ANMCO Position Paper: the use of non-vitamin K dependent new oral anticoagulant(s) in pulmonary embolism therapy and prevention

Abstract The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the ‘double drug single dose’ approach or with ‘single drug double dose’; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications. The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to conventional therapy and associated with fewer major bleeding events, which make their use in patients at higher risk of recurrences safer.

[1]  J. Hirsh,et al.  Edoxaban for the Treatment of Venous Thromboembolism in Patients with Cancer. , 2018, The New England journal of medicine.

[2]  A. Mafrici,et al.  Fulminant Pulmonary Embolism Successfully Treated with Thrombolysis , 2016 .

[3]  S. Vanni,et al.  Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model , 2016, European Respiratory Journal.

[4]  A. Moshyk,et al.  Clinical and economic benefits of extended treatment with apixaban for the treatment and prevention of recurrent venous thromboembolism in Canada , 2016, Journal of medical economics.

[5]  G. Raskob,et al.  Edoxaban for treatment of venous thromboembolism in patients with cancer , 2015, Thrombosis and Haemostasis.

[6]  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.

[7]  C. Zielinski,et al.  Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. , 2015, Thrombosis research.

[8]  M. D. de Gregorio,et al.  Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. , 2015, Chest.

[9]  M. Prins,et al.  Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism , 2015, Thrombosis and Haemostasis.

[10]  S. Goldhaber,et al.  A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. , 2015, JACC. Cardiovascular interventions.

[11]  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.

[12]  Bcps,et al.  Idarucizumab for dabigatran reversal , 2015 .

[13]  J. Kline,et al.  Immediate Discharge and Home Treatment With Rivaroxaban of Low‐risk Venous Thromboembolism Diagnosed in Two U.S. Emergency Departments: A One‐year Preplanned Analysis , 2015, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[14]  Kristine C. Willett,et al.  Dosing of Target-Specific Oral Anticoagulants in Special Populations , 2015, The Annals of pharmacotherapy.

[15]  G. Lippi,et al.  Cancer-associated thrombosis: investigating the role of new oral anticoagulants. , 2015, Thrombosis research.

[16]  E. Hawes,et al.  Heparin-Calibrated Chromogenic Anti-Xa Activity Measurements in Patients Receiving Rivaroxaban , 2015, The Annals of pharmacotherapy.

[17]  P. Prandoni The treatment of venous thromboembolism with novel oral anticoagulants: warnings and limitations. , 2015, Blood transfusion = Trasfusione del sangue.

[18]  M. Prins,et al.  Treatment of Pulmonary Embolism With Rivaroxaban: Outcomes by Simplified Pulmonary Embolism Severity Index Score from a Post Hoc Analysis of the EINSTEIN PE Study , 2015, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[19]  Y. Morishima,et al.  Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay. , 2015, American journal of clinical pathology.

[20]  F. Germini,et al.  Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. , 2015, Chest.

[21]  G. Hasenfuss,et al.  Age-adjusted high-sensitivity troponin T cut-off value for risk stratification of pulmonary embolism , 2015, European Respiratory Journal.

[22]  W. Ageno,et al.  Benefit–risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism , 2014, Thrombosis and Haemostasis.

[23]  F. Germini,et al.  Efficacy and safety of direct oral anticoagulants after pulmonary embolism: a meta-analysis. , 2014, International journal of cardiology.

[24]  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 .

[25]  W. Ageno,et al.  Meta‐analysis of the efficacy and safety of new oral anticoagulants in patients with cancer‐associated acute venous thromboembolism: comment , 2014, Journal of thrombosis and haemostasis : JTH.

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

[27]  Jose Luis Zamorano,et al.  The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS) , 2014 .

[28]  P. Dobesh,et al.  New Oral Anticoagulants for the Treatment of Venous Thromboembolism: Understanding Differences and Similarities , 2014, Drugs.

[29]  H. Büller,et al.  Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. , 2014, Blood.

[30]  R. Bauersachs Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups. , 2014, European journal of internal medicine.

[31]  L. Faxälv,et al.  Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti‐FXa assays , 2014, Journal of thrombosis and haemostasis : JTH.

[32]  J. Beyer-Westendorf,et al.  Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. , 2014, Blood.

[33]  P. Prandoni Treatment of patients with acute deep vein thrombosis and/or pulmonary embolism: efficacy and safety of non-VKA oral anticoagulants in selected populations. , 2014, Thrombosis research.

[34]  Huisman,et al.  Meta‐analysis of the efficacy and safety of new oral anticoagulants in patients with cancer‐associated acute venous thromboembolism , 2014, Journal of thrombosis and haemostasis : JTH.

[35]  D. Sobieraj,et al.  Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. , 2014, Thrombosis research.

[36]  M. Sebbane,et al.  Fibrinolysis for patients with intermediate-risk pulmonary embolism. , 2014, The New England journal of medicine.

[37]  S. Laporte,et al.  Consistency of safety profile of new oral anticoagulants in patients with renal failure , 2014, Journal of thrombosis and haemostasis : JTH.

[38]  S. Goldhaber,et al.  Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis , 2014, Circulation.

[39]  Ralf-Thorsten Hoffmann,et al.  Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism , 2014, Circulation.

[40]  A. Deal,et al.  Performance of coagulation tests in patients on therapeutic doses of rivaroxaban , 2014, Thrombosis and Haemostasis.

[41]  S. Schulman Advantages and limitations of the new anticoagulants , 2014, Journal of internal medicine.

[42]  Jeroen J. Bax,et al.  ESC Guidelines on the diagnosis and management of acute pulmonary embolism , 2014 .

[43]  K. Bauer Pros and cons of new oral anticoagulants. , 2013, Hematology. American Society of Hematology. Education Program.

[44]  G. Raskob,et al.  Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. , 2013, The New England journal of medicine.

[45]  G. Raskob,et al.  Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies , 2013, Thrombosis Journal.

[46]  Giancarlo Agnelli,et al.  Oral apixaban for the treatment of acute venous thromboembolism. , 2013, The New England journal of medicine.

[47]  A. Winkler,et al.  Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross‐sectional pharmacodynamic study based on peak and trough plasma levels , 2013, Journal of thrombosis and haemostasis : JTH.

[48]  M. Prins,et al.  Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep-vein thrombosis , 2013, Thrombosis and Haemostasis.

[49]  F. Klok,et al.  Long-term clinical course of acute pulmonary embolism. , 2013, Blood reviews.

[50]  G. Raskob,et al.  Edoxaban for the long‐term treatment of venous thromboembolism: rationale and design of the Hokusai‐venous thromboembolism study – methodological implications for clinical trials , 2013, Journal of thrombosis and haemostasis : JTH.

[51]  J. Reitsma,et al.  Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis , 2013, BMJ.

[52]  A. Camm,et al.  European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. , 2013, 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.

[53]  S. Goldhaber,et al.  Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. , 2013, The New England journal of medicine.

[54]  G. Raskob,et al.  Apixaban for extended treatment of venous thromboembolism. , 2013, The New England journal of medicine.

[55]  M. Sharifi,et al.  Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). , 2013, The American journal of cardiology.

[56]  Mapi Consultancy Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis , 2013 .

[57]  F. García-Bragado Dalmau [Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism]. , 2013, Revista clinica espanola.

[58]  C. Cuccia,et al.  Clinical features and short term outcomes of patients with acute pulmonary embolism. The Italian Pulmonary Embolism Registry (IPER). , 2012, Thrombosis research.

[59]  J. Douketis,et al.  Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH) , 2012, Journal of thrombosis and haemostasis : JTH.

[60]  Samuel Z Goldhaber,et al.  Pulmonary embolism and deep vein thrombosis , 2012, The Lancet.

[61]  P. Stein,et al.  Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. , 2012, The American journal of medicine.

[62]  G. Raskob,et al.  Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. , 2012, The New England journal of medicine.

[63]  P. J. O'Brien,et al.  Direct Thrombin Inhibitors , 2012, Journal of cardiovascular pharmacology and therapeutics.

[64]  Mark Crowther,et al.  Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. , 2012, Chest.

[65]  Paolo Prandoni,et al.  Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. , 2012, Chest.

[66]  W. Ageno,et al.  Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis , 2012 .

[67]  P. Kamphuisen,et al.  Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects , 2011, Circulation.

[68]  A. Tosetto,et al.  Questions and answers on the use of dabigatran and perspectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA). , 2011, Thrombosis and haemostasis.

[69]  P. Kamphuisen,et al.  Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents , 2011, Journal of thrombosis and haemostasis : JTH.

[70]  J. Gujral,et al.  Dabigatran falsely elevates point of care international normalized ratio results. , 2011, The American journal of medicine.

[71]  E. Nutescu,et al.  Drug and dietary interactions of warfarin and novel oral anticoagulants: an update , 2011, Journal of Thrombosis and Thrombolysis.

[72]  R. Gans,et al.  Oral rivaroxaban for symptomatic venous thromboembolism. , 2011, The New England journal of medicine.

[73]  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.

[74]  Lisa Moores,et al.  Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. , 2010, Archives of internal medicine.

[75]  D. Anderson,et al.  Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta‐analysis of the management outcome studies , 2010, Journal of thrombosis and haemostasis : JTH.

[76]  P. Wells,et al.  Systematic Review: Case-Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding Events Among Patients Treated for Venous Thromboembolism , 2010, Annals of Internal Medicine.

[77]  Georg Heinze,et al.  Risk Assessment of Recurrence in Patients With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism: The Vienna Prediction Model , 2010, Circulation.

[78]  K. Rathgen,et al.  Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate , 2010, Clinical pharmacokinetics.

[79]  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.

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

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

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

[83]  David Anderson,et al.  Subsegmental Pulmonary Embolism Diagnosed by Computed Tomography: Incidence and Clinical Implications. A Systematic Review and Meta-Analysis of the Management Outcome Studies. , 2009 .

[84]  Piotr Pruszczyk,et al.  [Guidelines on the diagnosis and management of acute pulmonary embolism]. , 2009, Giornale italiano di cardiologia.

[85]  B. Eriksson,et al.  Comparative Pharmacodynamics and Pharmacokinetics of Oral Direct Thrombin and Factor Xa Inhibitors in Development , 2009, Clinical pharmacokinetics.

[86]  Arnaud Perrier,et al.  Simplification of the revised Geneva score for assessing clinical probability of pulmonary embolism. , 2008, Archives of internal medicine.

[87]  Piotr Pruszczyk,et al.  Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism , 2008 .

[88]  S. Kahn,et al.  Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy , 2008, Canadian Medical Association Journal.

[89]  Patrick M Bossuyt,et al.  Further validation and simplification of the Wells clinical decision rule in pulmonary embolism , 2007, Thrombosis and Haemostasis.

[90]  G. Raskob,et al.  Idraparinux versus standard therapy for venous thromboembolic disease. , 2007, The New England journal of medicine.

[91]  Samuel Z Goldhaber,et al.  Treatment of Proximal Deep-Vein Thrombosis With the Oral Direct Factor Xa Inhibitor Rivaroxaban (BAY 59-7939): The ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) Study , 2007, Circulation.

[92]  M. Monreal,et al.  Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry , 2006, Journal of thrombosis and haemostasis : JTH.

[93]  Arnaud Perrier,et al.  Prediction of Pulmonary Embolism in the Emergency Department: The Revised Geneva Score , 2006, Annals of Internal Medicine.

[94]  K. Bauer New Anticoagulants: Anti IIa vs Anti Xa—Is One Better? , 2006, Journal of Thrombosis and Thrombolysis.

[95]  Roslyn A Stone,et al.  Derivation and validation of a prognostic model for pulmonary embolism. , 2005, American journal of respiratory and critical care medicine.

[96]  G. Wensing,et al.  Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59‐7939, an oral, direct factor Xa inhibitor , 2005, Clinical pharmacology and therapeutics.

[97]  Paul D Stein,et al.  Obesity as a risk factor in venous thromboembolism. , 2005, The American journal of medicine.

[98]  D. Ost,et al.  Duration of anticoagulation following venous thromboembolism: a meta-analysis. , 2005, JAMA.

[99]  H. Salem Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis , 2005 .

[100]  C. Francis,et al.  Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. , 2005, JAMA.

[101]  E. Wood,et al.  Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis , 2004, The Medical journal of Australia.

[102]  J. Eikelboom,et al.  Thrombolysis Compared With Heparin for the Initial Treatment of Pulmonary Embolism: A Meta-Analysis of the Randomized Controlled Trials , 2004, Circulation.

[103]  G. Raskob,et al.  Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis , 2004, Annals of Internal Medicine.

[104]  E. Schuetz,et al.  Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein , 2002, Journal of Pharmacology and Experimental Therapeutics.

[105]  G. Kovacs,et al.  Excluding Pulmonary Embolism at the Bedside without Diagnostic Imaging: Management of Patients with Suspected Pulmonary Embolism Presenting to the Emergency Department by Using a Simple Clinical Model and d-dimer , 2001, Annals of Internal Medicine.

[106]  M Gent,et al.  Derivation of a Simple Clinical Model to Categorize Patients Probability of Pulmonary Embolism: Increasing the Models Utility with the SimpliRED D-dimer , 2000, Thrombosis and Haemostasis.

[107]  G. Raskob,et al.  Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. , 1990, The New England journal of medicine.