First pass effect...always the goal!

September 2018

E D U C AT I O N A L S U P P L E M E N T

First pass effect‌ always the goal!

This educational supplement has been sponsored by CERENOVUS

neuronewsinternational.com

First pass effect...always the goal!

In this supplement:

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Introduction

First pass effect… always the goal!

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How understanding clot science impacts successful reperfusion in the first pass— ARISE II Osama Zaidat

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The effect of successful reperfusion in the first pass, a real-world setting: Karolinska University Hospital Patrick Brouwer

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Trapping clot with EMBOTRAP® device—our experience Tommy Andersson

Introduction

Ischaemic stroke is as quick as it is destructive; minutes, even seconds can be the difference between patients returning to a healthy life or a hindered one. The pressure is on physicians to act not only quickly but effectively. Every second and every action counts. Findings from the ARISE II and Karolinska University Hospital studies demonstrate how lives are restored through successful reperfusion in the first pass in a real-world setting.

Should we now be looking to consistent successful reperfusion in the first pass as the future of stroke care?

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Novel distal emboli protection technology: The EMBOTRAP® II device Matthew Gounis and Juyu Chueh Is ease of deliverability key to revascularisation? Hormozd Bozorghchami

About Cerenovus CERENOVUS, part of the Johnson & Johnson Medical Devices Companies, is a global leader in neurovascular care. Our commitment to changing the trajectory of stroke is inspired by our long heritage and dedication to helping physicians protect people from a lifetime of hardship. CERENOVUS offers a broad portfolio of devices used in the endovascular treatment of haemorrhagic and ischaemic stroke. For further information, please visit https://www.jnjmedicaldevices.com 2

All rights reserved. Published by BIBA Publishing, London T:+44 (0)207736 8788, publishing@bibamedical.com. The opinions expressed in this supplement are solely those of CERENOVUS and the physicians and may not reflect the views of NeuroNews.

Clot types vary by composition, consistency and clot size. The traditional classification of red, (red blood cell rich) and white clot (platelet and fibrin rich) is based on pathology. On stroke triage imaging they are classified based on density and size such as long and hyper-dense clot versus short and iso-dense clot on computerised tomography (CT) scan while on Magnetic resonance imaging (MRI) scan they are classified by low intensity susceptibility vessel sign (SVS) or blooming artefact sign.

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his may be an oversimplification of clot types,” explains Osama Zaidat, principal investigator of the Analysis of Revascularization in Ischaemic Stroke with EMBOTRAP® Device (ARISE II) study and Neuroscience and Stroke Director at Mercy Health St Vincent, Toledo, USA. Successful reperfusion may vary

Hybrid OR

First pass effect...always the goal!

How understanding clot science impacts successful reperfusion in the first pass—ARISE II

according to clot type; hyper-dense clots have been shown to be more amenable to successful reperfusion and mechanical thrombectomy.

Clot science

Significant emphasis has been placed on clot and thrombus composition research in the past few years to overcome the

Recently, clot research has been the focus of endovascular therapy researchers to try and identify the predictors of failure to achieve recanalisation based on clot type

Osama Zaidat

recalcitrant clot resistance to mechanical thrombectomy.

“Recently, clot research has been the focus of endovascular therapy researchers to try and identify the predictors of failure to achieve recanalisation based on clot type,” says Zaidat. “This has yielded

Reperfusion outcomes in the ARISE II study

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First pass effect...always the goal!

Achieving the highest rate of possible recanalisation success from the first attempt or pass should be the goal. excellent information, including that longer clots are more likely to be resistant to thrombolysis and may need devices that are specifically designed to retrieve them in one attempt.”

There is also an increasing interest in correlating the histopathological findings of clots retrieved during mechanical thrombectomy with complete success rate of recanalisation.

“Understanding clot types and composition would help guide the thrombectomy devices design and iteration to achieve the best reperfusion results.

Clot research is the basic foundation for the US FDA approved EMBOTRAP ® II revascularisation device. The EMBOTRAP® II device was designed and refined based on its strong foundation in clot science research to achieve a thrombectomy device that has the balance to address different types of clot with best potential likelihood of reperfusion success,” says Zaidat.

First pass reperfusion

Several studies have shown that repeated attempts (passes) leads to endothelial vessel injury and irritation with subsequent platelet activation, increased rate of complication, and prolonged procedure time. This is less than desirable in a procedure where every additional second may be the difference between a patient living a full, independent life, or a life of dependency.

“When we evaluated the influence of first pass effect on clinical efficacy and safety, we demonstrated the increased efficacy and improved safety in the group of patients who achieved substantial and excellent reperfusion from the first pass.1 Hence, achieving the highest rate of possible

Clinical outcomes at 90 days in the ARISE II study

recanalisation success from the first attempt or pass should be the goal,” says Zaidat The clot science research provides an understanding of what the clot types are and features that would render a given clot amenable to first pass versus those recalcitrant clot that require multiple passes and how future devices can be designed to tackle this type of clot or whether there are clots that require a combination of different types of thrombectomy devices (such as aspiration plus retrieval).

Furthermore, if there is acceptable clinical data on clot type, length and hardness and imaging surrogates with correlation to different device efficacy, a neurointerventionist will be able to pick the right device type or stent-retrieval size (diameter and length and design) to retrieve different clot type.

The EMBOTRAP® II device was developed using knowledge from clot science research. The device has different segments to engage with the clot and increase the likelihood of clot removal

success. Furthermore, the distal segment of the EMBOTRAP® II device is designed to capture any fragmentation that may happen while the clot is retrieved. Finally, the inner channel allows for temporary bypass and blood flow to the ischaemic stroke tissue.

ARISE II

The ARISE II study is the first study to evaluate the rate of reperfusion after each device pass using an independent imaging core lab. The results have demonstrated substantial reperfusion to mTICI 2b in greater than 50% of the patients or one out of two cases following a single EMBOTRAP® II device pass, and in 40% of the cases with an excellent or near complete reperfusion was achieved or in 2/5 cases following a single device attempt.

The use of the EMBOTRAP® II device led to a meaningful independent functional neurological outcome in 67% of the patients or in 2/3 cases at 90 days post stroke.

References 1. (Zaidat et al, First Pass Effect, New Measure for Thrombectomy Devices, Stroke, 2018).

Clots vary significantly

Erythrocyte-rich 4

Fibrin-dominant

It has been known for some time that stroke outcomes improve if first pass reperfusion is achieved. Patrick Brouwer (senior consultant Neurointerventionalist, Karolinska University Hospital, Stockholm, Sweden) talks about his centre’s experience of using the EMBOTRAP® II device and how trial results translate to the real world.

Why are real-world experiences so important?

As there is no ‘inclusion criterium’ for treatment in our centre, except the opinion of the treating physician, we are not aiming for the best possible overall result but the best possible individual result. If you only treat patients that have a high probability to end up with an mRS of 0-2, you have a different aim than when you want to have a patient improve from a potential outcome of mRS 5-6 to mRS3. It is important to understand how products perform in a real life setting to help us improve overall outcomes and push the boundaries of stroke treatment.

How do you think knowing the clot type will influence your successful reperfusion at Karolinska University Hospital?

We aim to keep the time from groin puncture to full recanalisation under half an hour. If the procedure takes more time it is clear that something odd is going on. This can be due to either patient anatomy or the composition of the clot that we are trying to remove. If we can predict the type of clot we can tailor our approach to this. With the EMBOTRAP ® II device we already retrieve the clot in 85% of cases but it seems that fibrin clots are more resilient. If we know

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Has using the EMBOTRAP® II device impacted on your and the Karolinska University Hospital’s treatment strategy?

The population described in randomised trials does not match the patients we encounter in the real-world situation and the conclusions drawn from these randomised studies will have to be evaluated and validated for the real-world population. This means that patients outside of the age groups, typically 18-80 years old, will be included as well. The same holds for the patients that have tandem occlusions, which are excluded from many trials, and patients with a pre-morbid mRS of 2 or more. Furthermore, patients with posterior fossa strokes or more distally located clots are not included in the trials and are part of the real-world population.

How does this differ from a trial setting?

more difficult. The care after the procedure, e.g. the antiplatelet regime after carotid stenting and rehabilitation, is also very important to the overall outcome of the patient, thrombectomy is only part of the solution.

First pass effect...always the goal!

The effect of successful reperfusion in the first pass in a real-world setting: Karolinska University Hospital

Patrick Brouwer

that the clot is of fibrin composition, we understand the difficulties we face during the procedure.

What effect does this have on patient recovery?

Patient recovery is strongly correlated to the recanalisation rate. If you get to a TICI 3 within 15 minutes the likeliness of having a better outcome is higher. This does not mean, however, that patients with swift recanalisation always do well. Sometimes the damage is already done. Conversely, it does not mean that a slow recanalisation will not lead to a treatment benefit. When we focus on thrombectomy and the speed of the procedure, we tend to forget the effect that other parameters can have.

Getting the clot out is no longer a problem.

Excluding patients that will not benefit from treatment (futile recanalisation) is

Using the EMBOTRAP ® II device makes me less concerned with doing thrombectomy procedures as I know it is going to work. If it doesn’t, none of the other devices will work in my hands, that has been clear so far. Up until now we knew that we would not be able to remove all the clots, as the clots are too different in consistency. However, with the progress that the engineers have made and as our understanding of clots grows, I know that we will soon be able to identify the types of clot before the procedure and tailor our thrombectomy procedure to be even more effective.

How did the outcomes of using the EMBOTRAP® II device differ in a real-world setting compared to a trial setting?

In our series, performed by physicians of various levels of training and experience, and also including each of our learning curves, we had very nice results. In fact, we received better results than some of the trials, which was surprising. Even the pooled data, such as the HERMES study, did not get to the same outcome that we reached. We included all patients who we thought might benefit from intra-arterial treatment without any predefined exclusion and inclusion criteria, and we had the radiological results core-lab assessed and the clinical data independently judged.

This makes the EMBOTRAP® II results robust.

Using the EMBOTRAP ® II device makes me less concerned with doing thrombectomy procedures as, I know it is going to work.

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First pass effect...always the goal!

Trapping clot with the EMBOTRAP® device—our experience Tommy Andersson (from Karolinska University Hospital, Stockholm, Sweden and AZ Groeninge, Kortrijk, Belgium) began using the EMBOTRAP® device in animal models and was involved in the first-in man (FIM) study. Here, he writes about why he uses the EMBOTRAP® II device.

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e, at Karolinska, were approached early on by Neuravi (now known as CERENOVUS) to test the EMBOTRAP ® device in our animal lab and help them to further develop and refine the retriever. This collaboration continued thereafter and we were also involved in the FIM-study starting in early 2013. The EMBOTRAP ® device quickly became our preferred choice of retriever and we recently presented our first 200 cases with the device, a kind of “real-life experience”.

Being able to remove the clot in a swift and efficient procedure is probably one of the most important parts in achieving a good clinical outcome for the patient.

The EMBOTRAP ® device, in conjunction with a balloon guide catheter, has in our experience proven to fulfil our expectations in that respect. Using it in this way, you are mostly able to have full or almost full reperfusion after one or two passes with the device. This “first-pass-effect” is, as has been recently pointed out, very important.

DISTAL, CLOSED END MESH

In my experience I would, however, say that being able to remove the clot in two passes is a desirable and mostly an achievable goal. You learn from the first pass, for instance that your positioning was perhaps not quite optimal, and you make adequate adjustment for a successful second pass. If you go beyond two or three passes the clot becomes increasingly difficult to remove with increased friction against the vessel wall and you enter a downwards spiral.

The EMBOTRAP® device has some unique features as compared to other retrievers; it is conceptually different.

Instead of depending on the radial force to penetrate the clot, it captures it in between petals. Less radial force means less friction during deployment and probably increases safety or at least reduces influence on the target vessel. Further, it has an inner channel which allows some blood flow after deployment, preferentially important for disrupting the pressure gradient imposed on

CLOSED CELL INNER CHANNEL

CLOT INLET WINDOWS OPEN, ARTICULATED OUTER CAGE

The EMBOTRAP® II device

The features of the EMBOTRAP ® II device in conjunction with flow-arrest achieved by a balloon guide catheter is in my experience the best protection from such unwanted events, especially in comparison with other methods available today.

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Tommy Andersson

the clot by the blood pressure. Finally, it is constructed with a closed distal end so that clots trapped inside do not escape. The fact that the EMBOTRAP® device carried these different and unique features was, from the beginning, the most important factor in making us interested in working together with CERENOVUS. Procedure time is obviously only one part of the complete time from onset to reperfusion. Still, if you have to spend up to one hour to remove the thromboemboli, precious time is lost and the patient may develop an infarct on the table. In addition, the stress level is increased, you start to do more “desperate” manoeuvres and the risk for complications increases. Of course, you should keep going even if it takes time and many attempts to remove the clot as the patient may be a “slow-progressor” with good pial collaterals, but certainly, the chance of a good patient outcome diminishes.

There has been quite a lot of focus on losing emboli to initially unaffected vascular territories but I think it is even more important not to lose clot fragments distally into the vascular territory which is obstructed. The features of the EMBOTRAP ® II device in conjunction with flow-arrest achieved by a balloon guide catheter is in my experience the best protection from such unwanted events, especially in comparison with other methods available today.

“Over the course of the thrombectomy procedure, clot fragments may become dislodged and lead to downstream emboli due to manipulation of an endovascular device such as a guidewire, microcatheter or stentriever,” says Matthew Gounis and Ju-yu Chueh (director, New England Centre for Stroke Research (NECStR), professor of the Department of Radiology and co-director, NECStR, assistant professor of Radiology at the University of Massachusetts, Worcester, USA).

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o help combat this, Gounis and his team have produced a model system of cerebrovascular occlusion, which is a composite that contains multiple elements, including a vascular replica, a flow loop, and validated clot models, to simulate mechanical thrombectomy.

Distal emboli generated during the thrombectomy procedure are collected for particulate analysis.

“Our recent research characterised the number and size of the >200µm distal emboli caused by the EMBOTRAP ® II device in comparison to the firstgeneration stent retrievers.

Complete particulate counts and size distribution were performed for fragments >200 μm,” say Gounis and Chueh.

The EMBOTRAP® II device has a two-layer structure.

The outer layer has an open design to optimise engagement with the clot with minimal compression, and the inner distal emboli protection zone captures the possible clot fragments produced during the thrombectomy.

“Our research shows that the EMBOTRAP®II device significantly reduces the formation of >1000µm emboli by 50%, as compared to the control device. For emboli with size between 200-1000µm, there is no significant difference between the EMBOTRAP® II and control in terms of risk of distal embolisation and number of distal emboli,” explains Gounis and Chueh.

The EMBOTRAP® II offers a size reduction of clot fragments when combining all particulates (size: >200µm) with the use of first-pass data (p=0.0222).

Hybrid OR

First pass effect...always the goal!

Novel distal emboli protection technology: The EMBOTRAP® II device The problem with novel distal emboli

Rapid reperfusion of ischaemic penumbra is associated with favourable outcomes and reduced mortality. Good clinical outcomes, defined as modified Rankin Scale (mRS) score of 0–2, are also found to be strongly associated with complete reperfusion.

A Thrombolysis in Cerebral Infarction (TICI) score of 3 is the desired result of acute ischaemic stroke treatment, and is assessed when complete perfusion is achieved, without clot fragmentation and distal embolisation. The presence of fragmented clots can cause distal embolisation potentially including the previously unaffected area or blockage of collateral flow to the potentially salvageable tissue. Although the success of endovascular revascularisation

Matthew Gounis

is often assessed by a variety of angiographic grading systems, small microemboli may not be seen on imaging, and their impacts on the clinical outcomes may be underestimated.

“In our recent study, only one inelastic model was used for emboli analysis. Subsequent studies should include clot models with different mechanical characteristics for a more comprehensive understanding of the risk of distal embolisation related to the mechanical thrombectomy,” they add.

Is ease of deliverability key to revascularisation?

Operator experience can make all the difference when it comes to good outcomes after stroke. It is vitally important that devices are intuitive to use and ease of deliverability is key to this: being able to move the stent retriever smoothly though the vessel to capture the clot is essential.

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ormozd Bozorgchami (assistant professor of Neurology, Oregon Health & Science University, Portland, USA) was a co-author of the ARISE II study. He explains what he believes makes the EMBOTRAP® II device so easy to use.

“In my experience, the EMBOTRAP® II device is quite straightforward to track, which means that it is easy to advance the device through the microcatheter, even when undertaking the most tortuous navigations.”

This, he says, means it is easier to push the

device up the catheter compared to other stent retrievers, reducing the strain on the operator.

He adds, “This trackability makes the EMBOTRAP® II device easier to use when operating as a single operator as there is less kick back of the introducer sheath.”

The trackability is also integral in improving patient outcomes, Bozorgchami explains: “The ease of tracking the device may make it faster to deploy, which could reduce procedure times” and, as the stent retriever is deployed, “the additional proximal markers on the

Hormozd Bozorgchami

EMBOTRAP® II device enables precise device positioning, making this much easier. This then maximises the length of device integrating with the thrombus, increasing the chance of successful reperfusion.”

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