Last week we published the first in a series of excerpts from experts on Thrombolysis, Thrombectomy and Acute Stroke Therapy, expert commentary which came out of the 14th International Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy.
In last weeks blog session some of the most dynamic researchers in stroke explored strokes changing demographics, global rates of thrombectomy, and how current treatments have changed the stroke landscape in this area.
This week the question is pondered Thrombolysis and thrombectomy—where, when, and who? Jeyaraj Pandian and Pooja Khatri will highlight the existing and projected distribution of thrombolysis centers worldwide, while others will tackle where and for who thrombolysis should be done?
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.
Thrombolysis and thrombectomy—where, when, and who?
Existing and projected distribution of thrombolysis centers worldwide
Jeyaraj Pandian, Pooja Khatri
In the US, the most recent analysis of the geographic distribution of thrombolysis centers from administrative data described access of the US population to all facilities that provided at least one case of intravenous alteplase for acute ischemic stroke (AIS). (1) The 2011 US Medicare Provider and Analysis Review (MEDPAR) data set was used, although it was limited by excluding patients younger than 65 years of age, except transplant and permanently disabled patients. Based on this analysis, 81% of US population may have access to intravenous-capable hospitals within 60 minutes by ground and 97% by air. These projections may be an overestimate, since provision of one dose of alteplase may not guarantee an appropriate level of thrombolysis readiness. Similar good penetration of thrombolysis centers is likely in Canada, based on even older numbers from a 1998 publication using 1996 interim census numbers by Scott et al (2). They used Geographic Information System (GIS) just like the US study, but identified hospitals capable of delivering intravenous alteplase as those with a Computed Tomography (CT) scanner and a neurologist and EM specialist on staff, as opposed to the actual administration of at least one dose of intravenous alteplase. 67.3%, 78.2%, and 85.3% of the total Canadian population were within 32, 64, and 105 kilometers, respectively, of an identified hospital.
Among the South Asian countries, India and Thailand have organized stroke programs with thrombolysis and thrombectomy capable centers. The intravenous thrombolysis rates in India (1.25 to 4.58%) and Thailand (4.78%) are growing every year. There are 75 centers in India currently offering mechanical thrombectomy with an overall of 1,000 procedures a year, and the government has approved the use of tenecteplase, a generic biosimilar which is cheaper than alteplase for acute stroke treatment. Over 4,800 patients have received tenecteplase in the country. In Thailand, 25 hospitals offer endovascular treatment for stroke. In Pakistan and Srilanka, intravenous thrombolysis is being used but only a few centers may provide EVT. For South Korea, government nationwide initiated 11 Regional Comprehensive Stroke Centers (CSCs) since 2008. After the initiation, door-to-needle time for the intravenous thrombolysis was shortened to less than 30 minutes in the CSCs and the chance of intraarterial thrombectomy was increased from 30% to 47% in 2016 after the initiation of the CSCs. However, the quality of acute stroke management including thrombolytic therapy has not been clearly known in the provincial area of South Korea.(3)
Where and for whom should thrombolysis be done
Phil Scott, Henry Ma, Didier Leys
Use of thrombolytic therapy in patients with acute ischemic stroke requires an initial recognition of stroke symptoms, confirmation of diagnosis and eligibility for therapy, proper delivery of thrombolytic agent, and a follow-up period post treatment. A prompt recognition of signs or symptoms associated with stroke in the prehospital setting is crucial in reducing delays to stroke identification and time from onset to hospital arrival, thus increasing the number of patients that may be eligible for thrombolytic therapy. Utilization of a single emergency number may speed healthcare access, along targeted education programs for physicians, hospital, and Emergency Medical Services (EMS) personnel have demonstrated utility in increasing thrombolytic treatment rates.
Confirmation of diagnosis requires a focused history and a through neurological examination to rule out other causes of acute neurological deficits. Minimal neuroimaging requirements include a noncontrast head CT, with a CT angiogram (CTA) as a tool to identify patients with a large vessel occlusion who would benefit from mechanical thrombectomy. New emerging technologies such as machine learning and biomarkers may aid in the near future to accurately identify a positive stroke. As evidence from clinical trials becomes available and the experience in thrombolytic administration increases, some of the exclusion criteria are changing from absolute to relative, allowing more patients to benefit from medical management. Therefore, the physician should evaluate on an individual case basis the benefits and risks of thrombolysis.
Delivery of thrombolytic therapy may occur in the field through Mobile Stroke Units (MSUs) or in the emergency department/hospital. European systems of stroke care have demonstrated that the prehospital intravenous administration of alteplase can be accomplished effectively and increases the proportion of patients receiving thrombolysis within 60 minutes of onset. Prehospital administration of alteplase may translate into better outcomes in patients with pre-stroke dependency compared to in-hospital administration.(4) Generalization of pre-hospital delivery of thrombolytics faces challenges in non-densely populated regions and in non-resource rich communities.
Expanding Thrombolytic Use Safely
Minimal resources needed to confirm eligibility for thrombolytic treatment are currently based on either a checklist approach identifying evidence-based inclusion and exclusion criteria or utilizing physicians with stroke thrombolytic expertise, again, provided either at the bedside or remotely via telemedicine. Further minimal requirements include initial selection of a specific thrombolytic agent to be used which includes cost, actual drug availability, physical drug stability, and physical drug delivery (availability of intravenous infusion pumps, etc.) which are important considerations in limited resource environments globally. Finally, minimal resource requirements for the management of post thrombolytic treated patients require cardiac and blood pressure monitoring and management capability. This can be implemented using, again, either a checklist approach by local post-thrombolytic care providers or accessing physicians with thrombolytic expertise either at the bedside or remotely via telemedicine and includes management of treatment complications.
Numerous points in the stroke chain of survival exist in which to improve and expand thrombolytic use safely. Improved prehospital systems reduce delays to stroke identification and treatment. Data indicate that public education to identify stroke symptoms and recognition of stroke as an emergency and that is sustained over time reduces delays. Utilization of a single emergency number (911 in the United States and 112 in the European Union) also speeds healthcare access. Targeted education programs for physicians, hospital personnel and EMS personnel have demonstrated utility in increasing thrombolytic treatment rates. Finally, consistent utilization of prehospital notification by EMS personnel has been demonstrated to reduce in-hospital delays to stroke treatment.
In communities where thrombolytics are administered only within a stroke unit, opportunities to safely expand its use include starting treatment prior to stroke unit admission through remote neurologic expertise either in person or by telemedicine. Interactive and multifaceted training programs for emergency physicians have demonstrated increased access to thrombolytics in the community setting. These programs frequently include an organized protocol for emergency evaluation.
The existing paradigm of excluding patients from thrombolytic use on the basis of time has the potential to lead to a future paradigm where patients are excluded on the basis of perfusion imaging. This reflects prominent advances in the fields of neuroimaging to provide meaningful information on local tissue viability in stroke. If ultimately proven efficacious, such a shift will remove the single most common barrier to thrombolytic treatment–time from symptom onset.
As experience with thrombolytic delivery increases and further data on thrombolytic use becomes available, some prior exclusion criteria are migrating from absolute to relative. Note should be made by the practicing clinician that the level of evidence for this migration frequently comes from non-randomized trials.
Discussion Panel
Chris Lewandowski, Wade Smith, Nerses Sanossian, Martin Ebinger
The use of intravenous thrombolysis in the Emergency Department (ED) is hindered by the limited clinical experience and teachings of the average emergency department physician. Neurologic complaints represent 8 percent of the total consults for ED physicians, with acute stroke representing 1-2%.It is estimated the ED doctor treats 2 acute ischemic stroke patients per decade with thrombolysis. The lack of experience and the low availability of neurologists on site doesn’t allow for physicians in the front line to take a more active role in the care of stroke patients. It is thought that by simplifying the review of eligibility and providing support for the use of thrombolysis more physicians may feel comfortable delivering thrombolytics to patients. Telemedicine has proven to be an essential tool in this process along with the active role of nurses and advanced nurse practitioners in acute stroke care.
In addition, further development of pre-hospital triage is needed. Progress has been made in education of the lay public about the importance of activating EMS as soon as stroke is suspected, prehospital stroke identification, and routing of stroke patients to designated acute stroke center hospitals. Areas of active investigation in prehospital stroke include in-ambulance therapy (i.e. neuroprotective agents), mobile stroke unit ambulances with imaging capabilities, and multi-tiered routing protocols. The goal of any prehospital system of stroke care is to deliver patients quickly and safely to the most capable hospital.
Any prehospital LVO triage instrument is likely to have significant rates of over-triage/false positive and under-triage/false negative. Over-triage may delay intravenous thrombolysis in patients without LVO through longer transport times and bypass of closer hospitals, leading to later thrombolytic treatment, as well as over-crowding of specialized centers. (5)
On the other hand, an under-triage screen may route a patient to a hospital without endovascular capabilities (under-triage), leading to later thrombectomy.
The goal of EMS triage is to get to the right hospital in the right amount of time. When done correctly this improves outcomes.(6-9) Proper EMS triage is more cost-effective than creating additional specialty receiving facilities.(10) In the setting of stroke, almost all published experience with existing EMS triage tools focuses on identifying patients with LVO, which conflicts with the purpose of triage itself which is to get the right patient to the right place in the right amount of time, regardless of diagnosis. We need to refine prehospital assessment of stroke patients to focus not only on LVO but on how to best get patients the care they need to improve outcomes and increase disability. This may require a regional approach, but making thrombectomy available to the greatest numbers of individuals in the shortest time will require development of new prehospital tools.
Key Points:
- Earlier identification of stroke syndromes, particularly in pre-hospital settings, is crucial to ensure the right patient is treated in the right place.
- Minimal requirements for thrombolysis are being and should continue to be rethought, as treatments are moving out of specialized centers and closer to patients, particularly through MSUs.
- As thrombolysis becomes a viable treatment options for greater numbers of patients through increasingly complicated imaging and decision-making pathways, the need for additional availability of Neurology expertise, or training of ED physicians, gains heightened relevance. Options include telemedicine, checklists, and consistent messaging to ED providers.
Existing and projected distribution of thrombectomy centers worldwide
Raul Nogueira, May Nour, Olvert Berkhemer
The mismatch between lower resources and the increased stroke incidence is a devastating challenge that demands a timely solution. Despite the increased number of centers capable of carrying out mechanical thrombectomy, long travel times and delay in identification of patients with LVO who should be transferred to comprehensive stroke centers limit stroke care. In the United States, the two most prevalent certifying bodies are the Joint Commission (JC) and the DNV-GL. There are 194 CSCs accredited by the JC as a facility with Neurointerventional coverage with a neurologist on site and a backup physician, with coverage for stroke neurology, neurosurgery, and neurocritical care coverage available 24/7. 67 current CSCs accredited by the DVN-GL are required to provide only neurointerventional coverage 24/7 and have the ability to either accommodate or transfer out neurosurgical emergencies. In March 16, 2018, the JC in collaboration with the American Heart Association/American Stroke Association certified the first Thrombectomy-capable Stroke Center (TSC) defined as a facility with EVT capability 24/7, have at least 15 patients with ischemic stroke in the past 12 months or at least 30 patients over the past 24 months, and was required to collect data for 13 standardized performance measures, and meet expectations of neurological expertise availability aligned with that of a CSC. These certifications served the goal of improving patient outcomes by facilitating access to care for stroke patients, so patients with a suspected LVO would get re-routed to the nearest CSC or TSC center rather than to a Primary Stroke Center (PSC).
In Canada, thrombectomy access is evolving with a projected creation of 6 centers across the country. Latin America has a very limited distribution of thrombectomy centers when compared with the increased morbidity and mortality associated with acute stroke. In Europe, 32% of the countries have overall EVT coverage with the rest not providing EVT due to high costs and lack of trained personnel and facilities. 29% of eligible EVT patients were treated in 2016, and around 52% of centers are available 24/7. (11)
Where should thrombectomy be done—centralized vs distributed model; what do the guidelines say and how do they square with reality?
Tudor Jovin, Bernard Yan, Diogo Haussen
The American Stroke Association 2018 guidelines regarding the provision of thrombectomy services to acute ischemic stroke clearly recognizes that patients should be treated at experienced thrombectomy centers with rapid access, qualified neurointerventionists, and comprehensive periprocedural care team.(12) Evidence for other neurological diseases, such as subarachnoid hemorrhage and carotid endarterectomy, prove a worse clinical course in patients treated by lower volume operators at low-volume centers. (13-22) This is buttressed by similar experiences in the field of coronary percutaneous intervention and trauma. (23) Importantly, both operator and center volumes metrics are to be considered together, since one affects the other when evaluating for quality of care.(24) The data on mechanical thrombectomy has accrued and uniformly point towards improved outcomes in patients treated in higher volume centers.(25,26)
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Discussion Panel
Carlos Molina, Ed Jauch, Albert Yoo
The question of who should be performing EVT, both in terms of physician qualifications as well as hospital qualifications, was a central question during this meeting, and one that pervaded nearly all the discussions of the first day. In this discussion section, the speakers noted that there is an ongoing debate regarding manpower needs for mechanical thrombectomy and more broadly for neurointerventional procedures, which include treatments such as aneurysm coiling and arteriovenous malformation embolization. However, this debate ignores the fact that most neurointerventionists coming out of training do not move to underserved communities. They move to metropolitan areas where established practices already exist. Healthcare systems shoulder some of the blame. Despite the presence of nearby comprehensive stroke centers, in the United States hospitals are incentivized to become comprehensive or thrombectomy-capable centers to capture EMS traffic and the higher reimbursements associated with thrombectomy care. As a result, neurointerventional practices are competing for smaller and smaller case volumes, and the debate has naturally shifted to focus on the better outcomes at high-volume centers as an argument to stem this tide.
Meanwhile, populations residing in rural markets are being neglected. Patients who suffer a large vessel stroke in these communities must be transported to the closest major city. Unfortunately, transport can take several hours even with air transport. Despite publications projecting adequate neurointerventional availability to much of the US population, there is a clear need to better distribute thrombectomy expertise to underserved areas, given the highly time sensitive nature of large vessel stroke. If there are not enough aneurysms or arteriovenous malformations to support a full-time neurointerventionist in a rural market, then other interventional disciplines (peripheral radiologists or when necessary even interventional cardiologists) may be trained to provide thrombectomy care. Alternatively, neurointerventional training and certification guidelines may need to be altered to accommodate this shift in modern neurointerventional practice, in which the largest need is for acute ischemic stroke, and as such requirements mandating high numbers of aneurysm and arteriovenous malformation treatments may be outdated. In such a system, additional thrombectomy-capable interventionists would be credentialed to treat large vessel strokes in regions where there is demonstrated need. Although thrombectomy care in the rural setting is likely to be less optimal than at high-volume centers in major cities, it may be better than the alternative which is to delay treatment by hours or to have a high proportion of cases that do not meet treatment criteria due to a combination of late arrival and large infarct volume (i.e., futile transfers).(27,28) The neurointerventional community along with other professional organizations should propose criteria for defining areas in need of local thrombectomy expertise and decide what constitutes adequate thrombectomy training and long-term quality assurance in these areas. Hybrid models including tele-neurointerventional expertise for intra-procedural decision making may help to bridge the quality gap. As technology continues to advance, remote robotic intervention may also be possible.
Key Points:
- At present, there is a palpable shortage of access to high quality EVT care. This shortage is present in developed as well as developing nations globally. This is an issue for both hospitals/stroke systems of care as well as physicians, and in particular, thrombectomy providers.
- Alternative models of stroke systems of care have developed to improve patient access. These models include improved pre-hospital routing paradigms, improved intra-hospital transfer paradigms, and models in which thrombectomy providers travel to outlying hospitals. All these systems however remain imperfect and limited, and ultimately, increased numbers of thrombectomy-capable physicians and provider teams are needed.
- There is a clear need for additional data examining outcomes data in low volume centers, and by low volume practitioners. The outcomes are likely to be poorer, but how much so? And is that decrement in outcome outweighed by the time delays associated with transfers?
Summary of new data from clinical trials of thrombolysis since International Stroke Conference (ISC) or European Stroke Organization Conference (ESOC)
WAKE UP and ECASS 4 primary results and secondary analyses
Werner Hacke
The primary results of two trials testing the efficacy of alteplase in patients with longer or unknown time window using advanced imaging selection were presented at ESOC 2018 in Gothenburg. The WAKE-UP trial was terminated early for lack of funding. It selected wake up stroke patients on the basis of the DWI-FLAIR Mismatch concept. Despite the early termination, the study showed a highly significant advantage in reaching modified Rankin Scale (mRS) 0,1 for alteplase in patients with a positive DWI-FLAIR mismatch (OR 1.63 95% CI 1.09-2.36, p=.02,).(29)
ECASS 4 used the classic DWI-Perfusion mismatch in patients between 4.5-9 hours or in wake-up strokes. It was also terminated prematurely because of futile recruitment because of massively increasing use of thrombectomy in this patient group. The OR point estimates were likely anticipated in favor of alteplase treatment (OR 1.23 for the categorical shift, OR 1.38 for mRS 0,1), but the confidence intervals were wide and clearly overlapped unity because of the small sample size.(30)
Further ECASS 4 secondary analyses presented in Montreal (WSC 2018) indicated that this type of selection is more useful in known, late time window than in unknown time window. Using the FLAIR-DWI Mismatch paradigm in a non-predefined sub analysis of ECASS 4 showed also a clear trend towards better results in the DWI-FLAIR Mismatch cohort, but with the caveat of increased late (stroke unrelated) mortality signal in the alteplase treated group. Again, due to the small sample size the CIs overlapped the unity line.
EXTEND
Henry Ma, Bruce Campbell, Mark Parsons, Stephen Davis, Geoffrey Donnan
EXTEND is a multicenter randomized, double-blind, placebo-controlled trial of alteplase in ischemic stroke patients presenting within 4.5-9 hours from onset or those with wake-up stroke (WUS). Selection was based on automated perfusion imaging software showing salvageable brain tissue. Primary outcome was excellent functional outcome (modified Rankin Scale, mRS 0-1) adjusted for age and baseline NIHSS at 3 months.(31) Other prespecified outcomes included independent functional outcome (mRS 0-2), early reperfusion, clinical improvement with NIHSS reduction of 8 points or reaching 0-1 at 24 hours, death and symptomatic intracerebral hemorrhage (sICH). After 225 of the planned 310 patients had been randomized, the study was terminated early after the publication of WAKE UP study and loss of clinical equipoise. Patients who received alteplase achieved significantly better functional outcomes at three months. Secondary end points, including reperfusion and early neurological improvement, were superior in the alteplase group while mortality was not significantly different. EXTEND is the first positive thrombolytic trial in the extended time window using automated penumbral selection software
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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.
