Development of an Oral Anticoagulation Strategy for Permanent Artificial Lung Support

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) systems for permanent respiratory support are currently under development as an alternative to lung transplantation. Direct oral anticoagulants are a promising alternative to heparin due to their oral administration and predictable pharmacology. METHODS: The efficacy of rivaroxaban for artificial surface anticoagulation was evaluated using 3 studies that determined (1) the pharmacological behavior of 0.25, 0.5, and 1 mg/kg doses of rivaroxaban in sheep; (2) the artificial surface anticoagulation efficacy of these 3 doses compared with heparin in a short-term mini-ECMO model; and (3) the efficacy of the optimal dose from study 2 with simulated oral pharmacokinetics in an extended-duration mini-ECMO model. RESULTS: Study 1 found that sheep have a higher volume of distribution (2.2 ± 0.4 L/kg) and a shorter half-life (1.4 ± 0.1 h) for rivaroxaban than humans but a similar linear relationship between prothrombin time and rivaroxaban plasma concentration. In study 2, device survival time in the heparin group (57.5 ± 13.0 min) was most similar to the 0.5 mg/kg rivaroxaban group (51.3 ± 8.8 min; P = 0.287). This dose was selected for study 3, and no difference was found in device survival time between heparin (6.3 ± 1.3 h) and the 0.5 mg/kg rivaroxaban infusion (6.3 ± 1.6 h; P = 0.837). Furthermore, the calculated rivaroxaban exposure was similar to the clinically approved oral rivaroxaban doses (24-h area under the plasma concentration curve = 2074 µg h/L). CONCLUSIONS: These results demonstrate that rivaroxaban has artificial surface anticoagulation efficacy similar to that of heparin at dosages that are feasible for oral administration in humans. Future studies will evaluate rivaroxaban anticoagulation using a 10-d full-scale ovine ECMO model.