**4. P2Y12 Monotherapy versus DAPT after PCI**

#### *4.1. Clopidogrel*

SMART-CHOICE (Comparison Between P2Y12 Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents) was an open-label RCT comparing 3-month DAPT followed by P2Y12 inhibitor monotherapy vs. standard 12-month DAPT after PCI in terms of major adverse cardiac and cerebrovascular events (MACCE) in a non-inferiority analysis [38]. A total of 2993 patients were enrolled. There were no restrictions on the type of P2Y12 inhibitor or clinical presentation. The P2Y12 inhibitor monotherapy was noninferior compared to DAPT in MACCE (Hazard ratio [HR], 1.19; 95% Confidence interval [CI], [−∞%–1.3%]; *p*noninferiority = 0.007). There were no significant differences in the primary endpoint components, but there was a significantly lower BARC 2–5 bleeding rate in the P2Y12 inhibitor monotherapy than the DAPT group (HR, 0.58; 95%CI [0.36–0.92]; *p* = 0.020).

Two main post-hoc analyses have been reported. First, the clopidogrel–only cohort (80% of the total sample size), there were no significant differences between clopidogrel monotherapy versus clopidogrel–based DAPT in MACCE (HR, 1.02; 95%CI, [0.64–1.65]; *p* = 0.100) and BARC 2–5 bleeding (HR, 0.71; 95%CI, [0.42–1.21]; *p* = 0.150) [39]. Second, in the platelet reactivity sub-study (*n* = 833), 108 (13.0%) patients had HPR who had a significantly increased risk of MACCE compared to those without HPR (8.7% vs. 1.5%; HR, 3.03; 95%CI, [1.06–8.69]; *p* = 0.038) [40]. However, the treatment effect of clopidogrel monotherapy for the 12-month MACCE was not significantly different compared with DAPT in patients with HPR or without HPR (HR, 0.71; 95%CI, [0.18–2.73]; *p* = 0.628 and HR, 2.58; 95%CI, [0.68–9.77]; *p* = 0.161; *p*interaction = 0.170). These results suggest that the main driver of adverse events was the HPR status rather than the allocated treatment, denoting the importance of optimizing platelet inhibition [41].

STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt–Chromium Stent) was a prospective, open-labeled RCT comparing 1 month of DAPT (clopidogrel or prasugrel 3.75 mg od) followed by clopidogrel monotherapy versus 12 months DAPT with aspirin and clopidogrel in patients who underwent PCI [42]. A total of 3045 participants were recruited. The primary endpoint was a composite of ischemic (cardiovascular death, MI, stroke, or stent thrombosis) and bleeding endpoints (Thrombolysis in Myocardial Infarction [TIMI] major or minor bleeding) at 12 months. Clopidogrel monotherapy group met the prespecified criteria for noninferiority and superiority compared to the standard DAPT (HR, 0.64; 95%CI, [0.42–0.98]; *p* < 0.001 for noninferiority, *p* = 0.04 for superiority). There was no difference in the ischemic endpoints (HR, 0.79; 95%CI, [0.49–1.29]; *p* = 0.340), but there was a significant lower bleeding rate in the clopidogrel monotherapy than 12 months of DAPT (HR, 0.26; 95%CI, [0.11–0.64]; *p* = 0.004).

STOPDAPT-2 ACS (Short and Optimal Duration of Dual Antiplatelet Therapy-2 Study for the Patients With ACS) trial was a prospective, open-label RCT with the same design as the STOPDAPT-2, but including only patients with ACS, the ACS cohorts of both trials were combined (3008 newly enrolled and 1161 pooled form previous trial, in total 4169 patients were randomized) [43]. At the 1-year follow-up, 1–2 months DAPT (aspirin and clopidogrel) followed by clopidogrel monotherapy failed to meet the noninferior criteria compared to the 12-month DAPT (HR, 1.44; 95%CI, [0.80–1.62]; *p*noninferiority = 0.06). The rate of major bleeding was significantly lower in the monotherapy group compared to the DAPT (HR, 0.46; 95%CI, [0.23–0.94]; *p* = 0.03). However, there was a significant increase in MI in the monotherapy group compared to the DAPT group (HR, 1.91; 95%CI, [1.06–3.44]; *p* = 0.03). The underlying reasons for which there was an increased risk of adverse events in the ACS cohort in patients treated with monotherapy compared to standard DAPT remains unclear but may be likely attributed to the presence of HPR among patients treated with clopidogrel only and no added antiplatelet effect given the withdrawal of aspirin.

STOPDAPT-2 Total Cohort the STOPDAPT investigators performed a prespecified pooled STOPDAPT-2 and STOPDAPT-2-ACS (*n* = 5997 in total), the rationale for this pooled analysis was that in both trials there had a lower-than-expected event rate that could affect

the trials results [44]. The authors followed the same methodology and endpoints as in the main trials. One-month DAPT was noninferior but not superior to 12-month DAPT for the primary endpoint (HR, 0.94; 95%CI, [0.70–1.27]; *p*noninferiority = 0.001 and *p*superiority = 0.68). There was no significant risk-difference for the cardiovascular endpoint between groups (HR, 1.24; 95% CI, [0.88–1.75]; *p* = 0.23), but one-month DAPT was associated with a lower risk of the bleeding than 12-month DAPT (HR, 0.38 95%CI, [0.21–0.70]; *p* = 0.002). When the results were analyzed according to clinical presentation (ACS vs. CCS), one-month DAPT was associated with a lower risk for major bleeding than 12-month DAPT in ACS or CCS patients (HR, 0.46; 95%CI, [0.23–0.94]; *p* = 0.03. and HR, 0.26; 95%CI, [0.09–0.79]; *p* = 0.02; *p*interaction = 0.40), but there was a numerical increase in cardiovascular events in ACS patients, but not in CCS patients (HR, 1.50; 95%CI, [0.99–2.27]; *p* = 0.053, and HR, 0.74; 95%CI, [0.38–1.45]; *p* = 0.39; *p*interaction = 0.08).

#### *4.2. Prasugrel*

ASET (Acetyl Salicylic Elimination Trial) was a pilot, prospective, open-label, singlearm non-randomized study assessing the safety of prasugrel monotherapy in patients with CCS. All participants (*n* = 201) were on standard DAPT at the time of the index PCI, after successful PCI with platinum-chromium everolimus-eluting stent (Pt-EES), aspirin was discontinued and prasugrel was loaded and maintained for 3 months [45]. The primary ischemic endpoint was the composite of cardiac death, spontaneous target vessel MI, or definite stent thrombosis. The primary bleeding endpoint was major bleeding. There was only one event (cardiac death following intracranial bleeding). The compelling results of the ASET trial should be interpreted in the light of its small and very selected population and low lesion complexity.

#### *4.3. Ticagrelor*

GLOBAL LEADERS (A Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation) trial was a prospective, open-label RCT. Patients were randomized after successful PCI with a biolimus A9-eluting stent to either aspirin plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy (90 mg, twice daily) or standard DAPT with clopidogrel (for patients with stable CAD) or ticagrelor (for patients with ACS) for 12 months, followed by aspirin monotherapy for another 12 months. A total of 15,968 patients were enrolled. The primary efficacy endpoint was all-cause death or non-fatal new Q-wave MI, and the primary safety endpoint was major bleeding, defined as BARC 3 or 5 bleeding. At 2 years, ticagrelor monotherapy was not superior to standard DAPT for reducing the primary efficacy (RR, 0.87; 95%CI, [0.75–1.01]; *p* = 0.073) or safety endpoints (RR, 0.97; 95%CI, [0.78–1.20]; *p* = 0.770). The adherence rate at two years was 77.6% in the experimental group and 93.1% in the control group, consistent with the premature ticagrelor discontinuation rate (25%) observed in other studies and mainly related to adverse events such as bleeding and dyspnea [46,47].

One of the main limitations of the GLOBAL LEADERS trial was the lack of independent event adjudication. Therefore, the prespecified GLASSY (GLOBAL LEADERS Adjudication Sub-Study) study was conducted following the same methodology as the main trial [48]. The study included approximately 47% of the main trial sample size enrolled in the top 20 enrolling sites. At 2 years, ticagrelor monotherapy was noninferior but not superior to standard 12 months DAPT for reducing the primary efficacy endpoint (RR, 0.85; 95%CI, [0.72–0.99]; *p*noninferiority < 0.001 and *p*superiority = 0.046 at alpha of 2.5%). There were no significant differences between groups in major bleeding regardless of the definition.

The prespecified [49–56] and selected post-hoc analyses [57–61] performed by the GLOBAL LEADERS investigators for exploring the effect size of the intervention on different subgroups are shown in Table S1.

TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention) was prospective, double-blind, placebo-controlled RCT that compared ticagrelor plus placebo vs. ticagrelor-based DAPT in event-free and high-risk PCI patients

who completed 3 months of DAPT with aspirin and ticagrelor [62]. The primary endpoint was defined as clinically relevant bleeding (BARC 2, 3, or 5). The key secondary endpoint was the composite of all-cause death, nonfatal MI, or nonfatal stroke. A total of 7119 patient were randomized. At 1 year, the incidence of clinically relevant bleeding was significantly lower in the ticagrelor monotherapy group than in the ticagrelor-based DAPT group (HR, 0.56; 95%CI, [0.45–0.68]; *p* < 0.001). The secondary endpoint of BARC type 3 or 5 bleeding was also significantly less in the ticagrelor monotherapy group (HR, 0.49; 95%CI, [0.33–0.74]; *p* < 0.001). In the key secondary ischemic composite endpoint, ticagrelor monotherapy was non-inferior to ticagrelor-based DAPT group (HR, 0.99; 95%CI, [0.78–1.24]; *p*noninferiority < 0.001).

The main results of the TWILIGHT trial have been shown to be consistent in several subgroup analyses such as age [63], gender [64], East Asian ethnicity [65], DM status [66], CKD status [67], prior MI [68], clinical presentation [69], stent used [70], and HBR status [71]. Overall, all indicate a reduced risk of clinically relevant bleeding and without a significant increase in ischemic events. A complete list of the prespecified and post-hoc analyses performed by the TWILIGHT investigators are shown in Table S2.

TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-eluting Stent for Acute Coronary Syndrome) trial was prospective, open-label RCT comparing ticagrelor monotherapy after 3 months of DAPT versus ticagrelor-based DAPT for 12 months in patients with ACS treated with PCI [72]. The primary outcome was a net adverse clinical event (NACE, composite of MACCE [composite of all-cause death, MI, stent thrombosis, stroke, or target vessel revascularization] and TIMI major bleeding). A total of 3056 patients were randomized. At 1 year, ticagrelor monotherapy significantly reduced NACE compared to ticagrelor-based DAPT (HR, 0.66; 95%CI, [0.48–0.92]; *p* = 0.01). There was significant reduction in major bleeding between two groups (HR, 0.56; 95%CI, [0.34–0.91]; *p* = 0.02), but not in MACCE (HR, 0.69; 95%CI, [0.45–1.06]; *p* = 0.09).

The main results of the TICO trial have been shown to be consistent in several subgroup analyses such as DM status [73], high-ischemic risk [74], ST-segment elevation myocardial infarction (STEMI) [75], and HBR status [76]. A complete list of the prespecified and post-hoc analyses performed by the TICO investigators are shown in Table S3.

#### *4.4. Meta-Analysis*

Several meta-analyses have been reported. However, the most comprehensive data reported are the individual patient data metanalysis by Valgimigli et al. [77]. In total, 24,096 patients from the GLASSY, SMART-CHOICE, STOPDAPT-2, TICO, and TWILIGHT trials were included. The primary efficacy endpoint was defined as a composite of all-cause death, MI, and stroke, and the key safety endpoint was major bleeding (BARC type 3 or 5). In the intention-treat analysis, P2Y12 monotherapy was non-inferior but not superior to DAPT for the primary endpoint (HR, 0.93; 95%CI, [0.79–1.09]; *p* = 0.005 for noninferiority; *p* = 0.380). The bleeding risk was significantly lower with P2Y12 inhibitor monotherapy than DAPT (HR, 0.49; 95%CI, [0.39–0.63]; *p* < 0.001). In the subgroup analysis, there was a significant interaction of sex in the effect size of P2Y12 monotherapy and DAPT, there was a significant reduction in the primary endpoint in women but not in men (HR, 0.64; 95%CI, [0.46–0.89] and HR, 1.00; 95%CI, [0.83–1.19]; *p*interaction = 0.02). The interaction was mainly driven by a reduction of cardiovascular mortality in women but not in men (HR, 0.31; 95%CI, [0.15–0.65] and HR, 0.86; 95%CI, [0.59–1.25]; *p*interaction = 0.02). Furthermore, there was no significant interaction of the type of P2Y12 inhibitor (clopidogrel vs. newer P2Y12 inhibitor [mainly ticagrelor]) in the primary endpoint (HR, 0.94; 95%CI, [0.66–1.33] and HR, 0.89; 95%CI, [0.75–1.06]; *p*interaction = 0.16) or major bleeding (HR, 0.60; 95%CI, [0.34–1.06] and HR, 0.47; 95%CI, [0.36–0.62]; *p*interaction = 0.41).
