Monday, April 1, 2019

Thrombolysis, Thrombectomy and Acute Stroke Therapy. Series. Part 4

In this current iteration of our series on Thrombolysis, Thrombectomy and Acute Stroke Therapy, taken from the report from the The 14thInternational Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy (TTST); we are exploring the future of thrombolysis. Global experts, including South Korea’s Professor Jong S Kim address the combining of thrombolysis with other approaches including magnetic enhanced lytics, perfluorcarbon, otaplimastat and glyburide; 

A summary of this meeting, and an extended report are available in the International Journal of Stroke, the flagship publication of the World Stroke Organization.  

Future of thrombolysis

Combining with anticoagulation

Andrew Barreto, Gary Ford, Opeolu Adeoye 

Current reperfusion therapy with intravenous alteplase alone in acute ischemic stroke is only able to recanalize approximately 50% of occluded arteries and 15 to 35% of patients who received thrombolysis experience early reocclussion within the first 2 hours. Although thrombectomy achieves higher recanalization rates, it is not available in  many regions and patients may not be eligible when they arrive at thrombectomy center. Augmentation of intravenous alteplase through the use of anticoagulants may have a potential significant public health impact if early administered, removing the need for transfer to a specialized center. Argatroban and eptifibatide have each demonstrated efficacy in 6 phase II clinical trials in combination with alteplase, with higher recanalization rates, no increased risk for symptomatic intracerebral hemorrhage, and an increase in excellent functional outcome at 3 months. The pivotal three-armed MOST clinical trial, to start in 2019, will determine the efficacy of this approach to combination therapy.

Combining thrombolysis with other approaches including magnetic enhanced lytics, perfluorcarbon, otaplimastat and glyburide

Keith Muir, Jong S Kim, Taylor Kimberly

Stagnant flow in the arterial segment proximal to the occlusion alters delivery of the thrombolytic agent to the blood clot surface, as alteplase can only diffuse passively. In vitro studies of Magnetically Enhanced Diffusion through iron nanoparticles with an externally applied magnetic field accelerates clot lysis and is now being pursued as an adjunct to intravenous alteplase and endovascular treatment in the setting of LVO. It is being evaluated in phase II clinical trials. 

Perfluorocarbon nanoparticles have been studied in both transient and permanent middle cerebral artery occlusion (MCAO) models offering the potential to halt the evolution of ischemic damage by delivering oxygen to brain parenchyma beyond the site of occlusion and help to reduce infarct volumes. A phase II safety trial is evaluating the ability of this modality to provide imaging of the penumbra in combination with oxygen challenge (BOLD MRI). 

Otaplimast is a new antioxidant agent that decreases free radicals by inhibiting inducible nitric oxide synthetase (iNOS) expression, possesses an anti-inflammatory action by inhibiting inflammatory cell migration, and has also exhibited blood-brain barrier stabilization by metalloproteinase deactivation. It has been studied in phase I and phase II clinical trials showing smaller growth of infarct size, improved outcome and no significant increase in hemorrhagic transformation. A phase II study had a small sample size, so further studies are needed to confirm efficacy. 

An intravenous form of glyburide is under clinical development for the treatment and prevention of cerebral edema after a large hemispheric infarction. In an animal transient MCAO model of severe cerebral ischemia, glyburide reduces edema and hemorrhagic transformation, with similar findings observed when high-dose intravenous alteplase was co-administered at the time of reperfusion, with a more pronounced effect of intravenous glyburide on plasma matrix metallopeptidase 9 (MMP-9) and water uptake in the subgroup treated with intravenous alteplase. These data highlight a potential effect of intravenous glyburide in combination with intravenous alteplase and/or with EVT in the setting of severe ischemia.

Discussion Panel

Sean Savitz, Bruce Campbell, Alastair Buchan, Mitchell S. V. Elkind 

In light of the recent successes with thrombolysis and thrombectomy, there is interest in reconsidering the role of neuroprotection and other strategies designed to limit reperfusion injury after stroke. It is unlikely, however, that the magnitude of benefit from these adjunctive therapies will be as large as those from thrombolysis or thrombectomy itself. Trials of such adjunctive therapies may therefore need to use trial approaches distinct from those of the thrombolytic trials. Neuroprotection trials are likely to require much larger sample sizes than thrombectomy trials. Alternatively, additional biomarker strategies could be used to identify patients most likely to benefit, and thereby improve trial efficiency. Imaging neuroinflammation or identifying serum-based biomarkers, such as complement levels, are newer strategies to develop target-based immunotherapies for acute stroke. 

In addition, a reassessment of trial outcomes of interest, and the timing of assessment, may also be of value. Recent epidemiological evidence has shown that after a period of initial recovery, stroke patients experience decline in function  (1) and cognition.(2) Animal models of stroke similarly show delayed cognitive decline after stroke. (3) Neuroimmune mechanisms, including the effect of infection occurring at the time of stroke, may contribute to this late decline.(4) Thus, we may also want to consider assessing outcome measures distinct from crude handicap scores, such as the modified Rankin Scale, for some therapeutic effects. It is possible that some therapies, when given early, will have more of an effect on preventing later problems with cognition, depression, or fatigue, and scales focused on these outcomes may be increasingly relevant in trials that enrol patients undergoing thrombolysis. Most acute stroke trials collect outcomes out to 90 days. However, some of these effects may not be seen for many months or even years after treatment; thus, longer follow-up assessments may be increasingly relevant.
The NINDS plans to initiate the SPAN program to accelerate high quality preclinical stroke research using the principles of multi-laboratory reproducibility recommended in the STAIR consensus. Six laboratories with candidate molecules for stroke neuroprotection will be selected and each will test all 6 compounds in different stroke models with the most successful candidate taken forward into human clinical trials.

Key Points:
  1. Thrombolysis has experienced a number of recent successes, with preserved safety and efficacy in additional patient cohorts. 
  2. Novel therapies that increase the efficacy of thrombolytics as well as freeze the penumbra and minimize the injury associated with reperfusion may continue this trend.

New lytics in the pipeline including tenecteplase, plasmin, and thrombin activated fibrinolysis inhibitor

Carlos Garcia Esperon, Jeff Saver, Michel Piotin 

Tenecteplase (TNK) is a genetically engineered recombinant tissue plasminogen activator that is currently the first line treatment for thrombolysis in myocardial infarction. In acute ischemic stroke TNK shows a pharmacokinetic advantage over alteplase, as it is given in a single dose as bolus instead of a continuous infusion with alteplase, and it may have less risk of hemorrhagic transformation. Current clinical trials are being conducted to determine if a high-dose tenecteplase is superior to a low-dose tenecteplase, with the EXTEND-IA TNK II study exploring whether 0.4mg/kg dose is superior to 0.25mg/kg in producing early reperfusion. There is also limited information on the use of TNK in the late window after 4.5 hours of stroke onset. Parsons et al (5,6) showed in a small sample that both 0.1 and 0.25mg/kg dose of tenecteplase achieved greater reperfusion than alteplase up to 6 hours since onset (79% vs 55%, p=0.004) with similar sICH rate.  The TWIST trial will aim to test 0.25 mg/kg TNK in a wake-up stroke population, using only with non-contrast CT selection. The TEMPO-2 trial is testing tenecteplase against best medical care alone in minor stroke patients with a proven intracranial occlusion. Future trials (under design) will aim to define the role of tenecteplase in the extended time window with multimodal imaging selection.

Future thrombolytic therapies in acute ischemic stroke
Recommended doses of alteplase used in AIS lead to an increase of nearly 1000 times the physiological blood concentration. Alteplase is the major intravascular plasminogen activator. It converts plasminogen to plasmin, which is able to cleave fibrin strands contained in a thrombus in small fibrin degradation products leading to thrombolysis. However, these treatments have important limitations. Because of numerous contraindications, very few patients are eligible to receive alteplase-mediated thrombolysis (~5 % of AIS patients). Moreover, intravenous alteplase is associated with an increased risk of hemorrhagic transformation and often fails to achieve successful recanalization, especially in the case of large vessel occlusions. In this context, different research ways to improve AIS thrombolysis have been recently developed. 
A first strategy could be to target circulating fibrinolysis inhibitors to increase the thrombolytic efficacy of intravenous alteplase. 

Thrombin Activated Fibrinolysis Inhibitor 
Thrombin activated fibrinolysis inhibitor (TAFI) is the main circulating fibrinolysis inhibitor. After activation by thrombin, thrombomodulin or plasmin, activated TAFI (TAFIa) is able to cleave C-terminal Lysine residues from fibrin networks, which prevents the formation of the ternary complex including plasminogen, alteplase, and fibrin resulting in the inhibition of new plasmin generation. In blood samples during EVT using a microcatheter placed in contact to the thrombus, there is a local increase of activated TAFIa in patients previously treated with intravenous alteplase. This could contribute to alteplase-induced thrombolysis resistance. In an experimental thromboembolic model of stroke, it was suggested that TAFIa inhibitor in association with a suboptimal dose of alteplase was associated with a reduced ischemic lesion growth compared to full alteplase dose. TAFIa alone in this study had no impact. (7) Regarding clinical studies, there are two ongoing phases 1-2 clinical trials assessing the safety of administering of a TAFIa inhibitor developed (NCT02586233 and NCT03198715). The first one is recruiting non-selected AIS with a primary endpoint of safety while the second is focused on AIS treated by EVT with also a primary endpoint of safety.

Von Willebrand Factor
The second strategy to enhance thrombolysis in AIS is to target non-fibrin AIS thrombus components. These thrombi contain platelet aggregates. Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (vWF) multimers.(8) Therefore, proteolysis of VWF multimers appears promising to disaggregate platelet-rich thrombi and restore vessel patency in AIS. A first study from Denorme et al found that AIS thrombi contained about 20% of vWF. The authors suggested that targeting vWF with the specific vWF-cleaving protease (ADAMTS13) could exert a thrombolytic effect in an experimental thrombo-embolic model of stroke associated with a reduced infarct volume.(9) 

A more recent publication assessed a potent thrombolytic effect of N-Acetylcysteine (NAC), an FDA-approved mucolytic drug. NAC has the ability to break-up vWF multimers by reducing intrachain disulfide bonds in large polymeric proteins. This publication found an increased recanalization rate with NAC infusion compared to saline especially with concomitant treatment with anti-GPIIb/IIIa therapy, suggesting a synergistic action of these two treatments.(10)

Neutrophil extracellular traps 
Neutrophil Extracellular Traps (NETs) are extracellular networks of chromatin with double-stranded DNA from neutrophils. They exert a platform of coagulation activation and platelet aggregation.(11) NETs contribute to the composition of all AIS thrombi especially in their outer layers. The presence of neutrophils and NETs in AIS thrombi was investigated by immunofluorescence analysis. Immunofluorescence detection confirmed that areas containing extracellular DNA colocalized with citrullinated histones and granular neutrophils proteins (such as myeloperoxidase), which correspond to NETs. NETs were constitutively present in all AIS thrombi.(12) Ex vivo, recombinant DNAse 1 accelerated alteplase-induced thrombolysis, whereas DNAse 1 alone was ineffective. Our results indicate that coadministration of DNAse 1 with alteplase could be of interest in the setting of AIS with LVO. 
Future thrombolytic therapies will involve an optimization of fibrinolysis therapy with TAFIa inhibitor infusion but the most promising way may consist of targeting non-fibrin contents of thrombi, especially, platelets, vWF and NETs. This reasoning supports a pharmacological “cocktail” for the future of AIS treatment including therapies targeting different contents of thrombi. The development of such add-on therapies may represent a unique opportunity not only to improve recanalization therapy, but also to reduce alteplase doses and the associated risk of intracranial bleeding, which is responsible for an increased mortality rate in alteplase-treated AIS patients. 

Do we need more exploration of alteplase dose?

Craig Anderson, Phil Gorelick, Kazunori Toyoda  
Seminal dose-escalation studies of the US National Institute of Neurological Disorders and Stroke (NINDS) alteplase study in the early 1990s determined a dose of 0.9mg/kg (10% bolus) of intravenous alteplase, on the basis of both major neurological improvement and concomitant paucity of brain hemorrhage, (13,14) for administration in the subsequent positive phase III clinical trials in acute ischemic stroke.(15) The 0.9 mg/kg dose has become the standard alteplase treatment regimen for AIS in North America and much of the rest of the world, except in Asia, where lower doses of alteplase are popular due to the: 

(i) perception of reduced major sICH, where the risks are considered higher in Asians; and flexibility of rounding to use of a single vial for reducing the cost of treatment in low resource settings.  

Japan was one of the last countries to approve the commercial use of alteplase in AIS in 2005 but at a dose of 0.6 mg/kg, based on data from a dose-comparison study of duteplase (16 )and the multicenter single-dose Japan Alteplase Clinical Trial.(17) Post-marketing studies, including the nationwide Japan post-Marketing Alteplase Registration Study (J-MARS)(18)and the multicenter Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) alteplase registry,(19) have shown similar efficacy and safety of alteplase at 0.6 mg/kg as compared the standard-dose of alteplase among AIS patients registered with the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) in Europe.(20)
The only randomized evaluation of low-dose versus standard-dose alteplase has been in the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). This large trial failed to clearly show non-inferiority in the primary outcome of death or disability, defined by conventional poor outcome scores 2 to 6 on the modified Rankin Scale.(21) The results were likely due to insufficient power for the stringent non-inferiority margin imposed, as the ordinal shift analysis of the full range of mRS scores was significant for non-inferiority.  Just as important, though, were the findings that sICH was halved, which translated into significant lower mortality at 7 days, in the low-dose group.

Overall, the evidence from observational studies, systematic reviews and meta-analyses, (22,23) is consistent in concluding, either of no clear difference or in favor of improved outcomes and reduced sICH with low-dose alteplase. The findings are consistent in sensitivity analyses by fixed dose comparisons and in studies confined to Asian populations.    

Our conclusions are that low-dose alteplase offers lower cost, reduced bleeding risk particularly of sICH, and near non-inferiority in relation to efficacy compared to standard-dose alteplase. Because use of low-dose alteplase has been the subject of considerable evaluation in many Asian countries, clinicians there are likely to be more amendable to the utilization of this treatment. However, given the considerable challenges to accepting standard-dose alteplase that have existed in many sectors of North America, and based on the interpretation of current evidence in the context of the FDA-approved dose, it may be difficult in successfully arguing in favor of using low-dose alteplase outside of Asia.  

Discussion Panel

Gregory J. del Zoppo, Steve Davis, Ritvij Bowry, Ken Uchino  

The potential of bolus-injection tenecteplase replacing alteplase is based on the NORTEST trial (24)(0.4 mg/kg TNK), which showed similar benefits in a mild stroke population.  The EXTEND-IA TNK trial showed that tenecteplase (0.25 mg/kg) compared with alteplase doubled reperfusion rates when administered before thrombectomy and was associated with improved clinical outcomes. An ongoing Phase III trial, TASTE, involves a head-to-head comparison of these thrombolytic agents.  Regarding practical matters, the panel commented on the pricing of these agents which needs to be considered in the context of delivering these drugs across the world in specific markets such as the US, Europe, Asia and Australia. The major barrier to worldwide tenecteplase or alteplase use includes its current lack of approval by influential regulatory bodies, such as the FDA, in many countries. It is hoped that ongoing clinical trials of tenecteplase will provide strong scientific evidence of its efficacy that will facilitate overcoming this barrier.  Others raised concerns regarding the manner in which new thrombolytic agents might fit into clinical practice, and the contributions of clinical research protocols to these efforts. If the role is to dissolve thrombi before endovascular procedures, the time from infusion to puncture at comprehensive stroke centers is short and the capacity of drip-and-ship facilities to conduct research is limited. Performing this research in the current infrastructure will be challenging, and would require novel approaches including remote electronic consent, or waiver or deferral of informed consent, telemedicine evaluation, and pre-hospital delivery of agents in a research setting.

In this context, the development of a new approach to intravenous thrombolysis will come under test soon. Recent work has demonstrated that alteplase exposes cleavage sites on fibrin so that pro-urokinase can bind and effect local plasminogen activation, and thrombus lysis. This approach will be tested prospectively for safety in patients presenting within 4.5 hours from symptom onset whereby alteplase (0.9 mg/kg) will be directly compared with low dose alteplase (5 mg) followed by the mutant His-Pro-urokinase over 60 minutes in a phase II trial. Mutant His-Pro-urokinase resists inhibition. It is expected that a lower incidence of intracerebral hemorrhage will be demonstrated, given the lower dose of alteplase. A published trial in acute myocardial infarction has demonstrated safety of the combination with comparable efficacy to alteplase.(25)

Key Points:

  1. Newer thrombolytic agents including TNK as well as future targets that enhance thrombolytic treatments may improve recanalization rates, and reduce hemorrhage.
  2. Low-dose alteplase offers lower cost, reduced bleeding risk and near non-inferiority in relation to efficacy compared to standard-dose alteplase.  On the other hand, given the considerable challenges to accepting standard-dose alteplase, it may be difficult in successfully arguing in favor of using low-dose alteplase outside of Asia.  


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2. Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B, Wadley VG. Trajectory of Cognitive Decline After Incident Stroke. JAMA. 2015;314:41–51. 
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10. Martinez de Lizarrondo S, Gakuba C, Herbig BA, Repessé Y, Ali C, Denis CV, Lenting PJ, Touzé E, Diamond SL, Vivien D, Gauberti M. Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi. Circulation. 2017;136:646–660. 
11. Ducroux C, Di Meglio L, Loyau S, Delbosc S, Boisseau W, Deschildre C, Ben Maacha M, Blanc R, Redjem H, Ciccio G, Smajda S, Fahed R, Michel J-B, Piotin M, Salomon L, Mazighi M, Ho-Tin-Noe B, Desilles J-P. Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke. Stroke. 2018;49:754–757. 
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About: International symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy 
The 14thInternational Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy (TTST) took place in Houston, Texas on October 21stand 22nd, 2018. TTST meetings began in 1990 during the initial simultaneous clinical investigations into thrombolysis taking place in the United States, Europe, and Japan. Since then, TTST has brought together invited experts on reperfusion therapy for acute stroke every two years, and rotates among venues in Europe, North America, and Asia. TTST has provided opportunities for stimulating controversial discussions on data from recent clinical trials, the status of major ongoing studies, and priorities for future research. Initially focused on thrombolytic therapy, recent TTST conferences have helped lay the groundwork for the success of thrombectomy clinical research.  

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