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Keywords:

  • overactive bladder;
  • tolterodine;
  • oxybutynin;
  • placebo;
  • trial;
  • efficacy;
  • side effects

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

OBJECTIVE

To compare extended-release (ER) tolterodine and immediate-release (IR) oxybutynin with placebo in Japanese and Korean patients with an overactive bladder (OAB).

PATIENTS AND METHODS

Men and women aged ≥ 20 years with symptoms of urinary urgency, urinary frequency (≥ 8 micturitions/24 h), urge incontinence (≥ 5 episodes/week) and symptoms of OAB for ≥ 6 months were randomized to double-blind treatment with tolterodine ER 4 mg once daily, oxybutynin IR 3 mg three times daily or placebo for 12 weeks. Efficacy assessments included changes from baseline in numbers of incontinence episodes per week, voids/24 h and mean volume voided/void. Patient perceptions of bladder condition, urgency and treatment benefit were also assessed.

RESULTS

In all, 608 patients were randomized to treatment with tolterodine (240), oxybutynin (246) or placebo (122). More patients prematurely withdrew on oxybutynin (23%) than with tolterodine (10.4%) or placebo (16.4%). After 12 weeks of treatment, the median number of incontinence episodes/week was reduced significantly more in the tolterodine (79%; P= 0.0027) and oxybutynin groups (76.5%; P= 0.0168) than on placebo (46.4%). There were also significantly greater improvements in the number of voids/24 h and volume voided/void with tolterodine and oxybutynin than with placebo. More patients in the tolterodine and oxybutynin than in the placebo groups reported improvements in perceived bladder condition, ability to hold urine and treatment benefit. Patients treated with oxybutynin reported more adverse events than those treated with tolterodine or placebo. Dry mouth was significantly more common with oxybutynin than with tolterodine (53.7% vs. 33.5%; P < 0.001), and occurred in 9.8% of placebo patients.

CONCLUSION

Tolterodine ER has similar efficacy but is better tolerated than oxybutynin IR in Japanese and Korean patients with OAB.


Abbreviations
OAB

overactive bladder

IR

immediate-release

ER

extended-release

KHQ

King's Health Questionnaire

ECG

electrocardiography.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

The overactive bladder (OAB) is characterized by symptoms of urinary urgency with or without urge incontinence, often combined with urinary frequency and/or nocturia [1]. Symptoms of OAB are suggestive of uncontrolled detrusor contractions during the filling phase of the voiding cycle, but can also result from other forms of urethrovesical dysfunction [1]. Detrusor contractions are mediated primarily by neurally released acetylcholine that stimulates bladder muscarinic receptors (although there are probably other transmitters involved) and so the pharmacological treatment of OAB has centred on the use of antimuscarinic agents.

Tolterodine is a potent muscarinic-receptor antagonist specifically developed for treating OAB [2]. Several clinical trials have shown that tolterodine is as effective as oxybutynin in patients with OAB [3–6] but the better selectivity of tolterodine than oxybutynin for the bladder over other tissues means that it is associated with a significantly lower frequency and severity of adverse events, most notably dry mouth [3–6]. Dry mouth is a common occurrence during antimuscarinic treatment and is associated with poor patient compliance and/or early cessation of therapy, even among those who recognize an improvement in their bladder symptoms [7,8].

Recently, a once-daily formulation of tolterodine that provides sustained release over 24 h has been developed. Compared with the immediate-release (IR) formulation, extended-release (ER) tolterodine is more effective in reducing urge incontinence episodes, and with a lower frequency of dry mouth [9]. Moreover, it is also expected that the greater convenience of once-daily administration will improve patient compliance [10]. An ER formulation of oxybutynin is also available but a direct comparison of the efficacy, tolerability and safety of the ER formulations of both tolterodine and oxybutynin has yet to be reported.

The OAB is a significant problem among Asian populations. In a recent large-scale epidemiological survey in 11 Asian countries, 53% of women and 45% of men reported symptoms of OAB [11,12]. Other surveys have reported a high prevalence of urge incontinence in Japan [13–15]. Despite this, most recent clinical trials of antimuscarinic therapy for OAB have been conducted in Caucasian populations and data for Asian patients are limited. In a recent trial, tolterodine IR was shown to be as effective and better tolerated than oxybutynin in Korean patients [6]. However, tolterodine ER has not previously been investigated in an Asian population. Thus we conducted a randomized, double-blind study to compare tolterodine ER and oxybutynin IR with placebo in Japanese and Korean patients with an OAB. This is the first ever study of the treatment of OAB in Japanese patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

This was a randomized, double-blind, placebo- and active comparator-controlled trial conducted at 69 centres in Japan (57) and Korea (12). The study was approved by the independent ethics committees/institutional review boards of the participating centres and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Men and women aged ≥ 20 years with symptoms of urinary urgency, urinary frequency (≥ 8 voids/24 h), urge incontinence (≥ 5 episodes/week) and symptoms of OAB for ≥ 6 months were eligible for inclusion. Patients were recruited based solely on their symptoms of OAB, irrespective of whether they had received previous antimuscarinic treatment and irrespective of their response to such therapy. Exclusion criteria included: demonstrable stress incontinence; total daily urine volume of > 3 L; average volume voided/void of > 200 mL; significant hepatic or renal disease; any contraindication to anticholinergic treatment, e.g. uncontrolled narrow-angled glaucoma, urinary retention or gastric retention; symptomatic or recurrent UTI; interstitial cystitis; haematuria or BOO; an indwelling catheter or intermittent self-catheterization; and electrostimulation or bladder training within 14 days before randomization or expected to commence during the study period. Concomitant treatment with any other anticholinergic drug or an unstable dosage of any drug with anticholinergic side-effects, any other drug for OAB (except for oestrogen started > 2 months before inclusion), potent CYP3A4 inhibitors, or any investigational drug, was not permitted during the study or in the 14 days before randomization. Pregnant or nursing women and women of childbearing potential not using reliable contraception were also excluded.

STUDY DESIGN

Eligible patients were enrolled into a 1- or 2-week wash-out/run-in period during which baseline voiding data (incontinence episodes, urinary frequency, volume voided/void, incontinence pad usage) were recorded using voiding diaries. Patients still eligible were then randomized in a 2 : 2 : 1 ratio to treatment with tolterodine ER 4 mg capsules once daily (Detrol® capsule/Detrusitol, Pharmacia Corporation, USA), oxybutynin IR 3 mg tablets three times daily (Pollakisu®, Aventis Pharma Ltd, Japan) or placebo. Patients were randomized using the method of random permuted blocks. Because the two active drugs differed in appearance and were administered according to different daily schedules, blinding was by a variation on the double-dummy technique, so that matching placebos for both tolterodine ER 4 mg and oxybutynin IR 3 mg were provided. Patients were instructed to take one tolterodine ER 4 mg or placebo capsule in the morning plus one oxybutynin IR 3 mg or placebo tablet in the morning, at midday, and in the evening. No dose adjustment was permitted during the study. Compliance was assessed by counting the returned study medication, with patients considered compliant if they had taken ≥ 75% of their medication.

EFFICACY AND TOLERABILITY ASSESSMENTS

Voiding diaries were completed over 7 consecutive days during the run-in period (baseline) and the final week of treatment. All incontinence episodes and voids during the 7-day periods were recorded. Volume voided/void and pad usage had to be recorded for at least two complete days.

The primary efficacy assessment was the percentage change in the median number of incontinence episodes per week from baseline to week 12. Secondary voiding diary endpoints were changes from baseline to week 12 in the median number of voids/24 h, median volume voided/void and median number of incontinence pads used/24 h. In addition to these objective measures, efficacy was also assessed subjectively by the patients; their perception of bladder condition (6-point scale; Table 1) and patient perception of urgency (3-point scale in response to the question: ‘Regarding your experiences of desire to void, which of the following would apply: (i) I was usually unable to hold urine; (ii) I was usually able to hold urine without leaking until I reached a toilet, if I went immediately; or (iii) I was usually able to finish what I was doing without leaking before going to the toilet’) were assessed at baseline and after 12 weeks of treatment. The patient assessment of treatment benefit (3-point scale; 1, no benefit; 2, a little benefit; or 3, much benefit) was also recorded at 12 weeks.

Table 1.  Baseline demographic and clinical characteristics (intent-to-treat and safety population)
CharacteristicTolterodine (239)Oxybutynin (244)Placebo (122)
  • *

    Percentage of only those patients who reported previous drug therapy.

Gender, M/F, n/N (%/%)  77/162 (32/68)  67/177 (27/73)  38/84 (31/69)
Mean (sd) [range] age, years  61.2 (11.8) [29–84]  57.9 (12.5) [26–84])  58.4 (14.0) [25–88]
Previous drug therapy for OAB, n,%  60 (25)  52 (21)  31 (25)
With poor efficacy, n,%*  32 (53)  26 (50)  15 (48)
Incontinence episodes/week:   
mean (sd)  20.3 (20.6)  21.8 (19.8)  19.0 (15.5)
median (range)  13.0 (4.0–168.0)  15.0 (4.7–120.0)  14.0 (5.0–75.0)
≥ 5 incontinence episodes/week, %  98.7  99.6100
Voids/24 h
mean (sd)  11.7 (3.6)  11.6 (3.1)  11.1 (3.0)
median (range)  10.8 (7.3–31.0)  11.0 (7.3–22.8)  10.3 (6.4–24.0)
≥ 8 voids/24 h, %  99.2  98.8  99.2
Volume voided/void, mL
mean (sd)125.8 (38.1)122.3 (36.3)130.7 (35.3)
median (range)122.2 (32.7–255.4)117.5 (38.6–227.5)132.9 (46.0–203.3)
Pad usage/24 h
mean (sd)  0.8 (1.7)  1.1 (2.1)  0.9 (1.6)
median (range)  0 (0.0–11.9)  0 (0–15.7)  0 (0.0–7.3)
Patients’ perception of bladder condition, %:
Does not cause me any problems  1.3  1.6  3.3
Causes me some very minor problems  2.9  2.5  1.6
Causes me some minor problems  9.2  9.8  13.1
Causes me (some) moderate problems  35.1  33.6  29.5
Causes me severe problems  39.3  41.0  37.7
Causes me many severe problems  12.1  11.5  14.8

The patients’ quality of life was assessed at baseline and after 12 weeks at study centres in Japan using the King's Health Questionnaire (KHQ), a urinary incontinence-specific instrument that has been translated into several languages, including Japanese [16].

Safety and tolerability were evaluated in terms of adverse events, premature withdrawal from treatment because of adverse events, clinical laboratory assessments (clinical chemistry, haematology and urine analysis) and electrocardiography (ECG) (in Japan only).

The study consisted of a screening visit (visit 1) at the start of the 2-week run-in and visits 2–6 at randomization, and after 4, 6 and 12 weeks of treatment and at the follow-up (1–2 weeks after the end of the treatment). At visits 1 and 5, blood and urine samples were taken for clinical chemistry, haematology and urine analysis (including a pregnancy test, at visit 1 only). Directly observed and spontaneously reported adverse events were recorded at visits 3–6 and classified by intensity as mild, moderate or severe; 12-lead ECGs were recorded at visits 1 and 5.

STATISTICAL ANALYSIS

Based on an assumed sd of 58% in a previous study, the aim was to enrol 600 patients (randomized 2 : 2 : 1), to detect a mean difference in efficacy of 20% between tolterodine ER and placebo (at 80% power and 5% significance level) and to show that tolterodine ER was not inferior to oxybutynin IR (at 80% power and 2.5% significance level). The efficacy was analysed on an intent-to-treat basis for all randomized patients who received at least one dose of study drug, using the last-observation-carried-forward for any missing 12-week values. anova was used to compare treatment groups, with factors for treatment, country and treatment–country interactions (removed from the model if P > 0.2). Two-sided t-tests with significance levels of 5% and 95% CIs were calculated based on the least-squares means. If data were not normally distributed, i.e. skewed, a pre-planned nonparametric analysis with anova based on the rank-transformation of the original variable was used. Assessments of patient perceptions were analysed as the proportions of patients who perceived an improvement, no change, or deterioration, with 95% CIs and P calculated for between-group comparisons. KHQ domains for incontinence impact and role limitation were analysed by analysis of covariance, with baseline value and age as covariates, and treatment and gender as included factors; 95% CIs and P values were calculated for the changes in mean domain scores between treatments; P values and 95% CIs were also reported for other KHQ domains.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

In all, 608 patients (Japan 293; Korea 315) were recruited and randomized to treatment with tolterodine ER (240), oxybutynin IR (246) or placebo (122). Three of these patients did not receive treatment and were therefore excluded from the intent-to-treat population. Baseline demographic and clinical characteristics were well matched among the three treatment groups (Table 1). Over two-thirds of the study population were women and about a quarter had previously received treatment for OAB, of whom half reported poor efficacy. There were no significant differences between patients in Japan and Korea, although the Korean population included a lower proportion of men, had a lower mean age and a greater mean body mass index.

Overall, 102 patients were prematurely withdrawn from the study, with a higher incidence reported for the oxybutynin (57, 23.2%) than placebo (20, 16.4%) and tolterodine groups (25, 10.4%). This was explained by the higher frequency of withdrawals for adverse events with oxybutynin than with placebo or tolterodine (Table 3). Other reasons for withdrawal were similar between treatment groups and included lack of efficacy (tolterodine 1.3%, oxybutynin 1.6%, placebo 3.3%), consent withdrawn (1.7%, 2.4% and 0.8%), loss to follow-up (1.7%, 0.8% and 2.5%) and protocol violation (0.4%, 1.2% and 0.8%). There was no difference in the numbers of premature withdrawals between Japan and Korea in either the tolterodine or oxybutynin groups. Treatment compliance was good, with > 90% of patients in each group taking ≥ 75% of their medication (tolterodine 98%, oxybutynin 93% and placebo 94%).

Table 3.  Adverse events reported by ≥ 5% of patients in any treatment group or commonly related to antimuscarinic therapy during 12 weeks of treatment with tolterodine, oxybutynin or placebo, with the withdrawals for dry mouth and all adverse events
Adverse event, n (%)Tolterodine (239)Oxybutynin (244)Placebo (122)
Dry mouth80 (33.5)131 (53.7)12 (9.8)
Dry eyes  3 (1.3)  7 (2.9)  0 (0)
Blurred vision  3 (1.3)  8 (3.3)  0 (0)
Dry skin  0 (0)  4 (1.6)  1 (0.8)
Constipation17 (7.1)  15 (6.1)  6 (4.9)
Abdominal pain/tenderness14 (5.9)  12 (4.9)  4 (3.3)
Dyspepsia  9 (3.8)  20 (8.2)  4 (3.3)
Headache10 (4.2)  11 (4.5)  8 (6.6)
Dizziness  4 (1.7)  6 (2.5)  2 (1.6)
Somnolence  1 (0.4)  4 (1.6)  4 (3.3)
Difficulty in micturition  3 (1.3)  21 (8.6)  2 (1.6)
Urinary hesitation  1 (0.4)  1 (0.4)  0 (0)
Urinary retention  1 (0.4)  8 (3.3)  0 (0)
Flushing/hot flushes  2 (0.8)  11 (4.5)  0 (0)
Withdrawals, %
Dry mouth  0.4    9.4  0.8
All events  5  17.1  9
Severity of dry mouth
mild25.1  33.2  6.5
moderate  7.9  12.3  3.3
severe  0.4  8.2  0

EFFICACY

As the efficacy data were not normally distributed nonparametric analyses were used. After 12 weeks of treatment, the percentage change in the median (range) number of incontinence episodes/week was reduced significantly more in the tolterodine (−78.6%, −100 to 483.3; P= 0.0027) and oxybutynin groups (−76.5%, − 100 to 116.7; P= 0.0168) than placebo (−46.4%, − 100 to 257.1). There was no significant difference between responses to tolterodine and oxybutynin (P = 0.4469).

There were also significantly greater reductions in the median number of voids/24 h with tolterodine (−2.0, P < 0.001) and oxybutynin (−2.1, P  = 0.0114) than with placebo (−1.1; Table 2). There was no statistically significant difference between the reductions with tolterodine and oxybutynin (P = 0.3132). The median volume voided/void increased significantly more in the tolterodine (17.2 mL, P = 0.0086) and oxybutynin (22.3 mL, P < 0.001) than in the placebo group (6.6 mL; Table 2). Pad usage/24 h was not significantly less with tolterodine or oxybutynin than with placebo (Table 2).

Table 2.  The median (range) absolute change from baseline in voiding diary variables after 12 weeks of treatment with tolterodine or oxybutynin or placebo in patients with OAB
GroupVoids/24 hVolume voided/void, mLPad usage/24 h
  • *

    Hodges-Lehmann estimate;

  • † data missing for one patient; tolterodine vs oxybutynin, not significant for all variables.

Absolute change
Tolterodine −2.0 (−11.3–4.0)17.2 (−134.5–339.5)0 (−11.4–2.9)
Oxybutynin −2.1 (−13.1–7.5)22.3 (−136.0–196.7)0 (−13–3.3)
Placebo −1.1 (−16–5)  6.6 (−75.5–151.4)0 (−5.9–6.0)
Median* (95% CI) difference:
Tolterodine vs placebo −0.8 (−1.3, −0.3)  9.1 (2.1, 15.7)0 (0, 0)
POxybutynin vs placebo<0.001−0.6 (−1.1, 0.0)  0.008615.4 (7.8, 23.9) –0 (0, 0)
P  0.0114<0.001

Improvements in voiding diary endpoints after 12 weeks of treatment were supported by improvements in the patients’ perception. Treatment groups were well-matched at baseline for patient perception of bladder condition, with over half of each group reporting that their bladder condition was severe. After 12 weeks of treatment, the proportion of patients who perceived an improvement in their bladder condition was greater in the tolterodine (72%) and oxybutynin (73%) groups than in the placebo group (59%). The difference between tolterodine and placebo was not statistically significant (P = 0.515) and there was no significant difference between active treatments (P = 0.9394). Few patients perceived a deterioration in their bladder condition in any of the groups (tolterodine and oxybutynin both 5%, placebo, 8%). Figure 1 shows the distribution of the degree of change in bladder condition. The distributions for tolterodine and oxybutynin are shifted to the right compared with placebo, indicating greater improvement. Similarly, more patients in the tolterodine (49%) and oxybutynin (57%) groups than in the placebo group (34%) reported an improvement in their ability to hold urine.

image

Figure 1. The degree of change in bladder condition after 12 weeks of treatment with tolterodine (green bars), oxybutynin (red bars) or placebo (black bars) in patients with OAB. Positive values represent an improvement and negative values a deterioration in bladder condition, based on a 6-point categorical scale.

Download figure to PowerPoint

Most patients also perceived treatment to have been beneficial, with significantly more patients reporting at least some benefit in the tolterodine (79%; P = 0.0091; little benefit 36%; much benefit, 42%) and oxybutynin (81%; P < 0.001; little benefit 29%; much benefit 53%) groups than in the placebo group (66%; little benefit 40%; much benefit 25%). There was no significant difference between tolterodine and oxybutynin in the assessment of treatment benefit (P = 0.2240).

Subgroup analyses showed that improvements in voiding-diary and patient-perception variables were greater with tolterodine and oxybutynin than with placebo in both Japan and Korea. The study was not designed to detect treatment differences within country-specific subgroups, but the greater efficacy of tolterodine than oxybutynin produced statistically significant differences, primarily in the Japanese population. Efficacy did not appear to differ between countries.

QUALITY OF LIFE

Treatment with tolterodine resulted in significantly greater mean reductions in both the incontinence impact domain (P = 0.0205) and role limitation domain scores (P = 0.0382) compared with placebo. Oxybutynin was also associated with better scores than was placebo. There was no significant difference between the improvements with tolterodine and oxybutynin for either domain. Compared with placebo, tolterodine was also associated with improvements in other KHQ domains, including physical limitations (P = 0.0048), social limitations (P = 0.0093), personal relationships (P = 0.0278), sleep/energy (P = 0.0316), severity (coping) measures (P = 0.0053), and the severity of urinary symptoms (P < 0.001). The differences in improvements between tolterodine and oxybutynin were not significant for any of these domains.

TOLERABILITY

Dry mouth was the most common adverse event, occurring in over half of patients in the oxybutynin, a third in the tolterodine and only 10% of the placebo group (Table 3). Dry mouth was significantly more common in patients receiving oxybutynin than tolterodine (P < 0.001). In addition to being more common the severity of dry mouth was also greater in the oxybutynin group, with 20 patients reporting it as severe, compared with just one in the tolterodine group and none in the placebo group. Other adverse events were reported much less frequently, with the only events reported by ≥ 5% of patients (in any treatment group) being constipation, abdominal pain/tenderness, dyspepsia, difficulty in voiding and headache. Other events that might be expected with antimuscarinic therapy, e.g. thirst and urinary retention, were reported by very few patients, but tended to be more common with oxybutynin than with tolterodine or placebo. Eye disorders occurred significantly more frequently among patients receiving oxybutynin than tolterodine (P < 0.0383). The incidence of nervous system disorders was lower in the tolterodine (8.4%) than in the oxybutynin (12.7%) or placebo (11.5%) groups.

More patients were withdrawn because of adverse events from the oxybutynin group than from the other two groups (Table 3). The difference in withdrawal rates between the oxybutynin and tolterodine groups was significant (P < 0.001). Dry mouth was the most commonly reported adverse event among patients who prematurely withdrew from treatment with oxybutynin. Other adverse events frequently reported by patients withdrawn from oxybutynin included difficulty in voiding, urinary retention, abdominal pain, dry skin, dyspepsia, facial oedema, headache and thirst. In comparison, abdominal pain was the most commonly reported event in patients who withdrew from tolterodine. Only three patients in the tolterodine group who prematurely withdrew reported an antimuscarinic-related adverse event (one each for dry mouth, blurred vision and difficulty in voiding).

In all, 15 patients reported serious adverse events (tolterodine eight, oxybutynin seven) but only one of these was considered possibly related to treatment (cardiac failure in a patient treated with oxybutynin). There were no deaths during the study and no clinically relevant changes in clinical laboratory or ECG values were reported.

The frequency and pattern of adverse events differed between the Japanese and Korean populations. Patients in Korea reported fewer adverse events overall, fewer serious adverse events and fewer types of adverse event than did patients in Japan. However, difficulty in voiding and feeling of incomplete emptying were more common in Korean patients, especially with oxybutynin. National differences in tolerability between countries did not appear to be treatment-related, as tolterodine was better tolerated than oxybutynin in both countries.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

Numerous clinical trials in recent years have shown that the symptoms of OAB can be treated effectively with antimuscarinic agents [3–5,9]. However, study populations in most of these trials have been predominantly Caucasian and, despite recent surveys showing a high prevalence of OAB in Asian countries, very few studies have assessed the benefits of antimuscarinic therapy in Asian patients.

The present is the first investigation of tolterodine ER in an Asian population, and the first study of antimuscarinic therapy for OAB in Japan. Oxybutynin IR was administered at a dosage of 3 mg three times daily, which is an approved regimen in the participating countries, although a dosage of 2 mg three times daily is also widely used.

In this study, both tolterodine and oxybutynin were more effective than placebo in patients with OAB. Both agents produced similar improvements in the number of incontinence episodes/week, voids/24 h and volume voided/void. These were significantly greater than those achieved with placebo, despite the high placebo response in this study, which is typical of trials in which patients with OAB complete voiding diaries [4,9]. Improvements in voiding were similar to those reported in a large-scale multinational study of similar design, in which a largely Caucasian population was randomized to double-blind treatment with tolterodine ER for 12 weeks [9]. Thus, it appears that the efficacy of tolterodine ER in Asian patients with OAB is comparable with that previously reported in Caucasians.

Objective improvements in voiding diary variables were accompanied by improvements in subjective endpoints. Almost three-quarters of patients (72%) perceived an improvement in their bladder condition after 12 weeks of treatment with tolterodine, compared with 59% with placebo; this was nearly significant (P = 0.0515). There was no significant difference between the tolterodine and oxybutynin (73%) groups in this variable. Patients with OAB show a strong placebo response; in the present study, patients receiving placebo had fewer incontinence episodes and a lower frequency of voiding, and an increase in volume voided/void compared with baseline values. These findings are consistent with the high proportion of patients in the placebo group reporting an improvement in their bladder condition. However, the present results for tolterodine are consistent with those of an open-label USA study, in which 70% of patients treated with tolterodine ER reported an improvement in bladder condition after 8 weeks [17].

Tolterodine was better tolerated than oxybutynin in the present study, with a lower overall incidence of adverse events. Dry mouth was the most commonly reported adverse event in all treatment groups, but was over 1.5 times more frequent with oxybutynin than with tolterodine (Table 3). The severity of dry mouth was also greater with oxybutynin than with tolterodine, with severe dry mouth in 20 patients in the oxybutynin group compared with just one in the tolterodine group. The higher frequency and severity of dry mouth with oxybutynin was the main reason for the more frequent withdrawal because of poor tolerability than with tolterodine (17% vs 5%). Previous trials have similarly reported dry mouth to be a frequent cause of discontinuation during oxybutynin therapy [3,6]. In clinical practice, such unwillingness or inability to continue therapy because of poor tolerability may impair the overall clinical effectiveness of antimuscarinic treatment, especially given the need for long-term therapy. To circumvent these tolerability and compliance concerns, an ER formulation of oxybutynin has been developed but it is not available in Japan and Korea and its efficacy in an Asian population has not been evaluated.

Other antimuscarinic side-effects occurred at a much lower frequency than dry mouth, but were still generally more frequent with oxybutynin than with tolterodine. These findings are consistent with previous comparative trials and reflect the greater selectivity of tolterodine for the bladder over other tissues than has oxybutynin [2,18].

One possible safety concern with antimuscarinic drug use is the potential for urinary retention, which can occur in a small proportion of patients. In this study, only 2% of patients (five) treated with tolterodine had an acute feeling of incomplete emptying or other voiding difficulties, compared with 12% (30) of those on oxybutynin. The low incidence of urinary retention with tolterodine is consistent with that reported in Caucasian populations and indicates similar safety in Asian patients. In addition, there were no cardiac or CNS safety concerns during the study, and no new safety concerns particular to this Asian population were identified.

Both tolterodine and oxybutynin were associated with significant improvements in quality of life compared with placebo. OAB has a profound and debilitating effect on patients, even those with no demonstrable incontinence, and can affect many areas of their everyday lives, including social, domestic, psychological, physical and sexual functioning [19,20]. Previous studies have shown that treatment with tolterodine can significantly improve many of these aspects of quality of life, and the present study showed a similar beneficial effect in Asians in most domains of the KHQ [21]. It also confirms the validity of the translated KHQ in this patient population.

In conclusion, tolterodine ER has similar efficacy but is better tolerated than oxybutynin IR in this patient population. The improved tolerability of tolterodine ER compared with oxybutynin IR resulted in fewer patients discontinuing therapy, which is likely to result in improved treatment effectiveness in clinical practice.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT
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    Nilvebrant L. The mechanism of action of tolterodine. Rev Contemp Pharmacother 2000; 11: 1327
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    Abrams P, Freeman R, Anderstrom 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: 80110
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    Drutz HP, Appell RA, Gleason D, Klimberg I, Radomski S. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999; 10: 2839
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    Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol 2001; 165: 14526
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    Lee JG, Hong JY, Choo M-S et al. Tolterodine: as effective but better tolerated than oxybutynin in Asian patients with symptoms of overactive bladder. Int J Urol 2002; 9: 24752
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    Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A medium-term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol 1997; 104: 98893
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    Grossklaus DJ, Franke JJ. Treatment of elderly women with urge incontinence in Middle Tennessee: a single institution practice-based study. Tenn Med 2000; 93: 45760
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    Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001; 57: 41421
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    Rovner ES, Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review. Eur Urol 2002; 41: 614
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    Lapitan MC, Chye PL. Asia-Pacific Continence Advisory Board. The epidemiology of overactive bladder among females in Asia: a questionnaire survey. Int Urogynecol J Pelvic Floor Dysfunct 2001; 12: 22631
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    Moorthy P, Lapitan MC, Lim PHC. Prevalence of overactive bladder in Asian males. International Continence Society. Seoul, Korea 2001 http://www.continet.org
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    Ushiroyama T, Ikeda A, Ueki M. Prevalence, incidence, and awareness in the treatment of menopausal urinary incontinence. Maturitas 1999; 33: 12732
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    Ueda T, Tamaki M, Kageyama S, Yoshimura N, Yoshida O. Urinary incontinence among community-dwelling people aged 40 years or older in Japan: prevalence, risk factors, knowledge and self-perception. Int J Urol 2000; 7: 95103
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    Homma Y, Gotoh M, Ando T, Fukuhara S. Development of Japanese version of QOL questionnaires for urinary incontinence. Jpn J Neurogenic Bladder 1999; 10: 22536
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    Sussman D, Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the Antimuscarinic Clinical Effectiveness Trial (ACET). Curr Med Res Opin 2002; 18: 17784
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    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: 104450
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APPENDIX

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

A complete list of the members of the Tolterodine Study Group in alphabetical order by country:

In Japan: Hironobu Akino, Yoshida-gun, Fukui; Shiro Baba, Sagamihara City, Kanagawa; Atsunobu Esa, Tennoji-ku, Osaka; Takuji Fujinaga, Koya, Wakayama; Junnosuke Fukui, Chuo-ku, Tokyo; Eitetsu Gon, Shizuoka; Momokazu Gotoh, Showa-ku, Nogoya; Takahiro Haginaka, Toyama; Yukio Homma, Tokyo; Kiyotaka Hoshinaga, Toyoake City, Aichi; Takahito Ikeuchi, Nagoya Shiritsudaigaku, Aichi; Hirohide Iriguchi, Kochi; Toshiya Ishida, Yokote City, Akita; Yoshio Ishida, Nakahara-ku, Kawasaki; Yasunori Ishii, Urawa, Saitama; Osamu Ishiko, Abeno-ku, Osaka; Shinji Kageyama, Hamamatsu City, Shizuoka; Hiroshi Kajikawa, Izumiohtsu City, Osaka; Yoshiyuki Kakehi, Kida-gun Kagawa; Tetsuo Katsumi, Kanazawa City, Ishikawa; Kazuki Kawabe, Tokyo; Mutsushi Kawakita, Moriguchi, Osaka; Takeshi Kawamura, Sumida-ku Tokyo; Kazuo Kitami, Fujisawa City, Kanagawa; Shinya Kobayashi, Sapporo City, Hokkaido; Kenjiro Kohri, Mizuho-ku, Nagoya; Hideki Komatsu, Minato-ku, Tokyo; Hitoshi Masuda, Bunkyo-ku, Tokyo; Shigeki Matsuo, Akita City; Hisashi Matsushima, Chiyoda-ku, Tokyo; Shigeyoshi Morimoto, Kishiwada City, Osaka; Hajime Morita, Bibai City, Hokkaido; Haruo Nakagawa, Sendai City, Miyagi; Yosuke Nakajima,Kanagawa-ku, Yokohama; Mikio Namiki, Kanazawa City, Ishikawa; Takashige Namima, Sendai City, Miyage; Osamu Nishizawa, Matsumoto, Nagano; Kazumi Noguchi, Yokohama City, Kanagawa; Ryosuke Noguchi, Mito City, Ibaraki; Yasutada Onodera, Aoba-ku, Yokohama; Seiichirou Ozono, Shijo-cho Kashihara, Nara; Masafumi Sahashi, Shizuoka; Shigeo Sakashita, Obihiro City, Hokkaido; Shoji Samma, Hiramatsu Nara City, Nara; Masayoshi Shimamura, Kanazawa City, Ishikawa; Naotake Shimoda, Akita; Atsushi Sone, Kurashiki; Takahide Sugiyama, Osaka Sayama City, Osaka; Kouji Suzuki, Uchinada, Ishikawa; Yasushi Suzuki, Morioka City, Iwate; Masashi Takaiwa, Yonezawa City, Yamagata; Hitoshi Takamoto, Kurashiki City, Okayama; Masayuki Takeda, Tamaho, Yamanashi; Mineo Takei, Hakata-ku, Fukuoka; Ikumasa Takenaka, Kida-gun, Kagawa; Shigeo Taketa, Kida-gun, Kagawa; Hideo Takeuchi, Kobe City, Hyogo; Toshiro Terachi, Tenri Nara; Takashi Tominaga, Chiyoda-ku, Tokyo; Sadamu Tsukamoto, Tuskuba-shi, Ibaraki; Osamu Ueki, Nanao City, Ishikawa; Toyoko Yamato, Okayama; Kousaku Yasuda, Koshigaya-city, Saitama; Teruhiko Yokoyama, Shikata-cho, Okayama; Masaki Yoshida, Kumamoto.

In Korea: Young Deuk Choi, Seoul; Myung-Soo Choo, Soeul; Seong Soo Jeon, Seoul; Hee Chang Jung, Taegu; Sae Woong Kim, Seoul; Heon-Young Kwon, Pusan; Jeong Gu Lee, Seoul; Jeong Zoo Lee, Pusan; Tack Lee, Inchon; Jae Seung Paick, Seoul; Myung Sik Shin, Kyunggi-do; Ha Na Yoon, Seoul.

EDITORIAL COMMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
  9. APPENDIX
  10. EDITORIAL COMMENT

The results in this report are relevant only in those countries in which the once-daily form of oxybutynin is unavailable. The once-daily form, because of less first-pass liver metabolism, has fewer side-effects than the immediate-release form, and represents the ‘reference standard’ of oral oxybutynin therapy [1]. Noteworthy in this article are: (i) the lack of any significant difference in efficacy variables between the active drugs; (ii) the presence of a difference in side-effect profile (dry mouth particularly); and (iii) the relatively small difference in efficacy variables between both active drugs and placebo, yet accounting for significant differences in quality of life. There is now a published direct comparison of the once-daily oral forms of tolterodine and oxybutynin [2]. Although both relieve symptoms and have fewer side-effects than the once-daily counterparts, it is clear that newer forms of pharmacological therapy, directed either at inhibiting cholinergic activation of the detrusor with greater efficacy and/or tolerability, or at inhibiting different motor or sensory mechanisms, would be welcome for the treatment of OAB.

A.J. WEIN, MD, Professor & Chair, Division of Urology, University of Pennsylvania Health System, Philadelphia, PA, USA

  • 1
    Wein AJ. Neuromuscular dysfunction of the lower urinary tract and its treatment. In WalshP, RetikA, VaughanED Jr, WeinAJ eds, Campbell's Urology. Eighth Edn. Philadelphia: WB Saunders, 2002: 93166
  • 2
    Diokno AC, Appell RA, Sand PK et al. for the OPERA Study Group. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA Trial. Mayo Clin Proc 2003; 78: 68795