HAY-SMITH - Which Anticholinergic Drug For Overactive Bladder Symptoms

Which anticholinergic drug for overactive bladder symptoms
in adults (Review)
Hay-Smith J, Ellis G, Herbison GP
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 1
http://www.thecochranelibrary.com
Which anticholinergic drug for overactive bladder symptoms in adults (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 1.1. Comparison 1 One anticholinergic versus another, Outcome 1 Cure/improvement. . . . . . . . 73
Analysis 1.2. Comparison 1 One anticholinergic versus another, Outcome 2 Leakage episodes in 24hrs. . . . . . 74
Analysis 1.3. Comparison 1 One anticholinergic versus another, Outcome 3 Change in leakage episodes in 24hrs. . 75
Analysis 1.4. Comparison 1 One anticholinergic versus another, Outcome 4 Micturitions in 24hrs. . . . . . . 76
Analysis 1.5. Comparison 1 One anticholinergic versus another, Outcome 5 Change in micturitions in 24 hrs. . . 77
Analysis 1.6. Comparison 1 One anticholinergic versus another, Outcome 6 Maximum cystometric capacity. . . . 78
Analysis 1.7. Comparison 1 One anticholinergic versus another, Outcome 7 Change in maximum cystometric capacity. 79
Analysis 1.9. Comparison 1 One anticholinergic versus another, Outcome 9 Change in volume at first contraction. . 80
Analysis 1.10. Comparison 1 One anticholinergic versus another, Outcome 10 Residual volume. . . . . . . . 81
Analysis 1.11. Comparison 1 One anticholinergic versus another, Outcome 11 Change in residual volume. . . . . 82
Analysis 1.12. Comparison 1 One anticholinergic versus another, Outcome 12 Withdrawals due to adverse events. . 83
Analysis 1.13. Comparison 1 One anticholinergic versus another, Outcome 13 Dry mouth. . . . . . . . . . 84
Analysis 2.1. Comparison 2 Different doses of tolterodine, Outcome 1 Cure/improvement. . . . . . . . . . 85
Analysis 2.3. Comparison 2 Different doses of tolterodine, Outcome 3 Change in leakage episodes per 24hrs. . . . 86
Analysis 2.5. Comparison 2 Different doses of tolterodine, Outcome 5 Change in number of micturitions per 24hrs. 87
Analysis 2.7. Comparison 2 Different doses of tolterodine, Outcome 7 Change in maximum cystometric capacity. . 88
Analysis 2.9. Comparison 2 Different doses of tolterodine, Outcome 9 Change in volume at first contraction. . . . 89
Analysis 2.11. Comparison 2 Different doses of tolterodine, Outcome 11 Change in residual volume. . . . . . . 90
Analysis 2.12. Comparison 2 Different doses of tolterodine, Outcome 12 Withdrawal due to adverse events. . . . 91
Analysis 2.13. Comparison 2 Different doses of tolterodine, Outcome 13 Dry mouth. . . . . . . . . . . . 92
Analysis 3.1. Comparison 3 Extended versus immediate release preparations, Outcome 1 Cure/improvement. . . . 93
Analysis 3.2. Comparison 3 Extended versus immediate release preparations, Outcome 2 Leakage episodes in 24hrs. 94
Analysis 3.3. Comparison 3 Extended versus immediate release preparations, Outcome 3 Change in leakage episodes per
24hrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Analysis 3.4. Comparison 3 Extended versus immediate release preparations, Outcome 4 Micturitions in 24 hrs. . . 96
Analysis 3.5. Comparison 3 Extended versus immediate release preparations, Outcome 5 Change in micturitions per
24hrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Analysis 3.6. Comparison 3 Extended versus immediate release preparations, Outcome 6 Maximum cystometric capacity. 98
Analysis 3.8. Comparison 3 Extended versus immediate release preparations, Outcome 8 Volume at first contraction. 99
Analysis 3.11. Comparison 3 Extended versus immediate release preparations, Outcome 11 Change in residual volume. 100
Analysis 3.12. Comparison 3 Extended versus immediate release preparations, Outcome 12 Withdrawal due to adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Analysis 3.13. Comparison 3 Extended versus immediate release preparations, Outcome 13 Dry mouth. . . . . . 102
Analysis 4.3. Comparison 4 One extended release preparation against another, Outcome 3 Change in leakage episodes in
24 hrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Analysis 4.5. Comparison 4 One extended release preparation against another, Outcome 5 Change in micturitions in 24
hrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Which anticholinergic drug for overactive bladder symptoms in adults (Review) i
Analysis 4.12. Comparison 4 One extended release preparation against another, Outcome 12 Withdrawals due to adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Analysis 4.13. Comparison 4 One extended release preparation against another, Outcome 13 Dry mouth. . . . . 104
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Which anticholinergic drug for overactive bladder symptoms in adults (Review) ii

[Intervention Review]
Which anticholinergic drug for overactive bladder symptoms

in adults
Jean Hay-Smith1 , Gaye Ellis2 , G Peter Herbison3

1
Rehabilitation Teaching and Research Unit, Department of Medicine, Wellington South, New Zealand. 2 Women’s and Children’s
Health, University of Otago, Dunedin, New Zealand. 3 Department of Preventive & Social Medicine, Dunedin School of Medicine,
University of Otago, Dunedin, New Zealand
Contact address: Jean Hay-Smith, Rehabilitation Teaching and Research Unit, Department of Medicine, Wellington School of Medicine
and Health Sciences, University of Otago, PO Box 7343, Wellington South, Wellington, New Zealand. jean.hay-smith@otago.ac.nz.
Editorial group: Cochrane Incontinence Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Review content assessed as up-to-date: 24 May 2005.
Citation: Hay-Smith J, Ellis G, Herbison GP. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane
Database of Systematic Reviews 2005, Issue 3. Art. No.: CD005429. DOI: 10.1002/14651858.CD005429.
ABSTRACT
Background
Around 16% to 45% of adults have overactive bladder symptoms (urgency with frequency and/or urge incontinence - ’overactive
bladder syndrome’). Anticholinergic drugs are common treatments.
Objectives
To compare the effects of different anticholinergic drugs for overactive bladder symptoms.
Search strategy
We searched the Cochrane Incontinence Group specialised trials register (searched 17 January 2002) and reference lists of relevant
articles. A search for full publications of abstracts identified in January 2002 was completed in July 2003.
Selection criteria
Randomised trials in adults with overactive bladder symptoms or detrusor overactivity that compared one anticholinergic drug with
another, or two doses of the same drug.
Data collection and analysis
Two authors independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane
Reviewers’ Handbook.
Main results
Forty nine trials, 39 parallel and 10 cross-over designs were included (11,332 adults). Most trials were described as double-blind, but
were variable in other aspects of quality. Crossover studies did not present data in a way that could be included in the meta-analysis.
Four trials collected quality of life data (the primary outcome measure) using validated measures; none reported useable data.
Oxybutynin versus tolterodine: There were no statistically significant differences for patient perceive improvement, leakage episodes or
voids in 24 hours, but fewer withdrawals due to adverse events (RR 0.57, 95% CI 0.43 to 0.75), and less risk of dry mouth (RR 0.60,
95% CI 0.54 to 0.66), with tolterodine.
Which anticholinergic drug for overactive bladder symptoms in adults (Review) 1
Different doses tolterodine: The usual recommended starting dose (2 mg twice daily) was compared with two lower (0.5 mg and 1 mg
twice daily), and one higher dose (4 mg twice daily). The effect of 1 mg, 2 mg and 4 mg doses was similar for leakage episodes and
micturitions in 24 hours, with greater risk of dry mouth with 2 and 4 mg doses.
Extended versus immediate release preparations of oxybutynin and/or tolterodine: There were no statistically significant differences
for cure/improvement, leakage episodes or micturitions in 24 hours, or withdrawals due to adverse events, but there were few data.
Overall, extended release preparations had less risk of dry mouth.
One extended release preparation versus another: There was less risk of dry mouth with oral extended release tolterodine than oxybutynin
(RR 0.75, 95% CI 0.59 to 0.95), but no difference between transdermal oxybutynin and oral extended release tolterodine although
some people withdrew due to skin reaction at the trandermal patch site.
Authors’ conclusions
Where the prescribing choice is between oral immediate release oxybutynin or tolterodine, tolterodine might be preferred for reduced
risk of dry mouth. With tolterodine, 2 mg twice daily is the usual starting dose, but a 1 mg twice daily dose might be equally effective
with less risk of dry mouth. If extended release preparations of oxybutynin or tolterodine are available, these might be preferred to
immediate release preparations because there is less risk of dry mouth. There is little or no evidence available about quality of life, costs,
or long-term outcome in these studies. There were insufficient data from trials of other anticholinergic drugs to draw any conclusions.
PLAIN LANGUAGE SUMMARY
Which anticholinergic drug for overactive bladder symptoms in adults
Many adults have symptoms of overactive bladder. A person with overactive bladder syndrome feels a very strong urge to pass urine,
and they may not make it to the toilet before they leak urine. Other common problems are a feeling of needing to urinate often during
the day and/or night. This problem seems to be caused by an overactive bladder muscle, and it becomes more common with age.
Treatments are conservative measures such as bladder training, or drugs. Anticholinergic drugs can reduce the overactivity of the bladder
muscle, and the feeling of urgency. The review found that there are several anticholinergic drugs prescribed for adults with overactive
bladder symptoms. The two most studied drugs are oxybutynin and tolterodine. These two drugs have similar effects, but on average
those taking oxybutynin were more likely to withdraw from the studies because of adverse effects, mainly dry mouth. However, both
drugs can give dry mouth, and this problem is less likely if an extended release formulation of either drug is used.
BACKGROUND
Urgency is the sudden and compelling desire to pass urine, which
is difficult to defer (Abrams 2002). Sometimes there is involuntary
leakage of urine with the feeling of urgency, and this is called urge
Overactive bladder syndrome incontinence. Urgency and urge incontinence usually result from
People with overactive bladder syndrome report urgency (with an involuntary increase in bladder pressure due to detrusor (blad-
or without urge incontinence), usually in combination with fre- der smooth muscle) over-activity. If further investigation of ur-
quency and/or nocturia (Abrams 2002). To be called overactive gency/urge incontinence with urodynamics demonstrates sponta-
bladder syndrome these symptoms cannot be caused by metabolic neous or provoked detrusor muscle contraction in the filling phase
problems such as diabetes, problems with the urinary tract such of the test then detrusor overactivity is diagnosed. If there is no
as urinary tract infection, or neurological diseases such as multi- defined cause for the overactivity this is called idiopathic detrusor
ple sclerosis. Overactive bladder syndrome may also be called urge overactivity, but if there is a relevant neurological condition then
syndrome or urgency-frequency syndrome. the term neurogenic detrusor overactivity (previously detrusor hy-
perreflexia) is used. M1 , M2 , and M3 subtypes are of interest in bladder activity. Mus-
Frequency is the complaint of needing to void too often during carinic receptors are found in other parts of the body too, e.g.
the day, while nocturia is waking once or more per night to void ( in the gut, salivary glands, tear ducts. Pharmacotherapy relies on
Abrams 2002). In clinical practice, a person who voids more than the use of drugs with anticholinergic properties. The rationale for
eight times during the day would be considered to have daytime using anticholinergic drugs in the treatment of overactive bladder
frequency; waking from sleep more than once at night to void syndrome is to block the parasympathetic acetylcholine pathway
would be considered nocturia. and thus abolish or reduce the intensity of detrusor muscle con-
Overactive bladder symptoms are very common in community traction. Unfortunately none of the anticholinergic drugs available
dwelling adults, with recent large studies showing prevalences of to date is specific to the muscarinic receptors in the bladder, and as
17% in Europe (Milsom 2001) and the USA (Stewart 2001), 31% a result the drugs can cause side effects by acting in other parts of
in Korea (Choo 2001) and 45% in Asian men (Moothy 2001). The the body too, e.g. dry mouth or eyes, constipation or nausea. For
Asian studies may have overestimated prevalence, because people the purpose of this review the term ’anticholinergic medications’
whose only symptom was frequency were counted as ’cases’ of will refer to both pure antimuscarinic drugs and antimuscarinic
overactive bladder. Several large population studies have reported drugs with mixed actions given specifically for bladder symptoms.
that the prevalence of overactive bladder symptoms increases with Drugs with mixed actions will be included where their clinical ef-
age in men and women (Brown 1999; Milsom 2001; Moller 2000; fect is thought to be antimuscarinic, rather than via direct action
Stewart 2001; Ueda 2000). Although the diagnosis of overactive on bladder muscle. Medications with secondary anticholinergic
bladder excludes people with known causes of detrusor overactiv- effects, e.g. tricyclic depressants will be excluded.
ity, e.g. neurological disorders, this combination of symptoms is The number of anticholinergic drugs available on the market
nevertheless common in such groups. In fact, urinary dysfunction is increasing and various studies, both observational and ran-
appears to be more common in the neurologically impaired than domised controlled trials, have evaluated effectiveness. A previous
unimpaired population; the most frequently reported problems Cochrane review compared anticholinergic drugs with no treat-
are urgency and/or frequency (Hennessey 1999). ment or placebo treatments (Hay-Smith 2003). While statisti-
Research on the amount of bother caused by overactive bladder cally significant, the differences between anticholinergic drugs and
syndrome, and the effect on quality of life, is only just beginning. placebo were small and of uncertain clinical significance, apart
However, it seems that frequency and/or urgency might be just from the rate of dry mouth which is a common side effect of an-
as bothersome as actual leakage (Milsom 2001), and overall the ticholinergic therapy.
effects of overactive bladder symptoms on quality of life are marked Despite this, anticholinergics are commonly used in primary and
(Jackson 1997). It also seems clear that many of the people affected secondary care settings for the treatment of overactive bladder syn-
by overactive bladder symptoms do not seek help from health care drome, and this has considerable resource implications (Kobelt
professionals (Milsom 2001; Ueda 2000). 1997). If anticholinergic therapy is prescribed, there is still un-
certainty about which anticholinergic drugs are most effective, at
which dose, and by which route of administration. There is also
Treatment of overactive bladder symptoms uncertainty about the role of anticholinergic drugs in different
patient groups (e.g. the elderly, male and female).
The two main treatment options for overactive bladder syndrome
There are many studies of the effects of anticholinergic drugs. Four
are bladder training and pharmacotherapy, i.e. drugs. A separate
Cochrane reviews will consider them. The present review com-
Cochrane review on bladder training (Wallace 2004) is available,
pares anticholinergic drugs with each other, to see whether dif-
and the scope of this review is confined to drug treatment.
ferent anticholinergic drugs have different effects. A previous re-
While the pathophysiology of the overactive bladder remains to
view compared anticholinergic drugs with no treatment or placebo
be fully elucidated, the two most widely accepted explanations
treatments (Hay-Smith 2003). Two further reviews will consider:
are the myogenic and neurogenic theories; these are not mutally
1) whether anticholinergic drugs are better than other active (non-
exclusive (Hashim 2004). In the first, partial denervation of the
drug) therapies (Patrick 2004); and 2) whether anticholinergic
detrusor muscle is thought to increase excitability. Changes in cen-
drugs are better than other drug treatments (Dublin 2004).
tral nervous system pathways that inhibit bladder activity, and/or
Two previous systematic reviews of anticholinergic drugs for urge
over-sensitivity of the sensory nerve endings in the bladder, are the
urinary incontinence were found (Haeusler 2002; Harvey 2001).
basis of the second. In both theories, the outcome is overactivity
Haeusler et al (Haeusler 2002) included only placebo controlled
of the detrusor muscle. The motor nerve supply to the bladder is
trials, and no comparisons of anticholinergic drugs. Harvey et al (
via the parasympathetic nervous system (via sacral nerves S2,3,4)
Harvey 2001) included trials that compared tolterodine and oxy-
(Abrams 1988; Ouslander 1982; Ouslander 1986), which affects
butynin; the review, using Cochrane methods, is now outdated be-
detrusor muscle contraction. This is mediated by acetylcholine
cause other relevant trials have been published. In addition, Har-
acting on muscarinic receptors at the level of the bladder. There
vey et al (Harvey 2001) did not include all possible anticholinergic
are currently five recognised subtypes of muscarinic receptor; the

drug comparisons. There is clearly a need for a regularly updated the following drugs were considered: emepronium bromide/car-
and comprehensive systematic review of the effectiveness of anti- rageenate, darifenacin, dicyclomine chloride, oxybutynin, propan-
cholinergic drugs, versus each other, in the management of adults theline bromide, propiverine, solifenacin (YM905), tolterodine,
with overactive bladder syndrome. and trospium chloride. Terodoline, an anticholinergic drug pre-
viously used in the treatment of overactive bladder, was excluded
because it was withdrawn from the market.
Other drugs with less direct anticholinergic effects were excluded,
OBJECTIVES e.g. smooth muscle relaxants (flavoxate hydrochloride, calcium
channel blockers, potassium channel openers, beta-adrenoceptor
To determine the effects of anticholinergic drugs in the treatment agonists, alpha-adrenoceptor antagonists, and prostaglandin syn-
of overactive bladder symptoms. thetase inhibitors) and tricyclic antidepressants.
The following comparisons were made:
1. A particular anticholinergic drug versus another in the manage- Types of outcome measures
ment of overactive bladder symptoms. The primary outcomes of interest were:
2. One route of anticholinergic drug administration versus another 1. Generic (e.g. Short Form 36) (Ware 1993) and condition spe-
(e.g. oral, transdermal, rectal, intravesical) cific quality of life (e.g. Incontinence Impact Questionnaire), for
example (Shumaker 1994), and psychosocial measures.
3. Higher doses of anticholinergic drugs versus lower doses. The secondary outcomes of interest were:
2. Patient’s observations e.g. symptom scores, perception of cure/
improvement, satisfaction with outcome.
METHODS 3. Quantification of symptoms e.g. number of leakage episodes,
frequency and volume (urinary diary).
4. Clinicians’ measures e.g. urodynamic measures (e.g. maximum
Criteria for considering studies for this review cystometric capacity), and clinical findings.
5. Socioeconomics - direct and indirect costs of interventions (for
patients and providers), resource implications of differences in
outcome, formal economic analysis (e.g. cost effectiveness, cost
Types of studies
utility), desire or need for further treatment.
All randomised or quasi randomised controlled trials of anticholin- 6. Other - e.g. adverse events, compliance measures, long term
ergic drugs for the treatment of overactive bladder symptoms or follow up and any other outcome not pre-specified but judged
detrusor overactivity. important when performing the review.
Types of participants
Search methods for identification of studies
All adult men and women with a symptomatic diagnosis of over-
active bladder syndrome, with or without a urodynamic diagnosis This review has drawn on the search strategy developed for
of detrusor overactivity. Although people with neurological disor- the Incontinence Review Group. Relevant trials were identi-
ders cannot, by definition, have overactive bladder syndrome they fied from the Cochrane Incontinence Group Specialised Reg-
often experience overactive bladder symptoms secondary to their ister of controlled trials, which is described under the Group’s
neurologic disease, and are offered anticholinergic drugs. There- details in The Cochrane Library (For more details please see the
fore, trials that recruited people with neurologic disorders com- ‘Specialized Register’ section of the
plaining of overactive bladder symptoms, and/or with a diagnosis Group’s module in The Cochrane Library). The register contains
of neurogenic detrusor overactivity, were included. trials identified from MEDLINE, CINAHL, the Cochrane Cen-
tral Register of Controlled Trials (CENTRAL) and handsearching
of journals and conference proceedings.
Types of interventions The date of the most recent search of the specialised register for
One arm of the study was allocated an anticholinergic drug and this review was: 17 January 2002.
at least one other arm used a different anticholinergic drug, an The trials in the Incontinence Group Specialised Register are also
anticholinergic drug given via a different route, or a different dose contained in the Cochrane Central Register of Controlled Trials
of the same anticholinergic drug. To be included the drug had to (CENTRAL).
be an anticholinergic/muscarinic antagonist, and be given for the The Incontinence Group Specialised Register was searched using
purpose of decreasing symptoms of overactive bladder. Trials of the Group’s own keyword system, the search terms used were:

topic.urine.incon* Data plots were examined for evidence of heterogeneity (dissim-
AND ilarity), and a formal (statistical) test of heterogeneity was used.
({design.cct*} OR {design.rct*}) Where heterogeneity was observed (based on I-squared and the
AND test for heterogeneity) an explanation was sought and offered in
({intvent.chem.drug.*}) the text. Where three or more trials contributed to a single data
Key: * = truncation symbol. plot, the data were reanalysed after removal of the trial(s) that were
(All searches were in the keywords field of Reference Manager 9.5 the apparent cause of the dissimilarity. The secondary analysis is
N, ISI ResearchSoft). reported in the text. Where clinically important (but not statisti-
The reference lists of relevant articles were searched for other pos- cally significant) heterogeneity was observed, this is also noted in
sible relevant trials. the text.
A further search (by first author, in MEDLINE and EMBASE)
was done in July 2003, to see if any of the abstracts identified in
2002 had reached full publication.
We did not impose any language or other restrictions on any of RESULTS
these searches.
Description of studies
Data collection and analysis See: Characteristics of included studies; Characteristics of excluded
studies.
Screening for eligibility

Included/excluded studies
Trials under consideration for inclusion in the review were assessed
independently for their appropriateness by two authors without Fifty-seven trial reports were identified. Eight were excluded (
prior consideration of their results. Any disagreements that were Appell 1997; Gaudenz 1978; Larsson 1999; Mundy 2001; Rosario
not resolved by discussion were considered by a third person. Ex- 1995; Tincello 2000; Wein 1999; Yoon 2001), and the reasons
cluded studies are listed with reasons for their exclusion. are listed in the Characteristics of excluded studies table. Forty-
nine trials were included in the review; 39 parallel designs and 10
crossover designs. One trial report contained data from two paral-
Assessment of methodological quality lel designs (Sussman 2002). The trials recruited a total of 11,332
adults, including 7,915 women and 2,190 men (NB: some trials
The authors independently made an assessment of methodological
did not report sex data). Sample sizes ranged from 10 (Di Stasi
quality using the Incontinence Group’s quality assessment tool,
2001a) to 1529 (VanKerrebroeck 2001).
which includes evaluation of quality of random allocation and
Trials made three types of comparison: comparisons of different
concealment, description of dropouts and withdrawals, analysis by
anticholinergic drugs, comparisons of different doses of the same
intention to treat, and blinding during treatment and at outcome
drug, and comparisons of immediate (IR) versus extended release
assessment. Disagreements were resolved by discussion with a third
(ER) preparations. Some trials had more than two arms, and made
person.
more than one comparison. Trials that compared an ER prepara-
tion of one drug with an IR preparation of another were included
Data extraction in the comparison of different anticholinergic drugs, and the com-
parison of IR versus ER preparations. Trials that compared ER
Data were independently abstracted by at least two authors and preparations of different drugs were included in the comparison of
cross-checked. Where data were collected but were not reported, different anticholinergic drugs, and the comparison of ER prepa-
or were reported in a form not suitable for inclusion in the formal rations.
analysis, further clarification was sought from trialists. Two trials were published in German (Froehlich 1998; Wehnert
1992) and one in Flemish (Kramer 1987). Information and data
were abstracted from the original papers.
Data analysis
Included trial data were processed as described in the Cochrane
Reviewers’ Handbook (Alderson 2004). Sample characteristics
A priori subgroup analyses were planned to investigate the effects
of age, sex, severity of symptoms, and cause of overactive bladder
symptoms (i.e. idiopathic versus neurogenic). Parallel arm studies

Inclusion and/or exclusion criteria were not always well defined. Lee 2001; Leung 2001; Malone-Lee 2001b; VanKerrebroeck
People with a presumed or urodynamic diagnosis of idiopathic 1997), (b) trospium (Froehlich 1998; Hofner 2000; Madersbacher
detrusor overactivity were included in five trials (Abrams 1998; 1995; Osca 1997), (c) propantheline (Gajewski 1986; Thuroff
Chapple 2002; Froehlich 1998; Madersbacher 1999; Rentzhog 1991), and (d) propiverine (Madersbacher 1999; Stohrer 2002);
1998), and six trials restricted entry to those with a presumed or (2) tolterodine versus: (a) oxybutynin (see above), (b) trospium (
urodynamic diagnosis of neurogenic detrusor overactivity (Abrams Junemann 2000), and (c) solifenacin (Chapple 2002).
1996; Gajewski 1986; Madersbacher 1995; Osca 1997; Stohrer Trials also compared different doses of the same drug:
2002; VanKerrebroeck 1998). Thirteen trials included people (1) tolterodine (Abrams 1996; Jacquetin 2001; Jonas 1997;
with urodynamic detrusor overactivity (both types, or type not Malone-Lee 2001a; Millard 1999; Rentzhog 1998; Sussman 2002;
further specified) (Birns 2000; Chaliha 1998; Davila 2001b; VanKerrebroeck 1998);
Drutz 1999; Jacquetin 2001; Jonas 1997; Junemann 2000; Le- (2) oxybutynin (Davila 2001a; Salvatore 1995; Sussman 2002);
ung 2001; Mazur 1995; Millard 1999; Salvatore 1995; Thuroff (3) trospium (Chaliha 1998; Junemann 1999);
1991; VanKerrebroeck 1997). In the remaining trials partici- (4) propiverine (Mazur 1995);
pants had symptoms consistent with overactive bladder syndrome (5) solifenacin (Chapple 2002).
(Anderson 1999; Appell 2001; Davila 2001a; Diokno 2003; Comparisons of IR and ER preparations included:
Dmochowski 2003; Hofner 2000; Homma 2002; Junemann (1) IR versus ER oxybutynin (Anderson 1999; Birns 2000; Davila
1999; Lee 2001; Malone-Lee 2001a; Malone-Lee 2001b; Sussman 2001b; Versi 2000);
2002; VanKerrebroeck 2001; Versi 2000). Mean age of the partic- (2) IR versus ER tolterodine (VanKerrebroeck 2001);
ipants ranged from 31.3 years (no standard deviation) to 75 years (3) IR oxybutynin versus ER tolterodine (Homma 2002);
(no standard deviation). Two trials restricted entry to older people (4) IR tolterodine versus ER oxybutynin (Appell 2001).
(Malone-Lee 2001a) (65 years or more); (Malone-Lee 2001b) (50 There were also comparisons of different ER preparations:
years or more). Apart from contraindications to anticholinergics, (5) ER oxybutynin versus ER tolterodine (Diokno 2003;
the most common exclusion criteria were evidence of voiding dys- Dmochowski 2003).
function or bladder outlet obstruction. Treatment duration ranged from two weeks to three months in
nearly all studies. The exceptions were one trial that investigated
the effect of a single dose (Froehlich 1998), and two studies that
Crossover studies
had treatment periods of one year or more (Hofner 2000; Salvatore
Five studies included people with urgency or urge incontinence ( 1995).
Bagger 1985; Holmes 1989; Kramer 1987; Wehnert 1992; Zeegers
1987). These people usually had urodynamics as well but it was
not one of the selection criteria. The other five required a diagnosis Crossover studies
of detrusor overactivity (Burton 1994; Di Stasi 2001a; Di Stasi
2001b; Massey 1986; Nilsson 1997). Three studies did not report Some studies were preceded by a week-long placebo washout pe-
age; in three other studies the mean age ranged from 42 to 54 riod. The length of treatment varied from one dose (Di Stasi 2001a;
years, one study had a range of ages of 17 to 55 years and another Di Stasi 2001b) to 60 days (Nilsson 1997) with a median length
16 to 78 years. There were a variety of exclusion criteria. of three weeks. For the one dose studies the washout period was
one week. Six of the 10 studies had no washout period. Three
washout periods were of one week and the other two weeks. Given
Interventions the short half life of the drugs used a washout period may not be
important. Four of the studies had two arms, three had three arms,
one had four arms and two had six arms. Some arms were the same
Parallel arm studies drug at different doses. Some studies had different combinations
In many trials treatment was preceded by a washout period, or of drugs so that they, for example, tested four drugs in a three
treatment with co-medications was specifically excluded. This in- arm study (Kramer 1987) and some had even more complicated
formation was not given in 15 of the 39 parallel arm studies, but arrangements with different doses (Massey 1986).
given the short half life of the drugs this may not be important ( Two studies compared oxybutynin with emepronium (Kramer
Appell 2001; Birns 2000; Chaliha 1998; Davila 2001a; Diokno 1987; Zeegers 1987), one oxybutynin with propiverine (Wehnert
2003; Drutz 1999; Gajewski 1986; Hofner 2000; Junemann 1999; 1992), one oxybutynin with propantheline (Holmes 1989), one
Lee 2001; Leung 2001; Osca 1997; Salvatore 1995; Sussman 2002 emepronium at different doses (Massey 1986), one immediate re-
(two studies)). lease with controlled release oxybutynin (Nilsson 1997), one oxy-
The following between drug comparisons were made: butynin three times a day with as needed (Burton 1994), and two
(1) oxybutynin versus: (a) tolterodine (Abrams 1998; Appell 2001; oral oxybutynin versus intravesical oxybutynin versus intravesical
Dmochowski 2003; Diokno 2003; Drutz 1999; Homma 2002; oxybutynin with an electric current applied (Di Stasi 2001a; Di

Stasi 2001b). Further characteristics of the trials are reported in the Character-
istics of Included Studies table.
Outcome measures
Overall there was a lack of consistency in the choice of outcome
Risk of bias in included studies
measures by trialists, and a lack of consistency in the way data The method of group allocation was rarely described. Perhaps au-
were reported. Fourteen trials reported outcomes of interest but no thors of drug trials feel that a statement about single or double
useable data were provided (Bagger 1985; Burton 1994; Chaliha blind design is sufficient to describe the randomisation process and
1998; Chapple 2002; Davila 2001a; Di Stasi 2001a; Di Stasi allocation concealment. While double blinding should adequately
2001b; Leung 2001; Massey 1986; Osca 1997; Salvatore 1995; conceal group allocation, this is not guaranteed. For the purposes
Stohrer 2002; Wehnert 1992; Zeegers 1987). Due to deficiencies of the review, the 30 parallel arm studies that stated group alloca-
in data reporting (e.g. point estimate without measure of variation) tion was ’double-blind’ were coded as having adequate allocation
many trials contributed little or no data to the review. The lack of concealment. In the other nine parallel arm studies it was not clear
similarity in measures limited the possibilities for combining data if allocation was adequately concealed (Davila 2001a; Froehlich
from individual trials. 1998; Gajewski 1986; Homma 2002; Leung 2001; Mazur 1995;
The primary outcome of interest in the review was quality of Salvatore 1995; Sussman 2002). Only one trial specifically stated
life. Validated incontinence specific quality of life measures were that outcome assessors were blind to group allocation (Leung
only reported by four trials (Davila 2001a; Dmochowski 2003; 2001). Some studies stated that the code was broken at the com-
Leung 2001; VanKerrebroeck 2001). The Incontinence Impact pletion of the study, and in some it was specified that this was
Questionnaire (IIQ) and the King’s Health Questionnaire (KHQ) after the analysis. This would imply that the final measurement
were each used by two trials, but no useable data were reported was done ’blinded’.
(see results). Therefore, the authors chose the patient’s perception Baseline comparability of the groups was not mentioned in 14
of cure/improvement as an alternate primary outcome. About a studies (Abrams 1996; Birns 2000; Chaliha 1998; Chapple 2002;
third of trials appeared to collect data on the patients’ perceptions Davila 2001a; Davila 2001b; Hofner 2000; Junemann 1999;
of symptomatic cure or improvement; but fewer reported these Junemann 2000; Lee 2001; Leung 2001; Osca 1997; Rentzhog
findings. 1998; VanKerrebroeck 1997). The remaining trials stated that
About half the studies used micturition diaries to record num- the groups were comparable at baseline, although two studies
ber of leakage episodes and number of micturitions over varying did not provide supporting data (Homma 2002; Stohrer 2002).
lengths of time. In order to combine these data in the pooled anal- In 17 trials the evaluation of treatment efficacy was conducted
ysis the number of leakage episodes and number of micturitions on intention to treat principles (Abrams 1998; Appell 2001;
in 24 hours was calculated. A wide range of urodynamic mea- Birns 2000; Diokno 2003; Dmochowski 2003; Froehlich 1998;
sures were reported. In view of the lack of correlation between Homma 2002; Jacquetin 2001; Junemann 1999; Madersbacher
urodynamic measures and clinical outcome the formal compar- 1999; Malone-Lee 2001a; Malone-Lee 2001b; Millard 1999;
isons were limited to maximum cystometric capacity, volume at Sussman 2002; VanKerrebroeck 1997; VanKerrebroeck 2001).
first contraction and residual volume. These were measures that Eight trials specifically stated that a per protocol analysis was used
trialists most consistently reported, which suggests that researchers to assess treatment efficacy (Abrams 1996; Anderson 1999; Drutz
and clinicians have thought these data were important in making 1999; Hofner 2000; Junemann 2000; Rentzhog 1998; Stohrer
judgements about the effects of the drugs on overactive bladder. 2002; VanKerrebroeck 1998). Baseline comparability is not an is-
Some authors reported post treatment urodynamic measures, and sue of concern for crossover studies.
others reported change in urodynamic measures, so both are in- The description of withdrawals or dropouts was not adequate in 15
cluded in the formal comparisons. Dry mouth was the adverse trials (Abrams 1996; Chaliha 1998; Chapple 2002; Davila 2001a;
event reported by the largest number of studies. No trial included Davila 2001b; Dmochowski 2003; Homma 2002; Junemann
socioeconomic data. 1999; Junemann 2000; Lee 2001; Leung 2001; Osca 1997;
In order to use the data from crossover studies in a meta-analysis Stohrer 2002; VanKerrebroeck 1998; VanKerrebroeck 2001).
it must be presented as the mean and standard deviation of the There were no dropouts from the trials using single intravesi-
difference between two treatments for continuous data, or a two cal or oral doses of medication (Di Stasi 2001a; Di Stasi 2001b;
by two table for binary data, as the correlation between measure- Froehlich 1998). In 16 trials the dropout rate was 10% or less (
ments on the same individual may be important. Only three of Bagger 1985; Birns 2000; Chapple 2002; Davila 2001b; Homma
the 10 crossover studies presented data in this way (Holmes 1989; 2002; Jacquetin 2001; Jonas 1997; Junemann 1999; Malone-Lee
Kramer 1987; Nilsson 1997), Holmes for three of our predeter- 2001a; Mazur 1995; Millard 1999; Rosario 1995; Thuroff 1991;
mined outcomes, and Kramer and Nilson for one each. These few VanKerrebroeck 2001; Versi 2000; Wehnert 1992). In the re-
data have not been included in the pooled estimates. mainder, drop out rates ranged from 11% (Dmochowski 2003;

Madersbacher 1995) to 39% (Salvatore 1995) in parallel designs, Primary outcome measure (01.01)
and 0% (Wehnert 1992) to 40% (Zeegers 1987) in the crossover Two trials collected quality of life data (Dmochowski 2003; Leung
studies. Very few parallel design trials included any follow up be- 2001), none of which was useable. Two trials reported the pa-
yond the initial assessment of outcome. In those trials that did fol- tient’s perception of change in symptoms (Abrams 1998; Malone-
low up participants this was usually for very short periods of time, Lee 2001b). There was no statistically significant difference be-
i.e. one or two weeks. The stated purpose of these short follow up tween the groups in the proportion of people reporting cure/im-
periods was adverse events monitoring. One study followed par- provement (145/307, 47% cured/improved in tolterodine group
ticipants for two years (Salvatore 1995). Long term follow up does and 136/306, 44% cured/improved in oxybutynin group: RR for
not provide information on the differences in treatment effects for cure/improvement 1.06, 95% CI 0.89 to 1.26). Patient reported
crossover studies. data were collected in three further trials, but were not included
The primary, or only, reference for 15 trials was a conference ab- in the pooled analysis because they were not dichotomous data
stract (Abrams 1996; Burton 1994; Chaliha 1998; Chapple 2002; (i.e. were not either/or data such as cure/no cure), were not able to
Davila 2001a; Hofner 2000; Homma 2002; Junemann 1999; be dichotomised by the authors, or were not reported (Lee 2001;
Junemann 2000; Lee 2001; Leung 2001; Osca 1997; Salvatore Leung 2001; VanKerrebroeck 1997).
1995; Stohrer 2002; VanKerrebroeck 1997). All of these trials were
complete at the time of reporting, and full publications were not
found with subsequent searching. All abstracts reported limited Secondary outcome measures (01.02, 01.03, 01.04, 01.05,
details of method, and few results. 01.12, 01.13)
Some of the large multicentre/multinational trials were reported
One trial (Appell 2001), reported data on number of leakage
in multiple publications. These publications usually presented
episodes in 24 hours; there was no statistically significant dif-
subsets of the main trial results (e.g. data from one country)
ference between IR tolterodine and ER oxybutynin groups. Five
and subsequent publications rarely provided further methodolog-
trials reported the change in number of leakage episodes in 24
ical detail. The most notable example is Van Kerrebroek 2001 (
hours (Abrams 1998; Dmochowski 2003; Drutz 1999; Lee 2001;
VanKerrebroeck 2001); 18 separate reports were identified. Where
Malone-Lee 2001b). There was no statistically significant differ-
there were multiple publications of the same trial the main trial
ence between the groups (WMD -0.15, 95% CI -0.47 to 0.16).
report was selected as the primary reference; the primary reference
Of the five trials, only one (Lee 2001), found a statistically signif-
is cited throughout the review for simplicity.
icant difference between the treatments and this appears to have
contributed to the statistically significant heterogeneity observed
in this comparison. Lee et al (Lee 2001) was reported as a confer-
Effects of interventions ence abstract; the minimal detail available meant it was difficult
to tell why this trial might be different from the others.
Very few of the crossover studies presented any data in a manner The same five trials reported change in micturitions in 24 hours;
that could be formally combined in a meta-analysis. Because of there was no statistically significant difference between the groups
this the results of the crossover studies are qualitatively assessed, (WMD -0.25, 95% CI -0.61 to 0.10). Again, Appell et al (Appell
after the results for the parallel arm studies are presented. 2001) reported data on number of micturitions in 24 hours. There
was a statistically significant difference in favour of the ER oxybu-
tynin group.
One anticholinergic versus another There were no useable data available for any of the three clinicians’
measures, maximum cystometric capacity, volume at first contrac-
tion, or residual volume.
Six trials reported withdrawals due to adverse events (Abrams
1. Oxybutynin versus tolterodine
1998; Diokno 2003; Dmochowski 2003; Drutz 1999; Lee 2001;
Ten parallel arm studies were included (Abrams 1998; Malone-Lee 2001b). There were fewer withdrawals amongst those
Appell 2001; Diokno 2003; Dmochowski 2003; Drutz 1999; taking tolterodine (72/1051, 7% tolterodine group and 126/1046,
Homma 2002; Lee 2001; Leung 2001; Malone-Lee 2001b; 12% oxybutynin group, RR 0.57, 95% CI 0.43 to 0.75). Statis-
VanKerrebroeck 1997). The following comparisons were made by tically significant heterogeneity was observed in this comparison.
one trial each: IR tolterodine versus ER oxybutynin, ER toltero- In Dmochowski et al Dmochowski 2003) some women withdrew
dine versus IR oxybutynin, ER oral tolterodine versus ER transder- because of reactions at the transdermal application site. This was
mal oxybutynin, and ER oral oxybutynin versus ER oral toltero- in addition to those who withdrew because of anticholinergic side
dine. The other six trials compared immediate release oral prepa- effects. If data from Dmochowski et al (Dmochowski 2003) are
rations of tolterodine and oxybutynin. Leung et al (Leung 2001), removed from the analysis there is still less risk of withdrawal due
reported as a conference abstract, gave no useable data. to adverse events in the tolterodine group (RR 0.62, 95% CI 0.47

to 0.82), but there is no longer statistically significant heterogene- Primary outcome measure (01.01)
ity. When pooled data from both trials were combined there was a
Dry mouth was the most frequently reported side effect; data were statistically significant difference in proportions reporting cure/
available from nine studies (Abrams 1998; Appell 2001; Diokno improvement in favour of oxybutynin (RR 0.71, 95% CI 0.53 to
2003; Dmochowski 2003; Drutz 1999; Homma 2002; Lee 2001; 0.96).
Malone-Lee 2001b; VanKerrebroeck 1997). Statistically signifi-
cant heterogeneity was observed in this comparison. If the data
from trials that compared IR with ER preparations (Appell 2001; Secondary outcome measures (01.06, 01.07, 01.08, 01.11,
Homma 2002), in addition to comparing tolterodine with oxybu- 01.12, 01.13)
tynin, were removed from the analysis heterogeneity was reduced, Neither trial reported data on leakage episodes or micturitions
but was still statistically significant. If data comparing transdermal in 24 hours. One trial reported maximum cystometric capacity
and oral methods of delivery were also removed the heterogeneity post treatment (Gajewski 1986), the other change in maximum
was no longer statistically significant. There was about half to a cystometric capacity (Thuroff 1991). Neither showed a statisti-
third the risk of dry mouth for those taking tolterodine (RR for cally significant difference between the treatments; the confidence
dry mouth 0.60, 95% CI 0.54 to 0.66). intervals were wide. Thuroff et al (Thuroff 1991) also reported
change in volume at first contraction and change in residual vol-
ume. There was no statistically significant difference between the
2. Oxybutynin versus trospium treatments for volume at first contraction, but residual volumes
were statistically significantly greater with oxybutynin.
Four parallel arm studies were included (Froehlich 1998; Hofner
There was no statistically significant difference in withdrawals due
2000; Madersbacher 1995; Osca 1997). Froehlich et al (Froehlich
to adverse events (RR 1.43, 95% CI 0.53 to 3.89). Thuroff et al (
1998) compared intravesical administration of single doses of tro-
Thuroff 1991) found no statistically significant difference between
spium and oxybutynin. The other three trials compared IR oral
the groups for dry mouth.
preparations of trospium and oxybutynin. Osca et al (Osca 1997),
One crossover trial assessed this comparison (Holmes 1989). Al-
reported as a conference abstract, gave no useable data.
though the maximum cystometric capacity was greater during
treatment with oxybutynin than when on propantheline, there
were no significant differences in other outcomes of interest. This
Primary outcome measure study was small so the risk of a type II error must be high.
None of the four trials collected data on the patient’s observations
of cure/improvement. 4. Oxybutynin versus propiverine
Two trials were included (Madersbacher 1999; Stohrer 2002); both
compared IR oral preparations of propiverine and oxybutynin.
Secondary outcome measures (01.06, 01.10, 01.12, 01.13)
Only one trial collected data on leakage episodes and micturi-
Primary outcome measure
tions in 24 hours (Hofner 2000), but data were presented without
a measure of variation. Two trials reported maximum cystomet- Neither trial reported useable data on the patient’s observations of
ric capacity and residual volume (Froehlich 1998; Madersbacher cure/improvement.
1995). There was no statistically significant difference between the
groups for either comparison. The confidence intervals for both
outcomes in both trials were wide. Secondary outcome measures (01.06, 01.10, 01.12, 01.13)
Madersbacher et al (Madersbacher 1995) found no statistically Neither trial reported useable data on leakage episodes or number
significant difference between the groups for withdrawal due to of micturitions in 24 hours. Both reported maximum cystomet-
adverse events. Two trials reported data on dry mouth (Hofner ric capacity post treatment; there was no statistically significant
2000; Madersbacher 1995); those taking trospium had lower rates difference between the groups (WMD -6.42, 95% CI -33.94 to
of dry mouth (RR 0.74, 95% CI 0.59 to 0.93). 21.10). Madersbacher et al (Madersbacher 1999) did not find any
statistically significant difference in residual volume.
Based on data from a single trial (Madersbacher 1999) there was
no statistically significant difference between the groups for with-
3. Oxybutynin versus propantheline
drawals due to adverse events. Combined data from both trials
Two trials were included (Gajewski 1986; Thuroff 1991); both found statistically significantly fewer reports of dry mouth in those
compared IR oral preparations of propantheline and oxybutynin. taking propiverine (RR 0.78, 95% CI 0.66 to 0.92).

One crossover study assessed this comparison (Wehnert 1992). • Primary outcome measure
None of the primary outcomes were statistically significantly dif-
All three trials measured the patient’s perception of change in
ferent. The maximum cystometric capacity was higher on oxybu-
symptoms, but the data could not be dichotomised to report cure/
tynin. This study was very small (n=10) so the risk of a type II
improvement.
error was high.
• Secondary outcome measures (02.03, 02.05, 02.07, 02.09,
02.11, 02.12, 02.13)
5. Other
Based on data from two trials (Rentzhog 1998; VanKerrebroeck
One trial compared trospium and tolterodine (Junemann 2000). 1998) there was no statistically significant difference between the
The trial was reported in a conference abstract. No useable data groups for the change in number of leakage episodes (WMD 0.71,
were published. Another trial compared solifenacin (YM905) and
95% CI -0.19 to 1.61), or change in number of micturitions per
tolterodine (Chapple 2002). This trial was also reported as a con-
24 hours (WMD 0.64, 95% CI -0.32 to 1.60).
ference abstract, without any useable data.
All three trials reported the urodynamic measures. There was no
Two crossover studies assessed the differences between oxybutynin statistically significant difference between the two doses for change
and emepronium (Kramer 1987; Zeegers 1987). Both found oxy- in maximum cystometric capacity (WMD -19.73, 95% CI -75.21
butynin to be better on most outcomes, but on a few they were to 35.76), change in volume at first contraction (WMD -18.14,
not statistically significantly different.
95% CI -68.61 to 32.33), or change in residual volume (WMD -
23.71, 95% CI -50.88 to 3.45).
Only Rentzhog et al (Rentzhog 1998) reported withdrawals due
Different doses of tolterodine
to adverse events; the single case was in the lower dose group. All
It is worth noting that the three trials that contributed the bulk of three trials published dry mouth data; there were fewer reports of
data in the following comparisons were all per protocol analyses dry mouth in the lower dose group (RR 0.36, 95% CI 0.13 to
(Abrams 1996; Rentzhog 1998; VanKerrebroeck 1998). None of 0.95).
the trials contributing to these comparisons collected quality of
life data, but as these were dose ranging (ie Phase II) studies quality
of life data would not usually be collected.
2. 2 mg versus 1 mg
Seven trials compared 1 mg with 2 mg IR oral tolterodine twice
daily (Abrams 1996; Jacquetin 2001; Jonas 1997; Malone-Lee
1. 2 mg versus 0.5 mg 2001a; Millard 1999; Rentzhog 1998; VanKerrebroeck 1998).
Three trials compared 0.5 mg and 2 mg IR oral tolterodine twice Malone-Lee et al (Malone-Lee 2001a) reported their data as me-
daily (Abrams 1996; Rentzhog 1998; VanKerrebroeck 1998). dians, with 95% CI, so the data could not be entered in the formal
comparisons (see Additional Tables) (Table 1; Table 2).
Table 1. Different doses. Change in leakage episodes in 24 hrs
Drug Study Dose/data Dose/data Difference
Tolterodine Malone-Lee (2001a) 1mg twice daily. Median 2mg twice daily. Median Median difference -0.4 (95%
change -0.3 (95% CI -0.8 to - change -0.7 (95% CI -1.3 to - CI not calculable)
0.1) n=61 0.2) n=73
Table 2. Different doses. Change in micturitions in 24 hrs

Table 2. Different doses. Change in micturitions in 24 hrs (Continued)
Tolterodine Malone-Lee (2001a) 1mg twice daily. Median 2mg twice daily. Median Median difference 0.0 (95%
change -0.7 (95% CI -1.9 to change -0.7 (95% CI -1.1 to - CI not calculable)
0.0) n=61 0.3) n=73
• Primary outcome measure (02.01) • Primary outcome measure (02.01)

Only Sussman et al (Sussman 2002) reported dichotomised cure/
Only Millard et al (Millard 1999) reported dichotomised cure/
improvement data. Those taking the higher dose were statistically
improvement data. Those taking 2 mg twice daily were statistically
significantly more likely to report cure/improvement.
significantly more likely to report cure/improvement (RR 0.69;
95% CI 0.53 to 0.89). • Secondary outcome measures (02.03, 02.05, 02.07, 02.09,
02.11, 02.12, 02.13)
• Secondary outcome measures (02.03, 02.05, 02.07, 02.09, Based on data from two trials (Rentzhog 1998; VanKerrebroeck
02.11, 02.12, 02.13) 1998) there was no statistically significant difference between the
two doses for change in number of leakage episodes (WMD -0.25,
Based on data from four trials (Jacquetin 2001; Millard 1999; 95% CI -1.32 to 0.82) or change in number of micturitions in 24
Rentzhog 1998; VanKerrebroeck 1998), there was no statistically hours (WMD 0.18, 95% CI -1.03 to 1.40).
significant difference between the two doses for the change in Three trials reported the urodynamic measures (Abrams 1996;
number of leakage episodes (WMD 0.22, 95% CI -0.21 to 0.64) Rentzhog 1998; VanKerrebroeck 1998). The change in maximum
or change in number of micturitions in 24 hours (WMD 0.03, cystometric capacity was statistically significantly greater with the
95% CI -0.48 to 0.53). higher dose (WMD 73.83, 95% CI 18.05 to 129.59), but the
difference between the groups for change in volume at first con-
Four trials reported the urodynamic measures (Abrams 1996; Jonas
traction favouring the higher dose was not statistically significant
1997; Rentzhog 1998; VanKerrebroeck 1998). There was no sta-
(WMD 47.72, 95% CI -10.80 to 106.25). The change in residual
tistically significant difference for change in maximum cystomet-
volume was statistically significantly greater with the higher dose
ric capacity (WMD -16.90, 95% CI -44.73 to 10.93), change
(WMD 92.98, 95% CI 25.56 to 159.40).
in volume at first contraction (WMD -13.51, 95% CI -44.54 to
Two trials (Rentzhog 1998; Sussman 2002) reported withdrawals
17.51), or change in residual volume (WMD -10.07, 95% CI -
due to adverse events; there was no statistically significant differ-
24.49 to 4.34).
ence between the groups (RR 0.91, 95% CI 0.54 to 1.54). How-
Pooled data from five trials (Jacquetin 2001; Jonas 1997; Malone- ever in the trial by Rentzhog et al (Rentzhog 1998), there were
Lee 2001a; Millard 1999; Rentzhog 1998) found no statistically no withdrawals due to adverse events in the lower dose group;
significant difference in the likelihood of withdrawal due to adverse it is not clear how stable the calculation of the point estimate
events (RR 0.70, 95% CI 0.36 to 1.40). All seven trials reported and confidence interval is in these circumstances. Three trials re-
dry mouth data; those taking the lower dose were less likely to ported useable data on dry mouth (Abrams 1996; Rentzhog 1998;
report dry mouth (RR 0.65, 95% CI 0.52 to 0.80). VanKerrebroeck 1998); although there were more reports in the
higher dose group, the difference was not statistically significantly
different (RR 1.67, 95% CI 0.91 to 3.08).
3. 4 mg versus 2 mg
Four trials compared 4 mg and 2 mg doses of tolterodine. Three tri- Different doses of other anticholinergics
als used oral IR preparations twice daily (Abrams 1996; Rentzhog
1998; VanKerrebroeck 1998), and one used an oral ER prepara-
tion taken once daily (Sussman 2002).
1. Oxybutynin

Salvatore et al (Salvatore 1995) compared two dose regimens of
oxybutynin. In one group the starting dose was 2.5 mg twice daily
increasing over six weeks to a maximum dose of 5 mg three times
a day. In the other group the starting dose was 5 mg at night,
increasing over six weeks to a maximum of 5 mg three times a
day. The trial was reported as a conference abstract, but did not
include any useable data.
Davila et al (Davila 2001a) compared three doses of transdermal
ER oxybutynin. The trial was reported in conference abstracts;
there were no useable data.
Sussman and Garely (Sussman 2002) compared 5 mg and 10 mg
doses of once daily oral ER oxybutynin. Useable data were pre-
sented for two outcomes, which showed statistically significantly
more reports of cure/improvement with the higher dose (see Addi-
tional Table) (Table 3), with no statistically significant difference
in proportion of withdrawals due to adverse events (see Additional
Table) (Table 4).
Table 3. Different doses. Cure/improvement
Oxybutynin Sussman (2002) 10mg oxybutynin ER. 146/244 5mg oxybutynin ER. 103/259 RR for difference 1.50 (95% CI
1.25 to 1.80)
Table 4. Different doses. Withdrawals due to adverse events
Oxybutynin Sussman (2002) 5mg ER. 39/313. 10mg ER. 46/307. RR 1.20 (95% CI 0.81 to 1.79)
Propiverine Mazur (1995) 15mg. 1/45 30mg. 1/47 RR 1.04 (95% CI 0.07 to 16.20)
45mg.1/49 30mg. 1/47 RR 0.96 (95% CI 0.06 to 14.90)
60mg. 3/40 30mg. 1/47 RR 3.53 (95% CI 0.38 to 32.57)

In a crossover study Burton (Burton 1994) assessed oxybutynin
three times a day versus oxybutynin taken when needed. Patient
preference favoured taken as needed, as did reports of dry mouth.
There was no statistically significant difference in frequency, leak-
age episodes or maximum cystometric capacity.
2. Trospium
Juneman et al (Junemann 1999) compared 40 mg once daily oral
trospium with 40 mg twice daily. The trial was reported in a con-
ference abstract. Useable data were reported for changes in maxi-
mum cystometric capacity, volume at first contraction and residual
volume; there was no statistically significant difference between
the groups for any of these outcomes (see Additional Tables) (
Table 5; Table 6; Table 7). Chaliha et al (Chaliha 1998) compared
twice daily 10 mg, 20 mg and 40 mg oral trospium. This trial was
also reported as a conference abstract, but no data were included
in the publication.
Table 5. Different doses. Change in maximum cystometric capacity
Trospium chloride Junemann (1999) 40mg twice daily. Mean 40mg once daily. Mean Mean difference 16.13 (95%
change 86.11 (SD 86.06) change 69.98 (SD 83.66) n= CI -15.31 to 47.57)
n=56 56
Table 6. Different doses. Change in volume at first contraction
change 135.41 (SD 130.95) change 113 (SD 155.23) CI -31.44 to 74.94)
n=56 n=56
Table 7. Different doses. Change in residual volume
change 16.00 (SD 44.78) change 14.59 (SD 41.00) CI -14.49 to 17.31)
n=56 n=56

3. Propiverine
Mazur et al (Mazur 1995) compared four daily doses of oral
propiverine hydrochloride, 15 mg, 30 mg, 45 mg and 60 mg.
Those in the 15 mg and 30 mg groups took medication twice daily;
for the higher doses this necessitated taking medication three and
four times daily respectively. The review compares 15 mg, 45 mg
and 60 mg with 30 mg propiverine. Useable data on number of
micturitions in 24 hours, volume at first contraction, withdrawals
due to adverse events and dry mouth were presented. Those tak-
ing 15 mg or 60 mg had statistically significantly more voids in
24 hours than those taking 30 mg propiverine (Table 8). There
were no statistically significant differences between the groups for
volume at first contraction or withdrawals due to adverse events
(Table 9; Table 4). There were statistically significantly fewer re-
ports of dry mouth in the 15 mg compared to the 30 mg dose
group, with no statistically significant difference for the other two
dose comparisons (Table 10).
Table 8. Different doses. Micturitions in 24 hours
Propiverine Mazur (1995) 15mg. Mean 9.5 (SD 4.7) n=45 30mg. Mean 7.3 (SD 2.4) n=45 Mean difference 2.20 (95% CI
0.66 to 3.74)
45mg. Mean 7.5 (SD 2.8) n=48 30mg. Mean 7.3 (SD 2.4) n=45 Mean difference 0.20 (95% CI -
0.86 to 1.26)
60mg. Mean 8.7 (SD 3.8) n=39 30mg. Mean 7.3 (SD 2.4) n=45 Mean difference 1.40 (95% CI
0.02 to 2.78)
Table 9. Different doses. Volume at first contraction
Propiverine Mazur (1995) 15mg. Mean 166 (SD 86) n=45 30mg. Mean 186 (SD 83) n=46 Mean difference -20.00 (95%
CI -54.74 to 14.74)
45mg. Mean 192 (SD 85) n=48 30mg. Mean 186 (SD 83) n=46 Mean difference 6.00 (95% CI -
22.96 to 39.96)
60mg. Mean 189 (SD 102) 30mg. Mean 186 (SD 83) n=46 Mean difference 3.00 (95% CI -
n=39 37.00 to 43.00)

Table 10. Different doses. Dry mouth
Propiverine Mazur (1995) 15mg. 3/45 30mg. 11/47 RR 0.28 (95% CI 0.08 to 0.95)
45mg.11/49 30mg. 11/47 RR 0.96 (95% CI 0.46 to 2.00)
60mg. 11/40 30mg. 11/47 RR 1.18 (95% CI 0.57 to 2.42)
• Secondary outcome measures (03.02, 03.06, 03.08, 03.11,

03.12, 03.13)
4. Solifenacin (YM905)
Chapple et al (Chapple 2002) compared four doses of once daily All four trials collected data on leakage episodes, but only Davila et
oral solifenacin, 2.5 mg, 5 mg, 10 mg and 20 mg. The trial was al (Davila 2001b) reported useable data. There was no statistically
reported in a conference abstract that contained no useable data. significant difference between the groups in the number of leakage
episodes in 24 hours post treatment. None of the trials reported
useable data on number of micturitions in 24 hours post treatment.
Davila et al (Davila 2001b) found a lower maximum cystomet-
5. Emepronium ric capacity and larger volume at first contraction in the ER, al-
Two crossover trials compared different doses of emepronium car- though only the latter was statistically significant. There was no
rageenate. Bagger (Bagger 1985) compared 500 mg or 1000 mg statistically significant difference between the groups for change in
per day and found no statistically significant differences in number residual volume measured using ultrasound (Anderson 1999) and
of micturitions in 72 hours, leakage episodes in 72 hours, or dry urodynamics (Davila 2001b). The confidence intervals in both
mouth. Massey and Abrams (Massey 1986) as part of a compli- studies were wide.
cated trial compared 1600 mg with 2000 mg and found no signif- All four trials reported withdrawals due to adverse events and dry
icant differences in micturitions in 24 hours, leakage episodes per mouth. There was no statistically significant difference in with-
24 hours, volume at first contraction, and maximum cystometric drawals due to adverse events between IR and ER groups. There
capacity. were no withdrawals due to adverse events in one arm of two trials;
it is not clear how stable the calculation of the point estimate and
confidence interval is in these circumstances. There were fewer
Extended versus immediate release preparations reports of dry mouth from those using ER preparations (RR 0.77,
95% CI 0.66 to 0.91). Statistically significant heterogeneity was
observed in this comparison. Visual inspection suggested that the
findings of Birns et al (Birns 2000) differed from those of the other
1. Extended (ER) versus immediate release (IR) oxybutynin three trials, but it was not clear why this trial might be clinically
Four trials were included (Anderson 1999; Birns 2000; Davila heterogenous.
2001b; Versi 2000). Three compared oral ER with oral IR oxy- One crossover trial assessed this comparison (Nilsson 1997). There
butynin (Anderson 1999; Birns 2000; Versi 2000). Davila et al was no statistically significant difference either in the number of
(Davila 2001b) compared transdermal ER with oral IR oxybu- voids per day, nor the numbers with dry mouth.
tynin.
• Primary outcome measure (03.01)
Only Birns et al (Birns 2000) reported the patient’s perception of 2. ER versus IR tolterodine
cure/improvement; there was no statistically significant difference. One trial was included in this comparison (VanKerrebroeck 2001).

• Primary outcome measure One extended release preparation versus another
Quality of life data were collected, but were not useable. No data
were collected on patient’s perception of cure or improvement.
1. Tolterodine versus oxybutynin
• Secondary outcome measures (03.03, 03.05, 03.12, 03.13)
Two trials were included (Diokno 2003; Dmochowski 2003). Dio-
kno et al (Diokno 2003) compared oral ER preparations; Dmo-
Van Kerrebroeck et al (VanKerrebroeck 2001) did not find any
chowski (Dmochowski 2003) compared oral ER tolterodine with
statistically significant differences between ER and IR tolterodine
transdermal ER oxybutynin.
for change in leakage episodes or change in micturitions in 24
hours. No urodynamic data were reported. There was no statis- • Primary outcome measure
tically significant difference between the groups for withdrawals
due to adverse events, but there were fewer reports of dry mouth No data were collected on patient’s perception of cure or improve-
for those using the ER preparation. ment.
• Secondary outcome measures (04.03, 04.05, 04.12, 04.13)
Dmochowski et al (Dmochowski 2003) did not find any statisti-

3. ER oxybutynin versus IR tolterodine cally significant difference in change in leakage episodes or mic-
turitions in 24 hours. Neither trial collected urodynamic data.
One trial was included (Appell 2001).
There was no statistically significant difference between the groups
for withdrawals due to adverse events, but statistically significant
• Primary outcome measure
heterogeneity was observed in this comparison. Dmochowski et al
No data were collected on patient’s perception of cure or improve- (Dmochowski 2003) recorded two reasons for withdrawal due to
ment. adverse events, anticholinergic side effects and/or reaction to the
skin patch. It may not be appropriate to combine these data.
• Secondary outcome measures (03.02, 03.04, 03.12, 03.13) There was no statistically significant difference between the groups
for dry mouth. Visual inspection of the data suggests clinical het-
Appell et al (Appell 2001) did not find a statistically significant dif- erogeneity. Diokno et al (Diokno 2003) found statistically signif-
ference between ER oxybutynin and IR tolterodine for the num- icantly fewer reports of dry mouth with oral ER tolterodine than
ber of leakage episodes in 24 hours, but there was a statistically sig- oral ER oxybutynin. Dmochowski et al (Dmochowski 2003) did
nificant difference in favour of oxybutynin for the number of mic- not find a difference in risk of dry mouth between oral ER toltero-
turitions in 24 hours. No urodynamic data were collected. There dine and transdermal ER oxybutynin, but there were fewer reports
was no statistically significant difference between the groups for of dry mouth with transdermal delivery. It is possible that there are
number of withdrawals due to adverse events, or for dry mouth. differences in dry mouth depending on the method of delivery.
Quality of life, socioeconomics, long-term follow up, and

4. ER tolterodine versus IR oxybutynin adherence
One trial was included (Homma 2002), and was reported in a Although quality of life was the primary outcome of interest only
conference abstract that did not include any useable data, apart four trials measured this using a validated instrument, and none
from dry mouth. of them reported useable data (Davila 2001a; Dmochowski 2003;
Leung 2001; VanKerrebroeck 2001). The trials by Davila et al (
• Primary outcome measure Davila 2001a) and Van Kerrebroeck et al (VanKerrebroeck 2001)
had four and three arms respectively, including a placebo arm. Both
No data were collected on patient’s perception of cure or improve- trials reported quality of life data for one of the active treatment
ment. arms versus placebo, rather than for comparisons of active treat-
ments (e.g. one drug dose versus another, one type of preparation
• Secondary outcome measures versus another). Dmochowski et al (Dmochowski 2003) reported
change from baseline for only one (travel) of the four (physical
Data on leakage episodes and micturitions were collected, but no activity, social relationships, travel, emotional health) domains of
useable data were reported. No urodynamic data were collected. the IIQ. Leung et al (Leung 2001) gave no data in their abstract.
Homma et al (Homma 2002) found that the risk of dry mouth No trial reported socioeconomic data. There were no data available
was less for those taking ER tolterodine (03.13). evaluating outcome beyond the end of the treatment period, which

was usually short (i.e. two weeks to three months). Some trials reported as a difference in means and either the standard devia-
used pill counts to assess adherence to taking medication. Eight tion, standard error or 95% confidence interval of that difference.
trials reported per protocol analyses, i.e. data from those who were This does coincide with what is of clinical interest, but can get
adherent. There were not sufficient data in any comparison to be complex when there are more than two treatments. Dichotomous
sure that size or direction of treatment effect was different in these outcomes (e.g. cure/not cured) should be reported so that it is
trials. clear whether the events on each treatment occurred in the same
or different people. Only three of the ten crossover trials reported
outcomes in this manner, but only one outcome of interest each.
Subgroup analysis In view of the number of trials, it is disappointing that it was not
The planned subgroup analyses were not appropriate; there were possible to combine more data. There was considerable variation
insufficient data in any comparison. in chosen outcomes, and also variation in how the same outcome
was measured and reported. Relatively few trials sought the pa-
tient’s opinion on satisfaction with, and acceptability of, treat-
ment but these are important factors in the choice of manage-
ment. Only four trials addressed quality of life, and none reported
DISCUSSION socioeconomic outcomes, and these areas need to be addressed in
future research. In view of the lack of validated ’normal’ values and
This review is the second of a series of reviews of anticholinergic the lack of correlation between urodynamic findings and clinical
drug therapy for overactive bladder symptoms and it should be outcome, the emphasis in some studies on urodynamic measures
viewed in that context. The first anticholinergic review consid- needs to be re-evaluated. In the vast majority of included trials,
ered whether anticholinergic drugs were better than placebo (Hay- the primary endpoint was measured after 12 weeks or less of treat-
Smith 2003). Two further reviews will consider: 1) whether anti- ment. Overactive bladder syndrome is a chronic condition, and
cholinergic drugs are better than other active (non-drug) therapies anticholinergic drugs are not curative; continued use of the drug is
(Patrick 2004); and 2) whether anticholinergic drugs are better likely to be needed if the benefits are to be maintained. The short
than other drug treatments (Dublin 2004). duration of most studies and the lack of long term follow up gives
little information about the long term effects and acceptability of
General Observations the different anticholinergic therapies.
None of the included trials reported results for those with or
Considering this review as a whole, it seemed that oxybutynin
without urge incontinence. A number of trials included men and
and tolterodine demonstrated similar efficacy, but those taking
women, but did not report outcome separately by sex. Therefore,
tolterodine had less risk of withdrawal due to adverse events and
it was not possible to investigate differences in effect based on sex,
less risk of dry mouth. However, those taking tolterodine did not
or on whether patients have incontinence or not.
always have less risk of dry mouth, because this also depended on
Some comparisons demonstrated statistically significant hetero-
the method of drug delivery. There was less risk of dry mouth with
geneity. Usually there was a plausible explanation for this, based
extended release preparations regardless of which drugs were being
on clinical heterogeneity. There were differences in the sample
compared. There was some evidence that, clinically (i.e. leakage
populations, but also differences in methods of drug delivery (i.e.
and micturition data), the effects of 1 mg versus 2 mg and 2 mg
oral, intravesical, transdermal, IR and ER preparations) and drug
versus 4 mg oral immediate release tolterodine twice daily were
doses.
similar but confidence intervals were wide. However, there was
It is worth noting that 14 of the 49 trials (29%) declared phar-
less risk of dry mouth with 1 mg. There were insufficient data in
maceutical company support (Abrams 1998; Appell 2001; Davila
any other comparison in the review to observe any clear patterns
2001a; Diokno 2003; Dmochowski 2003; Dorschner 2000; Drutz
of effect.
1999; Jacquetin 2001; Malone-Lee 2002; Rentzhog 1998; Thuroff
In contrast to many other treatments for urinary dysfunction there
1991; VanKerrebroeck 1998; VanKerrebroeck 2001; Versi 2000).
are a relatively large number of trials comparing anticholinergic
This support ranged from the supply of active and placebo tablets
drugs with each other. In general, the reported method of the
(in blinded packaging) through to full funding and data analysis.
parallel arm trials was of moderate to high quality. However, the
None of the remaining trials made any statement about the ab-
methods of group allocation were rarely described in sufficient
sence or presence of company involvement. One trial was funded
detail to be sure that group allocation was adequately concealed.
by a grant from a health research body (Gajewski 1986).
Only one trial clearly used blinded outcome assessors. The report-
ing of group allocation of dropouts and/or reasons for withdrawal
was adequate in about two thirds of trials. Crossover trials were
usually poorly reported. In order to be included in a meta-analysis One anticholinergic versus another
the results from crossover studies for continuous variables must be

Direct comparisons of tolterodine and oxybutynin suggested that able commercially, and there is little difference in the cost of 1 mg
the two drugs have similar effects on leakage episodes and micturi- and 2 mg tolterodine.
tions in 24 hours. Unfortunately, there were no quality of life data,
and few data on patients’ perceptions of outcome. It seemed dry
mouth was a common side effect of oral IR preparations of toltero-
dine and oxybutynin, with dry mouth more common in those tak- Different doses of other anticholinergics
ing oxybutynin. Those receiving tolterodine were between 18% There were insufficient trials and data to reach any conclusions
and 53% less likely to withdraw with adverse events, and between about the relative efficacy of different doses of oxybutynin, tro-
34% and 46% less likely to experience dry mouth. The one trial spium, propiverine, darifenacin, or solifenacin.
that suggested less dry mouth in those taking oxybutynin com-
pared oral ER tolterodine and transdermal ER oxybutynin.
There were insufficient trials and data to reach any conclusions
about the relative efficacy of trospium versus oxybutynin, propan- Extended versus immediate release
theline versus oxybutynin, propiverine versus oxybutynin, tro- preparations
spium versus tolterodine and solifenacin versus tolterodine. A Extended release (ER) preparations have been developed to reduce
comparison that might benefit from further research is trospium the side effects, particularly dry mouth, of anticholinergic medi-
versus oxybutynin and/or tolterodine (because trospium is a qua- cations. Although there were few data, there did not seem to be
ternary amine and oxybutynin and tolterodine are tertiary amines). important differences in the efficacy of ER and immediate release
Comparisons between established (e.g. oxybutynin and/or toltero- (IR) preparations. However, regardless of which drugs were be-
dine ) and newer (e.g. solifenacin, darifenacin) drugs would also ing compared, there was consistently less risk of dry mouth with
be of interest. ER preparations. For oxybutynin, dry mouth is between 9% and
34% less likely with ER preparations; the reduced risk is most pro-
nounced in a comparison of IR with transdermal ER oxybutynin.
Different doses of tolterodine For tolterodine, data from one large well conducted trial found
Doses that were higher or lowe than the supposed therapeutic dose between 6% and 38% less risk of dry mouth with the ER prepa-
of 2 mg twice daily were investigated, i.e. 0.5 mg or 1.0 mg versus ration. Although there are limited data, it seems ER preparations
2 mg, and 4 mg versus 2 mg tolterodine. The lowest dose (0.5 of oxybutynin and tolterodine might have the desired effect of re-
mg) appeared somewhat less effective than 2 mg, but 1 mg and ducing dry mouth. Therefore, comparisons of an IR preparation
4 mg doses of tolterodine appeared similar to the effect of 2 mg of one drug with the ER version of another probably do not add
for leakage episodes and micturitions in 24 hours. Unfortunately, much; comparisons of one ER preparation versus another are of
there were few data on patients’ perceptions of outcome. Urody- greater clinical importance.
namic measures suggested that 4 mg was associated with bigger
increases in maximum cystometric capacity, and volume at first
contraction. However, residual volume increased between 27 and
159 mls more with 4 mg than 2 mg tolterodine. Withdrawals due
One extended release preparation versus
to adverse events were similar in all dose groups. Dry mouth was
another
between 5% and 87% less likely with 0.5mg than 2mg tolterodine, Two trials compared ER tolterodine with ER oxybutynin. Data
and 20% and 48% less likely with 1mg than 2mg tolterodine. Dry from both trials suggest similar efficacy of the ER preparations.
mouth seemed more common with 4 mg than 2 mg tolterodine, However, the trial that compared oral ER tolterodine and oxybu-
although the difference was not statistically significant. Most data tynin found a similar proportion of withdrawals in each group, but
in these comparisons came from three trials; all were dose ranging dry mouth was between 6% and 51% less likely in the tolterodine
studies with per protocol analyses. Based on the data, it seems the group. In contrast, a comparison of oral ER tolterodine and trans-
clinical effectiveness of 1 mg and 2 mg twice daily oral IR toltero- dermal ER oxybutynin reported more withdrawals, but a tendency
dine is not clearly different, but with less risk of dry mouth with to less dry mouth, in the oxybutynin group. The addition of with-
the lower dose. Prescribing 0.5 mg or 4 mg tolterodine twice daily drawals because of skin reactions at the transdermal application
might be associated with reduced efficacy with the lower dose, and site, in addition to withdrawals for anticholinergic side effects,
potentially clinically important increases in residual volume and might explain the observed difference in withdrawal rates between
greater risk of dry mouth with the higher dose. It is not clear what the two trials. The apparent difference in risk of dry mouth might
the differences in outcome would be between 0.5 mg, 1 mg, 2 mg be associated with method of delivery, with transdermal delivery
and 4 mg doses in a more pragmatic clinical setting. Practically, associated with less dry mouth than oral preparations. Greater sali-
two other factors may influence decision making with regard to vary output with transdermal ER oxybutynin than oral ER oxy-
tolterodine dosage; these are that 0.5 mg tolterodine is not avail- butynin is observed in healthy volunteers (Appell 2003).

AUTHORS’ CONCLUSIONS • are large;
• more pragmatic than explanatory in design, because
Implications for practice
findings would be more useful if trial methods reflected usual
A previous review found that administration of anticholinergic clinical practice (pragmatic design) rather than very tightly
drugs for overactive bladder symptoms does give statistically sig- controlled, highly selected populations and per protocol analyses
nificant differences compared to placebo, although the clinical im- (explanatory design);
portance of the difference is less clear (Hay-Smith 2003). How-
• use adequate means to conceal group allocation (and report
ever, the use of anticholinergic medications for the relief of over-
the methods used);
active bladder symptoms is widespread, so the question of which
anticholinergic drug is better is of clinical interest. The three ques- • use blinded outcome assessors;
tions addressed by the review are which drug is better, what dose • use a standardised validated measure of condition specific
is most effective, and which method of delivery is best? (overactive bladder) quality of life as the primary outcome
The two most widely prescribed drugs (oxybutynin and toltero- measure;
dine) appear to have similar effects on patients’ perceptions of • include patient’s perception of change in symptoms, and
cure/improvement, leakage episodes, and number of micturitions, satisfaction with outcome, as secondary outcome measures;
but tolterodine has the lesser risk of withdrawals and dry mouth.
Where the prescribing choice is between IR oral preparations of • follow participants up for at least one year, because
tolterodine and oxybutynin, tolterodine might be preferred be- anticholinergic drugs are not curative and what success they have
cause there is less risk of dry mouth and people might be more is likely to depend on people continuing to take them;
able to continue taking the medication. • include economic outcomes.
If oral IR tolterodine is being prescribed it seems the clinical effect
Future versions of this review will not include urodynamic mea-
might be similar with 1 mg or 2 mg twice daily, but dry mouth
sures; these do not appear to correlate with clinical outcome, or
is less likely with the 1 mg dose. Although clinical observation
have important implications for clinical practice.
suggests that 2 mg twice daily is the more common starting dose,
the evidence to date suggests a starting dose of 1 mg twice daily The reporting of trials could also be improved, especially the meth-
might be equally effective with less risk of the most common ods of group allocation, and description of dropouts. Further, the
adverse event, dry mouth. reporting of all aspects of crossover studies needs to be dramatically
improved if they are to add anything to the body of knowledge
Where clinicians have the option of prescribing ER release prepa-
about these drugs.
rations, this method of delivery can be expected to reduce the risk
of dry mouth without any apparent loss of efficacy. There are in- With regard to drug comparisons, there have probably been suf-
sufficient data to recommend one ER preparation over another, al- ficient trials comparing oxybutynin and tolterodine to have es-
though dry mouth might be less common with oral ER tolterodine tablished that these two widely prescribed drugs have similar ef-
than oral ER oxybutynin, or transdermal ER oxybutynin than oral ficacy, but tolterodine has the better side effect profile. However
ER tolterodine. Some patients will have sufficient skin reaction to oxybutynin is cheaper, and is a registered and/or subsidised drug
transdermal patches that they discontinue this method of delivery. in more countries. There are few data in this review to compare
other anticholinergic drugs (e.g. trospium chloride, propanthe-
The short duration of most studies and the lack of long term
line, propiverine, darifenacin, solifenacin) with either oxybutynin
follow up gives little information about the long term effects and
or tolterodine; more data are needed to support the prescribing of
acceptability of the different anticholinergic drugs.
these drugs. Any new anticholinergic therapies, after their safely
There are insufficient data available to comment on the effect of has been established, should be compared to either oxybutynin or
different drugs on quality of life, and economic measures were tolterodine to establish if they have similar or better efficacy or
not reported. It is disappointing that none of the included trials side effect profile than either of these ’standard’ drug therapies.
reported even the most basic of cost descriptions.
It seems ER preparations do have the desired effect of reducing side
effects, particularly dry mouth, compared to oral IR preparations.
Implications for research
It is probably more clinically useful to concentrate research efforts
The meaning and usefulness of future trials and reviews would be on comparisons of different ER preparations or different methods
improved if attention is paid to the choice of outcome measures, of ER delivery, than comparisons of ER with IR preparations.
long term follow up, and some aspects of trial design. In particular
In the time taken to complete this review, further relevant trials
the authors recommend that future trials:
are known to have been reported. These will be considered when
the review is updated drawing on extended literature searches.

ACKNOWLEDGEMENTS
The authors would like to thank:
• Dr B Moehrer for help with assessment of trials published

in German, Italian and Flemish;
• F Teixeira for help with trials published in Spanish;
• Dr L Rentzhog for providing unpublished data;
• U Azman, P Collin, S Radley, D Richmond, C Chapple,
the authors of a previous protocol for this review.
REFERENCES
References to studies included in this review tolterodine tartrate in the treatment of overactive bladder: Results
of the OBJECT study. Mayo Clinical Proceedings 2001;76:358–63.
Dmochowski R, Appell R, Sand P, Zinner N, Roach M, Saltzstein
Abrams 1996 {published data only} D et al on behalf of the OBJECT Study Group. Randomized,
Abrams P, Jackson S, Mattiasson A, Krishnan K, Haendler L. A double-blind study of controlled-release oxybutynin and
randomised, double-blind, placebo controlled, dose ranging study tolterodine for overactive bladder (Abstract 327). Proceedings of
of the safety and efficacy of tolterodine in patients with the International Continence Society (ICS), 31st Annual Meeting,
hyperreflexia. Proceedings of the International Continence Society, 18-21 Sept, Seoul, Korea. 2001.
26th Annual Meeting, 27-30 Aug; Athens, Greece. 1996:276–7. Karram M. Randomized double-blind study to compare two
treatments for urinary frequency in women by age. Obstetrics &
Abrams 1998 {published data only} Gynecology 2002;99(4 Suppl):42S–43S.
∗
Abrams P, Freeman R, Anderstrom C, Mattiasson A. Tolterodine, Miklos JR, Sand PK, Albrecht D. Randomized, double-blind study
a new antimuscarinic agent: as effective but better tolerated than of extended-release oxybutynin and tolterodine for overactive
oxybutynin in patients with an overactive bladder. British Journal of bladder in female patients. International Urogynecolgy Journal 2001;
Urology 1998;81:801–10. 12(Suppl 3):S44.
Abrams P, Freeman RN, Anderstrom C, Mattiasson A. Efficacy and Sand PK, Appell R, Miklos JR, Dmochowski R, Albrecht D for the
tolerability of tolterodine vs. oxybutynin and placebo in patients OBJECT Study Group. Randomized, double-blind study to
with detrusor instability (Abstract). Journal of Urology 1997;157 compare extended-release oxybutynin and tolterodine for overactive
(4):103. bladder. Obstetrics & Gynecology 2001;97(4):S49.
Sand PK, Miklos JR, Albrecht D on behalf of the OBJECT Study
Anderson 1999 {published data only} Group. Central nervous system adverse events with anticholinergic
Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS medication for overactive bladder. International Urogynecolgy
for the OROS Oxybutynin Study Group. Once daily controlled Journal 2001;12(Supplement 3):S71.
versus immediate release oxybutynin chloride for urge urinary Staskin D, Appell R, Dmochowski R, Albrecht D on behalf of the
incontinence. Journal of Urology 1999;161(6):1809–12. OBJECT Study Group. Central nervous system adverse events
with anticholinergic medication for overactive bladder (Abstract
Appell 2001 {published data only}
71). Proceedings of the 2nd International Consultation on
Anderson RU, Dmochowski R, Lama DJ, Gottesman JE, Staskin
Incontinence, 1-3 July, Paris. 2001.
D, Antoci J et al on behalf of the OBJECT Study Group. Central
nervous system adverse events with anticholinergic medication for Bagger 1985 {published data only}
overactive bladder (Abstract 213). Proceedings of the International Bagger P, Fischer-Rasmussen W, Hansen RI. Emepronium
Continence Society (ICS), 31st Annual Meeting, 18-21 Sept, carregeenate: clinical effects and urinary excretion in treatment of
Seoul, Korea. 2001. female urge incontinence. Scandanavian Journal of Urology and
Appell R, Dmochowski R, Staskin D, Albrecht D on behalf of the Nephrology 1985;19(1):31–5.
OBJECT Study Group. Randomized, double-blind study of
extended-release oxybutynin and tolterodine for overactive bladder Birns 2000 {published data only}
in female patients (Abstract number 71). Poster session abstracts, ∗
Birns J, Lukkari E, Malone-Lee JG and the Oxybutynin CR
2nd International Consultation on Incontinence, Paris. July 2001. Clinical Trial Group. A randomized controlled trial comparing the
∗
Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama efficacy of controlled-release oxybutynin tablets (10 mg once daily)
D et al for the OBJECT Study Group. Prospective randomized with conventional oxybutynin tablets (5 mg twice daily) in patients
controlled trial of extended-release oxybutynin chloride and whose symptoms were stabilized on 5 mg twice daily of oxybutynin.
British Journal of Urology International 2000;85(7):793–8. Diokno 2003 {published data only}
Birns J, Malone-Lee and the Oxybutynin CR Study Group. Diokno AC, Appell RA, Sand PK, Mochowski RR, Gburek BM,
Controlled-release oxybutynin maintains efficacy with a 43% Klimberg IW, Kell SH. Prospective, randomized, double-blind
reduction in side effects compared with conventional oxybutynin study of the efficacy and tolerability of the extended-release
treatment (Abstract). Neurourology and Urodynamics 1997;16(5): formulations of oxybutynin and tolterodine for overactive bladder:
429–30. results of the OPERA trial. Mayo Clinic Proceedings 2003;78(6):
Burton 1994 {published data only} 687–95.
Burton G. A randomised cross over trial comparing oxybutynin Dmochowski 2003 {published data only}
taken three times a day or taken “when needed”. Neurourology and ∗
Dmochowski PR, Sand PK, Zinner NR, Gittelman MC, Davila,
Urodynamics 1994;13(4):351–2. GW, Sanders SW, for the Transdermal Oxybutynin Study Group.
Chaliha 1998 {published data only} Comparative efficacy and safety of transdermal oxybutynin and oral
Chaliha C, Halaska M, Stanton S. Trospium chloride for the tolterodine versus placebo in previously treated patients with urge
treatment of detrusor instability: a placebo-controlled dose-finding and mixed incontinence. Urology 2003;62(2):237–42.
study (Abstract). British Journal of Obstetrics and Gynaecology 1998; Dmochowski R, Davila W, Sanders S. Transdermal oxybutynin and
105(Suppl 17):92. controlled release oral tolterodine in patients with positive
treatment effect to anticholinergic therapy for overactive bladder
Chapple 2002 {published data only}
Chapple CR, Arano P, Bosch JHR, De Ridder D, Kramer G, (Abstract). Neurourology and Urodynamics 2002;21(4):380.
Ridder AM. YM905 appears effective and well tolerated in patients Drutz 1999 {published data only}
with symptomatic idiopathic detrusor overactivity in a European Drutz H, Appell RA. Clinical efficacy and safety of Tolterodine vs
placebo and tolterodine controlled, phase II, dose-finding study. Oxybutynin and placebo in patients with unstable bladder. Acta
Neurourology and Urodynamics 2002;21(4):381–82. Obstetrica et Gynecologica Scandinavica 1997;Suppl 167(5):24.
Davila 2001a {published data only}
∗
Drutz H. P, Appell R.A, Gleason D, Klimberg I, Radomski S.
∗
Davila GW, Sanders S for the Transdermal Oxybutynin Study Clinical efficacy and safety of tolterodine compared to oxybutynin
Group. Transdermal oxybutynin: A multi-center, prospective, and placebo in patients with overactive bladder. International
randomized, double-blind, placebo-controlled study in adults with Urogynecology Journal 1999;10(5):283–9.
urge urinary incontinence. International Urogynecology Journal Drutz HP, Appell RA. Enhanced tolerability of Tolterodine
2001;12(Suppl 3):S43. compared to Oxybutynin in a controlled clinical study (Abstract).
Davila GW, Sanders SW, Lyttle S, Gittelman MC, Zinner N, International Urogynecology Journal and Pelvic Floor Dysfunction
Saltzstein DR et al for the Transdermal Oxybutynin Study Group. 1997;8(1):S14.
Transdermal oxybutynin is safe, effective, and improves quality of Froehlich 1998 {published data only}
life in patients with overactive bladder (Abstract number 34). Froehlich GH, Englowski DM, Hilgers A. Urodynamic effects of
Neurourology and Urodynamics 2001;20(4):426–7. intravesical instillation of trospium chloride in man. Proceedings of
Davila 2001b {published data only} the International Continence Society (ICS), 27th Annual Meeting,
∗
Davila GW, Daugherty CA, Sanders SW for The Transdermal 23-26 Sept, Yokohama, Japan. 1997:159–60.
Oxybutynin Study Group. A short-term, multicenter, randomized ∗
Frohlich G, Burmeister S, Wiedemann A, Bulitta M. Intravesical
double-blind dose titration study of the efficacy and anticholinergic trospium chloride, oxybutynin and verapamil for relaxation of
side effects of transdermal compared to immediate release oral detrusor muscle. A placebo-controlled, randomised clinical trial
oxybutynin treatment of patients with urge urinary incontinence. [Intravesikale instillation von trospiumchlorid, oxybutynin und
Journal of Urology 2001;166:140–5. verapamil zur relaxation des harnblasen–detrusors].
Neimark M, Davila GW, Sanders S. Effects of transdermal and oral Arzneimittelforschung 1998;48(1):486–91.
oxybutynin and its metabolites on cystometrogram parameters
Gajewski 1986 {published data only}
(Abstract 220). Proceedings of the International Continence
Gajewski JB, Awad SA. Oxybutynin versus propantheline in
Society (ICS), 32nd Annual Meeting, 28-30 Aug, Heidelberg,
patients with multiple sclerosis and detrusor hyperreflexia. The
Germany. 2002.
Journal of Urology 1986;135:966–68.
Di Stasi 2001a {published data only}
Di Stasi SM, Giannantoni A, Vespasiani G, Navarra P, Capelli G, Hofner 2000 {published data only}
Massoud R, Stephen RL. Intravesical electromotive administration Hofner K, Halaska M, Primus G, Al-Shukri, Jonas U. Tolerability
of oxybutynin in patients with detrusor hyperreflexia unresponsive and efficacy of trospium chloride in a long-term treatment (52
to standard anticholinergic regimens. Journal of Urology 2001;165 weeks) in patients with urge-syndrome: a double-blind, controlled,
(2):491–8. multicentre clinical trial. Neurourology & Urodynamics 2000;19(4):
487–8.
Di Stasi 2001b {published data only}
Di Stasi SM, Giannantoni A, Navarra P, Capelli G, Stroti L, Porena Holmes 1989 {published data only}
M, Stephen RL. Intravesical oxybutynin: Mode of action assessed Holmes DM, Montz FJ, Stanton SL. Oxybutynin versus
by passive diffusion and electromotive administration with propantheline in the management of detrusor instability. A patient-
pharmacokinetics of oxybutynin and n-desethyl oxybutynin. regulated variable dose trial. British Journal of Obstetrics and
Journal of Urology 2001;166(6):2232–6. Gynaecology 1989;96(5):607–12.
Homma 2002 {published data only} from overactive bladder. International Urogynecology Journal 2001;
Homma Y, Paick JS, Lee JG, Kawabe K. Clinical efficacy and safety 12(Suppl 3):S70.
of tolterodine extended release for treatment of overactive bladder. ∗
Leung HYP, Yip SK, Cheon C, Liu YSJ, Lau J, Wong HKT, et
A phase III, 12-week, randomised, double-blind, placebo and active al.A randomized controlled trial of tolterodine and oxybutynin on
(oxybutynin) controlled study in Japan and Korea (Abstract 221). tolerability and clinical efficacy for treatment of Chinese women
Proceedings of the International Continence Society (ICS), 32rd with overactive bladder (Abstract 223). Proceedings of the
Annual Meeting, 28-30 Aug, Heidelberg, Germany. 2002. International Continence Society (ICS), 31st Annual Meeting, 18-
21 Sept, Seoul, Korea. 2001.
Jacquetin 2001 {published data only}
Leung PHY, Yip SK, Cheon C, Liu YS, Lau J, Wong HK, et al.A
∗
Jacquetin B, Wyndaele JJ. Tolterodine reduces the number of
randomized controlled trial of tolterodine versus oxybutynin in the
incontinence episodes in patients with an overactive bladder.
treatment of overactive bladder in Hong Kong Chinese women
European Journal of Obstetrics & Gynecology and Reproductive
(Abstract). Proceedings of the 2nd Scientific Meeting of Asian
Biology 2001;98(1):97–102.
Society for Female Urology, 26-27 Aug, Hong Kong. 2000.
Jacquetin B, Wyndaele JJ. Tolterodine reduces the number of
incontinence episodes in patients with detrusor overactivity Madersbacher 1995 {published data only}
(Abstract). International Urogynecolgy Journal and Pelvic Floor
∗
Madersbacher H, Stohrer M, Richter R, Burgdorfer H, Hachen
Dysfunction 1997;8(1):S 30. HJ, Murtz G. Trospium chloride versus oxybutynin: a randomized,
double-blind, multicentre trial in the treatment of detrusor
Jonas 1997 {published data only} hyperreflexia. British Journal of Urology 1995;75(4):452–6.
∗
Jonas U, Hofner K, Madersbacher H. Efficacy and safety of two Stohrer M, Madersbacher H, Richter R, Burgdorfer H. Trospium
doses of tolterodine versus placebo in patients with detrusor chloride versus oxybutynin: a randomized, double-blind,
overactivity and symptoms of frequency, urge incontinence, and multicenter trial on the treatment of detrusor hyperreflexia
urgency: urodynamic evaluation. World Journal of Urology 1997;15 (Abstract). Neurourology & Urodynamics 1992;11(4):466–8.
(2):144–51.
Madersbacher 1999 {published data only}
Jonas U, Hofner K, Madersbacher H, Holmdahl TH. Efficacy and
Madersbacher H, Halaska M, Voight R, Alloussi S, Hofner K. A
safety of two doses of tolterodine compared to placebo in patients
urodynamically controlled multicenter study in patients with urge
with detrusor overactivity (Abstract). Neurourology and
incontinence: tolerability and efficacy of propiverine hydrochloride
Urodynamics 1997;16(5):477–8.
in comparison to oxybutynin. Proceedings of the International
Junemann 1999 {published data only} Continence Society (ICS), 27th Annual Meeting, 23-26 Sept,
Junemann KP, Fusgen I. Placebo-controlled, randomised, double- Yokohama, Japan. 1997:153–4.
blind, multicentre clinical trial on the efficacy and tolerability of 1 x
∗
Madersbacher H, Halaska M, Voigt R, Alloussi S, Hofner K. A
40 mg and 2 x 40 mg trospium chloride (spasmo-lyt) daily for 3 placebo-controlled, multicentre study comparing the tolerability
weeks in patients with urge-syndrome (Abstract). Neurourology & and efficacy of propiverine and oxybutynin in patients with urgency
Urodynamics 1999;18(4):375–6. and urge incontinence. British Journal of Urology International
1999;84:646–51.
Junemann 2000 {published data only}
Malone-Lee 2001a {published data only}
Junemann KP, Al-Shukri S. Efficacy and tolerability of trospium
Halaska M, Madersbacher H, Voigt R, Hofner K, Martan A.
chloride and tolterodine in 234 patients with urge-syndrome: a
Propiverine in patients with urgency and urge incontinence - A
double-blind, placebo-controlled, multicentre clinical trial
placebo controlled, multicenter study comparing its tolerability and
(Abstract). Neurourology and Urodynamics 2000;19(4):488–90.
efficacy with oxybutynin [Abstract]. International Urogynaecology
Kramer 1987 {published data only} Journal 2000;11(Suppl 1):S46.
Kramer AEJL, Zeegers AGM, Kiesswetter H, Jonas U. Drug Malone-Lee JG, Walsh B, Maugourd MF and the Tolterodine in
treatment of urgency: a double blind trial of cetiprin®, dridase®, the Elderly Study Group. The safety and clinical efficacy of two
urispas® and placebo [Medicamenteuze behandeling van doses of Tolerodine, compared to placebo in elderly patients.
overmatige mictiedrang: Dubbel–blind onderzoek van cetiprin®, Proceedings of the International Continence Society (ICS), 27th
dridase®, urispas® en placebo (Flemish)]. TGO tijdschrift voor Annual Meeting, 23-26 Sept, Yokohama, Japan. 1997:155–6.
Therapie, Geneesmiddel, en Onderzoek 1987;12(7):256–61.
∗
Malone-Lee JG, Walsh JB, Maugourd MF and the Tolterodine in
the Elderly Study group. Tolterodine: a safe and effective treatment
Lee 2001 {published data only} for older patients with overactive bladder. Journal of the American
Lee JG, Hong JY, Choo MS, Kwon HY, Chung DY, Lee KS, et Geriatric Society 2001;49(6):700–5.
al.Tolterodine: as effective but better tolerated than oxybutynin in
Malone-Lee 2001b {published data only}
Asian patients with symptoms of overactive bladder. Proceedings of ∗
Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine:
the International Continence Society (ICS),31st Annual Meeting,
superior tolerability and comparable efficacy to oxybutynin in
18-21 Sept, Seoul, Korea. 2001.
individuals 50 years old or older with overactive bladder: a
Leung 2001 {published data only} randomized controlled trial. Journal of Urology 2001;165(5):
Leung HY, Yip SK, Cheon C, Liu YS, Lau J, Wong HK, Chung 1452–6.
KH. A randomized controlled trial of tolterodine versus oxybutynin Malone-Lee JG, Kobelt G. Treatment with tolterodine significantly
in the improvement of quality of life for Chinese women suffering improves social function and energy in patients with overactive
bladder. International Urogynecology Journal and Pelvic Floor antimuscarinic clinical effectiveness trial (ACET). Current Medical
Dysfunction 1999;10(Suppl 1):S78. Research and Opinions 2002;18(4):177–84.
Massey 1986 {published data only} Thuroff 1991 {published data only}
∗
Massey JA, Abrams P. Dose titration in clinical trials. An example ∗
Thuroff JW, Bunke B, Ebner A, Faber P, de Geeter P, Hannappel
using emepronium carrageenate in detrusor instability. British J, et al.Randomized, double-blind, multicenter trial on treatment of
Journal of Urology 1986;58(2):125–8. frequency, urgency and incontinence related to detrusor
Massey JA, Abrams PH. Dose-titrated emepronium carrageenate hyperactivity: oxybutynin versus propantheline verus placebo.
for detrusor instability. Proceedings of the International Journal of Urology 1991;145(4):813–7.
Continence Society (ICS), 14th Annual Meeting, Sept, Innsbruck, Thuroff JW, Bunke B, Ebner A, Faber P, de Geeter P, Hannappel J,
Austria. 1984:109–10. et al.Randomized, double-blind multicenter trial on treatment of
Mazur 1995 {published data only} frequency, urgency and incontinence related to detrusor
Mazur D, Wehnert J, Dorschner W, Schubert G, Herfurth G, hyperactivity : oxybutynin vs. propantheline vs. placebo (Abstract).
Alken RG. Clinical and urodynamic effects of propiverine in Neurourology and Urodynamics 1990;9(4):337–8.
patients suffering from urgency and urge incontinence. VanKerrebroeck 1997 {published data only}
Scandinavian Journal of Urology & Nephrology 1995;29(3):289–94. Van Kerrebroeck EVA, Serment G, Dreher E. Clinical efficacy and
Millard 1999 {published data only} safety of tolterodine compared to oxybutynin in patients with
∗
Millard R, Tuttle J, Moore K, Susset J, Clarke B, Dwyer P, et overactive bladder. Neurourology & Urodynamics 1997;16(5):
al.Clinical efficacy and safety of tolterodine compared to placebo in 478–9.
detrusor overactivity. Journal of Urology 1999;161(5):1551–5. VanKerrebroeck 1998 {published data only}
Moore K, Millard R, Dwyer P, Tuttle J. A randomized controlled Messelink EJ, Soler JM, Madersbacher H, Thuroff JW, Amarenco
multicentre trial of Tolterodine in detrusor instability/hyperreflexia G, van Kerrebroeck EV. Urodynamic aspects of the efficacy of
(Abstract). International Urogynecolgy Journal and Pelvic Floor tolterodine; a new anti muscarine drug in the treatment of detrusor
Dysfunction 1997;8(1):S129. hyperreflexia. Proceedings of the International Continence Society
Rosamilia A, Dwyer PL, Clarke B, Moore K, Millard RP, Tuttle J. (ICS), 25th Annual Meeting, 17-20 October, Sydney, Australia.
The clinical efficacy and safety of two doses of Tolterodine in 1995:95–6.
detrusor instability (Abstract). Acta Obstetrica et Gynecologica ∗
Van Kerrebroeck PE, Amarenco G, Thuroff JW, Madersbacher
Scandinavica 1997;5(Suppl 167):24. HG, Lock MTWT, Messelink EJ, et al.Dose-ranging study of
Nilsson 1997 {published data only} tolterodine in patients with detrusor hyperreflexia. Neurourology
Nilsson CG, Lukkari E, Haarala M, Kivela A, Hakonen T, and Urodynamics 1998;17:499–512.
Kiilholma P. Comparison of a 10mg controlled release oxybutynin VanKerrebroeck 2001 {published data only}
tablet with a 5mg oxybutynin tablet in urge incontinent patients. Chancellor M, Freedman S, Mitcheson HD, Antoci J, Primus G,
Neurourology and Urodynamics 1997;16:533–42. Wein A. Tolterodine, an effective and well tolerated treatment for
Osca 1997 {published data only} urge incontinence and other overactive bladder symptoms. Clinical
Osca JM, Martinez-Agullo E, Broseta E, Jimenez-Cruz JF. Drug Investigation 2000 Feb;19(2):83–91.
Trospium chloride versus oxybutynin in the treatment of bladder Garely A, on behalf of the Tolterodine Study Group. Once-daily
neurological disorders: A double blind randomized clinical trial tolterodine treatment significantly decreases perception of urgency
(Abstract). British Journal of Urology 1997;80(Suppl 2):12. and urge incontinence episodes in patients with overactive bladder
(Abstract). International Urology Journal 2001;12(Suppl 1):S18.
Rentzhog 1998 {published and unpublished data}
Kelleher CJ, on behalf of the Tolterodine Study Group. Health-
Rentzhog SL, Stanton L, Cardozo L, Nelson E, Falls M, Abrams P.
related quality of life of female patients receiving once-daily
Efficacy and safety of tolterodine in patients with detrusor
tolterodine treatment for overactive bladder (Abstract).
instability: a dose-ranging study. British Journal of Urology 1998;81
International Urogynecology Journal 2000;11(Suppl 1):S94.
(1):42–8.
Kelleher CJ, Pleil AM, Okano GJ, Reese PR. Long-term health-
Salvatore 1995 {published data only} related quality of life of patients with overactive bladder receiving
Salvatore S, Khullar V, Cardozo L, Kelleher CJ, Abbott D, Hill S. tolterodine (Abstract number 82). Neurourology & Urodynamics
Long term outcome of women with detrusor instability treated with 2001;20(4):504–6.
oxybutynin (Abstract). Neurourology & Urodynamics 1995;14(5): Kelleher CJ, Pleil AM, Reese PR. Health related quality of life of
460–2. patients with overactive bladder receiving tolterodine once-daily
Stohrer 2002 {published data only} (Abstract). Neurourology & Urodynamics 2000;19(4):519–21.
Stohrer M, Murtz G, Schnabel F, Kramer G, Gramatte T, Kirch W. Kreder KJ. Antimuscarinic therapy: relationship between efficacy
Efficacy and tolerance of propiverine in neurogenic detrusor and side effects in responders and non-responders (Abstract).
overactivity in comparison with oxybutynin (Abstract 341). Journal of Urology 2001;165(Suppl 5):S165.
Proceedings of the International Continence Society (ICS), 32nd Kreder KJ. Clinical effectiveness of antimuscarinic therapy : the
Annual Meeting, 28-30 August, Heidelberg, Germany. 2002. relationship between efficacy and tolerability. ICS Abstracts Seoul.
Sussman 2002 {published data only} 2001:Abstract number 140.
Sussman D, Garely A. Treatment of overactive bladder with once- Mallett V. On behalf of the Tolterodine Study Group. Health-
daily extended-release tolterodine or oxybutynin: the related quality of life of female patients receiving once-daily
tolterodine treatment for overactive bladder (Abstract). (Dridase®) – eine randomisierte cross–over–vergleichsstudie
International Urogynecolgy Journal 2001;12(Suppl 1):S4. (German)]. Aktuelle Urologie 1992;23:7–11.
Swift S. Efficacy and tolerability of once-daily tolterodine for Zeegers 1987 {published data only}
women with overactive bladder (Abstract 329). Proceedings of the Zeegers AGM, Kiesswetter H, Kramer AEJL, Jonas U. Conservative
International Continence Society (ICS), 31st Annual Meeting, 18- therapy of frequency, urgency and urge incontinence: a double-
21 Sept, Seoul, Korea. 2001. blind clinical trial of flavoxate hydrochloride, oxybutynin chloride,
Swift S. Once-daily tolterodine is effective and well tolerated in emepronium bromide and placebo. World Journal of Urology 1987;
women with overactive bladder (Abstract 57). Proceedings of the 5:57–61.
2nd International Consultation on Incontinence, 1-3 July, Paris.
2001. References to studies excluded from this review
Swift S, Garely A, Dimpfl T, Payne C on behalf of the Tolterodine
Appell 1997 {published data only}
Study Group. A new once-daily formulation of tolterodine provides
Appell RA. Clinical efficacy and safety of tolterodine in the
superior efficacy and is well tolerated in women with overactive
treatment of overactive bladder : a pooled analysis. Urology 1997;
bladder. International Urogynecology Journal 2003;14:50–5.
50(Suppl 6A):90–6.
Swift SE. Once-daily (OD) tolterodine treatment significantly
decreases perception of urgency and urge incontinence episodes in Gaudenz 1978 {published data only}
patients with overactive bladder (OAB) (Abstract). International Gaudenz R, Weil A. A comparison of flavoxate hydrochloride,
Urogynecolgy Journal 2000;11(Suppl 1):S15. emepronium bromide and propantheline for the treatment of
Swift SE. Once-daily administration of extended-release tolterodine female urinary incontinence due to bladder instability. Proceedings
is effective and well-tolerated in patients with oveactive bladder of the International Incontinence Society (ICS), 8th Annual
(Abstract). Proceedings of the XVI FIGO World Congress of Obstetrics Meeting. 1978:67–70.
and Gynaecology, 3-8 Sept, Washington DC 2000;Book 1:40. Larsson 1999 {published data only}
Swift SE. Overactive bladder in females: treatment with once-daily Larsson G, Hallen B, Nilvebrant L. Tolterodine in the treatment of
Tolterodine (Abstract). International Urogynecolgy Journal and overactive bladder : analysis of the pooled phase II efficacy and
Pelvic Floor Dysfunction 2001;12(Suppl 3):S71. safety data. Urology 1999;53(5):990–8.
∗
Van Kerrebroeck P, Kreder K, Jonas U, Zinner N. Tolterodine
Mundy 2001 {published data only}
once-daily: superior efficacy and tolerability in the treatment of
Mundy AR, Abrams P, Chapple CR, Neal DE. Darifenacin, the first
overactive bladder. Urology 2001;57:414–21.
selective M3 antagonist for overactive bladder: comparison with
Van Kerrebroeck PEV. Long-term (12 months) efficacy and
oxybutynin on ambulatory monitoring and salivary flow.
tolerability of tolterodine once-daily in the treatment of overactive
Proceedings of the International Continence Society (ICS), 31st
bladder (Abstract). Neurourology and Urodynamics 2001;20(4):
Annual Meeting, Seoul, Korea. 2001.
401–2.
Van Kerrebroeck PEVA, for the Tolterodine Study Group. Long- Rosario 1995 {published data only}
term tolerability and efficacy of once-daily (OD) tolterodine in the Rosario DJ, Leaker BR, Noble JG, Milroy E, Chapple CR. A
treatment of overactive bladder (OB) (Abstract). International double-blind placebo controlled crossover study of the effects of
Urogynecology Journal 2001;12(Suppl 3):S49. single doses of darifenacin on cystometric parameters in patients
Van Kerrebroeck PEVA, on behalf of the Tolterodine Study Group. with detrusor instability. Proceedings of the International
Significant decreases in perception of urgency and urge Continence Society (ICS), 25th Annual Meeting, 17-20 Oct,
incontinence episodes with once-daily tolterodine treatment in Sydney, Australia. 1995:223.
patients with overactive bladder [Abstract]. Neurourology and Tincello 2000 {published data only}
Urodynamics 2000;19(4):493–4. Tincello DG, Adams EJ, Sutherst JR, Richmond DH. Oxybutynin
for detrusor instability with adjuvant salivary stimulant pastilles to
Versi 2000 {published data only}
improve compliance: results of a multicentre, randomized
Appell R, Anderson RU, Gittelman M, Kaufman J, Mobley D,
controlled trial. British Journal of Urology International 2000;85(4):
Saltzstein D for the Ditropan XL Study Group. Comparison of
416–20.
urge incontinence treatments. Neurourolgy & Urodynamics 1999;18
Wein 1999 {published data only}
(4):376–7.
Wein AJ, Appell RA. A comparison of the efficacy response profile
∗
Versi E, Appell R, Mobley D, Patton W, Saltzstein D for the
of tolterodine and oxybutynin. International Urogynecology Journal
Ditropan XL Study Group. Dry mouth with conventional and
and Pelvic Floor Dysfunction 1999;10(Suppl 1):S150.
controlled-release oxybutynin in urinary incontinence. Obstetrics & ∗
Wein AJ, Appell RA. A comparison of the efficacy response profile
Gynecology 2000;95(5):718–21.
of tolterodine and oxybutynin. Proceedings of the International
Wehnert 1992 {published data only} Continence Society (ICS), 29th Annual Meeting, 22-26 Aug,
Wehnert VJ, Sage S. Treatment of bladder unstability and urge Denver, Colorado. 1999.
incontinence with propiverine hydrochloride (Mictonorm®) and Yoon 2001 {published data only}
oxybutynin chloride (Dridase®) - a randomised cross-over study Yoon DH, Lee JG. Comparative efficacy and tolerability between
[Therapie der blaseninstabilität und urge–inkontinenz mit propiverine and oxybutynin in patients with overactive bladder
Propiverin hydrochlorid (Mictonorm®) und Oxybutinin chlorid (Abstract 137). Proceedings of the International Continence

Society Meeting (ICS), 31st Annual Meeting, 18-21 Sept, Seoul, Database of Systematic Reviews 2002, Issue 3. [Art. No.:
Korea. 2001. CD003781. DOI: 10.1002/14651858.CD003781]
Hennessey 1999
Additional references
Hennessey A, Robertson NP, Swingler R, Compston DA. Urinary,
Abrams 1988 faecal and sexual dysfunction in patients with multiple sclerosis.
Abrams PH, Blaivas JG, Stanton SL, Andersen JT. Standardisation Journal of Neurology 1999;246(11):1027–32.
of terminology of lower urinary tract function. Neurourology & Jackson 1997
Urodynamics 1988;7(5):403–27. Jackson S. The patient with an overactive bladder - symptoms and
Abrams 2002 quality of life issues. Urology 1997;50(Suppl 6A):18–22.
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et Kobelt 1997
al.The standardisation of terminology of lower urinary tract Kobelt G. Economic considerations and outcome measurement in
function: Report from the standardisation sub-committee of the urge incontinence. Urology 1997;50(6A suppl):100–7.
International Continence Society. Neurourology and Urodynamics [MEDLINE: 98088168]
2002;21(2):167–78. Milsom 2001
Alderson 2004 Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ.
Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers’ How widespread are the symptoms of an overactive bladder and
Handbook 4.2.2 [updated March 2004]. Available from: http: how are they managed? A population-based prevalence study.
www.cochrane.org/resouces/handbook/hbook.htm(accessed 20/ British Journal of Urology International 2001;87(9):760–6.
04/2004). Moller 2000
Appell 2003 Moller LA, Lose G, Jorgensen T. The prevalence and
Appell RA, Chancellor MB, Zobrist RH, Thomas H, Sanders SW. bothersomeness of lower urinary tract symptoms in women 40-60
Pharmacokinetics, metabolism, and saliva output during years of age. Acta Obstetrica et Gynecologica Scandinavica 2000;79
transdermal and extended-release oral oxybutynin administration in (4):298–305.
health subjects. Mayo Clinic Proceedings 2003;78(6):696–702. Moothy 2001
Brown 1999 Moothy P, Lapitan MC, Lim PHC. Prevalence of overactive bladder
Brown JS, Grady D. Prevalence of urinary incontinence and in Asian males: an epidemiologic survey. Proceedings of the
associated risk factors in postmenopausal women. Heart & International Continence Society (ICS), 31st Annual Meeting,
Estrogen/Progestin Replacement Study (HERS) Research Group. Seoul, Korea. 2001.
Obstetrics & Gynecology 1999;94(1):66–70. Ouslander 1982
Ouslander JG, Kane RL, Abrass IB. Urinary incontinence in elderly
Choo 2001
nursing home patients. Journal of the American Medical Association
Choo M-S, Lee YS, Kim HY, Lee JB, Kwon DD, Lee T, et al.The
1982;248(10):1194–8. [MEDLINE: 82269350]
prevalence of overactive bladder in Korea. Proceedings of the
International Continence Society (ICS), 31st Annual Meeting, Ouslander 1986
Seoul, Korea. 2001. Ouslander JG, Hepps K, Raz S, Su HL. Genitourinary dysfunction
in a geriatric outpatient population. Journal of the American
Dublin 2004
Geriatric Society 1986;34(7):507–14. [MEDLINE: 86251890]
Dublin N, Alhasso AA, Stewart L. Anticholinergic drugs versus
other medications for overactive bladder syndrome in adults. Patrick 2004
Cochrane Database of Systematic Reviews 2004, Issue 2. [Art. No.: Patrick K, Alhasso AA, Stewart L. Anticholinergic drug versus non-
CD003190. DOI: 10.1002/14651858.CD003190.pub2] drug active therapies for overactive bladder syndrome in adults.
Cochrane Database of Systematic Reviews 2004, Issue 2. [Art. No.:
Haeusler 2002 CD003193. DOI: 10.1002/14651858.CD003193.pub2]
Haeusler G, Leitich H, van Trotsenburg M, Kaider A, Tempfer CB.
Shumaker 1994
Drug therapy of urinary urge incontinence: A systematic review.
Shumaker SA, Wyman JF, Uebersax JS, McClish D, Fantl JA.
Obstetrics and Gynecology 2002;100:1003–16.
Health related quality of life measures for women with urinary
Harvey 2001 incontinence: the Incontinence Impact Questionnaire and the
Harvey MA, Baker K, Wells GA. Tolterodine versus oxybutynin in Urogenital Distress Inventory. Quality of Life Research 1994;3:
the treatment of urge urinary incontinence: A meta-analysis. 291–306.
American Journal of Obstetrics and Gynecology 2001;185(1):56–61. Stewart 2001
Hashim 2004 Stewart WF, Corey R, Herzog AR, Wein A, Norton PA, Payne C et
Hashim H, Abrams P. Drug treatment of overactive bladder. al on behalf of the NOBLE Program Research Team. Prevalence of
Efficacy, cost and quality-of-life considerations. Drugs 2004;64 overactive bladder in women: results from the Noble Program.
(15):1643–56. International Urogynecology Journal 2001;12(3):S66.
Hay-Smith 2003 Ueda 2000
Hay-Smith J, Herbison P, Ellis G, Moore K. Anticholinergic drugs Ueda T, Tamaki M, Kageyama S, Yoshimura N, Yoshida O. Urinary
versus placebo for overactive bladder syndrome in adults. Cochrane incontinence among community-dwelling people aged 40 years or

older in Japan: prevalence, risk factors, knowledge and self-
perception. International Journal of Urology 2000;7(3):95–103.
Wallace 2004
Wallace SA, Roe B, Williams K, Palmer M. Bladder training for
urinary incontinence in adults. Cochrane Database of Systematic
Reviews 2004, Issue 1. [Art. No.: CD001308. DOI: 10.1002/
14651858.CD001308.pub2]
Ware 1993
Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health survey
manual and interpretation guide. Boston, MA: The Health Institute,
New England Medical Centre, 1993.
∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Abrams 1996
Methods RCT. Placebo controlled, parallel design.

Phase II.
Double-blind.
Masking of assessors not stated.
PP analysis.
Multicentre.
Participants 82 patients.
Inclusion criteria: objective signs of neurological disease and urinary frequency or incontinence and
urodynamically proven detrusor hyperreflexia.
Exclusion criteria: treatment within preceding 14 days with other anticholinergic drugs.
Interventions Group 1: placebo (n=15)

Group 2: tolterodine 0.5 mg bid (n=12)
Group 3: tolterodine 1 mg bid (n=14)
Group 5:tolterodine 4mg bid (n=10)
14 day treatment period.
2 week washout.
Outcomes Number of leakage episodes, frequency of micturition, volume voided.

Urodynamic parameters.
Adverse events.
Laboratory tests.
ECG.
Blood pressure.
Notes Abstract.
Dose reduction permitted within first week.
Dropouts not stated.
Incomplete subjective data.
No follow up.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate

Abrams 1998

Phase III.
Randomised 2:2:1
Double-blind.
ITT analysis.
Multicentre (42) Multinational (3).
Participants 293 male and female patients.

Inclusion criteria: At least 18 years with urodynamically confirmed overactive bladder, increased frequency
of micturition (at least 8/24 hours), UI (at least 1/24 hours), and/or urgency.
Exclusion criteria: clinically significant stress incontinence, detrusor hyperreflexia, hepatic, renal or haemo-
tological disorders, symptomatic or recurrent UTI, BOO, bladder training or electrostimulation therapy,
indwelling catheter or self catheterisation, pregnant or breastfeeding or women not using reliable contra-
ception.

Group 2 : tolterodine 2 mg bid (n=118)
Group 3: oxybutynin 5 mg tid (n=118)
12 week treatment period.
One week washout.
Outcomes Symptom questionnaire ( 6 point rating severity scale)

Number of leakage episodes, frequency of micturition, volume voided.
Adverse events.
Laboratory tests.
Blood pressure.
Notes Dose reduction to prevent withdrawal.

Two week follow up.
37 dropouts (Group 1:7, Group 2:10, Group 3:20)
Company support declared.
Risk of bias
Anderson 1999
Methods RCT. Parallel design.

Phase III.
Double-blind.
Multicentre (13)

Anderson 1999 (Continued)

Inclusion criteria: urge incontinence or mixed incontinence with a primary urge component with at least
6 urge incontinent episodes/week when not taking medication. Community dwelling in good health.
Exclusion criteria: those with known treatable genitourinary causes of incontinence, for example infection
and/or obstruction; those with greater than 100 ml post-void residual; men who had undergone prostate
surgery in the previous 9 months; those at risk for complete urinary retention or other disorders caused
by anticholinergic therapy; those receiving drugs other than oxybutynin, hyoscyamine or propantheline
which were considered effective in the treatment of urge incontinence; those with a positive urine drug
screen; pregnant or lactating women; those with glaucoma, severe narrowing of the gastrointestinal tract
or myasthenia gravis.
Interventions Group 1: Controlled release oxybutynin of 5, 10, 15, 20, 25 or 30 mg daily (n=53)
Group 2: immediate release oxybutynin 5 mg one to four times daily. (n=52)
Both groups dose titrated to maximum tolerated dose.
Final dose for 2 weeks after achieving effective dose.
1 week washout plus one week baseline period.

Post void residual (ultrasound)
Adverse events.
Laboratory tests.
ECG.
Compliance by pill count.
Notes All patients showed a previous response to oxybutynin.

Dose reduction permitted for adverse events.
13 dropouts (Group 1:7, Group 2:6)
Risk of bias
Appell 2001

Double-blind.
Multicentre (37)

Inclusion criteria: overactive bladder with between 7 and 50 episodes of urge incontinence/week and 10
or more voids/24 hours. Patients with mixed stress and urge incontinence eligible if majority of leakage
episodes related to urge incontinence.
Exclusion criteria: other causes of incontinence (e.g. UTI, interstitial cystitis, urinary tract obstruction,
urethral diverticulum, bladder tumour or stone, prostate cancer). Pelvic, vaginal, bladder or prostate

Appell 2001 (Continued)
surgery, or delivered a baby less than 6 months before study enrolment. Postvoid residual more than 150ml
or at risk of developing complete urinary retention if placed on antimuscarinics. Clinically important
medical problems or other organ abnormalities for whom administration of ER oxybutynin or tolterodine
would present undue risk. Haematuria or a positive urine culture; uncontrolled narrow-angle glaucoma,
obstructive uropathy, myasthenia gravis, pelvic organ prolapse to the hymenal ring, or gastrointestinal
conditions or risk of gastric retention.
Use of medications with anticholinergic activity used to treat other conditions. Use of an investigational
drug within previous month or with known allergies or hypersensitivities to oxybutynin or tolterodine.
Current alcohol or drug abuse. Pregnant or breast-feeding women. Inability to follow study schedule or
directions. Unable to swallow medication whole.
Interventions Group 1: oxybutynin extended release 10 mg/day (n=185)

Group 2: tolterodine immediate release 2 mg bid (n=193)
Outcomes Number of total leakage episodes, urge incontinence episodes,

frequency of micturition.
Adverse events.
Postvoid residual (ultrasound)
Laboratory tests.
ECG.
Notes Randomised by severity of urge incontinence.

Recruitment solely from specialty practices.
Fixed dose regimen.
No follow up.
Risk of bias
Bagger 1985
Methods RCT. Placebo controlled, cross-over design. Double-blind.

ITT analysis.
Participants 18 female patients.

Inclusion criteria: urge incontinence as defined by the International Continence Society.
Exclusion criteria: recent cystitis, pregnancy, vaginal vault prolapse and stress incontinence. Major neu-
rological disorders. Intake of drugs with presumed effect on bladder function.
Interventions Treatment 1: placebo

Treatment 2: emepronium carrageenate 500 mg per day

Bagger 1985 (Continued)
Group 3: emepronium carrageenate 1000 mg per day.

2 week period for each treatment.

Adverse events.
Laboratory tests.
Notes 1 dropout (Treatment 2)

No follow up.
Data not in useable form for this review.
Risk of bias
Birns 2000
Methods RCT. Parallel design. Double-blind.

ITT analysis.
Multicentre (15)

Inclusion criteria: detrusor instability or hyperreflexia. Outpatients of either sex, aged 18-76 years, with
voiding problems which were currently stabilized on and tolerant to treatment with the reference drug.
Patients to have bladder sensation, be able to keep a diary and willing to give consent.
Exclusion criteria: Any medical condition for which anticholinergic medication is contraindicated; a his-
tory of myasthenia gravis, glaucoma or functional or organic gastrointestinal obstructive disorders. Symp-
tomatic UTI’s, clinically significant BOO or symptoms of only nocturnal enuresis. Pregnant, lactating or
child-bearing age females not using adequate contraceptive measures. No other anticholinergic drugs or
drugs with anticholinergic side effects during the trial.
Interventions Group 1: oxybutynin extended release 10 mg once daily (n=63)

Group 2: oxybutynin immediate release 5 mg bid (n=67)
2 weeks screening on conventional oxybutynin followed by 4 weeks of double-blind treatment.
Outcomes Number of leakage episodes, frequency of micturition.

Adverse events.
Laboratory tests.
Notes 5 dropouts (Group 1:2, Group 2:3)

Dose reduction not permitted during treatment period.
Incomplete subjective data.

Birns 2000 (Continued)
Risk of bias
Burton 1994
Methods RCT. Cross-over design.


Inclusion criteria: urodynamically proven detrusor instability.
Exclusion criteria not stated.
Interventions Treatment 1: oxybutynin 2.5 mg tid

Treatment 2: oxybutynin 2.5 mg as necessary.
6 week treatment period for each treatment.
Two week washout between treatments.
Outcomes Symptomatic improvement (VAS)

Patient preference score.
Number of leakage episodes, frequency of micturition.
Pad test.
Adverse events (VAS)
Notes Abstract.
Risk of bias
Allocation concealment? Unclear B - Unclear
Chaliha 1998
Methods RCT. Placebo controlled,

parallel design. Double-blind.
Multicentre.
Participants 76 participants.
Inclusion criteria: Low compliance bladder, urodynamically confirmed detrusor instability.

Chaliha 1998 (Continued)
Interventions Group 1: trospium chloride 10 mg bid

Group 2: trospium chloride 20 mg bid Group 3: trospium chloride 40 mg bid
Group 4: placebo
Outcomes Urodynamic parameters.

Adverse events.
Biochemical analyses.
Tolerability score.
Notes Abstract
Numbers for each group not stated.
Risk of bias
Chapple 2002
Methods RCT.
Placebo and active controlled. Parallel design.
Phase II.
Double blind.
Multicentre.
Multinational.

Inclusion criteria: Urodynamic evidence of idiopathic detrusor overactivity within 6 months of study
inclusion. At least 8 micturitions/24 hours. At least 3 urinary incontinent or 3 urgency episodes over a 3
day period.
Interventions Group 1 placebo: (n=36)

Group 2: YM905 2.5 mg once daily (n=40)
Group 3: YM905 5 mg once daily (n=37)
Group 6: tolterodine 2mg bid (n=37)
2 week washout.

Adverse events.
Post void residual (ultrasound)

Chapple 2002 (Continued)
Laboratory tests.
ECG.
Vital signs.
Notes Abstract.
Group withdrawals not stated.
No follow up.
Risk of bias
Davila 2001a
Methods RCT. Placebo controlled,

parallel design.
Phase III.
Double-blind.

Inclusion criteria: at least 10 urge leakages per week; at least 8 voids per day; average urinary volume not
> 350 ml.
Interventions Group 1: placebo

Group 2: transdermal oxybutynin 1.3 mg/day twice a week

IIQ, UDI, SF36.
Adverse events.
Laboratory tests.
Notes Abstract
Numbers for each group not stated.
73 dropouts (group not stated)
No follow up.
Risk of bias

Davila 2001a (Continued)
Davila 2001b
Methods RCT. Placebo and active controlled.

Parallel design.
Double blind.
Multicentre.

Inclusion criteria: At least 18 years of age with history of urge or mixed incontinence, with predominance
of urge. Previous diagnosis of motor urge urinary incontinence with symptomatic improvement during
a minimum 6 weeks of oral oxybutynin. Minimum 3 incontinent episodes daily and a greater than 30%
increase after 2 week washout. Urodynamically confirmed detrusor instability and patient symptoms.
Interventions Group 1: oral oxybutynin plus placebo transdermal (n=38)

Group 2: transdermal oxybutynin plus oral placebo (n=38)
2 week washout.
Outcomes Symptom questionnaire (VAS)

Number of leakage episodes.
Adverse events.
Laboratory tests.
ECG.
Vital signs and site tolerability.
Notes Dose titration.

2 dropouts (Group 1:1, Group 2: 1)
Risk of bias
Di Stasi 2001a
Methods RCT. Placebo controlled, crossover design.

Double-blind.
Participants 10 patients with hyperreflexia unresponsive to standard oral and intravesical oxybutynin regimens.
Inclusion criteria: unacceptable detrusor activity suppression (clinical and urodynamic)by oral and in-
travesical passive diffusion oxybutynin; intolerable systemic side effects from oral oxybutynin; bladder

Di Stasi 2001a (Continued)
capacity at least 120 ml; no vesicoureteral reflux. One month washout of anticholinergic medications. No
UTI’s.
Interventions Treatment 1: placebo

Treatment 2: oral oxybutynin (5 mg)
Treatment 3: control intravesical with passive diffusion
Treatment 4: intravesical oxybutynin 5 mg/100 ml with passive diffusion
Treatment 5: control intravesical with electromotive administration
Treatment 6: intravesical oxybutynin 5mg/100ml with electromotive drug administration.
6 x 8 hourly sessions at weekly intervals.
Outcomes Urinary leakage, bladder volume.

Urodynamic hyperreflexic episodes.
Laboratory tests.
Notes Outcomes and population

different from other studies.
No follow up.
Risk of bias
Di Stasi 2001b
Methods RCT. Placebo controlled. Crossover design. Double blind. Masking of assessors not stated.
Participants 12 patients with hyperreflexia unresponsive to standard oral and intravesical

oxybutynin regimes.
Inclusion criteria: unacceptable detrusor activity suppression (clinical and urodynamic)by oral and in-
travesical passive diffusion oxybutynin; intolerable systemic side effects from oral oxybutynin; bladder
capacity at least 120ml; no vesicoureteral reflux. No UTI’s.
Interventions Treatment 1: Oral placebo

Treatment 2: Oral oxybutynin (5 mg)
Treatment 3: Intravesical sodium chloride
Treatment 4: Intravesical oxybutynin 15 mg in 0.45% sodium chloride
Treatment 5: Electromotive sodium chloride
Treatment 6: Electromotive oxybutynin (15 mg)
6 x 8 hourly sessions at weekly intervals.
Outcomes Bladder compliance, post-void residual volume,

urinary leakage episodes, uninhibited detrusor contraction components.

Di Stasi 2001b (Continued)
Notes Outcomes and population different from other studies.

Risk of bias
Diokno 2003
Methods RCT. Parallel design. Double blind. ITT analysis.

Multicentre (71)

Inclusion criteria: Women at least 18 years of age with overactive bladder (21-60 urge incontinent episodes/
week and an average of at least 10 voids/24 hours). More urge than non-urge incontinent episodes. History
of prior treatment with anticholinergics allowed and drug not queried. On stable dose for at least 90 days
before entering study.
Exclusion criteria: Treatable genitourinary conditions that could cause incontinence; post void residual
greater than 150 ml; risk of developing urinary retention; clinically important medical problems that
would put patient at risk of anticholinergic effects, haematuria, uncontrolled narrow angle glaucoma,
reduced gastrointestinal motility and known hypersensitivity to study medications.
Interventions Group 1: oxybutynin extended release (n=391)

Group 2: tolterodine extended release (n=399)
Outcomes Urge incontinence episodes, total incontinence episodes, micturition frequency over 7 days at baseline,
2,4,8 and 12 weeks.
Dry mouth and adverse events.
Notes 94 dropouts (Group 1:52; Group 2:42)

No follow up.
Risk of bias

Dmochowski 2003

Double-blind, double-dummy.
Multicentre (48)

Inclusion criteria: Adult patients with OAB and prior beneficial response to anticholinergics for up to one
year of therapy. At least 4 incontinent episodes, 24 or more voids, and less than 350 ml average voided
volume over three day urinary diary.

Group 2: extended release tolterodine (TOL-CR) 4mg once daily (n=123)
Group 3: oxybutynin transdermal (OXY-TDS) 3.9 mg/day twice weekly. (n=121)
2 week washout.

Adverse events
IIQ.
Notes 15 dropouts (Group 2: 2; Group 3: 13)

No follow up.
Risk of bias
Drutz 1999
Methods RCT. Placebo and comparator controlled, parallel design.

Randomised 1:2:2.
Double-blind.
PP analysis.
Multicentre (25). Multinational (2)
Participants 277 patients (male and female) Mean age 64.

Inclusion criteria: At least 18 years, understood and signed informed consent. Females to be post
menopausal, surgically sterile or using adequate contraception. Cystometric evidence of detrusor overac-
tivity plus urinary frequency (at least 8/day) and either UI (at least 1/24 hours and/or urgency.
Exclusion criteria: clinically evaluated stress incontinence; hepatic or renal disease; diseases that made
patient unsuitable for study; recurrent UTI; interstitial cystitis; uninvestigated haematuria or haematuria
secondary to malignant disease, indwelling catheter or intermittent catheterization; treatment with any
investigational drug in 2 months pre entry; previous treatment with tolterodine; electrostimulation or
bladder training within 14 days entry; treatment with any anticholinergic drug or urge incontinence drug
within 14 days; unstable dosage of any treatment with anticholinergic adverse effects or initiation of such

Drutz 1999 (Continued)
treatment during study; previously serious adverse effects on oxybutynin; average total voided/24 hours >
3000 ml; clinically significant voiding difficulty with risk of urinary retention (residual volume >200 ml
or flow rate< 10 ml/second).

Outcomes Number of leakage episodes, frequency of micturition and volume voided.

Adverse events.
Laboratory tests.
Blood pressure.
Notes Dose reduction permitted within first 2 weeks only as alternative to withdrawal.
57 dropouts (Group 1: 8,
Group 2: 14, Group 3: 35)
36% placebo, 36% tolterodine and 63% oxybutynin patients were excluded from the analysis.
No follow up.
Risk of bias
Froehlich 1998

Single-blind.
ITT analysis.

Inclusion criteria: urgency and/or UI confirmed on urodynamics or clinically.
Exclusion criteria: serious medical illness, contraindications to anticholinergic or calcium channel blocking
medication, peripheral denervation of bladder, pregnancy, severe cardiovascular or liver disease, renal
failure, maximum bladder capacity > 800 ml, unco-operative patients.
Interventions Group 1: intravesical oxybutynin 30mg/30mls (n=21)

Group 2: intravesical placebo (n=21)
Group 3: intravesical trospium chloride 40mg/30ml (n=21)
Group 4: intravesical verapamil 80mg (n=21)
Single instillation.

Adverse events.

Froehlich 1998 (Continued)
Notes Translated from German.

No subjective measures
No dropouts.
No follow up.
Risk of bias
Gajewski 1986

Double-blind.
Inclusion criteria: urinary symptoms (frequency, nocturia, urgency and urge incontinence). Detrusor
hyperreflexia confirmed by cystometry. Multiple sclerosis.
Exclusion criteria: UTI.
Interventions Group 1: oxybutynin 5 mg tid (n=19)

Group 2: propantheline 15 mg tid (n=15)
6-8 week treatment period.
Outcomes Urge incontinence, urgency, frequency and

nocturia graded according to severity.
Adverse events.
Notes Dropouts not

stated.
No follow up.
Support from Medical Research Council.
Risk of bias

Hofner 2000

Randomised 3:1.
Double-blind.
Multicentre (53)
Multinational (6)

Inclusion criteria: diagnosed urge syndrome or urge incontinence, solely or associated with stress incon-
tinence or neurogenic detrusor hyperactivity.
Interventions Group 1: trospium chloride 2x20 mg daily (n=268)

Group 2: oxybutynin 2x5 mg daily (n=90)
Outcomes Number of leakage episodes, frequency of micturition, urgency.

Adverse events.
Laboratory tests.
ECG and cardiovascular examination.
Patient and investigator tolerability assessment.
Notes Abstract.
2-4 week follow up.
Risk of bias
Holmes 1989
Methods RCT. Crossover design. Single blind.

Single centre.
ITT analysis.

Inclusion criteria: idiopathic detrusor instability confirmed by neurologic and urodynamic assessment.
Sterile urine.
Exclusion criteria: intravesical and urethral pathologies.
Interventions Treatment 1: oxybutynin 5 mg tid

Treatment 2: propantheline 15 mg tid.
Each treatment period one month with one week washout between.

Holmes 1989 (Continued)
Outcomes Assessment of patient improvement.

Frequency of micturition, nocturia.
Visual analogue scale for severity of incontinence and side effects.
Residual urine.
Notes Dropouts not stated.

No follow up.
Patient regulated variable dose regimen.
Risk of bias
Homma 2002

Phase III.
Randomised 2:2:1
Blinding not stated.
ITT analysis.
Multicentre (57)

Inclusion criteria: urge incontinence at least 5/week; urinary frequency at least 8/day.

Group 2: extended release tolterodine 4 mg once daily (n=239)
14 day washout.

Adverse events.
Notes Abstract.
No follow up.
Risk of bias

Homma 2002 (Continued)
Jacquetin 2001
Methods RCT. Placebo controlled, parallel group.

Phase III.
Double-blind.
Multicentre.
Multinational (4)

Inclusion criteria: Over 18 years with urodynamically verified detrusor overactivity, symptoms of urinary
frequency and either urge incontinence or urgency or both.
Exclusion criteria: stress incontinence, hepatic or renal disease, symptomatic or recurrent UTI, interstitial
cystitis, haematuria, clinically significant voiding difficulty, patients receiving bladder training, electros-
timulation, or having an indwelling catheter or intermittent catheterisation; pregnant or nursing women
or women of childbearing age not using reliable contraception.
Interventions Group: placebo (n=51)

2 week washout.
Outcomes Number of leakage episodes,

frequency of micturition, volume voided.
Adverse events.
Laboratory tests.
Blood pressure.
Notes 6 dropouts (Group 1:1, Group 2:3, Group 3:2)

2 week follow up.
Risk of bias

Jonas 1997

Double-blind.
Multinational(3).
Multicentre (58)
Participants 242 patients (male and female) Mean age 58.

Inclusion criteria: at least 18 years with detrusor overactivity and evidence of frequency in combination
with UI, urinary urgency or both.
Exclusion criteria: significant stress incontinence, hepatic or renal disease, any condition contraindicating
anticholinergic therapy, recurrent UTI’s, interstitial cystitis, uninvestigated hematuria or clinically signifi-
cant voiding difficulty with risk of urinary retention. Patients on any anticholinergic treatment or using an
indwelling catheter or who had electrostimulation or bladder training in the last 14 days prior to inclusion
visit.

2 week washout.

Adverse events.
Laboratory tests.
Blood pressure.
Notes 10 dropouts (Group 1: 3,

Group 2: 4,
Group 3: 3)
No follow up.
Risk of bias
Junemann 1999

Double-blind. Masking of assessors not stated.
ITT and PP analyses.
Multicentre (2)
Participants 175 patients with urge syndrome.

Inclusion and exclusion criteria not stated.

Junemann 1999 (Continued)
Interventions Group 1: trospium chloride 40 mg qid (n=56)

Group 2: trospium chloride 2 x 40 mg qid (n=56)
Group 3: placebo (n=58)
Outcomes Frequency of micturition.

Adverse events.
Notes Abstract
No follow up.
Risk of bias
Junemann 2000

Double-blind.
ITT analysis.
Multicentre.
Multinational (3).
Participants 234 patients

Inclusion criteria: urge syndrome (motor urge, sensory urge and combined motor urge and stress incon-
tinence)verified by urodynamics.
Interventions Group: trospium chloride 2 x 20 mg daily (n=57)

Group 2: tolterodine 2 x 2 mg daily (n=63)
3 week study.
10 day wash out.
Outcomes Frequency of micturition.

Adverse events.
Laboratory tests.
Physical examinations.
Notes Abstract
No follow up.

Junemann 2000 (Continued)
Risk of bias
Kramer 1987
Methods RCT. Crossover design.

Double-blind.
Multicentre (2)

Inclusion criteria: weight 56-85kg; frequency, urgency or urge incontinence confirmed by symptoms or
urodynamics.
Exclusion criteria: kidney, liver or circulatory disease; UTI; use of anticholinergics; glaucoma; Parkinson’s
disease.
Interventions Treatment 1: emepronium 200mg tid followed by oxybutynin 5 mg tid followed by placebo (n=30)
Treatment 2: emepronium 200 mg tid followed by flavoxate 200 mg tid followed by placebo (n=30)
Treatment consisted of two active drugs taken at random, followed by placebo, during consecutive 3 week
periods.
Emepronium (n=60), oxybutynin (n=30), flavoxate (n=30), placebo (n=60)
Outcomes Subjective outcomes.

Adverse events.
Notes Translated from Flemish.

19 dropouts ( Group 1: 10,
Group 2: 9)
No follow up.
Risk of bias

Lee 2001

Double-blind.
Multicentre.

Inclusion criteria: not clear.
Exclusion criteria: not stated.
Interventions Group 1: tolterodine 2 mg bid (n=112),

Group 2; oxybutynin 5 mg bid (n=116)
Outcomes Patient perception of treatment benefit and tolerability.

Adverse events.
Notes Abstract.
No follow up.
Risk of bias
Leung 2001

Double-blind.
Assessors masked.
Multicentre (2)

Inclusion criteria: urodynamically proven detrusor instability.
Exclusion criteria: psychiatric morbidity (MMSE), cardiovascular morbidity (ECG)
Interventions Group 1: tolterodine 2 mg bid

Group 2: oxybutynin 5 mg bid.
Outcomes Symptom questionnaire (VAS)

Urinary prevalence questionnaire.
Pad tests.
Adverse events.
Xerostomia Questionnaire.
Kings Health Questionnaire.

Leung 2001 (Continued)
SF36
Dowell Bryant Incontinence Cost Index.
Compliance by self reporting and pill count.
Notes Abstract.
Group numbers not stated.
2 week follow up for adverse events.
Risk of bias
Madersbacher 1995

Double-blind.
masking of assessors not stated.
Multicentre.

Inclusion criteria: detrusor hyperreflexia with spinal cord injury.
Exclusion criteria: acute UTI; glaucoma, known allergy to atropine, oxybutynin or trospium chloride;
tachycardia, renal, hepatic and/or cardiovascular insufficiency; intake of other anticholinergic drugs, age
below 18 years, body weight over 90 kg.
Interventions Group 1: trospium chloride 20 mg bid (n=52),

One week washout.

Adverse events.
Laboratory tests.
Notes 10 dropouts (Group 1: 3, Group 2: 7)

No follow up.
Risk of bias

Madersbacher 1999

Randomised 2:2:1.
Double-blind.
ITT analysis.
Multicentre (32). Multinational (2).
Participants 366 male and female patients

Inclusion criteria: history of urgency or urge incontinence, maximum cystometric bladder capacity at least
300 ml ; at least 18 years and body weight at least 45 kg.
Exclusion criteria: detrusor hyperreflexia, postoperative (bladder)incontinence, intravesical obstruction,
post void residual urine >15% maximum cystometric bladder capacity, acute UTI’s, angina pectoris,
glaucoma, megacolon, clinically relevant cardiac, renal or hepatic dysfunctions, tachy/dysrhythmias, fre-
quency or nocturia due to heart or renal insufficiency, or overt cerebral sclerosis. Use of other spasmolytics
or anticholinergics, B-sympathomimetics, calcium antagonists, dopamine agonists, prolactin inhibitors,
prostaglandin synthesis inhibitors, striated muscle relaxants or medication for Parkinsonism.
Interventions Group 1: propiverine 15 mg tid (n=149)

Group 2: oxybutynin 5 mg bid (n=145)
7 day washout.
Outcomes Frequency of micturition, urgency.

Clinical symptoms and overall assessment documented by physicians.
Incontinence questionnaire (Gaudenz)
Notes 42 dropouts ( Group 1: 19, Group 2: 16, Group 3: 7)

No follow up.
Risk of bias
Malone-Lee 2001a

Randomised 3:3:2.
Double-blind.
ITT analysis.

Inclusion criteria: at least 65 years with 8 or more voids per 24 hours and/or urge incontinence at least 1

Malone-Lee 2001a (Continued)
per 24 hrs.
Exclusion criteria: “standard”.

14 day washout.

Adverse events.
Biochemistry, haematology, ECG.
Notes 12 dropouts (Group 1: 1, Group 2: 4, Group 3: 7)

Two week follow up for adverse events.
Risk of bias
Malone-Lee 2001b

Double-blind.
Multicentre (44)
Multinational (2)

Inclusion criteria: at least 50 years of age with symptoms of urinary frequency (8 or more voids/24 hours)
with urgency and/or urge incontinence (1 or more/24 hours). Mobile patients who could attend clinic,
able to complete a voiding diary correctly and understand study procedures.
Exclusion criteria: significant stress incontinence; urinary outflow obstruction; symptomatic urinary in-
fection, interstitial cystitis, unexplained haematuria, urinary catheterisation, hepatic or renal disease,
concomitant antimuscarinic medication, electrostimulation therapy or bladder training, treatment with
tolterodine or oxybutynin in the 3 months before randomisation and exposure to any other investigational
drug in the preceding 2 months.
Interventions Group 1: tolterodine 2 mg bid (n=190)

Group 2: oxybutynin 2.5 mg increasing to 5 mg bid after 2 weeks of treatment (n=188)
2 week washout.
Outcomes Patient assessment (6 point scale)


Malone-Lee 2001b (Continued)
Pads/24 hours.
Adverse events.
Laboratory tests.
Blood pressure.
Notes Dose reduction permitted to prevent withdrawal only in oxybutynin group.

2 week follow up.
70 dropouts (Group 1: 29, Group 2: 41)
Risk of bias
Massey 1986

Double-blind.

Inclusion criteria: cystometrically proven detrusor instability.
Exclusion criteria: bacteriuria or concomitant medication likely to affect urinary tract such as beta blockers
or diuretics.
Interventions Treatment order randomised into groups between placebo (n=67) and low dose emepronium (1200
mg/day), medium dose emepronium (1600 mg/day) or high dose emepronium (2000 mg/day)
All patients took 2.5 tablets qid at all stages.
The titration period was 1 week at 1600mg/day.
No washout.
Each treatment period 28 days.
Outcomes Number of leakage episodes, frequency of micturition, voided volume.

Adverse events.
Residuals.
Laboratory tests.
Notes 24 dropouts.
No follow up.
Risk of bias

Massey 1986 (Continued)
Mazur 1995

Open randomisation.
Multicentre (10)

Inclusion criteria: urge incontinence/urgency.
Exclusion criteria: neurogenic bladder dysfunction, UTI, gastrointestinal obstruction, cardiovascular dis-
ease.
Potential pregnancy. Concomitant medication which could have an affect on detrusor function.
Interventions Group 1: propiverine hydrochloride 15 mg bid (n=46)

Group 2: propiverine hydrochloride 30 mg bid (n=47)
Group 3: propiverine hydrochloride 45 mg tid (n=49)
Group 4: propiverine hydrochloride 60 mg qid (n=43)
One week washout.
Outcomes Symptomatic improvement (VAS and ordinal scale).

Frequency of micturition, volume voided.
Adverse events.
Laboratory tests.
Notes No follow up.

6 dropouts (Group 1: 1, Group 2: 1, Group 3: 1, Group 4: 3)
Risk of bias

Millard 1999

Phase III.
Randomised 1:2:2.
Double-blind.
ITT analysis.
Multicentre.
Multinational (2).
Participants 316 patients (male and female)

Inclusion criteria: At least 18 years,with cystometrically proved detrusor overactivity ( idiopathic or hy-
perreflexia or contractions with an amplitude at least 10 cm water); at least 8 voids/24hours; at least 1
incontinent episode/24hours and/or urinary urgency; Premenopausal women required to use adequate
contraception.
Exclusion criteria: stress incontinence (cough test); clinically significant voiding difficulty; recurrent UTI’s;
interstitial cystitis, uninvestigated haematuria or any bladder cancer; indwelling catheter or self catheter-
isation; hepatic or renal disease; narrow angle glaucoma; electrostimulation or bladder training or anti-
cholinergic drug initiated 14 days before or any time during study; unstable dose of any treatment with
anticholinergic side effects; average total voided volume > 3000 ml/24 hours; treatment with any other
investigational drug during or 2 months pre study.

2 week washout.
Outcomes Patient rating of bladder condition (6 point Likert)

Leakage episodes, frequency of micturition, number of voids.
Achievement of normal voiding frequency (< 8/day) cured incontinence and complete cure.
Adverse events.
Laboratory tests.
ECG.
Blood pressure.
Notes No dose reductions permitted.

25 dropouts ( Group 1: 3, Group 2: 7; Group 3: 15)
No follow up.
Risk of bias

Nilsson 1997
Methods RCT. Crossover design. Double-blind.

Multicentre.

Inclusion criteria: subjective symptoms of urge incontinence, history of urge incontinence and detrusor
instability confirmed by cystometry. Patients screened between stress and urge incontinence. Unexposed
to oxybutynin within one month preceding study.
Exclusion criteria: concomitant medication with loop-diuretics, prazosin, anticholinergics or antidepres-
sants possessing anticholinergic properties.
Interventions Treatment 1: extended release oxybutynin 10 mg once daily

Treatment 2: immediate release oxybutynin 5 mg bid
Two 60 day treatment periods.
One month washout pre study. No washout between crossover.
Outcomes VAS and degree of disability questionnaire.

Frequency of micturition, maximal volume and total volume.
Pad test.
Adverse events.
Laboratory tests.
Notes 1 dropout (Treatment 1)

No follow up.
Risk of bias
Osca 1997

Double-blind.
Inclusion criteria: hyperactive neurogenic bladder.
Interventions Group 1: trospium chloride 20 mg bid

Group 2: oxybutynin 5 mg tid
Outcomes Urodynamic parameters

Residual urine.

Osca 1997 (Continued)
Adverse events.
Notes Abstract.
Risk of bias
Rentzhog 1998
Methods RCT. Placebo controlled, parallel design. Phase II.

Double-blind. Masking of assessors not stated.
PP analysis.

Inclusion criteria: aged 18-75 years with symptoms of urinary urgency, increased frequency and/or urge
incontinence. Urodynamically confirmed detrusor instability. Insignificant bacteriuria and normal labo-
ratory tests. No evidence of bladder outlet obstruction.
Exclusion criteria: stress incontinence or detrusor hyperreflexia; clinically significant cardiac, hepatic, renal
or haematological disorders; patients with contraindications to antimuscarinic agents; and pregnant or
lactating women of childbearing age who were not using reliable contraception.

Group 2: tolterodine 0.5 mg bid (n= 21)
Group 5: tolterodine 4 mg bid(n=16)
3 week washout.
Outcomes Symptomatic improvement (VAS).

Number of pads used.
Adverse events.
ECG.
Notes Dose reduction allowed to next lowest level.

16 dropouts ( Group 1: 3, Group 2: 4, Group 3: 1, Group 4: 3, Group 5: 5)
Two week telephone follow up.
Risk of bias

Rentzhog 1998 (Continued)
Salvatore 1995

Single centre.

Inclusion criteria: detrusor instability confirmed by videocystourethrography.
Interventions Group 1: oxybutynin 2.5 mg bid increased over 6 weeks to a maximum of 5 mg tid
Group 2: oxybutynin 5 mg once daily increased over 6 weeks to 5 mg tid
Outcomes Symptom questionnaire.

Adverse events.
Compliance.
Notes Abstract.
Dose adjusted to tolerability.
2 year follow up.
25 dropouts.
Risk of bias
Stohrer 2002

Double-blind.
ITT analysis.
Multicentre (20)

Inclusion criteria: At least 18 years with neurogenic detrusor overactivity. Maximum cystometric capacity
less than 300ml.
Interventions Group 1: propiverine 15 mg tid (n=46)


Stohrer 2002 (Continued)
One week washout.
Outcomes Number of leakage episodes, frequency of micturition.

Adverse events.
Notes Abstract.
40 dropouts.
No follow up
Risk of bias
Sussman 2002

Double-blind.
ITT analysis.
Multicentre (34)

Inclusion criteria: At least 18 years with overactive bladder defined by symptoms of urinary frequency and
urgency, with or without urge incontinence.
Exclusion criteria: pure stress incontinence; urinary retention, gastric retention or narrow-angle glau-
coma; significant hepatic or renal dysfunction; symptomatic or recurrent UTI; use of electrostimulation,
bladder training, pelvic floor exercise within one week of the first study visit or expected to start during
study; indwelling catheter or intermittent self-catheterisation; and any contraindication to antimuscarinic
treatment. Pregnant or breastfeeding or women not using realisable contraception. Treatment within one
week of first visit with any drug for urge incontinence (excepting oestrogen therapy started more than 2
months prior to first visit) or with any anticholinergic drug or potent inhibitors of cytochrome P450 3A4
isoenzymes.
Interventions Group 1: tolterodine extended release 2 mg (n=333)

Group 2: tolterodine extended release 4 mg (n=336)
Group 3: oxybutynin extended release 5 mg (n=313)
Group 4: oxybutynin extended release 10 mg (n=307)
Outcomes Changes in patient perception of bladder condition and patient assessment of treatment benefit.
Investigator assessment of treatment benefit.
Dry mouth.
Notes Two parallel design studies.

No dose adjustments.

Sussman 2002 (Continued)
209 dropouts (Group 1: 48, Group 2: 39, Group 3: 59, Group 4: 63)
No follow up.
Risk of bias
Thuroff 1991

Double-blind.
Multicentre.
Multinational (2).

Inclusion criteria: At least 15 years with symptoms of frequency, urgency and/or incontinence. Cystometry
findings related to either idiopathic (unstable detrusor) or neurogenic origins (detrusor hyperreflexia).
Exclusion criteria: No drugs affecting lower urinary tract function to be taken. Antihypertensive med-
ication allowed if regularly taken at consistent dosage. Minor tranquillizers allowed if taken for sleep
only. Pregnancy, congestive heart failure, severe renal/liver disease, myasthenia gravis, unable to swallow/
uncooperative patient, hiatal hernia/reflux esophagitis, gastro. tract obstruction, urinary tract obstruction,
residual >50 ml, untreated UTI, hyperreflexia without urge, lower urinary tract pathological conditions.
Interventions Group 1: oxybutynin 5 mg tid (n=63)

Group 2: propantheline 15 mg tid (n=54)
One week washout.
Outcomes Urinary symptoms (VAS).

Frequency of micturition. Urodynamic parameters.
Urine analysis.
Laboratory tests.
Adverse events.
Notes 15 dropouts (Group 1: 4, Group 2: 6, Group 3: 5)

No follow up.
Risk of bias

VanKerrebroeck 1997

Double-blind.
ITT analysis.
Multicentre.

Inclusion criteria: detrusor overactivity verified by cystometry. Mean micturition frequency at least 8/24
hours. mean urge incontinence at least 1/24 hours or urgency.
Interventions Group 1: tolterodine 2 mg bid (n=120)

2 week washout.
Outcomes Patient perception of bladder condition (6 point scale)

Adverse events.
Notes Abstract.
Dose reduction permitted in first 2 weeks.
38 dropouts (Group 1: 13, Group 2: 25)
Risk of bias
VanKerrebroeck 1998
Methods RCT. Placebo controlled, parallel design. Double-blind.

PP analysis.
Multicentre (14) Multinational (4).
.
Participants 90 male and female patients with objective evidence of neurological diseases or injuries that would affect
the lower urinary tract or its nervous supply.
Inclusion criteria: 18-75 years with symptoms of urgency, increased frequency of micturition/self catheter-
ization and/or urge incontinence. Urodynamically proven detrusor hyperreflexia. Insignificant bacteriuria
and normal laboratory tests.
Exclusion criteria: stress incontinence; cardiac, hepatic, renal or hematological disorders; bladder outlet
obstruction; poor general or mental health; contraindications to antimuscarinic agents and patients already
receiving therapy for urinary incontinence. Pregnant or lactating women and women of childbearing age
not using reliable contraception.

VanKerrebroeck 1998 (Continued)

Group 2: tolterodine 0.5 mg bid (n=20)
1 week run in preceded by 2 week washout.
Outcomes Subjective urinary symptoms (VAS).

Pad test.
Adverse events.
Laboratory tests.
Blood pressure.
ECG.
Notes Two week telephone follow up.

No dropouts.
Almost half patients using self catheterisation.
Dose reduction permitted.
Risk of bias
VanKerrebroeck 2001

Randomised 1:1:1.
Double-blind.
ITT analysis.
Multicentre (167) Multinational.

Inclusion criteria: at least 18 years of age with urinary frequency (8 or more /24 hours), urge incontinence
(at least 5/week) and symptoms of overactive bladder at least 6 months.
Exclusion criteria: stress incontinence, total daily urine > 3 litres, any contraindications to antimuscarinic
treatment, significant hepatic or renal disease, symptomatic or recurrent UTI. interstitial cystitis, hematuria
or BOO, current electrostimulation or bladder training therapy, indwelling catheter or intermittent self
catheterisation. Pregnant or nursing women, and women of childbearing potential not using adequate
contraception. Other treatments for overactive bladder not allowed apart from estrogen started > 2 months
before randomisation. No treatment by any other investigational drug allowed.

VanKerrebroeck 2001 (Continued)
Interventions Group 1: tolterodine extended release 4 mg once daily (n=507)

Group 2: tolterodine immediate release 2 mg bid (n=514)
Group 3 : placebo (n=508)
1 to 2 week washout.

Adverse events.
Laboratory tests.
Some subgroups with pad tests and ECG.
Quality of life health measures.
Notes No dose reductions permitted.

187 dropouts (no group data)
One week follow up.
Risk of bias
Versi 2000

Double-blind.
Multicentre (20)

Inclusion criteria: adult community dwelling, with 7-45 urge incontinent episodes per week and at least 4
days of incontinence per week. Previous response to anticholinergic medications or to oxybutynin before
enrolment.
Exclusion criteria: clinically significant medical problems, postvoid residual greater than 100 ml ; condi-
tions in which oxybutynin is contraindicated.
Interventions Group 1: oxybutynin controlled release 5 mg/day increasing weekly to 20 mg/day (n=111)
Group 2: oxybutynin immediate release 5 mg/day increasing weekly to 20 mg/day (n=115)
2 week washout followed by randomised titration period followed by 1 week maintenance period.
Outcomes Number of total leakage episodes, urge incontinence episodes.

Adverse events.
Laboratory tests.

Versi 2000 (Continued)
Notes 16 dropouts (Group 1: 7, Group 2: 9)

Dose reduction by 5 mg for side effects.
No follow up.
Risk of bias
Wehnert 1992

Single centre.
Inclusion criteria: urgency and urge incontinence.
Exclusion criteria: inflammatory bladder changes, bladder tumours, leucoplasia of bladder or trigone;
other urological and gynaecological pathology or inflammation, outflow obstruction, unstable urethra;
other use of anticholinergics or spasmolytics.
Interventions Treatment 1: oxybutynin 5 mg tid (n=10)

Treatment 2: propiverine 15 mg tid (n=10)
Treatment 3: placebo
3 x 3 week treatment period.
Outcomes VAS for effects and side effects.

Frequency of micturition.
Residuals.
Laboratory tests.
Notes Translated from German.

No dropouts.
No follow up.
Risk of bias

Zeegers 1987
Methods RCT. Placebo controlled, cross over design. Double-blind.

Multicentre.
Participants 60 male and female patients

Inclusion criteria: 56-85 kg, frequent voiding, urgency or urge incontinence. May include patients with
neurogenic bladder.
Exclusion criteria: kidney, liver or cardiovascular pathology, obstruction or infection, ongoing anticholin-
ergic therapy, glaucoma or Parkinson’s disease.
No age or sex restriction.
Interventions Treatment 1: flavoxate 200 mg tid / emepronium bromide 200 mg bid / placebo
Treatment 2: oxybutynin 5 mg tid /emepronium bromide 200 mg tid / placebo.
Treatment consisted of two active drugs taken at random, followed by placebo, during consecutive 3 week
periods.
All 60 patients thus tested placebo and emepronium; 30 tested flavoxate and 30 tested oxybutynin.
Outcomes Independent patient and physician subjective scores.

Number of leakage episodes, frequency, urgency and enuresis.
Residual urine.
Adverse events.
Notes 19 dropouts (group not stated)

No follow up.
Risk of bias
bid=twice daily
BOO = bladder outlet obstruction
ECG = electrocardiogram
IIQ = incontinence impact questionnaire
ITT = intention to treat
kg = kilograms
ml=millilitres
MMSE = mini mental state exam
PP=per protocol
RCT = randomised controlled trial
SF36=standard form 36
tid- three times daily
UDI = urogenital distress inventory
UTI = urinary tract infection
VAS = visual analogue scale

Characteristics of excluded studies [ordered by study ID]
Appell 1997 A meta-analysis of 4 studies.

Trials not reported separately.
Gaudenz 1978 Poorly reported trial.

No useable data.
No comparisons of interest.
Larsson 1999 A meta-analysis of 4 studies.

Trials not reported separately.
Some studies published separately
Mundy 2001 A randomised crossover study with darifenacin versus oxybutynin. Principal outcomes are comparison of ambulatory
urodynamic monitoring and salivary flow.
Rosario 1995 Does not involve the comparison of two anticholinergics. Outcomes incompatible with predetermined outcomes.
Tincello 2000 Comparison of oxybutynin versus oxybutynin + salivary pastilles
Wein 1999 A meta-analysis of 2 studies.

Both studies reported separately and included in this review.
Yoon 2001 Comparative study between oxybutynin and propiverine.

Not clear if random allocation to groups.

DATA AND ANALYSES
Comparison 1. One anticholinergic versus another
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Cure/improvement 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 Tolterodine versus 2 613 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.89, 1.26]
oxybutynin
1.2 Trospium chloride versus 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
oxybutynin
1.3 Propantheline versus 2 136 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.53, 0.96]
oxybutynin
1.4 Propiverine versus 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
oxybutynin
2 Leakage episodes in 24hrs 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.1 Tolterodine versus 1 378 Mean Difference (IV, Fixed, 95% CI) 0.32 [-0.05, 0.69]
oxybutynin
2.2 Trospium chloride versus 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
oxybutynin
2.3 Propantheline versus 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
oxybutynin
2.4 Propiverine versus 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
oxybutynin
3 Change in leakage episodes in 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
24hrs
3.1 Tolterodine versus 5 939 Mean Difference (IV, Fixed, 95% CI) -0.15 [-0.47, 0.16]
oxybutynin
oxybutynin
oxybutynin
oxybutynin
4 Micturitions in 24hrs 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
4.1 Tolterodine versus 1 378 Mean Difference (IV, Fixed, 95% CI) 0.62 [0.01, 1.23]
oxybutynin
oxybutynin
oxybutynin
oxybutynin
5 Change in micturitions in 24 hrs 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
5.1 Tolterodine versus 5 1165 Mean Difference (IV, Fixed, 95% CI) -0.25 [-0.61, 0.10]
oxybutynin
oxybutynin
5.3 Propantheline verus 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
oxybutynin
oxybutynin
6 Maximum cystometric capacity 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
6.1 Tolterodine versus 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
oxybutynin
6.2 Trospium chloride versus 2 127 Mean Difference (IV, Fixed, 95% CI) -22.44 [-77.22,
oxybutynin 32.33]
6.3 Propantheline versus 1 18 Mean Difference (IV, Fixed, 95% CI) -84.20 [-207.10,
oxybutynin 38.70]
6.4 Propiverine versus 2 338 Mean Difference (IV, Fixed, 95% CI) -6.42 [-33.94,
oxybutynin 21.10]
7 Change in maximum cystometric 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
capacity
oxybutynin
oxybutynin
oxybutynin 13.40]
oxybutynin
8 Volume at first contraction 0 Mean Difference (IV, Fixed, 95% CI) Subtotals only
oxybutynin
oxybutynin
oxybutynin
oxybutynin
9 Change in volume at first 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
contraction
oxybutynin
oxybutynin
oxybutynin 20.03]
oxybutynin
10 Residual volume 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
oxybutynin
10.2 Trospium chloride versus 2 127 Mean Difference (IV, Fixed, 95% CI) -14.39 [-83.62,
oxybutynin 54.84]
oxybutynin
10.4 Propiverine versus 1 247 Mean Difference (IV, Fixed, 95% CI) 1.70 [-2.69, 6.09]
oxybutynin
11 Change in residual volume 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
oxybutynin
oxybutynin
11.3 Propantheline versus 1 117 Mean Difference (IV, Fixed, 95% CI) -29.2 [-52.28, -6.12]
oxybutynin
oxybutynin
12 Withdrawals due to adverse 10 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
events
oxybutynin
12.2 Trospium chloride versus 1 95 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.10, 1.29]
oxybutynin
oxybutynin
12.4 Propiverine versus 1 294 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [0.61, 3.47]
oxybutynin
13 Dry mouth 14 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
oxybutynin
13.2 Trospium chloride versus 2 453 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.59, 0.93]
oxybutynin
oxybutynin
13.4 Propiverine versus 2 379 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.66, 0.92]
oxybutynin
Comparison 2. Different doses of tolterodine
No. of No. of

1.1 0.5mg versus 2mg 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.2 1mg versus 2mg 1 252 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.53, 0.89]
2.1 0.5mg versus 2mg 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
2.2 1mg versus 2mg 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
3 Change in leakage episodes per 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only
24hrs
3.1 0.5mg versus 2mg 2 58 Mean Difference (IV, Fixed, 95% CI) 0.71 [-0.19, 1.61]
3.2 1mg versus 2mg 4 441 Mean Difference (IV, Fixed, 95% CI) 0.22 [-0.21, 0.64]
3.3 4mg versus 2mg 2 54 Mean Difference (IV, Fixed, 95% CI) -0.25 [-1.32, 0.82]
4 Micturitions in 24hrs 0 Mean Difference (IV, Fixed, 95% CI) Subtotals only
5 Change in number of 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only
micturitions per 24hrs
5.1 0.5mg versus 2mg 2 58 Mean Difference (IV, Fixed, 95% CI) 0.64 [-0.32, 1.60]
capacity
7.1 0.5mg versus 2mg 3 86 Mean Difference (IV, Fixed, 95% CI) -19.73 [-75.21,
35.76]
7.2 1mg versus 2mg 4 285 Mean Difference (IV, Fixed, 95% CI) -16.90 [-44.73,
10.93]
7.3 4mg versus 2mg 3 80 Mean Difference (IV, Fixed, 95% CI) 73.83 [18.06,
129.59]
contraction
32.33]
17.51]
9.3 4mg versus 2mg 3 80 Mean Difference (IV, Fixed, 95% CI) 47.72 [-10.80,
106.25]
3.45]
4.34]
11.3 4mg versus 2mg 3 72 Mean Difference (IV, Fixed, 95% CI) 92.98 [26.56,
159.40]
12 Withdrawal due to adverse 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
events
12.1 0.5mg versus 2mg 1 35 Risk Ratio (M-H, Fixed, 95% CI) 2.05 [0.09, 46.91]
13.1 0.5mg versus 2mg 3 101 Risk Ratio (M-H, Fixed, 95% CI) 0.36 [0.13, 0.95]

Comparison 3. Extended versus immediate release preparations
No. of No. of

1.1 Extended release 1 125 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.67, 1.24]
oxybutynin versus immediate
release oxybutynin
1.2 Extended release 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
tolterodine versus immediate
release tolterodine
release tolterodine
release oxybutynin
2.1 Extended release 1 76 Mean Difference (IV, Fixed, 95% CI) -0.20 [-1.50, 1.10]
release oxybutynin
2.2 Extended release 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
release tolterodine
release tolterodine
release oxybutynin
3 Change in leakage episodes per 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
24hrs
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
4 Micturitions in 24 hrs 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
release oxybutynin
release tolterodine
4.3 Extended release 1 378 Mean Difference (IV, Fixed, 95% CI) -0.62 [-1.23, -0.01]
release tolterodine
release oxybutynin
5 Change in micturitions per 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
24hrs
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
6.1 Extended release 1 63 Mean Difference (IV, Fixed, 95% CI) -90.0 [-173.46, -
oxybutynin versus immediate 6.54]
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
capacity
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin

8.1 Extended release 1 63 Mean Difference (IV, Fixed, 95% CI) -73.0 [-168.80,
oxybutynin versus immediate 22.80]
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
contraction
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
11.1 Extended release 2 156 Mean Difference (IV, Fixed, 95% CI) 1.29 [-19.31, 21.88]
release oxybutynin
release tolterodine
release tolterodine

release oxybutynin
12 Withdrawal due to adverse 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
events
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
release oxybutynin
release tolterodine
release tolterodine
release oxybutynin
Comparison 4. One extended release preparation against another
No. of No. of

2 Leakage episodes in 24 hrs 0 Mean Difference (IV, Fixed, 95% CI) Subtotals only
3 Change in leakage episodes in 1 244 Mean Difference (IV, Fixed, 95% CI) -0.30 [-1.03, 0.43]
24 hrs
4 Micturitions in 24 hrs 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
5 Change in micturitions in 24 hrs 1 244 Mean Difference (IV, Fixed, 95% CI) -0.30 [-0.97, 0.37]
6 Maximum cystometric capacity 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
7 Change in maximum cystometric 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
capacity
8 Volume at first contraction 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
9 Change in volume at first 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
contraction
10 Residual volume 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
12 Withdrawals due to adverse 2 1034 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.37, 1.07]
events
13 Dry mouth 2 1034 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.63, 1.00]
Analysis 1.1. Comparison 1 One anticholinergic versus another, Outcome 1 Cure/improvement.
Review: Which anticholinergic drug for overactive bladder symptoms in adults
Comparison: 1 One anticholinergic versus another
Outcome: 1 Cure/improvement
Study or subgroup Other drug Oxybutynin Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Tolterodine versus oxybutynin

Abrams 1998 59/118 58/118 42.6 % 1.02 [ 0.79, 1.32 ]
Malone-Lee 2001b 86/189 78/188 57.4 % 1.10 [ 0.87, 1.38 ]
Subtotal (95% CI) 307 306 100.0 % 1.06 [ 0.89, 1.26 ]

Total events: 145 (Other drug), 136 (Oxybutynin)
Heterogeneity: Chi2 = 0.18, df = 1 (P = 0.67); I2 =0.0%
Test for overall effect: Z = 0.70 (P = 0.49)
2 Trospium chloride versus oxybutynin
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Heterogeneity: not applicable
Test for overall effect: not applicable
3 Propantheline versus oxybutynin
Gajewski 1986 5/11 12/15 21.8 % 0.57 [ 0.28, 1.14 ]
Thuroff 1991 25/50 40/60 78.2 % 0.75 [ 0.54, 1.04 ]
Subtotal (95% CI) 61 75 100.0 % 0.71 [ 0.53, 0.96 ]

4 Propiverine versus oxybutynin
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
0.2 0.5 1 2 5
Favours oxybutynin Favours other drug

Analysis 1.2. Comparison 1 One anticholinergic versus another, Outcome 2 Leakage episodes in 24hrs.
Outcome: 2 Leakage episodes in 24hrs
Study or subgroup Other drug Oxybutynin Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Appell 2001 193 1.33 (1.91) 185 1.01 (1.71) 100.0 % 0.32 [ -0.05, 0.69 ]
Subtotal (95% CI) 193 185 100.0 % 0.32 [ -0.05, 0.69 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4
Favours other drug Favours oxybutynin

Analysis 1.3. Comparison 1 One anticholinergic versus another, Outcome 3 Change in leakage episodes in
24hrs.
Outcome: 3 Change in leakage episodes in 24hrs

Abrams 1998 92 -1.3 (3.2) 88 -1.7 (3.1) 11.7 % 0.40 [ -0.52, 1.32 ]
Dmochowski 2003 123 -3.2 (2.8) 121 -2.9 (3) 18.6 % -0.30 [ -1.03, 0.43 ]
Drutz 1999 70 -1.7 (2) 41 -1.7 (1.7) 20.2 % 0.0 [ -0.70, 0.70 ]
Lee 2001 101 -2.2 (2.3) 97 -1.4 (1.8) 30.0 % -0.80 [ -1.37, -0.23 ]
Malone-Lee 2001b 104 -1.3 (2.36) 102 -1.8 (2.83) 19.5 % 0.50 [ -0.21, 1.21 ]
Subtotal (95% CI) 490 449 100.0 % -0.15 [ -0.47, 0.16 ]

Heterogeneity: Chi2 = 9.84, df = 4 (P = 0.04); I2 =59%
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4

Analysis 1.4. Comparison 1 One anticholinergic versus another, Outcome 4 Micturitions in 24hrs.
Outcome: 4 Micturitions in 24hrs

Appell 2001 193 10.21 (2.93) 185 9.59 (3.16) 100.0 % 0.62 [ 0.01, 1.23 ]
Subtotal (95% CI) 193 185 100.0 % 0.62 [ 0.01, 1.23 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4

Analysis 1.5. Comparison 1 One anticholinergic versus another, Outcome 5 Change in micturitions in 24
hrs.
Outcome: 5 Change in micturitions in 24 hrs

Abrams 1998 118 -2.7 (3.8) 117 -2.3 (2.7) 17.6 % -0.40 [ -1.24, 0.44 ]
Dmochowski 2003 123 -2.2 (2.6) 121 -1.9 (2.7) 28.1 % -0.30 [ -0.97, 0.37 ]
Drutz 1999 70 -2 (2.5) 41 -2 (2.3) 14.9 % 0.0 [ -0.92, 0.92 ]
Lee 2001 101 -2.6 (2.9) 97 -1.8 (4.2) 12.2 % -0.80 [ -1.81, 0.21 ]
Malone-Lee 2001b 189 -1.7 (3.3) 188 -1.7 (3.4) 27.2 % 0.0 [ -0.68, 0.68 ]
Subtotal (95% CI) 601 564 100.0 % -0.25 [ -0.61, 0.10 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
3 Propantheline verus oxybutynin
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4

Analysis 1.6. Comparison 1 One anticholinergic versus another, Outcome 6 Maximum cystometric capacity.
Outcome: 6 Maximum cystometric capacity
Study or subgroup Other drug oxybutynin Mean Difference Weight Mean Difference

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Froehlich 1998 21 453.4 (174.72) 21 428.3 (181.61) 25.8 % 25.10 [ -82.68, 132.88 ]
Madersbacher 1995 49 312 (139) 36 351 (154) 74.2 % -39.00 [ -102.60, 24.60 ]
Subtotal (95% CI) 70 57 100.0 % -22.44 [ -77.22, 32.33 ]

Gajewski 1986 6 198.3 (129) 12 282.5 (117.9) 100.0 % -84.20 [ -207.10, 38.70 ]
Subtotal (95% CI) 6 12 100.0 % -84.20 [ -207.10, 38.70 ]

Madersbacher 1999 126 311 (125) 121 322 (123) 79.2 % -11.00 [ -41.93, 19.93 ]
Stohrer 2002 46 309 (166) 45 298 (125) 20.8 % 11.00 [ -49.29, 71.29 ]
Subtotal (95% CI) 172 166 100.0 % -6.42 [ -33.94, 21.10 ]

Test for subgroup differences: Chi2 = 1.62, df = 2 (P = 0.44), I2 =0.0%
-100 -50 0 50 100


Analysis 1.7. Comparison 1 One anticholinergic versus another, Outcome 7 Change in maximum
cystometric capacity.
Outcome: 7 Change in maximum cystometric capacity

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Thuroff 1991 54 48.9 (130.1) 63 80.1 (113.5) 100.0 % -31.20 [ -75.80, 13.40 ]
Subtotal (95% CI) 54 63 100.0 % -31.20 [ -75.80, 13.40 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-100 -50 0 50 100


Analysis 1.9. Comparison 1 One anticholinergic versus another, Outcome 9 Change in volume at first
contraction.
Outcome: 9 Change in volume at first contraction

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Thuroff 1991 54 11.2 (175.6) 63 51 (150.8) 100.0 % -39.80 [ -99.63, 20.03 ]
Subtotal (95% CI) 54 63 100.0 % -39.80 [ -99.63, 20.03 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-100 -50 0 50 100


Analysis 1.10. Comparison 1 One anticholinergic versus another, Outcome 10 Residual volume.
Outcome: 10 Residual volume

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Froehlich 1998 21 216.6 (218.8) 21 204.8 (193.43) 30.7 % 11.80 [ -113.11, 136.71 ]
Madersbacher 1995 49 128 (168) 36 154 (210) 69.3 % -26.00 [ -109.18, 57.18 ]
Subtotal (95% CI) 70 57 100.0 % -14.39 [ -83.62, 54.84 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Madersbacher 1999 126 9.9 (18.2) 121 8.2 (17) 100.0 % 1.70 [ -2.69, 6.09 ]
Subtotal (95% CI) 126 121 100.0 % 1.70 [ -2.69, 6.09 ]

-100 -50 0 50 100


Analysis 1.11. Comparison 1 One anticholinergic versus another, Outcome 11 Change in residual volume.
Outcome: 11 Change in residual volume

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Thuroff 1991 54 -2.2 (14.7) 63 27 (92.1) 100.0 % -29.20 [ -52.28, -6.12 ]
Subtotal (95% CI) 54 63 100.0 % -29.20 [ -52.28, -6.12 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-100 -50 0 50 100


Analysis 1.12. Comparison 1 One anticholinergic versus another, Outcome 12 Withdrawals due to adverse
events.
Outcome: 12 Withdrawals due to adverse events

Abrams 1998 10/118 20/118 15.9 % 0.50 [ 0.24, 1.02 ]
Diokno 2003 19/399 20/391 16.1 % 0.93 [ 0.50, 1.72 ]
Dmochowski 2003 2/123 13/121 10.4 % 0.15 [ 0.03, 0.66 ]
Drutz 1999 8/109 26/112 20.4 % 0.32 [ 0.15, 0.67 ]
Lee 2001 11/112 19/116 14.8 % 0.60 [ 0.30, 1.20 ]
Malone-Lee 2001b 22/190 28/188 22.4 % 0.78 [ 0.46, 1.31 ]
Subtotal (95% CI) 1051 1046 100.0 % 0.57 [ 0.43, 0.75 ]

Madersbacher 1995 3/52 7/43 100.0 % 0.35 [ 0.10, 1.29 ]
Subtotal (95% CI) 52 43 100.0 % 0.35 [ 0.10, 1.29 ]

Gajewski 1986 4/15 4/19 65.7 % 1.27 [ 0.38, 4.24 ]
Thuroff 1991 3/54 2/63 34.3 % 1.75 [ 0.30, 10.09 ]
Subtotal (95% CI) 69 82 100.0 % 1.43 [ 0.53, 3.89 ]

Madersbacher 1999 12/149 8/145 100.0 % 1.46 [ 0.61, 3.47 ]
Subtotal (95% CI) 149 145 100.0 % 1.46 [ 0.61, 3.47 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.13. Comparison 1 One anticholinergic versus another, Outcome 13 Dry mouth.
Outcome: 13 Dry mouth

Abrams 1998 59/118 102/118 14.1 % 0.58 [ 0.48, 0.70 ]
Appell 2001 64/193 52/185 7.3 % 1.18 [ 0.87, 1.60 ]
Diokno 2003 89/399 116/391 16.2 % 0.75 [ 0.59, 0.95 ]
Dmochowski 2003 9/123 5/121 0.7 % 1.77 [ 0.61, 5.13 ]
Drutz 1999 21/70 28/41 4.9 % 0.44 [ 0.29, 0.66 ]
Homma 2002 80/239 131/244 17.9 % 0.62 [ 0.50, 0.77 ]
Lee 2001 39/112 73/116 9.9 % 0.55 [ 0.41, 0.74 ]
Malone-Lee 2001b 71/190 114/188 15.9 % 0.62 [ 0.50, 0.77 ]
VanKerrebroeck 1997 46/120 94/120 13.0 % 0.49 [ 0.38, 0.63 ]
Subtotal (95% CI) 1564 1524 100.0 % 0.65 [ 0.60, 0.71 ]

Test for overall effect: Z = 9.54 (P < 0.00001)
Hofner 2000 88/268 45/90 73.7 % 0.66 [ 0.50, 0.86 ]
Madersbacher 1995 26/52 22/43 26.3 % 0.98 [ 0.66, 1.46 ]
Subtotal (95% CI) 320 133 100.0 % 0.74 [ 0.59, 0.93 ]

Thuroff 1991 17/54 30/63 100.0 % 0.66 [ 0.41, 1.06 ]
Subtotal (95% CI) 54 63 100.0 % 0.66 [ 0.41, 1.06 ]

Madersbacher 1999 78/146 95/142 76.1 % 0.80 [ 0.66, 0.97 ]
Stohrer 2002 22/46 30/45 23.9 % 0.72 [ 0.50, 1.03 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
Subtotal (95% CI) 192 187 100.0 % 0.78 [ 0.66, 0.92 ]
0.1 0.2 0.5 1 2 5 10

Analysis 2.1. Comparison 2 Different doses of tolterodine, Outcome 1 Cure/improvement.
Comparison: 2 Different doses of tolterodine
Study or subgroup Other dose 2mg Risk Ratio Weight Risk Ratio
1 0.5mg versus 2mg

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Other dose), 0 (2mg)
2 1mg versus 2mg
Millard 1999 50/123 76/129 100.0 % 0.69 [ 0.53, 0.89 ]
Subtotal (95% CI) 123 129 100.0 % 0.69 [ 0.53, 0.89 ]

3 4mg versus 2mg
Sussman 2002 208/297 171/285 100.0 % 1.17 [ 1.03, 1.32 ]
Subtotal (95% CI) 297 285 100.0 % 1.17 [ 1.03, 1.32 ]

0.2 0.5 1 2 5
Favours 2mg Favours other dose

Analysis 2.3. Comparison 2 Different doses of tolterodine, Outcome 3 Change in leakage episodes per 24hrs.
Outcome: 3 Change in leakage episodes per 24hrs
Study or subgroup Other dose 2mg Mean Difference Weight Mean Difference
1 0.5mg versus 2mg

Rentzhog 1998 17 -0.6 (1.11) 11 -1.2 (1.4) 84.5 % 0.60 [ -0.38, 1.58 ]
VanKerrebroeck 1998 13 -1.1 (2.9) 17 -2.4 (3.5) 15.5 % 1.30 [ -0.99, 3.59 ]
Subtotal (95% CI) 30 28 100.0 % 0.71 [ -0.19, 1.61 ]

2 1mg versus 2mg
Jacquetin 2001 78 -1.1 (2.2) 79 -1.3 (1.8) 46.3 % 0.20 [ -0.43, 0.83 ]
Millard 1999 109 -1.7 (2.8) 117 -1.7 (2.5) 38.1 % 0.0 [ -0.69, 0.69 ]
Rentzhog 1998 15 -0.5 (1.7) 11 -1.2 (1.4) 12.9 % 0.70 [ -0.49, 1.89 ]
VanKerrebroeck 1998 15 -1.2 (3.9) 17 -2.4 (3.5) 2.8 % 1.20 [ -1.38, 3.78 ]
Subtotal (95% CI) 217 224 100.0 % 0.22 [ -0.21, 0.64 ]

3 4mg versus 2mg
Rentzhog 1998 11 -2 (1.7) 11 -1.2 (1.4) 67.4 % -0.80 [ -2.10, 0.50 ]
VanKerrebroeck 1998 15 -1.5 (1.7) 17 -2.4 (3.5) 32.6 % 0.90 [ -0.97, 2.77 ]
Subtotal (95% CI) 26 28 100.0 % -0.25 [ -1.32, 0.82 ]

-4 -2 0 2 4
Favours other dose Favours 2mg

Analysis 2.5. Comparison 2 Different doses of tolterodine, Outcome 5 Change in number of micturitions
per 24hrs.
Outcome: 5 Change in number of micturitions per 24hrs
1 0.5mg versus 2mg

Rentzhog 1998 17 -0.9 (2) 11 -3.4 (3.8) 15.5 % 2.50 [ 0.06, 4.94 ]
VanKerrebroeck 1998 13 0.2 (1.1) 17 -0.1 (1.8) 84.5 % 0.30 [ -0.74, 1.34 ]
Subtotal (95% CI) 30 28 100.0 % 0.64 [ -0.32, 1.60 ]

2 1mg versus 2mg
Jacquetin 2001 78 -1.4 (2.8) 79 -1.4 (4.3) 20.0 % 0.0 [ -1.13, 1.13 ]
Millard 1999 123 -2.3 (3) 129 -2.3 (2.1) 62.4 % 0.0 [ -0.64, 0.64 ]
Rentzhog 1998 15 -1.6 (2.6) 11 -3.4 (3.8) 3.8 % 1.80 [ -0.80, 4.40 ]
VanKerrebroeck 1998 15 -0.4 (2.1) 17 -0.1 (1.8) 13.8 % -0.30 [ -1.66, 1.06 ]
Subtotal (95% CI) 231 236 100.0 % 0.03 [ -0.48, 0.53 ]

3 4mg versus 2mg
Rentzhog 1998 11 -2.1 (1.4) 11 -3.4 (3.8) 25.6 % 1.30 [ -1.09, 3.69 ]
VanKerrebroeck 1998 15 -0.3 (2.2) 17 -0.1 (1.8) 74.4 % -0.20 [ -1.60, 1.20 ]
Subtotal (95% CI) 26 28 100.0 % 0.18 [ -1.03, 1.40 ]

-4 -2 0 2 4

Analysis 2.7. Comparison 2 Different doses of tolterodine, Outcome 7 Change in maximum cystometric
capacity.
Outcome: 7 Change in maximum cystometric capacity
1 0.5mg versus 2mg

Abrams 1996 12 28 (108) 16 61 (121) 42.5 % -33.00 [ -118.14, 52.14 ]
Rentzhog 1998 17 14 (167) 11 2 (126) 26.0 % 12.00 [ -96.84, 120.84 ]
VanKerrebroeck 1998 13 34 (116) 17 62 (160) 31.5 % -28.00 [ -126.80, 70.80 ]
Subtotal (95% CI) 42 44 100.0 % -19.73 [ -75.21, 35.76 ]

2 1mg versus 2mg
Abrams 1996 14 91 (118) 16 61 (121) 10.6 % 30.00 [ -55.65, 115.65 ]
Jonas 1997 99 18 (117) 98 44 (116) 73.2 % -26.00 [ -58.54, 6.54 ]
Rentzhog 1998 15 -25 (107) 11 2 (126) 9.1 % -27.00 [ -119.07, 65.07 ]
VanKerrebroeck 1998 15 82 (141) 17 62 (160) 7.1 % 20.00 [ -84.29, 124.29 ]
Subtotal (95% CI) 143 142 100.0 % -16.90 [ -44.73, 10.93 ]

3 4mg versus 2mg
Abrams 1996 10 107 (153) 16 61 (121) 24.9 % 46.00 [ -65.84, 157.84 ]
Rentzhog 1998 11 76 (89) 11 2 (126) 37.4 % 74.00 [ -17.16, 165.16 ]
VanKerrebroeck 1998 15 154 (98) 17 62 (160) 37.7 % 92.00 [ 1.20, 182.80 ]
Subtotal (95% CI) 36 44 100.0 % 73.83 [ 18.06, 129.59 ]

Test for subgroup differences: Chi2 = 8.60, df = 2 (P = 0.01), I2 =77%
-100 -50 0 50 100


Analysis 2.9. Comparison 2 Different doses of tolterodine, Outcome 9 Change in volume at first
contraction.
Outcome: 9 Change in volume at first contraction
Study or subgroup Other dose 2 mg Mean Difference Weight Mean Difference

1 0.5mg versus 2mg

Abrams 1996 12 19 (112) 16 50 (122) 33.6 % -31.00 [ -118.12, 56.12 ]
Rentzhog 1998 17 74 (137) 11 89 (146) 21.8 % -15.00 [ -123.10, 93.10 ]
VanKerrebroeck 1998 13 57 (108) 17 67 (100) 44.6 % -10.00 [ -85.54, 65.54 ]
Subtotal (95% CI) 42 44 100.0 % -18.14 [ -68.61, 32.33 ]

2 1mg versus 2mg
Abrams 1996 14 97 (100) 16 50 (122) 15.2 % 47.00 [ -32.48, 126.48 ]
Jonas 1997 99 67 (144) 98 89 (144) 59.5 % -22.00 [ -62.22, 18.22 ]
Rentzhog 1998 15 17 (150) 11 89 (146) 7.3 % -72.00 [ -186.92, 42.92 ]
VanKerrebroeck 1998 15 54 (110) 17 67 (100) 18.0 % -13.00 [ -86.20, 60.20 ]
Subtotal (95% CI) 143 142 100.0 % -13.51 [ -44.54, 17.51 ]

3 4mg versus 2mg
Abrams 1996 10 83 (144) 16 50 (122) 29.7 % 33.00 [ -74.42, 140.42 ]
Rentzhog 1998 11 115 (136) 11 89 (146) 24.6 % 26.00 [ -91.91, 143.91 ]
VanKerrebroeck 1998 15 136 (143) 17 67 (100) 45.7 % 69.00 [ -17.58, 155.58 ]
Subtotal (95% CI) 36 44 100.0 % 47.72 [ -10.80, 106.25 ]

-100 -50 0 50 100


Analysis 2.11. Comparison 2 Different doses of tolterodine, Outcome 11 Change in residual volume.
Study or subgroup Other dose 2 mg Mean Difference Weight Mean Difference

1 0.5mg versus 2mg

Abrams 1996 12 16 (74) 16 48 (111) 15.7 % -32.00 [ -100.64, 36.64 ]
Rentzhog 1998 17 6 (32) 11 30 (45) 78.6 % -24.00 [ -54.64, 6.64 ]
VanKerrebroeck 1998 9 67 (142) 12 64 (116) 5.7 % 3.00 [ -110.64, 116.64 ]
Subtotal (95% CI) 38 39 100.0 % -23.71 [ -50.88, 3.45 ]

2 1mg versus 2mg
Abrams 1996 14 29 (178) 16 48 (111) 1.8 % -19.00 [ -126.94, 88.94 ]
Jonas 1997 99 10 (46) 98 18 (63) 87.4 % -8.00 [ -23.42, 7.42 ]
Rentzhog 1998 15 10 (95) 11 30 (45) 6.9 % -20.00 [ -74.94, 34.94 ]
VanKerrebroeck 1998 12 29 (57) 12 64 (116) 3.9 % -35.00 [ -108.13, 38.13 ]
Subtotal (95% CI) 140 137 100.0 % -10.07 [ -24.49, 4.34 ]

3 4mg versus 2mg
Abrams 1996 10 110 (195) 16 48 (111) 25.1 % 62.00 [ -70.53, 194.53 ]
Rentzhog 1998 11 143 (192) 11 30 (45) 32.5 % 113.00 [ -3.54, 229.54 ]
VanKerrebroeck 1998 12 160 (138) 12 64 (116) 42.4 % 96.00 [ -6.00, 198.00 ]
Subtotal (95% CI) 33 39 100.0 % 92.98 [ 26.56, 159.40 ]

-100 -50 0 50 100


Analysis 2.12. Comparison 2 Different doses of tolterodine, Outcome 12 Withdrawal due to adverse events.
Outcome: 12 Withdrawal due to adverse events
Study or subgroup Other dose 2mg Risk Ratio Risk Ratio

1 0.5mg versus 2mg

Rentzhog 1998 1/21 0/14 2.05 [ 0.09, 46.91 ]
Subtotal (95% CI) 21 14 2.05 [ 0.09, 46.91 ]

2 1mg versus 2mg
Jacquetin 2001 3/97 2/103 1.59 [ 0.27, 9.33 ]
Jonas 1997 4/99 3/98 1.32 [ 0.30, 5.74 ]
Malone-Lee 2001a 4/61 7/73 0.68 [ 0.21, 2.23 ]
Millard 1999 2/123 8/129 0.26 [ 0.06, 1.21 ]
Rentzhog 1998 0/16 0/14 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 396 417 0.70 [ 0.36, 1.40 ]

3 4mg versus 2mg
Rentzhog 1998 1/16 0/14 2.65 [ 0.12, 60.21 ]
Sussman 2002 24/336 27/333 0.88 [ 0.52, 1.49 ]
Subtotal (95% CI) 352 347 0.91 [ 0.54, 1.54 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.13. Comparison 2 Different doses of tolterodine, Outcome 13 Dry mouth.
Study or subgroup Other dose 2mg Risk Ratio Weight Risk Ratio
1 0.5mg versus 2mg

Abrams 1996 2/12 3/16 21.0 % 0.89 [ 0.18, 4.51 ]
Rentzhog 1998 2/21 5/14 49.0 % 0.27 [ 0.06, 1.19 ]
VanKerrebroeck 1998 0/20 3/18 30.0 % 0.13 [ 0.01, 2.34 ]
Subtotal (95% CI) 53 48 100.0 % 0.36 [ 0.13, 0.95 ]

2 1mg versus 2mg
Abrams 1996 2/14 3/16 1.9 % 0.76 [ 0.15, 3.92 ]
Jacquetin 2001 20/97 35/103 22.9 % 0.61 [ 0.38, 0.97 ]
Jonas 1997 8/99 10/98 6.8 % 0.79 [ 0.33, 1.92 ]
Malone-Lee 2001a 30/61 48/73 29.5 % 0.75 [ 0.55, 1.01 ]
Millard 1999 29/123 50/129 33.0 % 0.61 [ 0.41, 0.89 ]
Rentzhog 1998 2/16 5/14 3.6 % 0.35 [ 0.08, 1.53 ]
VanKerrebroeck 1998 0/16 3/18 2.2 % 0.16 [ 0.01, 2.87 ]
Subtotal (95% CI) 426 451 100.0 % 0.65 [ 0.52, 0.80 ]

3 4mg versus 2mg
Abrams 1996 5/10 3/16 21.9 % 2.67 [ 0.81, 8.80 ]
Rentzhog 1998 9/16 5/14 50.5 % 1.58 [ 0.69, 3.59 ]
VanKerrebroeck 1998 3/17 3/18 27.6 % 1.06 [ 0.25, 4.54 ]
Subtotal (95% CI) 43 48 100.0 % 1.67 [ 0.91, 3.08 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.1. Comparison 3 Extended versus immediate release preparations, Outcome 1
Cure/improvement.
Comparison: 3 Extended versus immediate release preparations
Study or subgroup Extended release Immediate release Risk Ratio Weight Risk Ratio
1 Extended release oxybutynin versus immediate release oxybutynin

Birns 2000 33/61 38/64 100.0 % 0.91 [ 0.67, 1.24 ]
Subtotal (95% CI) 61 64 100.0 % 0.91 [ 0.67, 1.24 ]

Total events: 33 (Extended release), 38 (Immediate release)
2 Extended release tolterodine versus immediate release tolterodine
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
3 Extended release oxybutynin versus immediate release tolterodine
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
4 Extended release tolterodine versus immediate release oxybutynin
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
0.2 0.5 1 2 5
Favours IR Favours ER

Analysis 3.2. Comparison 3 Extended versus immediate release preparations, Outcome 2 Leakage episodes
in 24hrs.
Outcome: 2 Leakage episodes in 24hrs
Study or subgroup Extended release Immediate release Mean Difference Weight Mean Difference

Davila 2001b 38 2.4 (2.4) 38 2.6 (3.3) 100.0 % -0.20 [ -1.50, 1.10 ]
Subtotal (95% CI) 38 38 100.0 % -0.20 [ -1.50, 1.10 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Appell 2001 185 1.01 (1.71) 193 1.33 (1.91) 100.0 % -0.32 [ -0.69, 0.05 ]
Subtotal (95% CI) 185 193 100.0 % -0.32 [ -0.69, 0.05 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4
Favours ER Favours IR

Analysis 3.3. Comparison 3 Extended versus immediate release preparations, Outcome 3 Change in
leakage episodes per 24hrs.
Outcome: 3 Change in leakage episodes per 24hrs

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
VanKerrebroeck 2001 507 -1.7 (2.54) 514 -1.51 (2.41) 100.0 % -0.19 [ -0.49, 0.11 ]
Subtotal (95% CI) 507 514 100.0 % -0.19 [ -0.49, 0.11 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4

Analysis 3.4. Comparison 3 Extended versus immediate release preparations, Outcome 4 Micturitions in 24
hrs.
Outcome: 4 Micturitions in 24 hrs

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Appell 2001 185 9.59 (3.16) 193 10.21 (2.93) 100.0 % -0.62 [ -1.23, -0.01 ]
Subtotal (95% CI) 185 193 100.0 % -0.62 [ -1.23, -0.01 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4

micturitions per 24hrs.
Outcome: 5 Change in micturitions per 24hrs

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
VanKerrebroeck 2001 507 -1.8 (3.4) 514 -1.7 (3.3) 100.0 % -0.10 [ -0.51, 0.31 ]
Subtotal (95% CI) 507 514 100.0 % -0.10 [ -0.51, 0.31 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-4 -2 0 2 4

Analysis 3.6. Comparison 3 Extended versus immediate release preparations, Outcome 6 Maximum
cystometric capacity.
Outcome: 6 Maximum cystometric capacity

Davila 2001a 33 297 (176) 30 387 (162) 100.0 % -90.00 [ -173.46, -6.54 ]
Subtotal (95% CI) 33 30 100.0 % -90.00 [ -173.46, -6.54 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-100 -50 0 50 100


Analysis 3.8. Comparison 3 Extended versus immediate release preparations, Outcome 8 Volume at first
contraction.
Outcome: 8 Volume at first contraction

Davila 2001a 33 229 (189) 30 302 (198) 100.0 % -73.00 [ -168.80, 22.80 ]
Subtotal (95% CI) 33 30 100.0 % -73.00 [ -168.80, 22.80 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-100 -50 0 50 100


residual volume.

Anderson 1999 46 18 (72) 47 18.1 (64) 55.2 % -0.10 [ -27.81, 27.61 ]
Davila 2001b 33 16 (46) 30 13 (74) 44.8 % 3.00 [ -27.78, 33.78 ]
Subtotal (95% CI) 79 77 100.0 % 1.29 [ -19.31, 21.88 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
-100 -50 0 50 100

Analysis 3.12. Comparison 3 Extended versus immediate release preparations, Outcome 12 Withdrawal
due to adverse events.
Outcome: 12 Withdrawal due to adverse events

Anderson 1999 2/53 2/52 18.6 % 0.98 [ 0.14, 6.71 ]
Birns 2000 1/62 0/66 4.5 % 3.19 [ 0.13, 76.88 ]
Davila 2001b 0/38 1/38 13.8 % 0.33 [ 0.01, 7.93 ]
Versi 2000 3/111 7/115 63.2 % 0.44 [ 0.12, 1.67 ]
Subtotal (95% CI) 264 271 100.0 % 0.65 [ 0.26, 1.65 ]

VanKerrebroeck 2001 27/507 28/514 100.0 % 0.98 [ 0.58, 1.63 ]
Subtotal (95% CI) 507 514 100.0 % 0.98 [ 0.58, 1.63 ]

Appell 2001 14/185 15/193 100.0 % 0.97 [ 0.48, 1.96 ]
Subtotal (95% CI) 185 193 100.0 % 0.97 [ 0.48, 1.96 ]

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
0.1 0.2 0.5 1 2 5 10

Analysis 3.13. Comparison 3 Extended versus immediate release preparations, Outcome 13 Dry mouth.

Anderson 1999 36/53 45/52 29.5 % 0.78 [ 0.63, 0.97 ]
Birns 2000 14/62 11/66 6.9 % 1.35 [ 0.67, 2.75 ]
Davila 2001b 15/38 31/38 20.1 % 0.48 [ 0.32, 0.74 ]
Versi 2000 53/111 68/115 43.4 % 0.81 [ 0.63, 1.03 ]
Subtotal (95% CI) 264 271 100.0 % 0.77 [ 0.66, 0.91 ]

VanKerrebroeck 2001 118/505 156/512 100.0 % 0.77 [ 0.62, 0.94 ]
Subtotal (95% CI) 505 512 100.0 % 0.77 [ 0.62, 0.94 ]

Appell 2001 52/185 64/193 100.0 % 0.85 [ 0.62, 1.15 ]
Subtotal (95% CI) 185 193 100.0 % 0.85 [ 0.62, 1.15 ]

Homma 2002 80/239 131/244 100.0 % 0.62 [ 0.50, 0.77 ]
Subtotal (95% CI) 239 244 100.0 % 0.62 [ 0.50, 0.77 ]

0.1 0.2 0.5 1 2 5 10

Analysis 4.3. Comparison 4 One extended release preparation against another, Outcome 3 Change in
leakage episodes in 24 hrs.
Comparison: 4 One extended release preparation against another
Outcome: 3 Change in leakage episodes in 24 hrs
Study or subgroup Tolterodine Oxybutynin Mean Difference Weight Mean Difference

Dmochowski 2003 123 -3.2 (2.8) 121 -2.9 (3) 100.0 % -0.30 [ -1.03, 0.43 ]
Total (95% CI) 123 121 100.0 % -0.30 [ -1.03, 0.43 ]

-4 -2 0 2 4
Favours tolterodine Favours oxybutynin
Analysis 4.5. Comparison 4 One extended release preparation against another, Outcome 5 Change in
micturitions in 24 hrs.
Outcome: 5 Change in micturitions in 24 hrs
Study or subgroup Tolterodine Oxybutynin Mean Difference Weight Mean Difference

Dmochowski 2003 123 -2.2 (2.6) 121 -1.9 (2.7) 100.0 % -0.30 [ -0.97, 0.37 ]
Total (95% CI) 123 121 100.0 % -0.30 [ -0.97, 0.37 ]

-4 -2 0 2 4
Analysis 4.12. Comparison 4 One extended release preparation against another, Outcome 12 Withdrawals
due to adverse events.
Outcome: 12 Withdrawals due to adverse events
Study or subgroup Tolterodine Oxybutynin Risk Ratio Weight Risk Ratio

Diokno 2003 19/399 20/391 60.7 % 0.93 [ 0.50, 1.72 ]
Dmochowski 2003 2/123 13/121 39.3 % 0.15 [ 0.03, 0.66 ]
Total (95% CI) 522 512 100.0 % 0.62 [ 0.37, 1.07 ]

Total events: 21 (Tolterodine), 33 (Oxybutynin)
0.1 0.2 0.5 1 2 5 10

Analysis 4.13. Comparison 4 One extended release preparation against another, Outcome 13 Dry mouth.
Study or subgroup Tolterodine Oxybutynin Risk Ratio Weight Risk Ratio

Diokno 2003 89/399 116/391 95.9 % 0.75 [ 0.59, 0.95 ]
Dmochowski 2003 9/123 5/121 4.1 % 1.77 [ 0.61, 5.13 ]
Total (95% CI) 522 512 100.0 % 0.79 [ 0.63, 1.00 ]

Total events: 98 (Tolterodine), 121 (Oxybutynin)
0.1 0.2 0.5 1 2 5 10

WHAT’S NEW
Last assessed as up-to-date: 24 May 2005.
13 October 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 3, 2001
Review first published: Issue 3, 2005
25 May 2005 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Gaye Ellis took principal responsibility for trial screening, assessment and data extraction, and data entry. Peter Herbison (cross over
studies) and Jean Hay-Smith (parallel designs) independently screened, assessed and extracted data from the trials and crosschecked the
data entry. Jean Hay-Smith, Peter Herbison and Alastair Morris interpreted the data and wrote the discussion.
DECLARATIONS OF INTEREST
None declared.
SOURCES OF SUPPORT
Internal sources
• University of Otago, New Zealand.

• Royal North Shore Hospital, Australia.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)

Benzhydryl Compounds [∗ therapeutic use]; Cholinergic Antagonists [∗ therapeutic use]; Cresols [∗ therapeutic use]; Mandelic Acids
[∗ therapeutic use]; Phenylpropanolamine [∗ therapeutic use]; Randomized Controlled Trials as Topic; Urinary Incontinence [∗ drug
therapy]
MeSH check words

Adult; Humans

HAY-SMITH - Which Anticholinergic Drug For Overactive Bladder Symptoms

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

HAY-SMITH - Which Anticholinergic Drug For Overactive Bladder Symptoms

Uploaded by

Copyright:

Available Formats

Which anticholinergic drug for overactive bladder symptoms

Hay-Smith J, Ellis G, Herbison GP

Which anticholinergic drug for overactive bladder symptoms in adults (Review)

Which anticholinergic drug for overactive bladder symptoms in adults (Review) ii

Which anticholinergic drug for overactive bladder symptoms

Jean Hay-Smith1 , Gaye Ellis2 , G Peter Herbison3

Editorial group: Cochrane Incontinence Group.

PLAIN LANGUAGE SUMMARY

Which anticholinergic drug for overactive bladder symptoms in adults

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 3

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 4

Screening for eligibility

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 5

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 6

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 7

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 8

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 9

Table 1. Different doses. Change in leakage episodes in 24 hrs

Drug Study Dose/data Dose/data Difference

Table 2. Different doses. Change in micturitions in 24 hrs

Drug Study Dose/data Dose/data Difference

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 10

• Primary outcome measure (02.01) • Primary outcome measure (02.01)

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 11

Table 3. Different doses. Cure/improvement

Drug Study Dose/data Dose/data Difference

Table 4. Different doses. Withdrawals due to adverse events

Drug Study Dose/data Dose/data Difference

45mg.1/49 30mg. 1/47 RR 0.96 (95% CI 0.06 to 14.90)

60mg. 3/40 30mg. 1/47 RR 3.53 (95% CI 0.38 to 32.57)

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 12

Table 5. Different doses. Change in maximum cystometric capacity

Drug Study Dose/data Dose/data Difference

Table 6. Different doses. Change in volume at first contraction

Drug Study Dose/data Dose/data Difference

Table 7. Different doses. Change in residual volume

Drug Study Dose/data Dose/data Difference

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 13

Table 8. Different doses. Micturitions in 24 hours

Drug Study Dose/data Dose/data Difference

Table 9. Different doses. Volume at first contraction

Drug Study Dose/data Dose/data Difference

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 14

Drug Study Dose/data Dose/data Difference

45mg.11/49 30mg. 11/47 RR 0.96 (95% CI 0.46 to 2.00)

60mg. 11/40 30mg. 11/47 RR 1.18 (95% CI 0.57 to 2.42)

• Secondary outcome measures (03.02, 03.06, 03.08, 03.11,

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 15

• Secondary outcome measures (04.03, 04.05, 04.12, 04.13)

Dmochowski et al (Dmochowski 2003) did not find any statisti-

Quality of life, socioeconomics, long-term follow up, and

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 16

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 17

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 18

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 19

• Dr B Moehrer for help with assessment of trials published

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 24

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 25

Which anticholinergic drug for overactive bladder symptoms in adults (Review) 26

Characteristics of included studies [ordered by study ID]

Methods RCT. Placebo controlled, parallel design.

Interventions Group 1: placebo (n=15)