Randomized Phase IIIb Study Of Rapid Vitamin K Antagonist Reversal In Patients Requiring An Urgent Surgical Procedure: Four-Factor Prothrombin Complex Concentrate Is Superior To Plasma
Authors: Refaai Majed A. , Goldstein Joshua N. , Milling Truman J. , Lewis Brandon , Goldberg-Alberts Robert , Hug Bruce A. , Sarode Ravi 
Published: October 2019

Abstract

Background
A four-factor prothrombin complex concentrate (4F-PCC) has recently been approved by the FDA for urgent vitamin K antagonist (VKA, eg warfarin) reversal in patients with acute major bleeding. Rapid reversal of VKA-induced anticoagulation is often needed for patients requiring urgent surgical procedures. Plasma is currently the standard-of-care in the United States for VKA reversal prior to emergency surgery. This prospective, phase IIIb, open-label, noninferiority trial (NCT00803101) was designed to evaluate efficacy and safety of 4F-PCC in comparison with plasma in patients requiring VKA reversal prior to an urgent surgical procedure.

Methods
Patients (≥18 years) requiring rapid VKA reversal prior to an urgent surgical or invasive procedure were randomized (1:1) to receive a single dose of either 4F-PCC (CSL Behring) or plasma. Dose was based on baseline INR and weight. All patients were to receive vitamin K as early as possible. The coprimary endpoints were effective hemostasis (prevention of excessive perioperative bleeding, assessed from the start of study product infusion until the end of the procedure) and rapid INR reduction (≤1.3 at 0.5 h after end of infusion). Noninferiority and superiority were defined as lower limit 95% confidence interval (CI) >–10% and >0, respectively, for the group difference (4F-PCC – plasma) in proportions of patients reaching each coprimary endpoint. Effective hemostasis was defined as actual blood loss not exceeding predicted blood loss by 30% and 50 mL, ‘normal’ or ‘mildly abnormal’ hemostasis (subjectively assessed) and no administration of non-study coagulation products. Adverse events (AEs) were reported up to Day 10, serious AEs (SAEs) up to Day 45. A blinded Safety Adjudication Board reviewed thromboembolic SAEs and deaths.

Results
The efficacy analysis population comprised 168 (4F-PCC n=87; plasma n=81) patients. Effective hemostasis was achieved in 89.7% of patients in the 4F-PCC group versus 75.3% in the plasma group, demonstrating both noninferiority and superiority of 4F-PCC over plasma (difference 14.3% [95%CI 2.8;25.8]). Rapid INR reduction was achieved in 55.2% of patients in the 4F-PCC group versus 9.9% in the plasma group, demonstrating both noninferiority and superiority of 4F-PCC over plasma (difference 45.3% [95%CI 31.9;56.4]). The frequencies of mortality, SAEs, and thromboembolic events were similar between treatment groups. Significantly fewer fluid overload events occurred with 4F-PCC than with plasma (difference –9.1% [–18.6;–0.1]).

Conclusions
The study met both coprimary endpoints and found that 4F-PCC was superior to plasma for hemostatic efficacy and for rapid INR reduction. Overall, 4F-PCC had a favorable safety profile and was well tolerated in this population. This study demonstrates that 4F-PCC is an effective alternative to plasma for rapid VKA reversal in patients undergoing urgent surgical procedures.

Disclosures:
Off Label Use: According to the current US label, “Kcentra, Prothrombin Complex Concentrate (Human), is indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding”. Goldstein:CSL Behring: Consultancy, Research Funding. Milling:CSL Behring: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Goldberg-Alberts:CSL Behring: Employment. Hug:CSL Behring: Employment. Sarode:CSL Behring: Consultancy, Honoraria.