Efficacy and Tolerability of Tolterodine Extended Release in Male and Female Patients with Overactive Bladder

european urology 51 (2007) 1054–1064

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Neuro-urology

Efficacy and Tolerability of Tolterodine Extended Release in Male and Female Patients with Overactive Bladder Roger Dmochowski a,*, Paul Abrams b, Daniela Marschall-Kehrel c,d, Joseph T. Wang e, Zhonghong Guan e a

Vanderbilt University Medical Center, Nashville, TN, USA Bristol Urological Institute, Southmead Hospital, Bristol, United Kingdom c Urological Consultancy, Oberursel, Germany d Department of Urology, University of Tuebingen, Tuebingen, Germany e Pfizer Inc, New York, NY, USA b

Article info

Abstract

Article history: Accepted October 3, 2006 Published online ahead of print on October 20, 2006

Objectives: To evaluate the efficacy and tolerability of tolterodine extended release (ER) in men and women with overactive bladder (OAB). Methods: We analyzed data from two 12-wk, placebo-controlled trials of tolterodine ER (4 mg QD). Patients completed 7-d bladder diaries and rated the urgency sensation associated with each micturition on a 5-point urgency rating scale. Micturitions were categorized by urgency rating: total (1–5), non-OAB (1–2), OAB (3–5), or severe OAB (4–5). Changes in micturitions during 24-h, daytime, and nocturnal intervals were assessed. Results: At baseline, 73% (547 of 745) of men and 57% (539 of 953) of women were continent. By week 12, tolterodine ER (n = 848) reduced OAB and severe OAB micturitions during 24-h, daytime, and nocturnal intervals in both sexes compared with placebo (n = 850). Adverse event rates were low and similar across treatment and gender. Conclusions: In men and women with OAB, tolterodine ER reduced OAB and severe OAB micturitions, and was well tolerated.

Keywords: Frequency Overactive bladder Tolterodine Urgency Gender

# 2006 Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. Department of Urology, Room A1302, Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Tel. +1 615 343 5602; Fax: +1 615 322 8990. E-mail address: [email protected] (R. Dmochowski).

1.

Introduction

Overactive bladder (OAB) is a syndrome characterized by the symptoms of urgency, with or without urgency urinary incontinence (UUI), usually with

frequency and nocturia [1]. OAB is prevalent and costly to society, and it is anticipated that the prevalence and cost of OAB will increase in the future [2]. This observation is important because OAB exerts a considerable burden and reduces

0302-2838/$ – see back matter # 2006 Published by Elsevier B.V. on behalf of European Association of Urology.

doi:10.1016/j.eururo.2006.10.005

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health-related quality of life (HRQL) in affected individuals [3–5]. In fact, the impact of OAB on HRQL may be greater than that of diabetes [4]. Decreased HRQL is not specific to any particular OAB symptom; rather it has been shown to be associated with the individual symptoms of urgency [5,6], frequency [5], UUI [5,7,8], and nocturia [9]. OAB and its individual symptoms are also associated with substantial symptom bother [6,7,9]. The prevalence of OAB is similar in men (16%) and women (17%) [3,10]; however, women may experience OAB symptoms at a younger age and are also more likely to experience UUI [3,10]. In a study in which primary care patients were asked to identify their most bothersome OAB symptom, more men than women reported urgency and frequency as most bothersome, whereas more women than men considered UUI most bothersome [11]. Evidence suggests that there are also differences between men and women with OAB in attitudes toward seeking treatment for OAB, expectations of OAB treatment outcomes, beliefs about the etiology of OAB, and the impact of OAB on professional activities [12]. Antimuscarinic agents are a first-line treatment for OAB. They are generally effective in improving patients’ symptoms and HRQL, and are well tolerated [13]. In clinical trials of antimuscarinics for OAB, the patients typically enrolled are incontinent women; consequently, few data are available on whether antimuscarinics are equally efficacious, and well tolerated in men and women with OAB. We assessed the efficacy and tolerability of nighttime dosing of tolterodine extended release (ER) on urgency and urgency-related micturitions during 24-h, daytime, and nocturnal intervals in men and women using data pooled from two double-blind, placebo-controlled trials of patients with OAB and nocturia. Unique features of this analysis were that nearly 45% of the patients were

men, most of the patients (54–74%) were continent at baseline, and all patients experienced a fairly high number of nocturia episodes at study entry. In addition, all patients rated the degree of urgency associated with each micturition, allowing for the evaluation of treatment efficacy on micturitions by urgency level. 2.

Methods

Data were pooled from two 12-wk, multinational, randomized, double-blind, placebo-controlled trials. The results from these two studies have been reported previously [14,15]. Briefly, men and women (aged 18 yr) were eligible if they had urgency with or without UUI, a mean of 8 micturitions per 24 h, and a mean of 2.5 nocturnal micturitions for 6 mo. After a 2-wk, single-blind, placebo run-in period, eligible patients were randomized to tolterodine ER (4 mg) or placebo once daily in the evening (4 h before bed) for 12 wk. Patients completed 7-d bladder diaries in which they recorded their sleep cycles and each micturition and UUI episode. The primary end point in both studies was the change in mean number of nocturnal micturitions from baseline to week 12. For each micturition, patients recorded how urgently they needed to pass urine using a five-point urgency rating scale [16]. Recent retrospective analyses have validated this scale for measuring urgency in patients with OAB [17,18]. Micturitions were categorized post hoc according to urgency rating scores as total (1–5), non-OAB (1–2), OAB (3–5), and severe OAB (4–5) micturitions (Table 1). A rating of five was counted as a UUI episode and a micturition. All micturitions recorded in 7-d bladder diaries were included in the 24-h interval. Micturitions occurring between the time patients intended to fall asleep and the time the patients intended to awaken or actually awakened were included in the nocturnal interval [19]; all other micturitions were included in the daytime interval. Patients’ sum urgency ratings were calculated as the sum of urgency ratings for all 24-h micturitions; mean urgency ratings were calculated as the sum urgency ratings divided by the number of 24-h micturitions.

Table 1 – Five-point urgency rating scale Please record how urgently you needed to pass urine for each micturition. 1. No urgency: ‘‘I felt no need to empty my bladder but did so for other reasons.’’ 2. Mild urgency: ‘‘I could postpone voiding as long as necessary without fear of wetting myself.’’ 3. Moderate urgency: ‘‘I could postpone voiding for a short time without fear of wetting myself.’’ 4. Severe urgency: ‘‘I could not postpone voiding but had to rush to the toilet in order not to wet myself.’’ 5. Urgency urinary incontinence: ‘‘I leaked before arriving at the toilet.’’ OAB = overactive bladder.

Micturition category Total

Non-OAB

X

X

X

X

OAB

Severe OAB

X

X

X

X

X

X

X

X

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For the current analyses, all efficacy outcomes were stratified by gender. Efficacy analyses were based on data from the intent-to-treat population, defined as all randomized patients. Median percentage changes in micturitions were examined by urgency rating and time interval, in addition to absolute (mean) changes, because median percentage changes are less sensitive to baseline severity and allow for easier comparisons across studies. Differences between the sexes were determined by adding the treatment/patient gender interaction term and the patient gender term into the analysis of covariance (ANCOVA) model for numeric endpoints and into the logistic model for categorical end points. If the p value for the interaction term was >0.1, the interaction term was taken out, and the model was run again to check for an effect related to patients’ gender. Tolerability analyses were based on data from the safety population, defined as all randomized patients who received at least one dose of study medication and were stratified by gender.

3.

Results

Of the 1698 patients enrolled in the two trials, 848 were randomized to tolterodine ER (371 men, 477 women) and 850 to placebo (374 men, 476 women). Baseline demographic and clinical characteristics were similar between the tolterodine ER and placebo

groups (Table 2), but there were significant gender differences for age; UUI episodes; and total, OAB, and severe OAB micturitions ( p < 0.05). At baseline, 73% of men and 57% of women were continent (0 UUI episodes per week). Tolterodine ER significantly reduced mean total, OAB, and severe OAB micturitions during the 24-h interval compared with placebo in both men and women (Fig. 1). In the daytime interval, tolterodine ER significantly reduced total and severe OAB micturitions in men (Fig. 2A) and total, OAB, and severe OAB micturitions in women relative to placebo (Fig. 2B). Although tolterodine ER did not significantly decrease total micturitions during the nocturnal interval (the primary end point in both studies) in men or women, it did significantly decrease OAB micturitions in men, and OAB and severe OAB micturitions in women during the nocturnal interval compared with placebo (Fig. 3). Consistent with baseline findings, statistically significant differences ( p < 0.05) were observed between men and women at week 12 regardless of treatment condition in mean total, non-OAB, and severe OAB micturitions during the nocturnal interval; mean total and severe OAB micturitions during the daytime interval; and mean

Table 2 – Baseline demographic and clinical characteristics by treatment group and sex Placebo (n = 850) Men (n = 374)

Tolterodine ER (n = 848)

Women (n = 476)

Men (n = 371)

Women (n = 477)

Age, yr*

64

58

64

57

Race, n (%)y White Black Asian

335 (90) 18 (5) 8 (2)

414 (87) 27 (6) 7 (2)

328 (88) 17 (5) 10 (3)

417 (87) 28 (6) 2 (<1)

Continence status, n (%) 0 UUI episodes per week*

277 (74)

256 (54)

270 (73)

283 (59)

24-h micturitions per week Total (1–5)* Non-OAB (1–2) OAB (3–5)* Severe OAB (4–5)*

91.5 36.0 55.0 18.8

95.2 33.7 61.2 26.9

90.7 36.1 54.3 18.1

95.3 33.2 61.9 24.1

Daytime micturitions per week Total (1–5)* Non-OAB (1–2) OAB (3–5)* Severe OAB (4–5)*

67.1 27.6 39.1 13.0

69.5 26.2 43.1 18.7

66.6 28.1 38.2 12.2

69.8 25.9 43.7 16.2

Nocturnal micturitions per week Total (1–5)* Non-OAB (1–2) OAB (3–5)* Severe OAB (4–5)*

24.4 8.3 15.9 5.8

25.6 7.5 18.1 8.3

24.1 8.0 16.0 5.9

25.5 7.2 18.3 7.9

ER = extended release; OAB = overactive bladder; UUI = urgency urinary incontinence. Data presented are means unless otherwise noted. * p < 0.05, men vs women. y Data on race were not available for all patients.

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catheterization was low and similar between the tolterodine ER and placebo groups among both men (1.1% and 0.5%, respectively) and women (0.4% and 0.2%, respectively). Serious AEs occurred infrequently. Eleven patients in the tolterodine ER group (six men, five women) had 28 serious AEs; 10 patients in the placebo group (five men, five women) had 28 serious AEs. None of the serious AEs were considered related to study drug. Withdrawal rates among women were 12% in the tolterodine ER group and 13% in the placebo group, whereas 14% of men in both the tolterodine ER and placebo groups withdrew from the studies. Withdrawal rates due to AEs were low (approximately 3% of men and women in the tolterodine ER group, and 4% of men and women in the placebo group).

4.

Discussion

These two large, randomized, placebo-controlled trials are unique in that they enrolled a larger number of male patients (44%). In most OAB trials,

Fig. 1 – LS mean change in 24-h micturitions among (A) men and (B) women. Data were not available for one woman in the tolterodine ER group. *p < 0.05; **p < 0.01. ER = extended release; LS = least squares; OAB = overactive bladder.

total, non-OAB, and severe OAB micturitions during the 24-h interval after adjusting for baseline status, age, and country. Relative (i.e., median percentage) changes in micturition variables were consistent with numeric changes. Tolterodine ER significantly decreased total, OAB, and severe OAB micturitions during the 24-h and daytime intervals in both men and women (Table 3). During the nocturnal interval, only severe OAB micturitions in men were significantly decreased relative to placebo. In men and women, mean and sum urgency ratings were significantly decreased with tolterodine ER versus placebo for the 24-h, daytime, and nocturnal intervals (Table 4). Adverse event (AE) rates were low and comparable between men and women (Table 5). The most commonly reported AEs in the tolterodine ER group were dry mouth (11% of men, 12% of women), constipation (2% of men, 3% of women), and headache (1% of men, 4% of women). Notably, the incidence of acute urinary retention requiring

Fig. 2 – LS mean change in daytime micturitions among (A) men and (B) women. Data were not available for one woman in the tolterodine ER group. *p < 0.05; **p < 0.01; *** p < 0.001. ER = extended release; LS = least squares; OAB = overactive bladder.

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Fig. 3 – LS mean change in nocturnal micturitions among (A) men and (B) women. Data were not available for one woman in the tolterodine ER group. *p < 0.05; **p < 0.01. ER = extended release; LS = least squares; OAB = overactive bladder.

women typically make up about 80% of the patients enrolled. Therefore, by pooling data from two studies, we were able to examine whether gender differences exist in the efficacy and tolerability of tolterodine ER. The results of the current analysis suggest that with nighttime dosing, the efficacy and tolerability profiles of tolterodine ER are similar in men and women with OAB, despite baseline differences between men and women in UUI episodes and total, OAB, and severe OAB micturitions. Although the primary end point in both studies (change in mean number of nocturnal micturitions from baseline to week 12) was not met, tolterodine ER significantly reduced total micturitions during the 24-h and daytime intervals in both men and women relative to placebo. Notably, patients with OAB experience urgency to varying degrees. In the current study, assessment of baseline ratings revealed that about 40% of micturitions in men and 35% of micturitions in women were rated as non-OAB (one to two), whereas about 20% and 27% of micturitions in men and women,

respectively, were rated as severe OAB (four to five). Because urgency is the hallmark symptom of OAB, theoretically, micturitions associated with urgency should be considered OAB-related micturitions and should respond to antimuscarinic therapy. In our analysis, tolterodine ER reduced OAB and severe OAB micturitions during the 24-h interval, as well as severe OAB micturitions during the daytime and nocturnal intervals in both men and women. In addition to maintaining 24-h efficacy, the nighttime tolterodine ER dosing regimen was associated with a low incidence of AEs and few AE-related withdrawals, suggesting that nighttime dosing with tolterodine ER may lessen AEs associated with antimuscarinic treatment. The occurrence of acute urinary retention requiring catheterization was infrequent and similar between the tolterodine ER and placebo groups among both men (1.1% vs. 0.5%, respectively) and women (0.4% vs. 0.2%, respectively). Our results are consistent with the findings of a 12-wk, open-label study of 2250 patients with OAB treated with tolterodine immediate release (IR) that found only minimal and inconsistent effects of gender on treatment efficacy [20]. In that study, there were no gender-related differences in the effects of tolterodine IR on urgency or frequency, although treatment of incontinence with tolterodine IR was more likely to be successful in men than women. Gender appeared to have no effect on the overall tolerability of tolterodine IR. Although OAB prevalence rates are similar between men and women [3,10], there are important gender differences in the often presumed aetiology, symptomatology, and treatment of OAB. For instance, OAB symptoms may appear at a younger age in women than in men [10], and the prevalence of UUI is higher in women than in men [3,10]. The results of the current analysis are consistent with these findings. Furthermore, more women than men report that UUI is their most bothersome symptom [11], whereas men are more likely to report that OAB symptoms impact their professional activities than are women [12]. There are also gender-related differences in the pathologic mechanisms to which OAB symptoms are attributed, and as a result, treatment strategies are also different. In men, OAB symptoms are often considered to result from bladder outlet obstruction (BOO) related to prostatic pathology. As a result, OAB symptoms in men are often ignored, and presumed BOO is treated with an a-blocker or 5a-reductase inhibitor. In women, OAB symptoms are more often considered related to bladder dysfunction and treated with an antimuscarinic [21]. Importantly, however, urodynamic studies suggest that many

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Table 3 – Median percentage change in micturitions by time interval Women*

Men Placebo (n = 374)

Tolterodine ER (n = 371)

p value

Placebo (n = 476)

Tolterodine ER (n = 476)

p value

7.9 14.3 9.5 41.2

10.8 10.7 16.7 68.6

0.0484 0.4062 0.0223 0.0112

12.0 19.6 14.4 28.6

17.2 16.3 20.6 43.3

0.0012 0.298 0.011 0.314

Daytime micturitions per week Total (1–5) 5.6 Non-OAB (1–2) 14.0 OAB (3–5) 8.5 Severe OAB (4–5) 37.5

8.7 9.8 12.5 62.9

0.0407 0.5212 0.0369 0.0357

8.6 15.4 11.1 27.4

13.5 15.5 18.5 44.3

0.0001 0.742 0.001 0.443

Nocturnal micturitions per week Total (1–5) 17.6 Non-OAB (1–2) 28.6 OAB (3–5) 22.2 Severe OAB (4–5) 50.0

18.8 20.0 27.3 77.8

0.5887 0.4888 0.0738 0.015

21.7 50.0 25.7 40.0

25.8 34.8 32.1 52.6

0.153 0.274 0.058 0.084

24-h micturitions per week Total (1–5) Non-OAB (1–2) OAB (3–5) Severe OAB (4–5)

ER = extended release; OAB = overactive bladder. Data were not available for one woman in the tolterodine ER group.

*

men with OAB symptoms do not have BOO [22,23], and OAB symptoms persist in many men even after transurethral resection of the prostate [24]. Furthermore, previous studies have shown that many men with OAB symptoms who fail to respond to a-blocker therapy show improvement after treatment with tolterodine ER, either alone [25] or in combination with an a-blocker [26]. The occurrence of acute urinary retention requiring catheterization is low under either treatment regimen. Collectively, these findings and those of the current analysis suggest that tolterodine ER is effective and safe in both men and women with OAB symptoms. Importantly, the results of this analysis should be interpreted within the context of its limitations. One limitation is that this was a subanalysis of data

pooled from two double-blind, placebo-controlled trials. Although subanalyses can reveal important findings, there are drawbacks to using this approach. For instance, the power to detect true treatment differences is reduced, and the probability of detecting false-positive results is increased in subgroup analyses [27]. Thus, a randomized clinical trial designed to compare tolterodine ER efficacy and tolerability in men and women would provide more definitive data. A randomized, placebo-controlled, double-blind trial that is currently enrolling patients will provide stronger evidence regarding the efficacy and tolerability of tolterodine ER in men (ClinicalTrials.gov identifier number, NCT00282932) [28]. Another limitation is that the results of the validation

Table 4 – Change from baseline to week 12 in urgency ratings Urgency rating interval

Women*

Men Placebo (n = 374)

Tolterodine ER (n = 371)

p value

Placebo (n = 476)

Tolterodine ER (n = 476)

p value

Mean urgency rating 24 h Daytime Nighttime

0.03 (0.02) 0.02 (0.02) 0.04 (0.03)

0.12 (0.02) 0.09 (0.02) 0.17 (0.03)

0.010 0.035 0.0003

0.03 (0.02) 0.02 (0.02) 0.03 (0.02)

0.10 (0.02) 0.09 (0.02) 0.12 (0.02)

0.017 0.027 0.013

Sum urgency rating 24 h Daytime Nighttime

11.92 (1.30) 11.58 (3.06) 24.95 (3.74)

15.74 (1.31) 24.38 (3.07) 40.73 (3.75)

0.040 0.004 0.003

16.84 (1.23) 19.36 (2.68) 36.89 (3.60)

20.72 (1.23) 33.57 (2.68) 54.89 (3.60)

0.026 0.0002 0.0004

ER = extended release. Data presented are least squares means (SE). * Data were not available for one woman in the tolterodine ER group.

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Table 5 – Adverse events occurring in I2% of patients Adverse event, n (%)

Placebo (n = 850) Men (n = 374)

Dry mouth Headache Constipation Dizziness (not vertigo) Dyspepsia Back pain Nasopharyngitis

15 5 8 1 – – 8

Tolterodine ER (n = 848)

Women (n = 476)

(4.0) (1.3) (2.1) (0.3)

(2.1)

17 19 11 7 0 11 11

(3.6) (4.0) (2.3) (1.5) (0.0) (2.3) (2.3)

Men (n = 371) 40 4 8 4 – – 10

(10.8) (1.1) (2.2) (1.1)

(2.7)

*

Women (n = 477) 56 17 16 12 5 7 3

(11.7)* (3.6)y (3.4) (2.5)y (1.0) (1.5)y (0.6)*,z

ER = extended release. p < 0.05, treatment term within patient sex. y p < 0.05, patient sex term. z p < 0.10, treatment/sex interaction term. *

studies of the five-point urgency rating scale [16] used to measure urgency have only appeared in abstract form to date [17,18]. Additional data on the validity of this scale are needed.

5.

Conclusions

Men and women treated with tolterodine ER achieved significantly greater reductions than those given placebo in OAB and severe OAB micturition frequency. Tolterodine ER had no significant effects on normal, non-OAB micturitions. AE and withdrawal rates were low and comparable for men and women who received tolterodine ER under a nighttime dosing regimen. Nighttime dosing of tolterodine ER is a viable option for men and women who have effectively managed their OAB symptoms with daytime tolterodine ER dosing and would like to minimize the occurrence of antimuscarinic AEs without compromising efficacy.

Conflicts of interest The study described in this manuscript was funded by Pfizer Inc. Roger Dmochowski is a paid consultant for Pfizer Inc, as is Dr Abrams. Dr Marschall-Kehrel is a member of the Pfizer NEXUS team and has been invited to a Pfizer global advisory board. Joseph Wang and Dr Guan are employed by Pfizer Inc.

Acknowledgements This study was funded by Pfizer Inc. The author(s) would like to acknowledge the editorial assistance of Colin P. Mitchell, PhD, from Complete Healthcare Communications, Inc, in the preparation of this manuscript.

A complete list of the 037 Study Group follows: Oscar Aguirre, Colorado Gynecology and Continence Center, Denver, CO; Joseph A. Antoci, Connecticut Clinical Research, Waterbury, CT; Thomas Armbruster, Clinical Research of Tampa Bay, Spring Hill, FL; Thomas Arnau, Discovery Alliance, Incorporated, Awendaw, SC; Stephen Auerbach, California Professional Research, Newport Beach, CA; James Bailen, Metropolitan Urology, PSC, Jeffersonville, IN; Mira Baron, Rapid Medical Research, Incorporated, Cleveland, OH; Hal Bashein, Radiant Research, West Palm Beach, FL; Laurence Belkoff, Urology Surgery, PC, Bala Cynwyd, PA; Yitzhak Berger, Linked Urology Research Network, LLC, West Orange, NJ; Stephen Brady, Anchor Research Center, Naples, FL; Craig Canfield, Coastal Medical Research Group, Incorporated, San Luis Obispo, CA; Ronald Castellanos, Clinical Physiology Center, Fort Myers, FL; Stacy Childs, Wyoming Research Foundation, Incorporated, Cheyenne, WY; Franklin M. Chu, San Bernardino Urological Associates, San Bernardino, CA; Arnold Cinman, Tower Urology Medical Group, Los Angeles, CA; Randil L. Clark, North Idaho Urology, Coeur d’Alene, ID; Kevin Cline, Regional Urology, LLC, Shreveport, LA; David Cunningham, UroSearch, Ocala, FL; Adrian Dahdul, FutureCare Studies, Springfield, MA; G. Willy Davila, Department of Gynecology, Cleveland Clinic of Florida, Weston, FL; Eugene Dula, West Coast Clinical Research, Van Nuys, CA; Mitchell Efros, Acu Med, Garden City, NY; Mildred Farmer, Meridien Research/Gerontology, St. Petersburg, FL; Robert Feldman, Miami Research, Miami, FL; Jeffrey Frankel, Seattle, WA; Sheldon Freedman, Las Vegas, NV; Gamal Ghoniem, Department of Urology, Cleveland Clinic of Florida, Weston, FL; Phillip Ginsberg, Philadelphia, PA; Marc Gittelman, South Florida Medical Research, Aventura, FL; Andre S. Godet, Advanced Clinical Therapeutics, LLC, Anchorage, AK; Kenneth Goldberg, Texas Urology, Trinity Medical Center, Carrollton,

european urology 51 (2007) 1054–1064

TX; James Gottesman, Seattle Urological Associates, Seattle, WA; Christopher Graham, Urology San Antonio Research, San Antonio, TX; Michael Guerena, Research Across America, Oceanside, CA; David Guth, Northwest Physicians Research Network, Missoula, MT; Richard Harris, RMD Clinical Research, LLC, Melrose Park, IL; David R. Hassman, Comprehensive Clinical Research, Berlin, NJ; Gerard Henry, Wilson Urology, Van Buren, AR; Elizabeth Houser, PQR Incorporated, Austin, TX; David Jablonski, Winter-Park Urology Associates, Orlando, FL; Karny Jacoby, Integrity Medical Research, Seattle, WA; Jed Kaminetsky, New York, NY; Marshall Kaplan, Renstar Medical Research, Plantation, FL; Jamie Kapner, Scottsdale Urologic and Reproductive Practice, Scottsdale, AZ; Lawrence Karsh, Western Urologic Associates, Wheat Ridge, CO; Joel Kaufman, Urology Research Options, Aurora, CO; L. Dean Knoll, Medical Research Associates of Nashville, Nashville, TN; William Koltun, Medical Center for Clinical Research, San Diego, CA; Steven K. Lawton, Wichita Clinic, P.A., Wichita, KS; Lawrence Lind, North Shore-Long Island Jewish Health System, Great Neck, NY; David Lipsitz, NorthEast Urology Research, Concord, NC; Joseph Macaluso, Urologic Institute of New Orleans, Gretna, LA; Fleming Mattox, Greenville, SC; Kurt McCammon, Divine Tidewater Urology, Virginia Beach, VA; James McMurray, Medical Affiliated Research Center, Huntsville, AL; Charles Metzger, Glendora, CA; Jeffrey Michelson, Eastern Carolina Women’s Center, PA, New Bern, NC; H. David Mitcheson, Bay State Clinical Trials, Incorporated, Watertown, MA; David Mobley, Mercury Research, Incorporated, Houston, TX; Alfred Moffett, Moffett & Moffett, MD, PA, Leesburg, FL; William Moseley, San Diego UroResearch, San Diego, CA; Myron Murdock, 206 Research Associates, Greenbelt, MD; Gary Newman, Arizona Center for Clinical Research, West Sun City, AZ; Eric Nicely, Urology Consultants of Knoxville, Knoxville, TN; Harin Padma-Nathan, The Male Clinic, Beverly Hills, CA; Alan Palamara, OB/GYN Health Center, Medford, OR; Joseph D. Parkhurst, nTouch Research, Oklahoma City, OK; Ramon PerezMarrero, Advanced ARI Research Institute, New Port Richey, FL; Dennis Pessis, Affiliated Urologists LTD, Chicago, IL; Jill Peters-Gee, Women’s Specialty Care, Newington, CT; Walter Pittman, Urology Centers of Alabama, Homewood, AL; Alfred Poindexter, Advances in Health, Incorporated, Houston, TX; Wayne Poll, AKSM Clinical Research, Columbus, OH; Sharon E. Prohaska, nTouch Research-Kansas City, Kansas City, MO; Raymond Rackley, Urological Institute, Cleveland Clinic Foundation, Cleveland, OH; Doyle Renfroe, Mississippi Urology Clinic, PLLC,

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Jackson, MS; Henry Ritter, Jr, Peninsula Urology, Atherton, CA; Frederick C. Robinson, Piedmont Clinical Research Center, Ninety Six, SC; Paula Rookis, Alabama Research Center, Birmingham, AL; Eric Rovner, Division of Urology, University of Pennsylvania Health System, Philadelphia, PA; Ivan Sandoz, Radiant Research, Incorporated, Portland, OR; Douglas Schumacher, Radiant Research, Incorporated, Columbus, OH; Gregory Scott, Medical Care Clinics of America, North St. Petersburg, FL; Larry Seidman, Philadelphia Women’s Research, Philadelphia, PA; Scott Serels, Bladder Control Center of Norwalk, Norwalk, CT; Dhana Shrestha, Bay Area Health Clinic, Bay City, MI; Paul Siami, Welborn Clinic, Evansville, IN; Alfred Sidhom, Advanced Urology Medical Center, Anaheim, CA; Paul Sieber, Urological Associates of Lancaster, Lancaster, PA; James C. Sipio, Delaware Valley Clinical Research, Cherry Hill, NJ; Jeffrey A. Snyder, Genitourinary Surgical Consultants, Denver, CO; Christopher Steidle, Northeast Indiana Research, Fort Wayne, IN; Jacques Susset, MultiMed Research, Providence, RI; Kevin Tomera, Alaska Clinical Research Center, LLC, Anchorage, AK; Michael Twede, Physicians Research Options, Sandy, UT; Steven Varady, Radiant Research, Lake Worth, FL; Barton Wachs, Atlantic Urological Medical Group, Long Beach, CA; John Wegenke, University of Wisconsin Office of Clinical Trials, Madison, WI; Charles White, Coastal Clinical Research, Mobile, AL; Norris Whitlock, Matrix Research, LLC, Greenville, SC; Mitchell L. Wiatrak, Midwest Research Specialists, Milwaukee, WI; Peter Wisniewski, Medical Care Clinics of America, Lakeland, FL; Rafael S. Wurzel, Grove Hill Medical Center, New Britain, CT; and George Yamauchi, Advanced Urology Medical, Los Angeles, CA. A complete list of the 041 Study Group follows: Paul Abrams, Southmead Hospital, Bristol, United Kingdom; Luigi Aldera, 3004 Cape Town Medi Clinic, Cape Town, South Africa; Cal Andreou, Urology Clinic, Surrey, British Columbia, Canada; Pedro Aran˜o´, Fundacio´ Puigvert, I.U.N.A., Unidad de urodinamia, Barcelona, Spain; Kerstin Asplund, Kvinnoha¨lsan, Fro¨so¨n, Sweden; Jack Barkin, Toronto Urology Study Group, Toronto, Ontario, Canada; Edgardo Becher, Centro de Diagnostico Urolo´gico, Buenos Aires, Argentina; Eduardo Vazquez Blanco, GINEC, San Isidro, Buenos Aires, Argentina; H.-M. Blu¨mlein, Urologische Praxis, Forchheim, Germany; Einar Brekkan, Urologkliniken, Uppsala, Sweden; Pere Brescot, Fundacio´ Sanita`ria de Igualada, Barcelona, Spain; Ilse Breytenbach, Durbanville Hospital, Cape Town, South Africa; Milos Brodak, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic; Ian Brown, Niagra Falls, Ontario, Canada;

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J.L. Bruins, Streekziekenhuis, Koningin Beatrix, Winterswijk, The Netherlands; J Butler, Oakside Surgery, Devon, United Kingdom; T Cahill, The Frome Medical Centre, Somerset, United Kingdom; Ian Caldwell, Swan Lane Medical Centre, Bolton, United Kingdom; Neil Christopher, Addington Hospital, Durban, Kwa Zulu Natal, South Africa; L.C.E. Coetzee, Pretoria Urology Institute, Hatfield, Pretoria, South Africa; Robert Cook, Saltash Health Centre, Cornwall, United Kingdom; A Cowie, The Porch Surgery, Wiltshire, United Kingdom; Hanns-Gerd Dammann/Annette Herzner, Klinische Forschung Hamburg, Hamburg, Germany; K.P.J. Delaere, Atrium Medisch Centrum, Heerlen, The Netherlands; John Diamond, Garden Street Surgery, Derry, United Kingdom; Jens C. Djurhuus, Inst of Experimental Clin Research, Aarhus N, Denmark; M Duckworth, Lovemead Group Practice, Wiltshire, United Kingdom; Patrick Eavis, Oldfield Surgery, Bath, United Kingdom; David Eiley, Ultra-Med Medical Research, Pointe-Claire, Quebec, Canada; Ingrid Engelbrecht, Pretoria, South Africa; Aino FianuJonasson, Huddinge Universitetssjukhus, Stockholm, Sweden; Stanley Flax, DMJ Research and Development, Bramalea, Ontario, Canada; Robert Freeman, Derriford Hospital, Plymouth, United Kingdom; Christopher French, Riverside Professional Centre, Sydney, Nova Scotia, Canada; Justa Garcia, Hospital La Paz., Madrid, Spain; Gaunt, Rowden Surgery, Wilts, United Kingdom; Barry Gilliland, Obstetrics & Gynecologic Consultants, Saskatoon, Saskatchewan, Canada; Karin Glavind, Aalborg Sygehus Nord, Aalborg, Denmark; Bernard Goldfarb, North Bay, Ontario, Canada; Anthony Grizic, Chelmsford Medical Centre, Kwa Zulu Natal, South Africa; Peter Harden, Kenridge Hospital, Johannesburg, South Africa; Marie-Andre´e Harvey, Kingston General Hospital, Kingston, Ontario, Canada; David Haworth, Layton Medical Centre, Lancashire, United Kingdom; Jeremy Heaton, Kingston General Hospital, Kingston, Ontario, Canada; Anne-Mari Helkkula, Jyrkka¨la¨n terveysasema,Turku, Finland; Eva Hellmis, Urologische Gemeinschaftspraxis, Duisburg, Germany; Elke Hessdo¨rfer, Facha¨rztin fu¨r Urologie, Berlin, Germany; Martina Horn, Urologische Praxis, Lu¨beck, Germany; Daniel Jedlicka, Hospital Na Homolce, Praha, Czech Republic; Karl-Ulrich Johann, Facharzt fu¨r Urologie, Berlin, Germany; Karl Kassier, Medi Clinic, Kwa Zulu Natal, South Africa; Hannu Koistinen, Marian sairaala, HUS, Finland; Pa¨ivi Kokkila, Runosma¨en terveysasema, Turku, Finland; Tanja Konstantinova, Barnmorskemottagningen, Hospitalstorget, Linko¨ping, Sweden; Krishnan Korlipara, Pike View Medical Centre, Bolton, Lancs,United Kingdom; Sinikka Kyro¨npalo, SOK Tyo¨terveysasema, Tampere,

Finland; Andreas W. Lahm, Heilbronn, Germany; Othon Lalos, Norrlands Universitetssjukhus, Umea˚, Sweden; Morrie Liquornik, MOR Urology Inc., Newmarket Ontario, Canada; Gunnar Lose, Glostrup Hospital, Copenhagen, Glostrup, Denmark; Olavi Lukkarinen, Oulun Diakonissalaitos, TUTKO, Oulu, Finland; Alain Maillette, Groupe de recherche en urologie de la Mauricie, Trois-Rivieres, Quebec, Canada; Daniela Marschall-Kehrel, Oberursel, Germany; Robert Marsik, University Thomayer´s Hospital, Praha, Czech Republic; Osvaldo Mazza, Buenos Aires, Argentina; Catriona Mc Cracken, Portglenone Health Centre, Portglenone, United Kingdom; Camilo Medina, Bogota´, Colombia; Luciano L Micheletti, Centro Urolo´gico de Rosario, Santa Fe, Argentina; Alan Naud, Centre de Recherche, Quebec, Canada; Jorgen Nordling, University of Copenhagen, Herlev Hospital, Herlev, Denmark; Mark Bradley Noss, Upper Canada Medical Group, Brockville, Canada; Benjamin Okafo, Orillia Urology Associates, Orrillia, Ontario, Canada; Bruce Palmer, BW Palmer Urology Inc., Kentville, Canada; Jean Benoit Paradis, Clinique d´Urologie de Chicoutimi, Chicoutimi, Canada; Steve Parr-Burman, Lancashire, United Kingdom; Leena Passi-Metsomaa, Ruskon terveysasema, Rusko, Finland; J Patrick, The Bradford Health Centre, Wiltshire, United Kingdom; Allan Patrick, Ontario, Canada; Antonio Pessarrodona, Hospital Mutua de Terrassa, Terrassa, Spain; Montserrat Espuna Pons, Hospital Clı´nic de Barcelona, Barcelona, Spain; Alan Pontin, Groote Schuur Hospital, Cape ¨ rnsko¨ldsvik, Town, South Africa; Nils Poromaa, O Sweden; Jaykumar Purohit, Brannel Surgery, Cornwall, United Kingdom; Robert Ian Reid, Polyclinic Professional Centre, Charlottetown, Prince Edward Island, Canada; Salomon Romano, Instituto Medico Especializado, Buenos Aires, Argentina; S Rowlands, The Surgery, Wiltshire, United Kingdom; Torsten Sandin, Kirurgmottagningen, Ga¨vle, Sweden; A Schmidt, University of Stellenbosch, Parow, South Africa; P.M. Shearer, The Surgery, Ayr, United Kingdom; Jose Miguel Silva, Hospital Universitario San Ignacio, Bogota´, Colombia; Suzanne Sinclair, Gynekologiska mottagningen, Partille, Sweden; David Smart, Morningside Mediclinic, Johannesburg, South Africa; Matthias Solga, Berlin, Germany; Gary Steinhoff, G. Steinhoff Clin Reseach, Victoria, British Columbia, Canada; Lawrence Stewart, Western General Hospital, Edinburgh, United Kingdom; Douw G Steyn, Parklands Hospital, Kwa Zulu Natal, South Africa; Peter Stro¨berg, Sko¨vde, Sweden; Julia Taylor, Eastleigh Surgery, Westbury, United Kingdom; Alberto Tejada, Lima Peru´; Juan C Tejerizo, Centro Urolo´gico, Buenos Aires, Argentina; J Tilley, The Pulteney Practice, Bath, United Kingdom; Enrique

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Ubertazzi, Hospital Churruca, Buenos Aires, Argentina; Michael Urban, Praha, Czech Republic; Juan Fernando Uribe, Torre Fundadores, Medellin, Colombia; Leena Vasara, Tampereen la¨a¨ka¨rikeskus Oy, Koskiklinikka, Tampere, Finland; A.C. Viddeleer, Ede, The Netherlands; Volker von Behren, Wiesbaden, Germany; Wolfgang Warnack, Hagenow, Germany; Michael Weidenfeld, Wiesbaden, Germany; Peter Weitz, Frankfurt, Germany; J Wheal, Launceston Medical Center, Cornwall, United Kingdom; Chui Kin Yuen, Manitoba Clinic, Winnipeg, Canada; Joseph Zadra, The Male Health Centre, Barrie, Ontario, Canada; Luis Zegarra, Lima, Peru´. References [1] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003;61:37–49. [2] Reeves P, Irwin D, Kelleher C, et al. The current and future burden and cost of overactive bladder in five European countries. Eur Urol 2006;50:1050–7. [3] Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20:327–36. [4] Abrams P, Kelleher C, Lerr L, Rogers R. Overactive bladder significantly affects quality of life. Am J Manag Care 2000;6:S580–90. [5] Liberman JN, Hunt TL, Stewart WF, et al. Health-related quality of life among adults with symptoms of overactive bladder: results from a U.S. community-based survey. Urology 2001;57:1044–50. [6] Coyne KS, Payne C, Bhattacharyya SK, et al. The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey. Value Health 2004;7:455–63. [7] Coyne KS, Zhou Z, Thompson C, Versi E. The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int 2003;92:731–5. [8] Stach-Lempinen B, Sintonen H, Kujansuu E. The relationship between clinical parameters and health-related quality of life as measured by the 15D in incontinent women before and after treatment. Acta Obstet Gynecol Scand 2004;83:983–8. [9] Coyne KS, Zhou Z, Bhattacharyya SK, et al. The prevalence of nocturia and its effect on health-related quality of life and sleep in a community sample in the USA. BJU Int 2003;92:948–54. [10] Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87:760–6. [11] Elinoff V, Bavendam T, Glasser DB, et al. Symptom-specific efficacy of tolterodine extended release in patients with overactive bladder: The IMPACT trial. Int J Clin Pract 2006;60:752–8.

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[12] Irwin DE, Milsom I, Kopp Z, Abrams P, Cardozo L. Impact of overactive bladder symptoms on employment, social interactions and emotional well-being in six European countries. BJU Int 2006;97:96–100. [13] Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005;48:5–26. Corrigendum. Eur Urol 2005;48:875. [14] Rackley R, Weiss JP, Rovner ES, Wang JT, Guan Z. Nighttime dosing with tolterodine reduces overactive bladder-related nocturnal micturitions in patients with overactive bladder and nocturia. Urology 2006;67:731–6, discussion 36. [15] Abrams P, Nordling J, Guan Z, et al. Nighttime dosing of tolterodine reduces overactive bladder-related nocturnal frequency in patients with overactive bladder and nocturia. Eur Urol Suppl 2005;4(3):62 (abstract no. 240). [16] European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products. Note for guidance on the clinical investigation of medicinal products for the treatment of urinary incontinence. London. December 2002. CPMP/EWP/18/01. [17] Coyne KS, Matza L, Thompson C, Bavendam T, Jumadilova Z. A comparison of three approaches to analyze urinary urgency as a treatment outcome. Paper presented at: 35th Annual Meeting of the International Continence Society, August 28–September 2, 2005, Montreal, Quebec, Canada. [18] Coyne KS, Matza L, Thompson C, et al. From an OAB patient perspective: health-related quality of life improves when frequency and urgency improve. Paper presented at: 35th Annual Meeting of the International Continence Society, August 28–September 2, 2005, Montreal, Quebec, Canada. [19] van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:179–83. [20] Michel MC, Schneider T, Krege S, Goepel M. Does gender or age affect the efficacy and safety of tolterodine? J Urol 2002;168:1027–31. [21] Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 2006;49:651–9. [22] Hyman MJ, Groutz A, Blaivas JG. Detrusor instability in men: correlation of lower urinary tract symptoms with urodynamic findings. J Urol 2001;166:550–2. [23] Andersen JT, Nordling J, Walter S, Prostatism I. The correlation between symptoms, cystometric and urodynamic findings. Scand J Urol Nephrol 1979;13:229–36. [24] Machino R, Kakizaki H, Ameda K, et al. Detrusor instability with equivocal obstruction: A predictor of unfavorable symptomatic outcomes after transurethral prostatectomy. Neurourol Urodyn 2002;21:444–9. [25] Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 2005;174: 2273–6.

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[26] Lee JY, Kim HW, Lee SJ, et al. Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int 2004;94:817–20. [27] Lagakos SW. The challenge of subgroup analyses— reporting without distorting. N Engl J Med 2006;354:1667–9.

Editorial Comment Giacomo Novara, IRCCS Istituto Oncologico Veneto, Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV floor, Via Giustiniani 2, 35100, Padua, Italy [email protected] Despite the similar prevalence of overactive bladder (OAB) in men and women, most of the patients enrolled in the randomised controlled trials (RCTs) assessing efficacy and safety of anticholinergic drugs are women. Due to possible differences in age, etiology, symptoms, and comorbidity, data obtained in women with OAB need to be validated in men but pieces of evidence are limited (e.g., ref. [20] in the article). Dmochowski et al. are to be commended for their efforts to fill the gap in our knowledge. Specifically, their study is a pooled analysis of two RCTs that tested efficacy and tolerability of nighttime tolterodine extended release (ER). The original issue is that 745 patients (44% of the whole cohort) were men, allowing a subgroup analysis according to the patient’s gender. The results of the study are interesting, showing similar efficacy for male and female patients. In male patients, specifically, nighttime tolterodine ER decreased mean total micturitions as well as the micturitions driven by urgency during 24 h. In the daytime interval, similarly, the total number of micturitions and those due to severe urgency were significantly reduced, whereas the same did not happen for total micturitions during the nocturnal interval (which was the primary end point of both RCTs). Similar efficacy data were obtained with acceptable adverse event rates, with dry mouth being the most frequent (11%). Notably, in the treatment arms withdrawals due to adverse events

[28] ClinicalTrials.gov Web site. A randomized, double blind, placebo controlled trial of Detrol LA in men with overactive bladder [cited July 31, 2006]. Available at: URL: http://www.clinicaltrials.gov/ct/show/NCT00282932? order=3.

were as low as in the placebo groups and acute urinary retentions were not significantly increased, as already suggested in a systematic review addressing the use of anticholinergics in men [1]. As correctly stated by the authors, subgroup analyses from RCTs are not free of biases (e.g., ref. [27] in the article) and provide only a grade B recommendation for the use of the drug in men [2]. The ideal way to achieve high-quality evidence would be well-designed, adequately powered RCTs enrolling only men but, to date, such studies are not available. Do we have to use anticholinergics in men with OAB? The present study may provide a reasonable context for the use of tolterodine ER and, by extension, other antimuscarinic drugs in such patients. However, several interesting data are still lacking (e.g., long-term efficacy, long-term safety, and improvement in quality of life due to therapy). I hope that the expected RCTs will have longer follow-up times and use validated questionnaires, such as the recommended OAB-q [3], rather than an urgency rating scale whose extensive validation was not published. References [1] Novara G, Galfano A, Ficarra V, Artibani W. Anticholinergic drugs in patients with bladder outlet obstruction and lower urinary tract symptoms: a systematic review. Eur Urol 2006;50:675–83. [2] Phillips B, Ball C, Sackett D, et al. Levels of evidence and grades of recommendation. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/levels_ of_evidence.asp#levels. [3] Donovan J, Bosch R, Gotoh M, et al. Symptom and quality of life assessment. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence, 3rd International Consultation on Incontinence. Plymouth, UK: Health Publication; 2005. p. 519–84.