The REFLO-STEMI (REperfusion Facilitated by LOcal adjunctive therapy in ST-Elevation Myocardial Infarction) trial: a randomised controlled trial comparing intracoronary administration of adenosine or sodium nitroprusside with control for attenuation of microvascular obstruction during primary percut

The REFLO-STEMI (REperfusion Facilitated by LOcal adjunctive therapy in ST-Elevation Myocardial Infarction) trial: a randomised controlled trial comparing intracoronary administration of adenosine or sodium nitroprusside with control for attenuation of microvascular obstruction during primary percutaneous coronary intervention Sheraz A Nazir,1 Jamal N Khan,1 Islam Z Mahmoud,2 John P Greenwood,3 Daniel J Blackman,3 Vijay Kunadian,4 Martin Been,5 Keith R Abrams,6 Robert Wilcox,7 AA Jennifer Adgey,8 Gerry P McCann1 and Anthony H Gershlick1* 1Department of Cardiovascular Sciences, University of Leicester and the National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK 2Department of Cardiovascular Imaging, Division of Imaging Sciences & Biomedical Engineering, Rayne Institute, BHF Excellence Centre, St Thomas’ Hospital, King’s College London, London, UK 3Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK 4Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University and Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 5Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK 6Centre for Biostatistics and Genetic Epidemiology, Department of Health Sciences, School of Medicine, University of Leicester, Leicester, UK 7Faculty of Medicine and Health Sciences, Queen’s Medical Centre, Nottingham, UK 8Heart Centre, Royal Victoria Hospital, Belfast, UK *Corresponding author agershlick@aol.com Background: Microvascular obstruction (MVO) predicts shortand longer-term outcomes following primary percutaneous coronary intervention (PPCI) treatment of ST-elevation myocardial infarction (STEMI). The evidence base supporting the role of adenosine and sodium nitroprusside (SNP), the most evaluated adjunctive therapies aimed at attenuating MVO and infarct size, remains weak as the trials involved have had variable end points and used differing drug doses and modes of delivery. Objective: To determine whether intracoronary administration of adenosine or SNP following thrombus aspiration reduces infarct size and/or MVO measured by cardiac magnetic resonance (CMR) imaging in patients undergoing PPCI within 6 hours of onset of STEMI. Design: Multicentre, prospective, parallel, randomised controlled and open-label trial with blinded end point analysis. DOI: 10.3310/eme03090 EFFICACY AND MECHANISM EVALUATION 2016 VOL. 3 NO. 9 © Queen’s Printer and Controller of HMSO 2016. This work was produced by Nazir 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 Setting: Four high-volume UK PPCI centres. Participants: Patients with STEMI undergoing PPCI with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0/1 in the infarct-related artery and no significant bystander coronary artery disease on angiography. Interventions: Participants were anticoagulated with bivalirudin and allocated by an automated 24-hour telephone randomisation service to one of three groups: (1) standard PPCI (control), (2) PPCI with adjunctive adenosine 1–2 mg or (3) PPCI with adjunctive SNP 250 μg. The study drugs were delivered intracoronary immediately following thrombus aspiration and again following successful stenting. Main outcome measures: The primary outcome was infarct size (% total left ventricular end-diastolic mass; %LVM) measured by CMR imaging undertaken 48–96 hours post PPCI. Secondary outcome measures included MVO (hypoenhancement within the infarct core) on CMR imaging, electrocardiographic and angiographic markers of microvascular perfusion and major adverse cardiac events (MACEs) during a median of 6 months’ follow-up. The study aimed to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in infarct size). Results: The trial completed recruitment in April 2014 having randomised 247 patients (standard PPCI group, n = 86; PPCI + adenosine group, n = 82; PPCI + SNP group, n = 79). In total, 79% of participants were male and the mean ± standard deviation age of participants was 59.3 ± 12.3 years. CMR imaging was completed in 197 (80%) patients (standard PPCI, n = 65; PPCI + adenosine, n = 63; PPCI + SNP, n = 69) for the primary outcome. There was no significant difference in infarct size [%LVM, median, interquartile range (IQR)] between the adenosine group (10.1, 4.7–16.2), the SNP group (10.0, 4.2–15.8) and the control group (8.3, 1.9–14.0) (p = 0.062 and p = 0.160 vs. control, respectively). MVO (%LVM, median, IQR) was similar across the groups [1.0, 0.0–3.7 (p = 0.205) and 0.6, 0.0–2.4 (p = 0.244) for adenosine and SNP, respectively, vs. 0.3, 0.0–2.8 for the control]. Using per-protocol analysis, infarct size (%LVM) was increased in adenosine-treated patients compared with control patients (12.0 vs. 8.3; p = 0.031). Increased left ventricular volume and reduced left ventricular ejection fraction were also observed in the adenosine arm. There was a significant increase in MACEs in patients undergoing adenosine-facilitated PPCI compared with control patients, driven by heart failure, at 30 days [hazard ratio (HR) 5.39, 95% confidence interval (CI) 1.18 to 24.60; p = 0.04] and 6 months (HR 6.53, 95% CI 1.46 to 29.2; p = 0.01) post randomisation. Conclusions: High-dose intracoronary adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR imaging. Furthermore, adenosine may adversely affect mid-term clinical outcome and should not be used during PPCI to prevent reperfusion injury. Trial registration: ClinicalTrials.gov NCT01747174 and EudraCT 2010–023211–34. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership. ABSTRACT NIHR Journals Library www.journalslibrary. nihr.ac. uk viii