A Principled Approach to Characterize and Analyze Partially Observed Confounder Data from Electronic Health Records.

Objective: Partially observed confounder data pose challenges to the statistical analysis of electronic health records (EHR) and systematic assessments of potentially underlying missingness mechanisms are lacking. We aimed to provide a principled approach to empirically characterize missing data processes and investigate performance of analytic methods. Methods: Three empirical sub-cohorts of diabetic SGLT2 or DPP4-inhibitor initiators with complete information on HbA1c, BMI and smoking as confounders of interest (COI) formed the basis of data simulation under a plasmode framework. A true null treatment effect, including the COI in the outcome generation model, and four missingness mechanisms for the COI were simulated: completely at random (MCAR), at random (MAR), and two not at random (MNAR) mechanisms, where missingness was dependent on an unmeasured confounder and on the value of the COI itself. We evaluated the ability of three groups of diagnostics to differentiate between mechanisms: 1)-differences in characteristics between patients with or without the observed COI (using averaged standardized mean differences [ASMD]), 2)-predictive ability of the missingness indicator based on observed covariates, and 3)-association of the missingness indicator with the outcome. We then compared analytic methods including "complete case", inverse probability weighting, single and multiple imputation in their ability to recover true treatment effects. Results: The diagnostics successfully identified characteristic patterns of simulated missingness mechanisms. For MAR, but not MCAR, the patient characteristics showed substantial differences (median ASMD 0.20 vs 0.05) and consequently, discrimination of the prediction models for missingness was also higher (0.59 vs 0.50). For MNAR, but not MAR or MCAR, missingness was significantly associated with the outcome even in models adjusting for other observed covariates. Comparing analytic methods, multiple imputation using a random forest algorithm resulted in the lowest root-mean-squared-error. Conclusion: Principled diagnostics provided reliable insights into missingness mechanisms. When assumptions allow, multiple imputation with nonparametric models could help reduce bias.

smdi: an R package to perform structural missing data investigations on partially observed confounders in real-world evidence studies.

Objectives: Partially observed confounder data pose a major challenge in statistical analyses aimed to inform causal inference using electronic health records (EHRs). While analytic approaches such as imputation are available, assumptions on underlying missingness patterns and mechanisms must be verified. We aimed to develop a toolkit to streamline missing data diagnostics to guide choice of analytic approaches based on meeting necessary assumptions. Materials and methods: We developed the smdi (structural missing data investigations) R package based on results of a previous simulation study which considered structural assumptions of common missing data mechanisms in EHR. Results: smdi enables users to run principled missing data investigations on partially observed confounders and implement functions to visualize, describe, and infer potential missingness patterns and mechanisms based on observed data. Conclusions: The smdi R package is freely available on CRAN and can provide valuable insights into underlying missingness patterns and mechanisms and thereby help improve the robustness of real-world evidence studies.

Postapproval Comparative Safety Study of Tofacitinib and Biological Disease-Modifying Antirheumatic Drugs: 5-Year Results from a United States-Based Rheumatoid Arthritis Registry.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared 5-year adverse event (AE) incidence rates (IRs) between patients initiating tofacitinib and those initiating new biological disease-modifying antirheumatic drugs (bDMARDs) within the United States (US) Corrona RA registry. METHODS: IRs (number of first events/100 patient-years) of major adverse cardiovascular events (MACE), serious infection events (SIEs), herpes zoster (HZ), malignancies, and death were estimated among tofacitinib and bDMARD initiators, regardless of dose/schedule, between November 6, 2012 (US Food and Drug Administration tofacitinib approval), and July 31, 2018 (follow-up through January 31, 2019). Propensity score (PS) methods were used to control for nonrandom prescribing practices. Hazard ratios (HRs) were calculated to compare rates using multivariable-adjusted Cox regression. Different risk windows were used for acute (MACE, SIEs, HZ, and venous thromboembolic events [VTEs]) and long-term (malignancy and death) events. VTEs were assessed descriptively. RESULTS: For MACE, SIEs, and HZ, 1999 (3152.1 patient-years) and 8358 (12 869.4 years) tofacitinib and bDMARD initiators were included, respectively; for malignancy/death, 1999 (4505.6 patient-years) and 6354 (16 670.8 patient-years) initiators were included, respectively. AE rates were similar across cohorts, except for HZ, which was significantly higher with tofacitinib versus bDMARDs (PS-trimmed adjusted HR 2.32; 95% confidence interval [CI] 1.43-3.75). There were 45 (zero serious) and 88 (five serious) HZ events with tofacitinib and bDMARDs, respectively. Sensitivity analyses demonstrated similar results. VTE IRs (95% CI) were 0.29 (0.13-0.54) and 0.33 (0.24-0.45) for tofacitinib and bDMARDs, respectively. CONCLUSION: In this registry analysis, both cohorts had similar MACE, SIE, malignancy, death, and VTE rates; HZ rates were higher for tofacitinib initaitors than for bDMARD initiators.

Real-World Evidence to Contextualize Clinical Trial Results and Inform Regulatory Decisions: Tofacitinib Modified-Release Once-Daily vs Immediate-Release Twice-Daily for Rheumatoid Arthritis.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To provide additional clinical evidence in regulatory submissions for a modified-release (MR) once-daily (QD) tofacitinib formulation, we compared real-world adherence and effectiveness between patients initiating the MR QD formulation and patients initiating an immediate-release (IR) twice-daily (BID) formulation. METHODS: Two noninterventional cohort studies were conducted. First, adherence and two effectiveness proxies were compared between patients with RA who newly initiated tofacitinib MR 11 mg QD or IR 5 mg BID in the IBM® MarketScan® Commercial and Medicare Supplemental US insurance claims databases (March 2016-October 2018). Second, using data collected in the Corrona US RA Registry (February 2016-August 2019), two Clinical Disease Activity Index (CDAI)-based measures of effectiveness were compared between tofacitinib MR 11 mg QD and IR 5 mg BID, and against noninferiority criteria derived from placebo-controlled clinical trials of the tofacitinib IR formulation. Multiple sensitivity analyses of the registry data were conducted to reassure regulators of consistent results across different assumptions. RESULTS: In each study, approximately two-thirds of patients initiated the MR formulation. In the claims database study, improved adherence and at least comparable effectiveness were observed with tofacitinib MR vs IR over 12 months, particularly in patients without prior advanced therapy. In the registry study, the noninferiority of tofacitinib MR vs IR was demonstrated for both CDAI outcomes at ~6 months; this finding was robust across multiple sensitivity analyses. CONCLUSION: These results demonstrate the value of real-world evidence from complementary data sources in understanding the impact of medication adherence with a QD formulation in clinical practice. These analyses were suitable for regulatory consideration as an important component of evidence for the comparability of tofacitinib MR 11 mg QD vs IR 5 mg BID in patients with RA. TRIAL REGISTRATION: Claims database study: ClinicalTrials.gov identifier NCT04018001, retrospectively registered July 12, 2019. Corrona US RA Registry study: ClinicalTrials.gov identifier NCT04267380, retrospectively registered February 12, 2020.

Real-World Comparative Effectiveness of Tofacitinib and Tumor Necrosis Factor Inhibitors as Monotherapy and Combination Therapy for Treatment of Rheumatoid Arthritis.

INTRODUCTION: No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. METHODS: This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N = 558) or TNFi (from 1 November 2001; N = 8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. RESULTS: Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. CONCLUSIONS: In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. FUNDING: Pfizer Inc.

Outcomes of infliximab dose escalation in patients with rheumatoid arthritis.

INTRODUCTION: Dose escalation of infliximab in both primary and secondary nonresponders is widely reported; however, the usefulness of dose escalation has been disputed. The objective of this analysis is to evaluate trends in clinical efficacy following multiple infliximab dose escalations in patients with rheumatoid arthritis (RA). METHODS: Patients enrolled in a US RA registry were included if they initiated infliximab at 3 mg/kg every 8 weeks, received ≥ 1 infliximab dose escalation within 12 months of initiation, and had ≥ 1 visit following dose escalation. Trends in mean Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ) scores from visits following dose escalations were evaluated. RESULTS: In patients who received 2 or 3 dose escalations, the initial (1 or 2) dose escalations resulted in reduced mean CDAI scores, but subsequent escalations did not further reduce disease activity. In patients who received ≥ 4 dose escalations, mean CDAI scores did not further reduce disease activity over time. Mean HAQ scores were stable over time in patients who received 2 or 3 dose escalations. In patients who received ≥ 4 dose escalations, mean HAQ scores decreased following 1 dose escalation but progressively increased following subsequent dose escalations. CONCLUSION: Initial dose escalations (from 3 mg/kg to the equivalent of approximately 5 to 7 mg/kg) may be useful in controlling disease activity; however, there may be diminishing clinical benefit of further escalations, which can also increase the potential risk for infection and increase incremental drug costs. KEY POINTS: • Initial infliximab dose escalations (1 to 2) may be useful in lowering disease activity in patients with rheumatoid arthritis. • There does not appear to be a clinical benefit in infliximab dose escalations above the equivalent of 5 to 7 mg/kg.

One-year risk of serious infection in patients treated with certolizumab pegol as compared with other TNF inhibitors in a real-world setting: data from a national U.S. rheumatoid arthritis registry.

BACKGROUND: Registry studies provide a valuable source of comparative safety data for tumor necrosis factor inhibitors (TNFi) used in rheumatoid arthritis (RA), but they are subject to channeling bias. Comparing safety outcomes without accounting for channeling bias can lead to inaccurate comparisons between TNFi prescribed at different stages of the disease. In the present study, we examined the incidence of serious infection and other adverse events during certolizumab pegol (CZP) use vs other TNFi in a U.S. RA cohort before and after using a methodological approach to minimize channeling bias. METHODS: Patients with RA enrolled in the Corrona registry, aged ≥ 18 years, initiating CZP or other TNFi (etanercept, adalimumab, golimumab, or infliximab) after May 1, 2009 (n = 6215 initiations), were followed for ≤ 12 months. A propensity score (PS) model was used to control for baseline characteristics associated with the probability of receiving CZP vs other TNFi. Incidence rate ratios (IRRs) of serious infectious events (SIEs), malignancies, and cardiovascular events (CVEs) in the CZP group vs other TNFi group were calculated with 95% CIs, before and after PS matching. RESULTS: Patients were more likely to initiate CZP later in the course of therapy than those initiating other TNFi. CZP initiators (n = 975) were older and had longer disease duration, more active disease, and greater disability than other TNFi initiators (n = 5240). After PS matching, there were no clinically important differences between CZP (n = 952) and other TNFi (n = 952). Before PS matching, CZP was associated with a greater incidence of SIEs (IRR 1.53 [95% CI 1.13, 2.05]). The risk of SIEs was not different between groups after PS matching (IRR 1.26 [95% CI 0.84, 1.90]). The 95% CI of the IRRs for malignancies or CVEs included unity, regardless of PS matching, suggesting no difference in risk between CZP and other TNFi. CONCLUSIONS: After using PS matching to minimize channeling bias and compare patients with a similar likelihood of receiving CZP or other TNFi, the 1-year risk of SIEs, malignancies, and CVEs was not distinguishable between the two groups.

The pelvic floor complication scale: a new instrument for reconstructive pelvic surgery.

OBJECTIVE: The purpose of this study was to develop and test a unique, new pelvic floor surgery complication scale and compare it with an existing validated measure. STUDY DESIGN: Surgeons from 2 clinical trials networks rated complications based on perceived patient bother, severity, and duration of disability to develop a pelvic floor complication scale (PFCS). PFCS scores were calculated for subjects in 2 multicenter pelvic floor surgical trials. The PFCS and modified Clavien-Dindo scores were evaluated for associations with length of hospitalization, satisfaction, and quality-of-life measures (health utilities index, short form-36, urogenital distress inventory, and incontinence impact questionnaire). RESULTS: We calculated PFCS scores for 977 subjects. Higher PFCS and Clavien-Dindo scores similarly were associated with longer length of hospitalization (P < .01), lower satisfaction (P < .01), lower Health Utilities Index scores (P = .02), lower short form-36 scores (P = .02), higher urogenital distress Inventory scores (P < .01), and incontinence impact questionnaire scores (P < .01) at 3 months. No associations were present at 1 year. CONCLUSION: The PFCS compares favorably to the validated modified Clavien-Dindo instrument.

A randomized trial of urodynamic testing before stress-incontinence surgery.

BACKGROUND: Urodynamic studies are commonly performed in women before surgery for stress urinary incontinence, but there is no good evidence that they improve outcomes. METHODS: We performed a multicenter, randomized, noninferiority trial involving women with uncomplicated, demonstrable stress urinary incontinence to compare outcomes after preoperative office evaluation and urodynamic tests or evaluation only. The primary outcome was treatment success at 12 months, defined as a reduction in the score on the Urogenital Distress Inventory of 70% or more and a response of "much better" or "very much better" on the Patient Global Impression of Improvement. The predetermined noninferiority margin was 11 percentage points. RESULTS: A total of 630 women were randomly assigned to undergo office evaluation with urodynamic tests or evaluation only (315 per group); the proportion in whom treatment was successful was 76.9% in the urodynamic-testing group versus 77.2% in the evaluation-only group (difference, -0.3 percentage points; 95% confidence interval, -7.5 to 6.9), which was consistent with noninferiority. There were no significant between-group differences in secondary measures of incontinence severity, quality of life, patient satisfaction, rates of positive provocative stress tests, voiding dysfunction, or adverse events. Women who underwent urodynamic tests were significantly less likely to receive a diagnosis of overactive bladder and more likely to receive a diagnosis of voiding-phase dysfunction, but these changes did not lead to significant between-group differences in treatment selection or outcomes. CONCLUSIONS: For women with uncomplicated, demonstrable stress urinary incontinence, preoperative office evaluation alone was not inferior to evaluation with urodynamic testing for outcomes at 1 year. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00803959.).

Adverse events over two years after retropubic or transobturator midurethral sling surgery: findings from the Trial of Midurethral Slings (TOMUS) study.

OBJECTIVE: To describe surgical complications in 597 women over a 24-month period after randomization to retropubic or transobturator midurethral slings. STUDY DESIGN: During the Trial of Midurethral Slings study, the Data Safety Monitoring Board regularly reviewed summary reports of all adverse events using the Dindo Surgical Complication Scale. Logistic regression models were created to explore associations between clinicodemographic factors and surgical complications. RESULTS: A total of 383 adverse events were observed among 253 of the 597 women (42%). Seventy-five adverse events (20%) were classified as serious (serious adverse events); occurring in 70 women. Intraoperative bladder perforation (15 events) occurred exclusively in the retropubic group. Neurologic adverse events were more common in the transobturator group than in retropubic (32 events vs 20 events, respectively). Twenty-three (4%) women experienced mesh complications, including delayed presentations, in both groups. CONCLUSION: Adverse events vary by procedure, but are common after midurethral sling. Most events resolve without significant sequelae.

Lessons from a patient experience survey in a randomized surgical trial of treatment of stress urinary incontinence in women.

INTRODUCTION AND HYPOTHESIS: To understand the patient burden of study procedures/measures at completion of a randomized controlled trial (RCT) requiring extensive testing and follow-up visits. METHODS: A survey sent after completing the 2-year visit of an RCT comparing Burch colposuspension and fascial retropubic sling to treat stress urinary incontinence assessed degree of bother for seven study procedures, eight study-related factors, and possible motivations to participate in the study. RESULTS: A total of 450 study participants (88%) returned the survey. Urodynamic testing was the most bothersome procedure, followed by 24-h pad test and Q-tip test. Self-administered questionnaires were the least bothersome. Main reasons to participate in the study were to help others, obtain better knowledge about the condition, and be guided by a committed team of investigators/study coordinators. CONCLUSIONS: At the end of a large multicenter RCT, we learned from a confidential patient survey that the most burdensome activities involved invasive procedures, frequent visits, and multiple forms to fill out.

Perineal surface electromyography does not typically demonstrate expected relaxation during normal voiding.

AIMS: To describe perineal surface patch electromyography (EMG) activity during urodynamics (UDS) and compare activity between filling and voiding phases and to assess for a relationship between preoperative EMG activity and postoperative voiding symptoms. METHODS: 655 women underwent standardized preoperative UDS that included perineal surface EMG prior to undergoing surgery for stress urinary incontinence. Pressure-flow studies were evaluated for abdominal straining and interrupted flow. Quantitative EMG values were extracted from 10 predetermined time-points and compared between fill and void. Qualitative EMG activity was assessed for the percent of time EMG was active during fill and void and for the average amplitude of EMG during fill compared to void. Postoperative voiding dysfunction was defined as surgical revision or catheterization more than 6 weeks after surgery. Fisher's exact test with a 5% two-sided significance level was used to assess differences in EMG activity and postoperative voiding dysfunction. RESULTS: 321 UDS had interpretable EMG studies, of which 131 (41%) had EMG values at all 10 predetermined and annotated time-points. Quantitative and qualitative EMG signals during flow were usually greater than during fill. The prevalence of postoperative voiding dysfunction in subjects with higher preoperative EMG activity during void was not significantly different. Results were similar in the 42 subjects who had neither abdominal straining during void nor interrupted flow. CONCLUSIONS: Perineal surface patch EMG did not measure expected pelvic floor and urethral sphincter relaxation during voiding. Preoperative EMG did not predict patients at risk for postoperative voiding dysfunction.

Demographic and clinical predictors of treatment failure one year after midurethral sling surgery.

OBJECTIVE: To identify clinical and demographic factors predictive of midurethral sling failure. METHODS: Overall treatment failure was defined by one or more of the following objective outcomes: a positive stress test, positive 24-hour pad test or retreatment for stress urinary incontinence (SUI); subjective outcomes: self reported SUI by the Medical, Epidemiologic and Social Aspect of Aging questionnaire, incontinent episodes by 3-day diary, or retreatment for SUI, or a combination of these. Logistic regression models adjusting for sling type and clinical site were used to predict odds of overall treatment failure after univariable analysis. Models were also fit to compare factors associated with objective failure and subjective failure only. RESULTS: Previous UI surgery (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.14-3.47); maximum Q-tip excursion<30° (OR 1.89, 95% CI 1.16-3.05); Medical, Epidemiologic and Social Aspect of Aging questionnaire urge score per 10 points (OR 1.97, 95% CI 1.21-3.21); and pad weight per 10 g (OR 1.06, 95% CI 1.02-1.10) were predictors of overall failure. Having concomitant surgery (OR 0.44, 95% CI 0.22-0.90) was predictive of subjective failure only rather than objective failure. Age per 10 years (OR 1.48, 95% CI 1.14-1.90); Urogenital Distress Inventory score per 10 points (OR 1.09, 95% CI 1.02-1.17); pad weight per 10 g (OR 1.05, 95% CI 1.01-1.10) were predictive of objective failure compared with subjective failure only. Associations of risk factors and failure were similar independent of sling type (retropubic or transobturator). CONCLUSION: Twelve months after surgery, risk factors for overall and objective treatment failure were similar in women undergoing retropubic and transobturator sling procedures. This information may assist in counseling patients regarding efficacy of sling procedures and in setting expectations for women at increased odds for treatment failure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00325039. LEVEL OF EVIDENCE: II.

Preoperative voiding detrusor pressures do not predict stress incontinence surgery outcomes.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to determine whether preoperative voiding detrusor pressures were associated with postoperative outcomes after stress incontinence surgery. METHODS: Opening detrusor pressure, detrusor pressure at maximum flow (p (det) Q(max)), and closing detrusor pressure were assessed from 280 valid preoperative urodynamic studies in subjects without advanced prolapse from a multicenter randomized trial comparing Burch and autologous fascia sling procedures. These pressures were compared between subjects with and without overall success, stress-specific success, postoperative detrusor overactivity, and postoperative urge incontinence using independent sample t tests. RESULTS: There were no clinically or statistically significant differences in mean preoperative voiding detrusor pressures in any comparison of postoperative outcomes. CONCLUSIONS: We found no evidence that preoperative voiding detrusor pressures predict outcomes in women with stress predominant urinary incontinence undergoing Burch or autologous fascial sling procedures.

Retropubic versus transobturator midurethral slings for stress incontinence.

BACKGROUND: Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications. METHODS: We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points. RESULTS: A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life. CONCLUSIONS: The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)

The impact of obesity on urinary incontinence symptoms, severity, urodynamic characteristics and quality of life.

PURPOSE: We compared urinary incontinence severity measures and the impact of stress urinary incontinence in normal, overweight and obese women. MATERIALS AND METHODS: Baseline characteristics of subjects in the SISTEr (655) and the TOMUS (597) were analyzed. Body mass index was defined as normal (less than 25 kg/m(2)), overweight (25 to less than 30 kg/m(2)) and obese (30 kg/m(2) or greater). Independent urinary incontinence severity measures included a 3-day diary including incontinence episode frequency, Urogenital Distress Inventory scores and Valsalva leak point pressure from urodynamic testing. Impact was measured using the Incontinence Impact Questionnaire. Multivariable regression models were fit for each severity measure (Urogenital Distress Inventory, incontinence episode frequency, Valsalva leak point pressure and Incontinence Impact Questionnaire) on weight category. Covariates included age, race, diabetes and variables significantly associated with body mass index on bivariate analysis. RESULTS: Mean age (SD) of participants was 51.9 (10.3) in SISTEr and 52.9 (11.0) in TOMUS. In each trial 45% of subjects were obese. In SISTEr multivariable regression analyses showed that higher weight category was independently associated with higher mean Urogenital Distress Inventory score (p = 0.003), incontinence episode frequency (p <0.0001), Valsalva leak point pressure (p = 0.003) and Incontinence Impact Questionnaire score (p = 0.0004). In TOMUS higher weight category was not associated with Urogenital Distress Inventory score (p = 0.24) but was associated with higher incontinence episode frequency (p = 0.0003), Valsalva leak point pressure (p = 0.0006) and Incontinence Impact Questionnaire score (p <0.0001). CONCLUSIONS: Obese women undergoing surgery for stress urinary incontinence report more incontinence episodes, more symptom distress and worse quality of life despite better measure of urethral function (higher Valsalva leak point pressure) on urodynamics.

Design of the Value of Urodynamic Evaluation (ValUE) trial: A non-inferiority randomized trial of preoperative urodynamic investigations.

BACKGROUND AND PURPOSE: Urodynamic studies (UDS) are routinely obtained prior to surgery for stress urinary incontinence (SUI) despite a lack of evidence that UDS information has an actual impact on outcome. The primary aim of this non-inferiority randomized clinical trial is to determine whether women with symptomatic, uncomplicated SUI who undergo only a basic office evaluation (BOE) prior to SUI surgery (No UDS arm) have non-inferior treatment outcomes compared to women who have BOE and UDS (UDS arm). Secondary aims are: 1) to determine how often physicians use preoperative UDS results to alter clinical and surgical decision-making, 2) to compare the amount of improvement in incontinence outcomes, and 3) to determine the incremental cost and utility of performing UDS compared with not performing UDS. METHODS: After an initial basic office evaluation, women planning surgery for uncomplicated SUI who consent to study participation will be randomized to receive preoperative UDS or No UDS. Treatment will be planned and performed by the surgeon utilizing all the data available to them. We will compare results from the basic office evaluation (No UDS) with results from the basic office evaluation and preoperative UDS. RESULTS: The primary outcome will be measured at 12 months using responses to the Urogenital Distress Inventory and the Patient Global Index-Improvement. CONCLUSIONS: Randomized trials comparing the effects of different diagnostic alternatives on treatment outcomes pose study design challenges. A non-inferiority design is appropriate when comparing a less invasive and less expensive alternative with a standard of care approach.

Complications in women undergoing Burch colposuspension versus autologous rectus fascial sling for stress urinary incontinence.

PURPOSE: We determined the clinicodemographic factors associated with complications of continence procedures, the impact of concomitant surgery on the complication rate and the relationship between the incidence of cystitis and the method of postoperative bladder drainage. MATERIALS AND METHODS: We reviewed serious adverse events and adverse events in the Stress Incontinence Surgical Efficacy Trial, a randomized trial comparing Burch colposuspension to the autologous rectus fascial sling. Clinicodemographic variables were analyzed to determine those associated with adverse events using logistic regression analysis. Complications were stratified based on the presence or absence of concomitant surgery. Differences in complication rates (controlling for concomitant surgery) and cystitis rates (controlling for the bladder emptying method) were compared using Fisher's exact test. RESULTS: Blood loss (p = 0.0002) and operative time (p <0.0001) were significantly associated with an adverse event. Patients who underwent concomitant surgery had a significantly higher serious adverse event rate (14.2% vs 7.3%, p = 0.01) and adverse event rate (60.5% vs 48%, p <0.01) than patients who underwent continence surgery alone. Cystitis rates were higher in the sling vs the Burch group up to 6 weeks postoperatively regardless of concomitant surgery status (p <0.01). Intermittent self-catheterization increased the cystitis rate by 17% and 23% in the Burch and sling groups, respectively. CONCLUSIONS: Concomitant surgery at continence surgery increased the risk of complications. Sling surgery was associated with a higher risk of cystitis within the first 6 weeks postoperatively. Intermittent self-catheterization increased the risk of cystitis in each group. Complications were associated with surgical factors and not with patient related factors.

Two-year outcomes after surgery for stress urinary incontinence in older compared with younger women.

OBJECTIVE: To estimate whether perioperative and postoperative outcomes after Burch colposuspension or pubovaginal sling for stress urinary incontinence (SUI) differed with age. METHODS: This study was a prospective secondary analysis of the Stress Incontinence Surgical Treatment Efficacy Trial. Baseline characteristics, adverse events, and 2-year outcomes of women at least 65 years old were compared with those younger than 65 years using chi(2) and t tests. Multivariable analyses were performed, including age and outcomes that differed between age groups on univariable analysis, adjusting for variables that differed by age group at baseline and by surgical treatment group. RESULTS: Six-hundred fifty-five women were included in analyses of perioperative events and 520 for 2-year outcomes. Mean age (+/-standard deviation) was 69.7 (+/-3.7) years in the older group and 49.4 (+/-8.2) in the younger group. Older women had slightly longer time to normal activities (50 days compared with 42 days, P=.05), but there was no difference in time to normal voiding (14 days compared with 11 days, P=.42). Older women were more likely to have a positive stress test at follow-up (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.70-7.97, P=.001), less subjective improvement in stress (8 point lesser decrease, 95% CI 1.5-14.1, P=.02), and urge incontinence (7 point lesser decrease, 95% CI 1.5-12.2, P=.01) by the Medical and Epidemiologic Social Aspects of Aging questionnaire, and were more likely to undergo surgical retreatment for SUI (OR 3.9, 95% CI 1.30-11.48). Perioperative adverse events and length of stay did not differ between groups. CONCLUSION: Older women undergoing surgery for stress incontinence can expect to do as well as younger women with respect to perioperative outcomes, but experience 2-year outcomes that are worse.

Behavioral therapy to enable women with urge incontinence to discontinue drug treatment: a randomized trial.

BACKGROUND: Women with urge urinary incontinence are commonly treated with antimuscarinic medications, but many discontinue therapy. OBJECTIVE: To determine whether combining antimuscarinic drug therapy with supervised behavioral training, compared with drug therapy alone, improves the ability of women with urge incontinence to achieve clinically important reductions in incontinence episodes and to sustain these improvements after discontinuing drug therapy. DESIGN: 2-stage, multicenter, randomized clinical trial conducted from July 2004 to January 2006. SETTING: 9 university-affiliated outpatient clinics. PATIENTS: 307 women with urge-predominant incontinence. INTERVENTION: 10 weeks of open-label, extended-release tolterodine alone (n = 153) or combined with behavioral training (n = 154), followed by discontinuation of therapy and follow-up at 8 months. MEASUREMENTS: The primary outcome, measured at 8 months, was no receipt of drugs or other therapy for urge incontinence and a 70% or greater reduction in frequency of incontinence episodes. Secondary outcomes were reduction in incontinence, self-reported satisfaction and improvement, and scores on validated questionnaires measuring symptom distress and bother and health-related quality of life. Study staff who performed outcome evaluations, but not participants and interventionists, were blinded to group assignment. RESULTS: 237 participants completed the trial. According to life-table estimates, the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups (41% in both groups; difference, 0 percentage points [95% CI, -12 to 12 percentage points]). A higher proportion of participants who received combination therapy than drug therapy alone achieved a 70% or greater reduction in incontinence at 10 weeks (69% vs. 58%; difference, 11 percentage points [CI, -0.3 to 22.1 percentage points]). Combination therapy yielded better outcomes over time on the Urogenital Distress Inventory and the Overactive Bladder Questionnaire (both P <0.001) at both time points for patient satisfaction and perceived improvement but not health-related quality of life. Adverse events were uncommon (12 events in 6 participants [3 in each group]). LIMITATIONS: Behavioral therapy components (daily bladder diary and recommendations for fluid management) in the group receiving drug therapy alone may have attenuated between-group differences. Assigned treatment was completed by 68% of participants, whereas 8-month outcome status was assessed on 77%. CONCLUSION: The addition of behavioral training to drug therapy may reduce incontinence frequency during active treatment but does not improve the ability to discontinue drug therapy and maintain improvement in urinary incontinence. Combination therapy has a beneficial effect on patient satisfaction, perceived improvement, and reduction of other bladder symptoms.