Acute Coronary Syndrome: Picking the Right P2Y12 Receptor Blocker
The treatment of acute coronary syndrome (ACS) has had varying therapy strategies over the years. Due to the seriousness of the condition, strategies are added or dropped as new data and trials are conducted. While ACS therapy has a ranging scope of medications needed, this review has a focus aimed at antiplatelet therapy. The medications all fall within one class: P2Y12 receptor blockers. Those medications are prasugrel, ticagrelor, and clopidogrel.
Background
ACS is a term used to define myocardial ischemia or infarction in suspected or diagnosed patients. The 2018 joint task force, comprised of many of the world’s health organizations, define myocardial infarction, whether STEMI or NSTEMI, as:
“the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia”.
Out of the ischemia or infarction, three major conditions can arise that make up the general term of ACS. These three conditions are unstable angina (UA), ST-elevation myocardial infarction (STEMI), and non-ST-elevation myocardial infarction (NSTEMI).
While it is obvious that all three conditions have similarities, the classification of ACS was formed due to the ranging differences that arise in managing each specific condition. For the sake of antiplatelet therapy in ACS, dual antiplatelet therapy, consisting of aspirin and a P2Y12 receptor blocker, is relatively consistent throughout the ranging conditions with one major exception — which P2Y12 receptor blocker should be used.
Trials
Deciding on which P2Y12 receptor blocker to use has brought about a range of clinical trials trying to figure that answer out. While each trial has a focus of comparing one of the three medications versus just one other, putting it all together may bring more clarity on which options truly are the better options.
PLATO: Ticagrelor vs. Clopidogrel
The 2009 randomized control trial, PLATO, set out to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of vascular events in patients with NSTEMI or STEMI. The primary outcomes were the composite of death from vascular causes, MI, and stroke as well as any major bleeding events. Regarding the primary outcome, it occurred in 9.8% of patients on ticagrelor and 11.7% of patients on clopidogrel. There was no significant difference between the two drugs in regard to major bleeding events but ticagrelor was associated with a higher rate of major bleeding not relating to the procedures done.
“Treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding.”
TRITON-TIMI: Prasugrel vs Clopidogrel
The 2007 randomized control trial, TRITON-TIMI, set out to compare prasugrel and clopidogrel in ACS patients who underwent percutaneous coronary intervention (PCI). The primary endpoint was the composite of death, MI, or stroke. The primary endpoint occurred in 12.1% of patients on clopidogrel and 9.9% in patients on prasugrel. Major bleeding was observed in 2.4% of patients taking prasugrel and 1.8% of patients taking clopidogrel.
“Prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding.”
PRAGUE-18: Ticagrelor vs. Prasugrel
The 2016 randomized control trial, PRAGUE-18, set out to compare the efficacy and safety of prasugrel and ticagrelor in acute MI treated with PCI. The primary outcome was the composite of death, stroke, re-infarction, bleeding, or urgent target vessel revascularization. The primary endpoint did not differ between the two groups (4.0% prasugrel, 4.1% ticagrelor).
“This head-to-head comparison of prasugrel and ticagrelor does not support the hypothesis that one is more effective or safer than the other in preventing ischemic and bleeding events in the acute phase of myocardial infarction treated with a primary percutaneous coronary intervention strategy.”
ISAR-REACT 5: Ticagrelor vs. Prasugrel
The 2019 randomized control trial, ISAR-REACT 5, set out to assess whether ticagrelor is superior to prasugrel in patients with ACS and planned invasive strategy. The primary outcome was the composite of death, MI, or stroke. The primary endpoint occurred in 9.3% of patients on ticagrelor and 6.9% of patients on prasugrel. Major bleeding occurred in 5.4% of patients on ticagrelor and 4.8% of patients on prasugrel.
“The incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups.”
Conclusion
The desire to find the best antiplatelet therapy in the treatment of ACS is strong. When comparing the four trials, it can be said that clopidogrel was less effective in preventing the composite outcomes compared to the other two drugs: ticagrelor and prasugrel. The only upside to clopidogrel was the risk of major bleeding was lower compared to the other two. Determining the superior treatment between ticagrelor and prasugrel is more difficult to pick one over the other. The PRAGUE-18 trial found no difference between the two while the ISAR-REACT 5 trial found prasugrel to have a lower incidence of the primary outcome. If looking simply at these 4 trials, you could generalize that prasugrel would be the superior choice, but generalizing is rarely the deciding factor in the scientific community. We currently sit at a time where more head-to-head comparisons of prasugrel and ticagrelor are needed. While we sit, the current guideline for antiplatelet therapy in ACS is either ticagrelor or prasugrel.
Thank you for reading,
Aaron Forsythe LECOM School of Pharmacy
References:
“A Comparison of Prasugrel (CS-747) and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention — Full Text View.” Full Text View — ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT00097591.
“A Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome — Study Results.” A Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome — Study Results — ClinicalTrials.gov, clinicaltrials.gov/ct2/show/results/NCT00391872.
“Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction — Full Text View.” Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction — Full Text View — ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT02808767.
Lincoff, AM. Antiplatelet agents in acute ST-elevation myocardial infarction. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2020.
Motovska, Zuzana, et al. “Prasugrel Versus Ticagrelor in Patients With Acute Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention: Multicenter Randomized PRAGUE-18 Study.” Circulation, U.S. National Library of Medicine, 22 Nov. 2016, www.ncbi.nlm.nih.gov/pubmed/27576777.
“Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome — Full Text View.” Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome — Full Text View — ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT01944800.
Schüpke, Stefanie, et al. “Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes: NEJM.” New England Journal of Medicine, 17 Oct. 2019, www.nejm.org/doi/full/10.1056/NEJMoa1908973.
Seeder, GS. Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2020.
Wallentin, Lars, et al. “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes: NEJM.” New England Journal of Medicine, 10 Sept. 2009, www.nejm.org/doi/full/10.1056/NEJMoa0904327.
Wiviott, Stephen D., et al. “Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes: NEJM.” New England Journal of Medicine, 15 Nov. 2007, www.nejm.org/doi/full/10.1056/NEJMoa0706482.
