Practical aspects of using new oral anticoagulants in patients with atrial fibrillation
Averkova A. O.
Federal State Budgetary Institution, “Central Clinical Hospital with Outpatient Clinic” at the Department of Presidential Affairs, Marshala Timoshenko 15, Moscow 121359
Federal State Budgetary Institution, “Central Clinical Hospital with Outpatient Clinic” at the Department of Presidential Affairs, Marshala Timoshenko 15, Moscow 121359
Keywords: anticoagulants, CAD, treatment, atrial fibrillation
DOI: 10.18087 / rhj.2015.5.2118
Atrial fibrillation (AF) is one of important causes for ischemic stroke. In recent years, treatment with new anticoagulants (NAC) instead of warfarin and its analogues has been recommended for virtually all AP patients with a considerable risk of embolic events. The NACs available for prevention of stroke in patients with AF include dabigatran, rivaroxaban, and apixaban. Five large Phase III clinical studies using dabigatran, rivaroxaban, apixaban and edoxaban in patients with nonvalvular AF were completed in 2015. On the whole, the studies showed similar efficacy and safety of each NAC as compared with warfarin. Clear understanding differences between NACs and vitamin K antagonists (VKA) as well as responsible use of any anticoagulant in routine practice are important to obtain maximum benefit of using these drugs. Clinical experience of using NACs outside studies is still rather limited. Further studies of correct NAC treatment will undoubtedly become important with expanding application of NAC therapies.
- Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med. 1987 Sep;147 (9):1561–4.
- Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991 Aug;22 (8):983–8.
- Jorgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Acute stroke with atrial fibrillation. The Сopenhagen Stroke Study. Stroke. 1996 Oct;27 (10):1765–9.
- Lamassa M, Di Carlo A, Pracucci G, Basile AM, Trefoloni G, Vanni P et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke. 2001 Feb;32 (2):392–8.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007 Jun 19;146 (12):857–67.
- Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010 Oct;12 (10):1360–420.
- Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA et al. 2011 ACCF / AHA / HRS focused updates incorporated into the ACC / AHA / ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation / American Heart Association Task Force on practice guidelines. Circulation. 2011 Mar 15;123 (10):269–367.
- Сулимов В. А., Голицын С. П., Панченко Е. П., Попов С. В., Ревишвили А. Ш., Шубик Ю. В., Явелов И. С. Диагностика и лечение фибрилляции предсердий. Рекомендации РКО, ВНОА и АССХ, 2012 г. Российский кардиологичсекий журнал. 2013; 4 (102 Прил 3):1–100.
- Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Europace. 2012 Oct;14 (10):1385–413.
- January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC et al. 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 Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Dec 2;64 (21):e1–76.
- Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369 (22):2093–104.
- Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41–57.
- Ansell J. Warfarin versus new agents: interpreting the data. Hematology Am Soc Hematol Educ Program. 2010;2010:221–8.
- Harder S. Renal profiles of anticoagulants. J Clin Pharmacol. 2012 Jul;52 (7):964–75.
- Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361 (12):1139–51.
- Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365 (10):883–91.
- Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365 (11):981–92.
- Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364 (9):806–17.
- ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010 Mar;159 (3):340–347.e1.
- Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD et al. Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010 Mar;159 (3):331–9.
- Eikelboom JW, O’Donnell M, Yusuf S, Diaz R, Flaker G, Hart R et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010 Mar;159 (3):348–53.
- Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009 May;157 (5):805–10.
- Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med. 2010 Nov 4;363 (19):1875–6.
- Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens R, Turakhia MP et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association / American Stroke Association. Stroke. 2012 Dec;43 (12):3442–53.
- Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate / rhythm control. Can J Cardiol. 2012 Mar-Apr;28 (2):125–36.
- You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice guidelines. Chest. 2012 Feb;141 (2 Suppl): e531S-75S.
- Halperin JL, Wojdyla D, Piccini JP, Lokhnygina Y, Patel MR, Breithardt G et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the ROCKET-AF trial. Stroke. 2012;43: A148.
- Beasley BN, Unger EF, Temple R. Anticoagulant options-why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med. 2011 May 12;364 (19):1788–90.
- Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011 Oct;32 (19):2387–94.
- Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Heale JS, Oldgren J et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011 May 31;123 (21):2363–72.
- Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011 Oct;50 (10):675–86.
- Hariharan S, Madabushi R. Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment. J Clin Pharmacol. 2012 Jan;52 (1 Suppl): 119S-25S.
- Lehr T, Haertter S, Liesenfeld KH, Staab A, Clemens A, Reilly PA, Friedman J. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol. 2012 Sep;52 (9):1373–8.
- Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol. 1992 Mar 15;19 (4):851–5.
- Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011 Jan 18;123 (2):131–6.
- Flaker G, Lopes R, Al-Khatib S, Hermosillo A, Thomas L, Zhu J et al. Apixaban and warfarin are associated with a low risk of stroke following cardioversion for atrial fibrillation: results from the ARISTOTLE Trial. Eur Heart J. 2012;33 (Abstract Suppl): 686. Abstract 4048.
- Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE et al. Outcomes following cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013 May 14;61 (19):1998–2006.
- Farag M, Gorog DA. Rivaroxaban in atrial fibrillation cardioversion: insights from the X–VeRT trial. Future Cardiol. 2015 Mar;11 (2):147–51.
- Lip GY, Andreotti F, Fauchier L, Huber K, Hylek E, Knight E et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace. 2011 May;13 (5):723–46.
- Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA etal. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012 Jun;43 (6):1511–7.
- Alexander JH, Lopes R, McMurray J, Atar D, Wojdyla D, Aylward P et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in atrial fibrillation in patients taking concomitant aspirin. J Am Coll Cardiol. 2012 Mar 27;59 (13 Suppl): E1697.
- Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med. 2012 Mar 12;172 (5):397–402.
- Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2008 Apr 16; (2):CD000011.
- Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009 Jun 1;15 (6):e22–33.
- Coleman CI, Roberts MS, Sobieraj DM, Lee S, Alam T, Kaur R. Effect of dosing frequency on chronic cardiovascular disease medication adherence. Curr Med Res Opin. 2012 May;28 (5):669–80.
- Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost. 2010 Dec;104 (6):1263–71.
- Coleman CI, Limone B, Sobieraj DM, Lee S, Roberts MS, Kaur R, Alam T. Dosing frequency and medication adherence in chronic disease. J Manag Care Pharm. 2012 Sep;18 (7):527–39.
- Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit. 2010 Dec;32 (6):673–9.
- Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007 Sep;64 (3):292–303.
- Watanabe M, Siddiqui FM, Qureshi AI. Incidence and management of ischemic stroke and intracerebral hemorrhage in patients on dabigatran etexilate treatment. Neurocrit Care. 2012 Feb;16 (1):203–9.
- Wilcox R, Pendleton RC, Smock KJ, Rodgers GM. Hospital-based clinical implications of the novel oral anticoagulant, dabigatran etexilate, in daily practice. Hosp Pract (1995). 2011 Aug;39 (3):23–34.
- Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E. Assessment of laboratory assays to measure rivaroxaban – an oral, direct Factor Xa inhibitor. Thromb Haemost. 2010 Apr;103 (4):815–25.
- Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013 May;15 (5):625–51.
- Nematullah A, Alabousi A, Blanas N, Douketis JD, Sutherland SE. Dental surgery for patients on anticoagulant therapy with warfarin: a systematic review and meta-analysis. J Can Dent Assoc. 2009 Feb;75 (1):41.
- Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012 Jul 17;126 (3):343–8.
- Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace. 2013 Oct;15 (10):1407–11.
- Bin Abdulhak AA, Khan AR, Tleyjeh IM, Spertus JA, Sanders SU, Steigerwalt KE et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace. 2013 Oct;15 (10):1412–20.
- Patel MR, Hellkamp AS, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF Trial (rivaroxaban once-daily, oral, direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2013 Feb 12;61 (6):651–8.
- Ezekowitz MD, Wallentin L, Connolly SJ, Parekh A, Chernick MR, Pogue J et al. Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation. Circulation. 2010 Nov 30;122 (22):2246–53.
- Mahaffey KW, Wojdyla D, Hankey GJ et al. Clinical outcomes with rivaroxabane in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013 Jun 18;158 (12):861–8.
- Garcia DA, Wallentin L, Lopes RD et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from Apixaban for reduction in stroke and other thromboembolic Events in Atrial Fibrillation trial. Am Heart J. 2013 Sep;166 (3):549–58.
- Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol. 2012 Dec;35 (12):730–7.
- Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124 (14):1573–9.
- Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012 Aug;108 (2):217–24.
- Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med. 2011 Nov 24;365 (21):2039–40.
- van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A. Dabigatran – novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010 Jun;103 (6):1116–27.
- Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012 Aug 1;110 (3):453–60.
- Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2012 Sep 1;5 (5):711–9.
- Lip GY, Larsen TB, Skjoth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2012 Aug 21;60 (8):738–46.
- Lip GY, Skjøth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2‑VASc score. J Am Coll Cardiol. 2015 Apr 14;65 (14):1385–94.
Averkova A. O. Practical aspects of using new oral anticoagulants in patients with atrial fibrillation. Russian Heart Journal. 2015;14 (5):316–330