Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the guideline-recommended treatment for the prevention of atherothrombotic events in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). In ACS patients undergoing PCI, DAPT is initiated during the index event and continued for up to one year to prevent stent-related complications and ischemic recurrences. Currently, clopidogrel, prasugrel, and ticagrelor are the three available oral P2Y12 inhibitors. Among ACS patients undergoing PCI, prasugrel and ticagrelor are preferred over clopidogrel due to their superior effectiveness in reducing ischemic events, including stent thrombosis. Nevertheless, this ischemic benefit comes at the risk of an increased risk of bleeding due to the enhanced antiplatelet potency of prasugrel and ticagrelor. Importantly, bleeding complications have significant prognostic implications, including increased mortality, highlighting the importance of identifying antiplatelet strategies associated with an optimal balance of reducing bleeding risk while maintaining ischemic protection.

Most recurrent ischemic events, including stent thrombosis, occur early after the index event (i.e., 1-3 months post-PCI). Accordingly, it is common in clinical practice to use antiplatelet treatment regimens consisting of potent agents during the first months (i.e., enhanced platelet reactivity) after PCI, followed by approaches with less potent platelet inhibition. This bleeding avoidance strategy is defined as de-escalation and is endorsed by practice guidelines. De-escalation can occur using different strategies, including reducing platelet inhibition by a) discontinuing an antiplatelet agent (e.g., discontinuing either the P2Y12 inhibitor or aspirin) or b) switching from a more potent to a less potent P2Y12 inhibitor. Currently, de-escalation by aspirin discontinuation and maintaining P2Y12 inhibitor monotherapy is a guideline-recommended strategy regardless of bleeding risk and clinical presentation and appears to be a safer approach than discontinuation of a P2Y12 inhibitor and maintaining aspirin monotherapy. De-escalation by switching from a more potent (i.e., prasugrel or ticagrelor) to a less potent P2Y12 inhibitor (i.e., clopidogrel) can be performed either in a guided or unguided fashion. Guided de-escalation can use either genetic or platelet function tests to tailor antiplatelet therapy based on individual patient drug response, providing a personalized approach. In contrast, unguided de-escalation occurs without the use of these tests. Genetic testing for cytochrome P450 2C19 (CYP2C19) polymorphisms has the advantage over PFT in that it allows for the prediction of the response of clopidogrel without patients having to be on treatment. The accuracy of genetic testing to predict clopidogrel response can be improved by integrating clinical factors. In particular, the Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping (ABCD-GENE) score is a simple tool designed to identify patients at risk of impaired clopidogrel response and has been validated in several studies. However, to date, there are no prospective randomized studies evaluating the pharmacodynamic (PD) effects of an ABCD-GENE score-guided de-escalation strategy in patients undergoing PCI. Furthermore, no study has compared two de-escalation strategies guided by the ABCD-GENE score.