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Keywords:

  • urinary incontinence;
  • overactive bladder;
  • tolterodine;
  • men

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

A group of authors from the USA evaluated the efficacy and tolerability of tolterodine extended-release on objective and subjective endpoints in men with an overactive bladder. They found that it significantly reduced incontinent episodes and improved patient perception of treatment benefit in men with an overactive bladder

OBJECTIVE

To evaluate the efficacy and tolerability of tolterodine extended-release (ER) on objective and subjective endpoints in men with overactive bladder (OAB) and urgency urinary incontinence (UI).

PATIENTS AND METHODS

This was a post hoc analysis of data collected from men with OAB enrolled in a 12-week, double-blind, placebo-controlled trial of tolterodine ER (4 mg once daily; tolterodine ER registration trial) and included men with urinary frequency (≥8 micturitions/24 h) and urgency UI (≥5 episodes/week). UI episodes were assessed using 7-day bladder diaries. Patient perception of treatment benefit was evaluated after 12 weeks. Adverse events (AEs) were recorded throughout the study.

RESULTS

In all, 163 men with OAB (placebo, 86; tolterodine ER, 77; mean age 65 years) were evaluated. Baseline demographics and clinical characteristics were similar for the two treatment groups. Compared with placebo, tolterodine ER significantly reduced weekly UI episodes (median % change, −71% vs − 40%, P < 0.05; mean numeric change, − 11.9 vs −5.9, P = 0.02). Men receiving tolterodine ER had fewer micturitions/24 h, but this was not a significant difference from placebo (median % change, −12% vs − 4%, P = 0.22). Significantly more men treated with tolterodine-ER (63%) than placebo-treated men (46%) reported a benefit of treatment after 12 weeks (P = 0.04). The most commonly reported AEs associated with tolterodine-ER vs placebo were dry mouth (16% vs 7%), constipation (4% vs 9%), dyspepsia (4% vs 1%), dizziness (5% vs 1%), and somnolence (3% vs 1%). One of the men receiving tolterodine ER had symptoms suggestive of urinary retention that led to his withdrawal from the study. None of the men had acute urinary retention requiring catheterization.

CONCLUSION

In men with OAB and urgency UI, tolterodine ER was well tolerated and significantly reduced episodes of urgency UI, and improved patient perception of treatment benefit.


Abbreviations
ER

extended release

OAB

overactive bladder

U(UI)

urgency (urinary incontinence)

AE

adverse events

ancova

analysis of covariance.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence (UI), usually with frequency and nocturia [1]. A European study estimated that OAB affects 16% of men aged ≥ 40 years and 41% aged ≥ 75 years [2]. OAB can have a negative impact on health-related quality of life; men with OAB scored significantly lower than healthy controls on a generic health-related quality-of-life instrument assessing sleep quality, social functioning, and mental health [3,4].

OAB symptoms are often attributed to detrusor overactivity, a condition that is urodynamically distinguished by involuntary detrusor contractions during the bladder-filling phase [1]. BOO can induce detrusor overactivity by several mechanisms [5–8], but OAB symptoms can exist in the absence of BOO. In a study of 160 men with LUTS, including UI, urinary frequency, nocturia, or difficulty voiding, BOO was confirmed in 109 (68%) [9], and Laniado et al.[10] reported that only 48% of men with LUTS had urodynamically confirmed BOO. Thus, the α1-adrenoreceptor antagonists and 5α-reductase inhibitors that are often chosen as initial pharmacotherapies for LUTS secondary to BOO might not relieve OAB symptoms (i.e. UI, urgency and frequency) in all men. A study in the USA suggested that 16% of men with OAB symptoms have urgency UI [3]. Men with urgency UI have been under-represented in trials of pharmacotherapy for OAB, although 84% of men with urgency UI report some degree of symptom bother [11].

The present analysis assessed the efficacy and tolerability of tolterodine extended-release (ER) for reducing UI episodes in men with OAB and urgency UI who did not have clinically relevant BOO.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The tolterodine ER registration trial was a 12-week randomized, double-blind, placebo-controlled trial performed at 167 centres in Australia, Europe and North America [12]. Eligible patients were ≥ 18 years old with symptoms of urinary frequency (≥8 micturitions/24 h) and urgency UI (≥5 episodes/week). Key exclusion criteria were significant hepatic or renal disease, current or recurring UTI, stress UI, clinically relevant BOO (judged by the investigator and based on patient history), indwelling catheter or intermittent self-catheterization, and any condition for which antimuscarinic treatment is contraindicated. Patients taking any anticholinergic drug or treatment for OAB during the 14-day wash-out/run-in period before randomization, and those with a mean micturition (void) volume of >200 mL or total daily volume of >3000 mL on bladder diaries completed before randomization, were also excluded. All patients gave written informed consent before enrolment.

After an initial screening visit, patients entered a 2-week washout/run-in period during which they completed bladder diaries to determine baseline values for micturition frequency and episodes of UI. These values were used to further assess each patient's eligibility before randomization. Eligible patients were randomized to once-daily treatment with placebo or tolterodine ER (4 mg) for 12 weeks.

Bladder diaries were completed for the 7 days preceding the baseline visit, and visits at 4, 8, and 12 weeks. Patients were told to record all micturitions and UI episodes at the times they occurred. Perception of treatment benefit was assessed only at the 12-week visit using a two-step ordered categorical scale [13]. Patients were asked ‘Have you had any benefit from your treatment?’ If the answer was ‘yes’, the patient was asked to grade the benefit as ‘little benefit’ or ‘much benefit.’ Adverse events (AEs) were recorded throughout the study.

This post hoc analysis included only men with ≥ 5 urgency UI episodes/week. The primary efficacy endpoint was the change in number of UI episodes/week from baseline to 12 weeks. Daily micturitions and patient perception of treatment benefit were secondary endpoints. Relative changes in UI episodes/week and micturitions/24 h were analysed using a rank analysis of covariance (ancova) model fitted with terms for baseline values and treatment. Numeric changes in each endpoint were analysed using an ancova model also fitted with terms for baseline values and treatment. Patient perceptions of treatment benefit were compared using the chi-square test. All statistical tests were two-sided with a significance level of 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

A total of 163 men met the inclusion criteria for this study; each received at least one dose of study medication and was included in the safety analysis. The 86 men receiving placebo had a mean (sd) age of 66 (14) years, vs 64 (16) years for the 77 men receiving tolterodine ER. The men were predominantly (97%) white, and baseline demographic and clinical characteristics were similar between the groups (Table 1).

Table 1.  The demographic and baseline characteristics, and AEs occurring in ≥ 2% patients
VariablePlaceboTolterodine ER
  • *

    surgical repair of hernia (one), varices (one).

Number of patients8677
Mean (sd) age, years66 (14)64 (16)
Race, % White9896
 Black 1 3
 Asian or Pacific Islander 1 0
 Mixed 0 1
Urinary symptoms, mean (sd)
 UI episodes/week21 (18)22 (22)
 Micturitions/24 h12 (3)12 (4)
AEs, n (%)
Dry mouth 6 (7)12 (16)
Dizziness 1 (1) 4 (5)
Constipation 8 (9) 3 (4)
Dyspepsia 1 (1) 3 (4)
Flatulence 3 (4) 2 (3)
Headache 4 (5) 2 (3)
Pharyngitis 0 2 (3)
Somnolence 1 (1) 2 (3)
Upper respiratory infection 1 (1) 2 (3)
Chest pain 2 (2) 1 (1)
Erectile dysfunction 2 (2) 1 (1)
Dry eye 2 (2) 1 (1)
Back pain 2 (2) 0
Diarrhoea 2 (2) 0
Peripheral oedema 2 (2) 0
Surgical intervention 2 (2)* 0

Reductions in weekly UI episodes after 12 weeks of treatment were significantly greater in the tolterodine-ER group than in the placebo group (median % change, − 71% vs − 40%, P < 0.05; mean numeric change, −11.9 vs − 5.9, P = 0.02; Fig. 1). Although there was a greater reduction in the number of micturitions/24 h in the tolterodine-ER group than in the placebo group (median % change, −12% vs − 4%; mean numerical change, − 1.7 vs − 1.4), the differences were not statistically significant (P = 0.22 and 0.36, respectively). A significantly larger percentage of men receiving tolterodine ER reported an overall benefit of treatment (63% vs 46%, P = 0.04; Fig. 2). Except for dry mouth, the incidence of AEs in men receiving tolterodine ER was low and similar to placebo (Table 1). Interestingly, the incidence of dry mouth in this population (16%) was lower than in the total study population (23%). One man receiving tolterodine ER had symptoms suggestive of urinary retention, leading to his withdrawal from the study. None of the men had acute urinary retention requiring catheterization.

image

Figure 1. The mean numeric (A) and median percentage (B) reductions in UI episodes in tolterodine ER-treated vs placebo-treated men. *P < 0.05 vs placebo.

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image

Figure 2. Patient perception of treatment benefit in tolterodine ER- and placebo-treated men at 12 weeks. *P < 0.05 vs placebo.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Compared with placebo, tolterodine ER significantly reduced UI episodes in this population of men with OAB and urgency UI. These findings support previous studies showing that tolterodine effectively reduces the incidence of UI in patients with OAB [14,15]. Although men receiving tolterodine ER had fewer micturitions/24 h, a comparison of these changes with placebo was not statistically significant, perhaps because of the small sample size. However, perhaps the most meaningful outcome is that men receiving tolterodine ER were more likely to report a subjective benefit of treatment than were men receiving placebo.

Tolterodine ER was well tolerated in this subpopulation of men. The low overall incidence of AEs is supported by previous studies of tolterodine involving men and women [12,14,16,17]. The most commonly reported AE (dry mouth) was typical of antimuscarinic therapy. Additionally, only one of the men receiving tolterodine ER had symptoms suggestive of urinary retention. This is consistent with the theory that, at therapeutic doses, antimuscarinics affect the bladder storage phase with little effect on voiding contractions [18]. The present results also support previous findings in men with BPH and BOO [17–20], and suggest that the inhibitory effect of antimuscarinic agents on detrusor muscle contraction is unlikely to aggravate the voiding difficulties of men with OAB symptoms and possible BOO.

The population-based UrEpik study showed that up to 16% of men aged 40–79 years experience UI from some cause [19]. Coyne et al.[4] reported that patients with OAB and urgency UI report significantly greater symptom bother than continent patients with OAB do. Incontinent patients also score significantly lower on measures of health perception [20] than OAB patients who have symptoms of frequency and urgency alone do. Incontinence also exacerbates the economic burdens of OAB. Hu et al.[21] reported that the annual cost of OAB for institutionalized patients aged ≥ 65 years was ≈ US $3500 in the year 2000, but the cost for those with UI was ≈ $5300. The combined annual institutional and community costs of OAB and UI were $12.6 and $19.5 billion, respectively [21]. The authors concluded that the extra cost of incontinence was due, in part, to the positive association between incontinence and nursing home admission. Thus, control of UI is an important goal for the reduction of OAB-associated quality of life and economic costs.

In the present study, tolterodine ER was efficacious in reducing UI episodes in men with OAB. A significantly greater percentage of men receiving tolterodine ER reported treatment benefit than did men receiving placebo. Although urodynamic evaluations were not done to determine the presence or absence of BOO, many of the men were treated successfully and safely with tolterodine ER. However, if OAB symptoms persist with tolterodine ER treatment, urodynamic evaluation might be considered to identify other causes of the symptoms.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

C.G. Roehrborn is a paid consultant to sponsor; P. Abrams and S. Herschorn are both an investigator and consultant; E.S. Rovner is on the advisory board and speakers bureau for Pfizer; S. Kaplan is an investigator; Z. Guan is an employee of Pfizer. Source of funding: Pfizer Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES