Series 6
Thrombolysis, Thrombectomy and Acute Stroke Therapy. Series. Part 6
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.
Speeding thrombolysis and thrombectomy
How can we expand telestroke and other innovations?
Teddy Wu, Lee Schwamm, Larry Wechsler
Stroke is a rare event, accounting for less than 5% of emergency medical dispatches, emergency department visits and hospital admissions. Telestroke extends the reach of acute stroke expertise to rural and community hospitals increasing appropriate delivery of thrombolytic therapy and identifying patients eligible for mechanical thrombectomy. Most telestroke networks limit evaluations to the acute stroke setting either in the emergency department or in-house stroke alerts. When patients remain at originating hospitals after acute evaluation subsequent hospital care may not be the same as care delivered by vascular neurologists at a stroke center. Providing telestroke follow-up throughout the episode of care for stroke patients promotes efficient and cost-effective testing and selection of optimal treatment, reducing length of stay and improving outcomes.
Advancement of stroke care is dependent on completion of clinical trials. Traditional ways of patient recruitment into acute ischemic stroke trials at tertiary care centers can be inefficient and often patients at remote hospitals lack access to such trials. Transfer delays from remote hospitals to larger tertiary centers may preclude enrollment of these patients into time-sensitive acute stroke clinical trials. Telemedicine has the potential to enable stroke specialist to conduct acute stroke trials at remote hospitals to potentially enhance enrollment while also increasing access and opportunities for stroke patients at rural and community hospitals to receive promising new therapies.
Mobile Stroke Units—status and future perspective
Klaus Fassbender, Steve Davis, Anne W. Alexandrov
Many advantages of Mobile Stroke Units (MSUs) have already been noted in previous sections on systems of care. In addition to speeding tPA treatment into the first “golden hour”, MSUs should improve both the speed and accuracy of pre-hospital patient triage for thrombectomy. While MSUs are proliferating, cost-effectiveness remains to be established, and is being tested in the ongoing BEST-MSU study in the US.
An important component of cost is staffing. Staffing on MSUs varies among existing programs, and is dependent on manpower availability, technology requirements, and regulatory and credentialing mandates. Programs should consider models that are sustainable based on personnel expense and the local availability of expertise. Most countries and local governing authorities will require at least the presence of a licensed prehospital provider, such as a paramedic and/or emergency medical technician on board any vehicle that is licensed as an ambulance. CT technologists are required to perform all CT imaging acquisition functions. The main difference between MSU program staffing lies in the area of stroke expertise, with use of vascular neurologists, nurse practitioners, or telemedicine operations. Regardless of the staffing model utilized, MSU teams must collaborate closely to support optimal stroke diagnostic and treatment outcomes.
Discussion Panel
Martin Ebinger, Sandy Middleton, Silke Walter
The discussion evolved around the role of nurses in future stroke care. Patients cared for in stroke units who received facilitated implementation to manage fever, hyperglycemia and swallowing using the FeSS Protocols (fever, sugar, swallow) had 16% reduced death and disability107, with a sustained effect in terms of 20% increased likelihood of being alive out to a median of four years.108 It also has been shown to result in a $AUD 281M saving if only 60% of all eligible patients received this care over 12 months.109 This is as a result of evidence-based nursing care. Further, stroke unit coordinators, most usually nurses, have been shown to improve uptake of evidence-based stroke care and improve patient outcomes.110 However, the QASC Europe study is demonstrating the variable level of autonomy of stroke nurses across the world. Advancing stroke nursing care requires active support by neurologists. How can neurologists advance the role of the stroke nurse within their services? Can they identify nurses with potential who could lead FeSS protocol implementation and support introduction of other evidence-based stroke care processes to improve patient outcomes?
Involving stroke nurses in MSUs would support autonomy of nurses and strengthen their role in the service.22,111 In addition, a recent good example of the multifaceted uses of MSUs took place in Houston in 2017, when Hurricane Harvey caused power breakdown of a hospital. The Mobile Stroke Unit partly replaced the emergency department in this exceptional situation providing head CT imaging. This report sparked a discussion about Mobile Stroke Units replacing Stroke Units in underserved areas, though the panelists also reminded the audience that a Stroke Unit is more than the CT-scanner and a laboratory. Apart from nurses and doctors, Stroke Units consist of a dedicated team that also includes physiotherapists, occupational therapists, speech therapists, and social workers.
Key Points:
Implementation of evidence-based nursing care can improve patient outcomes but requires multi-disciplinary support.
Telemedicine and MSUs shrink the gap between patient, provider, and treatment.
The cost effectiveness of MSU implementation needs evaluation.
Nurses and advanced practice providers are well suited for deployment in these roles.
Other approaches to increasing perfusion
Andrei Alexandrov, Italo Linfante, Rolf Blauenfeldt
Placing the head of the bed at zero degrees may be the most important step in managing an LVO, since this significantly increases blood flow to ischemic regions. Use of this rescue maneuver has yet to be tested in LVO patients presenting in the hyperacute phase. The ZODIAC trial (NCT03728738) will examine the efficacy and safety of zero degree head positioning in hyperacute LVOs while being transferred for thrombectomy procedures.
The principle behind remote ischemic conditioning (RIC) is based in applying short-lasting, non-lethal ischemia in a distant tissue to protect against long-lasting ischemic injury in the brain. In practice, it is applied by inflating a cuff to a supra-systolic pressure on a extremity and holding that pressure for 5 minutes. This is followed by a reperfusion phase of 5 minutes. These 2 stages are one cycle, and it is then repeated for a total of 4 to 5 cycles. RIC seems to target multiple neuroprotectant mechanisms and cause an anti-inflammatory shift, as showed in many preclinical studies.112
Major ongoing RIC Trials
RICA– This clinical trial is being conducted in China. It is the largest trial looking at a population with either AIS or TIA with symptomatic intracranial atherosclerotic disease. Patients are treated with RIC once daily for one year and were then followed up to assess for stroke recurrence. Sample size is 2600 with its enrollment almost completed. Results are expected to be published in 2020.
RESCUE BRAIN – Clinical trial in France, with 10 participating centers where RIC is given within 6 hours from symptom onset in the in-hospital setting for AIS patients treated with either alteplase or intra-arterial treatment. Primary endpoint is infarct growth rate and enrollment has been completed. Results are expected early in 2019.
REMOTE-CAT – Pre-hospital trial (Catalonia, Spain) in which RIC is started within 8 hours from symptom onset in the ambulance. Target population is AIS patients who do or don’t receive reperfusion therapy. Primary endpoint is dichotomized modified Rankin Scale.
ReCAST-2 – Dose escalation study in the United Kingdom looking at the application of RIC in the in-hospital setting for AIS patients. Enrollment has been completed and results will be analyzed and depending on these planning of a large efficacy trial (ReCAST-3).
RESIST – Danish trial for pre-hospital RIC given within 4 hours from symptom onset in patients presenting with stroke symptoms. If patients are confirmed of having an AIS or ICH, patients are treated once again in-hospital after 6 hours. Current enrollment is 170 patients out of 1500 patients. Primary endpoint is modified Rankin Scale (shift analysis).
The effect of improved functional outcome is likely to be small, but RIC treatment is a cheap and feasible therapy without serious adverse events risk. Questions regarding which subset of patients will benefit from this intervention, standardized timing and dosing of cycles, and other applications beyond ischemic stroke are yet to be answered.
Recent data showing increasing blood flow in the leptomeningeal anastomosis by administering Hemoglobin Oxygen Carriers and Carboxyhemoglobin Transporters in MCAO may represent a way to slow down core progression by increasing collateral circulation and transporting oxygen in acute ischemic brain tissue.
Another proposed pathway to enhance collateral circulation is through sphenopalatine ganglion (SPG) stimulation. SPG stimulation, when started within 24 hours of symptom onset enhances the ipsilateral collateral flow of the anterior circulation and may reduce disability and increase the proportion of patients with good functional outcome.113,114 The Implant for Augmentation of Cerebral Blood Flow Trial, Effectiveness and Safety in a 24 Hour Window Study (ImpACT-24B - NCT00826059) involved 1000 patients at 73 centers in 18 countries, with a primary endpoint of improvement beyond expectations on the modified Rankin Scale at 3 months. A statistically significant relative improvement in outcome in the treatment was observed with similar results to previous trials.
Sonothrombolysis is another approach for improved thrombolytic efficacy. CLOTBUSTER (NCT01098981) had a signal of efficacy for in subgroup analysis (publication pending). A new phase III international trial called TRUST (NCT03519737) will assess the efficacy and safety of transcranial ultrasound using the Sonolysis Headframe as an adjunctive therapy to intravenous alteplase treatment in patients that arrive within conventional time window at spoke hospitals and are transferred for mechanical thrombectomy. The primary end-point is recanalization on diagnostic catheter angiography assessment prior to mechanical thrombectomy. The lead-in phase testing a novel therapeutic ultrasound device is being launched now at 4 US hub-and-spokes systems.
Other new and exciting updates
Pat Lyden, Dileep Yavagal, Simon de Meyer
Reperfusion of the ischemic territory that occurs too late can also exacerbate tissue damage by reperfusion injury. This problem does not only occur after successful thrombolysis but also often complicates stroke outcome after successful mechanical thrombectomy. Hence, there continues to be a critical need for novel therapies for AIS, including better ways for thrombolysis and better ways to guarantee neuroprotection upon recanalization.
Many previous neuroprotectant failures (promising drugs emerge from pre-clinical development only to fail in large stroke patient trials) might be traced to a fundamental dogmatic misconception of the mammalian brain. New understanding of the neurovascular unit indicates the brain uses at least 7 main categories of cell types: neurons, astrocytes, endothelial cells, oligodendroglia, pericytes, ependymal cells and microglia. Recently, emerging data suggests the elements of the neurovascular unit respond to injury (ischemia, trauma) and to treatment differently. Understanding this differential susceptibility to injury—and subsequent differential response to therapy—has led to a novel, striking re-interpretation of prior clinical therapeutic trial failures.
In some patients however, alteplase can cause internal bleeding and other complications. 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis associated hemorrhage. 3K3A-APC’s cytoprotective properties may be useful in protecting ischemic brain tissue from further damage, while reducing the risk of treatment-related bleeding. The NeuroNEXT trial NN104 (RHAPSODY) trial established the safety, tolerability and activity of 3K3A-APC, following the use of alteplase in subjects who have experienced moderately severe acute hemispheric ischemic stroke. Results were presented at the International Stroke Conference in January 2018 and confirmed that 3K3A-APC appears safe and tolerable, and that a suggestion of vascular protection (reduced hemorrhage) requires confirmation in a larger trial. The next phase of development includes further pre-clinical development, hopefully via the new Stroke Pre-clinical Assessment Network (SPAN) and further dose finding studies in patients via StrokeNET. Together, these development efforts will not only advance one drug to Phase 3 trial, these joint efforts among SPAN and StrokeNET will establish the validity of rigorous pre-clinical development in parallel and in concert with early proof of efficacy in stroke patients. The paradigm challenges the dogma “bench-to-bedside-to-bench” in favor of a more realistic, collaborative joint development effort in which basic and translational scientists work together in real-time.
The natural history of stroke recovery depends on endogenous stems cells in the adult and pediatric brain. This recovery is incomplete in most patients and exogenous cell-based therapy shows great promise to significantly enhance this stroke recovery. Among different cell types, mesenchymal stem cells (MSCs) are most attractive for clinical translation. MSCs are adult stem cells that are multipotent, non-hematopoietic stem cells found in the stromal fraction of the bone marrow, along with the connective tissue of most organs. They are an appealing cell source due to the relative ease in which they can be retrieved, developed, and expanded for therapeutic application. Among various routes of cell delivery for ischemic stroke, the intra-arterial route of stem cell transport is most attractive as it targets delivery of cells to the ischemic brain bypassing systemic trapping of cells seen with intravenous delivery and much less invasive than direct stereotactic or intraventricular delivery. Furthermore, intra-arterial delivery of cells leads to a wide distribution of cells in the ischemic brain as MSCs home in to ischemic tissue via the vasculature using the CXCR4-SDF-1 signaling pathway. Thus, intra-arterial cell delivery leads to a substantial number of MSCs in the core and penumbra of the infarct optimizing the trophic mechanism of benefit for stroke recovery: anti-inflammation, neuroprotection and stimulation of endogenous stem cells. This suggests great potential for clinical translation of intra-arterial delivered MSCs for ischemic stroke, especially considering the growing clinical application of endovascular treatment for AIS.
A major concern for intra-arterial delivery of cells is the potential for brain ischemia that could result from administered cells compromising blood flow in the microcirculation. Pre-clinical work addressing this issue shows that such ischemia depends on the dose of intra-arterial delivery and can be fully mitigated by lowering cell doses in small and larger animal models. Furthermore, the lower (MTD) dose of cells, when given at 24-48 hours after stroke onset is efficacious for functional recovery and reduction of infarct volume in rodent stroke models. The first randomized trial (Phase 2a) of intra-arterial cell therapy in 48 patients, RECOVER-Stroke was presented at the European Stroke Conference in 2015 and recently accepted for publication. The study showed safety of autologous intra-arterial cell delivery in anterior circulation ischemic stroke at a median of 18 days from stroke onset with no difference in efficacy. A larger phase 2b clinical trial with allogenic MSCs given between 24-36 hours is planned to move towards clinical translation of this this promising approach.
Limited data exist on clot composition and detailed characteristics of arterial thrombi associated with large vessel occlusion in acute ischemic stroke. Advances in endovascular thrombectomy and related imaging modalities have created a unique opportunity to analyze thrombi removed from cerebral arteries. Insights into thrombus composition may lead to future advancements in acute ischemic stroke treatment and improved clinical outcomes. Such detailed information can reveal novel insights and open improved recanalization. Some thrombi are particularly rich in von Willebrand factor, leading to the concept of developing a novel thrombolytic strategy using the von Willebrand factor-cleaving enzyme ADAMTS13. Similarly, the remarkable amount of extracellular DNA (derived from neutrophil extracellular traps) had led to using DNase1 as a prothrombolytic drug in experimental studies. The testing hypothesis that will be presented is one of using a thrombolytic cocktail (alteplase + ADAMT13 + DNAse) instead of alteplase alone.
Discussion Panel
E. Clarke Haley, Antoni Davalos, Markku Kaste, Chris Levi
Key Points:
Existing treatment with thrombolysis and thrombectomy still leaves half of patients with disability and substantial room for new experimental approaches. Initial optimal head positioning in LVO patients is being determined in an ongoing trials.
Ongoing approaches along this line include remote ischemic preconditioning, enhancing collaterals through oxygen carriers or sonothrombolysis, targeting the multiplicity of vulnerable cell populations in the neurovascular unit, stem cells, and a better understanding of clot composition.
These new approaches in acute stroke care and their potential applications are of importance in regions with no access to either thrombolysis or mechanical thrombectomy.
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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.
