Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial




Objective


The purpose of this study was to evaluate clinical outcomes associated with the initiation of treatment for urgency-predominant incontinence in women diagnosed by a simple 3-item questionnaire.


Study Design


We conducted a multicenter, double-blinded, 12-week randomized trial of pharmacologic therapy for urgency-predominant incontinence in ambulatory women diagnosed by the simple 3-item questionnaire. Participants (N = 645) were assigned randomly to fesoterodine therapy (4-8 mg daily) or placebo. Urinary incontinence was assessed with the use of voiding diaries; postvoid residual volume was measured after treatment.


Results


After 12 weeks, women who had been assigned randomly to fesoterodine therapy reported 0.9 fewer urgency and 1.0 fewer total incontinence episodes/day, compared with placebo ( P ≤ .001). Four serious adverse events occurred in each group, none of which was related to treatment. No participant had postvoid residual volume of ≥250 mL after treatment.


Conclusion


Among ambulatory women with urgency-predominant incontinence diagnosed with a simple 3-item questionnaire, pharmacologic therapy resulted in a moderate decrease in incontinence frequency without increasing significant urinary retention or serious adverse events, which provides support for a streamlined algorithm for diagnosis and treatment of female urgency-predominant incontinence.


Urinary incontinence affects up to one-third of adult women and is associated with depression, social isolation, physical inactivity, and institutionalization. Despite recommendations that nonspecialist clinicians assume a greater role in diagnosing and treating incontinence, rates of diagnosis and treatment outside of urology or urogynecology remain low.


One obstacle to the diagnosis and treatment of female incontinence is that professional organizations traditionally have recommended an extended evaluation to distinguish between the 2 most common types of incontinence in women: urgency and stress. In addition to a clinical history and urinalysis test, this evaluation includes a voiding diary, neurologic examination, pelvic examination, measurement of postvoid residual (PVR) volume, and cough stress test. Because there are approved medications to treat urgency but not stress incontinence, classification of incontinence has implications for treatment. However, the traditional extended evaluation to classify incontinence in women is not performed easily in primary care or general gynecology settings, which creates a barrier to treatment.


To address this problem, a simple 3-item, self-administered questionnaire (the 3 Incontinence Questions [3IQ]) was developed to identify and classify female incontinence ( Appendix , Supplementary Figure ). In a sample of 301 generally healthy women with ongoing incontinence symptoms, the 3IQ demonstrated good sensitivity and specificity in distinguishing between urgency and stress incontinence, compared with an extended evaluation. To examine the clinical consequences of using the 3IQ to guide treatment, we sought to examine the efficacy and safety of initiating pharmacologic therapy for urgency incontinence in women using a streamlined algorithm that was based on the 3IQ.


Materials and Methods


Study population


Participants were ambulatory women who were ≥18 years old who were recruited from the general community surrounding 13 clinical sites in the United States ( Supplementary Table 1 ). Women who reported clinically frequent incontinence during preliminary telephone screening (ie, ≥7 incontinence episodes per week in the past 3 months) were invited to come to an in-person visit to complete the 3IQ on paper to self-diagnose incontinence. Those who self-diagnosed as having urgency-predominant incontinence on the 3IQ (ie, those who indicated that they had incontinence that occurred most often when they “had the urge or the feeling that [they] needed to empty your bladder but could not get to the toilet fast enough”) were eligible to continue. Therefore, the study population consisted of women who indicated that they had either isolated urgency incontinence or mixed incontinence that was associated predominantly with urgency. Women completed the 3IQ on their own and did not receive assistance from research staff in diagnosing or classifying their incontinence. Consistent with the proposed use of the 3IQ in clinical practice, women subsequently underwent dipstick urinalysis testing to rule out urinary-tract infection or hematuria before enrollment; those who tested positive could return after completing treatment. Self-report bladder diaries were used to document baseline frequency of incontinence; those women whose diaries confirmed that they had at least 3 incontinence episodes in 3 days were eligible to continue.


Other eligibility criteria were selected to define a community-dwelling sample of women who would be considered appropriate for evaluation and treatment in primary care. Specifically, women were excluded if they self-reported complex medical histories that automatically would require a specialist evaluation for incontinence, such as antiincontinence surgery in the past 5 years, other pelvic surgery in the past 6 months, >3 urinary tract infections in the past year, lower urinary tract or rectal fistula, interstitial cystitis, symptomatic pelvic organ prolapse, urogenital cancer or radiation, congenital abnormality that leads to incontinence, or major neurologic disorder.


Because of the pharmacologic intervention that was used in this study, participants could not have specific contraindications to fesoterodine therapy (such as urinary or gastric retention, uncontrolled narrow-angle glaucoma, myasthenia gravis, severe ulcerative colitis, clinically significant hepatic or renal disease, toxic megacolon, potent CYP3A4 inhibitor treatment in the last 2 weeks, or pregnancy or nursing).


Randomization, masking, and treatments


Eligible women were allocated randomly in a 1:1 ratio to receive 12 weeks of pharmacologic treatment with flexible-dose fesoterodine therapy (Toviaz; Pfizer, Inc, New York, NY) 4-8 mg (fesoterodine group) or an identical placebo pill (placebo group) daily. Randomization was performed by computer in permuted blocks of 2-4 without stratification for clinical site. Active and placebo tablets were prepared by the University of California San Francisco pharmacy, where they were labeled by a pharmacist with randomization numbers and then distributed to clinical sites. Participants, clinical personnel, and statistical staff were masked to treatment assignment, and no unmasking occurred during the trial. All participants were asked to forgo other pharmacologic incontinence treatments and pelvic floor or bladder physical therapy for the 12-week trial period to avoid contamination of treatment effects.


According to previously established protocols for participant-directed dosing, participants were started initially on either fesoterodine 4 mg or an identical placebo pill daily. At their 2-week telephone call and their 4-week follow-up visit, women were offered the option of increasing their dose to fesoterodine 8 mg or an identical placebo daily. At their 8-week telephone call, they were invited to readjust their dose to a maximum of 8 or minimum of 4 mg daily.


Clinical efficacy outcomes


All clinical efficacy outcomes were assessed at baseline, 4 weeks, and 12 weeks. The primary efficacy outcome was a 12-week change in the average number of self-reported urgency incontinence episodes per day that were documented by a validated 3-day voiding diary in which women recorded all incontinence and voiding episodes and indicated which episodes were associated with a sensation of urgency (rated as none, mild, moderate, or severe). Secondary efficacy outcomes included a 12-week change in total incontinence frequency, diurnal and nocturnal voiding frequency, and frequency of voiding episodes that were associated with at least a moderate or severe sensation of urgency, also recorded in the voiding diary.


Additional secondary efficacy outcomes also included 12-week improvement in scores on validated questionnaires that assess the self-reported impact of women’s bladder symptoms: (1) the Overactive Bladder Questionnaire, a 33-item instrument that assesses symptom impact with a 100-point scale; (2) the Patient Perception of Bladder Condition, a single-item that assesses bladder problems with a 6-point Likert scale; (3) and the Patient Perception of Urgency Scale, a single-item measure that assesses perception of urinary urgency with a 3-point Likert scale.


Safety monitoring


Adverse events were assessed at all follow-up assessments at 2, 4, 8, and 12 weeks by asking participants to report any negative changes in their health. Adverse events that involved self-reported dry mouth, constipation, drowsiness, tachycardia, or urinary hesitancy or retention were classified as “potentially associated with antimuscarinic therapy.” Adverse events were considered to be “severe” if they prevented women from participating in any daily activities. Serious adverse events were defined as those that resulted in death, disability, or hospitalization. For all serious adverse events, site investigators used a standardized attribution scale to rate the likelihood of relationship to treatment.


Measurement of PVR volume was performed by bladder ultrasound scanning or catheterization at 12 weeks or early termination to provide objective assessment of posttreatment urinary retention. The protocol required women with a posttreatment PVR volume of ≥250 mL (confirmed by repeat assessment) to undergo an extended evaluation by a urology or urogynecology specialist at their site. Additionally, site investigators could refer participants for extended evaluations at any time in the event of a safety concern. The study was approved by the institutional review board at each site, and all participants provided written informed consent before enrollment. This trial was registered with clinicaltrials.gov ( NCT00862745 ).


Statistical analysis


A sample size of 636 participants was estimated to provide 90% power to detect a net reduction in the primary outcome of urgency incontinence frequency with a 2 sample t test and the assumption of a 15% drop-out rate. The effect size was based on pooled data from 2 previous trials that reported an average effect size of 0.92 episodes per day and a standard deviation of 3.2 episodes per day.


Baseline characteristics of participants in each treatment group were compared by the use of analysis of covariance models that were adjusted for clinical site. Changes in incontinence and voiding outcomes over 12 weeks were also examined using analysis of covariance, with adjustment for baseline values and site. Improvement in bladder-specific impact questionnaires was assessed by analysis of covariance to examine continuous change in questionnaires scores and by logistic regression to examine the odds of clinically meaningful improvement in scores (defined as an increase at least 10 points on the Overactive Bladder Questionnaire and at least 1 point on the Patient Perception of Bladder Condition and Patient Perception of Urgency Scale). For the primary analyses, only participants who took at least 1 dose of medication and provided follow-up data at ≥1 visits were included. Among those women who terminated the study early, the last postbaseline value of each outcome was carried forward to replace missing data at 12 weeks. Analyses were conducted without regard to adherence or final medication dosage.


Two additional sensitivity analyses were performed to address potential bias that was due to missing data through attrition or nonresponse. First, missing imputation analyses were performed on all participants with intent to treat. Twenty multiply-imputed datasets were created with the use of the Markov chain Monte Carlo method. Imputation models included demographics, treatment assignment, and interim (4-week) outcomes. Summary effect estimates and standard errors were computed by standard methods for imputed data. Second, complete case analyses were performed in which only participants with complete baseline and 12-week data were included.


Safety analyses compared the rates of (1) ≥1 adverse events, (2) ≥1 adverse events that were “potentially associated with antimuscarinic therapy,” (3) serious adverse events, and (4) posttreatment PVR volume of >250 mL between treatment groups, with the use of Fisher exact tests. All analyses were performed with SAS statistical software (version 9.1; SAS Institute Inc, Cary, NC).




Results


Participants and adherence


Between February 2009 and January 2010, 322 women were assigned randomly to receive fesoterodine therapy and 323 women were assigned randomly to receive placebo ( Figure ). All but 1 woman who was assigned to fesoterodine therapy and 2 women who were assigned to placebo took at least 1 dose of medication. Baseline characteristics of participants did not differ significantly by treatment assignment ( Table 1 ). The mean (±SD) age of participants was 56 ± 14 years old; the mean baseline frequency of urgency incontinence was 3.9 ± 3.0 episodes per day.




FIGURE


Recruitment, randomization, and retention in the BRIDGES trial

BRIDGES, BRinging simple urge Incontinence DiaGnosis and treatment to providerS; 3IQ, 3 incontinence questions.

Huang. Simplified diagnosis and treatment for urgency incontinence in women. Am J Obstet Gynecol 2012.


TABLE 1

Baseline characteristics of randomized participants by treatment assignment
































































































































Variable Fesoterodine (n = 322) Placebo (n = 323)
Demographic
Age, y a 56.2 ± 14.7 55.9 ± 14.2
Race/ethnicity, n b
White 215 (66.8) 212 (65.6)
Black 73 (22.7) 71 (22.0)
Latina/Hispanic 18 (5.6) 28 (8.7)
Asian/Pacific Islander 9 (3.0) 6 (1.9)
Multiethnic/other 7 (2.3) 6 (1.9)
Married, n (%) 141 (43.8) 133 (41.2)
Clinical
Excellent or very good overall health, n (%) c 255 (79.2) 252 (78.0)
Previous childbirth: parity ≥1, n (%) 256 (79.5) 256 (79.3)
No current menstrual periods, n (%) 229 (71.3) 229 (71.1)
History of hysterectomy, n (%) 99 (30.7) 95 (29.4)
Self-reported urinary tract infection in the past year, n (%) 50 (15.5) 50 (15.5)
Current cigarette smoking, n (%) 48 (14.9) 44 (13.7)
Current weekly alcohol consumption, n (%) 96 (29.9) 99 (30.7)
Current systemic hormone therapy, n (%) 35 (7.8) 27 (8.4)
Current stable diuretic therapy, n (%) 46 (14.3) 52 (16.1)
Incontinence/micturition
Urgency incontinence episodes per day a 3.8 ± 2.9 4.0 ± 3.0
Total incontinence episodes per day a 4.5 ± 3.4 4.8 ± 3.4
Diurnal voiding episodes per day a 8.6 ± 2.7 8.8 ± 3.1
Nocturnal voiding episodes per night a 1.3 ± 1.3 1.2 ± 1.2
Moderate urgency-associated voids per day a , d 7.5 ± 4.1 7.8 ± 4.5
Severe urgency-associated voids per day a , e 3.5 ± 3.3 3.7 ± 3.6
Bladder-specific questionnaires
Overactive Bladder Questionnaire score a , f 36.4 ± 20.8 36.8 ± 19.2
Patient perception of Bladder Condition score g , h 3.0 (3.0–4.0) 3.0 (2.0–4.0)
Patient perception of Urgency Scale score g , i 1.0 (1.0–2.0) 1.0 (1.0–2.0)

P > .05 for comparison of intervention and placebo groups for all variables listed.

Huang. Simplified diagnosis and treatment for urgency incontinence in women. Am J Obstet Gynecol 2012.

a Data are given as mean ± SD;


b Participants self-reported their primary racial/ethnic group as white/caucasian, black/African American, Latina/Hispanic, Asian, Pacific Islander, Native American/American Indian, or multiethnic;


c Assessed by asking women to rate their overall health as excellent, very good, good, fair, or poor;


d Defined as voiding episodes that were associated with at least a “moderate” sensation of urgency on voiding diary;


e Defined as voiding episodes that were associated with a “severe” sensation of urgency on voiding diary;


f Scores range from 0–100; higher scores indicate more severe or bothersome overactive bladder symptoms ;


g Data are given as median (interquartile range);


h Scores range from 1–6; higher scores indicate more severe bladder-related problems ;


i Scores range from 1–3, with higher scores indicating greater urgency.



Adherence to medication (which was assessed through pill counts) was similar in both treatment groups; 86.3% of women in the fesoterodine group and 87.0% in the placebo group completed 80% of the administrations ( P = .82). Of those in the fesoterodine group, final medication dosage was confirmed for 281 women who returned their unused pills. Ninety women (32.0%) remained at 4 mg dose for the entire study; 152 women (54.1%) increased to 8 mg and remained at this dose throughout the study, and 39 women (13.9%) increased to 8 mg but returned to 4 mg before the end of the study. Twenty-nine women in the fesoterodine group and 30 women in the placebo group discontinued the study medication during the 12-week trial ( Figure ).


Clinical efficacy outcomes


Follow-up data on urinary incontinence were obtained for 303 women in the fesoterodine group (94.4%) and 301 women in the placebo group (93.2%). Women with missing follow-up data tended to be younger (mean age, 50 ± 18 vs 56 ± 14 years old; P = .04), nonwhite (58.5% vs 32.1%; P = .02), and unmarried (77.0% vs 56.1%; P = .005) but did not differ from women who contributed follow-up data with respect to other characteristics, which included baseline incontinence frequency or bladder-specific questionnaire scores.


Over the 12-week study period, urgency incontinence frequency decreased by 0.9 more episodes per day among women in the fesoterodine group vs the placebo group ( P < .001; Table 2 ). Compared with placebo, women who were assigned to fesoterodine therapy also reported greater decreases in total incontinence frequency, diurnal and nocturnal voiding frequency, and frequency of voids that were associated with moderate or severe urgency, and also reported greater improvement in scores on bladder-specific impact questionnaires ( Table 3 ). Treatment effects on incontinence frequency were not changed significantly in analyses that used multiple imputation to account for missing data in participants with intent to treat ( Supplementary Table 2 ) or in complete case analyses in which women without complete data were excluded ( Supplementary Table 3 ).



TABLE 2

Change in urinary incontinence and other voiding outcomes per day over 12 weeks by treatment assignment






















































































































Variable Fesoterodine (n = 303) Placebo (n = 301) Least square mean difference (95% CI) a P value a
Urgency incontinence episodes per day
Mean ± SD –2.5 ± 2.5 –1.8 ± 2.7 –0.9 (–1.2 to –0.5) < .001
Median (IQR) –2.0 (–3.7 to –1.0) –1.3 (–2.7 to –0.3)
Total incontinence episodes per day
Mean ± SD –2.9 ± 2.7 –2.1 ± 2.9 –1.0 (–1.3 to –0.6) < .001
Median (IQR) –2.3 (–3.7 to –1.0) –1.7 (–3.3 to –0.7)
Diurnal voiding episodes per day
Mean ± SD –0.8 ± 2.3 –0.5 ± 2.3 –0.4 (–0.7 to –0.1) .03
Median (IQR) –1.0 (–2.0 to –0.7) –0.3 (–1.3 to –0.7)
Nocturnal voiding episodes per day
Mean ± SD –0.5 ± 1.1 –0.2 ± 1.2 –0.2 (–0.4 to –0.1) .006
Median (IQR) –0.3 (–1.0 to 0.0) –0.3 (–0.7 to –0.3)
Voids associated with at least moderate urgency b
Mean ± SD –2.1 ± 3.8 –1.4 ± 3.9 –0.9 (–1.4 to –0.3) .001
Median (IQR) –1.7 (–4.0 to 0.0) –0.7 (–3.0 to 0.7)
Voids associated with severe urgency c
Mean ± SD –1.7 ± 2.9 –1.4 ± 3.0 –0.6 (–0.9 to –0.2) .005
Median (IQR) –1.3 (–3.0 to 0.0) –1.0 (–2.3 to 0.0)

CI, confidence interval; IQR , interquartile range.

Huang. Simplified diagnosis and treatment for urgency incontinence in women. Am J Obstet Gynecol 2012.

a Derived from analysis of covariance models, adjusted for baseline level of symptoms as well as clinical site;


b Defined as voiding episodes that were associated with either a “moderate” or “severe” sensation of urgency on voiding diary;


c Defined as voiding episodes that were associated with a “severe” sensation of urgency on voiding diary.



TABLE 3

Improvement in Bladder-Specific Impact Questionnaire scores over 12 weeks by treatment assignment







































Questionnaire Average change in questionnaire scores Participants with “meaningful” improvement in scores a
Fesoterodine (n = 303) b Placebo (n = 301) b Least square mean difference (95% CI) c Fesoterodine (n = 303) a , d Placebo (n = 301) a , d Odds ratio (95% CI) e
Overactive Bladder Questionnaire f −17.1 ± 17.6 −12.0 ± 16.6 −5.58 (−8.01 to −3.16) 181 (63.1) 140 (49.3) 1.81 (1.19–2.77)
Patient perception of bladder condition g −1.2 ± 1.2 −0.6 ± 1.2 −0.50 (−0.69 to −0.32) 188 (65.5) 142 (49.8) 2.04 (1.42–2.93)
Patient perception of urgency scale h −0.5 ± 0.8 −0.3 ± 0.6 −0.21 (−0.12 to −0.30) 132 (46.0) 90 (31.6) 2.61 (1.73–3.96)

CI, confidence interval.

Huang. Simplified diagnosis and treatment for urgency incontinence in women. Am J Obstet Gynecol 2012.

a Defined as at least 10-point increase in Overactive Bladder Questionnaire score, at least 1-point increase in Patient Perception of Bladder Condition score, and at least 1-point increase in Patient Perception of Urgency Scale score;


b Data are given as mean ± SD;


c Derived from analysis of covariance models, adjusted for baseline questionnaire scores and clinical site;


d Data are given as number (percentage);


e Obtained through logistic regression models, adjusted for baseline proportion of the outcome and clinical site;


f A 31-item instrument in which scores range from 0–100; higher scores indicate more severe or bothersome overactive bladder symptoms ;


g A single-item measure scored on a 6-point Likert scale; higher scores indicate more severe bladder-related problems ;


h A single-item measure scored on a 3-point Likert scale; higher scores indicate greater urgency.

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May 15, 2017 | Posted by in GYNECOLOGY | Comments Off on Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial

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