Novel oral anticoagulants: focus on stroke prevention and treatment of venous thrombo-embolism

Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents.

[1]  B. Nieswandt,et al.  Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke , 2011, Journal of thrombosis and haemostasis : JTH.

[2]  J. Nunnelee.  Review of an article: oral rivaroxaban for symptomatic venous thromboembolism. The EINSTEIN Investigators et al. N Engl J Med 2010; 363(26):2499-2510. , 2011, Journal of vascular nursing : official publication of the Society for Peripheral Vascular Nursing.

[3]  Kenneth A Ellenbogen,et al.  2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. , 2011, Circulation.

[4]  Jun Zhu,et al.  Apixaban in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[5]  B. Eriksson,et al.  Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II) , 2011, Thrombosis and Haemostasis.

[6]  R. P. Zhu,et al.  Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation , 2011, Annals of Internal Medicine.

[7]  T. Lindahl,et al.  Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays , 2011, Journal of thrombosis and haemostasis : JTH.

[8]  G. Raskob,et al.  Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis , 2011, Journal of thrombosis and haemostasis : JTH.

[9]  Bruce L Davidson,et al.  Oral rivaroxaban for symptomatic venous thromboembolism. , 2010, The New England journal of medicine.

[10]  G. Raskob,et al.  Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. , 2010, The New England journal of medicine.

[11]  M. Gent,et al.  Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty , 2010, Thrombosis and Haemostasis.

[12]  S. Yusuf,et al.  Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial , 2010, The Lancet Neurology.

[13]  T. Ortel,et al.  Assays for Measuring Rivaroxaban: Their Suitability and Limitations , 2010, Therapeutic drug monitoring.

[14]  T. Lindahl,et al.  Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays , 2010, Thrombosis and Haemostasis.

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

[16]  A. Shenker,et al.  Clinical laboratory measurement of direct factor Xa inhibitors: Anti-Xa assay is preferable to prothrombin time assay , 2010, Thrombosis and Haemostasis.

[17]  F. Gao,et al.  Apixaban versus enoxaparin in patients with total knee arthroplasty , 2010, Thrombosis and Haemostasis.

[18]  Jeroen J. Bax,et al.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). , 2010, 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.

[19]  E. Antman,et al.  Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). , 2010, American heart journal.

[20]  A. Camm,et al.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). , 2010, European heart journal.

[21]  Salim Yusuf,et al.  Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial , 2010, The Lancet.

[22]  C. Francis,et al.  Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. , 2010, Thrombosis research.

[23]  H. Masumoto,et al.  Clinical Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Factor Xa Inhibitor Edoxaban in Healthy Volunteers , 2010, Journal of clinical pharmacology.

[24]  P. Cortez,et al.  Reversibility of the anti‐FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion , 2010, Journal of thrombosis and haemostasis : JTH.

[25]  M. Feuring,et al.  Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity , 2010, Thrombosis and Haemostasis.

[26]  G. Raskob,et al.  Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial , 2010, The Lancet.

[27]  S. Yusuf,et al.  Dabigatran Versus Warfarin in Patients With Atrial Fibrillation: An Analysis of Patients Undergoing Cardioversion , 2010, Circulation.

[28]  B. Gersh,et al.  Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. , 2010, American heart journal.

[29]  V. Laux,et al.  Rivaroxaban: A New Oral Factor Xa Inhibitor , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[30]  S. Goldhaber,et al.  Dabigatran versus warfarin in the treatment of acute venous thromboembolism. , 2009, The New England journal of medicine.

[31]  G. Raskob,et al.  Apixaban or enoxaparin for thromboprophylaxis after knee replacement. , 2009, The New England journal of medicine.

[32]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[33]  J. Harenberg.  Development of idraparinux and idrabiotaparinux for anticoagulant therapy , 2009, Thrombosis and Haemostasis.

[34]  T. Lüscher,et al.  Novel anticoagulants in clinical development: focus on factor Xa and direct thrombin inhibitors , 2009, Journal of cardiovascular medicine.

[35]  J. Mega,et al.  Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial , 2009, The Lancet.

[36]  Deepak L. Bhatt,et al.  Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome: Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial , 2009, Circulation.

[37]  M. Gent,et al.  Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial , 2009, The Lancet.

[38]  P. Wong,et al.  Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro , 2009, Thrombosis and Haemostasis.

[39]  A. Tripodi,et al.  Laboratory monitoring of anticoagulation: where do we stand? , 2009, Seminars in thrombosis and hemostasis.

[40]  W. Humphreys,et al.  Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans , 2009, Drug Metabolism and Disposition.

[41]  David J. Gladstone,et al.  Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated , 2009, Stroke.

[42]  M. Prins,et al.  Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose‐ranging study , 2008, Journal of thrombosis and haemostasis : JTH.

[43]  Bengt I Eriksson,et al.  Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial , 2008, The Lancet.

[44]  W. Ageno,et al.  Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. , 2008, The New England journal of medicine.

[45]  B. Eriksson,et al.  Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. , 2008, The New England journal of medicine.

[46]  G. Guyatt,et al.  Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). , 2008, Chest.

[47]  P. Lam,et al.  Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies , 2008, Journal of thrombosis and haemostasis : JTH.

[48]  P. Prandoni,et al.  Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders , 2008, Expert opinion on investigational drugs.

[49]  S. Frostick,et al.  Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial , 2007, Journal of thrombosis and haemostasis : JTH.

[50]  S. Frostick,et al.  Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial , 2007, The Lancet.

[51]  K. Rathgen,et al.  The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. , 2007, British journal of clinical pharmacology.

[52]  M. Aguilar,et al.  Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation , 2007, Annals of Internal Medicine.

[53]  Salim Yusuf,et al.  Comparison of fondaparinux and enoxaparin in acute coronary syndromes. , 2006, The New England journal of medicine.

[54]  S. Yusuf,et al.  Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. , 2006, JAMA.

[55]  T. Lüscher,et al.  Tissue Factor in Cardiovascular Diseases: Molecular Mechanisms and Clinical Implications , 2006, Circulation.

[56]  Mark Crowther,et al.  Systematic overview of warfarin and its drug and food interactions. , 2005, Archives of internal medicine.

[57]  K. Schlemmer,et al.  In vitro and in vivo studies of the novel antithrombotic agent BAY 59‐7939—an oral, direct Factor Xa inhibitor , 2005, Journal of thrombosis and haemostasis : JTH.

[58]  J. Hirsh,et al.  The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[59]  M. Schenone,et al.  The blood coagulation cascade , 2004, Current opinion in hematology.

[60]  A. Wittkowsky.  Warfarin and Other Coumarin Derivatives: Pharmacokinetics, Pharmacodynamics, and Drug Interactions , 2003, Seminars in vascular medicine.

[61]  George Davey Smith,et al.  Meta-analysis of randomised controlled trials , 1997, The Lancet.

[62]  T. Andersson,et al.  Drug-induced liver injury in humans: the case of ximelagatran. , 2010, Handbook of experimental pharmacology.

[63]  G. Raskob,et al.  Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. , 2009, The Journal of arthroplasty.

[64]  J. Stangier.  Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate , 2008, Clinical pharmacokinetics.

[65]  R. O'Reilly,et al.  Warfarin metabolism and drug-drug interactions. , 1987, Advances in experimental medicine and biology.