EuroHYP-1: European Multicenter, Randomized, Phase III Clinical Trial of Therapeutic Hypothermia plus Best Medical Treatment vs. Best Medical Treatment Alone for Acute Ischemic Stroke

Background: Recent randomized trials demonstrated the superiority of the mechanical thrombectomy over the best medical treatment in patients with acute ischemic stroke due to an occlusion of arteries of proximal anterior circulation. In this updated meta-analysis, we aimed to summarize the total clinical effects of the treatment, including the last trials. Methods: We performed literature search of Randomized Crontrolled Trials (RCTs) published between 2010 and October 2016, comparing endovenous thrombolysis plus mechanical thrombectomy (intervention group) with best medical care alone (control group). We identified 8 trials. Primary outcomes were reduced disability at 90 days from the event and symptomatic intracranial hemorrhage. Statistical analysis was performed pooling data into the 2 groups, evaluating outcome heterogeneity. The Mantel-Haenszel method was used to calculate odds ratios (ORs). Results: We analyzed data for 1845 patients (interventional group: 911; control group: 934). Mechanical thrombectomy contributed to a significant reduction in disability rate compared to the best medical treatment alone (OR: 2.087; 95% confidence interval [CI]: 1.718-2.535; P < .001). We calculated that for every 100 treated patients, 16 more participants have a good outcome as a result of mechanical treatment. No significant differences between groups were observed concerning the occurrence of symptomatic hemorrhage (OR: 1.021; 95% CI: 0.641-1.629; P = .739). Conclusion: Mechanical thrombectomy contributes to significantly increase the functional benefit of endovenous thrombolysis in patients with acute ischemic stroke caused by arterial occlusion of proximal anterior circulation, without reduction in safety. These findings are relevant for the optimization of the acute stroke management, including the implementation of networks between stroke centers.

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Therapeutic Hypothermia for Acute Ischemic Stroke: Ready to Start Large Randomized Trials?

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.44 ◽

2010 ◽

Vol 30 (6) ◽

pp. 1079-1093 ◽

Cited By ~ 129

Author(s):

H Bart van der Worp ◽

Malcolm R Macleod ◽

Rainer Kollmar ◽

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Therapeutic Hypothermia ◽

Animal Studies ◽

Brain Injuries ◽

Focal Cerebral Ischemia ◽

Perinatal Asphyxia ◽

Phase Iii ◽

Neuroprotective Strategy ◽

Critical Issues

Therapeutic hypothermia is a means of neuroprotection well established in the management of acute ischemic brain injuries such as anoxic encephalopathy after cardiac arrest and perinatal asphyxia. As such, it is the only neuroprotective strategy for which there is robust evidence for efficacy. Although there is overwhelming evidence from animal studies that cooling also improves outcome after focal cerebral ischemia, this has not been adequately tested in patients with acute ischemic stroke. There are still some uncertainties about crucial factors relating to the delivery of hypothermia, and the resolution of these would allow improvements in the design of phase III studies in these patients and improvements in the prospects for successful translation. In this study, we discuss critical issues relating first to the targets for therapy including the optimal depth and duration of cooling, second to practical issues including the methods of cooling and the management of shivering, and finally, of factors relating to the design of clinical trials. Consideration of these factors should inform the development of strategies to establish beyond doubt the place of hypothermia in the management of acute ischemic stroke.

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Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial

European Stroke Journal ◽

10.1177/2396987319844690 ◽

2019 ◽

Vol 4 (3) ◽

pp. 254-262 ◽

Cited By ~ 13

Author(s):

H Bart van der Worp ◽

Malcolm R Macleod ◽

Philip MW Bath ◽

Raj Bathula ◽

Hanne Christensen ◽

...

Keyword(s):

Clinical Trial ◽

Ischaemic Stroke ◽

Therapeutic Hypothermia ◽

Acute Ischaemic Stroke ◽

Phase Iii ◽

Phase Iii Clinical Trial

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Corrigendum to a systematic review and meta-analysis of randomized controlled trials of endovascular thrombectomy compared to best medical treatment for acute ischemic stroke

International Journal of Stroke ◽

10.1177/1747493016675982 ◽

2016 ◽

Vol 12 (1) ◽

pp. NP7-NP7

Keyword(s):

Systematic Review ◽

Ischemic Stroke ◽

Medical Treatment ◽

Randomized Controlled Trials ◽

Acute Ischemic Stroke ◽

Meta Analysis ◽

Controlled Trials ◽

Endovascular Thrombectomy ◽

Randomized Controlled ◽

Best Medical Treatment

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Abstract TP68: The Characteristics of Acute Ischemic Stroke Treatment Clinical Trials Over the Past Twenty Years: Implications for Future Trial Design

Stroke ◽

10.1161/str.48.suppl_1.tp68 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yi Dong ◽

Pratik Y Chhatbar ◽

Shimeng Liu ◽

Qiang Dong ◽

Bruce Ovbiagele ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Standard Care ◽

Trial Design ◽

Phase Iii ◽

Care Group ◽

Stroke Treatment ◽

Mesh Terms

Introduction: There was a 20 years span between the landmark NINDS r-tPA trials and the recent spate of positive endovascular trials of acute ischemic stroke. The evolution of clinical trial design, characteristics of subjects, and nature of background standard care have not been properly studied. Such information could have consequences for future clinical trial designs. Objective: To systematically search the literature for randomized controlled trials of acute ischemic stroke and identify key patterns. Methods: We interrogated Pubmed from 1995 to 2015 with MeSH terms (Fig 1A). Inclusion criteria are: 1) acute intervention delivered within 24 hours of onset; 2) randomized trial with a control (either placebo or standard care) group with ≥20 subjects in each arm; 3) mRS used as an outcome at 3 months; 4) published in the English language. Data were extracted and effect sizes were calculated for both mortality and favorable outcome (mRS: 0-1). We also extracted data for baseline characteristics and analyzed trends over time. Results: Forty-six clinical trials were included with 19951 subjects and 38.5% of them were females. There were 8 phase II and 11 phase III trials, nine out of 46 are positive trials . Average number of subjects per trial was 443 and number of patient enrollments per year ranged from 23-270. Study-wise odd’s ratio ranged 0.15 - 3.97 for mortality and 0.30- 3.06 for favorable outcomes. Rate of mortality was 13.6% (0-44%) and favorable outcomes ranged 6-37% in control and 7.5-74.8% in intervention arm. Median onset of treatment ranged from 90 - 972 minutes. There are trends of increased NIHSS score at baseline for studies over the years. The type of intervention and baseline NIHSS are major determinants of mortality rate. Conclusions: Patterns existed in the acute ischemic stroke treatment trials. Understanding these patterns may inform the stroke community to better design trials in the future.

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Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.031197 ◽

2021 ◽

Author(s):

Jie Xu ◽

Anxin Wang ◽

Xia Meng ◽

Gulbahram Yalkun ◽

Anding Xu ◽

...

Keyword(s):

Clinical Trial ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Scale Score ◽

Functional Outcomes ◽

Synergistic Effects ◽

Phase Iii ◽

Modified Rankin Scale ◽

Double Blind ◽

Female Patients

Background and Purpose: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS). Methods: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization. Results: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12–1.81]; P =0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49–3.43 versus 1.14, 0.85–1.52). Conclusions: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02430350.

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