Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.

Sarode R, Milling TJ, Jr., Refaai MA, et al.
Circulation 2013;128:1234-1243.
NATA Rating :
Review by : M. Levi
NATA Review

The authors compared prothrombin complex concentrate (PCC) with plasma for the reversal of vitamin K antagonists in 216 patients who presented with major hemorrhage in a randomized controlled trial. PCC was given at a dose of 25-50 IU (factor IX) per kg body weight and plasma was administered at a dose of 10-15 mL/kg body weight, both adjusted to the INR. Virtually all patients received vitamin K. Effective hemostasis rated as excellent or good was achieved in 71 of 98 patients in the PCC group (72%) compared to 68 of 104 patients in the plasma group. Rapid INR reduction (< 1.3) was observed in 62% of patients in the PCC group versus only 10% in the plasma group. INR normalization occurred in 69% of patients within one hour after administration of PCC, whereas none of the plasma-treated patients had normalization of the INR within one hour. Treatment-related adverse events were present in 10 patients in the PCC group and in 23 patients in the plasma group. Serious adverse events occurred in 32 patients in the PCC group (of which 2 were thrombotic and considered treatment-related) and in 26 patients from the plasma group (treatment-related: 2 myocardial ischemia, 1 respiratory failure and 1 fluid overload). Overall thrombotic adverse events occurred in 8 patients in the PCC group and 7 in the plasma group, respectively. This is an important and relevant study underlining the effectiveness and safety of PCCs in the rapid reversal of vitamin K antagonist-related hemorrhage. The significance of the study pertains to the fact that this was a randomized and controlled study and that clinically relevant outcomes were assessed. PCCs were as effective as plasma but in routine medical practice PCCs are probably much more convenient to use (e.g. the median duration of PCC administration was 17 minutes compared to 148 minutes for plasma). I do not understand why this trial was designed as a non-inferiority trial since evidence of superiority of PCCs would have been an even more relevant outcome. Nevertheless, this is an important trial with findings that support the use of PCCs in the reversal of vitamin K antagonists in the case of major bleeding. – Marcel Levi

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