Evaluation of Bivalirudin As an Alternative to Heparin for Systemic Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation*

Abstract

Objectives: Heparin is the universal anticoagulant for patients receiving extracorporeal membrane oxygenation support. However, heparin has many disadvantages, especially in young children, who develop heparin resistance. Recently our center has used bivalirudin, a direct thrombin inhibitor, for systemic anticoagulation in pediatric extracorporeal life support. Bivalirudin binds directly to thrombin with no need for antithrombin III and it inhibits both circulating and clot-bound thrombin. In this study, we sought to evaluate our experience with bivalirudin in pediatric extracorporeal life support. Design: Retrospective chart review study of patients receiving extracorporeal membrane oxygenation support between October 2014 and May 2018. Setting: Tertiary, academic PICU. Patients: Sixteen patients receiving heparin and 16 patients receiving bivalirudin on extracorporeal life support were included in the study. Interventions: None. Measurements and Main Results: Patients in the bivalirudin group had a median age of 31 months versus 59 months in the heparin group (p = 0.41). Recovery and extracorporeal membrane oxygenation decannulation were similar in both groups (56% in the heparin group and 62% in the bivalirudin group; p = 0.62). Time to reach goal therapeutic anticoagulation level was shorter in the bivalirudin group (11 vs 29 hr; p = 0.01). Bleeding events were fewer in the bivalirudin group, and there was no difference in the rate of thrombotic events between the two groups. Comprehensive cost analysis that includes anticoagulant, laboratories, and antithrombin III cost, showed that heparin anticoagulation therapy total cost was significantly higher than bivalirudin (1,184 dollars per day in heparin group vs 494 dollars per day in bivalirudin group; p = 0.03). Bivalirudin dose required to maintain target anticoagulation will increase over time, and this is associated with an increase in creatinine clearance and an increase in fibrinogen serum levels. Conclusions: This study showed that the use of bivalirudin in pediatric extracorporeal membrane oxygenation support is feasible, safe, reliable, and cost-effective in comparison to heparin. Further prospective randomized clinical trials are necessary to confirm our observations.

Bivalirudin for Maintenance Anticoagulation During Venovenous Extracorporeal Membrane Oxygenation for COVID-19

“…8 In a retrospective study of 32 pediatric ECMO patients, Hamzah et al reported a reduction in bleeding events in patients anticoagulated with bivalirudin. 7 Importantly, in this study bivalirudin was found to be more cost-effective despite higher drug acquisition costs. In a cohort of 44 shock patients (92% VA-ECMO), Berei et al found no differences in thrombotic events or mortality but suggested bivalirudin as a viable alternative to heparin-based protocols.…”

“…5 However, inherent limitations exist, including the requirement of the cofactor antithrombin III through which its action is mediated, unpredictable kinetics requiring frequent dose adjustments, and the highly antigenic nature of heparin that may trigger HIT. 7 COVID-19 may exacerbate variations in heparin sensitivity secondary to reduced antithrombin III levels. 16 Direct thrombin inhibitors have numerous pharmacokinetic and pharmacodynamic advantages versus heparin.…”

“…Over the last decade, an expanding body of evidence has established the safety of bivalirudin in mechanical circulatory support, with emerging data demonstrating superior balance between thrombosis and hemorrhage. [7][8][9] Ranucci et al identified reductions of aPTT variations, blood loss, and transfusion requirements with bivalirudin-based anticoagulation in a population of post-cardiotomy VA-ECMO patients. 9 Pieri et al again found a reduction in dose adjustment requirements and a reduced incidence of supratherapeutic aPTT with bivalirudin in 5 VV-ECMO and 5 VA-ECMO patients.…”

“…6 A growing body of evidence has emerged demonstrating the safety of 1 bivalirudin during ECMO, with some studies reporting a superior balance between thrombosis and hemorrhage. [7][8][9] Herein, the successful use of an anticoagulation strategy using a continuous infusion of bivalirudin in a 65-year-old female with severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring venovenous ECMO (VV-ECMO) is reported.…”

COVID-19 and ECMO: An Unhappy Marriage of Endothelial Dysfunction and Hemostatic Derangements

“…It is the authors' perspective that it is through the integration of diagnostic assessment of viscoelastic testing with dedicated management schemes, up to and including the titration of antifibrinolytic therapies, that unmasks the capacity of this technology to enhance clinical outcomes. In addition, the authors encourage further research leveraging direct thrombin inhibitors during ECMO given its effective and predictable anticoagulation performance, [21][22][23] as well as the high incidence of heparin-induced thrombocytopenia in these patients. 24 Additionally, ideally, prospective studies examining the incidence and risk factors for the manifestation of hyperfibrinolysis, as well as the ideal anticoagulation and monitoring strategy as it relates to COVID-19 patients on ECMO, will be needed to define best practice approaches for this challenging population.…”