ISC19

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Clinical Trials on VCID in Alzheimer’s Disease

Reem Waziry, MD, MPH, PhD

This year at ISC19, Dr. Eliezer Masliah MD highlighted key ongoing trials on vascular cognitive impairment and dementia (VCID) in Alzheimer’s disease (AD)1. Currently, there are 140 AD trials at different stages of development covering a wide array of topics that include pharmacological, neuropsychiatric or caregiver interventions. Many of the pharmacological trials target vascular interactions of AD with VCID.

Key ongoing pharmacological trials at early stages include The Calibrex in patients with cognitive impairment at risk of AD2. Another key trial targets blood pressure and vasculature in individuals with mild cognitive impairment. A third trial investigates anti-hypertensive drugs to receptive blockers. This includes a number of anti-hypertensive drugs with neurocognitive function (as the primary outcome) in individuals with already mild cognitive impairment or AD.

Non-pharmacological trials include a study from Minnesota and UC San Diego with 300 participants – these participants are individuals with mild cognitive impairment, or very prodromal stages, that investigate the impact of aerobic exercise on cognition3. There are a number of measurements of blood flow, brain atrophy and other outcomes. Other examples include a trial targeting healthy diet interventions, comparing Mediterranean intervention with or without exercise looking at well-being and global cognition.

Many of the above trials will be reporting between 2019 and 2022, bridging key gaps in clinical management and treatment of VCID and Neurocognitive disorders. For more info on ongoing trials, please refer to: https://www.ninds.nih.gov/Disorders/Clinical-Trials

 

REFERENCES:

  1. Masliah, Eliezer. Clinical Trials on VCID in Alzheimer’s Disease. NIH Clinical and Applied Research Programs in Vascular Contributions to Cognitive Impairment and Dementia (VCID) (Joint Government Agency Session) [oral presentation]. In: The International Stroke Conference of the American Heart Association; 2019 Feb 6–8; Honolulu, HI.
  2. gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT01984164, CAndesartan vs LIsinopril Effects on the BrRain (CALIBREX); 2013 Nov 14 [cited 2019 March 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT01984164
  3. gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT03313895, The ACT Trial: Effects of Combined Aerobic Exercise and Cognitive Training in MCI; 2017 Oct 18 [cited 2019 March 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT03313895

 
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Thomas Willis Lecture Award Lecture at ISC19

Anberitha Matthews, PhD

The International Stroke Conference 2019 (ISC19) was packed with all things stroke. In my previous blogs I outlined the expectations and highlights from the daily goings on in Hawaii. Here I will summarize the Willis Lecture presented by Frank Ray Sharp, MD, FAHA entitled “Molecular Markers and Mechanisms of Stroke.” ISC19 is a premier setting to disseminate the basic science behind cerebrovascular disease as it impacts patient care.

It is well established that ischemic stroke occurs as a result of narrowing of arteries to the brain due to disrupted laminar blood flow. My research has focused on the inflammatory response that leads to the lipid accumulation in the vessels; however, Dr. Sharp’s research, although focused on the brain (neuroscience), can be translated into studies affecting the atherosclerotic vessel.

Identifying canonical pathways and molecular functions of genes, such as histone deacetylase 9 (HDAC9) that are associated with large vessel atherosclerotic stroke, could assist in identifying factors that contribute to peripheral immune, lipid, and clotting systems resulting in vascular injury. For example, an intracerebral hemorrhage has T-cell receptors and CD36 genes (in addition to iNOS), toll-like receptors, macrophages, and T-helper pathways that are differentially expressed; whereas ischemic stroke displays more non-coding RNA. However, both have the potential to undergo angiogenesis, NFAT regulation of immune response, and glucocorticoid receptor signaling pathways. Based on this awareness, we can conclude that all strokes are not one and the same.

What is more, this body of research uncloaked the Biomarkers of Acute Stroke Etiology (BASE) study utilizing RNA targeting as a viable therapeutic model to improve ischemic stroke outcome. BASE is an ongoing observational study that works to identify serum markers that could potentially define the etiology of acute ischemic stroke. Patients in this study present within 24 hours of the onset of their stroke, blood samples are collected at various intervals to obtain RNA gene expression data. There is cutting-edge research being conducted on treating patients with a microRNA-122 mimic and inhibiting NOS2. Evidence is mounting on the role of microRNA-122, a compound that is produced in the liver and secreted into the blood, reduction contributing to a heightened inflammatory response and subsequently the onset of ischemic stroke. Additionally, NOS2 has been shown to be a major player in initiating the inflammatory cascade post-ischemic stroke. Thus, the utilization of a microRNA-122 mimic in addition to a NOS2 inhibitor can potentially modulate an infarct volume as well as lengthening the therapeutic window while extend vascular protection post-ischemic stroke.

There were so many aspects of ISC19 that it would be too exhaustive to cover them all in one blog post, but I would be remised to not mention the telerehabilitation in home versus therapy in clinic for patients with stroke. This rehabilitation method is conducted remotely and quite resembles palliative care. I may be “old school,” but this telemedicine has been on the incline, so we should understand more about how it works. Clinicians use telemedical devices to obtain data such as heart beat, ECG, blood pressure and oxygen saturation for cardiovascular rehabilitation. Employment of telehealthcare reduces the time in hospitals and subsequently bills related to medical care. Patients can conduct rehabilitation exercises at a time that is most convenient to them and hospital staff can connect remotely to the patient’s computer to customize the exercise based on the results of the test. Additionally, health conditions can be assessed in real time and various training forms can be initiated based on patient’s progress.

The take home here, is that science is changing and as a result medical care is changing. We as patients, scientist, and clinicians should gain awareness of how these changes affect us and how we can get/give the best care. Know your risk. Know your options.

Let me know your thoughts in the comments. Share your questions so we can learn more together. Follow me on Twitter @AnberithaT, Instagram @AnberithaMatthews and @AHAMeetings for more information on being heart smart.

Save the Date for ISC 2020, February 19 – 21, hosted in exciting Los Angeles, California!

 

 
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Andexanet Alpha: Novel Reversal Agent for Factor Xa Inhibitors

Siddharth Sehgal, MD

Over the last decade, several direct oral anticoagulants have become available for thromboembolic prophylaxis, as an alternative to the Vitamin K antagonist warfarin. These agents are either direct thrombin inhibitors (dabigatran) or Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). In my clinical practice, I frequently prescribe these medications for stroke prophylaxis from atrial fibrillation. During these discussions with patients, I provide information from clinical trials comparing warfarin and the DOACs. These medications have shown similar stroke prophylaxis efficacy and safety in terms of hemorrhage risk when compared to warfarin. One of the concerns for patients and clinicians has been a lack of a reversal agent for the DOACs. There is some evidence to suggest that patients have better outcomes in case of hemorrhagic events while on DOACs as compared to warfarin1.

Prothrombin complex concentrate along with Vitamin K is used to treat warfarin associated major bleeding. Idaruzicumab was approved by the FDA in 2015 for reversal of dabigatran related major hemorrhages. Still acute life threatening hemorrhage while on Factor Xa inhibitors remains difficult to treat due to a lack of a specific reversal agent.

Final results from the ANNEXA-4 study were presented at the International Stroke Conference 2019 held at Honolulu earlier this month. The results were simultaneously published in the NEJM2. This trial investigated Andexanet alfa, a modified recombinant inactive form of human factor Xa. This binds to and sequesters factor Xa inhibitor molecules. This leads to rapid lowering of factor Xa inhibitor activity. ANNEXA-4 investigators  enrolled 352 adult patients who presented due to acute major bleeding in the setting of using a factor Xa inhibitor within the last 18 hours. Patients were eligible if they had an acute major bleeding in a critical organ, such as intracranial or retroperitoneal hemorrhage, bleeding associated with significant hemodynamic compromise, or significant drop in the hemoglobin level. 64% of the patients enrolled had an intracranial hemorrhage as their qualifying event. Patients with severe intracranial hemorrhage (GCS<7 or hematoma volume>60 ml) were excluded from the trial. The drug was infused as an initial bolus dose followed by a 2 hour infusion. Blood levels of Factor Xa inhibitor and anti-Factor Xa activity was measured before, during and after the infusion. Patients with intracranial hemorrhage received a follow up brain CT or MRI at 1 hour and 12 hours after the infusion.

There was a 92% reduction in the median values of anti-Factor Xa activity after administration of the bolus dose in patients who were on rivaroxaban or apixaban. At 12 hours after the infusion, 82% patients were noted to have an excellent or good hemostatic efficacy as determined by  pre-specified criteria. This is comparable to the 72% rate noted with prothrombin complex concentrate treatment given for reversal of warfarin related major bleeding. Thrombotic events occurred in 10% of patients within 30 days after the infusion, with almost half of these events being ischemic stroke. Interestingly, this study did not show a direct correlation between anti-Factor Xa activity reduction and clinical response. Among patients with intracranial hemorrhage, there was a weak relationship that was observed between hemostatic efficacy and anti-Factor Xa activity reduction. Therefore the investigators do not recommend using the anti-Factor Xa activity level as a predictor of clinical response. This study was limited due to its non randomized design. A randomized clinical trial is currently being initiated by the study sponsors to overcome this limitation3.

The FDA approved andexanet alpha in May 2018 for reversal of anticoagulation in case of severe life threatening bleeding related to apixaban or rivaroxaban. Intracranial hemorrhage is one of the most feared complications of long term anticoagulation and now we have available, effective and safe reversal agents for all the prescribed oral anticoagulants. This provides a significant benefit and reassurance for patients who are taking these medications for thromboembolic prophylaxis.

 

References:

  1. Compared to warfarin, direct oral anticoagulants are associated with lower mortality in patients with blunt traumatic intracranial hemorrhage: A TQIP study. J Trauma Acute Care Surg. 2016 Nov;81(5):843-848.
  2. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. February 7, 2019 DOI: 10.1056/NEJMoa1814051
  3. ClinicalTrials.gov number (NCT03661528)

 
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Follow Your Heart But Take Your Mind With You: Insights on Vascular Dementia

Reem Waziry, MD, MPH, PhD

Cardiovascular diseases such as diabetes and hypertension are established risk factors for mild cognitive impairment (MCI) and vascular dementia (VD). Vascular pathology occurs alongside neurodegenerative disease pathology, and both are associated with interactive effects on the clinical presentation of VD1. Several cardiovascular risk factors of VD could be modified during the preclinical course of the disease during midlife rather than later in life or closer to VD onset2,3.

In this year at ISC19, Angela L. Jefferson reported results supporting that age-related aortic stiffness contributes to transmission of damaging pulsatility and reduction in blood flow. This contributes to blood brain barrier compromise, resulting in reduced cerebral perfusion and subsequent tissue damage4. Brain MRI results suggest that vascular dysregulation may drive neurodegeneration over time, possibly due to neurofibrillary tangle formation or synaptic degradation4.

Looking from another angle, Lawrence J. Fine presented on the interplay between CVD and VD in epidemiological studies. According to data from the American Heart Association, loss of a perfect cardiovascular health during midlife is concurrently associated with steep increase in risk of MCI and vascular dementia. A recent report from the Women Health Initiative Memory Study (WHIMS) assessed MCI and Parkinson’s disease (PD) in women with myocardial infarction (MI). The data suggests modest absolute numbers, but higher rates of MCI and Parkinson’s disease (PD) cases in women with myocardial infarction (MI) (adjusted HR for PD or MCI was 2.23, 95% CI 1.51 to 3.30)5.

Investigators of the SprintMind trial examined the effect of one or more intensive high blood pressure treatment than is currently recommended. SprintMind was a randomized controlled trial that compared intensive treatment (goal SBP < 120 mm hg) to standard treatment (goal SBP < 140 mm Hg). Patients with major CVD as strokes, diabetes and congestive heart failure were excluded. The results suggest that intensive blood pressure control causes no harm on cognition with actual reduction in MCI risk compared to standard treatment6.

Overall, these observations add novel insights on the association between CVD and VD. More data is needed to assess the extent to which CVD contributes to the occurrence of MCI and dementia in more diverse populations and over longer follow-up periods.

 

REFERENCES

  1. Yaffe, Kristine. “Prevention of cognitive impairment with intensive systolic blood pressure control.” Jama (2019).
  2. Gottesman, Rebecca F., et al. “Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) cohort.” Jama neurology 74.10 (2017): 1246-1254.
  3. Gottesman, Rebecca F., et al. “Association between midlife vascular risk factors and estimated brain amyloid deposition.” Jama 317.14 (2017): 1443-1450.
  4. Jefferson, Angela L., et al. “Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.” Circulation 138.18 (2018): 1951-1962.
  5. Haring, Bernhard, et al. “Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results from the Women’s Health Initiative Memory Study.” Journal of the American Heart Association 2.6 (2013): e000369.
  6. Williamson, Jeff D. “A randomized trial of intensive versus standard systolic blood pressure control and the risk of mild cognitive impairment and dementia: results from SPRINT MIND.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 14.7 (2018): P1665-P1666.

 

 
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What’s Happening Here At The International Stroke Conference in Hawaii?

Anberitha Matthews, PhD

Getting to Hawaii was quite the event! I underestimated the flight and how I would feel with such time zone changes. However, the International Stroke Conference 2019 (#ISC19) was worth all the efforts. The meeting objectives were sufficiently described in the program book and my previous blog. As promised, there were sessions to equip scientists and clinicians with tools in diagnosis, treatment, prevention, management, and rehabilitation of cerebrovascular disease as well as nursing. The sessions that I was able to partake in were the following:

  1. Clinical Rehabilitation and Recovery Oral – I spent the first part of the morning here learning about the biomarkers to improve stroke rehabilitation covered in the clinical trial data and predictors of post stroke depression using qualitative data in patient after ischemic stroke. Although these presentations were informative, I had my eye set on other topics as well, so I had to leave the session a tad early.
  2. Medical therapy for Symptomatic Carotid Stenosis: Time for Modern Data – Seemant Chaturvedi, MD shared his research on ‘Genetic Guidance for Antiplatelet Therapy’ followed by Brian Hoh, MD discussing the answers he found to the question ‘Do HTN Targets Matter?’ Studies presented here show there is a link between hypertension and changes in white matter in the brain that affect cognitive functions. Dr. Bath expounded on his recent article in Stroke (2018) sharing mechanisms of how this damage could potentially occur.
  3. Looking into the Brain Through the Eye: Re-examining the Retina as a Surrogate Marker for Cognitive Disorders – There is growing evidence that the dental and optical examinations can be a window into health. I previously blogged about the bacteria found in the mouth is also identified in atherosclerotic plaques. In this session, clinicians/scientist looked at the retina as a window to the brain and subsequently health. These sessions suggested the retina can assist in the post-mortem prediction of Alzheimer’s disease and stroke based on the linear relationship between number of plaques in the retina and the brain. Current research tools are extremely invasive thus predictions are not feasible in living patients. The tools described here included Optical Coherence Tomography (OCT, not to be confused with over-the-counter) as a diagnostic tool, adding to repertoire of skills to increase the ability to interpret cognitive impairment.

I am looking forward to the information presented on tomorrow. I will give more insights into what I think is the highlights of the meet in my next blog. Keep following me on Twitter @AnberithaT and be sure to ask any question that may be answered during the ISC19 or after.

 
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News from the International Stroke Conference: Minimally Invasive Surgery for ICH

Siddharth Sehgal, MD

Intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and is associated with a high early mortality and poor long term functional outcomes. It is the only subtype of stroke which still does not have a proven and effective treatment available. Clinical trials investigating craniotomy and surgical evacuation of the hematoma have not shown improvement in outcomes1,2. Current in-hospital treatment of ICH has mainly involved medical stabilization and management of complications. More recently, there has been an increased interest in minimally invasive surgical methods for hematoma removal as a treatment strategy for intracerebral hemorrhage3.

Results of the recently concluded MISTIE III trial were presented at the International Stroke Conference in Honolulu earlier this week. This was an open label phase 3 trial which evaluated if minimally invasive catheter evacuation followed by thrombolysis can improve functional outcomes in ICH. The trial enrolled 499 adult patients with spontaneous/non traumatic supratentorial intracerebral hemorrhage measuring at least 30 ml. The patients were randomized 1:1 into the MISTIE and standard medical care groups.  Patients with a vascular etiology, such as an AVM or with an infratentorial hemorrhage were excluded from the study. The MISTIE treatment involved image guided catheter evacuation of the hemorrhage utilizing local thrombolysis with 1 mg alteplase doses given every 8 hours, up to a total of 9 doses.

Primary outcome was defined as a good functional outcome measured by modified Rankin Scale score of 0-3 at 1 year. 45% patients in the MISTIE group achieved the target primary outcome as compared to 41% in the medical care group. The 30 day mortality rates were 9% in the MISTIE group and 15% in the standard medical group. These results were not statistically significant to indicate a benefit of the minimally invasive surgical treatment. There was no significant difference in the rates of symptomatic bleeding and brain bacterial infections between the two treatment arms. Removal of the hematoma volume was associated with a significant increase in the probability of good outcomes. Patients who achieved final hematoma volume of less than 15 ml were more likely to have a good functional outcome in the MISTIE group:  53.4% vs. 41.9%, with p =0.03.

Even though the results were neutral without a signal towards overall benefit, this study does show that the minimally invasive surgery can be safely performed without an increase in the rates of death or other serious adverse outcomes. This is a promising result and should encourage further studies evaluating minimally invasive surgical treatments for ICH. Three ongoing trials are evaluating minimally invasive surgical treatments for ICH: ENRICH, INVEST and MIND (www.clinicaltrials.gov). With improved procedural protocols in the future, lowered hematoma volumes could be obtained more consistently, which would lead to better functional outcomes for this devastating neurological condition.

References:

  1. Mendelow AD Gregson BA Fernandes HM et al.Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365: 387-397
  2. Mendelow AD Gregson BA Rowan EN Murray GD Gholkar A Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013; 382: 397-408
  3. Hanley DF Lane K McBee N et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017; 389: 603-611
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Going to Honolulu, Hawaii Bae-Bae!!!

Anberitha Matthews, PhD

The International Stroke Conference 2019 (ISC19) is held in conjunction with the International Society of Cerebral Blood Flow and Metabolism (ISCBFM) this year. This session promises a unique learning opportunity. The meeting expectations is for participants to be exposed to the most recent advances in basic stroke and how it translates into clinical research. Additionally, the program coordinators expect attendees to take away tools they can use in diagnosis, treatment, prevention, management, and rehabilitation of cerebrovascular disease. With the tools discussed during this conference, scientist/clinicians will have a new repertoire of skills to increase their ability to interpret the ever changing spectrum of stroke and the mechanism of stroke recovery, as well as the impact on cognitive impairment.

The dual effort of @AHAMeetings #ISC19 and #ISCBFM allows for this program to boast three separate pre-conferences symposia, including the State-of-the-Science Stroke Nursing Symposium, the ISC Pre-Conference Symposium I: Stroke in the Real World (focusing on rare causes of stroke), and the ISC Pre-Conference Symposium II: Stroke in the Lab World: Cutting-Edge Topics in Experimental Stroke Research. The expected attendance of over 4,500 professionals, exhibitors, and service from around the world makes for a networking friendly environment. There will be over 1,500 symposia including: a) debates, b) oral scientific abstract presentations, c) provocative poster sessions that include professor-moderated abstracts, and d) state-of-the-science technologies that include simulations. There are going to be over 21 categories covered related to stroke topics as well as clinical topics centered on risk, emergency care, neuroimaging, diagnosis or etiology and more! Basic science categories will focus on vascular biology, experimental mechanisms and models. If those are not enough, there will be specialized ones focused on pediatric stroke, intracerebral hemorrhage, nursing, preventive strategies, vascular cognitive impairment, aneurysms, subarachnoid hemorrhage, neurocritical care, vascular malformations, and ongoing clinical trials. Further, Miguel Perez-Pinzon, Chair of the ISC19 program committee, promises a chance to experience the island of Oahu for education and networking with thousands of cerebrovascular experts from around the globe. He described Oahu as “truly one island – tropical playground and urban fantasy.” Partake in one of the many outdoor activities, explore the rich Hawaiian history, or just enjoy one of the exquisite beaches.

I know it’s a lot of science and clinical data for one conference, and there is no way for any one person to attend every session. There will be a lot of vascular enthusiasts like me onsite, tweeting and blogging all the goings-ons. I will look forward to communicating with you on Twitter during this conference in Hawaii, but don’t forget to download the ISC19 Mobile Meeting Guide app, or visit strokeconference.org and the online program planner. Follow me on Twitter @AnberithaT for conference highlights and live tweeting. See you in Hawaii!!!

 

Save the Date for ISC 2020, February 19 – 21, hosted in exciting Los Angeles, California!

 
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How Far Can We Go in the Early Management of Acute Ischemic Stroke?

Reem Waziry, MD, MPH, PhD

(In anticipation of the International Stroke Conference 2019 – ISC19)

Not so long ago, the benefit of endovascular thrombectomy beyond six hours of ischemic stroke onset was uncertain, particularly among patients with ischemic brain tissue that has not yet undergone infarction. The volume of irreversibly injured ischemic tissue and the volume of brain tissue that is ischemic, but not yet infarcted, could be assessed by computed tomographic perfusion imaging or a combination of diffusion and perfusion magnetic resonance imaging.1,2

Early last year, the DAWN3 and DEFUSE 34 trials’ investigators presented findings at ISC18 that lead to immediate change in the guidelines5 with substantial implications for prevention of functional dependence among stroke survivors.

The DAWN trial was a multicentre, prospective, randomized, open labelled trial conducted at 26 centers in the United States, Canada, Europe and Australia, with at least 40 mechanical thrombectomy procedures performed annually. Patients were enrolled if they were last known to be well within 6 to 24 hours earlier and had occlusion of the intracranial internal carotid artery or proximal middle cerebral artery with a mismatch between the severity of clinical deficit and the infarct volume. The mismatch criteria were defined according to age, stroke severity, occlusion site, time to treatment and type of stroke onset. Primary end points included mean score for disability and functional independence at 90 days.

The mean score on the utility-weight modified Rankin scale and rate of functional independence at 90 days were 5.5 and 49% in the thrombectomy group, compared to 3.4 and 13% in the control group. The rate of symptomatic intracranial haemorrhage and death at 90 days did not differ between the two groups.

The DEFUSE 3 trial was a multicentre, randomized, open labelled trial that included 38 centers in the United States. Patients were enrolled if they were last known to be well within 6 to 16 hours and had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral artery or internal carotid artery occlusion, an initial infarct size of less than 70ml and ratio of ischemic tissue to infarct volume of 1.8 or more were randomly assigned to thrombectomy plus standard medical therapy or standard medical therapy alone. The primary outcome was the ordinal score on the modified Rankin scale at 90 days.

The 90-days mortality rate was 14% in the endovascular therapy group compared to 26% in the medical therapy group. The absolute difference in functional independence between groups was 28% points, indicating a better 90 day functional outcomes compared to patients who had standard medical therapy alone. This mainly applies to patients who had evidence of salvageable tissue determined on the basis of a formula that incorporates early infarct size and the volume of hypoperfused tissue on perfusion imaging.

The incidence of symptomatic cerebral haemorrhage was not statistically different, yet numerically higher in the endovascular compared to the medical therapy group. Mortality was numerically lower in the endovascular therapy group. In between group differences of 24-hour infarct volume and growth after thrombectomy were not significant. Further, patients treated within six hours after stroke onset had favourable outcomes compared to other trials. This difference could be attributed to the favourable collateral circulation and slower infarct growth in patients recruited in the DEFUSE 3 trial.

Enrollment in the DAWN trial was stopped at 31 months, because the results of an interim analysis met the prespecified criterion for trial discontinuation, which was a predictive probability of superiority of thrombectomy of at least 95% for the first primary end point. Similarly, the DEFUSE 3 trial was terminated early for efficacy after 182 patients had undergone randomization, given the interim analysis results exceeded the prespecified efficacy boundary (P<0.0025). Both the DAWN and DEFUSE 3 trials used the same automated perfusion software (RAPID) to measure the volume of early infarct and hypoperfused volume.

Further advancements are anticipated at ISC19, with key questions on benefits beyond those time points and among the broader population of ischemic stroke survivors.

 

REFERENCES

  1. Albers GW, Goyal M, Jahan R, et al. Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME. Ann Neurol 2016. 79: 76-89.
  2. Wheeler HM, Mlynash M, Inoue M, et al. Early diffusion-weighted imaging and perfusion-weighted imaging lesion volumes forecast final infarct size in DEFUSE2. Stroke 2013. 44: 681
  3. Nogueira, Raul G., et al. “Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct.” New England Journal of Medicine 2018. 378:11-21.
  4. Albers, Gregory W., et al. “Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging.” New England Journal of Medicine 378: 708-718.
  5. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018. 39:46-99.