Solifenacin and Tolterodine Are Equally Effective in the Treatment of Overactive Bladder Symptoms

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provided by Elsevier - Publisher Connector J Formos Med Assoc 2010;109(10):702–708

Contents lists available at ScienceDirect Volume 109 Number 10 October 2010 ISSN 0929 6646

Journal of the Journal of the Formosan Medical Association Formosan Medical Association New Delhi metallo-b-lactamase-1 HTLV-1 and adult T-cell leukemia Detection of nighttime melatonin level in Chinese original quiet sitting Solifenacin and Tolterodine in the treatment of overactive bladder symptoms

Formosan Medical Association Journal homepage: http://www.jfma-online.com Taipei, Taiwan

Original Article Solifenacin and Tolterodine are Equally Effective in the Treatment of Overactive Bladder Symptoms Chen-Hsun Ho,1,3 Ting-Chen Chang,2 Ho-Hsiung Lin,2 Shih-Ping Liu,1 Kuo-How Huang,1 Hong-Jeng Yu1*

Background/Purpose: Various antimuscarinic agents have been developed for the treatment of overactive bladder (OAB). More data comparing these agents are still required. This study evaluated the efficacy and safety of solifenacin and tolterodine in Taiwanese patients with OAB symptoms. Methods: This was a prospective, randomized, open-label study. A total of 75 patients (25 men and 50 women) with OAB symptoms were randomized to treatment with solifenacin (n = 39) or tolterodine (n = 36). Efficacy and safety variables were assessed and compared with the baseline and between the two groups. Results: At week 12, solifenacin and tolterodine demonstrated equal efficacy in reducing the number of micturition (–2.56 ± 3.31 vs. –2.44 ± 4.56, p = 0.58), urgency (–1.70 ± 3.07 vs. –1.15 ± 2.68, p = 0.37) and incontinence (–2.79 ± 2.82 vs. –4.67 ± 9.29, p = 0.28) episodes per 24 hours. There was no difference in improvement of the quality of life. The patient and physician assessments of treatment benefit were not statistically different for solifenacin and tolterodine (p = 0.23 and p = 0.52, respectively), with the majority showing benefits in both groups. The incidence of major adverse events, including dry mouth (18.0% vs. 8.3%, p = 0.31) and constipation (12.8% vs. 2.8%, p = 0.20) was not significantly different. Compared with baseline, the severity of dry mouth did not increase in either group. Conclusion: Both solifenacin and tolterodine are effective in treating key OAB symptoms, including urinary frequency, urgency and incontinence in the Taiwanese population. Both medications are comparably effective and safe, with the most common adverse effects being dry mouth and constipation.

Key Words: antimuscarinic agents, overactive bladder, solifenacin, tolterodine

Overactive bladder (OAB) is defined by the Inter- An epidemiological survey of 1581 Taiwanese national Continence Society as a syndrome that women has demonstrated that OAB affects 18.6% comprises urgency, with or without incontinence, of this population,2 and the prevalence rate is sim- usually accompanied by frequency and nocturia.1 ilar to that of western populations.3,4 In addition

©2010 Elsevier & Formosan Medical Association ...... Departments of 1Urology and 2Obstetrics and Gynecology, National Taiwan University Hospital, and 3Division of Urology, Department of Surgery, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan.

Received: October 4, 2009 *Correspondence to: Dr Hong-Jeng Yu, Department of Urology, National Taiwan Revised: September 16, 2009 University Hospital, 7 Chung-Shan South Road, Taipei, 100, Taiwan. Accepted: November 3, 2009 E-mail: [email protected]

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to its high prevalence rate, several lines of evidence Patients and Methods have shown that OAB adversely affects quality of life5 and is associated with an increased risk Subjects were enrolled from the outpatient clin- of urinary tract infection, skin infection, and fall ics of Urology, and Obstetrics and Gynecology at injury.6,7 These health-related consequences war- the National Taiwan University Hospital between rant appropriate management of OAB. February 2007 and May 2008. Patients were eligi- Treatment for OAB includes behavioral, phar- ble for the study if all of the following applied: macological, and surgical therapy. Among these (1) male or female aged ≥ 18 years; (2) informed choices, antimuscarinic agents remain the main- consent had been obtained; (3) the patient was stay of treatment.8 There are five subtypes of mus- willing and able to complete the micturition carinic receptors (M1–M5) throughout the human diary correctly; (4) the OAB symptoms, including body. In the urinary bladder, although M2 recep- urinary frequency, urgency, or urge incontinence, tors predominate in number, normal bladder con- had persisted for ≥ 3 months; (5) the patient must traction is mainly mediated by stimulation of M3 have experienced frequency, defined as ≥ eight receptors,9 which are also the target of antimus- micturitions per 24 hours. Exclusion criteria in- carinic agents. By blocking the muscarinic recep- cluded: (1) pregnant and lactating women or tors, antimuscarinic agents inhibit the abnormal those who intended to become pregnant during bladder contractions (detrusor overactivity) and the study; (2) clinically significant bladder out- subsequently reduce OAB symptoms. However, flow obstruction (such as men with benign pro- antimuscarinic agents also act on other muscarinic static hyperplasia or women with bladder outlet receptors throughout the body and therefore cause obstruction); (3) significant post-void residual adverse effects, including dry mouth, constipa- (PVR) volume (> 200 mL); (4) genuine stress uri- tion, drowsiness, and blurred vision. Clinically, nary incontinence; (5) evidence of symptomatic it is these adverse effects that limit the use of urinary tract infection, chronic inflammation, antimuscarinics. bladder stones, previous pelvic radiation ther- In recent decades, several new compounds have apy, or previous or current malignant disease of been developed to reduce these unfavorable ad- the pelvic organs; (6) patients with any medical verse effects. Tolterodine was the first agent in- condition that contraindicated the use of anti- troduced for this purpose. It is bladder-selective muscarinic medication; (7) uncontrolled narrow and has been shown in animal studies to have a angle glaucoma, urinary or gastric retention, or greater affinity in the bladder than in the salivary any other medical condition that, in the opinion glands.10 Clinically, tolterodine has been demon- of the investigator, contraindicated the use of strated to have less side effects than other anti- antimuscarinics. muscarinic agent.11 A newer antimuscarinic agent, Eligible patients were randomized to one of the solifenacin, has also proved to be bladder-selective following two treatment groups: 5 mg solifenacin and even M3-receptor-selective. Clinical trials have once daily or 4 mg tolterodine once daily. At base- shown that solifenacin is effective in the treatment line, a complete medical history, medication his- of OAB and is generally well tolerated.12 tory, physical examination, urinalysis, and blood Although several studies have compared both test (complete blood count and routine biochem- medications in western populations,13,14 to the istry) were obtained. Patients were instructed to best of our knowledge, a comparison based on a complete a 3-day voiding diary as a baseline con- Taiwanese population has not been reported. For dition before the intervention. Recorded items in this purpose, we conducted a prospective and the voiding diary included times of micturition, randomized trial to compare the efficacy and urgency and incontinence episodes, time of ris- safety of 5 mg solifenacin once daily and 4 mg ing and going to bed, void volume of each mic- tolterodine once daily. turition, and numbers of pads used. A validated

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six-point categorical scale, the Patient Perception (PPS). All efficacy analyses were based on the PPS. of Bladder Condition (PPBC), was used to assess Changes from baseline to endpoint for mean mic- the severity of OAB.15 Also, to evaluate the ad- turition number, mean urgency episodes, mean in- verse effect of dry mouth that either intervention continence episodes, and PPBC were compared can cause, a visual analogue scale (VAS) was used between the two treatment groups by Student’s to assess its severity. The response to the treat- t test. All safety analyses were based on the safety ment was assessed with a three-point scale (not, population. Adverse events as recorded by the a little, and much improved) by patients and investigators were coded using the World Health investigators. Organization Adverse Reaction Terminology cod- Visits were scheduled at weeks 4, 8 and 12. ing system.16 Comparisons of incidence rates be- Patients were instructed to complete a 3-day void- tween the treatment groups were performed using ing diary 3 days before each scheduled visit. Fisher’s exact test. All statistical tests were two- PPBC and VAS for dry mouth were evaluated at sided, with a significance level of α=0.05. each visit. All observed or spontaneously reported adverse events were also recorded at each visit. PVR volume was assessed by ultrasonography at the Results visit at week 12. From the diary data, we obtained the follow- A total of 75 patients (25 men and 50 women) ing parameters: micturition numbers, urgency were randomized into two group: 39 in the so- episodes, incontinence episodes, and total vol- lifenacin group (5 mg once daily) and 36 in the ume voided per 24 hours. Mean volume voided tolterodine group (4 mg once daily). Two patients per micturition was calculated as the total voided in the tolterodine group withdrew from the study volume divided by the micturition number. The without any efficacy assessment; three patients primary efficacy endpoint was the change from in the solifenacin group and one in the toltero- baseline to endpoint for the mean number of dine group did not complete the 12-week treat- micturitions per 24 hours. Secondary efficacy ment. Another patient in the solifenacin group endpoints included: (1) change from baseline to was prescribed with prohibited medication at the endpoint for mean volume voided per micturi- beginning of the study. The above seven patients tion; (2) change from baseline to endpoint for were excluded from the efficacy analyses based mean urgency episodes per 24 hours; (3) change on the PPS. from baseline to endpoint for mean incontinence The two treatment groups were not signifi- episodes per 24 hours; (4) change from baseline cantly different in demographic data, including to endpoint for PPBC; and (5) patient and physi- age, sex, height, weight, comorbidity, concomitant cian assessment of treatment benefit. Safety was medication for comorbidity, and baseline OAB assessed by counting the incidence of adverse parameters (Table 1). The Figure shows the efficacy events, by evaluating the change from baseline to analyses at week 12. In primary efficacy analysis, endpoint for patient assessment of dry mouth compared with the baseline, both treatment groups symptoms (VAS), and measuring PVR volume. demonstrated significant improvements in reduc- Patients who took at least one dose of study ing mean micturition numbers per 24 hours from medication were included in the safety popula- week 4. At week 12, the mean changes from base- tion. Patients who took at least one dose of the line in micturition number per 24 hours were study medication and provided efficacy data at not significantly different between the solifenacin baseline and endpoint visit were included in the and tolterodine groups (–2.56 ± 3.31 vs. −2.44 ± full analysis set. Patients in this set who com- 4.56, p = 0.58). In secondary efficacy analyses, both pleted the study without major deviations from groups had significant improvements in reducing the protocol were included in the per protocol set urgency and incontinence episodes per 24 hours.

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Table 1. Demographics and overactive bladder parameters of the 75 patients

Variables Solifenacin (n = 39) Tolterodine (n = 36) p

Sex, female 26 (66.7) 24 (66.7) ns Age (yr) 58.9 ± 15.1 55.3 ± 15.7 ns Height (cm) 160.6 ± 7.1 158.8 ± 7. 3 n s Weight (kg) 63.4 ± 9.5 60.5 ± 11.0 ns Baseline OAB parameters Symptom duration (yr) 4.2 ± 6.2 4.4 ± 4.9 ns Micturitions/24 hr 13.80 ± 4.95 13.69 ± 4.43 ns Voided volume/micturition (mL) 145.10 ± 61.02 135.70 ± 47.43 ns Urgency episodes/24 hr 4.57 ± 5.83 3.68 ± 4.45 ns Incontinence episodes/24 hr 3.21 ± 3.05 6.19 ± 5.83 ns Perceived bladder condition 3.9 ± 1.1 3.9 ± 1.2 ns Prior drug therapy 18 (46.2) 20 (55.5) ns Prior non-drug therapy 1 (2.6) 3 (8.3) ns Patients had comorbidities 28 (71.8) 31 (81.6) ns Patients received drugs for comorbidities 30 (76.9) 23 (63.9) ns

*Data presented as mean ± standard deviation or n (%). OAB = overactive bladder; ns = not significant.

ABMicturitions Urgency Incontinence 0.00 30 27.61 −0.50 Solifenacin −1.00 25 Tolterodine − −1.15 1.50 20 −2.00 −1.70 − 2.50 − 15 − −2.56 2.44 10.6 3.00 −2.79 −3.50 10 − 4.00 Solifenacin 5 −4.50 Tolterodine −5.00 −4.67 0

C 0

–1 Figure. (A) Mean reductions in micturitions, urgency episodes, and incontinence episodes per 24 hours after treatment for 12 weeks. (B) Mean changes in voided volume per micturition –1.4 –1.4 after treatment for 12 weeks. (C) Mean changes in Patient Solifenacin Perception of Bladder Condition scale after treatment for –2 Tolterodine 12 weeks.

At week 12, the mean changes from baseline (−2.79 ± 2.82 vs. −4.67 ± 9.29, p = 0.28). Compared were not significant for urgency episodes be- with the baseline, a significant increase in mean tween the solifenacin and tolterodine groups voided volume per micturition was only observed (−1.70 ± 3.07 vs. −1.15 ± 2.68, p = 0.37), nor were in the solifenacin group (27.61 ± 51.74mL), but the mean changes for incontinence episodes sig- not in the tolterodine group (10.60 ± 50.29 mL). nificant for the solifenacin and tolterodine groups The quality of life following treatment, as evaluated

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with PPBC, was significantly improved in both with the most common being dry mouth (18.0% groups. At week 12, the mean changes from base- vs. 8.3%, p = 0.31) and constipation (12.8% vs. line in PPBC were −1.40 ± 1.40 and −1.40 ± 1.60 2.8%, p = 0.20). Between the two groups, the in- in the solifenacin and tolterodine groups, respec- cidence of each adverse effect was not significantly tively, and did not differ significantly between different (Table 3). One patient in the solifenacin the two groups (p = 0.72). Patient and physician group withdrew from the study because of dizzi- assessment of treatment benefit showed that im- ness, and another in the tolterodine group with- provements were achieved in the majority of drew because of palpitations. The mean change patients in both groups, whereas the treatment in dry mouth symptoms, as assessed by VAS, was benefits were not significantly different between no different between the solifenacin and toltero- the two groups (Table 2). dine groups (0.36 ± 2.71 vs. –0.01 ± 2.29, p = 0.56). Table 3 shows the safety analyses: 15 (38.5%) The change in PVR volume was small in the so- and nine (25.0%) patients in the solifenacin and lifenacin and tolterodine groups (0.60 ± 44.6 vs. tolterodine group, respectively, suffered from at 3.51 ± 2.26 mL, p = 0.18) and was not clinically least one adverse effect, and the percentages did significant in either group. not differ between the two groups (p = 0.23). The reported adverse effects included dry mouth, constipation, hiccups, palpitations, and dizziness, Discussion

The present study was a prospective, randomized, Table 2. Patient and physician assessment of parallel study that compared the efficacy and treatment benefit safety of 5 mg solifenacin once daily and 4 mg Solifenacin Tolterodine tolterodine once daily. Although similar compar- By patients (%) isons between the two antimuscarinics have been Not improved 5.7 15.2 made in western populations,13,14 this is believed Little improved 77.1 57.6 to be the first that was based on a Taiwanese Much improved 17.1 27.3 population. The major findings included: (1) By physicians (%) both medications were significantly effective in Not improved 5.7 12.1 reducing OAB symptoms (micturition frequency, Little improved 62.9 66.7 urgency episodes, and incontinence episodes); Much improved 31.4 21.2 (2) the efficacy appeared not to differ between

Table 3. Safety analyses of solifenacin and tolterodine

Variables Solifenacin (n = 39) Tolterodine (n = 36) p

Patients with AEs† 15 (38.5) 9 (25.0) 0.23 Patients who discontinued 1 (2.6) 1 (2.8) 1.00 Dry mouth 7 (18.0) 3 (8.3) 0.31 Constipation 5 (12.8) 1 (2.8) 0.20 Hiccup 1 (2.6) 0 (0) 1.00 Palpitation 1 (2.6) 1 (2.8) 1.00 Dizziness 1 (2.6) 0 (0) 1.00 Fatique 1 (2.6) 0 (0) 1.00 Changes in VAS of dry mouth 0.36 ± 2.71 –0.01 ± 2.29 0.56 Changes in PVR volume (mL) 0.60 ± 44.60 3.51 ± 2.26 0.18

*Data presented as mean ± standard deviation or n (%); †the severity grading was based on WHO-ART, all the AEs were mild or moderate in nature; no severe AEs developed in both groups. AE = adverse event; VAS = visual analog scale; PVR = post-void residual.

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the two groups; (3) the most common adverse demonstrated similar efficacy in reducing mic- effects were dry mouth and constipation; and (4) turition frequency. However, solifenacin showed all the adverse effects were mild to moderate in greater efficacy in decreasing urgency episodes, nature, and discontinuation because of adverse incontinence, urge incontinence, and pad usage. effects was rare. More patients in the solifenacin group became Normal bladder contraction is mediated continent and reported improvements. In both through stimulation of muscarinic receptors (sub- groups, the majority of adverse effects were mild types M1–M5) in the detrusor muscle.17 Although to moderate in nature, and the discontinuation M2 receptors predominate in number, normal rates were comparable and low. These findings bladder contraction is mainly mediated by M3 suggest that solifenacin and tolterodine are effec- receptors.9 As the mainstay of treatment for OAB, tive in treating OAB symptoms. Furthermore, with antimuscarinics are thought to act on muscarinic a flexible dosing regimen, solifenacin could be receptors and therefore inhibit bladder contrac- superior to tolterodine with regard to the major- tion.8 In addition, muscarinic receptors have also ity of the efficacy variables. been found in urothelial and suburothelial cells.18 The major adverse effects of antimuscarinic Although their roles have not been entirely es- agents include dry mouth, constipation, and tablished, they might have a role in afferent sig- blurred vision.21,22 It is these adverse effects that naling.19 Increasing evidence suggests that the limit the clinical use of antimuscarinics. The num- therapeutic action of antimuscarinics is associ- ber of adverse effects reported in our trial was gen- ated with bladder sensation, rather than bladder erally in line with previous studies.13,14 In the contractility.20 The exact mechanism still requires present study, the incidence of adverse effects was further investigation. not significantly different between the two groups. Comparisons of solifenacin and tolterodine All the adverse effects were mild to moderate in have been conducted in western populations.13,14 nature, and only one patient in each group dis- Chapple et al14 conducted a multicenter random- continued their treatment because of intolerability. ized trial of 1281 OAB patients, of whom 1077 These findings suggest that both solifenacin and were treated. After placebo run-in, patients were tolterodine are well tolerated. Clinically, another randomized into four treatment groups with factor that limits the use of antimuscarinic agents tolterodine (2 mg twice daily), solifenacin (5 mg is the consideration that detrusor contraction daily), solifenacin (10 mg daily), or placebo for might be inhibited and urinary retention could a 12-week treatment period. Compared with develop. In our series, none experienced urinary placebo, all the three treatment groups demon- retention after taking either tolterodine or solife- strated a significant decrease in the mean num- nacin, suggesting that both drugs can be safely ber of micturitions per 24 hours and a significant used in patients without evidence of bladder out- increase in the mean voided volume per micturi- let obstruction and with a limited residual vol- tion. However, a significant decrease in the mean ume (< 200 mL). In fact, there is little evidence to number of urgency and incontinence episodes show that antimuscarinics significantly reduce was only observed in the solifenacin groups, and detrusor contraction during the voiding phase.8 not in the tolterodine group. The subsequent This is because antimuscarinics mainly act dur- Solifenacin and Tolterodine as an Active com- ing the storage phase, when there is normally no parator in a Randomized (STAR) trial, tested the parasympathetic activity.20 Furthermore, most an- efficacy of a flexible dose of solifenacin.13 Patients timuscarinics are competitive drugs. During the could increase their dose of solifenacin from 5 mg voiding phase, when there is a massive release of to 10mg after 4 weeks of treatment. Patients in the acetylcholine, the effects of these drugs are de- tolterodine group (4 mg) were escalated to 4 mg creased. Although a high dose of antimuscarinic tolterodine plus 4 mg placebo. Both medications drugs inevitably causes urine retention, clinically,

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there is little evidence that these drugs cause urine 7. Wagner TH, Hu TW, Bentkover J, et al. Health-related retention at their commercial doses.8 consequences of overactive bladder. Am J Manag Care 2002;8:S598–607. The major limitation of the present study, in 8. Andersson KE. Antimuscarinics for treatment of overac- comparison with previous studies in western coun- tive bladder. Lancet Neurol 2004;3:46–53. tries,13,14 was the relatively small patient number. 9. Hegde SS, Eglen RM. Muscarinic receptor subtypes mod- This could have decreased the power for detecting ulating smooth muscle contractility in the urinary bladder. a difference between the two medications. How- Life Sci 1999;64:419–28. 10. Stahl MM, Ekstrom B, Sparf B, et al. Urodynamic and ever, the present study is still valuable in providing other effects of tolterodine: a novel antimuscarinic drug experience in the use of both drugs in a Taiwanese for the treatment of detrusor overactivity. Neurourol Urodyn population, which has been rarely reported before. 1995;14:647–55. Another limitation was that only a few patients re- 11. Appell RA. Clinical efficacy and safety of tolterodine in the corded their voids at bedtime. Therefore, the effects treatment of overactive bladder: a pooled analysis. Urology 1997;50:90–9. on reducing nocturia could not be analyzed. 12. Cardozo L, Lisec M, Millard R, et al. Randomized, double- In conclusion, solifenacin and tolterodine dem- blind placebo controlled trial of the once daily antimuscarinic onstrated significant efficacy in treating key OAB agent solifenacin succinate in patients with overactive symptoms, including urinary frequency, urgency, bladder. J Urol 2004;172:1919–24. 13. Chapple CR, Martinez-Garcia R, Selvaggi L, et al. A com- and incontinence. The efficacy was equal between parison of the efficacy and tolerability of solifenacin succi- the two drugs. The most common adverse effects nate and extended release tolterodine at treating overactive were dry mouth and constipation, and all the ad- bladder syndrome: results of the STAR trial. Eur Urol verse effects were mild to moderate in severity. 2005;48:464–70. Discontinuation rates because of adverse effects 14. Chapple CR, Rechberger T, Al-Shukri S, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of were low. These findings suggest that both solife- the once-daily antimuscarinic agent solifenacin in patients nacin and tolterodine can be effective and safe in with symptomatic overactive bladder. BJU Int 2004;93: treating OAB in Taiwanese populations. 303–10. 15. Coyne KS, Matza LS, Kopp Z, et al. The validation of the patient perception of bladder condition (PPBC): a single- References item global measure for patients with overactive bladder. Eur Urol 2006;49:1079–86. 16. World Health Organization. International monitoring of 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of adverse reactions to drugs: adverse reaction terminology. terminology in lower urinary tract function: report from Uppsala: WHO Collaborating Centre for International Drug the standardisation sub-committee of the International Monitoring, 1992. Continence Society. Urology 2003;61:37–49. 17. Abrams P, Andersson KE. Muscarinic receptor antagonists 2. Chen GD, Lin TL, Hu SW, et al. Prevalence and correlation for overactive bladder. BJU Int 2007;100:987–1006. of urinary incontinence and overactive bladder in Taiwanese 18. Chess-Williams R. Muscarinic receptors of the urinary women. Neurourol Urodyn 2003;22:109–17. bladder: detrusor, urothelial and prejunctional. Auton 3. Irwin DE, Milsom I, Hunskaar S, et al. Population-based Autacoid Pharmacol 2002;22:133–45. survey of urinary incontinence, overactive bladder, and 19. Andersson KE. Bladder activation: afferent mechanisms. other lower urinary tract symptoms in five countries: Urology 2002;59:43–50. results of the EPIC study. Eur Urol 2006;50:1306–15. 20. Finney SM, Andersson KE, Gillespie JI, et al Antimus- 4. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence carinic drugs in detrusor overactivity and the overactive and burden of overactive bladder in the United States. bladder syndrome: motor or sensory actions? BJU Int World J Urol 2003;20:327–36. 2006;98:503–7. 5. Abrams P, Kelleher CJ, Kerr LA, et al. Overactive bladder 21. Chapple C, Khullar V, Gabriel Z, et al. The effects of anti- significantly affects quality of life. Am J Manag Care 2000; muscarinic treatments in overactive bladder: a systematic 6:S580–90. review and meta-analysis. Eur Urol 2005;48:5–26. 6. Brown JS, McGhan WF, Chokroverty S. Comorbidities as- 22. Staskin DR, MacDiarmid SA. Using anticholinergics to treat sociated with overactive bladder. Am J Manag Care 2000; overactive bladder: the issue of treatment tolerability. Am J 6:S574–9. Med 2006;119:9–15.

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