Symptomatic Steno-occlusion of Cerebral Arteries and Subsequent Ischemic Events in Patients with Acute Ischemic Stroke Jihoon Kang, MD,*†‡ Nayoung Kim, MD,* Chang W. Oh, MD, PhD,‡ O-Ki Kwon, MD, PhD,‡ Chol K. Jung, MD, PhD,x Wook-Joo Kim, MD, PhD,k Jung H. Park, MD,{ Youngchai Ko, MD,# Won-Young Noh, MD,* Min U. Jang, MD,* Jeong-Ho Hong, MD, PhD,* Ji S. Lee , PhD,** Juneyoung Lee, PhD,†† Myung S. Jang, AD,* Mi H. Yang, RN,* Moon-Ku Han, MD, PhD,* and Hee-Joon Bae, MD, PhD*
Background: We aimed to assess the impact of symptomatic steno-occlusion (SYSO) of cerebral arteries and its characteristics on subsequent ischemic event (SIE) in patients with acute ischemic stroke. Methods: Using a prospective stroke registry database, we identified consecutive patients with ischemic stroke who were hospitalized within 48 hours of symptom onset. SYSO denoted significant stenosis or occlusion of major cerebral arteries with ischemic lesions at the corresponding arterial territories and was characterized by its location and severity. Primary outcome was SIE that was defined as ischemic progression or recurrence within 1 year. Results: In total, 1546 patients (age, 67.4 6 13.0 years; median National Institutes of Health Stroke Scale score, 4) were enrolled in this study. The cumulative risk of SIE was 14.5% at 7 days, 14.9% at 14 days, 15.5% at 90 days, and 16.9% at 1 year. Patients with SYSO had significantly higher SIE rates compared with those without SYSO
From the *Department of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea; †Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University, Changwon, Korea; ‡Department of Neurosurgery, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea; xDepartment of Radiology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea; kDepartment of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea; {Department of Neurology, Dongguk University Gyeongju Hospital, Gyeongju, Korea; #Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea; **Department of Biostatistics, Soonchunhyang University Hospital, Seoul, Korea; and ††Department of Biostatistics, Korea University College of Medicine, Seoul, Korea. Received October 28, 2013; revision received December 9, 2013; accepted December 16, 2013. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065). Conflicts of interest: The sponsor of this study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The first and corresponding authors had full access to all the data in the study, and the corresponding author
had final responsibility for the decision to submit the article for publication. Disclosures: J.K., N.K., C.W.O., O.-K.K., C.K.J., W.-J.K., J.H.P., Y.K., W.-Y.N., M.U.J., J.-H.H., J.S.L., J.L., M.S.J., M.H.Y., and M.K.H. have nothing to disclose. H.J.B. is a principal investigator, a member of the steering committee, and/or a site investigator of multicenter clinical trials or clinical studies sponsored by Otsuka Korea, Bayer Korea, Handok Pahrmaceutical Company, SK Chemicals, ESAI-Korea, Daewoong Pharmaceutical Co Ltd, Daichi Sankyo, Pfizer, SanofiAventis Korea, and Yuhan Corporation; served as the consultant or scientific advisory board for Bayer Korea, Boehringer Ingelheim Korea, YuYu Pharmaceutical Company, and BMS Korea; and received lecture honoraria from MSD Korea, AstraZeneca Korea, BMS Korea, Novatis Korea, Otsuka Korea, Pfizer Korea, Daichi Sankyo Korea, and Handok Pharmaceutical Company. Address correspondence to Hee-Joon Bae, MD, PhD, Department of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.028
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp e347-e353
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e348 (23.0% versus 11.6%). Of the characteristics of SYSO, the location, not the severity, was significantly associated with SIE (P , .001 and P 5 .186, respectively). Multiple (adjusted hazard ratio, 5.85; 95% confidence interval, 1.81-18.85), intracranial internal carotid artery (ICA) (3.54; 1.21-8.21), and extracranial ICA SYSO (2.88; 1.01-8.21) raised the risk of SIE. Conclusions: Subsequent cerebral ischemic events (progression or recurrence) after an acute ischemic stroke occur mostly within several days of stroke onset and is associated with the location, but not the severity, of symptomatic steno-occlusion of cerebral arteries. Key Words: Ischemia—stroke—stenosis— occlusion—prognosis. Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved.
Introduction Detection of symptomatic steno-occlusion (SYSO) of cerebral arteries is essential for appropriate therapeutic decisions in patients with ischemic stroke.1 At the hyperacute stage of ischemic stroke, a major treatment target is to achieve reperfusion of cerebral arteries with SYSO, to prevent irreversible damage to the penumbra.2 With newly introduced reperfusion modalities, good outcomes can be achieved for more patients.3,4 The question of whether clinicians should intervene in cases of SYSO beyond the hyperacute stage remains unresolved because of uncertainties regarding the efficacy of, and indications for, late-stage intervention. Clinical trials for carotid endarterectomy have clearly demonstrated beneficial effects of late-stage intervention in preventing recurrence in patients with symptomatic stenosis.5 However, stenting for symptomatic stenosis of major intracranial cerebral arteries has not been shown to be superior to medical treatment because of, at least partly, high periprocedural risk.6,7 If patients with a high risk for subsequent stroke could be identified, then the high periprocedural risk of the stenting procedure might be outweighed by the potential benefits in such patients. Factors contributing to stroke recurrence are diverse, but location and severity of SYSO should be considered, and elapsed time after stroke onset is also regarded as an important factor.8-11 Overall, about 50% of 1-year recurrences occur within the first 90 days of stroke onset, and the first few weeks after onset are considered as the period of maximum risk.9 In this context, assessment of risk according to SYSO characteristics with consideration of elapsed time from stroke onset might be essential for predicting recurrence accurately; however, such comprehensive studies have not yet been conducted.8,10 The present study aimed to observe subsequent cerebral ischemic events during the first year after stroke and assess the effects of SYSO and its characteristics on these events. Because ischemic progression is another important cause of neurologic deterioration and it is difficult to differentiate it from recurrence at the acute stage,11,12 we compositely captured ischemic
progression and recurrence and combined them as a single outcome variable called ‘‘subsequent ischemic event (SIE).’’
Methods Standard Protocol Approval and Patient Consent This study was approved by the local Institutional Review Board with a waiver of informed consent because of its retrospective nature and minimal risk to participants.
Subjects and Data Collection Between July 2007 and December 2010, a consecutive series of patients who were admitted at the Seoul National University Bundang Hospital because of acute ischemic stroke within 48 hours of symptom onset were identified using a prospective stroke registry database.13 We excluded patients who did not undergo angiographic evaluation at presentation. For enrolled study subjects, we collected data on demographics, stroke characteristics, vascular risk factors, diagnostic workup, and in-hospital management directly from the registry database or by reviewing the electronic medical records.14 Investigated vascular risk factors were hypertension, diabetes mellitus, dyslipidemia, smoking, cardiac sources of cerebral embolism including atrial fibrillation,15 and history of stroke. Stroke characteristics included baseline stroke severity assessed by the National Institutes of Health Stroke Scale (NIHSS) score, elapsed time from stroke onset to arrival, and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment classification16). Regarding in-hospital management, revascularization treatment and its modalities and antithrombotic medications at discharge were considered.
Assessments of SYSO Experienced stroke neurologists (N.K. and J.K.) assessed the existence of SYSO and its characteristics. SYSO was defined as a significant stenosis or occlusion of major cerebral arteries with relevant ischemic lesions in their corresponding arterial territories, and SYSO
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was diagnosed on the basis of the first angiographic evaluation, including magnetic resonance angiography (MRA), computed tomography angiography (CTA), and conventional angiography. Investigated cerebral arteries were extracranial internal carotid artery (EICA), intracranial internal carotid artery (IICA), main stem of middle cerebral artery (M1), proximal branch of middle cerebral artery (M2), anterior cerebral artery, posterior cerebral artery, basilar artery, and vertebral artery. The severity of SYSO was graded as mild stenosis (,50% of diameter reduction), moderate to severe (50%-99%) stenosis, and occlusion. Tandem lesions were classified as a single SYSO, and the location and severity of proximal vessels were considered as representative. Cases with more than 1 SYSO were classified as multiple SYSO, and the highest degree was operationally defined as representative.
Outcome Measurements Since July 2007, neurologic deterioration during hospitalization and clinical events during the first year from stroke onset were captured prospectively by an experienced stroke nurse (M.H.Y.) and confirmed through weekly stroke registry meetings by consensus, as part of an institutional quality-of-care monitoring and improvement program for hospitalized patients with stroke.17 Ischemic progression and recurrence of ischemic stroke were combined as a single clinical outcome, SIE, in this study. Ischemic progression was defined as neurologic deterioration persisting for more than 24 hours and attributable to an increase in ischemic lesions at any time after stroke onset or to the development of new discrete lesions in the same vascular territory of the index stroke within 1 day of onset.12,18 Ischemic recurrence was defined as sudden neurologic deterioration lasting more than 24 hours attributable to newly developed, discrete lesions in a different vascular territory from the index stroke at any time after stroke onset or in the same vascular territory more than 1 day after onset. Neurologic deterioration was defined as (1) worsening of 2 points or more in the total NIHSS score, (2) worsening of 1 point or more in the level of consciousness subscale of the NIHSS score, (3) worsening of 1 point or more in the motor subscale of the NIHSS score, or (4) any newly developed neurologic deficits. Deterioration because of increased intracranial pressure, hemorrhagic transformation, or comorbid medical illness was excluded when defining SIE.19,20
Statistical Analysis Percentage, mean (SD), or median (interquartile range [IQR]) are reported depending on variable characteristics. Baseline characteristics were compared according to the presence and characteristics of SYSO using Pearson chi-square test, Student t test, Mann–Whitney U test, or Kruskal–Wallis test where appropriate. We estimated
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cumulative event rates of ischemic progression, recurrence, and SIE using the Kaplan–Meier product-limit method. Baseline characteristics were also compared between patients with and without SIE. Comparisons of cumulative event rates according to the presence and characteristics of SYSO were made using log-rank test. With respect to ischemic progression, recurrence, and SIE, adjusted odds ratios and 95% confidence intervals were estimated for the presence of SYSO in all study subjects and for the location and severity of SYSO in those with SYSO. Adjustment was made for variables with P values less than .2 for their associations with SIE and the presence of SYSO, respectively, when those associations were biologically plausible. Because reperfusion treatment could affect both SYSO and SIE, we checked the interaction between SYSO and reperfusion treatment for the development of SIE. For ischemic progression and recurrence, we repeated the interaction analysis. A 2-sided P value less than .05 was considered as a minimum level of statistical significance. The Statistical Package for the Social Sciences (Chicago, IL), version 18.0, was used for statistical analysis.
Results Among 1568 patients who were hospitalized because of acute ischemic stroke during the study period, 22 (1.4%) were excluded because of a lack of angiographic evaluation or loss to follow-up. In total, 1546 patients (age, 67.4 6 13.0 years; men, 59.6%) were enrolled for this study. Median baseline NIHSS score was 4 (IQR, 2-9) and median time from symptom onset to arrival was 5.4 hours (1.6-16.9). Angiographic evaluation for cerebrovascular status was performed with MRA in 98.6%, CTA in 31.6%, and conventional angiography in 25.3%. About half of the patients (47.4%) were evaluated by 2 or more modalities (Supplemental Fig 1). Evaluation for ischemic lesion was performed by MRI with and without diffusionweighted imaging in 89.8% and 8.8%, respectively, and noncontrast CT in 31.6%. During hospitalization, 89.1% were treated with antiplatelets, .4% with heparin or low–molecular weighted heparin, and 4.2% with antiplatelets plus heparin or low–molecular weighted heparin (Supplemental Table 1). At discharge, 69.7% were given antiplatelets, 16.2% warfarin, and 5.4% warfarin plus antiplatelets (Supplemental Table 2). SYSO was found at the initial angiographic evaluation in 828 patients (53.6%). As for the location, M1 was most frequently (32.7%) involved, followed by EICA (19.7%), IICA (12.1%), and vertebral artery (10.6%). As for severity, occlusion was most common (47.7%), followed by moderate to severe stenosis (42.1%) and mild stenosis (10.1%). The severity distribution was different according to the location of SYSO (P , .001, Supplemental Table 3). Occlusion was most frequent in
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Table 1. Baseline characteristics according the presence of SYSO Variables
No SYSO (n 5 718)
SYSO (n 5 828)
P value
Age, y, mean 6 SD Male History of stroke Baseline NIHSS score, median (IQR) Hypertension Diabetes mellitus Dyslipidemia Smoking Cardioembolism, high risk Atrial fibrillation Elapsed time from onset to arrival, h, mean 6 SD Stroke subtype SVO LAA Cardioembolism Other determined Undetermined Reperfusion treatment
65.7 6 13.2 431 (60.0%) 143 (19.9%) 3 (1-5) 458 (63.8%) 205 (28.6%) 157 (21.9%) 282 (39.3%) 92 (12.8%) 74 (10.3%) 11.8 6 12.1
69.0 6 12.7 491 (59.3%) 191 (23.1%) 5 (2-13) 549 (66.3%) 231 (27.9%) 155 (18.7%) 345 (41.7%) 221 (26.7%) 204 (24.6%) 9.6 6 11.5
,.001 .771 .133 ,.001 .301 .776 .124 .340 ,.001 ,.001 ,.001 ,.001
265 (36.9%) 109 (15.2%) 126 (17.5%) 23 (3.2%) 195 (27.2%) 48 (6.7%)
12 (1.4%) 422 (51.0%) 242 (30.4%) 38 (4.6%) 104 (12.6%) 232 (28.0%)
,.001
Abbreviations: IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SVO, small vessel occlusion; LAA, large-artery atherosclerosis. Values are presented as numbers (%), except for specific description. P values were calculated by Pearson chi-square test, t test, or Mann– Whitney U test, depending on the variable’s characteristics. Reperfusion treatment composed of intravenous thrombolysis, intra-arterial treatment, and combined treatment.
the posterior cerebral artery, and stenosis was most frequent in the EICA. Patients with SYSO were more likely to be older, to arrive earlier from symptom onset, to receive reperfusion treatment, and to have a higher baseline NIHSS, atrial fibrillation, and large-artery atherosclerosis as a stroke subtype (Table 1). With respect to the location of SYSO, baseline NIHSS score, hypertension, dyslipidemia, atrial fibrillation, and reperfusion treatment were differently distributed (Supplemental Table 3). With respect to severity, patients with occlusion were more likely to have a higher baseline NIHSS score, to have atrial fibrillation, to arrive earlier from stroke onset, and to receive reperfusion treatment (Supplemental Table 4). During a median follow-up of 331 days (IQR, 90-366), the cumulative rates of SIE were 14.5% at 7 days, 14.9% at
14 days, 15.5% at 90 days, and 16.9% at 1 year. By the end of the observation period, SIE had occurred in 254 patients (16.4%) and comprised progression in 70.1% and recurrence in 29.9% patients. All instances of progression and 60% of recurrence occurred within 2 weeks of stroke onset (Fig 1). SIE rates in patients with SYSO were 20.7%, which was significantly higher than the 11.6% in patients without SYSO (P ,.001) (Fig 2). Of the characteristics of SYSO, the location, but not the severity, was significantly associated with SIE (Fig 3). When SIE was separated into ischemic progression and recurrence, progression and recurrence rates also varied widely according to the location of SYSO (progression, 6.1%-36.4%; and recurrence, 0.0%-24.0%). A significant association between SYSO and SIE was found after adjusting for age, baseline NIHSS,
Figure 1. Cumulative event rates for ischemic progression, recurrence, and SIE for 1 year of observation. Because of uneven distribution of progression and recurrence events over time, 2 different scales were used on the x-axis, which was divided into an early and a late period separated by double oblique lines. The solid line depicts cumulative progression, the dotted line depicts cumulative recurrence, and the doubledotted line shows cumulative SIEs. Abbreviation: SIE, subsequent ischemic event.
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Figure 2. Comparison of cumulative SIE rates according to the presence of SYSO. The Kaplan– Meier survival curve describes cumulative SIE rates for patients with and without SYSO. P values were calculated by log-rank test. The xaxis has different scales before and after 14 days (separated by double oblique lines). Abbreviations: SIE, subsequent ischemic event; SYSO, symptomatic steno-occlusion.
dyslipidemia, atrial fibrillation, time from onset to arrival, and reperfusion treatment. The presence of SYSO raised the risk of SIE (adjusted hazard ratio, 1.51; 95% confidence interval, 1.19-1.99). Among the SYSO characteristics, multiple involvements, IICA SYSO, and EICA SYSO increased the likelihood of SIE (Table 2). The difference in SIE rates depending on the presence of SYSO was significant in patients with reperfusion treatment but not in those without (Fig 4, C). For both progression and recurrence, the same trend was observed (Fig 4, A, B). However, interaction analysis using Cox proportional hazard models did not reveal a significant interaction between SYSO and reperfusion treatment for the risk of SIE, ischemic progression, or recurrence (P . .1 for all interactions).
Discussion We found that SYSO detected at the acute stage of ischemic stroke increased the risk of SIE by about 50%. Of the characteristics of SYSO, the location, but not the severity, was associated with SIE occurrence. The association of SYSO location with early neurologic deterioration and stroke recurrence has already been reported.8,18 This study has merit in that recurrence, as well as progression, within 1 year of hospitalization
was systemically analyzed in relation to the presence of SYSO and SYSO characteristics. The fact that all the study subjects had undergone angiographic evaluation such as MRA, CTA, or conventional angiography, and CTA is one of the strengths of this study compared with previous studies, in which a large proportion of patients were evaluated by transcranial Doppler only.8,21 In this study, the degree of stenosis was not associated with subsequent stroke recurrence. This finding is inconsistent with the results of the Warfarin Aspirin Symptomatic Intracranial Disease Trial and the North American Symptomatic Carotid Endarterectomy Trial.5,22 However, those studies had a limitation in that they did not represent both ends of the severity. As in coronary atherosclerosis, mild unstable stenosis of the cerebral arteries increases the risk of SIEs.23 Similarly, near-occlusion and occlusion are not linearly associated with further ischemic events, which are more affected by other factors, such as collateral flow, rather than the severity of SYSO.24,25 Besides, patients with high-degree stenosis or occlusion received reperfusion treatment or aggressive management according to the current guidelines,26 which would be associated to decrease SIE rates.
Figure 3. Comparison of cumulative event rates according to location and severity of SYSO for 1 year of observation. SIE rates are shown according to the location (A) and the severity of SYSO (B). The dark gray box represents recurrence and the light gray box progression. ‘‘*’’ Denotes P value for progression; ‘‘†,’’ for recurrence, and ‘‘x,’’ for SIE. Abbreviations: SIE, subsequent ischemic event; SYSO, symptomatic steno-occlusion.
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Table 2. Effect of the presence of SYSO in all study subjects (N 5 1546), and of the location and severity of SYSO in subjects with SYSO (n 5 828)
SYSO presence No (n 5 718) Yes (n 5 828) SYSO location PCA (n 5 49) ACA (n 5 21) M1 (n 5 271) IICA (n 5 101) EICA (n 5 163) BA (n 5 58) VA (n 5 88) M2 (n 5 55) Multiple (n 5 22) SYSO severity Mild stenosis (n 5 84) Moderate stenosis (n 5 349) Occlusion (n 5 395)
HR for progression
HR for recurrence
HR for SIE
1 (Reference) 1.38 (.99-1.93)
1 (Reference) 2.07 (1.22-3.50)
1 (Reference) 1.51 (1.14-1.99)
1 (Reference) 3.12 (.70-14.04) 1.63 (.49-5.40) 2.61 (.76-9.02) 2.39 (.71-8.06) 2.02 (.53-7.68) 1.27 (.33-4.95) 1.12 (.27-5.52) 4.51 (1.16-17.53)
1 (Reference) .00 (.00-.00) 3.50 (.45-27.33) 8.30 (.99-69.27) 4.58 (.57-36.88) 3.95 (.40-39.26) 5.81 (.73-46.54) 1.25 (.08-20.48) 11.76 (1.16-119.41)
1 (Reference) 2.36 (.59-9.47) 2.00 (.71-5.62) 3.54 (1.21-8.21) 2.88 (1.01-8.21) 2.46 (.78-7.78) 2.30 (.76-6.92) 1.02 (.32-4.55) 5.85 (1.81-18.85)
1 (Reference) .91 (.49-1.69) .93 (.49-1.73)
1 (Reference) 1.20 (.40-3.63) 2.61 (.88-7.74)
1 (Reference) .96 (.56-1.66) 1.23 (.72-2.12)
Abbreviations: ACA, anterior cerebral artery; BA, basilar artery; CI, confidence interval; EICA, extracranial internal carotid artery; HR, hazard ratio; IICA, intracranial internal carotid artery; PCA, posterior cerebral artery; SYSO, symptomatic steno-occlusion; VA, vertebral artery. Adjusted hazard ratio of the presence and characteristics of SYSO for outcomes were obtained by Cox proportional hazard analysis. Adjusted variables were age, history of stroke, baseline NIHSS score, atrial fibrillation, dyslipidemia, time from onset to arrival, and reperfusion treatment.
We combined ischemic progression and recurrence into a single outcome measure, SIE. Because these 2 events share most of the pathophysiology and have a similar neurologic presentation,11,27 a composite measure is a more effective and manageable way to quantify the burden of future ischemic events, especially in the early phase of ischemic stroke. Time trend analysis of SIE occurrence focusing on the first few days revealed the need for rapid and exact prediction of SIE. Classically, stroke subtype has been emphasized in predicting recurrence.20,28 But fast and exact assessment of stroke subtype is difficult to achieve in real-world practices,29,30 and the use of SYSO characteristics, instead stroke subtype, can enable us to make an objective and timely prediction. Moreover,
this method could be easily linked to appropriate intervention planning.1 Because reperfusion treatment is usually applied to high-risk patients, a simple comparison between those with and without reperfusion treatment inevitably brought about an imbalance in measured and unmeasured outcome determinants. We should be careful in interpreting the effects of reperfusion treatment on SYSO. However, this study yielded 2 important findings about reperfusion treatment (Fig 4). First, there was a high incidence of SIE even after reperfusion treatment; about 25% of patients with or without SYSO experienced SIEs within up to 1 year. Second, reperfusion treatment might change the course of SYSO to result in a better outcome. Without reperfusion treatment, there was a significant difference
Figure 4. Comparisons of outcomes according to the presence of SYSO with stratification by reperfusion treatment. Progression (A), recurrence (B), and SIE (C) rates according to the presence of SYSO were compared using log-rank test (*). Interaction between SYSO and reperfusion treatment was assessed by Cox proportional hazard analysis with adjustment for age, history of stroke, baseline NIHSS score, dyslipidemia, atrial fibrillation, time from onset to arrival, and reperfusion treatment. Abbreviations: SIE, subsequent ischemic event; SYSO, symptomatic steno-occlusion.
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in SIE rates between those with and without SYSO, but with reperfusion treatment, there was no significant difference, although there was no significant statistical interaction between reperfusion treatment and the presence of SYSO in the multivariable models. We have to note several limitations of this study. First, this study was retrospectively conducted at a single community hospital. For reducing possible bias, we identified patients from the prospective registry database whose outcomes were captured prospectively for the purpose of monitoring the quality of care for hospitalized patients with stroke. Second, consensus is required for the use of SIE as a stroke outcome. At the acute period, a composite measure seems to be feasible and effective, but its usefulness should be confirmed in future clinical studies. In conclusion, this study showed that the risk of SIE was high at the acute period of an ischemic stroke and was associated with the location of SYSO.
Supplementary Data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013. 12.028.
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e353 11. Christensen H. Early recurrent stroke or neurological deterioration? Stroke 2005;36:231-232. author reply, 2. 12. Hong KS, Kang DW, Koo JS, et al. Impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke. Eur J Neurol 2008;15:1324-1331. 13. Kang J, Park TH, Lee KB, et al. Symptomatic stenoocclusion in patients with acute cerebral infarction: Prevalence, distribution, and functional outcome. J Stroke 2014;16:36-43. 14. Yu K-H, Bae H-J, Kwon SU, et al. Analysis of 10,811 cases with Acute Ischemic Stroke from Korean Stroke Registry: Hospital-Based Multicenter Prospective Registration Study. J Korean Neurol Assoc 2006;24:535-543. 15. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005;58:688-697. 16. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. 17. Investigators CRCfSC. CRCS-5 Statistics—2012 Report. Seoul, Korea: CRCS-5 2012. 18. Weimar C, Mieck T, Buchthal J, et al. Neurologic worsening during the acute phase of ischemic stroke. Arch Neurol 2005;62:393-397. 19. Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004;62:569-573. 20. Moroney JT, Bagiella E, Paik MC, et al. Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke 1998;29:2118-2124. 21. Oelerich M, Lentschig MG, Zunker P, et al. Intracranial vascular stenosis and occlusion: comparison of 3D timeof-flight and 3D phase-contrast MR angiography. Neuroradiology 1998;40:567-573. 22. Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006;113:555-563. 23. Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101: 948-954. 24. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003;361:107-116. 25. Grubb RL Jr, Derdeyn CP, Fritsch SM, et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998;280:1055-1060. 26. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:227-276. 27. Kang J, Ko Y, Park JH, et al. Effect of blood pressure on 3month functional outcome in the subacute stage of ischemic stroke. Neurology 2012;79:2018-2024. 28. Petty GW, Brown RD, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of functional outcome, survival, and recurrence. Stroke 2000; 31:1062-1068. 29. Landau WM, Nassief A. Editorial comment—time to burn the TOAST. Stroke 2005;36:902-904. 30. Madden KP, Karanjia PN, Adams HP Jr, et al. Accuracy of initial stroke subtype diagnosis in the TOAST study. Trial of ORG 10172 in Acute Stroke Treatment. Neurology 1995;45:1975-1979.
Background: We aimed to assess the impact of symptomatic steno-occlusion (SYSO) of cerebral arteries and its characteristics on subsequent ischemic event (SIE) in patients with acute ischemic stroke. Methods: Using a prospective stroke registry database, we identified consecutive patients with ischemic stroke who were hospitalized within 48 hours of symptom onset. SYSO denoted significant stenosis or occlusion of major cerebral arteries with ischemic lesions at the corresponding arterial territories and was characterized by its location and severity. Primary outcome was SIE that was defined as ischemic progression or recurrence within 1 year. Results: In total, 1546 patients (age, 67.4 6 13.0 years; median National Institutes of Health Stroke Scale score, 4) were enrolled in this study. The cumulative risk of SIE was 14.5% at 7 days, 14.9% at 14 days, 15.5% at 90 days, and 16.9% at 1 year. Patients with SYSO had significantly higher SIE rates compared with those without SYSO
From the *Department of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea; †Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University, Changwon, Korea; ‡Department of Neurosurgery, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea; xDepartment of Radiology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea; kDepartment of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea; {Department of Neurology, Dongguk University Gyeongju Hospital, Gyeongju, Korea; #Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea; **Department of Biostatistics, Soonchunhyang University Hospital, Seoul, Korea; and ††Department of Biostatistics, Korea University College of Medicine, Seoul, Korea. Received October 28, 2013; revision received December 9, 2013; accepted December 16, 2013. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065). Conflicts of interest: The sponsor of this study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The first and corresponding authors had full access to all the data in the study, and the corresponding author
had final responsibility for the decision to submit the article for publication. Disclosures: J.K., N.K., C.W.O., O.-K.K., C.K.J., W.-J.K., J.H.P., Y.K., W.-Y.N., M.U.J., J.-H.H., J.S.L., J.L., M.S.J., M.H.Y., and M.K.H. have nothing to disclose. H.J.B. is a principal investigator, a member of the steering committee, and/or a site investigator of multicenter clinical trials or clinical studies sponsored by Otsuka Korea, Bayer Korea, Handok Pahrmaceutical Company, SK Chemicals, ESAI-Korea, Daewoong Pharmaceutical Co Ltd, Daichi Sankyo, Pfizer, SanofiAventis Korea, and Yuhan Corporation; served as the consultant or scientific advisory board for Bayer Korea, Boehringer Ingelheim Korea, YuYu Pharmaceutical Company, and BMS Korea; and received lecture honoraria from MSD Korea, AstraZeneca Korea, BMS Korea, Novatis Korea, Otsuka Korea, Pfizer Korea, Daichi Sankyo Korea, and Handok Pharmaceutical Company. Address correspondence to Hee-Joon Bae, MD, PhD, Department of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.028
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp e347-e353
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e348 (23.0% versus 11.6%). Of the characteristics of SYSO, the location, not the severity, was significantly associated with SIE (P , .001 and P 5 .186, respectively). Multiple (adjusted hazard ratio, 5.85; 95% confidence interval, 1.81-18.85), intracranial internal carotid artery (ICA) (3.54; 1.21-8.21), and extracranial ICA SYSO (2.88; 1.01-8.21) raised the risk of SIE. Conclusions: Subsequent cerebral ischemic events (progression or recurrence) after an acute ischemic stroke occur mostly within several days of stroke onset and is associated with the location, but not the severity, of symptomatic steno-occlusion of cerebral arteries. Key Words: Ischemia—stroke—stenosis— occlusion—prognosis. Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved.
Introduction Detection of symptomatic steno-occlusion (SYSO) of cerebral arteries is essential for appropriate therapeutic decisions in patients with ischemic stroke.1 At the hyperacute stage of ischemic stroke, a major treatment target is to achieve reperfusion of cerebral arteries with SYSO, to prevent irreversible damage to the penumbra.2 With newly introduced reperfusion modalities, good outcomes can be achieved for more patients.3,4 The question of whether clinicians should intervene in cases of SYSO beyond the hyperacute stage remains unresolved because of uncertainties regarding the efficacy of, and indications for, late-stage intervention. Clinical trials for carotid endarterectomy have clearly demonstrated beneficial effects of late-stage intervention in preventing recurrence in patients with symptomatic stenosis.5 However, stenting for symptomatic stenosis of major intracranial cerebral arteries has not been shown to be superior to medical treatment because of, at least partly, high periprocedural risk.6,7 If patients with a high risk for subsequent stroke could be identified, then the high periprocedural risk of the stenting procedure might be outweighed by the potential benefits in such patients. Factors contributing to stroke recurrence are diverse, but location and severity of SYSO should be considered, and elapsed time after stroke onset is also regarded as an important factor.8-11 Overall, about 50% of 1-year recurrences occur within the first 90 days of stroke onset, and the first few weeks after onset are considered as the period of maximum risk.9 In this context, assessment of risk according to SYSO characteristics with consideration of elapsed time from stroke onset might be essential for predicting recurrence accurately; however, such comprehensive studies have not yet been conducted.8,10 The present study aimed to observe subsequent cerebral ischemic events during the first year after stroke and assess the effects of SYSO and its characteristics on these events. Because ischemic progression is another important cause of neurologic deterioration and it is difficult to differentiate it from recurrence at the acute stage,11,12 we compositely captured ischemic
progression and recurrence and combined them as a single outcome variable called ‘‘subsequent ischemic event (SIE).’’
Methods Standard Protocol Approval and Patient Consent This study was approved by the local Institutional Review Board with a waiver of informed consent because of its retrospective nature and minimal risk to participants.
Subjects and Data Collection Between July 2007 and December 2010, a consecutive series of patients who were admitted at the Seoul National University Bundang Hospital because of acute ischemic stroke within 48 hours of symptom onset were identified using a prospective stroke registry database.13 We excluded patients who did not undergo angiographic evaluation at presentation. For enrolled study subjects, we collected data on demographics, stroke characteristics, vascular risk factors, diagnostic workup, and in-hospital management directly from the registry database or by reviewing the electronic medical records.14 Investigated vascular risk factors were hypertension, diabetes mellitus, dyslipidemia, smoking, cardiac sources of cerebral embolism including atrial fibrillation,15 and history of stroke. Stroke characteristics included baseline stroke severity assessed by the National Institutes of Health Stroke Scale (NIHSS) score, elapsed time from stroke onset to arrival, and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment classification16). Regarding in-hospital management, revascularization treatment and its modalities and antithrombotic medications at discharge were considered.
Assessments of SYSO Experienced stroke neurologists (N.K. and J.K.) assessed the existence of SYSO and its characteristics. SYSO was defined as a significant stenosis or occlusion of major cerebral arteries with relevant ischemic lesions in their corresponding arterial territories, and SYSO
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was diagnosed on the basis of the first angiographic evaluation, including magnetic resonance angiography (MRA), computed tomography angiography (CTA), and conventional angiography. Investigated cerebral arteries were extracranial internal carotid artery (EICA), intracranial internal carotid artery (IICA), main stem of middle cerebral artery (M1), proximal branch of middle cerebral artery (M2), anterior cerebral artery, posterior cerebral artery, basilar artery, and vertebral artery. The severity of SYSO was graded as mild stenosis (,50% of diameter reduction), moderate to severe (50%-99%) stenosis, and occlusion. Tandem lesions were classified as a single SYSO, and the location and severity of proximal vessels were considered as representative. Cases with more than 1 SYSO were classified as multiple SYSO, and the highest degree was operationally defined as representative.
Outcome Measurements Since July 2007, neurologic deterioration during hospitalization and clinical events during the first year from stroke onset were captured prospectively by an experienced stroke nurse (M.H.Y.) and confirmed through weekly stroke registry meetings by consensus, as part of an institutional quality-of-care monitoring and improvement program for hospitalized patients with stroke.17 Ischemic progression and recurrence of ischemic stroke were combined as a single clinical outcome, SIE, in this study. Ischemic progression was defined as neurologic deterioration persisting for more than 24 hours and attributable to an increase in ischemic lesions at any time after stroke onset or to the development of new discrete lesions in the same vascular territory of the index stroke within 1 day of onset.12,18 Ischemic recurrence was defined as sudden neurologic deterioration lasting more than 24 hours attributable to newly developed, discrete lesions in a different vascular territory from the index stroke at any time after stroke onset or in the same vascular territory more than 1 day after onset. Neurologic deterioration was defined as (1) worsening of 2 points or more in the total NIHSS score, (2) worsening of 1 point or more in the level of consciousness subscale of the NIHSS score, (3) worsening of 1 point or more in the motor subscale of the NIHSS score, or (4) any newly developed neurologic deficits. Deterioration because of increased intracranial pressure, hemorrhagic transformation, or comorbid medical illness was excluded when defining SIE.19,20
Statistical Analysis Percentage, mean (SD), or median (interquartile range [IQR]) are reported depending on variable characteristics. Baseline characteristics were compared according to the presence and characteristics of SYSO using Pearson chi-square test, Student t test, Mann–Whitney U test, or Kruskal–Wallis test where appropriate. We estimated
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cumulative event rates of ischemic progression, recurrence, and SIE using the Kaplan–Meier product-limit method. Baseline characteristics were also compared between patients with and without SIE. Comparisons of cumulative event rates according to the presence and characteristics of SYSO were made using log-rank test. With respect to ischemic progression, recurrence, and SIE, adjusted odds ratios and 95% confidence intervals were estimated for the presence of SYSO in all study subjects and for the location and severity of SYSO in those with SYSO. Adjustment was made for variables with P values less than .2 for their associations with SIE and the presence of SYSO, respectively, when those associations were biologically plausible. Because reperfusion treatment could affect both SYSO and SIE, we checked the interaction between SYSO and reperfusion treatment for the development of SIE. For ischemic progression and recurrence, we repeated the interaction analysis. A 2-sided P value less than .05 was considered as a minimum level of statistical significance. The Statistical Package for the Social Sciences (Chicago, IL), version 18.0, was used for statistical analysis.
Results Among 1568 patients who were hospitalized because of acute ischemic stroke during the study period, 22 (1.4%) were excluded because of a lack of angiographic evaluation or loss to follow-up. In total, 1546 patients (age, 67.4 6 13.0 years; men, 59.6%) were enrolled for this study. Median baseline NIHSS score was 4 (IQR, 2-9) and median time from symptom onset to arrival was 5.4 hours (1.6-16.9). Angiographic evaluation for cerebrovascular status was performed with MRA in 98.6%, CTA in 31.6%, and conventional angiography in 25.3%. About half of the patients (47.4%) were evaluated by 2 or more modalities (Supplemental Fig 1). Evaluation for ischemic lesion was performed by MRI with and without diffusionweighted imaging in 89.8% and 8.8%, respectively, and noncontrast CT in 31.6%. During hospitalization, 89.1% were treated with antiplatelets, .4% with heparin or low–molecular weighted heparin, and 4.2% with antiplatelets plus heparin or low–molecular weighted heparin (Supplemental Table 1). At discharge, 69.7% were given antiplatelets, 16.2% warfarin, and 5.4% warfarin plus antiplatelets (Supplemental Table 2). SYSO was found at the initial angiographic evaluation in 828 patients (53.6%). As for the location, M1 was most frequently (32.7%) involved, followed by EICA (19.7%), IICA (12.1%), and vertebral artery (10.6%). As for severity, occlusion was most common (47.7%), followed by moderate to severe stenosis (42.1%) and mild stenosis (10.1%). The severity distribution was different according to the location of SYSO (P , .001, Supplemental Table 3). Occlusion was most frequent in
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Table 1. Baseline characteristics according the presence of SYSO Variables
No SYSO (n 5 718)
SYSO (n 5 828)
P value
Age, y, mean 6 SD Male History of stroke Baseline NIHSS score, median (IQR) Hypertension Diabetes mellitus Dyslipidemia Smoking Cardioembolism, high risk Atrial fibrillation Elapsed time from onset to arrival, h, mean 6 SD Stroke subtype SVO LAA Cardioembolism Other determined Undetermined Reperfusion treatment
65.7 6 13.2 431 (60.0%) 143 (19.9%) 3 (1-5) 458 (63.8%) 205 (28.6%) 157 (21.9%) 282 (39.3%) 92 (12.8%) 74 (10.3%) 11.8 6 12.1
69.0 6 12.7 491 (59.3%) 191 (23.1%) 5 (2-13) 549 (66.3%) 231 (27.9%) 155 (18.7%) 345 (41.7%) 221 (26.7%) 204 (24.6%) 9.6 6 11.5
,.001 .771 .133 ,.001 .301 .776 .124 .340 ,.001 ,.001 ,.001 ,.001
265 (36.9%) 109 (15.2%) 126 (17.5%) 23 (3.2%) 195 (27.2%) 48 (6.7%)
12 (1.4%) 422 (51.0%) 242 (30.4%) 38 (4.6%) 104 (12.6%) 232 (28.0%)
,.001
Abbreviations: IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SVO, small vessel occlusion; LAA, large-artery atherosclerosis. Values are presented as numbers (%), except for specific description. P values were calculated by Pearson chi-square test, t test, or Mann– Whitney U test, depending on the variable’s characteristics. Reperfusion treatment composed of intravenous thrombolysis, intra-arterial treatment, and combined treatment.
the posterior cerebral artery, and stenosis was most frequent in the EICA. Patients with SYSO were more likely to be older, to arrive earlier from symptom onset, to receive reperfusion treatment, and to have a higher baseline NIHSS, atrial fibrillation, and large-artery atherosclerosis as a stroke subtype (Table 1). With respect to the location of SYSO, baseline NIHSS score, hypertension, dyslipidemia, atrial fibrillation, and reperfusion treatment were differently distributed (Supplemental Table 3). With respect to severity, patients with occlusion were more likely to have a higher baseline NIHSS score, to have atrial fibrillation, to arrive earlier from stroke onset, and to receive reperfusion treatment (Supplemental Table 4). During a median follow-up of 331 days (IQR, 90-366), the cumulative rates of SIE were 14.5% at 7 days, 14.9% at
14 days, 15.5% at 90 days, and 16.9% at 1 year. By the end of the observation period, SIE had occurred in 254 patients (16.4%) and comprised progression in 70.1% and recurrence in 29.9% patients. All instances of progression and 60% of recurrence occurred within 2 weeks of stroke onset (Fig 1). SIE rates in patients with SYSO were 20.7%, which was significantly higher than the 11.6% in patients without SYSO (P ,.001) (Fig 2). Of the characteristics of SYSO, the location, but not the severity, was significantly associated with SIE (Fig 3). When SIE was separated into ischemic progression and recurrence, progression and recurrence rates also varied widely according to the location of SYSO (progression, 6.1%-36.4%; and recurrence, 0.0%-24.0%). A significant association between SYSO and SIE was found after adjusting for age, baseline NIHSS,
Figure 1. Cumulative event rates for ischemic progression, recurrence, and SIE for 1 year of observation. Because of uneven distribution of progression and recurrence events over time, 2 different scales were used on the x-axis, which was divided into an early and a late period separated by double oblique lines. The solid line depicts cumulative progression, the dotted line depicts cumulative recurrence, and the doubledotted line shows cumulative SIEs. Abbreviation: SIE, subsequent ischemic event.
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Figure 2. Comparison of cumulative SIE rates according to the presence of SYSO. The Kaplan– Meier survival curve describes cumulative SIE rates for patients with and without SYSO. P values were calculated by log-rank test. The xaxis has different scales before and after 14 days (separated by double oblique lines). Abbreviations: SIE, subsequent ischemic event; SYSO, symptomatic steno-occlusion.
dyslipidemia, atrial fibrillation, time from onset to arrival, and reperfusion treatment. The presence of SYSO raised the risk of SIE (adjusted hazard ratio, 1.51; 95% confidence interval, 1.19-1.99). Among the SYSO characteristics, multiple involvements, IICA SYSO, and EICA SYSO increased the likelihood of SIE (Table 2). The difference in SIE rates depending on the presence of SYSO was significant in patients with reperfusion treatment but not in those without (Fig 4, C). For both progression and recurrence, the same trend was observed (Fig 4, A, B). However, interaction analysis using Cox proportional hazard models did not reveal a significant interaction between SYSO and reperfusion treatment for the risk of SIE, ischemic progression, or recurrence (P . .1 for all interactions).
Discussion We found that SYSO detected at the acute stage of ischemic stroke increased the risk of SIE by about 50%. Of the characteristics of SYSO, the location, but not the severity, was associated with SIE occurrence. The association of SYSO location with early neurologic deterioration and stroke recurrence has already been reported.8,18 This study has merit in that recurrence, as well as progression, within 1 year of hospitalization
was systemically analyzed in relation to the presence of SYSO and SYSO characteristics. The fact that all the study subjects had undergone angiographic evaluation such as MRA, CTA, or conventional angiography, and CTA is one of the strengths of this study compared with previous studies, in which a large proportion of patients were evaluated by transcranial Doppler only.8,21 In this study, the degree of stenosis was not associated with subsequent stroke recurrence. This finding is inconsistent with the results of the Warfarin Aspirin Symptomatic Intracranial Disease Trial and the North American Symptomatic Carotid Endarterectomy Trial.5,22 However, those studies had a limitation in that they did not represent both ends of the severity. As in coronary atherosclerosis, mild unstable stenosis of the cerebral arteries increases the risk of SIEs.23 Similarly, near-occlusion and occlusion are not linearly associated with further ischemic events, which are more affected by other factors, such as collateral flow, rather than the severity of SYSO.24,25 Besides, patients with high-degree stenosis or occlusion received reperfusion treatment or aggressive management according to the current guidelines,26 which would be associated to decrease SIE rates.
Figure 3. Comparison of cumulative event rates according to location and severity of SYSO for 1 year of observation. SIE rates are shown according to the location (A) and the severity of SYSO (B). The dark gray box represents recurrence and the light gray box progression. ‘‘*’’ Denotes P value for progression; ‘‘†,’’ for recurrence, and ‘‘x,’’ for SIE. Abbreviations: SIE, subsequent ischemic event; SYSO, symptomatic steno-occlusion.
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Table 2. Effect of the presence of SYSO in all study subjects (N 5 1546), and of the location and severity of SYSO in subjects with SYSO (n 5 828)
SYSO presence No (n 5 718) Yes (n 5 828) SYSO location PCA (n 5 49) ACA (n 5 21) M1 (n 5 271) IICA (n 5 101) EICA (n 5 163) BA (n 5 58) VA (n 5 88) M2 (n 5 55) Multiple (n 5 22) SYSO severity Mild stenosis (n 5 84) Moderate stenosis (n 5 349) Occlusion (n 5 395)
HR for progression
HR for recurrence
HR for SIE
1 (Reference) 1.38 (.99-1.93)
1 (Reference) 2.07 (1.22-3.50)
1 (Reference) 1.51 (1.14-1.99)
1 (Reference) 3.12 (.70-14.04) 1.63 (.49-5.40) 2.61 (.76-9.02) 2.39 (.71-8.06) 2.02 (.53-7.68) 1.27 (.33-4.95) 1.12 (.27-5.52) 4.51 (1.16-17.53)
1 (Reference) .00 (.00-.00) 3.50 (.45-27.33) 8.30 (.99-69.27) 4.58 (.57-36.88) 3.95 (.40-39.26) 5.81 (.73-46.54) 1.25 (.08-20.48) 11.76 (1.16-119.41)
1 (Reference) 2.36 (.59-9.47) 2.00 (.71-5.62) 3.54 (1.21-8.21) 2.88 (1.01-8.21) 2.46 (.78-7.78) 2.30 (.76-6.92) 1.02 (.32-4.55) 5.85 (1.81-18.85)
1 (Reference) .91 (.49-1.69) .93 (.49-1.73)
1 (Reference) 1.20 (.40-3.63) 2.61 (.88-7.74)
1 (Reference) .96 (.56-1.66) 1.23 (.72-2.12)
Abbreviations: ACA, anterior cerebral artery; BA, basilar artery; CI, confidence interval; EICA, extracranial internal carotid artery; HR, hazard ratio; IICA, intracranial internal carotid artery; PCA, posterior cerebral artery; SYSO, symptomatic steno-occlusion; VA, vertebral artery. Adjusted hazard ratio of the presence and characteristics of SYSO for outcomes were obtained by Cox proportional hazard analysis. Adjusted variables were age, history of stroke, baseline NIHSS score, atrial fibrillation, dyslipidemia, time from onset to arrival, and reperfusion treatment.
We combined ischemic progression and recurrence into a single outcome measure, SIE. Because these 2 events share most of the pathophysiology and have a similar neurologic presentation,11,27 a composite measure is a more effective and manageable way to quantify the burden of future ischemic events, especially in the early phase of ischemic stroke. Time trend analysis of SIE occurrence focusing on the first few days revealed the need for rapid and exact prediction of SIE. Classically, stroke subtype has been emphasized in predicting recurrence.20,28 But fast and exact assessment of stroke subtype is difficult to achieve in real-world practices,29,30 and the use of SYSO characteristics, instead stroke subtype, can enable us to make an objective and timely prediction. Moreover,
this method could be easily linked to appropriate intervention planning.1 Because reperfusion treatment is usually applied to high-risk patients, a simple comparison between those with and without reperfusion treatment inevitably brought about an imbalance in measured and unmeasured outcome determinants. We should be careful in interpreting the effects of reperfusion treatment on SYSO. However, this study yielded 2 important findings about reperfusion treatment (Fig 4). First, there was a high incidence of SIE even after reperfusion treatment; about 25% of patients with or without SYSO experienced SIEs within up to 1 year. Second, reperfusion treatment might change the course of SYSO to result in a better outcome. Without reperfusion treatment, there was a significant difference
Figure 4. Comparisons of outcomes according to the presence of SYSO with stratification by reperfusion treatment. Progression (A), recurrence (B), and SIE (C) rates according to the presence of SYSO were compared using log-rank test (*). Interaction between SYSO and reperfusion treatment was assessed by Cox proportional hazard analysis with adjustment for age, history of stroke, baseline NIHSS score, dyslipidemia, atrial fibrillation, time from onset to arrival, and reperfusion treatment. Abbreviations: SIE, subsequent ischemic event; SYSO, symptomatic steno-occlusion.
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in SIE rates between those with and without SYSO, but with reperfusion treatment, there was no significant difference, although there was no significant statistical interaction between reperfusion treatment and the presence of SYSO in the multivariable models. We have to note several limitations of this study. First, this study was retrospectively conducted at a single community hospital. For reducing possible bias, we identified patients from the prospective registry database whose outcomes were captured prospectively for the purpose of monitoring the quality of care for hospitalized patients with stroke. Second, consensus is required for the use of SIE as a stroke outcome. At the acute period, a composite measure seems to be feasible and effective, but its usefulness should be confirmed in future clinical studies. In conclusion, this study showed that the risk of SIE was high at the acute period of an ischemic stroke and was associated with the location of SYSO.
Supplementary Data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013. 12.028.
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