Tolterodine: As effective but better tolerated than oxybutynin in Asian patients with symptoms of overactive bladder

Authors


Jeong Gu Lee md, Department of Urology, Korea University College of Medicine, Anam Hospital 5 ka 126-1, Anam-dong, Sungbuk-ku, Seoul 136-705, Korea. Email: jeongkl@kumc.or.kr

Abstract

Background: This double-blind, multicenter study compared the efficacy and tolerability of tolterodine (Pharmacia, Los Angeles, USA) with that of oxybutynin (Alza, Palo Alto, USA) in Asian patients with overactive bladder.

Methods: Two-hundred-and-twenty-eight adults with overactive bladder symptoms were randomized to receive tolterodine 2 mg twice daily (bid) (n = 112) or oxybutynin 5 mg bid (n = 116). After 8 weeks’ treatment, changes in micturition diary variables, patients’ perception of treatment benefit, and tolerability endpoints were determined.

Results: The mean (± SD) number of micturitions/24 h decreased by 2.6 ± 2.9 (−21%) with tolterodine and 1.8 ± 4.2 (−15%) with oxybutynin (both P = 0.0001 vs baseline). The mean number of incontinence episodes/24 h decreased by 2.2 ± 2.3 (−85%) in the tolterodine group and by 1.4 ± 1.8 (−58%) in the oxybutynin group (both P = 0.0001 vs baseline). Patient perception of treatment benefit was over 70% in each treatment group. Adverse events were significantly lower in the tolterodine group compared with oxybutynin-treated patients (55% vs 82%; P = 0.001). Dry mouth was reported by significantly fewer patients on tolterodine, compared with oxybutynin (35% vs 63%; P = 0.001) and withdrawals due to adverse events were lower in the tolterodine group than with those treated with oxybutynin (10% vs 16%). There were no safety concerns.

Conclusions: Tolterodine 2 mg bid is equally or more effective than oxybutynin 5 mg bid in the treatment of Asian patients with overactive bladder, and shows significantly better tolerability. This may enhance compliance during long-term treatment.

Introduction

Overactive bladder is characterized by symptoms of increased frequency of micturition (> 8 micturitions/24 h) and urgency of micturition (a strong desire to pass urine), with or without urge incontinence (an involuntary loss of urine).1,2 The condition is thought to affect one in every 11 American adults.3 Overactive bladder occurs in both men and women, increasing in prevalence with age,4 and exerts a profound effect on quality of life.5

Antimuscarinic agents are the mainstay of treatment for overactive bladder symptoms.6 While clinically effective, however, some of these agents (e.g. oxybutynin) are limited by a high incidence of adverse effects such as dry mouth.7 As patients with overactive bladder typically require long-term therapy to maintain symptom relief, poor tolerability of current antimuscarinic treatment has negative implications for compliance and, in turn, the successful management of this chronic condition. Consequently, there is a great need for an alternative treatment that is as effective as traditional antimuscarinic agents but has a superior tolerability profile.

Tolterodine is a new, potent, competitive muscarinic receptor antagonist that, unlike oxybutynin, demonstrates selectivity for the bladder over the salivary glands in vivo.8 This tissue selectivity profile, which cannot be explained by selectivity for a single muscarinic receptor subtype or by secondary pharmacological action(s) on the bladder smooth muscle,8 confers a more pronounced and sustained effect on the bladder than on salivation in humans.9 Clinically, tolterodine is effective against all the troublesome symptoms of overactive bladder, and demonstrates improvements that are meaningful to patients.10 Moreover, tolterodine is as effective as other antimuscarinic agents such as oxybutynin but has superior tolerability,11–13 which probably explains the high compliance rates during long-term treatment with this agent.14

Previous studies in patients with overactive bladder have largely comprised Caucasian populations. As such, little is known in terms of the efficacy and tolerability of antimuscarinic agents in other ethnic groups, despite the fact that overactive bladder is thought to significantly affect all races and societies. The aim of this study was to determine the efficacy and tolerability of tolterodine, compared with that of oxybutynin, in Asian patients with overactive bladder.

Methods

This double-blind, randomized, multicenter, parallel-group study was conducted at eight centers in South Korea. The study was performed according to Guidelines for Good Clinical Practice and current revisions to the Declaration of Helsinki. Ethical approval was obtained from an independent ethics committee for each study center prior to study commencement, and all patients provided written informed consent.

Study participants

Male and female subjects aged ≥ 18 years with symptoms of overactive bladder for ≥ 6 months were eligible for enrolment in the study. Symptoms, as measured by micturition diaries, were defined as urinary urgency and frequency (≥ 8 micturitions on average per 24 h), with or without urge incontinence. Patients were enrolled exclusively on the basis of symptoms (i.e. urodynamics was not performed), irrespective of whether they had received prior antimuscarinic therapy. Exclusion criteria were: (i) significant stress incontinence; (ii) women of childbearing age who were not using reliable contraception; (iii) pregnant or nursing women; (iv) treatment with any drug with known anticholinergic side-effects in the 2 weeks prior to the study; (v) significant renal or hepatic disease; (vi) any contraindication to antimuscarinic therapy (e.g. narrow-angle glaucoma, urinary or gastric retention, known hypersensitivity to tolterodine or oxybutynin); (vii) symptomatic acute or recurrent urinary tract infection; (viii) interstitial cystitis or hematuria; (ix) bladder outlet obstruction; and (x) patients receiving bladder training, electrostimulation therapy or having an indwelling catheter or on intermittent catheterization. Concomitant treatment for overactive bladder (other than estrogen replacement therapy started at least 2 months prior to randomization) was not permitted.

Assessment of efficacy

Patients initially attended a screening visit, during which a complete medical and drug history was taken, a full laboratory screen was performed and a midstream specimen of urine was obtained for culture. Eligible patients entered the prestudy 1–2-week-washout/run-in phase, during which the frequency of micturition and number of incontinence episodes were noted in a micturition diary (the 1-week-washout period was omitted for patients who were not receiving drug therapy prior to enrolment). Patients also recorded the volume voided per micturition in the micturition diary. After the run-in period, patients were randomized (1 : 1) using the method of computer-generated random-permuted blocks to oral therapy with tolterodine 2 mg twice daily (bid) or oxybutynin 5 mg bid. This was the approved and recommended dosage in South Korea. A double-dummy technique was used to maintain blinding. Dosage adjustment was not permitted during the study.

Micturition diary variables were assessed at the end of the 8-week study, along with routine laboratory safety tests. Patients’ perception of treatment benefit was also evaluated at this timepoint using a binomial scale. Patients who answered ‘yes’ to the question ‘Have you had any benefit from your treatment?’ were subsequently asked to evaluate the benefit as either ‘little’ or ‘much’.

Compliance was evaluated by counting the returned study medication. Patients were deemed compliant if > 75% of prescribed medication had been taken.

Tolerability

Clinical safety was evaluated in terms of adverse events that were spontaneously reported or directly observed during the 8-week treatment period and during 1 week of follow up. Adverse events were recorded and categorized by intensity (‘mild’– does not interfere with patient’s usual function; ‘moderate’– interferes to some extent with patient’s usual function; or ‘severe’– interferes significantly with patient’s usual function) and the likelihood of causal relationship to study treatment. Patients experiencing adverse events were withdrawn from the study if it was deemed medically necessary or at the patient’s request.

Statistical analysis

The study aimed to enrol 200 patients (100 patients per treatment group). Analysis of efficacy was performed for all randomized patients (intention-to-treat population), using the last observed data. Missing micturition data were extrapolated by the principle of the last observation carried forward from baseline. The primary efficacy variable was the mean number of micturitions/24 h. The mean number of incontinence episodes/24 h and patients’ perception of treatment benefit were secondary efficacy endpoints. The change from baseline to study end for micturition variables was calculated within groups. This was compared between groups using analysis of variance, with treatment, visit, patient-within-treatment and a treatment-by-visit interaction in the model. A model involving a center factor and a treatment-by-center interaction were also analyzed to check the variables for center homogeneity. Hypothesis testing was conducted using Type III sum of squares in adjusted means. Furthermore, 95% confidence intervals (CI) (corresponding to a ‘two one-sided test’) were calculated for differences between the two treatment groups in the change from baseline to last visit. Equivalence was assumed if the 95% CI was completely contained within the predefined limits of ± 1.5.

Between-group differences in the perception of treatment benefit and tolerability endpoints were analyzed using a chi-squared test. All other variables were analyzed descriptively.

With the sample size of 100 patients per group, an estimated standard deviation for the average decrease in mean number of micturitions/24 h was 3.4 with equivalence limits of ± 1.5 (the power was 75%).

Results

Patient population and demography

A total of 228 patients fulfilled the inclusion criteria and were randomized to receive either tolterodine 2 mg bid (n = 112) or oxybutynin 5 mg bid (n = 116). There were no statistically significant differences between the two treatment groups with respect to baseline demographic and clinical characteristics (Table 1). The mean age was 52 years and female patients predominated in both treatment groups (> 70%). This was consistent with previously observed Caucasian gender ratios for patients with overactive bladder.3 A total of 27% of all patients had received previous drug therapy for overactive bladder, although the majority reported poor efficacy and/or tolerability. A total of 68 patients (61%) in the tolterodine group and 74 patients (64%) in the oxybutynin group received concomitant medications during the study, typically for hypertension, diabetes mellitus and osteoporosis. Two patients, one from each treatment group, violated the exclusion criteria by receiving excluded medications but remained within the intention -to-treat efficacy analysis.

Table 1.  Demographic and clinical characteristics at baseline (intention-to-treat population)
CharacteristicTreatment group
Tolterodine 2 mg bid (n = 112)Oxybutynin 5 mg bid (n = 116)
  • *

    For those patients reporting incontinence episodes at baseline. bid, twice daily; n, number of patients.

Mean age, years (range)52 (27–82)52 (20–86)
Asian race [n (%)]112 (100)116 (100)
Male : female [n (%)]29 : 83 (26 : 74)24 : 92 (21 : 79)
Mean body mass index, kg/m2 (range)23 (17–32.5)23.5 (16–38)
Previous drug therapy for overactive bladder [n (%)]36 (32)26 (22)
 of which showed good efficacy response1915
 of which showed none/acceptable side-effects3123
Mean no. micturitions/24 h (range)12.2 (8.0–23.7)12.4 (7.7–29.7)
Patients with incontinence episodes [n (%)]46 (41)42 (36)
Mean no. incontinence episodes/24 h (range)*2.6 (0.3–9.3)2.4 (3.0–14.7)

A total of 41 patients (18%) withdrew from the study (tolterodine, n = 15; oxybutynin, n = 26), mainly due to tolerability problems (n = 29; tolterodine, n = 11; oxybutynin, n = 18). Other reasons for study withdrawal included: (i) withdrawal of consent (n = 5); (ii) protocol violations (n = 4); (iii) lost to follow up (n = 2); and (iv) lack of efficacy (n = 1). With the exception of adverse events, reasons for withdrawal were equally distributed between treatment arms. Acceptable compliance with study medication was achieved by 87% of tolterodine-treated patients and 77% of those in the oxybutynin-treated group.

Efficacy

After 8 weeks of treatment, the mean number of micturitions/24 h was significantly decreased in the tolterodine and oxybutynin groups versus baseline (Table 2). The change from baseline was greater following treatment with tolterodine (−21%) than with oxybutynin (−15%), although this did not reach statistical significance. The estimated difference in mean change from baseline was −0.71 (95% CI: −1.66 − 0.24; P = 0.14). Given that the 95% CI for the between-group difference was outside the predefined limits of ± 1.5, equivalence could not assumed.

Table 2.  Effect of 8-week treatment with either tolterodine or oxybutynin on micturition diary variables (intention-to-treat population)
VariableTreatment group
Tolterodine 2 mg bid (n = 112)Oxybutynin 5 mg bid (n = 116)
  1. bid, twice daily; n, number of patients; SD, standard deviation.

No. micturitions/24 h
 No. evaluable patients112116
 Mean (SD) change from baseline−2.6 (2.9)−1.8 (4.2)
 P-value0.00010.0001
No. incontinence episodes/24 h
 No. evaluable patients4642
 Mean (SD) change from baseline−2.2 (2.3)−1.4 (1.8)
 P-value0.00010.0001

At baseline, a total of 88 patients (tolterodine, n = 46; oxybutynin, n = 42) reported at least one incontinence episode/24 h. Among these patients, treatment with either tolterodine or oxybutynin for 8 weeks was associated with a significant reduction in the mean number of incontinence episodes/24 h versus baseline (Table 2). Tolterodine (−85%) was more effective than oxybutynin (−58%) in this respect, although this did not reach statistical significance. The estimated difference in mean change from baseline was −0.73 (95% CI: −1.60 − 0.15; P = 0.10). As seen with the micturitions/24 h, equivalence could not be demonstrated for this variable.

Overall, 73% of patients who completed the study reported benefit from treatment. Of this group, 45% and 46% in the tolterodine and oxybutynin groups, respectively, reported ‘much’ benefit. No statistically signifi-cant between-group differences were apparent.

Safety and tolerability

Of the 227 patients who were evaluated for safety after having taken at least one dose of study medication, 62 patients (55%) reported 101 adverse events in the tolterodine group and 94 patients (82%) reported 152 adverse events in the oxybutynin group. This difference was statistically significant (P = 0.001). Most adverse events were associated with the autonomic nervous system (and were therefore considered to be drug-related), followed by gastrointestinal and urinary effects. Urinary adverse events occurred more commonly in the oxybutynin group (17%) compared to the tolterodine group (9%).

Dry mouth was the most commonly reported adverse event in both treatment groups, although the incidence was significantly higher in the oxybutynin group compared with those receiving tolterodine (P = 0.001). There was also a higher frequency of moderate-to-severe dry mouth among oxybutynin recipients (Table 3). Micturition disorders were the second-most-common adverse event, less frequently reported by tolterodine recipients than oxybutynin-treated patients. Other adverse events, experienced by < 10% of patients in each group, were dyspepsia, abdominal pain and headache (Table 3).

Table 3.  Incidence of most commonly reported adverse events (reported by ≥ 5% of patients in either treatment group) during 8-week treatment with either tolterodine or oxybutynin for overactive bladder
Adverse event/intensityTreatment group [n (%)]
Tolterodine 2 mg bid (n = 112)Oxybutynin 5 mg bid (n = 115)
  1. bid, twice daily; n, number of patients.

Dry mouth39 (35)72 (63)
 Mild29 (26)40 (35)
 Moderate9 (8)26 (23)
 Severe1 (1)6 (5)
Micturition disorder10 (9)16 (14)
Dyspepsia8 (7)6 (5)
Abdominal pain6 (5)6 (5)
Headache4 (4)6 (5)

No deaths occurred during the study, although two serious adverse events were reported, neither of which was considered to be drug-related (acute pyelonephritis in an oxybutynin patient and fracture in a tolterodine patient). Both patients were withdrawn from the study and recovered without complications.

A total of 29 patients (tolterodine, n = 11; oxybutynin, n = 18) withdrew from the study due to adverse events, mainly due to dry mouth. Among the six tolterodine -treated patients citing dry mouth as a reason for discontinuation (amongst other adverse events), reported intensity was either ‘mild’ (n = 2) or ‘moderate’ (n = 4). For oxybutynin, 16 patients reported ‘mild’ (n = 2), ‘moderate’ (n = 9) or ‘severe’ (n = 5) dry mouth as a reason for discontinuation.

There were no clinically relevant changes in laboratory safety parameters in either treatment group during the study.

Discussion

An extensive research programme in more than 2500 patients has confirmed the therapeutic utility of tolterodine for the relief of overactive bladder symptoms.15 These observations, however, apply to study groups of mostly Caucasian patients, who may differ from other ethnic groups in their response to therapy. We therefore designed the present multicenter study to evaluate the efficacy and tolerability of tolterodine, compared to oxybutynin, in an Asian population of patients with overactive bladder. South Korea was chosen as representative of the larger Asian population. Oxybutynin was prescribed at a dosage of 5 mg bid, rather than 5 mg three times daily (as used in earlier comparative studies) ,11–13 as this is the approved and recommended dosage in South Korea and a number of other Asian countries.

Overall, the present study demonstrates that tolterodine 2 mg bid is equally or more effective than oxybutynin 5 mg bid for the symptomatic relief of overactive bladder in Asian patients. Tolterodine significantly reduced the mean number of micturitions/24 h by over 20% after an 8-week treatment period, compared with a 15% reduction for those on oxybutynin. The mean number of incontinence episodes/24 h was decreased by 85% after the 8-week treatment period, compared with a 58% reduction for those receiving oxybutynin. These observations were in accordance with earlier findings established for predominantly Caucasian populations.11–13,16

Tolterodine was well tolerated in the present study, and was significantly better tolerated than oxybutynin. The overall incidence of adverse events was significantly lower in patients receiving tolterodine than in those treated with oxybutynin, which may explain the lower rate of withdrawal due to adverse events among tolterodine recipients (10% vs 16% on oxybutynin). Dry mouth, characteristically associated with traditional antimuscarinic treatment, was the most common adverse event in both treatment groups, although the incidence and severity of dry mouth were greater in patients that were treated with oxybutynin. These findings were comparable with previous reports in which tolterodine was significantly better tolerated than oxybutynin when adverse events, particularly the frequency and intensity of dry mouth, were considered.11–13 It is interesting to note that the present investigation used a lower dosage of oxybutynin (5 mg bid) than in previous comparative studies (5 mg three times daily). Despite this difference, the superior tolerability of tolterodine at the recommended starting dosage of 2 mg bid was maintained.

In conclusion, the present study confirms the efficacy and favorable tolerability of tolterodine 2 mg bid in a representative population of Asian patients with the chronic and debilitating symptoms of overactive bladder. Moreover, tolterodine proved equally or more effective than oxybutynin 5 mg bid, with a significantly better tolerability profile. These findings support the use of tolterodine as the treatment of choice in the management of the symptoms of overactive bladder in Asian patients.

Acknowledgment

This study was supported by a grant from the Pharmacia Corporation.

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