Reversal strategies for non-vitamin K antagonist oral anticoagulants: a critical appraisal of available evidence and recommendations for clinical management—a joint position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology

Bleeding is the main adverse effect when using oral anticoagulants (OACs). The risk of major bleeding with vitamin K antagonists (VKAs) is dependent on the quality of anticoagulation control and estimated to be ∼1.3/100 patients/year in patients with INR 2.0–3.0.1,2 Multiple limitations of VKAs stimulated the development of non-vitamin K antagonist oral anticoagulants (NOACs) acting directly on coagulation factors, including factor FIIa (thrombin) and FXa. Pharmacological properties of the NOACs relevant for bleeding are summarized in the supplement including Supplementary material online, Table S1 and their main effects are summarized in Supplementary material online, Table S2 . The risk of bleeding in patients managed with NOACs was properly assessed in the four landmark Phase III trials in patients with atrial fibrillation (AF; Table 1 ). Major bleeding was the principal safety outcome in RE-LY,3,4 ARISTOTLE,5 and ENGAGE AF.6 In ROCKET-AF, the primary safety endpoint was the composite of major and non-major clinically relevant bleeding.7 The risk of major bleeding was significantly reduced with dabigatran 110 mg b.i.d., apixaban and both doses of edoxaban3–6 while the bleeding rates for dabigatran 150 mg b.i.d. and rivaroxaban were similar to those with warfarin ( Table 1 ). View this table: Table 1 Risk of bleeding with non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation (rates per 100 patients-years) Gastrointestinal (GI) bleeding accounts for ∼90% of major extracranial haemorrhages in patients with AF receiving VKAs.8 With the NOACs, dabigatran 150 mg b.i.d., rivaroxaban, and edoxaban 60 mg o.d. significantly increased rates of GI bleeding (∼1.5-fold) compared with warfarin.3,6,7 While rivaroxaban increases upper and lower GI bleeding …

[1]  G. Lip,et al.  Anticoagulation reversal in the era of the non-vitamin K oral anticoagulants. , 2016, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[2]  B. Cheung,et al.  Gastrointestinal haemorrhage in atrial fibrillation patients: impact of quality of anticoagulation control. , 2015, European heart journal. Cardiovascular pharmacotherapy.

[3]  A. Camm,et al.  Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. , 2015, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[4]  S. Glund,et al.  Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial , 2015, The Lancet.

[5]  G. Lip,et al.  Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding: A Nationwide Cohort Study , 2015, Circulation.

[6]  T. Steiner,et al.  Idarucizumab for Dabigatran Reversal. , 2015, The New England journal of medicine.

[7]  Jonathan H Seltzer,et al.  Novel oral anticoagulants and reversal agents: Considerations for clinical development. , 2015, American heart journal.

[8]  T. Steiner,et al.  Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran , 2015, Thrombosis and Haemostasis.

[9]  S. Glund,et al.  A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran , 2015, Thrombosis and Haemostasis.

[10]  S. Connolly,et al.  ANNEXATM-R: A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL, DEMONSTRATING REVERSAL OF RIVAROXABAN-INDUCED ANTICOAGULATION IN OLDER SUBJECTS BY ANDEXANET ALFA (PRT064445), A UNIVERSAL ANTIDOTE FOR FACTOR XA (FXA) INHIBITORS , 2015 .

[11]  Mark Levenson,et al.  Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation , 2015, Circulation.

[12]  E. Antman,et al.  Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate , 2015, Circulation.

[13]  R. Giugliano,et al.  A novel approach indirectly comparing benefit-risk balance across anti-thrombotic therapies in patients with atrial fibrillation. , 2015, European heart journal. Cardiovascular pharmacotherapy.

[14]  S. Glund,et al.  Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects , 2014 .

[15]  S. Connolly,et al.  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal of Edoxaban-Induced Anticoagulation in Healthy Subjects By Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors , 2014 .

[16]  J. Ansell,et al.  Use of PER977 to reverse the anticoagulant effect of edoxaban. , 2014, The New England journal of medicine.

[17]  S. Glund,et al.  Abstract 18403: Effect of Dabigatran on the Ability to Generate Fibrin at a Wound site and its Reversal by Idarucizumab, the Antidote to Dabigatran, in Healthy Volunteers: An Exploratory Marker of Blood Loss , 2014 .

[18]  P. Conley,et al.  Abstract 14657: Andexanet-alfa and PER977 (Arapazine) Correct Blood Loss in a Rabbit Liver Laceration Model - Only Andexanet Reverses Markers of fXa-mediated Anticoagulation , 2014 .

[19]  H. Tomita,et al.  Characteristics of Intracerebral Hemorrhage During Rivaroxaban Treatment: Comparison With Those During Warfarin , 2014, Stroke.

[20]  R. de Caterina,et al.  Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. , 2014, Journal of the American College of Cardiology.

[21]  Alexander Parkhomenko,et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials , 2014, The Lancet.

[22]  G. Lip,et al.  Patient outcomes using the European label for dabigatran , 2013, Thrombosis and Haemostasis.

[23]  A. Gómez-Outes,et al.  Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups , 2013, Thrombosis.

[24]  E. Antman,et al.  Edoxaban versus warfarin in patients with atrial fibrillation. , 2013, The New England journal of medicine.

[25]  H. Masumoto,et al.  Abstract 18809: PER977: A Synthetic Small Molecule Which Reverses Over-Dosage and Bleeding by the New Oral Anticoagulants , 2013, Circulation.

[26]  S. Yusuf,et al.  Management and Outcomes of Major Bleeding During Treatment With Dabigatran or Warfarin , 2013, Circulation.

[27]  S. Connolly,et al.  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal Of Rivaroxaban-Induced Anticoagulation In Healthy Subjects By Andexanet Alfa (PRT064445), An Antidote For Fxa Inhibitors , 2013 .

[28]  G. Lip,et al.  Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation , 2013, Thrombosis and Haemostasis.

[29]  J. Goldstein,et al.  Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding: A Randomized, Plasma-Controlled, Phase IIIb Study , 2013, Circulation.

[30]  H. Masumoto,et al.  A synthetic small molecule antidote for anticoagulants , 2013 .

[31]  A. Camm,et al.  EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. , 2013, European heart journal.

[32]  G. Lip,et al.  Efficacy and safety of dabigatran etexilate and warfarin in "real-world" patients with atrial fibrillation: a prospective nationwide cohort study. , 2013, Journal of the American College of Cardiology.

[33]  D. Lillicrap.  Translational medicine advances in von Willebrand disease , 2013, Journal of thrombosis and haemostasis : JTH.

[34]  H. Nar,et al.  A specific antidote for dabigatran: functional and structural characterization. , 2013, Blood.

[35]  P. Conley,et al.  A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa , 2013, Nature Medicine.

[36]  E. Dolgin.  Antidotes edge closer to reversing effects of new blood thinners , 2013, Nature Medicine.

[37]  D. Siegal,et al.  Acute management of bleeding in patients on novel oral anticoagulants. , 2013, European heart journal.

[38]  G. Lip,et al.  Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a "real-world" population with atrial fibrillation receiving anticoagulant therapy. , 2013, Chest.

[39]  E. Mathiowitz,et al.  Abstract 11395: Small Molecule Antidote for Anticoagulants , 2012 .

[40]  S. Hohnloser,et al.  Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial , 2012, The Lancet.

[41]  Gerhard Hindricks,et al.  2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. , 2012, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[42]  Jeroen J. Bax,et al.  2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. , 2012, European heart journal.

[43]  J. Douketis,et al.  Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors , 2012, American journal of hematology.

[44]  M. Crowther,et al.  Prothrombin complex concentrate (PCC, Octaplex) in patients requiring immediate reversal of vitamin K antagonist anticoagulation. , 2012, Thrombosis research.

[45]  S. Schulman,et al.  Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. , 2012, Thrombosis research.

[46]  D. Atar,et al.  Apixaban versus warfarin in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[47]  G. Breithardt,et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. , 2011, The New England journal of medicine.

[48]  W. Ageno,et al.  Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists , 2011, Thrombosis and Haemostasis.

[49]  I. Olkin,et al.  Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications , 2011, Annals of Internal Medicine.

[50]  Gregory Y H Lip,et al.  Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. , 2011, Journal of the American College of Cardiology.

[51]  M. Levi,et al.  Safety of recombinant activated factor VII in randomized clinical trials. , 2010, The New England journal of medicine.

[52]  S. Yusuf,et al.  Newly identified events in the RE-LY trial. , 2010, The New England journal of medicine.

[53]  Gregory Y H Lip,et al.  A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. , 2010, Chest.

[54]  Leon Poller,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[55]  Vivian Charles McAlister,et al.  Use of Recombinant Activated Factor VII in Patients Without Hemophilia: A Meta-Analysis of Randomized Control Trials , 2008, Annals of surgery.

[56]  S. Mayer,et al.  Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. , 2008, The New England journal of medicine.

[57]  S. Knaub,et al.  Prothrombin complex concentrate (Beriplex® P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial , 2008, Journal of thrombosis and haemostasis : JTH.

[58]  D. Singer,et al.  Death and disability from warfarin-associated intracranial and extracranial hemorrhages. , 2007, The American journal of medicine.

[59]  R. de Caterina,et al.  Anticoagulants in heart disease: current status and perspectives. , 2007, European heart journal.

[60]  Dougald M Monroe,et al.  The use of recombinant factor VIIa in the treatment of bleeding disorders. , 2004, Blood.

[61]  R. Zimlichman,,et al.  Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. , 2004, Thrombosis research.

[62]  S. Kitchen,et al.  Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients , 2002, British journal of haematology.