Madison Beall

Background: Acute myocardial infarction (AMI), also known as a heart attack, is the result of a limited or complete blockage of blood flow to the heart leading to myocardial necrosis.¹ AMIs are treated by using a dual therapy consisting of a P2Y12 receptor inhibitor and aspirin, a cyclooxygenase inhibitor.² A P2Y12 inhibitor directly targets the P2Y12 receptor on platelets to reduce platelet aggregation.³ The mechanism of action behind their anticoagulant capabilities is due to their ability to prevent ADP from binding to the platelet’s P2Y12 receptor, consequently, diminishing platelet aggregation and lessening the infarct size.³ However, the degree of infarct reduction is contingent on the type of P2Y12 receptor inhibitor used; therefore, one must navigate through the different generations of drugs to select the most effective P2Y12 inhibitor for the patient.^3,4

Objective: This narrative review aims to compare the efficacy of P2Y12 receptor inhibitors- Clopidogrel, Prasugrel, and Ticagrelor- to determine the most effective and safe treatment for acute myocardial infarction.

Search Methods: An outline search was executed using the PubMed database from 2017 to 2023 using the following MeSH terms: “acute myocardial infarction” “heart attack” “dual therapy” “P2Y12 inhibitor” and “P2Y12 antagonist”.

Results: Clopidogrel and Prasugrel belong to the older, Thienopyridine generation that displays three unique findings: target only the P2Y12 receptor, irreversibly inhibit platelet aggregation, and require hepatic biotransformation to become active.^4,5 Due to the CYP p450 metabolic activation, Clopidogrel had little to no reduction in infarct size in the critical first minutes.³ Additionally, Prasugrel did not show any significant effect on remodeling or enhancing heart function.⁶ The newer, Cyclopentyltriazolopyrimidine generation, including Ticagrelor, sought to improve these negative outcomes and render unique long-term cardioprotective effects by improving the remodeling of cardiac tissue and increasing the number of stem cells to advance cell proliferation.⁶ Ticagrelor is a reversible inhibitor and does not require transformation, yielding a faster reduction of infarct sizes compared to the prodrug P2Y12 inhibitors.³ Ticagrelor has the unique ability to bind to both P2Y12 receptors and ENT-1(equilibrate nucleoside transporter-1), which causes an accumulation of extracellular adenosine initiating a physiological response that increases blood velocity to the heart.⁷ Additionally, Ticagrelor has the exclusive ability to reduce edema formation causing a decline in the death of myocytes, which improves remodeling capabilities.² While Ticagrelor renders numerous positive effects, researchers noted a higher incidence of dyspnea and arrhythmia when compared to clopidogrel.⁵ However, when comparing the safety of P2Y12 inhibitors, Ticagrelor had decreased incidence of cardiovascular mortality, stroke, and myocardial infarction compared to Clopidogrel.⁶

Conclusion: Notwithstanding the side effects of dyspnea, Ticagrelor is the favored  P2Y12 receptor inhibitor due to its distinctive capability to quickly reduce infarct size, enhance cardiac remodeling, recruit stem cells, diminish edema formation, and advance cell proliferation compared to other P2Y12 inhibitors, Clopidogrel and Prasugrel.

Works Cited.

1. Saleh M, Ambrose JA. Understanding myocardial infarction. F1000Res. 2018;7:F1000 Faculty Rev-1378. doi:10.12688/f1000research.15096.1
2. Vilahur G, Gutiérrez M, Casani L, et al. P2Y12 antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessments in pigs. Cardiovascular Research. 2018;114 (14): 1860-1870. doi.org/10.1093/cvr/cvy201
3. Yang XM, Gadde S, Audia JP, et al. Ticagrelor Does Not Protect Isolated Rat Hearts, Thus Clouding Its Proposed Cardioprotective Role Through ENT 1 in Heart Tissue. J Cardiovasc Pharmacol Ther. 2019;24(4):371-376. doi:10.1177/1074248419829169
4. Schüpke S, Neumann F-J, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. New England Journal of Medicine. 2019;381(16):1524-1534. doi:10.1056/nejmoa1908973
5. Wang Y, Meng X, Wang A, et al. Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA. N Engl J Med. 2021;385(27):2520-2530. doi:10.1056/NEJMoa2111749
6. Birnbaum Y, Tran D, Chen H, et al. Ticagrelor Improves Remodeling, Reduces Apoptosis, Inflammation, and Fibrosis and Increases the Number of Progenitor Stem Cells After Myocardial Infarction in a Rat Model of Ischemia-Reperfusion. Cell Physiol Biochem. 2019;53(6):961-981. doi:10.33594/000000189
7. D’Amario D, Restivo A, Leone AM, et al. Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial. Trials. 2020;21(1):192. Published 2020 Feb 17. doi:10.1186/s13063-020-4116-7