Elsevier

The Lancet

Volume 385, Issue 9982, 23–29 May 2015, Pages 2077-2087
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(14)61685-8Get rights and content

Summary

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.

Introduction

Patients receiving therapy with a vitamin K antagonist (VKA) have an increased risk of bleeding during surgical and procedural interventions.1 Therefore, guidelines recommend temporary interruption of VKA therapy 5 days before elective surgery to minimise perioperative bleeding.1 However, when patients need an urgent procedure, VKA reversal is often performed in the acute setting. Findings from a 2012 clinical trial underlined the risks involved, showing that the frequency of periprocedural bleeding in patients receiving VKA therapy was 3·3% for elective procedures, but 21·6% for emergency procedures.2 Although vitamin K alone can be effective, reversal can take several hours.3 Therefore, emergency reversal additionally necessitates the rapid replacement of vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X).

In some countries, including the USA, plasma is the most commonly used agent for rapid VKA reversal. Although plasma contains the vitamin K-dependent coagulation factors, it needs ABO typing and thawing before use, and is associated with long infusion times.4, 5, 6 More importantly, it can be associated with severe adverse outcomes including transfusion-related acute lung injury and transfusion-associated circulatory overload.7 Non-activated prothrombin complex concentrates contain vitamin K-dependent coagulation factors and are categorised as three-factor (3F-PCC) or four-factor (4F-PCC) prothrombin complex concentrates (depending on whether they contain clinically relevant amounts of factor VII).8 Prothrombin complex concentrates are stored at room temperature as a lyophilised powder, do not need ABO typing, can be prepared within minutes, and can be delivered in smaller volumes with shorter infusion times than can plasma.4

Adequately powered comparative trials investigating the optimum means of VKA reversal have not been done in patients needing urgent interventions, and the best method to promptly reverse VKAs remains unclear. The only plasma-controlled randomised clinical trial was a single-centre study of 40 patients (20 per group) undergoing semiurgent cardiac surgery, which was underpowered to detect significant differences in haemostatic efficacy.9 We therefore did a randomised clinical trial to compare 4F-PCC with plasma for urgent VKA reversal in patients needing urgent surgical or invasive procedures.

Section snippets

Study design and participants

In a randomised, open-label, active-controlled, non-inferiority, multicentre, phase 3b clinical trial, we enrolled patients in 33 hospitals (18 in the USA, two in Belarus, four in Bulgaria, two in Lebanon, one in Romania, and six in Russia).

Patients with an international normalised ratio (INR) of 2·0 or higher receiving VKA therapy and needing an urgent surgical or invasive procedure within 24 h were eligible for the study. The decision about the need for surgical treatment and rapid VKA

Results

181 patients were enrolled in the trial between Feb 3, 2009, and Nov 28, 2012 (figure 1); the study completed on Feb 21, 2013. We randomly assigned 90 patients to receive 4F-PCC and 91 patients to receive plasma. The mITT population included 179 patients (89 in the 4F-PCC group and 90 in the plasma group) who were randomly assigned and were either eligible or received treatment (two patients who were randomly assigned but not eligible and not treated were excluded). The ITT-S population

Discussion

Because non-inferiority was achieved for both the primary and the co-primary endpoints, non-inferiority was achieved for 4F-PCC compared with plasma overall in this open-label phase 3b study. To our knowledge, this trial is the first adequately powered comparison of 4F-PCC and plasma for rapid VKA reversal in patients needing urgent surgical or invasive interventions. Not only was 4F-PCC non-inferior to plasma for haemostatic efficacy (the comparison we were primarily powered to test), but it

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