Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction (EXAMI): study protocol for a randomized controlled trial

Martijn Scholte, Leo Timmers, Flip Jp Bernink, Robert N Denham, Aernout M Beek, Otto Kamp, Michaela Diamant, Anton Jg Horrevoets, Hans Wm Niessen, Weena Jy Chen, Albert C van Rossum, Niels van Royen, Pieter A Doevendans, Yolande Appelman, Martijn Scholte, Leo Timmers, Flip Jp Bernink, Robert N Denham, Aernout M Beek, Otto Kamp, Michaela Diamant, Anton Jg Horrevoets, Hans Wm Niessen, Weena Jy Chen, Albert C van Rossum, Niels van Royen, Pieter A Doevendans, Yolande Appelman

Abstract

Background: Myocardial infarction causes irreversible loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. Infarct size is a major prognostic factor and reduction of infarct size has therefore been an important objective of strategies to improve outcomes. In experimental studies, glucagon-like peptide 1 and exenatide, a long acting glucagon-like peptide 1 receptor agonist, a novel drug introduced for the treatment of type 2 diabetes, reduced infarct size after myocardial infarction by activating pro-survival pathways and by increasing metabolic efficiency.

Methods: The EXAMI trial is a multi-center, prospective, randomized, placebo controlled trial, designed to evaluate clinical outcome of exenatide infusion on top of standard treatment, in patients with an acute myocardial infarction, successfully treated with primary percutaneous coronary intervention. A total of 108 patients will be randomized to exenatide (5 μg bolus in 30 minutes followed by continuous infusion of 20 μg/24 h for 72 h) or placebo treatment. The primary end point of the study is myocardial infarct size (measured using magnetic resonance imaging with delayed enhancement at 4 months) as a percentage of the area at risk (measured using T2 weighted images at 3-7 days).

Discussion: If the current study demonstrates cardioprotective effects, exenatide may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with acute myocardial infarction.

Trial registration: ClinicalTrials.gov: NCT01254123.

Figures

Figure 1
Figure 1
Flowchart of the study design. This figure illustrates the study design. A total of 108 patients will be randomized to Exenatide (n = 54) or placebo (n = 54) infusion. The treatment will be initiated just prior to PCI and will be continued for 72 hours. Echocardiography and MRI will be performed during hospital admission (within 2-7 days for echo and within 3-7 days for MRI) and at 4 months follow up.
Figure 2
Figure 2
Blood glucose monitoring and control. The blood glucose levels are targeted between 4-10 mmol/L. Hypoglycemia will be treated with intravenous glucose infusion and hyperglycemia with intravenous insulin infusion as indicated in the flowchart.

References

    1. Gibbons RJ, Valeti US, Araoz PA, Jaffe AS. The quantification of infarct size. J Am Coll Cardiol. 2004;44:1533–1542. doi: 10.1016/j.jacc.2004.06.071.
    1. Burns RJ, Gibbons RJ, Yi Q, Roberts RS, Miller TD, Schaer GL, Anderson JL, Yusuf S. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol. 2002;39:30–36.
    1. O'Neill W, Timmis GC, Bourdillon PD, Lai P, Ganghadarhan V, Walton J Jr, Ramos R, Laufer N, Gordon S, Schork MA. et al.A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med. 1986;314:812–818. doi: 10.1056/NEJM198603273141303.
    1. Eefting F, Rensing B, Wigman J, Pannekoek WJ, Liu WM, Cramer MJ, Lips DJ, Doevendans PA. Role of apoptosis in reperfusion injury. Cardiovasc Res. 2004;61:414–426. doi: 10.1016/j.cardiores.2003.12.023.
    1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–1135. doi: 10.1056/NEJMra071667.
    1. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation. 1997;96:1152–1156.
    1. van der Horst IC, Zijlstra F, van 't Hof AW, Doggen CJ, de Boer MJ, Suryapranata H, Hoorntje JC, Dambrink JH, Gans RO, Bilo HJ. Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol. 2003;42:784–791. doi: 10.1016/S0735-1097(03)00830-1.
    1. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:57–65. doi: 10.1016/0735-1097(95)00126-K.
    1. Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G. Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation. 1998;98:2227–2234.
    1. Ceremuzynski L, Budaj A, Czepiel A, Burzykowski T, Achremczyk P, Smielak-Korombel W, Maciejewicz J, Dziubinska J, Nartowicz E, Kawka-Urbanek T. et al.Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc Drugs Ther. 1999;13:191–200. doi: 10.1023/A:1007787924085.
    1. Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, Paolasso E, Ahmed R, Xie C, Kazmi K. et al.Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. Jama. 2005;293:437–446.
    1. Goke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem. 1993;268:19650–19655.
    1. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995;358:219–224. doi: 10.1016/0014-5793(94)01430-9.
    1. Vila Petroff MG, Egan JM, Wang X, Sollott SJ. Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res. 2001;89:445–452. doi: 10.1161/hh1701.095716.
    1. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005;54:146–151. doi: 10.2337/diabetes.54.1.146.
    1. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962–965. doi: 10.1161/01.CIR.0000120505.91348.58.
    1. Davidson MB, Bate G, Kirkpatrick P. Exenatide. Nat Rev Drug Discov. 2005;4:713–714. doi: 10.1038/nrd1828.
    1. Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, Verlaan CW, Kerver M, Piek JJ, Doevendans PA. et al.Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 2009;53:501–510. doi: 10.1016/j.jacc.2008.10.033.
    1. Sonne DP, Engstrom T, Treiman M. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart. Regul Pept. 2008;146:243–249. doi: 10.1016/j.regpep.2007.10.001.
    1. King AB, Wolfe G, Healy S. Clinical observations of exenatide treatment. Diabetes Care. 2006;29:1984.
    1. Aletras AH, Tilak GS, Natanzon A, Hsu LY, Gonzalez FM, Hoyt RF Jr, Arai AE. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113:1865–1870. doi: 10.1161/CIRCULATIONAHA.105.576025.
    1. Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S, Arheden H. Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single-photon emission computed tomography. JACC Cardiovasc Imaging. 2009;2:569–576. doi: 10.1016/j.jcmg.2008.11.018.
    1. Wright J, Adriaenssens T, Dymarkowski S, Desmet W, Bogaert J. Quantification of myocardial area at risk with T2-weighted CMR: comparison with contrast-enhanced CMR and coronary angiography. JACC Cardiovasc Imaging. 2009;2:825–831. doi: 10.1016/j.jcmg.2009.02.011.

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