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.