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Page 2 of 13 Carciotto et al. Vessel Plus 2024;8:33 https://dx.doi.org/10.20517/2574-1209.2024.01

unguided de-escalation, where P2Y12 inhibitors are adjusted based on clinical judgment, and the guided de-
escalation, incorporating genetic or platelet function tests to tailor the therapy. Several randomized controlled trials
(RCTs) demonstrated that both unguided and guided de-escalation strategies can reduce bleeding without
compromising ischemic outcomes. However, some gaps in evidence are still present and further investigation is
needed. Ongoing and upcoming RCTs aim to address uncertainties, including direct comparisons between de-
escalation strategies, optimal timing for intervention, and personalized approaches guided by genetic testing.
Furthermore, the review emphasizes the need for standardization in implementing de-escalation strategies in
routine clinical practice.

Keywords: Dual antiplatelet therapy, P2Y12 inhibitors, acute coronary syndrome, percutaneous coronary
intervention, de-escalation, bleeding

INTRODUCTION
Dual antiplatelet therapy (DAPT), the combination of acetylsalicylic acid and a P2Y receptor inhibiting
12
agent, represents the backbone of pharmacological management in acute coronary syndrome (ACS)
patients . Indeed, compared with aspirin alone, DAPT improves outcomes in ACS patients , preventing
[1-3]
[4,5]
procedure-related thrombotic complications, such as peri-procedural myocardial infarction (MI) or stent
thrombosis (ST) , as well as long-term spontaneous ischemic events both in the coronary and extra-
[6,7]
[8,9]
coronary vasculature . However, this benefit is counterbalanced by an increase in bleeding, which is more
[3]
evident when potent P2Y12 inhibitors, prasugrel and ticagrelor, are used . Because ACS patients are
considered by definition at elevated likelihood risk of ischemic events, current international guidelines
recommend a default 12-month DAPT strategy with either ticagrelor or prasugrel in patients with ACS,
unless contraindicated . Nevertheless, the growing recognition of the prognostic significance of bleeding
[10]
[11]
events in individuals with ACS or those treated with percutaneous coronary interventions (PCI) ,
combined with the introduction of new stent platforms associated with low rates of adverse events such as
ST, has led to questions about the use of 12-month DAPT as a default strategy and has stimulated interest in
the use of antithrombotic strategies that could reduce bleeding without hampering the ischemic benefits.
These are known as bleeding reduction strategies [12,13] . Moreover, increasing evidence supporting the
difference in temporal trends of ischemic and bleeding risks after ACS/PCI has suggested that modulation
of antithrombotic therapy 1-3 months after the index may be beneficial [8,12] . Certainly, the likelihood of
ischemic/thrombotic events is most pronounced in the initial months following PCI and tends to diminish
subsequently, whereas the bleeding risk tends to remain relatively constant over time [Figure 1] . Hence,
[8]
various bleeding reduction strategies have been proposed in recent years, including shortening the course of
DAPT, and other de-escalation strategies to modulate P2Y12i potency. In this manuscript, we will focus on
describing de-escalation strategies for P2Y12i switching from a potent P2Y12i to clopidogrel or potent
P2Y12i dose reduction. Different from other DAPT modulation strategies, de-escalation by switching or
dose-reduction may enable a more nuanced reduction of antiplatelet potency on the P2Y12 inhibitor
pathway, unlike shortening DAPT which can either result in no action (if ASA alone is chosen) or excessive
action (if a potent P2Y12 inhibitor alone is chosen) .
[14]

De-escalation of prasugrel or ticagrelor to clopidogrel may be either guided or unguided, either if the
therapy selection is based on the use or not of platelet function (PFT) or genetic testing to lead clopidogrel
administration based on individual patient’s responsiveness. In fact, the superior effectiveness and lower
security of both prasugrel and ticagrelor compared with clopidogrel is in part attributable to their more
predictable pharmacodynamic effects . On the contrary, clopidogrel is characterized by a significant
[15]
variability in response among patients, due to both acquired and genetic factors, including the
polymorphisms of the gene that transcribes the CYP2C19 enzyme. The latter is accountable for the two-step