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

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).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 [lessthan or equal to] 1.5 in all patients of both groups - 10 min after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 min (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 min after infusion. However, no differences were found in hematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.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.