NeuroNews issue 51 – OUS

September 2023 | Issue 51

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Featured in Laurent Pierot: does the future this issue: What of endovascular aneurysm care hold? page 6

ESOC: New data on ICH treatments, stroke thrombectomy and more page 13

New data on AVM intervention “refute” complication rates seen in ARUBA trial

Profile Ameer Hassan page 20

(NVQI-QOD) AVM registry to results from ARUBA itself, reviewing patient information from 18 US centres.

The researchers analysed the records for ARUBA-eligible patients with similar demographics and AVM characteristics, finding that more patients survived and did well clinically after AVM treatment, as compared to those in the ARUBA study.

Only 8.7% of those operated on in their study died or had a stroke, compared to 30.7% in ARUBA, while just 25.4% of patients from the database experienced postoperative physical impairment, contrasting with the 46.2% observed in ARUBA. Nearly 10 years on from the “controversial” The study authors also found no difference in the risk of stroke results of ARUBA, an analysis of patients who and/or death between the different surgical modalities used. would have been eligible for the seminal trial has In addition to the “remarkably lower”, statistically significant seen unruptured arteriovenous malformation complication rate in their NVQI-QOD study versus ARUBA, (AVM) treatments achieve a “remarkably lower” Moore highlighted the fact that the 8.7% rate of complications complication rate—a finding that senior author of is also superior to that seen in the original trial (10.1%). this new research Nina Moore (Cleveland Clinic, Speculating on the reasons behind these discrepancies between Cleveland, USA) says should “refute” the original the two studies, she noted that the high rate (>50%) of refused study’s negative safety outcomes. enrolment in ARUBA; specialised nature of the centres contributing data to the NVQI-QOD; treatment distribution hese findings are important for all treatment options differences, including a smaller percentage of microsurgeries for unruptured AVMs: open surgical resection in the original trial; and the “rapid strides” made and “wealth [microsurgery], radiosurgery, and of experience” behind endovascular therapy, are all endovascular embolisation,” Moore told potential factors.

NeuroNews. “There is a cumulative risk “Our results suggest that intervention for of cerebral AVM rupture over a patient’s unruptured brain AVMs at comprehensive stroke lifespan. The ARUBA trial had a relatively centres across the USA is safe and effective,” short follow-up time period and, [as per] our Moore summarised, also pointing to larger findings, leaving an unruptured AVM alone is patient numbers in their analysis versus the ARUBA Nina Moore likely a greater risk than treatment by any method.” treatment arm, and stating that these fresh, “real-world” (L) and Anas The long-term ARUBA trial randomised patients data should therefore “refute” ARUBA’s near-decade Alrohimi to medical management (MM) alone versus MM plus old findings. interventional treatment in unruptured AVMs, and found the “Seeing through these data that neurointerventionists and former to be non-inferior to the latter. The trial has been widely neurosurgeons can safely treat unruptured brain AVMs via criticised since its publication in 2014, primarily owing to the different surgical modalities is very encouraging,” Alrohimi limitations of its design and methodology and, by extension, the added. “In this constantly evolving field, it is crucial we poor generalisability of its results. continue to investigate new procedures that impact the Presenting a far more recent analysis of 173 patients patients’ outcomes.” who met ARUBA’s inclusion criteria at the Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July– 4 August, San Diego, USA), primary author Anas Alrohimi (Cleveland Clinic, Cleveland, USA) stated that, contrary to ARUBA’s “controversial” findings, subsequent research has indicated that unruptured AVMs can be successfully operated on in carefully selected patients. Moore, Alrohimi et al conducted a new, retrospective study in which they compared real-world data from ARUBA-eligible patients in the NeuroVascular Quality Initiative-Quality Outcomes Database

“T

[As per] our findings, leaving an unruptured AVM alone is likely a greater risk than treatment by any method.”

“Striking errors” prompt call to retract and revise recent SCS review page 31

Craniotomy and decompressive craniectomy achieve similar outcomes in acute subdural haematoma THE TWO PREVAILING techniques used during surgical treatments of traumatic acute subdural haematomas (SDHs)—craniotomy and decompressive craniectomy—have demonstrated broadly similar efficacy outcomes in a randomised controlled trial (RCT). However, reporting their findings in the New England Journal of Medicine (NEJM), researchers note an increased rate of additional cranial surgery in patients who underwent the former procedure, and a higher proportion of wound complications in those who received the latter.

Peter Hutchinson (University of Cambridge, Cambridge, UK), the trial’s chief investigator, said: “The international randomised trial RESCUE-ASDH is the first multicentre study to address a very common clinical question: which technique is optimal for removing an acute SDH—a craniotomy or a decompressive craniectomy?

This was a large trial, and the results convincingly show that there is no statistical difference in the 12-month disability-related and quality-of-life outcomes between the two techniques.”

In their report, Hutchinson and colleagues initially highlight the fact that, while a craniectomy may help to prevent intracranial hypertension, as it does not involve replacing the bone flap removed during surgical Continued on page 2

September 2023 | Issue 51

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Craniotomy and decompressive craniectomy achieve similar outcomes in acute subdural haematoma Continued from page 1

evacuation, it is “unclear” whether the procedure is associated with better outcomes as a result.

To investigate this further, they conducted a prospective, multicentre RCT—referred to as RESCUE-ASDH— enrolling a total of 450 patients (>16 years old) with a head injury in whom evacuation of an acute SDH was warranted. Some 228 patients were randomised to undergo a craniotomy during surgery, while 222 were assigned to decompressive craniectomy. Disability-related outcomes were the researchers’ key focus, with the study’s primary outcome being ratings on the eight-point extended Glasgow outcome scale (GOSE) at 12 months. Secondary outcomes included six-month GOSE ratings and 12-month quality-oflife measures (EQ-5D-5L).

Disclosing the results from RESCUE-ASDH, Hutchinson et al relay that, at 12 months, overall GOSE ratings “did not differ significantly” between the two groups (common odds ratio [OR], 0.85; 95% confidence interval [CI], 0.60–1.18; p=0.32). They detail that, more specifically, death had occurred in 30.2% of patients in the craniotomy group and 32.2% in the craniectomy group; a vegetative state occurred in 2.3% and 2.8%, respectively, and a lower- or upper-good recovery occurred in 25.6% and 19.9%. Six-month GOSE ratings and 12-month quality-of-life measures were also similar across both procedural techniques.

Notable differences were, however, seen between the two groups regarding further cranial surgeries, with 14.6% of patients who underwent a craniotomy requiring additional procedures within two weeks post-randomisation, compared to just 6.9% in the craniectomy patient cohort—a percentage-point difference of 7.6 (95% CI, 0.01–0.14).

In addition, a statistically significant difference in wound complication rates was also observed, with surgical-site infections and other, similar complications occurring in 3.9% of craniotomy patients versus 12.2% in the craniectomy group (p=0.001).

Limitations of the study outlined by Hutchinson et al include the fact that clinicians were aware of the trialgroup assignments; outcome data being obtained by postal questionnaires or telephone interviews rather than clinical examination and in-person interviews; and a small percentage of patients in each group undergoing the alternate treatment to their initially assigned procedure.

Angelos Kolias (University of Cambridge, Cambridge, UK), the trial’s co-chief investigator, said: “Based on the trial findings, we recommend that—after removing the blood clot—if the bone flap can be replaced without compression of the brain, surgeons should do so, rather than performing a pre-

emptive decompressive craniectomy. This approach will save patients from having to undergo a skull reconstruction, which carries the risk of complications and additional healthcare costs, further down the line.”

In an editorial published concurrently in NEJM with these RESCUE-ASDH results, Shankar Gopinath (Baylor College of Medicine, Houston, USA) avers that RCT data on whether or not to replace a patient’s bone flap during many acute SDH surgeries “have been lacking” and, as such, describes Hutchinson et al’s findings as “welcome”.

“In the past decade, the majority of patients would undergo craniotomy, but for the past few years craniectomy has been performed more often than craniotomy,” Gopinath writes. “With these results, I expect that surgeons will be reassured that it is relatively safe to perform the quicker procedure of removal of the bone, knowing that—if the bone is left in place—compression of the brain under the haematoma and the need for reoperation can largely be prevented. Because the incidence of local infections was low in both trial groups, but was admittedly higher with craniectomy, the trial also showed that the price paid for choosing the quicker procedure is medical complications; most of which are treatable, such as infection related to repairing or replacing the skull defect—a trade-off for fewer intracranial risks that might be considered satisfactory.”

With these results, I expect that surgeons will be reassured that it is relatively safe to perform the quicker procedure of removal of the bone, knowing that [...] compression of the brain under the haematoma and the need for reoperation can largely be prevented.”

Shankar Gopinath

Peter Hutchinson (L) and Angelos Kolias

News in brief

The latest stories from the neuro world

n CONTINUED EXPANSION OF STROKE THROMBECTOMY TAKES SPOTLIGHT AT SNIS 2023: The diversification of mechanical thrombectomy treatments into new indications and populations of ischaemic stroke patients was at the fore of this year’s Society of NeuroInterventional Surgery (SNIS) annual meeting programme. The early administration of antiplatelet medications, large-core infarct volume patients, and children with large vessel occlusion stroke, all featured.

For more on this story go to page 4. n FLOW-DIVERTER PERFORMANCE “COMPARABLE” BETWEEN PCOMAS AND OTHER SUPRACLINOID ANEURYSMS: The concluding findings of a systematic review and meta-analysis published in the journal Neurosurgery

by Santiago Ortega-Gutierrez (Iowa City, USA) and colleagues indicate that flow-diverter performance in posterior communicating artery (PComA) aneurysms is “comparable” to the outcomes observed in other supraclinoid aneurysm subtypes.

For more on this story go to page 8. n FIRST-TIME DATA RELEASES “CONFIRM” ROADSAVER CAROTID STENT SAFETY AND EFFICACY: Presenting firsttime data from large, multicentre European studies at the 2023 Leipzig Interventional Course, Arne Schwindt (Münster, Germany) and Ralf Langhoff (Berlin, Germany) delivered results supporting the safety and efficacy of Terumo’s Roadsaver dual-layer micromesh stent in carotid artery disease patients.

For more on this story go to page 24.

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September 2023 | Issue 51

Stroke Thrombectomy

SNIS

Continued expansion of stroke thrombectomy takes spotlight at SNIS 2023 The diversification of mechanical thrombectomy treatments into new indications and populations of ischaemic stroke patients was at the fore of this year’s Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August, San Diego, USA) programme. Large-core infarct volume patients and children with large vessel occlusion (LVO) stroke are among the latest groups in which the benefits of endovascular stroke interventions have been elucidated, as per data presented at SNIS 2023.

H

owever, the opening day of the conference saw a study delivered that, if bolstered by further research, may have even wider implications in the field. Findings from a single-institution registry were presented to attendees, and revealed that administering antiplatelet medication within 24 hours of a thrombectomy procedure may help stroke patients recover more successfully as well as preventing high-risk individuals from experiencing additional strokes.

While antiplatelet medication prevents blood clots from forming—and potentially causing strokes—by keeping platelets from sticking together, it can also cause brain bleeding if administered soon after a thrombectomy.

To find a way to safely use antiplatelets without causing additional risks, researchers reviewed data from 190 patients who underwent this treatment between 2016 and 2020, and categorised patients by those who received antiplatelet medication less than 24 hours after surgery, and those who received the medication later.

They noted that emergent LVO stroke patients who received antiplatelet medication within 24 hours of a thrombectomy were significantly more physically independent at discharge from the hospital than patients who received the antiplatelet medication later. This difference was maintained longer-term as well, with patients who received early antiplatelet medication having much better physical functioning scores both one month and three months after surgery.

In addition, there was no sign that giving patients antiplatelet medication earlier led to an increased risk of brain bleeding after surgery.

“Continuously working to improve patient outcomes is one of our top priorities,” said Hepzibha Alexander (Ascension Providence Hospital, Southfield, USA), lead author of the study. “Finding a new way to safely use this already-essential medication is an exciting step forward in helping patients thrive after stroke.”

Thrombectomy in more severe strokes

A study also presented on the first day of SNIS 2023 found that US rates of stroke thrombectomy are projected to increase “dramatically” based on new eligibility criteria.

Recent studies—including the MAGNA metaanalysis and TESLA trial, both of which were disclosed earlier this year at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany)— have suggested that thrombectomy is a viable option for treating ischaemic stroke patients with large-core infarct volumes, opening up the potential for more people to undergo the procedure. To read more about these trials, turn to page 17.

Examining the projected increase in thrombectomy volumes based on findings from these large-core studies, researchers reviewed nationwide hospital admission data from 2016–2019 for people who were classified as having an ischaemic stroke in the USA. Using the new eligibility criteria for largecore ischaemic strokes, they then reclassified some

patients—who did not receive stroke surgery—as new candidates for a thrombectomy procedure.

According to the study authors’ projections, this new eligibility criteria could increase rates of thrombectomies in the USA by 14–37%. These additional surgeries present new opportunities for patients to get the correct care, but may prove difficult to manage for hospitals without sufficient

The SNIS annual meeting also featured the latebreaking presentation by SNIS past president Michael Chen (Rush University Medical Center, Chicago, USA) of an analysis that sought to elucidate the “surprisingly low” intracranial haemorrhage (ICH) rate of 0.6% observed in the SELECT2 trial—another recent randomised controlled trial (RCT) supporting thrombectomy’s benefits in large-core stroke patients.

In an effort to better understand baseline characteristics and outcomes associated with patients experiencing any ICH, and to potentially allay ongoing concerns surrounding ICH risks linked to thrombectomy procedures, Chen et al performed a subgroup analysis of SELECT2 data. They found that patients receiving thrombectomy had a higher rate of any ICH when compared with those receiving medical management. However, while thrombectomy patients with ICH had a higher incidence of early neurological worsening, there was no difference in 90-day modified Rankin scale (mRS), mortality and discharge dispositions between those with or without ICH. Chen noted that, based on these findings, there appears to be an inverse relationship between core size and ICH relevance—meaning that the trend between large-core infarct volumes and ICH is ‘juxtaposed’ to that of smaller-core strokes. He further concluded that measures to reduce the incidence of ICH in large-core thrombectomy cases are “likely inconsequential”.

Parity between adult and child patients

Michael Chen

Seeing that our best standard treatment for adults with severe stroke is also extremely effective for children is encouraging. It is very meaningful to know that we can safely use this time-tested, minimally invasive procedure to get children back to their families, recovering quickly, and thriving.”

Matt Findlay

neurointerventionists on staff to perform them.

“These outcomes are inspiring, and this information gives us an important opportunity to evaluate current stroke treatment efforts across the country,” said Osman Mir (Texas Stroke Institute, Plano, USA), lead author of the study. “In addition, these numbers clearly show that we need to invest more fully in our capacity to ensure that every stroke patient across the USA can access this high-quality treatment if—or when—they need it.”

Another study presented during the conference led researchers to note that mechanical thrombectomy—in addition to its usage in adults with LVO stroke—is also safe and effective for treating children.

Owing to the fact that, although thrombectomies are performed in children, data regarding safety and efficacy are “less robust” than in adults, researchers conducted a systematic review and meta-analysis comparing post-thrombectomy outcomes for acute ischaemic stroke due to an LVO in children versus adults.

They reviewed eight studies involving 192 children who received a stroke thrombectomy, and compared these children’s post-thrombectomy improvements with those of adults who underwent the same procedure. Their primary outcome was a change in National Institutes of Health stroke scale (NIHSS) score from presentation to 24 hours after thrombectomy.

The analysis revealed that children experienced better outcomes than adults in many of the study’s secondary measures, including higher rates of good neurological outcomes after surgery (90-day mRS 0–2; 76.1% vs 46%); better rates of recanalisation (88.5% vs 72.3%); fewer major periprocedural complications (4.7% vs 30.4%), and lower mortality rates (1% vs 12.9%).

In addition, as per the primary outcome, a mean NIHSS score reduction of 7.37 was observed among the included children, while assessments of data from 634 adult patients across five clinical trials demonstrated a mean NIHSS score reduction of 6.87.

As such, the magnitude of NIHSS reduction was similar between adults and children.

“Seeing that our best standard treatment for adults with severe stroke is also extremely effective for children is encouraging,” said Matt Findlay (University of Utah School of Medicine, Salt Lake City, USA).

“It is very meaningful to know that we can safely use this time-tested, minimally invasive procedure to get children back to their families, recovering quickly, and thriving.”

Writing in the Journal of NeuroInterventional Surgery, where these findings have since been published, the researchers conclude that thrombectomy is safe and effective in paediatric acute ischaemic stroke patients—“endorsing consideration of this intervention in children presenting with LVO”.

Issue 51 | September 2023

Smartphone app reliably and autonomously recognises physical stroke signs in study DURING A LATE-BREAKING abstract session at this year’s Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August, San Diego, USA), researchers discussed a smartphone application that can reliably, autonomously recognise patients’ physical signs of stroke thanks to the power of machine learning algorithms.

In the study, researchers from the

Novel Approaches University of California Los Angeles (UCLA) David Geffen School of Medicine (Los Angeles, USA) and multiple medical institutions in Bulgaria used data from 240 patients with stroke at four metropolitan stroke centres.

Within 72 hours of the start of the patients’ symptoms, researchers used smartphones to record videos of patients and test their arm strength in order to detect patients’ facial asymmetry, arm weakness, and speech changes—all typical signs of a stroke.

To evaluate facial asymmetry, the study authors used smartphone-enabled machine learning to analyse 68 facial landmark points. To test arm weakness, they used data from a smartphone’s standard internal 3D accelerometer, gyroscope, and magnetometer.

To determine speech changes, the researchers used mel-frequency cepstral coefficients—a typical sound recognition method that translates sound

‘Care hotel’ model can lower costs and shorten hospital stays after elective neurointerventions Using a ‘care hotel’ model, which discharges patients to a specialty hospital hotel after smaller surgeries, can lower costs and shorten patients’ time in the hospital following some elective neuroendovascular interventions. That is according to a study presented recently at the Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August 2023, San Diego, USA).

AS STATED IN AN SNIS PRESS release, rising healthcare costs pose a significant financial burden across the USA—and this has been especially prevalent since the start of the COVID-19 pandemic. Researchers at the Mayo Clinic Florida (Jacksonville, USA) recently tried a new approach: moving patients to a care hotel after surgery.

In a study detailing a singleinstitutional experience, and in which the safety and feasibility of this care hotel model was evaluated, Mayo Clinic researchers reviewed data for 78 patients who were slated to have elective neuroendovascular interventions, including aneurysm treatments. A total of 42 patients were enrolled, received same-day surgery and were discharged to a care hotel instead of being admitted to the hospital after their procedures.

While staying at the care hotel, patients were monitored by nurses and had immediate access to the

42

patients receiving neuroendovascular interventions enrolled

on-campus hospital if needed. All patients were discharged home the following day, except for one person with lingering numbness who was hospitalised for two days. Based on economic calculations, this resulted in savings of US$1,500–US$2,600 per procedure. One hospital bed was also saved for other potential patients who required hospitalisation.

Overall, the study authors found this fast-track model to be safe, feasible and cost-effective for qualified patients.

“Using a care hotel can help carefully selected patients reduce their time in the hospital after non-emergency procedures while maintaining high-quality care and outcomes,” said Rabih Tawk (Mayo Clinic Florida, Jacksonville, USA).

“It is a promising model, as they can save time and money while recovering in a more comfortable place, and the hospitals can keep more beds available for emergency cases.”

US$1,500–US$2,600 cost saving per procedure

waves into images—to compare normal and slurred speech patterns.

They then tested the app using neurologists’ reports and brain scan data, finding that the app was sensitive and specific enough to diagnose stroke accurately in nearly all cases.

“It is exciting to think how this app and the emerging technology of machine learning will help more patients identify stroke symptoms upon onset,” said Radoslav Raychev (UCLA David Geffen School of Medicine, Los Angeles, USA), who delivered these findings at SNIS 2023, and is the CEO and co-founder of Neuronics Medical, which develops the FAST.AI app assessed in the present study. “Quickly and accurately assessing symptoms is imperative to ensure that people with stroke survive and regain independence.

We hope the deployment of this app changes lives and the field of stroke care.”

At SNIS, Raychev concluded that these preliminary results confirm smartphone-enabled machine learning algorithms can identify acute stroke features “with accuracy comparable to neurologists’ clinical impression”.

It is exciting to think how this app and the emerging technology of machine learning will help more patients identify stroke symptoms upon onset.”

Less invasive ‘liquid biopsy’ holds potential to identify genetic mutations in some paediatric AVMs A study presented at the recent Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August, San Diego, USA) indicates that it may be possible to use a less invasive technique to identify the gene mutations responsible for some arteriovenous malformations (AVMs) in paediatric patients.

A

VMs—including vein of Galen malformations (VOGMs), which are usually diagnosed soon after birth—are tangled blood vessels that disrupt blood flow and oxygen circulation, and are most often found in the brain and spinal cord. These vessels can rupture and cause brain haemorrhage, stroke and brain damage in children and adults.

Kartik Many complex AVMs in children Bhatia are caused by a few specific gene mutations but, as outlined by an SNIS press release, it is difficult to find out which mutation is responsible—and, therefore, which treatment to use—without taking a surgical biopsy of the AVM. In addition, surgical biopsies come with a risk of brain bleeding.

As such, researchers in Australia opted to try using ‘liquid biopsy’, taking blood samples from veins near or within the AVM to identify the gene mutations and move forward with treatment plans for the affected children. They were particularly interested in the local mutations in VOGMs, which have not been previously identified because the risk of a surgical biopsy was considered too high.

In their study, entitled “Liquid biopsy identifies somatic KRAS [Kirsten rat sarcoma viral oncogene homologue] mutations in paediatric cranio-spinal arteriovenous malformations: preliminary results”, the researchers were cleared to take liquid biopsies from 11 patients with documented brain or spine AVMs. So far, seven patients received genetic testing, and three of those patients were found to have AVM-related gene mutations. Two patients have commenced treatment with gene-directed targeted medications, with improved health or reduced symptoms since their treatment.

“These early results are promising and show that liquid biopsy is a potential option for identifying gene targets for pharmacotherapy in these complex AVM cases in children that cannot be safely biopsied by open surgery,” said Kartik Bhatia (Sydney Children’s Hospitals Network, Sydney, Australia), who presented these findings during the late-breaking abstracts session at SNIS 2023.

“Being able to more easily and safely identify these gene mutations means that more children with these disorders may be able to get access to treatment that improves their quality of life.”

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September 2023 | Issue 51

Aneurysm Care

INTERVIEW

Continued improvement of flow diverters and intrasacculars holds key to truly advancing aneurysm care Laurent Pierot’s (Reims University Hospitals, Reims, France) long career in the treatment of intracranial aneurysms predates not only what many consider to be the advent of the interventional neuroradiology (INR) specialty, the ISAT trial, but also the introduction of the Guglielmi detachable coil (GDC) in 1990. Speaking with NeuroNews, he draws on the major shifts and trends he has observed over the past three decades to speculate on what INR’s future may hold.

“I

started training with Jacques Moret a little bit before the GDCs were available, in 1985,” he recalls. “At that time, we were still treating aneurysms with a balloon—you can imagine, it was a big mess. We started the procedure at 9am and finished at around 3pm!”

But, he continues, the ISAT trial—published in The Lancet in 2002—“changed everything” by establishing the role of endovascular coiling alongside neurosurgical clipping as a viable aneurysm therapy.

While this may remain the single most important moment in the relatively short history of INR, Pierot has witnessed numerous other advancements in aneurysm care over the past 20 years—even playing a direct role in many of them.

Balloons and stents have both been used as adjunctive, supporting devices during coil embolisation procedures, with Pierot and many of his colleagues in France preferring the former technique, while those in the USA and Germany are traditionally more reluctant to use balloon-assisted coiling and thus tend to gravitate towards stenting.

“What we were always missing was a study demonstrating the benefits of stenting in terms of recanalisation,” Pierot notes. “There were some subgroup analyses, yes, but what we needed was a randomised controlled trial [RCT]; and we still do not have it. For that reason, I do not use many stents, because we have no proof that it is reducing the recanalisation rate and, now, most of the time, I will use flow diverters, as their benefit is clearly established.”

Here, Pierot touches on the next key development in endovascular aneurysm treatment: the introduction of flow diversion, and devices like Pipeline (Medtronic), Silk (Balt) and Surpass (Stryker), nearly 15 years ago. He notes that, while earlier flow-diverter trials like PUFS indicated “excellent” efficacy results but at the cost of relatively high complication rates, more recent studies indicate that modern flow-diversion technologies can achieve comparable safety outcomes to coiling.

“In 10 years, the safety has dramatically improved, with a reduction in complication rates—probably due to the improvement of devices and also the skills of the physicians,” Pierot avers, before highlighting the FRED (Microvention/Terumo) and P64 (Phenox/ Wallaby) flow diverters that have come to the fore more recently.

Present day

Along the timeline of INR innovation, the latest major introduction has been that of intrasaccular devices, most notably with the well-established Woven EndoBridge (WEB; Microvention/Terumo) and, more recently, the Contour (Cerus/Stryker) system in Europe. Pierot describes the arrival of the WEB device

on the market as a “tremendous change” in clinical practice, and one that opened up vital new possibilities in the treatment of more challenging intracranial aneurysms.

“You have to realise that we were facing these very wide-neck bifurcation aneurysms and I remember, before WEB, I can tell you that I was not very comfortable treating these kinds of aneurysms, because it was a difficult task,” he notes. “So, WEB really changed the face of the treatment of this aneurysm subgroup.”

With coiling, flow diversion and now intrasaccular devices all constituting staple parts of an interventional neuroradiologist’s armoury, Pierot feels there is a certain equilibrium that can be seen across current technologies used to treat aneurysms.

“I am sure of one thing and, when I discuss with industry, they say the same thing: as of now, the number of coils, globally, is not increasing—except in developing countries where the evolution of endovascular aneurysm treatment is still happening,” Pierot says. “But, in the USA and Europe, the rate of coiling is more or less stable. And, in my mind, the future of aneurysm treatment is clearly flow diverters and intrasaccular devices.”

Far from the seismic shifts brought about by GDCs, the ISAT study, and the principle of flow diversion being established, Pierot believes more incremental improvements to these already available tools are on the horizon.

“For the time being, I do not see so many innovations coming onto the market,” he continues, “and I think the most important innovation we will have is surface modification of flow diverters because—if it works—maybe we will be able to use flow diverters in ruptured aneurysms.”

able to use a flow diverter with single antiplatelet therapy [SAPT] in more ruptured aneurysm cases, and during the acute bleeding phase,” Pierot says, alluding to the potential held by surface modification as a means for removing the need for patients to receive dual antiplatelet therapy (DAPT) following flowdiverter placement.

Flow-diverter technologies like the Pipeline Shield (Medtronic) and P64 MW with hydrophilic coating (HPC; Phenox/Wallaby) are notable examples of existing devices ‘coated’ with agents designed to reduce platelet aggregation—meaning patients can, in theory, receive SAPT rather than DAPT without an increased risk of haemorrhagic complications.

Pierot has been heavily involved in several trials that have proved key to establishing today’s INR practices, including ATENA and CLARITY— which evaluated coiling in unruptured and ruptured aneurysms, respectively—as well as the first three European studies assessing WEB. And, now, as the principal investigator for the COATING study involving the P64 MW with HPC, he is at the forefront of what he believes may be the next major leap forward in endovascular aneurysm care.

In addition to establishing the principle of surface modification, if successful, he believes COATING could be the “first step” towards opening the door for flow diversion to be deployed across a greater range of aneurysm types, with further subsequent trials being necessary to truly ascertain if surface-modified devices can be used in ruptured aneurysms.

“And, for unruptured aneurysms, it is completely clear in my mind that we no longer have to use coils— at least as the primary treatment,” Pierot goes on. “We have to use intrasaccular devices or flow diverters, and coiling is for a limited number of indications.”

He also feels that a question mark remains over the respective indications of intrasaccular devices and flow diverters in bifurcation aneurysms, noting that a comparative study may be required in this space.

“In the beginning, WEB was the most indicated device for bifurcation aneurysms, and flow diversion was criticised because it means you are obliged to cover one branch of the bifurcation, leading to its occlusion or reduction in size and potentially causing a stroke,” Pierot says, adding that, as such, he was “very reluctant” to use flow diverters in these cases.

However, technological improvements and fresh studies over the past few years have led to these devices being considered a far more viable option in bifurcation aneurysms.

Ruptured versus unruptured

As things stand, the two endovascular options for the vast majority of ruptured aneurysm cases are coils and intrasaccular devices. According to Pierot, while a comparative RCT to evaluate the two against one another has never been conducted, both techniques are “very safe” and any differences between the two on this front “will not be large”.

In addition, both have demonstrated their efficacy, with large-scale studies showing the WEB device can achieve “similar protection” against rebleeding as compared to coiling.

Conversely, the use of flow diversion in ruptured aneurysms is currently limited to a handful of “very specific” indications, such as ‘blisterlike’ aneurysms, which are too small to be treated via coil or intrasacculardevice placement.

“But maybe what will change in the future is that we will be

Laurent Pierot

Issue 51 | September 2023

Aneurysm Care

And, while Contour is more of a newcomer in the intrasaccular space, and is yet to be bolstered by the same evidence base behind WEB, Pierot believes more stringent evaluations of the device could be imminent following its acquisition by Stryker earlier this year. He goes on to note that available data on this device are “very limited”, and that large-scale studies will be needed to confirm its safety, as well as long-term follow-up results to evaluate efficacy.

Nevertheless, Pierot does highlight a key theoretical benefit of Contour: the fact it comes in a far smaller number of sizes compared to WEB and, thus, could help to reduce the complexity of some treatment decisions.

Looking forward

Pierot chooses to divide possible future advancements in aneurysm care into two categories, with the first concerning more novel technologies like robotics, which could lead to improved precision and even remote procedures further down the line, and artificial intelligence, which has the potential to support patient selection and treatment decisions. He also notes that flat-panel computed tomography and other imaging advances made by the likes of Philips and Siemens Healthineers, have occurred alongside the expansion of INR treatments, and will continue to do so.

The second, however—the devices themselves— is where improvements will truly alter the current indications of endovascular aneurysm treatments, he feels. Pierot highlights the significant changes longstanding flow diverters like Pipeline and Surpass

I am sure of one thing and, when I discuss with industry, they say the same thing: as of now, the number of coils, globally, is not increasing—except in developing countries where the evolution of endovascular aneurysm treatment is still happening.”

have undergone through the past decade, reporting from experience that newer generations of both are now easier to use as well as producing improved outcomes.

Some device innovations can be seen across much of the INR industry already; for example, Pierot notes, many companies are currently striving to reduce the sizes of their microcatheters in an effort to improve navigability and, thus, the safety of endovascular procedures. Others are more recent and carry less certainty—Pierot highlights a recent revival of interest in the use of liquid embolic agents to treat intracranial aneurysms, but admits scepticism given previous failings of Onyx (Medtronic) in this space.

“I think what we need is interaction,” Pierot concludes, speculating on what the INR community—physicians and industry alike—can do to push the field forward.

“We need to have interaction with the companies, and we need to have discussions with the engineers to see what new technologies and improvements to existing technologies they can bring us. And, we have to give them our feedback to ensure the continuous improvement of these devices.”

In coiling, he states that device improvements have been made over the course of the past 30 years but that, now, all shapes and sizes are available, and further significant advances are unlikely; “it is done”, Pierot comments regarding this area.

“So, what we have to work on is the continued improvement of flow diversion—for example, flow diversion with a material that will disappear after several days or weeks is something companies are working on—and of intrasaccular devices,” he states. “The main goal in aneurysm treatment is to maintain a high level of safety while improving efficacy and decreasing the rate of recanalisation.”

Closing the conversation, Pierot suggests ease of use is a key consideration regarding future devices, particularly as the INR specialty expands and draws in a greater number of young, less experienced operators.

“It is a concept I was not too supportive of at the beginning, but we now have an increasing number of physicians in the field so, for them, it is important to have a technology that is not too complicated to use,” he opines. “The ideal device would be one that is positioned at the level of the neck, blocking it, without placing anything inside the aneurysm sac, in order to stimulate endothelialisation and closure of the neck. So, the companies have to make a device like this to treat aneurysms in the future!”

1.

2.

From top right: 1. Guglielmi detachable coil 2. Pipeline flow diverter 3. P64 MW with hydrophilic coating 4. WEB embolisation system

4.

3.

7

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September 2023 | Issue 51

Aneurysm Care

Flow-diverter performance “comparable” between PComAs and other supraclinoid aneurysms The concluding findings of a systematic review and meta-analysis published in the journal Neurosurgery indicate that flow-diverter performance in posterior communicating artery (PComA) aneurysms is “comparable” to the outcomes observed in other supraclinoid aneurysm subtypes.

A

uthors Santiago Ortega-Gutierrez (University of Iowa Hospitals and Clinics, Iowa City, USA) et al note that effectiveness was “acceptable” and safety was “favourable” in their analysis of the existing literature in this space.

“However, effectiveness was suboptimal in patients with foetal-type PComAs; alternative treatments should be considered in these cases,” they add.

The authors preface their report by noting that, while flow diverters have demonstrated a safe and effective profile overall, their use in PComA aneurysms “remains controversial”—leading them to evaluate flow-diverter use in these case types via a

systematic review and meta-analysis.

A search from inception to June 2022 was performed for flow diversion in PComA aneurysms.

The researchers’ primary effectiveness measure was the rate of complete aneurysm occlusion (RaymondRoy occlusion classification [RROC] 1), with primary safety outcomes being a composite of treatment-related ischaemic/haemorrhagic events causing morbidity and mortality. PComA patency at follow-up was also among the review’s secondary safety measures.

A total of 13 studies including 397 patients (mean age=48 years) with 403 aneurysms (mean size=5.3mm) were included in the analysis. According to the authors, the majority of these aneurysms (65%) were unruptured. Regarding the key effectiveness metric, complete occlusion at final follow-up was 73%. The authors further report that adjunctive coils were used in 10% of aneurysms and that the retreatment rate was 2%.

The primary safety composite outcome was 4% and mortality was 1%, while PComA patency at final followup was 76%. Finally, as per subgroup analyses, patients

Insights from interventional neuroradiologists on coping with severe complications

Isabelle Demarre Point of View Given the potentially devastating consequences that can occur if an ischaemic stroke or acute intracranial aneurysm procedure goes wrong, an interventional neuroradiologist’s practice is inherently pressurised and extraordinarily demanding—even relative to the average physician. To gain insights on how they manage this everyday burden, Isabelle Demarre (Paris, France) conducted a survey among a number of doctors working in the interventional neuroradiology (INR) space. Here, she discusses the findings of this research and how they may be actioned moving forward.

A

lthough severe complications or deaths are rare in INR practice, the professional and personal psychological impact has barely been studied. As such, an exploratory, qualitative, retrospective and multicentric research project was conducted using a scientific framework. Eleven French interventional neuroradiologists were interviewed including a diversity of genders and years of experience.

The results showed that, even with complications in INR practice being rare, they are difficult to bear and become a real burden over the years. During the interviews, all

the interventional neuroradiologists expressed feelings such as helplessness, guilt, reduced self-confidence, and questioning of their skills. However, most of them do not want to show or express their emotions because they believe that they have neither a place in their professional environment nor in their personal one. And, occasionally, the fear of judgement can be a significant deterrent.

They seek to avoid being overwhelmed by their emotions, which become particularly strong when they put themselves in the place of the patient and/ or their family—especially in the case

with foetal PComAs had a lower complete occlusion rate (42%) than those with non-foetal PComAs (77%)—leading the authors to conclude that alternative treatments “should be considered” in these cases.

403 PComA aneurysms

73%

4%

Complete occlusion at final follow-up

Ischaemic/haemorrhagic events causing morbidity or mortality

2%

76%

Retreatment

PComA patency at final follow-up

of children and asymptomatic patients.

All the interventional neuroradiologists reported experiencing the announcement of a complication as a difficult moment, particularly when they have created a certain bond and established a relationship of trust with the patient and/or their family. To cope with such situations, interventional neuroradiologists mobilise various resources and implement several strategies.

Resources and strategies

When complications occur, all the participants agreed on the importance of team support. For instance, collegial decisions help to share the responsibility of the complication and might reduce the mental load of the operator. Subsequently, case reviews and moments of conviviality are other important resources.

Similarly, team cohesion is very essential. During announcements, it helps the operator to face the patient and/or their family, and to protect interventional neuroradiologists from possible legal proceedings. Most of them highlighted the morbidity and mortality meetings, which provide a time to exchange views on the technical aspects of the complications and probably help to avoid reproducing mistakes made by others. However, while these meetings are more oriented towards facts than feelings, it is also important to share and exchange feelings in order to become fully aware of them, and to associate the emotions felt to be able to better cope with them.

Besides these resources, some interviewees were willing to participate in a professional group supervised by a psychologist, which allows them to share and express feelings about their experience. And, a few participants agreed on the importance of having private support, such as a psychologist, to have the opportunity to speak freely.

The specificity of INR practice

Contrary to other specialties, INR practice deals with acute or elective cases, and symptomatic or asymptomatic cases, as well as adults and children.

It could raise different questions for the operator and, thus, lead to some psychological struggles, such as the decision of whether or not to treat or an asymptomatic patient. To intervene may save the patient’s life from the rupture of an aneurysm but may also lead to a complication causing severe disability or death. Taking this responsibility seems to be an extra weight for the operator, which increases their mental load.

In conclusion, it is essential for interventional neuroradiologists to express their emotions, either in the professional space or in their personal sphere. Doing so shall allow one to be fully aware of them, and assess and accept them. Lightening their mental load will help to alleviate the burden and may even prevent interventional neuroradiologists from experiencing burnout or post-traumatic stress.

Isabelle Demarre is a psychologist at Assistance Publique-Hôpitaux de Paris (AP-HP) in Paris, France.

“[…]

Even with complications in interventional neuroradiology practice being rare, they are difficult to bear and become a real burden over the years.”

Issue 51 | September 2023

Industry Insights

9

INTERVIEW

Observation, creativity and happy accidents: Transitioning from clinical life to industry work When it comes to advising young physicians on how to navigate the more commercial, industry-entwined commitments that their career will most likely bring further down the line, there are few better-placed physicians than Ajay Wakhloo (Burlington, USA)—an interventional neuroradiologist-turnedinventor and “accidental” businessman who was heavily involved in the development of multiple devices used by today’s neurointerventionists.

I

n January of this year, having most recently worked at the Lahey Hospital and Medical Center in Burlington, Wakhloo retired from his clinical and academic obligations to focus solely on research and development (R&D) via the three start-up companies he is currently involved with. These endeavours include photobiomodulation as a means for bringing regenerative medicine and ‘expedited healing’ into the world of endovascular aneurysm treatments.

“Before that, I was doing about 20% industry and 80% clinical work—so I was a little bit concerned about leaving the clinical space and missing it,” Wakhloo admits. “But, I have to say, the device world and new technology is something that makes a big difference to patient care, and I find the innovation part very attractive too.”

Sitting down with NeuroNews at the recent Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August 2023, San Diego, USA), Wakhloo recalls that such overt levels of physician involvement with medical technology companies was “not visible, and not as prevalent” as it is today compared to when he was training.

“It has changed—there is an acceptance now that it is part of a doctor’s life,” he states. “You saw today [at SNIS] how many of the presentations were sponsored by companies, and how many of the big stroke trials are now sponsored by industry, and nobody takes offence at that. Thirty or forty years ago, it was almost taboo.

“I think that, at a certain point, every physician who is clinically active and has made certain achievements will be involved in industry work, by default. It is just the nature of things, even in medicine. That is where I see the future; a tighter relationship between industry and academia, and I think that needs to be fostered. It is happening in our field right now and I find that exciting.”

Surpassing expectations

Wakhloo is perhaps best known for the significant role he played in the introduction of flow-diversion treatments to intracranial aneurysm care. However, when he initially made this breakthrough discovery as a fellow at the University of Freiburg (Freiburg im Breisgau, Germany) back in 1989, his motivations had little to do with one day being heralded as a neurointerventional pioneer, much less the commercial opportunities that would later follow.

“That was an accident,” he concedes, discussing how initial descriptions of the fundamental mechanism of flow diversion from him and his colleagues resulted in him ultimately co-founding and leading Surpass Medical, which developed one of the first approved flow diverters—an eponymous device that, along with the company itself, was acquired by Stryker in 2012.

“When I was working on the flow-diverter concept, I made an observation that led to further digging and research, but it never occurred to me to commercialise that concept,” he continues.

“Until then, I was mainly involved as a consultant with the major medical technology companies, but establishing a company, and building a device and then selling it, that was really an accident in my life.”

With the flow-diverter concept now established and widely published, companies like Covidien (Pipeline; now Medtronic) and Balt (Silk) picked up the idea and ran with it. And, today, the use of flow diverters in endovascular aneurysm treatments is the proverbial tip of the iceberg. As Wakhloo says, this space has “exploded” since its inception, with researchers now looking to utilise these devices in stroke as well as several other parts of the body, from the kidneys to the heart. “We thought it would be for some challenging giant or large aneurysms where coiling does not work,” he adds, “but some people are telling me that the market is worth over US$3 billion worldwide today!”

Speaking from experience

For his part, Wakhloo reinvested the money he made from selling Ajay Surpass to Stryker and became far Wakhloo more focused on the “interesting path” of industry work. Since then, he has had a number of other albeit less prominent successes, developing new balloon technologies and aspiration catheters at Inneuroco, and forming part of the team that initialling conceptualised transradial access for neurovascular procedures—now marketed

by Medtronic as ‘Rist’.

A breakthrough that—from a purely commercial standpoint, at least—Wakhloo jokes he would rather forget is the one that ultimately paved the way for one of today’s most commonly used stroke thrombectomy devices: the stent retriever. He recalls how he inadvertently uncovered and later published this concept while searching for a means to retrieve coils that had been unwantedly left in patients’ aneurysms following embolisation procedures.

“That is an example of an idea with huge implications—for [me], as an inventor, very financially rewarding—but I did not patent it,” Wakhloo explains. “Now, my advice to the younger generations would be to keep a historical file of who you talked to about the idea, what you have disclosed, where you have presented it; it becomes a very important document. Even when you sign an NDA [non-disclosure agreement], it does not mean a lot, because people can circumvent your idea with small tweaks and whatnot.”

Wakhloo also advises fledgling inventors to apply for a patent once their concept has been prototyped and is considered feasible, but before presenting it at conferences or discussing it publicly.

“Keep it confidential,” he continues. “Of course, you will have partners and colleagues you trust to disclose it to. And, once you get feedback that you are not insane and this is something really good, write a patent with a lawyer and file it. Generally, it is not that expensive; around US$4,000 or US$5,000, if you

have the cash or you can put that amount together with colleagues.”

Advice for budding innovators

Here, Wakhloo credits much of his success to a longstanding colleague, biomedical engineer and fellow inventor Barry Lieber, who he partnered with through the development of the flow diverter and continues to work closely with today within each of his start-up endeavours.

“We know what we need on the clinical side, and a good engineer understands your language,” Wakhloo says, also highlighting the importance of having a team of clinician colleagues—either as investors or advisors—who are supportive of your idea, because “you do not want to be alone in that vacuum”.

He goes on to stress the need for doctors to disclose all of their industry-related activities, and potential conflicts of interest they may create, to the academic and medical institutions that employ them—ideally having these discussions prior to “embarking on that journey” with industry. Wakhloo further warns that there are discrepancies in how different centres will react to a physician’s R&D efforts; some may provide financial support for things like legal processes and prototyping in exchange for a share in any future commercial spoils, while others will be opposed to their staff doing any industry-related work, or demand a far greater stake in said work.

The potential financial support a would-be inventor’s medical institution will likely provide is a key detail because, as Wakhloo states, device prototyping and subsequent in-vitro or animal studies can cost “several million dollars”, and attracting investment is “not easy”.

“It is your leadership, and your skillset, that will convince the community and the investors of why this is a concern,” he adds. “And, nowadays, it boils down to a business plan—have you worked it all out? Is there a need for the technology? Does it make sense? Is there a commercial value in the product?

These things can be fairly challenging.”

However, with all of this being said about the logistics and practicalities of carving a path into the world of industry, Wakhloo’s salient piece of advice is this: “Do not think about yourself becoming a hero—it is actually about the patient”. Citing the motivations that led him to first outline flow-diverter technologies and, less directly, stent-retrieval devices, Wakhloo says he “never thought” about the monetary, commercial aspects, and that these were more of an unintended byproduct of his quest to uncover something that would improve patients’ lives.

“Instead of focusing only on the excitement of innovation, I think it is important for a young physician or clinician to ‘look behind the shadows’— start looking at your daily operations and asking, ‘why did this not work?’ he notes. “Why does a technology not work; why does it only work 50% of the time, or only in a certain group of patients?

What is it that bothers you when you drive home from work? And, put yourself in the seat of the patient. What would they like to see? What are they complaining about?”

Wakhloo concludes that, with this in mind, observation is a “critical skill”, and one that—when coupled with a creative streak—is “very important” in the sphere of innovation. “Whether it is a small thing or a big, transformational technology, the driving force should be the patient, and if it is something they will benefit from,” he also asserts.

September 2023 | Issue 51

10 Advertorial THIS ADVERTORIAL IS SPONSORED BY MEDTRONIC

Old but still gold—why coiling remains a vital tool for treating intracranial aneurysms Alberto Nania (National Health Service [NHS] Lothian, Edinburgh, UK) speaks to NeuroNews to outline how, despite the rapid proliferation of new technologies and clinical data in the interventional neuroradiology (INR) space over the past 20 years, coil embolisation remains a fundamental tool in the treatment of intracranial aneurysms.

“I

f you think about coiling, and you think about the ISAT trial, it is the foundation of INR practice as far as haemorrhagic stroke and aneurysm treatment is concerned,” Nania posits. “So, it has passed the test of time—it has been around for decades, its safety profile has improved since the early 2000s, because the technology has changed, and I think its efficacy is better as the materials have also changed.”

While coil embolisation may be a cornerstone of the specialty of INR itself, rapid advancements over the past two decades have given rise to other devices and approaches used in the treatment of intracranial aneurysms. Prominent examples include flowdiverting stents and intrasaccular technologies—both of which have come along more recently, and thus may be considered more innovative and ‘sexier’ than coiling, according to Nania.

“Is coiling still the gold standard? I think, for most aneurysms, it is,” he continues. “Compared to 15–20 years ago, the horizons of INR treatment have broadened quite significantly. There are a lot more indications for which we can offer endovascular treatments and, with that in mind, there are a number of circumstances in which coiling is not the gold standard.”

Nania feels however that, far from coiling being ‘replaced’ as the go-to approach, this is simply a case of INR expanding and enabling a greater variety of aneurysm cases to be treated. An example he highlights is a giant symptomatic cavernous aneurysm; “almost everyone would treat that with a flow-diverting stent now, but that is because we are [talking about] something that could not be treated in the past”, he avers.

“So, for most cases, it does remain the gold standard, and I think it really is the basis of aneurysm treatment,” Nania goes on. “If you think about ruptured aneurysms in particular, in most cases—if the neck of the aneurysm will allow you to coil—I think you should coil. “The concept and the strategy have been around for such a long time, and we know that it works; it is proven to be effective [and safe]. And, overall, it is probably more widely applicable than intrasaccular device or flow diverter placement too, because you can use a smaller, ‘softer’ microcatheter and go more distal, overcoming tortuosity-related problems with [things like] intermediate catheters.”

Nania attributes the continued relevance of coiling, in no small part, to the work done by neurovascular companies to advance the microcatheters, the guidewires, and the coils themselves, allowing an established technique to “reach new levels”, such as in the treatment of very distal aneurysms.

Medtronic and others in the INR space have “invested massively” to make these devices “a lot easier to use, and a lot better”, he adds. And, discussing the wider role of coiling in the arsenal of an interventional neuroradiologist, he describes it as a “key skill”, and one that can be “very rewarding”.

“It does have a learning curve,” Nania notes. “I do not coil an aneurysm the same way I did four or

five years ago, and in another five years’ time I will hopefully get even better. So, there is a lot of reward in learning a skill that you can keep practising. There are limitations to what coiling can do, and those have to be remembered—wide-neck bifurcation aneurysms, blisters, giants, and so on—so nowadays it has to be complemented by a number of other devices. But, it is still a pillar of the INR armamentarium, in my view.”

To coil or not to coil?

Laying out his own paradigm for when to use coiling and, equally, when an alternative approach may be preferrable, Nania says that ‘ruptured’ and ‘unruptured’ are the two main categories when it comes to intracranial aneurysms. In ruptured cases,

If you think about coiling, and you think about the ISAT trial, it is the foundation of interventional neuroradiology practice as far as haemorrhagic stroke and aneurysm treatment is concerned.” he believes that coiling is the way to go, provided the aneurysm is big enough to hold a coil (>1mm).

However, patients with very wide-necked aneurysms, or high-grade subarachnoid haemorrhage, are likely to require a “speedier procedure” and, as such, intrasaccular devices can play a “big role” in these cases.

“For ruptured cases, by and large, the priority is to avoid more complex situations, such as with double microcatheters; apply the principle of ‘keeping it simple’… and coil as often as you can,” Nania states. “In the unruptured cases, you have a lot more tools to play with—you may complement [coiling] with a stent, or a flow diverter, and for wide-neck aneurysms you are obviously spoilt for choice with complex treatments like Y-stenting, stentcoiling, flow diversion and the intrasaccular devices.”

Another point raised

by Nania is that of cost, which is “very important” Alberto Nania

for certain healthcare systems. Here, the example he puts forward is that of a small aneurysm (~4mm) that can be treated with either coiling or an intrasaccular device, claiming that it will inevitably be “much cheaper” to coil.

“To contextualise this by looking at my own practice in Edinburgh,” he continues, “last year, we treated almost 280 aneurysms in total—between ruptured and unruptured. In acute cases, coil usage was at almost 80% and, in elective cases, it was almost 50%. So, I think it is still fundamental in both situations.”

Ballooning remains relevant

Paraphrasing one of the physicians he trained under, Nania asserts that ballooning is and always has been a “core technique”, not just within aneurysm coiling, but as a means for increasing safety and reducing the likelihood of complications in other procedures like mechanical thrombectomies.

“In aneurysm coiling, it has to be recognised that ballooning increases the complexity of the procedure a little bit because you have a double microcatheter; you have to worry slightly more about your support, your access and your sizes, and it tends to lengthen the duration of the procedure a little,” he says. “But, it does allow you to tackle aneurysms that, due to their morphology or configuration, simply could not be coiled otherwise. It massively increases the range of capabilities of your coiling procedure.”

On a technical level, the introduction of a balloon can support the operator in cases with challenging anatomies. As Nania adds, “you can trust the balloon to protect particular branches, and to overcome the difficulties of projection”.

“So, it is great in terms of its enhanced capabilities we used in conjunction with coils,” he claims.

“Perhaps, if you look at INR practice in general, [ballooning] has lost some ground regarding frequency of use because there are so many other options now—for example, in bifurcation aneurysms, there are now intrasaccular devices that have taken out a lot of the work that used to be done via balloonassisted coiling. But, it is still core, and it is still essential to learn and to master as a technique.”

What does the future hold?

“It is very hard to predict but, the way I see it, coiling will remain a huge stakeholder, at least over the next 5–10 years,” Nania says. “Its role might change in the sense of being complemented by a lot of other devices but, if anything, I see these devices complementing coiling during the same procedure rather than taking cases away. In recent years, other devices have been coming to the market to address inherent shortcomings of the technique itself, but I see very few devices that can completely replace coiling, and there will still be space for coiling in the future for sure.”

According to Nania, the main message here— particularly for newer generations of interventional neuroradiologists, who “may be distracted” by more novel technologies and approaches—is that coiling remains “a pillar of our specialty”.

“It needs practice, and it needs time dedicated to it, but it has incredible rewards,” Nania concludes. “It is proven to be effective and, alongside mechanical thrombectomy, it remains a key therapy that [younger interventional neuroradiologists] should learn before digging too deep into flow diverters or intrasacculars.”

DISCLAIMER: The data and content included in this presentation express only the clinical perspective of the presenter. They are completely independent and do not necessarily reflect the opinions of Medtronic.

Interventional Neuroradiology 11

Issue 51 | September 2023

LINNC 2023 examines neuroprotection, steerable microcatheters and other ‘next frontiers’

A bright future?

Neuroprotective agents and steerable microcatheter technologies were among a number of potential new interventional neuroradiology (INR) frontiers showcased and discussed at this year’s LINNC Paris Course (5–7 June 2023, Paris, France)—with faculty member Ricardo Hanel (University of Florida, Jacksonville, USA) commenting on the final day of the meeting that “the future is bright” in interventional stroke care.

of December 2022—including stroke interventions, intrasaccular sidewall/ angulated aneurysm implantations and venous access procedures. Elaborating further, he reported that no devicerelated safety events have been observed to date, while access success and guidewire usage rates of 93% and 25%, respectively, have also been achieved.

Despite the navigability benefits offered by this steerable device, including features like 180-degree distal tip deflection and a lock-to-treat stability mechanism, Berenstein noted a handful of potential limitations—such as in more proximal, tortuous anatomies, and in transradial access cases. Nonetheless, LINNC course director Jacques Moret

EXCITEMENT IN neuroprotection has been reignited in recent times thanks to a number of promising research findings, and the HEMERA-1 safety study—presented

by Italo Linfante (Florida International University, Miami, USA)—intends to add to this growing body of evidence in acute ischaemic stroke.

Linfante began with reference to the fact that, while mechanical thrombectomy has “changed the world”, there is still “room for improvement” in this space. He also highlighted the cerebral collateral circulation’s potential as a target for neuroprotection, with neuroprotective agents like pegylated bovine carboxyhaemoglobin (PP-007; Prolong Pharmaceuticals) currently being assessed for their ability to slow down infarct core expansion and, thus, improve clinical outcomes.

PP-007 is able to provide targeted oxygen delivery, doing so more efficiently than red blood cells over a 24-hour period; has plasma-expansion properties; and triggers carbon dioxideinduced vasodilation, the speaker stated, before touching on the promise it showed previously when tested in both normotensive and spontaneously hypertensive rats with middle cerebral artery (MCA) occlusions.

The drug has since progressed to human trials, with the randomised, Phase 1, contemporaneously controlled, multicentre HEMERA-1 study evaluating its safety and tolerability across 16 acute ischaemic stroke patients. These patients were randomised 3:1 to receive either two hours of PP-007 infusion plus standard of care or standard of care alone. Linfante noted that, in this study, ‘standard of care’ consisted of a thrombectomy procedure and did not include intravenous thrombolysis (IVT).

The HEMERA-1 investigators observed a transient rise in systolic blood pressure during PP-007 infusion (20–40mmHg), but reported no safety concerns. As per the study’s secondary, efficacy-related endpoints, Linfante and colleagues found improved leptomeningeal anastomosis collateral perfusion and reduced infarct volumes, as well as better National Institutes of Health stroke scale (NIHSS) scores in the PP-007 cohort, and a trend towards lower modified Rankin scale (mRS)

linked to a number of other conditions, including pulsatile tinnitus—which he has started treating with venous stenting at his centre—as well From top left: Ricardo Hanel, Italo as chronic migraines, headaches Linfante, Alejandro Berenstein, Aymeric Rouchaud and and high blood pressure. He also Vitor Mendes Pereira pointed to middle meningeal artery embolisation as a promising treatment option in subdural haematoma, and one for which key clinical trials are currently (Bicêtre Hospital, Paris, France) closed on the horizon, and highlighted Vis-M the session by describing it as a “real high-frequency optical coherence breakthrough” for the INR field. tomography’s (HF-OCT; Gentuity) Elsewhere, Aymeric Rouchaud potential in neurovascular patient (Limoges University Hospital, Limoges, management and perioperative France) gave delegates an update on treatment guidance. the Clotild smart guidewire system Following this, Hanel took to (Sensome), an artificial intelligence the podium to provide a number of (AI)-powered device that uses microconcluding messages on the future of sensor technology to perform impedance interventional stroke care. Speculating measurements and provide physicians on how this space may evolve over the with information on the occlusion they next five years, he informed LINNC are treating. Citing Sun Tzu, the speaker attendees that “the future is bright”, with averred that a battle can be won before improved atrial fibrillation detection; it starts, “if you know your enemy”. innovations like smartphone face The overall goal of the Clotild recognition and ChatGPT (OpenAI) for device, Rouchaud stated, is to help stroke diagnostics; direct-to-angio suite guide thrombectomy procedures and hospital models; robotics; and even ultimately make them more effective. nanoparticle-based drug delivery all The future could see this technology offering prospects in the field. being used to assess clot composition, “The best way to predict [the future] clot length and vessel wall pathology— is to help build it,” Hanel noted. “In the all in real time—the speaker continued. past few days, we have heard a bunch He also highlighted Clotild’s “seamless of different people tell us how they are integration” into operators’ existing shaping the future—and five years is workflows. LINNC course director not that far off. It is not even 10 years Laurent Spelle (Bicêtre Hospital, Paris, since MR CLEAN was published, in France) commented that this final point 2014. We have come a long way, and is “very important”, as the device can one [inescapable fact] is that mechanical be introduced without adding significant thrombectomy will continue to be part time on to procedures. of our lives and continue to grow.”

scores at 90 days. However, the speaker was quick to acknowledge that these preliminary findings come from a “very small number of patients”, and that HEMERA-1 was strictly a safety study.

Linfante closed his presentation by averring that the study “warrants further, expanded evaluation of the safety and efficacy of PP-007 in large vessel occlusion [LVO] acute ischaemic stroke”. Extension of HEMERA-1 will also include patients who receive IVT—either alteplase or tenecteplase.

Collateral augmentation and targeted oxygen delivery represent “promising strategies” for improving outcomes in the thrombectomy era, Linfante concluded, adding that pleotropic agents offer additional benefits.

HEMERA-1 was well-received

by LINNC’s expert panel; Tommy Andersson (Karolinska University Hospital, Stockholm, Sweden) stated a belief that “we are past the era of discussing how to do [thrombectomy], and now it is about how we optimise the clinical outcomes”, before declaring that “this is the future”. Raul Nogueira (University of Pittsburgh, Pittsburgh, USA) corroborated this view, as ‘macro-reperfusion’ is often achieved with thrombectomy, while ‘microreperfusion’ remains a challenge, and Hanel rounded off the discussion by predicting that “we are going to have drugs that we can give in the field”, adding “we will see a lot from this direction” in the coming years.

Catheters and guidewires

A number of the latest neurovascular device innovations also featured at LINNC 2023, including a novel, ‘articulating’ microcatheter technology called the Bendit21 (Bendit Technologies). Alejandro Berenstein (Mount Sinai Health System, New York City, USA) told attendees, “I want to show you transformative technology that will put us in a new world” at the outset of his presentation, outlining the “revolution” such technologies may bring about in INR, but also endovascular surgery more generally, including in the peripheral and cardiac spaces.

The speaker delivered proven clinical outcomes with the US Food and Drug Administration (FDA)-cleared Bendit21 microcatheter, stating that it has been used in 64 clinical cases—as

Vitor Mendes Pereira (St Michael’s Hospital, Toronto, Canada), who is also a LINNC course director, chose to examine multiple potential ‘next frontiers’ in INR via another presentation, with the first being stenoses in the cerebral veins. Pereira urged his colleagues to appreciate the need to distinguish between ‘extrinsic’ and ‘intrinsic’ venous stenosis types i.e. if the stenosis is caused by or directly causing intracranial hypertension— also drawing attention to the risk of ‘intrinsic’ patients going blind if incorrectly treated with medication.

The speaker went on to note that venous outflow congestion has been

September 2023 | Issue 51

12 Advertorial THIS ADVERTORIAL IS SPONSORED BY PENUMBRA

The physics of aspiration thrombectomy—what matters?

Much of the clinical success that can be achieved with aspiration-based mechanical thrombectomy is dependent on the characteristics and features of the specific device being used. In an effort to elucidate precisely how these factors actually impact device performance and, ultimately, thrombectomy outcomes, Paolo Machi (Geneva, Switzerland) has published findings on a wealth of laboratory testing carried out by him and his colleagues in recent years. Here, he discusses this research and outlines the most important attributes in an aspiration catheter technology.

the operator’s visibility of the catheter on imaging and lowers the chances of them advancing it too far, preventing other potential complications.

Machi’s research to date on RED 62, which is currently one of his go-to devices in clinical practice, has revealed “good trackability”—comparable to other market-leading aspiration catheters—and positive outcomes regarding aspiration parameters like force and flow rate. “These were the main findings of our [lab] testing,” he adds. “We also tested the RED 68 and 72 [devices], and they are performing better than previous versions of the Penumbra catheters. So, there is an evolution there.”

In the first few months of 2023, Machi and his colleagues in Geneva have already used RED catheters in more than 40 aspiration thrombectomy cases. And, as he says, having introduced them into his practice thanks in part to the devices’ impressive display during benchtop testing, he is “happy with the results” achieved and will continue utilising them for acute stroke treatments. “We wanted to introduce them into our practice to acquire knowledge and experience, and to evaluate results, and we are confident that we will keep on using them in the future,” Machi relays.

Manual versus continuous aspiration

Above: Machi’s testing lab Opposite: RED catheters Below: Paolo Machi

“M

y research is based on benchtop evaluations of devices used for neurovascular treatments—both ischaemic and haemorrhagic,” Machi tells NeuroNews. “We do testing for all types of devices, including stent retrievers, coils and flow diverters, and also aspiration catheters. For the last five years, we have been working with several companies who develop aspiration catheters, and we perform tests that are partly related to what is needed for regulatory purposes, but we also create tests designed to evaluate specific features of devices that are [relevant] to clinical practice.”

According to Machi, trackability, aspiration force and flow rate are among the most important parameters when it comes to aspiration thrombectomy—and, as such, are also among the key factors he attempts to analyse in the lab. “The idea behind this is that we want to establish knowledge, in the lab, that we can then [translate] to clinical practice for the benefit of our patients,” he adds.

Machi’s lab testing ranges from evaluating catheter construction under a microscope, to in vitro experiments assessing aspiration performance, such as trackability and retrieval force. Alongside his colleagues, he has published several papers on the findings of these experiments, including a study confirming the influence the angle of interaction between aspiration catheter and clot has on direct thromboaspiration efficacy,1 as well as a model indicating that—in ‘combined thrombectomy’ cases—the relative positions of the stent retriever and microcatheter within the aspiration catheter affect flow rate, but not aspiration force.2

Trackability is key

“We need to advance the catheter through the brain vessels and up to the clot, so it is very important for us as operators to make sure we get in contact with the clot smoothly and easily,” Machi continues,

highlighting the role trackability plays relative to the success of a thrombectomy procedure. “The very first objective during an aspiration procedure is to get in contact with the clot, so trackability is probably the main characteristic for any catheter device.”

“Then we have aspiration force and flow rate— these [factors] are more closely related to specific parameters, including the diameter of the device and how it ‘reacts’ to the clot,” he says. Here, he recalls cases with older technologies in which the distal tip of an aspiration catheter has collapsed, decreasing its diameter and, in turn, reducing the flow rate and the aspiration force that can be achieved.

Another reason why the structural integrity of an aspiration catheter’s distal tip is key can be realised in combined thrombectomy cases, whereby a stent retriever device is deployed distally to the catheter.

According to Machi, a catheter’s ability to retain its lumen integrity prevents any “conflict” between the two devices, thus reducing the likelihood of the clot fragmenting, or shifting position so that it is no longer coaxial to the catheter itself.

Benefits of RED

“What we see in the RED family of catheters (Penumbra) is that the distal tip contains [an articulating marker band with a shorter polymer tip for optimal visualisation and placement], and this reduces the chance of it collapsing during [direct] aspiration procedures,” Machi avers, “but also probably improves the interaction with the stent retriever in combined thrombectomy cases.” Another feature of RED he is keen to highlight is the fact that the section of the distal tip that extends beyond its radiopaque markers is shorter as compared to prior devices. According to Machi, this improves

‘Continuous aspiration’ involving a pump is considered by many to be capable of producing superior outcomes versus ‘manual aspiration’, which involves the use of a syringe-like device, as its ability to provide strong, sustained suction increases the likelihood of clot ingestion while minimising emboli to new territory (ENT) risks. Machi himself prefers a continuous aspiration approach—stating that this is largely for “physical reasons”.

“When we look at the aspiration force curves, there is a phase in which the force increases, as we begin aspirating,” he says. “And, when you aspirate strongly with a syringe, you immediately get very high aspiration forces that could be similar to what you have with a pump.” However, this is where the forces achievable with these two aspiration types diverge, according to Machi.

“With a syringe, you have a peak, but then you have a curve coming down as you empty the syringe and it fills with air,” he goes on. “So, basically, the force is not [maintained] at a high level over time. However, if you take the pump, you have the same peak at the beginning of aspiration, but—because the volume [that can be filled] is bigger—the force reaches a plateau, and this plateau continues for a longer period of time.”

“This means that, while you manage the case and manoeuvre to get the clot out of the patient, you can count on that ‘third arm’, which is the pump,” Machi adds. “If you have somebody helping you, the shorter duration with the syringe may not be a problem—but, if you are treating a patient alone, or you are on call in the middle of the night, then you are happy to have the pump helping you to aspirate.”

References: 1. Bernava G, Rosi A, Boto J, et al. Experimental evaluation of direct thromboaspiration efficacy according to the angle of interaction between the aspiration catheter and the clot. J Neurointerv Surg. 2021; 13(12): 1152–6.

2. Bernava G, Brina O, Reymond P, et al. In vitro evaluation of how the presence of the stent retriever and microcatheter influences aspiration parameters in thrombectomy according to their position inside the aspiration catheter. Interv Neuroradiol. 2022. DOI: 10.1177/15910199221135040.

PAOLO MACHI is the head of the interventional neuroradiology unit at the University Hospital of Geneva and a professor in the Faculty of Medicine at the University of Geneva (Geneva, Switzerland).

DISCLAIMER: The opinions and clinical experiences presented herein are for informational purposes only. The results may not be predictive of all patients. Individual results may vary depending on a variety of patient-specific attributes.

Issue 51 | September 2023

Late-breaking data 13

ESOC

Latest trial results prompt call to “elevate” intracranial haemorrhage management Following the presentation of new trials assessing intracranial haemorrhage (ICH) treatment approaches, INTERACT3 and ENRICH, Craig Anderson (The George Institute for Global Health, Sydney, Australia)—who delivered first-time data from the former—posited that, “maybe, the time is right to elevate ICH to the same level we see in acute [ischaemic] stroke”, also calling for a “more active approach” to ICH management moving forward.

THE EUROPEAN STROKE Organisation Conference (ESOC; 24–26 May, Munich, Germany) saw a late-breaking update from the ENRICH study presented by Alex Hall and Jonathan Ratcliff (both Emory University, Atlanta, USA), with the speakers reporting that minimally invasive parafascicular surgery (MIPS; Nico Corporation) was found to be safe, resulted in substantial clot evacuation, and led to functional outcome benefits.

ENRICH compared MIPS to medical management in a total of 300 ICH patients who began treatment within 24 hours of symptom onset across 37 US centres. Its primary endpoint was functional outcome (utility-weighted modified Rankin scale [UW-mRS] score) at six months. Patients were block randomised to receive MIPS or medical management according to their ICH location and Glasgow coma scale (GCS) score. Hall and Ratcliff noted that, following enrolment of 175 patients, the study population was altered to focus only on those with lobar-located ICHs. Complete follow-up data were available in a total of 286 patients.

A primary analysis compared the mean UWmRS at six months between treatment groups, and found higher rates of mRS 0–2 and mRS 0–3 in the surgical cohort. The ENRICH

investigators also observed an estimated mean treatment effect of 0.374 with medical management and 0.458 with MIPS (a difference of 0.084). As such, superiority of the intervention— measured via Bayesian posterior probability—was 0.9813, exceeding the prespecified threshold to claim substantial superiority versus medical management (0.975). The ENRICH investigators concluded that the overall benefit of MIPS appears to stem from the “strong positive effect” observed in participants with lobar ICH. In their presentation, Hall and Ratcliff also reported MIPS as being associated with improved rates of survival versus medical management, as well as shorter lengths of intensive care unit (ICU) and hospital stays.

Maybe, the time is right to elevate intracranial haemorrhage to the same level we see in acute [ischaemic] stroke.”

Craig Anderson

“This is the first trial to demonstrate functional benefit in surgical clot evacuation among patients with supratentorial ICH,” said Hall, with Ratcliff adding that “the data from this trial will help inform future ICH research and practice”.

The findings drew positive comments from delegates, with session moderator Else Charlotte Sandset (Oslo University Hospital, Oslo, Norway) saying she is “very optimistic” to see something positive in ICH, before Werner Hacke (University of Heidelberg, Heidelberg, Germany) thanked the researchers and claimed that “we have been waiting for this for decades”.

Anderson then took to the podium to present results from INTERACT3—a pragmatic, international, multicentre, blinded-endpoint, stepped-wedge cluster randomised controlled trial conducted at sites spanning nine low- and middleincome countries, and one high-income country. The trial sought to evaluate whether the implementation of a goaldirected ‘care bundle’ incorporating early, intensive lowering of systolic blood pressure, and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, could improve outcomes in patients with acute spontaneous ICH.

Early anticoagulation after ischaemic stroke “reasonable” and “unlikely to cause harm” An international clinical trial presented at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany) has demonstrated that—in people with ischaemic stroke and atrial fibrillation—anticoagulation can safely be started earlier than current guidelines recommend.

“OUR STUDY FINALLY BRINGS SCIENTIFIC evidence for a common dilemma in early secondary prevention after an ischaemic stroke,” said study leader Urs Fischer (University Hospital of Bern, Bern, Switzerland), who delivered these findings from the ELAN trial. “In view of our results, early treatment initiation is reasonable if indicated, or if desired, for logistic or other reasons. It is probably better and is unlikely to cause harm.”

Direct oral anticoagulants (DOACs) are used to prevent blood clots in people with atrial fibrillation, but it is unclear how early after stroke they should be started; there are safety concerns surrounding a potential increased risk of bleeding, which may be highest in the first few days post-stroke, but the possible benefit of such drugs may also be highest in these first few days. In the presence of this uncertainty,

international guidelines currently recommend a delay before starting DOACs. However, as per Fischer’s presentation earlier today, the chances of suffering a recurrent event with early DOAC treatment are likely to be lower compared to a later start—without an increase in risk of complications. The ELAN study included 2,013 participants with an acute ischaemic stroke and atrial fibrillation recruited from 103 different stroke units in 15 countries across Europe, the Middle East and Asia between 2017 and 2022.

Based on the size and location of their infarct on imaging—and, thus, the severity of their stroke— participants were randomly assigned to an early treatment start, or a later, guideline-recommended treatment start. An early start was defined as being within 48 hours of a minor/moderate stroke or day

A total of 7,036 patients from 121 hospitals were enrolled, with 3,221 being assigned to the care-bundle group and 3,815 receiving ‘usual care’. The care-bundle group demonstrated a significantly lower likelihood of a poor functional outcome, signified by a shift in mRS scores that was also consistent across a range of subgroups and sensitivity analyses, including additional adjustments for country- and patientrelated variables, Anderson reported.

In addition, patients in the carebundle group experienced fewer serious adverse events than those in the usual-care group (16% vs 20%), while lower mortality rates, and health-related quality of life and hospital length-ofstay benefits, were also associated with the intervention. INTERACT3 indicated a ‘number needed to treat’ of just 35 to reduce mortality and provide greater functional benefits versus usual care.

Concluding, Anderson re-emphasised that intensive blood pressure lowering and other management algorithms for physiological control resulted in improved functional outcomes. The speaker also said hospitals should incorporate the approach into clinical practice as part of active protocols, with a view to enabling a “better standard of care for ICH” globally.

6–7 following a major stroke, while a late start was defined as day 3–4 following a minor stroke, day 6–7 following a moderate stroke, or day 12–14 following a major stroke.

The primary outcome in the ELAN trial was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage (ICH), extracranial bleeding, systemic embolism, or vascular death, within 30 days after randomisation. At 30 days, the primary outcome occurred in 29 patients (2.9%) in the early treatment group and 41 (4.1%) in the late treatment group. At 90 days, the difference in the rate of the composite outcome was -1.9%. In addition, recurrent ischaemic stroke at 30 days occurred in 14 patients (1.4%) in the early treatment group and 25 (2.5%) in the late treatment group, while—“most importantly”, according to Fischer—symptomatic ICH was similar across the groups, occurring in two patients (0.2%) in both.

“The study also suggests that the incidence of symptomatic intracerebral haemorrhage is low with early anticoagulation, if imaging-based classification is used,” stated Jesse Dawson (University of Glasgow, Glasgow, UK), who led ELAN alongside Fischer.

As a next step, the researchers plan to explore whether the risk and benefit is similar in different subgroups of the ELAN trial population, especially in stroke patients who are more severely affected.

September 2023 | Issue 51

14 Carotid Interventions

ESOC

Interim data find “no evidence of benefit” for carotid revascularisation additional to optimised therapy Interim results from the ECST-2 randomised controlled trial (RCT) have shown no evidence that carotid stenosis patients with a low-to-intermediate stroke risk, treated with optimised medical therapy, will benefit from additional carotid revascularisation via carotid endarterectomy (CEA) or carotid artery stenting (CAS).

N

evertheless, Paul Nederkoorn (Amsterdam UMC, Amsterdam, The Netherlands)—who presented these late-breaking findings at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany)—noted that a longer clinical follow-up is now required. The aforementioned interim results were observed at two years, with ECST-2 set to continue following patients for a total of five years.

In an attempt to provide an update to the original European carotid surgery trial (ECST), which was published in the late 1990s and found CEA to be effective in symptomatic patients with carotid stenosis >80%, ECST-2 hypothesised that there would be no benefit from additional carotid revascularisation alongside optimised medical therapy in patients who have carotid stenosis ≥50% and a low-to-intermediate risk of stroke. Nederkoorn stated during his

presentation that, in the decades following the ECST no differences across any of the predefined subgroups and NASCET RCTs, medical management—both in ECST-2—including between symptomatic and trials’ comparator—has improved “significantly”. asymptomatic stenoses. There was, however, a slight ECST-2 was designed as a multicentre, prospective trend towards optimised medical therapy being associated RCT with blinded-outcome adjudication, and saw with a greater treatment effect in patients with an patients randomised to either immediate carotid increased risk of ipsilateral stroke (CAR score >10%). revascularisation plus optimised medical therapy From this interim analysis of the ECST-2 intentionor optimised medical therapy alone. Patients were to-treat population, the investigators concluded that considered eligible if they had an asymptomatic or there is no evidence patients with stenosis ≥50% symptomatic carotid stenosis ≥50% and and a low-to-intermediate stroke risk will an estimated five-year stroke risk <20%, benefit from revascularisation in addition to calculated using the Carotid Artery Risk optimised therapy.

(CAR) score. Recruitment was halted after As well as emphasising that, despite this the inclusion of 428 patients, Nederkoorn finding, further follow-up is both warranted reported. and planned in ECST-2, Nederkoorn For the composite endpoint defined for stated that a complete, two-year analysis these interim results—the two-year rate including evaluations of silent infarcts on of any stroke, myocardial infarction (MI) Paul Nederkoorn magnetic resonance imaging (MRI) is now or periprocedural death—Nederkoorn scheduled too. Also, the results of an MR and colleagues found a hazard ratio of 0.96 with plaque-imaging sub-study from ECST-2 will soon optimised medical therapy alone in comparison to be available, which Nederkoorn told NeuroNews is a optimised medical therapy plus revascularisation “crucial tool” within a novel prediction rule that is still (95% confidence interval [CI] 0.53–1.76). The to be designed but may elucidate future stroke risks speaker noted that there was “a sign of more harm” and treatment decisions in these patients. initially with revascularisation, signified by a higher A discussion at ESOC saw Seemant Chaturvedi rate of stroke, MI or periprocedural death in the first (University of Maryland School of Medicine, few months following randomisation, but that these Baltimore, USA) posit that the medical therapy rates converged later on and Kaplan-Meier analyses given in the trial’s comparator arm could have been ultimately showed no significant difference between optimised “even further” in accordance with some the two groups at 24 months. current guideline recommendations, potentially While the numbers involved were “very small, improving that group’s outcomes to a still-greater precluding valid conclusions”, Nederkoorn reported extent—a point that Nederkoorn agreed with.

Two-year rate of stroke, MI or periprocedural death with optimised therapy alone...

“Sonolysis is back” after safely reducing endarterectomy stroke risk in randomised trial Positive results from a clinical trial involving a novel therapeutic procedure known as sonolysis—deployed during a carotid endarterectomy (CEA)—were presented at the recent European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany).

“THE RANDOMISED CLINICAL trial confirmed the results of pilot studies that sonolysis using diagnostic 2-MHz probe is safe and significantly reduces the risk of stroke, transient ischaemic attack [TIA], and silent brain infarctions detected using brain MRI [magnetic resonance imaging],” said David Školoudík (University of Ostrava, Ostrava, Czech Republic), principal investigator for SONOBIRDIE—the trial in question.

“In clinical practice, this could mean not only an increase in the safety of CEA, but also an expansion of indications for this procedure.”

As an ESO press release details, CEA is a well-established approach in the treatment of carotid artery stenosis, but carries stroke risks both during and immediately after the procedure that are

“not negligible”, meaning methods for reducing said risks are needed.

Transcranial Doppler (TCD), which uses ultrasound beams with a specific frequency, is a non-invasive procedure that has been shown to have some potential effect on accelerating spontaneous or induced reopening of otherwise occluded arteries.

In the multicentre, randomised, double-blinded, sham-controlled SONOBIRDIE trial, this novel therapeutic approach—also referred to as sonolysis—was evaluated for safety and effectiveness in reducing risks of stroke, mini-stroke or any infarction detected on brain imaging during CEA. Patients from 16 European centres were recruited between 2015 and 2022. All of these patients had severe internal carotid artery stenosis (≥70%)

Hazard ratio = 0.96

with a clinical indication for CEA and were aged 40–85 years. They were randomised either to sonolysis or to a sham procedure. Neurological exams and MRI were performed both before and after CEA to detect any stroke, TIA or death within 30 days.

Overall, the study recruited 1,004 patients with a mean age of 68 years, 31% of whom were women.

According to Školoudík, members of the SONOBIRDIE data and safety monitoring board “unanimously recommended” stopping the trial early due to “clear evidence” of effectiveness

In clinical practice, this could mean not only an increase in the safety of carotid endarterectomy, but also an expansion of indications for this procedure.”

...versus optimised therapy plus revascularisation

in November 2020—at which point 507 patients had been randomised to the sonolysis group and 497 had been randomised to sham treatment.

As per interim analyses, the investigators found that sonolysis during CEA was associated with a “significant reduction” in risks of stroke, TIA or death at 30 days, with rates of this composite primary endpoint being 2.2% in the sonolysis group versus 7.6% in the sham treatment group.

The same trend was seen for both symptomatic strokes (1.8% vs 7.5%) and new ischaemic lesions on MRI (8.6% vs 17.4%), Školoudík also detailed.

Multivariate analyses presented by Školoudík revealed that female gender appeared to be the only baseline characteristic associated with an increased risk of a negative outcome with sonolysis.

However, atrial fibrillation and anticoagulation were not linked to a significant difference between the two groups (sonolysis and sham treatment).

The concluding finding of SONOBIRDIE—periprocedural stroke and TIA risks being safely and effectively reduced in the trial using a diagnostic 2-MHz probe—led ESOC session moderator Carlos Molina (Vall d’Hebron Hospital, Barcelona, Spain) to remark that “sonolysis is back”.

Issue 51 | September 2023

New data represent “fantastic news” in IVT despite lack of efficacy with tenecteplase Results from the TIMELESS trial represent “fantastic news” on the safety of intravenous tenecteplase in selected late-window stroke patients, despite the drug failing to meet prespecified study endpoints.

THAT IS ACCORDING TO Gregory Albers (Stanford Medicine, Stanford, USA), who delivered these first-time data at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany).

The Phase 3, double-blinded, randomised, placebo-controlled TIMELESS study sought to investigate if tenecteplase—administered in ischaemic stroke patients with large vessel occlusions and a favourable

Intravenous Thrombolysis 15 perfusion-imaging profile, presenting between 4.5 and 24 hours after time last known well—would improve clinical outcomes, as measured by modified Rankin scale (mRS) scores at day 90.

Patients meeting the eligibility criteria of an internal carotid artery (ICA) occlusion or an M1/M2 occlusion in the middle cerebral artery, and favourable perfusion imaging, were randomised 1:1 to receive either intravenous thrombolysis (IVT) with tenecteplase (0.25mg/kg; maximum 25mg) or a placebo drug. The study enrolled a total of 458 patients.

Regarding the primary efficacy endpoint in TIMELESS’ intentionto-treat analysis, Albers reported that some themes favouring tenecteplase were observed, in that there was a trend toward more patients having an excellent outcome when given the drug. However, these signals were not maintained across the full spectrum of stroke outcomes, he continued, and no significant difference was seen between the two groups in terms of overall odds of achieving less disability at 90 days.

In addition to comparable 0–2 mRS rates of 46% and 42% in the tenecteplase and placebo groups, respectively, the speaker highlighted an increased rate of complete recanalisation at 24 hours with tenecteplase (77%) versus placebo

(64%)—as per secondary endpoints. effect when they received tenecteplase, Arriving at what he described as while those without a planned “fantastic news”, Albers then disclosed thrombectomy had a trend towards safety outcomes from the trial. He slightly better outcomes when treated said that “no hint of safety concern” with placebo. was observed despite a treatment Another finding shared by Albers was window of 24 hours, reporting low that older patients, and patients with rates of symptomatic/any intracranial higher National Institutes of Health haemorrhage (ICH), serious stroke scale (NIHSS) scores, adverse event, or death, with did not appear to experience no significant discrepancies a reduced likelihood of a between groups. favourable treatment effect According to Albers, when compared to younger TIMELESS therefore patients and those with lower constitutes the first time Gregory Albers NIHSS scores—and there tenecteplase—or any was no sign that tenecteplase thrombolytic drug for ischaemic was less effective when administered stroke—has been shown to produce no later on in the 4.5-to-24-hour treatment safety-related concerns across “a very window either. extended time window” (treatment was Prior to concluding, the speaker given up to 24 hours since last known also highlighted what he feels may well) in a large-scale stroke trial. be the “most provocative finding” Briefly touching on “interesting from TIMELESS: the fact that, in a findings” from analyses of the study’s large, prespecified subgroup of M1 subgroups, the speaker said that, occlusion stroke patients, there was although the average time from drug a substantial trend towards greater administration to groin puncture was treatment responses in those who lower than he and his co-investigators received tenecteplase versus placebo, would ideally have wanted, longer as compared to stroke patients with dwell times yielded “no apparent M2 or ICA occlusions. However, he advantage” in terms of patient noted that this aspect of the trial was outcomes. And, based on common odds an exploratory, hypothesis-generating ratios, patients in whom mechanical analysis and, as such, “no formal thrombectomy was planned appeared conclusions should be drawn from these to have a marginally better treatment data” without further investigations.

IRIS data shed new light on how treatment delays may impact thrombolysis efficacy A collaboration analysing several major clinical trials has found that endovascular therapy (EVT) plus intravenous thrombolysis (IVT) is likely to be superior to EVT alone— also known as direct EVT—in the majority of ischaemic stroke patients, but that one of the most important factors in determining this is time from symptom onset to treatment.

I

n light of this, Johannes Kaesmacher (Bern University Hospital, Bern, Switzerland)—who presented findings from the IRIS collaboration at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany)—commented that the decision to administer IVT before EVT “should take into account time-dependent treatment effects, rather than the overall effect” of thrombolytics.

The IRIS collaboration involved a pooled analysis of the six major randomised controlled trials (RCTs) that have compared direct EVT and EVT plus IVT to date: DEVT, DIRECT-MT, DIRECT-SAFE, MR CLEANNO IV, SKIP and SWIFT-DIRECT. These trials evaluated whether direct EVT has either a superior or non-inferior impact on functional outcomes, as compared to ‘bridging thrombolysis’ prior to EVT, in patients with an acute ischaemic stroke caused by an anterior circulation large vessel occlusion.

The IRIS investigators conducted a meta-analysis of individual participant data from these trials—which included a total of 2,313 patients—hypothesising that there would be a “significant treatment-effect heterogeneity” between the administration of an intravenous thrombolytic drug (alteplase or tenecteplase) prior to EVT and delays in treatment.

More specifically, they anticipated that patients with shorter intervals from onset to randomisation would

benefit from IVT, while patients with longer intervals would not.

To this end, Kaesmacher and colleagues deployed an ordinal, mixed-method model regression analysis, adjusted for relevant baseline characteristics, with 90-day ordinal shifts in modified Rankin scale (mRS) scores being the primary outcome.

The investigators’ initial hypothesis was ultimately fulfilled in the results of their primary outcome analysis, as a higher proportion of the 928 patients with an onset-to-expected-IVT time <134 minutes achieved an excellent functional outcome (mRS 0–2) when treated with EVT plus IVT, as compared to those treated with direct EVT. However, the same improvement in outcomes was not seen in the 1,385 patients with an onset-to-expected-IVT time ≥134 minutes, as EVT plus IVT and direct EVT led to broadly comparable benefits in this later time window.

A similar yet less-pronounced trend towards greater benefit with EVT plus IVT was observed regarding good functional outcomes (mRS 0–3) in the <134-minute group—but, again, not in the ≥134-minute group—as well.

These findings led Kaesmacher et al to conclude that, up to two hours and 15 minutes, they were able to establish the superiority of IVT prior to EVT versus EVT alone, but that the same superiority trend

could not be established beyond this timepoint. In his presentation, Kaesmacher noted that these findings from IRIS were borne out by the “only available data”, thus far, on randomised comparisons of EVT with and without IVT. Another first-time data presentation at ESOC 2023 saw Jasper Daems (Erasmus University Medical Center, Rotterdam, The Netherlands) deliver results with a clinical model for predicting individualised treatment benefits of IVT before EVT—also derived from IRIS’ ischaemic stroke patient population. Daems and his colleagues set out to capture potential betweenpatient heterogeneity in benefit and support clinical decision-making with said model.

Their study excluded patients treated with tenecteplase or urokinase, meaning all EVT-plus-IVT patients in their analysis received intravenous alteplase, and resulting in a population of 2,284 (median age=71 years) IRIS patients. The researchers found that differences in predicted outcomes between direct EVT and EVT plus IVT were “generally small”, and favoured the latter for “most patients”.

However, Daems also stated that the expected benefits of both treatment approaches vary between individual cases, and that certain patients—mostly those presenting later than 3.5 hours from symptom onset—were predicted to experience potential benefits from direct EVT. The speaker further noted that a greater likelihood of achieving mRS 0–2, equivalent to >3%, was predicted in patients who received EVT plus IVT <2 hours from symptom onset.

Concluding his talk, Daems told the ESOC audience that the model discussed may be able to identify patients in whom a larger-than-average benefit, no benefit, or even harm, can be expected if IVT is given prior to EVT. Additionally, he noted that, after further validation, the model could hold the capacity to inform and support “personalised treatment decisions” regarding IVT administration before EVT in ischaemic stroke patients.

September 2023 | Issue 51

16 Endovascular Therapy

ESOC

Combined thrombectomy technique fails to demonstrate superiority over aspiration alone New data from the VECTOR randomised controlled trial—presented at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany)—have indicated that a mechanical thrombectomy in which a stent retriever is deployed alongside contact aspiration, a ‘combined technique’, is not significantly superior to contact aspiration alone, as per expanded thrombolysis in cerebral infarction (eTICI) 2c–3 after three passes. However, the study’s secondary outcomes appeared to indicate a greater benefit with the combined technique.

DELIVERING THESE FINDINGS, the combined-technique group compared Romain Bourcier (Nantes University to 52.3% in the aspiration-only group.

Hospital, Nantes, France) initially Bourcier noted that these effect sizes were highlighted the current uncertainty over calculated following adjustments for a which of the multiple specific approaches number of variables, including centre, to thrombectomy in acute ischaemic stroke age, intravenous thrombolysis patients can produce the best outcomes.

(IVT), occlusion site and Romain Bourcier The prospective, multicentre VECTOR general anaesthesia. study was designed to shed some light on this matter, Secondary angiographic evaluating if a first-line treatment strategy involving outcomes revealed a combined strategy (Embotrap II/III stent retriever significantly greater first[Cerenovus] plus contact aspiration) could achieve pass reperfusion rates with better reperfusion outcomes compared to first-line the combined technique contact aspiration alone. versus aspiration alone, The study included patients with an acute ischaemic corresponding to an stroke caused by red thrombi in the anterior circulation, absolute increase of 11%. identified via a positive susceptibility vessel sign on Additional assessments magnetic resonance imaging (MRI). also found significant Its objective, Bourcier detailed, was to demonstrate improvements in ≥eTICI superiority with the combined technique—defined as 2b rates with the combined with combined a high grade of reperfusion (eTICI 2c–3)—over an technique versus aspiration technique aspiration-only approach. A total of 526 patients were alone after the initial randomised in VECTOR, with 263 being allocated strategy—although there was no to the combined-technique group and 258 receiving significant difference in eTICI 3 rates aspiration alone as their first-line treatment. between groups. Reperfusion outcomes at As per the trial’s primary efficacy outcome, a the end of the entire endovascular procedure, i.e. high reperfusion score after the assigned first-line following any necessary second-line interventions, approach—and prior to any subsequent secondary were found to be broadly similar across the two interventions—was achieved 57.8% of the time in groups, although ≥eTICI 2b, ≥eTICI 2c and

eTICI 3 rates were all marginally higher in the cohort of patients who received first-line aspiration alone.

Bourcier went on to report “no difference” in functional outcomes between the two groups, signified by changes in mean 24-hour National Institutes of Health stroke scale (NIHSS) and three-month modified Rankin scale (mRS) scores.

Finally, the speaker touched on safety outcomes seen in VECTOR, detailing comparable rates of embolisation in new territories (ENT) between groups, before noting an increased rate of 24-hour symptomatic intracranial haemorrhage (ICH) in the combined group (11.6%) versus the aspiration-only group (7.2%).

As such, despite a number of secondary analyses indicating improved reperfusion outcomes can be achieved by deploying a stent retriever alongside contact aspiration, the combined technique assessed in VECTOR ultimately demonstrated no superiority versus aspiration alone, as per the trial’s primary efficacy endpoint.

Bourcier further remarked that questions remain regarding the most appropriate, clinically relevant angiographic endpoint through which to measure success in thrombectomy, and how specific clot types can impact procedural outcomes.

“We pave the way for future trials integrating an assessment of the occlusion type,” he added. with aspiration The speaker then only concluded with a nod to future subgroup analyses of VECTOR, which plan to evaluate discrepancies between clot locations (internal carotid artery [ICA] versus middle cerebral artery [MCA]), and the effect of giving or withholding IVT alongside these different thrombectomy techniques.

High reperfusion score after assigned first-line approach

57.8%

Vision recovery among potential benefits of endovascular therapy in PCA occlusion stroke A multicentre study presented at the recent European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany) has found that vision recovery and an increased likelihood of early neurological improvement are among the potential benefits endovascular therapy (EVT) can offer in posterior cerebral artery (PCA) occlusion stroke.

HOWEVER, THE SAME STUDY indicated that EVT was not linked to improved odds for reduced disability, and was also associated with higher mortality and symptomatic intracranial haemorrhage (sICH) rates, as compared to medical management (MM).

Findings from PLATO—a casecontrol study conducted at 27 sites, and including consecutive patients with isolated PCA occlusions presenting 0–24 hours from symptom onset—were delivered for the first time by Simon Nagel (Heidelberg University Hospital, Heidelberg, Germany). Nagel and his colleagues included 1,023 patients (median age=74 years, 57.6% male) in the study, 379 (37%) of whom received

EVT. The majority of PCA occlusions were either located in the P1 (41.2%) or P2 (49.2%) segments.

Regarding the trial’s co-primary endpoint, which contrasted 90-day ordinal modified Rankin scale (mRS) scores between the two groups, there was no statistically significant difference with EVT versus MM. However, Nagel did report EVT being associated with greater odds of achieving a decrease >2 points on the National Institutes of Health stroke scale (NIHSS) at 24 hours or upon discharge, as well as “complete vision recovery”, compared to MM. This was the case following adjustments for numerous comorbidities and variables, including

52.3%

age, sex, NIHSS score, baseline mRS, occlusion location, and whether or not intravenous thrombolysis (IVT) was administered.

The presenter further detailed a Simon higher likelihood Nagel of an excellent functional outcome (mRS 0–1) with EVT—despite increased mortality (10.1% vs 5%) and sICH (6.2% vs 1.7%) rates versus the MM group. As such, Nagel concluded that “these results support continued enrolment into ongoing trials comparing EVT versus MM in patients with distal vessel occlusion”, referring primarily to the DISTAL, ESCAPE-MeVO and

DISCOUNT studies.

A brief discussion between Nagel and session moderator Marc Ribó (Hospital Vall d’Hebron, Barcelona, Spain) culminated in an ESOC audience member suggesting that mRS is primarily focused on mobility, and may not take vision-related outcomes into account as much as it should.

Nagel agreed with this view, citing it as a key motivation for vision recovery being included as a separate outcome measure in PLATO. Findings from the PLATO study have since been published in full in the journal Stroke.

These results support continued enrolment into ongoing trials comparing endovascular therapy versus medical management in patients with distal vessel occlusion.”

Issue 51 | September 2023

Endovascular Therapy 17

Endovascular therapy: ‘strong, generalisable evidence’ sustains positivity in large-core stroke The latest randomised controlled trial (RCT) assessing endovascular therapy (EVT) in ischaemic stroke with a large-core infarct volume may have narrowly failed to meet its prespecified primary endpoint, but that has done little to dampen the community’s enthusiasm over the clinical benefits this intervention can provide for a currently underserved patient population.

T

he final day of this year’s European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany) saw Amrou Sarraj (Case Western Reserve University, Cleveland, USA) deliver late-breaking findings from MAGNA—a meta-analysis of individual patient data (IPD) from three published RCTs, all of which have demonstrated clinically meaningful benefits with EVT in large-core strokes.

“The MAGNA IPD meta-analysis provides strong evidence for clinically meaningful benefit in reducing disability for patients with extensive ischaemic injury on non-contrast CT [computed tomography], CTP [CT perfusion] or MRI [magnetic resonance imaging],” Sarraj stated. “The results from the previously published large-core trials, and from this pooled dataset, provide unequivocal evidence on the efficacy and safety of EVT in patients with large-core infarcts. The benefit persists across the spectrum of age, clinical severity and time with clear benefit up to an estimated ischaemic core volume of 150ml.”

Touching on new data from the TESLA trial—presented early on in the same session by Albert Yoo (Texas Stroke Institute, Plano, USA) and Osama Zaidat (Mercy Hospital, Toledo, USA)—Sarraj noted that, while the study failed to achieve its primary endpoint goal, the reported “positive efficacy signals” and “good safety outcomes” constitute another piece of evidence supporting the addition of EVT to standard care in these patients.

MAGNA-nimous new evidence

Discussing the ongoing expansion of EVT in acute ischaemic stroke care, Sarraj initially noted that patients with large-core infarcts have been excluded from many prior trials evaluating this intervention. However, three more recent RCTs—RESCUE-Japan LIMIT, ANGEL-ASPECT and SELECT2— have offered strong, positive indications regarding its safety and ability to improve functional outcomes.

In an effort to further explore the evidence favouring EVT over standard care in patients presenting up to 24 hours from time last known well, data from all three trials were collated by the MAGNA investigators

and analysed across key clinical and imaging subgroups. Their primary efficacy endpoint was the distribution of modified Rankin scale (mRS) scores at 90 days, while secondary endpoints included functional independence (mRS 0–2), independent ambulation (mRS 0–3), symptomatic intracranial haemorrhage (sICH) and mortality.

Patients were considered eligible if their anterior-circulation large vessel occlusion (LVO) had an ischaemic core with an Alberta stroke programme early CT score (ASPECTS) ≤5 on non-contrast CT or MRI, or if the core volume was ≥50ml. In total, 1,009 patients (41% female) were included, of whom 506 received EVT and 503 received standard care.

MAGNA analyses found that EVT improved functional outcomes as well as functional independence and independent ambulation compared to standard care, but was also associated with more frequent early neurological worsening. Sarraj described this as a “continuation” of a similar trend seen in SELECT2. In addition, no significant difference in mortality was identified between EVT and standard care, and sICH rates were similar between the two groups. According to Sarraj, key subgroup analyses also “consistently favoured” EVT, and the benefits of EVT were found to have reached statistical significance over standard care across ASPECTS 3, 4 and 5. EVT was statistically significantly superior in ischaemic cores with volumes ranging from <70ml up to 149ml, but not in those ≥150ml.

After re-emphasising the persistent benefit of EVT across many of the endpoints assessed and a “wide spectrum” of large-core infarct patients in MAGNA, Sarraj concluded by stating that “clinical judgement is required to weigh [up] the influence of individual patient factors” on these benefits, including co-morbidity, frailty, and tolerance of disability. He further noted that the “consistency in the results” and “magnitude of the treatment effect” emphasise the generalisability of these findings “across the large-core population”.

“There is no going back,” Sarraj summarised. “We showed efficacy, we showed safety, and we really look forward to the guidelines changing

sooner rather than later.”

The MAGNA investigators’ attention will now turn toward the newly available results from TESLA, and two more as-yet unpublished large-core infarct trials—LASTE and TENSION— as they plan to update their metaanalysis once these data are available.

“This will increase the accuracy of the estimation of the treatment effect, and will give even more power to look further into the details related to subgroups and selected imaging modalities,” Sarraj added.

TESLA: positives and negatives

The first-time presentation of TESLA results at ESOC 2023 saw investigators relay a “strong suggestion” across several domains that EVT can provide benefits in large-core stroke patients— despite the intervention narrowly failing to reach its prespecified superiority threshold versus standard care.

The TESLA study—a prospective, multicentre, assessor-blinded RCT with adaptive-enrichment design—set out to build on positive findings from previous RCTs, but chose to home in on large-core infarct patients identified using non-contrast CT (NCCT) imaging only, as opposed to advanced imaging evaluations. Yoo also commented that RESCUE-Japan LIMIT, ANGELASPECT and SELECT2 were all restricted to populations with ASPECTS 3–5, Amrou Sarraj whereas TESLA included those with ASPECTS 2–5.

A total of 302 acute ischaemic stroke patients with an anteriorAlbert Yoo circulation LVO, presenting within 24 hours from time last known well, were randomised to receive either EVT plus standard care or standard Osama Zaidat care alone across 47 US sites.

TESLA’s primary efficacy endpoint was the difference in distribution of 90-day utility-weighted mRS (UW-mRS) scores between the two treatment arms, while its primary safety endpoint was 90-day mortality. Key secondary endpoints included 90-day ordinal mRS shift, mRS 0–2, mRS 0–3, and 24-hour sICH, according to Yoo. The investigators reported that the study’s intention-to-treat (ITT) population consisted of 152 patients in the EVT group and 148 in the control group—a “very good” follow-up rate for an RCT. Assessing TESLA’s primary endpoint in this population, they found a treatment benefit with EVT, as the intervention led to an average 90-day UW-mRS of 2.93 compared to 2.27 with

standard care. However, Zaidat reported that this meant EVT had a Bayesian probability of superiority of 0.957 over the control arm, falling just short of the prespecified threshold of >0.975 needed to declare efficacy.

Discussing secondary endpoint outcomes in the ITT population, Zaidat said that the most notable benefits with EVT versus standard care came regarding major neurological improvement, also highlighting a “strong suggestion” in favour of EVT regarding mRS 0–3 rates and average quality-of-life scores. Despite this, the speaker went on to note “no significant modification” of EVT’s effect across any ITT subgroups, and “similar” point estimates for ASPECTS 2–3 vs 4–5.

Zaidat then delivered more positive results in a cohort of 249 ITT patients whose NCCT ASPECTS 2–5 was specifically determined by a core lab.

A 90-day UW-mRS of 3.15 with EVT versus 2.32 with standard care led to a Bayesian probability of superiority of 0.98 in this prespecified secondary analysis, eclipsing the primary-endpoint threshold of >0.975.

Finally, Zaidat relayed that EVT was associated with “no major safety concerns” regarding all-cause mortality at 90 days; sICH at 24 hours; neurological deterioration within 5–7

The results from the previously published largecore trials, and from this pooled dataset, provide unequivocal evidence on the efficacy and safety of EVT in patients with large-core infarcts.”

Amrou Sarraj

days/at discharge; or decompressive hemicraniectomy rates, adding that there was therefore “almost no difference across the four major safety factors we look at in most [stroke] trials”. However, EVT was found to be associated with higher rates of parenchymal haematoma, type 1 haemorrhage infarction, and subarachnoid haemorrhage.

The speaker concluded that future research should focus on individual, patient-level meta-analyses of TESLA and the other major large-core RCTs to “address patient selection based on NCCT” and “confirm outcomes with this pragmatic approach”, as the trials’ larger, combined sample size “might identify potential thresholds of futility” when using only NCCT ASPECTS.

September 2023 | Issue 51

18 Advertorial THIS ADVERTORIAL IS SPONSORED BY VESALIO

NeVaTM: Tailor-made to achieve first-pass success across all clot types

As a frequent user and advocate of Vesalio’s NeVa stent retrievers in ischaemic stroke treatment, Vladimir Kalousek (Sisters of Charity Hospital, Zagreb, Croatia) outlines his experience to date—including with the most recent addition to the NeVa family of mechanical thrombectomy devices, the NeVa NET. HAVING STARTED USING NEVA DEVICES IN May 2018, Kalousek and his colleagues in Zagreb have now utilised these one-of-a-kind stent retrievers in more than 300 cases.

“As with every new device or technology, there is a learning curve, but we have overcome this rather quickly, and appreciate the advantages that allow us to achieve good results that benefit our patients,” he says.

NeVa devices are structured with multiple ‘drop zones’: large, open pockets, offset at 90-degrees to one another on the stent’s structure, which ensure the clot can be captured and secured within the device while the operator is retrieving from a distal to a proximal location.

According to Kalousek, DROP ZONE™ technology increases the likelihood of a procedure being completed successfully at the first retrieval attempt,

or ‘pass’, as compared to older, previous-generation devices. This is key because, as the current literature indicates, completing a thrombectomy procedure within a minimal number of passes increases the chances of a positive clinical outcome for the patient.

Another feature of NeVa that Kalousek believes enhances its first-pass capabilities is the presence of multiple sizes, some of which come with longer working lengths.

These longer versions offer extended clot interaction to help tackle more challenging cases and create a certain amount of “room for error”, allowing the operator greater freedom when positioning the device while creating multiple opportunities to secure clots within a single pass.

“On a daily basis, we are doing thrombectomy without knowing what kind of clot we are going

technology is in achieving positive patient outcomes.

NeVa stent retrievers Via a prospective, multicentre, open-label, singlearm, US Food and Drug Administration (FDA)demonstrate CLEAR regulated investigational device exemption (IDE) study, they enrolled a total of 139 acute ischaemic advantages in LVO stroke patients with National Institutes of Health scale (NIHSS) scores of 8–25 and intracranial acute ischaemic stroke stroke LVOs treatable within eight hours of onset. The

Results from the CLEAR study have validated the safety and effectiveness of Vesalio’s NeVa stent retrievers in the treatment of large vessel occlusion (LVO) acute ischaemic stroke, finding statistically superior first-pass successful reperfusion rates versus predicate devices and superior 90-day clinical outcomes compared to those seen in other studies.

THE INITIAL FINDINGS FROM THE CLEAR study were reported for the first time at the 2023 International Stroke Conference (ISC; 8–10 February, Dallas, USA) on behalf of CLEAR investigators— one of whom is Rishi Gupta (WellStar Health System, Atlanta, USA).

“The key findings of the study were that first-pass TICI [thrombolysis in cerebral infarction] 2c–3 with the DROP ZONE technology yielded a nearly 50% success rate, and reperfusion success with the device met the superiority threshold when compared to the composite results of the ARISE II [Cerenovus] and TIGER [Rapid Medical] trials,” Gupta states.

“The technology was highly successful, with a low utilisation of balloon guide catheter devices, which may be due to the effectiveness of the DROP ZONE technology in ensnaring the clot via internalisation.

More impressively, first-pass TICI 2b–3 was achieved in 73.8% of procedures with the device.”

Gupta and the other CLEAR investigators’ primary aim was to assess the safety and effectiveness of the NeVa device in revascularising LVOs—and, in doing so, evaluate how successful Vesalio’s DROP ZONE

CLEAR study was conducted at 25 centres in the USA and Europe.

The study’s key safety endpoint of all-cause mortality at 90 days and/or symptomatic intracranial haemorrhage (sICH) at 24 hours post-procedure was analysed across this intention-to-treat (ITT) population.

Its primary effectiveness endpoint— successful reperfusion rate (TICI 2b–3) within three NeVa passes without rescue—was examined within a modified ITT population including 107 patients.

The performance goal for this endpoint was 72%, based on predicate device data from the

The technology was highly successful, with a low utilisation of balloon guide catheter devices, which may be due to the effectiveness of the DROP ZONE technology in ensnaring the clot via internalisation.”

Rishi Gupta

for,” he adds. “So, you need to have a device that enables you to be prepared and have great results in all types of clots.”

Kalousek says that DROP ZONE technology allows NeVa to achieve this. He explains that Neva’s optimised radial force allows the drop zones to successfully encapsulate the clot inside the device structure and subsequently extract it without further complications.

He goes on to state that operators are “good to go” in both smaller, softer clots, as well as bigger, harder ones.

“When you have a large clot, or a carotid T or tandem occlusion, go and try NeVa,” Kalousek says, offering words of advice to his colleagues in the neurointerventional space. He also recommends placing the device

You need to have a device that enables you to […] have great results in all types of clots.”

Vladimir Kalousek

ARISE II and TIGER studies, with a non-inferiority margin of 10%.

Not only was NeVa able to successfully demonstrate non-inferiority or ‘substantial equivalence’ to said predicate devices, as per this prespecified goal, it also demonstrated post-hoc superiority here, achieving a 90.7% rate of eTICI 2b–3 within three passes.

Gupta describes this finding as being “highly encouraging” when it comes to the performance of the NeVa stent retriever and its DROP ZONE technology for successful reperfusion in LVO stroke patients.

As per CLEAR’s secondary efficacy endpoints, prespecified hierarchical testing across the modified ITT population found that NeVa achieved a superior rate of first-pass eTICI 2b–3 (73.8%) compared to predicate devices (57.8%). Among other noteworthy secondary endpoint findings was a 90-day ‘good’ clinical outcome (modified Rankin scale [mRS] 0–2) of 65.1% with NeVa versus 54.7% from predicate device data.

In addition, the primary safety endpoint analysis in the study revealed a 12.2% rate of all-cause mortality at 90 days and/or sICH at 24 hours post-procedure.

This compared favourably to the 17.7% rate that constituted the performance goal derived from predicate devices.

Secondary endpoint analyses of CLEAR’s ITT population further indicated a 9.4% 90-day mortality rate; a 4.3% rate of procedure-related serious adverse events; and a 3.6% rate of NeVa device-related serious adverse events.

“Although CLEAR is a single-arm study, its encouraging results offer clinicians an opportunity to more efficiently and effectively remove thrombus in patients suffering from an LVO,” Gupta reiterates.

“Future iterations of adding a net at the end of the device hold promise for reducing distal embolisation, thereby further increasing effective reperfusion rates.”

DISCLAIMER: The NeVa and NeVa NET devices are CE-mark approved but are not currently available in the USA.

Issue 51 | September 2023

Advertorial 19

distally to the clot and slowly pulling it proximally, adding, “either you will have a first-pass effect, or you will achieve a pretty good debulking of a large portion of the clot”.

Fast-forward to NeVa NET

In September 2022, a recent addition to Vesalio’s family of NeVa devices—the NeVa NET, designed to maximise clot retention, received CE-mark approval.

Upon being introduced to the device at last year’s European Society of Minimally Invasive Neurological Therapy (ESMINT) congress (7–9 September 2022, Nice, France) and finding it to be a “very interesting” concept, Kalousek wasted little time in adding the NeVa NET to his practice.

“I observed that we had quite a few cases of distal clot fragmentation during mechanical thrombectomy—and I was wondering if, in the future, a device would be developed to prevent distal emboli caused by this fragmentation,” he notes.

“So, in December 2022, we started using the NeVa NET and, in the majority of the 30 cases we have performed, we have seen some clot particles engaged in the net section, inside the tip of the device.”

According to Kalousek, the aforementioned DROP ZONE technology is a key factor here, enabling the clot to drop inside of the frame of the stent retriever rather than “partially stick out”.

This allows the clot to be “protected”, making it less likely to fragment during the procedure.

Coupled with this, the newly introduced microfiltration technology, a finely braided net integrated

NeVa

NeVa NET

into the device’s closed distal tip, increases the likelihood of a potential friable clot particle remaining within the device structure rather than migrating into distal vascular territories.

“I believe that, in stroke treatment, this technology has really helped us become more effective, more secure, safer and faster, resulting in quicker restoration of blood flow for the patient,” he continues.

“But, of course, the true numbers are yet to be seen as NeVa NET expands worldwide.”

“Impressive” and “compelling” data support NeVa NET’s capacity to retain clot

This message is echoed in Gounis and colleagues’ conclusion asserting that these preclinical results support the use of NeVa NET in a clinical trial “to determine if this novel design improves first-pass full reperfusion”.

Another in-vitro evaluation of Vesalio’s proprietary device—recently published in the Journal of NeuroInterventional Surgery—led Marc Ribo (Vall d’Hebron University Hospital, Barcelona, Spain) and colleagues also conclude that, when faced with fragment-prone clots, NeVa NET’s filter tip “significantly reduces” the number of large clots (>1mm) that embolise distally during a thrombectomy procedure.

They state in their report that this may, in turn, increase the likelihood of the device enabling complete recanalisation at the first pass.

“When performing a thrombectomy, [the aim should be] for the highest degree of TICI 3 recanalisation, in the first performed pass, with the chosen device or device combination,”

Ribo says. “Currently, most studies show first-pass recanalisation rates around 50%—meaning that, in half of the patients, the clot remains in the initial location or significant fragments are embolised to distal branches.”

Ribo and colleagues’ study compared NeVa NET to the open-tip Solitaire X and the closed-tip EmboTrap II (Cerenovus) stent retrievers via benchtop testing.

A total of 150 single-attempt thrombectomy cases were performed—50 per each device—on a vascular model with a middle cerebral artery (M1-MCA) occlusion created using stiff-friable clot analogues.

In addition to demonstrating a capability to decrease the incidence of large clot fragments migrating to distal territories, the filter-tip NeVa NET achieved a numerically higher first-pass recanalisation rate compared to its open- and closed-tip competitors and prevented clot fragments >1mm from embolising distal territories in 44% of cases (vs 16% with Solitaire and 20% with EmboTrap).

“The visual inspection of the retrieved NeVa NET showed how these particles remained entangled in the [micro]filter at the distal tip of the device,” Ribo adds.

“The next step is to confirm these positive laboratory findings in stroke patients and see if NeVa NET will further improve the first-pass TICI 2c or greater recanalisation rates of the NeVa device in prospective, multicentre registries.”

Coupled with the animal data showing vascular safety, these [findings] are compelling for predicting excellent clinical results.”

When performing a thrombectomy, [the aim should be] for the highest degree of TICI 3 recanalisation in the first performed pass.”

Preclinical assessments of the device have produced “compelling” results and signal promising potential regarding how it may perform in real-world clinical practice.

EARLIER THIS YEAR, MATTHEW GOUNIS (University of Massachusetts Chan Medical School, Worcester, USA) and colleagues published one such paper in the Journal of Vascular and Interventional Neurology, detailing in-vitro and animal studies in which the NeVa NET was compared to the longestablished Solitaire stent retriever (Medtronic).

Among the researchers’ key findings was that the NeVa NET required fewer passes than Solitaire to achieve thrombolysis in cerebral infarction (TICI) 3 reperfusion, while Solitaire generated more clot fragments than NeVa NET including four times as many fragments larger than 1mm in size.

“Incorporating a distal filter in a closed-end stent retriever is an impressive development, and one perhaps long overdue,” says Gounis, contextualising these findings. “Excellent work from around the world is showing that reducing distal emboli during the thrombectomy procedure improves clinical outcomes; so, this is a welcomed innovation.”

Gounis also describes the results from their in-vitro study as “impressive”, as the study involved using a vascular phantom with patient-specific anatomy whereby the number and size of distal emboli during a simulated thrombectomy can be measured quantitatively.

“The NeVa NET device demonstrated a dramatic and statistically significant reduction in the number of clot fragments generated, as well as improved efficacy with fewer passes needed to achieve complete recanalisation,” he adds. “This combination of improved safety and efficacy is the goal of newer generations of thrombectomy devices. Coupled with the animal data showing vascular safety, these are compelling for predicting excellent clinical results.”

Kalousek goes on to state that, to his knowledge, the DROP ZONE and micro-filtration technologies are both “unique” in the neurovascular market, and that NeVa is his preferred first-line device in proximal occlusions, such as carotid T and MCA occlusions.

He concludes, “if I want to be as fast and effective as possible, I will use NeVa in my practice”, citing the fact he has achieved “great results” in tougher anatomies, in older patients, and in cases where prior generations of stent retrievers would have struggled.

Matthew Gounis

Marc Ribo

September 2023 | Issue 51

20 Interview

PROFILE

Ameer Hassan

Having initially sought out a career in plastic surgery, Ameer Hassan (Harlingen, USA) switched gears to interventional neurology in 2005—a change of heart he attributes to his “greatest mentor”—and never looked back. In addition to being triple board-certified in neurology, vascular neurology and neuroendovascular surgery, he is head of the Neuroscience Department and director of the Endovascular Surgical Neuroradiology and Clinical Neuroscience Research at Valley Baptist Medical Center, and is currently approaching the end of a two-year stint as president of the Society of Vascular and Interventional Neurology (SVIN). In conversation with NeuroNews, he reflects on his career to date, and assesses ways of improving global access to critical stroke treatments.

From a young age, I was naturally drawn to medicine, often wearing a toy stethoscope around my neck even at the age of five. Initially, I had aspirations of becoming a plastic surgeon, influenced by the success of several family members in that field. However, everything changed when I crossed paths with Adnan Qureshi during my time at the University of Medicine and Dentistry of New Jersey (Newark, USA). During a research rotation, he invited me to observe a stroke case and scrub in for the procedure. This was before the US approval of the Merci device, and we were primarily focused on angioplasty and intra-arterial lytics. Witnessing the profound impact the procedure had on the patients and their families—seeing their joy and gratitude—forever changed my life. The experience solidified my passion for interventional neurology, and it was the compassionate and transformative approach that Dr Qureshi embodied that inspired me deeply. It was in that moment that I realised I wanted to dedicate my life to this field.

Who have your mentors been and how have they impacted your career?

My father and mother instilled a strong work ethic in me from a young age, having us start working at the age of 10 during summers and requiring us to contribute to purchasing our first car. This upbringing taught me the value of hard work and financial responsibility. In the field of medicine, my greatest mentor has been Dr Qureshi. Since my days as a medical student, resident, and fellow, I aspired to emulate him. Driven by a passion for innovation and pushing boundaries, his astonishing work ethic served as a constant inspiration. Without his influence, I believe I may have never found my path in this field.

What has your experience been as the SVIN president?

I dedicated substantial efforts to develop a new initiative called SVIN University, which will be presented at the annual meeting in November. This comprehensive programme will incorporate our existing educational initiatives, such as materials for emergency room nurses, physicians, emergency medical services personnel, and the general public.

Additionally, SVIN University will introduce new programmes aimed at educating medical device representatives and engineers. By expanding our educational reach, we aim to foster a well-rounded understanding of neurointerventional practices among various stakeholders in the medical field.

What do you feel has been the most important development in the field of neurology during your career?

Hands down, mechanical thrombectomy stands out as the most important development in the field of neurology. In the last three decades, no other treatment

has exhibited such a remarkably low number needed to treat, nor facilitated the recovery of numerous individuals affected by a life-threatening and debilitating disease. However, there is still much work to be done; hence, the SVIN Mission Thrombectomy initiative is committed to expanding access to this life-saving procedure. Our goal is to raise awareness, advocate for improved resources, reduce disparity, and foster collaboration among medical professionals, and we strive to make thrombectomy a standard treatment option globally. Together, we can continue to advance the frontiers of thrombectomy and create a future where access to this life-saving procedure is no longer a privilege, but a fundamental right for all.

Which technology you are currently involved with excites you the most?

My startup, Quantanosis.AI, is dedicated to leveraging histotripsy/microtripsy technology to revolutionise the treatment of large vessel occlusion (LVO) in the middle cerebral artery. Our mission is to democratise

Together, we can continue to advance the frontiers of thrombectomy and create a future where access to this life-saving procedure is no longer a privilege, but a fundamental right for all.” stroke treatment globally. Once we establish the safety and efficacy of this technology in human trials, we anticipate being able to provide treatment for millions of individuals suffering from LVOs worldwide. We are particularly focused on addressing the healthcare challenges faced by low-income and very low-income countries and, as such, we plan on offering our system to hospitals in these regions at significant discounts, enabling them to have unlimited use and expand access to life-saving stroke treatments.

Besides your own work, what is the most interesting piece of neurointerventional research you have seen in the past year?

Without a doubt, my greatest curiosity lies in the potential of neuroprotectants and stem cells in aiding patients who have already suffered significant ischaemic infarcts. If we can enhance their neuroplasticity and facilitate functional recovery, it would address the most significant unmet need in our field and could help revolutionise patient outcomes.

alisonlang.com

What initially drew you to medicine, and the field of neurology specifically?

As a fairly active Twitter user, how would you assess the positives and negatives social media brings to the medical field?

In general, the medical field has witnessed numerous cases and the utilisation of various devices without full disclosure. However, I believe that, overall, the etiquette surrounding these practices has significantly improved, leading to the development of a global community. It is remarkable to see how advancements in communication technology have brought together professionals from different parts of the world. For instance, many of my overseas friends, whom I initially connected with on Twitter, now reach out to me for assistance with arteriovenous malformation embolisation or intracranial stenosis cases. They often enquire about our typical setup and approach. With the advent of remote telehealth platforms, we have

Issue 51 | September 2023

Interview 21 been able to provide real-time guidance by proctoring and allowing them to observe our live cases. This has been beneficial in educating professionals globally— especially in countries where access to novel devices and techniques may be limited.

Could you outline how you are able to balance your religious commitments with your clinical practice?

I prioritise my religious obligations and integrate them into my daily routine. Successfully balancing my Muslim religious commitments with my busy neurointerventional practice has been achieved through careful time management (scheduling blocks of time for prayer); community and global involvement (via our foundations); open communication (the majority of my patients are catholic); and self-care (fasting has been proved to be healthy and beneficial). By prioritising my faith, establishing a supportive work environment, and nurturing my wellbeing, I have found a sustainable balance that enriches both my professional and spiritual journey.

What advice would you give to those embarking on a career in neurology?

I consistently advise my medical students and residents to pursue their passions rather than chasing fame or fortune. I emphasise the importance of seeking out what truly brings them happiness and envisioning themselves immersed in that field for the next three decades. What I particularly appreciate about our medical specialty is its perpetual innovation and commitment to research.

This aspect constantly stimulates our intellect and fuels our dedication to assisting those who require our help.

What are your interests outside of the field of medicine?

I find immense joy in travelling with my beloved family and exploring new destinations—we have seen six of the seven wonders of the world. We have had the privilege of dining at exquisite Michelin Star restaurants, relishing culinary masterpieces around the world. We also enjoy hitting the slopes every year; my daughter learned to ski in Val d’Isère at the age four, when my son was three, while I was attending my first ABC WIN seminar. I am an avid enthusiast of Formula One racing and car shows, where I can immerse myself in the captivating world of speed and automotive engineering, and a passionate collector of watches.

My true passion is helping others, as I have started two non-profit organisations. The Hassan Family Health Foundation has established a clinic in my parents’ hometown in Egypt, providing healthcare services to those in need. Moreover, my wife and I founded the Stroke Research and Education Foundation, aiming to expand stroke education in the Rio Grande Valley, empowering the community with vital knowledge.

Fact file Current appointments

Head of Neuroscience Department; director of Endovascular Surgical Neuroradiology and Clinical Neuroscience Research, Valley Baptist Neuroscience Institute Professor of Neurology, University of Texas Rio Grande Valley School of Medicine, Edinburg, USA Professor of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, USA

Education

2012: Fellow in Endovascular Surgical Neuroradiology, University of Minnesota/Fairview Hospital and Hennepin County Medical Center, Minneapolis, USA 2010: Fellow in Stroke and Neurocritical Care, University of Minnesota/Fairview Hospital 2009: Resident in Neurology, University of Medicine and Dentistry of New Jersey 2006: Intern in Internal Medicine, University of Medicine and Dentistry of New Jersey

Honours (selected)

2021–2023: President, Society of Vascular and Interventional Neurology (SVIN) 2019: Distinguished Service Award at the SVIN Annual Meeting 2017: Valley Baptist Physician of the Year 2015: Fellow of the American Heart Association 2012: American Academy of Neurology Institute’s Annual Meeting Award

September 2023 | Issue 51

22 Advertorial THIS ADVERTORIAL IS SPONSORED BY CERENOVUS

World-renowned clot science drives outstanding EMBOTRAP stent retriever outcomes in MASTRO I The EMBOTRAP® family of revascularisation devices (CERENOVUS) is innovative within the stent retriever space due to its differentiated design based on a wealth of clot-science research. As a physician currently using EMBOTRAP in mechanical thrombectomy procedures to treat ischaemic stroke patients, Waleed Brinjikji (Mayo Clinic, Rochester, USA) is excited about the outstanding EMBOTRAP clinical outcomes from the recently published MASTRO I meta-analysis study, and believes these positive results are due in no small part to the work being done by the CERENOVUS Neuro Thromboembolic Initiative (NTI) and product development teams.

“I

was actually invited to the first CLOT Summit meeting in 2015, and that is when I was introduced to all the clot-science work that NTI was doing,” Brinjikji recalls. “They were definitely ahead of the curve in terms of creating clot analogues that would mimic what goes on inside of our patients—and then devising devices specifically designed to extract clot based on this range of clot analogues.”

Brinjikji goes on to describe both the research being done by NTI, and the subsequent design of CERENOVUS’ neurovascular devices, as “very patient focused.” He iterates that this research has played a key role in changing neurointerventionists’ perceptions of the importance of clot science, from the selection of specific devices and techniques for a case, to understanding how certain clot characteristics impact stroke aetiologies and, ultimately, treatment outcomes.

The stroke-causing clots themselves—but also other factors, such as different vascular anatomies and pressure conditions—can all be replicated by researchers in the NTI labs, enabling optimised device design through “truly understanding the problem.”

“I would say that, if it was not for NTI at CERENOVUS, I do not think this whole field of clot science would have exploded over the past 10 years in the way it has,” Brinjikji adds. “CERENOVUS is clearly interested in bringing stroke science forward— for example, through the EXCELLENT registry and the [annual] CLOT Summit—and the ultimate goal here is to, at some point in the future, have tailored therapies based on clot [science].”

Brinjikji further posits that these efforts are helping to create “real, natural academic collaborations,” noting that the positive results of such collaborations can be seen in data from the ARISE II study and MASTRO I publication, both of which have demonstrated improved outcomes with CERENOVUS’ EMBOTRAP stent retriever versus those seen previously in the literature.

From insight to innovation

CERENOVUS via NTI has enabled the refinement and optimisation of the CERENOVUS portfolio of products. EMBOTRAP was the first device to benefit directly from this world-renowned research, and has undergone various iterations based on clot science—

EMBOTRAP III revascularisation device

as well as physician feedback—over the past few years.

“They are designing devices tailored around the wide range of clots we encounter during our stroke thrombectomies, whether it is the red cell-rich clots that are more prone to fragmentation or the fibrin-rich clots that are a bit tougher to extract,” says Brinjikji.

Discussing the specific features that he feels set EMBOTRAP apart from other stent retrievers, Brinjikji first cites its closed distal end, which offers effective clot control and allows the operator to gain confidence that the clot has been secured in full. He

I would say that, if it was not for NTI at CERENOVUS, I do not think this whole field of clot science would have exploded over the past 10 years in the way it has.” also highlights its multi-segmented design, which aids in maintaining wall apposition while retrieving the clot, along with the inner channel, which can provide a reperfusion conduit.

“The inner channel of the device is effective as a temporary bypass as you are leaving it [deployed] for a few minutes while retrieving clot,” he continues, “but I also noticed that it does a good job of almost pinning the clot between the tines of the EMBOTRAP stent retriever. Those are features that make it clear this has been designed with the clot in mind and ultimately provide consistently positive outcomes.

“The most important thing during a thrombectomy procedure is getting that first-pass TICI [thrombolysis in cerebral infarction] 3, and devices that allow you to achieve that, such as the EMBOTRAP, are essential.”

In Brinjikji’s view, EMBOTRAP’s aforementioned features result in an increased likelihood of consistently reaching that first-pass TICI 3 goal, and subsequently a greater chance of an excellent outcome for the patient, which is why the device is his first-line stent retriever of choice.

“It works very consistently,” he explains. “It is

Waleed Brinjikji

easily deliverable through your standard microcatheter, which is extremely important—even in tortuous anatomy, which is really nice. And, EMBOTRAP does produce high first-pass TICI 3 rates.”

Impact on clinical outcomes

One of the most recent and most telling pieces of evidence on EMBOTRAP, according to Brinjikji, is MASTRO I—a ‘living’ systematic review and metaanalysis that has already produced some positive data on the device’s capabilities but is also now set to be updated in the future to expand on these promising findings.

The meta-analysis sought to compare various safety and efficacy outcomes between EMBOTRAP, and two of the current stent retriever market leaders: Trevo (Stryker) and Solitaire (Medtronic).

As Brinjikji points out, no randomised controlled trials (RCTs) offering direct comparisons between stent retriever devices have been completed to date, but—as a meta-analysis of observational studies in epidemiology (MOOSE) checklist-compliant study featuring a robust outlier analysis—MASTRO I is methodologically solid and offers the next best thing to an RCT. “And the results almost speak for themselves,” he adds. “It is very exciting to see that there are indeed some differences in the efficacy and outcomes of patients treated with different types of stent retrievers—what the data suggest is that not all stent retrievers are the same. I think that the number-one message to take home, and the most important thing, was that we saw a statistically significantly better rate of 90-day mRS [modified Rankin scale] 0–2, compared to both Trevo and Solitaire, when using EMBOTRAP.” More specifically, the meta-analysis found a 57.4% rate of mRS 0–2 with EMBOTRAP, versus 50% with Trevo (p=0.013) and 45.3% with Solitaire (p<0.001).

EMBOTRAP also demonstrated a statistically significantly lower rate of symptomatic intracranial haemorrhage (sICH) compared to Solitaire (3.9% vs 7.75%; p=0.028). Hypothesising possible explanations for this, Brinjikji notes that numerically higher firstpass and TICI 3 rates seen with EMBOTRAP versus the other stent retrievers may be a contributing factor.

“When you look at the literature, EMBOTRAP provides extremely positive clinical and angiographic outcomes and, when you look at that, you have to say there is something special in the device design that is allowing us to achieve better outcomes,” he goes on.

“And I think it all comes back to the clot science—the device was designed with clot science in mind.”

While he is quick to acknowledge the potential limitations of MASTRO I, such as its inclusion of observational studies and heterogeneity of data across the analysed studies, Brinjikji feels it constitutes an intriguing piece of evidence nonetheless.

“There are some single-centre or small multicentre studies being done to compare devices directly, so I think the field may be starting to move towards that, but in terms of the evidence we have right now it is pretty interesting—and I think MASTRO I at least provides some food for thought,” he concludes.

Waleed Brinjikji is an interventional neuroradiologist and associate professor of Radiology and Neurosurgery—and co-principal investigator of the Neurovascular Lab—at the Mayo Clinic in Rochester, USA. Brinjikji is a paid a consultant of CERENOVUS, part of Johnson & Johnson MedTech.

248420-230516 EMEA

Issue 51 | September 2023

MeVO Stroke 23

Is thrombectomy set to become the standard of care for medium vessel occlusions?

Johanna Ospel Point of View With multiple large clinical trials currently underway to assess thrombectomy treatments in patients with medium vessel occlusion (MeVO) stroke, Johanna Ospel (Calgary, Canada) takes a look at the possibility of endovascular therapy (EVT) becoming the standard of care for these cases further down the line.

S

ince 2015, EVT has become the standard of care for acute ischaemic stroke patients with large vessel occlusions (LVOs) meeting certain eligibility criteria.1 In the following years, treatment criteria have been expanded to the late time window, patients with large baseline infarcts and basilar occlusions. Life has become much busier for neurointerventionists and the majority of LVO patients, including those with proximal M2 occlusions, who are admitted to a hospital are nowadays treated with EVT in many countries.

Current MeVO treatments

But, what happens with smaller occlusions, such as distal M2 or M3 occlusions? Treatment of these so-called

MeVOs is much more variable—while some centres follow very aggressive treatment regimens and routinely attempt EVT in MeVO patients, others pursue medical treatment only, especially when staff and financial resources are limited.

There are good arguments for both approaches. MeVOs are smaller, more likely to recanalise with intravenous thrombolysis (IVT) and the procedural complication risk is expected to be higher; clearly, there is less to gain and more to lose compared to LVOs. On the other hand, data from prospective cohort studies have clearly shown that the prognosis of medically treated MeVO stroke is poor, with one in three patients not being functionally independent at 90 days and one in 11

patients dying within three months after their stroke.2

Ongoing EVT trials

Clearly, high-level evidence from randomised trials is necessary to standardise management of MeVO stroke and offer the best possible treatment to our MeVO patients. To do so, several randomised MeVO trials have been initiated: ESCAPE-MeVO in Canada, DISTAL in Switzerland, DISCOUNT in France and DISTALS in the USA. Except for DISTALS, which uses successful reperfusion as a primary outcome, all the other trials aim to demonstrate clinical benefit of MeVO EVT on the modified Rankin scale (mRS). The choice of the primary outcome is a tricky one when it comes to MeVO stroke, as reperfusion success is an angiographic outcome that is not immediately meaningful to patients, and therefore not sufficient to change guidelines.

The most commonly used and widely accepted clinical outcome is the mRS—a relatively crude measurement scale, which is used as the primary outcome in the other MeVO trials. But, since MeVO patients are less severely affected than LVO patients, they generally do well, and demonstrating benefit on the mRS could be challenging because the scale may lack the necessary granularity to detect the subtle deficits caused by MeVO stroke.

Will randomised studies give us the answer?

Randomised trial results are not necessarily generalisable to the ‘realworld setting’ because of the strict trial eligibility criteria, since EVT-capable hospitals participating in such trials may differ from those who do not, and because of the Hawthorne effect whereby physicians and other hospital staff are

aware that a given MeVO patient is part of a trial and may treat these patients differently from non-trial patients.

Even if the currently ongoing MeVO trials end up showing benefit of MeVO EVT, not all MeVO patients will benefit from EVT performed by any neurointerventionist in any hospital.

It may well be that less experienced neurointerventionists should be more cautious and opt for medical treatment in more distal MeVOs until they have gained the skillset and experience to safely treat these small occlusions.

On the other hand, if the MeVO trials fail to show EVT’s benefit, this does not mean that no benefit exists. The sample size may be too small or, perhaps, the right endovascular tools do not exist yet.

Over time, as more and more MeVOs get treated, smaller and more flexible catheters and stent retrievers will be developed, which will make MeVO EVT safer and shift the risk-benefit balance.

So, will MeVO EVT become the standard of care after all? Only time will tell. Irrespective of what trial results will be, sound clinical reasoning and a careful evaluation of the potential treatment risks and benefits will remain essential in every patient.

Johanna Ospel is a neuroradiology fellow and stroke researcher in the Departments of Diagnostic Imaging and Clinical Neurosciences at the University of Calgary in Calgary, Canada. She is also the chief scientific officer for Let’s Get Proof.

References: 1. Goyal M, Menon B K, van Zwam W H, et al.

Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet.

2016; 387(10029): 1723–31. DOI: 10.1016/S01406736(16)00163-X. 2. Ospel J M, Menon B K, Demchuk A M, et al. Clinical Course of Acute Ischemic Stroke due to Medium Vessel Occlusion With and Without Intravenous Alteplase Treatment. Stroke. 2020; 51: 3232–40. DOI: 10.1161/STROKEAHA.120.030227.

Of 440 included patients, 55.5% were treated “No significant difference” between with aspiration thrombectomy versus 44.5% with a stent retriever. Dmytriw et al report stentaspiration and stent-retriever retriever thrombectomy as being associated with 15% reduction in the likelihood of successful thrombectomy in medium vessel occlusions arecanalisation—but this difference was not found to

When utilised as a first-line technique for medium vessel occlusion (MeVO) stroke, aspiration and stent-retriever thrombectomy have demonstrated “no significant difference” in imaging-related or clinical outcomes. That is according to a multicentre, propensity score-matched analysis including more than 400 patients, the results of which have been published in the journal Stroke: Vascular and Interventional Neurology.

“ALTOGETHER, THESE FINDINGS DO NOT suggest one technique […] to be associated with any greater probability of technical success, safety, or better long-term functional outcomes,” write authors Adam A Dmytriw (Massachusetts General Hospital, Boston, USA) et al. “The technical success rates with either technique were high (80–90%) and are consistent with those reported from secondary analyses of clinical trials.”

Led by first author James Siegler (Cooper Neurological Institute, Camden, USA), the researchers set about evaluating MeVO thrombectomy outcomes according to first-line techniques in a large, multicentre registry referred to as ‘MAD-MT’. This consortium was founded by Dmytriw and Adrien

Guenego (Erasme University Hospital, Brussels, Belgium). Imaging, procedural and clinical outcomes were assessed, with acute proximal or distal MeVO patients being treated at 37 sites across 10 countries and analysed according to the first-line thrombectomy technique they received—aspiration or stent retriever.

Multivariable logistic regression and propensityscore matching were used to estimate the odds of the primary outcome—expanded thrombolysis in cerebral infarction (eTICI) scores of 2b–3, defined as ‘successful recanalisation’—between the two treatment groups. Secondary outcomes included the ‘first-pass effect’, eTICI scores of 2c–3, intracerebral haemorrhage, 90-day modified Rankin scale (mRS) scores, and 90-day mortality.

be significant after multivariable adjustments across the total cohort, or in the propensity score-matched cohort, in which both groups included a total of 105 patients. Furthermore, there was no significant association between thrombectomy technique and secondary outcomes in the propensity score-matched, adjusted models, the authors relay. As such, they conclude that—as per this large, heterogenous, multinational cohort of MeVO patients—there appears to be “no significant technical or functional advantage” to using either specific technique.

But, despite this cohort being “one of the largest to date” to report outcomes associated with first-line aspiration versus stent-retriever thrombectomy in MeVO/distal vessel occlusions, they acknowledge the non-randomised allocation of techniques, missing reperfusion data and between-site variations as limitations of their analysis. Dmytriw et al add that multiple ongoing trials are “anticipated to shed light” on further treatment considerations, including clot composition and hyperdense vessel sign.

September 2023 | Issue 51

24 Carotid Stenting

CAROTID

First-time data releases “confirm” Roadsaver carotid stent safety and efficacy Presenting first-time data from large multicentre European studies at this year’s Leipzig Interventional Course (LINC 2023; 6–9 June, Leipzig, Germany), Arne Schwindt (St Franziskus Hospital Münster, Münster, Germany) and Ralf Langhoff (Sankt Gertrauden Hospital, Berlin, Germany) delivered results that “confirm” the safety and efficacy of the Roadsaver (Terumo) dual-layer micromesh carotid stent (DLMS).

FIRST TO THE PODIUM, SCHWINDT identified 30-day outcomes in male versus female patients treated using the Roadsaver device. He defined that the majority of patients were treated using a femoral approach, adding that radial access was more common in the female group. The researchers found no difference in the use of embolic protection in their cohort, however Schwindt noted that in the cases where protection was employed, female patients more frequently received distal protection.

Their primary endpoint concerned any major adverse event (MAE) between the female and male groups. Additionally, Schwindt explained that, of their 2,000-patient cohort, participants were evenly split between symptomatic and asymptomatic.

Schwindt and his team found that the MAE rate in their patient population was 2.2%—recorded as 2% for males and 2.6% for females—which he reported to the LINC 2023 audience—was not statistically significant.

Study finds carotid stent fracture rate to be negligible but longterm research needed Findings that consider the incidence of carotid stent fractures and their impact on stent durability were elucidated

by Neeta Karani (Bronson Healthcare, Kalamazoo, USA) during a plenary session at this year’s Vascular Annual Meeting (VAM; 14–17 June 2023, National Harbor, USA).

R

esearch from Karani and colleagues—including senior author Robert Molnar (Michigan Vascular Center, Flint, USA)— comes against the backdrop of the recent approval of transcarotid artery revascularisation (TCAR) for

Arne Schwindt presenting at LINC 2023

Schwindt did pinpoint a trend toward higher stroke risk in their study’s female group, but this was also not statistically significant. Among the entire cohort, stroke risk was seen in 1.9%—which expanded to 1.6% in male and 2.6% in female patients.

“We saw that the majority of these events still take place within 48 hours to three days after the procedure,” Schwindt noted, “but we see these curves flatten out and nothing much happens towards the end of the 30-day period.” Concluding his presentation, Schwindt emphasised the “very low” MAE rate in both male and female patients and “[similarly]” low 30-day rates of minor or major stroke, despite a “small trend” toward lower incidence in males.

Schwindt stated: “Given that both groups undercut the stroke rates defined by the S2 guidelines from Germany, the currently most strict guidelines concerning clinical outcome, CAS with dual layer micromesh stent can be concerned as a valid treatment

asymptomatic patients by the Centers for Medicare and Medicaid Services (CMS), which, by proxy, has increased the number of carotid artery stenting (CAS) procedures being performed today.

Subsequently, Karani, alongside co-author Subbaiah Perla (Oakland University, Rochester, USA), identified a number of carotid stent fractures in their practice, and so set about investigating the prevalence of this condition and its influence on the efficacy of CAS. Conducting a prospective trial, the researchers enrolled 200 patients who had undergone CAS between January 2002 and November 2021. Karani et al then evaluated these patients for stent fractures via anterior-posterior (AP) and lateral cervical X-rays. These X-rays were independently reviewed by three vascular surgeons who, upon complete consensus, identified those patients who had definitive stent fractures.

Additionally, Karani and colleagues applied a modification to their study that allowed for a second X-ray to be obtained at a later date to assess the potential for late fracture development in their patient cohort.

Their primary outcome measure

option for males and females alike.”

Following this, Langhoff presented first-time data on the 30-day safety results in patients treated using the Roadsaver device—their investigation assessed the influence of predilatation on outcomes. “A major difference,” Langhoff posited, became apparent when observing transient ischaemic attack (TIA), which in patients who had received predilatation, was seen to be “significantly” more prevalent. His team identified a 1.6% to 2% split, which emphasised the effect of predilatation that Langhoff himself “did not expect”.

Summarising their findings, Langhoff stated that there was low overall need for predilatation in realworld elective carotid artery stenting (CAS) patients treated with the Roadsaver DLMS. Equally, he noted that there were low and comparable 30-day MAE rates between the groups with and without predilatation, “[confirming]” the safety of the Roadsaver device when performing CAS.

was defined as the incidence of carotid stent fracture, followed by a secondary measure which was an evaluation of the clinical implications associated with the condition upon confirmed identification.

In the 200 patients who consented and were enrolled in the study, a total of 227 stent procedures were performed over the duration of Karani and her team’s investigation. In the first wave of X-rays obtained by the team, they identified 18 stent fractures, amounting to a stent fracture rate of 7.9%. Karani went on to report that 103 patients additionally received a second/delayed X-ray, which amounted to a total of 117 X-rays obtained. In these patients, a further six stent fractures were discovered for a delayed fracture rate of 5.6%.

The total number of fractures found by the researchers amounted to 24, representing an overall stent fracture rate of 10.6%. Karani explained that, of those with stent fractures, duplex assessment in the follow-up period pinpointed only Neeta one severe Karani

case of recurrent stenosis that required intervention—further designating a 4.2% reintervention rate for their patient cohort. Karani expanded on the study’s conclusions, noting a total delayed fracture rate of 5.6%.

“While we have identified that carotid stent fractures do occur, the follow-up duplex examinations revealed minimal restenosis, with only one reintervention required. Our study indicates that the CAS fracture rate is approximately 10% and the clinical sequelae appear to be negligible,” Karani posited in her presentation at VAM 2023.

Furthermore, Karani and her team posit that their research intends to emphasise the need for further prospective studies with long-term outcomes that acknowledge the increased occurrence of carotid stenting in the treatment of patients today. In doing so, they seek to highlight that future research in this arena should draw particular attention to stent fractures and reintervention rates as matters of pointed importance.

Issue 51 | September 2023

TCAR 25

Safety benefits mean TCAR may be preferable approach in radiationinduced carotid stenosis A study presented recently at the Vascular Annual Meeting (VAM; 14–17 June, National Harbor, USA) has found that the long-term outcomes of transcarotid artery revascularisation (TCAR) are “not significantly affected” by prior head and neck radiation.

OWING TO SUBSTANTIALLY increased risks of mortality with transfemoral carotid artery stenting (CAS), as well as both stroke and mortality with carotid endarterectomy (CEA), researchers believe TCAR “may be the preferred treatment modality for patients with radiationinduced carotid stenosis”.

Bala Ramanan (University of Texas [UT] Southwestern Medical Center, Dallas, USA) delivered these findings from a study that sought to evaluate the effect of radiation on long-term outcomes after various carotid revascularisation techniques—TCAR, CAS and CEA— based on patients (≥65 years old) in the Society for Vascular Surgery’s

(SVS) multicentre Vascular Quality Initiative (VQI) linked to the Vascular Implant Surveillance and Interventional Outcomes Network (VISION) database.

Primary endpoints in the study were three-year death, stroke and reintervention rates. From a total of 1,244 patients with prior radiation and 54,925 without prior radiation, the researchers performed propensity matching on 1,223 patients (CEA=655; TCAR=292; CAS=287).

Ramanan et al found no significant differences in 30-day outcomes for death, stroke, or major adverse cardiovascular events, across all three procedures—although the priorradiation group had higher rates of cranial injury (3.7% vs 1.8%) and

More research needed but lithotripsy plus TCAR ‘an answer’ in certain carotid disease patients Earlier this year, researchers debuted single-centre experiences indicating that intravascular lithotripsy (IVL) may be able to expand transcarotid artery revascularisation (TCAR) into patients with traditionally prohibitive calcific disease. With a multicentre case series now further suggesting IVL’s utility, but also revealing potential safety concerns versus conventional TCAR or carotid endarterectomy (CEA), principal investigator Misty Humphries (University of California Davis, Sacramento, USA) gives NeuroNews the lowdown on these findings.

Could you very briefly outline the motives behind this research?

TCAR has been shown to be highly effective and safe, but there are still anatomic exclusion criteria— specifically, severe calcification. There are also many patients who are just not a candidate for traditional CEA for various reasons. The use of IVL has the potential to open TCAR technology up to more patients.

How do these more recent, multicentric findings build on your publication from earlier in the year?

With our initial presentation, we discussed how

90-day readmission (23.5% vs 18.3%) after CEA. Prior radiation significantly increased mortality risks after CEA and CAS, and the three-year risk of stroke associated with CEA was also significantly higher in radiated patients compared to nonradiated patients.

Prior radiation did not, however, significantly affect death or stroke in patients undergoing TCAR. The researchers also found that prior radiation did not impact the rates of

short-and long-term reintervention after any of the three procedures.

“We plan to look at our institutional data to get more granular results regarding the long-term outcomes of patients undergoing revascularisation for radiation-induced carotid stenosis,” Ramanan said, in conversation with NeuroNews. “However, since this is a relatively uncommon issue, we may need to pool data from multiple institutions to validate the results of the study.”

655

292

287

Endarterectomy patients

TCAR patients

Stenting patients

No significant differences in 30-day death, stroke or major adverse cardiovascular events

we do the procedure. That presentation How significant is it that a was our own institutional data. When we technical success rate of analysed our own experience, we had no 100% was achieved? complications, and the technology appeared Technical success of 100% means we can safe. But, in this larger, multicentre cohort, do the procedure. The real question is how we see a risk of transient ischaemic attack to do the procedure effectively and safely.

(TIA) post-procedure that was not present.

I do not think we know that yet.

Misty Humphries Multicentre studies like this demonstrate what can happen when technology is How concerning is the expanded to more practitioners of various skill levels. increased stroke/TIA rate versus

Why was freedom from stroke/TIA selected as the study’s primary safety endpoint?

Stroke and TIA are the two outcomes patients care about most. We saw this with the CREST trial data that were analysed. All of my research is patientcentred and, for me to use technology, I want to know that it is safe—not just for what providers care about, but for what patients care about as well.

What were the key safety and efficacy findings of the study?

IVL combined with TCAR seems to be highly effective, allowing full stent expansion. The safety of the combined treatment needs to be studied in a prospective trial. There are not a significant amount of known data on the risk of stroke and TIA in patients with severe calcium after carotid artery stenting (CAS) because these patients are typically excluded from trials.

The best data we have were presented at the Society for Clinical Vascular Surgery (SCVS) annual symposium (25–29 March, Miami, USA) earlier this year. In a review of Vascular Quality Initiative (VQI) patients who underwent TCAR and CAS, patients with severe calcium had a higher risk of stroke/TIA than those who did not. This tells us that it is the disease process, and we need to learn more about this.

conventional TCAR or CEA—would the benefits of IVL plus TCAR still outweigh these risks?

Studies that break out results based on the degree of calcium are lacking because these patients are excluded from TCAR trials. The VQI data presented at SCVS 2023 show that patients with higher degrees of calcium have increased stroke rates with TCAR and CAS. I truly believe that heavily calcified

Multicentre studies like this demonstrate what can happen when technology is expanded to more practitioners of various skill levels.” patients are better served with CEA, but there are some patients that cannot undergo CEA and, in those patients, IVL with TCAR is an answer. We are just exploring how to do this procedure in the best way for patients. We also need to do a prospective trial where we control for all factors, such as Plavix (clopidogrel) resistance, and procedural or postprocedural hypotension.

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Issue 51 | September 2023

Carotid Endarterectomy 27

CAROTID

Efforts to move towards routine patch closure or eversion endarterectomy among all carotid surgeons “warranted” A nationwide cohort study of more than 9,000 patients shows that the “controversial” practice of arteriotomy closure for carotid endarterectomy (CEA) is associated with an increased risk of ipsilateral stroke and “should be avoided”. Instead, authors Magnus Jonsson (Karolinska University Hospital, Stockholm, Sweden) et al argue, endarterectomy should be performed with either routine patch closure or using the eversion technique.

THE STUDY—PUBLISHED IN the European Journal of Vascular and Endovascular Surgery (EJVES)—also shows that the long-term durability of different patch materials is equivalent, and bovine pericardium and eversion have a lower risk of late infections.

Jonsson et al initially note that current European guidelines recommend both eversion CEA and conventional CEA with routine patch closure, rather than routine primary closure. However, they add, “many surgeons prefer selective patching and there remains much controversy about the relative benefits of the different surgical techniques and patches for CEA”. Therefore, the present study aimed to evaluate the short- and longterm outcomes after CEA based on surgical technique and patch material.

The investigators detail that there are several available patch types on the market at present. “Dacron, vein and polytetrafluoroethylene (PTFE) have been used for a long time,” they state, adding that bovine pericardium has been used in more recent years.

“Bovine pericardium may have the advantage of greater resistance to late infections and smaller haematomas than other patch types, but there are few long-term follow-up studies comparing pericardium with other patch materials,” they comment.

The researchers conducted a registry-based study on all primary CEAs performed for symptomatic carotid artery stenosis in Sweden from July 2008 to December 2019, which numbered 9,205 in total. This was cross-linked with data from the Swedish stroke registry, Riksstroke, and chart review for evaluation of any events occurring during followup, they detail. The primary endpoint was ipsilateral stroke <30 days and secondary endpoints included reoperations due to neck haematoma and <30-day ipsilateral stroke, >30-day ipsilateral stroke, all stroke >30 days and all-cause mortality.

Reporting the results of their study in EJVES, Jonsson and colleagues reveal that 2,495 patients underwent eversion CEA and 6,710 conventional CEA for

Revascularisation capable of improving mood in depressed patients with carotid atherosclerosis A PROSPECTIVE STUDY HAS demonstrated carotid intervention can improve mood in depressed patients with advanced carotid disease, in addition to enabling cognitive improvements irrespective of baseline depression.These findings were presented at the Vascular Annual Meeting (VAM; 14–17 June, National Harbor, USA) by Bahaa Succar (University of Arizona, Tucson, USA).

Speaking to NeuroNews, Succar said: “This study provides valuable information regarding the use of carotid interventions, particularly for patients with asymptomatic carotid artery stenosis. Since stroke and mortality rates are relatively low for carotid interventions and best medical therapy, mood and cognitive assessments could offer an additional perspective to help clinicians tailor the treatment

symptomatic carotid stenosis. They the Swedevasc registry—with its found that the most commonly used almost 100% coverage for all carotid patch material was Dacron (n=3,921), procedures performed in Sweden—and followed by PTFE (n=588) and bovine the possibility for cross linkage of data pericardium (n=413). based on unique personal identifiers to Furthermore, Jonsson et al relay that assess long-term survival and stroke a total of 1,788 patients underwent outcome “result in high generalisability conventional CEA with primary and low loss to follow-up in this closure, and 273 patients (3%) study”. had a stroke within 30 days On the other hand, given of intervention. the study assessed carotid They also share the procedures performed over a finding that that primary 10-year period, Jonsson and closure was associated with colleagues acknowledge that an increased risk of ipsilateral “changes in practice over time Magnus stroke and stroke or death may be a confounder affecting Jonsson within 30 days: odds ratio results for factors not captured 1.7 (95% confidence interval [CI] by the registry”. The authors elaborate 1.2–2.4, p=0.002); and 1.5 (95% CI that this may include changes in 1.2–2), respectively. During follow-up, medical management of patients prior which was a median of 4.2 years, the to surgery—including preoperative investigators report that 592 patients thrombolysis or antiplatelet therapy— had any form of stroke and 1,492 died. as well as changes in periprocedural “There was no significant difference in routines, such as use of different long-term risk of ipsilateral stroke, all techniques for cerebral monitoring stroke or death depending on surgical during surgery. technique or patch material,” the Considering the wider importance authors add. of their research, the authors say their “There was an increased risk of study “underlines the variation in ipsilateral stroke <30 days in patients surgical techniques used for CEA in operated on with primary closure Sweden,” underscoring the fact that up compared with eversion CEA and patch to 20% are operated on with primary angioplasty,” Jonsson and colleagues closure without patch. Jonsson et al summarise, further noting that there reiterate in their conclusion that, due to was no difference between primary its association with an increased closure, different patch types or risk of postprocedural stroke, the eversion after the perioperative phase. technique “should not be used”. They The authors also stress that the also note that their report underlines results of their study “should be the fact that selective primary closure interpreted within the context of the “remains common practice” by some strengths and limitations associated surgeons, and stress that “further with retrospective analysis of educational efforts to move towards prospectively collected registry routine patch closure or eversion data”. Focusing first on the latter, endarterectomy among all carotid they note that “the high validity” of surgeons are warranted”.

approach when counselling a patient.”

Outlining the backdrop to their work, the researchers note that the impact carotid interventions may have on neurocognitive function in patients with advanced carotid atherosclerosis is yet to be fully elucidated. In addition, little is currently known about the impact carotid interventions can have on mood.

As such, they set out to investigate this phenomenon in a “well-defined cohort of patients”, prospectively recruiting a total of 158 people undergoing carotid revascularisation. Screening for depression was performed preoperatively, and at one, six and 12 months post-intervention using the long form of the geriatric depression scale (GDS) questionnaire.

The cohort was divided into ‘depressed’ and ‘non-depressed’ based on preoperative GDS scores >9 and ≤9, respectively. Patients also received other neuropsychometric tests to assess memory and executive function concurrently at the designated timepoints—with scores being adjusted against age and education to generate scaled comparisons.

During VAM 2023, Succar reported that, at baseline, depression (GDS >9) was observed in 49 subjects (31%), whereas 109 (69%) were not depressed (GDS score ≤9), and the average preoperative GDS scores were 15 and 4 in the

depressed and non-depressed groups, respectively.

A “significant improvement” in average GDS scores was observed within the depressed group at one month (13), six months (13.2) and one year (11.6) post-intervention compared to preoperatively, whereas the non-depressed group had similar postoperative GDS scores at all timepoints compared to baseline.

“Improvements in mood are only among those who had baseline depression,” the researchers conclude. “Further studies with larger sample sizes are warranted to investigate the association between depression, carotid disease, and carotid intervention.”

Further studies with larger sample sizes are warranted to investigate the association between depression, carotid disease, and carotid intervention.”

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Issue 51 | September 2023

Subarachnoid Haemorrhage 29

US and Chinese experts introduce new aneurysmal subarachnoid haemorrhage guidelines Expert groups from the USA and China have separately introduced new guidelines relating to the management of aneurysmal subarachnoid haemorrhage (aSAH).

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he updated guidelines—spearheaded by the American Heart Association/American Stroke Association (AHA/ASA)—are intended to provide “patient-centric recommendations for clinicians to prevent, diagnose and manage” aSAH patients, while the latest Chinese recommendations attempt to tackle the “unclarity and inconsistency” of current standards specifically in aSAHrelated hydrocephalus.

“Aneurysmal subarachnoid haemorrhage is a significant global public health threat, and a severely morbid and often deadly condition,” write Brian Hoh (University of Florida, Gainesville, USA) and colleagues in the journal Stroke—where the AHA/ ASA guideline update is now published. “The 2023 aneurysmal subarachnoid haemorrhage guideline provides recommendations based on current evidence for the treatment of these patients.”

What do the new AHA/ASA guidelines say?

Replacing the 2012 version of a similar guideline document on aSAH management, Hoh et al’s publication sets out to present an “evidence-based approach”, with a key goal being to “improve quality of care, and align with patients’ and their families’ and caregivers’ interests”.

“Many of the recommendations from the previous aneurysmal subarachnoid haemorrhage guidelines have been updated with new evidence, and new recommendations have been created when supported by published data,” they add. “It also identifies knowledge gaps and areas of care in need of further research.”

The authors report that a comprehensive search for literature published since the 2012 guideline, “derived from research principally involving human subjects”, and published in English, was conducted last year—and that the guideline writing group reviewed documents on related subject matter previously published by the AHA as well.

A key emphasis of the 2023 guidelines is that improving timely and equitable access to healthcare system resources like comprehensive stroke centres is “important” to improve overall patient outcomes, and timely transfer to centres with expertise in aSAH is “recommended”. Prompt evaluation, identification of aneurysmal source, and treatment of ruptured aneurysms are recommended— preferably within 24 hours—owing to the fact that acute rebleeding after an initial aSAH is associated with increased mortality and poor clinical outcomes.

Several other prevailing messages are established within the new AHA/ASA guidelines. These include the need for risk assessments and relevant expertise when deciding on how best to intervene; optimal approaches to new-onset seizures, delayed cerebral ischaemia and other medical complications; and cerebrovascular imaging usage and subsequent monitoring in planning for aneurysm remnants, recurrence, or regrowth, post-treatment.

The important role played by multidisciplinary care is also a recurring theme throughout, with

Hoh et al noting that aSAH management with dedicated neurocritical care units, experience with higher case volumes, physician expertise in aneurysm treatment, expert nursing care, and multidisciplinary teams, is associated with lower mortality and an increased likelihood of good functional outcomes.

Similarly, a multidisciplinary approach to identify discharge needs and design rehabilitation treatment is recommended in the guidelines. Validated screening tools to identify deficits, as well as interventions for mood disorders and counselling, “may be beneficial” too, the authors add.

Chinese guidelines home in on hydrocephalus

The authors of a Chinese expert consensus on aSAH-related hydrocephalus—now published in the Chinese Neurosurgical Journal—describe the pathophysiology of this clinical syndrome as “complex”, also noting that “there is no standard diagnostic criteria and treatment protocol in China, [or] abroad, currently”; nor is there consensus among clinicians on whether active treatment is needed or what treatment is preferred.

“Therefore, diagnosis and treatment of aSAHrelated hydrocephalus have been puzzled by the unclarity and inconsistency of standards,” they continue. To address these problems, Shuo Wang (Capital Medical University, Beijing, China) led an expert group to compose a consensus with reference to much of the updated literature, both in China and elsewhere globally, in an effort to meet the “urgent need” for clarity and consistent standards.

“Hydrocephalus is a common complication following aSAH and currently, the diagnosis and

treatment of aSAH-related hydrocephalus is clouded by a lack of clarity and inconsistency of standards,” explained Wang. “We wanted to make definite progress toward removing the ambiguity tied to its treatment.”

In terms of occurrence, the experts identified that aSAH-related hydrocephalus is determined by the location of the aneurysm, intraventricular haemorrhage, and volume of the SAH. Disturbances in cerebrospinal fluid (CSF) circulation drive the pathogenesis of aSAH-related hydrocephalus, enlarge the ventricular system, and damage the brain’s white matter. In terms of factors contributing to the risk of this syndrome, the experts concluded that age, volume of SAH, and the location and size of aneurysms, are related to the occurrence.

The consensus states that the standard-of-care approach to diagnosis should include reviewing a patient’s history of aSAH-related hydrocephalus, identifying its clinical manifestations, and a head computed tomography (CT) scan to detect abnormal enlargement of the ventricles. It also posits that the main objective of aSAH-related hydrocephalus treatment should be to release excessive intracranial pressure or address pathological changes to brain tissue to prevent further damage and loss of neurological function. This can include medications inhibiting CSF secretion or surgical interventions, such as CSF drainage, shunt surgery, and intracranial diversion.

Furthermore, the consensus guidelines recommend external ventricular drainage and ensuring the safe removal of the CSF drainage tube in the case of acute hydrocephalus. A ventriculoperitoneal shunt is recommended by Wang et al for cases of chronic hydrocephalus. The effectiveness of a shunt procedure can be confirmed with a positive lumbar puncture preceding surgery. The consensus concludes by suggesting measures to minimise postoperative complications—recommending strict aseptic surgical procedures; anti-siphon and pressure-adjustable shunt catheters; monitoring of clinical manifestations; and use of imaging and laboratory examinations for management.

“This expert consensus applies to adults, but it is a good reference point for clinical diagnosis and treatment,” Wang added. “Further research will certainly refine the process of aSAH-related hydrocephalus diagnosis and treatment.”

Many of the recommendations from the previous aneurysmal subarachnoid haemorrhage guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.”

Brian Hoh et al

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Issue 51 | September 2023

31

Cochrane Library urged to retract and revise recent SCS review over “striking errors” Pain physicians have urged the Cochrane Library to retract and revise a recent review of spinal cord stimulation (SCS) in the treatment of low back pain, citing “striking errors” across the publication’s methodology, executions and conclusions.

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riting in the Cochrane Database of Systematic Reviews earlier this year, lead researcher Adrian Traeger (Sydney Musculoskeletal Health, Sydney, Australia) and colleagues concluded a Cochrane review of the existing literature by stating that SCS therapy does not provide long-term relief or sustained benefits, and may cause harm.

However, the veracity of these findings and how they were reached have since been challenged via a commentary piece from Shravani Durbhakula (Johns Hopkins School of Medicine, Baltimore, USA) et al, published in the journal Pain Medicine.

“Generalisations about CLBP [chronic low back pain] care interventions—drawn from data limited by narrow search criteria—are problematic and misleading,” Durbhakula and colleagues assert.

“The reader is left questioning whether Traeger et al intended to provide a balanced assessment of the published literature on SCS for CLBP from conception, given their 2020 letter to the editor, and stated conflicts of interest that include royalties from two books: Surgery, the ultimate placebo and Hippocrasy: How doctors are betraying their oath.

“Furthermore, while a pain physician was acknowledged at the end of the publication, the extent of this physician’s involvement was too limited to warrant authorship. Inclusion of a physician author with content expertise in pain medicine and neuromodulation could have offered insight into the limitations addressed here, provided a balanced interpretation of the published literature, and aided with recommendations of appropriate scope.”

Durbhakula et al state that the review contains “significant methodological issues”, adding that its authors “extrapolate questionable findings to generate overreaching conclusions” that have the potential to negatively impact the care of CLBP patients.

One point they are particularly critical of is Traeger et al’s identification of parallel-arm studies that evaluate SCS plus conventional medical management (CMM) versus CMM alone—describing the authors’ interpretation and inclusion/ exclusion of such studies as “misguided”. In addition, they claim the authors have effectively “grouped apples and oranges” with the three parallel, medium follow-up trials originally included in their subanalysis.

“We re-emphasise that the populations in the Kumar et al, Rigoard et al and Kapural et al studies are too distinct for inclusion in a meta-analysis of low back pain, and that Kumar et al should have been excluded as it enrolled patients with predominantly leg pain over low back pain,” Durbhakula and colleagues elaborate as part of a separate, later letter to the editor, which is also published in Pain Medicine.

In addition to pointing out that the SCS modalities used differed across the included parallel-arm studies, the authors go on to criticise the removal of one of these three studies prior to secondary analyses on “questionable grounds”.

“The elimination of an outlier when there are only two studies is nonsensical and raises serious concerns about Traeger et al selectively ‘cherry-picking’ studies to fit an agenda […],” they continue.

Durbhakula and colleagues argue that, as such, the authors’ conclusions on SCS’ probable lack of efficacy are derived from a single study—a single study from 2022 that carries

“many flaws” and a “lack of validity” described by several pain physicians and scientists working in neuromodulation across the globe.

“We respectfully urge the Cochrane Library to retract and revise the Traeger et al study or, at minimum, publish a corrigendum addressing our concerns,” Durbhakula et al conclude.

They go on to state that an appropriate revision should include re-evaluation of the search methodology to ensure a comprehensive selection of studies; appropriate interpretation and synthesis of studies based on their inclusion/exclusion criteria, allowing for valid findings; diversification of authorship to include contributions from individuals with clinical and content expertise in neuromodulation for CLBP; and conclusions of appropriate scope.

“By doing this, the Cochrane Library can contribute to a more accurate and balanced understanding of SCS for CLBP, ultimately benefitting patients, clinicians, researchers, payers, and policymakers,” the authors add.

Generalisations about chronic low back pain care interventions— drawn from data limited by narrow search criteria—are problematic and misleading.”

Shravani Durbhakula

Non-invasive VNS approach could enhance poststroke recovery outcomes A novel approach to vagus nerve stimulation (VNS) may enable successful post-stroke recovery without the need for “invasive and often-uninsured” traditional VNS therapies.

A PAPER PUBLISHED IN THE journal Neurorehabilitation and Neural Repair by Medical University of South Carolina (MUSC) researchers outlines a method by which sensors are placed on the upper arm and in the ear of the patient. A connected computer then sends timed electrical impulses to the vagus nerve during motor rehabilitation.

According to Bashar Badran (MUSC, Charleston, USA) and colleagues, this may lead to accelerated treatment outcomes and improved motor function after stroke versus established VNS procedures, whereby a device is implanted into the neck to provide direct stimulation. Known as motor-activated auricular VNS (MAAVNS), the new approach could allow patients to gain the same amount of motor function improvement in four weeks that those with an implanted device can reach in six weeks—without requiring surgery.

“Motor rehabilitation is time consuming and expensive, and oftentimes does not produce the results that patients want,” said Badran.

“Technology like the MAAVNS system can boost the effects of conventional motor rehabilitation, and help patients get the most out of their therapy in a simple and relatively inexpensive manner. It is very exciting.”

The MAAVNS system can be incorporated into occupational therapy settings with little impact on the current standard of care, according to the researchers. It also detects when the patient is moving, delivering hundreds of repetitions of electrical stimulation per hour and allowing them to focus on specific movements they want to improve.

Badran noted that the stimulation being administered alongside movement is “critical”, with work being done out of MUSC showing outcomes are “much better” when timed in conjunction with patient movement in this ‘closed-loop’ setup.

While the sample size for their pilot study was small, Badran and his team will be conducting a larger clinical trial next to further evaluate the effects of non-invasive VNS therapy.

September 2023 | Issue 51

32

Education and collaboration key to continued advancement of painful diabetic neuropathy care

allow treatment to be tailored to each patient’s unique pain profile. Today’s SCS devices come in rechargeable and recharge-free formats, making it easier for patients to find a system that works best for their needs and lifestyles. Some systems allow magnetic resonance imaging (MRI) access under certain conditions, which obviates the need to remove the device if patients need to undergo an MRI after they have started SCS therapy. Mobile applications are also available with some SCS devices, which can help keep patients informed and connected to their care teams while they undergo SCS therapy.

Todd Bromberg

An established evidence base

Point of View The neuromodulation space has proliferated significantly over the past few years, and one area in which this is most notable is with the expansion of spinal cord stimulation (SCS)—not only in terms of technological advancements, but also regarding the gamut of conditions it is used in. Here, Todd Bromberg (Chalfont, USA) takes a closer look at how SCS is impacting the treatment of a currently underserved group of diabetes patients.

I

n patients with diabetes, high serum glucose levels can lead to damage of the peripheral nerves—a condition known as diabetic peripheral neuropathy (DPN). DPN can be painful and debilitating, and patients with painful DPN can experience numbness, and burning or stabbing sensations in areas surrounding affected nerves, most often in the legs and feet. This can negatively impact quality of life, making it difficult to ambulate and sleep, and numbness can lead to additional health complications. Loss of sensation may also allow cuts or sores in the feet to go untreated, potentially leading to infections that may become lifethreatening and/or require amputation.

The first step in managing/preventing painful DPN is helping patients maintain and achieve strict glucose control.

Beyond this, traditionally there have been four approaches to managing symptoms: medical management with pharmaceuticals; non-pharmacological options, such as sympathetic nerve blocks; mental health interventions, including psychotherapy to help address the mental health impacts, cognitivebehavioural therapy, and biofeedback; and alternative therapies, such as acupuncture and hypnosis.

Neuromodulation comes to the fore

More recently, SCS has been approved for the treatment of painful DPN. SCS is a form of neuromodulation that applies electrical impulses to targeted areas of the spine in order to modulate, or change, how those pain signals communicate pain to the brain. SCS has a long track record for treating chronic low-back and leg pain, and extending this therapy to the treatment of DPN follows decades of safe and effective use for other medical conditions. In SCS, stimulation is delivered to the

spinal cord using a neurostimulator, which is a small device similar to a pacemaker that is implanted under the skin. The electrical impulses travel from the device to the spine over thin, insulated wires called leads. The mild electrical impulses delivered by the neurostimulator interrupt the pain signals between the spinal cord and the brain, helping to alleviate pain.

Prior to device implantation, patients undergo a temporary trial for 3–10 days with an external neurostimulator to determine their response to the therapy; patients who experience benefit (≥50% pain reduction) have the option of proceeding to implantation.

Once the device is implanted, the patient’s physician will help adjust the settings to achieve optimal pain relief. The development of novel waveforms in recent years—such as differential targeted multiplexed therapy (Medtronic)1, burst therapy (Abbott)2, and high-frequency therapy (Nevro)3— enables customised treatment that can provide highly personalised pain management.

Implantable SCS devices have been used for the treatment of chronic pain since 1981. Over the past 40-plus years, continued innovation in SCS technology has enabled the use of smaller devices, and has produced novel algorithms that

SCS has been used successfully to treat chronic pain—primarily in the lower back and leg—for four decades. More recently, however, SCS has been added to the armamentarium of treatments for DPN-related pain. SCS is thought to work for painful DPN in the same way as chronic low-back and upper-leg pain; by modulating pain impulses and blocking pain signals from reaching the brain. The US Food and Drug

While SCS is a well-known therapy for chronic pain among pain specialists and neurologists, it is less familiar to the podiatrists, endocrinologists, and primary care physicians.”

Administration (FDA) first approved the use of SCS for the treatment of painful DPN in July 2021 and, today, three SCS manufacturers—Medtronic, Abbott and Nevro—have FDA clearance to market their therapies for this condition.

Data from multiple randomised controlled trials (RCTs) show that patients with painful DPN treated with SCS have a 53% reduction in pain at six months compared to 0% in control groups.4-6 Eighty-six percent of patients treated with SCS experienced treatment

Painful diabetic peripheral neuropathy treated with SCS

53%

86%

Pain reduction in patients at six months

Treatment success at one year

>50% Meaningful pain relief through five years

success after SCS therapy for one year, and more than 50% experienced meaningful pain relief through five years.7 Based on these clinical data, patients with painful DPN are 17 times more likely to experience pain relief if treated with SCS versus conventional treatments alone.4-6 More than 50% of patients continue to receive clinically meaningful pain relief (>30% reductions in pain) 8–10 years post-implant.9 These clinical findings support the use of SCS in the treatment of painful DPN for patients who cannot effectively manage their pain with conventional medical therapies. Assuring that patients who may benefit from SCS have access to this life-changing therapeutic approach for painful DPN requires collaboration and coordination among multiple care providers. While SCS is a well-known therapy for chronic pain among pain specialists and neurologists, it is less familiar to the podiatrists, endocrinologists, and primary care physicians. It is important for all physicians to become educated about SCS for relieving pain related to DPN. Physicians who implant SCS can facilitate awareness and understanding of this therapy for the treatment of painful DPN by serving as a resource for podiatrists, endocrinologists and primary care physicians in their community.

SCS is an exciting option for helping to improve outcomes for patients with painful DPN. Working together, the medical community can help facilitate adoption of SCS and give more patients the opportunity to achieve effective pain relief. And, with the incidence of diabetes increasing8, it has never been more important for all physicians to remain educated about the treatment options for patients living with DPN. References: 1. Fishman M, Cordner H, Justiz R, et al. 12-month results from multicenter, open-label, randomized controlled clinical trial comparing differential target multiplexed spinal cord stimulation and traditional spinal cord stimulation in subjects with chronic intractable back pain and leg pain. Pain Pract. 2021; 21(8): 912–23.

2. Kirketeig T, Schultheis C, Zuidema X, et al. Burst spinal cord stimulation: A clinical review. Pain Med. 2019; Suppl 1: S31–S40.

3. Petersen E A, Stauss T G, Scowcroft J A, et al. Effect of high-frequency (10kHz) spinal cord stimulation in patients with painful diabetic neuropathy: A randomized clinical trial. JAMA Neurol. 2021; 78(6): 687–98.

4. Medtronic. Medtronic Pain Therapy Clinical Summary M221494A016 Rev B. United States; 2022.

5. De Vos C C, Meier K, Zaalberg P B, et al. Spinal cord stimulation in patients with painful diabetic neuropathy: A multicenter randomized clinical trial.

Pain. 2014; 155(11): 2426–31.

6. Slangen R, Schaper N C, Faber C G, et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: A prospective two-center randomized controlled trial. Diabetes Care. 2014; 37(11): 3016–24.

7. Van Beek M, Geurts J W, Slangen R, et al. Severity of neuropathy is associated with long-term spinal cord stimulation outcomes in painful diabetic peripheral neuropathy: Five-year follow-up of a prospective twocenter clinical trial. Diabetes Care. 2018; 41(1): 32–8.

8. World Health Organization. Diabetes: Key facts.

Available at https://www.who.int/news-room/factsheets/detail/diabetes.

9. Zuidema X, et al. Long-term evaluation of spinal cord stimulation in patients with painful diabetic polyneuropathy: an eight-to-ten-year prospective cohort study. Neuromodulation. 30 December 2022. https://doi.org/10.1016/j.neurom.2022.12.003.

Todd Bromberg is a pain management specialist and neurologist at Delaware Valley Pain & Spine Institute in Chalfont, USA. Disclosures: The author is a consultant for Medtronic, and Medtronic provided technical support for and reviewed the contents of this article prior to publication.

Issue 51 | September 2023

33

Highly targeted brain stimulation achieves “very exciting” outcomes in acute ischaemic stroke Highly targeted electrical stimulation to the brain has shown promise as a treatment option for acute ischaemic stroke, according to a pilot study led by University of California Los Angeles (UCLA) Health researchers in Los Angeles, USA. THE STUDY IS THE FIRST IN HUMANS TO TEST the feasibility of using high-definition cathodal transcranial direct current stimulation (HD C-tDCS) to treat acute ischaemic stroke, as per a UCLA Health press release. In the study, now published in JAMA Network Open, researchers tested HD C-tDCS as a novel therapy for the most common type of stroke. They initially noted that electrical currents appeared to have an effect on the brain’s blood flow, and theorised it may be possible to use HD C-tDCS to enhance blood flow to parts of the brain impacted by stroke and protect the threatened brain tissue from irreversible injury.

The pilot study involved 10 acute stroke patients who presented to the emergency department, or were admitted at neuro-intensive care and stroke units; were ineligible for currently available treatments like intravenous thrombolysis or mechanical thrombectomy; and were within 24 hours of stroke onset. Seven patients were randomised to receive active HD C-tDCS treatment, and three received ‘sham’ stimulation.

Using scans that acute stroke patients receive upon arrival, the researchers located the stroke area with low blood flow to which the HD C-tDCS treatment was subsequently delivered.

“This treatment was aimed at being as targeted and as individualised as possible—only to the area of the brain that has low blood flow or is suffering from stroke,” said the lead researcher on this project, Mersedeh Bahr-Hosseini (UCLA Health, Los Angeles, USA). “With this high-definition form of C-tDCS, we were able to refine this electrical field to focus it just on this area.”

The first set of patients, which included three patients in the treatment arm and one in the sham group, received 20 minutes of a single milliamp of stimulation. In the remaining patients, the dose was escalated to two milliamps for 20 minutes.

Researchers were able to efficiently provide the treatment in emergency settings, and found that it was well tolerated by the patients. Bahr-Hosseini said the most exciting finding was that, in patients receiving HD C-tDCS, a median of 66% of the penumbra—the threatened brain tissue surrounding the core of the stroke—was rescued in the first 24 hours after stroke, compared to 0% in the sham group. According to brain scans performed soon after treatment, patients who received HD C-tDCS showed signs of improved blood flow that was greater in patients receiving two milliamps compared to one milliamp, while blood flow decreased in the sham group.

“That was also very exciting, because it showed a possibly true biological effect of the treatment,” Bahr-Hosseini added.

Researchers are now planning a new multicentre study with Johns Hopkins (Baltimore, USA), Duke University (Durham, USA), and the University of Pennsylvania (Philadelphia, USA), to gather more data on the treatment’s safety and efficacy. The next study will also include patients who are eligible for clot-dissolving intravenous thrombolytics.

This treatment was aimed at being as targeted and as individualised as possible—only to the area of the brain that has low blood flow or is suffering from stroke.”

Novel ‘infraslow pink noise’ stimulation found to be safe and feasible in chronic tinnitus A technique called high-definition transcranial infraslow pink noise stimulation (HD-tIPNS) has been deemed both safe and feasible for treating tinnitus in a placebo-controlled pilot study.

HOWEVER, WRITING IN THE journal Neuromodulation: Technology at the Neural Interface, Dirk De Ridder (University of Otago, Dunedin, New Zealand) et al report that electroencephalography (EEG) changes observed in the study were “unsupported by clinical benefit”. As such, they state that “further research is essential to evaluate the potential of this multifocal network stimulation approach”.

“Tinnitus has been linked to activity and connectivity changes in the auditory cortex (AC), parahippocampus (PHC), and posterior cingulate cortex (PCC),” the authors write, introducing the premise for their study. “Although previous studies have targeted these areas individually, no study has yet modulated them simultaneously.

Furthermore, novel stimulation designs may be superior to traditional alternating or direct current stimulation.”

On this basis, De Ridder and

colleagues investigated the feasibility and safety of HD-tIPNS for treating chronic tinnitus targeting the AC, PHC, and PCC via a pilot study with a double-blind, randomised, placebocontrolled, parallel-arm design. A total of 20 chronic tinnitus patients received 12 sessions—three per week for four weeks—of either HD-tIPNS or ‘acti-sham’ stimulation, with clinical outcomes being collected at baseline, three days and 10 days after treatment.

Primary outcomes included feasibility, safety, and resting-state EEG measures, while secondary outcomes included tinnitus and quality-of-life metrics assessed using questionnaires. The study’s dropout rate of 13% and the fact the treatment approach was “acceptable” to participants, supports the feasibility of the protocol, they add.

De Ridder et al relay that there were no long-term adverse events

observed, with only mild side-effects like headaches and dizziness being reported, indicating the safety of this form of stimulation. In addition, tinnitus measures were similar between HD-tIPNS and acti-sham stimulation.

Resting-state EEG analyses also revealed decreased beta-1 activity in the PCC 10 days after acti-sham treatment, and the HD-tIPNS group demonstrated decreased beta-1 activity in the inferior parietal lobule three days after treatment. Finally, De Ridder and colleagues report finding an increase in functional connectivity in the beta-1 frequency between the left and right PHC in the HD-tIPNS group— compared to the acti-sham group— three days after treatment.

Dirk De Ridder

Flexible nanoelectrodes can “pave the way” for higherresolution devices ENGINEERS AT RICE University (Houston, USA) have created nanoelectrodes that are minimally invasive and exceptionally flexible—and, as such, have the potential to function as an implanted platform, enabling long-term, highresolution neurostimulation therapy.

In a study now published in Cell Reports, Rice Neuroengineering Initiative researchers attempted to overcome challenges relating to rigidity and bulkiness that hamper many traditional devices intended for brain stimulation. Their work revealed that minute, implantable devices were able to establish stable and enduring tissueelectrode interfaces in rodents, with minimal scarring or deterioration.

The researchers claim that, due to their “exceptional biocompatibility and precise spatiotemporal stimulus control”, these devices have the potential to facilitate the advancement of novel brain stimulation therapies, ultimately benefitting patients with impaired sensory or motor functions.

They further highlight the significance of their electrode’s ultra-flexible design in achieving enhanced tissue integration.

“When a larger current is employed, neuron activation becomes more widespread and diffuse,” said corresponding author Lan Luan (Rice University, Houston, USA). “However, we successfully reduced the current and demonstrated a significantly more focused activation. This achievement can pave the way for the development of higher-resolution stimulation devices.”

The researchers successfully achieved a significant reduction in the required current for neuronal activation—meaning the electrodes were able to deliver more subtle electrical pulses. Such precise and low-intensity stimulation holds “great potential” and marks a “substantial advancement” compared to traditional implantable electrodes utilised for treating conditions like Parkinson’s disease, epilepsy, and obsessive-compulsive disorder, according to a Rice University statement, as conventional electrodes often lead to “adverse tissue reactions and unintended alterations in neural activity”.

This is because, as corresponding author Chong Xie (Rice University, Houston, USA) explained, traditional electrodes typically activate thousands or sometimes even millions of neurons at the same time.

“While this simultaneous stimulation may have the desired therapeutic effect in certain cases, it lacks the necessary precision and control, especially when it comes to encoding sensory information,” he said.

September 2023 | Issue 51

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‘Intelligent suit’ supported by AI and electrical stimulation could enhance spinal cord injury recovery Experts in Germany are working on an ‘intelligent suit’ with which they hope to significantly improve rehabilitation after a serious spinal cord injury. This artificial intelligence (AI)-supported solution will be developed over the next three years at Friedrich-Alexander-Universität ErlangenNürnberg (FAU; Erlangen, Germany), in collaboration with Heidelberg University and Heidelberg University Hospital (both Heidelberg, Germany).

“ALTHOUGH GREAT PROGRESS HAS BEEN made in recent years, the therapies which are currently available do not correspond to the principles of motor learning,” said Claudio Castellini (FAU, Erlangen, Germany), discussing the limitations of existing spinal cord injury treatments intended to help restore arm and hand function. “Firstly, especially weak muscles are not targeted sufficiently, and, secondly, patients are not actively encouraged to execute useful motor exercises.

Our experience has shown that this leads to patient engagement waning over time.”

Castellini and colleagues intend to overcome these drawbacks with their AI-based technology, which combines the electrical stimulation of muscles with support for mobility using artificial tendons, and reacts to patients’ intended movements. The

German Research Foundation has provided a total of approximately €1 million in funding for the project, dubbed ‘HIT-Reha’ and launched on 1 June 2023.

Injuries to the spinal cord often lead to the impediment of many daily activities. However, injuries like this are not necessarily irreversible. For example, if the long nerve fibres are not separated entirely from the brain, some remnants of motor control remain.

“In such cases, there is a good chance of regaining at least some mobility,” said Castellini. “The potential for regeneration is particularly high in the first 12 months after the injury, when new neurons can be generated and new networks created.”

The rehabilitation of arm and hand function is mainly based on the repeated execution of mobility exercises. Patients are supported by qualified therapists or, at times, also by robots. The methods used include functional electrical simulation (FES), in which electrodes trigger targeted muscle contractions, as well as exoskeletons or suits; orthoses that support and assist movement using pulley mechanisms, or inflatable air chambers. However, these current rehabilitation measures are not sufficiently tailored to patients’ individual requirements and abilities, meaning the full potential for treatment fails to be realised.

Over the next three years, Castellini and colleagues aim to develop a suit that they hope will significantly improve the success of therapy after spinal cord injuries. Their ‘exo-suit’ consists of a compression jacket, arm cuffs and gloves, and combines the support systems available to date, such as FES and pulley mechanics, but with one special addition: AI-supported recognition of patients’ intended movements.

“Integrated sensors measure muscle activity,” explained Marek Sierotowicz (FAU, Erlangen, Germany). “Self-learning algorithms take this input and use it to calculate the patient’s intended movement, and adjust the assistance systems accordingly.”

Specifically, this means that the AI tells the FES system and the exo-suit where muscle contractions should be triggered or pulleys tautened in order to support the intended movement. FAU is predominantly responsible for developing methods to perceive the patient’s intended movements. For this to work, researchers first have to construct a complete virtual model of the anatomical structure of the muscles and skeleton, and train it accordingly.

“We will carry out our initial tests with people who are not disabled and gather as much data as possible,” added Sierotowicz. “The better we train AI, the more reliably we will be able to recognise movement patterns and the more accurately the assistance systems will be able to work in the future.”

In addition to providing precise movement support, the intelligent interplay between EFS and robotic pulley systems may also ensure a more gentle treatment is delivered, as experience has shown that using FES alone requires a high intensity of stimulation and patients often find it unpleasant. The researchers feel their invention will lead to a significant improvement in the success of rehabilitation after a spinal cord injury, as outlined in an FAU press release.

The potential for regeneration is particularly high in the first 12 months after the injury, when new neurons can be generated and new networks created.”

Claudio Castellini

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Issue 51 | September 2023

35

Nalu presents new study data on pain management with PNS and SCS systems

Saluda Medical announces data showing costdominance of EVOKE system over open-loop SCS

Saluda Medical has announced the publication of new health economic data in the Clinical Journal of Pain that provides “the strongest ever economic case” for the use of its Evoke closedloop spinal cord stimulation (SCS) with physiologic SmartLoop technology over open-loop SCS therapy, as per a company press release.

The analysis sought to determine the cost-effectiveness of using the Evoke system over open-loop SCS for the treatment of chronic intractable pain by examining the costs and outcomes associated with each therapy. Results from the analysis indicate that the Evoke system becomes cost-dominant at five years in the base-case analysis and dominant at as early as two years post-implant in a scenario analysis.

The analysis was based on results from the EVOKE study, which demonstrated the highest reported outcomes in SCS at 36 months with zero explants due to loss of efficacy for patients who received closedloop therapy, according to Saluda. It considered certain costs relating to device list prices and healthcare use for responders, high-responders, and nonresponders, as well as explants due to loss of efficacy.

“This new analysis reinforces the economic case for utilising devices which have demonstrated longterm therapy durability,” said Corey Hunter (Ainsworth Institute of Pain Management, New York City, USA).

“Cost-dominance over another therapy at two years is exceedingly rare in medicine, and this reported dominance of the Evoke system over open-loop SCS should have a profound impact on patients, payers, and hospital systems, as they continue to prioritise increased clinical utility at a lower cost.”

enrolment up to the final planned sample size, as the interim results are “positively favourable”.

The MOOD trial—conducted in 12 clinical sites across the USA and one in Israel—is a prospective, multicentre, placebo-controlled, randomised, double-blind clinical trial. The study’s primary endpoint assesses changes in depression symptoms from baseline to eight weeks post-treatment initiation, comparing use of Relivion DP to a control group, in patients suffering from MDD who have failed to achieve satisfactory improvement from previous antidepressant medications.

Full study results will be announced and submitted to the US Food and Drug Administration (FDA), and for CE-mark approval, after the last patient completes the treatment protocol. This is expected in the second quarter of 2024, a Neurolief press release states.

Mainstay publishes threeyear data from postmarket follow up of ReActiv8 patients

Mainstay Medical has announced the publication of three-year clinical data from the post-market clinical followup (PMCF) study of 33 ReActiv8 patients at five medical centres across the UK. ReActiv8 is an implantable medical device designed to treat adults with intractable chronic low back pain (CLBP) associated with multifidus muscle dysfunction via restorative neurostimulation.

The three-year results, published in the British Journal of Pain, demonstrate that a substantial portion of patients experienced statistically significant improvements in measures of pain (numerical rating scale [NRS]), disability (Oswestry disability index [ODI]) and quality of life (EQ-5D-5L).

These results indicate that the response to ReActiv8 for these patients is durable and improves over time, validating ReActiv8’s restorative Neurolief reports positive mechanism of action, a Mainstay press results of interim analysis release notes. In addition, these realfrom MOOD trial in world outcomes are consistent with depression patients three-year data from 133 patients in the Neurolief has announced positive pivotal ReActiv8-B clinical trial, which results from a planned interim analysis were announced in September 2022. of the ongoing, randomised controlled “These results demonstrate durability MOOD pivotal trial, which is studying and safety of this therapy in chronic Relivion DP—a novel, headset-like back pain sufferers who would have neuromodulation device for the continued to be crippled and dominated treatment of major depressive by their symptoms but for disorder (MDD).

ReActiv8,” said Simon At a meeting of the study’s Thomson (Mid and South independent data monitoring Essex University Hospitals, committee (DMC), statistical Essex, UK), corresponding results from a pre-planned author of the PMCF study. efficacy and safety interim “These patients, drawn from Simon analysis were reviewed. usual UK pain clinics, are Thomson Based on data from 80% now as good as those seen in of the originally planned the continuation cohort from study sample size, the DMC issued a the more highly selected, randomised recommendation to continue patient ReActiv8-B trial.”

Nalu Medical, a company that has miniaturised neurostimulation implants for the management of chronic intractable pain for both peripheral nerve stimulation (PNS) and spinal cord stimulation (SCS) indications, presented new data from several studies at this year’s American Society of Pain and Neuroscience (ASPN) conference (13–16 July, Miami Beach, USA).

These presentations included an interim analysis of six-month outcomes from the COMFORT PNS randomised controlled trial (RCT), which showed a 100% responder rate (≥50% reduction in pain) for subjects suffering from chronic peripheral neuralgia treated with the Nalu PNS system (n=15).

Nalu implant

Additional highlights from the presentation included 78% mean pain relief from baseline; 65% mean Oswestry disability index (ODI) score improvement; and 100% improvement measured by patient global impression of change (PGIC) reported by patients.

Another key presentation at ASPN 2023 pertained to the SCS nPower US study, and explored how multiple endpoints may be an indication of valid clinical benefit. In addition to 86% of subjects implanted with the Nalu SCS system reporting significant pain relief in back and leg(s), the vast majority of patients (97%) achieved a minimal clinically important difference (MCID) in one functional metric or more.

Further highlights from the presentation included an 88% reported improved PGIC; 94% reported improved activities of daily living (ADL); and 77% reported improved quality of life (QoL). Nalu attributes these results from SCS nPower US to advanced engineering and the patented pulse stimulation pattern (PSP) waveform, which leverages multiple mechanisms of action.

Enspire raises US$17.6 million to fund advances in DBS plus rehab for stroke patients

Enspire DBS Therapy recently announced that it has raised US$17.6 million of committed capital in a Series B financing led by existing investor Cleveland Clinic Innovations.

Also participating in the round were JobsOhio Growth Capital Fund and an undisclosed investor. The company plans to use the proceeds to initiate the RESTORE pivotal clinical trial using deep brain stimulation (DBS) and rehabilitation therapy—DBS plus rehab—to treat patients with chronic

upper extremity impairment due to stroke.

RESTORE will evaluate the safety and effectiveness of DBS plus rehab for treating arm weakness and reduced function after a stroke to support marketing approval of this therapy. Each study participant will be implanted with a commercially available, third-party DBS system and receive a five-month outpatient rehabilitation therapy programme. After five months of blinded randomised testing, participants assigned to activecontrol treatment (rehab only) will cross over to receive DBS treatment and participate in a second five-month therapy programme.

According to Enspire, the first-inhuman, proof-of-concept EDEN study of DBS plus rehab, conducted at the Cleveland Clinic (Cleveland, USA), led to this Series B financing being raised.

DBS therapy for stroke is currently approved under investigational use, and clinical studies for this indication are being conducted under Enspire’s approved investigational device exemption (IDE) from the US Food and Drug Administration (FDA)—as per a company press release.

Magnus announces first treatments in OLO trial of novel depression therapy

Magnus Medical has announced that the first participants have been treated in the Open Label Optimisation (OLO) clinical trial evaluating the effectiveness of the company’s neuromodulation system with SAINT technology for the treatment of major depressive disorder (MDD).

“SAINT therapy is the beginning of a revolution in psychiatry: fast, effective and personalised treatments that give hope to patients who have failed to receive relief from traditional approaches,” said David Carreon (Acacia Mental Health, Sunnyvale, USA), a primary investigator and the first to enrol in the OLO study at his centre. “It could profoundly change the way we care for those with treatmentresistant depression and be a model for addressing other conditions as well.

Our clinic specialises in caring for the hardest and most hopeless, depressed patients by providing the best treatments available. We have started to enrol participants and are eager to find out whether the overwhelmingly positive results seen at the initial trials at Stanford will translate to our own patients.”

Up to nine clinics nationwide will participate in the OLO study, enrolling up to 1,000 adults suffering from a major depressive episode who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode.

Treatment will be delivered on an accelerated timeline—10 sessions a day, composed of 10-minute treatments of SAINT therapy with 50-minute breaks, for five consecutive days. Trial results are expected in 2027, as per a Magnus press release.

September 2023 | Issue 51

36 Market Watch

Clinical News Viz.ai presents study findings demonstrating realworld impact of AI-driven stroke technology

Mahesh Jayaraman

Imperative announces late-breaking data showing benefits of ‘angled-tip’ aspiration catheters

Imperative Care has announced late-breaking data from the Neurovascular Quality InitiativeQuality Outcome Database (NVQIQOD) evaluating its Zoom stroke solution, which were presented at the Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August 2023, San Diego, USA) by incoming SNIS president Mahesh Jayaraman (Brown University, Providence, USA).

“The angled-tip Zoom aspiration catheters have become a valuable tool for stroke thrombectomy procedures due to their proven trackability and ability to engage clot effectively,” said Jayaraman. “These real-world data demonstrate that treatment with the Zoom aspiration catheters led to high rates of successful reperfusion in patients with ischaemic stroke, with no safety concerns.”

As per safety and clinical performance data from 211 patients with large or medium vessel occlusions who were treated with Zoom aspiration catheters, an aspiration-first technique was used in 67.8% of patients, and a combined technique involving aspiration with a stent retriever was used in 32.2%. Adjunctive therapies including intra- or extra-cranial angioplasty and/or stenting were performed in 9% of patients.

Results from the analysis produced the following findings: median time from arterial puncture to recanalisation was 22 minutes; thrombolysis in cerebral infarction (TICI) ≥2b reperfusion was achieved in 91.9% of patients, and in 59% of patients after the first pass; overall, TICI ≥2c reperfusion was achieved in 59.2% of patients; among patients with 90-day follow-up data, 53.2% were functionally independent (modified Rankin scale [mRS] 0–2); and the overall rate of symptomatic intracranial haemorrhage was 2.8%.

In July, Imperative also announced US Food and Drug Administration (FDA) 510(k) clearance of its Zoom 88 large distal platform (LDP) support—a portfolio expansion of the original Zoom 88 LDP—as well as the successful completion of initial cases using Zoom 88 support in the USA.

Viz.ai has announced the presentation of three new abstracts that demonstrate the real-world impact of the Viz neuro suite at the Society of NeuroInterventional Surgery (SNIS) annual meeting (31 July–4 August, San Diego, USA). These independent studies demonstrate the clinical, health equity and patient benefits of artificial intelligence (AI)-driven technology, and reiterate Viz.ai’s commitment to transforming patient care, as per a company press release.

One study entitled, “Viz LVO [large vessel occlusion] versus Rapid LVO in detection of large vessel occlusion on CT [computed tomography] angiography for acute stroke”,

by Adam Delora (HCA Houston Healthcare Kingwood, Houston, USA) et al, highlighted the superior performance of the Viz LVO solution in detecting suspected LVO on CT angiography for acute stroke.

Additionally, an abstract entitled, “Rural versus metropolitan stroke activation incidence: using Viz.ai to determine disease penetrance”, by Justin Fraser (University of Kentucky, Lexington, USA) et al, demonstrated the value of data to visualise the level of disparities in care and redistribute resources to increase access to stroke care in rural areas.

Lastly, data from an abstract entitled, “Radiographic and clinical outcome-based assessment of middle meningeal artery embolisation for chronic subdural haematoma patients at a community hospital”, by Dorothea Altschul (Valley Health System, Ridgewood, USA) et al, explored the successful implementation of AIpowered solutions to assess and treat chronic subdural haematoma patients.

“It was remarkable to have the ability to educate patients about their disease at the bedside and show patients their scans with volume measurements,” said lead investigator Altschul. “We used this tool not only for care coordination but also for care education.”

Route 92 announces publication of first-in-human study featuring FreeClimb 70 reperfusion system Route 92 Medical has announced the publication of a retrospective, first-in-human study featuring its FreeClimb 70 reperfusion system in the journal Interventional Neuroradiology.

The study, conducted across five US centres and one international site, reports “impressive” M1 first-pass effect (FPE) results, with no procedural complications, and illustrates the system’s efficiency, as per a company press release.

“The FreeClimb 70 reperfusion system’s performance in this study confirms its potential to enhance patient outcomes significantly,” said Fabio Settecase (Sutter West Bay Medical Group, San Francisco, USA), the lead author on the study. “Its rapid delivery, effectiveness and safety profile, combined with its efficiency, make it an exceptional advancement in stroke intervention technology.”

The FreeClimb 70 reperfusion system, which received US Food and Drug Administration (FDA) 510(k) clearance in April 2023, is the first fully integrated solution designed around Route 92’s Tenzing 7 delivery catheter.

The system’s advanced design eliminates the ‘ledge effect’ commonly found in large-bore catheters, and offers “superior navigation and predictable access” to occluded distal vessels— typically without the need for a guidewire—according to the company.

The newly published study included 30 consecutive patients and showed an M1 FPE of 61%—which Route 92 claims is one of the highest endovascular thrombectomy FPE rates ever published. The FreeClimb 70 reperfusion system demonstrated a 100% success rate in navigating to the occlusion site, with a median time of only 12 minutes from groin puncture to first pass.

In this early clinical experience with Tenzing, additional support or anchoring devices like stent retrievers were not needed to deliver the aspiration catheter to the target, helping to reduce procedure costs.

Notably, 70% of cases did not require a leading guidewire to advance the Tenzing to the occlusion, highlighting the system’s ability to enhance stroke treatment while potentially reducing risks like vessel perforation and dissection, according to the company’s recent release.

iVascular passes halfway point in recruitment for SEMTIC study

iVascular has announced that the SEMTIC study, evaluating the safety and efficacy of its comprehensive stroke thrombectomy treatment, is one step closer to providing its first outcome data, with more than 50% of patients having now been enrolled.

The primary objective of SEMTIC is to determine the safety and efficacy of three devices collectively designed and manufactured by iVascular for neurothrombectomy procedures. The treatment combines the benefits of the company’s iNedit balloon distal access catheter and iNdeep microcatheter to facilitate placement of the iNtercept stent retriever and temporarily restrict blood flow in patients with acute ischaemic stroke caused by a large vessel occlusion (LVO).

A complete cohort of 225 patients will ultimately be enrolled across 20 sites in four countries: Spain (14 sites), Belgium (one site), Germany (three

iVascular thrombectomy treatment

sites) and France (two sites). To date, recruitment has been completed in multiple Spanish centres.

“The recruitment is going well so far. To date, 115 patients have been recruited—all of them from centres across Spain. The first results will be reported by the beginning of 2024,” said principal coordinating investigator Juan Macho and co-investigator San Roman (both Hospital Clinic de Barcelona, Barcelona, Spain).

Anuncia announces first successful implant of ReFlow mini flusher in hydrocephalus patient

Anuncia Medical has announced the successful first implant of the company’s US Food and Drug Administration (FDA)-cleared ReFlow mini flusher device.

Performed on by Samuel Cheshier (Intermountain Primary Children’s Hospital, Salt Lake City, USA), the patient previously required at least 11 brain surgeries to manage their hydrocephalus—a chronic neurological condition in which excess cerebrospinal fluid (CSF) accumulates in the brain.

“Neurosurgeons treating hydrocephalus have been waiting too long for a non-surgical option to help keep implanted shunts flowing,” Cheshier said. “The ReFlow is easy to implant with my preferred shunt type and just makes sense. I welcome having this tool in my toolkit.”

The second-generation ReFlow mini flusher is indicated for use in patients living with hydrocephalus or similar conditions. The reduced size and profile of the technology is designed to better support a broader hydrocephalus patient population, from infants to older adults, as per an Anuncia press release.

Used in line with any shunt system brand, the ReFlow mini flusher is designed to flush the patient’s CSF back into the ventricular catheter to maintain, restore or increase hydrocephalus shunt flow.

The first-generation ReFlow device was successfully implanted in more than 30 patients with hydrocephalus and is the subject of 11 clinical studies/ reports in total. In May this year, a study on the improved outcomes of nine ReFlow patients was published in the journal Pediatric Neurosurgery.

And, after successfully launching in June 2023, the ReFlow mini flusher is now being shipped to leading institutions for use by neurosurgeons in the USA, Anuncia claims.

It is also expected that the ReFlow mini flusher will be available internationally in the future.

Issue 51 | September 2023

Market Watch 37

Clinical News Rapid Medical announces new data showing advantages of Comaneci for intracranial aneurysms Rapid Medical has announced new clinical data demonstrating the “significant advantages” of its novel Comaneci embolisation assist device over established techniques to treat ruptured wide-neck intracranial aneurysms.

A recent meta-analysis published in World Neurosurgery found that Comaneci is associated with lower haemorrhagic and thromboembolic complication rates, higher complete occlusion rates, and similar residual retreatment rates, as compared to stentand balloon-assisted coiling (SAC/ BAC) techniques.

As the only adjustable, nonocclusive device for haemorrhagic stroke treatment—so claims a Rapid Medical press release—Comaneci’s visible mesh conforms to the anatomy, providing stent-like support without the complications of a permanent stent or halting blood flow like a balloon. It has been used in over 12,000 procedures worldwide in wide-neck aneurysm treatments and, in Europe only, to open arteries constricted by vasospasm.

In their recently published metaanalysis, researchers at the University at Buffalo (Buffalo, USA) and George Washington University (Washington DC, USA) compared the three devices by pooling more than 3,200 ruptured aneurysm cases across 64 studies. No significant differences were found

Comaneci device

between SAC and BAC. However, Comaneci-assisted coiling showed significantly lower thromboembolic and aneurysmal complication rates, and periprocedural complications, than both SAC and BAC. Furthermore, it demonstrated statistically better complete occlusion rates versus SAC and equivalent rates to BAC.

AptaTargets announces publication of APRIL trial data on novel neuroprotective agent

AptaTargets has announced the publication in JAMA Neurology of positive results from APRIL—a Phase 1b/2a clinical trial evaluating the safety and efficacy of the neuroprotective drug ApTOLL in combination with endovascular therapy (EVT) in patients with acute ischaemic stroke.

The results from the study have proven to be clinically relevant, the release notes, as the administration

of 0.2mg/kg of ApTOLL within six hours after acute ischaemic stroke—in combination with EVT—was safe and well-tolerated, as well as being associated with a reduction in mortality from 18% to 5% along with a reduction in 90-day functional disability compared to a placebo.

APRIL is a double-blind, randomised, multicentre, placebocontrolled, Phase 1b/2a clinical trial that started in 2020, and has been conducted in 14 comprehensive stroke centres across Spain and France. In total, the study included 151 patients: 32 in Phase 1b and 119 in Phase 2a.

The study population were men and non-pregnant women between 18 and 90 years old with an incapacitating stroke at the time of randomisation.

Patients received ApTOLL or placebo intravenously prior to undergoing EVT. The total population analysed consisted of 139 patients, of whom 42 received 0.05mg/kg of ApTOLL; 42 received 0.02mg/kg of ApTOLL; and 55 received placebo. The primary endpoint was safety—as determined by death, symptomatic intracranial haemorrhage, malignant stroke and recurrent stroke. The secondary endpoints, concerning efficacy, included the mean final infarct volume measured at 72 hours; stroke symptom severity assessed via the National Institutes of Health stroke scale (NIHSS) at 72 hours; and disability as per the modified Rankin scale (mRS) at 90 days.

Microvention publishes five-year WEB-IT data and introduces two new device sizes

Microvention, a wholly owned subsidiary of Terumo Corporation, has announced the publication of fiveyear follow-up data from the WEBIT trial. With these now-published five-year clinical trial data, the Woven EndoBridge (WEB) aneurysm embolisation system is the “most wellstudied intrasaccular device available in the marketplace today”, with seven good clinical practice (GCP) studies and more than 200 peer-reviewed publications. That is according to a Microvention press release.

Five-year data on the device are now available from the US WEB-IT and European WEBCAST 1 and 2 trials, while CLARYS, CLEVER, FROBS and WEB-IT China constitute the remainder of the seven GCP studies on WEB to date.

“From the GCP studies, there is currently a total of 1,464 patient years and counting, from 601 patients, during which no patient has experienced bleeding or re-bleeding from a WEBtreated aneurysm—a remarkable track record of effectiveness over a large, accumulated experience,” said David

Fiorella (Stony Brook Cerebrovascular Center, Stony Brook, USA), coprincipal investigator of WEB-IT. “It is great to have long-term followup on this large, adjudicated GCP study,” added Adam Arthur (University of Tennessee Health Science Center, Memphis, USA), WEB-IT co-principal investigator. “At this time, there is no device that has been shown to be safer for aneurysm patients than WEB. So, if a patient with a wide-neck bifurcation aneurysm can be treated with WEB, that ought to be the primary consideration.”

In addition, Microvention has announced that WEB is now available in two additional sizes (SL 6×2 and SL 7×2), claiming that this will allow for the treatment of different sizes and shapes of aneurysms. The device is designed to treat brain aneurysms inside the aneurysm sac, disrupting blood flow while sealing the neck and protecting the dome with Microvention’s MicroBraid technology.

David Fiorella (L), Adam Arthur

Brainomix announces improved thrombectomy access at UK hospitals with AI technology

Brainomix has announced that more stroke patients are benefitting from life-changing treatment thanks to the company’s e-Stroke artificial intelligence (AI) platform, according to a recent report from the Oxford Academic Health Science Network (AHSN). E-Stroke imaging technology uses AI to automatically process computed tomography (CT) and magnetic resonance imaging (MRI) scans, and alert doctors in real-time about those patients who would benefit most from mechanical thrombectomy treatments.

With this in mind—according to a Brainomix press release—24 hospitals across England are taking part in an independent, detailed evaluation of e-Stroke led by the Oxford AHSN to assess its impact on patient and clinical outcomes, pathways and productivity.

E-Stroke securely processes CT and MRI brain scans in less than two minutes and sends the results to the doctors’ smartphones as well as hospital systems. It also connects specialists at different hospitals in a network to improve communication and coordination of care.

Interim findings from an independent evaluation of e-Stroke by the Oxford AHSN have showed that the average treatment rate in the e-Stroke hospitals was more than 55% higher than the national average—having been the same at baseline. Treatment rates

rose to 5.7% at e-Stroke hospitals compared to the national average of 3.6%, an uplift that reflects hundreds more patients receiving life-changing thrombectomy treatments and avoiding the long-term effects of stroke, as per the recent release from Brainomix.

Also, some of the highest performing hospitals taking part in the evaluation reached thrombectomy rates >10%—a target set out in the National Health Service (NHS) Long Term Plan.

Philips enrols first US and French patients in global WE-TRUST study

Royal Philips has announced enrolment of the first patients in both the USA and France into the large-scale WETRUST study—a multicentre, prospective randomised controlled trial assessing whether a direct-to-angiosuite (DTAS) workflow improves outcomes for early time-window stroke patients compared to the conventional magnetic resonance (MR)/computed tomography (CT) scan before transfer to the angio-suite pathway.

Recruited at the Baptist Stroke and Cerebrovascular Center (Jacksonville, USA), a comprehensive stroke centre, the first US patient enrolment represents an “important international expansion” of WE-TRUST, according to Philips.

The study is already running in several European and South American countries including Spain, Turkey, Germany, The Netherlands, Brazil, and Argentina.

In addition, Bicêtre Hospital (Paris, France) successfully recruited the first French patient in the study, also marking a “significant milestone” in its international expansion, Philips claims.

“By using the direct-to-angio approach, we were able to diagnose and treat this patient faster than conventional methods,” said Laurent Spelle (Bicêtre Hospital, Paris, France).

“Our goal is to find more effective and efficient ways to diagnose, treat, and manage stroke, ultimately enhancing the quality of life for patients. By joining WE-TRUST, we can help build the clinical evidence for the DTAS workflow—a new treatment approach that has great potential to improve patient outcomes.”

Recently, Philips also announced that the results of a retrospective health economics analysis looking at data from the single-centre ANGIOCAT trial, published in the Journal of NeuroInterventional Surgery, show that its DTAS treatment pathway for stroke patients can save more than $US3,000 per patient.

Philips’ Azurion system

September 2023 | Issue 51

38 Market Watch

Industry News Stryker announces commercial launch of Q guidance system with cranial guidance software

Stryker has commercially launched its Q guidance system with cranial guidance software to provide surgeons with an image-based planning and intraoperative guidance system that assists in positioning instruments, and identifying patient anatomy during cranial surgery.

The software can be used for craniotomies, skull base and transsphenoidal procedures, shunt placements, and biopsies, as detailed in a press release from the company.

According to Stryker, the Q guidance system with cranial guidance software uses both active and passive tracking technology to provide “groundbreaking” planning and guidance capabilities. These technologies include a proprietary camera; dual PC system; diffusion tensor imaging (DTI) and tractography; precision targeting system; and electromagnetic catheter placement.

“With Stryker’s new camera technology, we were able to quickly register patients using the CranialMask Tracker,” said J D Day (University of Arkansas for Medical Sciences Health, Little Rock, USA). “The new user interface and workflows are slick, and our staff loves the intuitive new views like 3D targeting and the new skull stripping feature.”

The Q guidance system with cranial guidance software was also used at six early product surveillance sites in May of this year.

EOSolutions announces US FDA 510(k) submission of Thinline 8Fr vascular access sheath

EOSolutions has announced the US Food and Drug Administration (FDA) 510(k) submission, through a design consulting firm, of the Thinline 8Fr sheath—a vascular access solution designed to complement the “remarkable features” of the company’s Dr Banner balloon guide catheter (BGC) product.

Together, the Thinline sheath and the Dr Banner BGC provide a full system with a 0.091-inch inner diameter (ID) to ensure maximal compatibility through an 8Fr sheath profile, providing physicians with a comprehensive toolkit and greater freedom for device delivery, an EOSolutions press release states.

According to the company, the Thinline sheath offers a slim, low-profile design that facilitates smooth percutaneous introduction of compatible devices, while its optimised profile enables physicians to safely introduce next-generation large-bore devices, such as the Dr Banner BGC,

through its 0.125-inch ID. In May this year, EOSolutions announced the introduction of the Dr Banner BGC, stating that it boasts “unmatched features” for neurovascular procedures and— developed in collaboration with Inneuroco—sets “new benchmarks” in catheter technology, providing physicians with “unparalleled capabilities”. Key features of the device include improved proximal stability, distal trackability, and a super-compliant polyurethane balloon.

ERIC stent retriever

Microvention announces commercial availability of ERIC retrieval device in the USA

Microvention, a wholly owned subsidiary of Terumo, has announced that the ERIC retrieval device is now commercially available in the USA for ischaemic stroke treatment, having received 510(k) clearance from the US Food and Drug Administration (FDA) on 31 March 2022.

“The ERIC retrieval device’s ability to rapidly interact and trap the embolus, coupled with its low-profile design, facilitates synergistic use with SOFIA catheters [Microvention/Terumo] and reduces time to recanalisation,” said Adel Malek (Tufts Medical Center, Boston, USA). “We are excited to have been the first centre in Massachusetts to have clinical experience using the ERIC device and since then have integrated ERIC into our stroke practice.”

ERIC delivers thrombus control inside and outside of the device; offers no clot integration wait-time to drive procedure efficiency; and offers versatile treatment options for mechanical thrombectomy, as per a press release from Microvention. The device is a self-expanding, laser-cut clot retriever with multiple retrieval cages, located on a pusher wire delivery system. ERIC is designed to control the thrombus through its cagelike design and also has an atraumatic design intended to conform to the natural vessel.

ERIC is offered in three sizes that treat a wide vessel size range of 5.5mm down to 1.5mm, and is compatible with Microvention’s HEADWAY 17 and HEADWAY 21 microcatheters.

As part of an initial limited release, the first ERIC cases in the USA were performed by the neurovascular team at

Riverside Methodist in Columbus, USA in February 2023.

Microvention states in the release that ERIC delivers safe and effective outcomes, showing similar results in terms of successful revascularisation, and clinical and safety outcomes, when compared to other retrieval devices.

RapidAI announces US$75 million growth investment led by Vista Credit Partners

RapidAI has announced US$75 million in Series C funding led by Vista Credit Partners, a subsidiary of Vista Equity Partners and strategic financing partner focused on the enterprise software, data and technology markets. A press release details that the funding aims to drive platform innovation to support more disease states and go-to-market functions to accelerate growth in new regions and product verticals.

RapidAI claims that its artificial intelligence (AI) and workflow technology sets the standard for stroke care. The company has built a portfolio of stroke solutions, including Rapid non-contrast computed tomography (NCCT) Stroke, which provides hospitals of all sizes and imaging capabilities greater access to imaging and decision support to address a wider population of patients.

In addition, the company notes that it has recently expanded into new disease states with US Food and Drug Administration (FDA)-cleared modules for cerebral aneurysm management, and the identification and notification of suspected central pulmonary embolism. RapidAI is also currently developing additional modules for other disease states.

StrokeViewer

Nicolab awarded three-year contract to supply AIpowered stroke software in Australia

Nicolab has been awarded a “prestigious” three-year contract to supply stroke workflow software and advanced artificial intelligence (AI) diagnostics for the Victorian Stroke Telemedicine (VST) service in Viewbank, Australia.

The VST service—a virtual platform that connects healthcare professionals across multiple hospitals—aims to deliver “exceptional stroke care” regardless of a patient’s location, a press release states. By leveraging Nicolab’s state-of-the-art StrokeViewer solution, clinicians gain real-time access to critical brain imaging analysis and diagnostic insights, which is intended to enable remote consultations and expedited treatment decisions.

The release goes on to note that

patients residing in regional areas face a 19% higher risk of suffering from strokes, and that the VST service attempts to bridge this gap by fostering collaboration among stroke consultants, patients, and local clinicians, empowering them to provide immediate and comprehensive care.

Presently, the network connects 17 hospitals in the Australian state of Victoria and two hospitals in Tasmania to an esteemed panel of stroke specialists who offer treatment advice for patients exhibiting acute stroke symptoms.

“Through AI-powered stroke diagnostics and the expertise of stroke specialists, our staff can accurately diagnose the stroke type and initiate appropriate treatment promptly,” explained Chris Bladin (Ambulance Victoria, Melbourne, Australia). “This expedites the commencement of treatment and facilitates the prioritisation of patients requiring transfer to specialised treatment facilities.”

Adept Medical launches new Head Immobiliser for improved imaging and head fixation

Adept Medical has announced the launch of the Head Immobiliser—a radiolucent support for a range of interventional radiology and neuroradiology procedures.

Now commercially available, the positioning device can help mitigate the costs of retakes, from reducing the amount of mid-procedure interventions caused by head movement in awake patients, to enabling interventionists to consider conscious sedation as an option, as well as minimising patient exposure to radiation.

As per an Adept press release, the Head Immobiliser uses vacuum suction to lock the hood shape, and with it, the patient’s skull, reducing unwanted movement comfortably. This helps to align the 3D roadmap and angiography, ensuring interventions are performed under optimal conditions, providing benefits to patient management and procedural workflow.

With an aluminium equivalence of 2.23mm through the hood, the Head Immobiliser has been designed to have minimal interference with X-Ray imaging too. Compatible with most imaging tables, it is easy to set up, and takes up minimal space in the operating theatre, the release adds.

Hubly Surgical closes oversubscribed seed funding round following US FDA approval

Hubly Surgical has announced the successful closure of its Series seed funding round at an oversubscribed US$3 million. As per a company announcement, this investment comes on the heels of a recent US Food and Drug Administration (FDA) clearance for the Hubly Drill—a patented device designed to mitigate the challenges of

Issue 51 | September 2023

Market Watch 39

Industry News bedside cranial access by being the “first and only” cordless, singleuse cranial drill with advanced features for safety and efficiency in any setting, including outside of the operating room.

“Burr holes are one of the most common neurosurgical procedures we perform,” said Matthew Potts (Northwestern University, Evanston, USA). “And, at the bedside, they are often done using a cumbersome handcranked drill. I know first-hand how antiquated this solution is and how dangerous this procedure can be.

I am excited that Hubly has developed an improved intracranial drill for burrhole placement.”

The funds recently raised by the company will be “instrumental” in bringing the Hubly Drill to market and driving further advancements in the surgical field, a press release notes.

Hubly plans to expand its commercial launch to three additional regions in the USA, increasing access to its flagship cranial drill product, as well as investing in post-market clinical data collection and new product development efforts in partnership with Ontogen Medtech to address further patient indications.

Artiria granted US FDA clearance for real-time, deflectable guidewire

Artiria Medical, a Swiss neurovascular company, has announced that its realtime, deflectable guidewire has been granted 510(k) clearance by the US Food and Drug Administration (FDA).

This milestone opens a “new pathway” to a “more advanced and effective approach” to stroke treatment, and related neurovascular and peripheral conditions, as per a company press release.

Artiria’s guidewire offers “the next level of control” for physicians as well as an improved way to navigate the complex network of the cerebral arteries, the release adds. The distal tip of the device can be shaped, in real time, without it being removed from the patient, while the support profile of the wire can be adjusted over the duration of a procedure, as needed.

Neurovascular interventions are often hindered by the time-consuming task of navigating through the dense maze of the brain’s arteries, Artiria states in the release—adding that its latest innovation provides a novel solution to this that can be seamlessly integrated into existing clinical practices.

Artiria’s neurovascular guidewire

As per the release, next steps for the company involve gaining clinical experience through collaboration with USA-based centres in order to demonstrate the clinical effectiveness of its newly approved product. And, as stated by co-founder and CEO Guillaume Petit-Pierre, Artiria plans to begin its clinical activities in the USA “very soon”.

Aidoc launches AI-powered Full Brain solution to “significantly expand” stroke detection Aidoc has announced the launch of its “revolutionary” Full Brain solution, which the company claims will significantly expand the anatomy analysed by artificial intelligence (AI) to identify suspected strokes, allowing for identification and care coordination of patients with medium vessel occlusions (MeVOs), as well as posterior and anterior large vessel occlusions (LVOs).

An Aidoc press release states that

the Full Brain solution represents a significant advancement in medical technology aiding patient care, being the “first and only” AI technology to identify suspected posterior and anterior LVOs and MeVOs. The prevalence of these newly covered conditions, posterior LVOs and MeVOs, is significant across the globe, the release continues, and their addition to Aidoc’s AI-powered stroke identification technology will enable approximately twice as many patients to receive faster access to life-saving therapy.

“AI has shown remarkable success in enhancing workflow for patients with anterior LVOs, nearly halving the time to treatment,” said Brian Mason (University of Illinois Champaign, Champaign, USA). “However, this is just the beginning. With Aidoc’s Full Brain solution, we can now broaden these advancements to benefit a significantly larger patient population, leading to improved care and ultimately better patient outcomes.”

Extending beyond acute ischaemic stroke, the Full Brain solution employs diverse AI technologies—such as image-based identification and natural language processing—to identify and orchestrate care for patients suffering from intracerebral haemorrhage, subdural haemorrhage, and brain aneurysms, making it the “most complete” neurovascular AI solution, the release adds.

Conference calendar 4–6 September Congress of the European Society of Minimally Invasive Neurological Therapy (ESMINT) Marseille, France

20–24 September European Society of Neuroradiology (ESNR) Annual Meeting Vienna, Austria

9–13 September Congress of Neurological Surgeons (CNS) Annual Meeting Washington DC, USA

10–12 October World Stroke Congress (WSC) Toronto, Canada

esmint.eu/esmint-congress

cns.org/annualmeeting

esnr.org/en/46th-esnr-annualmeeting-6456

worldstrokecongress.org

15–19 October XXVI World Congress of Neurology (WCN) Montreal, Canada

3–4 November LINNC Seminar - Asia Edition Seoul, South Korea

18–19 October Stroke Live Course (SLICE) Worldwide Virtual

16–18 November Society of Vascular and Interventional Neurology (SVIN) Annual Meeting Miami, USA

wcn-neurology.com

masterandfellow.com/slice/ww

linnc.com/Course-information/ LINNC-Seminar-2023-Asia-Edition

svin.org/i4a/pages/index. cfm?pageid=3601

26–30 November Radiological Society of North America (RSNA) Annual Meeting Chicago, USA rsna.org/annual-meeting/futureand-past-meetings

4–6 December Barts Research and Advanced Interventional Neuroradiology (BRAIN) Conference London, UK brainconference.co.uk

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a. Devices shown at same scale. Tests performed and data on file at Penumbra, Inc. All testing was completed by the same operator during the same testing session under the same −29.2 inHg of power aspiration. Bench test results may not be indicative of clinical performance. Clinical results may vary. Data on file at Penumbra, Inc. b. Data on file at Penumbra, Inc. Photographs taken by and on file at Penumbra, Inc. Product availability varies by country. Prior to use, please refer to the Instructions for Use for complete product indications, contraindications, warnings, precautions, potential adverse events, and detailed instructions for use. For the complete Risk Statements, please visit: http://bit.ly/2BYj7Yj. Please contact your local Penumbra representative for more information.

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