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May 2019 | Educational Supplement

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Committed to innovation excellence

Frontiers in flow diversion

Endovascular treatment of intracranial aneurysms (IAs) has become the first choice approach thanks to coil embolisation demonstrating superiority over surgical clipping for a wide range of ruptured and unruptured IAs.1,2,3 However, subsets of large, giant and wide-neck IAs, including fusiform and blister aneurysms, still pose significant challenges in achieving a complete and durable obliteration.4 THE INTRODUCTION OF FLOW diverters have shifted the paradigm of treating aneurysms from intrasaccular embolisation to luminal reconstruction.

Unlike in surgical clipping and coil embolisation where a complete aneurysm occlusion can be achieved immediately, aneurysms treated with flow diverters tend to occlude over time. Obliteration occurs in three distinct steps: (1) intra-aneurysmal flow reduction, (2) promotion of progressive aneurysm thrombosis overtime and, (3) endothelialisation of the flow diverter at the aneurysm neck, eventually “sealing off” the aneurysm from the blood circulation.4 Similar to a stent, a dual anti-platelet regimen is generally required to reduce the thromboembolic risk that is inherent to these intraluminal devices.

Stryker’s flow diversion journey

Wakhloo’s pioneering research in the principles of flow diversion culminated in the formation of Surpass Medical in 2005 and in the development of the Surpass Flow Diverter (FD). Stryker’s commitment to Complete Stroke Care led to its acquisition of Surpass Medical in 2012. The second generation Surpass technology, Surpass Streamline FD received both CE approval in 2015 and premarket approval on July 13, 2018 to treat unruptured large or giant saccular wide-neck or fusiform IAs.7 Stryker’s next generation flow diverter, Surpass Evolve, received CE approval in March 2019 and, as of this publication, is in the early evaluation phase.

CoCr devices with fewer wires and devices made from Nitinol. Many physicians have remarked that the Surpass Streamline implant opens more reliably and without kinking when compared to other flow diverters.

Surpass Streamline FD comes preloaded inside a delivery catheter with a distal outer diameter of 3.7F and a proximal shaft diameter of 3.9F. This over-the-wire platform allows for: (1) a protection of the implant from torsional forces reducing risk of implant twisting during delivery, (2) an application of greater compressive forces to enable an implant opening and achieve an optimal vessel wall apposition and, (3) to maintain a standard 0.014-inch guidewire across the aneurysm for continued distal access and

Flow diversion fundamentals

It has taken over two decades of research and development for flow diverters to evolve from a concept to a reliable technology, appropriate for clinical practice. Flow diverters are typically (in most cases single layer) braided, tubular devices made of Cobalt Chromium (CoCr) or Nickel-Titanium (Nitinol) alloy integrated with radiopaque wires. Porosity and pore (mesh) density are two major parameters that need to be balanced when designing a flow diverter to optimise a flow reduction into the target aneurysm without compromising flow to adjacent perforators and side branches covered by the implant.4 In the early 1990s, Ajay Wakhloo and colleagues proposed the relationship between pore density of a stent and aneurysm occlusion rates in a canine model.

They demonstrated increased aneurysm obliteration rates in stents with a higher pore density.5 In the late 2000s, Sadasivan et al further showed that at equal porosities, higher aneurysm occlusion rates were achieved in devices with the greater pore density.6 Sadasivan et al also observed that to maintain a consistent flow diversion profile and lessen flow impinging zones within the aneurysm, vessel size and local flow velocities needed to be considered.6 This required an increase in the number of wires of implants for larger arteries with an increased blood flow.

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Figure 1: The Surpass story

The Surpass Streamline FD is a selfexpandable, CoCr alloy braided implant with 12 platinum wires for radiopacity.

Based on early research by Wakhloo, the Surpass stent was designed to have a pore density of at least 20 pores per mm2, while maintaining a porosity of approximately 70%. To accomplish this, the number of wires changes with stent diameter. The 3 and 4mm stents are composed of 72 wires, while the 5mm stent is composed of 96 wires. Surpass Streamline FD is unique in its ability to maintain consistent pore density across the neck of the aneurysm, independent of vessel size. Due to the high number of CoCr wires, Surpass Streamline FD also has a higher outward radial force when compared to other

provides stability to the FD delivery system for controlled implant deployment/recapture and redeployment. The downside of an over-the-wire delivery system though is that it can make tracking of the delivery system to the aneurysm site more challenging, especially in tortuous vessels. We therefore recommended a stable and supportive access setup comprising of a long sheath and an intermediate catheter (Figure 2). Many operators now, using the co-axial system, take the AXS Catalyst 5 (CAT 5) intermediate catheter through the AXS Infinity Long Sheath distal to the aneurysm and then navigate the Surpass Streamline system over the wire through this supportive construct.

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Figure 2: Schematic representation of the Surpass Streamline FD, recommended access setup

Figure 3: (A)–(B) DSA images of two right paraophthalmic and a petro-cavernous, ICA saccular aneurysms. Vessel diameter: Dist – 4.52mm - Prox – 4.57mm. (C) AXS Infinity Plus Long Sheath 90cm placed in the horizontal petrous segment. (D) AXS Offset DeliveryAssist Catheter (DAC) used to navigate AXS Catalyst 5 (CAT 5) DAC 115cm into position.

CAT 5 positioned in the MCA (M1). (E)–(G) A Surpass Streamline 5x50mm delivery system was introduced over a Synchro 0.014” Standard guidewire and through the CAT 5. The delivery system was positioned distal to the aneurysm and slack from CAT 5 was removed.

Deployment began by slightly advancing the inner pusher while keeping the outer catheter stable. Delivery System was loaded to deploy on the outer curvature to ensure a good wall apposition and facilitate implant opening. Upon complete deployment, the inner pusher catheter was advanced over the guidewire through the deployed implant and past the aneurysm. The outer catheter was sleeved over the pusher followed by the CAT 5. The passage of both the outer catheter and CAT 5 ensured further opening of the distal portion of the implant. (H) Slight malapposition at the distal end of the FD was corrected using a Transform 4x10 Occlusion Balloon Catheter. (I) Implant positioning and satisfactory distal and proximal apposition was confirmed. Images courtesy of Brad Bohnstedt, OU Medical Center.

can be helpful to reduce the ledge and thus improve the navigability of the intermediate catheter distal to the aneurysm. Following use of Surpass Streamline in more than ten of his patients (Figure 3), Bradley Bohnstedt, a vascular neurosurgeon from OU Medical Center (Oklahoma City, USA), stated: “I have seen a reassuring consistency in device position, deployment, and wall apposition.”

Surpass Streamline FD is the second only flow diverter to have secured a premarket approval in the USA. The US Food and Drug Association (FDA) awarded the approval based on the clinical outcomes in the SCENT

Investigational Device Exemption (IDE) trial.7 The SCENT trial was designed to evaluate the safety and efficacy of Surpass Streamline FD in treating patients with unruptured large and giant IAs of the internal carotid artery (ICA) to the terminus. The trial demonstrated single stent efficacy (1.1 FDs deployed on average [range 1–3] compared to three FDs in the PUFS trial [range 1–15]) and included challenging posterior communicating artery (PCommA) aneurysms.8 Surpass Streamline FD achieved a technical success rate of 97.8% and a primary

3.25mm–5mm implants are composed of 64 wires while the 2.5mm implant has 48 wires.

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effectiveness endpoint of 62.8%, defined as the per cent of patients with complete occlusion without clinically significant stenosis (≤ 50% stenosis) of the parent artery, and any retreatment of the target aneurysm at 12 months follow-up. Almost 90% of the patients were also free from any neurological event and/or death.+ The efficacy data in the SCENT trial was in line with other flow diversion studies as well as Surpass-specific, international clinical studies like De Vries et al who, in their single centre study, also demonstrated single stent efficacy with 94% complete occlusion at six months.9 The SCENT trial was the largest, prospective, multicentre clinical trial on flow diversion, involving 26 centres and 180 patients with data generalisable to realworld outcomes. Philip Meyers, professor of radiology and neurological surgery at New York Presbyterian/Columbia University Medical Center (New York, USA) and co-principal investigator (Co-PI) for the trial concluded: “Surpass Streamline is the first flow diverter indicated for large and giant posterior communicating artery aneurysms. These unruptured aneurysms are more challenging due to their location and surrounding anatomy. Having Surpass approved for this and other locations is an important advantage for physicians and patients.”

What the future holds

The use of flow diverters in treating different types of IAs is becoming more ubiquitous. Physicians are demanding continued improvements to implant deliverability to site of treatment while ensuring reliable deployment and optimal vessel wall apposition of the implant.

As of this publication, Stryker has begun early commercialising of its next generation flow diverter, Surpass Evolve, which recently received CE approval in Europe.

This flow diverter leverages the reliable opening and optimal flow diversion profile of the Surpass platform, while improving overall procedural ease of use.

Despite having reduced wire count, Surpass Evolve is designed to have a comparable pore density to the existing Surpass implant, primarily due to its higher braid angle. This has the additional benefit of improving implant conformability. With a completely redesigned delivery system, the CoCr, 64-wire,++ Surpass Evolve FD is engineered to be delivered through the Excelsior XT-27 Standard Straight, 0.027inch microcatheter.

As with the previous generation, the new

The primary safety endpoint failure rate, defined as major ipsilateral stroke or neurological death, was 10.6%

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Figure 4: (A) DSA image of a right paraclinoid segment, unruptured, ICA sidewall aneurysm.

Vessel diameter: 3.6mm (distal) and 3.25mm (proximal) with moderate tortuosity and a high-riding genu (B)–(C) Deployment of Surpass Evolve 4x15mm Flow Diverter through an Excelsior XT-27 Standard, Stratight microcatheter. Proximal support was provided by a Neuron Max 088 Sheath and an AXS Catalyst 5 DAC. Precise placement of the implant was acheieved by unsheathing the stent just proximal to the carotid bifurcation, followed by loading to fully expand the implant along its length. (D)–(E) Early stasis was observed in the aneurysmal sac immediately after the procedure. Images courtesy of Vitor Pereira, Toronto Western Hospital (Toronto, Canada).

delivery system also allows the implant to be resheathed and redeployed.

After conducting first clinical procedures, Vitor Vitor Pereira Mendes Pereira, neuroradiologist at Toronto Western Hospital (Toronto, Canada) stated, “Surpass Evolve represents an exciting advancement in the treatment of complex brain aneurysms. The device is easy to use, highly responsive and demonstrates a strong flow diversion for aneurysm healing.” Figures four and five summarise one of the first cases that Pereira performed with the Surpass Evolve FD including results from the normalised Mean Aneurysm Flow Amplitude (MAFA) study; a metric to quantify aneurysmal flow reduction that occurs due to flow diverter implantation and thereby assesses the efficacy of a flow diverter.10 A wider group of patients can be better served with disruptive flow technologies like flow diverters. This can be supported by (1) continual development of relevant, high performing technologies focused on physician need, (2) raising the bar on new technologies through sustained focus on establishing their clinical safety and efficacy and, (3) partnering with clinicians and regulators to support indication expansion efforts.

References

Figure 5: High resolution, contrast-enhanced, cone-beam computed tomography (VasoCT) confirmed (A) precise placement of distal portion of the flow diverter, proximal to ICA terminus (B) complete neck coverage of aneurysm including satisfactory wall apposition of flow diverter to parent artery and, (C) optimal wall apposition at aneurysm neck (D) Changes in blood flow patterns within vessel and aneurysmal sac pre (D-left) and post (D-right) flow diverter placement. The normalised mean aneurysm flow amplitude ratio (MAFA-R) was calculated to be 0.53. Images courtesy of Vitor Pereira.

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1. Molyneux, A, Kerr, R, & International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. (2002). International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. Journal of stroke and cerebrovascular diseases, 11(6), 304-314.

2. Sluzewski, M, van Rooij, WJ, Slob, MJ, et al. (2004). Relation between aneurysm volume, packing, and compaction in 145 cerebral aneurysms treated with coils. Radiology, 231(3), 653-658.

3. Alshekhlee, A, Mehta, S, Edgell, RC, et al. (2010). Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm. Stroke, 41(7), 1471-1476.

4. Wakhloo AK, Lieber BB, The Beginnings of Flow Diversion: A Historical Review. In. Flow Diversion of Cerebral Aneurysms,

by Min S. Park et al., Thieme, 2018, pp 1-13 .

5. Wakhloo, Ajay K., et al. "Self-expanding and balloonexpandable stents in the treatment of carotid aneurysms: an experimental study in a canine model." American Journal of Neuroradiology 15.3 (1994): 493-502.

6. Sadasivan, Chander, et al. "An original flow diversion device for the treatment of intracranial aneurysms: evaluation in the rabbit elastase-induced model." Stroke 40.3 (2009): 952-958.

7. Meyers, PM, Coon, A, Kan, P, Wakhloo, A, & Hanel, R. (2019). Abstract WMP36: Surpass™ IntraCranial Aneurysm EmbolizatioN System Pivotal Trial to Treat Large OR Giant Wide Neck Aneurysms (SCENT Trial): One Year Outcomes.

Stroke, 50(Suppl_1), AWMP36-AWMP36.

8. Becske, Tibor, et al. "Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial." Radiology 267.3 (2013): 858-868.

9. De Vries, Joost, et al. "New generation of flow diverter (Surpass) for unruptured intracranial aneurysms: a prospective single-center study in 37 patients." Stroke 44.6 (2013): 1567-1577.

10. Pereira, V. Mendes, et al. "E-081 Assessment of the MAFA Ratio as a Quantitative Prognostic Marker of Aneurysm Occlusion after Flow Diverter Treatment."(2016): A84-A85.

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Frontlines of stent-assisted coiling

Results from Stryker's Neurovascular division internal bench test comparing the performance of various coils, when used in conjunction with a Neuroform Atlas stent in wide neck aneurysms, show that Target coils are the most conformable and gain the most volume fill from wall to wall around the neck.

WHILE THE ENDOVASCULAR treatment of intracranial aneurysms with coils is a well-established modality, initially wide neck and complex aneurysms were considered to be unsuitable candidates for endovascular treatment.

Over the last few years however, the use of self-expanding stents in conjunction with endovascular coils has become widely accepted and been proven as a safe and effective modality to treat these more difficult cases.

Stent-assisted coiling provides a safe alternative to clipping by using the stent as a scaffold within the vasculature to keep the coil mass intact within the aneurysm and promote full aneurysm occlusion. The stents also, over time, help prevent recanalisation due to their haemodynamic and biologic attributes.

The Stryker Neuroform Atlas stent has become a highly regarded tool in treating these wide neck aneurysms through stentassisted coiling due to the stent's enhanced conformability, high deployment accuracy and overall ease of use. Given the consistent performance of the Atlas stent, the other variable impacting success in these wide neck aneurysm cases is the performance of the different coils available today, and how they interact with the stent and the aneurysm wall.

In cases where a Neuroform Atlas has been used, an effect termed “saddling” or “bridging the arch” has been used to describe the way in which the coils conform or lay upon the stent and up against the aneurysm wall. The better the coils conform to the shape of the stent and wrap around it to fill the voids three-dimensionally to provide the best neck coverage and increase likelihood of aneurysm occlusion. An internal bench test was conducted

by Stryker's Neurovascular division to assess the performance of the coils in seeking voids and filling the space around the neck when they are used with Neuroform Atlas stent. The study was intended to measure and compare the performance of various coils in conforming and wrapping around an Atlas stent in a wide neck.

Testing was conducted using a C-Arm in the Angio Lab at Stryker Neurovascular, Fremont, CA, USA. The silicone model used represented a left internal carotid with a widenecked large anterior communicating artery (AComm) aneurysm. The aneurysm had a neck May 2019

as evidenced by the high percent filled values and low unfilled space values. This is attributed to the Target coil open loop design and conformability, wherein the design of the coil promotes framing around the aneurysm and the adjunctive stent. Smart Coils were next in performance, and Hydroframe coils were least effective at exhibiting “saddling”. This bench test demonstrated that Target coils produce better aneurysm filling when used together with a Neuroform Atlas stent, which may result in

Image demonstrating coils “saddling” the stent during bench testing

Image courtesy of Erik F. Hauck, MD demonstrating coils “saddling” the stent in a clinical case. Image used with permission

of 6.79mm, height of 8.48mm, width of 7.4mm and a depth of 10.77mm. Neuroform Atlas stents (3mm) were used in all tests as control devices and testing included the following coils: Target (Stryker), Hydroframe (Microvention), Smart (Penumbra), Optima (Balt), and Axium Prime ES (Medtronic).

To create the coil “saddling” effect, a Neuroform Atlas 3mm diameter stent was delivered to the aneurysm through a SL-10 microcatheter for each of the products tested.

The coils were deployed into the aneurysm through the stent struts, by a jailed catheter tip.

Every attempt was made to replicate the access and deployment parameters (i.e. microcatheter tip placement). Coils from each manufacturer were chosen for matching total packing density across groups.

The overall coil volume was considered to provide the best possible match. Additionally, the coils were deployed in a descending sequence where the coils with largest diameter were deployed first.

CT images were after each stent and set of coils were deployed. These 3D images were rotated to determine the optimum viewing angle of the saddling effect, i.e. the angle of rotation for which it was easiest to estimate the stent apex inside the aneurysm while also viewing the coil fill in the space on each side of the saddle.

Effective saddling was demonstrated by a high per cent fill of the space around the adjunctive stent and aneurysm wall. Target coils were most effective at filling the space

better aneurysm occlusion. The highly effective scaffolding provided by the Neuroform Atlas stent paired with the open loop design of the Target coils helps to achieve the desired outcomes when treating wide neck cases.

Due to the results of this bench test it can be concluded that the Target coils may produce better results when used together with a Neuroform Atlas stent.

The highly effective scaffolding provided by the Neuroform Atlas stent paired with the open loop design of the Target coils help achieve the desired outcomes when treating these complex wide neck cases. The ability of the Target coil to conform and cover the neck better than the other coils tested will lead to higher aneurysm occlusion rates and a lower recurrent rate.

References 1. Spiotta et al., 2012. Comparison of techniques for stent assisted coil embolization of aneurysms. JNeurointrev Surg.

2012 Sep;4(5):339-44.

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Full-length visibility: The key to first pass efficacy Just as improved stroke management and first-generation retrievers pushed the goal from TICI 2a (on the thrombolysis in cerebral infarction scale) to a minimum acceptable standard of TICI 2b, improvements in technique, patient pathway optimisation, and advances in device technology have pushed TICI 2b revascularisation rates around the world above 90%, all while 90-day good outcomes remain steady at around 50%.

IT IS WELL UNDERSTOOD THAT revascularisation rates impact outcome rates. Regardless, recent studies have provided greater insight into how stroke interventionalists may impact outcomes through improvements in thrombectomy.

More specific interventional variables have been shown to independently predict good outcomes and may be the key to breaking the 50% good outcomes barrier. Time to revascularisation, rescue therapy rate, and successful first pass revascularisation, also referred to as first pass efficacy have all been identified as predictors of good outcomes.

First pass efficacy has emerged as the gold standard for mechanical thrombectomy because it encompasses aspects of each of the above variables, weighing revascularisation success with procedural speed. Logically, a single high efficiency pass without bailout should be how we measure acute success.

Despite similar final revascularisation rates, stent-retriever thrombectomy has consistently shown less need for rescue therapy when compared to aspiration first thrombectomy, while first pass efficacy has been studied most substantially in stent retriever thrombectomy.

Successful revascularisation (TICI ≥2b) within one pass has been evaluated across many different types of stent retrievers.

Recently, the ARISE II trial (Analysis of revascularisation in ischaemic stroke with EmboTrap; n=227) exhibited 51.5% first pass efficacy using the EmboTrap device (Cerenovus), while a subanalysis of the North American SOLITAIRE Stent-Retriever Acute Stroke (NASA1) registry showed complete revascularisation in one pass with Solitaire (Medtronic) in 25.1% of the 354 patients. The Arterial Revascularisation Therapies Study (ARTS2), inclusive of 42 patients, found that 43% of cases achieved first pass efficacy with a mix of Trevo XP (Stryker) and Solitaire.

Thus far, the highest reported rate of first pass efficacy in peer-reviewed publications was found in the Trevo Registry as 62.3% of the 2,008 patients achieved successful

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Trevo 2000 (n=2,008) First pass ≥2b Final TICI ≥2b mRS ≤2 90-day

62.3% 92.8% 52.3%

Trevo 2000 table

revascularisation after one pass. The mean number of passes with Trevo in this study was 1.7.

The Trevo 2000 Registry is the largest published dataset of consecutively studied thrombectomy patients to date. This prospective, open-label, core-lab, multicentre registry has resulted in a growing number of sub-analyses based on Trevo Retriever thrombectomy, including real-world confirmation of the DAWN trial results to reduce disability up to 24 hours, as well as improved outcomes when presenting directly to endovascular-capable centres.

In addition, when it comes to interventional-specific endpoints, the first pass efficacy results in the Trevo Registry stand out as highly promising. These data also raise the question of exactly what aspects of Trevo in particular allow physicians to achieve such results.

A combination of in vitro and clinical considerations suggest that the answer may lie in visibility. In accordance, Trevo has been uniquely designed to provide full length visibility of every cell along the full length of the device.

Nogueira and colleagues have postulated that using an active deployment technique increases retriever radial force and wall apposition by up to 75% while enlarging cells by 50%, thereby facilitating integration and internalisation of the thrombus into the device.

Their data showed significant improvement in first pass efficacy and final TICI 3 compared to standard unsheathing retrieval.4 Weismann et al have corroborated these results, while van der Marel and colleagues have also illustrated in vitro that active deployment improves clot integration, especially in hard clot.5,6 Each of these studies

warns that adding forward pressure to the device requires careful visual assessment to avoid device damage or clot disruption.

The ability to see the full length of the device allows it to be utilised in an intentional manner to maximise clot integration and retrieval.

Furthermore, in a population with high atherosclerotic disease, Imahori and colleagues demonstrated that Trevo Retriever achieved TICI 2b/3 after one pass in 42% of the population. Most interestingly, they identified a significant difference in retriever diameter expansion into the clot between first pass efficacy cases and non-first pass efficacy cases (60% vs. 34% of vessel diameter, p<0.01), identifying an algorithm to identify likelihood of successful retrieval intraprocedure.7 These practical data allow physicians to make critical decisions in order for them to maximise the chances for revascularisation success—which may be

Significant increase in hard clot integration with Trevo XP. van der Marel et al.

improved through full length radiopacity of the device as it interacts with the clot.

Stryker’s interventional specialty continues to identify meaningful ways to maximise the information provided through the full-length visibility of Trevo. Alongside focusing on efficient acute outcomes like first pass efficacy, these advances contribute to further driving improved patient outcomes upward.

References 1. Malisch, TW, et al. Clinical and Angiographic Outcomes with the Combined Local Aspiration and Retriever in the north American Solitaire Stent-Retriever Acute STroke (NASA) Registry. Interv Neurol, 2018. 7(1-2): pgs 26-35.

2. Massari, F. et. al. ARTS (Aspiration-Retriever Technique for Stroke): Initial Clinical Experience. Interven Neuroradiol, 2016.

22(3): p 325-32.

3. Haussen DC, et al. Optimizating Clot Retrieval in Acute Stroke The Push and Fluff Technique for Closed-Cell Stentrievers.

Stroke. 2015 Oct;46(10):2838-42.

4. Wiesmann M, et al. Active push deployment technique improves stent/ vessel wall interaction in endovascular treatment of acute stroke with stent retrievers. J NeuroIntervent Surg 2017;9:253–256.

5. van der Marel K, et al. Quantitative assessment of device–clot interaction for stent retriever thrombectomy. J NeuroIntervent Surg 2016;8:1278–1282.

6. Imahori T, et al. Stent Expansion and In-Stent Thrombus Sign in the Trevo Stent Retriever Predict Recanalization and Possible Etiology During Mechanical Thrombectomy: A Case Series of 50 Patients with Acute Middle Cerebral Artery Occlusion. World Neurosurg. 2018 Dec 28. pii: S18788750(18)32910-3.

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Beyond the FDA target: WEAVE intracranial Stent trial, the final results The final results of the WEAVE trial, tested in 152 consecutive patients treated on-label, conveyed an “extremely low” periprocedural stroke and death rate (2.6%) when using Wingspan for US Food and Drug Administration (FDA)approved indication. Surpassing the 4% FDA target for 150 patients, the WEAVE trial also had the highest on-label enrolment of any stenting trial for intracranial atherosclerotic disease (ICAD) in the USA performed to date.

STUDY INVESTIGATORS CONCLUDED that the data “suggest reevaluation of stenting as a treatment option for symptomatic patients with ICAD is indicated, given the low periprocedural complication rate and excellent safety profile achieved with experienced interventionalists, and proper patient selection following the on-label usage guidelines”.

Around 8–10% of strokes in the USA are as a result of ICAD, equating to approximately 50,000–70,000 symptomatic cases per year. In China, however, the annual rate of stroke due to ICAD is 22–40%. The incidence as well as ambiguous patient presentation of the disease— given that the variable for ICAD is similar to that of acute ischaemic stroke and large vessel occlusion—has governed a series of ICAD Wingspan stent trials over the past decade.

The purpose of the WEAVE trial is to assess the periprocedural safety of the Wingspan Stent system in the treatment of symptomatic ICAD. The primary endpoint of this prospective, single-arm, post-market surveillance study was stroke bleed or death rate within 72 hours of the procedure in on-label treated patients.

Outcomes of 100% of the patients were adjudicated by study neurologists. Secondary analyses include the periprocedural data collected on any additional patients stented with the Wingspan stent who did not qualify for on-label use.

The initial trial design sought to enrol 389 onlabel patients with a goal periprocedural stroke and death rate of <6.6%. The trial was stopped in October 2017, following interim data analysis on the first 100 on-label patients indicating a lower than expected event rate. FDA-revision Bayesian analysis (of 100 on-label patients) warranted completion of the study at 150 patients if the primary endpoint of periprocedural stroke and death was 4% or lower.

This target event rate of 4% was met, as the total percentage of on-label patients with stroke or death within 72 hours was 2.6% (4/152). Off-

It will need a new phase 3 trial to impact the treatment of ICAD.

How will the results of this trial impact patients?

Yu: The results of this trial will give patients with ICAD and recurrent stroke new hope and some confidence in intracranial stenting.

Alexander: Many patients with ICAD who have repetitively failed medical therapy are not currently offered stenting as an option, due to poor results from prior trials. This very successful stenting trial may give patients more options in the future.

What is the most valuable lesson learned from this trial?

Michael J Alexander

Wengui Yu

label use, however, appeared to increase the risk of periprocedural stroke and death significantly (23.9%, p=0.0001), especially when treatment was a statistically significant difference in outcomes between the two cohorts (p=0.0001).

Of the 152 patients in the primary analysis group, 25% of lesions were within the internal carotid artery, 40.8% in the middle cerebral artery, 20.4% were vertebral and 13.2% were basilar, with the remaining in the posterior cerebral artery. “WEAVE did not ‘shy away’ from higher risk perforator location,” said the study authors.

Moreover, the lessons learned from the SAMMPRIS trial (Stenting versus aggressive medical therapy for intracranial arterial stenosis), which was designed “suboptimally” based on known risk factors with poor patient selection, helped guide aspects of the WEAVE trial, such as data collection on perforator proximity.

Speaking to NeuroNews, lead author Michael J Alexander (Cedars Sinai Medical Center, Los Angeles, USA) and senior author Wengui Yu (Irvine Medical Center, Orange County, USA) expand on the implications of the WEAVE trial’s final results.+

How will the findings from WEAVE impact the treatment of ICAD?

Alexander: The WEAVE trial results may help give clinical support to the consideration once again of endovascular stenting for symptomatic ICAD as an effective option for patients, and be the impetus for future randomised clinical trials.

Yu: They will lead to rethinking of the management of ICAD for stroke prevention.

Alexander: Just as the endovascular treatment of large vessel occlusion has evolved since the IMS3 (Interventional management of stroke) trial, ICAD stenting has evolved since SAMMPRIS. We have learned that delayed stenting, proper antiplatelet therapy and blood pressure control, and experienced endovascular technique dramatically improve patient outcomes.

Yu: Proper patient selection, time of stenting (≥8 days of last stroke), the experience of interventionalists, and standard periprocedural care are essential for reduced risk of periprocedural complication.

How did the WEAVE results address the main concerns of the SAMMPRIS trial?

Yu: The main concern of the SAMMPRIS trial is the 14.7% periprocedural complication rate and safety of the Wingspan Stent. The WEAVE trial has successfully addressed this safety concern and demonstrated a low complication rate in properly selected patients with procedures performed by experienced interventionalists more than eight days after last stroke. The risk of haemorrhagic complication was 0.7% (1/152) in the WEAVE trial as compared to 5.2% (11/213) in the SAMMPRIS trial.

Alexander: The SAMMPRIS trial results implied that stenting was not a safe treatment option for ICAD. The WEAVE trial’s 2.6% periprocedural complication rate showed that stenting with Wingspan is safe with proper patient selection, experienced operators, and refined periprocedural medical management.

How have the results of this trial changed your practice?

Alexander: The results of WEAVE help me advise patients better with scientific data for clinical recommendations for their ICAD, once they have failed medical therapy.

Full study can be found here: https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.118.023996

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“No one size fits all”: CT elicits similar outcomes to CT perfusion

Amidst the fast-paced evolution of stroke treatment, Amrou Sarraj, associate professor of neurology at UT Health in Houston, Texas (USA), and the principal investigator of the SELECT trial, outlines the trial’s key findings. Acknowledging the importance of industry partnerships, he highlights the potential clinical implications of SELECT II in terms of expanding the indications for thrombectomy while triaging new populations of patients. SELECT compared CT and perfusion image correlation with clinical outcome; assessed the relationship between imaging and time (0–6 hours vs. >6 hours), and determined how imaging modality affects treatment decisions and whether there was a potential benefit with thrombectomy in patients who were not assessed in prior trials.

To what extent does imaging represent a barrier to achieving better outcomes?

I think of imaging more as a facilitator of treatment. However, if physicians abide to findings of certain studies utilising advance imaging modalities—some patients who may still have good outcome with thrombectomy may be denied the treatment. Imaging becomes a barrier when we question: “Does it apply 100% to the clinical trials’ inclusion criteria and guidelines?” Although clinical trials such as DAWN and DEFUSE 3 utilised certain imaging criteria and parameters based on their definition of small core—this does not mean that you need 100% agreement with their imaging criteria in every patient treated in the real-world in order to carry out thrombectomy.

Do you believe too many studies abide too strictly to a specific inclusion criterion?

Yes. Yet, when you are putting together the inclusion criteria for a clinical trial, you want to put your trial in the best position to succeed.

However, if you have a clinical trial with a set criterion of Alberta Stroke Program Early CT Score (ASPECTS) of 6, this does not mean that an ASPECTS of 5 or 4 do not benefit—they were just not tested; the same goes for certain perfusion volumes.

What was the rationale behind the SELECT trial?

Different clinical trials used different imaging modalities and inclusion criteria for patients to test the benefit of thrombectomy treatment compared to medical management. Some used simple CT, while both DAWN and DEFUSE 3 used advanced perfusion images and utilised the RAPID software mismatch determination.

This resulted in polarised opinions. Thus, our rationale was based on the fact that there is no clear optimal selection imaging modality.

The correlation between CT and CT perfusion was never evaluated. Furthermore, a prospective direct comparison of the correlation between the imaging modalities findings and thrombectomy clinical outcomes was

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not examined before. We wanted to examine thrombectomy clinical outcomes in patients outside the clinical trials imaging criteria.

Can you tell us about the design of the trial?

The trial was a prospective cohort study, which was the best design in terms of feasibility. We looked at patients who received thrombectomy as well as medical management in a multicentre fashion in nine centres across the USA. We had a defined imaging profile; all of the patients received CT, CT angiography and CT perfusion with RAPID mismatch determination.

The trial enrolled patients with anterior circulation occlusion as well as middle cerebral artery, M1, M2 and internal carotid artery occlusions, zero up to 24 hours. The baseline modified Rankin Scale had to be zero or one.

We did not include patients beyond 24 hours, or those with distal occlusions.

What were the main findings of SELECT?

We found a high level of agreement—84%— between the imaging modalities. This shows that if you have this level of agreement and you want to simplify your algorithm, then perhaps only in certain cases will further imaging be necessary. Secondly, the good outcome rates were around 56% for good CT and 57% for good CT perfusion.

We also tested the hypothesis that in late window perfusion images are required. Yet our results showed that those with a good profile on CT in the late window had similar good outcomes to those with good profile on CTP. Also, those who had CT as a selection modality had as good of an outcome as those who had CT perfusion. Another interesting finding was that those who had discordance in the imaging profile between CT and CT perfusion, a good percentage of the patients still achieved good outcomes with thrombectomy.

How applicable are these results to the acute ischaemic stroke patient triage?

This is a real-world prospective cohort

multicentre study, reflecting real-world findings. The study demonstrates that you can, to an extent, treat patients based on simple imaging modalities. Therefore, the hospitals that do not have advanced perfusion images may still utilise simple CT for triaging patients prior to thrombectomy and treating them with Amrou Sarraj pretty close outcomes to CT perfusion, both in the early and late window. I guess the old adage remains; no one size fits all.

Do you intend to validate these results with an RCT in SELECT II?

Where before most clinical trials included patients with minimal ischaemic changes, now it is time to expand the limits of the treatment, to include patients with a larger area of ischaemic infarct, lower ASPECTS on the CT, larger volume on the perfusion images and test if the thrombectomy is safe and efficacious in these patients. Alongside this, it is important to test if there thrombectomy outcomes will differ in those patients with large strokes on CT versus perfusion images.

In SELECT II, we will randomise patients with large core into a medical management plus thrombectomy versus medical management alone.

We will be including patients with ASPECTS 3–5 and perfusion core infarct 50cc and larger to assess if thrombectomy improves clinical outcomes in these patients with large strokes without increasing the risk of adverse safety outcomes.

In relation to imaging, we aim to test the heterogeneity of the treatment effect based on CT versus perfusion imaging. Finally, we will look if there was a benefit with thrombectomy in cases where discordance was observed; May 2019

Committed to clinical excellence

those who showed that CT was good and perfusion was poor, and vice versa.

What may the results of SELECT II mean for the future of stroke treatment?

We will include patients that were largely excluded from prior trials due to the extent and size of their ischaemic changes. If we find that thrombectomy is superior to best medical management in SELECT II, the clinical implications are widespread. This

superiority will extend the indications to a new patient population who could be treated with thrombectomy from the current cutoff of an ASPECTS of 6 to an ASPECTS of 3, and an infarct core of 50 or 70cc to a larger size.

If we find that the safety concerns do not increase with the intervention, that will be of a significant impact in changing treatment decisions. And, if we find no difference in the selection between CT and perfusion images, this will mean that this new population can be triaged based on either modality.

Pooled analysis of endovascular treatment trials: dramatic treatment effect continues alongside the late window paradox Endovascular treatment (EVT) for acute ischaemic stroke patients with large vessel occlusion initiated beyond six hours from time last seen well is a highly effective therapy. This finding was maintained across all subgroups in the AURORA pooled analysis of endovascular stroke trials, including those defined by time, age, mode of presentation and Alberta stroke program early CT score (ASPECTS). The data were presented by Raul G Nogueira (Grady Memorial Hospital, Atlanta, USA) at the Stroke Live Course (SLICE; 1–3 October, Nice, France).

ACCORDING TO NOGUEIRA, STUDIES regarding the impact of time on the effectiveness of EVT have not previously accounted for collateral flow and the presence of mismatch. He then emphasised the current findings indicate that “Time does not matter, as long as you have a mismatch.” In the current context, a mismatch is defined as a clinical deficit that is disproportionately severe relative to the infarct burden.

The idea of AURORA was to combine multiple trials that enrolled patients treated in the late window into a pooled analysis. These include DAWN and DEFUSE 3 data, as well as the ESCAPE trial patient cohort (enrolled between six and 12 hours), and the REVASCAT patients (enrolled between six and eight hours).

The authors also plan to add the POSITIVE trial patients to their final analysis. Nogueira reported that the baseline characteristics of the patients that fulfilled the criteria for the AURORA trial (EVT within the six to 24 window) were balanced between the thrombectomy cohort (n=242) and the control cohort (n=216) in terms of baseline characteristics including ASPECTS scores and occlusion location. Only the National Institutes of Health Stroke Scale (NIHSS) scores were found May 2019

to differ significantly at baseline, at 16.3±5.4 for the thrombectomy cohort and 17.4±5.9 for the controls (p=0.05). Importantly, Nogueira also noted that the majority of the patient population of AURORA had a strong mismatch.

Through comparing the safety profile of AURORA to the early window (zero to six-hour) intervention trials in the HERMES metanalysis, Nogueira acknowledged that the outcomes regarding rates of symptomatic intracranial haemorrhage were found to be very similar for the endovascular treatment groups in both trials (5% for AURORA and 4.4% for HERMES): “What this shows is that you can treat patients at the late window with similar safety as the early window as long as they have a mismatch.”

Furthermore, as the modified Rankin Scale (mRS) scores of 0–2 at 90-days were 47% for EVT compared with 17% for controls, Nogueira reported that the number needed to treat (NNT) for one additional independent outcome at 90 days was 3.3 while the NNT for any ≥1-point improvement in 90-day mRS was only 2.5.

Additionally, the utility-weighted mRS scores were 5.5±3.6 for EVT compared to 3.5±3.4 for controls, which Nogueira noted was “similar to the DAWN population, which is not surprising.”

How important is the role of the industry in support these types of trials?

Good partnerships between industry and scientists can help move the field forward significantly. Both SELECT and SELECT II are investigator-initiated trials supported by grants from Stryker Neurovascular. I believe we are working together to answer important scientific questions that can help expand the treatment limits to include new populations and ultimately help to improve the lives of more patients.

A finding of particular interest, according to Nogueira, includes that time had little effect regarding time from last seen well to randomisation for treated patients Raul G Nogueira (odds ratio [OR] per 60 minutes: 0.98 [0.92, 1.05]; p=0.558). In contrast, the controls tended to get worse over time (OR per 60 minutes: 0.83 [0.74, 0.94]; p=0.004). Therefore, the treatment effect size is higher at the tail end; a finding alluded as the Late Window Paradox. “We do not know exactly why this occurs, it could be due to the delayed benefit of some of the intravenous tPA patients, or maybe the late patients are more prone to collateral failure,” postulated Nogueira, “but this was independently seen in both DAWN and DEFUSE 3, and now again in the current pooled analysis.”

Moreover, he reported that no interaction was found between treatment times and the rates of symptomatic haemorrhage or 90-day mortality; indicative of the fact that treatment is not more dangerous as time goes on.

Of importance, Nogueira cautioned while these findings should open up a window of opportunity for more patients they do not nullify the importance of fast times to treatment and he remarked: “It becomes critical to acknowledge that the chances of having a clinical-core mismatch decay over time; therefore, time is still brain!”

In conclusion, Nogueira said that, in patients with a sustained clinical-core mismatch, endovascular treatment initiated beyond six hours from last seen well is a highly effective therapy and no less effective than treatment initiated within six hours; a finding that was maintained across all subgroups of the studied patients.

Furthermore, the safety profile is not only acceptable but it is no different than that observed with treatment administered within six hours.

Moving forward with the current findings, Nogueira stated: “It is time to analyse trial data, but incorporate physiology and clinical judgement into our decision-making.” # AP-002513 v0.1

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Committed to health-economics excellence

The added value of StrokEnomics®

Stryker's dedication to its complete stroke care mission includes illustrating economic valuations aimed at increasing patient access and quality of care around the world.

StrokEnomicsTM, THE BRAND NAME associated with health economics at Stryker's Neurovascular division, is a programme that helps illustrate the economic value of Stryker’s solutions, supporting both physicians and patients. In addition to further training for physicians, StrokEnomics assists in the holistic assessment of the adoption of treatment, ultimately aiming to enhance both patient access and quality of care around the world.

In the current context of healthcare budget constraints, StrokEnomics aims to provide solutions to the specific needs of physicians.

These needs include having enough staff members to treat patients 24/7, funding of the procedure, having the correct equipment and being able to afford the latest devices.

Initially, the adoption of a treatment is based on both the results of randomised clinical trials and real-world data.

horizon, including transportation costs, acute costs and long-term costs.

The effectiveness results that arise from clinical trials can be extrapolated to a patient’s lifetime horizon. For example, in five studies, MR CLEAN,1 EXTENDIA,2 ESCAPE,3 SWIFT PRIME,4 and REVASCAT,5 mechanical thrombectomy with stent retriever plus IV t-PA was found to be cost-effective compared to IV t-PA alone.

Although there is a higher cost associated with the stent retriever itself, it is offset by the cost savings resulting from lower long-term care costs due to improved patient outcomes.

The cost-effectiveness of the technique used within DAWN6—the trial suggesting evidence for the efficacy of treating latewindow patients (beyond six to 24 hours after symptom onset)—was also analysed.

The analysis demonstrated that Stryker’s

Subsequently, there is a focus on the treatments’ economic evidence, based on the cost-effectiveness analysis as well as budget impact analysis. StrokEnomics helps provide the most efficient strategy based on these analyses, and by taking into account treatment efficacy and long-term costs.

The efficiency is defined by the incremental cost-effectiveness ratio This ratio is the difference in terms of the cost and effectiveness of two treatment approaches, for example: stent retrievers plus IV t-PA, versus IV t-PA alone. This difference not only refers to the product price, but also the overall cost of the two approaches throughout a patient’s lifetime

stent retriever—Trevo—plus standard medical care (compared to standard medical care alone), was cost-effective in the UK for the National Health Service (NHS) on a 20-year time horizon.

Specifically, the cost-effectiveness results of the DAWN study patients indicated that at 12 hours after symptom onset, mechanical thrombectomy is cost-

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effective, having elicited an incremental cost-effectiveness ratio of US$1,564 per quality-adjusted life year (QALY).

Moreover, at 24 hours after symptom onset, the extracted incremental cost-effectiveness ratio was US$3,712 per QALY, providing further evidence for the cost-effectiveness of the technique.

Through such analyses, it can be said that there is no doubt that investing in mechanical thrombectomy treatment is worth it for payers. Thus, through StrokEnomics, Stryker remains committed to partnering with providers to effectively navigate the increasingly complex healthcare environment.

Alongside seeking to improve the scientific knowledge of certain treatment techniques, to help inform decisionmakers, Stryker leverages knowledge and experience through collaborative consultation. Developing comprehensive, customised strategies, Stryker explores targeted opportunities and delivers proven solutions that help drive both economic value, and patient outcomes.

References 1. Berkhemer, OA, Fransen, PS, Beumer, D, et al. (2015). A randomized trial of intraarterial treatment for acute ischemic stroke. New England Journal of Medicine, 372(1), 11-20.

2. Campbell, BC, Mitchell, PJ, Kleinig, TJ, et al. (2015).

Endovascular therapy for ischemic stroke with perfusionimaging selection. New England Journal of Medicine, 372(11), 1009-1018.

3. Goyal, M, Demchuk, AM, Menon, BK, et al. (2015).

Randomized assessment of rapid endovascular treatment of ischemic stroke. New England Journal of Medicine, 372(11), 1019-1030.

4. Saver, JL, Goyal, M, Bonafe, A, et al. (2015). Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke.

New England Journal of Medicine, 372(24), 2285-2295.

5. Jovin, TG, Chamorro, A, Cobo, E, et al. (2015). Thrombectomy within 8 hours after symptom onset in ischemic stroke. New England Journal of Medicine, 372(24), 2296-2306.

6. Nogueira, RG, Jadhav, AP, Haussen, DC, et al. (2018).

Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. New England Journal of Medicine, 378(1), 11-21.

May 2019

Committed to training excellence

SKILL� Stroke Knowledge Initiatives for Learning and Leadership

Stryker is maintaining their global commitment to advancing patient care. Nurses and physicians through to technicians and key caregivers can all benefit from Stryker’s tailored ischaemic and haemorrhagic stroke programme, as it supports the need to address the challenges of patient management, with the ultimate goal of improving lives.

STRYKER’S SKILL E-LAB PROVIDES AN interactive, experiential e-learning platform.

This in-depth form of digital communication enables those in need of flexible learning to benefit from further knowledge on anatomy, pathology, patient management, procedures, techniques and more, with the online resource directly accessible to the user’s desktop or laptop.

Moreover, SKILL also incorporates further education opportunities for neurointerventional fellows through the NeuroElite fellows programme. While the curriculum provides a dynamic platform for the exchange of knowledge during the fellow’s final year of residency, the programme also provides networking events aimed at promoting discussion with peers.

The interactive and personalised course enables access to resources and training sessions led by respected experts. Designed to further facilitate and support the training of neurointerventional fellows, the programme

includes hands-on product experience, simulation trainings and national symposiums.

SKILL's centres of excellence play a key role in the educational programme and offer a full range of learning opportunities to participants, including: live cases, case discussions, lectures and practice with flow models, simulators and animal labs; the course equips its participants with the resources and knowledge to stay ahead of evolving patient management trends.

Emphasising the importance of building a strong foundation of basic sciences, professional standards, and clinical training, Stryker’s centres of excellence around the globe offers a full training pathway.

While on-site education from leading experts and institutions is provided, each course is also customised based on learning needs, with progressive levels of training to advance neurointerventional education.

With Stryker’s worldwide network of SKILL training centres, fellows and

healthcare professionals can enjoy a unique global training experience. Fully equipped labs and customised curriculums offer targeted and personalised training with comprehensive, state-of-the-art facilities and resources. Maintaining their dedication to improving patient care, Stryker’s globally connected training centres deliver further hands-on learning opportunities, involving: simulation, flow models, emerging virtual technologies and C-arm and other leadingedge lab equipment.

Specifically, through these training centres, Stryker offers computer-assisted medical simulation technology for the experiential training of neurointerventional procedures.

With a realistic, reproducible and safe environment, these simulations allow users and participants to assess and enhance their procedural skills. Additionally, this technology enables healthcare professionals to create a personalised curriculum, and customise programmes with progressive levels of training.

Complementing this technology, Stryker’s training centres also allow healthcare professionals to develop the technical aspects of neuroendovascular procedures and treatments, through the use of flow models. Performed under real-time simulated fluoroscopy, participants can reinforce their skills in treatments such as: diagnostic angiography, aneurysm embolisation with coils, balloon and stentassisted coiling, mechanical thrombectomy, angioplasty, and stenting.

These SKILL training centres of excellence, alongside Stryker’s e-lab platform and NeuroElite fellows programme, combine to provide a truly innovative and holistic approach to both ischaemic and haemorrhagic stroke education. With the shared and ultimate goal of improving patient lives, Stryker is committed to partnering with fellows and healthcare professionals alike to advance patient care with the right medical education at the right time in their career.

SKILL training centres provide a truly innovative and holistic approach to both ischaemic and haemorrhagic stroke education.”

All rights reserved. Published by BIBA Publishing, London T:+44 (0)20 7736 8788, publishing@bibamedical.com.

The opinions expressed in this supplement are solely those of Stryker and the featured physicians and may not reflect the views of NeuroNews.

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