Abstract
BACKGROUND: 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. METHODS: Patients 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 C(max) (peak thrombin generation) prior to and ten minutes subsequent to PCC treatment. RESULTS: Thirteen 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 C(max) (TG) by 54% (p = 0.001) during PCC treatment. In addition, the Quick value (prothrombin time: Quick(PT)) significantly improved by 28% and the activated partial thromboplastin time (aPTT) was decreased by 7% ten minutes after PCC administration. C(max) was reduced at baseline, but not ETP, aPTT or Quick(PT). Lag time until initiation (TG, t(lag)), thromboelastometry clotting time (CT(EXTEM)) and time to peak (TG, t(max)) 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. CONCLUSIONS: This study shows that use of PCC improved ETP, C(max,) Quick(PT) and aPTT. However, of these parameters, only C(max) was reduced at the defined baseline. It can be concluded that CT(EXTEM,) t(lag) and t(max) 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 REGISTRATION: EudraCT trial No. 2013-004484-31.