Xia Wang1,2, Thompson G Robinson3, Tsong-Hai Lee4, Qiang Li1, Hisatomi Arima5, Philip M Bath6, Laurent Billot1, Joseph Broderick7, Andrew M Demchuk8, Geoffrey Donnan9, Jong S Kim10, Pablo Lavados11,12, Richard I Lindley2,13, Sheila O Martins14, Veronica V Olavarria11, Jeyaraj D Pandian15, Mark W Parsons16, Octavio M Pontes-Neto17, Stefano Ricci18, Vijay K Sharma19,20, Nguyen H Thang21, Ji-Guang Wang22,23,24, Mark Woodward1,2,25, Craig S Anderson1,2,26,27, John Chalmers1,2. 1. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. 2. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. 3. Department of Cardiovascular Sciences and National Institute for Health Research Biomedical Research Unit, University of Leicester, Leicester, England. 4. Stroke Center and Department of Neurology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan. 5. Department of Public Health, Fukuoka University, Fukuoka, Japan. 6. Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, England. 7. Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, University of Cincinnati, Cincinnati, Ohio. 8. Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. 9. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia. 10. Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, Korea. 11. Departamento de Neurología, Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile. 12. Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile. 13. Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia. 14. Stroke Division of Neurology Service, Hospital de Clinicas de Porto Alegre, University of Rio Grande do Sul, Porto Alegre, Brazil. 15. Department of Neurology, Christian Medical College, Ludhiana, Punjab, India. 16. Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, New South Wales, Australia. 17. Department of Neurosciences and Behavioural Sciences, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil. 18. Uo Neurologia, USL Umbria 1, Sedi di Citta di Castello e Branca, Italy. 19. Yong Loo Lin School of Medicine, National University Hospital, Singapore. 20. Division of Neurology, National University Hospital, Singapore. 21. Department of Cerebrovascular Disease, The People's 115 Hospital, Ho Chi Minh City, Vietnam. 22. The Shanghai Institute for Hypertension, Shanghai, China. 23. Rui Jin Hospital, Shanghai, China. 24. Shanghai Jiaotong University School of Medicine, Shanghai, China. 25. The George Institute for Global Health, University of Oxford, Oxford, England. 26. Neurology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. 27. The George Institute China at Peking University Health Science Center, Beijing, China.
Abstract
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 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.
RCT Entities:
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 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.
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