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Reduced perception of urgency in treatmentof overactive bladder with extended-release tolterodine
ORIGINAL RESEARCH
Reduced Perception of Urgency in Treatment of Overactive Bladder With Extended-Release Tolterodine Robert Freeman, MD, FRCOG, Simon Hill, MRCOG, Richard Millard, FRCS, FRACS, Mark Slack, MMed, MRCOG, and John Sutherst, MD, FRCOG, for the Tolterodine Study Group OBJECTIVE: To evaluate the effect of once-daily, extendedrelease tolterodine on urinary urgency in patients with overactive bladder. METHODS: Patients with urinary frequency (eight or more micturitions per 24 hours) and urge incontinence (five or more episodes per week) were randomized to oral treatment with tolterodine extended release 4 mg once daily (n ⴝ 398) or placebo (n ⴝ 374) for 12 weeks. Efficacy was assessed by use of patient perception evaluations. RESULTS: The results presented are a secondary analysis of this double-blind, placebo-controlled study. Of patients treated with tolterodine extended release, 44% reported improved urgency symptoms (compared with 32% for placebo), and 62% reported improved bladder symptoms (placebo, 48%) (both P < .001 compared with placebo). The odds of reducing urgency and improving bladder symptoms were 1.68 and 1.78 times greater, respectively, for patients in the tolterodine extended release group than for patients receiving placebo. In response to urgency, there was a more than six-fold increase in the proportion of patients able to finish a task before voiding in the tolterodine extended release group. The proportion of patients unable to hold urine upon experiencing urgency was also decreased by 58% with tolterodine, compared with 32% with placebo (P < .001). The proportion of patients reporting “much benefit” from treatment was greater for tolterodine extended release than for placebo (43% versus 24%; P < .001). The only adverse events with an incidence of greater than 5% were dry mouth, headache, and constipation, with only dry mouth markedly more frequent with tolterodine than with placebo. CONCLUSION: Tolterodine extended release has demonstrable efficacy in reducing the severity of urinary urgency and is associated with improvements in overactive bladder From the Urogynaecology Unit, Derriford Hospital, Plymouth; Department of Obstetrics and Gynaecology, Queen’s Park Hospital, Blackburn; Departments of Obstetrics and Gynaecology, Hinchingbrooke and Cambridge Hospitals, Cambridgeshire; Urodynamic Unit, BUPA Murrayfield Hospital, Wirral, United Kingdom; and Department of Urology, Prince of Wales and Prince Henry Hospitals, Sydney, Australia.
symptoms that are meaningful to patients. (Obstet Gynecol 2003;102:605–11. © 2003 by The American College of Obstetricians and Gynecologists.)
Overactive bladder1 is a common, chronic, and debilitating medical condition characterized by increased urinary urgency and frequency, with or without urge incontinence. The condition affects people of all ages and occurs in both men and women. Although overactive bladder symptoms are widespread and have a profound effect on the daily lives of sufferers,2–5 many patients are undiagnosed and therefore untreated. Urgency is the central symptom of overactive bladder, and a number of studies of this condition show that the symptoms of frequency and urgency are as commonly reported as urge incontinence.6 In fact, approximately half of patients with overactive bladder are continent, and for these individuals urgency is the key problem. A treatment that relieves urgency would be beneficial, but to date there are no specific data demonstrating an effect of antimuscarinic agents on urgency, despite these agents commonly being used for the treatment of overactive bladder. Tolterodine is the first antimuscarinic agent developed specifically for the treatment of overactive bladder. Unlike existing antimuscarinic agents, tolterodine shows functional selectivity for the bladder in vivo,7 producing a greater effect on the bladder than on salivation.8,9 A large, multicenter, double-blind, placebo-controlled, 12-week study was performed to evaluate the effect of treatment with tolterodine extended-release and immeFinancial Disclosure This study was supported by Pharmacia Corporation, Peapack, New Jersey. Investigator fees were paid by Pharmacia into the research funds of the authors and used to employ research staff, fund research, and purchase equipment. None of the authors own stock in Pharmacia or hold stock options. Pharmacia owns the data.
VOL. 102, NO. 3, SEPTEMBER 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
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diate-release formulations in patients with overactive bladder. Data on diary voiding variables have previously been published.10 This article reports the effect of the extended-release formulation of tolterodine on urgency and other patient-perception variables during treatment.
MATERIALS AND METHODS This is a secondary analysis from a multinational, double-blind, placebo-controlled study that was conducted in 167 centers in Europe (n ⫽ 89), North America (n ⫽ 74), and Australia and New Zealand (n ⫽ 4).10 The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. The local ethics committee of each center approved the study protocol, and all patients gave written, informed consent before the start of the study. Male and female patients at least 18 years old with urinary frequency (eight or more micturitions per 24 hours), urgency, and urge incontinence (five or more incontinence episodes per week) were eligible for inclusion, provided they had experienced symptoms of overactive bladder for at least 6 months. Micturition diaries completed before randomization were used to document urinary frequency and urge incontinence. Urodynamics were not performed, and patients were recruited solely on the basis of their symptoms and irrespective of whether they had received prior antimuscarinic therapy and the outcome of that treatment. Exclusion criteria were stress incontinence, total daily urine volume greater than 3 L, any contraindications to antimuscarinic treatment, significant hepatic or renal disease, symptomatic or recurrent urinary tract infections, interstitial cystitis, hematuria or bladder outlet obstruction, electrostimulation or bladder training, indwelling catheter, or intermittent self-catheterization. Pregnant or nursing women or women of childbearing potential not using reliable contraceptive methods were also excluded. Any treatment for overactive bladder, including use of anticholinergic drugs or drugs that inhibit cytochrome P450 3A4 isoenzymes, within 14 days preceding randomization was not permitted. An exception was made for those patients receiving estrogen treatment who had been started more than 2 months before randomization. At an initial screening visit, a complete medical and drug history was taken, along with a full laboratory screen and a midstream specimen of urine for culture and urinalysis. Patients were then enrolled into a 2-week washout and run-in period, during which the number of incontinence episodes and frequency of micturition were recorded in micturition diaries for 7 consecutive days.
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The volume voided (mL) for every micturition and the number of incontinence pads used were also recorded. Eligible patients were subsequently randomized (1:1) by a random-permuted-blocks procedure (in blocks of six because the original trial comprised three treatment arms) prepared by an independent statistician, to oral therapy with tolterodine extended-release capsules 4 mg once daily or matching placebo for 12 weeks. No dosage adjustment was allowed during the study. A follow-up visit was performed 1 week after study completion to record adverse events and changes in concomitant medication. Efficacy of treatment was assessed by the change in patient perception of urgency and bladder condition from baseline to week 12. Findings for changes in micturition diary variables have been reported elsewhere,10 with statistically significant improvements in all diary variables in the active treatment group compared with placebo. To evaluate the effect of treatment on patients’ perception of urgency, each patient completed a three-point urgency perception scale at baseline and after 12 weeks’ treatment. Patients were asked to describe their typical experience when he or she felt the desire to urinate. The possible response options were as follows: 1 ⫽ “I am usually not able to hold urine,” 2 ⫽ “I am usually able to hold urine until I reach the toilet if I go immediately,” and 3 ⫽ “I am usually able to finish what I am doing before going to the toilet.” The psychometric qualities (reliability, construct validity, and responsiveness) of the urgency perception scale were validated with secondary analyses of the clinical and patient assessment data gathered during the three separate clinical studies of tolterodine. Construct validity was assessed by correlations between the urgency perception scale and patient micturition diary variables and other patient assessments, including perception of bladder condition and perception of treatment benefit. Analyses of variance with Student-NewmanKeuls’ post hoc pairwise comparisons were performed to assess the responsiveness and discriminant validity of the urgency perception scale (Cardozo L, Coyne K, Versi E. Validation of the urgency perception scale (UPS). Poster presented at the International Society for Pharmacoeconomics and Outcomes Research 7th Annual Meeting; Arlington, Virginia; May 19 –21, 2002. Available at: www.ispor.org/meetings/va0502/ presentations/sesion1/PUK9.pdf). Patients were also asked to rate their perception of severity of problems caused by their bladder symptoms on a six-point rating scale (1 ⫽ no problems, 2 ⫽ very minor problems, 3 ⫽ minor problems, 4 ⫽ moderate problems, 5 ⫽ severe problems, and 6 ⫽ many severe
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problems) at baseline and after 12 weeks’ treatment. Improvement in urgency was defined as an increase in the urgency perception scale score of at least one point, whereas a decrease in the urgency perception scale score of at least one point was used to define deterioration between baseline and study end. Patients’ global selfevaluation of treatment at study end was graded as no benefit, little benefit, or much benefit. Analyses by sex of patients’ perceptions of urgency and bladder symptoms were performed. All directly observed adverse events and all those spontaneously reported by patients during the 12-week treatment period and 1 week of follow-up were categorized in terms of intensity (mild, moderate, or severe) and causality. A serious adverse event was defined as death or risk of death, hospitalization, persistent incapacity or a congenital abnormality, or neonatal death after exposure in pregnancy. Laboratory assessments for clinical chemistry (bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, creatinine, sodium, potassium, and thyroid-stimulating hormone) and hematologic variables (erythrocytes, hemoglobin, platelets, and leukocytes) were assessed at the end of treatment. Patients could be withdrawn from the study if it was considered medically necessary or at the patient’s request. Returned unused medication was the basis for determining treatment compliance. Patients with less than 75% compliance with treatment at study end were excluded from the per-protocol analysis. Descriptive statistics were used to characterize the patient sample, with t tests and 2 tests used to examine group differences. Because this was a secondary analysis of the trial, with outcomes based in patient perception, all data analyses were performed on the per-protocol patient population, which consisted of patients who completed the study without protocol violations; the analysis contained no imputed data. Change scores from baseline to 12 weeks were calculated for all variables. Counts and percentages were used to describe categoric data, and comparisons between the two treatment groups were performed with 2 statistics. Odds ratios [ORs] were calculated to evaluate the likelihood of improvement in urgency and bladder condition by treatment group. RESULTS The study population comprised 772 patients with overactive bladder (84% female). At randomization, the number in the two groups was comparable, but owing to the higher number of protocol violations in the placebo group (placebo, n ⫽ 134; tolterodine extended release, n ⫽ 109),10 the number of patients in the active arm is
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greater in the per-protocol analysis (placebo, n ⫽ 374; tolterodine extended release, n ⫽ 398). Reasons for protocol violations were as follows: randomized but has not taken any study medication; less than 4.5 incontinence episodes per week at baseline; missing, incomplete, or invalid micturition chart; concomitant use of prohibited medications; and compliance less than 75%. Included within these violations were premature withdrawals due to adverse events (placebo, n ⫽ 33; tolterodine extended release, n ⫽ 27). Dry mouth was among the reasons for withdrawal in six and 12 patients receiving placebo and tolterodine extended release, respectively. Baseline and demographic characteristics are presented in Table 1, and there were no differences between the treatment groups. Categoric analysis showed that a significantly greater proportion of patients receiving tolterodine extended release experienced an improvement in urgency during the study than of those randomized to placebo (Table 2), with an OR of 1.68 (95% confidence interval [CI] 1.25, 2.25). Also, a significantly (P ⫽ .002) smaller proportion of patients taking tolterodine than taking placebo showed deterioration in this parameter. Baseline assessment of the total patient population showed that the two groups were balanced for severity and quality of urgency. The impact of urgency on patient activity is shown in Figure 1. Treatment with tolterodine extended release resulted in a more than six-fold increase (5% to 33%) in the proportion of patients able to finish tasks before voiding in response to urgency; this increase was almost double that seen with placebo (6% to 18%) (P ⬍ .001). Among patients who were unable to hold their urine upon experiencing urgency, a 58% reduction was apparent for the tolterodine extended release group, compared with a 32% decrease for placebo recipients (P ⬍ .001). Analysis of urgency was also performed by sex. Male patients in both the tolterodine extended-release (25.4%) and placebo (26.6%) groups experienced similar improvements in urgency (OR 0.94, 95% CI 0.42, 2.11). However, female patients in the tolterodine extended-release group experienced a greater improvement in urgency compared with those in the placebo group (46.6% versus 26.6%). This was reflected by a significant OR of 1.81 (95% CI 1.31, 2.49) (P ⫽ .001). The two treatment groups were well balanced with respect to the baseline distribution of patients’ perception of bladder symptoms. Thus, approximately 85% of patients in each treatment group reported “moderate to many severe problems” as a result of their bladder symptoms. After 12 weeks’ treatment, the proportion of tolterodine-treated patients reporting an improvement in their bladder symptoms was significantly greater than
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that observed with placebo (62% versus 48%; P ⬍ .001). The odds of improving bladder symptoms were 1.78 times greater for patients in the tolterodine extendedrelease group than for those in the placebo group (95% CI 1.34, 2.37). In male patients, 55.9% in the tolterodine extended-release group perceived an improvement in their bladder symptoms, compared with 43.8% in the placebo group. As with urgency, a greater proportion of female patients in the tolterodine extended-release group (62.8%) perceived an improvement in their bladder symptoms, compared with those in the placebo group (48.4%). This was reflected by a significant OR of 1.80 (95% CI 1.32, 2.47) (P ⫽ .001).
Table 2. Effect of 12 Weeks’ Treatment With Either Extended-Release Formulation of Tolterodine or Placebo on Subjective Assessment of Urinary Urgency in Patients With Overactive Bladder Treatment group Urgency assessment
Tolterodine ER 4 mg once daily (n ⫽ 398)
Placebo (n ⫽ 374)
Improvement No change Deterioration
173 (44)* 203 (51) 22 (6)†
118 (32) 212 (57) 44 (12)
ER ⫽ extended release. Data are presented as n (percent). * P ⬍ .001 vs placebo. † P ⬍ .002 vs placebo.
Table 1. Patient Demographic Data Treatment group Tolterodine ER 4 mg once daily (n ⫽ 398)
Characteristic Male:female (n) Age (y) Race White Black Asian or Pacific Islander Mixed Previous drug therapy for overactive bladder With poor efficacy (%) No. of incontinence episodes per week No. of micturitions per 24 h Volume voided per micturition (mL) Patient perception of bladder condition No problems Very minor problems Minor problems Moderate problems Severe problems Many severe problems Patient perception of urgency Not able to hold urine Able to hold urine until toilet visit Able to finish tasks before toilet visit
59:339 60.6 (22–89)
Placebo (n ⫽ 374) 64:310 61 (22–93)
381 (95.7) 12 (3.0) 4 (1.0)
354 (94.7) 13 (3.5) 3 (0.8)
1 (0.3) 224 (56.3)
4 (1.1) 192 (51.3)
39.7
40.6
22.9 (5–168)
23.5 (5–168)
11.0 (2.3–51.3)
11.2 (2.3–28.4)
139.1 (36–271)
134.5 (21–374)
DISCUSSION 5 (1.3)
3 (0.8) 9 (2.4)
48 (12.1) 191 (48.0) 118 (29.6) 36 (9.0)
44 (11.8) 153 (40.9) 130 (34.8) 35 (9.4)
117 (29.4)
121 (32.4)
262 (65.8)
231 (61.8)
19 (4.8)
22 (5.9)
ER ⫽ extended release. Data are presented as n (percent) or mean (range) unless otherwise noted.
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Of those patients treated with tolterodine extended release, 43% rated their treatment as providing “much benefit,” compared with 24% of placebo recipients (P ⬍ .001) (Table 3). Overall, a significantly greater proportion of patients perceived any benefit with tolterodine extended release compared with placebo (78% versus 55%; P ⬍ .001). The odds of a patient reporting any benefit were 2.87 times greater for patients receiving tolterodine extended release, compared with those receiving placebo (95% CI 2.10, 3.92). The most common adverse events in either treatment group are shown in Table 4. Dry mouth was the most common adverse effect in both groups. Constipation and headache rates in the tolterodine extended-release group were not significantly different from those with placebo. There were no safety concerns in any of the parameters studied.
Urgency Reduction With Tolterodine
Urgency is a central symptom of the overactive bladder, and yet it is difficult to define or quantify. This study has attempted to examine the nature of urgency and the impact of antimuscarinic treatment. It is clear that any significant treatment for overactive bladder must reduce urgency. In the present study, urgency was measured qualitatively and quantitatively. In the scoring system used, an increase from “1” to “2” meant the difference between incontinence and being dry. An increase in score from “2” to “3” meant that the patients improved from having their daily life affected by urgency to being able to continue with normal activities and being able to ignore the symptom. Both changes are important, but the degree of importance is not necessarily linear for the scoring system and may vary between patients.
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Figure 1. Proportion of overactive bladder patients able to finish tasks before visiting a toilet (a) and not able to hold urine (b) in response to urinary urgency, at baseline and after 12 weeks’ treatment with either extended-release (ER) tolterodine or placebo; *** P ⬍ .001 vs placebo. Freeman. Urgency Reduction With Tolterodine. Obstet Gynecol 2003.
All patients entering the study had to have five or more episodes of incontinence per week, but the data on urgency show that at baseline patients were only incontinent about one third of the time in response to an urgency episode. Thus, although enrolled patients admitted to having urge incontinence, the majority of “urge” episodes were indeed dry, although they did have an impact on activity most of the time. After treatment in response to an urgency episode, patients taking placebo were almost twice as likely to become incontinent (Figure 1b). Furthermore, in terms of impact on activity, treatment with tolterodine was twice as effective as placebo. Thus, treatment with tolterodine extended release
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resulted in a change in the severity and nature of urgency. The mechanisms by which tolterodine alters the nature of urgency remain to be established. In this study, urodynamics were not performed because many patients do not exhibit detrusor contractions on urodynamic testing and yet experience urgency (sensory urgency). This might be because of micromotions of the bladder wall,11 and as such the antimuscarinic properties of tolterodine could inhibit such muscle activity. If, however, urgency was caused by a malfunction in the afferent system, then this demonstrated action of tolterodine on urgency is inexplicable based on our current under-
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Table 3. Effect of 12 Weeks’ Treatment With Either a New Extended-Release Formulation of Tolterodine or Placebo on Patient-Perceived Treatment Benefit in Patients With Overactive Bladder Treatment group Perception of treatment benefit
Tolterodine ER 4 mg once daily (n ⫽ 398)
Placebo (n ⫽ 374)
Much benefit Little benefit No benefit
172 (43.2)* 138 (34.7) 88 (22.1)
88 (23.5) 118 (31.6) 168 (44.9)
ER ⫽ extended release. Data are presented as n (percent). * P ⬍ .001 vs placebo.
standing of muscarinic activity in the bladder. It is not clear whether the efficacy of tolterodine is more pronounced in motor or sensory urgency. For any treatment of overactive bladder to be truly beneficial, statistically significant changes in micturition diary variables should lead to a clinically meaningful improvement from the patient’s perspective. This is particularly relevant in terms of urinary urgency, which exerts a marked effect on the quality of life of the affected individual because of its unpredictable nature. Indeed, many patients develop elaborate coping mechanisms, such as urinating at the first sign of urgency or voiding to a timed schedule, to cope with their condition and remain continent or reduce their level of incontinence. In a previous report of the present study that detailed micturition diary variables,10 statistically significant improvements (over placebo and the immediate-release formulation) were observed during treatment with tolterodine extended release, which was well tolerated and showed a low frequency of dry mouth. On the basis Table 4. Summary of Common Adverse Events During 12 Weeks’ Treatment With a New Extended-Release Formulation of Tolterodine, Compared With Placebo, for Overactive Bladder Treatment group
Adverse event
Tolterodine ER 4 mg once daily (n ⫽ 398)
Placebo (n ⫽ 374)
Dry mouth Constipation Headache Abdominal pain Xerophthalmia Diarrhea Urinary tract infection Nausea
95 (23.9) 23 (5.8) 23 (5.8) 16 (4.0) 15 (3.8) 8 (2.0) 7 (1.8) 5 (1.3)
28 (7.5) 16 (4.3) 14 (3.7) 6 (1.6) 7 (1.9) 7 (1.9) 12 (3.2) 5 (1.3)
ER ⫽ extended release. Data are presented as n (percent).
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of these findings (ie, good efficacy and improved tolerability), it was expected that a concomitant improvement in patient perceptions would be observed. This report deals with the data on patient perceptions. Overall, a significantly greater proportion of patients taking tolterodine reported an improvement in these indices, relative to placebo. Analysis by sex revealed significant differences between tolterodine extended release and placebo for both patients’ perception of urgency and patients’ perception of bladder symptoms in women only. The proportion of patients reporting “much benefit” from treatment with tolterodine extended release was double that for placebo, an improvement that was highly statistically significant. These data highlight the need to perform subjective evaluations in conjunction with standard voiding diary end points in such trials to determine the overall benefit of therapy. For example, although an agent, such as oxybutynin, might be effective in reducing clinical end points, such as the number of episodes of urge incontinence, the frequent occurrence of adverse effects might limit the overall benefit from treatment. This is reflected in dropout rates. Withdrawal rates as high as 30% have been reported for oxybutynin,12 compared with 5% for tolterodine.10 In a direct comparison of oxybutynin and tolterodine immediate release, dropout rates were 17% and 8%, respectively.13 In conclusion, the extended-release formulation of tolterodine 4 mg once daily produced improvements in the symptoms of overactive bladder that are meaningful to patients. Indeed this study demonstrates that treatment with tolterodine extended release significantly improves the nature and severity of urgency in patients with overactive bladder. REFERENCES 1. Abrams P, Wein AJ. The overactive bladder: A widespread but treatable condition. Stockholm: Eric Sparre Medical, 1998. 2. Jackson S. The patient with overactive bladder—symptoms and quality of life issues. Urology 1997;50 Suppl 6A:18–22. 3. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997;104:1374–9. 4. Kobelt G, Kirchberger I, Malone-Lee J. Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU Int 1999;83:583–90. 5. Wein AJ, Rovner ES. The overactive bladder: An overview for primary care health providers. Int J Fertil Womens Med 1999;44:56–66. 6. Milsom I, Abrams P, Cardozo L, Roberts RG, Thu¨roff J, Wein AJ. How widespread are the symptoms of an over-
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7. 8.
9.
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11.
active bladder and how do we manage them? A population-based prevalence study. BJU Int 2001;87:760–6. Nilvebrant L. The mechanism of action of tolterodine. Rev Contemp Pharmacother 2000;11:13–27. Stahl MMS, Eckström B, Sparf A, Mattiasson A, Anders son K-E. Urodynamic and other effects of tolterodine: A novel antimuscarinic drug for the treatment of detrusor overactivity. Neurourol Urodyn 1995;14:647–55. Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 2000;55 Suppl 5A:47–9. Van Kerrebroeck PEVA, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: Superior efficacy and tolerability in the treatment of overactive bladder. Urology 2001;57: 414–21. Coolsaet BL, Van Duyl WA, Van Os-Bossagh P, De
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Bakker HV. New concepts in relation to urge and detrusor activity. Neurourol Urodyn 1993;12:463–71. 12. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: A pooled analysis. Urology 1997;50 Suppl 6A:90–6. 13. Abrams P, Freeman R, Anderström C, Mattiasson A. Tolterodine, a new antimuscarinic agent: As effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998;81:801–10. Address reprint requests to: Robert Freeman, MD, FRCOG, Derriford Hospital, Urogynaecology Unit, Directorate of Obstetrics and Gynaecology, Plymouth PL6 8DH, United Kingdom; E-mail: [email protected]. Received May 28, 2002. Received in revised form January 3, 2003. Accepted January 21, 2003.
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Reduced Perception of Urgency in Treatment of Overactive Bladder With Extended-Release Tolterodine Robert Freeman, MD, FRCOG, Simon Hill, MRCOG, Richard Millard, FRCS, FRACS, Mark Slack, MMed, MRCOG, and John Sutherst, MD, FRCOG, for the Tolterodine Study Group OBJECTIVE: To evaluate the effect of once-daily, extendedrelease tolterodine on urinary urgency in patients with overactive bladder. METHODS: Patients with urinary frequency (eight or more micturitions per 24 hours) and urge incontinence (five or more episodes per week) were randomized to oral treatment with tolterodine extended release 4 mg once daily (n ⴝ 398) or placebo (n ⴝ 374) for 12 weeks. Efficacy was assessed by use of patient perception evaluations. RESULTS: The results presented are a secondary analysis of this double-blind, placebo-controlled study. Of patients treated with tolterodine extended release, 44% reported improved urgency symptoms (compared with 32% for placebo), and 62% reported improved bladder symptoms (placebo, 48%) (both P < .001 compared with placebo). The odds of reducing urgency and improving bladder symptoms were 1.68 and 1.78 times greater, respectively, for patients in the tolterodine extended release group than for patients receiving placebo. In response to urgency, there was a more than six-fold increase in the proportion of patients able to finish a task before voiding in the tolterodine extended release group. The proportion of patients unable to hold urine upon experiencing urgency was also decreased by 58% with tolterodine, compared with 32% with placebo (P < .001). The proportion of patients reporting “much benefit” from treatment was greater for tolterodine extended release than for placebo (43% versus 24%; P < .001). The only adverse events with an incidence of greater than 5% were dry mouth, headache, and constipation, with only dry mouth markedly more frequent with tolterodine than with placebo. CONCLUSION: Tolterodine extended release has demonstrable efficacy in reducing the severity of urinary urgency and is associated with improvements in overactive bladder From the Urogynaecology Unit, Derriford Hospital, Plymouth; Department of Obstetrics and Gynaecology, Queen’s Park Hospital, Blackburn; Departments of Obstetrics and Gynaecology, Hinchingbrooke and Cambridge Hospitals, Cambridgeshire; Urodynamic Unit, BUPA Murrayfield Hospital, Wirral, United Kingdom; and Department of Urology, Prince of Wales and Prince Henry Hospitals, Sydney, Australia.
symptoms that are meaningful to patients. (Obstet Gynecol 2003;102:605–11. © 2003 by The American College of Obstetricians and Gynecologists.)
Overactive bladder1 is a common, chronic, and debilitating medical condition characterized by increased urinary urgency and frequency, with or without urge incontinence. The condition affects people of all ages and occurs in both men and women. Although overactive bladder symptoms are widespread and have a profound effect on the daily lives of sufferers,2–5 many patients are undiagnosed and therefore untreated. Urgency is the central symptom of overactive bladder, and a number of studies of this condition show that the symptoms of frequency and urgency are as commonly reported as urge incontinence.6 In fact, approximately half of patients with overactive bladder are continent, and for these individuals urgency is the key problem. A treatment that relieves urgency would be beneficial, but to date there are no specific data demonstrating an effect of antimuscarinic agents on urgency, despite these agents commonly being used for the treatment of overactive bladder. Tolterodine is the first antimuscarinic agent developed specifically for the treatment of overactive bladder. Unlike existing antimuscarinic agents, tolterodine shows functional selectivity for the bladder in vivo,7 producing a greater effect on the bladder than on salivation.8,9 A large, multicenter, double-blind, placebo-controlled, 12-week study was performed to evaluate the effect of treatment with tolterodine extended-release and immeFinancial Disclosure This study was supported by Pharmacia Corporation, Peapack, New Jersey. Investigator fees were paid by Pharmacia into the research funds of the authors and used to employ research staff, fund research, and purchase equipment. None of the authors own stock in Pharmacia or hold stock options. Pharmacia owns the data.
VOL. 102, NO. 3, SEPTEMBER 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(03)00623-9
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diate-release formulations in patients with overactive bladder. Data on diary voiding variables have previously been published.10 This article reports the effect of the extended-release formulation of tolterodine on urgency and other patient-perception variables during treatment.
MATERIALS AND METHODS This is a secondary analysis from a multinational, double-blind, placebo-controlled study that was conducted in 167 centers in Europe (n ⫽ 89), North America (n ⫽ 74), and Australia and New Zealand (n ⫽ 4).10 The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. The local ethics committee of each center approved the study protocol, and all patients gave written, informed consent before the start of the study. Male and female patients at least 18 years old with urinary frequency (eight or more micturitions per 24 hours), urgency, and urge incontinence (five or more incontinence episodes per week) were eligible for inclusion, provided they had experienced symptoms of overactive bladder for at least 6 months. Micturition diaries completed before randomization were used to document urinary frequency and urge incontinence. Urodynamics were not performed, and patients were recruited solely on the basis of their symptoms and irrespective of whether they had received prior antimuscarinic therapy and the outcome of that treatment. Exclusion criteria were stress incontinence, total daily urine volume greater than 3 L, any contraindications to antimuscarinic treatment, significant hepatic or renal disease, symptomatic or recurrent urinary tract infections, interstitial cystitis, hematuria or bladder outlet obstruction, electrostimulation or bladder training, indwelling catheter, or intermittent self-catheterization. Pregnant or nursing women or women of childbearing potential not using reliable contraceptive methods were also excluded. Any treatment for overactive bladder, including use of anticholinergic drugs or drugs that inhibit cytochrome P450 3A4 isoenzymes, within 14 days preceding randomization was not permitted. An exception was made for those patients receiving estrogen treatment who had been started more than 2 months before randomization. At an initial screening visit, a complete medical and drug history was taken, along with a full laboratory screen and a midstream specimen of urine for culture and urinalysis. Patients were then enrolled into a 2-week washout and run-in period, during which the number of incontinence episodes and frequency of micturition were recorded in micturition diaries for 7 consecutive days.
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The volume voided (mL) for every micturition and the number of incontinence pads used were also recorded. Eligible patients were subsequently randomized (1:1) by a random-permuted-blocks procedure (in blocks of six because the original trial comprised three treatment arms) prepared by an independent statistician, to oral therapy with tolterodine extended-release capsules 4 mg once daily or matching placebo for 12 weeks. No dosage adjustment was allowed during the study. A follow-up visit was performed 1 week after study completion to record adverse events and changes in concomitant medication. Efficacy of treatment was assessed by the change in patient perception of urgency and bladder condition from baseline to week 12. Findings for changes in micturition diary variables have been reported elsewhere,10 with statistically significant improvements in all diary variables in the active treatment group compared with placebo. To evaluate the effect of treatment on patients’ perception of urgency, each patient completed a three-point urgency perception scale at baseline and after 12 weeks’ treatment. Patients were asked to describe their typical experience when he or she felt the desire to urinate. The possible response options were as follows: 1 ⫽ “I am usually not able to hold urine,” 2 ⫽ “I am usually able to hold urine until I reach the toilet if I go immediately,” and 3 ⫽ “I am usually able to finish what I am doing before going to the toilet.” The psychometric qualities (reliability, construct validity, and responsiveness) of the urgency perception scale were validated with secondary analyses of the clinical and patient assessment data gathered during the three separate clinical studies of tolterodine. Construct validity was assessed by correlations between the urgency perception scale and patient micturition diary variables and other patient assessments, including perception of bladder condition and perception of treatment benefit. Analyses of variance with Student-NewmanKeuls’ post hoc pairwise comparisons were performed to assess the responsiveness and discriminant validity of the urgency perception scale (Cardozo L, Coyne K, Versi E. Validation of the urgency perception scale (UPS). Poster presented at the International Society for Pharmacoeconomics and Outcomes Research 7th Annual Meeting; Arlington, Virginia; May 19 –21, 2002. Available at: www.ispor.org/meetings/va0502/ presentations/sesion1/PUK9.pdf). Patients were also asked to rate their perception of severity of problems caused by their bladder symptoms on a six-point rating scale (1 ⫽ no problems, 2 ⫽ very minor problems, 3 ⫽ minor problems, 4 ⫽ moderate problems, 5 ⫽ severe problems, and 6 ⫽ many severe
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problems) at baseline and after 12 weeks’ treatment. Improvement in urgency was defined as an increase in the urgency perception scale score of at least one point, whereas a decrease in the urgency perception scale score of at least one point was used to define deterioration between baseline and study end. Patients’ global selfevaluation of treatment at study end was graded as no benefit, little benefit, or much benefit. Analyses by sex of patients’ perceptions of urgency and bladder symptoms were performed. All directly observed adverse events and all those spontaneously reported by patients during the 12-week treatment period and 1 week of follow-up were categorized in terms of intensity (mild, moderate, or severe) and causality. A serious adverse event was defined as death or risk of death, hospitalization, persistent incapacity or a congenital abnormality, or neonatal death after exposure in pregnancy. Laboratory assessments for clinical chemistry (bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, creatinine, sodium, potassium, and thyroid-stimulating hormone) and hematologic variables (erythrocytes, hemoglobin, platelets, and leukocytes) were assessed at the end of treatment. Patients could be withdrawn from the study if it was considered medically necessary or at the patient’s request. Returned unused medication was the basis for determining treatment compliance. Patients with less than 75% compliance with treatment at study end were excluded from the per-protocol analysis. Descriptive statistics were used to characterize the patient sample, with t tests and 2 tests used to examine group differences. Because this was a secondary analysis of the trial, with outcomes based in patient perception, all data analyses were performed on the per-protocol patient population, which consisted of patients who completed the study without protocol violations; the analysis contained no imputed data. Change scores from baseline to 12 weeks were calculated for all variables. Counts and percentages were used to describe categoric data, and comparisons between the two treatment groups were performed with 2 statistics. Odds ratios [ORs] were calculated to evaluate the likelihood of improvement in urgency and bladder condition by treatment group. RESULTS The study population comprised 772 patients with overactive bladder (84% female). At randomization, the number in the two groups was comparable, but owing to the higher number of protocol violations in the placebo group (placebo, n ⫽ 134; tolterodine extended release, n ⫽ 109),10 the number of patients in the active arm is
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greater in the per-protocol analysis (placebo, n ⫽ 374; tolterodine extended release, n ⫽ 398). Reasons for protocol violations were as follows: randomized but has not taken any study medication; less than 4.5 incontinence episodes per week at baseline; missing, incomplete, or invalid micturition chart; concomitant use of prohibited medications; and compliance less than 75%. Included within these violations were premature withdrawals due to adverse events (placebo, n ⫽ 33; tolterodine extended release, n ⫽ 27). Dry mouth was among the reasons for withdrawal in six and 12 patients receiving placebo and tolterodine extended release, respectively. Baseline and demographic characteristics are presented in Table 1, and there were no differences between the treatment groups. Categoric analysis showed that a significantly greater proportion of patients receiving tolterodine extended release experienced an improvement in urgency during the study than of those randomized to placebo (Table 2), with an OR of 1.68 (95% confidence interval [CI] 1.25, 2.25). Also, a significantly (P ⫽ .002) smaller proportion of patients taking tolterodine than taking placebo showed deterioration in this parameter. Baseline assessment of the total patient population showed that the two groups were balanced for severity and quality of urgency. The impact of urgency on patient activity is shown in Figure 1. Treatment with tolterodine extended release resulted in a more than six-fold increase (5% to 33%) in the proportion of patients able to finish tasks before voiding in response to urgency; this increase was almost double that seen with placebo (6% to 18%) (P ⬍ .001). Among patients who were unable to hold their urine upon experiencing urgency, a 58% reduction was apparent for the tolterodine extended release group, compared with a 32% decrease for placebo recipients (P ⬍ .001). Analysis of urgency was also performed by sex. Male patients in both the tolterodine extended-release (25.4%) and placebo (26.6%) groups experienced similar improvements in urgency (OR 0.94, 95% CI 0.42, 2.11). However, female patients in the tolterodine extended-release group experienced a greater improvement in urgency compared with those in the placebo group (46.6% versus 26.6%). This was reflected by a significant OR of 1.81 (95% CI 1.31, 2.49) (P ⫽ .001). The two treatment groups were well balanced with respect to the baseline distribution of patients’ perception of bladder symptoms. Thus, approximately 85% of patients in each treatment group reported “moderate to many severe problems” as a result of their bladder symptoms. After 12 weeks’ treatment, the proportion of tolterodine-treated patients reporting an improvement in their bladder symptoms was significantly greater than
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that observed with placebo (62% versus 48%; P ⬍ .001). The odds of improving bladder symptoms were 1.78 times greater for patients in the tolterodine extendedrelease group than for those in the placebo group (95% CI 1.34, 2.37). In male patients, 55.9% in the tolterodine extended-release group perceived an improvement in their bladder symptoms, compared with 43.8% in the placebo group. As with urgency, a greater proportion of female patients in the tolterodine extended-release group (62.8%) perceived an improvement in their bladder symptoms, compared with those in the placebo group (48.4%). This was reflected by a significant OR of 1.80 (95% CI 1.32, 2.47) (P ⫽ .001).
Table 2. Effect of 12 Weeks’ Treatment With Either Extended-Release Formulation of Tolterodine or Placebo on Subjective Assessment of Urinary Urgency in Patients With Overactive Bladder Treatment group Urgency assessment
Tolterodine ER 4 mg once daily (n ⫽ 398)
Placebo (n ⫽ 374)
Improvement No change Deterioration
173 (44)* 203 (51) 22 (6)†
118 (32) 212 (57) 44 (12)
ER ⫽ extended release. Data are presented as n (percent). * P ⬍ .001 vs placebo. † P ⬍ .002 vs placebo.
Table 1. Patient Demographic Data Treatment group Tolterodine ER 4 mg once daily (n ⫽ 398)
Characteristic Male:female (n) Age (y) Race White Black Asian or Pacific Islander Mixed Previous drug therapy for overactive bladder With poor efficacy (%) No. of incontinence episodes per week No. of micturitions per 24 h Volume voided per micturition (mL) Patient perception of bladder condition No problems Very minor problems Minor problems Moderate problems Severe problems Many severe problems Patient perception of urgency Not able to hold urine Able to hold urine until toilet visit Able to finish tasks before toilet visit
59:339 60.6 (22–89)
Placebo (n ⫽ 374) 64:310 61 (22–93)
381 (95.7) 12 (3.0) 4 (1.0)
354 (94.7) 13 (3.5) 3 (0.8)
1 (0.3) 224 (56.3)
4 (1.1) 192 (51.3)
39.7
40.6
22.9 (5–168)
23.5 (5–168)
11.0 (2.3–51.3)
11.2 (2.3–28.4)
139.1 (36–271)
134.5 (21–374)
DISCUSSION 5 (1.3)
3 (0.8) 9 (2.4)
48 (12.1) 191 (48.0) 118 (29.6) 36 (9.0)
44 (11.8) 153 (40.9) 130 (34.8) 35 (9.4)
117 (29.4)
121 (32.4)
262 (65.8)
231 (61.8)
19 (4.8)
22 (5.9)
ER ⫽ extended release. Data are presented as n (percent) or mean (range) unless otherwise noted.
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Of those patients treated with tolterodine extended release, 43% rated their treatment as providing “much benefit,” compared with 24% of placebo recipients (P ⬍ .001) (Table 3). Overall, a significantly greater proportion of patients perceived any benefit with tolterodine extended release compared with placebo (78% versus 55%; P ⬍ .001). The odds of a patient reporting any benefit were 2.87 times greater for patients receiving tolterodine extended release, compared with those receiving placebo (95% CI 2.10, 3.92). The most common adverse events in either treatment group are shown in Table 4. Dry mouth was the most common adverse effect in both groups. Constipation and headache rates in the tolterodine extended-release group were not significantly different from those with placebo. There were no safety concerns in any of the parameters studied.
Urgency Reduction With Tolterodine
Urgency is a central symptom of the overactive bladder, and yet it is difficult to define or quantify. This study has attempted to examine the nature of urgency and the impact of antimuscarinic treatment. It is clear that any significant treatment for overactive bladder must reduce urgency. In the present study, urgency was measured qualitatively and quantitatively. In the scoring system used, an increase from “1” to “2” meant the difference between incontinence and being dry. An increase in score from “2” to “3” meant that the patients improved from having their daily life affected by urgency to being able to continue with normal activities and being able to ignore the symptom. Both changes are important, but the degree of importance is not necessarily linear for the scoring system and may vary between patients.
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Figure 1. Proportion of overactive bladder patients able to finish tasks before visiting a toilet (a) and not able to hold urine (b) in response to urinary urgency, at baseline and after 12 weeks’ treatment with either extended-release (ER) tolterodine or placebo; *** P ⬍ .001 vs placebo. Freeman. Urgency Reduction With Tolterodine. Obstet Gynecol 2003.
All patients entering the study had to have five or more episodes of incontinence per week, but the data on urgency show that at baseline patients were only incontinent about one third of the time in response to an urgency episode. Thus, although enrolled patients admitted to having urge incontinence, the majority of “urge” episodes were indeed dry, although they did have an impact on activity most of the time. After treatment in response to an urgency episode, patients taking placebo were almost twice as likely to become incontinent (Figure 1b). Furthermore, in terms of impact on activity, treatment with tolterodine was twice as effective as placebo. Thus, treatment with tolterodine extended release
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resulted in a change in the severity and nature of urgency. The mechanisms by which tolterodine alters the nature of urgency remain to be established. In this study, urodynamics were not performed because many patients do not exhibit detrusor contractions on urodynamic testing and yet experience urgency (sensory urgency). This might be because of micromotions of the bladder wall,11 and as such the antimuscarinic properties of tolterodine could inhibit such muscle activity. If, however, urgency was caused by a malfunction in the afferent system, then this demonstrated action of tolterodine on urgency is inexplicable based on our current under-
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Table 3. Effect of 12 Weeks’ Treatment With Either a New Extended-Release Formulation of Tolterodine or Placebo on Patient-Perceived Treatment Benefit in Patients With Overactive Bladder Treatment group Perception of treatment benefit
Tolterodine ER 4 mg once daily (n ⫽ 398)
Placebo (n ⫽ 374)
Much benefit Little benefit No benefit
172 (43.2)* 138 (34.7) 88 (22.1)
88 (23.5) 118 (31.6) 168 (44.9)
ER ⫽ extended release. Data are presented as n (percent). * P ⬍ .001 vs placebo.
standing of muscarinic activity in the bladder. It is not clear whether the efficacy of tolterodine is more pronounced in motor or sensory urgency. For any treatment of overactive bladder to be truly beneficial, statistically significant changes in micturition diary variables should lead to a clinically meaningful improvement from the patient’s perspective. This is particularly relevant in terms of urinary urgency, which exerts a marked effect on the quality of life of the affected individual because of its unpredictable nature. Indeed, many patients develop elaborate coping mechanisms, such as urinating at the first sign of urgency or voiding to a timed schedule, to cope with their condition and remain continent or reduce their level of incontinence. In a previous report of the present study that detailed micturition diary variables,10 statistically significant improvements (over placebo and the immediate-release formulation) were observed during treatment with tolterodine extended release, which was well tolerated and showed a low frequency of dry mouth. On the basis Table 4. Summary of Common Adverse Events During 12 Weeks’ Treatment With a New Extended-Release Formulation of Tolterodine, Compared With Placebo, for Overactive Bladder Treatment group
Adverse event
Tolterodine ER 4 mg once daily (n ⫽ 398)
Placebo (n ⫽ 374)
Dry mouth Constipation Headache Abdominal pain Xerophthalmia Diarrhea Urinary tract infection Nausea
95 (23.9) 23 (5.8) 23 (5.8) 16 (4.0) 15 (3.8) 8 (2.0) 7 (1.8) 5 (1.3)
28 (7.5) 16 (4.3) 14 (3.7) 6 (1.6) 7 (1.9) 7 (1.9) 12 (3.2) 5 (1.3)
ER ⫽ extended release. Data are presented as n (percent).
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of these findings (ie, good efficacy and improved tolerability), it was expected that a concomitant improvement in patient perceptions would be observed. This report deals with the data on patient perceptions. Overall, a significantly greater proportion of patients taking tolterodine reported an improvement in these indices, relative to placebo. Analysis by sex revealed significant differences between tolterodine extended release and placebo for both patients’ perception of urgency and patients’ perception of bladder symptoms in women only. The proportion of patients reporting “much benefit” from treatment with tolterodine extended release was double that for placebo, an improvement that was highly statistically significant. These data highlight the need to perform subjective evaluations in conjunction with standard voiding diary end points in such trials to determine the overall benefit of therapy. For example, although an agent, such as oxybutynin, might be effective in reducing clinical end points, such as the number of episodes of urge incontinence, the frequent occurrence of adverse effects might limit the overall benefit from treatment. This is reflected in dropout rates. Withdrawal rates as high as 30% have been reported for oxybutynin,12 compared with 5% for tolterodine.10 In a direct comparison of oxybutynin and tolterodine immediate release, dropout rates were 17% and 8%, respectively.13 In conclusion, the extended-release formulation of tolterodine 4 mg once daily produced improvements in the symptoms of overactive bladder that are meaningful to patients. Indeed this study demonstrates that treatment with tolterodine extended release significantly improves the nature and severity of urgency in patients with overactive bladder. REFERENCES 1. Abrams P, Wein AJ. The overactive bladder: A widespread but treatable condition. Stockholm: Eric Sparre Medical, 1998. 2. Jackson S. The patient with overactive bladder—symptoms and quality of life issues. Urology 1997;50 Suppl 6A:18–22. 3. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997;104:1374–9. 4. Kobelt G, Kirchberger I, Malone-Lee J. Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU Int 1999;83:583–90. 5. Wein AJ, Rovner ES. The overactive bladder: An overview for primary care health providers. Int J Fertil Womens Med 1999;44:56–66. 6. Milsom I, Abrams P, Cardozo L, Roberts RG, Thu¨roff J, Wein AJ. How widespread are the symptoms of an over-
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active bladder and how do we manage them? A population-based prevalence study. BJU Int 2001;87:760–6. Nilvebrant L. The mechanism of action of tolterodine. Rev Contemp Pharmacother 2000;11:13–27. Stahl MMS, Eckström B, Sparf A, Mattiasson A, Anders son K-E. Urodynamic and other effects of tolterodine: A novel antimuscarinic drug for the treatment of detrusor overactivity. Neurourol Urodyn 1995;14:647–55. Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 2000;55 Suppl 5A:47–9. Van Kerrebroeck PEVA, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: Superior efficacy and tolerability in the treatment of overactive bladder. Urology 2001;57: 414–21. Coolsaet BL, Van Duyl WA, Van Os-Bossagh P, De
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Bakker HV. New concepts in relation to urge and detrusor activity. Neurourol Urodyn 1993;12:463–71. 12. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: A pooled analysis. Urology 1997;50 Suppl 6A:90–6. 13. Abrams P, Freeman R, Anderström C, Mattiasson A. Tolterodine, a new antimuscarinic agent: As effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998;81:801–10. Address reprint requests to: Robert Freeman, MD, FRCOG, Derriford Hospital, Urogynaecology Unit, Directorate of Obstetrics and Gynaecology, Plymouth PL6 8DH, United Kingdom; E-mail: [email protected]. Received May 28, 2002. Received in revised form January 3, 2003. Accepted January 21, 2003.
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