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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?
Methods:
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.”
Results:
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.
Conclusions:
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.
Perspective:
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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