**9. Practical Implications**

The P2Y12 monotherapy is an emerging strategy to be considered among the available bleeding avoidance strategies in selected patients taking into consideration the following. First, the safety and efficacy of monotherapy outside of RCTs are very limited, underscoring that the eligible patients are those who meet the specific selection criteria of the RCTs [85]. It should be underscored that these trials are heterogeneous in terms of enrolled populations (Western countries vs. East Asian countries) which could impact the thrombotic and bleeding risk profiles of the studied populations. Furthermore, previous studies have shown that different bleeding avoidance strategies (i.e., abbreviated DAPT vs. de-escalation) are associated with different impact on clinical outcomes, suggesting that the selected strategy should be tailored according to patient characteristics and desired outcomes [84]. Moreover, procedural characteristics could also raise the concern about the outcomes in patients treated with complex PCI. Nevertheless, post-hoc analyses of these trials have not shown impaired outcomes among patients treated with complex PCI [86]. Second, the clinical presentation and the selected P2Y12 inhibitor appear to impact outcomes. In particular, prasugrel, and ticagrelor are recommended over clopidogrel in patients with ACS. In the GLOBAL LEADERS, TWILIGHT, and TICO trials, patients with ACS treated with ticagrelor monotherapy reduced bleeding without affecting ischemic outcomes. However, in patients with ACS and clopidogrel monotherapy, the STOPDAPT-2 ACS trial

showed reduced bleeding but increased ischemic events [43]. On the other hand, in CCS, clopidogrel appears to be a safe and effective drug, as shown in the SMART-CHOICE and STOPDAPT-2 trials [39,42]. Moreover, ticagrelor can also be an option in CCS with high ischemic risk as reported in the TWILIGHT trial [62]. Third, most of these trials were designed with run-in phases and randomized only event-free patients after a short course of DAPT (i.e., 1–3 months). Therefore, in daily clinical practice, the decision to drop aspirin and continue P2Y12 inhibitor monotherapy should be made according to these protocols. Ultimately, P2Y12 inhibitor monotherapy has been compared mainly with standard DAPT (i.e., guideline-recommended duration) up to one year after the index PCI or randomization. Therefore, the clinical benefit of P2Y12 inhibitor monotherapy compared to other DAPT regimens and beyond the following 12–15 months of PCI is uncertain. Nevertheless, the only recent piece of information about P2Y12 monotherapy for long-term 24 months in event-free patients who were on DAPT for 6–18 months after PCI) comes from the HOST-EXAM trial, which suggests that clopidogrel monotherapy is safe and effective strategy compared to aspirin monotherapy [79].

### **10. Conclusions**

Although DAPT with aspirin and a P2Y12 inhibitor is the standard care and guidelinerecommended strategy in patients treated with PCI, recent pharmacodynamic studies have shown limited synergistic effects of aspirin in addition to potent oral P2Y12 inhibitors and have challenged the need for DAPT to achieve optimal platelet inhibition. In fact, while DAPT is associated with a reduction in ischemic events, it also increases bleeding, the risk of which is proportional to the intensity and duration of DAPT. As thrombotic complications mostly occur early after PCI, while bleeding accrues over the time, bleeding reduction strategies have been developed so that enhanced antithrombotic effects are present in the early phases post-PCI end then reduced afterwards. To this extent, several RCTs have assessed the role of P2Y12 inhibitor monotherapy compared to a standard DAPT regimen. Overall, P2Y12 inhibitor monotherapy is safe and effective for reducing bleeding without compromising ischemic outcomes in event-free patients treated with PCI after a short course of DAPT. In particular, ticagrelor has shown optimal results in patients with ACS, whereas clopidogrel and ticagrelor have been safe and effective for preventing recurrent events in CCS. The P2Y12 inhibitor monotherapy has already been incorporated in European and American guidelines as a reasonable antiplatelet strategy in patients treated with PCI. Over ten RCTs are ongoing to confirm previous findings and provide new insights P2Y12 inhibitor monotherapy immediately after PCI, the role of prasugrel, and outcomes in patients with STEMI. Ultimately, ongoing research is warranted to define whether P2Y12 inhibitor monotherapy should be preferred over aspirin for long-term secondary prevention in patients with CCS.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcdd9100340/s1, Table S1: Prespecified and selected post-hoc analyses of GLOBAL LEADERS trial; Table S2: Prespecified and selected post-hoc analyses of TWILIGHT trial; Table S3: Prespecified and selected post-hoc analyses of TICO trial.

**Author Contributions:** X.Z.: writing—original draft preparation, L.O.-P. and D.J.A.: writing—review and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** Angiolillo declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, and

Sanofi; D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. Other authors have nothing to declare.
