RESUMO
Importance: Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding. Objective: To evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery. Design, Setting, and Participants: This phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches. Interventions: Single intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively. Main Outcome and Measure: The primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale. Results: A total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, -0.080 to 0.082; P < .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, -0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC). Conclusions and Relevance: This randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal. Trial Registration: ClinicalTrials.gov Identifier: NCT02740335.