Four-Factor Prothrombin Complex Concentrate Superior to Plasma for Warfarin Reversal Required Prior to Urgent Surgery

Historically, donor plasma has been the standard of care in the U.S. for vitamin K antagonist (VKA; e.g., warfarin) reversal prior to emergency surgery. In April 2013, the first nonactivated four-factor prothrombin complex concentrate (4F-PCC; Kcentra, CSL Behring) was approved for urgent VKA reversal in patients with acute major bleeding. A Phase IIIb randomized, prospective, open-label noninferiority clinical trial was designed to evaluate the efficacy and safety of 4F-PCC in comparison with plasma in patients requiring VKA reversal prior to an urgent surgery or other invasive procedure.

The efficacy analysis population comprised 168 patients, including 87 in the 4F-PCC arm and 81 in the plasma arm. Dosing of 4F-PCC (15, 35 or 50 units/kg) or plasma (10, 12 or 15 mL/kg) was based on baseline INR and weight. The co-primary endpoints were effective hemostasis and rapid INR reduction (≤1.3 at 0.5 hour after end of infusion).

Effective hemostasis was achieved in 89.7 percent of patients in the 4F-PCC group versus 75.3 percent in the plasma group, demonstrating both noninferiority and superiority of 4F-PCC over plasma. Rapid INR reduction was achieved in 55.2 percent of patients in the 4F-PCC group versus 9.9 percent in the plasma group, again demonstrating both noninferiority and superiority of 4F-PCC. Rates of mortality, serious adverse events and thromboembolic events were similar between the treatment groups. Significantly fewer fluid overload events occurred with 4FPCC than with plasma (difference -9.1 percent). The investigators concluded that 4F-PCC is an effective alternative to plasma for rapid VKA reversal in patients undergoing urgent surgical procedures.