Dr. Albert Yoo is currently an interventional neuroradiologist, Medical Director and Director of Endovascular Fellowship & Research at the Texas Stroke Institute. He is an incredibly knowledgeable figure in the stroke world after his many years of research and training. He has participated in several major trials of intra-arterial stroke treatment, including MR CLEAN, THERAPY, MR RESCUE, DAWN, ARISE II, and GOLIATH trials. He is currently involved in the TESLA trial which he sheds more light on during this interview. 

How did you come to do what you do?

I stumbled upon it. I was always interested in Neurosciences. In medical school it was a very hard decision between becoming a neurologist, a neurosurgeon or a neuroradiologist. But during my neurosurgery orientation I saw the interventional suite and it was pretty soon after that I realised it was my path because it’s a nice intersection between imaging and therapy. 

After the dust settles, which stroke biomarker do you think will prevail? 

I am impressed with the simpler imaging approaches. A non-contrast CT and CT angiogram are very powerful tools. Part of their power is that they are available virtually everywhere and as we think about moving the field forward not only should we ensure that our imaging selection does not exclude patients who might benefit, we should keep an eye towards standardizing treatment decision making and delivery across all stroke centres.

Do you expect that collateral assessment like multiphase CTA will ever go out of fashion, and if so do you ever think that’s justified? 

Obviously collaterals are important because they sustain the brain tissue until the occlusion is recanalized. However, the clinical question is whether we need to be so fine in grading the strength of the collateral perfusion. I don’t think so. If you have a measure of the infarct size with ASPECTS and the infarct is not too big, then as far as collateral evaluation, all you need to exclude is the complete absence of collaterals. If there are no visible collaterals, patients will not do well regardless of rapid reperfusion as MR CLEAN and other studies have shown. Otherwise, it doesn’t matter whether the collaterals are intermediate or robust because in either case there is treatment benefit. I believe that traditional single-phase CTA is sufficient to say whether the collaterals are absent or at least partially present.

If there was a large increase in the use of MRI in acute stroke care across the world, due to increased availability for example, would you be happy with this and why?

Yes I think MRI is the most accurate imaging modality for determining the size of the infarct at presentation and to me that’s a key imaging finding to decide whether or not to pursue treatment, but as you are alluding to there needs to be improved availability of MRI as well as faster MRI workflow. With clinical experience, centers can have treatment times with MRI that are just as fast as with CT. This was shown in the recent GOLIATH trial that was conducted at Aarhus University hospital which uses MRI as their primary imaging approach. 

Do you think there is still a space for EVT patient selection within the 6-hour time window?

Within the 6-hour time window you need to have a very strong reason not to treat. That being said imaging is still necessary. You need a CT scan to rule out hemorrhage, and this same scan will tell you whether the ASPECTS is too low. You also need a CTA to evaluate the level of occlusion, and this scan will tell you whether the collaterals are absent. When it’s early you pretty much have to have evidence of zero collaterals or a very large stroke to not go to the angio suite. Fortunately, CT/CTA is very quick to perform. 

You are working on the TESLA trial, a very exciting project which could potentially have a huge impact for the field, what outcome are you hoping for and why? And what do you think the outcome will mean for the role of ASPECTS in stroke?

As an interventionist my hope is to provide evidence that expands the treatment population. We have very strong evidence in patients who have small infarcts and good collaterals. What is uncertain is whether patients with moderately large to very large infarcts will have a benefit with rapid reperfusion. I think there is a subset there which will benefit just based on the existing data, and probably many of these patients are not being treated currently.

Paradoxically, it will make ASPECTS more important because the trial will have established a threshold ASPECTS value that is critical for determining treatment response. At the same time, there would be a rationale to test whether more advanced imaging modalities can identify subgroups within the low ASPECTS population that might respond to treatment.

Recently there was a large Chinese trial that showed the non-inferiority of Direct EVT which was a pretty big deal, do you think this result will hold up in other trials? 

It’s important to remember that this trial only applies to the subset of patients who present directly to the endovascular centre where the time period over which IV tPA has a chance to work is very small, so it’s a result that is not surprising and I’m sure it will be confirmed in future trials. I think the key point to remember is that IV tPA is still useful in patients who are being transferred (drip-and-ship patients) for consideration of endovascular therapy. The real question is how does this trial result change practice for patients who present front door (direct admit to Endovascular Center)? There is a rationale based on cost to just forgo the tPA but cost issues aside there were still signals of benefit for tPA for early recanalisation obviating the need for intervention and overall reperfusion. In addition, there may be patient subgroups that might benefit from IV tPA that could not be detected with adequate power such as those in whom the occlusion cannot be reached. Also remember this is a moving target. It is likely that we will be using tenecteplase instead of alteplase soon. Do these results apply to tenecteplase? Probably not because we know that tenecteplase performs better than IV tPA for endovascular eligible patients. About 75% of subjects in EXTEND-IA TNK received intravenous thrombolysis at the endovascular centre.

EXTEND-IA TNK showed significant benefit of tenecteplase over IV tPA as a bridge to endovascular therapy. In more general stroke populations, there is strong evidence for the noninferiority of tenecteplase. Taken together, there is sufficient evidence to support using tenecteplase in place of alteplase. The fact that tenecteplase can be given as a single bolus dose further adds to its clinical utility.

What are your thoughts on nerinetide? Do you think it has the potential to be a game changer?

Neuroprotection as a bridge to intra-arterial reperfusion is a very attractive idea. This concept was tested in ESCAPE-NA1. Unfortunately, the primary analysis of this trial was neutral. The secondary finding that benefit was seen only in patients who did not receive bridging alteplase must be regarded as exploratory and requires confirmation. I believe that a subsequent trial is being planned in the IV tPA-ineligible population.

How do you think artificial intelligence benefits acute stroke care?

I think it works brilliantly as a screening tool to alert the team that there is high suspicion of LVO. The communication gets everyone coordinated in a parallel fashion. From the early experience at our center, it seems to really help with the workflow and speeds the time to intra-arterial treatment. Of course, the algorithms are not perfect but they don’t need to be. They just need to screen and capture most patients so that the LVO can be confirmed by the physicians. It is likely that AI will become increasingly involved in the actual selection of patients. We are seeing this in the realm of CT perfusion. In my opinion CT perfusion over selects — it selects patients away from treatment that should be treated and there is evidence to that effect. But I think AI algorithms as applied to imaging findings on noncontrast CT and also CTA collaterals will be very helpful. If you have a tool that has been validated to accurately tell you that the ASPECTS score is this or the CTA collaterals are not absent then it becomes a tool that can standardize treatment decision-making across centres. I think there are a lot of things that will continue to develop as these tools are utilised more and more.

Do you think covid-19 will have a positive or negative effect on progress of stroke research in the future?

I think it’s too early to say. Certainly, in the short-term there’s been a major impact. What we’ve seen in TESLA is that stroke volumes are down broadly. I think the likely reason is that patients aren’t seeking care as aggressively as they used to out of fear of coming to the hospital. But the crisis has highlighted opportunities to improve trial methodology in the future. As one example, we are finding that centers are now adopting electronic consent as a means to enroll patients whose LARs are not able to be in the hospital. This will help enrollment beyond the Covid-19 era.

Do you think it’s better to focus on complex stroke imaging techniques which will have a greater effect on the Western world or is it better to focus on more pragmatic techniques that would benefit more broadly including developing countries?

This is an issue that I think is so important. Many physicians in First World industrialized nations get very enamoured with advanced imaging technologies just because they are advanced and provide an “easy” answer. But I’ve studied the spectrum of acute stroke imaging over the past decade, and I find that the “easy” answer particularly as it relates to CT perfusion is often wrong and tells the physician to not treat when in fact the patient should be treated. The major misconception among physicians that use CTP is that perfusion can tell you whether the tissue is dead. This is obviously wrong. CTP forecasts tissue viability but just like the weather, the reality is often very different. Numerous studies have demonstrated this. 

The simple imaging techniques are powerful for multiple reasons. First, because noncontrast CT images ischemic edema which is a sequelae of neuronal death, it can tell you with a high degree of confidence whether the brain tissue is dead. Second, CTA is an efficient means of identifying the location of the occlusion and whether the collaterals are futile. Third, these tools are low cost and available to any hospital. I believe as a field that we should be rooting for these simple, pragmatic imaging approaches if we are going to impact care around the world, particularly in less developed countries. Clearly, doing a noncontrast CT and CTA is much more feasible than doing advanced imaging like CT perfusion or MRI. Committing resources towards developing AI algorithms that are based on the simple, pragmatic imaging approaches I think is very important as they will help to standardize treatment delivery worldwide.

 

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