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CLINICAL STATEMENTS AND GUIDELINES

April 1, 2025 Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 e790

egy and their risk of bleeding (Figure 4).1–5,9,10 Clinically available oral P2Y12 inhibitors include clopidogrel, prasugrel, and ticagrelor. Clopidogrel is the least potent oral P2Y12 inhibitor and requires more time to reach its maximal platelet inhibition after a loading dose, because it requires biotransformation in the liver to form its active metabolite. Pharmacodynamic variability in response in clopidogrel has been well described,14,15 and hyporesponders may be at increased risk of MACE and stent thrombosis when treated with clopidogrel after PCI.16,17 Ticagrelor and prasugrel are more potent than clopidogrel and achieve more rapid onset of inhibition of platelet activation but with increased risk of bleeding compared with clopidogrel. Of note, ticagrelor may cause subjective transient dyspnea in approximately 10% to 15% of patients after ACS.5 The topic of duration of dual antiplatelet therapy is addressed in Section 11.1, “DAPT Strategies in the First 12 Months Postdischarge.”

Recommendation-Specific Supportive Text

1 Several trials have demonstrated the clinical ben-

efit of oral P2Y12 inhibitors in ACS for reducing MACE but with increased risk of bleeding. In randomized placebo-controlled trials in both NSTE- ACS and STEMI, the addition of clopidogrel to aspirin reduced risk of MACE irrespective of management strategy.1–3 In patients with STEMI treated with fibrinolytic therapy, the addition of clopidogrel to aspirin reduces 30-day MACE, including recurrent MI, and improves survival.2,3 Moreover, in randomized trials, the use of prasugrel and ticagrelor further reduced risk of MACE, as well as stent thrombosis, when compared with clopidogrel in patients with STEMI (not receiving concurrent fibrinolytic therapy) or NSTE-ACS.4,5 The benefits of oral P2Y12 inhibitors have also been demonstrated in patients after coronary artery bypass graft (CABG) surgery.18–21 Guidance on dosing interruption for patients referred for CABG is in Table 8. Duration of administration after CABG is described in Section 11.1, “DAPT Strategies in the First 12 Months Postdischarge.” 2.	 In a secondary analysis of the randomized,

double-blind TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction) of prasugrel versus clopidogrel in addition to aspirin among patients with ACS, subgroup analyses using an outcome of net clinical benefit (MACE events plus bleeding) demonstrated net harm with prasugrel versus clopidogrel among patients with previous transient ischemic attack or stroke.4 Dose reduction of prasugrel should be considered in patients ≥75 years of age and in those with a body weight <60 kg (Table 7). 3.	 The randomized, double-blind TRITON-TIMI 38 and PLATO trials demonstrated that prasugrel (TRITON-TIMI 38) or ticagrelor (PLATO) reduced the rate of the composite endpoint of

Figure 4. Initial Choice of P2Y12 Inhibitor in Patients Not Requiring an Oral Anticoagulant. Colors correspond to Class of Recommendation in Table 2. ACS indicates acute coronary syndromes; ASA, aspirin; CABG, coronary artery bypass grafting; NSTE-ACS, non–ST-segment elevation ACS; PCI, percutaneous coronary intervention; and STEMI, ST-segment elevation myocardial infarction.

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