High-dose four-factor prothrombin complex concentrate for vitamin K antagonist reversal before urgent surgery: subanalysis of the LEX-209 randomized, active-controlled trial.

BACKGROUND: Four-factor prothrombin complex concentrates (4F-PCCs) reverse vitamin K antagonist (VKA)-induced acquired coagulation factor deficiency. However, limited data exist on the benefits and risks of 4F-PCC treatment in patients with supratherapeutic international normalized ratio (INR) values (>6), for whom a high dose of 4F-PCC (50 IU/kg) is indicated. OBJECTIVE: To assess the hemostatic efficacy and safety of high-dose 4F-PCC in patients on VKA therapy before urgent surgery with an INR > 6. METHODS: The LEX-209 Phase 3 randomized, active-controlled study (NCT02740335) enrolled adults taking VKAs before urgent surgery with a substantial bleeding risk. Patients were randomized to either investigational or control 4F-PCC. This post hoc subanalysis included patients with baseline INR > 6, who were given high-dose 4F-PCC (50 IU/kg). Outcomes were analyzed according to original treatment assignment. The primary endpoint was hemostatic efficacy assessed by a blinded Independent Endpoint Adjudication Board. RESULTS: Twenty-three patients had an INR > 6 (mean ± SD INR, 9.1 ± 3.2). The mean ± SD dose of 4F-PCC administered was similar in the investigational (n = 15) and control (n = 8) 4F-PCC groups (49.7 ± 1.2 IU and 49.2 ± 2.3 IU of factor IX/kg, respectively). Effective hemostasis was achieved in 100% of patients in both groups, with adequate increments in vitamin K-dependent factors. No drug-related treatment-emergent adverse events or thromboembolic events were reported. CONCLUSIONS: In this small sample, 4F-PCC, at the maximum permitted dose, was effective for VKA reversal in patients requiring urgent surgery, with no adverse safety signal observed.