Journal of Cardiology 63 (2014) 169–170
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Editorial
Atrial fibrillation and coronary artery disease: Resembling twins?
Keywords: Atrial fibrillation Coronary artery disease Risk factor Anti-thrombotic therapy
Atrial fibrillation (AF) represents the most common arrhythmia, and it substantially increases the risk of stroke and death. The prevalence of AF is gradually increasing in Japan, as the population ages [1]. Coronary artery disease (CAD) is also prevalent among elderly people, and thus there are many patients who have both disorders. Furthermore, AF and CAD share common mechanistic backgrounds; long-lasting injuries in the atrial or arterial wall due to hemodynamic or metabolic stress are the underlying mechanisms. Patients with AF more often have concomitant CAD, compared with healthy sinus rhythm controls [2,3], and patients with atherosclerosis more often have concomitant AF [4]. Furthermore, patients with acute coronary syndrome showed worse outcomes if they had concomitant AF; in-hospital, 30-day, and 1-year adverse outcome [5]. However, there has been limited information focusing on the association of AF and CAD in Japanese patients. In this large-scale long-term registry of patients with any kind of cardiovascular disease in a single center in an urban district of Japan, Senoo et al. carried out retrospective surveillance of the prevalence and prognosis of CAD in patients with AF [6]. Prevalence of CAD in AF patients In this paper [6], the prevalence of CAD in AF patients was reported to be 6.4%, which is much lower than reports from Western countries (18–34%, as stated in the paper), and also even lower than other studies in Japan: 10.1% in the J-RHYTHM registry [7], 15.0% in the Fushimi AF Registry [8], and 19% in the Hokuriku AF trial [9]. However, the lower prevalence in the present study is perhaps mainly due to the younger age of the registered patients in this study (63.2 years in this study, 69.7 years in the J-RHYTHM registry, 74.2 years in the Fushimi AF Registry, and 72 in the Hokuriku AF trial). Since the patients were enrolled from one of the most specialized cardiovascular centers of Japan, those patients were supposed to undergo comprehensive assessment of CAD, and thus it is unlikely that CAD was underdiagnosed. The lower prevalence of CAD in Japanese patients compared with Western
DOI of original article: http://dx.doi.org/10.1016/j.jjcc.2013.08.007.
countries is, as the authors discussed in the paper, most likely to be attributed to the differences in patients’ risk profiles. Especially in the elderly generation, differences in the life-style including the status of diet or nutrition between Japan and Western countries are more distinct. Incidence of coronary events in AF patients There has been limited information regarding the incidence of coronary events in AF patients, and the data are varied among studies, since the selection criteria (and thus the risk profiles) of the patients or the definition of coronary events were heterogeneous. This makes it difficult to make a precise comparison across studies. In this paper by Senoo et al., the incidence rate of coronary events was 1.9%/year, under the definition of “coronary events” as hospitalization for myocardial infarction, unstable angina, or stable angina. The actual distribution of each event is not indicated, but the incidence of acute coronary syndrome (myocardial infarction or unstable angina) is assumed to be substantially lower than this value. The international large-scale randomized trials of novel oral anticoagulants in AF patients reported as follows: 0.53% (myocardial infarction) in the warfarin arm of the RE-LY trial [10], not available in the ROCKET-AF trial [11], and 0.61% (myocardial infarction) in the warfarin arm of the ARISTOTLE trial [12]. The registry studies of Japanese AF patients reported as follows: not available in the J-RHYTHM registry [7], 0.4% (myocardial infarction) in Fushimi AF Registry (preliminary data reported at the European Society of Cardiology congress 2013 [13]), not available in the Hokuriku AF trial [9]. The REACH registry reported a much higher number: 1.36% non-fatal myocardial infarction and 5.95% unstable angina in AF patients [4]. However, in the REACH registry, patients with highrisk profiles (either established atherosclerotic disease or ≥3 risk factors for atherosclerosis) were enrolled, but low-to-intermediate risk patients were not included. The incidence of coronary events is varied depending on the risk profiles of each patient population, but the presence of CAD should carefully be watched during the management of any AF patients. CHADS2 score to predict coronary event CHADS2 score is a well-established risk stratification scheme for the prediction of stroke in patients with AF [14], but it was also reported to be useful, to some extent, for the prediction of coronary events [4]. Also in this study, there was a significant linear association between CHADS2 score and annual coronary events. However, the independent predictors of the incidence of coronary events were limited to a history of CAD and older age. AF and CAD
0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.09.010
170
Editorial / Journal of Cardiology 63 (2014) 169–170
share a number of common backgrounds, but the pathogenesis and the triggers of acute events may be different.
[2]
Concomitant use of anti-thrombotic therapy in patients with AF and CAD Anti-thrombotic therapy is indicated for the treatment of both AF and CAD. Oral anticoagulant (OAC) therapy is the mainstay of treatment for AF patients at risk for stroke. Patients with AF who have concomitant CAD may be put on antiplatelet drug (APD) therapy in addition to OAC. However, the incremental benefit of APD added to OAC in patients with AF is unclear. Indeed, the use of OAC + APD was independently associated with significantly increased risk for bleeding compared with the use of OAC alone. To date, there have been limited data available to define current patterns of use of concomitant APD along with OAC in AF patients. Furthermore, the risks of such combinations in community practice remain poorly defined. The WOEST study is an open-label, multicenter trial in patients who require OAC and APD after stent implantation by percutaneous coronary intervention [15]. Patients taking warfarin (controlled by monitoring of international normalized ratio) were randomly assigned to receive warfarin plus clopidogrel alone (double therapy) or plus clopidogrel and aspirin (triple therapy). As a result, markedly fewer bleeding episodes were seen with double therapy than with triple therapy. Additionally, mortality at 1 year, a secondary endpoint, was significantly lower with double therapy than with triple therapy. This trial raised the possibility that a less is more strategy may be favorable among AF patients on OAC. Despite the increasing attention to the excess risk of bleeding in the combination therapy, the therapeutic regimens are not always appropriate; the ORBIT-AF registry recently reported that many AF patients receiving OAC are often treated with APD, even when they do not have atherosclerotic vascular diseases [16]. The WOEST trial was under-powered to draw definite conclusions, but adequately powered, prospective clinical studies of these regimens are warranted to assess the benefit or harm of such strategies. Physicians need to assess the severity or activity of both AF and CAD, and carefully weigh whether the potential benefits of adding APD are worth the risk among patients with AF on OAC. Summary AF and CAD resemble twins; they have common mechanistic backgrounds and common risk factors based on the underlying aging process, and similar therapeutic strategy to prevent thrombosis. However, there are also distinct differences in the pathogenesis and the mechanisms of acute events. Therefore, different riskstratification schemes and different strategies for the prevention of events are required. There has not been a comprehensive report examining the prevalence of CAD and the incidence of coronary events in Japanese patients with AF, and the present study provides important information on this issue. The accumulation of these prospective clinical data will be essential for the better management of AF patients, especially from the viewpoint of optimization of anti-thrombotic treatment. References [1] Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, Aizawa Y, Yamashita T, Atarashi H, Horie M, Ohe T, Doi Y, Shimizu A, Chishaki A, Saikawa T, et al.
[3]
[4]
[5]
[6] [7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol 2009;137:102–7. Weijs B, Pisters R, Haest RJ, Kragten JA, Joosen IA, Versteylen M, Timmermans CC, Pison L, Blaauw Y, Hofstra L, Nieuwlaat R, Wildberger J, Crijns HJ. Patients originally diagnosed with idiopathic atrial fibrillation more often suffer from insidious coronary artery disease compared to healthy sinus rhythm controls. Heart Rhythm 2012;9:1923–9. Kakkar AK, Mueller I, Bassand JP, Fitzmaurice DA, Goldhaber SZ, Goto S, Haas S, Hacke W, Lip GY, Mantovani LG, Turpie AG, van Eickels M, Misselwitz F, Rushton-Smith S, Kayani G, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS ONE 2013;8:e63479. Goto S, Bhatt DL, Rother J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau CS, Hirsch AT, Mas JL, Wilson PW, Corbalan R, Aichner F, et al. Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. Am Heart J 2008;156:855–63. Hersi A, Alhabib KF, Alsheikh-Ali AA, Sulaiman K, Alfaleh HF, Alsaif S, AlMahmeed W, Asaad N, Haitham A, Al-Motarreb A, Suwaidi J, Shehab A. Prognostic significance of prevalent and incident atrial fibrillation among patients hospitalized with acute coronary syndrome: findings from the Gulf RACE-2 Registry. Angiology 2012;63:466–71. Senoo K. Coronary artery diseases in patients with Japanese nonvalvular atrial fibrillation. J Cardiol 2014;63:123–7. Atarashi H, Inoue H, Okumura K, Yamashita T, Kumagai N, Origasa H. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: a report from the J-RHYTHM Registry. Circ J 2011;75:1328–33. Akao M, Chun Y, Wada H, Esato M, Hashimoto T, Abe M, Hasegawa K, Tsuji H, Furuke K. Current status of clinical background of patients with atrial fibrillation in a community-based survey: the Fushimi AF Registry. J Cardiol 2013;61:260–6. Furusho H, Takamura M, Takata S, Sakagami S, Hirazawa M, Kato T, Murai H, Okajima M, Kaneko S. Current status of anticoagulation therapy for elderly atrial fibrillation patients in Japan: from Hokuriku atrial fibrillation trial. Circ J 2008;72:2058–61. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, AlKhalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. Akao M, Ogawa H, Masunaga N, Ishii M, Abe M, Esato M, Chun YH, Tsuji H, Wada H, Hasegawa K. Incidence of thromboembolic events in patients with atrial fibrillation in Japan: one-year follow-up from the Fushimi AF registry. Eur Heart J 2013;34(Suppl. 1):98. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van’t Hof AW, ten Berg JM. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–15. Steinberg BA, Kim S, Piccini JP, Fonarow GC, Lopes RD, Thomas L, Ezekowitz MD, Ansell J, Kowey P, Singer DE, Gersh B, Mahaffey KW, Hylek E, Go AS, Chang P, et al. Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation 2013;128:721–8.
Masaharu Akao (MD, PhD) ∗ Department of Cardiology, National Hospital Organization Kyoto Medical Center, 1-1, Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan ∗ Tel.:
+81 075 641 9161; fax: +81 075 643 4325. E-mail address: [email protected] 17 September 2013 Available online 1 November 2013
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Editorial
Atrial fibrillation and coronary artery disease: Resembling twins?
Keywords: Atrial fibrillation Coronary artery disease Risk factor Anti-thrombotic therapy
Atrial fibrillation (AF) represents the most common arrhythmia, and it substantially increases the risk of stroke and death. The prevalence of AF is gradually increasing in Japan, as the population ages [1]. Coronary artery disease (CAD) is also prevalent among elderly people, and thus there are many patients who have both disorders. Furthermore, AF and CAD share common mechanistic backgrounds; long-lasting injuries in the atrial or arterial wall due to hemodynamic or metabolic stress are the underlying mechanisms. Patients with AF more often have concomitant CAD, compared with healthy sinus rhythm controls [2,3], and patients with atherosclerosis more often have concomitant AF [4]. Furthermore, patients with acute coronary syndrome showed worse outcomes if they had concomitant AF; in-hospital, 30-day, and 1-year adverse outcome [5]. However, there has been limited information focusing on the association of AF and CAD in Japanese patients. In this large-scale long-term registry of patients with any kind of cardiovascular disease in a single center in an urban district of Japan, Senoo et al. carried out retrospective surveillance of the prevalence and prognosis of CAD in patients with AF [6]. Prevalence of CAD in AF patients In this paper [6], the prevalence of CAD in AF patients was reported to be 6.4%, which is much lower than reports from Western countries (18–34%, as stated in the paper), and also even lower than other studies in Japan: 10.1% in the J-RHYTHM registry [7], 15.0% in the Fushimi AF Registry [8], and 19% in the Hokuriku AF trial [9]. However, the lower prevalence in the present study is perhaps mainly due to the younger age of the registered patients in this study (63.2 years in this study, 69.7 years in the J-RHYTHM registry, 74.2 years in the Fushimi AF Registry, and 72 in the Hokuriku AF trial). Since the patients were enrolled from one of the most specialized cardiovascular centers of Japan, those patients were supposed to undergo comprehensive assessment of CAD, and thus it is unlikely that CAD was underdiagnosed. The lower prevalence of CAD in Japanese patients compared with Western
DOI of original article: http://dx.doi.org/10.1016/j.jjcc.2013.08.007.
countries is, as the authors discussed in the paper, most likely to be attributed to the differences in patients’ risk profiles. Especially in the elderly generation, differences in the life-style including the status of diet or nutrition between Japan and Western countries are more distinct. Incidence of coronary events in AF patients There has been limited information regarding the incidence of coronary events in AF patients, and the data are varied among studies, since the selection criteria (and thus the risk profiles) of the patients or the definition of coronary events were heterogeneous. This makes it difficult to make a precise comparison across studies. In this paper by Senoo et al., the incidence rate of coronary events was 1.9%/year, under the definition of “coronary events” as hospitalization for myocardial infarction, unstable angina, or stable angina. The actual distribution of each event is not indicated, but the incidence of acute coronary syndrome (myocardial infarction or unstable angina) is assumed to be substantially lower than this value. The international large-scale randomized trials of novel oral anticoagulants in AF patients reported as follows: 0.53% (myocardial infarction) in the warfarin arm of the RE-LY trial [10], not available in the ROCKET-AF trial [11], and 0.61% (myocardial infarction) in the warfarin arm of the ARISTOTLE trial [12]. The registry studies of Japanese AF patients reported as follows: not available in the J-RHYTHM registry [7], 0.4% (myocardial infarction) in Fushimi AF Registry (preliminary data reported at the European Society of Cardiology congress 2013 [13]), not available in the Hokuriku AF trial [9]. The REACH registry reported a much higher number: 1.36% non-fatal myocardial infarction and 5.95% unstable angina in AF patients [4]. However, in the REACH registry, patients with highrisk profiles (either established atherosclerotic disease or ≥3 risk factors for atherosclerosis) were enrolled, but low-to-intermediate risk patients were not included. The incidence of coronary events is varied depending on the risk profiles of each patient population, but the presence of CAD should carefully be watched during the management of any AF patients. CHADS2 score to predict coronary event CHADS2 score is a well-established risk stratification scheme for the prediction of stroke in patients with AF [14], but it was also reported to be useful, to some extent, for the prediction of coronary events [4]. Also in this study, there was a significant linear association between CHADS2 score and annual coronary events. However, the independent predictors of the incidence of coronary events were limited to a history of CAD and older age. AF and CAD
0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.09.010
170
Editorial / Journal of Cardiology 63 (2014) 169–170
share a number of common backgrounds, but the pathogenesis and the triggers of acute events may be different.
[2]
Concomitant use of anti-thrombotic therapy in patients with AF and CAD Anti-thrombotic therapy is indicated for the treatment of both AF and CAD. Oral anticoagulant (OAC) therapy is the mainstay of treatment for AF patients at risk for stroke. Patients with AF who have concomitant CAD may be put on antiplatelet drug (APD) therapy in addition to OAC. However, the incremental benefit of APD added to OAC in patients with AF is unclear. Indeed, the use of OAC + APD was independently associated with significantly increased risk for bleeding compared with the use of OAC alone. To date, there have been limited data available to define current patterns of use of concomitant APD along with OAC in AF patients. Furthermore, the risks of such combinations in community practice remain poorly defined. The WOEST study is an open-label, multicenter trial in patients who require OAC and APD after stent implantation by percutaneous coronary intervention [15]. Patients taking warfarin (controlled by monitoring of international normalized ratio) were randomly assigned to receive warfarin plus clopidogrel alone (double therapy) or plus clopidogrel and aspirin (triple therapy). As a result, markedly fewer bleeding episodes were seen with double therapy than with triple therapy. Additionally, mortality at 1 year, a secondary endpoint, was significantly lower with double therapy than with triple therapy. This trial raised the possibility that a less is more strategy may be favorable among AF patients on OAC. Despite the increasing attention to the excess risk of bleeding in the combination therapy, the therapeutic regimens are not always appropriate; the ORBIT-AF registry recently reported that many AF patients receiving OAC are often treated with APD, even when they do not have atherosclerotic vascular diseases [16]. The WOEST trial was under-powered to draw definite conclusions, but adequately powered, prospective clinical studies of these regimens are warranted to assess the benefit or harm of such strategies. Physicians need to assess the severity or activity of both AF and CAD, and carefully weigh whether the potential benefits of adding APD are worth the risk among patients with AF on OAC. Summary AF and CAD resemble twins; they have common mechanistic backgrounds and common risk factors based on the underlying aging process, and similar therapeutic strategy to prevent thrombosis. However, there are also distinct differences in the pathogenesis and the mechanisms of acute events. Therefore, different riskstratification schemes and different strategies for the prevention of events are required. There has not been a comprehensive report examining the prevalence of CAD and the incidence of coronary events in Japanese patients with AF, and the present study provides important information on this issue. The accumulation of these prospective clinical data will be essential for the better management of AF patients, especially from the viewpoint of optimization of anti-thrombotic treatment. References [1] Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, Aizawa Y, Yamashita T, Atarashi H, Horie M, Ohe T, Doi Y, Shimizu A, Chishaki A, Saikawa T, et al.
[3]
[4]
[5]
[6] [7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol 2009;137:102–7. Weijs B, Pisters R, Haest RJ, Kragten JA, Joosen IA, Versteylen M, Timmermans CC, Pison L, Blaauw Y, Hofstra L, Nieuwlaat R, Wildberger J, Crijns HJ. Patients originally diagnosed with idiopathic atrial fibrillation more often suffer from insidious coronary artery disease compared to healthy sinus rhythm controls. Heart Rhythm 2012;9:1923–9. Kakkar AK, Mueller I, Bassand JP, Fitzmaurice DA, Goldhaber SZ, Goto S, Haas S, Hacke W, Lip GY, Mantovani LG, Turpie AG, van Eickels M, Misselwitz F, Rushton-Smith S, Kayani G, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS ONE 2013;8:e63479. Goto S, Bhatt DL, Rother J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau CS, Hirsch AT, Mas JL, Wilson PW, Corbalan R, Aichner F, et al. Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. Am Heart J 2008;156:855–63. Hersi A, Alhabib KF, Alsheikh-Ali AA, Sulaiman K, Alfaleh HF, Alsaif S, AlMahmeed W, Asaad N, Haitham A, Al-Motarreb A, Suwaidi J, Shehab A. Prognostic significance of prevalent and incident atrial fibrillation among patients hospitalized with acute coronary syndrome: findings from the Gulf RACE-2 Registry. Angiology 2012;63:466–71. Senoo K. Coronary artery diseases in patients with Japanese nonvalvular atrial fibrillation. J Cardiol 2014;63:123–7. Atarashi H, Inoue H, Okumura K, Yamashita T, Kumagai N, Origasa H. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: a report from the J-RHYTHM Registry. Circ J 2011;75:1328–33. Akao M, Chun Y, Wada H, Esato M, Hashimoto T, Abe M, Hasegawa K, Tsuji H, Furuke K. Current status of clinical background of patients with atrial fibrillation in a community-based survey: the Fushimi AF Registry. J Cardiol 2013;61:260–6. Furusho H, Takamura M, Takata S, Sakagami S, Hirazawa M, Kato T, Murai H, Okajima M, Kaneko S. Current status of anticoagulation therapy for elderly atrial fibrillation patients in Japan: from Hokuriku atrial fibrillation trial. Circ J 2008;72:2058–61. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, AlKhalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. Akao M, Ogawa H, Masunaga N, Ishii M, Abe M, Esato M, Chun YH, Tsuji H, Wada H, Hasegawa K. Incidence of thromboembolic events in patients with atrial fibrillation in Japan: one-year follow-up from the Fushimi AF registry. Eur Heart J 2013;34(Suppl. 1):98. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van’t Hof AW, ten Berg JM. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–15. Steinberg BA, Kim S, Piccini JP, Fonarow GC, Lopes RD, Thomas L, Ezekowitz MD, Ansell J, Kowey P, Singer DE, Gersh B, Mahaffey KW, Hylek E, Go AS, Chang P, et al. Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation 2013;128:721–8.
Masaharu Akao (MD, PhD) ∗ Department of Cardiology, National Hospital Organization Kyoto Medical Center, 1-1, Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan ∗ Tel.:
+81 075 641 9161; fax: +81 075 643 4325. E-mail address: [email protected] 17 September 2013 Available online 1 November 2013
