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.
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. 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. 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. Women reporting incontinence tend to be referred to specialists prior to being offered treatment, 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. 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. In this trial, women who flexibly dosed 4-8 mg of fesoterodine daily reported fewer urgency incontinence episodes over 12 weeks compared with placebo.
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. 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, 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.
Participants also completed validated questionnaires assessing the self-reported impact of their bladder symptoms, including the following: (1) the Overactive Bladder Questionnaire (OAB-q), a 33 item instrument assessing bladder symptom impact; (2) the Patient Perception of Bladder Condition (PPBC) a single-item measure assessing the patient’s current perception of her bladder problems; and (3) and the Patient Perception of Urgency Scale (PPUS), 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. 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.
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).
| Demographic | Value |
|---|---|
| Mean (SD) age (y) | 56.9 (13.8) |
| Race/ethnicity, n (%) b | |
| White | 340 (68.3) |
| Black | 103 (20.7) |
| Latina | 11 (2.2) |
| Asian/Pacific Islander | 32 (6.4) |
| Multiethnic/other | 12 (2.4) |
| Married, n (%) | 223 (44.8) |
| Clinical | |
| Excellent or very good overall health, n (%) c | 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) |
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.
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.
| Variable | RCT baseline a (n = 498) | Open label | |||
|---|---|---|---|---|---|
| Open label baseline b (n = 497) c | Month 3 (n = 491) | Month 6 (n = 464) | Month 9 (n = 454) | ||
| From 3 day voiding diaries d | |||||
| Urgency incontinence episodes per day e | |||||
| 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) f | 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 g | |||||
| 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 h | |||||
| 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 i | |||||
| 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 j | |||||
| 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 k | |||||
| 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 l | |||||
| 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) |
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;
k PPBC scores range from 1 to 6, with higher scores indicating more severe bladder-related problems;
l PPUS scores range from 1 to 3, with higher scores indicating greater urgency.
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