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

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posted on 16.01.2018, 15:44 by Xia Wang, Thompson G. Robinson, Tsong-Hai Lee, Qiang Li, Hisatomi Arima, Philip M. Bath, Laurent Billot, Joseph Broderick, Andrew M. Demchuk, Geoffrey Donnan, Jong S. Kim, Pablo Lavados, Richard I. Lindley, Sheila O. Martins, Veronica V. Olavarria, Jeyaraj D. Pandian, Mark W. Parsons, Octavio M. Pontes-Neto, Stefano Ricci, Vijay K. Sharma, Nguyen H. Thang, Ji-Guang Wang, Mark Woodward, Craig S. Anderson, John Chalmers, Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) Investigators
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.

Funding

Funding was principally received from the National Health and Medical Research Council (NHMRC) of Australia. Additional funding was from the Stroke Association of the United Kingdom, the National Council for Scientific and Technological Development of Brazil, and the Ministry for Health, Welfare and Family Affairs of the Republic of Korea.

History

Citation

JAMA Neurology, 2017, 74 (11), pp. 1328-1335

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

AM (Accepted Manuscript)

Published in

JAMA Neurology

Publisher

American Medical Association (AMA)

eissn

2168-6157

Copyright date

2017

Available date

01/11/2018

Notes

The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en