Journal Article Page
Jump to
European Urology
Volume 54, issue 3, pages 483-708, September 2008Reviews
The Effects of Antimuscarinic Treatments in Overactive Bladder: An Update of a Systematic Review and Meta-Analysis
Christopher R. Chapple a 
, Vik Khullar b, Zahava Gabriel c, Dominic Muston c, Caty Ebel Bitoun d, David Weinstein d.
Accepted 11 June 2008, Published online 20 June 2008, pages 543 - 562
Abstract Full-Text PDF (788 KB) Create Platinum Slide Series Place a comment
Abstract
Context
Antimuscarinic agents are currently the first-line pharmacotherapy for overactive bladder.
Objectives
A systematic review published in 2005 was updated, including data on a newly licensed antimuscarinic (fesoterodine). The primary aim of this study was to systematically review evidence on the efficacy of licensed administration of antimuscarinic treatments in overactive bladder from randomised controlled trials. Secondary aims were to review evidence on tolerability and safety and health-related quality of life (HRQL).
Evidence acquisition
All relevant data sources from randomised controlled trials were searched, and two independent reviewers considered publications for inclusion and extracted relevant data. Meta-analysis was used to pool efficacy, tolerability, safety, and HRQL outcomes by treatment. Efficacy was measured by continent days, mean voided volume, urgency episodes, and micturition frequency. Tolerability and safety were measured by means of adverse event and withdrawal rates. HRQL was measured by various instruments.
Evidence synthesis
An additional 1118 references were retrieved with data on 83 studies extracted. Antimuscarinics were found to be more effective than placebo. Tolerability was good; few of the antimuscarinics were found to have significantly higher withdrawal rates in comparison to placebo. No serious adverse event for any product was statistically significant compared to placebo. Dry mouth (mild, moderate, severe) was the most commonly reported adverse event (29.6% on treatment vs 7.9% on placebo), followed by pruritus (15.4% on treatment vs 5.2% on placebo). Improvements were seen in HRQL with treatment by darifenacin, fesoterodine, oxybutynin transdermal delivery system, propiverine extended release (ER), solifenacin, tolterodine ER and immediate release, and trospium. Limitations of the study include restrictions on the types of patients typically included in overactive bladder trials and topics that have not been adequately addressed in the current antimuscarinic literature.
Conclusions
Antimuscarinics are efficacious, safe, and well-tolerated treatments that improve HRQL. Profiles of each drug and dosage differ and should be considered in making treatment choices.
Keywords: Antimuscarinic, Overactive bladder, Detrusor overactivity, Incontinence, Meta-analysis, Systematic review.
Article Outline
1. Introduction
Overactive bladder (OAB) refers to the common and bothersome group of storage lower urinary tract symptoms (LUTS). The International Continence Society (ICS) defines OAB syndrome as urgency with or without urge urinary incontinence (UUI), usually with frequency and nocturia [1]. Prevalence rates for OAB are estimated to be approximately 12% in North America and Europe [2]. Both men and women are equally affected by OAB, and the incidence rate increases with age [2]. This condition has a serious impact on individuals as well as on society as a whole [3], and [4]; to illustrate, the annual cost of OAB has been estimated as to be as high as &z.euro;3.98 billion in Germany alone [5]. OAB can be managed with bladder and behavioural training, biofeedback, electrical stimulation, pharmacologic treatments, or with a combination of therapies [6]. Antimuscarinic agents are the first-line pharmacotherapy for OAB treatment [7].
A systematic review of the tolerability, safety, and efficacy of licensed antimuscarinic treatments in OAB was published in October 2005 [8]. This review represented an update to that published in 2003 by Herbison et al [9]. Since then, there have been considerable changes to the evidence base. A large number of new trials with existing agents have been published, particularly for solifenacin and darifenacin. Some of these new trials are head-to-head trials, an area identified as a research priority in the 2005 review. Additionally, there are data on a newly developed antimuscarinic, fesoterodine [10]. Fesoterodine is rapidly and extensively hydrolyzed by nonspecific ubiquitous esterases to 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine and is responsible for all of the antimuscarinic activity of fesoterodine [11], [12], and [13]. Fesoterodine has two active doses, 4 and 8 mg [14], and [15], and clinical studies have shown that plasma concentrations are dose proportional [16].
This meta-analysis was conducted to update the 2005 data. The primary aim of this study was to review all of the evidence on the efficacy of licensed antimuscarinic therapy for OAB available from randomised controlled trials. The efficacy outcomes of interest were the changes in the number of micturitions, urgency and incontinence episodes per day, volume voided per micturition, and both the proportion of patients returning to continence or undergoing global improvements in their storage LUTS. Secondary aims were to review evidence on tolerability, safety, and effects of treatment on health-related quality of life (HRQL).
2. Methods
2.1. Publication searches
The review undertook a comprehensive search of all major literature databases and the abstract books from several major conferences: American Urological Association, ICS, European Association of Urology, International Urogynaecological Association, International Consultation of Incontinence, and Societe Internationale d’Urologie. As with the 2005 review, there were no restrictions on the inclusion of publications by language; publications in languages other than English were translated into English.
The literature database search for the previous 2005 review was carried out on August 31, 2004, for publications published since 1966 in the MEDLINE, EMBASE, Cochrane Controlled Trials Register, and Cumulative Index to Nursing and Allied Health Literature databases. The literature database search for this review was carried out on October 18, 2007, and included all publications published in 2004 or later in the same databases. Conference proceedings had previously been searched to the end of 2004. For the review update, we added evidence from further proceedings of each conference up to October 2007. The overlap in date ranges for the searches led to duplication in retrieved publications but was designed to ensure that no evidence was missed.
2.2. Study procedures
The same rigorous processes were followed in this review as in the last. This review was conducted and reported according to QUORUM guidelines [17]. A team of reviewers independently determined the eligibility of each publication by applying a set of criteria (Table 1). Two different reviewers considered each publication, and discrepancies were resolved through discussion. Cited references from included trials and reviews of similar trials were also searched. Many studies were reported in more than one publication, and all studies that met the inclusion criteria were included in the review. However, only one extraction dataset per study was compiled from all publications relating to that study, so as to avoid the error of double-counting patients in subsequent analyses. Two independent reviewers extracted study characteristics and placed the baseline and outcomes data, including publications in parallel, into a Microsoft Access database (Microsoft Corporation, Redmond, WA, USA). The methodological quality of publications was assessed as previously reported [8]. A third reviewer checked the resulting extractions and resolved any discrepancies. Safety and tolerability outcome data were extracted from all studies; efficacy outcome data were extracted only from studies reporting that patients and investigators had been blinded to treatment allocation. Table 2 provides a list of outcomes extracted.
Table 1 Study inclusion and exclusion criteria for the review
| Criterion | Included | Excluded |
|---|---|---|
| Population | Age: ≥18 yr | Age: <18 yr |
| Race: any | ||
| Gender: male or female | ||
| Qualifying event/disease/factors: Idiopathic OAB/DO/UI (including UUI) | Qualifying event/disease/factors: >50% of patients with DO consequent upon neurogenic pathology | |
| ≤50% of patients with DO consequent upon neurogenic pathology | SUI | |
| UUI | MUI (stress-predominant incontinence) | |
| MUI (urge-predominant incontinence) | >50% of patients with BOO/BPH/BPO/benign prostatic enlargement or previous LUTD surgery | |
| ≤50% of patients with BOO/BPH/BPO/benign prostatic enlargement or previous LUTD surgery | ||
| Any severity of disease at baseline | ||
| Perspective of study | Prospective (concurrent) | Retrospective (nonconcurrent, historical) |
| Comparative | Noncomparative | |
| Type of study | RCT (Blinded RCTs only for clinical efficacy data, open-label RCTs and blinded RCTs for safety and tolerability data) | Nonrandomised CCT |
| Open-label follow-up of RCT | ||
| Cohort | ||
| Crossover trials with a wash-out period between treatments | Observational | |
| Case-control | ||
| Case study | ||
| Crossover trials without a wash-out period between treatments | ||
| Language | All | None |
| Trial Length | ≥2 wk | <2 wk* |
| Sample Size | Any | None |
| Intervention/treatments | Oral and TDS monotherapy with antimuscarinics; UK licensed doses: | Oral monotherapy with antimuscarinics: Flavoxate (Urispas®) |
| • Darifenacin (Enablex®): all doses | Propantheline (Pro-Banthine®) | |
| • Oxybutynin IR (Cystrin®, Ditropan®): 2.5–5 mg bid, tid, 5 mg qid | ||
| • Oxybutynin ER (Ditropan XL®): 5 mg od, 10 mg od, 15 mg od, 20 mg od | ||
| • Oxybutynin TDS (Kentera®, Oxytrol®): 3.9 mg od | All intravesical antimuscarinic formulations | |
| • Propiverine IR (Detrunorm®): 15 mg od, bid, tid, qid | ||
| • Propiverine ER (Detrunorm XL®): all doses | ||
| • Solifenacin (Vesicare®): all doses | ||
| • Tolterodine IR (Detrusitol SR®, Detrol®): 1 mg bid, 2 mg bid | ||
| • Tolterodine ER (Detrusitol XL®, Detrol LA®, Detrusitol Neo®, Dereustiol Retard®): 2 mg od, 4 mg od | Combination therapy with antimuscarinics, and an α-blocker | |
| • Trospium (Regurin®): 20 mg bid | ||
| • Fesoterodine (Toviaz®): all doses. | Combination therapy with one of the included drugs and a nonpharmacological treatment when not all the treatment arms receive the same nonpharmacological treatment | |
| Combination therapy with one of the included drugs and a nonpharmacological treatment if all the treatment arms receive the same nonpharmacological treatment | ||
| Control intervention/treatments | Placebo or any of the included drugs, including a different formulation of the same drug | Nonpharmacological treatment (bladder training, electronic stimulation, physiotherapy) |
| Usual care | ||
| No intervention | ||
| Included trial outcomes | Any | None |
Abbreviations: BOO, bladder outlet obstruction; BPH, benign prostatic hyperplasia; BPO, benign prostatic obstruction; CCT, controlled clinical trial; DO, detrusor overactivity; ER, extended release; IR, immediate release; LA, extended release; LUTD, lower urinary tract disease; MUI, mixed urinary incontinence; OAB, overactive bladder; RCT, randomised controlled trial; SUI, stress urinary incontinence; TDS, transdermal system; UI, urinary incontinence; UUI, urge urinary incontinence; XL, extended release.
*
Table 2 Efficacy, tolerability, safety, and HRQL/PRO outcomes extracted from included studies
| Efficacy* | Change from baseline in the number of urgency episodes/24 frame="topbot" rowsep="0" colsep="0">h |
| Change from baseline in the number of incontinence episodes/24 h | |
| Change from baseline in the number of pads used per day | |
| Change from baseline in the number of daytime incontinence episodes/24 h | |
| Number of patients returned to continence at trial end point (recording no incontinence episodes on last voiding diary entry) | |
| Change from baseline in the number of nocturnal incontinence episodes/24 h | |
| Change from baseline in number of nocturnal awakenings related to overactive bladder/24 h | |
| Number of patients achieving normal micturition frequency (≤7 or ≤8 micturitions/24 h) at trial end point | |
| Change from baseline in the volume of urine voided per micturition (ml) | |
| Change from baseline in the number of micturitions/24 h | |
| Change from baseline in maximum cystometric capacity (ml) | |
| Tolerability | Total withdrawals |
| Withdrawals due to adverse events | |
| Withdrawals due to death | |
| Safety | Any adverse event |
| Any serious adverse event | |
| Blurred vision, confusion, dizziness, palpitations, tremor, vertigo | |
| Constipation, diarrhoea, dry mouth (any severity), dry mouth (mild), dry mouth (moderate), dry mouth (severe), dry mouth (mild/moderate), dry mouth (moderate/severe), dyspepsia, nausea, vomiting | |
| Fatigue, headache, insomnia, somnolence, increased sweating, urinary retention, UTI, erythema, pruritus | |
| HRQL/PRO | Generic: SF-36, SF-12 |
| Disease-specific: Incontinence Impact Questionnaire (IIQ), KHQ, UDI, OAB-q | |
| Number of patients reporting improvement in disease | |
| VAS scores of improvement in disease |
Abbreviations: HRQL, health-related quality of life; KHQ, King's Health Questionnaire; OAB-q, Overactive Bladder Questionnaire; PRO, patient-reported outcome; UDI, Urogenital Distress Inventory; UTI, urinary tract infection; VAS, visual analog scale; SF-36, Short-form 36; SF-12, Short-form 12.
*
2.2.1. Treatment dosing
There were seven drugs included in this review (darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, and trospium), each of which could be delivered through various formulations at various doses and frequencies. Data from arms of studies in which drug doses delivered to patients fell outside the European licensed range were not extracted (Table 1). Treatments were stratified according to whether the drug formulation was immediate release (IR), for which administration was oral and the dose frequency was generally more than once per day, or extended release (ER), for which administration was oral and the dose frequency was generally once per day. The only exception was in the case of oxybutynin administered via a transdermal system (TDS) patch. Treatments were stratified into categories according to the total daily dose at the start of the study and whether the study allowed flexible dosing.
2.3. Statistical analysis
Meta-analysis was conducted where possible to pool results for each outcome of interest and for each combination of treatment by daily dose category and formulation using the meta-analysis command METAN written for Stata v.9 (StataCorp LP, College Station, TX, USA) [18]. Dichotomous outcomes were summarised as risk ratios (RR) using the Mantel-Haenszel method; continuous outcomes were summarised as nonstandardised (also known as weighted) mean differences using inverse variance weighting. Fixed rather than random effects models were used because the stratification was judged to largely remove the likelihood of substantial clinical or statistical heterogeneity [19].
As with the previous review, trials with more than two treatment arms were analysed as if they were conducted as trials of each paired treatment comparison. For simplicity, consistency with the previous review [8] and consistency between trials, analyses of such trials were not adjusted for multiple comparisons (using Bonferonni correction methods or similar).
3. Results
3.1. Trial flow
This review retrieved 1118 references in addition to the 11 663 retrieved for the 2005 review. Of the newly retrieved references, 88 publications were included to add to the 123 included from the previous review for a total of 211 publications. There were on average 2.5 publications per included trial. From these publications, data on 83 trials were extracted (Appendix A). Ten trials included for this review were excluded from this meta-analysis; eight were excluded because they contained no data relevant or suitable for meta-analysis [20], [21], [22], [23], [24], [25], [26], and [27]; one was excluded because the treatment dosing was mixed or unclear [28]; and one was excluded because randomisation was unclear [29]. Fig. 1 is a diagram of the study flow, showing the relationship between studies considered now and those considered at the 2005 review.
00749-5/assets/gr1/gr1_584x482.jpg)
3.1.1. Trial characteristics
Summaries of the patient and study design characteristics of the included trials are presented in Table 3. Twenty-four trials were published in abstract format only, and 59 trials were published as full publications. Forty-six trials (55%) had placebo arms. There was at least one placebo-controlled trial for all of the included antimuscarinic formulations, apart from the oxybutynin ER formulation.
Table 3 Summary of included trials
| Trial | Treatment arms | No. of randomised patients | Trial length (weeks) | Patient baseline characteristics | ||
|---|---|---|---|---|---|---|
| Disease | Proportion of patients with prior therapy (%) | Mean number of incontinence episodes per day | ||||
| New trials for this review | ||||||
| Abrams 2006 | 20 mg/day propiverine ER, 45 mg/day propiverine IR, 15 mg/day oxybutynin IR, placebo | 77 | 2 | OAB | – | – |
| Chapple 2004 (A) | 4 and 8 mg/day fesoterodine, placebo | 728 | 12 | OAB | – | – |
| Chapple 2007 | 4 and 8 mg/day fesoterodine, 4 mg/day tolterodine ER, placebo | 1135 | 12 | OAB | 41.6 | 3.7 |
| Corcos 2006 | 5, 10, and 15 mg/day oxybutynin ER | 237 | 4 | UUI | 57.8 | 3.1 |
| Giannitsas 2004 (A) | 4 mg/day tolterodine IR, 15 mg/day oxybutynin IR | 128 | 6 | OAB | – | – |
| Herschorn 2007 (A) | 4 mg/day tolterodine ER, placebo | 402 | 12 | OAB | – | – |
| Hirani 2004 (A) | 20 mg/day propiverine ER, 45 mg/day propiverine IR, 15 mg/day oxybutynin IR, placebo | 77 | 2 | OAB | – | – |
| Homma 2006 | 26 cm2, 39 cm2, and 52 cm2 oxybutynin TDS, placebo | 659 | 8 | OAB | – | 3.0 |
| Khullar 2005 (A) | 4 mg/day tolterodine ER, placebo | 520 | 12 | OAB | – | – |
| Khullar 2007 (A) | 4 mg/day tolterodine ER, placebo | 79 | 12 | OAB | – | – |
| Lee 2006 (A) | 20 mg/day propiverine ER, placebo | 264 | 12 | OAB | – | – |
| Madersbacher 2005 (A) | 30 and 45 mg/day propiverine IR | 464 | – | OAB | – | – |
| Minassian 2007 | 5 mg/day oxybutynin ER, 7.5 mg/day oxybutynin IR | 72 | 12 | OAB | – | – |
| Nitti 2006 (A) | 4 and 8 mg/day fesoterodine, placebo | 836 | 12 | OAB | – | – |
| Olshansky 2006 (A) | 4 mg/day tolterodine IR, 15 mg/day darifenacin ER, placebo | 450 | 12 | OAB | – | – |
| Rackley 2006 | 4 mg/day tolterodine ER, placebo | 850 | 12 | OAB | – | 0.7 |
| Robinson 2007 | 4 mg/day tolterodine ER, placebo | 364 | 6 | OAB | – | 2.6 |
| Rogers 2007 (A) | 4 mg/day tolterodine ER, placebo | 413 | 12 | OAB | – | – |
| Rovner 2005 (A) | 4 and 8 mg/day fesoterodine, placebo | 173 | 8 | UUI | – | – |
| Salvatore 2005 | 5 mg/day oxybutynin ER and IR | 96 | 4 | OAB | – | – |
| STAR | 5 mg/day solifenacin titrated, 4 mg/day tolterodine ER | 1204 | 12 | OAB | – | 2.7 |
| SUNRISE (A) | 5 mg/day solifenacin, placebo | 865 | 16 | OAB | – | – |
| VENUS (A) | 5 mg/day solifenacin, placebo | 739 | 12 | OAB | – | – |
| Wang 2006 | 7.5 mg/day oxybutynin IR, placebo | 74 | 12 | OAB | – | – |
| Yamaguchi 2007 | 5 & 10 mg/day solifenacin, 20 mg/day propiverine ER | 1593 | 12 | OAB | – | 2.2 |
| Yaycioglu 2005 | 4 mg/day tolterodine IR, 15 mg/day oxybutynin IR | 52 | 4 | OAB | – | – |
| Zinner 2005 | 15 mg/day oxybutynin IR, 15 mg/day darifenacin ER, placebo | 76 | 2 | OAB | – | 2.9 |
| Zinner 2006 | 15 mg/day darifenacin, placebo | 445 | 12 | OAB | 53.7 | – |
| Trial from 2005 review, but supplemented by new publication | ||||||
| Burgio 1998 | 7.5 mg/day oxybutynin IR, placebo | 197 | 8 | MUI | 33.3 | 2.2 |
| Cardozo 2004 | 5 and 10 mg/day solifenacin, placebo | 911 | 12 | OAB | 33.9 | – |
| Hill 2006 | 7.5 and 15 mg/day darifenacin ER, placebo | 439 | 12 | OAB | 22.8 | – |
| Jünemann 2005 | 4 mg/day tolterodine IR, 30 mg/day propiverine IR | 202 | 4 | OAB | – | – |
| Jünemann 2006 | 30 mg/day propiverine ER & IR, placebo | 988 | 5 | OAB | – | 3.4 |
| OPERA | 4 mg/day tolterodine ER, 10 mg/day oxybutynin ER | 790 | 12 | OAB | 47.0 | 6.1 |
| Rudy 2006 | 40 mg/day trospium, placebo | 658 | 12 | OAB | 50.3 | – |
| Steers 2005 | 7.5 mg/day darifenacin ER titrated, placebo | 398 | 12 | OAB | 23.8 | – |
| Trials from 2005 review with no new publications | ||||||
| Abrams 1998 | 4 mg/day tolterodine IR, 15 mg/day oxybutynin IR, placebo | 293 | 12 | DO (30% post LUT surgery) | 60 | 3.3 |
| Abrams 2001 (A) | 4 mg/day tolterodine IR, placebo | 221 | 12 | DO/BOO | – | – |
| Alloussi 1998 | 40 mg/day trospium, placebo | 309 | 3 | DO | – | – |
| Anderson 1999 | 5 mg/day oxybutynin IR and ER | 105 | 2 | UUI/MUI | 100 | 4.2 |
| Barkin 2004 | 15 mg/day oxybutynin IR and ER | 125 | 6 | UUI | – | 3.5 |
| Birns 2000 | 10 mg/day oxybutynin IR and ER | 130 | 4 | DO | 100 | – |
| Brambila 2000 | 15 mg/day oxybutynin IR, placebo | 44 | 6 | Urgency/UUI | – | – |
| Cardozo 2000 | 40 mg/day trospium, placebo | 208 | 3 | DO | – | – |
| Chaliha 1998 (A) | 40 mg/day trospium, placebo | 76 | 3 | DO | – | – |
| Chapple 2004 | 5 & 10 mg/day solifenacin, 4 mg/day tolterodine IR | 225 | 4 | DO | – | 1.7 |
| Chapple 2004b | 5 & 10 mg/day solifenacin, 4 mg/day tolterodine IR, placebo | 1081 | 12 | OAB | 40 | 2.6 |
| Davila 2001 | 5 mg/day oxybutynin IR titrated, 2.6 mg per fortnight oxybutynin TDS titrated | 76 | 4 | UUI | – | – |
| Dmochowski 2002 | 3.9 mg/day oxybutynin TDS, placebo | 520 | 12 | DO | 23 | 5.5 |
| Dmochowski 2003 | 4 mg/day tolterodine ER, 3.9 mg/day oxybutynin TDS, placebo | 361 | 12 | OAB and UUI/MUI | – | – |
| Dorschner 2003 | 45 mg/day propiverine IR, placebo | 107 | 4 | Urgency/UUI/MUI | – | 0.9 |
| Drutz 1999 | 4 mg/day tolterodine IR, 15 mg/day oxybutynin IR, placebo | 277 | 12 | DO (UUI) | 55 | 3.7 |
| Haab 2004 | 7.5 and 15 mg/day darifenacin ER, placebo | 561 | 12 | DO | 21 | 2.4 |
| Halaska 1994 (A) | 45 mg/day propiverine IR, placebo | 93 | 4 | Urgency/UUI | – | – |
| Halaska 2003 | 40 mg/day trospium, 10 mg/day oxybutynin IR | 358 | 52 | DO/UUI | 51 | 2.1 |
| Homma 2003 | 4 mg/day tolterodine ER, 9 mg/day oxybutynin IR, placebo | 608 | 12 | OAB | 25 | 3.1 |
| Jacquetin 2001 | 2 and 4 mg/day tolterodine IR, placebo | 251 | 4 | DO | 71 | 3.2 |
| Jonas 1997 | 2 and 4 mg/day tolterodine IR, placebo | 242 | 4 | DO | – | – |
| Jünemann 2000 (A) | 40 mg/day trospium, 4 mg/day tolterodine IR, placebo | 234 | 3 | DO | – | – |
| Khullar 2004 | 4 mg/day tolterodine ER, placebo | 854 | 8 | MUI | 34 | 3 |
| Kirschner-Hermans 1997 (A) | 10 mg/day oxybutynin IR, placebo | 36 | 3 | Incontinence | – | – |
| Lee 2002 | 4 mg/day tolterodine IR, 10 mg/day oxybutynin IR | 228 | 8 | OAB | 32 | 2.6 |
| Leung 2002 | 4 mg/day tolterodine IR, 10 mg/day oxybutynin IR | 106 | 10 | DO | – | – |
| Madersbacher 1999 | 10 mg/day oxybutynin IR, 45 mg/day propiverine IR, placebo | 366 | 4 | Urgency/UUI | – | – |
| Malone-Lee 2001 | 2 and 4 mg/day tolterodine IR, placebo | 177 | 4 | OAB | 70 | 5.1 |
| Malone-Lee 2001b | 4 mg/day tolterodine IR, 10 mg/day oxybutynin IR | 379 | 10 | OAB | 32 | 2.9 |
| Malone-Lee 2002 (A) | 4 mg/day tolterodine ER, placebo | 308 | 12 | DO | – | – |
| Millard 1999 | 2 and 4 mg/day tolterodine IR, placebo | 316 | 12 | DO | 50 | 3.9 |
| Miller 2002 (A) | 7.5 mg/day oxybutynin IR, placebo | 110 | 8 | UUI | – | – |
| Moisey 1980 | 15 mg/day oxybutynin IR, placebo | 30 | 4 | DO | – | – |
| Moore 1990 | 9 mg/day oxybutynin IR, placebo | 53 | Unclear | DO | – | – |
| Neimark 2002 (A) | oxybutynin IR and TDS (dose unreported) | 68 | 6 | OAB (basis of diagnosis unclear) | – | – |
| OBJECT | 10 mg/day oxybutynin ER, 4 mg/day tolterodine ER | 378 | 12 | OAB | 41 | 4.1 |
| Rentzhog 1998 | 2 and 4 mg/day tolterodine IR, placebo | 81 | 2 | DO | 64 | 4.1 |
| Riva 1984 | 15 mg/day oxybutynin IR, placebo | 30 | 3 | UUI/OAB | – | – |
| Szonyi 1995 | 5 mg/day oxybutynin IR, placebo | 60 | 6 | DO | – | – |
| Tapp 1990 | 15 mg/day oxybutynin IR, placebo | 37 | 2 | DO | – | – |
| Thuroff 1991 | 15 mg/day oxybutynin IR, placebo | 169 | 4 | UUI | – | – |
| Uchida 2002 (A) | 5 and 10 mg/day solifenacin, placebo | 265 | 4 | OAB | – | 3.7 |
| Van Kerrebroeck 2001 | 4 mg/day tolterodine ER and IR, placebo | 1529 | 12 | OAB | 54 | 3.3 |
| Versi 2000 | 5 mg/day oxybutynin IR and ER, titrated | 226 | Titration period + 1 wk | UUI | 100 | 3.2 |
| Xia 2001 | 5 mg/day oxybutynin ER, 2 mg/day tolterodine ER | 210 | 6 | OAB | – | 3 |
| Zinner 2004 | 40 mg/day trospium, placebo | 523 | 12 | OAB (UUI) | 54 | 4.3 |
Abbreviations: (A), trial published in abstract form only; BOO, bladder outlet obstruction; DO, detrusor overactivity; ER, extended release; IR, immediate release; MUI, mixed urinary incontinence; OAB, overactive bladder; OBJECT, Overactive Bladder: Judging Effective Control and Treatment trial; OPERA, Overactive Bladder: Performance of Extended Release Agents trial; STAR, Solifenacin and Tolterodine as an Active comparator in a Randomised trial; SUNRISE, Solifenacin in the treatment of UrgeNcy symptoms of overactive bladder in a RISing dose, randomised, placebo-controlled, double-blind Efficacy trial; TDS, transdermal system; UUI, urgency urinary incontinence; VENUS, Vesicare Efficacy and safety in patieNts with Urgency Study.
Most trials were parallel-group studies, the remaining ten trials being crossover in design. At least 72 of the trials were double-blind, five did not report blinding clearly, and the remaining six were single-blind or open-label studies. Study lengths ranged from 2 to 52 wk, with 34 trials of 12-wk length. The number of patients in trials ranged from 30 to 1593 patients, with five trials of >1000 patients [14], [30], [31], [32], and [33] and 20 trials with fewer than 100 patients. The mean age of patients included in the trials was 58 yr (range: 40–75 yr).
3.2. Efficacy
Efficacy results are summarized in Table 4. Greater proportions of patients treated with antimuscarinics than with placebo returned to continence, and these differences were statistically significant. The pooled RR varied between 1.3 and 3.5 across treatments and nominally were strongly statistically significant (p < 0.01) with the exception of fesoterodine, for which no data were available, and propiverine IR 45 mg/day, for which evidence was available from only one study [34]. There were no statistically significant differences among treatments in meta-analyses of active-controlled trials for this outcome.
Table 4 Efficacy of antimuscarinics compared to placebo: Results from meta-analyses*
| Fesoterodine 4 mg/day vs placebo | Fesoterodine 8 mg/day vs placebo | Oxybutynin IR 7.5–10 mg/day vs placebo | Oxybutynin IR 15 mg/day vs placebo | Oxybutynin TDS 3.9–4.0 mg/day vs placebo | Propiverine IR 30 mg/day vs placebo | Propiverine IR 45 mg/day vs placebo | Propiverine ER 20 mg/day vs placebo | Propiverine ER 30 mg/day vs placebo | Solifenacin 5 mg/day vs placebo | Solifenacin 10 mg/day vs placebo | Tolterodine ER 4 mg/day vs placebo | Tolterodine IR 2 mg/day vs placebo | Tolterodine IR 4 mg/day vs placebo | Trospium chloride 40 mg/day vs placebo | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean change in incontinence episodes/day | −0.81 | −1.08 | – | −0.74 | −0.58 | – | – | −0.53 | – | −0.77 | −0.81 | −0.4 | −0.21 | −0.5 | – |
| −1.27 to −0.35 | −1.52 to −0.64 | – | −1.23 to −0.26 | −1.05 to −0.11 | – | – | −0.92 to −0.14 | – | −1.02 to −0.52 | −1.06 to −0.56 | −0.42 to −0.38 | −0.56 to 0.14 | −0.67 to −0.32 | – | |
| p < 0.01 | p < 0.01 | – | p < 0.01 | p = 0.02 | – | – | p = 0.01 | – | p < 0.01 | p < 0.01 | p < 0.01 | p = 0.23 | p < 0.01 | – | |
| 410 (1) | 434 (1) | – | 312 (2) | 612 (2) | – | – | 578 (1) | – | 1157 (2) | 1170 (2) | 3095 (5) | 605 (3) | 2614 (7) | – | |
| Mean change in micturitions/day | −0.81 | −0.93 | – | −0.92 | −0.54 | – | 0 | −0.93 | – | −0.99 | −1.3 | −0.77 | −0.67 | −0.71 | – |
| −1.27 to −0.35 | −1.37 to −0.49 | – | −1.43 to −0.40 | −0.99 to −0.10 | – | −1.33 to 1.33 | −1.28 to −0.58 | – | −1.23 to −0.75 | −1.56 to −1.04 | −0.96 to −0.58 | −1.07 to −0.27 | −0.93 to −0.50 | – | |
| p < 0.01 | p < 0.01 | – | p < 0.01 | p = 0.02 | – | – | p < 0.01 | – | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | – | |
| 544 (1) | 555 (1) | – | 431 (3) | 608 (2) | – | 98 (1) | 779 (1) | – | 1803 (2) | 1789 (2) | 3223 (5) | 637 (3) | 3121 (7) | – | |
| Mean change in urgency episodes/day | −0.81 | −1.29 | – | – | – | – | – | −1.02 | – | −1.25 | −1.56 | −1.05 | – | −0.64 | – |
| −1.35 to –0.27 | −1.83 to −0.75 | – | – | – | – | – | −1.44 to −0.6 | – | −1.57 to −0.93 | −1.88 to −1.23 | −1.37 to −0.73 | – | −1.16 to −0.12 | – | |
| p < 0.01 | p < 0.01 | – | – | – | – | – | p < 0.01 | – | p < 0.01 | p < 0.01 | p < 0.01 | – | p = 0.02 | – | |
| 544 (1) | 555 (1) | – | – | – | – | – | 779 (1) | – | 1786 (2) | 1771 (2) | 1416 (2) | – | 994 (1) | – | |
| Mean change in volume voided per micturition (ml) | 18.35 | 24.25 | – | 39.52 | 23 | – | 27.9 | 24.95 | – | 24.71 | 31.87 | 16.92 | 13.07 | 17.21 | – |
| 9.01 to 27.69 | 14.99 to 33.51 | – | 30.19 to 48.85 | 10.3 to 35.7 | – | −8.18 to 63.98 | 19.89 to 30.01 | – | 20.58 to 28.85 | 27.58 to 36.16 | 13.17 to 20.66 | 6.63 to 19.51 | 13.95 to 20.47 | – | |
| p < 0.01 | p < 0.01 | – | p < 0.01 | p < 0.01 | – | p = 0.13 | p < 0.01 | – | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | – | |
| 543 (1) | 553 (1) | – | 382 (2) | 355 (1) | – | 98 (1) | 776 (1) | – | 1799 (2) | 1785 (2) | 3091 (5) | 637 (3) | 3120 (7) | – | |
| Patients returned to continence at end point | – | – | 3.53 | – | 1.75 | 1.33 | 1.8 | 1.51 | 1.42 | 1.51 | 1.61 | 1.72 | – | – | 2 |
| – | – | 1.94 to 6.41 | – | 1.26 to 2.43 | 1.09 to 1.63 | 0.96 to 3.38 | 1.26 to 1.81 | 1.16 to 1.73 | 1.26 to 1.82 | 1.34 to 1.93 | 1.24 to 2.39 | – | – | 1.4 to 2.86 | |
| – | – | p < 0.01 | – | p < 0.01 | p < 0.01 | p = 0.07 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | – | – | p < 0.01 | |
| – | – | 110 (1) | – | 355 (1) | 597 (1) | 76 (1) | 578 (1) | 593 (1) | 557 (1) | 553 (1) | 357 (1) | – | – | 821 (2) | |
| Patients with improvement in disease | 1.49 | 1.51 | 4.11 | – | – | – | – | – | – | – | – | 1.34 | – | – | – |
| 1.09 to 2.03 | 1.11 to 2.05 | 1 to 16.89 | – | – | – | – | – | – | – | – | 0.98 to 1.83 | – | – | – | |
| p = 0.01 | p = 0.01 | P = 0.05 | – | – | – | – | – | – | – | – | p = 0.07 | – | – | – | |
| 544 (1) | 555 (1) | 44 (1) | – | – | – | – | – | – | – | – | 562 (1) | – | – | – |
Row 1: effect size (RR for dichotomous outcomes, unstandardised [weighted] mean difference for continuous outcomes).Row 2, 3: 95% CI.Row 4: p value vs a null hypothesis of no difference in effect (RR: 1; mean difference: 0).Row 5: Number of patients (studies) which contributed to meta-analysis.Abbreviations: CI, confidence interval; ER, extended release; IR, immediate release; RR, risk ratio.
*
Active treatments were more effective than placebo in terms of the mean change in the number of incontinence episodes per day. Statistically significant results were obtained for interventions involving each licensed drug with the exception of trospium chloride, which was not reported. Pooled differences in mean changes ranged from 0.4 to 1.1 incontinence episodes per day. Tolterodine was not significantly more effective as IR 2 mg/day but was significantly more effective at the higher 4-mg/day dose as ER and IR when compared to placebo. There were no statistically significant differences among active treatments with the exception of fesoterodine 8 mg/day, which the meta-analyses found on the basis of one study [14] to be statistically significantly favourable to tolterodine ER 4 mg/day (mean difference: 0.48; 95% CI, 0.04–0.92 episodes per day; p = 0.03).
Active treatments were more effective than placebo in terms of the mean change in the number of micturitions per day. Statistically significant results were obtained for interventions involving each licensed drug, with the exception of trospium chloride, which was not reported. Pooled differences in mean changes ranged from 0.5 to 1.3 episodes per day. There was some evidence from three trials [30], [31], and [35] favouring solifenacin 10 mg/day over tolterodine IR 4 mg/day (difference in mean change: 0.73; 95% CI, 0.19–1.27 micturitions per day; p = 0.01) and from four trials [36], [37], [38], and [39] favouring solifenacin 10 mg/day over solifenacin 5 mg/day (difference in mean change: 0.30; 95% CI, 0.04–0.55 micturitions per day; p = 0.02). Otherwise, there were no statistically significant differences among active treatments.
Fesoterodine, propiverine, solifenacin, and tolterodine were statistically significantly more effective than placebo in terms of the mean change in the number of urgency episodes per day, where reported. The outcomes for oxybutynin and trospium chloride were not suitable for meta-analysis. Pooled differences in mean changes varied between 0.64 and 1.56 episodes per day. There was, again, some evidence favouring solifenacin 10 mg/day over tolterodine IR 4 mg/day (difference in mean change: 1.02; 95% CI, 0.37–1.67 episodes per day; p < 0.01) and propiverine IR 20 mg/day (difference in mean change: 0.48; 95% CI 0.06–0.90 episodes per day; p = 0.03), and evidence favouring solifenacin 5 mg/day over tolterodine IR 4 mg/day (difference in mean change: 0.80; 95% CI, 0.17–1.43 episodes per day; p = 0.01). Otherwise, there were no statistically significant differences among active treatments.
Active treatments were all statistically significantly more effective than placebo in terms of the mean change in the volume voided per micturition (milliliter) where reported for each licensed drug other than trospium chloride, for which this outcome was not reported. Differences in pooled mean changes were 13–40 ml. Propiverine was not statistically more effective as IR 45 mg/day based on evidence from data from two trials [40], and [41] but was statistically more effective in this outcome as ER 20 mg/day based on evidence from one trial [24]. The following statistically significant differences among active treatments were found: solifenacin 10 mg/day was favoured over tolterodine IR 4 mg/day (14.8; 95% CI, 6.2–23.4; p < 0.01); solifenacin 10 mg/day was favoured over solifenacin 5 mg/day (7.3; 95% CI, 2.2–12.3; p < 0.01); solifenacin 10 mg/day was favoured over propiverine ER 20 mg/day (7.0; 95% CI, 1.0–12.9; p = 0.02); fesoterodine 8 mg/day was favoured over tolterodine ER 4 mg/day (10.0; 95% CI, 0.8–19.2; p = 0.03); and oxybutynin IR 15 mg/day was favoured over tolterodine IR 4 mg/day (13.3; 95% CI, 4.3–22.3; p < 0.01).
Proportions of patients with improvements in their bladder condition (ie, storage symptoms) from two trials were suitable for meta-analysis [14], and [42]. The proportion of patients was statistically significantly higher for fesoterodine 4 mg/day and 8 mg/day than for placebo (RR: 1.49; 95% CI, 1.09–2.03; p = 0.01; and RR: 1.51; 95% CI, 1.11–2.05; p = 0.01, respectively). Results were also reported in this outcome for oxybutynin IR 7.5–10 mg/day and tolterodine ER 4 mg/day but were not statistically significant. There were no statistically significant differences among active treatments.
3.3. Tolerability
Summaries of the results of the meta-analyses of tolerability outcomes are shown in Table 5. Withdrawals due to any cause were a frequently reported outcome. Oxybutynin IR 15 mg/day and oxybutynin IR 7.5–10 mg/day were associated with statistically significantly higher risk of withdrawal from trial due to any cause than placebo (RR: 1.33; 95% CI, 1.01–1.76; p = 0.04; and RR: 1.72; 95% CI, 1.18–2.49; p < 0.01, respectively). Otherwise, no statistically significant differences in proportions of patients who withdrew from trials for any causes were found between placebo and any active treatments (Fig. 2).
Table 5 Tolerability of antimuscarinics compared to placebo control: Results from meta-analyses*
| Darifenacin 7.5 mg/day vs placebo | Darifenacin 7.5 mg/day titrated vs placebo | Darifenacin 15 mg/day vs placebo | Fesoterodine 4 mg/day vs placebo | Fesoterodine 8 mg/day vs placebo | Oxybutynin IR 5 mg/day vs placebo | Oxybutynin IR 7.5–10 mg/day vs placebo | Oxybutynin IR 15 mg/day vs placebo | Propiverine IR 30 mg/day vs placebo | |
|---|---|---|---|---|---|---|---|---|---|
| Total withdrawals | 0.74 | 1.25 | 0.98 | 1.3 | 1.08 | 1.6 | 1.33 | 1.72 | 1.21 |
| 0.43–1.27 | 0.62–2.51 | 0.70–1.36 | 0.85–2 | 0.69–1.68 | 0.59–4.33 | 1.01–1.76 | 1.18–2.49 | 0.61–2.4 | |
| p = 0.27 | p = 0.54 | p = 0.88 | p = 0.23 | p = 0.73 | p = 0.36 | p = 0.04 | p < 0.01 | p = 0.59 | |
| 938 (2) | 398 (1) | 1416 (4) | 557 (1) | 573 (1) | 60 (1) | 1054 (5) | 751 (5) | 597 (1) | |
| Withdrawals due to adverse events | 0.67 | 2.16 | 1.83 | 1.4 | 1.33 | 1.5 | 1.91 | 1.89 | 7.67 |
| 0.11–3.95 | 0.75–6.25 | 0.95–3.55 | 0.69–2.82 | 0.65–2.71 | 0.27–8.34 | 1.18–3.1 | 1.23–2.9 | 1.02–57.66 | |
| p = 0.66 | p = 0.16 | p = 0.07 | p = 0.35 | p = 0.44 | p = 0.64 | p = 0.01 | p < 0.01 | p = 0.05 | |
| 217 (1) | 398 (1) | 657 (2) | 926 (2) | 929 (2) | 60 (1) | 488 (1) | 743 (4) | 597 (1) |
| Propiverine IR 45 mg/day vs placebo | Propiverine ER 20 mg/day vs placebo | Propiverine ER 30 mg/day vs placebo | Solifenacin 5 mg/day vs placebo | Solifenacin 10 mg/day vs placebo | Tolterodine ER 4 mg/day vs placebo | Tolterodine IR 2 mg/day vs placebo | Tolterodine IR 4 mg/day vs placebo | Trospium chloride 40 mg/day vs placebo | |
|---|---|---|---|---|---|---|---|---|---|
| Total withdrawals | 1.31 | 1.07 | 1.08 | 0.83 | 0.81 | 0.87 | 1.32 | 0.98 | 1 |
| 0.68–2.52 | 0.69–1.68 | 0.54–2.17 | 0.64–1.07 | 0.63–1.05 | 0.68–1.1 | 0.66–2.65 | 0.76–1.26 | 0.73–1.37 | |
| p = 0.41 | p = 0.76 | p = 0.83 | p = 0.15 | p = 0.1 | p = 0.24 | p = 0.44 | p = 0.87 | – | |
| 293 (1) | 805 (1) | 593 (1) | 2710 (4) | 2689 (4) | 2113 (5) | 398 (2) | 2261 (6) | 832 (2) | |
| Withdrawals due to adverse events | – | 2.39 | 5.68 | 1.16 | 1.53 | 0.71 | 0.9 | 0.88 | 1.27 |
| – | 1.20–4.78 | 0.74–43.71 | 0.79–1.72 | 1.02–2.3 | 0.53–.95 | 0.44–1.83 | 0.66–1.17 | 0.86–1.88 | |
| – | p = 0.01 | p = 0.1 | p = 0.44 | p = 0.04 | p = 0.02 | p = 0.77 | p = 0.39 | p = 0.23 | |
| – | 805 (1) | 593 (1) | 3575 (5) | 2689 (4) | 3777 (5) | 851 (5) | 3973 (11) | 1490 (3) | |
| Withdrawals due to deaths | – | – | – | 0.34 | 1.55 | 1 | 0.21 | 1 | – |
| – | – | – | 0.01–8.20 | 0.29–8.21 | 0.06–15.98 | 0.01–4.29 | 0.22–4.49 | – | |
| – | – | – | p = 0.5 | p = 0.61 | – | p = 0.31 | – | – | |
| – | – | – | 600 (1) | 1678 (2) | 1015 (1) | 251 (1) | 1324 (2) | – |
Row 1: effect size (risk ratio [RR]).Row 2: 95% CI.Row 3: p value vs a null hypothesis of no difference in effect (RR: 1).Row 4: Number of patients (studies) which contributed to meta-analysis.Abbreviations: ER, extended release; IR, immediate release.
*
00749-5/assets/gr2/gr2_584x457.jpg)
Fig. 2 Forest plot of relative risk of all-cause withdrawals versus placebo for each included treatment and dose.
The following statistically significant differences among active treatments were found: oxybutynin IR 7.5–10 mg/day was associated with a significantly greater risk of withdrawal due to any cause than oxybutynin ER 5 mg/day (RR; 2.22; 95% CI, 1.08–4.57; p = 0.03); oxybutynin IR 7.5–10 mg/day carried a greater risk of withdrawal than tolterodine ER 4 mg/day (RR: 2.22; 95% CI, 1.45–3.45; p < 0.01) and tolterodine IR 4 mg/day (RR: 1.41; 95% CI, 1.02–1.92; p = 0.04); oxybutynin IR 15 mg/day carried a greater risk of withdrawal than tolterodine IR 4 mg/day (RR: 2.44; 95% CI, 1.64–3.57; p < 0.01) and oxybutynin ER 15 mg/day (RR: 1.83; 95% CI, 1.02–3.30; p = 0.04).
Tolterodine ER 4 mg/day was the only formulation found to be associated with a statistically significantly lower risk than placebo of withdrawal due to an adverse event (RR: 0.71; 95% CI, 0.53–0.95; p = 0.02). Four formulations were found to be associated with a statistically significantly higher risk of withdrawal due to adverse events than placebo: oxybutynin IR 7.5–10 mg/day (RR: 1.91; 95% CI, 1.18–3.10; p = 0.01), oxybutynin IR 15 mg/day (RR: 1.89; 95% CI, 1.23–2.90; p < 0.01), propiverine ER 20 mg/day (RR: 2.39; 95% CI, 1.20–4.78; p = 0.01), and solifenacin 10 mg/day (RR: 1.53; 95% CI, 1.02–2.30; p = 0.04). Additionally, tolterodine ER 4 mg/day was associated with lower risk of this outcome than oxybutynin TDS 3.9 mg/day (RR: 0.15; 95% CI, 0.03–0.66; p = 0.01) and oxybutynin IR 15 mg/day (RR: 0.32; 95% CI, 0.17– 0.57; p < 0.01); tolterodine IR 4 mg/day was associated with a lower risk than oxybutynin IR 15 mg/day (RR: 0.47; 95% CI, 0.33–0.69; p < 0.01); and oxybutynin ER 5 mg/day was associated with a lower risk than oxybutynin ER 15 mg/day (RR: 0.27; 95% CI, 0.08–0.92; p = 0.04). There were no other statistically significant differences among active treatments.
Withdrawal due to death was infrequently reported, possibly due to the low incidence of mortality relative to other outcomes in OAB patients in trials of this length. No statistically significant differences were reported among treatments (active and placebo) in any of the analyses conducted.
3.4. Safety
Summaries of the results of the meta-analyses of safety outcomes are shown in Table 6. Every treatment in the review, with two exceptions, was statistically significantly associated with a greater risk of adverse events than placebo (Fig. 3). The two exceptions were tolterodine IR 2 mg/day (RR: 1.00; 95% CI, 0.89–1.12; p = 0.97) and oxybutynin TDS 3.9 mg/day (RR: 1.59; 95% CI, 0.96–2.63; p = 0.07). Where statistically significant, the pooled RR for any adverse event in comparison to placebo varied between 1.13 and 2.00. No treatment was shown to be significantly associated with serious adverse events.
Table 6 Adverse events of antimuscarinics compared to placebo: Results from meta-analyses*
| Darifenacin 7.5 mg/day vs placebo | Darifenacin 7.5 mg/day titrated vs placebo | Darifenacin 15 mg/day vs placebo | Fesoterodine 4 mg/day vs placebo | Fesoterodine 8 mg/day vs placebo | Oxybutynin IR 5 mg/day vs placebo | Oxybutynin IR 7.5–10 mg/day vs placebo | Oxybutynin IR 15 mg/day vs placebo | Oxybutynin IR 20 mg/day vs placebo | Oxybutynin TDS 3.9–4.0 mg/day vs placebo | |
|---|---|---|---|---|---|---|---|---|---|---|
| Any adverse event | 1.26 | 2.0 | 1.32 | 1.31 | 1.54 | – | 1.72 | 1.29 | – | 1.59 |
| 1.10–1.44 | 1.38–2.91 | 1.18–1.48 | 1.08–1.59 | 1.29–1.84 | – | 1.38–2.14 | 1.19–1.40 | – | 0.96–2.63 | |
| p < 0.01 | p < 0.01 | p < 0.01 | p = 0.01 | p < 0.01 | – | p < 0.01 | p < 0.01 | – | p = 0.07 | |
| 938 (2) | 395 (1) | 1262 (3) | 555 (1) | 570 (1) | – | 289 (1) | 748 (4) | – | 355 (1) | |
| Any serious adverse event | 2.62 | 0.59 | 0.60 | – | – | – | 15.00 | 0.74 | – | – |
| 0.91–7.56 | 0.16–2.17 | 0.19–1.84 | – | – | – | 0.86–261.2 | 0.29–1.91 | – | – | |
| p = 0.08 | p = 0.43 | p = 0.37 | – | – | – | p = 0.06 | p = 0.53 | – | – | |
| 938 (2) | 395 (1) | 1262 (3) | – | – | – | 488 (1) | 568 (2) | – | – | |
| Dry mouth (any severity) | 2.57 | 2.15 | 4.40 | 3.01 | 3.95 | 1.08 | 2.96 | 4.42 | 2.9 | 1.41 |
| 1.79–3.68 | 1.16–3.99 | 3.34–5.79 | 2.17–4.20 | 2.87–5.44 | 0.90–1.29 | 2.46–3.55 | 3.53–5.53 | 1.73–4.87 | 0.73–2.73 | |
| p < 0.01 | p = 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p = 0.41 | p < 0.01 | p < 0.01 | p < 0.01 | p = 0.31 | |
| 938 (2) | 395 (1) | 1611 (5) | 1010 (3) | 1016 (3) | 57 (1) | 923 (4) | 1006 (7) | 62 (1) | 612 (2) |
| Propiverine IR 30 mg/day vs placebo | Propiverine IR 45 mg/day vs placebo | Propiverine ER 20 mg/day vs placebo | Propiverine ER 30 mg/day vs placebo | Solifenacin 5 mg/day vs placebo | Solifenacin 10 mg/day vs placebo | Tolterodine ER 4 mg/day vs placebo | Tolterodine IR 2 mg/day vs placebo | Tolterodine IR 4 mg/day vs placebo | Trospium chloride 40 mg/day vs placebo | |
|---|---|---|---|---|---|---|---|---|---|---|
| Any adverse event | 1.90 | 1.42 | 1.58 | 1.69 | 1.23 | 1.32 | 1.19 | 1.00 | 1.13 | 1.30 |
| 1.40–2.56 | 1.17–1.74 | 1.02–2.43 | 1.24–2.29 | 1.10–1.37 | 1.06–1.66 | 1.06–1.32 | 0.89–1.12 | 1.05–1.21 | 1.15–1.45 | |
| p < 0.01 | p < 0.01 | p = 0.04 | p < 0.01 | p < 0.01 | p = 0.02 | p < 0.01 | p = 0.97 | p < 0.01 | p < 0.01 | |
| 597 (1) | 457 (3) | 62 (1) | 593 (1) | 1230 (3) | 488 (2) | 2634 (4) | 851 (5) | 2119 (10) | 1409 (4) | |
| Any serious adverse event | 15.89 | – | – | 11.91 | – | – | 0.88 | 2.06 | 0.82 | 2.24 |
| 0.96–264.24 | – | – | 0.71–201.1 | – | – | 0.58–1.33 | 0.60–7.03 | 0.50–1.36 | 0.49–10.25 | |
| p = 0.05 | – | – | p = 0.09 | – | – | p = 0.53 | p = 0.25 | p = 0.45 | p = 0.3 | |
| 597 (1) | – | – | 593 (1) | – | – | 3199 (4) | 398 (2) | 2335 (6) | 517 (2) | |
| Dry mouth (any severity) | 3.54 | 3.13 | 4.10 | 3.38 | 3.32 | 5.90 | 3.00 | 2.41 | 3.44 | 3.17 |
| 2.03–6.18 | 1.27–7.71 | 2.76–6.07 | 1.93–5.90 | 2.55–4.32 | 4.59–7.59 | 2.47–3.64 | 1.67–3.49 | 2.92–4.04 | 2.37–4.24 | |
| p < 0.01 | p = 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | p < 0.01 | |
| 597 (1) | 164 (2) | 867 (2) | 593 (1) | 3691 (6) | 2951 (5) | 4129 (6) | 838 (5) | 4071 (11) | 1389 (3) |
Row 1: effect size (RR).Row 2: 95% CI.Row 3: p value vs a null hypothesis of no difference in effect (RR: 1).Row 4: Number of patients (studies) which contributed to meta-analysis.Abbbreviations: CI, confidence interval; ER, extended release; IR, immediate release; RR, risk ratio.
*
00749-5/assets/gr3/gr3_584x457.jpg)
Fig. 3 Forest plot of relative risk of any- or all-cause adverse event versus placebo for each included treatment and dose.
In accordance with the data on tolerability, there were favourable results for tolterodine formulations relative to other active treatments. The risk of adverse events was statistically significantly lower with tolterodine IR 2 mg/day than with oxybutynin ER 5 mg/day (RR: 0.59; 95% CI, 0.43–0.82; p < 0.01) and lower with tolterodine IR 4 mg/day than with oxybutynin IR 7.5 to 10 mg/day (RR: 0.83; 95% CI, 0.75–0.91; p < 0.01) and oxybutynin IR 15 mg/day (RR: 0.86; 95% CI, 0.79–0.95; p < 0.01). One trial provided data suggestive of a higher risk of adverse events with fesoterodine 8 mg/day than with fesoterodine 4 mg/day (RR: 1.17; 95% CI, 1.00–1.37; p = 0.04) and tolterodine ER 4 mg/day (RR: 1.18; 95% CI, 1.01–1.37; p = 0.04). The remaining statistically significant result favoured trospium 40 mg/day over oxybutynin IR 7.5–10 mg/day (RR: 0.85; 95% CI, 0.73–0.98; p = 0.02).
No treatment in the review was statistically significantly associated with a greater risk of serious adverse events than placebo or other active treatment. A study by Jünemann et al [34], however, reported that 26 (3.3%) of 786 patients receiving 30 mg/day propiverine ER and IR in a trial had experienced serious adverse events compared to none of the 202 patients receiving placebo. No data were available for propiverine at other doses from this or other studies.
Table 7 ranks the frequency of reporting by patients of specific adverse events in antimuscarinic arms of the trials included in this review. Dry mouth was the most frequently reported adverse event, reported by 29.6% and 7.9% of active treatment and placebo-arm patients, respectively. The next most common adverse event was pruritus (15.4% on treatment vs 5.2% on placebo) [43], and [44].
Table 7 Proportion of patients in placebo arms of included trials who experienced adverse events
| Outcome | Patients receiving placebo treatment | Patients receiving antimuscarinic treatment | ||
|---|---|---|---|---|
| Proportion of patients reporting adverse event | Number of patients followed up | Proportion of patients reporting adverse event | Number of patients followed up | |
| Any adverse event | 39.9% | 4860 | 53.4% | 9199 |
| Dry mouth (any severity) | 7.9% | 7581 | 29.6% | 15896 |
| Dry mouth (mild/moderate) | 8.5% | 899 | 29.3% | 3006 |
| Dry mouth (mild) | 5.7% | 1606 | 19.3% | 7348 |
| Pruritus | 5.2% | 249 | 15.4% | 246 |
| Dry mouth (moderate/severe) | 2.7% | 857 | 13.1% | 3884 |
| Vertigo | 16.7% | 24 | 8.3% | 24 |
| Constipation | 3.9% | 6526 | 7.7% | 14496 |
| Confusion | 11.3% | 62 | 7.7% | 65 |
| Erythema | 2.0% | 249 | 6.9% | 246 |
| Dry mouth (moderate) | 0.9% | 1494 | 6.1% | 5967 |
| Headache | 4.9% | 4218 | 5.9% | 9784 |
| Urinary tract infection | 3.6% | 1543 | 5.0% | 4428 |
| Dyspepsia | 2.1% | 2618 | 4.7% | 6477 |
| Blurred vision | 2.6% | 4332 | 3.8% | 10608 |
| Diarrhoea | 3.1% | 1745 | 3.7% | 4238 |
| Dizziness | 2.5% | 2460 | 3.5% | 7154 |
| Nausea | 3.1% | 2545 | 3.2% | 7429 |
| Somnolence | 1.9% | 1211 | 3.1% | 3752 |
| Dry mouth (severe) | 0.2% | 1648 | 2.3% | 6300 |
| Any serious adverse event | 1.9% | 3637 | 2.2% | 7391 |
| Sweating increased | 0.0% | 190 | 1.8% | 109 |
| Vomiting | 2.8% | 144 | 1.7% | 1462 |
| Insomnia | 1.8% | 559 | 1.6% | 2605 |
| Fatigue | 0.6% | 842 | 1.6% | 1929 |
| Urinary retention | 0.2% | 1762 | 1.1% | 5391 |
In OAB trials, the severity of dry mouth, defined as the subjective assessment of the subject experiencing the adverse event, is a commonly recorded outcome. Dry mouth of any severity (mild, moderate, or severe) was found to be highly statistically significantly more common in all interventions than placebo (p ≤ 0.01). Where significant, the pooled RR varied between 2.15 and 5.90. It was apparent that the RR generally increased with drug dose for darifenacin, fesoterodine, solifenacin, and tolterodine, although this trend was not apparent for oxybutynin and propiverine.
Mild dry mouth was found to be statistically significantly more common in patients treated with oxybutynin, propiverine, solifenacin, and tolterodine than with placebo. Event rates were not significant for fesoterodine, and no data were available for meta-analysis for darifenacin. The pooled RR varied between 1.91 and 6.66. The RR for solifenacin 10 mg/day was higher than for solifenacin 5 mg/day. The risk of this adverse event in patients treated with tolterodine ER 4 mg/day was statistically significantly less than in those treated with oxybutynin 7.5 mg/day IR (RR: 0.76; 95% CI, 0.57–1.00; p = 0.05).
The following adverse events were reported at statistically significantly higher levels in active treatments than in placebo: blurred vision (oxybutynin IR 15 and 20 mg/day; propiverine 20, 30, and 45 mg/day; solifenacin 10 mg/day; and tolterodine ER 4 mg/day); constipation (darifenacin 7.5 mg/day, with and without titration, and 15 mg/day; propiverine ER 20 mg/day and IR 3 and 4.5 mg/day; solifenacin 5 and 10 mg/day; tolterodine 4 mg/day; and trospium 40 mg/day); erythema (oxybutynin TDS 3.9 mg/day); fatigue (tolterodine ER 4 mg/day); pruritus (oxybutynin TDS 3.9 mg/day); increased sweating (solifenacin 5 mg/day); and urinary retention (oxybutynin IR 7.5–10 mg/day).
The following adverse events were reported at statistically significantly higher levels in first-named active treatments than in second-named active treatments: blurred vision (solifenacin 10 mg/day vs solifenacin 5 mg/day, solifenacin 10 mg/day vs tolterodine IR 4 mg/day, propiverine IR 45 mg/day vs oxybutynin IR 7.5–10 mg/day); constipation (solifenacin 10 mg/day vs propiverine ER 20 mg/day, solifenacin 5 mg/day vs tolterodine ER and IR 4 mg/day, darifenacin 15 mg/day vs tolterodine IR 4 mg/day); fatigue (tolterodine ER 4 mg/day vs fesoterodine 4 or 8 mg/day); nausea (oxybutynin IR 15 mg/day titrated vs oxybutynin ER 15 mg/day titrated; oxybutynin IR 7.5–10 mg/day vs propiverine IR 45 mg/day); and vomiting (tolterodine ER 4 mg/day vs oxybutynin ER 7.5 to 10 mg/day).
3.5. Health-related quality of life
The importance of HRQL as an outcome in OAB trials is becoming increasingly appreciated. Of the 83 included trials in this review, 37 (44%) reported HRQL findings, and of those, 15 were either new studies added in the update or supplementary information from those studies previously included. Although the HRQL data were limited by inconsistencies among the instruments used and few reported domains, statistically significant differences in HRQL compared to placebo were reported for darifenacin, fesoterodine, oxybutynin TDS, propiverine ER and IR, solifenacin, tolterodine ER and IR, and trospium (Table 8). An update of a separate meta-analysis of the effects of antimuscarinics on HRQL [45] will address this topic in greater detail.
Table 8 Summary of the effects of antimuscarinics on HRQL (all significant differences between antimuscarinics and placebo reported in included trials)
| Significant impact reported for: | ||
|---|---|---|
| Global HRQL Domains | ||
| Overall HRQL | Contilife: Overall HRQL | Solifenacin |
| IIQ: Overall HRQL | Oxybutynin TDS; Tolterodine ER; Trospium | |
| ICIQ-SF: Overall score | Fesoterodine; Tolterodine ER | |
| KHQ: Overall score | Oxybutynin IR; Propiverine ER, IR | |
| KHQ: General health | Solifenacin; Propiverine | |
| OAB-q: Overall HRQL | Darifenacin; Tolterodine ER; Solifenacin | |
| PISQ: Overall score | Tolterodine ER | |
| SQOL-F: Overall score | Tolterodine ER | |
| Daily activities | Contilife: Daily activities | Solifenacin; Tolterodine IR |
| Physical limitations | KHQ: Physical limitations | Tolterodine IR, ER; Darifenacin; Solifenacin; Propiverine |
| Travel | IIQ: Travel | Oxybutynin TDS; Tolterodine ER; Trospium |
| Sleep and energy | KHQ: Sleep and energy | Tolterodine IR, ER; Solifenacin; Propiverine |
| OAB-q: Sleep | Solifenacin | |
| Basle: Tired–fresh | Propiverine IR | |
| Self-image | Contilife: Self-image | Solifenacin |
| Emotions | Contilife: Emotional consequences | Solifenacin |
| OAB-q: Concern | Tolterodine ER; Solifenacin | |
| KHQ: Emotional problems | Tolterodine IR, ER; Solifenacin; Propiverine | |
| HAD: Anxiety | Tolterodine ER | |
| IIQ: Feelings | Trospium | |
| Relationships | IIQ: Relationships | Trospium |
| KHQ: Role limitations | Tolterodine IR, ER; Darifenacin; Solifenacin; Propiverine | |
| KHQ: Personal relationships | Tolterodine ER; Solifenacin; Propiverine | |
| Sexuality | Contilife: Sexuality | Solifenacin |
| Social limitations | KHQ: Social limitations | Tolterodine ER; Solifenacin; Propiverine |
| Basle: Taciturn–talkative | Propiverine IR | |
| Basle: Retiring–gregarious | Propiverine IR | |
| OAB-q: Social interaction | Tolterodine ER | |
| Coping | KHQ: Severity (coping) | Tolterodine IR, ER |
| OAB-q: Coping | Tolterodine ER; Solifenacin | |
| Disease-specific domains | ||
| Symptom severity | KHQ: Symptom severity | Tolterodine IR, ER; Darifenacin; Solifenacin; Propiverine |
| OAB-q: Bother | Solifenacin | |
| UDI: Irritative symptoms | Oxybutynin TDS; Tolterodine ER | |
| OAB-q: Symptom bother | Tolterodine ER | |
| Incontinence | KHQ: Incontinence impact | Tolterodine IR, ER; Darifenacin; Solifenacin; Propiverine |
| GAQ: Stress score | Propiverine IR | |
| UDAAQ: Warning time | Darifenacin | |
| UDAAQ: Leakage | Darifenacin | |
| Urgency | GAQ: Urge score | Propiverine IR |
Abbreviations: Basle, Basle Subjective Well-Being Survey; Contilife, Quality of Life Assessment Questionnaire Concerning Urinary Incontinence; ER, extended release; GAQ, Gaudenz Appraisal Questionnaire; HAD, Hospital Anxiety Depression Scale Questionnaire; HRQL, health-related quality of life; ICIQ-SF, International Consultation on Incontinence Questionnaire-Short Form; IIQ, Incontinence Impact Questionnaire; IR, immediate release; KHQ, King's Health Questionnaire; OAB-q, Overactive Bladder Questionnaire; PISQ, Pelvic Organ Prolapse/Urinary Incontinence Questionnaire; SQOL-F, Sexual Quality of Life-Female; UDAAQ, Urinary Daily Activity Assessment Questionnaire; UDI, Urinary Distress Inventory.
4. Discussion
We present here the updated results of the largest systematic review conducted to date on the efficacy, safety, and tolerability of antimuscarinic treatments for OAB. Considerably more evidence is presented in this review than in the previous review published in 2005 [8]. The number of trials extracted increased from 56 to 83, reflecting the sizeable amount of newly published research in this field and the inclusion of the new agent fesoterodine in the review, which received marketing authorisation in April 2007 [10].
Antimuscarinics proved to be efficacious compared to placebo in this update, just as they did in the prior systematic review. The relative efficacy of each antimuscarinic is less clear, although there are some statistically significant results in favour of the higher dosage of propiverine, fesoterodine, and solifenacin over placebo and lower dose antimuscarinics.
More data are presented to demonstrate the tolerability of antimuscarinics relative to placebo. As in the previous review, oxybutynin treatment was found to be significantly associated with greater rates of withdrawal. A new aspect which has appeared in this therapeutic area is that of dose flexibility with newer agents; this allows titration towards optimal efficacy versus tolerability. The relative tolerability of each antimuscarinic is less clear, though there are consistently favourable data available for tolterodine ER 4 mg/day.
Antimuscarinics were associated with greater risks of adverse events than placebo, the most common being dry mouth, pruritus, and headache; however, there was no association between treatment with antimuscarinics and risk of serious adverse events, with the possible exception of propiverine ER 30 mg/day [34]. There was a wide range in incidence of dry mouth (range: 4–70%), as might be expected given the variability in study protocols and subject populations. However, the incidence of dry mouth was generally similar for ER antimuscarinics and appeared to increase with higher dosages.
Constipation may be the most burdensome and bothersome adverse effect for the majority of those on antimuscarinic treatment. Constipation is common, particularly in elderly patients, and increased risk of constipation with medications is a concern for HRQL along with the increased financial burden for health care costs in this population [46]. Moreover, there is evidence that constipation can aggravate symptoms of OAB [47]. There appears to be a trend for a lower incidence of constipation as an adverse effect with fesoterodine.
Antimuscarinics may cause central nervous system (CNS) adverse events, such as dizziness, somnolence, insomnia, or cognitive effects. Antimuscarinics differ in their propensity to cross the blood–brain barrier due to differences in lipophilicity, and thus in the likelihood that they will produce CNS adverse events [48], [49], and [50]. Oxybutynin may be the most likely to cross the blood–brain barrier; trospium is least likely. Elderly patients who have cerebrovascular disease or other comorbidities that alter the permeability of the brain–blood barrier, reduced muscarinic receptor densities in the brain, age-related changes in drug elimination, or who are taking multiple medications might be at greater risk for CNS adverse events [51].
Despite the systematic search, collation, and presentation of evidence into the efficacy, safety, and tolerability of antimuscarinics in OAB, there are limitations to this study. Many outcomes and many treatments (including placebo) were compared, stratified by dose and mode of administration. This methodology creates a large number of potential comparisons and, although it is mitigated through the unavailability of data for more obscure active treatment comparisons, the strong potential for false-positive results clearly exists. It is therefore worth adopting a cautious approach to the interpretation of p values, particularly for uncommonly reported outcomes in comparisons among active treatments in which few data may have been available. Additionally, we used frequency, incontinence, urgency, and mean voided volume to assess the efficacy of antimuscarinics; these are all commonly used efficacy outcomes in OAB trials. However, a consensus has not yet been reached on the optimal way to measure urgency, which is the hallmark symptom of OAB, and there is variation among patients in the OAB symptoms and the degree of symptom bother that they experience.
This study is also limited by restrictions on the types of patients typically included in OAB trials as well as by topics that have not been adequately addressed in the current antimuscarinic literature. For example, most of the studies restrict the study population to patients with limited comorbidities, and there is an evident gap in the literature base concerning the evaluation of elderly patients with significant comorbidity. Moreover, potentially important CNS adverse events, such as memory impairment, have traditionally not been evaluated in antimuscarinic trials; this is an area for future research, particularly in patient populations that may be at increased risk for such effects. Little data are also available on efficacy and tolerability of antimuscarinic agents in treatment-naïve subjects versus subjects previously treated with antimuscarinics. This information is often not reported, and different studies use wash-out periods of varying length.
Finally, a systematic review is to some extent reliant on the unbiased selection of outcomes in the reviewed studies [52]. We found that histograms of p values from the meta-analyses were highly skewed, a result suggestive of outcomes that were statistically significant in individual studies being more commonly reported than equally valid but not statistically significant results from those trials. The development of a standard set of outcomes to be included in all OAB studies would alleviate this issue for future research and more pragmatic, direct head-to-head comparative studies are highly recommended.
A strength of the meta-analytic technique is that it provides an overall perspective of differences between efficacy and safety among individual antimuscarinic drugs using all suitable data and large numbers of trial participants and is therefore less susceptible to the weaknesses of individual studies. Head-to-head trials designed to mirror clinical practice, such as the STAR trial [30], are very useful, but for any individual head-to-head study, it must always be borne in mind that results may be atypical for one agent or influenced by trial design and must always be interpreted in the context of the body of literature.
5. Conclusions
This comprehensive systematic review and meta-analysis has evaluated all data currently available on antimuscarinic therapy for OAB. Conclusions derived from such a comparison between antimuscarinics must be interpreted cautiously, taking into account the different inclusion and exclusion criteria, investigative sites, geographical locations, and study durations for individual trials. The ceiling may have been reached for the therapeutic efficacy of antimuscarinics, with the only new innovation being that of dose flexibility with the newer antimuscarinics such as darifenacin, solifenacin, and fesoterodine. Dose flexibility allows for individual titration of therapy to produce a maximum efficacy versus tolerability in individual cases. Certainly the new agents have greater tolerability than drugs such as oxybutinin, and once-a-day formulations of all of the agents seem to be better tolerated by patients and potentially more efficacious in improving OAB symptoms as well as in terms of patient perception of treatment impact. Therapeutic agents with different mechanisms of action are currently being studied, and alternative treatments with improved efficacy and tolerability may eventually be developed. However, the evidence to date suggests that antimuscarinics are efficacious, safe, and well-tolerated treatments for OAB, which improve HRQL, and these agents currently remain the first-line pharmacologic treatment for OAB.
Author contributions: Christopher R. Chapple had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein.
Acquisition of data: Chapple, Muston, Bitoun, Weinstein.
Analysis and interpretation of data: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein.
Drafting of the manuscript: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein.
Critical revision of the manuscript for important intellectual content: Chapple, Khullar, Gabriel, Muston, Bitoun, Weinstein.
Statistical analysis: Gabriel, Muston, Weinstein.
Obtaining funding: Chapple.
Administrative, technical, or material support: Gabriel, Muston, Bitoun, Weinstein
Supervision: Chapple, Gabriel, Muston, Bitoun, Weinstein.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Chapple is a scientific consultant and researcher with Allergan, Astellas, Novartis, and Pfizer. Khullar is a consultant, investigator, researcher or speaker with Astellas, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Schwartz Pharma. Gabriel and Muston were consultants with Heron Evidence Ltd. at the time this research was conducted. Gabriel, Bitoun, and Weinstein are currently employees of Pfizer.
Funding/Support and role of the sponsor: Research grant from Pfizer Ltd for review.
Acknowledgment statement: The authors acknowledge the contribution of Melanie Plested of Heron Evidence Development Ltd in the extraction and collation of review evidence. Editorial support was provided by Donald G. Buerk, PhD, from Complete Healthcare Communications, Inc.
Appendix A. Supplementary data
References
- [1] P. Abrams, L. Cardozo, M. Fall, et al.. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21 (2002) (167 - 178) Crossref.
- [2] I. Milsom, P. Abrams, L. Cardozo, et al.. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87 (2001) (760 - 766) Crossref.
- [3] K.S. Coyne, C. Payne, S.K. Bhattacharyya, et al.. The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey. Value Health 7 (2004) (455 - 463) Crossref.
- [4] A. Tubaro. Defining overactive bladder: epidemiology and burden of disease. Urology 64 (Suppl 1) (2004) (2 - 6) Crossref.
- [5] T. Klotz, B. Brüggenjürgen, M. Burkart, A. Resch. The economic costs of overactive bladder in Germany. Eur Urol 51 (2007) (1654 - 1663) discussion 1662–3 Abstract, Full-text, PDF, Crossref.
- [6] A.J. Wein, R.R. Rackley. Overactive bladder: a better understanding of pathophysiology, diagnosis and management. J Urol 175 (2006) (S5 - 10)
- [7] K.-E. Andersson. Antimuscarinics for the treatment of overactive bladder. Lancet Neurol 3 (2004) (46 - 53) Crossref.
- [8] C. Chapple, V. Khullar, Z. Gabriel, J.A. Dooley. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 48 (2005) (5 - 26) Abstract, Full-text, PDF, Crossref.
- [9] P. Herbison, J. Hay-Smith, G. Ellis, K. Moore. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 326 (2003) (841 - 844) Crossref.
- [10] Summary of Community decisions on marketing authorizations in respect of medicinal products from 1 April 2007 to 30 April 2007. Available at: http://eur-lex.europa.eu/LexUriServ/site/en/oj/2007/c_115/c_11520070525en00030009.pdf.
- [11] Toviaz (fesoterodine fumarate) [full prescribing information]. New York, NY: Pfizer Inc; 2007.
- [12] P. Cole. Fesoterodine, an advanced antimuscarinic for the treatment of overactive bladder: A safety update. Drugs Future 29 (2004) (715 - 720) Crossref.
- [13] L. Nilvebrant, K.E. Andersson, P.G. Gillberg, M. Stahl, B. Sparf. Tolterodine—a new bladder-selective antimuscarinic agent. Eur J Pharmacol 327 (1997) (195 - 207) Crossref.
- [14] C. Chapple, P. van Kerrebroeck, A. Tubaro, et al.. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 52 (2007) (1204 - 1212) Corrigendum. Eur Urol 2008;53:1319 Abstract, Full-text, PDF, Crossref.
- [15] V. Nitti, R. Dmochowski, P. Sand, et al.. Efficacy, safety, and tolerability of fesoterodine in subjects with overactive bladder. J Urol 178 (2007) (2488 - 2494) Crossref.
- [16] W. Cawello, S. Auer, W. Hammes, R. Sachse, R. Horstmann. Multiple dose pharmacokinetics of fesoterodine in human subjects [abstract]. Naunyn Schmiedebergs Arch Pharmacol 365 (Suppl 1) (2002) (428)
- [17] D. Moher, D.J. Cook, S. Eastwood, et al.. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 354 (1999) (1896 - 1900) Crossref.
- [18] Harris R, Bradburn M, Deeks J, et al. METAN: Stata module for fixed and random effects meta-analysis. Available at: http://ideas.repec.org/c/boc/bocode/s456798.html.
- [19] M. Egger, G.D. Smith, D.G. Altman. Systematic reviews in health care: meta-analysis in context. 2nd ed (BMJ, London, UK, 2001)
- [20] S. Herschorn, J. Heessakkers, D. Castro-Diaz, et al.. Tolterodine extended release (TER) improves objective and subjective outcomes after 1 week of treatment in patients with overactive bladder (OAB) [abstract]. Int Urogynecol J 18 (Suppl 1) (2007) (S78)
- [21] K. Hirani, P. Rahmanou, A. Lamba, et al.. Does the bladder contractility change with anticholinergic therapy in women with detrusor overactivity?. Neurourol Urodyn 23 (2004) (594 - 595)
- [22] Y. Homma, N. Koyama. Minimal clinically important change in urinary incontinence detected by a quality of life assessment tool in overactive bladder syndrome with urge incontinence. Neurourol Urodyn 25 (2006) (228 - 235) Crossref.
- [23] Khullar V, Hill S, Solanki J. Assessment of health-related quality of life in patients with overactive bladder taking tolterodine extended release versus placebo. Paper presented at: Annual Meeting of the International Continence Society; August 31–September 2, 2005; Montreal, Canada.
- [24] Lee KS, Choo MS, Paick JS, et al. Propiverine hydrochloride reduced frequency and perception of urgency in treatment of overactive bladder: a 12 week prospective, randomized, double-blind, placebo controlled study. Paper presented at: Annual Meeting of the International Continence Society; November 29–December 1, 2006; Christchurch, New Zealand.
- [25] Madersbacher H, Hessdoerfer E, Martan A, et al. Safety, tolerability and efficacy of propiverine long-term treatment. Paper presented at: Annual Meeting of the International Continence Society; August 31–September 2, 2005; Montreal, Canada.
- [26] Neimark M, Davila GW, Sanders S. Effects of transdermal and oral oxybutynin and its metabolites on cystometrogram parameters. Paper presented at: Annual Meeting of the International Continence Society; August 28–30, 2002; Heidelberg, Germany.
- [27] V. Nitti, R. Dmochowski, T. Williams, O. Alvarez-Jacinto. Efficacy, safety, and tolerability of fesoterodine in patients with overactive bladder: A phase 3 placebo controlled trial in the United States. J Urol 175 (2006) (57) Abstract 176
- [28] G.W. Davila, C.A. Daugherty, S.W. Sanders. A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol 166 (2001) (140 - 145)
- [29] C. Chaliha, M. Halaska, S.L. Stanton. Trospium chloride for the treatment of detrusor instability: a placebo-controlled dose-finding study. Br J Obstet Gynaecol 105 (Suppl 17) (1998) (276)
- [30] C.R. Chapple, R. Martinez-Garcia, L. Selvaggi, et al.. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 48 (2005) (464 - 470)
- [31] C.R. Chapple, T. Rechberger, S. Al-Shukri, et al.. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 93 (2004) (303 - 310) Crossref.
- [32] P. van Kerrebroeck, K. Kreder, U. Jonas, N. Zinner, A. Wein. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 57 (2001) (414 - 421) Crossref.
- [33] O. Yamaguchi, E. Marui, H. Kakizaki, et al.. Randomized, double-blind, placebo- and propiverine-controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder. BJU Int 100 (2007) (579 - 587) Crossref.
- [34] K.P. Jünemann, E. Hessdorfer, I. Unamba-Oparah, et al.. Propiverine hydrochloride immediate and extended release: comparison of efficacy and tolerability in patients with overactive bladder. Urol Int 77 (2006) (334 - 339)
- [35] C.R. Chapple, P. Arano, J.L. Bosch, et al.. Solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo- and tolterodine-controlled phase 2 dose-finding study. BJU Int 93 (2004) (71 - 77) Crossref.
- [36] L. Cardozo, M. Lisec, R. Millard, et al.. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 172 (2004) (1919 - 1924) Crossref.
- [37] L. Cardozo, G. Nagy, L. Kiss, et al.. Solifenacin in the treatment of urgency symptoms of overactive bladder in a flexible dose, placebo controlled trial. Int Urogynecol J 17 (Suppl 2) (2006) (52)
- [38] S. Serels, M. Andoh, N. Smith. Solifenacin treatment in patients with OAB reduces symptom bother and improves health-related quality of life. Urology 68 (Suppl 1) (2006) (73) Crossref.
- [39] T. Uchida, D. Tempel, S. Ridge, I. Grimes, N. Smith. US PII study results: efficacy and safety of YM905, a bladder-selective treatment for OAB. Int Urogynecol J 13 (Suppl 1) (2002) (S12)
- [40] W. Dorschner, J.U. Stolzenburg, R. Griebenow, et al.. The elderly patient with urge incontinence or urge-stress incontinence—efficacy and cardiac safety of propiverine [in German]. Aktuelle Urol 34 (2003) (102 - 108)
- [41] M. Halaska, W. Dorschner, M. Frank. Treatment of urgency and incontinence in elderly patients with propiverine hydrochloride. Neurourol Urodyn 13 (1994) (428 - 430)
- [42] A.C. Wang, S.Y. Chih, M.C. Chen. Comparison of electric stimulation and oxybutynin chloride in management of overactive bladder with special reference to urinary urgency: a randomized placebo-controlled trial. Urology 68 (2006) (999 - 1004) Crossref.
- [43] R.R. Dmochowski, G.W. Davila, N.R. Zinner, et al.. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. J Urol 168 (2002) (580 - 586)
- [44] R.R. Dmochowski, P.K. Sand, N.R. Zinner, et al.. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 62 (2003) (237 - 242) Crossref.
- [45] V. Khullar, C. Chapple, Z. Gabriel, J.A. Dooley. The effects of antimuscarinics on health-related quality of life in overactive bladder: a systematic review and meta-analysis. Urology 68 (Suppl) (2006) (38 - 48)
- [46] D.A. Ginsberg, S.E. Phillips, J. Wallace, K.L. Josephson. Evaluating and managing constipation in the elderly. Urol Nurs 27 (2007) (191 - 200) 12; quiz 201
- [47] M.T. Rosenberg, D.K. Newman, C.T. Tallman, S.A. Page. Overactive bladder: recognition requires vigilance for symptoms. Cleve Clin J Med 74 (Suppl 3) (2007) (S21 - S29)
- [48] G.G. Kay, L.J. Granville. Antimuscarinic agents: implications and concerns in the management of overactive bladder in the elderly. Clin Ther 27 (2005) (127 - 138)
- [49] R. Scheife, M. Takeda. Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly. Clin Ther 27 (2005) (144 - 153) Crossref.
- [50] G. Kay, T. Crook, L. Rekeda, et al.. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 50 (2006) (317 - 326) Abstract, Full-text, PDF, Crossref.
- [51] P. Abrams, K.E. Andersson, J.J. Buccafusco, et al.. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 148 (2006) (565 - 578) Crossref.
- [52] P.R. Williamson, C. Gamble, D.G. Altman, J.L. Hutton. Outcome selection bias in meta-analysis. Stat Methods Med Res 14 (2005) (515 - 524) Crossref.
Footnotes
a Sheffield Teaching Hospital NHS Trust, Royal Hallamshire Hospital, Urology Research, Sheffield, UK
b Imperial College, St. Mary's Hospital, London, UK
c Heron Evidence Development Ltd., UK
d Pfizer, France
Corresponding author. Sheffield Teaching Hospital, Glossop Road, Sheffield S10 2JK, United Kingdom. Tel. +44 114 271 2559; Fax: +44 114 279 7841.
Contents
Copyright © 