Direct Oral Anticoagulants in Atrial Fibrillation: Practical Considerations and Remaining Issues

Abstract

Preventing thromboembolic events, while minimizing bleeding risks, remains challenging when managing patients with atrial fibrillation. Despite large and successful trial programs, several clinical concerns remain which commonly relate to fears of over- or underexposure to drugs and unfavorable outcomes. After a short summary of the main phase III trial findings, this short review discusses the evidence and clinical relevance of common clinical concerns (correct direct oral anticoagulant [DOAC] dosing; DOAC in moderate-to-severe renal impairment; and the relevance of fasting, nasogastric tube feeding, or high body mass index) on DOAC plasma levels. Finally, the need for specific DOAC antidotes will be addressed.

Keywords

direct oral anticoagulants - atrial fibrillation - stroke

Publication History

Received: 16 October 2020

Accepted: 03 December 2020

Article published online:
15 February 2021

• References

• 1 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22 (08) 983-988
• 2 Kirchhof P, Benussi S, Kotecha D. et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
• 3 Kirchhof P, Ammentorp B, Darius H. et al. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboembolic events--European Registry in Atrial Fibrillation (PREFER in AF). Europace 2014; 16 (01) 6-14
• 4 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
• 5 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
• 6 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
• 7 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
• 8 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
• 9 Bristol-Myers Squibb-Pfizer. Eliquis 5 mg film-coated tablets Summary of product characteristics 2020. Available from: https://www.medicines.org.uk/emc/product/2878/smpc
• 10 Boehringer-Ingelheim. Pradaxa 150 mg hard capsules Summary of product characteristics 2020. Available from: http://www.medicines.org.uk/EMC/medicine/24839/SPC/Pradaxa+150
• 11 Daiichi Sankyo UK Limited. Lixiana 60mg Film-Coated Tablets Summary of product characteristics 2020. Available from: https://www.medicines.org.uk/emc/product/6905/smpc
• 12 Bayer Pharma AG. Xarelto 20 mg film-coated tablets Summary of product characteristics 2019. Available from: https://www.medicines.org.uk/emc/product/2793/smpc
• 13 Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 2013; 29 (7, Suppl): S24-S33
• 14 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
• 15 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 (23) 2779-2790
• 16 Steinberg BA, Shrader P, Thomas L. et al; ORBIT-AF Investigators and Patients. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry. J Am Coll Cardiol 2016; 68 (24) 2597-2604
• 17 Yu HT, Yang PS, Jang E. et al. Label adherence of direct oral anticoagulants dosing and clinical outcomes in patients with atrial fibrillation. J Am Heart Assoc 2020; 9 (12) e014177
• 18 Lee KN, Choi JI, Boo KY. et al. Effectiveness and safety of off-label dosing of non-vitamin K antagonist anticoagulant for atrial fibrillation in Asian patients. Sci Rep 2020; 10 (01) 1801
• 19 Ruff CT, Giugliano RP, Braunwald E. et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385 (9984): 2288-2295
• 20 XARELTO® (rivaroxaban). Tablets Prescribing Information: Janssen Pharmaceuticals, Inc.; 2020 [03/2020]. Accessed January 11, 2021 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202439s031,022406s035lbl.pdf
• 21 Königsbrügge O, Ay C. Atrial fibrillation in patients with end-stage renal disease on hemodialysis: magnitude of the problem and new approach to oral anticoagulation. Res Pract Thromb Haemost 2019; 3 (04) 578-588
• 22 COUMADIN (warfarin sodium). Tablets Prescribing Information: Bristol-Myers Squibb Company; 2011 [10/2011]. Accessed January 11, 2021 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf
• 23 Kuno T, Takagi H, Ando T. et al. Oral anticoagulation for patients with atrial fibrillation on long-term hemodialysis. J Am Coll Cardiol 2020; 75 (03) 273-285
• 24 Van Der Meersch H, De Bacquer D, De Vriese AS. Vitamin K antagonists for stroke prevention in hemodialysis patients with atrial fibrillation: a systematic review and meta-analysis. Am Heart J 2017; 184: 37-46
• 25 De Vriese AS, Caluwé R, Pyfferoen L. et al. Multicenter randomized controlled trial of vitamin K antagonist replacement by rivaroxaban with or without vitamin K2 in hemodialysis patients with atrial fibrillation: the Valkyrie study. J Am Soc Nephrol 2020; 31 (01) 186-196
• 26 Siontis KC, Zhang X, Eckard A. et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation 2018; 138 (15) 1519-1529
• 27 Miao B, Sood N, Bunz TJ, Coleman CI. Rivaroxaban versus apixaban in non-valvular atrial fibrillation patients with end-stage renal disease or receiving dialysis. Eur J Haematol 2020; 104 (04) 328-335
• 28 Mavrakanas TA, Garlo K, Charytan DM. Apixaban versus no anticoagulation in patients undergoing long-term dialysis with incident atrial fibrillation. Clin J Am Soc Nephrol 2020; 15 (08) 1146-1154
• 29 Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 2015; 131 (11) 972-979
• 30 Vranckx P, Valgimigli M, Heidbuchel H. The significance of drug-drug and drug-food interactions of oral anticoagulation. Arrhythm Electrophysiol Rev 2018; 7 (01) 55-61
• 31 Steffel J, Verhamme P, Potpara TS. et al; ESC Scientific Document Group. 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 (16) 1330-1393
• 32 SAVAYSA™ (edoxaban). Tablets Prescribing Information Parsippany; New Jersey, United States: Daiichi Sankyo, Inc.; 2020 [04/2020]. Accessed January 11, 2021 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206316s016lbl.pdf
• 33 ELIQUIS (apixaban). Tablets Prescribing Information Princeton, New Jersey, United States: Bristol-Myers Squibb Company; 2020 [11/2019]. Accessed January 11, 2021 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202155s024lbl.pdf
• 34 PRADAXA® (dabigatran etexilate mesylate). Tablets Prescribing Information; Ridgefield, Connecticut, United States: Boehringer Ingelheim Pharmaceuticals, Inc.; 2020 [07/2020]. Accessed January 11, 2021 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022512s039lbl.pdf
• 35 Lucijanic M, Jurin I, Jurin H. et al. Patients with higher body mass index treated with direct / novel oral anticoagulants (DOAC/NOAC) for atrial fibrillation experience worse clinical outcomes. Int J Cardiol 2020; 301: 90-95
• 36 Güler E, Babur Güler G, Demir GG, Hatipoğlu S. A review of the fixed dose use of new oral anticoagulants in obese patients: Is it really enough?. Anatol J Cardiol 2015; 15 (12) 1020-1029
• 37 De Caterina R, Lip GYH. The non-vitamin K antagonist oral anticoagulants (NOACs) and extremes of body weight-a systematic literature review. Clin Res Cardiol 2017; 106 (08) 565-572
• 38 Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (06) 1308-1313
• 39 Proietti M, Guiducci E, Cheli P, Lip GY. Is there an obesity paradox for outcomes in atrial fibrillation? A systematic review and meta-analysis of non-vitamin k antagonist oral anticoagulant trials. Stroke 2017; 48 (04) 857-866
• 40 Sandhu RK, Ezekowitz J, Andersson U. et al. The ‘obesity paradox’ in atrial fibrillation: observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Eur Heart J 2016; 37 (38) 2869-2878
• 41 Balla SR, Cyr DD, Lokhnygina Y. et al. Relation of risk of stroke in patients with atrial fibrillation to body mass index (from patients treated with rivaroxaban and warfarin in the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation trial). Am J Cardiol 2017; 119 (12) 1989-1996
• 42 Boriani G, Ruff CT, Kuder JF. et al. Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019; 40 (19) 1541-1550
• 43 Costa OS, Beyer-Westendorf J, Ashton V. et al. Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data. J Thromb Thrombolysis 2020
• 44 Perales IJ, San Agustin K, DeAngelo J, Campbell AM. Rivaroxaban versus warfarin for stroke prevention and venous thromboembolism treatment in extreme obesity and high body weight. Ann Pharmacother 2020; 54 (04) 344-350
• 45 Kushnir M, Choi Y, Eisenberg R. et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol 2019; 6 (07) e359-e365
• 46 Spyropoulos AC, Ashton V, Chen YW, Wu B, Peterson ED. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: comparative effectiveness, safety, and costs. Thromb Res 2019; 182: 159-166
• 47 Martin AC, Thomas W, Mahir Z. et al. Direct oral anticoagulant concentrations in obese and high body weight patients: a cohort study. Thromb Haemost 2020; (e-pub ahead of print)
• 48 Piran S, Traquair H, Chan N, Bhagirath V, Schulman S. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study. Res Pract Thromb Haemost 2018; 2 (04) 684-688
• 49 Netley J, Howard K, Wilson W. Effects of body mass index on the safety and effectiveness of direct oral anticoagulants: a retrospective review. J Thromb Thrombolysis 2019; 48 (03) 359-365
• 50 Tittl L, Endig S, Marten S, Reitter A, Beyer-Westendorf I, Beyer-Westendorf J. Impact of BMI on clinical outcomes of NOAC therapy in daily care - results of the prospective Dresden NOAC Registry (NCT01588119). Int J Cardiol 2018; 262: 85-91
• 51 Mahlmann A, Gehrisch S, Beyer-Westendorf J. Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis 2013; 36 (04) 533-535
• 52 Kuramatsu JB, Sembill JA, Huttner HB. Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage. Crit Care 2019; 23 (01) 206
• 53 Milling Jr TJ, Frontera J. Exploring indications for the use of direct oral anticoagulants and the associated risks of major bleeding. Am J Manag Care 2017; 23 (4, Suppl): S67-S80
• 54 Piccini JP, Garg J, Patel MR. et al; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014; 35 (28) 1873-1880
• 55 Peck KA, Calvo RY, Schechter MS. et al. The impact of preinjury anticoagulants and prescription antiplatelet agents on outcomes in older patients with traumatic brain injury. J Trauma Acute Care Surg 2014; 76 (02) 431-436
• 56 Prexl O, Bruckbauer M, Voelckel W. et al. The impact of direct oral anticoagulants in traumatic brain injury patients greater than 60-years-old. Scand J Trauma Resusc Emerg Med 2018; 26 (01) 20
• 57 Bruckbauer M, Prexl O, Voelckel W. et al. Impact of direct oral anticoagulants in patients with hip fractures. J Orthop Trauma 2019; 33 (01) e8-e13
• 58 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
• 59 Connolly SJ, Milling Jr TJ, Eikelboom JW. et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375 (12) 1131-1141
• 60 January CT, Wann LS, Calkins H. et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140 (02) e125-e151
• 61 Cuker A, Burnett A, Triller D. et al. Reversal of direct oral anticoagulants: guidance from the anticoagulation forum. Am J Hematol 2019; 94 (06) 697-709
• 62 Christensen H, Cordonnier C, Kõrv J. et al. European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral haemorrhage. Eur Stroke J 2019; 4 (04) 294-306