Recanalization Therapy for Internal Carotid Artery Occlusion Presenting as Acute Ischemic Stroke Jeong-Ho Hong, MD,* Jihoon Kang, MD,† Min Uk Jang, MD,‡ Beom Joon Kim, MD,x Moon-Ku Han, MD,x Tai Hwan Park, MD,k Sang-Soon Park, MD,k Kyung Bok Lee, MD,{ Byung-Chul Lee, MD,# Kyung-Ho Yu, MD,# Mi Sun Oh, MD,# Jae Kwan Cha, MD,** Dae-Hyun Kim, MD,** Jun Lee, MD,†† Soo Joo Lee, MD,‡‡ Youngchai Ko, MD,‡‡ Jong-Moo Park, MD,xx Kyusik Kang, MD,xx Yong-Jin Cho, MD,kk Keun-Sik Hong, MD,kk Ki-Hyun Cho, MD,{{ Joon-Tae Kim, MD,{{ Juneyoung Lee, PhD,## Ji Sung Lee, PhD,*** and Hee-Joon Bae, MDx
Background: We aimed to describe the current status and clinical outcomes of recanalization therapy for internal carotid artery occlusion (ICAO) presenting as acute ischemic stroke. Methods: Using a nationwide stroke registry database in Korea, we identified consecutive ischemic stroke patients with ICAO hospitalized within 12 hours of onset between March 2010 and November 2011. Results: ICAO accounted for 10.6% (322 of 3028) of acute ischemic strokes within 12 hours of onset. Among the 322 ICAO patients, 53% underwent recanalization therapy, 41% intravenous thrombolysis (IVT) alone, and 59% endovascular treatment (EVT). Twenty-two percent of those with mild deficits (National Institutes of Health Stroke Scale ,4) and 50% of those 80 years of age or more received recanalization therapy. Compared with no treatment, recanalization therapy was not significantly associated with a favorable outcome (3-month modified Rankin scale, 0-2) (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], .80-3.91; P 5 .16). However, compared with IVT, EVT significantly improved the odds of favorable outcome (OR, 2.86; 95% CI, 1.19-6.88; P 5 .02) without significant increase of symptomatic intracranial hemorrhage (OR, 2.18; 95% CI, .42-11.43; P 5 .36) and 3-month mortality (OR, .53; 95% CI, .23-1.18; P 5 .12). Successful recanalization rate (Thrombolysis in Cerebral
From the *Department of Neurology, Keimyung University Dongsan Medical Center, Daegu; †Department of Neurology, Sungkyunkwan University Samsung Changwon Hospital School of Medicine, Changwon; ‡Department of Neurology, Chuncheon Sacred Heart Hospital, Chuncheon; xDepartment of Neurology, Seoul National University Bundang Hospital, Seongnam; kDepartment of Neurology, Seoul Medical Center, Seoul; {Department of Neurology, Soonchunhyang University College of Medicine, Asan; #Department of Neurology, Hallym University College of Medicine, Anyang; **Department of Neurology, Dong-A University College of Medicine, Busan; ††Department of Neurology, Yeungnam University School of Medicine, Daegu; ‡‡Department of Neurology, Eulji University Hospital, Eulji University College of Medicine, Daejeon; xxDepartment of Neurology, Eulji General Hospital, Eulji University School of Medicine, Seoul; kkDepartment of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang; {{Department of Neurology, Chonnam National Univer-
sity Medical School, Gwangju; ##Department of Biostatistics, Korea University College of Medicine, Seoul; and ***Biostatistical Consulting Unit, Soonchunhyang University Medical Center of Biostatistics, Seoul, Korea. Received March 14, 2014; revision received April 6, 2014; accepted April 14, 2014. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea. (HI10C2020). Address correspondence to Hee-Joon Bae, MD, PhD, Department of Neurology, Stroke Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04.025
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 8 (September), 2014: pp 2183-2189
2183
J.-H. HONG ET AL.
2184 Infarction $2a) by EVT was 76%. Conclusions: In Korea, one tenth of acute ischemic stroke was caused by ICAO, and about 50% were treated by recanalization therapy. EVT was widely used as a recanalization modality (about 60% of cases) despite lack of evidence. However, its effectiveness and safety were acceptable. Key Words: Endovascular recanalization—thrombolysis—carotid artery—acute stroke— revascularization. Ó 2014 by National Stroke Association
Internal carotid artery occlusion (ICAO) accounts for 8.8%-9.1% cases of acute ischemic stroke1,2 and results in an extremely poor outcome.3 Recanalization rates of ICAO by intravenous (IV) administration of tissue plasminogen activator (tPA) are only 4%-8%.4,5 To overcome the low recanalization rate of IV tPA, new generation endovascular devices have been developed with rapid progress,6 and use of these devices in ICAO yielded 63%-100% recanalization rates.7-9 However, clinical trials to compare the possible options of recanalization therapy and determine the best are lacking, and no clear treatment guidelines exist.10,11 Moreover, the current status of treatment regimens at a national level has not been known well.
Aims This study aimed to explore the use of recanalization therapy, the methods used for this therapy, and the clinical outcomes among acute ischemic stroke patients with ICAO presenting within 12 hours of the onset of symptoms. Data were derived from a nationwide stroke registry database in Korea.
Methods Since 2006, the Clinical Research Center for Stroke project sponsored by the Korean Government has begun to facilitate multicenter collaborative stroke research and to develop and implement clinical practice guidelines for stroke in Korea. For achieving these purposes, information on demographics, stroke characteristics, vascular risk factors, diagnostic work-up, in-hospital management, and clinical outcomes of stroke patients who are admitted to participating hospitals are collected prospectively through a web-based stroke registry database (http://www.stroke-crc.or.kr/ecrf). Our study was designed as a retrospective observational study in the 10 university hospitals or regional stroke centers participating in the fifth subdivision of Clinical Research Center for Stroke, which is dedicated to epidemiologic research. Consecutive patients with ischemic stroke or transient ischemic attack (TIA), who were hospitalized within 12 hours of onset between March 2010 and November 2011, were identified using the registry database. Among them, patients with ICAO
diagnosed by magnetic resonance or computed tomography (CT) angiography, carotid duplex, or conventional cerebral angiography and with relevant acute ischemic lesions on magnetic resonance imaging or CT in case of ischemic stroke or relevant symptoms in case of TIA were enrolled for this study. From the registry database, we obtained demographics, risk factors, initial stroke severity as indexed by the National Institutes of Health Stroke Scale (NIHSS), stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification,12 onset-to-arrival time, ICAO location, comorbid intracranial artery occlusion, modalities of recanalization therapy, endovascular devices and the modified Rankin Scale (mRS), and mortality at 3 months. In addition, the conventional cerebral angiography for patients who received endovascular treatment (EVT) and the CT or magnetic resonance imaging with/without angiography for patients who underwent any type of recanalization therapies were assembled and the recanalization status and the development of symptomatic intracerebral hemorrhage (sICH) were assessed by a core laboratory retrospectively. In patients treated with recanalization therapy, follow-up brain imaging was carried out not routinely but if a patient had any neurologic deterioration. To describe the status of recanalization therapy according to baseline NIHSS and onset-to-arrival time, baseline NIHSS was categorized into the following categories: 0-3 (mild), 4-9 (moderate), 10-25 (severe), and 26-44 (profound). Onset-to-arrival time was divided into 0-3 hours, 3-6 hours, and 6-12 hours. Stroke onset time was defined as the time when patients were lastly seen normal. Methods of EVT were categorized as follows: (1) intraarterial (IA) lytics, IA use of chemical thrombolytic agents; (2) microcatheter, multiple passes of the aggressive microcatheter and microwire clot maceration13; (3) mechanical thrombectomy, use of devices, such as the Penumbra System and the Solitaire, to perform mechanical clot disruption; and (4) carotid stent placement. Favorable outcome was defined as 3-month mRS scores of 0-2, sICH as deterioration in NIHSS of $4 points with parenchymal hematoma type 2 (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy definition),14 and successful recanalization was the Thrombolysis in Cerebral Infarction (TICI) grade $2a. The TICI grade was assessed by two experienced stroke neurologists
RECANALIZATION OF INTERNAL CAROTID OCCLUSION
2185
Table 1. Baseline characteristics
Characteristics Age, mean 6 SD Age .80 y, n (%) Sex (male), n (%) Premorbid mRS, n (%) #1 $2 Baseline NIHSS, median (IQR) 0-3, n (%) 4-9, n (%) 10-25, n (%) 26-44, n (%) Onset-to-arrival time, h, median (IQR) #3, n (%) 3-6, n (%) .6, n (%) TOAST classification, n (%) Large artery atherosclerosis Cardioembolism Other causes or unclassified Risk factors, n (%) History of stroke or TIA Hypertension Diabetes mellitus Hyperlipidemia Atrial fibrillation Site of occlusion Extracranial Intracranial Comorbid intracranial occlusion, n (%)
No recanalization Recanalization therapy, therapy, N 5 171 N 5 151 69.9 6 11.9 31 (20.5) 91 (60.3)
69.8 6 12.8 31 (18.1) 94 (55.0)
132 (87.4) 19 (12.6) 12 (5-17) 32 (21.2) 24 (15.9) 92 (60.9) 3 (2.0) 4.5 (2.4-8.2) 49 (32.5) 44 (29.1) 58 (38.4)
162 (94.7) 9 (5.3) 15 (11-19) 9 (5.3) 23 (13.5) 137 (80.1) 2 (1.2) 1.6 (.8-3.3) 127 (74.3) 26 (15.2) 18 (10.5)
60 (40.8) 53 (36.1) 28 (23.1)
46 (26.9) 84 (49.1) 41 (24.0)
44 (29.1) 91 (60.3) 40 (26.5) 60 (39.7) 52 (34.4)
32 (18.7) 133 (77.8) 54 (31.6) 58 (33.9) 91 (53.1)
102 (67.5) 49 (32.5) 52 (34.4)
113 (66.1) 58 (33.9) 81 (47.4)
P .90* .59y .34y .02y
,.001z ,.001y ,.001z ,.001y
IV thrombolysis Endovascular treatment, alone, N 5 101 N 5 70 71.1 6 13.2 19 (27.1) 42 (60.0)
68.8 6 12.5 12 (11.9) 52 (51.5)
67 (95.7) 3 (4.3) 14 (9-18) 4 (5.7) 15 (21.4) 50 (71.4) 1 (1.4) 1.4 (.8-2.9) 56 (80.0) 13 (18.6) 1 (1.4)
95 (94.1) 6 (5.9) 16 (12-19) 5 (5.0) 8 (7.9) 87 (86.1) 1 (1.0) 1.7 (.8-3.5) 71 (70.3) 13 (12.9) 17 (16.8)
24 (34.3) 31 (44.3) 15 (21.4)
22 (21.8) 53 (52.5) 26 (25.7)
11 (15.7) 54 (77.1) 18 (25.7) 24 (34.3) 35 (50)
21 (20.8) 79 (78.2) 36 (35.6) 34 (33.7) 56 (55.4)
48 (68.6) 22 (31.4) 33 (47.1)
65 (64.4) 36 (35.6) 48 (47.5)
.02y
.03y .001y .32y .28y ,.001y .78y
.02y
P .24* .01y .27y .46y
.06z .08y
.01z .01y .19y
.40y .87y .17y .93y .48y .57y
.57y
Abbreviations: IQR, interquartile range; IV, intravenous; mRS, modified Rankin Scale; NIHSS, National Institutes of Health stroke scale; SD, standard deviation; TIA, transient ischemic attack; TOAST, Trial of ORG 10172 in Acute Stroke Treatment. *Student t test. yPearson c2 test. zMann–Whitney U test.
(M.U.J. and J-H.H.) who were blinded to clinical information; disagreement between the 2 raters was resolved by consensus. Kendall’s coefficient of concordance for inter-observer agreement15 was .979 (P value ,.0001). To compare baseline characteristics according to recanalization modalities, Pearson c2 test or Fisher exact test was used for categorical variables and Student t test or Mann–Whitney U test was for continuous variables when appropriate. Multivariable logistic regression analysis was performed to examine the effectiveness and safety of recanalization therapy versus no recanalization therapy, of EVT regardless of IV tPA versus intravenous thrombolysis (IVT) alone, and of combined thrombolysis (CMT, the EVT preceded by IV tPA) versus IVT. When analyzing 3-month mRS and mortality as outcome variables, patients who were lost to follow-up
were excluded. For multivariable analysis, variables whose P values were ,.1 in the comparisons of baseline characteristics (Table 1, Table S1 in Appendix) and whose associations with outcomes of interest were biologically plausible were chosen for adjustment. Statistical analyses were performed using IBM SPSS 19.0.1 (IBM Corporation, Armonk, NY) and SAS statistical software, version 9.2 for Windows (SAS, Cary, NC). P values ,.05 were judged to be significant. In all participating centers, approval was obtained from local institutional review boards for collection of anonymized clinical data without patients’ consent into the registry database to monitor and improve the quality of stroke care. We got further approval for collection of additional data and use of the registry database for this study.
2186
Figure 1. Flow chart of enrolled subjects and recanalization modalities. Abbreviations: F/U, follow-up; IA, intra-arterial; IV, intravenous; TIA, transient ischemic attack; tPA, tissue plasminogen activator.
Results During the study period, 3028 patients with acute ischemic stroke or TIA were hospitalized within 12 hours of symptom onset, and 322 (10.6%) had symptomatic ICAO (Fig 1). The mean age was 69.8 6 12.4 years (median, 71 years; range, 23-92). The proportion of cardioembolic stroke was 43%. Favorable outcome was observed in 27%, and 3-month mortality was 25%. Follow-up loss rate at 3 months was 3.4%. Of the 322 patients with symptomatic ICAO, 53% (n 5 171) were treated with recanalization therapy, 41% with IVT, and 59% with EVT (Fig 1). Of 101 patients in the EVT group, 65% were treated with IV tPA before EVT. Comparisons between patients treated with and without recanalization therapy showed that those treated with recanalization therapy were more likely to arrive at the hospital earlier and to have higher NIHSS at presentation, cardioembolic stroke, hypertension, atrial fibrillation, and comorbid intracranial occlusion, and were less likely to have premorbid mRS $2, large artery atherosclerosis, and a history of stroke or TIA (Table 1). Recanalization therapy rates according to the baseline NIHSS scores were the highest (60%) in patients with baseline NIHSS scores of 10-25 (Fig 2). As expected, recanalization therapy rates decreased with increase of onset-to-arrival time. Comparisons between the IVT and EVT groups showed that patients in the EVT group were more likely to arrive at the hospital later and likely to be less than 80 years of
J.-H. HONG ET AL.
age and tended to have higher baseline NIHSS scores (Table 1). The proportion of EVT among those treated with recanalization therapy according to baseline NIHSS scores was also highest (64%) in patients with baseline NIHSS scores of 10-25 (Fig 2). Among 18 patients who arrived after 6 hours from onset and received recanalization therapy, 17 were treated with EVT. Comparisons between the IVT and CMT groups are presented in Table S1 in Appendix. The CMT group was more likely to have higher baseline NIHSS and tended to be less than 80 years of age and to arrive at the hospital later. Among patients treated with IV tPA (n 5 136), the dose of alteplase was .9 mg/kg in 56% and .6 mg/kg in 44%. The preferred dose was .9 mg/kg in the IVT group and .6 mg/kg in the CMT group (Table 2). Two thirds of the EVT group used intra-arterial thrombolytics, and urokinase was a most commonly used lytic agent (median dose, 100,000 units; range, 10,000-400,000 units). Thrombectomy devices were used in 69% of the EVT group, and the most commonly used method was the microcatheter followed by the Solitaire. The recanalization rates by EVT were 76% for TICI grade $2a and 61% for TICI $2b. The proportion of favorable outcome and the 3-month mortality were comparable between patients treated with and without recanalization therapy (26% vs. 28% and 24% vs. 26%, respectively). After adjustment, there was no significant increase in favorable outcome but a significant decrease in 3-month mortality by recanalization therapy (Table 3). Compared with IVT, EVT and CMT significantly improved the 3-month functional outcome. However, increase of sICH and decrease of 3-month mortality by EVT and CMT were not statistically significant. Detailed results of multivariable analyses are presented in Tables S2 through S4 in Appendix. Baseline NIHSS was a significant determinant of 3-month favorable outcome and 3-month mortality in most models. Comparisons of baseline characteristics and clinical outcomes according to the method of EVT in the EVT group are shown in Table S5 in Appendix. In these comparisons, a final method used was chosen as representative. There was no notable difference in age, baseline NIHSS, and preceding IV tPA. Favorable outcome and successful recanalization (TICI grade $2a) were observed most frequently in those treated with stenting, and 3month mortality and sICH were observed most frequently in those treated with a thrombectomy device. Figure 2. Current status of recanalization therapy stratified according to baseline NIHSS and onset-to-arrival time. Black color: number of patients with acute symptomatic internal carotid artery occlusion. Blue color: number of patients receiving recanalization therapy. Brown color: number of patients receiving endovascular treatment. Abbreviations: NIHSS, National Institutes of Health Stroke Scale. (Color version of figure is available online.)
RECANALIZATION OF INTERNAL CAROTID OCCLUSION
Table 2. Methods of recanalization therapy IV thrombolysis, (n 5 136) IV tPA dose, .9 mg/kg IV thrombolysis alone Combined thrombolysis IV tPA dose, .6 mg/kg IV thrombolysis alone Combined thrombolysis Endovascular treatment (n 5 101)* IA lytics Urokinase ReoPro Tirofiban Others IA devices Microcatheter Penumbra Penumbra followed by Solitaire Solitaire Stenting
76/136 (55.9%) 58/70 (82.9%) 18/66 (27.3%) 60/136 (44.1%) 12/70 (17.1%) 48/66 (72.7%) 67/101 (66%) 58 (86.6%) 4 (6.0%) 17 (25.4%) 2 (2.0%) 97/101 (96%) 77 (76.2%) 6 (5.9%) 27 (26.7%) 37 (36.6%) 20 (19.8%)
Abbreviations: IA, intra-arterial; IV, intravenous; tPA, tissue plasminogen activator. *Duplication was allowed in intra-arterial lytics and devices.
2187
Discussion About 11% of patients with acute ischemic stroke or TIA presenting within 12 hours of onset had ICAO, and approximately half of them underwent recanalization therapy. Fifty-nine percent of those receiving recanalization therapy were eventually treated by endovascular methods. The proportion of symptomatic ICAO in this study was slightly higher than those in previous studies; 9.1% using carotid Doppler in a multicenter acute stroke trial conducted in North America1 and 8.8% in a multicenter clinical registry-based study in Germany.2 The time window for inclusion in these studies was within 24 hours of onset.1,2 The contribution of cardioembolism in the acute symptomatic ICAO seems to be much higher than that reported for all ischemic stroke patients in Korea (17%).16 This is the first study to describe the characteristics of patients treated with recanalization therapy in acute symptomatic ICAO. Indications for recanalization therapy were broader than expected with regard to age, stroke severity, and time window. The role of age and stroke severity in determining the use of recanalization
Table 3. Clinical outcomes according to thrombolytic modalities Clinical outcomes Favorable outcome (3-month mRS #2) No recanalization therapy Recanalization therapy IVT EVT IVT CMT sICH (SITS-MOST definition) IVT EVT IVT CMT 3-Month mortality No recanalization therapy Recanalization therapy IVT EVT IVT CMT
Rate of outcome
Adjusted OR
95% CI
P value
41/145 (28.1%) 42/165 (25.5%) 13/67 (19.4%) 29/98 (29.6%) 13/67 (19.4%) 17/64 (26.6%)
1* 1.77 1y 2.86 1z 2.65
.80-3.91 1.19-6.88 1.02-6.87
.16 .02 .05
2/70 (2.9%) 6/101 (5.9%) 2/70 (2.9%) 4/66 (6.1%)
1x 2.18 1x 2.12
.42-11.43 .35-12.97
.36 .42
38/146 (26.0%) 39/165 (23.6%) 19/67 (28.4%) 20/98 (20.4%) 19/67 (28.4%) 15/64 (23.4%)
1* .46 1y .53 1z .40
.24-.90 .23-1.18 .16-1.01
.02 .12 .05
Abbreviations: CI, confidence interval; CMT, combined thrombolysis; EVT, endovascular treatment (regardless of intravenous tPA); IVT, intravenous thrombolysis (alone); mRS, modified Rankin Scale; NIHSS, National Institutes of Health stroke scale; OR, odds ratio; sICH, symptomatic intracranial hemorrhage; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy; TOAST, Trial of ORG 10172 in Acute Stroke Treatment. *Adjusted for initial NIHSS, premorbid mRS #1, onset-to-arrival time, comorbid intracranial occlusion and history of stroke or transient ischemic attack, hypertension, and atrial fibrillation. yAdjusted for age, initial NIHSS, onset-to-arrival time, and history of diabetes mellitus. zAdjusted for initial NIHSS, onset-to-arrival time, and TOAST classification. xAdjusted for initial NIHSS and onset-to-arrival time.
J.-H. HONG ET AL.
2188 17
therapy is still being debated. Current consensus is based on the eligibility criteria of clinical trials: age #80 years, stroke severity $10 NIHSS points, and time limit ,6-8 hours of onset have been suggested.18-23 However, these factors do not reflect the fact that clinical outcomes and rates of recanalization differ according to occlusion sites.24,25 Crude mortality and proportions of favorable outcome were similar between patients treated with and without recanalization therapy (Table 3). With adjustments for potential confounders, a significant reduction of mortality and a trend, although not significant, toward functional independency at 3 months by recanalization therapy was observed. In addition, compared with IVT, EVT improved 3-month functional outcome without a significant increase in sICH and 3-month mortality. However, it should be noted that sICH developed twice as frequently in the EVT group compared with the IVT group (5.9% vs. 2.9%). Until now, recanalization therapy for ICAO presenting as acute ischemic stroke has been subjected to criticism because of lack of direct evidence.11 However, subgroup analysis of the Interventional Management of Stroke III trial and a recent systematic review, together with our results, suggest the superiority of EVT over IVT alone in this situation.10 Further solid evidence is required. Use of low-dose alteplase (.6 mg/kg) for IVT was unexpectedly frequent, especially in the CMT group. Its use might be based on recent Japanese studies26,27 and Interventional Management of Stroke I and II trials.18,19 The ENhanced Control of Hypertension ANd Thrombolysis in strokE Disease trial may solve the controversy related to tPA dose, but the aim of this trial is to compare 2 different doses of tPA in patients receiving IVT alone regardless of occlusion status.28 Patients with ICAO tend to have a larger thrombus burden than those with other intracranial occlusions.29 There is no study about IV tPA dose for acute symptomatic ICAO whether it is used alone or before EVT. Endovascular devices were used in 96% of the EVT group. Only 4% were treated with IA lytics alone. About 70% of the devices were either the Penumbra System or the Solitaire. Recent endovascular trials have been criticized for infrequent application of newly developed devices in the EVT arms.20,30 A pooled analysis on intracranial ICAO cases from the MERCI and Multi MERCI Part I trials showed that successful recanalization, 3-month favorable outcome (mRS # 2), 3-month mortality, and sICH were observed in 63%, 25%, 46%, and 10% of patients, respectively.8 In the present study, each outcome in patients treated by the thrombectomy device was 74%, 26%, 25%, and 10%, respectively (Table S5 in Appendix). Lower mortality and higher successful recanalization rate are quite notable, which might correspond with the success of the Solitaire With the Intention For Thrombectomy trial.31
Our study also suggests emergent carotid stenting as another treatment option for ICAO presenting as acute ischemic stroke. Although there is no consensus on acute carotid stenting, studies including ours showed relatively high successful recanalization and favorable outcome rates. A possible explanation might be because internal carotid artery occlusion have relevance to regional atherosclerotic plaque and acute stenting rather than other treatment modalities making flow restoration easier to improve immediately.32 Limitations of this study should be noted. Our study subjects came from selected university hospitals or regional stroke centers and were only Koreans and thus may not be representative of the general stroke population. The sample size might not be enough to detect clinically significant differences in the subgroup analysis according to thrombolytic modalities and final methods of EVT. In addition, the marked imbalance of clinical features among treatment groups and the heterogeneity in EVT methods and IV tPA doses further limit generalization of the study results. Current medical technology did not allow us to determine whether symptomatic ICAO was caused by acute or chronic occlusion of ICA too.
Supplementary Data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04. 025.
References 1. Adams HP Jr, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999;53:122-125. 2. Weimar C, Goertler M, Harms L, Diener HC. Distribution and outcome of symptomatic stenoses and occlusions in patients with acute cerebral ischemia. Arch Neurol 2006;63:1287-1291. 3. Meyer FB, Sundt TM Jr, Piepgras DG, Sandok BA, Forbes G. Emergency carotid endarterectomy for patients with acute carotid occlusion and profound neurological deficits. Ann Surg 1986;203:82-89. 4. Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010;41:2254-2258. 5. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78-86. 6. Meyers PM, Schumacher HC, Connolly ES Jr, Heyer EJ, Gray WA, Higashida RT. Current status of endovascular stroke treatment. Circulation 2011;123:2591-2601. 7. Machi P, Lobotesis K, Maldonado IL, Costalat V, Vendrell JF, Riquelme C, et al. Endovascular treatment of tandem occlusions of the anterior cerebral circulation
RECANALIZATION OF INTERNAL CAROTID OCCLUSION
8.
9.
10.
11.
12.
13.
14.
15. 16.
17. 18.
19. 20.
with solitaire FR thrombectomy system. Initial experience. Eur J Radiol 2012;81:3479-3484. Flint AC, Duckwiler GR, Budzik RF, Liebeskind DS, Smith WS. Mechanical thrombectomy of intracranial internal carotid occlusion: pooled results of the MERCI and Multi MERCI Part I trials. Stroke 2007;38: 1274-1280. Jovin TG, Gupta R, Uchino K, Jungreis CA, Wechsler LR, Hammer MD, et al. Emergent stenting of extracranial internal carotid artery occlusion in acute stroke has a high revascularization rate. Stroke 2005;36:2426-2430. Mokin M, Kass-Hout T, Kass-Hout O, Dumont TM, Kan P, Snyder KV, et al. Intravenous thrombolysis and endovascular therapy for acute ischemic stroke with internal carotid artery occlusion: a systematic review of clinical outcomes. Stroke 2012;43:2362-2368. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:870-947. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. Noser EA, Shaltoni HM, Hall CE, Alexandrov AV, Garami Z, Cacayorin ED, et al. Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute stroke? Stroke 2005;36:292-296. Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos A, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke 2008; 39:3316-3322. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159-174. Hong K-S, Bang OY, Kang D-W, Yu K-H, Bae H-J, Lee JS, et al. Stroke Statistics in Korea: Part I. Epidemiology and Risk Factors: a report from the Korean Stroke Society and Clinical Research Center for Stroke. J Stroke 2013;15:2. Balucani C, Grotta JC. Selecting stroke patients for intraarterial therapy. Neurology 2012;78:755-761. Investigators IMSS. Combined intravenous and intraarterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004; 35:904-911. The Interventional Management of Stroke (IMS) II Study. Stroke 2007;38:2127-2135. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intra-
2189
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
venous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282:2003-2011. Flint AC, Cullen SP, Faigeles BS, Rao VA. Predicting longterm outcome after endovascular stroke treatment: the totaled health risks in vascular events score. AJNR Am J Neuroradiol 2010;31:1192-1196. Hallevi H, Barreto AD, Liebeskind DS, Morales MM, Martin-Schild SB, Abraham AT, et al. Identifying patients at high risk for poor outcome after intra-arterial therapy for acute ischemic stroke. Stroke 2009;40:1780-1785. Linfante I, Llinas RH, Selim M, Chaves C, Kumar S, Parker RA, et al. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke 2002;33:2066-2071. Demchuk AM. IMS III: Comparison of outcomes between IV and IV/IA treatment in baseline CTA confirmed ICA, M1, M2 and basilar occlusions. International Stroke Conference 2013. 2013;Invited Symposium. Nakagawara J, Minematsu K, Okada Y, Tanahashi N, Nagahiro S, Mori E, et al. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-Marketing Alteplase Registration Study (J-MARS). Stroke 2010;41:1984-1989. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, 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. An international randomised controlled trial to establish the effects of low-dose rtPA and the effects of early intensive blood pressure lowering in patients with acute ischaemic stroke. Available at: http://clinicaltrials.gov/ ct2/show/NCT01422616. Accessed July 11, 2013. Barreto AD, Albright KC, Hallevi H, Grotta JC, Noser EA, Khaja AM, et al. Thrombus burden is associated with clinical outcome after intra-arterial therapy for acute ischemic stroke. Stroke 2008;39:3231-3235. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-913. Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012;380. Kappelhof M, Marquering HA, Berkhemer OA, Majoie CB. Intra-arterial treatment of patients with acute ischemic stroke and internal carotid artery occlusion: a literature review. J Neurointerv Surg 2014.
Background: We aimed to describe the current status and clinical outcomes of recanalization therapy for internal carotid artery occlusion (ICAO) presenting as acute ischemic stroke. Methods: Using a nationwide stroke registry database in Korea, we identified consecutive ischemic stroke patients with ICAO hospitalized within 12 hours of onset between March 2010 and November 2011. Results: ICAO accounted for 10.6% (322 of 3028) of acute ischemic strokes within 12 hours of onset. Among the 322 ICAO patients, 53% underwent recanalization therapy, 41% intravenous thrombolysis (IVT) alone, and 59% endovascular treatment (EVT). Twenty-two percent of those with mild deficits (National Institutes of Health Stroke Scale ,4) and 50% of those 80 years of age or more received recanalization therapy. Compared with no treatment, recanalization therapy was not significantly associated with a favorable outcome (3-month modified Rankin scale, 0-2) (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], .80-3.91; P 5 .16). However, compared with IVT, EVT significantly improved the odds of favorable outcome (OR, 2.86; 95% CI, 1.19-6.88; P 5 .02) without significant increase of symptomatic intracranial hemorrhage (OR, 2.18; 95% CI, .42-11.43; P 5 .36) and 3-month mortality (OR, .53; 95% CI, .23-1.18; P 5 .12). Successful recanalization rate (Thrombolysis in Cerebral
From the *Department of Neurology, Keimyung University Dongsan Medical Center, Daegu; †Department of Neurology, Sungkyunkwan University Samsung Changwon Hospital School of Medicine, Changwon; ‡Department of Neurology, Chuncheon Sacred Heart Hospital, Chuncheon; xDepartment of Neurology, Seoul National University Bundang Hospital, Seongnam; kDepartment of Neurology, Seoul Medical Center, Seoul; {Department of Neurology, Soonchunhyang University College of Medicine, Asan; #Department of Neurology, Hallym University College of Medicine, Anyang; **Department of Neurology, Dong-A University College of Medicine, Busan; ††Department of Neurology, Yeungnam University School of Medicine, Daegu; ‡‡Department of Neurology, Eulji University Hospital, Eulji University College of Medicine, Daejeon; xxDepartment of Neurology, Eulji General Hospital, Eulji University School of Medicine, Seoul; kkDepartment of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang; {{Department of Neurology, Chonnam National Univer-
sity Medical School, Gwangju; ##Department of Biostatistics, Korea University College of Medicine, Seoul; and ***Biostatistical Consulting Unit, Soonchunhyang University Medical Center of Biostatistics, Seoul, Korea. Received March 14, 2014; revision received April 6, 2014; accepted April 14, 2014. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea. (HI10C2020). Address correspondence to Hee-Joon Bae, MD, PhD, Department of Neurology, Stroke Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04.025
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 8 (September), 2014: pp 2183-2189
2183
J.-H. HONG ET AL.
2184 Infarction $2a) by EVT was 76%. Conclusions: In Korea, one tenth of acute ischemic stroke was caused by ICAO, and about 50% were treated by recanalization therapy. EVT was widely used as a recanalization modality (about 60% of cases) despite lack of evidence. However, its effectiveness and safety were acceptable. Key Words: Endovascular recanalization—thrombolysis—carotid artery—acute stroke— revascularization. Ó 2014 by National Stroke Association
Internal carotid artery occlusion (ICAO) accounts for 8.8%-9.1% cases of acute ischemic stroke1,2 and results in an extremely poor outcome.3 Recanalization rates of ICAO by intravenous (IV) administration of tissue plasminogen activator (tPA) are only 4%-8%.4,5 To overcome the low recanalization rate of IV tPA, new generation endovascular devices have been developed with rapid progress,6 and use of these devices in ICAO yielded 63%-100% recanalization rates.7-9 However, clinical trials to compare the possible options of recanalization therapy and determine the best are lacking, and no clear treatment guidelines exist.10,11 Moreover, the current status of treatment regimens at a national level has not been known well.
Aims This study aimed to explore the use of recanalization therapy, the methods used for this therapy, and the clinical outcomes among acute ischemic stroke patients with ICAO presenting within 12 hours of the onset of symptoms. Data were derived from a nationwide stroke registry database in Korea.
Methods Since 2006, the Clinical Research Center for Stroke project sponsored by the Korean Government has begun to facilitate multicenter collaborative stroke research and to develop and implement clinical practice guidelines for stroke in Korea. For achieving these purposes, information on demographics, stroke characteristics, vascular risk factors, diagnostic work-up, in-hospital management, and clinical outcomes of stroke patients who are admitted to participating hospitals are collected prospectively through a web-based stroke registry database (http://www.stroke-crc.or.kr/ecrf). Our study was designed as a retrospective observational study in the 10 university hospitals or regional stroke centers participating in the fifth subdivision of Clinical Research Center for Stroke, which is dedicated to epidemiologic research. Consecutive patients with ischemic stroke or transient ischemic attack (TIA), who were hospitalized within 12 hours of onset between March 2010 and November 2011, were identified using the registry database. Among them, patients with ICAO
diagnosed by magnetic resonance or computed tomography (CT) angiography, carotid duplex, or conventional cerebral angiography and with relevant acute ischemic lesions on magnetic resonance imaging or CT in case of ischemic stroke or relevant symptoms in case of TIA were enrolled for this study. From the registry database, we obtained demographics, risk factors, initial stroke severity as indexed by the National Institutes of Health Stroke Scale (NIHSS), stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification,12 onset-to-arrival time, ICAO location, comorbid intracranial artery occlusion, modalities of recanalization therapy, endovascular devices and the modified Rankin Scale (mRS), and mortality at 3 months. In addition, the conventional cerebral angiography for patients who received endovascular treatment (EVT) and the CT or magnetic resonance imaging with/without angiography for patients who underwent any type of recanalization therapies were assembled and the recanalization status and the development of symptomatic intracerebral hemorrhage (sICH) were assessed by a core laboratory retrospectively. In patients treated with recanalization therapy, follow-up brain imaging was carried out not routinely but if a patient had any neurologic deterioration. To describe the status of recanalization therapy according to baseline NIHSS and onset-to-arrival time, baseline NIHSS was categorized into the following categories: 0-3 (mild), 4-9 (moderate), 10-25 (severe), and 26-44 (profound). Onset-to-arrival time was divided into 0-3 hours, 3-6 hours, and 6-12 hours. Stroke onset time was defined as the time when patients were lastly seen normal. Methods of EVT were categorized as follows: (1) intraarterial (IA) lytics, IA use of chemical thrombolytic agents; (2) microcatheter, multiple passes of the aggressive microcatheter and microwire clot maceration13; (3) mechanical thrombectomy, use of devices, such as the Penumbra System and the Solitaire, to perform mechanical clot disruption; and (4) carotid stent placement. Favorable outcome was defined as 3-month mRS scores of 0-2, sICH as deterioration in NIHSS of $4 points with parenchymal hematoma type 2 (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy definition),14 and successful recanalization was the Thrombolysis in Cerebral Infarction (TICI) grade $2a. The TICI grade was assessed by two experienced stroke neurologists
RECANALIZATION OF INTERNAL CAROTID OCCLUSION
2185
Table 1. Baseline characteristics
Characteristics Age, mean 6 SD Age .80 y, n (%) Sex (male), n (%) Premorbid mRS, n (%) #1 $2 Baseline NIHSS, median (IQR) 0-3, n (%) 4-9, n (%) 10-25, n (%) 26-44, n (%) Onset-to-arrival time, h, median (IQR) #3, n (%) 3-6, n (%) .6, n (%) TOAST classification, n (%) Large artery atherosclerosis Cardioembolism Other causes or unclassified Risk factors, n (%) History of stroke or TIA Hypertension Diabetes mellitus Hyperlipidemia Atrial fibrillation Site of occlusion Extracranial Intracranial Comorbid intracranial occlusion, n (%)
No recanalization Recanalization therapy, therapy, N 5 171 N 5 151 69.9 6 11.9 31 (20.5) 91 (60.3)
69.8 6 12.8 31 (18.1) 94 (55.0)
132 (87.4) 19 (12.6) 12 (5-17) 32 (21.2) 24 (15.9) 92 (60.9) 3 (2.0) 4.5 (2.4-8.2) 49 (32.5) 44 (29.1) 58 (38.4)
162 (94.7) 9 (5.3) 15 (11-19) 9 (5.3) 23 (13.5) 137 (80.1) 2 (1.2) 1.6 (.8-3.3) 127 (74.3) 26 (15.2) 18 (10.5)
60 (40.8) 53 (36.1) 28 (23.1)
46 (26.9) 84 (49.1) 41 (24.0)
44 (29.1) 91 (60.3) 40 (26.5) 60 (39.7) 52 (34.4)
32 (18.7) 133 (77.8) 54 (31.6) 58 (33.9) 91 (53.1)
102 (67.5) 49 (32.5) 52 (34.4)
113 (66.1) 58 (33.9) 81 (47.4)
P .90* .59y .34y .02y
,.001z ,.001y ,.001z ,.001y
IV thrombolysis Endovascular treatment, alone, N 5 101 N 5 70 71.1 6 13.2 19 (27.1) 42 (60.0)
68.8 6 12.5 12 (11.9) 52 (51.5)
67 (95.7) 3 (4.3) 14 (9-18) 4 (5.7) 15 (21.4) 50 (71.4) 1 (1.4) 1.4 (.8-2.9) 56 (80.0) 13 (18.6) 1 (1.4)
95 (94.1) 6 (5.9) 16 (12-19) 5 (5.0) 8 (7.9) 87 (86.1) 1 (1.0) 1.7 (.8-3.5) 71 (70.3) 13 (12.9) 17 (16.8)
24 (34.3) 31 (44.3) 15 (21.4)
22 (21.8) 53 (52.5) 26 (25.7)
11 (15.7) 54 (77.1) 18 (25.7) 24 (34.3) 35 (50)
21 (20.8) 79 (78.2) 36 (35.6) 34 (33.7) 56 (55.4)
48 (68.6) 22 (31.4) 33 (47.1)
65 (64.4) 36 (35.6) 48 (47.5)
.02y
.03y .001y .32y .28y ,.001y .78y
.02y
P .24* .01y .27y .46y
.06z .08y
.01z .01y .19y
.40y .87y .17y .93y .48y .57y
.57y
Abbreviations: IQR, interquartile range; IV, intravenous; mRS, modified Rankin Scale; NIHSS, National Institutes of Health stroke scale; SD, standard deviation; TIA, transient ischemic attack; TOAST, Trial of ORG 10172 in Acute Stroke Treatment. *Student t test. yPearson c2 test. zMann–Whitney U test.
(M.U.J. and J-H.H.) who were blinded to clinical information; disagreement between the 2 raters was resolved by consensus. Kendall’s coefficient of concordance for inter-observer agreement15 was .979 (P value ,.0001). To compare baseline characteristics according to recanalization modalities, Pearson c2 test or Fisher exact test was used for categorical variables and Student t test or Mann–Whitney U test was for continuous variables when appropriate. Multivariable logistic regression analysis was performed to examine the effectiveness and safety of recanalization therapy versus no recanalization therapy, of EVT regardless of IV tPA versus intravenous thrombolysis (IVT) alone, and of combined thrombolysis (CMT, the EVT preceded by IV tPA) versus IVT. When analyzing 3-month mRS and mortality as outcome variables, patients who were lost to follow-up
were excluded. For multivariable analysis, variables whose P values were ,.1 in the comparisons of baseline characteristics (Table 1, Table S1 in Appendix) and whose associations with outcomes of interest were biologically plausible were chosen for adjustment. Statistical analyses were performed using IBM SPSS 19.0.1 (IBM Corporation, Armonk, NY) and SAS statistical software, version 9.2 for Windows (SAS, Cary, NC). P values ,.05 were judged to be significant. In all participating centers, approval was obtained from local institutional review boards for collection of anonymized clinical data without patients’ consent into the registry database to monitor and improve the quality of stroke care. We got further approval for collection of additional data and use of the registry database for this study.
2186
Figure 1. Flow chart of enrolled subjects and recanalization modalities. Abbreviations: F/U, follow-up; IA, intra-arterial; IV, intravenous; TIA, transient ischemic attack; tPA, tissue plasminogen activator.
Results During the study period, 3028 patients with acute ischemic stroke or TIA were hospitalized within 12 hours of symptom onset, and 322 (10.6%) had symptomatic ICAO (Fig 1). The mean age was 69.8 6 12.4 years (median, 71 years; range, 23-92). The proportion of cardioembolic stroke was 43%. Favorable outcome was observed in 27%, and 3-month mortality was 25%. Follow-up loss rate at 3 months was 3.4%. Of the 322 patients with symptomatic ICAO, 53% (n 5 171) were treated with recanalization therapy, 41% with IVT, and 59% with EVT (Fig 1). Of 101 patients in the EVT group, 65% were treated with IV tPA before EVT. Comparisons between patients treated with and without recanalization therapy showed that those treated with recanalization therapy were more likely to arrive at the hospital earlier and to have higher NIHSS at presentation, cardioembolic stroke, hypertension, atrial fibrillation, and comorbid intracranial occlusion, and were less likely to have premorbid mRS $2, large artery atherosclerosis, and a history of stroke or TIA (Table 1). Recanalization therapy rates according to the baseline NIHSS scores were the highest (60%) in patients with baseline NIHSS scores of 10-25 (Fig 2). As expected, recanalization therapy rates decreased with increase of onset-to-arrival time. Comparisons between the IVT and EVT groups showed that patients in the EVT group were more likely to arrive at the hospital later and likely to be less than 80 years of
J.-H. HONG ET AL.
age and tended to have higher baseline NIHSS scores (Table 1). The proportion of EVT among those treated with recanalization therapy according to baseline NIHSS scores was also highest (64%) in patients with baseline NIHSS scores of 10-25 (Fig 2). Among 18 patients who arrived after 6 hours from onset and received recanalization therapy, 17 were treated with EVT. Comparisons between the IVT and CMT groups are presented in Table S1 in Appendix. The CMT group was more likely to have higher baseline NIHSS and tended to be less than 80 years of age and to arrive at the hospital later. Among patients treated with IV tPA (n 5 136), the dose of alteplase was .9 mg/kg in 56% and .6 mg/kg in 44%. The preferred dose was .9 mg/kg in the IVT group and .6 mg/kg in the CMT group (Table 2). Two thirds of the EVT group used intra-arterial thrombolytics, and urokinase was a most commonly used lytic agent (median dose, 100,000 units; range, 10,000-400,000 units). Thrombectomy devices were used in 69% of the EVT group, and the most commonly used method was the microcatheter followed by the Solitaire. The recanalization rates by EVT were 76% for TICI grade $2a and 61% for TICI $2b. The proportion of favorable outcome and the 3-month mortality were comparable between patients treated with and without recanalization therapy (26% vs. 28% and 24% vs. 26%, respectively). After adjustment, there was no significant increase in favorable outcome but a significant decrease in 3-month mortality by recanalization therapy (Table 3). Compared with IVT, EVT and CMT significantly improved the 3-month functional outcome. However, increase of sICH and decrease of 3-month mortality by EVT and CMT were not statistically significant. Detailed results of multivariable analyses are presented in Tables S2 through S4 in Appendix. Baseline NIHSS was a significant determinant of 3-month favorable outcome and 3-month mortality in most models. Comparisons of baseline characteristics and clinical outcomes according to the method of EVT in the EVT group are shown in Table S5 in Appendix. In these comparisons, a final method used was chosen as representative. There was no notable difference in age, baseline NIHSS, and preceding IV tPA. Favorable outcome and successful recanalization (TICI grade $2a) were observed most frequently in those treated with stenting, and 3month mortality and sICH were observed most frequently in those treated with a thrombectomy device. Figure 2. Current status of recanalization therapy stratified according to baseline NIHSS and onset-to-arrival time. Black color: number of patients with acute symptomatic internal carotid artery occlusion. Blue color: number of patients receiving recanalization therapy. Brown color: number of patients receiving endovascular treatment. Abbreviations: NIHSS, National Institutes of Health Stroke Scale. (Color version of figure is available online.)
RECANALIZATION OF INTERNAL CAROTID OCCLUSION
Table 2. Methods of recanalization therapy IV thrombolysis, (n 5 136) IV tPA dose, .9 mg/kg IV thrombolysis alone Combined thrombolysis IV tPA dose, .6 mg/kg IV thrombolysis alone Combined thrombolysis Endovascular treatment (n 5 101)* IA lytics Urokinase ReoPro Tirofiban Others IA devices Microcatheter Penumbra Penumbra followed by Solitaire Solitaire Stenting
76/136 (55.9%) 58/70 (82.9%) 18/66 (27.3%) 60/136 (44.1%) 12/70 (17.1%) 48/66 (72.7%) 67/101 (66%) 58 (86.6%) 4 (6.0%) 17 (25.4%) 2 (2.0%) 97/101 (96%) 77 (76.2%) 6 (5.9%) 27 (26.7%) 37 (36.6%) 20 (19.8%)
Abbreviations: IA, intra-arterial; IV, intravenous; tPA, tissue plasminogen activator. *Duplication was allowed in intra-arterial lytics and devices.
2187
Discussion About 11% of patients with acute ischemic stroke or TIA presenting within 12 hours of onset had ICAO, and approximately half of them underwent recanalization therapy. Fifty-nine percent of those receiving recanalization therapy were eventually treated by endovascular methods. The proportion of symptomatic ICAO in this study was slightly higher than those in previous studies; 9.1% using carotid Doppler in a multicenter acute stroke trial conducted in North America1 and 8.8% in a multicenter clinical registry-based study in Germany.2 The time window for inclusion in these studies was within 24 hours of onset.1,2 The contribution of cardioembolism in the acute symptomatic ICAO seems to be much higher than that reported for all ischemic stroke patients in Korea (17%).16 This is the first study to describe the characteristics of patients treated with recanalization therapy in acute symptomatic ICAO. Indications for recanalization therapy were broader than expected with regard to age, stroke severity, and time window. The role of age and stroke severity in determining the use of recanalization
Table 3. Clinical outcomes according to thrombolytic modalities Clinical outcomes Favorable outcome (3-month mRS #2) No recanalization therapy Recanalization therapy IVT EVT IVT CMT sICH (SITS-MOST definition) IVT EVT IVT CMT 3-Month mortality No recanalization therapy Recanalization therapy IVT EVT IVT CMT
Rate of outcome
Adjusted OR
95% CI
P value
41/145 (28.1%) 42/165 (25.5%) 13/67 (19.4%) 29/98 (29.6%) 13/67 (19.4%) 17/64 (26.6%)
1* 1.77 1y 2.86 1z 2.65
.80-3.91 1.19-6.88 1.02-6.87
.16 .02 .05
2/70 (2.9%) 6/101 (5.9%) 2/70 (2.9%) 4/66 (6.1%)
1x 2.18 1x 2.12
.42-11.43 .35-12.97
.36 .42
38/146 (26.0%) 39/165 (23.6%) 19/67 (28.4%) 20/98 (20.4%) 19/67 (28.4%) 15/64 (23.4%)
1* .46 1y .53 1z .40
.24-.90 .23-1.18 .16-1.01
.02 .12 .05
Abbreviations: CI, confidence interval; CMT, combined thrombolysis; EVT, endovascular treatment (regardless of intravenous tPA); IVT, intravenous thrombolysis (alone); mRS, modified Rankin Scale; NIHSS, National Institutes of Health stroke scale; OR, odds ratio; sICH, symptomatic intracranial hemorrhage; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy; TOAST, Trial of ORG 10172 in Acute Stroke Treatment. *Adjusted for initial NIHSS, premorbid mRS #1, onset-to-arrival time, comorbid intracranial occlusion and history of stroke or transient ischemic attack, hypertension, and atrial fibrillation. yAdjusted for age, initial NIHSS, onset-to-arrival time, and history of diabetes mellitus. zAdjusted for initial NIHSS, onset-to-arrival time, and TOAST classification. xAdjusted for initial NIHSS and onset-to-arrival time.
J.-H. HONG ET AL.
2188 17
therapy is still being debated. Current consensus is based on the eligibility criteria of clinical trials: age #80 years, stroke severity $10 NIHSS points, and time limit ,6-8 hours of onset have been suggested.18-23 However, these factors do not reflect the fact that clinical outcomes and rates of recanalization differ according to occlusion sites.24,25 Crude mortality and proportions of favorable outcome were similar between patients treated with and without recanalization therapy (Table 3). With adjustments for potential confounders, a significant reduction of mortality and a trend, although not significant, toward functional independency at 3 months by recanalization therapy was observed. In addition, compared with IVT, EVT improved 3-month functional outcome without a significant increase in sICH and 3-month mortality. However, it should be noted that sICH developed twice as frequently in the EVT group compared with the IVT group (5.9% vs. 2.9%). Until now, recanalization therapy for ICAO presenting as acute ischemic stroke has been subjected to criticism because of lack of direct evidence.11 However, subgroup analysis of the Interventional Management of Stroke III trial and a recent systematic review, together with our results, suggest the superiority of EVT over IVT alone in this situation.10 Further solid evidence is required. Use of low-dose alteplase (.6 mg/kg) for IVT was unexpectedly frequent, especially in the CMT group. Its use might be based on recent Japanese studies26,27 and Interventional Management of Stroke I and II trials.18,19 The ENhanced Control of Hypertension ANd Thrombolysis in strokE Disease trial may solve the controversy related to tPA dose, but the aim of this trial is to compare 2 different doses of tPA in patients receiving IVT alone regardless of occlusion status.28 Patients with ICAO tend to have a larger thrombus burden than those with other intracranial occlusions.29 There is no study about IV tPA dose for acute symptomatic ICAO whether it is used alone or before EVT. Endovascular devices were used in 96% of the EVT group. Only 4% were treated with IA lytics alone. About 70% of the devices were either the Penumbra System or the Solitaire. Recent endovascular trials have been criticized for infrequent application of newly developed devices in the EVT arms.20,30 A pooled analysis on intracranial ICAO cases from the MERCI and Multi MERCI Part I trials showed that successful recanalization, 3-month favorable outcome (mRS # 2), 3-month mortality, and sICH were observed in 63%, 25%, 46%, and 10% of patients, respectively.8 In the present study, each outcome in patients treated by the thrombectomy device was 74%, 26%, 25%, and 10%, respectively (Table S5 in Appendix). Lower mortality and higher successful recanalization rate are quite notable, which might correspond with the success of the Solitaire With the Intention For Thrombectomy trial.31
Our study also suggests emergent carotid stenting as another treatment option for ICAO presenting as acute ischemic stroke. Although there is no consensus on acute carotid stenting, studies including ours showed relatively high successful recanalization and favorable outcome rates. A possible explanation might be because internal carotid artery occlusion have relevance to regional atherosclerotic plaque and acute stenting rather than other treatment modalities making flow restoration easier to improve immediately.32 Limitations of this study should be noted. Our study subjects came from selected university hospitals or regional stroke centers and were only Koreans and thus may not be representative of the general stroke population. The sample size might not be enough to detect clinically significant differences in the subgroup analysis according to thrombolytic modalities and final methods of EVT. In addition, the marked imbalance of clinical features among treatment groups and the heterogeneity in EVT methods and IV tPA doses further limit generalization of the study results. Current medical technology did not allow us to determine whether symptomatic ICAO was caused by acute or chronic occlusion of ICA too.
Supplementary Data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04. 025.
References 1. Adams HP Jr, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999;53:122-125. 2. Weimar C, Goertler M, Harms L, Diener HC. Distribution and outcome of symptomatic stenoses and occlusions in patients with acute cerebral ischemia. Arch Neurol 2006;63:1287-1291. 3. Meyer FB, Sundt TM Jr, Piepgras DG, Sandok BA, Forbes G. Emergency carotid endarterectomy for patients with acute carotid occlusion and profound neurological deficits. Ann Surg 1986;203:82-89. 4. Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010;41:2254-2258. 5. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78-86. 6. Meyers PM, Schumacher HC, Connolly ES Jr, Heyer EJ, Gray WA, Higashida RT. Current status of endovascular stroke treatment. Circulation 2011;123:2591-2601. 7. Machi P, Lobotesis K, Maldonado IL, Costalat V, Vendrell JF, Riquelme C, et al. Endovascular treatment of tandem occlusions of the anterior cerebral circulation
RECANALIZATION OF INTERNAL CAROTID OCCLUSION
8.
9.
10.
11.
12.
13.
14.
15. 16.
17. 18.
19. 20.
with solitaire FR thrombectomy system. Initial experience. Eur J Radiol 2012;81:3479-3484. Flint AC, Duckwiler GR, Budzik RF, Liebeskind DS, Smith WS. Mechanical thrombectomy of intracranial internal carotid occlusion: pooled results of the MERCI and Multi MERCI Part I trials. Stroke 2007;38: 1274-1280. Jovin TG, Gupta R, Uchino K, Jungreis CA, Wechsler LR, Hammer MD, et al. Emergent stenting of extracranial internal carotid artery occlusion in acute stroke has a high revascularization rate. Stroke 2005;36:2426-2430. Mokin M, Kass-Hout T, Kass-Hout O, Dumont TM, Kan P, Snyder KV, et al. Intravenous thrombolysis and endovascular therapy for acute ischemic stroke with internal carotid artery occlusion: a systematic review of clinical outcomes. Stroke 2012;43:2362-2368. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:870-947. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. Noser EA, Shaltoni HM, Hall CE, Alexandrov AV, Garami Z, Cacayorin ED, et al. Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute stroke? Stroke 2005;36:292-296. Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos A, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke 2008; 39:3316-3322. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159-174. Hong K-S, Bang OY, Kang D-W, Yu K-H, Bae H-J, Lee JS, et al. Stroke Statistics in Korea: Part I. Epidemiology and Risk Factors: a report from the Korean Stroke Society and Clinical Research Center for Stroke. J Stroke 2013;15:2. Balucani C, Grotta JC. Selecting stroke patients for intraarterial therapy. Neurology 2012;78:755-761. Investigators IMSS. Combined intravenous and intraarterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004; 35:904-911. The Interventional Management of Stroke (IMS) II Study. Stroke 2007;38:2127-2135. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intra-
2189
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
venous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282:2003-2011. Flint AC, Cullen SP, Faigeles BS, Rao VA. Predicting longterm outcome after endovascular stroke treatment: the totaled health risks in vascular events score. AJNR Am J Neuroradiol 2010;31:1192-1196. Hallevi H, Barreto AD, Liebeskind DS, Morales MM, Martin-Schild SB, Abraham AT, et al. Identifying patients at high risk for poor outcome after intra-arterial therapy for acute ischemic stroke. Stroke 2009;40:1780-1785. Linfante I, Llinas RH, Selim M, Chaves C, Kumar S, Parker RA, et al. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke 2002;33:2066-2071. Demchuk AM. IMS III: Comparison of outcomes between IV and IV/IA treatment in baseline CTA confirmed ICA, M1, M2 and basilar occlusions. International Stroke Conference 2013. 2013;Invited Symposium. Nakagawara J, Minematsu K, Okada Y, Tanahashi N, Nagahiro S, Mori E, et al. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-Marketing Alteplase Registration Study (J-MARS). Stroke 2010;41:1984-1989. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, 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. An international randomised controlled trial to establish the effects of low-dose rtPA and the effects of early intensive blood pressure lowering in patients with acute ischaemic stroke. Available at: http://clinicaltrials.gov/ ct2/show/NCT01422616. Accessed July 11, 2013. Barreto AD, Albright KC, Hallevi H, Grotta JC, Noser EA, Khaja AM, et al. Thrombus burden is associated with clinical outcome after intra-arterial therapy for acute ischemic stroke. Stroke 2008;39:3231-3235. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-913. Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012;380. Kappelhof M, Marquering HA, Berkhemer OA, Majoie CB. Intra-arterial treatment of patients with acute ischemic stroke and internal carotid artery occlusion: a literature review. J Neurointerv Surg 2014.
