Effect of Behavioral and Pelvic Floor Muscle Therapy Combined With Surgery vs Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary Incontinence: The ESTEEM Randomized Clinical Trial

Vivian W Sung; Diane Borello-France; Diane K Newman; Holly E Richter; Emily S Lukacz; Pamela Moalli; Alison C Weidner; Ariana L Smith; Gena Dunivan; Beri Ridgeway; John N Nguyen; Donna Mazloomdoost; Benjamin Carper; Marie G Gantz

doi:10.1001/jama.2019.12467

. 2019 Sep 17;322(11):1066–1076. doi: 10.1001/jama.2019.12467

Effect of Behavioral and Pelvic Floor Muscle Therapy Combined With Surgery vs Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary Incontinence

The ESTEEM Randomized Clinical Trial

Vivian W Sung ^1,^✉, Diane Borello-France ², Diane K Newman ³, Holly E Richter ⁴, Emily S Lukacz ⁵, Pamela Moalli ⁶, Alison C Weidner ⁷, Ariana L Smith ⁸, Gena Dunivan ⁹, Beri Ridgeway ¹⁰, John N Nguyen ¹¹, Donna Mazloomdoost ¹², Benjamin Carper ¹³, Marie G Gantz ¹³, for the NICHD Pelvic Floor Disorders Network

¹The Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, Alpert Medical School of Brown University, Providence, Rhode Island

²Department of Physical Therapy, Rangos School of Health Sciences, Duquesne University, Pittsburgh, Pennsylvania

³The Division of Urology, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia

⁴Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham

⁵The Division of Female Pelvic Medicine & Reconstructive Surgery, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Diego, La Jolla

⁶Women’s Center for Bladder and Pelvic Health, Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

⁷Division of Urogynecology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina

⁸The Division of Urology, Department of Surgery, Perelman School of Medicine, University of Pennsylvania Health System, Philadelphia

⁹The Division of Urogynecology, Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque

¹⁰Center for Urogynecology and Reconstructive Pelvic Surgery, Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio

¹¹The Division of Female Pelvic Medicine & Reconstructive Surgery, Department of Obstetrics & Gynecology, Kaiser Permanente, Downey, California

¹²Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland

¹³Social, Statistical, & Environmental Sciences, RTI International, Research Triangle Park, North Carolina

Group Information: NICHD Pelvic Floor Disorders Network appears at the end of the article.

^✉

Corresponding Author: Vivian W. Sung, MD, MPH, Women and Infants Hospital of Rhode Island, Division of Urogynecology and Reconstructive Pelvic Surgery, 101 Plain St, Fifth Floor, Providence, RI 02903 (vsung@wihri.org).

Accepted for Publication: July 31, 2019.

Author Contributions: Dr Gantz and Mr Carper had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sung, Borello-France, Newman, Richter, Lukacz, Moalli, Weidner, Smith, Dunivan, Ridgeway, Gantz.

Acquisition, analysis, or interpretation of data: Sung, Lukacz, Moalli, Weidner, Smith, Dunivan, Ridgeway, Nguyen, Mazloomdoost, Carper, Gantz.

Drafting of the manuscript: Sung, Newman, Richter, Lukacz, Moalli, Weidner, Smith, Dunivan, Ridgeway, Mazloomdoost, Carper, Gantz.

Critical revision of the manuscript for important intellectual content: Sung, Borello-France, Newman, Richter, Lukacz, Moalli, Weidner, Smith, Dunivan, Ridgeway, Nguyen, Mazloomdoost, Gantz.

Statistical analysis: Newman, Richter, Carper, Gantz.

Obtained funding: Sung, Lukacz, Moalli, Smith, Gantz.

Administrative, technical, or material support: Newman, Richter, Moalli, Dunivan, Nguyen, Gantz.

Supervision: Sung, Richter, Weidner, Smith, Dunivan, Mazloomdoost, Gantz.

Other - training of interventionists for the behavioral protocol: Borello-France.

Conflict of Interest Disclosures: Dr Sung reported receiving grants from the National Institute of Child Health and Human Development (NICHD), National Institute on Aging (NIA), and Patient-Centered Outcomes Research Institute (PCORI). Dr Borello-France reported receiving grants from the NICHD. Dr Newman reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and editorial fees from Digital Science Press. Dr Richter reported receiving grants from the NICHD, PCORI through Brown University, Renovia, the National Institutes of Health (NIH) through Washington University, and the NICHD, and other support from BlueWind Medical and UpToDate. Dr Lukacz reported receiving grants from the NICHD, the NIDDK, Boston Scientific, and Cogentix/Uroplasty, personal fees from Axonics, and other support from UpToDate. Dr Moalli reported receiving grants from Boston Scientific, the NIH, the NICHD, the Department of Defense, and Caldera. Dr Weidner reported receiving grants from the NIH and other support from UroCure. Dr Smith reported receiving editorial fees for a section in Gray's Anatomy. Dr Dunivan reported receiving grants from the NIDDK, NICHD, and Viveve and travel reimbursement for work for American College of Obstetricians and Gynecologists and American Board of Obstetrics and Gynecology. Dr Ridgeway reported receiving grants from the NICHD and personal fees from Coloplast Inc and Ethicon Inc. Dr Nguyen reported receiving grants from the NIDDK, Boston Scientific, and the NICHD. Dr Mazloomdoost reported receiving grants from Boston Scientific and being an employee of the NIH. Dr Carper reporting receiving grants from the NICHD. Dr Gantz reported receiving grants from the NICHD. No other disclosures were reported.

Funding/Support: Supported by grants from the NICHD and NIH Office of Research on Women’s Health (U10 HD041261, U10 HD069013, U10 HD054214, U10 HD054215, U10 HD041267, U10 HD069025, U10 HD069010, U10 HD069006, and U01 HD069031).

Role of the Funder/Sponsor: The NIH and NICHD staff had input into the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The NICHD Pelvic Floor Disorders Network members are Women and Infants Hospital of Rhode Island: Deborah L. Myers, MD, Charles R. Rardin, MD, B. Star Hampton, MD, Cassandra Carberry, MD, Kyle Wohlrab, MD, Nicole Korbly, MD, Ann Meers, RN, Alexandra Lynch, BA, Kathryn Rhodes, BA, Wendy Fox, PT, DPT, Leslie Choquette, MSPT, Michelle Clark, MSPT, and Melissa Nassaney, DPT; University of Alabama at Birmingham: R. Edward Varner, MD, Alicia Ballard, MD, David R. Ellington, MD, Robert L. Holley, MD, Velria Willis, BSN, Nancy Saxon, BSN, Kathy Carter, BSN, Robin Willingham, BSN Julie Burge, BS, and Ryanne Johnson, MSN, CRNP; San Diego Site (University of California San Diego and Kaiser Permanente): Charles Nager, MD, Mike Albo, MD, Marianna Alperin, MD, JoAnn Columbo, BSc; Cindy Furey, RPT; Patricia Riley, RN, Lynn Hall RNP, Christine Doan, PA, Karen VandeVegte, PT, Karl M. Luber, MD, Jasmine Tan-Kim, MD, Keisha Y. Dyer, MD, Gouri B. Diwadkar, MD, Shawn A. Menefee, MD, Linda M. Mackinnon, MPH, and Gisselle Zazueta-Damian; Kaiser Permanente Downey: Sharon Jakus-Waldman, MD, MPH, Christina Liao, MD, Nancy Flores, RA, Mary Simmons, PT, DPT, and Arty Patel, PT, DPT, CSCS; University of Pittsburgh Medical Center: Halina Zyczynski, MD, Gary Sutkin, MD, Michael Bonidie, MD, Mary Ackenbom, MD, Judy Gruss, RN, Jaqueline Noel, MS, Lindsay Baranski, MS, Lori Geraci, BA, Ellen Eline, CRNP, and Karen Mislanovich, RN; Duke University Medical Center: Cindy Amundsen, MD, Anthony Visco, MD, Nazema Siddiqui, MD, MHS; Amie Kawasaki, MD, Shantae McLean, MPH, Mary Raynor, RN, Dominique Clark, BA, Weatherly Cook, RN, Nicole Longoria, PA-C, Akira Hayes, MS, and Ingrid Harm-Ernandes, PT; University of Pennsylvania Health System: Lily Arya, MD, Heidi Harvie, MD, Uduak Andy, MD, Lorraine Flick, MS, Michelle Kinglee, AS, Mary Wang, DNP, Donna Thompson, MSN, CRNP, and Teresa Carney, RN, BSN; University of New Mexico: Rebecca Rogers, MD, Yuko Komesu, MD, Peter Jeppson, MD, Sara Cichowski, MD, Karen Taylor, BA, Cassandra Castaneda, BA, Reynette Beynon, BA, Amanda Summers, BA, Sue Lee, BS, Kathleen Hopkins, MA, Julia Middendorf, RN, BSN, Christy Miller, BS, MPT, Erin Yane, BA, MPT, and Barbara White, BS; Cleveland Clinic Foundation: Matthew Barber, MD, Marie Paraiso, MD, Megan Tarr, MD, Eric Jelovsek, MD, Cecile Unger, MD, Ly Pung, RN, Annette Graham, RN, Kathleen Dastoli, RN, Maryori Edington, AAS, Elizabeth O’Dougherty, PT, Jill Dubbs, DPT, and Megan Edgehouse, PT; and Research Triangle Institute: Dennis Wallace, PhD, Carolyn Huitema, MS, Tracy Nolen, PhD, Kevin A. Wilson, MS, Brenda Hair, AAS, Kendra Glass, Daryl Matthews, AA, Maura Bearden, BS, James W. Pickett II, BS, Yan Tang, MS, Amanda Shaffer, MS, Kristin Zaterka-Baxter, BS, Lindsay Morris, BS, Kathryn Cleffi, MPH, and Carla Bann, PhD.

PFDN Data Safety and Monitoring Board Members: Kay Dickersin, PhD, Johns Hopkins Bloomberg School of Public Health, Luohua Jiang, PhD, Texas A&M Health Science University, Missy Lavender, MBA, Women’s Health Foundation, Kate O’Dell, PhD, UMass Memorial Medical Center, Kate Ryan, National Women’s Health Network, Paul Tulikangas, MD, University of Connecticut Hartford Hospital, Lan Kong, PhD, Penn State University College of Medicine, Donna McClish, PhD, Virginia Commonwealth University, Leslie Rickey, MD, MPH, Yale New Haven Hospital, David Shade, JD, The Johns Hopkins University, and Ashok Tuteja, MD, MPH, University of Utah, Susan Yount, PhD, American College of Nurse Midwives.

Data Sharing Statement: See Supplement 4.

^✉

Corresponding author.

PMCID: PMC6749544 PMID: 31529007

Key Points

Question

Does combining perioperative behavioral and pelvic floor muscle therapy with midurethral sling result in greater improvement in mixed urinary incontinence symptoms than does a sling alone?

Findings

In this randomized clinical trial that included 480 women, incontinence symptoms (measured by the Urogenital Distress Inventory Long Form; range, 0-300 points; minimal clinically important difference, 35 points) decreased by 128.2 points in the combined therapy group and 114.7 points in the surgery alone group, resulting in a statistically significant between-group difference that did not meet the threshold for clinical importance.

Meaning

Among women with mixed urinary incontinence, the addition of perioperative behavioral and pelvic floor muscle therapy to midurethral sling surgery resulted in a difference in urinary incontinence symptoms that may not be clinically important.

Abstract

Importance

Mixed urinary incontinence, including both stress and urgency incontinence, has adverse effects on a woman’s quality of life. Studies evaluating treatments to simultaneously improve both components are lacking.

Objective

To determine whether combining behavioral and pelvic floor muscle therapy with midurethral sling is more effective than sling alone for improving mixed urinary incontinence symptoms.

Design, Setting, and Participants

Randomized clinical trial involving women 21 years or older with moderate or severe stress and urgency urinary incontinence symptoms for at least 3 months, and at least 1 stress and 1 urgency incontinence episode on a 3-day bladder diary. The trial was conducted across 9 sites in the United States, enrollment between October 2013 and April 2016; final follow-up October 2017.

Interventions

Behavioral and pelvic floor muscle therapy (included 1 preoperative and 5 postoperative sessions through 6 months) combined with midurethral sling (n = 209) vs sling alone (n = 207).

Main Outcomes and Measures

The primary outcome was change between baseline and 12 months in mixed incontinence symptoms measured by the Urogenital Distress Inventory (UDI) long form; range, 0 to 300 points; minimal clinically important difference, 35 points, with higher scores indicating worse symptoms.

Results

Among 480 women randomized (mean [SD] age, 54.0 years [10.7]), 464 were eligible and 416 (86.7%) had postbaseline outcome data and were included in primary analyses. The UDI score in the combined group significantly decreased from 178.0 points at baseline to 30.7 points at 12 months, adjusted mean change −128.1 points (95% CI, −146.5 to −109.8). The UDI score in the sling-only group significantly decreased from 176.8 to 34.5 points, adjusted mean change −114.7 points (95% CI, −133.3 to −96.2). The model-estimated between-group difference (−13.4 points; 95% CI, −25.9 to −1.0; P = .04) did not meet the minimal clinically important difference threshold. Related and unrelated serious adverse events occurred in 10.2% of the participants (8.7% combined and 11.8% sling only).

Conclusions and Relevance

Among women with mixed urinary incontinence, behavioral and pelvic floor muscle therapy combined with midurethral sling surgery compared with surgery alone resulted in a small statistically significant difference in urinary incontinence symptoms at 12 months that did not meet the prespecified threshold for clinical importance.

Trial Registration

ClinicalTrials.gov Identifier: NCT01959347

This superiority trial compared behavioral and pelvic floor muscle therapy plus midurethral sling surgery with midurethral sling surgery alone in treating women with mixed urinary incontinence.

Introduction

Urinary incontinence is common, affecting up to 58% of women and has a negative effect on quality of life.¹ Up to half of women with urinary incontinence have mixed urinary incontinence, which includes both stress and urgency urinary incontinence, termed mixed urinary incontinence. Mixed incontinence is often considered more severe because it is more challenging to manage than either urinary condition alone and responds poorly to treatment.^2,3,4 Treatment guidelines are largely based on the logic that women with mixed incontinence are eligible for treatments used for either stress or urgency incontinence. First-line treatment can include behavioral and pelvic floor muscle training, followed by overactive bladder medication.^5,6,7,8 A combination of conservative approaches can also be used, but many women eventually undergo surgery.

Guidelines and recommendations for mixed urinary incontinence treatment caution that surgery could worsen the urgency component.^5,6,8 Observational data supporting that midurethral sling surgery remains effective for treating the stress component exists.⁹ However, limited studies have evaluated approaches to improve urgency incontinence outcomes after midurethral sling among women with mixed incontinence.

One strategy used successfully for other conditions that has the potential to treat stress and urgency incontinence concurrently includes combining conservative therapy with surgery,^10,11,12 but the efficacy among women with mixed incontinence remains unclear. The Effects of Surgical Treatment Enhanced With Exercise for Mixed Urinary Incontinence (ESTEEM) trial was conducted to test whether perioperative behavioral and pelvic floor muscle therapy combined with midurethral sling surgery would improve symptoms at 12 months compared with sling alone.

Methods

Study Design and Oversight

This was a multicenter, randomized, superiority trial. The study was approved by the institutional review boards of 9 clinical recruiting sites in the Pelvic Floor Disorders Network. All participants provided written informed consent. Interval review of safety was conducted by an independent data and safety monitoring board. Study methods have previously been published,¹³ and the study protocol appears in Supplement 1. The final statistical analysis plan appears in Supplement 2.

Patients

Eligibility was designed to include patients with a wide range of clinically bothersome mixed urinary incontinence symptoms (Figure 1). Women 21 years or older, reporting moderately to severely bothersome stress and urgency incontinence symptoms for at least 3 months and documenting at least 1 stress and 1 urgency incontinence episode on a 3-day bladder diary were eligible. These criteria provided both subjective and objective documentation. Exclusion criteria included anterior or apical prolapse at or beyond the hymen, planned concomitant surgery for anterior or apical prolapse, prior sling, or current overactive bladder medication use (patients were eligible after a 3-week washout of overactive bladder medication). We collected race/ethnicity data to help describe the study population, based on patient self-identification and categorized by National Institutes of Health guidelines.

Interventions and Randomization

Both retropubic and transobturator midurethral sling techniques were allowed because previous trials support equivalent outcomes.^14,15,16,17 The combined treatment included the addition of 1 preoperative and 5 postoperative visits through 6 months, was conducted by centrally trained interventionists, and included (1) education on pelvic floor anatomy, bladder function, and voiding habits; (2) pelvic floor muscle training; (3) bladder training; and (4) strategies to control stress and urgency symptoms. Details of the trial intervention have been published.¹⁸ Patients were randomly assigned 1:1 within the electronic data management system using a randomly permuted block design (randomly ordered blocks of 2 and 4), stratified by clinical site and urgency severity. Surgeons and outcome assessors were masked. Patients and interventionists were not masked.

Primary and Secondary Outcomes

All outcomes reported herein (primary, secondary, and exploratory) were prespecified. The study was powered for primary and secondary outcomes. The primary outcome was change in symptoms at 12 months, measured using the Urogenital Distress Inventory (UDI) long from total score (range, 0-300 points; minimal clinically important difference [MCID], 35; SD, 50.4).¹⁹ The UDI is a validated patient-reported outcome questionnaire that includes 3 symptom subscales: irritative symptoms (urgency incontinence, frequency, nocturia, and urgency); stress incontinence; and obstructive symptoms. Each subscale ranges from 0 to 100 points, with higher scores indicating greater symptom severity.²⁰ Secondary outcomes included change in UDI-stress (MCID, 8 points; SD, 21.5)²¹ and UDI-irritative (MCID, 15 points; SD, 25.6)¹⁹ subscale scores between groups at 12 months.

Other Prespecified (Exploratory) Outcomes

Other outcomes included 3-day bladder diary measures: total number of incontinence episodes, number of urgency and stress incontinence episodes, number of voids, and number of pads used per day. Women reporting on average more than 8 voids over 24 hours were considered to have high voiding frequency. Normalization of voiding frequency was defined as improving from high voiding frequency to 8 or fewer voids over 24 hours. Incontinence–specific quality of life was measured using the Incontinence Impact Questionnaire^20,21 (IIQ), a score range from 0 to 400 points (MCID, 16 points). Higher scores indicate worse quality of life. Patients completed the Patient Global Impression of Improvement²² (PGI-I score range response from 1, very much better to 7, very much worse), which was dichotomized into 2 categories for analysis as responses 1 or 2 (much better and very much better) compared with all other categories. The PGI of Severity²² (PGI-S range response, 1 normal to 4 severe) was dichotomized into 2 categories as responses 1 or 2 (normal or mild) compared with all other categories. Overactive bladder–specific questionnaires included the Overactive Bladder Treatment Satisfaction Questionnaire²³ (OAB-q-SS responses are presented on 4-, 5-, and 6-point Likert scales; range, 0-100 points; higher scores indicate greater satisfaction) and the Symptom and Health-Related Quality of Life (OAB-q-HRQL) questionnaires²⁴ (range, 0-100 points; MCID, 10 points for both²⁵). Higher scores on the symptoms questionnaire indicate increased severity; higher scores on the HRQL questionnaire indicate better quality of life. Additional lower urinary tract symptom treatments, clinically important complications, and adverse events were collected. All questionnaires were administered at 3, 6, and 12 months after surgery and prior to initiating any off-protocol urinary treatment. Participants completed questionnaires on paper.

Statistical Analysis

Using simulated data accounting for the possibility of additional urinary treatments (estimated to be 30% after sling only in women with mixed urinary incontinence²⁶), sample sizes were estimated to detect published MCIDs for the UDI total score, UDI-irritative, and UDI-stress subscale scores to allow assessment of urgency and stress symptom outcomes separately.¹³ Assuming a 2-sided α of .05, 75 women per group provided 90% power to detect a mean between-group difference of 35 points (SD, 50.4)¹⁹ in change from baseline in UDI total scores at 12 months (primary outcome). For the UDI-irritative subscale (MCID, 15 points; SD, 25.6),¹⁹ and UDI-stress subscale (MCID, 8 points; SD, 21.5),²¹ 92 and 200 women per group, respectively, were needed for 90% power with a 2-sided α of .05 (secondary outcomes). After adjusting 200 per group for 15% dropout, 472 was the target sample size. These published MCIDs were based on predominantly stress or predominantly urgency urinary incontinence populations and not a mixed incontinence population; therefore, an exploratory analysis was planned to estimate the MCIDs in the current study population and compare these estimates with observed between-group differences (eMethods Supplement 3).

Baseline characteristics were compared between groups using t tests for continuous variables, and χ² for categorical variables. The primary analysis population included eligible, randomized participants with outcome data at 1 time point or more. A general linear mixed-model estimated change from baseline in UDI total score at 3, 6, and 12 months. Treatment group, time as a linear effect, site, urgency severity, additional treatment for urinary symptoms, and interactions between treatment group, time, and additional treatment were included as fixed effects. Correlation between repeated measures on the same participant was modeled using a compound symmetry covariance structure with different estimates for participants with and without additional treatment. Because any additional urinary treatment after surgery was expected to improve outcomes, the protocol specified that outcomes after additional treatment would be treated as missing, and the randomized treatment effect was estimated as a weighted average that accounted for the percent of women in each group who underwent additional treatment. Treatment groups were compared at 12 months using a 2-sided test at an α level of .05. Sensitivity analyses were conducted using multiple imputation to estimate missing values including outcomes following additional treatment, and (post hoc) including site as a random effect.

Other outcomes were analyzed with the methods used for the primary analysis for continuous variables, or analogous generalized linear mixed models for categorical outcomes. Time to additional treatment was assessed using Kaplan-Meier curves and compared using a log-rank test. Proportionality was confirmed by examining Schoenfeld residuals. All randomized patients were included in adverse event assessment. No α adjustments were made for evaluation of multiple outcomes. Seventy-one comparisons were conducted, which could result in 3 to 4 differences with P values <.05 by chance alone. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc).

Results

Study Population

Between November 2013 and July 2017, 480 women were randomized (242 combined, 238 sling only) (Figure 1). Sixteen women discovered to be ineligible after randomization were excluded from efficacy analysis but included in adverse event analyses (7 combined, 9 sling only). The analysis population included 416 of the 464 eligible women (209 combined, 207 sling only), 402 of whom were assessed at 12 months (198 of 235 [84%] combined, 204 of 229 [89%] sling only).

Baseline demographic and clinical characteristics are provided in Table 1; and eTable 1 (in Supplement 3). Overall the mean daily total incontinence episodes was 5.6 (SD, 3.4); stress, 2.4 (SD, 2.0); and urgency, 2.8 (SD, 2.5).

Table 1. Baseline Characteristics of Eligible and Randomized Patients.

Characteristic	No./Total (%) of Women
Characteristic	Combined Sling and Training (n = 235)	Sling Only (n = 229)
Age, mean (SD), y	54.3 (11.0)	53.6 (10.4)
Race, No. (%)	233	228
White	181 (77.7)	181 (79.4)
Black/African American	22 (9.4)	19 (8.3)
American Indian/Alaskan Native	7 (3.0)	3 (1.3)
Asian	2 (0.9)	1 (0.4)
>1 Race	2 (0.9)	1 (0.4)
Other^a	19 (8.2)	23 (10.1)
Hispanic/Latina ethnicity	49/233 (21.0)	56/225 (24.9)
BMI, mean (SD)	31.7 (6.5)	32.3 (7.1)
Current smoker	32/235 (13.6)	28/228 (12.3)
Stress urinary incontinence diagnosis by positive stress test	163/235 (69.4)	159/227 (70.0)
Stress urinary incontinence diagnosis by urodynamic assessment	224/233 (96.1)	209/229 (91.3)
No. of vaginal deliveries, median (IQR)	2.0 (1.0-3.0)	2.0 (2.0-3.0)
Total number of deliveries, median (IQR)	2.0 (2.0-3.0)	2.0 (2.0-3.0)
Menopausal status, No. (%)^b	235	228
Premenopausal	65 (27.7)	76 (33.3)
Postmenopausal	138 (58.7)	124 (54.4)
Not sure	32 (13.6)	28 (12.3)
Previous overactive bladder medication tried	92/234 (39.3)	88/229 (38.4)
Diabetes (type 1 or 2)	27/234 (11.5)	33/229 (14.4)
Prior supervised behavioral or pelvic floor muscle training	24/234 (10.3)	28/229 (12.2)

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Abbreviations: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; IQR, interquartile range.

^{^a}

Participants were able to select an “other” race category, which was accompanied by a free response field. The primary other race response was Hispanic/Latina followed by some multiple race specifications not included in the other categories.

^{^b}

Participants were able to select premenopausal, postmenopausal, or that they were unsure of menopausal status.

Primary Outcome

Primary and secondary outcomes appear in Table 2. For the primary outcome, the unadjusted mean UDI total scores for the combined group at baseline was 178.0 and at 12-months, 30.7 points, for an adjusted mean change of −128.1 points (95% CI, −146.5 to −109.8) vs the sling group unadjusted mean scores of 176.8 at baseline and 34.5 points at 12 months, for an adjusted mean change of −114.7 points (95% CI, −133.3 to −96.2). Compared with the sling-only group, the combined group had greater improvements in the UDI total score (Figure 2), but the model-estimated between-group difference (−13.4 points, 95% CI, −25.9 to −1.0, P = .04; Table 2) did not meet the MCID threshold. Sensitivity analyses were consistent with the primary analysis (multiple imputation results and site as random-effect results appear in eTables 2 and 3, in Supplement 3).

Table 2. Primary and Secondary Outcomes Through 12 Months^a.

Outcome Type	Baseline^b		3 Months^b		6 Months^b		12 Months^b
Outcome Type	Combined Sling and Training (n = 235)	Sling Only (n = 229)	Combined Sling and Training (n = 194)	Sling Only (n = 198)	Combined Sling and Training (n = 182)	Sling Only (n = 176)	Combined Sling and Training (n = 181)	Sling Only (n = 174)
UDI Total Score (Primary)^c
Score, unadjusted, mean (SD)	178.0 (42.8)	176.8 (40.5)	35.4 (44.1)	37.2 (44.4)	30.4 (40.1)	36.6 (49.6)	30.7 (42.6)	34.5 (44.7)
Difference from baseline, adjusted mean (95% CI)			−125.7 (−143.4 to −107.9)	−119.9 (−137.6 to −102.3)	−126.5 (−144.2 to −108.8)	−118.2 (−135.8 to −100.7)	−128.1 (−146.5 to −109.8)	−114.7 (−133.3 to −96.2)
Difference-in-difference, adjusted mean (95% CI)			−5.7 (−15.8 to 4.4)		−8.3 (−18.0 to 1.5)		−13.4 (−25.9 to −1.0)
P value			.27		.10		.04
UDI-Irritative Score (Secondary)^d
Score, unadjusted mean (SD)	66.0 (19.6)	67.6 (19.7)	15.5 (20.5)	16.9 (21.9)	12.2 (17.7)	16.4 (24.0)	12.2 (18.7)	15.1 (21.2)
Difference from baseline, adjusted mean (95% CI)			−42.7 (−50.7 to −34.6)	−41.1 (−49.1 to −33.1)	−43.4 (−51.5 to −35.4)	−40.4 (−48.3 to −32.4)	−45.0 (−53.4 to −36.6)	−38.9 (−47.4 to −30.3)
Difference in difference, adjusted mean (95% CI)			−1.6 (−6.2 to 3.1)		−3.1 (−7.5 to 1.4)		−6.1 (−12.1 to −0.2)
P value			.51		.18		.04
UDI-Stress Score (Secondary)^d
Score, unadjusted mean (SD)	86.0 (17.6)	84.9 (18.0)	14.6 (22.7)	14.6 (21.0)	14.1 (21.5)	15.3 (23.9)	13.3 (22.0)	15.3 (23.5)
Difference from baseline, adjusted mean (95% CI)			−66.4 (−75.2 to −57.7)	−65.1 (−73.8 to −56.4)	−66.6 (−75.3 to −58.0)	−64.0 (−72.6 to −55.3)	−67.1 (−76.1 to −58.1)	−61.6 (−70.7 to −52.6)
Difference in difference, adjusted mean (95% CI)			−1.3 (−6.4 to 3.8)		−2.7 (−7.5 to 2.2)		−5.5 (−11.5 to 0.6)
P value			.62		.28		.08

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Abbreviation: UDI, Urogenital Distress Inventory.

^{^a}

Difference from baseline, difference in difference, and P values are derived from longitudinal treatment models that accounted for multiple observations per participant and were adjusted for time since baseline and interaction between treatment and time, re-treatment and interactions with treatment and time, baseline incontinence severity, and clinical site, which accounted for multiple observations per participant.

^{^b}

Sample sizes present the number of participants with observed data at each time point excluding data after retreatment.

^{^c}

The UDI total score ranges from 0 to 300; the minimum clinically important difference (MCID) is 35 points, with higher scores indicating greater symptom severity.

^{^d}

The UDI subscales range from 0 to 100; the MCID is 15 points for irritative and 8 points for stress incontinence, with higher scores indicating greater symptom severity.

Figure 2. — The unadjusted change from baseline of the primary outcome of the study is shown in the analysis population at each time point after baseline by treatment group. See the Methods section for UDI total score range definitions.

Secondary Outcomes

The unadjusted mean UDI-irritative scores for the combined group were 66.0 points at baseline and 12.2 points, at 12 months, for an adjusted mean change of −45.0 points (95% CI, −53.4 to −36.6) vs sling-group unadjusted mean scores of 67.6 points at baseline and 15.1 points at 12 months, for an adjusted mean change of −38.9 points (95% CI, −47.4 to −30.3). The model-estimated between-group difference (−6.1 points; 95% CI, −12.1 to −0.2; P = .04) did not meet the MCID threshold. The unadjusted mean UDI-stress scores for the combined group were 86.0 at baseline and 13.3 at 12 months, for an adjusted mean change of −67.1 points (95% CI, −76.1 to −58.1) vs the sling group unadjusted mean scores of 84.9 at baseline and 15.3 at 12 months, for an adjusted mean change of −61.6 (95% CI, −70.7 to −52.6). The model-estimated between-group difference (−5.5 points; 95% CI, −11.5 to 0.6; P = .08) was not statistically significant (Table 2).

Other Outcomes

Prespecified exploratory and adverse event outcomes appear in Table 3 and Table 4. Bladder diary outcomes were more favorable for the combined group, including significantly greater mean reductions in urgency incontinence episodes (−1.1 vs −0.4 daily episodes; adjusted difference, −0.7; 95% CI, −1.2 to −0.1; P = .02) and total incontinence (−2.4 vs −1.4; daily episodes difference, −1.0; 95% CI, −1.7 to −0.2; P = .009). The combined group had significantly greater improvements in IIQ scores, which reached the MCID.²¹

Table 3. Prespecified Exploratory Through 12 Months^a.

Outcome Type	Combined Sling and Training					Sling Only						P Value
	Baseline		12 Months, Unadjusted		Difference From Baseline, Adjusted Mean (95% CI)	Baseline		12 Months, Unadjusted		Difference From Baseline, Adjusted Mean (95% CI)	Difference in Difference or Odds Ratio (95% CI)
	No.^b	Mean (SD) No. (%)	No.	Mean (SD) No. (%)	Difference From Baseline, Adjusted Mean (95% CI)	No.	Mean (SD) No. (%)	No.	Mean (SD) No. (%)	Difference From Baseline, Adjusted Mean (95% CI)	Difference in Difference or Odds Ratio (95% CI)
Bladder Diary Outcomes
Incontinence episodes per day
Stress	235	2.4 (2.2)	164	0.1 (0.5)	−1.2 (−1.9 to −0.5)	229	2.4 (1.7)	161	0.1 (0.5)	−1.0 (−1.6 to −0.3)	−0.2 (−0.6 to 0.1)	.22
Urge	235	2.7 (2.3)	164	0.4 (0.9)	−1.1 (−1.8 to −0.3)	229	2.8 (2.7)	161	0.6 (1.7)	−0.4 (−1.2 to 0.4)	−0.7 (−1.2 to −0.1)	.02
Total	235	5.6 (3.3)	164	0.7 (1.4)	−2.4 (−3.5 to −1.3)	229	5.6 (3.4)	161	0.9 (2.0)	−1.4 (−2.5 to −0.3)	−1.0 (−1.7 to −0.2)	.009
Pads, No. per day	235	3.6 (3.2)	164	0.8 (1.5)	−1.8 (−2.7 to −0.9)	229	3.3 (2.8)	161	0.8 (1.7)	−0.9 (−1.8 to 0.0)	−0.9 (−1.5 to −0.3)	.003
Voids, No. per day
Daytime	235	8.1 (2.6)	164	6.1 (1.4)	−2.2 (−3.1 to −1.4)	229	8.2 (2.6)	161	7.1 (2.2)	−1.3 (−2.1 to −0.5)	−0.9 (−1.5 to −0.4)	<.001
Nighttime	235	1.6 (1.3)	164	0.9 (1.0)	−0.6 (−0.9 to −0.2)	229	1.5 (1.2)	161	1.0 (1.2)	−0.3 (−0.7 to 0.0)	−0.2 (−0.5 to 0.0)	.07
Void frequency, No. (%)^c
Normalization			108	80 (74.1)				105	48 (45.7)		4.75 (2.18 to 10.37)	<.001
High voiding			164	34 (20.7)				161	68 (42.2)		0.33 (0.18 to 0.61)	<.001
Other Outcomes at 12 Months
IIC total score^d	233	184.6 (95.8)	180	24.3 (58.3)	−131.7 (−165.8 to −97.5)	229	181.1 (95.8)	174	28.0 (61.8)	−102.0 (−136.5 to −67.5)	−29.7 (−51.9 to −7.4)	.009
OAB score
Symptom severity^e	232	62.2 (21.3)	179	12.9 (18.2)	−36.5 (−44.8 to −28.1)	228	63.8 (21.7)	173	15.4 (20.2)	−32.6 (−41.0 to −24.1)	−3.9 (−9.6 to 1.8)	.18
HRQL^e	233	50.9 (23.7)	179	93.1 (15.6)	33.8 (25.2 to 42.4)	228	50.7 (23.9)	172	92.1 (15.7)	29.1 (20.4 to 37.8)	4.7 (−1.0 to 10.4)	.10
Treatment satisfaction^f			178	82.7 (22.4)	77.0 (69.8 to 84.2)			174	81.9 (26.5)	73.2 (65.7 to 80.8)	3.8 (−2.5 to 10.0)	.24
PGI, No. (%)
Severity^g	234	47 (20.1)	179	163 (91.1)		229	41 (17.9)	174	155 (89.1)		1.65 (0.80 to 3.39)	.17
Improvement^h			180	158 (87.8)				174	147 (84.9)		1.73 (0.92 to 3.25)	.09
Additional treatment, No. (%)			235	20 (8.5)				229	36 (15.7)		0.47 (0.26 to 0.85)	.01

Open in a new tab

Abbreviation: HRQL, health-related quality of life; IIC, Incontinence Impact Questionnaire; MCID minimally clinically important difference; OAB, Overactive Bladder Questionnaire; PGI Patient Global Impression questionnaire.

^{^a}

Difference from baseline, difference in difference, odds ratios, and P values were derived from longitudinal treatment models that accounted for multiple observations per participant and were adjusted for time since baseline and interaction between treatment and time, re-treatment and interactions with treatment and time, baseline incontinence severity, and clinical site.

^{^b}

Sample sizes present the number of participants with observed data at each time point excluding data after re-treatment.

^{^c}

High voiding frequency indicates more than 8 voids per day; normalization of voiding frequency was calculated for participants with high-voiding frequency at baseline; and normalization occurred if voids decreased to 8 or fewer per day.

^{^d}

Score ranges from 0 to 400 points; MCID is 16 points (higher scores indicate worse quality of life).

^{^e}

Score ranges from 0 to 100, MCID is 10 points (higher scores indicate greater symptom severity), and HRQL score ranges from 0 to 100, MCID is 10 points (higher scores indicate better HRQL).

^{^f}

Score ranges from 0 to 100, with a higher score indicating greater treatment satisfaction.

^{^g}

Normal to mild are compared with moderate to severe.

^{^h}

Much better to very much better are compared with all other categories.

Table 4. Adverse Events Through 12 Months.

	Combined Sling and Training		Sling Only
	No. of Patients	No. (%) of Events	No. of Patients	No. (%) of Events
Worsening urgency^a	242	11 (4.5)	238	5 (2.1)
New or worsening symptoms
Abdominal or genital pain^a	242	28 (11.6)	238	36 (15.1)
Dyspareunia^a	242	29 (12.0)	238	35 (14.7)
Sensation of difficulty emptying bladder^a	242	32 (13.2)	238	31 (13.0)
Vaginal mesh exposure	242	4 (1.7)	238	1 (0.4)
ED for complication^b	242	5 (2.1)	238	0
Reoperation^c	242	3 (1.2)	238	4 (1.7)

Open in a new tab

Abbreviation: ED, emergency department; MCID minimally clinically important difference.

^{^a}

Adverse symptoms reported at or beyond 3 months were defined based on patient verbal report to clinician or a reported response on a postbaseline patient questionnaire of urgency incontinence, abdominal or genital pain, or difficulty emptying bladder or dyspareunia that was worse than the baseline reported response.

^{^b}

Reasons for ED visits were urinary retention (n = 3), acute pyelonephritis (n = 1), lower abdominal pain (n = 1).

^{^c}

Reoperations were for sling release (n = 3), mesh excision (n = 2), cystotomy (n = 2).

At 12 months, the combined group was significantly less likely to receive additional treatment for lower urinary tract symptoms than were the sling-only group (8.5% vs 15.7%, adjusted odds ratio, 0.47; 95% CI, 0.26-0.85). Time to additional treatment was greater in the combined group, as shown in the Kaplan-Meier curve, Figure 3 (log-rank test, P = .008). Additional treatments for lower urinary tract symptoms included overactive bladder medication (18 combined, 30 sling only), sling revision for incomplete bladder emptying (1 combined, 1 sling only), or referral to physical therapy (1 combined, 1 sling only). Other treatments in the sling-only group included posterior tibial nerve stimulation (n=1), continence pessary (n=1), and voiding dysfunction medication (n=2). The last time point at which each re-treated participant was included in statistical models appear in eTable 4 in Supplement 3.

Figure 3. — The probability-of-outcome curve shows length of time after initiation of the intervention until occurrence of receiving additional treatment for any urinary symptom. There was a significant difference in survival times between the treatment groups. The median time to treatment for retreated individuals was 122 days (interquartile range [IQR], 87-210) for the combined treatment group (sling and behavioral and pelvic muscle training) and 113 days (IQR, 72-223) for the sling-only group.

Complications related to the intervention appear in eTable 5 in Supplement 3 and all collected adverse events (related or unrelated as determined by the site investigator at the time of event reporting) appear in eTable 6 in Supplement 3. Serious adverse events occurred in overall 10.2% of the study population (8.7% combined and 11.8% sling only). Of these, 2.3% were considered to be possibly, probably, or definitely related to the intervention per the site investigator. Vaginal mesh exposure occurred in overall 1% (1.7% of combined and 0.4% sling only). Worsening urgency incontinence occurred in 4.5% of combined and 2.1% in the sling-only group.

MCID Estimates From Study Data

The PGI-I measure was selected as the most clinically relevant anchor with MCIDs of 26.1 for the UDI total score, 10.2 for the UDI-irritative, and 5.4 for the UDI-stress subscale scores. These estimates did not change the overall findings.

Discussion

In this clinical trial involving women with mixed urinary incontinence, behavioral and pelvic floor muscle therapy combined with midurethral sling surgery, compared with surgery alone, resulted in a small statistically significant difference in urinary incontinence symptoms at 12 months. However, this difference did not meet the prespecified threshold for clinical importance.

This intervention was designed to concurrently improve both components of mixed urinary incontinence, a difficult-to-treat condition. Previous studies have shown that combined treatment improves continence after prostatectomy^27,28 and recovery after hip arthroplasty.²⁹ For pelvic floor disorders, the data are inconsistent. In 1 study,¹² pelvic organ prolapse, stress incontinence, or both resulted in better urinary and quality-of-life outcomes 3 months after surgery for those who received combined treatment. Alternatively, another study¹⁰ found combined treatment did not improve outcomes among women undergoing surgery for prolapse and stress incontinence compared with surgery alone.

Previous studies and treatment guidelines have reported that the sling procedure can worsen urgency urinary incontinence,^5,6,7,8 resulting in additional treatment rates to be as high as 25%.^9,26 Clinical guidelines recommend treating the urgency component prior to consideration of surgery because of this concern. Both groups in this study reported large reductions in urgency symptoms and had a lower rate (12%) of undergoing additional urinary treatments. Although the ESTEEM trial did not specifically evaluate whether treating urgency incontinence before surgery is beneficial, this study population was not actively receiving treatment for bothersome urgency incontinence, yet still improved. It is possible that time spent medically managing the urgency component may unnecessarily delay surgery. Additionally, overactive bladder medications can have limited efficacy, poor adherence, and adverse effects including potentially irreversible anticholinergic cognitive changes.³⁰ This information may help to guide patient care, referral patterns, and future research.

The overall number of serious adverse events and complications in this study is comparable with previous studies evaluating midurethral sling.^15,17 Although the overall serious adverse event rate was 10% in this trial, the majority were not deemed to be related to the intervention. The rate of vaginal mesh exposure in this study was 1%, comparable with previously reported rates between 0.3% and 2.7%, and the reoperation rate was less than 2%, also consistent with prior studies.^15,17 The overall rate of worsening urgency incontinence was low at less than 5%.

There is currently no objective criterion standard or clinically meaningful marker for measuring mixed urinary incontinence severity.^31,32 Patient-reported outcomes were chosen as the primary outcome because the severity of urinary incontinence is primarily dependent on patient perspective. This trial was powered to detect published MCIDs to guide interpretation of a clinically meaningful difference between groups. For any individual woman, the published MCID estimate may not correlate with her personal perception and definition of improvement. Patients with changes in scores less than these estimates may still perceive important improvements. Important secondary and exploratory outcomes may also be informative, and it is important to interpret a trial based on the totality of findings.³³ In this study, prespecified exploratory outcomes including bladder diary parameters, additional lower urinary tract treatments, and quality of life were improved in the combined group. Other subjective outcomes including the PGI-I and OAB symptom questionnaires were not significantly different between groups.

Strengths of the study include a large, nationally representative sample, adequately powered to determine differences in mixed, stress, and urgency urinary incontinence symptoms separately, and the use of patient-reported outcomes that account for the individual’s own symptom assessment. Inclusion criteria for symptom severity included patient report of bother and objective evidence of stress and urgency incontinence by bladder diary, increasing the generalizability of the study findings. The study intervention was standardized with centralized training of interventionists, including a published description of the program focused on evidence-based components. In addition, the surgical treatment of mixed urinary incontinence has remained controversial and the current study provides information needed for patient counseling and treatment guidelines.

Limitations

This study has several limitations. First, there was a lack of well-established MCIDs for women with mixed urinary incontinence when this study was designed. Recognizing this, MCID estimates were explored for this population with no effect on the findings. Second, participants were not masked, although it would be expected that masking would result in even smaller differences between groups. Third, a ceiling effect for the UDI as it relates to the population with mixed urinary incontinence is possible, limiting the ability to detect larger differences. Fourth, the combined intervention was perioperative and did not assess a postoperative approach that could be reserved for women who have persistent symptoms. Future analyses can help inform which patients are at risk of having persistent symptoms after midurethral sling and help focus future treatment efforts on this high-risk group.

Conclusions

Among women with mixed urinary incontinence, behavioral and pelvic floor muscle therapy combined with midurethral sling surgery, compared with surgery alone, resulted in a small statistically significant difference in urinary incontinence symptoms at 12 months that did not meet the prespecified threshold for clinical importance.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(837.8KB, pdf)}

Supplement 2.

Statistical Analysis Plant

Click here for additional data file.^{(665KB, pdf)}

Supplement 3.

eMethods. Estimation of minimal clinical important differences for the Urogenital Distress Inventory in the ESTEEM population – description of methods

eTable 1. Other Baseline Characteristics of Eligible and Randomized Participants

eTable 2. Comparison of Primary Analysis and Multiple Imputation Results

eTable 3. Primary and Secondary Outcomes Through 12 Months, Post-Hoc Sensitivity Analysis with Site as a Random Effect

eTable 4. Timepoint at which Each Retreated Participant was Included in Statistical Models

eTable 5. Post-operative Complications

eTable 6. All Adverse Events by System Organ Class and Preferred Term Reported

Click here for additional data file.^{(654.6KB, pdf)}

Supplement 4.

Data Sharing Statement

Click here for additional data file.^{(16.2KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

Click here for additional data file.^{(837.8KB, pdf)}

Supplement 2.

Statistical Analysis Plant

Click here for additional data file.^{(665KB, pdf)}

Supplement 3.

eMethods. Estimation of minimal clinical important differences for the Urogenital Distress Inventory in the ESTEEM population – description of methods

eTable 1. Other Baseline Characteristics of Eligible and Randomized Participants

eTable 2. Comparison of Primary Analysis and Multiple Imputation Results

eTable 3. Primary and Secondary Outcomes Through 12 Months, Post-Hoc Sensitivity Analysis with Site as a Random Effect

eTable 4. Timepoint at which Each Retreated Participant was Included in Statistical Models

eTable 5. Post-operative Complications

eTable 6. All Adverse Events by System Organ Class and Preferred Term Reported

Click here for additional data file.^{(654.6KB, pdf)}

Supplement 4.

Data Sharing Statement

Click here for additional data file.^{(16.2KB, pdf)}

[joi190091r1] 1.Minassian VA, Bazi T, Stewart WF. Clinical epidemiological insights into urinary incontinence. Int Urogynecol J. 2017;28(5):687-696. doi: 10.1007/s00192-017-3314-7 [DOI] [PubMed] [Google Scholar]

[joi190091r2] 2.Dooley Y, Lowenstein L, Kenton K, FitzGerald M, Brubaker L. Mixed incontinence is more bothersome than pure incontinence subtypes. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(10):1359-1362. doi: 10.1007/s00192-008-0637-4 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Effect of Behavioral and Pelvic Floor Muscle Therapy Combined With Surgery vs Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary Incontinence

Vivian W Sung, MD, MPH

Diane Borello-France, PT, PhD

Diane K Newman, DNP

Holly E Richter, PhD, MD

Emily S Lukacz, MD

Pamela Moalli, MD, PhD

Alison C Weidner, MD, MMCi

Ariana L Smith, MD

Gena Dunivan, MD

Beri Ridgeway, MD

John N Nguyen, MD

Donna Mazloomdoost, MD

Benjamin Carper, MS

Marie G Gantz, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Oversight

Patients

Figure 1. Screening, Randomization, Treatment, and Follow-up of Women Participating in the Effects of Surgical Treatment Enhanced With Exercise for Mixed Urinary Incontinence (ESTEEM) Trial.

Interventions and Randomization

Primary and Secondary Outcomes

Other Prespecified (Exploratory) Outcomes

Statistical Analysis

Results

Study Population

Table 1. Baseline Characteristics of Eligible and Randomized Patients.

Primary Outcome

Table 2. Primary and Secondary Outcomes Through 12 Monthsa.

Figure 2. Unadjusted Reduction From Baseline in Urinary Symptoms Based on Total Score From Urogenital Distress Inventory (UDI) Long Form Total.

Secondary Outcomes

Other Outcomes

Table 3. Prespecified Exploratory Through 12 Monthsa.

Table 4. Adverse Events Through 12 Months.

Figure 3. Kaplan-Meier Probability Curve for Additional Treatment Between Groups.

MCID Estimates From Study Data

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Table 2. Primary and Secondary Outcomes Through 12 Months^a.

Table 3. Prespecified Exploratory Through 12 Months^a.