**1. Introduction**

Percutaneous coronary intervention (PCI) with stent implantation has emerged as the predominant revascularization strategy in patients with obstructive coronary artery disease (CAD) [1–3]. After PCI, antiplatelet therapy plays a pivotal role in preventing stent-related complications such as stent thrombosis and secondary prevention for non-stent-related ischemic events such as myocardial infarction (MI) and stroke [4–6]. The combination of aspirin and an oral P2Y12 receptor inhibitor, known as dual antiplatelet therapy (DAPT), has become the guideline-recommended standard strategy after PCI based on data derived from more than 35 randomized clinical trials (RCTs) [1,2,7–10].

Clopidogrel is the most prescribed oral P2Y12 inhibitor [11]. In particular, clopidogrel is the only guideline recommended P2Y12 inhibitor after PCI in patients with chronic coronary syndromes (CCS) [1,2,7,8]. However, clopidogrel is a prodrug that requires hepatic cytochrome P450 2C19 (CYP2C19) metabolism to its active form, which leads to high variability in its pharmacodynamic (PD) effects [12,13]. Importantly, patients who persist with high platelet reactivity (HPR) while on clopidogrel are at increased risk of thrombotic events after PCI [14]. Indeed, patients with acute coronary syndromes (ACS) are at increased risk for HPR. Thus, the newer generation P2Y12 inhibitors prasugrel and ticagrelor characterized by potent and predictable antiplatelet effects are preferred over clopidogrel as the standard of care in patients with ACS [1,2,9,15].

Even though the efficacy of DAPT is well established, it is also associated with an unavoidable increased risk of bleeding, which is associated with poor outcomes, including

**Citation:** Zhou, X.; Angiolillo, D.J.; Ortega-Paz, L. P2Y12 Inhibitor Monotherapy after Percutaneous Coronary Intervention. *J. Cardiovasc. Dev. Dis.* **2022**, *9*, 340. https:// doi.org/10.3390/jcdd9100340

Academic Editor: Krzysztof J. Filipiak

Received: 11 September 2022 Accepted: 5 October 2022 Published: 6 October 2022

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increased mortality [16]. Several investigations have led to defining the phenotype of patients more prone to bleeding, setting the foundation for introducing the high bleeding risk (HBR) concept [17]. In 2019, the Academic Research Consortium (ARC) formally defined HBR patients as those who are at risk of ≥4% of having type 3 or 5 bleeding according to the bleeding academic research consortium (BARC) or ≥1% of intracranial hemorrhage (ICH), both at 1 year [18]. Moreover, the ARC-HBR proposed a diagnostic criterion based on clinical and laboratory characteristics that has been classified into major and minor criteria, the presence of 1 major or 2 minor criteria are needed to fulfil the HBR definition.

Overall, these observations have prompted investigations evaluating "bleeding avoidance strategies" for patients undergoing PCI. The goal of these approaches is to minimize bleeding risk while preserving efficacy. Bleeding reduction strategies are directed to optimize the choice, duration, and modulation of DAPT (Figure 1). Amongst these, the strategy of discontinuation of aspirin after a short period of DAPT and maintaining P2Y12 inhibitor monotherapy has been a subject of extensive investigation. This strategy was first investigated in patients requiring concomitant use of an oral anticoagulant agent. The details of this approach go beyond the scope of this manuscript and are described elsewhere [19,20]. In this manuscript, we provide an overview of P2Y12 inhibitor monotherapy after a short course of DAPT in patients undergoing PCI without an indication of anticoagulation as well as the impact of P2Y12 inhibitor monotherapy compared to aspirin for long term secondary prevention in patients with CCS.

**Figure 1.** Selected bleeding avoidance strategies in patients without AF undergoing PCI. AF, atrial fibrillation; ACS, acute coronary syndrome; ASA, aspirin; CAD, coronary artery disease; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention; PFT, platelet function test; RCT, randomized controlled trial.

## **2. Rationale for P2Y12 Inhibitor Monotherapy**

Platelet activation is a complex biological mechanism involving multiple activating factors such as thromboxane A2 and adenosine diphosphate (ADP), which represent the targets of aspirin and P2Y12 inhibitors, respectively [21]. Aspirin irreversibly blocks cyclooxygenase-1 (COX-1), the key enzyme in the arachidonic acid pathway of thromboxane A2 generation. On the other hand, P2Y12 inhibitors prevent ADP-mediated platelet activation by receptor blocking effect [22]. The exact mechanism can vary according to the type of drug. Clopidogrel and prasugrel (thienopyridines) require conversion to an active metabolite and mediate irreversible inhibition. Meanwhile, ticagrelor (nonthienopyridine) is a direct and reversible receptor antagonist [13]. Prasugrel and ticagrelor provide more potent and predictable platelet inhibition compared to clopidogrel [23,24]. These better PD profiles of prasugrel and ticagrelor compared to clopidogrel translate into lower ischemic/thrombotic events in pivotal RCTs, at the expense of increased bleeding events [25,26]. All these pivotal investigations have been performed on a background of aspirin therapy, under the notion that aspirin and P2Y12 inhibitors (mainly demonstrated with clopidogrel) have synergetic effects on platelet inhibition, representing the foundation for the use of DAPT [27,28].

Although DAPT has remained the standardized therapy after PCI, the usage and duration of aspirin have been challenged based on three major arguments. First, the synergism between aspirin and P2Y12 inhibitors was mainly established by early studies on aspirin with clopidogrel [28]. In the presence of potent P2Y12 blockade, in vitro pharmacodynamic investigations have shown that aspirin does not provide much additional antiplatelet effect [29]. This was also confirmed in a series of ex vivo pharmacodynamic studies [30–32]. While withdrawal of aspirin indeed eliminates its specific inhibitory effects mediated by the COX-1 pathway, other platelet signaling pathways are still affected by potent P2Y12 blockade [20,33]. Second, aspirin is associated with gastrointestinal (GI) adverse effects, from mild dyspepsia to ulceration and GI bleeding [34]. Systemically, aspirin irreversibly and non-selectively inhibits COX enzyme, leads to systemic prostaglandin depletion that compromises gastric mucosal barrier function and increases acid secretion [34]. Locally, aspirin may reduce surface hydrophobicity and destabilize the phospholipid barrier, which makes the mucosa susceptible to direct injury by gastric acid [35]. Although several approaches are used to mitigate aspirin gastric injury (i.e., consumption with food, proton pump inhibitors, and new aspirin formulations), the most effective way to reduce aspirin GI effects is by minimizing aspirin treatment duration [36]. Third, the introduction of newer drug-eluting stents has markedly decreased the rate of stent thrombosis, and the widespread usage of lipid-lowering therapies has further reduced the incidence of MI unrelated to the stent, which was assumed to be in part driven by the beneficial effects of DAPT [37].
