title: A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  Eudra CT number 2007-000602-73.
authors.forename: Delphine
authors.initials: D
authors.lastname: Kerebel
authors.forename: Luc-Marie
authors.initials: LM
authors.lastname: Joly
authors.forename: Didier
authors.initials: D
authors.lastname: Honnart
authors.forename: Jeannot
authors.initials: J
authors.lastname: Schmidt
authors.forename: Damien
authors.initials: D
authors.lastname: Galanaud
authors.forename: Claude
authors.initials: C
authors.lastname: Negrier
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kursten
authors.forename: Pierre
authors.initials: P
authors.lastname: Coriat
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects*; D001779:Blood Coagulation Factors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004632:Emergency Medical Services / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D020300:Intracranial Hemorrhages / Q000139:chemically induced* / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D000925:Anticoagulants; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates