Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial

Zien Zhou; Candice Delcourt; Chao Xia; Sohei Yoshimura; Cheryl Carcel; Takako Torii-Yoshimura; Shoujiang You; Alejandra Malavera; Xiaoying Chen; Maree L Hackett; Mark Woodward; John Chalmers; Jianrong Xu; Thompson G Robinson; Mark W Parsons; Andrew M Demchuk; Richard I Lindley; Grant Mair; Joanna M Wardlaw; Craig S Anderson

doi:10.1212/WNL.0000000000011598

Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial

Zien Zhou, Candice Delcourt, Chao Xia, Sohei Yoshimura, Cheryl Carcel, Takako Torii-Yoshimura, Shoujiang You, Alejandra Malavera, Xiaoying Chen, Maree L Hackett, Mark Woodward, John Chalmers, Jianrong Xu, Thompson G Robinson, Mark W Parsons, Andrew M Demchuk, Richard I Lindley, Grant Mair, Joanna M Wardlaw, Craig S Anderson

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: To determine any differential efficacy and safety of low- versus standard-dose intravenous alteplase for lacunar versus non-lacunar acute ischemic stroke (AIS), we performed post-hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose-arm.

METHODS: In a cohort of 3297 ENCHANTED participants, we identified those with lacunar or non-lacunar AIS with different levels of confidence (definite/probable/possible) according to pre-specified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration [END] or death) and treatment effects of low- versus standard-dose alteplase across lacunar and non-lacunar AIS with adjustment for baseline covariables.

RESULTS: Of 2588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n=490) or non-lacunar AIS (n=2098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% CI] 0.60 [0.47-0.77]) and other clinical or safety outcomes, compared to participants with non-lacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- versus standard-dose alteplase on all outcomes across lacunar and non-lacunar AIS (all Pinteraction ≥0.07).

CONCLUSIONS: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard-dose for definite/probable lacunar AIS.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.

CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at www.clinicaltrials.gov: NCT01422616.

Original language	English
Journal	Neurology
Early online date	3 Feb 2021
DOIs	https://doi.org/10.1212/WNL.0000000000011598
Publication status	E-pub ahead of print - 3 Feb 2021

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Zhou, Z., Delcourt, C., Xia, C., Yoshimura, S., Carcel, C., Torii-Yoshimura, T., You, S., Malavera, A., Chen, X., Hackett, M. L., Woodward, M., Chalmers, J., Xu, J., Robinson, T. G., Parsons, M. W., Demchuk, A. M., Lindley, R. I., Mair, G., Wardlaw, J. M., & Anderson, C. S. (2021). Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial. Neurology. https://doi.org/10.1212/WNL.0000000000011598

Zhou, Zien ; Delcourt, Candice ; Xia, Chao ; Yoshimura, Sohei ; Carcel, Cheryl ; Torii-Yoshimura, Takako ; You, Shoujiang ; Malavera, Alejandra ; Chen, Xiaoying ; Hackett, Maree L ; Woodward, Mark ; Chalmers, John ; Xu, Jianrong ; Robinson, Thompson G ; Parsons, Mark W ; Demchuk, Andrew M ; Lindley, Richard I ; Mair, Grant ; Wardlaw, Joanna M ; Anderson, Craig S. / Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke : The ENCHANTED Trial. In: Neurology. 2021.

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title = "Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial",

abstract = "OBJECTIVE: To determine any differential efficacy and safety of low- versus standard-dose intravenous alteplase for lacunar versus non-lacunar acute ischemic stroke (AIS), we performed post-hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose-arm.METHODS: In a cohort of 3297 ENCHANTED participants, we identified those with lacunar or non-lacunar AIS with different levels of confidence (definite/probable/possible) according to pre-specified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration [END] or death) and treatment effects of low- versus standard-dose alteplase across lacunar and non-lacunar AIS with adjustment for baseline covariables.RESULTS: Of 2588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n=490) or non-lacunar AIS (n=2098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% CI] 0.60 [0.47-0.77]) and other clinical or safety outcomes, compared to participants with non-lacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- versus standard-dose alteplase on all outcomes across lacunar and non-lacunar AIS (all Pinteraction ≥0.07).CONCLUSIONS: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard-dose for definite/probable lacunar AIS.CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at www.clinicaltrials.gov: NCT01422616.",

author = "Zien Zhou and Candice Delcourt and Chao Xia and Sohei Yoshimura and Cheryl Carcel and Takako Torii-Yoshimura and Shoujiang You and Alejandra Malavera and Xiaoying Chen and Hackett, {Maree L} and Mark Woodward and John Chalmers and Jianrong Xu and Robinson, {Thompson G} and Parsons, {Mark W} and Demchuk, {Andrew M} and Lindley, {Richard I} and Grant Mair and Wardlaw, {Joanna M} and Anderson, {Craig S}",

note = "Copyright {\textcopyright} 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2021",

month = feb,

day = "3",

doi = "10.1212/WNL.0000000000011598",

language = "English",

journal = "Neurology",

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Zhou, Z, Delcourt, C, Xia, C, Yoshimura, S, Carcel, C, Torii-Yoshimura, T, You, S, Malavera, A, Chen, X, Hackett, ML, Woodward, M, Chalmers, J, Xu, J, Robinson, TG, Parsons, MW, Demchuk, AM, Lindley, RI, Mair, G , Wardlaw, JM & Anderson, CS 2021, 'Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial', Neurology. https://doi.org/10.1212/WNL.0000000000011598

Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke : The ENCHANTED Trial. / Zhou, Zien; Delcourt, Candice; Xia, Chao; Yoshimura, Sohei; Carcel, Cheryl; Torii-Yoshimura, Takako; You, Shoujiang; Malavera, Alejandra; Chen, Xiaoying; Hackett, Maree L; Woodward, Mark; Chalmers, John; Xu, Jianrong; Robinson, Thompson G; Parsons, Mark W; Demchuk, Andrew M; Lindley, Richard I; Mair, Grant ; Wardlaw, Joanna M; Anderson, Craig S.

In: Neurology, 03.02.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Low- versus Standard-dose Alteplase in Acute Lacunar Ischemic Stroke

T2 - The ENCHANTED Trial

AU - Zhou, Zien

AU - Delcourt, Candice

AU - Xia, Chao

AU - Yoshimura, Sohei

AU - Carcel, Cheryl

AU - Torii-Yoshimura, Takako

AU - You, Shoujiang

AU - Malavera, Alejandra

AU - Chen, Xiaoying

AU - Hackett, Maree L

AU - Woodward, Mark

AU - Chalmers, John

AU - Xu, Jianrong

AU - Robinson, Thompson G

AU - Parsons, Mark W

AU - Demchuk, Andrew M

AU - Lindley, Richard I

AU - Mair, Grant

AU - Wardlaw, Joanna M

AU - Anderson, Craig S

PY - 2021/2/3

Y1 - 2021/2/3

N2 - OBJECTIVE: To determine any differential efficacy and safety of low- versus standard-dose intravenous alteplase for lacunar versus non-lacunar acute ischemic stroke (AIS), we performed post-hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose-arm.METHODS: In a cohort of 3297 ENCHANTED participants, we identified those with lacunar or non-lacunar AIS with different levels of confidence (definite/probable/possible) according to pre-specified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration [END] or death) and treatment effects of low- versus standard-dose alteplase across lacunar and non-lacunar AIS with adjustment for baseline covariables.RESULTS: Of 2588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n=490) or non-lacunar AIS (n=2098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% CI] 0.60 [0.47-0.77]) and other clinical or safety outcomes, compared to participants with non-lacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- versus standard-dose alteplase on all outcomes across lacunar and non-lacunar AIS (all Pinteraction ≥0.07).CONCLUSIONS: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard-dose for definite/probable lacunar AIS.CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at www.clinicaltrials.gov: NCT01422616.

AB - OBJECTIVE: To determine any differential efficacy and safety of low- versus standard-dose intravenous alteplase for lacunar versus non-lacunar acute ischemic stroke (AIS), we performed post-hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose-arm.METHODS: In a cohort of 3297 ENCHANTED participants, we identified those with lacunar or non-lacunar AIS with different levels of confidence (definite/probable/possible) according to pre-specified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration [END] or death) and treatment effects of low- versus standard-dose alteplase across lacunar and non-lacunar AIS with adjustment for baseline covariables.RESULTS: Of 2588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n=490) or non-lacunar AIS (n=2098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% CI] 0.60 [0.47-0.77]) and other clinical or safety outcomes, compared to participants with non-lacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- versus standard-dose alteplase on all outcomes across lacunar and non-lacunar AIS (all Pinteraction ≥0.07).CONCLUSIONS: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard-dose for definite/probable lacunar AIS.CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at www.clinicaltrials.gov: NCT01422616.

U2 - 10.1212/WNL.0000000000011598

DO - 10.1212/WNL.0000000000011598

M3 - Article

C2 - 33536271

JO - Neurology

JF - Neurology

SN - 0028-3878

ER -