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Adherence and persistence to oral medication in patients with overactive bladder (OAB) in a real-world setting – a systematic literature review

ForJournal: peerBMJ Open review only Manuscript ID bmjopen2018021889

Article Type: Research

Date Submitted by the Author: 25Jan2018

Complete List of Authors: Yeowell, Gillian; Manchester Metropolitan University, Health Professions Department (Physiotherapy) Smith, Philip; Manchester Metropolitan University Nazir, Jameel; Astellas Pharma Europe Ltd Hakimi, Zalmai; Astellas Pharma BV Siddiqui, Emad; Astellas Pharma Europe Ltd Fatoye, Francis; Manchester Metropolitan University

Overactive bladder, persistence, adherence, antimuscarinics, β3 adrenergic Keywords: receptor agonists, systematic literature review

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Adherence and persistence to OAB medication 1 2 3 Adherence and persistence to oral medication in patients with 4 5 6 overactive bladder (OAB) in a real-world setting – a systematic 7 8 literature review 9 10 11 12 13 1 1 2 3 2 14 Gillian Yeowell , Philip Smith , Jameel Nazir , Zalmai Hakimi , Emad Siddiqui , Francis 15 1 16 Fatoye For peer review only 17 18 19 20 21 1Manchester Metropolitan University, Manchester, UK 22

23 2 24 Astellas Pharma Europe Ltd., Chertsey, UK 25 26 3Astellas Pharma Europe B.V., Leiden, the Netherlands 27 28

29 30 31 Correspondence: 32

33 Gillian Yeowell http://bmjopen.bmj.com/ 34 Health Professions Department (Physiotherapy) 35 36 Birley Building 37 Birley Fields Campus 38 39 53 Bonsall Street 40 Manchester M15 6GX

41 on September 29, 2021 by guest. Protected copyright. 42 Email: [email protected] 43 Tel: 0161 247 2967 44 45 46 47 48 Running head: Adherence and persistence to OAB medication 49 50 51 52 53 Key Words: Overactive bladder, persistence, adherence, antimuscarinics, β3adrenergic 54 55 receptor agonists, systematic literature review 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 ABSTRACT 4 5 Purpose To evaluate persistence and adherence of oral pharmacotherapy used in the 6 7 treatment of overactive bladder (OAB) in a realworld setting. 8 9 10 Materials and Methods Systematic literature searches of six electronic publication 11 12 databases were performed to identify database studies of OAB patients treated with 13 14 antimuscarinics and/or mirabegron. Studies reporting persistence and adherence data solely 15 16 from patient interviewsFor or subjectivepeer questionnaires review were excluded. only Reference lists of 17 18 identified studies and relevant systematic reviews were assessed to identify additional 19 20 relevant studies. 21 22 23 Results The search identified 3897 studies, of which 30 were selected for extraction. 24 25 Overall, persistence ranged from 5–47%. In studies reporting data for antimuscarinics and 26 27 mirabegron (n=3), persistence at 1 year was 12–25% and 32–38%, respectively. Median 28 29 time to discontinuation was ˂5 months for antimuscarinics (except one study [6.5 months]) 30 31 and 5.6–7.4 months for mirabegron. The proportion of patients adherent at 1 year varied 32

33 between 15–44%. In studies reporting adherence for antimuscarinics and mirabegron, http://bmjopen.bmj.com/ 34 35 adherence was higher with mirabegron (mean medication possession ratio (MPR): 0.59 vs 36 37 0.41–0.53; mean proportion of days covered: 0.66 vs 0.55; and median MPR: 0.65 vs 0.19– 38 39 0.49). Reported determinants of persistence and adherence included female gender, older 40

41 age group, using an extendedrelease formulation and treatment experience. on September 29, 2021 by guest. Protected copyright. 42 43 44 Conclusion Most patients with OAB discontinued oral OAB pharmacotherapy and were 45 46 nonadherent 1 year after treatment initiation. However, mirabegron was associated with 47 48 greater persistence and adherence compared to antimuscarinics, supporting mirabegron as 49 50 a firstline pharmacological treatment option for patients with OAB. 51 52 53 54 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 STRENGTHS AND LIMITATIONS 4 5 • This systematic literature review includes data for mirabegron, which was approved in 6 7 2013 and not covered in previous systematic reviews examining persistence and 8 9 adherence to overactive bladder medication. 10 11 12 • Only observational database studies were included in this study, providing a more 13 14 accurate picture of rates of adherence and persistence to overactive bladder medication, 15 16 which are generallyFor lower peer in routine clinicalreview practice compared only to randomized clinical 17 18 trials. 19 20 21 • This systematic literature review provides a global picture of adherence and persistence 22 23 to OAB medication based on the inclusion of data from Canada, Czech Republic, 24 25 Denmark, Germany, Norway, Spain, the United Kingdom and the United States. 26 27 28 • Although determinants of persistence and adherence were evaluated in this study, other 29 30 factors such as influence persistence with treatment in patients with overactive bladder 31 32 including patient expectations, appropriate counselling and patient satisfaction with

33 http://bmjopen.bmj.com/ 34 treatment could not be assessed. 35 36 37 • The definitions and calculations of persistence and adherence were not uniform across 38 39 the literature and the terms were often used interchangeably, limiting the ability to 40

41 compare across studies. on September 29, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 INTRODUCTION 4 5 Overactive bladder (OAB) is defined as a condition with characteristic symptoms of urinary 6 7 urgency, usually accompanied by frequency and nocturia, with or without urgency 8 9 1 incontinence, in the absence of urinary tract infection (UTI) or other obvious pathology. OAB 10 11 affects 11.8–24.7% of adults in North America and Europe, and the prevalence increases 12 13 with age.2 In addition to age, risk factors for developing OAB include diabetes, UTIs and 14 15 obesity.3 4 16 For peer review only 17 18 OAB symptoms are associated with a negative impact on healthrelated quality of life 19 20 (HRQoL) and a significant economic burden. Indeed, bothersome OAB symptoms may lead 21 22 to depression and anxiety, and sleep disturbances, which can adversely affect a patient’s 23 24 daily, social and professional functioning.5 6 Whilst the cost of pharmaceutical treatment 25 26 represents only a small fraction of the total therapy cost, the provision of containment 27 28 products (eg, pads), treatment for clinical depression, nursing home stays and loss of 29 30 productivity due to work absenteeism are the main cost drivers in OAB.7 8 For example, the 31 32 total annual cost of OAB was estimated to be $24.9 billion in the United States in 20079 and

33 http://bmjopen.bmj.com/ 34 €9.7 billion across five European countries (Germany, Italy, Spain, Sweden and the United 35 36 Kingdom) and Canada in 2005.8 37 38 39 Behavioural and lifestyle modifications are routinely the initial treatment strategy for 40

41 OAB, and pharmacotherapy is recommended only if conservative management is not on September 29, 2021 by guest. Protected copyright. 42 43 effective.10 As OAB is a chronic condition, it is important that patients continue with treatment 44 45 to control symptoms.11 Lack of adherence and persistence to medication are considered the 46 47 leading causes of preventable morbidity in patients with chronic conditions12 13 and are also 48 49 associated with greater indirect costs.13 Although antimuscarinics are the current mainstay of 50 51 oral pharmacotherapy, they are often associated with bothersome anticholinergic side 52 53 effects, such as dry mouth and constipation; tolerability is one of the most common reasons 54 55 for treatment discontinuation.11 1417 In a systematic review of antimuscarinic treatment in 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 patients with OAB, rates of discontinuation at 12 weeks ranged from 4–31% in clinical trials 4 16 5 and 43–83% in medical claims databases. 6 7 8 The other class of oral pharmacotherapy approved for the treatment of OAB is 9 10 β3adrenergic receptor agonists. Mirabegron is currently the only commercially available

11 1820 12 agent of this class licensed in countries across Europe, North America and Asia. Due to 13 14 a distinct mechanism of action, the incidence of typical anticholinergic side effects with

15 21 16 mirabegron is generallyFor similar peer to placebo, review which may translate only into better treatment 17 22 23 18 persistence. In addition, results of a recent economic analysis found that increased 19 20 persistence with mirabegron treatment vs antimuscarinics was associated with reduced

21 24 22 healthcare resource use and work hours lost, resulting in lower total costs. 23 24 In general, rates of persistence and adherence with antimuscarinics and mirabegron are 25 26 typically lower in routine clinical practice compared to interventional clinical trials.11 25 To help 27 28 identify factors affecting longterm persistence and adherence to OAB pharmacotherapy, a 29 30 contemporary, comprehensive review of realworld evidence is needed. As mirabegron was 31 32 a relatively new OAB treatment, it was not included in previous systematic reviews.

33 http://bmjopen.bmj.com/ 34 Therefore, the current analysis aims to systematically review prospective and retrospective 35 36 observational database studies conducted with antimuscarinics and/or mirabegron to 37 38 determine the rates and determinants of persistence and adherence. 39 40

41 METHODS on September 29, 2021 by guest. Protected copyright. 42 43 44 This systematic literature review (SLR) was conducted in accordance with guidelines for the 45 46 Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA).26 The 47 48 protocol for the review was registered a priori with the International Prospective Register of 49 50 Systematic Reviews (registered January 18, 2017 with PROSPERO CRD42017059894). 51 52 53 Searches were performed April 27, 2017 via the following electronic databases: Allied 54 55 and Complementary Medicine Database (AMED); Cumulative Index to Nursing and Allied 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Health Literature (CINAHL); MEDLINE; Database of Abstracts of Reviews of Effects (DARE); 4 5 Health Technology Assessment (HTA) database; and the Centre for Reviews and 6 7 Dissemination (CRD) database. The search terms were persisten* OR adheren* OR 8 9 complian* OR discont* OR tolera* OR utili* OR database [Title], AND "bladder" OR 10 11 "overactive bladder" OR "OAB" OR urin* OR incontinen* [Title], OR oxybutynin OR 12 13 tolterodine OR fesoterodine OR trospium OR darifenacin OR solifenacin OR propiverine OR 14 15 imidafenacin OR mirabegron OR flavoxate OR hyoscyamin* OR anticholinerg* OR 16 For peer review only 17 antimuscarin* [Title]. 18 19 20 All search results were exported into EndNote Web (Thomas Reuter, CA, USA) 21 22 bibliography software and duplicates removed electronically and manually. The full electronic 23 24 search strategy is outlined in the Supplemental information. 25 26 Inclusion and exclusion criteria 27 28 29 Inclusion criteria were: prospective and retrospective observational database studies 30 31 investigating persistence and adherence to oral medication for the treatment of OAB in 32 adults, which were published on any date, in a peerreviewed source. Exclusion criteria 33 http://bmjopen.bmj.com/ 34 35 were: abstract unavailable; studies not yet fully completed; randomised controlled trials 36 37 (RCTs); systematic reviews; narrative literature reviews; conference papers; single case 38 39 studies/reports; studies investigating OAB medication among only healthy, asymptomatic 40 participants; studies from which oralonly OAB persistence/adherence results cannot be

41 on September 29, 2021 by guest. Protected copyright. 42 43 isolated from other results (ie, transdermal patches); and studies containing patients aged 44 45 <18 years (where the data pertaining to these patients could not be removed from the 46 results). Populations with lower urinary tract symptoms due to stress incontinence and 47 48 benign prostatic hyperplasia were also excluded. 49 50 51 Study selection 52 53 54 Duplicates were removed and title and abstract screening was performed by two 55 56 independent researchers (PS and GY). Fulltext articles were obtained and studies were 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 26 3 excluded if they did not meet the inclusion criteria. Any disagreement in study selection 4 5 was resolved through discussion and consultation with another member of the project team 6 7 (FF) where necessary. During screening, openlabel extension studies of RCTs were 8 9 excluded as the trial designs were unlikely to reflect a realworld setting. Studies using data 10 11 from hospital records, in addition to largescale databases, were included provided that 12 13 persistence and adherence data were directly recorded rather than extracted from 14 15 supplemental patient interviews or subjective questionnaires. The literature search was 16 For peer review only 17 supplemented by screening for potential additional relevant studies identified from the 18 19 reference lists of eligible articles. 20 21 22 Data extraction 23 24 Parameters that may affect persistence or adherence were collected, including patient 25 26 characteristics (age and sex); interventions (initial [index] OAB drug and formulation) and 27 28 comorbidities. The definitions, outcomes and determinants of treatment persistence and 29 30 adherence were also collected, where reported. The extracted data were evaluated by one 31 32 researcher and verified by a second researcher.

33 http://bmjopen.bmj.com/ 34 35 RESULTS 36 37 38 Brief overview of studies 39 40 Overall, 3897 articles were identified from the literature search; 3,614 were screened for

41 on September 29, 2021 by guest. Protected copyright. 42 title/abstract and 75 assessed for eligibility (figure 1). A total of 30 articles were included in 43 44 the SLR (supplementary table 1), including three identified from reference lists.2729 45 46 47 The data were collected from patients treated in Europe (12 studies) and North America 48 49 (18 studies) (supplementary table 1) and were included in the analysis. The number of 50 51 participants included in the published studies ranged from 377 to 103 250. Where stated, the 52 53 mean age of the participants ranged from 44 to 80 years and the duration of followup 54 55 ranged from 6 months to 7 years. Interventions included bethanechol, darifenacin, 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 fesoterodine, flavoxate, hyoscyamine, imipramine, mirabegron, oxybutynin, propiverine, 4 5 solifenacin, tolterodine and trospium chloride. Definitions of adherence and persistence 6 7 differed across the studies (supplementary table 1). In general, medication possession rate 8 9 (MPR) or proportion of days covered (PDC) by prescription were typically used as a 10 11 surrogate for adherence to drug. Persistence was typically defined as the proportion of 12 13 patients continuing therapy/refilling prescriptions for the followup period (without 14 15 discontinuing the index drug or switching to other OAB drug[s]) and/or the median time to 16 For peer review only 17 discontinuation (TTD). 18 19 20 Persistence 21 22 Overall, persistence rates decreased over time, regardless of agent (supplementary table 2). 23 24 25 Antimuscarinic studies 26 27 Data for persistence (or discontinuation) at approximately 6 months was available in 14 28 29 articles2841 which reported data on antimuscarinics only. Yeaw 2009 was an exception due 30 31 to the inclusion of bethanechol (a muscarinic receptor agonist), which accounted for ˂1.5% 32 29

33 of the pharmacy claims for OAB medications. The proportion of patients persistent at http://bmjopen.bmj.com/ 34 35 6 months was <50% except for the studies of SicrasMainar et al,3638 where persistence 36 37 ranged from 57–71%. In addition, two studies reported discontinuation rates of 6–43% after 38 35 41 39 1 month of initial treatment. 40

41 on September 29, 2021 by guest. Protected copyright. 42 At 1 year, persistence rates for antimuscarinics, in 19 studies, ranged from around 5% 43 15 23 30 32 34 36 37 39 40 4249 44 up to 47%. Median TTD was ˂5 months (30 to 128 days) for all 45 15 23 28 32 42 49 50 34 46 medications across all studies, with the exception of Krhut et al (6.5 months). 47 30 32 44 50 51 48 At 2 years, over 75% of patients discontinued treatment. Rates of treatment 49 28 31 33 42 47 50 switching were infrequently reported, and where provided, were ≤17% of patients.

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Adherence and persistence to OAB medication 1 2 3 Antimuscarinic and mirabegron studies 4 5 In all four studies, a greater proportion of patients persisted with mirabegron compared with 6 7 antimuscarinics. In one study, persistence rates for tolterodine and mirabegron at 6 months 8 9 were 19% and 35%, respectively.27 Persistence at 1 year ranged from 12–25% for 10 11 antimuscarinics and from 32–38% for mirabegron, as reported in three studies15 23 49 and was 12 13 significantly greater with mirabegron vs antimuscarinics in two studies.15 23 Overall, 14 15 mirabegron, solifenacin and fesoterodine were associated with the highest rates of 16 15 23For peer review only 17 persistence. 18 19 20 Median TTD (or median persistence) in the overall study populations was longer with 21 22 mirabegron (5.6–7.4 months) compared with the assessed antimuscarinics (1.0– 23 15 23 27 49 24 3.6 months). 25 26 27 Adherence 28 29 Adherence rates to all OAB medications reduced over time in all studies and varied across 30 31 studies (supplementary table 2). 32

33 http://bmjopen.bmj.com/ 34 Antimuscarinic studies 35 36 At 1 year, the proportion of adherent patients varied between 1%41 and 36%,42 across those 37 38 studies that provided these data. Few studies reported adherence beyond 1 year. However, 39 40 Sears et al reported that 34% of patients were adherent at the end of 3 years,52 which was

41 on September 29, 2021 by guest. Protected copyright. 42 comparable to the adherence rates reported by some other studies at just 1 year.42 47 43 44 45 Antimuscarinic and mirabegron studies 46 47 In the three studies, adherence at 1 year was significantly higher in patients receiving 48 49 mirabegron compared with antimuscarinics (mean MPR: 0.59 vs 0.41 to 0.53; mean PDC: 50 51 0.66 vs 0.55; and median MPR: 0.65 vs 0.19 to 0.49).15 23 49 The proportion of patients 52 53 adherent at 1 year was also greater with mirabegron compared with antimuscarinics (mean 54 55 MPR ≥0.80: 43% vs 22–35%; mean PDC ≥0.80: 44% vs 31%).15 23 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Determinants of persistence and adherence 4 5 Determinants of persistence and adherence were reported in 24 of the 30 studies. As 6 7 expected, most studies reported medication type as a determinant of persistence/adherence 8 9 (figure 2; supplementary table 2). In general, persistence and adherence were higher in: 10 11 older patients compared with younger patients;23 27 28 3033 40 4245 47 50 53 female patients 12 13 compared with their male counterparts,28 30 33 4345 53 except in one study;52 patients receiving 14 15 extendedrelease (ER) formulations compared with immediaterelease formulations;42 50 and 16 For peer review only 17 treated patients compared to treatment naïve patients (or untreated in the preindex period 18 19 [6 months or 1 year]).15 23 30 Comorbidities, including diabetes, Parkinson’s disease, epilepsy, 20 21 dementia, multiple sclerosis and hypertension, were correlated with increased treatment 22 43 44 53 23 persistence and adherence; exceptions were chronic obstructive pulmonary disease 24 44 53 25 and migraine. 26 27 28 Other reported determinants of favorable persistence and adherence included higher 29 30 31 30 treatment doses; low daily quantity of tablets, absence of UTI; higher baseline OAB 31 33 32 costs; treatment by urologists vs gynecologists/general practitioners; the absence of side

33 http://bmjopen.bmj.com/ 44 34 effects (headache, stomach upset and glaucoma); White vs Black, Hispanic and Asian 35 41 45 45 36 patients and patients of other ethnicities; lower medication copayment; and use of

37 41 38 fewer medications. 39 40 DISCUSSION 41 on September 29, 2021 by guest. Protected copyright. 42 43 This systematic review provides an overview of persistence and adherence with oral 44 45 pharmacotherapies used to treat patients with OAB in reallife clinical practice. A wealth of 46 47 data were collected from 30 observational studies performed in Europe and North America 48 49 totaling over 500 000 patients. A number of key findings were identified, including greater 50 51 persistence and adherence with mirabegron vs antimuscarinics,15 23 27 49 in females vs 52 53 males,28 33 43 45 53 in older vs younger patients,23 27 28 3033 40 4245 47 50 53 and in previously treated 54 55 vs untreated patients.15 23 30 56 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Across the studies, persistence appeared to reduce very quickly after initiation of 4 27 35 41 5 treatment for all OAB therapies, with low rates (<50%) already evident at 1 month. 6 7 Longer followup periods showed that large proportions of patients discontinued treatment by 8 15 23 29 32 3941 43 44 50 9 1 year (62–100%) and by the end of 3 years, less than 10% of patients 10 50 11 continued on any antimuscarinic. These steep reductions in rates of persistence over time 12 13 were mirrored by the reported adherence rates. 14 15 16 The chronic Fornature of OABpeer means that review longterm use of onlymedication is essential to 17 18 manage OAB symptoms and improve health outcomes. It is therefore important for patients 19 20 to receive firstline treatment that has a good efficacytolerability profile and evidence of 21 22 favorable persistence vs other treatment options. Among the antimuscarinics, solifenacin

23 15 23 37 47 24 and fesoterodine were generally associated with better persistence and adherence. 25 26 In studies that assessed both mirabegron and antimuscarinics, persistence with mirabegron 27 was statistically significantly greater (p˂0.001).15 23 27 Adherence to mirabegron was also 28 29 greater; however, mean/median MPR values in the overall mirabegron populations did not 30 31 indicate medication adherence (˂0.80). Although these studies did not directly assess the 32

33 http://bmjopen.bmj.com/ reason(s) for the observed benefits of mirabegron, proposed reasons include lower rates of 34 35 bothersome anticholinergic adverse events, particularly drymouth, compared with 36 37 antimuscarinics and unmet expectations of antimuscarinic treatment.15 23 27 38 39 40 It is well established that poor medication persistence and adherence reduces the ability

41 on September 29, 2021 by guest. Protected copyright. 42 to achieve optimum clinical benefits and limits treatment success, especially for chronic 43 44 conditions such as OAB.1214 40 The unwillingness of patients to continue to take longterm 45 46 treatment has been observed across many chronic conditions, with nonadherence to 47 48 medication observed in ~50% of patients.12 An analysis across six chronic conditions found 49 50 1year persistence and adherence rates to be low for all conditions, and lowest for OAB 51 52 medications (antimuscarinics),29 suggesting an unmet treatment need. However, this study 53 54 was performed prior to the availability of mirabegron for use in routine clinical practice, and 55 56 therefore an updated analysis of persistence in chronic conditions might be warranted. 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 As alluded to above, persistence and adherence to treatment is expected to improve 4 5 outcomes for patients with OAB. Two studies have reported that patients compliant and 6 7 adherent to OAB medication experienced significantly improved urinary symptoms and 8 54 55 9 HRQoL compared with patients who were nonpersistent. These data are consistent with 10 11 studies describing other chronic diseases, such as diabetes and depression, where good 12 13 56 13 adherence resulted in improved health outcomes as well as reduced complications and 14 57 15 disability, and improved HRQoL and life expectancy. Moreover, greater persistence and 16 For peer review only 17 adherence to treatment for OAB is associated with significantly lower medical, sick leave and

18 45 19 shortterm disability costs. Indeed, economic models based on realworld inputs suggest 20 21 that improved persistence with mirabegron translates into benefits of reduced healthcare 22 23 resource use, and lower direct and indirect costs of treatment compared with

24 24 58 25 antimuscarinics. Additionally, mirabegron is reported to be cost effective vs six 26 27 antimuscarinics from commercial and Medicare perspectives in the United States, due to

28 59 29 fewer projected adverse events and comorbidities, and data suggesting better persistence. 30 31 Independent variables for treatment discontinuation were studied by at least half of the 32

33 http://bmjopen.bmj.com/ papers included in our literature review, of which sex, age, comorbidities and previous 34 35 experience of OAB medications were shown to be important factors in more than two 36 37 studies. Only six studies reported switchrates and although these were low, the treatment 38 39 strategy of cycling antimuscarinic agents in patients who do not achieve symptom relief is 40

41 common in clinical practice. Yet recent analysis of realworld data suggests that switching on September 29, 2021 by guest. Protected copyright. 42 43 antimuscarinics may provide suboptimal care.51 In contrast, switching to mirabegron from 44 45 antimuscarinic therapy has proved beneficial in over 50% of patients with OAB in an 46 47 observational study.60 48 49 50 This review represents a large pooled analysis of realworld data for persistence and 51 52 adherence to oral OAB medication across different geographical locations (Canada, Czech 53 54 Republic, Denmark, Germany, Norway, Spain, the United Kingdom and the United States); 55 56 however, there were no identifiable trends between data and countries. The definitions and 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 calculations of persistence and adherence were not uniform across the literature and the 4 5 terms were often used interchangeably. This lack of consistency led to some limitations on 6 7 the ability to compare across studies. Other limitations to performing crossstudy 8 9 comparisons or pooled analyses in this SLR include differences in the individual study 10 11 populations and/or study designs, resulting in considerable variations between data. For 12 13 example, the median TTD for oxybutynin ER and tolterodine ER were determined to be 5.1 14 50 15 and 5.5 months, respectively, by one study, but only 60 and 56 days, respectively, by 16 15For peer review only 17 another study. 18 19 20 Furthermore, it is very difficult to capture the specific reasons for treatment 21 22 discontinuation from prescriptiondriven or medical claim data rather than patientderived

23 15 24 data. The current review excluded data from RCTs to better reflect patient behavior in the

25 11 26 general OAB population in reallife clinical practice. Only one paper included in our review 27 reported that antimuscarinic side effects were significantly associated with discontinuation,44 28 29 despite reports that such side effects are bothersome and a common reason for 30 31 discontinuation of antimuscarinic treatment.11 16 25 Additional factors that could not be 32

33 http://bmjopen.bmj.com/ assessed by our study, but can influence persistence with treatment in OAB patients are 34 35 patient expectations, appropriate counselling and patient satisfaction with treatment.11 14 25 36 37 38 In addition to the limitations listed above, it should be noted that SicrasMainar et al36 37 39 40 reported data on the same patient group (in terms of demographics and the

41 on September 29, 2021 by guest. Protected copyright. 42 timeframe/geographical source). This is also the case for two studies published by Sicras 43 44 Mainar et al in 2013 and 2014.48 61 Also, this SLR excluded data on nonoral 45 46 pharmacotherapies (eg, onabotulinum toxin A) and combination mirabegron plus 47 48 antimuscarinic therapies, where additional efficacy has been reported compared to the 49 50 monotherapies.62 Further research on persistence and adherence to these OAB therapies is 51 52 needed to better evaluate current treatment options. Additional studies are also required to 53 54 improve our understanding of persistence and adherence in OAB, including qualitative 55 56 studies to examine the reasons for discontinuation and realworld studies to examine 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 resource use associated with OAB medication in relation to adherence and persistence. As 4 5 OAB is a chronic disease, clinicians should not only take into consideration the efficacy and 6 7 side effects of an agent when deciding on treatment options, but also ensure that realistic 8 9 patient expectations from treatment are set through patient education and counselling. The 10 11 patient’s lifestyle should also be considered as this is likely to impact adherence and 12 13 persistence with OAB therapy. 14 15 16 CONCLUSIONSFor peer review only 17 18 Persistence and adherence were greater with mirabegron compared with antimuscarinics, 19 20 and appeared to be greater with solifenacin and fesoterodine compared with other 21 22 antimuscarinics. In addition, greater persistence and adherence were generally observed in 23 24 patients who were female, older, treatmentexperienced and receiving ER formulations. 25 26 Together with the efficacy and tolerability data from clinical trials, these realworld data 27 28 suggest a benefit from using mirabegron as firstline oral pharmacotherapy for patients with 29 30 OAB. 31 32

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Adherence and persistence to OAB medication 1 2 3 Contributorship Statement 4 5 6 GY, PS, JN, ZH, ES and FF were involved in conceptualisation and design of the study and 7 8 critical review of the manuscript. FF, PS and GY performed the data extraction. All authors 9 10 approved the final manuscript as submitted. 11 12 13 Competing Interests 14 15 16 ZH, JN and ES areFor employed peer by Astellas. review FF has received aonly grant from Astellas for study 17 18 design, data extraction and manuscript development. 19 20 21 Funding 22 23 24 The study was supported by Astellas Pharma Global Development. 25 26 27 Data Sharing Statement 28 29 30 The search strategy and all data supporting this study are provided as supplementary 31 32 information accompanying this paper.

33 http://bmjopen.bmj.com/ 34 35 Acknowledgments 36 37 38 Medical writing support was provided by Claire Chinn, PhD, and Kinnari Patel, PhD, of 39 40 Bioscript Medical and funded by Astellas Pharma Global Development.

41 on September 29, 2021 by guest. Protected copyright. 42 43 Abbreviations and Acronyms 44 45 46 ER = extendedrelease 47 48 HRQoL = healthrelated quality of life 49 50 51 MPR = medication possession rate 52 53 54 OAB = overactive bladder 55 56 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 PDC = proportion of days covered 4 5 6 PRISMA = Preferred Reporting Items for Systematic Reviews and MetaAnalyses 7 8 9 RCTs = randomised controlled trials 10 11 12 SLR = systematic literature review 13 14 TTD = time to discontinuation 15 16 For peer review only 17 UTI = urinary tract infection 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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Adherence and persistence to OAB medication 1 2 3 REFERENCES 4 5 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary 6 7 tract function: report from the Standardisation Subcommittee of the International 8 9 Continence Society. Neurourol Urodyn 2002;21(2):16778. 10 11 12 2. Eapen RS, Radomski SB. Review of the epidemiology of overactive bladder. Res Rep 13 14 Urol 2016;8:716. doi: 10.2147/RRU.S102441 15 16 For peer review only 17 3. Brown JS, McGhan WF, Chokroverty S. Comorbidities associated with overactive bladder. 18 19 Am J Manag Care 2000;6(11 Suppl):S5749. 20 21 22 4. Subak LL, Richter HE, Hunskaar S. Obesity and urinary incontinence: epidemiology and 23 24 clinical research update. J Urol 2009;182(6 Suppl):S27. doi: 25 26 10.1016/j.juro.2009.08.071 27 28 29 5. Coyne KS, Payne C, Bhattacharyya SK, et al. The impact of urinary urgency and 30 31 frequency on healthrelated quality of life in overactive bladder: results from a 32

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41 on September 29, 2021 by guest. Protected copyright. 42 15. Chapple CR, Nazir J, Hakimi Z, et al. Persistence and adherence with mirabegron 43 44 versus antimuscarinic agents in patients with overactive bladder: a retrospective 45 46 observational study in UK clinical practice. Eur Urol 2017;72(3):38999. doi: 47 48 10.1016/j.eururo.2017.01.037 49 50 51 16. Sexton CC, Notte SM, Maroulis C, et al. Persistence and adherence in the treatment of 52 53 overactive bladder syndrome with anticholinergic therapy: a systematic review of the 54 55 literature. Int J Clin Pract 2011;65(5):56785. doi: 10.1111/j.17421241.2010.02626.x 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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41 22. Kobayashi M, Nukui A, Kamai T. Comparative efficacy and tolerability of antimuscarinic on September 29, 2021 by guest. Protected copyright. 42 43 agents and the selective beta3adrenoceptor agonist, mirabegron, for the treatment 44 45 of overactive bladder: which is more preferable as an initial treatment? Low Urin 46 47 Tract Symptoms 2016:Epub ahead of print. doi: 10.1111/luts.12153 48 49 50 23. Wagg A, Franks B, Ramos B, et al. Persistence and adherence with the new beta3 51 52 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: early 53 54 experience in Canada. Can Urol Assoc J 2015;9(910):34350. doi: 55 56 10.5489/cuaj.3098 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 24. Nazir J, Berling M, McCrea C, et al. Economic impact of mirabegron versus 4 5 antimuscarinics for the treatment of overactive bladder in the UK. 6 7 Pharmacoeconomics Open 2017;1:2536. 8 9 10 25. Basra RK, Wagg A, Chapple C, et al. A review of adherence to drug therapy in patients 11 12 with overactive bladder. BJU Int 2008;102(7):7749. doi: 10.1111/j.1464 13 14 410X.2008.07769.x 15 16 For peer review only 17 26. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 18 19 metaanalyses: the PRISMA statement. Int J Surg 2010;8(5):33641. doi: 20 21 10.1016/j.ijsu.2010.02.007 22 23 27. Nitti VM, Rovner ES, Franks B, et al. Persitence with mirabegron versus tolterodine in 24 25 patients with overactive bladder. Am J Pharm Benefits 2016;8(2):e25e33. 26 27 28 28. Wagg A, Diles D, Berner T. Treatment patterns for patients on overactive bladder 29 30 therapy: a retrospective statistical analysis using Canadian claims data. JHEOR 31 32 2015;3(1):4355.

33 http://bmjopen.bmj.com/ 34 35 29. Yeaw J, Benner JS, Walt JG, et al. Comparing adherence and persistence across 6 36 37 chronic medication classes. J Manag Care Pharm 2009;15(9):72840. doi: 38 39 10.18553/jmcp.2009.15.9.728 40

41 on September 29, 2021 by guest. Protected copyright. 42 30. Brostrom S, Hallas J. Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 43 44 2009;65(3):30914. doi: 10.1007/s0022800806009 45 46 47 31. Desgagne A, LeLorier J. Incontinence drug utilization patterns in Quebec, Canada. Value 48 49 Health 1999;2(6):4528. doi: 10.1046/j.15244733.1999.26005.x 50 51 52 32. Gomes T, Juurlink DN, Mamdani MM. Comparative adherence to oxybutynin or 53 54 tolterodine among older patients. Eur J Clin Pharmacol 2012;68(1):979. doi: 55 56 10.1007/s0022801110908 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 33. Ivanova JI, HayesLarson E, Sorg RA, et al. Healthcare resource use and costs of 4 5 privately insured patients who switch, discontinue, or persist on antimuscarinic 6 7 therapy for overactive bladder. J Med Econ 2014;17(10):74150. doi: 8 9 10.3111/13696998.2014.941066 10 11 12 34. Krhut J, Gartner M, Petzel M, et al. Persistence with first line anticholinergic medication 13 14 in treatmentnaive overactive bladder patients. Scand J Urol 2014;48(1):7983. doi: 15 16 10.3109/21681805.2013.814707For peer review only 17 18 19 35. Perfetto EM, Subedi P, Jumadilova Z. Treatment of overactive bladder: a model 20 comparing extendedrelease formulations of tolterodine and oxybutynin. Am J Manag 21 22 Care 2005;11(4 Suppl):S1507. 23 24 25 36. SicrasMainar A, NavarroArtieda R, RuizTorrejon A, et al. Impact of loss of work 26 27 productivity in patients with overactive bladder treated with antimuscarinics in Spain: 28 29 study in routine clinical practice conditions. Clin Drug Investig 2015;35(12):795805. 30 31 doi: 10.1007/s4026101503422 32

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41 on September 29, 2021 by guest. Protected copyright. 42 43 38. SicrasMainar A, RejasGutierrez J, NavarroArtieda R, et al. Use of health care 44 45 resources and associated costs in noninstitutionalized vulnerable elders with 46 47 overactive bladder treated with antimuscarinic agents in the usual medical practice. 48 49 Actas Urol Esp 2014;38(8):5307. doi: 10.1016/j.acuro.2014.02.001 50 51 52 39. Suehs BT, Davis C, Franks B, et al. Effect of potentially inappropriate use of 53 54 antimuscarinic medications on healthcare use and cost in individuals with overactive 55 56 bladder. J Am Geriatr Soc 2016;64(4):77987. doi: 10.1111/jgs.14030 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 40. Wagg A, Compion G, Fahey A, et al. Persistence with prescribed antimuscarinic therapy 4 5 for overactive bladder: a UK experience. BJU Int 2012;110(11):176774. doi: 6 7 10.1111/j.1464410X.2012.11023.x 8 9 10 41. Yu YF, Nichol MB, Yu AP, et al. Persistence and adherence of medications for chronic 11 12 overactive bladder/urinary incontinence in the California Medicaid program. Value 13 14 Health 2005;8(4):495505. doi: 10.1111/j.15244733.2005.00041.x 15 16 For peer review only 17 42. D'Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among 18 19 extendedrelease and immediaterelease overactive bladder medications in a 20 regional managed care plan. J Manag Care Pharm 2008;14(3):291301. doi: 21 22 10.18553/jmcp.2008.14.3.291 23 24 25 43. Johnston S, Janning SW, Haas GP, et al. Comparative persistence and adherence to 26 27 overactive bladder medications in patients with and without diabetes. Int J Clin Pract 28 29 2012;66(11):104251. doi: 10.1111/j.17421241.2012.03009.x 30 31 32 44. Kalder M, Pantazis K, Dinas K, et al. Discontinuation of treatment using anticholinergic

33 http://bmjopen.bmj.com/ 34 medications in patients with urinary incontinence. Obstet Gynecol 2014;124(4):794 35 36 800. doi: 10.1097/AOG.0000000000000468 37 38 39 45. Kleinman NL, Odell K, Chen CI, et al. Persistence and adherence with urinary 40

41 antispasmodic medications among employees and the impact of adherence on costs on September 29, 2021 by guest. Protected copyright. 42 43 and absenteeism. J Manag Care Spec Pharm 2014;20(10):104756. doi: 44 45 10.18553/jmcp.2014.20.10.1047 46 47 48 46. Manack A, Motsko SP, HaagMolkenteller C, et al. Epidemiology and healthcare 49 50 utilization of neurogenic bladder patients in a US claims database. Neurourol Urodyn 51 52 2011;30(3):395401. doi: 10.1002/nau.21003 53 54 55 56 57 58 22 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 47. Mauseth SA, Skurtveit S, Spigset O. Adherence, persistence and switch rates for 4 5 anticholinergic drugs used for overactive bladder in women: data from the Norwegian 6 7 Prescription Database. Acta Obstet Gynecol Scand 2013;92(10):120815. doi: 8 9 10.1111/aogs.12196 10 11 12 48. SicrasMainar A, Rejas J, NavarroArtieda R, et al. Antimuscarinic persistence patterns 13 14 in newly treated patients with overactive bladder: a retrospective comparative 15 16 analysis.For Int Urogynecol peer J 2014;25(4):48592. review doi: 10.1007/s0019201322504 only 17 18 19 49. Sussman D, Yehoshua A, Kowalski J, et al. Adherence and persistence of mirabegron 20 21 and anticholinergic therapies in patients with overactive bladder: a realworld claims 22 data analysis. Int J Clin Pract 2017;71(34):e12824. doi: 10.1111/ijcp.12824 23 24 25 50. Gopal M, Haynes K, Bellamy SL, et al. Discontinuation rates of anticholinergic 26 27 medications used for the treatment of lower urinary tract symptoms. Obstet Gynecol 28 29 2008;112(6):13118. doi: 10.1097/AOG.0b013e31818e8aa4 30 31 32 51. Chancellor MB, MigliaccioWalle K, Bramley TJ, et al. Longterm patterns of use and

33 http://bmjopen.bmj.com/ 34 treatment failure with anticholinergic agents for overactive bladder. Clin Ther 35 36 2013;35(11):174451. doi: 10.1016/j.clinthera.2013.08.017 37 38 39 52. Sears CL, Lewis C, Noel K, et al. Overactive bladder medication adherence when 40

41 medication is free to patients. J Urol 2010;183(3):107781. doi: on September 29, 2021 by guest. Protected copyright. 42 43 10.1016/j.juro.2009.11.026 44 45 46 53. Pelletier EM, Vats V, Clemens JQ. Pharmacotherapy adherence and costs versus 47 48 nonpharmacologic management in overactive bladder. Am J Manag Care 2009;15(4 49 50 Suppl):S10814. 51 52 53 54 55 56 57 58 23 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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33 http://bmjopen.bmj.com/ 34 Med Econ 2017;20(6):61422. doi: 10.1080/13696998.2017.1294595 35 36 37 59. Wielage RC, Perk S, Campbell NL, et al. Mirabegron for the treatment of overactive 38 39 bladder: costeffectiveness from US commercial healthplan and Medicare 40

41 Advantage perspectives. J Med Econ 2016;19(12):113543. doi: on September 29, 2021 by guest. Protected copyright. 42 43 10.1080/13696998.2016.1204307 44 45 46 60. Liao CH, Kuo HC. High satisfaction with direct switching from antimuscarinics to 47 48 mirabegron in patients receiving stable antimuscarinic treatment. Medicine 49 50 (Baltimore) 2016;95(45):e4962. doi: 10.1097/MD.0000000000004962 51 52 53 61. SicrasMainar A, Rejas J, NavarroArtieda R, et al. Health economics perspective of 54 55 fesoterodine, tolterodine or solifenacin as firsttime therapy for overactive bladder 56 57 58 24 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 syndrome in the primary care setting in Spain. BMC Urol 2013;13:51. doi: 4 5 10.1186/147124901351 6 7 8 62. Drake MJ, Chapple C, Esen AA, et al. Efficacy and safety of mirabegron addon therapy 9 10 to solifenacin in incontinent overactive bladder patients with an inadequate response 11 12 to initial 4week solifenacin monotherapy: a randomised doubleblind multicentre 13 14 phase 3B study (BESIDE). Eur Urol 2016;70(1):13645. doi: 15 16 10.1016/j.eururo.2016.02.030For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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Adherence and persistence to OAB medication 1 2 3 FIGURE LEGENDS 4 5 Figure 1 Search strategy and selection of studies presented in the Preferred Reporting 6 7 Items for Systematic Reviews and MetaAnalyses (PRISMA) flow diagram 8 9 10 *Studies were excluded for the following reasons: outcome measure(s) of persistence and/or adherence, relevant 11 12 to this systematic review (such as medication possession rate, proportion of days covered, discontinuation rate), 13 were not presented within the full text of the article (n=17); adherence/persistence data were drawn from surveys, 14 15 interviews or selfreports (n=13); cohort contained a portion of patients under 18 years of age (who could not be 16 For peer review only 17 removed or isolated from results/data) (n=7); participants had prior awareness/knowledge of partaking in a study 18 related to OAB medication (ie, openlabel extension to a study or prior written consent) (n=6); a full article text 19 20 was not available (ie, only a conference abstract) or the full text was not in English; or nonoral OAB medications 21 22 were included within the presented results (and could not be removed or isolated from results/data) (n=1) 23 24 §Three of these studies were identified by reviewing reference lists of included studies and relevant systematic 25 26 literature reviews 27 28

29 30 31 Figure 2 Frequency for reported determinants of discontinuation 32

33 http://bmjopen.bmj.com/ 34 *In one study the relationship was not statistically significant 35 36 37 **Includes dose, formulation, race, prior infection, financial burden, prescriber profession, side effects, medication 38 copayment and polypharmacy 39 40

41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 26 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 Figure 1 Search strategy and selection of studies presented in the Preferred Reporting Items for Systematic 46 Reviews and Meta-Analyses (PRISMA) flow diagram 47 48 215x279mm (300 x 300 DPI) 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 2 Frequency for reported determinants of discontinuation 30 273x182mm (300 x 300 DPI) 31 32

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Adherence and persistence to OAB medication 1 2 3 Supplemental Table 1: Patient characteristics, interventions and definitions/variables of persistence, adherence and discontinuation reported in the studies. 4 5 6 Author (year) and Definition of persistence/adherence/discontinuation and Length of 7 country (database) Participants Drug/intervention* independent variables on persistence follow-up 8 9 Brostrøm and Hallas n=2477 Any prescription of OAB Patients who continued taking a particular drug for up to 7 years with Up to 7 (2009)1 Male: n=836 (33.8%) medication: no more than 120-day gaps were regarded as experiencing single- years 10 Odense University Female: n=1641 (66.2%) flavoxate (n=21) treatment episodes 11 Pharmacoepidemio- Mean age: 68.3 yearsa oxybutynin TD (n=48) 12 logical Database tolterodine (n=1478) Variables: age, gender, prior use of OAB agents and use of (OPED); Denmark) For peersolifenacin (n=774) reviewanti-diabetic drugs only 13 (1999–2006) trospium (n=271) 14 darifenacin (n=52) 15 Chancellor et al (2013)2 n=103 250 First (new) prescription of OAB To be considered a discontinuation, patients were required to have a 2 years 16 a

IMS Lifelink Database, Male: n≈25 916 (25.1%) medication in adults ≥18 years: gap of at least 45 days in therapy basedhttp://bmjopen.bmj.com/ on fill dates and days’ 17 Connecticut; USA Female: n≈77 334a (74.9%) tolterodine ER (n=43 881)a supply 18 (2005–2008) Mean (SD) age: 58.7 (15.7) solifenacin (n=15 488)a 19 years oxybutynin (n=15 075)a Adherence rate was defined as the proportion of patients filling more 20 darifenacin (n=10 532)a than one prescription with an MPR of ≥80% a 21 oxybutynin ER (n=10 325) oxybutynin TD (n=2272)a 22 tolterodine (n=2581)a 23 trospium (n=2478)a 24 trospium ER (n=413)a 25 Chapple et al (2017)3 n=21 996 First (new) prescription of OAB Treatment was defined as discontinued on September 29, 2021 by guest. Protected copyright. if the maximum allowable 1 year 26 Clinical Practice Male: n=6513 (29.6%) medication in adults ≥18 years: gap duration was at least 1.5 times the intended duration of the most 27 Research Datalink Female: n=15 483 (70.4%) mirabegron (n=1203) recent prescription 28 (CPRD); UK Mean (SD) age: 63.9 (16.3) darifenacin (n=126) (2013–2014) years fesoterodine (n=1287) Adherence rate was defined as mean MPR at 12 months 29 flavoxate (n=144) 30 oxybutynin ER (n=1144) 31 oxybutynin IR (n=5779) 32 propiverine (n=95) solifenacin (n=8191) 33 tolterodine ER (n=1561) 34 tolterodine IR (n=1523) 35 trospium chloride (n=943) 36 37 38 39 40 41 1 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Kleinman et al (2014)11 n=2960 First index of OAB medication in Persistence was measured as the number of days from index UA 1 year Human Capital Male: n=878 (29.7%) adults aged 18 to 64 years: prescription until first ≥30-day gap in UA medication supply 7 Management Services Female: n=2082 (70.3%) darifenacin 8 [HCMS] Research Mean age: 46.6 years fesoterodine Adherence was measured as the percentage of the annual post- 9 Reference Database; oxybutynin index period with available medication 10 USA flavoxateb 11 (2001–2011) solifenacin tolterodine 12 For peertrospium review only 13 hyoscyamineb 14 imipramineb 15 Krhut et al (2014)12 n=377 First (new) index of OAB Persistence was assessed according to the patient records 1 year 16 Dept. of Urology and Male: n=52 (13.8%) medication within patients 17 Dept. of Gynaecology Female: n=325 (86.2%) attending hospital as an outpatient: http://bmjopen.bmj.com/ 18 and Obstetrics, Mean (SD) age: 60.3 (13.8) trospium (n=189) University Hospital years propiverine (n=41) 19 Ostrava; Czech Republic tolterodine ER (n=9) 20 (2009–2010) solifenacin (n=48) 21 fesoterodine (n=90) 22 Manack et al (2011)13 n=46 271c Patients with neurogenic bladder Continuation was defined as ≥365 days of OAB oral drug use 1 year 23 Thomson Reuters Male: n=19 727 (42.6%) origin (such as spinal cord injury beginning at the index date with ≤90 days between the end of 24 MarketScan® Female: n=26 544 (57.4%) and multiple sclerosis) receiving an therapy and end of eligibility 25 Commericial and Mean (SD) age: 62.5 (19.6) oral OAB medication on September 29, 2021 by guest. Protected copyright. Medicare Supplemental years Discontinuation was defined as ≥6 months of no OAB oral drug use 26 Databases; USA between the end of therapy and the end of eligibility 27 (2002–2007) 28 Mauseth et al (2013)14 n=32 178 Adult patients aged ≥18 years with Persistence defined as the population who had not discontinued the 1 year 29 The Norwegian Male: n=0 (0.0%) a first index (new) prescription of: drug during a period of 365 days after the index date 30 Prescription Database; Female: n=32 178 (100.0%) tolterodine (n=12 389) 31 Norway No mean age reported. The solifenacin (n=13 682) A switch was defined as a prescription for another of the drugs 32 (2004–2010) majority of patients (60.5%) darifenacin (n=4399) included in the study within 365 days after the index date were aged ≥60 years fesoterodine (n=1708) 33 Adherence was measured using MPR (sum of days of supply for all 34 tablets purchased, except those received at the last fill, divided by 35 the total number of days from the first to the last filling) 36 37 Variables: age and initial antimuscarinic 38 39 40 41 4 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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29 Variables: gender and drug formulation 30 31 Sicras-Mainar et al n=3094 Adults aged 20 to 64 with a first Discontinuation was defined as when the patient switched to another 1 year (2016)d,19 Male: n≈1170a (37.8%) index (new) prescription of: active substance, another drug was added (combination) or the 32 Primary care medical Female: n≈1924a (62.2%) fesoterodine (n=859) medication was discontinued completely or discontinued for ≥60 days 33 databases; Spain Mean age: 54.0 years solifenacin (n=1330) without renewal and ≥2 prescriptions 34 (2008–2013) tolterodine (n=905) 35 Compliance was calculated using MPR

36 Variables: concomitant medication (antidepressants, antibiotics) and 37 index drug 38 39 40 41 5 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Sicras-Mainar et al n=3094 Adults aged ≥20 years with a first Persistence was defined as the time, measured in months, without 1 year (2015)d,20 Male: n≈1170a (37.8%) index (new) prescription of: stopping the initial treatment or switching to another medication at 7 Primary care medical Female: n≈1924a (62.2%) fesoterodine (n=859) least 30 days after the initial prescription 8 databases; Spain Mean (SD) age: 54.0 (9.2) years solifenacin (n=1330) 9 (2008–2013) tolterodine (n=905) Compliance was defined according to ISPOR criteria and was 10 calculated based on the MPR, which was evaluated from the first to 11 the last prescription and represented the number of days of medication taken over the number of days in treatment (commencing 12 For peer reviewfrom the start date)only 13 14 Sicras-Mainar et al n=552 Adults aged ≥75 years with a first Persistence was defined as the time, in weeks, with no drop-out from 1 year (2014a)21 Male: n≈272a (49.2%) index (new) prescription of: initial treatment or with no switch to another medication at least 15 Primary care medical Female: n≈280a (50.8%) fesoterodine (n=58) 30 days following initial prescription 16 databases; Spain Mean (SD) age: 80.2 (4.0) years solifenacin (n=252) 17 (2008–2010) tolterodine (n=212) Compliance was defined according to http://bmjopen.bmj.com/ ISPOR criteria and was 18 calculated based on the medication use/possession rate 19 Sicras-Mainar et al n=1971 Adults aged ≥18 years with a first Discontinuation was defined by either the absence of prescription 1 year 20 (2014b)e,22 Male: n=821 (41.7%) index (new) prescription of: coverage for the initial therapy for the remainder of the 52-week 21 Primary care medical Female: n=1150 (58.3%) fesoterodine (n=302) follow-up period or a switch to an alternative antimuscarinic during databases; Spain Mean (SD) age: 70.1 (10.6) solifenacin (n=952) this time-period 22 (2008–2010) years tolterodine (n=717) 23 Variables: index drug 24 Sicras-Mainar et al n=1971 Adults aged ≥18 years with a first Persistence was defined as patients who remained on treatment 1 year on September 29, 2021 by guest. Protected copyright. 25 (2013)e,23 Male: n=821 (41.7%) index (new) prescription of: during the 52-week period following the index date 26 Primary care medical Female: n=1150 (58.3%) fesoterodine (n=302) 27 databases; Spain Mean (SD) age: 70.1 (10.6) solifenacin (n=952) Compliance was defined according to ISPOR criteria and was 28 (2008–2010) years tolterodine (n=717) calculated based on the MPR 29 Suehs et al (2016)24 n=46 140a Adults aged 65 to 89 yearsf with a Persistence was assessed as time in days from the index date to 1 year 30 Medicare Advantage Male: n=15 479a (33.5%)a first index (new) prescription of any discontinuation of index antimuscarinic treatment a a 31 Prescription Plan - Female: n=30 661 (66.5%) antimuscarinic OAB medication Administrative Claims Mean age: 75.5 yearsa Adherence was assessed as PDC with the index OAB treatment over 32 Data; USA three predefined post index observation periods: 3, 6, and 12 months 33 (2007–2013) 34 Treatment discontinuation was identified using a permissible gap 35 between refills of 15 days 36 37 38 39 40 41 6 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Sussman et al (2017)25 n=71 980a Adults aged ≥18 years with a Persistence was measured by evaluating treatment failure (defined 1 year Truven MarketScan® Male: n=21 225a (29.5%)a prescription of: as either treatment discontinuation or treatment switching). A 7 Claims Database; USA Female: n=50 755a (70.5%)a mirabegron medication supply gap of ≥30 days was used to define treatment 8 (2012–2013) Mean age: 62.3 yearsa any anticholinergic OAB discontinuation 9 medication 10 Adherence was defined as the PDC (ie, the number of days covered 11 by the index therapy divided by the number of days between the index date and the end of the follow-up [365 days]). A PDC of <80% 12 For peer reviewwas considered only nonadherent 13 26 14 Wagg et al (2012) n=4833 Adults aged ≥40 years with a first Persistence was defined as the mean time [in days] until 1 year Prescription Database; Demographics were not index (new) prescription of: discontinuation (a gap in treatment exceeding 1.5 times than the 15 UK (2007–2008) explicitly reported, the majority darifenacin length of the previous prescription without a refill) 16 of prescriptions appeared to be flavoxate 17 issued to patients aged oxybutynin ER http://bmjopen.bmj.com/ 18 ≥60 years oxybutynin IR propiverine 19 solifenacin 20 tolterodine ER 21 tolterodine IR 22 trospium 23 Wagg et al (2015)27 n=19 485 Adults aged ≥18 years with a first Adherence was defined by the MPR over 1 year 1 year 24 Canadian National Male: n=4992 (25.6%)a index (new) prescription of: a 25 Private Drug Plan Female: n=14 493 (74.3%) mirabegron (n=1683) To calculate time to end of persistence on September 29, 2021 by guest. Protected copyright. (defined by a gap in therapy Database; Canada Mean age not reported; the fesoterodine (n=1415) of ≥30 days or switching to another medication), prescription claims 26 (2013) majority of patients (77.8%)a oxybutynin ER (n=1260) for a target drug were tracked for 12 months after the index claim 27 were aged ≥46 years oxybutynin IR (n=5356) date 28 solifenacin (n=6032) 29 tolterodine ER (n=3739) Variables: age, gender, treatment-naïve vs treatment-experienced, 30 index antimuscarinic, number of coexisting medications 31 Wagg et al (2015)28 n=31 707 Adult patients receiving a first Discontinuation was defined as patients experiencing a gap in 4 years a 32 IMS Brogan public and Male: n=9395 (29.6%) index (new) prescription of: therapy longer than 60 days private prescription Female: n=22 312 (70.4%)a oxybutynin IR 33 claims databases; Mean age not reported oxybutynin ER 34 Canada tolterodine IR 35 (2007–2012) tolterodine ER 36 solifenacin 37 darifenacin trospium 38 flavoxate 39 40 41 7 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Yeaw et al (2009)29 n=7722 Adult patients receiving a first Persistence was calculated for the post-index period until the patient 2 years PharMetrics Patient- Male: n=1686 (21.8%) index (new) prescription of: discontinued therapy, was lost to follow-up due to disenrollment from 7 Centric Database Female: n=6036 (78.2%) tolterodine the health plan (minimum of 12 months), or the maximum 24-month 8 (pharmacy claims); USA Mean (SD) age: 43.7 (18.3) oxybutynin follow-up period ended, whichever event occurred first. A patient was 9 (2005) years solifenacin considered persistent until an excessive gap in days supplied 10 darifenacin occurred; refill gaps of 30, 60, and 90 days were used to calculate 11 trospium persistence for all cohorts bethanechol 12 For peerflavoxate reviewAdherence was only measured using the PDC for each of the six drug 13 hyoscyamine class cohorts. This was calculated by taking patients’ total days 14 supplied of index class medications for the 360-day period following 15 the index date and dividing by 360 16 Yu et al (2015)30 n=2496 Adult patients aged ≥18 years Persistence was measured by the length of continuous 1 year 17 California Medi-Cal Male: n=534 (21.4%) receiving a prescription of an OAB pharmacological treatment (patients discontinuedhttp://bmjopen.bmj.com/ their treatment if 18 administrative files; USA Female: n=1962 (78.6%) drug, including: they failed to refill OAB/UI agents within 30 days after the expected (1999–2002) Mean (SD) age: 63.15 (16.14) tolterodine (n=1093) end date of the previous prescription) 19 years oxybutynin ER (n=524) 20 oxybutynin (n=812) Patients who switched from one agent of OAB/UI drug to another 21 other OAB agents (n=67) within 30 days were considered persistent on therapy. 22 Adherence was defined as MPR over 181 days for the 6-month 23 follow-up period 24 25 Variables: age, gender, ethnicity, index on September 29, 2021 by guest. Protected copyright. drug, OAB-associated 26 comorbidities (UTIs), medication use history, length of hospital stay 27 and number of drug classes prescribed 28 COPD = chronic obstructive pulmonary disease; ER = extended release; ISPOR = International Society for Pharmacoeconomics and Outcomes Research; IR = immediate release; MPR = medication possession ratio (measured as the proportion of days with any OAB medication on hand, over the length of the evaluation period); OAB = overactive bladder; 29 PDC = proportion of days covered; PIM = potentially inappropriate medication; SD = standard deviation; TD = transdermal; UA = urinary antispasmodic; UI = urinary incontinence; UTIs = 30 urinary tract infections 31 32 *The sum of the patients prescribed individual drugs may not match the total number of patients perhaps due to switching in some studies 33 34 aCalculated from data presented in the article; bused only in an OAB context; c26 922 continued, discontinued or restarted an OAB medication in the study period, but no demographics d 19 20 35 for this specific sub-group are reported; Sicras-Mainar et al (2016) and Sicras-Mainar et al (2015) relate to the same patient group in terms of demographics and the timeframe/geographical source of adherence/persistence data; eSicras-Mainar et al (2014)22 and Sicras-Mainar et al (2013)23 relate to the same patient group in terms of demographics 36 and the timeframe/geographical source of adherence/persistence data; fthis cohort was split into two groups – patients who were assigned OAB medication appropriately [non-PIM], or 37 potentially inappropriately [PIM]. Inappropriateness was defined as patients having “drug–disease or syndrome interaction or indication of signiﬁcant anticholinergic medication burden at 38 the time of initiation of an antimuscarinic OAB treatment” 39 40 41 8 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 37 of 64 BMJ Open

Adherence and persistence to OAB medication 1 2 3 References BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 5 6 1. Brostrom S, Hallas J: Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 2009; 65: 309. 7 8 2. Chancellor MB, Yehoshua A, Waweru C et al: Limitations of anticholinergic cycling in patients with 9 overactive bladder (OAB) with urinary incontinence (UI): results from the CONsequences of Treatment Refractory Overactive bLadder (CONTROL) study. Int Urol Nephrol 2016; 48: 1029. 10 11 3. Chapple CR, Nazir J, Hakimi Z et al: Persistence and adherence with mirabegron versus antimuscarinic 12 agents in patients with overactive bladder: a retrospective observational study in UK clinical practice. 13 Eur Urol 2017; 72: 389. 14 15 4. D'Souza AO, Smith MJ, Miller LA et al: Persistence, adherence, and switch rates among extended- 16 release and immediate-release overactive bladder medications in a regional managed care plan. J 17 Manag Care Pharm 2008; 14: 291. 18 For peer review only 5. Desgagne A, LeLorier J: Incontinence drug utilization patterns in Quebec, Canada. Value Health 1999; 19 2: 452. 20 21 6. Gomes T, Juurlink DN, Mamdani MM: Comparative adherence to oxybutynin or tolterodine among older 22 patients. Eur J Clin Pharmacol 2012; 68: 97. 23 24 7. Gopal M, Haynes K, Bellamy SL et al: Discontinuation rates of anticholinergic medications used for the 25 treatment of lower urinary tract symptoms. Obstet Gynecol 2008; 112: 1311. 26 27 8. Ivanova JI, Hayes-Larson E, Sorg RA et al: Healthcare resource use and costs of privately insured 28 patients who switch, discontinue, or persist on anti-muscarinic therapy for overactive bladder. J Med Econ 2014; 17: 741. 29 30 9. Johnston S, Janning SW, Haas GP et al: Comparative persistence and adherence to overactive bladder 31 medications in patients with and without diabetes. Int J Clin Pract 2012; 66: 1042. 32 33 10. Kalder M, Pantazis K, Dinas K et al: Discontinuation of treatment using anticholinergic medications in 34 patients with urinary incontinence. Obstet Gynecol 2014; 124: 794. 35 36 11. Kleinman NL, Odell K, Chen CI et al: Persistence and adherence with urinary antispasmodic medications among employees and the impact of adherence on costs and absenteeism. J Manag Care

37 http://bmjopen.bmj.com/ Spec Pharm 2014; 20: 1047. 38 39 12. Krhut J, Gartner M, Petzel M et al: Persistence with first line anticholinergic medication in treatment- 40 naive overactive bladder patients. Scand J Urol 2014; 48: 79. 41 42 13. Manack A, Motsko SP, Haag-Molkenteller C et al: Epidemiology and healthcare utilization of neurogenic 43 bladder patients in a US claims database. Neurourol Urodyn 2011; 30: 395. 44 14. Mauseth SA, Skurtveit S, Spigset O: Adherence, persistence and switch rates for anticholinergic drugs

45 on September 29, 2021 by guest. Protected copyright. 46 used for overactive bladder in women: data from the Norwegian Prescription Database. Acta Obstet Gynecol Scand 2013; 92: 1208. 47 48 15. Nitti VM, Rovner ES, Franks B et al: Persitence with mirabegron versus tolterodine in patients with 49 overactive bladder. Am J Pharm Benefits 2016; 8: e25. 50 51 16. Pelletier EM, Vats V, Clemens JQ: Pharmacotherapy adherence and costs versus nonpharmacologic 52 management in overactive bladder. Am J Manag Care 2009; 15: S108. 53 54 17. Perfetto EM, Subedi P, Jumadilova Z: Treatment of overactive bladder: a model comparing extended- 55 release formulations of tolterodine and oxybutynin. Am J Manag Care 2005; 11: S150. 56 18. Sears CL, Lewis C, Noel K et al: Overactive bladder medication adherence when medication is free to 57 patients. J Urol 2010; 183: 1077. 58 59 60

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3 19. Sicras-Mainar A, Navarro-Artieda R, Ruiz-Torrejon A et al: Persistence and concomitant medication in BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 patients with overactive bladder treated with antimuscarinic agents in primary care. An observational 5 baseline study. Actas Urol Esp 2016; 40: 96. 6 7 20. Sicras-Mainar A, Navarro-Artieda R, Ruiz-Torrejon A et al: Impact of loss of work productivity in patients 8 with overactive bladder treated with antimuscarinics in Spain: study in routine clinical practice conditions. Clin Drug Investig 2015; 35: 795. 9 10 21. Sicras-Mainar A, Rejas-Gutierrez J, Navarro-Artieda R et al: Use of health care resources and 11 associated costs in non-institutionalized vulnerable elders with overactive bladder treated with 12 antimuscarinic agents in the usual medical practice. Actas Urol Esp 2014; 38: 530. 13 14 22. Sicras-Mainar A, Rejas J, Navarro-Artieda R et al: Antimuscarinic persistence patterns in newly treated 15 patients with overactive bladder: a retrospective comparative analysis. Int Urogynecol J 2014; 25: 485. 16 17 23. Sicras-Mainar A, Rejas J, Navarro-Artieda R et al: Health economics perspective of fesoterodine, tolterodine or solifenacin as first-time therapy for overactive bladder syndrome in the primary care 18 setting in Spain.For BMC Urol peer 2013; 13: 51. review only 19 20 24. Suehs BT, Davis C, Franks B et al: Effect of potentially inappropriate use of antimuscarinic medications 21 on healthcare use and cost in individuals with overactive bladder. J Am Geriatr Soc 2016; 64: 779. 22 23 25. Sussman D, Yehoshua A, Kowalski J et al: Adherence and persistence of mirabegron and 24 anticholinergic therapies in patients with overactive bladder: a real-world claims data analysis. Int J Clin 25 Pract 2017; 71: e12824. 26 26. Wagg A, Compion G, Fahey A et al: Persistence with prescribed antimuscarinic therapy for overactive 27 bladder: a UK experience. BJU Int 2012; 110: 1767. 28 29 27. Wagg A, Franks B, Ramos B et al: Persistence and adherence with the new beta-3 receptor agonist, 30 mirabegron, versus antimuscarinics in overactive bladder: early experience in Canada. Can Urol Assoc 31 J 2015; 9: 343. 32 33 28. Wagg A, Diles D, Berner T: Treatment patterns for patients on overactive bladder therapy: a 34 retrospective statistical analysis using Canadian claims data. JHEOR 2015; 3: 43. 35 29. Yeaw J, Benner JS, Walt JG et al: Comparing adherence and persistence across 6 chronic medication 36 classes. J Manag Care Pharm 2009; 15: 728.

37 http://bmjopen.bmj.com/ 38 30. Yu YF, Nichol MB, Yu AP et al: Persistence and adherence of medications for chronic overactive 39 bladder/urinary incontinence in the California Medicaid program. Value Health 2005; 8: 495. 40 41 42 43 44

45 on September 29, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Adherence and persistence to OAB medication 1 2 3 Supplemental Table 2. Summary of adherence and persistence rates and determinants 4 5 6 Author (year) Persistence* Adherence* Determinants of persistence and adherence 7 8 Brostrøm and Proportion of patients continued (all drugs except Not reported Gender, age, medication dose, treatment status, medication 1 9 Hallas (2009) trospium chloride): type <50% at 6 months Retention was longer: in females; in older people; with higher 10 <25% at 1 year doses; with previous experience of other OAB drugs; trospium vs 11 <10% at ≥2 years other OAB drugs 12 Proportion of patients continuedFor trospium: peer review only 13 46% at 6 months 14 36% at 1 year 15 22% at 2 years 16 16% at 3 years http://bmjopen.bmj.com/ 17 Chancellor et al Proportion of patients discontinued at 2 years:a Proportion of patients with MPR Not reported 18 (2013)2 tolterodine ER: 84.7% ≥0.80 over study period (in those 19 solifenacin: 85.2% filling >1 prescription): 20 oxybutynin: 91.1% tolterodine ER: 51.1% darifenacin: 85.7% solifenacin: 49.4% 21 oxybutynin ER: 84.0% oxybutynin: 30.1% 22 tolterodine: 85.1% darifenacin: 51.9% 23 trospium: 88.1% oxybutynin ER: 51.8% 24 trospium ER: 87.1% tolterodine: 42.6% 25 trospium: 42.4% on September 29, 2021 by guest. Protected copyright. Proportion of patient switched at 2 years:a trospium ER: 54.3% 26 tolterodine ER: 5.7% 27 solifenacin: 5.2% 28 oxybutynin: 4.7% 29 darifenacin: 6.0% oxybutynin ER: 6.7% 30 tolterodine: 9.7% 31 trospium: 6.9% 32 trospium ER: 6.4% 33 34 35 36 37 38 39 40 41 1 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Chapple et al Median time to discontinuation (days): Mean (SD) MPR at 1 year: Medication type 3 6 (2017) mirabegron: 169 mirabegron: 0.59 (0.33) Mirabegron was associated with a statistically significantly darifenacin: 56 darifenacin: 0.46 (0.34) greater median time to discontinuation (adjusted HR range 1.31– 7 fesoterodine: 78 fesoterodine: 0.53 (0.33) 2.31; p<0.0001 all comparisons) and 12-month persistence rates 8 flavoxate: 30 flavoxate: 0.44 (0.32) (adjusted OR range 0.18–0.71; p≤0.0001 all comparisons) vs 9 oxybutynin ER: 60 oxybutynin ER: 0.49 (0.32) antimuscarinics in all patients 10 oxybutynin IR: 35 oxybutynin IR: 0.41 (0.32) 11 propiverine: 56 propiverine: 0.51 (0.32) The mean MPR with mirabegron was significantly greater vs solifenacin: 67 solifenacin: 0.53 (0.34) antimuscarinics in all patients (p values 0.03 to <0.0001), and in 12 tolterodine ER: 56 For peertolterodine review ER: 0.50 (0.34) treatmentonly-naïve subcohorts, except for flavoxate (p values 0.02 13 trospium chloride: 60 trospium chloride: 0.48 (0.33) to <0.0001) 14 15 Proportion of patients persistent at 1 year: Proportion of patients with mirabegron: 38% MPR ≥0.8 at 1 year: 16 darifenacin: 16% mirabegron: 43% 17 fesoterodine: 24% darifenacin: 29% http://bmjopen.bmj.com/ 18 flavoxate: 8.3% fesoterodine: 35% 19 oxybutynin ER: 17% flavoxate: 24% oxybutynin IR: 12% oxybutynin ER: 31% 20 propiverine: 21% oxybutynin IR: 22% 21 solifenacin: 25% propiverine: 25% 22 tolterodine ER: 21% solifenacin: 35% 23 trospium chloride: 19% tolterodine ER: 32% 24 trospium chloride: 29% 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 2 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Desgagné et al Proportion of patients refilled initial prescription: Not reported Age 4 b 6 (1999) Short-term ; Compared with patients aged <77.5 years, those who were older oxybutynin: 39.3% were less likely to discontinue vs: 7 flavoxate: 36.6% 77.5–83.5 years: RR 0.90, 95% CI 0.85–0.96, p<0.001 8 >83.5 years: RR 0.86, 95% CI 0.81–0.92, p<0.001 9 Long-termc; 10 oxybutynin: 63.9% Medication dose 11 flavoxate: 55.5% Higher quantity of tablets per day (2–4 tablets/day) was associated with increased risk of early discontinuation, compared 12 Proportion of patients discontinuedFor at 3 months: peer review withonly low daily quantity (1 tablet per day) (RR 1.45, 95% CI 1.37– 13 oxybutynin: 78% 1.53, p<0.001) 14 flavoxate: 83% 15 Medication type Proportion of patients discontinued at 6-months: Patients receiving flavoxate had an increased risk of 16 oxybutynin: 89% discontinuation compared with those receiving oxybutynin (RR 17 flavoxate: 94% 1.13, 95% CI 1.05–1.22, http://bmjopen.bmj.com/ p<0.001) 18 19 Proportion of patients switched at 4-years:

20 Patients without renewal of the original claim: 21 oxybutynin: 1.3% 22 flavoxate: 3.1% 23 24 Patients with any number of renewals before switch: oxybutynin: 2.2% on September 29, 2021 by guest. Protected copyright. 25 flavoxate: 5.9% 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 3 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 D'Souza et al Proportion of patients persistent at 1 year (without a gap Proportion of patients with Medication formulation 5 6 (2008) >45 days): MPR ≥0.80 at 1 year: Adherence with IR drugs approximately half that for ER drugs oxybutynin ER: 15.3% oxybutynin ER: 36.1% (OR 0.504, 95% CI 0.306–0.704, p<0.001) 7 oxybutynin IR: 6.5% oxybutynin IR: 14.8% 8 tolterodine ER: 15.0% tolterodine ER: 35.2% Age 9 tolterodine IR: 11.4% tolterodine IR: 23.5% Patients aged ≥65 years were 1.5 times more likely to achieve an 10 overall: 13.2% overall: 30.3% MPR ≥0.80 than patients aged <65 years 11 Proportion of patients not refilled index medication: 12 oxybutynin ER: 39.4% For peer review only 13 oxybutynin IR: 59.3% 14 tolterodine ER: 42.7% 15 tolterodine IR: 46.1% overall: 44.5% 16 17 Median time to discontinuation (days): http://bmjopen.bmj.com/ 18 oxybutynin ER: 34 19 oxybutynin IR: 0 tolterodine IR: 32 20 tolterodine ER: 33 21 overall: 31 22 23 Proportion of patients switched at 1 year: 24 oxybutynin ER: 16.5% oxybutynin IR: 19.4% on September 29, 2021 by guest. Protected copyright. 25 tolterodine IR: 13.7% 26 tolterodine ER: 9.9% 27 overall: 13.3% 28 29 30 31 32 33 34 35 36 37 38 39 40 41 4 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Gomes et al Median time to discontinuation (days): Not reported Medication type 6 6 (2012) oxybutynin: 68 Over the 2-year follow-up, the time to discontinuation was longer tolterodine: 128 with tolterodine than oxybutynin (p<0.0001) 7 8 Proportion of patients persistent at: 9 6 months 10 oxybutynin: 30.6% 11 tolterodine: 42.9%

12 1 year For peer review only 13 oxybutynin: 18.9% 14 tolterodine: 27.3% 15 18 months 16 oxybutynin: 13.1% 17 tolterodine: 18.9% http://bmjopen.bmj.com/ 18 19 2 years: oxybutynin: 9.4% 20 tolterodine: 13.6% 21 22 23 24 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 5 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Gopal et al Over 3 years, 91% of 49,419 episodes of medication Not reported Medication formulation 7 6 (2008) prescription resulted in discontinuation In comparison with the multiple-dosing drug classes at 6 months, both oxybutynin ER (57%, 95% CI 55.1–59.2) and tolterodine ER 7 Cumulative incidence of discontinuation at 6 months, (54%, 95% CI 52.3–57.4) had lower incidences of discontinuation 8 1 year, 2 years and 3 years (unadjusted): 9 Overall: 58.8, 77.2, 87.5, 92.0% Medication type 10 Trospium and tolterodine were associated with the longest 11 Cumulative incidence of discontinuation, at 6 months, median time to discontinuation (5.47 months each), followed by 1 year, 2 years and 3 years (adjusted for age, year of propiverine (5.43 months) and solifenacin (5.0 months). 12 initiation, switch, number ofFor previous drug classes,peer review Terodilineonly and flavoxate had the shortest median time to 13 number of prior episodes and smoking status): discontinuation (4 months each) 14 oxybutynin: 71, 86, 94, 96% 15 oxybutynin ER: 57, 80, 93, 97% tolterodine: 61, 81, 92, 95% 16 tolterodine ER: 54, 76, 91, 97% 17 trospium: 56, 80, 94, 98% http://bmjopen.bmj.com/ 18 propiverine: 61, 84, 95, 98% 19 solifenacin: 53, 91, 98, 99% terodiline: 89, 99%, N/A, N/A 20 flavoxate: 85, 96, 99, 99% 21 22 Median time to discontinuation (months): 23 oxybutynin: 4.67 24 oxybutynin ER: 5.13 tolterodine: 5.47 on September 29, 2021 by guest. Protected copyright. 25 tolterodine ER: 5.37 26 trospium: 5.47 27 propiverine: 5.43 28 solifenacin: 5.00 terodiline: 4.00 29 flavoxate: 4.00 30 overall: 4.76 31 32 Overall switch rate: 15% 33 34 35 36 37 38 39 40 41 6 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Ivanova et al Proportion of patients discontinued at 6 months: 61.0% Not reported Age 8 6 (2014) Patients who discontinued (50.5 years) or switched (52.6 years) Proportion of patients switched at 6 months: 8.0% medication were significantly younger than those who persisted 7 (53.4 years; p<0.001) 8 Proportion of patients persistent at 6 months: 31.0% 9 Increasing age was associated with reduced odds of 10 Proportion of patients discontinued at 6 months: discontinuation (adjusted OR 0.97, 95% CI 0.96–0.97, p<0.0001) 11 oxybutynin: 30.6% tolterodine: 30.5% Gender 12 solifenacin: 24.5% For peer review Beingonly male was associated with greater odds of discontinuation 13 darifenacin: 8.4% (adjusted OR 1.11, 95% CI 1.00–1.23, p=0.0475) 14 trospium: 4.1% 15 fesoterodine: 1.9% Medication type Patients who persisted with medication contained a significantly 16 Mean time to discontinuation: 54.7 days higher proportion of solifenacin users than those in groups who 17 switched or discontinued http://bmjopen.bmj.com/ (30.1% vs 19.7% vs 24.5%, 18 42.7% of patients never refilled their indexed prescription respectively, p<0.001) and a lower proportion of oxybutynin 19 (22.6% vs 29.6% vs 30.6%, respectively, p<0.001)

20 Compared to patients treated with solifenacin, patients were 21 significantly more likely to discontinue when treated with 22 tolterodine (adjusted OR 1.30, 95% CI 1.16–1.45, p<0.0001) or 23 oxybutynin (adjusted OR 1.80, 95% CI1.59–2.03, p<0.0001) 24 Presence of infection on September 29, 2021 by guest. Protected copyright. 25 Patients with UTI were more likely to discontinue compared with 26 those without UTI (adjusted OR 1.31, 95% CI 1.19–1.45, 27 p<0.0001) 28 Financial burden 29 Patients with lower log of baseline OAB-related costs were more 30 likely to discontinue (adjusted OR 0.96, 95% CI 0.94–0.98, 31 p<0.0001) 32 33 34 35 36 37 38 39 40 41 7 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Johnston et al Mean time of continuation at 1 year (days): Mean MPR at 1 year; Age and gender 9 6 (2012) diabetic: 164 diabetic: 0.473 The odds of adherence generally increase with age, and females not diabetic: 146.9 not diabetic: 0.424 had higher odds of adherence than men 7 (p<0.001 difference) (p<0.001 difference) 8 Diabetes 9 Proportion of patients discontinued at 1 year: The diabetes cohort had greater odds of achieving an MPR ≥0.80 10 diabetic: 71.5% (OR 1.215, 95% CI 1.169–1.263, p<0.0001) vs non-diabetes 11 not diabetic: 76.2% cohort during the 12-month evaluation period (p<0.001 difference) 12 For peer review Theonly diabetes cohort had greater odds of ﬁlling a second OAB 13 medication prescription (OR 1.166, 95% CI 1.127–1.205, 14 p<0.0001) vs non-diabetes cohort during the 12-month evaluation 15 period 16 17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 8 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Kalder et al Proportion of patients discontinued at: Not reported Gender 10 6 (2014) 1 year: 74.8% At 3 years, there was a significantly higher risk of discontinuation 2 years: 77.6% in male than female patients (HR 1.14, 95% CI 1.11–1.18, 7 3 years: 87% p<0.001) 8 9 Age 10 Discontinuation was higher in younger patients than older 11 patients: ≤60 years: 89.7% 12 For peer review 61only–70 years: 87.9% 13 71–80 years: 86.8% 14 >80 years: 83.0% 15 Prescriber’s profession 16 Discontinuation rate was higher in patients treated by 17 gynecologists and generalhttp://bmjopen.bmj.com/ practitioners compared with urologists 18 (HR 1.60 [95% CI 1.52–1.67] p<0.001; HR 1.24 [95% CI 1.20– 19 1.29] p<0.001)

20 Side effects 21 A higher risk of discontinuation in patients experiencing side 22 effects: 23 headache: HR 1.27, 95% CI 1.12–1.43, p=0.002 24 stomach upset: HR 1.20, 95% CI 1.12–1.27, p<0.001 glaucoma: HR 1.46, 95% CI 1.16–1.84, p<0.001 on September 29, 2021 by guest. Protected copyright. 25 26 Medication type 27 Patients using propiverine (HR 0.94, 95% CI 0.88–0.99, p=0.022) 28 or solifenacin (HR 0.93, 95% CI 0.87–0.98, p=0.003) had a significantly lower risk of treatment discontinuation compared with 29 oxybutynin. However, the absolute difference was relatively small 30 31 Comorbidities 32 Diabetes, Parkinson’s disease, epilepsy, dementia, and multiple sclerosis was associated with a lowered risk of treatment 33 discontinuation 34 35 A prior diagnosis of migraine was associated with a higher risk of 36 treatment discontinuation 37 38 39 40 41 9 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Kleinman et al Median time until a ≥30-day medication gap: 64 days Proportion of patients with Gender 11 6 (2014) PDC ≤10% at 1 year: 45.4% Compared to the group with PDC ≥80%, the group with PDC Proportion of patients persistent: <80% contained a lower proportion of females (69.5% vs 76.3%, 7 beyond 1 month: 70% Proportion of patients with p=0.006) 8 at 9 months: 10% PDC ≥80% at 1 year: 12.7% 9 at 1 year: 5% Age 10 Compared to those with PDC ≥80%, patients with PDC <80% 11 were younger (mean age: 46.18 years vs 49.79 years, p<0.001)

12 For peer review Raceonly 13 Compared to the group with a PDC ≥80%, the group with PDC 14 <80% contained a lower proportion of White patients (38.6% vs 15 50.0%, p<0.001) and higher proportion of Black and Hispanic patients (6.7% vs 3.7%, p=0.025; 11.6% vs 6.3%, p=0.002) 16 17 Medication co-paymenthttp://bmjopen.bmj.com/ 18 Compared to the group with a PDC ≥80%, those with PDC <80% 19 paid a higher mean medication co-payment ($20.15 vs $14.68, p<0.001) 20 21 Krhut et al Median (SD) time to discontinuation: Not reported Medication type 12 22 (2014) 6.53 (3.84) months Persistence was significantly higher in patients treated with anticholinergic medication with an ER formulation than in patients 23 Proportion of patients persistent at: treated with IR anticholinergics (ER: 7.10 [SD 3.90] months vs 24 3 months: 59.7% IR: 6.18 [SD 3.75] months, p=0.023) 25 6 months: 39.3% on September 29, 2021 by guest. Protected copyright. 26 9 months: 33.6% 27 1 year: 27.2% 28 Manack et al Mean (SD) duration of therapy: Not reported Not reported 13 29 (2011) 201.9 (120.9) days

30 Proportion of patients that: 31 continued OAB medication ≥1 year: 28.9% 32 discontinued OAB medication and did not restartd: 37.5% 33 discontinued and restarted OAB medicatione: 33.5% 34 35 36 37 38 39 40 41 10 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Mauseth et al Proportion of patients persistent at 1 year: Mean MPR at 1 year: 0.62f Age 14 6 (2013) tolterodine: 39.0% Persistence was lowest in the age group 18–39 years (20.9%), solifenacin: 39.4% Proportion of patients with generally increased with age, and was highest in the age groups 7 darifenacin: 34.3% MPR ≥0.80f at 1 year: 70–79 years (43.5%) and ≥80 years (43.3%) 8 fesoterodine: 29.1% tolterodine: 33.7% 9 overall: 38.0% solifenacin: 35.7% Medication type 10 darifenacin: 37.0% At 1 year, persistence was highest for tolterodine (39.0%) and 11 Proportion of patients switched at 1 year: fesoterodine: 38.5% solifenacin (39.4%), both of which entered the market first. tolterodine: 12.0% overall: 35.2% Persistence for darifenacin and fesoterodine, which were 12 overall: 10.3% For peer review launchedonly later, was 34.3% and 29.1%, respectively 13 14 Proportion of patients filled only one prescription: 31.9% 15 Nitti et al Proportion of patients persistent at: Not reported Age 16 (2016)15 1 month; Compared with patients aged <65 years, patients aged ≥65 years 17 mirabegron: 68.4% were less likely to discontinuehttp://bmjopen.bmj.com/ over 6 months with tolterodine 18 tolterodine ER: 47.1% (HR 0.88, 95% CI 0.80–0.96, p=0.0064) and mirabegron (HR 0.68, 95% CI 0.52–0.90, p=0.0068) 19 3 months; 20 mirabegron: 48.7% Prior treatment 21 tolterodine ER: 28.6% Compared to patients without prior use of OAB medication, 22 patients with prior OAB medication use were less likely to 6 months; discontinue over 6 months with tolterodine (HR 0.76, 95% CI 23 mirabegron: 34.7% 0.68–0.85), p<0.0001) and mirabegron (HR 0.68, 95% CI 0.53– 24 tolterodine ER: 18.5% 0.88, p=0.0025) 25 on September 29, 2021 by guest. Protected copyright. 26 Median persistence (days): Medication type mirabegron: 170 The risk of discontinuation was lower with mirabegron compared 27 tolterodine ER: 90 with tolterodine (HR 0.72, 95% CI 0.61–0.85, p<0.0001) 28 g 29 Pelletier et al Not reported Mean cohort PDC at 1 year: 0.32 Demographics (gender, age, comorbidities) (2009)16 Proportion of patients with Female and older subjects were more likely to adhere. Those 30 PDC ≥0.80 at 1 year: 14.4% with a history of hypertension, diabetes, or multiple sclerosis 31 were more adherent. Subjects with COPD were less adherent 32 33 34 35 36 37 38 39 40 41 11 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Perfetto et al Cumulative discontinuation rates at: Not reported Not reported 17 6 (2005) 1 month; tolterodine ER: 6% 7 oxybutynin ER: 11% 8 9 3 months; 10 tolterodine ER: 55% 11 oxybutynin ER: 62%

12 6 months; For peer review only 13 tolterodine ER: 69% 14 oxybutynin ER: 76% 15 11 months; 16 tolterodine ER: 79% 17 oxybutynin ER: 85% http://bmjopen.bmj.com/ 18 19 Overall, at 11 months, 21% of patients remained on tolterodine ER and 15% of patients remained on 20 oxybutynin ER 21 22 Sears et al Proportion of patients without prescription refills over Median MPR at 3 years: Gender (2010)18 3 years: 35.1% oxybutynin 5 mg IR: 0.68 Male patients had a higher median MPR than female patients 23 oxybutynin 5 mg ER: 0.83 (0.86 vs 0.81, p<0.001) 24 Median persistence (days): oxybutynin 10 mg ER: 0.84 25 overall: 273 tolterodine 1 mg IR: 0.71 Medication adherence was on September 29, 2021 by guest. Protected copyright. higher in males than in females 26 patients with at least 1 refill: 582 tolterodine 2 mg IR: 0.73 (0.370 vs 0.328, p<0.001) tolterodine 2 mg ER: 0.88 27 Overall medication persistence duration was 273 days tolterodine 4 mg ER: 0.89 Of patients refilling their prescription at least once, the median 28 when all cases were analyzed and 582 days when those overall: 0.82 number of days persisted was longer in females than in males 29 with at least 1 refill were analyzed (606.0 days vs 547.0 days, p=0.01) 30 Proportion of patients with 31 MPR ≥0.80 at 3 years: 34.0% Medication type Of patients refilling their prescription at least once, median 32 medication persistence was longest in 5 mg oxybutynin IR (634 33 days, 95% CI 596.1–671.9) and lowest with 10 mg oxybutynin ER 34 (504 days, 95% CI 137.0–871.0) 35 36 37 38 39 40 41 12 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Sicras-Mainar Proportion of patients persistent (without switching or Mean MPR at 1 year was: Medication type 19 6 et al (2016) experiencing a gap of >60 days) at: 0.880, 0.877 or 0.875, depending Persistence at 6 months and 1 year was statistically significantly 6 months; upon geographical location higher with fesoterodine than solifenacin and tolterodine 7 fesoterodine: 71.4% (p<0.05). 8 solifenacin: 67.1% 9 tolterodine: 64.8% Persistence at 1 year was significantly lower with solifenacin than 10 fesoterodine (p<0.01) 11 1 year; fesoterodine: 40.2% 12 solifenacin: 34.7% For peer review only 13 tolterodine: 33.6% 14 Sicras-Mainar Proportion of patients persistent at: Mean MPR at 1 year: Not reported 15 et al (2015)f,20 3 months: 86.2% fesoterodine: 0.900 16 6 months: 67.6% solifenacin: 0.870 17 9 months: 48.4% tolterodine: 0.861 http://bmjopen.bmj.com/ 18 1 year: 35.9% overall: 0.877

19 Mean (SD) treatment duration (without stopping, 20 switching or a gap >30 days): 21 fesoterodine: 8.1 22 solifenacin: 7.8 tolterodine: 7.7 23 overall: 7.9 24 25 Sicras-Mainar Proportion of patients persistent (without switching or Mean MPR at 1 year: Medication type on September 29, 2021 by guest. Protected copyright. et al (2014)21 experiencing a gap of >30 days): fesoterodine: 0.907 At 3 months, persistence was higher with fesoterodine than with 26 3 months; solifenacin: 0.935 tolterodine and solifenacin 27 fesoterodine: 94.8% tolterodine: 0.936 28 solifenacin: 76.2% 29 tolterodine: 70.8%

30 6 months; 31 fesoterodine: 70.7% 32 solifenacin: 59.5% 33 tolterodine: 57.1% 34 1 year; 35 fesoterodine: 46.6% 36 solifenacin: 36.5% 37 tolterodine: 33.5% 38 39 40 41 13 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Sicras-Mainar Proportion of patients persistent at 1 year: Mean MPR at 1 year: Medication type g,22 6 et al (2014) fesoterodine: 35.8% fesoterodine: 0.937 The mean duration of treatment was numerically higher with solifenacin: 31.9% solifenacin: 0.948 fesoterodine compared to solifenacin and tolterodine, but no 7 tolterodine: 30.9% tolterodine: 0.935 statistical between-medication differences were found. However, 8 adjusted HRs for remaining on treatment at 1 year significantly 9 favored fesoterodine compared with solifenacin (HR 1.24 [95% 10 CI 1.05–1.47]; p=0.011) and tolterodine (HR 1.28 [95% CI 1.07– 11 1.52]; p=0.006) 12 Sicras-Mainar Mean MPR at 1 year: Medication type et al (2013)g,23 For peerfesoterodine: review 0.945 Theonly mean duration of treatment was numerically higher with 13 solifenacin: 0.954 fesoterodine compared to solifenacin and tolterodine, but no 14 tolterodine: 0.946 statistical between-medication differences were found 15 Suehs et al Proportion of patients not refilling their index medication: Mean PDC at: Medication use appropriateness 16 24

(2016) PIM: 41.4% 3 months; At 1 year, there was no statisticalhttp://bmjopen.bmj.com/ difference between PIM status 17 Non-PIM: 47.8% PIM: 0.62 and OAB treatment discontinuation in the multivariable adjusted 18 (p<0.01) Non-PIM: 0.59 model based on the primary analysis definition (15-day deﬁnition 19 OR 0.977, 95% CI 0.891–1.072, p=0.63; 30-day definition OR 20 Mean number of days persistent (before discontinuation 6 months; 0.939, 95% CI 0.871–1.013, p=0.10) or experiencing a gap >15 days): PIM: 0.45 21 PIM: 87.6 Non-PIM: 0.42 22 Non-PIM: 80.9 23 (p<0.001) 1 year; 24 PIM: 0.32 25 Proportion of patients persistent at: Non-PIM: 0.30 on September 29, 2021 by guest. Protected copyright. 3 months; (all p<0.001 differences) 26 PIM: 23.9% 27 Non-PIM: 20.3% Proportion of patients with 28 PDC ≥0.80: 29 6 months; 3 months; PIM: 13.2% PIM: 37.0% 30 Non-PIM: 11.4% Non-PIM: 35.0% 31 32 1 year; 6 months; 33 PIM: 5.1% PIM: 23.3% 34 Non-PIM: 4.5% Non-PIM: 19.7% (all p<0.001 differences) 35 1 year; 36 PIM: 12.7% 37 Non-PIM: 10.7% 38 (all p<0.001 differences) 39 40 41 14 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Sussman et al Proportion of patients discontinued at 1 year (gap of ≥30 Mean PDC: Medication type 25 6 (2017) days): mirabegron: 0.66 Users of mirabegron appeared to achieve greater persistence mirabegron: 67.1% anticholinergic: 0.55 and adherence at 1 year than users of anticholinergics 7 anticholinergic: 84.1% 8 Proportion of patients with 9 Median time to discontinuation (days): PDC ≥0.80 at 1 year: 10 mirabegron: 131 mirabegron: 43.6% 11 anticholinergic: 30 anticholinergic: 30.9% 12 For peer review only 13 14 15 16 17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 15 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Wagg et al Time (days) to discontinuation (or a gap >1.5 times the Not reported Age 26 6 (2012) length of the previous prescription without a refill): Over 1 year, the majority of patients aged ≥60 years were more darifenacin: 135.9 likely to persist than younger patients. Graphical results only 7 flavoxate: 77.4 8 oxybutynin ER: 146.7 Medication type 9 oxybutynin IR: 119.3 Patients receiving solifenacin spent the longest mean duration on 10 propiverine: 141.1 therapy compared with other OAB medications 11 solifenacin: 158.7 (5 mg); 216.0 (10 mg) tolterodine ER: 156.7 12 tolterodine IR: 151.7 For peer review only 13 trospium: 138.5 14 15 Proportion of patients persistent at 3 months: darifenacin: 52% 16 flavoxate: 28% 17 oxybutynin ER: 44% http://bmjopen.bmj.com/ 18 oxybutynin IR: 40% 19 propiverine: 47% solifenacin: 58% 20 tolterodine ER: 47% 21 tolterodine IR: 46% 22 trospium: 42% 23 24 Proportion of patients persistent at 6 months: darifenacin: 30% on September 29, 2021 by guest. Protected copyright. 25 flavoxate: 16% 26 oxybutynin ER: 35% 27 oxybutynin IR: 29% 28 propiverine: 36% solifenacin: 46% 29 tolterodine ER: 36% 30 tolterodine IR: 33% 31 trospium: 33% 32 Proportion of patients persistent at 1 year: 33 darifenacin: 17.4% 34 flavoxate: 13.5% 35 oxybutynin ER: 26.1% 36 oxybutynin IR: 21.7% 37 propiverine: 26.8% solifenacin: 35% 38 tolterodine ER: 28.2% 39 tolterodine IR: 24.1% 40 trospium: 25.9% 41 16 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Wagg et al Proportion of patients persistent at 1 year (without Median MPR at 1 year: Age 27 6 (2015) switching or experiencing a gap ≥30 days): mirabegron: 0.645 As age increased, median MPR increased for OAB medications: mirabegron: 31.7% fesoterodine: 0.492 <46 years: 0.273 7 fesoterodine: 21.0% oxybutynin ER: 0.328 45–64 years: 0.372 8 oxybutynin ER: 18.9% oxybutynin IR: 0.186 ≥65 years: 0.492 9 oxybutynin IR: 13.8% solifenacin: 0.459 (p<0.001 difference compared to ≥65 years) 10 solifenacin: 22.0% tolterodine ER: 0.454 11 tolterodine ER: 19.7% Treatment status Patients with prior experience of OAB medication use achieved a 12 Median duration of treatmentFor (days): peer review higheronly MPR than treatment-naïve patients (0.546 vs 0.328, 13 mirabegron: 221 p<0.001) 14 solifenacin: 108 15 fesoterodine: 100 Medication type tolterodine ER: 100 Compared with antimuscarinics, patients taking mirabegron 16 oxybutynin ER: 100 demonstrated greater persistence and statistically significantly 17 oxybutynin IR: 75 greater adherence (64.5%http://bmjopen.bmj.com/ vs 18.6%–49.2%, p<0.001) than those 18 taking antimuscarinics 19 Proportion of patients persistent at 1 year: treatment-naïve:19.0% 20 treatment-experienced: 30.0% 21 22 Median days on therapy: 23 treatment-naïve: 90 24 treatment-experienced: 205 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 17 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Wagg et al Proportion of patients persistent at 6 months: ˂40% Not reported Medication type 28 6 (2015) Initial treatment with solifenacin, darifenacin, tolterodine ER and Proportion of patients discontinued at 4 years: tolterodine was associated with a significantly lower risk of 7 oxybutynin: 93% discontinuation compared with oxybutynin as the first medication 8 tolterodine IR: 90% (HRs 0.68, 0.72, 0.77 and 0.84, respectively; p<0.001 vs 9 tolterodine ER: 90% oxybutynin for each) 10 solifenacin: 90% 11 darifenacin: 91% Patients receiving flavoxate as initial treatment had a significantly trospium: 94% higher risk of discontinuation compared with those who received 12 flavoxate: 98% For peer review oxybutyninonly (HR 2.48, p<0.0001) 13 overall: 91.4% 14 There was no statistically significant difference in the risk of 15 Median duration of first-line treatment (days): discontinuation with trospium as first-line compared with oxybutynin: 60 oxybutynin (p=0.1074) 16 tolterodine IR: 90 17 tolterodine ER: 100 Age http://bmjopen.bmj.com/ 18 solifenacin: 106 Compared with patients aged 40–64 years, patients aged <20, 19 darifenacin: 91 20–39, 65–74 and ≥75 years had a higher risk of discontinuation trospium: 90 (HRs 1.08–1.19, all p≤0.0022) 20 flavoxate: 10 21 Gender 22 Males had a slightly higher risk of discontinuation than females 23 (HR 1.03, 95% CI 1.00–1.06, p=0.0341) 24 Yeaw et al Proportion of patients remaining on therapy (without a Proportion of patients with mean Not reported 25 (2009)29 refill gap >60 days) at: MPR at 1 year: 35% on September 29, 2021 by guest. Protected copyright. 26 6 months: 28% 27 1 year: 18% 28 Yu et al Proportion of patients without index prescription refill Mean MPR at: Medication type 30 29 (2005) within the first 6 months: 36.9% 6 months: 0.34 Compared with oxybutynin, patients receiving tolterodine were 1 year: 0.22 less likely to have discontinued at 6 months (HR 0.74, 95% CI 30 Proportion of patients discontinued at: 0.67–0.81, p<0.01) 31 1 month: 42.7% Proportion of patients with MPR 32 2 months: 66.8% ≥0.80 at: Polypharmacy 33 5 months days: 77.6% 6 months: 4.9% The use of multiple drugs was associated with a higher risk of 34 9 months: 86.3% 1 year: 0.7% discontinuation by the 6-month follow up (HR 1.26, 95% CI 1.09– 1.46, p<0.01) 35 At a 1-year follow-up, the rate of discontinuation was 36 increased to 88.6% Other significant predictors of higher persistence included: White 37 ethnicity, previous hospitalization length, and starting treatment 38 with tolterodine 39 40 41 18 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 CI = confidence interval; COPD = chronic obstructive pulmonary disease; ER = extended release; HR = hazard ratio; IR = immediate release; MPR = medication possession ratio; 4 OAB = overactive bladder; OR = odds ratio; PIM = potentially inappropriate medication; PDC = proportion of days covered; RR = risk ratio; SD = standard deviation; UTIs = urinary tract 5 infections 6 *In cases where reported values differ from published values, they were derived from the published data; acohort discontinuation percentages are also quoted for 3, 6, 12 and 18 months. 7 However, these figures included some non-oral OAB medications. Therefore, these have not been included; bwithin 1.5x the duration of the initial prescription; cover a 4-year period; 8 dstopped receiving an OAB medication for ≥6 months between end of therapy and end of the study’s eligibility period; estopped receiving an OAB medication for <6 months before 9 restarting an OAB medication; fpatients who filled only one prescription were given an MPR of zero; gno exact figures were quoted within the article text 10 11 12 For peer review only 13 14 15 16 17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 19 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 58 of 64

Adherence and persistence to OAB medication 1 2 3 References BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 5 6 1. Brostrom S, Hallas J: Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 2009; 65: 309. 7 8 2. Chancellor MB, Migliaccio-Walle K, Bramley TJ et al: Long-term patterns of use and treatment failure 9 with anticholinergic agents for overactive bladder. Clin Ther 2013; 35: 1744. 10 3. Chapple CR, Nazir J, Hakimi Z et al: Persistence and adherence with mirabegron versus antimuscarinic 11 agents in patients with overactive bladder: a retrospective observational study in UK clinical practice. 12 Eur Urol 2017; 72: 389. 13 14 4. Desgagne A, LeLorier J: Incontinence drug utilization patterns in Quebec, Canada. Value Health 1999; 15 2: 452. 16 17 5. D'Souza AO, Smith MJ, Miller LA et al: Persistence, adherence, and switch rates among extended- 18 release and immediateFor-release peer overactive review bladder medications only in a regional managed care plan. J Manag Care Pharm 2008; 14: 291. 19 20 6. Gomes T, Juurlink DN, Mamdani MM: Comparative adherence to oxybutynin or tolterodine among older 21 patients. Eur J Clin Pharmacol 2012; 68: 97. 22 23 7. Gopal M, Haynes K, Bellamy SL et al: Discontinuation rates of anticholinergic medications used for the 24 treatment of lower urinary tract symptoms. Obstet Gynecol 2008; 112: 1311. 25 26 8. Ivanova JI, Hayes-Larson E, Sorg RA et al: Healthcare resource use and costs of privately insured 27 patients who switch, discontinue, or persist on anti-muscarinic therapy for overactive bladder. J Med 28 Econ 2014; 17: 741. 29 9. Johnston S, Janning SW, Haas GP et al: Comparative persistence and adherence to overactive bladder 30 medications in patients with and without diabetes. Int J Clin Pract 2012; 66: 1042. 31 32 10. Kalder M, Pantazis K, Dinas K et al: Discontinuation of treatment using anticholinergic medications in 33 patients with urinary incontinence. Obstet Gynecol 2014; 124: 794. 34 35 11. Kleinman NL, Odell K, Chen CI et al: Persistence and adherence with urinary antispasmodic 36 medications among employees and the impact of adherence on costs and absenteeism. J Manag Care Spec Pharm 2014; 20: 1047.

37 http://bmjopen.bmj.com/ 38 12. Krhut J, Gartner M, Petzel M et al: Persistence with first line anticholinergic medication in treatment- 39 naive overactive bladder patients. Scand J Urol 2014; 48: 79. 40 41 13. Manack A, Motsko SP, Haag-Molkenteller C et al: Epidemiology and healthcare utilization of neurogenic 42 bladder patients in a US claims database. Neurourol Urodyn 2011; 30: 395. 43 44 14. Mauseth SA, Skurtveit S, Spigset O: Adherence, persistence and switch rates for anticholinergic drugs used for overactive bladder in women: data from the Norwegian Prescription Database. Acta Obstet

45 on September 29, 2021 by guest. Protected copyright. 46 Gynecol Scand 2013; 92: 1208. 47 15. Nitti VM, Rovner ES, Franks B et al: Persitence with mirabegron versus tolterodine in patients with 48 overactive bladder. Am J Pharm Benefits 2016; 8: e25. 49 50 16. Pelletier EM, Vats V, Clemens JQ: Pharmacotherapy adherence and costs versus nonpharmacologic 51 management in overactive bladder. Am J Manag Care 2009; 15: S108. 52 53 17. Perfetto EM, Subedi P, Jumadilova Z: Treatment of overactive bladder: a model comparing extended- 54 release formulations of tolterodine and oxybutynin. Am J Manag Care 2005; 11: S150. 55 56 18. Sears CL, Lewis C, Noel K et al: Overactive bladder medication adherence when medication is free to patients. J Urol 2010; 183: 1077. 57 58 19. Sicras-Mainar A, Navarro-Artieda R, Ruiz-Torrejon A et al: Persistence and concomitant medication in 59 patients with overactive bladder treated with antimuscarinic agents in primary care. An observational 60 baseline study. Actas Urol Esp 2016; 40: 96.

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3 20. Sicras-Mainar A, Navarro-Artieda R, Ruiz-Torrejon A et al: Impact of loss of work productivity in patients BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 with overactive bladder treated with antimuscarinics in Spain: study in routine clinical practice 5 conditions. Clin Drug Investig 2015; 35: 795. 6 7 21. Sicras-Mainar A, Rejas-Gutierrez J, Navarro-Artieda R et al: Use of health care resources and associated costs in non-institutionalized vulnerable elders with overactive bladder treated with 8 antimuscarinic agents in the usual medical practice. Actas Urol Esp 2014; 38: 530. 9 10 22. Sicras-Mainar A, Rejas J, Navarro-Artieda R et al: Antimuscarinic persistence patterns in newly treated 11 patients with overactive bladder: a retrospective comparative analysis. Int Urogynecol J 2014; 25: 485. 12 13 23. Sicras-Mainar A, Rejas J, Navarro-Artieda R et al: Health economics perspective of fesoterodine, 14 tolterodine or solifenacin as first-time therapy for overactive bladder syndrome in the primary care 15 setting in Spain. BMC Urol 2013; 13: 51. 16 17 24. Suehs BT, Davis C, Franks B et al: Effect of potentially inappropriate use of antimuscarinic medications on healthcare use and cost in individuals with overactive bladder. J Am Geriatr Soc 2016; 64: 779. 18 For peer review only 19 25. Sussman D, Yehoshua A, Kowalski J et al: Adherence and persistence of mirabegron and 20 anticholinergic therapies in patients with overactive bladder: a real-world claims data analysis. Int J Clin 21 Pract 2017; 71: e12824. 22 23 26. Wagg A, Compion G, Fahey A et al: Persistence with prescribed antimuscarinic therapy for overactive 24 bladder: a UK experience. BJU Int 2012; 110: 1767. 25 26 27. Wagg A, Franks B, Ramos B et al: Persistence and adherence with the new beta-3 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: early experience in Canada. Can Urol Assoc 27 J 2015; 9: 343. 28 29 28. Wagg A, Diles D, Berner T: Treatment patterns for patients on overactive bladder therapy: a 30 retrospective statistical analysis using Canadian claims data. JHEOR 2015; 3: 43. 31 32 29. Yeaw J, Benner JS, Walt JG et al: Comparing adherence and persistence across 6 chronic medication 33 classes. J Manag Care Pharm 2009; 15: 728. 34 35 30. Yu YF, Nichol MB, Yu AP et al: Persistence and adherence of medications for chronic overactive bladder/urinary incontinence in the California Medicaid program. Value Health 2005; 8: 495. 36

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1 2 3 Supplemental Information BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 5 Literature Search Strategies 6 7 The following databases were searched; 8 9 • Allied and Complementary Database [AMED] (via OVID) 10 • Cumulative Index to Nursing and Allied Health Literature [CINAHL] (via EBSCOhost) 11 • MEDLINE (via EBSCOhost) 12 13 • Database of Reviews of Effects [DARE] (via CRD, University of York) 14 • Health Technology Assessment [HTA] (via CRD, University of York) 15 • Centre for Reviews and Dissemination [CRD] (via CRD, University of York) 16 17 The searches were conducted on the 24th April 2017 18 For peer review only 19 The date span of the searches; 20 21 • AMED – 1985 to April 2017 22 • CINAHL – 1937 to April 2017 23 • MEDLINE – 1946 to April 2017 24 25 • DARE / HTA / CRD – 1994 to April 2017 26 27 28 Searches (AMED)* 29 30 persisten* OR adheren* OR complian* OR discont* OR tolera* OR utili* OR 31 1 – 32 database [In Article Title] 33 34 Bladder" OR "Overactive Bladder" OR "OAB" OR urin* OR incontinen* [In 2 – 35 Article Title] 36

37 Oxybutynin OR Tolterodine OR Fesoterodine OR Trospium OR Darifenacin OR http://bmjopen.bmj.com/ 38 39 Solifenacin OR Propiverine OR Imidafenacin OR Mirabegron OR Flavoxate OR 40 3 – Hyoscyamin* OR Anticholinerg* OR Antimuscarin* 41 42 [In Article Title] 43 44 4 (#1 AND #2 OR #3) 18

45 on September 29, 2021 by guest. Protected copyright. 46 Searches (CINAHL & MEDLINE)* 47 persisten* OR adheren* OR complian* OR discont* OR tolera* OR utili* OR 48 5 – 49 database [In Article Title] 50 51 Bladder" OR "Overactive Bladder" OR "OAB" OR urin* OR incontinen* [In 52 6 – Article Title] 53 54 Oxybutynin OR Tolterodine OR Fesoterodine OR Trospium OR Darifenacin OR 55 56 Solifenacin OR Propiverine OR Imidafenacin OR Mirabegron OR Flavoxate OR 57 7 – 58 Hyoscyamin* OR Anticholinerg* OR Antimuscarin* 59 [In Article Title] 60

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1 2 3 8 (#5 AND #6 OR #7) 3,855 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 5 Searches (DARE / HTA / CRD)* 6 7 persisten* OR adheren* OR complian* OR discont* OR tolera* OR utili* OR 9 – 8 database [In Article Title] 9 10 Bladder" OR "Overactive Bladder" OR "OAB" OR urin* OR incontinen* [In 11 10 – 12 Article Title] 13 14 Oxybutynin OR Tolterodine OR Fesoterodine OR Trospium OR Darifenacin OR 15 Solifenacin OR Propiverine OR Imidafenacin OR Mirabegron OR Flavoxate OR 16 11 – 17 Hyoscyamin* OR Anticholinerg* OR Antimuscarin* 18 For peer review only 19 [In Article Title] 20 12 (#9 AND #10 OR #11) 24 21 22 13 Total from #4, #8 and #12 3,897 23 24 14 Remove duplicates from 13 using EndNoteWeb 3,614 25 * Boolean operators were used. No other limits or filters were applied to each database. 26 27 28 29 30 31 32 33 34 35 36

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page # page Reported on on Reported Suppl. Tables 1 Suppl. and N/A* N/A* 7, 8 7, 8 6, 7 6, 7 6, 7 6, 7 6, Suppl.Info 6, Suppl.Info 5, 6 5, 6 6 5 5 4, 5 4, 5 2 1 up) report up) characteristics and (e.g., years BMJ Open http://bmjopen.bmj.com/ analysis). analysis). -

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For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml provide registration provide information including registration number. State the State principal summarymeasures (e.g., risk ratio,means). difference in Describe methods Describe used for assessing risk studies of of bias individual (including specification of this whether atwasdone the study or outcomeand how this level), information to is be used datainsynthesis. any List and define List variables all for data which sought were (e.g., PICOS,fundingsources) any assumptionsand simplifications and made. Describe method Describe of dataextraction from reports(e.g., forms, piloted inindependently, duplicate) and any processesfor and obtaining confirming from data investigators. State the State process for studies selecting (i.e., screening, eligibility, includedin systematic and,if review, applicable,included the in meta Present full electronicPresent search strategyfor least one at database, including limits any used, such that it could repeated. be Describe all Describe information sources databases (e.g., of with dates coverage, contact study with authors to identify studies) additional in the search and datelast searched. Specify study Specify characteristics PICOS, (e.g., length of follow - Indicate Indicate review if a protocolexists, if canand it where Webaccessed (e.g.,be address), and, if available, Provide anProvide statement explicit of questions being addressedwithreference to participants, interventions, comparisons,outcomes, study design and (PICOS). Describe the Describe rationale for review inthe the context of what already is known. Provide a structured a Provide summary including, asapplicable: background; objectives;datasources; study eligibility criteria, participants,and interventions;study appraisal synthesis and methods; results; limitations; conclusionsand implications findings; key of systematic registration review number. Identify the Identify report systematic asa meta-analysis, review, both.or Checklist item item Checklist considered, language, publicationstatus) used ascriteria for eligibility, giving rationale.

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Summarymeasures 13 Riskindividual in of bias studies Data Data items Data collection Data process 10 Study selection Study Search Search Information sourcesInformation Eligibility criteria Eligibility Protocol and registrationProtocol 5 METHODS METHODS Objectives Objectives Rationale Rationale INTRODUCTION INTRODUCTION Structuredsummary ABSTRACT ABSTRACT Title Title TITLE TITLE Section/topic Section/topic 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

2 2 2 2 page # page Reported on on Reported 14, 15 15 14, 14 14 13 13 14 14 N/A N/A N/A* N/A* N/A N/A Suppl. Tables 1 Suppl. and N/A N/A N/A* N/A* Suppl. Tables 1 Suppl. and 7, 26 7, 26 N/A N/A N/A* N/A*

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For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Describe sources Describe of funding for systematic the review support and (e.g., other supply of data); role of funders forsystematic the review. Provide a a Provide general interpretationof the results thecontext in of other evidence, and implications for future research. Discussstudy limitations at and outcome(e.g., level risk review-level ofand at bias), (e.g., incomplete retrievalof identifiedresearch, reporting bias). Summarizethe main findings the strengthincluding ofevidencefor main each outcome; their consider key relevanceto groups (e.g., healthcare providers, makers).users, and policy Give results ofresults Give additional analyses, if (e.g.,done sensitivity subgroupor analyses, meta-regression Item [see 16]). Present results Present of any assessmentof risk across of (see Itembias studies 15). Present results Present of each meta-analysis done, including confidence intervalsand measures of consistency. For all outcomes Forall considered(benefits harms),or for study: each present, (a) simple summary datafor each groupintervention (b) effectestimates confidence and intervals, forest ideally witha plot. Present Present dataon risk of ofstudy and, each bias ifavailable, outcome any assessmentlevel (see item 12). For each study, Foreach present characteristics for which data extracted were (e.g., study PICOS,follow-upsize, period)and provide the citations. Give numbersGive screened,of studies assessed for eligibility, and includedin the review, reasons with for exclusions each at stage, ideally flowdiagram. with a Describe methods Describe of additional analyses (e.g., sensitivity subgroupor analyses, meta-regression),if done, Specify Specify assessment any riskofthat may bias cumulative affectof evidence(e.g., the publication bias, reporting selective withinstudies). Checklist item item Checklist indicating indicating which were pre Describe the Describe methods of handling dataand combining ofresults studies, if done, includingmeasures of (e.g., consistency I

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N/A, not applicable not N/A, Funding Funding FUNDING FUNDING Conclusions Limitations Summaryof evidence 24 DISCUSSION DISCUSSION Riskacross of bias studies 22 Synthesisof results Results of Results individual studies 20 Riskstudies within of bias 19 Study characteristics Study 18 Study selection Study RESULTS RESULTS Riskacross of bias studies 15 Section/topic Section/topic Synthesisof results Additional Additional analysis Additional Additional analyses 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 63 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from Page 64 of

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For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml PRISMA2009 Checklist PRISMA2009 Checklist PRISMA2009 Checklist PRISMA2009 Checklist Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. A risk of bias tool for database studies is not available not studiesis for database tool bias risk * of A From: doi:10.1371/journal.pmed1000097 doi:10.1371/journal.pmed1000097 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB) – a systematic literature review

ForJournal: peerBMJ Open review only Manuscript ID bmjopen2018021889.R1

Article Type: Research

Date Submitted by the Author: 12Jun2018

Primary Subject Urology Heading:

Secondary Subject Heading: Urology

Overactive bladder, persistence, adherence, antimuscarinics, β3 adrenergic Keywords: http://bmjopen.bmj.com/ receptor agonists, systematic literature review

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Adherence and persistence to OAB medication 1 2 3 Real-world persistence and adherence to oral antimuscarinics and 4 5 6 mirabegron in patients with overactive bladder (OAB) – a 7 8 systematic literature review 9 10 11 12 13 1 1 2 3* 2 14 Gillian Yeowell , Philip Smith , Jameel Nazir , Zalmai Hakimi , Emad Siddiqui , Francis 15 1 16 Fatoye For peer review only 17 18 19 20 21 1Manchester Metropolitan University, Manchester, UK 22

23 2 24 Astellas Pharma Europe Ltd., Chertsey, UK 25 26 3Astellas Pharma Europe B.V., Leiden, the Netherlands 27 28 *An employee of Astellas Pharma Inc. when the research was conducted 29 30 31 Correspondence: 32

33 Gillian Yeowell http://bmjopen.bmj.com/ 34 Health Professions Department (Physiotherapy) 35 36 Birley Building 37 Birley Fields Campus 38 39 53 Bonsall Street 40 Manchester M15 6GX

Adherence and persistence to OAB medication 1 2 3 ABSTRACT 4 5 Purpose To evaluate persistence and adherence of oral pharmacotherapy used in the 6 7 treatment of overactive bladder (OAB) in a realworld setting. 8 9 10 Materials and Methods Systematic literature searches of six electronic publication 11 12 databases were performed to identify observational studies of OAB patients treated with 13 14 antimuscarinics and/or mirabegron. Studies obtaining persistence and adherence data from 15 16 sources other thanFor electronic peer prescription review claims were excluded. only Reference lists of identified 17 18 studies and relevant systematic reviews were assessed to identify additional relevant 19 20 studies. 21 22 23 Results The search identified 3897 studies, of which 30 were included. Overall, persistence 24 25 ranged from 5–47%. In studies reporting data for antimuscarinics and mirabegron (n=3), 1 26 27 year persistence was 12–25% and 32–38%, respectively. Median time to discontinuation 28 29 was ˂5 months for antimuscarinics (except one study [6.5 months]) and 5.6–7.4 months for 30 31 mirabegron. The proportion of patients adherent at 1 year varied between 15–44%. In 32

33 studies reporting adherence for antimuscarinics and mirabegron, adherence was higher with http://bmjopen.bmj.com/ 34 35 mirabegron (mean medication possession ratio (MPR): 0.59 vs 0.41–0.53; mean proportion 36 37 of days covered: 0.66 vs 0.55; and median MPR: 0.65 vs 0.19–0.49). Reported determinants 38 39 of persistence and adherence included female gender, older age group, use of extended 40

41 release formulation and treatment experience. on September 29, 2021 by guest. Protected copyright. 42 43 44 Conclusion Most patients with OAB discontinued oral OAB pharmacotherapy and were 45 46 nonadherent 1 year after treatment initiation. In general, mirabegron was associated with 47 48 greater persistence and adherence compared to antimuscarinics. Combined with existing 49 50 clinical trial evidence, this realworld review merits consideration of mirabegron for firstline 51 52 pharmacological treatment among patients with OAB. 53 54 55 The protocol for this systemic review is registered with PROSPERO: CRD42017059894 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 STRENGTHS AND LIMITATIONS 4 5 • This systematic literature review includes data for mirabegron, which was approved in 6 7 2013 and not covered in previous systematic reviews examining persistence and 8 9 adherence to overactive bladder medication (OAB). 10 11 12 • Only observational database studies were included in this study, with the intention to 13 14 provide a more accurate picture of rates of adherence and persistence to OAB 15 16 medication, whichFor are generallypeer lower review in routine clinical practiceonly compared to 17 18 randomized clinical trials. 19 20 21 • This systematic literature review provides a global picture of adherence and persistence 22 23 to OAB medication based on the inclusion of data from Canada, Czech Republic, 24 25 Denmark, Germany, Norway, Spain, the United Kingdom and the United States. 26 27 28 • Although determinants of persistence and adherence were evaluated in this study, the 29 30 influence of other factors such as patient expectations, appropriate counselling and 31 32 patient satisfaction with treatment could not be assessed.

33 http://bmjopen.bmj.com/ 34 35 • The definitions and calculations of persistence and adherence were not uniform across 36 37 the literature. These terms were often used interchangeably, limiting the ability to 38 39 compare across studies. 40

41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

41 OAB, and pharmacotherapy is recommended only if conservative management is not on September 29, 2021 by guest. Protected copyright. 42 43 effective.10 As OAB is a chronic condition, it is important that patients continue with treatment 44 45 to control symptoms.11 Lack of persistence (time from treatment initiation to 46 47 discontinuation),12 and adherence (extent to which a patient acts in accordance with the 48 49 prescribed interval and dose of a dosing regimen)12 to medication are considered the leading 50 51 causes of preventable morbidity in patients with chronic conditions;13 14 they are also 52 53 associated with greater indirect costs.14 Studies have reported that patients compliant and 54 55 adherent to OAB medication experienced significantly improved urinary symptoms and 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 15 16 3 HRQoL compared with patients who were nonpersistent . Although antimuscarinics are 4 5 the current mainstay of oral pharmacotherapy, they are often associated with bothersome 6 7 anticholinergic side effects, such as dry mouth and constipation; tolerability is one of the 8 11 1720 9 most common reasons for treatment discontinuation. In a systematic review of 10 11 antimuscarinic treatment in patients with OAB, rates of discontinuation at 12 weeks ranged 12 19 13 from 4–31% in clinical trials and 43–83% in medical claims databases. 14 15 16 The other classFor of oral peerpharmacotherapy review approved for theonly treatment of OAB is 17 18 β3adrenergic receptor agonists. Mirabegron is currently the only commercially available

19 2123 20 agent of this class licensed in countries across Europe, North America and Asia. Due to 21 22 mirabegron’s mechanism of action, the incidence of side effects typically reported with

23 24 24 antimuscarinic treatment are low with mirabegron and generally similar to placebo, which

25 25 26 26 may translate into better treatment persistence. In addition, results of a recent economic 27 analysis found that increased persistence with mirabegron treatment vs antimuscarinics was 28 29 associated with reduced healthcare resource use and work hours lost, resulting in lower total 30 31 costs.27 32

33 http://bmjopen.bmj.com/ 34 In general, rates of persistence and adherence with antimuscarinics and mirabegron are 35 36 typically lower in routine clinical practice compared to interventional clinical trials.11 28 To help 37 38 identify factors affecting longterm persistence and adherence to OAB pharmacotherapy, a 39 40 contemporary, comprehensive review of realworld evidence is needed. As mirabegron was

41 on September 29, 2021 by guest. Protected copyright. 42 a relatively new OAB treatment, it was not included in previous systematic reviews. 43 44 Therefore, the current analysis aims to systematically review prospective and retrospective 45 46 observational database studies conducted with antimuscarinics and/or mirabegron to 47 48 determine the rates and determinants of persistence and adherence. 49 50 51 METHODS 52 53 54 This systematic literature review (SLR) was conducted in accordance with guidelines for the 55 29 56 Metaanalysis of Observational Studies in Epidemiology (MOOSE) . The protocol for the 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 review was registered a priori with the International Prospective Register of Systematic 4 5 Reviews (registered January 18, 2017 with PROSPERO CRD42017059894). 6 7 8 Searches were performed April 27, 2017 via the following electronic databases: Allied 9 10 and Complementary Medicine Database (AMED); Cumulative Index to Nursing and Allied 11 12 Health Literature (CINAHL); MEDLINE; Database of Abstracts of Reviews of Effects (DARE); 13 14 Health Technology Assessment (HTA) database; and the Centre for Reviews and 15 16 Dissemination (CRD)For database. peer The search review terms were persisten* only OR adheren* OR 17 18 complian* OR discont* OR tolera* OR utili* OR database [Title], AND "bladder" OR 19 20 "overactive bladder" OR "OAB" OR urin* OR incontinen* [Title], OR oxybutynin OR 21 22 tolterodine OR fesoterodine OR trospium OR darifenacin OR solifenacin OR propiverine OR 23 24 imidafenacin OR mirabegron OR flavoxate OR hyoscyamin* OR anticholinerg* OR 25 26 antimuscarin* [Title]. 27 28 All search results were exported into EndNote Web (Thomas Reuter, CA, USA) 29 30 bibliography software and duplicates removed electronically and manually. The full electronic 31 32 search strategy is outlined in the Supplemental information.

33 http://bmjopen.bmj.com/ 34 35 Patient and public involvement 36 37 38 Patients and or the public were not involved in this study. 39 40

41 Inclusion and exclusion criteria on September 29, 2021 by guest. Protected copyright. 42 43 Inclusion criteria were: prospective and retrospective observational database studies 44 45 investigating persistence and adherence to oral medication for the treatment of OAB in 46 47 adults, conducted in any geographical location and published on any date, within a peer 48 49 reviewed source. Exclusion criteria were: abstract unavailable; studies not yet fully 50 51 completed; randomised controlled trials (RCTs); systematic reviews; narrative literature 52 53 reviews; conference papers; single case studies/reports; studies investigating OAB 54 55 medication among only healthy, asymptomatic participants; studies from which oralonly 56 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 OAB persistence/adherence results cannot be isolated from other results (ie, transdermal 4 5 patches); and studies containing patients aged <18 years (where the data pertaining to 6 7 these patients could not be removed from the results) and studies not published in English. 8 9 Populations with lower urinary tract symptoms due to stress incontinence and benign 10 11 prostatic hyperplasia were also excluded. 12 13 14 Study selection 15 16 Duplicates wereFor removed andpeer title and abstractreview screenings wereonly performed by two 17 18 independent researchers (PS and GY). Fulltext articles were obtained and studies were 19 30 20 excluded if they did not meet the inclusion criteria. Any disagreement in study selection 21 22 was to be resolved through discussion and consultation with another member of the project 23 24 team (FF) where necessary. During screening, openlabel extension studies of RCTs were 25 26 excluded as the trial designs were unlikely to reflect a realworld setting. Studies utilising 27 28 data from hospital records, in addition to largescale databases, were included provided that 29 30 persistence and adherence data were determined from prescription claims data rather than 31 32 extracted from supplemental patient interviews, patientsupplied pill counts or subjective

33 http://bmjopen.bmj.com/ 34 questionnaires. The literature search was supplemented by screening for potential additional 35 36 relevant studies identified from the reference lists of eligible articles. 37 38 39 Data extraction 40

41 Parameters that may affect persistence or adherence were collected, including patient on September 29, 2021 by guest. Protected copyright. 42 43 characteristics (age and sex); interventions (initial [index] OAB drug and formulation) and 44 45 comorbidities. The definitions, outcomes and determinants of treatment persistence and 46 47 adherence were also collected, where reported. The extracted data were evaluated by one 48 49 researcher and verified by a second researcher. 50 51 52 Data analysis 53 54 A descriptive analysis of extracted results is presented. No metaanalysis was planned due 55 56 to the expected heterogeneity of reporting methodologies and data across studies. 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 RESULTS 4 5 6 Brief overview of studies 7 8 Overall, 3897 articles were identified from the literature search; 3,614 were screened for 9 10 title/abstract and 75 were assessed for eligibility (figure 1). Thirty articles were included in 11 12 the SLR (supplementary table 1), including three identified from reference lists.3133 The 13 14 articles described the findings of 28 independent studies. There was nil disagreement 15 16 between the twoFor independent peer researchers review (PS, GY) during theonly screening process. 17 18 19 The data were collected from patients treated in Europe (12 studies) and North America 20 21 (18 studies) (supplementary table 1) and were included in the analysis. The number of 22 23 participants included in the published studies ranged from 377 to 103 250. Where stated, the 24 25 mean age of the participants ranged from 44 to 80 years and the duration of followup 26 27 ranged from 6 months to 7 years. Prescribed antimuscarinic interventions for patients with 28 29 OAB included darifenacin, fesoterodine, flavoxate, hyoscyamine, imipramine, oxybutynin, 30 31 propiverine, solifenacin, tolterodine and trospium chloride. Mirabegron was prescribed in four 32 18 31 32 34

33 studies. Uncommon oral interventions included imipramine, a tricyclic anti http://bmjopen.bmj.com/ 34 35 35 depressant with an unknown mechanism of action in the context of OAB, and bethanechol, 36 33 37 a muscarinic receptor agonist. The methods used to quantify adherence and persistence 38 39 differed across the studies (supplementary table 1). In general, medication possession rate 40 (MPR) or proportion of days covered (PDC) by prescription were typically used as a 41 on September 29, 2021 by guest. Protected copyright. 42 43 measure of adherence to a drug. Persistence was typically defined as the proportion of 44 45 patients continuing therapy/refilling prescriptions for the followup period (without 46 47 discontinuing the index drug or switching to other OAB drug[s]) and/or the median time to 48 49 discontinuation (TTD). 50 51 52 Persistence 53 54 Overall, persistence rates decreased over time, regardless of agent (supplementary table 2). 55 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Antimuscarinic studies 4 5 Data for persistence (or discontinuation) at approximately 6 months was available in 14 6 7 articles32 33 3647 which reported data on antimuscarinics only. Yeaw 2009 was an exception 8 9 due to the inclusion of bethanechol (a muscarinic receptor agonist), which accounted for 10 11 ˂1.5% of the pharmacy claims for OAB medications.33 The proportion of patients persistent 12 13 at 6 months was <50% except for the studies of SicrasMainar et al,4244 where persistence 14 15 ranged from 57–71%. In addition, two studies reported discontinuation rates of 6–43% after 16 For peer41 47 review only 17 1 month of initial treatment. 18 19 20 At 1 year, persistence rates for antimuscarinics across 19 studies ranged from around 21 18 26 3436 38 40 42 43 45 46 4853 22 5% up to 47%. Median TTD was ˂5 months (30 to 128 days) for all 23 18 26 32 34 38 48 54 40 24 medications across all studies, with the exception of Krhut et al (6.5 months). 25 36 38 50 54 55 26 At 2 years, over 75% of patients discontinued treatment. Rates of treatment 27 32 37 39 48 52 28 switching were infrequently reported, and where provided, were ≤17% of patients. 29 54 55 30 31 32 Antimuscarinic and mirabegron studies 33 http://bmjopen.bmj.com/ 34 35 In all four studies, a greater proportion of patients persisted with mirabegron compared with 36 37 antimuscarinics. In one study, persistence rates for tolterodine and mirabegron at 6 months 38 31 39 were 19% and 35%, respectively. Persistence at 1 year ranged from 8–25% for 40 18 26 34

41 antimuscarinics and from 32–38% for mirabegron, as reported in three studies. Where on September 29, 2021 by guest. Protected copyright. 42 43 tested inferentially, 1year persistence was statistically significantly greater with mirabegron 44 18 45 compared to antimuscarinics (p <0.0001), with the exception of oxybutynin (p = 0.002). The 46 47 risk of discontinuing within 1 year was also greater with antimuscarinics compared to 48 18 32 49 mirabegron (p <0.001). Overall, mirabegron, solifenacin and fesoterodine were 50 18 26 51 associated with the highest rates of persistence. 52 53 54 Across the four studies, 40–81% and 83–96% of the mirabegron and antimuscarinic patient 55 56 cohorts were treatment naïve, having received no OAB drug for at least 6 months prior to 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 18 31 32 34 3 their first index of OAB treatment. Studies typically found that treatmentnaive 4 5 patients prescribed mirabegron or antimuscarinics had lower persistence than treatment 6 7 experienced patients prescribed the same OAB treatments. In the three studies that 8 9 assessed persistence in treatmentexperienced and treatmentnaïve populations, 10 11 persistence was higher with mirabegron treatment (significantly in two studies) compared 12 18 31 32 13 with antimuscarinics. 14 15 16 Median TTDFor in the overall peer study populations review was longer onlywith mirabegron (5.6–7.4 17 18 26 31 34 18 months) compared with the assessed antimuscarinics (1.0–3.6 months). 19 20 21 Adherence 22 23 Adherence rates to all OAB medications reduced over time in all studies and varied across 24 25 studies (supplementary table 2). 26 27 28 Antimuscarinic studies 29 30 At 1 year, the proportion of adherent patients varied between 1%47 and 36%,48 across those 31 32 studies that provided these data. Few studies reported adherence beyond 1 year. However,

33 http://bmjopen.bmj.com/ 56 34 Sears et al reported that 34% of patients were adherent at the end of 3 years, which was 35 48 52 36 comparable to the adherence rates reported by some other studies at just 1 year. 37 38 39 Antimuscarinic and mirabegron studies 40

41 In the three studies, adherence at 1 year was significantly higher in patients receiving on September 29, 2021 by guest. Protected copyright. 42 43 mirabegron compared with antimuscarinics (mean MPR: 0.59 vs 0.41 to 0.53; mean PDC: 44 45 0.66 vs 0.55; and median MPR: 0.65 vs 0.19 to 0.49).18 26 34 The proportion of patients 46 47 adherent at 1 year was also greater with mirabegron compared with antimuscarinics (mean 48 49 MPR ≥0.80: 43% vs 22–35%; mean PDC ≥0.80: 44% vs 31%).18 26 Within treatmentnaïve 50 51 patients specifically, adherence was greater with mirabegron compared to antimuscarinics 52 18 53 0.59 vs. 0.39–0.51, p values 0.02 to <0.0001). 54 55 56 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Determinants of persistence and adherence 4 5 Determinants of persistence and adherence were reported in 24 of the 30 studies. As 6 7 expected, most studies reported medication type as a determinant of persistence/adherence 8 9 (figure 2; supplementary table 2). In general, persistence and adherence were higher in: 10 11 older patients compared with younger patients;26 31 32 3539 46 4850 52 54 57 female patients 12 13 compared with their male counterparts,32 35 36 39 49 50 57 except in one study;56 patients 14 15 receiving extendedrelease (ER) formulations compared with immediaterelease 16 48 54For peer review only 17 formulations; and treated patients compared to treatment naïve patients (or untreated in 18 19 the preindex period [6 months or 1 year]).18 26 36 Comorbidities, including diabetes, 20 21 Parkinson’s disease, epilepsy, dementia, multiple sclerosis and hypertension, were 22 49 50 57 23 correlated with increased treatment persistence and adherence; exceptions were 24 50 57 25 chronic obstructive pulmonary disease and migraine. 26 27 28 Other reported determinants of favorable persistence and adherence included higher 29 36 37 30 treatment doses; low daily quantity of tablets, absence of UTI; higher baseline OAB 31 39 32 costs; treatment by urologists vs gynecologists/general practitioners; the absence of side

33 http://bmjopen.bmj.com/ 50 34 effects (headache, stomach upset and glaucoma); White vs Black, Hispanic and Asian 35 35 47 35 36 patients and patients of other ethnicities; lower medication copayment; and use of

37 47 38 fewer medications. 39 40 DISCUSSION 41 on September 29, 2021 by guest. Protected copyright. 42 43 This systematic review provides an overview of persistence and adherence with oral 44 45 pharmacotherapies used to treat patients with OAB in reallife clinical practice. A wealth of 46 47 data were collected from 30 articles, which described 28 observational studies performed in 48 49 Europe and North America totaling over 500 000 patients. A number of key findings were 50 51 identified, including greater persistence and adherence with mirabegron vs 52 53 antimuscarinics,18 26 31 34 in females vs males,32 35 39 49 57 in older vs younger patients,26 31 32 35 54 55 39 46 4850 52 54 57 and in previously treated vs untreated patients.18 26 36 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Across the studies, persistence appeared to reduce very quickly after initiation of 4 31 41 47 5 treatment for all OAB therapies, with low rates (<50%) already evident at 1 month. 6 7 Longer followup periods showed that large proportions of patients discontinued treatment by 8 18 26 33 38 4547 49 50 54 9 1 year (62–100%) and by the end of 3 years, less than 10% of patients 10 54 11 continued on any antimuscarinic. These steep reductions in rates of persistence over time 12 13 were mirrored by the reported adherence rates. 14 15 16 The chronic Fornature of OABpeer means that review consistent and longterm only use of medication is 17 18 essential to manage OAB symptoms and improve health outcomes. It is therefore important 19 20 for patients to receive a firstline treatment that has a good efficacytolerability profile and 21 22 evidence of favorable persistence and adherence vs other treatment options. Among the 23 24 antimuscarinics, solifenacin and fesoterodine were generally associated with better

25 18 26 43 52 26 persistence and adherence. In studies that assessed both mirabegron and 27 antimuscarinics, persistence in the mirabegron cohorts, including the treatmentnaïve 28 29 populations, was statistically significantly greater (p˂0.001).18 26 31 Due to the recommended 30 31 treatment sequence for OAB 10 58, the majority of patients that receive mirabegron are 32

33 http://bmjopen.bmj.com/ treatmentexperienced; however, these studies suggest a benefit of mirabegron treatment 34 35 regardless of treatment status. Adherence to mirabegron was also greater; however, 36 37 mean/median MPR values in the overall mirabegron populations did not indicate medication 38 39 adherence (MPR/PDC˂0.80). Although these studies did not directly assess the reason(s) 40

41 for the observed benefits of mirabegron, proposed reasons include a distinct mechanism of on September 29, 2021 by guest. Protected copyright. 42 43 action, lower rates of bothersome anticholinergic adverse events, particularly drymouth, 44 45 compared with antimuscarinics and unmet expectations of antimuscarinic treatment.18 26 31 46 47 48 It is well established that poor medication persistence and adherence reduces the ability 49 50 to achieve optimum clinical benefits and limits treatment success, especially for chronic 51 52 conditions such as OAB.13 14 17 46 The unwillingness of patients to continue to take longterm 53 54 treatment has been observed across many chronic conditions, with nonadherence to 55 56 medication observed in ~50% of patients.13 An analysis across six chronic conditions found 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 1year persistence and adherence rates to be low for all conditions, and lowest for OAB 4 33 5 medications (antimuscarinics), suggesting an unmet treatment need. However, this study 6 7 was performed prior to the availability of mirabegron for use in routine clinical practice, and 8 9 therefore an updated analysis of persistence in chronic conditions might be warranted. 10 11 12 As alluded to above, persistence and adherence to treatment is expected to improve 13 14 outcomes for patients with OAB. In two studies, better OAB treatment persistence and 15 16 adherence wereFor associated peer with improved review clinical outcomes only and HRQoL compared with 17 15 16 18 patients who were nonpersistent. These data are consistent with studies describing 19 20 other chronic diseases, such as diabetes and depression, where good adherence resulted in

21 14 59 22 improved health outcomes as well as reduced complications and disability, and improved

23 60 24 HRQoL and life expectancy. Moreover, greater persistence and adherence to treatment for 25 26 OAB is associated with significantly lower medical, sick leave and shortterm disability 27 costs.35 Indeed, economic models based on realworld inputs suggest that improved 28 29 persistence with mirabegron translates into benefits of reduced healthcare resource use, and 30 31 lower direct and indirect costs of treatment compared with antimuscarinics.27 61 Additionally, 32

33 http://bmjopen.bmj.com/ mirabegron is reported to be cost effective vs six antimuscarinics from commercial and 34 35 Medicare perspectives in the United States, due to fewer projected adverse events and 36 37 comorbidities, and data suggesting better persistence.62 38 39 40 Independent variables for treatment discontinuation were studied by at least half of the

41 on September 29, 2021 by guest. Protected copyright. 42 papers included in our literature review, of which sex, age, comorbidities and previous 43 44 experience of OAB medications were shown to be important factors in more than two 45 46 studies. Only six studies reported switchrates and although these were low, the treatment 47 48 strategy of cycling antimuscarinic agents in patients who do not achieve symptom relief is 49 50 common in clinical practice. Yet recent analysis of realworld data suggests that switching 51 52 antimuscarinics may provide suboptimal care.55 In contrast, switching to mirabegron from 53 54 antimuscarinic therapy has proved beneficial in over 50% of patients with OAB in an 55 56 observational study.63 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 This review represents a large pooled analysis of realworld data for persistence and 4 5 adherence to oral OAB medication across different geographical locations (Canada, Czech 6 7 Republic, Denmark, Germany, Norway, Spain, the United Kingdom and the United States); 8 9 however, there were no identifiable trends between data and countries. The definitions and 10 11 calculations of persistence and adherence were not uniform across the literature and the 12 13 terms were often used interchangeably. This lack of consistency led to some limitations on 14 15 the ability to compare across studies. Other limitations to performing crossstudy 16 For peer review only 17 comparisons or pooled analyses in this SLR include differences in the individual study 18 19 populations and/or study designs, resulting in considerable variations between data. For 20 21 example, the median TTD for oxybutynin ER and tolterodine ER were determined to be 5.1

22 54 23 and 5.5 months, respectively, by one study, but only 60 and 56 days, respectively, by

24 18 25 another study. 26 27 Furthermore, it is very difficult to capture the specific reasons for treatment 28 29 discontinuation from prescriptiondriven or medical claim data rather than patientderived 30 31 data.18 The current review excluded data from RCTs to better reflect patient behavior in the 32

33 http://bmjopen.bmj.com/ general OAB population in reallife clinical practice.11 Only one paper included in our review 34 35 reported that antimuscarinic side effects were significantly associated with discontinuation,50 36 37 despite reports that such side effects are bothersome and a common reason for 38 39 discontinuation of antimuscarinic treatment.11 19 28 Additional factors that could not be 40

41 assessed by our study, but can influence persistence with treatment in OAB patients are on September 29, 2021 by guest. Protected copyright. 42 43 patient expectations, appropriate counselling and patient satisfaction with treatment.11 17 28 44 45 46 In addition to the limitations listed above, it should be noted that SicrasMainar et al42 43 47 48 reported data on the same patients (in terms of demographics and the 49 50 timeframe/geographical source). This is also the case for two studies published by Sicras 51 52 Mainar et al in 2013 and 2014.53 64 Also, this SLR excluded data on nonoral 53 54 pharmacotherapies (eg, onabotulinum toxin A) and combination mirabegron plus 55 56 antimuscarinic therapies, where additional efficacy has been reported compared to the 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 65 3 monotherapies. Further research on persistence and adherence to these OAB therapies is 4 5 needed to better evaluate current treatment options. Additional studies are also required to 6 7 improve our understanding of persistence and adherence in OAB, including qualitative 8 9 studies to examine the reasons for discontinuation and realworld studies to examine 10 11 resource use associated with OAB medication in relation to adherence and persistence. As 12 13 OAB is a chronic disease, clinicians should not only take into consideration the efficacy and 14 15 side effects of an agent when deciding on treatment options, but also ensure that realistic 16 For peer review only 17 patient expectations from treatment are set through patient education and counselling. The 18 19 patient’s lifestyle should also be considered as this is likely to impact adherence and 20 21 persistence with OAB therapy. 22 23 24 CONCLUSIONS 25 26 Persistence and adherence were greater with mirabegron compared with antimuscarinics, 27 28 and appeared to be greater with solifenacin and fesoterodine compared with other 29 30 antimuscarinics. In addition, greater persistence and adherence were generally observed in 31 32 patients who were female, older, treatmentexperienced and receiving ER formulations.

33 http://bmjopen.bmj.com/ 34 Together with the efficacy and tolerability data from clinical trials, realworld data examined 35 36 in this review warrants consideration of using mirabegron as firstline oral pharmacotherapy 37 38 for patients with OAB. 39 40

41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 Acknowledgments 4 5 6 Medical writing support was provided by Claire Chinn, PhD, and Kinnari Patel, PhD, of 7 8 Bioscript Medical and funded by Astellas Pharma Global Development. 9 10 11 Contributorship Statement 12 13 14 GY, PS, JN, ZH, ES and FF were involved in conceptualisation and design of the study and 15 16 critical review ofFor the manuscript. peer FF, PS reviewand GY performed onlythe data extraction. All authors 17 18 approved the final manuscript as submitted. 19 20 21 Competing Interests 22 23 24 JN and ES are employed by Astellas Pharma Inc. ZH was employed by Astellas Pharma Inc. 25 as the time of the study. FF has received a grant from Astellas for study design, data 26 27 extraction and manuscript development. 28 29 30 Funding 31 32

33 The study was supported by Astellas Pharma Global Development. http://bmjopen.bmj.com/ 34 35 36 Data Sharing Statement 37 38 39 The search strategy and all data supporting this study are provided as supplementary 40

41 information accompanying this paper. on September 29, 2021 by guest. Protected copyright. 42 43 44 Abbreviations and Acronyms 45 46 47 ER = extendedrelease 48 49 50 HRQoL = healthrelated quality of life 51 52 53 MPR = medication possession rate 54 55 56 OAB = overactive bladder 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

41 on September 29, 2021 by guest. Protected copyright. 42 EpiLUTS. BJU Int 2011;108(9):145971. doi: 10.1111/j.1464410X.2010.10013.x 43 44 45 7. Herschorn S. Global perspective of treatment failures. Can Urol Assoc J 2013;7(910 46 47 Suppl 4):S1701. doi: 10.5489/cuaj.1613 48 49 50 8. Irwin DE, Mungapen L, Milsom I, et al. The economic impact of overactive bladder 51 52 syndrome in six Western countries. BJU Int 2009;103(2):2029. doi: 10.1111/j.1464 53 54 410X.2008.08036.x 55 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 9. Onukwugha E, Zuckerman IH, McNally D, et al. The total economic burden of overactive 4 5 bladder in the United States: a diseasespecific approach. Am J Manag Care 6 7 2009;15(4 Suppl):S907. 8 9 10 10. Lucas M, Bedretdinova D, Berghmans L, et al. European Association of Urology. 11 12 Guidelines on urinary incontinence. 2015. http://uroweb.org/wpcontent/uploads/20 13 14 UrinaryIncontinence_LR1.pdf (accessed October 2016). 15 16 For peer review only 17 11. Kim TH, Lee KS. Persistence and compliance with medication management in the 18 19 treatment of overactive bladder. Investig Clin Urol 2016;57(2):8493. doi: 20 21 10.4111/icu.2016.57.2.84 22 23 12. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology 24 25 and definitions. Value Health 2008;11(1):447. doi: 10.1111/j.1524 26 27 4733.2007.00213.x 28 29 30 13. Brown MT, Bussell J, Dutta S, et al. Medication adherence: truth and consequences. Am 31 32 J Med Sci 2016;351(4):38799. doi: 10.1016/j.amjms.2016.01.010

33 http://bmjopen.bmj.com/ 34 35 14. World Health Organization. Adherence to longterm therapies: evidence for action. 2003. 36 37 http://www.who.int/chp/knowledge/publications/adherence_report/en/ (accessed 38 39 November 2016). 40

41 on September 29, 2021 by guest. Protected copyright. 42 15. Andy UU, Arya LA, Smith AL, et al. Is selfreported adherence associated with clinical 43 44 outcomes in women treated with anticholinergic medication for overactive bladder? 45 46 Neurourol Urodyn 2016;35(6):73842. doi: 10.1002/nau.22798 47 48 49 16. Kim TH, Choo MS, Kim YJ, et al. Drug persistence and compliance affect patient 50 51 reported outcomes in overactive bladder syndrome. Qual Life Res 2016;25(8):2021 52 53 9. doi: 10.1007/s111360151216z 54 55 56 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 17. Benner JS, Nichol MB, Rovner ES, et al. Patientreported reasons for discontinuing 4 5 overactive bladder medication. BJU Int 2010;105(9):127682. doi: 10.1111/j.1464 6 7 410X.2009.09036.x 8 9 10 18. Chapple CR, Nazir J, Hakimi Z, et al. Persistence and adherence with mirabegron 11 12 versus antimuscarinic agents in patients with overactive bladder: a retrospective 13 14 observational study in UK clinical practice. Eur Urol 2017;72(3):38999. doi: 15 16 10.1016/j.eururo.2017.01.037For peer review only 17 18 19 19. Sexton CC, Notte SM, Maroulis C, et al. Persistence and adherence in the treatment of 20 21 overactive bladder syndrome with anticholinergic therapy: a systematic review of the 22 literature. Int J Clin Pract 2011;65(5):56785. doi: 10.1111/j.17421241.2010.02626.x 23 24 25 20. Veenboer PW, Bosch JL. Longterm adherence to antimuscarinic therapy in everyday 26 27 practice: a systematic review. J Urol 2014;191(4):10038. doi: 28 29 10.1016/j.juro.2013.10.046 30 31 32 21. European Medicines Agency. Mirabegron summary of product characteristics. 2016.

33 http://bmjopen.bmj.com/ 34 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_ 35 36 _Product_Information/human/002388/WC500137309.pdf (accessed December 37 38 2016). 39 40

41 22. Food and Drug Administration. Drug approval package. Myrbetriq (mirabegron) extended on September 29, 2021 by guest. Protected copyright. 42 43 release tablets. 2012. 44 45 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202611Orig1s000TOC.cf 46 47 m. 48 49 50 23. Pharmaceuticals and Medical Devices Agency. Betanis. Review of deliberation results. 51 52 2011; (August 2017). http://www.pmda.go.jp/files/000204240.pdf. 53 54 55 56 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 24. Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical 4 5 treatments for the management of overactive bladder: a systematic literature review 6 7 and mixed treatment comparison. Eur Urol 2014;65(4):75565. doi: 8 9 10.1016/j.eururo.2013.11.010 10 11 12 25. Kobayashi M, Nukui A, Kamai T. Comparative efficacy and tolerability of antimuscarinic 13 14 agents and the selective beta3adrenoceptor agonist, mirabegron, for the treatment 15 16 of overactiveFor bladder: peer which is more review preferable as an only initial treatment? Low Urin 17 18 Tract Symptoms 2016:Epub ahead of print. doi: 10.1111/luts.12153 19 20 26. Wagg A, Franks B, Ramos B, et al. Persistence and adherence with the new beta3 21 22 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: early 23 24 experience in Canada. Can Urol Assoc J 2015;9(910):34350. doi: 25 26 10.5489/cuaj.3098 27 28 29 27. Nazir J, Berling M, McCrea C, et al. Economic impact of mirabegron versus 30 31 antimuscarinics for the treatment of overactive bladder in the UK. 32

33 Pharmacoeconomics Open 2017;1:2536. http://bmjopen.bmj.com/ 34 35 36 28. Basra RK, Wagg A, Chapple C, et al. A review of adherence to drug therapy in patients 37 38 with overactive bladder. BJU Int 2008;102(7):7749. doi: 10.1111/j.1464 39 40 410X.2008.07769.x

41 on September 29, 2021 by guest. Protected copyright. 42 43 29. Stroup DF, Berlin JA, Morton SC, et al. Metaanalysis of observational studies in 44 45 epidemiology: a proposal for reporting. Metaanalysis Of Observational Studies in 46 47 Epidemiology (MOOSE) group. JAMA 2000;283(15):200812. 48 49 50 30. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 51 52 metaanalyses: the PRISMA statement. Int J Surg 2010;8(5):33641. doi: 53 54 10.1016/j.ijsu.2010.02.007 55 56 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 31. Nitti VM, Rovner ES, Franks B, et al. Persitence with mirabegron versus tolterodine in 4 5 patients with overactive bladder. Am J Pharm Benefits 2016;8(2):e25e33. 6 7 8 32. Wagg A, Diles D, Berner T. Treatment patterns for patients on overactive bladder 9 10 therapy: a retrospective statistical analysis using Canadian claims data. JHEOR 11 12 2015;3(1):4355. 13 14 15 33. Yeaw J, Benner JS, Walt JG, et al. Comparing adherence and persistence across 6 16 For peer review only 17 chronic medication classes. J Manag Care Pharm 2009;15(9):72840. doi: 18 19 10.18553/jmcp.2009.15.9.728 20 21 34. Sussman D, Yehoshua A, Kowalski J, et al. Adherence and persistence of mirabegron 22 23 and anticholinergic therapies in patients with overactive bladder: a realworld claims 24 25 data analysis. Int J Clin Pract 2017;71(34):e12824. doi: 10.1111/ijcp.12824 26 27 28 35. Kleinman NL, Odell K, Chen CI, et al. Persistence and adherence with urinary 29 30 antispasmodic medications among employees and the impact of adherence on costs 31 32 and absenteeism. J Manag Care Spec Pharm 2014;20(10):104756. doi:

33 http://bmjopen.bmj.com/ 34 10.18553/jmcp.2014.20.10.1047 35 36 37 36. Brostrom S, Hallas J. Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 38 39 2009;65(3):30914. doi: 10.1007/s0022800806009 40

41 on September 29, 2021 by guest. Protected copyright. 42 37. Desgagne A, LeLorier J. Incontinence drug utilization patterns in Quebec, Canada. Value 43 44 Health 1999;2(6):4528. doi: 10.1046/j.15244733.1999.26005.x 45 46 47 38. Gomes T, Juurlink DN, Mamdani MM. Comparative adherence to oxybutynin or 48 49 tolterodine among older patients. Eur J Clin Pharmacol 2012;68(1):979. doi: 50 51 10.1007/s0022801110908 52 53 54 39. Ivanova JI, HayesLarson E, Sorg RA, et al. Healthcare resource use and costs of 55 56 privately insured patients who switch, discontinue, or persist on antimuscarinic 57 58 22 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 therapy for overactive bladder. J Med Econ 2014;17(10):74150. doi: 4 5 10.3111/13696998.2014.941066 6 7 8 40. Krhut J, Gartner M, Petzel M, et al. Persistence with first line anticholinergic medication 9 10 in treatmentnaive overactive bladder patients. Scand J Urol 2014;48(1):7983. doi: 11 12 10.3109/21681805.2013.814707 13 14 15 41. Perfetto EM, Subedi P, Jumadilova Z. Treatment of overactive bladder: a model 16 For peer review only 17 comparing extendedrelease formulations of tolterodine and oxybutynin. Am J Manag 18 19 Care 2005;11(4 Suppl):S1507. 20 21 42. SicrasMainar A, NavarroArtieda R, RuizTorrejon A, et al. Impact of loss of work 22 23 productivity in patients with overactive bladder treated with antimuscarinics in Spain: 24 25 study in routine clinical practice conditions. Clin Drug Investig 2015;35(12):795805. 26 27 doi: 10.1007/s4026101503422 28 29 30 43. SicrasMainar A, NavarroArtieda R, RuizTorrejon A, et al. Persistence and concomitant 31 32 medication in patients with overactive bladder treated with antimuscarinic agents in

33 http://bmjopen.bmj.com/ 34 primary care. An observational baseline study. Actas Urol Esp 2016;40(2):96101. 35 36 doi: 10.1016/j.acuro.2015.09.004 37 38 39 44. SicrasMainar A, RejasGutierrez J, NavarroArtieda R, et al. Use of health care 40

41 resources and associated costs in noninstitutionalized vulnerable elders with on September 29, 2021 by guest. Protected copyright. 42 43 overactive bladder treated with antimuscarinic agents in the usual medical practice. 44 45 Actas Urol Esp 2014;38(8):5307. doi: 10.1016/j.acuro.2014.02.001 46 47 48 45. Suehs BT, Davis C, Franks B, et al. Effect of potentially inappropriate use of 49 50 antimuscarinic medications on healthcare use and cost in individuals with overactive 51 52 bladder. J Am Geriatr Soc 2016;64(4):77987. doi: 10.1111/jgs.14030 53 54 55 56 57 58 23 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 46. Wagg A, Compion G, Fahey A, et al. Persistence with prescribed antimuscarinic therapy 4 5 for overactive bladder: a UK experience. BJU Int 2012;110(11):176774. doi: 6 7 10.1111/j.1464410X.2012.11023.x 8 9 10 47. Yu YF, Nichol MB, Yu AP, et al. Persistence and adherence of medications for chronic 11 12 overactive bladder/urinary incontinence in the California Medicaid program. Value 13 14 Health 2005;8(4):495505. doi: 10.1111/j.15244733.2005.00041.x 15 16 For peer review only 17 48. D'Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among 18 19 extendedrelease and immediaterelease overactive bladder medications in a 20 regional managed care plan. J Manag Care Pharm 2008;14(3):291301. doi: 21 22 10.18553/jmcp.2008.14.3.291 23 24 25 49. Johnston S, Janning SW, Haas GP, et al. Comparative persistence and adherence to 26 27 overactive bladder medications in patients with and without diabetes. Int J Clin Pract 28 29 2012;66(11):104251. doi: 10.1111/j.17421241.2012.03009.x 30 31 32 50. Kalder M, Pantazis K, Dinas K, et al. Discontinuation of treatment using anticholinergic

33 http://bmjopen.bmj.com/ 34 medications in patients with urinary incontinence. Obstet Gynecol 2014;124(4):794 35 36 800. doi: 10.1097/AOG.0000000000000468 37 38 39 51. Manack A, Motsko SP, HaagMolkenteller C, et al. Epidemiology and healthcare 40

41 utilization of neurogenic bladder patients in a US claims database. Neurourol Urodyn on September 29, 2021 by guest. Protected copyright. 42 43 2011;30(3):395401. doi: 10.1002/nau.21003 44 45 46 52. Mauseth SA, Skurtveit S, Spigset O. Adherence, persistence and switch rates for 47 48 anticholinergic drugs used for overactive bladder in women: data from the Norwegian 49 50 Prescription Database. Acta Obstet Gynecol Scand 2013;92(10):120815. doi: 51 52 10.1111/aogs.12196 53 54 55 56 57 58 24 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 53. SicrasMainar A, Rejas J, NavarroArtieda R, et al. Antimuscarinic persistence patterns 4 5 in newly treated patients with overactive bladder: a retrospective comparative 6 7 analysis. Int Urogynecol J 2014;25(4):48592. doi: 10.1007/s0019201322504 8 9 10 54. Gopal M, Haynes K, Bellamy SL, et al. Discontinuation rates of anticholinergic 11 12 medications used for the treatment of lower urinary tract symptoms. Obstet Gynecol 13 14 2008;112(6):13118. doi: 10.1097/AOG.0b013e31818e8aa4 15 16 For peer review only 17 55. Chancellor MB, MigliaccioWalle K, Bramley TJ, et al. Longterm patterns of use and 18 19 treatment failure with anticholinergic agents for overactive bladder. Clin Ther 20 21 2013;35(11):174451. doi: 10.1016/j.clinthera.2013.08.017 22 23 56. Sears CL, Lewis C, Noel K, et al. Overactive bladder medication adherence when 24 25 medication is free to patients. J Urol 2010;183(3):107781. doi: 26 27 10.1016/j.juro.2009.11.026 28 29 30 57. Pelletier EM, Vats V, Clemens JQ. Pharmacotherapy adherence and costs versus 31 32 nonpharmacologic management in overactive bladder. Am J Manag Care 2009;15(4

33 http://bmjopen.bmj.com/ 34 Suppl):S10814. 35 36 37 58. National Institute for Health and Care Excellence. Mirabegron for treating symptoms of 38 39 overactive bladder, 2013. 40

41 on September 29, 2021 by guest. Protected copyright. 42 59. Thompson C, Peveler RC, Stephenson D, et al. Compliance with antidepressant 43 44 medication in the treatment of major depressive disorder in primary care: a 45 46 randomized comparison of fluoxetine and a tricyclic antidepressant. Am J Psychiatry 47 48 2000;157(3):33843. doi: 10.1176/appi.ajp.157.3.338 49 50 51 60. Anderson BJ, Vangsness L, Connell A, et al. Family conflict, adherence, and glycaemic 52 53 control in youth with short duration Type 1 diabetes. Diabet Med 2002;19(8):63542. 54 55 56 57 58 25 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 61. Hakimi Z, Nazir J, McCrea C, et al. Clinical and economic impact of mirabegron 4 5 compared with antimuscarinics for the treatment of overactive bladder in Canada. J 6 7 Med Econ 2017;20(6):61422. doi: 10.1080/13696998.2017.1294595 8 9 10 62. Wielage RC, Perk S, Campbell NL, et al. Mirabegron for the treatment of overactive 11 12 bladder: costeffectiveness from US commercial healthplan and Medicare 13 14 Advantage perspectives. J Med Econ 2016;19(12):113543. doi: 15 16 10.1080/13696998.2016.1204307For peer review only 17 18 19 63. Liao CH, Kuo HC. High satisfaction with direct switching from antimuscarinics to 20 mirabegron in patients receiving stable antimuscarinic treatment. Medicine 21 22 (Baltimore) 2016;95(45):e4962. doi: 10.1097/MD.0000000000004962 23 24 25 64. SicrasMainar A, Rejas J, NavarroArtieda R, et al. Health economics perspective of 26 27 fesoterodine, tolterodine or solifenacin as firsttime therapy for overactive bladder 28 29 syndrome in the primary care setting in Spain. BMC Urol 2013;13:51. doi: 30 31 10.1186/147124901351 32

33 http://bmjopen.bmj.com/ 34 65. Drake MJ, Chapple C, Esen AA, et al. Efficacy and safety of mirabegron addon therapy 35 36 to solifenacin in incontinent overactive bladder patients with an inadequate response 37 38 to initial 4week solifenacin monotherapy: a randomised doubleblind multicentre 39 40 phase 3B study (BESIDE). Eur Urol 2016;70(1):13645. doi:

41 on September 29, 2021 by guest. Protected copyright. 42 10.1016/j.eururo.2016.02.030 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 26 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

Adherence and persistence to OAB medication 1 2 3 FIGURE LEGENDS 4 5 Figure 1 Search strategy and selection of studies presented in the Preferred Reporting 6 7 Items for Systematic Reviews and MetaAnalyses (PRISMA) flow diagram 8 9 10 *Studies were excluded for the following reasons: outcome measure(s) of persistence and/or adherence, relevant 11 12 to this systematic review (such as medication possession rate, proportion of days covered, discontinuation rate), 13 were not presented within the full text of the article (n=17); adherence/persistence data were drawn from surveys, 14 15 interviews or selfreports (n=13); cohort contained a portion of patients under 18 years of age (who could not be 16 For peer review only 17 removed or isolated from results/data) (n=7); participants had prior awareness/knowledge of partaking in a study 18 related to OAB medication (ie, openlabel extension to a study or prior written consent) (n=6); a full article text 19 20 was not available (ie, only a conference abstract) or the full text was not in English (n=1); or nonoral OAB 21 22 medications were included within the presented results (and could not be removed or isolated from results/data) 23 (n=1) 24 25 § 26 Three of these studies were identified by reviewing reference lists of included studies and relevant systematic 27 literature reviews 28 29 30 31 32

33 Figure 2 Frequency for reported determinants of discontinuation http://bmjopen.bmj.com/ 34 35 36 *In one study the relationship was not statistically significant 37 38 **Includes dose, formulation, race, prior infection, financial burden, prescriber profession, side effects, medication 39 40 copayment and polypharmacy

41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 27 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 29, 2021 by guest. Protected copyright. 42 43 44 45 Figure 1 Search strategy and selection of studies presented in the Preferred Reporting Items for Systematic 46 Reviews and Meta-Analyses (PRISMA) flow diagram 47 48 279x361mm (300 x 300 DPI) 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 64 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 2 Frequency for reported determinants of discontinuation 30 273x182mm (300 x 300 DPI) 31 32

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Sicras-Mainar et al n=3094 Adults aged ≥20 years with a first Persistence was defined as the time, measured in months, without 1 year (2015)d,20 Male: n≈1170a (37.8%) index (new) prescription of: stopping the initial treatment or switching to another medication at 7 Primary care medical Female: n≈1924a (62.2%) fesoterodine (n=859) least 30 days after the initial prescription 8 databases; Spain Mean (SD) age: 54.0 (9.2) years solifenacin (n=1330) 9 (2008–2013) tolterodine (n=905) Compliance was defined according to ISPOR criteria and was 10 calculated based on the MPR, which was evaluated from the first to 11 the last prescription and represented the number of days of medication taken over the number of days in treatment (commencing 12 For peer reviewfrom the start date)only 13 14 Sicras-Mainar et al n=552 Adults aged ≥75 years with a first Persistence was defined as the time, in weeks, with no drop-out from 1 year (2014a)21 Male: n≈272a (49.2%) index (new) prescription of: initial treatment or with no switch to another medication at least 15 Primary care medical Female: n≈280a (50.8%) fesoterodine (n=58) 30 days following initial prescription 16 databases; Spain Mean (SD) age: 80.2 (4.0) years solifenacin (n=252) 17 (2008–2010) tolterodine (n=212) Compliance was defined according to http://bmjopen.bmj.com/ ISPOR criteria and was 18 calculated based on the medication use/possession rate 19 Sicras-Mainar et al n=1971 Adults aged ≥18 years with a first Discontinuation was defined by either the absence of prescription 1 year 20 (2014b)e,22 Male: n=821 (41.7%) index (new) prescription of: coverage for the initial therapy for the remainder of the 52-week 21 Primary care medical Female: n=1150 (58.3%) fesoterodine (n=302) follow-up period or a switch to an alternative antimuscarinic during databases; Spain Mean (SD) age: 70.1 (10.6) solifenacin (n=952) this time-period 22 (2008–2010) years tolterodine (n=717) 23 Variables: index drug 24 Sicras-Mainar et al n=1971 Adults aged ≥18 years with a first Persistence was defined as patients who remained on treatment 1 year on September 29, 2021 by guest. Protected copyright. 25 (2013)e,23 Male: n=821 (41.7%) index (new) prescription of: during the 52-week period following the index date 26 Primary care medical Female: n=1150 (58.3%) fesoterodine (n=302) 27 databases; Spain Mean (SD) age: 70.1 (10.6) solifenacin (n=952) Compliance was defined according to ISPOR criteria and was 28 (2008–2010) years tolterodine (n=717) calculated based on the MPR 29 Suehs et al (2016)24 n=46 140a Adults aged 65 to 89 yearsf with a Persistence was assessed as time in days from the index date to 1 year 30 Medicare Advantage Male: n=15 479a (33.5%)a first index (new) prescription of any discontinuation of index antimuscarinic treatment a a 31 Prescription Plan - Female: n=30 661 (66.5%) antimuscarinic OAB medication Administrative Claims Mean age: 75.5 yearsa Adherence was assessed as PDC with the index OAB treatment over 32 Data; USA three predefined post index observation periods: 3, 6, and 12 months 33 (2007–2013) 34 Treatment discontinuation was identified using a permissible gap 35 between refills of 15 days 36 37 38 39 40 41 6 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Sussman et al (2017)25 n=71 980a Adults aged ≥18 years with a Persistence was measured by evaluating treatment failure (defined 1 year Truven MarketScan® Male: n=21 225a (29.5%)a prescription of: as either treatment discontinuation or treatment switching). A 7 Claims Database; USA Female: n=50 755a (70.5%)a mirabegron medication supply gap of ≥30 days was used to define treatment 8 (2012–2013) Mean age: 62.3 yearsa any anticholinergic OAB discontinuation 9 medication 10 Adherence was defined as the PDC (ie, the number of days covered 11 by the index therapy divided by the number of days between the index date and the end of the follow-up [365 days]). A PDC of <80% 12 For peer reviewwas considered only nonadherent 13 26 14 Wagg et al (2012) n=4833 Adults aged ≥40 years with a first Persistence was defined as the mean time [in days] until 1 year Prescription Database; Demographics were not index (new) prescription of: discontinuation (a gap in treatment exceeding 1.5 times than the 15 UK (2007–2008) explicitly reported, the majority darifenacin length of the previous prescription without a refill) 16 of prescriptions appeared to be flavoxate 17 issued to patients aged oxybutynin ER http://bmjopen.bmj.com/ 18 ≥60 years oxybutynin IR propiverine 19 solifenacin 20 tolterodine ER 21 tolterodine IR 22 trospium 23 Wagg et al (2015)27 n=19 485 Adults aged ≥18 years with a first Adherence was defined by the MPR over 1 year 1 year 24 Canadian National Male: n=4992 (25.6%)a index (new) prescription of: a 25 Private Drug Plan Female: n=14 493 (74.3%) mirabegron (n=1683) To calculate time to end of persistence on September 29, 2021 by guest. Protected copyright. (defined by a gap in therapy Database; Canada Mean age not reported; the fesoterodine (n=1415) of ≥30 days or switching to another medication), prescription claims 26 (2013) majority of patients (77.8%)a oxybutynin ER (n=1260) for a target drug were tracked for 12 months after the index claim 27 were aged ≥46 years oxybutynin IR (n=5356) date 28 solifenacin (n=6032) 29 tolterodine ER (n=3739) Variables: age, gender, treatment-naïve vs treatment-experienced, 30 index antimuscarinic, number of coexisting medications 31 Wagg et al (2015)28 n=31 707 Adult patients receiving a first Discontinuation was defined as patients experiencing a gap in 4 years a 32 IMS Brogan public and Male: n=9395 (29.6%) index (new) prescription of: therapy longer than 60 days private prescription Female: n=22 312 (70.4%)a oxybutynin IR 33 claims databases; Mean age not reported oxybutynin ER 34 Canada tolterodine IR 35 (2007–2012) tolterodine ER 36 solifenacin 37 darifenacin trospium 38 flavoxate 39 40 41 7 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 4 Author (year) and Definition of persistence/adherence/discontinuation and Length of country (database) Participants Drug/intervention* independent variables on persistence follow-up 5 6 Yeaw et al (2009)29 n=7722 Adult patients receiving a first Persistence was calculated for the post-index period until the patient 2 years PharMetrics Patient- Male: n=1686 (21.8%) index (new) prescription of: discontinued therapy, was lost to follow-up due to disenrollment from 7 Centric Database Female: n=6036 (78.2%) tolterodine the health plan (minimum of 12 months), or the maximum 24-month 8 (pharmacy claims); USA Mean (SD) age: 43.7 (18.3) oxybutynin follow-up period ended, whichever event occurred first. A patient was 9 (2005) years solifenacin considered persistent until an excessive gap in days supplied 10 darifenacin occurred; refill gaps of 30, 60, and 90 days were used to calculate 11 trospium persistence for all cohorts bethanechol 12 For peerflavoxate reviewAdherence was only measured using the PDC for each of the six drug 13 hyoscyamine class cohorts. This was calculated by taking patients’ total days 14 supplied of index class medications for the 360-day period following 15 the index date and dividing by 360 16 Yu et al (2015)30 n=2496 Adult patients aged ≥18 years Persistence was measured by the length of continuous 1 year 17 California Medi-Cal Male: n=534 (21.4%) receiving a prescription of an OAB pharmacological treatment (patients discontinuedhttp://bmjopen.bmj.com/ their treatment if 18 administrative files; USA Female: n=1962 (78.6%) drug, including: they failed to refill OAB/UI agents within 30 days after the expected (1999–2002) Mean (SD) age: 63.15 (16.14) tolterodine (n=1093) end date of the previous prescription) 19 years oxybutynin ER (n=524) 20 oxybutynin (n=812) Patients who switched from one agent of OAB/UI drug to another 21 other OAB agents (n=67) within 30 days were considered persistent on therapy. 22 Adherence was defined as MPR over 181 days for the 6-month 23 follow-up period 24 25 Variables: age, gender, ethnicity, index on September 29, 2021 by guest. Protected copyright. drug, OAB-associated 26 comorbidities (UTIs), medication use history, length of hospital stay 27 and number of drug classes prescribed 28 COPD = chronic obstructive pulmonary disease; ER = extended release; ISPOR = International Society for Pharmacoeconomics and Outcomes Research; IR = immediate release; MPR = medication possession ratio (measured as the proportion of days with any OAB medication on hand, over the length of the evaluation period); OAB = overactive bladder; 29 PDC = proportion of days covered; PIM = potentially inappropriate medication; SD = standard deviation; TD = transdermal; UA = urinary antispasmodic; UI = urinary incontinence; UTIs = 30 urinary tract infections 31 32 *The sum of the patients prescribed individual drugs may not match the total number of patients perhaps due to switching in some studies 33 34 aCalculated from data presented in the article; bused only in an OAB context; c26 922 continued, discontinued or restarted an OAB medication in the study period, but no demographics d 19 20 35 for this specific sub-group are reported; Sicras-Mainar et al (2016) and Sicras-Mainar et al (2015) relate to the same patient group in terms of demographics and the timeframe/geographical source of adherence/persistence data; eSicras-Mainar et al (2014)22 and Sicras-Mainar et al (2013)23 relate to the same patient group in terms of demographics 36 and the timeframe/geographical source of adherence/persistence data; fthis cohort was split into two groups – patients who were assigned OAB medication appropriately [non-PIM], or 37 potentially inappropriately [PIM]. Inappropriateness was defined as patients having “drug–disease or syndrome interaction or indication of signiﬁcant anticholinergic medication burden at 38 the time of initiation of an antimuscarinic OAB treatment” 39 40 41 8 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 38 of 64

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Sicras-Mainar Proportion of patients persistent at 1 year: Mean MPR at 1 year: Medication type g,22 6 et al (2014) fesoterodine: 35.8% fesoterodine: 0.937 The mean duration of treatment was numerically higher with solifenacin: 31.9% solifenacin: 0.948 fesoterodine compared to solifenacin and tolterodine, but no 7 tolterodine: 30.9% tolterodine: 0.935 statistical between-medication differences were found. However, 8 adjusted HRs for remaining on treatment at 1 year significantly 9 favored fesoterodine compared with solifenacin (HR 1.24 [95% 10 CI 1.05–1.47]; p=0.011) and tolterodine (HR 1.28 [95% CI 1.07– 11 1.52]; p=0.006) 12 Sicras-Mainar Mean MPR at 1 year: Medication type et al (2013)g,23 For peerfesoterodine: review 0.945 Theonly mean duration of treatment was numerically higher with 13 solifenacin: 0.954 fesoterodine compared to solifenacin and tolterodine, but no 14 tolterodine: 0.946 statistical between-medication differences were found 15 Suehs et al Proportion of patients not refilling their index medication: Mean PDC at: Medication use appropriateness 16 24

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Wagg et al Proportion of patients persistent at 1 year (without Median MPR at 1 year: Age 27 6 (2015) switching or experiencing a gap ≥30 days): mirabegron: 0.645 As age increased, median MPR increased for OAB medications: mirabegron: 31.7% fesoterodine: 0.492 <46 years: 0.273 7 fesoterodine: 21.0% oxybutynin ER: 0.328 45–64 years: 0.372 8 oxybutynin ER: 18.9% oxybutynin IR: 0.186 ≥65 years: 0.492 9 oxybutynin IR: 13.8% solifenacin: 0.459 (p<0.001 difference compared to ≥65 years) 10 solifenacin: 22.0% tolterodine ER: 0.454 11 tolterodine ER: 19.7% Treatment status Patients with prior experience of OAB medication use achieved a 12 Median duration of treatmentFor (days): peer review higheronly MPR than treatment-naïve patients (0.546 vs 0.328, 13 mirabegron: 221 p<0.001) 14 solifenacin: 108 15 fesoterodine: 100 Medication type tolterodine ER: 100 Compared with antimuscarinics, patients taking mirabegron 16 oxybutynin ER: 100 demonstrated greater persistence and statistically significantly 17 oxybutynin IR: 75 greater adherence (64.5%http://bmjopen.bmj.com/ vs 18.6%–49.2%, p<0.001) than those 18 taking antimuscarinics 19 Proportion of patients persistent at 1 year: treatment-naïve:19.0% 20 treatment-experienced: 30.0% 21 22 Median days on therapy: 23 treatment-naïve: 90 24 treatment-experienced: 205 25 on September 29, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 17 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 Author (year) Persistence* Adherence* Determinants of persistence and adherence 4 5 Wagg et al Proportion of patients persistent at 6 months: ˂40% Not reported Medication type 28 6 (2015) Initial treatment with solifenacin, darifenacin, tolterodine ER and Proportion of patients discontinued at 4 years: tolterodine was associated with a significantly lower risk of 7 oxybutynin: 93% discontinuation compared with oxybutynin as the first medication 8 tolterodine IR: 90% (HRs 0.68, 0.72, 0.77 and 0.84, respectively; p<0.001 vs 9 tolterodine ER: 90% oxybutynin for each) 10 solifenacin: 90% 11 darifenacin: 91% Patients receiving flavoxate as initial treatment had a significantly trospium: 94% higher risk of discontinuation compared with those who received 12 flavoxate: 98% For peer review oxybutyninonly (HR 2.48, p<0.0001) 13 overall: 91.4% 14 There was no statistically significant difference in the risk of 15 Median duration of first-line treatment (days): discontinuation with trospium as first-line compared with oxybutynin: 60 oxybutynin (p=0.1074) 16 tolterodine IR: 90 17 tolterodine ER: 100 Age http://bmjopen.bmj.com/ 18 solifenacin: 106 Compared with patients aged 40–64 years, patients aged <20, 19 darifenacin: 91 20–39, 65–74 and ≥75 years had a higher risk of discontinuation trospium: 90 (HRs 1.08–1.19, all p≤0.0022) 20 flavoxate: 10 21 Gender 22 Males had a slightly higher risk of discontinuation than females 23 (HR 1.03, 95% CI 1.00–1.06, p=0.0341) 24 Yeaw et al Proportion of patients remaining on therapy (without a Proportion of patients with mean Not reported 25 (2009)29 refill gap >60 days) at: MPR at 1 year: 35% on September 29, 2021 by guest. Protected copyright. 26 6 months: 28% 27 1 year: 18% 28 Yu et al Proportion of patients without index prescription refill Mean MPR at: Medication type 30 29 (2005) within the first 6 months: 36.9% 6 months: 0.34 Compared with oxybutynin, patients receiving tolterodine were 1 year: 0.22 less likely to have discontinued at 6 months (HR 0.74, 95% CI 30 Proportion of patients discontinued at: 0.67–0.81, p<0.01) 31 1 month: 42.7% Proportion of patients with MPR 32 2 months: 66.8% ≥0.80 at: Polypharmacy 33 5 months days: 77.6% 6 months: 4.9% The use of multiple drugs was associated with a higher risk of 34 9 months: 86.3% 1 year: 0.7% discontinuation by the 6-month follow up (HR 1.26, 95% CI 1.09– 1.46, p<0.01) 35 At a 1-year follow-up, the rate of discontinuation was 36 increased to 88.6% Other significant predictors of higher persistence included: White 37 ethnicity, previous hospitalization length, and starting treatment 38 with tolterodine 39 40 41 18 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

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Adherence and persistence to OAB medication 1 2 3 References BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 4 5 6 1. Brostrom S, Hallas J: Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 2009; 65: 309. 7 8 2. Chancellor MB, Migliaccio-Walle K, Bramley TJ et al: Long-term patterns of use and treatment failure 9 with anticholinergic agents for overactive bladder. Clin Ther 2013; 35: 1744. 10 3. Chapple CR, Nazir J, Hakimi Z et al: Persistence and adherence with mirabegron versus antimuscarinic 11 agents in patients with overactive bladder: a retrospective observational study in UK clinical practice. 12 Eur Urol 2017; 72: 389. 13 14 4. Desgagne A, LeLorier J: Incontinence drug utilization patterns in Quebec, Canada. Value Health 1999; 15 2: 452. 16 17 5. D'Souza AO, Smith MJ, Miller LA et al: Persistence, adherence, and switch rates among extended- 18 release and immediateFor-release peer overactive review bladder medications only in a regional managed care plan. J Manag Care Pharm 2008; 14: 291. 19 20 6. Gomes T, Juurlink DN, Mamdani MM: Comparative adherence to oxybutynin or tolterodine among older 21 patients. Eur J Clin Pharmacol 2012; 68: 97. 22 23 7. Gopal M, Haynes K, Bellamy SL et al: Discontinuation rates of anticholinergic medications used for the 24 treatment of lower urinary tract symptoms. Obstet Gynecol 2008; 112: 1311. 25 26 8. Ivanova JI, Hayes-Larson E, Sorg RA et al: Healthcare resource use and costs of privately insured 27 patients who switch, discontinue, or persist on anti-muscarinic therapy for overactive bladder. J Med 28 Econ 2014; 17: 741. 29 9. Johnston S, Janning SW, Haas GP et al: Comparative persistence and adherence to overactive bladder 30 medications in patients with and without diabetes. Int J Clin Pract 2012; 66: 1042. 31 32 10. Kalder M, Pantazis K, Dinas K et al: Discontinuation of treatment using anticholinergic medications in 33 patients with urinary incontinence. Obstet Gynecol 2014; 124: 794. 34 35 11. Kleinman NL, Odell K, Chen CI et al: Persistence and adherence with urinary antispasmodic 36 medications among employees and the impact of adherence on costs and absenteeism. J Manag Care Spec Pharm 2014; 20: 1047.

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1 MOOSE Checklist for Meta-analyses of Observational Studies 2 3 Reported on Item No Recommendation 4 Page No 5 Reporting of background should include 6 7 1 Problem definition 3–5 8 2 Hypothesis statement N/A 9 10 3 Description of study outcome(s) 7 11 4 Type of exposure or intervention used 6–8 12 13 5 Type of study designs used 6 14 6 Study population 6–7 15 16 Reporting of search strategyFor should peerinclude review only 17 7 Qualifications of searchers (eg, librarians and investigators) 7 18 6-7, Figure 1, 19 8 Search strategy, including time period included in the synthesis and key words Supplemental 20 Information 21 9 Effort to include all available studies, including contact with authors 7 22 23 5–6, 10 Databases and registries searched Supplemental 24 Information 25 Search software used, name and version, including special features used (eg, Supplemental 11 26 explosion) Information 27 12 Use of hand searching (eg, reference lists of obtained articles) 6–7 28 29 6–7, Supplemental 30 13 List of citations located and those excluded, including justification Tables 1 and 31 2 32 14 Method of addressing articles published in languages other than English 6

33 http://bmjopen.bmj.com/ 34 15 Method of handling abstracts and unpublished studies 6–7 35 16 Description of any contact with authors N/A 36 37 Reporting of methods should include 38 Description of relevance or appropriateness of studies assembled for assessing the 17 6–7 39 hypothesis to be tested Rationale for the selection and coding of data (eg, sound clinical principles or 40 18 6–7 convenience) 41 on September 29, 2021 by guest. Protected copyright. Documentation of how data were classified and coded (eg, multiple raters, blinding and 42 19 6–7 43 interrater reliability) Assessment of confounding (eg, comparability of cases and controls in studies where 44 20 N/A appropriate) 45 Not 46 Assessment of study quality, including blinding of quality assessors, stratification or performed – 21 47 regression on possible predictors of study results see response 48 to reviewers 49 22 Assessment of heterogeneity 7 50 Description of statistical methods (eg, complete description of fixed or random effects 51 models, justification of whether the chosen models account for predictors of study 23 7 52 results, dose-response models, or cumulative meta-analysis) in sufficient detail to be 53 replicated 54 Figures 1 and 55 2 and 24 Provision of appropriate tables and graphics 56 Supplemental 57 Tables 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 64 of 64 BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from

1 Reporting of results should include 2 Figure 2 and 3 Supplemental 25 Graphic summarizing individual study estimates and overall estimate 4 Tables 1 and 5 2 6 Supplemental 7 26 Table giving descriptive information for each study included Tables 1 and 8 2 9 27 Results of sensitivity testing (eg, subgroup analysis) N/A 10 28 Indication of statistical uncertainty of findings N/A 11

13 14 15 Reported 16 Item No For peerRecommendation review only on Page 17 No 18 Reporting of discussion should include 19 20 29 Quantitative assessment of bias (eg, publication bias) N/A 21 Figure 1 30 Justification for exclusion (eg, exclusion of non-English language citations) 22 legend 23 Not 24 performed – see 25 31 Assessment of quality of included studies 26 response to 27 reviewers 28 29 Reporting of conclusions should include 30 32 Consideration of alternative explanations for observed results 12–14 31 Generalization of the conclusions (ie, appropriate for the data presented and within the 33 13-15 32 domain of the literature review)

33 34 Guidelines for future research 15 http://bmjopen.bmj.com/ 34 35 35 Disclosure of funding source 16 36 From: Stroup DF, Berlin JA, Morton SC, et al, for the Meta-analysis Of Observational Studies in Epidemiology 37 (MOOSE) Group. Meta-analysis of Observational Studies in Epidemiology. A Proposal for Reporting. JAMA. 38 2000;283(15):2008-2012. doi: 10.1001/jama.283.15.2008. 39 40

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Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB) – a systematic literature review

ForJournal: peerBMJ Open review only Manuscript ID bmjopen2018021889.R2

Article Type: Research

Date Submitted by the Author: 12Sep2018