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Long-term efficacy and safety of questionnaire-based initiation of urgency urinary incontinence treatment

      Objective

      The objective of the study was to determine the longer-term efficacy and safety of initiating treatment for urgency-predominant urinary incontinence (UUI) in women diagnosed using a simple questionnaire rather than an extensive evaluation.

      Study Design

      Women completing a 12 week randomized controlled trial of fesoterodine therapy for UUI diagnosed by questionnaire were invited to participate in a 9 month, open-label continuation study. UUI and voiding episodes were collected using voiding diaries. Participant satisfaction was measured by questionnaire. Safety was assessed by the measurement of postvoid residual volume and adverse event monitoring; if necessary, women underwent a specialist evaluation. The longitudinal changes in UUI and voiding episodes were evaluated using linear mixed models adjusting for baseline.

      Results

      Of the 567 women completing the randomized trial, 498 (87.8%) took at least 1 dose of medication during this open-label study. Compared with the baseline visit in the randomized trial, fesoterodine was associated with a reduction in total incontinence episodes per day and urgency incontinence episodes per day at the end of the open-label study (adjusted mean [SE], 4.6 [0.12] to 1.2 [0.13] and 3.9 [0.11] to 0.9 [0.11], respectively, P < .0001 for both). Most women were satisfied with treatment (89%, 92%, and 93% at 3, 6, and 9 months, respectively). Twenty-six women experienced 28 serious adverse events, 1 of which was considered possibly treatment related. Twenty-two women had a specialist evaluation: 5 women's incontinence was misclassified by the 3 Incontinence Questions; none experienced harm because of misclassification.

      Conclusion

      Using a simple validated questionnaire to diagnose and initiate treatment for UUI in community-dwelling women is safe and effective, allowing timely treatment by primary care practitioners.

      Key words

      For Editors' Commentary, see Contents
      Urinary incontinence affects up to a third of women in the United States, resulting in more than $20 billion in health care costs annually.
      • Subak L.L.
      • Brown J.S.
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      • et al.
      The “costs” of urinary incontinence for women.
      In addition to its direct costs, incontinence is associated with falls, fractures, increased caregiver burden, and increased nursing home care, making the actual costs likely much higher.
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      Urinary incontinence: does it increase risk for falls and fractures?.
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      Urinary incontinence and depression in middle-aged United States women.
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      • Herzog A.R.
      Informal caregiving time and costs for urinary incontinence in older individuals in the United States.
      Many women with incontinence fail to receive appropriate treatment, both because primary care providers do not routinely ask about incontinence and because patients do not volunteer the information.
      • Shaw C.
      • Tansey R.
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      Barriers to help seeking in people with urinary symptoms.
      • Shaw C.
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      A qualitative study of the assessment and treatment of incontinence in primary care.
      • Williams K.S.
      • Assassa R.P.
      • Smith N.
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      • Mayne C.
      Good practice in continence care: the development of nurse-led service.
      Women reporting incontinence tend to be referred to specialists prior to being offered treatment,
      Agency for Healthcare Research and Quality (AHCPR) Urinary Incontinence in Adults Guideline Update Panel. Managing acute and chronic urinary incontinence.
      • Scientific Committee of the First International Consultation on Incontinence
      Assessment and treatment of urinary incontinence.
      a model that increases the cost of care delivery and delays therapy.
      In 1996, the Agency for Healthcare Research and Quality recommended that primary care providers take a larger role in diagnosing and treating incontinence. In response, streamlined diagnostic measures such as the 3 Incontinence Questions (3IQ) have been developed to help classify women's incontinence in primary care practice. The 3IQ is a brief validated, reproducible questionnaire with good sensitivity and specificity in distinguishing between urgency and stress incontinence.
      • Brown J.S.
      • Bradley C.S.
      • Subak L.L.
      • et al.
      The sensitivity and specificity of a simple test to distinguish between urge and stress urinary incontinence.
      However, the longer-term efficacy and safety of treating incontinence based on this streamlined questionnaire are not known.
      To address this issue, we conducted the Bringing Simple Urge Incontinence Diagnosis and Treatment to Providers (BRIDGES) study, a 12 week randomized, double-blind, placebo-controlled clinical trial (RCT) of antimuscarinic therapy in ambulatory women who self-diagnosed as having urgency-predominant urinary incontinence (UUI) using the 3IQ.
      • Huang A.J.
      • Hess R.
      • Arya L.A.
      • et al.
      Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial.
      In this trial, women who flexibly dosed 4-8 mg of fesoterodine daily reported fewer urgency incontinence episodes over 12 weeks compared with placebo.
      • Huang A.J.
      • Hess R.
      • Arya L.A.
      • et al.
      Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial.
      In this manuscript, we report the results of a 9 month open-label study, in which women completing the 12 week trial were invited to take fesoterodine daily for an additional 9 months. The purpose of this open-label study was to determine the longer-term efficacy and safety of initiating treatment for UUI in women diagnosed using a simple questionnaire rather than a more extensive evaluation.

      Materials and Methods

      Study population

      Eligibility criteria for BRIDGES have been described previously.
      • Huang A.J.
      • Hess R.
      • Arya L.A.
      • et al.
      Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial.
      Briefly, ambulatory women aged 18 years and older with self-reported UUI were recruited from the general communities surrounding 13 clinical sites in the United States. During the initial in-person visit, potential participants reporting at least weekly incontinence completed the 3IQ on paper, without assistance from the research staff. Those whose 3IQ indicated UUI (vs stress-predominant, equally mixed, or other incontinence) were eligible to continue in the study. Consistent with the proposed use of the 3IQ in clinical practice,
      • Brown J.S.
      • Bradley C.S.
      • Subak L.L.
      • et al.
      The sensitivity and specificity of a simple test to distinguish between urge and stress urinary incontinence.
      women had dipstick urinalysis testing to rule out urinary tract infection and hematuria before enrollment.
      Other eligibility criteria were selected to define a community-dwelling sample of women who would be considered appropriate for evaluation and treatment in a primary care practice. Women were excluded if they self-reported complex medical histories (regardless of severity), including major neurological conditions (stroke, Parkinson's disease, spinal cord lesion, or multiple sclerosis), recent urological surgeries (antiincontinence surgery in the past 5 years or other pelvic surgeries in the past 6 months), more than 3 urinary tract infections in the past year, lower urinary tract or rectal fistula, interstitial cystitis, symptomatic pelvic prolapse, pelvic radiation, congenital abnormality leading to incontinence, or pelvic cancer that would require a specialist evaluation for incontinence, or if they had known contraindications to antimuscarinic therapy.
      All women who completed the 12 week RCT were offered participation in the preplanned 9 month, open-label study of fesoterodine, in which participants were seen in person at open-label baseline and at 1, 3, 6, and 9 months and participated in a telephone visit at 2 weeks. The timing of study procedures and measurements is shown in the Appendix; Supplementary Table. Institutional review boards at each site approved the study, all participants provided written informed consent before enrollment, and the study was registered with clinicaltrial.gov (NCT00862745).

      Fesoterodine distribution

      At baseline of the open-label study, all participants were started on fesoterodine 4 mg daily; women in the active arm of the RCT had been taking 4 or 8 mg previously, whereas those in the control arm had been taking placebo. Participants were invited to self-adjust their medication dose at the 1, 3, 6, and 9 month follow-up visits. Medication adherence was assessed through pill counts at each of these visits.

      Urinary symptom assessment (efficacy)

      At baseline, 3 month, 6 month, and 9 month open-label visits, trained research study staff reviewed the participant-completed validated 3 day voiding diary to assess changes in UUI, our primary efficacy outcome. In this diary, women recorded all voiding and incontinence episodes, classified their incontinence episodes by type (urgency, stress, or do not know), and rated the severity of voiding episodes associated with a sensation of urgency as none, mild, moderate, or severe.
      • Brown J.S.
      • McNaughton K.S.
      • Wyman J.F.
      • et al.
      Measurement characteristics of a voiding diary for use by men and women with overactive bladder.
      • Anderson R.U.
      • Mobley D.
      • Blank B.
      • Saltzstein D.
      • Susset J.
      • Brown J.S.
      Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group.
      Participants also completed validated questionnaires assessing the self-reported impact of their bladder symptoms, including the following: (1) the Overactive Bladder Questionnaire (OAB-q),
      • Matza L.S.
      • Thompson C.L.
      • Krasnow J.
      • Brewster-Jordan J.
      • Zyczynski T.
      • Coyne K.S.
      Test-retest reliability of four questionnaires for patients with overactive bladder: the overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ).
      a 33 item instrument assessing bladder symptom impact; (2) the Patient Perception of Bladder Condition (PPBC)
      • Matza L.S.
      • Thompson C.L.
      • Krasnow J.
      • Brewster-Jordan J.
      • Zyczynski T.
      • Coyne K.S.
      Test-retest reliability of four questionnaires for patients with overactive bladder: the overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ).
      • Coyne K.S.
      • Matza L.S.
      • Kopp Z.
      • Abrams P.
      The validation of the patient perception of bladder condition (PPBC): a single-item global measure for patients with overactive bladder.
      a single-item measure assessing the patient's current perception of her bladder problems; and (3) and the Patient Perception of Urgency Scale (PPUS),
      • Cardozo L.
      • Coyne K.S.
      • Versi E.
      Validation of the urgency perception scale.
      a single-item measure assessing the patient's perception of her voiding urgency.

      Participant satisfaction (efficacy)

      To assess participants' subjective, personal evaluation of treatment effectiveness and willingness to continue therapy, a modified 4 item version of the Overactive Bladder Satisfaction (OAB-S) was administered at the 3 month, 6 month, and 9 month open-label visits.
      • Piault E.
      • Evans C.J.
      • Espindle D.
      • Kopp Z.
      • Brubaker L.
      • Abrams P.
      Development and validation of the Overactive Bladder Satisfaction (OAB-S) Questionnaire.
      Participants were asked to rate satisfaction with the fesoterodine medication and satisfaction with the change in urine leakage using a 5 point scale ranging from very satisfied to very dissatisfied. At 9 months (or early termination), participants were also asked whether they would continue using fesoterodine. If they said no, they were asked to select the reason for discontinuation; choices included the following: (1) I do not like taking pills, (2) my symptoms have not improved enough, (3) the side effects of the medication are too bothersome, and (4) other, with the opportunity to specify another reason.

      Adverse events (safety)

      At each study contact, participants were asked to report any negative changes in their health (ie, adverse events). Adverse events involving dry mouth, constipation, drowsiness, tachycardia, or urinary hesitancy or retention were classified as potentially associated with antimuscarinic therapy. Serious adverse events were defined as those that resulted in death, disability, or in-patient hospitalization. For all serious adverse events, site investigators rated the likelihood of relationship to treatment using a standardized attribution scale.
      To objectively assess posttreatment urinary retention, measurement of postvoid residual volume (PVR) was performed (based on site preference) by bladder ultrasound (8 sites), urinary catheterization (4 sites), or either (1 site) at the open label baseline, 3 month, and 9 month visits or at early termination. If the initial PVR measurement was greater than 250 mL, another PVR measurement was obtained on the same day.

      Extended evaluation (safety)

      Participants were offered extended evaluations with their site urologist or urogynecologist if they had 2 PVRs greater than 250 mL on the same day, if they reported lack of incontinence improvement, or otherwise expressed dissatisfaction with their treatment on the OAB-S questionnaire.
      Additionally, if site investigators had safety concerns, they could refer participants for evaluation at any time. Each participant could undergo only 1 extended evaluation during the study. During the extended evaluation, the site specialist collected and/or reviewed all data (medical, reproductive, surgical, and incontinence history; medication inventory; 3 day voiding diary; physical and pelvic exam; PVR; stress cough test) to diagnose the incontinence type (urgency predominant, stress predominant, or other predominant) and assessed outcomes. If the resulting specialist diagnosis was not UUI, the specialist indicated whether the delay in the correct diagnosis resulted in harm to the participant and made alternative treatment recommendations.
      A central independent specialist associated with the coordinating center and not employed by the sponsor also reviewed the extended evaluation data for each participant and made a diagnosis based on her own clinical judgment. If, after review, the diagnosis was not UUI, she also noted whether the delay in correct diagnosis caused harm, our primary safety outcome, and made alternate treatment recommendations. If the site and central independent specialists disagreed, they discussed the case and arrived at a consensus diagnosis and treatment plan, which was shared with the site investigator and participant.

      Statistical analysis

      Summary statistics were evaluated from the baseline RCT visit, open-label baseline, and open-label follow-up visits. Continuous variables were summarized using mean, median, SD, and interquartile range. Categorical variables were described using absolute and relative frequency. Participant satisfaction, adverse events, and extended evaluations are described for all time points in the open-label portion of the study.
      Voiding diary endpoints (urinary incontinence and voiding outcomes) were summarized at all of the previously mentioned time points and evaluated compared with the initial RCT visit using linear mixed models adjusted for the independent predictors of these changes, including standard overactive bladder risk factors, and were specified to account for repeated measures, site clusters, and transformed outcomes to approximate normal distribution.
      All covariables with a univariable significance of P ≤ .10 (age, marital status, health status, parity, menopausal status, hysterectomy, urinary tract infection, smoking status, and current diuretic therapy) were included in all multivariable models. All analyses were performed using SAS statistical software, version 9.2 (SAS Institute, Cary, NC).

      Results

      Participants and dosing

      Between February 2009 and January 2010, 322 women were randomized to fesoterodine, and 323 to placebo; 567 women completed the randomized portion of the study. Of those women completing the RCT, 498 (87.8%) continued in the open-label study (Figure 1). There were no significant differences with regard to age, race, health status, parity, smoking, alcohol use, number or type of incontinence episodes per day, response to treatment or side effects during the RCT, or bladder symptoms between women who did or did not participate in the open-label study. Among these 498 women, 254 women had been on placebo and 244 on fesoterodine during the RCT.
      Figure thumbnail gr1
      Figure 1Recruitment and retention of participants in the 9 month open-label extension study (n = 498)
      Randomized controlled trial1: among ambulatory women with urgency incontinence diagnoses using a 3 Incontinence Questions (the 3 IQ), rather than an extended, evaluation randomized pharmacologic therapy (fesoterodine 4 and/or 8 mg) for 12 weeks; ∗∗Early terminations are explained in detail in .
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      On average, these 498 participants were 56.9 years old (SD, 13.8; range, 21–90). Eighty percent self-rated their health as excellent or very good (Table 1). Four hundred fifty-four women completed the 9 month open-label study; there were no significant differences in baseline characteristics between women with and without follow-up data in the open-label study (data not shown).
      Table 1Characteristics of women enrolled in the 9 month open-label study (n= 498)
      All data obtained at the prerandomization baseline of the 12 week randomized controlled trial
      DemographicValue
      Mean (SD) age (y)56.9 (13.8)
      Race/ethnicity, n (%)
      Participants self-reported their primary racial/ethnic group as white, black/African American, Latina/Hispanic, Asian, Pacific Islander, Native American/American Indian, or multiethnic
       White340 (68.3)
       Black103 (20.7)
       Latina11 (2.2)
       Asian/Pacific Islander32 (6.4)
       Multiethnic/other12 (2.4)
      Married, n (%)223 (44.8)
      Clinical
       Excellent or very good overall health, n (%)
      Overall health was assessed by asking women to rate their overall health as excellent, very good, good, fair, or poor.
      399 (80.1)
       Previous childbirth (parity ≥1), n (%)400 (80.3)
       No current menstrual periods, n (%)363 (73.2)
       History of hysterectomy, n (%)155 (31.1)
       Current cigarette smoking, n (%)66 (13.3)
       Current weekly alcohol consumption, n (%)156 (31.3)
       Current systemic hormone therapy, n (%)40 ( 8.0)
       Current stable diuretic therapy, n (%)79 (15.9)
      SD, standard deviation.
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      a All data obtained at the prerandomization baseline of the 12 week randomized controlled trial
      b Participants self-reported their primary racial/ethnic group as white, black/African American, Latina/Hispanic, Asian, Pacific Islander, Native American/American Indian, or multiethnic
      c Overall health was assessed by asking women to rate their overall health as excellent, very good, good, fair, or poor.
      Although all women started the open-label study on 4 mg/d of fesoterodine, 221 (44.3%) had changed to 8 mg daily by 3 months. After 3 months, only 28.2% of the women changed medication doses before the end of the open-label study (Figure 2). With participant-directed flexible dosing, 264 participants (53.0%) increased their dose of fesoterodine to 8 mg and remained at this dose throughout the study, 162 (32.5%) remained at 4 mg for the entire study, and 72 participants (14.4%) increased to 8 mg but returned to 4 mg before the end of the study. Based on pill counts, 89.2% of the 498 participants were taking at least 75% of doses at 1 month, 85.1% at 3 months, 87.2% at 6 months, and 88.5% at 9 months. Only 1.6%, 2.9%, 3.4%, and 4.6% of the participants were taking no medication at 1 month, 3 months, 6 months, and 9 months, respectively.
      Figure thumbnail gr2
      Figure 2Percentage of participants taking various doses of medication
      Percentage of participants taking 4 mg, 8 mg, a combination of 4 mg and 8 mg, and no medication at each time point during the open-label follow-up study are shown.
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      Of the women originally enrolled in the open-label study, 44 (8.8%) withdrew before the end of the study. A slightly higher proportion of women assigned to the placebo in the RCT lead-in withdrew during the open-label study compared with those assigned to fesoterodine in the RCT (11.4% vs 6.2%, P = .04). Among these 44 women, the most common reasons for withdrawal were adverse events (n = 16, including 2 serious adverse events), loss to follow-up (n = 11), lack of improvement (n = 5), and other patient circumstances (n = 5) (eg, family illness, relocation). At their final visits, 6 women indicated that they would continue using the study drug, even though they withdrew for other reasons, 26 stopped using the study drug, and 12 withdrew without indicating a preference.

      Urinary symptom assessment (efficacy)

      Bladder diaries were completed for 96.7%, 97.4%, and 96.25% of participants at 3 months, 6 months, and 9 months, respectively. The portion of diaries rated by the study coordinators as most likely to be complete and accurate was 95.2%, 96.0%, and 95.9%, respectively. The research staff rated less than 1% of diaries as not likely to be complete and accurate at all time points.
      Over the 9 months of the open-label study, participants reported a decrease in total incontinence episodes and in UUI episodes, daytime and nighttime micturitions, and moderate and severe urge sensations as well as an improvement in self-report of overactive bladder symptoms and perception of bladder condition compared with the initial RCT visit (Table 2). Nearly all women (94%) who had improved incontinence (defined as any decrease in UUI episodes) exhibited improvement by 2 weeks.
      Table 2Urinary incontinence and voiding outcomes
      VariableRCT baseline
      RCT: the prerandomization visit of the 12 week RCT


      (n = 498)
      Open label
      Open label baseline
      Baseline open-label bladder diaries included data on RCT participants that had been on fesoterodine or placebo; all comparisons are significant at P < .001 compared with the initial RCT visit and adjusted for site, age, marital status, health status, parity, menopausal status, hysterectomy, urinary tract infection, smoking status, and current diuretic therapy


      (n = 497)
      One participant failed to appear for the baseline open-label visit but was enrolled in open label at the subsequent visit
      Month 3

      (n = 491)
      Month 6

      (n = 464)
      Month 9

      (n = 454)
      From 3 day voiding diaries
      Values reflect events per day based on participant completion of a 3 day voiding diary
      Urgency incontinence episodes per day
      Self-report on diary as an urgency or stress incontinence episode
       Adjusted means (SE)3.90 (0.11)1.75 (0.11)1.08 (0.11)0.97 (0.11)0.95 (0.11)
       Median (IQR)
      Interquartile range; medians are unadjusted
      3.0 (2.0–5.0)1.0 (0.0–2.3)0.3 (0.0–1.3)0.3 (0.0–1.0)0.3 (0.0–1.0)
      Total incontinence episodes per day
       Adjusted means (SE)4.64 (0.12)2.11 (0.13)1.36 (0.13)1.22 (0.13)1.16 (0.13)
       Median (IQR)3.7 (2.3–6.0)1.0 (0.3–2.7)0.7 (0.0–1.7)0.3 (0.0–1.3)0.3 (0.0–1.3)
      Daytime incontinence episodes per day
       Adjusted means (SE)4.03 (0.11)1.84 (0.11)1.19 (0.11)1.09 (0.11)1.06 (0.11)
       Median (IQR)3.2 (2.0–5.0)1.0 (0.3–2.3)0.3 (0.0–1.7)0.3 (0.0–1.3)0.3 (0.0–1.3)
      Daytime voiding episodes per day
       Adjusted means (SE)8.67 (0.14)7.99 (0.14)7.59 (0.14)7.67 (0.14)7.70 (0.14)
       Median (IQR)8.3 (6.7–10.0)7.7 (6.3–9.3)7.3 (6.0–9.0)7.3 (6.0–8.7)7.3 (5.8–9.2)
      Nocturnal voiding episodes per night
      Self-report on the diary as to the time the participant went to bed for the evening and when the participant woke in the morning
       Adjusted means (SE)1.24 (0.05)0.89 (0.05)0.75 (0.05)0.75 (0.05)0.74 (0.05)
       Median (IQR)1.0 (0.3–2.0)0.7 (0.0–1.3)0.3 (0.0–1.3)0.3 (0.0–1.3)0.3 (0.0–1.2)
      Moderate urgency-associated voids per day
      Moderate urgency-associated voids were defined as voiding episodes associated with at least a moderate sensation of urgency on voiding diary
       Adjusted means (SE)7.65 (0.20)5.76 (0.20)5.07 (0.20)4.87 (0.20)4.96 (0.20)
       Median (IQR)6.7 (4.7–9.7)5.0 (2.3–8.0)4.7 (1.7–7.3)4.3 (1.7–6.7)4.3 (2.0–7.0)
      Severe urgency-associated voids per day
      Severe urgency-associated voids were defined as voiding episodes associated with a severe sensation of urgency on voiding diary
       Adjusted means (SE)3.44 (0.12)1.90 (0.12)1.29 (0.12)1.30 (0.13)1.38 (0.13)
       Median (IQR)2.3 (1.0–4.7)0.7 (0.0–2.7)0.7 (0.0–1.7)0.3 (0.0–1.7)0.7 (0.0–1.7)
      Self-report bladder-specific questionnaires
       OAB-q score
      OAB-q scores range from 0 to 100, with higher scores indicating more severe or bothersome overactive bladder symptoms;13,14
      Adjusted means (SE)36.70 (0.85)21.65 (0.85)15.39 (0.85)14.90 (0.86)14.86 (0.86)
      Median (IQR)33.6 (21.8–47.3)15.8 (6.7–31.5)9.7 (3.6–20.0)9.1 (3.6–18.8)8.5 (3.6–18.8)
       PPBC score
      PPBC scores range from 1 to 6, with higher scores indicating more severe bladder-related problems;14
      Adjusted means (SE)3.04 (0.06)2.12 (0.06)1.52 (0.06)1.49 (0.06)1.44 (0.06)
      Median (IQR)3.0 (2.0–4.0)2.0 (1.0–3.0)1.0 (1.0–2.0)1.0 (0.0–2.0)1.0 (0.0–2.0)
       PPUS score
      PPUS scores range from 1 to 3, with higher scores indicating greater urgency.15
      Adjusted means (SE)1.38 (0.03)1.01 (0.03)0.86 (0.03)0.80 (0.03)0.80 (0.03)
      Median (IQR)1.0 (1.0–2.0)1.0 (1.0–1.0)1.0 (0.0–1.0)1.0 (0.0–1.0)1.0 (0.0–1.0)
      IQR, interquartile range; OAB-q, Overactive Bladder Questionnaire; PPBC, Patient Perception of Bladder Condition; PPUS, Patient Perception of Urgency Scale; RCT, randomized, double-blind, placebo-controlled clinical trial; SE, standard error.
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      a RCT: the prerandomization visit of the 12 week RCT
      b Baseline open-label bladder diaries included data on RCT participants that had been on fesoterodine or placebo; all comparisons are significant at P < .001 compared with the initial RCT visit and adjusted for site, age, marital status, health status, parity, menopausal status, hysterectomy, urinary tract infection, smoking status, and current diuretic therapy
      c One participant failed to appear for the baseline open-label visit but was enrolled in open label at the subsequent visit
      d Values reflect events per day based on participant completion of a 3 day voiding diary
      e Self-report on diary as an urgency or stress incontinence episode
      f Interquartile range; medians are unadjusted
      g Self-report on the diary as to the time the participant went to bed for the evening and when the participant woke in the morning
      h Moderate urgency-associated voids were defined as voiding episodes associated with at least a moderate sensation of urgency on voiding diary
      i Severe urgency-associated voids were defined as voiding episodes associated with a severe sensation of urgency on voiding diary
      j OAB-q scores range from 0 to 100, with higher scores indicating more severe or bothersome overactive bladder symptoms;
      • Brown J.S.
      • McNaughton K.S.
      • Wyman J.F.
      • et al.
      Measurement characteristics of a voiding diary for use by men and women with overactive bladder.
      • Anderson R.U.
      • Mobley D.
      • Blank B.
      • Saltzstein D.
      • Susset J.
      • Brown J.S.
      Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group.
      k PPBC scores range from 1 to 6, with higher scores indicating more severe bladder-related problems;
      • Anderson R.U.
      • Mobley D.
      • Blank B.
      • Saltzstein D.
      • Susset J.
      • Brown J.S.
      Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group.
      l PPUS scores range from 1 to 3, with higher scores indicating greater urgency.
      • Matza L.S.
      • Thompson C.L.
      • Krasnow J.
      • Brewster-Jordan J.
      • Zyczynski T.
      • Coyne K.S.
      Test-retest reliability of four questionnaires for patients with overactive bladder: the overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ).
      We examined the difference in efficacy based on assignment (fesoterodine or placebo) in the RCT phase of the study. Although there were differences between groups at open-label baseline and 3 months, these differences disappeared at 6 and 9 months (data not shown).

      Satisfaction with treatment (efficacy)

      Nearly all participants who continued in the open-label self-dosing study reported being very satisfied or somewhat satisfied with the study medication at each follow-up visit (89%, 92%, and 93% at 3, 6, and 9 months, respectively) as well as the change in their urine leakage at each follow-up visit (93%, 92%, and 92% at 3, 6, and 9 months, respectively). The vast majority of women at each visit (98%, 98%, and 87% at 3, 6, and 9 months, respectively) reported that they would continue using fesoterodine.

      Adverse events (safety)

      Two hundred forty-one women (48%) experienced at least 1 moderate or severe adverse event, including dry mouth (6.0%), urinary tract infection (5.6%); or cold/flu (5.0%) (Table 3). Of these, 59 women experienced an anticholinergic adverse event that was plausibly related to the study medication; 15 reduced their medication dose, and 17 discontinued medication as a result of an adverse event. Twenty-six women experienced 1 or more serious adverse events; 1 of these (hospitalization for intestinal blockage) was identified as related to study treatment by the site principal investigator.
      Table 3Moderate and severe adverse events and PVR volume among women in the open-label study (n = 498)
      VariableValue
      Adverse events
      Adverse events were assessed in the 498 women who took at least 1 dose of the study drug and completed at least 1 follow-up visit. Common adverse events reported were as follows: dry mouth (n = 30); urinary tract infection (n = 28); cold/flu (n = 25); constipation (n = 23); dry throat (n = 10); back pain (n = 9); cough (n = 8); respiratory infection (n = 8); diarrhea (n = 7); headache (n = 7); runny/stuffy nose or sinus congestion (n = 7); bronchitis (n = 5); abdominal pain (n = 4); allergy (n = 4); heartburn (n = 4); hematuria (n = 4); back strain (n = 3); chest pain (n = 3); dry eyes (n = 3); dyspepsia (n = 3); kidney infection (n = 3); pneumonia (n = 3); sciatica (n = 3); shortness of breath (n = 3); sinus infection (n = 3); vertigo (n = 3); and weight gain (n = 3)
       Reported at least 1 moderate or severe adverse event, n (%)241 (48.4)
      Reported a potentially anticholinergic adverse event, n (%)
      Potentially anticholinergic adverse events were defined a priori as constipation, dry mouth, or self-reported urinary hesitancy or retention
      59 (11.9)
       Reported a serious adverse event, n (%)
      Serious adverse events were defined as adverse events that resulted in death, disability, or hospitalization
      26 (5.2)
       Serious adverse event possibly related to treatment, n (%)
      Serious adverse events possibly related to treatment were defined as serious adverse events that were rated by site investigators as having a possible, probable, or definite relationship to study medication
      1 (0.2)
      PVR volume
      PVR volume was measured at 3 or 9 months or early termination among women taking at least 1 dose of study medication. PVR data were unavailable for 20 participants (17 refused, and 3 were lost to follow-up).
       Mean (SD) PVR volume38.4 (48.3)
       PVR volume of ≥250 mL, n (%)3 (0.6)
      PVR, postvoid residual volume; SD, standard deviation.
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      a Adverse events were assessed in the 498 women who took at least 1 dose of the study drug and completed at least 1 follow-up visit. Common adverse events reported were as follows: dry mouth (n = 30); urinary tract infection (n = 28); cold/flu (n = 25); constipation (n = 23); dry throat (n = 10); back pain (n = 9); cough (n = 8); respiratory infection (n = 8); diarrhea (n = 7); headache (n = 7); runny/stuffy nose or sinus congestion (n = 7); bronchitis (n = 5); abdominal pain (n = 4); allergy (n = 4); heartburn (n = 4); hematuria (n = 4); back strain (n = 3); chest pain (n = 3); dry eyes (n = 3); dyspepsia (n = 3); kidney infection (n = 3); pneumonia (n = 3); sciatica (n = 3); shortness of breath (n = 3); sinus infection (n = 3); vertigo (n = 3); and weight gain (n = 3)
      b Potentially anticholinergic adverse events were defined a priori as constipation, dry mouth, or self-reported urinary hesitancy or retention
      c Serious adverse events were defined as adverse events that resulted in death, disability, or hospitalization
      d Serious adverse events possibly related to treatment were defined as serious adverse events that were rated by site investigators as having a possible, probable, or definite relationship to study medication
      e PVR volume was measured at 3 or 9 months or early termination among women taking at least 1 dose of study medication. PVR data were unavailable for 20 participants (17 refused, and 3 were lost to follow-up).
      Thirty-five women (including 26 of the 44 women who withdrew) stopped taking medication during the open-label study. Of these women, 20 reported discontinuing fesoterodine because the side effects were too bothersome, 13 because of no improvement, and 9 for another, nonspecific reason (women could select more than 1 reason). Six of these participants later restarted the study medication.
      Three participants had PVRs greater than 250 mL (1 at month 3 and 2 at month 9) and were scheduled for extended evaluations; 1 participant did not return for the evaluation. There was no difference in PVR based on measurement technique (ultrasound or catheter measurements, Kruskal-Wallis, P = .09).

      Summary of extended evaluations (safety)

      Eighty-three women were offered extended evaluations during the open-label study; 22 completed extended evaluations and 61 did not. There was no difference in having an indication for an extended evaluation or completing an extended evaluation based on treatment assignment in the RCT. The indications for the majority of the 61 declined extended evaluations were based on the women's decision to not continue fesoterodine (n = 58) rather than serious adverse events or an elevated PVR (Table 4). Five women had other health issues (eg, elevated blood pressure, discontinued contraception). Several chose to see their own physician instead of the site specialist.
      Table 4Summary of indications for the extended evaluation (ExE; n [%])
      May total greater than 100% because participants could have more than 1 reason for ExE
      Indication to ExEOffered ExE (n = 83)Completed ExE (n = 22)
      PVR volume >250 mL twice in 1 day3 (3)2 (9)
      Side effects too bothersome39 (43)9 (40)
      Symptoms did not improve32 (35)14 (64)
      Urinary tract infection1 (1)1 (5)
      Other
      Other reasons included physician recommendation, other health reasons, participant circumstances, wait and see what happens upon medication discontinuation, and other
      16 (19)0 (0)
      No reason
      One woman had an ExE with her private physician without having a study indication for ExE.
      1 (1)1 (5)
      ExE, extended evaluation; PVR, postvoid residual volume.
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      a May total greater than 100% because participants could have more than 1 reason for ExE
      b Other reasons included physician recommendation, other health reasons, participant circumstances, wait and see what happens upon medication discontinuation, and other
      c One woman had an ExE with her private physician without having a study indication for ExE.
      In 17 of the 22 completed extended evaluations, the site and central specialists agreed that the diagnosis based on the 3IQ was correct (urgency-predominant incontinence). In only 5 of the cases, the specialists decided that the participant's incontinence was misclassified by the 3IQ. Three women had other forms of incontinence (eg, incomplete emptying) and 2 women did not have incontinence. In 4 of the 22 completed evaluations, the site specialist and central specialist disagreed about the diagnosis and reached a consensus diagnosis after discussion. For all of the 22 evaluations, the site specialist and central specialist agreed that none of the missed diagnoses resulted in participant harm.

      Comment

      We conducted a 9 month, open-label follow-up study after a 12 week RCT to assess the longer-term safety and efficacy of antimuscarinic therapy in community-dwelling women diagnosed with UUI using a simple 3 item questionnaire, the 3IQ. To our knowledge, this study is the first of its kind to evaluate longer-term clinical outcomes associated with using a simple, questionnaire-based screening instrument to diagnose and treat UUI in women without more extensive specialist evaluation.
      These findings support the longer-term safety of using the 3IQ to guide treatment for UUI in women. Although 28 serious adverse events (in 26 women) were reported, only 1 case (0.2%) was considered possibly related to treatment. Based on a review of the completed specialist-based extended evaluations, a minority of participants (1%) were misdiagnosed as having UUI. If we extrapolate that rate to all of the 83 women offered extended evaluations, 4% of participants were possibly misdiagnosed. No participants experienced harm from the use of the 3IQ to make the initial diagnosis followed by treatment.
      Although 48% of the women experienced an adverse event, only 53 women in this study discontinued treatment, similar to the adverse event rate
      • Appell R.A.
      • Abrams P.
      • Drutz H.P.
      • Van Kerrebroeck P.E.
      • Millard R.
      • Wein A.
      Treatment of overactive bladder: long-term tolerability and efficacy of tolterodine.
      • Haab F.
      • Cardozo L.
      • Chapple C.
      • Ridder A.M.
      • Solifenacin Study Group
      Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome.
      • Kreder K.
      • Mayne C.
      • Jonas U.
      Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder.
      and discontinuation rates
      • Appell R.A.
      • Abrams P.
      • Drutz H.P.
      • Van Kerrebroeck P.E.
      • Millard R.
      • Wein A.
      Treatment of overactive bladder: long-term tolerability and efficacy of tolterodine.
      • Haab F.
      • Cardozo L.
      • Chapple C.
      • Ridder A.M.
      • Solifenacin Study Group
      Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome.
      • Kreder K.
      • Mayne C.
      • Jonas U.
      Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder.
      • Diokno A.
      • Sand P.
      • Labasky R.
      • et al.
      Long-term safety of extended-release oxybutynin chloride in a community-dwelling population of participants with overactive bladder: a one-year study.
      of other long-term UUI treatment studies in which participants had more extensive evaluations before initiating therapy. These adverse events (Table 3) are symptoms that primary care practitioners are comfortable assessing and treating and that occur routinely among primary care patients not taking antimuscarinics (eg, cold and flu, back strain). The reduction in UUI frequency was also similar to that seen in other long-term studies with more extensive evaluations for eligibility.
      • Appell R.A.
      • Abrams P.
      • Drutz H.P.
      • Van Kerrebroeck P.E.
      • Millard R.
      • Wein A.
      Treatment of overactive bladder: long-term tolerability and efficacy of tolterodine.
      • Kreder K.
      • Mayne C.
      • Jonas U.
      Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder.
      Overall, women in our study reported they were very satisfied with improvement in urine leakage, and the vast majority indicated that they would continue treatment.
      By 3 months, most women saw improvement in their incontinence, became bothered by medication side effects, or felt the need to change their medication dose. These results suggest that 3 months may be a sufficient time frame for an initial empiric trial of therapy after 3IQ diagnosis. In clinical practice, the patient and clinician should discuss next steps (eg, continued therapy, dose adjustment, flexible dosing, more extensive evaluation) after a 3 month medication trial.
      Our study has several limitations that deserve mention. Although we used a simple diagnostic tool that can be implemented in primary care, women were diagnosed within the context of a research study rather than primary care practices. As such, women were actively queried for side effects at regular intervals. When implementing the 3IQ in primary care, it would be useful to provide primary care practitioners with common antimuscarinic side effects as well as the 3IQ questions.
      The study was conducted with only 1 antimuscarinic medication, fesoterodine, and therefore, we cannot comment on safety, efficacy, or satisfaction with other medications in this class. In addition, what should be done next for the women who do not improve on fesoterodine, such as a trial of a second antimuscarinic medication or a referral to a specialist, cannot be answered by this study. In addition, this open-label study was conducted only in women, and it is not known whether the results can be generalized to men, in whom the 3IQ has not been validated, or in women who have less frequent UUI.
      Finally, we do not have data on the 20 of the 498 participants (4%) who did not attend an early termination or final study visit and cannot comment on safety, efficacy, or satisfaction with treatment in that group.
      For more than 15 years, recommendations have existed to increase diagnosis and treatment of incontinence in the primary care setting. Given new evidence of the safety and efficacy of using the 3IQ to diagnose incontinence type, there is reason to believe that a streamlined approach to diagnosing and treating UUI is likely to result in good clinical outcomes in community-dwelling women without major comorbidities. Increased access to treatment for women with UUI in primary care practices could have significant implications for women's quality of life.

      Acknowledgments

      We thank the BRIDGES participants. Drs Hess, Huang, and Brown and Mr Schembri had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The study funders provided no manuscript preparation assistance.

      Appendix

      Supplementary TableOpen-label study measures
      Study measureTime point
      Baseline randomized controlled trialBaseline open label2 week phone1 month3 months6 months9 months
      Or early termination
      3-day voiding diaryXXXXX
      PPBC
      The PPBC is a single-item measure scored on a 6 point Likert scale, with higher scores indicating more severe bladder-related problems;13,14
      XXXXX
      PPUS
      The PPUS is a single-item measure scored on a 3 point Likert scale, with higher scores indicating greater urgency;15
      XXXXX
      OAB-q
      The OAB-q is a 31 item instrument in which scores range from 0 to 100, with higher scores indicating more severe or bothersome overactive bladder symptoms;14
      XXXXX
      Patient-directed dose adjustmentXXXXX
      Adverse events (self-report)XXXXXXX
      PVRXXXX
      OAB-S
      The OAB-S is a validated disease-specific satisfaction measure our team adapted to assess participant satisfaction with treatment;19
      XXX
      Referral for extended evaluation (ExE)
      Extended evaluations were offered if the participant had 2 PVR volumes greater than 250 mL on the same day or the participant reported a lack of clinical improvement as captured on the OAB-S form or a safety issue was identified by the site principal investigator.
      XXX
      Medication distributionXXXXX
      ExE, extended evaluation; IQR, interquartile range; OAB-q, Overactive Bladder Questionnaire; OAB-S, Overactive Bladder Satisfaction; PPBC, Patient Perception of Bladder Condition; PPUS, Patient Perception of Urgency Scale; PVR, postvoid residual volume; SE, standard error.
      Hess. Questionnaire-based initiation of urgency urinary incontinence treatment. Am J Obstet Gynecol 2013.
      a Or early termination
      b The PPBC is a single-item measure scored on a 6 point Likert scale, with higher scores indicating more severe bladder-related problems;
      • Brown J.S.
      • McNaughton K.S.
      • Wyman J.F.
      • et al.
      Measurement characteristics of a voiding diary for use by men and women with overactive bladder.
      • Anderson R.U.
      • Mobley D.
      • Blank B.
      • Saltzstein D.
      • Susset J.
      • Brown J.S.
      Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group.
      c The PPUS is a single-item measure scored on a 3 point Likert scale, with higher scores indicating greater urgency;
      • Matza L.S.
      • Thompson C.L.
      • Krasnow J.
      • Brewster-Jordan J.
      • Zyczynski T.
      • Coyne K.S.
      Test-retest reliability of four questionnaires for patients with overactive bladder: the overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ).
      d The OAB-q is a 31 item instrument in which scores range from 0 to 100, with higher scores indicating more severe or bothersome overactive bladder symptoms;
      • Anderson R.U.
      • Mobley D.
      • Blank B.
      • Saltzstein D.
      • Susset J.
      • Brown J.S.
      Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group.
      e The OAB-S is a validated disease-specific satisfaction measure our team adapted to assess participant satisfaction with treatment;
      • Appell R.A.
      • Abrams P.
      • Drutz H.P.
      • Van Kerrebroeck P.E.
      • Millard R.
      • Wein A.
      Treatment of overactive bladder: long-term tolerability and efficacy of tolterodine.
      f Extended evaluations were offered if the participant had 2 PVR volumes greater than 250 mL on the same day or the participant reported a lack of clinical improvement as captured on the OAB-S form or a safety issue was identified by the site principal investigator.

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