et al 2004 [26]	Soli 5 mg qd (279)	12 wk	≥3	NR	3%	14%	NR	7%	NR	4%	NR
Chapple et al 2004 [26]	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
Chapple et al 2006* [27]	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%
Chapple et al 2005* [28]	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
Foote et al 2005* [29]	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
Zinner et al 2005 [30]	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%
Chapple et al 2007 [33]	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%
Nitti et al 2008 [34]	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.

3.1.1. 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], [14], [15], [35], and [36], while two further studies compared different doses of the ER formulation [16], and [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], and [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], 1.03–3.51; p = 0.04), dry mouth (OR: 1.45; 95% CI, 1.02–2.05; p = 0.04), and moderate-to-severe or severe dry mouth (OR: 1.49; 95 CI, 1.02–2.16; 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).

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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.

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	3	268	1.9	1.03–3.51	0.04	Oxybutynin ER
Withdrawals due to adverse events	2	158	1.51	0.49–4.65	0.47	None
Dry mouth	5	619	1.45	1.02–2.05	0.04	Oxybutynin ER
Moderate-to-severe or severe dry mouth	3	456	1.49	1.02–2.16	0.04	Oxybutynin ER
Headache	3	288	1.77	0.84–3.72	0.13	None
Constipation	2	230	1.11	0.56–2.22	0.76	None
Vision abnormality	4	393	0.92	0.50–1.69	0.79	None

RCT, randomized control trial; IR, immediate release; ER, extended release; OR, odds ratio; CI, confidence interval.

3.1.2. 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], [21], and [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], and [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], and [39]. Comparing the tolterodine IR 1 mg and tolterodine IR 2 mg doses, micturitions per 24 h (weighted mean difference [WMD], 0.11; 95% CI, −0.45–0.66; p = 0.70), volume voided per micturition (WMD, −8.68; 95% CI, −18.62–1.26; p = 0.09), and UUI episodes per 24 h (WMD, −0.06; 95% CI, −0.51–0.39; 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, 1.037–0.72; p < 0.0001).

Regarding the comparison of tolterodine IR and tolterodine ER formulations, patients randomized to tolterodine ER formulation experienced a lower number of micturitions per 24 h (WMD, 0.34; 95% CI, 0.02–0.66; p = 0.03) and a higher volume voided per micturition (WMD, −9.12; 95% CI, −14.13–−4.12; p = 0.0004), but a similar number of incontinence episodes and pad use per day (Table 4). Evaluating 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, 1.13–1.71; p = 0.002) but a higher rate of headache (OR: 0.53; 95% CI, 0.34–0.81; p = 0.004). Withdrawals due to adverse events and constipation were similarly prevalent in both cases (Table 4; Fig. 3).

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 per 24 h	2	1846	0.34	0.02–0.66	0.03	Tolterodine ER
Volume voided per micturition	2	1846	−9.12	−14.13–4.12	0.0004	Tolterodine ER
Incontinence episodes per 24 h	2	1846	0.09	−0.15–0.32	0.46	None
Pad use per 24 h	2	1846	0	−0.15–0.15	1	None

Adverse events	RCT (no.)	Participants (no.)	OR	95% CI, OR	Test for overall effect (p value)	Difference favors
Withdrawals due to adverse events	2	1846	0.98	0.65–1.48	0.92	None
Dry mouth	2	1846	1.39	1.13–1.71	0.002	Tolterodine ER
Headache	2	1846	0.53	0.34–0.81	0.004	Tolterodine IR
Constipation	2	1846	1.10	0.76–1.59	0.63	None

IR, immediate release; ER, extended release; UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.

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Fig. 3 Forest plots of efficacy and safety after tolterodine immediate release (IR) and tolterodine extended release (ER). (A) Micturitions per 24 h; (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.

3.1.3. Propiverine

A single study evaluated the efficacy of 21-d treatment with different doses of propiverine IR (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], and [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).

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	2	866	1.20	0.90–1.58	0.21	None
Dry mouth	2	866	1.16	0.84–1.58	0.36	None
Headache	2	866	1.54	0.59–4.02	0.38	None
Constipation	2	866	1.29	0.69–2.41	0.42	None
Vision abnormality	2	866	1.95	0.89–4.02	0.10	None

RCT, randomized control trial; OR, odds ratio; CI, confidence interval.

3.1.4. Solifenacin

Four RCTs evaluated the efficacy of different doses of solifenacin [25], [26], [41], and [42]. The two studies by Gittelman et al [41], and [42] were not included in Table 1, and Table 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], and [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 = 0.0005), dry mouth (p < 0.0001), and constipation (p < 0.0001) were significantly more common among the patients treated by solifenacin 10 mg [27].

3.1.5. Darifenacin

Our systematic search identified two RCTs evaluating the efficacy of darifenacin at different doses [30], and [31] and two pooled analyses of RCTs [28], and [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, 0.47–0.81; p = 0.0005), withdrawals due to adverse events (OR: 0.30; 95% CI, 0.11–0.80; p = 0.02), dry mouth (OR: 0.46; 95% CI, 0.34–0.62; p < 0.0001), and constipation (OR: 0.62; 95% CI, 0.44–0.87; 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, 0.26–0.63; p < 0.0001) and constipation (OR: 0.27; 95% CI, 0.16–0.44; p < 0.0001; Table 6; Fig. 4).

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	2	886	0.62	0.47–0.81	0.0005	Darifenacin 7.5 mg
Withdrawal due to adverse event	2	886	0.30	0.11–0.80	0.02	Darifenacin 7.5 mg
Dry mouth	2	886	0.46	0.34–0.62	<0.0001	Darifenacin 7.5 mg
Headache	2	886	0.90	0.50–1.64	0.74	None
Constipation	2	886	0.62	0.44–0.87	0.006	Darifenacin 7.5 mg
Darifenacin 15 mg vs darifenacin 30 mg
Withdrawal due to adverse event	2	374	0.40	0.09–1.74	0.22	None
Dry mouth	2	374	0.40	0.26–0.63	<0.0001	Darifenacin 15 mg
Constipation	2	374	0.27	0.16–0.44	<0.00001	Darifenacin 15 mg

RCT, randomized control trial; OR, odds ratio; CI, confidence interval; NR, not reported.

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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.

3.1.6. Fesoterodine

Three RCTs compared different doses of fesoterodine, the most recently released anticholinergic drug [32], [33], and [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, 0.53–0.87; p = 0.002), dry mouth (OR: 0.46; 95% CI, 0.36–0.60; p < 0.0001) and vision abnormality (OR: 0.38; 95% CI, 0.17–0.86; p = 0.02) were more common in those patients receiving fesoterodine 8 mg (Table 7).

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	2	1116	0.68	0.53–0.87	0.002	Fersoterodine 4 mg
Withdrawal due to adverse event	3	1211	0.60	0.36–1	0.05	None
Dry mouth	3	1211	0.46	0.36–0.60	<0.0001	Fersoterodine 4 mg
Constipation	2	1116	0.67	0.39–1.15	0.15	None
Headache	2	1116	1.66	0.86–3.20	0.13	None
Vision abnormality	2	1116	0.38	0.17–0.86	0.02	Fersoterodine 4 mg
Acute urinary retention	2	1116	0.62	0.20–1.92	0.41	None

RCT, randomized control trial; OR, odds ratio; CI: confidence interval.

3.2. Comparisons of different drugs

Table 8, and Table 9 summarize the efficacy and safety data from the available RCTs comparing different drugs.

Table 8 Efficacy data from the randomized control trials (RCTs) comparing different drugs

Reference	Dose (no. of cases)	Treatment duration	Jadad score	Mean change in daytime micturitions per 24 h	Mean change in nighttime micturitions per 24 h	Mean change in micturitions per 24 h	Mean change in VV per micturitions (ml)	Mean change in urgency episodes per 24 h	Mean change in UUI episodes per 24 h	Mean change in incontinence episodes per 24 h	Mean change in pads used per 24 h
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
Van Kerrebroeck 1997 [45]	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
Abrams et al 1998 [46]	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
Drutz et al 1999 [47]	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
Appell et al 2001 [48]	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%)
Malone–Lee et al 2001 [49]	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
Lee et al 2002 [50]	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
Diokno et al 2003 [51]	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%)	+22.3 (18%)	NR	NR	NR	0
Homma et al 2003 [52]	Tolt ER 4 mg qd (240)					−2.1 (17%)	+17.2 (14%)				0
Giannitsas et al 2004 [53]	Oxy IR 5 mg tid (107)	6+6 wk (crossover)	≥3	NR	NR	−0.8 (9%)	+43.8 (22%)	NR	NR	NR	NR
Giannitsas et al 2004 [53]	Tolt IR 2 mg bid (107)					−0.9 (10%)	+40.6 (21%)
Homma et al 2004 [54]	Oxy IR 3 mg tid (122)	12 wk	≥3	NR	NR	19.1%*	+22*	NR	NR	87%*	NR
Homma et al 2004 [54]	Tolt ER 4 mg qd (114)					17.9%*	+12.6*			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
Madersbacher et al 1999 [55]	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
Halaska et al 2003 [56]	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%)

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
Junemann et al 2000 [57]	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*	+28.43*	−3.04*	NR	−0.91*	−0.43*
Junemann et al 2005 [58]	Propi 15 mg bid (100)					−2.75*	+31.76*	−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%)	+24.4 (20%)	−2.05 (38%)	−0.91 (58%)	−1.14 (59%)	NR
	Soli 5 mg qd (264)					−2.19 (17%)	+32.9 (25%)	−2.85 52%)	−1.41 (65%)	−1.42 (59%)
	Soli 10 mg qd (261)					−2.61 (20%)	+39.2 (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%)
Chapple et al 2005 [59]	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%)	+24.3 (17%)	−1.67 (29%)	−0.91 (43%)	−0.90 (42%)	−0.80 (27%)
Chapple et al 2007 [60]	Soli 5 mg qd (578)				−0.51 (23%)	−1.71 (14%)	+28.5 (19%)	−1.98 (33%)	−1.22 (53%)	−1.30 (53%)	−1.21 (37%)

Tolterodine vs fesoterodine
Chapple et al 2007 [33]	Tolt ER 4 mg qd (290)	12 wk	≥3	−1.35 (14%)	−0.4 (25%)	−1.73 (14%)	+23.64 (15%)	−2.03 (16%)	−1.74 (70%)	NR	NR
	Feso 4 mg qd (272)			−1.37 (14%)	−0.39 (29%)	−1.76 (17%)	+27.72 (17%)	−1.88 (18%)	−1.95 (80%)
	Feso 8 mg (288)			−1.48 (17%)	−0.39 (23%)	−1.88 (19%)	+33.62 (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.

Table 9 Safety data from the randomized control trials (RCTs) comparing different drugs

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%
Thuroff et al 1991 [61]	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
Van Kerrebroeck et al 1997 [45]	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
Abrams et al 1998 [46]	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
Drutz et al 1999 [47]	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%
Appell et al 2001 [48]	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%
Malone-Lee et al 2001 [49]	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
Lee et al 2002 [50]	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
Leung et al 2002 [62]	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
Diokno et al 2003 [51]	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%
Homma et al 2003 [52]	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
Homma et al 2004 [54]	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%
Altan-Yacioglu et al 2005 [63]	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%
Madersbacher et al 1999 [55]	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%
Halaska et al 2003 [56]	Trospium 20 mg bid (267)			68%	4%	33%		4%			3%

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
Junemann et al 2000 [37]	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%
Junemann et al 2005 [58]	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%
Chapple et al 2005 [59]	Tolt ER 4 mg qd (599)	12 wk	≥3	NR	3%	24%	1%	NR	2%	NR	2%
Chapple et al 2005 [59]	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
Chapple et al 2007 [60]	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.

3.2.1. Oxybutynin versus tolterodine

Twelve RCTs compared efficacy and safety of oxybutynin and tolterodine [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [62], and [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], [46], [47], [49], [50], [53], [62], and [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], and [53]. Micturitions per 24 h, volume voided per micturition, UUI episodes, and incontinence episodes per 24 h were overlapping for the IR formulations of the two drugs. Regarding adverse events, occurrence of any adverse event (OR: 2.30; 95% CI, 1.70–3.11; p ≤ 0.00001), withdrawal due to adverse events (OR: 1.82; 95% CI, 1.33–2.49; p = 0.0002), dry mouth of any grade (OR: 3.98; 95% CI, 3.16–5.02; p ≤ 0.00001), and moderate-to-severe or severe dry mouth (OR: 7.21; 95% CI, 4.50–11.52; p ≤ 0.00001) were significantly more common in those patients receiving oxybutynin IR (Table 10 and Fig. 5).

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 per 24 h	4	1041	0.02	−0.33–0.36	0.92	None
Volume voided per micturition	3	813	1.89	−7.73–11.51	0.70	None
Urgency urinary incontinence episodes per 24 h	1	378	0.50	−0.11–1.11	0.11	None
Incontinence episodes per 24 h	2	449	−0.11	−0.54–0.32	0.61	None

Adverse events	RCT (no.)	Participants (no.)	OR	95% CI, OR	Test for overall effect (p value)
Adverse events	5	1181	2.30	1.70–3.11	<0.00001	Tolterodine IR
Withdrawals due to adverse events	6	1409	1.82	1.33–2.49	0.0002	Tolterodine IR
Dry mouth	6	1355	3.98	3.16–5.02	<0.00001	Tolterodine IR
Moderate to severe or severe dry mouth	4	894	7.21	4.50–11.52	<0.00001	Tolterodine IR
Headache	3	826	0.83	0.52–1.34	0.45	None
Constipation	1	378	0.68	0.30–1.50	0.33	None
Vision abnormality	2	430	1.39	0.69–2.82	0.36	None

UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.

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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.

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 < 0.0001), 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], and [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, 1.80– 3.30; p < 0.00001) and severe dry mouth (OR: 16.87; 95% CI, 3.23–87.95; p = 0.0008) 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 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].

3.2.2. Oxybutynin versus propantheline

Two studies compared oxybutynin IR 5 mg three times daily and propantheline 15 mg three times daily [61], and [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.

3.2.3. Oxybutynin versus propiverine

Two studies compared oxybutynin with propiverine [55], and [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].

3.2.4. 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 per 24 h, 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].

3.2.5. 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 treatment. 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].

3.2.6. 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.

3.2.7. 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 per 24 h, and number of incontinence episodes per 24 h 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].

3.2.8. Tolterodine versus solifenacin

Two studies reported data on the comparisons between solifenacin and tolterodine [26], [59], and [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 per 24 h (p = 0.004 for non-inferiority), 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 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 per 24 h and most of the secondary end points [60].

In the two RCTS comparing solifenacin and tolterodine [26], and [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, 1.70–4.54; p < 0.0001) was more common in the solifenacin arm (Table 11).

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	2	1987	1.27	0.74–2.18	0.39	None
Dry mouth	2	1987	1.21	0.97–1.50	0.08	None
Constipation	2	1987	2.78	1.70–4.54	<0.0001	Tolterodine ER
Vision abnormality	2	1987	1.34	0.68–2.64	0.40	None

CI, confidence interval; OR, odds ratio.

3.2.9. 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 < 0.0001) and dry eye (p = 0.02), compared with tolterodine 4 mg [33].

3.3. Comparison of different routes of administration

Table 12, and Table 13 summarize the efficacy and safety data from the available RCTs comparing different routes of administration of anticholinergic drugs.

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	Mean change in micturitions per 24 h	Mean change in VV per micturitions (ml)	Mean change in incontinence episodes per 24 h
Davila et al 2001 [64]	Oxy IR 2.5 mg bid or tid (38)	4 wk	≥3	NR	NR	−0.8 (23%)
Davila et al 2001 [64]	Oxy TDS twice a week (38)					−0.4 (17%)

Dmochowski et al 2003 [65]	Tolt ER 4 mg qd (123)	12 wk	≥3	−2.2 (18%)	+29 (19%)	−3.2 (64%)
Dmochowski et al 2003 [65]	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%
Davila et al 2001 [64]	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
Dmochowski et al 2003 [65]	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.

Two RCTs compared the oral and transdermal routes of administration of oxybutynin [64], and [65]. 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 per 24 h (WMD: 0.05; 95% CI, −0.58–0.67; p = 0.88). Dry mouth (OR: 3.67; 95% CI, 1.73–7.81; p = 0.0007) and constipation (OR: 2.78; 95% CI, 1.27–6.08; p = 0.01) were significantly more common in those patients taking the drug orally, while localized application side effects (OR: 0.26; 95% CI, 0.14– 0.49; p < 0.0001) and withdrawal due to adverse events (OR: 0.14; 95% CI, 0.03–0.62; p = 0.01) were significantly more frequent in those patients receiving active transdermal formulations (Table 14; Fig. 6).

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	1	244	1.31	0.71–2.43	0.38	None
Localized application site reactions	2	320	0.26	0.14–0.49	<0.0001	Oral
Withdrawals due to adverse events	1	244	0.14	0.03–0.62	0.01	Oral
Dry mouth	2	320	3.67	1.73–7.81	0.0007	Transdermal
Constipation	2	320	2.78	1.27–6.08	0.01	Transdermal
Vision abnormality	1	76	1.37	0.45–4.17	0.57	None

RCT, randomized control trials; OR, odds ratio; CI, confidence interval.

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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.

3.4. Publication bias

“Funnel plots” of the studies used in this meta-analysis were generated for all of the evaluated comparisons. Only four studies [15], [21], [45], and [62] lay outside the 95% CI with an even distribution around the vertical, suggesting little evidence of publication bias (plots not shown).

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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 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 meta-analyses 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-inferiority of solifenacin compared to tolterodine ER [59], while our meta-analysis showed similar rates of adverse events, with the exception of constipation, which was more common in the solifenacin arm. A single trial is currently available on fesoterodine, suggesting that the new drug might be more efficacious than tolterodine ER. With regard to the routes of administration, the transdermal route does not seem to provide any significant advantage compared to the oral intake, considering the higher rate of side effects from localized application and withdrawal due to adverse events.

Providing clear indications for the clinical practice, however, is quite difficult. With regard to the selection of the first drug to use in naïve patients, the RCTs comparing different drugs often enrolled a large number of patients who had previously been treated with other drugs. Considering this issue as a mandatory starting point, according to our data, the first drug which might be used in naïve patients is oxybutynin ER, tolterodine ER 4 mg, solifenacin 5 mg, or solifenacin 10 mg. Similarly, darifenacin 15 mg and fesoterodine 4 mg might be considered as valuable options, but further evaluation is needed, and further RCTs are ongoing.

In case of insufficient clinical efficacy, the choice of the second drug cannot really be based on evidence because, to our knowledge, no randomized trials were aimed at identifying the most efficient drug in the case of lack of success with some of the other first-line choices. Making assumptions from the available data, in case of lack of efficacy of the first-line ER drug, fesoterodine 8 mg and solifenacin 10 mg might be a possible option, due to the results of the two available trials comparing fesoterodine or solifenacin to tolterodine ER [26], [33], and [59], although an increased rate of adverse events must be taken into account. In case of failure of the first-line ER drug due to intolerable adverse events, the availability of clear evidence-based recommendations is limited. In case of dry mouth, a transdermal formulation might provide some advantages compared to the oral one, and some authors suggested that it might be used as first-line therapy [66], but the meta-analysis suggested that localized application site reactions are very common and might significantly impact the patients’ compliance with this formulation. On the other hand, if constipation is the most bothersome adverse event, it can be managed by shifting from solifenacin to tolterodine ER. However, despite the lack of evidence, it might be wise to suggest that the patients take one of the other oral drugs before starting more invasive treatments, but controlled studied are needed to provide evidence-based answers to these clinical questions. Conversely, those patients taking IR formulations of anticholinergic drugs without successful results might be offered dose titration in case the patients did not experienced significantly adverse events, but ER formulations might be the preferred choice.

The overall quality of the randomized controlled trials available in the field of OAB was good, with most of the RCTs having a Jadad score ≥3. However, almost all the trials evaluated short-term therapy (mostly 12 wk), with only a single study continuing the drug therapy for 52 wk [56], and some adverse events, such as the impact on cognitive function, should be better evaluated. Moreover, almost all of the studies provided efficacy data derived from bladder diaries [67]; a more suitable evaluation should also include subjective outcomes, such as the so-called patient-reported outcomes [7], which are lacking in most of the studies. However, virtually all the evidence has been derived from pharmaceutical company–sponsored trials, which, to date, have been the only way to realize those very expensive, good-quality, large-scale trials. However, the studies’ designs reflect the needs of the companies for registrational studies, rather than addressing the questions that are more relevant for clinical practice.

According to the criteria of the Overview Quality Assessment Questionnaire (OQAQ) [68], our systematic review can be considered to be a good-quality review. However, due to the limitations of the Review Manager software, which allows the evaluation of continuous variables only if they are expressed as means and standard deviations, it was not possible to perform meta-analysis for some clinically relevant efficacy outcomes due to the lack of data in the published reports. Although all the authors of the RCTs were contacted with the aim of obtaining the needed data in the appropriate format, the attempt was not successful in most cases.

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5. Conclusions

Many of the available RCTs in the field of muscarinic receptor antagonists for overactive bladder are of good methodological quality. ER formulations should be preferred to the IR formulations due to the more favorable profile of efficacy and adverse events. With regard to IR formulations, dose escalation might yield some improvements in the efficacy, but at the cost of a significant increase in the rate of adverse events. More clinical studies are needed to determine which of the available drugs should be used as first-, second-, and third-line treatments.

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Author contributions: Walter Artibani 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: Novara, Ficarra, Artibani.

Acquisition of data: Galfano, Secco, D’Elia.

Analysis and interpretation of data: Novara, Galfano, Ficarra, Artibani.

Drafting of the manuscript: Novara.

Critical revision of the manuscript for important intellectual content: Galfano, Secco, D’Elia, Cavalleri, Ficarra, Artibani.

Statistical analysis: Novara.

Obtaining funding: None.

Administrative, technical, or material support: Cavalleri.

Supervision: Ficarra, Artibani.

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: Dr Novara has been a consultant, investigator, or speaker for Bioxell, GlaxoSmithKleine, Pfizer Inc., and Pierre Fabre. Dr Galfano has been a consultant or investigator for Astellas, Bayer, Bioxell, Novartis, and Pfizer Inc. Prof Ficarra has been a consultant, investigator or speaker for Bioxell, Novartis, and Pfizer Inc. Prof Artibani has been a consultant, investigator, or speaker for Astellas, Bayer, Bioxell, Novartis, Pfizer Inc., Pierre Fabre, and UCB. Drs Secco, D’Elia, and Cavalleri have nothing to disclose.

Funding/Support and role of the sponsor: None.

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Footnotes

^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

Corresponding author. Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV Floor, Via Giustiniani 2, 35128, Padua, Italy. Tel. +39 049 8212720; Fax: +39 049 8218757.

Article information

PII: S0302-2838(08)00802-6
DOI: 10.1016/j.eururo.2008.06.080
© 2008 European Association of Urology. Published by Elsevier B.V.

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Contents

European Urology

Journal Article Page

European Urology

Reviews

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

Abstract

Context

Objective

Evidence acquisition

Evidence synthesis

Conclusion

Take Home Message

Article Outline

1. Introduction

2. Methods

3. Results

3.1. Comparisons of different doses and formulations of the same drug

3.1.1. Oxybutynin

3.1.2. Tolterodine

3.1.3. Propiverine

3.1.4. Solifenacin

3.1.5. Darifenacin

3.1.6. Fesoterodine

3.2. Comparisons of different drugs

3.2.1. Oxybutynin versus tolterodine

3.2.2. Oxybutynin versus propantheline

3.2.3. Oxybutynin versus propiverine

3.2.4. Oxybutynin versus trospium

3.2.5. Oxybutynin versus darifenacin

3.2.6. Tolterodine versus trospium

3.2.7. Tolterodine versus propiverine

3.2.8. Tolterodine versus solifenacin

3.2.9. Tolterodine versus fesoterodine

3.3. Comparison of different routes of administration

3.4. Publication bias

4. Discussion

5. Conclusions

Footnotes

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