Dabigatran Level Before Reversal Can Predict Hemostatic Effectiveness of Idarucizumab in a Real-World Setting

Abstract

Background: Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption. Methods and Results: This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding (n = 61), urgent procedures (n = 24), or overdose without bleeding (n = 2). Among patients with major bleeding (n = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, p = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, p = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline. Conclusion: This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.

Keywords: bleeding; dabigatran; hemostatic effectiveness; idarucizumab; perioperative; rebound; reversal.

Figure 1

Initial plasma dabigatran could predict hemostatic effectiveness after reversal. The receiver operating characteristic (ROC) area under the curve (AUC) of the association between baseline plasma dabigatran level and hemostatic efficacy (effective or ineffective) in evaluable patients with major bleeding receiving idarucizumab. Arrow shows that a dabigatran level higher than 264 ng/mL before reversal was a predictor of ineffective hemostasis, with an area under the ROC curve of 0.729 (95% CI 0.50 − 0.97).

Figure 2

Initial plasma dabigatran level and biological or clinical outcomes. (A) Kaplan–Meier 90-day survival curve patients after idarucizumab administration according to baseline plasma dabigatran cutoff of 264 ng/mL. Percent survival rate was stratified by dabigatran plasma level at baseline < or ≥264 ng/mL for (n = 33 and 14, respectively) and did not significantly differ between groups (p = 0.36). (B) Initial plasma dabigatran concentrations in patients according to the presence or absence of dabigatran rebound after idarucizumab. Among the 87 patients who had a laboratory test prior to idarucizumab injection, only 16 had plasma dabigatran determination both at baseline and during follow-up. At baseline, patients with no rebound had a significant lower mean of dabigatran level (138 ng/mL ± 114, p = 0.0002) than patients with rebound (1,189 ng/mL ± 869). The dashed red line is a reference line indicating the predefined cutoff of 264 ng/mL. (C) Proportion of cases of dabigatran rebound after reversal according to the cutoff of 264 ng/mL before reversal. No dabigatran rebound was observed after reversal in patients with dabigatran <264 ng/mL at baseline (n = 9, blue bar). Among patients with dabigatran ≥264 ng/mL at baseline, rebound was observed in six patients within a median time of 34 h post-reversal (red bar).

Figure 3

The usefulness of dabigatran plasma concentration to guide reversal management and predict hemostatic efficacy after idarucizumab injection.