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Cardioembolic Stroke Is the Most Serious Problem in the Aging Society: Japan Standard Stroke Registry Study
Cardioembolic Stroke Is the Most Serious Problem in the Aging Society: Japan Standard Stroke Registry Study Yuji Kato, MD, PhD,* Takeshi Hayashi, MD, PhD,* Norio Tanahashi, MD, PhD,* Shotai Kobayashi, MD, PhD,† and the Japan Standard Stroke Registry Study Group
Background: Japan has the fastest aging society in the world. Older patients have a different stroke risk profile and different stroke features compared with younger patients. The aim of the present study was to examine the stroke subtypes, risk factor profiles, stroke severities, and functional outcomes in the different age groups. Methods: A total of 78,096 patients with acute ischemic stroke, including transient ischemic attacks, were included in a multicenter, hospital-based registration study based on a computerized database involving 95 Japanese institutes between 2000 and 2012. Results: The frequency of atrial fibrillation increased even after the age of 90 years; consequently, the proportion of patients experiencing cardioembolic stroke also increased in the same age group. Furthermore, more severe symptoms on arrival and worse functional outcomes were observed with increasing age. The frequency of hypertension increased with age, peaking in patients in their 70s, and decreasing slightly thereafter. The frequency of diabetes mellitus and hyperlipidemia peaked in patients in their 50s or 60s and gradually decreased thereafter. Conclusion: The findings of the present study suggest that in the currently aging society, cardioembolic stroke is the most important stroke subtype. The roles of hypertension, diabetes mellitus, and hyperlipidemia are greatest in stroke patients in their 50s to 60s. In older patients, the role of atrial fibrillation is more significant. Key Words: Age stratification—ischemic stroke—epidemiology— Japanese. Ó 2014 by National Stroke Association
Introduction The stroke mortality is higher, and coronary heart disease mortality is lower in Japanese populations compared with Western populations,1 even though the incidence and mortality of stroke, particularly intracerebral hemor-
From the *Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, Saitama; and †Department of Neurology, Shimane University, Shimane, Japan. Received November 14, 2014; accepted November 19, 2014. Address correspondence to Yuji Kato, MD, PhD, Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.11.019
rhage, have markedly decreased from the 1960s to the 1970s.1-3 This may be attributed to the reduction in blood pressure levels and the improvement of a lower nutrition status. Consequently, stroke has retracted to being the fourth leading cause of death. However, the prevalence of stroke has been increasing and is still the most frequent cause of a bedridden state. Japan is the fastest aging society in the world and, as a result, is facing a rapid increase in its disabled population and in associated health care costs. Older age groups have different stroke risk profiles and different stroke features compared with younger age groups.4 Nevertheless, there are few studies on stroke, comparing different age groups.5-9 The aim of the present study was to examine stroke subtypes, risk factor profiles, stroke severities, and functional outcomes in different age groups using the Japan Standard Stroke Registry Study database.10-13
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-4
1
Y. KATO ET AL.
2
Figure 1. Sex and age distribution. Men were more commonly septuagenarians or younger, and women were more common octogenarians or older.
Methods Japan Standard Stroke Registry Study is an ongoing multicenter stroke registration study based on a computerized database involving 95 Japanese institutes. From January 2000 to December 2012, 101,164 patients with acute stroke were registered. Among them, 78,096 patients with ischemic stroke were enrolled in the present study. Stroke subtypes were defined according to the National Institute for Neurological Disorders and Stroke Classification of Cerebrovascular Disease III system: atherothrombotic, cardioembolic, lacuna, and stroke of other etiologies.14 Underlying risk factors, such as hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation, were assessed. The National Institutes of Health Stroke Scale (NIHSS) was used on admission to evaluate stroke severity. A modified Rankin Scale score was used at hospital discharge to assess stroke outcomes.
Results Among the 78,096 enrolled patients, there were 72,775 cases of cerebral infarction and 5321 cases of transient ischemic attacks (TIAs), all of which were included in the analysis. Of the enrolled patients, 47,465 were men
and 30,631 were women. The sex and age distributions of patients registered in the study are shown in Figure 1. Women were older than men at stroke onset (75.5 6 12.1 and 69.7 6 11.6 years, respectively). Regarding ischemic stroke subtype, the absolute distribution is shown in Figure 2, A, whereas the relative distribution, excluding TIAs and stroke of other etiologies, is shown in Figure 2, B. The absolute numbers of cardioembolic stroke increased in the 80- to 84-year-old age group. The proportion of cardioembolic strokes increased consistently, with age, among patients in their 50s to those older than 90 years. In patients older than 80 years, cardioembolic stroke was the most common stroke subtype. The absolute numbers of lacunar and atherothrombotic infarctions increased with age and reached their peaks among patients 70- to 74-year old and 75-to 80-year old, respectively. The frequencies of hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation in the different age groups are shown in Figure 3. The frequency of hypertension increased, with age, up to the 70s, but decreased slightly thereafter (Fig 3, A). The frequency of diabetes mellitus was 19% in the under 50 years age group, reached its peak in patients in their 60s, and gradually decreased thereafter (Fig 3, B). The frequency of hyperlipidemia reached its peak in patients in their 50s and gradually decreased thereafter (Fig 3, C). The frequency of atrial fibrillation increased with age (Fig 3, D). The initial NIHSS scores are shown in Figure 4. The initial NIHSS score was higher in the older age groups. The plots in Figure 5 represent the distribution of modified Rankin Scale grades in the different age groups. Functional outcomes declined with increasing age.
Discussion This was a nationwide multicenter registration study on how age affects the characteristics and functional outcomes of Japanese patients with acute ischemic stroke, including TIA. In the present study, the rate of cardioembolic stroke increased with age, and the older groups were more likely to have severe symptoms on arrival and poorer outcomes.
Figure 2. (A) Absolute distribution of stroke subtypes by age group. The number of patients with cardioembolic stroke reached its peak among the 80- to 84-year-old patients. In patients older than 80 years, cardioembolism was the most common stroke subtype. (B) Relative distribution of stroke subtypes, by age group, excluding transient ischemic attacks and strokes of undefined etiologies. The proportion of cardioembolic stroke increased consistently as patients increased in age from 50 to older than 90 years. Abbreviation: TIA, transient ischemic attack.
ISCHEMIC STROKE IN DIFFERENT AGE GROUPS IN JAPAN
A
Figure 3. The frequencies of various risk factors by age group. The frequency of hypertension increased with age up to the 70s but slightly decreased thereafter. The frequencies of diabetes mellitus and hyperlipidemia reached their peaks in patients in their 50s or 60s and gradually decreased thereafter. The frequency of atrial fibrillation increased with age.
3
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Hypertension
100%
100%
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60%
60%
40%
40%
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0% <50
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Hyperlipidemia
100%
80%
80%
60%
60%
40%
40%
20%
20% <50
50s
60s
The profile of risk factors in patients with ischemic stroke varies with age. A significantly higher frequency of atrial fibrillation was observed among older patients, corroborating the findings from previous studies.5-8 In addition, this study showed that the frequency of atrial fibrillation further increased in patients older than 90 years. Consequently, the frequency of cardioembolic stroke also increased in patients older than 90 years. The higher rate of atrial fibrillation in these patients is in accordance with the more severe stroke presentation in older patients; cardioembolic stroke often has a more severe presentation because of large-vessel occlusions causing more devastating strokes.15,16 In the past, in Japan, few elderly patients with atrial fibrillation were treated with warfarin as a primary prevention.17 The reasons for not using anticoagulant therapy include increased bleeding tendency, active ulcers,
70s
80s
≥90 years
50s
60s
70s
80s
70s
80s
≥90 years
Atrial fibrillation
100%
0%
Diabetes mellitus
0%
<50
50s
60s
≥90 years
malignant tumors, poor adherence, recurrent falls, and dementia.17 However, aggressive anticoagulant therapy should be beneficial in very old patients with atrial fibrillation because appropriate treatment would delay the onset and improve the outcome of stroke. Novel oral anticoagulants, which offer several advantages over warfarin, may be suitable alternatives for stroke prevention in older patients.18 Patients in their 50s and 60s more frequently presented with risk factors that are affected by lifestyle, including diabetes mellitus and hyperlipidemia. Patients aged 70 years or more, especially those older than 90 years, had less frequent hypertension, diabetes mellitus, and hyperlipidemia. We believe that these risk factors are associated with a shorter life expectancy, which may possibly explain their lower prevalence among older patients.19
Initial NIHSS score
30
20
10
0 <50
50s
60s
70s
80s
≥90 years
Figure 4. Box-and-whisker plot of the initial National Institutes of Health Stroke Scale scores by age group. Boxes represent interquartile ranges. Lines across the boxes indicate median values. Whiskers represent the 10th and 90th percentile values. Strokes become more severe with increasing age.
Figure 5. mRS scores at discharge, by age group. Outcomes worsen with increasing age. Abbreviation: mRS, modified Rankin Scale.
Y. KATO ET AL.
4
The high life expectancy in Japan has led the world for more than 20 years.20 The higher stroke mortality and lower coronary heart disease mortality are features specific to Japan compared with other industrialized countries.1 Given that society is rapidly aging, the prevalence of atrial fibrillation will only increase in the future. Patients with atrial fibrillation are at risk of severe stroke; however, early administration of appropriate anticoagulant therapy may prevent the development of embolic events.15,16 Thus, the findings of the present study suggest that cardioembolic stroke is the most important stroke subtype in the currently aging society. A strength of the present study is the large study population. To the best of our knowledge, this is the largest study on ischemic stroke and aging. Japan is the fastest aging society in the world, and therefore, the present study might be beneficial for other industrialized countries. Limitations of the present study were that not all the inpatients, in the participating hospitals during the study period, may have been enrolled and that 3-month poststroke outcomes were not available in this registry. Acknowledgment: JSSRS was developed with support (‘‘21st Century Type Promoting Development of Clinical Research Fund’’) from the Japanese Ministry of Welfare during 1999 to 2001.
References 1. Ueshima H. Explanation for the Japanese paradox: prevention of increase in coronary heart disease and reduction in stroke. J Atheroscler Thromb 2007;14:278-286. 2. Chalmers J, Arima H, Hata J. Cost-effective reduction in stroke: lessons from the Japanese hypertension detection and control program. J Hypertens 2012;30:1706-1707. 3. Hata J, Ninomiya T, Hirakawa Y, et al. Secular trends in cardiovascular disease and its risk factors in Japanese: half-century data from the Hisayama Study (1961-2009). Circulation 2013;128:1198-1205. 4. Pohjasvaara T, Erkinjuntti T, Vataja R, et al. Comparison of stroke features and disability in daily life in patients with ischemic stroke aged 55 to 70 and 71 to 85 years. Stroke 1997;28:729-735. 5. Rojas JI, Zurru MC, Romano M, et al. Acute ischemic stroke and transient ischemic attack in the very old-risk factor profile and stroke subtypes between patients older 80 years and patients aged less than 80 years. Eur J Neurol 2007;14:895-899.
6. Kammersgaard LP, Jørgensen HS, Reith J, et al. Short- and long-term prognosis for very old stroke patients. The Copenhagen Stroke Study. Age Ageing 2004;33:149-154. 7. Arboix A, Garcıa-Eroles L, Massons J, et al. Acute stroke in very old people: clinical features and predictors of inhospital mortality. J Am Geriatr Soc 2000;48:36-41. 8. Bentsen L, Christensen L, Christensen A, et al. Outcome and risk factors presented in old patients above 80 years of age versus younger patients after ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:1944-1948. 9. Wu CY, Wu HM, Lee JD, et al. Stroke risk factors and subtypes in different age groups: a hospital-based study. Neurol India 2010;58:863-868. 10. Kobayashi S, Japan Stroke Scale Registry Study Group. International experience in stroke registry: Japanese Stroke Databank. Am J Prev Med 2006;31:S240-S242. 11. Toyoda K, Okada Y, Kobayashi S. Early recurrence of ischemic stroke in Japanese patients: the Japan standard stroke registry study. Cerebrovasc Dis 2007; 24:289-295. 12. Hosomi N, Naya T, Ohkita H, et al. Predictors of intracerebral hemorrhage severity and its outcome in Japanese stroke patients. Cerebrovasc Dis 2009;27:67-74. 13. Maeda K, Toyoda K, Minematsu K, et al. Effects of sex difference on clinical features of acute ischemic stroke in Japan. J Stroke Cerebrovasc Dis 2013;22: 1070-1075. 14. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990;21:637-676. 15. Saxena R, Lewis S, Berge E, et al. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the international stroke trial. Stroke 2001;32:2333-2337. 16. Kimura K, Minematsu K, Yamaguchi T, for the Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC). Atrial fibrillation as a predictive factor for severe stroke and early death in 15831 patients with acute ischemic stroke. J Neurol Neurosurg Psychiatr 2005; 76:679-683. 17. Inoue H, Nozawa T, Okuma K, et al. Attitude of Japanese cardiologists toward anticoagulation for nonvalvular atrial fibrillation and reasons for its underuse. Jpn Circ J 2004;68:417-421. 18. Yates SW. Novel oral anticoagulants for stroke prevention in atrial fibrillation: a focus on the older patient. Int J Gen Med 2013;6:167-180. 19. Gur AY, Tanne D, Bornstein NM, et al. Stroke in the very elderly: characteristics and outcome in patients aged $85 years with a first-ever ischemic stroke. Neuroepidemiology 2012;39:57-62. 20. Life expectancy in Japan. Available at: http://www. mhlw.go.jp/toukei/saikin/hw/life/life12/dl/life12-04. pdf. Accessed December 10, 2014.
Background: Japan has the fastest aging society in the world. Older patients have a different stroke risk profile and different stroke features compared with younger patients. The aim of the present study was to examine the stroke subtypes, risk factor profiles, stroke severities, and functional outcomes in the different age groups. Methods: A total of 78,096 patients with acute ischemic stroke, including transient ischemic attacks, were included in a multicenter, hospital-based registration study based on a computerized database involving 95 Japanese institutes between 2000 and 2012. Results: The frequency of atrial fibrillation increased even after the age of 90 years; consequently, the proportion of patients experiencing cardioembolic stroke also increased in the same age group. Furthermore, more severe symptoms on arrival and worse functional outcomes were observed with increasing age. The frequency of hypertension increased with age, peaking in patients in their 70s, and decreasing slightly thereafter. The frequency of diabetes mellitus and hyperlipidemia peaked in patients in their 50s or 60s and gradually decreased thereafter. Conclusion: The findings of the present study suggest that in the currently aging society, cardioembolic stroke is the most important stroke subtype. The roles of hypertension, diabetes mellitus, and hyperlipidemia are greatest in stroke patients in their 50s to 60s. In older patients, the role of atrial fibrillation is more significant. Key Words: Age stratification—ischemic stroke—epidemiology— Japanese. Ó 2014 by National Stroke Association
Introduction The stroke mortality is higher, and coronary heart disease mortality is lower in Japanese populations compared with Western populations,1 even though the incidence and mortality of stroke, particularly intracerebral hemor-
From the *Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, Saitama; and †Department of Neurology, Shimane University, Shimane, Japan. Received November 14, 2014; accepted November 19, 2014. Address correspondence to Yuji Kato, MD, PhD, Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.11.019
rhage, have markedly decreased from the 1960s to the 1970s.1-3 This may be attributed to the reduction in blood pressure levels and the improvement of a lower nutrition status. Consequently, stroke has retracted to being the fourth leading cause of death. However, the prevalence of stroke has been increasing and is still the most frequent cause of a bedridden state. Japan is the fastest aging society in the world and, as a result, is facing a rapid increase in its disabled population and in associated health care costs. Older age groups have different stroke risk profiles and different stroke features compared with younger age groups.4 Nevertheless, there are few studies on stroke, comparing different age groups.5-9 The aim of the present study was to examine stroke subtypes, risk factor profiles, stroke severities, and functional outcomes in different age groups using the Japan Standard Stroke Registry Study database.10-13
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-4
1
Y. KATO ET AL.
2
Figure 1. Sex and age distribution. Men were more commonly septuagenarians or younger, and women were more common octogenarians or older.
Methods Japan Standard Stroke Registry Study is an ongoing multicenter stroke registration study based on a computerized database involving 95 Japanese institutes. From January 2000 to December 2012, 101,164 patients with acute stroke were registered. Among them, 78,096 patients with ischemic stroke were enrolled in the present study. Stroke subtypes were defined according to the National Institute for Neurological Disorders and Stroke Classification of Cerebrovascular Disease III system: atherothrombotic, cardioembolic, lacuna, and stroke of other etiologies.14 Underlying risk factors, such as hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation, were assessed. The National Institutes of Health Stroke Scale (NIHSS) was used on admission to evaluate stroke severity. A modified Rankin Scale score was used at hospital discharge to assess stroke outcomes.
Results Among the 78,096 enrolled patients, there were 72,775 cases of cerebral infarction and 5321 cases of transient ischemic attacks (TIAs), all of which were included in the analysis. Of the enrolled patients, 47,465 were men
and 30,631 were women. The sex and age distributions of patients registered in the study are shown in Figure 1. Women were older than men at stroke onset (75.5 6 12.1 and 69.7 6 11.6 years, respectively). Regarding ischemic stroke subtype, the absolute distribution is shown in Figure 2, A, whereas the relative distribution, excluding TIAs and stroke of other etiologies, is shown in Figure 2, B. The absolute numbers of cardioembolic stroke increased in the 80- to 84-year-old age group. The proportion of cardioembolic strokes increased consistently, with age, among patients in their 50s to those older than 90 years. In patients older than 80 years, cardioembolic stroke was the most common stroke subtype. The absolute numbers of lacunar and atherothrombotic infarctions increased with age and reached their peaks among patients 70- to 74-year old and 75-to 80-year old, respectively. The frequencies of hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation in the different age groups are shown in Figure 3. The frequency of hypertension increased, with age, up to the 70s, but decreased slightly thereafter (Fig 3, A). The frequency of diabetes mellitus was 19% in the under 50 years age group, reached its peak in patients in their 60s, and gradually decreased thereafter (Fig 3, B). The frequency of hyperlipidemia reached its peak in patients in their 50s and gradually decreased thereafter (Fig 3, C). The frequency of atrial fibrillation increased with age (Fig 3, D). The initial NIHSS scores are shown in Figure 4. The initial NIHSS score was higher in the older age groups. The plots in Figure 5 represent the distribution of modified Rankin Scale grades in the different age groups. Functional outcomes declined with increasing age.
Discussion This was a nationwide multicenter registration study on how age affects the characteristics and functional outcomes of Japanese patients with acute ischemic stroke, including TIA. In the present study, the rate of cardioembolic stroke increased with age, and the older groups were more likely to have severe symptoms on arrival and poorer outcomes.
Figure 2. (A) Absolute distribution of stroke subtypes by age group. The number of patients with cardioembolic stroke reached its peak among the 80- to 84-year-old patients. In patients older than 80 years, cardioembolism was the most common stroke subtype. (B) Relative distribution of stroke subtypes, by age group, excluding transient ischemic attacks and strokes of undefined etiologies. The proportion of cardioembolic stroke increased consistently as patients increased in age from 50 to older than 90 years. Abbreviation: TIA, transient ischemic attack.
ISCHEMIC STROKE IN DIFFERENT AGE GROUPS IN JAPAN
A
Figure 3. The frequencies of various risk factors by age group. The frequency of hypertension increased with age up to the 70s but slightly decreased thereafter. The frequencies of diabetes mellitus and hyperlipidemia reached their peaks in patients in their 50s or 60s and gradually decreased thereafter. The frequency of atrial fibrillation increased with age.
3
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Hypertension
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100%
80%
80%
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Hyperlipidemia
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The profile of risk factors in patients with ischemic stroke varies with age. A significantly higher frequency of atrial fibrillation was observed among older patients, corroborating the findings from previous studies.5-8 In addition, this study showed that the frequency of atrial fibrillation further increased in patients older than 90 years. Consequently, the frequency of cardioembolic stroke also increased in patients older than 90 years. The higher rate of atrial fibrillation in these patients is in accordance with the more severe stroke presentation in older patients; cardioembolic stroke often has a more severe presentation because of large-vessel occlusions causing more devastating strokes.15,16 In the past, in Japan, few elderly patients with atrial fibrillation were treated with warfarin as a primary prevention.17 The reasons for not using anticoagulant therapy include increased bleeding tendency, active ulcers,
70s
80s
≥90 years
50s
60s
70s
80s
70s
80s
≥90 years
Atrial fibrillation
100%
0%
Diabetes mellitus
0%
<50
50s
60s
≥90 years
malignant tumors, poor adherence, recurrent falls, and dementia.17 However, aggressive anticoagulant therapy should be beneficial in very old patients with atrial fibrillation because appropriate treatment would delay the onset and improve the outcome of stroke. Novel oral anticoagulants, which offer several advantages over warfarin, may be suitable alternatives for stroke prevention in older patients.18 Patients in their 50s and 60s more frequently presented with risk factors that are affected by lifestyle, including diabetes mellitus and hyperlipidemia. Patients aged 70 years or more, especially those older than 90 years, had less frequent hypertension, diabetes mellitus, and hyperlipidemia. We believe that these risk factors are associated with a shorter life expectancy, which may possibly explain their lower prevalence among older patients.19
Initial NIHSS score
30
20
10
0 <50
50s
60s
70s
80s
≥90 years
Figure 4. Box-and-whisker plot of the initial National Institutes of Health Stroke Scale scores by age group. Boxes represent interquartile ranges. Lines across the boxes indicate median values. Whiskers represent the 10th and 90th percentile values. Strokes become more severe with increasing age.
Figure 5. mRS scores at discharge, by age group. Outcomes worsen with increasing age. Abbreviation: mRS, modified Rankin Scale.
Y. KATO ET AL.
4
The high life expectancy in Japan has led the world for more than 20 years.20 The higher stroke mortality and lower coronary heart disease mortality are features specific to Japan compared with other industrialized countries.1 Given that society is rapidly aging, the prevalence of atrial fibrillation will only increase in the future. Patients with atrial fibrillation are at risk of severe stroke; however, early administration of appropriate anticoagulant therapy may prevent the development of embolic events.15,16 Thus, the findings of the present study suggest that cardioembolic stroke is the most important stroke subtype in the currently aging society. A strength of the present study is the large study population. To the best of our knowledge, this is the largest study on ischemic stroke and aging. Japan is the fastest aging society in the world, and therefore, the present study might be beneficial for other industrialized countries. Limitations of the present study were that not all the inpatients, in the participating hospitals during the study period, may have been enrolled and that 3-month poststroke outcomes were not available in this registry. Acknowledgment: JSSRS was developed with support (‘‘21st Century Type Promoting Development of Clinical Research Fund’’) from the Japanese Ministry of Welfare during 1999 to 2001.
References 1. Ueshima H. Explanation for the Japanese paradox: prevention of increase in coronary heart disease and reduction in stroke. J Atheroscler Thromb 2007;14:278-286. 2. Chalmers J, Arima H, Hata J. Cost-effective reduction in stroke: lessons from the Japanese hypertension detection and control program. J Hypertens 2012;30:1706-1707. 3. Hata J, Ninomiya T, Hirakawa Y, et al. Secular trends in cardiovascular disease and its risk factors in Japanese: half-century data from the Hisayama Study (1961-2009). Circulation 2013;128:1198-1205. 4. Pohjasvaara T, Erkinjuntti T, Vataja R, et al. Comparison of stroke features and disability in daily life in patients with ischemic stroke aged 55 to 70 and 71 to 85 years. Stroke 1997;28:729-735. 5. Rojas JI, Zurru MC, Romano M, et al. Acute ischemic stroke and transient ischemic attack in the very old-risk factor profile and stroke subtypes between patients older 80 years and patients aged less than 80 years. Eur J Neurol 2007;14:895-899.
6. Kammersgaard LP, Jørgensen HS, Reith J, et al. Short- and long-term prognosis for very old stroke patients. The Copenhagen Stroke Study. Age Ageing 2004;33:149-154. 7. Arboix A, Garcıa-Eroles L, Massons J, et al. Acute stroke in very old people: clinical features and predictors of inhospital mortality. J Am Geriatr Soc 2000;48:36-41. 8. Bentsen L, Christensen L, Christensen A, et al. Outcome and risk factors presented in old patients above 80 years of age versus younger patients after ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:1944-1948. 9. Wu CY, Wu HM, Lee JD, et al. Stroke risk factors and subtypes in different age groups: a hospital-based study. Neurol India 2010;58:863-868. 10. Kobayashi S, Japan Stroke Scale Registry Study Group. International experience in stroke registry: Japanese Stroke Databank. Am J Prev Med 2006;31:S240-S242. 11. Toyoda K, Okada Y, Kobayashi S. Early recurrence of ischemic stroke in Japanese patients: the Japan standard stroke registry study. Cerebrovasc Dis 2007; 24:289-295. 12. Hosomi N, Naya T, Ohkita H, et al. Predictors of intracerebral hemorrhage severity and its outcome in Japanese stroke patients. Cerebrovasc Dis 2009;27:67-74. 13. Maeda K, Toyoda K, Minematsu K, et al. Effects of sex difference on clinical features of acute ischemic stroke in Japan. J Stroke Cerebrovasc Dis 2013;22: 1070-1075. 14. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990;21:637-676. 15. Saxena R, Lewis S, Berge E, et al. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the international stroke trial. Stroke 2001;32:2333-2337. 16. Kimura K, Minematsu K, Yamaguchi T, for the Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC). Atrial fibrillation as a predictive factor for severe stroke and early death in 15831 patients with acute ischemic stroke. J Neurol Neurosurg Psychiatr 2005; 76:679-683. 17. Inoue H, Nozawa T, Okuma K, et al. Attitude of Japanese cardiologists toward anticoagulation for nonvalvular atrial fibrillation and reasons for its underuse. Jpn Circ J 2004;68:417-421. 18. Yates SW. Novel oral anticoagulants for stroke prevention in atrial fibrillation: a focus on the older patient. Int J Gen Med 2013;6:167-180. 19. Gur AY, Tanne D, Bornstein NM, et al. Stroke in the very elderly: characteristics and outcome in patients aged $85 years with a first-ever ischemic stroke. Neuroepidemiology 2012;39:57-62. 20. Life expectancy in Japan. Available at: http://www. mhlw.go.jp/toukei/saikin/hw/life/life12/dl/life12-04. pdf. Accessed December 10, 2014.