Anticholinergic drugs versus non‐drug active therapies for non‐neurogenic overactive bladder syndrome in adults

Bhavan Prasad Rai; June D Cody; Ammar Alhasso; Laurence Stewart

doi:10.1002/14651858.CD003193.pub4

. 2012 Dec 12;2012(12):CD003193. doi: 10.1002/14651858.CD003193.pub4

Anticholinergic drugs versus non‐drug active therapies for non‐neurogenic overactive bladder syndrome in adults

Bhavan Prasad Rai ¹, June D Cody ², Ammar Alhasso ^3,^✉, Laurence Stewart ³

Editor: Cochrane Incontinence Group

PMCID: PMC7017858 PMID: 23235594

Abstract

Background

Overactive bladder syndrome is defined as urgency with or without urgency incontinence, usually with frequency and nocturia. Pharmacotherapy with anticholinergic drugs is often the first line medical therapy, either alone or as an adjunct to various non‐pharmacological therapies after conservative options such as reducing intake of caffeine drinks have been tried. Non‐pharmacologic therapies consist of bladder training, pelvic floor muscle training with or without biofeedback, behavioural modification, electrical stimulation and surgical interventions.

Objectives

To compare the effects of anticholinergic drugs with various non‐pharmacologic therapies for non‐neurogenic overactive bladder syndrome in adults.

Search methods

We searched the Cochrane Incontinence Group Specialised Register (searched 4 September 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE, and the reference lists of relevant articles.

Selection criteria

All randomised or quasi‐randomised, controlled trials of treatment with anticholinergic drugs for overactive bladder syndrome or urgency urinary incontinence in adults in which at least one management arm involved a non‐drug therapy. Trials amongst patients with neurogenic bladder dysfunction were excluded.

Data collection and analysis

Two authors evaluated the trials for appropriateness for inclusion and risk of bias. Two authors were involved in the data extraction. Data extraction was based on predetermined criteria. Data analysis was based on standard statistical approaches used in Cochrane reviews.

Main results

Twenty three trials were included with a total of 3685 participants, one was a cross‐over trial and the other 22 were parallel group trials. The duration of follow up varied from two to 52 weeks. The trials were generally small and of poor methodological quality.

During treatment, symptomatic improvement was more common amongst those participants on anticholinergic drugs compared with bladder training in seven small trials (73/174, 42% versus 98/172, 57% not improved: risk ratio 0.74, 95% confidence interval 0.61 to 0.91). Augmentation of bladder training with anticholinergics was also associated with more improvements than bladder training alone in three small trials (23/85, 27% versus 37/79, 47% not improved: risk ratio 0.57, 95% confidence interval 0.38 to 0.88). However, it was less clear whether an anticholinergic combined with bladder training was better than the anticholinergic alone, in three trials (for example 74/296, 25% versus 95/306, 31% not improved: risk ratio 0.80, 95% confidence interval 0.62 to 1.04). The other information on whether combining behavioural modification strategies with an anticholinergic was better than the anticholinergic alone was scanty and inconclusive. Similarly, it was unclear whether these complex strategies alone were better than anticholinergics alone.

In this review, seven small trials comparing an anticholinergic to various types of electrical stimulation modalities such as Intravaginal Electrical Stimulation (IES), transcutaneous electrical nerve stimulation (TENS), the Stoller Afferent Nerve Stimulation System (SANS) neuromodulation and percutaneous posterior tibial nerve stimulation (PTNS) were identified. Subjective improvement rates tended to favour the electrical stimulation group in three small trials (54% not improved with the anticholinergic versus 28/86, 33% with electrical stimulation: risk ratio 0.64, 95% confidence interval 1.15 to 2.34). However, this was statistically significant only for one type of stimulation, percutaneous posterior tibial nerve stimulation (risk ratio 2.21, 95% confidence interval 1.13 to 4.33), and was not supported by significant differences in improvement, urinary frequency, urgency, nocturia, incontinence episodes or quality of life.

The most commonly reported adverse effect among anticholinergics was dry mouth, although this did not necessarily result in withdrawal from treatment. For all comparisons there were too few data to compare symptoms or side effects after treatment had ended. However, it is unlikely that the effects of anticholinergics persist after stopping treatment.

Authors' conclusions

The use of anticholinergic drugs in the management of overactive bladder syndrome is well established when compared to placebo treatment. During initial treatment of overactive bladder syndrome there was more symptomatic improvement when (a) anticholinergics were compared with bladder training alone, and (b) anticholinergics combined with bladder training were compared with bladder training alone. Limited evidence from small trials might suggest electrical stimulation is a better option in patients who are refractory to anticholinergic therapy, but more evidence comparing individual types of electrostimulation to the most effective types of anticholinergics is required to establish this. These results should be viewed with caution in view of the different classes and varying doses of individual anticholinergics used in this review. Anticholinergics had well recognised side effects, such as dry mouth.

Plain language summary

Anticholinergic drugs versus non‐drug active therapies for overactive bladder syndrome in adults without neurological problems

Overactive bladder syndrome occurs in adults who have urinary urgency with or without urgency urinary incontinence (leakage of urine). People usually empty their bladders frequently during the day and also at night (nocturia). It is a major problem affecting quality of life, in over 22 million people. It affects men and women, and is more common in women and in older people. It is also expensive for both patients and the health service. It is not clear exactly why it occurs, and there are many treatments including drugs and behavioural treatments such as bladder training and pelvic floor exercises. It is not clear which treatments work best, have the fewest side effects and which are most economical. Twenty three trials with 3685 participants were included in the review. Participants were more likely to improve if they were using an anticholinergic drug compared with bladder training alone, and also when using a combination of an anticholinergic drug plus bladder training. More people reported an improvement in their overactive bladder symptoms when using electrical stimulation than an anticholinergic drug, but this was only significant in one trial for one type of electrical stimulation, percutaneous posterior tibial nerve stimulation. These results have to be viewed with caution as different types and doses of the anticholinergic drugs were used in the trials. The main adverse effect reported was dry mouth, in about a third of the people taking an anticholinergic drug.

Background

Description of the condition

Overactive bladder syndrome is a symptom triad defined as "urgency, with or without urgency incontinence, usually with frequency and nocturia" (Abrams 2002). Alternative terminologies for overactive bladder syndrome are urge syndrome or urge‐frequency syndrome.

In a survey of 16,776 adults that was performed in Europe (France, Germany, Italy, Spain, Sweden, and the United Kingdom), 16.6% had overactive bladder syndrome. Urge incontinence was reported by 36% of those with overactive bladder symptoms (Milsom 2001). In a similar study in the United States, the National Overactive Bladder Evaluation (NOBLE) program estimated that 33 (16.5%) million people had overactive bladder syndrome. Of these, 12 million (37%) were incontinent (Stewart 2001). The estimated prevalence of an overactive bladder amongst people aged 40 years and above is 15.6% and 17.4% in men and women respectively, and the prevalence increases with age in both sexes. The symptoms of urgency or frequency, or both, are equally common in men and women but urgency incontinence is more prevalent in women (Milsom 2001). Patients with symptoms of overactive bladder syndrome who have demonstrated detrusor contractions during the filling phase of urodynamic assessment are termed as having detrusor overactivity. If detrusor overactivity is associated with a neurological condition it is termed as neurogenic detrusor overactivity. In the absence of a relevant neurological condition it is termed 'idiopathic detrusor overactivity'. In this review only idiopathic detrusor overactivity was considered.

Overactive bladder syndrome has economic and quality of life implications. It has been estimated that the economic cost of overactive bladder was USD 12.02 billion in 2000 in the United States (Hu 2003). It is also associated with poorer quality of life indices as shown by the Short Form (SF)‐36 questionnaire, King's Health Questionnaire, a higher depression score and a poorer quality of sleep (Stewart 2001).

The current European Association of Urology (EAU) guidelines suggest following a stepwise management pattern for the treatment of patients with overactive bladder and urgency urinary incontinence. The first step is conservative measures, which may include reducing the intake of caffeine drinks, optimising fluid intake, weight loss, usage of intravaginal oestrogens in postmenopausal women (Cody 2012), and short term usage of desmopressin in young adults with enuresis. The next option is bladder training (Wallace 2004), which can be combined with pelvic floor exercises in the presence of concomitant stress incontinence. The next step is the administration of anticholinergic medications. The options for patients refractory to conservative measures and anticholinergic treatment and with detrusor overactivity are intravesical botulinum toxin A injection (Duthie 2011), electrical stimulation, neuromodulation with implanted electrodes (Herbison 2009) and surgical interventions with high morbidity, such as clam ileocystoplasty and urinary diversion (Cody 2012a). In view of the complications associated with surgical intervention, it is commonly the last treatment option in patients with detrusor overactivity.

Description of the intervention

Pharmacotherapy is one of the main treatment options in the management of overactive bladder syndrome. Anticholinergics are classified based on pharmacokinetics (lipophilicity and molecular size) into tertiary and quaternary amines, or based on muscarinic receptor selectivity into non‐selective antagonists, M2‐M3 selective antagonists and M3 selective antagonists.

Tertiary amines are solifenacin, darifenacin, tolterodine, oxybutynin.
Qaternary amines are trospium and propantheline.
Non‐selective anticholinergics are tolterodine, trospium, oxybutynin, propiverine hydrochloride (HCl) and propantheline.
Solfenacin and darifenacin are M2‐M3 selective and M3 selective antagonists, respectively.

Quaternary amines do not cross the blood brain barrier and hence are thought to have fewer cognitive side effects in comparison with tertiary amines. In view of their receptor selectivity, M2‐M3 selective and M3 selective antagonists are thought to have fewer adverse effects. The number of anticholinergic drugs available on the market is increasing and their effectiveness has been assessed in both observational and randomised controlled trials (Madhuvrata 2012; Thuroff 1991; Van Kerrebroeck 1998). Anticholinergics are increasingly being used in primary and secondary care settings, particularly for the treatment of urgency urinary incontinence, and this has considerable resource implications (Kobelt 1997).

Comparators

Bladder training is often used as first line therapy in patients with overactive bladder syndrome whether or not they are incontinent. This modality involves encouraging patients to gradually increase the interval between voiding episodes. Employed in conjunction with a bladder chart, patients and clinicians can chart progress through both the volumes voided and the time interval between each void. It has been claimed that up to 50% of patients will achieve long term benefit with this approach (Holmes 1983).

Pelvic floor muscle training (PFMT) has been advocated as a means of improving pelvic floor control and reducing symptoms of overactive bladder and urgency urinary incontinence. PFMT is more commonly recommended for stress urinary incontinence than for symptoms of overactive bladder syndrome (Dumoulin 2010).

A combination of bladder training with biofeedback‐assisted PFMT, sometimes referred to as behavioural therapy, has been shown to improve bladder control by teaching patients new skills or habits and is a recognised form of non‐drug active therapy in the management of overactive bladder syndrome (Cardozo 1978).

Electrical stimulation involves the use of either implanted or external electrodes to stimulate reflex inhibition of pelvic efferents or activation of hypogastric efferents to down regulate detrusor muscle activity. This is mediated through stimulation of afferent input in the sacral root, S2 to S4 (Fall 1985; Shaker 1998).

External electrodes are broadly classified into endocavitary and percutaneous electrodes (Gameiro 2012). Endocavitary electrodes can be placed intravaginally or rectally. Percutanous approaches include transcutaneous electrical nerve stimulation (TENS) and posterior tibial nerve stimulation (PTNS).

When the electrodes are placed on the perineal skin surface it is termed TENS.
PTNS involves non‐invasive electrical stimulation of S2 to S4 sacral nerves via a 34‐G needle placed on the medial malleolus of the ankle. It was first described by Dr Marshall Stoller and the protocol was termed the Stoller Afferent Nerve Stimulation (SANS) protocol.

Sacral nerve stimulation is a technique which involves implanted electrodes. It is a two stage invasive procedure where an electrode is placed percutaneously alongside S3 in the sacral foramina (Herbison 2009).

Surgical management of overactive bladder and urgency urinary incontinence is uncommon and is generally reserved for the most severe cases that have not responded to conservative management (Cody 2012).

How the intervention might work

The pathophysiology of the overactive bladder remains to be fully elucidated. However, the involvement of the autonomic nervous system in bladder and detrusor function is recognised (de Groat 1997). The motor nerve supply to the bladder is via the parasympathetic nervous system (via sacral nerves S2, S3, S4) (Abrams 1988; Ouslander 1982; Ouslander 1986), which stimulates detrusor muscle contraction. This is mediated by acetylcholine acting on muscarinic (M) receptors at the level of the bladder. The bladder contains both M2 and M3 muscarinic receptor subtypes. Although the M2 subtype is more abundant, it is the M3 subtype which is mainly responsible for bladder contraction (Andersson 2002). 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. For the purpose of this review, the term 'anticholinergic' refers to both anticholinergic and antimuscarinic drugs.

Why it is important to do this review

There are numerous drug and non‐drug treatments for overactive bladder. While anticholinergics are well established in practice, based on their efficacy versus no treatment or placebo (Nabi 2006), it is less certain how they compare to other established treatments such as bladder training and electrical stimulation.

This review compares anticholinergic drugs with other active (non‐drug) therapies which include bladder training (BT) and pelvic floor muscle training (PFMT). Anticholinergic drugs are also compared with various combinations of bladder training and PFMT with and without anticholinergics to assess if any particular combination shows superior efficacy. The review also compares anticholinergics with various forms of electrical stimulation including neuromodulation.

Other Cochrane reviews covering treatments for overactive bladder syndrome and urinary incontinence that might be of interest to the reader include:

anticholinergic drugs versus placebo (Nabi 2006);
which anticholinergic? (Madhuvrata 2012);
anticholinergic drugs versus other medications (Dublin 2004);
PFMT versus no treatment (Dumoulin 2010);
bladder training (Wallace 2004);
botulinum toxin injections (Duthie 2011); and
sacral neuromodulation with implanted devices (Herbison 2009).

Objectives

The following comparisons were made (for people with overactive bladder syndrome with or without urgency urinary incontinence).

1. Anticholinergic drugs versus bladder training (BT) alone.

2. Anticholinergic drugs versus pelvic floor muscle training (PFMT) alone.

3. Anticholinergic drugs versus external electrostimulation (endocavitary, percutaneous or sacral nerve modulation).

4. Anticholinergic drugs versus surgery.

5. Anticholinergic drugs in combination with non‐drug therapies versus non‐drug therapies alone.

6. Anticholinergic drugs in combination with non‐drug therapies versus anticholinergic drugs alone.

7. Anticholinergic drugs versus combination non‐drug therapies.

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 syndrome and urgency urinary incontinence.

Types of participants

All adult men and women with idiopathic overactive bladder syndrome or urgency urinary incontinence (symptomatic or urodynamic diagnosis), or both. Participants with likely neurogenic causes for their symptoms were excluded.

Types of interventions

At least one arm of the trial used an anticholinergic drug and at least one other arm used a non‐drug treatment (such as bladder training, PFMT or surgery).

Types of outcome measures

The primary measure of outcome was the number of participants whose symptoms were 'not cured' while on treatment. Data for the following outcome measures were sought.

A. Participants' observations

1. Number not cured during treatment (self‐reported, subjective)*  2. Number not cured after treatment (self‐reported, subjective)*  3. Number not improved (worse or unchanged) during treatment (self‐reported, subjective)*  4. Number not improved (worse or unchanged) after treatment (self‐reported, subjective)*  5. Number with nocturia during treatment  6. Number with nocturia after treatment

* Definitions based on criteria as reported by trialists for each trial

B. Quantification of symptoms

7. Number of pad changes over 24 hours (from self‐reported number of pads used)  8. Number of incontinent episodes over 24 hours (from self‐completed urinary diary)  9. Mean volume or weight of urine loss on pad test  10. Number of micturitions over 24 hours (from self‐completed urinary diary)  11. Frequency of sensation of urgency

C. Clinician's observations

12. Number not cured (worse, unchanged or improved) versus cured within first year (objective test)  13. Number not cured (worse, unchanged or improved) versus cured after first year (objective test)  14. Number not cured (worse, unchanged or improved) versus cured after 5 years (objective test)  15. Urodynamic‐diagnosed detrusor overactivity

D. Quality of life

16. General health status measures e.g. Short Form‐36 (Ware 1993)  17. Condition‐specific health measures (specific instruments designed to assess impact of urinary voiding problems)  18. Measures of psychological health

E. Socioeconomic measures

19. Health economic measures: costs of treatments; differential costs of treatment effect differences; formal cost effectiveness measures

F. Adverse events

20. Number experiencing adverse effects  21. Number withdrawing from treatment or trial arm  22. Number changing dose of treatment

G. Other outcomes

Non‐prespecified outcomes judged important when performing the review

Search methods for identification of studies

We did not impose any language or other limits on any of the searches.

Electronic searches

This review has drawn on the search strategy developed for the Incontinence Group. Relevant trials were identified from the Incontinence Group Specialised Register, which is described under the Incontinence Group's module in The Cochrane Library. The register contains trials identified from MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL) and handsearching of journals and conference proceedings. The date of the most recent search of the register was 4 September 2012. The trials in the Incontinence Group Specialised Trials 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:

{design.rct* or design.cct*}  AND  {TOPIC.URINE.INCON*} OR {TOPIC.URINE.overactivebladder*}  AND  {{INTVENT.CHEM.DRUG.ANTICHOLINERGIC} AND {INTVENT.*}} OR {relevant.review.anticholinergicVSnondrug}  (All searches were of the keyword field of Reference Manager 12, Thomson Reuters).

Searching other resources

We checked all reference lists of identified trials and other relevant articles.

Data collection and analysis

Selection of studies

Reports of studies identified as possibly eligible for the review were evaluated for appropriateness for inclusion by the review authors working independently and without prior consideration of the results. Studies were excluded from the review if they were neither randomised nor quasi‐randomised trials.

Data extraction and management

Data extraction was undertaken independently by two review authors and cross‐checked. Where data may have been collected but were not reported, further clarification was sought from the researchers. Included trial data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Trial data were considered in relation to the seven main hypotheses. Any difference of opinion related to the data extracted was discussed and resolved with a third review author.

Assessment of risk of bias in included studies

At least two review authors assessed risk of bias using the Cochrane Collaboration assessment criteria:

quality of random allocation and concealment;
description of drop‐outs and withdrawals;
'blinding' at treatment and outcome assessment.

Any disagreements were resolved by discussion with a third review author.

Measures of treatment effect

For categorical outcomes we related the number of participants reporting an outcome to the numbers at risk in each group to derive a risk ratio (RR). For continuous variables we used means and standard deviations to derive a mean difference. For cross‐over trials and trials where continuous data were reported without measures of dispersion (for example, standard deviations) the data were entered into 'Other data' tables and comparisons made only on the direction of effect. Cross‐over trials were identified by the suffix '#'.

Assessment of heterogeneity

Differences between trials were further investigated when significant statistical heterogeneity was found at the 10% level, or from consideration of the I² statistic (Higgins 2011) or appeared obvious from visual inspection of the results.

Data synthesis

When appropriate, meta‐analysis was undertaken. A fixed‐effect model was used for calculation of summary statistics (pooled estimates) and 95% confidence intervals (CIs).

Subgroup analysis and investigation of heterogeneity

Subcategories were identified according to the type(s) of drugs being compared or the different types of other interventions.

Results

Description of studies

Results of the search

Fifty studies were identified, of which 27 were excluded (see table 'Characteristics of excluded studies' for details). Of the 23 included trials, with 3685 participants, one was a cross‐over trial (Soomro 2001 #) and the other 22 were parallel group trials. The flow of literature through the assessment process is shown in Figure 1.

Included studies

A detailed description of the 23 trials is given in the table 'Characteristics of included studies'. Four trials were in abstract form (Collas 1994; Milani 1987; Park 2002; Wise 1993), 18 were full publications (Burgio 1998; Burgio 2008; Burgio 2010; Burgio 2011; Chancellor 2008; Colombo 1995; Kaya 2011; Mattiasson 2003; Mattiasson 2009; Millard 2004; Ozdedeli 2010; Peters 2009; Smith 1996; Song 2006; Soomro 2001 #; Svihra 2002; Szonyi 1995; Wang 2006) and one was a doctor of medicine (MD) thesis (Macaulay 1988).

Comparisons

The trials made the following comparisons.

1. Seven trials assessed various anticholinergics versus bladder training (Collas 1994; Colombo 1995; Macaulay 1988; Milani 1987; Park 2002; Song 2006; Szonyi 1995).

2. Seven trials assessed various electrical stimulation modalities versus an anticholinergic drug:

two trials used probantheline (dose range 7.5 mg to 45 mg twice daily or three times daily) and one trial oxybutynin 5 mg bd daily (Wise 1993) versus intravaginal electrical stimulation (Smith 1996);
one trial used oxybutynin (dose range 2.5 mg twice daily to 5 mg three times daily) versus transcutaneous electrical nerve stimulation (TENS) (Soomro 2001 #), this was a cross‐over trial;
one trial used oxybutynin 5 mg three times daily versus Stoller Afferent Nerve Stimulation System neuromodulation (Svihra 2002);
one trial used trospium hydrochloride versus intravaginal electrical stimulation (Ozdedeli 2010);
one trial used oxybutynin 2 mg twice a day without dose titration versus intravaginal electrical stimulation (Wang 2006);
one trial used extended‐release tolterodine 4mg versus percutaneous tibial nerve stimulation (Peters 2009).

3. Two trials assessed a combination of an anticholinergic drug with bladder training versus bladder training alone (Park 2002; Szonyi 1995).

4. Four trials assessed a combination of an anticholinergic drug with bladder training versus the drug alone (Mattiasson 2003; Mattiasson 2009; Park 2002; Song 2006).

5. One trial assessed an anticholinergic drug (tolterodine) versus PFMT plus the anticholinergic drug (tolterodine) (Millard 2004).

6. One trial assessed an anticholinergic drug (oxybutynin) versus bladder training plus biofeedback‐assisted PFMT (Burgio 1998).

7. Four trials assessed anticholinergics versus anticholinergics and behavioural modification therapy (Burgio 2008; Burgio 2010; Burgio 2011; Chancellor 2008).

8. One trial compared anticholinergics versus physiotherapy (inferential current therapy plus pelvic floor exercises plus bladder training) versus combination therapy (Kaya 2011).

Participants

Six trials had both male and female participants (Chancellor 2008; Mattiasson 2003; Mattiasson 2009; Peters 2009; Soomro 2001 #; Szonyi 1995) and 15 had female participants only (Burgio 1998; Burgio 2010; Colombo 1995; Kaya 2011; Macaulay 1988; Milani 1987; Millard 2004; Ozdedeli 2010; Park 2002; Smith 1996; Song 2006; Svihra 2002; Wang 2006; Wise 1993), one trial included men only (Burgio 2011), while one did not specify the gender of the participants (Collas 1994). The trials all included participants with non‐neurogenic overactive bladder symptoms or did not specify the cause of the overactive bladder symptoms.

Follow up

The duration of follow up varied from two to 52 weeks.

Excluded studies

Details of the excluded studies are given in the table 'Characteristics of excluded studies'.

Risk of bias in included studies

The methodology and risk of bias of individual trials is summarised in the table 'Characteristics of included studies'.

The risk of bias for individual trials have also been summarised in Figure 2 and Figure 3.

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

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

In one trial, outcome data were estimated manually from graphs (Macaulay 1988); in another, data were reported in a way that could not be interpreted for the purpose of the review (Wise 1993); and in two trials outcomes were reported as median percentage change and interquartile ranges, which could not be analysed in RevMan (Mattiasson 2003; Ozdedeli 2010). Standard deviations were not reported in two trials (Mattiasson 2009; Song 2006).

Allocation

In eight trials (Burgio 1998; Burgio 2008; Chancellor 2008; Colombo 1995; Kaya 2011; Mattiasson 2003; Ozdedeli 2010; Szonyi 1995) the random sequence generation was deemed at low risk of bias. In the remaining studies the authors were unable to judge the level of risk for selection bias as the reporting was inadequate. In three trials (Burgio 2008; Ozdedeli 2010; Wang 2006) the allocation concealment was deemed low risk. In the remaining trials the authors were unable to judge the level of risk for allocation concealment as the reporting was inadequate.

Blinding

In four trials (Burgio 1998; Burgio 2008; Szonyi 1995; Wang 2006) the blinding was deemed at low risk of bias. There was high risk of performance bias and detection bias in five trials (Burgio 2010; Chancellor 2008; Mattiasson 2009; Ozdedeli 2010; Peters 2009).

Incomplete outcome data

Drop‐outs and withdrawals were described in six trials (Chancellor 2008; Colombo 1995; Mattiasson 2009; Peters 2009; Song 2006; Wang 2006). In one trial (Svihra 2002) no actual numbers were provided for one group, and the trialists referred to "comparable therapeutic results" in their reporting. Similarly, no data were reported in another trial (Wise 1993).

Effects of interventions

Comparison 1: anticholinergic drugs versus bladder training (BT)

Seven trials addressed this comparison (Collas 1994; Colombo 1995; Macaulay 1988; Milani 1987; Park 2002; Song 2006; Szonyi 1995).

One trial compared tolterodine 4 mg daily versus bladder training (Park 2002).
Two trials compared oxybutynin 5 mg daily versus bladder training (Collas 1994; Szonyi 1995).
One trial compared oxybutynin 15 mg daily versus bladder training (Colombo 1995).
One trial compared oxybutynin 45 mg daily versus bladder training (Milani 1987).
One trial compared probantheline 45 mg daily versus bladder training (Macaulay 1988).
One trial compared tolterodine 2mg twice daily versus bladder training (Song 2006).

Participants' observations

Data describing cure rates during and after treatment were only available from two small trials (56 people). They tended to favour the anticholinergic groups but the differences were not statistically significant: not cured during treatment 7/28 (25%) versus 14/28 (50%) (RR 0.52, 95% CI 0.26 to 1.04; Analysis 1.1) (Colombo 1995; Macaulay 1988); not cured after treatment 9/28 (32%) versus 16 out of 28 (57%) (RR 0.58, 95% CI 0.16 to 2.21; Analysis 1.2) (Colombo 1995; Macaulay 1988). In the latter comparison there was statistical heterogeneity (I² = 73%) as one trial suggested no difference whereas the other favoured the anticholinergic. However, in one trial oxybutynin 15 mg daily was used (Colombo 1995) and in the other probantheline 45 mg daily was used (Macaulay 1988). Variation in anticholinergic efficacy could have contributed to this finding.

1.1 — Comparison 1 Anticholinergic drugs versus bladder training, Outcome 1 Numbers not cured at end of treatment (subjective).

1.2 — Comparison 1 Anticholinergic drugs versus bladder training, Outcome 2 Numbers not cured at follow up after treatment (subjective).

Data describing subjective improvement during treatment were available for all seven trials (346 participants), including three different anticholinergics. The trials favoured the anticholinergics in terms of number of participants not improved: 73/174 (42%) versus 98/172 (57%); this result was statistically significant (RR for number of people not improved 0.74, 95% CI 0.61 to 0.91; Analysis 1.3) (Collas 1994; Colombo 1995; Macaulay 1988; Milani 1987; Park 2002; Song 2006; Szonyi 1995).

1.3 — Comparison 1 Anticholinergic drugs versus bladder training, Outcome 3 Numbers not improved at end of treatment (subjective).

There were no useable data regarding whether this improvement continued after stopping treatment. Song et al (Song 2006) reported no change in nocturia between an anticholinergic and bladder training after treatment stopped.

Quantification of symptoms

Two trials (Macaulay 1988; Song 2006) reported frequency of micturition. There was no statistical difference between the two groups for number of micturitions per 24 hours (Analysis 1.10), but the trials were small.

1.10 — Comparison 1 Anticholinergic drugs versus bladder training, Outcome 10 Number of micturitions per 24 hours.

Quality of life and economic outcome

There were no data describing quality of life or economic outcomes.

Adverse events and withdrawals

Four trials (Colombo 1995; Milani 1987; Park 2002; Song 2006) reported this outcome and found more adverse events in the anticholinergic groups: overall 51/132 (39%) versus 2/126 (2%) (RR 14.50, 95% CI 5.02 to 41.87; Analysis 1.19). Data on withdrawals from treatment were available from two trials (Colombo 1995; Song 2006): 5/74 in the anticholinergic group compared with 2/65 in the bladder training group withdrew from treatment (RR 1.98, 95% CI 0.46 to 8.50. Analysis 1.20).

1.19 — Comparison 1 Anticholinergic drugs versus bladder training, Outcome 19 Numbers experiencing adverse events.

1.20 — Comparison 1 Anticholinergic drugs versus bladder training, Outcome 20 Numbers withdrawing from treatment.

Long term outcome

No data were reported describing the long term outcome, although bladder training might be expected to continue to be effective after stopping instruction sessions.

Comparison 2: anticholinergic drugs versus pelvic floor muscle training (PFMT) alone

No eligible trials were identified.

Comparison 3: anticholinergic drugs versus external electrostimulation

Seven trials addressed this comparison (Ozdedeli 2010; Peters 2009; Smith 1996; Soomro 2001 #; Svihra 2002; Wang 2006; Wise 1993) but the Wise trial did not report usable data.

Four trials used different classes or doses of anticholinergics versus intravaginal electrical stimulation (Ozdedeli 2010; Smith 1996; Wang 2006; Wise 1993).
One trial used oxybutynin (dose range 2.5 mg twice daily to 5 mg three times a day) versus transcutaneous electrical nerve stimulation (TENS) (Soomro 2001 #). This was a cross‐over trial and the data could not be entered into the analysis.
One trial used oxybutynin 5 mg three times daily versus Stoller Afferent Nerve Stimulation System neuromodulation (Svihra 2002).
One trial used extended release tolterodine 4mg versus percutaneous tibial nerve stimulation (PTNS) (Peters 2009).

Participants' observations

Data from three trials compared the number of people subjectively not cured at the end of the treatment period (Peters 2009; Smith 1996; Wang 2006). There was no statistical difference between anticholinergic drugs and electrostimulation (RR 0.94, 95% CI 0.84 to 1.05; Analysis 3.1). One trial (Peters 2009) compared the number of people objectively not cured, showing no statistically significant difference between the two groups (RR 1.00, 95% CI 0.91 to 1.1; Analysis 3.2).

3.1 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 1 Numbers not cured at end of treatment (subjective).

3.2 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 2 Numbers not cured at end of treatment (objective).

The combined data from three trials for number of people not improved at the end of the treatment period favoured the electrical stimulation group (RR 1.64, 95% CI 1.15 to 2.34; Analysis 3.3). The three trials compared different types of anticholinergic drugs (oxybutynin, probantheline and extended release tolterodine) with different types of electrostimulation: intravaginal (Smith 1996; Wang 2006) or PTNS (Peters 2009). This result is driven mainly by the result of the slightly larger Peters trial comparing extended release tolterodine against PTNS and demonstrating a statistically significant difference favouring PTNS.

3.3 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 3 Numbers not improved end of treatment (subjective).

However, the Peters trial (Peters 2009) did not find a statistically significant difference between the groups for number of people objectively not improved (Analysis 3.4) or for for nocturia (Analysis 3.5).

3.4 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 4 Numbers not improved end of treatment treatment (objective).

3.5 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 5 Nocturia.

Quantification of symptoms

The Peters trial (Peters 2009) found no statistically significant differences between extended release tolterodine and PTNS for number of micturitions per day (Analysis 3.6), sensation of urgency (Analysis 3.8) and the number of incontinence episodes per day (Analysis 3.9). One study reported there were no statistically significant differences between the groups in terms of number of pad changes per day comparing propantheline and intravaginal electrical stimulation ('Other data' Analysis 3.7) (Smith 1996).

3.6 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 6 Number of micturitions per day.

3.8 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 8 Sensation of urgency.

3.9 — Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 9 Number of incontinence episodes per day.

3.7. Analysis.

Comparison 3 Anticholinergic drugs versus external electrostimulation, Outcome 7 Number of pad changes per day‐IVS.

Number of pad changes per day‐IVS
Study	Anticholinergic	Electric stimulation
Smith 1996	8.1, range 0‐16	6.5, range 0‐18

Number of micturitions per day
Study	Trospium hydrochloride 45mg Median (Range)	Intravaginal Electrical Stimulation Median (Range)
Ozdedeli 2010	6 (3.3‐14.7) week 6 (17 participants)	7 (0.6‐15) week 6 (18 participants)

Number of micturitions per day
Study	Antichol. + BT	BT ALONE	Average SD
percentage change from baseline
Park 2002	30.3%	32.6%	27.1%

Sensation of urgency
Study	Antichol + BT	Antichol. + BT
percentage change from baseline
Park 2002	63.2%	48.4%

Number of incontinence episodes per day
Study	Anticholinergic + behavioural	Anticholinergic alone
Percentage change from baseline
Mattiasson 2003	87%	81%

Date	Event	Description
13 November 2012	New citation required and conclusions have changed	Nine new studies added
13 November 2012	New search has been performed	9 new studies added: Burgio 2008; Burgio 2010; Chancellor 2008; Kaya 2011; Mattiasson 2009; Ozdedeli 2010; Peters 2009; Song 2006; Wang 2006
12 September 2008	Amended	Converted to new review format.
22 August 2006	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Numbers not cured at end of treatment (subjective)	2	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.26, 1.04]
1.1 Oxybutinin	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.02, 1.39]
1.2 Probantheline 45mg daily	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.34, 1.49]
2 Numbers not cured at follow up after treatment (subjective)	2	56	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.16, 2.21]
2.1 Oxybutinin	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.45, 2.78]
2.2 Probantheline 45mg daily	1	29	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.10, 0.83]
3 Numbers not improved at end of treatment (subjective)	7	346	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.61, 0.91]
3.1 Oxybutynin 5mg daily	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.29, 0.84]
3.2 Oxybutynin 15mg daily	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.05, 4.53]
3.3 Oxybutynin 45mg daily	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.62, 1.07]
3.4 Probantheline 45mg daily	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.74, 1.32]
3.5 Tolterodine 4mg daily	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.53, 1.27]
4 Numbers not improved at follow up after treatment (subjective)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Numbers with nocturia at end of treatment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Numbers with nocturia at follow up after treatment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Number of pad changes per 24hrs	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8 Number of incontinence episodes per 24 hours	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Mean weight of urine loss on pad test	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Number of micturitions per 24 hours	2	87	Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐2.87, 2.45]
10.1 Probantheline 45mg daily	1	29	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐3.29, 3.49]
10.2 Tolterodine	1	58	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐4.99, 3.59]
11 Frequency of sensation of urgency	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Numbers not cured within first year (objective)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Numbers not cured after first year (objective)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Number not cured after 5 years (objective)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Urodynamic diagnosed detrusor overactivity	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 General health status (SF‐36)	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Condition‐specific health measures	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Socioeconomic measures	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Numbers experiencing adverse events	4	258	Risk Ratio (M‐H, Fixed, 95% CI)	14.50 [5.02, 41.87]
19.1 Oxybutynin 15mg daily	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	9.24 [2.30, 37.12]
19.2 Oxybutynin 45mg daily	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	28.26 [1.75, 457.09]
19.3 Tolterodine 4mg daily	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	17.76 [2.43, 129.70]
20 Numbers withdrawing from treatment	2	139	Risk Ratio (M‐H, Fixed, 95% CI)	1.98 [0.46, 8.50]
20.1 Oxybutynin 15mg daily	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [0.36, 9.58]
20.2 Tolterodine 4mg daily	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	2.45 [0.10, 57.85]
21 Numbers changing dose of treatment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
22 Other outcomes	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Numbers not cured at end of treatment (subjective)	3	171	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.84, 1.05]
1.1 Oxybutinin 2.5 mg tds vs Intravaginal stimulation	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.88, 1.36]
1.2 Probantheline vs Intravaginal stimulation	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.39, 1.06]
1.3 E R Tolterodine 4mg vs PTNS	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.90, 1.06]
2 Numbers not cured at end of treatment (objective)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.1 E R Tolterodine 4mg vs PTNS	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Numbers not improved end of treatment (subjective)	3	171	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.15, 2.34]
3.1 Oxybutinin 2.5 mg tds vs Intravaginal stimulation	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.82, 2.60]
3.2 Probantheline vs Intravaginal stimulation	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	1.3 [0.74, 2.28]
3.3 E R Tolterodine 4mg vs PTNS	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	2.21 [1.13, 4.33]
4 Numbers not improved end of treatment treatment (objective)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.1 E R Tolterodine 4mg vs PTNS	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Nocturia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1 E R Tolterodine 4mg vs PTNS	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Number of micturitions per day	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.1 E R Tolterodine 4mg vs PTNS	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Number of pad changes per day‐IVS			Other data	No numeric data
8 Sensation of urgency	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.1 E R Tolterodine 4mg vs PTNS	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Number of incontinence episodes per day	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.1 E R Tolterodine 4mg vs PTNS	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Number of micturitions per day			Other data	No numeric data
11 Sensation of urgency			Other data	No numeric data
12 Number of incontinence episodes per day			Other data	No numeric data
13 Numbers experiencing adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
13.1 Trospium HCl versus intravaginal electrical stimulation	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Numbers withdrawing from treatment	2	149	Risk Ratio (M‐H, Fixed, 95% CI)	2.92 [0.48, 17.80]
14.1 Oxybutinin 2.5 mg tds vs Intravaginal stimulation	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	2.88 [0.32, 25.92]
14.2 E R Tolterodine 4mg vs PTNS	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 71.89]
15 Quality of Life	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
15.1 E R Tolterodine 4mg vs PTNS	1		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 Numbers not cured end of treatment (subjective)	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.75, 1.16]
1.1 Oxybutynin 5mg daily +Bladder Training vs. Bladder Training	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.75, 1.16]
2 Numbers not improved end of treatment (subjective)	3	164	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.38, 0.88]
2.1 Tolterodine 4mg daily +Bladder Training vs.Bladder Training	2	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.38, 1.02]
2.2 Oxybutynin 5mg daily + Bladder Training vs. Bladder Training	1	57	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.21, 1.08]
3 Number of micturitions per day			Other data	No numeric data
3.1 percentage change from baseline			Other data	No numeric data
4 Sensation of urgency			Other data	No numeric data
4.1 percentage change from baseline			Other data	No numeric data
5 Numbers experiencing adverse events	2	107	Risk Ratio (M‐H, Fixed, 95% CI)	17.57 [2.43, 127.09]
5.1 Tolterodine 4mg daily +Bladder Training vs.Bladder Training	2	107	Risk Ratio (M‐H, Fixed, 95% CI)	17.57 [2.43, 127.09]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Numbers not cured at follow up after treatment (objective)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.1 Anticholinergic and behavioural modification therapy vs. Anticholinergic	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Numbers not improved end of treatment (subjective)	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 Tolterodine + Bladder training vs. Tolterodine	3	602	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.62, 1.04]
2.2 Tolterodine + PFMT vs. Tolterodine	1	475	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.85, 1.94]
2.3 Anticholinergic and behavioural modification therapy vs. Anticholinergic	2	364	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.36, 0.95]
3 Numbers with nocturia end of treatment	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Darifenacin and behavioural modification therapy vs. Darifenacin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Trospium chloride + Inferential current therapy + pelvic floor exercises + Bladder training vs. Trospium chloride	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Number of micturitions per 24 hours	6		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1 Solifenacin + Bladder training vs. Solifenacin	1	602	Mean Difference (IV, Random, 95% CI)	‐0.69 [‐1.11, ‐0.27]
4.2 Tolterodine + PFMT vs. Tolterodine	1	475	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.87, 0.97]
4.3 Anticholinergic and behavioural modification therapy vs. Anticholinergic	3	705	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.98, 0.50]
4.4 Anticholinergic and Inferential current therapy + pelvic floor exercises + Bladder training vs.Anticholinergic .	1	30	Mean Difference (IV, Random, 95% CI)	‐2.0 [‐3.88, ‐0.12]
5 Frequency of sensation of urgency	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.1 Anticholinergic + Bladder training vs. Anticholinergic	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Tolterodine 4mg + PFMT vs tolterodine alone	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Anticholinergic and behavioural modification therapy vs. Anticholinergic	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Number of pad changes per day	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.1 Anticholinergic + Bladder training vs. Anticholinergic	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Anticholinergic and behavioural modification therapy vs. Anticholinergic	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Number of incontinence episodes per 24 hours	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1 Anticholinergic + Bladder training vs. Anticholinergic	1	602	Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.42, 0.12]
7.2 Anticholinergic + PFMT vs. Anticholinergic	1	475	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.12, 0.72]
7.3 Anticholinergic vs.Anticholinergic and Behavioural modification therapy	2	438	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.47, 0.35]
7.4 Anticholinergic and Inferential current therapy + pelvic floor exercises + Bladder training vs.Anticholinergic .	1	30	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐2.12, 0.12]
8 Numbers experiencing adverse events	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.1 Anticholinergic + Bladder training vs. Anticholinergic	4	1257	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.88, 1.07]
9 Numbers withdrawing from treatment	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 Anticholinergic + Bladder training vs. Anticholinergic	2	706	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.44, 1.53]
9.2 Anticholinergic and behavioural modification therapy vs. Anticholinergic	1	395	Risk Ratio (M‐H, Random, 95% CI)	1.64 [0.93, 2.87]
10 Numbers changing dose of treatment	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.1 Anticholinergic + Bladder training vs. Anticholinergic	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Number of incontinence episodes per day			Other data	No numeric data
11.1 Percentage change from baseline			Other data	No numeric data
12 Quality of Life	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12.1 Anticholinergic + Bladder training vs. Anticholinergic	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Anticholinergic and Inferential current therapy + pelvic floor exercises + Bladder training vs.Anticholinergic .	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	RCT (double blinded between active drug and placebo)  ITT
Participants	n = 197  women  Inclusion: 55yrs of age or older, ambulatory, urge incontinence occurring at least twice per week for at least 3 months  Exclusion: continual leakage, postvoid residual urine volume more than 200mls, uterine prolapse past introitus, narrow‐angle glaucoma, unstable angina, decompensated congestive heart failure, history of malignant arrhythmias or impaired mental status  mean age 67.7 (SD 7.5)
Interventions	I ‐ (65) behavioural treatment: Visit 1 ‐ anorectal biofeedback used to help identify pelvic muscles and teach how to contract them while keeping abdominal muscles relaxed, Visit 2 ‐ teach how to respond adaptively to the sensation of urgency ("urge strategies"), participants were encouraged to pause, sit down if possible, relax the entire body and contract pelvic muscles repeatedly to diminish urgency and inhibit detrusor contraction and prevent urine loss, when urgency subsides they proceed to the toilet at normal pace, Visit 3 ‐ Pelvic muscle biofeedback was repeated for subjects who had not achieved at least 50% reduction in frequency of accidents as documented on bladder diaries. Combined bladder‐sphincter biofeedback was used to teach patients how to contract pelvic muscles against increasing volumes of fluid and during detrusor contraction, Visit 4 ‐ a review process "fine‐tune" home practice and encourage persistence: this include 45 pelvic muscle exercises every day (15 exercises 3 times per day). Patients were advised to practice in various positions, including lying, sitting and standing and also during activities. Finally patients were instructed to practice interrupting or slowing urinary stream during voiding once per day  II ‐ (67) oxybutynin (2.5mg tds)  III ‐ (65) placebo  Duration: 8 weeks
Outcomes	Numbers not cured (subjective): I: 44/63, II: 50/65  Numbers not improved (subjective): I: 6/63, II: 15/65  Incontinence episode/24hours ‐ mean (SD): I: 0.40 (0.67), n = 63, II: 0.81 (1.40), n = 65 Adverse outcomes: dry mouth I: 23/63 (34.9%), II: 65/65 (96.9%), III: 36/62 (54.8%), inability to void I: 4/63 (6.3%), II: 14/65 (21.5%), III: 2/62 (3.2%), constipation I: 14/63 (22.2%), II: 25/65 (38.5%), III: 23/62 (37.1%), blurred vision I: 6/63 (9.5%), II: 10/65 (15.4%), III: 6/62 (9.7%), confusion I: 4/63 (6.3%), II: 5/65 (7.7%), III: 7/62 (11.3%)
Notes	Ref ID: 5719  Combination (behavioural) treatment versus anticholinergic (oxybutynin)  Full publication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was performed with computer‐generated random numbers using a block size of 6
Allocation concealment (selection bias)	Unclear risk	Unclear from the methodology
Blinding (performance bias and detection bias)   All outcomes	Low risk	Assignment to drug treatment or the placebo control condition was double blinded
Incomplete outcome data (attrition bias)   All outcomes	High risk	After 8 weeks 169 out of 197 participants completed the study

Study	Reason for exclusion
Castleden 1986 #	This is a dose escalation study and comparison against placebo only and there is no non‐drug therapeutic arm
Enzelsberger 1991	Emepronium bromide is a tricyclic antidepressant
Gelber 1997	Study population: neuropathic bladder following stroke, with normal urodynamics
Goode 2011	This was a part of BE‐DRI study and the objective was find factors that influence patient satisfaction
Henalla 1989	Terodiline withdrawn from worldwide market because of serious cardiotoxicity
Henalla 1991	Terodiline withdrawn from worldwide market because of serious cardiotoxicity
Jarvis 1981	No good evidence of efficacy for flavoxate, and not recommended by WHO and is not in regular use anymore
Kelleher 1994	Not electric stimulation
Kim 2008	Objective of the study was to assess bladder training versus combination of propiverine + bladder training for urinary frequency not OAB
Klarskov 1981	Terodiline withdrawn from worldwide market because of serious cardiotoxicity
Klarskov 1986	Terodiline withdrawn from worldwide market because of serious cardiotoxicity
Koonings 1987	Mixed urinary incontinence not relevant comparing surgery for SUI component versus surgery and anticholinergics
Koonings 1988	Mixed urinary incontinence not relevant comparing surgery for sui component versus surgery and anticholinergics
Locher 2002	Not a treatment trial testing anticholinergics but "to assess the effects of age and patients' attribution of incontinence to aging on health‐behaviours associated with incontinence"
MacDiarmid 2010a	Not compared with anticholinergics
Osman 2003	Not OAB
Ouslander 1987	Assessement of habit training in functionally impaired nursing home patients (dementia)
Ouslander 1988	Assessement of habit training in functionally impaired nursing home patients (dementia)
Ouslander 1995 #	Prompted voiding is not bladder training and not part of our study protocol
Pennisi 1994	Not RCT, only address urinary stress Incontinence
Peters 2010	Not compared with anticholinergics
Visco 2011	RCT comparing anticholinergics and Botilinum toxin. However study data is expected in mid‐2012
Weil 1995	No anticholinergic arm
Weil 2000	No anticholinergic arm
Wise 1992	Not confirmed to have been randomised
Wiseman 1990	Terodiline withdrawn from worldwide market because of serious cardiotoxicity
Wiseman 1991	Terodiline withdrawn from worldwide market because of serious cardiotoxicity

Methods	Two stage multicentre randomised controlled trial 9 university based clinical centres in the US n = 307
Participants	Community dwelling women with urge‐predominant incontinence. Most had symptoms of stress incontinence
Interventions	Stage 1: drug therapy versus drug therapy + behavioural therapy for 10 weeks Stage 2: discontinuation of both drug and behavioral training sessions at end of stage 1. Instructed participants receiving combination therapy to continue their behavioural program after discontinuation of drug therapy. Participants were provided with a 2 month supply of the drug at no cost if they requested to resume drug therapy and did not have a urinary tract infection. Presented option of free drugs only after a patient requested to resume drug therapy. Follow‐up at 8 months Drug used ‐ extended release tolterodine tartrate at a dose of 4 mg per day. If not well tolerated, the dose could be decreased to 2 mg or another antimuscarinic medication could be substituted Behavioural therapy consisted of pelvic floor muscle training (using vaginal palpation); behavioural strategies to diminish urgency, suppress bladder contractions, and prevent both stress and urge incontinence; delayed voiding to increase voiding intervals for those who voided more than 8 times per day; and individualised fluid management for those with excessive urine output (>70oz/day)
Outcomes	Primary outcome at end of stage 2 (8 months) defined as not receiving drugs or any other therapy for urge incontinence and a 70% or greater reduction in frequency of incontinence episodes from baseline to end of stage 2 as recorded on the bladder diary Numbers not cured after stage 2 (at 8 months): 75 versus 78 Numbers not improved after stage 2 (at 8 months): 43 versus 85  Numbers not improved end of stage 1 (10 weeks treatment): 16 versus 35 Secondary outcomes (urgency and voids/day) were described in a second paper Improvement in score post‐treatment ‐ mean scores on the urgency severity scale decreased significantly from baseline to 10 weeks within both the drug alone and combined drug plus behavior groups, but the change between groups was not statistically significant, P = 0.30 Voids in 24 hours mean (SD) = 7.74 (2.45) n = 136 versus 6.94 (1.69) n = 133
Notes	The study was supported by grants from National Institute of Diabetes and Kidney Diseases, whose program staff were involved in the design and conduct of the study, analysis and interpretation of data, and preparation and review of manuscript. Additional support, including provision of study drugs and funding, was contributed by Pfizer, whose staff reviewed and commented on the manuscript but were not involved in other aspects of the research
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done at the coordinating centre through a web‐based automated randomisation system. A permuted block randomisation schedule, stratified by type of incontinence (urge only versus mixed), the number of incontinence episodes per week: 7 to 13 per week versus more than 14 per week
Allocation concealment (selection bias)	Low risk	Randomisation was done at the coordinating centre through a web‐based automated randomisation system. Clinical site ensured concealment of the allocation sequence*
Blinding (performance bias and detection bias)   All outcomes	Low risk	Open label, study staff who performed evaluations, but not participants and interventionists, were blinded to group assignment
Incomplete outcome data (attrition bias)   All outcomes	High risk	220 out of 307 completed assessment at the end of 8 months

Methods	RCT ITT
Participants	N = 64 Drug therapy = 32 Drug therapy plus behavioural therapy = 32 Community dwelling women with urge predominant incontinence
Interventions	Drug therapy versus drug therapy plus behavioural therapy (PFMT and urge suppression techniques) for 8 weeks (4 visits). Follow up at 6 and 12 months Drug used ‐ extended‐release oxybutynin (Individual dose titration between 5mg to 30mg) Behavioural therapy ‐ pelvic floor exercises and urge suppression techniques
Outcomes	1) Not improved during treatment = 3/31 versus 6/28 2) Incontinence episode/24hours for 8 weeks ‐ mean (SD) ‐0.40(0.93), N = 31 (drug therapy) versus mean (SD) ‐0.84 (2.14), n = 28 (drug therapy + behavioural therapy) 3) Number of micturitions/24hrs mean (SD) = 8.2 (1.9) versus 8.4 (3.0)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stratified blocked randomisation, stratified by age, type of incontinence and severity of incontinence. Method of generation not mentioned
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	Questionnaires were completed by subjects before the visit and collected in a sealed envelope to ensure the nurse was blinded to these outcomes. Because participants were aware that behavioral treatment was provided in 1 study arm and they could potentially seek such treatment on their own, they were asked at each visit about any contact with other healthcare providers, new medications and hospitalisations open label
Incomplete outcome data (attrition bias)   All outcomes	High risk	31 out of 32 in drug group completed at 8 weeks compared with 27 out of 32 in the combined group 28 out of 32 in drug group completed at 6 months compared with 25 out of 32 in the combined group 28 out of 32 in drug group completed at 12 months compared with 22 out of 32 in the combined group

Methods	Two site randomised controlled trial
Participants	143 community dwelling male veterans with over active bladder manifested by urgency and frequent urination, with or without urge incontinence
Interventions	Nurse practitioners implemented behavioural and drug therapies over period of 8 weeks. Behavioural consisted of pelvic floor muscle training, delayed voiding, monitoring with bladder diaries and urge suppression techniques Drug group individually titrated extended release oxybutynin 5 to 30 mg/d
Outcomes	Assessed at baseline and 2 weeks after the fourth and final treatment visit (8 weeks) Primary outcome ‐ post‐treatment 24 hour voiding frequency measured according to 7 day bladder diary. Also measured nocturia, urgency, incontinence Secondary outcomes ‐ Global Perception of Improvement
Notes	Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stratified according to voiding frequency and presence or absence of incontinence
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Research assistant blind to treatment group scored bladder diaries

Methods	Randomised, open label, parallel‐group, multicentre study ITT
Participants	n = 395 were randomised darifenacin alone = 190  darifenacin plus behavioural modification programme (BMP) = 205
Interventions	Darifenacin treatment (with voluntary up‐titration from 7.5 mg once daily to 15 mg once daily at week 2) alone versus combination with a Behavioural Modification Programme (BMP) for men and women with dry or wet OAB BMP comprised a simple regimen for which training could be given in a primary physicians office, including timed voiding, dietary modifications and Kegel‐type exercises, and was meant to reflect real life clinical practice. Complex regimens that would require a trained physical therapist were avoided as would not be practical in primary care
Outcomes	Change in the number (per day) of micturitions  Urge urinary incontinence (UUI) episodes Urgency episodes Pads used  Nocturnal voids Health related quality of life (HRQoL) Tolerability and safety assessments included adverse events and the number of discontinuations
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Validated, computer‐generated randomisation scheme used
Allocation concealment (selection bias)	Unclear risk	The randomisation scheme was reviewed by the sponsor's Quality Assurance group and locked after approval
Blinding (performance bias and detection bias)   All outcomes	High risk	Open label
Incomplete outcome data (attrition bias)   All outcomes	Low risk	173 out of 190 (91.1%) in drugs group completed compared with 175 out of 205 (85.4%). The proportion of patients discontinuing from the combination groups was higher (14.6% versus 8.9%)

Methods	RCT
Participants	n = 57  mean age 82 (72‐98 years)
Interventions	I (28) ‐ BT plus oxybutynin 2.5mg bd  II (29) ‐ BT plus placebo  Duration: 6 weeks
Outcomes	Numbers NOT improved during treatment: I: 6/28, II: 13/29
Notes	Oxybutynin versus BT  Abstract form, no details on methodology  poor quality  Ref ID: {7039}
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear from the methodology
Allocation concealment (selection bias)	Unclear risk	Unclear from the methodology
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the publication
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No mention in the publication

Methods	Randomised trial
Participants	n = 81 women, severe (socially embarrassing urge urinary incontinence)  Three patterns: detrusor instability, low compliance bladder and sensory bladder  Exclusion: stable bladder, neurological disease, detrusor hyper‐reflexia, age > 65yrs, coexisting GSI, genital prolapse, post‐void residual > 50mls, previous gynae or urogynae surgery, previous drug therapy for urge urinary incontinence, urethral diverticulae, fistulae, urinary tract neoplasm, bacterial or interstitial cystitis, calculi or previous radiotherapy  Mean age grp I 48yrs (31‐65), mean age grp II 49yrs (24‐65)
Interventions	I ‐ (14) oxybutynin orally 5 mgs tds  II ‐ (13) Bladder training: bladder training consisted of 6 weeks education, by simple but full explanation of the problem. At start of programme the maximum interval between two micturitions was identified and the patients were encouraged to initially hold their urine until this interval plus 30min had elapsed. Afterwards the women were asked to progressively increase the interval by 30min every 4 or 5 days. The goal was to achieve a delay between voids by up to 3 or 4 hours  Duration: 6 weeks follow up at 6mths after end of study  Cure was defined as reporting of total disappearance of urge incontinence and did not require protective pads or further therapies  Clinical improvement was established when urge incontinence was subjectively less troublesome but the patient still wore protective pads and required further therapies  All other cases were regarded as clinical failures
Outcomes	Numbers not cured during treatment: I: 1/14, II: 2/13  Numbes not cured after treatment (at 6 months follow up): I: 5/14, II: 0/13  Numbers not improved during treatment: I: 14/14, II:10/13 Adverse events: dry mouth, constipation, nausea, dizziness, decrease in visual acuity and tachycardia.  Numbers experiencing adverse events: I: 18/38, II: 2/39  Numbers withdrawn: I: 4/42, II: 2/39 (reasons for withdrawal: I: dry mouth x3, glaucoma x1, II: patient claimed treatment was time consuming) these cases we excluded from final analysis
Notes	Ref ID {6056}  anticholinergic (oxybutynin) versus bladder training  not clear in cure definition what authors meant by not needing further therapies (e.g. no need for second line treatment)  Gave clinical results in subsets i.e. DI, low compliance and sensory urgency but not the same break down in cystometry results
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random assignment
Allocation concealment (selection bias)	Unclear risk	Unclear from the methodology
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in paper
Incomplete outcome data (attrition bias)   All outcomes	High risk	The treatment was discontinued in 6 cases (4 in the drug group because of side effects and 2 in bladder training because the patient claimed it was time consuming

Methods	RCT
Participants	N = 46 Women admitted to Dept of Obstetrics and Gynaecology with idiopathic detrusor overactivity
Interventions	A: Trospium chloride 15mg three times a day (N = 14) B: Physiotherapy (N = 15) C: Trospium chloride 15mg three times a day + physiotherapy (N = 16) Physiotherapy = bladder training + pelvic floor exercises + inferential therapy
Outcomes	Number of voids/day (mean (SD) = 8.9 (2.8) versus 6.7 (3.8) versus 6.9 (2.4) Nocturia before treatment (mean (SD) = 2.9 (1.8) versus 2.7 (2.7) versus 2.8 (1.5) Nocturia after treatment (mean (SD) = 2.1 (1.8) versus 0.4 (0.9) versus 1.1 (0.9) Incontinence per day (mean (SD) = 1.5 (2.0) versus 0.1 (0.20) versus 0.5 (0.8) QoL score (mean (SD) = 26.3 (19.5) versus 12.6 (15.1) versus 10.1 (12.2) Adverse effect: dry mouth was the most reported side effect (7/31, 22.58%) in the pharmacotherapy and combined therapy groups, 1 patient in the pharmacotherapy group withdrew from the study because of visual impairment
Notes	Turkey
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated block randomisation list created by a statistician
Allocation concealment (selection bias)	Unclear risk	No mention
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in paper
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Only one patient in the pharmacotherapy group did not complete the study. All outcomes reported

Methods	Multicentre  RCT  ITT
Participants	n = 501  Inclusion: women and men, > 18yrs age,  urinary frequency > 8 x day and urgency (with or without urge urinary incontinence)  Exclusion: any contraindication to antimuscarinics, electrotherapy or bladder training in last 3 months, catheterised patients or those using CISC, pregnancy or lactation, already on anticholinergic therapy or concomitant treatment for OAB (except oestrogen replacement included)
Interventions	I (244) Tolterodine 2mg bd with bladder retraining. mean age grp I 62 yrs (range 19‐86)  II ‐ (257) Tolterodine 2mg bd mean age group II 63 (range 22‐86)  Duration: 24 weeks
Outcomes	Numbers not improved: I: 57/239, II: 73/250  Number of Incontinence episodes/day ‐ median % change (Interqurtile range): I: ‐87 (‐100, ‐20), II: ‐81 (‐100, ‐41.8), P = 028  Number of micturitions/day ‐ median % change (interquartile range): I: ‐33 (‐42.3, 21.3), II: ‐25 (p38.8, ‐13.0), P<0.001  Adverse events: I: 158/244, II: 177/257 (dry mouth, headache and constipation)
Notes	Ref ID {pending}  Tolterodine versus tolterodine + bladder training  Withdrawals not stated  No usable data
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	Low risk	391 patients (78%) completed 24 weeks of treatment, and completion rates were comparable for the two groups (tolterodine + BT, 77%; tolterodine alone, 79%). The main reasons for withdrawal were: adverse events (15%), lack of efficacy (3%), withdrawal of consent (2%), and protocol violations (1%). The two treatment groups were comparable in terms of the reasons for withdrawal, and 74% of patients in each treatment group were compliant in taking their medication throughout the study

Methods	Multicentre, prospective, randomized, parallel‐group, open label study
Participants	N = 643 Men or women over 18 with OAB
Interventions	Flexible‐dose solifenacin 5/10 mg (323 participants) versus solifenacin + simplified bladder training (320 participants) At week 8, patients in both groups could request a dose increase to solifenacin 10 mg od for the remaining 8 weeks of the study
Outcomes	At 8 weeks using solifenacin 5 mg Mean number of micturitions/24h after 8 weeks = 9.32 versus 8.60 Change from baseline in micturitions/24h from baseline = ‐2.18 versus ‐2.87 Change from baseline in urgency from baseline = ‐1.99 versus ‐1.98 Change from baseline in urge incontinence episodes from baseline = ‐1.01 versus ‐1.16 Change in number of pads/24 from baseline = ‐1.19 versus ‐1.07 Change in patient perception of bladder condition from baseline = ‐1.24 versus ‐1.23 Change in treatment satisfaction VAS from baseline = 3.32 versus 3.50 Change in I‐QOL scores from baseline = 20.65 versus 19.68 At 16 weeks using solifenacin 5/10mg Mean number of micturitions/24h after 8 weeks = 9.32 versus 8.60 (SD not given) Change from baseline in micturitions/24h from baseline = ‐2.42 versus ‐3.11 Change from baseline in urgency from baseline = ‐2.20 versus ‐2.50 Change from baseline in urge incontinence episodes from baseline = ‐1.13 versus ‐1.38 Change in number of pads/24 from baseline = ‐1.29 versus ‐1.11 Change in patient perception of bladder condition from baseline = ‐1.58 versus ‐1.63 Change in treatment satisfaction VAS from baseline = 3.72 versus 4.18 Change in I‐QOL scores from baseline = 24.51 versus 25.34 Adverse effects solifenacin n = 323 versus solifenacin +simplified bladder training n = 320 Number experiencing adverse effects = 150 versus 149  Number withdrawing from treatment or trial arm = 19 versus 15 Number changing dose of treatment = 137 versus 125
Notes	81 centres in 16 countries in Europe and Australia
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the paper
Allocation concealment (selection bias)	Unclear risk	No mention in the paper
Blinding (performance bias and detection bias)   All outcomes	High risk	Open label. Investigator or research nurse reviewed the bladder diaries with the patient to ensure accuracy of completion
Incomplete outcome data (attrition bias)   All outcomes	High risk	"Full analysis set included all patients randomised at baseline who took one or more doses of study medication and who provided primary efficacy data at baseline and week 4 or 8". Safety population included all patients who took at least one dose of study medication

Methods	Randomised trial of idiopathic urge syndrome
Participants	n = 81 women with idiopathic urge syndrome  Exclusions; women >65, previous pelvic radiotherapy, pelvic masses or malignancy, urinary tract or renal pathology, central nervous system disease, 2nd or 3rd degree genital prolapse
Interventions	I ‐ (37) bladder retraining BR  II ‐ (38) oxybutynin 15mgs tds  Duration: 4 weeks for oxybutynin. 12 weeks for bladder re‐training
Outcomes	Numbers NOT cured during treatment: I: 10/37, II: 10/38  Numbers NOT improved during treatment: I: 30/37 II: 25/38  Numbers NOT cured after treatment: I: 13/37, II: 22/38  Adverse events: I: 0/37, II: 14/38 (dryness of mouth)
Notes	Ref ID {9033}  Oxybutynin versus bladder training  Abstract form
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the methods
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	High risk	6 patients discontinued from the study (4 in the drug group because of side effects and 2 in bladder training because the patient claimed it was time consuming)

PERMALINK

Anticholinergic drugs versus non‐drug active therapies for non‐neurogenic overactive bladder syndrome in adults

Bhavan Prasad Rai

June D Cody

Ammar Alhasso

Laurence Stewart

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

Comparators

How the intervention might work

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

A. Participants' observations

B. Quantification of symptoms

C. Clinician's observations

D. Quality of life

E. Socioeconomic measures

F. Adverse events

G. Other outcomes

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

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

Results

Description of studies

Results of the search

1.

Included studies

Comparisons

Participants

Follow up

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Effects of interventions

Comparison 1: anticholinergic drugs versus bladder training (BT)

Participants' observations

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

Quantification of symptoms

1.10. Analysis.

Quality of life and economic outcome

Adverse events and withdrawals

1.19. Analysis.

1.20. Analysis.

Long term outcome

Comparison 2: anticholinergic drugs versus pelvic floor muscle training (PFMT) alone

Comparison 3: anticholinergic drugs versus external electrostimulation

Participants' observations

3.1. Analysis.

3.2. Analysis.

3.3. Analysis.

Methods	RCT
Participants	Females with OAB N = 35
Interventions	Trospium hydrochloride 45mg versus intravaginal electrical stimulation
Outcomes	Frequency of sensation of urgency/day at 6th week ‐ median (range) 2.7 (0‐8.0) versus 1.7 (0‐13.0) Number of incontinence episodes/day at 6th weeks ‐ 1 (0‐5) versus 0.3 (0‐9) Number of micturitions/day at 6th week ‐ 6 (3.3‐14.7) versus 7 (0.6 ‐15) IIQ‐7 at 18th week ‐ 51.2 (4.8‐68.1) versus 4.8 (0‐57.8) BDI at 18th week ‐ 10 (5‐40) versus 9.0 (6‐18)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The researcher randomised each patient into one of the two groups by opening sealed envelopes. The randomisation list was generated by a blinded researcher (the third author) using a table of random numbers
Allocation concealment (selection bias)	Low risk	The randomisation results were kept in sealed envelopes, one for each patient
Blinding (performance bias and detection bias)   All outcomes	High risk	There was no complete blindness in the study, since stimulation was applied by a separate researcher, while examination and data collection were carried out by a different researcher
Incomplete outcome data (attrition bias)   All outcomes	High risk	Two patients in Group 1 (one patient discontinued the study when all her complaints were resolved and one patient developed haematuria) and 2 patients in Group 2 (due to menorrhagia in 1 patient and vaginal pain after vaginal probe placement in 1 patient) could not complete the study

Methods	Randomised study
Participants	n = 74  women with overactive bladder  No exclusion criteria
Interventions	I (24): bladder training  II (24): tolterodine 2mg bd, orally  III (26): tolterodine 2 mg bd, orally + bladder training  Duration of study: 12 weeks Bladder training consisted of explanation of pelvic anatomy and physiology, bladder inhibition by Kegal exercises whenever she feels urgency and bi‐weekly phone calls from an expert nurse to confirm that patient is doing it well
Outcomes	Numbers not improved during treatment: I: 12/24, II: 10/24, III: 8/26  Adverse events: I: 0/24, II: 6/24, III: 7/26
Notes	Ref ID [pending]  tolterodine versus bladder training alone versus tolterodine + bladder training  Abstract form
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the methods
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Overall discontinuation numbers not given

Methods	Multicentre RCT
Participants	A total of 100 ambulatory adults with OAB symptoms,with or without a history of previous anticholinergic drug use, with at least 8 voids per 24 hours documented by history and physical and voiding diary were randomised to 1:1 to 12 weeks of treatment with weekly percutaneous tibial nerve stimulation or to 4 mg daily extended‐release tolterodine Exclusion criteria  1) OAB pharmacotherapy within the previous month  2) primary complaint of stress urinary incontinence 3) demonstrated sensitivity to tolterodine or its ingredients  4) pacemakers or implantable defibrillators 5) excessive bleeding, urinary or gastric retention, nerve damage or neuropathy 6) uncontrolled narrow angle glaucoma 7) positive urinalysis for infection 8) pregnancy, or current pregnancy or planning to become pregnant during the trial
Interventions	A (44): percutaneous tibial nerve stimulation (50) B (42): extended‐release tolterodine 4mg (40) for 12 weeks
Outcomes	Participant observation percutaneous tibial nerve stimulation (44) versus extended‐release tolterodine 4mg (42) for 12 weeks Cured total (%) ‐ 1 (2.3) versus 2 (4.8) Improved total (%) ‐ 34 (77.3) versus 21 (50.0) No improvement/worsening total (%) ‐ 9 (20.5) versus 19 (45.2)  Cured or improved total (%) 35 (79.5) versus 23 (54.8) Clinician observation percutaneous tibial nerve stimulation(44) versus extended‐release tolterodine 4mg (43) for 12 weeks Cured total (%) ‐ 2 (4.5) versus 2 (4.7) Improved total (%) ‐ 33 (75.0) versus 24 (55.8) No improvement/worsening total (%) ‐ 9 (20.5) versus 17 (39.5)  Cured or improved total (%) ‐ 35 (79.5) versus 26 (60.5) Voids/day No./Total No. (%) = 30/41 (73.2) versus 32/43 (74.4)  Nocturia No./Total No. (%) = 28/40 (70.0) versus 26/42 (61.0)  Urge incontinence No./Total No. (%) = 24/30 (80.0) versus 27/37 (73.0)  Moderate to severe urgency episodes/day No./Total No. (%) = 29/41 (70.7) versus 31/41 (75.6)  Voided vol (cc) No./Total No. (%) = 31/41 (75.6) versus 28/43 (65.1)
Notes	Multicentre: 11 centres in US
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random block design stratified, stratified by investigational site, generation sequence not mentioned. Randomised 1:1
Allocation concealment (selection bias)	Unclear risk	Randomisation was done at investigational site, however no mention of allocation concealment
Blinding (performance bias and detection bias)   All outcomes	High risk	Non‐blinded, bladder diary analysed by a biostatistician
Incomplete outcome data (attrition bias)   All outcomes	High risk	100 (50 in each group) adults were randomised. Of the patients who completed 12 weeks of therapy 41 receiving PTNS and 43 on tolterodine completed the voiding diary. Three patients in the drug group discontinued due to unsuccessful treatment

Methods	RCT  ITT
Participants	n = 38 females  Age: 24‐82 years  Inclusion: urinary incontinence  Exclusion: Type 3 stress incontinence; pregnancy suspected; history of prolonged urinary retention; vaginal vault prolapse; diminished sensory perception; cardiac pacemaker; mixed incontinence with major and minor component indistinguishable
Interventions	I (20): probantheline, 7.5 mg ‐ 45 mg bd ‐ tds, orally  II (18): electrical stimulation, twice daily for 4 months, 12.5 and 5 MHz frequency: the intravaginal electric stimulation system was approved by FDA, electric pulse generator by a 9 volt alkaline battery with a 12.5 HZ and 50Hz frequency. Compliance monitored by a built‐in digital readout on the number of hours used (patient not aware of it)  Duration of study: 4 months
Outcomes	Numbers not cured during treatment: I: 10/20, II: 14/18  Numbers not improved during treatment: I: 10/20, II: 9/18  Numbers of pad changes/day ‐ average (range): I: 8.1 (0‐16), II: 6.5 (0‐18)  Number of incontinence episodes/day ‐ average (range): I: 1.7 (0‐8), II: 1.4 (0‐8)
Notes	Ref ID {2900}  Anticholinergic (probantheline) versus electric stimulation (intravaginal)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the methods
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Only one patient did not complete the study

Methods	RCT
Participants	n = 139 Women with symptoms of urgency and frequency, with or without urge incontinence
Interventions	Bladder training versus tolterodine 2 mg twice daily versus combination of bladder training and tolterodine 2mg twice daily treatment for 12 weeks
Outcomes	Bladder training (26) versus tolterodine 2 mg twice daily (32) versus combination (31) Number not improved = 12 versus 12 versus 9 Number of voids per day N, mean (SD): 8.1 versus 8.1 versus 7.9 Nocturia before treatment = 1.5 versus 1.7 versus 1.2 Nocturia after treatment = 0.6 versus 0.6 versus 0.6 Number withdrawing from tolterodine versus combination treatment = 2/32 versus 2/31 Adverse effects: tolterodine total number (%) versus combination total number (%)   Dry mouth:7 (21.9%) versus 9 (28.9%)  Hesitancy: 3 (9.4%) versus 2 (6.5%)  Decreased appetite/constipation: 2 (6.3%) versus 2 (6.5%)  Headache: 1 (3.1%) versus 0
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Paper states 'randomly assigned' no mention of how this was done
Allocation concealment (selection bias)	Unclear risk	No mention in paper
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No blinding of participants or care providers, no mention of blinding of outcome assessor
Incomplete outcome data (attrition bias)   All outcomes	High risk	Bladder training group 26 out of 46 (56%) completed. Tolterodine 32 out of 47 (68%) completed. Combination therapy 31 out of 46 (67%) completed. Out of 139 patients 89 completed the 12 week regimen

Methods	RCT, ITT, cross‐over
Participants	n = 43  Age‐ mean 50 ± 15 years  Sex: F:M 30:13  Inclusion: patients with a history of frequency, urgency and urge incontinence who had not previously been treated at the department, including some who had previously received treatment from a general practitioner at least 6 months before  Exclusion: not specified
Interventions	I (43): oxybutynin, 2.5 mg BD, up to 5 mg TDS, orally  II (43): TENS, 20 HZ, 6 hours daily After 6 weeks of treatment in the first arm, patients were re‐assessed. Patients completed a post‐treatment side effects questionnaire. After a washout period of 2 weeks, patients were started on the second arm of treatment, and the same assessment was repeated after 6 weeks of treatment  Total duration of study: 14 weeks
Outcomes	Numbers not improved during treatment: I: 20/40, II: 20/38 Number of voids per day N, mean (SD): I 43, 9 (SD 5), II 43, 9 (SD 4), P≤0.003 compared with baseline of 43, 11 (SD 5) Number of incontinence episodes: "no statistical difference between treatment arms" Number of micturitions per day: "statistically significant (p< 0.0001)" compared with baseline QoL: "No statistical difference found in any of the parameters of SF‐36" Adverse events: dry mouth, blurred vision, dry skin and skin irritation
Notes	Ref ID [ pending]  Oxybutynin versus electric stimulation (TENS)  Cross‐over
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the methods
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All outcomes reported

Methods	Randomised trial  ITT
Participants	n = 28 females  Age, mean (range): 54 years (45‐63)  Inclusion: overactive bladder  Exclusion: bladder neck obstruction
Interventions	I ‐ (9) SANS, neuromodulation: modified non‐invasive SANS, using a surface electrode on the skin over the medial ankle and stimulated the tibial nerve with different values which cannot be set by the original SANS. Frequency of stimulation was 1Hz and duration of square impulse was 0.1ms. surface stimulation of 30min duration was repeated once a week for a period of 5 weeks  II ‐ (10) oxybutynin orally 5mg tds  III ‐ (9) control
Outcomes	Numbers not cured during treatment: I: 2/9, II: "comparable therapeutic results"  Numbers not improved during treatment: I: 7/9, II: "comparable therapeutic results"
Notes	Ref ID: {15769}  Results vague: actual data for the oxybutynin arm are not available,and only mention "comparable therapeutic results"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the methods
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Unclear

Methods	Randomized double blind  ITT
Participants	n = 60  Mean age (SD) 82.19 (6.96), range 72‐98 years  Inclusion: either sex, over 70, symptoms of urinary frequency, urgency and urge incontinence, mobile, able to attend opd, able to keep diary chart, willing to give consent  Exclusion: UTI at time of recruitment, severe hepatic or renal disease, glaucoma, uncontrolled diabetes, concomitant anticholinergics (imipramine/propantheline)  Patients in both groups well matched for age, sex (14:1 women:men), urodynamic characteristics
Interventions	I (30) placebo + BR  II (30) oxybutynin 2.5mg bd + BR  Duration: 57 days Bladder training: patients were asked to delay micturition for as long as possible whenever they experience the need to pass urine and to try by this means to reduce their frequency
Outcomes	Numbers not cured during treatment: I: 25/28, II: 20/24  Numbers not improved during treatment: I: 16/28, II: 7/24  Adverse events: dry mouth, blurred vision, heartburn, constipation, dry skin.  Poor compliance: I: 20%, II: 20%
Notes	Ref ID {2906}  anticholinergic (oxybutynin) + BR versus BR
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation was achieved by allocating tablets in random permutations of blocks of four patients at a time
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	One patient in the placebo group and two randomised to active treatment failed to attend the first review and so no data were available for analysis. Not all patients kept the diary charts as requested, but diary data were available for analysis from 28 patients on placebo and 24 patients on active treatment. Five patients on placebo withdrew early , Eight patients on oxybutynin withdrew early

Methods	Placebo‐controlled RCT
Participants	N = 68 Patients with OAB
Interventions	Intravaginal electrical stimulation (24 participants) versus oxybutynin 2.5mg without dose titration (23 participants) versus placebo (21 participants). 12 weeks duration
Outcomes	Number cured after treatment ES versus oxybutynin = 4 versus 2 Number improved after treatment ES versus oxybutynin = 10 versus 7 Number cured after treatment ES versus oxybutynin =10 versus 14 Number of micturitions/24 hrs = 7.8 versus 7.4 Frequency of urgency episodes after treatment = 1 versus 6 Mean urine volume after treatment = 355 versus 336 Number withdrawing due to dry mouth drug group = 3
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The allocation of the three groups was undertaken by sequentially opening of sealed envelope, prepared by the Biostatistics Center for Chang Gung Medical College in blocks of six
Allocation concealment (selection bias)	Low risk	The allocation of the three groups was undertaken by sequentially opening of sealed envelope, prepared by the Biostatistics Center for Chang Gung Medical College in blocks of six
Blinding (performance bias and detection bias)   All outcomes	Low risk	Physiotherpists conducted treatments unaware of the progress and outcome of the interventions. Patients receiving pharmacotherapy and investigators were unaware of regimen from central pharmacy whether active drug or placebo
Incomplete outcome data (attrition bias)   All outcomes	Low risk	6 patients dropout from the study, however all three groups had similar number of patients. All pre‐stated objectives reported

Methods	Randomised not placebo controlled
Participants	n = 60 women with urodynamically proven detrusor instability
Interventions	I ‐ (32) oxybutynin 5mg bd  II ‐ (28) intravaginal maximal electrical stimulation 20HZ frequency with variable current of 0‐90mA
Outcomes	Adverse events: I: 7/32, II: not specified  No usable data for interpretation
Notes	Ref ID {12049}  Anticholinergic (oxybutynin) versus electric stimulation (intravaginal electric stimulation), no detailed methodology  few actual figures /data listed  no exclusion criteria  Abstract form
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention in the methods
Allocation concealment (selection bias)	Unclear risk	No mention in the methods
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No mention in the methods
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No mention in the methods