DEFUSE 3

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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.

 

 
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A different kind of extended window for stroke treatment

Neal Parikh, MD

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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Of Mice And Men

Wei Ling Lau, MD

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

Neal Parikh, MD

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.