Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study

Abstract

Background: Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal.

Methods and results: In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio 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 noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event.

Conclusions: 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels.

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

Keywords: anticoagulants; hemorrhage; plasma; prothrombin complex concentrates; vitamin K antagonist.

Conflict of interest statement

Disclosures

Dr Sarode received consulting fees and honoraria from CSL Behring GmbH. Dr Mangione and B. Durn are employees of CSL Behring LLC. Dr Schneider is an employee of CSL Behring GmbH. Dr Goldstein received consulting fees, honoraria, and a research grant from CSL Behring GmbH. Dr Milling received consulting fees from CSL Behring. Dr Refaai reports no conflicts..

Figures

Figure 1.

Patient flow. 4F-PCC indicates 4-factor prothrombin complex concentrate; ITT-E, intention-to-treat efficacy; ITT-S, intention-to-treat safety; and PP, per protocol.

Figure 2.

A, Time to international normalized ratio (INR) correction (intention-to-treat efficacy population). B, Median INR by time point (intentionto-treat efficacy population). 4F-PCC indicates 4-factor prothrombin complex concentrate; and IQR, interquartile range.

Figure 3.

Mean coagulation protein levels before and after infusion (intention-to-treat efficacy population). 4F-PCC indicates 4-factor prothrombin complex concentrate; F, factor; PC, protein C; and PS, protein S.