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A different kind of extended window for stroke treatment

To fanfare at International Stroke Conference 2018, the results of the DEFUSE 31 extended window thrombectomy study were announced. The American Heart Association/American Stroke Association acute ischemic stroke guidelines were immediately updated to reflect the practice-changing findings. 

A few months later, Lee Schwamm and colleagues published their findings from MR WITNESS.2 In this study, patients with unwitnessed stroke onset between 4.5 and 24 hours underwent advanced magnetic resonance imaging to identify those individuals with radiographic evidence of hyperacute stroke. Based on prior work, it was known that evolution of imaging characteristic with respect to the fluid-attenuated inversion recovery (FLAIR) sequence correlates with time from onset. Patients who met imaging criteria based on the mismatch between FLAIR signal change and diffusion restriction were given tPA.

The researchers enrolled 80 individuals at multiple centers. Patients were treated at a median of 11 hours from their last known well. The rates of adverse events were very low and within the range of adverse event rates observed in prior stroke treatment trials. 

The standard stroke treatment paradigm allows patients to be treated within 4.5 hours of symptom onset. In general, patients treated beyond this window are at greater risk of brain hemorrhage and poor outcomes. The results of this Phase 2a study challenge the 4.5 hour time window. Like DEFUSE 3, this study uses advanced imaging to personalize acute stroke treatment. A frequent reason for patients to not receive tPA for stroke treatment has been that patients often present to hospitals too late. Expanding the time window for non-large vessel occlusion strokes, which are the vast majority of strokes but nonetheless disabling, has great public health implications. With the rest of the stroke community, I look forward to results of an efficacy trial.

References

  1. Albers GW, Marks MP, Kemp SK, Christensen S, Tsai JP, Santiago O, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM 2018; 378:708-718.
  2. Schwamm LH, Wu O, Song SS, Ford AL, Hsia AW, Muzikansky A, Betensky RA, et al. Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results. Ann Neurol 2018 Apr 24 [Epub ahead of print].

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @NealSParikhMD and contributes to Blogging Stroke as a blogger.

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Parsing The Updated 2018 Acute Ischemic Stroke Guidelines: Smoking Cessation

The 2018 International Stroke Conference was headlined by the practice-changing results of DEFUSE 3 and related acute stroke care guideline updates. Having returned to our institutions, neurologists are parsing the updated 2018 acute ischemic stroke guidelines1 and wondering how best to operationalize the latest data.
 
Overshadowed by updated guidelines regarding the extended window and buried among changes regarding the utility of indiscriminate use of routine diagnostic testing, was a change regarding smoking cessation.
 
While the guidelines committee did not find any randomized trials of pharmacological smoking cessation aides specifically for stroke patients, they cite a randomized trial in acute coronary patients:2 patients randomized to receive a pharmacological cessation aide had a significant improvement in abstinence. In terms of observational data, a recent study found that patients with stroke who quit smoking had a reduced rate of cardiovascular disease and mortality over 5 years.3 Based partially on such evidence, the updated guidelines provide a IIb recommendation that “for smokers with an acute ischemic stroke, in-hospital initiation of varenicline might be considered”.1
 
A class I recommendation to “strongly advise every patient with acute ischemic stroke who has smoked in the past year to quit” remains in place and is buttressed with a IIb option to consider “interventions that incorporate both pharmacotherapy and behavioral support”.1
 
While Get With the Guidelines-Stroke has seen a substantial improvement in “appropriate” smoking cessation interventions at the time of hospital discharge,4 a distinction between counselling and pharmacotherapy was not made. Therefore, whether effective smoking cessation interventions are being initiated is unknown.
 
Whereas the extended window guidelines influence care for a small group of acute stroke patients, the smoking cessation guidelines apply to every single acute stroke and TIA patient who is an active smoker. Neurologists, particularly stroke neurologists and hospitalists, should familiarize themselves with the updated guidelines, the relevant data, and pharmacological interventions. 
 
References:

  1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 Guidelines for the Early Management of Patients with Acute Ischemic Stroke. Stroke 2018. DOI: 10.1161/STR.0000000000000158.
  2. Eisenberg MJ, Windle SB, Roy N, Old W, Grondin FR, Bata I, et al. Varenicline for Smoking Cessation in Hospitalized Patients with Acute Coronary Syndrome. Circulation. 2016:133;21-30.
  3. Epstein KA, Viscoli CM, Spence JD, Young LH, Inzucchi SE, Gorman M, et al. Smoking cessation and outcome after ischemic stroke or TIA. Neurology. 2017:89;1723-1729. 
  4. Ormseth CH, Sheth KN, Saver JL, Fonarow GC, Schwamm LH. The American Heart Association’s Get With the Guidelines (GWTG)-Stroke development and impact on stroke care. Stroke and Vascular Neurology 2017;2:doi:10.1136/svn-2017-000092

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @NealSParikhMD and contributes to Blogging Stroke as a blogger.

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An Early Career Perspective On International Stroke Conference 2018

I have come to look forward to the annual International Stroke Conference each year. Due to the largess of my mentors and support of my residency program, I have had the good fortune of attending the conference each year since my third year of residency. As a third-year resident, I had decided to pursue fellowship training in vascular neurology, and attending the conference amplified my enthusiasm for the field and inspired me to contribute to stroke science. This fueled my passion for stroke research, which ultimately led me to my current fellowship in stroke and neuro-epidemiology at Columbia University. 

First, I want to advocate for resident-level participation in the conference. Exposure to late-breaking science, hearing from leaders in the field, and socializing with members of your institution’s stroke division – these are invaluable opportunities. Now, returning for a third time, I have begun to feel a member of the community. Early attendance may inspire residents to pursue research and provide them with a sense of the scope of current investigation and the priorities of the field. 

This years, as a fellow, I attended the conference with more specific goals. I outlined research areas that I am interested in and scrutinized the program in advance to identify key talks and poster presentations. This allowed me to identify opportunities for future study and to meet individuals to collaborate with. Equally importantly, I had a reunion with friends and classmates from medical school and residency. Speaking with friends 1-3 years ahead in their careers is particularly informative because they provide good guidance. Last, the release of game-changing data created an electric atmosphere that motivated me and surely other early career attendees as well. 

Some of my early career colleagues have reported avoiding the conference when not presenting data. For the reasons outlined above, I encourage residents interested in stroke and stroke fellows to attend and earnestly participate regardless of whether they have data to present. I also encourage program directors and chief residents to encourage resident participation and to make schedule adjustments to permit attendance. Medical students should be similarly included. 

I look forward to attending the conference in Honolulu next year! 

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @NealSParikhMD and contributes to Blogging Stroke as a blogger.

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Of Mice And Men

I have run into zealous naysayers from both camps. From a clinical researcher: “Human trials are the ultimate, difficult to run, very different from animal studies which may have no clinical relevance.” From a bench scientist: “Epidemiologic studies are trash in, trash out. Well designed animal studies are real science that will advance health.”
 
There’s an element of truth to both sides. Patient trials are complex and costly, liable to inter-subject variation (diabetic nephropathy is notorious), lag-time bias, selection bias, and in the case of non-blinded trials there is potential treatment effect due to patient preference (see blog by #AHAEarlyCareerBlogger @LeonieKlompstra). Thus truly successful RCTs are uncommon. At #ISC18, it was remarkable to hear the findings from the DEFUSE 3 trial which showed that in select patients with suitable brain imaging profile, thrombectomy for ischemic stroke beyond the traditional 6-hour window (a 6-16 hour timeframe was specified) conferred improved functional and mortality outcomes compared to medical therapy alone. The trial was terminated early due to efficacy superiority, with a staggering number needed to treat (NNT) of two. The NNT declaration incited spontaneous cheering from the audience – uncommon at scientific meetings where we politely applaud at the end of talks – because it is rare to see such robust positive RCT outcomes.
 
For identifying at-risk cohorts or new targets for preventative healthcare, epidemiology is essential. The inherent limitation here is that correlation is not causality. With a large database (thousands of patients) sophisticated tools for multivariate and time-varying adjustments can result in a dizzying array of associations that have to be carefully interpreted. (Simple illustrative case: positive correlation between higher number of firemen in areas with more fires. The firemen didn’t cause the fires. I hope.)
 
Animal studies have their niche in that they allow for evaluation of disease or drug pathways in a living model when a human study is not feasible. Animal studies are fraught with their own set of flaws, the most prominent being translational failure due to the model not adequately replicating human disease. Dr. Jun Chen gave the Thomas Willis Lecture at #ISC18 and pointed out the importance of streamlining integrative methods in stroke models to make them clinically relevant. The majority of animal trials will not translate into approved clinical interventions, but still serve to advance our understanding of pathophysiology and drug effects. Some major discoveries (including insulin, erythropoietin, klotho, aspirin, and numerous anti-cancer therapies) would not have been possible without judicious animal research.
 
Advancements in patient care would not be possible without both basic science and patient trials (some impressive folks out there wear both hats!). Bench and clinical research each have their strengths and limitations and deserve to be critically interpreted, while prioritizing exchange of ideas and constructive feedback to collectively move medicine forward.
 
Wei Ling Lau Headshot
Wei Ling Lau, MD is Assistant Professor in Nephrology at University of California-Irvine, where she studies vascular calcification and brain microbleeds in chronic kidney disease. She is currently funded by an AHA Innovative Research Grant, and has been a speaker for CardioRenal University and the American Society of Nephrology.

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DEFUSE 3 Definitively Expands The Endovascular Therapy Window

Writing from the 2018 International Stroke Conference, it is difficult to report on anything other than the game-changing results of DEFUSE 3. After years of clinical suspicion that endovascular therapy works, definitive evidence establishing the role of endovascular therapy in acute stroke care was first presented at the International Stroke Conference in 2015. Since then, there has been great interest in maximizing the yield of this highly effective therapy. Extending the original window of 0-8 hours has been of particular interest.

Imagine being called the emergency department to find a patient who woke up severely disabled by their stroke only to determine that the last time they were seen well was at dinner the night before. Unable to definitively conclude that their stroke began within the last 6-8 hours, you are unable to provide any therapy beyond standard supportive medical care. The patient worsens while in the hospital and is discharged to a nursing home or subacute rehabilitation facility. 

This is not an uncommon situation. So, learning today that the window for intervention can be extended safely and effectively to 16 hours was moving. The DEFUSE 3 data showed that properly selected patients stand to benefit immensely from endovascular therapy, and these data will arm neurologists with yet another highly impactful intervention to offer patients. By confirming the results of the DAWN trial, which extended the window to a full 24 hours, DEFUSE 3 settles the issue. 

Now, stroke systems of care need to quickly adapt to this new reality so that we can help patients benefit from the remarkable progress of stroke treatment science.
 
Reference:

  1. Nogueira, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. NEJM. 2018; 378:11-21.
    Albers et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM. 2018. Ahead of print.

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @NealSParikhMD and contributes to Blogging Stroke as a blogger.

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Stroke Advances In 2017: An Overview, Reflections, And A Call To Action

2017 gave us numerous dramatic advances in stroke neurology. We were treated to compelling data regarding the favorability of patent foramen ovale closure in well-selected individuals with cryptogenic stroke.1,2,3 Endovascular therapy matured with the extension of the treatment time window.4 We even saw promising rehabilitation data regarding surgical nerve transfer for chronic spastic arm paralysis.5 Conversely, some widely used therapies such as head positioning6 and oxygen supplementation7 were shown to be ineffective. The list of figurative leaps goes on.
 
As an early career neurologist in a vascular neurology fellowship, I found myself reflecting on the year’s advances, in part to find my place in the field. While thoroughly inspired by the major advances of 2017, I couldn’t help but dwell on the findings of a secondary analysis of the Insulin Resistance Intervention After Stroke (IRIS) trial.
 
The IRIS trial randomized non-diabetic patients with stroke or TIA to pioglitazone or placebo and followed them for several cardiovascular outcomes.8 The primary analysis was published in 2016; patients randomized to pioglitazone had a lower risk of recurrent stroke or heart attack.
 
In a secondary analysis published in Neurology in 2017, Katherine Epstein and colleagues evaluated the association of smoking cessation and recurrent stroke, myocardial infarction, and death.9 In an observational design, they followed individuals who were smoking at the time of their index stroke and quit, and compared them to individuals who did not quit. The 5-year risk of stroke, MI, or death was 16% in quitters versus 23% in non-quitters (adjusted hazard ratio 0.66). Quitters had half the risk of death compared to non-quitters.
 
Granted, this was observational data. Individuals who were motivated to quit smoking may have made other healthy decisions. And, these results are not ground breaking either – we know that smoking cessation is “the most important thing one can do for one’s health” (as we are taught to tell patients in medical school).
 
Regardless, the results are memorable. While advances in acute stroke care, surgical interventions, and novel pharmacotherapies are a testament to scientific ingenuity, we must not neglect the low-hanging fruit. Are neurologists trained to effectively aide in smoking cessation? What are the best tools for this purpose? Are such services adequately incentivized? Some argue that advances in stroke systems of care may now yield more public health gains than scientific advances. If we accept this notion, we must acknowledge that it does not apply exclusively to the acute stroke treatment arena.
 
Included in the AHA/ASA’s Life’s Simple 7 paradigm, and a focus of the FDA’s newest public education campaign entitled “Every Try Counts”,10 smoking cessation deserves our fullest attention. To support these programs and to empower our patients to quit, we must identify and incorporate the best tools available into our practice.  

References

  1. Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al. Patent Foramen Ovale Closure or Anticoagulation vs Antiplatelets after Stroke. NEJM. 2017:377;1011-1021.
  2. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, et al. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. NEJM. 2017:377;1022-1032.
  3. Søndergaard LKasner SERhodes JFAndersen GIversen HKNielsen-Kudsk JE, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. NEJM. 2017:377;1033-1042.
  4. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 Hours After Stroke with a Mismatch between Deficit and Infarct. NEJM. 2018:378;11-21.
  5. Zheng MX, Hua XY, Feng JT, Li T, Lu YC, Shen YD, et al.
  6. Anderson CS, Arima H, Lavados P, Billot L, Hacket ML, Olavarria VV, et al. Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke. NEJM. 2017:376;2437-2447.
  7. Roffe C, Nevatte T, Sim J, Bishop J, Ives N, Ferdinand P, et al. Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial. JAMA. 2017:318;1125-1135.
  8. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. NEJM. 2016:374;1321-31.
  9. Epstein KA, Viscoli CM, Spence JD, Young LH, Inzucchi SE, Gorman M, et al. Smoking cessation and outcome after ischemic stroke or TIA. Neurology. 2017:89;1723-1729.
  10. Every Try Counts Campaign. Food and Drug Administration. https://www.fda.gov/tobaccoproducts/publichealtheducation/publiceducationcampaigns/everytrycountscampaign/default.htm

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @ NealSParikhMD and contributes to Blogging Stroke as a blogger.