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EDITORIAL COMMENTARY
Treatment of atrial fibrillation in East Asia: What is perception and what is reality? Jonathan P. Piccini, Sr, MD, MHS, FHRS From the Duke Center for Atrial Fibrillation, Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina.
Atrial fibrillation (AF) is a global problem, affecting more than 33 million people throughout the world.1 Despite the ubiquity of AF, there are differences across populations, race, and ethnicity. Asians are known to have a lower risk of developing AF compared with Caucasians.2 There is also some evidence that East Asians have a lower risk of stroke attributable to AF.3,4 In addition to the lower risk of AF and AF-related stroke in East Asia, the risks of oral anticoagulation are greater in East Asians, principally owing to a higher risk of intracranial hemorrhage (ICH) compared with other ethnic groups.3,5 Because of these concerns, oral anticoagulation for the prevention of stroke in nonvalvular AF is often avoided in East Asia or underdosed with lower international normalized ratio targets (1.6–2.5).3,4,6 The goals of care in AF are always the same: to prevent stroke, to control heart rate, and to eliminate symptoms. Are the perceptions of lower stroke risk and diminished benefit of oral anticoagulation in East Asia justified or are they overstated? While we know that there are differences between AF populations, should our approaches to treatment be different in one neighborhood, country, or culture to the next? In this issue of HeartRhythm, Siu et al7 describe the risk of stroke and ICH in a large contemporary Chinese population with nonvalvular AF. After analyzing the baseline characteristics and outcomes in nearly 10,000 patients treated between 1997 and 2011 at Queen Mary Hospital in Hong Kong, they found that only 26% of the patients with a CHADS2 score of 2 or greater received oral anticoagulation. The annual risk of stroke in untreated patients was 9.3% per year. Surprisingly, the annual risk of stroke in the lowest-risk patients (CHA2DS2-VASc score ¼ 0) was 2.4%. In this East Asian cohort, the performance of the CHA2DS2-VASc score for predicting stroke was poor, with a C-statistic of 0.53, which Dr Piccini has received research funding from Boston Scientific, GE Healthcare, Janssen Pharmaceuticals, and ResMed and provides consulting to Biosense Webster, Johnson & Johnson, Medtronic, and Spectranetics. Address reprint requests and correspondence: Dr Jonathan P. Piccini, Duke Center for Atrial Fibrillation, Duke University Medical Center, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27710. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
is only marginally better than a coin toss (C-statistic ¼ 0.5). The annual risk of ICH was 0.5% without treatment, 0.77% in those treated with aspirin, and 0.8% in those treated with warfarin. Finally, and most importantly, net clinical benefit8 favored oral anticoagulation in all patients with a CHA2DS2VASc score of 1 or greater regardless of bleeding risk. The results of Siu et al are striking. The Hong Kong cohort described by these authors is a high-risk population, which is in stark contrast to the common perception that East Asian patients with nonvalvular AF have lower risk compared with other populations. The rate of stroke in those patients with a CHA2DS2-VASc core of 0 was 2.4% per year. This rate is dramatically higher than the 0% observed in the original description of the CHA2DS2-VASc score in the Euro Heart Survey or the 0.8% described in the National Danish Registry validation study.9,10 As most clinicians would consider anticoagulated patients with an annual stroke risk of 2.4%, it raises the question as to whether the CHA2DS2VASc score can accurately identify low-risk patients in this region. The overall predictive power of the CHA2DS2-VASc score was lower than that observed in non-Asian cohorts. For example, in the Swedish Atrial Fibrillation cohort study, the CHA2DS2-VASc scoring system exhibited a C-statistic of 0.67. Why was the stroke rate so high in the Hong Kong cohort and why was the CHA2DS2-VASc score unable to identify truly low-risk patients? There are several possibilities. First, the cohort was a hospital-based registry and therefore may have been biased to higher event rates, although this seems unlikely since other CHA2DS2-VASc validations have included hospitalized patients.9,10 Another possibility is underrecognition of comorbidities. It is possible that many of the patients with a CHA2DS2-VASc score of 0 may have had undiagnosed hypertension or diabetes. However, it is also possible that other (non-CHA2DS2-VASc) factors were influencing the risk of stroke in these patients, including tobacco use, metabolic syndrome, or impaired renal function. Recent reports suggest that the inclusion of the metabolic syndrome improves stroke risk stratification in Taiwanese patients.11 In addition, patients from East Asia enrolled in the ROCKET AF trial had worse renal function than do their http://dx.doi.org/10.1016/j.hrthm.2014.05.016
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 Q5 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 Q6108
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non-Asian counterparts and higher risks of stroke despite lower CHA2DS2-VASc scores.12 The other striking feature of the Hong Kong cohort was the extremely limited use of oral anticoagulation in them. In patients with a CHADS2 score of 2 or greater, aspirin was often preferred over warfarin for stroke prevention (43% vs 26%). Aspirin therapy in the Hong Kong cohort was not a safer alternative, as it led to a risk of ICH similar to that warfarin. Thus, the East Asia data from Siu et al reinforce what we have learned from numerous randomized clinical trials: the optimal treatment for patients with nonvalvular AF at moderate to high risk of stroke is oral anticoagulation. There are several additional limitations that we need to bear in mind when considering the data from Siu et al. First, it was a single-center study and it may not be representative of other cohorts in China, let alone other parts of East Asia. While treatment at baseline was known, drug adherence in follow-up and the quality of warfarin therapy (time in therapeutic range) were not available. It is possible (and likely) that some of the strokes in this cohort were noncardioembolic and may have been unrelated to AF (ie, vascular disease). Finally, because of the time span of the study, these data do not include non–vitamin K antagonists. Since these anticoagulants have a lower risk of ICH,13 it is likely that the net clinical benefit of oral anticoagulation would be even greater with these alternative agents. What do these data tell us about stroke prevention in East Asia (and elsewhere)? First and foremost, the findings from Siu et al and other recent reports highlight the fact that East Asian AF cohorts are at higher risk for stroke compared with persons outside of East Asia.7,12 Consistent with risk-benefit analyses in other populations, oral anticoagulation is the optimal method of stroke prevention in patients with nonvalvular AF at intermediate to high risk for stroke. Aspirin should not be substituted for oral anticoagulation, as it provides inferior protection without a reduction in bleeding. An unanswered question in East Asia, and highlighted in the recent AHA/ACC/HRS guidelines,14 is “What level of risk merits oral anticoagulation?” While the patients with a CHA2DS2-VASc score of 0–1 had a substantial risk of stroke,
Heart Rhythm, Vol 0, No 0, Month 2014 these findings need to be validated in other cohorts. Furthermore, given the limited discriminatory power of the CHA2DS2-VASc scoring system in this cohort and its inability to define low-risk patients, better stroke risk stratification techniques are needed for East Asian populations. In the end, the findings from Siu et al remind us that when it comes to treatment of AF and prevention of stroke, perception is not always reality.
References 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2013;XX:XX– XX. 2. Dewland TA, Olgin JE, Vittinghoff E, Marcus GM. Incident atrial fibrillation among Asians, Hispanics, blacks, and whites. Circulation 2013;128:2470–2477. 3. Tse HF, Wang YJ, Ahmed Ai-Abdullah M, et al. Stroke prevention in atrial fibrillation—an Asian stroke perspective. Heart Rhythm 2013;10:1082–1088. 4. Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J Epidemiol 2008;18:209–216. 5. Zhang LF, Yang J, Hong Z, et al. Proportion of different subtypes of stroke in China. Stroke 2003;34:2091–2096. 6. Huang CX, Zhang S, Ma CS, Yang YZ, Huang DJ, Cao KJ. Current knowledge and management recommendations of atrial fibrillation. Chinese J Arrhythm 2010;14:328–369. 7. Siu CW, Lip GYH, Lam K, Tse HF. Risk of stroke and intracranial hemorrhage in 9,727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 2014;XX: XX–XX. 8. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297–305. 9. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010;137:263–272. 10. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 11. Tsai CT, Chang SH, Chang SN, et al. Additive effect of the metabolic syndrome score to the conventional CHADS(2) score for the thromboembolic risk stratification of patients with atrial fibrillation. Heart Rhythm 2014;11:352–357. 12. Wong KS, Hu DY, Oomman A, et al. rivaroxaban for stroke prevention in east asian patients from the ROCKET AF trial. Stroke 2014;XX:XX–XX. 13. 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 metaanalysis of randomised trials. Lancet 2014;383:955–962. 14. January CT, Wann LS, Alpert JS, 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. Circulation 2014;XX:XX–XX.
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EDITORIAL COMMENTARY
Treatment of atrial fibrillation in East Asia: What is perception and what is reality? Jonathan P. Piccini, Sr, MD, MHS, FHRS From the Duke Center for Atrial Fibrillation, Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina.
Atrial fibrillation (AF) is a global problem, affecting more than 33 million people throughout the world.1 Despite the ubiquity of AF, there are differences across populations, race, and ethnicity. Asians are known to have a lower risk of developing AF compared with Caucasians.2 There is also some evidence that East Asians have a lower risk of stroke attributable to AF.3,4 In addition to the lower risk of AF and AF-related stroke in East Asia, the risks of oral anticoagulation are greater in East Asians, principally owing to a higher risk of intracranial hemorrhage (ICH) compared with other ethnic groups.3,5 Because of these concerns, oral anticoagulation for the prevention of stroke in nonvalvular AF is often avoided in East Asia or underdosed with lower international normalized ratio targets (1.6–2.5).3,4,6 The goals of care in AF are always the same: to prevent stroke, to control heart rate, and to eliminate symptoms. Are the perceptions of lower stroke risk and diminished benefit of oral anticoagulation in East Asia justified or are they overstated? While we know that there are differences between AF populations, should our approaches to treatment be different in one neighborhood, country, or culture to the next? In this issue of HeartRhythm, Siu et al7 describe the risk of stroke and ICH in a large contemporary Chinese population with nonvalvular AF. After analyzing the baseline characteristics and outcomes in nearly 10,000 patients treated between 1997 and 2011 at Queen Mary Hospital in Hong Kong, they found that only 26% of the patients with a CHADS2 score of 2 or greater received oral anticoagulation. The annual risk of stroke in untreated patients was 9.3% per year. Surprisingly, the annual risk of stroke in the lowest-risk patients (CHA2DS2-VASc score ¼ 0) was 2.4%. In this East Asian cohort, the performance of the CHA2DS2-VASc score for predicting stroke was poor, with a C-statistic of 0.53, which Dr Piccini has received research funding from Boston Scientific, GE Healthcare, Janssen Pharmaceuticals, and ResMed and provides consulting to Biosense Webster, Johnson & Johnson, Medtronic, and Spectranetics. Address reprint requests and correspondence: Dr Jonathan P. Piccini, Duke Center for Atrial Fibrillation, Duke University Medical Center, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27710. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
is only marginally better than a coin toss (C-statistic ¼ 0.5). The annual risk of ICH was 0.5% without treatment, 0.77% in those treated with aspirin, and 0.8% in those treated with warfarin. Finally, and most importantly, net clinical benefit8 favored oral anticoagulation in all patients with a CHA2DS2VASc score of 1 or greater regardless of bleeding risk. The results of Siu et al are striking. The Hong Kong cohort described by these authors is a high-risk population, which is in stark contrast to the common perception that East Asian patients with nonvalvular AF have lower risk compared with other populations. The rate of stroke in those patients with a CHA2DS2-VASc core of 0 was 2.4% per year. This rate is dramatically higher than the 0% observed in the original description of the CHA2DS2-VASc score in the Euro Heart Survey or the 0.8% described in the National Danish Registry validation study.9,10 As most clinicians would consider anticoagulated patients with an annual stroke risk of 2.4%, it raises the question as to whether the CHA2DS2VASc score can accurately identify low-risk patients in this region. The overall predictive power of the CHA2DS2-VASc score was lower than that observed in non-Asian cohorts. For example, in the Swedish Atrial Fibrillation cohort study, the CHA2DS2-VASc scoring system exhibited a C-statistic of 0.67. Why was the stroke rate so high in the Hong Kong cohort and why was the CHA2DS2-VASc score unable to identify truly low-risk patients? There are several possibilities. First, the cohort was a hospital-based registry and therefore may have been biased to higher event rates, although this seems unlikely since other CHA2DS2-VASc validations have included hospitalized patients.9,10 Another possibility is underrecognition of comorbidities. It is possible that many of the patients with a CHA2DS2-VASc score of 0 may have had undiagnosed hypertension or diabetes. However, it is also possible that other (non-CHA2DS2-VASc) factors were influencing the risk of stroke in these patients, including tobacco use, metabolic syndrome, or impaired renal function. Recent reports suggest that the inclusion of the metabolic syndrome improves stroke risk stratification in Taiwanese patients.11 In addition, patients from East Asia enrolled in the ROCKET AF trial had worse renal function than do their http://dx.doi.org/10.1016/j.hrthm.2014.05.016
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non-Asian counterparts and higher risks of stroke despite lower CHA2DS2-VASc scores.12 The other striking feature of the Hong Kong cohort was the extremely limited use of oral anticoagulation in them. In patients with a CHADS2 score of 2 or greater, aspirin was often preferred over warfarin for stroke prevention (43% vs 26%). Aspirin therapy in the Hong Kong cohort was not a safer alternative, as it led to a risk of ICH similar to that warfarin. Thus, the East Asia data from Siu et al reinforce what we have learned from numerous randomized clinical trials: the optimal treatment for patients with nonvalvular AF at moderate to high risk of stroke is oral anticoagulation. There are several additional limitations that we need to bear in mind when considering the data from Siu et al. First, it was a single-center study and it may not be representative of other cohorts in China, let alone other parts of East Asia. While treatment at baseline was known, drug adherence in follow-up and the quality of warfarin therapy (time in therapeutic range) were not available. It is possible (and likely) that some of the strokes in this cohort were noncardioembolic and may have been unrelated to AF (ie, vascular disease). Finally, because of the time span of the study, these data do not include non–vitamin K antagonists. Since these anticoagulants have a lower risk of ICH,13 it is likely that the net clinical benefit of oral anticoagulation would be even greater with these alternative agents. What do these data tell us about stroke prevention in East Asia (and elsewhere)? First and foremost, the findings from Siu et al and other recent reports highlight the fact that East Asian AF cohorts are at higher risk for stroke compared with persons outside of East Asia.7,12 Consistent with risk-benefit analyses in other populations, oral anticoagulation is the optimal method of stroke prevention in patients with nonvalvular AF at intermediate to high risk for stroke. Aspirin should not be substituted for oral anticoagulation, as it provides inferior protection without a reduction in bleeding. An unanswered question in East Asia, and highlighted in the recent AHA/ACC/HRS guidelines,14 is “What level of risk merits oral anticoagulation?” While the patients with a CHA2DS2-VASc score of 0–1 had a substantial risk of stroke,
Heart Rhythm, Vol 0, No 0, Month 2014 these findings need to be validated in other cohorts. Furthermore, given the limited discriminatory power of the CHA2DS2-VASc scoring system in this cohort and its inability to define low-risk patients, better stroke risk stratification techniques are needed for East Asian populations. In the end, the findings from Siu et al remind us that when it comes to treatment of AF and prevention of stroke, perception is not always reality.
References 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2013;XX:XX– XX. 2. Dewland TA, Olgin JE, Vittinghoff E, Marcus GM. Incident atrial fibrillation among Asians, Hispanics, blacks, and whites. Circulation 2013;128:2470–2477. 3. Tse HF, Wang YJ, Ahmed Ai-Abdullah M, et al. Stroke prevention in atrial fibrillation—an Asian stroke perspective. Heart Rhythm 2013;10:1082–1088. 4. Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J Epidemiol 2008;18:209–216. 5. Zhang LF, Yang J, Hong Z, et al. Proportion of different subtypes of stroke in China. Stroke 2003;34:2091–2096. 6. Huang CX, Zhang S, Ma CS, Yang YZ, Huang DJ, Cao KJ. Current knowledge and management recommendations of atrial fibrillation. Chinese J Arrhythm 2010;14:328–369. 7. Siu CW, Lip GYH, Lam K, Tse HF. Risk of stroke and intracranial hemorrhage in 9,727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 2014;XX: XX–XX. 8. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297–305. 9. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010;137:263–272. 10. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 11. Tsai CT, Chang SH, Chang SN, et al. Additive effect of the metabolic syndrome score to the conventional CHADS(2) score for the thromboembolic risk stratification of patients with atrial fibrillation. Heart Rhythm 2014;11:352–357. 12. Wong KS, Hu DY, Oomman A, et al. rivaroxaban for stroke prevention in east asian patients from the ROCKET AF trial. Stroke 2014;XX:XX–XX. 13. 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 metaanalysis of randomised trials. Lancet 2014;383:955–962. 14. January CT, Wann LS, Alpert JS, 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. Circulation 2014;XX:XX–XX.
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