Abstract
BackgroundDirect oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events. The aim of this study was to test the efficacy of reversing the DOAC rivaroxaban using four-factor PCC (prothrombin complex concentrate), a non-specific reversing agent.MethodsPatients with life-threatening bleeding events during rivaroxaban treatment were included and administered 25 U kg−1 of PCC. Blood samples were collected immediately prior to as well as after PCC treatment at predefined time intervals. The primary endpoint was defined as the difference in thrombin generation (TG) parameters ETP (endogenous thrombin potential) and Cmax (peak thrombin generation) prior to and ten minutes subsequent to PCC treatment.ResultsThirteen patients, of whom the majority suffered from intra-cranial haemorrhage (ICH) or subdural haemorrhage (SDH), were included and administered PCC. The results show that the ETP (TG) significantly (p = 0.001) improved by 68% and Cmax (TG) by 54% (p = 0.001) during PCC treatment. In addition, the Quick value (prothrombin time: QuickPT) significantly improved by 28% and the activated partial thromboplastin time (aPTT) was decreased by 7% ten minutes after PCC administration. Cmax was reduced at baseline, but not ETP, aPTT or QuickPT. Lag time until initiation (TG, tlag), thromboelastometry clotting time (CTEXTEM) and time to peak (TG, tmax) correlated best with measured rivaroxaban levels and were out of normal ranges at baseline, but did not improve after PCC administration. In 77% of the patients bleeding (ICH/SDH-progression) ceased following PCC administration. During the study three participants passed away due to other complications not related to PCC treatment. The possibility of thrombosis formation was also evaluated seven days after administering PCC and no thromboses were found.ConclusionsThis study shows that use of PCC improved ETP, Cmax, QuickPT and aPTT. However, of these parameters, only Cmax was reduced at the defined baseline. It can be concluded that CTEXTEM, tlag and tmax correlated best with the measured rivaroxaban levels. The study drug was found to be safe. Nonetheless, additional studies specifically targeting assessment of clinical endpoints should be performed to further confirm these findings.Clinical trial registrationEudraCT trial No. 2013–004484-31.
Highlights
Direct oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events
Patients, who for medical reasons were not able to give their consent to participate in this clinical trial, were enrolled based on the principle of deferred consent according to § 43a (1), Austrian Medicinal Products Law (“Österreichisches Arzneimittelgesetz”)
The original curve is corrected for the estimated α macroglobulin-bound thrombin activity. From this curve the following parameters can be obtained: total amount of generated thrombin present in the reaction from the point of initiation until return to baseline, which is measured by the calculated increase in the extinction rate, and known as “endogenous thrombin potential” (ETP), sometimes referred to as “area under the curve” (AUC), peak thrombin generation (Cmax), lag phase until initiation, and time to peak thrombin activity
Summary
Direct oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events. The aim of this study was to test the efficacy of reversing the DOAC rivaroxaban using four-factor PCC (prothrombin complex concentrate), a non-specific reversing agent. The off-label use of coagulation factor concentrates, four-factor prothrombin complex concentrate, in the management of rivaroxaban-related, life-threatening bleeding is the most recommended/used therapy [8, 9]: In healthy male volunteers, PCC was seen to reverse the anticoagulant effect of rivaroxaban [10, 11]. Managing life-threatening bleeding events under DOAC remains a challenge for physicians since in vivo data regarding efficacy of anticoagulation reversal are still lacking
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