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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 29  |  Issue : 5  |  Page : 223-228

Comparative persistence, switch rates, and predictors for discontinuation of antimuscarinics for overactive bladder: A 10-year nationwide population-based study in Taiwan


1 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
3 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Center of Teaching and Research, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
5 Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan

Date of Web Publication3-Sep-2018

Correspondence Address:
Yung-Shun Juan
Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, No. 100, Tz-You 1st Road, Kaohsiung 807, Kaohsiung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_2_18

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  Abstract 


Objectives: Although antimuscarinic drugs are considered the gold standard for overactive bladder (OAB), high discontinuation rates have been observed. However, no information is known about this in Taiwan. We investigated the persistence and switch rates among different antimuscarinics prescribed for OAB and evaluated whether different comorbidities impacted the persistence with prescribed antimuscarinics in Taiwan. Materials and Methods: We obtained retrospective claims from a Taiwanese health insurance database for patients with OAB; any first claim for the target drugs (tolterodine extended release [ER], tolterodine immediate release [IR], oxybutynin ER, oxybutynin IR, solifenacin, propiverine, and flavoxate) between January 2004 and December 2013 was included. The prescription claims were tracked for 1 year to calculate the time of persistence and switch rates. Comorbidities, including hypertension, diabetes mellitus, and hyperlipidemia, were recorded. Significant factors for discontinuation were investigated by using a Cox proportional hazards model. Results: A total of 24,381 patients with OAB were prescribed the target antimuscarinics. The most prescribed drug during the 10-year period was flavoxate (8339 patients). Of the 3481 patients with chronic OAB, the drug with the longest mean persistence was solifenacin (125 days). At 12 months, the persistence rate varied from 7.6% for oxybutynin ER to 4.3% for propiverine. The switch rates varied from 40.3% for propiverine to 25.7% for solifenacin. The Cox proportional hazards model showed that hyperlipidemia was the only comorbidity significantly associated with discontinuation (hazards ratio: 1.12, 95% confidence interval: 1.03–1.21, P = 0.006). Conclusions: In this large nationwide Taiwanese study, 12-month persistence was generally low for all antimuscarinics. Solifenacin was associated with the longest mean persistence and the lowest switch rates, oxybutynin ER had the highest 12-month persistence rate, and hyperlipidemia was significantly associated with lower persistence.

Keywords: Antimuscarinics, compliance, overactive bladder, Taiwan


How to cite this article:
Chen HW, Chen YC, Wu WJ, Li CC, Chang YH, Geng JH, Shen JT, Jang MY, Yang KF, Juan YS. Comparative persistence, switch rates, and predictors for discontinuation of antimuscarinics for overactive bladder: A 10-year nationwide population-based study in Taiwan. Urol Sci 2018;29:223-8

How to cite this URL:
Chen HW, Chen YC, Wu WJ, Li CC, Chang YH, Geng JH, Shen JT, Jang MY, Yang KF, Juan YS. Comparative persistence, switch rates, and predictors for discontinuation of antimuscarinics for overactive bladder: A 10-year nationwide population-based study in Taiwan. Urol Sci [serial online] 2018 [cited 2018 Nov 15];29:223-8. Available from: http://www.e-urol-sci.com/text.asp?2018/29/5/223/240363




  Introduction Top


Overactive bladder (OAB) is a long-term condition, with a prevalence of up to 20.8% in the Taiwanese population.[1] The troublesome symptoms of OAB, characterized as urinary urgency, increased daytime frequency, and nocturia, with or without urgency incontinence, were shown to have a greater effect on the quality of life.[2] Treatment includesfirst-line lifestyle intervention, such as education, bladder training, and pelvic floor muscle training; drug treatments are considered after conservative approaches have been undertaken. Antimuscarinic drugs have been the gold standard and most widely used oral pharmacotherapy for OAB for many years. However, owing to the lack of selectivity for the bladder and the effects on other organ systems, the intolerable adverse events of antimuscarinics, such as dry mouth, constipation, cognitive effects, and visual impairment, limit their usefulness, which generally leads to low persistence.[3] In reality, high discontinuation rates have been observed for antimuscarinics not only in the UK and the United States, but also in Asia.[3],[4],[5],[6],[7] In open-label observational studies conducted in Korea, the discontinuation rates of antimuscarinics at 12 months were between 21% and 78%.[5],[6],[7] Approaches to overcome the low persistence rates of antimuscarinics used for the treatment of OAB include the development of extended-release (ER) formulations; the introduction, in 2004, of agents with greater M3 selectivity, such as solifenacin; and the exploration of the underlying factors that influence patient persistence. Building on these results, the present study provides thefirst large-scale, 10-year nationwide survey in Taiwan. The aims of our study were to investigate the persistence and switch rates among different antimuscarinics prescribed for OAB and to evaluate whether different comorbidities affected the persistence with the prescribed antimuscarinics.


  Materials and Methods Top


Study design

This was a retrospective, longitudinal, observational, cohort study of patients who were prescribed the target antimuscarinics for OAB treatment in clinical practice in Taiwan. The primary objective was to investigate the persistence and switch rates of treatment in the different target antimuscarinic drugs in immediate-release (IR) and ER formulations. The secondary objectives were to evaluate whether the different comorbidities impacted the persistence with the prescribed antimuscarinics.

Data source and study population

Adults (≥18 years old) who were prescribed one of the target drugs (tolterodine ER, tolterodine IR, oxybutynin ER, oxybutynin IR, solifenacin, propiverine, and flavoxate) between January 2004 and December 2013 (the selection period) were considered eligible for the study. Data were collected up to December 2014, to allow each patient a potential treatment period of at least 12 months. Only patients with a new prescription were included; prescriptions for combination therapy with two target drugs were excluded. Patients with chronic OAB were defined as those taking the target drugs for at least 3 months, including those who switched to the other target drugs. The clinical characteristics and the comorbidities, including hypertension, diabetes mellitus, and hyperlipidemia, were recorded for all patients.

Study outcomes

The persistence with treatment was assessed by using two endpoints: mean time to discontinuation and the persistence rate, followed for up to 12 months. The time to discontinuation was defined as the number of days between the index date and thefirst discontinuation date. Each patient was tracked until continuous treatment was ceased, with a break in therapy defined as an interval >1.5 times the expected number of days of therapy of the previous prescription, from the start of the prescription. The switch rate was calculated as the proportion of patients who changed from the initial antimuscarinic to any of the other target drugs, including within-drug changes to a different dose form (IR to ER or ER to IR).

Statistical analysis

Cox proportional hazards regression was applied to investigate the effects of potential factors on persistence duration. The independent variables included age, gender, and comorbidities, such as diabetes mellitus, hypertension, and hyperlipidemia. The analyses were computed by using IBM SPSS Statistics version 22.0 (IBM® Corporation, NY, USA), and P ≤ 0.05 was considered statistically significant.


  Results Top


Between January 2004 and December 2013, a total of 61,380 patients were diagnosed with OAB and 24,381 patients were prescribed with the target antimuscarinic agents. The percentage of patients with OAB who were prescribed antimuscarinics each year was between 33.6% and 44.9%, with an average treatment rate of 39.7% during the selection period [Table 1]. The most commonly prescribed drugs during the 10-year period were flavoxate (8339 patients), oxybutynin ER (4342 patients), and oxybutynin IR (3396 patients) [Table 2]. More women (15,553 patients) received antimuscarinic agents than men (8825 patients). The mean age of patients who were prescribed antimuscarinics was 54.1 years. Nearly 44.6% of the patients who were prescribed the target antimuscarinic also had hypertension, 40.3% had hyperlipidemia, and 25.9% had diabetes mellitus.
Table 1: Number of patients with overactive bladder diagnosis and antimuscarinic prescription between 2004 and 2013

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Table 2: Demographic data of all patients who were prescribed target antimuscarinics between January 2004 and December 2013

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[Figure 1] reveals the persistence days (defined as the mean number of days for which a patient remained on a particular therapy) that chronic OAB patients remained on therapy with each antimuscarinic. Among the patients with chronic OAB (3421 patients), the longest persistence was associated with solifenacin 5 mg (124.9 days); flavoxate had the shortest persistence day (99.7 days), compared with other antimuscarinics.
Figure 1: Mean time that patients remained on therapy with each antimuscarinic. Numbers are patients with chronic overactive bladder starting antimuscarinic treatment

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[Figure 2] reveals the percentage of patients remaining on each antimuscarinic over 12 months. At 3 months, 73.8% of patients who commenced solifenacin (5 mg) remained on the treatment, compared with tolterodine IR (71.6%), oxybutynin IR (64.3%), tolterodine ER (60.5%), propiverine (58.1%), oxybutynin ER (56.9%), and flavoxate (54.2%). After 6 months, 26.4% of patients who commenced oxybutynin IR remained on the treatment compared with those receiving solifenacin (25.7%), propiverine (25.6%), tolterodine IR (25.1%), tolterodine ER (22.1%), flavoxate (21.2%), and oxybutynin ER (20.2%). After 12 months, 7.6% of patients were still receiving oxybutynin ER, compared with those receiving solifenacin (7.3%), tolterodine ER (6.7%), oxybutynin IR (6.5%), flavoxate (6.2%), tolterodine IR (4.6%), and propiverine (4.3%).
Figure 2: Percentage of patients remaining on each antimuscarinic over 12 months

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Solifenacin was associated with the lowest switch rate and the longest mean duration from the initial drug to switch to the other target drugs (25.7%, 148 days), followed by oxybutynin ER (28.3%, 123 days), tolterodine ER (28.4%, 132 days), oxybutynin IR (31.2%, 115 days), tolterodine IR (32%, 118 days), flavoxate (32.4%, 106 days), and propiverine (40.3%, 103 days) [Table 3].
Table 3: Number of cases, percentage, and mean time at which patients switched to the other antimuscarinic

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The Cox proportional hazards model showed that hyperlipidemia was the only comorbidity significantly associated with the discontinuation of antimuscarinics (hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 1.03–1.21; P = 0.006) [Table 4]. There was no significant association among discontinuation rates, age, and gender.
Table 4: Factors of discontinuation analyzed by Cox proportional hazards model

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  Discussion Top


The present study is, to date, the most extensive investigation conducted in Taiwan to explore the persistence patterns and switch rates of patients with OAB using different antimuscarinics, including ER and IR dose forms, and to determine whether different comorbidities impacted the persistence with the prescribed antimuscarinics.

Consistent with previous reports, the persistence for all prescribed antimuscarinic agents was generally low over the evaluation period. In our study, the overall number of patients who were prescribed target antimuscarinics was 24,381, but the number of patients with chronic OAB who took antimuscarinics for at least 3 months was 3421, which indicates that up to 86% of patients discontinued antimuscarinics within 3 months. Among the patients with chronic OAB, our results demonstrated the persistence with all antimuscarinics dropped markedly within thefirst 6 months and was further reduced at 1 year. The persistence with all target antimuscarinics in our study at 1 year (4.3%–7.6%) was lower than the range reported in the literature (8%–29%),[3],[8],[9],[10],[11] even though the patients who stopped antimuscarinics within 3 months were excluded. This finding demonstrated the suboptimal persistence with antimuscarinics for patients with OAB in real-life settings in Taiwan.

In this study, although more patients were prescribed flavoxate overall, solifenacin had the longest mean persistence, the lowest switch rates, and was associated with the highest rate of persistence at 3 months. These results were consistent with recent retrospective studies conducted in the UK and the Netherlands through the analysis of the prescription data of antimuscarinic agents (solifenacin, darifenacin, tolterodine ER/IR, propiverine, oxybutynin ER/IR, and flavoxate in the UK and solifenacin, flavoxate, oxybutynin IR, and tolterodine IR in the Netherlands) over 12-month and 9-month periods, respectively. Both studies showed that solifenacin resulted in higher levels of persistence than other antimuscarinic agents, although the persistence was generally low for all the antimuscarinics during the evaluation period.[3],[11]

To overcome the low persistence rates, ER formulations were recently suggested to be prescribed owing to the lower rates of dry mouth and convenience of once-daily administration.[12],[13] ER formulations were reported to offer advantages in terms of efficacy and safety compared with IR formulations and were associated with higher adherence than the IR formulations.[14],[15],[16],[17] Our study also demonstrated that the 12-month persistence of ER formulations was high than that of the IR formulations for both tolterodine and oxybutynin. In our study, oxybutynin ER was associated with the highest persistence at 12 months.

The significant predictive factors for higher persistence included White ethnicity, previous hospitalization length, starting with oxybutynin ER, and previous use of topical drugs or antipsychotics; whereas polypharmacy, a previous history of depression, and urinary tract infection were associated with reduced adherence.[8],[18],[19] The investigation of whether the comorbidities affected the persistence with antimuscarinics was evaluated in two previous studies.[8],[19] One failed to show a significant association, but the other showed a negative influence on persistence. However, they both used the Charlson Comorbidity Index as the severity of comorbidities instead of investigating the comorbidities themselves, which may have led to the confounded factors. In the present study, we investigated the three-most common chronic comorbidities in Taiwan and found that hyperlipidemia was a risk factor for discontinuation, which has not previously been reported. The reasons for treatment discontinuation in patients with hyperlipidemia were possibly unknown multidrug interactions, a lack of efficacy, poor tolerability, or inconvenient dosing. Although the reasons were not recorded in the present study, our findings suggested that the short-period prescription of antimuscarinics should be considered for patients with OAB and hyperlipidemia.

Previous studies have found crosscurrents between age and persistence.[3],[9],[18],[20] Two contrasting explanations for the influence of persistence were reported. Older patients who have a more severe experience of OAB may derive more relief from medication, whereas older patients who require more medication to control OAB symptoms and other comorbid conditions have hampered persistence owing to intolerable side effects. In our study, the Cox proportional hazards regression showed no association between age and persistence.

This study reflects the 10-year experience of antimuscarinics for the therapy of OAB in Taiwan. The study limitations include the retrospective design, the use of prescription records to estimate outcomes, and the inability to capture the reasons for discontinuation. Further studies are necessary to better understand the reasons underlying the low persistence with antimuscarinics and the explanation of why patients with hyperlipidemia in our study were more likely to discontinue treatment, including a lack of efficacy, poor tolerability, inconvenient dosing, or unknown multidrug interactions.


  Conclusions Top


In this large nationwide Taiwanese study, 12-month persistence was generally low for all antimuscarinics. Solifenacin was associated with the longest mean persistence and the lowest switch rates compared with other antimuscarinics. Oxybutynin ER had a higher 12-month persistence rate. Hyperlipidemia was significantly associated with lower persistence with antimuscarinics. Our findings have suggested important considerations for clinicians that prescribe antimuscarinics for patients with OAB in Taiwan, as well as for payers considering the economic implications of available treatments for OAB.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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