Anticoagulant Effects Of Apixaban Research Articles

Clot time ratio (CTR) and treatment outcomes in Apixaban-treated atrial fibrillation patients

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1–Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1–Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events.

Reversal of anticoagulant effects of apixaban with non-specific prohaemostatic agents: an in vitro study

Background: As any potent anticoagulant, apixaban, an oral factor Xa inhibitor, exposes to a risk of haemorrhagic complications. Thus in the absence of specific antidote, bleeding management is challenging. Aim: To investigate the efficacy of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and partially activated PCC (aPCC) to compensate, in vitro, the anticoagulant effects of apixaban. Methods: Whole blood (WB) from healthy volunteers was spiked with therapeutic (200 ng.ml-1) or overdose (680 ng.ml-1) amount of apixaban and either rFVIIa (equivalent to 90 and 120 μg.kg-1), PCC (25 and 50 UI.kg-1), or aPCC (80 and 160 UI.kg-1). Reversal was assessed on WB with thromboelastography, and on platelet poor plasma using standard laboratory assays (PT, aPTT) as well as thrombin generation test (TGT). Increase of clot turbidity was also recorded to explore the dynamics of fibrin polymerization. Results: Apixaban concentration dependently lengthened PT, aPTT, and the clotting time (CT) in ROTEM®. It also increased lag time (LT) and decreased endogenous thrombin potential (ETP) as well as peak height in the TGT. Apixaban delayed and slowed down fibrin formation and polymerization with subsequent alteration of the resulting clot. rFVIIa had predominant effects on kinetics parameters. Addition of rFVIIa overcorrected PT, aPTT, and CT at apixaban therapeutic concentration and partly restored them in overdose situation. rFVIIa also decreased LT, and accelerated fibrin polymerization at therapeutic dose. Addition of PCC shortened PT and CT, increased peak height and ETP, but paradoxically lengthened aPTT and little modified the turbidity profile. Addition of aPCC shortened PT, aPTT, and LT in the TGT, whereas it did not affected CT in ROTEM®. aPCC also increased peak high, overcorrected ETP, and induced earlier and faster fibrin polymerization. Conclusions: These non-specific prohaemostatic agents corrected partially or completely several laboratory parameters. In particular aPCC, improving most of them was the most seducing. Further investigation is nevertheless necessary: reversal of aPCC was not confirmed in WB, increasing concentration of the prohaemostatic agents had no additive effect, and putative efficacy was strongly dependent on the observed parameter (rFVIIa was best on CT; PCC on ETP). Overall our observations underline the need for robust endpoints and clinical trials.

Inhibitory Effect of Apixaban Compared With Rivaroxaban and Dabigatran on Thrombin Generation Assay

The effect of the oral direct activated factor X (factor Xa) inhibitor apixaban on tissue factor–induced thrombin generation in human plasma was investigated in vitro using the calibrated automated thrombogram (CAT) method and compared with the oral direct factor Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran. Pooled citrated, anticoagulated, platelet-poor human plasma was spiked with apixaban, rivaroxaban, or dabigatran at concentrations of 0.01 to 10 μM. The inhibitory potencies of the compounds were quantified by 5 CAT parameters: the control thrombin lag time (LT) and time to thrombin peak (TTP) for the doubling of inhibitor concentration (IC2x); and the control endogenous thrombin potential (ETP), thrombin peak, and maximum rate of thrombin generation (Vmax) for the inhibitor concentration, which inhibited 50% (IC50). The inhibitors modified CAT concentration dependently. Their inhibitory potencies, expressed as IC2x LT, IC2x TTP, IC50 ETP, IC50 peak thrombin, and IC50 Vmax, were as follows: 0.10 ± 0.01, 0.19 ± 0.02, 0.65 ± 0.11, 0.089 ± 0.019, and 0.049 ± 0.007 μM for apixaban; 0.049 ± 0.007, 0.070 ± 0.009, 0.43 ± 0.07, 0.048 ± 0.008, and 0.022 ± 0.005 μM for rivaroxaban; and 0.063 ± 0.019, 0.18 ± 0.06, 0.50 ± 0.08, 0.55 ± 0.06, and 0.57 ± 0.27 μM for dabigatran. In summary, apixaban, rivaroxaban, and dabigatran have similar potencies in the prolongation of LT and TTP. The CAT parameters that are related to the rate of thrombin generation during the propagation phase (ie, peak thrombin and Vmax) are more sensitive to activities of apixaban and rivaroxaban than dabigatran. The ETP is the least sensitive parameter for measuring the activities of these inhibitors. Recombinant activated factor VII at 5 and 50 μg/mL reversed the anticoagulant effects of apixaban more at 0.2 μM than at 2 μM. Our study suggests that the CAT method is a sensitive assay to monitor the pharmacodynamic and pharmacokinetic properties of apixaban, rivaroxaban, and dabigatran, and may provide insight into the mechanism of action of these inhibitors. Recombinant activated factor VII may have some potential to reverse the anticoagulant effects of apixaban in vitro.

Apixaban for the Prevention of Thromboembolism in Adults after Elective Hip or Knee Replacement Surgery, and in Symptomatic Venous Thromboembolism

The anticoagulant effect of apixaban is due to direct inhibition of FXa in the coagulation cascade. The main advantages apixaban has over the current anti-coagulant drugs is that it is active after oral administration, and its coagulation effect does not require monitoring. Apixaban has been compared to enoxaparin in the prevention of venous thromboembolism associated with knee and hip replacement, where it is as efficacious as enoxaparin, but causes less bleeding. However, apixaban is not the only FXa inhibitor that could replace enoxaparin for this indication, as the FXa inhibitor rivaroxaban is as efficacious and safe as enoxaparin in preventing thromboembolism associated with these surgical procedures. Until the results of the AMPLIFY Phase III trial are known, it is too early to consider apixaban as an alternative to enoxaparin in symptomatic thromboembolism. Apixaban should not be used to prevent thromboembolism in medical immobilised subjects or acute coronary syndromes, as it causes excess bleeding in these conditions without benefit.