In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.

Four-factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37.5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2.5 days. Fifteen min after infusion of PCC 37.5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% (P = 0.03; pre-rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h (P = 0.001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0.14) and was not different from placebo over 24 h (P = 0.31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37.5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min (P < 0.001). Placebo did not have an effect on coagulation parameters. 37.5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37.5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.