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Original Investigation
November 2017

Low-Dose vs Standard-Dose Alteplase for Patients With Acute Ischemic Stroke: Secondary Analysis of the ENCHANTED Randomized Clinical Trial

Author Affiliations
  • 1The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
  • 2Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  • 3Department of Cardiovascular Sciences and National Institute for Health Research Biomedical Research Unit, University of Leicester, Leicester, England
  • 4Stroke Center and Department of Neurology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan
  • 5Department of Public Health, Fukuoka University, Fukuoka, Japan
  • 6Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, England
  • 7Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, University of Cincinnati, Cincinnati, Ohio
  • 8Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
  • 9The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
  • 10Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, Korea
  • 11Departamento de Neurología, Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile
  • 12Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
  • 13Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
  • 14Stroke Division of Neurology Service, Hospital de Clinicas de Porto Alegre, University of Rio Grande do Sul, Porto Alegre, Brazil
  • 15Department of Neurology, Christian Medical College, Ludhiana, Punjab, India
  • 16Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, New South Wales, Australia
  • 17Department of Neurosciences and Behavioural Sciences, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil
  • 18Uo Neurologia, USL Umbria 1, Sedi di Citta di Castello e Branca, Italy
  • 19Yong Loo Lin School of Medicine, National University Hospital, Singapore
  • 20Division of Neurology, National University Hospital, Singapore
  • 21Department of Cerebrovascular Disease, The People’s 115 Hospital, Ho Chi Minh City, Vietnam
  • 22The Shanghai Institute for Hypertension, Shanghai, China
  • 23Rui Jin Hospital, Shanghai, China
  • 24Shanghai Jiaotong University School of Medicine, Shanghai, China
  • 25The George Institute for Global Health, University of Oxford, Oxford, England
  • 26Neurology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
  • 27The George Institute China at Peking University Health Science Center, Beijing, China
JAMA Neurol. 2017;74(11):1328-1335. doi:10.1001/jamaneurol.2017.2286
Key Points

Question  Does low-dose intravenous alteplase offer benefits over standard-dose intravenous alteplase in older, Asian, or severely affected patients with acute ischemic stroke?

Finding  This secondary analysis of a randomized clinical trial that involved 3310 patients with acute ischemic stroke found no clear differential benefits of low-dose alteplase compared with standard-dose alteplase in disability outcomes, irrespective of age, race/ethnicity, and neurological severity. Increasing age and neurological severity, but not ethnicity, are associated with greater risk of death or disability following acute ischemic stroke in treated, thrombolysis-eligible patients.

Meaning  Decisions about using a lower dose of alteplase for thrombolysis-eligible patients with acute ischemic stroke should not be based solely on age, ethnicity, or neurological severity.


Importance  A lower dose of intravenous alteplase appears to be a safer treatment option than the standard dose, reducing the risk of symptomatic intracerebral hemorrhage. There is uncertainty, however, over how this effect translates into an overall clinical benefit for patients with acute ischemic stroke (AIS).

Objective  To assess whether older, Asian, or severely affected patients with AIS who are considered at high risk of bleeding after thrombolysis may benefit more from low-dose rather than standard-dose alteplase treatment.

Design, Setting, and Participants  This study is a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded, end-point clinical trial of low-dose vs standard-dose intravenous alteplase for patients with AIS. From March 1, 2012, to August 31, 2015, a total of 3310 patients who had a clinical diagnosis of AIS as confirmed by brain imaging and who fulfilled the local criteria for thrombolysis treatment were included in the alteplase-dose arms. Patients were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus and 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus and 90% as infusion over 1 hour) alteplase. Of the 3310 randomized patients, 13 patients were excluded for missing consent, mistaken randomization, and duplicate randomization numbers. This secondary analysis was conducted between May 1, 2016, and April 28, 2017.

Main Outcomes and Measures  The primary end point was a poor outcome defined by the combination of death and any disability as scored by the modified Rankin Scale (scores range from 2 to 6, with the highest score indicating death) at 90 days.

Results  Of the 3297 patients included in the analysis, 1248 (37.9%) were women, and the mean (SD) age was 67 (13) years. No significant differences in the treatment effects were observed between low- and standard-dose alteplase for poor outcomes (death or disability) by age, ethnicity, or severity (all P > .37 for interaction). Similarly, the treatment effects of low- vs standard-dose alteplase on function outcome (ordinal shift of the modified Rankin Scale) in Asians (odds ratio, 1.05; 95% CI, 0.90-1.22) was consistent with non-Asians (odds ratio, 0.93; 95% CI, 0.76-1.14) (P = .32 for interaction). There were generally consistent reductions in rates of symptomatic intracerebral hemorrhage with low-dose alteplase, although this reduction was not statistically significant by age, ethnicity, or severity.

Conclusions and Relevance  This analysis found that the effects of low-dose alteplase were not clearly superior to the effects of standard-dose alteplase on death or disability in key demographic subgroups of patients with AIS. Further investigation is required to identify patients with AIS who may benefit from low-dose alteplase.

Trial Registration  clinicaltrials.gov Identifier: NCT01422616