Intravenous Thrombolysis with Neuroprotective Therapy by Edaravone for Ischemic Stroke Patients Older than 80 Years of Age

doi:10.1016/j.jstrokecerebrovasdis.2013.02.010

Journal of Stroke and Cerebrovascular Diseases

Volume 22, Issue 7, October 2013, Pages 1175-1183

https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.02.010 Get rights and content

Background

Alteplase, a recombinant tissue plasminogen activator (tPA), was approved for patients with acute ischemic stroke within 3 hours of stroke onset in Japan in October 2005 at a dose of 0.6 mg/kg. The aim of this study was to assess the safety and efficacy of alteplase in elderly patients in Japan.

Methods

One hundred twenty-nine consecutive patients who were admitted to our 5 hospital groups and who received intravenous tPA within 3 hours of stroke onset between January 2010 and December 2011 were divided into 2 groups by age (<80 years of age [younger group] and >80 years of age [older group]) and by treatment with or without edaravone. Clinical backgrounds and outcomes were investigated.

Results

The National Institutes of Health Stroke Scale score on admission was not different in both groups, but the National Institutes of Health Stroke Scale scores 7 days after stroke onset were significantly higher in the older group (score 8; P < .05) than in the younger group (score 4), and the ratio of patients with a modified Rankin Scale score of 4 to 6 was significantly greater in the older group (41.7%; P < .05) than in the younger group (22.2%). However, there was no difference in asymptomatic and symptomatic intracerebral hemorrhage rates between the younger and older groups (asymptomatic 20.2% v 18.8%; symptomatic 2.6% v 2.1%). Patients with edaravone showed a higher recanalization rate (61.9%; P < .01) and a better modified Rankin Scale score at 3 months poststroke (P < .01) than the nonedaravone group.

Conclusions

These data suggest that intravenous alteplase (0.6 mg/kg) within 3 hours of stroke onset was safe and effective, even for very old patients (≥80 years of age), but resulted in poor outcomes relating not to tPA but to aging. In addition, edaravone may be a good partner for combination therapy with tPA to enhance recanalization and reduce hemorrhagic transformation.

Section snippets

Patients

This study retrospectively evaluated 129 consecutive patients (67 men and 62 women) between 34 and 101 years of age (mean ± SD 73.3 ± 13.9 years) with acute cerebral infarction who were admitted to our hospital groups (Okayama University Hospital, Okayama National Hospital Medical Center, Kurashiki Heisei Hospital, Okayama Kyokuto Hospital, and Okayama Citizens’ Hospital). These patients received intravenous tPA within 3 hours of stroke onset between January 2010 and December 2011 (a 2-year

Results

The patients’ baseline clinical characteristics, risk factors for stroke, type of cerebral infarction, and responsible occluded artery are shown in Table 1. Among the 129 patients who received intravenous tPA, 79 cases (61.2%) were cardiogenic embolism, 44 (34.1%) atherothrombosis, and 4 (3.1%) lacunar infarction. The responsible occluded arteries among the 129 patients were the middle cerebral artery (MCA) for 71 cases (55.0%) and internal carotid artery (ICA) for 20 cases (15.5%). The median

Discussion

The baseline clinical characteristics in the present study were comparable to those in the other studies5, 6, 7, 8, 9, 10 in that the older group had a significantly lower proportion of men, a higher proportion of patients with HT, a higher proportion of cardiogenic embolism, a lower proportion of patients with atherothrombosis, and a lower proportion of smokers than the younger group (Table 1). The number of patients who had taken oral antiplatelet drugs and warfarin, the ratio of responsible

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Cited by (25)

Edaravone for Acute Ischemic Stroke: A Systematic Review and Meta-analysis
2022, Clinical Therapeutics
Citation Excerpt :
Consequently, 13 studies were included for data synthesis, including 9 RCTs.15–23 and 4 cohort studies.24–27 The selection process is detailed in Figure 1.
The management of acute stroke is challenging. The aim of this meta-analysis was to determine the efficacy and tolerability of edaravone, with or without thrombolytic therapy, in the treatment of patients with acute ischemic stroke.
The PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) and cohort studies. Mean differences (MD), risk ratios (RR), 95% confidence interval (CI), and heterogeneity were calculated.
Totals of nine RCTs and four cohort studies were included, for a total of 2102 patients. In patients with acute ischemic stroke, edaravone monotherapy was associated with significantly improved Barthel Index of functioning in activities for daily living (MD, 23.95; 95% CI, 18.48 to 29.41; P < 0.001) and neurologic deficit, (as measured using the National Institutes of Health Stroke Scale score) (MD = –3.49; 95% CI, –5.76 to 1.22; P = 0.003), on short-term follow-up. However, edaravone was not associated with an improved rate of death or disability (RR = 0.75; 95% CI, 0.45 to 1.23; P = 0.25) on long-term follow-up.When plus to thrombolytic therapy, edaravone was associated with significant improvements in recanalization rate (RR = 1.71; 95% CI, 1.05 to 2.77; P = 0.03) and neurologic deficit (MD = 3.97; 95% CI, 5.14 to 2.79; P < 0.001), without an increase in the prevalence of bleeding events (RR = 1.11; 95% CI, 0.76 to 1.62; P = 0.59). However, edaravone did not have a significant effect on death or disability (RR = 0.85; 95% CI, 0.69 to 1.04; P = 0.12).
Based on the findings from the present meta-analysis, edaravone was an effective and well-tolerated neuroprotective agent in these patients with ischemic stroke. With the use of edaravone, activities of daily living and neurologic deficits, along with recanalization rates, were improved on short-term follow-up, but the long-term effects still need confirmation in larger-scale clinical trials.
Edaravone for acute ischemic stroke – Systematic review with meta-analysis.
2022, Clinical Neurology and Neurosurgery
Ischemic stroke is a major cause of death and disability. Despite major advances in reperfusion therapies, most patients don´t benefit from these treatments as the time window for such interventions is limited. Therefore, other treatment options are desirable. Edaravone has been demonstrated in previous studies to reduce neurologic deficits in stroke patients.
To test the hypothesis that edaravone reduces functional dependence in ischemic stroke patients.
Systematic review and meta-analysis of randomized controlled trials and observational studies comparing edaravone to placebo in adult patients with ischemic stroke. The efficacy outcomes of interest were good and excellent functional outcomes at 90 days, defined as modified Rankin Scale (mRS) scores of 0–2 and 0–1 respectively. The safety outcomes of interest were intracranial hemorrhage and mortality.
19 studies were included. Edaravone treatment was associated with improved chances of 90-day good (OR=1.31, 95% CI 1.06–1.67) and excellent (OR=1.26, 95% CI 1.04–1.54) functional outcomes. Mortality was also lower in edaravone treated patients (OR=0.50, 95% CI 0.45–0.56). There were no differences in terms of intracranial hemorrhage. Most studies were observational and performed in Asian populations, especially Japan. Heterogeneity was high for all outcomes but reduced when analysis was restricted to randomized trials.
Edaravone is a promising treatment for ischemic stroke patients, with a more favorable time window. However, more randomized studies including patient populations outside Asia are required to confirm this hypothesis.
Effects of edaravone, the free radical scavenger, on outcomes in acute cerebral infarction patients treated with ultra-early thrombolysis of recombinant tissue plasminogen activator
2018, Clinical Neurology and Neurosurgery
Citation Excerpt :
Therefore, edaravone combined with rt-PA resulted in synergic effect for the treatment of acute cerebral infarction. Drug combination could promote recanalization of vascular and reduce cerebral infarction area, reduce the risk of bleeding [21]. The patient baseline distributions were well balanced between two groups.
Edaravone, a free radical scavenger, alleviates blood-brain barrier disruption in conjunction with suppression of the inflammatory reaction in acute cerebral infarction. Thrombolysis with recombinant tissue plasminogen activator (rtPA) is an established therapy for acute cerebral infarction patients. The purpose of this study was to assess the effects of edaravone on outcomes in acute cerebral infarction patients treated with ultra-early thrombolysis of iv-rt-PA.
We conducted a retrospective cohort study using the database of Ningbo First Hospital. We identified patients who were admitted with a primary diagnosis of acute cerebral infarction and treated with intravenous rtPA(iv-rtPA) within 3 h of symptom onset from March 1st in 2014 to October 31st in 2016.Thenceforth,the patients were divided into 2 groups by treatment with(edaravone group) or without edaravone(non-edaravone group). Glasgow Coma Scale (GCS) scores and mRS score at admission were used. Clinical background, risk factors for acute cerebral infarction hemorrhagic transformation, 7-day mortality, recanalization rate, bleeding complications and blood rheology indexes were collected. We also collected the following factors: National Institutes of Health Stroke Scale scores, barthel index.
136 patients treated without edaravone during hospitalization were selected in non-edaravone group while edaravone group included 132 patients treated with edaravone during hospitalization. The patient baseline distributions were well balanced between non-edaravone group and edaravone group. The rate of hemorrhagic transformation in non-edaravone group was higher than that in edaravone group (P ＜ 0.05). The NIHSS scores 7 days and 14 days after symptom onset were higher in non-edaravone group than in edaravone group (both P ＜ 0.05). Edaravone group showed a higher recanalization rate and a lower bleeding complications rate at discharge than the non-edaravone group (both P ＜ 0.05). The differences of all the blood rheology indexes between the two groups were statistically significant (all P ＜ 0.05).
Edaravone may improve outcomes of acute cerebral infarction patients treated with ultra-early thrombolysis of iv-rt-PA.
Large-Vessel Occlusion Is Associated with Poor Outcome in Stroke Patients Aged 80 Years or Older Who Underwent Intravenous Thrombolysis
2016, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
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
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).
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.
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.
The baseline NIHSS score and LVO were independent predictors for functional outcome in elderly stroke patients received IV tPA.
Neuroprotection for ischaemic stroke: Current status and challenges
2015, Pharmacology and Therapeutics
Stroke is the third cause of death worldwide and the main cause of chronic, severe adult disability. We focus on acute ischaemic stroke, which accounts for approximately 80% of all strokes. The current therapy aims at restoring cerebral blood flow within a narrow time window in order to prevent damaging the “penumbra” which surrounds the infarct core. Intravenous thrombolysis remains the fundamental treatment worldwide, though not ideal for various restrictions and complications, limiting to 10% or less the percentage of patients treated within the appropriate time window.
Neuroprotection is an alternative or adjunct approach to thrombolysis, targeting cerebral parenchyma in the acute ischaemic phase. Furthermore, neurorepair attempts to restore neuronal function in the after-stroke phase in those patients (treated or untreated) with significant impairment.
In the past decades, the efficacy and safety of numerous candidate neuroprotective agents were shown in various animal stroke models. However, in clinical trials, promising pre-clinical studies have not been translated into positive outcomes. Our review will analyse the possible reasons for this failure and the new approaches and recommendations to overcome it, as well as novel strategies targeting additional events in ischaemia cascade. The combination of thrombolysis with pharmacological and non-pharmacological neuroprotective approaches has also been tested. Finally, the neurorepair strategy will be described with special emphasis on the role of cell-based therapies and ischaemic conditioning.
Hopefully, the future therapy of ischaemic stroke will encompass a combination of neuroprotection (to stabilise penumbra), thrombolysis, antithrombotics (for secondary prevention) and neurorepair based on cell therapy plus rehabilitation.
Effects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator
2014, Journal of the Neurological Sciences
Citation Excerpt :
Thus, there is a possibility that edaravone may improve the neurological outcomes in acute ischemic stroke patients treated with rtPA. However, clinical data supporting the effectiveness of edaravone were based on limited studies with small samples [8,9]. We therefore investigated whether edaravone could improve early outcomes of acute ischemic stroke patients treated with rtPA, using a Japanese national inpatient database.
We investigated whether edaravone could improve early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator (rtPA).
We conducted a retrospective cohort study using the Japanese Diagnosis Procedure Combination database. We identified patients admitted with a primary diagnosis of ischemic stroke from 1 July 2010 to 31 March 2012 and treated with rtPA on the same day of stroke onset or the following day. Thereafter, we selected those who received edaravone on the same day of rtPA administration (edaravone group), and those who received rtPA without edaravone (control group). The primary outcomes were modified Rankin Scale (mRS) scores at discharge. One-to-one propensity-score matching was performed between the edaravone and control groups. An ordinal logistic regression analysis for mRS scores at discharge was performed with adjustment for possible variables as well as clustering of patients within hospitals using a generalized estimating equation.
We identified 6336 eligible patients for inclusion in the edaravone group (n = 5979; 94%) and the control group (n = 357; 6%) as the total population. In 356 pairs of the propensity-matched population, the ordinal logistic regression analysis showed that edaravone was significantly associated with lower mRS scores of patients at discharge (adjusted odds ratio: 0.74; 95% confidence interval: 0.57–0.96).
Edaravone may improve early outcomes in acute ischemic stroke patients treated with rtPA.

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: Supported in part by a Grant-in-Aid for Scientific Research (B) 21390267, (C) 24591263 and Challenging Research 24659651, and by Grants-in-Aid from the Research Committees from the Ministry of Health, Labour and Welfare of Japan.

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Review ArticleIntravenous Thrombolysis with Neuroprotective Therapy by Edaravone for Ischemic Stroke Patients Older than 80 Years of Age

Background

Methods

Results

Conclusions

Section snippets

Patients

Results

Discussion

Lancet

J Stroke Cerbrovasc Dis

Am J Emerg Med

Mayo Clin Proc

J Neurol Sci

Brain Res

Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT)

Stroke

Age disparities in stroke quality of care and delivery of health services

Stroke

Imaging of the brain in acute ischaemic stroke: Comparison of computed tomography and magnetic resonance diffusion-weighted imaging

J Neurol Neurosurg Psychiatry

Evaluation of initial diffusion-weighted image findings in acute stroke patients using a semiquantitative score

Magn Reson Med Sci

The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke

N Engl J Med

Thrombolysis for acute ischemic stroke. Results of the Canadian Alteplase for Stroke Effectiveness Study

CMAJ

Review Article
Intravenous Thrombolysis with Neuroprotective Therapy by Edaravone for Ischemic Stroke Patients Older than 80 Years of Age