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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 April 1, 2025 e791

cardiovascular death, MI, or stroke by 16% to 20% when compared with clopidogrel, as well as reduced the risk of stent thrombosis.4,5 In the PLATO trial, a nominal reduction in all-cause death with ticagrelor compared with clopidogrel was also observed.5 In TRITON-TIMI 38, the P2Y12 inhibitor (prasugrel or clopidogrel) was only administered in patients with NSTE-ACS once the anatomy was deemed suitable for PCI. In the PLATO trial, 72% were managed with a planned invasive strategy and results in the invasively managed population were highly consistent with the overall trial for reducing MACE, as well as cardiovascular and all-cause death individually.6 Both prasugrel and ticagrelor increase the risk of non-CABG major bleeding compared with clopidogrel.4,5 Prasugrel has been shown to increase life-threatening bleeds.4 Limited data exist to compare the efficacy and safety of prasugrel versus ticagrelor head-to-head. One open-label randomized trial reported a lower rate of MACE with similar bleeding with prasugrel administered at the time of PCI compared with ticagrelor used as upstream therapy in patients with ACS undergoing invasive evaluation.22

4 The randomized, double-blind PLATO trial of

ticagrelor versus clopidogrel included patients with ACS managed with or without a planned invasive strategy. Among the 28% of patients (n=5216) who were managed without a planned invasive strategy, a 15% reduction was observed in the primary endpoint of vascular death, MI, or stroke with ticagrelor versus clopidogrel that was highly consistent with the 16% reduction in MACE in the overall trial. Similarly, the findings for bleeding were consistent with the overall trial result.5,7

5 In the randomized, double-blind, placebo-con-

trolled CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, among patients with NSTE-ACS receiving aspirin and who were medically managed or underwent revascularization, the administration of clopidogrel significantly reduced the composite of cardiovascular death, MI, or stroke.1 Although prasugrel and ticagrelor further reduce major cardiovascular events compared with clopidogrel in patients with ACS undergoing PCI, these more potent agents also further increase the risk of bleeding.4,5 Clopidogrel is an effective alternative P2Y12 inhibitor for use in patients with high bleeding risk or contraindications to prasugrel or ticagrelor. In an open-label trial with a high crossover rate among older patients with ACS undergoing PCI, patients treated with clopidogrel had a similar rate of ischemic events and less bleeding compared with ticagrelor.23 Significant interpatient variability in the pharmacodynamic response to clopidogrel has been described.15

6 In a prospective substudy among the patients

who underwent PCI (n=2658) in the CURE trial, those who were pretreated with clopidogrel (median 6 days) prior to PCI had a significantly lower rate of MACE both before PCI and by 30 days.8 Clopidogrel is a prodrug that requires metabolism by the cytochrome P450 enzyme system to form its active metabolite and therefore may require several hours before significant antiplatelet effect is observed following a loading dose. A meta-analysis of trials of clopidogrel in patients with ACS undergoing PCI found that pretreatment with clopidogrel significantly reduced the risk for 30-day cardiovascular death or MI.11 However, less is known regarding the need for pretreatment in the era of more potent P2Y12 inhibitors with more rapid onset of antiplatelet action. In a randomized trial of prasugrel pretreatment versus administration at the time of PCI, pretreatment (median of only 4.4 hours) did not improve ischemic outcomes, but significantly increased bleeding.24 In the PLATO trial, knowledge of coronary anatomy prior to administration of the study drug was not required; however, upstream use of ticagrelor was not specifically compared with a strategy of administration at time of PCI. Therefore, it remains unknown whether a benefit exists for administration of ticagrelor prior to PCI in patients with NSTE-ACS. For this reason, routine pretreatment in patients undergoing an early invasive management strategy (<24 hours) is not supported by clinical trial data. However, it may be reasonable to consider pretreatment with clopidogrel or ticagrelor in patients undergoing an invasive management strategy with the timing of angiography anticipated to be ≥24 hours from administration of the loading dose.

Table 8.  Management of Oral P2Y12 Inhibitors for Patients Who Require CABG Surgery* Clopidogrel Elective CABG: Interrupt for 5 d before surgery.

Urgent CABG: Interruption for at least 24 h (ideally) and proceeding earlier than 5 d may be reasonable.

Prasugrel Elective CABG: Interrupt for 7 d before surgery.

Urgent CABG: Interruption for at least 24 h (ideally) and proceeding earlier than 7 d may be reasonable.

Ticagrelor Elective CABG: Interrupt for 3-5 d before surgery.

Urgent CABG: Interruption for at least 24 h (ideally) and proceeding earlier than 5 d may be reasonable.

*For all patients, oral P2Y12 inhibitor should be resumed after surgery when bleeding risk not excessive (typically 24-72 hours).

CABG indicates coronary artery bypass grafting.

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