*3.2. Use of Cangrelor in Combination with Potent Oral P2Y12 Inhibitors*

As already mentioned, the first trials of cangrelor mainly involved patients with stable or unstable CAD and a limited proportion of patients with STEMI. Thus, there was an urgent need for clinical and pharmacodynamic information on the wide use of cangrelor in combination with ticagrelor, the fastest oral formulation of P2Y12 inhibitors, for patients who have STEMI treated with pPCI. The CANTIC Study (Platelet Inhibition with Cangrelor and Crushed TICagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention) was the first prospective randomized study designed in patients undergoing pPCI to explore the occurrence of drug–drug interaction (DDI) when cangrelor or placebo are concomitantly administered with ticagrelor [55]. Fifty STEMI patients scheduled for pPCI were randomized into two groups: one group received blinded 2 h cangrelor bolus followed by infusion, the other group received placebo. Additionally, both groups received

180 mg of crushed ticagrelor. Platelet reactivity was measured with VerifyNow P2Y12 pointof-care testing as P2Y12 reaction units (PRU) and vasodilator-stimulated phosphoprotein (VASP). Following PCI, all patients were prescribed aspirin indefinitely and ticagrelor 90 mg twice daily for at least 12 months. PRU levels were significantly lower in patients randomized to cangrelor than in those randomized to placebo as early as 5 min after the bolus (*p* < 0.001). PRU levels at 30 min (primary endpoint) were significantly lower with cangrelor versus placebo (63 vs. 214; *p* < 0.001) and remained significantly lower in the cangrelor group until completion of the 2 h infusion. In the placebo group, PRU levels decreased over time, with significant differences from baseline observed only 1 h after drug administration (*p* < 0.001), which became more marked after 2 h (*p* < 0.001). At the end of the infusion, there was an increase in PRU levels in the cangrelor group with significant differences at 1 h (*p* = 0.001) and 2 h (*p* = 0.027) after the infusion. In the placebo group, PRU levels continued to decrease at 1 h (*p* = 0.059) and 2 h (*p* = 0.007) after the infusion and remained similar at 1 and 2 h after having stopped the infusion. Rates of high platelet reactivity (HPR), as defined by PRU > 208, were significantly higher with placebo than with cangrelor at any study time point during the infusions (Table 2). A DDI during concomitant administration of cangrelor and ticagrelor was therefore ruled out, since no differences in PRU levels were found between the two groups after drug infusion was stopped. Indeed, patients in the cangrelor group did not have HPR, differently than placebo group where HPR status was reduced but still present in already half of the individuals at the end of the PCI and in one-third of the patients at the end of the placebo infusion. HPR levels were low overall and similar between groups after discontinuation of drug infusion. This consideration is consistent with the absence of DDI between cangrelor and ticagrelor. Despite several limitations, including the limited number of patients, the results were consistent with another nonrandomized pharmacodynamic study of the combination of cangrelor and ticagrelor for pPCI [56] and with a smaller open-label randomized trial [57]. The study demonstrated that in patients undergoing pPCI, the combination of cangrelor and ticagrelor results in a more rapid and potent platelet inhibitory effect compared to ticagrelor alone, with important implications for clinical practice such as a more versatile use of ticagrelor with respect to timing of its administration in patients treated with cangrelor.


**Table 2.** Characteristics of patients randomized in the CANTIC trial [55].

The findings of the CANTIC study were confirmed by the recently published results of the prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) SWAP-5 (Pharmacodynamic and Pharmacokinetic Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment: The Switching Antiplatelet-5 Study) trial, which aimed to rule out DDI among cangrelortreated patients who were pre-treated with ticagrelor [58]. Indeed, many patients in real-world clinical practice, in whom there may be the desire to use cangrelor to achieve enhanced P2Y12 inhibitory effects during PCI, are pre-treated with ticagrelor [59]. This may include patients in whom the full antiplatelet effects of ticagrelor may be delayed by several hours due to impaired absorption such as in patients presenting with ACS, especially STEMI, or treated with opioids [60,61]. In ticagrelor-pretreated patients there was a significant reduction in PRU at 30 min and 1 h after the start of the cangrelor infusion compared to the placebo group. At 2 h after stopping the cangrelor or placebo infusion, PRUs were low and similar in both groups (16.9 vs. 12.6), satisfying the primary endpoint of non-inferiority. No differences were found in PK/PD profiles such as plasma levels of ticagrelor and its metabolite between the two groups after drug infusion discontinuation, thus the absence of a DDI was also confirmed [58]. SWAP-5 Study was conducted in patients with stable CAD and not in patients with ACS undergoing PCI. Hence, the magnitude of the PK/PD findings observed may not be reflective of those in the acute setting. Several other studies are ongoing and will provide further insights into the use of cangrelor in patients undergoing pPCI. More data on transition to potent oral P2Y12 receptor inhibitors is desirable, for instance for patients who require a fast-acting intravenous agent such as cangrelor in emergency situations, such as cardiac arrest or cardiogenic shock, or for those who have been preloaded with oral antiplatelet agents and have angiographic findings requiring an additional antiplatelet agent.

The first results of the CAMEO Registry, aimed at retrospectively addressing optimal platelet inhibition during early management of patients with MI prior to coronary angiography or coronary artery bypass grafting, demonstrated inter-hospital variability in how cangrelor was administered and switched to an oral P2Y12 inhibitor [62]. These findings highlight opportunities for optimization of cangrelor dosing, infusion duration, and the transition of care from the catheterization lab to the coronary intensive care unit. Data from recently published Cangrelor OHCA (Out-of-Hospital Cardiac Arrest) Study showed that in comatose survivors of OHCA undergoing PCI and target temperature management, cangrelor safely induced immediate and profound platelet inhibition without significant DDI with ticagrelor; nevertheless the study is a single-center and non-placebocontrolled trial [63]. Furthermore, the ongoing multicenter, randomized, double blind trial DAPT-SHOCK-AMI (Dual Antiplatelet Therapy for Shock Patients with Acute Myocardial Infarction; ClinicalTrials.gov Identifier: NCT03551964) will provide results on the comparison between the combination of cangrelor and crushed ticagrelor versus ticagrelor alone in patients with AMI complicated by initial cardiogenic shock and treated with pPCI. The ARCANGELO (Italian Prospective Study on Cangrelor) is a recently published multicenter, observational, prospective cohort study that included patients with ACS undergoing PCI who had not received an oral P2Y12 inhibitor before the PCI procedure and in whom oral therapy with P2Y12 inhibitors was not feasible or desirable; this study aimed to assess the safety of cangrelor in daily practice [64]. The primary endpoint is the incidence of any hemorrhage, according to Bleeding Academic Research Consortium (BARC) criteria, in the 30 days following the PCI, calculated as the ratio between the number of patients experiencing at least one event during the 30-day observation period and the total number of evaluable patients. The different types of bleedings according to the GUSTO criteria and MACE at various timeframes (from 48 h to 30 days) were investigated, too. The preliminary results showed that all bleedings were classified as BARC Type 1–2, BARC Grade 3a bleeding occurred in one (0.3%) patient, while more severe bleedings were not reported. A total of 17 bleedings were observed in the 320 patients who completed the study. MACE was observed in four patients (two AMI, one sudden cardiac death, one

non-cardiovascular death). None bleeding was classified as related to cangrelor. The final analysis of data will assess a more precise evaluation of the study endpoints; however, the use of cangrelor in patients with ACS undergoing PCI does not appear to be associated with severe bleedings. The ongoing SWAP-6 (Pharmacodynamic and Pharmacokinetic Profiles on Switching from Cangrelor to Prasugrel in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The Switching Antiplatelet-6 Study; ClinicalTrials.gov Identifier: NCT04668144) trial will further clarify pharmacodynamic effects to rule out a DDI when cangrelor and prasugrel are concomitantly administered in patients undergoing coronary stenting. Currently, a single study has suggested that prasugrel can be administered at the beginning of the cangrelor infusion, with no evidence of drug interactions [65]. Whether this evidence applies to patients with STEMI is unknown and this treatment strategy remains off-label [66].

FABOLUS-FASTER (Facilitation through Aggrastat or Cangrelor Bolus and Infusion over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is a trial that compared, for the first time, the pharmacodynamic effects of cangrelor with the GPI inhibitor tirofiban and the pharmacodynamic and pharmacokinetic effects of prasugrel 60 mg in chewed or whole tablets in patients with STEMI undergoing pPCI [67]. Patients were randomly assigned (1:1:1) to cangrelor (*n* = 40), tirofiban (*n* = 40) (both given as a bolus and 2 h infusion followed by a loading dose of 60 mg prasugrel at the time of infusion interruption) or prasugrel 60 mg loading dose (*n* = 42). Patients in the prasugrel group underwent further 1:1 sub-randomization to oral administration of the loading dose as chewed (*n* = 21) or whole (*n* = 21) tablets. Briefly, the aim of the study was to test three primary hypotheses: non-inferiority of cangrelor versus tirofiban, superiority of both tirofiban and cangrelor versus chewed prasugrel, and superiority of chewed prasugrel versus whole prasugrel. Cangrelor did not reach non-inferiority as compared to tirofiban in terms of ADP-induced platelet aggregation (Table 3) due to a lower platelet aggregation in patients treated with tirofiban than cangrelor or chewed prasugrel up to 2 h. Interestingly, residual platelet reactivity was lower with cangrelor compared to chewed prasugrel within the first hour, but higher thereafter.

**Table 3.** Rates of high residual platelet reactivity (>59%) at Light Transmittance Aggregometry (LTA) after ADP 20 μmol/L stimulation in FABOLUS FASTER trial [67].


Tirofiban was associated with lower TRAP-induced platelet aggregation than cangrelor or chewed prasugrel (*p* < 0.001 at any time point for both comparisons) whereas there was no difference between cangrelor and chewed prasugrel or between the two prasugrel groups. The FABOLUS-FASTER study strengthened the notion of the superiority of parenteral over oral antiplatelet drugs in the acute phase of STEMI treatment in terms of platelet inhibition; however, the observed superiority of tirofiban versus cangrelor remains a mechanistic observation, and whether it could be translated into better clinical outcomes without impairing risk of bleeding remains to be elucidated. Large-scale studies re-evaluating the comparative risks and benefits of a short infusion of parenteral platelet inhibitors such

as cangrelor or GPI versus the newer oral P2Y12 receptor blockers alone in contemporary pPCI practice remain desirable. Based on the observations from the FABOLUS-FASTER that cangrelor followed by prasugrel is associated with a rebound in platelet activation over 2 to 4 h and on the data of CANTIC Study [55] and Alexopoulos [20] showing some HRPR during and after the cangrelor infusion, it could be hypothesized that when cangrelor is used, ticagrelor may be the preferred oral P2Y12 inhibitor.

#### **4. Current Recommendations for the Transition from Cangrelor to Oral P2Y12 Inhibitors**

At the end of cangrelor infusion, which should be prolonged at least for two hours, patients who underwent PCI with stent implantation should receive a loading dose of an oral P2Y12 inhibitor, beyond aspirin. The timing for the P2Y12 inhibitor loading dose is related to the pharmacology of the specific drug. Clopidogrel active metabolite is rapidly degraded if it does not bind P2Y12 receptor. So, if the receptor is already occupied by cangrelor, a more potent P2Y12 inhibitor, clopidogrel active metabolite is degraded, getting no platelet inhibition following the cangrelor infusion cessation. Therefore, loading dose of 600 mg clopidogrel must be administered only after cangrelor infusion cessation. This is also widely supported by CHAMPION platelet sub-study, where there was no apparent significant pharmacodynamic interaction when clopidogrel was administered at the end of the cangrelor infusion [68].

Prasugrel is a thienopyridine requiring activation with similar pharmacodynamics to clopidogrel. Therefore, the loading dose administration of prasugrel should be administered at the end of cangrelor infusion as well. A study examining the transition from cangrelor to thienopyridines showed a transient recovery of platelet reactivity during the switch and found the optimal administration time of prasugrel, to limit the recovery of platelet function, at 30 min prior to cangrelor cessation [69]. This is in line with the more potent binding power to P2Y12 receptor of prasugrel compared to clopidogrel. In accordance with this study, the EMA recommends the administration of a prasugrel loading dose (60 mg) either 30 min prior to the cangrelor cessation or immediately after; the FDA recommends it only immediately after cangrelor cessation.

Ticagrelor is a reversible P2Y12 inhibitor, and it binds a different site of the receptor compared to cangrelor. Previous studies have demonstrated that there are no DDI between ticagrelor and cangrelor, suggesting that ticagrelor can be given at any time during cangrelor infusions or at the end of it [70]. Both the FDA and EMA have recommended the administration of a ticagrelor loading dose (180 mg) either during the cangrelor infusion or immediately after the infusion cessation.

For clopidogrel and prasugrel, the recommended transitions from cangrelor may result in a brief inadequate P2Y12 inhibition, due to the delayed onset of action of clopidogrel and prasugrel. This is consistent with the results of a recent observational pharmacodynamic registry confirming that the switch from cangrelor to clopidogrel could expose patients to a variable period of inadequate platelet inhibition, while ticagrelor given as early as possible after starting cangrelor infusion may avoid any rebound effect in platelet reactivity [71]. Therefore, it is reasonable to prefer ticagrelor as the maintenance P2Y12 inhibitor in oral DAPT, as it can be started prior to the cessation of cangrelor.

#### **5. Antiplatelet Bridging for CABG and Non-Cardiac Surgery**

Patients treated with a P2Y12 inhibitor, who require a major cardiac or non-cardiac surgery, have worse outcomes due to an increased risk for peri- and post-operative bleedings, reoperation and need for blood transfusions. The European guidelines recommended to delay, if it is possible, a non-emergent surgery after PCI with DES implantation until completion of the full course of DAPT, or at least after one month of DAPT [72]. In cases when surgery cannot be delayed for a longer period, a minimum of 1 month of DAPT should be considered, because the higher risk of adverse cardiac events is within the first 30 days after PCI. In any case of patients who need earlier surgery, it is recommended to

withhold P2Y12 inhibitor at least 7 days for prasugrel, 5 days for clopidogrel and 3 days for ticagrelor before surgery (Figure 1). However, cessation of DAPT in the setting of recent ACS or PCI with stent implantation is associated with a time-dependent increased risk for worse outcomes. It is particularly true for ACS patients with high ischemic risk features, who need at least 6 months of DAPT.

**Figure 1.** Time frames of P2Y12 inhibitor discontinuation and restarting in patients undergoing cardiac or non-cardiac surgery. Elaborated from Valgimigli et al. [72].

For patients with a very high risk of ST who cannot delay surgery, bridging therapy with intravenous, reversible platelet inhibitor may be considered (Figure 1). Due to its profile of being a rapid onset/offset, potent and reversible P2Y12 inhibitor, cangrelor was tested as a P2Y12 inhibitor 'bridge' after discontinuation of thienopyridines, in patients undergoing surgery (BRIDGE trial). In this trial, 210 participants who were planned to undergo non-emergent CABG and had received an oral P2Y12 inhibitor were randomized to either cangrelor as bridge therapy or placebo. Aspirin therapy was maintained. Cangrelor, compared with placebo, resulted in higher proportions of suppressed platelet activity, without a significant increase in CABG-related bleeding (11.8 vs. 10.4%; *p* = 0.76), despite some participants receiving cangrelor infusion for up to 7 days [73].

Based on the BRIDGE trial protocol, a recent consensus document standardized management of antithrombotic therapy in patients treated with coronary stents in various types of surgery [74]. It is recommended to stop prasugrel 7 days, clopidogrel and ticagrelor 5 days before surgery. Cangrelor as bridge therapy should be started within 72 h from P2Y12 discontinuation, at the dose of 0.75 μg/kg/min without bolus and continued until 1–6 h before skin incision. Clopidogrel should be started, with a new loading dose of 300 or 600 mg, as soon as possible after surgery (within 1–6 h). If oral administration is not possible due to intubation, cangrelor should be restarted. Prasugrel and ticagrelor are discouraged. The MONET BRIDGE study was designed to assess the use of cangrelor as a platelet-inhibiting bridge for patients who discontinue DAPT before cardiac and noncardiac surgery within 12 months from coronary stent implantation [75]. It demonstrated that perioperative bridging therapy with cangrelor is a feasible approach for patients with DES at high thrombotic risk and undergoing surgery requiring interruption of DAPT: no ischemic outcomes occurred after surgery and up to 30-days follow-up. Moreover, the mean hemoglobin drop was <2 g/dL; nine patients received blood transfusions consistent

with the type of surgery, but no life-threatening or fatal bleeding occurred. More studies are warranted to support the efficacy and safety of a standardized bridging strategy by identifying the patient population that would receive the maximum clinical benefit from bridge therapy. In addition to MONET BRIDGE, the MARS (Management of Antiplatelet Regimen During Surgical Procedures; ClinicalTrials.gov Identifier: NCT03981835) trial is currently studying the area of perioperative antiplatelet therapy management through a multi-center, observational US national registry designed to collect preoperative, intraoperative and postoperative clinical strategies, therapeutic interventions, and 30-day outcomes data of ~1500 patients post-PCI scheduled to undergo cardiac or noncardiac surgery.

#### **6. Future Directions**

The current available oral P2Y12 has a relatively slow onset of action, so drug-naïve patients, and especially those with ACS, undergoing PCI lack the protection conferred by antiplatelet therapy for a too long period and may be exposed to a greater thrombotic risk. Cangrelor proved its effectiveness in drug-naïve patients undergoing PCI, both in the stable and the acute setting, by reducing early and 30-day ischemic outcomes, with particular emphasis for ischemia driven revascularization and early ST. Cangrelor appears to be a very safe drug with a low rate of bleeding and specifically of major (BARC 3–5) events. The results of ongoing randomized trials with new short-acting and potent parenteral antiplatelet agents will be likely to open a new debate about the optimal choice and timing to administer parenteral DAPT in patients with STEMI, since we could have available, at the same time, a drug to be self-administered at home (selatogrel), a drug to be administered in the ambulance (zalunfiban) and a drug to be administered in the hospital (cangrelor). Further RCTs are needed about the combination of parenteral and potent oral P2Y12 inhibitors in patients with ACS and about the optimal switching strategies. Available studies so far support the most adopted practice to administer ticagrelor at the same time of cangrelor bolus or as soon as possible after initiation of cangrelor infusion.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** This study did not require ethical approval.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
