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preceding persons’ first intramuscular B12 injection, 25.5% Corresponding Author: William K. Silverstein, MD, Core Internal Medicine, Faculty of Medicine, University of Toronto, Department of Medicine, University (n = 37 487) had a normal B12 level, whereas 38.2% (n = 56 128) Health Network, 200 Elizabeth St, Eaton Building 14-217, Toronto, M5G did not have a B12 level documented. Findings were similar over 2C4, Canada ([email protected]). a 24-month look-back period (data not shown). Only 43.1% Author Contributions: Drs Cheung, Croxford, and Dharma had full access to all (n = 24 175) of the 56 128 people without a B12 level docu- of the data in the study and take responsibility for the integrity of the data and

mented in the year preceding their first B12 prescription had the accuracy of the data analysis. Drs Lin and Cheung contributed equally as ever had one measured. This was performed a mean (SD) 1033.5 co–senior authors to this study. Study concept and design: Silverstein, Lin, Dharma, Cheung. (488.1) days prior to their first prescription (range, 366-2801 Acquisition, analysis, or interpretation of data: Lin, Dharma, Croxford, days). Only 35.3% (n = 8539) of these 24 175 persons had mar- Earle, Cheung. Drafting of the manuscript: Silverstein, Cheung. ginally deficient B12 levels. The estimated annual cost of in- Critical revision of the manuscript for important intellectual content: Lin, appropriate B prescribing was $45.6 million, assuming a 64% 12 Dharma, Croxford, Earle, Cheung. inappropriate prescription rate. Finally, only 1.7% (n = 2498) Statistical analysis: Dharma, Croxford, Cheung.

of persons prescribed intramuscular B12 demonstrated any Obtained funding: Cheung. deficiency with a malabsorptive indication. Administrative, technical, or material support: Silverstein, Dharma, Cheung. Study supervision: Lin, Cheung. Conflict of Interest Disclosures: Dr Lin reported that she was a consultant for Discussion | Most parenteral B in Ontario was prescribed to 12 Pfizer and that she was on the advisory board of Amgen. No other disclosures persons without evidence of deficiency in the year preced- were reported.

ing their first B12 prescription. Potential drivers of this Funding/Support: This study was supported by research funding from the include patient demands and poor physician awareness of Sunnybrook Hospital Foundation. This study was also supported by ICES, which 3,4 is funded by an annual grant from the Ontario Ministry of Health and Long-Term the evidence informing B12 supplementation. It is also Care (MOHLTC). questionable whether parenteral supplementation is Role of the Funder/Sponsor: The funders had no role in the design and required over oral supplementation because oral B raises 12 conduct of the study; collection, management, analysis, and interpretation of B12 serum levels and improves sequelae of deficiency as well the data; preparation, review, or approval of the manuscript; and decision to

as, if not better than, intramuscular B12, even for pernicious submit the manuscript for publication. anemia.1 Plausible reasons why physicians prefer parenteral Disclaimer: No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information B12 include low quality of evidence supporting oral B12, soci- compiled and provided by the Canadian Institute for Health Information (CIHI). ety guidelines recommending intramuscular B12 for all The opinions, results and, conclusions reported in this article are those of the patients, poor physician understanding of how to prescribe authors and are independent from the funding sources and CIHI.

oral B12, and physician misperception that patients prefer Additional Contributions: We thank IMS Brogan Inc for use of their Drug 1,3,5,6 parenteral over oral B12. Information Database. No contributors received compensation for their Our study’s limitations include only looking 2 years be- assistance. fore a person’s first documented prescription; using this 1. Chan CQH, Low LL, Lee KH. Oral vitamin B12 replacement for the treatment of pernicious anemia. Front Med (Lausanne). 2016;3(38):38. abridged period might have misclassified persons undergo- 2. van Walraven CG, Naylor CD. Use of vitamin B injections among elderly ing treatment for chronic B deficiency, and so with normal 12 12 patients by primary care practitioners in Ontario. CMAJ. 1999;161(2):146-149. B levels, as receiving inappropriate supplementation. We were 12 3. Graham ID, Jette N, Tetroe J, Robinson N, Milne S, Mitchell SL. Oral also unable to access information on oral B12, and could not cobalamin remains medicine’s best kept secret. Arch Gerontol Geriatr.2007;44

understand why B12 was prescribed without laboratory evi- (1):49-59. doi:10.1016/j.archger.2006.02.003 dence of deficiency. Further studies should examine this 4. Tilburt JC, Wynia MK, Sheeler RD, et al. Views of US physicians about issue, to inform quality improvement initiatives aimed at controlling health care costs. JAMA. 2013;310(4):380-388. doi:10.1001/jama. 2013.8278 reducing this unnecessary care. 5. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and William K. Silverstein, MD folate disorders. Br J Haematol. 2014;166(4):496-513. doi:10.1111/bjh.12959 Yulia Lin, MD, FRCPC 6. Kwong JC, Carr D, Dhalla IA, Tom-Kun D, Upshur RE. Oral vitamin B12 therapy Christoffer Dharma, MSc in the primary care setting: a qualitative and quantitative study of patient Ruth Croxford, MSc perspectives. BMC Fam Pract. 2005;6(1):8. doi:10.1186/1471-2296-6-8 Craig C. Earle, MD, MSc, FRCPC Matthew C. Cheung, MD, SM, FRCPC Association of Mirabegron With the Risk of Arrhythmia in Adult Patients 66 Years or Older— Author Affiliations: Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Silverstein, Lin, Earle, Cheung); Division of Medical Oncology A Population-Based Cohort Study & Hematology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada Recently, mirabegron, the first β3-adrenoceptor agonist, has (Lin, Earle, Cheung); Department of Laboratory Medicine & Molecular been prescribed to treat overactive bladder (OAB) more Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada frequently than antimuscarinic agents.1 The β-3 agonist medi- (Lin); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Lin); ICES, Toronto, Ontario, Canada cations have limited adverse (Dharma, Croxford, Earle, Cheung). effects compared with anti- 2,3 Accepted for Publication: April 20, 2019. Supplemental content muscarinic agents. How-

Published Online: July 15, 2019. doi:10.1001/jamainternmed.2019.1859 ever, β3-adrenoreceptors are Correction: This article was corrected on August 26, 2019, to fix errors in the associated with increases in contractile force and reductions dates of data analysis in the Methods section. in inotropic effects,4 actions which raise concerns of cardio-

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Table 1. Baseline Characteristics of Users by Overactive Bladder-Treatment Group

No. (%) Standardized Characteristic Mirabegron Other OAB Drugs Differencea New users, No. 16 948 21 870 NA Age, median (IQR), y 76 (71-82) 76 (71-82) NA Male 6342 (37.4) 7287 (33.3) NA Neighborhood income quintileb 1 2907 (17.2) 4100 (18.7) 0.05 2 3241 (19.1) 4417 (20.2) 0.02 3 3353 (19.8) 4338 (19.8) 0.01 4 3629 (21.4) 4543 (20.8) 0.02 5 3745 (22.1) 4363 (19.9) 0.05 Living in urban community 14 867 (87.7) 18 911 (86.5) 0.01 Living in long-term care 351 (2.1) 511 (2.3) 0.02 Charlson comorbidity score No hospitalization 11 213 (66.2) 14 759 (67.5) 0.02 0 2565 (15.1) 3113 (14.2) 0.02 1 1196 (7.1) 1549 (7.1) <0.01 2+ 1974 (11.6) 2449 (11.2) <0.01 Comorbidities Frailty 2910 (17.2) 3398 (15.5) 0.03 Chronic obstructive pulmonary disease 4560 (26.9) 5819 (26.6) <0.01 Diabetes 5951 (35.1) 7806 (35.7) 0.02 Hypertension 13 190 (77.8) 17 203 (78.7) 0.02 CV events in the past 5 y Acute myocardial infarction 425 (2.5) 531 (2.4) <0.01 Transient ischemic attack 1015 (6.0) 1215 (5.6) 0.02 Peripheral vascular disease 195 (1.2) 244 (1.1) 0.01 Atrial fibrillation 1098 (6.5) 1469 (6.7) 0.02 Angina 484 (2.9) 675 (3.1) 0.02 Ventricular arrhythmia 35 (0.2) 36 (0.2) <0.01 Congestive heart failure 1766 (10.4) 2347 (10.7) 0.02 Health care use in past year, visits, median (IQR) Emergency department 0 (0-1) 0 (0-1) 0.03 Physician 8 (4-15) 8 (4-14) 0.01 Cardiologist 0 (0-0) 0 (0-0) 0.01 Urologist 0 (0-1) 0 (0-0) 0.10 Different medications, No., median (IQR), No. 8 (5-11) 8 (5-11) 0.03 Concurrent recent CV medication use Angiotensin-converting enzyme 4033 (23.8) 5160 (23.6) <0.01 Angiotensin receptor blocker 3667 (21.6) 4611 (21.1) 0.01 Statin 7729 (45.6) 9641 (44.1) 0.01 Other lipid lowering agents 950 (5.6) 1148 (5.2) 0.01 β-Blocker 3606 (21.3) 4684 (21.4) 0.02 Abbreviations: CV, cardiovascular; Calcium-channel blocker 4360 (25.7) 5580 (25.5) <0.01 IQR, interquartile range; NA, not Diuretics 4380 (25.8) 5839 (26.7) 0.02 applicable; OAB, overactive bladder. Platelet inhibitor 1066 (6.3) 1287 (5.9) 0.01 a Standardized difference of >0.1 used Benign prostatic hyperplasia treatments 3197 (18.9) 3217 (14.7) 0.06 to signify a meaningful difference. b Switched therapy within 1 y 960 (5.7) 1306 (6.0) 0.023 Neighborhood income quintile is based on each participant’s postal Days on therapy, median (IQR) 104 (30-249) 81 (30-199) 0.194 code.

vascular (CV) adverse effects. These adverse effects have been Methods | We used health care administrative data from 38 818 reinforced by trials, finding a small increase in heart rate, blood patients 66 years or older who initiated treatment between June pressure, and QTc intervals.2-4 Real-world data among older 1, 2015, and March 31, 2017 (eTable 1 in the Supplement). Data patients with CV comorbidities are lacking.5 We conducted a were analyzed from June 1, 2015, to March 31, 2017. In On- population-based cohort study to evaluate the risk of cardiac tario, all health care services and medications are publicly arrhythmias and other CV events in a population of patients funded for individuals 65 years and older. Information is re- 66 years and older receiving mirabegron. corded by the Ministry of Health and Long-term Care and data

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Table 2. Results of Primary and Secondary Outcomes

Incidence Rate Events, No. (%) per 100 Person-Years Mirabegron Other OAB Drugs Other Hazard Ratio Variable (n = 16 948) (n = 21 870) Mirabegron OAB Drugs (95% CI) Primary outcome (hospitalization for arrhythmia 284 (1.7) 340 (1.6) 3.6 3.8 0.93 (0.80-1.09) or tachycardia) Secondary outcome (hospitalization for myocardial 233 (1.4) 247 (1.1) 3.0 2.8 1.06 (0.89-1.27) infarction or stroke) Subgroup analysis (primary outcome: no previous 177 (1.1) 190 (0.9) 2.4 2.3 0.95 (0.75-1.20) atrial fibrillation or ventricular arrhythmias at baseline) Aged 75 y or older 221 (2.5) 255 (2.2) 5.2 5.3 0.93 (0.76-1.13)

Abbreviation: OAB, overactive bladder.

are securely held in databases at ICES6 and are linked using with higher prevalence of comorbidities than in previous clini- unique identifiers (eAppendix in the Supplement). Use of these cal trials.2,3 In previous studies, the prevalence of diabetes data was authorized under section 45 of the Ontario Personal ranged between 6% and 9% and that of hypertension ranged Health Information Protection Act, which does not require between 10% and 29%.2,3 In contrast, a 79% prevalence of hy- review by a research ethics board. pertension and 36% prevalence of diabetes were found in the We identified new users of OAB treatments and followed present study. Moreover, the mean age of patients in this co- up for 1 year or until they discontinued or switched therapy hort, 77 years, was higher than that of previous trials, where (eAppendix in the Supplement). New users were defined as mean ages ranged from 58 to 60. having no OAB treatment in the previous year. The primary out- Our study was limited by our inability to ascertain life- come was any hospitalization or emergency department visit style factors and over-the-counter medication use, and the po- for arrhythmia or tachycardia (eTable 2 in the Supplement). tential for confounding by indication owing to prescriber per- The secondary outcome was any hospitalization or visit for ceptions of mirabegron risk. However, we anticipate these myocardial infarction (MI) or stroke. Patients receiving mira- factors have minimal consequences given the use of strin- begron were matched with up to 4 patients receiving other OAB gent matching criteria and the HDPS. agents (anticholinergic agents) on age (±3 y), sex, index date The findings of this study suggest that mirabegron was not (±3 mo), and high-dimensional propensity score (HDPS; within associated with a higher risk of CV events compared with other 0.2 SD). We compared characteristics between groups using treatments. Our findings are not meant to endorse preferen- standardized differences and used Cox proportional hazards tial use of mirabegron but to support a growing body of evi- regression models accounting for the matched nature of the dence that mirabegron is not associated with an excess risk of data to compare mirabegron with other agents. We con- CV events compared with other treatments in older patients. ducted 2 subgroup analyses limited to (1) those with no pre- These results appear to support current prescribing patterns vious atrial fibrillation or ventricular arrhythmias at baseline, and give a balanced view of real-world safety. and (2) those older than 75 years. Analyses were conducted using SAS, version 9.2 (SAS Institute Inc). All outcomes are Mina Tadrous, PharmD, PhD based on 95% CIs from Cox proportional hazards regression Rano Matta, MD, MASc model hazard ratios (HRs). Simon Greaves, MSc Sender Herschorn, MD Results | We matched 16 948 patients who received mirabegron Muhammad M. Mamdani, PharmD, MA, MPH to 21 870 patients who received of other OAB drugs (Table 1). David N. Juurlink, MD, PhD The median age was 76 (interquartile range, 71-83), and 64.9% Tara Gomes, MHSc, PhD were female (25 189). Hypertension (30 393 [78.3%]) and dia- betes (13 757 [35.4%]) were highly prevalent in the cohort. The Author Affiliations: Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada (Tadrous); Institute for Clinical Evaluative 1-year cumulative incidence (adjusted for person-years) of ar- Sciences (ICES), Toronto, Ontario, Canada (Tadrous, Matta, Greaves, Mamdani, rhythmia or tachycardia events was similar between exposure Juurlink, Gomes); Leslie Dan Faculty of Pharmacy, University of Toronto, groups (3.6% for mirabegron vs 3.8% for other OAB drugs; HR, Toronto, Ontario, Canada (Tadrous, Mamdani, Gomes); Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada (Tadrous, Gomes); 0.93; 95% CI, 0.80-1.09; Table 2). Mirabegron was not associ- Division of Urology, University of Toronto, Toronto, Ontario, Canada (Matta, ated with an increased risk of MI or stroke compared with other Herschorn); Institute of , Management and Evaluation, University OAB drugs (HR 1.06; 95% CI, 0.89-1.27). Results were consis- of Toronto, Toronto, Ontario, Canada (Matta, Mamdani, Juurlink, Gomes); tent in subgroup analysis (2.4% for mirabegron vs 2.3% for other Sunnybrook Research Institute, Toronto, Ontario, Canada (Herschorn, Juurlink); Li Ka Shing Centre for Healthcare Analytics Research and Training, St Michael’s OAB drugs; HR, 0.95; 95% CI, 0.75-1.20). Hospital, Toronto, Ontario, Canada (Mamdani). Accepted for Publication: April 27, 2019. Discussion | A lack of evidence exists for assessing the safety of Corresponding Author: Mina Tadrous, PharmD, PhD, Women's College mirabegron in older patients with CV risk factors, and our work Research Institute, Women's College Hospital, 76 Grenville St, highlights the CV safety of mirabegron in a cohort of patients Toronto, ON M5S 1B2 ([email protected]).

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Published Online: July 15, 2019. doi:10.1001/jamainternmed.2019.2011 reductase inhibitors (5-ARIs). As noted, the prediagnostic use AuthorContributions:MrGreaveshadfullaccesstoallthedatainthestudyandtakes of 5-ARIs is associated with delayed prostate cancer diagno- responsibility for the integrity of the data and the accuracy of the data analysis. sis, more advanced disease, and worse prostate cancer– Concept and design: Tadrous, Matta, Mamdani, Gomes. specific and all-cause mortality compared with nonusers who Acquisition, analysis, or interpretation of data: Tadrous, Greaves, Herschorn, Mamdani, Juurlink, Gomes. underwent prostate-specific antigen (PSA) screening. Drafting of the manuscript: Tadrous, Matta. Although the recommendation of how to make the adjust- Critical revision of the manuscript for important intellectual content: All authors. ment of PSA suppression by 5-ARIs is not completely clear,2,3 Statistical analysis: Tadrous, Matta, Greaves, Mamdani. Obtained funding: Gomes. the association of corrected PSA to prostate volume (PSA den- Administrative, technical, or material support: Tadrous, Mamdani, Gomes. sity [PSAD]) is a tool that has been recognized as having greater Supervision: Tadrous, Mamdani, Juurlink, Gomes. specificity compared with using total PSA and has shown Conflict of Interest Disclosures: Dr Tadrous reported receiving grants from to be a significant predictor of different indices of cancer Ministry of Health and Long-term Care during the conduct of the study. aggressiveness.4 Dr Herschorn reported receiving grants and personal fees from Astellas, personal fees from Pfizer, grants from Ipsen and Ixaltis, and grants and personal Moreover, several studies have shown prostate volume to fees from Allergan outside the submitted work. Dr Mamdani reported other have a significant role predicting prostate cancer with PSA val- support from NovoNordisk, Allergan, and other support from Amgen outside ues in the gray zone and thus propose it as a tool that must be the submitted work. Dr Gomes reported receiving grants from Ontario Ministry taken into consideration in the diagnostic approach.5 It is pre- of Health and Long-Term Care during the conduct of the study. No other disclosures were reported. sumed that users of 5-ARIs are patients with larger prostates, and Funding/Support: This study was funded by a grant (HSRF; 06673) from the a fundamental tool to avoid misinterpretation could be PSAD. Ontario Ministry of Health and Long-Term Care (MOHLTC) Although Sarkar and colleagues1 described multiple vari- Research Fund and supported by the Institute for Clinical Evaluative Sciences ables listed in Table 1 of their article, no mention is made of (ICES), a nonprofit research institute sponsored by the Ontario MOHLTC. these fundamental clinical parameters at the time of diagno- Role of the Funder/Sponsor: The funding organizations had no role in the sis. This information could help elucidate differences be- design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; tween groups by (1) assessing the degree of PSA misinterpre- and decision to submit the manuscript for publication. tation in real-life clinical practice, (2) knowing if for the same Disclaimer: The opinions, results and conclusions reported in this article are comparative PSAD there are still worse prostate cancer char- those of the authors and are independent from the funding sources. No acteristics in 5-ARI users, or (3) identifying a subgroup for which 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 there is not an increased risk of delayed or worst prostate can- by CIHI. However, the analyses, conclusions, opinions and statements cer with the use of this medication. expressed herein are those of the author, and not necessarily those of CIHI. In summary, we believe PSAD is a determining factor to Additional Contributions: We thank Brogan Inc, Ottawa for use of their Drug be considered and it should be used to correlate to other clini- Product and Therapeutic Class Database. cal and laboratory factors to accurately describe differences 1. Tadrous M, Elterman D, Khuu W, Mamdani MM, Juurlink DN, Gomes T. between groups in the study by Sarkar and colleagues. 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.4541 Camilo A. Medina, MD 2. Kelleher C, Hakimi Z, Zur R, et al. Efficacy and tolerability of mirabegron Laura Zuluaga, MD compared with antimuscarinic monotherapy or combination therapies for Mauricio Plata, MD, MSc overactive bladder: a systematic review and network meta-analysis. Eur Urol. 2018;74(3):324-333. doi:10.1016/j.eururo.2018.03.020 Author Affiliations: Department of Urology, Fundación Santa Fe de Bogotá, 3. Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical Bogotá DC, Colombia. treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4):755-765. doi:10. Corresponding Author: Camilo A. Medina, MD, Department of Urology, 1016/j.eururo.2013.11.010 Fundación Santa Fe de Bogotá, Cra 7 No 118-09, Bogotá DC, Colombia ([email protected]). 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 Conflict of Interest Disclosures: Dr Plata reports receiving grants from synthase pathway in human ventricle. J Clin Invest. 1998;102(7):1377-1384. GlaxoSmithKline outside of the submitted work. No other disclosures doi:10.1172/JCI2191 are reported. 5. Rosa GM, Ferrero S, Nitti VW, Wagg A, Saleem T, Chapple CR. Cardiovascular 1. Sarkar RR, Parsons JK, Bryant AK, et al. Association of treatment with safety of β3-adrenoceptor agonists for the treatment of patients with 5α-reductase inhibitors with time to diagnosis and mortality in prostate cancer. overactive bladder syndrome. Eur Urol. 2016;69(2):311-323. doi:10.1016/ JAMA Intern Med. 2019;179(6):812-819. doi:10.1001/jamainternmed.2019.0280 j.eururo.2015.09.007 2. GrossmanDC,CurrySJ,OwensDK,etal;USPreventiveServicesTaskForce.Screen- 6. Data & Analytic Services. ICES web site. https://www.ices.on.ca/. Accessed ingforprostatecancer:USPreventiveServicesTaskForceRecommendationStatement. July 9, 2018. JAMA. 2018;319(18):1901-1913. doi:10.1001/jama.2018.3710 3. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer early detection recommendations. National Comprehensive Cancer Network. COMMENT & RESPONSE https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. Published 2019. 5α-Reductase Inhibitor Use in Patients 4. Verma A, St Onge J, Dhillon K, Chorneyko A. PSA density improves With Prostate Cancer prediction of prostate cancer. Can J Urol. 2014;21(3):7312-7321. To the Editor The article by Sarkar and colleagues1 recently pub- 5. Erdogan A, Polat S, Keskin E, Turan A. Is prostate volume better than PSA density and free/total PSA ratio in predicting prostate cancer in patients with lished in JAMA Internal Medicine contributes to deeper knowl- PSA 2.5-10 ng/mL and 10.1-30 ng/mL? [published online March 12, 2019] Aging edge of prostate cancer diagnosis in patients who are using 5-α Male. doi:10.1080/13685538.2019.1578741

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