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Translation of experimental cardioprotective capability of P2Y12 inhibitors into clinical outcome in patients with ST-elevation myocardial infarction

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An Editorial to this article was published on 26 May 2021

Abstract

We studied the translational cardioprotective potential of P2Y12 inhibitors against acute myocardial ischemia/reperfusion injury (IRI) in an animal model of acute myocardial infarction and in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). P2Y12 inhibitors may have pleiotropic effects to induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. We compared the cardioprotective effects of clopidogrel, prasugrel, and ticagrelor on infarct size in an in vivo rat model of acute myocardial IRI, and investigated the effects of the P2Y12 inhibitors on enzymatic infarct size (48-h area-under-the-curve (AUC) troponin T release) and clinical outcomes in a retrospective study of STEMI patients from the CONDI-2/ERIC-PPCI trial using propensity score analyses. Loading with ticagrelor in rats reduced infarct size after acute myocardial IRI compared to controls (37 ± 11% vs 52 ± 8%, p < 0.01), whereas clopidogrel and prasugrel did not (50 ± 11%, p > 0.99 and 49 ± 9%, p > 0.99, respectively). Correspondingly, troponin release was reduced in STEMI patients treated with ticagrelor compared to clopidogrel (adjusted 48-h AUC ratio: 0.67, 95% CI 0.47–0.94). Compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure within 12 months was reduced in STEMI patients loaded with ticagrelor (HR 0.63; 95% CI 0.42–0.94) but not prasugrel (HR 0.84, 95% CI 0.43–1.63), prior to PPCI. Major adverse cardiovascular events did not differ between clopidogrel, ticagrelor, or prasugrel. The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.

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References

  1. Alexopoulos D, Moulias A, Koutsogiannis N, Xanthopoulou I, Kakkavas A, Mavronasiou E, Davlouros P, Hahalis G (2013) Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study. Circ Cardiovasc Interv 6:277–283. https://doi.org/10.1161/CIRCINTERVENTIONS.113.000293

    Article  CAS  PubMed  Google Scholar 

  2. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G (2012) Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 5:797–804. https://doi.org/10.1161/CIRCINTERVENTIONS.112.972323

    Article  CAS  PubMed  Google Scholar 

  3. Audia JP, Yang XM, Crockett ES, Housley N, Haq EU, O’Donnell K, Cohen MV, Downey JM, Alvarez DF (2018) Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function. Basic Res Cardiol 113:32. https://doi.org/10.1007/s00395-018-0692-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Aytekin A, Ndrepepa G, Neumann FJ, Menichelli M, Mayer K, Wohrle J, Bernlochner I, Lahu S, Richardt G, Witzenbichler B, Sibbing D, Cassese S, Angiolillo DJ, Valina C, Kufner S, Liebetrau C, Hamm CW, Xhepa E, Hapfelmeier A, Sager HB, Wustrow I, Joner M, Trenk D, Fusaro M, Laugwitz KL, Schunkert H, Schupke S, Kastrati A (2020) Ticagrelor or prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 142:2329–2337. https://doi.org/10.1161/CIRCULATIONAHA.120.050244

    Article  CAS  PubMed  Google Scholar 

  5. Baker JE, Konorev EA, Gross GJ, Chilian WM, Jacob HJ (2000) Resistance to myocardial ischemia in five rat strains: is there a genetic component of cardioprotection? Am J Physiol Heart Circ Physiol 278:H1395-1400. https://doi.org/10.1152/ajpheart.2000.278.4.H1395

    Article  CAS  PubMed  Google Scholar 

  6. Barletta KE, Ley K, Mehrad B (2012) Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol 32:856–864. https://doi.org/10.1161/ATVBAHA.111.226845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barrabes JA, Inserte J, Mirabet M, Quiroga A, Hernando V, Figueras J, Garcia-Dorado D (2010) Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost 104:128–135. https://doi.org/10.1160/TH09-07-0440

    Article  CAS  PubMed  Google Scholar 

  8. Bergmeijer TO, Godschalk TC, Janssen PWA, Berge KVD, Breet NJ, Kelder JC, Hackeng CM, Ten Berg JM (2017) How long does it take for clopidogrel and ticagrelor to inhibit platelets in patients undergoing primary percutaneous coronary intervention? A detailed pharmacodynamic analysis: time course of platelet reactivity in STEMI (TOPS). Semin Thromb Hemost 43:439–446. https://doi.org/10.1055/s-0037-1599156

    Article  CAS  PubMed  Google Scholar 

  9. Birnbaum Y, Birnbaum GD, Birnbaum I, Nylander S, Ye Y (2016) Ticagrelor and rosuvastatin have additive cardioprotective effects via adenosine. Cardiovasc Drugs Ther 30:539–550. https://doi.org/10.1007/s10557-016-6701-2

    Article  CAS  PubMed  Google Scholar 

  10. Bonello L, Laine M, Camoin-Jau L, Noirot F, Guieu R, Dignat-George F, Paganelli F, Frere C (2015) Onset of optimal P2Y12-ADP receptor blockade after ticagrelor and prasugrel intake in Non-ST elevation acute coronary syndrome. Thromb Haemost 114:702–707. https://doi.org/10.1160/TH15-02-0149

    Article  PubMed  Google Scholar 

  11. Botker HE (2020) The future of cardioprotection-pointing toward patients at elevated risk as the target populations. J Cardiovasc Pharmacol Ther 25:487–493. https://doi.org/10.1177/1074248420937871

    Article  PubMed  Google Scholar 

  12. Botker HE (2021) Searching myocardial rescue through intermittent upper arm occlusion and lizard saliva. Basic Res Cardiol 116:5. https://doi.org/10.1007/s00395-021-00843-1

    Article  PubMed  Google Scholar 

  13. Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. https://doi.org/10.1007/s00395-018-0696-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. https://doi.org/10.1016/S0140-6736(09)62001-8

    Article  PubMed  Google Scholar 

  15. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T (2006) Variable selection for propensity score models. Am J Epidemiol 163:1149–1156. https://doi.org/10.1093/aje/kwj149

    Article  PubMed  Google Scholar 

  16. Brookhart MA, Wyss R, Layton JB, Sturmer T (2013) Propensity score methods for confounding control in nonexperimental research. Circ Cardiovasc Qual Outcomes 6:604–611. https://doi.org/10.1161/CIRCOUTCOMES.113.000359

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cohen MV, Downey JM (2020) What are optimal P2Y12 inhibitor and schedule of administration in patients with acute coronary syndrome? J Cardiovasc Pharmacol Ther 25:121–130. https://doi.org/10.1177/1074248419882923

    Article  PubMed  Google Scholar 

  18. Cohen MV, Yang XM, White J, Yellon DM, Bell RM, Downey JM (2016) Cangrelor-mediated cardioprotection requires platelets and sphingosine phosphorylation. Cardiovasc Drugs Ther 30:229–232. https://doi.org/10.1007/s10557-015-6633-2

    Article  CAS  PubMed  Google Scholar 

  19. Committee CS (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348:1329–1339. https://doi.org/10.1016/s0140-6736(96)09457-3

    Article  Google Scholar 

  20. Crump RK, Hotz VJ, Imbens GW, Mitnik OA (2009) Dealing with limited overlap in estimation of average treatment effects. Biometrika 96:187–199. https://doi.org/10.1093/biomet/asn055

    Article  Google Scholar 

  21. Csoka B, Nemeth ZH, Rosenberger P, Eltzschig HK, Spolarics Z, Pacher P, Selmeczy Z, Koscso B, Himer L, Vizi ES, Blackburn MR, Deitch EA, Hasko G (2010) A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation. J Immunol 185:542–550. https://doi.org/10.4049/jimmunol.0901295

    Article  CAS  PubMed  Google Scholar 

  22. Davidson SM, Andreadou I, Barile L, Birnbaum Y, Cabrera-Fuentes HA, Cohen MV, Downey JM, Girao H, Pagliaro P, Penna C, Pernow J, Preissner KT, Ferdinandy P (2019) Circulating blood cells and extracellular vesicles in acute cardioprotection. Cardiovasc Res 115:1156–1166. https://doi.org/10.1093/cvr/cvy314

    Article  CAS  PubMed  Google Scholar 

  23. Davidson SM, Ferdinandy P, Andreadou I, Botker HE, Heusch G, Ibanez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, Garcia-Dorado D, Action CC (2019) Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J Am Coll Cardiol 73:89–99. https://doi.org/10.1016/j.jacc.2018.09.086

    Article  PubMed  Google Scholar 

  24. De Backer O, Ratcovich H, Biasco L, Pedersen F, Helqvist S, Saunamaki K, Tilsted HH, Clemmensen P, Olivecrona G, Kelbaek H, Jorgensen E, Engstrom T, Holmvang L (2015) Prehospital administration of P2Y12 inhibitors and early coronary reperfusion in primary PCI: an observational comparative study. Thromb Haemost 114:623–631. https://doi.org/10.1160/TH15-01-0026

    Article  PubMed  Google Scholar 

  25. Dost T (2020) Cardioprotective properties of the platelet P2Y12 receptor inhibitor prasugrel on cardiac ischemia/reperfusion injury. Pharmacol Rep 72:672–679. https://doi.org/10.1007/s43440-019-00046-5

    Article  CAS  PubMed  Google Scholar 

  26. Franchi F, Rollini F, Rivas A, Wali M, Briceno M, Agarwal M, Shaikh Z, Nawaz A, Silva G, Been L, Smairat R, Kaufman M, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Bass TA, Angiolillo DJ (2019) Platelet inhibition with cangrelor and crushed ticagrelor in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 139:1661–1670. https://doi.org/10.1161/CIRCULATIONAHA.118.038317

    Article  CAS  PubMed  Google Scholar 

  27. Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T, Yellon DM, Investigators ET (2015) Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408–1417. https://doi.org/10.1056/NEJMoa1413534

    Article  CAS  PubMed  Google Scholar 

  28. Hausenloy DJ, Chilian W, Crea F, Davidson SM, Ferdinandy P, Garcia-Dorado D, van Royen N, Schulz R, Heusch G (2019) The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection. Cardiovasc Res 115:1143–1155. https://doi.org/10.1093/cvr/cvy286

    Article  CAS  PubMed  Google Scholar 

  29. Hausenloy DJ, Kharbanda RK, Moller UK, Ramlall M, Aaroe J, Butler R, Bulluck H, Clayton T, Dana A, Dodd M, Engstrom T, Evans R, Lassen JF, Christensen EF, Garcia-Ruiz JM, Gorog DA, Hjort J, Houghton RF, Ibanez B, Knight R, Lippert FK, Lonborg JT, Maeng M, Milasinovic D, More R, Nicholas JM, Jensen LO, Perkins A, Radovanovic N, Rakhit RD, Ravkilde J, Ryding AD, Schmidt MR, Riddervold IS, Sorensen HT, Stankovic G, Varma M, Webb I, Terkelsen CJ, Greenwood JP, Yellon DM, Botker HE, Investigators C-E-P (2019) Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet 394:1415–1424. https://doi.org/10.1016/S0140-6736(19)32039-2

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hernán MA, Robins JM (2020) Causal inference: what if. Chapman & Hall/CRC, Boca Raton (forthcoming)

    Google Scholar 

  31. Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658. https://doi.org/10.1161/CIRCRESAHA.116.308640

    Article  CAS  PubMed  Google Scholar 

  32. Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348

    Article  CAS  PubMed  Google Scholar 

  33. Heusch G (2020) Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 17:773–789. https://doi.org/10.1038/s41569-020-0403-y

    Article  PubMed  Google Scholar 

  34. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon D (2015) Remote ischemic conditioning. J Am Coll Cardiol 65:177–195. https://doi.org/10.1016/j.jacc.2014.10.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johnsen J, Pryds K, Salman R, Lofgren B, Kristiansen SB, Botker HE (2016) The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection. Basic Res Cardiol 111:10. https://doi.org/10.1007/s00395-016-0529-6

    Article  PubMed  Google Scholar 

  36. Khan JN, Greenwood JP, Nazir SA, Lai FY, Dalby M, Curzen N, Hetherington S, Kelly DJ, Blackman D, Peebles C, Wong J, Flather M, Swanton H, Gershlick AH, McCann GP (2016) Infarct size following treatment with second- versus third-generation P2Y12 antagonists in patients with multivessel coronary disease at ST-segment elevation myocardial infarction in the CvLPRIT Study. J Am Heart Assoc 5(6):e003403. https://doi.org/10.1161/JAHA.116.003403

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kim EK, Park TK, Yang JH, Song YB, Choi JH, Choi SH, Chun WJ, Choe YH, Gwon HC, Hahn JY (2017) Ticagrelor versus clopidogrel on myocardial infarct size in patients undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 69:2098–2099. https://doi.org/10.1016/j.jacc.2017.02.034

    Article  CAS  PubMed  Google Scholar 

  38. Kleinbongard P, Botker HE, Ovize M, Hausenloy DJ, Heusch G (2019) Co-morbidities and co-medications as confounders of cardioprotection-Does it matter in the clinical setting? Br J Pharmacol. https://doi.org/10.1111/bph.14839

    Article  Google Scholar 

  39. Kleinbongard P, Skyschally A, Heusch G (2017) Cardioprotection by remote ischemic conditioning and its signal transduction. Pflug Arch 469:159–181. https://doi.org/10.1007/s00424-016-1922-6

    Article  CAS  Google Scholar 

  40. Lieder HR, Irmert A, Kamler M, Heusch G, Kleinbongard P (2019) Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning. Physiol Rep 7:e14146. https://doi.org/10.14814/phy2.14146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, Faxon DP, Rupprecht HJ, Budaj A, Avezum A, Widimsky P, Steg PG, Bassand JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani AE, White HD, Chrolavicius S, Gao P, Fox KA, Yusuf S, investigators C-Ot (2010) Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 376:1233–1243. https://doi.org/10.1016/S0140-6736(10)61088-4

    Article  CAS  PubMed  Google Scholar 

  42. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA, Clopidogrel in Unstable angina to prevent Recurrent Events trial I (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358:527–533. https://doi.org/10.1016/s0140-6736(01)05701-4

    Article  CAS  PubMed  Google Scholar 

  43. Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K, Collaborators RIS (2015) A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397–1407. https://doi.org/10.1056/NEJMoa1413579

    Article  CAS  PubMed  Google Scholar 

  44. Mohammad HMF, Makary S, Atef H, El-Sherbiny M, Atteia HH, Ibrahim GA, Mohamed AS, Zaitone SA (2020) Clopidogrel or prasugrel reduces mortality and lessens cardiovascular damage from acute myocardial infarction in hypercholesterolemic male rats. Life Sci 247:117429. https://doi.org/10.1016/j.lfs.2020.117429

    Article  CAS  PubMed  Google Scholar 

  45. Montalescot G, van 't Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, Cantor WJ, Cequier A, Chettibi M, Goodman SG, Hammett CJ, Huber K, Janzon M, Merkely B, Storey RF, Zeymer U, Stibbe O, Ecollan P, Heutz WM, Swahn E, Collet JP, Willems FF, Baradat C, Licour M, Tsatsaris A, Vicaut E, Hamm CW, Investigators A (2014) Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 371:1016–1027.https://doi.org/10.1056/NEJMoa1407024

  46. Mustafa SJ, Morrison RR, Teng B, Pelleg A (2009) Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology. Handb Exp Pharmacol. https://doi.org/10.1007/978-3-540-89615-9_6

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ozyuncu N, Goksuluk H, Tan TS, Esenboga K, Atmaca Y, Erol C (2020) Does the level of myocardial injury differ in primary angioplasty patients loaded first with clopidogrel and the ones with ticagrelor? Anatol J Cardiol 24:107–112. https://doi.org/10.14744/AnatolJCardiol.2020.22903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Penna C, Aragno M, Cento AS, Femmino S, Russo I, Bello FD, Chiazza F, Collotta D, Alves GF, Bertinaria M, Zicola E, Mercurio V, Medana C, Collino M, Pagliaro P (2020) Ticagrelor conditioning effects are not additive to cardioprotection induced by direct NLRP3 inflammasome inhibition: role of RISK, NLRP3, and redox cascades. Oxid Med Cell Longev 2020:9219825. https://doi.org/10.1155/2020/9219825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ramakers BP, Riksen NP, Stal TH, Heemskerk S, van den Broek P, Peters WH, van der Hoeven JG, Smits P, Pickkers P (2011) Dipyridamole augments the antiinflammatory response during human endotoxemia. Crit Care 15:R289. https://doi.org/10.1186/cc10576

    Article  PubMed  PubMed Central  Google Scholar 

  50. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteza M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM, Investigators TA (2012) Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 367:1297–1309. https://doi.org/10.1056/NEJMoa1205512

    Article  CAS  PubMed  Google Scholar 

  51. Roubille F, Lairez O, Mewton N, Rioufol G, Ranc S, Sanchez I, Cung TT, Elbaz M, Piot C, Ovize M (2012) Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol 107:275. https://doi.org/10.1007/s00395-012-0275-3

    Article  CAS  PubMed  Google Scholar 

  52. Sabbah M, Nepper-Christensen L, Kober L, Hofsten DE, Ahtarovski KA, Goransson C, Kyhl K, Ghotbi AA, Schoos MM, Sadjadieh G, Kelbaek H, Lonborg J, Engstrom T (2020) Infarct size following loading with Ticagrelor/Prasugrel versus Clopidogrel in ST-segment elevation myocardial infarction. Int J Cardiol 314:7–12. https://doi.org/10.1016/j.ijcard.2020.05.011

    Article  PubMed  Google Scholar 

  53. Schupke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wohrle J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, Akin I, Bott-Flugel L, Fischer M, Landmesser U, Katus HA, Sibbing D, Seyfarth M, Janisch M, Boncompagni D, Hilz R, Rottbauer W, Okrojek R, Mollmann H, Hochholzer W, Migliorini A, Cassese S, Mollo P, Xhepa E, Kufner S, Strehle A, Leggewie S, Allali A, Ndrepepa G, Schuhlen H, Angiolillo DJ, Hamm CW, Hapfelmeier A, Tolg R, Trenk D, Schunkert H, Laugwitz KL, Kastrati A, Investigators I-RT (2019) Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med 381:1524–1534. https://doi.org/10.1056/NEJMoa1908973

    Article  CAS  PubMed  Google Scholar 

  54. Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483. https://doi.org/10.1007/s00395-009-0040-4

    Article  PubMed  Google Scholar 

  55. Spreeuwenberg MD, Bartak A, Croon MA, Hagenaars JA, Busschbach JJ, Andrea H, Twisk J, Stijnen T (2010) The multiple propensity score as control for bias in the comparison of more than two treatment arms: an introduction from a case study in mental health. Med Care 48:166–174. https://doi.org/10.1097/MLR.0b013e3181c1328f

    Article  PubMed  Google Scholar 

  56. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F (2007) The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost 5:1545–1551. https://doi.org/10.1111/j.1538-7836.2007.02598.x

    Article  CAS  PubMed  Google Scholar 

  57. Sugidachi A, Ohno K, Ogawa T, Jakubowski J, Hashimoto M, Tomizawa A (2013) A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats. Br J Pharmacol 169:82–89. https://doi.org/10.1111/bph.12108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sugidachi A, Yamaguchi S, Jakubowski JA, Ohno K, Tomizawa A, Hashimoto M, Niitsu Y (2011) Selective blockade of P2Y12 receptors by prasugrel inhibits myocardial infarction induced by thrombotic coronary artery occlusion in rats. J Cardiovasc Pharmacol 58:329–334. https://doi.org/10.1097/FJC.0b013e3182244a6f

    Article  CAS  PubMed  Google Scholar 

  59. Terkelsen CJ, Sorensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, Vach W, Johnsen SP, Thuesen L, Lassen JF (2010) System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA 304:763–771. https://doi.org/10.1001/jama.2010.1139

    Article  CAS  PubMed  Google Scholar 

  60. Ubaid S, Ford TJ, Berry C, Murray HM, Wrigley B, Khan N, Thomas MR, Armesilla AL, Townend JN, Khogali SS, Munir S, Martins J, Hothi SS, McAlindon EJ, Cotton JM (2019) Cangrelor versus ticagrelor in patients treated with primary percutaneous coronary intervention: impact on platelet activity, myocardial microvascular function and infarct size: a randomized controlled trial. Thromb Haemost 119:1171–1181. https://doi.org/10.1055/s-0039-1688789

    Article  PubMed  Google Scholar 

  61. van den Berg TN, El Messaoudi S, Rongen GA, van den Broek PH, Bilos A, Donders AR, Gomes ME, Riksen NP (2015) Ticagrelor does not inhibit adenosine transport at relevant concentrations: a randomized cross-over study in healthy subjects in vivo. PLoS ONE 10:e0137560. https://doi.org/10.1371/journal.pone.0137560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. van der Hoeven NW, Janssens GN, Everaars H, Nap A, Lemkes JS, de Waard GA, van de Ven PM, van Rossum AC, Escaned J, Mejia-Renteria H, Ten Cate TJF, Piek JJ, von Birgelen C, Valgimigli M, Diletti R, Riksen NP, Van Mieghem NM, Nijveldt R, van Leeuwen MAH, van Royen N (2020) Platelet inhibition, endothelial function, and clinical outcome in patients presenting with st-segment-elevation myocardial infarction randomized to ticagrelor versus prasugrel maintenance therapy: long-term follow-up of the REDUCE-MVI trial. J Am Heart Assoc 9:e014411. https://doi.org/10.1161/JAHA.119.014411

    Article  PubMed  PubMed Central  Google Scholar 

  63. van Giezen JJ, Sidaway J, Glaves P, Kirk I, Bjorkman JA (2012) Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 17:164–172. https://doi.org/10.1177/1074248411410883

    Article  CAS  PubMed  Google Scholar 

  64. van Leeuwen MAH, van der Hoeven NW, Janssens GN, Everaars H, Nap A, Lemkes JS, de Waard GA, van de Ven PM, van Rossum AC, Ten Cate TJF, Piek JJ, von Birgelen C, Escaned J, Valgimigli M, Diletti R, Riksen NP, van Mieghem NM, Nijveldt R, van Royen N (2019) Evaluation of microvascular injury in revascularized patients with ST-segment-elevation myocardial infarction treated with ticagrelor versus prasugrel. Circulation 139:636–646. https://doi.org/10.1161/CIRCULATIONAHA.118.035931

    Article  PubMed  Google Scholar 

  65. Vannini L, Muro A, Sanchis J, Ortiz-Perez JT, Flores Umanzor E, Lopez-Lereu MP, Badimon L, Sabate M, Brugaletta S (2016) Can new generation P2Y12 inhibitors play a role in microvascular obstruction in STEMI? Int J Cardiol 223:226–227. https://doi.org/10.1016/j.ijcard.2016.08.182

    Article  PubMed  Google Scholar 

  66. Vilahur G, Arzanauskaite M, Sutelman P (2020) Ticagrelor in post-STEMI adverse ventricular remodeling: there is more than meets the platelet. JACC Cardiovasc Interv 13:2235–2237. https://doi.org/10.1016/j.jcin.2020.09.006

    Article  PubMed  Google Scholar 

  67. Vilahur G, Gutierrez M, Casani L, Lambert C, Mendieta G, Ben-Aicha S, Capdevila A, Pons-Llado G, Carreras F, Carlsson L, Hidalgo A, Badimon L (2018) P2Y12 antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessments in pigs. Cardiovasc Res 114:1860–1870. https://doi.org/10.1093/cvr/cvy201

    Article  CAS  PubMed  Google Scholar 

  68. Vilahur G, Gutierrez M, Casani L, Varela L, Capdevila A, Pons-Llado G, Carreras F, Carlsson L, Hidalgo A, Badimon L (2016) Protective effects of ticagrelor on myocardial injury after infarction. Circulation 134:1708–1719. https://doi.org/10.1161/CIRCULATIONAHA.116.024014

    Article  CAS  PubMed  Google Scholar 

  69. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Investigators P, Freij A, Thorsen M (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057. https://doi.org/10.1056/NEJMoa0904327

    Article  CAS  PubMed  Google Scholar 

  70. Weisshaar S, Litschauer B, Eipeldauer M, Hobl EL, Wolzt M (2017) Ticagrelor mitigates ischaemia-reperfusion induced vascular endothelial dysfunction in healthy young males—a randomized, single-blinded study. Br J Clin Pharmacol 83:2651–2660. https://doi.org/10.1111/bcp.13378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, Gan LM (2013) Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 61:723–727. https://doi.org/10.1016/j.jacc.2012.11.032

    Article  CAS  PubMed  Google Scholar 

  72. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, Investigators T-T (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015. https://doi.org/10.1056/NEJMoa0706482

    Article  CAS  PubMed  Google Scholar 

  73. Wu Q, Gui P, Wu J, Ding D, Purusram G, Dong N, Yao S (2011) Effect of limb ischemic preconditioning on myocardial injury in patients undergoing mitral valve replacement surgery. A randomized controlled trial. Circ J 75:1885–1889. https://doi.org/10.1253/circj.cj-10-1130

    Article  PubMed  Google Scholar 

  74. Yang XM, Cui L, Alhammouri A, Downey JM, Cohen MV (2013) Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart. Cardiovasc Drugs Ther 27:403–412. https://doi.org/10.1007/s10557-013-6474-9

    Article  CAS  PubMed  Google Scholar 

  75. Yang XM, Gadde S, Audia JP, Alvarez DF, Downey JM, Cohen MV (2019) Ticagrelor does not protect isolated rat hearts, thus clouding its proposed cardioprotective role through ENT 1 in heart tissue. J Cardiovasc Pharmacol Ther 24:371–376. https://doi.org/10.1177/1074248419829169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV (2013) Platelet P2Y(1)(2) blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 18:251–262. https://doi.org/10.1177/1074248412467692

    Article  CAS  PubMed  Google Scholar 

  77. Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV (2013) Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther 27:109–115. https://doi.org/10.1007/s10557-012-6436-7

    Article  CAS  PubMed  Google Scholar 

  78. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y (2015) Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 35:1805–1814. https://doi.org/10.1161/ATVBAHA.115.305655

    Article  CAS  PubMed  Google Scholar 

  79. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. https://doi.org/10.1056/NEJMra071667

    Article  CAS  PubMed  Google Scholar 

  80. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial I (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502. https://doi.org/10.1056/NEJMoa010746

    Article  CAS  PubMed  Google Scholar 

  81. Ziegler M, Wang X, Peter K (2019) Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target. Cardiovasc Res 115:1178–1188. https://doi.org/10.1093/cvr/cvz070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The ERIC-PPCI trial was funded by a British Heart Foundation Clinical Study Grant (CS/14/3/31002) and a University College London Hospital/University College London Biomedical Research Clinical Research grant. The CONDI-2 trial was funded by Danish Innovation Foundation grants (11–108354 and 11–115818), Novo Nordisk Foundation (NNF13OC0007447), and Trygfonden (109624). DJH was supported by the British Heart Foundation (FS/10/039/28270), Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017), and its Collaborative Centre Grant scheme (NMRC/CGAug16C006). This article is based on the work of COST Action EU-CARDIOPROTECTION (CA16225) and supported by COST (European Cooperation in Science and Technology).

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Authors and Affiliations

  1. Department of Clinical Medicine, Cardiology, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark

    Marie V. Hjortbak, Jacob M. Seefeldt, Thomas R. Lassen & Hans Erik Bøtker

  2. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

    Kevin K. W. Olesen, Rebekka V. Jensen & Hans Erik Bøtker

  3. London School of Hygiene and Tropical Medicine, Clinical Trials Unit, London, UK

    Alexander Perkins, Matthew Dodd & Tim Clayton

  4. The Hatter Cardiovascular Institute, University College London, London, UK

    Derek Yellon & Derek J. Hausenloy

  5. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore

    Derek J. Hausenloy

  6. National Heart Research Institute Singapore, National Hearts Centre, Singapore Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore

    Derek J. Hausenloy

  7. Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore

    Derek J. Hausenloy

  8. Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Singapore, Singapore

    Derek J. Hausenloy

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  1. Marie V. Hjortbak
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  2. Kevin K. W. Olesen
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  4. Thomas R. Lassen
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  7. Matthew Dodd
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  8. Tim Clayton
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  9. Derek Yellon
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  10. Derek J. Hausenloy
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  11. Hans Erik Bøtker
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Consortia

the CONDI-2/ERIC-PPCI investigators

Contributions

All authors have participated in parts of the conception and design of the study or analysis and interpretation of data. Authors responsible for the animal experiments: MVH, JMS, TRL, RVJ, and HEB. Authors responsible for the clinical analyses: KKWO, MVH, AP, MD, TC, DY, DJH, and HEB. All authors have contributed to drafting the manuscript, and all have read and approved the manuscript.

Corresponding author

Correspondence to Marie V. Hjortbak.

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Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

The ethical approval of the animal experiments of the study was approved by the Danish Veterinary and Food Administration (Authorization number: 2018-15-0201-01475). The clinical part of the study was authorized on ClinicalTrials.gov as NCT02342522.

Additional information

A comment to this article is available at https://doi.org/10.1007/s00395-021-00876-6.

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Hjortbak, M.V., Olesen, K.K.W., Seefeldt, J.M. et al. Translation of experimental cardioprotective capability of P2Y12 inhibitors into clinical outcome in patients with ST-elevation myocardial infarction. Basic Res Cardiol 116, 36 (2021). https://doi.org/10.1007/s00395-021-00870-y

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