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The DAWN Trial: An Update on Thrombectomy for Stroke

Evie Marcolini, MD and Anand Swaminathan, MD FAAEM
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Nurses Edition Commentary

Kathy Garvin, RN and Lisa Chavez, RN
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EM:RAP 2018 June Written Summary 447 KB - PDF

The DAWN Trial: An Update on Thrombectomy for Stroke

Anand Swaminathan MD and Evie Marcolini MD

Take Home Points

  • Multiple studies have shown benefit to endovascular intervention in a highly selected cohort of stroke patients.
  • The DAWN study found benefit to endovascular intervention in patients with ICA or MCA stroke and a last known well time of 6 to 24 hours prior to presentation.
  • The average duration of symptoms was 13 hours.
  • This was an industry funded study using a single device.
  • It is unclear how this will impact EMS triage and transport to stroke centers.

 

  • In 1996, NIMS was published and stroke care was altered forever. The harms and benefits of alteplase were widely discussed. In 2014, the discussion shifted again and centered around endovascular therapy for stroke.
  • In 2014, the MR CLEAN trial was published and followed by multiple articles over the next 12 months.
    • Berkhemer, OA et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015 Jan 1;372(1):11-20. PMID: 25517348
      • The MR CLEAN trial showed that endovascular therapy improved outcome for patients with acute ischemic stroke. This was important because three studies were published in 2013 in the New England Journal of Medicine which did not show improvement in outcome with endovascular therapy.
    • After the MR CLEAN publication, REVASCAT, EXTEND-IA , SWIFT PRIME closed their books early and showed results with improved outcome. This was a defining moment for stroke neurology and identified endovascular intervention as an option in addition to
    • Part of the reason they were able to demonstrate benefit is that they selected the right patients. They used CT and MR perfusion imaging to select the best patients for endovascular therapy. They looked for patients with a small core infarct and a larger penumbra. Tissue in the penumbra may be salvaged. They also had a short time to groin puncture. In MR CLEAN, the study was supported by the government which led to good enrollment.
    • There were some limitations to these studies. With the exception of MR CLEAN, all of the other trials were stopped early which likely overestimated benefit. They used a very narrow group of patients as candidates. At some centers, only 1-2 patients a month were enrolled.
  • When the NIMS study was published, it led to the creation of stroke centers and ambulances bypassed hospitals to go to stroke centers. What has been the impact of these endovascular studies on overall care of strokes? Now that we can show that endovascular therapy works, every hospital with the capability wants to be a comprehensive stroke center because they will catch these patients. This impacts how EMS triages patients and where they go for care. However, it may be difficult to justify maintaining an interventional team if only 1-2 of these procedures are performed every month. We may see indication creep.
  • Nogueira, RG et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. DOI: 10.1056/NEJMoa1706442
    • This study used either diffusion weighted imaging or CT perfusion to assess patients with delayed presentation to determine who would be eligible for intervention.
    • This addresses the problem of wake-up strokes. Guidelines currently recommend a consideration of endovascular therapy for patients with anterior large vessel obstruction within 6 hours of their last seen normal time.
    • Now that we can determine the presence of viable tissue, can we extend the time period even farther?
    • This study looked at patients 6 to 24 hours out. The trial was stopped early as they found benefit in the treatment arm over the control arm. This trial looked at patients with ICA and MCA stroke only. The patients had to have a mismatch that was predefined as to volume.
    • They did find a benefit.
    • On average, patients enrolled in the study were 13 hours after the last seen normal time.
    • There are some limitations to the study.
      • It was industry funded and only used the Trevo device. Many of the authors are on their payroll.
      • The authors used the utility-weighted modified Rankin scale instead of the traditional modified Rankin scale. The utility-weighted scale gives more weight to good outcomes than bad outcomes. This may skew the results toward the intervention and makes it difficult to compare results from this study to others.
    • The bottom-line: the DAWN group found that using the endovascular intervention resulted in better outcomes up to 24 hours after symptom onset. This is a shift in the paradigm that time=brain to a perspective that patients may still have salvageable brain tissue a long time after symptom onset.
    • Still, in these studies, the earlier we get to these patients, the better they do.
    • This study was in large vessel strokes.
  • Should we be doing diffusion weighted imaging and CT angiograms in every stroke patient before considering treatment? This would be unreasonable. We need to be smart about this. Look at the patient’s function and goals to determine if it makes sense to do advanced imaging. Marcolini would not do DWI or CT perfusion on every case. We have to be careful of indication creep.
  • We need to be smart regarding administration of tPA as well. Giving alteplase to patients later on in their disease course has increased risk. We know that giving it earlier decreases the risk of bleed.
  • If you suspect a large vessel stroke, should you obtain the perfusion study more rapidly to facilitate intervention? If the patient presents with clinical signs of a large vessel occlusion anterior stroke, Marcolini has her team activated and they often receive a CT and CTA prior to transport for intervention. The CT perfusion or DWI studies are performed in patients where they are unsure if there is a large ischemic penumbra with a small infarct. The imaging modalities need to be tailored to the patient in front of you.
  • It is important for us to know the area of distribution in considering eligibility of intervention. For those at smaller hospitals, you need to be careful in determining which patients are eligible for intervention and need transfer to a center for additional procedures.
  • Does this change how we triage patients in the EMS setting? This raises questions that have yet to be answered but are under investigation. Where should EMS bring these patients? If EMS is closer to a hospital without endovascular capability, should they stop there for tPA or divert to a comprehensive stroke center? This is an issue in rural areas. How can EMS differentiate between a large vessel occlusion and all other strokes encountered? New stroke scales are in development to help EMS in this process.
  • Should we still be giving systemic alteplase? In cardiology, they don’t give systemic alteplase if they are close to a center where they can receive PCI. If they are more than 90 minutes away, they are given alteplase and transported for PCI. Is this where stroke management is heading?  There are studies in progress examining this question.  Is it better to give endovascular therapy with tPA or go directly to a comprehensive stroke center?

 Recent Related Material

EMA 2018 March - Abstract 13 -Thrombectomy 6-24 Hrs After Stroke Deficit & Infarct Mismatch

Kevin G. -

the written summary says: " We need to be smart regarding administration of tPA as well.
Giving alteplase to patients later on in their disease course has
increased risk. We know that giving it earlier decreases the risk
of bleed." what it should it should say is "... decreases the risk of bleed compared to giving it later."

this is what you mean, but of course the risk of bleed is increased by a lesser amount, not decreased.

Evie M., M.D. -

Kevin, that was indeed implied as part of the context, but thanks for adding clarification.

Mark M., MD -

It is important to emphasize what little applicability the DAWN trial has for most ERs in the US. It took almost 3 years from 26 very large centers (doing more than 40 thrombectomies annually) across 3 countries to find 207 patients whose NIHSS >10 with very strict criteria found on CT perfusion requiring specialized software.

The only way the DAWN trial has any applicability is if a lot of EDs are not just guilty of "indication creep" but rather choose to "blindly run" their programs without following many of the very specific conditions required in the DAWN trial.

Evie M., M.D. -

Mark,
You make a good point in that the indication for thrombectomy is specific, and will not be applicable to many of our patients with stroke. However, we will not find those patients if we are not screening patients with stroke. Opening up the time window for stroke evaluation makes it possible that these patients will be found and treated. Let's not confuse "indication creep" with proper application of stroke assessment tools. The prehospital providers and emergency physicians are the front line for finding these patients - if we are not opening the time window, patients who may have qualified will lose the opportunity for thrombectomy. Indication creep is a function of performing the intervention on an inappropriate patient - has less to do with the assessment and evaluation of the stroke patient.

Mike J., M.D. -

Couple things,

At this point we have no useful tools other than CTA to determine LVO stroke. The literature is rife with scoring tools, but none have adequate sensitivity/specificity to find these strokes. At my shop, we go immediately to CT/CTA from EMS for patients with a positive Cincinnati stroke scale, within the appropriate time frame, (for us this is <6hrs for Anterior Circ <12 for posterior). We have not moved to CT perfusion as of yet. Your statement that CTA/CTP for all may be applicable in larger centers with rapid access to neurointervention. In rural areas it may be that it is MORE Important to do CTA/CTP sooner, to facilitate transfer to a neurointerventional facility. In my world this can take 5-6 hours and thus, earlier dx=earlier tx.

Ian L., Dr -

There are possible advances in the efficacy and safety of Thrombolytics in large vessel occlusion with the Extend IT trial published from Australia finding Tenecteplase IV superior to Ateleplase in a trial of 200 plus patients with middle cerebral artery and other large artery strokes .
With research better Thrombolytics safer and efficacious ought be discovered that with better endovascular therapy ought improve treatment of stroke .
For TIA large artery occlusion can be sought and maximal medical dietary (vegan low salt) graded exercise and stress reduction therapy offered .

KB -

I am writing for a clarification.

Does this new study indicate we should not give tpa if the patient is a potential transfer for endovascular approach?

My particular hospital has a goal of tpa in 270 minutes and this is often a narrow window to obtain.

Also, there are hurdles to achieving a timely cta at my hospital. Should I only call about an evaluation for endovascular treatment if i have both the ct and cta?

Thank you for the clarification.

Anand S., M.D. -

KB
Great questions
In the majority of studies, systemic tPA given to all eligible patients meaning if they presented < 4.5 hours after onset, they got lytics AND neurointerventional therapy. In the studies looking at longer time to therapy (DAMN, DEFUSE 3), if patients presented > 4.5, they were either treated with neurointerventional or standard treatment alone.
While I'm not much of a fan of tPA in stroke overall, current guidelines support using it in patients presenting at < 4.5 hours and then considering further treatment (ie endovascular/neurointerventional).
If CTA is difficult to obtain, you should probably be prepared to transfer patients with suspected LVO (large vessel occlusion) prior to obtaining CTA. From a resource standpoint, this means that it's important to be able to delineate clinically who could have an LVO. We don't have ideal ways to do this. Most of these studies looked at NIHSS > 6 as a trigger to consider LVO though there are other approaches being investigated.
Bottom line, if you are not a stroke center and you have a patient in whom you suspect LVO, you should be transferring to a stroke center.
Of course, I say all this understanding that this will lead to increased transfers and resource utilization with small gains as the group of patients for endovascular therapy is small.

KB -

Thank you!

Ian L., Dr -

Intensive LifeSyle Changes for Reversal of Coronary Heart Disease : a paper authored by Dean Ornish et al in JAMA 1998; 280:2001-2007 :
Objectives :To determine feasibility of patients to sustain intensive lifestyle changes for a total of 5 years (without lipid lowering drugs ) on coronary heart disease .
They had twenty patients in an intensive group and twenty in a usual care for the early 1990s standards of care .
Angiograms to measure Stenosis at baseline one year and 5 years .
Conclusion : " More regression of coronary atherosclerosis occurred after 5 years than one year in the experimental group with 10% fat Vegetarian diet moderate aerobic exercise stress management training smoking cessarption and group psycholosocial support reduction training
Also half the cardiovascular events in the high intensity healthy lifestyle experimental group than usual care .
So in high risk for ischaemic stroke patients a repeat trial with the low salt plant based diet graded exercise stress reduction psychosocial support plus maximal medical therapy with measurement by MRA angiogram for Large vessel stenosis Monitor of atrial fibrillation events and carotid artery narrowing and Adverse Cerebrovascular Events for High Risk patients from aged 60 for one to five years ought add gravity to recommendations to impact motivation and guideline recommendation .

Jonathan G. -

question for Dr Evie,

Can you give us an example of how/when you fit CT Perfusion into the imaging algorithm?

Thanks

Evie M., M.D. -

Great question, and it comes up a lot. Briefly, here's how I think about it:
Pt comes in as stroke alert - exam and get noncon CT.
If there's a bleed - do what you need to do and admit (reverse anticoag and lower BP prn)
If no bleed - consider tPA within the guidelines
also ask yourself: is the exam consistent with large vessel occlusion (LVO)?
If so - get a CTA and CTP if you have the capability and are in the time window (this will give you information re: penumbra tissue that's at risk vs core tissue that's already dead and not salvageable. if large penumbra and small core = great candidate for thrombectomy if within the window, which now is 24 hours depending on the case. if large core and small penumbra = poor candidate because of higher risk for reperfusion hemorrhage)
If not - call neurology and your interventionalist to discuss whether they would consider thrombectomy and proceed from there with agreed upon imaging.

Now I can hear some people screaming because if not LVO, then considering thrombectomy is outside the indication! Yes it is, but if your patient has a basilar artery occlusion, you are only going to help and can't make the outcome any worse. Think about that - its worth a discussion.

Swami and Salim have put together a more detailed graphic of this and explanation with references at REBELEM:
http://rebelem.com/stroke-workflow-in-2018/

Jonathan G. -

Thanks so much Dr Marcolini!

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