Removal of dabigatran using sorbent hemadsorption

Abstract

Background: The Redual PCI trial has demonstrated the safety of dabigatran and ticagrelor or clopidogrel combination in preventing strokes in patients with atrial fibrillation. There was 15.4% risk of hemorrhage in the dabigatran/ticagrelor or clopidrogel arm, lower than that of triple therapy with warfarin, aspirin and ticagrelor or clopidogrel. While idarucizumab is an effective antidote for dabigatran, there is no good method for antagonizing both dabigatran and ticagrelor. We tested in this study a hemadsorbtion method for removing dabigatran that we had previously successfully applied in the removal of ticagrelor from human blood.

Methods: 100 mL 4% BSA solution pre-incubated with dabigatran was passed through 10, 20 and 40 mL sorbent columns and dabigatran concentration was measured from the affluent and effluent solution using LC-MS/MS. For testing the effect of dabigatran removal on the aPTT value one human volunteer was administered oral dabigatran etexilate mesilate 150 mg. Plasma was collected 4 h after dabigatran administration and then in three experiments 20 mL of collected plasma was circulated through three different 10 mL CytoSorb columns over a duration of 5 min. aPTT was measured from plasma at baseline prior to drug administration, then post blood collection (mixed plasma) and from the adsorbed plasma as well.

Results: Dabigatran concentration, as measured by LC-MS/MS, decreased from 1456 ± 331 nM (greater than the therapeutic level of 743 nM) to 67 ± 59 nM (P = 0.002) with the 10 mL CytoSorb column, while with the 40 mL column it dropped to undetectable levels. In one human volunteer experiment the aPTT was on average 29.2 ± 0.4 in the 3 baseline samples, 34.7 ± 1.8 s after oral dabigatran (mixed plasma), and 25 ± 0.7 s after plasma was passed through CytoSorb (adsorbed plasma) (P = 0.000025 and 0.0000002 for comparison between baseline plasma and mixed plasma, as well as the dabigatran mixed plasma and post-adsorption values respectively).

Conclusion: Dabigatran is robustly removed by a sorbent hemadsorption method already proven successful for the P2Y12 receptor antagonist ticagrelor. Dabigatran removal restores the aPTT to below baseline values, suggesting that sorbent hemadsorption could clinically reverse the anticoagulant effect of this drug.

Keywords: Adsorption; Dabigatran; Hemadsorption; Removal; Sorbent; aPTT.