Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction

CLINICAL RESEARCH European Heart Journal (2012) 33, 1491–1499 doi:10.1093/eurheartj/ehr309 Acute coronary syndromes Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction 1 Department of Cardiology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; 2Department of Cardiology, Skejby, Aarhus, Denmark; 3Department of Cardiology, Gentofte Hospital, Copenhagen, Denmark; and 4Department of Biomedical Sciences and The Danish National Foundation Research Centre for Heart Arrhythmia, University of Copenhagen, Denmark Received 30 May 2011; revised 18 July 2011; accepted 3 August 2011; online publish-ahead-of-print 14 September 2011 See page 1426 for the editorial comment on this article (doi:10.1093/eurheartj/ehr382) Aims Exenatide, a glucagon-like-peptide-1 analogue, increases myocardial salvage in experimental settings with coronary occlusion and subsequent reperfusion. We evaluated the cardioprotective effect of exenatide at the time of reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). ..................................................................................................................................................................................... Methods A total of 172 patients with STEMI and Thrombolysis in Myocardial Infarction flow 0/1 were randomly assigned to exenatide or placebo (saline) intravenously. Study treatment was commenced 15 min before intervention and mainand results tained for 6 h after the procedure. The primary endpoint was salvage index calculated from myocardial area at risk (AAR), measured in the acute phase, and final infarct size measured 90 + 21 days after pPCI by cardiac magnetic resonance (CMR). In 105 patients evaluated with CMR, a significantly larger salvage index was found in the exenatide group than in the placebo group (0.71 + 0.13 vs. 0.62 + 0.16; P ¼ 0.003). Infarct size in relation to AAR was also smaller in the exenatide group (0.30 + 0.15 vs. 0.39 + 0.15; P ¼ 0.003). In a regression analysis, there was a significant correlation between the infarct size and the AAR for both treatment groups and an analysis of covariance showed that datapoints in the exenatide group lay significantly lower than for the placebo group (P ¼ 0.011). There was a trend towards smaller absolute infarct size in the exenatide group (13 + 9 vs. 17 + 14 g; P ¼ 0.11). No difference was observed in left ventricular function or 30-day clinical events. No adverse effects of exenatide were observed. ..................................................................................................................................................................................... Conclusion In patients with STEMI undergoing pPCI, administration of exenatide at the time of reperfusion increases myocardial salvage. ----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Reperfusion injury † Exenatide † Acute myocardial infarction † Cardiac magnetic † Resonance † Primary percutaneous coronary intervention Introduction ST-segment elevation myocardial infarction (STEMI) is a major cause of mortality and morbidity.1 The recommended treatment for STEMI is reperfusion therapy with primary percutaneous coronary intervention (pPCI), which reduces mortality and morbidity.2 However, acute restoration of myocardial blood flow may in itself jeopardize the cardiomyocytes. This phenomenon, known as reperfusion injury, may account for as much as 50% of the final myocardial infarct size,3 a major determinant of the prognosis in patients with STEMI.4 In spite of constant improvements in the treatment of patients with acute myocardial infarction, there is still a need to protect the heart during reperfusion. * Corresponding author. Tel: +45 35858444, Fax: +45 35452705, Email: Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: Jacob Lønborg 1*, Niels Vejlstrup 1, Henning Kelbæk 1, Hans Erik Bøtker 2, Won Yong Kim 2, Anders B. Mathiasen 1, Erik Jørgensen 1, Steffen Helqvist 1, Kari Saunamäki 1, Peter Clemmensen 1, Lene Holmvang 1, Leif Thuesen 2, Lars Romer Krusell 2, Jan S. Jensen 3, Lars Køber 1, Marek Treiman 4, Jens Juul Holst 4, and Thomas Engstrøm 1 1492 Methods Trial This randomized, double-blind, placebo-controlled trial was performed at Copenhagen University Hospital Rigshospitalet, Denmark, and Aarhus University Hospital Skejby, Denmark. All patients were informed orally and in writing, and all gave their written consent before inclusion. The study was performed according to the Helsinki Declaration of Good Clinical Practice, and The Danish National Committee on Biomedical Research Ethics approved the protocol. Exenatide was purchased with institutional grant support; the manufacturer had no impact on the design, execution, or data analysis of the study. The study was registered at www.clinicaltrial.gov; identifier: NCT00835848. Study population Patients were eligible if they were 18 years or older and presented within 12 h from the onset of symptoms and signs of STEMI to the catheterization laboratory. An ECG was obtained either in the ambulance or at the referring hospital. STEMI was defined as significant ST-segment elevation in at least two contiguous leads. The following ST-segment elevation criteria were used: 1 mV ST-segment elevation in the limb lead (II, III and aVF, I, aVL) and V4 – V6, and 2 mm ST-segment elevation in V1 – V3. The patients were not considered for enrolment if they presented with unconsciousness, cardiogenic shock, hypoglycaemia, diabetic ketoacidosis, previous myocardial infarction, stent thrombosis, known renal insufficiency, or previous coronary artery bypass operation. Furthermore, patients were excluded if they met one of the following angiographic exclusion criteria: any other lesion than the culprit with a diameter stenosis .70% on the coronary angiography and Thrombolysis in Myocardial Infarction (TIMI) flow grade .1 before intervention. Angiography, treatment, and primary percutaneous coronary intervention Patients eligible for pPCI were pre-treated with aspirin (300 mg orally or 500 mg intravenously), clopidogrel (600 mg orally), and heparin (10 000 U intravenously). After randomization, coronary angiography was performed to identify the culprit lesion. Direct stenting, thrombectomy, and choice of stent were left to the discretion of the operator. Predilatation with a small-sized balloon was allowed before stenting. Ischaemic postconditioning was not allowed and balloon angioplasty alone was limited to cases in which a stent could not be deployed or was considered harmful. Glycoprotein IIb/IIIa receptor antagonists were administered when no contraindications were present. All patients (...truncated)