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Carciotto et al. Vessel Plus 2024;8:33 https://dx.doi.org/10.20517/2574-1209.2024.01 Page 5 of 13

post-hoc analysis of PCI complexity of the trial showed that in this subset of patients, de-escalating the
prasugrel dose did not elevate the risk of major adverse cardiovascular events (MACE) and led to a
[16]
reduction in bleeding events classified as BARC class 2 or higher .

The TALOS-AMI trial aimed to investigate the non-inferiority of unguided de-escalation from ticagrelor to
clopidogrel after 30 days of standard DAPT in individuals experiencing acute MI treated with PCI . It was
[20]
an open-label, multicenter, randomized trial that included 2,697 individuals with AMI who received DAPT
with aspirin and ticagrelor and were free from major ischemic or bleeding events in the first month after
percutaneous revascularization. They were randomized in a 1:1 ratio to either switch to clopidogrel, or to
continue their prior treatment. At 12 months, the primary endpoint - a composite of death from CV causes,
acute MI, cerebrovascular events, or BARC ≥ 2 type bleeding - was registered in 4.6% of patients treated
with clopidogrel and 8.4% in the control group. The rate of ischemic events in the two groups was similar
and bleeding was less frequent in the de-escalation group (3.0% vs. 5.6%) .
[20]

A recent meta-analysis that included these three trials has shown that unguided de-escalation lowers
bleeding without increasing the ischemic events .
[21]
Further limitations of current evidence on unguided de-escalation arise from the fact that the trials
predominantly involved non-complex PCI procedures and were conducted mostly (~86%) on East Asians,
which limits the applicability of the evidence from these trials to other ethnic groups due to the unique
bleeding and ischemic risk profiles exhibited by East Asians. Finally, it is crucial to acknowledge that this
approach does not consider the individual variations in response to clopidogrel. As a result, nearly 30% of
treated patients are expected to experience incomplete or no platelet inhibition when de-escalated to
clopidogrel.

Recently, the PLINY THE ELDER trial, a randomized, crossover, non-inferiority study that enrolled 50
elderly ACS patients (mean age 79.6 ± 4.0 years) undergoing PCI, evaluated the pharmacodynamic and
pharmacokinetic profiles of ticagrelor 60 mg versus 90 mg. The primary endpoint was P2Y12 inhibition,
measured by pre-dose P2Y12 reaction units (PRU) using the VerifyNow-P2Y12 assay. Ticagrelor 60 mg was
found to be non-inferior to the 90 mg dose in terms of platelet inhibition (PRU 26.4 ± 32.1 vs. 30.4 ± 39.0,
confidence interval: -16.27 to 8.06; P = 0.002 for non-inferiority), suggesting that the lower dose could be a
viable option for this population .
[22]

Guided de-escalation
PFT can identify patients with HPR while on clopidogrel treatment [15,23] . These tests may take place in a
laboratory setting or be conducted as near-patient tests. The latter is often preferred as it can be performed
at the patient’s bedside by non-expert personnel and provide results more quickly (0.5-2 h). Although PFTs
have the key advantage of directly assessing platelet reactivity associated with increased event rates, they
have several limitations. These include intra- and inter-patient variability and the need to perform them
while the patient is on treatment with clopidogrel after reaching the steady-state phase .
[23]

The use of genetic testing to identify carriers of CYP2C19 LoF alleles may overcome these limitations. As
previously mentioned, genetic testing evaluates CYP2C19 polymorphisms, identifying LoF alleles that are
linked to intermediate or poor metabolism of clopidogrel. However, genotyping is only one of the factors
that influence platelet reactivity in patients who assume clopidogrel . Multiple clinical and demographic
[23]
[24]
factors also contribute to the overall picture . Scores such as the ABCD-GENE score, incorporating genetic
data alongside clinical characteristics like weight, age, chronic renal disease, and diabetes mellitus, have the