In vitro efficacy of direct oral anticoagulants in plasma from patients with liver cirrhosis

Introduction Liver cirrhosis (LC) is a complex pathology which confers a prothrombotic state. The anticoagulation of LC-patients remains challenging because of the unknown efficacy of heparins and direct oral anticoagulants (DOAC), monitoring difficulty (particularly for coumarins), and alterations in drug metabolism. Here, we aimed to analyse the in vitro efficacy of DOAC (apixaban, edoxaban, rivaroxaban, and dabigatran) in LC-patients’ plasma.

Method We included 22 LC-patients and 9 healthy donors. Plasma samples were spiked with either Owren’s veronal buffer or DOAC (final target concentrations: 50, 150 ng/ml; additional concentration of 300 ng/ml for dabigatran). We have chosen these concentrations because they represent peak and through levels observed in clinical studies of a therapeutic anticoagulation with these drugs. After spiking, apixaban and dabigatran concentrations were verified and ex vivo thrombin generation were analysed using ST Genesia with DrugScreen reagents (Stago, Asnières-sur-Seine, France). Analysis for edoxaban and rivaroxaban has just started at the time of the writing of this abstract. Ratios for velocity index and peak height assessed without and with anticoagulants were calculated and compared between LC-patients and healthy donors for each target concentration using Mann-Whitney test ([Fig. 1]).

Fig. 1  Ratios for velocity index and peak height after spiking with DOAC; Ratios for velocity index and peak height according to apixaban (a, b) and dabigatran (c, d) concentrations in patients with liver cirrhosis (red) and healthy donors (blue). The lines represent the linear regression lines. PH, peak height; VI, velocity index.

Results Ratios for velocity index and peak height according to apixaban and dabigatran concentrations are presented in Fig. 1. At a target concentration of 150 ng/ml, in apixaban treated samples the peak height ratio was slightly but significantly higher [median 0.74 (LC, red) vs. 0.60 (control, blue), p-value 0.0329] and the velocity index ratio significantly higher (0.42 vs. 0.27, p-value 0.0076) in LC-plasma compared to controls. With dabigatran, both ratios were significantly lower (0.58 vs. 0.80, p-value <0.0001; 0.51 vs. 0.94, p-value <0.0001) in the LC-group compared to controls.

Conclusion We demonstrated a slightly lower anticoagulant efficacy of apixaban and a clearly higher efficacy of dabigatran in LC plasma compared to control samples. Based on these preliminary data and on DOAC metabolism, apixaban appears to have a safer profile than dabigatran for LC-patients. First data obtained with edoxaban and rivaroxaban seem to confirm discordant anticoagulant efficacies of DOAC in normal versus LC-plasma.

Publikationsverlauf

Artikel online veröffentlicht:
20. Februar 2023