To determine the course of overactive bladder (OAB) symptoms after 4 weeks of no treatment following a 12-week study of the efficacy and safety of flexible-dose fesoterodine in patients with OAB who were enrolled in the UK healthcare system. There are limited data available on the natural time course of OAB symptoms after the cessation of treatment.
Patients and methods
In the open-label UK Study Assessing Flexible-dose Fesoterodine in Adults trial, patients aged ≥18 years with self-reported OAB symptoms for ≥3 months, a mean of at least eight micturitions per 24 h and three or more urgency episodes per 24 h on a 3-day bladder diary at baseline, and at least moderate bladder-related problems reported on the Patient Perception of Bladder Condition (PPBC) at baseline, were treated with fesoterodine for 12 weeks.
All patients received fesoterodine 4 mg once daily for the first 4 weeks, at which time they could choose to increase the dose to 8 mg once daily, based on a discussion of treatment efficacy and tolerability with the investigator, or they could remain on fesoterodine 4 mg for the remaining 8 weeks.
The 12-week treatment period was followed by a 4-week follow-up period of no fesoterodine treatment.
Patients completed 3-day bladder diaries and the PPBC at baseline, week 4, end of treatment (week 12) and end of the follow-up period (week 16); the King's Health Questionnaire at baseline, end of treatment (week 12) and end of the follow-up period (week 16); and the Benefit, Satisfaction and Willingness to Continue questionnaire at week 12.
After 12 weeks of fesoterodine treatment, patients had clinically meaningful improvements in bladder diary variables and King's Health Questionnaire domains; 79% (254/322) of patients reported an improvement on the PPBC.
After 4 weeks of no treatment, most patients deteriorated back to week 4 levels or worse on all bladder diary and patient-reported outcomes.
Patients who expressed a benefit from fesoterodine treatment, satisfaction with their treatment or a willingness to continue treatment showed greater improvement from baseline to week 12 and greater deterioration from week 12 to week 16 than patients who did not respond positively on the Benefit, Satisfaction and Willingness to Continue questionnaire.
Both men and women showed a meaningful deterioration in bladder diary variables and patient-reported outcomes at week 16; baseline symptom severity, age and week 4 dose escalation status did not appear to affect outcome deterioration at week 16.
At 4 weeks after fesoterodine was discontinued, patients showed an increase in the frequency of OAB symptoms, an increase in the severity of bladder-related problems and a reduction in health-related quality of life.
Many patients with OAB who respond to antimuscarinics may require treatment for more than 12 weeks because symptoms recur as early as 4 weeks after the cessation of therapy.
Study Assessing Flexible-Dose Fesoterodine in Adults
urgency urinary incontinence
Urinary Sensation Scale
Overactive bladder (OAB) is a bothersome condition that negatively affects many aspects of health-related quality of life (HRQL), including physical function, emotional well-being, social and sexual relationships, and work productivity [1-3]. Antimuscarinics are currently the first-line pharmacological treatment for patients with OAB symptoms . In clinical trials, the antimuscarinic fesoterodine has been shown to significantly improve bladder diary variables, HRQL and other patient-reported outcomes in subjects with OAB [5-10].
As seen with patients with other chronic conditions, adherence to long-term medication prescriptions among patients with OAB is suboptimal [11, 12]. The limited evidence available suggests that any improvements in OAB symptoms achieved during treatment will deteriorate after the withdrawal of antimuscarinic medication [13, 14]; however, there is little information available regarding the factors that influence this deterioration. Additionally, treatment guidelines for OAB and urgency urinary incontinence (UUI), such as those provided by the International Consultation on Incontinence and the European Association of Urology [4, 15, 16], do not provide recommendations regarding the duration of antimuscarinic treatment. The present study aimed to assess changes in bladder diary variables, HRQL and self-reported severity of bladder-related symptoms in patients with OAB during the 4-week no-treatment period of the previously reported UK Study Assessing Flexible-Dose Fesoterodine in Adults (SAFINA)  trial that followed the 12-week fesoterodine treatment period.
Patients and Methods
The 12-week open-label SAFINA trial was conducted at 39 sites in the UK from February 2009 to January 2010 (ClinicalTrials.gov identifier: NCT00806494). All patients were treated with fesoterodine 4 mg once daily for the first 4 weeks. At week 4, based on a discussion of treatment efficacy and tolerability between the patient and the investigator, the investigator could increase the fesoterodine dose to 8 mg once daily for those patients who sought greater symptom improvement and reported good tolerability. No further dose adjustments were allowed during the remaining 8 weeks of treatment. After the 12-week treatment period, patients completed a 4-week no-treatment follow-up period, during which they did not receive fesoterodine.
The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and also in compliance with the International Conference on Harmonisation Good Clinical Practice Guidelines. All local regulatory requirements were followed, especially those protecting the safety of the study participants. Written informed consent was obtained from each patient before the start of any protocol-specified procedure.
Men and women outpatients aged ≥18 years were eligible for enrolment in the SAFINA trial if they had self-reported OAB symptoms for ≥3 months before screening, a mean of at least eight micturitions and three or more urgency episodes per 24 h as verified in a 3-day bladder diary completed before baseline, and self-report of at least some moderate bladder-related problems on the Patient Perception of Bladder Condition (PPBC) at baseline. Urgency episodes were defined as micturitions rated ≥3 on the five-point Urinary Sensation Scale (USS) .
Key exclusion criteria included neurological conditions that could have an impact on OAB symptoms; stage 3 or greater pelvic organ prolapse; a history of lower urinary tract surgery within the past 6 months, interstitial cystitis or a significant pain component associated with OAB symptoms; haematuria; bladder outlet obstruction; history of acute urinary retention requiring catheterization; symptoms of incontinence considered as being predominantly a result of stress urinary incontinence; urinary tract infection; treatment with antimuscarinic OAB medication within 2–3 weeks before baseline; and intermittent or unstable use of diuretics, α-blockers, tricyclic antidepressants, oestrogen therapy and 5-α-reductase inhibitors (or initiation within 2 weeks before baseline or during the study). Women who were pregnant, lactating, intending to become pregnant or of childbearing potential and not using an appropriate method of contraception also were ineligible.
Each patient completed a 3-day bladder diary at baseline and week 4, week 12 (end of treatment) and week 16 (end of follow-up) in which they recorded the time that they arose and went to bed, the time of all micturitions and incontinence pad use, and rated the sensation associated with each micturition using the five-point USS (1 = no urgency, 5 = UUI) . Bladder diary endpoints assessed included changes per 24 h in the mean number of micturitions, nocturnal micturitions, urgency episodes (USS rating ≥3), severe urgency episodes (USS rating ≥4), UUI episodes and incontinence pad use.
Patients also completed the PPBC at baseline, week 4, week 12 and week 16, and the King's Health Questionnaire (KHQ) at baseline, week 12 and week 16. The PPBC is a self-administered, single-item, validated questionnaire that patients use to describe the severity of their bladder-related problems on a scale from 1 (no problems at all) to 6 (many severe problems) . The KHQ is a 21-item, self-administered quality-of-life questionnaire with nine domains (general health perception, incontinence impact, role limitations, physical limitations, social limitations, personal relationships, emotions, sleep/energy, severity of urinary symptoms) . A change of five points on the KHQ domains represents the minimal important difference or the smallest change that is clinically meaningful to the patient .
Patients completed the Benefit, Satisfaction and Willingness to Continue (BSW) questionnaire at week 12. The BSW is a three-item questionnaire designed to assess a patient's impression of treatment benefit, satisfaction with treatment and willingness to continue treatment .
All patient-reported outcomes were analyzed using the full analysis set, defined as patients who took one or more dose of study medication and had baseline and post-baseline data for one or more efficacy endpoint during the study. Some patients who discontinued between weeks 12 and 16 provided data at the time of withdrawal. Missing values were imputed using the last observation carried forward method. Endpoints based on changes from baseline to week 12 (end of treatment) and week 12 to week 16 (end of follow-up) were summarized descriptively, including mean, sd and 95% CI values. Changes in PPBC responses were summarized using frequency counts and percentages. Collection of data and endpoints at week 16 were prespecified in the protocol, as were the analyses of overall changes from week 12 to week 16. However, other exploratory subgroup analyses using the data collected at week 16 were conducted post hoc.
Of 418 patients screened, 331 patients were randomized and treated with fesoterodine, 281 (85%) patients completed 12 weeks of treatment and 251 (76%) completed the 16-week study. Thus, of the 80 patients who withdrew before study completion, 50 (15%) withdrew during the 12-week active-treatment period and 30 (9%) withdrew during the 4-week no-treatment follow-up period. Forty-nine (15%) patients withdrew for reasons not related to study treatment and 31 (9%) withdrew for reasons related to study treatment (adverse events, n = 25; lack of efficacy, n = 6). The reasons for discontinuation among the 30 patients who withdrew during the no-treatment follow-up period were lost to follow up (n = 7), no longer willing to participate (n = 2), protocol violation (n = 5) and ‘other’ (n = 16); most of those who withdrew for ‘other’ reasons indicated that they were not willing to be off treatment. The baseline demographics and clinical characteristics of the enrolled patients are shown in Table 1.
Table 1. Baseline demographics and clinical characteristics (n = 331)
At week 4, 195 of the 331 (59%) patients elected to increase their fesoterodine dose from 4 mg to 8 mg. After 12 weeks of treatment with flexible-dose fesoterodine, patients showed clinically meaningful improvements from baseline in all bladder diary variables and KHQ domain scores, except for General Health Perception, and more than 75% of patients reported improvement on the PPBC. The improvements in bladder diary variables observed at week 12 were not maintained at week 16, 4 weeks after fesoterodine was discontinued (Fig. 1). By week 16, all bladder diary variables returned to a level similar to that observed after 4 weeks of treatment (Fig. 2). On the KHQ, increases in scores (indicating a worsening HRQL) were observed on all nine domains between week 12 and week 16 (Fig. 3). With the exception of the General Health Perception domain, these increases exceeded the five-point minimal important difference , suggesting a clinically meaningful deterioration in HRQL after treatment cessation. On the PPBC, 160 (61%) patients reported a worsening of the severity of their bladder-related condition during the 4-week no-treatment period, 74 (28%) patients had no change and 27 (10%) patients reported an improvement in their bladder condition (Fig. 4).
At week 16 (after 4 weeks of no fesoterodine treatment), each assessed bladder diary variable was worse than or equal to the levels observed at week 4 for most patients (Table 2). A plot of micturition frequency at baseline against the change in micturition frequency between week 12 and week 16 showed that the baseline severity of micturition frequency did not appear to be related to the amount of its deterioration after treatment cessation (Fig. 5). Both men and women showed deterioration in bladder diary variables, PPBC scores and KHQ domain scores; women tended to show greater deterioration in some outcomes, although differences in the number of patients (men, n = 51; women, n = 209) render any comparison difficult (Table 3). Patients' age and whether or not patients had increased the fesoterodine dose from 4 mg to 8 mg at week 4 generally did not appear to influence the level of deterioration in either bladder diary variables or patient-reported outcomes (Table 3).
Table 2. Comparison of response at week 16 with response at week 4
Bladder diary variable
Week 16 response same or worse than week 4 response, n (%)
UUI, urgency urinary incontinence.
Nocturnal micturitions/24 h
Urgency episodes/24 h
Severe urgency episodes/24 h
UUI episodes/24 h
Incontinence pad use/24 h
Table 3. Changes in outcomes from week 12 to week 16 by sex, age and dose escalation status
Men (n = 51)
Women (n = 209)
<65 years (n = 161)
≥65 years (n = 99)
Maintained 4-mg dose at week 4 (n = 105)
Escalated to 8-mg dose at week 4 (n = 155)
PPBC, Patient Perception of Bladder Condition; UUI, urgency urinary incontinence.
Bladder diary variables per 24 h, mean (95% CI)
Severe urgency episodes
Incontinence pads used
King's Health Questionnaire score, mean (95% CI)
General health perception
The magnitude of symptom worsening seen at week 16 did appear to be related to how much benefit patients derived from treatment, how satisfied they were with treatment and their willingness to continue treatment (based on responses on the BSW questionnaire). Patients who reported ‘much benefit’, were ‘very satisfied’ with treatment and who were ‘very willing’ to continue treatment had a greater worsening of all diary variables and KHQ domain scores than did those who reported that they did not benefit from treatment, were not satisfied with treatment and did not wish to continue treatment (Fig. 6). Similarly, 71% (154/216) of all patients who reported an improvement in bladder-related problems on the PPBC from baseline to week 12 reported a worsening of bladder-related problems from week 12 to week 16, whereas only 13% (6/45) of patients who reported no change or worsening of bladder-related problems from baseline to week 12 reported a deterioration from week 12 to week 16.
In the 12-week SAFINA trial, fesoterodine decreased the number of micturitions per 24 h (primary endpoint) compared to baseline in patients with OAB symptoms. Similar results were seen for the secondary bladder diary endpoints (urgency, nocturnal micturitions, UUI and incontinence pad use). Improvement from baseline also was observed in KHQ and PPBC scores.
In clinical practice, many patients receive treatment for OAB for ≤3 months. However, there are few data available in the literature on the consequences of stopping OAB treatment at this time point. In the present study, we examined the impact of fesoterodine treatment cessation on bladder diary variables and KHQ and PPBC scores in men and women enrolled in the SAFINA trial who completed a 4-week follow-up period during which no active treatment was given. Improvements observed during 12 weeks of treatment deteriorated during the no-treatment period.
Neither baseline micturition frequency, nor age appeared to be associated with the magnitude of deterioration in bladder diary variable frequency or KHQ domain scores. Whether or not patients chose to dose escalate at week 4 also did not appear to affect deterioration in bladder diary variables or KHQ scores; this is important because data from the present study, as well as other studies, have shown that dose escalation is associated with greater baseline symptom severity and a poorer response to treatment before the dose escalation choice point [17, 23, 24]. However, the treatment response at week 12 was generally similar between patients who did and did not dose escalate at week 4. Both men and women showed a meaningful deterioration in bladder diary variable frequency and KHQ domain scores after treatment cessation. The level of deterioration in some outcomes appeared to be greater among women, although differences in the number of men (n = 51) and women (n = 209) in the present study make it difficult to draw meaningful conclusions from this comparison. Notably, patients with a greater perceived treatment benefit at the end of the 12-week treatment period, as reflected by positive responses on the BSW, did show greater deterioration in bladder diary variable frequency and KHQ scores than patients with negative responses.
These findings generally confirm and expand upon the results of previous studies on the effect of antimuscarinic cessation conducted in women with OAB. In one study, 68 women with OAB symptoms were treated with propiverine 20 mg daily; those who showed improvement after 4 weeks of treatment received an 8 additional weeks of treatment followed by a 4-week period of no treatment. Similar to the present study, overactive bladder symptoms were significantly improved after the 12-week treatment period, and then deteriorated significantly over 4 weeks of no treatment to a level comparable to that observed after 4 weeks of treatment . Of the 68 women, 35% reported a worsening of symptoms and requested to resume propiverine at the end of the no-treatment period. Patients who requested to resume treatment were significantly older and had significantly higher scores on the Indevus Urgency Severity Scale at baseline than patients who did not request further treatment; there was no difference in baseline micturition frequency or nocturia between patients who did and did not request to resume treatment .
In a study of 108 women with OAB, patients who initially responded to 1 month of treatment with tolterodine extended release (ER) 4 mg once daily were randomly assigned to either discontinue tolterodine ER or continue treatment for an additional 2 or 5 months, after which all patients discontinued tolterodine ER and entered a 3-month no-treatment follow-up period . Bladder diary variables, Overactive Bladder Questionnaire Symptom Bother and HRQL scores, PPBC scores and Urgency Perception Scale scores were significantly improved at the end of treatment, and the level of improvement did not differ by treatment duration. After 3 months of treatment cessation, all outcomes significantly worsened compared to the end of the treatment period, regardless of whether patients had been treated for 1, 3 or 6 months; 49% of the women experienced symptom relapse within 1 month and 62% within 3 months of treatment discontinuation. Fifty-three percent requested retreatment after 1 month and 65% did so after 3 months. Baseline HRQL score was the only predictor of retreatment.
Another study evaluated 307 women with UUI who were randomized to receive 10 weeks of treatment with tolterodine ER 4 mg once daily alone or tolterodine ER combined with behavioural training, followed by cessation of tolterodine ER treatment . Although a higher proportion of women in the combination treatment group than in the tolterodine ER only group achieved a ≥70% reduction in UUI episodes at week 10, behavioural training did not help women maintain the reduction in UUI episodes after tolterodine ER was discontinued.
The results reported in the present study have important implications for clinical practice, and the British National Formulary guidance  regarding the duration of antimuscarinic treatment for OAB may need further review in light of our findings. The data from the present study provide prospective evidence that the beneficial effects on OAB symptoms and patient-reported outcomes after 12 weeks of treatment with an antimuscarinic drug are not maintained as early as 4 weeks after treatment is stopped. Therefore, many patients may need treatment for longer than 12 weeks; additional research is needed to provide guidance on the appropriate duration of treatment. Perhaps counterintuitively, patients experiencing the greatest subjective benefit and satisfaction with treatment after 12 weeks (i.e. those who may appear to the clinician to be most ready to discontinue treatment) may show the greatest deterioration after treatment cessation.
An important strength of the SAFINA trial is that the open-label, flexible-dose study design reflects fesoterodine treatment in a clinical-practice setting in the UK. Unlike previous studies examining the effect of treatment cessation on OAB symptoms, the SAFINA study population was not limited to women or to those who showed a significant response after 4 weeks of antimuscarinic treatment. Based on individual patient response and tolerability to fesoterodine 4 mg once daily at week 4, the fesoterodine dose could be increased to 8 mg once daily, similar to the real-world decision process of clinicians and patients regarding fesoterodine dose titration to optimize treatment efficacy and tolerability. A possible limitation of the present study is that open-label treatment does not permit an assessment of the effects of placebo. Additionally, the withdrawal of 22 patients after the 12-week active treatment phase as a result of an unwillingness to participate in the 4-week no-treatment phase may have biased the results toward a better outcome after treatment discontinuation because these patients may have had the greatest need for treatment.
In summary, OAB treatment with a flexible-dose fesoterodine regimen decreased micturition frequency, nocturnal micturitions, urgency episodes, UUI episodes and incontinence pad use after 12 weeks of treatment. Analyses aiming to understand the impact of cessation of fesoterodine after 12 weeks of treatment showed that all bladder diary variables, severity of bladder-related problems and HRQL deteriorated shortly after the last dose of fesoterodine was taken. The week 12 BSW response (but not baseline micturition frequency or dose escalation status) appeared to be related to a worsening of outcomes after treatment cessation. Further research is needed to help identify those patients who may benefit from a longer duration of antimuscarinic treatment.
The authors gratefully acknowledge the contributions of Imran Kausar. The present study was sponsored by Pfizer Inc. Editorial assistance was provided by Patricia B. Leinen, and Colin P. Mitchell, from Complete Healthcare Communications, Inc. and was funded by Pfizer Inc.