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Large-Vessel Occlusion Is Associated with Poor Outcome in Stroke Patients Aged 80 Years or Older Who Underwent Intravenous Thrombolysis
ARTICLE IN PRESS
Large-Vessel Occlusion Is Associated with Poor Outcome in Stroke Patients Aged 80 Years or Older Who Underwent Intravenous Thrombolysis Wusheng Zhu, MD, PhD,*† Lulu Xiao, MD,* Monica Lin, Xinfeng Liu, MD, PhD,* and Bernard Yan, FRACP†
BSc,†
Objective: We aimed to investigate the association between large-vessel occlusion (LVO) and functional outcome in elderly stroke patients treated with intravenous (IV) tissue plasminogen activator (tPA). Methods: This was a retrospective study of acute ischemic stroke patients who received IV tPA within 4.5 hours after stroke onset between 2007 and 2013. Patients were categorized into 2 groups based on age (≥80 or < 80 years). LVO was evaluated by computed tomography angiography (CTA) before thrombolysis. Favorable outcome was defined as a modified Rankin Scale (mRS) score of 2 or lower at 3 months, or equal to the prestroke mRS score. Results: Of 359 thrombolysis patients, 175 patients with CTA before a standard dose of IV tPA therapy (0.9 mg/kg body weight; maximum 90 mg) were included. Sixty-five patients were in the group aged 80 years or above with a median age of 84 (interquartile range: 82.5, 86) years. LVO was observed more often in the group with unfavorable outcome compared with the group with favorable outcome in older stroke patients (60.6% versus 21.9%, P = .002). The baseline National Institutes of Health Stroke Scale (NIHSS) score (odds ratio .864; 95% confidence interval [CI], .779-.959; P = .006) and LVO (odds ratio .233; 95% CI, .059.930; P = .039) were independent associative factors for the unfavorable outcome in older patients treated with IV tPA after adjustment for patient characteristics. Conclusions: The baseline NIHSS score and LVO were independent predictors for functional outcome in elderly stroke patients received IV tPA. Key Words: Stroke—elderly—intravenous thrombolysis—CT angiography—modified Rankin scale. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, China; and †Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. Received April 18, 2016; revision received June 14, 2016; accepted July 10, 2016. Sources of funding: This study was supported by projects of the National Natural Science Foundation of China (NSFC 81220108008). Author contributions: Drs. Zhu and Yan participated in the conception and design of the study, acquisition of raw data, analysis of data, drafting of the article, and revision of the manuscript. Ms. Lin participated in the acquisition of raw data. Dr. Xiao and Liu participated in the conception and design of the study. Drs. Zhu and Dr Xiao contributed equally to this work. Address correspondence to Bernard Yan, FRACP, Melbourne Brain Centre at the Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.07.021
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■
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ARTICLE IN PRESS W. ZHU ET AL.
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Introduction A recent meta-analysis of individual patient data from randomized trials showed that alteplase significantly improves the overall good outcome when stroke patients received alteplase within 4.5 hours of stroke onset.1 Elderly patients have been accounted for 30% of all acute ischemic stroke patients.2 However, there is no consensus regarding thrombolysis for stroke patients over 80 years.3 Although some large-scale randomized controlled clinical trials exclude acute stroke patients aged 80 years or older from intravenous (IV) thrombolysis for its under-representation,4,5 there has been an increase in the proportion of elderly patients who underwent IV thrombolysis in recent years.6-9 Moreover, it is becoming clear that a proportion of stroke patients aged 80 years or older derive significant benefit from IV thrombolysis,9-12 even in patients aged 90 years or older.7,9,10 It is critical to clarify outcome predictors for this group of patients. The baseline National Institutes of Health Stroke Scale (NIHSS) score has been validated as the predictor of mortality and unfavorable outcome in stroke patients aged 80 years or older who underwent thrombolysis,13 but vascular imaging predictors remain uncertain. Large-vessel occlusion (LVO) is a predictor of poor outcome in acute ischemic stroke.14 Computed tomography angiography (CTA) is an accurate tool for the assessment of LVO; however, CTA may be more risky in patients aged 80 years or older because of higher prevalence of renal failure. Therefore, it is important to establish the utility of CTA prior to recommending its routine use in 80-year-old patients. The aim of the present study was to investigate the association between LVO and outcome in acute ischemic stroke patients aged 80 years or older who underwent IV tissue plasminogen activator (tPA) therapy, to test the hypothesis that LVO is associated with poor outcomes in these patients.
Methods Patients We analyzed the medical records of 359 acute ischemic stroke patients admitted to the Royal Melbourne Hospital who were treated with IV tPA within 4.5 hours of stroke onset, between December 2007 and February 2013.15 Eligibility criteria included patients with computed tomography (CT)-confirmed acute ischemic stroke who were administered .9 mg/kg of IV tPA within 4.5 hours of onset of symptoms. The following characteristics were included: age, sex, prestroke modified Rankin Scale (mRS) score, onset-to-treatment time, vascular risk factors (hypertension, diabetes, hypercholesterolemia, atrial fibrillation, smoking, ischemic heart disease, and previous stroke), baseline NIHSS score, CTA before IV tPA, CT or magnetic resonance imaging after IV tPA, and
3-month mRS score. The patients were divided into 2 groups by age: older group (aged ≥80 years) and younger group (aged <80 years). Patients diagnosed with stroke mimics,16 or patients who received IV tPA plus intraarterial (IA) therapy were excluded from our study.
Imaging CTA was routinely performed in acute ischemic stroke patients before thrombolysis at the Royal Melbourne Hospital from December 2007, unless contraindicated (e.g., known contrast allergy or renal impairment). LVO was identified as proximal vessel occlusion as follows14: internal carotid artery, middle cerebral artery (M1 and M2 segments), anterior cerebral artery (A1 segment), V4 segment of vertebral artery, basilar artery, and posterior cerebral artery (P1 segment). CT or magnetic resonance imaging scans were performed approximately within 24 hours of IV tPA to identify the hemorrhagic transformation and the extent of infarction. Symptomatic intracerebral hemorrhage was defined as blood at any site in the brain associated with a worsening of the NIHSS score by 4 points or higher within 24 hours.4 The presence of LVO was assessed on CTA image by 2 independent experienced stroke neurologists (W.Z. and B.Y.). The symptoms of the acute ischemic stroke patients were consistent with LVO.
Outcome The primary outcome was the 3-month mRS score. Favorable outcome was defined as an mRS score of 2 or lower at 3 months, or equal to the prestroke mRS score.6,17 Secondary outcomes were symptomatic intracerebral hemorrhage after IV tPA and mortality at 3 months post stroke.
Statistical Analysis Statistical analysis was performed using the SPSS (version 19; SPSS Inc., Chicago, IL). Between-group differences were made using the Student t-test or the Mann–Whitney U-test for continuous variables, chi-square test, or the Fisher exact test for categorical variables. Logistic regression was used to test predictors of unfavorable outcome in elderly stroke patients (aged ≥80 years) who received IV tPA. The model was adjusted for patient characteristics (diabetes, hypertension, smoking, atrial fibrillation, prior stroke history, hypercholesterolemia, LVO, and NIHSS score on admission). All statistical tests were 2-sided, and P values less than .05 were considered to be statistically significant.
Results Baseline Characteristics In our tPA database, 243 acute ischemic stroke patients who underwent CTA before IV tPA therapy were screened (243 of 359 thrombolysis patients, 67.7%).
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Sixty-eight patients were excluded from the study: 40 patients underwent bridging therapy (IV tPA plus IA), 17 patients were lost to follow-up, 6 patients did not have baseline NIHSS scores, and 5 patients were stroke mimics. We finally included 175 patients who had the following characteristics: 104 male patients (59.4%), 126 patients with pre-mRS score of 0, 3 patients with a pre-mRS score of 1, 13 patients with a pre-mRS score of 2, 19 patients with pre-mRS score of 3, and 14 patients with pre-mRS score of 4. The median age was 74 years (interquartile range [IQR]: 64-83), and the median baseline NIHSS score was 9 (IQR: 5-16).
Comparison of Baseline Characteristics and Outcome between Older and Younger Patients Of the 175 patients, 65 (37.1%) were 80 years old or older with a median age of 84 years (IQR: 82.5-86.0). Of the 65 patients, 32 (49.2%) were male and the mean baseline NIHSS score was 11 (IQR: 5-17). As for younger patients (aged <80 years), the mean age was 68 (IQR: 5873) years and the median baseline NIHSS score was 8 (IQR: 5-14). Older stroke patients were more likely to have arterial hypertension (75.4% versus 59.1%, P = .029), history of atrial fibrillation (41.5% versus 25.5%, P = .027),
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previous stroke history (18.5% versus 9.1%, P = .071), high prestroke mRS score (P < .001), and high mortality rate (23.1% versus 8.2%, P = .006). The patients were less likely to be a male (49.2% versus 65.5%, P = .035) or current smokers (9.2% versus 28.2%, P = .003) or have favorable outcome. There was no difference in the prevalence of LVO between older and younger patients (41.5% versus 39.1%, P = .749). A comparison of baseline characteristic and outcome between older and younger groups is shown in Table 1.
Factors Associated with Functional Outcome in Older Patients The factors associated with functional outcome in older stroke patients treated with IV tPA are given in Table 2. High baseline NIHSS score (14.9 ± 6.9 versus 8.7 ± 6.0, P<.001) and LVO (60.6% versus 21.9%, P = .002) occurred more frequently in the unfavorable outcome group than in the favorable outcome group. After adjustment for patient characteristics, logistic regression showed that baseline NIHSS score (odds ratio .864; 95% confidence interval, .779-.959; P = .006) and LVO (odds ratio .233; 95% confidence interval, .059-.930; P = .039) remained the significant predictors for unfavorable outcome in older patients treated with tPA (Table 3).
Table 1. Baseline characteristics and outcome of older (age ≥ 80) and younger (age < 80) stroke patients who underwent thrombolysis
Characteristics
Age 80 years or older (n = 65)
Age younger than 80 (n = 110)
Male, n (%) Age (years), median (IQR) Prestroke mRS score of 0-2, n (%) Onset to treat time (min), mean (SD) Baseline NIHSS score, median (IQR) Hypertension, n (%) Diabetes, n (%) Hypercholesterolemia, n (%) Atrial fibrillation, n (%) Previous stroke history, n (%) Current smoker, n (%) Ischemic heart disease, n (%) Peripheral vascular disease, n (%) Large-vessel occlusion, n (%) Internal carotid artery, n (%) Middle cerebral artery, n (%) Posterior cerebral artery, n (%) Favorable outcome, n (%) Symptomatic ICH, n (%) Mortality, n (%)
32 (49.2) 84 (82.5-86.0) 44 (67.7) 159.8 ± 50.1 11 (5-17) 49 (75.4) 11 (16.9) 37 (56.9) 27 (41.5) 12 (18.5) 6 (9.2) 18 (27.7) 1 (1.5) 27 (41.5) 7 (10.8) 18 (27.7) 2 (3.1) 32 (49.2) 4 (6.2) 15 (23.1)
72 (65.5) 68 (58-73) 98 (89.1) 160.1 ± 58.4 8 (5-14) 65 (59.1) 31 (28.2) 53 (48.2) 28 (25.5) 10 (9.1) 31 (28.2) 22 (20.0) 6 (5.5) 43 (39.1) 10 (9.1) 32 (29.1) 1 (.9) 77 (70) 3 (2.7) 9 (8.2)
P value .035* <.001* <.001* .967 .194 .029* .092 .264 .027* .071 .003* .242 .261 .749
.006* .426 .006*
Abbreviations: ICH, intracranial hemorrhage; IQR, interquartile range; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. *P < .05.
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Table 2. Factors associated with 3-month functional outcome in older (age ≥ 80) stroke patients received IV tPA
Factors
Favorable outcome (n = 32)
Unfavorable outcome (n = 33)
Male, n (%) Onset to treat time (min), mean (SD) Baseline NIHSS score, mean (SD) Hypertension, n (%) Diabetes, n (%) Hypercholesterolemia, n (%) Atrial fibrillation, n (%) Previous stroke history, n (%) Smoking, n (%) Ischemic heart disease, n (%) Large-artery occlusion, n (%) Internal carotid artery, n (%) Middle cerebral artery, n (%) Posterior cerebral artery, n (%) Symptomatic ICH, n (%) ICH, n (%)
16 (50.0) 158.8 ± 52.3 8.7 ± 6.0 25 (78.1) 5 (15.6) 20 (62.5) 13 (40.6) 5(15.6) 3 (9.4) 8 (25.0) 7 (21.9) 1 (3.1) 6 (18.8) 0 (0) 0 (0) 3 (9.4%)
16 (48.5) 160.8 ± 48.6 14.9 ± 6.9 24 (72.7) 6 (18.2) 17 (51.5) 14 (42.4) 7 (21.2) 3 (9.1) 10 (30.3) 20 (60.6) 6 (18.2) 12 (36.4) 2 (6.1) 4 (12.1) 9 (27.2%)
P value .903 .869 <.001* .614 .783 .371 .883 .562 1.000 .633 .002*
.114 .063
Abbreviations: ICH, intracranial hemorrhage; IQR, interquartile range; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. *P < .05.
Table 3. Multivariate analysis for favorable outcomes at 3 months in older (age ≥ 80) stroke patients treated with IV tPA Favorable outcome Factors
OR
95% CI
P value
Large-vessel occlusion Baseline NIHSS score
.233 .864
.059-.930 .779-.959
.039* .006*
Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio. *P < .05.
Discussion The major result of our study demonstrated that LVO was significantly related to unfavorable outcome in elderly stroke patients aged ≥80 years who received IV tPA. Age has been shown to be associated with unfavorable collateral circulation.18,19 Based on our results, we suggest that elderly stroke patients with LVO be selected to undergo IA therapy. Compared with elderly stroke patients receiving IV tPA alone, the risk of in-hospital mortality for patients undergoing IA therapy plus IV tPA has not increased.20 IA therapy has been shown to have an equal recanalization rate and hemorrhage rate between elderly patients and younger patients.21 Elderly stroke patients may achieve favorable outcomes after recanalization by endovascular treatment.22,23 However, the study of Chandra et al showed that elderly patients had poor clinical outcome and higher mortality at 90 days, compared with nonelderly
patients after IA therapy.24,25 A meta-analysis showed that elderly patients had higher rates of mortality and intracerebral hemorrhage at 3 months than younger patients after IA therapy.24,25 Results of the meta-analysis have shown that ASPECTS and NIHSS scores were independent predictors of favorable outcome in elderly patients for anterior circulation LVO after mechanical thrombectomy.26 The risks and benefits of IA therapy needed to be assessed before performance of the treatment.25 The baseline NIHSS score was the important independent predictor of unfavorable outcome in elderly stroke patients treated with tPA in our study, which was consistent with previous findings.13 Besides, the mortality rate at 3 months was higher in older patients than in younger patients in our study, which is now well acknowledged. Each patient underwent emergency CTA before IV tPA therapy in our study. CTA is an accurate and safe tool for evaluating intracranial vessel stenosis or occlusion.27,28 CTA detects LVO with 100% sensitivity and specificity compared to digital subtraction angiography.29 In our study, CTA was routinely performed in stroke patients before thrombolysis, unless contraindicated (e.g., known contrast allergy or renal impairment). Results have shown that the safety of elderly patients who underwent CTA may be acceptable if the patients were selected. Several limitations of our study have to be addressed. First, our study was a relatively small singlecenter cohort study and longitudinal studies are required to confirm our findings. Second, 40 patients who received bridging therapy (IV tPA plus IA) were excluded in our study. The exclusion of these patients introduced select bias in the proportion of LVO in our study. Third,
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despite careful adjustment for confounding factors, unreported confounders could have biased the conclusion of our study. However, a randomized controlled trial with adequate power to avoid unmeasured confounding is extremely difficult to organize.
Conclusions LVO and baseline NIHSS score are the independent predictors of outcome in elderly stroke patients who underwent IV tPA therapy.
References 1. Baigent C, Blackwell L, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929-1935. 2. Derex L, Nighoghossian N. Thrombolysis, stroke-unit admission and early rehabilitation in elderly patients. Nat Rev Neurol 2009;5:506-511. 3. European Stroke Organisation (ESO) Executive Committee. ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507. 4. Hacke W, Kaste M, Fieschi C, et al. Randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-1251. 5. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329. 6. Boulouis G, Dumont F, Cordonnier C, et al. Intravenous thrombolysis for acute cerebral ischaemia in old stroke patients ≥ 80 years of age. J Neurol 2012;259:1461-1467. 7. Balestrino M, Carlino V, Bruno C, et al. Safe and effective outcome of intravenous thrombolysis for acute ischemic stroke in patients aged 90 years or older. Eur Neurol 2013;70:84-87. 8. Singer OC, Hamann GF, Misselwitz B, et al. Time trends in systemic thrombolysis in a large hospital-based stroke registry. Cerebrovasc Dis 2012;33:316-321. 9. Kono S, Deguchi K, Morimoto N, et al. Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. J Stroke Cerebrovasc Dis 2013;22:1175-1183. 10. De Keyser J, Gdovinova Z, Uyttenboogaart M, et al. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007;38:26122618. 11. IST-3 Collaborative Group, Sandercock P, Wardlaw JM, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352-2363. 12. Matsuo R, Kamouchi M, Fukuda H, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for ischemic stroke patients over 80 years old: the Fukuoka Stroke Registry. PLoS ONE 2014;9:e110444.
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13. Toni D, Lorenzano S, Agnelli G, et al. Intravenous thrombolysis with rt-PA in acute ischemic stroke patients aged older than 80 years in Italy. Cerebrovasc Dis 2008;25:129-135. 14. Nedeltchev K, Schwegler B, Haefeli T, et al. Outcome of stroke with mild or rapidly improving symptoms. Stroke 2007;38:2531-2535. 15. Zhu W, Churilov L, Campbell BC, et al. Does large vessel occlusion affect clinical outcome in stroke with mild neurologic deficits after intravenous thrombolysis? J Stroke Cerebrovasc Dis 2014;23:2888-2893. 16. Guillan M, Alonso-Canovas A, Gonzalez-Valcarcel J, et al. Stroke mimics treated with thrombolysis: further evidence on safety and distinctive clinical features. Cerebrovasc Dis 2012;34:115-120. 17. Moulin S, Padjen-Bogosavljevic V, Marichal A, et al. Influence of differences in case mix on the better outcome of smokers after intravenous thrombolysis for acute cerebral ischemia. Eur Neurol 2012;67:178-183. 18. Arsava EM, Vural A, Akpinar E, et al. The detrimental effect of aging on leptomeningeal collaterals in ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:421-426. 19. Menon BK, Smith EE, Coutts SB, et al. Leptomeningeal collaterals are associated with modifiable metabolic risk factors. Ann Neurol 2013;74:241-248. 20. Willey JZ, Ortega-Gutierrez S, Petersen N, et al. Impact of acute ischemic stroke treatment in patients >80 years of age: the specialized program of translational research in acute stroke (SPOTRIAS) consortium experience. Stroke 2012;43:2369-2375. 21. Kim D, Ford GA, Kidwell CS, et al. Intra-arterial thrombolysis for acute stroke in patients 80 and older: a comparison of results in patients younger than 80 years. AJNR Am J Neuroradiol 2007;28:159-163. 22. Egashira Y, Yoshimura S, Sakai N, et al. Efficacy of endovascular revascularization in elderly patients with acute large vessel occlusion: analysis from the RESCUEJapan Retrospective Nationwide Survey. J Stroke Cerebrovasc Dis 2013;22:627-632. 23. Ghobrial GM, Chalouhi N, Rivers L, et al. Multimodal endovascular management of acute ischemic stroke in patients over 75 years old is safe and effective. J Neurointerv Surg 2013;1:i33-i37. 24. Duffis EJ, He W, Prestigiacomo CJ, et al. Endovascular treatment for acute ischemic stroke in octogenarians compared with younger patients: a meta-analysis. Int J Stroke 2014;9:308-312. 25. Chandra RV, Leslie-Mazwi TM, Oh DC, et al. Elderly patients are at higher risk for poor outcomes after intra-arterial therapy. Stroke 2012;43:2356-2361. 26. Kurre W, Aguilar-Perez M, Niehaus L, et al. Predictors of outcome after mechanical thrombectomy for anterior circulation large vessel occlusion in patients aged ≥80 years. Cerebrovasc Dis 2013;36:430-436. 27. Bash S, Villablanca JP, Jahan R, et al. Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. AJNR Am J Neuroradiol 2005;26:1012-1021. 28. Hopyan JJ, Gladstone DJ, Mallia G, et al. Renal safety of CT angiography and perfusion imaging in the emergency evaluation of acute stroke. AJNR Am J Neuroradiol 2008;29:1826-1830. 29. Nguyen-Huynh MN, Wintermark M, English J, et al. How accurate is CT angiography in evaluating intracranial atherosclerotic disease? Stroke 2008;39:1184-1188.
Large-Vessel Occlusion Is Associated with Poor Outcome in Stroke Patients Aged 80 Years or Older Who Underwent Intravenous Thrombolysis Wusheng Zhu, MD, PhD,*† Lulu Xiao, MD,* Monica Lin, Xinfeng Liu, MD, PhD,* and Bernard Yan, FRACP†
BSc,†
Objective: We aimed to investigate the association between large-vessel occlusion (LVO) and functional outcome in elderly stroke patients treated with intravenous (IV) tissue plasminogen activator (tPA). Methods: This was a retrospective study of acute ischemic stroke patients who received IV tPA within 4.5 hours after stroke onset between 2007 and 2013. Patients were categorized into 2 groups based on age (≥80 or < 80 years). LVO was evaluated by computed tomography angiography (CTA) before thrombolysis. Favorable outcome was defined as a modified Rankin Scale (mRS) score of 2 or lower at 3 months, or equal to the prestroke mRS score. Results: Of 359 thrombolysis patients, 175 patients with CTA before a standard dose of IV tPA therapy (0.9 mg/kg body weight; maximum 90 mg) were included. Sixty-five patients were in the group aged 80 years or above with a median age of 84 (interquartile range: 82.5, 86) years. LVO was observed more often in the group with unfavorable outcome compared with the group with favorable outcome in older stroke patients (60.6% versus 21.9%, P = .002). The baseline National Institutes of Health Stroke Scale (NIHSS) score (odds ratio .864; 95% confidence interval [CI], .779-.959; P = .006) and LVO (odds ratio .233; 95% CI, .059.930; P = .039) were independent associative factors for the unfavorable outcome in older patients treated with IV tPA after adjustment for patient characteristics. Conclusions: The baseline NIHSS score and LVO were independent predictors for functional outcome in elderly stroke patients received IV tPA. Key Words: Stroke—elderly—intravenous thrombolysis—CT angiography—modified Rankin scale. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, China; and †Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. Received April 18, 2016; revision received June 14, 2016; accepted July 10, 2016. Sources of funding: This study was supported by projects of the National Natural Science Foundation of China (NSFC 81220108008). Author contributions: Drs. Zhu and Yan participated in the conception and design of the study, acquisition of raw data, analysis of data, drafting of the article, and revision of the manuscript. Ms. Lin participated in the acquisition of raw data. Dr. Xiao and Liu participated in the conception and design of the study. Drs. Zhu and Dr Xiao contributed equally to this work. Address correspondence to Bernard Yan, FRACP, Melbourne Brain Centre at the Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.07.021
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■
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ARTICLE IN PRESS W. ZHU ET AL.
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Introduction A recent meta-analysis of individual patient data from randomized trials showed that alteplase significantly improves the overall good outcome when stroke patients received alteplase within 4.5 hours of stroke onset.1 Elderly patients have been accounted for 30% of all acute ischemic stroke patients.2 However, there is no consensus regarding thrombolysis for stroke patients over 80 years.3 Although some large-scale randomized controlled clinical trials exclude acute stroke patients aged 80 years or older from intravenous (IV) thrombolysis for its under-representation,4,5 there has been an increase in the proportion of elderly patients who underwent IV thrombolysis in recent years.6-9 Moreover, it is becoming clear that a proportion of stroke patients aged 80 years or older derive significant benefit from IV thrombolysis,9-12 even in patients aged 90 years or older.7,9,10 It is critical to clarify outcome predictors for this group of patients. The baseline National Institutes of Health Stroke Scale (NIHSS) score has been validated as the predictor of mortality and unfavorable outcome in stroke patients aged 80 years or older who underwent thrombolysis,13 but vascular imaging predictors remain uncertain. Large-vessel occlusion (LVO) is a predictor of poor outcome in acute ischemic stroke.14 Computed tomography angiography (CTA) is an accurate tool for the assessment of LVO; however, CTA may be more risky in patients aged 80 years or older because of higher prevalence of renal failure. Therefore, it is important to establish the utility of CTA prior to recommending its routine use in 80-year-old patients. The aim of the present study was to investigate the association between LVO and outcome in acute ischemic stroke patients aged 80 years or older who underwent IV tissue plasminogen activator (tPA) therapy, to test the hypothesis that LVO is associated with poor outcomes in these patients.
Methods Patients We analyzed the medical records of 359 acute ischemic stroke patients admitted to the Royal Melbourne Hospital who were treated with IV tPA within 4.5 hours of stroke onset, between December 2007 and February 2013.15 Eligibility criteria included patients with computed tomography (CT)-confirmed acute ischemic stroke who were administered .9 mg/kg of IV tPA within 4.5 hours of onset of symptoms. The following characteristics were included: age, sex, prestroke modified Rankin Scale (mRS) score, onset-to-treatment time, vascular risk factors (hypertension, diabetes, hypercholesterolemia, atrial fibrillation, smoking, ischemic heart disease, and previous stroke), baseline NIHSS score, CTA before IV tPA, CT or magnetic resonance imaging after IV tPA, and
3-month mRS score. The patients were divided into 2 groups by age: older group (aged ≥80 years) and younger group (aged <80 years). Patients diagnosed with stroke mimics,16 or patients who received IV tPA plus intraarterial (IA) therapy were excluded from our study.
Imaging CTA was routinely performed in acute ischemic stroke patients before thrombolysis at the Royal Melbourne Hospital from December 2007, unless contraindicated (e.g., known contrast allergy or renal impairment). LVO was identified as proximal vessel occlusion as follows14: internal carotid artery, middle cerebral artery (M1 and M2 segments), anterior cerebral artery (A1 segment), V4 segment of vertebral artery, basilar artery, and posterior cerebral artery (P1 segment). CT or magnetic resonance imaging scans were performed approximately within 24 hours of IV tPA to identify the hemorrhagic transformation and the extent of infarction. Symptomatic intracerebral hemorrhage was defined as blood at any site in the brain associated with a worsening of the NIHSS score by 4 points or higher within 24 hours.4 The presence of LVO was assessed on CTA image by 2 independent experienced stroke neurologists (W.Z. and B.Y.). The symptoms of the acute ischemic stroke patients were consistent with LVO.
Outcome The primary outcome was the 3-month mRS score. Favorable outcome was defined as an mRS score of 2 or lower at 3 months, or equal to the prestroke mRS score.6,17 Secondary outcomes were symptomatic intracerebral hemorrhage after IV tPA and mortality at 3 months post stroke.
Statistical Analysis Statistical analysis was performed using the SPSS (version 19; SPSS Inc., Chicago, IL). Between-group differences were made using the Student t-test or the Mann–Whitney U-test for continuous variables, chi-square test, or the Fisher exact test for categorical variables. Logistic regression was used to test predictors of unfavorable outcome in elderly stroke patients (aged ≥80 years) who received IV tPA. The model was adjusted for patient characteristics (diabetes, hypertension, smoking, atrial fibrillation, prior stroke history, hypercholesterolemia, LVO, and NIHSS score on admission). All statistical tests were 2-sided, and P values less than .05 were considered to be statistically significant.
Results Baseline Characteristics In our tPA database, 243 acute ischemic stroke patients who underwent CTA before IV tPA therapy were screened (243 of 359 thrombolysis patients, 67.7%).
ARTICLE IN PRESS LARGE-VESSEL OCCLUSION AND ELDERLY STROKE PATIENTS AFTER IV TPA
Sixty-eight patients were excluded from the study: 40 patients underwent bridging therapy (IV tPA plus IA), 17 patients were lost to follow-up, 6 patients did not have baseline NIHSS scores, and 5 patients were stroke mimics. We finally included 175 patients who had the following characteristics: 104 male patients (59.4%), 126 patients with pre-mRS score of 0, 3 patients with a pre-mRS score of 1, 13 patients with a pre-mRS score of 2, 19 patients with pre-mRS score of 3, and 14 patients with pre-mRS score of 4. The median age was 74 years (interquartile range [IQR]: 64-83), and the median baseline NIHSS score was 9 (IQR: 5-16).
Comparison of Baseline Characteristics and Outcome between Older and Younger Patients Of the 175 patients, 65 (37.1%) were 80 years old or older with a median age of 84 years (IQR: 82.5-86.0). Of the 65 patients, 32 (49.2%) were male and the mean baseline NIHSS score was 11 (IQR: 5-17). As for younger patients (aged <80 years), the mean age was 68 (IQR: 5873) years and the median baseline NIHSS score was 8 (IQR: 5-14). Older stroke patients were more likely to have arterial hypertension (75.4% versus 59.1%, P = .029), history of atrial fibrillation (41.5% versus 25.5%, P = .027),
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previous stroke history (18.5% versus 9.1%, P = .071), high prestroke mRS score (P < .001), and high mortality rate (23.1% versus 8.2%, P = .006). The patients were less likely to be a male (49.2% versus 65.5%, P = .035) or current smokers (9.2% versus 28.2%, P = .003) or have favorable outcome. There was no difference in the prevalence of LVO between older and younger patients (41.5% versus 39.1%, P = .749). A comparison of baseline characteristic and outcome between older and younger groups is shown in Table 1.
Factors Associated with Functional Outcome in Older Patients The factors associated with functional outcome in older stroke patients treated with IV tPA are given in Table 2. High baseline NIHSS score (14.9 ± 6.9 versus 8.7 ± 6.0, P<.001) and LVO (60.6% versus 21.9%, P = .002) occurred more frequently in the unfavorable outcome group than in the favorable outcome group. After adjustment for patient characteristics, logistic regression showed that baseline NIHSS score (odds ratio .864; 95% confidence interval, .779-.959; P = .006) and LVO (odds ratio .233; 95% confidence interval, .059-.930; P = .039) remained the significant predictors for unfavorable outcome in older patients treated with tPA (Table 3).
Table 1. Baseline characteristics and outcome of older (age ≥ 80) and younger (age < 80) stroke patients who underwent thrombolysis
Characteristics
Age 80 years or older (n = 65)
Age younger than 80 (n = 110)
Male, n (%) Age (years), median (IQR) Prestroke mRS score of 0-2, n (%) Onset to treat time (min), mean (SD) Baseline NIHSS score, median (IQR) Hypertension, n (%) Diabetes, n (%) Hypercholesterolemia, n (%) Atrial fibrillation, n (%) Previous stroke history, n (%) Current smoker, n (%) Ischemic heart disease, n (%) Peripheral vascular disease, n (%) Large-vessel occlusion, n (%) Internal carotid artery, n (%) Middle cerebral artery, n (%) Posterior cerebral artery, n (%) Favorable outcome, n (%) Symptomatic ICH, n (%) Mortality, n (%)
32 (49.2) 84 (82.5-86.0) 44 (67.7) 159.8 ± 50.1 11 (5-17) 49 (75.4) 11 (16.9) 37 (56.9) 27 (41.5) 12 (18.5) 6 (9.2) 18 (27.7) 1 (1.5) 27 (41.5) 7 (10.8) 18 (27.7) 2 (3.1) 32 (49.2) 4 (6.2) 15 (23.1)
72 (65.5) 68 (58-73) 98 (89.1) 160.1 ± 58.4 8 (5-14) 65 (59.1) 31 (28.2) 53 (48.2) 28 (25.5) 10 (9.1) 31 (28.2) 22 (20.0) 6 (5.5) 43 (39.1) 10 (9.1) 32 (29.1) 1 (.9) 77 (70) 3 (2.7) 9 (8.2)
P value .035* <.001* <.001* .967 .194 .029* .092 .264 .027* .071 .003* .242 .261 .749
.006* .426 .006*
Abbreviations: ICH, intracranial hemorrhage; IQR, interquartile range; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. *P < .05.
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Table 2. Factors associated with 3-month functional outcome in older (age ≥ 80) stroke patients received IV tPA
Factors
Favorable outcome (n = 32)
Unfavorable outcome (n = 33)
Male, n (%) Onset to treat time (min), mean (SD) Baseline NIHSS score, mean (SD) Hypertension, n (%) Diabetes, n (%) Hypercholesterolemia, n (%) Atrial fibrillation, n (%) Previous stroke history, n (%) Smoking, n (%) Ischemic heart disease, n (%) Large-artery occlusion, n (%) Internal carotid artery, n (%) Middle cerebral artery, n (%) Posterior cerebral artery, n (%) Symptomatic ICH, n (%) ICH, n (%)
16 (50.0) 158.8 ± 52.3 8.7 ± 6.0 25 (78.1) 5 (15.6) 20 (62.5) 13 (40.6) 5(15.6) 3 (9.4) 8 (25.0) 7 (21.9) 1 (3.1) 6 (18.8) 0 (0) 0 (0) 3 (9.4%)
16 (48.5) 160.8 ± 48.6 14.9 ± 6.9 24 (72.7) 6 (18.2) 17 (51.5) 14 (42.4) 7 (21.2) 3 (9.1) 10 (30.3) 20 (60.6) 6 (18.2) 12 (36.4) 2 (6.1) 4 (12.1) 9 (27.2%)
P value .903 .869 <.001* .614 .783 .371 .883 .562 1.000 .633 .002*
.114 .063
Abbreviations: ICH, intracranial hemorrhage; IQR, interquartile range; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. *P < .05.
Table 3. Multivariate analysis for favorable outcomes at 3 months in older (age ≥ 80) stroke patients treated with IV tPA Favorable outcome Factors
OR
95% CI
P value
Large-vessel occlusion Baseline NIHSS score
.233 .864
.059-.930 .779-.959
.039* .006*
Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio. *P < .05.
Discussion The major result of our study demonstrated that LVO was significantly related to unfavorable outcome in elderly stroke patients aged ≥80 years who received IV tPA. Age has been shown to be associated with unfavorable collateral circulation.18,19 Based on our results, we suggest that elderly stroke patients with LVO be selected to undergo IA therapy. Compared with elderly stroke patients receiving IV tPA alone, the risk of in-hospital mortality for patients undergoing IA therapy plus IV tPA has not increased.20 IA therapy has been shown to have an equal recanalization rate and hemorrhage rate between elderly patients and younger patients.21 Elderly stroke patients may achieve favorable outcomes after recanalization by endovascular treatment.22,23 However, the study of Chandra et al showed that elderly patients had poor clinical outcome and higher mortality at 90 days, compared with nonelderly
patients after IA therapy.24,25 A meta-analysis showed that elderly patients had higher rates of mortality and intracerebral hemorrhage at 3 months than younger patients after IA therapy.24,25 Results of the meta-analysis have shown that ASPECTS and NIHSS scores were independent predictors of favorable outcome in elderly patients for anterior circulation LVO after mechanical thrombectomy.26 The risks and benefits of IA therapy needed to be assessed before performance of the treatment.25 The baseline NIHSS score was the important independent predictor of unfavorable outcome in elderly stroke patients treated with tPA in our study, which was consistent with previous findings.13 Besides, the mortality rate at 3 months was higher in older patients than in younger patients in our study, which is now well acknowledged. Each patient underwent emergency CTA before IV tPA therapy in our study. CTA is an accurate and safe tool for evaluating intracranial vessel stenosis or occlusion.27,28 CTA detects LVO with 100% sensitivity and specificity compared to digital subtraction angiography.29 In our study, CTA was routinely performed in stroke patients before thrombolysis, unless contraindicated (e.g., known contrast allergy or renal impairment). Results have shown that the safety of elderly patients who underwent CTA may be acceptable if the patients were selected. Several limitations of our study have to be addressed. First, our study was a relatively small singlecenter cohort study and longitudinal studies are required to confirm our findings. Second, 40 patients who received bridging therapy (IV tPA plus IA) were excluded in our study. The exclusion of these patients introduced select bias in the proportion of LVO in our study. Third,
ARTICLE IN PRESS LARGE-VESSEL OCCLUSION AND ELDERLY STROKE PATIENTS AFTER IV TPA
despite careful adjustment for confounding factors, unreported confounders could have biased the conclusion of our study. However, a randomized controlled trial with adequate power to avoid unmeasured confounding is extremely difficult to organize.
Conclusions LVO and baseline NIHSS score are the independent predictors of outcome in elderly stroke patients who underwent IV tPA therapy.
References 1. Baigent C, Blackwell L, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929-1935. 2. Derex L, Nighoghossian N. Thrombolysis, stroke-unit admission and early rehabilitation in elderly patients. Nat Rev Neurol 2009;5:506-511. 3. European Stroke Organisation (ESO) Executive Committee. ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507. 4. Hacke W, Kaste M, Fieschi C, et al. Randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-1251. 5. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329. 6. Boulouis G, Dumont F, Cordonnier C, et al. Intravenous thrombolysis for acute cerebral ischaemia in old stroke patients ≥ 80 years of age. J Neurol 2012;259:1461-1467. 7. Balestrino M, Carlino V, Bruno C, et al. Safe and effective outcome of intravenous thrombolysis for acute ischemic stroke in patients aged 90 years or older. Eur Neurol 2013;70:84-87. 8. Singer OC, Hamann GF, Misselwitz B, et al. Time trends in systemic thrombolysis in a large hospital-based stroke registry. Cerebrovasc Dis 2012;33:316-321. 9. Kono S, Deguchi K, Morimoto N, et al. Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. J Stroke Cerebrovasc Dis 2013;22:1175-1183. 10. De Keyser J, Gdovinova Z, Uyttenboogaart M, et al. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007;38:26122618. 11. IST-3 Collaborative Group, Sandercock P, Wardlaw JM, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352-2363. 12. Matsuo R, Kamouchi M, Fukuda H, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for ischemic stroke patients over 80 years old: the Fukuoka Stroke Registry. PLoS ONE 2014;9:e110444.
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13. Toni D, Lorenzano S, Agnelli G, et al. Intravenous thrombolysis with rt-PA in acute ischemic stroke patients aged older than 80 years in Italy. Cerebrovasc Dis 2008;25:129-135. 14. Nedeltchev K, Schwegler B, Haefeli T, et al. Outcome of stroke with mild or rapidly improving symptoms. Stroke 2007;38:2531-2535. 15. Zhu W, Churilov L, Campbell BC, et al. Does large vessel occlusion affect clinical outcome in stroke with mild neurologic deficits after intravenous thrombolysis? J Stroke Cerebrovasc Dis 2014;23:2888-2893. 16. Guillan M, Alonso-Canovas A, Gonzalez-Valcarcel J, et al. Stroke mimics treated with thrombolysis: further evidence on safety and distinctive clinical features. Cerebrovasc Dis 2012;34:115-120. 17. Moulin S, Padjen-Bogosavljevic V, Marichal A, et al. Influence of differences in case mix on the better outcome of smokers after intravenous thrombolysis for acute cerebral ischemia. Eur Neurol 2012;67:178-183. 18. Arsava EM, Vural A, Akpinar E, et al. The detrimental effect of aging on leptomeningeal collaterals in ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:421-426. 19. Menon BK, Smith EE, Coutts SB, et al. Leptomeningeal collaterals are associated with modifiable metabolic risk factors. Ann Neurol 2013;74:241-248. 20. Willey JZ, Ortega-Gutierrez S, Petersen N, et al. Impact of acute ischemic stroke treatment in patients >80 years of age: the specialized program of translational research in acute stroke (SPOTRIAS) consortium experience. Stroke 2012;43:2369-2375. 21. Kim D, Ford GA, Kidwell CS, et al. Intra-arterial thrombolysis for acute stroke in patients 80 and older: a comparison of results in patients younger than 80 years. AJNR Am J Neuroradiol 2007;28:159-163. 22. Egashira Y, Yoshimura S, Sakai N, et al. Efficacy of endovascular revascularization in elderly patients with acute large vessel occlusion: analysis from the RESCUEJapan Retrospective Nationwide Survey. J Stroke Cerebrovasc Dis 2013;22:627-632. 23. Ghobrial GM, Chalouhi N, Rivers L, et al. Multimodal endovascular management of acute ischemic stroke in patients over 75 years old is safe and effective. J Neurointerv Surg 2013;1:i33-i37. 24. Duffis EJ, He W, Prestigiacomo CJ, et al. Endovascular treatment for acute ischemic stroke in octogenarians compared with younger patients: a meta-analysis. Int J Stroke 2014;9:308-312. 25. Chandra RV, Leslie-Mazwi TM, Oh DC, et al. Elderly patients are at higher risk for poor outcomes after intra-arterial therapy. Stroke 2012;43:2356-2361. 26. Kurre W, Aguilar-Perez M, Niehaus L, et al. Predictors of outcome after mechanical thrombectomy for anterior circulation large vessel occlusion in patients aged ≥80 years. Cerebrovasc Dis 2013;36:430-436. 27. Bash S, Villablanca JP, Jahan R, et al. Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. AJNR Am J Neuroradiol 2005;26:1012-1021. 28. Hopyan JJ, Gladstone DJ, Mallia G, et al. Renal safety of CT angiography and perfusion imaging in the emergency evaluation of acute stroke. AJNR Am J Neuroradiol 2008;29:1826-1830. 29. Nguyen-Huynh MN, Wintermark M, English J, et al. How accurate is CT angiography in evaluating intracranial atherosclerotic disease? Stroke 2008;39:1184-1188.