Which anticholinergic drug for overactive bladder symptoms in adults

Priya Madhuvrata; June D Cody; Gaye Ellis; G Peter Herbison; E Jean C Hay‐Smith

doi:10.1002/14651858.CD005429.pub2

. 2012 Jan 18;2012(1):CD005429. doi: 10.1002/14651858.CD005429.pub2

Which anticholinergic drug for overactive bladder symptoms in adults

Priya Madhuvrata ^1,^✉, June D Cody ², Gaye Ellis ³, G Peter Herbison ⁴, E Jean C Hay‐Smith ⁵

Editor: Cochrane Incontinence Group

PMCID: PMC12989262 PMID: 22258963

Abstract

Background

Around 16% to 45% of adults have overactive bladder symptoms, urgency with frequency or urgency urinary incontinence, or both, termed 'overactive bladder syndrome'. Anticholinergic drugs are common treatments.

Objectives

To compare the effects of different anticholinergic drugs for overactive bladder symptoms.

Search methods

We searched the Cochrane Incontinence Group Specialised Trials Register (searched 8 March 2011) and reference lists of relevant articles.

Selection criteria

Randomised trials in adults with overactive bladder symptoms or detrusor overactivity that compared one anticholinergic drug with another, or two doses of the same drug.

Data collection and analysis

Two authors independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

Eighty‐six trials, 70 parallel and 16 cross‐over design, were included (involving 31,249 adults). Most trials were described as double‐blind but were variable in other aspects of quality. Cross‐over studies did not present data in a way that could be included in the meta‐analyses. Twenty‐nine collected quality of life data (the primary outcome measure) using validated measures, but only 15 reported useable data.

Tolterodine versus oxybutynin: there were no statistically significant differences for quality of life, patient reported cure or improvement, leakage episodes or voids in 24 hours, but fewer withdrawals due to adverse events with tolterodine (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.40 to 0.66, data from eight trials) and less risk of dry mouth (RR 0.65, 95% CI 0.60 to 0.71, data from 10 trials).

Solifenacin versus tolterodine: there were statistically significant differences for quality of life (standardised mean difference (SMD) ‐0.12, 95% CI ‐0.23 to ‐0.01, data from three trials), patient reported cure or improvement (RR 1.25, 95% CI 1.13 to 1.39, data from two trials), leakage episodes in 24 hours (weighted mean difference (WMD) ‐0.30, 95% CI ‐0.53 to ‐0.08, data from four studies) and urgency episodes in 24 hours (WMD ‐0.43, 95% CI ‐0.74 to ‐0.13, data from four trials), all favouring solifenacin. There was no difference in withdrawals due to adverse events and dry mouth but after sensitivity analysis dry mouth rates (RR 0.69, 95% CI 0.51 to 0.94) were statistically significantly lower with solifenacin when compared to immediate release (IR) tolterodine.

Fesoterodine versus extended release tolterodine: three trials contributed to the meta analyses. There were statistically significant differences for quality of life (SMD ‐0.20, 95% CI ‐0.27 to ‐0.14), patient reported cure or improvement (RR 1.11, 95% CI 1.06 to 1.16), leakage episodes (WMD ‐0.19, 95% CI ‐0.30 to ‐0.09), frequency (WMD ‐0.27, 95% CI ‐0.47 to ‐0.06) and urgency episodes (WMD ‐0.44, 95% CI ‐0.72 to ‐0.16) in 24 hours, all favouring fesoterodine. Those taking fesoterodine had a higher risk of withdrawal due to adverse events (RR 1.45, 95% CI 1.07 to 1.98) and higher risk of dry mouth (RR 1.80, 95% CI 1.58 to 2.05) at 12 weeks.

Different doses of tolterodine: the standard recommended starting dose (2 mg twice daily) was compared with two lower doses (0.5 mg and 1 mg twice daily) and one higher dose (4 mg twice daily). The effects of 1 mg, 2 mg and 4 mg doses were similar for leakage episodes and micturitions in 24 hours, with a greater risk of dry mouth with the 2 and 4 mg doses at two to 12 weeks.

Different doses of solifenacin: the standard recommended starting dose of 5 mg once daily was compared to 10 mg. While frequency and urgency were less (better) with 10 mg compared to 5 mg, there was a higher risk of dry mouth with 10 mg solifenacin at four to 12 weeks.

Different doses of fesoterodine:the recommended starting dose of 4 mg once daily was compared to 8 mg and 12 mg. The clinical efficacy (patient reported cure, leakage episodes, micturition per 24 hours) of 8 mg was better than 4 mg fesoterodine but with a higher risk of dry mouth with the 8 mg dose.There was no statistically significant difference between 4 mg and 12 mg in efficacy but the dry mouth was significantly higher with 12 mg at eight to 12 weeks.

Extended versus immediate release preparations of oxybutynin or tolterodine, or both: there were no statistically significant differences for cure or improvement, leakage episodes or micturitions in 24 hours or withdrawals due to adverse events, but there were few data. Overall, extended release preparations had less risk of dry mouth at two to 12 weeks.

One extended release preparation versus another: there was less risk of dry mouth with oral extended release tolterodine than oxybutynin (RR 0.75, 95% CI 0.59 to 0.95) but no difference between transdermal oxybutynin and oral extended release tolterodine, although some people withdrew due to a skin reaction at the transdermal patch site at 12 weeks.

Authors' conclusions

Where the prescribing choice is between oral immediate release oxybutynin or tolterodine, tolterodine might be preferred for reduced risk of dry mouth. With tolterodine, 2 mg twice daily is the usual starting dose but a 1 mg twice daily dose might be equally effective, with less risk of dry mouth. If extended release preparations of oxybutynin or tolterodine are available, these might be preferred to immediate release preparations because there is less risk of dry mouth.

Between solifenacin and immediate release tolterodine, solifenacin might be preferred for better efficacy and less risk of dry mouth. Solifenacin 5 mg once daily is the usual starting dose, which could be increased to 10 mg once daily for better efficacy but with increased risk of dry mouth.

Between fesoterodine and extended release tolterodine, fesoterodine might be preferred for superior efficacy but has a higher risk of withdrawal due to adverse events and higher risk of dry mouth.There is little or no evidence available about quality of life, costs, or long‐term outcomes in these studies. There were insufficient data from trials of other anticholinergic drugs to draw any conclusions.

Keywords: Adult; Humans; Benzhydryl Compounds; Benzhydryl Compounds/adverse effects; Benzhydryl Compounds/therapeutic use; Cholinergic Antagonists; Cholinergic Antagonists/adverse effects; Cholinergic Antagonists/therapeutic use; Cresols; Cresols/adverse effects; Cresols/therapeutic use; Mandelic Acids; Mandelic Acids/adverse effects; Mandelic Acids/therapeutic use; Phenylpropanolamine; Phenylpropanolamine/adverse effects; Phenylpropanolamine/therapeutic use; Quinuclidines; Quinuclidines/adverse effects; Quinuclidines/therapeutic use; Randomized Controlled Trials as Topic; Solifenacin Succinate; Tetrahydroisoquinolines; Tetrahydroisoquinolines/adverse effects; Tetrahydroisoquinolines/therapeutic use; Tolterodine Tartrate; Urinary Bladder, Overactive; Urinary Bladder, Overactive/drug therapy; Urinary Incontinence; Urinary Incontinence/drug therapy

Plain language summary

Which anticholinergic drug for overactive bladder symptoms in adults

Many adults have symptoms of overactive bladder. A person with overactive bladder syndrome feels a very strong urge to pass urine and they may not make it to the toilet before they leak urine. Other common problems are a feeling of needing to urinate often during the day or night, or both. This problem seems to be caused by an overactive bladder muscle, and it becomes more common with ageing. Treatments are conservative measures, such as bladder training or drugs. Anticholinergic drugs can reduce the overactivity of the bladder muscle and the feeling of urgency. The review found that there are several anticholinergic drugs prescribed for adults with overactive bladder symptoms. The two most studied drugs are oxybutynin and tolterodine. These two drugs have similar effects but, on average, those taking oxybutynin were more likely to withdraw from the studies because of adverse effects, mainly dry mouth. However, both drugs can give dry mouth and this problem is less likely if an extended release formulation of either drug is used. Two newer drugs are solifenacin and fesoterodine. Solifenacin has a better effect and less risk of dry mouth compared to tolterodine. Fesoterodine has a better effect than extended release tolterodine but withdrawal from studies due to adverse effects and dry mouth was more likely.

Background

Description of the condition

People with overactive bladder syndrome report urgency (with or without urgency urinary incontinence), usually in combination with frequency or nocturia, or both (Abrams 2002). Overactive bladder syndrome may also be called urge syndrome or urgency‐frequency syndrome.

Urgency is the sudden and compelling desire to pass urine, which is difficult to defer (Abrams 2002). Sometimes there is involuntary leakage of urine with the feeling of urgency and this is called urgency urinary incontinence. Urgency and urgency urinary incontinence usually result from an involuntary increase in bladder pressure due to detrusor (bladder smooth muscle) over‐activity. If further investigation of urgency and urge incontinence with urodynamics demonstrates spontaneous or provoked detrusor muscle contraction in the filling phase of the test then detrusor overactivity is diagnosed. If there is no defined cause for the overactivity this is called idiopathic detrusor overactivity, but if there is a relevant neurological condition then the term neurogenic detrusor overactivity (previously detrusor hyperreflexia) is used.

Frequency is the complaint of needing to void too often during the day, while nocturia is waking once or more times per night to void (Abrams 2002). In clinical practice, a person who voids more than eight times during the day would be considered to have daytime frequency; waking from sleep more than once at night to void would be considered nocturia.

Overactive bladder symptoms are very common in community dwelling adults, with large studies showing prevalences of 12% in Japan (Homma 2005); 15% in Hong Kong Chinese (Brieger 1996); 17% in Europe (Milsom 2001), Canada (Corcos 2004; Herschorn 2008) and the USA (Stewart 2001); 13% to 31% in Korea (Choo 2001; Choo 2007) and 45% in Asian men (Moothy 2001). These studies reported that the prevalence in adult males varied from 10% to 17% and in females it varied from 10% to 31%. The Asian studies may have overestimated prevalence, because people whose only symptom was frequency were counted as 'cases' of overactive bladder. Different definitions and different age groups studied may be the reason for differences in prevalence.

Several large population studies have reported that the prevalence of overactive bladder symptoms increases with age in men and women (Brown 1999; Corcos 2004; Homma 2005; Irwin 2006; Milsom 2001; Moller 2000; Stewart 2001; Ueda 2000). Although the diagnosis of overactive bladder excludes people with known causes of detrusor overactivity, for example neurological disorders, this combination of symptoms is nevertheless common in such groups. In fact, urinary dysfunction appears to be more common in the neurologically impaired than unimpaired population; the most frequently reported problems are urgency or frequency, or both (Hennessey 1999).

It seems that frequency and urgency might be just as bothersome as actual leakage (Milsom 2001), and overall the effects of overactive bladder symptoms on quality of life are marked (Coyne 2003; Jackson 1997; Liberman 2001). It also seems clear that many of the people affected by overactive bladder symptoms do not seek help from healthcare professionals (Milsom 2001; Ueda 2000) because symptoms and bother do not necessarily go hand‐in‐hand and patients who are not bothered may need no treatment.

Description of the intervention

The two main treatment options for overactive bladder syndrome are bladder training and pharmacotherapy, that is drugs. A separate Cochrane review on bladder training (Wallace 2004) is available, and the scope of the current review is confined to drug treatment.

While the pathophysiology of the overactive bladder remains to be fully elucidated, the two most widely accepted explanations are the myogenic and neurogenic theories, which are not mutually exclusive (Hashim 2004). In the first, partial denervation of the detrusor muscle is thought to increase excitability. Changes in central nervous system pathways that inhibit bladder activity and over‐sensitivity of the sensory nerve endings in the bladder are the basis of the second. In both theories, the outcome is overactivity of the detrusor muscle. The motor nerve supply to the bladder is via the parasympathetic nervous system (via sacral nerves S2, 3, 4) (Abrams 1988; Ouslander 1982; Ouslander 1986), which affects detrusor muscle contraction. This is mediated by acetylcholine acting on muscarinic receptors at the level of the bladder. There are currently five recognised subtypes of muscarinic receptor; the M₁, M₂ and M₃ subtypes are of interest in bladder activity. Muscarinic receptors are found in other parts of the body too, for example in the gut, salivary glands, tear ducts, brain and heart. Pharmacotherapy relies on the use of drugs with anticholinergic properties. The rationale for using anticholinergic drugs in the treatment of overactive bladder syndrome is to block the parasympathetic acetylcholine pathway and thus abolish or reduce the intensity of detrusor muscle contraction. Unfortunately no anticholinergic drug available to date is specific to the muscarinic receptors in the bladder and, as a result, the drugs can cause side effects by acting in other parts of the body too, for example dry mouth or eyes, constipation or nausea. For the purpose of this review the term 'anticholinergic medications' will refer to both pure antimuscarinic drugs and antimuscarinic drugs with mixed actions that are given specifically for bladder symptoms. Drugs with mixed actions will be included where their clinical effect is thought to be antimuscarinic rather than via a direct action on bladder muscle. Medications with secondary anticholinergic effects, for example tricyclic antidepressants will be excluded.

Why it is important to do this review

The number of anticholinergic drugs available on the market is increasing and various studies, both observational and randomised controlled trials, have evaluated their effectiveness. A previous Cochrane review compared anticholinergic drugs with no treatment or placebo treatments (Nabi 2006). The use of anticholinergic drugs by people with overactive bladder syndrome results in statistically significant improvements in symptoms associated with a modest improvement in quality of life. Dry mouth is a common side effect of therapy but does not seem to have an effect on the numbers of withdrawals.

Anticholinergics are commonly used in primary and secondary care settings for the treatment of overactive bladder syndrome, and this has considerable resource implications (Kobelt 1997). If anticholinergic therapy is prescribed, there is still uncertainty about which anticholinergic drugs are most effective, at what dose, and by which route of administration. There is also uncertainty about the role of anticholinergic drugs in different patient groups (for example the elderly, men and women).

There are many studies of the effects of anticholinergic drugs. Four Cochrane reviews consider them. The present review compares anticholinergic drugs with each other to see whether different anticholinergic drugs have different effects. Previous reviews compared:

1) anticholinergic drugs with no treatment or placebo treatments (Nabi 2006);

2) whether anticholinergic drugs are better than other active (non‐drug) therapies (Alhasso 2006 ); and

3) whether anticholinergic drugs are better than other drug treatments (Roxburgh 2007). Anticholinergics for nocturia is considered in the review 'Drugs for nocturia in adults' (Cannon 2003).

Six previous systematic reviews of anticholinergic drugs for urgency urinary incontinence were found (Chapple 2008a; Haeusler 2002; Harvey 2001; Hartmann 2009; McDonagh 2009; Novara 2008). Haeusler et al (Haeusler 2002) included only placebo controlled trials, and no comparisons of anticholinergic drugs. Harvey et al (Harvey 2001) included trials that compared tolterodine and oxybutynin; the review, using Cochrane methods, is now outdated because other relevant trials have since been published. In addition, Harvey et al (Harvey 2001) did not include all possible anticholinergic drug comparisons. Chapple et al (Chapple 2008a) included placebo controlled trials, trials using different anticholinergics and different doses of anticholinergics. They concluded that anticholinergics were safe, efficacious and well tolerated with an improvement in quality of life. Novara et al (Novara 2008) included trials comparing different doses, formulations and routes of administration of anticholinergics. They concluded that extended release (ER) formulations should be preferred to immediate release (IR) ones. With regard to IR formulations, dose escalation might yield some improvement in efficacy with a significant increase in adverse events. A systematic review of the effects of antimuscarinics on health related quality of life in overactive bladder showed no significant differences among antimuscarinic agents (Khullar 2006). A network meta‐analysis of adverse events of antimuscarinics showed most currently used antimuscarinics to be an equivalent first choice to start the treatment of overactive bladder, except oral oxybutynin dosage of ≥ 10 mg/day, which may have unfavourable adverse events (Kessler 2011). Since the publication of the above systematic reviews more trials have been published for fesoterodine, and trials on a new anticholinergic called imedafenacin have been reported.

Therefore, there is clearly a need for a regularly updated and comprehensive systematic review of the effectiveness of anticholinergic drugs versus each other in the management of adults with overactive bladder syndrome.

Objectives

To determine the differential effects of anticholinergic drugs in the treatment of overactive bladder symptoms.

The following comparisons were made.

1. A particular anticholinergic drug versus another in the management of overactive bladder symptoms.

2. Higher doses of anticholinergic drugs versus lower doses.

3. Extended versus immediate release anticholinergic drugs.

4. One route of anticholinergic drug administration versus another (e.g. oral, transdermal, rectal, intravesical).

Methods

Criteria for considering studies for this review

Types of studies

All randomised or quasi‐randomised controlled trials of anticholinergic drugs for the treatment of overactive bladder symptoms or detrusor overactivity.

Types of participants

All adult men and women with a symptomatic diagnosis of overactive bladder syndrome with or without a urodynamic diagnosis of detrusor overactivity. Although people with neurological disorders cannot, by definition, have overactive bladder syndrome, they often experience overactive bladder symptoms secondary to their neurologic disease and are offered anticholinergic drugs. Therefore, trials that recruited people with neurologic disorders complaining of overactive bladder symptoms or with a diagnosis of neurogenic detrusor overactivity, or both, were included.

Types of interventions

One arm of the study was allocated an anticholinergic drug and at least one other arm used a different anticholinergic drug, an anticholinergic drug given via a different route, or a different dose of the same anticholinergic drug. To be included the drug had to be an anticholinergic, muscarinic antagonist and be given for the purpose of decreasing symptoms of overactive bladder. Trials of the following drugs were considered: emepronium bromide or carrageenate, intravesical atropine, darifenacin, dicyclomine chloride, oxybutynin, propantheline bromide, propiverine, solifenacin, tolterodine, trospium chloride, fesoterodine and imedafenacin. Terodoline, an anticholinergic drug previously used in the treatment of overactive bladder, was excluded because it was withdrawn from the market.

Other drugs with less direct anticholinergic effects were excluded, for example smooth muscle relaxants (flavoxate hydrochloride, calcium channel blockers, potassium channel openers, beta‐adrenoceptor agonists, alpha‐adrenoceptor antagonists, prostaglandin synthetase inhibitors) and tricyclic antidepressants.

Types of outcome measures

The primary outcomes of interest were as follows.   1. Condition‐specific quality of life (e.g. Incontinence Impact Questionnaire) (Shumaker 1994), generic quality of life (e.g. Short Form 36) (Ware 1993), and psychosocial measures.

The secondary outcomes of interest were the following.   2. Patients' observations e.g. symptom scores, perception of cure or improvement, satisfaction with outcome.   3. Quantification of symptoms e.g. number of leakage episodes, frequency, urgency and volume (urinary diary).   4. Clinicians' measures e.g. urodynamic measures (such as maximum cystometric capacity) and clinical findings.   5. Socioeconomics: direct and indirect costs of interventions (for patients and providers), resource implications of differences in outcome, formal economic analysis (e.g. cost effectiveness, cost utility), desire or need for further treatment.   6. Other e.g. adverse events, compliance measures, long‐term follow up and any other outcome not pre‐specified but judged important when performing the review.

Search methods for identification of studies

We did not impose language or other restrictions on any of these searches detailed below.

Electronic searches

This review has drawn on the search strategy developed for the Incontinence Review Group. Relevant trials were identified from the Cochrane Incontinence Group Specialised Register of controlled trials, which is described under the Group's details in The Cochrane Library (For more details please see the ‘Specialized Register’ section of the Group’s module in The Cochrane Library). The register contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, CINAHL and handsearching of journals and conference proceedings. (Direct searching within EMBASE did not take place for this review, only indirect searching via the EMBASE records on CENTRAL which may be from one year up to almost two years out of date depending on the issue of CENTRAL searched.)   The date of the most recent search of the specialised register for this review was 8 March 2011.

The trials in the Incontinence Group Specialised Register are also contained in CENTRAL.

The Incontinence Group Specialised Register was searched using the Group's own keyword system; the search terms used were:   topic.urine.incon*   AND   ({design.cct*} OR {design.rct*})   AND   ({intvent.chem.drug.antichol*})   Key: * = truncation symbol.   (All searches were in the keywords field of Reference Manager 12, Thomson Reuters).

Searching other resources

The reference lists of relevant articles were searched for other possible relevant trials.

Data collection and analysis

Selection of studies

Trials under consideration for inclusion in the review were assessed independently for their appropriateness by two authors, without prior consideration of their results. Any disagreements that were not resolved by discussion were considered by a third person. Excluded studies are listed with the reasons for their exclusion.

Data extraction and management

Data were independently abstracted by at least two authors and cross‐checked. Where data were collected but were not reported, or were reported in a form not suitable for inclusion in the formal analysis, further clarification was sought from trialists.

Assessment of risk of bias in included studies

The authors independently made an assessment of risk of bias using the Cochrane Collaboration's assessment tool, which includes evaluation of quality of random allocation and concealment, description of dropouts and withdrawals, analysis by intention to treat, and blinding during treatment and at outcome assessment. Disagreements were resolved by discussion with a third person.

Measures of treatment effect

Included trial data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The effect measure used for dichotomous data was risk ratio (RR) with the Mantel‐Hanszel fixed‐effect method; and for continuous data, mean difference or standardised mean difference with the inverse variance fixed‐effect method. Data from studies that reported change from baseline score were combined in the meta‐analysis with studies which reported end of treatment scores.

Unit of analysis issues

In order to use the data from cross‐over studies in a meta‐analysis, they must be presented as the mean and standard deviation of the difference between two treatments for continuous data or a two by two table for binary data, as the correlation between measurements on the same individual may be important. Only four of the 16 cross‐over studies presented data in this way (Fader 2007; Holmes 1989; Kramer 1987; Nilsson 1997), Holmes for three of our pre‐determined outcomes and Kramer and Nilson for one each. These few data have not been included in the pooled estimates.

Dealing with missing data

When data were missing, the original investigators were contacted to request missing data. Data imputation was not performed, instead we included data on only those results that were known.

Data synthesis

If appropriate, the results of included studies were combined for each outcome in a formal meta‐analysis to produce an overall estimate of treatment effect using a fixed‐effect model.

Subgroup analysis and investigation of heterogeneity

A priori subgroup analyses were planned to investigate the effects of age, sex, severity of symptoms and cause of overactive bladder symptoms (that is idiopathic versus neurogenic). Studies were assessed for both clinical and methodological heterogeneity. Data plots were examined for evidence of statistical heterogeneity (dissimilarity) and a formal (statistical) test of heterogeneity was used. Where heterogeneity was observed (based on the I² statistic and the test for heterogeneity) an explanation was sought and offered in the text. Where three or more trials contributed to a single data plot, the data were re‐analysed after removal of the trial(s) that were the apparent cause of the dissimilarity. The secondary analysis was reported in the text. Where clinically important (but not statistically significant) heterogeneity was observed, this was also noted in the text.

Sensitivity analysis

Sensitivity analysis was performed by excluding studies comparing different preparations (extended release and immediate release) and different routes of administration of anticholinergics. The results of the sensitivity analysis were reported in the text.

Results

Description of studies

See: 'Characteristics of included studies'; 'Characteristics of excluded studies'.

Results of the search

A total of 1108 records were identified by the search and screened for eligibility; 200 full‐text articles were obtained.

Included studies

One hundred and eighty reports of 86 trials were included in the review, 70 parallel design and 16 cross‐over design. One trial report contained data from two parallel design trials (Sussman 2002). Figure 1 shows the flow of literature through the assessment process. The trials recruited a total of 31,249 adults, including 22,996 women and 5426 men (note: some trials did not report by gender). Sample sizes ranged from 10 (Di Stasi 2001a) to 2417 (Kaplan 2010). Data were available for the quantitative synthesis from 158 reports of 68 studies.

Trials made four types of comparison:

comparisons of different anticholinergic drugs;
comparisons of different doses of the same drug;
comparisons of immediate release (IR) versus extended release (ER) preparations; and
comparisons of ER preparations.

Some trials had more than two arms and made more than one comparison. Trials that compared an ER preparation of one drug with an IR preparation of another were included in the comparison of different anticholinergic drugs and the comparison of IR versus ER preparations. Trials that compared ER preparations of different drugs were included in the comparison of different anticholinergic drugs and the comparison of ER preparations.

Three trials were published in German (Froehlich 1998; Osca 1997; Wehnert 1992), one in Flemish (Kramer 1987) and two in Chinese (Qiu 2002; Xia 2001a). Information and data were abstracted from the original papers.

Sample characteristics

Parallel group trials

Inclusion and exclusion criteria were not always well defined.

People with a urodynamic diagnosis of idiopathic detrusor overactivity were included in nine trials (Abrams 1998; Altan‐Yaycioglu 2005; Chapple 2002; Chapple 2004c; Froehlich 1998; Junemann 2005; Madersbacher 1999; Nitti 2005; Rentzhog 1998).
Seven trials restricted entry to those with a presumed or urodynamic diagnosis of neurogenic detrusor overactivity (Abrams 1996; Gajewski 1986; Madersbacher 1995; Menarini 2006; Stohrer 2002; Stohrer 2009; VanKerrebroeck 1998).
Fourteen trials included people with urodynamic detrusor overactivity (both idiopathic and neurogenic types, or type not further specified) (Birns 2000; Chaliha 1998; Davila 2001b; Drutz 1999; Jacquetin 2001; Jonas 1997; Junemann 2000; Leung 2001; Mazur 1995; Millard 1999; Osca 1997; Salvatore 1995; Thuroff 1991; VanKerrebroeck 1997).
In the remaining trials participants had symptoms consistent with overactive bladder syndrome (Anderson 1999; Appell 2001; Barkin 2004; But 2010; Cardozo 2004; Chapple 2004b; Chapple 2005b; Chapple 2007; Choo 2008; Corcos 2006; Davila 2001a; Diokno 2003; Dmochowski 2003; Haab 2004; Herschorn 2009; Herschorn 2010; Hill 2006; Ho 2010; Hofner 2000; Homma 2002; Homma 2006; Homma 2008; Homma 2008; Junemann 1999; Junemann 2006; Kaplan 2010; Lee 2001; Malone‐Lee 2001a; Malone‐Lee 2001b; Minassian 2007; Nitti 2007; Romanzi 2005; Qiu 2002; Sussman 2002; VanKerrebroeck 2001; Versi 2000; Xia 2001a; Yamaguchi 2007; Zellner 2007).

Mean age of the participants ranged from 31.3 years (no standard deviation) to 75 years (no standard deviation). Three trials restricted entry to older people, either 65 years or more (Malone‐Lee 2001a; Minassian 2007) or 50 years or more (Malone‐Lee 2001b).

Cross‐over studies

Eight studies included people with urgency or urge incontinence (Abrams 2006; Bagger 1985; Holmes 1989; Kramer 1987; Wehnert 1992; Yamanishi 2009; Zeegers 1987; Zinner 2005). These people usually had urodynamics as well but it was not one of the selection criteria. Eight further trials required that participants have a diagnosis of detrusor overactivity (Burton 1994; Chapple 2005c; Di Stasi 2001a; Di Stasi 2001b; Fader 2007; Giannitsas 2004a; Massey 1986; Nilsson 1997). Three studies did not report age; in eight other studies the mean age ranged from 42 to 72 years. Three studies reported age ranges; one study had a range of ages of 17 to 55 years, another 16 to 78 years and the third had an age range of 47 to 56 years.

Interventions in parallel arm studies

In many trials treatment was preceded by a washout period, or treatment with co‐medications was specifically excluded, or had a placebo run‐in period. This information was not given in 20 of the 70 parallel arm studies but given the short half life of the drugs this may not be important (Altan‐Yaycioglu 2005; Appell 2001; Birns 2000; But 2010; Chaliha 1998; Davila 2001a; Diokno 2003; Drutz 1999; Gajewski 1986; Ho 2010; Hofner 2000; Junemann 1999; Lee 2001; Leung 2001; Osca 1997; Romanzi 2005; Salvatore 1995; Stohrer 2009; Sussman 2002 (two studies)).

The following between‐drug comparisons were made.

(1) Oxybutynin versus:

(a) tolterodine (Abrams 1998; Altan‐Yaycioglu 2005; Appell 2001; Diokno 2003; Dmochowski 2003; Drutz 1999; Homma 2002; Lee 2001; Leung 2001; Malone‐Lee 2001b; Qiu 2002; VanKerrebroeck 1997; Xia 2001a),

(b) trospium (Froehlich 1998; Hofner 2000; Madersbacher 1995; Osca 1997; Zellner 2007),

(d) propiverine (Madersbacher 1999; Stohrer 2002), and

(e) solifenacin (Herschorn 2010).

(2) Tolterodine versus:

(a) oxybutynin (see above),

(b) solifenacin (Chapple 2002; Chapple 2004b; Chapple 2005b; Choo 2008; Ho 2010),

(d) fesoterodine (Chapple 2007; Herschorn 2009; Kaplan 2010),

(e) trospium (Junemann 2000), and

(f) darifenacin (Romanzi 2005).

(3) Propiverine versus:

(a) solifenacin (Yamaguchi 2007), and

(b) imedafenacin (Homma 2009).

(4) Solifenacin versus:

(a) oxybutynin (see above),

(b) tolterodine (see above),

(d) darifenacin (But 2010).

Trials also compared different doses of the same drug:   (1) oxybutynin (Corcos 2006; Davila 2001a; Homma 2006; Salvatore 1995; Sussman 2002);

(2) tolterodine (Abrams 1996; Jacquetin 2001; Jonas 1997; Malone‐Lee 2001a; Millard 1999; Rentzhog 1998; Sussman 2002; VanKerrebroeck 1998);

(3) propiverine (Abrams 2006; Mazur 1995);

(4) trospium (Chaliha 1998; Junemann 1999; Menarini 2006);   (5) solifenacin (Cardozo 2004; Chapple 2002; Chapple 2004b; Choo 2008; Yamaguchi 2007);

(6) darifenacin (Haab 2004; Hill 2006);

(7) fesoterodine (Chapple 2004c; Chapple 2007; Nitti 2005; Nitti 2007);

(8) imedafenacin (Homma 2008).

Comparisons of ER and IR preparations included:   (1) ER oxybutynin versus IR oxybutynin (Anderson 1999; Barkin 2004; Birns 2000; Davila 2001b; Minassian 2007; Versi 2000);   (2) ER oxybutynin versus IR tolterodine (Appell 2001);

(3) ER tolterodine versus IR tolterodine (VanKerrebroeck 2001);   (4) ER tolterodine versus IR oxybutynin(Homma 2002);   (5) ER versus IR propiverine (Junemann 2006; Stohrer 2009).

There were also comparisons of different ER preparations:   (1) ER oxybutynin versus ER tolterodine (Diokno 2003; Dmochowski 2003).

Treatment duration ranged from two weeks to three months in nearly all studies, with a median length of three months. The exceptions were one trial that investigated the effect of a single dose (Froehlich 1998), one trial that had a treatment period of one week (Chapple 2005c) and two studies that had treatment periods of one year or more (Hofner 2000; Salvatore 1995).

Interventions in cross‐over studies

Some studies were preceded by a week‐long placebo washout period. The length of treatment varied from one dose (Di Stasi 2001a; Di Stasi 2001b) to 60 days (Nilsson 1997) with a median length of three weeks. For the one dose studies the washout period was one week. Seven of the 16 studies had no washout period. Four washout periods were of one week and the other two weeks. Given the short half life of the drugs used a washout period may not be important. Seven of the studies had two arms, three had three arms, three had four arms and three had six arms. Some arms were the same drug at different doses. Some studies had different combinations of drugs so that they, for example, tested four drugs in a three arm study (Kramer 1987) and some had even more complicated arrangements with different doses (Massey 1986).

The trials made the following comparisons:

two studies compared oxybutynin with emepronium (Kramer 1987; Zeegers 1987);
two oxybutynin with propiverine (Abrams 2006; Wehnert 1992);
one oxybutynin with propantheline (Holmes 1989);
two oxybutynin with darifenacin (Chapple 2005c; Zinner 2005);
one oxybutynin and intravesical atropine (Fader 2007);
one oxybutynin and tolterodine (Giannitsas 2004a);
one solifenacin and propiverine (Yamanishi 2009);
two emepronium at different doses (Bagger 1985; Massey 1986);
one IR with ER oxybutynin (Nilsson 1997);
one oxybutynin three times a day compared with as needed (Burton 1994);
and two oral oxybutynin versus intravesical oxybutynin versus intravesical oxybutynin with an electric current applied (Di Stasi 2001a; Di Stasi 2001b).

Outcome measures

Overall there was a lack of consistency in the choice of outcome measures by trialists and a lack of consistency in the way data were reported. Sixteen trials reported outcomes of interest but no useable data were provided (Bagger 1985; Burton 1994; But 2010; Chaliha 1998; Chapple 2002; Chapple 2007; Davila 2001a; Di Stasi 2001a; Di Stasi 2001b; Leung 2001; Massey 1986; Osca 1997; Salvatore 1995; Stohrer 2002; Wehnert 1992; Zeegers 1987). Due to deficiencies in data reporting (for example point estimates without measures of variation) many trials contributed little or no data to the review. The lack of similarity in measures limited the possibilities for combining data from individual trials.

The primary outcome of interest in the review was quality of life (Qol). Validated incontinence specific quality of life measures were reported by 29 trials (Barkin 2004; But 2010; Chapple 2002; Chapple 2004b; Chapple 2004c; Chapple 2005b; Chapple 2007; Choo 2008; Davila 2001a; Dmochowski 2003; Fader 2007; Herschorn 2009; Herschorn 2010; Ho 2010; Homma 2002; Homma 2006; Homma 2008; Homma 2009; Junemann 2005; Junemann 2006; Kaplan 2010; Leung 2001; Minassian 2007; Nitti 2005; Nitti 2007; VanKerrebroeck 2001; Yamaguchi 2007; Yamanishi 2009; Zellner 2007) of which only 15 reported useable data. The Incontinence Impact Questionnaire (IIQ) and Urogenital Distress Inventory (UDI) were used by five trials of which two did not report useable data. The King's Health Questionnaire (KHQ) was used by 17 trials but no useable data were reported by 11 trials (see results). The Overactive Bladder questionnaire (OAB‐q) was used by one trial. Two trials used the Patient's Perception of Bladder Condition (PPBC). Two trials used both OAB‐q and PPBC of which one reported no useable data. One trial used the Contilife questionnaire. One trial mentioned that quality of life (Qol) data were collected using a validated questionnaire but did not report the questionnaire used or the data. Therefore, the authors chose the patient's perception of cure or improvement as an alternative primary outcome. About a third of trials appeared to collect data on the patients' perceptions of symptomatic cure or improvement but fewer reported these findings.

About half the studies used micturition diaries to record number of leakage episodes, number of micturitions and urgency episodes over varying lengths of time. In order to combine these data in the pooled analysis the numbers of leakage episodes, micturitions and urgency episodes in 24 hours were calculated.

A wide range of urodynamic measures were reported. In view of the lack of correlation between urodynamic measures and clinical outcome the formal comparisons were limited to maximum cystometric capacity, volume at first contraction and residual volume. These were measures that trialists most consistently reported, which suggests that researchers and clinicians have thought these data were important in making judgements about the effects of the drugs on overactive bladder. Some authors reported post‐treatment urodynamic measures and others reported changes in urodynamic measures, so both are included in the formal comparisons. Dry mouth was the adverse event reported by the largest number of studies. No trial included socioeconomic data.

Further characteristics of the trials are reported in the 'Characteristics of included studies' table.

Excluded studies

Twenty reports of 18 studies were excluded (Abrams 2005; Appell 1997; Armstrong 2007; Cardozo 2006; Chapple 2004; Chapple 2005; Chapple 2006a; Dmochowski 2005; Gaudenz 1978; Hirani 2004; Larsson 1999; Mundy 2001; Nagels 2004; Rosario 1995; Takeda 2003; Tincello 2000; Wein 1999; Yoon 2001) and the reasons are listed in the Characteristics of excluded studies table.

Risk of bias in included studies

Allocation

The allocation sequence was adequately generated in 19 trials (Birns 2000; Chapple 2005b; Chapple 2005c; Corcos 2006; Fader 2007; Giannitsas 2004a; Herschorn 2009; Herschorn 2010; Homma 2002; Kaplan 2010; Lee 2001; Leung 2001; Nitti 2007; Stohrer 2002; Thuroff 1991; VanKerrebroeck 2001; Versi 2000; Xia 2001a; Zellner 2007) and was unclear in the remaining trials other than Sussman, which was quasi‐randomised. While double blinding should adequately conceal group allocation, this is not guaranteed. Allocation was known to be adequately concealed only in 12 trials (Anderson 1999; Chapple 2005b; Fader 2007; Haab 2004; Herschorn 2009; Kaplan 2010; Leung 2001; Minassian 2007; Thuroff 1991; Versi 2000; Xia 2001a; Zellner 2007) and in the remaining studies it was not clear if allocation was adequately concealed.

Blinding

Although 70 trials were double blinded, only three trials specifically stated that outcome assessors were blind to group allocation (Abrams 2006; Altan‐Yaycioglu 2005; Leung 2001). Some studies stated that the code was broken at the completion of the study and in some it was specified that this was after the analysis. This would imply that the final measurement was done blinded.

Incomplete outcome data

In 44 trials the evaluation of treatment efficacy was conducted based on intention‐to‐treat principles (see Characteristics of included studies). Thirteen trials specifically stated that a per protocol analysis was used to assess treatment efficacy (Abrams 1996; Anderson 1999; Drutz 1999; Fader 2007; Giannitsas 2004a; Ho 2010; Hofner 2000; Homma 2008; Junemann 2000; Rentzhog 1998; Stohrer 2002; Stohrer 2009; VanKerrebroeck 1998)

The description of withdrawals or dropouts was not adequate in 38 trials. There were no dropouts from the trials using single intravesical or oral doses of medication (Altan‐Yaycioglu 2005; Di Stasi 2001a; Di Stasi 2001b; Froehlich 1998; Qiu 2002). In 32 trials the dropout rate was 10% or less (Bagger 1985; Birns 2000; Cardozo 2004; Chapple 2002; Chapple 2004b; Chapple 2005b; Chapple 2005c; Davila 2001b; Fader 2007; Haab 2004; Herschorn 2009; Ho 2010; Homma 2002; Homma 2009; Jacquetin 2001; Jonas 1997; Junemann 1999; Junemann 2005; Junemann 2006; Kaplan 2010; Malone‐Lee 2001a; Mazur 1995; Millard 1999; Menarini 2006; Rosario 1995; Thuroff 1991; VanKerrebroeck 2001; Versi 2000; Wehnert 1992; Yamaguchi 2007; Zellner 2007; Zinner 2005). In the remainder, dropout rates ranged from 11% (Dmochowski 2003; Hill 2006; Homma 2008; Madersbacher 1995) to 39% (Salvatore 1995) in parallel group designs, and 0% (Wehnert 1992) to 40% (Zeegers 1987) in the cross‐over studies.

The risk of bias summary is shown in Figure 2 (Figure 2).

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Other potential sources of bias

Baseline comparability of the groups was not mentioned in 18 studies (Abrams 1996; Birns 2000; But 2010; Chaliha 1998; Chapple 2002; Davila 2001a; Davila 2001b; Herschorn 2010; Hofner 2000; Junemann 1999; Junemann 2000; Lee 2001; Leung 2001; Osca 1997; Qiu 2002; Rentzhog 1998; Romanzi 2005; VanKerrebroeck 1997). The remaining trials stated that the groups were comparable at baseline, although two studies did not provide supporting data (Homma 2002; Stohrer 2002). Baseline comparability is not an issue of concern for cross‐over studies.

The primary, or only, reference for 12 trials was a conference abstract (Abrams 1996; Burton 1994; But 2010; Chaliha 1998; Chapple 2004c; Junemann 1999; Junemann 2000; Nitti 2005; Romanzi 2005; Stohrer 2009; VanKerrebroeck 1997; Yamanishi 2009). All of these trials were complete at the time of reporting, and full publications were not found with subsequent searching. All abstracts reported limited details of method and few results.

Some of the large multicentre and multinational trials were reported in multiple publications. These publications usually presented subsets of the main trial results (for example data from one country) and subsequent publications rarely provided further methodological detail. The most notable example is Van Kerrebroek 2001 (VanKerrebroeck 2001) for which 21 separate reports were identified. Where there were multiple publications of the same trial the main trial report was selected as the primary reference; the primary reference is cited throughout the review for simplicity.

Very few parallel design trials included any follow up beyond the initial assessment of the outcome. In those trials that did follow up participants this was usually for very short periods of time, that is one or two weeks. The stated purpose of these short follow‐up periods was adverse events monitoring. One study followed participants for two years (Salvatore 1995). Long‐term follow up does not provide information on the differences in treatment effects for cross‐over studies.

It is worth noting that 30 of the 86 trials (38%) declared pharmaceutical company support (Abrams 1998; Appell 2001; Barkin 2004; Chapple 2004b; Chapple 2005b; Chapple 2005c; Chapple 2007; Choo 2008; Davila 2001a; Diokno 2003; Dmochowski 2003; Drutz 1999; Haab 2004; Herschorn 2009; Hill 2006; Homma 2006; Homma 2009; Jacquetin 2001; Junemann 2006; Kaplan 2010; Malone‐Lee 2001a; Nitti 2005; Nitti 2007; Rentzhog 1998; Thuroff 1991; VanKerrebroeck 1998; VanKerrebroeck 2001; Versi 2000; Yamaguchi 2007; Zinner 2005). This support ranged from the supply of active and placebo tablets (in blinded packaging) through to full funding and data analysis. None of the remaining trials made any statement about the absence or presence of company involvement. One trial was funded by a grant from a health research body (Gajewski 1986).

Effects of interventions

Very few of the cross‐over studies presented any data in a manner that could be formally combined in a meta‐analysis. Because of this, the results of the cross‐over studies are described narratively, after the results for the parallel arm studies are presented.

Comparison 1: one anticholinergic versus another

Tolterodine versus oxybutynin

Thirteen parallel arm studies (Abrams 1998; Altan‐Yaycioglu 2005; Appell 2001; Diokno 2003; Dmochowski 2003; Drutz 1999; Homma 2002; Lee 2001; Leung 2001; Malone‐Lee 2001b; Qiu 2002; VanKerrebroeck 1997; Xia 2001a) and one cross‐over study (Giannitsas 2004a) were included. The following comparisons were made, by one trial each: IR oral tolterodine 4 mg versus ER oral oxybutynin 10 mg (Appell 2001), ER oral tolterodine 4 mg versus IR oral oxybutynin 9 mg (Homma 2002), ER oral tolterodine 4 mg versus ER transdermal oxybutynin 3.9 mg/day (Dmochowski 2003), and ER oral tolterodine 4 mg versus ER oral oxybutynin 10 mg (Diokno 2003). The other nine trials compared IR oral preparations of tolterodine and oxybutynin, of which four trials compared 4 mg IR tolterodine versus 10 mg IR oxybutynin (Lee 2001; Leung 2001; Malone‐Lee 2001b; Xia 2001a), four trials compared 4 mg IR tolterodine versus 15 mg IR oxybutynin (Abrams 1998; Altan‐Yaycioglu 2005; Drutz 1999; VanKerrebroeck 1997) and one trial (Qiu 2002) compared 1 mg IR tolterodine versus 5 mg IR oxybutynin. The treatment duration ranged from 3 weeks to 12 weeks with a median of 12 weeks.

Quality of life

Three trials collected condition‐specific quality of life (Qol) data (Dmochowski 2003; Homma 2002; Leung 2001), one of which reported no data (Leung 2001). Homma et al (Homma 2002) showed no statistically significant difference in any of the 10 domains of quality of life as measured by the King's Health Questionnnaire (KHQ) (Table 1) at 12 weeks. Dmochowski et al reported change from baseline for only one of the four domains of IIQ (travel) and UDI (irritative symptoms) and showed no statistically significant difference between the groups (Table 2) at 12 weeks. The combined results (incontinence impact domain of KHQ (Homma 2002) and UDI irritative symptoms (Dmochowski 2003)) showed no significant difference between oxybutynin and tolterodine (SMD ‐0.00, 95% CI ‐0.18 to 0.18) (Analysis 1.1).

1. One anticholinergic versus another. Qol KHQ.

KHQ Domain	Study	Drug/dose/data	Drug/dose/data	Mean difference (95% CI)
Incontinence Impact	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	2.90 (‐4.12 to 9.92)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	‐2.20 (‐6.59 to 4.19)
Role limitation	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	3.80 (‐1.6 to 9.23)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	0.00 (‐5.09 to 5.09)
Physical limitation	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	2.60 (‐3.43 to 8.63)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	‐1.70 (‐6.74 to 3.34)
Social limitation	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	‐0.80 (‐5.98 to 4.38)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	‐1.00 (‐5.42 to 3.42)
Personal relationships	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	1.40 (‐1.41 to 4.21)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	2.40 (‐3.74 to 8.54)
Emotions	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	1.60 (‐5.23 to 8.43)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	‐3.00 (‐8.15 to 2.15)
Sleep and energy	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	3.30 (‐2.86 to 9.46)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	‐4.30 (‐9.12 to 0.52)
Severity coping measure	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	1.40 (‐2.95 to 5.75)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	‐1.70 (‐6.15 to 2.75)
General health perception	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	2.20 (‐2.98, 7.38)
	Chapple 2007	Fesoterodine 8mg, n=265	ER tolterodine 4mg, n = 269	1.20 (‐2.28 to 4.68)
Symptom severity	Homma 2002	ER Tolterodine 4mg ER, n = 114	IR Oxybutynin 3 mg tid, n = 122	1.90 (‐1.61 to 5.41)

Qol	Study	Drug/dose/data	Drug/dose/data	Mean difference (95% CI)
IIQ (Travel)	Dmochowski 2003	ER tolterodine 4 mg, n = 29	TDS oxybutynin 3.9 mg, n= 25	1.00 (‐5.79 to 7.79)
UDI (Irritative symptoms)	Dmochowski 2003	ER tolterodine 4 mg, n = 26	TDS oxybutynin 3.9 mg, n= 26	‐3.00 (‐9.52 to 3.52)

Condition specific Qol
Study	Trospium 45 mg, Median change (range)	Oxybutynin 7.5 mg, Median change (range)
Zellner 2007	‐16.17 (‐84.57 to 48.16), n = 810	‐15.76 (‐84.75 to 69.31), n = 798

Study	Dose/data	Dose/data	Risk ratio(95% CI)
Fader 2007	Oral oxybutynin IR 5mg bid 39/57	Intravesical atropine 6.67 mg in 20 ml od 0.9% saline 11/57	0.28(0.16 TO 0.49)

KHQ Domain	Study	Oxybutynin TDS 3.9 mg/data	Oxybutynin TDS 2.6 mg/data	Mean difference (95% CI)
Incontinence Impact	Homma 2006	n = 162	n = 158	‐1.90 (‐7.03 to 3.23)
Role limitation	Homma 2006	n = 162	n = 158	‐2.8 (‐7.44 to 1.84)
Physical limitation	Homma 2006	n = 162	n = 158	‐3.10 (‐8.42 to 2.22)
Social limitation	Homma 2006	n = 162	n = 158	‐3.10 (‐7.34 to 1.14)
Personal relationships	Homma 2006	n = 162	n = 158	‐2.00 (‐6.45 to 2.45)
Emotions	Homma 2006	n = 162	n = 158	‐3.30 (‐8.52 to 1.92)
Sleep and energy	Homma 2006	n = 162	n = 158	‐0.30 (‐4.48 to 3.88)

Drug	Study	Dose/data	Dose/data	Difference
Tolterodine	Malone‐Lee (2001a)	1mg twice daily. Median change ‐0.3 (95% CI ‐0.8 to ‐0.1) n=61	2mg twice daily. Median change ‐0.7 (95% CI ‐1.3 to ‐0.2) n=73	Median difference ‐0.4 (95% CI not calculable)

Change in incontinence episodes per week
Study	15mg, median change (95%CI)	7.5mg, median change (95%CI)
Darifenacin 3.75mg versus 7.5mg
Haab 2004	‐8.6 ( 95% CI not reported), n=53	‐9.0(95% CI not reported), n=229
Darifencin 15mg versus 7.5mg
Haab 2004	‐10.4(95% CI not reported), n=115	‐9.0 (95% CI not reported), n=229
Hill 2006	‐10.4(95% CI not reported),n=106	‐8.1( 95% CI not reported), n=107
Darifenacin 30 mg versus 7.5mg
Hill 2006	‐11.4(95% CI not reported), n=114	‐8.1(95% CI not reported), n=107

Change in micturition per day
Study	30mg, median change (95% CI)	7.5mg, median change, (95%CI)
Darifenacin 3.75mg versus 7.5mg
Haab 2004	‐1.7( 95% CI not reported), n=53	‐1.6(95%CI not reporetd), n= 229
Darifenacin 15mg versus 7.5mg
Haab 2004	‐1.7(95% CI not reported), n=115	‐1.6(95% CI not reported), n= 229
Hill 2006	‐1.9 ( CI not reported), n=106	‐1.7 ( CI not reported), n=107
30mg versus 15mg
Hill 2006	‐2.2 (CI not reported), n=114	‐1.7 ( CI not reported), n=107

Change in urgency episodes per day
Study	30mg, median change( 95% CI)	7.5mg, median change(95% CI)
Darifenacin 3.75mg versus 7.5mg
Haab 2004	‐1.8(95% CI not reported), n= 53	‐2.0(95% CI not reported), n= 229
Darifenacin 15mg versus 7.5mg
Haab 2004	‐2.0(95% CI not reported), n= 115	‐2.0(95% CI not reported), n= 229
Hill 2006	‐2.3 ( CI not reported), n=106	‐1.8( CI not reported), n=107
30mg versus 7.5mg
Hill 2006	‐3.0 (CI not reported), n=114	‐1.8( CI not reported), n=107

KHQ Domain	Study	Fesoterodine 8 mg/ data	Fesoterodine 4 mg/ data	Mean difference (95% CI)
Incontinence Impact	Chapple 2007	n = 265	n = 250	‐2.0 (‐7.35 to 3.35)
Role limitation	Chapple 2004c	n = 156	n = 173	‐0.13 (‐3.96 to 3.70)
	Chapple 2007	n =260	n = 247
	Nitti 2005	n = 45	n = 43
Physical limitation	Chapple 2007	n =260	n = 247	‐2.70 (‐8.04 to 2.64)
Social limitation	Chapple 2007	n =260	n = 247	‐1.70 (‐6.39 to 2.99)
Personal relationships	Chapple 2007	n =260	n = 247	‐1.50 (‐7.72 to 4.72)
Emotions	Chapple 2007	n =260	n = 247	‐3.80 (‐9.19 to 1.59)
Sleep and energy	Chapple 2004c	n = 156	n = 173	‐2.76 (‐6.04 to 0.52)
	Chapple 2007	n =264	n = 246
	Nitti 2005	n = 45	n = 43
Severity coping measure	Chapple 2007	n = 263	n = 248	‐0.80 (‐5.49 to 3.89)
General health perception	Chapple 2007	n = 265	n = 250	‐0.9 (‐4.55 to 2.75)

IIQ Domain	Study	ER oxybutynin/dose/data	IR oxybutynin/dose/data	Mean difference (95% CI)
Total IIQ score	Barkin 2004	15 mg, n = 53	15 mg, n = 41	0.30 (‐0.19 to 0.79)
Activities	Minassian2007	5 mg, n = 37	7.5 mg, n = 28	0.10 (‐0.45 to 0.65)
Travel	Minassian2007	5 mg, n = 37	7.5 mg, n = 28	0.10 (‐0.47 to 0.67)
Physical activities	Minassian2007	5 mg, n = 37	7.5 mg, n = 28	0.40 (‐0.45 to 1.25)
Feelings	Minassian2007	5 mg, n = 37	7.5 mg, n = 28	0.10 (‐0.50 to 0.70)
Relationship	Minassian2007	5 mg, n = 37	7.5 mg, n = 28	‐0.10 (‐0.57 to 0.37)

KHQ Domain	Study	ER Tolterodine 4mg /data	IR Tolterodine 4 mg/data	Mean difference (95% CI)
Incontinence Impact	Vankerrebroeck 2001	n = 487	n = 514	1.84 (‐1.74 to 5.42)
Role limitation	Vankerrebroeck 2001	n = 487	n = 514	‐1.11 (‐4.86 to 2.64)
Physical limitation	Vankerrebroeck 2001	n = 487	n = 514	‐1.68 (‐5.39 to 2.03)
Social limitation	Vankerrebroeck 2001	n = 487	n = 514	‐0.66 (‐3.47 to 2.15)
Personal relationships	Vankerrebroeck 2001	n = 487	n = 514	‐0.96 (‐4.04 to 2.12)
Emotions	Vankerrebroeck 2001	n = 487	n = 514	2.06 (‐0.94 to 5.06)
Sleep and energy	Vankerrebroeck 2001	n = 487	n = 514	‐0.94 to (‐3.85 to 1.97)
Severity coping measure	Vankerrebroeck 2001	n = 487	n = 514	‐1.58 (‐4.19 to 1.03)
General health perception	Vankerrebroeck 2001	n = 487	n = 514	0.40 (‐1.68 to 2.48)
Symptom severity	Vankerrebroeck 2001	n = 487	n = 514	‐0.04 (‐0.49 to 0.42)

Date	Event	Description
7 December 2011	New citation required and conclusions have changed	37 trials added
28 November 2011	New search has been performed	37 new studies added
13 October 2008	Amended	Converted to new review format.
25 May 2005	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Condition specific QoL	8		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Tolterodine versus oxybutynin	2	480	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.18, 0.18]
1.2 Trospium chloride versus oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Propantheline versus oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Propiverine versus oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Darifenacin versus oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.6 Solifenacin versus Oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.7 Solifenacin versus tolterodine	3	1293	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.23, ‐0.01]
1.8 Propiverine versus tolterodine	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.9 Fesoterodine versus tolterodine	3	3492	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.27, ‐0.14]
1.10 Solifenacin versus propiverine	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.11 Imidafenacin versus propiverine	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Quality of life (Generic)	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.1 Tolterodine versus oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Trospium chloride versus oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Propantheline versus oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Propiverine versus oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.5 Darifenacin versus oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.6 Solifenacin versus Oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.7 Solifenacin versus tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.8 propiverine versus tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.9 Fesoterodine versus tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.10 Solifenacin versus propiverine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.11 Imidafenacin versus propiverine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Cure/improvement	15		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 Tolterodine versus oxybutynin	5	1381	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.93, 1.11]
3.2 Trospium chloride versus oxybutynin	2	1880	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.90, 1.11]
3.3 Propantheline versus oxybutynin	2	136	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.53, 0.96]
3.4 Propiverine versus oxybutynin	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Darifenacin versus oxybutynin	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Solifenacin versus Oxybutynin	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.7 Solifenacin versus tolterodine	2	1252	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [1.13, 1.39]
3.8 Propiverine versus tolterodine	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.9 Fesoterodine versus tolterodine	3	3691	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [1.06, 1.16]
3.10 Solifenacin versus propiverine	1	767	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.81, 1.21]
3.11 Imidafenacin versus propiverine	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Leakage episodes in 24hrs ( End of tx and change from baseline)	19		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
4.1 Tolterodine versus oxybutynin	7	1374	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.16, 0.31]
4.2 Trospium chloride versus oxybutynin	1	1572	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.32, 0.12]
4.3 Propantheline versus oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Condition specific QoL	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Oxybutynin ER 10mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Oxybutynin ER 15mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Transdermal Oxy 1.3mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Transdermal Oxy 2.6mg versus 3.9mg	1	320	Mean Difference (IV, Fixed, 95% CI)	1.90 [‐3.23, 7.03]
1.5 Transdermal Oxy 5.2mg versus 3.9mg	1	314	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐4.02, 6.62]
2 Quality of life (Generic)	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.1 Oxybutynin ER 10mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Oxybutynin ER 15mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Transdermal Oxy 1.3mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Transdermal Oxy 2.6mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.5 Transdermal Oxy 5.2mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Cure/improvement	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 Oxybutynin ER 10mg versus 5mg	1	503	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [1.25, 1.80]
3.2 Oxybutynin ER15mg versus 5mg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Transdermal Oxy 1.3mg versus 3.9mg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Transdermal Oxy 2.6mg versus 3.9mg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Transdermal Oxy 5.2mg versus 3.9mg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Leakage episodes in 24 hrs (End of tx and change from baseline)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
4.1 Oxybutynin ER 10mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Oxybutynin ER15mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Transdermal Oxy 1.3mg versus 3.9mg	1	249	Mean Difference (IV, Fixed, 95% CI)	1.02 [0.26, 1.78]
4.4 Transdermal Oxy 2.6mg versus 3.9mg	2	578	Mean Difference (IV, Fixed, 95% CI)	0.62 [0.24, 0.99]
4.5 Transdermal Oxy 5.2mg versus 3.9mg	1	316	Mean Difference (IV, Fixed, 95% CI)	0.37 [‐0.05, 0.79]
5 Micturitions in 24 hrs(End of tx and change from baseline)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
5.1 Oxybutynin ER 10mg versus 5mg	1	154	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.30, 0.70]
5.2 Oxybutynin ER15mg versus 5mg	1	160	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.94, 0.94]
5.3 Transdermal Oxy 1.3mg versus 3.9mg	1	249	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐0.13, 1.13]
5.4 Transdermal Oxy 2.6mg versus 3.9mg	1	254	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐0.10, 1.10]
5.5 Transdermal Oxy 5.2mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Urgency episodes 24 hrs (End of tx and change from baseline)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.1 Oxybutynin ER10mg versus 5mg	1	154	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.05, 0.65]
6.2 Oxybutynin ER 15mg versus 5mg	1	160	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐1.56, ‐0.04]
6.3 Transdermal Oxy 1.3mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Transdermal Oxy 2.6mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.5 Transdermal Oxy 5.2mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Maximum cystometric capacity (End of tx and change from baseline)	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.1 Oxybutynin ER 10mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Oxybutynin ER 15mg versus 5mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Transdermal Oxy 1.3mg versus 3.9mg	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Condition specific QoL	5	2099	Std. Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.01, 0.16]
1.1 Extended release oxybutynin versus immediate release oxybutynin	2	159	Std. Mean Difference (IV, Fixed, 95% CI)	0.37 [0.05, 0.69]
1.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Extended release tolterodine versus immediate release tolterodine	1	981	Std. Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.06, 0.19]
1.4 Extended release tolterodine versus immediate release oxybutynin	1	236	Std. Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.15, 0.36]
1.5 Extended release propiverine versus immediate release propiverine	1	723	Std. Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.14, 0.15]
2 Quality of life (Generic)	1		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 Extended release oxybutynin versus immediate release oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Extended release tolterodine versus immediate release tolterodine	1	1021	Std. Mean Difference (IV, Fixed, 95% CI)	0.05 [‐0.07, 0.18]
2.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.5 Extended release propiverine versus immediate release propiverine	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Cure/improvement	3	1869	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.89, 1.03]
3.1 Extended release oxybutynin versus immediate release oxybutynin	1	125	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.67, 1.24]
3.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Extended release tolterodine versus immediate release tolterodine	1	1021	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.86, 1.05]
3.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Extended release propiverine versus immediate release propiverine	1	723	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.08]
4 Leakage episodes in 24hrs (End of tx and change from baseline)	6	2324	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.35, ‐0.00]
4.1 Extended release oxybutynin versus immediate release oxybutynin	2	170	Mean Difference (IV, Fixed, 95% CI)	0.39 [‐0.31, 1.08]
4.2 Extended release oxybutynin versus immediate release tolterodine	1	378	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.69, 0.05]
4.3 Extended release tolterodine versus immediate release tolterodine	1	1021	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.49, 0.11]
4.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Extended release propiverine versus immediate release propiverine	2	755	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.45, 0.11]
5 Micturitions in 24 hrs(End of tx and change from baseline)	4	2216	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.38, 0.15]
5.1 Extended release oxybutynin versus immediate release oxybutynin	1	94	Mean Difference (IV, Fixed, 95% CI)	1.0 [‐0.11, 2.11]
5.2 Extended release oxybutynin versus immediate release tolterodine	1	378	Mean Difference (IV, Fixed, 95% CI)	‐0.62 [‐1.23, ‐0.01]
5.3 Extended release tolterodine versus immediate release tolterodine	1	1021	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.51, 0.31]
5.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.5 Extended release propiverine versus immediate release propiverine	1	723	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.51, 0.41]
6 urgency episodes in 24 hrs(End of tx and change from baseline)	2	817	Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.22, 0.43]
6.1 Extended release oxybutynin versus immediate release oxybutynin	1	94	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐0.02, 0.82]
6.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Extended release tolterodine versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.5 Extended release propiverine versus immediate release propiverine	1	723	Mean Difference (IV, Fixed, 95% CI)	‐0.31 [‐0.82, 0.20]
7 Maximum cystometric capacity (End of tx and change from baseline)	1	63	Mean Difference (IV, Fixed, 95% CI)	‐90.0 [‐173.46, ‐6.54]
7.1 Extended release oxybutynin versus immediate release oxybutynin	1	63	Mean Difference (IV, Fixed, 95% CI)	‐90.0 [‐173.46, ‐6.54]
7.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Extended release tolterodine versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.5 Extended release propiverine versus immediate release propiverine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Volume at first contraction(End of tx and change from baseline)	2	123	Mean Difference (IV, Fixed, 95% CI)	‐35.09 [‐82.77, 12.60]
8.1 Extended release oxybutynin versus immediate release oxybutynin	1	63	Mean Difference (IV, Fixed, 95% CI)	‐73.0 [‐168.80, 22.80]
8.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 Extended release tolterodine versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.5 Extended release propiverine versus immediate release propiverine	1	60	Mean Difference (IV, Fixed, 95% CI)	‐22.60 [‐77.58, 32.38]
9 Residual volume (End of tx and change from baseline)	2	156	Mean Difference (IV, Fixed, 95% CI)	1.29 [‐19.31, 21.88]
9.1 Extended release oxybutynin versus immediate release oxybutynin	2	156	Mean Difference (IV, Fixed, 95% CI)	1.29 [‐19.31, 21.88]
9.2 Extended release oxybutynin versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Extended release tolterodine versus immediate release tolterodine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.5 Extended release propiverine versus immediate release propiverine	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Withdrawal due to adverse events	9	2917	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.65, 1.13]
10.1 Extended release oxybutynin versus immediate release oxybutynin	6	732	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.50, 1.18]
10.2 Extended release oxybutynin versus immediate release tolterodine	1	378	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.48, 1.96]
10.3 Extended release tolterodine versus immediate release tolterodine	1	1021	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.58, 1.63]
10.4 Extended release tolterodine versus immediate release oxybutynin	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.5 Extended release propiverine versus immediate release propiverine	1	786	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.34, 1.59]
11 Dry mouth	11	3458	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.72, 0.86]
11.1 Extended release oxybutynin versus immediate release oxybutynin	6	728	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.71, 0.91]
11.2 Extended release oxybutynin versus immediate release tolterodine	1	378	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.62, 1.15]
11.3 Extended release tolterodine versus immediate release tolterodine	1	1017	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.62, 0.94]
11.4 Extended release tolterodine versus immediate release oxybutynin	1	483	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.50, 0.77]
11.5 Extended release propiverine versus immediate release propiverine	2	852	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.74, 1.22]

Methods	RCT. Placebo controlled, parallel design.   Phase II.   Double‐blind.   Masking of assessors not stated.   PP analysis.   Multicentre.
Participants	82 patients.   Inclusion criteria: objective signs of neurological disease and urinary frequency or incontinence and urodynamically proven detrusor hyperreflexia.   Exclusion criteria: treatment within preceding 14 days with other anticholinergic drugs.
Interventions	Group 1: placebo (n=15)   Group 2: tolterodine 0.5 mg bid (n=12)   Group 3: tolterodine 1 mg bid (n=14)   Group 4: tolterodine 2 mg bid (n=16)   Group 5:tolterodine 4mg bid (n=10)   14 day treatment period.   2 week washout.
Outcomes	Number of leakage episodes, frequency of micturition, volume voided.   Urodynamic parameters.   Adverse events.   Laboratory tests.   ECG.   Blood pressure.
Notes	Abstract.   Dose reduction permitted within first week.   Dropouts not stated.   Incomplete subjective data.   No follow up.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no further description.
Allocation concealment (selection bias)	Unclear risk	No description
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐blind.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Dropouts not stated.

Methods	Randomised, cross‐over design, placebo controlled. Multicentre (8 centres in UK). ITT analysis.
Participants	77 patients (18 men, 59 women). Age range 47‐56 years. Inclusion criteria: aged > 18 years with 2 or more of following OAB symptoms: urinary frequency (7 or more micturitions /day), urge incontinence (one or more episodes/week) urinary urgency (7 or more episodes preceding micturition/week). Exclusion criteria: evidence of significant hepatic, renal or cardiac abnormalities, stress incontinence, evidence of untreated narrow angle glaucoma,urinary and gastric retention, bladder outlet obstruction > 40 (Abrams‐Griffiths number), indwelling catheter, recent urological surgery, use of investigational drugs in the 30 days preceding the study.
Interventions	Group 1: propiverine 20 mg once daily (20mg/day) Group2: propiverine 15 mg tid (45mg/day) Group 3: oxybutynin 5 mg tid (15mg/day) Group 4: placebo By design, fewer patients were randomised to placebo than active drug Two 2‐week treatment period with 2‐week washout period Each subject received 2 of the 4 possible treatment
Outcomes	AUM (Ambulatory urodynamic monitoring)parameters: number of IDC (involuntary detrusor contraction), duration of IDC and IDC amplitude and area under the curve Adverse events Salivary flow rate Visual near point Heart Rate, heart rate variability, St Georges index and PNN50 ‐ ECG
Notes	10 dropouts, no information about reasons for dropout or the groups from which patients withdrew. No useable data other than adverse events. Not all patients received all treatment, no information to carry out paired analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no other description.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Low risk	States double blind, urodynamic traces were analysed by a blinded central reader, no other information apart from that.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Total of 10 withdrawals, incomplete reporting about the groups from which patients withdrew.

Methods	Randomised, parallel design. Single centre (Turkey).
Participants	52 Female patients. Inclusion: female with urodynamically proven detrusor overactivity Normal screening ophthalmic examination. Exclusion: dry eyes, ocular surface disorders, glaucoma or issues that could affect visual acuity or accommodation.
Interventions	Group1: tolterodine 2 mg bid (n = 28) Group 2: oxybutynin 5 mg tid (n = 24) No run‐in period, 4 weeks treatment period
Outcomes	Visual accommodation Pupillary diameter in dim and bright light Intraocular pressure and tear secretion Adverse events : Dry mouth, burning sensation in the eyes, foreign body sensation in the eyes, and ocular dryness. Outcomes assessed at baseline and at 4 weeks after medication.
Notes	No withdrawals, all patients completed 4 weeks of treatment. Outcomes not of interest other than adverse events.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Staes randomly assigned, no other information.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	High risk	Stated single blinded, outcome assessor blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients in both the groups completed 4 weeks of treatment.

Methods	RCT. Parallel design.   Phase III.   Masking of assessors not stated.   Multicentre (13).
Participants	105 male and female patients.   Inclusion criteria: urge incontinence or mixed incontinence with a primary urge component with at least 6 urge incontinent episodes/week when not taking medication. Community dwelling in good health.   Exclusion criteria: those with known treatable genitourinary causes of incontinence, for example infection and/or obstruction; those with greater than 100 ml post‐void residual; men who had undergone prostate surgery in the previous 9 months; those at risk for complete urinary retention or other disorders caused by anticholinergic therapy; those receiving drugs other than oxybutynin, hyoscyamine or propantheline which were considered effective in the treatment of urge incontinence; those with a positive urine drug screen; pregnant or lactating women; those with glaucoma, severe narrowing of the gastrointestinal tract or myasthenia gravis.
Interventions	Group 1: Controlled release oxybutynin of 5, 10, 15, 20, 25 or 30 mg daily (n=53)   Group 2: immediate release oxybutynin 5 mg one to four times daily. (n=52)   Both groups dose titrated to maximum tolerated dose.   Final dose for 2 weeks after achieving effective dose.   1 week washout plus one week baseline period.
Outcomes	Number of leakage episodes, frequency of micturition, volume voided.   Post‐void residual (ultrasound)   Adverse events.   Laboratory tests.   ECG.   Compliance by pill count.
Notes	All patients showed a previous response to oxybutynin.   Dose reduction permitted for adverse events.   13 dropouts (Group 1:7, Group 2:6)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised, no other description.
Allocation concealment (selection bias)	Low risk	A ‐ Adequate.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	13 dropouts (Group 1:7, Group 2:6).

Methods	RCT. Parallel design.   Masking of assessors not stated.   Multicentre (37)
Participants	378 male and female patients.   Inclusion criteria: overactive bladder with between 7 and 50 episodes of urge incontinence/week and 10 or more voids/24 hours. Patients with mixed stress and urge incontinence eligible if majority of leakage episodes related to urge incontinence.   Exclusion criteria: other causes of incontinence (e.g. UTI, interstitial cystitis, urinary tract obstruction, urethral diverticulum, bladder tumour or stone, prostate cancer). Pelvic, vaginal, bladder or prostate surgery, or delivered a baby less than 6 months before study enrolment. Postvoid residual more than 150ml or at risk of developing complete urinary retention if placed on antimuscarinics. Clinically important medical problems or other organ abnormalities for whom administration of ER oxybutynin or tolterodine would present undue risk. Haematuria or a positive urine culture; uncontrolled narrow‐angle glaucoma, obstructive uropathy, myasthenia gravis, pelvic organ prolapse to the hymenal ring, or gastrointestinal conditions or risk of gastric retention.   Use of medications with anticholinergic activity used to treat other conditions. Use of an investigational drug within previous month or with known allergies or hypersensitivities to oxybutynin or tolterodine. Current alcohol or drug abuse. Pregnant or breast‐feeding women. Inability to follow study schedule or directions. Unable to swallow medication whole.
Interventions	Group 1: oxybutynin extended release 10 mg/day (n=185)   Group 2: tolterodine immediate release 2 mg bid (n=193)   12 week treatment period.
Outcomes	Number of total leakage episodes, urge incontinence episodes,   frequency of micturition.   Adverse events.   Postvoid residual (ultrasound)   Laboratory tests.   ECG.
Notes	Randomised by severity of urge incontinence.   Recruitment solely from specialty practices.   Fixed dose regimen.   47 dropouts (Group 1:25, Group 2:22)   No follow up.   Company support declared.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no other description.
Allocation concealment (selection bias)	Unclear risk	No information.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	47 dropouts (Group 1:25, Group 2:22) with similar reasons for withdrawal between groups.

Methods	RCT. Placebo controlled, cross‐over design. Double‐blind.   Masking of assessors not stated.   ITT analysis.
Participants	18 female patients.   Inclusion criteria: urge incontinence as defined by the International Continence Society.   Exclusion criteria: recent cystitis, pregnancy, vaginal vault prolapse and stress incontinence. Major neurological disorders. Intake of drugs with presumed effect on bladder function.
Interventions	Treatment 1: placebo   Treatment 2: emepronium carrageenate 500 mg per day   Group 3: emepronium carrageenate 1000 mg per day.   2 week period for each treatment.
Outcomes	Number of leakage episodes, frequency of micturition, volume voided.   Adverse events.   Laboratory tests.
Notes	1 dropout (Treatment 2)   No follow up.   Data not in useable form for this review.   Company support declared.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no description.
Allocation concealment (selection bias)	Unclear risk	No information.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	One withdrawal, due to claustrophobia.

Methods	RCT: parallel design. 1:1 randomisation. Multicentre (18 Canadian centres) ITT analysis.
Participants	125 (men and women). Inclusion criteria: men and women ≥ 18 years, ≥ 7 episodes of UI per week, ≥ 8 voids per day. Exclusion criteria: Postvoid residual >100mls, unstable dosage of any drug with anticholinergic or diuretic/antidiuretic side effects, allergy or previous life threatening side effects with anticholinergic / antispasmodic medications, primary diagnosis of stress urinary incontinence, conditions contraindicating anticholinergic therapy, daily fluid intake > 3L, hepatic or renal disease, diagnosed painful bladder syndrome, uninvestigated voiding difficulty with risk of urinary retention, uninvestigated hematuria,or hematuria secondary to malignant disease, UTI or history of UTI (>3 UTI’s/ year), indwelling catheter, bladder training within 14 days of screening, drug/alcohol abuse, untreated psychiatric condition affecting completion of voiding diaries, chronic untreated constipation, bladder outlet obstruction, pregnancy or breast feeding and failure to use reliable contraception in women of childbearing potential.
Interventions	Group1: CR oxybutynin 15 mg once daily (n=65) Group 2: IR oxybutynin 5 mg tid (n= 60) 3 weeks no treatment baseline period, 2 weeks dose titration period and 4 week stable dose period.
Outcomes	UI episode Frequency of voids Urgency using Purdue urgency questionnaire Volume voided per micturition Pads used Adverse events Treatment withdrawals IIQ and UDI scores
Notes	ITT population included all patients randomised to active treatment who had ≥ 1 post‐baseline evaluation. Efficacy population included all randomised patients who completed ≥2 weeks in the stable dose period and did not have major protocol violation. 35 dropouts (oxybutynin CR :13 and oxybutynin IR :22). Study sponsored by Purdue Pharma, Canada.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No description.
Allocation concealment (selection bias)	Unclear risk	No information.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double dummy drug packaging technique.
Incomplete outcome data (attrition bias)   All outcomes	High risk	There was differential withdrawal, 22 withdrawals in the IR oxybutynin group and 13 in the CR oxybutynin group.

Methods	RCT. Cross‐over design.   Masking of assessors not stated.
Participants	80 female patients.   Inclusion criteria: urodynamically proven detrusor instability.   Exclusion criteria not stated.
Interventions	Treatment 1: oxybutynin 2.5 mg tid   Treatment 2: oxybutynin 2.5 mg as necessary.   6 week treatment period for each treatment.   Two week washout between treatments.
Outcomes	Symptomatic improvement (VAS).   Patient preference score.   Number of leakage episodes, frequency of micturition.   Pad test.   Urodynamic parameters.   Adverse events (VAS)
Notes	Abstract.   Data not in useable form for this review.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no other description.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No description.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Dropouts not stated.

Methods	Randomised, open label pilot study. Multicentre study.
Participants	77 women randomised. Inclusion criteria: women with overactive bladder.
Interventions	Group1: solifenacin (n=40) Group2: darifenacin (n= 37) 12 weeks treatment period.
Outcomes	Urgency frequency, severity and botherness (VAS score). UDI and IIQ questionnaire. Success of treatment based on VAS.
Notes	Abstract. No useable data reported. Dose of solifenacin and darifenacin used in the study not reported in the abstract
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no further information.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	High risk	Open label.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	16 dropouts, 8 in solifenacin and 8 in darifenacin group. Reasons for dropout not stated.

PERMALINK

Which anticholinergic drug for overactive bladder symptoms in adults

Priya Madhuvrata

June D Cody

Gaye Ellis

G Peter Herbison

E Jean C Hay‐Smith

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

1.

Sample characteristics

Parallel group trials

Cross‐over studies

Interventions in parallel arm studies

(1) Oxybutynin versus:

(2) Tolterodine versus:

(3) Propiverine versus:

(4) Solifenacin versus:

Interventions in cross‐over studies

Outcome measures

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

2.

Other potential sources of bias

Effects of interventions

Comparison 1: one anticholinergic versus another

Tolterodine versus oxybutynin

Quality of life

1. One anticholinergic versus another. Qol KHQ.

2. One anticholinergic versus another. Qol IIQ/UDI.

1.1. Analysis.

Patient observations

1.3. Analysis.

Quantification of symptoms

1.4. Analysis.

1.5. Analysis.

Clinician measures

Adverse events

1.10. Analysis.

1.11. Analysis.

Trospium versus oxybutynin

Quality of life (Qol)

Methods	RCT, placebo controlled, parallel design. Muticentre, multinational (84 centres). ITT analysis
Participants	911 randomised 907 treated (safety population) 857 efficacy population Inclusion: men and women 18years old or older with symptoms of OAB (including urinary frequency with urgency and /or urge incontinence) for three months or more were eligible for screening and study enrolment.To be eligible for randomisation after 2 week run in period, patients and to report an average micturition frequency of 8 or more per 24 hours and at least 3 episodes of urgency and or 3 episodes of urinary incontinence during the 3 day diary period. Exclusion:Clinically significant BOO, a postvoid residual volume of >200mls, incontinence for which stress was determined to be the predominant factor, presence of neurological cause for detrusor muscle overactivity, evidence of UTI or bladder stones, previous pelvic irradiation, previous or current malignant disease of the pelvic organs, any medical condition contraindicating the use of antimuscarinic medication (narrow angle glaucoma, urinary or gastric retention), non‐pharmacological treatment OAB including electrostimulation therapy or start of a bladder training programme during the 2 weeks before or during the study, diabetic neuropathy, use of any drug with anticholinergic side effects, and participation in a clinical trial within 30 days before study entry. Women of child bearing potential who were pregnant or nursing, intending to become pregnant during the study or who were not using reliable contraceptive methods were ineligible.
Interventions	Group 1: placebo once daily (n=301) Group 2: solifenacin 5 mg once daily (n=299) Group 3: solifenacin 10 mg once daily (n= 307) 2 weeks placebo run in period 12 weeks treatment period.
Outcomes	Primary outcome: change from baseline in mean number of micturition per 24 hours. Secondary outcomes: urgency episodes per 24 hours, nocturia, urge incontinence, all incontinence episodes and volume voided per micturition. Laboratory screening, ECG, adverse events, PVR with bladder scanner. Outcomes assessed at baseline, 4,8,12 weeks.
Notes	Efficacy analysis included all randomised patients who received at least 1 dose of study medication and who had efficacy data from baseline and at least 1 on treatment visit. 77 discontinued treatment (placebo: 31, solifenacin 5mg: 22, solifenacin 10mg: 24).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no other information.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind, no further information.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	22 dropouts in 5mg solifenacin group and 24 in 10mg solifenacin group with similar reasons for withdrawal across groups. Endpoint data consisted of the last available on treatment visit carried forward.

Methods	RCT.   Placebo and active controlled. Parallel design.   Phase II.   Double blind.   Masking of assessors not stated.   Multicentre(33).   Multinational.
Participants	225 male and female patients.   Inclusion criteria: Urodynamic evidence of idiopathic detrusor overactivity within 6 months of study inclusion. At least 8 micturitions/24 hours. At least 3 urinary incontinent or 3 urgency episodes over a 3 day period. Exclusion: Neurogenic detrusor overactivity, significant outlet obstruction, urinary retention, urodynamic stress incontinence, bladder stones, interstitial cystitis, malignant disease of pelvic organs, previous pelvic irradiation and diabetic neuropathy.
Interventions	Group 1 placebo: (n=38)   Group 2: Solifenacin 2.5 mg once daily (n=41)   Group 3: Solifenacin 5 mg once daily (n=37)   Group 4: Solifenacin 10 mg once daily (n=35)   Group 5: Solifenacin 20 mg once daily (n=37)   Group 6: tolterodine 2mg bid (n=37)   4 week treatment period.   2 week washout.
Outcomes	Number of leakage episodes, frequency of micturition, volume voided.   Adverse events.   Post void residual (ultrasound)   Laboratory tests.   ECG.   Vital signs.
Notes	33 dropouts (Group1: 6, Group2: 5, Group 3: 3, Group 4: 7, Group 5: 7, Group 6: 5).   2 week follow up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no other information.
Allocation concealment (selection bias)	Unclear risk	No description
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	33 dropouts (Group1: 6, Group2: 5, Group 3: 3, Group 4: 7, Group 5: 7, Group 6: 5). with similar reasons for dropouts between groups.

Methods	RCT: placebo controlled, parallel design, phase 3 study. Multicentre (98 centres internationally). ITT analysis .
Participants	1081 male and female patients randomised. Inclusion criteria: average micturition frequency of 8 or more per 24 hours and at least 3 episodes of urgency and or 3 episodes of urinary incontinence during the 3‐day diary period. Exclusion criteria: clinically significant BOO, a postvoid residual volume of >200mls, incontinence for which stress was determined to be the predominant factor, presence of neurological cause for detrusor muscle overactivity, evidence of UTI or bladder stones, previous pelvic irradiation, previous or current malignant disease of the pelvic organs, any medical condition contraindicating the use of antimuscarinic medication (narrow angle glaucoma, urinary or gastric retention), non pharmacological treatment OAB including electrostimulation therapy or start of a bladder training programme during the 2 weeks before or during the study, diabetic neuropathy, use of any drug with anticholinergic side effects, and participation in a clinical trial within 30 days before study entry. Women of child bearing potential who were pregnant or nursing, intending to become pregnant during the study or who were not using reliable contraceptive methods were ineligible.
Interventions	Group 1: placebo (n= 267) Group 2: solifenacin 5 mg once daily (n=279) Group 3: solifenacin 10 mg once daily (n=269) Group 4: tolterodine 2 mg bid (n=266) 2 week placebo run‐in period. 12 week treatment period.
Outcomes	Urgency episodes/24hrs and all incontinence episodes and urge incontinence episodes/24hrs, micturition per 24 hours, and Volume voided per micturition Laboratory screening ECG Adverse events PVR Outcomes assessed at baseline, 4, 8 and 12 weeks.
Notes	No follow up. 109 dropouts (Group 1: 32, Group 2: 28, Group 3: 20 and Group 4: 29). Company support declared.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised, no description.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind, to maintain blinding all the patients took medication twice daily using placebo capsules and tablets as necessary.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Dropouts balanced in numbers across the intervention groups with similar reasons for dropouts (Group.1:11%, group.2:10%, group.3: 7% and group.4: 11%).

Methods	Randomised, placebo controlled, dose ranging phase 2 trial. Multicentre (86 European centres).
Participants	728 patients randomised. Inclusion criteria: men and women with symptoms of OAB for at least 6 months, aged between 18 and 78 years. Subjects were required to have had an urodynamic assessment demonstrating detrusor overactivity within 12 months prior to enrolment.
Interventions	Group 1: placebo (n=183) Group 2: fesoterodine 4 mg once daily (n=186) Group 3: fesoterodine 8 mg once daily (n=173) Group 4: fesoterodine 12 mg once daily (n=186) 1 week placebo run in period. 12 week treatment period.
Outcomes	Change in average number of micturitions per 24 hours Change in average number of urge incontinence episodes per week Change in micturitions during day time, nocturia, average voided volume per micturition, urgency episodes per week, severity of Urgency using a 4 grade scale, subjects evaluation of bother and subjects assessment of treatment efficacy. Adverse events Lab tests, Vitals (blood pressure and heart rate), ECG and residual volume.
Notes	Abstract. The primary analysis set for this study were the full analysis set. Data obtained from clinicalstudyresults.org 119 dropouts (Group 1: 21, Group 2: 29, Group 3: 30 and Group 4: 39).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no other description.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Low risk	states double blind.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Differential withdrawals with dropouts in placebo :21 (11.5%), fesoterodine 4mg: 29 (15.6%); fesoterodine 8mg: 30 (17.3%) and fesoterodine 12mg: 39 (21%).

Methods	RCT: parallel design. Double blind, double dummy Masking of assessors not stated. ITT analysis. Multicentre (117 centres).
Participants	1200 randomised. Inclusion criteria: men and women aged at 18 years who had OAB symptoms for 3 months or more. An average of ≥ 8 micturitions per 24 hours, an average of ≥1 incontinence episode per 24 hours or an average of ≥1 urgency episode per 24 hours. Exclusion criteria: stress incontinence or mixed incontinence where stress was predominant (mixed incontinence was allowed otherwise) and patients with neurological cause of abnormal detrusor overactivity.
Interventions	Group 1: solifenacin 5 mg once daily (n=593) Group 2: tolterodine ER 4 mg once daily (n=607) 2 week placebo run‐in period. 12 week treatment period. After 4 weeks of treatment patients had the option to request a dose increase but were dummied through out as dose increase was allowed only for solifenacin to 10mg once daily.
Outcomes	Number of micturitions per 24 hours, number of episodes of urgency, urge incontinence, incontinence and nocturia Health‐related Qol ‐ 6 point categorical scale Pad usage per 24 hours Volume voided per micturition Adverse events Outcomes assessed at 4, 8 and 12 weeks.
Notes	1177 full analysis set (578 patients on solifenacin and 599 on tolterodine ER). 1049 per protocol set (525 patients on solifenacin and 524 on tolterodine ER). Change from baseline in micturition frequency was based on PPS population, all other results presented from FAS. All other results presented are from FAS. 97 dropouts (Group 1: 41, Group 2: 56). No follow up. Company supported declared.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation, stratified by centre.
Allocation concealment (selection bias)	Low risk	central allocation by automated clinical trial service used to assign patient number and provide the medication number indicted by the central randomisation system.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind, double dummy, blinded by encapsulation.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	97 dropouts (Group 1: 41, Group 2: 56) with similar reasons for withdrawal. Last observation carried forward.

Methods	Randomised 2 way cross‐over study in three cohorts of patients.
Participants	65 randomised, 59 completed treatment. Inclusion: male and female patients aged 18‐75 years with cystometric evidence of DO either idiopathic or neurogenic, with ≥2 associated symptoms (average of ≥7 micturitions per day, ≥7 episodes of urgency /week necessitating change of clothing or pads). Exclusion: previous bladder surgery for detrusor overactivity, prostatectomy in the last 6 months, bladder stones, treatment with diuretics, antimuscarinics, tricyclic antidepressants or digoxin within th previous 2 weeks, stress and mixed incontinence, unless DO was the principal urodynamic observation and the patient was experiencing < 1 stress incontinence leak/week. Pregnant, breast feeding and not using adequate contraception, if intending to start or modify bladder retraining programme, if their alcohol intake exceeded normal limits or if they had any condition in which anticholinergics would be contraindicated.
Interventions	Cohort 1: darifenacin 2.5 mg tid or oxybutynin 2.5mg tid Cohort 2: darifenacin 15 mg once daily or oxybutynin 5mg tid Cohort 3: darifenacin 30 mg once daily or oxybutynin 5mg tid First treatment for 7 days followed by a washout of 14 days then the second treatment for 7 days. Compliance determined from unused drug.
Outcomes	Ambulatory urodynamics: duration of activity, activity index and number of phasic detrusor contraction. Salivary flow at baseline, 2,1,0.5 hrs before and 1,2,3 and 4 hrs after final dose of each treatment. Visual near point measured at baseline, predose, 2 and 4 hours after final dose. Heart rate : PNN50 and St Georges index were measured at baseline and at endpoint. Adverse events and discontinuation rates. Lab tests haematology, biochemistry, urine analysis.
Notes	Study funded by Pfizer. Non‐clinical outcomes not of interest other than adverse events. Data not in useable form.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random permuted block.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blinding was maintained by double dummy technique in cohort 2 and 3.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	6 withdrawals, insufficient reporting of attrition.

Methods	RCT, Parallel design, Phase 3. Masking of assessors not stated. ITT analysis. Multicentre (16 Korean centres).
Participants	357 male and female patients randomised. Inclusion criteria: men and women aged at 18 years who had OAB symptoms for 3 months or more. An average of ≥ 8 micturitions per 24 hrs, 3 episodes of urgency or 3 urge incontinence episodes during the 3 day voiding diary period. Exclusion criteria: significant bladder outlet obstruction, PVR > 200mls, stress incontinence or mixed incontinence where stress was predominant and patients with neurological cause of abnormal detrusor overactivity.
Interventions	Group 1: solifenacin 5 mg once daily (n=118) Group 2: solifenacin 10 mg once daily (n=118) Group 3: tolterodine 2 mg bid (n=118) 2 week placebo run in, 12 week treatment period.
Outcomes	Micturition frequency/24hours, volume per void, urgency incontinence/24hours, urgency episodes/24hours, nocturia/24hours PVR KHQ Adverse events Lab tests, vital signs. Outcomes assessed at 4, 8 and 12 weeks.
Notes	61 dropouts (Group 1: 22, Group 2: 21, Group 3: 18). Efficacy data included all randomised patients who had efficacy data available from baseline and at least one treatment visit (n=329). No follow up. Company support declared.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised, no other description.
Allocation concealment (selection bias)	Unclear risk	Double blind, no other information.
Blinding (performance bias and detection bias)   All outcomes	Low risk	All patients took medication twice using placebo tablets and capsule as necessary.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Withdrawals solifenacin 5mg: 22, solifenacin 10mg: 21 and tolterodine IR 4mg:18 with similar reasons for withdrawals. Last observation carried forward.

Methods	RCT, parallel design,1:1:1 randomisation. Multicentre (22 centres) Canadian. ITT analysis.
Participants	Canada. Inclusion: men and women ≥ 18 years with UI (one or more episodes/diary), frequency (eight or more voids per day) or urgency (one or more episodes per diary). Exclusion: screening postvoid residual volume >100ml, allergy/ serious side effects with anticholinergic medication, primary diagnosis of stress urinary incontinence, conditions contraindicating anticholinergic therapy, hepatic renal disease, interstitial cystitis, haematuria secondary to malignancy, recurrent UTI(more than 3/year),indwelling catheter/bladder training within 14 days of screening, drug/alcohol abuse, untreated psychiatric condition affecting participation, pregnancy and nursing women and women of child bearing potential not using reliable contraception.
Interventions	237 randomised 190 completed all 4 weeks Group 1: oxybutynin ER 5 mg once daily (n=77) Group 2: oxybutynin ER 10 mg once daily (n=77) Group 3: oxybutynin ER 15 mg once daily (n=83) Two weeks washout period, 4 week treatment period.
Outcomes	Change in UUI Voids Volume voided per void Urgency (number /day) Patient satisfaction (0‐4scale) Adverse effects (mild/mod/severe) DMSS index Tolerability Outcomes assessed at baseline and at 4 weeks after treatment.
Notes	2 week washout period, 4 week treatment period. Intention‐to‐treat analysis of efficacy and safety was used for all randomised patients. Withdrawals (oxybutynin ER 5mg: 9, oxybutynin ER 10mg: 20, oxybutynin ER 15mg: 18).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random numbers.Randomisation was stratified according to the severity of UI,using a block size of 6 within a stratum to ensure group comparability.
Allocation concealment (selection bias)	Unclear risk	No description.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind, were given three tablets to take identical in size, colour and composition to the active tablet.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Differential withdrawal between groups, 9/77 dropped out in the 5mg group, 20 /77 withdrew in the 10 mg group and 18/83 in the 15 mg group.

Methods	RCT. Placebo controlled,   parallel design.   Phase III.   Double blind.   Masking of assessors not stated.
Participants	520 male and female patients.   Inclusion criteria: at least 10 urge leakages per week; at least 8 voids per day; average urinary volume not > 350 ml.
Interventions	Group 1: placebo (n=132)   Group 2: transdermal oxybutynin 1.3 mg/day twice a week (n=130)   Group 3: transdermal oxybutynin 2.6 mg/day twice a week (n=133)   Group 4: transdermal oxybutynin 3.9 mg/day twice a week (n=125)   2 week washout 12 week treatment period.
Outcomes	Number of leakage episodes, frequency of micturition, volume voided.   IIQ, UDI, SF36.   Adverse events.   Laboratory tests.
Notes	73 dropouts (group not stated).   No follow up.   Company support declared.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised.
Allocation concealment (selection bias)	Unclear risk	No information.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	73 dropouts (group not stated).

Methods	RCT. Placebo and active controlled.   Parallel design.   Double blind.   Masking of assessors not stated.   Multicentre.
Participants	76 male and female patients.   Inclusion criteria: at least 18 years of age with history of urge or mixed incontinence, with predominance of urge. Previous diagnosis of motor urge urinary incontinence with symptomatic improvement during a minimum 6 weeks of oral oxybutynin. Minimum 3 incontinent episodes daily and a greater than 30% increase after 2 week washout. Urodynamically confirmed detrusor instability and patient symptoms.
Interventions	Group 1: oral oxybutynin plus placebo transdermal (n=38)   Group 2: transdermal oxybutynin plus oral placebo (n=38)   6 week treatment period.   2 week washout.
Outcomes	Symptom questionnaire (VAS)   Number of leakage episodes.   Urodynamic parameters.   Adverse events.   Laboratory tests.   ECG.   Vital signs and site tolerability.
Notes	Dose titration.   2 dropouts (Group 1:1, Group 2: 1).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States randomised, no description
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	2 dropouts (Group 1:1, Group 2: 1)