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Table 1.  Baseline Characteristics of Users by Overactive Bladder-Treatment Group
Baseline Characteristics of Users by Overactive Bladder-Treatment Group
Table 2.  Results of Primary and Secondary Outcomes
Results of Primary and Secondary Outcomes
1.
Tadrous  M, Elterman  D, Khuu  W, Mamdani  MM, Juurlink  DN, Gomes  T.  Publicly funded overactive bladder drug treatment patterns in Ontario over 15 years: an ecological study.  Can Urol Assoc J. 2018;12(3):E142-E145. doi:10.5489/cuaj.4541PubMedGoogle ScholarCrossref
2.
Kelleher  C, Hakimi  Z, Zur  R,  et al.  Efficacy and tolerability of mirabegron compared with antimuscarinic monotherapy or combination therapies for overactive bladder: a systematic review and network meta-analysis.  Eur Urol. 2018;74(3):324-333. doi:10.1016/j.eururo.2018.03.020PubMedGoogle ScholarCrossref
3.
Maman  K, Aballea  S, Nazir  J,  et al.  Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison.  Eur Urol. 2014;65(4):755-765. doi:10.1016/j.eururo.2013.11.010PubMedGoogle ScholarCrossref
4.
Gauthier  C, Leblais  V, Kobzik  L,  et al.  The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle.  J Clin Invest. 1998;102(7):1377-1384. doi:10.1172/JCI2191PubMedGoogle ScholarCrossref
5.
Rosa  GM, Ferrero  S, Nitti  VW, Wagg  A, Saleem  T, Chapple  CR.  Cardiovascular safety of β3-adrenoceptor agonists for the treatment of patients with overactive bladder syndrome.  Eur Urol. 2016;69(2):311-323. doi:10.1016/j.eururo.2015.09.007PubMedGoogle ScholarCrossref
6.
Data & Analytic Services. ICES web site. https://www.ices.on.ca/. Accessed July 9, 2018.
Research Letter
July 15, 2019

Association of Mirabegron With the Risk of Arrhythmia in Adult Patients 66 Years or Older—A Population-Based Cohort Study

Author Affiliations
  • 1Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
  • 2Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada
  • 3Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
  • 4Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
  • 5Division of Urology, University of Toronto, Toronto, Ontario, Canada
  • 6Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
  • 7Sunnybrook Research Institute, Toronto, Ontario, Canada
  • 8Li Ka Shing Centre for Healthcare Analytics Research and Training, St Michael’s Hospital, Toronto, Ontario, Canada
JAMA Intern Med. 2019;179(10):1436-1439. doi:10.1001/jamainternmed.2019.2011

Recently, mirabegron, the first β3-adrenoceptor agonist, has been prescribed to treat overactive bladder (OAB) more frequently than antimuscarinic agents.1 The β-3 agonist medications have limited adverse effects compared with antimuscarinic agents.2,3 However, β3-adrenoreceptors are associated with increases in contractile force and reductions in inotropic effects,4 actions which raise concerns of cardiovascular (CV) adverse effects. These adverse effects have been reinforced by trials, finding a small increase in heart rate, blood pressure, and QTc intervals.2-4 Real-world data among older patients with CV comorbidities are lacking.5 We conducted a population-based cohort study to evaluate the risk of cardiac arrhythmias and other CV events in a population of patients 66 years and older receiving mirabegron.

Methods

We used health care administrative data from 38 818 patients 66 years or older who initiated treatment between June 1, 2015, and March 31, 2017 (eTable 1 in the Supplement). Data were analyzed from June 1, 2015, to March 31, 2017. In Ontario, all health care services and medications are publicly funded for individuals 65 years and older. Information is recorded by the Ministry of Health and Long-term Care and data are securely held in databases at ICES6 and are linked using unique identifiers (eAppendix in the Supplement). Use of these data was authorized under section 45 of the Ontario Personal Health Information Protection Act, which does not require review by a research ethics board.

We identified new users of OAB treatments and followed up for 1 year or until they discontinued or switched therapy (eAppendix in the Supplement). New users were defined as having no OAB treatment in the previous year. The primary outcome was any hospitalization or emergency department visit for arrhythmia or tachycardia (eTable 2 in the Supplement). The secondary outcome was any hospitalization or visit for myocardial infarction (MI) or stroke. Patients receiving mirabegron were matched with up to 4 patients receiving other OAB agents (anticholinergic agents) on age (±3 y), sex, index date (±3 mo), and high-dimensional propensity score (HDPS; within 0.2 SD). We compared characteristics between groups using standardized differences and used Cox proportional hazards regression models accounting for the matched nature of the data to compare mirabegron with other agents. We conducted 2 subgroup analyses limited to (1) those with no previous atrial fibrillation or ventricular arrhythmias at baseline, and (2) those older than 75 years. Analyses were conducted using SAS, version 9.2 (SAS Institute Inc). All outcomes are based on 95% CIs from Cox proportional hazards regression model hazard ratios (HRs).

Results

We matched 16 948 patients who received mirabegron to 21 870 patients who received of other OAB drugs (Table 1). The median age was 76 (interquartile range, 71-83), and 64.9% were female (25 189). Hypertension (30 393 [78.3%]) and diabetes (13 757 [35.4%]) were highly prevalent in the cohort. The 1-year cumulative incidence (adjusted for person-years) of arrhythmia or tachycardia events was similar between exposure groups (3.6% for mirabegron vs 3.8% for other OAB drugs; HR, 0.93; 95% CI, 0.80-1.09; Table 2). Mirabegron was not associated with an increased risk of MI or stroke compared with other OAB drugs (HR 1.06; 95% CI, 0.89-1.27). Results were consistent in subgroup analysis (2.4% for mirabegron vs 2.3% for other OAB drugs; HR, 0.95; 95% CI, 0.75-1.20).

Discussion

A lack of evidence exists for assessing the safety of mirabegron in older patients with CV risk factors, and our work highlights the CV safety of mirabegron in a cohort of patients with higher prevalence of comorbidities than in previous clinical trials.2,3 In previous studies, the prevalence of diabetes ranged between 6% and 9% and that of hypertension ranged between 10% and 29%.2,3 In contrast, a 79% prevalence of hypertension and 36% prevalence of diabetes were found in the present study. Moreover, the mean age of patients in this cohort, 77 years, was higher than that of previous trials, where mean ages ranged from 58 to 60.

Our study was limited by our inability to ascertain lifestyle factors and over-the-counter medication use, and the potential for confounding by indication owing to prescriber perceptions of mirabegron risk. However, we anticipate these factors have minimal consequences given the use of stringent matching criteria and the HDPS.

The findings of this study suggest that mirabegron was not associated with a higher risk of CV events compared with other treatments. Our findings are not meant to endorse preferential use of mirabegron but to support a growing body of evidence that mirabegron is not associated with an excess risk of CV events compared with other treatments in older patients. These results appear to support current prescribing patterns and give a balanced view of real-world safety.

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Article Information

Accepted for Publication: April 27, 2019.

Corresponding Author: Mina Tadrous, PharmD, PhD, Women's College Research Institute, Women's College Hospital, 76 Grenville St, Toronto, ON M5S 1B2 (mina.tadrous@wchospital.ca).

Published Online: July 15, 2019. doi:10.1001/jamainternmed.2019.2011

Author Contributions: Mr Greaves had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tadrous, Matta, Mamdani, Gomes.

Acquisition, analysis, or interpretation of data: Tadrous, Greaves, Herschorn, Mamdani, Juurlink, Gomes.

Drafting of the manuscript: Tadrous, Matta.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Tadrous, Matta, Greaves, Mamdani.

Obtained funding: Gomes.

Administrative, technical, or material support: Tadrous, Mamdani, Gomes.

Supervision: Tadrous, Mamdani, Juurlink, Gomes.

Conflict of Interest Disclosures: Dr Tadrous reported receiving grants from Ministry of Health and Long-term Care during the conduct of the study. Dr Herschorn reported receiving grants and personal fees from Astellas, personal fees from Pfizer, grants from Ipsen and Ixaltis, and grants and personal fees from Allergan outside the submitted work. Dr Mamdani reported other support from NovoNordisk, Allergan, and other support from Amgen outside the submitted work. Dr Gomes reported receiving grants from Ontario Ministry of Health and Long-Term Care during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was funded by a grant (HSRF; 06673) from the Ontario Ministry of Health and Long-Term Care (MOHLTC) Health System Research Fund and supported by the Institute for Clinical Evaluative Sciences (ICES), a nonprofit research institute sponsored by the Ontario MOHLTC.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The opinions, results and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed herein are those of the author, and not necessarily those of CIHI.

Additional Contributions: We thank Brogan Inc, Ottawa for use of their Drug Product and Therapeutic Class Database.

References
1.
Tadrous  M, Elterman  D, Khuu  W, Mamdani  MM, Juurlink  DN, Gomes  T.  Publicly funded overactive bladder drug treatment patterns in Ontario over 15 years: an ecological study.  Can Urol Assoc J. 2018;12(3):E142-E145. doi:10.5489/cuaj.4541PubMedGoogle ScholarCrossref
2.
Kelleher  C, Hakimi  Z, Zur  R,  et al.  Efficacy and tolerability of mirabegron compared with antimuscarinic monotherapy or combination therapies for overactive bladder: a systematic review and network meta-analysis.  Eur Urol. 2018;74(3):324-333. doi:10.1016/j.eururo.2018.03.020PubMedGoogle ScholarCrossref
3.
Maman  K, Aballea  S, Nazir  J,  et al.  Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison.  Eur Urol. 2014;65(4):755-765. doi:10.1016/j.eururo.2013.11.010PubMedGoogle ScholarCrossref
4.
Gauthier  C, Leblais  V, Kobzik  L,  et al.  The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle.  J Clin Invest. 1998;102(7):1377-1384. doi:10.1172/JCI2191PubMedGoogle ScholarCrossref
5.
Rosa  GM, Ferrero  S, Nitti  VW, Wagg  A, Saleem  T, Chapple  CR.  Cardiovascular safety of β3-adrenoceptor agonists for the treatment of patients with overactive bladder syndrome.  Eur Urol. 2016;69(2):311-323. doi:10.1016/j.eururo.2015.09.007PubMedGoogle ScholarCrossref
6.
Data & Analytic Services. ICES web site. https://www.ices.on.ca/. Accessed July 9, 2018.
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