Seelhammer, Troy G.

Empirical evidence suggests direct thrombin inhibitors (DTIs) produce more favorable hemostatic outcomes than heparin in patients supported by extracorporeal membrane oxygenation (ECMO), yet the exact mechanisms responsible are unknown. We systematically searched databases and registers for studies comparing DTIs to heparin in humans receiving ECMO. A total of 28 studies were identified, most of which (n = 25) used bivalirudin, while the rest (n = 3) used argatroban. In random-effects meta-analysis, DTIs achieved the therapeutic anticoagulation range faster (mean difference = −6.96 hours, 95% confidence interval [CI] = −11.98 to −1.95, p = 0.006) and maintained the therapeutic range for a greater proportion of time (mean difference = 18.6%, 95% CI = 8.78–28.42, p < 0.001) than heparin. Subgroup analysis revealed these effects were similarly significant in adult patients and when bivalirudin was the DTI; however, they were not significant in pediatric patients or when argatroban was the DTI. Sensitivity analysis confirmed robustness of the primary findings in only low-risk of bias studies and in only studies published as full papers. In summary, DTIs—specifically bivalirudin—were associated with faster time to therapeutic anticoagulation and maintained the goal range for a greater percentage of time than heparin during ECMO support.

Activated partial thromboplastin time (aPTT) is the standard for monitoring bivalirudin but demonstrates a nonlinear response at higher drug concentrations. The objective of this study was to assess the relationship between bivalirudin dose and aPTT in patients receiving extracorporeal membrane oxygenation (ECMO) to determine a threshold where aPTT unresponsiveness occurs. Two hundred fourteen adults receiving bivalirudin during ECMO between 2018 and 2022 were included. Piecewise regression in a linear mixed effects model was used to determine a bivalirudin dose threshold of 0.21 mg/kg/hr for aPTT unresponsiveness. For doses of less than 0.21 mg/kg/hr (n = 135), every 0.1 mg/kg/hr dose increase led to an aPTT increase of 11.53 (95% confidence interval [CI] = 9.85–13.20) seconds compared to only a 3.81 (95% CI = 1.55–6.06) seconds increase when dose was greater than or equal to 0.21 mg/kg/hr (n = 79) (p interaction < 0.001). In multivariable logistic regression, venovenous configuration (odds ratio [OR] = 2.83, 95% CI = 1.38–5.77) and higher fibrinogen concentration (OR = 1.22, 95% CI = 1.05–1.42) were associated with greater odds of unresponsiveness, whereas older age (OR = 0.79, 95% CI = 0.63–0.98), kidney dysfunction (OR = 0.48, 95% CI = 0.25–0.92), and a higher baseline aPTT (OR = 0.89, 95% CI = 0.82–0.97) were associated with lower odds. Alternative methods are necessary to ascertain bivalirudin’s hemostatic impact when doses exceed 0.21 mg/kg/hr during ECMO.