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

Study Questions:

Compared to plasma, what are outcomes related to the use of four-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with acute major bleeding?


This was a multicenter, prospective, randomized, open-label, active-controlled, noninferiority phase IIIb trial. Patients receiving VKA therapy with an elevated international normalized ratio (INR) (≥2.0 within 3 hours before study treatment) and experiencing an acute major bleeding event were randomly assigned to receive either 4F-PCC or plasma. The two coprimary endpoints were hemostatic efficacy of the intervention assessed over a 24-hour period from the start of infusion and rapid INR reduction (<1.3) at 0.5 hours after the end of infusion. Hemostatic efficacy was assessed by a blinded, independent Endpoint Adjudication Board as “excellent,” “good,” or “poor/none.”


The intent-to-treat-efficacy population included 202 patients (4F-PCC, n = 98; plasma n = 104). Median baseline INR was 3.90 for the 4F-PCC group and 3.60 for the plasma group. With effective hemostasis (efficacy rating of excellent or good) achieved in 71 (72.4%) patients in the 4F-PCC group versus 68 (65.4%) in the plasma group, 4F-PCC was noninferior to plasma. Rapid INR reduction was achieved in 61 (62.2%; 95% confidence interval [CI], 52.6-71.8) patients in the 4F-PCC group versus only 10 (9.6%; 95% CI, 3.9-15.3) in the plasma group, demonstrating superiority of 4F-PCC over plasma. The safety profiles of 4F-PCC and plasma were similar; there was no evidence of increased thromboembolic risk associated with 4F-PCC.


The authors concluded that 4F-PCC is noninferior to plasma for hemostatic efficiency and rapid INR reduction, and may be an alternative to plasma for urgent VKA reversal.


In the first randomized clinical trial to compare 4F-PCC and plasma for urgent VKA reversal, the authors established the noninferiority of 4F-PCC. As the authors suggested, 4F-PCC may be a preferred reversal mechanism in time- and volume-critical situations. Future studies should better characterize the comparative safety profile of 4F-PCC.

Clinical Topics: Anticoagulation Management

Keywords: Vitamin K, International Normalized Ratio, Blood Coagulation, Warfarin, Prothrombin, Hemostatics, Confidence Intervals, Blood Coagulation Factors, Hemostasis, Hemorrhage

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