New 4F-PCC Effective Alternative for Quick vitamin K antagonists Reversal in Urgent Surgeries: JAMA

In a study involving 208 adults on vitamin K antagonists, effective hemostasis was achieved in 94.3% of patients using the investigational 4F-PCC compared to 94.2% with the control 4F-PCC, demonstrating noninferiority in hemostatic performance, the researchers reported in JAMA Network Open.

Vitamin K antagonists, commonly used to prevent blood clots, can complicate emergency surgical situations due to their anticoagulant effects. Rapid and effective reversal of these medications is crucial to minimize bleeding risks during surgery. Ravi Sarode, Department of Internal Medicine (Hematology/Oncology), University of Texas Southwestern Medical Center, Dallas, and colleagues aimed to evaluate the hemostatic noninferiority of an investigational 4F-PCC to a control 4F-PCC for rapid VKA reversal before urgent surgery.

For this purpose, the researchers conducted a phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) across 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, to November 8, 2021, with the study concluding in February 2022.

The trial involved adult patients on VKA who had an international normalized ratio (INR) of 2 or higher and required urgent surgery with a substantial bleeding risk (≥50 mL). Participants were randomly assigned in a 1:1 ratio to receive a single infusion of either the investigational 4F-PCC or the control 4F-PCC.

The interventions involved administering a single intravenous infusion based on body weight and baseline INR levels. Patients received doses of 25, 35, or 50 IU/kg doses of either the investigational or control 4F-PCC, depending on their baseline INR: 2 to less than 4, 4 to 6, or over 6, respectively. Data analysis was conducted using both intention-to-treat and per-protocol methods to evaluate the efficacy and safety of the investigational 4F-PCC compared to the control.

The primary endpoint was hemostatic efficacy after the surgery. An independent adjudication board, blinded to the treatment allocation, evaluated hemostatic efficacy using an objective 4-point scale.

The researchers reported the following findings:

• A total of 208 patients (median age, 67.5 years; 56.7% males) received the investigational (n = 105) or the control (n = 103) 4F-PCC.
• The median dose was 25 IU/kg in the investigational group and 25 IU/kg in the control group, with a median infusion time of 12 minutes and 13 minutes and a median time from infusion to surgery start of 1.42 hours and 1.50 hours, respectively.
• The baseline median INR was 3.05 in the investigational group and 3.00 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 versus 94.2% of patients, 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.
• Thrombotic events (2.9% versus 0%, respectively) and mortality (4.8% versus 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).

This randomized clinical trial demonstrated that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for the rapid reversal of vitamin K antagonists in patients requiring urgent surgery with significant bleeding risk. Both 4F-PCCs showed similar safety profiles.

"These findings support the use of the investigational 4F-PCC as a viable therapeutic option for patients needing prompt VKA reversal before surgery," the researchers concluded.

Reference:

Sarode R, Goldstein JN, Simonian G, et al. Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(8):e2424758. doi:10.1001/jamanetworkopen.2024.24758