Page 16 - Read Online

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

either aspirin or P2Y i monotherapy, unguided de-escalation, and guided (PFT or genetic tests) de-
12
[43]
escalation . The study found no differences in efficacy between the strategies. However, unguided de-
escalation was associated with the lowest risk of MACE and major or minor bleeding. On the other hand,
short DAPT followed by P2Y inhibitor reduced the risk of major bleeding and all-cause death .
[43]
12
De Filippo et al. conducted a systematic review and network meta-analysis to compare different de-
escalation strategies . Six strategies were assessed: ASA and prasugrel for 12 months; ASA and low-dose
[44]
prasugrel for 12 months; ASA and ticagrelor for 12 months; ASA + P2Y12 inhibitor for 1-3 months, then
single antiplatelet therapy with potent P2Y12 inhibitor or DAPT with clopidogrel; ASA and clopidogrel for
12 months; ASA and clopidogrel for 3-6 months. A total of 75,064 patients with ACS from 23 different
RCTs were included. The study showed that short DAPT and DAPT with clopidogrel regimens may reduce
bleeding events compared with standard DAPT with potent P2Y12 inhibitors. However, any regimen that
includes clopidogrel may potentially increase ST risk, while this risk may be mitigated especially during the
initial period with potent P2Y12i. In addition, it is important to highlight that some specific de-escalation
strategies, such as a dose de-escalation to ticagrelor 60 mg as recently studied in the PLINY THE ELDER
[44]
trial, were still not present in the current meta-analysis and may merit further evaluation in the future . On
top of differences in study design and strategy, small differences in these meta-analyses regarding the study
safety endpoint may also be justified by varying definitions of bleeding. Taken together, it can be concluded
that a short-term DAPT followed by P2Y inhibitor monotherapy may represent the bleeding reduction
12
strategy associated with the best performance in ACS. However, it should be noted that these network meta-
analyses rely on indirect comparisons, providing hypothesis-generating evidence that, considering their
limitations such as wider confidence intervals than direct comparisons and the wide array of potential
sources of heterogeneity in the experimental arms, has to be taken with a grain of salt while waiting for
confirmation by RCTs. Moreover, the generic definition of “P2Y inhibitor monotherapy” should be
12
interpreted in light of the profound variability in the pharmacodynamic and clinical response to different
P2Y inhibitors (i.e., clopidogrel versus ticagrelor). Finally, there are practical considerations that should be
12
considered. Although ticagrelor monotherapy may be effective for up to 12 months after ACS, there is
uncertainty about the appropriate course of action thereafter. This is because ticagrelor 90 mg bid is not
recommended for secondary prevention beyond 12 months after ACS. Likewise, a de-escalation antiplatelet
strategy, which involves the adjustment of P2Y inhibitor intensity by reducing the dose of a potent P2Y
12
12
inhibitor, faces the same limitation after 12 months post-ACS. Currently, there is no approved reduced dose
of prasugrel or ticagrelor monotherapy for secondary prevention. Additionally, individuals with a history of
ACS are likely to undergo subsequent PCI in their lifetime, requiring the use of DAPT with clopidogrel.
This is because prasugrel or ticagrelor is not recommended in patients with CCS, except for those at very
high ischemic risk . As studies supporting the use of a reduced dose of prasugrel or ticagrelor are lacking,
[10]
clopidogrel, the currently most commonly prescribed P2Y inhibitor, is likely to remain a crucial
12
antiplatelet agent in the near future. Administering a drug known to be ineffective in nearly 30% of patients
as a single antiplatelet therapy is problematic, particularly in an era where precision medicine is consistently
emphasized. Against this backdrop, the application of instruments that allow for a guided choice of
antiplatelet therapy may represent a practical and valuable strategy that deserves increasing consideration
for ACS patients undergoing PCI.

GAPS IN EVIDENCE AND FUTURE PERSPECTIVES
Over the last two decades, extensive research has focused on modulating antiplatelet therapy, primarily
concerning therapy duration. Recently, however, other modulation strategies for effective de-escalation
have been explored, such as P2Y12 inhibitor (P2Y12i) switching or dose reduction. Nonetheless, substantial
gaps in evidence remain in this area, and multiple randomized trials are expected [Table 2]. While