*2.3. Parenteral P2Y12 Inhibitors*

Parenteral administration of a P2Y12 inhibitor allows for immediate antiplatelet effects, skipping the delay and variability in intestinal absorption velocity and providing an enhanced platelet inhibition during the time window of inadequate response to oral agents. This is notable especially in high-risk patients undergoing PCI, who require an immediate platelet inhibition.

Cangrelor is an adenosine triphosphate-analog that is a highly specific and a direct reversible antagonist for the P2Y12 receptor on the surface of platelets. This leads to blockage of ADP-induced GP IIb/IIIa receptors and inhibition of platelet aggregation. After administration, cangrelor does not need bioactivation and is immediately ready for platelet inhibition. It is available as a lyophilized powder and it is administered initially as a 30 mcg/kg intravenous bolus prior to PCI and then continued with a 4 mcg/kg/min infusion for at least 2 h or for the duration of PCI, whichever is longer. It reaches an immediate (~2 min) onset of action and has a very short offset with a rapid (30–60 min) restoration of platelet function after its discontinuation. There is neither dosage adjustment required for renal or hepatic impairment, nor for age. It has a short plasma half-life of 3–5 min as it is rapidly inactivated via dephosphorylation by nucleotidases in the blood and the major metabolite is considered inactive. Cangrelor allows high levels of platelet inhibition (>95%) and provides further decrease in platelet aggregation in patients treated than with the more potent oral P2Y12 inhibitors [33]. This reduces the risk of periprocedural and early postprocedural complications such as MI, repeat coronary revascularization and ST. Cangrelor is the only parenteral P2Y12 receptor inhibitor that has received approval. In 2015, both the US FDA and the EMA approved it in P2Y12 naïve patients undergoing PCI, both with ACS and with CAD. A large RCT showed faster and enhanced platelet inhibition in the peri-PCI period, translating into reduced ischemic events leading to clinical approval of the drug [34]. We will discuss later the CHAMPION program and more recent randomized clinical trials that have been designed to compare cangrelor vs. the more potent P2Y12 inhibitors (prasugrel and ticagrelor).

Some parenteral antithrombotic drugs that interact with multiple pathways are currently being developed for the treatment of ACS, with the aim of further reducing ischemic events without significantly increasing bleeding complications [35]. Selatogrel is a reversible binding P2Y12 inhibitor formulated for subcutaneous (SC) administration. Its molecular structure derives from incorporation of the pyrimidine group of ticagrelor into a family of compounds previously studied as P2Y12 receptor antagonists [36,37]. Preclinical studies have suggested that selatogrel is potent and selective, but also that it may have a broader therapeutic index than clopidogrel or ticagrelor with regards to increased bleeding risk while maintaining antithrombotic effect [38]. Selatogrel has a rapid onset and one study of the radiolabeled drug suggested that there were no significant plasma metabolites, and that elimination was largely fecal, predicting no significant drug–drug interactions [39]. Phase II trials in both ACS and stable, chronic CAD are now being reported with promising results. Selatogrel reliably and potently inhibits platelet reactivity within 30 min after subcutaneous administration and for approximately 8 h in patients with chronic coronary syndrome, the effect fading within 24 h [40]. In patients with AMI, a single subcutaneous injection of selatogrel rapidly induced a profound and dose-dependent inhibition of platelet activity, independently from age, sex or clinical presentation, without major bleeding events and with short-term dyspnea as the only relevant adverse event [41]. The clinical context in which selatogrel may find its place remains to be determined; however, as it provides potent, rapid and reversible P2Y12 inhibition without the need for intravenous access or infusion, it could represent a promising pre-treatment option for early prehospital administration by healthcare professionals or even from self-administration by patients during a suspected re-infarction [42]. A large-scale clinical outcomes trial (SOS-AMI, Selatogrel Outcome Study in Suspected Acute Myocardial Infarction) in patients with a recent history of AMI, employing an autoinjector for early and convenient subcutaneous self-administration of selatogrel by the patient him/herself, is now ongoing (ClinicalTrials.gov Identifier: NCT04957719).

RUC-4 (zalunfiban) is a second-generation GP IIb/IIIa inhibitor (GPI) which has shown a good safety profile and a high and limited-duration antiplatelet efficacy in both stable [43] and STEMI [44] patients. Zalunfiban is now being investigated in a large-scale Phase 3 RCT testing pre-hospital subcutaneous injection in STEMI patients (CELEBRATE, A Phase 3 Study of Zalunfiban in Subjects with ST-elevation MI, ClinicalTrials.gov Identifier: NCT04825743).

#### **3. Efficacy and Safety of Cangrelor: Main Evidence Available**

#### *3.1. The CHAMPION Program*

The pharmacologic profile of cangrelor makes it not only an attractive agent for protection of ischemic events in patients undergoing PCI, but also a safe one in case of procedural complications, such as bleeding or need for emergent surgery, given its fast offset of effects, obviating the need for an antidote for reversal [45–47]. The efficacy and safety of cangrelor in the setting of PCI were evaluated in three large randomized controlled, double-blind, phase III trials (Table 1):


**Table 1.** Overview of the CHAMPION Program trials.

The CHAMPION-PLATFORM trial enrolled 5362 patients with stable angina, unstable angina or NSTE-ACS undergoing PCI [48]. Patients were randomized to either cangrelor or placebo, bolus and infusion initiated during PCI, followed by 600 mg of clopidogrel at the end of the cangrelor infusion or at the end of the PCI for the placebo group. The primary endpoint of a composite of death, MI or ischemia-driven revascularization at 48 h was not significatively different between cangrelor or placebo (7.0 vs. 8.0%; *p* = 0.17) but cangrelor, had significantly lower rate of ST (0.2 vs. 0.6%; *p* = 0.02) and death from any cause (0.2 vs. 0.7%; *p* = 0.02) at 48 h. Cangrelor had no differences compared to

placebo for major or minor bleeding according to the TIMI criteria and for severe or moderate bleeding according to the GUSTO study [49]. There was only a difference in major bleeding according to the ACUITY criteria, due to an excess of groin hematomas in the cangrelor group. However, the rates of blood transfusion were not significantly different. The CHAMPION-PCI trial (n = 8877) had a similar design to the prior trial but clopidogrel was given at the start of the placebo infusion, before PCI. The trial population was basically the same but also included ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI (pPCI). The primary and secondary endpoints were the same as for CHAMPION-PLATFORM. However, in CHAMPION-PCI there were no statistically significant differences between the cangrelor and clopidogrel groups for any endpoint. The incidence of bleeding was significatively higher in the cangrelor group only by ACUITY minor (17.6 vs. 15.2%; *p* = 0.003) or GUSTO mild (19.6 vs. 16.9%; *p* = 0.001) criteria [50]. These discouraging results could be explained by the MI definition used in these trials which was considered obsolete and did not appropriately discriminate periprocedural MI especially from the first MI in ACS patients, being based mainly on CK and CKMB assays [51]. An analysis of these two trials using the universal MI definition demonstrated that the primary endpoint of a composite of death, MI and ischemia-driven revascularization was significantly reduced with cangrelor compared with the control (3.1 vs. 3.8%; *p* = 0.037). This difference was seen early, within the prior 6 h, according to the cangrelor time of action. Even acute ST was lower with cangrelor compared to placebo (0.2 vs. 0.4%; *p* = 0.018). In addition, cangrelor caused more rate of major and minor bleeding by ACUITY criteria and more hematomas, though they did not need more blood transfusions, according to trial results [52]. The benefit of cangrelor in ischemic endpoints seen in this analysis led to conduct of a similar trial, incorporating the universal definition of MI, the CHAMPION PHOENIX [34]. Enrolled patients (n=11,145), who were P2Y12 inhibitor naïve, underwent PCI for stable angina, NSTEMI or STEMI. They received cangrelor and a loading dose of clopidogrel (600 mg) at the end of infusion, or placebo and a loading dose of clopidogrel (300 or 600 mg) before or after PCI. Cangrelor led to a significantly lower rate of the primary endpoint (composite of death, MI, ischemia-driven revascularization or ST at 48 h) (4.7 vs. 5.9%; *p* = 0.005), particularly driven by a reduction in the periprocedural MIs; it led also to a significantly lower rate of the secondary endpoint of intraprocedural ST at 48 h [53]. Bleeding outcomes defined as GUSTO major and moderate criteria were not significantly different between the cangrelor group and the clopidogrel group. Bleeding measured using the more sensitive ACUITY criteria was consistently increased with cangrelor relative to clopidogrel in both stable and ACS patients. However, the need for blood transfusions was similar between the groups [53]. A post-hoc analysis combined the primary efficacy and safety endpoints to provide a composite of net adverse clinical events. Cangrelor compared with clopidogrel consistently reduced net adverse clinical events, in both ST and ACS subsets, both early at 48 h and at 30 days. These results were confirmed, at 48 h and 30 days, by a pooled analysis of all three CHAMPION trials [54].
