ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Low-Dose vs Standard-Dose Alteplase in AcuteLacunar Ischemic StrokeThe ENCHANTED Trial

Zien Zhou MD Candice Delcourt MD PhD Chao Xia MD Sohei Yoshimura MD PhD Cheryl Carcel MD PhD

Takako Torii-Yoshimura MD Shoujiang You MD PhD Alejandra Malavera MD

Xiaoying Chen BPharm BMgt Maree L Hackett PhD Mark Woodward PhD John Chalmers MD PhD

Jianrong Xu MD PhD Thompson G Robinson MD Mark W Parsons MD PhD Andrew M Demchuk MD

Richard I Lindley MD Grant Mair MD Joanna M Wardlaw MD and Craig S Anderson MD PhD

Neurologyreg 202196e1512-e1526 doi101212WNL0000000000011598

Correspondence

Dr Anderson

canderson

georgeinstituteorgau

AbstractObjectiveTo determine any differential efficacy and safety of low- vs standard-dose IV alteplase forlacunar vs nonlacunar acute ischemic stroke (AIS) we performed post hoc analyzes from theEnhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alte-plase dose arm

MethodsIn a cohort of 3297 ENCHANTED participants we identified those with lacunar or non-lacunar AIS with different levels of confidence (definiteaccording to prespecified definitionsbased on clinical and adjudicated imaging findings Logistic regression models were used todetermine associations of lacunar AIS with 90-day outcomes (primary modified Rankin Scale[mRS] scores 2ndash6 secondary other mRS scores intracerebral hemorrhage [ICH] and earlyneurologic deterioration or death) and treatment effects of low- vs standard-dose alteplaseacross lacunar and nonlacunar AIS with adjustment for baseline covariables

ResultsOf 2588 participants with available imaging and clinical data we classified cases as definiteprobable lacunar (n = 490) or nonlacunar AIS (n = 2098) for primary analyses Regardless ofalteplase dose received lacunar AIS participants had favorable functional (mRS 2ndash6 adjustedodds ratio [95 confidence interval] 060 [047ndash077]) and other clinical or safety outcomescompared to participants with nonlacunar AIS Low-dose alteplase (versus standard) had nodifferential effect on functional outcomes (mRS 2ndash6 104 [087ndash124]) but reduced the risk ofsymptomatic ICH in all included participants There were no differential treatment effects oflow- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all pinter-action ge007)

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Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

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From The George Institute for Global Health Faculty of Medicine (ZZ CD CX S Yoshimura CC TT-Y AM XC MLH MW JC CSA) and South Western Clinical School(MWP) University of New South Wales Sydney Australia Department of Radiology (ZZ JX) Ren Ji Hospital School of Medicine Shanghai Jiao Tong University China Departmentof Neurology (CD CC CSA) Royal Prince Alfred Hospital Sydney Health Partners Sydney Medical School (CD CC) University of Sydney Australia Department of Neuro-surgery (CX) West China Hospital Sichuan University Chengdu China Department of Cerebrovascular Medicine (S Yoshimura TT-Y) National Cerebral and CardiovascularCenter Osaka Department of Neurology and Neuroscience (TT-Y) Nagoya City University Graduate School of Medical Science Japan Department of Neurology (S You) theSecond Affiliated Hospital of Soochow University Suzhou China The George Institute for Global Health School of Public Health (MW) Imperial College London Department ofCardiovascular Sciences and NIHR Leicester Biomedical Research Center (TGR) University of Leicester UK Melbourne Brain Centre Royal Melbourne Hospital UniversityDepartment of Medicine (MWP) University of Melbourne Australia Departments of Clinical Neurosciences and Radiology Hotchkiss Brain Institute Cumming School of Medicine(AMD) University of Calgary Canada Westmead Applied Research Centre (RIL) University of Sydney Australia Division of Neuroimaging Sciences Edinburgh Imaging andCentre for Clinical Brain Sciences (GM JMW) and UK Dementia Research Institute (JMW) University of Edinburgh and The George Institute China at Peking University HealthScience Center (CSA) Beijing China

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The article processing charge was paid by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution License 40 (CC BY) which permits unrestricted use distribution and reproduction in anymedium provided the original work is properly cited

e1512 Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology

ConclusionsWe found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definiteprobable lacunar AIS

Classification of EvidenceThis study provides Class II evidence that for patients with lacunar AIS low-dose alteplase had no additional benefit or safetyover standard-dose alteplase

Clinical Trial RegistrationClinicaltrialsgov identifier NCT01422616

In routine clinical practice patients with lacunar acute is-chemic stroke (AIS) are eligible to receive IV thrombolysisgiven comparable favorable outcomes to other common AISpathologic subtypes1ndash3 These results were confirmed in arecent subgroup analysis of the Efficacy and Safety of Mag-netic Resonance ImagingndashBased Thrombolysis in Wake-UpStroke (WAKE-UP) trial where the safety and efficacy ofstandard-dose IV alteplase were comparable between lacunarand nonlacunar subtypes defined on baseline MRI4 Similarconsistency of effect of IV alteplase between lacunar andnonlacunar AIS defined by the Oxfordshire CommunityStroke Project (OCSP) syndromic classification was found inthe third International Stroke Trial (IST-3)5 Despite thisevidence some clinical concern persists over whether themodest risk of thrombolysis-related intracerebral hemorrhage(ICH) could offset the modest benefits of IV thrombolysis forlacunar AIS where the natural course is generally more benigncompared to other AIS subtypes6 from there being no or smallthrombotic lytic target on the presumption of a single pene-trating artery occlusion78

In the alteplase-dose arm of the Enhanced Control of Hy-pertension and Thrombolysis Stroke Study (ENCHAN-TED)9 a lower dose (06 mgkg) of IV alteplase was shownto have a lower risk of ICH compared to standard dose (09mgkg) in thrombolysis-eligible patients with AIS Whether itis the same for lacunar AIS is unclear Herein we reportfurther analyses of the efficacy and safety of low- vs standard-dose IV alteplase in the ENCHANTED participants with la-cunar (versus nonlacunar) AIS who were identified by thecombination of clinical and adjudicated imaging findings

MethodsPrimary ResearchQuestion and Evidence LevelIs there are any differential efficacy and safety of low- vsstandard-dose IV alteplase between participants with lacunar andnonlacunar AIS in the alteplase dose arm of the ENCHANTEDtrial This study provides Class II evidence that for patients withlacunar AIS low-dose alteplase has no additional benefit orsafety over standard-dose alteplase

Design and ParticipantsENCHANTED was an international multicenter 2 times 2quasifactorial prospective randomized open-label blinded-endpoint trial that assessed the effectiveness of low-dose (06mgkg 15 as bolus 85 as infusion during 1 hour) vsstandard-dose (09 mgkg 10 as bolus 90 as infusionduring 1 hour) IV alteplase and more intensive vs guideline-recommended control of blood pressure (BP) in adultparticipants with AIS The study design participant charac-teristics and main results of the alteplase-dose arm have beenreported9ndash11 for 3310 patients with AIS recruited from 111centers in 13 countries Key demographic and clinical char-acteristics were recorded at the time of enrollment withclinical severity defined according to the NIH Stroke Scale(NIHSS) at baseline 24 hours and at day 7 (or on dischargefrom hospital if earlier) A final clinical diagnosis of AISsubtypes based upon the opinion of site investigations gen-erally according to the Trial of Org 10172 in Acute StrokeTreatment (TOAST) classification system12 was made atday 7 postrandomization (or on discharge from hospital ifearlier)

GlossaryAIS = acute ischemic stroke BP = blood pressure CI = confidence interval CSVD = cerebral small vessel disease CTA = CTangiographyDICOM =Digital Imaging and Communications inMedicine ECASS = EuropeanndashAustralian Cooperative AcuteStroke Study ENCHANTED = Enhanced Control of Hypertension and Thrombolysis Stroke Study END = early neurologicdeterioration ICH = intracerebral hemorrhage IST-3 = the third International Stroke Trial LVO = large vessel occlusionMRA = magnetic resonance angiography mRS = modified Rankin Scale NIHSS = NIH Stroke Scale NINDS = NationalInstitutes of Neurological Diseases and Stroke OCSP = Oxfordshire Community Stroke Project OR = odds ratio sICH =symptomatic intracerebral hemorrhage SITS-MOST = the Safe Implementation of Thrombolysis in StrokendashMonitoring StudyTICI = Thrombolysis in Cerebral Infarction TOAST = Trial of Org 10172 in Acute Stroke Treatment classificationWAKE-UP = Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke trial

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1513

Standard Protocol Approvals Registrationsand Participant ConsentsThe study protocol was approved by the appropriate ethicscommittee at each participating center and written informedconsent was obtained from participants or an appropriatelegal surrogate according to the Declaration of Helsinki TheENCHANTED trial was registered at ClinicalTrialsgov(Unique identifier NCT01422616)

Imaging AnalysisUncompressed digital images of all baseline and follow-updigital CT MRI and angiographic images were uploaded intothe study brain imaging database in Digital Imaging andCommunications in Medicine (DICOM) format identifiedonly by the participantrsquos unique study identification numberImages were analyzed centrally for any ICH by a trial adjudi-cation panel blind to clinical data treatment date and se-quence of scan Assessors graded any identified symptomaticICH (sICH) using a range of standard definitions from the SafeImplementation of Thrombolysis in StrokendashMonitoring Study(SITS-MOST) National Institute of Neurologic Disease andStroke (NINDS) the EuropeanndashAustralian Cooperative AcuteStroke Study II (ECASS) ECASS III and IST-3 (additionalMethods I doiorg105061dryadt1g1jwt0s)

The ENCHANTED Imaging Analysis Project was establishedin August 2016 with the aim of defining the presence extentand severity of and swelling from acute ischemic changes(including arterial territory border zone small subcortical andbrainstemcerebellar infarcts) coexisting old vascular lesionsand their subtypes white matter lesions and brain volume losson all collected images by an imaging analysis team of trainedindividuals blind to all clinical data using an electronic scoringsystem modified from IST-313 All observed infarct lesions onbaseline (prerandomization) CT or MRI were coded accordingto the IST-3 criteria for infarct site and size Separately andsubsequent to primary scan reads a neuroradiologist (ZZ) andneurosurgeon (XC) sought the ischemic lesion on 24-hourfollow-up images while viewing the baseline images for thosewith no infarct lesion identified at baseline They also assessedlarge vessel occlusion (LVO) on baseline CT angiography(CTA) or magnetic resonance angiography (MRA) accordingto a modified Thrombolysis in Cerebral Infarction (TICI) scorefor an abnormal artery in IST-314 All the imaging data werecross-checked (ZZ) and a final rating made before unmaskingthe clinical data and randomization code for analyses

Definitions of Lacunar and Nonlacunar AISDifferent levels of confidence (definiteprobablepossible)were used around the definitions of lacunar and nonlacunarAIS based on adjudicated imaging findings clinical severityand clinical diagnosis (additional Methods II doiorg105061dryadt1g1jwt0s) In brief definite lacunar AIS wasdefined when all 4 criteria were met (1) the presence of acuteinfarct lesion (maximum diameter le20 mm) in the territory ofpenetrating arteries with a rounded ovoid or tubular shapeon axial CT or diffusion-weighted imagingapparent diffusion

coefficient map (typical examples are shown in figure 1)15 (2)no LVO adjudicated centrally (on CTAMRA) or reportedby site investigators (on CTAMRAdigital subtraction an-giography) (3) the final diagnosis was reported as ldquosmallvessel or perforating vessel lsquolacunarrsquo diseaserdquo according to theTOAST criteria that involved any of the standard clinicallacunar syndromes with the lack of large vessel atheroma orcerebral cortical dysfunction and (4) infarct side on images isconsistent with that reported by site investigators Definitenonlacunar AIS was defined as having acute infarct lesion withmaximum diameter gt20 mm or LVO on angiography Par-ticipants were classified as nonlacunar if they had lacunar andnonlacunar infarcts

Given that the clinical diagnosis of lacunar syndrome plusbaseline NIHSS score lt7 had a high specificity to predictimaging-confirmed lacunar stroke in IST-316 probable lacu-nar and nonlacunar AIS were discriminated mainly by base-line NIHSS scores and final diagnosis in the situation thatthere was no acute infarct lesion identified on images or theimages were not collected from the sites For those withconflicting clinical and adjudicated imaging information thatcompromised the confidence of discrimination we classifiedas possible lacunar or nonlacunar AIS according to the clinicaldiagnosis and LVO status

OutcomesThe primary outcome of these analyses was the compositeendpoint of disability or death (modified Rankin Scale [mRS]scores 2ndash6) at 90 days postrandomization Secondary efficacyoutcomes included major disability or death (mRS 3ndash6)death (mRS 6) and ordinal shift of the full range of mRSscores at 90 days Secondary safety outcomes were sICHdefined according to several criteria from other studies fatalICHwithin 7 days ICH identified by central adjudicators andany ICH adjudicated centrally or reported by site investiga-tors Other clinical outcomes included early neurologic de-terioration (END) (ge4-point increase in NIHSS scores) ordeath within 24 hours or 7 days

Statistical AnalysisContinuous or categorical variables at baseline were presentedas mean (SD) median (interquartile range) or number (per-centage) Baseline differences between participants with lacu-nar and nonlacunar AIS were evaluated using analysis ofvariance χ2 test or Wilcoxon signed-rank test as appropriateAssociations of lacunar AIS with 90-day function safety andother secondary outcomes were estimated in logistic regressionmodels with adjustment for randomized treatment and keyprognostic covariates (age sex ethnicity baseline NIHSSscore time from symptom onset to randomization premorbidfunction [mRS score 0 or 1] prior use of antithromboticagents history of diabetes or cardiovascular disease andassigned to intensive blood pressurendashlowering group) Thetreatment effect of low- vs standard-dose alteplase was de-termined in logistic regression models and the heterogeneity ofalteplase dose effect across participants with lacunar and

e1514 Neurology | Volume 96 Number 11 | March 16 2021 NeurologyorgN

nonlacunar AIS was estimated by adding an interaction term tostatistical models Proportional odds regression models wereused to analyze ordinal mRS scores The primary analysespertain to participants with definiteprobable lacunar andnonlacunar AIS after excluding those with a possible diagnosticclassification Sensitivity analyses of the treatment effects oflow- vs standard-dose alteplase were performed in participantswith definite lacunarnonlacunar AIS and in all participantswith possible lacunarnonlacunar AIS We also performed anexploratory analysis of the treatment effects in a subset of la-cunar AIS identified at baseline (infarct size le15 mm and noadjudicated LVO) Data were reported as odds ratios (ORs)and 95 confidence intervals (CIs) and a 2-sided p lt 005 wasconsidered statistically significant All analyses were performedusing SAS version 71 and Stata version 120

Data AvailabilityAdditional methods (I and II) and data (supplementary tables1ndash3) are available from Dryad (doiorg105061dryadt1g1jwt0s) Individual de-identified participant data used in thisanalysis will be shared by request from any qualified investigatorvia the ResearchOffice of TheGeorge Institute forGlobalHealth

ResultsBaseline CharacteristicsAmong 3297 AIS participants in the ENCHANTED alteplasedose arm 2588 (785) were classifiable (definite lacunarn = 195 probable lacunar n = 295 definite nonlacunar n =1697 and probable nonlacunar n = 401 AIS) for inclusion in

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-upMRI (C)right centrum semiovale (red arrow) identified on baseline and 24-hour follow-upMRI (D) left internal border zone (red arrow) identified on baseline MRI (E)right thalamus (red arrow) identified onbaseline and 24-hour follow-upCT and (F) brainstem (red arrow) identified on 24-hour follow-upMRI DWI =diffusion-weighted imaging ENCHANTED = Enhanced Control of Hypertension and Thrombolysis Stroke Study

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1515

the primary analysis (figure 2) Compared to the 709 excludedparticipants they were more likely to be older have higherbaseline NIHSS scores be Asian have a history of cardio-vascular disease and have a final diagnosis of LVO but theyalso had shorter time interval from symptom onset to ran-domization (supplementary table 1 doiorg105061dryadt1g1jwt0s) Table 1 shows that all the baseline clinical char-acteristics were significantly different between definiteprobable lacunar and nonlacunar AIS except for sex historyof diabetes and prior use of statinother lipid-loweringagents Participants with lacunar (versus nonlacunar) AISwere younger and had milder neurologic impairment higherbaseline BP and a lower proportion with conventional car-diovascular risk factors except smoking In keeping with thelacunar pattern of stroke few participants had multiple lesionsin both anterior and posterior circulation but they were morelikely to have a lesion only in the posterior circulation Theywere also less likely to have brain atrophy or a hyperdensevessel sign on CT or hyperintense arteries on MRI

Lacunar AIS and OutcomesCompared to participants with definiteprobable nonlacunarAIS those with definiteprobable lacunar AIS had better 90-day functional outcomes whether defined by the outcome ofmRS scores 2ndash6 (unadjusted OR 026 95 CI 021ndash033)mRS scores 3ndash6 (020 015ndash026) ordinal shift in the full rangeof scores (027 023ndash033) or death alone (004 001ndash012)(table 2) They were also less likely to have ICH and END ordeath after IV thrombolysis The findings persisted with ad-justment of baseline covariables and randomized alteplase dose

Lacunar AIS and Alteplase DoseThe overall treatment effects of low- vs standard-dose alte-plase on function safety and other outcomes in these 2588participants were comparable to the main results of theENCHANTED trial that low-dose vs standard-dose alteplasereduced the risk of sICH (SITS-MOST criteria adjusted OR039 95 CI 021ndash073 NINDS criteria 067 050ndash089ECASS II criteria 056 039ndash080 ECASS III criteria 037021ndash067 IST-3 criteria 054 033ndash087) but with no dif-ference in effect on functional outcomes (mRS 2ndash6 adjustedOR 104 95 CI 087ndash124 mRS 3ndash6 101 085ndash121)There was no heterogeneity of treatment effects on all out-comes for definiteprobable lacunar vs nonlacunar AIS afteradjustment for baseline covariables (all pinteraction ge007)(figures 3 and 4) Similar results were seen in the sensitivityanalyses for definite lacunar and nonlacunar AIS (all pinteractionge016) (figures 4 and 5) and definiteprobablepossible la-cunar and nonlacunar AIS (all pinteraction ge012) (data avail-able on request)

Specifically in the definite subgroup of lacunar AIS therewere no significant differences on the primary efficacy out-come (mRS 2ndash6) (337 vs 329 adjusted OR 096 95 CI049ndash187) or major disability or death (mRS 3ndash6) (202 vs153 adjusted OR 131 95 CI 054ndash319) between low-dose and standard-dose alteplase groups (figure 5) There wasone case of sICH (09) meeting NINDS and IST-3 criteriain participants with definite lacunar AIS treated by low-dosealteplase but no case of sICH was observed after use ofstandard-dose alteplase In participants with definite lacunar

Figure 2 Flowchart of Participants Included in Analyses

DefPro = definite or probable

e1516 Neurology | Volume 96 Number 11 | March 16 2021 NeurologyorgN

Table 1 Baseline Characteristics of Participants With DefiniteProbable Lacunar and Nonlacunar Stroke

Low-dose LACS (n = 241)nonlacunar stroke (n = 1059)

Standard-dose LACS (n = 249)nonlacunar stroke (n = 1039)

Total LACS (n = 490)nonlacunar stroke(n = 2098)

pValuea

Age y

LACS 639 (128) 631 (125) 635 (127) lt0001b

Nonlacunar stroke 678 (127) 678 (126) 678 (127)

Female

LACS 82 (340) 91 (365) 173 (353) 031

Nonlacunar stroke 402 (380) 390 (375) 792 (378)

Asian ethnicity

LACS 179 (743) 174 (699) 353 (720) lt0001b

Nonlacunar stroke 675 (637) 6631038 (639) 13382097 (638)

Clinical features

Systolic BP mm Hg

LACS 1516 (178) 1537 (194) 1526 (187) lt0001b

Nonlacunar stroke 1480 (197) 1483 (202) 1482 (199)

Diastolic BP mm Hg

LACS 866 (117) 867 (129) 866 (123) lt0001b

Nonlacunar stroke 840 (132) 842 (130) 841 (131)

Heart rate beats per minute

LACS 761 (117) 777 (127) 769 (122) 0001b

Nonlacunar stroke 793 (166) 797 (163) 795 (165)

NIHSS scorec

LACS 4 (3ndash6) 5 (4ndash6) 5 (3ndash6) lt0001b

Nonlacunar stroke 11 (7ndash16) 11 (7ndash16) 11 (7ndash16)

GCS scored

LACS 15 (15ndash15) 15 (15ndash15) 15 (15ndash15) lt0001b

Nonlacunar stroke 14 (12ndash15) 15 (12ndash15) 15 (12ndash15)

Medical history

Previous stroke

LACS 39 (162) 30 (120) 69 (141) 003b

Nonlacunar stroke 185 (175) 197 (190) 382 (182)

Hypertension

LACS 142 (589) 148 (594) 290 (592) 003b

Nonlacunar stroke 671 (634) 6781038 (653) 13492097 (643)

Atrial fibrillation

LACS 9 (37) 11 (44) 20 (41) lt0001b

Nonlacunar stroke 2881056 (273) 2591038 (250) 5472094 (261)

Coronary artery disease

LACS 23 (95) 16 (64) 39 (80) lt0001b

Continued

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1517

Table 1 Baseline Characteristics of Participants With DefiniteProbable Lacunar and Nonlacunar Stroke (continued)

Low-dose LACS (n = 241)nonlacunar stroke (n = 1059)

Standard-dose LACS (n = 249)nonlacunar stroke (n = 1039)

Total LACS (n = 490)nonlacunar stroke(n = 2098)

pValuea

Nonlacunar stroke 184 (174) 1711038 (165) 3552097 (169)

Valvularother heart disease

LACS 4 (17) 7 (28) 11 (22) lt0001b

Nonlacunar stroke 92 (87) 951038 (92) 1872097 (89)

Diabetes

LACS 50 (207) 52 (209) 102 (208) 059

Nonlacunar stroke 203 (192) 2111038 (203) 4142097 (197)

Hypercholesterolemia

LACS 34 (141) 32 (129) 66 (135) 004b

Nonlacunar stroke 194 (183) 1711038 (165) 3652097 (174)

Current smoker

LACS 63 (261) 85 (341) 148 (302) lt0001b

Nonlacunar stroke 2221057 (210) 2331037 (225) 4552094 (217)

Prestroke function withoutdisabilitye

LACS 36 (149) 33 (133) 69 (141) 0005b

Nonlacunar stroke 1941058 (183) 2161037 (208) 4102095 (196)

Medication on admission

Antihypertensive agents

LACS 93 (386) 103 (414) 196 (400) 0002b

Nonlacunar stroke 507 (479) 4961038 (478) 10032097 (478)

Warfarin anticoagulation

LACS 1240 (04) 1 (04) 2489 (04) lt0001b

Nonlacunar stroke 39 (37) 291037 (28) 682096 (32)

Aspirinother antiplateletagent

LACS 46240 (192) 47 (189) 93489 (190) 001b

Nonlacunar stroke 287 (271)f 2251037 (217)f 5122096 (244)

Statinother lipid-loweringagent

LACS 40240 (167) 38 (153) 78489 (160) 011

Nonlacunar stroke 2151058 (203) 1851037 (178) 4002095 (191)

Time from stroke onset toCTMRI scan h

LACS 18 (13ndash25) 19 (13ndash26) 18 (13ndash25) lt0001b

Nonlacunar stroke 17 (11ndash23) 16 (11ndash23) 16 (11ndash23)

Imaging features

Infarct at left side

LACS 78153 (510) 78150 (520) 156303 (515) 014

Continued

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Table 1 Baseline Characteristics of Participants With DefiniteProbable Lacunar and Nonlacunar Stroke (continued)

Low-dose LACS (n = 241)nonlacunar stroke (n = 1059)

Standard-dose LACS (n = 249)nonlacunar stroke (n = 1039)

Total LACS (n = 490)nonlacunar stroke(n = 2098)

pValuea

Nonlacunar stroke 400841 (476) 384833 (461) 7841674 (468)

Infarct at right side

LACS 70153 (458) 66150 (440) 136303 (449) 011

Nonlacunar stroke 407841 (484) 428833 (514) 8351674 (499)

Infarct at midline or bilateralside

LACS 5153 (33) 6150 (40) 11303 (36) 076

Nonlacunar stroke 34841 (40) 21833 (25) 551674 (33)

Infarct in anterior circulationonly

LACS 117153 (765) 114150 (760) 231303 (762) 009

Nonlacunar stroke 689841 (819) 658833 (790) 13471674 (805)

Infarct in posterior circulationonly

LACS 35153 (229) 36150 (240) 71303 (234) lt0001b

Nonlacunar stroke 103841 (122) 120833 (144) 2231674 (133)

Infarct in anterior and posteriorcirculation

LACS 1153 (07) 0150 (00) 1303 (03) lt0001b

Nonlacunar stroke 49841 (58) 55833 (66) 1041674 (62)

With FLAIR-HAs or hyperdensevessel sign

LACS 3151 (20) 5156 (32) 8307 (26) lt0001b

Nonlacunar stroke 306835 (366) 305826 (369) 6111661 (368)

With old vascular lesions

LACS 70153 (458) 59150 (393) 129303 (426) 083

Nonlacunar stroke 362841 (430) 362833 (435) 7241674 (432)

With brain atrophy

LACS 94153 (614) 79150 (527) 173303 (571) lt0001b

Nonlacunar stroke 574841 (683) 589833 (707) 11631674 (695)

With white matter changes

LACS 64153 (418)f 46150 (307)f 110303 (363) 082

Nonlacunar stroke 301841 (358) 318833 (382) 6191674 (370)

Site reported LVO or assessedcentrally

LACS 0 (00) 0 (00) 0 (00) lt0001b

Nonlacunar stroke 2701041 (259) 2621027 (255) 5322068 (257)

Time from stroke onset torandomization h

LACS 30 (23ndash37) 28 (22ndash36) 29 (22ndash36) lt0001b

Continued

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1519

AIS who received low-dose alteplase 3 (28) had adjudi-cated ICH and 1 more had ICH reported by a site in-vestigator while any ICH occurred in 2 (22) participantswith definite lacunar AIS assigned to the standard-dose groupIn a smaller subset of definite lacunar AIS identified at baselinewith size lt15 mm and no adjudicated LVO 4 of the 9 par-ticipants (444) in the low-dose group and 2 of the 7 par-ticipants (286) in the standard-dose group had mRS 2ndash6 at90 days postrandomization and no ICH occurred in eithertreatment group (supplementary table 2 doiorg105061dryadt1g1jwt0s)

DiscussionIn these post hoc analyzes of the ENCHANTED trial we did notidentify any benefit nor any harm from the use of low-dosealteplase vs standard-dose alteplase to treat patients with lacunarAIS compared to those with other subtypes of AIS As well ashaving a range of significantly different characteristics the 90-dayoutcomes were better for those with lacunar than nonlacunarAIS which provided some internal consistency for the classifi-cations used in our study However given the low event rate ofsICHwith fewer than 5 events in the primary analysis for definiteor probable lacunar AIS we are limited in the conclusions thatcan be drawn as towhether a lower dose of IV alteplase should bepreferred because of the good prognosis for lacunar AIS

Our results on thrombolysis outcomes for lacunar AIS areconsistent with prior observational studies217ndash21 Howeverthe net benefit of thrombolysis for lacunar AIS is still debatedmainly because the evidence is drawn from subgroup analyzesof trials such as WAKE-UP4 and IST-35 where there is lowstatistical power In addition accurate identification of lacunar

AIS is challenging especially in the absence of an acute lesionon the initial CT and even MRI (in nearly one third ofpatients with nondisabling stroke)22 The pragmatic approachof applying a lacunar syndrome classification system in studieshas moderate diagnostic sensitivity and specificity15 whichmay potentially mix patients with nonlacunar AIS with thetarget population of lacunar AIS and nondifferentially biasresults towards IV thrombolysis

We were unable to confirm in ENCHANTED participantsany benefit of low-dose over standard-dose alteplase in lacu-nar AIS The fact that there were few cases of sICH in the low-dose alteplase group and no sICH in the standard-dosegroup highlights the potential for chance and imprecise es-timates of treatment effects when there are few events Evenwith current imaging techniques and clinical criteria it isdifficult to discriminate lacunar AIS due to occlusion of a deeppenetrating arteriole presumed caused by progressive lip-ohyalinosis from thrombosis related to atherosclerosis orembolus Platelet activation triggered by disintegration of theendothelium from intrinsic cerebral small vessel disease(CSVD) may also be relevant in this type of AIS8 It is pos-sible therefore that IV thrombolysis may have a differentialeffect dependent on the cause of lacunar stroke being moreeffective when there is underlying thromboembolism In la-cunar AIS we noted a significant imbalance in the frequencyof background white matter lesions between the low-dose andstandard-dose alteplase groups (418 vs 307) whichcould partly account for more ICH in the former (supple-mentary table 3 doiorg105061dryadt1g1jwt0s)23 Againhowever due to the few sICH events in patients with lacunarAIS we cannot confirm whether the increase in sICH by low-dose alteplase was confounded by CSVD

Table 1 Baseline Characteristics of Participants With DefiniteProbable Lacunar and Nonlacunar Stroke (continued)

Low-dose LACS (n = 241)nonlacunar stroke (n = 1059)

Standard-dose LACS (n = 249)nonlacunar stroke (n = 1039)

Total LACS (n = 490)nonlacunar stroke(n = 2098)

pValuea

Nonlacunar stroke 26 (19ndash33) 26 (19ndash34) 26 (19ndash34)

Assigned to intensive BP lowering

LACS 48 (199) 48 (193) 96 (196) lt0001b

Nonlacunar stroke 127 (120) 139 (134) 266 (127)

Assigned to standard BP lowering

LACS 41 (170) 48 (193) 89 (182) 0008b

Nonlacunar stroke 145 (137) 138 (133) 283 (135)

Abbreviations BP = blood pressure FLAIR = fluid-attenuated inversion recovery GCS = Glasgow Coma Scale HAs = hyperintense arteries LACS = lacunarstroke LVO = large vessel occlusion NIHSS = NIH Stroke ScaleData are n () mean (SD) or median (Q1 Q3) The p values are based on χ2 analysis of variance or Wilcoxon signed-rank testa Total lacunar stroke vs total nonlacunar strokeb Significantc Scores on the NIHSS range from 0 to 42 with higher scores indicating more severe neurologic deficitsd Scores on the GCS range from 15 (normal) to 3 (deep coma)e mRS = 0f p lt 005 by randomization treatment

e1520 Neurology | Volume 96 Number 11 | March 16 2021 NeurologyorgN

Some strengths of our study include the large prospectivemulticenter cohort of patients with AIS who had systematiccomplete and high-quality data collected prospectively where wewere able to adjust for multiple covariables in statistical modelsFurthermore the imaging assessment was completed blind toclinical features and other data using a rigorously defined ap-proach developed for the IST-3 study However we acknowledgelimitations that include insufficient statistical power and

inevitable selection bias from the data being derived from aclinical trial where a large number of participants were from Asiaand had mild to moderate stroke Moreover given the pragmaticnature of ENCHANTED few participants had a baseline brainMRI and the identification of lacunar AIS required analysis offollow-up images with comparison to those obtained at baselineWhereas this approachmay have altered the imaging appearancesof acute ischemic lesions after use of IV thrombolysis24 and

Table 2 Thrombolysis Outcomes in DefiniteProbable Lacunar Versus Nonlacunar Stroke

Lacunar nN () Nonlacunar nN ()

Lacunar vs nonlacunar stroke

OR (95 CI)a p Value aOR (95 CI)ab p Value

90-day functional outcomes

mRS 2ndash6 147481 (306) 12842052 (626) 026 (021 033) lt0001c 060 (047 077) lt0001c

mRS 3ndash6 75481 (156) 9872052 (481) 020 (015 026) lt0001c 051 (038 069) lt0001c

mRS 6 3490 (06) 2822098 (134) 004 (001 012) lt0001c 013 (004 043) lt0001c

mRS 0 185481 (385) 3702052 (180) 027 (023 033) lt0001c 064 (052 078) lt0001c

1 149481 (310) 3982052 (194)

2 72481 (150) 2972052 (145)

3 47481 (98) 2782052 (135)

4 21481 (44) 2652052 (129)

5 4481 (08) 1622052 (79)

6 3481 (06) 2822052 (137)

Safety outcomes (sICH or ICH)

SITS-MOST 1490 (02) 482098 (23) 009 (001 063) 002c 009 (001 070) 002c

NINDS 4490 (08) 2112098 (101) 007 (003 020) lt0001c 010 (004 027) lt0001c

ECASS II 2490 (04) 1322098 (63) 006 (002 025) lt0001c 008 (002 031) lt0001c

ECASS III 1490 (02) 572098 (27) 007 (001 053) 001c 008 (001 058) 001c

IST-3 2490 (04) 742098 (35) 011 (003 046) 0002c 013 (003 054) 0005c

Fatal ICH 0490 (00) 322098 (15) mdash mdash mdash mdash

Adjudicated any ICH 17490 (35) 5242098 (250) 011 (007 018) lt0001c 018 (011 029) lt0001c

Any ICH 18490 (37) 5822098 (277) 010 (006 016) lt0001c 016 (010 027) lt0001c

Other secondary outcomes

END or death

Within 24 h 20490 (41) 2162098 (103) 037 (023 059) lt0001c 030 (018 050) lt0001c

Within 7 d 27490 (55) 3362098 (160) 031 (020 046) lt0001c 036 (024 056) lt0001c

Abbreviations aOR = adjusted odds ratio CI = confidence interval ECASS = EuropeanndashAustralian Cooperative Acute Stroke Study END = early neurologicdeterioration ICH = intracerebral hemorrhage IST-3 = third International Stroke Trial mRS = modified Rankin Scale NIHSS = NIH Stroke Scale NINDS =National Institutes of Neurologic Diseases and Stroke OR = odds ratio sICH = symptomatic intracerebral hemorrhage SITS-MOST = Safe Implementation ofThrombolysis in StrokendashMonitoring Studya Refers to the effect of IV thrombolysis in definiteprobable lacunar stroke vs nonlacunar stroke after pooling the 2 groups of randomized alteplase dose asone cohortb Adjusted for key prognostic covariates (age sex ethnicity baseline NIHSS score time from stroke onset to randomization premorbid function [mRS score0 or 1] prior use of antithrombotic agents [aspirin other antiplatelet agent or warfarin] history of diabetes or cardiovascular disease [stroke atrialfibrillation coronary artery disease valvular or other heart disease] assigned to intensive blood pressurendashlowering group and randomization to low-dosealteplase group) for functional outcomes Adjusted for minimization and key prognostic covariates (age baseline NIHSS score time from stroke onset torandomization assigned to intensive blood pressurendashlowering group and randomization to low-dose alteplase group) for safety outcomes and neurologicdeterioration within 24 hours and 7 daysc Significant

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1521

Figure 3 Thrombolysis Outcomes in Participants With DefiniteProbable Lacunar and Nonlacunar Stroke by RandomizedTreatment

Adjusted for key prognostic covariates (age sex ethnicity baseline NIH Stroke Scale [NIHSS] score time from stroke onset to randomization premorbidfunction [modified Rankin Scale (mRS) scores 0 or 1] prior use of antithrombotic agents [aspirin other antiplatelet agent or warfarin] history of diabetes orcardiovascular disease [stroke atrial fibrillation coronary artery disease valvular or other heart disease] assigned to intensive blood pressurendashloweringgroup) for functional outcomes Adjusted for minimization and key prognostic covariates (age baseline NIHSS score time from stroke onset to randomi-zation and assigned to intensive blood pressurendashlowering group) for safety outcomes and neurologic deterioration within 24 hours or 7 daysdaggerSite reportedor adjudicated centrally CI = confidence interval ECASS = EuropeanndashAustralian 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 = symptomaticintracerebral hemorrhage SITS-MOST = Safe Implementation of Thrombolysis in StrokendashMonitoring Study

e1522 Neurology | Volume 96 Number 11 | March 16 2021 NeurologyorgN

limited the identification of all true lacunar AIS our results arecomparable with previous work showing that nearly one-third ofpatients with nondisabling AIS lack an infarct lesion on acuteMRI (median 4 days poststroke)22 In the ENCHANTED alte-plase arm 271 (7892916) of participants had no infarct lesionon either the baseline or 24-hour follow-up images Thus we hadto use a combination of clinical and adjudicated imaging data toclassify asmany cases as possible into lacunar and nonlacunar AISwhich likely closely represents that used in routine practiceRelatively small samples in lacunar AIS compromised the power

of a reliable assessment of any interaction especially for sICHMoreover regarding the outcomes of major disability or death apinteraction of 007 might have been due to chance rather than truedifferential treatment effects of low- vs standard-dose alteplaseacross definiteprobable lacunar and nonlacunar AIS Futureresearch in systematic reviews and clinical registries may be re-quired to confirm or refute these findings

We found no clear evidence that low-dose IV alteplase wasany better or safer than standard-dose alteplase in the

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

Adjusted for key prognostic covariates (age sex ethnicity baseline NIH Stroke Scale [NIHSS] score time from stroke onset to randomization premorbidfunction [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 pressurendashlowering group)

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1523

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 premorbidfunction [modified Rankin Scale (mRS) scores 0 or 1] prior use of antithrombotic agents [aspirin other antiplatelet agent or warfarin] history of diabetes orcardiovascular disease [stroke atrial fibrillation coronary artery disease valvular or other heart disease] assigned to intensive blood pressurendashloweringgroup) for functional outcomes Adjusted for minimization and key prognostic covariates (age baseline NIHSS score time from stroke onset to randomi-zation and assigned to intensive blood pressurendashlowering group) for safety outcomes and neurologic deterioration within 24 hours or 7 days daggerSite reportedor adjudicated centrally CI = confidence interval ECASS = EuropeanndashAustralian 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 = symptomaticintracerebral hemorrhage SITS-MOST = Safe Implementation of Thrombolysis in StrokendashMonitoring Study

e1524 Neurology | Volume 96 Number 11 | March 16 2021 NeurologyorgN

ENCHANTED participants who had lacunar AIS Accordingto standard eligibility criteria patients with lacunar AIS shouldreceive standard dose IV alteplase as with other AIS subtypes

AcknowledgmentThe authors thank the investigators study teams and patientsfor participating in the ENCHANTED trial The researchteam acknowledges the support of the National Institute forHealth Research Clinical Research Network (NIHR CRN)for conduct of the trial in England ZZ received overseasvisiting funding from Ren Ji Hospital School of MedicineShanghai Jiao Tong University (2016ndash2018) and a ScientiaPhD Scholarship from the University of New South WalesSydney (2018ndash2022) during the conduct of the study CSAholds an NHMRC Senior Investigator Fellowship

Study FundingThis study is supported by grants from the National Healthand Medical Research Council (NHMRC) of Australia(project grant numbers 1020462 and 1101113) the StrokeAssociation of the UK (TSA 201201 and 201501) theMinistry of Health and the National Council for Scientific andTechnological Development of Brazil (CNPQ 4673222014-7 4023882013-5) the Ministry for Health Welfareand Family Affairs of the Republic of Korea (HI14C1985)(for the alteplase-dose arm) and a research grant fromTakeda for conduct of the study in China

DisclosureDr Xia received a scholarship from China Scholarship Council(CSC) Prof Hackett reports a fellowship and research grantsfrom the National Health and Medical Research Council(NHMRC) of Australia Prof Woodward reports a NationalHealth and Medical Research Council Investigator Grant(APP1174120) and Program Grant (APP1149987) and is aconsultant to Amgen Freeline and Kyowa Hakko Kirin ProfChalmers reports research grants and honoraria from Servier forthe ADVANCE trial outside the submitted work Prof Rob-inson reports grants from The Stroke Association UK and wasa National Institute for Health Research (NIHR) Senior In-vestigator during the conduct of the study Prof Parsons reportspersonal fees from serving on Advisory Board for BoehringerIngelheim (which markets alteplase outside of North America)during the conduct of the study Prof Demchuk reports per-sonal fees from Medtronic personal fees from Daiichi Sankyoand a patent to Circle NVI issued outside the submitted workProf Lindley reports grants from NHMRC of Australia duringthe conduct of the study Dr Mair reports grants from TheStroke Association UK during the conduct of the study ProfWardlaw reports grants from The Stroke Association UK theFondation Leducq the British Heart Foundation The Euro-pean Union the Row Fogo Charitable Trust the AlzheimerrsquosSociety Alzheimerrsquos Research UK and UK Medical ResearchCouncil during the conduct of the study Prof Andersonreports receiving honorarium from Takeda during the conductof the study Other authors have nothing to disclose for thepresent study Go to NeurologyorgN for full disclosures

Publication HistoryReceived by Neurology July 6 2020 Accepted in final formDecember 7 2020

Appendix Authors

Name Location Contribution

Zien ZhouMD

The George Institute forGlobal Health Australiaand Ren Ji Hospital Schoolof Medicine Shanghai JiaoTong University China

Designed andconceptualized studymajor role in theacquisition of dataanalyzed the datainterpreted the datadrafted the manuscript forintellectual content revisedthe manuscript forintellectual content

CandiceDelcourtMD PhD

The George Institute forGlobal Health Australia

Major role in theacquisition of datainterpreted the datarevised the manuscript forintellectual content

Chao XiaMD

The George Institute forGlobal Health Australia

Major role in theacquisition of datainterpreted the datarevised the manuscript forintellectual content

SoheiYoshimuraMD PhD

The George Institute forGlobal Health Australia

Major role in theacquisition of data revisedthe manuscript forintellectual content

CherylCarcel MDPhD

The George Institute forGlobal Health Australia

Major role in theacquisition of data revisedthe manuscript forintellectual content

TakakoTorii-YoshimuraMD

The George Institute forGlobal Health Australia

Major role in theacquisition of data revisedthe manuscript forintellectual content

ShoujiangYou MDPhD

Second Affiliated Hospitalof Soochow UniversityChina

Major role in theacquisition of data revisedthe manuscript forintellectual content

AlejandraMalaveraMD

The George Institute forGlobal Health Australia

Major role in theacquisition of data revisedthe manuscript forintellectual content

XiaoyingChenBPharmBMgt

The George Institute forGlobal Health Australia

Major role in theacquisition of data revisedthe manuscript forintellectual content

Maree LHackettPhD

The George Institute forGlobal Health Australia

Interpreted the datarevised the manuscript forintellectual content

MarkWoodwardPhD

The George Institute forGlobal Health Australiaand UK

Interpreted the datarevised the manuscript forintellectual content

JohnChalmersMD PhD

The George Institute forGlobal Health Australia

Interpreted the datarevised the manuscript forintellectual content

JianrongXu MDPhD

Ren Ji Hospital School ofMedicine Shanghai JiaoTong University China

Designed andconceptualized studyinterpreted the datarevised the manuscript forintellectual content

Continued

NeurologyorgN Neurology | Volume 96 Number 11 | March 16 2021 e1525

References1 Hsia AW Sachdev HS Tomlinson J et al Efficacy of IV tissue plasminogen activator

in acute stroke does stroke subtype really matter Neurology 20036171ndash752 Fuentes B Martınez-Sanchez P Alonso de Lecintildeana M et al Efficacy of intravenous

thrombolysis according to stroke subtypes the Madrid Stroke Network data Eur JNeurol 2012191568ndash1574

3 Mustanoja S Meretoja A Putaala J et al Outcome by stroke etiology in patientsreceiving thrombolytic treatment descriptive subtype analysis Stroke 201142102ndash106

4 Barow E Boutitie F Cheng B et al Functional outcome of intravenous thrombolysis inpatients with lacunar infarcts in the WAKE-UP trial JAMA Neurol 201976641ndash649

5 Lindley RI Wardlaw JM Whiteley WN et al Alteplase for acute ischemic strokeoutcomes by clinically important subgroups in the third International Stroke TrialStroke 201546746ndash756

6 Bamford J Sandercock P Jones L et al The natural history of lacunar infarction theOxfordshire Community Stroke Project Stroke 198718545ndash551

7 Norrving B Lacunar infarcts no black holes in the brain are benign Pract Neurol20088222ndash228

8 Regenhardt RW Das AS Lo EH Caplan LR Advances in understanding the path-ophysiology of lacunar stroke a review JAMA Neurol 2018751273ndash1281

9 Anderson CS Robinson T Lindley RI et al Low-dose versus standard-dose in-travenous alteplase in acute ischemic stroke N Engl J Med 20163742313ndash2323

10 Huang Y Sharma VK Robinson T et al Rationale design and progress of theEnhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHAN-TED) trial an international multicenter 2 times 2 quasi-factorial randomized controlledtrial of low- vs standard-dose rt-PA and early intensive vs guideline-recommendedblood pressure lowering in patients with acute ischaemic stroke eligible for throm-bolysis treatment Int J Stroke 201510778ndash788

11 Anderson CS Woodward M Arima H et al Statistical analysis plan for evaluatinglow- vs standard-dose alteplase in the Enhanced Control of Hypertension andThrombolysis Stroke Study (ENCHANTED) Int J Stroke 2015101313ndash1315

12 Adams HP Jr Bendixen BH Kappelle LJ et al Classification of subtype of acuteischemic stroke definitions for use in a multicenter clinical trial TOAST Trial of Org10172 in Acute Stroke Treatment Stroke 19932435ndash41

13 Wardlaw JM Sandercock P Cohen G et al Association between brain imaging signsearly and late outcomes and response to intravenous alteplase after acute ischaemicstroke in the third International Stroke Trial (IST-3) secondary analysis of a rand-omised controlled trial Lancet Neurol 201514485ndash496

14 Mair G von Kummer R Adami A et al Arterial obstruction on computed tomo-graphic or magnetic resonance angiography and response to intravenous thrombo-lytics in ischemic stroke Stroke 2017 48353ndash360

15 Wardlaw JM Smith EE Biessels G et al Neuroimaging standards for research intosmall vessel disease and its contribution to ageing and neurodegeneration LancetNeurol 201312822ndash838

16 Arba F Mair G Phillips S et al Improving clinical detection of acute lacunar strokeanalysis from the IST-3 Stroke 2020511411ndash1418

17 Matusevicius M Paciaroni M Caso V et al Outcome after intravenous thrombolysisin patients with acute lacunar stroke an observational study based on SITS in-ternational registry and a meta-analysis Int J Stroke 201914878ndash886

18 Zivanovic Z Gubi M Vlahovic D et al Patients with acute lacunar infarction havebenefit from intravenous thrombolysis J Stroke Cerebrovasc Dis 201928435ndash440

19 Eggers CCJ Bocksrucker C Seyfang L et al The efficacy of thrombolysis in lacunarstroke evidence from the Austrian Stroke Unit Registry Eur J Neurol 201724780ndash787

20 ShobhaN Fang J Hill MD Do lacunar strokes benefit from thrombolysis Evidence fromthe registry of the Canadian Stroke Network Int J Stroke 20138(suppl A100)45ndash49

21 Fluri F Hatz F Rutgers MP et al Intravenous thrombolysis in patients with strokeattributable to small artery occlusion Eur J Neurol 2010171054ndash1060

22 Makin SD Doubal FN Dennis MS et al Clinically confirmed stroke with negativediffusion-weighted imaging magnetic resonance imaging longitudinal study of clinicaloutcomes stroke recurrence and systematic review Stroke 2015463142ndash3148

23 Pantoni L Fierini F Poggesi A Thrombolysis in acute stroke patients with cerebralsmall vessel disease Cerebrovasc Dis 2014375ndash13

24 Nagaraja N Forder JR Warach S et al Reversible diffusion-weighted imaging lesionsin acute ischemic stroke a systematic review Neurology 202094571ndash587

Appendix (continued)

Name Location Contribution

ThompsonGRobinsonMD

University of Leicester UK Designed andconceptualized studyinterpreted the datarevised the manuscript forintellectual content

Mark WParsonsMD PhD

University of New SouthWales Australia

Designed andconceptualized studyinterpreted the datarevised the manuscript forintellectual content

Andrew MDemchukMD

University of CalgaryCanada

Designed andconceptualized studyinterpreted the datarevised the manuscript forintellectual content

Richard ILindley MD

University of SydneyAustralia

Designed andconceptualized studyinterpreted the datarevised the manuscript forintellectual content

Grant MairMD

University of Edinburgh UK Interpreted the datarevised the manuscript forintellectual content

Joanna MWardlawMD

University of Edinburgh UK Designed andconceptualized studyinterpreted the datarevised the manuscript forintellectual content

Craig SAndersonMD PhD

The George Institute forGlobal Health Australiaand China

Designed andconceptualized studyinterpreted the datadrafted the manuscript forintellectual content revisedthe manuscript forintellectual content

e1526 Neurology | Volume 96 Number 11 | March 16 2021 NeurologyorgN

DOI 101212WNL0000000000011598202196e1512-e1526 Published Online before print February 3 2021Neurology

Zien Zhou Candice Delcourt Chao Xia et al ENCHANTED Trial

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

This information is current as of February 3 2021

ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2021 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

httpnneurologyorgcontent9611e1512fullincluding high resolution figures can be found at

References httpnneurologyorgcontent9611e1512fullref-list-1

This article cites 24 articles 9 of which you can access for free at

Citations httpnneurologyorgcontent9611e1512fullotherarticles

This article has been cited by 1 HighWire-hosted articles

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httpnneurologyorgcgicollectionmriMRI

httpnneurologyorgcgicollectioninfarctionInfarction

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httpnneurologyorgcgicollectionall_clinical_trialsAll Clinical trials

httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the

Errata

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Reprints

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ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2021 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

httpnneurologyorgcontent9611e1512fullincluding high resolution figures can be found at

References httpnneurologyorgcontent9611e1512fullref-list-1

This article cites 24 articles 9 of which you can access for free at

Citations httpnneurologyorgcontent9611e1512fullotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionmriMRI

httpnneurologyorgcgicollectioninfarctionInfarction

httpnneurologyorgcgicollectionctCT

httpnneurologyorgcgicollectionall_clinical_trialsAll Clinical trials

httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the

Errata

contentearly20210527WNL0000000000012302fullpdf or page

nextAn erratum has been published regarding this article Please see

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2021 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

Neurology Publish Ahead of PrintDOI 101212WNL0000000000012302

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

In the Article ldquoLow-Dose vs Standard-Dose Alteplase in Acute Lacunar Ischemic Stroke The ENCHANTED Trialrdquo by Z Zhou et al1the first sentence under Methods in the Abstract should read ldquoIn a cohort of 3297 ENCHANTED participants we identified those with lacunar or non-lacunar AIS with different levels of confidence (definiteprobablepossible) according to prespecified definitions based on clinical and adjudicated imaging findingsrdquo The publisher regrets the error

REFERENCE

1Zhou Z Delcourt C Xia C et al Low-dose vs standard-dose alteplase in acute lacunar ischemic stroke the ENCHANTED trial Neurology 202196(11)e1512-e1526 doi101212WNL0000000000011598

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composition and review of proofs Errors that could affect the content may be corrected during

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Copyright copy 2021 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Published Ahead of Print on May 27 2021 as 101212WNL0000000000012302