American Heart Association


Tenecteplase for Thrombolysis of Acute Ischemic Stroke: The Debate Continues

Ammad Mahmood, MBChB

Putaala J, Saver JL, Nour M, Kleindorfer D, McDermott M, Kaste M. Should Tenecteplase be Given in Clinical Practice for Acute Ischemic Stroke Thrombolysis? Stroke. 2021;52:3075–3080.

Guaranteed to feature on the program at this year’s stroke meetings (virtual or otherwise), the debate regarding the potential use of tenecteplase for thrombolysis in acute ischemic stroke rolls on. The authors of this commentary present an excellent summary of the pros and cons of choosing tenecteplase over alteplase, summarizing and critiquing the evidence base in both camps, before reaching a balanced conclusion reflecting the current equipoise in the stroke community.

By |August 26th, 2021|clinical, controversy, treatment|Comments Off on Tenecteplase for Thrombolysis of Acute Ischemic Stroke: The Debate Continues

ESO-WSO 2020: Three Rounds of Controversies in Recovery and Brain Repair After Stroke

Aurora Semerano, MD

European Stroke Organisation-World Stroke Organization 2020 Virtual Conference
November 7-9, 2020

The Controversies sessions during the ESO-WSO 2020 Conference are intriguing live Q&A sessions focused on grey zones in stroke care, with stroke experts defending their points of view and facing each other in interesting rounds of discussion. On the second day of the conference, the session addressed the following topics about recovery and brain repair after stroke.

Round 1:

Brain Repair is the Right Target to Improve Outcome — John Krakauer (United States of America)
Basing on primate experimental stroke, Dr. Krakauer showed that a certain rate of spontaneous recovery exists after stroke; however, training helps to amplify, rescue, and maintain spontaneous recovery. The main question remains: How does it happen? According to Dr. Krakauer, training-induced recovery in monkeys is not driven by cortical reorganization. Conversely, brain repair occurs via training-induced strengthening of pre-existing alternative cortico-subcortical connections. The recipe for brain repair after stroke is traced: an integrated interaction between behavior, residual architecture, and plasticity.

Brain Repair Does Not Work, Reorganisation is Key — Belen R. Ballester (Spain)
Dr. Ballester dismantled in 15 minutes three common pessimistic beliefs about recovery after stroke. Behavior drives functional and structural reorganization and can meaningfully interact with spontaneous recovery. For this purpose, high repetitive task-oriented and task-specific training is needed. Possibilities for recovery extend well beyond the classical time window of 3-6 month, and plasticity by means of structural and connectivity changes is still present beyond 1 year after stroke. Finally, it is not an invariable destiny of stroke patients to deteriorate in the chronic phase; learning and training can prevent deterioration.

By |December 4th, 2020|clinical, Conference, controversy|Comments Off on ESO-WSO 2020: Three Rounds of Controversies in Recovery and Brain Repair After Stroke

ISC Crossfire Debate: Should Anticoagulation Therapy Not Be Started in Patients with Anticoagulation-related Lobar Intracerebral Hemorrhage?

International Stroke Conference
January 24–26

Abbas Kharal, MD, MPH

The topic of whether or not anticoagulation should be restarted after an anticoagulation-related lobar intracerebral hemorrhage (ICH) remains a hot debate among neurologists around the world. Although with the advent of better imaging-based risk predictors for lobar ICH, including cerebral microbleeeds and sulcal siderosis on MRI, raising concern for cerebral amyloid angiopathy and posing higher recurrent ICH risks, there are also accordingly more safer options available now for oral anticoagulation, e.g. direct thrombin inhibitors and surgical alternatives like left atrial appendage closure, which may help lower mitigate the risks of recurrent lobar intracerebral hemorrhage. However, there still remains insufficient data to help definitively guide our management decisions when deciding whether or not it is truly safe to resume anticoagulation in such high-risk patients with a prior anticoagulation-related intracerebral hemorrhage.

An interesting crossfire debate was held on this very topic at the International Stroke Conference’s closing event between Dr. Stephan Mayer from Henry Ford Hospital, who spoke glamorously in favor of not resuming AC in such patients, and Dr. Alessandro Biffi from Massachusetts General Hospital, a world renowned cerebrovascular epidemiologist who has published extensively on the topic of intracerebral hemorrhage and anticoagulation risks, who spoke against the notion of holding oral anticoagulation in all patients with AC-related lobar ICH. Dr. Mayer raised concerns about the high risk of recurrent ICH being approximately 10.4% per year based on previously published data from Dr. Biffi and colleagues, which, when paired with the presumed increase in mortality associated with it from previously published data, appears to outweigh any potential benefits of resuming anticoagulation in such patients. Dr. Mayer went on to conclude that resuming anticoagulation in such patients would be “nuts!”

By |January 29th, 2018|Conference, controversy|Comments Off on ISC Crossfire Debate: Should Anticoagulation Therapy Not Be Started in Patients with Anticoagulation-related Lobar Intracerebral Hemorrhage?

Stroke Controversies: Debate

International Stroke Conference (ISC)
February 17-19, 2016

February 19, 2016
Another standing room only session at the ISC 2016, the Stroke Controversies: Debate was a spirited back and forth session exploring three topics of clinical equipoise between thought leaders in their respective fields, of which there are no easy answers.
Debate #1: Should we bypass primary stroke centers (PSC)? Arguing in favor, Dr. Goyal points out that tPA does not work very well for proximal large vessel occlusions, the NNT is as low as 2.6 for endovascular therapy, time is brain and we lose time (and therefore brain) transferring from a PSC to a comprehensive stroke center (CSC). Dr. Johnston agreed that in some cases, i.e. if the patient does not qualify for tPA, it may be reasonable, but endovascular treatment is only proven safe and efficacious for a minority of patients. As of now, there is no way to effectively screen patients in the field, and bypassing a PSC may in these situations delay treatment with tPA.

I interpreted this as a debate between pragmatism and idealism. The ideal might be bypassing a PSC, but pragmatically, within our current system of stroke care, this may lead to saving time for a subset of patients with large vessel occlusion at the expense of delaying tPA for the majority of patients, especially within the context of the resources that we have. We need a better work flow to minimize delays in transfers if we continue to rely on PSCs, or alternatively, better screening measures in the field if we want to bypass them.

Debate #2: Embolic stroke, atrial fibrillation, and cerebral microbleeds: Is there a role for anticoagulation? Dr. Diener presented the pro side, arguing that afib increases the risk of stroke and while some microbleeds, such as with amyloid angiopathy, may be a contraindication, others are markers of small vessel disease. NOACs have a more favorable profile for ICH than warfarin and has been demonstrated to not increase microbleeds. Dr. Greenberg, however, iterated the dismal outcome of anticoagulation related ICH (up to 50%), and pointed out that microbleeds lead to 5 ICH events/100 person years. A decision analysis modeling the risk/benefit ratio of anticoagulation has previously identified an ICH risk of 1.4% as the tipping point where risk of anticoagulation outweighed benefits.

There is no easy resolution to this debate. With safer NOACs being introduced, it would seem reasonable to anticoagulate, even in the presence of microbleeds. In parallel, as treatments of ICH continue to advance, the mortality of anticoagulation related ICH will hopefully decline to the point where we will no longer fear it.

Debate #3: Should we assess the outcome of severe strokes early (3 months) or late in clinical trial? Both Dr. Dawson, who argued in favor of an early assessment, as well as Dr. Broderick, who argued in favor or a late assessment, used data from the MISTIE II and IMS III to support their points, which perhaps points to the true equipoise in this question. Dr. Dawson’s point was that in general, the longer a trial is conducted, the more confounders are introduced and often, additional time does not add information that significantly changes the interpretation of the results. Given the resources available, a better approach may be to recruit more patients within a shorter trial rather than follow less patients for a longer time frame. Dr. Broderick argued that especially with severe strokes, there are patients who recover later, and delayed follow up allows for better cost effect analysis.

Much like the first debate, some of this is a question of what is practical vs what is ideal. Delayed recovery is still important for the patient and the physician, and a later assessment allows us to fully capture all of these patients; it will allow us to answer the question of the sustainability of recovery. However, with limited funds for trials, it may be difficult to implement this. 

– Peggy Nguyen, MD

By |February 19th, 2016|Conference, controversy|Comments Off on Stroke Controversies: Debate

Anticoagulation in stroke patients with atrial fibrillation and multiple cerebral microbleeds: A controversial topic

Embolic Stroke, Atrial Fibrillation, and Microbleeds: Is there a role for anticoagulation?

José G. Merino, MD

Anticoagulation with vitamin K antagonists or one of the new oral anticoagulants (NOACs) is indicated to prevent recurrent stroke for most stroke patients with atrial fibrillation (AF). In these patients the risk of stroke is very high, around 7% to 10% per year, but Coumadin and other anticoagulants can decrease the risk substantially. The most feared risk of anticoagulation -intracerebral hemorrhage (ICH)- is relatively low and the benefits of treatment outweigh the risks.
But does the presence of certain comorbidities change the risk-benefit equation and make anticoagulation too risky for some patients? Patients who have had a lobar ICH, for example, may have an increased risk for recurrent ICH and thus may not be candidates for anticoagulation. Are patients with cerebral microbleeds (CMBs) also ineligible for anticoagulation?

In Stroke, a Controversies article addresses the hypothetical case of a 73-year old man with stroke, AF and 8 cortical CMBs. Hans-Cristoph Diener argues that anticoagulation, perhaps with a NOAC, is indicated because of the very high risk of recurrent stroke in patients with AF and the uncertainty about the risk of ICH in patients with CMBs. Steven Greenberg disagrees and argues that the risk of anticoagulation may be greater than the potential benefit because patients with cortical CMBs may have cerebral amyloid angiopathy (CAA), a condition that leads to ICH, and the fatality rate for anticoagulated patients with ICH is very high. Until there is a better understanding on the relationship between CMBs, anticoagulation, ICH, recurrent stroke and clinical outcome, clinicians must be mindful that anticoagulation may harm their patients with multiple cortical CMBs, particularly when CAA is suspected.

Both authors, along with Magdy Selim and Carlos Molina, editors of the Controversy Section, agree that the decision about anticoagulation in patients with multiple cortical CBMs is challenging and urge clinicians to engage patients in the decision about anticoagulation in this setting by acknowledging the gaps in our understanding of the relationship of AF, CAA, recurrent stroke, ICH and the use of anticoagulants; informing patients (and their families) about alternative strategies and possible outcomes; and eliciting their preferences (how do they weigh the reduced risk of recurrent stroke with increased risk of ICH, for example.) This controversy highlights the value of shared decision making in the face of clinical uncertainty.

By |February 19th, 2016|controversy|Comments Off on Anticoagulation in stroke patients with atrial fibrillation and multiple cerebral microbleeds: A controversial topic

Controversies in Stroke: Is CTP Ready for “Prime Time?”

Computed Tomography Perfusion in Acute Ischemic Stroke

Mark N. Rubin, MD

David S. Liebeskind, MD; Mark W. Parsons, PhD; Max Wintermark, MD. Computed Tomography Perfusion Is Beyond Prime Time. Stroke. 2015

Magdy Selim, MD, PhD; Carlos A. Molina, MD. Computed Tomography Perfusion in Acute Ischemic Stroke: Is It Ready for Prime Time? Stroke. 2015
Michael H. Lev, MD. and Ramón G. González, MD, PhD.Computed Tomography Perfusion Is Not Ready for Prime Time. Stroke. 2015

In the East Coast vs West Coast (yes, Australia is honorarily part of our West Coast) stroke-neuroimaging-related battle of the year, these major players in the science of acute stroke treatment and imaging “discuss” whether or not computed tomography perfusion (CTP), clinically available for decades but recently in the treatment trial spotlight, should be broadly implemented in hyperacute stroke.

Team West Coast kicked things off with reminding us how simple and broadly available CTP is in the United States, extolled the virtues of its ability to give us mission-critical data for acute stroke therapy while easily integrated into already common CT-based stroke imaging protocols, then, for the knockout, also reminded us about how resounding positive the CTP-based selection trials were for therapy.

Team East Coast took the skeptical approach – perhaps with a bit of irony considering their contribution to CTP stroke science – citing that CTP is too imprecise on an individual patient level and diffusion magnetic resonance imaging (MRI) provides much more accurate “tissue data.”

For what it’s worth, in my experience I find the truth West-of-Center in this debate. Although I agree CTP is widely available, it is not always fast (performance or processing), does give a fair amount of radiation, can be obscured by patient motion and/or poor cardiac output, and is best for “gestalt” as the Partners suggest as CBV does not always cleanly match up with DWI changes. Dr. Liebeskind’s own colleague let us know every minute matters, and it is not clearly established that all patients should undergo this test – however many minutes it may take – if not of clear benefit.

That said, it has its uses, particularly in ischemic stroke of unknown time of onset but suspect within 6 hours and severe strokes (most typically associated with large-artery syndromes) for which an endovascular intervention is being considered. I also agree with the West Coast group that acute MRI is not feasible regionally, let alone nationally, let alone globally. If the mission is to reduce ischemic stroke morbidity and mortality broadly, then our diagnostics must be broadly applicable and MRI is cost-prohibitive in this sense.

Make sure you read this edition of Controversies in Stroke for yourself, as it’s rather crispy.

By |September 16th, 2015|controversy|Comments Off on Controversies in Stroke: Is CTP Ready for “Prime Time?”

Poststroke Angiogenesis: Architect and/or Demolition Crew?

Mark N. Rubin, MD

Greenberg DA. Poststroke Angiogenesis, Pro: Making the Desert Bloom. Stroke. 2015

Adamczak J, and Hoehn M. Poststroke angiogenesis, Con: The Dark Side of Angiogenesis. Stroke. 2015

This installment of the “Controversy” series involves what to make of post-stroke angiogenesis: the hypoxia-triggered generation of new capillaries after a stroke of any subtype. The fact that angiogenesis exists in the post-stroke setting–experimental and clinical–is not the point of debate but to what degree this process influences patient outcome. Experimental, pathological case study and treatment trial data exist in this field, but a fundamental clinical question remains unanswered: does manipulating this pathophysiologic process make patients better?

Dr. Greenberg from the Buck Institute for Research on Aging proposes that post-stroke angiogenesis is a viable therapeutic target, mostly because it is fairly well understood at a biochemical level, broadly applicable across the patient population and there are myriad promising biochemical targets in the process that have not yet been investigated. Furthermore, there is the optimistic view that angiogenesis allows for more rapid clearing of ischemic debris, setting a clean slate for post-stroke neuronal reorganization (e.g., functional recovery). Prof. Doctors Adamczak and Hoehn from the Max Planck Institute argue that angiogenesis is more demolition crew than architect. While not arguing that restoration of cerebral blood flow is beneficial to neuronal tissue, they point out the double-edged sword of pro-angiogenic factors (namely Vascular Endothelial Growth Factor, better known as VEGF), which also promote increased cerebral edema which is injurious to brain. They cite evidence that supporting anti-angiogenic factors actually decreases infarct volume.

Dr. Liu from UCSF ties the debate together with a resounding “you’re probably both right but we don’t know enough in general. Plus, how does this all relate to collateralization, which is so hot right now?” She also suggests a careful marriage of nanotechnology and pharmacotherapy may help deliver the right mix of biochemicals–whichever those may be–to the right place at the right time, thus mitigating the known inefficacy and/or risks of systemic delivery of pro-angiogenic factors.

Read on for details of the Basic Science Controversy In Stroke!

Stroke controversy: Should a patient with a severe stroke be transferred from a primary to a comprehensive stroke center?

Early Transfer of Stroke Patients to Comprehensive Stroke Centers: David and Goliath

This month’s Stroke controversy addresses whether patients with moderately severe stroke should be transferred to a comprehensive stroke center (CSC) in the acute stage or whether the transfer can be done later if complications develop or more complex issues arise.  Drs. Kevin Sheth and Peter Langhorne, the two panelists, present their views on the need to transfer a 55 year old man with 75% left carotid artery stenosis who presents with a left MCA syndrome and NIHSS score of 20 five hours after symptom onset.

Dr. Seth argues for early transfer even if the patient is outside the time window for a reperfusion therapy because he is at high risk for neurologic deterioration and the staff at a CSC may closely monitor him to identify any complications and intervene in a timely manner if necessary. The staff at a CSC may also implement secondary stroke prevention strategies early on, including carotid endarterectomy for this patient. Dr. Langhorne, on the other hand, maintains that an ambulance ride will not help the patient and that many small hospitals can care for the patient as long as they have a well-run stroke unit. He reminds us that a stroke unit admission is the only intervention proven to improve survival after stroke and maintains that staff in a stroke unit should be able to monitor for complications and institute secondary prevention measures. If carotid endarterectomy is not available at the smaller hospital, the patient may be transferred to a larger center within the first two weeks after the stroke.

Both authors address the possible need for a hemicraniectomy if the patient develops significant brain swelling but disagree in terms of the  risk in a patient with an NIHSS score of 20 and, if an intervention is needed, the timing when the neurosurgical team should get involved.

In a Solomonic discussion, Drs. Molina and Selim, the moderators of the debate, acknowledge the validity of the issues raised by the debaters. They conclude that system and patient factors play a role in the decision to transfer a patient, and suggest that telemedicine is a way to make the decision easier. I agree with them. Well organized primary stroke centers must have the infrastructure required for managing most patients in the acute stage. The decision to transfer a patient to a comprehensive stroke center must take into account availability of local resources, the condition of the patient, the expertise of the treatment team and, ideally, the advice of the stroke specialists at the CSC. The way forward cannot be prescriptive.

– José G. Merino, MD

By |November 25th, 2014|controversy|1 Comment