Predictive Factors for Early Clinical Improvement after Intra-arterial Thrombolytic Therapy in Acute Ischemic Stroke Hye Seon Jeong, MD,*† Hyun-Jo Kwon, MD, PhD,*† Chang Woo Kang, MD,*‡ Hee-Jung Song, MD, PhD,*‡ Hyeon Song Koh, MD, PhD,*‡ Sang Min Park, MD,*† Jung Geol Lim, MD,*† Ji Eun Shin, PhD,x Suk Hoon Lee, PhD,x and Jei Kim, MD*†
Background: In acute ischemic stroke, the speed of improvement after intra-arterial thrombolytic therapy (IAT)–mediated recanalization varies. This study aimed to identify clinical and radiological variables that are predictive of early improvement (EI) after IAT in acute ischemic stroke. Methods: This single-center retrospective cohort study included 141 consecutive patients who underwent IAT for terminal internal carotid and/or middle cerebral artery (MCA) occlusions. EI was defined as a National Institutes of Health Stroke Scale (NIHSS) score less than 3 or NIHSS score improvement of 8 points or more within 72 hours of IAT. The EI and non-EI groups were compared in terms of clinical and radiological findings before and after IAT. Results: Forty-nine patients showed EI (34.8%). Multivariate analysis revealed that atrial fibrillation (odds ratio [OR] .35, 95% confidence interval [CI] .14-.89, P 5 .028) and hyperdense MCA sign (OR .39, CI .15-.97, P 5 .042) were related with lack of EI. The independent EI predictors were less extensive parenchymal lesion on baseline computed tomography (OR 4.92, CI 1.74-13.9, P 5 .003), intermediate to good collaterals (OR 3.28, CI 1.16-9.31, P 5 .026), and recanalization within 6 hours of symptom onset (OR 5.2, CI 1.81-14.94, P 5 .002). EI associated with favorable outcomes (modified Rankin scale score 0-2) at discharge (88% versus 7%; P , .001) and 3 months after discharge (92% versus 18%; P , .001). Conclusions: The clinical and radiological variables maybe useful for predicting EI and favorable long-term outcomes after IAT. Key Words: Acute ischemic stroke—intra-arterial thrombolysis—early improvement—predicting factors. Ó 2014 by National Stroke Association
Introduction To obtain a favorable clinical outcome, patients with acute ischemic stroke should undergo rapid and complete recanalization of the occluded intracranial vessel.1,2
From the *Daejeon-Chungnam Regional Cerebrovascular Center, Hospital and School of Medicine, Chungnam National University, Daejeon; †Department of Neurology, Hospital and School of Medicine, Chungnam National University, Daejeon; ‡Department of Neurosurgery, Hospital and School of Medicine, Chungnam National University, Daejeon; and xDepartment of Information and Statistics, College of Natural Science, Chungnam National University, Daejeon, South Korea. Received October 14, 2013; revision received November 26, 2013; accepted December 4, 2013.
Although intravenous thrombolytic therapy (IVT) can induce prompt recanalization and, thereby, improve the clinical outcomes in ischemic stroke,3 the recanalization rate after IVT remains unsatisfactory.4 To improve
Conflicts of Interest: The authors have no financial conflicts of interest. Address correspondence to Jei Kim, MD, Department of Neurology, Hospital and School of Medicine, Chungnam National University Hospital, 282 Moonwha-ro, Joongu, Daejeon 301-721, South Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.008
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 4 (April), 2014: pp e283-e289
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recanalization rates in acute ischemia, intra-arterial thrombolytic therapy (IAT) has been introduced. This approach dramatically increased the occluded vessel recanalization rate.5 However, the speed with which IAT-treated patients with ischemia improve clinically varies, even when the therapy is given within the appropriate time window. Several studies have suggested that the recanalization grade and speed,6 clot burden, and/ or pial collateral formation7,8 associate with early favorable outcomes after IAT. However, the relationships between early clinical improvement and clinical and radiological variables before and after IAT are poorly understood. The present study was performed to identify the clinical and radiological variables that are predictive of early clinical improvement in acute ischemia after IAT.
Methods The clinical and imaging data of consecutive patients with acute cerebral infarction who were admitted to Chungnam National University Hospital, Daejeon, South Korea, between January 2007 and December 2012 and who underwent IAT to recanalize acute intracranial artery occlusions were analyzed retrospectively. IAT was performed in all patients whose National Institutes of Health Stroke Scale (NIHSS) score was 4 or more,9 who were older than 18 years, who had arrived at the emergency room (ER) within 6 hours of symptom onset, and whose occlusion of a unilateral middle cerebral artery (MCA) and/or terminal internal carotid artery was confirmed by angiography. Patients with acute cerebral infarctions caused by occlusion of the distal common carotid artery, proximal internal carotid artery, basilar artery, or extracranial vertebral artery were excluded. Finally, the clinical and radiological data of 141 consecutive patients were reviewed. The study protocol was reviewed and approved by the Institutional Review Board of Chungnam National University Hospital.
Critical Pathways for IVT and IAT Thrombolysis was executed by following the critical pathway for IVT and/or IAT that was established at the Regional Cerebrovascular Center of Chungnam National University Hospital.10 Briefly, brain computed tomography (CT) was first performed within 3 hours of symptom onset. If the initial CT scan did not reveal hemorrhage or low density greater than one third of the MCA territory, .9 mg/kg recombinant tissue plasminogen activator (tPA) was infused for 1 hour after a bolus injection of 10% of the calculated tPA amount. IAT was started if the neurologic status of the patient did not improve after IVT and mismatches between diffusion-weighted images (DWI) and perfusion-weighted images (PWI) remained on magnetic resonance imaging scans. If a patient arrived between 3 and 6 hours after symptom onset, IAT was per-
formed without IVT after confirming the presence of DWI–PWI mismatching. For the patients who arrived beyond 6 hours or the patients with unknown time of onset, DWI–PWI mismatching was the decision-making rule for the IAT. For these patients, mechanical thrombectomy was done without any use of thrombolytic agent.
The IAT From January 2007 to October 2010, the IAT procedure involved aggressive mechanical clot disruption (AMCD) within the occluded arterial lumen with a microcatheter and/or a J-shaped guide wire tip.11 To facilitate clot lysis, urokinase was also injected in some patients. During November 2010 to December 2012, the IAT procedure involved stent-assisted thrombectomy (SAT) with a retrievable stent (Solitaire AB, ev3).10 If the recanalized artery became reoccluded after SAT, intra-arterial urokinase injection, balloon angioplasty, and/or stenting were performed.
Evaluation of Clinical Variables The patient demographics, vascular risk factors, laboratory and imaging findings, vital signs before treatment, severity of ischemic stroke, and clinical outcomes were collected retrospectively. For risk factor evaluations, hypertension and hypercholesterolemia were defined on the basis of the treatment history before admission. Patients were considered to have diabetes if they had a history of type 1 or 2 diabetes. Smoking history was coded as never, previous, or current. Atrial fibrillation was diagnosed on the basis of electrocardiogram (EKG) or EKG– Holter monitoring during admission. Clinical severity and progression were assessed by calculating NIHSS scores before and immediately after intervention, at discharge, and at 3 months after discharge. A patient was considered to show early improvement (EI) of initial clinical manifestations if the NIHSS score dropped below 3 or the NIHSS improved by 8 points or more within 72 hours after IAT. Clinical outcomes after IAT were assessed by determining the modified Rankin scale (mRS) at discharge and 3 months after discharge. An mRS score of 0-2 was considered to indicate a good clinical outcome.
Evaluation of Radiological Variables The radiological severity on initial CT was based on the presence of the hyperdense MCA sign12 and the Alberta Stroke Program Early Computed Tomography (ASPECT) score.13 The initial CT ASPECT score was categorized as high (8-10) or low (0-7). The speed of occluded vessel recanalization was evaluated by determining the time from arrival at the ER to groin puncture for IAT (door to puncture) and from puncture to occluded vessel recanalization (puncture to recanalization). The recanalization status after IAT was graded by using the Thrombolysis
EARLY CLINICAL IMPROVEMENT AFTER IA THROMBOLYSIS 14
in Cerebral Infarction Scale. Successful recanalization was defined as Thrombolysis in Cerebral Infarction Scale grades 2-3.15 The collateral circulation status in the occluded hemisphere was determined by examining the angiographic findings obtained before starting the IAT procedure. American Society of Interventional and Therapeutic Neuroradiology criteria were used to classify the collateral circulation extent as poor (grades 0-1) or intermediate to good (grades 2-4).16 Post-IAT radiological complications were rated on the basis of CT images collected within 24 hours after IAT. Hemorrhagic transformation was classified into 4 categories: (1) small petechiae, (2) confluent petechiae, (3) small hematoma (#30% of the infarcted area), and (4) large hematoma (.30% of the infarcted area).17 Symptomatic intracerebral hemorrhage (ICH) was defined as an increase in the NIHSS score by 4 or more points plus a large hematoma or outside hemorrhage.17 The follow-up CT scan was also examined for post-IAT subarachnoid hemorrhage (SAH), which was classified using Fisher grade18: extensive SAH was defined as diffuse extension of high-density changes into the basal cistern and interhemispheric sulci or combined with intraventricular hemorrhage.19
Statistical Analysis The EI and non-EI groups were compared in terms of the clinical and radiological variables observed before and after IAT. T tests were used to compare these groups in terms of NIHSS score changes between admission and discharge and the time intervals from symptom onset/ start of IAT to occluded vessel recanalization. Fisher exact test was used to compare the groups in terms of recanalization rates, collateral circulation, ASPECT scores, hemorrhagic complications, and the frequency of a good clinical outcome at discharge and 3 months after discharge. Finally, to evaluate whether any of these variables independently influenced EI after IAT, all possible variables that achieved P less than .1 in the t tests or Fisher exact tests were entered into a backward likelihood ratio logistic regression model. All statistical analyses were performed using SPSS 19.0 (SPSS Inc., Chicago, IL).
Results Patient Characteristics The clinical and radiological data of 141 consecutive patients (85 men, 56 women, mean age: 68.0 6 11.7 years) who underwent IAT for acute cerebral infarction were reviewed retrospectively. Of these patients, 49 (34.8%) had EI (Table 1). The remaining 92 patients (ie, the non-EI group) included 38 patients with partial improvement (defined as an NIHSS improvement ,8 points) and 54 patients who showed no improvement or aggravation of the initial deficits.
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Analysis of patient demographic and risk factors revealed that the 2 groups only differed in terms of the incidence of atrial fibrillation: 21 of the 49 EI patients (43%) and 62 of the 92 non-EI (67%) had arterial fibrillation (P 5 .004; Table 1). In terms of the baseline clinical and treatment characteristics, the EI patients had a lower initial NIHSS score (median [quartile]: 11 [7-16]) than the non-EI patients (13 [11-15]; P 5 .047), even though the 2 groups were similar in the time from symptom onset to arrival at the ER (EI, 110 minutes; non-EI, 120 minutes; P 5 .279; Table 1). In addition, the EI patients were more likely to have MCA occlusion (82%) than the non-EI group (64%, P 5 .023). Approximately half of each group received an intravenous tPA injection before IAT (P 5.07). Both groups also underwent AMCD and SAT for IAT at similar frequencies (P 5 .341).
Differences between the EI and Non-EI Groups in Clinical Variables The 2 groups did not differ in median door-to-puncture time (EI, 104 minutes; non-EI, 100 minutes; P 5 .933), but the EI group had a shorter puncture-to-recanalization time (median [range]: 60 [16-190] versus 70 [9-180] minutes; P 5 .033). The EI patients were also more likely to undergo recanalization within 6 hours of symptom onset (86% versus 49%; P , .001). In addition, the EI group had a higher rate of successful recanalization (100% versus 76%; P , .001; Table 2). At discharge, the EI patients exhibited a larger improvement in the NIHSS score (median [quartiles]: 9 [7-13] points) than the non-EI patients (0 [0-4] points, P , .001). Most EI patients had good clinical outcomes (mRS score 0-2) at discharge (88%), unlike the non-EI patients (7%, P ,.001). The large difference in good outcome maintained until 3 months after discharge (EI, 92%; nonEI patients, 19%, P , .001). Death after IAT only occurred in non-EI patients during hospitalization (11%, P 5 .012) and 3 months after discharge (17%, P 5 .001; Table 2).
Differences between EI and Non-EI Groups in Radiological Variables The EI patients were more likely to have a high ASPECT score (8-10) on the initial CT scan than the nonEI patients (88% versus 48%; P , .001). The EI group was also less likely to have the hyperdense MCA sign on the initial CT scan than the non-EI group (44% versus 79%; P , .001; Table 3). When the whole patient cohort was divided according to the presence of the hyperdense MCA sign, analysis of the various vascular risk factors revealed that the hyperdense MCA sign only associated significantly with atrial fibrillation: 62 of the 92 patients with the sign (67%) had atrial fibrillation compared with 20 of the 49 patients without the sign (43%; P 5 .022). On initial cerebral angiography, the EI patients were
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Table 1. Baseline patient characteristics Early improvement
Age, y (mean 6 SD) Sex, male:female Risk factors Hypertension Diabetes Smoking Atrial fibrillation Initial NIHSS score, median (quartiles) Onset-to-door time, min, median (range)* Occlusion site T-ICA MCA Use of intravenous tPA IAT procedure AMCD SAT
Yes (n 5 49)
No (n 5 92)
P value
66.1 6 12.0 30:19 (61:39)
69.2 6 11.5 55:37 (60:40)
.154 .507
22 (45) 13 (27) 13 (27) 21 (43) 11 (7-16) 110 (15-269)
47 (51) 17 (19) 15 (16) 62 (67) 13 (11-15) 120 (15-297)
9 (18) 40 (82) 29 (59)
33 (36) 59 (64) 41 (45)
14 (29) 35 (71)
22 (24) 70 (76)
.301 .184 .111 .004 .047 .279 .023
.070 .341
Abbreviations: AMCD, aggressive mechanical clot disruption; IAT, intra-arterial thrombolysis; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; T-ICA, terminal internal carotid artery; tPA, tissue plasminogen activator; SAT, stent-assisted thrombectomy. Data are n (%) values except while stated otherwise. *Time from symptom onset to arrival at the emergency room.
more likely to have intermediate to good collaterals than the non-EI patients (86% versus 53%; P , .001). The EI patients were less likely to develop petechial hemorrhage or hematoma (34%), as indicated by the follow-up CT scan after IAT, than the non-EI patients
(78%; P ,.001; Table 3). None of the EI patients developed symptomatic ICH compared with 11 of the 92 non-EI patients (11%; P 5 .007). Similarly, extensive SAH only occurred in the non-EI patients (14%; P 5 .003; Table 3).
Table 2. Clinical variables of the patients with and without EI EI
Procedure times, min, median (range) Door-to-groin puncture time Groin puncture-to-recanalization time Symptom onset-to-recanalization time #6 h .6 h Successful recanalization, TICI (2a-3) Clinical outcomes At discharge NIHSS score improvement, median (quartile) mRS score 0-2 Death 3 Months after discharge mRS score 0-2 Death*
Yes (n 5 49)
No (n 5 92)
P value
104 (25-214) 60 (16-190)
100 (17-240) 70 (11-180)
.933 .033 ,.001
42 (86) 7 (14) 49 (100)
45 (49) 47 (51) 70 (76)
,.001
9 (7-13) 43 (88) 0
0 (0-4) 6 (7) 10 (11)
,.001 ,.001 .012
45 (92) 0
17 (19) 16 (17)
,.001 .001
Abbreviations: EI, early improvement; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; TICI, thrombolysis in cerebral infarction. Data are n (%) values except where stated otherwise. *The death rate 3 months after discharge also contains patients who died during hospitalization.
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Table 3. Radiological variables of the patients with and without EI EI Yes (n 5 49)
No (n 5 92)
P value
10 (8-10) 6 (12) 43 (88) 21 (44)
7 (6-9) 48 (52) 44 (48) 71 (79)
,.001 ,.001
42 (86) 7 (14)
49 (53) 43 (47)
32 (65) 16 (32) 1 (2) 0 0
21 (23) 50 (55) 21 (23) 11 (12) 13 (14)
Initial ASPECT score, median (quartiles) 0-7 8-10 Presence of hyperdense MCA sign Collateral circulation before IAT Intermediate–good Poor Hemorrhagic transformation None Small or confluent petechiae Small or large hematoma Symptomatic ICH Extensive SAH within 24 h
,.001 ,.001 ,.001
.007 .003
Abbreviations: ASPECT, the Alberta Stroke Program Early Computed Tomography; IAT, intra-arterial thrombolytic therapy; ICH, intracerebral hemorrhage; MCA, middle cerebral artery; SAH, subarachnoid hemorrhage. Data are n (%) values except where stated otherwise.
Multiple Regression Analysis to Identify Clinical and Radiological Variables That Predict Early Improvement after IAT Multiple logistic regression analysis was performed with the clinical and radiological variables that were significant on univariate analysis (Tables 1-3). Lack of EI associated independently with the presence of atrial fibrillation (odds ratio [OR] .35; 95% confidence interval [CI]: .14-.89; P 5 .028) and the hyperdense MCA sign (OR .39, 95% CI: .15-.97; P 5 .042; Table 4). In contrast, EI associated independently with a high ASPECT score (OR 4.92; 95% CI: 1.74-13.9; P 5 .003) in the initial CT images, the presence of moderate–good collaterals (OR 3.28; 95% CI: 1.16-9.31; P 5 .026), and recanalization within 6 hours of symptom onset (OR 5.2; 95% CI: 1.81-14.94, P 5 .002; Table 4). Table 4. Multiple logistic regression analysis to identify factors that predict early improvement
Variables Presence of atrial fibrillation Presence of hyperdense MCA sign High initial ASPECT score (8-10) Presence of collateral circulation Recanalization within 6 h
Odds ratio
95% CI
P value
.35 .39
.14-.89 .15-.97
.028 .042
4.92
1.74-13.9
.003
3.28
1.16-9.31
.026
5.2
1.81-14.94
.002
Abbreviations: ASPECT, the Alberta Stroke Program Early Computed Tomography; CI, confidence interval; MCA, middle cerebral artery.
Discussion Although several clinical and radiological variables are predictive of EI after IVT,20 the clinical and radiological factors that relate to EI after IAT remain poorly understood. The present study showed that EI after IAT associated significantly with several clinical and radiological variables that were measured before and after IAT. Moreover, the patients who showed EI after IAT had better clinical outcomes at discharge and 3 months after IAT than non-EI patients. The first notable difference between the EI and non-EI patients related to the extensiveness of the infarcted lesion and the presence of the hyperdense MCA sign on the initial CT scan. The infarcted lesion extensiveness on baseline CT is a radiological factor that associates with clinical outcome and mortality after IVT or IAT.21,22 In the present study, the EI patients had less severe lesion extensiveness on baseline CT than the non-EI patients. The hyperdense MCA sign is frequently observed on baseline CT12 in acute ischemia and usually associates significantly with a larger final infarct size and poor clinical outcome.23 Indeed, in the present study, the hyperdense MCA sign observed on initial CT associated independently with the lack of EI. Thus, an extensive infarcted lesion and the presence of a hyperdense MCA before IAT may be predictive of non-EI and poor clinical outcomes. These factors should be considered before deciding to perform IAT. In the present study, atrial fibrillation also associated independently with non-EI. The presence of chronic atrial fibrillation induces systemic24 and intracerebral25 hemodynamic alterations. Thus, if an embolus develops in a large intracranial vessel of a patient with atrial fibrillation,
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the reduced cerebral blood flow caused by the atrial fibrillation could exacerbate the abrupt interruption of the cerebral blood flow in the occluded hemisphere caused by the occlusion.25Atrial fibrillation may also hamper the prompt development of collateral circulation after the occlusion of large intracranial vessels.25 Such disturbed systemic and intracerebral hemodynamic alterations could influence the clinical outcome of patients with acute ischemia. Indeed, a previous cohort study reported that strokes are more likely to be severe in patients with atrial fibrillation than in patients without atrial fibrillation.26 Even though larger studies with a better design are needed to understand how atrial fibrillation affects the clinical outcomes in acute ischemia, the present study supports the notion that atrial fibrillation may be an important clinical variable because it signals slow improvement after IAT and poor clinical outcomes in patients with acute ischemia. The EI patients in the present study had significantly better collateral circulation on baseline cerebral angiography than the non-EI patients. To decrease the irreversible damage in the territory of an occluded vessel, collateral development is certainly needed.27 Indeed, a previous study showed that the early development of collateral flow to the occluded artery territory was predictive of good clinical outcomes and decreases in the infarct volume after thrombolytic therapy.8 Our study results also supports the notion that good collaterals are needed for rapid neurologic improvement after IAT. Several studies have shown that to achieve EI after thrombolytic therapy, the recanalization must be complete and rapid.1-3 In the present study, the EI patients achieved recanalization more rapidly than the non-EI patients, even though the 2 groups did not differ in terms of the time interval between symptom onset and arrival at the ER or groin puncture. In addition, the EI patients were significantly more likely than the non-EI patients to have occluded vessel recanalization within 6 hours of symptom onset. Moreover, the EI patients had successful recanalization more frequently than the non-EI patients. Thus, both rapid and successful recanalization may contribute to the early clinical improvement and good outcomes of patients who receive IAT. The EI patients in the present study almost never developed extensive SAH or symptomatic ICH. In contrast, severe hemorrhagic complications were relatively frequent in the non-EI patients. Several other studies have also shown that severe hemorrhagic complications after IVT28 or IAT29 associate with poor clinical outcomes. Thus, even though the regression analysis in the present study did not identify the development of extensive parenchymal hematoma and SAH in the 24 hours after IAT as an independent variable for EI, it remains possible that this radiological variable associates with poor clinical improvement during long-term follow-up after IAT.
A recent study suggested that in patients who receive IVT, several clinical and radiological variables are predictive of functional outcomes, including age, baseline glucose level, onset-to-treatment time, the presence of a hyperdense artery, early infarct signs, and baseline NIHSS.20 In contrast, in the present study, the statistically significant independent predictors of EI after IAT were radiological variables including early recanalization time, early collateral development, and high ASPECT score on baseline CT. In addition, the EI patients were less likely to have atrial fibrillation and the hyperdense MCA sign on initial CT than the non-EI patients. The previous variables of EI in the study on IVT were suggested after the evaluations of the clinical status and initial CT for patients after arrival at ER. However, the variables of EI in the present study were the radiological findings after cerebral angiography for IAT. Even though the present study on IAT identified different predictors of EI than the study on IVT,20 the variables we identified may be useful for anticipating EI and good clinical outcomes after IAT than the previous variables observed in the study on IVT. In conclusion, the present study identified several clinical and radiological variables that are measured before and after IAT that associated significantly with EI after IAT. EI associated with good clinical outcomes at both discharge and 3 months after discharge. The main limitation of our study was that the clinical data were collected retrospectively from a small number of patients in a single stroke center. Future randomized prospective studies with large sample sizes that test the predictive power of the variables identified by the present study are warranted.
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Background: In acute ischemic stroke, the speed of improvement after intra-arterial thrombolytic therapy (IAT)–mediated recanalization varies. This study aimed to identify clinical and radiological variables that are predictive of early improvement (EI) after IAT in acute ischemic stroke. Methods: This single-center retrospective cohort study included 141 consecutive patients who underwent IAT for terminal internal carotid and/or middle cerebral artery (MCA) occlusions. EI was defined as a National Institutes of Health Stroke Scale (NIHSS) score less than 3 or NIHSS score improvement of 8 points or more within 72 hours of IAT. The EI and non-EI groups were compared in terms of clinical and radiological findings before and after IAT. Results: Forty-nine patients showed EI (34.8%). Multivariate analysis revealed that atrial fibrillation (odds ratio [OR] .35, 95% confidence interval [CI] .14-.89, P 5 .028) and hyperdense MCA sign (OR .39, CI .15-.97, P 5 .042) were related with lack of EI. The independent EI predictors were less extensive parenchymal lesion on baseline computed tomography (OR 4.92, CI 1.74-13.9, P 5 .003), intermediate to good collaterals (OR 3.28, CI 1.16-9.31, P 5 .026), and recanalization within 6 hours of symptom onset (OR 5.2, CI 1.81-14.94, P 5 .002). EI associated with favorable outcomes (modified Rankin scale score 0-2) at discharge (88% versus 7%; P , .001) and 3 months after discharge (92% versus 18%; P , .001). Conclusions: The clinical and radiological variables maybe useful for predicting EI and favorable long-term outcomes after IAT. Key Words: Acute ischemic stroke—intra-arterial thrombolysis—early improvement—predicting factors. Ó 2014 by National Stroke Association
Introduction To obtain a favorable clinical outcome, patients with acute ischemic stroke should undergo rapid and complete recanalization of the occluded intracranial vessel.1,2
From the *Daejeon-Chungnam Regional Cerebrovascular Center, Hospital and School of Medicine, Chungnam National University, Daejeon; †Department of Neurology, Hospital and School of Medicine, Chungnam National University, Daejeon; ‡Department of Neurosurgery, Hospital and School of Medicine, Chungnam National University, Daejeon; and xDepartment of Information and Statistics, College of Natural Science, Chungnam National University, Daejeon, South Korea. Received October 14, 2013; revision received November 26, 2013; accepted December 4, 2013.
Although intravenous thrombolytic therapy (IVT) can induce prompt recanalization and, thereby, improve the clinical outcomes in ischemic stroke,3 the recanalization rate after IVT remains unsatisfactory.4 To improve
Conflicts of Interest: The authors have no financial conflicts of interest. Address correspondence to Jei Kim, MD, Department of Neurology, Hospital and School of Medicine, Chungnam National University Hospital, 282 Moonwha-ro, Joongu, Daejeon 301-721, South Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.008
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 4 (April), 2014: pp e283-e289
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recanalization rates in acute ischemia, intra-arterial thrombolytic therapy (IAT) has been introduced. This approach dramatically increased the occluded vessel recanalization rate.5 However, the speed with which IAT-treated patients with ischemia improve clinically varies, even when the therapy is given within the appropriate time window. Several studies have suggested that the recanalization grade and speed,6 clot burden, and/ or pial collateral formation7,8 associate with early favorable outcomes after IAT. However, the relationships between early clinical improvement and clinical and radiological variables before and after IAT are poorly understood. The present study was performed to identify the clinical and radiological variables that are predictive of early clinical improvement in acute ischemia after IAT.
Methods The clinical and imaging data of consecutive patients with acute cerebral infarction who were admitted to Chungnam National University Hospital, Daejeon, South Korea, between January 2007 and December 2012 and who underwent IAT to recanalize acute intracranial artery occlusions were analyzed retrospectively. IAT was performed in all patients whose National Institutes of Health Stroke Scale (NIHSS) score was 4 or more,9 who were older than 18 years, who had arrived at the emergency room (ER) within 6 hours of symptom onset, and whose occlusion of a unilateral middle cerebral artery (MCA) and/or terminal internal carotid artery was confirmed by angiography. Patients with acute cerebral infarctions caused by occlusion of the distal common carotid artery, proximal internal carotid artery, basilar artery, or extracranial vertebral artery were excluded. Finally, the clinical and radiological data of 141 consecutive patients were reviewed. The study protocol was reviewed and approved by the Institutional Review Board of Chungnam National University Hospital.
Critical Pathways for IVT and IAT Thrombolysis was executed by following the critical pathway for IVT and/or IAT that was established at the Regional Cerebrovascular Center of Chungnam National University Hospital.10 Briefly, brain computed tomography (CT) was first performed within 3 hours of symptom onset. If the initial CT scan did not reveal hemorrhage or low density greater than one third of the MCA territory, .9 mg/kg recombinant tissue plasminogen activator (tPA) was infused for 1 hour after a bolus injection of 10% of the calculated tPA amount. IAT was started if the neurologic status of the patient did not improve after IVT and mismatches between diffusion-weighted images (DWI) and perfusion-weighted images (PWI) remained on magnetic resonance imaging scans. If a patient arrived between 3 and 6 hours after symptom onset, IAT was per-
formed without IVT after confirming the presence of DWI–PWI mismatching. For the patients who arrived beyond 6 hours or the patients with unknown time of onset, DWI–PWI mismatching was the decision-making rule for the IAT. For these patients, mechanical thrombectomy was done without any use of thrombolytic agent.
The IAT From January 2007 to October 2010, the IAT procedure involved aggressive mechanical clot disruption (AMCD) within the occluded arterial lumen with a microcatheter and/or a J-shaped guide wire tip.11 To facilitate clot lysis, urokinase was also injected in some patients. During November 2010 to December 2012, the IAT procedure involved stent-assisted thrombectomy (SAT) with a retrievable stent (Solitaire AB, ev3).10 If the recanalized artery became reoccluded after SAT, intra-arterial urokinase injection, balloon angioplasty, and/or stenting were performed.
Evaluation of Clinical Variables The patient demographics, vascular risk factors, laboratory and imaging findings, vital signs before treatment, severity of ischemic stroke, and clinical outcomes were collected retrospectively. For risk factor evaluations, hypertension and hypercholesterolemia were defined on the basis of the treatment history before admission. Patients were considered to have diabetes if they had a history of type 1 or 2 diabetes. Smoking history was coded as never, previous, or current. Atrial fibrillation was diagnosed on the basis of electrocardiogram (EKG) or EKG– Holter monitoring during admission. Clinical severity and progression were assessed by calculating NIHSS scores before and immediately after intervention, at discharge, and at 3 months after discharge. A patient was considered to show early improvement (EI) of initial clinical manifestations if the NIHSS score dropped below 3 or the NIHSS improved by 8 points or more within 72 hours after IAT. Clinical outcomes after IAT were assessed by determining the modified Rankin scale (mRS) at discharge and 3 months after discharge. An mRS score of 0-2 was considered to indicate a good clinical outcome.
Evaluation of Radiological Variables The radiological severity on initial CT was based on the presence of the hyperdense MCA sign12 and the Alberta Stroke Program Early Computed Tomography (ASPECT) score.13 The initial CT ASPECT score was categorized as high (8-10) or low (0-7). The speed of occluded vessel recanalization was evaluated by determining the time from arrival at the ER to groin puncture for IAT (door to puncture) and from puncture to occluded vessel recanalization (puncture to recanalization). The recanalization status after IAT was graded by using the Thrombolysis
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in Cerebral Infarction Scale. Successful recanalization was defined as Thrombolysis in Cerebral Infarction Scale grades 2-3.15 The collateral circulation status in the occluded hemisphere was determined by examining the angiographic findings obtained before starting the IAT procedure. American Society of Interventional and Therapeutic Neuroradiology criteria were used to classify the collateral circulation extent as poor (grades 0-1) or intermediate to good (grades 2-4).16 Post-IAT radiological complications were rated on the basis of CT images collected within 24 hours after IAT. Hemorrhagic transformation was classified into 4 categories: (1) small petechiae, (2) confluent petechiae, (3) small hematoma (#30% of the infarcted area), and (4) large hematoma (.30% of the infarcted area).17 Symptomatic intracerebral hemorrhage (ICH) was defined as an increase in the NIHSS score by 4 or more points plus a large hematoma or outside hemorrhage.17 The follow-up CT scan was also examined for post-IAT subarachnoid hemorrhage (SAH), which was classified using Fisher grade18: extensive SAH was defined as diffuse extension of high-density changes into the basal cistern and interhemispheric sulci or combined with intraventricular hemorrhage.19
Statistical Analysis The EI and non-EI groups were compared in terms of the clinical and radiological variables observed before and after IAT. T tests were used to compare these groups in terms of NIHSS score changes between admission and discharge and the time intervals from symptom onset/ start of IAT to occluded vessel recanalization. Fisher exact test was used to compare the groups in terms of recanalization rates, collateral circulation, ASPECT scores, hemorrhagic complications, and the frequency of a good clinical outcome at discharge and 3 months after discharge. Finally, to evaluate whether any of these variables independently influenced EI after IAT, all possible variables that achieved P less than .1 in the t tests or Fisher exact tests were entered into a backward likelihood ratio logistic regression model. All statistical analyses were performed using SPSS 19.0 (SPSS Inc., Chicago, IL).
Results Patient Characteristics The clinical and radiological data of 141 consecutive patients (85 men, 56 women, mean age: 68.0 6 11.7 years) who underwent IAT for acute cerebral infarction were reviewed retrospectively. Of these patients, 49 (34.8%) had EI (Table 1). The remaining 92 patients (ie, the non-EI group) included 38 patients with partial improvement (defined as an NIHSS improvement ,8 points) and 54 patients who showed no improvement or aggravation of the initial deficits.
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Analysis of patient demographic and risk factors revealed that the 2 groups only differed in terms of the incidence of atrial fibrillation: 21 of the 49 EI patients (43%) and 62 of the 92 non-EI (67%) had arterial fibrillation (P 5 .004; Table 1). In terms of the baseline clinical and treatment characteristics, the EI patients had a lower initial NIHSS score (median [quartile]: 11 [7-16]) than the non-EI patients (13 [11-15]; P 5 .047), even though the 2 groups were similar in the time from symptom onset to arrival at the ER (EI, 110 minutes; non-EI, 120 minutes; P 5 .279; Table 1). In addition, the EI patients were more likely to have MCA occlusion (82%) than the non-EI group (64%, P 5 .023). Approximately half of each group received an intravenous tPA injection before IAT (P 5.07). Both groups also underwent AMCD and SAT for IAT at similar frequencies (P 5 .341).
Differences between the EI and Non-EI Groups in Clinical Variables The 2 groups did not differ in median door-to-puncture time (EI, 104 minutes; non-EI, 100 minutes; P 5 .933), but the EI group had a shorter puncture-to-recanalization time (median [range]: 60 [16-190] versus 70 [9-180] minutes; P 5 .033). The EI patients were also more likely to undergo recanalization within 6 hours of symptom onset (86% versus 49%; P , .001). In addition, the EI group had a higher rate of successful recanalization (100% versus 76%; P , .001; Table 2). At discharge, the EI patients exhibited a larger improvement in the NIHSS score (median [quartiles]: 9 [7-13] points) than the non-EI patients (0 [0-4] points, P , .001). Most EI patients had good clinical outcomes (mRS score 0-2) at discharge (88%), unlike the non-EI patients (7%, P ,.001). The large difference in good outcome maintained until 3 months after discharge (EI, 92%; nonEI patients, 19%, P , .001). Death after IAT only occurred in non-EI patients during hospitalization (11%, P 5 .012) and 3 months after discharge (17%, P 5 .001; Table 2).
Differences between EI and Non-EI Groups in Radiological Variables The EI patients were more likely to have a high ASPECT score (8-10) on the initial CT scan than the nonEI patients (88% versus 48%; P , .001). The EI group was also less likely to have the hyperdense MCA sign on the initial CT scan than the non-EI group (44% versus 79%; P , .001; Table 3). When the whole patient cohort was divided according to the presence of the hyperdense MCA sign, analysis of the various vascular risk factors revealed that the hyperdense MCA sign only associated significantly with atrial fibrillation: 62 of the 92 patients with the sign (67%) had atrial fibrillation compared with 20 of the 49 patients without the sign (43%; P 5 .022). On initial cerebral angiography, the EI patients were
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Table 1. Baseline patient characteristics Early improvement
Age, y (mean 6 SD) Sex, male:female Risk factors Hypertension Diabetes Smoking Atrial fibrillation Initial NIHSS score, median (quartiles) Onset-to-door time, min, median (range)* Occlusion site T-ICA MCA Use of intravenous tPA IAT procedure AMCD SAT
Yes (n 5 49)
No (n 5 92)
P value
66.1 6 12.0 30:19 (61:39)
69.2 6 11.5 55:37 (60:40)
.154 .507
22 (45) 13 (27) 13 (27) 21 (43) 11 (7-16) 110 (15-269)
47 (51) 17 (19) 15 (16) 62 (67) 13 (11-15) 120 (15-297)
9 (18) 40 (82) 29 (59)
33 (36) 59 (64) 41 (45)
14 (29) 35 (71)
22 (24) 70 (76)
.301 .184 .111 .004 .047 .279 .023
.070 .341
Abbreviations: AMCD, aggressive mechanical clot disruption; IAT, intra-arterial thrombolysis; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; T-ICA, terminal internal carotid artery; tPA, tissue plasminogen activator; SAT, stent-assisted thrombectomy. Data are n (%) values except while stated otherwise. *Time from symptom onset to arrival at the emergency room.
more likely to have intermediate to good collaterals than the non-EI patients (86% versus 53%; P , .001). The EI patients were less likely to develop petechial hemorrhage or hematoma (34%), as indicated by the follow-up CT scan after IAT, than the non-EI patients
(78%; P ,.001; Table 3). None of the EI patients developed symptomatic ICH compared with 11 of the 92 non-EI patients (11%; P 5 .007). Similarly, extensive SAH only occurred in the non-EI patients (14%; P 5 .003; Table 3).
Table 2. Clinical variables of the patients with and without EI EI
Procedure times, min, median (range) Door-to-groin puncture time Groin puncture-to-recanalization time Symptom onset-to-recanalization time #6 h .6 h Successful recanalization, TICI (2a-3) Clinical outcomes At discharge NIHSS score improvement, median (quartile) mRS score 0-2 Death 3 Months after discharge mRS score 0-2 Death*
Yes (n 5 49)
No (n 5 92)
P value
104 (25-214) 60 (16-190)
100 (17-240) 70 (11-180)
.933 .033 ,.001
42 (86) 7 (14) 49 (100)
45 (49) 47 (51) 70 (76)
,.001
9 (7-13) 43 (88) 0
0 (0-4) 6 (7) 10 (11)
,.001 ,.001 .012
45 (92) 0
17 (19) 16 (17)
,.001 .001
Abbreviations: EI, early improvement; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; TICI, thrombolysis in cerebral infarction. Data are n (%) values except where stated otherwise. *The death rate 3 months after discharge also contains patients who died during hospitalization.
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Table 3. Radiological variables of the patients with and without EI EI Yes (n 5 49)
No (n 5 92)
P value
10 (8-10) 6 (12) 43 (88) 21 (44)
7 (6-9) 48 (52) 44 (48) 71 (79)
,.001 ,.001
42 (86) 7 (14)
49 (53) 43 (47)
32 (65) 16 (32) 1 (2) 0 0
21 (23) 50 (55) 21 (23) 11 (12) 13 (14)
Initial ASPECT score, median (quartiles) 0-7 8-10 Presence of hyperdense MCA sign Collateral circulation before IAT Intermediate–good Poor Hemorrhagic transformation None Small or confluent petechiae Small or large hematoma Symptomatic ICH Extensive SAH within 24 h
,.001 ,.001 ,.001
.007 .003
Abbreviations: ASPECT, the Alberta Stroke Program Early Computed Tomography; IAT, intra-arterial thrombolytic therapy; ICH, intracerebral hemorrhage; MCA, middle cerebral artery; SAH, subarachnoid hemorrhage. Data are n (%) values except where stated otherwise.
Multiple Regression Analysis to Identify Clinical and Radiological Variables That Predict Early Improvement after IAT Multiple logistic regression analysis was performed with the clinical and radiological variables that were significant on univariate analysis (Tables 1-3). Lack of EI associated independently with the presence of atrial fibrillation (odds ratio [OR] .35; 95% confidence interval [CI]: .14-.89; P 5 .028) and the hyperdense MCA sign (OR .39, 95% CI: .15-.97; P 5 .042; Table 4). In contrast, EI associated independently with a high ASPECT score (OR 4.92; 95% CI: 1.74-13.9; P 5 .003) in the initial CT images, the presence of moderate–good collaterals (OR 3.28; 95% CI: 1.16-9.31; P 5 .026), and recanalization within 6 hours of symptom onset (OR 5.2; 95% CI: 1.81-14.94, P 5 .002; Table 4). Table 4. Multiple logistic regression analysis to identify factors that predict early improvement
Variables Presence of atrial fibrillation Presence of hyperdense MCA sign High initial ASPECT score (8-10) Presence of collateral circulation Recanalization within 6 h
Odds ratio
95% CI
P value
.35 .39
.14-.89 .15-.97
.028 .042
4.92
1.74-13.9
.003
3.28
1.16-9.31
.026
5.2
1.81-14.94
.002
Abbreviations: ASPECT, the Alberta Stroke Program Early Computed Tomography; CI, confidence interval; MCA, middle cerebral artery.
Discussion Although several clinical and radiological variables are predictive of EI after IVT,20 the clinical and radiological factors that relate to EI after IAT remain poorly understood. The present study showed that EI after IAT associated significantly with several clinical and radiological variables that were measured before and after IAT. Moreover, the patients who showed EI after IAT had better clinical outcomes at discharge and 3 months after IAT than non-EI patients. The first notable difference between the EI and non-EI patients related to the extensiveness of the infarcted lesion and the presence of the hyperdense MCA sign on the initial CT scan. The infarcted lesion extensiveness on baseline CT is a radiological factor that associates with clinical outcome and mortality after IVT or IAT.21,22 In the present study, the EI patients had less severe lesion extensiveness on baseline CT than the non-EI patients. The hyperdense MCA sign is frequently observed on baseline CT12 in acute ischemia and usually associates significantly with a larger final infarct size and poor clinical outcome.23 Indeed, in the present study, the hyperdense MCA sign observed on initial CT associated independently with the lack of EI. Thus, an extensive infarcted lesion and the presence of a hyperdense MCA before IAT may be predictive of non-EI and poor clinical outcomes. These factors should be considered before deciding to perform IAT. In the present study, atrial fibrillation also associated independently with non-EI. The presence of chronic atrial fibrillation induces systemic24 and intracerebral25 hemodynamic alterations. Thus, if an embolus develops in a large intracranial vessel of a patient with atrial fibrillation,
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the reduced cerebral blood flow caused by the atrial fibrillation could exacerbate the abrupt interruption of the cerebral blood flow in the occluded hemisphere caused by the occlusion.25Atrial fibrillation may also hamper the prompt development of collateral circulation after the occlusion of large intracranial vessels.25 Such disturbed systemic and intracerebral hemodynamic alterations could influence the clinical outcome of patients with acute ischemia. Indeed, a previous cohort study reported that strokes are more likely to be severe in patients with atrial fibrillation than in patients without atrial fibrillation.26 Even though larger studies with a better design are needed to understand how atrial fibrillation affects the clinical outcomes in acute ischemia, the present study supports the notion that atrial fibrillation may be an important clinical variable because it signals slow improvement after IAT and poor clinical outcomes in patients with acute ischemia. The EI patients in the present study had significantly better collateral circulation on baseline cerebral angiography than the non-EI patients. To decrease the irreversible damage in the territory of an occluded vessel, collateral development is certainly needed.27 Indeed, a previous study showed that the early development of collateral flow to the occluded artery territory was predictive of good clinical outcomes and decreases in the infarct volume after thrombolytic therapy.8 Our study results also supports the notion that good collaterals are needed for rapid neurologic improvement after IAT. Several studies have shown that to achieve EI after thrombolytic therapy, the recanalization must be complete and rapid.1-3 In the present study, the EI patients achieved recanalization more rapidly than the non-EI patients, even though the 2 groups did not differ in terms of the time interval between symptom onset and arrival at the ER or groin puncture. In addition, the EI patients were significantly more likely than the non-EI patients to have occluded vessel recanalization within 6 hours of symptom onset. Moreover, the EI patients had successful recanalization more frequently than the non-EI patients. Thus, both rapid and successful recanalization may contribute to the early clinical improvement and good outcomes of patients who receive IAT. The EI patients in the present study almost never developed extensive SAH or symptomatic ICH. In contrast, severe hemorrhagic complications were relatively frequent in the non-EI patients. Several other studies have also shown that severe hemorrhagic complications after IVT28 or IAT29 associate with poor clinical outcomes. Thus, even though the regression analysis in the present study did not identify the development of extensive parenchymal hematoma and SAH in the 24 hours after IAT as an independent variable for EI, it remains possible that this radiological variable associates with poor clinical improvement during long-term follow-up after IAT.
A recent study suggested that in patients who receive IVT, several clinical and radiological variables are predictive of functional outcomes, including age, baseline glucose level, onset-to-treatment time, the presence of a hyperdense artery, early infarct signs, and baseline NIHSS.20 In contrast, in the present study, the statistically significant independent predictors of EI after IAT were radiological variables including early recanalization time, early collateral development, and high ASPECT score on baseline CT. In addition, the EI patients were less likely to have atrial fibrillation and the hyperdense MCA sign on initial CT than the non-EI patients. The previous variables of EI in the study on IVT were suggested after the evaluations of the clinical status and initial CT for patients after arrival at ER. However, the variables of EI in the present study were the radiological findings after cerebral angiography for IAT. Even though the present study on IAT identified different predictors of EI than the study on IVT,20 the variables we identified may be useful for anticipating EI and good clinical outcomes after IAT than the previous variables observed in the study on IVT. In conclusion, the present study identified several clinical and radiological variables that are measured before and after IAT that associated significantly with EI after IAT. EI associated with good clinical outcomes at both discharge and 3 months after discharge. The main limitation of our study was that the clinical data were collected retrospectively from a small number of patients in a single stroke center. Future randomized prospective studies with large sample sizes that test the predictive power of the variables identified by the present study are warranted.
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