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Clinical Trial

A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal

Delphine Kerebel et al. Crit Care. .

Abstract

Introduction: Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.

Methods: We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).

Results: A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.

Conclusions: Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.

Trial registration: Eudra CT number 2007-000602-73.

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Figures

Figure 1
Figure 1
Changes in mean INR values after 4-factor PCC infusion in 25 and 40 IU/kg groups. *Significant difference with P <0.05. All patients were present during the 24 h. At inclusion, INR was calculated for 29 patients in the 25 IU/kg group and 30 patients in the 40 IU/kg group, at 10 min in 27 and 29, at 1 h in 26 and 28, at 3 h in 28 and 30, and at 24 h in 22 and 30, respectively. INR, international normalised ratio; PCC, prothrombin complex concentrate.
Figure 2
Figure 2
Changes in coagulation factors after 4-factor PCC infusion in 25 and 40 IU/kg groups. *Results are presented as mean and 95% confidence interval. PCC, prothrombin complex concentrate.
Figure 3
Figure 3
Individual patient infusion speed at each study centre. White dots refer to patients in the 25 IU/kg group and black dots refer to those in the 40 IU/kg group.
See this image and copyright information in PMC

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