Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital.

Abstract

In 2013, the United States Food and Drug Administration (FDA) approved Kcentra® (CSL Behring GmbH, Kankakee, IL, USA), for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy (e.g. warfarin) in adult patients with acute major bleeding or need for urgent surgery/invasive procedure. This four-factor prothrombin complex concentrate (4F-PCC) contains coagulation factors II, VII, IX, and X, proteins C and S, antithrombin III and human albumin. The dose is expressed as units of factor IX activity. When used to reverse the anticoagulant effects of warfarin, an individualised dose should be determined based on body weight and degree of anticoagulation determined by the current international normalised ratio (INR)1. Unlike warfarin, the factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) do not have an FDA-approved antidote or reversal agent1–4. Current guidelines only provide recommendations for the reversal of the effects of direct oral anticoagulants (DOACs) in the setting of an intracranial haemorrhage, and there are limited data on the safety and efficacy of the use of clotting factors such as Kcentra® for life-threatening bleeding or urgent reversal for invasive surgical procedures1,5,6. Despite the low quality of evidence, the Neurocritical Care Society and the Society of Critical Medicine suggest administration of a 4F-PCC or activated PCC if intracranial haemorrhage occurs within three to five terminal half-lives of drug exposure or in the context of liver failure. There is limited published literature, beyond case reports or case series, on the effect of three-factor PCC on haemostasis in patients on DOACs and these concentrates are not, therefore, recommended6. More data are available for haemostasis in patients experiencing major bleeding while on vitamin K antagonists, but considering that the mechanisms of action of these two classes of medications are different, extrapolation of efficacy data is difficult. In the absence of large, randomised clinical trials, current data suggest that 4F-PCC can be utilised to reverse the effects of DOACs7–11. In a randomised, placebo-controlled, crossover study 12 healthy male volunteers received rivaroxaban 20 mg twice daily or dabigatran 150 mg twice daily for 2.5 days and were then exposed to a single bolus of 50 units/kg of 4F-PCC or a similar volume of saline. After a wash-out period, the procedure was repeated with the other anticoagulant. Rivaroxaban caused significant prolongation of the prothrombin time which was immediately and completely reversed by 4F-PCC. Additionally, the endogenous thrombin potential was inhibited by rivaroxaban and normalised by 4F-PCC. In the dabigatran samples, activated partial thromboplastin time, ecarin clotting time, and thrombin time were increased and remained elevated after administration of 4F-PCC7. An additional study retrospectively evaluated the safety and efficacy of 4F-PCC administration in the reversal of coagulopathy mediated by rivaroxaban (n=16) or apixaban (n=2) in the setting of spontaneous intracranial haemorrhage. Dosing of 4F-PCC was based on the manufacturer’s recommendation for reversal of vitamin K antagonists, taking into account presenting INR and body weight. One patient had progressive haemorrhage and another experienced a thromboembolic event. Study investigators noted a potential reduction in haemorrhagic complications and haematoma expansion in patients presenting with traumatic and spontaneous intracranial haemorrhages. Favourable outcomes, as defined by the study investigators, were observed in six of the 18 patients (33%) while six patients died in hospital8. Durie and colleagues reported on the use of 4F-PCC in a 60-year old male who was anticoagulated with apixaban prior to being admitted with blunt abdominal trauma and haemodynamic instability secondary to a motor vehicle collision. In the trauma admitting area, the patient received 4 units of packed red blood cells and was taken emergently to the operating room where he was resuscitated with 5 litres of crystalloid, 10 additional units of packed red blood cells, 6 units of fresh frozen plasma, 2 units of platelets, 1.25 litres of cell saver and 5,000 units of 4F-PCC. Although haemoglobin, haematocrit, and platelet counts remained stable until day 3, the patient continued to require transfusions due to symptomatic blood loss and ultimately died on day 49. Edoxaban is the most recently approved FXa inhibitor; however, early trials already suggest that its effects can be reversed by 4F-PCC3,10. In a phase I study, a single 60 mg dose of edoxaban was administered to 110 patients followed by 50 units/kg, 25 units/kg, or 10 units/kg of 4F-PCC. Punch biopsies were used to determine a dose-dependent reversal of edoxaban’s anticoagulation effect. Complete reversal, with regards to bleeding duration, bleeding volume and endogenous thrombin potential, was achieved with PCC 50 units/kg. Complete reversal was not noted for prothrombin time10. Based on available data, an institutional protocol has been designed for emergency reversal of oral FXa inhibitors (Figure 1). The recommended dose of 4F-PCC for reversal is 50 units/kg. Reversal of dabigatran with 4F-PCC is not recommended based on conflicting data7. The objective of this review is to characterise the current use of 4F-PCC and determine adherence to institutional recommendations. Open in a separate window Figure 1 Factor Xa inhibitor reversal algorithm.