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

Abstract

Objectives: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).Background: P2Y12 inhibitors have pleiotropic effects that may induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. Methods: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-hour 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.Results: 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-hour 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. Conclusions:The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.

The platelet paradox of injury versus protection in myocardial infarction—has it been overlooked?

“…Furthermore, ticagrelor administration has been associated in a pig model of MI with enhanced expression and activation of adenosine monophosphate-activated (AMPK) and reduced aquaporine-4 levels in the ischemic myocardium as compared to clopidogrel-treated animals [52,53]. In the study by Dr. Hjortbak [23], the authors reproduced the clinical data in an in vivo rat model of IR-ticagrelor reduced infarct size, clopidogrel and prasugrel did not. Doses and timing of the P2Y 12 receptor antagonists were chosen from the literature.…”

“…In the study by Dr. Hjortbak and collaborators [23], the authors retrospectively examined data from the CONDI-2/ ERIC-PPCI trial. The CONDI-2/ERIC-PPCI trial was an international, multicentre, single-blinded, randomized controlled trial comprising 5401 ST-segment elevation myocardial infarction (STEMI) patients [19].…”

“…There was no difference between the control group and the RIC group in the combined primary endpoint of cardiac death or heart failure or in major cardiovascular and cerebral adverse events or myocardial damage [19]. Now, the group by Dr. Botker has taken advantage of these neutral findings to retrospectively investigate the potential protective effects of the most commonly prescribed P2Y 12 receptor antagonists-clopidogrel, prasugrel and ticagrelor-on cardiac damage post-MI and clinical outcome [23]. Undoubtedly, this retrospective analysis touches upon a topic of high clinical interest.…”

“…On the other hand, this multicentre study expands on the reported existence of potential differences in cardioprotection achieved with the most widely prescribed P2Y 12 receptor antagonists and demonstrates a benefit of ticagrelor over clopidogrel and prasugrel in clinical outcomes. As such, as compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure was reduced in STEMI patients treated with ticagrelor, but not prasugrel [23]. Platelet P2Y 12 receptor antagonists are thought to induce cardioprotection through conditioning mimetic effects [45,56] and thus to potentially limit further protection from additional ischemic conditioning [8,25].…”

The Role of Purinergic Signaling in Heart Transplantation

“…Contrary to P2X receptors, emerging evidence has revealed a cardioprotective role of P2Y receptors, which has been extensively reviewed elsewhere ( 76 ). Notably, P2Y12 receptor antagonists (i.e., antiplatelet agents) have shown promising myocardial protection independent of platelet antiaggregatory effects in cardiac IRI and translated clinical studies ( 104 , 105 ).…”