- Email: [email protected]
Predicting Stroke Outcome Using Clinical- versus Imaging-based Scoring System
Accepted Manuscript Predicting stroke outcome using clinical- versus imaging-based scoring system Joon Hyun Baek, MD. Kitae Kim, MD. Yeong-Bae Lee, MD, PhD. Kee-Hyung Park, MD, PhD. Hyeon-Mi Park, MD. Dong-Jin Shin, MD. Young Hee Sung, MD. Dong Hoon Shin, MD, PhD. Oh Young Bang, MD, PhD. PII:
S1052-3057(14)00509-6
DOI:
10.1016/j.jstrokecerebrovasdis.2014.10.009
Reference:
YJSCD 1877
To appear in:
Journal of Stroke & Cerebrovascular Diseases
Received Date: 29 May 2014 Revised Date:
3 September 2014
Accepted Date: 23 October 2014
Please cite this article as: Baek JH, Kim K, Lee Y-B, Park K-H, Park H-M, Shin D-J, Sung YH, Shin DH, Bang OY, Predicting stroke outcome using clinical- versus imaging-based scoring system, Journal of Stroke & Cerebrovascular Diseases (2014), doi: 10.1016/j.jstrokecerebrovasdis.2014.10.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Predicting stroke outcome using clinical- versus imagingbased scoring system
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Joon Hyun Baek, MD.,1 Kitae Kim, MD.,1 Yeong-Bae Lee, MD, PhD.,1 Kee-Hyung Park, MD, PhD.,1 Hyeon-Mi Park, MD.,1 Dong-Jin Shin, MD.,1
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Department of Neurology, Gachon University Gil Medical Center, Incheon, South Korea
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Young Hee Sung, MD.,1 Dong Hoon Shin, MD, PhD.,1* Oh Young Bang, MD, PhD.2
*Corresponding author address: Dong Hoon Shin, MD.
Department of Neurology, Gachon University Gil Medical Center 1198, Guwol-Dong, Namdong-Gu, Incheon, 405-760, South Korea Tel: +82-32-460-3346 Fax:+83-32-460-3344 1
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E-mail: [email protected]
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Predicting stroke outcome using clinical- versus imaging-based scoring system
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Running title: Comparison of Scoring Systems for Stroke Outcome
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Character count for the title: 69 Total word count for the text: 2127
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Number of references: 23 Number of figures: 2
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Number of tables: 2
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Abstract Background: Several models to predict outcome in ischemic stroke patients receiving intravenous (i.v.) alteplase can be divided into clinical-based and imaging-based systems.
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ASPECTS (Alberta Stroke Program Early CT Score) and DRAGON (Dense cerebral artery sign/early infarct signs on admission CT scan, prestroke modified Rankin Scale [mRS] score, Age, Glucose level at baseline, Onset-to-treatment time, and baseline NIHSSscore) are
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typical imaging-based and clinical-based scoring systems, respectively. Therefore, we
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compared predictability of stroke outcome of clinical (DRAGON)- and imaging (ASPECTS)based scoring systems.
Methods: We analyzed patients who were diagnosed with middle cerebral artery territory stroke and treated with i.v. alteplase at Gachon University Gil Hospital over five years and compared performance of two scoring systems for prediction of good functional outcome
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(mRS 0-2) with Pearson's correlation and area under the curve-receiver operating characteristic (AUC-ROC). In addition, we analyzed predicting power of several clinical factors and two scoring systems by multiple regression analysis.
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Results: Study population (n=120) had mean age of 66.2±13.2. ASPECTS (r=-0.841,
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p<0.0001) and DRAGON (r=0.657, p<0.0001) were significantly correlated with good functional outcome. In addition, statistical comparisons suggested that ASPECTS (AUCROC, 0.972; 95% confidence interval [CI], 0.947-0.996) is significantly superior to DRAGON (AUC-ROC, 0.854; 95% CI, 0.786-0.922) in predicting functional outcome (difference between areas 0.118±0.0332; 95% CI, 0.0559-0.180, p=0.0002). Multiple regression analysis revealed that ASPECTS was the independent predictor of good prognosis (OR 6.59 per 1-point increase; 95% CI 2.35-18.49; p<0.0001; and OR 77.67 for ASPECTS ≥8; 95% CI 14.30-421.79; p<0.0001). 1
ACCEPTED MANUSCRIPT Conclusion: ASPECTS is superior method for predicting functional outcome in acute ischemic stroke patients receiving i.v. alteplase compared to DRAGON and integration of
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ASPECTS score into clinical care pathway as decision-making tool can be reasonable.
Keywords: Cerebral infarct; Outcomes; Stroke care; Thrombolysis; ASPECTS score;
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DRAGON score; Prognosis
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Introduction The currently available approved therapy for acute ischemic stroke are the infusion of intravenous (i.v.) alteplase within 4.5 hours of the onset of stroke symptoms and endovascular
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clot removal. Patients with acute ischemic stroke who received i.v. alteplase within three hours of the onset of symptoms were at least 30% more likely to have minimal or no disability at three months than those who received placebo and about half of the patient to
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achieve recanalization.1, 2
Scoring systems, that have been developed to predict 3-month functional outcome after
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ischemic stroke after i.v. alteplase, can be divided into clinical-based and imaging-based systems. The clinical-based scoring systems commonly use several variables like age, gender, baseline NIH Stroke Scale (NIHSS) score, blood glucose level on admission, and onset-totreatment time (OTT). Imaging-based systems evaluate the baseline extent of brain infarcts to
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predict the functional outcome.3-5 ASPECTS (Alberta Stroke Program Early CT Score) and DRAGON (Dense cerebral artery sign/early infarct signs on admission CT scan, prestroke modified Rankin Scale [mRS] score, Age, Glucose level at baseline, Onset-to-treatment time,
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and baseline NIHSSscore) are the typical imaging-based and clinical-based scoring systems, respectively. ASPECTS is a 10-point topographic CT scan score used in patients with middle
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cerebral artery (MCA) stroke and an ASPECTS score less than or equal to 7 predicts worse functional outcome at 3 months as well as symptomatic hemorrhage.6 DRAGON score is a new 10- point scoring method based on glucose level, age, severity of stroke, abnormal CT finding, and time since stroke symptoms started. Ninety-six percent of patients who had a score of zero to two had a good 3-month outcome and no patient who had DRAGON scores of eight to ten was independent in daily activities three months later.7 The clinical care pathway for acute stroke can provide specialized multidisciplinary 3
ACCEPTED MANUSCRIPT stroke care and ensure the equity of care preventing poor coordination and inefficiency by involvement of the expertise of several professionals to the management of acute stroke patient, ultimately improving the outcomes.8, 9 Integration of scoring systems designed to
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predict 3-month functional outcome with clinical care pathway can help clinicians to make better decisions in treatment of acute stroke, especially when clinicians decide to progress to add-on treatment such as endovascular treatment.
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Our aim is to investigate the predictability of clinical (DRAGON)- and imaging (ASPECTS)-based scoring systems for stroke outcome in anterior ischemic stroke patients
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treated with i.v. alteplase and to determine which scoring system is better to integrate to
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clinical care pathway.
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Patients and methods Patients Consecutive patients visited over five years, who were diagnosed with middle cerebral artery
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territory stroke and treated with i.v. alteplase at the Gachon University Gil Medical Center, were retrospectively analyzed on baseline demographic characteristics and 3-month functional outcome. All patients underwent baseline brain CT scan immediately when
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reaching the emergency department. Patients were excluded from this study if they had transient ischemic stroke symptom with negative imaging findings, had a posterior circulation
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stroke, or had a contraindication for administration of i.v. alteplase.10 ASPECTS and DRAGON score were used to evaluate initial CT scans.
Scoring systems
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We measured the parameters of DRAGON and ASPECTS in all enrolled patients. The ASPECTS was determined from two standardized axial CT cuts, one at the level of the thalamus and basal ganglion and one adjacent to the most superior margin of the ganglionic
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structures.11 A single point was subtracted for an area of early ischemic change, such as focal swelling or parenchymal hypoattenuation, for each of the defined regions. A normal CT scan
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received an ASPECTS of 10 points, whereas a score of zero indicated diffuse ischemic involvement throughout the MCA territory. The DRAGON score (0–10 points) consists of Dense cerebral artery sign/early infarct signs on admission CT scan (both=2, either=1, none=0), prestroke modified Rankin Scale score>1 (yes=1), Age (≥80 years=2, 65–79 years=1, <65 years=0), Glucose level at baseline (>8 mmol/L [>144 mg/dL]=1), Onset-to-treatment time (>90 minutes=1), and baseline NIHSS score (>15=3, 10–15= 2, 5–9 =1, 0–4=0).7 As opposed to the ASPECTS score system, 5
ACCEPTED MANUSCRIPT a score of zero indicated no risk factors. Two reviewers blinded to the patients’ outcome independently assessed the ASPECT and DRAGON scores. In cases of disagreement between
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two blinded reviewers, the final decision was reached by consensus.
Statistical analysis
Variables were analyzed using the independent t-test, or χ2 test, as appropriate for
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continuous and categorical variables: age, sex, hypertension, diabetes mellitus, cardiac problem, previous stroke, hypercholesterolemia, current smoking, hemoglobin, glucose, total
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cholesterol, C-reactive protein, and homocysteine according to clinical outcome. To identify whether each scoring systems was associated with good functional outcome, Pearson's correlation coefficients were calculated. We measured the area under the receiver operating characteristic curve (AUC-ROC) of both scoring systems and compared the prediction of
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good functional outcome (defined as mRS 0-2) by pairwise comparison of ROC curves. Multiple regression analysis was performed to predict the factors associated with good functional outcome. Potential predictors that were not significant (p>0.2) in the univariate
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analysis were deleted from the full multivariate model. The final multivariate model was adjusted for gender. We used SPSS 12.0 (SPSS V12.0K, SPSS Inc., Chicago, Illinois, USA)
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and MedCalc for statistical analysis above mentioned. We rejected null hypotheses of no difference if p-values were less than .05, or, equivalently, if the 95% confidence intervals [CIs] of risk point estimates excluded 1.
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Results General Demographics Table 1 presents the details relating to the baseline demographics according to good
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functional outcome. One hundred sixty eight patients were treated with thrombolysis using i.v. alteplase of the 4162 patients who were admitted with ischemic stroke for 5 years. The time interval between the onset of symptoms to treatment of i.v. alteplase was 2.12±0.03 hours. Of
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168 patients, 48 patients were excluded in this study; 38 patients had anterior cerebral artery
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territory or posterior circulation stroke, one was stroke mimic (Todd's palsy), and 9 were transferred after i.v. tPA infusion at local hospital but pretreatment CT imaging data were not available or incompatible with our image system. We identified 120 patients who met the criteria. The mean age was 66.2±13.2 years and there were 44 females. Patient with good outcome (mRS 0-2) were younger (p<0.0001), had higher baseline level of hemoglobin (p=
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0.041) and total cholesterol (p=0.013), and less frequently had atrial fibrillation (p=0.045).
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Relationship between scoring systems and good functional outcome Interobserver agreement was 0.898 for ASPECTS and 0.984 for DRAGON scores.
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Pearson's correlation analysis showed that both ASPECTS (r=-0.841, p<0.0001) and DRAGON (r=0.657, p<0.0001) were significantly and strongly correlated with good functional outcome (Figure 1). The area under the ROC curve shows the discriminative capabilities of each scoring system to determine prognosis. Figure 2 shows that ASPECTS demonstrated a high discriminative capability, with AUC-ROC of 0.972 (95% CI 0.947-0.996, p<0.001) for favorable functional outcome compared to DRAGON (AUC-ROC 0.854, 95% CI 0.786-0.922, p<0.001). ROC curves for each reader's ASPECTS and DRAGON scores were presented as supplement 1. Pairwise comparison of ROC curves between two scoring 7
ACCEPTED MANUSCRIPT systems showed that ASPECTS is significantly superior to DRAGON (difference between areas 0.118±0.0332; 95% CI 0.0559-0.180, p=0.0002). The optimal cut points for ASPECTS and DRAGON were 8 and 3 (sensitivity: 88.1% specificity: 94.9%; sensitivity: 64.3%
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specificity: 88.5%, respectively).
Multiple regression analysis for predicting good functional outcome
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Table 2 shows the crude odds ratios (OR) of the univariate regression analysis for good functional outcome. Age, basal NIHSS score, atrial fibrillation, ASPECTS, DRAGON,
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ASPECTS (≥8), and DRAGON (≤3) were significant predictors of functional prognosis in univariate analysis. When these factors were entered into the final multivariate model for functional outcome, ASPECTS was the only independent predictor of good prognosis (OR 6.59 per 1-point increase; 95% CI 2.35-18.49; p<0.0001 in model 1 that use the APECTS and
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DRAGON as ordinary variables; and OR 77.67 for ASPECTS ≥8; 95% CI 14.30-421.79; p<0.0001in model 2 that use the ASPECTS and DRAGON as categorical variables after
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dichotomization by cut-off value).
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Discussion The major finding of this study is that imaging based scoring system (ASPECTS) is superior to clinical-based system (DRAGON or NIHSS) for predicting functional outcome
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after i.v. alteplase administration. Integrated care pathways have been designed to introduce management practice and incorporate emerging research evidence into clinical practice to increase therapeutic
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effectiveness such as reduction in mortality and dependency and improvement of functional outcome by collaborative care of specialist staffs.9 Because development of a care pathway is
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an interdisciplinary task, several steps including formation of a team of appropriate professionals, and research to determine current practice and identify evidence for best practice are necessary for development of integrated care pathway. The success of integrated care pathway depends on the quality of implementation and useful decision-making scoring
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system.
Thrombolytic therapy using i.v. alteplase and endovascular clot removal are effective methods to date although numerous methods and drugs have been proposed to treat the stroke
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in hyperacute stage.12 Many trials to maximize the use of i.v. alteplase have been conducted because current guidelines for usage of alteplase based mainly on clinical factors have
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limitation to detect the possible candidate and exclude the potentially harmful candidate for receiving i.v. alteplase. First the strict clinical factor-oriented guideline for i.v. alteplase administration has been loosened, especially exclusion of several contraindications from European guideline based on clinical information such as advanced age and the combination of diabetes and prior stroke.13 Second, to overcome the limitation of clinical information based current guidelines, many trials measured collateral flow and diffusion-perfusion mismatch by using MRI or CT perfusion to extend the therapeutic window and reduce futile 9
ACCEPTED MANUSCRIPT recanalization.14, 15 Scoring systems can be divided into clinical-based and imaging-based systems. Clinicalbased scoring systems include Stroke-TPI, iScore, DRAGON, SPAN-100, and ASTRAL.7, 16Beside age and baseline NIHSS score, various clinical parameters including gender, blood
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glucose level on admission, blood pressure, and OTT were used in this system. However, age and severity of deficits at presentation are primary determinants of stroke outcome, and more complex scores incorporate other variables that can add to their predictive power but at the
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expense of becoming less practical.16
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Imaging-based systems such as diffusion-weighted imaging (DWI) infarct volume measurement and ASPECTS scorings using noncontrast CT, CTA-SI, and DWI date were used to evaluate the baseline extent of brain infarcts and predict functional outcome.3-5, 20-22 Those studies suggest that baseline infarct extent is important in prediction for functional
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clinical outcome and occurrence of complication such as hemorrhage after i.v. alteplase treatment, although only noncontrast CT scan is recommended in current AHA-ASA guideline for neuroimaging in i.v. alteplase administration.
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We think that the effort for development and application of scoring system for imagingbased selection for i.v. alteplase is necessary and should be continued. In clinical practice, the
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use of i.v. alteplase is limited because of numerous contraindications for thrombolysis in acute ischemic stroke listed in the license of alteplase arising from findings of randomized clinical trials. Our result, demonstrating the superiority of imaging-based scoring system (ASPECTS) over the clinical-based scoring system (DRAGON) for prediction of clinical outcome after i.v. alteplase, supports the usefulness of imaging-based information for decision-making in hyperacute ischemic stroke treatment and consideration of baseline infarct extent using imaging data can provide additional benefit to current guidelines for i.v. 10
ACCEPTED MANUSCRIPT alteplase administration, which is mainly based on clinical factors such as age and basal glucose level. Usage of ASPECTS system for decision tool in progression into recanalization therapy can reduce time consumed in decision making, especially when the NIHSS of stroke
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is moderate to severe or onset time of stroke is unclear and the possibility of futile recanalization, the frequency of which has been reported from 26% to 49% in many mechanical thrombectomy trials.23
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Our study is not without its share of limitations. First, interobserver agreement for ASPECTS is relatively low. Second, we used DRAGON as clinical based scoring system in
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our study. Although DRAGON consists of almost clinical variables, DRAGON includes an image information component. However, DRAGON includes the most clinical variables among other clinical-based scoring systems and has powerful predicting power for clinical outcome. Third, information on pretreatment vascular status and the occurrence of
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recanalization was not available in the present study. However, it should be mentioned that vascular study is not required before thrombolysis under current guidelines and is not included in both DRAGON and ASPECTS system. Lastly, our results should be interpreted
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with caution because this is a single center study with a retrospective design. Further prospective studies are needed to confirm our results and whether scoring systems should be
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applied regarding whether to administer IV tPA. In conclusion, integration of a useful scoring scale into the care pathway can improve the effectiveness of integrated care pathway for better outcomes of patients with acute ischemic stroke. ASPECTS showed better predictive power than the DRAGON score in this study. Therefore, the integration of ASPECTS as a guideline into the care pathway can be reasonable.
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Acknowlegement This work was supported by Gachon University Gil Medical Center, Incheon, Republic of
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Korea (Grant number: 2013-52).
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Disclosure Statement
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The authors have no conflicts of interest to declare.
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Figure Legends Figure 1. Correlation between functional outcome and ASPECTS/DRAGON Both ASPECTS (r=-0.841, p<0.0001) and DRAGON (r=0.657, p<0.0001) were significantly
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and strongly correlated with favorable functional outcome.
Figure 2. ROC curve for discriminating favorable functional outcome (mRS ≤2).
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AUC-ROC of ASPECTS (0.972, 95% confidence interval [CI] 0.947-0.996, p<0.001) demonstrated higher than AUC-ROC of DRAGON (0.854, 95% CI 0.786-0.922, p<0.001) for
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favorable functional outcome (difference between areas 0.118±0.0332; 95% CI 0.0559-0.180,
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p=0.0002).
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ACCEPTED MANUSCRIPT Table 1. Clinical findings by 3-month prognosis (mRS 0-2)
60.0±13.0 30 (71.4)
69.5±12.1 46 (59.0)
<0.0001 0.234
52 (66.7) 20 (25.6) 35 (44.9) 19 (24.4) 9 (11.5) 18 (23.1)
0.082 0.360 0.045 0.097 0.538 0.085
13.5±1.9 141.9±60.3 175.6±37.5 1.0±1.7 6.0±1.5
0.041 0.336 0.013 0.238 0.688
5.3±1.7 0 1 (1.3) 1 (1.3) 7 (9.0) 21 (26.9) 15 (19.2) 16 (20.5) 12 (15.4) 4 (5.1) 1 (1.3) 0 (0) 4.5±1.8 1 (1.3) 2 (2.6) 8 (10.3) 11 (14.1) 20 (25.6) 15 (19.2) 9 (11.5) 8 (10.3) 2 (2.6) 2 (2.6) 0 (0)
<0.0001
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14.2±1.6 131.9±38.8 198.5±37.4 1.7±4.2 5.9±1.4
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21 (50.0) 7 (16.7) 11 (26.2) 17 (40.5) 3 (7.1) 4 (9.5)
Poor outcome
3.2±1.1 0 (0) 1 (2.4) 13 (31.0) 13 (31.0) 11 (26.2) 3 (7.1) 1 (2.4) 0 (0) 0 (0) 0 (0) 0 (0) 8.8±1.1 0 0 0 0 0 0 1 (2.4) 4 (9.5) 11 (26.2) 11 (26.2) 15 (35.7)
p
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(mRS≥3, n=78)
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General demographics Age, years Male, n (%) Risk factors, n (%) Hypertension Diabetes mellitus Atrial fibrillation Hyperlipidemia Cardiac disease Previous stroke Baseline laboratory findings Hemoglobin, g/dl Glucose, mg/dl Total cholesterol, mg/dl CRP, mg/dl Uric acid, mg/dl Predicting Scoring systems DRAGON score, n (%) 0 1 2 3 4 5 6 7 8 9 10 ASPECT score, n (%) 0 1 2 3 4 5 6 7 8 9 10
Good outcome (mRS 0-2, n=42)
<0.0001
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p
Adjusted (95% CI)
p
Age, per 1-year increase
0.94 (0.91-0.97)
<0.0001
-
-
Basal NIHSS score
0.79 (0.72-0.87)
<0.0001
-
-
Atrial fibrillation
2.29 (1.01-5.21)
0.047
-
-
Hypertension
2.00 (0.93-4.30)
0.076
-
-
Hyperlipidemia
0.49 (0.22-1.10)
0.083
-
-
Baseline glucose (>144 mg/dL)
0.44 (0.18-1.04)
0.061
-
-
Female
0.58 (0.26-1.29)
0.179
-
-
Onset to alteplase time
1.01 (1.00-1.01)
0.224
-
-
Dense MCA/early infarct on CT
5.41 (2.32-12.60)
<0.0001
-
-
6.59 (2.35-18.49)
<0.0001
77.67 (14.30-421.79)
<0.0001
Model 1
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Scoring systems
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General demographics
5.51 (2.78-10.94)
<0.0001
DRAGON, per 1-point increase
0.32 (0.21-0.50)
<0.0001
136.90 (34.69-540.22)
<0.0001
13.80 (5.40-35.28)
<0.0001
Model 2
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ASPECTS (≥8)
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ASPECTS, per 1-point increase
DRAGON (≤3)
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Supplement 1. ROC curves for each readers ASPECTS and DRAGON scores to predict good outcome (mRS ≤2).
Reader 1 Reader 2 Reference lines
S1052-3057(14)00509-6
DOI:
10.1016/j.jstrokecerebrovasdis.2014.10.009
Reference:
YJSCD 1877
To appear in:
Journal of Stroke & Cerebrovascular Diseases
Received Date: 29 May 2014 Revised Date:
3 September 2014
Accepted Date: 23 October 2014
Please cite this article as: Baek JH, Kim K, Lee Y-B, Park K-H, Park H-M, Shin D-J, Sung YH, Shin DH, Bang OY, Predicting stroke outcome using clinical- versus imaging-based scoring system, Journal of Stroke & Cerebrovascular Diseases (2014), doi: 10.1016/j.jstrokecerebrovasdis.2014.10.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Predicting stroke outcome using clinical- versus imagingbased scoring system
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Joon Hyun Baek, MD.,1 Kitae Kim, MD.,1 Yeong-Bae Lee, MD, PhD.,1 Kee-Hyung Park, MD, PhD.,1 Hyeon-Mi Park, MD.,1 Dong-Jin Shin, MD.,1
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Department of Neurology, Gachon University Gil Medical Center, Incheon, South Korea
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Young Hee Sung, MD.,1 Dong Hoon Shin, MD, PhD.,1* Oh Young Bang, MD, PhD.2
*Corresponding author address: Dong Hoon Shin, MD.
Department of Neurology, Gachon University Gil Medical Center 1198, Guwol-Dong, Namdong-Gu, Incheon, 405-760, South Korea Tel: +82-32-460-3346 Fax:+83-32-460-3344 1
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E-mail: [email protected]
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Predicting stroke outcome using clinical- versus imaging-based scoring system
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Running title: Comparison of Scoring Systems for Stroke Outcome
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Character count for the title: 69 Total word count for the text: 2127
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Number of references: 23 Number of figures: 2
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Number of tables: 2
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Abstract Background: Several models to predict outcome in ischemic stroke patients receiving intravenous (i.v.) alteplase can be divided into clinical-based and imaging-based systems.
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ASPECTS (Alberta Stroke Program Early CT Score) and DRAGON (Dense cerebral artery sign/early infarct signs on admission CT scan, prestroke modified Rankin Scale [mRS] score, Age, Glucose level at baseline, Onset-to-treatment time, and baseline NIHSSscore) are
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typical imaging-based and clinical-based scoring systems, respectively. Therefore, we
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compared predictability of stroke outcome of clinical (DRAGON)- and imaging (ASPECTS)based scoring systems.
Methods: We analyzed patients who were diagnosed with middle cerebral artery territory stroke and treated with i.v. alteplase at Gachon University Gil Hospital over five years and compared performance of two scoring systems for prediction of good functional outcome
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(mRS 0-2) with Pearson's correlation and area under the curve-receiver operating characteristic (AUC-ROC). In addition, we analyzed predicting power of several clinical factors and two scoring systems by multiple regression analysis.
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Results: Study population (n=120) had mean age of 66.2±13.2. ASPECTS (r=-0.841,
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p<0.0001) and DRAGON (r=0.657, p<0.0001) were significantly correlated with good functional outcome. In addition, statistical comparisons suggested that ASPECTS (AUCROC, 0.972; 95% confidence interval [CI], 0.947-0.996) is significantly superior to DRAGON (AUC-ROC, 0.854; 95% CI, 0.786-0.922) in predicting functional outcome (difference between areas 0.118±0.0332; 95% CI, 0.0559-0.180, p=0.0002). Multiple regression analysis revealed that ASPECTS was the independent predictor of good prognosis (OR 6.59 per 1-point increase; 95% CI 2.35-18.49; p<0.0001; and OR 77.67 for ASPECTS ≥8; 95% CI 14.30-421.79; p<0.0001). 1
ACCEPTED MANUSCRIPT Conclusion: ASPECTS is superior method for predicting functional outcome in acute ischemic stroke patients receiving i.v. alteplase compared to DRAGON and integration of
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ASPECTS score into clinical care pathway as decision-making tool can be reasonable.
Keywords: Cerebral infarct; Outcomes; Stroke care; Thrombolysis; ASPECTS score;
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DRAGON score; Prognosis
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Introduction The currently available approved therapy for acute ischemic stroke are the infusion of intravenous (i.v.) alteplase within 4.5 hours of the onset of stroke symptoms and endovascular
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clot removal. Patients with acute ischemic stroke who received i.v. alteplase within three hours of the onset of symptoms were at least 30% more likely to have minimal or no disability at three months than those who received placebo and about half of the patient to
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achieve recanalization.1, 2
Scoring systems, that have been developed to predict 3-month functional outcome after
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ischemic stroke after i.v. alteplase, can be divided into clinical-based and imaging-based systems. The clinical-based scoring systems commonly use several variables like age, gender, baseline NIH Stroke Scale (NIHSS) score, blood glucose level on admission, and onset-totreatment time (OTT). Imaging-based systems evaluate the baseline extent of brain infarcts to
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predict the functional outcome.3-5 ASPECTS (Alberta Stroke Program Early CT Score) and DRAGON (Dense cerebral artery sign/early infarct signs on admission CT scan, prestroke modified Rankin Scale [mRS] score, Age, Glucose level at baseline, Onset-to-treatment time,
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and baseline NIHSSscore) are the typical imaging-based and clinical-based scoring systems, respectively. ASPECTS is a 10-point topographic CT scan score used in patients with middle
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cerebral artery (MCA) stroke and an ASPECTS score less than or equal to 7 predicts worse functional outcome at 3 months as well as symptomatic hemorrhage.6 DRAGON score is a new 10- point scoring method based on glucose level, age, severity of stroke, abnormal CT finding, and time since stroke symptoms started. Ninety-six percent of patients who had a score of zero to two had a good 3-month outcome and no patient who had DRAGON scores of eight to ten was independent in daily activities three months later.7 The clinical care pathway for acute stroke can provide specialized multidisciplinary 3
ACCEPTED MANUSCRIPT stroke care and ensure the equity of care preventing poor coordination and inefficiency by involvement of the expertise of several professionals to the management of acute stroke patient, ultimately improving the outcomes.8, 9 Integration of scoring systems designed to
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predict 3-month functional outcome with clinical care pathway can help clinicians to make better decisions in treatment of acute stroke, especially when clinicians decide to progress to add-on treatment such as endovascular treatment.
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Our aim is to investigate the predictability of clinical (DRAGON)- and imaging (ASPECTS)-based scoring systems for stroke outcome in anterior ischemic stroke patients
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treated with i.v. alteplase and to determine which scoring system is better to integrate to
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clinical care pathway.
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Patients and methods Patients Consecutive patients visited over five years, who were diagnosed with middle cerebral artery
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territory stroke and treated with i.v. alteplase at the Gachon University Gil Medical Center, were retrospectively analyzed on baseline demographic characteristics and 3-month functional outcome. All patients underwent baseline brain CT scan immediately when
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reaching the emergency department. Patients were excluded from this study if they had transient ischemic stroke symptom with negative imaging findings, had a posterior circulation
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stroke, or had a contraindication for administration of i.v. alteplase.10 ASPECTS and DRAGON score were used to evaluate initial CT scans.
Scoring systems
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We measured the parameters of DRAGON and ASPECTS in all enrolled patients. The ASPECTS was determined from two standardized axial CT cuts, one at the level of the thalamus and basal ganglion and one adjacent to the most superior margin of the ganglionic
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structures.11 A single point was subtracted for an area of early ischemic change, such as focal swelling or parenchymal hypoattenuation, for each of the defined regions. A normal CT scan
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received an ASPECTS of 10 points, whereas a score of zero indicated diffuse ischemic involvement throughout the MCA territory. The DRAGON score (0–10 points) consists of Dense cerebral artery sign/early infarct signs on admission CT scan (both=2, either=1, none=0), prestroke modified Rankin Scale score>1 (yes=1), Age (≥80 years=2, 65–79 years=1, <65 years=0), Glucose level at baseline (>8 mmol/L [>144 mg/dL]=1), Onset-to-treatment time (>90 minutes=1), and baseline NIHSS score (>15=3, 10–15= 2, 5–9 =1, 0–4=0).7 As opposed to the ASPECTS score system, 5
ACCEPTED MANUSCRIPT a score of zero indicated no risk factors. Two reviewers blinded to the patients’ outcome independently assessed the ASPECT and DRAGON scores. In cases of disagreement between
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two blinded reviewers, the final decision was reached by consensus.
Statistical analysis
Variables were analyzed using the independent t-test, or χ2 test, as appropriate for
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continuous and categorical variables: age, sex, hypertension, diabetes mellitus, cardiac problem, previous stroke, hypercholesterolemia, current smoking, hemoglobin, glucose, total
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cholesterol, C-reactive protein, and homocysteine according to clinical outcome. To identify whether each scoring systems was associated with good functional outcome, Pearson's correlation coefficients were calculated. We measured the area under the receiver operating characteristic curve (AUC-ROC) of both scoring systems and compared the prediction of
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good functional outcome (defined as mRS 0-2) by pairwise comparison of ROC curves. Multiple regression analysis was performed to predict the factors associated with good functional outcome. Potential predictors that were not significant (p>0.2) in the univariate
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analysis were deleted from the full multivariate model. The final multivariate model was adjusted for gender. We used SPSS 12.0 (SPSS V12.0K, SPSS Inc., Chicago, Illinois, USA)
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and MedCalc for statistical analysis above mentioned. We rejected null hypotheses of no difference if p-values were less than .05, or, equivalently, if the 95% confidence intervals [CIs] of risk point estimates excluded 1.
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Results General Demographics Table 1 presents the details relating to the baseline demographics according to good
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functional outcome. One hundred sixty eight patients were treated with thrombolysis using i.v. alteplase of the 4162 patients who were admitted with ischemic stroke for 5 years. The time interval between the onset of symptoms to treatment of i.v. alteplase was 2.12±0.03 hours. Of
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168 patients, 48 patients were excluded in this study; 38 patients had anterior cerebral artery
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territory or posterior circulation stroke, one was stroke mimic (Todd's palsy), and 9 were transferred after i.v. tPA infusion at local hospital but pretreatment CT imaging data were not available or incompatible with our image system. We identified 120 patients who met the criteria. The mean age was 66.2±13.2 years and there were 44 females. Patient with good outcome (mRS 0-2) were younger (p<0.0001), had higher baseline level of hemoglobin (p=
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0.041) and total cholesterol (p=0.013), and less frequently had atrial fibrillation (p=0.045).
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Relationship between scoring systems and good functional outcome Interobserver agreement was 0.898 for ASPECTS and 0.984 for DRAGON scores.
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Pearson's correlation analysis showed that both ASPECTS (r=-0.841, p<0.0001) and DRAGON (r=0.657, p<0.0001) were significantly and strongly correlated with good functional outcome (Figure 1). The area under the ROC curve shows the discriminative capabilities of each scoring system to determine prognosis. Figure 2 shows that ASPECTS demonstrated a high discriminative capability, with AUC-ROC of 0.972 (95% CI 0.947-0.996, p<0.001) for favorable functional outcome compared to DRAGON (AUC-ROC 0.854, 95% CI 0.786-0.922, p<0.001). ROC curves for each reader's ASPECTS and DRAGON scores were presented as supplement 1. Pairwise comparison of ROC curves between two scoring 7
ACCEPTED MANUSCRIPT systems showed that ASPECTS is significantly superior to DRAGON (difference between areas 0.118±0.0332; 95% CI 0.0559-0.180, p=0.0002). The optimal cut points for ASPECTS and DRAGON were 8 and 3 (sensitivity: 88.1% specificity: 94.9%; sensitivity: 64.3%
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specificity: 88.5%, respectively).
Multiple regression analysis for predicting good functional outcome
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Table 2 shows the crude odds ratios (OR) of the univariate regression analysis for good functional outcome. Age, basal NIHSS score, atrial fibrillation, ASPECTS, DRAGON,
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ASPECTS (≥8), and DRAGON (≤3) were significant predictors of functional prognosis in univariate analysis. When these factors were entered into the final multivariate model for functional outcome, ASPECTS was the only independent predictor of good prognosis (OR 6.59 per 1-point increase; 95% CI 2.35-18.49; p<0.0001 in model 1 that use the APECTS and
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DRAGON as ordinary variables; and OR 77.67 for ASPECTS ≥8; 95% CI 14.30-421.79; p<0.0001in model 2 that use the ASPECTS and DRAGON as categorical variables after
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dichotomization by cut-off value).
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Discussion The major finding of this study is that imaging based scoring system (ASPECTS) is superior to clinical-based system (DRAGON or NIHSS) for predicting functional outcome
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after i.v. alteplase administration. Integrated care pathways have been designed to introduce management practice and incorporate emerging research evidence into clinical practice to increase therapeutic
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effectiveness such as reduction in mortality and dependency and improvement of functional outcome by collaborative care of specialist staffs.9 Because development of a care pathway is
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an interdisciplinary task, several steps including formation of a team of appropriate professionals, and research to determine current practice and identify evidence for best practice are necessary for development of integrated care pathway. The success of integrated care pathway depends on the quality of implementation and useful decision-making scoring
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system.
Thrombolytic therapy using i.v. alteplase and endovascular clot removal are effective methods to date although numerous methods and drugs have been proposed to treat the stroke
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in hyperacute stage.12 Many trials to maximize the use of i.v. alteplase have been conducted because current guidelines for usage of alteplase based mainly on clinical factors have
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limitation to detect the possible candidate and exclude the potentially harmful candidate for receiving i.v. alteplase. First the strict clinical factor-oriented guideline for i.v. alteplase administration has been loosened, especially exclusion of several contraindications from European guideline based on clinical information such as advanced age and the combination of diabetes and prior stroke.13 Second, to overcome the limitation of clinical information based current guidelines, many trials measured collateral flow and diffusion-perfusion mismatch by using MRI or CT perfusion to extend the therapeutic window and reduce futile 9
ACCEPTED MANUSCRIPT recanalization.14, 15 Scoring systems can be divided into clinical-based and imaging-based systems. Clinicalbased scoring systems include Stroke-TPI, iScore, DRAGON, SPAN-100, and ASTRAL.7, 16Beside age and baseline NIHSS score, various clinical parameters including gender, blood
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glucose level on admission, blood pressure, and OTT were used in this system. However, age and severity of deficits at presentation are primary determinants of stroke outcome, and more complex scores incorporate other variables that can add to their predictive power but at the
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expense of becoming less practical.16
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Imaging-based systems such as diffusion-weighted imaging (DWI) infarct volume measurement and ASPECTS scorings using noncontrast CT, CTA-SI, and DWI date were used to evaluate the baseline extent of brain infarcts and predict functional outcome.3-5, 20-22 Those studies suggest that baseline infarct extent is important in prediction for functional
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clinical outcome and occurrence of complication such as hemorrhage after i.v. alteplase treatment, although only noncontrast CT scan is recommended in current AHA-ASA guideline for neuroimaging in i.v. alteplase administration.
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We think that the effort for development and application of scoring system for imagingbased selection for i.v. alteplase is necessary and should be continued. In clinical practice, the
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use of i.v. alteplase is limited because of numerous contraindications for thrombolysis in acute ischemic stroke listed in the license of alteplase arising from findings of randomized clinical trials. Our result, demonstrating the superiority of imaging-based scoring system (ASPECTS) over the clinical-based scoring system (DRAGON) for prediction of clinical outcome after i.v. alteplase, supports the usefulness of imaging-based information for decision-making in hyperacute ischemic stroke treatment and consideration of baseline infarct extent using imaging data can provide additional benefit to current guidelines for i.v. 10
ACCEPTED MANUSCRIPT alteplase administration, which is mainly based on clinical factors such as age and basal glucose level. Usage of ASPECTS system for decision tool in progression into recanalization therapy can reduce time consumed in decision making, especially when the NIHSS of stroke
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is moderate to severe or onset time of stroke is unclear and the possibility of futile recanalization, the frequency of which has been reported from 26% to 49% in many mechanical thrombectomy trials.23
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Our study is not without its share of limitations. First, interobserver agreement for ASPECTS is relatively low. Second, we used DRAGON as clinical based scoring system in
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our study. Although DRAGON consists of almost clinical variables, DRAGON includes an image information component. However, DRAGON includes the most clinical variables among other clinical-based scoring systems and has powerful predicting power for clinical outcome. Third, information on pretreatment vascular status and the occurrence of
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recanalization was not available in the present study. However, it should be mentioned that vascular study is not required before thrombolysis under current guidelines and is not included in both DRAGON and ASPECTS system. Lastly, our results should be interpreted
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with caution because this is a single center study with a retrospective design. Further prospective studies are needed to confirm our results and whether scoring systems should be
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applied regarding whether to administer IV tPA. In conclusion, integration of a useful scoring scale into the care pathway can improve the effectiveness of integrated care pathway for better outcomes of patients with acute ischemic stroke. ASPECTS showed better predictive power than the DRAGON score in this study. Therefore, the integration of ASPECTS as a guideline into the care pathway can be reasonable.
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Acknowlegement This work was supported by Gachon University Gil Medical Center, Incheon, Republic of
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Korea (Grant number: 2013-52).
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Disclosure Statement
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The authors have no conflicts of interest to declare.
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Figure Legends Figure 1. Correlation between functional outcome and ASPECTS/DRAGON Both ASPECTS (r=-0.841, p<0.0001) and DRAGON (r=0.657, p<0.0001) were significantly
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and strongly correlated with favorable functional outcome.
Figure 2. ROC curve for discriminating favorable functional outcome (mRS ≤2).
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AUC-ROC of ASPECTS (0.972, 95% confidence interval [CI] 0.947-0.996, p<0.001) demonstrated higher than AUC-ROC of DRAGON (0.854, 95% CI 0.786-0.922, p<0.001) for
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favorable functional outcome (difference between areas 0.118±0.0332; 95% CI 0.0559-0.180,
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p=0.0002).
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ACCEPTED MANUSCRIPT Table 1. Clinical findings by 3-month prognosis (mRS 0-2)
60.0±13.0 30 (71.4)
69.5±12.1 46 (59.0)
<0.0001 0.234
52 (66.7) 20 (25.6) 35 (44.9) 19 (24.4) 9 (11.5) 18 (23.1)
0.082 0.360 0.045 0.097 0.538 0.085
13.5±1.9 141.9±60.3 175.6±37.5 1.0±1.7 6.0±1.5
0.041 0.336 0.013 0.238 0.688
5.3±1.7 0 1 (1.3) 1 (1.3) 7 (9.0) 21 (26.9) 15 (19.2) 16 (20.5) 12 (15.4) 4 (5.1) 1 (1.3) 0 (0) 4.5±1.8 1 (1.3) 2 (2.6) 8 (10.3) 11 (14.1) 20 (25.6) 15 (19.2) 9 (11.5) 8 (10.3) 2 (2.6) 2 (2.6) 0 (0)
<0.0001
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14.2±1.6 131.9±38.8 198.5±37.4 1.7±4.2 5.9±1.4
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21 (50.0) 7 (16.7) 11 (26.2) 17 (40.5) 3 (7.1) 4 (9.5)
Poor outcome
3.2±1.1 0 (0) 1 (2.4) 13 (31.0) 13 (31.0) 11 (26.2) 3 (7.1) 1 (2.4) 0 (0) 0 (0) 0 (0) 0 (0) 8.8±1.1 0 0 0 0 0 0 1 (2.4) 4 (9.5) 11 (26.2) 11 (26.2) 15 (35.7)
p
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(mRS≥3, n=78)
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General demographics Age, years Male, n (%) Risk factors, n (%) Hypertension Diabetes mellitus Atrial fibrillation Hyperlipidemia Cardiac disease Previous stroke Baseline laboratory findings Hemoglobin, g/dl Glucose, mg/dl Total cholesterol, mg/dl CRP, mg/dl Uric acid, mg/dl Predicting Scoring systems DRAGON score, n (%) 0 1 2 3 4 5 6 7 8 9 10 ASPECT score, n (%) 0 1 2 3 4 5 6 7 8 9 10
Good outcome (mRS 0-2, n=42)
<0.0001
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p
Adjusted (95% CI)
p
Age, per 1-year increase
0.94 (0.91-0.97)
<0.0001
-
-
Basal NIHSS score
0.79 (0.72-0.87)
<0.0001
-
-
Atrial fibrillation
2.29 (1.01-5.21)
0.047
-
-
Hypertension
2.00 (0.93-4.30)
0.076
-
-
Hyperlipidemia
0.49 (0.22-1.10)
0.083
-
-
Baseline glucose (>144 mg/dL)
0.44 (0.18-1.04)
0.061
-
-
Female
0.58 (0.26-1.29)
0.179
-
-
Onset to alteplase time
1.01 (1.00-1.01)
0.224
-
-
Dense MCA/early infarct on CT
5.41 (2.32-12.60)
<0.0001
-
-
6.59 (2.35-18.49)
<0.0001
77.67 (14.30-421.79)
<0.0001
Model 1
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Scoring systems
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General demographics
5.51 (2.78-10.94)
<0.0001
DRAGON, per 1-point increase
0.32 (0.21-0.50)
<0.0001
136.90 (34.69-540.22)
<0.0001
13.80 (5.40-35.28)
<0.0001
Model 2
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ASPECTS (≥8)
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ASPECTS, per 1-point increase
DRAGON (≤3)
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Supplement 1. ROC curves for each readers ASPECTS and DRAGON scores to predict good outcome (mRS ≤2).
Reader 1 Reader 2 Reference lines