- Email: [email protected]
Influence of Antiplatelet Drugs on the Outcome of Subarachnoid Hemorrhage Differs with Age
Influence of Antiplatelet Drugs on the Outcome of Subarachnoid Hemorrhage Differs with Age 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: The aim of this study was to examine the risk factor profiles and functional outcomes of subarachnoid hemorrhage (SAH) in different age groups, focusing on the effect of antiplatelet drugs when used before stroke. Methods: A total of 5344 patients with SAH were included in a multicenter, hospital-based registration study involving 95 Japanese institutes from 2000 to 2012. Patients’ profiles and use of antithrombotic agents were retrospectively reviewed. A modified Rankin Scale score of 4 or more at discharge was defined as poor outcome. Results: The frequency of antithrombotic agent use increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% for those 90 years or older. Poorer outcomes were evident as age increased. The frequency of hypertension increased with age, whereas current smoking and heavy drinking reached its peak among patients in their 40s and 50s, respectively. The use of antiplatelet agents significantly improved outcome in patients younger than 60 years (P 5 .04). In contrast, in the older group ($60 years), the use of antiplatelet agents tended to worsen the outcome; patients aged 70-79 years who had used these agents had a significantly worse outcome compared with those who had not (P 5 .03). Conclusions: In the present study, the influence of antiplatelet agents was different among age groups. The potential beneficial effects of antiplatelet agents must be weighed against their potential adverse effects in the context of SAH, considering the differences in age-related outcomes. Key Words: Age stratification—subarachnoid hemorrhage—antiplatelet drugs—Japanese. Ó 2015 by National Stroke Association
Introduction Subarachnoid hemorrhage (SAH) accounts for 5.5% of all strokes in Japan,1 but its relative impact is significant.
From the *Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, Saitama; and †Department of Neurology, Shimane University, Shimane, Japan. Received April 7, 2015; revision received May 29, 2015; accepted June 10, 2015. Address correspondence to Yuji Kato, MD, PhD, Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.06.021
The incidence of SAH in Japan has been reported to be one of the highest in the world.2 In the past, SAH was considered a potentially fatal disease that mainly affected middle-aged patients (,60 years).3 Because of better general health and improved life expectancy, however, the number of elderly patients with SAH is increasing. Compared with younger age groups, older age groups have different stroke risk profiles and clinical features, but only a few studies on SAH have compared different age groups.4,5 Furthermore, the influence of antiplatelet drugs before onset of SAH has not been clearly determined—some studies have indicated that aspirin protected brain from cerebral aneurysm rupture,6-8 whereas another showed it increased rebleeding rates.9 The aim of the present study was to examine the risk factor profiles and functional outcomes of SAH among different age groups using the Japan Standard Stroke
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-4
1
Y. KATO ET AL.
2 1
Registry Study database. Particular focus was placed on the effect of antiplatelet drug use before onset of SAH.
Methods The Japan Standard Stroke Registry Study is an ongoing multicenter stroke registration study based on a computerized database involving 95 Japanese institutes.1 From January 2000 to December 2012, 101,164 patients with acute stroke were registered. Among them, 5334 patients with SAH were enrolled in the present study. Data on patients’ characteristics (age and sex) and underlying risk factors, such as hypertension, current smoking, and heavy drinking (.46 g of alcohol/d), were retrospectively reviewed. Use of antithrombotic (antiplatelet and/or anticoagulant) agents before stroke was also assessed. Patients were assessed according to a modified Rankin Scale at discharge and those with a score of 4 or more were defined as having a poor outcome. Data obtained during the study period were analyzed and compared among different age groups. Outcomes in antiplatelet users and nonusers were compared using the chi-square tests or Fisher exact tests when sample sizes were limited. Probability values were considered statistically significant at P values less than .05.
Results Of the 5344 enrolled patients, 1772 were men and 3572 were women. Their sex and age distributions are shown in Figure 1. The peak age of stroke onset was higher for women than for men (65.2 6 14.3 and 57.0 6 13.1 years, respectively). The female/male ratio increased from 1.2:1 in patients younger than 60 years to 3.3:1 in those older than 60 years. Figure 2 shows the frequencies of hypertension, current smoking, heavy drinking, and use of antithrombotic 200 Total
Men
Women
Number of patients
150
100
50
0 20
30
40
50
60
70
80
90
100
Age (years)
Figure 1. Age and sex distribution of Japanese patients with subarachnoid hemorrhage (SAH). The occurrence of SAH peaked in the 50s for men and 70s for women.
agents in different age groups. The frequency of hypertension increased with age (Fig 2, A). In contrast, the frequency of current smoking decreased with age (Fig 2, B). The frequency of heavy drinking reached its peak among patients in their 50s and decreased thereafter (Fig 2, C). The frequency of antithrombotic agent use increased with age; peak use (10.9%) occurred among patients in their 80s, and it remained constant at 7.5% in patients older than 90 years (Fig 2, D). Figure 3 shows the percentage of poor functional outcomes at discharge by age group, depicting outcome comparisons among patients who used antiplatelet agents before stroke and those who did not. Poorer outcomes were evident with an increase in age. In the younger than 60-year age group, the use of antiplatelet agents significantly improved the prognosis (P 5 .04). In contrast, in the older group ($60 years), the use of antiplatelet agents tended to make the prognosis worse: patients aged 70-79 years who had used antiplatelet agents had a significantly worse outcome compared with patients who had not used antithrombotic drugs (P 5 .03).
Discussion This was a nationwide, multicenter registration study investigating how age affects the characteristics and functional outcomes of Japanese patients with SAH. In the present study, the younger patients taking antiplatelet agents had a significantly improved outcome compared with those who did not, whereas older patients taking antiplatelet agents were more likely to have poorer outcome. Consistent with the results from this study, increasing age is a known risk factor for poor outcome after aneurysmal SAH.4,5 One study has also demonstrated that anticoagulant therapy is associated with a worse outcome.10 However, the influence of antiplatelet use on outcome after SAH is less clear. For instance, a few studies failed to reveal any significant impact of pre-hemorrhage aspirin use on outcome after aneurysmal SAH.8,9 In the present study, the influence of antiplatelet agents was found to differ among age groups. This is the first study to report that pre-hemorrhage antiplatelet use significantly improved prognosis, albeit only in younger patients (,60 years). In previous studies, the trend toward reduced risk of SAH was particularly pronounced in patients receiving aspirin.6-8 The underlying mechanisms associated with reduced risk were attributed to a possible inhibitory effect of aspirin on the inflammatory cascade implicated in intracranial aneurismal formation11—the cause of SAH in approximately 85% of cases.12 These data suggested that aspirin may potentially be used as therapeutic agent to prevent intracranial aneurysm growth and rupture.13 Based on the available data, one hypothesis that merits testing is
INFLUENCE OF ANTIPLATELET DRUGS ON THE OUTCOME OF SAH
3
\ Hypertension 80%
60%
60
40
40 20
20 0
<50
50s
60s
70s
80s
≥90 years
0
<50
50s
60s
70s
80s
≥90 years
agents 20%
15% Antiplatelet agents
Anticoagulant agents
Antiplatelet plus anticoagulant agents
15
10
10 5
5 0
<50
50s
60s
70s
80s
≥90 years
0
<50
50s
60s
70s
80s
≥90 years
Figure 2. Frequencies of various risk factors in each age group. The frequency of hypertension increased with age (A), whereas that of current smoking decreased with age (B) and that of heavy drinking reached its peak among patients in their 50s and decreased thereafter (C). The frequency of use of antithrombotic agents increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% in patients older than 90 years (D).
that aspirin, when taken in advance, may also ameliorate symptoms in cases where it cannot be prevented. Additionally, there are theoretical benefits of aspirin therapy in patients with SAH. Animal models of SAH showed a direct correlation among platelet activation, prostaglandin synthesis, and cerebral vasospasm.14-16 One author reported reduced complications from vasospasm among patients taking aspirin before they developed SAH.17
ns
100%
Antiplatelet agents (n=217)
Ratio of poor outcome
No antithrombotic agents (n=4811)
p = 0.03
80
60 40
ns
ns p = 0.04
20 0 <60
60s
70s
80s
≥90 years
Figure 3. Rate of poor outcome (modified Rankin Scale score of 4 or higher) in each age group was expressed according to the use of antiplatelet agents. Poorer outcomes were evident with increasing age. In the younger than 60year age group, the use of antiplatelet agents significantly improved prognosis (P 5 .04). In contrast, in the older group ($60 years), the use of antiplatelet agents tended to worsen the prognosis; patients aged 70-79 years had a significantly worse outcome (P 5 .03).
Various agents can prevent cerebral vasospasm. Cilostazol inhibits phosphodiesterase 3 activity in smooth muscle cells and platelets, leading to relaxation of intact smooth muscle cells and inhibition of platelet aggregation. Thus, it attenuates cerebral vasospasm18,19 and prevents endothelial damage,20,21 which result in reduction of delayed cerebral ischemia after aneurysmal SAH.22 In contrast to the younger group, in the older group ($60 years), the use of antiplatelet agents made the prognosis worse. Previous aspirin use carries the theoretical risks of exacerbating the initial hemorrhage, increasing the rate of rebleeding and complicating surgical procedures intended to secure the source of bleeding,9 although these factors are also true for younger patients. Our data suggest that the aneurysm formation and progression to rupture are not simple. Recent human and animal studies have shown that inflammation plays a key role in these processes.23 In young people, the beneficial effects of antiplatelet agents on aneurysm development and associated rapture may overweigh their antihemostatic effects. On the other hand, bleeding may last longer in older patients with SAH treated with these agents, which could account for poorer outcome. Hence, we need to consider the differences in etiology and age to assess the safety and efficacy of aspirin in preventing SAH. To explain the beneficial effect of antiplatelet agents, we should consider the factors associated (but not related) with drug therapy; those who take antiplatelets for
Y. KATO ET AL.
4
atherosclerotic diseases visit the hospital frequently; therefore, health problems such as hypertension or dyslipidemia might be controlled better. In aged patients, however, bleeding risk may outweigh the earlier mentioned benefits. The primary strength of the present study is the relatively large patient population used for our analysis. To the best of our knowledge, this is the largest study on SAH and aging. Japan has the fastest aging society in the world, and the present study might be beneficial for aging populations in other industrialized countries. One potential limitation of the present study is that not all the inpatients in the participating hospitals during the study period may have been enrolled. In addition, some data were not available in the registry for the present study, including the details of antithrombotic agents, severity of stroke (Fisher and Hunt–Hess classifications), occurrence of vasospasm after SAH, surgical treatment, and the 3-month poststroke outcomes of patients. Acknowledgment: Japan Standard Stroke Registry Study was developed with support (‘‘21st Century Type Promoting Development of Clinical Research Fund’’) from the Japanese Ministry of Welfare (grant number: H11-21 century(life)-33) during 1999 to 2001.
References 1. Kobayashi S, Japan Stroke Scale Registry Study Group. International experience in stroke registry: Japanese Stroke Databank. Am J Prev Med 2006;31:S240-S242. 2. Kozak N, Hayashi M. Trends in the incidence of subarachnoid hemorrhage in Akita Prefecture, Japan. J Neurosurg 2007;106:234-238. 3. van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001;124:249-278. 4. Sch€ oller K, Massmann M, Markl G, et al. Aneurysmal subarachnoid hemorrhage in elderly patients: long-term outcome and prognostic factors in an interdisciplinary treatment approach. J Neurol 2013;260:1052-1060. 5. Lanzino G, Kassell NF, Germanson TP, et al. Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse? J Neurosurg 1996; 85:410-418. 6. Hasan DM, Mahaney KB, Brown RD Jr, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 2011;42:3156-3162. 7. Garcıa-Rodrıguez LA, Gaist D, Morton J, et al. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology 2013;81:566-574. 8. Gross BA, Rosalind Lai PM, Frerichs KU, et al. Aspirin and aneurysmal subarachnoid hemorrhage. World Neurosurg 2014;82:1127-1130.
9. Toussaint LG III, Friedman JA, Wijdicks EF, et al. Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage. J Neurosurg 2004;101:921-925. 10. Rinkel GJ, Prins NE, Algra A. Outcome of aneurysmal subarachnoid hemorrhage in patients on anticoagulant treatment. Stroke 1997;28:6-9. 11. Hasan DM, Chalouhi N, Jabbour P, et al. Evidence that acetylsalicylic acid attenuates inflammation in the walls of human cerebral aneurysms: preliminary results. J Am Heart Assoc 2013;2:e000019. 12. Feigin VL, Lawes CM, Bennett DA, et al. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003;2:43-53. 13. Chalouhi N, Jabbour P, Hasan D, et al. Aspirin for prevention of subarachnoid hemorrhage: the stage is set for a randomized controlled trial. Neurosurgery 2014; 74:E147-E148. 14. Ellis EF, Nies AS, Oates JA. Cerebral arterial smooth muscle contraction by thromboxane A2. Stroke 1977; 8:480-483. 15. Okamoto S, Handa H, Toda N. Role of intrinsic arachidonate metabolites in the vascular action of erythrocyte breakdown products. Stroke 1984;15:60-64. 16. Toda N, Shimizu K, Ohta T. Mechanism of cerebral arterial contraction induced by blood constituents. J Neurosurg 1980;53:312-322. 17. Juvela S. Aspirin and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Neurosurg 1995;82:945-952. 18. Yoshimoto T, Shirasaka T, Fujimoto S, et al. Cilostazol may prevent cerebral vasospasm following subarachnoid hemorrhage. Neurol Med Chir (Tokyo) 2009; 49:235-240. 19. Senbokuya N, Kinouchi H, Kanemaru K, et al. Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial. J Neurosurg 2013;118:121-130. 20. Hashimoto A, Miyakoda G, Hirose Y, et al. Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis 2006; 189:350-357. 21. Yamaguchi-Okada M, Nishizawa S, Mizutani A, et al. Multifaceted effects of selective inhibitor of phosphodiesterase III, cilostazol, for cerebral vasospasm after subarachnoid hemorrhage in a dog model. Cerebrovasc Dis 2009;28:135-142. 22. Vergouwen MD, Vermeulen M, Coert BA, et al. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab 2008;28:1761-1770. 23. Hudson JS, Hoyne DS, Hasan DM. Inflammation and human cerebral aneurysms:current and future treatment prospects. Future Neurol 2013;8 http://dx.doi.org/10.2 217/fnl.13.40.
Background: The aim of this study was to examine the risk factor profiles and functional outcomes of subarachnoid hemorrhage (SAH) in different age groups, focusing on the effect of antiplatelet drugs when used before stroke. Methods: A total of 5344 patients with SAH were included in a multicenter, hospital-based registration study involving 95 Japanese institutes from 2000 to 2012. Patients’ profiles and use of antithrombotic agents were retrospectively reviewed. A modified Rankin Scale score of 4 or more at discharge was defined as poor outcome. Results: The frequency of antithrombotic agent use increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% for those 90 years or older. Poorer outcomes were evident as age increased. The frequency of hypertension increased with age, whereas current smoking and heavy drinking reached its peak among patients in their 40s and 50s, respectively. The use of antiplatelet agents significantly improved outcome in patients younger than 60 years (P 5 .04). In contrast, in the older group ($60 years), the use of antiplatelet agents tended to worsen the outcome; patients aged 70-79 years who had used these agents had a significantly worse outcome compared with those who had not (P 5 .03). Conclusions: In the present study, the influence of antiplatelet agents was different among age groups. The potential beneficial effects of antiplatelet agents must be weighed against their potential adverse effects in the context of SAH, considering the differences in age-related outcomes. Key Words: Age stratification—subarachnoid hemorrhage—antiplatelet drugs—Japanese. Ó 2015 by National Stroke Association
Introduction Subarachnoid hemorrhage (SAH) accounts for 5.5% of all strokes in Japan,1 but its relative impact is significant.
From the *Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, Saitama; and †Department of Neurology, Shimane University, Shimane, Japan. Received April 7, 2015; revision received May 29, 2015; accepted June 10, 2015. Address correspondence to Yuji Kato, MD, PhD, Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.06.021
The incidence of SAH in Japan has been reported to be one of the highest in the world.2 In the past, SAH was considered a potentially fatal disease that mainly affected middle-aged patients (,60 years).3 Because of better general health and improved life expectancy, however, the number of elderly patients with SAH is increasing. Compared with younger age groups, older age groups have different stroke risk profiles and clinical features, but only a few studies on SAH have compared different age groups.4,5 Furthermore, the influence of antiplatelet drugs before onset of SAH has not been clearly determined—some studies have indicated that aspirin protected brain from cerebral aneurysm rupture,6-8 whereas another showed it increased rebleeding rates.9 The aim of the present study was to examine the risk factor profiles and functional outcomes of SAH among different age groups using the Japan Standard Stroke
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-4
1
Y. KATO ET AL.
2 1
Registry Study database. Particular focus was placed on the effect of antiplatelet drug use before onset of SAH.
Methods The Japan Standard Stroke Registry Study is an ongoing multicenter stroke registration study based on a computerized database involving 95 Japanese institutes.1 From January 2000 to December 2012, 101,164 patients with acute stroke were registered. Among them, 5334 patients with SAH were enrolled in the present study. Data on patients’ characteristics (age and sex) and underlying risk factors, such as hypertension, current smoking, and heavy drinking (.46 g of alcohol/d), were retrospectively reviewed. Use of antithrombotic (antiplatelet and/or anticoagulant) agents before stroke was also assessed. Patients were assessed according to a modified Rankin Scale at discharge and those with a score of 4 or more were defined as having a poor outcome. Data obtained during the study period were analyzed and compared among different age groups. Outcomes in antiplatelet users and nonusers were compared using the chi-square tests or Fisher exact tests when sample sizes were limited. Probability values were considered statistically significant at P values less than .05.
Results Of the 5344 enrolled patients, 1772 were men and 3572 were women. Their sex and age distributions are shown in Figure 1. The peak age of stroke onset was higher for women than for men (65.2 6 14.3 and 57.0 6 13.1 years, respectively). The female/male ratio increased from 1.2:1 in patients younger than 60 years to 3.3:1 in those older than 60 years. Figure 2 shows the frequencies of hypertension, current smoking, heavy drinking, and use of antithrombotic 200 Total
Men
Women
Number of patients
150
100
50
0 20
30
40
50
60
70
80
90
100
Age (years)
Figure 1. Age and sex distribution of Japanese patients with subarachnoid hemorrhage (SAH). The occurrence of SAH peaked in the 50s for men and 70s for women.
agents in different age groups. The frequency of hypertension increased with age (Fig 2, A). In contrast, the frequency of current smoking decreased with age (Fig 2, B). The frequency of heavy drinking reached its peak among patients in their 50s and decreased thereafter (Fig 2, C). The frequency of antithrombotic agent use increased with age; peak use (10.9%) occurred among patients in their 80s, and it remained constant at 7.5% in patients older than 90 years (Fig 2, D). Figure 3 shows the percentage of poor functional outcomes at discharge by age group, depicting outcome comparisons among patients who used antiplatelet agents before stroke and those who did not. Poorer outcomes were evident with an increase in age. In the younger than 60-year age group, the use of antiplatelet agents significantly improved the prognosis (P 5 .04). In contrast, in the older group ($60 years), the use of antiplatelet agents tended to make the prognosis worse: patients aged 70-79 years who had used antiplatelet agents had a significantly worse outcome compared with patients who had not used antithrombotic drugs (P 5 .03).
Discussion This was a nationwide, multicenter registration study investigating how age affects the characteristics and functional outcomes of Japanese patients with SAH. In the present study, the younger patients taking antiplatelet agents had a significantly improved outcome compared with those who did not, whereas older patients taking antiplatelet agents were more likely to have poorer outcome. Consistent with the results from this study, increasing age is a known risk factor for poor outcome after aneurysmal SAH.4,5 One study has also demonstrated that anticoagulant therapy is associated with a worse outcome.10 However, the influence of antiplatelet use on outcome after SAH is less clear. For instance, a few studies failed to reveal any significant impact of pre-hemorrhage aspirin use on outcome after aneurysmal SAH.8,9 In the present study, the influence of antiplatelet agents was found to differ among age groups. This is the first study to report that pre-hemorrhage antiplatelet use significantly improved prognosis, albeit only in younger patients (,60 years). In previous studies, the trend toward reduced risk of SAH was particularly pronounced in patients receiving aspirin.6-8 The underlying mechanisms associated with reduced risk were attributed to a possible inhibitory effect of aspirin on the inflammatory cascade implicated in intracranial aneurismal formation11—the cause of SAH in approximately 85% of cases.12 These data suggested that aspirin may potentially be used as therapeutic agent to prevent intracranial aneurysm growth and rupture.13 Based on the available data, one hypothesis that merits testing is
INFLUENCE OF ANTIPLATELET DRUGS ON THE OUTCOME OF SAH
3
\ Hypertension 80%
60%
60
40
40 20
20 0
<50
50s
60s
70s
80s
≥90 years
0
<50
50s
60s
70s
80s
≥90 years
agents 20%
15% Antiplatelet agents
Anticoagulant agents
Antiplatelet plus anticoagulant agents
15
10
10 5
5 0
<50
50s
60s
70s
80s
≥90 years
0
<50
50s
60s
70s
80s
≥90 years
Figure 2. Frequencies of various risk factors in each age group. The frequency of hypertension increased with age (A), whereas that of current smoking decreased with age (B) and that of heavy drinking reached its peak among patients in their 50s and decreased thereafter (C). The frequency of use of antithrombotic agents increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% in patients older than 90 years (D).
that aspirin, when taken in advance, may also ameliorate symptoms in cases where it cannot be prevented. Additionally, there are theoretical benefits of aspirin therapy in patients with SAH. Animal models of SAH showed a direct correlation among platelet activation, prostaglandin synthesis, and cerebral vasospasm.14-16 One author reported reduced complications from vasospasm among patients taking aspirin before they developed SAH.17
ns
100%
Antiplatelet agents (n=217)
Ratio of poor outcome
No antithrombotic agents (n=4811)
p = 0.03
80
60 40
ns
ns p = 0.04
20 0 <60
60s
70s
80s
≥90 years
Figure 3. Rate of poor outcome (modified Rankin Scale score of 4 or higher) in each age group was expressed according to the use of antiplatelet agents. Poorer outcomes were evident with increasing age. In the younger than 60year age group, the use of antiplatelet agents significantly improved prognosis (P 5 .04). In contrast, in the older group ($60 years), the use of antiplatelet agents tended to worsen the prognosis; patients aged 70-79 years had a significantly worse outcome (P 5 .03).
Various agents can prevent cerebral vasospasm. Cilostazol inhibits phosphodiesterase 3 activity in smooth muscle cells and platelets, leading to relaxation of intact smooth muscle cells and inhibition of platelet aggregation. Thus, it attenuates cerebral vasospasm18,19 and prevents endothelial damage,20,21 which result in reduction of delayed cerebral ischemia after aneurysmal SAH.22 In contrast to the younger group, in the older group ($60 years), the use of antiplatelet agents made the prognosis worse. Previous aspirin use carries the theoretical risks of exacerbating the initial hemorrhage, increasing the rate of rebleeding and complicating surgical procedures intended to secure the source of bleeding,9 although these factors are also true for younger patients. Our data suggest that the aneurysm formation and progression to rupture are not simple. Recent human and animal studies have shown that inflammation plays a key role in these processes.23 In young people, the beneficial effects of antiplatelet agents on aneurysm development and associated rapture may overweigh their antihemostatic effects. On the other hand, bleeding may last longer in older patients with SAH treated with these agents, which could account for poorer outcome. Hence, we need to consider the differences in etiology and age to assess the safety and efficacy of aspirin in preventing SAH. To explain the beneficial effect of antiplatelet agents, we should consider the factors associated (but not related) with drug therapy; those who take antiplatelets for
Y. KATO ET AL.
4
atherosclerotic diseases visit the hospital frequently; therefore, health problems such as hypertension or dyslipidemia might be controlled better. In aged patients, however, bleeding risk may outweigh the earlier mentioned benefits. The primary strength of the present study is the relatively large patient population used for our analysis. To the best of our knowledge, this is the largest study on SAH and aging. Japan has the fastest aging society in the world, and the present study might be beneficial for aging populations in other industrialized countries. One potential limitation of the present study is that not all the inpatients in the participating hospitals during the study period may have been enrolled. In addition, some data were not available in the registry for the present study, including the details of antithrombotic agents, severity of stroke (Fisher and Hunt–Hess classifications), occurrence of vasospasm after SAH, surgical treatment, and the 3-month poststroke outcomes of patients. Acknowledgment: Japan Standard Stroke Registry Study was developed with support (‘‘21st Century Type Promoting Development of Clinical Research Fund’’) from the Japanese Ministry of Welfare (grant number: H11-21 century(life)-33) during 1999 to 2001.
References 1. Kobayashi S, Japan Stroke Scale Registry Study Group. International experience in stroke registry: Japanese Stroke Databank. Am J Prev Med 2006;31:S240-S242. 2. Kozak N, Hayashi M. Trends in the incidence of subarachnoid hemorrhage in Akita Prefecture, Japan. J Neurosurg 2007;106:234-238. 3. van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001;124:249-278. 4. Sch€ oller K, Massmann M, Markl G, et al. Aneurysmal subarachnoid hemorrhage in elderly patients: long-term outcome and prognostic factors in an interdisciplinary treatment approach. J Neurol 2013;260:1052-1060. 5. Lanzino G, Kassell NF, Germanson TP, et al. Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse? J Neurosurg 1996; 85:410-418. 6. Hasan DM, Mahaney KB, Brown RD Jr, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 2011;42:3156-3162. 7. Garcıa-Rodrıguez LA, Gaist D, Morton J, et al. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology 2013;81:566-574. 8. Gross BA, Rosalind Lai PM, Frerichs KU, et al. Aspirin and aneurysmal subarachnoid hemorrhage. World Neurosurg 2014;82:1127-1130.
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