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Content uploaded by Réza Behrouz
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REVIEW
Intravenous tenecteplase in acute ischemic stroke:
an updated review
Re
´za Behrouz
Received: 18 August 2013 / Revised: 4 September 2013 / Accepted: 6 September 2013
ÓSpringer-Verlag Berlin Heidelberg 2013
Abstract Tenecteplase in a genetically engineered vari-
ant of alteplase. Although the two have the same mecha-
nism of action, tenecteplase has properties that makes it a
seemingly more advantageous thrombolytic. Because of its
rapid single-bolus administration, its use is favored over
alteplase in the treatment of acute myocardial infarction.
Over the past few years, several clinical studies have been
conducted to assess the safety, feasibility, and efficacy of
tenecteplase in ischemic stroke. In spite of the mixed
results of these studies, experimentation with tenecteplase
continues in from of clinical trials. In this article, the utility
of tenecteplase in ischemic stroke will be discussed.
Keywords Stroke Cerebrovascular disease
Tenecteplase Alteplase Tissue plasminogen
activator Thrombolytics Thrombolysis
Pharmacology
Introduction
In the spring of 1996, the Food and Drug Administration
(FDA) approved the use of intravenous (IV) alteplase
(TPA) in the treatment of acute ischemic stroke (AIS)
within 3 h of symptom onset. This approval was largely
based on the favorable results of the NINDS-TPA study.
NINDS-TPA showed that, compared to placebo, patients
treated with IV TPA were at least 30 % more likely to have
minimal or no disability at 3 months [1]. The therapeutic
window was extended to 4.5 h based on the pooled analysis
of several European and Australian studies, above all, the
third European Cooperative Acute Stroke Study (ECASS
III) [2].
Since the successful outcomes of IV TPA in the treat-
ment of AIS patients, neurologists have been curious and
intrigued by the utility of other types of thrombolytics in
this clinical scenario. Experimentation with these medica-
tions dates back to the mid-1990s [3]. Clinical trials have
been conducted using various thrombolytics including
ancrod, desmoteplase, and tenecteplase (TNK) [4–6]. TNK
in particular appears to be a promising alternative to TPA.
Currently approved for the treatment of acute ST elevation
myocardial infarction (MI), TNK is a genetically modified
form of TPA. In this article, the utility of TNK in ischemic
stroke will be discussed.
Pharmacokinetics and initial safety analysis
TNK is synthesized by restructuring the TPA protein. This
involves substitution of amino acids in three sites (Fig. 1),
providing TNK with properties that are theoretically more
ideal for systemic thrombolysis. The mechanism of action
of TNK is the same as TPA, albeit with several advanta-
geous disparities. It has 14-fold greater fibrin specificity
than TPA, a longer half-life, slower plasma clearance, and
80-fold greater resistance to inhibition by plasminogen
activator inhibitor type 1 (PAI-1) [6]. Its half-life of
approximately 18 min allows for rapid, single-bolus
administration [6]. A comparison of the properties of TPA
and TNK is demonstrated in Table 1[7].
The second Assessment of the Safety and Efficacy of a
New Thrombolytic (ASSENT-2) trial was a study that
R. Behrouz (&)
Division of Cerebrovascular Diseases and Neurological Critical
Care, Department of Neurology, The Ohio State University
College of Medicine, 395 West 12th Avenue, Suite 766,
Columbus, OH 43215, USA
e-mail: reza.behrouz@osumc.edu
123
J Neurol
DOI 10.1007/s00415-013-7102-0
assessed the safety of TNK in acute MI [8]. The results
demonstrated that, compared to TPA, TNK at 0.5 mg/kg
was associated with similar mortality and intracerebral
hemorrhage (ICH) rates, but reduced incidence of non-
cerebral bleeding complications [8]. Then a study in rabbit
models of AIS showed that hemorrhagic transformation of
experimental infarcts was less frequent with TNK than
equivalent doses of TPA (although not statistically signif-
icant) [9]. These agreeable characteristics invoked the
interest of neurologists to consider assessing the safety and
benefit of TNK in patients with AIS.
Clinical investigations
The safety of TNK in AIS was demonstrated in an open-
label, dose-escalation study by Haley et al. [10]. A total of
88 patients were treated with IV TNK at four doses: 0.1,
0.2, 0.4, and 0.5 mg/kg. Symptomatic ICH was reported in
two of the 13 (2 %) patients who received 0.5 mg/kg and
none in the first three tiers (0.1, 0.2, and 0.4 mg/kg).
Modified Rankin scale (mRS) scores at 3 months were
similar to those of historical controls treated with TPA
[10]. The results of this study ushered into the decision to
pursue outcome comparisons with IV TPA in subsequent
trials.
Four main clinical trials have been performed compar-
ing the efficacy of TNK with TPA in AIS patients
(Table 2). The first study, conducted in Australia by Par-
sons et al, was a prospective, non-randomized trial com-
paring TNK to TPA administered within 3–6 h of AIS
onset. All patients underwent pretreatment and 24-h com-
puted tomography (CT) or magnetic resonance imaging
(MRI) angiogram and perfusion. Only those with perfusion
lesion at least 20 % greater than the infarct core and an
associated vessel occlusion received TNK. IV TPA was
administered within the 3-h window as a control group.
The investigators reported that patients who were treated
with IV TNK at a dose of 0.1 mg/kg within 3–6 h had
better reperfusion, less infarct growth, and greater early
clinical improvement than patients who received IV TPA at
0.9 mg/kg in the 3-h window [11].
Fig. 1 Amino acid sequence
differences between alteplase
and tenecteplase. Three sites are
modified on the alteplase
protein to create tenecteplase.
At position 103, threonine is
replaced by asparagine. At
position 117, asparagine is
replaced by glutamine. At
position 296–299, a lysine–
histamine–arginine–arginine
sequence is replaced by a tetra-
alanine chain
Table 1 Comparison of pharmacokinetic properties of TPA and TNK
Agent Fibrin
specificity
Thrombolytic
potency
PAI-1
resistance
Fibrinogen
depletion
PRT
activity
Clearance
(mL/kg/min)
TPA ?? ? - ?? ?? 16.1
TNK ??? ??? ?? ? ??? 1.9
PAI-1 plasminogen activator inhibitor type 1, PRT platelet-rich thrombus
Table 2 A list of studies using TNK in cerebral ischemia
References Number Study type Window FO, TNK (%) FO, TPA (%) psICH TNK (%) sICH TPA (%) p
Parsons et al. [11] 50 NR 3–6 h, IB 67 20 0.001 0 11 NS
Haley et al. [12] 110 R 0–3 h 44 42 [0.3 6 3.2 –
Molina et al. [13] 122 NR 0–4.5 h 24.5 11 – 2.3 3.7 –
Parsons et al. [14] 75 R 0–6 h, IB 64 36 0.02 4 12 NS
NR non-randomized, Rrandomized, IB imaging-based, FO favorable outcome, sICH symptomatic ICH
J Neurol
123
A second study, which was part of the Specialized
Programs of Translational Research in Acute Stroke
(SPOTRIAS), compared IV TNK to TPA given within 3 h
of symptom onset. This was the first randomized, multi-
center, double-blind, controlled clinical trial comparing
0.1, 0.25, and 0.4 mg/kg TNK with 0.9 mg/kg TPA in
patients with AIS within the standard therapeutic window
(3 h). The 0.4 mg/kg dose was discarded as inferior after
only 73 patients were randomized. The trial was stopped
prematurely due to slow enrollment with no definitive
conclusion regarding superiority (or non-inferiority). The
rates of symptomatic ICH were 15.8, 6.5, and zero in the
0.4 mg/kg, 0.25 mg/kg, and 0.1 mg/kg groups, respec-
tively. This rate was 3.2 % in the TPA group. No con-
vincing verdict regarding outcomes could be achieved [12].
If the selected dose of TNK showed promise, approxi-
mately 1,900 patients were to be randomized in phase III to
the selected dose of TNK or TPA.
Molina reported a non-randomized trial involving 122
consecutive patients with stroke due to middle cerebral
artery occlusion who fulfilled criteria for intravenous
thrombolysis (0–4.5 h). Patients were allocated to receive
0.9 mg/kg standard IV TPA or 0.4 mg/kg IV TNK. Com-
plete recanalization at 2 h was seen in 42.4 % and 33.4 %
patients treated with TNK and TPA, respectively
(p=0.014). TNK increased 2.5-fold the rate of dramatic
clinical recovery at 24 h as compared with TPA (24.5
versus 11 %) [13]. Symptomatic ICH rates were 2.3 and
3.7 % in the TNK and TPA groups, respectively.
Finally, in 2012, Parsons et al. [14] presented the
results of their second trial—this time randomized. This
was a phase IIb, open-label, blinded trial comparing IV
TNK to TPA in 75 AIS patients. The study had three
arms with two different TNK doses (0.1 or 0.25 mg/kg)
and TPA at a dose of 0.9 mg/kg administered within
0–6 h of symptom onset. Patients were included based on
multimodal CT imaging. The eligibility criteria were a
baseline perfusion lesion at least 20 % greater than the
infarct core on CT perfusion associated with a large
vessel occlusion on CT angiography. Primary end points
were lesion reperfusion rate at 24 h (using perfusion-
weighted MRI) and the extent of clinical improvement at
24 h measured by NIHSS. Patients in the TPA group
received treatment at a mean of 2.7 h, as compared with
3.1 h for those in the pooled TNK groups. Only three
patients were treated after 4.5 h. Both TNK arms had
greater reperfusion (p=0.004) and clinical improvement
(p\0.001) at 24 h than the TPA group. There was no
significant difference in ICH rates between the three
groups. The combined results of the two TNK groups
showed superiority of TNK to TPA with regard to the
proportion of patients with excellent or good recovery at
3 months (mRS of 0–2; 72 versus 44 %; p=0.02) [14].
Critics suggested that there was a selection bias for small
cerebral infarctions, hence making the trial inapplicable to
most AIS cases [15]. Moreover, the overall ratio of infarct
to territory-at-risk was smaller in the TNK group, swaying
the results in favor of TNK. Nonetheless, Parsons et al.
did establish the superiority of TNK to TPA to a rea-
sonable extent. Although it is not the standard of practice
to obtain multimodal imaging in the 3-h therapeutic
window, Parsons et al. did so in an aim to prove that IV
TNK resulted in greater reperfusion when the baseline
images were compare to the 24 h perfusion scans.
Contemporary studies
There are two active studies evaluating the use of TNK in
AIS. TNK-TPA evaluation for minor ischemic stroke with
proven occlusion (TEMPO-1) is a single-group, open-label
study conducted in multiple centers throughout Canada
[16]. The primary objective of this study is to demonstrate
the safety and feasibility of TNK to treat minor (NI-
HSS \6) AIS patients with proven acute symptomatic
vascular occlusions. There will be two TNK dose tiers at
0.1 mg/kg and 0.25 mg/kg. TEMPO-1 will enroll patients
within a 12 h time window and perform a CT angiogram
between 4 and 8 h after treatment to determine whether the
occluded artery has recanalized. Outcomes will be assessed
at 24 and 48 h, and at 5, 30, and 90 days. TEMPO-1
anticipates enrolling 50 subjects, 25 per tier.
Alteplase-tenecteplase trial evaluation for stroke
thrombolysis (ATTEST) is a pilot evaluation of TNK
compared to TPA in AIS patients currently eligible for IV
TPA treatment [17]. Originating in Scotland, ATTEST is a
prospective, randomized, blinded clinical trial evaluating
outcomes using brain imaging as a biomarker. Patients will
receive IV TNK at 0.25 mg/kg or IV TPA at 0.9 mg/kg
within 0–4.5 h from symptom onset. The primary endpoint
is percent penumbral salvage at 24–48 h. Secondary mea-
sures are clinical improvement at 24 h, recanalization and
ICH rates at 24–48 h, and functional outcome at 30 and
90 days. It is hoped that the combined results of these
studies would at least clear the path for more large-scale
trials.
Conclusion
TNK is a promising drug in the treatment of AIS, but at this
time, its standard use outside of a clinical trial and in lieu
of TPA is improbable. The future prospect of a large-scale,
randomized trial comparing TNK to TPA may not be so
dubious, but also not devoid of challenges. In order to
proceed with such trial, it has to be persuasively
J Neurol
123
established that TNK is not inferior and at least as safe as
TPA in the treatment of AIS. Overcoming this impediment
requires deviation from the standard of care—that is,
administration of TNK in place of TPA. Because this is
regarded as an ‘‘off-label’’ use, the FDA would be hesitant
to issue an investigational new drug (IND) authorization.
Then there is the question of financial support. The
National Institutes of Health (NIH) is unlikely willing to
fund a study comparing a drug with class I evidence in
efficacy to another drug whose clinical superiority and
advantages have not been positively ascertained. Securing
funding from pharmaceutical companies is a challenge in
its own because these firms have their fiscal welfare at
stake. Their chief question is how funding a clinical trial
will affect their economic advancement or lack thereof.
TPA is manufactured by three different companies:
Genentech Inc. in the United States, Roche in Canada, and
Boehringer Ingelheim in Europe. TNK is also made by
these companies in their respective marketing territory. In
all likelihood, replacement of TPA by TNK before the
former becomes generic will have significant financial
setbacks for the three companies. By enjoying approved
indications for TPA in AIS and TNK in MI, both products
can be marketed with equally substantial profits. If TNK
and TPA were not made by the same manufacturer, things
may have been different. The testament to that is the
continuous, persistent support of the desmoteplase in acute
stroke (DIAS) study series by the Denmark-based company
H. Lundbeck A/S, the manufacturer of desmoteplase [18].
Notwithstanding the existence of these obstacles, if the
interest in TNK for AIS therapy remains alive, a steadfast
campaign aimed to push for a phase III trial is should be
embarked upon. Until then, the utility of TNK in AIS
remains largely an enigma.
Conflicts of interest Dr. Behrouz has received educational grant
from Genentech Inc. The author declares that he has no conflict of
interest.
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