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Page 10 of 13 Carciotto et al. Vessel Plus 2024;8:33 https://dx.doi.org/10.20517/2574-1209.2024.01

Future research should also directly compare different de-escalation strategies, including unguided de-
escalation, PFT-guided de-escalation, and genetic testing-guided de-escalation. These comparisons could
focus on clinical endpoints and the cost-effectiveness of implementing PFT and genetic testing technologies.
Additionally, determining the optimal timing for treatment de-escalation is crucial for future studies.
Current research often uses an arbitrary one-month post-PCI period for unguided de-escalation. It is
unclear whether this timeframe could be adjusted earlier or later. Antiplatelet therapy de-escalation aims to
optimize outcomes by reducing bleeding risk while maintaining ischemic protection. However, studies
focusing on specific patient subgroups, particularly those at high bleeding risk with a greater baseline risk of
hemorrhagic complications, are currently lacking. De-escalation strategies may be particularly beneficial for
this subgroup.

The Dan-DAPT clinical trial focuses on optimizing antithrombotic therapy for myocardial infarction
patients at high bleeding risk. This phase 4 study, conducted across multiple hospitals in Denmark, uses a
randomized, parallel assignment design with single masking. It targets patients treated with PCI and drug-
eluting stents, identified as HBR using the PRECISE-DAPT score , excluding those with a long-term
[45]
indication to oral anticoagulants (OAC). A total of 2,808 participants are randomized to either standard
dual antiplatelet therapy (DAPT) with prasugrel/ticagrelor and aspirin for 6 months followed by aspirin
monotherapy, or an experimental strategy involving genetic testing-guided de-escalation of P2Y12
inhibitors in CYP2C19*2/3 loss-of-function allele carriers and a short-term DAPT for 3 months followed by
aspirin monotherapy. The study’s primary outcomes are BARC type 2-5 bleedings over a one-year period
and a composite of net adverse clinical events (NACE).

The ADEN study will include HBR patients after experiencing ACS. In this multicenter trial, 2,468 HBR
patients, as per HBR-ARC criteria, will be randomized 1 to 3 months post-ACS into two arms: a control
arm continuing high-potency antiplatelet therapy (ticagrelor or prasugrel) and an intervention arm
switching to low-potency antiplatelets (aspirin or clopidogrel) guided by genetic testing. The primary
outcome is the rate of BARC 2-5 bleeding at 1 year. Secondary outcomes include major adverse
cardiovascular events (MACE).

Finally, the DESC-HBR trial will assess the impact of treatment de-escalation in HBR patients post-ACS. It
will randomize 200 HBR patients, identified by PRECISE-DAPT or HBR-ARC criteria, at 1 month post-
ACS to four treatment arms: a control group continuing full-dose potent P2Y12 inhibition with ticagrelor
or prasugrel, and three experimental arms de-escalated to clopidogrel 75 mg, ticagrelor 60 mg bid, or
prasugrel 5 mg. The primary outcome is the proportion of patients in the optimal platelet reactivity (OPR)
range, measured by the VerifyNow system. A key secondary outcome is the incidence of major, minor, and
nuisance bleeding according to the BARC definition within a 5-month period.

There is also a current gap in long-term data on the effects of treatment de-escalation in larger populations.
The VERONICA study will assess a platelet function test (PFT)-guided de-escalation strategy in patients
recently experiencing ACS. It will involve 634 patients one month post-ACS, using the VerifyNow system to
measure platelet reactivity units (PRU). Patients with PRU ≤ 30 will be randomized 1:1 to either continue
with potent P2Y12 for up to 12 months or switch to clopidogrel. The primary endpoint is the combined net
i
clinical benefit at 12 months, including death from CV causes, nonfatal AMI, nonfatal cerebrovascular
events, and bleeding BARC ≥ 2.

The GUARANTEE study aims to determine whether personalized therapy based on CYP2C19 genetic
profiling can improve patient outcomes. This trial will include 4,009 patients and use a randomized, open-