Evaluation of clinical outcomes in patients treated with heparin or direct thrombin inhibitors during extracorporeal membrane oxygenation: a systematic review and meta-analysis

Abstract

Background The number of patients treated with extracorporeal membrane oxygenation (ECMO) devices is increasing. Anticoagulation therapy is crucial to prevent thrombosis during ECMO therapy. Predominantly, heparin has been used as primary anticoagulant but direct thrombin inhibitors (DTI) have been established as alternatives. The aim of this systematic review and meta-analysis was to evaluate clinical outcomes in patients treated with heparin compared to different DTI during ECMO. Methods A systematic search was conducted. Full scientific articles were sought for inclusion if heparin anticoagulation was compared to DTI (argatroban/bivalirudin) in ECMO patients. Risk of bias was assessed by Newcastle Ottawa scale. Primary endpoint was in-hospital mortality. Bleeding events, thrombotic events, hours of ECMO support, days of hospital stay, percentage of time within therapeutic range and time to therapeutic range were extracted from full texts as secondary endpoints. Results were presented as Forrest-plots. GRADE was used for confidence assessment in outcomes. Results Systematic search identified 4.385 records, thereof 18 retrospective studies for a total of 1942 patients, complied with the predefined eligibility criteria:15 studies investigated bivalirudin and 3 studies investigated argatroban versus heparin. Risk of bias was high for most studies. In-hospital mortality, major bleeding events and pump-related thrombosis were less frequent in DTI group as compared to heparin [mortality—OR 0.69, 95% CI 0.54–0.86; major bleeding—OR 0.48, 95% CI 0.29–0.81; pump thrombosis—OR 0.55, 95% CI 0.40–0.76]. Additionally, percentage of time within therapeutic range was higher for DTI [SMD 0.54, 95% CI 0.14–0.94]. GRADE approach revealed a very low level of certainty for each outcome. Conclusion In this meta-analysis, DTI and especially bivalirudin showed beneficial effects on clinical outcomes in ECMO patients as compared to heparin. However, due to the lack of randomized trials, certainty of evidence is low. Trial Registration This systematic review and meta-analysis was prospectively registered at PROSPERO data base (reference number CRD42021237252). Graphical Abstract

Correlation between partial thromboplastin time and thromboelastography in adult critically ill patients requiring bivalirudin for extracorporeal membrane oxygenation

“…Research investigating TEG-guided bivalirudin dosing in ECMO is absent resulting in aPTT as the only commonly employed measure of anticoagulation intensity. 19,21 Our study adds to the scant literature evaluating the correlation of a static monitoring parameter (aPTT) to TEG associated with bivalirudin in adult ECMO patients, which previously had only been described in children. One retrospective study compared the correlation between aPTT and rotational thromboelastometry (ROTEM) in pediatric patients on either ECMO support or ventricular assist devices who were anticoagulated with bivalirudin.…”

“…One report showed a non‐significant trend towards improved survival to ECMO decannulation with bivalirudin (72.9%) compared with heparin (62.3%) ( p = 0.054); the 1‐year survival rates following ECMO decannulation associated with bivalirudin were significantly higher than for patients administered heparin (66.9% vs. 54.3%, respectively, p = 0.029) 17 . Pooled data in one meta‐analysis showed a significant reduction in in‐hospital mortality in ECMO patients treated with bivalirudin compared with heparin (OR = 0.71, 95% confidence interval, 0.54–0.94); interestingly, argatroban was not associated with an impact on mortality 19 . It should be emphasized that the retrospective study designs were not adequately powered to detect mortality differences between study groups, which may have introduced bias.…”

“…17 Pooled data in one meta-analysis showed a significant reduction in inhospital mortality in ECMO patients treated with bivalirudin compared with heparin (OR = 0.71, 95% confidence interval, 0.54-0.94); interestingly, argatroban was not associated with an impact on mortality. 19 It should be emphasized that the retrospective study designs were not adequately powered to detect mortality differences be- other important clinical outcomes including bleeding and thrombosis (systemic and ECMO in-circuit) rates. Bivalirudin has been associated with a two-fold reduction of ECMO in-circuit thrombosis rates compared with heparin (17.3% vs. 32.7%, respectively, p = 0.003).…”

“…19 Furthermore, bivalirudin may be associated with lower major bleeding risks in ECMO patients compared with heparin. 17, 19 Comparing the rates of bleeding, systemic thrombosis, and in-circuit thrombosis in our study to other previously published reports is challenging. We evaluated clinically relevant bleeding which included patients with interruption of bivalirudin based on clinically suspected as well as known bleeding as part of our definition.…”

Current and future strategies to monitor and manage coagulation in ECMO patients

“…The dose of bivalirudin is maintained at 0.03–0.2 mg/kg/h to maintain therapeutic targets, with [ 19 , 32 , 33 ] or without [ 34 ] an additional initial amount of 0.5 mg/kg. In a meta-analysis, it has been reported that in-hospital mortality, major bleeding events and pump-related thrombosis were less frequent in DTI compared to heparin [ 40 ].…”