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Tenecteplase in a genetically engineered variant of alteplase. Although the two have the same mechanism 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.
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Intravenous tenecteplase in acute ischemic stroke:
an updated review
´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
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) [46]. 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
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
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–
sequence is replaced by a tetra-
alanine chain
Table 1 Comparison of pharmacokinetic properties of TPA and TNK
Agent Fibrin
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
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
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
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
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J Neurol
... Furthermore, the higher dose of TNK (0.25 mg/kg) was superior to both the lower TNK dose of 0.1 mg/kg and to rtPA for all efficacy outcomes, including the 3-month mRS (Parsons et al. 2012). Although TNK is approved for the treatment of acute myocardial infarction, its use in the treatment of AIS outside of the setting of a clinical trial still is unapproved (Bivard, Lin, and Parsonsb 2013;Behrouz 2014). Recently the Tenecteplase in Stroke Patients between 4 and 24 Hours "TIMELESS" study was initiated. ...
... Furthermore, the higher dose of TNK (0.25 mg/kg) was superior to both the lower TNK dose of 0.1 mg/kg and to rtPA for all efficacy outcomes, including the 3-month mRS (Parsons et al. 2012). Although TNK is approved for the treatment of acute myocardial infarction, its use in the treatment of AIS outside of the setting of a clinical trial still is unapproved (Bivard, Lin, and Parsonsb 2013;Behrouz 2014). Recently the Tenecteplase in Stroke Patients between 4 and 24 Hours "TIMELESS" study was initiated. ...
Non-traumatic subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke associated with substantial morbidity and mortality. Effective management comprises of multi-disciplinary care involving emergency physicians, neurologists, cerebrovascular neurosurgeons, neuro-endovascular specialists, neuro-intensivists, physical medicine and rehabilitation services, as well as neuro-radiologists. In this chapter, we have discussed the patho-physiology; best practices guidelines for acute management of SAH, early identification and treatment of bleeding source and principles of critical care involved in preventing and treating delayed complications.
... When comparing tenecteplase to tPA, some research suggests that there is no difference in patient outcome with either option. 56,76 Furthermore, a recent sub-group analysis of the Tenecteplase versus Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial suggests that tenecteplase is more effective in opening occluded vessels than tPA. 77 An important feature of tenecteplase is its ease of use. ...
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Emergency management of stroke has been directed at the delivery of recombinant tissue plasminogen activator (tPA) in a timely fashion. Because of the many limitations attached to the delivery of tPA and the perceived benefits accrued to tPA, its use has been limited. Mechanical thrombectomy, a far superior therapy for the largest and most disabling strokes, large vessel occlusions (LVOs), has changed the way acute strokes are managed. Aside from the rush to deliver tPA, there is now a need to identify LVO and refer those patients with LVO to physicians and facilities capable of delivering urgent thrombectomy. Other parts of emergency department management of stroke are directed at identifying and mitigating risk factors for future strokes and at preventing further damage from occurring. We review here the most recent literature supporting these advances in stroke care and present a framework for understanding the role that emergency physicians play in acute stroke care.
... In the last 15 years, the interest to find a better fibrinolytic agent increased and the attention was moved to tenecteplase-an approved agent for the treatment of acute myocardial infarction with some theoretical pharmacologic advantages over alteplase: greater fibrin specificity and resistance to inactivation by plasminogen activator inhibitor-1, no procoagulant action, and a longer plasma half-life [28]. Between several phase II and III clinical studies with tenecteplase, available information regarding the non-inferiority or superiority vs. alteplase remains inconclusive, despite evidence on the safety of a 0.25-mg/ kg dosage having emerged [29]. ...
Patient-level health outcomes for acute ischemic stroke have significantly improved in the last decade primarily because of superior overall case management, availability of tailored drug interventions, and advances in endovascular procedures. Nevertheless, disease registries show a “quality gap” across social determinants of health and between in-hospital and community-onset strokes. Several factors, including financing and infrastructure constraints, limited expertise, and clinical uncertainty, still prevent adherence to evidence-based clinical guidelines and optimal care pathways. This paper critically appraises existing evidence on the use of drug therapies in acute ischemic stroke, in an attempt to resolve physician-related subjective barriers for effective acute management of the disease. We conclude that intravenous administration of rt-PA (recombinant tissue-type plasminogen activator, alteplase) is an essential component of acute-phase pharmacologic treatment and a driver for the improvement of overall ischemic stroke health outcomes. The safety profile of alteplase and similar treatments are well within the patient benefit zone of eligible patients when compared to non-treatment alternatives. Monomodal neuroprotective drugs with single or pleiotropic mechanisms of action have failed to support long-term sustainable results. Drugs with complex mechanisms of action that promote neurorecovery, such as cerebrolysin, are valid options for adjunctive treatment of acute ischemic stroke. Recent years have shown clear improvements in the methodology and design of clinical trials, with an increase in overall internal and external validity. A better understanding of study limitations has not hindered, but enhanced their potential to contribute, together with sometimes superior data sources, to health decision making.
... TNK has a similar mechanism of action but has 14-fold greater fibrin specificity, 80-fold greater resistance to inactivation by plasminogen activator inhibitor-1, no procoagulant action, longer half-life (18 min), and slower plasma clearance compared to alteplase. [20,21] [ Table 1] Hence, the availability of a thrombolytic agent which can be given as a single intravenous bolus in acute ischemic stroke was exciting. evIdence foR tenecteplAse In Acute IschemIc stRoke Haley et al. showed the safety of TNK in acute ischemic stroke in an open labeled dose escalation study involving 88 patients using 4 doses of TNK (0.1, 0.2, 0.4, and 0.5 mg/kg). ...
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Vascular neurology is witnessing unprecedented innovations in the management of acute ischemic stroke, especially in reperfusion strategies. The emergence of mechanical thrombectomy with new generation devices has revolutionized the treatment of acute ischemic stroke with large vessel occlusion. The reperfusion strategies are evolving with the extension of the window period for thrombolysis and endovascular therapy through the concept of “tissue clock” in addition to the established “time clock.” The newer generation of thrombolytic drugs like tenecteplase are promising exciting times ahead in acute stroke care. In this “viewpoint,'” the evolution of reperfusion therapy in acute ischemic stroke will be discussed followed by recent innovations in reperfusion strategies.
... However, its efficacy is limited by its short half-life, requiring continuous infusion for approximately 1 h, low recanalization rate, and risk of intracerebral hemorrhage [2][3][4]. In contrast, tenecteplase, a three-point genetically mutated variant of alteplase, has a longer half-life and slower plasma clearance, allowing for single-bolus administration, enhanced fibrin specificity, and greater resistance against plasminogen activator inhibitor-1, resulting in a faster clot lysis compared with alteplase [5][6][7][8]. ...
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Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence, we conducted a study to evaluate the efficacy and safety of tenecteplase compared with alteplase in acute ischemic stroke. Electronic databases were searched for randomized clinical trials (RCTs) comparing tenecteplase with alteplase in acute ischemic stroke patients eligible for thrombolysis. We evaluated various efficacy and safety outcomes using random-effects models for both pairwise and Bayesian network meta-analyses along with meta-regression analyses. We included 5 RCTs with a total of 1585 patients. Compared with alteplase, tenecteplase treatment was associated with significantly greater complete recanalization (odd ratio [OR] 2.01; 95% confidence interval [CI] 1.04–3.87; p = 0.04) and early neurological improvement (OR 1.43; 95% CI 1.01–2.03; p = 0.05). There were no differences between the two thrombolytics in terms of excellent recovery (modified Rankin Scale [mRS] 0–1; OR 1.17; 95% CI 0.95–1.44; p = 0.13), functional independence (mRS 0–2; OR 1.24; 95% CI 0.78–1.98), poor recovery (mRS 4–6; OR 0.78; 95% CI 0.49–1.25; p = 0.31), complete/partial recanalization (OR 1.51; 95% CI 0.70–3.26; p = 0.30), any intracerebral hemorrhage (OR 0.81; 95% CI 0.56–1.17; p = 0.26), symptomatic intracerebral hemorrhage (OR 0.98; 95% CI 0.52–1.83; p = 0.94), or mortality (OR 0.83; 95% CI 0.54–1.26; p = 0.38). In network meta-analysis, there were better efficacy and imaging-based outcomes with tenecteplase 0.25 mg/kg without increased risk of safety outcomes. Our results demonstrate that in acute ischemic stroke, thrombolysis with tenecteplase is at least as effective and safe as alteplase.
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Intravenous thrombolysis is a standard of care treatment for patients with acute is-chemic stroke. Tissue plasminogen activator (tPA) has been the main thrombolytic agent used since the publication of the seminal National Institutes of Neurological Disorders and Stroke trial in 1995. There is now mounting evidence to support the routine use of Tenecteplase (TNK) to treat acute ischemic stroke. TNK is a genetically modified tPA with higher fibrin specificity, longer half-life, and reduced systemic coagulopathy. In this illustrated review, we compare the indications, doses, mechanisms of action, efficacy and safety of TNK and tPA. We provide an overview of published clinical trials studying TNK in acute ischemic stroke, including dose-escalation studies and head-to-head comparisons with tPA. Finally, we summarize current acute stroke guideline recommendations and suggest treatment algorithms to manage the two main complications of intravenous thrombolysis: symptomatic intracerebral hemorrhage and angioedema.
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Atherosclerosis is the preliminary lipid disorder in which arterial blood vessels become hard and thicken due to multiple plaque formation within blood vessels. These soft multiple plaques suddenly ruptures out, leading to the formation of thrombus that rapidly slow down or stop the blood flow and obstruct the oxygen supply to the targeted tissues. These free floating thrombi can be circulated anywhere in the cardiovascular system including lung, brain, heart or deep veins of leg and leads to serious complications as atherothrombotic diseases (myocardial or cerebral infarction), coronary artery diseases (CAD), peripheral vascular diseases, pulmonary thrombosis, cerebro-vascular disease and heart failure. Pulmonary thrombosis is a inexorable condition commonly appear in Covid-19 pneumonia patients due to fully or partially block blood supply to artery of lung and is characterized by inexplicable breathing difficulties, hemoptysis and chest pain. Similarly cardiac arrhythmias is on rise worldwide and is leading cause of morbidity, mortality and disabilities, is associated with shortness of breath, synapse, angina or finally even death. A Cardio vascular disease (CVD) is the highly implacable disease and often impacting most productive and precious years of individuals throughout the world and hence requires very accurate diagnosis and treatment. Commonly used conventional antithrombotic drugs such as t-PA, Urokinase, Streptokinase, Ateplase, Anisteplase and so forth, play deciding role in CVD management and other related disorders. However, available thrombolytics still have noticeable shortcomings including bleeding, lysis of hemolytic plug, antigenicity, defective coagulation, gastrointestinal and cerebral hemorrhage. In view of the inadequacies of conventional thrombolytics, efforts have made to understand significant value of herbal drugs for treating coronary arterial disease and related problems. As diabetes mellitus, hypertension, smoking cigarettes, dislipidemia, dyspnea and pneumonia are the prime causes of increasing severity of atherosclerosis and Covid-19 diseases, includes aggregation of platelets which eventually results in thrombus formation and hypoxia. Moreover, covid- 19 death rate is more common among people with such diseases and disorders. Hence food and dietary herbals with antithrombotic characteristics may be used to improve such diseases which ultimately maintain the health and regain healthy state of mind. The present review is focused on the availability of medicinal plants that have antithrombotic, anti- platelets and fibrinolytic potential, which can be explored for the effective treatment of thrombotic diseases, lifestyle disorders and future pandemics like Covid-19.
The introduction of thrombolytic therapy in the 1990s has transformed acute ischemic stroke treatment. Thus far, intravenous recombinant tissue plasminogen activator (rt-PA) also known as alteplase is the only thrombolytic proven to be efficacious and approved by the United States Food and Drug Administration. But the thrombolytic agent tenecteplase (TNK) is emerging as a potential replacement for rt-PA. TNK has greater fibrin specificity, slower clearance, and higher resistance to plasminogen activator inhibitor-1 than rt-PA. Hence, TNK has the potential to provide superior lysis with fewer hemorrhagic complications. Also, easier bolus-only administration makes TNK a very practical rt-PA alternative. In several clinical trials, TNK has shown similar efficacy and safety to rt-PA, and the potential to be at least noninferior to rt-PA in some settings. TNK may be superior to rt-PA for reperfusing large vessel occlusions in patients with salvageable penumbra, although this has not yet translated to improved clinical outcomes. Further phase 3 studies are in progress comparing rt-PA with TNK for acute ischemic stroke during the first 4.5 hours. Studies are also in progress to evaluate the use of TNK for extended applications, such as wake-up stroke.
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Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).
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Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.
Background and PurposeThere is no acute therapy proven to be of benefit for ischemic stroke. Ancrod is a potentially effective therapy because of the advantageous consequences of fibrinogen lowering. Methods We studied the safety and efficacy of ancrod in patients with acute ischemic stroke administered within 6 hours of stroke onset. In a double-blind, randomized, placebocontrolled trial 64 patients received intravenous ancrod and 68 received placebo for 7 days. Neurological outcome, disability, and brain infarct volume were measured. Results There was no significant difference in overall mean scores on the Scandinavian Stroke Scale. No increase in bleeding occurred in the ancrod-treated patients. The target reduction of plasma fibrinogen levels of less than 100 mg/dL was achieved in only 15 (23%) of 64 ancrod-treated patients. Those patients with ancrod-induced 6-hour fibrinogen levels 130 mg/dL or less had a marginally significantly better neurological outcome on the Scandinavian Stroke Scale, mortality, and Barthel Index than ancrod-treated patients with higher fibrinogen levels. Conclusions Ancrod appears safe and potentially effective when administered to patients within 6 hours of onset of ischemic stroke.
Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke. METHODS: The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS: RESULTS: In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30). CONCLUSIONS: Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.
Background: Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in phase III of clinical development. In comparison to alteplase, it has high fibrin selectivity, is associated with minimal or no neurotoxicity, and has no apparent negative effect on the blood-brain barrier. The safety and efficacy of desmoteplase is being studied in the Desmoteplase in Acute Ischemic Stroke clinical trial program. Three studies (Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke, Desmoteplase in Acute Ischemic Stroke, and Desmoteplase in Acute Ischemic Stroke-2) have been completed, two large randomized, double-blind, placebo-controlled, phase III trials are ongoing at >200 sites worldwide (Desmoteplase in Acute Ischemic Stroke-3 and Desmoteplase in Acute Ischemic Stroke-4, n = 800; DIAS-3 and DIAS-4), and a randomized, double-blind, placebo-controlled, dose-escalation phase II trial is ongoing in Japan (Desmoteplase in Acute Ischemic Stroke-Japan, n = 48; DIAS-J). Aims: The objective of DIAS-3 and DIAS-4 is to evaluate the safety and efficacy of a single IV bolus injection of 90 μg/kg desmoteplase given three- to nine-hours after onset of ischemic stroke (National Institutes of Health Stroke Scale 4-24, age 18-85 years). The objective of DIAS-J is to evaluate the safety and tolerability of desmoteplase 70 and 90 μg/kg three- to nine-hours after ischemic stroke onset in Japanese patients. Methods: Patients are included with occlusion or high-grade stenosis (thrombolysis in myocardial infarction 0-1) in proximal cerebral arteries on magnetic resonance or computed tomography angiography but excluded with extended ischemic edema on computed tomography or diffusion-weighted imaging. Conclusion: Desmoteplase is the only thrombolytic agent in late-stage development for acute ischemic stroke that is now tested in patients with proven stroke pathology. The results of the Desmoteplase in Acute Ischemic Stroke clinical trial program will show whether patients with major artery occlusions but not extended ischemic brain damage can be safely and effectively treated up to nine-hours after onset.
Arterial recanalization and subsequent reperfusion have extensively demonstrated their ability to restore the brain function when performed shortly after acute ischemic stroke. However, arterial recanalization does not necessarily lead to brain tissue reperfusion. This review provides an update of current approaches to improve the efficacy profile of brain tissue reperfusion within and beyond the therapeutic window, including the use of novel thrombolytic agents, bridging intravenous and intra-arterial therapies, and mechanical clot retrieval or aspiration. There are still several challenges in the near future of reperfusion therapy for acute ischemic stroke, such as improving the ultra-early access to treatment within the "golden hour," extending the therapeutic window beyond the current 4.5-hour time window, and developing novel thrombolitics or combined approaches to improve treatment efficacy.
Background: In the European Cooperative Acute Stroke Study III (ECASS III), alteplase administered 3.0-4.5 h after the onset of stroke symptoms resulted in a significant benefit in the primary endpoint (modified Rankin scale [mRS] score 0-1) versus placebo, with no difference in mortality between the treatment groups. Compared with the 0-3 h window, there was no excess risk of symptomatic intracranial haemorrhage. We assessed the usefulness of additional endpoints and did subgroup and sensitivity analyses to further investigate the benefit of alteplase. Methods: In a double-blind, multicentre study in Europe, patients with acute ischaemic stroke were randomly assigned to intravenous alteplase (0.9 mg/kg bodyweight) or placebo. Additional outcome analyses included functional endpoints at day 90 or day 30 (mRS 0-1 [day 30], mRS 0-2, Barthel index > or =85, and global outcome statistic [day 30]) and treatment response (8-point improvement from baseline or 0-1 score on the National Institutes of Health stroke scale [NIHSS], and a stratified responder analysis by baseline NIHSS score). The subgroup analyses were based on the mRS 0-1 at day 90, symptomatic intracranial haemorrhage, and death. Analyses were by intention to treat and per protocol. This study is registered with, number NCT00153036. Findings: 418 patients were assigned to alteplase and 403 to placebo. Although not significant in every case, all additional endpoints showed at least a clear trend in favour of alteplase. Alteplase was effective in various subgroups, including older patients (<65 years: odds ratio 1.61, 95% CI 1.05-2.48; > or =65 years: 1.15, 0.80-1.64; p=0.230), and the effectiveness was independent of the severity of stroke at baseline (NIHSS 0-9: 1.28, 0.84-1.96; NIHSS 10-19: 1.16, 0.73-1.84; NIHSS > or =20: 2.32, 0.61-8.90; p=0.631). The incidence of symptomatic intracranial haemorrhage seemed to be independent of previous antiplatelet drug use (no: 2.41, 1.09-5.33; yes: 2.33, 0.79-6.90; p=0.962) and time from onset of symptoms to treatment (181-210 min: 1.62, 0.26-10.25; 211-240 min: 1.97, 0.82-4.76; 241-270 min: 3.15, 1.01-9.79; p=0.761), but not of age dichotomised at 65 years (<65 years: 0.74, 0.28-1.96; > or =65 years: 5.79, 2.18-15.39; p=0.004). Interpretation: Our results support the use of alteplase up to 4.5 h after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0-3 h. Funding: Boehringer Ingelheim.
Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase. We conducted a prospective, nonrandomized, pilot study of 0.1 mg/kg IV tenecteplase given 3 to 6 hours after ischemic stroke onset. For a control group, we used patients contemporaneously treated with sub-3-hour 0.9 mg/kg IV alteplase following standard selection criteria. All patients underwent pretreatment and 24-hour perfusion/angiographic imaging with CT or MRI. Eligibility criteria for tenecteplase (but not alteplase) treatment included a perfusion lesion at least 20% greater than the infarct core, with an associated vessel occlusion. Primary outcomes, assessed blind to treatment group, were reperfusion (reduction in baseline-24-hour mean transit time lesion) and major vessel recanalization. Fifteen patients received tenecteplase, and 35 patients received alteplase. The tenecteplase group had greater reperfusion (mean 74% vs 44% in the alteplase group, p = 0.01) and major vessel recanalization (10/15 tenecteplase vs 7/29 alteplase, p = 0.01). Despite later time to treatment, more tenecteplase patients (10/15 vs 7/35 alteplase, p = 0.001) had major neurologic improvement at 24 hours (NIH Stroke Scale reduction > or = 8). Four of the alteplase patients and none of the tenecteplase patients had parenchymal hematoma at 24 hours. Tenecteplase 0.1 mg/kg, using advanced imaging guidance in an extended time window, may have significant biologic efficacy in acute ischemic stroke. The imaging selection differences between the tenecteplase and alteplase groups prevent a conclusive efficacy comparison. Nonetheless, these results lend support for randomized trials comparing tenecteplase with alteplase, preferably incorporating penumbral/angiographic imaging selection.
Rapid restoration of patency of the infarct-related artery is the key to preserving myocardium and improving survival. This understanding has led to the application of genetic engineering to develop new plasminogen activators with specific clinical features. These novel activators may provide faster and more complete reperfusion in a greater number of patients, and do so with less risk of bleeding and intracranial hemorrhage. This article reviews the pharmacologic profiles and clinical performance of several novel plasminogen activators engineered from the human tissue plasminogen activator molecule or developed from animal and bacterial proteins.