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Leo Pharma Chair in Thromboembolism Research, McMaster University
Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart & Vascular Center
Investigator, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital
Professor of Medicine at Uniformed Services University of the Health Sciences
Executive Director, Thrombosis and Atherosclerosis Research Institute
Head of the Thrombosis Research Unit, Center for Vascular Medicine, University Hospital Dresden
Professor of Cardiovascular Medicine at University of Birmingham
Professor of Medicine at Hofstra North Shore - LIJ School of Medicine
Associate Chair, Emergency Medicine, Baylor College of Medicine
Director of the Cardiac Care Unit, Duke University Medical Center
Hematologist at Brigham and Women's Hospital and Dana Farber Cancer Institute
Head of Atherothrombosis, Inflammation, and Platelets; University of Freiburg
Medical Education and Scientific Support at Boehringer Ingelheim
Executive Vice President of Clinical and Medical Affairs at Perosphere
Director of Cardiac Catheterization Laboratories & Interventional Cardiology Guthrie Health Services at Guthrie Health Systems Robert Packer Hospital
Professor of Surgery and Director, Surgical Critical Care and Trauma Surgery Fellowships at The University of Texas Health Science Center at Houston
Cardiologist at Royal Brompton Hospital and Imperial College London
Director of the Institute of Cardiology at "G. d'Annunzio" University, Chieti
Hematology-Oncology Fellow at Boston Medical Center
Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.
Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti–factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.
Among the apixaban-treated participants, anti–factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti–factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.
Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers NCT02207725 and NCT02220725.)
Leo Pharma Chair in Thromboembolism Research, McMaster University
Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart & Vascular Center
Investigator, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital
Professor of Medicine at Uniformed Services University of the Health Sciences
Executive Director, Thrombosis and Atherosclerosis Research Institute
Head of the Thrombosis Research Unit, Center for Vascular Medicine, University Hospital Dresden
Professor of Cardiovascular Medicine at University of Birmingham
Professor of Medicine at Hofstra North Shore - LIJ School of Medicine
Associate Chair, Emergency Medicine, Baylor College of Medicine
Director of the Cardiac Care Unit, Duke University Medical Center
Hematologist at Brigham and Women's Hospital and Dana Farber Cancer Institute
Head of Atherothrombosis, Inflammation, and Platelets; University of Freiburg
Medical Education and Scientific Support at Boehringer Ingelheim
Executive Vice President of Clinical and Medical Affairs at Perosphere
Director of Cardiac Catheterization Laboratories & Interventional Cardiology Guthrie Health Services at Guthrie Health Systems Robert Packer Hospital
Professor of Surgery and Director, Surgical Critical Care and Trauma Surgery Fellowships at The University of Texas Health Science Center at Houston
Cardiologist at Royal Brompton Hospital and Imperial College London
Director of the Institute of Cardiology at "G. d'Annunzio" University, Chieti
Hematology-Oncology Fellow at Boston Medical Center