- Email: [email protected]
kg Alteplase
Low Alberta Stroke Program Early Computed Tomography Score within 3 Hours of Onset Predicts Subsequent Symptomatic Intracranial Hemorrhage in Patients Treated with 0.6 mg/kg Alteplase Teruyuki Hirano, MD,* Makoto Sasaki, MD,† Noriaki Tomura, MD,‡ Yasunobu Ito, MD,‡ and Shotai Kobayashi, MD,x for the Japan Alteplase Clinical Trial Group*
Background: The significance of early ischemic changes (EICs) on computed tomography (CT) in selecting candidates for thrombolysis remains controversial. The Alberta Stroke Program Early CT Score (ASPECTS) provides a semiquantitative scale that scores EICs within the middle cerebral artery territory using a 10-point grading system. We examined whether ASPECTS can predict the response to intravenous thrombolysis within 3 hours of stroke onset and incidence of secondary hemorrhage. Methods: Data from the Japan Alteplase Clinical Trial (J-ACT), in which 103 patients were included, were evaluated to assess the efficacy and safety of 0.6 mg/kg alteplase within 3 hours. All CT hardcopies were reevaluated retrospectively using the ASPECTS system. Multivariate logistic regression analysis was undertaken to determine whether an effect of ASPECTS existed on a defined favorable outcome as 0 or 1 on the modified Rankin Scale at 3 months, and symptomatic intracranial hemorrhage (sICH) within 36 hours. Results: The median ASPECTS value was 10 (range 3 to 10), and 56.3% revealed no evidence of EICs. ASPECTS had no effect on the patients’ outcome, although a higher age and National Institutes of Health Stroke Scale score were negatively associated with a favorable outcome. On the other hand, lower ASPECTS was significantly associated with sICH (odds ratio [OR] 2.224; 95% confidence interval [CI] 1.227-4.032; P 5 .0084) and systolic blood pressure (OR 1.090; 95% CI 1.007-1.180; P 5 .0323) and the pre-ictal use of antiplatelet medications (OR 15.551; 95% CI 1.144-211.374; P 5 .0393). Conclusions: In J-ACT, patients with low ASPECTS values have an increased risk of thrombolysis-related sICH. Key Words: Acute ischemic stroke— computed tomography—diagnostic imaging—intracranial hemorrhage—tissue plasminogen activator. Ó 2012 by National Stroke Association
From the *Department of Neurology, Faculty of Life Sciences, Kumamoto University, Kumamoto; †Iwate Medical University, Morioka; ‡South Tohoku Research Institute for Neuroscience, Southern Tohoku General Hospital, Koriyama; and xShimane University Hospital, Izumo, Japan. Received March 17, 2011; revision received May 2, 2011; accepted May 13, 2011. Supported by Kyowa Hakko Kirin Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Dr. Hirano received honoraria from Mitsubishi Tanabe Pharma and Kyowa Hakko Kirin. Dr. Sasaki received honoraria from Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin,
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and Lundbeck. Drs. Tomura, Ito, and Kobayashi have no conflicts of interest. Japan Alteplase Clinical Trial (J-ACT) ClinicalTrials.gov identifier: NCT00147316. Address correspondence to Teruyuki Hirano, MD, Department of Neurology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan. E-mail: terry07@kumamoto-u. ac.jp. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.05.018
Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 8 (November), 2012: pp 898-902
ASPECTS AND HEMORRHAGE AFTER THROMBOLYSIS
The importance of early ischemic changes (EICs) involving more than one-third of the middle cerebral artery (MCA) territory on baseline computed tomography (CT) in the decision to thrombolyze a patient with ischemic stroke remains controversial. This concept was introduced by the European Cooperative Acute Stroke Study (ECASS),1 which investigated a 6-hour time window. On the other hand, a National Institutes of Neurological Disorders and Stroke (NINDS) study2 focused on a 3-hour time window and used CT only to exclude intracranial hemorrhage. In this trial, the extent of EICs did not influence the patient eligibility or modify the treatment effect. The Japan Alteplase Clinical Trial (J-ACT)3 examined the efficacy and safety of 0.6 mg/kg alteplase for ischemic stroke within 3 hours after onset, and showed that the outcome and the incidence of symptomatic intracranial hemorrhage (sICH) were comparable to those obtained in the NINDS study. To assess the significance of EICs in Japanese stroke patients treated within 3 hours, we reevaluated the baseline CT scans of all patients enrolled in the J-ACT using the Alberta Stroke Program Early CT Score (ASPECTS)4 system. We tested the hypothesis that extensive EICs defined by systemic ASPECTS evaluation could predict a poor response to 0.6 mg/kg alteplase and a high incidence of secondary hemorrhage.
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Table 1. Clinical backgrounds of 103 patients enrolled in the Japan Alteplase Clinical Trial Age, y (mean 6 SD) No. of females (%) Baseline NIHSS score, median (range) Baseline JSS, mean 6 SD Baseline Japan Coma Scale, median (range) Stroke subtype Cardiogenic embolism Atherothrombotic Lacunar Other/not differentiated Blood pressure, mean 6 SD Systolic, mm Hg Diastolic, mm Hg Concomitant disease Hypertension Diabetes Heart disease Previous medication, mean 6 SD Antiplatelets Antihypertensives Blood glucose, mg/dL (mean 6 SD) Electrocardiogram abnormality
70.9 6 9.8 39 (37.9%) 15 (5-30) 13.064.6 3, 0-30
80 (77.7%) 12 (11.7%) 2 (1.9%) 9 (8.7%) 151.0 6 19.0 82.3 6 11.9 55 (53.4%) 19 (18.4%) 69 (67.0%) 30 (29.1%) 42 (40.8%) 141.3 6 48.3 72 (69.9%)
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; JSS, Japan Stroke Scale; SD, standard deviation.
Methods J-ACT was undertaken as a multicenter, single dose, open-label cohort study to verify the efficacy and safety of intravenous 0.6 mg/kg alteplase in acute hemispheric stroke. In total, 103 patients were enrolled in the trial, and all received the trial drug within 3 hours of symptom onset. The study method and results of J-ACT have been described previously.3 The clinical backgrounds of the 103 patients are summarized in Table 1. The protocol was defined according to the NINDS rt-PA stroke study,2 with slight modifications. In particular, patients who had EICs affecting more than one-third of the MCA territory documented by the attending physician were excluded. Patients were treated with a single alteplase dose of 0.6 mg/kg (not exceeding 60 mg), 10% being given as a bolus, followed by continuous infusion of the remainder over 1 hour. Use of antithrombotic agents was prohibited for 24 hours after the treatment, and blood pressure was maintained at ,180/105 mm Hg. The primary endpoints were a favorable outcome defined as 0 or 1 on the modified Rankin Scale (mRS) after 3 months, and the incidence of sICH within 36 hours after the alteplase administration. The definition of sICH was the presence of any intracranial hemorrhages confirmed on CT scans accompanied by a neurologic worsening of the National Institutes of Health Stroke Scale (NIHSS) score of 4 points or more (Fig 1). For the present study, all baseline CT hardcopy images were assessed using ASPECTS by the image reading
panel, which consisted of 1 expert neurologist (TH) and 1 expert neuroradiologist (MS). They were blinded to all clinical data except for the lesion side. First, the 2 raters assessed the images independently, but if disagreement arose between their ratings, they consulted to reach a consensus.
Statistical Analysis From the full analysis set of J-ACT, we used the following 24 baseline characteristics: sex, age, body weight, time from onset, cardiogenic embolism, systolic blood pressure, diastolic blood pressure, blood glucose, platelet count, electrocardiogram abnormality, atrial fibrillation, pre-ictal use of heparin, pre-ictal oral anticoagulant, preictal antiplatelets, NIHSS score, Japan Stroke Scale (JSS) score,5 Japan Coma Scale,6 history of stroke, hypertension, diabetes mellitus, hyperlipidemia, heart disease, pre-ictal mRS score of 0, and pre-ictal antihypertensives. Among the 4 factors involving blood pressure—systolic blood pressure, diastolic blood pressure, history of hypertension, and pre-ictal antihypertensives—one representative factor was selected by univariate logistic regression analysis. Similarly, representative factors for stroke severity, heart disease, and diabetes were also selected from the relevant candidate factors (Table 2). Descriptive statistics were then used to assess the effects of selected baseline characteristics, including
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Figure 1. Representative patient with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) value on baseline computed tomographic (CT) scan. This 72-year-old man suffered from consciousness disturbance and right hemiplegia with initial National Institutes of Health Stroke Scale score of 20. The baseline CT scan revealed extensive early ischemic change (ASPECTS 3). A follow-up CT scan at 24 hours revealed symptomatic intracranial hemorrhage.
ASPECTS on a favorable outcome, death, and sICH. For the models predicting a favorable outcome and death, ASPECTS was dichotomized at #7 versus .7, because an ASPECTS .7 is reported to predict beneficial response to thrombolysis.7 Among the 17 characteristics, variables that reached P , .15 in the univariate logistic regression
Table 2. Selections for representative factors involving blood pressure, stroke severity, heart disease, and diabetes using univariate logistic regression analysis Group Blood pressure Systolic blood pressure (/10 mm Hg) Diastolic blood pressure (/10 mm Hg) History of hypertension Pre-ictal antihypertensives Stroke severity NIHSS (every 1 point) JSS score (every 1 point) Japan Coma Scale Heart disease Electrocardiogram abnormality Atrial fibrillation History of heart disease Diabetes Blood glucose (/10 mg/dL) History of diabetes
P value
Odds ratio
.1727
0.861
.2739
1.211
.1796 .3127
0.575 0.324
.0004 .0044 .0131
0.853 0.875 3.351
.0150 .3384 .2876
0.339 0.673 0.633
.1233 .2947
1.069 0.552
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; JSS, Japan Stroke Scale.
analysis were included in a stepwise logistic regression analysis, where age and sex were forcibly entered into the model to adjust for the possible confounding effects of these factors. The level of significance was set at P , .05 in the final model. The odds ratios (ORs) and 95% confidence intervals (CIs) were also determined. SAS software (version 8.02; SAS Inc, Cary, NC) was used for statistical analysis.
Results Among the 103 CT scans available for ASPECTS evaluation, 69 scans were deemed to be of sufficient quality to allow reasonable interpretation, although the remaining 34 scans were evaluated systematically and a consensus was also reached for them. The interobserver k value for the baseline ASPECTS was 0.4948 (Fleiss-Cohen kappa coefficient weighted). The distribution of ASPECTS values was skewed with a median of 10 (range 3 to 10; Fig 2). In 56.3% (n 5 58) of the baseline CT scans, the ASPECTS values were 10 (no evidence of EICs). Among the 103 patients enrolled in J-ACT, 38 patients (36.9%) achieved a favorable outcome, 10 patients (9.7%) died, and 6 patients (5.8%) exhibited sICH. The patients with a favorable outcome were significantly younger (67.6 6 10.1 v 72.9 6 9.1 years; P 5 .008) and milder (NIHSS score: median 11 v 17; P , .001) than those without it. The fatally diseased patients were older (77.0 6 9.2 v 70.3 6 9.7 years; P 5 .038) and more severe (NIHSS score: median 21 v 14; P , .001) than those who survived. No factors differed significantly between the patients with and without sICH.
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Figure 2. Histogram of the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) distribution in 103 patients enrolled in the Japan Alteplase Clinical Trial. The number of patients with symptomatic intracranial hemorrhage in each ASPECTS class is indicated in parentheses.
Figure 3. Relationship between functional outcome (modified Rankin Scale at 3 months) and baseline Alberta Stroke Program Early Computed Tomography Score dichotomized at .7 and #7.
Concerning factors related to blood pressure, stroke severity, heart disease, and diabetes, univariate logistic regression analysis revealed that systolic blood pressure, NIHSS, electrocardiogram abnormality, and blood glucose had the smallest P values among the candidate factors, respectively (Table 2). In the stepwise logistic regression analysis, when age, sex, and 15 other factors including the ASPECTS value were entered into the model, the final model for a favorable outcome included age (OR 0.927; 95% CI 0.881-0.975; P 5 .0033) and NIHSS score (OR 0.829; 95% CI 0.752-0.915; P 5.0002) as factors (Table 3). Similarly, the final model for death within 3 months included age (OR 1.108; 95% CI 1.089-1.215; P 5 .0282) and NIHSS score (OR 1.267; 95% CI 1.011-1.474; P 5 .0022). The dichotomized ASPECTS value had no significant relationship to a favorable outcome or death (Fig 3). On the other hand, when a logistic regression model for sICH was evaluated, lower ASPECTS was significantly associated with sICH within 36 hours (OR 2.224; 95% CI 1.227-4.032; P 5 .0084), higher systolic blood pressure (OR 1.090; 95% CI 1.007-1.180; P 5 .0323), and pre-ictal use of antiplatelets (OR 15.551; 95% CI 1.144-211.374; P 5 .0393).
Discussion The results of the present study indicated that extensive EICs expressed as a low ASPECTS value on baseline CT scans are a predictor of sICH. Although the presence of EICs or a low ASPECTS value did not influence the treatment effect of alteplase, exclusion of patients with large ischemic lesions, high blood pressure, and pre-ictal use of antiplatelets is considered crucial in reducing the risk of thrombolysis-related hemorrhage. Our results were consistent with the previous report of the European-Australian Acute Stroke Study (ECASS) II investigators,8 which showed that dichotomized ASPECTS at #7 indicated a higher likelihood of thrombolysis-related parenchymal hemorrhage. One important difference from our study, however, was their 6-hour time window. In contrast, in the 3-hour time window study (the NINDS rt-PA study), no relationship was observed between ASPECTS and intracranial hemorrhage.9 Although J-ACT evaluated a 3-hour time window and excluded patients with EICs involving more than one-third of the MCA territories, the prognostic value of ASPECTS in detecting subsequent hemorrhage still remained significant. One possible explanation could be the difference in stroke
Table 3. Final models for a favorable outcome, death, and symptomatic intracranial hemorrhage obtained from stepwise logistic regression analyses Odds ratio Final model for a favorable outcome Age, y NIHSS score Final model for death within 3 months Age, y NIHSS score Final model for symptomatic intracranial hemorrhage within 36 hours ASPECTS Systolic blood pressure, mm Hg Preictal antiplatelets
95% CI
P value
0.927 0.829
0.881-0.975 0.752-0.915
.0033 .0002
1.108 1.267
1.011-1.215 1.089-1.474
.0282 .0022
1.227-4.032 1.007-1.180 1.144-211.374
.0084 .0323 .0393
2.224 1.090 15.551
Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale.
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subtype. A higher proportion of cardioembolic stroke patients (77.7%) was enrolled in J-ACT.3 Ethnic difference is another possibility. Asian populations are more prone to hemorrhage than white populations,10 although J-ACT used a reduced dose of alteplase amounting to two thirds of the American/European standard. These factors could explain the conflicting results between NINDS and J-ACT. It is not easy to evaluate EICs in the emergency setting, even for experienced stroke physicians or neuroradiologists.11 In fact, 13 patients (12.6%) in our study were evaluated as ASPECTS #7 by retrospective assessment of CT scan hardcopies, although J-ACT used CT exclusion criteria of EICs with more than one-third of the MCA. In addition, another logistic regression model for sICH replacing ASPECTS with the presence of EICs as judged by the attending physician revealed that no factors including EICs remained significant for predicting sICH (data not shown). This finding emphases the importance of systematic evaluation of EICs, such as with the ASPECTS system. The present study had several limitations. First, the number of patients enrolled in J-ACT was small. Second, the data for ASPECTS used in the analysis were evaluated retrospectively. The same quality of evaluation might not be obtained in clinical practice. Third, the quality of the CT images was unsatisfactory in as much as one-third of the patients, although the 2 experts on the image reading panel did reach a consensus with a reasonable score compared to the final infarct size and location. These inevitable biases could have masked the influence of ASPECTS on the treatment effect. Finally, information about arterial occlusion was not obtained. In the Interventional Management of Stroke (IMS) trial, internal carotid occlusion was associated with hemorrhage compared to MCA occlusion.12 A lower ASPECTS score might reflect the presence of more proximal arterial occlusion.13 In conclusion, extensive EICs defined by the ASPECTS system can predict subsequent sICH in patients within 3 hours after onset treated with 0.6 mg/kg alteplase. Although ASPECTS failed to elucidate the candidates for good responders, it can help to eliminate patients at high risk of thrombolysis-related hemorrhage.
References 1. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-1025. 2. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587. 3. Yamaguchi T, Mori E, Minematsu K, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke 2006; 37:1810-1815. 4. Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy: Alberta Stroke Programme Early CT Score. Lancet 2000;355:1670-1674. 5. Gotoh F, Terayama Y, Amano T, et al. Development of a novel, weighted, quantifiable stroke scale: Japan stroke scale. Stroke 2001;32:1800-1807. 6. Ohta T, Waga S, Handa W, et al. New grading of level of disordered consciousness [in Japanese]. No Shinkei Geka 1974;2:623-627. 7. Hill MD, Rowley HA, Adler F, et al. Selection of acute ischemic stroke patients for intraarterial thrombolysis with prourokinase by using ASPECTS. Stroke 2003;34:1925-1931. 8. Dzialowski I, Hill MD, Coutts SB, et al. Extent of early ischemic changes on computed tomography (CT) before thrombolysis: Prognostic value of the Alberta Stroke Program Early CT Score in ECASS II. Stroke 2006;37:973-978. 9. Demchuk AM, Hill MD, Barber PA, et al. Importance of early ischemic computed tomography changes using ASPECTS in NINDS rtPA stroke study. Stroke 2005; 36:2110-2115. 10. Klatsky AL, Friedman GD, Sidney S, et al. Risk of hemorrhagic stroke in Asian American ethnic groups. Neuroepidemiology 2005;25:26-31. 11. Wardlaw JM, Dorman PJ, Lewis SC, et al. Can stroke physicians and neuroradiologists identify signs of early cerebral infarction on CT? J Neurol Neurosurg Psychiatry 1999;67:651-653. 12. The IMS Study Investigators. Hemorrhage in the interventional management of stroke study. Stroke 2006; 37:847-851. 13. Barber PA, Demchuk AM, Hill MD, et al. The probability of middle cerebral artery MRA flow signal abnormality with quantified CT ischaemic change: Targets for future therapeutic studies. J Neurol Neurosurg Psychiatry 2004;75:1426-1430.
Background: The significance of early ischemic changes (EICs) on computed tomography (CT) in selecting candidates for thrombolysis remains controversial. The Alberta Stroke Program Early CT Score (ASPECTS) provides a semiquantitative scale that scores EICs within the middle cerebral artery territory using a 10-point grading system. We examined whether ASPECTS can predict the response to intravenous thrombolysis within 3 hours of stroke onset and incidence of secondary hemorrhage. Methods: Data from the Japan Alteplase Clinical Trial (J-ACT), in which 103 patients were included, were evaluated to assess the efficacy and safety of 0.6 mg/kg alteplase within 3 hours. All CT hardcopies were reevaluated retrospectively using the ASPECTS system. Multivariate logistic regression analysis was undertaken to determine whether an effect of ASPECTS existed on a defined favorable outcome as 0 or 1 on the modified Rankin Scale at 3 months, and symptomatic intracranial hemorrhage (sICH) within 36 hours. Results: The median ASPECTS value was 10 (range 3 to 10), and 56.3% revealed no evidence of EICs. ASPECTS had no effect on the patients’ outcome, although a higher age and National Institutes of Health Stroke Scale score were negatively associated with a favorable outcome. On the other hand, lower ASPECTS was significantly associated with sICH (odds ratio [OR] 2.224; 95% confidence interval [CI] 1.227-4.032; P 5 .0084) and systolic blood pressure (OR 1.090; 95% CI 1.007-1.180; P 5 .0323) and the pre-ictal use of antiplatelet medications (OR 15.551; 95% CI 1.144-211.374; P 5 .0393). Conclusions: In J-ACT, patients with low ASPECTS values have an increased risk of thrombolysis-related sICH. Key Words: Acute ischemic stroke— computed tomography—diagnostic imaging—intracranial hemorrhage—tissue plasminogen activator. Ó 2012 by National Stroke Association
From the *Department of Neurology, Faculty of Life Sciences, Kumamoto University, Kumamoto; †Iwate Medical University, Morioka; ‡South Tohoku Research Institute for Neuroscience, Southern Tohoku General Hospital, Koriyama; and xShimane University Hospital, Izumo, Japan. Received March 17, 2011; revision received May 2, 2011; accepted May 13, 2011. Supported by Kyowa Hakko Kirin Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Dr. Hirano received honoraria from Mitsubishi Tanabe Pharma and Kyowa Hakko Kirin. Dr. Sasaki received honoraria from Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin,
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and Lundbeck. Drs. Tomura, Ito, and Kobayashi have no conflicts of interest. Japan Alteplase Clinical Trial (J-ACT) ClinicalTrials.gov identifier: NCT00147316. Address correspondence to Teruyuki Hirano, MD, Department of Neurology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan. E-mail: terry07@kumamoto-u. ac.jp. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.05.018
Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 8 (November), 2012: pp 898-902
ASPECTS AND HEMORRHAGE AFTER THROMBOLYSIS
The importance of early ischemic changes (EICs) involving more than one-third of the middle cerebral artery (MCA) territory on baseline computed tomography (CT) in the decision to thrombolyze a patient with ischemic stroke remains controversial. This concept was introduced by the European Cooperative Acute Stroke Study (ECASS),1 which investigated a 6-hour time window. On the other hand, a National Institutes of Neurological Disorders and Stroke (NINDS) study2 focused on a 3-hour time window and used CT only to exclude intracranial hemorrhage. In this trial, the extent of EICs did not influence the patient eligibility or modify the treatment effect. The Japan Alteplase Clinical Trial (J-ACT)3 examined the efficacy and safety of 0.6 mg/kg alteplase for ischemic stroke within 3 hours after onset, and showed that the outcome and the incidence of symptomatic intracranial hemorrhage (sICH) were comparable to those obtained in the NINDS study. To assess the significance of EICs in Japanese stroke patients treated within 3 hours, we reevaluated the baseline CT scans of all patients enrolled in the J-ACT using the Alberta Stroke Program Early CT Score (ASPECTS)4 system. We tested the hypothesis that extensive EICs defined by systemic ASPECTS evaluation could predict a poor response to 0.6 mg/kg alteplase and a high incidence of secondary hemorrhage.
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Table 1. Clinical backgrounds of 103 patients enrolled in the Japan Alteplase Clinical Trial Age, y (mean 6 SD) No. of females (%) Baseline NIHSS score, median (range) Baseline JSS, mean 6 SD Baseline Japan Coma Scale, median (range) Stroke subtype Cardiogenic embolism Atherothrombotic Lacunar Other/not differentiated Blood pressure, mean 6 SD Systolic, mm Hg Diastolic, mm Hg Concomitant disease Hypertension Diabetes Heart disease Previous medication, mean 6 SD Antiplatelets Antihypertensives Blood glucose, mg/dL (mean 6 SD) Electrocardiogram abnormality
70.9 6 9.8 39 (37.9%) 15 (5-30) 13.064.6 3, 0-30
80 (77.7%) 12 (11.7%) 2 (1.9%) 9 (8.7%) 151.0 6 19.0 82.3 6 11.9 55 (53.4%) 19 (18.4%) 69 (67.0%) 30 (29.1%) 42 (40.8%) 141.3 6 48.3 72 (69.9%)
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; JSS, Japan Stroke Scale; SD, standard deviation.
Methods J-ACT was undertaken as a multicenter, single dose, open-label cohort study to verify the efficacy and safety of intravenous 0.6 mg/kg alteplase in acute hemispheric stroke. In total, 103 patients were enrolled in the trial, and all received the trial drug within 3 hours of symptom onset. The study method and results of J-ACT have been described previously.3 The clinical backgrounds of the 103 patients are summarized in Table 1. The protocol was defined according to the NINDS rt-PA stroke study,2 with slight modifications. In particular, patients who had EICs affecting more than one-third of the MCA territory documented by the attending physician were excluded. Patients were treated with a single alteplase dose of 0.6 mg/kg (not exceeding 60 mg), 10% being given as a bolus, followed by continuous infusion of the remainder over 1 hour. Use of antithrombotic agents was prohibited for 24 hours after the treatment, and blood pressure was maintained at ,180/105 mm Hg. The primary endpoints were a favorable outcome defined as 0 or 1 on the modified Rankin Scale (mRS) after 3 months, and the incidence of sICH within 36 hours after the alteplase administration. The definition of sICH was the presence of any intracranial hemorrhages confirmed on CT scans accompanied by a neurologic worsening of the National Institutes of Health Stroke Scale (NIHSS) score of 4 points or more (Fig 1). For the present study, all baseline CT hardcopy images were assessed using ASPECTS by the image reading
panel, which consisted of 1 expert neurologist (TH) and 1 expert neuroradiologist (MS). They were blinded to all clinical data except for the lesion side. First, the 2 raters assessed the images independently, but if disagreement arose between their ratings, they consulted to reach a consensus.
Statistical Analysis From the full analysis set of J-ACT, we used the following 24 baseline characteristics: sex, age, body weight, time from onset, cardiogenic embolism, systolic blood pressure, diastolic blood pressure, blood glucose, platelet count, electrocardiogram abnormality, atrial fibrillation, pre-ictal use of heparin, pre-ictal oral anticoagulant, preictal antiplatelets, NIHSS score, Japan Stroke Scale (JSS) score,5 Japan Coma Scale,6 history of stroke, hypertension, diabetes mellitus, hyperlipidemia, heart disease, pre-ictal mRS score of 0, and pre-ictal antihypertensives. Among the 4 factors involving blood pressure—systolic blood pressure, diastolic blood pressure, history of hypertension, and pre-ictal antihypertensives—one representative factor was selected by univariate logistic regression analysis. Similarly, representative factors for stroke severity, heart disease, and diabetes were also selected from the relevant candidate factors (Table 2). Descriptive statistics were then used to assess the effects of selected baseline characteristics, including
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Figure 1. Representative patient with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) value on baseline computed tomographic (CT) scan. This 72-year-old man suffered from consciousness disturbance and right hemiplegia with initial National Institutes of Health Stroke Scale score of 20. The baseline CT scan revealed extensive early ischemic change (ASPECTS 3). A follow-up CT scan at 24 hours revealed symptomatic intracranial hemorrhage.
ASPECTS on a favorable outcome, death, and sICH. For the models predicting a favorable outcome and death, ASPECTS was dichotomized at #7 versus .7, because an ASPECTS .7 is reported to predict beneficial response to thrombolysis.7 Among the 17 characteristics, variables that reached P , .15 in the univariate logistic regression
Table 2. Selections for representative factors involving blood pressure, stroke severity, heart disease, and diabetes using univariate logistic regression analysis Group Blood pressure Systolic blood pressure (/10 mm Hg) Diastolic blood pressure (/10 mm Hg) History of hypertension Pre-ictal antihypertensives Stroke severity NIHSS (every 1 point) JSS score (every 1 point) Japan Coma Scale Heart disease Electrocardiogram abnormality Atrial fibrillation History of heart disease Diabetes Blood glucose (/10 mg/dL) History of diabetes
P value
Odds ratio
.1727
0.861
.2739
1.211
.1796 .3127
0.575 0.324
.0004 .0044 .0131
0.853 0.875 3.351
.0150 .3384 .2876
0.339 0.673 0.633
.1233 .2947
1.069 0.552
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; JSS, Japan Stroke Scale.
analysis were included in a stepwise logistic regression analysis, where age and sex were forcibly entered into the model to adjust for the possible confounding effects of these factors. The level of significance was set at P , .05 in the final model. The odds ratios (ORs) and 95% confidence intervals (CIs) were also determined. SAS software (version 8.02; SAS Inc, Cary, NC) was used for statistical analysis.
Results Among the 103 CT scans available for ASPECTS evaluation, 69 scans were deemed to be of sufficient quality to allow reasonable interpretation, although the remaining 34 scans were evaluated systematically and a consensus was also reached for them. The interobserver k value for the baseline ASPECTS was 0.4948 (Fleiss-Cohen kappa coefficient weighted). The distribution of ASPECTS values was skewed with a median of 10 (range 3 to 10; Fig 2). In 56.3% (n 5 58) of the baseline CT scans, the ASPECTS values were 10 (no evidence of EICs). Among the 103 patients enrolled in J-ACT, 38 patients (36.9%) achieved a favorable outcome, 10 patients (9.7%) died, and 6 patients (5.8%) exhibited sICH. The patients with a favorable outcome were significantly younger (67.6 6 10.1 v 72.9 6 9.1 years; P 5 .008) and milder (NIHSS score: median 11 v 17; P , .001) than those without it. The fatally diseased patients were older (77.0 6 9.2 v 70.3 6 9.7 years; P 5 .038) and more severe (NIHSS score: median 21 v 14; P , .001) than those who survived. No factors differed significantly between the patients with and without sICH.
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Figure 2. Histogram of the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) distribution in 103 patients enrolled in the Japan Alteplase Clinical Trial. The number of patients with symptomatic intracranial hemorrhage in each ASPECTS class is indicated in parentheses.
Figure 3. Relationship between functional outcome (modified Rankin Scale at 3 months) and baseline Alberta Stroke Program Early Computed Tomography Score dichotomized at .7 and #7.
Concerning factors related to blood pressure, stroke severity, heart disease, and diabetes, univariate logistic regression analysis revealed that systolic blood pressure, NIHSS, electrocardiogram abnormality, and blood glucose had the smallest P values among the candidate factors, respectively (Table 2). In the stepwise logistic regression analysis, when age, sex, and 15 other factors including the ASPECTS value were entered into the model, the final model for a favorable outcome included age (OR 0.927; 95% CI 0.881-0.975; P 5 .0033) and NIHSS score (OR 0.829; 95% CI 0.752-0.915; P 5.0002) as factors (Table 3). Similarly, the final model for death within 3 months included age (OR 1.108; 95% CI 1.089-1.215; P 5 .0282) and NIHSS score (OR 1.267; 95% CI 1.011-1.474; P 5 .0022). The dichotomized ASPECTS value had no significant relationship to a favorable outcome or death (Fig 3). On the other hand, when a logistic regression model for sICH was evaluated, lower ASPECTS was significantly associated with sICH within 36 hours (OR 2.224; 95% CI 1.227-4.032; P 5 .0084), higher systolic blood pressure (OR 1.090; 95% CI 1.007-1.180; P 5 .0323), and pre-ictal use of antiplatelets (OR 15.551; 95% CI 1.144-211.374; P 5 .0393).
Discussion The results of the present study indicated that extensive EICs expressed as a low ASPECTS value on baseline CT scans are a predictor of sICH. Although the presence of EICs or a low ASPECTS value did not influence the treatment effect of alteplase, exclusion of patients with large ischemic lesions, high blood pressure, and pre-ictal use of antiplatelets is considered crucial in reducing the risk of thrombolysis-related hemorrhage. Our results were consistent with the previous report of the European-Australian Acute Stroke Study (ECASS) II investigators,8 which showed that dichotomized ASPECTS at #7 indicated a higher likelihood of thrombolysis-related parenchymal hemorrhage. One important difference from our study, however, was their 6-hour time window. In contrast, in the 3-hour time window study (the NINDS rt-PA study), no relationship was observed between ASPECTS and intracranial hemorrhage.9 Although J-ACT evaluated a 3-hour time window and excluded patients with EICs involving more than one-third of the MCA territories, the prognostic value of ASPECTS in detecting subsequent hemorrhage still remained significant. One possible explanation could be the difference in stroke
Table 3. Final models for a favorable outcome, death, and symptomatic intracranial hemorrhage obtained from stepwise logistic regression analyses Odds ratio Final model for a favorable outcome Age, y NIHSS score Final model for death within 3 months Age, y NIHSS score Final model for symptomatic intracranial hemorrhage within 36 hours ASPECTS Systolic blood pressure, mm Hg Preictal antiplatelets
95% CI
P value
0.927 0.829
0.881-0.975 0.752-0.915
.0033 .0002
1.108 1.267
1.011-1.215 1.089-1.474
.0282 .0022
1.227-4.032 1.007-1.180 1.144-211.374
.0084 .0323 .0393
2.224 1.090 15.551
Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale.
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subtype. A higher proportion of cardioembolic stroke patients (77.7%) was enrolled in J-ACT.3 Ethnic difference is another possibility. Asian populations are more prone to hemorrhage than white populations,10 although J-ACT used a reduced dose of alteplase amounting to two thirds of the American/European standard. These factors could explain the conflicting results between NINDS and J-ACT. It is not easy to evaluate EICs in the emergency setting, even for experienced stroke physicians or neuroradiologists.11 In fact, 13 patients (12.6%) in our study were evaluated as ASPECTS #7 by retrospective assessment of CT scan hardcopies, although J-ACT used CT exclusion criteria of EICs with more than one-third of the MCA. In addition, another logistic regression model for sICH replacing ASPECTS with the presence of EICs as judged by the attending physician revealed that no factors including EICs remained significant for predicting sICH (data not shown). This finding emphases the importance of systematic evaluation of EICs, such as with the ASPECTS system. The present study had several limitations. First, the number of patients enrolled in J-ACT was small. Second, the data for ASPECTS used in the analysis were evaluated retrospectively. The same quality of evaluation might not be obtained in clinical practice. Third, the quality of the CT images was unsatisfactory in as much as one-third of the patients, although the 2 experts on the image reading panel did reach a consensus with a reasonable score compared to the final infarct size and location. These inevitable biases could have masked the influence of ASPECTS on the treatment effect. Finally, information about arterial occlusion was not obtained. In the Interventional Management of Stroke (IMS) trial, internal carotid occlusion was associated with hemorrhage compared to MCA occlusion.12 A lower ASPECTS score might reflect the presence of more proximal arterial occlusion.13 In conclusion, extensive EICs defined by the ASPECTS system can predict subsequent sICH in patients within 3 hours after onset treated with 0.6 mg/kg alteplase. Although ASPECTS failed to elucidate the candidates for good responders, it can help to eliminate patients at high risk of thrombolysis-related hemorrhage.
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