Efficacy and Mechanism Evaluation

Effect of Remote Ischaemic preconditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA study): a multicentre double-blind randomised controlled clinical trial Derek J Hausenloy,1,2,3,4*† Luciano Candilio,1† Richard Evans,5 Cono Ariti,5 David P Jenkins,6 Shyamsunder Kolvekar,7 Rosemary Knight,5 Gudrun Kunst,8 Christopher Laing,9 Jennifer M Nicholas,5 John Pepper,10 Steven Robertson,5 Maria Xenou,1 Timothy Clayton5 and Derek M Yellon1,2 1Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, UK 2National Institute for Health Research, University College London Hospitals Biomedical Research Centre, London, UK 3National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 4Cardiovascular and Metabolic Disorders Program, Duke–National University of Singapore, Singapore 5Clinical Trials Unit, London School of Hygiene & Tropical Medicine, London, UK 6Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, UK 7The Heart Hospital, University College London Hospitals NHS Foundation Trust, London, UK 8Department of Anaesthetics and Pain Therapy, King’s College London and King’s College Hospital, London, UK 9University College London Centre for Nephrology, Royal Free Hospital, London, UK 10National Institute for Health Research Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK *Corresponding author derek.hausenloy@duke-nus.edu. sg †Derek J Hausenloy and Luciano Candilio are joint first authors Background: Novel cardioprotective strategies are required to improve clinical outcomes in higher-risk patients undergoing coronary artery bypass graft (CABG) with or without valve surgery. Remote ischaemic preconditioning (RIPC) in which brief episodes of non-lethal ischaemia and reperfusion are applied to the arm or leg has been demonstrated to reduce perioperative myocardial injury (PMI) following CABG with or without valve surgery. Objective: To investigate whether or not RIPC can improve clinical outcomes in this setting in the Effect of Remote Ischaemic preconditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA) study in patients undergoing CABG surgery. Design: Multicentre, double-blind, randomised sham controlled trial. Setting: The study was conducted across 30 cardiothoracic centres in the UK between March 2010 and March 2015. DOI: 10.3310/eme03040 EFFICACY AND MECHANISM EVALUATION 2016 VOL. 3 NO. 4 © Queen’s Printer and Controller of HMSO 2016. This work was produced by Hausenloy et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii Participants: Eligible patients were higher-risk adult patients (aged > 18 years of age; additive European System for Cardiac Operative Risk of ≥ 5) undergoing on-pump CABG with or without valve surgery with blood cardioplegia. Interventions: Patients were randomised to receive either RIPC (four 5-minute inflations/deflations of a standard blood pressure cuff placed on the upper arm) or the sham control procedure (simulated RIPC protocol) following anaesthetic induction and prior to surgical incision. Anaesthetic management and perioperative care were not standardised. Main outcome measures: The combined primary end point was the rate of major adverse cardiac and cerebral events comprising cardiovascular death, myocardial infarction, coronary revascularisation and stroke within 12 months of randomisation. Secondary end points included perioperative myocardial and acute kidney injury (AKI), intensive care unit and hospital stay, inotrope score, left ventricular ejection fraction, changes in quality of life and exercise tolerance. Results: In total, 1612 patients (sham control group, n= 811; RIPC group, n= 801) were randomised in 30 cardiac surgery centres in the UK. There was no difference in the primary end point at 12 months between the RIPC group and the sham control group (26.5% vs. 27.7%; hazard ratio 0.95, 95% confidence interval 0.79 to 1.15; p= 0.58). Furthermore, there was no evidence for any differences in either adverse events or the secondary end points of PMI (72-hour area under the curve for serum high-sensitivity troponin T), inotrope score, AKI, intensive therapy unit and hospital stay, 6-minute walk test and quality of life. Conclusions: In patients undergoing elective on-pump CABG with or without valve surgery, without standardisation of the anaesthetic regimen, RIPC using transient arm ischaemia–reperfusion did not improve clinical outcomes. It is important that studies continue to investigate the potential mechanisms underlying RIPC, as this may facilitate the translation of this simple, non-invasive, low-cost intervention into patient benefit. The limitations of the study include the lack of standardised pre-/perioperative anaesthesia and medication, the level of missing and incomplete data for some of the secondary end points and the incompleteness of the data for the echocardiography substudy. Trial registration: ClinicalTrials.gov NCT01247545. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and NIHR partnership, and the British Heart Foundation. ABSTRACT NIHR Journals Library www.journalslibrary. nihr.ac. uk viii