Low-Dose vs Standard-Dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial

Abstract

Objective: To determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar 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 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified 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 or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables.

Results: Of 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar 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- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all p interaction ≥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: Clinicaltrials.gov identifier NCT01422616.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Examples of Lacunar Ischemic Stroke at Different Locations From ENCHANTED

Lacunar stroke at (A) left lentiform (red arrow) identified on 24-hour follow-up CT; (B) left internal capsule (red arrow) identified on 24-hour follow-up MRI; (C) right centrum semiovale (red arrow) identified on baseline and 24-hour follow-up MRI; (D) left internal border zone (red arrow) identified on baseline MRI; (E) right thalamus (red arrow) identified on baseline and 24-hour follow-up CT; and (F) brainstem (red arrow) identified on 24-hour follow-up MRI. DWI = diffusion-weighted imaging; ENCHANTED = Enhanced Control of Hypertension and Thrombolysis Stroke Study.

Figure 2. Flowchart of Participants Included in Analyses

Def/Pro = definite or probable.

Figure 3. Thrombolysis Outcomes in Participants With Definite/Probable Lacunar and Nonlacunar Stroke by Randomized Treatment

*Adjusted for key prognostic covariates (age, sex, ethnicity, baseline NIH Stroke Scale [NIHSS] score, time from stroke onset to randomization, premorbid function [modified Rankin Scale (mRS) scores 0 or 1], prior use of antithrombotic agents [aspirin, other antiplatelet agent, or warfarin], history of diabetes or cardiovascular disease [stroke, atrial fibrillation, coronary artery disease, valvular or other heart disease], assigned to intensive blood pressure–lowering group) for functional outcomes. Adjusted for minimization and key prognostic covariates (age, baseline NIHSS score, time from stroke onset to randomization, and assigned to intensive blood pressure–lowering group) for safety outcomes and neurologic deterioration within 24 hours or 7 days.†Site reported or adjudicated centrally. CI = confidence interval; ECASS = European–Australian Cooperative Acute Stroke Study; END = early neurologic deterioration; ICH = intracerebral hemorrhage; IST-3 = third International Stroke Trial; NINDS = National Institutes of Neurologic Diseases and Stroke; sICH = symptomatic intracerebral hemorrhage; SITS-MOST = Safe Implementation of Thrombolysis in Stroke–Monitoring Study.

Figure 4. Randomized Treatment Effects on the Ordinal Modified Rankin Scale (mRS) Score by Lacunar and Nonlacunar Stroke

*Adjusted for key prognostic covariates (age, sex, ethnicity, baseline NIH Stroke Scale [NIHSS] score, time from stroke onset to randomization, premorbid function [mRS scores 0 or 1], prior use of antithrombotic agents [aspirin, other antiplatelet agent, or warfarin], history of diabetes or cardiovascular disease [stroke, atrial fibrillation, coronary artery disease, valvular or other heart disease], assigned to intensive blood pressure–lowering group).

Figure 5. Thrombolysis Outcomes in Participants With Definite Lacunar and Nonlacunar Stroke by Randomized Treatment

*Adjusted for key prognostic covariates (age, sex, ethnicity, baseline NIH Stroke Scale [NIHSS] score, time from stroke onset to randomization, premorbid function [modified Rankin Scale (mRS) scores 0 or 1], prior use of antithrombotic agents [aspirin, other antiplatelet agent, or warfarin], history of diabetes or cardiovascular disease [stroke, atrial fibrillation, coronary artery disease, valvular or other heart disease], assigned to intensive blood pressure–lowering group) for functional outcomes. Adjusted for minimization and key prognostic covariates (age, baseline NIHSS score, time from stroke onset to randomization, and assigned to intensive blood pressure–lowering group) for safety outcomes and neurologic deterioration within 24 hours or 7 days. †Site reported or adjudicated centrally. CI = confidence interval; ECASS = European–Australian Cooperative Acute Stroke Study; END = early neurologic deterioration; ICH = intracerebral hemorrhage; IST-3 = third International Stroke Trial; NINDS = National Institutes of Neurologic Diseases and Stroke; sICH = symptomatic intracerebral hemorrhage; SITS-MOST = Safe Implementation of Thrombolysis in Stroke–Monitoring Study.