1 Intravenous Thrombolysis and Endovascular Therapy for Acute Ischemic Stroke With Internal Carotid Artery Occlusion A Systematic Review of Clinical Outcomes Maxim Mokin, MD, PhD; Tareq Kass-Hout, MD; Omar Kass-Hout, MD, MPH; Travis M. Dumont, MD; Peter Kan, MD, MPH; Kenneth V. Snyder, MD, PhD; L. Nelson Hopkins, MD; Adnan H. Siddiqui, MD, PhD; Elad I. Levy, MD Background and Purpose Strokes secondary to acute internal carotid artery (ICA) occlusion are associated with extremely poor prognosis. The best treatment approach to acute stroke in this setting is unknown. We sought to determine clinical outcomes in patients with acute ischemic stroke attributable to ICA occlusion treated with intravenous (IV) systemic thrombolysis or intra-arterial endovascular therapy. Methods Using the PubMed database, we searched for studies that included patients with acute ischemic stroke attributable to ICA occlusion who received treatment with IV thrombolysis or intra-arterial endovascular interventions. Studies providing data on functional outcomes beyond 30 days and mortality and symptomatic intracerebral hemorrhage (sich) rates were included in our analysis. We compared the proportions of patients with favorable functional outcomes, sich, and mortality rates in the 2 treatment groups by calculating 2 and confidence intervals for odds ratios. Results We identified 28 studies with 385 patients in the IV thrombolysis group and 584 in the endovascular group. Rates of favorable outcomes and sich were significantly higher in the endovascular group than the IV thrombolysis-only group (33.6% vs 24.9%, P and 11.1% vs 4.9%, P 0.001, respectively). No significant difference in mortality rate was found between the groups (27.3% in the IV thrombolysis group vs 32.0% in the endovascular group; P 0.12). Conclusions According to our systematic review, endovascular treatment of acute ICA occlusion results in improved clinical outcomes. A higher rate of sich after endovascular treatment does not result in increased overall mortality rate. (Stroke. 2012;43: ) Key Words: acute stroke endovascular internal carotid artery thrombolysis tissue plasminogen activator Intravenous (IV) systemic thrombolysis with tissue plasminogen activator (tpa) is currently approved as the first-line treatment for acute ischemic stroke. 1 However, IV thrombolysis is less effective in achieving successful recanalization of large vessels, such as the proximal middle cerebral artery or the basilar artery. 2,3 Recanalization rates are especially low after IV thrombolysis in the setting of acute occlusion of the internal carotid artery (ICA). 4 6 In a recent study comparing the effect of IV tpa with placebo within the 3- to 6-hour therapeutic window, most patients with ICA occlusion did not achieve good clinical outcomes, whether treated with IV tpa or placebo. 7 Intra-arterial (IA) endovascular therapy in the setting of acute stroke shows higher recanalization rates when compared with IV thrombolysis alone. 2,8 A meta-analysis of studies including the IV or IA approach to acute treatment for stroke demonstrates a strong association between recanalization rates and improved functional outcomes. 8 Strokes secondary to acute ICA occlusion are associated with extremely poor prognosis. Patients usually present with high National Institutes of Health Stroke Scale scores because of profound neurological deficits and are at high risk for Received February 27, 2012; accepted June 7, From the Departments of Neurology (M.M., T.K.H., O.K.H., K.V.S.), Neurosurgery (T.M.D., P.K., K.V.S., L.N.H., A.H.S., E.I.L.), and Radiology (K.V.S., L.N.H., A.H.S., E.I.L.), and Toshiba Stroke Research Center (K.V.S., L.N.H., A.H.S., E.I.L.), School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY; Departments of Neurology (M.M., T.K.H., O.K.H.) and Neurosurgery (T.M.D., P.K., K.V.S., L.N.H., A.H.S., E.I.L.), Kaleida Health, Buffalo, NY. M.M. and T.K. conceived and designed the research. M.M. and T.K. are responsible for data acquisition. M.M., O.K., L.N.H. and E.I.L. are responsible for data analysis and interpretation. M.M. and O.K. performed statistical analysis. A.H.S., E.I.L., K.V.S. and L.N.H. handled funding and supervision. M.M., T.K., T.M.D., and P.K. drafted the manuscript. All authors made critical revisions of the manuscript for important intellectual content. All authors approved the final version of the manuscript. The online-only Data Supplement is available at Correspondence to Elad I. Levy, MD, FACS, FAHA, University at Buffalo Neurosurgery, State University of New York, 100 High Street, B4, Buffalo, NY American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA
2 Mokin et al ICA Occlusion in Acute Stroke 2363 Figure. Flow diagram showing screening and selection of studies for systematic analysis. disability or death. 9,10 No completed randomized trials exist to answer the question of whether an endovascular approach leads to improved clinical outcomes in patients with acute ICA occlusion when compared with treatment with IV thrombolysis alone. Clinical data to determine the best treatment approach in the setting of acute ICA occlusion are lacking. We performed a systematic analysis of published studies to determine clinical outcomes in patients with acute ischemic stroke attributable to occlusion of the ICA (any segment) treated with IV thrombolysis alone or endovascular IA therapy with or without previous IV thrombolysis. To our knowledge, this is the first systematic review of previously published literature that compares outcomes of IV vs IA approaches to acute stroke treatment in this population of patients. Materials and Methods Using the PubMed database and search terms of internal carotid artery, occlusion, stroke, intravenous, intra-arterial, and thrombolysis, we identified studies published between January 1, 1990 and November 30, 2011, that included patients with acute ischemic stroke attributable to ICA occlusion who had received treatment with IV thrombolysis or IA endovascular interventions. When studies also contained patients with sites of occlusion other than the ICA, we only counted cases of ICA occlusion. Only studies with 10 cases of stroke associated with ICA occlusion were included in our analysis to minimize the chance of anecdotal Table 1. outcomes. A description of the study selection process is shown in the Figure. Supplemental Table I lists studies that were excluded from final analysis after detailed review, along with specific reasons for exclusion. The ICA occlusion site had to be confirmed by at least 1 imaging modality, such as carotid Doppler, transcranial Doppler, computed tomographic angiography, magnetic resonance angiography, or conventional digital subtraction angiography. Studies in which ICA occlusion was suspected on the basis of clinical presentation alone were excluded. Each study had to report symptomatic intracerebral hemorrhage (sich) rates, functional neurological outcomes, and mortality rates beyond 30 days. Functional neurological outcomes were based on modified Rankin Scale score or Barthel Index; a favorable outcome was defined as modified Rankin Scale score of 2 or Barthel Index of 90 to 100, except for 1 study in which favorable outcome was defined as modified Rankin Scale 2 or National Institutes of Health Stroke Scale score Most studies reported modified Rankin Scale and Barthel Index at 90 days. If no 90-day follow-up data were available, then we utilized outcomes data limited to a 30-day to 12-month period. Studies that only reported clinical outcomes at discharge were excluded from analysis. Most studies reported the rate of sich separately from that of all ICH. When the authors did not specifically define if hemorrhages were symptomatic, we considered hemorrhages associated with any decline in neurological status as symptomatic. In studies that did not provide any clinical details but described radiographic type of hemorrhage, cases of parenchymal hematomas were classified as sich. Studies that did not contain any of this information for cases of ICH were excluded from analysis. Studies selected for analysis were divided into 2 groups. The IV thrombolysis group included pooled data from studies that used systemic thrombolysis only for treatment of ICA occlusion (Table 1). The endovascular group consisted of pooled data from studies including patients in whom endovascular treatment was performed alone or after systemic thrombolysis failed (Table 2). In addition, for studies, when available, we noted descriptions of demographic data and treatment (Supplemental Tables II, III, and recanalization rates (Table 2). If specific ICA occlusion segments (cervical ICA, T-occlusion, or tandem occlusion) were identified by the authors and reported together with corresponding clinical data, then we also performed specific subgroup analyses by pooling appropriate studies together. Studies that reported clinical outcomes and sich rates in those subgroups of patients are shown in Supplemental Tables IV, V). SAS software version 9.2 (SAS Institute, Cary, NC) was used for statistical analysis. The 2 test was used to calculate the statistical significance of outcomes between the IV thrombolysis and endovascular groups. P 0.05 was considered significant. The logistic Studies of Intravenous Thrombolysis in Acute Ischemic Stroke With Internal Carotid Artery Occlusion Study Treatment Description Patients, n Favorable Outcome, n (%) Definition of Favorable Outcome Mortality, n (%) sich, n (%) Paciaroni IV tpa within 4.5 h (29) mrs 0 2 at 3 mo 65 (26) 12 (5)* Kimura IV tpa within 3 h 21 2 (10) mrs 0 2 at 3 mo 5 (24) 0 (0) Saqqur IV tpa within 3 h 25 5 (20) mrs 0 2 at 3 mo 7 (28) 3 (12) Rubiera IV tpa within 3 h 44 8 (18) mrs 0 2 at 3 mo 12 (27) 0 (0) Wunderlich IV tpa within 3 h (n 12) and 15 3 (20) mrs 0 2 at 3 mo 3 (20) 4 (27)* 6h(n 3) Rudolf IV tpa within 3 h 15 5 (33) mrs 0 2 at 3 mo 4 (27) 0 (0) Endo IV urokinase or tpa within 6 h 12 0 (0) mrs 0 2 at 1 mo 9 (75) 0 (0) Total (25) 105 (27) 19 (5) IV indicates intravenous; mrs, modified Rankin Scale; sich, symptomatic intracerebral hemorrhage; tpa, tissue plasminogen activator. *Cases of parenchymal hematomas are classified as sich.
3 2364 Stroke September 2012 Table 2. Studies of Intra-Arterial Endovascular Therapy in Acute Ischemic Stroke With Internal Carotid Artery Occlusion Study Treatment Description Patients, n Favorable Outcome, n (%) Definition of Favorable Outcome Mortality, n (%) sich, n (%) Successful Recanalization, Definition Successful Recanalization, n (%) Mechanical thrombectomy 14 6 (43) mrs 0 2 or NIHSS Costalat 2 (14) 0 (0) TICI 3 10 (71) at3mo Fesl IA tpa, mechanical thrombectomy, 14 3 (21) mrs 0 2 at 3 mo 6 (43) 7 (50)* TIMI 2/3 11 (79) aspiration thrombectomy, stenting Hauck IA tpa, mechanical thrombectomy, (50) mrs 0 2 at 3 mo 7 (32) 0 (0) TIMI 2/3 15 (68) stenting Malik IA tpa or urokinase, angioplasty, stenting, mechanical thrombectomy, aspiration thrombectomy (42) mrs 0 2 at 3 mo 19 (25) 8 (10)* TIMI 2/3 58 (75) IA urokinase, angioplasty, stenting, Miteff 11 6 (55) mrs 0 2 at 3 mo 1 (9) 1 (9) TIMI 2/3 10 (91) mechanical thrombectomy Watanabe IA urokinase, angioplasty 10 1 (10) mrs 0 2 at 3 mo 4 (40) 2 (20) TICI 2/3 5 (50) Shi IA tpa, mechanical thrombectomy (28) mrs 0 2 at 3 mo 47 (47) 11 (11) TIMI 2/3 62 (63) Lin IA tpa or urokinase, angioplasty, stenting, mechanical thrombectomy (23) mrs 0 2 at 3 mo 28 (37) 8 (11) TIMI 2/3 35 (47) Yoo IA urokinase, angioplasty, stenting, mechanical thrombectomy 16 2 (13) mrs 0 2 at 3 mo 5 (31) 1 (6)* Mori score 2 4 Kim IA urokinase 10 5 (50) mrs 0 2 at 3 mo 0 (0) 1 (10) TIMI 2/3 6 (60) Arnold IA urokinase (23) mrs 0 2 at 3 mo 16 (37) 4 (9) TIMI 2/3 25 (58) Dabitz IA tpa, angioplasty, stenting 10 7 (70) mrs 0 2 at 9 wk 1 (10) 4 (40)* TIMI 2/3 7 (70) Suh IA fibrinolytic thrombolysis, angioplasty, (33) mrs 0 2 at 1 y 6 (18) 9 (27)* NR NR stenting, mechanical thrombectomy Imai IA urokinase, angioplasty, mechanical thrombectomy, aspiration thrombectomy 14 6 (43) mrs 0 2 at 3 mo 2 (14) 0 (0) TIMI 2/3 7 (50) Jovin Angioplasty, stenting 15 6 (40) mrs 0 2 at 1 mo 3 (20) 0 (0) NR NR Nedeltchev IA urokinase, aspiration thrombectomy, (56) mrs 0 2 at 3 mo 5 (20) 2 (8) TIMI 2/3 11 (44) stenting Sorimachi IA urokinase, mechanical 11 4 (36) mrs 0 2 at 3 mo 1 (9) 0 (0) NR NR thrombectomy Arnold IA urokinase, angioplasty, stenting 24 4 (17) mrs 0 2 at 3 mo 10 (42) 1 (4) TIMI 2/3 15 (63) Zaidat IA tpa or urokinase, mechanical 18 6 (33) mrs 0 2 at 3 mo 9 (50) 3 (17) NR NR thrombectomy Ernst IA tpa 10 8 (80) mrs 0 2 after 2 mo 1 (10) 1 (10) TIMI 2/3 7 (70) Endo IA tpa or urokinase, angioplasty 21 5 (24) mrs 0 2 at 1 mo 10 (48) 1 (5) Successful 8 (38) Urbach IA urokinase 12 4 (33) BI at 3 mo 4 (33) 1 (8)* Moderate and complete 5 (42) Total (34) 187 (32) 65 (11) BI indicates Barthel Index; IA, intraarterial; IV, intravenous; mrs, modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported; sich, symptomatic intracerebral hemorrhage; TICI, Thrombolysis in Cerebral Infarction; TIMI, Thrombolysis in Myocardial Infarction; tpa, tissue plasminogen activator. *cases with parenchymal hematomas were classified as sich. 9 (56) function was used to calculate 95% confidence intervals for odds ratios. Results We identified 28 articles comprising a total of 969 patients with ICA occlusion acute ischemic strokes that met our inclusion criteria. There were 385 patients in the IV thrombolysis group and 584 patients in the endovascular group. 11,12,19 38 Studies used for analysis for each group, including methodological and baseline characteristics of the included studies, as well as treatment outcomes, are listed in Table 1 and Supplemental Table II for the IV thrombolysis
4 Mokin et al ICA Occlusion in Acute Stroke 2365 Table 3. Overall Outcomes From Systemic Intravenous Thrombolysis vs Endovascular Intra-Arterial Treatment Outcomes IV Thrombolysis Group (n 385) Endovascular Group (n 584) P OR (95% CI) Favorable outcome, n(%) 96 (24.9%) 196 (33.6%) ( ) sich, n(%) 19 (4.9%) 65 (11.1%) ( ) Mortality, n(%) 105 (27.3%) 187 (32.0%) ( ) CI indicates confidence interval; IV, intravenous; OR, odds ratio; sich, symptomatic intracerebral hemorrhage. group and in Table 2 and Supplemental Table III for the endovascular group. In the IV thrombolysis group, all studies used tpa for the treatment protocol, except for 1 study conducted by Endo et al 12 that also included patients treated with IV urokinase. In the endovascular group, 12 studies had treatment protocols that included a combined IV thrombolysis and IA endovascular approach, and 10 studies contained patients treated with an IA endovascular approach alone. A comparison of overall outcomes from both groups is shown in Table 3. Favorable outcomes were significantly more frequent in patients who underwent endovascular treatment than in patients treated with IV thrombolysis alone (33.6% vs 24.9%; P 0.004). The rate of sich was significantly higher in the endovascular group when compared to the IV thrombolysis group (11.1% vs 4.9%; P 0.001). However, the mortality rate was not significantly different between the 2 groups (27.3% in the IV thrombolysis group vs 32.0% in the endovascular group; P 0.12). Subgroup analysis of outcomes in patients with cervical ICA occlusion (Table 4) showed a significantly higher rate of favorable outcomes (43.5% vs 26.3%; P ) and sich (11.4% vs 3.9%; P ), but not mortality (26.4% vs 27.2%; P 0.85), in the endovascular group when compared with the IV thrombolysis group. In patients with ICA terminus occlusion (Table 5), the rates of favorable outcome (28.5% vs 19.2%; P 0.34), sich (9.9% vs 23.1%; P 0.082), and mortality (29.8% vs 30.8%; P 0.91) were not significant between the endovascular group and the IV thrombolysis group. Discussion Pooled data from all of the studies included in our analysis suggest that an endovascular approach to stroke caused by acute ICA occlusion results in higher rates of favorable outcomes than treatment with systemic thrombolysis alone. A meta-analysis of trials of thrombolytic and mechanical recanalization therapies in acute stroke has demonstrated high recanalization rates and strong correlation with improved outcomes and reduced mortality from endovascular treatment. 8 Nevertheless, the endovascular approach to acute stroke management has been criticized for lack of direct evidence for clinical efficacy, bias of the neurointerventional community toward procedures and devices, and substantially higher costs associated with endovascular treatment when compared with IV tpa Failure of intracranial stenting to demonstrate efficacy in secondary stroke prevention over medical therapy alone was recently demonstrated in a randomized trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis 42 ), adding more skepticism to the future of endovascular treatment in acute stroke. Therefore, we focused our analysis on clinical outcomes, ie, modified Rankin Scale or Barthel Index at 3 months, instead of recanalization rates, when designing this systematic review. Our analysis demonstrates that the risk of sich is significantly higher in patients who are treated with an endovascular approach. Several factors may be responsible for the increased rate of hemorrhagic complications from IA interventions. IV thrombolysis with tpa is currently approved only within the first 4.5 hours of stroke onset (except for high-risk patients in whom treatment is recommended within 3 hours). 1 Patients who are treated with endovascular techniques often receive treatment beyond this time window because of late presentation to the hospital. Although we were not able to calculate median times from stroke onset to treatment between the 2 groups because of lack of data, 12 of 22 studies in the endovascular group included treatment protocols in which endovascular revascularization was attempted after IV thrombolysis failure. In patients undergoing a combined IV and IA approach, endovascular treatment is usually started after IV infusion of the thrombolytic agent is complete with no evidence of clinical improvement. Pooled analyses of major IV thrombolysis trials indicate no significant relationship between timing of treatment and risk of ICH within the first 6 hours. 43,44 However, when IV thrombolysis was administered beyond 6 hours, higher rates of hemorrhage were observed. 4 Because data on clinical stroke severity or presence of early computed tomography changes were not available for all studies included in our analysis, we were unable to determine whether these factors could also explain higher rates of sich in the endovascular group. Table 4. Outcomes From Systemic Intravenous Thrombolysis vs Endovascular Intra-Arterial Treatment in Patients With Cervical Internal Carotid Artery Occlusion Outcomes IV Thrombolysis Group (n 338) Endovascular Group (n 193) P OR (95% CI) Favorable outcome, n (%) 89 (26.3%) 84 (43.5%) ( ) sich, n (%) 13 (3.9%) 22 (11.4%) ( ) Mortality, n (%) 92 (27.2%) 51 (26.4%) ( ) CI indicates confidence interval; IV, intravenous; OR, odds ratio; sich, symptomatic intracerebral hemorrhage.
5 2366 Stroke September 2012 Table 5. Outcomes From Systemic Intravenous Thrombolysis vs Endovascular Intra-Arterial Treatment in Patients With Internal Carotid Artery Terminus Occlusion Outcomes IV Thrombolysis Group (n 26) Endovascular Group (n 151) P OR (95% CI) Favorable outcome, n(%) 5 (19.2%) 43 (28.5%) ( ) sich, n(%) 6 (23.1%) 15 (9.9%) ( ) Mortality, n(%) 8 (30.8%) 45 (29.8%) ( ) CI indicates confidence interval; IV, intravenous; OR, odds ratio, sich, symptomatic intracerebral hemorrhage. It previously has been argued that the presence of ICH is not directly responsible for clinical deterioration or death. 45 In our study, although the rate of sich was significantly higher after an endovascular approach, it did not result in increased overall mortality. When considered together with our finding of a higher rate of favorable functional outcomes, it suggests that an endovascular approach in treating strokes with ICA occlusion results in overall better clinical outcomes, when compared to systemic thrombolysis alone. This conclusion can be criticized because it is not supported by evidence from randomized trials. Besides, the rate of sich can be influenced by the clinical definition applied by the investigators (eg, National Institute of Neurological Disorders and Stroke 46 vs European-Australasian Acute Stroke Study 47 classification). Some studies included in our analysis 14,18,21,23,29,34,35,37 did not specifically report the rate of clinical sich but rather only the rate of radiographic parenchymal hematomas, which we classified as sich. Also, because of high variability in clinical data reporting in studies included in our analysis, we were not able to determine whether outcome results were compared among patients with similar baseline characteristics, such as admission National Institutes of Health Stroke Scale scores. Five of 7 studies from the IV thrombolysis group followed the current American Heart Association recommended acute stroke management protocol. 1 Only 2 small studies (total of 27 patents) 12,15 had IV thrombolysis protocol administered outside the currently recommended treatment window (treatment was administered within 0 6 hours of stroke onset). Because most patients in the IV thrombolysis group received treatment according to current guidelines (358 of 385 patients), this group is an accurate representation of present outcomes of systemic thrombolysis for ICA occlusion. The study by Paciaroni et al 14 had more patients treated with IV thrombolysis alone than the other 6 articles combined, which could significantly influence clinical outcomes for the entire IV thrombolysis group. The articles included in our systematic review varied in design and contained both prospective and retrospective studies. Some of those were single-center studies, whereas others were conducted at multiple centers from several countries. Centers differ in their treatment protocols and interpretation and reporting of results, which should be considered when interpreting the results of our systematic analysis. Another limitation is that we included studies in which ICA occlusion was detected with different imaging modalities. Although in all IA studies catheter angiography was performed to confirm and identify the precise location and extent of ICA occlusion, in IV thrombolysis studies/study arms, predominantly noninvasive tests were obtained. Computed tomography and magnetic resonance angiography and especially Doppler ultrasound techniques differ in the ability to detect large vessel occlusion. Studies suggest that both carotid and transcranial Doppler tests are accurate in detecting carotid artery occlusion; however, in patients with tandem intracranial occlusions, transcranial Doppler can lead to false-positive results. 48,49 Because some studies from the IV tpa group 14,15 were designed to include only patients with cervical ICA occlusion, this could explain an overall small number of patients with carotid terminus occlusion in the IV tpa group of our systematic review. Thus, a high hemorrhage rate in the IV tpa patients with carotid terminus occlusion (23%), as well as other clinical outcomes, did not reach statistical significance and should be interpreted with caution given the small numbers. Conclusion Our findings suggest that endovascular treatment of stroke attributable to ICA occlusion might lead to improved functional outcomes by comparison with systemic thrombolysis alone. Multimodal endovascular therapy might represent an effective treatment strategy for patients with ICA occlusion. Acknowledgments The authors thank Paul H. Dressel, BFA, for help with preparation of the Figure, and Debra J. Zimmer, CMA-A, AAS, for editorial assistance. Disclosures Dr Hopkins received grant/research support from St Jude Medical and Toshiba; is a consultant for Abbott, Boston Scientific, Cordis, Micrus, and W. L. Gore; has financial interest in AccessClosure, Augmenix, Boston Scientific, Claret Medical, Micrus, Valor Medical; holds a board/trustee/officer position at AccessClosure, Claret Medical; is on the Abbott Vascular speakers bureau; and received honoraria from Boston Scientific, Cleveland Clinic, Complete Conference Management, Cordis, Memorial Healthcare System, SCAI, University of Southern California, and VIVA Physicians. Dr Tareq Kass-Hout received research funding from Genentech Medical Educational and Research Department. E.I.L. received research grant support/other research support (devices) and honoraria from Boston Scientific; research support from Codman & Shurtleff and ev3/covidien; has ownership interests in Intratech Medical and Mynx/Access Closure; is a consultant for Codman & Shurtleff, ev3/covidien, and TheraSyn Sensors; and received fees for carotid stent training from Abbott Vascular and ev3/covidien. Dr Siddiqui received research grants from National Institutes of Health (not related to present study) and University at Buffalo; has financial interests in Hotspur, Intratech Medical, StimSox, and Valor Medical; is a consultant for Codman & Shurtleff, Concentric Medical, ev3/covidien, GuidePoint Global Consulting, and Penumbra; is on the speakers bureaus of Codman & Shurtleff and Genentech; is on the advisory board of Codman & Shurtleff; and received honoraria from Annual Peripheral Angioplasty and All That Jazz and American Association of Neuro-
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