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Anticoagulation for Atrial Fibrillation: State of the Art and Recommendations for a Quickly Moving Target
Canadian Journal of Cardiology 29 (2013) S1eS3
Editorial
Anticoagulation for Atrial Fibrillation: State of the Art and Recommendations for a Quickly Moving Target Stanley Nattel, MD,a John Cairns, MD,b Jeffrey S. Healey, MSc, MD,c and Mario Talajic, MDa a
Department of Medicine, Montreal Heart Institute and Universite de Montre al, Montreal, Que bec, Canada b
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada c
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Atrial fibrillation (AF) will affect about 1 in 4 individuals over his or her lifetime; the population prevalence is 1%, rising to more than 10% in those > 80 years.1 The most significant and dreaded complication of AF is thromboembolic stroke: 70% of AF-related strokes result in death or severe disability. AF accounts for about 15% of all strokes and is the single most important cause in the elderly.2 Since its approval for human use in 1954, warfarin and other vitamin K antagonist (VKA) drugs had been, until recently, the only available oral anticoagulants for the prevention of stroke in patients with AF.3 Warfarin therapy was initially advised only for patients with AF who also had rheumatic mitral valve disease or a mitral valve prosthesis. However, the use of anticoagulants for stroke prevention in AF has changed dramatically over the past 20 years (Fig. 1). Epidemiologic evidence emerged that age-corrected annual stroke rates among patients with nonvalvular AF were similar to those with rheumatic valvular disease.3 This realization, combined with the possibility of safer VKA regimens because of standardization of prothrombin times using the international normalized ratio (INR) and evidence for the efficacy of moderate anticoagulation intensity, led to the conduct of clinical trials of VKA among patients with nonrheumatic AF. In 6 major trials, VKAs were shown to reduce the risk of stroke by twothirds, although the annual risk of major hemorrhage was about 1.3%.3 However, the safe and effective use of VKAs remains challenging for patients and physicians. Seemingly minor events like diet changes, alterations in concomitant drug therapy, and intercurrent illnesses can tip the balance toward life-threatening thromboembolic events or bleeding. Because of the narrow toxic-therapeutic index of VKAs, patients require close follow-up, regular monitoring of INRs, and frequent dose adjustments. Several new oral
Received for publication May 1, 2013. Accepted May 2, 2013. Corresponding author: Dr Stanley Nattel, 5000 Belanger St E, Montreal H1T 1C8, Quebec, Canada. Tel.: þ1-514-376-3330; fax: þ1-514-3761355. E-mail: [email protected] See page S2 for disclosure information.
anticoagulants (NOACs), the actions of which are independent of vitamin Kedependent coagulation factor synthesis and do not require regular laboratory monitoring, were developed in the 1990s. The successful completion of large phase III randomized controlled trials, followed by the recent approval of 3 NOACs, has created dramatic changes in the art of stroke prevention in patients with AF. The Canadian Cardiovascular Society (CCS) was the first major organization to recommend preferential use of NOACs for most patients with an indication for oral anticoagulation in its 2010 atrial fibrillation guidelines.4 Subsequently, other major societies adopted similar positions. With the rapid increases in information about, availability of, and use of NOACs, the CCS updated its guidelines for stroke prevention in AF within 2 years.5 At the time of the update (last year), the CCS AF Guidelines Committee recognized that sufficiently solid clinical trial data that would permit authoritative guidelines were lacking in relation to a wide range of important clinical management decisions regarding anticoagulation in patients with AF. At that point, it was suggested that a series of state of the art articles by experts in the field addressing such issues should be published as a supplement to the Canadian Journal of Cardiology (CJC). The present issue is the fruit of that reflection. Ahmad et al.6 begin by providing an overview of the epidemiology and risk determinants of stroke in patients with AF. These authors argue that in view of the superior safety of the NOACs and the finite stroke risk in most patients with AF, our clinical focus should shift to pinpointing the truly low-risk patient with AF who does not require anticoagulation, rather than identifying high-risk individuals. Glotzer and Ziegler7 follow with a discussion of the emerging role of silent AF as a stroke factor and the possible value of anticoagulants in preventing stroke for the many individuals who have AF and do not even know it. They emphasize the importance of prospective research to establish whether anticoagulating patients with silent AF prevents strokes, and if so, developing improved monitoring methods to efficiently identify at-risk individuals. Gong and Kim8 then review the pharmacokinetics of NOACs and the future of rational pharmacokinetically based dose selection. Their detailed
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.05.001
S2
Canadian Journal of Cardiology Volume 29 2013
Figure 1. Time line illustrating the evolution of oral anticoagulation from the first use of warfarin to the introduction of the new oral anticoagulants (NOACs). AFASAK, Atrial Fibrillation, Aspirin, Anticoagulation trial; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-term Anticoagulation Therapy; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.
analysis of the influence of pharmacokinetic factors on the plasma concentrationetime relationship argues for the establishment of dosing regimens that better consider the major determinants of individual patient NOAC drug disposition. Liew et al.9 review the methods and value of assessing anticoagulation intensity of NOACs and discuss the important problem of bleeding management in anticoagulated patients. They indicate that there are still no established indications for anticoagulation intensity assessment of NOACs and review the state of development of antidotes for NOACs in patients with life-threatening bleeding. Mandzia and Hill10 discuss the issue of acute stroke management in patients with AF. They consider the complexities of anticoagulation management according to the phase of stroke evolution in the unique context of the role that anticoagulants can play as either causative or therapeutic agents. Healey and Brambatti11 deal with the challenges of anticoagulation management in patients with AF at risk of stroke when they undergo invasive procedures associated with bleeding. The increasing recognition of the benefit of not interrupting anticoagulation for invasive procedures is emphasized, as are the differences resulting from the much briefer action of NOACs vs VKAs. Cairns and McMurtry12 consider the problem of patients with AF who have acute or chronic coronary artery disease, with indications for antiplatelet drug therapy that will further enhance the hemorrhagic risk. They emphasize the importance of prospective randomized trials to provide evidence-based recommendations. An area of particular importance and uncertainty identified in the CCS AF guidelines update was anticoagulation management of patients with AF with concomitant renal insufficiency.5 This issue is addressed here in detail by Hart et al.13. Finally, Whitlock et al.14 review the experience with nonpharmacologic approaches to stroke prevention in AF and consider when (if ever) they can replace oral anticoagulants. They conclude that for now such approaches should be considered purely investigational.
We hope that the present issue of the CJC will provide valuable knowledge to clinicians grappling with difficult management decisions and will serve to inform the elaboration of evidence-based practice guidelines in this rapidly moving arena. Funding Sources Funded by the Canadian Institutes of Health Research. Publication of this article is supported by Bayer Canada and by Pfizer and Bristol-Myers Squibb. Disclosures The authors have no conflicts of interest to disclose. References 1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110: 1042-6. 2. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229-34. 3. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M; CCS Atrial Fibrillation Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011;27:74-90. 4. Gillis AM, Skanes AC. Comparing the 2010 North American and European atrial fibrillation guidelines. Can J Cardiol 2011;27:7-13. 5. Skanes AC, Healey JS, Cairns JA, et al; Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36.
Nattel et al. Anticoagulation for AF 6. Ahmad Y, Lip GYH, Lane DA. Recent developments in understanding epidemiology and risk determinants of atrial fibrillation as a cause of stroke. Can J Cardiol 2013;29(7 suppl):S4-13. 7. Glotzer TV, Ziegler PD. Silent Atrial fibrillation as a stroke risk factor and anticoagulation indication. Can J Cardiol 2013;29(7 suppl):S14-23. 8. 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):S24-33. 9. Liew A, Eikelboom JW, O’Donnell M, Hart RG. Assessment of anticoagulation intensity and management of bleeding with old and new oral anticoagulants. Can J Cardiol 2013;29(7 suppl):S34-44. 10. Mandzia JL, Hill MD. Acute stroke management in patients with known or suspected atrial fibrillation. Can J Cardiol 2013;29(7 suppl):S45-53.
S3
11. Healey JS, Brambatti M. Periprocedural management of oral anticoagulation in patients with atrial fibrillation: approach in the era of new oral anticoagulants. Can J Cardiol 2013;29(7 suppl):S54-9. 12. Cairns JA, McMurtry MS. Oral antithrombotic therapy in atrial fibrillation associated with acute or chronic coronary artery disease. Can J Cardiol 2013;29(7 suppl):S60-70. 13. Hart RG, Eikelboom JW, Brimble KS, McMurtry MS, Ingram AJ. Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol 2013;29(7 suppl):S71-8. 14. Whitlock RP, Hanif H, Danter M. Nonpharmacologic approaches to stroke prevention in atrial fibrillation. Can J Cardiol 2013;29(7 suppl): S79-86.
Editorial
Anticoagulation for Atrial Fibrillation: State of the Art and Recommendations for a Quickly Moving Target Stanley Nattel, MD,a John Cairns, MD,b Jeffrey S. Healey, MSc, MD,c and Mario Talajic, MDa a
Department of Medicine, Montreal Heart Institute and Universite de Montre al, Montreal, Que bec, Canada b
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada c
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Atrial fibrillation (AF) will affect about 1 in 4 individuals over his or her lifetime; the population prevalence is 1%, rising to more than 10% in those > 80 years.1 The most significant and dreaded complication of AF is thromboembolic stroke: 70% of AF-related strokes result in death or severe disability. AF accounts for about 15% of all strokes and is the single most important cause in the elderly.2 Since its approval for human use in 1954, warfarin and other vitamin K antagonist (VKA) drugs had been, until recently, the only available oral anticoagulants for the prevention of stroke in patients with AF.3 Warfarin therapy was initially advised only for patients with AF who also had rheumatic mitral valve disease or a mitral valve prosthesis. However, the use of anticoagulants for stroke prevention in AF has changed dramatically over the past 20 years (Fig. 1). Epidemiologic evidence emerged that age-corrected annual stroke rates among patients with nonvalvular AF were similar to those with rheumatic valvular disease.3 This realization, combined with the possibility of safer VKA regimens because of standardization of prothrombin times using the international normalized ratio (INR) and evidence for the efficacy of moderate anticoagulation intensity, led to the conduct of clinical trials of VKA among patients with nonrheumatic AF. In 6 major trials, VKAs were shown to reduce the risk of stroke by twothirds, although the annual risk of major hemorrhage was about 1.3%.3 However, the safe and effective use of VKAs remains challenging for patients and physicians. Seemingly minor events like diet changes, alterations in concomitant drug therapy, and intercurrent illnesses can tip the balance toward life-threatening thromboembolic events or bleeding. Because of the narrow toxic-therapeutic index of VKAs, patients require close follow-up, regular monitoring of INRs, and frequent dose adjustments. Several new oral
Received for publication May 1, 2013. Accepted May 2, 2013. Corresponding author: Dr Stanley Nattel, 5000 Belanger St E, Montreal H1T 1C8, Quebec, Canada. Tel.: þ1-514-376-3330; fax: þ1-514-3761355. E-mail: [email protected] See page S2 for disclosure information.
anticoagulants (NOACs), the actions of which are independent of vitamin Kedependent coagulation factor synthesis and do not require regular laboratory monitoring, were developed in the 1990s. The successful completion of large phase III randomized controlled trials, followed by the recent approval of 3 NOACs, has created dramatic changes in the art of stroke prevention in patients with AF. The Canadian Cardiovascular Society (CCS) was the first major organization to recommend preferential use of NOACs for most patients with an indication for oral anticoagulation in its 2010 atrial fibrillation guidelines.4 Subsequently, other major societies adopted similar positions. With the rapid increases in information about, availability of, and use of NOACs, the CCS updated its guidelines for stroke prevention in AF within 2 years.5 At the time of the update (last year), the CCS AF Guidelines Committee recognized that sufficiently solid clinical trial data that would permit authoritative guidelines were lacking in relation to a wide range of important clinical management decisions regarding anticoagulation in patients with AF. At that point, it was suggested that a series of state of the art articles by experts in the field addressing such issues should be published as a supplement to the Canadian Journal of Cardiology (CJC). The present issue is the fruit of that reflection. Ahmad et al.6 begin by providing an overview of the epidemiology and risk determinants of stroke in patients with AF. These authors argue that in view of the superior safety of the NOACs and the finite stroke risk in most patients with AF, our clinical focus should shift to pinpointing the truly low-risk patient with AF who does not require anticoagulation, rather than identifying high-risk individuals. Glotzer and Ziegler7 follow with a discussion of the emerging role of silent AF as a stroke factor and the possible value of anticoagulants in preventing stroke for the many individuals who have AF and do not even know it. They emphasize the importance of prospective research to establish whether anticoagulating patients with silent AF prevents strokes, and if so, developing improved monitoring methods to efficiently identify at-risk individuals. Gong and Kim8 then review the pharmacokinetics of NOACs and the future of rational pharmacokinetically based dose selection. Their detailed
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.05.001
S2
Canadian Journal of Cardiology Volume 29 2013
Figure 1. Time line illustrating the evolution of oral anticoagulation from the first use of warfarin to the introduction of the new oral anticoagulants (NOACs). AFASAK, Atrial Fibrillation, Aspirin, Anticoagulation trial; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-term Anticoagulation Therapy; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.
analysis of the influence of pharmacokinetic factors on the plasma concentrationetime relationship argues for the establishment of dosing regimens that better consider the major determinants of individual patient NOAC drug disposition. Liew et al.9 review the methods and value of assessing anticoagulation intensity of NOACs and discuss the important problem of bleeding management in anticoagulated patients. They indicate that there are still no established indications for anticoagulation intensity assessment of NOACs and review the state of development of antidotes for NOACs in patients with life-threatening bleeding. Mandzia and Hill10 discuss the issue of acute stroke management in patients with AF. They consider the complexities of anticoagulation management according to the phase of stroke evolution in the unique context of the role that anticoagulants can play as either causative or therapeutic agents. Healey and Brambatti11 deal with the challenges of anticoagulation management in patients with AF at risk of stroke when they undergo invasive procedures associated with bleeding. The increasing recognition of the benefit of not interrupting anticoagulation for invasive procedures is emphasized, as are the differences resulting from the much briefer action of NOACs vs VKAs. Cairns and McMurtry12 consider the problem of patients with AF who have acute or chronic coronary artery disease, with indications for antiplatelet drug therapy that will further enhance the hemorrhagic risk. They emphasize the importance of prospective randomized trials to provide evidence-based recommendations. An area of particular importance and uncertainty identified in the CCS AF guidelines update was anticoagulation management of patients with AF with concomitant renal insufficiency.5 This issue is addressed here in detail by Hart et al.13. Finally, Whitlock et al.14 review the experience with nonpharmacologic approaches to stroke prevention in AF and consider when (if ever) they can replace oral anticoagulants. They conclude that for now such approaches should be considered purely investigational.
We hope that the present issue of the CJC will provide valuable knowledge to clinicians grappling with difficult management decisions and will serve to inform the elaboration of evidence-based practice guidelines in this rapidly moving arena. Funding Sources Funded by the Canadian Institutes of Health Research. Publication of this article is supported by Bayer Canada and by Pfizer and Bristol-Myers Squibb. Disclosures The authors have no conflicts of interest to disclose. References 1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110: 1042-6. 2. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229-34. 3. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M; CCS Atrial Fibrillation Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011;27:74-90. 4. Gillis AM, Skanes AC. Comparing the 2010 North American and European atrial fibrillation guidelines. Can J Cardiol 2011;27:7-13. 5. Skanes AC, Healey JS, Cairns JA, et al; Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36.
Nattel et al. Anticoagulation for AF 6. Ahmad Y, Lip GYH, Lane DA. Recent developments in understanding epidemiology and risk determinants of atrial fibrillation as a cause of stroke. Can J Cardiol 2013;29(7 suppl):S4-13. 7. Glotzer TV, Ziegler PD. Silent Atrial fibrillation as a stroke risk factor and anticoagulation indication. Can J Cardiol 2013;29(7 suppl):S14-23. 8. 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):S24-33. 9. Liew A, Eikelboom JW, O’Donnell M, Hart RG. Assessment of anticoagulation intensity and management of bleeding with old and new oral anticoagulants. Can J Cardiol 2013;29(7 suppl):S34-44. 10. Mandzia JL, Hill MD. Acute stroke management in patients with known or suspected atrial fibrillation. Can J Cardiol 2013;29(7 suppl):S45-53.
S3
11. Healey JS, Brambatti M. Periprocedural management of oral anticoagulation in patients with atrial fibrillation: approach in the era of new oral anticoagulants. Can J Cardiol 2013;29(7 suppl):S54-9. 12. Cairns JA, McMurtry MS. Oral antithrombotic therapy in atrial fibrillation associated with acute or chronic coronary artery disease. Can J Cardiol 2013;29(7 suppl):S60-70. 13. Hart RG, Eikelboom JW, Brimble KS, McMurtry MS, Ingram AJ. Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol 2013;29(7 suppl):S71-8. 14. Whitlock RP, Hanif H, Danter M. Nonpharmacologic approaches to stroke prevention in atrial fibrillation. Can J Cardiol 2013;29(7 suppl): S79-86.