How NOAC Selection and Reversal Can Help Protect Our ...€¦ · agents. Approval of dabigatran was achieved in 2010 in the US and in 2011 in Europe, and since then other novel oral
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Introduction: Keeping pace with advances in anticoagulationMore than 30 million people globally are estimated to have
atrial fibrillation.1 The presentation of data with dabigatran
in 2009 in the Evaluation of Long Term Anticoagulant
Therapy (RE-LY) study introduced the modern era of stroke
prevention in patients with AF using direct oral anticoagulant
agents. Approval of dabigatran was achieved in 2010 in
the US and in 2011 in Europe, and since then other novel
oral anticoagulant agents (NOACs) have been approved,
including rivaroxaban, apixaban, and edoxaban.2-5 The 2015
approval of idarucizumab for dabigatran specific reversal
is another landmark development in the NOAC field, as is
the recent approval for andexanet–alpha as a reversal agent
for factor Xa-inhibitors. NOACs address many of the limita-
tions associated with using vitamin K antagonists, including
the narrow therapeutic window and the need for frequent
monitoring with warfarin; warfarin’s slow onset and offset
of action, its variability in dose response; and the increased
risk of intracranial hemorrhage (ICH) with warfarin.4-9
However, clinical practice challenges persist. Registries and
observational data consistently show that NOAC therapy is
underused in eligible patients and in some countries aspirin
is still used in patients who are eligible for OAC therapy.
In addition, reduced NOAC doses are sometimes used in
clinical practice in patient populations that were not tested
in clinical trials.10-13 In addition, in emergency situations
when anticoagulation needs to be removed quickly, it
Received – 16 July 2019; Accepted – 19 July 2019
Abstract The global burden of atrial fibrillation remains high. The approval of several novel oral anticoagulant agents (NOACs) as well as of idarucizumab for dabigatran reversal and andexanet-alpha for factor Xa-inhibitors represent landmark developments in the NOAC field. Although NOACs have also shown a positive net clinical benefit, even in patients with one additional stroke risk factor, clinical practice challenges persist. NOAC therapy is often underused in eligible patients despite clear recommendations in international guidelines. Moreover, it remains challenging to implement appropriate strategies for reversing NOACs in emergency settings. A symposium, How NOAC Selection and Reversal Can Help Protect Our Patients: Your Questions Answered, was held during the 5th European Stroke Organization Conference in May 2019 in Milan, Italy. This symposium reviewed advances in anticoagulation, including: NOAC selection; dosing strategies; evidence concerning anticoagulation reversal strategies; and strategies for using reversal agents before surgery, in patients with intracerebral hemorrhage, and in patients presenting with ischemic stroke prior to thrombolysis.
HOW NOAC SELECTION AND REVERSAL CAN HELP PROTECT OUR PATIENTS: YOUR QUESTIONS ANSWERED
CNS 2019: 5:(1). JULY 2019 41
18. Diener HC, Connolly SJ, Ezekowitz MD, 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. Lancet Neurol 2010;9:1157-63.
19. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-38.
20. Behrouzi R, Punter M. Diagnosis and management of cerebral venous thrombosis. Clin Med (Lond) 2018;18:75-9.
21. Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE-LY trial. New Engl J Med 2014;371:1464-5.
22. Ezekowitz MD, Eikelboom J, Oldgren J, et al. Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation. Europace 2016;18:973-8.
23. Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. The New England journal of medicine 2017;377:1513-24.
24. Graham DJ, Reichman ME, Wernecke M, et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA internal medicine 2016;176:1662-71.
25. Lip GY, Keshishian A, Kamble S, et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis. Thromb Haemost 2016;116:975-86.
26. Graham DJ, Baro E, Zhang R, et al. Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. Am J Med 2019.
27. Huisman MV, Rothman KJ, Paquette M, et al. Two-year follow-up of patients treated with dabigatran for stroke prevention in atrial fibrillation: Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry. Am Heart J 2018;198:55-63.
28. Xian Y, O'Brien EC, Liang L, et al. Association of Preceding Antithrom botic Treatment With Acute Ischemic Stroke Severity and In-Hospital Outcomes Among Patients With Atrial Fibrillation. JAMA 2017;317:1057-67.
6. Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008;29:155-65.
7. Khoo CW, Tay KH, Shantsila E, Lip GY. Novel oral anticoagulants. Int J Clin Pract 2009;63:630-41.
9. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. New Engl J Med 2010;363:1875-6.
10. Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non–Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction. J Am Coll Cardiol 2017;69:2779-90.
12. Mazurek M, Huisman MV, Rothman KJ, et al. Regional Differences in Antithrombotic Treatment for Atrial Fibrillation: Insights from the GLORIA-AF Phase II Registry. Thromb Haemost 2017;117:2376-88.
13. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893-962.
14. Ben Freedman S, Gersh BJ, Lip GYH. Misperceptions of aspirin efficacy and safety may perpetuate anticoagulant underutilization in atrial fibrillation. European Heart Journal 2014;36:653-6.
15. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011;365:883-91.
16. Lopes RD, Al-Khatib SM, Wallentin L, 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. Lancet (London, England) 2012;380:1749-58.
17. Lip GY, Clemens A, Noack H, Ferreira J, Connolly SJ, Yusuf S. Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database. Thromb Haemost 2014;111:933-42.
HOW NOAC SELECTION AND REVERSAL CAN HELP PROTECT OUR PATIENTS: YOUR QUESTIONS ANSWERED
CNS 2019: 5:(1). JULY 2019 42
39. Steiner T RP, van Ryn J, et al. . Reversal of Dabigatran Anticoagulation with Idarucizumab in Patients with Intracranial Hemorrhage: Subanalysis of RE-VERSE AD. International Stroke Conference. Los Angeles, CA: https://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_498744.pdf; 2018.
40. Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012;43:1511-7.
41. Kermer P, Eschenfelder CC, Diener H-C, Grond M. Abstract 84: Idarucizumab in Patients Treated With Dabigatran Suffering Cerebral Ischemia or Intracranial Hemorrhage: A Retrospective Case Series From Germany. Stroke 2019;50:A84-A.
42. Kermer P, Eschenfelder CC, Diener HC, et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany - A national case collection. Int J Stroke 2017;12:383-91.
29. Nielsen PB, Skjoth F, Sogaard M, Kjaeldgaard JN, Lip GY, Larsen TB. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2017;356:j510.
30. Goldstein JN, Refaai MA, Milling TJ, Jr., et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet (London, England) 2015;385:2077-87.
31. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554-62.
32. Pollack CV, Jr., Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. New Engl J Med 2017;377:431-441
33. Fanikos J et al. RE-VECTO: Idarucizumab drug administration surveillance program results. The Congress on Open Issues in Thrombosis and Hemostasis 2018 jointly with the 9th Russian Conference on Clinical Hemostasiology and Hemorheology. Abstract;68.
34. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19:446-51.
35. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. New Engl J Med 2015;373:2413-24.
36. Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. New Engl J Med 2019;380:1326-35.
37. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330-93.
38. Culbreth SE, Rimsans J, Sylvester K, Pallin DJ, Connors JM. Andexanet alfa-The first 150 days. Am J Hematol 2019;94:E21-e4.