Dual antiplatelet therapy (DAPT) with low-dose aspirin and a P2Y12 inhibitor is the current standard of care in patients with coronary artery disease experiencing an acute event or undergoing percutaneous coronary intervention. However, the ischemic benefits are counterbalanced by a significant increase in bleeding events. Over time, different DAPT de-escalation strategies have been developed to reduce the bleeding risk while maintaining the ischemic protection, but there is currently no head-to-head comparison between them. The purpose of this clinical trial is to conduct a head-to-head comparison on the pharmacodynamic efficacy of DAPT de-escalation by dose reduction to low-dose prasugrel (5 mg od) and DAPT de-escation by switching from standard-dose more potent P2Y12 receptor inhibitor to standard-dose clopidogrel (75 mg). To determine if the PD profiles of these two strategies are comparable, we aim to conduct a non-inferiority study.

The combination of low-dose aspirin and a P2Y12 receptor inhibitor, commonly referred as dual antiplatelet therapy (DAPT), is guideline-recommended for preventing atherothrombotic events in patients experiencing an acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). In ACS patients undergoing PCI, DAPT is initiated at the time of the event and maintained for up to one year to mitigate the risks of stent-related complications and ischemic recurrences.4 There are 3 currently available oral P2Y12 inhibitors: clopidogrel, prasugrel, and ticagrelor. Among ACS patients undergoing PCI, prasugrel and ticagrelor are recommended over clopidogrel because of their enhanced efficacy in reducing ischemic events, including stent thrombosis. However, the increased antiplatelet potency of prasugrel and ticagrelor enhances the risk of bleeding, which has detrimental effects on the overall patient prognosis. The increased risk of mortality in patients experiencing bleeding events underscores the need for antiplatelet strategies that reduce bleeding risk while maintaining significant ischemic protection.

The majority of recurrent ischemic events, including stent thrombosis, tend to occur within the first 1 to 3 months after the index PCI procedure. As a result, in clinical practice it is common to use more potent antiplatelet therapies during the early (i.e., 1-3) months post-PCI, when platelet reactivity is heightened, and transition to therapies with lower platelet inhibition thereafter. This strategy, aimed at reducing bleeding risks while providing ischemic protections, is referred to as de-escalation and its implementation is supported by practice guidelines. In line with Academic Research Consortium (ARC) definitions, de-escalation can be implemented in 3 ways: a) by switching from a more potent to a less potent P2Y12 inhibitor; b) by dose reduction (e.g., lowering prasugrel or ticagrelor doses as an alternative to the initial regimen) or c) by stopping one antiplatelet drug (e.g., either the P2Y12 inhibitor or aspirin). Of the available de-escalation strategies, two of these allow patients to remain on a DAPT regimen maintaining the synergistic effect of targeting two different platelet activation pathways: de-escalation by switch and de-escalation by dose reduction. Notably, pharmacodynamic (PD) response to clopidogrel is characterized by a significant interindividual variability, which is partially mediated by specific alleles encoding the cytochrome P450 2C19. Thus, carriers of these alleles may be at increased risk of thrombotic events if a DAPT de-escalation by switch to clopdogrel is pursued.

In contrast, de-escalation by dose reduction has limited supporting evidence and low adoption in clinical practice. With a de-escalation by dose reduction strategy, patients remain on a potent P2Y12 inhibitor (i.e., prasugrel or ticagrelor) but at lower doses, which can reduce side effects, such as bleeding, without compromising efficacy, as these drugs have a more predictable PD response compared to clopidogrel. To date, clinical trial data on dose reduction after the early acute phase (i.e., 1-3 months) in patients with ACS undergoing PCI is limited and shown only with prasugrel. Notably, a recent head-to-head randomized controlled trial favoring prasugrel over ticagrelor, along with the availability of generic formulations of prasugrel, has led to a shift in antiplatelet prescriptions toward prasugrel. However, although there is extensive evidence comparing various de-escalation strategies with standard-of-care DAPT regimens, there are very few studies directly comparing de-escalation strategies with each other, setting the rationale for this investigation. To determine if the pharmcodynamic profiles of DAPT de-escalation by dose-reduction and by switching to clopidogrel are comparable, we aim to conduct a non-inferiority study.

Inclusion Criteria:

1. Patients who have undergone PCI and are on maintenance treatment with DAPT, consisting of low-dose aspirin with either prasugrel (10 mg qd) or ticagrelor (90 mg bid) as part of standard of care. In particular, patients who underwent PCI in the setting of an acute coronary syndrome will be eligible for randomization after ≥90 days post-PCI, while patients who underwent PCI in the setting of a chronic coronary syndrome ≥30 days post-PCI.
2. Age ≥18 years.
3. Provide written informed consent.

Exclusion Criteria:

1. Prior history of stent thrombosis
2. Prior cerebrovascular event
3. PCI within 30 days
4. Predicted poor metabolizer of clopidogrel based on CYP2C19 genotyping (e.g., *2/*2 or *3/*3),
5. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban) or chronic low-molecular-weight heparin (at venous thrombosis treatment, not for prophylaxis)
6. Hemodynamic instability
7. Hypersensitivity to Aspirin, Clopidogrel, or Prasugrel
8. Known hematologic malignancies or thrombocytopenia (platelet count <80x106/mL)
9. Known hemoglobinopathies or anemia (hemoglobin <9 g/dL)
10. Pregnant and breastfeeding women [women of childbearing age must use reliable birth control (i.e., oral contraceptives) while participating in the study].