Argatroban versus heparin in patients without heparin-induced thrombocytopenia during venovenous extracorporeal membrane oxygenation: a propensity-score matched study

Abstract

Background During venovenous extracorporeal membrane oxygenation (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH). We tested the hypothesis that Argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO. Methods We conducted a propensity-score matched observational non-inferiority study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the medical intensive care unit at the University Hospital Regensburg. Anticoagulation was realized with UFH until August 2017 and with Argatroban from September 2017 onwards. Target activated partial thromboplastin time was 50 ± 5seconds in both groups. Primary composite endpoint was major thrombosis and/or major bleeding. Major bleeding was defined as a drop in hemoglobin of ≥ 2 g/dl/day or in transfusion of ≥ 2 packed red cells/24 h, or retroperitoneal, cerebral, or pulmonary bleeding. Major thrombosis was defined as obstruction of > 50% of the vessel lumen diameter by means of duplex sonography. We also assessed technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anticoagulation (including HIT-testing). Results Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving Argatroban. The primary endpoint occurred in 79% of patients in the Argatroban group and in 83% in the UFH group (non-inferiority for Argatroban, p = 0.026). The occurrence of technical complications was equally distributed (Argatroban 49% vs. UFH 42%, p = 0.511). The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median [IQR]: 141 [104;198]/nl vs. 107 [54;171]/nl, p = 0.010). Anticoagulation costs per day of ECMO were higher in the Argatroban group (€26 [13.8;53.0] vs. €0.9 [0.5;1.5], p < 0.001) but not after accounting for blood products and HIT-testing (€63 [42;171) vs. €40 [17;158], p = 0.074). Conclusion In patients without HIT on vvECMO, Argatroban was non-inferior to UFH regarding bleeding and thrombosis. The occurrence of technical complications was similarly distributed. Argatroban may have less impact on platelet decrease during ECMO, but this finding needs further evaluation. Direct drug costs were higher for Argatroban but comparable to UFH after accounting for HIT-testing and transfusions.

Coagulation abnormalities in patients with COVID‐19 on venovenous ECLS increased risk for technical complications and support times but had no impact on survival

“…All patients in this study were on therapeutic anticoagulation (continuous infusion) with either unfractionated heparin (UFH), argatroban or Clexane (Enoxaparin). 21 Target activated partial thromboplastin time (aPTT) was 50–60 s and was adjusted depending on thrombus burden or bleeding events. If there was suspicion of heparin‐induced thrombocytopenia or insufficient thrombus control in the circuit with UFH, the anticoagulation was switched to argatroban with an aPTT target of >60 s. In six patients, anticoagulation was switched to Enoxaparin during ECLS, monitored by anti‐Factor Xa activity.…”

Direct Thrombin Inhibition in Extracorporeal Membrane Oxygenation

“…This represents an advantage in the setting of V-A ECMO compared to bivalirudin, which has a shorter half-life (25 min) thus increased risk of clot formation in areas of blood flow stagnation. Compared to UFH, no significant differences were seen in patient 3,7,19 or circuit-related 19 thromboembolic complications.…”

“…Most studies reported no increased hemorrhagic risk in argatroban versus UFH anticoagulated patients on ECMO 3,7,19 Although some studies observed higher rates of bleeding for argatroban, this usually occurred in the perioperative period or in patients with HIT and associated thrombocytopenia. 7 Although argatroban has no specific reversal agents, reversal of argatroban-related severe bleeding by recombinant factor VII has been described.…”

“…Fisser and colleagues found that anticoagulation costs with argatroban vs UFH were comparable. 19 Furthermore, a recent report by Cho et al 20 found that argatroban was more cost effective compared to UFH (given the frequent need for AT replenishment and multiple laboratory assays). Thus, despite a higher drug price, the use of argatroban may be a cost-effective strategy.…”

Venous thromboembolic events in the setting of extracorporeal membrane oxygenation support in adults: A systematic review

“…The efficacy of unfractionated heparin has been contrasted with other anticoagulants for ECMO therapy. Argatroban, a direct thrombin inhibitor, was evaluated for its efficacy as an equivalent alternative to heparin [56]. ECMO patients without heparin-induced thrombocytopenia received either Argatroban or heparin, and Argatroban was indeed proven to have similar efficacy to heparin.…”