**6. Guidelines on P2Y12 Inhibitor Monotherapy**

Several scientific societies have incorporated P2Y12 monotherapy among their recommendations in patients treated with PCI. The 2020 European Society of Cardiology (ESC) guidelines for the management of non-ST-elevation acute coronary syndrome (NSTE-ACS) recommend stopping aspirin after 3–6 months should be considered, depending on the balance between the ischemic and bleeding risk [9]. The 2021 American College of Cardiology (ACC), American Heart Association (AHA), and Society for Cardiovascular Angiography and Interventions (SCAI) guidelines for coronary artery revascularization which were developed after the ESC guidelines and thus had more data available, state that in selected patients undergoing PCI, shorter duration DAPT (1–3 months) is reasonable, with subsequent transition to P2Y12 inhibitor monotherapy to reduce the risk of bleeding events (Table 2) [2]. For long-term secondary prevention, clopidogrel is recommended in patients who cannot take aspirin due to intolerance or hypersensitivity [8].

**Table 2.** Clinical guidelines recommendations concerning P2Y12 inhibitor monotherapy.


\* Details of the specific methodology of level of evidence and class of recommendation are provided in each guideline. ESC, European Society of cardiology; American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions; NSTE-ACS, non-ST elevation acute coronary syndrome; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.

#### **7. Ongoing Studies of P2Y12 Inhibitor Monotherapy**

The role of P2Y12 monotherapy in patients treated with PCI is currently a topic of extensive research with more than 10 ongoing RCTs (Table 3 and Figure 3). Overall, most of the ongoing trials are focused on ACS patients. In particular, ULTIMATE-DAPT is a placebocontrolled RCT that will recruit event-free patients after 1 month of DAPT and compare ticagrelor plus placebo or ticagrelor-based DAPT for 11 months. The MATE and CAGEFREE II trials are investigating a de-escalation strategy consisting of 1 month of DAPT, followed by 5 months of ticagrelor monotherapy, and finalized by 6 months of clopidogrel or aspirin monotherapy. Among HBR or ACS patients, STOPDAPT-3 will compare a short course if clopidogrel-based DAPT with standard clopidogrel DAPT duration. The BULK-STEMI will determine the efficacy of ticagrelor monotherapy after 3 months of ticagrelor-based DAPT in patients presenting with STEMI. Two studies, ASET-JAPAN and NEO-MINDSET, will also assess the role of prasugrel monotherapy, with peri-PCI aspirin only instead of shortterm aspirin in other studies. Moreover, in the setting of prolonged antiplatelet therapy after a standard DAPT, SMART-CHOICE II, OPT-BIRISK, and SMART-CHOICE III trials will assess different long-term P2Y12 monotherapy regimens vs. DAPT or ASA monotherapy.

**Figure 3.** Ongoing randomized controlled trials of P2Y12 inhibitor monotherapy in patients treated with PCI. ASA, aspirin; DAPT, dual antiplatelet therapy; DAPT-C, clopidogrel-based antiplatelet therapy; DAPT-T, ticagrelor-based dual antiplatelet therapy; DAPT-T/P, ticagrelor-based or prasugrelbased dual antiplatelet therapy; Invest., investigational group; PCI, percutaneous coronary intervention. \* OPT-BIRISK trial is randomizing patients with high ischemic or bleeding risk who already finished 9–12 months of DAPT.

**Table 3.** Ongoing clinical trials for P2Y12 inhibitor monotherapy in patients undergoing PCI.


#### **Table 3.** *Cont.*


ACS, acute coronary syndrome; ASA, aspirin; BARC, Bleed Academic Research Consortium; BRS, Bioresorbable scaffold; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; RCT, randomized controlled trial; STEMI, ST elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction. The dosages without specific notes are: aspirin, 81–100 mg daily; ticagrelor, 90 mg twice daily; prasugrel, 10 mg daily.

#### **8. Gaps in Evidence**

There are still several gaps in the knowledge that require further research. First, five out of seven trials studying P2Y12 monotherapy enrolled exclusively East Asian populations, who have lower ischemic risk and a higher tendency of serious bleeding than Caucasians (i.e., East Asian Paradox), limiting extrapolation of many of the study findings to other ethnicities [82]. Second, as a potent P2Y12 inhibitor, compared to ticagrelor, prasugrel has advantages including its once daily regimen and the less respiratory side effect, which greatly improves adherence. However, there are no dedicated RCTs of prasugrel monotherapy. Third, although HBR patients could benefit more from P2Y12 monotherapy as a bleeding reduction strategy, there are no dedicated RCTs in HBR patients and the current evidence is derived from post-hoc analysis. Fourth, four out seven trials used clopidogrel as the main P2Y12 inhibitor, platelet function testing or CYP2C19 genotyping to assess the probability of HPR was not performed in any of these trials and it is unclear if adverse events could be related to clopidogrel poor responders [41,83]. Ultimately, P2Y12 monotherapy has been mainly compared with standard DAPT regimens and it is unknown how this strategy compares with other bleeding avoidance strategies, including short

DAPT with discontinuation of P2Y12 inhibitor and maintaining aspirin or de-escalation DAPT approaches (e.g., switching from ticagrelor/prasugrel to clopidogrel or reducing the dose of ticagrelor/prasugrel) [84]. The current gaps in knowledge and ongoing trials are summarized in Table 4.

**Table 4.** Current gaps in the evidence and potential research opportunities in the P2Y12 monotherapy.



ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; HPR, high platelet reactivity; RCT, randomized controlled trial; STEMI, ST elevation myocardial infarction; NSTEMI.
