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Pamela B. Conley - One of the best experts on this subject based on the ideXlab platform.

  • measuring residual anti xa activity of direct factor xa inhibitors after reversal with Andexanet Alfa
    International Journal of Laboratory Hematology, 2021
    Co-Authors: Matthieu Bourdin, Pamela B. Conley, Delphine Perrotin, Olivier Mathieu, Tristan Herve, Francois Depasse, Genevieve Contant
    Abstract:

    INTRODUCTION Andexanet Alfa (AnXa) was developed for anticoagulant effect reversal of direct factor Xa inhibitors (DXaI) (apixaban, rivaroxaban, edoxaban) in emergency situations. Regular anti-Xa assays are not suitable to evaluate anti-Xa activity after AnXa administration because of the high sample dilution resulting in the AnXa-DXaI dissociation which gives inaccurately high DXaI measured concentrations. This study aimed at developing dedicated STA-Liquid anti-Xa test set-ups for accurately measuring DXaI after reversal with AnXa. METHODS Modified anti-Xa test set-ups, with reduced sample dilution, were developed to overcome regular assays limitations and to improve measured accuracy with results comparable to Portola microplate reference method used in clinical studies. Both regular and optimized assays were used to measure DXaI concentration in AnXa-containing samples. Quality controls, normal pooled plasma spiked with five DXaI and three AnXa concentrations, samples from DXaI-treated patients spiked with AnXa and ex vivo healthy volunteers having received both DXaI and AnXa were used. RESULTS The lower limit of quantitation of optimized anti-Xa assays was <10 ng/mL with CVs ≤10%. DXaI samples containing 300 ng/mL and 1 µmol/L AnXa resulted in DXaI residual concentrations of 29-72 ng/mL depending on the DXaI (76%-90% reversal), compared to 20-28 ng/mL with reference method (92%-94% reversal) and 135-165 ng/mL with regular assays (about 50% reversal). CONCLUSION Modified test set-ups are automated alternative to reference method with improved precision and reproducibility. They can be run in all laboratories where regular anti-Xa assays are performed using commercially available reagents.

  • abstract p3 Andexanet Alfa for acute bleeding during treatment with edoxaban
    Stroke, 2021
    Co-Authors: Alexander P Benz, Pamela B. Conley, Stuart J Connolly, John W Eikelboom, Saskia Middeldorp, Truman J Milling, Mark Crowther, Patrick Yue, Annexa Investigators
    Abstract:

    Introduction: We previously reported results of a prospective cohort study evaluating Andexanet Alfa (Andexanet) for anticoagulation reversal in patients with acute bleeding on a factor Xa inhibito...

  • analytical performance of modified anti fxa assays for Andexanet Alfa containing plasma samples on the acl top top 50 coagulation analyzers
    Blood, 2020
    Co-Authors: Anuja Khan, Pamela B. Conley, Krisjela Shishko, Ryan Marett, Sam Arcidiacono, Vy Nguyen, Khanh Linh Bui, Anne M Winkler
    Abstract:

    Background: Assay parameters for anti-FXa activity assays for apixaban and rivaroxaban on the ACL TOP/TOP 50 analyzers have been modified to minimize the effect of sample dilution suitable for analyzing Andexanet-containing samples with drug-specific calibrators [1].The modified assays showed a dose-dependent reversal of rivaroxaban and apixaban anti-FXa activity in Andexanet-containing samples similar to the 96-well format anti-FXa activity assay used in the Andexanet clinical studies. In the current study, further assay optimization and verification of analytical performance was performed for the modified apixaban and rivaroxaban assays. Methods: Calibration curves for the modified anti-FXa assays (apixaban, rivaroxaban) were further optimized to improve precision at 100 ng/mL. The calibration curves consisted of 5 dilution levels. The number of replicates at each level was increased from 3 to 4, and outlier removal was enabled to improve the % coefficient of variation (%CV). The limit of blank (LoB), detection (LoD) and quantitation (LoQ) for modified assays on the ACL TOP/TOP 50 were determined in accordance with the minimum requirements of two lots of calibrators and reagent, one instrument system, and three days in accordance with CLSI [2]. The linear ranges were tested for 3 lots of calibrators on 4 analyzers. The samples for the linearity tests consisted of a minimum of 9 to 11 levels extending below and above the anticipated linear range. A 5-day precision was performed with diluted controls encompassing the modified assay calibration range and Andexanet-containing samples on a minimum of two analyzers with one lot of drug-specific calibrator to verify analytical performance. Results: Analytical performance with optimized calibration settings was evaluated with a minimum of 9 calibration curves generated with 3 calibrator lots and demonstrated improvement in the r2 and %CV at each level. The analytical parameters for the modified apixaban assay generated with 3 lots of calibrator and reagent on 4 analyzers are as follows: LoB of ~2.1 ng/mL, LoD of 3.5 ng/mL, and LoQ of 5.9 ng/mL. The analytical parameters for the modified rivaroxaban assay were generated with 2 lots of calibrators and reagents with a LoB of 2.3 ng/mL, and LoD of 3.6 ng/mL. Three lots of calibrators and reagents were used to generate an LoQ of 5.4 ng/mL. The linear range was determined to be 10-100 ng/mL and met the acceptance criteria for r2≥ 0.95 and slope of 0.90 - 1.10 for both assays. Conclusions: Results of this study demonstrate that modified apixaban and rivaroxaban LoQ and linearity meet the assay requirements. Modified test parameters will be user-defined on the ACL TOP/TOP 50 analyzers and can be used to measure apixaban or rivaroxaban levels when Andexanet is present in the samples. References: 1. Khan, A. et al. Blood(2019) 134 (Supplement1): 1153. American Society of Hematology- Modified Anti-FXa assays for measuring the residual activity of apixaban and rivaroxaban in Andexanet Alfa-containing samples on the ACL TOP Family® coagulation analyzers. 2. CLSI EP17-A2.Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition.Wayne, PA: Clinical and Laboratory Standards Institute; 2012. Disclosures Lu:Portola Pharmaceuticals, Inc.:Current Employment.Bui:Portola Pharmaceuticals, Inc,:Current Employment.Conley:Portola Pharmaceuticals, Inc.:Current Employment.

  • a phase 2 pk pd study of Andexanet Alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers
    Blood Advances, 2020
    Co-Authors: Pamela B. Conley, Janet M. Leeds, Janice Castillo, Mark Crowther, Mark Karbarz, Gallia Levy, Vandana Mathur, John T. Curnutte
    Abstract:

    As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet Alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of Andexanet Alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet Alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of Andexanet Alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of Andexanet Alfa administration, compared with placebo, were observed when Andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet Alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet Alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

  • modified anti fxa assays for measuring the residual activity of apixaban and rivaroxaban in Andexanet Alfa containing samples on the acl top family coagulation analyzers
    Blood, 2019
    Co-Authors: Anuja Khan, Pamela B. Conley, Krisjela Shishko, Sam Arcidiacono, Khanh Linh Bui, Anne M Winkler
    Abstract:

    Background: Andexanet Alfa (AnXa) is a modified human FXa protein approved in the US and EU for reversal of direct factor Xa (FXa) inhibitors (apixaban, rivaroxaban) due to life-threatening or uncontrolled bleeding. AnXa reverses the anticoagulant effect of FXa inhibitors by binding and sequestering FXa inhibitor. Commercially available anti-FXa assays measure FXa inhibitors using drug specific calibrators and controls. However, there are limitations when these assays are used for measuring AnXa-containing patient samples. One of the limitations is the large sample dilution in the assay setup, which causes dissociation of the inhibitor from the AnXa-inhibitor complex (due to the reversible binding equilibrium of the AnXa-inhibitor), resulting in an erroneous elevation of the anti-FXa activity following AnXa administration. We have developed modified assay parameters for the drug-specific anti-FXa activity assays, apixaban and rivaroxaban, on the ACL TOP Family instruments, which minimizes the effect of sample dilution suitable for analyzing AnXa-containing samples. Methods: Pooled normal human plasma was spiked with different concentrations of apixaban (230, 460, 920 ng/mL, 0.5 - 2.0 μM) or rivaroxaban (218, 436, 872 ng/mL, 0.5 - 2.0 μM) and AnXa at different AnXa:inhibitor molar ratios (0, 0.5,1.0, 2.0). The reversal activity of AnXa for apixaban and rivaroxaban was measured by a modified anti-FXa assay in a 96-well format previously used in the AnXa preclinical and clinical studies. The same set of contrived samples was assessed using the apixaban and rivaroxaban assays on the ACL TOP 700 with HemosIL Anti-Xa with HemosIL Apixaban or HemosIL Rivaroxaban Calibrators and Controls according to the manufacturer's recommendations. The ACL TOP 700 assay parameters were modified with an optimized plasma to reagent volume ratio to reduce the overall sample dilution. The calibration curves for both assays were optimized to report in the 0-100 ng/mL range. Results: When assessed by modified anti-FXa assays in the 96-well format (with an overall 2-fold sample dilution), AnXa dose-dependently reversed the anti-FXa activity of both apixaban and rivaroxaban spiked in plasma. % Reversal increased as a function of the molar ratios (AnXa:inhibitor) with ~50% (1:2), > 95% (1:1), and >99% reversal (2:1) respectively. Conversely, the Anti-FXa setup with the HemosIL Anti-Xa reagents and calibrators showed Conclusions: The modified parameters for apixaban and rivaroxaban on the ACL TOP Family instruments minimized the dilution effect seen in the commercially released assays for the AnXa-containing samples and the data showed a similar trend in % reversal compared to the 96-well plate manual assays. Disclosures Bui: Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Lu: Portola Pharmaceuticals: Employment, Equity Ownership. Conley: Portola Pharmaceuticals, Inc.: Employment, Equity Ownership.

John T. Curnutte - One of the best experts on this subject based on the ideXlab platform.

  • 30 day mortality following Andexanet Alfa in annexa 4 compared with prothrombin complex concentrate pcc therapy in the orange study for life threatening non vitamin k oral anticoagulant noac related bleeding
    Journal of the American College of Cardiology, 2020
    Co-Authors: Alexander T Cohen, John T. Curnutte, Stuart J Connolly, Patrick Yue, Megan Lewis, Augusta Connor, P K Maccallum, Joachim Tan, Laura Green
    Abstract:

    Life-threatening NOAC related major bleeding is associated with high mortality. Off-label PCC is currently recommended in some guidelines as well as the approved specific antidote, Andexanet Alfa (Andexanet). There are no randomised controlled trials comparing these therapies and hence we undertook

  • a phase 2 pk pd study of Andexanet Alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers
    Blood Advances, 2020
    Co-Authors: Pamela B. Conley, Janet M. Leeds, Janice Castillo, Mark Crowther, Mark Karbarz, Gallia Levy, Vandana Mathur, John T. Curnutte
    Abstract:

    As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet Alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of Andexanet Alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet Alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of Andexanet Alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of Andexanet Alfa administration, compared with placebo, were observed when Andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet Alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet Alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

  • full study report of Andexanet Alfa for bleeding associated with factor xa inhibitors
    The New England Journal of Medicine, 2019
    Co-Authors: John T. Curnutte, Stuart J Connolly, Michele D Bronson, John W Eikelboom, Mark Crowther, Patrick Yue, Michael C Gibson, John H Lawrence, Pamela B. Conley
    Abstract:

    Abstract Background Andexanet Alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. Methods We evaluated 352 patients who had acute major b...

  • Andexanet Alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model
    PLOS ONE, 2018
    Co-Authors: Polly Pine, Janet M. Leeds, Francis Deguzman, Pratikhya Pratikhya, Joyce Lin, John Malinowski, Stanley J. Hollenbach, John T. Curnutte, Pamela B. Conley
    Abstract:

    INTRODUCTION Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet Alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. OBJECTIVE To evaluate the ability of Andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. MATERIALS AND METHODS In vitro studies characterized the interaction of Andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+Andexanet vehicle (control), edoxaban (1 mg/kg)+Andexanet vehicle, edoxaban+Andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+Andexanet prior to injury. RESULTS Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, Andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). CONCLUSION These data demonstrate that Andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

  • Andexanet Alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model
    PloS one, 2018
    Co-Authors: Polly Pine, Janet M. Leeds, Francis Deguzman, Pratikhya Pratikhya, Joyce Lin, John Malinowski, Stanley J. Hollenbach, John T. Curnutte, Pamela B. Conley
    Abstract:

    INTRODUCTION Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet Alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. OBJECTIVE To evaluate the ability of Andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. MATERIALS AND METHODS In vitro studies characterized the interaction of Andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+Andexanet vehicle (control), edoxaban (1 mg/kg)+Andexanet vehicle, edoxaban+Andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+Andexanet prior to injury. RESULTS Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, Andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P

Janet M. Leeds - One of the best experts on this subject based on the ideXlab platform.

  • a phase 2 pk pd study of Andexanet Alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers
    Blood Advances, 2020
    Co-Authors: Pamela B. Conley, Janet M. Leeds, Janice Castillo, Mark Crowther, Mark Karbarz, Gallia Levy, Vandana Mathur, John T. Curnutte
    Abstract:

    As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet Alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of Andexanet Alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet Alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of Andexanet Alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of Andexanet Alfa administration, compared with placebo, were observed when Andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet Alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet Alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

  • transient or extended reversal of apixaban anticoagulation by Andexanet Alfa is equally effective in a porcine polytrauma model
    BJA: British Journal of Anaesthesia, 2019
    Co-Authors: Oliver Grottke, Janet M. Leeds, Pamela B. Conley, Necib Akman, Till Braunschweig, Rolf Rossaint, Markus Honickel
    Abstract:

    Abstract Background Andexanet Alfa (Andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated Andexanet for reversing apixaban anticoagulation in a porcine polytrauma model. Methods Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single Andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss. Results Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P Conclusion Andexanet effectively reversed apixaban anticoagulation and reduced blood loss induced by severe trauma. Andexanet bolus alone had a similar impact on survival and blood loss as bolus plus infusion. Therefore, a 2 h Andexanet infusion after the bolus may not be necessary to restore normal haemostatic mechanisms.

  • Andexanet Alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model
    PloS one, 2018
    Co-Authors: Polly Pine, Janet M. Leeds, Francis Deguzman, Pratikhya Pratikhya, Joyce Lin, John Malinowski, Stanley J. Hollenbach, John T. Curnutte, Pamela B. Conley
    Abstract:

    INTRODUCTION Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet Alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. OBJECTIVE To evaluate the ability of Andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. MATERIALS AND METHODS In vitro studies characterized the interaction of Andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+Andexanet vehicle (control), edoxaban (1 mg/kg)+Andexanet vehicle, edoxaban+Andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+Andexanet prior to injury. RESULTS Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, Andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P

  • Andexanet Alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model
    PLOS ONE, 2018
    Co-Authors: Polly Pine, Janet M. Leeds, Francis Deguzman, Pratikhya Pratikhya, Joyce Lin, John Malinowski, Stanley J. Hollenbach, John T. Curnutte, Pamela B. Conley
    Abstract:

    INTRODUCTION Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet Alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. OBJECTIVE To evaluate the ability of Andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. MATERIALS AND METHODS In vitro studies characterized the interaction of Andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+Andexanet vehicle (control), edoxaban (1 mg/kg)+Andexanet vehicle, edoxaban+Andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+Andexanet prior to injury. RESULTS Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, Andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). CONCLUSION These data demonstrate that Andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

  • safety pharmacokinetics and reversal of apixaban anticoagulation with Andexanet Alfa
    Blood Advances, 2017
    Co-Authors: Deborah M Siegal, Janet M. Leeds, Janice Castillo, Mark Karbarz, Vandana Mathur, Athiwat Hutchaleelaha, Uma Sinha, Michael M Kitt, Matthew W Mcclure, Stanley J. Hollenbach
    Abstract:

    Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet Alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of Andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of Andexanet (n = 24) or placebo (n = 8). In phase 2, Andexanet (n = 36) or placebo (n = 18) was administered following steady-state apixaban dosing (5 mg twice daily for 6 days); safety, pharmacokinetics, and pharmacodynamics were assessed. Andexanet plasma concentration increased proportionally with dose, with rapid elimination (terminal elimination half-life, 4.35-7.5 hours). Following apixaban treatment, Andexanet rapidly (≤2 minutes) and dose dependently reduced unbound apixaban concentration vs placebo (51% to 89% vs 5% reduction; all P < .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all P < .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all P < .01), maintaining these effects during continuous 45- and 120-minute infusions. Andexanet was well tolerated. Nine subjects had mild/moderate infusion reactions not associated with hemodynamic changes or respiratory compromise that generally resolved without intervention or dose reduction. There were no thrombotic events or other serious safety issues. In conclusion, Andexanet reversed apixaban-mediated effects on pharmacodynamic markers of anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. This trial was registered at www.clinicaltrials.gov as #NCT01758432.

Stuart J Connolly - One of the best experts on this subject based on the ideXlab platform.

  • abstract p3 Andexanet Alfa for acute bleeding during treatment with edoxaban
    Stroke, 2021
    Co-Authors: Alexander P Benz, Pamela B. Conley, Stuart J Connolly, John W Eikelboom, Saskia Middeldorp, Truman J Milling, Mark Crowther, Patrick Yue, Annexa Investigators
    Abstract:

    Introduction: We previously reported results of a prospective cohort study evaluating Andexanet Alfa (Andexanet) for anticoagulation reversal in patients with acute bleeding on a factor Xa inhibito...

  • 30 day mortality following Andexanet Alfa in annexa 4 compared with prothrombin complex concentrate pcc therapy in the orange study for life threatening non vitamin k oral anticoagulant noac related bleeding
    Journal of the American College of Cardiology, 2020
    Co-Authors: Alexander T Cohen, John T. Curnutte, Stuart J Connolly, Patrick Yue, Megan Lewis, Augusta Connor, P K Maccallum, Joachim Tan, Laura Green
    Abstract:

    Life-threatening NOAC related major bleeding is associated with high mortality. Off-label PCC is currently recommended in some guidelines as well as the approved specific antidote, Andexanet Alfa (Andexanet). There are no randomised controlled trials comparing these therapies and hence we undertook

  • full study report of Andexanet Alfa for bleeding associated with factor xa inhibitors
    The New England Journal of Medicine, 2019
    Co-Authors: John T. Curnutte, Stuart J Connolly, Michele D Bronson, John W Eikelboom, Mark Crowther, Patrick Yue, Michael C Gibson, John H Lawrence, Pamela B. Conley
    Abstract:

    Abstract Background Andexanet Alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. Methods We evaluated 352 patients who had acute major b...

  • Andexanet Alfa for the management of acute major bleeding associated with fxa inhibitors p5 059
    Neurology, 2017
    Co-Authors: Stuart J Connolly, John T. Curnutte, Pamela B. Conley, John W Eikelboom, Truman J Milling, Michael C Gibson, Peter Verhamme, Alex Gold, Jeannot Schmidt, Saskia Middeldorp
    Abstract:

    Objective: This is an interim report of the Effects of FXA Inhibitors (ANNEXA-4) study designed to evaluate the use of Andexanet in patients with acute major bleeding. Background: Factor Xa (FXa) inhibitors are effective, but the risk of major bleeding is a concern and no specific antidotes are available for reversal. Andexanet Alfa has been developed as a specific reversal agent for FXa inhibitors. It has been shown to reverse the inhibition of FXa in healthy volunteers. Design/Methods: The interim report of this multicenter, prospective, open-label, single-group study included patients (safety population, n=67; efficacy population, n=47) who had acute major bleeding within 18 hours after taking FXa inhibitor (rivaroxaban or apixaban). Patients received Andexanet bolus followed by a 2-hour infusion. Efficacy assessments included anti-FXa activity and clinical hemostatic efficacy (adjudicated by an independent committee) during a 12-hour period. All patients were followed for 30 days. Results: The mean age was 77 years; most patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. After Andexanet bolus, the median anti-FXa activity decreased by 89% (95% confidence interval [CI], 58 to 94) among rivaroxaban patients, and by 93% (95% CI, 87 to 94) among apixaban patients; these levels were sustained during the 2-hour infusion. Twelve hours after Andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 79% (37/47) patients (95% CI, 64 to 89). Thrombotic events occurred in 18% (12/67) patients during the 30-day follow-up. Anticoagulation was re-started in 18 patients (27%) by 30 days; therapeutic anticoagulation was re-started in 1 patient before a thrombotic event occurred. Conclusions: This descriptive preliminary analysis showed that Andexanet substantially reduced anti-FXa activity in patients with acute major bleeding associated with FXa inhibitors, with effective hemostasis occurring in 79%. Thrombotic events occurred at rates consistent with the high risk profile of the patients. Study Supported by: Funded by Portola Pharmaceuticals; ANNEXA-4 Clinical Trials gov number, NCT02329327. Disclosure: Dr. Connolly has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals as a consultant. Dr. Milling has received personal compensation for activities with CSI Behring, Janssen, BI, and Portola. Dr. Eikelboom has nothing to disclose. Dr. Gibson has received personal compensation for activities with Portola Pharmaceuticals as a consultant and has been an investigator on clinical trials funded by Portola Pharmaceuticals. Dr. Curnutte has received personal compensation for activities with Portola as an employee. Dr. Gold has received personal compensation for activities with Portola as an employee. Dr. Lu has received personal compensation for activities with Portola as an employee. Dr. Conley has received personal compensation for activities with Portola as an employee. Dr. Verhamme has nothing to disclose. Dr. Schmidt has nothing to disclose. Dr. Middeldorp has nothing to disclose. Dr. Cohen has received personal compensation for activities with Portola as a consultant and investigator. Dr. Beyer-Westendorf has nothing to disclose. Dr. Albaladejo has nothing to disclose. Dr. Lopez-Sendon has nothing to disclose. Dr. Goodman has received personal compensation for activities with Portola as an employee. Dr. Leeds has received personal compensation for activities with Portola as an employee. Dr. Siegal has received personal compensation for activities with Portola as a consultant. Dr. Zotova has nothing to disclose. Dr. Nakamya has nothing to disclose. Dr. Lim has nothing to disclose. Dr. Crowther has received personal compensation for activities with Portola as a consultant.

  • Andexanet Alfa for acute major bleeding associated with factor xa inhibitors
    The New England Journal of Medicine, 2016
    Co-Authors: Stuart J Connolly, John T. Curnutte, Pamela B. Conley, Michele D Bronson, John W Eikelboom, Truman J Milling, Michael C Gibson, Peter Verhamme, Alex Gold, Jeannot Schmidt
    Abstract:

    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 .).

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  • abstract p3 Andexanet Alfa for acute bleeding during treatment with edoxaban
    Stroke, 2021
    Co-Authors: Alexander P Benz, Pamela B. Conley, Stuart J Connolly, John W Eikelboom, Saskia Middeldorp, Truman J Milling, Mark Crowther, Patrick Yue, Annexa Investigators
    Abstract:

    Introduction: We previously reported results of a prospective cohort study evaluating Andexanet Alfa (Andexanet) for anticoagulation reversal in patients with acute bleeding on a factor Xa inhibito...

  • a phase 2 pk pd study of Andexanet Alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers
    Blood Advances, 2020
    Co-Authors: Pamela B. Conley, Janet M. Leeds, Janice Castillo, Mark Crowther, Mark Karbarz, Gallia Levy, Vandana Mathur, John T. Curnutte
    Abstract:

    As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet Alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of Andexanet Alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet Alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of Andexanet Alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of Andexanet Alfa administration, compared with placebo, were observed when Andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet Alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet Alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

  • reversal of direct oral anticoagulants guidance from the anticoagulation forum
    American Journal of Hematology, 2019
    Co-Authors: Adam Cuker, Mark Crowther, Allison Burnett, Darren M Triller, Jack Ansell, Elizabeth M Van Cott, Diane Wirth, Scott Kaatz
    Abstract:

    Two specific reversal agents for direct oral anticoagulants (DOACs) have been approved in the United States: idarucizumab for dabigatran reversal and Andexanet Alfa for apixaban and rivaroxaban reversal. Non-specific prohemostatic agents such as prothrombin complex concentrate (PCC) and activated PCC have also been used for DOAC reversal. The goal of this document is to provide comprehensive guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of DOAC reversal agents. We discuss indications for reversal, provide guidance on how the individual reversal agents should be administered, and offer suggestions for stewardship at the health system level.

  • full study report of Andexanet Alfa for bleeding associated with factor xa inhibitors
    The New England Journal of Medicine, 2019
    Co-Authors: John T. Curnutte, Stuart J Connolly, Michele D Bronson, John W Eikelboom, Mark Crowther, Patrick Yue, Michael C Gibson, John H Lawrence, Pamela B. Conley
    Abstract:

    Abstract Background Andexanet Alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. Methods We evaluated 352 patients who had acute major b...

  • Andexanet Alfa for the treatment of hemorrhage
    Expert Review of Hematology, 2018
    Co-Authors: Andrea Cervi, Mark Crowther
    Abstract:

    ABSTRACTIntroduction: While associated life-threatening and fatal bleeding events are less frequent with the direct factor Xa inhibitors compared to vitamin K antagonists, significant concern surro...