Dabigatran and reversal during cardiopulmonary bypass: In vitro human volunteer studies and a porcine model

Objectives To characterize how dabigatran, unfractionated heparin (UFH), and their reversal agents influence activated clotting time (ACT) and dabigatran-sensitive assays during cardiopulmonary bypass (CPB). Design In vitro human whole blood experiments and a controlled porcine cardiopulmonary bypass model. Setting Laboratory and animal operating suite. Participants Healthy volunteers ( n = 3) provided whole blood for in vitro testing; 9 pigs underwent 90-min cardiopulmonary bypass. Interventions Whole blood was incubated with unfractionated heparin and/or dabigatran with reversal by protamine or idarucizumab. Pigs received unfractionated heparin alone ( n = 2; protamine at CPB end); dabigatran alone ( n = 4; idarucizumab at CPB end); or dabigatran plus unfractionated heparin ( n = 3; on-pump idarucizumab during bypass and protamine at CPB end). Measurements and Main Results ACT, dTT-derived dabigatran concentration, circuit pressures, and arterial filters were assessed. In vitro, UFH and dabigatran each prolonged ACT, although dabigatran produced only modest ACT prolongation at clinically relevant concentrations; combined exposure produced greater ACT prolongation than either drug alone and was reversed by the drug-specific antidotes. In vivo, UFH achieved target ACT with no gross circuit dysfunction. Dabigatran-only anticoagulation at supratherapeutic concentrations was associated with arterial filter thrombosis in 2 of 4 pigs. In the combination group, on-pump idarucizumab reduced dabigatran levels and was followed by an abrupt ACT decrease in 2 of 3 pigs, prompting supplemental UFH boluses. Conclusions In this porcine feasibility model and dosing strategy, dabigatran alone did not provide reliable circuit anticoagulation and was associated with filter thrombosis signals. When idarucizumab is administered during CPB after heparinization, ACT can decrease abruptly, because the dabigatran contribution to ACT prolongation is removed, potentially resulting in inadequate anticoagulation.