Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone

Authors


K.J. Kreder Jr, MD, Department of Urology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
e-mail: karl-kreder@uiowa.edu

Abstract

OBJECTIVE

To examine the efficacy of tolterodine, an antimuscarinic agent with a bladder-selective profile, in patients with mixed incontinence (MI, stress and urge) compared with patients with urge incontinence (UI) alone.

PATIENTS AND METHODS

The study included 239 patients with MI (urge predominating) and 755 with urge incontinence alone from a single-blind, multicentre trial of 1380 patients (80% female) with an overactive bladder. Those completing the trial were analysed ‘per-protocol’. After a 7-day washout and a 3-day run-in to collect baseline information, patients were treated with tolterodine twice daily for 16 weeks. The two groups were compared for incontinence episodes/24 h, voiding frequency, nocturia episodes and pad usage after 16 weeks of treatment.

RESULTS

After 16 weeks the median changes from baseline for all voiding variables were statistically significant for the MI and the UI groups (P < 0.001), with no apparent significant between-group differences. The median percentage reduction in incontinence episodes from baseline was 67% for the MI and 75% for the UI groups (P = 0.39). ‘Dry’ rates for the MI and UI groups at the end of the study were 39% (66/171) and 44% (243/552), respectively, whilst 24% of patients in each group (MI 40/170; UI 130/551) achieved a voiding pattern of < 8 voids/24 h. ‘Cure’ rates for nocturia and the reduction in the number of patients not using pads used were also similar between the groups.

CONCLUSION

Tolterodine is as effective in reducing leakage and other symptoms of an overactive bladder in patients with MI as it is in patients with UI alone.

INTRODUCTION

Overactive bladder (OAB), defined as urinary urgency with or with no urge incontinence (UI), often in combination with urinary frequency and/or nocturia [1], and stress incontinence are common complaints among the general population [2,3]. Indeed, UI in combination with stress incontinence, so called ‘mixed incontinence’ (MI), is frequently encountered by physicians, and is the most common form of urinary incontinence in women [2,4].

For many patients with MI the urge component is often the most troublesome aspect of their condition, because of its unpredictability and the large volume of urine that could potentially be lost. Treatment with an antimuscarinic agent has therefore been advocated as a reversible first-line therapy for such patients with MI, based on the confirmed efficacy of antimuscarinic therapy in patients with OAB alone [5]. However, to date there have been no published reports of the efficacy of antimuscarinic drug therapy in patients with MI.

Tolterodine is available as both an immediate-release tablet and an extended-release capsule formulation, and the efficacy of both has been reported [6–12]. The aim of the present study was to examine the efficacy of immediate-release tolterodine in patients with MI compared with those with UI alone.

PATIENTS AND METHODS

This was a subgroup analysis from a previously reported single-blind, flexible-dose study (unpublished data). In all, 1380 patients (1098 women, 80%) aged ≥ 18 years with OAB, recruited solely on the basis of their symptoms as determined by a physician assessment, i.e. urinary frequency (≥ 8 voids/24 h) and either urgency or UI (≥ one incontinence episode/24 h), were enrolled in the study. A cohort of 994 reporting incontinence was divided into two groups; those with MI with the urge component predominating and those with UI alone. The study was conducted according to Good Clinical Practice Guidelines and the latest revisions of the Declaration of Helsinki, the study protocol having been approved by the institutional review board of each participating centre. Each patient provided written informed consent before the conduct of study procedures.

Relevant exclusion criteria were: patients with MI with the stress component predominating; patients with contraindications to antimuscarinic therapy; significant hepatic or renal disease; those who were symptomatic or who had a history of recurrent UTI; haematuria or interstitial cystitis; significant voiding difficulty with risk of urinary retention; and patients receiving bladder training, electrostimulation therapy, or having an indwelling catheter or an intermittent catheterization, and women with reproductive potential. Pregnant or nursing women were also excluded from enrolment. Concomitant treatment for OAB (other than oestrogen-replacement therapy started at least 2 months before study commencement) and use of anticholinergic agents was not permitted during the study.

After an initial screening visit and a 7-day washout period, patients underwent a 3-day run-in period to collect baseline voiding diary information, including the voiding frequency over 24 h and at night (between 24.00 and 06.00 hours, i.e. nocturia episodes), mean volume voided per void, number of episodes of incontinence and use of incontinence pads. Eligible patients subsequently commenced oral twice-daily treatment with tolterodine for 16 weeks. Dosage was initiated at 1 mg twice daily for 4 weeks, after which the dose could be increased to 2 mg twice daily (and subsequently reduced to 1 mg if necessary), based on the patient's response.

Tolterodine 1 mg and 2 mg tablets were of identical appearance so patients were unaware of their actual dose. The efficacy of tolterodine in the MI and UI groups was subsequently compared for patients completing the study for changes in voiding diary variables after 16 weeks of treatment, as determined from voiding diaries completed over the preceding 3 days.

The treatment efficacy was analysed statistically for those patients who completed the study on a per-protocol basis. Changes in voiding diary variables from baseline were compared between groups using median values and appropriate nonparametric tests, because the data were not normally distributed. Statistical tests were two-sided with P < 0.05 considered to indicate significance. Further descriptive analysis was completed for ‘cure’ rates of individual symptoms at the completion of the study, i.e. the patients who achieved dryness (i.e. absence of incontinence), those with nocturia at baseline (≥ two episodes of night-time voiding) who achieved a reduction in nocturia frequency to ≤ two episodes/24 h, those who stopped using pads (for those using pads at baseline), and those who achieved a voiding frequency of < 8 voids/24 h. Voiding frequency data were further analysed to determine the ‘percentage normalization’ for each patient (achieving a voiding frequency of < 8 voids/24 h), calculated as (number of patients with < 8 at 16 weeks/number of patients with > 8 at baseline) × 100.

RESULTS

In all, 1380 patients were enrolled into the original study, of whom 1378 received at least one dose of study medication. Among the cohort of 994 patients with urinary leakage at baseline, 755 (76%) had UI alone and the remaining 239 had symptoms of MI with the urge component predominating. In all, 723 patients from this cohort completed the study and were evaluable on a per-protocol basis (MI 171; UI 552).

Overall, the per-protocol populations for the MI and UI groups were well matched for baseline characteristics (Table 1). There was a significantly higher proportion of women (P < 0.001) and pad users (P = 0.028) in the MI group but otherwise there were no statistically significant differences between the groups.

Table 1.  Baseline characteristics, the effect of tolterodine, and ‘cure’ rates after 16 weeks (per-protocol population)
CharacteristicMIUI
  • *

    Patients experiencing ≥ 2 nocturia episodes/24 h;

  • P  < 0.001, Wilcoxon signed-rank test.

N171552
No. of women (%)165 (96.5)464 (84)
Median (range):
age, years  62 (21–88)  65 (20–88)
no. of incontinence
episodes/24 h
 3 (1–19)  3 (1–15)
Duration of symptoms
> 5 years, n (%)
 91 (53)259 (47)
Previous surgery affecting
lower urinary tract,
n (%)
 65 (38)233 (42)
Previous drug therapy
for OAB, n (%)
 85 (50)275 (50)
N (%) of patients:
using pads122 (71)342 (62)
with nocturia*100 (58.5)334 (60.5)
Tolterodine
No. of evaluable patients170551
Volume voided/void, mL:
Median (range):
at baseline169 (62–506)164 (31–524)
change at 16 weeks  26.5 (−261–195)  27 (−345–389)
‘Cure’ rates, n (%)
Patients who achieved
dryness
 66/171 (39)243/552 (44)
Patients (with nocturia
at baseline) and
nocturia frequency
≤ 2 episodes/24 h
 83/100 (83)254/334 (76)
Pad users (at baseline)
with no pad usage
 26/122 (21)  93/342 (27)
Patients with normalized
voiding frequency (< 8 voids/24 h)
 40/170 (23.5)130/551 (24)

Most patients in each group had their tolterodine dose increased to 2 mg twice daily at 4 weeks and were maintained at this level for the remainder of the study (MI 106, 62%; UI 479, 66%). In the investigator's opinion, 95% of all patients were compliant in taking their medication throughout the study, and no differences were apparent between the groups.

Voiding diary variables

Relative to baseline, there were statistically significant improvements in all voiding diary variables for both groups after 16 weeks of treatment with tolterodine. For the number of incontinence episodes, there was a median (interquartile rage) reduction of 67% (−100% to −33.3%) from baseline for the MI group, which was not significantly different from that in those with UI alone, at 75% (−100% to −33.3%). This improvement was paralleled by reductions in pad usage (−40% and −50%), nocturia (−50% and −33%) and voiding frequency/24 h (−15% and −17%), whilst volume voided per void was increased (Table 1). There were no significant between-group differences for the improvement in voiding diary variables during tolterodine therapy.

‘Cure’ rates were generally similar between the MI and UI groups after 16 weeks of treatment (Table 1); for voiding frequency, 24% (170/721) of patients had fewer daily voids, to < 8 voids/24 h, and there was no significant difference between the groups. Further analysis, taking into account the baseline number of voids (i.e. > 8 voids/24 h), showed that the median percentage reduction of voiding frequency for patients with MI was comparable with that in patients with UI alone (−67% and −60%, respectively).

Discussion

Antimuscarinic therapy is often used as a reversible first-line treatment option for patients with MI in whom the urge component is predominant. However, there is little information to aid physicians in their choice of antimuscarinic agent for such patients. The present study shows that tolterodine, an antimuscarinic agent with a bladder-selective profile, is effective for treating patients with MI. Thus, more than half of patients had a > 67% reduction in incontinence episodes after 16 weeks of treatment, an improvement that was paralleled by significant improvements in voiding frequency, nocturia and volume voided per void. The latter findings are consistent with the increase in functional bladder capacity during urodynamic investigations with tolterodine [10]. There was also a significant decrease in pad usage, which is likely to have considerable economic impact for patients and healthcare providers alike.

Overall, the efficacy of tolterodine in patients with MI was similar to that in a parallel cohort of patients with UI alone, and was in line with earlier studies with tolterodine in patients with OAB [6,8,9,11,13]. From these findings, initial treatment with tolterodine therefore appears warranted for patients reporting mixed symptoms of stress and UI, provided other local or metabolic pathological causes of such symptoms have been excluded.

Stress incontinence was a minor component of the mixed symptoms; patients with MI whose most bothersome symptom was stress incontinence were excluded from the study. Tolterodine is a muscarinic receptor antagonist that inhibits involuntary detrusor muscle contraction [14]. However, stress incontinence (resulting from an involuntary leakage of urine during an increase in abdominal pressure in the absence of detrusor contraction [15]), should not be susceptible to the effects of tolterodine. Despite this, the presence of stress incontinence in patients with MI did not result in a significantly lower efficacy of tolterodine than with patients with UI alone.

Patients with OAB, including those with concomitant stress incontinence, experience a variety of symptoms. As such, a favourable outcome should not be considered simply as achieving ‘dryness’ (i.e. absence of incontinence) but also in terms of other urinary symptoms. In the present study we therefore evaluated the therapeutic effect of tolterodine in terms of arbitrary, clinically relevant ‘cure’ rates for the various urinary symptoms experienced by patients.

Overall, 39% of patients with MI had no urinary leakage by the end of the study, compared with 44% of those with UI alone. The slightly lower ‘dry rate’ for the MI group is probably explained by occasional leakage caused by the stress component. The minor contribution of stress incontinence also probably explains the slightly lower rates of zero pad usage for the MI group than in those with UI alone (21% and 27%, respectively).

An interesting finding was that, irrespective of diagnostic group, the so called ‘cure’ rates for incontinence and pad usage showed a comparable divergence. For example, in those with MI, 39% achieved dryness, but only 21% of pad users reported no reliance on pads at the end of the study. This finding is probably explained by a minor proportion of patients who continued the habitual use of pads despite having been ‘cured’ of incontinence [16]. Indeed, about half of all patients had been having symptoms for > 5 years before enrolment, and in these patients such habitual coping behaviours may have become deep-rooted. Prolonged treatment may therefore be required before patients are fully confident in their enhanced bladder control provided by tolterodine, after which further reductions in pad usage may become apparent.

Nocturia may represent a significant symptom for patients with either OAB or MI, as frequent disruption of sleep can lead to daytime impairment [17]. However, the effect of antimuscarinic therapy on this symptom has not been extensively studied. In the present study there was a marked improvement in nocturia during tolterodine therapy, and such benefits were particularly apparent for patients with MI. Indeed, 83% of patients in the MI group had fallen into the normal range, arbitrarily defined as ≤ two episodes of nocturia, at the end of the study. This definition of a ‘normal range’ was used, because needing to get up at least once at night to void is considered ‘normal’ with increasing age [18], the median age in the present study being 64 years.

In summary, tolterodine is as effective in reducing urinary leakage and other symptoms of OAB in patients with MI as it is in patients with UI alone. From these findings, tolterodine can be considered an effective first-line treatment option for patients presenting with MI in which urge predominates.

Acknowledgements

This study was supported by the Pharmacia Corporation.

Abbreviations
MI

mixed incontinence

UI

urge incontinence

OAB

overactive bladder.

Ancillary