The authors thank Drs. Erdoes, Koster, and Levy for their very cogent and detailed analysis of our study. We agree with many of the points they made, specifically the very limited effect dabigatran has on coagulation due to its specificity for thrombin. Most would agree, however, if only one enzyme in the coagulation system can be inhibited, thrombin is the obvious choice given its central place in the coagulation cascade, and its many indirect effects via feedback loops as indicated by Erdoes et al. Furthermore, by far the largest published successful experience with any drug class as a substitute for heparin in cardiopulmonary bypass (CPB) is with direct thrombin inhibitors, particularly bivalirudin. We have previously shown that the anti-Xa agent rivaroxaban has a synergistic anticoagulant effect with dabigatran and this combination may prove to be a better substitute for heparin than a direct thrombin inhibitor alone.
We would like to make one clarification. Erdoes et al. noted that the Chandler loop (Neuffen, Germany) is an imperfect model of CPB, more resembling an extracorporeal membrane oxygenation circuit being a closed system. Although we did use the Chandler loop system for dabigatran dose ranging, for the rabbit bypass experiment we used a commercially available CPB circuit with a Capiox FX05 (Terumo Cardiovascular, USA) oxygenator with integrated arterial line filter and open hard-shell reservoir (fig 1). This is not an extracorporeal membrane oxygenation circuit. However, the authors were correct in stating that the lack of a cardiotomy suction meant that an important source of thrombin activation, tissue factor, was most likely present in a lower concentration than in a typical open cardiac operation with liberal use of the pump suction.
Developing a novel anticoagulant and reversal system to replace heparin for cardiopulmonary bypass is a complex process, and we are at the beginning and moving stepwise with due deliberation. It gives one pause to think that one day a real patient may be put on CPB based on our science. Before that happens, there are many more bridges to cross.