11 However, neither 4F-PCCs or tranexamic acid reduced bleeding duration or bleeding volume at the punch biopsy site. 9 Two other studies in healthy volunteers receiving rivaroxaban 20 mg twice per day for 3 to 4 days to reach supratherapeutic steady-state concentrations suggested that 4F-PCCs normalized PT more effectively than 3-factor PCCs 10 and that 4F-PCCs, but not tranexamic acid, reduced PT and increased endogenous thrombin potential. 8 In 6 healthy nonbleeding volunteers who received rivaroxaban 20 mg twice per day for 2.5 days, a supratherapeutic plasma concentration was induced, but 4F-PCCs corrected the rivaroxaban-associated prolonged prothrombin time (PT) and increased endogenous thrombin generation potential. 4F-PCCs corrected rivaroxaban-induced thrombin generation in 10 healthy volunteers in a dose-dependent manner. The efficacy of PCCs in the reversal of direct FXa–related bleeding has been evaluated in healthy volunteers. On the basis of evidence with very low certainty from single-arm case series, it is difficult to determine whether 4F-PCC in addition to cessation of direct oral FXa inhibitor is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor–related major bleeding. The pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval, 0.61-0.76) in 2 studies using the International Society on Thrombosis and Haemostasis (ISTH) criteria and 0.77 (95% CI, 0.63-0.92) in 8 studies that did not use the ISTH criteria all-cause mortality was 0.16 (95% CI, 0.07-0.26), and thromboembolism rate was 0.04 (95% CI, 0.01-0.08). Ten case series with 340 patients who received PCC for direct FXa inhibitor–related major bleeding were included. A systematic literature search was conducted using Medline, Embase, and the Cochrane Register of Controlled Trials up to September 2018.

In a systematic review, we evaluated the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) as an alternative for managing direct FXa inhibitor–related major bleeding. A targeted antidote for reversal of direct factor Xa (FXa) inhibitors is now available for clinical use in the United States, but it is costly and has limited availability.

Xa inhibitor reversal