The purpose of the study was to determine the efficacy and safety of nonantimuscarinic treatments for overactive bladder. Medline, Cochrane, and other databases (inception to April 2, 2014) were used. We included any study design in which there were 2 arms and an n > 100, if at least 1 of the arms was a nonantimuscarinic therapy or any comparative trial, regardless of number, if at least 2 arms were nonantimuscarinic therapies for overactive bladder. Eleven reviewers double-screened citations and extracted eligible studies for study: population, intervention, outcome, effects on outcome categories, and quality. The body of evidence for categories of interventions were summarized and assessed for strength. Ninety-nine comparative studies met inclusion criteria. Interventions effective to improve subjective overactive bladder symptoms include exercise with heat and steam generating sheets (1 study), diaphragmatic (1 study), deep abdominal (1 study), and pelvic floor muscle training exercises (2 studies). Pelvic floor exercises are more effective in subjective and objective outcomes with biofeedback or verbal feedback. Weight loss with diet and exercise, caffeine reduction, 25-50% reduction in fluid intake, and pelvic floor muscle exercises with verbal instruction and or biofeedback were all efficacious. Botulinum toxin A improves urge incontinence episodes, urgency, frequency, quality of life, nocturia, and urodynamic testing parameters. Acupuncture improves quality of life and urodynamic testing parameters. Extracorporeal magnetic stimulation improves urodynamic parameters. Mirabegron improves daily incontinence episodes, nocturia, number of daily voids, and urine volume per void, whereas solabegron improves daily incontinence episodes. Short-term posterior tibial nerve stimulation is more efficacious than pelvic floor muscle training exercises and behavioral therapy for improving: urgency, urinary incontinence episodes, daily voids, volume per void, and overall quality of life. Sacral neuromodulation is more efficacious than antimuscarinic treatment for subjective improvement of overactive bladder and quality of life. Transvaginal electrical stimulation demonstrates subjective improvement in overactive bladder symptoms and urodynamic parameters. Multiple therapies, including physical therapy, behavioral therapy, botulinum toxin A, acupuncture, magnetic stimulation, mirabegron, posterior tibial nerve stimulation, sacral neuromodulation, and transvaginal electrical stimulation, are efficacious in the treatment of overactive bladder.
Overactive bladder (OAB) is a common problem affecting up to 17% of the female population. Antimuscarinic medications are commonly used for treatment, and a significant number of outpatient visits in the United States annually are associated with one of these medications. One study found that 68 of 1000 ambulatory visits by women were affiliated with an OAB-related medication, and 8.1 million adult women in the United States were using an OAB-related anticholinergic medication in 2009. However, these medications are often marked by lack of efficacy, poor compliance, low patient satisfaction, and bothersome side effects. Furthermore, a recent systematic review confirms that these medications often reduce voids by less than 2 episodes a day and only rarely result in complete resolution of symptoms. International guidelines for OAB emphasize behavioral modification and lifestyle therapy as first-line treatment, but there is a paucity of data regarding the effectiveness of these treatments.
The expanding options for nonantimuscarinic treatment of OAB includes various forms of physical therapy, beta-3 agonist medications, neuromodulation, electrical or magnetic stimulation, acupuncture, and botulinum toxin injection. Many providers are unfamiliar with the evidence surrounding the efficacy and adverse events of these therapies. Emerging evidence demonstrates that nonantimuscarinic treatments, such as onabotulinum toxin A or nerve stimulation, may be as efficacious and acceptable as anticholinergics for OAB. Clinicians are often unsure where in the treatment paradigm to use these options, or consider them much later than ideal. Even the most commonly used nonantimuscarinic treatment for urgency symptoms, pelvic floor physiotherapy, has a lack of evidence regarding long-term outcomes and comparison with other treatments. The many women who have OAB would benefit greatly from their provider’s familiarity with the wide array of nonantimuscarinic options available for treatment.
In this systematic review, we aimed to determine the efficacy and safety of nonantimuscarinic treatments for women with OAB.
Methods
Eligibility criteria and study selection
We included adults (≥18 years old) with OAB symptoms of urgency, frequency, nocturia, urgency urinary incontinence (UUI), diagnoses of refractory OAB, refractory UUI, OAB syndrome (urgency, with or without UUI, frequency, and nocturia). We accepted any study (retrospective, prospective, cohort, randomized, controlled trials [RCT], case series, case control, cross-sectional, crossover) in which there were 2 arms and a number greater than 100, if at least 1 of the arms was a nonantimuscarinic therapy for overactive bladder. We also accepted any comparative study, regardless of number, if at least 2 arms were nonantimuscarinic therapies for overactive bladder. We excluded studies with participants having diabetic neuropathy or bladder dysfunction, greater than 50% of subjects with urodynamic stress incontinence, painful bladder syndrome, diabetes insipidus, nocturnal enuresis, vesico-ureteral reflux, neurogenic bladder, bladder cancer, and urinary tract infection (as an explicit eligibility criterion). We also excluded studies with >50% men or subjects who were restricted to residential facilities such as nursing homes.
The abstracts were collectively divided among the 11 group members. If there was a discrepancy between the 2 extractors regarding an abstract (ie, inclusion or not) the abstract was then reviewed by the principal investigator for the group to resolve the discrepancy. Online software (Abstrackr, http:abstrackr.cebm.brown.edu ) was used for the screening process. Potentially eligible full-text articles were again screened in the same fashion.
Information sources
The Society of Gynecologic Surgeons Systematic Review Group, including gynecologic surgeons and systematic review methodologists, performed a systematic search to identify studies comparing nonantimuscarinic treatments for OAB. We searched Medline, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Commonwealth Agricultural Bureaux Abstracts from inception until April 2, 2014. The search included numerous terms for OAB and possible treatments including: OAB, urinary incontinence, enuresis, urgency, frequency, nocturia, detrusor instability, diapers, mirabegron, botulinum toxins, neuromuscular agents, muscle/bladder training, exercises, biofeedback, electrical stimulation, behavioral therapy, related terms; and terms for comparative studies and systematic reviews. The search was restricted to English language publications.
Search strategy
Searches of relevant databases initially identified 2975 citations that were screened. Figure 1 describes the flow of screened included and excluded abstracts. There were 156 manuscripts screened as full texts after abstract screening, and 99 of these manuscripts met all criteria for inclusion in the systematic review.
Data extraction
We first extracted lists of reported outcomes from each article. Outcomes of potential interest (subjective, objective, voiding diary, validated questionnaires, urodynamic testing, catheterizations, and adverse event data) that appeared in at least 2 studies were included for final extraction ( Appendix A ). We extracted data on study characteristics, participant characteristics, intervention details, outcome definitions, length of follow-up, and results.
Assessment of risk of bias and strength of evidence
Each study was assessed on the basis of the Cochrane Risk of Bias Tool. This tool included questions regarding randomization, allocation concealment, outcome assessor and participant blinding, amount and handling of missing data, dropouts, crossovers, similarity of participants at baseline and of co-interventions, compliance, intention-to-treat analysis (evaluation of potential confounders), and clarity and accuracy of reporting ( Table 1 ). Studies were graded as good (A), fair (B), or poor (C) quality, based on the likelihood of bias ( Tables 1 and 2 ), and completeness of reporting, based on a system approved by the Agency for Healthcare Research and Quality. Outcome quality could vary within the same study. All extracted data, including quality assessment, were confirmed by a second reviewer. When a discrepancy between extracted outcome study qualities arose, that discrepancy was resolved by a third reviewer.
| Author | Location | Year | Study Design | Subjects, n | Study Grade | Random sequence generation (selection bias) | Allocation Concealment (selection bias) | Outcome Assessment Bias (detection bias) | Patient Blinding Bias (performance bias) | Incomplete outcome data (attrition bias) | Crossover Bias | Baseline Bias | Compliance Bias |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Brubaker | USA | 2008 | RCT | 43 | A | low | Low | Low | Low | Low | Low | Low | Low |
| Bryant | Australia | 2002 | RCT | 95 | B | Unclear | Unclear | High | Unclear | Unclear | Unclear | Low | Unclear |
| Burgio | USA | 2002 | RCT | 222 | A | Low | Low | Unclear | Unclear | Low | Low | Low | Low |
| Burgio | USA | 1998 | RCT | 197 | A | Low | Unclear | Low | High | Low | Low | Low | Unclear |
| Brubaker | USA | 2012 | RCT | 313 | A | Unclear | Unclear | Low | Low | Low | Unclear | Unclear | Low |
| But | Slovenia | 2003 | RCT | 52 | C | Unclear | Low | Low | Low | Low | Low | Unclear | Unclear |
| Chapple | USA, Canada, South Africa, Australia, New Zealand, Europe | 2013 | RCT | 2444 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Chapple | Belgium, Czech Republic, Germany, Poland, Russia, UK, US | 2013 | RCT | 548 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Cohen | USA | 2009 | nRCS, prospective | 44 | B | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear | Low |
| H-Leung | Japan | 2007 | RCT | 109 | B | Low | Low | Unclear | High | High | Low | Low | High |
| Marencak | UK, Sweden, Slovakia, Norway, Lithuania | 2011 | RCT | 178 | A | Low | Unclear | Unclear | Low | Low | Low | Low | Low |
| Morris | Australia | 2007 | RCT | 34 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Nitti | United States and Canada | 2013 | RCT | 557 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Nitti | USA, Netherlands, Canada, Spain, UK | 2013 | RCT | 3542 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Ohlstein | Argentina, Australia, Finland, France, | 2012 | RCT | 258 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Peters | USA | 2010 | RCT | 220 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Manescksa | Ireland | 2012 | RCT | 22 | A | Low | Unclear | Unclear | Unclear | Low | Low | Low | Low |
| Alewijnse | Netherlands | 2003 | RCT | 103 | A | Low | Low | High | High | Unclear | Low | Unclear | Unclear |
| Arruda | Brazil | 2008 | RCT | 64 | B | High | High | High | Low | Unclear | Unclear | Low | Low |
| Barroso | Brazil | 2005 | RCT | 36 | B | Unclear | High | Low | Low | Low | Low | Low | Low |
| Berghmans | The Netherlands | 2002 | RCT | 68 | C | Low | Low | Low | High | High | Unclear | High | High |
| Betschart | Switzerland | 2013 | RCT | 22 | A | Low | Low | Low | Low | Unclear | Low | Low | Unclear |
| Bolukbas | Istanbul, Turkey | 2005 | nRCS, prospective | 22 | C | High | High | High | High | Unclear | Unclear | High | Unclear |
| Brubaker | USA | 1997 | RCT | 113 | A | Low | Low | Low | Low | Low | Unclear | Low | High |
| Ceseroli | Italy | 1993 | nRCS, prospective | 60 | C | High | High | High | High | High | High | High | High |
| Hasan | England | 1996 | nRCS, prospective | 180 | C | High | High | High | High | High | Unclear | High | Unclear |
| Schreiner | Brazil | 2010 | RCT | 51 | B | Low | Unclear | Low | High | Low | Low | Low | Low |
| Spruijt | Netherlands | 2003 | RCT | 47 | B | Low | Unclear | Low | High | Low | Low | Low | Unclear |
| Subak | USA | 2009 | RCT | 338 | A | Low | Low | Low | Unclear | Low | Low | Low | Low |
| Subak | USA | 2005 | RCT | 48 | A | Low | Low | Low | High | Low | Low | Low | Unclear |
| Sutherland | USA | 2007 | Single arm, retrospective | 104 | C | High | Unclear | High | High | High | Unclear | High | Unclear |
| Suzuki | Japan | 2007 | RCT | 39 | B | Low | Unclear | Unclear | Low | High | Low | Low | Low |
| Svihra | Slovakia | 2002 | RCT | 28 | B | Unclear | Unclear | Unclear | High | Low | Low | Unclear | High |
| Taylor | UK | 1979 | RCT | 40 | B | Unclear | Unclear | Low | Low | Unclear | Low | Unclear | Unclear |
| Tincello | UK | 2012 | RCT | 240 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Van Voskuilen | Netherlands | 2006 | Single arm, retrospective | 149 | C | High | Unclear | High | High | High | Unclear | High | Unclear |
| Kim | Japan | 2011 | RCT | 146 | A | Low | Unclear | Low | High | Low | Low | Low | Unclear |
| Kim | Japan | 2011 | RCT | 127 | B | Low | Unclear | High | High | Low | Low | Low | High |
| Kuo | Taiwan | 2011 | RCT | 105 | A | Low | Low | Low | Unclear | Low | Low | Low | Low |
| Levin | USA | 2012 | Single arm, retrospective | 149 | C | High | High | High | High | Low | Low | Low | Low |
| Wang | Taiwan | 2006 | RCT | 68 | B | Low | Low | High | High | Low | Low | Low | Low |
| Wang | Taiwan | 2004 | RCT | 103 | B | Low | Low | Unclear | High | Low | Low | Low | Low |
| Weil | Netherlands | 2000 | RCT | 44 | B | Low | High | High | High | Low | Low | Low | Unclear |
| Wing | USA | 2010 | RCT | 338 | A | Low | Unclear | Low | Low | Low | Low | Low | Unclear |
| Wing | USA | 2010 | RCT | 338 | A | Low | Unclear | Low | Low | Low | Low | Low | Unclear |
| Denys | France | 2012 | RCT | 121 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Dmochowski | USA, UK | 2010 | RCT | 313 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Dougherty | USA | 2002 | RCT | 178 | B | Low | High | Unclear | High | Low | Unclear | Low | High |
| Dowson | UK | 2011 | RCT | 23 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Dowson | UK | 2012 | Single arm, prospective | 100 | C | Unclear | Unclear | High | High | High | Unclear | Unclear | Unclear |
| Engberg | USA, Canada, South Africa, Australia, New Zealand, Europe | 2009 | RCT | 9 | C | Unclear | Unclear | Low | Low | Low | Unclear | Low | Low |
| Finazzi-Agro | Italy | 2010 | RCT | 32 | A | Low | Unclear | Low | Low | Low | High | Low | Low |
| Fonda | Australia | 1995 | RCT | 73 | C | Unclear | High | Unclear | High | Low | Unclear | Low | Unclear |
| Flynn | USA | 2009 | RCT | 22 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Sahai | UK | 2008 | RCT | 34 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Pham | USA | 2008 | nRCS, retrospective | 95 | C | High | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear |
| Pinto | USA | 2011 | RCT | 338 | A | Low | High | Unclear | Unclear | Low | Low | Low | Low |
| Ramsay | Scotland | 1996 | RCT | 74 | B | Low | High | Unclear | High | High | Unclear | Low | Unclear |
| Ravindra | UK | 2013 | nRCS, retrospective | 207 | C | High | High | Unclear | High | Unclear | Low | Low | High |
| Rovner | USA | 2011 | RCT | 313 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Sahai | UK | 2007 | RCT | 34 | A | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Scheepens | Netherlands | 2002 | RCT | 33 | C | High | High | Unclear | High | High | Unclear | Unclear | Unclear |
| Schmid | Switzerland | 2006 | Single arm, prospective | 100 | B | Unclear | Unclear | Low | Low | Unclear | Unclear | Low | low |
| Schmidt | USA, Netherlands, Canada | 1999 | RCT | 98 | B | Low | High | Unclear | High | Low | High | Low | Low |
| Bower | Australia | 1998 | RCT | 126 | B | Unclear | Unclear | Low | Low | Low | Unclear | Low | Low |
| Hung | Taiwan | 2010 | RCT | 70 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Kuo | Taiwan | 2011 | Single arm, retrospective | 105 | C | High | High | High | High | Low | Low | Unclear | Low |
| Leong | Netherlands | 2011 | Single arm, retrospective | 180 | C | High | High | High | High | High | Unclear | High | High |
| Rios | Brazil | 2007 | RCT | 116 | C | Unclear | Unclear | Low | Low | Low | Low | Unclear | Low |
| Rufford | UK | 2003 | RCT | 40 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Siegel | Italy, Canada, USA, Netheralands, Germany | 2000 | Single arm, prospective | 581 | C | High | High | High | High | High | Unclear | High | Low |
| Wiseman | UK | 1991 | RCT | 74 | B | Low | Unclear | Low | Low | Low | Low | Low | Low |
| Gameiro | Brazil | 2010 | RCT | 103 | B | Low | High | Unclear | High | Low | Low | Low | Low |
| Groenendijk | Netherlands, USA, Sweden, Italy, Germany | 2007 | Single arm, prospective | 111 | C | High | High | High | High | Unclear | Unclear | High | Low |
| Hashim | UK | 2008 | RCT | 24 | B | Low | Unclear | Unclear | Unclear | Unclear | High | Low | High |
| Herschorn | Europe and north america | 2013 | RCT | 1305 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Hui | China | 2006 | RCT | 58 | A | Low | Unclear | Unclear | High | Low | Low | Low | Low |
| Indrekvam | Norway | 2002 | Single arm, prospective | 6396 | C | High | High | High | High | Low | Low | Low | High |
| Khullar | Europe | 2013 | RCT | 1978 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Ugurlucan | Turkey | 2013 | RCT | 52 | C | Low | High | High | High | High | Low | Low | Unclear |
| Firoozi | USA | 2013 | nRCS, prospective | 36 | C | High | High | Unclear | High | Unclear | Unclear | Low | Low |
| Kumari | India | 2008 | RCT | 198 | B | Low | Low | High | High | Low | Low | Low | Low |
| Lamb | England, UK | 2009 | RCT | 174 | A | Low | Low | Low | High | Low | Unclear | Low | Low |
| Lucioni | USA | 2006 | nRCS, prospective | 40 | C | High | High | Low | Unclear | High | Low | Unclear | Low |
| O’Reilly | Australia | 2008 | RCT | 63 | A | Low | Low | Low | Low | Low | Low | Low | Unclear |
| Oldham | UK | 2013 | RCT | 124 | A | Low | Low | Low | High | Low | Low | Low | Low |
| Peters | USA | 2011 | nRCS, prospective | 141 | C | Unclear | Unclear | High | High | High | Low | Low | Low |
| Resnick | USA | 2013 | Single arm, prospective | 183 | C | Low | Low | High | High | Low | Low | Low | Unclear |
| Sander | Denmark | 2000 | Single arm, prospective | 408 | C | High | High | High | High | High | Low | Low | Unclear |
| Wallis | Australia | 2012 | RCT | 122 | A | Low | Low | High | Low | Low | Low | Low | Low |
| Subak | USA | 2002 | RCT | 123 | B | Unclear | High | High | High | High | Unclear | Low | Low |
| Amaro | Brazil | 2005 | RCT | 40 | A | Low | Low | Unclear | Low | Low | Low | Unclear | Low |
| Emmons | USA | 2005 | RCT | 74 | A | Low | High | Low | Low | Low | Low | Low | Low |
| Gordon | Israel | 1998 | RCT | 40 | B | High | Unclear | Low | Low | Unclear | Low | High | Unclear |
| Hassouna | Canada, USA, Netherlands | 2000 | RCT | 51 | B | Unclear | Low | High | High | Low | Low | Unclear | Unclear |
| Naglie | Canada | 2002 | RCT | 76 | A | Low | Low | Low | Low | Low | Low | Unclear | Low |
| Schmidt | Brazil | 2009 | RCT | 32 | B | Unclear | High | Unclear | High | Low | Low | Low | Low |
| Van Kerrebroeck | Netherlands, England, Canada,Germany, Sweden, Switzerland,USA | 2007 | Single arm, prospective | 152 | C | Unclear | High | High | High | High | Unclear | Unclear | Unclear |
| Visco | USA | 2012 | RCT | 249 | A | Low | Low | Low | Low | Low | Low | Low | Low |
| Bias type | Low (n = 99) | High (n = 99) | Unclear (n = 99) |
|---|---|---|---|
| Random sequence generation (selection bias) | 62.6% | 19.3% | 18.1% |
| Allocation concealment (selection bias) | 35.3% | 28.4% | 36.3% |
| Outcome assessment bias (detection bias) | 50.5% | 27.3% | 22.2% |
| Patient blinding bias (performance bias) | 44.4% | 45.5% | 10.1% |
| Incomplete outcome data (attrition bias) | 67.7% | 18.2% | 14.1% |
| Crossover bias | 69.7% | 5.0% | 25.3% |
| Baseline bias | 73.7% | 10.1% | 16.2% |
| Compliance bias | 60.6% | 11.1% | 28.3% |
For each intervention, we generated an evidence profile by grading the strength of evidence for each outcome according to the Grades for Recommendation, Assessment, Development and Evaluation system. The process considered the methodologic quality, consistency of results across studies, directness of the evidence, and imprecision or sparseness of evidence to determine an overall quality of evidence. Four quality rating categories were possible: high (A), moderate (B), low (C), and very low (D). Strength of evidence was determined by group consensus.
Data synthesis
For reporting in this review, these outcomes were divided into the following categories: subjective, objective, voiding diary, validated symptom questionnaires, and quality of life, based on validated questionnaires, urodynamic testing, catheterizations, and adverse events.
Data from the completed data abstraction forms were used to develop evidence profiles. The evidence profiles were created for each of the major nonantimuscarinic forms of therapy for OAB. We compared interventions versus control, interventions versus antimuscarinic agent(s), and interventions versus other intervention(s). The final interventions and comparators were as follows: (1) behavioral therapy (including weight loss, fluid management, diet modification, bladder training, and pelvic floor muscle training exercises), (2) complementary and alternative medical therapy (most commonly acupuncture), (3) biofeedback, (4) botulinum toxin A formulations, (5) mirabegron, (6) magnetic stimulation, (7) vaginal electrical stimulation, (8) sacral neuromodulation, and (9) posterior tibial nerve therapy.
After the extraction forms were completed, a summary table was created. This table listed the complete list of manuscripts and all of the data in the various different study designs and outcome categories. After the summary table was created, we created evidence profiles. Each evidence profile was constructed for the individual treatment option. On the basis of the evidence in the literature, we attempted to make an evidence profile for each therapeutic option as noted above, comparing the intervention with control, antimuscarinic therapy, and other interventions. Evidence profiles were created for physical therapy, behavioral therapy, botulinum toxin A, complementary and alternative medicine, magnetic stimulation, mirabegron, posterior tibial nerve stimulation, sacral neuromodulation, and transvaginal electrical stimulation.
We developed guideline statements incorporating the balance between benefits and harms of the compared interventions when the data were sufficient to support these statements. Each guideline was graded into 2 parts: a strength of the recommendation and an overall quality of evidence. The strength of a recommendation indicates the extent to which one can be confident that adherence to the recommendation will do more good than harm. Grades for Recommendation, Assessment, Development, and Evaluation 1 recommendations are strong, worded as “we recommend,” and indicate that benefits do, or do not, outweigh risks, burden, and costs (what most practitioner[s] would do in a given clinical scenario). Grades for Recommendation, Assessment, Development, and Evaluation 2 recommendations are worded as “we suggest” and imply that the magnitude of the benefits, risks, burden, and costs are less certain. In either case, support for recommendations may come from high-quality, moderate-quality, or low-quality studies, labeled, respectively, A, B, and C. The review and guidelines were presented for public comment at the Society of Gynecologic Surgeons annual scientific meeting in April 2015 and posted on the Society of Gynecologic Surgeons website, after which comments were solicited for 4 weeks.
Results
Study selection
Eleven reviewers screened abstracts and titles in duplicate, with discrepancies resolved by a third reviewer, using online software (Abstrackr, http:abstrackr.cebm.brown.edu ). Potentially eligible full-text articles were again screened in duplicate.
Risks of bias of included studies
Each study was assessed on the basis of the Cochrane Risk of Bias Tool. This included questions regarding randomization, allocation concealment, outcome assessor and participant blinding, amount and handling of missing data, dropouts, and crossovers, similarity of participants at baseline and of co-interventions, compliance, intention-to-treat analysis, handling of potential confounders, and clarity and accuracy of reporting. From these data, we were able to quantify various types of bias among the extracted manuscripts including selection, detection, performance, attrition, crossover, baseline, and compliance ( Table 2 ). Studies were graded as good (A), fair (B), or poor (C) quality, based on the likelihood of bias and completeness of reporting, in accordance with the system approved by the Agency for Healthcare Research and Quality mentioned above ( Table 1 ). Of the 99 manuscripts extracted, 45 of 99 (45.4 %) were study quality (A), 27 of 99 (27.3%) were study quality (B), and 27 of 99 (27.3%) were study quality (C).
Synthesis of results
Physical therapy versus control
The heat- and steam-generating sheet is a thin, flexible filmed sheet (120 mm 204 mm; Kao, Tokyo, Japan) that generates heat and steam immediately after unsealing. When the sheet is placed on the body, the temperature of the skin surface rises to 38-40°C, and it continues to generate heat and steam for over 5 hours. The participants gathered at classes every 2 weeks, where heat- and steam-generating sheets were provided for 2 weeks, and the urinary diaries were collected. The participants in the heat- and steam-generating group were asked to place the heat- and steam-generating sheet on their lower back once a day immediately after waking up. The participants recorded the time of day that they placed and removed the sheet in their urinary diary ( Table 3 ).
| Therapy group | Outcome | Intervention vs comparator | Follow-up time | Quality of evidence | Adverse events |
|---|---|---|---|---|---|
| Physical therapy vs control | Subjective outcome: cure of overactive bladder symptoms | Exercises with heat and steam generating sheets were superior to control | 3 Months | 1A Study | None |
| Physical therapy vs control | Objective outcomes: walking speed, grip strength, adductor muscle strength | Stretching, pelvic floor muscle exercises and fitness exercises (with multidimensional approach) were superior to control | 24 Months | 1B Study | None |
| Physical therapy vs control | Subjective outcomes: severity of incontinence symptoms objective outcomes: pad weight | Pelvic floor muscle exercises plus biofeedback were superior to control for improvement in outcomes | 24 Months | 1B Study | None |
| Physical therapy vs control | Subjective outcomes: general health and well-being (less need to avoid activities due to need to use toilet) -daily incontinence episodes -daily voids -leakage volume | Diaphragmatic, deep abdominal and pelvic floor muscle re-training were superior to control for improvement in outcomes | 4 Months | 1A Study | None |
| Physical therapy vs antimuscarinic | Subjective outcomes: urgency and objective number of daily voids, pad use, and post-void residual volumes | Pelvic floor muscle exercises were similar to oxybutynin for improvement in outcomes | 12 Weeks | 1B Study | Oxybutynin was associated with more dry mouth, blurry vision, constipation, confusion, and dizziness |
| Physical therapy vs antimuscarinic | Subjective outcomes: nocturia symptoms objective outcomes: maximum cystometric capacity on urodynamic testing | Oxybutynin was superior to pelvic floor muscle exercises for improvement in outcomes | 12 Weeks | 1B Study | Oxybutynin was associated with more dry mouth, blurry vision, constipation, confusion, and dizziness |
| Physical therapy vs other intervention | Quality-of-life outcome: International Consultation on Incontinence Questionnaire | Electrical stimulation was superior to pelvic floor muscle exercises for improvement in outcomes | 12 Weeks | 1A Study | No data |
| Physical therapy vs other intervention | Objective outcome: pelvic floor muscle contraction strength | Biofeedback-assisted pelvic floor muscle exercises were similar to electrical stimulation combined with pelvic floor muscle exercises | 3 months | 2B studies | No data |
| Physical therapy vs other intervention | Quality-of-life outcome: Kings Health Questionnaire | Biofeedback-assisted pelvic floor muscle exercises combined with electrical stimulation was superior to pelvic floor muscle exercises alone for improvement in outcomes | 12 Weeks | 1B Study | No data |
| Physical therapy vs other intervention | Subjective outcome: overactive bladder symptoms | Biofeedback or verbal feedback were superior to self-help book for improvement in outcomes | 12 Weeks | 1A Study | None |
| Physical therapy vs other intervention | Objective outcomes: daily pad use and in visual analog scale scores | Biofeedback with pelvic floor muscle exercises were superior to pelvic muscle exercises alone for improvement in outcomes | 6 Weeks | 1C Study | No data |
| Physical therapy vs other intervention | Quality-of-life outcome: Kings Health Questionnaire | Electrical stimulation and biofeedback assisted pelvic floor muscle exercises were superior to pelvic floor muscle exercises alone in one study and similar in one study | 12 Weeks | 2B Studies | No data |
| Physical therapy vs other intervention | Subjective outcome: wearing less protection, overactive bladder symptoms, improved muscle strength | Vaginal weighted cones were similar to pelvic muscle exercises | 12 Weeks | 1C Study | No data |
| Behavioral therapy vs control | Subjective outcomes and improvement in voiding diary outcomes | Bladder training with pelvic floor muscle exercises were similar to control for subjective outcomes, and superior to control for voiding diary outcomes | No data | 1C Study 1B Study | None |
| Behavioral therapy vs control | Bladder diary outcomes: daily voids and daily urgency episodes | Education on caffeine reduction was superior to control for improvement in outcomes | No data | 1B Study | None |
| Behavioral therapy vs control | Voiding diary outcomes: daily urge incontinence episodes, stress incontinence episodes, and smaller volume accidents | Weight loss with diet and exercise were superior to control for improvement in outcomes | No data | 1A Study | None |
| Behavioral therapy vs control | Voiding diary outcomes: daily urgency and nocturia | A 25-50% reduction in fluid intake was associated with improvement in outcomes | No data | 1B Study | None |
| Behavioral therapy vs antimuscarinic | Bladder dairy outcome: 24-hour incontinence episodes | Bladder training plus terodiline were similar to control | 6 Weeks | 1B Study | Increased rate of dry mouth noted when terodiline was used |
| Behavioral therapy vs other intervention | Objective: Visual Analog Scale score | Outpatient bladder training and physiotherapy were superior to inpatient bladder training alone for improvement in outcomes | 3 Months | 1B Study | None |
| Behavioral therapy vs other intervention | Subjective outcomes: nocturia symptoms Quality-of-life outcomes: International Consultation on Incontinence Questionnaire-short form Bladder diary outcomes: stress incontinence episodes and daily urgency urinary incontinence episodes | Pelvic floor muscle exercises (instruction to perform without physiotherapy guidance) plus bladder training and posterior tibial nerve stimulation were superior pelvic floor muscle exercises and bladder training alone for improvement in outcomes | 12 Weeks | 1B Study | None |
| Behavioral therapy vs other intervention | Voiding diary outcome: daily stress incontinence and urge incontinence episodes Quality-of-life outcome: Short Form-36 health survey | Immediate intervention weight loss was superior to delayed intervention weight loss for improvement in outcomes | No data | 1A Study | None |
| Toxin A vs control | Subjective outcomes: urgency, frequency, quality of life | Onabotulinum and abobotulinum toxin A was superior to placebo for improvement in outcomes | 30 Days to 6 months | 10A Studies | Onabotulinum and abobotulinum toxin A had greater: urinary retention, elevated post-void residual volumes, need for self-intermittent catheterization, and urinary tract infections |
| Onabotulinum toxin A vs control | Subjective outcomes: urgency, frequency, and nocturia | 100 Units of onabotulinum toxin A was more effective than 50 units for improvement in outcomes | 30 Days to 6 months | 10A Studies | Onabotulinum toxin A had greater urinary retention, elevated post-void residual volumes, need for self-intermittent catheterization, and urinary tract infections |
| Onabotulinum toxin vs antimuscarinic | Subjective outcome: cure Objective outcome: OAB questionnaire Voiding diary outcome: Daily UUI episodes | Both anticholinergics and onabotulinumtoxin A were similar in efficacy for reduction in UUI episodes and OAB scores, but onabotulinumtoxin A was superior to anticholinergics for subjective cure of UUI | 6 Months | 1A Study | Onabotulinum toxin A: increased risk of urinary retention, need for self-catheterization, and urinary tract infections. Antimuscarinic medication was associated with an increased risk of dry mouth |
| Onabotulinum toxin vs other intervention | No data | No data | No data | No data | No data |
| Acupuncture vs control | Quality-of-life outcome: Incontinence impact questionnaire-7, and urodynamic distress inventory-6 Urodynamic outcome: maximum cystometric capacity | Acupuncture was superior to control for improvement in quality of life for improvement in outcomes | No data | 1A Study 1C Study | Arthralgia, lead migration, blurry vision, dry eyes, nasopharangitis, itching, dizziness, nausea, headache, bruising at the needle site, and insomnia noted with acupuncture |
| Acupuncture vs control | Quality-of-life outcomes: International Consultation on Incontinence Questionnaire, Kings Health Questionnaire, bladder diary outcomes: 24-hour voiding frequency, urgency | Acupuncture was similar to for improvement in outcomes | 8 Weeks | 1A Study | None |
| Acupuncture vs antimuscarinic | No data | No data | No data | No data | No data |
| Antimuscarinic vs other intervention | No data | No data | No data | No data | No data |
| Magnetic stimulation vs control | Quality-of-life outcome: International consultation on incontinence questionnaire-short form Voiding diary outcomes: overactive bladder cure, daily urge incontinence episodes | Functional magnetic stimulation was superior to control for improvement in outcomes | 8-24 Weeks | 1C Study 1B Study | None |
| Magnetic stimulation vs control | Urodynamic outcomes: increasing the volume of first contraction, maximum detrusor pressure, and maximum cystometric capacity | Extracorporeal magnetic stimulation was superior to sham chair for improvement in outcomes | 10-24 Weeks | 1A Study 1B Study | None |
| Magnetic stimulation vs antimuscarinic | No data | No data | No data | No data | No data |
| Functional magnetic stimulation vs functional electrical stimulation | Subjective outcome: severity of symptoms | Functional magnetic stimulation was similar functional electrical stimulation for improvement in outcomes | 8 Weeks | 1C Study | None |
| Mirabegron vs control | Voiding diary outcome: daily incontinence episodes | Mirabegron (25-50 mg) was superior to control for improvement in outcomes | 12 Weeks | 1A Study | None |
| Mirabegron vs control | Voiding diary outcome: daily incontinence episodes | Mirabegron (50-100 mg) was superior to control for improvement in outcomes | 12 Months | 1A Study | Increase in upper respiratory tract infections, dizziness, nausea, and back pain |
| Solebegron vs control | Subjective outcome: daily incontinence episodes | Solebegron (125 mg) was superior to placebo for improvement in outcomes | 4 Weeks | 1A Study | Increase in headache, nasopharangitis, dry mouth, constipation, nausea, increase in urinary tract infections, arthralgia, hypertension, abdominal pain, dizziness, extremity pain, depression, general pain, musculoskeletal chest pain |
| Mirabegron vs antimuscarinic | Subjective outcome: nocturia Bladder diary outcomes: daily incontinence episodes, number of daily voids, urine volume per void | Mirabegron (100 mg) was similar to tolterodine extended release (4 mg) for improvement in outcomes | 12 Weeks | 1A Study | There were similar rates of hypertension, urinary tract infection, dry mouth, nasopharangitis, headache, influenza, constipation, arthralgia, tachycardia, back pain, dizziness, diarrhea, and sinusitis |
| Mirabegron vs other intervention | No data | No data | No data | No data | No data |
| Posterior tibial nerve stimulation vs control | Subjective outcome: urgency Quality-of-life outcomes: overactive bladder questionnaire score and Short Form-36 bladder diary outcomes: reduction in urgency urinary incontinence, daily voids, daily incontinence episodes, volume per void | Posterior tibial nerve stimulation was superior to control for improvement in outcomes | 4-13 Weeks | 2A Studies | Posterior tibial nerve stimulation was associated with ankle bruising, discomfort at needle site, bleeding at needle site, and tingling in the leg |
| Posterior tibial nerve stimulation vs antimuscarinic | Subjective outcome: improvement in symptoms | Posterior tibial nerve stimulation was similar to oxybutynin | 5 Weeks | 1B Study | None |
| Posterior tibial nerve stimulation vs other intervention | Bladder diary outcomes: daily voids | Posterior tibial nerve stimulation was superior to pelvic floor muscle exercises and behavioral therapy for improvement in outcomes | 12 Weeks | 1B Study | None |
| Sacral neuromodulation vs control | Subjective outcomes: cure, wearing less protection, urgency intensity Bladder diary outcomes: reduction in daily incontinence episodes, daily voids, urine volume per void Quality of life: Short Form-36 | Sacral neuromodulation was superior to control for improvement in outcomes | 6 Months | 2B Studies | Pain at the implantable pulse generator site, extremity pain, adverse change in bowel function, cardiac arrhythmia, vaginal pain, anal pain, and skin irritation at the implantation site |
| Sacral neuromodulation vs control | Bladder diary outcome: daily voids | Transelectrical modulation/sacral neuromodulation were similar to control for improvement in outcomes | 3 Weeks | 1C Study | No data |
| Sacral neuromodulation vs antimuscarinic | Bladder diary outcomes: number of pads used in 24 hours, daily incontinence episodes, leakage volume Urodynamic outcomes: first sensation, improved involuntary detrusor contraction volume, and quality of life | Sacral neuromodulation was superior to anticholinergics for improvement in outcomes | 6 Months | 1B Study | Sacral neuromodulation was associated with an adverse change in bowel habits, electrically induced discomfort, pain at the implantable pulse generator site, infection |
| Transelectrical stimulation vs control | Subjective outcome: improvement in overactive bladder symptoms Objective outcome: 24-hour voiding diary frequency Urodynamic outcome: detrusor overactivity | Transvaginal electrical stimulation was superior to control for improvement in outcomes | 8 Weeks to 3 Months | 1A Study 1C Study | Uncomfortable stimulator and back pain |
| Transelectrical stimulation vs control | Bladder diary outcome: voids per 24 hours Subjective outcome: nocturia Bladder diary outcome: daily urgency episodes Urodynamic outcome: maximum cystometric capacity | Transvaginal electrical stimulation was superior to placebo for improvement in outcomes | 2 Months | 1B Study 1A Study | No data |
| Transelectrical stimulation vs antimuscarinic | No data | No data | No data | No data | No data |
| Transelectrical stimulation vs other intervention | Subjective outcome: improvement or cure in overactive bladder symptoms Objective outcome: pad weight test Bladder diary outcome: voids per 24 hours | Functional electrical stimulations similar to functional magnetic stimulation | 2 Months | 1C Study | No data |
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