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Carciotto et al. Vessel Plus 2024;8:33 https://dx.doi.org/10.20517/2574-1209.2024.01 Page 3 of 13

Figure 1. P2Y inhibitor de-escalation in patients with ACS. Estimated risk of ischemic and bleeding events. While ischemic risk
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progressively weans off after the ACS, bleeding risk remains higher when patient is treated with dual antiplatelet therapy. ACS: Acute
coronary syndrome.

oxidation of clopidogrel’s pro-drug into its active metabolite [15,16] . Therefore, individuals carrying one or two
loss-of-function (LoF) alleles, identified as intermediate metabolizer and poor metabolizer, respectively,
exhibit reduced CYP2C19 enzyme activity. This leads to lower concentrations of clopidogrel’s active
metabolism product and higher platelet reactivity (HPR), serving as an indicator of increased thrombotic
risk. Up to 30% of patients undergoing PCI may be poor or non-responders. Two tools can be used to
identify poor responders: genetic tests that detect patients carrying CYP2C19 LoF alleles and platelet
function tests (PFT) that directly assess platelet reactivity phenotype in response to clopidogrel . The
[17]
application of these instruments in patients with ACS allows for a guided de-escalation of P2Y inhibiting
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therapy, consisting of the selective administration of clopidogrel among patients deemed to be responder to
clopidogrel, with prasugrel or ticagrelor being used only in clopidogrel poor or non-responders .
[15]

This review critically appraises the available evidence supporting the de-escalation of antiplatelet therapy in
ACS [Table 1]. It discusses the future perspective and possible implications of using this strategy as the new
standard of care for ACS patients. It also considers other bleeding reduction strategies that have been
investigated, such as DAPT shortening.

RANDOMIZED CONTROLLED TRIALS ON DE-ESCALATION STRATEGIES
Unguided de-escalation
Unguided de-escalation is a practical approach consisting of the modulation of P2Y receptor inhibition
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after the period associated with the highest rates of thrombotic complications has weaned off, such as the
first 1-3 months post-ACS/PCI. In this setting, the modulation of P2Y receptor inhibition is based on the
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clinical judgment of the physician and does not take into account the individual responsiveness to
clopidogrel.

The effectiveness and security of changing from powerful P2Y12 to clopidogrel 30 days after an ACS was
i
first validated in the TOPIC trial , a randomized, controlled trial conducted in France. The study enrolled
[18]
646 patients with ACS who were over 18 years old and were treated with aspirin and a potent P2Y i after
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PCI. The patients were free from major adverse events at one month. Patients who suffered major bleeding
in the last 12 months, as per the Bleeding Academic Research Consortium (BARC) criteria, and those with
indications for long-term anticoagulation, or thrombocytopenia were excluded. After one month from the