Cangrelor on Top of anticoagUlation in Patients With myocaRdial Infarction-related Cardiogenic Shock/Cardiac Arrest receiVIng VA-ECMO

Veno-Arterial Extra Corporeal Membrane Oxygenation (VA-ECMO) is increasingly used to support patients throughout a spectrum of hemodynamic instability states ranging from severe cardiogenic shock (CS) to refractory cardiac arrest (CA). VA-ECMO, is thus often employed in clinical practice for the management of CS/CA complicating acute coronary syndromes (ACS). The interface of blood and VA-ECMO mechanical components, along with rotational forces generated by pump impellers configures a unique combination of prothrombotic and pro-haemorrhagic milieu (haemocompatibility). In this setting of competing thrombotic and hemorrhagic risks, optimal anti-thrombotic therapy remains ill-defined for patients undergoing percutaneous coronary intervention (PCI) for ACS on VA-ECMO. Theoretically, dual anti-platelet therapy (DAPT) consisting of aspirin plus an oral P2Y12 inhibitor should be associated with systemic anticoagulation (triple antithrombotic therapy). Platelet activation during ECMO support confers increased thrombotic risk, which, in the setting of ACS-related CS/CA, is worsened by the pro-thrombotic and pro-inflammatory state, the low-cardiac output with subsequent blood stasis and tissue hypoperfusion and possibly the need for myocardial revascularization procedure with stent implantation. At the same time, blood interaction with device foreign surfaces has been associated to reduced platelet surface expression of GpIb-GpIV, lower activated surface GpIIb-IIIa levels and blunted ADP-mediated aggregation, which translate into increased bleeding risk. Bleeding complications, however, exceed ischemic risk and triple antithrombotic therapy may confer an excess risk in this population prone to bleeding and may jeopardize patients' outcome. In this context of delicate haemostatic equilibrium several pharmacokinetic and pharmacodynamic factors limit the use of standard DAPT in addition to systemic anticoagulation, including the irreversible inhibiting effect of aspirin on platelets and the relatively long duration of action of oral P2Y12 inhibitors.

In addition, while GpIIb-IIIa inhibitors may offer a parenteral alternative antiplatelet agent, their use has been associated with increased transfusion need during VA-ECMO. The study hypothesis is that an anti-thrombotic regimen comprising cangrelor, an intravenous non-thienopyridine, reversible adenosine-diphosphate P2Y12 receptor antagonist, may reduce bleeding risk while providing adequate antithrombotic effect in patients on VA ECMO due to CS/CA who underwent PCI. Both the rapid onset and offset of action of this agent make it a particularly attractive option in patients at a high risk of both thrombotic and haemorrhagic complications, since a combination of a low starting dose of cangrelor coupled with regular platelet function tests potentially guarantees achieving adequate anti-platelet effect at the lowest possible cangrelor dose, in order to prevent ischemic events while minimizing bleeding risk.

Systemic anticoagulation will be performed with bivalirudin, titrated to achieve effective systemic anticoagulation and an activated thromboplastin time (aPTT) of 55-70'', as for routine clinical practice. Cangrelor will be started without bolus at a low dose of 0.125 mcg/kg/min and titrated (by 0.125 mcg/kg/min steps) based on the results of platelet function assay to guarantee effective platelet P2Y12 pathway inhibition. Platelet function will be assessed with the Multiplate analyser with the aim to reach and ADP-test \<46 U. Platelet assay will be performed at baseline, 30 min after cangrelor infusion start, 12 hours after cangrelor infusion start, after any cangrelor dose modulation, regularly every 24 hours, at time of any thrombotic/bleeding event, and up to 48 hours from oral P2Y12-inhibitor initiation. Treatment with cangrelor will be discontinued at the end of VA-ECMO support, and patients will be loaded with oral P2Y12-inhibitors, as recommended for clinical practice.