Utilization and Outcomes of Children Treated with Direct Thrombin Inhibitors on Paracorporeal Ventricular Assist Device Support

Abstract

Thrombotic and bleeding complications have historically been major causes of morbidity and mortality in pediatric ventricular assist device (VAD) support. Standard anticoagulation with unfractionated heparin is fraught with problems related to its heterogeneous biochemical composition and unpredictable pharmacokinetics. We sought to describe the utilization and outcomes in children with paracorporeal VAD support who are treated with direct thrombin inhibitors (DTIs) antithrombosis therapy. Retrospective multicenter review of all pediatric patients (aged <19 years) treated with a DTI (bivalirudin or argatroban) on paracorporeal VAD support, examining bleeding and thrombotic adverse events. From May 2012 to 2018, 43 children (21 females) at 10 centers in North America, median age 9.5 months (0.1–215 months) weighing 8.6 kg (2.8–150 kg), were implanted with paracorporeal VADs and treated with a DTI. Diagnoses included cardiomyopathy 40% (n = 17), congenital heart disease 37% (n = 16; single ventricle n = 5), graft vasculopathy 9% (n = 4), and other 14% (n = 6). First device implanted included Berlin Heart EXCOR 49% (n = 21), paracorporeal continuous flow device 44% (n = 19), and combination of devices in 7% (n = 3). Adverse events on DTI therapy included; major bleeding in 16% (n = 7) (2.6 events per 1,000 patient days of support on DTI), and stroke 12% (n = 5) (1.7 events per 1,000 patient days of support on DTI). Overall survival to transplantation (n = 30) or explantation (n = 8) was 88%. This is the largest multicenter experience of DTI use for anticoagulation therapy in pediatric VAD support. Outcomes are encouraging with lower major bleeding and stroke event rate than that reported in literature using other anticoagulation agents in pediatric VAD support.

A Review of Bivalirudin for Pediatric and Adult Mechanical Circulatory Support

“…In a study by Blume et al [27] that included pediatric patients from as early as 1993, 77% of patients on VAD support were successfully bridged to transplant. VanderPluym et al [28] tracked 43 patients in North America from 2013 to 2018 and found the indication for VAD was primarily bridge to transplant (72%), followed by bridge to recovery (19%), and bridge to decision (9%). As with bivalirudin use in pediatric ECMO, varying protocols, or the absence of a protocol in most cases, results in lack of standardization with regard to initial infusion rates and anticoagulation targets.…”

“…The initial infusion rate of 0.3 mg/kg/h utilized by both VanderPluym et al [28] and Bates et al [25], case series reports of 43 and 14 pediatric patients, respectively, was identical to that of Nagle et al [7] and Ezetendu et al [17]. Meanwhile, in a case report by Medar et al [29], the authors stated an initial bivalirudin infusion rate of 0.15 mg/kg/h, 50% that of VanderPluym et al [28] and Bates et al [25]. Campbell et al [20] reported that the median initial rate was similar between VAD and ECMO patients, at 0.1 mg/ kg/h.…”

“…Again, initial infusion rates were similar across studies, but anticoagulation targets and the average dosing required to maintain the pre-specified goals varied drastically. For example, in the largest study examined, infusion rates began at a median of 0.3 mg/kg/h, yet maximum doses necessary to maintain aPTT goals ranged from 0.1 to 3.9 mg/kg/h [28]. In the case report by Medar et al [29], this high variability was replicated; in one patient alone, maintenance infusion rates ranged from 0.15 to 2.3 mg/kg/h across a full VAD course of 122 days.…”

“…Finally, VanderPluym et al [28] reported a median duration of VAD support of 57 days across the 43 pediatric patients examined. Duration of therapy ranged extensively, from 3 to 342 days.…”

First human implantation of a miniaturized axial flow ventricular assist device in a child with end-stage heart failure

“…In this patient, clotting complications persisted until the patient was transitioned to bivalirudin in May of 2018, as unpublished data from the ACTION network suggested bivalirudin may be more favorable for other small devices. 7 Because of this case, in August 2018 the PumpKIN investigators changed the Jarvik anti-thrombotic guideline for the US Feasibility Trial from heparin to bivalirudin, which the FDA approved in 2018. A second important lesson is the need for the medical team to gain comfort using the H-Q curves to estimate pump index (Figure 2).…”