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Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) studies, dual antiplatelet therapy (DAPT) including aspirin and a potent P2Y12 receptor inhibitor (prasugrel or ticagrelor) is recommended as the default DAPT strategy for ACS patients.238,239 Clopidogrel, which is characterized by less effective and more variable platelet inhibition, should only be used when prasugrel or ticagrelor are contraindicated/not available, or in some patients considered otherwise at HBR (e.g. ≥1 major or ≥2 minor ARC-HBR criteria).233,240–242 In addition, the use of clopidogrel may be considered in older patients (e.g. ≥70 years).242,243 Prasugrel should be considered in preference to ticagrelor for ACS patients who proceed to PCI. The Intracoronary Stenting and Antithrombotic Regimen Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 RCT is the largest head-to-head comparison of 1-year DAPT with prasugrel vs. DAPT with ticagrelor in patients with ACS planned for invasive evaluation, >80% of whom underwent PCI.244 A treatment strategy with prasugrel (LD given as soon as possible after randomization for patients undergoing PPCI and after delineation of coronary anatomy for patients presenting with NSTE-ACS) vs. ticagrelor (LD given as soon as possible after randomization in all cases) significantly reduced the composite endpoint of death, MI, or stroke (6.9% vs. 9.3%, P = 0.006) without any increase in bleeding complications (4.8% vs. 5.4%, P = 0.46). Limitations of this study include an open-label design and limited data on medically managed or CABG-treated patients.

6.1.2 Timing of loading dose of oral antiplatelet

therapy Both aspirin and oral P2Y12 inhibitors achieve platelet inhibition more rapidly following an oral LD. Pre-treatment refers to a strategy in which an antiplatelet drug, usually a P2Y12 receptor inhibitor, is given before coronary angiography and, therefore, before the coronary anatomy is known. Although a potential benefit with pre-treatment in the setting of ACS has been hypothesized, large-scale randomized trials supporting a routine pre-treatment strategy with P2Y12 receptor inhibitors are lacking. Caution in relation to pre-treatment may be of particular relevance in patients at HBR (e.g. those receiving an oral anticoagulant [OAC]).

6.1.2.1 Pre-treatment in patients with suspected ST-elevation

myocardial infarction The Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC) trial is the only randomized study testing the safety and efficacy of different timings of P2Y12 receptor inhibitor initiation in patients with a working diagnosis of STEMI undergoing PPCI.245 In this trial, patients were randomized to receive a ticagrelor LD either during transfer to a PPCI centre or immediately before angiography.245 The median difference between the timing of P2Y12 receptor inhibitor loading with the two treatment strategies was 31 min. In this study, the pre-treatment strategy failed to meet the pre-specified primary endpoint of improved ST-segment elevation resolution or Thrombolysis In Myocardial Infarction (TIMI) flow before intervention. Rates of major and minor bleeding events were identical in both treatment arms. These results were supported by real-world data obtained from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry in STEMI patients.246 Prasugrel pre-treatment has not been directly investigated in patients with STEMI. 6.1.2.2 Pre-treatment in patients with non-ST-elevation acute

coronary syndrome The randomized A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) trial not only demonstrated a lack of benefit with respect to ischaemic outcomes with prasugrel pre-treatment, but also a substantially higher bleeding risk.247 In this study, the median time from first LD to the start of coronary angiography in the pre-treatment group was 4.4 h. With respect to pre-treatment data for ticagrelor, the ISAR-REACT 5 trial showed that a ticagrelor-based strategy with routine pre-treatment was inferior to a prasugrel-based strategy with a deferred LD in NSTE-ACS patients.244 The DUBIUS (Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers) trial also attempted to address this question but was stopped early for futility as there was no difference between upstream vs. downstream oral P2Y12 administration in patients with NSTE-ACS (both NSTEMI and UA) scheduled for coronary angiography within 72 h of hospital admission.248

6.1.2.3 Summary of pre-treatment strategies

In patients with a working diagnosis of STEMI undergoing PPCI, pretreatment with a P2Y12 receptor inhibitor may be considered.245 In patients with a working diagnosis of NSTE-ACS, routine pre-treatment with a P2Y12 receptor inhibitor before knowing the coronary anatomy in patients anticipated to undergo an early invasive strategy (i.e. <24 h) is not recommended.244,245,247 For patients with a working diagnosis of NSTE-ACS, where there is an anticipated delay to invasive angiography (i.e. >24 h), pre-treatment with a P2Y12 receptor inhibitor may be considered according to the bleeding risk of the patient. In all ACS patients proceeding to PCI who did not receive P2Y12 receptor inhibitor pretreatment, an LD is recommended at the time of PCI.

6.1.3 Intravenous antiplatelet drugs

Peri-interventional i.v. antiplatelet drugs include P2Y12 receptor inhibitors (cangrelor) and glycoprotein (GP) IIb/IIIa inhibitors (eptifibatide and tirofiban). Most of the trials evaluating GP IIb/IIIa inhibitors in PCI-treated ACS patients pre-date the era of routine DAPT, in particular, early initiation of DAPT including an LD of a potent P2Y12 receptor inhibitor.249,250 There is no strong evidence for any additional benefit with the routine use of GP IIb/IIIa inhibitors in ACS patients scheduled for coronary angiography. Nevertheless, their use should be considered for bailout if there is evidence of no-reflow or a thrombotic complication during PCI. Another potential use for GP IIb/IIIa inhibitors is in the setting of high-risk PCI in patients who have not been pre-treated with P2Y12 receptor inhibitors. Cangrelor is a direct reversible, short-acting P2Y12 receptor inhibitor that has been evaluated during PCI for CCS and ACS in clinical trials against clopidogrel, both with administration before (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [CHAMPION PCI]) and after (CHAMPION PLATFORM and CHAMPION PHOENIX [A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention]) PCI.251–253 A meta-analysis of these trials showed that the benefit of cangrelor with respect to major ischaemic endpoints was counterbalanced by an increase in minor bleeding complications.254 It is also important to note that the benefit of cangrelor with respect to ischaemic endpoints was attenuated in CHAMPION PCI with upfront administration of clopidogrel, and

ESC Guidelines                                                                                                                                                                                          3753

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