Dataset Information

Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa.

ABSTRACT: Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux.

SUBMITTER: Siddiqui F

PROVIDER: S-EPMC7098205 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa.

Siddiqui Fakiha F Tafur Alfonso A Bontekoe Emily E Iqbal Omer O Jeske Walter W Mehrotra Siddharth S Hoppensteadt Debra D Ramacciotti Eduardo E Fareed Jawed J

Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 20200101

Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anti ...[more]

PMID: 31914798

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Project description:ObjectiveTo determine the efficacy and safety of enoxaparin compared with unfractionated heparin during percutaneous coronary intervention.DesignSystematic review and meta-analysis.Data sourcesMedline and Cochrane database of systematic reviews, January 1996 to May 2011.Study selectionRandomised and non-randomised studies comparing enoxaparin with unfractionated heparin during percutaneous coronary intervention and reporting on both mortality (efficacy end point) and major bleeding (safety end point) outcomes.Data extractionSample size, characteristics, and outcomes, extracted independently and analysed.Data synthesis23 trials representing 30,966 patients were identified, including 10,243 patients (33.1%) undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction, 8750 (28.2%) undergoing secondary percutaneous coronary intervention after fibrinolysis, and 11,973 (38.7%) with non-ST elevation acute coronary syndrome or stable patients scheduled for percutaneous coronary intervention. A total of 13,943 patients (45.0%) received enoxaparin and 17,023 (55.0%) unfractionated heparin. Enoxaparin was associated with significant reductions in death (relative risk 0.66, 95% confidence interval 0.57 to 0.76; P<0.001), the composite of death or myocardial infarction (0.68, 0.57 to 0.81; P<0.001), and complications of myocardial infarction (0.75, 0.6 to 0.85; P<0.001), and a reduction in incidence of major bleeding (0.80, 0.68 to 0.95; P=0.009). In patients who underwent primary percutaneous coronary intervention, the reduction in death (0.52, 0.42 to 0.64; P<0.001) was particularly significant and associated with a reduction in major bleeding (0.72, 0.56 to 0.93; P=0.01).ConclusionEnoxaparin seems to be superior to unfractionated heparin in reducing mortality and bleeding outcomes during percutaneous coronary intervention and particularly in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.

Project description:Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ?0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Dataset Information

Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa.

Publications

Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa.

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