Efficacy and Safety of a Four-Factor Prothrombin Complex Concentrate (4F-PCC) in Patients on Vitamin K Antagonists Presenting with Major Bleeding: A Randomized, Plasma-Controlled, Phase IIIb Study
Background—Patients experiencing major bleeding while taking vitamin K antagonists (VKAs) require rapid VKA reversal. We performed a prospective clinical trial to compare non-activated four-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent VKA reversal.
Methods and Results—In this phase IIIb, multicenter, open-label, non-inferiority trial, non-surgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, X, and proteins C, S) or plasma. Primary analyses examined whether 4F-PCC was non-inferior to plasma for the co-primary endpoints of 24-hour hemostatic efficacy from start of infusion and INR correction (≤1.3) at 0.5 hours after end of infusion. The intent-to-treat-efficacy population comprised 202 patients (4F-PCC n=98; plasma n=104). Median (range) baseline INR was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating non-inferiority (difference 7.1% [95%CI: -5.8;19.9]). Rapid INR reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference 52.6% [95%CI: 9.4;65.9]). Assessed coagulation factors were higher in the 4F-PCC group than plasma group from 0.5-3 hours after infusion start (p-values<0.02). The safety profile (adverse events [AEs], serious AEs, thromboembolic events and deaths) was similar between groups; 66/103 (4F-PCC group) and 71/109 (plasma group) patients experienced ≥1 AE.
Conclusions—4F-PCC is an effective alternative to plasma for urgent reversal of VKA therapy in major bleeding events as demonstrated by clinical assessments of bleeding and laboratory measurements of INR and factor levels.
Clinical Trial Registration Information—http://clinicaltrials.gov/. Identifier: NCT00708435.
- Received February 27, 2013.
- Revision received June 18, 2013.
- Accepted July 12, 2013.