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BMJ Confidential: For Review Only A matche d cohort study to evaluate the risk of fall and fracture with the initiation of a prostate-selective alpha antagonist Journal: BMJ Manuscript ID BMJ.2015.028205.R1 Article Type: Research BMJ Journal: BMJ Date Submitted by the Author: 22-Sep-2015 Complete List of Authors: Welk, Blayne; Western University, McArthur, Eric; Institute for Clinical Evaluative Sciences,, Fraser, Lisa-Ann; Western University, Medicine Hayward, Jade; Institute for Clinical Evaluative Sciences,, Dixon, Stephanie; Institute for Clinical Evaluative Sciences,, Hwang, Joseph; Case Western Reserve University School of Medicine, Ordon, Michael; University of Toronto, Surgery (Urology) Keywords: BPH, Fall, Fracture, Alpha antgonist https://mc.manuscriptcentral.com/bmj Page 1 of 44 BMJ 1 2 The risk of fall and fracture with the initiation of a prostate-selective alpha antagonist: a 3 population based cohort study 4 5 6 Blayne Welk MD MSc 1,2,3 , Eric McArthur MSc 2, Lisa-Ann Fraser MD MSc 4, Jade Hayward 2, 7 Stephanie Dixon MSc PhD 2,3 , Y. Joseph Hwang MSc 5, Michael Ordon MD MSc 6 8 Confidential: For Review Only 9 1 Department of Surgery, Western University, London, Ontario, Canada 10 11 2 Institute for Clinical Evaluative Sciences, London, Ontario, Canada 12 3 Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada 13 4 Department of Medicine, Western University, London, Ontario 14 5 MD Candidate, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA 15 6 Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada 16 17 18 Corresponding Author 19 Blayne Welk, MD MSc 20 Assistant Professor, Department of Surgery and Epidemiology and Biostatistics (Urologist), 21 Western University 22 23 Room B4-667 24 St Joseph's Health Care 25 268 Grosvenor Street London ON N6A 4V2 26 Telephone: 519 646-6367 | Fax: 519 646-6037 27 [email protected] 28 29 30 Eric McArthur, Research Analyst, Institute for Clinical Evaluative Sciences 31 Lisa-Ann Fraser, Assistant Professor of Medicine (Endocrinology), Western University 32 Jade Hayward, Research Assistant, Institute for Clinical Evaluative Sciences 33 34 Stephanie Dixon, Epidemiologist, Institute for Clinical Evaluative Sciences 35 Joseph Hwang, Medical Student, Case Western Reserve University School of Medicine 36 Michael Ordon, Assistant Professor of Surgery (Urologist), University 37 38 Addresses: 39 40 Mr McArthur: [email protected] 41 LHSC – Victoria Hospital 42 ELL-101, 800 Commissioners Rd. E. 43 London, Ontario N6A 4G5 44 519-685-8500 ext. 56555 45 46 47 Dr Fraser: [email protected] 48 St Joseph's Health Care 49 268 Grosvenor St 50 London, Ontario N6A 4V2 51 52 519-646-6245 53 54 Ms Hayward: [email protected] 55 LHSC – Victoria Hospital 56 ELL-101, 800 Commissioners Rd. E. 57 58 London, Ontario N6A 4G5 59 519-685-8500 ext. 56555 60 1 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 44 1 2 3 Dr Dixon: [email protected] 4 5 LHSC – Victoria Hospital 6 ELL-101, 800 Commissioners Rd. E. 7 London, Ontario N6A 4G5 8 519-685-8500Confidential: ext. 56555 For Review Only 9 10 11 Mr Hwang: [email protected] 12 603-105 La Rose Ave 13 Etobicoke ON M9P 1A9 14 15 Dr Ordon: [email protected] 16 17 St Michaels Hospital 18 30 Bond St, Toronto, ON M5B 1W8 19 (416) 360-4000 20 21 The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of 22 23 all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, 24 formats and media (whether known now or created in the future), to i) publish, reproduce, 25 distribute, display and store the Contribution, ii) translate the Contribution into other languages, 26 create adaptations, reprints, include within collections and create summaries, extracts and/or, 27 abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) 28 29 to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the 30 Contribution to third party material where-ever it may be located; and, vi) license any third party to 31 do any or all of the above. 32 33 34 Word count: 3043 35 Abstract 343 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 2 https://mc.manuscriptcentral.com/bmj Page 3 of 44 BMJ 1 2 Abstract 3 4 5 6 7 Importance: Oral alpha antagonists are commonly used in older men to treat urinary symptoms. 8 Confidential: For Review Only 9 One of the side effects of these medications is hypotension, the consequence of which may be 10 11 12 serious falls or fractures. 13 14 15 16 17 Objectives: To determine the risk of fall and fracture among men initiating prostate-specific alpha 18 19 antagonist medication. 20 21 22 23 24 Design: Population-based, retrospective, matched cohort study 25 26 27 28 29 Setting: Ontario, Canada from 2003 through 2013. 30 31 32 33 34 Participants: Population based sample of men ≥66 years of age that were (or were not) newly 35 36 started on an alpha antagonist. 37 38 39 40 41 Exposures: Prostate-specific alpha antagonists: tamsulosin, alfuzosin, and silodosin. 42 43 44 45 46 Main Outcome Measure: The primary outcome was a hospital emergency room visit or inpatient 47 48 admission for a fall or fracture. We hypothesized a priori that prostate-specific alpha antagonist 49 50 exposure would increase the risk of these events. 51 52 53 54 55 Results: We identified 147,084 men who initiated prostate-specific alpha antagonist therapy. 56 57 58 These men were matched 1:1 (using a propensity score model) to an equal number of men who 59 60 3 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 44 1 2 did not initiate alpha antagonist therapy. These groups were similar across 98 different 3 4 5 covariates including demographics, comorbid conditions, medication usage, healthcare 6 7 utilization and prior medical investigation. The relative proportion of alpha antagonist use was 8 Confidential: For Review Only 9 tamsulosin ( n=123,537, 84%), alfuzosin (n=20,827, 14%) and silodosin (n=2,720, 2%). We found 10 11 12 that men initiating a prostate-specific alpha antagonist had a significantly increased risk of both 13 14 falling (OR 1.14, 95% CI 1.07 to 1.21, absolute risk increase 0.17%, 95% CI 0.08 to 0.25%) and of 15 16 17 sustaining a fracture (OR 1.16, 95% CI 1.04 to 1.29, absolute risk increase 0.06%, 95% CI 0.02 to 18 19 0.11%). This increased risk was not observed in the time period prior to alpha antagonist 20 21 initiation. Secondary outcomes of hypotension and head trauma were also significantly increased 22 23 24 among men exposed to prostate-specific alpha antagonists (OR 1.80, 95% CI 1.59 to 2.03 and OR 25 26 1.15, 95% CI 1.04 to 1.27 respectively). 27 28 29 30 31 Conclusions and Relevance: Prostate-specific alpha antagonists are associated with a small, but 32 33 34 significantly increased risk of fall, fracture, and head trauma, likely as a result of medication- 35 36 induced hypotension. Caution should continue to be exercised with the initiation of these 37 38 medications. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 4 https://mc.manuscriptcentral.com/bmj Page 5 of 44 BMJ 1 2 Introduction 3 4 5 6 7 As men age, a significant number will develop bothersome lower urinary tract symptoms, such as 8 Confidential: For Review Only 9 urinary frequency, urgency, nocturia and a weak urinary stream. These symptoms are often 10 11 12 attributed to benign prostatic hyperplasia (BPH) and are frequently treated due to their negative 13 14 impact on quality of life[1]. The introduction of several alpha antagonist medications in the 15 16 17 1990’s fundamentally changed the treatment of BPH and lower urinary tract symptoms[2,3]. 18 19 These medications relax the prostatic smooth muscle, and improve urinary flow rates and 20 21 symptoms[1,2]. 22 23 24 25 26 Nonspecific (first generation) alpha antagonists, such as doxazosin and terazosin, act on all ααα1 27 28 29 receptor subtypes (ααα1A, B, D ), and are used for both the treatment of BPH and for hypertension. 30 31 32 This nonselective ααα1 receptor activity requires dose titration over 1-2 weeks to avoid 33 34 symptomatic hypotension from ααα1B antagonism. These nonspecific alpha antagonists have 35 36 37 generally fallen into disfavor as antihypertensives since the ALLHAT trial[4]. In this randomized, 38 39 double-blind trial, traditional antihypertensive medicines (including nonspecific alpha 40 41 42 antagonists) were compared with newer classes of antihypertensives; the doxazosin arm was 43 44 stopped early due to a higher rate of cardiac dysfunction . Similarly, among men with BPH 45 46 47 symptoms these nonspecific alpha antagonists have largely been replaced by prostate-specific 48 49 (second generation) alpha antagonists[5]. These newer medications do not need dose titration 50 51 and are solely indicated for male urinary symptoms from BPH. They include alfuzosin (which 52 53 54 exhibits clinical uroselectivity), and tamsulosin and silodosin (which exhibit true ααα1A receptor 55 56 57 selectivity, which is the primary alpha receptor in the prostate)[6-9].