INTRODUCTION

The impact of preloading strategies with P2Y12 inhibitors, especially ticagrelor, on periprocedural myocardial injury in patients with non-ST elevation myocardial infarction (NSTEMI) undergoing early invasive interventions is a crucial consideration in contemporary cardiovascular care.1 Ticagrelor, known for its direct and reversible mode of action, distinguishes itself among oral P2Y12 inhibitors, eliminating the need for metabolism to exert platelet-inhibiting effects. Approved for treating patients with acute coronary syndrome (ACS) based on the PLATO trial, which included NSTEMI and (ST elevation myocardial infarction) STEMI patients, ticagrelor demonstrated a reduction in ischemic events compared with clopidogrel, with no significant differences in major bleeding.2

In exploring a specific preloading strategy with ticagrelor, Karaca et al3 conducted a study focusing on NSTEMI patients undergoing an early invasive strategy. The study enrolled 232 patients in the ticagrelor pretreatment group, receiving the medication as soon as possible after admission, and 87 patients in the no-pretreatment group, who received a loading dose of ticagrelor after coronary angiography. Despite similar baseline characteristics, the pretreatment group exhibited a higher incidence of hypertension and higher hemoglobin levels. Notably, patients in the ticagrelor pretreatment group demonstrated significantly reduced myocardial injury both until coronary angiography and during the periprocedural period (12–24 hours post-PCI (percoutaneous coronary intervention)) compared with the no-pretreatment group. These findings suggest that ticagrelor pretreatment may be associated with a decrease in periprocedural myocardial injury in NSTEMI patients undergoing PCI within 24 hours of admission, emphasizing the potential clinical benefits of this strategy.

The observed reduction in periprocedural myocardial injury associated with ticagrelor pretreatment in NSTEMI patients undergoing early invasive interventions reported by Karaca et al may be elucidated through a more in-depth exploration of the underlying pathophysiological mechanisms. Ticagrelor's unique mode of action involves direct and reversible binding to the P2Y12 receptor, resulting in rapid and potent platelet inhibition. This characteristic allows ticagrelor to suppress platelet activation and aggregation swiftly and effectively, particularly crucial during coronary angiography and PCI where thrombotic events are a significant concern.3

The concept of preloading with ticagrelor is intricately linked to optimizing its pharmacological effects, aiming to establish a heightened antiplatelet state before the invasive procedure. By doing so, ticagrelor may create a more robust barrier against platelet-mediated thrombosis, potentially reducing the risk of myocardial injury during the intervention. The emphasis on early and sustained platelet inhibition aligns with the goal of preventing acute ischemic events in the vulnerable peri-interventional period.4

Beyond its primary role as a P2Y12 receptor inhibitor, the impact of ticagrelor on adenosine presents an additional layer of complexity to its potential benefits. Ticagrelor has been associated with increased adenosine levels due to its ability to inhibit adenosine reuptake. Adenosine, known for its vasodilatory and anti-inflammatory properties, holds promise in attenuating ischemia–reperfusion injury. By enhancing adenosine's effects, ticagrelor may contribute to a protective milieu, mitigating the deleterious consequences of the reperfusion phase during interventions.5 Further investigations into the nuanced interplay of these mechanisms will undoubtedly enhance our understanding and potentially open avenues for more targeted therapeutic strategies in the realm of cardiovascular care.6 The concept of pretreatment as a potentially beneficial strategy in NSTEMI patients originated from the studies, such as CURE, PCI-CURE, and CREDO, which observed early benefits with clopidogrel administration.7 Subsequently, PLATO demonstrated the early advantage of ticagrelor over clopidogrel in invasively managed NSTEMI patients, regardless of angiography timing.2 The ISAR-REACT 5 trial,8 comparing ticagrelor and prasugrel after defining coronary anatomy, indicated greater efficacy with prasugrel at 1 year, but the trial had significant differences from DUBIUS. Hypothesizing the potential superiority of a no-pretreatment strategy, the aim of the DUBIUS was to address the bleeding–ischemic balance, drawing on insights from unfavorable outcomes of ACCOAST with prasugrel pretreatment.9,10 The trial, focused on patients eligible for ticagrelor or prasugrel as recommended by guidelines, sought to differentiate outcomes from routine clopidogrel pretreatment, considering its slower onset and less intense platelet inhibition. Despite these considerations, the DUBIUS study revealed low and comparable rates of composite 30-day major ischemic and bleeding events between downstream and ticagrelor-based pretreatment strategies,9 challenging assumptions about the clear superiority of one strategy over the other and introducing nuanced perspectives to the debate on ticagrelor preloading strategies in NSTEMI patients.

However, the ongoing discourse concerning the broader efficacy and safety of ticagrelor preloading strategies persists (Table 1), as also underscored in the discussions surrounding the ATLANTIC trial.11 Some argue that positive secondary end points, such as the observed reduction in definite stent thrombosis in ATLANTIC, may provide weak evidence for pretreatment, given the trial's failure to meet its primary end points or show reductions in other crucial clinical outcomes. Proponents of pretreatment posit that administering the drug earlier may offer potential protection against thrombotic complications sooner.11 Despite ATLANTIC being categorized as a negative trial, certain clinicians interpret it as weakly supportive of pretreatment, particularly in definite STEMI cases, especially when radial artery access is planned. Nonetheless, the short time difference between ticagrelor administrations in both arms of ATLANTIC may have affected the trial's ability to demonstrate the clear superiority of pretreatment, contributing to the ongoing debate surrounding the role of P2Y12 inhibitors in reperfusion support for STEMI patients.12

TABLE 1. - Overview of Key Completed and Ongoing Clinical Studies on Oral P2Y12 Inhibitor Study Name Status Type Clinical Trial Main Aim Results Publication Year ACCOAST8 Completed RCT NCT01015287 First occurrence of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or the need for rescue therapy with glycoprotein IIb/IIIa inhibitors through day 7 after randomization No reduction in major ischemic events, increased major bleeding 2015 ATLANTIC10 Completed RCT NCT01347580 Assess the efficacy of prehospital versus in-hospital initiation of ticagrelor therapy in terms of the coprimary end points, thrombolysis in myocardial infarction 3 flow achieved and complete (≥70%) ST segment elevation resolution before PCI Safe but no improvement in pre-PCI coronary reperfusion 2013 DUBIUS9 Completed RCT NCT02618837 Evaluate the impact on outcomes of antithrombotic strategies based on the administration of newer P2Y12 receptor blockers (prasugrel and ticagrelor) in NSTEACS patients with an initial invasive indication Downstream strategy superior, downstream ticagrelor noninferior to downstream prasugrel 2020 ISAR-REACT 57 Completed RCT NCT01944800 Composite of death, myocardial infarction or stroke at 1 y after randomization Prasugrel superior to ticagrelor in the composite end point 2020 PLATO2 Completed RCT NCT00391872 Test the hypothesis that ticagrelor is superior to clopidogrel for the prevention of vascular events in patients with non-ST elevation ACS or ST elevation ACS Ticagrelor significantly reduced death from vascular causes, MI, or stroke without increased major bleeding 2014

MI, myocardial infarction; RCT, randomized control trial.

The collective evidence underscores the need for further studies and evidence to refine guidelines and provide clarity in the evolving landscape of cardiovascular care, particularly in the context of ticagrelor preloading strategies. In this optic, the study of Karaca et al adds valuable insights into the growing body of evidence.

REFERENCES 1. Sibbing D, Kastrati A, Berger PB. Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why, and which agent? Eur Heart J. 2016;37:1284–1295. 2. Lindholm D, Varenhorst C, Cannon CP, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014;35:2083–2093. 3. Karaca OF, Cimci M, Raimoglou D, et al. Impact of preloading strategy with ticagrelor on periprocedural myocardial injury in patients with non-ST elevation myocardial infarction undergoing early invasive strategy. J Cardiovasc Pharmacol. 2024. [Epub ahead of print]. Doi: 10.1097/FJC.0000000000001540. 4. Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014;34:1077–1090. 5. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol. 2014;63:872–877. 6. Caturano A, D'Angelo M, Mormone A, et al. Oxidative stress in type 2 diabetes: impacts from pathogenesis to lifestyle modifications. Curr Issues Mol Biol. 2023;45:6651–6666. 7. Mayer K, Bongiovanni D, Karschin V, et al. Ticagrelor or prasugrel for platelet inhibition in acute coronary syndrome patients: the ISAR-REACT 5 trial. J Am Coll Cardiol. 2020;76:2569–2571. 8. Montalescot G, Collet JP, Ecollan P, et al. Effect of prasugrel pre-treatment strategy in patients undergoing percutaneous coronary intervention for NSTEMI: the ACCOAST-PCI study. J Am Coll Cardiol. 2014;64:2563–2571. 9. Tarantini G, Mojoli M, Varbella F, et al. Timing of oral P2Y12 inhibitor administration in patients with non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2020;76:2450–2459. 10. Montalescot G, Lassen JF, Hamm CW, et al. Ambulance or in-catheterization laboratory administration of ticagrelor for primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: rationale and design of the randomized, double-blind Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) study. Am Heart J. 2013;165:515–522. 11. Serebruany V, Cherepanov V, Dukhanin A. Significant excess of early deaths after prehospital ticagrelor: the ATLANTIC trial challenge. Thromb Haemost. 2015;114:7–8. 12. Montalescot G. Non-ST-segment elevation acute coronary syndrome: the last nail in the coffin of pre-treatment. J Am Coll Cardiol. 2020;76:2460–2462.