Nej Mo a 1109842

8/10/2019 Nej Mo a 1109842

1/15

o r i gi n a l a r t i c l e

A Randomized Trial of Tenecteplase

versus Alteplase for Acute Ischemic StrokeMark Parsons, M.D., Neil Spratt, M.D.,Andrew Bivard, B.Sc.,

Bruce Campbell, M.D., Kong Cung, M.D., !erdinand Mite"", M.D.,Bill #$Brien, M.D., Cristoper Bladin, M.D., Patrick Mc%ldu"", P.D.,

Cris Allen, M.D., &rant Bateman, M.D., &eo""re' Donnan, M.D.,Stepen Davis, M.D., and Cristoper (evi, M.D.

ABSTRACT

T h e n e w e n gl a n d j o u r n a l o f m e d i c i n e

1

8/10/2019 Nej Mo a 1109842

2/15


8/10/2019 Nej Mo a 1109842

3/15

BACKGROUND

Intravenous alteplase is the onl! approved treatment for acute ischemic stroke" Tenec#

teplase$ a geneticall! engineered mutant tissue plasminogen activator$ is an alternativethrom%ol!tic agent"

METHODS

In this phase B trial$ we randoml! assigned &' patients to receive alteplase ()"* mg per

kilogram of %od! weight+ or tenecteplase ()"1 mg per kilogram or )"' mg per kilo#gram+ less than , hours after the onset of ischemic stroke" To favor the selection of

patients most likel! to %enefit from throm%ol!tic therap!$ the eligi%ilit! criteria were aperfusion lesion at least )- greater than the infarct core on computed tomographic(CT+ perfusion imaging at %aseline and an associated vessel occlusion on CT angiog#

raph!" The coprimar! end points were the proportion of the perfusion lesion that wasreperfused at . hours on perfusion#weighted magnetic resonance imaging and the

e/tent of clinical improvement at . hours as assessed on the 0ational Institutes ofealth Stroke Scale (0ISS$ a .#point scale on which higher scores indicate more

severe neurologic deficits+"

RESULTS

The three treatment groups each comprised ' patients" The mean (2S3+ 0ISS scoreat %aseline for all patients was 1.".2",$ and the time to treatment was "*2)"4 hours"

Together$ the two tenecteplase groups had greater reperfusion (56)")).+ and clinicalimprovement (57)"))1+ at . hours than the alteplase group" There were no

significant %etween#group differences in intracranial %leeding or other serious ad#verse events" The higher dose of tenecteplase ()"' mg per kilogram+ was superior to

the lower dose and to alteplase for all efficac! outcomes$ including a%sence of seriousdisa%ilit! at *) da!s (in &- of patients$ vs" .)- with alteplase8 5 6 )")+"

CONCLUSIONS

Tenecteplase was associated with significantl! %etter reperfusion and clinical outcomes

than alteplase in patients with stroke who were selected on the %asis of CT perfusionimaging" (9unded %! the Australian 0ational ealth and :edical Research Council8Australia 0ew ;ealand Clinical Trials Registr! num%er$ ACTR01,)4))).,,

8/10/2019 Nej Mo a 1109842

4/15

h r o m % o l ! t i c t r e a t m e n t w i t h a l t e #

plase$ a recom%inant tissue plasminogenactivator$ for acute ischemic stroke is of

proven %enefit"1owever$ alteplase is far from

ideal$ with incomplete and often dela!ed reperfu#sion in man! patients"Tenecteplase$ a geneticall!

engineered mutant tissue plasminogen activator$

has some pharmacokinetic advantages over alte#plase"

8/10/2019 Nej Mo a 1109842

5/15

Table 1. Characteritic !" the Patie#t at Baeli#e.$

Characteritic Alte%lae &N ' ()*Te#ecte%lae

)>G* 9> )>G*

Diabetes mellitus 7 no. )H* 9 )G* F );:* > ):G*

Blood glucose 7 mmolliter >.GE9.9 .9E:.< .;E9.F

/'perlipidemia 7 no. )H* @ );>* 9; ):* 9 )>* G )9>*

Distal section o" "irst segment o" middle cerebral arter' ):

8/10/2019 Nej Mo a 1109842

6/15

STUDY O-ERSIGHT

The steering committee$ comprising five of the au#thors$ designed and oversaw the trial and vouches

for the completeness and accurac! of the data andthe anal!sis" The data anal!sis was undertaken %!

four of the authors" ?ne of the authors$ a %iostat#

istician$ was responsi%le for the un%linding of thetreatment assignments after the data%ase was

cleaned and locked$ and performed the prespeci#fied statistical anal!ses" Boehringer Ingelheim

sup#

8/10/2019 Nej Mo a 1109842

7/15

8/10/2019 Nej Mo a 1109842

8/15

outcomes$ at an alpha level of )")'$ in the pooled

tenecteplase groups"5rimar! h!potheses were tested %! means of

an unadjusted StudentFs t#test of means" Thisanal!sis was repeated after adjustment for poten#

tial confounding %aseline varia%les that differed%etween the alteplase and pooled tenecteplase

groups (57)"1)+ (Ta%le 1+" Secondar! outcomeswith a nonparametric distri%ution were tested with

the use of the =ilco/on rank#sum test$ and cat#egorical varia%les were compared with the use of

the chi#suare test of proportions or 9isherFs e/acttest" In the event of support for the primar! h!#

pothesis$ the protocol specified an anal!sis tocompare efficac! and safet! outcomes %etween thetwo tenecteplase groups and %etween each of the

tenecteplase groups and the alteplase group"

After the initial trial registration %ut %efore the

completion of the stud!$ the trial end points weremodified$ as informed %! several studies",$1SDTS

STUDY PATIENTS

9igure 1 shows the screening profile of the trial"

Between ))4 and )11$ a total of &,4 patientspresenting with strokelike s!mptoms underwent

screening within , hours after s!mptom onset8 ofthese patients$ &' (G 3ere treated wit alteplase outside trial;> 2nderwent endovascular terap'

G< /ad basilar1arter' occlusion:G 3ere treated wit alteplase outside trial9: 2nderwent endovascular terap'

FF /ad large core on C- per"usion imaging>G 3ere treated wit alteplase outside trial

9 3ere treated wit alteplase outside trial;> /ad occlusion but did not ave C-

per"usion mismatc

:G 3ere treated wit alteplase outside trial9 /ad poor18ualit' C-

9> 3ere treated wit alteplase outside trial:< /ad M+ contraindication

:< 3ere treated wit alteplase outside trial

9: 3ere potentiall' eligible "or tenecteplaseversus alteplase stud'

: Did not undergo randomiLationG< 3ere treated wit alteplase outside trial9: 2nderwent endovascular terap'

2nderwent randomiLation

: +eceived alteplase: +eceived tenecteplase,

8/10/2019 Nej Mo a 1109842

9/15

who were eligi%le for intravenous throm%ol!sis

%ut did not meet the CT criteria for this stud!received open#la%el alteplase (

8/10/2019 Nej Mo a 1109842

10/15

Table (. St/0 O/tc!+e i# the Alte%lae a#0 P!!le0 Te#ecte%lae Gr!/%.$

J

Plus0minus values are means ESD. (esion volumes are rounded to te nearest milliliter. -wo patients did not undergo M+at :G ours owing to clinical deterioration )one in te lower1dose tenecteplase group and one in te alteplase group* and werenot included in te anal'sis o" te primar' reper"usion outcome )or oter imaging1based e""icac' outcomes*. !ive patientsdied be"ore da' @< and were not included in te anal'sis o" in"arct growt at da' @

8/10/2019 Nej Mo a 1109842

11/15

Alte%lae

8/10/2019 Nej Mo a 1109842

12/15

Boehringer Ingelheim Australia and Ba!er Australia8 3r" 3avis$consultanc! fees from ?rsan Technologies and >ver 5harma8

and 3r" Devi$ consultanc! fees from Boehringer Ingelheim Aus#tralia" 0o other potential conflict of interest relevant to this ar#ticle was reported"

3isclosure forms provided %! the authors are availa%le withthe full te/t of this article at0>@:"org"

=e thank the stud! coo rdinators at each of the centers :ichelleRussell (central coordinator$ @ohn unter ospital+$ La%riel Silver

(Ro!al :el%ourne ospital+$ and ;ofia Ross (Bo/ ill ospital+"
http://nejm.org/http://nejm.org/http://nejm.org/

8/10/2019 Nej Mo a 1109842

13/15

REERENCES


1

8/10/2019 Nej Mo a 1109842

14/15

1. Dees MR$ Bluhmki >$ vonMummer R$ et al" Time to

treatment with intravenousalteplase and outcome in

stroke an updated pooledanal!sis of >CASS$

ATDA0TIS$ 0I03S$ and>5IT>T trials" Dancet )1)8ffect of

incomplete (spontaneous andpostthrom%ol!tic+recanalization after middle

cere%ral arter! occlusion amagnetic resonance imaging

stud!" Stroke )).8C @r$ Thompson @D$Lrotta @C$ et al" 5hase IIBNIII

trial of tenecteplase in acuteischemic stroke results of aprematurel! terminated

randomized clinical trial"Stroke )1)8.1&)"

6. 5arsons :=$ :iteff 9$Bateman LA$ et al" Acuteischemic stroke imaging#guided tenecteplase treatment

in an e/#tended time window"0eurolog! ))*8& *1'#1"

7. acke =$ Maste :$ Bluhmki>$ et al" Throm%ol!sis withalteplase < to ."' hours after

acute ischemic stroke" 0 >ngl @:ed ))48ffects ofalteplase %e!ond < h afterstroke in the >choplanar

Imaging Throm%ol!tic>valuation Trial (>5IT>T+ a

place%ocontrolled randomisedtrial" Dancet 0eurol))48&**#

8/10/2019 Nej Mo a 1109842

15/15

# e 6 + (33 t h a # # i 5 e r a r 1 a r t i c l e

The 0>@: ))th Anniversar! cele%ration includes pu%lication of a seriesof invited review and 5erspective articles throughout )1"

>ach article e/plores a stor! of progress in medicine over the past )) !ears"

The collection of articles is availa%le at the 0>@: ))th Anniversar! we%site$httpNN0>@:))"0>@:"org "


1 '
http://nejm200.nejm.org/http://nejm200.nejm.org/http://nejm200.nejm.org/

Documents

Nej Mo a 1109842