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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 April 1, 2025 e827

Synopsis The addition of an oral P2Y12 inhibitor to aspirin (DAPT) reduces the risk of early and late thrombotic events among patients with ACS regardless of whether they are managed with an invasive strategy.1–3 Notwithstanding these salutary benefits, prolonged exposure to DAPT results in excess bleeding that may lead to DAPT interruption,22 which in turn may increase the risk of recurrent ischemic events.23 Identifying individuals most likely to realize a net clinical benefit or harm from prolonged DAPT has emerged as an important clinical priority. Several tools have been developed that predict the risk of ischemic and/or bleeding events and may be useful when considering how best to personalize care for an individual patient.24–27 Moreover, alternative antiplatelet strategies have been compared with conventional DAPT with the intent to reduce bleeding while maintaining ischemic efficacy. Growing evidence suggests that a strategy of aspirin discontinuation with ticagrelor monotherapy reduces bleeding.7–11 Although clopidogrel monotherapy has been studied,28,29 interpatient variability in pharmacodynamic response to clopidogrel is substantial30 and may increase thrombotic risk in certain individuals. To that end, a strategy of clopidogrel monotherapy may increase risk of MACE in patients after ACS when compared with more prolonged DAPT.29 Additional approaches include aspirin monotherapy31,32 or a strategy of “de-escalation” (ie, switching from ticagrelor or prasugrel to clopidogrel),16–20 although the safety of these strategies in terms of their effects on risk of MACE is less firmly established. Efficacy and safety of shorter DAPT strategies have not been rigorously studied in patients not undergoing PCI. Figure 11 summarizes the guideline recommendations for DAPT management in patients with ACS during the first 12 months post discharge. Recommendation-Specific Supportive Text

1 Patients with ACS are characterized by a sustained

prothrombotic state,33 thus highlighting the need for continued antithrombotic therapy beyond the index presentation. The double-blind placebo-controlled CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial (n=12 562) demonstrated that DAPT with clopidogrel yields a consistent reduction in both early and late composite ischemic events as compared with aspirin alone among patients with NSTE-ACS who were primarily managed medically.3,34 The treatment effect was consistent among those treated with or without revascularization.4 Subsequent studies showed that DAPT with prasugrel or ticagrelor administered for 1 year provides incremental reductions in ischemic events, albeit with excess bleeding, as compared with clopidogrel.1,2 Although concordant benefits were also observed among trial participants requiring surgical revascularization, the safety and efficacy of DAPT should be considered in the context of CABG as a postrandomization event and the high proportion of patients who did not resume study drug after surgery.4–6 An important consideration in extending the results of clinical trials that established the benefits of DAPT to contemporary cohorts is that patients at elevated risk for bleeding were typically excluded in early studies. Therefore, the default strategy for a minimum DAPT duration of 1 year is most applicable to those patients without high bleeding risk presenting with ACS. Moreover, the choice of P2Y12 inhibitor may vary in relation to treatment approach, as described in Section 4.3.2, “Oral P2Y12 Inhibitors During Hospitalization.” In select patients who have tolerated DAPT, it may be reasonable to extend treatment beyond 1 year after considering risks for long-term bleeding and thrombosis.35–37

2 Results from several randomized trials have con-

sistently shown that aspirin withdrawal followed by ticagrelor monotherapy after 1 to 3 months of ticagrelor-based DAPT results in less bleeding without clear excess in MACE, as compared with continued DAPT among patients with ACS undergoing PCI.7–11 Although studies examining this strategy were characterized by relatively low rates of ischemic events, study-level38 and individual patient data pooled analyses39–41 have yielded similar results. Although data with clopidogrel have been mixed, concerns have been raised that a strategy of clopidogrel monotherapy started 1 to 2 months after PCI may increase risk of MACE in patients with ACS when compared with longer DAPT.29 It remains unknown whether this may be explained by excess thrombotic risk in patients displaying inadequate platelet inhibition to clopidogrel, observed in 30% to 40% of patients after PCI.30,42 Results from a randomized trial showed that a strategy of P2Y12 inhibitor discontinuation followed by aspirin alone after 6 months of DAPT resulted in excess thrombotic risk among patients with ACS undergoing PCI (n=2712; 38% STEMI), albeit with less bleeding.32 Similar findings were observed with earlier P2Y12 inhibitor discontinuation 3 months after PCI.31,43 Although the ontreatment pharmacodynamic effects of ticagrelor and prasugrel are similar, the safety of a strategy of prasugrel monotherapy has not been established in patients ≥1 month post ACS; low-dose prasugrel monotherapy (3.75 mg daily) in Japanese patients very early after PCI with ACS or at high bleeding risk may increase 30-day MACE compared with DAPT.44

3 PPIs reduce the risk of gastrointestinal bleeding

among patients receiving aspirin,14 DAPT,13 or an oral

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