Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial

Abstract

Background: Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures.

Methods: In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101.

Findings: 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8-25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9-56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients).

Interpretation: 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures.

Funding: CSL Behring.

Figure 1. Patient flow

4F-PCC=four-factor prothrombin complex concentrate. mITT=modified intention-to-treat. ITT-E=intention-to-treat efficacy. ITT-S=intention-to-treat safety. *Study included viral follow-up to day 90. †One death occurred after study day 45 (day 48; worsening of cardiopulmonary disease). ‡Eight deaths in total in plasma group; one plasma death occurred in a completed patient and one plasma death occurred in a patient with a protocol violation. §Patient not able to be reached for follow-up.

Figure 2. Study overview (ITT-E population)

Data are mean (SD) or median (IQR). ITT-E=intention-to-treat efficacy. 4F-PCC=four-factor prothrombin complex concentrate. INR=international normalised ratio.

Figure 3. Primary and co-primary endpoints

Figure shows effective haemostasis (haemostatic efficacy rating of excellent or good) and rapid INR reduction (INR ≤1·3 at 0·5 h after end of infusion) by non-inferiority analysis in the ITT-E population. Treatment difference refers to between-group difference of 4F-PCC minus plasma. Tinted area shows zone of non-inferiority, bounded by non-inferiority margin (dotted line) set at −10%. Superiority margin was set at 0% (solid line), meaning that 4F-PCC is superior to plasma if the lower limit of the 95% CI is to the right of the solid line. 4F-PCC=four-factor prothrombin complex concentrate. INR=international normalised ratio. ITT-E=intention-to-treat efficacy.

Figure 4. Secondary endpoints

Figure shows INR correction and factor-level repletion in the ITT-E population. Data are proportion of patients or mean percentage of normal levels (SD). 4F-PCC=four-factor prothrombin complex concentrate. INR=international normalised ratio. ITT-E=intention-to-treat efficacy.