**5. P2Y12 Inhibitor versus Aspirin Monotherapy for Long-Term Secondary Prevention**

CAPRIE (A Randomized Blinded Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events) trial was a prospective double-blind RCT reported in 1996 comparing clopidogrel monotherapy with aspirin (325 mg daily) monotherapy in patients with atherosclerotic vascular disease (defined as recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease) [78]. A total of 19,185 patients were enrolled with a mean follow-up of 1.91 years. The primary endpoint was a composite of ischemic stroke, MI, or vascular death, which was significantly lower in the clopidogrel monotherapy group than the aspirin group (relative risk reduction, 8.7%; 95%CI, [0.3–16.5]; *p* = 0.043). Clopidogrel monotherapy had a significant lower rate of gastrointestinal hemorrhage events (patients ever reporting: 2.0% vs. 2.7%; *p* < 0.05 and severe gastrointestinal hemorrhage: 0.5% vs. 0.7%; *p* < 0.05). Moreover, clopidogrel monotherapy had a better upper GI tolerability than aspirin alone, with significant less indigestion/nausea/vomiting reported (patients ever reporting: 15.0% vs. 17.56%; *p* < 0.05) [78]. Despite the benefits of clopidogrel over aspirin, aspirin has remained the mainstay of therapy considering its reduced costs with clopidogrel being recommended over aspirin only in patients who could not tolerate or with hypersensitivity to aspirin. However, over two decades later with the availability of generic formulations of clopidogrel, there has been a re-appraisal for P2Y12 inhibitor monotherapy for long-term secondary prevention.

HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) trial was a prospective, open-label RCT comparing clopidogrel monotherapy or aspirin monotherapy for 24 months in event-free patients who were on DAPT for 6–18 months after PCI (*n* = 5530) [79]. The primary endpoint was a composite of all-cause death, non-fatal MI, stroke, readmission due to ACS, and major bleeding (BARC 3–5). At 2 years, clopidogrel monotherapy significantly reduced the primary endpoint compared to aspirin monotherapy (HR, 0.73; 95%CI, [0.59–0.90]; *p* = 0.003), driven by both the ischemic composite endpoint (HR, 0.68; 95%CI, [0.52–0.87]; *p* = 0.003) and major bleeding (HR, 0.63; 95%CI, [0.41–0.97]; *p* = 0.035).

GLOBAL LEADERS investigators performed a post-hoc landmark analysis between the first and second year of follow-up in patients who were event free during the first year [80]. In particular, during this period, patients were on ticagrelor monotherapy and aspirin monotherapy. There was a lower rate of MI in the ticagrelor monotherapy compared to the aspirin monotherapy group (adjusted HR, 0.74; 95%CI, [0.58–0.96]; *p* = 0.022), but at the expense of a higher rate of major bleeding (adjusted HR, 1.89; 95%CI, [1.03–3.45]; *p* = 0.005).

#### *Meta-Analysis*

The P2Y12 inhibitor or aspirin monotherapy as secondary prevention in patients with coronary artery disease: an individual patient data meta-analysis of randomized trials (PANTHER) trial assessed the role of long-term P2Y12 monotherapy compared to aspirin monotherapy for the prevention of recurrent events in patients with CAD [81]. This analysis included 24,325 patients from seven RCTs. The primary endpoint was the composite of cardiovascular or vascular death, any non-fatal MI, and any non-fatal stroke. At a median of 557 days, P2Y12 monotherapy was associated with a significant reduction in the primary endpoint compared to aspirin monotherapy (HR, 0.88; 95%CI, [0.79–0.97]; *p* = 0.014). The P2Y12 monotherapy was associated with a significant reduction in MI (HR, 0.89; 95%CI, [0.81–0.98]; *p* = 0.020) and definite/probable stent thrombosis (HR, 0.46; 95%CI, [0.23–0.92]; *p* = 0.028) without a significant reduction in major bleedings (HR, 0.87; 95%CI, [0.70–1.09]; *p* = 0.230), and all cause-death (HR, 1.04; 95%CI, [0.91–1.20]; *p* = 0.560). Concerning the bleeding causes, P2Y12 monotherapy was associated with a significant reduction in gastrointestinal bleeding (HR, 0.75; 95%CI, [0.57–0.97]; *p* = 0.027) and ICH (HR, 0.32; 95%CI, [0.14–0.75]; *p* = 0.009).
