Oral Anticoagulation in 2017
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Published:
Sep 20, 2018
Keywords:
warfarin, dabigatran, anti-Xa agents, idarucizumab
Main Article Content
Abstract
In this paper we describe the properties and clinical use of new anticoagulants:dabigatran (a direct thrombin inhibitor) and direct anti-Xa agents (rivaroxaban, apixaban,edoxaban ). Major studies that have been performed with these agents in comparisonwith warfarin are reported. Recommendations for use in clinical practice are provided.Information on the disappearance of the anticoagulant effect after stopping drug intakeand on the administration of agents that neutralize the effect of the new anticoagulantis provided.
Article Details
How to Cite
1.
Vanassche T, Frans FVDW. Oral Anticoagulation in 2017. BKK Med J [Internet]. 2018 Sep. 20 [cited 2024 Nov. 22];14(2):81. Available from: https://he02.tci-thaijo.org/index.php/bkkmedj/article/view/222564
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Reviews Article
This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
References
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4. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapyfor atrial fibrillation: Antithrombotic Therapy and Preventionof Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines. Chest2012;141:e531S-75S.
5. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelinesfor the management of atrial fibrillation developed incollaboration with EACTS: The Task Force for the managementof atrial fibrillation of the European Society of Cardiology(ESC)Developed with the special contribution of theEuropean Heart Rhythm Association (EHRA) of theESCEndorsed by the European Stroke Organisation (ESO).Eur Heart J 2016.
6. Heidbuchel H, Verhamme P, Alings M, et al. EHRA PracticalGuide on the use of new oral anticoagulants in patients withnon-valvular atrial fibrillation: executive summary. Eur Heart J2013.
7. Stangier J. Clinical pharmacokinetics and pharmacodynamicsof the oral direct thrombin inhibitor dabigatran etexilate. ClinPharmacokinet 2008;47:285-95.
8. Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral directfactor Xa inhibitor, inhibits human clot-bound factor Xaactivity in vitro. Thromb Haemost 2009;101:780-2.
9. Laux V, Perzborn E, Kubitza D, et al. Preclinical and clinicalcharacteristics of rivaroxaban: a novel, oral, direct factor Xainhibitor. Semin Thromb Hemost 2007;33:515-23.
10. Partida RA, Giugliano RP. Edoxaban: pharmacologicalprinciples, preclinical and early-phase clinical testing. FutureCardiol 2011;7:459-70.
11. Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, directand highly selective factor Xa inhibitor: in vitro, antithromboticand antihemostatic studies. J Thromb Haemost 2008;6:820-9.
12. EMA EMA. PRADAXA - EPAR Product Information -Summary of Product Characteristics. 2016.
13. Blech S, Ebner T, Ludwig-Schwellinger E, et al. Themetabolism and disposition of the oral direct thrombininhibitor, dabigatran, in humans. Drug Metab Dispos2008;36:386-99.
14. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokineticprofile of the oral direct thrombin inhibitor dabigatranetexilate in healthy volunteers and patients undergoing totalhip replacement. J Clin Pharmacol 2005;45:555-63.
15. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics,pharmacodynamics and tolerability of dabigatran etexilate, anew oral direct thrombin inhibitor, in healthy male subjects.Br J Clin Pharmacol 2007;64:292-303.
16. Stangier J, Rathgen K, Stahle H, et al. Influence of renalimpairment on the pharmacokinetics and pharmacodynamicsof oral dabigatran etexilate: an open-label, parallel-group,single-centre study. Clin Pharmacokinet 2010;49:259-68.
17. European Medicines Agency E. XARELTO - EPAR ProductInformation - Summary of Product Characteristics. 2016.
18. European Medicines Agency E. ELIQUIS - EPAR ProductInformation - Summary of Product Characteristics. 2016.
19. European Medicines Agency E. LIXIANA - EPAR ProductInformation - Summary of Product Characteristics. 2016.
20. Heidbuchel H, Verhamme P, Alings M, et al. UpdatedEuropean Heart Rhythm Association Practical Guide on theuse of non-vitamin K antagonist anticoagulants in patientswith non-valvular atrial fibrillation. Europace 2015;17:1467-507.
21. Buller H, Deitchman D, Prins M, et al. Efficacy and safety ofthe oral direct factor Xa inhibitor apixaban for symptomaticdeep vein thrombosis. The Botticelli DVT dose-ranging study.J Thromb Haemost 2008;6:1313-8.
22. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism andpharmacokinetics after oral administration to humans. DrugMetab Dispos 2009;37:74-81.
23. Kubitza D, Becka M, Roth A, et al. Dose-escalation study ofthe pharmacokinetics and pharmacodynamics of rivaroxabanin healthy elderly subjects. Curr Med Res Opin 2008;24:2757-65.
24. Lang D, Freudenberger C, Weinz C. In vitro metabolism ofrivaroxaban, an oral, direct factor Xa inhibitor, in livermicrosomes and hepatocytes of rats, dogs, and humans. DrugMetab Dispos 2009;37:1046-55.
25. Wang L, Zhang D, Raghavan N, et al. In vitro assessment ofmetabolic drug-drug interaction potential of apixaban throughcytochrome P450 phenotyping, inhibition, and inductionstudies. Drug Metab Dispos 2010;38:448-58.
26. Zhang D, He K, Raghavan N, et al. Comparative metabolismof 14C-labeled apixaban in mice, rats, rabbits, dogs, andhumans. Drug Metab Dispos 2009;37:1738-48.
27. Buller HR. Oral Rivaroxaban for the Treatment of SymptomaticVenous Thromboembolism: A Pooled Analysis of theEINSTEIN DVT and EINSTEIN PE Studies. Blood 2012;120.
28. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al.Oral rivaroxaban for symptomatic venous thromboembolism.N Engl J Med 2010;363:2499-510.
29. EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oralrivaroxaban for the treatment of symptomatic pulmonaryembolism. N Engl J Med 2012;366:1287-97.
30. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versuswarfarin in the treatment of acute venous thromboembolism.N Engl J Med 2009;361:2342-52.
31. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for thetreatment of acute venous thromboembolism. N Engl J Med2013;369:799-808.
32. Hokusai VTEI, Buller HR, Decousus H, et al. Edoxabanversus warfarin for the treatment of symptomatic venousthromboembolism. N Engl J Med 2013;369:1406-15.
33. Geldhof V, Vandenbriele C, Verhamme P, et al. Venousthromboembolism in the elderly: efficacy and safety ofnon-VKA oral anticoagulants. Thromb J 2014;12:21.
34. Schulman S, Kearon C, Kakkar AK, et al. Extended Use ofDabigatran, Warfarin, or Placebo in Venous Thromboembolism.New Engl J Med 2013;368:709-18.
35. Agnelli G, Buller HR, Cohen A, et al. Apixaban for ExtendedTreatment of Venous Thromboembolism. N Engl J Med 2012.
36. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban orAspirin for Extended Treatment of Venous Thromboembolism.N Engl J Med 2017;376:1211-22.
37. Hart RG, Benavente O, McBride R, et al. Antithrombotictherapy to prevent stroke in patients with atrial fibrillation: ameta-analysis. Ann Intern Med 1999;131:492-501.
38. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism:a decade of progress in stroke prevention. Ann InternMed 1999;131:688-95.
39. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatranversus warfarin in patients with atrial fibrillation. N Engl JMed 2009;361:1139-51.
40. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versuswarfarin in nonvalvular atrial fibrillation. N Engl J Med2011;365:883-91.
41. Granger CB, Alexander JH, McMurray JJ, et al. Apixabanversus warfarin in patients with atrial fibrillation. N Engl JMed 2011;365:981-92.
42. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versuswarfarin in patients with atrial fibrillation. N Engl J Med2013;369:2093-104.
43. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison ofthe efficacy and safety of new oral anticoagulants withwarfarin in patients with atrial fibrillation: a meta-analysis ofrandomised trials. Lancet 2014;383:955-62.
44. Eikelboom JW, Brueckmann M, Van de Werf F. Dabigatranin patients with mechanical heart valves. N Engl J Med2014;370:383-4.
45. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatranversus warfarin in patients with mechanical heart valves.N Engl J Med 2013;369:1206-14.
46. Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics andpharmacodynamics of dabigatran etexilate, an oral directthrombin inhibitor, with coadministration of digoxin. J ClinPharmacol 2012;52:243-50.
47. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate--anovel, reversible, oral direct thrombin inhibitor: interpretationof coagulation assays and reversal of anticoagulant activity.Thromb Haemost 2010;103:1116-27.
48. Douxfils J, Mullier F, Loosen C, et al. Assessment of theimpact of rivaroxaban on coagulation assays: laboratoryrecommendations for the monitoring of rivaroxaban andreview of the literature. Thromb Res 2012;130:956-66.
49. Douxfils J, Chatelain C, Chatelain B, et al. Impact of apixabanon routine and specific coagulation assays: a practical laboratoryguide. Thromb Haemost 2013;110:283-94.
50. Douxfils J, Chatelain B, Chatelain C, et al. Edoxaban: Impacton routine and specific coagulation assays. A practical laboratoryguide. Thromb Haemost 2016;115:368-81.
51. Vanden Daelen S, Peetermans M, Vanassche T, et al. Monitoringand reversal strategies for new oral anticoagulants. Expert RevCardiovasc Ther 2015;13:95-103.
52. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, andefficacy of idarucizumab for the reversal of the anticoagulanteffect of dabigatran in healthy male volunteers: a randomised,placebo-controlled, double-blind phase 1 trial. Lancet2015;386:680-90.
53. Glund S, Stangier J, Schmohl M, et al. Idarucizumab, aSpecific Antidote for Dabigatran: Immediate, Complete andSustained Reversal of Dabigatran Induced Anticoagulation inElderly and Renally Impaired Subjects. Blood 2014;124.
54. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumabfor Dabigatran Reversal. N Engl J Med 2015;373:511-20.
55. Vanassche T, Verhamme P, Greinacher A. Reversal ofdabigatran by idarucizumab: when and how? Expert RevHematol 2016.
56. Ghadimi K, Dombrowski KE, Levy JH, et al. Andexanet alfafor the reversal of Factor Xa inhibitor related anticoagulation.Expert Rev Hematol 2016;9:115-22.
57. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfafor the Reversal of Factor Xa Inhibitor Activity. N Engl J Med2015;373:2413-24.
2. Wells PS, Holbrook AM, Crowther NR, et al. Interactions ofwarfarin with drugs and food. Ann Intern Med 1994;121:676-83.
3. Schwarz UI, Ritchie MD, Bradford Y, et al. Geneticdeterminants of response to warfarin during initialanticoagulation. N Engl J Med 2008;358:999-1008.
4. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapyfor atrial fibrillation: Antithrombotic Therapy and Preventionof Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines. Chest2012;141:e531S-75S.
5. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelinesfor the management of atrial fibrillation developed incollaboration with EACTS: The Task Force for the managementof atrial fibrillation of the European Society of Cardiology(ESC)Developed with the special contribution of theEuropean Heart Rhythm Association (EHRA) of theESCEndorsed by the European Stroke Organisation (ESO).Eur Heart J 2016.
6. Heidbuchel H, Verhamme P, Alings M, et al. EHRA PracticalGuide on the use of new oral anticoagulants in patients withnon-valvular atrial fibrillation: executive summary. Eur Heart J2013.
7. Stangier J. Clinical pharmacokinetics and pharmacodynamicsof the oral direct thrombin inhibitor dabigatran etexilate. ClinPharmacokinet 2008;47:285-95.
8. Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral directfactor Xa inhibitor, inhibits human clot-bound factor Xaactivity in vitro. Thromb Haemost 2009;101:780-2.
9. Laux V, Perzborn E, Kubitza D, et al. Preclinical and clinicalcharacteristics of rivaroxaban: a novel, oral, direct factor Xainhibitor. Semin Thromb Hemost 2007;33:515-23.
10. Partida RA, Giugliano RP. Edoxaban: pharmacologicalprinciples, preclinical and early-phase clinical testing. FutureCardiol 2011;7:459-70.
11. Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, directand highly selective factor Xa inhibitor: in vitro, antithromboticand antihemostatic studies. J Thromb Haemost 2008;6:820-9.
12. EMA EMA. PRADAXA - EPAR Product Information -Summary of Product Characteristics. 2016.
13. Blech S, Ebner T, Ludwig-Schwellinger E, et al. Themetabolism and disposition of the oral direct thrombininhibitor, dabigatran, in humans. Drug Metab Dispos2008;36:386-99.
14. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokineticprofile of the oral direct thrombin inhibitor dabigatranetexilate in healthy volunteers and patients undergoing totalhip replacement. J Clin Pharmacol 2005;45:555-63.
15. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics,pharmacodynamics and tolerability of dabigatran etexilate, anew oral direct thrombin inhibitor, in healthy male subjects.Br J Clin Pharmacol 2007;64:292-303.
16. Stangier J, Rathgen K, Stahle H, et al. Influence of renalimpairment on the pharmacokinetics and pharmacodynamicsof oral dabigatran etexilate: an open-label, parallel-group,single-centre study. Clin Pharmacokinet 2010;49:259-68.
17. European Medicines Agency E. XARELTO - EPAR ProductInformation - Summary of Product Characteristics. 2016.
18. European Medicines Agency E. ELIQUIS - EPAR ProductInformation - Summary of Product Characteristics. 2016.
19. European Medicines Agency E. LIXIANA - EPAR ProductInformation - Summary of Product Characteristics. 2016.
20. Heidbuchel H, Verhamme P, Alings M, et al. UpdatedEuropean Heart Rhythm Association Practical Guide on theuse of non-vitamin K antagonist anticoagulants in patientswith non-valvular atrial fibrillation. Europace 2015;17:1467-507.
21. Buller H, Deitchman D, Prins M, et al. Efficacy and safety ofthe oral direct factor Xa inhibitor apixaban for symptomaticdeep vein thrombosis. The Botticelli DVT dose-ranging study.J Thromb Haemost 2008;6:1313-8.
22. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism andpharmacokinetics after oral administration to humans. DrugMetab Dispos 2009;37:74-81.
23. Kubitza D, Becka M, Roth A, et al. Dose-escalation study ofthe pharmacokinetics and pharmacodynamics of rivaroxabanin healthy elderly subjects. Curr Med Res Opin 2008;24:2757-65.
24. Lang D, Freudenberger C, Weinz C. In vitro metabolism ofrivaroxaban, an oral, direct factor Xa inhibitor, in livermicrosomes and hepatocytes of rats, dogs, and humans. DrugMetab Dispos 2009;37:1046-55.
25. Wang L, Zhang D, Raghavan N, et al. In vitro assessment ofmetabolic drug-drug interaction potential of apixaban throughcytochrome P450 phenotyping, inhibition, and inductionstudies. Drug Metab Dispos 2010;38:448-58.
26. Zhang D, He K, Raghavan N, et al. Comparative metabolismof 14C-labeled apixaban in mice, rats, rabbits, dogs, andhumans. Drug Metab Dispos 2009;37:1738-48.
27. Buller HR. Oral Rivaroxaban for the Treatment of SymptomaticVenous Thromboembolism: A Pooled Analysis of theEINSTEIN DVT and EINSTEIN PE Studies. Blood 2012;120.
28. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al.Oral rivaroxaban for symptomatic venous thromboembolism.N Engl J Med 2010;363:2499-510.
29. EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oralrivaroxaban for the treatment of symptomatic pulmonaryembolism. N Engl J Med 2012;366:1287-97.
30. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versuswarfarin in the treatment of acute venous thromboembolism.N Engl J Med 2009;361:2342-52.
31. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for thetreatment of acute venous thromboembolism. N Engl J Med2013;369:799-808.
32. Hokusai VTEI, Buller HR, Decousus H, et al. Edoxabanversus warfarin for the treatment of symptomatic venousthromboembolism. N Engl J Med 2013;369:1406-15.
33. Geldhof V, Vandenbriele C, Verhamme P, et al. Venousthromboembolism in the elderly: efficacy and safety ofnon-VKA oral anticoagulants. Thromb J 2014;12:21.
34. Schulman S, Kearon C, Kakkar AK, et al. Extended Use ofDabigatran, Warfarin, or Placebo in Venous Thromboembolism.New Engl J Med 2013;368:709-18.
35. Agnelli G, Buller HR, Cohen A, et al. Apixaban for ExtendedTreatment of Venous Thromboembolism. N Engl J Med 2012.
36. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban orAspirin for Extended Treatment of Venous Thromboembolism.N Engl J Med 2017;376:1211-22.
37. Hart RG, Benavente O, McBride R, et al. Antithrombotictherapy to prevent stroke in patients with atrial fibrillation: ameta-analysis. Ann Intern Med 1999;131:492-501.
38. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism:a decade of progress in stroke prevention. Ann InternMed 1999;131:688-95.
39. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatranversus warfarin in patients with atrial fibrillation. N Engl JMed 2009;361:1139-51.
40. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versuswarfarin in nonvalvular atrial fibrillation. N Engl J Med2011;365:883-91.
41. Granger CB, Alexander JH, McMurray JJ, et al. Apixabanversus warfarin in patients with atrial fibrillation. N Engl JMed 2011;365:981-92.
42. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versuswarfarin in patients with atrial fibrillation. N Engl J Med2013;369:2093-104.
43. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison ofthe efficacy and safety of new oral anticoagulants withwarfarin in patients with atrial fibrillation: a meta-analysis ofrandomised trials. Lancet 2014;383:955-62.
44. Eikelboom JW, Brueckmann M, Van de Werf F. Dabigatranin patients with mechanical heart valves. N Engl J Med2014;370:383-4.
45. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatranversus warfarin in patients with mechanical heart valves.N Engl J Med 2013;369:1206-14.
46. Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics andpharmacodynamics of dabigatran etexilate, an oral directthrombin inhibitor, with coadministration of digoxin. J ClinPharmacol 2012;52:243-50.
47. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate--anovel, reversible, oral direct thrombin inhibitor: interpretationof coagulation assays and reversal of anticoagulant activity.Thromb Haemost 2010;103:1116-27.
48. Douxfils J, Mullier F, Loosen C, et al. Assessment of theimpact of rivaroxaban on coagulation assays: laboratoryrecommendations for the monitoring of rivaroxaban andreview of the literature. Thromb Res 2012;130:956-66.
49. Douxfils J, Chatelain C, Chatelain B, et al. Impact of apixabanon routine and specific coagulation assays: a practical laboratoryguide. Thromb Haemost 2013;110:283-94.
50. Douxfils J, Chatelain B, Chatelain C, et al. Edoxaban: Impacton routine and specific coagulation assays. A practical laboratoryguide. Thromb Haemost 2016;115:368-81.
51. Vanden Daelen S, Peetermans M, Vanassche T, et al. Monitoringand reversal strategies for new oral anticoagulants. Expert RevCardiovasc Ther 2015;13:95-103.
52. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, andefficacy of idarucizumab for the reversal of the anticoagulanteffect of dabigatran in healthy male volunteers: a randomised,placebo-controlled, double-blind phase 1 trial. Lancet2015;386:680-90.
53. Glund S, Stangier J, Schmohl M, et al. Idarucizumab, aSpecific Antidote for Dabigatran: Immediate, Complete andSustained Reversal of Dabigatran Induced Anticoagulation inElderly and Renally Impaired Subjects. Blood 2014;124.
54. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumabfor Dabigatran Reversal. N Engl J Med 2015;373:511-20.
55. Vanassche T, Verhamme P, Greinacher A. Reversal ofdabigatran by idarucizumab: when and how? Expert RevHematol 2016.
56. Ghadimi K, Dombrowski KE, Levy JH, et al. Andexanet alfafor the reversal of Factor Xa inhibitor related anticoagulation.Expert Rev Hematol 2016;9:115-22.
57. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfafor the Reversal of Factor Xa Inhibitor Activity. N Engl J Med2015;373:2413-24.