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

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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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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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.

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Correspondence to Marie V. Hjortbak.

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The authors declare no conflicts of interest.

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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.

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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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Keywords

  • P2Y12 inhibitor
  • Cardioprotection
  • Ischemic conditioning
  • Myocardial infarction