The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII in apixaban‐treated patients in vitro

Abstract

Essentials An antidote for apixaban is not yet available.We tested the effect of different haemostatic agents to reverse the apixaban effect in vitro.Activated prothrombin complex concentrate (aPCC) was superior to prothrombin complex concentrate and recombinant activated factor VII.Even low doses of aPCC reversed the apixaban effect completely in vitro. BackgroundThe number of patients under treatment with FXa inhibitors is increasing, but there is no concensus on how to reverse their anticoagulant effect in case of a life‐threatening bleeding. A specific antidote is not yet commercially available. Prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are suggested available reversal agents.ObjectivesTo find the most effective reversal agent to apixaban and to determine the optimal dose.Patients/Methods PCC, aPCC, and rFVIIa at concentrations imitating 80%, 100%, and 125% of suggested therapeutic doses were added to blood drawn from apixaban‐treated patients (n=30). aPCC was also tested in a 50% dose. Samples from healthy subjects (n=40) were used as controls. Thromboelastometry in whole blood (WB) and thrombin generation in platelet‐poor plasma (PPP) were measured to assess the reversal effect.Results aPCC shortened clotting time (CT) in WB, and increased the peak thrombin concentration and velocity index in PPP to a greater extent than PCC and rFVIIa. No significant differences were seen between rFVIIa and aPCC on thrombin generation lag time, or between PCC and aPCC on endogenous thrombin potential (ETP). The 50% dose of aPCC had a slightly inferior effect, but was comparable to the other reversal agents.ConclusionsIn this in vitro study the 80% dose of aPCC (40 IU/kg) reversed the anticoagulant effect of apixaban more effectively than the corresponding dose of rFVIIa and PCC both in WB (CT) and PPP (peak, ETP).

Andexanet versus prothrombin complex concentrates: Differences in reversal of factor Xa inhibitors in in vitro thrombin generation

“…Factor replacement therapies, such as four-factor prothrombin complex concentrates (4F-PCCs), are approved for reversal of anticoagulation with vitamin K antagonists (VKA; eg, warfarin) and serve to replace factors VII (FVII), IX (FIX), X (FX), and II (FII) rendered functionally deficient by the anticoagulant. 11 Although 4F-PCCs have been studied for FXa inhibitor reversal in nonclinical in vitro/ex vivo assays, [12][13][14] animal models, 15 healthy volunteers, [16][17][18][19][20][21][22][23] and observational clinical studies in patients taking FXa inhibitors, [24][25][26][27] the effectiveness and clinical benefit of 4F-PCCs on hemostatic efficacy and reversal of key biomarkers are mixed, 7,[28][29][30][31] and their potential mechanism of action has not been critically elucidated. There have been no controlled studies evaluating the effectiveness of 4F-PCCs for reversal of FXa inhibitor-mediated bleeding (or anticoagulation), and they are not approved for this indication.…”

A Low-Dose 4F-PCC Protocol for DOAC-Associated Intracranial Hemorrhage

“…3 However, the evidence for 4F-PCC in DOAC-associated bleeding is derived primarily from animal models 4 and healthy volunteers. 5 –12 Among studies that have evaluated use of PCCs for DOAC-associated bleeding, 2 small retrospective and 3 prospective studies provide hemostasis and/or thrombosis outcomes in patients with DOAC-associated bleeding. 13 –17…”

Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series

“…In vitro studies have shown that aPCC at the suggested dose might overcorrect the hemostatic parameters [ 7 , 9 ], and patients treated with apixaban already have a risk of thromboembolic complications. Another study has shown that 25 IU/kg reverses the hemostatic parameters altered by apixaban quickly and sufficiently [ 10 ]. A single case report also supports the use of this dose [ 15 ].…”