*2.1. Oral P2Y12 Inhibitors*

While ticlopidine was the first P2Y12 inhibitor to be associated with low-dose aspirin for DAPT, its unfavorable safety profile made it obsolete after the introduction of clopidogrel. Clopidogrel is a second-generation thienopyridine and an irreversible P2Y12 receptor antagonist that is administered as an inactive pro-drug and requires enzymatic liver conversion into its active metabolite by a series of cytochrome P450 (CYP) enzymes. After activation, clopidogrel irreversibly binds to P2Y12, an ADP receptor, on the surface of platelets, resulting in an inactivation of the glycoprotein (GP) IIb/IIIa receptor and destabilization of the platelet aggregate [6]. The recommended regimen is a loading dose of 600 mg followed by a maintenance dose of 75 mg once daily. No dose adjustment is required in CKD patients. The onset of action is particularly delayed and variable, ranging from 2 to 6 h and the offset of effect ranges from 3 to 10 days. The evidence provided by the landmark CURE trial established DAPT with clopidogrel as the standard of care after acute coronary syndrome (ACS) and after coronary stent implantation [13]. However, clopidogrel has too much inter-individual variability in platelet inhibition and has significant non responsiveness and resistance in some patients. The enzymatic liver conversion is one of the main causes of variability of clopidogrel action. CYP2C19 is one of the most important polymorphic CYP enzymes across different populations and this is associated with worse outcomes, for instance, in those with the CYP2C19\*2 variant [14]. Likewise, all comedications that are inhibitors of CYP2C19 suppress clopidogrel bioactivation (e.g., some proton pump inhibitors, statins and calcium channel blockers) [15]. Moreover, poor intestinal absorption can delay the onset of action of clopidogrel, which can be worsened by concomitant administration of opioids for angina relief. Inadequate P2Y12 inhibition, especially in the setting of ACS, contributes to more frequent periprocedural complications such as need for recurrent revascularization, MI, and ST. This highlighted the need for a more potent and consistent platelet inhibition that was introduced with novel generation P2Y12 inhibitors.

Prasugrel is thienopyridine as well and an irreversible P2Y12 receptor antagonist that is administered as an inactive pro-drug and requires an enzymatic liver activation. Differently than clopidogrel, it gains a faster, greater, and more consistent degree of platelet inhibition [16]. The recommended regimen is a loading dose of 60 mg followed by a maintenance dose of 10 mg once daily, reduced to 5 mg in patients ≥75 years old or <60 kg. No dose adjustment is required in CKD patients. The onset of action is rapid, ranging from 0.5 to 4 h and the offset of effect ranges from 5 to 10 days. The TRITON-TIMI 38 trial compared prasugrel versus clopidogrel in P2Y12 inhibitor-naïve ACS patients referred to PCI [4]. Prasugrel determined a reduction in primary ischemic endpoint compared to clopidogrel, counterbalanced by a significant increase in the rate of major bleeding. Prasugrel was also compared to ticagrelor, the other potent P2Y12 inhibitor, in the recent ISAR-REACT 5 randomized trial. Prasugrel was superior in reducing the rate of death, MI, and stroke without any increase in bleeding complications [17]. Thus, prasugrel is the recommended P2Y12 inhibitor in ACS patients without high bleeding risk proceeding to PCI [18].

Ticagrelor is a direct oral reversible P2Y12 receptor inhibitor, which belongs to a novel chemical class, the cyclopentyl triazolopyrimidine. Following intestinal absorption, ticagrelor does not need to be metabolized for platelet inhibition. The recommended dose is a loading dose of 180 mg followed by a maintenance dose of 90 mg twice a day. No dose adjustment is required in CKD patients. The onset of action is rapid as well, ranging from 0.5 to 2 h and the offset of effect ranges from 3 to 4 days. The PLATO trial proved the superiority of ticagrelor compared to clopidogrel in ACS patients regarding the rate of

death from vascular causes, MI, or stroke, without significant difference in major bleeding rates [5]. Nevertheless, ticagrelor also led to more patients stopping medication because of side effects, mainly dyspnea. As it is not associated with pulmonary or cardiac dysfunction, alterations in the mechanisms and the neurological pathways of the sensation of dyspnea may be involved in its pathogenesis [19].

## *2.2. Drawbacks of Oral P2Y12 Inhibitors*

Despite potent P2Y12 inhibitors (prasugrel and ticagrelor) provide lower rates of ischemic events compared to clopidogrel, significant concerns remain about their onset of action. Moreover, their administration does not counterbalance the high residual platelet reactivity (HRPR) up to 4–6 h after the standard loading dose [20–22]. For this reason, strategies have been tested to increase the bioavailability of oral P2Y12 inhibitors, such as crushing or chewing tablets. However, pharmacokinetic and pharmacodynamic data remain limited [23–25]. So far, clopidogrel remains the P2Y12 inhibitor recommended in stable coronary artery disease (CAD) patients, unless specific high-risk procedural characteristics are present, such as complex left main or multivessel stenting, suboptimal stent deployment, or other conditions associated with high risk of stent thrombosis; in such cases, initial treatment with either prasugrel or ticagrelor may be considered according to European guidelines [26] if the tradeoff between risk of ischemia and bleeding is favorable [27]. All these therapies are limited by their need to be absorbed in the gastrointestinal (GI) tract before becoming available and this leads to an inevitable delay between drug intake and time of reaching effective platelet inhibition. Gastric emptying, intestinal motility, blood perfusion of the mucosa and its permeability are all factors influencing the absorption rate of medications [28]. Moreover, it has been reported that the velocity of platelet inhibition after oral intake was influenced by the clinical presentation: faster for stable CAD undergoing PCI, slower for NSTE-ACS patients, and the slowest for STEMI patients [20,29]. This phenomenon can be explained by a decreased cardiac output in ACS patients, which leads to a sympathetic system activation, and a vasoconstriction of the peripheral arteries that shunts the blood to vital organs, impairing gastric emptying, intestinal motility, and permeability of the hypo-perfused mucosa [30]. Elevated central pressure due to reduced cardiac output also leads to the release of atrial natriuretic peptide, which inhibits intestinal permeability and motility [31]. In acute settings, nausea and vomiting are common, reducing drug absorption as well. Finally, concomitant treatment with morphine, an opioid analgesic usually used to alleviate chest pain, delays gastric emptying, reduces intestinal peristalsis, and itself induces nausea and vomiting. Another barrier concerns the inability for oral administration of medications in intubated or unconscious patients. A new formulation of ticagrelor in orodispersible tablets that promptly releases its components upon contact with the oral cavity has recently become available and has been tested in a prospective trial of high-risk ACS patients. Although a superior grade of platelet inhibition was not obtained as compared with standard ticagrelor tablets, the trial confirmed the feasibility and safety of administration of ticagrelor without the need of swallowing water, that may prove to be convenient in critical ACS patients [32].

That said, following intake of oral P2Y12 inhibitors there is a variable timeframe of hours of inadequate antiplatelet protection. While the risk for ST is low with new generation stents, the delayed antiplatelet effects may still increase the risk of peri-procedural MI and impaired coronary/myocardial reperfusion, translating into worse clinical outcomes. Pretreatment whenever possible could reduce this delay, but most recent ESC guidelines do not recommend (class III) pre-treatment with oral P2Y12 inhibitors in NSTE-ACS patients, because several trials showed no ischemic benefits and more bleeding complications [18]. In addition, treatment of stable CAD patients does not include a P2Y12 inhibitor before coronary angiography. These observations underscore the need to define strategies that can bridge the gap in platelet inhibitory effects following intake of oral P2Y12 inhibitors.
