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Keywords:

  • antimuscarinic;
  • fesoterodine;
  • gender;
  • health-related quality of life;
  • overactive bladder;
  • tolterodine

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Objective

  • To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men.

Subjects and Methods

  • Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed.
  • Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h.
  • Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo.
  • Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the ‘diary-dry’ rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary).
  • The primary endpoint was the change from baseline to week 12 in UUI episodes.

Results

  • At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n = 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005).
  • Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001).
  • In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04).
  • The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%).
  • Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%).

Conclusion

  • This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women.
  • In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Antimuscarinics are used as first-line pharmacological treatment for overactive bladder (OAB) [1]. One of the most frequently prescribed antimuscarinic medications is extended-release (ER) tolterodine, which has been shown to markedly improve OAB symptoms and health-related quality of life (HRQL) [2-4]. The maximum approved once-daily dose of ER tolterodine is 4 mg, with a 2-mg dose for certain populations including patients with mild to moderate hepatic impairment or severe renal impairment [5]. The 4-mg maximum dose may be limiting, as it does not allow titration to a higher dose.

Cytochrome P450 (CYP) enzymes, primarily CYP 2D6 in most individuals, metabolize tolterodine into 5-hydroxymethyl tolterodine (5-HMT) in the liver [6]. Both tolterodine and 5-HMT exert antimuscarinic activity, but the metabolic efficiency of CYP 2D6 varies markedly among individuals [7, 8], leading to variability among patients in exposure to the active moieties of tolterodine and 5-HMT [6]. 5-HMT is also the active metabolite of fesoterodine; however, fesoterodine is rapidly and extensively hydrolysed by non-specific esterase pathways into 5-HMT, such that antimuscarinic activity after oral administration of fesoterodine is primarily attributable to 5-HMT [9]. Thus, fesoterodine is associated with less interindividual variability in drug exposure to 5-HMT compared with tolterodine [10, 11]. Fesoterodine has two approved doses, 4 mg and 8 mg once daily, which allows additional flexibility and therapeutic options for patients with OAB [12, 13]. Both doses have been shown to be effective and well tolerated [14, 15].

Fesoterodine and ER tolterodine significantly reduce urgency urinary incontinence (UUI) episodes and improve key bladder diary variables and measures of HRQL, symptom bother and other patient-reported outcomes compared with placebo [14-16]. Currently, there is a growing emphasis on comparative effectiveness research that establishes the clinical value of one treatment over another [17]. Two 12-week, placebo-controlled, head-to-head studies have demonstrated the superiority of the maximum available dose of fesoterodine (8 mg) over the maximum available dose of ER tolterodine (4 mg) for improving bladder-diary variables and HRQL in patients with OAB symptoms [18, 19]. In the present study, we report a prespecified pooled analysis of data from these two head-to-head studies to evaluate the efficacy of fesoterodine 8 mg compared with that of ER tolterodine 4 mg among women and men.

Subjects and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

This was a prespecified sub-group analysis of data from men and women enrolled in two identically designed, 12-week, randomized, placebo-controlled, head-to-head studies [18, 19]. Eligible participants were aged ≥18 years with self-reported OAB symptoms for ≥3 months and a mean of ≥1 UUI episode and ≥8 micturitions per 24 h in 3-day bladder diaries at baseline.

The study participants were randomly assigned to fesoterodine 8 mg, ER tolterodine 4 mg, or placebo in a 2:2:1 ratio. Participants randomized to fesoterodine started treatment on the 4-mg dose for 1 week; all participants in this group then had their dose titrated to fesoterodine 8 mg for the remaining 11 weeks of the study. The ER tolterodine group received 4 mg once daily for 12 weeks. Those starting on placebo or ER tolterodine received sham dose escalation at week 1. To maintain blinding, a double-dummy design was used; all participants received one tablet (fesoterodine or matching placebo) and one capsule (ER tolterodine or matching placebo) daily.

Both studies were approved by the appropriate institutional review boards or independent ethics committees and followed the International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent before entering the study.

The 3-day bladder diaries were completed at baseline, and at weeks 1, 4 and 12. Subjects recorded the time of each micturition, time of rising and going to bed, and degree of urgency associated with each void. The degree of urgency was based on the five-point Urinary Sensation Scale (USS) on which a score of 1 = no urgency, 2 = mild urgency, 3 = moderate urgency, 4 = severe urgency, 5 = UUI. Urgency episodes were defined by a USS score ≥3 and severe urgency episodes by a USS score ≥4. Voided volume of each micturition was recorded on a single day of the 3-day diary. Nocturnal micturitions were defined as micturitions recorded between the time the individual went to bed until he or she arose to start the next day.

The Patient Perception of Bladder Condition (PPBC) [20], a validated measure of bladder-related problems rated from 1 (no problems at all) to 6 (many severe problems), and the Urgency Perception Scale (UPS) [21], a validated measure of overall urgency associated with typical urination rated as 1 (‘usually not able to hold urine’), 2 (‘usually able to hold urine until reaching a toilet if I go immediately’), or 3 (‘usually able to finish what I am doing before going to the toilet’), were completed at baseline and weeks 1, 4 and 12. The OAB questionnaire (OAB-q) [22], a validated HRQL measure with an eight-item Symptom Bother scale and a 25-item HRQL scale with four domains (Concern, Coping, Sleep and Social Interaction), was completed at baseline and at week 12. All scales and domain scores were transformed to range from 1–100. Higher Symptom Bother scores indicate greater bother, and higher HRQL scores indicate better HRQL. The minimally important difference that is clinically meaningful is 10 points for all scales and domains [23].

Treatment-emergent adverse events (TEAEs) were monitored during the studies and assessed descriptively.

The statistical methods and all endpoints were predefined in the pooled statistical analysis plan. The present analyses were performed separately for men and for women. Tolerability was assessed descriptively based on the safety analysis set, i.e. randomized individuals who took ≥1 dose of double-blind study drug. Efficacy was assessed using the full analysis set, i.e. those in the safety set who had ≥1 valid baseline or post-baseline efficacy assessment. Efficacy endpoints included the change from baseline to weeks 4 and 12 in the number of UUI episodes, total micturitions, nocturnal micturitions, urgency episodes, severe urgency episodes and frequency–urgency sum per 24 h; the change from baseline to weeks 4 and 12 in mean voided volume (MVV) per micturition; and the 3-day ‘diary-dry’ rate at weeks 4 and 12. Frequency–urgency sum was defined as the sum of USS ratings associated with all micturitions over the course of 24 h averaged over the diary period. The 3-day diary-dry rate at weeks 4 and 12 was defined as the proportion of participants with >0 UUI episodes in baseline bladder diaries who reported no UUI episodes in their week 4 and 12 diaries, respectively. The primary endpoint in both studies was the change from baseline to week 12 in the number of UUI episodes per 24 h.

In quality assurance audits conducted during the studies by the sponsor, significant Good Clinical Practice violations and data irregularities were identified for 107 participants from two sites in one study [18] and for 77 participants from three sites in the other study [19]; these individuals were excluded from all efficacy analyses. This decision was made before the database unblinding. These 184 individuals were also excluded from the pooled efficacy analyses, but were included in the pooled safety analysis set. Additionally, ∼1% of subjects in each treatment group reported a mean of <1 UUI episode per 24 h in their 3-day baseline diary, and were thus in violation of study inclusion criteria. These subjects were included in all safety and efficacy analyses except for changes in UUI episodes and 3-day diary-dry rates.

Treatment differences in all diary endpoints were assessed in a step-down fashion by first comparing fesoterodine with placebo, and then with ER tolterodine only if the difference vs placebo was significant. The pairwise comparison for ER tolterodine vs placebo was also performed. Regression diagnostics were performed for all diary endpoints to verify model assumptions, and quantile-quantile plots were used to determine whether any data were not normally distributed. The residuals derived from analyses of covariance for changes from baseline in UUI episodes, MVV and severe urgency episodes were not normally distributed (proportion of non-normal observations >5%), therefore, these endpoints were analysed using a Van Elteren test (a stratified Wilcoxon–Mann–Whitney test), stratified by protocol and baseline quartile of the diary variable analysed, as specified in the statistical analysis plan. Treatment mean changes were estimated using Winsorized means, calculated by replacing 5% of the sample distribution tails with values at the 5th and 95th percentiles, which are less sensitive to outliers in the sample distribution tails, while still being a robust estimator of the sample mean. The other diary endpoints and OAB-q scores are presented as least squares means; treatment differences were estimated using an analysis of covariance model with baseline value as covariate and treatment and study as factors. The Cochran–Mantel–Haenszel test stratified by study was used to assess treatment differences in 3-day ‘diary-dry’ rate and categorical changes in PPBC scores and UPS scores. Missing post-baseline data were imputed based on the last-observation-carried-forward principle; baseline data were not carried forward. All tests were two-sided based on an α-level of 5%.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Subjects

A total of 4129 participants were randomized (3453 women and 676 men); 4108 subjects received treatment (3435 women and 673 men) and were included in this pooled analysis (Fig. 1). Discontinuation rates were similar in women and men; 324 (9.4%) women (fesoterodine, n = 141; ER tolterodine, n = 123; placebo, n = 60) and 76 (11.5%) men (fesoterodine, n = 38; ER tolterodine, n = 21; placebo, n = 17). Baseline demographic and clinical characteristics were generally similar among the treatment groups and between men and women (Table 1). The MVV per micturition appeared to be higher among men than women at baseline. Baseline UUI appeared to be more severe in women; a greater proportion of women reported that they were ‘not able to hold urine’ on the UPS (∼40 vs ∼25%) at baseline and women reported more UUI episodes per 24 h than men (2.6 vs 2.1).

figure

Figure 1. Disposition of participants. *Includes protocol violation, not meeting entrance criteria, and other reasons.

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Table 1. Baseline demographic and clinical characteristics
 WomenMenOverall
PlaceboER tolterodineFesoterodinePlaceboER tolterodineFesoterodinePlaceboER tolterodineFesoterodine
  1. *Demographic data represent the safety set. Baseline diary variable data represent the full analysis set for all subjects reporting the symptoms at baseline (Women: placebo, n = 643; ER tolterodine, n = 1315; fesoterodine, n = 1307; Men: placebo, n = 132; ER tolterodine, n = 268; fesoterodine, n = 259; Overall: placebo, n = 775; ER tolterodine, n = 1583; fesoterodine, n = 1566); Patient-reported outcome data represent the full analysis set.

No. of patients*6791382137413327526581216571639
Mean (sd) age, years58.5 (13.2)57.8 (13.4)57.5 (13.0)61.8 (13.9)60.8 (14.1)59.8 (14.3)59.1 (13.4)58.3 (13.5)57.9 (13.2)
Range18.0–95.018.0–90.018.0–90.021.0–85.019.0–92.021.0–89.018.0–95.018.0–92.018.0–90.0
Women, n (%)      679 (84)1382 (83)1374 (84)
Men, n (%)      133 (16)275 (17)265 (16)
Race, n (%)         
White549 (81)1093 (79)1102 (80)96 (72)199 (72)181 (68)645 (79)1292 (78)1283 (78)
Asian52 (8)116 (8)110 (8)27 (20)54 (20)58 (22)79 (10)170 (10)168 (10)
Black28 (4)68 (5)67 (5)3 (2)7 (3)11 (4)31 (4)75 (5)78 (5)
Other50 (7)105 (8)95 (7)7 (5)15 (6)15 (6)57 (7)120 (7)110 (7)
Mean (sd) OAB duration, years7.0 (7.8)7.0 (8.0)7.1 (8.2)5.5 (5.6)4.7 (4.5)5.3 (7.1)6.8 (7.5)6.7 (7.6)6.8 (8.1)
Range0.3–73.40.3–68.40.3–66.20.3–34.20.2–28.40.3–55.30.3–73.40.2–68.40.3–66.2
Subjects with >0 UUI episodes/24 h at baseline, n (%)670 (99)1363 (99)1356 (99)131 (99)272 (99)260 (98)801 (99)1635 (99)1616 (99)
Bladder diary variables, mean (sd)         
UUI episodes per 24 h2.6 (2.1)2.6 (2.2)2.6 (2.1)2.1 (1.7)2.2 (1.9)2.1 (1.7)2.5 (2.1)2.5 (2.1)2.5 (2.1)
MVV per micturition, mL146.2 (56.5)145.3 (59.5)148.3 (58.2)155.0 (54.9)154.6 (59.1)159.8 (55.8)147.7 (56.3)146.9 (59.5)150.1 (58.0)
Total micturitions per 24 h11.7 (3.2)11.7 (3.2)11.7 (3.3)12.2 (3.6)12.2 (3.0)11.9 (3.2)11.8 (3.2)11.8 (3.2)11.7 (3.2)
Nocturnal micturitions per 24 h2.2 (1.3)2.2 (1.3)2.2 (1.3)2.3 (1.2)2.3 (1.2)2.5 (1.5)2.2 (1.3)2.2 (1.3)2.2 (1.3)
Urgency episodes per 24 h9.4 (3.9)9.5 (3.7)9.5 (3.9)9.4 (4.4)9.8 (3.6)9.7 (3.9)9.4 (4.0)9.5 (3.6)9.5 (3.9)
Severe urgency episodes per 24 h6.0 (3.6)6.1 (3.6)6.2 (3.9)5.5 (3.6)6.2 (3.6)6.1 (3.6)5.9 (3.6)6.1 (3.6)6.2 (3.9)
Frequency–urgency sum per 24 h40.8 (13.8)41.0 (13.4)41.1 (14.6)40.7 (14.1)42.1 (12.4)41.1 (13.3)40.8 (13.9)41.2 (13.2)41.1 (14.4)
PPBC score, n (%)         
1 – No problems at all3 (1)7 (1)4 (<1)3 (2)2 (1)1 (<1)6 (1)9 (1)5 (<1)
2 – Some very minor problems14 (2)39 (3)31 (2)5 (4)7 (3)9 (4)19 (3)46 (3)40 (3)
3 – Some minor problems42 (7)74 (6)86 (7)8 (6)20 (8)23 (9)50 (7)94 (6)109 (7)
4 – Some moderate problems201 (32)437 (34)417 (32)48 (36)94 (36)101 (40)249 (32)531 (34)518 (34)
5 – Severe problems280 (44)547 (42)541 (42)57 (43)111 (42)92 (36)337 (44)658 (42)633 (41)
6 – Many severe problems96 (15)200 (15)216 (17)11 (8)31 (12)27 (11)107 (14)231 (15)243 (16)
UPS score, n (%)         
1 – Not able to hold urine264 (42)535 (41)533 (41)37 (28)67 (25)60 (24)301 (39)602 (38)593 (38)
2 – Able to hold urine (without leaking) until I reach a toilet if I go immediately347 (55)725 (56)720 (56)90 (68)185 (69)173 (68)437 (57)910 (58)893 (58)
3 – Able to finish the ongoing work before going to the toilet (without leaking)25 (4)44 (3)42 (3)5 (4)15 (6)20 (8)30 (4)59 (4)62 (4)
Mean (sd) OAB-q score         
Symptom bother58.3 (18.8)59.8 (19.7)59.4 (19.9)56.3 (17.0)55.3 (17.8)54.8 (17.6)58.0 (18.5)59.0 (19.5)58.6 (19.6)
Total HRQL55.1 (21.7)53.3 (22.6)54.5 (21.9)56.4 (20.3)58.3 (21.7)60.2 (20.5)55.3 (21.4)54.2 (22.5)55.4 (21.7)
Concern50.8 (24.4)48.7 (25.8)49.5 (25.3)53.4 (22.5)56.8 (25.3)58.3 (23.1)51.2 (24.1)50.1 (25.9)50.9 (25.2)
Coping47.6 (26.2)45.8 (26.9)47.4 (26.2)51.4 (23.0)52.0 (25.7)54.3 (24.4)48.2 (25.7)46.9 (26.8)48.5 (26.0)
Sleep54.0 (25.5)52.3 (26.8)52.9 (25.7)54.0 (24.4)53.7 (24.6)56.6 (22.1)54.0 (25.3)52.5 (26.4)53.5 (25.2)
Social interaction74.5 (23.8)72.9 (24.2)74.3 (23.3)71.3 (23.2)75.2 (23.0)75.8 (22.4)74.0 (23.7)73.3 (24.0)74.6 (23.2)

Efficacy

Women

At week 12, women receiving fesoterodine 8 mg had significantly greater improvements from baseline in UUI episodes per 24 h than those receiving ER tolterodine 4 mg (P ≤ 0.007) and placebo (P < 0.001; Fig. 2). The 3-day diary-dry rates were significantly higher in women receiving fesoterodine 8 mg than in the ER tolterodine 4 mg (P = 0.002) and placebo (P < 0.001) groups (Fig. 2). The fesoterodine 8 mg group also had significantly greater improvements in micturitions, urgency episodes, severe urgency episodes, frequency–urgency sum and MVV compared with the ER tolterodine 4 mg and placebo groups (all P < 0.004) and also in nocturnal micturitions compared with the placebo group (both P < 0.04; Fig. 2). Improvements on the PPBC (P < 0.001), UPS (P < 0.001), and OAB-q Symptom Bother (P < 0.001) and HRQL scales (P < 0.001) and in all HRQL domains (Concern, P < 0.001; Coping, P < 0.002; Sleep, P < 0.005; Social Interaction, P < 0.001) were significantly greater among women receiving fesoterodine 8 mg than among those receiving ER tolterodine 4 mg or placebo (Figs 3-5).

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Figure 2. Change from baseline to week 12 in bladder diary variables and diary-dry rate at week 12 for each gender. Error bars represent the sem. Data represent the full analysis set for participants reporting symptoms at baseline. *P < 0.05 vs placebo; P < 0.05 vs ER tolterodine; P < 0.05 vs fesoterodine. LS, least squares.

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figure

Figure 3. Categorical changes from baseline to week 12 in men and women for PPBC scores. Data represent the full analysis set. FESO, fesoterodine; PBO, placebo; TOL ER, ER tolterodine. *P < 0.05 vs placebo; P < 0.05 vs ER tolterodine.

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Figure 4. Categorical changes from baseline to week 12 in UPS scores. Data represent the full analysis set. FESO, fesoterodine; PBO, placebo; TOL ER, ER tolterodine *P < 0.05 vs placebo; P < 0.05 vs ER tolterodine.

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Figure 5. Changes from baseline to week 12 in OABq scores. Data represent the full analysis set. Error bars represent sem. LS, least squares. *P < 0.05 vs placebo; P < 0.05 vs ER tolterodine.

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Administration of ER tolterodine 4 mg to women also resulted in significantly greater improvements from baseline in UUI episodes per 24 h at week 12 (P < 0.001), as well as all other diary variables (P ≤ 0.002) except nocturnal micturitions (P > 0.05) when compared with placebo (Fig. 2). Three-day diary-dry rates were significantly greater in the ER tolterodine 4 mg group than in the placebo group (P < 0.001; Fig. 2). Greater improvements than those for placebo were observed for scores on the PPBC (P = 0.001; Fig. 3), UPS (P = 0.005; Fig. 4), and OAB-q Symptom Bother (P < 0.001) and HRQL (P = 0.007) scales, as well as the Concern (P = 0.002) and Coping (P = 0.005) domains (Fig. 5).

Men

At week 12, the fesoterodine 8 mg group had significantly greater improvements than the ER tolterodine 4 mg group in severe urgency episodes (P = 0.035) and OAB-q Symptom Bother scores (P = 0.003). Improvements were significantly greater with fesoterodine 8 mg than with placebo for micturitions, urgency episodes, severe urgency episodes, frequency–urgency sum and PPBC scores (all P < 0.02; Figs 2 and 3). There were no differences in improvements in UPS scores between any treatment groups (all P > 0.13; Fig. 4). Men taking fesoterodine had significant improvements vs placebo on the OAB-q Symptom Bother and HRQL scales and on all four HRQL domains (all P < 0.005; Fig. 5).

Compared with placebo, men receiving tolterodine had significantly greater improvements in micturitions, nocturnal micturitions, frequency–urgency sum, PPBC scores and scores on the OAB-q HRQL scale and Coping, Sleep and Social Interaction domains at week 12 (all P < 0.05; Figs 2, 3 and 5).

Safety and Tolerability

Both active treatments were well tolerated by both genders. Discontinuations owing to TEAEs for women and men were similar (Table 2). Dry mouth and constipation were the most frequently reported TEAEs in both men and women (Table 2), and most TEAEs were of mild or moderate severity. The incidence of dry mouth was 29% in women and 21% in men taking fesoterodine, 15% in women and 13% in men taking ER tolterodine, and 6% in women and 5% in men in the placebo group. Severe dry mouth was reported in 28 women (2%), eight women (<1%) and one woman (<1%), and in six men (2%), no men (0%) and one man (1%) in the fesoterodine, ER tolterodine, and placebo groups, respectively. Constipation was reported by 5% of men and women receiving fesoterodine, 4% of women and 3% of men in the tolterodine group, and 2% of women and 1% of men in the placebo group. Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine 4 mg, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine 4 mg, <1%; placebo, 2%).

Table 2. Most commonly reported TEAEs
 WomenMenOverall
Placebo (n = 679)TER (n = 1382)FESO (n = 1374)Placebo (n = 133)TER (n = 275)FESO (n = 265)Placebo (n = 812)TER (n = 1657)FESO (n = 1639)
  1. *All causality TEAEs reported by ≥2% of either men or women in the safety set in either active treatment group and with a higher incidence than in the placebo group.

Any TEAEs*, n (%)236 (35)573 (42)700 (51)34 (26)82 (30)112 (42)270 (33)655 (40)812 (50)
Discontinued owing to TEAEs13 (2)48 (3)69 (5)3 (2)8 (3)18 (7)16 (2)56 (3)86 (5)
Event, n (%)         
Dry mouth40 (6)206 (15)399 (29)6 (5)36 (13)55 (21)46 (6)242 (15)454 (28)
Constipation16 (2)51 (4)67 (5)1 (1)7 (3)12 (5)17 (2)58 (4)79 (5)
Headache13 (2)37 (3)59 (4)1 (1)6 (2)6 (2)14 (2)43 (3)65 (4)
Diarrhea6 (1)23 (2)24 (2)1 (1)3 (1)1 (<1)7 (1)26 (2)25 (2)
Urinary tract infection7 (1)21 (2)26 (2)0 (0)1 (<1)3 (1)7 (1)22 (1)29 (2)
Polyuria7 (1)21 (2)27 (2)3 (2)3 (1)2 (1)10 (1)24 (1)29 (2)
Dyspepsia3 (<1)16 (1)25 (2)0 (0)2 (1)8 (3)3 (<1)18 (1)33 (2)
Nausea8 (1)20 (1)20 (2)2 (2)0 (0)3 (1)10 (1)20 (1)23 (1)
Nasopharyngitis14 (2)16 (1)16 (1)2 (2)6 (2)5 (2)16 (2)22 (1)21 (1)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

With the growing importance of healthcare policy and reform, there is currently an emphasis on comparative effectiveness research that establishes the clinical value of one treatment over another [17]; however, to date there have been few published placebo-controlled, head-to-head studies prospectively designed to assess the superiority of one antimuscarinic over another for the treatment of adults with OAB. The limitations of previous comparative antimuscarinic studies include their design as non-inferiority rather than superiority trials, and the use of immediate-release formulations of oxybutynin or tolterodine as comparator agents. The two prospective, head-to-head studies used for the present pooled analysis showed that fesoterodine 8 mg was more effective than ER tolterodine 4 mg in improving bladder diary variables and patient-reported outcomes [18, 19]. This prespecified, pooled analysis expands on the findings of the two original trials by comparing fesoterodine 8 mg and ER tolterodine 4 mg in the pooled subject population stratified by gender. To the authors' knowledge, this is the first study to compare antimuscarinic efficacy separately in women and men. The results show that among women, fesoterodine 8 mg is significantly more effective than ER tolterodine 4 mg or placebo for improving most diary endpoints, including the primary endpoint of UUI episodes, as well as urgency episodes, severe urgency episodes, micturition frequency, frequency–urgency sum, and MVV per micturition. Additionally, the diary-dry rate at week 12 was significantly higher in the fesoterodine 8 mg group than in the ER tolterodine 4 mg and placebo groups. The fesoterodine 8 mg group also had significantly greater improvements in self-reported symptom bother, HRQL, urgency, and overall severity of bladder-related problems compared with the ER tolterodine 4 mg and placebo groups. This clearly suggests that the greater improvements in diary variables with fesoterodine 8 mg were clinically meaningful to the women in this study.

Among men, those receiving fesoterodine 8 mg showed significantly greater improvements in severe urgency episodes and symptom bother compared with those receiving ER tolterodine 4 mg; however, improvements in other study endpoints, including the primary endpoint of UUI episodes, were not significantly greater with fesoterodine 8 mg than with ER tolterodine 4 mg. This may be attributable at least in part to the smaller number of men enrolled in the two studies. Improvements from baseline to week 12 were significantly greater with fesoterodine 8 mg compared with placebo for micturitions, urgency episodes, severe urgency episodes, and frequency–urgency sum, as well as for scores on the PPBC, the OAB-q Symptom Bother and HRQL scales, and all HRQL domains. By contrast, improvements in the ER tolterodine 4 mg group were not significantly different from placebo for urgency episodes, severe urgency episodes, or OAB-q Symptom Bother scores at week 12. The ER tolterodine group did have significantly greater improvements compared with the placebo group in micturitions, nocturnal micturitions, and frequency–urgency sum, as well as scores on the PPBC, the OAB-q HRQL scale, and most HRQL domains at week 12.

The present findings are consistent with a post hoc analysis of data from a fixed-dose fesoterodine study that included ER tolterodine as an active control, in which fesoterodine 8 mg was associated with significantly greater improvements than ER tolterodine 4 mg in UUI episodes, severe urgency plus UUI, MVV per micturition, and number of continent days per week [24].

The present findings are also consistent with post hoc analyses of data pooled from two fixed-dose placebo-controlled trials demonstrating the efficacy of fesoterodine in women and men [25, 26]. In women, fesoterodine 8 mg produced significantly greater improvements in UUI episodes and number of continent days per week than ER tolterodine 4 mg (included as an active control in one of the two trials) and fesoterodine 4 mg [25]. All active treatments produced significantly greater improvements in all diary variables and significantly higher rates of self-reported treatment response than did placebo [25]. This is certainly an important point, showing that the 4 mg doses of both fesoterodine and tolterodine 4 mg are superior to placebo and that the higher dose of fesoterodine is able to provide even greater efficacy. The desirability of the higher dose is reflected in a recently published dose escalation trial that allowed patients to titrate up as they desired from fesoterodine 4 and 8 mg, with 63% of patients ending up at the higher dose [27]. In men, fesoterodine 4 and 8 mg had significantly greater improvements in micturitions, UUI episodes and urgency episodes, and a significantly higher treatment response rate compared with placebo; men in the fesoterodine 8 mg group also had a significantly greater increase in MVV per micturition than the placebo group [26]. The fesoterodine 8 mg group had significantly greater improvements in UUI episodes and MVV per micturition than the fesoterodine 4 mg group (the ER tolterodine 4 mg arm was not included in this analysis) [26]. The results of the present study extend these previous findings by demonstrating treatment differences between fesoterodine 8 mg and ER tolterodine 4 mg in men and women in a prespecified analysis of data from trials with a prospective superiority design, and by assessing treatment differences in several patient-reported outcomes, including symptom bother, HRQL, severity of bladder-related problems, and severity of urgency in men and women.

Urgency urinary incontinence is a bothersome symptom for many patients with OAB [28] and has a greater impact on HRQL than stress urinary incontinence [29]. Although the overall prevalence of OAB is similar in men and women [30], the prevalence and impact of individual OAB symptoms, including UUI, differs by gender. Among individuals with OAB, the prevalence of UUI is higher in women compared with men, and women are more likely to experience UUI at a younger age [28, 31]. In comparison, men with OAB are more likely than women to report bother associated with urinary incontinence (77 vs 67%), but women are more likely to adopt coping techniques (73 vs 51%) [32]. Men and women with symptoms of OAB may also differ in their healthcare-seeking behaviour, expectations of OAB treatment outcomes, beliefs about the aetiology of OAB, and the perception of the impact of OAB on their daily lives [33]. In the present study, women had a higher baseline UUI severity with a mean 2.6 UUI episodes per 24 h compared with 2.1 in men, and a greater proportion of women than men noted an inability to hold urine on the UPS (25 vs 40%). These baseline differences may explain the lack of statistical significance for the measurement of UUI improvement in the men resulting from treatment with either tolterodine 4 mg or fesoterodine 8 mg.

The observation that the baseline MVV per micturition was greater in men than in women is consistent with previous findings showing that women void more frequently and at lower volumes than men [34]. Evidence for a relationship between the severity of urgency sensation and MVV among individuals with OAB has been shown [19, 35, 36]. It is notable that ∼15% fewer women than men reported being ‘not able to hold urine’ on the UPS.

The tolerability profiles of both active treatments were generally favourable in both men and women in this pooled analysis. Overall, in the fesoterodine, ER tolterodine, and placebo groups, the incidence of dry mouth was 28, 15 and 6%, respectively; constipation was 5, 4, and 2%, respectively; and headache was 4, 3, and 2%, respectively. The proportion of TEAEs was ∼10% lower in men than women; however, the rates of dry mouth and constipation, both associated with antimuscarinic treatment [37], were similar in men and women and comparable to rates reported in previous studies [14, 15]. For both men and women, the higher incidence of TEAEs in the fesoterodine group compared with the ER tolterodine 4 mg and the placebo groups was primarily attributable to the higher incidence of dry mouth in the fesoterodine group. A similar increase was not seen for constipation, which had comparable rates in both active treatment groups. Urinary retention rates were low (≤2%) in all treatment groups in both women and men; in men, the rate of urinary retention with fesoterodine was equal to that with placebo.

The availability of two doses of fesoterodine allows flexible dosing in clinical practice. It is recommended that patients begin treatment on the 4-mg dose, but patients can opt to adjust fesoterodine dosage, in consultation with a clinician, from 4 to 8 mg in response to individual efficacy and tolerability needs. This represents a clinical advantage over the tolterodine single-dose regimen. A recent 12-week, randomized, placebo-controlled study showed that flexible-dose fesoterodine was associated with significant improvements in diary variables, including UUI episodes, micturitions, urgency episodes and frequency–urgency sum, as well as improvements on the PPBC, UPS, and OAB-q [27]. In addition, the majority (80%) of patients enrolled in a 12-week open-label flexible-dose fesoterodine study reported being satisfied with treatment, with half of patients opting for the higher dose [38]. Subanalyses of data from these flexible-dose fesoterodine trials have demonstrated important differences between subjects who do and do not opt for dose escalation. For example, the incidence of OAB symptoms at baseline and the impact of OAB symptoms (as reported on patient-reported outcomes) were greater for subjects who escalated the dose during the trial compared with those who did not [39, 40]. Before the dose escalation choice point, subjects who escalated showed a lower efficacy response to fesoterodine 4 mg than subjects who did not escalate, whereas the rate of adverse events was greater among subjects who did not escalate compared with those who did [39, 40]. By the end of treatment, the efficacy and tolerability responses were similar among subjects who did and did not escalate, even though they were receiving different doses [39, 40].

The present study has several limitations. First, the objective of the trials pooled for this analysis was to compare the highest available doses of fesoterodine and ER tolterodine and, thus, it was necessary to use a fixed-dose design; however, this does not represent the use of flexible dosing of fesoterodine in clinical practice. Some subjects for whom fesoterodine 4 mg would have been the optimum dose were probably treated with fesoterodine 8 mg in these trials, which may have affected both efficacy and tolerability for these subjects. Secondly, these trials were not prospectively designed to assess fesoterodine vs ER tolterodine separately in women and men and the number of men in the present study was considerably smaller than the number of women.

In summary, this pooled analysis provides substantial evidence supporting the superiority of fesoterodine 8 mg over ER tolterodine 4 mg and placebo in reducing UUI episodes and improving most other diary endpoints, as well as patient assessments of bladder-related problems, urgency episodes, symptom bother, and HRQL in women. In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency episodes and symptom bother and to placebo for many diary and patient-reported outcomes. Both fesoterodine and ER tolterodine 4 mg were well tolerated in women and men.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

This study was sponsored by Pfizer Inc. Dana Creanga is an employee of SmithHanley Consulting, who were paid contractors to Pfizer in connection with the development of this manuscript. Editorial assistance was provided by Diane DeHaven-Hudkins, PhD and Colin P. Mitchell, PhD, from Complete Healthcare Communications, Inc. and was funded by Pfizer Inc.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

This study was sponsored by Pfizer Inc. D.G. is a consultant for Allergan, AMS/Boston Scientific, Medtronic, Tengion and Pfizer. T.S. is a consultant and speaker for Pfizer Inc, Bayer AG, Astellas Inc, Takeda Pharmaceutical Company Ltd, and Recordati S.p.A. C.K. is a consultant and speaker for Astellas and Pfizer and a consultant for Allergan. P.V.K. is a lecturer and advisory board member for Astellas Inc., Ferring Pharmaceuticals Inc. and Medtronic Inc., and an advisory board member for Allergan Inc. S.S. has no conflicts to declare. D.C. is a paid consultant to Pfizer Inc. D.M. is an employee and shareholder of Pfizer Inc.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
Abbreviations
ER

extended release

OAB

overactive bladder

UUI

urgency urinary incontinence

PPBC

Patient Perception of Bladder Condition

UPS

Urgency Perception Scale

OAB-q

Overactive Bladder Questionnaire

HRQL

health-related quality of life

CYP

cytochrome P450

5-HMT

5-hydroxymethyl tolterodine

USS

Urinary Sensation Scale

TEAE

treatment-emergent adverse event

MVV

mean voided volume