Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2019-033150 on 24 September 2019. Downloaded from http://bmjopen.bmj.com/ on April 30, 2021 at Univesity Autonomous of Barcelona. Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) international randomised controlled trial Flavia K Borges,‍ ‍ 1,2 P J Devereaux,2,3 Meaghan Cuerden,4 Mohit Bhandari,5 Ernesto Guerra-Farfán,6 Ameen Patel,1 Alben Sigamani,7 Masood Umer,8 John Neary,1 Maria Tiboni,1 Vikas Tandon,1 Mmampapatla Thomas Ramokgopa,9,10 Parag Sancheti,11 Bobby John,12 AbdelRahman Lawendy,13 Mariano Balaguer-Castro,‍ ‍ 14 Richard Jenkinson,15,16 Paweł Ślęczka,17 Aamer Nabi Nur,18 Gavin C A Wood,19 Robert Feibel,20 John Stephen McMahon,21 Alen Sigamani,22 Bruce M Biccard,23 Giovanni Landoni,24,25 Wojciech Szczeklik,26 To cite: Borges FK, Chew Yin Wang,‍ ‍ 27 Jordi Tomas-Hernandez,6 Valsa Abraham,12 Jessica Vincent,2 Devereaux PJ, Cuerden M, Protected by copyright. et al. Effects of accelerated Valerie Harvey,2 Shirley Pettit,2 Jessica Sontrop,28 Amit X Garg,3,4,28 On behalf of versus standard care surgery HIP ATTACK investigators on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture Accelerated surgical TreaTment And Abstract Strengths and limitations of this study Care tracK (HIP ATTACK) Introduction Inflammation, dehydration, hypotension and international randomised bleeding may all contribute to the development of acute ►► Hip fracture accelerated surgical treatment and care controlled trial. BMJ Open kidney injury (AKI). Accelerated surgery after a hip fracture track is a large international trial designed to ad- 2019;9:e033150. doi:10.1136/ can decrease the exposure time to such contributors and dress whether early surgery can improve outcomes bmjopen-2019-033150 may reduce the risk of AKI. in patients with a hip fracture. ►► Prepublication history and Methods and analysis Hip fracture Accelerated surgical ►► This substudy will provide robust estimates on the additional material for this TreaTment And Care tracK (HIP ATTACK) is a multicentre, effects of early versus later surgery on the risk of paper are available online. To international, parallel-group randomised controlled trial acute kidney injury. view these files, please visit (RCT). Patients who suffer a hip fracture are randomly ►► Patients and providers are not blinded to the inter- the journal online (http://​dx.​doi.​ allocated to either accelerated medical assessment and vention; however, objective measures are used to org/​10.​1136/​bmjopen-​2019-​ surgical repair with a goal of surgery within 6 hours of 033150). assess outcomes and outcome assessors are blind- diagnosis or standard care where a repair typically occurs ed to the intervention assignment. 24 to 48 hours after diagnosis. The primary outcome of Received 22 July 2019 this substudy is the development of AKI within 7 days of Revised 28 August 2019 Accepted 29 August 2019 randomisation. We anticipate at least 1998 patients will participate in this substudy. 90-day risk of mortality is 10%–20%. Short- Ethics and dissemination We obtained ethics approval ening the time to surgery shows promise for for additional serum creatinine recordings in consecutive reducing patient morbidity and mortality,3–5 © Author(s) (or their patients enrolled at 70 participating centres. All patients and this strategy is currently being tested in employer(s)) 2019. Re-use provide consent before randomisation. We anticipate comparison with usual care in a multinational permitted under CC BY-NC. No reporting substudy results by 2021. randomised controlled trial: the Hip fracture commercial re-use. See rights and permissions. Published by Trial registration number NCT02027896; Pre-results. Accelerated surgical TreaTment And Care BMJ. tracK (HIP ATTACK) trial.6 HIP ATTACK has For numbered affiliations see two coprimary outcomes: the 90-day risk of end of article. Introduction (1) all-cause mortality and (2) major periop- Correspondence to Each year, millions of adults worldwide erative complications. Dr Amit X Garg; sustain a hip fracture and require surgical One lesser known complication of hip ​amit.​garg@l​ hsc.​on.​ca repair.1 2 Complications are common, and the fracture is acute kidney injury (AKI). The Borges FK, et al. BMJ Open 2019;9:e033150. doi:10.1136/bmjopen-2019-033150 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-033150 on 24 September 2019. Downloaded from http://bmjopen.bmj.com/ on April 30, 2021 at Univesity Autonomous of Barcelona. development of AKI associates with a longer hospital which there is no reversing agent available; (6) patients on stay, increased healthcare costs and a higher risk of therapeutic vitamin K antagonist with a history of heparin death.7–9 Approximately 15%–20% of patients who induced thrombocytopaenia (7) patients refusing partici- undergo surgery for a hip fracture will experience AKI, pation and (8) patients previously enrolled in the trial. with 0.5%–1.8% receiving dialysis as a result.10–12 A hip All patients enrolled in HIP ATTACK after the centre of fracture exposes patients to trauma, pain, bleeding, hypo- enrolment initiated kidney data collection will be included tension and dehydration, which can lead to decreased in the final substudy analysis with the exception of the renal perfusion and a heightened inflammatory state, all following: of which can contribute to the development of AKI.13 14 A i. Patients with prerandomisation end-stage kidney dis- shorter time to surgery after a hip fracture can decrease ease defined as prerandomisation estimated glomer- the exposure time to such contributors and therefore ular filtration rate (eGFR) <15 mL/min per 1.73 m2, may reduce the risk of AKI. receipt of chronic dialysis or a kidney transplant. These This protocol describes a planned kidney substudy of patients will be excluded because the prevention of the HIP ATTACK trial to determine if a strategy of accel- AKI is no longer relevant. We expect less than 2% of erated medical assessment and surgical repair, compared randomised patients to be excluded for this reason. with usual care, reduces the risk of AKI in patients who ii. Patients with no prerandomisation serum creatinine suffer a hip fracture. To do this, we worked with the inves- measurement since this measure is needed to identify tigators of the main trial during its planning stages and AKI, which is defined by an acute increase in serum arranged to provide substudy funding to trial centres creatinine from the prerandomisation value. We ex- to collect additional follow-up measures of serum creat- pect approximately 24% of patients to be excluded inine. A subgroup analysis by baseline chronic kidney for this reason. disease (CKD), the most prominent risk factor for AKI, will also be conducted.15 Randomisation Randomisation was performed at the time of consent via an interactive web randomisation system maintained by Methods and analysis the trial coordinating centre at the Population Health Protected by copyright. Overview of the main HIP ATTACK trial Research Institute, part of McMaster University in The HIP ATTACK trial is a multinational, parallel-group Hamilton, Ontario, Canada. This method ensures that the superiority randomised controlled trial of patients who randomisation sequence is concealed from participating present to the emergency department with a hip frac- centres and patients. Patients were randomly allocated ture requiring surgical repair. The main trial protocol (1:1) to receive the intervention of accelerated medical is described elsewhere.6 Briefly, patients who sustained clearance and surgery or usual care. The randomisation a hip fracture were randomly allocated (1:1) to receive was performed using random permuted blocks of varying accelerated medical assessment and surgical repair (with sizes that were unknown to research personnel and inves- the goal of having the surgery performed within 6 hours tigators. Stratification occurred by centre and planned after the orthopaedic diagnosis) or usual care (where surgery type (open reduction and internal fixation or a repair typically occurs 24–48 hours after diagnosis). arthroplasty). Due to the nature of the trial intervention, Enrolment occurred between March 2014 and May 2019, it was not possible to blind research personnel, health- and 3001 patients from 70 centres in 18 countries were care providers or participants to the randomised alloca- randomised. Follow-up assessments will continue until tion; however, data collectors and outcome adjudicators August 2019 for the primary analysis. All participating were unaware of the patient’s randomised allocation. centres obtained ethics board approval to conduct the trial, and all patients provided informed consent to trial Trial intervention participation before enrolling. The trial intervention was an accelerated medical assess- ment and surgical repair, with the goal of performing Patient recruitment, eligibility and informed consent the surgery within 6 hours of the orthopaedic diagnosis. Patients were recruited from the emergency department. Patients underwent medical clearance by an on-call Eligibility criteria for the main HIP ATTACK trial are medical specialist (ie, an internist, geriatrician, cardiol- fully detailed in the published protocol.6 Eligible patients ogist or anaesthesiologist) who was able to quickly come included those aged 45 years or older diagnosed with a to the emergency department and perform the assess- hip fracture with a low-energy mechanism (eg, a fracture ment. Specialists used their own clinical judgement sustained from a fall not beyond standing height) requiring and weighed the potential risks and benefits of rapidly surgery. To align with the ability to deliver the trial interven- clearing patients for surgery.3 6 The patient’s orthopaedic tion, the diagnosis had to be made during working hours. surgeon and anaesthesiologist also had to agree that the Exclusion criteria were as follows: (1) patients requiring patient was an appropriate surgical candidate. Following emergent surgery or emergent interventions for another medical clearance, research personnel informed all rele- reason; (2) open hip fracture; (3) bilateral hip fractures; (4) vant parties (ie, the surgical booking clerk, orthopaedic periprosthetic fracture; (5) therapeutic anticoagulation for surgeon and anaesthesiologist), and patients were moved 2 Borges FK, et al. BMJ Open 2019;9:e033150. doi:10.1136/bmjopen-2019-033150 Open access BMJ Open: first published as 10.1136/bmjopen-2019-033150 on 24 September 2019. Downloaded from http://bmjopen.bmj.com/ on April 30, 2021 at Univesity Autonomous of Barcelona. to the next available orthopaedic trauma room or elective postrandomisation serum creatinine—prerandomisa- operating room such that their surgeries were prioritised tion serum creatinine)/prerandomisation serum cre- over scheduled elective cases. All other perioperative care atinine) times 100. was at the discretion of the attending team. Further logis- 6. Absolute change in serum creatinine in the first 7 days tical details are provided in the pilot report and the main after randomisation, defined as follows: peak postran- trial protocol.3 6 domisation serum creatinine—prerandomisation se- Patients randomly allocated to the usual-care group rum creatinine. were placed on the wait list for surgery according to local standard practices. Statistical considerations Sample size Substudy data collection The main HIP ATTACK trial enrolled 3001 patients, and The prerandomisation (baseline) serum creatinine concen- more than 90% of these patients were enrolled after tration was obtained from a review of medical records in the initiation of the renal substudy protocol. We expect the 30-day period before hip fracture surgery (as part of that approximately 74% of these patients will be eligible routine care, most patients have their serum creatinine for inclusion in the kidney substudy. A sample of 1998 tested at the time of emergency room presentation). The patients will provide over 80% power to detect a relative most recent test result before randomisation will serve as risk (RR) reduction of 30% for the primary outcome the baseline value. To accurately capture postrandomis- of AKI (two-sided α=0.05), comparing the accelerated ation AKI, all study centres were given substudy funds to approach to usual care, assuming the incidence of AKI measure and record daily serum creatinine values for 7 days is 14% in the usual-care group, after accounting for 4% after randomisation or until hospital discharge, whichever missing AKI status. Approximately 10%–12% of patients came first. The highest serum creatinine value recorded develop postoperative AKI.17 18 In hip fracture patients, between randomisation and hospital discharge was also AKI incidence is even higher, around 15%–20%.10–12 With recorded. Research personnel followed all patients daily these data in mind, we used a conservative 14% AKI inci- during their time in hospital to improve adherence to the dence for the usual care group to perform the sample scheduled creatinine measurements. Receipt of new dial- size calculation to ensure we would have adequate statis- Protected by copyright. ysis for kidney failure was recorded at hospital discharge tical power to detect a 30% RR reduction in the primary and at 30 days after randomisation. outcome, if it in truth exists. Substudy outcomes The primary outcome of the kidney substudy is AKI, Statistical analysis plan defined as an increase in the serum creatinine concentra- In the primary analysis (intention to treat), a modified tion from the prerandomisation value of ≥26.5 μmol/L Poisson regression model which accounts for the treating (≥0.3 mg/dL) within 48 hours after randomisation or an centre will be used to estimate the RR and 95% CI for increase of ≥50% within 7 days after randomisation.16 AKI comparing the intervention group to the usual-care group.19 20 For patients enrolled in the substudy without a Secondary definitions of AKI postrandomisation serum creatinine value (expected for Six secondary assessments of AKI will be examined to ≤4% of patients), for the primary analysis model-based assess whether the primary results are robust: multiple imputation methods, using all available data, will 1. A composite of AKI (primary outcome definition) be used to impute AKI status.18 21 22 Parameters will be esti- or death within 48 hours after randomisation which mated using standard methods while allowing for extra will serve to account for the potential impact of early imputation variability.23 A two-tailed p value <0.05 will be deaths on outcome ascertainment. considered statistically significant. In our experience, with 2. Stage 2 AKI (or higher), defined as a postrandomis- previous AKI perioperative substudies of large clinical ation increase in serum creatinine of 100% or more trials, the unadjusted and adjusted results were virtually from the prerandomisation value within 7 days after identical,18 24 25 and therefore we have not prespecified randomisation or an increase to an absolute value of any adjusted analyses for this substudy. 353.6 μmol/L or more (≥4.0 mg/dL) within 7 days af- ter randomisation (when the primary outcome defini- Prespecified supporting analyses tion of AKI is met) or receipt of dialysis within 30 days Several supporting analyses will be conducted to examine after randomisation. whether there is concordance with the primary analysis. 3. Stage 3 AKI, defined as a postrandomisation increase in These will include a complete case analysis, an examination serum creatinine of 200% or more from the prerando- of six secondary assessments of AKI and a subgroup analysis misation value within 7 days after randomisation or an of patients with prerandomisation CKD. increase to an absolute value of 353.6 μmol/L or more (≥4.0 mg/dL) within 7 days after randomisation or re- Complete case analysis ceipt of dialysis within 30 days after randomisation. We will perform a complete case analysis restricted to 4. Receipt of dialysis within 30 days after randomisation. patients with at least one postrandomisation serum creat- 5. Percentage change in serum creatinine in the first 7 inine measurement which is expected to involve greater days after randomisation, defined as follows: ((peak than 96% of patients in the primary analysis. Borges FK, et al. BMJ Open 2019;9:e033150. doi:10.1136/bmjopen-2019-033150 3 Open access BMJ Open: first published as 10.1136/bmjopen-2019-033150 on 24 September 2019. Downloaded from http://bmjopen.bmj.com/ on April 30, 2021 at Univesity Autonomous of Barcelona. Alternative secondary assessments of AKI the risk of AKI compared with a usual care. The strengths We will examine six secondary assessments of AKI (four of this substudy include its randomised trial methodology categorical and two continuous, as described above). with concealed allocation, patient recruitment from 70 RR estimates will be estimated using modified Poisson centres across 18 countries and standardised collection regression models and continuous outcomes using linear of postrandomisation serum creatinine. The primary regression models. We will visually inspect the point outcome and statistical analysis plan are prespecified, and estimates and 95% CIs and assess concordance with the multiple sensitivity analyses are planned to examine the primary analysis. Given our sample size, analyses of severe robustness of the primary results. AKI will have limited statistical power for small effects. This substudy has some limitations. First, given the trial’s design, we expect that approximately 76% of patients’ Subgroup analysis baseline (prerandomisation) serum creatinine will be The risk of AKI will be examined in patients with and obtained at the time of emergency room presentation without CKD as defined by a prerandomisation eGFR for hip fracture, and depending on the circumstances <60 mL/min per 1.73 m² as assessed with the Chronic of the fracture, some of these patients’ serum creatinine Kidney Disease Epidemiology Collaboration (CKD-EPI) concentrations may be unstable or elevated. Instability in equation.26 We hypothesise a greater absolute risk reduc- baseline serum creatinine may make it difficult to detect tion of AKI with accelerated versus routine surgery in an acute rise in postrandomisation serum creatinine, patients with CKD compared with patients without CKD. which is needed for the identification of AKI. To examine The p value for the interaction (CKD × intervention this issue, we will compare the mean baseline serum creat- group) will be assessed in a regression model for binary inine concentration in a subset of patients with serum outcome data. creatinine measurements before and after hip fracture. Second, similar to other perioperative studies,18 24 25 urine Patient and public involvement statement output data are not collected in HIP ATTACK given the There was no direct patient involvement in designing this difficulties with accurate measurement in the setting of substudy. Previously, we reported the patient involvement international data collection. Third, the most clinically in the main trial in the HIP ATTACK protocol paper.6 relevant renal outcome would be new kidney failure Protected by copyright. treated with dialysis. Although we are measuring this Ethics and dissemination outcome, we anticipate that it will occur infrequently We obtained ethics approval in all centres, and all patients (<1%), and therefore the analysis of this outcome will provided informed consent before randomisation (see have limited statistical power. Finally, we have over 80% online supplementary material). The dissemination power to detect a 30% or more relative risk reduction in policy will include publication in a peer-reviewed journal our primary outcome of AKI. As previously described, and presentations at relevant conferences. The clinical we will examine changes in the perioperative concentra- results of this substudy will be incorporated in the HIP tion of serum creatinine as a continuous measure, which ATTACK dissemination plan, including reporting the might be of particular relevance if the primary outcome is results in the HIP ATTACK open website (http://www.​ not significant and there are concerns that this is due to a hipattacktrial.​com), the HIP ATTACK Twitter account (@ lack of statistical power. HIPATTACKTrial), LinkedIn Profile, the Facebook page In summary, this prespecified substudy of HIP ATTACK, and the Reducing Global Perioperative Risk Multimedia a large multinational trial, will address the question Resource Center. This is an online media linked to Else- whether a strategy of accelerated medical clearance and vier’s entire international readership, through which we surgery for hip fracture improves renal outcomes. will disseminate the full-text articles, links to abstracts Author affiliations and data summaries. We expect the substudy results to be 1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada reported by 2021. 2 Department of Perioperative Medicine, Population Health Research Institute, Hamilton, Ontario, Canada 3 Departments of Health Research Methods, Evidence, and Impact (HEI), McMaster Discussion University, Hamilton, Ontario, Canada 4 HIP ATTACK is a multinational randomised controlled Division of Nephrology, Department of Medicine, Western University, London, trial that will determine if a strategy of accelerated medical Ontario, Canada 5 Department of Surgery, McMaster University, Hamilton, Ontario, Canada clearance and surgery compared with usual care improves 6 Department of Orthopaedic Surgery and Traumatology, University Hospital Vall outcomes for patients with a hip fracture. The present d'Hebron, Barcelona, Spain protocol describes a prespecified kidney substudy of HIP 7 Clinical Research, Narayana Hrudayalaya Limited, Bangalore, India ATTACK that will examine the effect of this strategy on the 8 Department of Orthopaedic Surgery, Aga Khan University, Karachi, Pakistan 9 risk of AKI. Department of Orthopaedic Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa AKI is a known consequence of surgery. By adding addi- 10 Department of Orthopaedic Surgery, University of the Witwatersrand, tional serum creatinine measurements to HIP ATTACK, Johannesburg, South Africa we will efficiently and reliably determine whether a strategy 11 Department of Orthopaedic Surgery, Sancheti Institute for Orthopaedics & of accelerated medical clearance and hip surgery reduces Rehabilitation, Pune, India 4 Borges FK, et al. BMJ Open 2019;9:e033150. doi:10.1136/bmjopen-2019-033150 Open access BMJ Open: first published as 10.1136/bmjopen-2019-033150 on 24 September 2019. Downloaded from http://bmjopen.bmj.com/ on April 30, 2021 at Univesity Autonomous of Barcelona. 12 Department of Orthopaedic Surgery, Christian Medical College and Hospital Ashraf; Aga Khan University (166) P.M. Hashmi, R.H. Lakdawala, M.J. Khattak, H. Ludhiana, Ludhiana, India Rashid, D. Begum; Poland (86) – SPZOZ Myślenice (81): J.W. Rycombel, W. Satora, 13 Department of Surgery, Western University, London, Ontario, Canada W. Ambroży, A. Grzelak; Medical University in Lodz (1): W. Machala; SPZOZ Szpital 14 Department of Orthopaedic Surgery and Traumatology, Parc Taulí Hospital Powiatowy w Bochni im M. Wieckiej (4): J. Gucwa; South Africa (131) – University of Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma Witwatersrand (114): G. Firth, A. Grisillo-Biscardi, G. Karera, M. Fourtounas; Groote de Barcelona, Sabadell, Spain Schuur Hospital (12): M. Nejthardt; Tygerberg Hospital, Stellenbosch University (5):S. 15 Department of Surgery and Institute of Health Policy Management and Evaluation, Chetty; Spain (534) – Vall d'Hebron University Hospital (300): Jordi Teixidor-Serra, University of Toronto, Toronto, Ontario, Canada V. Molero-García, J. Minguell-Monyart, Y. García-Sánchez, J.A. Porcel-Vázquez, J. 16 Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Selga-Marsà, M. Villar-Casares, J. Mestre-Torres; Hospital Universitario Costa del Canada Sol (17): E. Guerado, E. Cruz; Hospital de la Santa Creu I Sant Pau (26): E. Popova, 17 Orthopaedic Department, SPZOZ, Myslenice, Poland J.D. Caso, J.L. Higa-Sansone, R. Anaya; Hospital Universitari Mútua Terrassa (41): 18 P. Castillón, M. Bernaus, S. Quintas; Parc Taulí Hospital Universitari (87): P. Torner, Department of Orthopaedic Surgery, Shifa International Hospital, Islamabad, F.A. Marcano-Fernández, M. Jornet-Gibert, J. Cámara-Cabrera; Consorci Sanitari Pakistan 19 del Garraf (37): A. D. Andrés, O.M. Pérez, L.A. Ivanov; Hospital Clínico Universitario Department of Surgery, Queen's University, Kingston, Ontario, Canada 20 de Valladolid (26): H.J. Aguado; Thailand (36) – Ramathibodi Hospital (36): P. Sa- Division of Orthopaedic Surgery, Department of Surgery, University of Ottawa, ngasoongsong; United Kingdom (82) – Chelsea and Westminster Hospital (17): M.P. Ottawa, Ontario, Canada Vizcaychipi; Peterborough City Hospital (6): M.J. Parker; West Middlesex University 21 Department of Surgery, Markham Stouffville Hospital, Markham, Ontario, Canada Hospital (32): M.A. Kadry, S. Thayaparan; Sherwood Forest Hospitals (11): J. John; 22 Department of Orthopaedic, Government TD Medical College, Allapuzha, India Calderdale & Huddersfield NHS Foundation Trust (16): A.S.E. Mayor; United States 23 Department of Anaesthesia and Perioperative Medicine, University of Cape Town, (76) – Tufts Medical Center (15): S.P. Ryan; The Ohio State University (13): S.D. Rondebosch, South Africa Bergese; Lahey Hospital & Medical Center (3): A.J. Marcantonio; University of 24 Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Scientific Maryland (18): G.P. Slobogean; University of California San Francisco (27): M.T. Institute, Milan, Italy Marmor; Venezuela (29) – Hospital Universitario de Caracas (29): I.A. Escalante 25 Department of Anaesthesia and Intensive Care, Vita-Salute San Raffaele Elguezabal, C.G. Sanchez Valenciano University, Milan, Italy 26 Contributors FKB, PJD, MC, JMS and AXG: wrote the first draft of the protocol Department of Intensive Care and Perioperative Medicine, Jagiellonian University manuscript. FKB, PJD, MC, MB, EGF, AP, AS, MU, JN, MT, VT, MTR, PSa, BJ, ARL, Medical College, Krakow, Poland MBC, RJ, PSl, ANN, GCAW, RF, JSM, AS, BMB, GL, WS, CYW, JTH, VA, JV, VH, SP, JMS, 27 Department of Anaesthesiology, University Malaya, Kuala Lumpur, Malaysia AXG planned the conceptualisation and the design of the study and the protocol. All 28 Department of Epidemiology and Biostatistics, Western University, London, authors contributed to critical revisions of the current manuscript. Ontario, Canada Funding This work was supported by the following grants: Canadian Institute of Health and Research (CIHR) Foundation Award, CIHR’s Strategy for Patient Oriented Collaborators Population Health Research Institute Coordinating Centre: V. Harvey Protected by copyright. Research (SPOR), through the Ontario SPOR Support Unit, which is supported by (Trial Coordinator), J. Vincent, S. Dragic-Taylor, S. Molnar, S. Pettit, J.R. Wells Trial the CIHR and the Province of Ontario, as well as the Ontario Ministry of Health and Monitoring Committee: R. Roberts, Chairperson (McMaster University), F. McAlister Long-Term Care, and a grant from Smith & Nephew to recruit 300 patients in Spain. (University of Alberta), D. Sackett (McMaster University), J. Wright (University Grants to support this substudy were provided by the Department of Medicine at of Oxford)Participating Countries, Centres, and Investigators (recruitment in Western University. Dr Devereaux was supported by a Tier 1 Canada Research Chair brackets): Belgium (47) – Cliniques Universitaires Saint-Luc (32): L. Veevaete, B. in Perioperative Medicine. Dr Amit Garg was supported by the Dr Adam Linton Chair le Polain de Waroux, A. Dekleermaker; UZ Brussel (15): P. Forget, M. Reul; Canada in Kidney Health Analytics and a CIHR Clinician Investigator Award. (983) – Juravinski Hospital and Cancer Centre (293): D. Cowan, A. Worster, G. Guyatt, C. Kearon, D. Simpson, K. Gregus, K. Lawrence; St. Joseph's Healthcare Disclaimer The conduct, trial analyses, the composing of this manuscript and its (134): A. Adili, V. Khanna, D. Conen, J. Farrell; Sunnybrook Health Sciences Centre final contents are solely the author’s incumbency. (81): H.J. Kreder, S. Choi, S. Shadowitz, J.S. Lee; Thunder Bay Regional Health Competing interests None declared. Sciences Centre (37): D. Puskas, C. Cullinan, K. Droll; St. Michael's Hospital (44): A. Nauth, T. Daniels, M.R. Vicente; William Osler Health System, Etobicoke General Patient consent for publication Not required. Hospital (13): A. Sharma; Vancouver General Hospital (5): P. Guy; Kingston Health Ethics approval Hamilton Integrated Research Ethics Board. number 14-058. All Sciences Centre (75): M. Sivilotti, M. Jaeger; S. Mann, F. Howells; Markham other Ethics board are listed on the Supplementary File, Ethics Committees – pages Stouffville Hospital (58): L.M. McLean, H. Shirali; London Health Sciences Centre, 4 to 6. Victoria Hospital (92): G.K. Dresser, D.W. Sanders, E.H. Schemitsch, W. Kishta; The Provenance and peer review Not commissioned; externally peer reviewed. Ottawa Hospital, General Campus (60): C. Gallant, S. Halman, K.M. McIlquham, V. Thiruganasambandamoorthy; QE II Health Sciences Centre (25): C.P. Coles, K. Trask; Open access This is an open access article distributed in accordance with the Humber River Hospital (2): A.W. Duncan; University of Alberta (30): M.J. Jacka, Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which M. Menon; Concordia Hospital (12): T.R. Turgeon; University of Calgary (13): N.J. permits others to distribute, remix, adapt, build upon this work non-commercially, White; Grand River Hospital (8): S. Giilck; Royal Victoria Hospital (1): G. Crawford; and license their derivative works on different terms, provided the original work is China (28) – Beijing Chaoyang Hospital (28): J. Zhou; Colombia (1) – Fundación properly cited, appropriate credit is given, any changes made indicated, and the use Cardioinfantil (1): J.M. Muñoz McCausland; France (46) – Centre Hospitalier Lyon is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. Sud (43): P. Chaudier, M. Douplat; Nîmes University Hospital (3): P. Landais; Hong Kong (12) – The University of Hong Kong, Queen Mary Hospital (12): C.X. Fang; India (471) – PGIMER (23): M.S. Dhillon; Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata (9): S.U. Singh; JIPMER (45): S. Adinarayanan, D. References 1. Leslie WD. Trends in hip fracture rates in Canada. JAMA 2009;302. Sharma; Government TD Medical College Alappuzha (50): M. Stephen, M. Ashraf; 2. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Sancheti Institute for Orthopaedics & Rehabilitation (102): C.V. Pradhan, M.P. Bull World Health Organ 2003;81:646–56. Borate, A. 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