Pharmacologic and Nonpharmacologic Treatments for Urinary Incontinence in Women

Urinary incontinence (UI), the involuntary loss of urine, affects about 17% of nonpregnant women (1), and its prevalence increases with age, particularly after menopause. Incontinence may have a negative effect on a woman's physical, psychological, and social well-being and may impose substantial lifestyle restrictions. The most common types of UI in women are stress, urgency, and mixed incontinence. Stress UI is the involuntary loss of urine with effort or physical exertion or on sneezing or coughing, urgency UI is associated with a sudden compulsion to urinate that is difficult to defer, and mixed UI has features of both types (2). Nonpharmacologic and pharmacologic interventions are available to manage UI. Nonpharmacologic approaches mostly aim to strengthen the pelvic floor or change behaviors that influence bladder function, whereas pharmacologic treatments primarily address bladder and urethral sphincter function. We conducted a broad systematic review of the clinical effects and harms of all nonsurgical treatments for stress, urgency, and mixed UI in nonpregnant women. Although some causes of UI are amenable to surgery, we focused only on nonsurgical interventions. The review (available at www.effectivehealthcare.ahrq.gov) was commissioned by the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI) (3). This article presents the network meta-analysis (NMA) that focuses on symptomatic cure and improvement outcomes; the technical report presents details of other outcomes, including adverse events and quality of life (3). Methods The Evidence-based Practice Center at Brown University used established systematic review methods, as outlined in the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews (4). The review is registered with PROSPERO (CRD42017069903). Detailed descriptions of the review and NMA methods may be found in Supplement 1 and in the full report (3). Supplement. Network Meta-analysis Model and Inconsistency Analysis Results (Supplement 1); Literature Search Strategies (Supplement 2); Network Meta-analysis Results (Supplement 3); and Evidence Profile for Pharmacologic and Nonpharmacologic Interventions for UI (Supplement 4) Data Sources and Searches We updated a systematic review conducted in 2012 (5) and included all eligible studies from that earlier work. We searched MEDLINE, the Cochrane Central Register of Controlled Trials (Wiley), the Cochrane Database of Systematic Reviews (Wiley), EMBASE (Elsevier), CINAHL (EBSCO), and PsycINFO (American Psychological Association) to identify relevant primary research studies published since 2011. See Supplement 2 for search strategies. For the full report (3), final searches were conducted on 4 December 2017. We also included other eligible studies identified by AHRQ, PCORI, peer reviewers, manufacturers, and other stakeholders. On 10 August 2018, we performed an updated search for randomized controlled trials (RCTs) on MEDLINE, the U.S. Food and Drug Administration Web site, and ClinicalTrials.gov. After 2 rounds of pilot screening were conducted for training purposes, a team of 6 researchers independently double-screened all identified citations (abstracts) using Abstrackr (http://abstrackr.cebm.brown.edu); conflicts were resolved by group discussion. The full texts of all potentially relevant studies were rescreened in duplicate. Study Selection We included studies of adult women with stress, urgency, or mixed UI, excluding those who were pregnant, hospitalized, or institutionalized and those with UI due to urinary tract infection or neurogenic bladder; however, we allowed up to 10% of study participants to fall into any of the exclusion categories. We included comparisons of pharmacologic, nonpharmacologic (nonsurgical), and placebo (or sham or no) treatments for stress, urgency, or mixed UI. Among eligible interventions, we included those that sometimes require minor surgery (such as device implantation for sacral neuromodulation) or might be performed in an office setting (such as periurethral bulking and bladder onabotulinum toxin A [BTX] injection). Studies had to report categorical symptomatic cure (for example, cured vs. not cured), improvement, or satisfaction after treatment; quality-of-life score after treatment; or adverse events related to treatment. This article focuses on the clinical outcomes of cure and improvement. As commonly understood, symptomatic cure means resolution of incontinence; it does not imply permanent cure. We included RCTs with no minimum sample size and nonrandomized comparative studies with at least 50 women per intervention group. All studies had to have a minimum follow-up of 4 weeks. We included only peer-reviewed publications and studies with complete results data in ClinicalTrials.gov or available from the U.S. Food and Drug Administration. We included translatable studies in any language. Four studies, 2 in Russian and 2 in Persian, could not be translated and were excluded. The non-English studies included were published in Spanish (2 studies), French (1 study), and Chinese (1 study). Data Extraction and Quality Assessment Each new study was extracted and assessed for methodological quality by 1 methodologist. The extraction and assessment were reviewed and confirmed by at least 1 other experienced methodologist. Disagreements were resolved by discussion among the team members. Studies were extracted into a customized form in the Systematic Review Data Repository (https://srdr.ahrq.gov/projects/1153). To assess quality, we used the Cochrane Risk of Bias Tool for RCTs (6). For nonrandomized comparative studies, we evaluated outcome assessor blinding; attrition bias; group similarity at baseline; adherence; and whether groups were selected similarly, analyses were adjusted for differences between groups, and interventions were described adequately. We graded strength of evidence (SoE) according to the AHRQ methods guide (7). We assessed SoE for each outcome category for our main conclusion statements across all intervention categories. For each SoE assessment, we considered the number of studies, study designs, study limitations (that is, risk of bias and overall methodological quality), directness of the comparisons (in the network), consistency of study results, precision of any estimates of effect (imprecise if the 95% CI extended beyond both 0.80 and 1.25), likelihood of reporting bias, other limitations, and overall findings across studies. On the basis of these assessments, we assigned an SoE rating of high, moderate, or low or deemed the evidence insufficient to estimate an effect. Data Synthesis and Analysis Categorization of Interventions Where feasible, we used guidelines from the National Institute for Health and Care Excellence and the American Urological Association to categorize interventions (8, 9). First, we classified the 53 specific interventions for which there were any outcomes of interest (including adverse events) into 16 categories (Table 1). Then, we divided the categories further on the basis of whether they are recommended primarily for stress or urgency UI. Behavioral therapy is recommended for both stress and urgency UI and thus appeared in both categories. Neuromodulation is recommended primarily for urgency UI, but several RCTs evaluated it in women with stress UI; thus, it also was included in both categories. Next, we stratified the interventions according to whether they are recommended as first-, second-, or third-line therapies (8, 9). Table 1. Categories of Interventions Evaluated by Eligible Studies Network Meta-analysis We conducted frequentist (maximum-likelihood) pairwise comparisons and NMAs of odds ratios (ORs) with mixed-effects (random intercepts and fixed intervention slopes) or full random-effects (random intercepts and slopes) multilevel models within the generalized linear and latent mixed modeling framework. We assessed consistency qualitatively, deeming direct and indirect effects in agreement if they were in the same direction and if the CI of one included the point estimate of the other, and quantitatively, using a node-split approach (10). Further details are provided in Supplement 1. We conducted separate sets of NMAs for each UI outcome (cure and improvement). Originally, we considered performing separate NMA sets for each UI type (stress, urgency, and mixed); however, many studies did not restrict their eligibility to women with a specific UI type, and very few studies reported specifically on women with mixed UI. Therefore, for each UI outcome, we ran an overall NMA that included all eligible studies regardless of UI type or line of therapy. Then, we summarized comparisons of interventions on the basis of whether they are used (or recommended) primarily for urgency or stress UI and whether they are first- and second-line therapies or third-line therapies (8, 9). We ran separate sets of NMAs for specific interventions and for intervention categories. The analyses are presented in the full report (3). We ran separate NMAs of the subsets of studies that included only women with stress or urgency UI and compared these results with the overall analyses. Role of the Funding Source This topic was nominated and funded by PCORI for systematic review by an Evidence-based Practice Center in partnership with AHRQ. Program officers from AHRQ and PCORI provided comments on draft versions of the protocol and full evidence report (3). Neither PCORI nor AHRQ participated directly in the literature search; determination of study eligibility criteria; data analysis or interpretation; or preparation, review, or approval of the manuscript for publication. Results The 2018 search returned 7840 new citations, 7117 of which were excluded during abstract screening (Figure 1). Of the 723 abstracts accepted at the initial screening and retrieved for full-text review, 613 were found to be irrelevant