Stroke

TOPICAL REVIEW

Tenecteplase Thrombolysis for Acute Ischemic

Stroke
Steven J. Warach , MD, PhD; Adrienne N. Dula , PhD; Truman J. Milling Jr, MD

ABSTRACT: Tenecteplase is a fibrinolytic drug with higher fibrin specificity and longer half-life than the standard stroke
thrombolytic, alteplase, permitting the convenience of single bolus administration. Tenecteplase, at 0.5 mg/kg, has regulatory
approval to treat ST-segment–elevation myocardial infarction, for which it has equivalent 30-day mortality and fewer systemic
hemorrhages. Investigated as a thrombolytic for ischemic stroke over the past 15 years, tenecteplase is currently being
studied in several phase 3 trials. Based on a systematic literature search, we provide a qualitative synthesis of published
stroke clinical trials of tenecteplase that (1) performed randomized comparisons with alteplase, (2) compared different
doses of tenecteplase, or (3) provided unique quantitative meta-analyses. Four phase 2 and one phase 3 study performed
randomized comparisons with alteplase. These and other phase 2 studies compared different tenecteplase doses and
effects on early outcomes of recanalization, reperfusion, and substantial neurological improvement, as well as symptomatic
intracranial hemorrhage and 3-month disability on the modified Rankin Scale. Although no single trial prospectively
demonstrated superiority or noninferiority of tenecteplase on clinical outcome, meta-analyses of these trials (1585 patients
randomized) point to tenecteplase superiority in recanalization of large vessel occlusions and noninferiority in disability-free
3-month outcome, without increases in symptomatic intracranial hemorrhage or mortality. Doses of 0.25 and 0.4 mg/kg have
been tested, but no advantage of the higher dose has been suggested by the results. Current clinical practice guidelines for
stroke include intravenous tenecteplase at either dose as a second-tier option, with the 0.25 mg/kg dose recommended for
large vessel occlusions, based on a phase 2 trial that demonstrated superior recanalization and improved 3-month outcome
relative to alteplase. Ongoing randomized phase 3 trials may better define the comparative risks and benefits of tenecteplase
and alteplase for stroke thrombolysis and answer questions of tenecteplase efficacy in the >4.5-hour time window, in wake-
up stroke, and in combination with endovascular thrombectomy.

Key Words: fibrin ◼ half-life ◼ percutaneous coronary intervention ◼ tenecteplase ◼ tissue-type plasminogen activator

T
enecteplase is a type of tPA (tissue-type plasmino- or simply tPA) recombinant tPA, for the treatment of
gen activator) of increasing interest for the throm- ST-segment–elevation myocardial infarction (STEMI) in
bolytic treatment of acute ischemic stroke due to 1987 and later for the treatment of acute massive pul-
advantageous drug characteristics and ease of adminis- monary embolism, for occluded central venous catheters,
tration. Endogenous tPA is a serine protease in endothe- and for ischemic stroke. Serious bleeding complica-
lial cells that catalyzes the cleavage of plasminogen to tions, especially intracranial bleeding, limited recanaliza-
plasmin and subsequent degradation of fibrin in thrombi tion rates, and rapid clearance requiring a 1- to 3-hour
as part of coagulation homeostasis.1 Synthesis of this infusion with alteplase therapy motivated the develop-
wild-type tPA by recombinant DNA technology,2 enabled ment of thrombolytics with more desirable properties.7
therapeutic fibrinolysis targeting arterial thrombi for the Mutagenesis studies produced a variant of alteplase
reversal of acute ischemic disease.3–6 The US Food and with 14-fold greater fibrin specificity, 10-fold greater
Drug Administration approved alteplase, also known as conservation of fibrinogen, 80-fold increased resistance
(r-tPA [recombinant tissue-type plasminogen activator], to plasminogen activator inhibitor-1 activity, more rapid

Correspondence to: Steven Warach, MD, PhD, Dell Medical School, The University of Texas at Austin, 1601 Trinity St, Room 10.542, Austin, Texas 78712. Email steven.
warach@austin.utexas.edu
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.029749.
For Sources of Funding and Disclosures, see page 3449.
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

3440   November 2020 Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749

Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

thrombolysis, and reduced plasma clearance.8–12 These fewer noncerebral bleeding complications (26%–29%;
pharmacokinetic properties produced an agent with a P=0.0003), while showing no difference in the incidence

Topical Review
longer plasma half-life that could achieve thromboly- of intracranial hemorrhage (0.9% in both groups). No dif-
sis as a single bolus injection. Initially named with the ferences were observed in the rates of reinfarction.
abbreviation of its 3 mutation sites T103N, N117Q, and As primary percutaneous coronary intervention (PCI)
KHRR, a 4-amino acid stretch in the serine-protease became first line treatment of STEMI, tenecteplase treat-
domain, (296-299)AAAA, TNK-tPA moved through clin- ment for STEMI was relegated to cases where PCI was
ical trials in acute myocardial infarction under its newly not available in a timely fashion. ASSENT-4, a random-
adopted name, tenecteplase.13 More detailed discussions ized trial of tenecteplase-facilitated PCI versus primary
of tenecteplase pharmacology may be found elsewhere PCI in 1667 patients, found that rather than enhancing
in the cited references and in Table I in the Data Sup- the effects of PCI, tenecteplase before PCI was asso-
plement.14–19 Several practical advantages of the rapid ciated with a higher rate of in-hospital major adverse
single bolus tenecteplase administration make it of inter- events including in-hospital death, intracranial hemor-
est relative to alteplase, which requires both bolus plus rhage (1%), and reinfarction, despite more than twice as
infusion preparation and administration. Alteplase infu- many patients in the tenecteplase group having an open
sion requires a second, dedicated intravenous catheter infarct artery at the time of the first angiogram.27 This
insertion that may delay treatment initiation if intravenous counterintuitive finding may have been due to the nar-
access is difficult to obtain. Because of the very short row window of potential benefit in STEMI (1–3 hours)
plasma half-life of alteplase, a gap between the end of which may have negated the restoration of flow effect
bolus and start of infusion, a common occurrence per- on the ischemic myocardium.28 These patients were still
haps exacerbated by the pressure to minimize door to exposed to the potential harm of thrombolysis, that is,
needle times, will result in an under dosing.20–22 cerebral and myocardial hemorrhage, making the net
Based on a systematic literature search, we provide a effect unfavorable. The benefit/harm ratio may be dif-
qualitative synthesis of stroke clinical trials of tenecteplase ferent for stroke thrombolysis before thrombectomy.29–31
that (1) performed randomized comparisons with The STREAM trial (Strategic Reperfusion Early After
alteplase, (2) compared different doses of tenecteplase, Myocardial Infarction) compared prehospital intravenous
or (3) provided unique quantitative meta-analyses. We tenecteplase (with concomitant antiplatelet and anticoagu-
include a discussion of STEMI tenecteplase clinical tri- lant medicines) to primary PCI on arrival to a PCI-capable
als as background. We searched the Cochrane Stroke hospital, randomizing 1892 patients with STEMI <3 hours
Group Trials Register (last searched in May 2020), the from symptom onset who were unable to receive PCI within
CENTRAL (Cochrane Database of Systematic Reviews one hour of first medical contact. 32–34 Eighty percent of the
and the Cochrane Central Register of Controlled Trials; prehospital patients were randomized to treatment in the
The Cochrane Library 2020, Issue 2), MEDLINE (Ovid) ambulance, the remainder at a referring community hospi-
(1966 to May 2020), and the Stroke Trials Registry tal. Patients in the tenecteplase group (pharmaco-invasive
(searched May 2020). Meta-analyses and trials includ- strategy) that did not have evidence of reperfusion by 90
ing the topics “tenecteplase AND stroke” were included. minutes after fibrinolytic treatment by electrocardiographic
MeSH heading included “stroke”, and timespan included or clinical criteria were given rescue PCI, but otherwise had
all years. The search was refined by including multicenter their coronary arteriogram 6 to 24 hours after randomiza-
study, clinical trial, meta-analysis, clinical trial phase III, tion. The median time from symptom onset to start treat-
comparative study, clinical trial phase II, or randomized ment was 100 minutes for prehospital tenecteplase group
controlled trials. Case reports, editorials, and comments and 178 minutes for the primary PCI group. Reperfusion
were excluded. Twenty-eight full-text records were criteria at 90 minutes after treatment were met by 63.7%
included. See Figure I in the Data Supplement for full of the tenecteplase group, in 86% of whom Thrombolysis
explanation of search and results. in Myocardial Infarction (TIMI) grade flow of 2 or 3 was
later observed on nonurgent angiogram, indicating com-
plete filling of the distal coronary arterial bed. In the primary
STEMI CLINICAL TRIALS PCI group, TIMI 2 or 3 flow on the initial angiogram was
Tenecteplase went into clinical trial comparisons with found in only 30.6%. The prehospital tenecteplase group
alteplase as a single bolus thrombolytic. Patients in the reported nominally fewer (12.4%–14.3%) primary clinical
tenecteplase randomized trials in acute myocardial infarc- composite end point events of all-cause death, cardiogenic
tion also received heparin and aspirin co-administered with shock, congestive heart failure, and reinfarction at 30 days;
either lytic.17,23–27 The definitive phase 3 double-blinded however, there were no significant differences on that
trial, ASSENT (Assessment of the Safety and Efficacy of outcome or on 1-year all-cause mortality.32,34 Early in the
a New Thrombolytic)-2 found equivalent 30-day mortal- trial, an excess of intracranial hemorrhage was observed
ity (7%) in 16 949 patients randomized between the 2 in patients 75 years or older treated with the standard 0.5
treatments.23 The tenecteplase group had significantly mg/kg dose of tenecteplase. The protocol was amended

Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749 November 2020   3441

 Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

lowering the dose to 0.25 mg/kg for those 75 and older, Stroke Trial)43 used 0.4 mg/kg to a maximum of 40 mg and
and no further intracranial hemorrhages occurred in that found comparable safety to alteplase in the largest cohort
Topical Review

age group.32–34 The similarly designed STREAM-2 trial is of tenecteplase-treated patients with stroke yet published
comparing safety and efficacy of the pharmaco-invasive (n=549). To compare 0.25 to 0.4 mg/kg, the EXTEND-IA
strategy at 0.25 mg/kg of tenecteplase to primary PCI in TNK (Tenecteplase Versus Alteplase Before Endovascular
patients age 60 and greater.35 Therapy for Ischemic Stroke Study) part 2 randomized 300
Tenecteplase achieved regulatory approval in the US patients with stroke due to acute large vessel occlusion
(TNKase; Genentech) and Europe (Metalyse; Boehringer before endovascular thrombectomy.44 Both dose groups
Ingelheim) in the year 2000 as a tiered weight-based dose had identical rates (19.3%) of substantial reperfusion on
of 0.5 mg/kg to a maximum of 50 mg given as a 5 to 10 the initial angiogram and no statistical differences in clini-
second bolus for the treatment of STEMI. Clinical trials of cal outcome, sICH or mortality, although the number of
tenecteplase for pulmonary embolism,36 for catheter clear- sICH events was higher in the 0.4 mg/kg group (7–2). The
ance,37,38 and for ischemic stroke (see below) have also been authors conclude that the higher dose does not confer a
reported, but these are not currently Food and Drug Admin- clinical advantage but may offer a margin of reassurance
istration approved indications. A version of tenecteplase is if a patient’s weight is overestimated for the 0.25 mg/kg
marketed as a biosimilar in India for both STEMI and stroke dose. A network meta-analysis of the 5 randomized trials
indications under different commercial names and differ- of tenecteplase versus alteplase found better efficacy on
ent doses, but in vitro studies from Boehringer Ingelheim clinical and imaging end points with the 0.25 mg/kg dose
reported less purity and reduced thrombolysis with that ver- and fewer sICH with 0.1 mg/kg relative to 0.4 mg/kg.45
sion, questioning its status as a biosimilar.39

Randomized Comparisons of Tenecteplase With

STROKE CLINICAL TRIALS Alteplase
Dose Selection of Tenecteplase for Ischemic Investigators have published 5 randomized trials of
Stroke tenecteplase versus standard dose alteplase (0.9 mg/
kg) for ischemic stroke (Table 2). The TNK-S2B (Study
Doses of tenecteplase from 0.1 to 0.5 mg/kg have been of Tenecteplase [TNK] in Acute Ischemic Stroke) was the
tested in clinical trials of ischemic stroke and are summa- only one to blind the treatment assisgnment,41 whereas
rized in Table 1. Haley et al40 performed the initial studies the other completed and ongoing randomized trials of
with a planned maximum dose of 0.6 mg/kg and 25-patient tenecteplase use variations of the prospective random-
cohorts. At doses 0.1, 0.2, and 0.4 mg/kg, there were no ized open-label blinded end point design. We summarize
occurrences of the primary end point, symptomatic intra- the trials and select meta-analysis according to the out-
cranial hemorrhage (sICH). The study was terminated at come measures.
the 0.5 mg/kg tier after 2 of 13 patients had sICH. The
follow-up phase 2b/3 randomized double-blind trial com- Early Recanalization and Reperfusion
pared standard dose alteplase (0.9 mg/kg) to 3 doses of In TAAIS, patients with CT evidence of relevant intracra-
tenecteplase 0.1, 0.25, and 0.4 mg/kg treated within 3 nial occlusion and a penumbral pattern with mismatch of
hours from stroke onset.41 Using a combined measure of at least 20% and 20 mL were randomized to alteplase,
early neurological improvement and sICH, the 0.4 mg/kg 0.1 mg/kg tenecteplase, or 0.25 mg/kg tenecteplase
dose, which had sICH in 3 of 19 treated was eliminated within 6 hours from onset (n=25 per group).42 The
as inferior. The trial was terminated prematurely for slow study found significant benefit on the co-primary end
enrollment with no significant differences between the 2 point of better reperfusion (P=0.004) in the pooled
viable doses and did not proceed to phase 3. The TAAIS tenecteplase group, as well on secondary outcomes of
(Tenecteplase versus Alteplase for Acute Ischaemic partial or complete recanalization by 24 hours and infarct
Stroke), also referred to as the Australian-TNK trial, ran- growth by 24 hours or 90 days. ATTEST (Alteplase-
domized patients with middle cerebral artery occlusion on Tenecteplase Trial Evaluation for Stroke Thrombolysis)
computed tomography angiography and penumbral mis- randomized patients with stroke based on noncontrast
match on computed tomography (CT) perfusion to 0.1 or CT to 0.25 mg/kg tenecteplase or alteplase within 4.5
0.25 mg/kg tenecteplase (n=25 per group) and observed hours from onset and acquired computed tomography
significantly higher rates of early recanalization, reperfu- angiography and CTP to test the hypothesis of supe-
sion, and neurological improvement in the 0.25 mg/kg rior penumbral salvage with tenecteplase.46 Selection
dose group along with better 90-day clinical outcome on was not limited to patients with occlusion or mismatch
the modified Rankin Scale (mRS) score of 0 to 1.42 but relevant analyses were. No difference was observed
The tenecteplase dose 0.25 mg/kg to a maximum of on the primary outcome of percent penumbral salvage
25 mg was most frequently used in subsequent stroke at 24 to 48 hours after treatment (n=35, 36) nor on
trials, however, the NOR-TEST (Norwegian Tenecteplase recanalization at that time (n=32, 35). EXTEND-IA

3442   November 2020 Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749

Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

Table 1. Clinical Trials Comparing Doses of Tenecteplase

Key eligibility Primary hypothesis/ Primary Key safety Date Clinical trial

Topical Review
Trial name criteria Trial type Enrollment outcome outcome results outcomes published number
Pilot dose- Time window: Phase: 88 total Primary hypothesis: 0.1, 0.2, 0.4 See primary 2005 n/a
escalation 0–3 h. 1/2, dose- enrollment. Tenecteplase is safe mg/kg no outcome
safety study of NIHSS: NIHSS escalation 0.1 mg/kg for acute ischemic symptomatic results.
tenecteplase in ≥1. Maximum safety study. tenecteplase stroke ≤3 h from ICHs.
acute ischemic age: none. Randomized: (n=25). onset at doses that 0.5 mg/kg was
stroke Vascular imaging: no. 0.2 mg/kg may be associated closed after 2
not reported. Blinded tenecteplase with improvement in of 13 patients
Perfusion treatment: (n=25). clinical neurological (15%) had
imaging: not no. 0.4 mg/kg outcome. symptomatic
reported. Blinded tenecteplase Primary outcome: ICH.
Prestroke mRS: outcome (n=25). symptomatic ICH
not specified. assessment: 0.5 mg/kg within 36 h.
yes. tenecteplase
(n=13).
TEMPO-1 Time window: Phase: 50 total Primary hypothesis: No serious Symptomatic 2015 NCT01654445
0–12 h, ≤90 2, safety, enrollment. The treatment drug-related ICH: 0.25 mg/
min of CT/CTA. feasibility. 0.1 mg/kg of minor stroke adverse events kg group, 1/25
NIHSS: <6. Randomized: tenecteplase with intracranial in 0.1 mg/kg (4%).
Maximum age: no, tiered. (n=25). occlusion with group. Mortality: 0.25
none. Vascular Blinded 0.2 mg/kg tenecteplase is In the 0.25 mg/ mg/kg group,
imaging: acute treatment: tenecteplase safe and feasible. kg group, one 1/25 (4%).
occlusion no. (n=25). Primary outcome: symptomatic
relevant to Blinded Rate of expected ICH.
symptoms. outcome serious adverse
Perfusion assessment: events.
imaging: not no.
reported.
Prestroke mRS:
Barthel index ≥90
or mRS score ≤1.
Determining the Time window: Phase: 2. 300 total Primary hypothesis: Reperfusion: Symptomatic 2020 NCT03340493
optimal dose of 0–4 h. Randomized: enrollment. Superior no difference, ICH: 0.40
TNK EXTEND-IA NIHSS: none. yes. 0.25 mg/kg recanalization 0.40 mg/kg mg/kg
Part 2 Maximum age: Blinded tenecteplase with 0.4 mg/kg tenecteplase, group—7/150
none. treatment: (n=150). vs 0.25 mg/kg. 29/150 (4.7%) and
Vascular imaging: no. 0.4 mg/kg Primary outcome: (19.3%), 0.25 mg/kg
Arterial occlusion Blinded tenecteplase Substantial 0.25 mg/kg group—2/150
on CTA of the outcome (n=150). angiographic tenecteplase, (1.3%),
ICA, M1, M2, or assessment: reperfusion (mTICI 29/150 unadjusted
basilar artery. yes. score=2b/3) (19.3%), risk difference,
Perfusion or absence of adjusted RR, 3.3% [−0.5%
imaging: not retrievable thrombus 1.03 [0.66– to 7.2%]; RR,
reported. at initial angiogram. 1.61]; P=0.89. 3.50 [0.74–
Prestroke mRS 16.62]; P=0.12.
score ≤3. Mortality:
26/150 (17%)
deaths in the
0.40 mg/kg
group and
22/150 (15%)
in the 0.25
mg/kg group
(adjusted RR,
1.27 [0.77–
2.11]; P=0.35).

CTA indicates computed tomography angiography; EXTEND-IA TNK, Tenecteplase Versus Alteplase before Endovascular Therapy for Ischemic Stroke; ICH,
intracranial hemorrhage; mRS, modified Rankin Scale; mTICI, modified Treatment in Cerebral Ischemia; NIHSS, National Institutes of Health Stroke Scale; and TEMPO-1,
RR, relative risk; TNK-tPA Evaluation for Minor Ischemic Stroke With Proven Occlusion.

TNK part 1 was designed to test the primary hypothesis 54 to 56 minutes, substantial reperfusion of >50% or
of noninferiority of tenecteplase 0.25 mg/kg relative to absence of a retrievable thrombus was found in 22%
alteplase in the 4.5-hour window for early reperfusion of patients randomized to tenecteplase relative to 10%
of an occluded internal carotid, middle cerebral, or basi- of alteplase patients (P=0.002 for noninferiority and
lar arteries in patients eligible for endovascular throm- P=0.03 for superiority). EXTEND-IA TNK part 2 con-
bectomy.31 With a median time interval from the start firmed the high rate of early reperfusion (19.3%) with
of the intravenous lytic to the diagnostic angiogram of either 0.25 or 0.4 mg/kg dose.44

Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749 November 2020   3443

 Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

Table 2. Clinical Trials Comparing Tenecteplase and Alteplase

Primary Primary
Topical Review

Key eligibility hypothesis/ outcome Key safety Adverse outcomes Year Clinical trial
Trial name criteria Trial type Enrollment outcome results outcome results reported published number
TNK-S2B Time window: Phase: 2B/3. 112 Total Primary No 6 symptomatic Angioedema: 2010 NCT00252239
0–3 h. Randomized: enrollment. hypothesis: differences ICHs: 0.4 mg/ not reported.
NIHSS: yes. 0.1 mg/kg Results will in 3-month kg tenecteplase: Hypotension: 1
aphasia Blinded teneceteplase be a clear functional 3/19 (15.8% serious systemic
score >1, treatment: (n=31). recommendation handicap [3.4–39.6]). hemorrhage in
motor power yes. 0.25 mg/kg to continue to (mRS score 0.25 mg/kg 0.25-mg/kg group
>1, vision Blinded teneceteplase phase 3 study. ≥4) between tenecteplase: (a retroperitoneal
>2, or outcome (n=31). Primary remaining 2/31 (6.5% hemorrhage)
attention >2. assessment: 0.4 mg/kg outcome: tenecteplase [0.8–21.4]). resulting in
Maximum yes. teneceteplase functional doses (0.1 0.1 mg/kg life-threatening
age: none. (n=19). handicap at 3 mg/kg: 7 tenecteplase: hypotension and
Vascular 0.9 mg/kg mo (mRS score (22.6%), (0/31 [0–11.2]). neurological
imaging: not alteplase ≥4). [9.6–41.1], 0.9 mg/kg worsening.
required. (n=31). 0.25 mg/kg: alteplase: 1/31 Anaphylaxis:
Perfusion 11 (35.5%), (3.2% [0.1– not reported.
imaging: not [19.2–54.6]) 16.7]). Mortality Reocclusion: not
reported. and alteplase from all causes reported.
Prestroke (10 (32.3%), within 3 mo New ischemic
mRS: not [16.7–51.4]). (95% CIs). stroke: not
specified. 0.4 mg/kg reported.
tenecteplase: Non-CNS bleeding
3/19, (15.8% (need for blood
[3.4–39.6]). transfusion): not
0.25 mg/kg reported.
tenecteplase:
7/31 (22.6%
[9.6–41.1]).
0.1 mg/kg
tenecteplase:
2/31 (6.5%
[0.8–21.4]).
0.9 mg/kg
alteplase: 8/31
(25.8% [11.9–
44.6]).
TAAIS trial Time window: Phase: 2B. 75 total Primary Pooled Symptomatic Angioedema: 2012 ACTRN12608
0–6 h. Randomized: enrollment. hypothesis: tenecteplase ICH: 3/25 not reported. 000466347
NIHSS: >4. yes. 0.1 mg/kg Tenecteplase groups (0.1 (12%) alteplase Hypotension:
Maximum Blinded teneceteplase will be superior mg/kg and and 2/50 (4%) not reported.
age: 85. treatment: (n=25). to alteplase 0.25 mg/kg) tenecteplase Anaphylaxis:
Vascular yes. 0.25 mg/kg with respect had greater pooled. not reported.
imaging: Blinded teneceteplase to one or both reperfusion Mortality: No Reocclusion: not
Visible outcome (n=25). co-primary at 24 h differences were reported.
occlusion assessment: 0.9 mg/kg outcomes. compared found at 90 days: New ischemic
on CTA. yes. alteplase Co-primary with the 3/25 (12%) stroke: one death
Perfusion (n=25). outcome: alteplase alteplase, 4/50 due to late second
imaging: Reperfusion group (8%) tenecteplase stroke in 0.1 mg/kg
>20% by proportional (79.3±28.8% pooled. tenecteplase group.
mismatch on reduction of vs Non-CNS bleeding
CTP. perfusion lesion 55.4±38.7%, (need for blood
Prestroke at 24 h. P=0.004). transfusion): not
mRS: ≤2 Co-primary Pooled reported.
outcome: tenecteplase
Change in groups (0.1
NIHSS from mg/kg and
prestroke to 0.25 mg/kg)
24 h. had greater
clinical
improvement
at 24 h
compared
with the
alteplase
group
(8.0±5.5%
vs 3.0±6.3%,
P<0.001).

(Continued )

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Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

Table 2. Continued

Primary Primary

Topical Review
Key eligibility hypothesis/ outcome Key safety Adverse outcomes Year Clinical trial
Trial name criteria Trial type Enrollment outcome results outcome results reported published number
ATTEST Time window: Phase: 2. 104 total Primary No significant Mortality: No Angioedema: ≤7 2015 NCT01472926
0–4.5 h. Randomized: enrollment. hypothesis: differences for differences days—1/52 (2%) in
NIHSS: ≥1. yes. 0.25 mg/kg Tenecteplase percentage were found in tenecteplase group.
Maximum Blinded teneceteplase will exhibit a of penumbra mortality between Hypotension: 7–90
age: none. treatment: (n=52). 15% absolute salvaged tenecteplase days—2/52 (4%) in
Vascular no. 0.9 mg/kg superior between 8/47 (17%) tenecteplase group.
imaging: Blinded alteplase recanalization tenectplase and alteplase Anaphylaxis:
CT and outcome (n=52). rate compared 68% (28/47) 6/49 (12%), not reported.
CTA before assessment: with alteplase and alteplase P=0.51; (OR, 1.3 Reocclusion: not
treatment. yes. with quicker 68% (23/49) [0.4 to −3.7]). reported.
Perfusion recanalization. groups Symptomatic New ischemic
imaging: Purpose was to (P=0.81) ICH: (ECASS stroke: ≤7
>20% determine effect with a mean II) no difference, days—2/52 (4%)
mismatch. size to inform on difference of tenecteplase in tenecteplase
Prestroke design of larger 1.3% [−9.6 to 3/52 (6%) and group, 7-90
mRS: not definitive study. −12.1]. alteplase 4/51 days: 4/52 (8%)
specified Primary (8%) groups, in tenecteplase
outcome: P=0.5; (OR, and 2/51 (4%) in
Percent 0.6 [0.1–3.2]). alteplase.
penumbral Symptomatic ICH: Non-CNS bleeding
salvage at (SITS-MOST) (need for blood
24–48 h no difference, transfusion): days
tenecteplase 7–90—2 (4%) in
1/52 (2%) and tenecteplase group
alteplase 2/51
(4%) groups,
P=0.50; (OR, 0.4
[0.04–5.1]).
NOR-TEST Time window: Phase: 3, 1050 total Primary Primary Symptomatic ICH: Angioedema: ≤7 2017 NCT01949948
0–4.5 h. superiority. enrollment. hypothesis: outcome no difference, days—1/549 (<1%)
NIHSS: ≥1. Randomized: 0.4 mg/kg Tenecteplase achieved by tenecteplase tenecteplase,
Maximum Yes. tenecteplase would result in 354/549 15/549 (3%) and 2/551 (<1%)
age: none. Blinded (n=549). a 9% absolute (64%) of alteplase 13/551 alteplase,
Vascular treatment: 0.9 mg/kg increase in tenectplase (2%), P=0.70; 8–90 days—0
imaging: no. alteplase the proportion and 345/551 (OR, 1.16 [0.51– both groups.
CTA or MRA Blinded (n=551). of patients (63%) of 2.68]). Hypotension:
required, but outcome achieving mRS alteplase Mortality: no not reported.
evidence assessment: score 0–1 at 3 groups, difference, Anaphylaxis:
of arterial yes. mo compared P=0.52, tenecteplase not reported.
occlusion with alteplase. with OR, 1.8 29/549 (5%) and Reocclusion: not
not. Primary [0.84–1.38]. alteplase 26/551 reported.
Perfusion outcome: Good (5%), P=0.68; New ischemic
imaging: functional (OR, 1.12 [0.63– stroke: ≤7 days
wake-up outcome (mRS 2.02]). −9/549 (2%)
patients score ≤1) at 90 Mortality substudy tenecteplase,
DWI/FLAIR days. in moderate- 5/551 (<1%)
mismatch severe strokes: alteplase, 8-90
required. increased in days—4/549 (<1%)
Prestroke tenecteplase (10 tenecteplase,
mRS: ≤2 [26.3%] vs 4 6/551 (1%)
[9.1%]; P=0.045) alteplase.
at 90 days. Non-CNS bleeding
(need for blood
transfusion):
≤7 days—GI
1/549 (<1%)
tenecteplase, 0
alteplase; other
extracranial
4/549 (<1%)
tenecteplase,
9/551 (2%)
alteplase,
8-90 days—GI
2/549 (<1%)
tenecteplase, 0
alteplase; other
extracranial
1/549 (<1%)
tenecteplase,
4/551 (<1%)
alteplase.
(Continued )

Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749 November 2020   3445

 Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

Table 2. Continued

Primary Primary
Topical Review

Key eligibility hypothesis/ outcome Key safety Adverse outcomes Year Clinical trial
Trial name criteria Trial type Enrollment outcome results outcome results reported published number
EXTEND-IA Time window: Phase: 2, 202 total Primary The primary Symptomatic ICH: Not reported 2018 NCT02388061
TNK 0–4.5 h noninferiority, enrollment. hypothesis: outcome no difference,
thrombolysis, superiority. 0.25 mg/kg Noninferiority (mTICI 2b or tenecteplase
EVT ≤6 h. Randomized: tenecteplase of tenecteplase 3) occurred 1/101 (1%) and
NIHSS: ≥1. yes. (n=101). was tested, in 22/101 alteplase 1/101
Maximum Blinded 0.9 mg/kg followed by (22%) of (1%).
age: none. treatment: alteplase superiority. the patients Mortality: no
Vascular no. (n=101). Primary treated with difference,
imaging: ICA, Blinded outcome: tenecteplase tenecteplase
M1, M2, or outcome Angiographic vs 10/101 10/101 (10%)
basilar artery assessment: reperfusion (10%) of and alteplase
occlusion on yes. (mTICI) score of those treated 18/101 (18%).
CTA or MRA. 2b/3 or absence with alteplase
Perfusion of retrievable (P=0.002 for
imaging: not thrombus at noninferiority;
reported. initial angiogram. P=0.03 for
Prestroke superiority).
mRS: ≤3

ATTEST indicates Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis; CNS, central nervous system; CTA, computed tomography angiography; CTP, computed
tomography perfusion; DWI, diffusion weighted imaging; ECASS II, European Cooperative Acute Stroke Study II; EXTEND-IA TNK, Tenecteplase versus Alteplase before Endovascular
Therapy for Ischemic Stroke; FLAIR, fluid attenuated inversion recovery; ICH, intracranial hemorrhage; mRS, modified Rankin Scale; mTICI, modified Treatment in Cerebral Ischemia;
NIHSS, National Institutes of Health Stroke Scale; NOR-TEST, Norwegian Tenecteplase Stroke Trial; OR, odds ratio; SITS-MOST, Safe Implementation of Treatments in Stroke
Monitoring Study; TAAIS, Tenecteplase Versus Alteplase for Acute Ischaemic Stroke; and TNK-S2, Study of Tenecteplase [TNK] in Acute Ischemic Stroke.

Meta-analysis of these 3 trials (Table II in the Data population of stroke, which skews toward mild. In a subset of
Supplement) reported an overall benefit of tenecteplase 87 NOR-TEST patients with NIHSS score ≥15, there was
on complete recanalization (30%–15%, P=0.04) but no difference in mRS or sICH, but the tenecteplase group
not on complete or partial recanalization (54%–41%, had a higher rate of mortality at 3 months (P=0.045).49
P=0.3).45 Pooled analyses of TAAIS and ATTEST patients There were no differences between treatment arms in a
found that among those meeting more stringent imaging subset of patients 80 years or older or wake-up strokes
selection criteria (absolute mismatch volume >15 mL, treated within 4.5 hour of symptom discovery.50,51 NOR-
mismatch ratio >1.8, baseline ischemic core <70 mL, and TEST 2 (URL: https://www.clinicaltrials.gov; Unique iden-
volume of severely hypoperfused tissue <100 mL) the tifier: NCT03854500) is testing 0.4 mg/kg tenecteplase
tenecteplase-treated patients had significant benefit on versus alteplase with a minimum NIHSS score >5.
median penumbral salvage, median infarct growth and In a planned secondary analysis of EXTEND-IA
complete recanalization relative to the control group.47,48 TNK part 1, patients receiving tenecteplase had a more
favorable 3-month mRS on an adjusted ordinal logistic
Early Neurological Improvement
regression (P=0.04) with 64% achieving functional inde-
Criteria for major early clinical improvement varied across
pendence (mRS score 0–2) relative to 51% of alteplase
the 5 trials (Table 2), but they all involved a substantial
treated patients (P=0.06).31
improvement on the National Institutes of Health Stroke
In a pooled analysis of patients from TAAIS and
Scale (NIHSS) by 24 to 72 hours. Only TAAIS found a
ATTEST, patients with target mismatch on perfusion
difference between the 2 treatments, an advantage for
CT (33 tenecteplase, 35 alteplase), treatment with
the tenecteplase treated patients (P<0.001).42 Meta-
tenecteplase was associated with better 3-month mRS
analysis reported an overall benefit on the proportion
score of 0 to 1 (P=0.032) than those treated with
of tenecteplase-treated patients with early neurological
alteplase, whereas the entire pooled sample did not show
improvement (45%–41%, P=0.05) with a greater ben-
a difference on 3-month mRS.48 TASTE trial (Tenecteplase
efit in those treated with 0.25 mg/kg.45
Versus Alteplase for Stroke Thrombolysis Evaluation;
Three-Month Clinical Outcome on mRS ACTRN12613000243718) is an ongoing phase 3 trial
Among the 5 randomized comparisons, NOR-TEST was selecting patients with demonstrated arterial occlusion
the largest and the only phase 3 trial with 3-month mRS as and target penumbral pattern on imaging for randomiza-
its primary end point, testing for superiority of tenecteplase tion to 0.25 mg/kg tenecteplase or alteplase.
over alteplase.43 Randomizing ≈1100 patients to either 0.4 Burgos and Saver52 conducted a formal noninferiority
mg/kg tenecteplase or standard dose alteplase, no dif- meta-analysis of the 5 randomized tenecteplase versus
ferences were found on 3-month mRS, sICH or mortal- alteplase comparisons across the dose ranges of 0.1 to
ity, either in the intention to treat or per protocol analysis, 0.4 mg/kg, n=1585. The primary analysis was noninfe-
which eliminated the stroke mimics from consideration. riority on freedom from disability (mRS score, 0–1) at 3
The median NIHSS score was 4, characteristic of a broad months using a noninferiority margin of 6.5%, as was used

3446   November 2020 Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749

Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

in a completed thrombolytic comparison randomized trial.53 Late Time Window Ongoing Trials
More stringent noninferiority margins, 5% and 1.3%, were TWIST (Tenecteplase in Wake-up Ischaemic Stroke Trial;

Topical Review
also explored guided by surveys of stroke experts. Nonin- URL: https://www.clinicaltrials.gov; Unique identifier:
feriority based on all analyzed thresholds was evidenced NCT03181360) is an ongoing phase 3 trial randomizing
by rates of 3-month mRS score of 0 to 1 outcomes nomi- to tenecteplase 0.25 mg/kg or standard care if patient
nally higher with tenecteplase than alteplase, with 95% can be randomized within 4.5 hours of awakening with
CIs within all 3 noninferiority margins. The corresponding the new stroke symptoms (Table III in the Data Supple-
P values for noninferiority were <0.0001, 0.0002, and ment). TWIST uses only noncontrast CT for imaging
0.02, respectively (personal email communication from selection but will analyze whether CT angiography or CT
Drs Burgo, Gornbein, and Saver, May 16, 2020). perfusion identifies patients more likely to benefit from
Ongoing large phase 3 clinical trials randomizing 0.25 tenecteplase, as measured by mRS at 3 months.
mg/kg tenecteplase or alteplase (Table III in the Data TIMELESS (Tenecteplase in Stroke Patients Between
Supplement) include the ATTEST-2 (URL: https://www. 4.5 and 24 Hours; URL: https://www.clinicaltrials.gov;
clinicaltrials.gov; Unique identifier: NCT02814409) test- Unique identifier: NCT03785678) is an ongoing random-
ing the superiority of tenecteplase and AcT (Alteplase ized, double-blind, placebo-controlled trial of tenecteplase
Compared to Tenecteplase in Patients With Acute 0.25 mg/kg in patients with large vessel occlusion (inter-
Ischemic Stroke), which will test the noninferiority of nal carotid or middle cerebral artery) with a target mis-
tenecteplase in real world practice (URL: https://www. match profile on MR or CT, similar to the criteria used
clinicaltrials.gov; Unique identifier: NCT03889249). in the DEFUSE 3 trial (Endovascular Therapy Follow-
Safety Outcomes ing Imaging Evaluation for Ischemic Stroke).57 Although
In total from the 5 trials, 24 of 828 tenecteplase patients planned thrombectomy is not required for eligibility, it is
experienced sICH (2.9%) as did 20 of 747 alteplase likely that the majority of subjects will be referred for
patients (2.7%). Mortality was 7.6% for tenecteplase mechanical recanalization therapy. The primary outcome
and 8.2% for alteplase.45,52 Thrombolytic complications will test difference on the mRS at 3 months.
of angioedema and extracranial bleeding have been CHABLIS-T (Chinese Acute Tissue-Based Imaging
reported for both tenecteplase and alteplase with no Selection for Lysis in Stroke -Tenecteplase; URL: https://
apparent differences in the rate of occurrence.43,46 www.clinicaltrials.gov; Unique identifier: NCT04086147)
is an ongoing phase 2 trial randomizing between 0.25
Thrombolysis in the Later Time Window and 0.32 mg/kg dose using similar imaging require-
Clinical trial evidence supported the benefit of intravenous ments as TIMELESS and assessing early favorable out-
alteplase over placebo patients treated >4.5 hours from come (reperfusion at 4–6 hours or no sICH by 36 hours).
the time last known well, if they met imaging criteria. The
criteria were either diffusion weighted imaging positive
and FLAIR negative magnetic resonance imaging, sug- DISCUSSION
gesting that the true duration of ischemia was likely to
be <4.5 hours54 or the presence of a target penumbra on Although the current body of clinical trial evidence and
perfusion imaging.55 Some tenecteplase studies permit- meta-analyses evaluating tenecteplase relative to alteplase
ted enrollment of patients with time last known well >4.5 point in the direction of superior early recanalization in
hours. The TAAIS trial42 enrolled up to 6 hours, and NOR- large vessel occlusions and noninferior disability-free out-
TEST43 included wake-up strokes if time from symptom come at 3 months, additional clinical trials are needed to
discovery to randomization was <4.5 hours, and magnetic definitively characterize the relative risks and benefits of
resonance imaging criteria were met, but neither had spe- tenecteplase in the treatment of ischemic stroke. Except
cifically tested for efficacy in the later time window. for NOR-TEST, completed stroke trials of tenecteplase
TEMPO-1 (TNK-tPA Evaluation for Minor Ischemic have been phase 2 trials with smaller sample sizes, focused
Stroke With Proven Occlusion) gave 0.1 or 0.25 mg/ primarily on safety, dose comparisons, and early clinical
kg to sequential groups of 25 patients up to 12 hours or biological end points, with the inherent limitations and
from onset (median time to treatment of 208 minutes) potential selection biases of such trials, as small samples
in minor stroke (NIHSS score <6) due to proven arte- may not sufficiently control by randomization all factors that
rial occlusion.56 The 0.25 mg/kg group had a higher influence the primary efficacy and safety outcomes. The
rate of complete recanalization, which correlated with phase III NOR-TEST43 had a large sample but one with
favorable 90-day mRS, and one sICH. TEMPO-2 lower median stroke severity on the NIHSS than usual for
(URL: https://www.clinicaltrials.gov; Unique identifier: thrombolytic trials, and thus its results may not generalize
NCT02398656) is an ongoing phase 3 trial random- to a more typical sample of thrombolytic stroke patients.
izing similarly selected patients to 0.25 mg/kg versus Overall, the published trials individually or in aggregate
standard of care antiplatelet treatment to test for benefit have not adequately, comprehensively, or systematically
of tenecteplase on 90-day mRS. assessed the relative frequency of direct and secondary

Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749 November 2020   3447

 Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

serious adverse effects of the 2 lytics, other than sICH and may confirm whether there is any disadvantage of the 0.4
mortality. Adverse events of expected low frequency, such mg/kg dose relative to standard dose alteplase.
Topical Review

as oro-lingual angioedema or other hypersensitivity reac- The only signal of clinical efficacy of superiority over
tions, will require large samples to produce reliable rates alteplase in stroke came from 2 small trials (TAAIS and
of occurrence. Reocclusion or recurrent stroke should be EXTEND-IA TNK, part 1) that selected an enriched
consistently reported, given the potential of lytics for para- sample by inclusion of only patients with imaging evi-
doxical thrombin activation, for events occurring within a dence of a target large vessel occlusion. It is unknown if
time period more likely to be related to lytic treatment than superiority on clinical end points would be confirmed on
to variability in secondary prevention measures. Incidence a larger sample or generalize to the broader population
of malignant cerebral edema, which may occur with early of patients with stroke. Based on results of tenecteplase
reperfusion even in the absence of hemorrhagic transfor- from STEMI trials, which showed equivalence rather than
mation, and of decompressive surgery to treat malignant superiority of tenecteplase to alteplase on clinical end
edema and reduce the incidence of mortality have not points23 and no clinical benefit even when earlier recana-
been reported in the published trials. Noncerebral bleed- lization was achieved before PCI,27,32,34 and on NOR-TEST,
ing should be reported according to standard definitions of which did not demonstrate superiority of tenecteplase, it
major and minor bleeding. may not be reasonable to expect to demonstrate clinical
Another limitation of the randomized comparisons has superiority of tenecteplase over alteplase in stroke, or at
been the frequent use of the prospective randomized least not at a large enough effect size to be demonstra-
open-label blinded end point design, a practice that con- ble in a feasibly sized ischemic stroke trial. NOR-TEST
tinues in ongoing trials. The open label design eliminates assumed an effect size for tenecteplase superiority to
the need for both a dummy and an active treatment since alteplase of 9%,43 probably an overestimate given that
the administration of each—one a quick bolus, the other a the effect size of alteplase versus placebo in positive
bolus and hour-long infusion—are different. Unlike trials stroke trials has been in the 7% to 12% range. One
of procedures that have no practical means of masking, may question whether ongoing phase 3 trials testing
the comparison of 2 different intravenous regimens can the superiority of tenecteplase over alteplase, specifi-
be blinded and had been for ASSENT-223 and for the cally those trials that are not limiting the sample to only
initial National Institute of Neurological Disorders and patients with target occlusions, are sufficiently powered
Stroke tenecteplase stroke trial of Haley et al.40 Blinded to demonstrate tenecteplase superiority at an effect
outcome assessments do not fully eliminate the poten- size appropriate to expectations. It may take very large
tial bias introduced by open label treatment,58,59 which samples or pooling of data from large trials to detect
tends to favor the novel treatment. It is unknown to what efficacy differences between alteplase and tenecteplase
extent open-label treatment biases patient management in stroke. However, proof of superiority may not be nec-
decisions, for example, decompressive hemicraniectomy essary for acceptance of tenecteplase as preferable to
for malignant edema, that may ultimately affect even the alteplase. Designs to sequentially test for noninferiority,
more objective end points, for example, mortality. For rec- followed by superiority if noninferiority is established, as
ognition, interpretation and reporting of adverse events designed into EXTEND-IA TNK part 1, may be a more
and for outcome measures that depend on patient self- efficient approach to produce results applicable to clini-
report, such as the mRS, bias introduced by unmasked cal practice, as failure to demonstrate superiority on the
treatment is still a concern in a prospective randomized primary end point, leaves the question of noninferiority
open-label blinded end point design. In such designs, unanswered. Among the ongoing phase 3 randomized
supportive results on more objective end points such as comparisons with alteplase only AcT (URL: https://www.
recanalization or infarct volume would strengthen con- clinicaltrials.gov; Unique identifier: NCT03889249) is
clusions based on patient self-report of disability. designed to test noninferiority as its primary hypothesis.
There has been no evidence to support an advantage An appropriate degree of caution is warranted in con-
of the 0.4 mg/kg dose relative to 0.25 mg/kg in the sidering whether the results of tenecteplase in STEMI
treatment of ischemic stroke. Rather, trials that directly trials generalize to stroke. In contrast to expectations
compared the 2 doses tended to favor the 0.25 mg/kg from preclinical studies, superior recanalization rates
dose. The National Institute of Neurological Disorders and with tenecteplase over alteplase have not been dem-
Stroke tenecteplase trial eliminated the 0.4 mg/kg as onstrated in clinical studies of tenecteplase in STEMI,17
inferior41 and EXTEND-IA-TNK part 2 reported a higher whereas they were in stroke.45 Earlier recanalization
number of sICH events in the 0.4 mg/kg group rela- with tenecteplase before endovascular in ASSENT-4
tive to the 0.25 mg/kg.44 Furthermore, the small subset and STREAM trials did not translate to clinical benefit,
of severe NOR-TEST patients randomized to 0.4 mg/kg whereas it did for EXTEND-IA-TNK, part 1.31 Chief
had a higher rate of mortality than those randomized to among the differences with treatment of STEMI that
alteplase.49 The ongoing NOR-TEST 2 trial (URL: https:// may limit the generalization to stroke are the concomi-
www.clinicaltrials.gov; Unique identifier: NCT03854500) tant use of antiplatelet and anticoagulant medicines, the

3448   November 2020 Stroke. 2020;51:3440–3451. DOI: 10.1161/STROKEAHA.120.029749

Warach et al Tenecteplase Thrombolysis for Ischemic Stroke

nature and cause of arterial occlusions, and the primary clarify the effects of the higher dose. Ongoing random-
outcomes of interest. ized phase 3 trials are testing the superiority or noninfe-

Topical Review
riority of tenecteplase relative to alteplase within the 4.5
Clinical Practice Guidelines
hour window, or addressing questions of tenecteplase
It is not known what plans the drug manufactures may have
efficacy in the greater than 4.5-hour time window, in
with regard to seeking regulatory approval for a stroke indi-
wake-up stroke, and in combination with endovascular
cation for tenecteplase in the 0 to 4.5 hour window or how
thrombectomy. We encourage completion of these trials,
the results of ongoing trials or the penetrance of biosimilars
analysis of pooled data across completed trials, and cre-
into the marketplace may influence their strategy. For the
ation of an international registry of tenecteplase in non-
time being, practice patterns with regard to tenecteplase
investigational practice. Through those efforts we may
use for stroke may be largely shaped by the professional
identify important differences between tenecteplase and
societies’ clinical practice guidelines. Five authoritative clini-
alteplase and more precisely quantify the comparative
cal practice guidelines have been issued since the publica-
clinical outcomes and adverse effects that will inform
tion of all of the completed randomized trials of tenecteplase
optimal thrombolysis of ischemic stroke.
versus alteplase (Table IV in the Data Supplement), but no 2
are in agreement with regard to a recommendation to use
tenecteplase in stroke or on the strength of that recom- ARTICLE INFORMATION
mendation based on the same available evidence. The most
Affiliation
recent American Heart Association/American Stroke Asso- Department of Neurology, Dell Medical School, University of Texas at Austin.
ciation Guidelines for the Early Management of Patients
With Acute Ischemic Stroke recommend tenecteplase as an Sources of Funding
No external funding supported this work. The authors’ salaries are supported in
alternative that may be considered for large vessel occlu-
part by Lone Star Stroke Research Consortium of the State of Texas, National
sion (at 0.25 mg/kg) or minor, non-large vessel occlusion (at Heart, Lung, and Blood Institute, Dell Medical School, and Ascension Healthcare.
0.4 mg/kg), class IIb recommendations.60 The noninferiority
Disclosures
meta-analysis52 and the randomized EXTEND-IA TNK part
Dr Warach is a consultant, Chair Independent Data Safety Committee, TIMELESS
2 (0.25–0.4 mg/kg) comparison44 were published after the trial (Tenecteplase in Stroke Patients Between 4.5 and 24 Hours), Genentech.
guideline writing committee’s literature search closed, and so Dr Milling is a TIMELESS trial site Principal Investigator, Genentech; Consultant,
are not accounted for in the current guideline. Other, inter- Portola Pharmaceuticals; ANNEXA-I Executive Committee, Population Health
Research Institute, McMaster University. The other authors report no conflicts.
national guidelines variably support a role for tenecteplase
in the treatment of acute ischemic stroke (Table IV in the Supplemental Materials
Data Supplement). The 2019 Australian Stroke Founda- Expanded Materials and Methods
Figure I
tion gives the 2 drugs equal status for large vessel occlu- Tables I–IV
sions and tenecteplase as an alternative in other strokes.61 References 9, 11, 12, 15, 19, 68–70
The 2018 European Stroke Organisation guideline recom-
mended against the routine use of tenecteplase in clinical
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