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A Randomized Trial of Tenecteplase
versus Alteplase for Acute Ischemic Stroke
Mark Parsons, M.D., Neil Spratt, M.D., Andrew Bivard, B.Sc.,
Bruce Campbell, M.D., Kong Cung, M.D., !erdinand Mite"", M.D.,
Bill #$Brien, M.D., Cristoper Bladin, M.D., Patrick Mc%ldu"", P.D.,
Cris Allen, M.D., &rant Bateman, M.D., &eo""re' Donnan, M.D.,
Stepen Davis, M.D., and Cristoper (evi, M.D.
ABSTRACT
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BACKGROUND
Intravenous alteplase is the onl! approved treatment for acute ischemic stroke" Tenec#
teplase$ a geneticall! engineered mutant tissue plasminogen activator$ is an alternative
throm%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 a
perfusion 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 was
reperfused at . hours on perfusion#weighted magnetic resonance imaging and the
e/tent of clinical improvement at . hours as assessed on the 0ational Institutes of
1ealth Stroke Scale (0I1SS$ a .#point scale on which higher scores indicate more
severe neurologic deficits+"
RESULTS
The three treatment groups each comprised ' patients" The mean (2S3+ 0I1SS score
at %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 clinical
improvement (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 seri ous
disa%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 perfusion
imaging" (9unded %! the Australian 0ational 1ealth and :edical Research Council8
Australia 0ew ;ealand Clinical Trials Registr! num%er$ ACTR01,)4))).,,<.&"+
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!rom te Departments o" Neurolog'
)M.P., N.S., A.B., K.C., !.M., B.#., C.(.*,
Clinical +esearc Design, ,n"ormation
-ecnolog', and Statistical Support
)P.M.*, and +adiolog' )C.A., &.B.*, .on
/unter /ospital0/unter Medical +e1
searc ,nstitute, 2niversit' o" Newcastle,
Newcastle, NS34 te Department o"
Neurolog', +o'al Melbourne /ospital
)B.C., S.D.*, and !lore' Neuroscience ,n1
stitutes )&.D.*, 2niversit' o" Melbourne,
Melbourne, 5,C4 and te Department o"
Neurosciences, Bo6 /ill /ospital0%astern
/ealt, Monas 2niversit' )C.B.*, Mel1
bourne, 5,C 7 all in Australia. Address
reprint re8uests to Dr. Parsons at te De1
partment o" Neurolog', .on /unter /os1
pital, (ocked Bag No. 9, /unter +egion
Mail Centre, Newcastle, NS3 :;9<, Aus1
tralia, or at mark.parsons=neealt.nsw
.gov.au .
N %ngl . Med :<9:4;>>?9<@@19<A.
Copyright 2012 Massachusetts Medical Society.
hr om%ol !t i c t r e a t me n t wi t h a l t e #
plase$ a recom%inant tissue plasminogen
activator$ for acute ischemic stroke is of
proven %enefit"
1
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"
<
A %alance %etween efficac! and risk of
%leeding in the treatment of stroke appears to %e
achieved at a lower dose of tenecteplase than the
dose used for m!ocardial infarction"
.
A recent dose#
ranging stud! of tenecteplase involving patients
with acute ischemic stroke$ which used standard
clinical selection criteria$ showed that a dose of
)". mg per kilogram of %od! weight was associ#
ated with e/cess intracranial hemorrhage" The trial
was stopped prematurel!$ owing to slow enroll#
ment$ with no difference shown %etween doses of
)"1 mg per kilogram and )"' mg per kilogram"
'
In a nonrandomized pilot trial$ we found that
patients who received tenecteplase at a dose of
)"1 mg per kilogram had superior outcomes on
imaging (reperfusion and infarct growth+ and
greater earl! clinical improvement than patients
who received alteplase at a dose of )"* mg per ki#
logram"
,
1owever$ onl! the patients who received
tenecteplase were treated on the %asis of computed
tomographic (CT+ perfusion and angiographic im#
aging" =e conducted a phase B$ randomized trial
to compare the standard dose of alteplase with two
different doses of tenecteplase" CT perfusion and
angiographic imaging was used to select patients
who would %e the most likel! to %enefit from earl!
reperfusion (i"e"$ patients with large#vessel occlu#
sion and a large perfusion lesion in the a%sence of
a large infarct core+"
:>T1?3S
STUDY DESIGN AND PATIENTS
In this randomized$ open#la%el$ %linded trial$ pa#
tients with acute ischemic stroke underwent CT
perfusion and angiographic imaging %efore receiv#
ing treatment with intravenous tenecteplase or alte#
plase$ which was administered within , hours after
the onset of the stroke" 5atients underwent mag#
netic resonance imaging (:RI+ at . hours and at
*) da!s for assessment of imaging outcomes" The
trial was performed %etween ))4 and )11 in
three large stroke centers in Australia" The stud!
design is shown in the Supplementar! Appendi/$
which is availa%le with the full te/t of this article
at 0>@:"org "
=e enrolled patients with first#ever hemispheric
ischemic stroke who were 14 !ears of age or older$
had a score greater than . on the 0ational Insti #
tutes of 1ealth Stroke Scale (0I1SS8 a .#point
scale that Auantifies neurologic deficits in 11 cat#
egories$ with higher scores indicating more severe
deficits+$ and a premor%id score of or less on the
modified Rankin scale (which ranges from ) to
,$ with ) indicating no s!mptoms and , indicating
death+ (Ta%le 1+" >/clusion criteria were standard
contraindications to alteplase"
&$4
In addition$ we used specific selection criteria
for this trial that were %ased on the results of CT
imaging"
,
The CT angiographic criterion was the
presence of intracranial occlusion in the anterior
cere%ral$ middle cere%ral$ or posterior cere%ral ar#
ter!" 5atients with internalcarotidarter! and verte#
%ro%asilar occlusions were e/cluded" The CT perfu#
sion criterion was a hemispheric perfusion lesion
on transit#time maps that was at least )- greater
than the infarct#core lesion$ with a volume of at
least ) ml" The infarct#core lesion on CT perfu#
sion maps of cere%ral %lood volume had to %e less
than one third the territor! of the middle cere%ral
arter! or less than one half the territor! of the
anterior cere%ral or posterior cere%ral arter!"
The review of CT images was performed at a
clinical imaging workstation with the use of
instrument#specific proprietar! software" The
on#console image anal!sis was performed %! the
treating stroke neurologists$ all of whom had
e/perience in the evaluation of CT perfusion and
angiographic imaging"
*
5atients were randoml! assigned in a 1B1B1 ratio
to the standard dose of alteplase ()"* mg per kilo#
gram$ the first 1)- administered as an initial %o#
lus and the remainder over a 1#hour period$ with
a ma/imum dose of *) mg+ or to tenecteplase
()"1 mg per kilogram$ administered as a single
%olus$ with a ma/imum dose of 1) mg8 or )"' mg
per kilogram$ administered as a single %olus$ with
a ma/imum dose of ' mg+" A central %lock ran#
domization was performed %! the Centre for
Clinical >pidemiolog! and Biostatistics$ Cniversit!
of 0ewcastle$ in %locks of 1' to allow the data and
safet! monitoring %oard to review %linded safet!
data after the recruitment of ever! 1' patients"
Randomization was performed %! means of a cen#
tral telephone service" The treating clinician was
aware of the treatment assignments"
.
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Table 1. Characteritic !" the Patie#t at Baeli#e.$
Characteritic Alte%lae &N ' ()*
Te#ecte%lae
<.9 mgBkg
)N C :D*
<.:D mgBkg
)N C :D*
Cli#ical
Age 7 'r A<EF.G A:E>.@ >FE@.G
Male se6 7 no. )H* 9: )GF* 9; )D:* 9; )D:*
/'pertension 7 no. )H* 9D )><* 9> )>G* 9> )>G*
Diabetes mellitus 7 no. )H* 9 )G* F );:* > ):G*
Blood glucose 7 mmolBliter >.GE9.9 A.9E:.< A.;E9.F
/'perlipidemia 7 no. )H* @ );>* 9; )D:* 9D )><*
Atrial "ibrillation 7 no. )H* > ):G* @ );>* 9; )D:*
Current smoking 7 no. )H* 9 )G* @ );>* D ):<*
Current medications 7 no. )H*
Antiplatelet agent 99 )GG* 99 )GG* 9: )GF*
Anticoagulant 9 )G* 9 )G* 9 )G*
N,/SS scoreI 9G.<E:.; 9G.DE:.; 9G.>E:.;
-ime to treatment 7 r :.AE<.F ;.9E<.@ ;.<E<.A
I+a,i#,
5olume o" in"arct core 7 ml
Median 9; F 99
,nter8uartile range :0G9 90:D 90;D
5olume o" per"usion lesion 7 ml
Median A> F< A@
,nter8uartile range :909FD ::09@@ ;909GA
#cclusion site 7 no. )H*
Anterior cerebral arter' < < 9 )G*
Pro6imal section o" "irst segment o" middle cerebral arter' 99 )GG* > ):G* F );:*
Midsection o" "irst segment o" middle cerebral arter' : )F* G )9>* G )9>*
Distal section o" "irst segment o" middle cerebral arter' D ):<* 9< )G<* A ):F*
Second segment o" middle cerebral arter' G )9>* : )F* G )9>*
Posterior cerebral arter' 9 )G* 9 )G* 9 )G*
-erminal internal carotid arter' < 9 )G* <
None : )F* 9 )G* <
J Plus0minus values are means ESD. (esion volumes are rounded to te nearest milliliter. -ere were no signi"icant di"1
"erences between te alteplase group and te pooled tenecteplase groups e6cept tat te alteplase group ad "ewer
people wit diabetes )P C <.<9*, "ewer smokers )P C <.<9*, and a lower mean blood glucose level )P C <.<D*. -o convert te
values "or glucose to milligrams per deciliter, divide b' <.<DDD9. -ere were no signi"icant di""erences in baseline
caracteristics between te two tenecteplase groups.
I Scores on te National ,nstitutes o" /ealt Stroke Scale )N ,/SS* range "rom < to G:4 iger scores indicate more severe
neurologic de"icits.
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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 and
the 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 the
treatment assignments after the data%ase was
cleaned and locked$ and performed the prespeci#
fied statistical anal!ses" Boehringer Ingelheim
sup#
plied tenecteplase at a discount %ut was not in#
volved in the stud! design$ stud! conduct$ data
management$ data anal!sis$ or manuscript prepa#
ration" Alteplase was supplied %! the treating hos#
pital$ %ecause it is the standard treatment"
=ritten informed consent was provided %! the
patients or their health care pro/ies" The stud!
protocol (availa%le at 0>@:"org+ and informed#
consent procedures were approved %! the institu#
tional review %oard at each participating center"
PROCEDU RES
CT perfusion and angiographic imaging was per#
formed with multidetector scanners (1,# or ,.#slice+
%efore randomization" =hole#%rain CT imaging$
without the administration of contrast material was
followed %! CT perfusion imaging$ comprising two
,)#second series$ each performed after an intrave#
nous %olus of .) ml of iodinated contrast agent at
a concentration of <&) mg per milliliter$ followed
%! a .)#ml saline flush at a rate of , ml per sec#
ond"
1)
>ach perfusion series covered an a/ial sec#
tion of . to .) mm$ acAuired as adjacent slices of
' to 4 mm"
11
CT angiograph! was performed after
CT perfusion imaging$ with images acAuired from
the carotid %ifurcation to the top of the lateral
ventricles"
:RI was performed with the use of 1"'#T
scanners" Standardized seAuences were o%tained
. hours after treatment and included an a/ial
gradient#echo T#weighted series$ a diffusion#
weighted echoplanar spin#echo seAuence$ timeof#
flight magnetic resonance angiograph!$ perfusion#
weighted imaging$ and a fluid#attenuated inversion
recover! (9DAIR+ seAuence"
1$1<
At *) da!s after
treatment$ 9DAIR imaging was repeated to mea#
sure the final infarct volume"
OUTCOMES
The coprimar! outcomes were the percentage of
the perfusion lesion that was reperfused . hours
after treatment$ as assessed on perfusionweighted
:RI$ and the e/tent of clinical improvement at .
hours$ as measured %! the change on the 0I1SS
score from %efore treatment to . hours after treat#
ment"
,$1.
Secondar! imaging efficac! outcomes
were the e/tent of infarct growth at . hours and at
*) da!s and vessel recanalization at . hours"
1'$1,
Secondar! clinical efficac! outcomes were ma#
jor neurologic improvement at . hours (defined
as a reduction from %aseline of 4 or more points
on the 0I1SS+$ e/cellent recover! at *) da!s (de#
fined as a score of ) or 1 on the modified Rankin
scale+$ and e/cellent or good recover! at *) da!s
(defined as a score of ) to +"1$&$1&$14 These scores
on the modified Rankin scale have %een used as
primar! outcomes in all major phase < trials of
throm%ol!tic agentsB a score of ) indicates no
s!mptoms$ 1 minor s!mptoms %ut no clinicall!
significant disa%ilit!$ and slight disa%ilit!"
1$&$1*
Secondar! imaging safet! outcomes were the
occurrence of large parench!mal hematoma
(E<)- of the infarct volume+$ parench!mal
hematoma of an! size$ and s!mptomatic intracra#
nial hemorrhage" Secondar! clinical safet! out#
comes were poor outcome (i"e"$ severe disa%ilit!+ or
death at *) da!s$ defined as a score of ' or ,$ re#
spectivel!$ on the modified Rankin scale" See the
Supplementar! Appendi/ for details of outcomes"
All anal!ses of imaging outcomes were per#
formed centrall! on de#identified data" Assessors
were unaware of the treatment assignments and
clinical information" CT and :RI data were ana#
l!zed with the use of commercial software (:IStar$
Apollo :edical Imaging+"
)
See the Supplementar!
Appendi/ for details of the imaging outcomes"
Scoring on the 0I1SS was performed immedi#
atel! %efore %aseline imaging and at . hours"
Scoring on the modified Rankin scale was per#
formed at %aseline and on da! *)" The clinical
assessments at . hours and on da! *) were per#
formed %! a trained o%server who was not involved
in the patientsF clinical care and who was unaware
of the treatment assignments" The o%server cal#
culated the patientsF scores on the 0I1SS or the
modified Rankin scale in the presence of a stud!
coordinator$ who ensured that the o%server re#
mained unaware of the treatment assignments"
STATISTICAL ANALYSIS
Before the completion of the stud!$ a %iostatistician
developed the statistical anal!sis plan to test the
prespecified trial h!potheses defined in the proto#
col" The primar! h!pothesis was that a comparison
%etween the alteplase group and the pooled te#
necteplase groups would show the superiorit! of
tenecteplase with respect to one or %oth copri#
mar! outcomes (percent reperfusion and change
in the 0I1SS score at . hours+" An alpha level of
)")' was prespecified for each of the two pri#
mar! end points" =e calculated the sample size for
the current stud! on the %asis of our pilot stud!$
with power set at 4)- and an assumption of supe#
riorit! with respect to one of the two coprimar!
&
T e n e c t e
p
l a s e v s " A l t e
p
l a s e f o r I s c h e m i c S t r o k e
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" This
anal!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! outcomes
with 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#sAuare test of proportions or 9isherFs e/act
test" In the event of support for the primar! h!#
pothesis$ the protocol specified an anal!sis to
compare efficac! and safet! outcomes %etween the
two 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 were
modified$ as informed %! several studies"
,$1<$1&$)
This led to the modification of the reperfusion
primar! outcome from a%solute volume change to
proportional change"
,$1<
Infarct growth replaced
Gmismatch salvageH (i"e"$ the volume of mismatch
tissue on CT perfusion imaging at %aseline that
did not progress to infarction on follow#up :RI+
as a secondar! outcome$ and the intracranial#
hemorrhage outcomes were e/panded (see the
Supplementar! Appendi/+" The prespecified sta#
tistical anal!sis plan was %ased on these slightl!
modified end points" 1owever$ after the stud!
and the per#protocol prespecified anal!ses were
completed$ we performed post hoc anal!ses of
the original end points (see the Supplementar!
Appendi/+"
R>SCDTS
STUDY PATIENTS
9igure 1 shows the screening profile of the trial"
Between ))4 and )11$ a total of &,4 patients
presenting with strokelike s!mptoms underwent
screening within , hours after s!mptom onset8 of
these patients$ &' (<-+ were enrolled in the stud!"
The majorit! of patients screened (1,. I&4-J+
were not eligi%le for intravenous throm%ol!sis on
the %asis of standard clinical e/clusions (9ig" 1+"
This left ,). patients (-+ potentiall! eligi%le
for intravenous throm%ol!sis$ 1& ('-+ of whom
met the additional CT selection criteria" The major
reasons for e/clusion that were %ased on these cri#
teria were internalcarotidarter! occlusion (11, pa#
tients I.-J+$ a large infarct core on CT perfusion
imaging (44 I<-J+$ and an a%sence of intracranial
vessel occlusion (1,) I,-J+" :ost of the patients
:A>F Patients were assessed witin
> r a"ter s'mptom onset
:9>G 3ere not eligible on te basis o" standard
contraindications to alteplase
GD: Did not ave a stroke
;9: /ad intracranial emorrage
>;> /ad mild or rapidl' resolving s'mptoms
DA: /ad coe6isting conditions )including
disabilit' be"ore stroke*
@> /ad e6tensive earl' iscemic cange
on noncontrast C-
GF /ad undergone surger' recentl'
GF /ad ,N+ K9.D
><G 3ere potentiall' eligible "or
intravenous trombol'sis
GAA 3ere e6cluded on te basis o" additional
e6clusion criteria
99> /ad internal1carotid1arter' occlusion
>G 3ere treated wit alteplase outside trial
;> 2nderwent endovascular terap'
G< /ad basilar1arter' occlusion
:G 3ere treated wit alteplase outside trial
9: 2nderwent endovascular terap'
FF /ad large core on C- per"usion imaging
>G 3ere treated wit alteplase outside trial
9<< Did not ave occlusion but ad C-
per"usion mismatc
A: 3ere treated wit alteplase outside trial
>< Did not ave occlusion or C- per"usion
mismatc
;> 3ere treated wit alteplase outside trial
;> /ad occlusion but did not ave C-
per"usion mismatc
:G 3ere treated wit alteplase outside trial
9A /ad poor18ualit' C-
9> 3ere treated wit alteplase outside trial
:< /ad M+, contraindication
:< 3ere treated wit alteplase outside trial
9:A 3ere potentiall' eligible "or tenecteplase
versus alteplase stud'
D: Did not undergo randomiLation
G< 3ere treated wit alteplase outside trial
9: 2nderwent endovascular terap'
AD 2nderwent randomiLation
:D +eceived alteplase
:D +eceived tenecteplase, <.9 mgBkg :D
+eceived tenecteplase, <.:D mgBkg
.i,/re 1. St/01 E#r!ll+e#t.
#" te :A>F patients wo were screened "or participation in te stud', AD
underwent randomiLation to te tree treatment groups. ,N+ denotes
international normaliLed ratio.
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who were eligi%le for intravenous throm%ol!sis
%ut did not meet the CT criteria for this stud!
received open#la%el alteplase (<) of .&& patients
I,&-J+8 some received endovascular therap! (.4 of
.&& I1)-J+" ?f the 1& patients who met the ad#
ditional CT selection criteria$ &' were enrolled" The
reasons that ' eligi%le patients were not enrolled
were the patientFs or ph!sicianFs preference for
open#la%el alteplase treatment (.) patients+ and a
decision %! the treating clinician to proceed with
endovascular therap! (1 patients+"
?f the &' enrolled patients$ ' were randoml!
assigned to each of the three treatment groups"
Ta%le 1 shows the %aseline characteristics of these
patients" The mean (2S3+ 0I1SS score for all pa#
tients in the trial was relativel! high at 1.".2","
:ost %aseline clinical characteristics were well
matched among the three groups$ %ut the alte#
plase group included fewer persons who smoked
(5 6 )")1+8 this group also included fewer persons
with dia%etes (5 6 )")1+$ which was reflected in a
lower %lood glucose level at %aseline in the al #
teplase group (5 6 )")'+" 5atients in the alteplase
group received treatment at a mean of "& hours$
as compared with <"1 hours for those in the pooled
tenecteplase groups (56)"),+" ?nl! < patients were
treated after ."' hours" There were no significant
differences in the imaging characteristics at %ase#
line among the treatment groups" There were no
significant differences in the site of occlusion at
%aseline$ %ut on central %linded review of the CT
angiographic data$ the vessel#occlusion criteria
were not met in . patients (Ta%le 1+" ?ne patient
had an occlusion of the terminal internal carotid
arter!$ and < patients ( in the alteplase group+ had
no definite occlusion"
E..ICACY
There was a significant %enefit associated with
tenecteplase for %oth coprimar! end points of the
stud! (Ta%le +$ with greater reperfusion (56)")).+
and greater clinical improvement (57)"))1+ at .
hours in the pooled tenecteplase groups than in
the alteplase group" The magnitude and signifi#
cance of the reperfusion and earl! clinical improve#
ment in the pooled tenecteplase groups did not
change after correction for im%alances at %aseline
(Ta%le +" Tenecteplase was also %eneficial with
respect to secondar! outcomes" In the pooled te#
necteplase groups$ as compared with the alteplase
group$ infarct growth was reduced$ and a higher
proportion of patients had an e/cellent or good
recover! (modified Rankin scale score of ) to +
at *) da!s (&- vs" ..-$ 5 6 )")+"
SA.ETY
Seven patients diedB < in the alteplase group
(1-+$ < in the group that received the lower dose
of tenecteplase (1-+$ and 1 in the group that re#
ceived the higher dose of tenecteplase (.-+" Two
deaths in the alteplase group were due to massive
hemispheric infarction$ and one to s!mptomatic
intracranial hemorrhage" In the lower#dose tenec#
teplase group$ one death was due to s!mptomatic
intracranial hemorrhage$ one to aspiration pneu#
monia$ and one to a late second stroke" The one
death in the higher#dose tenecteplase group was
due to multiple coe/isting conditions (pneumonia$
m!ocardial infarction$ and acuteonchronic renal
failure+" Two of the ') patients in the tenecteplase
group (.-+ had large parench!mal hematomas$
as compared with . of the ' in the alteplase
group (1,-$ 5 6 )")*+" 9ive of the , patients with
large parench!mal hematomas also had s!mp#
tomatic deterioration of . or more points on the
0I1SS at . hours and poor outcome at *) da!s
(modified Rankin scale score of ' or ,+" 5oor
outcome at *) da!s occurred in & patients in the
alteplase group (4-+ and in ' (1)-+ in the
pooled tenecteplase groups (5 6 )")*+"
DOSE2TIER ANALYSIS
The higher dose of tenecteplase ()"' mg per ki#
logram+ was associated with improvement on all
imaging efficac! outcomes$ as compared with
alteplase (see the Supplementar! Appendi/+" In
addition to an increased proportion of patients
with earl! clinical improvement$ the outcomes at
< months were %etter in the higher#dose tenecte#
plase group8 &- of patients in this group had an
e/cellent recover! (no clinicall! significant disa%il#
it!+$ as compared with .)- of those in the alteplase
group (5 6 )")+" There were no more adverse out#
comes with either dose of tenecteplase than with
alteplase (see the Supplementar! Appendi/+" The
patients who received the lower dose of tenecte#
plase had greater clinical improvement at . hours
than did the patients who received alteplase
(56)").+$ %ut other efficac! outcomes were eAuiv#
alent %etween the two groups"
There was an efficac! dose response %etween
the two tenecteplase dose tiers$ including higher
*
T h e n e w e n
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l a n d j o u r n a l o f m e d i c i n e
Table (. St/01 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 were
not included in te anal'sis o" te primar' reper"usion outcome )or oter imaging1based e""icac' outcomes*. !ive patients
died be"ore da' @< and were not included in te anal'sis o" in"arct growt at da' @<. !ive patients were not included in te
anal'sis o" recanaliLation outcomes? te two wo did not undergo M+, at :G ours and te tree witout occlusions at
baseline.
I -e mean percentage o" reper"usion remained signi"icant )P C <.<<;* a"ter adMustment "or te baseline variables o" status
wit respect to diabetes and smoking, blood glucose level, and time to treatment.
N -e mean cange in te N,/SS score at :G ours remained signi"icant )P C <.<<9* a"ter adMustment "or te baseline
variables o" status wit respect to diabetes and smoking, blood glucose level, and time to treatment.
O -is outcome was de"ined as a large parenc'mal ematoma and clinical worsening )an increase in te N,/SS score o" G
or more points*.
9A,:9,::
P +ecover' was assessed wit te modi"ied +ankin scale, wic ranges "rom < to >, wit iger scores indicating greater
disabilit'. %6cellent recover' was de"ined as a score o" < or 9, e6cellent or good recover' as < to :, and a poor outcome as D
or >.
Q -e mismatc salvage was de"ined as te volume o" mismatc on computed tomograpic per"usion imaging at baseline tat
did not progress to in"arction.
Alte%lae
&N ' ()* O/tc!+e
Te#ecte%lae
&N ' )3* P -al/e
DD.GE;F.A A@.;E:F.F <.<<G
;.<E>.; F.<ED.D R<.<<9
9G ; <.<G
< to 9GG 1 9 to 9:9
9: : <.<9
1 9 to 99; 1: to 9;;
FB:: );>* :FBGF )DF* <.<@
9DB:: )>F* G:BGF )FF* <.<D
G )9>* : )G* <.<@
D ):<* ; )>* <.99
; )9:* : )G* <.;;
@ );>* ;: )>G* <.<:
9< )G<* :A )DG* <.:D
99 )GG* ;> )A:* <.<:
A ):F* D )9<* <.<@
; )9:* G )F* <.>F
;F.:E;<.@ >@.;E;G.> <.<<:
DD.FE;@.@ F<.AE:>.D <.<<:
DF.;E;F.@ F;.;E:>.: <.<<;
Median
,nter8uartile range
,n"arct growt at @< da's 7 ml
Median
,nter8uartile range
Complete recanaliLation at :G r 7 no.Btotal no. )H*
Complete or partial recanaliLation at :G r 7 no.Btotal no. )H*
T e n e c t e
p
l a s e v s " A l t e
p
l a s e f o r I s c h e m i c S t r o k e
S'mptomatic intracranial ematoma 7 no. )H*O
1)
%6cellent or good recover' at @< da's 7 no. )H*P
Secondar' clinical sa"et' outcome
Poor outcome at @< da's 7 no. )H*P
5olume reper"usion at :G r 7 ml
Mismatc salvage at :G r 7 mlQ
Primar' imaging e""icac' outcome
+eper"us ion at :G r 7 HI
Primar' clinical e""icac' outcome
,mprovement in N,/SS score between baseline and :G rN
Secondar' imaging e""icac' outcome
,n"arct growt at :G r 7 ml
Secondar' imaging sa"et' outcome
(arge parenc'mal ematoma 7 no. )H*
An' parenc'mal ematoma 7 no. )H*
Secondar' clinical e""icac' outcome
MaMor neurologic improvement at :G r, reduction o" SF in N,/SS
score 7 no. )H*
%6cellent recover' at @< da's 7 no. )H*P
Deat 7 no. )H*
Post oc secondar' imaging outcome
Mismatc salvage at @< da's 7 mlQ
Alte%lae <. 9 mgB kg <.:D mgBkg
Te#ecte%lae
.i,/re (. B!4 Pl!t "!r the Pri+ar1 E#0 P!i#t
"!r the I#0i5i0/al D!e Tier.
Panel A sows te reper"usion rates at :G ours, and
Panel B sows te canges in te N,/SS score at :G
ours. Negative values "or te cange in te N,/SS
score indicate improvement. -e oriLontal line inside
eac bo6 indicates te median, te top and bottom o" te
bo6 indicate te inter8uartile range, te I bars indicate te
Dt and @Dt percentiles, and te circles indicate outliers.
-e median value "or tenecteplase at a dose o" <.:D mg
per kilogram was 9<<H, wic overlaps wit te ADt
percentile )top o" bo6*.
reperfusion and recanalization rates at the higher
dose (9ig" $ and the Supplementar! Appendi/+"
This translated into greater clinical improvement
at . hours and an increase in the num%er of pa#
tients with e/cellent recover! (no clinicall! signifi#
cant disa%ilit!+ at *) da!s (5 6 )")1+"
3ISCCSSI?0
In this stud!$ using CT perfusion and angiographic
imaging to select patients for throm%ol!tic treat#
ment of acute ischemic stroke$ we found that te#
necteplase was superior to alteplase with respect to
the coprimar! end points of reperfusion and
clinical improvement at . hours" It is convention#
al in studies of acute stroke to use a primar! out#
come that assesses disa%ilit! status at *) da!s"
1owever$ reperfusion needs to %e measured at a
shorter interval after earl! reperfusion treatment in
order to assess %iologic efficac!$ so we chose a pri#
mar! clinical outcome that was most likel! to %e
sensitive to earl! reperfusion" A longer#term clinical
%enefit was also seen$ particularl! with the higher
dose of tenecteplase" The improved reperfusion and
clinical response with tenecteplase did not come at
a cost of increased intracranial hemorrhage" There
was also a doseKresponse relationship$ with the
higher dose of tenecteplase %eing superior to %oth
the lower dose of tenecteplase and alteplase for all
imaging and clinical efficac! outcomes" These pos#
itive findings are encouraging %ut preliminar!$ ow#
ing to the small size of the stud!"
The results of this stud! suggest that it is ap#
propriate to proceed to a phase < trial of tenec#
teplase versus alteplase in the time window that is
currentl! approved for stroke throm%ol!sis" =e
%elieve that the dose response seen in the current
stud! provides sufficient justification to use tenec#
teplase at a dose of )"' mg per kilogram as the
comparator" 1owever$ for this phase B trial$ we
used criteria %ased on CT perfusion and angio#
graphic imaging to select patients for inclusion
who would %e most likel! to have a clinical %enefit
from earl! and effective reperfusion" These selec#
tion criteria enhanced the power of the stud! to
detect a difference in efficac! %etween tenecte#
plase and alteplase with the use of a relativel!
small sample" A large num%er of patients who
were eligi%le for throm%ol!sis on the %asis of stan#
dard clinical and noncontrast CT criteria were e/#
cluded from this trial %ecause of these additional
imaging selection reAuirements" =e therefore can#
not e/trapolate our results to the majorit! of pa#
tients who are eligi%le for throm%ol!sis" A phase <
stud! would %e needed to determine whether the
efficac! of tenecteplase e/tends to this %roader
population of patients"
Supported %! a grant from the Australian 0ational 1ealth and
:edical Research Council"
3r" 5arsons reports receiving advisor!#%oard fees from Ba!er
Australia8 3r" Camp%ell$ consultanc! fees from Dund%eck$ speaker
pa!ments from Boehringer Ingelheim Australia$ and grant support
from Cardiovascular Dipid Australia8 3r" Bladin$ advisor!#%oard
fees from Ba!er Australia8 3r" 3onnan$ consultanc! fees from
A Ditrib/ti!# !" Re%er"/i!# Rate
9<<
T h e n e w e n
g
l a n d j o u r n a l o f m e d i c i n e
11
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 with
the full te/t of this article at 0>@:"org "
=e thank the stud! coo rdinators at each of the centersB :ichelle
Russell (central coordinator$ @ohn 1unter 1ospital+$ La%riel Silver
(Ro!al :el%ourne 1ospital+$ and ;ofia Ross (Bo/ 1ill 1ospital+"
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Copyright 2012 Massachusetts Medical Society.
# e 6 + (33t 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 series
of 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$
httpBNN0>@:))"0>@:"org "
T h e n e w e n
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l a n d j o u r n a l o f m e d i c i n e
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