Anderson, CS, Robinson, T, Lindley, RI, Arima, H, Lavados, PM, Lee, TH, Broderick, JP, Chen, X, Chen, G, Sharma, VK, Kim, JS, Thang, NH, Cao, Y, Parsons, MW, Levi, C, Huang, Y, Olavarria, VV, Demchuk, AM, Bath, PM, Donnan, GA, Martins, S, Pontes-Neto, OM, Silva, F, Ricci, S, Roffe, C, Pandian, J, Billot, L, Woodward, M, Li, Q, Wang, X, Wang, J and Chalmers, J (2016) Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. The New England Journal of Medicine, 374 (24). pp. 2313-2323. ISSN 1533-4406

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Abstract

BACKGROUND
Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage.

METHODS
Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control.

RESULTS
The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07).

CONCLUSIONS
This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via NEJM Group at http://www.nejm.org/doi/full/10.1056/NEJMoa1515510#t=article Please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > RC Internal medicine > RC666 Diseases of the circulatory (Cardiovascular) system
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 27 Jun 2016 11:26
Last Modified: 09 Jul 2018 09:38
URI: http://eprints.keele.ac.uk/id/eprint/1942

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