A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal |
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| Authors: | Delphine Kerebel Luc-Marie Joly Didier Honnart Jeannot Schmidt Damien Galanaud Claude Negrier Friedrich Kursten Pierre Coriat Lex206 Investigator Group |
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| Affiliation: | 1.French Army Hospital Sainte-Anne, 2 Boulevard Saint-Anne, 83000 Toulon, France;2.CHU Rouen, 1 Rue de Germont, 76000 Rouen, France;3.CHU Dijon, 4 Rue Gaffarel, 21079 Dijon, France;4.CHU Clermont-Ferrand, 58 Rue Montalembert, 63000 Clermont-Ferrand, France;5.CHU Pitié-Salpêtrière, 47-83 Boulevard de l''Hôpital, 75651 Paris, France;6.CHU Lyon, 103 Grande Rue de la Croix-Rousse, 69004 Lyon, France;7.Octapharma AG, Oberlaaer Strasse 235, 1100 Vienna, Austria |
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| Abstract: | IntroductionProthrombin 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.MethodsWe 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).ResultsA 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.ConclusionsRapid 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 registrationEudra CT number 2007-000602-73. |
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