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CLINICAL STATEMENTS AND GUIDELINES April 1, 2025 Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 e828 anticoagulant.12,15 Because the conversion of clopidogrel to its active metabolite and the metabolism of certain PPIs depend on some common hepatic enzymes (eg, CYP2C19), the potential for a drugdrug interaction exists when both agents are coadministered. The results of several ex vivo studies found that clopidogrel-induced platelet inhibition is attenuated with use of certain PPIs, a pharmacodynamic effect that is most pronounced with omeprazole.45,46 Nonetheless, results from a double-blind, placebo-controlled randomized trial showed no significant differences in ischemic events between omeprazole versus placebo among patients treated with clopidogrel, but PPI use markedly decreased the risk of gastrointestinal bleeding.13 Moreover, post hoc analyses from several randomized trials have shown that ischemic risk is not increased when a clinically indicated PPI is used with clopidogrel.47,48 Importantly, the antiplatelet effects and clinical efficacy of ticagrelor and prasugrel are not appreciably modified with concomitant PPI use.48–50 Therefore, it is recommended to administer a PPI in patients with ACS at elevated bleeding risk treated with DAPT or oral anticoagulant. 4. De-escalation implies modulating DAPT intensity by switching from ticagrelor or prasugrel to clopidogrel.51 De-escalation can be guided by the results of platelet function assays that quantify the degree of platelet inhibition among patients treated with clopidogrel. Patients with adequate response may continue to receive clopidogrel, whereas nonresponders are switched to a more potent P2Y12 inhibitor. Clopidogrel responsiveness may also be inferred with use of genotyping assays that identify polymorphisms in genes involved in clopidogrel metabolism.52 Clinical trials examining guided de-escalation after PCI have either shown a lack of benefit,16 noninferiority,20 or reductions in minor bleeding17 versus conventional DAPT. By contrast, unguided de-escalation is performed without antecedent knowledge of platelet responsiveness. Randomized trials have suggested that unguided de-escalation 1 month after PCI reduces bleeding without incurring ischemic risk as compared with longer term prasugrel- or ticagrelor-based DAPT.18,19 Pooled analyses have shown that de-escalation (guided or unguided) yields comparable efficacy to DAPT with respect to ischemic events while reducing bleeding.53,54 However, trials of ticagrelor and prasugrel have suggested that the benefit of more potent P2Y12 inhibitor therapy extends beyond the early phase post ACS, but with increased bleeding.1,2,55 5 In the MASTER DAPT (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Standard DAPT Regimen) trial, patients at high risk of bleeding who had completed a 4-week course of DAPT after successful PCI with drugeluting stents were randomly allocated to single antiplatelet therapy or more prolonged DAPT (≥2 Figure 11. DAPT Strategies in the First 12 Months Postdischarge. Colors correspond to Class of Recommendation in Table 2. *High bleeding risk discussed in Section 11.1, “Recommendation-Specific Supportive Text” item 5, and outlined in Table 22. ACS indicates acute coronary syndromes; DAPT, dual antiplatelet therapy; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; and SAPT, single antiplatelet therapy. Downloaded from http://ahajournals.org by on October 7, 2026