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 375 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 15mg for 25days. Fifteen min after infusion of PCC 375 iu/kg, ETP increased from 47 +/- 16% to 64 +/- 22% (P=003; pre-rivaroxaban ETP: 92 +/- 14%) and remained higher than after placebo over 24h (P=0001). PCC 25 iu/kg did not modify ETP within 15min (53 +/- 11% to 59 +/- 12%; P=014) and was not different from placebo over 24h (P=031). ETP reached pre-rivaroxaban levels within 6h after PCC 375 iu/kg infusion and within 12-24h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15min (P<0001). Placebo did not have an effect on coagulation parameters. 375 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 375 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.