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Keywords:

  • fesoterodine;
  • overactive bladder syndrome;
  • urgency urinary incontinence;
  • frequency

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Study Type – Therapy (RCT) Level of Evidence 1b

OBJECTIVES

To determine whether baseline urgency urinary incontinence (UUI) episodes predict the need for increased doses of fesoterodine in patients with overactive bladder (OAB), as clinicians would benefit from data that help to predict which patients require higher doses of antimuscarinics to manage UUI episodes.

PATIENTS AND METHODS

In this pooled analysis of data from two double-blind, placebo-controlled trials, patients were randomized to placebo or fesoterodine 4 or 8 mg for 12 weeks and stratified into tertiles (>0–<2, 2–<4, or ≥4) according to the number of UUI episodes/24 h as recorded in 3-day bladder diaries at baseline. The change in mean UUI episodes/24 h from baseline to end of study was assessed using analysis of covariance.

RESULTS

In a post hoc analysis of data from two clinical trials, there were significant reductions from baseline in UUI episodes for fesoterodine 4 and 8 mg vs placebo in patients (n) with >0–<2 (422), 2–<4 (424) and ≥4 (481) UUI episodes at baseline (all P < 0.01). In patients with 2–<4 and ≥4 UUI episodes at baseline, fesoterodine 8 mg gave significantly greater mean reductions (−1.92 and −4.17, respectively) vs fesoterodine 4 mg (−1.43 and −3.31) (P < 0.05). The most common adverse events were dry mouth (placebo, 8%; fesoterodine 4 mg, 19%; and 8 mg, 35%) and constipation (placebo, 2%; fesoterodine 4 mg, 5%; and 8 mg, 6%).

CONCLUSION

Fesoterodine 4 and 8 mg significantly reduced UUI episodes vs placebo; this effect appeared to be greater with fesoterodine 8 mg in patients with ≥2 UUI episodes/24 h at baseline. Fesoterodine was well tolerated, although higher doses increased the incidence of adverse events. These findings might aid the clinical identification of patients with OAB who would most benefit from increasing the dose of fesoterodine from 4 to 8 mg.


Abbreviations
(U)UI

(urgency) urinary incontinence

OAB

overactive bladder

5-HMT

5-hydroxymethyl tolterodine

AE

adverse event

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Antimuscarinic agents are effective and generally well-tolerated in the management of the overactive bladder (OAB), but the treatment response varies considerably among patients and individual agents [1]. The reduction in episodes of urgency urinary incontinence (UUI) with antimuscarinic treatment was reported at 43–77%, with up to 57% of patients achieving complete dryness based on bladder diaries [2–4].

Increases in the dose of antimuscarinic medication should provide additional therapeutic benefits for many patients with OAB [5], but the results of dose-escalation studies with antimuscarinic agents in the treatment of OAB have yielded mixed results. In a parallel fixed-dose study, controlled-release oxybutynin 15 mg was significantly more effective than the 10- or 5-mg dose in reducing UUI episodes [6]. By contrast, the results of fixed-dose studies for solifenacin [2,7], and fixed- and flexible-dose studies for darifenacin [3,8,9] in the treatment of OAB have shown no clear and consistent therapeutic benefit with higher dosing. However, in a recently published fixed-dose pooled study, fesoterodine 8 mg was statistically significantly more effective than the 4-mg dose in reducing UUI and urgency episodes/24 h, mean volume voided/void, treatment response, and continent days/week [10].

Fesoterodine, a new nonselective oral antimuscarinic agent, exerts its pharmacological effects as a competitive muscarinic receptor antagonist. Fesoterodine undergoes rapid and extensive conversion by nonspecific esterases to its active moiety, 5-hydroxymethyl tolterodine (5-HMT) [11,12]. 5-HMT is also the active metabolite of tolterodine [13,14], but metabolism of tolterodine to 5-HMT requires cytochrome P450 2D6–mediated oxidation in the liver [15].

To date, clinical studies have offered no clear guidance that would identify which patients with OAB would benefit from higher antimuscarinic drug dosing. The ability of clinicians to predict therapeutic outcomes to antimuscarinic therapies based on the number of UUI episodes would enhance the practical management of OAB. The primary purpose of this pooled analysis was to further investigate the potential clinical implications of varying the dose of fesoterodine by examining the reduction in UUI episodes/24 h based on fesoterodine dose (4 or 8 mg) in patients stratified by baseline UUI frequency.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The treatment protocol for this study was described in detail previously [10]. This pooled analysis included data from two multicentre, double-blind, placebo-controlled trials [16,17]. In one study, patients were randomized to receive placebo, fesoterodine 4 mg or 8 mg, or tolterodine extended-release 4 mg daily for 12 weeks [16]. For the current analysis, data from the tolterodine arm were not included. In the other study, patients were randomized to receive placebo, fesoterodine 4 mg, or fesoterodine 8 mg daily for 12 weeks [17].

Eligible subjects reported OAB (urinary frequency, eight or more voids/24 h) and urinary urgency (six or more episodes during a 3-day diary evaluation) or UUI (three or more episodes during a 3-day diary evaluation), and at least moderate bladder-related problems on a 6-point Likert scale [18]. The current analysis included only incontinent patients (>0 UUI episodes/24 h at baseline).

Key exclusion criteria included the presence of lower urinary tract pathology that could, in the investigator’s opinion, trigger urgency or UI (e.g. significant stress UI, urolithiasis, interstitial cystitis, urothelial tumours); pelvic organ prolapse ≥ grade III; clinically relevant BOO; a postvoid residual urine volume of >100 mL; polyuria (>3 L/24 h); symptomatic or recurrent UTIs; current treatment with antimuscarinic agents; a neurogenic cause for OAB symptoms; clinically relevant arrhythmia, unstable angina, or a QTcB interval >500 ms; current treatment; or treatment within the past 4 weeks with electrostimulation or bladder training.

The efficacy analysis was based on the number of UUI episodes/24 h from a 3-day bladder diary completed before randomization (baseline) and at 12 weeks or end of the study. The primary endpoint was the change in the number of UUI episodes/24 h from baseline to week 12 or end of the study, stratified by the number of baseline UUI episodes recorded in the 3-day bladder diaries at baseline as: >0–<2, 2–<4, and ≥4. The UUI frequency thresholds used in this study were intended to divide the patients with UI into approximate tertiles, thus maximizing the statistical power for detecting between-group differences.

A parametric analysis was used, by analysis of covariance with treatment and region as factors and baseline value as a covariate; nonparametric analysis was by the Wilcoxon rank sum test. The last-observation-carried-forward method was used to impute missing values for early withdrawals. Safety was assessed for all patients who took at least one dose of trial medication after randomization.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

In all, 1327 patients with UI (baseline UUI frequency >0) were included in the current analysis, with 422, 445 and 460 randomized to placebo, fesoterodine 4 mg or 8 mg, respectively (Table 1). The patients were primarily women (≈82%) and white (≈89%). The mean time from the first OAB diagnosis was ≈9 years; only 5–6% of patients had been diagnosed with OAB for <1 year. About half the patients had previously received pharmacological treatment for OAB, and thus, those patients included in this analysis had long-standing OAB.

Table 1.  The baseline demographic and clinical characteristics by treatment group*
Mean (sd) or n (%) characteristicPlaceboFesoterodine, mg
48
  • *

    Safety population (patients who took one or more dose of study medication) with at least one UUI episode/24 h at baseline.

  • The proportion of patients reporting that >33% of total volume voided in the baseline period occurred during sleeping time.

No. of patients422445460
Women346 (82)364 (82)381 (83)
Age, years   
 <65281 (67)289 (65)300 (65)
 ≥65141 (33)156 (35)160 (35)
Race   
 White374 (89)386 (87)411 (89)
 Black 22 (5) 23 (5) 22 (5)
 Asian  7 (2)  7 (2)  6 (1)
 Other 19 (5) 29 (7) 21 (5)
Body mass index, kg/m2 29.3 (7.1) 29.1 (6.7) 28.7 (6.1)
Relative nocturnal polyuria 77 (18.2) 85 (19.1) 87 (18.9)
Previous OAB treatment221 (52.4)216 (48.5)231 (50.2)
Time since OAB diagnosis, years  8.7 (9.7)  9.3 (10.9)  9.2 (10.7)

At baseline, 422, 424 and 481 patients had a 24-h UUI episode frequency of >0–<2, 2–<4 or ≥4, respectively (Table 2). Patients with UUI frequencies of ≥4 were somewhat older (≈61 years) than those with frequencies of >0–<2 (≈56 years) or 2–<4 (≈58 years). Also, a greater proportion of patients with ≥4 UUI episodes were women (86%) than those with >0–<2 (79%) or 2–<4 (82%) episodes. Those patients with ≥2 UUI episodes/24 h tended to have a higher incidence of relative nocturnal polyuria (defined as the proportion of patients reporting that >33% of total volume voided in the baseline period occurred during sleeping time) than those with >0–<2 episodes (Table 2).

Table 2.  Baseline demographic and clinical characteristics by number of UUI episodes*
Characteristic, n (%)UUI episodes per 24-h
>0–<22–<4≥4
  • *

    Safety population (patients who took at least one dose of study medication with at least one UUI episode/24 h at baseline.

  • The proportion of patients reporting that >33% of total volume voided in the baseline period occurred during sleeping time.

No. of patients422424481
Women332 (79)347 (82)412 (86)
Age, years   
 <65306 (73)293 (69)271 (57)
 =65 116 (27)131 (31)210 (43)
Race   
 White370 (87)368 (87)433 (90)
 Black 28 (7) 19 (4) 20 (4)
 Asian  6 (1)  5 (1)  9 (2)
 Other 18 (4) 32 (6) 19 (4)
Relative nocturnal polyuria 63 (15) 79 (19)107 (22)
Previous OAB treatment184 (44) 211 (50)273 (57)

At the end of treatment, for all UUI groups combined, fesoterodine 4 and 8 mg produced significantly (P < 0.01) greater reductions in mean UUI episodes than placebo, and fesoterodine 8 mg yielded significantly (P < 0.05) greater reductions than fesoterodine 4 mg (Table 3).

Table 3.  The change from baseline to end of treatment in number of UUI episodes/24 h stratified by number of baseline UUI episodes
UUI episodes/24 hPlaceboFesoterodine, mg
48
  1. LS, least squares; *P < 0.01 vs placebo; P < 0.05 vs fesoterodine 4 mg.

No. of patients 416 427 441
(>0)    
 Mean n UUI episodes at baseline    3.7    3.9    3.8
 LS mean change  −1.12  −1.85*  −2.33*†
 Median change, % −42.9 −75.0* −83.3*†
>0–<2n135 130 147
 Mean n UUI episodes at baseline    1.1    1.0    1.1
 LS mean change  −0.06  −0.55*  −0.63*
 Median change, % −50.0−100.0*−100.0*
2–<4n137 144 132
 Mean n UUI episodes at baseline    2.7    2.8    2.7
 LS mean change  −0.86  −1.43*  −1.92*†
 Median change, % −44.4 −68.3* −85.7*†
≥4n144 153 162
 Mean n UUI episodes at baseline    7.0    7.3    7.0
 LS mean change  −2.23  −3.31*  −4.17*†
 Median change,% −37.2 −61.5* −70.7*

Among patients with >0–<2 UUI episodes/24 h at baseline, both fesoterodine 4 and 8 mg significantly reduced UUI episodes relative to placebo; there was no significant difference between active treatment groups. Among patients with 2–<4 or ≥4 UUI episodes/24 h at baseline, both active treatments produced significant reductions compared with placebo (P < 0.01), and fesoterodine 8 mg gave significantly greater reductions than fesoterodine 4 mg (P < 0.05). The magnitude of the mean reduction in UUI episodes was greatest in patients with ≥4 UUI episodes at baseline, as was the difference in mean reduction in UUI episodes between fesoterodine 8 mg vs 4 mg groups (Fig. 1).

image

Figure 1. Least squares mean (sem) (A) and relative (median percentage, B) change from baseline to end of treatment in number of UUI episodes/24 h stratified by number of baseline UUI episodes. FESO, fesoterodine; LS, least squares mean; PBO, placebo. *P < 0.01 vs PBO; †P < 0.05 vs FESO 4 mg.

Download figure to PowerPoint

In the current analysis, which included incontinent patients treated with either placebo or fesoterodine, the safety and tolerability results were similar to those in previous studies [10]. The most common adverse events (AEs), dry mouth and constipation, were dose-related (Table 4). Overall, the percentage of patients experiencing at least one treatment-emergent AE was similar among UUI groups: >0–<2 (54%), 2–<4 (56%) and ≥4 (58%). There was no substantial change in the incidence of dry mouth based on the number UUI episodes at baseline (Table 4). The incidence of dry mouth in the three tertile groups was 33%, 40% and 33%, respectively, for patients receiving fesoterodine 8 mg; and 20%, 16% and 20%, respectively, for those receiving fesoterodine 4 mg.

Table 4.  Treatment-emergent AEs by treatment at end of study and number of baseline UUI episodes*
UUI episodes/24 hPlaceboFesoterodine, mg
48
>0–<22–<4≥4Total>0–<22–<4≥4Total>0–<22–<4≥4Total
  1. AA, alanine aminotransferase; GGT, γ-glutamyltransferase; URTI, upper respiratory tract infection. *AEs occurring in ≥2% of patients receiving fesoterodine.

No. of patients137138147422131149165445154137169460
AE, n (%)
Any AE61 (45)60 (44)75 (51)196 (46)74 (57)80 (54)97 (59)251 (56)93 (60)96 (70)108 (64)297 (65)
Dry mouth10 (7)15 (11)7 (5)32 (8)26 (20)24 (16)33 (20)83 (19)50 (33)55 (40)56 (33)161 (35)
Constipation2 (2)5 (4)2 (1)9 (2)10 (8)6 (4)5 (3)21 (5) 11 (7)7 (5)9 (5)27 (6)
UTI7 (5)3 (2)5 (3)15 (4)3 (2)5 (3)7 (4)14 (3)5 (3)4 (3)14 (8)23 (5)
Headache3 (2)7 (5)4 (3)14 (3)10 (8)4 (3)6 (4)20 (5)5 (3)3 (2)3 (2) 11 (3)
Dyspepsia003 (2)3 (<1)2 (2)03 (2)5 (1)1 (<1)2 (2)6 (4)9 (2)
Nausea02 (1)4 (3)6 (1)1 (<1)2 (1)1 (<1)4 (<1)1 (<1)6 (4)2 (1)9 (2)
Dry eye00003 (2)02 (1)5 (1)7 (5)2 (2)1 (<1)10 (2)
Dry throat00001 (<1)2 (1)2 (1)5 (1)1 (<1)3 (2)5 (3)9 (2)
URTI3 (2)5 (4)1 (<1)9 (2)4 (3)8 (5)2 (1)14 (3)4 (3)1 (<1)2 (1)7 (2)
AA increase01 (<1)2 (1)3 (<1)01 (<1)2 (1)3 (<1)1 (<1)3 (2)3 (2)7 (2)
GGT increase01 (<1)01 (<1)01 (<1)1 (<1)2 (<1)3 (2)3 (2)1 (<1)7 (2)
Cough02 (1)1 (<1)3 (1)3 (2)2 (1)2 (1)5 (1)3 (2)1 (<1)1 (<1)5 (1)
Dysuria1 (<1)01 (<1)2 (<1)3 (2)3 (2)1 (<1)7 (2)02 (2)3 (2)5 (1)
Dizziness4 (3)2 (1)3 (2)9 (2)1 (<1)2 (1)3 (2)6 (1)01 (<1)4 (3)5 (1)
Keratoconjunctivitis02 (1)001 (<1)001 (<1)4 (3)1 (<1)1 (<1)6 (1)
Nasopharyngitis1 (<1)2 (1)5 (3)8 (2)6 (5)2 (1)5 (3)13 (3)3 (2)02 (1)5 (1)
Influenza2 (2)1 (<1)2 (1)5 (1)4 (3)3 (2)3 (2)10 (2)1 (<1)1 (<1)1 (<1)3 (<1)
Back pain1 (<1)1 (<1)02 (<1)4 (3)2 (1)5 (3) 11 (3)2 (1)01 (<1)3 (<1)

In this 12-week study, 66 patients (5%) discontinued before study completion as a result of AEs (placebo, 13, 3%; fesoterodine 4 mg, 21, 5%; fesoterodine 8 mg, 32, 7%). For patients receiving fesoterodine 8 mg, the discontinuation rate due to AEs was lower in patients with ≥4 UUI episodes at baseline than in the other groups (Table 5).

Table 5.  Discontinuations due to AEs by treatment and number of baseline UUI episodes
AEs, n (%)24-h UUI episodes
>0–<22–<4≥4
Treatment
Placebo 4 (3) 0 9 (6)
Fesoterodine 4 mg 5 (4) 6 (4)10 (7)
Fesoterodine 8 mg14 (9)12 (9) 6 (4)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The results of this analysis confirm previous findings that fesoterodine 8 mg has better efficacy on several key OAB measurements, e.g. the reduction in UUI episodes, than fesoterodine 4 mg [10], and extend those findings by showing that fesoterodine 8 mg is more effective in patients stratified by the number of UUI episodes at baseline. Notably, because patients were randomized to treatment groups, within each UUI stratum, the demographic characteristics of patients in the fesoterodine 4- and 8-mg groups were closely matched. The demographic characteristics of patients within the UUI strata were also generally similar, although there tended to be a higher proportion aged ≥65 years in the ≥4 UUI group.

While fesoterodine 4 and 8 mg significantly reduced UUI episodes compared with placebo, regardless of the number of baseline 24-h UUI episodes, the reduction in patients with 2–<4 or ≥4 UUI episodes at baseline was significantly greater in those receiving fesoterodine 8 mg than 4 mg. Therefore, the 8-mg dose of fesoterodine might provide additional clinical benefit over the 4-mg dose in patients with ≥2 UUI episodes/24 h. Further, the results imply that the number of daily UUI episodes at baseline might be a clinically useful factor to help predict which patients can benefit from a higher fesoterodine dose.

The results of this study are consistent with the mechanism of action of fesoterodine. 5-HMT, the active metabolite of fesoterodine, has a balanced nonselective antimuscarinic action against M2 and M3 muscarinic receptor subtypes in the bladder, with only minimal difference in affinity for these sites [19]. Recent in vivo study findings discerned a correlation between increases in certain muscarinic receptor subtypes in the human bladder and clinical symptoms in OAB; M2 and M3 subtype increases correlated with scores of urgency including UI, and the M2 subtype correlated with urinary frequency scores [20]. Further, in phase I studies, fesoterodine had a dose-dependent pharmacokinetic profile [19] and low pharmacokinetic variability [21]. Together, these findings provide a mechanistic basis for more beneficial effects with fesoterodine 8 mg on UUI episodes.

Fesoterodine was generally well tolerated, and the most common AEs (dry mouth and constipation) are typical of the anticholinergic drug class for OAB [22], and dose-related. The incidence of dry mouth, the most common AE, increased from 19% in the 4-mg group to 35% in the 8-mg group, with most cases being mild to moderate in severity; discontinuation rates due to dry mouth were low (<1%). The incidence of constipation, the second most common AE, had only a modest increase from 5% with fesoterodine 4 mg to 6% with fesoterodine 8 mg. The M3 receptor subtype, which predominates over the M2 subtypes in the gastrointestinal tract, mediates gastrointestinal motility [19,23]. The absence of preferential affinity for any specific muscarinic receptor subtype with fesoterodine [19] might be responsible for the low rate of constipation.

No notable increase in AEs, e.g. dry mouth or constipation, was apparent based on the number of UUI episodes at baseline within either fesoterodine dose group. Rather, fesoterodine dose was related to the increased incidence of AEs. Interestingly, the influence of baseline UUI severity might have affected the decision of a patient to continue with treatment, because the study discontinuation rate due to AEs was lower in patients with ≥4 UUI episodes at baseline than in those with fewer episodes. These findings suggest a favourable tolerability profile for fesoterodine in patients who require higher doses to optimally manage at least two UUI episodes daily. This might have been manifested as a reduced discontinuation rate and might in clinical practice produce a higher compliance rate.

This post hoc analysis included substantially many patients (1327) and represented a broad spectrum of those with OABs. Among OAB symptoms, UUI tends to be particularly bothersome [24,25] and has a substantial negative effect on the heal-related quality of life of patients with OAB [26]. Thus, it is perhaps not unexpected that baseline UUI severity is a good predictor of the optimum fesoterodine dose in many patients with OAB. However, the lack of a significant difference between the fesoterodine 4-mg and 8-mg doses in patients with >0–<2 UUI episodes might be due to a ‘floor effect’. Further, there is evidence that the OAB symptom(s) that cause the most bother varies among individuals [27]; therefore UUI severity alone might not predict the optimum dose for every patient with OAB. Clinicians should also discuss the level of bother or impact of individual OAB symptoms with their patients, or perhaps ask the patient to complete a brief, user-friendly questionnaire to assess symptom bother, such as the Overactive Bladder-Validated 8, the Overactive Bladder Bother Rating Scale, or the Self-Assessment Goal Achievement Questionnaire [28–30], as well as patient tolerability, and use this information in addition to UUI severity to guide prescribing decisions for individual patients.

In conclusion, phase III studies showed better efficacy with fesoterodine 8 mg than 4 mg in several key OAB outcomes. In the present analysis, reductions in UUI episodes with fesoterodine were more profound in patients with 2–<4 or ≥4 daily UUI episodes at baseline. The results provide guidance for clinicians in predicting which patients might benefit from the 8-mg dose to receive the best treatment outcome: in patients with at least two daily UUI episodes, the 8-mg fesoterodine dose might provide greater benefit than the 4-mg dose.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This study was sponsored by Pfizer Inc. Editorial support was provided by Simon Slater, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Linda Cardozo is a paid consultant for Pfizer Inc.; Vik Khullar is a paid consultant and investigator for Pfizer Inc.; Joseph T. Wang and Zhonghong Guan are employees of Pfizer Inc.; Peter K. Sand is an investigator, advisor and speaker for Pfizer Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES
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