EMBRACE STEMI study: A Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention

European Heart Journal

Volumn 37, Issue 16, 2016, Pages 1296-1303

  Gibson, C Michael ^a   Giugliano, Robert P ^b   Kloner, Robert A ^c,d   Bode, Christoph ^e   Tendera, Michal ^f   Jánosi, András ^g   Merkely, Bela ^h   Godlewski, Jacek ⁱ   Halaby, Rim ^a   Korjian, Serge ^a   Daaboul, Yazan ^a   Chakrabarti, Anjan K ^j   Spielman, Kathryn ^a   Neal, Brandon J ^a   Weaver, W Douglas ^k  

^a HARVARD MEDICAL SCHOOL   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c HUNTINGTON MEDICAL RESEARCH INSTITUTES   (United States)

^d UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^e UNIVERSITY OF FREIBURG   (Germany)

^f MEDICAL UNIVERSITY OF SILESIA   (Poland)

^g National Institute of Cardiology Budapest   (Hungary)

^h SEMMELWEIS UNIVERSITY   (Hungary)

ⁱ Krakowski Szpital Specjalistyczny Im Jana Pawła II   (Poland)

^j EASTERN VIRGINIA MEDICAL SCHOOL   (United States)

^k HENRY FORD HOSPITAL   (United States)

more..

Author keywords

Mitochondrial dysfunction; MTP 131; PCI; Reperfusion injury; STEMI

Indexed keywords

CREATINE KINASE MB; ELAMIPRETIDE; PLACEBO; ARGINYL-2,'6'-DIMETHYLTYROSYL-LYSYL-PHENYLALANINAMIDE; OLIGOPEPTIDE;

ADULT; AGED; ANGIOGRAPHY; AREA UNDER THE CURVE; ARTICLE; ATRIOVENTRICULAR BLOCK; CARDIAC MUSCLE CELL; CARDIAC PATIENT; CARDIOGENIC SHOCK; CARDIOVASCULAR MAGNETIC RESONANCE; CARDIOVASCULAR MORTALITY; CAUSE OF DEATH; CELL SURVIVAL; CEREBROVASCULAR ACCIDENT; CONGESTIVE HEART FAILURE; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAPHY; FEMALE; HEART INFARCTION; HEART VENTRICLE FIBRILLATION; HEART VENTRICLE TACHYCARDIA; HUMAN; HYPONATREMIA; LEFT ANTERIOR DESCENDING CORONARY ARTERY; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; OUTCOME ASSESSMENT; PERCUTANEOUS CORONARY INTERVENTION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REPERFUSION INJURY; SKIN ALLERGY; ST SEGMENT ELEVATION; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; TRANSIENT ISCHEMIC ATTACK; CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL;

DOUBLE-BLIND METHOD; HUMANS; OLIGOPEPTIDES; PERCUTANEOUS CORONARY INTERVENTION; ST ELEVATION MYOCARDIAL INFARCTION;

EID: 84964733977     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehv597     Document Type: Article

References (36)

1. Brener SJ, Maehara A, Dizon JM, Fahy M, Witzenbichler B, Parise H, El-Omar M, Dambrink J-H, Mehran R, Oldroyd K, Gibson CM, Stone GW. Relationship between myocardial reperfusion, infarct size, and mortality. J Am Coll Cardiol 2013; 6:718-724.
2. Kelle S, Roes SD, Klein C, Kokocinski T, de Roos A, Fleck E, Bax JJ, Nagel E. Prognostic value of myocardial infarct size and contractile reserve using magnetic resonance imaging. J Am Coll Cardiol 2009;54:1770-1777.
3. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest 1985;76:1713-1719.
4. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357: 1121-1135.
5. Halestrap A. Mitochondrial permeability transition pore opening during myocardial reperfusion-A target for cardioprotection. Cardiovasc Res 2004;61: 372-385.
6. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier J-P, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473-481.
7. Atar D, Arheden H, Berdeaux A, Bonnet JL, Carlsson M, Clemmensen P, Cuvier V, Danchin N, Dubois-RandeJL, Engblom H, Erlinge D, Firat H, Halvorsen S, Hansen HS, Hauke W, Heiberg E, Koul S, Larsen AI, Le Corvoisier P, Nordrehaug JE, Paganelli F, Pruss RM, Rousseau H, Schaller S, Sonou G, Tuseth V, Veys J, Vicaut E, Jensen SE. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J 2015;36:112-119.
8. Szeto HH. Mitochondria-Targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal 2008;10:601-620.
9. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH. Cellpermeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 2004;279:34682-34690.
10. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol 2014;171: 2017-2028.
11. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol 2014;171:2029-2050.
12. Brown DA, Hale SL, Baines CP, del, Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Moukdar F, Shaikh SR, Fisher-Wellman KH, Neufer PD, Kloner RA. Reduction of early reperfusion injury with the mitochondriatargeting peptide bendavia. J Cardiovasc Pharmacol Ther 2014;19:121-132.
13. Kloner RA, Hale SL, DaiW, Gorman RC, Shuto T, Koomalsingh KJ, Gorman JH III, Sloan RC, Frasier CR, Watson CA, Bostian PA, Kypson AP, Brown DA. Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-Targeting cytoprotective peptide. J Am Heart Assoc 2012;1:e001644.
14. Sabbah HN, Rastogi S, Gupta RC, Zhang K, Wang M. Long-Term therapy with Bendavia (MTP-131), a novel mitochondria-Targeting peptide, normalizes skeletal muscle fiber type composition in dogs with chronic heart failure. Eur Heart J 2013;34(Suppl. 1): doi: 10.1093/eurheartj/eht307. Published online ahead of print 1 August 2013.
15. DaiW, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondriatargeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. J Cardiovasc Pharmacol 2014;64:543-553.
16. Szeto HH, Liu S, Soong Y, WuD, Darrah SF, Cheng FY, Zhao Z, Ganger M, Tow CY, Seshan SV. Mitochondria-Targeted peptide accelerates ATP recovery and reduces ischemic kidney injury. J Am Soc Nephrol 2011;22:1041-1052.
17. Eirin A, Li Z, Zhang X, Krier JD, Woollard JR, Zhu XY, Tang H, Herrmann SM, Lerman A, Textor SC, Lerman LO. A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis. Hypertension 2012;60:1242-1249.
18. Chakrabarti AK, Feeney K, Abueg C, Brown DA, Czyz E, Tendera M, Janosi A, Giugliano RP, Kloner RA, Weaver WD, Bode C, Godlewski J, Merkely B, Gibson CM. Rationale and design of the EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary percutaneous coronary intervention and stenting for ST-segment elevation myocardial infarction. Am Heart J 2013;165: 509-514.e7.
19. Stone GW, Dixon SR, Grines CL, Cox DA, Webb JG, Brodie BR, Griffin JJ, Martin JL, Fahy M, Mehran R, Miller TD, Gibbons RJ, O?Neill WW. Predictors of infarct size after primary coronary angioplasty in acute myocardial infarction from pooled analysis from four contemporary trials. Am J Cardiol 2007;100: 1370-1375.
20. Gibson CM, Kirtane AJ, Murphy SA, Karha J, Cannon CP, Giugliano RP, Roe MT, Harrington RA, Ohman EM, Antman EM. Distance from the coronary ostium to the culprit lesion in acute ST-elevation myocardial infarction and its implications regarding the potential prevention of proximal plaque rupture. J Thromb Thrombolysis 2003;15:189-196.
21. Karha J, Murphy SA, Kirtane AJ, de Lemos JA, Aroesty JM, Cannon CP, Antman EM, Braunwald E, Gibson CM. Evaluation of the association of proximal coronary culprit artery lesion location with clinical outcomes in acute myocardial infarction. Am J Cardiol 2003;92:913-918.
22. Schroder R, Wegscheider K, Schroder K, Dissmann R, Meyer-SabellekW. Extent of early ST segment elevation resolution: a strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. A substudy of the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial. J Am Coll Cardiol 1995;26:1657-1664.
23. Timmer JR, Svilaas T, Ottervanger JP, Henriques JP, Dambrink JH, van, den, Broek SA, van, der, Horst IC, Zijlstra F. Glucose-insulin-potassium infusion in patients with acute myocardial infarction without signs of heart failure: the Glucose-Insulin-Potassium Study (GIPS)-II. J Am Coll Cardiol 2006;47: 1730-1731.
24. Mentzer RM Jr, Bartels C, Bolli R, Boyce S, Buckberg GD, Chaitman B, Haverich A, Knight J, Menasche P, Myers ML, Nicolau J, Simoons M, Thulin L, Weisel RD. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann Thorac Surg 2008;85:1261-1270.
25. Pizzetti G, Mailhac A, Li Volsi L, Di Marco F, Lu C, Margonato A, Chierchia SL. Beneficial effects of diltiazem during myocardial reperfusion: a randomized trial in acute myocardial infarction. Ital Heart J 2001;2:757-765.
26. Theroux P, Gregoire J, Chin C, Pelletier G, de Guise P, Juneau M. Intravenous diltiazem in acute myocardial infarction. Diltiazem as adjunctive therapy to activase (DATA) trial. J Am Coll Cardiol 1998;32:620-628.
27. The Magnesium in Coronaries (MAGIC) Trial Investigators. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial. Lancet 2002;360:1189-1196.
28. Armstrong PW, Granger CB, Adams PX, Hamm C, Holmes D Jr, O?Neill WW, Todaro TG, Vahanian A, Van deWerf F. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA 2007;297:43-51.
29. Baran KW, Nguyen M, McKendall GR, Lambrew CT, Dykstra G, Palmeri ST, Gibbons RJ, Borzak S, Sobel BE, Gourlay SG, Rundle AC, Gibson CM, Barron HV. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 2001;104:2778-2783.
30. Atar D, Petzelbauer P, Schwitter J, Huber K, Rensing B, Kasprzak JD, Butter C, Grip L, Hansen PR, Suselbeck T, Clemmensen PM, Marin-Galiano M, Geudelin B, Buser PT. Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction results of the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial. J Am Coll Cardiol 2009;53:720-729.
31. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 2005;45:1775-1780.
32. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473-481.
33. Atar D, Arheden H, Berdeaux A, Bonnet JL, Carlsson M, Clemmensen P, Cuvier V, Danchin N, Dubois-Rande JL, Engblom H, Erlinge D, Firat H, Halvorsen S, Hansen HS, Hauke W, Heiberg E, Koul S, Larsen AI, Le Corvoisier P, Nordrehaug JE, Paganelli F, Pruss RM, Rousseau H, Schaller S, Sonou G, Tuseth V, Veys J, Vicaut E, Jensen SE. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J 2014;36:112-119.
34. Ibanez B, Macaya C, Sanchez-Brunete V, Pizarro G, Fernandez-Friera L, Mateos A, Fernandez-Ortiz A, Garcia-Ruiz JM, Garcia-Alvarez A, Iniguez A, Jimenez-Borreguero J, Lopez-Romero P, Fernandez-Jimenez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vazquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Perez de Prado A, Fernandez-Campos MJ, Casado I, Garcia-Rubira JC, Garcia-Prieto J, Sanz-Rosa D, Cuellas C, Hernandez-Antolin R, Albarran A, Fernandez-Vazquez F, de la Torre-Hernandez JM, Pocock S, Sanz G, Fuster V. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation 2013;128:1495-1503.
35. Stone GW, Maehara A, Witzenbichler B, Godlewski J, Parise H, Dambrink JH, Ochala A, Carlton TW, Cristea E, Wolff SD, Brener SJ, Chowdhary S, El-Omar M, Neunteufl T, Metzger DC, Karwoski T, Dizon JM, Mehran R, Gibson CM. Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 2012;307:1817-1826.
36. Gibson CM. Time is myocardium and time is outcomes. Circulation 2001;104: 2632-2634.