Efficient removal of apixaban with extracorporeal hemoadsorption

Abstract

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): CytoSorbents Medical Incorporation Background A hemadsorption device containing biocompatible porous polymer beads is easily incorporated into extracorporeal circuits including cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT), and hemoperfusion. This device has been shown to safely and effectively remove the P2Y12 receptor antagonist ticagrelor and the direct oral anticoagulant (DOAC) rivaroxaban during CPB in patients undergoing emergent cardiac surgery. Importantly, drug removal was associated with significant reductions in surgical bleeding and improved clinical outcomes resulting in CE Mark approval. Apixaban, another DOAC, has gained increasing popularity given its proven efficacy and lower risk of bleeding in clinical use. However, a pressing unmet medical need exists for the mitigation of the bleeding risk encountered in patients on apixaban who require urgent or emergent surgery. Currently approved reversal agents are only indicated in the case of uncontrolled or life-threatening bleeding, but not as preventive measures to mitigate surgical bleeding. Purpose To demonstrate the ability of the extracorporeal hemoadsorption device to remove apixaban from whole blood. Methods The hemoadsorption device was evaluated for removal of apixaban in an in vitro benchtop model using bovine whole blood. The 4L of blood were continuously circulated through a 300 mL porous polymer device over 6 hours at a flow rate of 300 mL/min to evaluate the drug removal kinetics of apixaban. Starting apixaban concentration of 300ng/mL was utilized in the model to reflect standard therapeutic levels. Plasma levels of apixaban over time were measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS). A control setup utilized an identical flow circuit, minus the hemoadsorption device. Results Mean plasma concentration of apixaban was reduced to ∼9.1 ng/mL (equivalent to ∼96.3% removal) over the first 60 min of hemoperfusion with the device. Specifically, mean percent remaining plasma concentration of apixaban following device treatment was 42.2%, 18.6%, 8% and 3.7% after 15, 30, 45 and 60 min of therapy, respectively. Overall, ∼99.7% blood concentration of apixaban was removed over the total 6 h. Drug concentrations remained unchanged in the control circuit, with a statistically significant difference between the control and treatment groups at all time points except 0 h (p < 0.01). Conclusion Apixaban is efficiently removed with hemoadsorption using porous polymer device technology. Drug concentrations were reduced >96% after 60 min. Similarly, efficient benchtop removal utilizing the same technology was observed for ticagrelor and rivaroxaban, and subsequently translated into significant clinical benefit in patients requiring emergent cardiac surgery. The results of the current study hold significant promise for the future clinical applicability of apixaban removal. Abstract Figure. Percent of remaining apixaban over time