Reversal of Apixaban Anticoagulation By 4-Factor Prothrombin Complex Concentrates in Healthy Subjects

INTRODUCTION: Apixaban is a novel oral anticoagulant (NOAC) that specifically inhibits factor Xa (FXa). It is approved in several countries for the prevention of venous thromboembolism following knee or hip replacement surgery, to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the treatment of venous thromboembolism. Currently there is no specific reversal agent for apixaban.

Prothrombin complex concentrates (PCC) are used to stop severe bleeding in patients on warfarin therapy or with blood clotting factor deficiency. Recently, several preclinical and limited clinical studies have shown that reversal of the anticoagulant effect of direct FXa inhibitors can be achieved by administration of PCC. This study evaluated the effect of two non-activated 4-factor PCCs, Cofact (a heparin-free formulation) and Beriplex P/N (formulation containing heparin) on apixaban pharmacodynamics (PD) and pharmacokinetics (PK) in healthy subjects.

METHODS: This was an open label, randomized, placebo-controlled, three-period crossover study in 15 healthy adult subjects. Within each period, subjects received apixaban 10 mg twice daily on days 1 to 3 with the last dose administered on the morning of day 4 to attain steady-state concentrations. On day 4, 3 hours after apixaban administration, subjects received a 30-minute infusion of either 50 IU/kg Cofact or Beriplex P/N, or an equivalent volume of saline solution. Treatment periods were separated by an 11 day washout, after which the alternate treatment was administered. The primary outcome was the assessment of changes in endogenous thrombin potential (ETP) as measured by a thrombin generation assay (TGA). Secondary objectives included the changes in other measures of apixaban PD such as other TGA parameters (e.g. peak height, lag time, velocity index), prothrombin time (PT), anti-FXa activity (AXA, measured by Rotachrom Anti-Xa assay), assessments of safety and tolerability, and assessment of the PK of apixaban with and without PCC administration.

RESULTS: All 15 subjects (mean age 33 ± 7y) were included in the analysis. As expected, the mean apixaban PK profiles were consistent across all treatment groups. Following administration of apixaban in the absence of PCC, changes in ETP and other PD measures generally followed the apixaban plasma concentration-time profile with the greatest changes occurring around the time of apixaban maximum plasma concentration and returning to baseline as apixaban plasma concentration decreased. Following completion of the 30-minute Cofact infusion, mean ETP was comparable to the Day 4 apixaban predose value (i.e., at trough apixaban concentration) and was within the baseline value (apixaban naive) within 3.5 hours. Following completion of the 30-minute Beriplex infusion, mean ETP was comparable to Day 4 apixaban predose value within 30 minutes and was within the baseline value (apixaban naive) within 5.5 hours. Irrespective of the PCC administered, mean ETP continued to increase beyond the baseline value for approximately 15 hours before returning towards baseline. Reversal of apixaban PD was also evident in changes for TGA peak height and PT. The effect of apixaban as well as the PCCs on PT was influenced by the type of thromboplastin used in the assay. PCC administration appears to have little effect on TGA lag time and TGA velocity index. In concordance with apixaban concentration, AXA did not appear to be affected by PCC administration. Apixaban administration with and without PCC treatment appeared to be safe and well tolerated with no serious adverse events, bleeding-related events, or signs of thrombosis.

CONCLUSIONS: This was the first human study investigating the effect of 4-factor PCCs on apixaban pharmacodynamics and demonstrates that both Cofact and Beriplex P/N reversed the steady-state pharmacodynamic effects of apixaban in several coagulation assessments. These results suggest that 4-factor PCCs may be useful in the management of bleeding attributed to apixaban, and support further evaluation in healthy subjects and apixaban-treated patients to better understand PCC dosing requirements and potential safety concerns.

Study supported by: Bristol-Myers Squibb and Pfizer Inc.