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BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 29, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-021889 on 21 November 2018. Downloaded from 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 bmjopen-2018-021889 Article Type: Research Date Submitted by the Author: 25-Jan-2018 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 http://bmjopen.bmj.com/ on September 29, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 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 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, β3-adrenergic 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 real-world 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 first-line 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 health-related 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 14-17 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.
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