Skip to main content
SpringerLink
Log in

Transitioning Between Anticoagulants

  • Chapter
  • First Online:
Anticoagulation Therapy

  • 2042 Accesses

Abstract

There has been rapid growth in the development of anticoagulant drugs. Unfortunately, an “ideal” anticoagulant—one that is rapid-acting and fully reversible, does not require monitoring, and can be used in patients with end-stage renal disease and moderate-severe liver dysfunction—is not available to date. Currently, the differences in the pharmacokinetic and pharmacodynamic properties of each agent allow for a unique, individualized anticoagulation plan for different patients with different underlying indications for anticoagulation therapy. Because of the multiple options for both parenteral and oral anticoagulation available, transitioning between anticoagulants is becoming increasingly common both in the inpatient and outpatient settings. Given the absence of prospective randomized data comparing different strategies for transition between anticoagulants, suggested strategies are largely extrapolated from pharmacokinetic data, as well as from expert opinions. Despite limited data, better understanding on how to safely implement a transition from one anticoagulant drug to another is of utmost importance to minimize the risk of recurrent thromboembolic events and hemorrhagic complications during such periods of transition between different drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:188S–203S.

    Article  CAS  Google Scholar 

  2. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med. 1995;155:601–7.

    Article  CAS  Google Scholar 

  3. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med. 1996;100:269–77.

    Article  CAS  Google Scholar 

  4. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334:677–81.

    Article  CAS  Google Scholar 

  5. Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasma Study Group. N Engl J Med. 1996;334:682–7.

    Article  CAS  Google Scholar 

  6. Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:265S–86S.

    Article  CAS  Google Scholar 

  7. Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140:867–73.

    Article  Google Scholar 

  8. The MATISSE Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695–702.

    Article  Google Scholar 

  9. Harenberg J. Development of idraparinux and idrabiotaparinux for anticoagulant therapy. Thromb Haemost. 2009;102:811–5.

    Article  CAS  Google Scholar 

  10. Büller HR, Gallus AS, Zpillion G, et al. Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial. Lancet. 2012;379:123–9.

    Article  Google Scholar 

  11. The EQUINOX Investigators. Efficacy and safety of once weekly idrabiotaparinux in the treatment of patient with symptomatic deep venous thrombosis. J Thromb Haemost. 2011;9:92–9.

    Article  Google Scholar 

  12. Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med. 2004;164:361–9.

    Article  CAS  Google Scholar 

  13. Joseph L, Casanegra AI, Dhariwal M, et al. Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia. J Thromb Haemost. 2014;12:1044–55.

    Article  CAS  Google Scholar 

  14. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.

    Article  CAS  Google Scholar 

  15. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.

    Article  CAS  Google Scholar 

  16. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.

    Article  CAS  Google Scholar 

  17. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.

    Article  CAS  Google Scholar 

  18. Schulman S, Kearon K, Kakkar AJ, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–52.

    Article  CAS  Google Scholar 

  19. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.

    Article  Google Scholar 

  20. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.

    Article  Google Scholar 

  21. Agnelli G, Büller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699–708.

    Article  CAS  Google Scholar 

  22. Agnelli G, Büller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.

    Article  CAS  Google Scholar 

  23. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.

    Article  Google Scholar 

  24. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13):1211–22. https://doi.org/10.1056/NEJMoa1700518.

    Article  CAS  PubMed  Google Scholar 

  25. Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e120S–51S.

    Article  CAS  Google Scholar 

  26. Abildgaard U. Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest. 1968;21:89–91.

    Article  CAS  Google Scholar 

  27. Rosenberg R, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci U S A. 1979;76:1218–22.

    Article  CAS  Google Scholar 

  28. Lindahl U, Backstrom G, Hook M, et al. Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci U S A. 1979;76:3198–202.

    Article  CAS  Google Scholar 

  29. Rosenberg R, Bauer K. The heparin-antithrombin system: a natural anticoagulant mechanism. 3rd ed. Philadelphia, PA: Lippincott; 1994.

    Google Scholar 

  30. Casu B, Oreste P, Torri G, et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Biochem J. 1981;97:599–609.

    Article  Google Scholar 

  31. Choay J, Lormeau J, Petitou M, et al. Structural studies on a biologically active hexasaccharide obtained from heparin. Ann N Y Acad Sci. 1981;370:644–9.

    Article  CAS  Google Scholar 

  32. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (6th Edition). Chest. 2001;119:64S–94S.

    Article  CAS  Google Scholar 

  33. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e24S–43S.

    Article  CAS  Google Scholar 

  34. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncologia. 2013;31:2189–204.

    Article  CAS  Google Scholar 

  35. Carrier M, Cameron C, Delluc A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134:1214–9.

    Article  CAS  Google Scholar 

  36. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest. 2016;149:315–52.

    Article  Google Scholar 

  37. Choay J, Petitou M, Lormeau JC, et al. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun. 1983;116:492–9.

    Article  CAS  Google Scholar 

  38. Thunberg L, Bäckström G, Lindahl U. Further characterization of the antithrombin-binding sequence in heparin. Carbohydr Res. 1982;100:393–410.

    Article  CAS  Google Scholar 

  39. Choay J. Biologic studies on chemically synthesized pentasaccharide and tetrasaccharide fragments. Semin Thromb Hemost. 1985;11:81–5.

    Article  CAS  Google Scholar 

  40. Toschi V, Lettino M, Gallo R, et al. Biochemistry and biology of hirudin. Coron Artery Dis. 1996;7:420–8.

    Article  CAS  Google Scholar 

  41. Wallis RB. Hirudins: from leeches to man. Semin Thromb Hemost. 1996;22:185–96.

    Article  CAS  Google Scholar 

  42. Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost. 1993;69:157–63.

    CAS  PubMed  Google Scholar 

  43. Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol. 2000;12(Suppl F):33F–6F.

    PubMed  Google Scholar 

  44. Hursting MJ, Alford KL, Becker JC, et al. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost. 1997;23:503–16.

    Article  CAS  Google Scholar 

  45. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy. 2000;20:318–29.

    Article  CAS  Google Scholar 

  46. Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A. 1974;71:2730–3.

    Article  CAS  Google Scholar 

  47. Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin. J Biol Chem. 1974;249:6347–50.

    CAS  PubMed  Google Scholar 

  48. Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978;17:1371–7.

    Article  CAS  Google Scholar 

  49. Friedman PA, Rosenberg RD, Hauschka PV, Fitz-James A. A spectrum of partially carboxylated prothrombins in the plasmas of coumarin-treated patients. Biochim Biophys Acta. 1977;494:271–6.

    Article  CAS  Google Scholar 

  50. Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. J Biol Chem. 1985;260:279–87.

    CAS  PubMed  Google Scholar 

  51. Choonara IA, Malia RG, Haynes BP, et al. The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. Br J Clin Pharmacol. 1988;25:1–7.

    Article  CAS  Google Scholar 

  52. Wessler S, Gitel SN. Warfarin. From bedside to bench. N Engl J Med. 1984;311:645–52.

    Article  CAS  Google Scholar 

  53. Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest. 1993;92:2131–40.

    Article  CAS  Google Scholar 

  54. Breckenridge AM. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol. 1978;15:19–26.

    CAS  PubMed  Google Scholar 

  55. Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979;4:1–15.

    Article  CAS  Google Scholar 

  56. Nutescu EA, Chuatrisom I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326–43.

    Article  CAS  Google Scholar 

  57. Nutescu EA, Shapiro NL, Chevalier A. New anticoagulant agents: direct thrombin inhibitors. Cardiol Clin. 2008;26:169–87. v–vi.

    Article  Google Scholar 

  58. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292–303.

    Article  CAS  Google Scholar 

  59. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e44S–88S.

    Article  CAS  Google Scholar 

  60. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47:285–95.

    Article  CAS  Google Scholar 

  61. Stangier J, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49:259–68.

    Article  CAS  Google Scholar 

  62. Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost. 2009;101:780–2.

    CAS  PubMed  Google Scholar 

  63. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37:74–81.

    Article  CAS  Google Scholar 

  64. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873–80.

    Article  CAS  Google Scholar 

  65. Mueck W, Becka M, Kubitza D, et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in healthy subjects. Int J Clin Pharmacol Ther. 2007;45:335–44.

    Article  CAS  Google Scholar 

  66. Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743–53.

    Article  CAS  Google Scholar 

  67. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376:975–83.

    Article  CAS  Google Scholar 

  68. Warkentin TE, Greinacher A, Craven S, et al. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost. 2005;94:958–64.

    CAS  PubMed  Google Scholar 

  69. Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis. 2005;19:183–8.

    Article  CAS  Google Scholar 

  70. Argatroban. Highlights of prescribing information. Revised 05/2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022485s009lbl.pdf.

  71. Watson H, Davidson S, Keeling D. Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol. 2012;159:528–40.

    PubMed  Google Scholar 

  72. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin. Pharmacotherapy. 2005;25:157–64.

    Article  CAS  Google Scholar 

  73. Bartholomew J. Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Chest. 2005;127:27S–34S.

    Article  Google Scholar 

  74. Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost. 2005;11:279–87.

    Article  CAS  Google Scholar 

  75. Kinkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e495S–530S.

    Article  Google Scholar 

  76. Pradaxa. Highlights of prescribing information. Revised 11/2015. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf.

  77. Eliquis. Highlights of prescribing information. Revised 07/2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202155s012lbl.pdf.

  78. Xarelto. Highlights of prescribing information. Revised 05/2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202439s017lbl.pdf.

  79. Savaysa. Highlights of prescribing information. Revised 09/2016. https://hemonc.org/w/images/9/96/Edoxaban.pdf.

  80. Shatzel JJ, Crapster-Pregont M, Seloughery TG. Non-vitamin K antagonist oral anticoagulants for heparin-induced thrombocytopenia. A systematic review of 54 reported cases. Thromb Haemost. 2016;116:397–400.

    Article  Google Scholar 

  81. Baruch L, Sherman O. Potential inaccuracy of point-of-care INR in dabigatran-treated patients. Ann Pharmacother. 2011;45(7–8):e40.

    PubMed  Google Scholar 

  82. Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban: an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815–25.

    Article  CAS  Google Scholar 

  83. Moore KT, Byra W, Vaidyanathan S, et al. Switching from rivaroxaban to warfarin: an open-label pharmacodynamic study in healthy subjects. Br J Clin Pharmacol. 2014;79:907–17.

    Article  Google Scholar 

  84. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17:1467–507.

    Article  Google Scholar 

  85. Ruff CT, Giugliano RP, Braunwald E, Mercuri M, Curt V, Betcher J, et al. Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol. 2014;64:576–84.

    Article  Google Scholar 

  86. Granger C, Alexander JH, Hanna M, Wang J, Mohan P, Lawrence J, et al. Events after discontinuation of randomized treatment at the end of the ARISTOTLE trial. Eur Heart J. 2012;33(Suppl):685–6. (Abstract).

    Google Scholar 

  87. Granger CB, Lopes RD, Hanna M, Ansell J, Hylek EM, Alexander JH, et al. Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J. 2015;169:25–30.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Section of Vascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    Maya Serhal & Marcelo P. V. Gomes

Authors
  1. Maya Serhal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcelo P. V. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcelo P. V. Gomes .

Editor information

Editors and Affiliations

  1. Associate Professor of Cardiology, Department of Cardiology, Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Manhasset, New York, USA

    Joe F. Lau

  2. Assistant Professor, Division of Internal Medicine, Frankel Cardiovascular Center at the University of Michigan, Ann Arbor, Michigan, USA

    Geoffrey D. Barnes

  3. Professor of Medicine and Pathology, Division of Hematology, Department of Medicine, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA

    Michael B. Streiff

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Serhal, M., Gomes, M.P.V. (2018). Transitioning Between Anticoagulants. In: Lau, J., Barnes, G., Streiff, M. (eds) Anticoagulation Therapy . Springer, Cham. https://doi.org/10.1007/978-3-319-73709-6_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-73709-6_7

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-73708-9

  • Online ISBN: 978-3-319-73709-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation