NeuroNews issue 52 - US

’S Y NIC STR TRO REGI MED IRE-A FOCUS ge 14 P a INS IN rn to p Tu

December 2023 Issue 52

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Featured in this issue:

10

Neurovascular device regulation: “The tables have turned”

Profile Phil White

CAROTID INTERVENTIONS CMS expands US stenting coverage

page 20

page 27

SVIN

Equipoise between general anaesthesia and sedation likely remains following SEGA trial results

The multicentre, randomised SEGA trial has found that acute ischaemic stroke patients who receive endovascular therapy (EVT) under general anaesthesia experience better functional outcomes at 90 days compared to those who receive the procedure under conscious sedation. However, experts have indicated that definitive conclusions from this finding should be made with caution, and clinical equipoise likely remains between the two approaches.

R

esults from SEGA were presented for the first time at the recent Society of Vascular and Interventional Neurology (SVIN) annual meeting (16–18 November 2023, Miami, USA) by Peng Roc Chen (University of Texas Health [UTHealth] Houston, USA).

Chen initially detailed that, across a cohort of 260 patients with strokes caused by an anterior-circulation large vessel occlusion, outcomes following EVT under either general anaesthesia or conscious sedation were compared in the trial.

As per SEGA’s primary effectiveness endpoint, general anaesthesia was associated with a higher likelihood of functional independence—measured via modified Rankin scale (mRS) scores—at 90 days. The investigators have reported an odds ratio (OR) of 1.22 favouring general anaesthesia. Overall, a higher percentage of patients experienced mRS scores of 0–1 (30%) and 0–2 (47%) with general anaesthesia as compared to conscious sedation (28% and 39%, respectively) as well.

In addition, one of the trial’s secondary endpoints showed that general anaesthesia led to an increased chance of successful reperfusion (modified thrombolysis in cerebral infarction [mTICI] score ≥2b) versus conscious sedation, with Chen reporting a relative risk (RR) ratio of 1.02 favouring the former.

These data led the SEGA investigators to conclude that patients receiving EVT under general anaesthesia are more likely to achieve a higher grade of angiographic reperfusion, and are also more likely to reach an outcome of functional independence at three months, than those who are treated under sedation.

“I applaud Dr Roc Chen and the SEGA team for their efforts; however, I maintain that clinical equipoise persists,” said outgoing SVIN president Ameer Hassan (Valley Baptist Medical Center, Harlingen, USA). “Two distinct camps exist, each steadfast in their belief in the validity of their respective

data from multiple trials. Currently, I am inclined to think that—if general anaesthesia is readily available at your institution and does not cause a delay exceeding eight minutes in arterial puncture—there may be potential advantages. Unfortunately, at my institution, the delays caused by anaesthesia are more than double.”

Peng Roc Chen “While these results indicate that general anaesthesia may be associated with a higher likelihood of functional independence and better angiographic reperfusion, it is crucial to approach the conclusions cautiously, since the detailed study data are not yet published,” added Panagiotis Papanagiotou (University of Athens, Greece). “Previous studies have indicated that the sedation method may not significantly impact treatment outcomes. The observed differences in this study could be attributed to lower reperfusion rates with sedation. Therefore, we await the full publication of the study to gain a deeper understanding of the causes behind these differences in reperfusion rates.”

Two distinct camps exist, each steadfast in their belief in the validity of their respective data from multiple trials.”

Ameer Hassan

Intrathecal drug delivery systems deemed effective in managing cancer-related pain page 31

TENSION results show improved functional outcomes and reduced mortality with stroke thrombectomy NEW RESULTS FROM THE TENSION study—presented recently at the 15th World Stroke Congress (WSC; 10–12 October, Toronto, Canada) by Götz Thomalla (University Medical Center HamburgEppendorf, Hamburg, Germany)— have demonstrated improved functional outcomes and reduced mortality rates among stroke patients treated via mechanical thrombectomy.

“TENSION shows that, just using a pragmatic, standard-of-care approach to acute stroke imaging, we can guide thrombectomy in stroke patients with a large core, improve outcomes, and save lives,” said Thomalla.

According to Thomalla and his colleagues’ publication of these findings in The Lancet, recent evidence—primarily from the RESCUE-Japan LIMIT, ANGELASPECT and SELECT2 randomised trials—suggests a beneficial effect with thrombectomy in patients experiencing an acute ischaemic stroke caused by a large infarct.

“However, previous trials have relied on multimodal brain imaging, whereas non-contrast CT [computed tomography] is mostly used in clinical practice,” the authors note. As such, Continued on page 2

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December 2023 | Issue 52

Cover Story

TENSION results show improved functional outcomes and reduced mortality with stroke thrombectomy Continued from page 1

the generalisability of the three aforementioned trials is somewhat limited, and their results are yet to trigger a change in guidelines or clinical practice.

TENSION, a prospective, multicentre, open-label, randomised controlled study, was conducted at 40 hospitals in Europe and one site in Canada. Overall, 253 patients with acute ischaemic stroke due to a large vessel occlusion in the anterior circulation and a large, established infarct indicated by an Alberta stroke programme early computed tomographic score (ASPECTS) of 3–5, were randomly assigned (1:1) to receive either thrombectomy alongside standard of care, or standard of care alone, within an extended time window (up to 12 hours) from symptom onset.

The primary outcome was functional outcome across the entire range of modified Rankin scale (mRS) scores at 90 days—assessed by investigators masked to treatment assignment—in TENSION’s intention-to-treat population.

Safety endpoints included rates of mortality and symptomatic intracranial haemorrhage (ICH).

While many of these aspects are similar to the other randomised trials supporting thrombectomy in large-core stroke patients to date, Thomalla et al emphasise that the

modalities used in their study (82% non-contrast CT and 18% magnetic resonance imaging [MRI]) were based on standard-of-care stroke imaging and are therefore reflective of global clinical practice. This differs from the previous trials in which, by design, perfusion imaging or post-processing via commercial software was required.

TENSION was stopped early due to positive efficacy signals following its first preplanned interim analysis. As per the data presented by Thomalla at WSC 2023, there was a shift in the distribution of mRS scores towards better outcomes in favour of thrombectomy plus standardof-care treatment as compared to standard of care alone at 90 days. In the trial, there was also a lower rate of mortality in the patients treated with thrombectomy, and comparable rates of symptomatic ICH between groups (6% for thrombectomy and 5% for standard of care).

“Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with [an] established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection,” Thomalla and colleagues write, concluding their paper in The Lancet.

In addition to the significance of the fact that TENSION utilised imaging modalities that are more widely accessible and commonly used in daily clinical practice than those employed by the other large-core trials published thus far, the authors highlight the lower 90-day mortality rate associated with thrombectomy in their study—a phenomenon that was not borne out in the results of RESCUE-Japan LIMIT, ANGEL-ASPECT, or SELECT2.

TENSION shows that, just using a pragmatic, standard-of-care approach to acute stroke imaging, we can guide thrombectomy in stroke patients with a large core, improve outcomes, and save lives.”

LATEST NEWS THE STORIES IN BRIEF FROM THE

NEURO WORLD

n REMOTE TELEPROCTORING HELPS INTERVENTIONISTS OVERCOME WARTIME RESTRICTIONS IN UKRAINE: Remote teleproctoring has demonstrated promising results in providing hands-on mechanical thrombectomy training and overcoming wartime migration restrictions in Ukraine, according to initial experiences published recently in the journal Interventional Neuroradiology.

For more on this story go to page 7. n CURRENT INTRACRANIAL ANEURYSM LITERATURE REFLECTS “A FAILURE OF THE PEER-REVIEW PROCESS”: A systematic review and meta-analysis of 1,356 studies and more than 410,000 patients have found that “methodological flaws and incomplete reporting” occur frequently in studies advocating the safety, effectiveness or durability of intracranial aneurysm treatments. This forms a “potential public health hazard” for patients and, in the view of the authors, a “failure of the peerreview process”.

For more on this story go to page 13. n LATEST TRIAGE-STROKE AND RACECAT DATA PUT THE BRAKES ON ALTERNATIVE STROKE TRANSFER PROTOCOLS: Recently published data from two large randomised controlled trials have indicated there may be minimal benefits, or even negative effects, associated with bypassing local or primary stroke centres and transporting patients straight to thrombectomy-capable comprehensive stroke centres (CSCs). However, investigators are in agreement that additional research is required to further elucidate the impact of transferring stroke patients directly to CSCs.

For more on this story go to page 17.

Götz Thomalla

Editor-in-chief: Prof Philip M Meyers | Publisher: Stephen Roger Greenhalgh Greenhalgh | Content | Content director: director: Urmila Urmila Kerslake Kerslake | Head | Head of of Global Global News: News: Sean Sean Langer Langer Editor: Jamie Bell jamie@bibamedical.com | Editorial contribution: Jocelyn Hudson and Bryan Kay Design: Terry Hawes, Wes Mitchell and David Reekie Advertising: Michael Broughton michael@bibamedical.com Subscriptions: subscriptions@bibamedical.com Published by: BIBA News, which is a subsidiary of BIBA Medical Ltd | BIBA Medical, Europe, 526 Fulham Road, Fulham, London, SW6 5NR, United Kingdom Tel: +44 (0) 20 7736 8788 BIBA Medical, North America, 155 North Wacker Drive, Suite 4250, Chicago, IL 60606, United States Tel: +1 708-770-7323 Printed by: Print Tech Solutions Reprint requests and all correspondence regarding the newspaper should be addressed to the editor at the United Kingdom address. © BIBA Medical Ltd, 2023. All rights reserved.

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December 2023 | Issue 52

Intravenous Thrombolysis

Mobile stroke units increase odds of averting strokes and achieving complete recovery Receiving intravenous tissue plasminogen activator (IV-tPA) in an ambulance-based mobile stroke unit (MSU) increases the likelihood of averting strokes and the odds of a patient achieving complete recovery compared with standard hospital emergency care, according to researchers at Weill Cornell Medicine, NewYorkPresbyterian (both New York City, USA), University of Texas Health (UTHealth) Houston, Memorial Hermann-Texas Medical Center (both Houston, USA), and five other medical centres across the USA. THE STUDY, RECENTLY PUBLISHED ONLINE in the Annals of Neurology, determined that MSU care was associated with both increased odds of averting stroke compared with hospital emergency medical service (EMS)—18% versus 11%, respectively—and also a higher percentage of patients having an early symptom resolution—31% versus 21%, respectively— within 24 hours after stroke.

“While this is known to improve patient outcomes, how many patients fully recover afterward was not clear from prior research,” said lead author Babak

Benjamin Navi (Weill Cornell Medicine, New York City, USA), who is also acting medical director of the MSU, operated by NewYork-Presbyterian in collaboration with Weill Cornell Medicine, Columbia University Irving Medical Center (New York City, USA) and the Fire Department of New York. “On average, the faster you treat someone, the more likely you are to have a good functional outcome, because you are able to preserve more brain tissue. The brain can only sustain reduced blood flow for so long before permanent injury develops.”

Using multicentre trial data from 2014–2020, the researchers evaluated 1,009 patients, 644 of whom received IV-tPA in an MSU and 365 of whom received EMS care. Overall, patients received IV-tPA—a thrombolytic drug that is well-established in stroke care—at a median interval of 87 minutes after the onset of stroke symptoms. The study found that, with IV-tPA treatment in this timeframe, about one in four patients who had a suspected stroke recovered within 24 hours, and one in six averted a stroke with no demonstrable trace of brain injury on magnetic resonance imaging (MRI).

For patients treated by an MSU, the time from symptom onset to treatment was 37 minutes faster versus EMS care, meaning many more patients received “vital” IV-tPA within the “crucial” first hour, according to the researchers. MSU care—which expedites thrombolysis administration—further increased the odds of averting a stroke, with nearly one third of patients recovering to normal within 24 hours. In addition, the researchers found other factors that contributed to better patient outcomes, including treatment within the first 45 minutes, younger age, female gender, history of high cholesterol, lower blood pressure, lower stroke severity, and no blockage of

Tenecteplase shown to be noninferior to alteplase in suitable ischaemic stroke patients The ATTEST-2 trial has found that tenecteplase was non-inferior to alteplase, the more established of the two thrombolytic agents, in suitable acute ischaemic stroke patients. Preliminary results from the study were presented by principal investigator Keith Muir (University of Glasgow, UK) at the 15th World Stroke Congress (WSC; 10–12 October, Toronto, Canada).

“T

his result adds to the growing evidence that tenecteplase should be a first-line thrombolytic agent for the treatment of suitable acute ischaemic stroke patients, and has significant advantages over current treatment in its ease of use,” Muir stated.

ATTEST-2—a large, prospective, multicentre randomised controlled trial funded by the British Heart Foundation and UK Stroke Association—sought to compare alteplase and tenecteplase in patients eligible for intravenous thrombolysis (IVT), within current guidelines (<4.5 hours after onset; no upper age limit), based on non-contrast computed tomography (CT) imaging.

Muir and colleagues conducted the study across 40 UK hospitals, randomising a total of 1,858 acute ischaemic stroke patients to receive either a standard dose of alteplase (0.9mg/kg) as a bolus followed by an infusion, or a bolus dose of tenecteplase (0.25mg/kg).

As per the trial’s primary endpoint, tenecteplase was deemed to have

achieved non-inferiority versus alteplase in terms of modified Rankin scale (mRS) score distribution at 90 days. Muir reported a trend favouring tenecteplase over alteplase for all mRS scores except zero, with an adjusted common odds ratio of 1.07 also supporting the novel drug. However, he added, tenecteplase did not fulfil the prespecified statistical criteria to demonstrate superiority over its more established counterpart.

ATTEST-2 further revealed—as per one of its secondary endpoints—that there was a greater proportion of patients who achieved an excellent functional outcome (mRS 0–1) after receiving tenecteplase, with an absolute difference of 1% versus alteplase. An odds ratio of 1.05 here once again constituted statistically significant noninferiority but not superiority versus alteplase. In addition, the number of patients achieving a good functional outcome (mRS 0–2) indicated a benefit with tenecteplase over alteplase, with investigators finding an absolute

large blood vessels.

According to Navi, this study highlights the need for optimising stroke systems of care, and further expediting the delivery of IV-tPA through MSUs should be “a priority” to increase the proportion of averted strokes. Navi is also hoping that Medicare in the USA will assign MSU services a billing code in the near future so that it can be embedded within stroke systems of care and become a financially viable model. He is currently working with researchers from UTHealth Houston on a study to evaluate the cost effectiveness of MSUs, which is expected to be published in 2024.

“Such studies will hopefully lead to a shift in regulations and reimbursements, and how MSUs are led, managed and integrated within emergency medical services,” Navi added.

Co-principal investigators for BEST-MSU—the prospective study that produced the data for this secondary analysis—were James Grotta (Memorial Hermann-Texas Medical Center, Houston, USA), director of the Mobile Stroke Unit Consortium, and Jose-Miguel Yamal (UTHealth Houston School of Public Health, Houston, USA), while John Volpi (Houston Methodist, Houston, USA) also contributed to these efforts.

The brain can only sustain reduced blood flow for so long before permanent injury develops.”

difference of 3.4%. However, they did not undertake non-inferiority for this endpoint, and this was not identified as a statistically superior discrepancy.

The ATTEST-2 researchers found that the rate of early neurological recovery, as per the National Institutes of Health stroke scale (NIHSS), and overall safety did not differ significantly between the two groups. Muir reported a small reduction in mortality rates with tenecteplase, but stated that there were marginally increased intracranial and extracranial haemorrhage rates in this group as well.

At WSC 2023, Muir noted that this and several other IVT studies have now hinted at an improved level of efficacy with tenecteplase, but also said these findings should be considered with caution, having been derived from trials with various key differences between them. A more thorough and properly adjusted meta-analysis of patient data from multiple studies

he added.

Earlier this year, findings from the North American TIMELESS study provided encouragement on tenecteplase’s safety but failed to demonstrate substantial efficacy versus a placebo. However, TIMELESS involved a distinct patient population treated in a significantly later time window compared to ATTEST-2.

Over the past few years, other trials have seen similarly mixed results. AcT (Canada) and TRACE II (China) aimed for non-inferiority, and were able to achieve this. NOR-TEST (Norway) tested a notably higher dose of tenecteplase and failed to demonstrate superiority compared to alteplase.

EXTEND-IA TNK (Australia and New Zealand) indicated superior outcomes regarding its primary endpoint of early recanalisation but no significant differences in terms of clinical endpoints. In addition, results from the global TWIST trial—also published in 2023— showed a trend towards benefit with tenecteplase in wake-up stroke patients but was stopped prematurely due to an underpowered analysis, while more granular research from EXTEND-IA TNK Part 2 and NOR-TEST 2 has suggested a higher dosage of the drug (0.4mg/kg) carries no benefits and may even be harmful.

mRS 0–1:

Absolute difference of

Tenecteplase versus alteplase

1%

mRS 0–2:

Absolute difference of comparing tenecteplase and alteplase in acute ischaemic stroke is currently on the horizon,

3.4%

Issue 52 | December 2023

SVIN Highlights

New SOFAST data show high technical success and first-pass rates with Sofia aspiration catheter Fresh data from the SOFAST study have indicated high rates of technical success and first-pass reperfusion with the Sofia 6Fr Flow Plus aspiration catheter (Microvention/Terumo), indicating that the device is both safe and effective in large vessel occlusion (LVO) acute ischaemic stroke patients.

I

n his presentation of SOFAST’s results at the Society of Vascular and Interventional Neurology (SVIN) annual meeting (16–18 November 2023, Miami, USA), Dheeraj Gandhi (University of Maryland School of Medicine, Baltimore, USA) initially reported that Sofia is a “very atraumatic and flexible” aspiration catheter technology that allows operators to safely navigate through tortuous anatomies “with ease”.

The prospective, multicentre, single-arm, observational, post-market SOFAST study attempted to evaluate the device further as a first-line treatment option in suitable LVO stroke patients, with a total of 108 participants being enrolled across 13 global sites.

“When we look at first-line aspiration treatment with the Sofia catheter alone [in SOFAST], a remarkable 87% of patients had mTICI [modified thrombolysis in cerebral infarction] ≥2b revascularisation status at the end of

the procedure, 79.6% had mTICI ≥2c, and 52.8% had an mTICI score of 3,” Gandhi reported, outlining the findings of the study’s primary effectiveness endpoint. “And, just looking at firstpass rates with the Sofia catheter alone, 70.4% of patients had a first-pass effect [mTICI ≥2c], and 75% had a modified first-pass effect—meaning an mTICI score of 2b or better.”

The speaker went on to relay that, at the end of all the procedures in the study—including following the use of adjunctive devices—97.2% achieved an outcome of mTICI ≥2b, 85.2% achieved mTICI ≥2c, and 55.6% achieved mTICI 3.

Another finding Gandhi highlighted was that, across the whole study, the majority of all patients who achieved mTICI 3 did so following a single pass with the Sofia catheter alone (50.9%).

In addition, this iteration of the Sofia catheter “remarkably” demonstrated a 0% rate of embolisation to new

territories (ENT)—a secondary that these results indicate the Sofia 6Fr outcome measure that compares “very Flow Plus catheter is a safe and effective favourably” with previously published approach to aspiration thrombectomy study data. in patients with acute ischaemic stroke Regarding clinical outcomes, secondary to an LVO, the speaker Gandhi reported that concluded by noting that roughly two thirds the device was associated (66.7%) of patients with particularly short experienced a good median times for both clot functional outcome, engagement (12 minutes) achieving a score of 2 and recanalisation (17 or less on the modified minutes).

Rankin scale (mRS) A discussion directly at 90 days. There following Gandhi’s were also no major presentation at SVIN safety concerns, he saw session moderator Dheeraj Gandhi continued, with 9.3% Pascal Jabbour (Thomas presenting at SVIN 2023 of cases demonstrating Jefferson University variable degrees of vasospasm— Hospital, Philadelphia, USA) note that none of which were symptomatic or the findings of this study suggest that required treatment—as well as 90-day the latest, most expensive technologies mortality and symptomatic intracranial are “not always the answer”, as the Sofia haemorrhage (sICH) rates of 7.4% catheter has been around for 10 years and 0.9%, respectively. but is still producing leading outcomes In addition to reemphasising the fact in the neurointerventional space.

When we look at first-line aspiration treatment with the Sofia catheter alone [in SOFAST], a remarkable 87% of patients had mTICI ≥2b revascularisation status at the end of the procedure, 79.6% had mTICI ≥2c, and 52.8% had an mTICI score of 3.”

Tenecteplase deemed a safe and feasible adjunct to thrombectomy in ALLY pilot study Intra-arterial tenecteplase has demonstrated potential as a safe and feasible adjunct to mechanical thrombectomy in patients with acute ischaemic stroke caused by a distal large vessel occlusion (LVO) who achieve “successful but incomplete” reperfusion, as per findings from the ALLY pilot study.

PRESENTING THESE RESULTS AT THE Society of Vascular and Interventional Neurology (SVIN) annual meeting (16–18 November 2023, Miami, USA), Fazal Zaidi (University of Toledo/ Promedica Toledo Hospital, Toledo, USA) revealed that tenecteplase was not associated with any major complications, and that there was evidence of the thrombolytic drug being linked to improved distal perfusion on angiographic images.

Zaidi also noted that ALLY is the first US study to have investigated intra-arterial tenecteplase in patients with residual, distal LVOs who achieved final reperfusion scores of 2b or 2c on the thrombolysis in cerebral infarction (TICI) scale post-thrombectomy.

ALLY—a prospective, single-centre, single-arm pilot study—enrolled adult patients aged 18–85 years with anterior-circulation LVO occlusions in their internal carotid artery (ICA)/middle cerebral artery (MCA) and a premorbid modified Rankin scale (mRS) score of ≤3. According to Zaidi, all enrolled patients received at least one 1.5mg bolus dose of tenecteplase, with additional treatments—up to a maximum of 4.5mg—being administered at the operator’s discretion.

5

Angiographic runs were obtained before and after the final treatment, with all patients having magnetic resonance (MR) or computed tomography (CT) imaging follow-up after 24 hours of treatment. In addition, clinical assessments were made using mRS and National Institutes of Health stroke scale (NIHSS) scores.

Clinical outcomes with tenecteplase

Zaidi relayed that, from a total population of 20 patients who initially achieved TICI 2b or 2c following a thrombectomy, two (10%) reached TICI 3 reperfusion—but, despite this, there was no change in the average Fazal Zaidi final reperfusion score across the whole cohort. And, compared to age matched control group, the ALLY study indicated improved 90-day clinical outcomes with tenecteplase, as shown by a 50% rate of mRS 0–2 and a 60% rate of mRS 0–3 (versus roughly 40% and 50%, respectively, with controls).

At SVIN, Zaidi concluded that—based on these mRS scores and the fact the drug was not associated with any major complications—ALLY showed tenecteplase (1.5–4.5mg) to be a safe adjunct to thrombectomy in the setting of TICI 2b/c reperfusion, adding that future randomised studies will be required to assess tenecteplase’s efficacy in these patients.

50% rate of mRS 0–2

60% rate of mRS 0–3

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December 2023 | Issue 52

Advertorial

THIS ADVERTORIAL IS SPONSORED BY MEDTRONIC

INSPIRE-S registry offers comprehensive, real-world data on acute ischaemic stroke devices As part of the company’s ongoing commitment to offering physicians access to highquality clinical data and, subsequently, enabling evidence-based practice to flourish, Medtronic has established a global registry—dubbed ‘INSPIRE-S’—producing realworld findings relating to the treatment of acute ischaemic stroke patients. Sitting down with NeuroNews, Marc Ribó (Vall d’Hebron University Hospital, Barcelona, Spain), who is part of the INSPIRE-S steering committee, outlines what he feels are the key benefits held by a large registry of this kind.

“T

he strength of the INSPIRE-S whose pre-stroke mRS score was either ≥3 registry is that it captures or “unavailable”, the rate of good functional safety and efficacy [data] in outcomes rose to 55.4%. real-life practice, and across all types of As per several other prespecified hospitals—bigger and smaller hospitals, endpoints of this analysis, the presenter and high- and low-volume centres, in further highlighted a 91.6% overall rate different countries around Europe, South of successful revascularisation (expanded Marc Ribó America and Asia,” he says, averring that, thrombolysis in cerebral infarction [eTICI] as such, the investigators may also be able to identify ≥2b50); a first-pass effect (eTICI≥2c) rate of 47.5%; discrepancies between different regions and centres. and symptomatic intracranial haemorrhage (sICH) Having predominantly enrolled stroke patients and clinical events classification (CEC) across more than 30 hospitals in Europe to date, -adjudicated neurological death rates of 0.8%, and including in Belgium, Finland, France, Germany, 6.6%, respectively.

Greece, Poland, Portugal, Spain, Switzerland and the UK, INSPIRE-S has more recently expanded into Argentina, as well as Hong Kong and Israel, with an additional cohort currently being enrolled in China too.

In INSPIRE-S, data are being collected on two key product families from Medtronic’s ReactTM catheter neurovascular portfolio: the company’s SolitaireTM revascularisation devices, SolitaireTM X and its ReactTM catheters, both of which revascularisation device are widely used in the treatment of acute ischaemic stroke patients. According to © 2024, November Medtronic, Inc. REPRINTED WITH PERMISSION-ALL RIGHTS RESERVED Ribó, these technologies are being evaluated as “standalone” mechanical thrombectomy solutions, but also in combination, whereby a stent In discussion with NeuroNews, Ribó notes that the retriever and an aspiration catheter registry’s combination therapy cohort was the first are deployed simultaneously to maximise the part of INSPIRE-S to meet its enrolment target, with likelihood of procedural success being achieved final data from the stent retriever- and aspirationin the lowest possible number of attempts. only groups set to feature in future presentations and publications. He goes on to state that both of these Clinical and technical outcomes remaining registry arms are “filling up”, and that Earlier this year, at the LINNC Paris Course (5–7 June the hope is for these analyses to be completed and 2023, Paris, France), Ribó delivered the most recent available in 2024. major update from INSPIRE-S, initially reporting that more than 800 acute ischaemic stroke patients have Complementing randomised trials been enrolled in this prospective, global registry to “The INSPIRE-S registry is a way [for us] to collect date. The presenter relayed findings from an interim data on the safety and efficacy of Medtronic’s products analysis solely focused on one of the registry’s three for acute ischaemic stroke from real-world, standard, patient cohorts—the combination therapy group, in daily clinical practice,” Ribó says. “Generally, we which eligible patients were treated with Solitaire have [published] data available about the performance alongside React, or another market-approved of devices in clinical studies—and this has high value, aspiration catheter device. but is also performed under certain conditions that are Ribó highlighted the fact that Solitaire was used not [reflective of] daily practice.” specifically in combination with React in the vast According to Ribó, while controlled trials often majority of cases (68/71); a balloon guide catheter contribute to the initial regulatory approval of a (BGC) was used at the first pass in 32.9% of cases; and most of the patients in the combination therapy cohort (80.8%) presented with M1/M2 middle cerebral artery (MCA) occlusions.

Across 258 enrolled patients, the registry’s primary effectiveness measure of a good functional outcome (modified Rankin scale [mRS] 0–2 or return to pre-stroke mRS) at 90 days post-intervention was achieved in 51.8% of the patients who received combination therapy and for whom site-reported data were available at three months. Ribó also highlighted the fact that, following the exclusion of 32 patients

The strength of the INSPIRE-S registry is that it captures safety and efficacy [data] in reallife practice, and across all types of hospitals.”

device, their restrictive nature means that their data and the outcomes they produce may not be the same as those seen in a real-world clinical setting.

“This is why these registries are complementary to the information that we get from clinical studies,” he continues, “and they are able to be expanded to a wide number of centres—some of which may not be as used to participating in clinical trials—and we can also see the effect in a [patient] population that is not strictly the same as the one fulfilling the inclusion/ exclusion criteria of a clinical trial.

“Anybody who receives treatment with these devices is registered, or at least should be registered, in INSPIRE-S, and in the end we collect a different kind of information that is hopefully similar to—or sometimes even better than—the results obtained in clinical studies.”

Here, Ribó alludes to what is likely to be considered as the main potential limitation to these types of registries: the fact that individual participating centres and investigators can be selective over which patients they ultimately include in the data they submit for core-lab adjudication.

“It is important that they report all the patients treated, and do not just cherry pick those in which the outcome was good,” he adds. “This is a potential bias, which is difficult to avoid—investigators might, in some cases, be reluctant to report cases in which the outcomes were not so good. And that does not happen in clinical trials, because you include the patient before they are treated and, independent of the outcome, they are going to be in the trial.”

Ribó notes that what can be done, and what is being done by those leading INSPIRE-S, is to speak to the participating centres and impress upon them the importance of reporting their data “fairly”, rather than being tempted to exclude any cases with poorer outcomes, “for the sake of the registry”. He goes on to claim that, “otherwise, the information is useless—if you only report the ‘good’ patients, the registry is not worth doing”.

Future directions

“Of course, for Medtronic, these are great results— they have shown a recanalisation rate over 90% with basically no safety concerns,” Ribó adds, drawing the conversation to a close.

“But, the results will also be able to give us tips regarding some secondary questions. Is it better to do a manual aspiration or use a pump? It seems [based on INSPIRE-S] that it does not matter. Is it better to use React 71 or 68, according to the location of the occlusion? For proximal occlusions, it seems that it is always better to maximise the diameter of the catheter. Is [combination therapy] effective regardless of the aetiology of the stroke; cardioembolic or atherosclerotic? This does appear to be the case.”

Based on these indications, Ribó notes that it is “reassuring” to see that the efficacy of revascularisation with a combined approach remains consistent across different stroke aetiologies, times from symptom onset, and clot locations. He also states that—owing to the granularity of the data collected within INSPIRE-S—these questions and many others, from the impact of stent-retriever size on recanalisation, to the efficacy of introducing a BGC alongside this combined approach, can now be investigated further.

“So, that is another strength of this registry: it is a very comprehensive registry that captures many details of the procedure and, from there, you can do many, many detailed analyses,” Ribó summarises. “We cannot do a clinical trial for each of these little niches, so the only way—and it is a very good way—is a registry.”

DISCLAIMERS:

Solitaire™ is a trademark of Medtronic, Inc. React™ is a trademark of Medtronic, Inc.

Issue 52 | December 2023

Surgical Training

Remote teleproctoring helps neurointerventionists overcome wartime restrictions in Ukraine Remote teleproctoring has demonstrated promising results in providing hands-on mechanical thrombectomy training and overcoming wartime migration restrictions in Ukraine, according to initial experiences published recently in the journal Interventional Neuroradiology.

“TELEPROCTORING BRINGS together specialists who are engaged in INR [interventional neuroradiology] all around the world and improves treatment outcomes globally,” Dmytro Shchehlov (National Academy of Medical Sciences [NAMS] of Ukraine, Kyiv, Ukraine), head of the AllUkrainian Association of Endovascular Neuroradiology, told NeuroNews.

“It is extremely relevant in Ukraine right now—not only because of wartime migration restrictions, but also considering [the country’s] lack of high-qualified and confident physicians able to perform INR procedures without senior mentors who can provide meaningful advice during complex cases, or for complication avoidance.”

Shchehlov—who co-authored the recent paper alongside Mykola Vyval (NAMS of Ukraine, Kyiv, Ukraine), Jens Fiehler, and Anna Kyselyova (both University Medical Center Hamburg-Eppendorf, Hamburg, Germany)—went on to note that, at present, a select few regional Ukrainian hospitals are equipped with remote telemedical facilities, but added that their number “continues to increase”.

“And teleproctoring should undoubtedly be used in more distant corners where specialists take their first steps in INR using new devices, or need to overcome some difficult situations,” he continued.

Setting the scene for their report in Interventional Neuroradiology, Shchehlov and colleagues initially note that “INR has not yet received official certification as a surgical subspecialty in Ukraine”, and that “consequently, there is uncertainty surrounding the availability of a neurosurgical internship and a structured INR training programme to provide neuroendovascular procedures”.

The authors go on to state that thrombectomy becoming the standard of care for large vessel occlusion (LVO) acute ischaemic stroke in recent years has further amplified the country’s need for INR specialists—which “far exceeds the current supply”. While INR facilities have been established in an attempt to address this, they lack highly skilled staff, according to Shchehlov et al. And, following the relaxation of COVID19-related migration restrictions, the Ukrainian medical system is now facing “new limitations” due to ongoing wartime conditions.

“In such circumstances, international cooperation becomes crucial to ensuring

attended the practical session and 141 joined online via Zoom. Prior to the telemedical session, mentors provided detailed lectures on thrombectomy techniques using aspiration with a stent retriever. The first part of the session was streamed live from Hamburg, where mentors demonstrated thrombectomy procedures on a flow model and engaged in detailed discussions, while the second part—conducted in Kyiv—consisted of a hands-on session during which eight participants performed thrombectomies under the supervision of mentors.

Following completion of the course,

Ukrainian neurointerventional mentees taking part in hands-on training

the safe and effective implementation of new technologies into routine medical practice,” the authors aver.

With this in mind, researchers at the NAMS of Ukraine’s Research and Practical Centre for Endovascular Neuroradiology in Kyiv set about integrating the remote, international teleproctoring of hands-on courses into their education protocols. Shchehlov and colleagues note that such approaches can serve as a “practical adjunct option, providing specialists with the latest scientific data and techniques”.

To establish a connection with the Department of Diagnostic and Interventional Neuroradiology in Hamburg—and provide a hands-on mechanical thrombectomy course to a total of 149 enrolled participants— Ukrainian physicians utilised the Tegus telemedical system (Tegus Medical).

“The Tegus system has been designed around interventionalists’ needs,” said co-author Fiehler, who also disclosed that that he owns stocks and shares in the company in question, speaking to NeuroNews. “It is robust and very intuitive to use. There are not many buttons but, in the background, what runs is a very high-resolution streaming technology with extremely low latency.

In this instance, we used the system for teaching and training purposes, which is much more relaxed than the stressful situations in which Tegus support is requested from trusted colleagues to help with first uses of devices, or in case of complications. It was sent to our Ukrainian colleagues who were able to put it together in just a few steps—a kind of ‘plug-and-play’ approach.”

Shchehlov and colleagues report that, of the 149 enrolled participants, eight

participants were asked to complete a survey regarding its effectiveness.

A total of 51 participants (34.2%) completed the survey, with 39 of these respondents (76.5%) being male and 29 (56.8%) being less than 40 years of age.

“It is noteworthy that all participants (100%) considered the practical neurointerventional course to be highly significant,” Shchehlov et al relay.

“Interestingly, prior to the course, only three participants (5.9%) expressed extreme confidence in mechanical thrombectomy, while 15 participants (29.4%) had no confidence in their abilities. A majority of the participants— specifically 38 individuals (74.5%)— expressed their intention to apply the acquired knowledge and skills in their daily practice, and reported being completely satisfied with the course.

Furthermore, an overwhelming majority of 49 participants (96.1%) expressed their willingness to recommend this training to others. We effectively incorporated teleproctoring into our practical training and discovered it to be a promising strategy, considering the future’s uncertainty and the existence of Ukrainian wartime migration restrictions. It may be possible to connect new professionals with seasoned mentors and beneficial firsthand experience through teleproctoring practical courses.”

In addition to reporting “promising results” in overcoming wartime restrictions with remote teleproctoring, the authors suggest that these approaches “can be applied in similar circumstances” as well.

“Access to a telemedical platform has given us the opportunity to conduct neurointerventional courses dedicated

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to the treatment of aneurysms, AVMs [arteriovenous malformations] and strokes in Ukraine. These first courses were extremely successful and received much positive feedback. I want to thank all involved—especially Prof Fiehler and Prof Hans Henkes [Klinikum Stuttgart, Stuttgart, Germany], who supported this initiative and helped in its implementation,” said Shchehlov, also noting that he and his colleagues plan to deploy the Tegus system further for new devices, educational courses and internal usage moving forward.

This positive outlook notwithstanding, the authors acknowledge the limitations they encountered during the teleproctoring course, including the diversity of manufactured devices with unique characteristics across different countries, which “can be confusing”.

Shchehlov and colleagues therefore advocate “advanced device preparation” and “the presence of more experienced colleagues alongside participants”, stating that the latter can help prevent potential mistakes from being overlooked while trainees are focusing on the crucial steps of a procedure.

“However, to the best of our knowledge, this is the first attempt to utilise teleproctoring for a remote hands-on course in INR,” the authors state, concluding their Interventional Neuroradiology report. “Despite the current limitations, we believe that international teleproctoring handson courses have a unique advantage: they break boundaries and provide the opportunity to learn from the best specialists worldwide, transcending the challenges posed by war, distance, and restrictions. INR is a lifelong journey that requires significant mental and physical effort, and every opportunity to enhance knowledge and skills should be fully utilised.”

Discussing key differences between remote teleproctoring and ‘the real thing’ with NeuroNews, Fiehler asserted that the former enables ad-hoc participation in emergency procedures, adding: “How else would you proctor [an acute] stroke case?”

“It is way more efficient too—you can join for the decisive 10 minutes of a procedure without wasting time watching the groin puncture,” he continued. “Another positive is that you can actually see better because you can zoom in from higher above—on both the hands and the monitors—and you can switch viewing angles in fractions of a second. The communication is surprisingly good as well. For many trainees, it is less intimidating to have the proctor ‘in your ear only’, and you can talk much more as a remote proctor because there is no risk of exposing your colleague in front of others. And, on a meta-level, remote proctoring is way more cost-efficient [and environmentally friendly] than travelling to proctor.

The major downside is missing out on red wine with your colleagues on the evening before the procedure—it will likely complement rather than replace the real thing but, in my mind, remote proctoring is here to stay and to grow.”

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December 2023 | Issue 52

Mechanical Thrombectomy

EVT with poor reperfusion linked to worse outcomes than medical management ENDOVASCULAR THERAPY (EVT) treatments that achieve poor reperfusion have been found to result in inferior clinical outcomes compared to best medical management (BMM) in large vessel occlusion (LVO) acute ischaemic stroke patients.

That is according to a substudy of the HERMES collaboration—a patient-level meta-analysis of seven randomised EVT trials: ESCAPE, EXTEND-IA, MR CLEAN, PISTE, REVASCAT, SWIFT PRIME, and THRACE. Writing in the Journal of NeuroInterventional Surgery (JNIS), Mayank Goyal (University of Calgary, Canada) and colleagues detail that

comparisons were drawn between the outcomes in LVO stroke patients undergoing EVT plus BMM (treatment arm) who experienced poor reperfusion— defined as a modified thrombolysis in cerebral infarction [mTICI] score of 0–1 on the final, core lab-adjudicated intracranial angiography run—and in patients treated with BMM only (control arm).

Specifically, the authors relay, baseline characteristics and functional outcomes (90-day modified Rankin scale [mRS] score) were compared between the two groups, with multivariable ordinal logistic regression being used to adjust for baseline variables.

From a pool of 1,764 HERMES patients, 972 were included in Goyal and colleagues’ analysis—893 in the control arm and 79 in the treatment arm with a final mTICI of 0–1. Interestingly, the researchers note, patients in the treatment arm demonstrated worse median mRS scores at 90 days compared with those in the control arm, as per an adjusted analysis (4 [interquartile range (IQR) 3–6] vs 4 [IQR 2–5]),

Is it time to consider a paradigm shift from mechanical thrombectomy to full reperfusion?

Adrien Guenego Point of View In light of recent evidence indicating that thrombectomies with poor reperfusion may lead to inferior clinical outcomes versus medical management in ischaemic stroke, Adrien Guenego (Brussels, Belgium) assesses the need for a “fundamental change” over decision-making and how success is measured.

B

ased on multiple eligibility criteria, international guidelines recommend mechanical thrombectomy as the standard of care for acute ischaemic stroke.

Since its introduction for anterior large vessel occlusion less than six hours after onset in 2015, indications and trials have expanded each year to large-core infarcts, late-time window strokes, and distal occlusions.

The techniques for mechanical thrombectomy have also evolved, with the development of specific devices such as large-bore catheters, mini-stent retrievers and distal aspiration catheters achieving successful reperfusion rates of over 70–80%, and a strong emphasis on improving the first-pass effect.

However, are we paying enough attention to the angiographic and tissue perfusion outcomes after mechanical thrombectomy? Is it sufficient to merely attempt recanalisation of an occluded vessel?

A fundamental change in how we approach and assess this procedure would represent a paradigm shift in mechanical thrombectomy for acute ischaemic stroke.

Recent history

The focus of previous randomised controlled trials (RCTs) was primarily on whether to perform a thrombectomy, and determining the correct indications for its application. In the 2016 HERMES meta-analysis, 71% of patients assigned to thrombectomy achieved successful reperfusion (modified thrombolysis in cerebral infarction [mTICI] score 2b or 3), meaning that, in 29% of cases, neurointerventionists experienced poor angiographic success and had to discontinue the treatment.1 In the early years of thrombectomy, the prevailing paradigm was to offer mechanical thrombectomy to selected patients and not necessarily to achieve full reperfusion at all costs.

Indeed, the traditional approach since 2015 has primarily been to evaluate the appropriateness of attempting thrombectomy based on factors such as time elapsed since stroke onset, clot location, and the patient’s overall health.

This involved making multiple passes to achieve a successful recanalisation (mTICI 2b or higher) while minimising potential complications—how many times have we heard or said,

with an adjusted common odds ratio (OR) of 0.59.

Regarding safety-related outcomes, Goyal and colleagues relay that the rate of symptomatic intracranial haemorrhage (ICH) was not significantly different between the treatment arm (3.9%) and the control arm (3.5%; adjusted OR 0.94).

The authors’ concluding message in JNIS is that the results of this HERMES substudy “emphasise the need for additional efforts to further improve technical EVT success rates”.

Median 90-day mRS scores

“thrombectomy failure after ‘X’ number of attempts”? Achieving 100% complete reperfusion for all patients is, of course, an unattainable goal, as in any absolute position, and one should exercise caution when reviewing scientific manuscripts or commercial claims purporting such efficacy.

Yet, after eight years of increasing experience in mechanical thrombectomy, we still face uncertainties for 20–30% of our patients when complete recanalisation is not immediately achieved. Should we shift our focus not only to performing thrombectomy but also ensuring complete reperfusion for (nearly) each patient undergoing endovascular treatment? This transformation would significantly impact patient selection, the approach to endovascular treatment, and the evaluation of its effectiveness.

Switching gears

As scientific and clinical experience has advanced, there is mounting evidence that merely attempting a thrombectomy and achieving what we term a successful recanalisation (mTICI 2b or higher) may not be sufficient, and a failed attempt at recanalisation may even be harmful for the patient. A potential paradigm shift in light of this is driven by several factors: Reperfusion may extend beyond reopening the proximal blood vessel to salvaging at-risk brain tissue and distal small vessels Complete reperfusion is associated with better functional outcomes for stroke patients The composition (nature) of the clot can impact the quality of reperfusion Advances in imaging techniques, such as perfusion imaging and collateral assessment, enable clinicians to better assess the extent of ischaemic damage, and make informed decisions regarding thrombectomy and reperfusion strategies.

This shift toward complete reperfusion has driven more individualised treatment strategies, and sparked research and innovation in the field. These innovations include bail-out stenting in case of stent-retriever or aspiration

4 IQR 3–6

4 IQR 2–5

EVT + BMM with poor reperfusion

BMM only

failure; intra-arterial or intravenous lysis after mechanical thrombectomy; thrombectomy for secondary occlusions in distal vessels after a proximal endovascular treatment, and the use of neuroprotective medications. While most of these strategies lack Level 1 evidence, they are under evaluation in prospective and retrospective trials. And, as Mayank Goyal (Calgary, Canada) and colleagues recently highlighted in a HERMES substudy—in case of acute ischaemic stroke with large vessel occlusion—endovascular treatment with poor reperfusion is inferior to medical management, but medical management is inferior to endovascular treatment with complete reperfusion.2 In summary, the shift from merely attempting a mechanical thrombectomy to striving for complete reperfusion necessitates a more patient-centred approach. This involves leveraging the full array of tools available to neurointerventionists to minimise the group of patients undergoing endovascular treatment who experience poor reperfusion. Patient selection, clinical judgment, and a careful evaluation of the treatment’s risks and benefits, remain crucial.

Every neurointerventionist should ask themselves: where should we “draw the line” in terms of reperfusion outcomes?

Is TICI 2b sufficient? And, which factors influence my decision-making process before performing a thrombectomy?

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

Endovascular thrombectomy after largevessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016; 387(10029): 1723–31.

2. R ex N, Ospel J M, Brown S B et al.

Endovascular therapy in acute ischemic stroke with poor reperfusion is associated with worse outcomes compared with best medical management: a HERMES substudy.

J Neurointerv Surg. 2023. doi: 10.1136/jnis2023-020411.

Adrien Guenego is an interventional and diagnostic neuroradiologist at the Université libre de Bruxelles’ Hôpital Erasme in Brussels, Belgium.

The author declared no relevant disclosures.

Issue 52 | December 2023

Mechanical Thrombectomy

US registry study reveals 75% of acute stroke patients wait more than two hours for CSC transfer A new study led by researchers from the University of Chicago Medicine (Chicago, USA) has revealed that nearly 75% of acute stroke patients wait more than two hours to be transferred to a comprehensive stroke centre (CSC)—a treatment delay that creates an increased risk of long-term disability.

“I

n neurology, we often say that ‘time is brain’,” said Shyam Prabhakaran (University of Chicago, USA), senior author on the study, which has been published in the Journal of the American Medical Association. “For every 15 minutes that pass without treatment, prior research shows there is a steady decrease in the chances of good outcomes for stroke patients. Getting to the right hospital quickly can be lifesaving.”

Analysing recent data from over 100,000 patients at 1,925 hospitals across the USA, the researchers found that the median time between initial arrival and departure for transfer— known as door-in-door-out (DIDO)

time—was 174 minutes, with almost three in four patients waiting longer than the recommended maximum of 120 minutes.

The researchers also note that these intervals do not include the subsequent transport time between hospitals, meaning that it can be three hours or more before a patient receives critical interventions to treat their stroke, such as a mechanical thrombectomy procedure.

Furthermore, the data revealed that patients who were elderly, Hispanic, Black or female were more likely to have high DIDO times than their respective counterparts. Although many factors, such as variations in disease

presentation, could contribute to these differences, Prabhakaran stated that the results should nevertheless prompt greater focus on health equity when it comes to stroke care.

“Our findings expose disparities that should not exist,” he said. “If you are having a stroke, it does not matter if you are a man or a woman, or Black or white—you should be able to get the same care.”

In addition, Prabhakaran urged healthcare providers and policymakers alike to be vigilant against and combat systemic biases that exist in healthcare.

However, he also emphasised that DIDO times are too high across the board, and that healthcare systems and patients should work together to bring them down. The data published recently by him and his colleagues uncovered multiple factors that lowered DIDO times. When emergency medical

Our findings expose disparities that should not exist.”

‘Minimal differences’ in clinical outcomes between stroke thrombectomy with or without thrombolysis, meta-analysis signals There are likely to be minimal differences in clinical outcomes between acute stroke patients presenting directly to endovascular treatment centres who undergo mechanical thrombectomy alone, and those who receive intravenous thrombolysis (IVT) plus thrombectomy. That is according to a meta-analysis examining six randomised controlled trials (RCTs) and more than 2,300 patients, published in The Lancet, which ultimately could not establish non-inferiority of thrombectomy alone in these patients.

OUTLINING THE LATEST DATA FROM the Improving Reperfusion strategies in Ischemic Stroke (IRIS) collaboration, Charles Majoie, Yvo Roos (both Amsterdam University Medical Centers [UMC], Amsterdam, The Netherlands) et al initially note that IVT is recommended before endovascular thrombectomy treatment, but its value “has been questioned” in patients who are admitted directly to centres capable of both treatments.

“Existing RCTs have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive,” they add—also stating that the IRIS collaboration has been formed to assess the noninferiority of endovascular thrombectomy alone, as compared to IVT plus thrombectomy.

To this end, Majoie, Roos et al conducted a systematic review and individual participant data meta-analysis, searching PubMed and MEDLINE for relevant articles published from database inception to 9 March 2023. They ultimately identified six RCTs on the topic of interest—DIRECT-MT, DEVT, SKIP, MR CLEAN-NO IV, SWIFT DIRECT and DIRECTSAFE—with the respective authors of each agreeing to take part, and individual participant data from all the trials being provided and collated centrally.

The researchers’ primary outcome was the 90day modified Rankin scale (mRS) score, they detail.

Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0.82 for the

95% confidence interval (CI) around the adjusted common odds ratio (OR) for a shift towards improved functional independence outcomes with ordinal regression.

The researchers report using mixed-effects models for all their analyses.

Charles Majoie The six RCTs deemed eligible for analysis provided data on 2,313 patients—1,153 of whom were randomly assigned to receive thrombectomy alone and 1,160 of whom were randomly assigned to receive IVT plus thrombectomy.

“The risk of bias of the included studies was low to Yvo Roos moderate,” Majoie, Roos et al relay. “Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution.”

The researchers found a median 90-day mRS score of 3 (interquartile range [IQR] 1–5) in the thrombectomy-only cohort of patients and 2 (IQR 1–4) in patients who received IVT plus thrombectomy, with an adjusted common OR of 0.89 (95% CI

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services (EMS) called ahead to notify medical centres that stroke patients were en route via ambulance, for example, median DIDO times were reduced by roughly 20 minutes.

“If you are a patient, one of the lessons from this is that calling 911 has immediate benefits, not only for stabilising you but for the downstream effects that it carries,” said Prabhakaran.

To follow up on this research, Prabhakaran et al are leading a National Institutes of Health (NIH)-funded study entitled, “Hospital implementation of a stroke protocol for emergency evaluation and disposition”—a multicentre, cluster randomised clinical trial to test interventions aimed at reducing DIDO times and improving functional outcomes in acute stroke patients requiring inter-hospital transfer.

Such studies are intended to identify best practices and determine the benefits of improving stroke systems of care in diverse geographic regions of the USA. “We have to think about ways to help smaller hospitals redesign the clinical pathways they use to evaluate and consider patients for transfer, and then expedite the procedures to make those transfers faster,” Prabhakaran added.

0.76–1.04). In addition, any intracranial haemorrhage (ICH) occurred less frequently with thrombectomy alone as compared to IVT plus thrombectomy (adjusted common OR 0.82, 95% CI 0.68–0.99), while symptomatic ICH and mortality rates did not differ significantly between the two patient cohorts.

After concluding that their study did not establish non-inferiority of thrombectomy alone versus IVT plus thrombectomy in patients presenting directly at endovascular treatment centres, Majoie, Roos et al deliver the following message: “Further research could focus on cost-effectiveness analysis, and on individualised decisions when patient characteristics, medication shortages or delays are expected to offset a potential benefit of administering IVT before endovascular treatment.”

As the researchers were unable to exclude the possibility that omitting IVT could lead to worse outcomes, further investigations are now planned—for example, via dedicated substudies—to explore the impact individual patient differences may have on the efficacy of thrombolysis.

“It is crucial to recognise that the actual benefit of additional IVT is likely to be small and may vary depending on factors, such as the time from stroke onset, in stroke patients admitted directly to endovascular treatment centres,” co-lead author Majoie is quoted as saying in an Amsterdam UMC press release. “It is imperative that IVT does not cause any delays, restrict access to, or take precedence over endovascular treatment, considering the limited and uncertain effect it has compared to the large impact of endovascular treatment itself.”

It is imperative that IVT does not cause any delays, restrict access to, or take precedence over endovascular treatment.”

December 2023 | Issue 52

10 Medical Device Regulation

“The tables have turned”— US FDA regulation is becoming the envy of Europe Discussions at this year’s European Society of Minimally Invasive Neurological Therapy (ESMINT) congress (4–6 September, Marseille, France) revealed the extent of the disparities between the current regulatory systems in Europe and the USA, with experts and attendees outlining how “the tables have turned” over the past few years, potentially enticing more neurovascular device manufacturers to seek US Food and Drug Administration (FDA) clearance as their first port of call.

E

SMINT past-president Christian Taschner (University of Freiburg, Freiburg, Germany) opened the session by disclosing the results from a survey of physicians working in the neurointerventional space. He noted that the “vast majority” of those who participated emphasised the significance of clinical evidence in their selection of new medical devices for endovascular procedures, and that—across three different scenarios presented to survey participants—prospective, multicentre registries and randomised controlled trials (RCTs) emerged as the preferred modalities for assessing new neurovascular devices.

Against this backdrop, two subsequent presentations examined certain components of the existing regulatory systems in the USA and Europe. Carlos Peña (The Jacobs Institute, Buffalo, USA) initially drew on his years of experience as former director for the Office of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health (CDRH), advising ESMINT attendees to engage the FDA at an early stage, and attempt to utilise the regulator’s pre-submission process as a means for guiding product development and application preparation.

“If your strategy does not include a pre-submission step, it is probably not a very good strategy,” he stated, also highlighting the fact it does not cost anything for companies to engage in this voluntary process, and briefly extoling the benefits of the FDA’s Early Feasibility Studies (EFS) programme in discussion with session moderator Adnan Siddiqui (University of Buffalo/The Jacobs Institute, Buffalo, USA).

Following this, Miguel Antunes of the European Medicines Agency (EMA)’s Experts Panels and Groups Office outlined the main roles of the medical device expert panels set up under the recently introduced Medical Device Regulation (MDR). As part of the scrutiny mechanism for certain high-risk medical devices, he explained, the panels’ advisors issue an opinion on the assessment performed by notified bodies regarding clinical evaluation of a Class III implantable device, or a Class IIb active device for the delivery or withdrawal of a medicinal product.

The expert panels also serve advisory functions to several stakeholders—namely the European Commission, European Union (EU) member states, and manufacturers. Regarding the latter, the EMA reports having started a project piloting the provision of advice to Class III medical device developers on their clinical development strategy or clinical investigation proposals, as of February 2023. Antunes went on to draw attention to the fact that, during this pilot, no user fees are required to be paid and that it would be possible to submit a letter of interest for the second phase of the pilot until 15 September 2023.

European challenges

Despite this indication of a certain level of consistency between the two regulatory systems in the USA and

Europe, discussions soon turned to the well-known setbacks observed following the introduction of the new MDR, and the challenges it has created for companies looking to gain clearance for their devices in the EU. After acknowledging that it may be a somewhat “provocative” comment, Christophe Cognard (Toulouse University Hospital, Toulouse, France) noted that, currently, the process of gaining US FDA clearance appears to be less complex and generally easier than securing European approval for a neurovascular device. This prompted Hendrik Lambert, chief medical officer at Spanish medical technology firm Anaconda Biomed, to claim that “this is not just a provocative comment—it is true”.

Speaking to NeuroNews following this ESMINT session, Lambert elaborated that “the problems the MDR has created are multiple, and the combination of those problems has an exponential [negative] effect on the CE-mark certification of existing and new products”.

Chief among these problems, he continued, is the fact that all existing products—more than 500,000 devices and in-vitro diagnostics (IVDs)—that had been approved under the previous Medical Device Directive (MDD) are now losing their CE-mark and need to be re-approved under the MDR, requiring new clinical data.

“As there is no grandfathering option, even products that have been on the market for decades need to be recertified, although they are clearly safe and effective,” Lambert said. “It is very hard for those manufacturers to collect new data on long-lasting, existing products.”

Another ongoing challenge he highlighted is the fact that, under the MDR, all of the notified bodies in Europe have lost their licence and need to be recertified “after a very excessive auditing process lead by a combination of competent authorities”.

“As a consequence,” Lambert asserted, “the number of notified bodies that are currently approved is one

third of the number it was before—from about 90 before MDR to slightly over 30 today. It is impossible to recertify such a high number of products with a strongly reduced number of notified bodies. The delays for certification are huge for both existing products and for new, unapproved products. For existing products, the original transition period was initially three years, but has now been extended several times to—currently—the end of 2027. For new products, a typical approval time is 1.5-to-two years.

In the USA, for a 510(k) [clearance], it is three-to-six months or less.”

Explaining the root of this discrepancy, Lambert noted that the MDR considers any product used in the proximity of the heart or brain to be a Class III device. Thus, these products require high amounts of documentation—even if they are “simple and inherently safe” devices like catheters or guidewires.

However, this is not the case in the USA, he added.

“Once the product is approved, there is an excess of documentation with clinical data required to be submitted periodically—mostly annually—for the full lifetime of the device,” he averred. “This is a very high burden for manufacturers, and a strong limitation on innovation. The MDR has created a lot of uncertainty around planning and the path to approval.

Uncertainty is the biggest enemy to investors and, hence, innovation.”

“The tables have turned”

Further ratifying Cognard’s earlier point, Lambert also affirmed that many global companies—even those based in Europe—are currently more likely to favour seeking US FDA approval as a first port of call versus attempting to navigate the European MDR. “The FDA has established powerful and transparent processes for EFS to stimulate innovation,” he stated. “Also, many products used in cardiology and neurointervention require a Class III certification process in Europe but can be cleared through a lighter 510(k) path in the USA. The road to approval in the USA is more predictable and, afterwards, it gives them access to a larger market compared to Europe.”

Weighing in on the discussion at ESMINT, session moderator Ajay Wakhloo, CEO and president of clinical-stage biotechnology firm Prometheus Therapeutics, offered yet another corroborating statement from a US perspective, noting that “we used to envy Europeans” when it came to medical device approvals. He also recalled having previously required compassionate use provisions—often referred to by the FDA as Expanded Access—in order to use CE-marked products to treat cancers, among other conditions.

“But, now, the tables have turned,” he continued.

“The FDA in the USA has very clear guidelines and it is very easy to speak in advance about submissions.”

Wakhloo further asserted that, “in the modern era,

The MDR has created a lot of uncertainty around planning and the path to approval. Uncertainty is the biggest enemy to investors and, hence, innovation.”

Hendrik Lambert

Issue 52 | December 2023 we should be able to create a dictionary where both bodies speak the same language”, before adding that “there must be a way to simplify this”. Subsequently, Antunes clarified that the EMA plays a “very different” and “more limited” role in the regulation of medical devices compared to the US FDA. In terms of premarket assessment of medical devices, notified bodies “would probably be the rough counterpart of the FDA” in Europe, he added, also noting that—because it is anticipated that manufacturers may seek scientific advice in both the USA and the EU—ongoing discussions are taking place regarding possible future points for regulatory alignment.

The session’s final presentation saw Bassil Akra, owner and CEO of global consultancy company AKRA TEAM, offer advice on how best to navigate a neurovascular device through the current European regulations. With the enduring challenges the EU MDR has raised in mind, he highlighted the benefits of ‘voluntary consultation’, whereby manufacturers can seek scientific insight from an expert panel for certain high-risk devices before undertaking performance evaluations and clinical studies.

A discussion following this presentation saw Akra agree with Antunes’ earlier point that notified bodies, rather than the EMA, are more comparable to the US FDA in Europe. Akra then built on this statement, encouraging the European Commission to empower notified bodies and make them even more like the FDA by ensuring they are involved in the early stages of regulatory pathways in order to make matters “clearer” for companies.

“It does not make sense,” he noted, “to have the EMA overseeing the final work of the clinicians at the notified body, but to have a single competent organisation or authority doing the assessment of the clinical and performance evaluations of devices— someone needs to be responsible!” And, commenting on the difficulties many manufacturers are currently encountering in Europe, he added: “I do not blame notified bodies—I blame the new system [MDR] and the expectations it brings.”

Akra also shone a spotlight on problems relating to the involvement of the designated authorities in member states who “bring a lot of inconsistency” to the implementation of EU requirements. “They create inconsistency on the EU level but also in their

Hendrik Lambert (far left) addresses Miguel Antunes in front of the ESMINT panel (left to right: Ajay Wakhloo, Adnan Siddiqui, Bassil Akra, Carlos Peña, Paolo Machi and Christian Taschner)

Medical Device Regulation

11

The European system is currently undergoing a big shift, which needs to be assessed with a focus on the implications for the EU healthcare system, and availability of medical devices and IVDs to healthcare professionals and patients.”

Bassil Akra

own member state by setting different expectations for the notified bodies depending on their size and establishment level,” he stated. “Too many cooks spoil the broth.”

A path forward?

Akra went on to posit that large-scale registries are likely to be of critical importance under the EU MDR moving forward—ideally, ones predicated on the same safety and performance criteria, in a standardised way, so as to establish a strong evidence base on the device in question. He pointed out that this would help in establishing a platform to support approvals and postmarket surveillance of devices intended for vulnerable and/or limited patient populations.

Wrapping up the session, Siddiqui noted that “there is a lot of weight placed on precedence” under US FDA regulation, whereby manufacturers can cite previous examples of similar device approvals to support their case as well as interact with the agency on differences of opinion around the data.

This led Akra to highlight another discrepancy between systems in Europe and the USA right now:

the fact there is no such process under the MDR. According to Akra, manufacturers can appeal to the European regulator as part of device classification disputes, but not when it comes to the actual regulatory, quality or clinical certification decisions on their product.

“You can appeal a decision made by a notified body,” he concluded, “but only to the same notified body—and they will already have formed their view. This is the problem created by a system having many contributors, including the EU Commission, designating authorities, [competent] authorities, notified bodies, and the EMA, but no full empowerment or responsibility for timely device availability on the EU market.”

Following ESMINT, Akra spoke to NeuroNews to offer the following advice to European device manufacturers: “They should read the MDR, request a pre-submission meeting with the notified body during which they inform them about their strategy, and get details regarding any administrative expectations that must be considered. Such a meeting is helpful to build relationships and understand expectations. They should not expect a pre-submission meeting like [those offered by] the US FDA, since notified bodies are not allowed to consult, but it is still important for building a relationship.”

And, when asked by NeuroNews to speculate on the short-term future of device regulation under the MDR, Lambert and Akra put forward somewhat differing perspectives.

“Unfortunately, no positive signs have been observed yet,” Lambert said. “I hope the European authorities will understand soon that a recertification of all existing products with a limited number of notified bodies cannot be sustained, and that certification of new products is a priority to ensure innovation in Europe. So far, we have not seen any sign from the authorities to put the MDR in question, or initiate a discussion with the related parties for modification or improvement.”

“The European system is currently undergoing a big shift, which needs to be assessed with a focus on the implications for the EU healthcare system, and availability of medical devices and IVDs to healthcare professionals and patients,” Akra added. “I personally believe that the system will balance again soon, since everyone knows that the intention of legislation is to ensure higher levels of safety and protection to the patient, by delivering effective devices. And overregulating might harm the patient and therefore [should] be avoided in the interest of a good, functioning healthcare system.”

December 2023 | Issue 52

12 Intracranial Aneurysms

Understanding brain aneurysms: Prevalence, burden, and empowering patients

Aruˉ nė Simanavičienė Audrius Širvinskas Point of View In a guest piece for NeuroNews, Arūnė Simanavičienė (Kaunas, Lithuania) and Audrius Širvinskas (Vilnius, Lithuania) highlight the work being done by the Brain Aneurysm Foundation in Lithuania, and its attempts to boost awareness of the finer details of intracranial aneurysm care among both patients and physicians.

B

rain aneurysms, though often silent, pose a significant health risk globally. These weakened bloodvessel bulges can lead to devastating consequences if they rupture.

Understanding the prevalence, health burden and impact on patients’ lives is crucial for informed decision-making and effective management. Equally important is the awareness from the patient’s perspective, ensuring they are well-informed about associated risks and the steps they can take to mitigate them.

Though not as common as some other medical conditions, brain aneurysms are more prevalent than one might think. According to recent studies, it is estimated that up to 5% of the global population could have an unruptured brain aneurysm. This figure may vary by region, with certain populations exhibiting a higher predisposition due to genetic factors, lifestyle, or other underlying health conditions. This prevalence underscores the importance of understanding and addressing this potentially life-threatening condition.

In addition, the health burden associated with brain aneurysms cannot be underestimated. An aneurysm rupture can lead to a haemorrhagic stroke, often resulting in severe neurological deficits or even death. Survivors of ruptured aneurysms may face long and arduous recoveries, sometimes requiring extensive rehabilitation and lifelong care. Additionally, the emotional toll on both patients and their families can be immense, as they grapple with the sudden and often unpredictable nature of this condition.

For those living with unruptured aneurysms, the impact is no less significant. The constant awareness of the lurking danger can lead to anxiety and stress, potentially affecting a person’s overall quality of life. The

fear of a rupture can permeate daily activities and decision-making, causing individuals to modify their lifestyles out of caution. This can lead to missed opportunities, strained relationships, and a reduced sense of wellbeing.

Awareness and management

Empowering patients with knowledge about brain aneurysms is crucial. Many individuals may not realise they are at risk or even have an aneurysm, as these conditions often remain asymptomatic until a rupture occurs. Understanding the risk factors, such as family history, smoking, high blood pressure, and certain genetic conditions, allows individuals to take proactive steps toward early detection and intervention.

Regular medical checkups play a pivotal role in managing brain aneurysms. Imaging studies, such as magnetic resonance imaging (MRI) or computed tomography (CT) scans, can help track the size and growth of an aneurysm over time. This information is invaluable in determining the appropriate course of action, whether it be surgical intervention or continued monitoring. Early detection and intervention significantly improve outcomes and reduce the risk of rupture.

Adopting a healthy lifestyle can also contribute to aneurysm management.

Controlling blood pressure, maintaining a balanced diet, staying physically active, and avoiding tobacco use, are essential steps in minimising the risk of an aneurysm’s growth or rupture.

Additionally, managing stress through techniques like meditation, yoga or counselling can be beneficial in reducing anxiety associated with an aneurysm diagnosis.

While awareness is crucial, it is equally important to dispel unfounded fears. Misinformation or poor

communication can lead some patients to live in constant fear of a rupture, even when the risk is minimal. Clear and honest communication between healthcare providers and patients is imperative in providing reassurance and dispelling unnecessary anxiety.

Patient experience

Jolanta, a knowledgeable and proactive woman, who works in the medical field, faced difficulty in identifying and treating her aneurysm. A former smoker, she switched to shisha and e-cigarettes after her daughter’s birth. In 2009, she experienced severe headaches, along with numbness, pain and odd noises on the left side of her head. Opting for an MRI over a tomogram, a young doctor noticed a suspicious spot suggesting an aneurysm. Dismissing it, Jolanta focused on her fear of a brain tumour.

Taking the MRI home, she stored it with other documents, never revisiting the potential aneurysm. After years of fruitless consultations, she halted her search. A decade later, stress at work and intimacy with her husband preceded the aneurysm’s rupture. Overwhelmed, Jolanta fainted, awakening to excruciating pain and nausea, and calling for help. Recalling her father’s fatal brain aneurysm at 50, she realised she was now the same age. Despite advising the paramedics to take her to a tomographist, Jolanta believes they should have prioritised the emergency room instead.

Brain Aneurysm Foundation in Lithuania

The Brain Aneurysm Foundation in Lithuania has demonstrated commendable efforts in raising awareness and providing crucial information on this critical health issue.

Through impactful campaigns in 2021 and 2022, we reached a wide audience through various platforms, including the public broadcaster Lithuanian National Radio and Television (LRT) and outdoor advertising channels. Our online campaigns have also seen substantial growth, engaging 466,000 people in 2021 and 554,000 in 2022. Impressively, more than 6,300 individuals have filled out an online risk assessment form (PHASE).

The foundation’s emphasis on personal stories has been particularly effective, fostering a sense of community and understanding among patients. Our patients’ Facebook group, with nearly 400 members, serves as a platform for sharing experiences. In 2023, the Brain Aneurysm Foundation in Lithuania played a pivotal role in publishing the inspirational memoir, The Optimist, by a brain aneurysm rupture survivor, further amplifying its advocacy.

Our foundation’s relentless dedication, in collaboration with partners and the courage of patients, has yielded tangible results. A recent survey indicates that 55% of Lithuanians now comprehend what a brain aneurysm entails, marking a notable 15% increase since 2020. Additionally, patients

are becoming more informed about treatment options, with 39% recognising both clipping and embolisation as viable methods, compared to 29% in 2020. This progress is a testament to the foundation’s unwavering commitment to enhancing public understanding and, ultimately, saving lives.

Minimising SAH

Subarachnoid haemorrhage (SAH) is a critical medical condition characterised by bleeding into the space surrounding the brain. While it can have devastating consequences, some measures can be taken to minimise the occurrence of SAH cases—and prioritising awareness and preventive measures is crucial.

Firstly, advocating for regular blood pressure screenings and management of hypertension is paramount, as elevated blood pressure is a significant risk factor. Additionally, promoting a healthy lifestyle, including a balanced diet and regular exercise, aids in maintaining vascular health. Discouraging tobacco use and excessive alcohol consumption further mitigates SAH risk. Encouraging early detection through routine checkups and prompt treatment of any neurological symptoms is vital. Finally, educating the public about familial predispositions and providing access to genetic counselling can facilitate early intervention in high-risk individuals.

In conclusion, understanding the prevalence, burden and impact of brain aneurysms is imperative for informed decision-making and effective patient management. The global prevalence of unruptured aneurysms highlights the need for heightened awareness and proactive measures. The health burden, both in terms of physical and emotional consequences, underscores the urgency of early detection and intervention.

Empowering patients with knowledge about risk factors, regular monitoring and potential lifestyle changes is pivotal in reducing the incidence of SAH cases.

The commendable efforts of organisations like the Brain Aneurysm Foundation in Lithuania serve as a beacon of hope, illustrating how awareness campaigns and personal narratives can significantly enhance public understanding and save lives.

Together, through education, advocacy, and proactive healthcare, we can make strides toward minimising the impact of brain aneurysms on individuals and their communities.

Arūnė Simanavičienė is a lecturer at Kauno Kolegija in Kaunas, Lithuania, and has been chief executive officer of the Brain Aneurysm Foundation in Lithuania (Smegenų aneurizmos fondas) since May 2021.

Audrius Širvinskas is head of the interventional neuroradiology department at Republican Vilnius University Hospital in Vilnius, Lithuania, and a co-founder and expert for the Brain Aneurysm Foundation in Lithuania The authors declared no relevant disclosures beyond their connections to the Brain Aneurysm Foundation in Lithuania.

Issue 52 | December 2023

Intracranial Aneurysms 13

Current intracranial aneurysm literature reflects “a failure of the peer-review process” A systematic review and meta-analysis of 1,356 studies and more than 410,000 patients have found that “methodological flaws and incomplete reporting” occur frequently in studies advocating the safety, effectiveness or durability of intracranial aneurysm treatments—forming a “potential public health hazard” for patients and, in the view of the authors, a “failure of the peer-review process”.

WRITING IN JAMA NETWORK OPEN, Victor Volovici (Erasmus University Medical Center, Rotterdam, The Netherlands) and colleagues initially highlight an “unprecedented rise” in medical device numbers across various specialties, before also averring that the history of medicine “is laden with examples in which the mechanistic logic that underpins the development of a device does not translate to better outcomes for patients and might, instead, be harmful”.

In addition, Volovici and colleagues note that they conducted the present review in light of “the ongoing discussion within the stroke community regarding the best treatment of intracranial aneurysms and proper patient selection”, as well as “the paucity of substantial, properly generalisable randomised evidence” on these treatments.

In an effort to critically evaluate published claims of safety, effectiveness and durability with intracranial aneurysm treatments, the authors searched Embase, MEDLINE, Web of Science, and The Cochrane Central Register of Clinical Trials, for relevant studies published between 1 January 1995 and 1 October 2022, also retrieving grey literature from Google Scholar.

Their key objective was to analyse for methods and completeness of reporting, and compare the results of studies with positive, uncertain and negative concluding messages.

“All studies making any kind of claims of safety, effectiveness or durability in the field of intracranial aneurysm treatment were included,” Volovici and colleagues state, also detailing that data extraction was performed by 10 independent reviewers; an academic neuro-linguist “without involvement in intracranial aneurysm research” evaluated the conclusion of each study as positive, uncertain, or negative; and that they followed Preferring reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.

Upon inclusion of 1,356 studies comprising a total of 410,993 treated patients—the majority of which involved endovascular interventions (79%)—Volovici and colleagues’ analysis revealed that:  There was no difference in the proportion of patients with a poor outcome or in-hospital mortality between studies claiming a technique was either safe, uncertain, or not safe  There was no difference in the proportion of intracranial aneurysms completely occluded at final follow-up between studies claiming a technique was effective, uncertain, or noneffective—and a similar trend was observed in terms of durability between studies with a positive, uncertain or negative conclusion  When limiting the results to studies on unruptured aneurysms, only the rate of in-hospital mortality was different between the studies with a positive and uncertain conclusion regarding safety  Fewer than 2% of studies provided any definition of safety, effectiveness or durability, and only one of the 1,356 studies provided a threshold under which the technique of interest would be considered unsafe  Incomplete reporting was found in 546 (40%) of the included studies, while “the conclusion in the abstract was more positive than the conclusion in the text” in 68 studies (5%)

 Ten of the 17 randomised controlled trial (RCT) reports included showed “a high risk of bias”, and all but one of these demonstrated “a high or concerning risk of bias in essential domains”.

“Proving safety and effectiveness of a new technique is important prior to the widespread implementation of such a technique in clinical practice, and its prerequisite is common sense: a new technique should be compared with the current standard of care,” Volovici and colleagues write, discussing these findings.

They go on to assert that, “ideally”, such comparisons should be done in a multicentre RCT with predefined timepoints; blinded, uniform assessment of clinically and radiologically relevant outcomes; and predefined analyses as well as predefined safety and effectiveness outcomes. The authors add, however, that “these desiderates are currently almost entirely absent in published studies”. Speaking to NeuroNews to clarify this point, Volovici said that, “of course, those studies are expensive and, more importantly—because we are already treating patients very well on average— the numbers needed to be enrolled to prove superiority are in the thousands”.

“Comparing a new technique with current practice in a prospective manner should be considered the bare minimum for any safety or effectiveness claim to be

Comparing a new technique with current practice in a prospective manner should be considered the bare minimum for any safety or effectiveness claim to be allowed in a report.” allowed in a report,” the authors continue. “Of course, safety may also be claimed when the incidence of complications is low—but, without a control group, one cannot infer whether the technique should be implemented in practice.”

The majority of papers included in the present review were single-group and retrospective in nature and, as Volovici and colleagues state, “single-group studies lack a critical benchmark, in that the results obtained cannot be reflected against the results of current standard clinical practice, which makes any claim of safety, effectiveness or durability weak, or unjustifiable”.

Touching on the US Food and Drug Administration’s (FDA) 510(k) clearance protocol, the authors add that, while this process accelerates innovation, “there is evidence to suggest that the […]

Victor process is less robust Volovici

and may lead to more recalls”, as compared to device approvals based on high-level evidence from clinical trials. They further claim that the scientific literature backing this process “may be methodologically less sound and sometimes even lacking”.

“A thorough, critical evaluation of the evidence used to back the FDA approval of these devices is necessary,” Volovici and colleagues state. “In our view, the current literature reflects a failure of the peer-review process. In a field with a very high level of technological advance, and with techniques that all carry a certain morbidity and mortality risk, reviewers and editors should be critical and hesitant to accept manuscripts with poor methods and reporting, and make sure that conclusions are supported by study results.”

Volovici and colleagues do acknowledge a number of limitations carried by their own review and analysis of the current literature—including missing study data, discrepancies between different medical definitions, and case-mix variability. However, they conclude by re-emphasising that methodological flaws and incomplete reporting occurred “often” across the studies they evaluated, adding that studies making unfounded claims about safety and effectiveness when they are not fit to do so “can hereby form a potential public health hazard” for intracranial aneurysm patients.

“The field of intracranial aneurysm treatment can be improved by applying proper methods and reporting, and performing comparative studies in which new technologies are compared with current best clinical practice,” the authors add.

Speaking to NeuroNews following the publication of these findings, Volovici tackled the “very important question” of whether or not it is realistic to expect that physicians and researchers in the aneurysm care space will, in future, make any significant strides to remedy something that appears to have become entrenched across several decades.

“For one, researchers need to better substantiate how and why they are doing these studies,” he said. “We treat these patients very well already, the results are very good, and we have good solutions for intracranial aneurysms—what is the incremental value, in terms of health economics, of a new device? And, conversely, is it at least as safe as best practice, and is it more effective; because the point of innovation is to fare better, right? If these issues cannot be addressed, and these desiderates demonstrated, then why is a new device necessary in the first place? Which health issues does it address?

“Secondly, peer reviewers and editors should be wary of accepting unedited conclusions claiming safety or effectiveness when studies cannot support these conclusions from a methodological perspective.

Lastly, durability is the ‘orphan child’ of the lot. How durable are these techniques? We have no clue, and durability may be most important of all—the point of the treatment is to prevent bleeding! Only about 140 of these studies deal with durability, and most studies have a maximum of 19 months’ follow-up.”

Concluding, Volovici also highlighted a notable pattern revealed by time series analyses assessing temporal trends in intracranial aneurysm research: safety results “have been improving over the years”, but effectiveness results have not, which he feels “should also cause concern”. Volovici further reported that regression analyses in this review “seem to suggest” that the quality of research has decreased, on average, following the advent of stent-assisted coiling, with more studies claiming safety and effectiveness on “poor methodological grounds” since the wider adoption of this technique in the early 2000s.

December 2023 | Issue 52

14 Advertorial THIS ADVERTORIAL IS SPONSORED BY MEDTRONIC

INSPIRE-A registry helps pave way for standardised assessment of flow-diverter imaging outcomes

As a prospective, independently adjudicated registry boasting a highly comprehensive patient dataset, INSPIRE-A is a “very unique” phenomenon in the field of endovascular aneurysm care—and one that may be able to provide answers for a number of research questions within this space. Jens Fiehler (University Medical Center HamburgEppendorf, Hamburg, Germany) recently sat down with NeuroNews to elaborate on the registry’s strengths and outline some of the data it has produced to date.

H

aving currently enrolled over 1,400 patients from more than 40 sites across many European countries, as well as China, Australia, Israel, South Africa, and the United Arab Emirates (UAE), INSPIRE-A is both high-volume and global in its nature.

Sponsored by Medtronic—and endorsed by the European Society of Minimally Invasive Neurological Therapy (ESMINT)—the registry is continuously monitoring results in intracranial aneurysm patients treated with Medtronic neurovascular medical devices. These include the Flex, Shield and Vantage flow diverters, all of which belong to the PipelineTM embolisation device family, as well as the Artisse intrasaccular system (all Medtronic).

Homing in on what makes INSPIRE-A such a potent tool for evaluating these devices, Fiehler highlights the fact that site data from the registry are monitored externally—information on safety outcomes is assessed by a clinical events committee, while efficacy is evaluated by an imaging core laboratory led by Fiehler himself in Hamburg.

“So, it is not self-adjudicated by multiple interventionists, but by external entities,” he states, “and I think that is very unique; it is a lot of effort, but it is worth the effort, because the data are much more precise [compared to with self-adjudication]. There is plenty of evidence in the literature on how nice interventionists are to themselves.”

Fiehler believes that last point is an important one; presenting initial findings from INSPIRE-A at the most recent LINNC Paris Course (5–7 June 2023, Paris, France), he drew attention to the potential influence of operator bias on clinical outcomes, and highlighted the fact that self-adjudicated aneurysm occlusion rates have been observed to be roughly 25% lower after undergoing centralised analyses at an external core laboratory.

The core laboratory being utilised within INSPIRE-A, known as Eppdata, is run by Fiehler and his colleagues, having been spun out of the University of Hamburg in 2015 with the primary purpose of producing analyses with the highest levels of accuracy and precision possible. Today, the laboratory receives imaging data from every continent—apart from Antarctica, Fiehler concedes—and more than 200 hospitals worldwide. He also notes that Eppdata and Medtronic joined forces several years ago in what has proved to be a “very fruitful” partnership.

A new standard?

The “beauty”, as Fiehler describes it, of processing such a wealth of imaging data in a “highly standardised fashion” at the same core laboratory— as seen in INSPIRE-A—is that it enables in-depth comparisons of different devices and their specific characteristics.

“When the new [Pipeline] Vantage came around, there were some observations suggesting that the braid was not completely stable—and Medtronic pushed us very hard to go through all of the Vantage cases again, look at the braid stability, and compare it with the Pipeline Shield and Pipeline Flex cases,”

he says. “Because we did everything in a standardised way, we were able to directly compare the [changes in braid structure], and we have actually come up with a new scale for braid deformations as a result.”

The scale Fiehler refers to here is part of a new white paper currently being worked on, and offers recommended radiological evaluation criteria for future trials assessing flow diverters in aneurysm therapy as well as a common terminology for industry.

According to Fiehler, they propose a standardised methodology for imaging outcomes, including how and when to report them. Braid structure-related changes termed fish-mouthing, foreshortening, braid-hump deformation, and braid collapse, form the basis for these new standards.

The key aim of these standards Jens Fiehler is to aid comparisons between different brands and generations of flow diverters, offering more universal analyses and potentially even informing device development further down the line. They boast “good inter-rater reliability”, Fiehler says, but are also “realistic” in how they are applied.

“The previous scores that we are all aware of are almost all on aneurysm occlusion, but nobody has really covered the stability of the braid—this just did not exist,” he continues. “So, it was a great effort by a group of interventionists who [performed] a metaanalysis of the literature on the subject, and this new scale has been used to assess all of the flow diverters in INSPIRE-A.”

Fish-mouthing and stenosis

Initially, Fiehler notes that the typical neurological endpoints of interest in aneurysm care—primarily death, stroke and disability status—were all “extremely similar” across the 425 patients treated with Pipeline Vantage, and a comparator group treated with Pipeline Shield, in INSPIRE-A. He relays a 0.7% rate of neurological death and a 1.4% rate of major stroke with Vantage, adding that there were no statistically significant differences between these and the equivalent figures within the Shield cohort.

[INSPIRE-A] is not self-adjudicated by the interventionists, but by external entities, and I think that is very unique; it is a lot of effort, but it is worth the effort, because the data are much more precise.”

When asked to outline some of the more intriguing talking points revealed by his team’s newly devised imaging scale, Fiehler states that—in line with the braid-stability observations mentioned earlier—a higher rate of distal fish-mouthing, whereby the focal end of the flow diverter converges to form a cone shape, was seen with Vantage as compared to both Shield and Flex. These observations were made among a cohort of 103 patients treated with Vantage for whom follow-up digital subtraction angiography (DSA) imaging data were available at one year.

However, he goes on to describe this as a “transient phenomenon”, as well as a moderate one, having only been detected in the first six months postimplantation, with Vantage braid structures returning to normal in approximately half of the cases after 12 months. As such, this observation was an “interesting, but not very alarming” one.

“And, it had no relation to clinical symptoms whatsoever,” Fiehler posits. “We observed it; it was clearly there and can be reproduced, but there was no increase in the rate of clinical events like stroke or haemorrhage.

And it is very reassuring that we did a secondary deep-dive into the data, and we saw something—it was definitely there, no question about that—but, at the same time, it has no clinical consequences, as far as we know.”

While Fiehler notes that, strictly speaking, “we cannot rule out” that fish-mouthing in flow diverters may cause clinical problems in certain instances, INSPIRE-A found that the overall number of complications remained the same with Vantage versus the other devices being assessed. If clinical consequences do exist, he says, they are “very subtle”, and were not visible throughout this “very large number of patients”.

“I really have to applaud Medtronic for pushing us to work hard to find something,” he continues.

“They wanted us to be very critical in terms of what we saw, and there was no attempt whatsoever to say, ‘okay, maybe it is not so bad’—nothing like that. If anything, it was the other way around, and it was really [positive] experience, to be honest.”

Other observations Fiehler highlights from INSPIRE-A include an improved complete aneurysm occlusion rate of 80.6% with Vantage compared to 74.7% with Shield. In addition, he points to an increased rate of 25–50% parent artery stenosis with the Vantage technology (8.7%), noting that this proved to be higher than those seen in patients treated with either Shield (5.4%) or Flex as part of the registry. However, he goes on to state that these stenosis rates—much like the distal fish-mouthing phenomenon—did not link to any clinical concerns, further averring that a great deal of variability in the rate of stenoses is not uncommon among newergeneration flow diverters available on the market.

“I think INSPIRE-A, and INSPIRE-S, are hugely valuable datasets, because they are very nicely curated by data managers and independent adjudicators,” Fiehler offers by way of a closing remark, also noting that such large repositories may even lend themselves to research involving artificial intelligence applications, and the training of machinelearning models, as well as pretreatment planning and more individualised treatment approaches, in the future.

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.

Issue 52 | December 2023

Flow Diverters 15

Study finds “eye-opening” variability across physician estimations of flow-diverter deployment A comparative study recently demonstrated the promise held by PreSize Neurovascular (Oxford Heartbeat) software in consistently and accurately making predictions about flow-diverter placement in intracranial aneurysm treatments. However, according to lead study author Ansaar Rai (West Virginia University Rockefeller Neuroscience Institute, Morgantown, USA), a potentially even more revealing aspect of this research was the discrepancy observed across a number of experienced physicians, and their attempts to estimate flow-diverter deployments manually.

“THE RESULTS SHOWED THAT there was significant variability amongst the physicians,” Rai tells NeuroNews.

“And, there was no difference between the degrees of experience—so, for a very experienced physician and a somewhat experienced physician, there was not much of a signal that the more experienced physician would do better.”

In a study now published in the Journal of NeuroInterventional Surgery (JNIS), eight experienced neurointerventionists were provided with volumetric data on a patient’s anatomy from their preoperative angiogram, alongside images annotated with the distal landing location of a deployed Surpass Evolve (Stryker) flow diverter, from 51 previously treated cases of unruptured internal carotid artery (ICA) aneurysms. The physicians were, however, blinded to “all other procedural details”. They were then asked to perform “a planning routine reflecting their normal practice”, and estimate the point at which the flow diverter’s proximal end would land.

According to Rai, while imaging technologies themselves have progressed significantly in recent times, methods for predicting flowdiverter implantations—including the “behaviour” of the device inside a patient’s vasculature—are currently “lagging behind”. He notes that neurointerventionists rely primarily on their experience, alongside any information provided by the vendor about the device in question, to make such predictions in a “very manual way” that is also “completely based on operator intuition”. Rai also highlights that the aneurysm not fully closing, insufficient coverage of lateral branches and poor wall apposition are among the various consequences stemming from imprecise flow-diverter deployment.

Each of these can lead to subsequent devices needing to be deployed as well as an increased risk of complications.

In their JNIS paper, Rai et al state that, while operator-dependent approaches are “intrinsically prone to errors”—and it has long been suspected that physician estimates vary in precision—such variability “has never been previously documented”.

They therefore set out to chart these estimations in a cohort of experienced neurointerventionists spanning the USA,

UK, Australia and Finland. And, across the same 51 historical cases, they also evaluated the predictive performance of PreSize—an artificial intelligence (AI)powered software providing real-time planning support, 3D reconstructions of patient-specific anatomies, and simulations of device deployments within a safe, virtual environment.

Predictions made using both of these approaches were subsequently compared with the postprocedural observed positioning and deployed stent length—put simply, “what actually happened”—in each case, according to Rai. Bland-Altman plots were used to make these comparisons, while accordance between predictions from each of the neurointerventionists was determined via intraclass correlation coefficients (ICCs).

Rai and colleagues’ salient finding is this: the mean accuracy of neurointerventionist-estimated flow-diverter length after deployment was 81.3% (±15%), with outliers as low as 7%, versus PreSize’s accuracy of 94.9% (±4%), with its lowest evaluated accuracy across the study sample being 84%. From this, they conclude that the software demonstrated a “significantly higher accuracy” in comparison with conventional sizing methods (p<0.001).

The Bland-Altman plots also showed that PreSize’s accuracy was better than the mean accuracy across the eight physicians in each and every one of the 51 cases included in the study.

As Rai notes in conversation with NeuroNews, much of the inaccuracy and case-by-case inconsistency associated with traditional sizing approaches was ultimately confirmed by this research.

There was no particular case that all the included neurointerventionists performed poorly on, nor an individual neurointerventionist who performed consistently better or worse than the rest of the group. Average accuracies achieved by the individual physicians ranged from 73.1–87.6%, and an ICC of 0.64 also indicated “poor-to-moderate interrater agreement” between their predictions. Furthermore, no discernible trends were found between accuracy and a number of vasculature/morphologyrelated factors, including aneurysm size, vessel diameter and tortuosity, indicating that physician predictions were similarly variable regardless of how theoretically

challenging the case was.

Rai has already presented these data at multiple scientific meetings, and reports that such wide variability— between individual physicians and specific cases alike—being laid out in a quantified manner has proved to be “even more eye-opening” than the superior performance of PreSize. While manual estimations were known to have suboptimal accuracy, such “extreme differences” still perhaps exceeded what many would have anticipated.

However, the second major aspect of Rai et al’s study can be seen to offer a more positive outlook. Their analyses revealed that PreSize was “significantly more consistent and quantitatively accurate” in predicting the deployed length and location of flow diverters.

This rang true whether the physicians and their estimations were considered as a composite group, or individually.

Rai says that variability with the technology was “much less broad” too. The mean absolute error between controls (real-world deployed lengths),

being used in several European centres.

Here, Rai also cites an anecdotal advantage of PreSize—the fact it is presented on a relatively simple and easy-to-use dashboard, and does not add a significant amount of time to the procedure. And, while the technology in its current form is something of an ‘add-on’, yet to be fully integrated into the established imaging systems many neurointerventionists use today, Rai believes progress is coming on this front too. Once deployed more widely and backed by an even greater wealth of evidence, he foresees this type of simulation technology being incorporated into existing workstations by major imaging vendors like Philips and Siemens Healthineers, and usage likely becoming “part and parcel” of flow-diverter procedures.

“I am positive that will happen—and I do not think it is even that far off,” Rai adds. “Once this happens, usage will increase, because you make it easier for the operator. Assessing the cerebrovascular anatomy, planning the procedure and selecting an implant [will be] no different dependent on the acuity of the case.

You do the same thing over and over, and it just becomes a part of the workflow every single time. It will be used universally, I have no doubts about that.”

PreSize Neurovascular platform

and the prediction methods used in the study, was 4mm (range, 0.03–30.2mm) for the neurointerventionists compared to just 1mm (range, 0.01–3.9mm) for PreSize. And, unlike six of the eight neurointerventionists included in the study, PreSize demonstrated “no overor underestimation bias” overall. In addition, a small, negative correlation with aneurysm size was the only trend found between the technology’s accuracy and any of the aforementioned vascular/morphological factors.

Discussing the results’ wider significance, Rai adds: “This is not the first study that has evaluated a software or AI-assisted tool for predicting device behaviour; but, it is the first that has actually validated such a tool against a large cohort of physicians via head-tohead comparison. That validation is important because, if someone comes to me with a software claiming it can do ‘X, Y and Z’, my first question is: how reliable is it, and what level of evidence [is supporting] those predictions?”

“Having used the PreSize technology, I can say I wish it was available and FDA [Food and Drug Administration]approved in the USA,” he continues, going on to explain that his centre and many others are currently using the software solely under research protocols rather than in everyday practice. PreSize is, however, CE-marked and is already

He also notes that simulation tools like PreSize could expand beyond elective, unruptured aneurysms and flow diverters, and—“eventually”— move into more urgent, acute cases like ruptured intracranial aneurysms, and potentially even the deployment of intrasaccular devices, because “the ability is definitely there”.

Returning to the present JNIS study, Rai acknowledges that “this is not definitive” and “by no means settles the question”; while its large cohort of cases and blinded setup contribute to it being a “good study”, additional research endeavours that are fully prospective and randomised in nature will be needed to bolster existing evidence. Pertinently, a neurointerventional study assessing PreSize’s real-world performance in a clinical setting is currently underway in the UK and plans to enrol 100 patients.

With promise already shown in this paper and others, and plenty more evaluations to come, Rai believes it is only a matter of time before simulation technologies like PreSize find their way into many neurointerventionists’ everyday practice. “My message would be that I think this is where the future is headed,” he avers. “Tools like this will be incorporated into our cath-lab workstations, and this will be significant as, to a large extent, it will take the need for guesswork away from physicians.”

December 2023 | Issue 52

16 Stroke Care

WSO predicts 50% more deaths unless “catastrophic” gaps in global stroke services are addressed Between now and 2050—unless “urgent action is taken”—the number of people who die from stroke globally is estimated to increase by 50%, to 9.7 million deaths per year, with annual costs as high as US$2.3 trillion also a possibility. That is according to a new report published in The Lancet Neurology by the World Stroke Organization (WSO).

T

he report centres around “pragmatic solutions to reduce the global burden of stroke”, with the authors’ analysis forecasting growing health and economic impacts from stroke between 2020 and 2050—which are set to “disproportionately” affect low- and middle-income countries (LMICs). Based on a review of evidence-based guidelines, recent surveys, and in-depth interviews with stroke experts around the world, the authors have attempted to make evidencebased, pragmatic recommendations to reduce the global burden, including measures to improve stroke surveillance, prevention, acute care, and rehabilitation.

Globally, the number of people who suffer a stroke, and die from or remain disabled by the condition, has almost doubled over the past 30 years. The “vast majority” of those affected are in LMICs, where prevalence of the condition is increasing at a faster rate than in high-income countries (HICs). According to the WSO, if the current trends continue, one of the World Health Organization’s (WHO) key sustainable development goals (SDGs) will not be met. SDG 3.4 aims to reduce the 41 million premature deaths from non-communicable diseases—including stroke—by one third by 2030.

“Stroke exerts an enormous toll on the world’s population, leading to the death and permanent disability of millions of people each year, and costing billions of dollars,” said Valery Feigin (Auckland University of Technology, Auckland, New Zealand), co-chair of the WSO—Lancet Neurology Commission, which led the recent report. “Precisely forecasting the health and economic impacts of stroke decades into the future is inherently challenging given the levels of uncertainty involved, but these estimates are indicative of the ever-increasing burden we will see in the years ahead unless urgent, effective action is taken.”

Rising burden in LMICs and huge economic costs

In their new report, the authors used the Global Burden of Disease (GBD) study methods to provide estimates of stroke burden between 2020 and 2050 in HICs and LMICs, and by major GBD world regions and age.

Taking into account population growth and ageing in most countries, their analysis indicates the number of people who die annually from stroke globally will increase by 50%, rising from 6.6 million in 2020 to 9.7 million in 2050.

The number of stroke deaths in LMICs is projected to rise sharply too—widening the gap with HICs that already exists—by increasing from 5.7 million in 2020 to 8.8 million in 2050. In contrast, stroke deaths in HICs are estimated to remain largely unchanged at around 900,000 between 2020 and 2050. This indicates

that the proportion of global stroke deaths that occur in LMICs will increase from 86% in 2020 to 91% in 2050.

“Asia accounted for by far the greatest share of global stroke deaths in 2020—61%, around 4.1 million deaths—and this is forecast to rise to around 69% by 2050; around 6.6 million deaths,” said Jeyaraj Pandian (Christian Medical College and Hospital, Ludhiana, India), president-elect of the WSO and one of the lead authors of the commission’s report. “Though smaller relative to Asia, the number of annual global stroke deaths occurring in sub-Saharan African countries will rise from 6% in 2020 (403,000) to 8% (765,000) in 2050. We have to closely examine what is causing this increase, including the growing burden of uncontrolled risk factors—especially high blood pressure, and lack of stroke prevention and care services in these regions.

Without urgent action, stroke deaths in Southeast Asia, East Asia, and Oceania could increase by almost two million, from 3.1 million in 2020 to potentially 4.9 million in 2050.”

The global death rate among people aged over 60 years is predicted to fall by 36%—566 deaths per 100,000 in 2020 to 362 per 100,000 in 2050. However, among those under 60 years of age, it is predicted to fall by less than 25%, from 13 per 100,000 in 2020 to 10 per 100,000 in 2050. The report’s authors say the lesser reduction among younger people might relate to increasing levels of diabetes and obesity in this age group.

Economic forecasting indicates the combined cost of stroke, including direct costs and loss of income, will rise from US$891 billion per year in 2017 to up to US$2.31 trillion in 2050.

The bulk of these economic impacts are forecast to be felt in Asia and Africa, according to the WSO-led report. Projections indicate large increases in direct costs and income losses from stroke in middle-income countries, and increases in direct costs in HICs. They also forecast increased economic impacts in lowincome countries, but these geographies’ overall share in global costs is likely to remain small, given their overall low share in global population and stroke cases.

providing population-wide access to evidencebased stroke care. Based on the findings of the qualitative analysis, the authors make 12 evidencebased recommendations across stroke surveillance, prevention, acute care, and rehabilitation, including: Establishing low-cost surveillance systems to provide accurate epidemiological stroke data to guide prevention and treatment Raising public awareness and action to improve healthy lifestyles and prevent stroke through population-wide use of mobile and digital technologies, such as training and awareness-raising videos and apps Prioritising effective planning of acute stroke care services, capacity building, training, provision of appropriate equipment, treatment and affordable medicines, and adequate resource allocation at national and regional levels Adapting evidence-based recommendations to regional contexts, including training, and support and supervision of community health workers to assist in long-term stroke care Establishing local, national and regional ecosystems involving all relevant stakeholders to co-create, coimplement and monitor stroke surveillance, prevention, acute care, and rehabilitation.

“One of the most common problems in implementing stroke prevention and care recommendations is the lack of funding,” said Feigin.

“Our commission recommends introducing legislative regulations and taxations of unhealthy products (such as salt, alcohol, sugary drinks, trans-fats) by each and every government in the world.

Such taxation would not only reduce consumption of these products—and therefore lead to the reduction of burden from stroke and major other non-communicable diseases—but also generate a large revenue sufficient to fund not only prevention programmes and services for stroke and other major disorders, but also reduce poverty, inequality in health service provision, and improve wellbeing of the population.”

“Investing in evidence-based measures to reduce the global burden of stroke will deliver benefits that go far beyond health alone,” added commission co-chair Mayowa Owolabi (University of Ibadan, Ibadan, Nigeria). “As well as delivering health and economic benefits relating to stroke, many of our recommendations would also facilitate reductions in poverty and inequality, and boost local economies.”

“The gaps in stroke services across the world are catastrophic,” stated Sheila Martins (Federal University of Rio Grande do Sul, Porto Alegre, Brazil), president of the WSO. “We need a drastic improvement today, not in 10 years. The WSO is committed to supporting and to accelerating the implementation of these recommendations globally through the WSO Implementation Task Force, with stroke experts, to advise the establishment of stroke prevention and care.”

Martins further highlighted the WSO’s intention to contribute to these efforts via educational programmes, as well as through the Global Stroke Alliance meetings, which rotate globally and “facilitate discussions between stroke experts and policymakers, giving the technical support to governments to elaborate national plans for stroke and to include stroke care in the Universal Health Coverage packages”.

9.7 million

estimated deaths per year

with potential annual costs of

$2.3 trillion

“We need a drastic improvement today, not in 10 years.”

Sheila Martins

Evidence-based recommendations moving forward

To identify key barriers and facilitators to highquality stroke surveillance, prevention, acute care and rehabilitation, the report’s authors further conducted a qualitative analysis of in-depth interviews with 12 stroke experts from six HICs and six LMICs. Among the major barriers identified were low awareness of stroke and its risk factors—which include high blood pressure, diabetes mellitus, high cholesterol, obesity, unhealthy diet, sedentary lifestyle and smoking—and limited surveillance data on stroke risk factors, events, management, and outcomes of stroke.

Major facilitators included well-developed stroke organisations and networks that can build capacity for stroke care and research, and universal healthcare

Issue 52 | December 2023

Stroke Care 17

TRIAGE AND TRANSPORT

Research indicates women are less likely to be routed to comprehensive stroke centres than men DESPITE HAVING WORSE stroke symptoms and living within comparable distances to comprehensive stroke centres (CSCs), women with large vessel occlusion (LVO) acute ischaemic stroke are less likely to be routed to these types of centres compared to men, according to a new study from University of Texas Health (UTHealth) Houston.

Led by authors Sunil Sheth and Youngran Kim (both UTHealth Houston, USA), the study was recently published in the Journal of the American Heart Association.

“Timely treatment of stroke is incredibly important; the faster a doctor is able to get the vessel open, the better the patient’s chance of having a good outcome,” said Sheth. “These routing systems in hospitals are designed to get patients to the best care as quickly as possible. We do not know exactly why women were less likely than men to be routed to comprehensive stroke centres, but we do know that gender is an implicit bias. Getting to the granular level of what went into a hospital’s routing decision will be very important for future studies.”

Researchers identified consecutive patients with LVO acute ischaemic stroke from a prospectively collected, multi-hospital registry for the Greater Houston area from January 2019 to June 2020. They compared prehospital routing of men and women to CSCs— which are capable of performing endovascular therapy (EVT) to remove the clot blocking an artery.

Among 503 patients, 82% were routed to CSCs. Women made up 46% of the study participants. Compared with men, women were older (73 vs. 65 years of age), and presented with a greater average National Institutes of Health stroke scale (NIHSS) score (14 vs. 12), meaning their symptoms were worse.

“The greater NIHSS score in women may be partially attributed to their older age, as age itself is a known contributing factor to sex differences in stroke severity,” said Kim. “Moreover, elderly women are more likely to live alone and experience social isolation,

Latest TRIAGE-STROKE and RACECAT data put the brakes on alternative stroke transfer protocols

which can result in delayed recognition of stroke symptoms and subsequent delays in seeking medical attention.”

After adjusting for differences in stroke type, age, travel distance, and other relevant factors, the researchers found that women were approximately 9% less likely than men to be routed to CSCs in the study. Additionally, patients living within a 10-mile distance of the nearest CSC were 38% more likely to be routed to one.

“Older age at onset and severe stroke in women, compounded by a higher likelihood of age-related risk factors, can contribute to the higher rate of death from stroke and higher risk for disability after stroke in women,” Kim added. “Therefore, appropriate triage and prehospital routing can be even more critical for women. Whether LVOs in women are less likely to be identified using current screening tools due to older age, premorbidity, or non-traditional symptoms, needs to be investigated.”

Their prespecified secondary analysis included a total of 302 patients from the RACECAT study, of whom 137 were transported directly to a thrombectomy-capable centre while 165 were transferred locally to the closest stroke centre. The analysis’ primary outcome was a shift in 90-day mRS score across the intention-to-treat population, Recently published data from two large randomised controlled trials (RCTs) have with cumulative ordinal logistic regression being indicated there may be minimal benefits—or even negative effects—associated with used to estimate a common OR. A multitude of bypassing local or primary stroke centres (PSCs) and transporting patients straight to secondary outcomes included 90-day mortality, early thrombectomy-capable comprehensive stroke centres (CSCs). However, investigators neurological deterioration/mortality, ICH volume and are in agreement that additional research is required to further elucidate the impact of enlargement, and rate of adverse events until day five. transferring stroke patients directly to CSCs. Relaying their results, Ramos-Pachón et al note that direct transfer to a CSC resulted in worse esults from the first of these studies—the 67% of patients in the PSC group versus 78% in the functional outcomes at 90 days compared with TRIAGE-STROKE trial, which compared CSC group, and thrombectomy was performed in transfer to the nearest local stroke centre (mean mRS, transport strategies in patients with suspected 53% versus 63% of the patients, respectively.

4.93 vs. 4.66; adjusted common OR, 0.63). Direct acute large vessel occlusion (LVO) stroke—were “This trial investigated the benefit of bypassing CSC transfer “also suggested potentially higher published earlier this month in the journal Stroke by PSCs,” Behrndtz et al conclude. “Lack of power 90-day mortality” versus local stroke centre Anne Behrndtz (Aarhus University Hospital, Aarhus, prevented the results from showing effect transfer (48.9% vs. 37.6%), and the rates Denmark) et al. “Equipoise remains between transport on functional outcome for patients going of medical complications during initial strategies and the best transport strategy is not well directly to CSCs.” transfer (22.6% vs. 5.6%) and in-hospital established,” the authors initially posit, outlining the pneumonia (35.8% vs. 17.6%) were also existing knowledge gap they sought to ameliorate.

New RACECAT data higher in the former group of patients.

In TRIAGE-STROKE, patients eligible for In May 2022, investigators published “In this secondary analysis of the intravenous thrombolysis (IVT) with suspected LVOs overall results from the multicentre, RACECAT randomised clinical trial, were randomised 1:1 to admission to the nearest PSC, population-based RACECAT RCT—the Anna Ramos- bypassing the closest stroke centre prioritising IVT, or direct CSC admission, prioritising primary objective of which was to assess resulted in reduced chances of functional Pachón endovascular therapy (EVT). The primary outcome the impact of bypassing local centres when independence at 90 days for patients who was 90-day functional improvement for all acute transferring ischaemic stroke patients—in the Journal received a final diagnosis of ICH,” they conclude. ischaemic stroke patients i.e. a shift towards a lower of the American Medical Association (JAMA).

“These results suggest that transfer protocols based modified Rankin scale (mRS) score.

Similarly to TRIAGE-STROKE, it ultimately on bypassing local stroke centres may result in worse From September 2018 to May 2022, found no effect on clinical outcomes functional outcomes for patients with ICH—although Behrndtz and colleagues enrolled 171 between differing transport protocols. And, this finding requires replication in other settings.” patients, of whom 104 were found to now, a more recent, secondary analysis of have had an acute ischaemic stroke. The RACECAT, published in JAMA Neurology Final thoughts authors report that the trial was halted by researchers Anna Ramos-Pachón Speaking to NeuroNews following publication of before full recruitment, and also detail (Hospital Germans Trias i Pujol, Barcelona, these new TRIAGE-STROKE data, Behrndtz said: “I that baseline characteristics were “well Spain) et al, has revealed a comparable fully agree with Dr Ramos-Pachón [and colleagues] balanced” across the patient population. A trend in patients experiencing intracranial that, as long as we do not have solid evidence for Anne primary analysis of the mRS shift (ordinal bypassing these patients, and we know that we harm Behrndtz haemorrhage (ICH). Initially, the authors deliver logistic regression) revealed an odds ratio a similar message to Behrndtz et al, stating patients with ICH, we should go local when triaging (OR) for functional improvement at day 90 of 1.42. that “the effect of different protocols among patients patients with severe neurological deficits. However, In addition, the onset to groin time (EVT) for patients receiving a final diagnosis of ICH is unknown”. As further research should address improvement of stroke with LVO was 35 minutes shorter when patients were such, they attempted to evaluate whether prehospital diagnosis in the field.” transported to a CSC first, whereas onset to needle transfer protocols bypassing the nearest PSC in favour Ramos-Pachón told NeuroNews that she “totally (IVT) was 30 minutes shorter when patients were of direct transport to a CSC would prove harmful or agrees” with this sentiment, also echoing Behrndtz’s transported to a PSC first. IVT was administered in beneficial among these patients. point on the need for additional research in this space.

R

Stroke Care 19

Issue 52 | December 2023

Missing outcome data is common and ‘does not occur at random’ in thrombectomy registries

The phenomenon of missing outcome data (MOD) within stroke registries of mechanical thrombectomy cases “is not a rare event and does not occur completely at random”.

That is a key concluding message from research carried out and recently published in the Journal of NeuroInterventional Surgery (JNIS) by Timo Uphaus, Marianne Hahn (both University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany) and colleagues.

“W

e have reported factors associated with missing data on 90-day functional outcome in a large, multicentre registry of mechanical thrombectomy in acute stroke care,” Uphaus, Hahn et al state in their JNIS article. “These include patients with higher pre-stroke disability; patients treated later after symptom onset; patients not receiving bridging IVT [intravenous thrombolysis]; and patients with relevant disability at discharge from the treating hospital, which are at increased risk of MOD. “These patient groups may therefore be underrepresented in acute stroke care studies based on complete case analysis, compared with the actual cohort treated by mechanical thrombectomy.

In contrast, patients with inhouse mortality after mechanical thrombectomy treatment are likely to have complete data on 90-day stroke outcome and might therefore be disproportionately present. In addition to patients with higher pre-stroke and post-stroke disability, increased efforts to perform 90-day followup should also be undertaken for patients with a shorter duration of hospital stay, and those discharged to institutional care or hospital.”

The authors initially aver that MOD is a “common problem” in clinical trials and registries—especially in analyses based on complete cases—and creates a potential bias when drawing conclusions from these data. They go on to note that identifying factors associated with MOD may help to increase follow-up rates and assess the need for imputation strategies and,

as such, they set about investigating MOD in a multicentre, prospective registry study of mechanical thrombectomy for large vessel occlusion (LVO) ischaemic stroke.

“While registries depicting mechanical thrombectomy in routine care are valuable tools to analyse Timo Uphaus patterns of care and functional outcome after LVO in distinct populations, missing data may impact the accuracy and generalisability of these analyses,” the authors add. “Bias may result from case selection on the basis of complete data and cannot be fully adjusted for by imputation of missing data, because MOD is significantly dependent on other observed (and unobserved) variables, and the outcome itself.”

Uphaus, Hahn and colleagues analysed a total of 13,082 patients enrolled in the German stroke registry-endovascular treatment (GSR-ET) from May 2015 to December 2021 with regard to MOD (90-day modified Rankin scale [mRS]). The authors detail that univariate logistic regression analyses were used to identify factors that were unbalanced between patients with and without MOD, while subgroup analyses were performed to identify patients for whom increased efforts to perform clinical follow-up after hospital discharge are needed as well.

Some 19.7% of these patients were identified as having MOD at 90-day follow-up. MOD was found

to be more common with higher (mRS 3–5) compared to lower (mRS 0–2) pre-stroke disability (32.2% vs 13.7%, respectively), as well as with higher post-stroke disability upon discharge (odds ratio [OR]=1.234).

In addition, absence of bridging IVT and longer time to treatment were associated with a greater rate of MOD—but MOD was less common with futile recanalisation (thrombolysis in cerebral infarction [TICI] score of 0–2a) versus successful recanalisation (TICI 2b–3; 12.4% vs 15%, respectively). In patients discharged alive with well-documented baseline characteristics, the authors also report shorter hospital stay (OR=0.992), and discharge to institutional care or hospital (OR=1.754), as being associated with MOD. “MOD in routine-care mechanical thrombectomy registry data was not random,” Uphaus, Hahn et al conclude. “Increased efforts to perform clinical follow-up are needed, especially in the case of higher preMarianne Hahn stroke and post-stroke disability, and discharge to hospital or institutional care. Increased follow-up rates may then also improve the validity and generalisability of findings from routine care mechanical thrombectomy datasets.”

In their JNIS paper, the authors highlight the strengths of their analysis, including usage of an “up-to-date, large and complex nationwide cohort” of more than 13,000 thrombectomy procedures, creating a “strong data foundation”. And, because 30 centres were involved in enrolment and data acquisition took place over more than six years, they report being able to “minimise the impact of site- and time-specific factors influencing MOD”.

However, Uphaus, Hahn and colleagues also acknowledge several limitations hampering their research, such as the fact they did not capture sociodemographic characteristics and other, additional patient factors previously reported as being associated with missing data, as well as “unique organisational structures” potentially restricting the generalisability and transferability of these results to other stroke registries.

status received Patients in lower socioeconomic socioeconomic the aforementioned treatments, compared to 20% of those living in status areas less likely to the neighbourhoods with the highest status. receive acute stroke therapies, socioeconomic And, when taking into account other factors that could affect treatment— Canadian study finds such as age, high blood pressure and PEOPLE WHO LIVE IN neighbourhoods with lower socioeconomic status are less likely to receive clot-busting medications or undergo mechanical thrombectomy procedures after they have a stroke compared to those living in neighbourhoods with a higher socioeconomic status.

That is according to a study published recently in the journal Neurology by a group of researchers from Toronto, Canada.

“These treatments can greatly reduce death and disability from stroke, but previous studies have shown that few people actually receive the treatments,” said study author Amy Ying Xin Yu (University of Toronto, Canada).

“We wanted to see how socioeconomic disparities play a role, especially in an area where everyone

has access to universal healthcare.”

The study looked at everyone living in Ontario, Canada who had an ischaemic stroke during a five-year period—resulting in a cohort totalling 57,704 people—and assessed how many of those people had their blood clots treated with clot-busting drugs, via intravenous thrombolysis, or surgery via a thrombectomy.

Researchers also looked at participants’ neighbourhoods and divided them into five groups based on the socioeconomic statuses of their neighbourhoods.

Writing in Neurology, the researchers state that this was determined by factors like the percentage of adults without a high school diploma, unemployment rate, and income level.

A total of 17% of those living in the neighbourhoods with the lowest

diabetes—they concluded that people in the neighbourhoods with the lowest socioeconomic status were 24% less likely to be treated than people in the neighbourhoods with the highest

Our study underscores the need for tailored interventions to address socioeconomic disparities in access to acute stroke treatments.”

socioeconomic status.

The researchers also found, however, that there was no difference in treatment between the neighbourhood with the lowest status, and the three middle-ranked neighbourhoods of the five.

“Our study underscores the need for tailored interventions to address socioeconomic disparities in access to acute stroke treatments, including educational and outreach programmes to increase awareness about the signs and symptoms of stroke in various languages, and efforts to distribute resources more equitably across neighbourhoods,” Yu said.

“Further research is needed to examine the specific causes of these disparities, so we can find ways to address the larger systemic issues that need to be improved to better serve people from under-resourced neighbourhoods.”

One limitation of the study that was noted by the researchers is that they did not have information on other factors that could affect stroke treatment, such as the time at which symptoms started or how severe the stroke was.

December 2023 | Issue 52

20 Interview

PROFILE

(International Subarachnoid Aneurysm Trial), but now I have to say, unquestionably, mechanical thrombectomy for large vessel occlusion (LVO) stroke—although, without ISAT, I do not think many countries would have had the trained workforce available to deliver stroke thrombectomy!

PHIL WHITE

What is the most pressing unmet need in interventional neuroradiology right now?

Phil White’s career as a physician and researcher has seen him play a role in numerous major stroke trials, and serve as an educator to many in the interventional neuroradiology (INR) space via the European Course in Minimally Invasive Neurological Therapy (ECMINT). Today, he is the chair of Interventional and Diagnostic Neuroradiology at Newcastle University (Newcastle, UK), and is also currently the only specifically appointed INR professor in the country. Here, White gives NeuroNews an insight into several aspects of his esteemed career and discusses some of the neurointerventional world’s hottest topics.

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

Medicine drew me from my early teenage years for reasons that attract many others— the breadth of the subject, the extensive and fascinating knowledge base, being at the cutting edge of science, and offering a stable career platform whilst also helping people.

My involvement in neuroradiology was, to an extent, fortuitous, in that I was very interested in pursuing a career in radiology research and Joanna Wardlaw had recently been appointed into an academic post in Edinburgh, UK as I was coming through radiology training there.

Providentially, a Scottish-based neuroscience research fellowship—the Davie Cooper Scottish Aneurysm Study—became available at the right time for me to apply and I was fortunate to be appointed into it. The rest is history.

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

Three key mentors stand out for me. Joanna Wardlaw in the fields of neuroradiology and imaging research. Joanna was my cosupervisor for my Doctor of Medicine (MD) thesis and research, and has been an absolute inspiration ever since. If I was a fraction as bright or productive as Joanna, I would be very pleased indeed. Sadly, I am not.

In neurointervention, my main trainer was the renowned and inimitable Robin Sellar in Edinburgh. He taught me most of what I know with regard to neurointervention and, above all, Robin made it all great fun, which was fantastic. While he has sadly not been in good health of late, I was privileged to be a colleague of Robin’s for almost 15 years. I also learnt a lot from and was mentored very well

by Anil Gholkar in Newcastle, UK, and Anil also subsequently became a work colleague.

Anil is totally unflappable, always has time for people, and is an inspirational leader. I have learnt a great deal from Anil and tried to put that into practice in teaching and leadership roles in particular.

Could you briefly outline how you came to be the only current, appointed professor of interventional neuroradiology in the UK?

James Byrne was the first but has now retired.

I was the second to hold the title of university chair and professor by appointment, as opposed to the honorary title of professor.

After 11 years as a full-time NHS consultant in Edinburgh, my burgeoning research portfolio and activity meant it made sense to move into an academic post in order to be able to maintain and indeed develop that

research. After a short period as a reader in neuroradiology at the University of Edinburgh, I took up the position as the first chair of neuroradiology (interventional and diagnostic) in Newcastle in 2012.

How important is the ECMINT course and what makes it an effective educational tool?

ECMINT is a crucial educational tool for European neurointerventionists. It was started

by James Byrne and Shelley Renowden in 2013. It takes two years to complete a full cycle of four weeklong intensive courses and offers a comprehensive theoretical knowledge base regarding current neurointerventional practice. Completion of ECMINT is linked to qualifying to sit the European Diploma in Neurointervention (EDNI), which is also linked to the European Society of Minimally Invasive Neurological Therapy (ESMINT).

We currently have nearly 150 delegates—70% in person and 30% online, and the great majority are based in Europe, although we do have participants from all other continents except Antarctica. So, over the last 10 years, a considerable number of younger European neurointerventionists have attended it. As it runs in a University of Oxford college over a prolonged period, and we eat and drink together, ECMINT offers them a unique opportunity to make careerlong friends— nationally and internationally—and build support networks and collaborations, including with the distinguished faculty. I really wish something like it had existed in the 1990s when I was training!

What is your proudest achievement to date in the neuroradiology space?

Jointly—and I really cannot put one above the other—it is co-running ECMINT with Shelley Renowden and now with Adam Rennie from London, UK, and co-running the PISTE (Pragmatic Ischaemic Stroke Thrombectomy Evaluation) trial with Keith Muir from Glasgow, UK. Although PISTE had to stop early due to accruing evidence from other trials, we demonstrated that the NHS in the UK could deliver mechanical thrombectomy, with results comparable to other countries, despite no formal investment in it at that stage.

This robust, NHS-based trial evidence greatly facilitated the rapid approval of national commissioning of mechanical thrombectomy

by NHS England in 2017.

What do you feel has been the neurointerventional field’s most important development during your career?

A decade ago, I would have said ISAT

FACT FILE APPOINTMENTS (SELECTED) 2012–present: Chair and professor of Interventional and Diagnostic Neuroradiology at Newcastle University (Newcastle, UK) 2012–present: Honorary consultant neuroradiologist at Newcastle upon Tyne Hospitals NHS Foundation Trust 2000–2011: Consultant neuroradiologist and honorary senior lecturer/honorary reader at University of Edinburgh (Edinburgh, UK) EDUCATION 2002: Research MD with Distinction (University of Edinburgh) 1994: MSc in Clinical Imaging (University of Edinburgh) 1990: MB ChB with Honours (First Class; University of Liverpool, UK) 1988: BSc with Honours (First Class) in Pharmacology (University of Liverpool) HONOURS (SELECTED) 2020: Presidential Medal, British Society of Neuroradiology 2019–2022: Elected Chair, UK Neurointerventional Group 2018: Diploma, European Board of Neurointervention 2002: Scientific Award, European Society of Neuroradiology 1996: Fellowship, Royal College of Radiologists

We have lots of exciting developments in terms of both techniques and devices, but the key to getting those implemented universally is robust proof. That really means randomised trials or, for some aspects, robust ‘big data’ analysis. There are many things we do that are not truly evidence-based—unruptured intracranial aneurysm therapy for one—and device data are often of very poor quality.

There is a balance to be struck between innovation and evidence, and I am not sure we are there yet in neurointervention the way they may be in, say, interventional cardiology.

Which research areas or clinical studies are likely to have the greatest impact on neurointerventional care over the next five years?

Trials in minimally invasive treatments for chronic subdural haematoma (SDH) and primary intracerebral haemorrhage (ICH) are likely to have the greatest impact. Middle meningeal artery (MMA) embolisation could well become another major 24/7 service for neurointervention. I can see neurointerventionists—and in particular those with current/prior neurosurgical practise and training—having an interest in getting involved in minimally invasive ICH neurosurgery, should trials be conclusive in its favour. Whether that means superiority or non-inferiority on primary endpoints, or benefits in terms of key secondary parameters, those upcoming trials could open a door and ultimately expand endovascular treatments wider and wider, as seen in aneurysms and stroke. It is a starting point, but it could herald a lot more activity.

We also hope to obtain robust randomised controlled trial (RCT) data regarding dural venous sinus stenting (DVSS) for idiopathic intracranial hypertension (IIH) in the UK soon, which could lead the way in burgeoning venous neurointerventional practices. Fergus Robertson in London and myself are the co-lead interventional neuroradiologists for an RCT led from Birmingham comparing venous sinus stenting and shunting in severe IIH—we have got the trial up and running, and we are now beginning to recruit patients.

A bit like MMA embolisation, if we can show that stenting is as good as shunting but leads to fewer recurrent treatments or is preferred by patients, this is likely to be a foot in the door that leads to stenting being more widely practised. Subsequently, we may obtain evidence to expand DVSS out to a much broader group of IIH patients who have more benign symptoms despite medication, and potentially to other venous indications as well.

How would you assess the impact tenecteplase is set to have on stroke care?

I think what we have seen in our practice is that it is a useful addition, but it is an evolution rather than a revolution—it is a small yet worthwhile advance. The main advantage of

Issue 52 | December 2023

alisonlang.com

Interview 21

tenecteplase over alteplase is that it does not require an infusion, and that is really helpful for speeding up the process in all stroke patients heading for a thrombectomy and particularly in drip-and-ship patients. There are currently issues with the supply of the drug worldwide but, once it becomes available, I think alteplase will largely be confined to the history books in stroke.

What are your thoughts on recent attempts to boost stroke thrombectomy access in the UK by opening the procedure up to other specialties like cardiologists and radiologists?

This has been a frustratingly slow burn. In early 2017, the UK Neurointerventional Group (UKNG), British Society of Interventional Radiology (BSIR) and Royal College of Radiologists (RCR) agreed on a mechanism to train up interventional radiologists in thrombectomy! Uptake in such training has occurred but has been limited by workforce gaps and overstretch. For non-radiologists, the UKNG—including during my time as UKNG

chairperson—has supported this in principle, but working through UK General Medical Council (GMC) processes has been very slow and was only finally approved earlier in 2023.

However, without dedicated funding and a stronger NHS commitment to INR engagement with it, such training is likely to remain more ad hoc than we would want.

What advice would you give to people embarking on a career in neuroradiology?

1. Train in a busy, integrated neurosciences centre that has an enthusiastic neuroradiology team i.e. one that is clearly active in research, teaching, leadership and professional societies 2. Train/practise in more than one centre— learning that there is more than one way to do things is important 3. If you are training in neurointervention, then attend ECMINT (but I would say that) 4. Find a good mentor(s)—ESMINT can help if you need it.

you required a neurointerventional "We have lots Ifprocedure yourself, who would of exciting you ideally want to see leading treatment? developments that I think if I required an emergency procedure in terms then I would say Rene Chapot; very good hands, and I think he is also quite lucky! Rene of both is still very busy and he has such a mass of techniques experience with acute cases. I would probably and devices, choose him or Adam Arthur from people who practising today—but I would want to be but the key to are awake telling them what to do as well! getting those are your interests outside implemented What of medicine? universally is Equestrianism, particularly endurance riding; especially fell-walking; clay pigeon robust proof.” walking, shooting; and my family.

If you had not opted for a career in medicine, what do you think you would be doing for a living today?

I have absolutely no idea except that, if I could have afforded it—which I cannot—being a gentleman farmer seems like a great option!

December 2023 | Issue 52

22 Novel Technologies

Upcoming technologies set to forebear “new era” in prehospital stroke care

Jeffrey Saver Point of View While the latest thrombectomy techniques, thrombolytic drug candidates and even neuroprotective agents are the source of much discussion in today’s neurovascular space, there is also significant room for improvement within another step along the stroke care pathway: patient triage. For NeuroNews, Jeffrey Saver (Los Angeles, USA) provides a snapshot of the novel technologies being used to improve diagnoses, transfer decisions and, ultimately, patient outcomes.

W

hen a stroke occurs, the prehospital system must respond quickly and intelligently, as treatments are extremely time- and place-dependent. With every nine minutes of delay in the onset of intravenous thrombolysis, one of every 100 patients experiences a more severe disability.

As such, it is essential that patients with stroke—or on-scene witnesses— activate the 911 system as soon as possible after onset. Further, when prehospital personnel arrive on the scene, they must distinguish patients with stroke from those with strokemimicking conditions and bring the neurovascular patients directly to certified stroke centres capable of providing lytic therapy rapidly.

In addition, with every four minutes of delay in the start of endovascular thrombectomy, one of every 100 patients experiences a worse disability outcome.

It is therefore desirable that prehospital personnel also distinguish patients with ischaemic strokes due to large vessel occlusion (LVO) from those with small and medium vessel occlusions, and transport the LVO patients directly to advanced stroke centres capable of performing thrombectomy procedures— if not too distant.

Some patients with intracerebral haemorrhage (ICH) may require immediate ventricular drainage or haematoma evacuation. It is therefore preferable that ICH patients are brought directly to neurosurgical care hospitals, if nearby, though not transported long distances because of their high rate of deterioration before hospital arrival.

Existing solutions

Currently, for these routing decisions, prehospital systems rely on the classic foundation of history and physical exam.

Formalised history and examination have enabled implementation of useful regional systems of stroke care but work imperfectly. To detect stroke onset, patients and families are taught the facearm-speech-time (FAST) mnemonic; but stroke deficits may prevent patients from recognising or acting on symptoms, and the 20% of strokes that occur in sleep are detected only after a delay.

To distinguish strokes from stroke mimics, paramedics use standardised stroke recognition scales, such as the Los Angeles prehospital stroke screen (LAPSS) scale and the Cincinnati prehospital stroke scale (CPSS).

However, these only have an accuracy of 60–75%. And, to distinguish LVO from non-LVO stroke, paramedics use standardised stroke severity scales, such as the Los Angeles motor scale (LAMS) or the rapid arterial occlusion evaluation (RACE) scale—but these also only have 60–75% accuracy too. Further, no validated assessment exists to distinguish ICH from ischaemic stroke.

Novel tools and technologies

Fortunately, we stand poised at the threshold of a new era in which mobile health technologies promise to dramatically enhance prehospital diagnostic performance. Immediate detection of stroke onset will occur through wearable and environmental sensor technologies. Already, the Apple Watch detects patient falls from stroke and automatically notifies the emergency medical services (EMS) system.

Other wearables under development include electroencephalogram (EEG) headbands to monitor for stroke onset during sleep, and bilateral wristbands with accelerometers that monitor for hemiparesis onset in both waking and sleeping patients.

The rise of ubiquitous external video

and audio monitoring in modern life provides abundant further opportunities for stroke onset detection technology.

Smartphone, video meeting, security and home robot cameras with artificial intelligence visual recognition systems will be able to monitor continuously for onset of facial weakness, limb weakness, or ataxia. Voice assistant, smartphone and home robot audio systems will similarly be able to monitor continuously for the first onset of aphasia or dysarthria. As a result, hyperacute entry into the EMS system will occur for many more patients.

When prehospital personnel respond, their patient assessments will be technologically enhanced. Many biotech companies are currently developing ‘stroke helmet’ technologies that paramedics can place on the patient’s heads to rapidly probe their brain status. Alterations in brain physiology by cerebrovascular insults change the brain’s energetic response to these probes in distinctive ways. Among the wide variety of technologies being developed for paramedic use, some are updates of longstanding neurodiagnostic approaches: ultrasound, EEG, and near infrared. Of particular interest are entirely new approaches including microwaves, electrical impedance and cranial vibrations. All of these technologies have the potential to improve paramedic performance across each of the three key prehospital diagnostic distinctions—stroke versus non-stroke; LVO ischaemic stroke versus non-LVO ischaemic stroke; and haemorrhagic stroke versus ischaemic stroke.

Cautious optimism

One of the innovations with which I am involved, the Harmony device (MindRhythm) that assesses alterations in head pulsation, has advanced to the stage of validation testing in the prehospital setting. Others likely will also soon be entering prehospital assessment. We must be wary of overenthusiasm for technological solutions. Many hurdles still need to be overcome before we have a technologically optimised triage system of prehospital stroke care.

But, as Amara’s Law states, while we overestimate the effect of a particular technology in the short run, we underestimate the effect in the long run. I fully expect that mobile health technology will powerfully reshape prehospital stroke care over the next decade.

References for this article are available online and can be viewed at www.neuronewsinternational.com/upcomingtechnologies-set-to-forebear-new-era-in-prehospitalstroke-care.

Jeffrey Saver works at the University of California Los Angeles (UCLA; Los Angeles, USA), where he is medical director of the Stroke Unit at the UCLA Medical Center, a professor of neurology at the UCLA School of Medicine, and co-director of the UCLA Stroke Center.

DISCLOSURES: The author is a member of MindRhythm’s strategic advisory board.

Smart ‘brainwave cap’ could help diagnose stroke patients in ambulances A SPECIALISED ‘BRAIN-WAVE cap’, designed by researchers in The Netherlands, may be able to diagnose stroke patients while they are in an ambulance—thus allowing them to receive appropriate treatments more quickly. The researchers’ findings were recently published in the journal Neurology.

“Our research shows that the brain-wave cap can recognise patients with large ischaemic stroke with great accuracy,” said Jonathan Coutinho (Amsterdam University Medical Center [UMC], Amsterdam, The Netherlands), one of the inventors of the device.

“This is very good news, because the cap can ultimately save lives by routing these patients directly to the right hospital.”

Coutinho, alongside Wouter Potters and Henk Marquering (both Amsterdam UMC), invented the brain-wave cap, which allows an electroencephalography (EEG) to be carried out in an ambulance to determine whether or not there is an ischaemic stroke present, and if the blocked cerebral blood vessel is large or small. This distinction plays a key role in which treatment option should be selected—a blood-thinning medication given intravenously and/ or a mechanical thrombectomy procedure.

“When it comes to stroke, time is literally brain,” Coutinho continued.

“The sooner we start the right treatment, the better the outcome. If the diagnosis is already clear in the ambulance, the patient can be routed directly to the right hospital, which saves valuable time.”

Between 2018 and 2022, the smart brain-wave cap was tested in 12 Dutch ambulances, with data being collected from almost 400 patients and ultimately demonstrating a “high level of accuracy” with the device.

“This study shows that the brain-wave cap performs well in an ambulance setting,” Coutinho added.

“For example, with the measurements of the cap, we can distinguish between a large or small ischaemic stroke.”

In order to develop the brain-wave cap into a product and bring it to the market, TrianecT—an Amsterdam UMC spin-off company—was founded in 2022. Additionally, a follow-up study named AI-STROKE is currently ongoing. In the study, even more measurements will be collected in order to develop an algorithm for improved recognition of large ischaemic stroke in the ambulance.

These efforts are in line with the conclusion of Coutinho and his colleagues’ recent Neurology publication, in which they state that— despite the potential shown by EEG to detect anterior large vessel occlusion stroke in the prehospital setting—EEG data quality “needs to be improved” prior to its future implementation within such settings.

Issue 52 | December 2023

Novel Technologies 23

Current evidence on AI-based autonomous interventions “inadequate” despite potential benefits The existing body of evidence supporting artificial intelligence (AI) and the autonomous navigation of endovascular procedures is “inadequate”, despite the theoretical benefits held by this “promising” concept.

THIS IS AMONG THE CONCLUDING searched PubMed and IEEEXplore databases messages delivered by Thomas Booth (Kings College to identify reports of AI applied to autonomous Hospital, London, UK) and his research team navigation methods in endovascular surgery. Following following a systematic review of the recent literature in preferred reporting items for systematic reviews and this sphere—findings from which are now published in meta-analysis (PRISMA) evaluations, eligible articles Frontiers in Human Neuroscience. were assessed using quality assessment of diagnostic “The concept of fully autonomous navigation in accuracy studies 2 (QUADAS-2). endovascular interventions is promising; however, with A total of 14 studies were included for analysis— a TRL [technology readiness level] of 3, the technology within which the data-driven models used for is yet to complete validation even in a laboratory autonomous navigation consisted of reinforcement environment,” Booth et al state. learning (64%) and/or learning from expert “Due to the inadequate evidence demonstration (50%). Reinforcement supporting its use—the limited number learning proved to have been a particularly of studies and its low level—it is far popular methodology in recent years, from being used in clinical practice. It the authors add, with the majority of first must be demonstrated that it can studies (80%) published beyond 2018 reliably provide benefits over currently utilising it. available treatments before it can The included studies conducted progress toward clinical trials.” evaluations on either physical phantoms Decreased operation times, improved (71%) or in-silico models (29%). decision-making during surgery, and reduced Experiments within or around the blood Thomas operator radiation exposure, as well as an vessels of the heart were included in 10 of Booth increased access to treatments like mechanical the 14 studies, while non-anatomical vessel thrombectomy, are among the potential advantages of platforms “idealised” for simple navigation were used the autonomous navigation of catheters and guidewires in three studies and the porcine liver venous system in endovascular interventional surgery, Booth and was utilised in one. colleagues initially posit. They further note that, if “We observed that risks of bias and poor proven to be safe and effective in clinical trials, the generalisability were present across all studies,” the benefits of autonomous navigation are “numerous”. authors write. “No procedures were performed on The technology’s ability to offset the need for expertise patients in any of the studies reviewed. Moreover, all in specialties currently facing skilled-operator studies were limited due to the lack of selection criteria, shortages, and the fact it is not limited by human reference standards, and reproducibility, which resulted factors like fatigue and loss of focus, are additional in a low level of evidence for clinical translation.” positives highlighted by the authors.

The authors go on to stress that there is “no In an effort to assess how close these theoretical high-level evidence” demonstrating that AI-based, benefits are to being realised, the research team autonomous navigation of catheters and guidewires in

AI algorithm shows promise for early intracerebral haemorrhage detection in retrospective study SHEBA MEDICAL CENTER IN Tel Aviv, Israel has revealed the results from a “groundbreaking” study in the International Journal of Emergency Medicine, validating an artificial intelligence (AI) algorithm developed

by Aidoc for intracerebral haemorrhage (ICH) detection.

The study demonstrated that machine learning analysis of head computed tomography (CT) scans upon admission to the emergency department can enable earlier detection of ICH, reducing the overall mortality rate associated with the haemorrhage, a press release states.

Along with Sheba neurology and radiology experts, David Orion (Sheba Medical Center, Tel Aviv, Israel) conducted the retrospective cohort study across 587 patients with a confirmed diagnosis of ICH in a Level 1 trauma centre.

The study compared 289 patients between January 2017 and January 2018 who did not have their CT scan analysed by AI, to 298 patients between January 2019 and January 2020 who had an AI analysis, examining the impact on 30- and 120-day all-cause mortality in both groups.

endovascular intervention is non-inferior or superior to manual procedures—adding that such technologies are yet to surpass TRL 3 owing to no clinical validation nor comprehensive laboratory validation having been published to date.

“There are no standardised in-silico, in-vitro or ex-vivo experimental reference standard designs, nor are there standardised performance measures, meaning comparison of studies quantitatively is of limited value,” the research team continue.

However, outlining the main strength held by the studies they analysed, the authors note that a range of machine-learning techniques were employed, with the majority focusing on identifying an entirely new machine-learning technique that would improve on previous efforts rather than using previously published algorithms and applying them to “extending the experimental environment”. Exploring various approaches, they further state, is advantageous for research, “especially in the rapidly evolving field of machine learning”, as the fast pace of development increases the likelihood that more effective algorithms are created.

“Although it is plausible that autonomous navigation may eventually benefit patients while reducing occupational hazards for staff, there is currently no high-level evidence to support this assertion,” the authors add, also emphasising once again that the field is currently at an experimental, proof-of-concept stage.

“For the technology to progress, reference standards and minimum reporting standards need to be established to allow meaningful comparisons of new system development,” Booth et al conclude, further pointing to “clear regulation” as a key requirement moving forward.

Technology readiness level

3

12 456789

Findings from the trial demonstrated that AI analysis of CT scans drove earlier detection of ICH, enabling physicians to begin administering therapeutic interventions sooner. And, as a result of these early interventions, the study demonstrated a relative decrease of more than 30% in the rate of absolute mortality in the AI-scanned cohort.

“Intracerebral haemorrhages are one of the most critical medical conditions in emergency care, with early detection vital for preventing loss of life and further morbidities,” said Orion. “This study shows the tremendous impact of AI to drive improved patient outcomes, helping to save lives and improve overall quality of life.”

The study also examined the impact of AI analysis and early treatment initiation on patient comorbidities, and found that patients in the AI cohort had

a significantly lower modified Rankin scale (mRS) score—a measure of the degree of disability or dependence in the daily activities of patients with neurological disabilities—at discharge than those in the non-AI group.

This study shows the tremendous impact of AI to drive improved patient outcomes, helping to save lives and improve overall quality of life.”

December 2023 | Issue 52

24 Advertorial THIS ADVERTORIAL IS SPONSORED BY MEDTRONIC

APRO catheters offer ‘goldstandard’ trackability with robustness and stent-retriever compatibility to match As the co-founder and chief executive officer of Chestnut Medical, Aaron Berez played a leading role in bringing flow diverters to market with the development of the Pipeline embolisation device (Medtronic) for intracranial aneurysm treatment. Today, his main focus is somewhat different, as he and his colleagues at Alembic seek to raise the bar in neurovascular catheter technology, but Berez ultimately remains in a similar position—attempting to drive innovation in the neurointerventional space forward once more.

[APRO] offers a level of trackability that places it in the elite tier of catheters, but it is a little bit more robust than those other offerings as well. This helps with flow and clot extraction—but also via the […] ability to pair it with Solitaire.”

Daniel Sahlein

“C

atheter designs are always a balance between making something that is very soft, flexible and easily trackable but, on the other hand, robust enough that it can withstand usage and perform well,” Berez tells NeuroNews. “And I have a bias towards making something that is easy to use and tracks well because, if it is not, no one is ever going to use it and they will not find out how good it is.”

Casting an eye over the current marketplace of aspiration catheters for mechanical thrombectomy, Berez points out that many existing technologies do offer a high level of trackability and, thus, are used widely by physicians. However, he continues, these same catheters are “not very durable or robust”, and this can lead to problems, for example, when deploying them in combination with a stent-retriever device due to the increased degree of friction this combined technique creates.

“Stent retrievers, in general, are being used less, but they are still used in a fair number of cases,” Berez asserts, also noting that somewhere between one-third and one-half of all centres still employ these devices in their thrombectomy practices.

As such, with APRO®—a technology being distributed by Medtronic since 2023—Berez and the Alembic team sought to develop a catheter that would offer comparable trackability to today’s gold standard, but would simultaneously be robust enough to maintain its shape during use; would not collapse while aspirating; and could be used in conjunction with ancillary devices like stent retrievers.

Key features

Berez notes multiple characteristics of the APRO catheter that, in his view, enable it to achieve this overarching goal. The first feature he draws attention to is a “lubricious liner” material on the device’s surface that extends all the way to the tip of the catheter. The key benefit of this, according to Berez, is that it promotes improved interaction with stent-retriever devices, and thus is well-suited to physicians who favour a combined thrombectomy approach whereby an aspiration catheter is deployed in conjunction with the SolitaireTM revascularisation device (Medtronic) or an alternative stent retriever.

He also details the “extensive length” of hydrophilic coating on the APRO device, which reduces friction and makes the catheter’s surface “glide” across the blood vessels while it is being deployed and advanced.

“What that means is the force that you have to apply to advance the catheter is reduced, making it easier to advance and putting less stress on the vessel,” Berez clarifies.

He further notes that the reinforced construction and design of the device with braids, coils and polymers allows it to resist “ovalisation” and kinking while traversing bends in the patient’s vasculature, and

The APRO catheter©

© 2024, November Medtronic, Inc. REPRINTED WITH PERMISSION-ALL RIGHTS RESERVED

maintain its shape under aspiration force as well.

Touching on the different iterations of the device that are either currently or soon-to-be available, Berez states that the largest catheter in the APRO family—the APRO 70, which has Aaron Berez an inner diameter of 0.07 inches— is already on sale in the USA, having gained Food and Drug Administration (FDA) clearance late last year. Smaller sizes are in the works, he continues, with APRO 55 having been submitted to the FDA and US clearance anticipated at the beginning of 2024 and an even smaller version of the catheter not far behind.

“What we are trying to do is provide physicians with catheters that are easy to use, and can be used together to treat a wide range of intracranial occlusions—from small vessels in the periphery [of the neurovasculature] to large vessels like the MCA [middle cerebral artery], and even larger vessels like the ICA [internal carotid artery],” Berez adds. “The goal of aspiration thrombectomy is to reestablish flow quickly and safely, and APRO can do that. And, in properly selected patients, that can result in less brain damage and smaller infarct sizes.”

The trackability seems consistent and reliable. I have also been advancing the APRO catheter with larger 0.035-inch neurovascular guidewires alone to gain intracranial access.”

Michael Chen

DISCLAIMERS: Solitaire™ is a trademark of Medtronic, Inc. Phenom™ is a trademark of Medtronic, Inc. APRO® is a registered trademark of Palmera Medical and is manufactured

by Alembic LLC™. The APRO catheter is currently only approved and available in the USA. Indications, contraindications, warnings and instructions for APRO® 70 Catheter can be found in each device package. Indications, contraindications, warnings and instructions for use for all other products can be viewed at www.medtronic.com/manuals.

Issue 52 | December 2023

Advertorial 25

APRO tailored to “effective” combined approach in stroke thrombectomy “I TYPICALLY USE COMBINATION THERAPY, which means pairing SolitaireTM [Medtronic] with an aspiration catheter, and I do so because I think it is the most effective way of extracting a clot in the setting of acute ischaemic stroke,” says Daniel Sahlein (Goodman Campbell Brain and Spine, Indianapolis, USA), providing NeuroNews with a snapshot of his paradigm for mechanical thrombectomy procedures.

To support this statement, Sahlein draws on his team’s “very large” interventional stroke practice— which, at time of writing, is on pace to perform roughly 300 thrombectomies across all of 2023.

“We have tried many different techniques, and we feel that combination therapy works best,” he says. “We are doing an average of six thrombectomies a week— which means we are doing up to 10 or 15 in some weeks—and we can really see, with our own eyes, the difference in efficacy between the different techniques.

“Combination therapy, I think, works best, and the technique that works best to cleanly extract a clot also leads to better clinical outcomes—and there is overwhelming evidence to support this contention. So, that is the strategy that I personally favour.”

Here, Sahlein cites the five major randomised controlled trials, published in 2015, that helped to establish the superior efficacy of mechanical thrombectomy over standard medical care at the time.

These trials all saw the Solitaire revascularisation device being used to deliver the majority of thrombectomy treatments.

Subsequent studies have indicated that “good recanalisation” is achievable via an aspiration-only approach but, he stresses, these outcomes are still inferior to those demonstrated when a stent retriever and an aspiration catheter are deployed in tandem.

And, according to Sahlein, while COMPASS and aspiration catheter he prefers to use in conjunction ASTER both found broadly similar outcomes between with Solitaire—is more of a newcomer on this stent retriever- and aspiration-only approaches, a particular scene. closer look at more granular data from these studies He details that he has been using APRO reveals some “compelling” pieces of evidence catheters since July 2023, integrating them into his supporting combination therapy as well. thrombectomy practice almost immediately after In COMPASS, he explains, some 15% of stent it became available in the USA earlier in the year. retriever-first cases did use concomitant aspiration, Discussing the key benefits of the device, Sahlein which Sahlein feels is “a lot” given the potential avers that it offers a level of trackability that places benefits of combining the two techniques. it in “the elite tier of catheters”, but that “it In addition, 21% of patients in COMPASS’ is a little bit more robust than those other aspiration-first arm ended up using a stent offerings” as well. retriever in subsequent passes—with all of “This [robustness] helps in more than one these using aspiration with the stentriever or way,” he continues. “One of them is if you a “true” combined approach. are going to pair it with Solitaire, and another Although ASTER reported equivalent one is the fact that, under maximal negative clinical outcomes between its stent retrieverpressure, some of these catheters actually and aspiration-first arms, Sahlein highlights have a tendency to collapse slightly—and Daniel Sahlein that modified Rankin scale (mRS) 0–2 rates you can even see that at the proximal end of were roughly 5% higher with a stent retriever. the catheter during a case.”

He also points out that this superiority was achieved According to Sahlein, the robustness of APRO despite the stent-retriever group potentially being makes it less susceptible to these potential difficulties, “hamstrung” by having 6% more carotid terminus firstly by enabling it to resist negative pressure and occlusions—technically challenging cases typically maintain its full luminal diameter—which helps associated with worse clinical outcomes—than the with flow and clot extraction—but also via the aspiration group. Sahlein avers that evaluations of aforementioned ability to pair it with Solitaire. aspiration-only compared to combination therapy “At this point, there are a number of tools [in stroke found a 5% higher rate of good recanalisation with thrombectomy] that are more on the commoditised the latter technique when looking at technical efficacy side of things; they are all fairly similar in terms of after first-line treatment alone (using cohort-assigned performance, and within the same class,” Sahlein thrombectomy technique only versus first pass with concludes, outlining the thought process that led him subsequent potential crossover). Overall analyses of to choose APRO in the first place. “And so, for me these data reveal technical success outcomes that “tip personally, I choose in part based on who I would like towards use of a stent retriever”, he notes, with clinical to partner with and who I think represents best-in-class outcomes leaning even more heavily toward favouring in terms of their commitment to serving neurovascular stent-retriever usage. “I think that use of Solitaire patients; their commitment to investing in research to really augments and improves aspiration in many move the field forward; and in terms of their current ways, and does not detract in any way,” he adds.. portfolio. I see Medtronic leading in all of these areas Sahlein’s stent retriever of choice for this combined in their neurovascular work and so, all things [being] approach is Solitaire—a well-established industry equal, if you have a tool that falls into a category that leader that played a pivotal role in cementing is a little more commoditised, selecting this tool based thrombectomy as a new standard of care in selected on who you desire to partner with in this space, I stroke patients. However, APRO® (Medtronic)—the think, is a great way to go about doing things.”

Why “consistent and reliable” APRO catheter is well-suited to aspiration-first thrombectomy

Paying mind to current debates surrounding the benefits of stent retrievers, aspiration catheters, or a combination of the two, in the treatment of acute ischaemic stroke patients, Michael Chen (Rush University Medical Center, Chicago, USA) discusses why he prefers the aspiration-first approach—and chooses to deploy the APRO® catheter in his thrombectomy practice.

Why is ADAPT your chosen first-line technique when it comes to thrombectomy?

As outlined in the paper describing ADAPT [A Direct Aspiration First Pass Technique], published nearly 10 years ago in the Journal of NeuroInterventional Surgery by Turk et al and colleagues, the initial primary advantages were speed, safety and cost. Effectiveness was still modest at the time, with a <50% rate of firstpass effect. Since then, there have been significant improvements in catheter trackability—at the distal tip, the transition zones, the hydrophilic coating and proximal support to help track around tortuous vessels, and move past edges caused by branch origins, such as the ophthalmic artery. Future

iterations include different aspiration forces being applied, and compatible guide catheters that track as high as the cavernous carotid or higher, all promise to improve the rate of firstpass complete reperfusion. Personally, I prefer hydrophilic catheters to be the primary contact with the endothelial cell wall rather than a nitinol laser-cut stent with outward radial force.

What characteristics do you look for in an aspiration catheter?

Although much of the recent design iterations have focused on increasing the size of the inner lumen diameter to maximise aspiration force, the bigger challenge has been balancing this feature with catheter trackability. The

construction of the catheter a couple minutes or wiping wall, with or without certain them down several times with liners, hydrophilic exteriors, a wet Telfa dressing. A good and use of braiding, are sign of a highly trackable, among the elements that hydrophilic catheter surface have undergone iterations. is one that is very slippery as All of this adds up to query you are trying to advance it whether it is possible, after into the rotating haemostatic Michael Chen positioning the tip of the valve of the guide catheter— aspiration catheter at the which I have certainly noticed proximal face of the clot, for the with APRO. The trackability seems catheter to then be independently consistent and reliable. I have also advanced under aspiration to envelop used it in conjunction with a stent the entire length of the clot. The one retriever and encountered no issues performance characteristic that captures with any deformation of the catheter all the essential design elements, to tip. Although, as per instructions for me, is whether—after positioning the use (IFU), it is recommended to be used catheter tip at the mid-M1 segment—it with microcatheter, I have also been can then be advanced under aspiration, advancing the APRO catheter with larger by itself, to the dominant M2 branch.

0.035-inch neurovascular guidewires Truth be told, particular guide catheters alone to gain intracranial access. that can be placed distally, such as near the cavernous segment, greatly help the Why did you opt to switch performance of aspiration catheters. to APRO in your practice?

I think the performance of the Sofia What are your clinical aspiration catheter [Microvention/ experiences with the APRO Terumo] proved the value of high catheter to date? trackability with these devices. It is My first-hand clinical experiences with reassuring to know that the APRO the APRO catheter to date have been catheter is tested and able to achieve favourable. I do take the time to hydrate high trackability while maintaining the exterior of the catheters by either sufficient structural integrity after letting them sit in a bowl of saline for multiple stent-retriever passes.

December 2023 | Issue 52

26 Carotid Interventions

CAROTID 20.2%), and were more often of Black/African Rates of stroke, death and myocardial infarction vs.

American ethnicity (7.5% vs. 4.3%), as compared with their male counterparts. post-TCAR do not differ by patient sex “There were no differences by sex in term of

While sex disparities regarding the outcomes of carotid revascularisation have “long been a concern”, new prospective data published in the Journal of Vascular Surgery (JVS) indicate that no such disparity exists between male and female patients treated with transcarotid artery revascularisation (TCAR; Silk Road Medical)—one of the most prominent approaches used to treat carotid artery stenosis.

W

riting in JVS on behalf of the ROADSTER trial investigators, Vikram Kashyap (Frederik Meijer Heart and Vascular Institute at Corewell Health, Grand Rapids, USA) and colleagues report “exceptionally low” rates of stroke, death and myocardial infarction (MI) derived from prospective TCAR trial data. They further note that these low rates “do not differ by patient sex”.

Previously, several studies of carotid revascularisation have demonstrated increased frequencies of postoperative death and stroke for female patients after either carotid endarterectomy (CEA), or transfemoral carotid artery stenting (CAS). In addition, adverse events after transfemoral stenting are higher in female patients, particularly in symptomatic cases, the authors relay.

In prospectively analysing results from the ROADSTER 1, ROADSTER 2 and ROADSTER Extended Access TCAR trials, Kashyap and colleagues’

objective was to investigate post-TCAR outcomes stratified by patient sex. They hypothesised that the results would be similar between males and females.

All included patients had verified carotid stenoses meeting the criteria for carotid intervention (≥80% in asymptomatic and ≥50% in symptomatic patients), and were included based on anatomical or clinical high-risk criteria for carotid stenting.

The researchers’ primary outcomes were a combination of stroke/death (S/D) and stroke/ death/MI (S/D/M) at 30 days, while secondary outcomes were the individual components of stroke, death, and MI. Kashyap and colleagues included a total of 910 patients for analysis, roughly two thirds of whom were male (n=604; 66.4%).

They note that female patients were more often <65 years old (20.6% Vikram vs. 15%) or ≥80 years old (22.6% Kashyap

No relationship found between DW-MRI lesions and long-term stroke risk following carotid revascularisation A secondary analysis of existing clinical trial data has indicated that new ischaemic brain lesions detected via diffusionweighted magnetic resonance imaging (DW-MRI) following carotid artery revascularisation—either with carotid artery stenting (CAS) or carotid endarterectomy (CEA)—do not appear to have a relationship with long-term stroke risks.

“THE RESULTS FROM our TIA following a CAS procedure, but analysis do not support the role of that the trial failed to demonstrate ischaemic brain lesions discovered any association between DW-MRI on [DW-MRI] after carotid lesions and recurrent stroke/TIA risks revascularisation procedures as risk following CEA. markers for long-term recurrent “The establishment of the longerstroke or TIA [transient ischaemic term clinical relevance of the attack],” authors Gert J de Borst [DW-MRI] lesions after carotid (University Medical Center Utrecht, revascularisation procedures is The Netherlands) et al essential in the process of write, concluding their implementing a universally report in the journal accepted surrogate outcome,” Stroke. “However, as new De Borst and colleagues note. periprocedural [DW“Today, thus far, there are MRI] lesions seem to be a no data describing adverse marker for early recurrent Gert J de Borst events in [DW-MRI]-positive cerebrovascular events, patients beyond five-year future randomised studies are needed follow-up. Therefore, in this study, we to evaluate whether the effect of intended to determine the long-term treatment on these lesions corresponds cerebrovascular outcome in [DWto the effect of treatment on procedural MRI]-positive compared with [DWstroke before surrogacy can be MRI]-negative patients after carotid validated.” revascularisation procedures.”

The researchers initially posit that The authors report that their five-year follow-up findings from study—a secondary, observational, the randomised International Carotid prospective cohort analysis—included Stenting Study (ICSS) indicate an 162 patients with symptomatic increased risk of recurrent stroke or carotid stenosis who were previously

comorbidities, current or prior smoking status, prior stroke, symptomatic status, or prevalence of anatomical and/or clinical high-risk criteria,” the authors disseminate. “General anaesthetic use, stent brands used and procedure times did not differ by sex—although flow reversal times were longer in female patients, [and] more contrast [was] used in procedures for female patients.”

In addition, both the 30-day rates of S/D (2.7% male vs. 1.6% female) and S/D/M (3.6% male vs.

2.6% female) were similar between the two groups of sex-stratified patients. The researchers also found that these key outcome measures did not differ when patients were stratified by symptom status either.

Comparable findings were identified in terms of secondary outcomes—including stroke rates at 30 days—too.

“Univariate analysis demonstrated that history of a prior ipsilateral stroke was associated with increased odds of S/D (odds ratio [OR] 4.19) and S/D/M (OR 2.78), as was symptomatic presentation with increased odds for S/D (OR 2.78),” Kashyap and colleagues aver in conclusion.

randomised to CAS or CEA in ICSS, and were subsequently included in the ICSS MRI substudy. They further relay that the primary composite clinical outcome of their analysis was the time to any stroke or TIA during follow-up.

Patients with new DW-MRI lesions on post-treatment MRI scans (DWI+) were compared with patients without new lesions (DWI–), De Borst et al add.

For the 162 patients included in the ICSS-MRI substudy between January 2004 and October 2008, 110 general practitioners (GPs) ultimately provided long-term follow-up data for the present study. Discussing the baseline characteristics of this patient population, De Borst et al note that those in the DWI+ group were more often treated with CAS, while total cholesterol at randomisation was higher in the DWI− group.

Cumulative incidence of any stroke or TIA after 12.5 years

35.3% 31.1%

in DWIpositive patients

in DWInegative patients

Relaying their results, the authors state that the median follow-up time was 8.6 years, and that Kaplan-Meier cumulative incidence for the primary outcome after 12.5 years of followup was 35.3% in DWI+ patients and 31.1% in DWI− patients. With respective hazard ratios of 1.5 and 1.3, univariable and multivariable regression analyses did not show significant differences between these two patient cohorts, they add.

Separate analyses, specifically relating to CAS and CEA, showed that the higher primary outcome rate in DWI+ patients across the entire cohort was mainly caused by CAS group events.

“In the ICSS MRI substudy, both the presence and count of [DW-MRI] lesions were associated with recurrent stroke/TIA occurring after the posttreatment scan, with most events seen in the first six months after treatment,” De Borst and colleagues write. “The results of the present study showed that this association was no longer present after 12.5 years of follow-up.

In addition, the analyses with [DWMRI] counts were largely influenced by the small number of patients with high [DW-MRI] lesions, which lost the association with the clinical outcomes after bootstrapping the HR CIs [hazard-ratio confidence intervals].

“This supports the hypothesis that [DW-MRI] lesions are caused by thromboembolic material or atherosclerotic plaque debris during and after the carotid revascularisation procedure, and therefore might be used as surrogate markers of early recurrent stroke/TIA but not for long-term ischaemic events.”

Issue 52 | December 2023

Carotid Interventions 27

CMS confirms broadened US coverage of carotid artery stenting The US Centers for Medicare & Medicaid Services (CMS) has released its final decision regarding National Coverage Determination (NCD) 20.7 for carotid artery stenting (CAS), essentially confirming the coverage expansion outlined in a proposal from July.

THE CMS OUTLINED IN THE final decision memo, dated 11 October 2023, that it had found coverage of percutaneous transluminal angioplasty (PTA) of the carotid artery concurrent with stenting to be “reasonable and necessary” with the placement of a US Food and Drug Administration (FDA)-approved carotid stent alongside an FDA-cleared embolic protection device for Medicare patients who have symptomatic carotid stenosis ≥50% and asymptomatic carotid stenosis ≥70%.

In addition to expanding Medicare coverage to individuals previously only eligible for CAS coverage in clinical trials, and removing the limitation of coverage to only high-surgical-risk individuals, the CMS’ final decision takes away several facility standards and approval requirements as well as leaving coverage for any CAS procedure not described in the NCD to Medicare Administrative Contractor (MAC) discretion.

This expansion—the first revisiting of US CAS coverage in more than a decade—has received support from medical societies spanning a range of disciplines, including the Society of NeuroInterventional Surgery (SNIS), Society of Interventional Radiology (SIR), Society for Cardiovascular Angiography and Interventions (SCAI), and Vascular Interventional Advances (VIVA) Foundation. A number of companies in the vascular space have also voiced endorsements for the expanded coverage, including Boston Scientific and Cordis.

However, one group that publicly expressed reservations over the initial proposal from July—and has done so again following the CMS’ announcement of its final decision—is the Society for Vascular Surgery (SVS).

In a communique to its members on 12 October, the SVS claimed the final decision from the CMS contained “few substantive changes from what was proposed in July”, before adding that “while this outcome was anticipated, the SVS remains concerned”.

The proposal

These now-confirmed adjustments to NCD 20.7 stemmed from a formal request to the CMS from the Multi-Specialty Carotid Alliance (MSCA) in June 2022. The basis of this request was the fact that—since the CMS’ prior consideration of reimbursement in 2009—there have been “substantial advances” in the

field of CAS. These include data from a number of randomised controlled trials (RCTs) including CREST, SPACE-2, ACST-2 and ACT-1; multiple prospective registry-based studies and pooled meta-analyses; new techniques and devices; and, “perhaps most importantly”, improvements in operators’ understanding of how to better select candidates for CAS to avoid periprocedural complications.

“Given these advances, the current CMS coverage decision is outdated,” the MSCA stated in its initial request.

“The current evidence strongly supports Medicare coverage for CAS performed by qualified operators in appropriately selected patients (both high surgical risk and average surgical risk) for symptomatic patients with ≥50% and ≤99% carotid stenosis, and asymptomatic patients with ≥70% and ≤99% stenosis. Further, given the maturity of the CAS procedure and the medical specialty societies’ guidelines and recommendations for best practices, facility and operator requirements should be managed at the local facility level as it is for other procedures, rather than strictly managed by the Medicare coverage policy.”

The reaction

The group’s proposal led the CMS to initiate a national coverage analysis and open an initial public comment period running from 12 January to 11 February 2023. During this time, a number of leading societies voiced support for an update to the existing coverage policy regarding CAS procedures. For example, on 7 February, the American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS) and AANS/CNS Cerebrovascular Section sent a letter to the CMS urging the agency to update its NCD policy for carotid stenting.

“In 2009, the AANS and the CNS disagreed with proposals to expand coverage for CAS to asymptomatic patients based on the available evidence at that time,” they stated. “However, as noted in the letter, since then, multiple RCTs have been published, physicians from several different specialties have amassed extensive real-world experience, and data have been collected as part of national registries.

Therefore, neurosurgery now urges CMS to revisit the coverage for CAS.” Other societies that commented during this period and were seen to favour the proposed coverage update

included the Society of Vascular and Interventional Neurology (SVIN), and—jointly—the American College of Cardiology (ACC) and American Heart Association (AHA), with the latter group writing that “we support expansion of access to this widely performed procedure that has wellestablished safety and health outcomes”.

Through this period, many of the aforementioned societies—the SNIS, SIR, SCAI and VIVA—also backed the concept of expanding NCD 20.7.

The most notable opponent of a change in these coverage policies was the SVS—along with the SVS Patient Safety Organization (PSO) Vascular Quality Initiative (VQI). On 9 February, the SVS commented that it “does not recommend any change in the current policy”, also averring that “the procedures covered within NCD 20.7 are not without significant risk for patients, even when provided by a highly experienced vascular surgeon”.

“If CMS moves forward with this reconsideration, we strongly encourage an emphasis on the collection of realtime data, paired with the continuation of the credentialing process and requirements for reporting standards,” the SVS added. “These elements are critical for ensuring a high degree of patient safety.”

The CMS ultimately noted that, during this initial 30-day period,

The MSCA applauds this decision, which will ensure that Medicare patients will have access to the full range of therapies that are available.” it received a total of 193 timely comments, with the majority (146) supporting the expansion of coverage criteria in one or more areas. Seven of these comments were submitted on behalf of companies, with Abbott and Medtronic among those endorsing policy changes, and most of the remaining comments coming from individual healthcare professionals— mostly physicians.

One company that voiced opposition to NCD 20.7 being amended was transcarotid artery revascularisation (TCAR) pioneer Silk Road Medical, which argued that there is “insufficient evidence” to warrant “broad, unrestricted expansion” of CAS coverage, as requested by the MSCA. Following this, the CMS later opened another 30-day comment period between 11 July and 10 August 2023 to source additional input from the field. Notably, this second period immediately followed the CMS’ posting of a proposed decision memorandum

outlining potential alterations to CAS coverage. The agency reported having received 760 timely comments in total, adding that these were “closely split” over its proposals, with 381 comments expressing “at least some degree of support” for expanded coverage of CAS, and 358 expressing opposition.

The outcome

The posting of the CMS’ final decision memorandum—ultimately confirming the policy changes it had outlined earlier in the year—was applauded by the vast majority of the vascular, cardiovascular and neurointerventional societies who had initially endorsed expanded CAS coverage.

In a press release, the MSCA said: “As the entity that made the formal request for this consideration, the MSCA applauds this decision, which will ensure that Medicare patients will have access to the full range of therapies that are available, including carotid endarterectomy [CEA], transfemoral CAS, transradial CAS, and TCAR. The MSCA also wishes to emphasise that optimal medical therapy [OMT] remains the foundation for treatment, and CAS, CEA or TCAR should be offered only to those who are deemed appropriate for revascularisation on top of OMT.” In addition, the MSCA’s statement posited that the CMS’ “thorough analysis” and the “challenging deliberations that they undertook” ultimately led to a decision that is “in the best interest of Medicare beneficiaries and the American public”.

“The MSCA now urges all stakeholders to join forces to ensure safe and proper implementation of this decision, so that patients receive the highest quality and most appropriate care,” it continued. “The MSCA looks forward to working with CMS, medical societies and other professional medical organisations, industry partners, and patient representatives, to achieve this goal.”

Meanwhile, in a preliminary response, the SVS said it was “disappointed” in the CMS’ decision to finalise expanded coverage under NCD 20.7 “without any substantive revisions”.

“We believe the coverage expansion outlined in the updated NCD 20.7 is premature given the pending results of the National Institutes of Health-funded CREST-2 trial and holds significant potential to increase risk in achieving quality of care and patient safety, particularly for our most vulnerable elderly patients,” it added. “SVS remains concerned about the potential impact of this decision and will continue to stress the fundamental importance of vigilant reporting and monitoring of outcomes, requiring requisite training and experience in patient selection and performance of the procedure, and the need for a verified multi-specialty ‘shared decision-making’ tool, which is referenced in the decision but does not yet exist.”

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Issue 52 | December 2023

Charing Cross Symposium 29

CX 2024: New technologies and “special cases” underpin carotid and acute stroke programme With a renewed focus on challenging cases, novel technologies and, overall, the most pressing issues in carotid treatments and acute stroke care, the 2024 Charing Cross (CX) Symposium (23–25 April, London, UK) intends to maximise audience participation across its Acute Stroke, Carotid and Neurointervention Controversies programme.

AS PART OF A RECENT MEETING previewing the CX 2024 programme— broadcast live from the CX Studio on Thursday 26 October—session moderator and CX co-chair Dittmar Böckler (University of Heidelberg, Germany) was asked whether carotid endarterectomy (CEA) remains the gold standard in treating carotid artery stenosis, as it has been for decades.

“Based on randomised trials, registries and guideline recommendations, CEA definitively remains the gold standard, but we need different options for individualised patient care as well,” he said. “Best medical treatment, and compliance to it, is very important, and we also need complementary carotid stenting in certain indications.

The challenge in stroke prevention and treatment is when to use which modality.”

Following this, CX Executive Board member Barbara Rantner (Ludwig Maximilian University of Munich, Germany), who helped curate the upcoming Acute Stroke, Carotid and Neurointervention Controversies programme, provided a preview of what delegates can expect from this session.

“There are a lot of controversies [on the programme], and this is a key element of the acute stroke session,” she said. “We have tried to address critical issues; not only in the carotid but also in the vertebral basilar circulation. This year, we are focusing a little bit more on symptomatic stenoses and we will discuss these issues with experts from all over the world.”

Teasing out some of the programme elements she feels will be especially interesting, Rantner highlighted one debate on whether or not CEA is still the standard of care over best medical treatment—even in patients with symptomatic internal carotid artery (ICA) stenosis. She also drew attention to a second debate examining the optimal treatment strategy—CEA or carotid artery stenting (CAS)—in tandem lesions, where “intracranial thrombectomy is necessary, and the underlying extracranial carotid artery needs to be treated” as well.

Domenci Valenti (King’s College Hospital, London, UK), whose recent addition to the Acute Stroke, Carotid and Neurointervention section of the CX Executive Board is sure to

OBITUARY

Roger M Greenhalgh (6th February 1941– 6th October 2023) ROGER MALCOLM GREENHALGH, the surgeon internationally renowned for his unparalleled contribution to vascular education, training and research, died peacefully on 6 October, aged 82. At the time of his death, he was emeritus Professor of Surgery at Imperial College in London and head of its Vascular Surgery Research Group.

Professor Greenhalgh received recognition for his lifelong contributions to vascular surgery from multiple prestigious groups, including, most recently, an honorary Fellowship of the American College of Surgeons in October 2018, and the first ‘Living Legend’ or International Lifetime Achievement Award from the Society for Vascular Surgery (SVS) in June 2018 after being nominated by the European Society for Vascular Surgery (ESVS).

Enrico Ascher (New York University, New York, USA), who presented the award and is a past president of the SVS, said of Professor Greenhalgh at the time: “He leads by example. Not only by

bring a wealth of fresh ideas to the in the USA, but is currently unavailable symposium programme, then picked in Europe. out the introduction of a ‘Carousel’ During the livestream, Valenti whereby physicians will present “very described this as an alternative method to difficult cases for which there is not more traditional CEA and transfemoral yet a standardised treatment defined by CAS approaches that is “emerging very guidelines” as a potential highlight. fast” and seems to be “very popular” “These are special cases where we with US vascular surgeons, as it creates do not necessarily know what to do,” the possibility of treating carotid disease he added. “We want to show what we patients via a hybrid procedure. Michael did, and what went right and what went Stoner (University of Rochester, USA) is wrong, because among those set to this will stimulate present on TCAR the audience to at CX 2024. contribute actively The addition during the session.” of another new Rantner and name to the Valenti are among CX programme those delivering committee, Carousel cases Kyriakos Lobotesis throughout the (Imperial College programme, with London, UK), other prominent looks set to expand interventionists discussions at including Levansri Makalanda next year’s meeting even Clockwise from (Barts Health NHS Trust, further, into the wider realm top left: Dittmar London, UK) set to present of neurointervenional surgery.

Böckler, Stephen experiences too.

During the Acute Stroke, Greenhalgh, “I am very much looking Carotid and Neurointervention Barbara Rantner and Domenico forward to the Carousel of Controversies sessions, Valenti case presentations,” Böckler delegates can expect an commented. “This is going to really increased focus on novel technologies, encourage people to stand up, go to including novel filter systems and the microphone and participate in the stent designs, as well as flow-diversion discussion—and I think Professor treatments for intracranial aneurysms [Roger] Greenhalgh would have loved to and the expansion of mechanical have participated in this session!” thrombectomy for ischaemic stroke.

In another example of the CX 2024 “I think the vascular community may programme bringing forth new ideas be very interested to hear about those and examining the latest developments new technology advances,” Rantner said. in acute stroke care, a number of The CX 2024 Acute Stroke, Carotid presentations will cover transcarotid and Neurointervention Controversies artery revascularisation (TCAR)—a programme is set to take place in relatively recent addition to the Theatre 3 of the symposium’s new home armamentarium of carotid artery stenosis at ExCeL London on the morning of treatments that has been widely adopted Wednesday 24 April.

his contributions, or his political influence, or his knowledge, or trials, but actually as a person. As a person who is totally committed to his profession, to his family, to his friends, to his peers. He thinks first about them, and not about himself. That is what makes him a moral leader, and what sets him apart.”

Writing in the European Journal of Vascular and Endovascular Surgery following Professor Greenhalgh’s receipt of this award, his long-time research partner Janet Powell (Imperial College London, UK) described him as a “brilliant” clinician with a “long and distinguished” research career, also noting that “medical students and junior doctors have queued for the opportunity to work in his team”. Professor Greenhalgh’s surgical skills were recognised on innumerable occasions; he was selected by the White House Medical Unit as the surgeon who would operate Roger Greenhalgh on President George H W receiving the first Bush, if needed, during his SVS Living Legend award from visit to London in 1991.

Enrico Ascher In the days following his passing, Professor Greenhalgh’s clinical and academic achievements were acknowledged by several international surgical societies. The ESVS shared that his pioneering work

will have a “lasting impact on patient care, surgical techniques, and the advancement of evidence-based medicine in the field”. Leading members of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) also wrote that Professor Greenhalgh was “not only a pioneer in the operating theatre and in the advancement of vascular surgery, but also a compassionate and dedicated physician who touched the lives of countless individuals”.

Among Professor Greenhalgh’s many contributions to vascular research are the UK Small Aneurysms Trial (UKSAT) and the UK endovascular aneurysm repair (EVAR 1 and 2) trials, for which he was principal investigator, as well as the MIMIC, VGST and IMPROVE studies. He also founded the Charing Cross (CX) series of international symposia and annual books in 1978, and was chair of the CX Symposium until his death—most recently presiding over its 45th edition in April 2023.

Professor Roger Greenhalgh, MA MD MChir FRCS, was married to Karin Maria (née Gross), who died in April 2020 from COVID-19.

They were happily married for over 55 years and her constant support was integral to his success.

To read the full obituary, visit: neuronewsinternational.com/obituary-roger-mgreenhalgh-6th-february-1941-6th-october-2023.

December 2023 | Issue 52

30 New Frontiers

INTERVIEW

Recent breakthroughs represent “baby steps” towards wider use of brain-computer interfaces “The possibility to restore mobility to patients could have tremendous benefits,” says Mitchell Elkind, chief clinical science officer of the American Heart Association (AHA), and a tenured professor of neurology and epidemiology at Columbia University (New York City, USA), outlining the significant potential held by brain-computer interface (BCI) technologies in conversation with NeuroNews. “For those with limited function, even small gains can be life-altering. These gains may lead not only to increased ability to go out of the home, interact with friends and neighbours, and enjoy life; but they may also lead to positive mental health benefits, as patients may then be less depressed.”

IN RECENT WEEKS AND months, a number of breakthroughs involving BCIs have been made public.

Late last year, the Wyss Center for Bio and Neuroengineering in Geneva, Switzerland presented positive animalmodel results with its implantable Ability BCI system—describing this as an “important step” on the road to eventual human trials of the device.

More recently, Onward Medical and Precision Neuroscience have shared major updates in this space.

In May, Onward published a paper in Nature detailing how its spinal cord stimulation (SCS) therapy had been used alongside a wireless BCI to give a patient augmented control over movement of his paralysed legs. The following month, Precision announced the successful completion of first-inhuman implantations of its Layer 7 Cortical Interface as part of a pilot study evaluating the device.

And, over the past year, Synchron has provided several updates regarding its endovascular BCI offering— including completed enrolment for its US COMMAND trial in September, with a total of six severe quadriparesis patients having been implanted with the company’s motor neuroprosthesis technology to date. Another innovation that has perhaps featured in more mainstream media coverage than any other is Neuralink’s N1 implant—on 19 September, the company announced recruitment had opened for its first-inhuman PRIME study following reviewboard approval.

However, despite once again asserting that BCIs hold “a great deal of promise for neurological disorders in general, including stroke as well as spinal cord injury [SCI]”, Elkind feels it is appropriate to distinguish between the different conditions and instances in which these innovative devices could— in theory—be used.

A bridge too far?

According to Elkind, fundamental distinctions between stroke, and conditions like SCI or amyotrophic

lateral sclerosis (ALS), create “certain challenges” when it comes to restoring physical function.

“That is because stroke primarily affects the brain itself,” he explains.

“When the brain and the primary nerve tissue are injured—as is usually [the case] with a stroke—the neural connections that underpin the ability to move are the ones that are affected.

[In those instances], a BCI may be less successful in capturing brain activity to trigger physical function, and I think we have more to learn about how to interpret the brain signals in stroke patients to allow them to regain movement.

“Where these technologies probably work best—at least right now—is by [creating] a bridge between the brain, where the signal originates, and the lower spine or the peripheral nervous system, where the movement is carried out. It is one thing to bridge two parts of the nervous system, each of which is working relatively normally. But, when the originator of the neural information, the brain itself, is damaged because of a stroke, that is a [bigger] problem. It

is like the difference between having a fuse blown versus a wire in an electrical system cut.”

However, Elkind does highlight one relatively small stroke subset in which logic dictates BCIs may carry more promise: those affecting the brain stem, in between the base of the brain and the spinal cord. Brain stem strokes can be ischaemic or haemorrhagic in nature, and like spinal cord injuries can involve weakness on one or both sides of the body. The complex array of symptoms associated with brain stem strokes may also include vertigo, dizziness and severe imbalance, as well as double vision, slurred speech, and decreased consciousness. “[The brain stem] is an area that does act more like a bridge, similar to the spinal cord, and so injury to the brain stem may be able to be bypassed by one of these BCIs,” Elkind notes.

“And, for patients who have the most feared type of brain stem stroke— locked-in syndrome, where the pons (which literally means bridge) is damaged by a stroke and messages cannot get through—these devices may be very helpful. We need to see more evidence supporting that, but this could potentially be a gamechanger for these specific patients.”

Complexity of the problem

The degree of recovery that can be achieved in patients with reduced movement and function is dependent, Elkind adds, on both the location and the severity of the damage suffered. He also points to the fact that “disabilities after neural injury come in many different shapes and sizes”.

“For patients who are locked in, and unable to move anything from the face down, the ability to use a computer independently is a great leap forward.

Affected individuals have written beautiful books using lesser systems,” he avers. “The mechanical adaptations that will allow movement would likely

Where these technologies probably work best—at least right now—is by [creating] a bridge between the brain, where the signal originates, and the lower spine or the peripheral nervous system, where the movement is carried out.”

come later and seem less technically challenging than the ability to interpret neural activity using a computer interface in the first place.”

Here, Elkind alludes to another key variable in functional recovery: the extent of the patient’s impairment, but also the exact type of functionality being targeted. Fundamentally, he feels, BCI technologies in their current form are likely best-suited to restoring movements involving the hips and legs—because the signals sent to those larger muscle groups to facilitate walking, for example, are “much simpler”.

“You can imagine it is easier, at this stage, to develop computers that can make walking happen at the level of the spinal cord,” he goes on. “To move the hands and the fingers is a lot more complicated. A lot more of the space in our brains is devoted to the movement of our fingers, and our mouths, and our tongues, compared to the hips and the shoulders. So, to help people who have speech difficulty, as well as people with weakness of the hands and the fingers, [is more challenging], and I think we are a long way from somebody being able to play the piano or perhaps even write with a pen [using a BCI].

“Recent studies have been in very small numbers of patients with particular types of injuries. These are baby steps, and I expect it will be at least five years before technical kinks are worked out and larger trials are being done; and it may be 10 years before they begin to enter clinical practice; and another 10 years before they become an established standard of care. We know that medications shown to be effective take 15–17 years to make their way into clinical practice, so this may take as long or longer.

Epilepsy surgery has had similarly slow uptake. These treatments will likely be expensive, and it will be important for them to demonstrate significant clinical effects.”

Mitchell Elkind Mitchell Elkind

Issue 52 | December 2023

31

Intrathecal drug delivery effective for managing cancer-related pain, as per existing literature Two separate systematic reviews and meta-analyses—both published recently in Neuromodulation: Technology at the Neural Interface—have concluded that intrathecal drug delivery (IDD) systems are effective in the management of cancer-related pain, with one report also finding an average reduction in opioid consumption of >50% after IDD.

A

uthored by Rui Duarte (University of Liverpool, Liverpool, UK) and colleagues, the first of these papers initially posits that IDD—a therapeutic option that involves the targeted delivery of analgesics to the intrathecal space—and spinal cord stimulation (SCS) systems have been proposed and assessed for the management of cancer pain, but “remain underused”.

As such, Duarte et al conducted a systematic review to evaluate the effectiveness and safety of IDD and SCS for cancer pain, searching a number of electronic databases for randomised controlled trials and observational studies of adults with pain related to cancer, or its treatment, who received an implantable IDD Rui Duarte or SCS system from 1988 to 2021. Their primary outcome was the change in pain intensity from baseline to the last available follow-up measured using a visual analogue scale or numerical rating scale. A total of 3,043 participants who received either IDD or SCS for cancer pain across 22 studies were included.

Duarte and colleagues report that eight studies reporting data for 405 participants with an IDD system could be included in the meta-analysis of pain intensity that showed a statistically significant reduction at the latest post-treatment follow-up time versus baseline, while six studies reporting data for 325 participants with an IDD system could be included in the meta-analysis of pain intensity that showed a statistically significant reduction up to one month after treatment versus baseline. A meta-analysis including studies of participants with either an IDD system or an SCS device showed “similar results”, and improvements in other outcomes following IDD implantation were also observed..

According to Duarte and colleagues, post-dural puncture headache was the most frequently reported complication, and urinary retention, nausea, and vomiting were all commonly

reported side-effects.

“Our results suggest that IDD is an effective and safe management option, and provides pain relief for patients with cancer pain,” the authors conclude. “Statistically and clinically significant results were observed for reduction in pain intensity up to one month, and the latest post-treatment follow-up, compared with baseline. However, the results should be interpreted with caution because of the limitations of the evidence available.”

In the second recently published systematic review of IDD in cancer pain management—authored by Christophe Perruchoud (Hôpital de la Tour, Meyrin, Switzerland) and colleagues—researchers identified studies evaluating the Christophe Perruchoud efficacy and/or safety of IDD with external or implanted pumps in patients with cancer-related pain between 1990 and 2019.

They went on to perform a meta-analysis of the existing data, using mean changes from baseline in pain levels at short-, mid-, and long-term intervals to examine IDD’s efficacy. Secondary objectives of their study included the effects of IDD on systemic opioid use (changes in opioid [oral morphine equivalent] daily dose) and infection rates.

Perruchoud and colleagues state that, overall, pain levels were found to have decreased from baseline, noting that—on a 0–10 scale—mean differences were -4.34 at 4–5 weeks; -4.34 at 6–12 weeks; and -3.32 at >6 months. In addition, weighted mean oral morphine equivalent consumption was reduced by 308.24mg/d, while weighted mean infection rates were roughly 3% for external and implanted pumps.

The authors describe the latter as being “comparable with other indications”.

As such, Perruchoud et al deliver a similar concluding message to Duarte et al, reporting that “meta-analyses show a statistically significant and sustained decrease in cancer pain with IDD, compared with baseline”.

Mean decreases in pain level from baseline (0–10)

4.35 4–5 weeks

4.35 6–12 weeks

3.32 >6 months

Boston, Nevro announce major acquisitions of neuromodulation companies BOSTON SCIENTIFIC Corporation and Nevro Corporation have both recently announced major acquisitions of companies in the neuromodulation space, incorporating Relievant Medsystems and Vyrsa Technologies into their respective pain management portfolios.

In November 2023, Boston announced the close of its acquisition of Relievant—the company behind the US Food and Drug Administration (FDA)cleared Intracept intraosseous nerve ablation system, which is used to treat a form of chronic low back pain (CLBP) called vertebrogenic pain.

The Intracept system—a basivertebral nerve ablation therapy—will be an addition to Boston’s existing chronic pain portfolio that already includes spinal cord stimulation (SCS), radiofrequency ablation, and an interspinous spacer procedure.

That is according to a press release from Boston.

This acquisition includes an upfront cash payment of US$850 million and undisclosed additional contingent payments based on sales performance over the next three years, the release adds.

In announcing its own recent acquisition in the final weeks of 2023, Nevro described Vyrsa as a privately held medical technology company focused on minimally invasive treatment options for patients with chronic sacroiliac (SI) joint pain.

Under the terms of this transaction, which signed and closed on 30 November, Nevro paid US$40 million at closing, and agreed to pay up to an additional US$35 million in cash or stock tied to the achievement of certain development and sales milestones, as detailed in a press release.

The release also claims that Vyrsa, which was established in 2021, is the only SI joint company that manufactures and supports a complete portfolio of US FDA-cleared, “state-of-the-art” SI joint fusion devices. Vyrsa’s portfolio allows physician utilisation of the established SI joint fusion Category I CPT codes at all approved sites of service for SI joint fusion procedures in the USA, according to Nevro.

The Vyrsa acquisition is projected to be accretive to Nevro in 2024 for revenue, as well as adjusted earnings before interest, taxes, depreciation and amortisation (AEBITDA), the release also states.

December 2023 | Issue 52

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New BENEFIT-02 trial data support effectiveness of Resonance multiphase stimulation paradigm Biotronik Neuro has announced that results from the BENEFIT-02 trial—the “first of its kind” to clinically evaluate a multiphase stimulation paradigm—support the effectiveness of Resonance multiphase stimulation used in the company’s Prospera spinal cord stimulation (SCS) system for the treatment of patients with chronic pain.

THE RESULTS FROM BENEFIT-02 HAVE been published in Neuromodulation: Technology at the Neural Interface by principal investigator Leonardo Kapural (Carolinas Pain Institute and Center for Clinical Research, Winston-Salem, USA) and colleagues.

“Former studies have shown good results with previously commercialised SCS technology, yet in practice we are still looking for ways to reduce patient burden and improve outcomes. This study is particularly exciting because it is the first in a series to explore how to do that,” said Kapural.

A Biotronik press release states that, in contrast with other currently available SCS therapies, Resonance requires less power and uses a proprietary, integrated circuit design to deliver a continuous, spatially and temporally distributed therapeutic pulse pattern across the spinal cord.

BENEFIT-02—a prospective, multicentre, randomised, single-blind, feasibility study—is part of a comprehensive research programme supporting Biotronik’s Prospera SCS system, which received US Food and Drug Administration (FDA) approval in March 2023. BENEFIT-02 assessed the safety and effectiveness of Biotronik’s new charge-distributed multiphase stimulation paradigm during an extended SCS trial. It included participants with chronic low

back and/or leg pain, and a baseline numerical rating scale (NRS) score for overall pain intensity ≥6.

After a successful commercial SCS trial, participants were randomised to multiphase SCS therapy, receiving approximately 600–1500Hz (therapy A) or 300–600Hz (therapy B) of stimulation. Following washout, therapy was delivered via an investigational external pulse generator and existing leads during an 11- to 12-day testing period.

Among the 65 patients completing the study, there was no statistically significant difference in mean NRS reduction or percentage pain relief between multiphase therapies A and B. In the at-home setting, 63.9% of participants reported greater pain relief with multiphase than with commercial SCS therapy, along with an increase in average sleep quality and physical activity.

Additionally, adverse events were rare, and Leonardo none were classified by Kapural investigators as serious.

On average, multiphase therapy required less power than its commercial counterparts.

“The short-term multiphase stimulation results here—combined with early findings from the long-term BENEFIT-03 study—show great promise for the future of SCS,” Kapural stated.

BENEFIT-03 is the first long-term evaluation of the Prospera SCS system with Resonance multiphase stimulation alongside automatic, daily, objective device monitoring, and remote programming, Biotronik claims. Interim data from the ongoing study are already available, with six-month results presented at the American Society of Pain and Neuroscience (ASPN) annual conference (13–16 July 2023, Miami, USA) demonstrating significant pain reduction in both inclinic and at-home settings, and less severe disability.

Former studies have shown good results with previously commercialised SCS technology, yet in practice we are still looking for ways to reduce patient burden and improve outcomes. This study is particularly exciting because it is the first in a series to explore how to do that.”

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Issue 52 | December 2023

33

NANS leads multi-society response to “methodologically flawed” SCS re-review in Washington state THE NORTH AMERICAN Neuromodulation Society (NANS) has led a multi-society response to the Washington State Health Care Authority (WSHCA) following its review of the current evidence on spinal cord stimulation (SCS). As per a NANS press release, the state of Washington is the only entity in the USA and western Europe that does not approve SCS for any diagnosis, for any patient, with insurance covered by the Health Care Authority—a decision affecting about 2.5 million Washingtonians. This situation has lasted for more than 12 years, the release also details.

Last year, a group of pain physicians across the state requested that the WSHCA re-review the existing evidence on SCS. Their request was granted, but the subsequent report issued by the WSHCA was—according to NANS—“so methodologically flawed that it should not be used to make any coverage policy decisions”.

As stated on the WSHCA website, the authority’s SCS re-review—dated 1 September 2023—is a draft evidence report, the current status of which is “in progress”.

Working with the Multisociety Pain Workgroup (MPW), which

Medical necessity “should drive all remote monitoring decisions” in SCS, expert panel states The principle of medical necessity “should drive all remote monitoring decisions” relating to spinal cord stimulation (SCS) technologies, according to recommendations recently published in Neuromodulation: Technology at the Neural Interface by a panel of pain management experts. The panel also asserts that, while the expansion of SCS device capabilities holds the potential to improve outcomes and drive individualised patient care, “more clinical evidence is needed”.

“E

merging SCS remote monitoring and programming technologies provide a unique opportunity to address challenges of in-person visits and improve patient care, although clinical guidance on implementation is needed,” the experts, led by Peter Staats (National Spine and Pain Centers, Atlantic Beach, USA), write.

“The goal of this document is to establish best clinical practices for integration of remote device management into the care of patients with SCS, including remote monitoring and remote programming.”

Staats et al note that a panel of experts in the SCS sphere—including interventional pain physicians and neurosurgeons—met in July 2022, with additional experts contributing to the development of the recommendations after this meeting via survey responses and correspondence.

The recommendations state that the overall goal of remote management is “not only to reduce the need for office visits but, more significantly, to identify new SCS-related issues and reduce response time for prompt resolution with the goal of improving patient

consists of physicians working across anaesthesiology, interventional pain, radiology, physiatry, neurosurgery and other specialties, NANS has authored a “forceful response” to the re-review via a letter now published online. The letter was submitted on behalf of more than 95,000 members from numerous prominent US medical groups, including the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology

We cannot, as much as we would like [to], agree that the analysis used in the draft rereview has any clinical validity.”

outcomes and satisfaction”.

In its recent publication, the panel identifies several metrics for remote monitoring and classifies them into three categories: device-related (e.g. stimulation usage); measurable physiologic or disease-related (e.g. patient physical activity or pedometry); and patientreported (e.g. sleep quality and pain intensity).

It also makes recommendations for the frequency of reviewing remote monitoring metrics, but further states that “providers should tailor follow-up to individual patient needs”, and advises that periodic reviews of remote monitoring metrics occur separately from automatic monitoring system notifications.

In addition, the panel keenly emphasises in its report that these recommendations “are offered with the assumptions that appropriate patient selection, surgical technique and postoperative care are observed”—and goes on to stress that the recommendations “are not intended to replace clinical judgment”.

Staats et al highlight reliance on cellular network connectivity or WiFi access; patients, caregivers and healthcare providers being unfamiliar with such technologies; and poor patient or caregiver compliance with regularly recording patient-reported metrics, as being among the key limitations of remote management approaches for current SCS technologies.

“In many settings,” they continue, “remote SCS device management will not replace in-person visits but instead complement them. If an SCS-related

Peter Staats

(ASNR), Congress of Neurological Surgeons (CNS), North American Spine Society (NASS) and Society for Interventional Radiology (SIR).

In concluding this response, NANS reiterates that the re-review is “deeply flawed”, and that it would be “a mistake” for the committee to accept or act upon it unless a number of “radical changes” are made.

“While our societies and our members have repeatedly attempted to provide ‘sound clinical judgement’ as our input to the process, we have reached the point where the SCS care that we know has been shown to be a safe, effective and cost-effective therapy—under conditions when there is appropriate patient selection, and best practices are followed to limit complication and explant rates—is unrecognisable to us in the draft rereview,” the letter adds. “As a result, we cannot, as much as we would like [to], agree that the analysis used in the draft re-review has any clinical validity.”

problem persists despite optimisation through remote follow-up, an in-person clinic visit should be scheduled.

“If remote monitoring activities lead to identification of a new pain issue that is unrelated to the SCS device (e.g. pain in a new area, a change in the pain condition), further evaluation including possible inclinic follow-up should be initiated.

“Overall, using remote SCS device management will enhance the efficiency and productivity of in-person visits by providing focused rationale and supporting data before the visit.”

The cadence of patient follow-up is “multifactorial”, the panel also writes, adding that device analysis for each patient with an SCS implant is “iterative”, before once again emphasising that decisions surrounding inperson and remote monitoring should be “founded on medical necessity”.

Prior to concluding, the panel notes that its paper constitutes “the first guidance” on the topic at hand, acknowledging that recommendations “will evolve over time” to address new technical innovations, and changes in governmental and payer policy.

“As seen previously with remote management in the field of cardiology, remote monitoring for SCS is progressing, and more data are needed to further define the role of this technology in the future,” Staats et al add.

“The consensus panel concluded that the best methods to achieve this goal are to use large registries based on long-term, big data and conduct prospective studies evaluating the effects of remote SCS management on patient care.

“Although more evidence will be required, the authors’ shared consensus is that remote device management provides an opportunity to improve patient care in both clinical outcomes and healthcare utilisation.”

In many settings, remote SCS device management will not replace in-person visits but instead complement them.”

December 2023 | Issue 52

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Researchers develop non-surgical DBS technology capable of boosting memory RESEARCHERS AT THE UK DEMENTIA Research Institute (DRI) have developed a new form of deep brain stimulation (DBS) that does not require surgery and could provide an alternative treatment option for brain diseases like Alzheimer’s.

The technology—based on temporal interference (TI), whereby differing frequencies of electrical field are delivered through electrodes placed on the head—has been successfully trialled with 20 healthy volunteers for the first time by Nir Grossman (Imperial College London, UK), Ines Violante (University of Surrey, Guildford, UK), and colleagues.

This new UK DRI-funded research, published recently in the journal Nature Neuroscience, has shown that the TI technology was able to focally stimulate the hippocampus and improve memory function in healthy adults. Scientists hope this

novel DBS approach could soon be used to improve symptoms of memory loss in Alzheimer’s patients, without requiring invasive brain surgery, and have begun trialling the technique in people experiencing the early stages of the disease.

The technology was initially described by the team at Imperial College London in 2017—and shown to work, in principle, in mice. And now, for the first time, this more recent study has indicated that TI is effective at stimulating deep regions within the human brain.

In the study, researchers first used post-mortem brain measurements to validate that TI electric fields can be remotely focused in the hippocampus. They then applied the TI stimulation to healthy human volunteers while they were memorising pairs of faces and names. Using functional magnetic resonance imaging (fMRI), they showed that TI stimulation selectively affected the hippocampal activity evoked by the memory task. Finally, the researchers repeated the procedure for a longer period of 30 minutes to show stimulation leads to improved memory accuracy.

According to a UK DRI press release, this has broad applications and will allow scientists to stimulate different deep brain regions to discover their functional roles for the first time, accelerating the

Evolving the standard of care: What is next for functional neurosurgery?

John Rolston Point of View The proliferation of new technologies and advancements in the neurosciences space has showed little sign of slowing in recent years and—as John Rolston (Boston, USA) avers in this guest piece for NeuroNews—patients with brain function diseases may well reap the benefits of such progress in the near future.

S

everal subspecialties exist within neurosurgery to treat disorders that affect the nervous system.

Functional neurosurgery focuses on diseases of brain function, such as epilepsy, Parkinson’s or essential tremor. For many patients with these diseases, the brain might look normal on magnetic resonance imaging (MRI)—even when the disease is causing invisible damage. For example, surgeons operating on brain tumours might be able to clearly identify a tumour invading the brain while brain function diseases, like epilepsy, are not clearly visible.

In the last 20 years, considerable advances have occurred around the techniques, technologies and approaches devoted to functional neurosurgery.

These combined advances helped lead to improved stereotactic accuracy, better outcomes, a lower rate of complications and an increasing number of patients benefitted. To treat brain function

diseases, functional neurosurgeons often turn to deep brain stimulation (DBS), a treatment method using electrodes to change the patterns of activity in the brain to restore a more normal function.

DBS for addressing brain function diseases

Brain stimulation is considered the standard of care for many brain function diseases. First approved by the US Food and Drug Administration (FDA) as a treatment for tremor in 1997, DBS was more recently approved as an epilepsy treatment option in 2018. Patients eligible for DBS experience symptoms despite the use of medications and other treatments. For example, DBS could be considered when a medication loses effectiveness, and patients begin to experience a fluctuation in their symptoms or loss of ability to perform day-to-day functions. DBS then becomes a treatment option.

Most DBS devices consist of

discovery of new therapeutic targets.

“Until now, if we wanted to electrically stimulate structures deep inside the brain, we needed to surgically implant electrodes into the brain, which of course carries risk for the patient, and can lead to complications,” said Grossman. “With our new technique, we have shown, for the first time, that it is possible to remotely stimulate specific regions deep within the human brain without the need for surgery.

This opens up an entirely new avenue of treatment for brain diseases like Alzheimer’s, which affect deep brain structures. We hope it will help to scale up the availability of DBS therapies by drastically reducing cost and risk. We are now testing whether repeated treatment with the stimulation over the course of a number of days could benefit people in the early stages of Alzheimer’s. We hope that this will restore normal brain activity in the affected areas, which could improve symptoms of memory impairment.”

The UK DRI group is now also trialling this technology in people in the early stages of Alzheimer’s disease. Participants will receive multiple sessions of non-invasive TI stimulation to test whether it could successfully restore activity in affected areas of the brain and improve symptoms of memory loss.

electrodes implanted inside specific deep brain structures, and the electrodes are then connected to a pacemakerlike machine called a pulse generator that is implanted on the chest wall via a subcutaneous wire. However, some versions can be placed directly in the skull. Stimulation parameters are then relayed by a computer to the pulse generator, assigning proper amplitudes, frequencies, and pulse width.

DBS can stop the symptoms of many diseases and can adapt with the patient over time, and as the disease changes.

Recent innovations are seeing promising findings from pulse generator systems that will be able to sense activity from the brain and adapt minute by minute, allowing for customisation for each patient’s disease and leading to a more effective treatment option over time.

What is next in functional neurosurgery?

The clinical use of DBS is among the most important advances in clinical neurosciences over the past two decades, and physicians are looking into the possibility of expanding the treatment option for other applications.

In fact, researchers are currently conducting clinical trials exploring DBS as a treatment for obsessive-compulsive disorder (OCD), depression, and loss of control (LOC) eating.

The clinical use of DBS is among the most important advances in clinical neurosciences over the past two decades.”

Closed-loop DBS also enables potential new insights for clinicians.

This procedure offers the ability to listen to brain signals, detecting when a patient’s mood might be changing or when their Parkinson’s symptoms might be flaring up, and allowing for adjustment in the electrodes being distributed on a minute-to-minute basis.

Focused ultrasound is also at the forefront of discussion, as it offers an incisionless option where areas of the brain that are overactive or causing problems are removed using sound waves. Focused ultrasound is US FDA approved for treatment of essential tremor and Parkinson’s disease, and researchers are also measuring the success of this treatment for Alzheimer’s and OCD. Another exciting advancement is the evolution of cell and gene therapy— something that neurosurgery researchers have been studying for some time but can now expand their dataset due to the ability to create stem cells, sometimes even using the person’s own tissue. An upcoming clinical study at Brigham and Women’s Hospital will explore how induced pluripotent stem cells can be used to treat Parkinson’s.

We are seeing an acceleration in advances throughout functional neurosurgery, offering physicians greater numbers of safe and effective treatment options for their patients to achieve the best outcomes and return to living active lives.

References for this article are available online and can be viewed at www.neuronewsinternational.com/evolvingthe-standard-of-care-what-is-next-for-functionalneurosurgery.

John Rolston is a neurosurgeon and neuroscientist at Brigham and Women’s Hospital in Boston, USA. His key research areas of interest include epilepsy surgery and movement disorder surgery.

The author declared no relevant disclosures.

Issue 52 | December 2023

35

final report of the ECHO MAC clinical study, nine out of 10 patients preferred the optional closed-loop setting compared to fixed-output stimulation, Medtronic claims in its recent release.

Inceptiv

Medtronic receives CEmark approval for Inceptiv closed-loop SCS to treat chronic pain

Medtronic has received CE-mark approval for its Inceptiv closed-loop rechargeable spinal cord stimulator in the treatment of chronic pain. Inceptiv is the first Medtronic spinal cord stimulation (SCS) device to offer a closed-loop feature that senses each person’s unique biological signals and adjusts stimulation moment to moment, as needed, to keep therapy in harmony with the motions of daily life.

Medtronic claims that—in contrast to more traditional, open-loop SCS technologies—Inceptiv is able to sense the body’s neural response to stimulation 50 times per second, every second of every day. When neural response increases, such as when the patient coughs, sneezes, or bends, Inceptiv automatically decreases stimulation. As neural response decreases, stimulation returns to the pre-set optimal level. This is done “seamlessly” to provide consistent therapy while patients perform a full range of daily activities, according to a company press release.

“Today, fixed-output spinal cord stimulation does not account for patient movements, which can alter the distance between the spinal cord and implanted epidural leads,” said Dirk Rasche (University Hospital of Schleswig-Holstein, Lübeck, Germany). “This can compromise the patient’s experience and therapeutic effectiveness. The Inceptiv closedloop feature will allow for a more consistent and optimal delivery of therapy, and reduced need for manual programming adjustments by the patient. Together with the compatibility of multiple types of waveform options, inclusive of DTM [differential target multiplexed] SCS, and industry-leading MRI [magnetic resonance imaging] access, I believe this latest generation of rechargeable neurostimulator represents a significant leap forward in SCS therapy and a milestone of modern neuromodulation.”

The Inceptiv device utilises a closedloop capability with evoked compound action potentials (ECAPs)—a direct measure of how much neural tissue is activated in the spinal cord in response to electrical stimuli, providing real-time information that enables the system to respond to patient movements. In the

Surgical Information Sciences initiates VISION study to support DBS for Parkinson’s patients

Surgical Information Sciences (SIS) has announced the commencement of its post-market VISION study evaluating visualisation of the subthalamic nucleus (STN) and globus pallidus internus (GPi) for deep brain stimulation (DBS) surgery in patients with Parkinson’s disease.

This study aims to evaluate the potential of the company’s technology in enhancing the accuracy of DBS implant placement for Parkinson’s patients. It will involve the participation of 90 patients across multiple sites, and represents “a significant step in the pursuit of improved treatment for those living with this challenging condition”, as per an SIS press release.

DBS has shown promise in managing parkinsonian symptoms, but its success is “closely tied” to the precision of implant placement within the STN and GPi. SIS believes that its cuttingedge visualisation technology has the potential to significantly improve the accuracy of this procedure, ultimately leading to improved patient outcomes, the release adds.

“The VISION study presents an opportunity to assist surgeons and programming physicians in treating patients with Parkinson’s disease,” said Patrick Senatus (Hartford Hospital, Hartford, USA). “By enhancing visualisation, the accuracy of DBS implant placement may be improved through further customising targeting of therapeutic brain regions. I am enthusiastic about the possibilities that this research holds.”

Boston gains expanded US FDA approval of SCS therapy for painful diabetic peripheral neuropathy

Boston Scientific has announced that the US Food and Drug Administration (FDA) has approved an expanded indication of the WaveWriter Alpha spinal cord stimulator (SCS) systems for the treatment of painful diabetic peripheral neuropathy (DPN).

The WaveWriter Alpha SCS systems were previously approved by the US FDA in December 2020 for the management of chronic intractable pain of the trunk and/or limbs including unilateral or bilateral pain associated with failed back surgery syndrome, complex regional pain syndrome types I and II, intractable low back pain and leg pain. This new approval expands the indications to include DPN of the

lower extremities for paraesthesiabased stimulation, as per a Boston press release.

As a non-opioid treatment option, the WaveWriter Alpha SCS systems are intended for chronic intractable pain of the lower extremities associated with DPN. The system provides therapy for pain relief by sending mild electric pulses to the spinal cord to interrupt pain signals travelling to the brain.

Mainstay announces completion of US enrolment in RESTORE clinical trial

Mainstay Medical has announced the completion of enrolment in its RESTORE randomised clinical study of ReActiv8 for the treatment of intractable chronic low back pain.

The study is designed to provide a direct comparison to optimised medical management for the purpose of testing the hypothesis that the addition of ReActiv8 restorative neurostimulation therapy to current care paradigms results in significant improvements in back pain-related disability.

The RESTORE study is a multicentre, prospective randomised controlled trial that has been conducted at 25 leading centres in the USA, according to Mainstay.

ReActiv8

A total of 226 eligible patients were randomised to either continue with their optimal medical management or ReActiv8 restorative neurostimulation therapy plus optimal medical management. Patient-reported outcomes are being collected at regular intervals out to the one-year primary endpoint, at which time the patients in the control arm are offered implantation with the ReActiv8 system. Assessment of the patients will also continue for an additional year.

“This type of randomised controlled clinical trial in this difficult-to-treat and underserved patient population will produce high-quality data comparing ReActiv8 to the current standard of care,” the co-principal investigators for RESTORE stated. “Once the data are published, they will meaningfully add to the growing body of clinical evidence regarding ReActiv8 and firmly establish the role of this therapy in treating mechanical low back pain patients. The RESTORE trial represents a substantial addition to the clinical evidence behind treatment options for this patient population, who have extremely limited options beyond temporary palliative treatments and drugs. Directly addressing the underlying issue of muscular dysfunction can represent a substantial advancement in treatment options.”

Saluda receives US FDA approval for MRI labelling of Evoke spinal cord stimulation system

Saluda Medical has announced that the US Food and Drug Administration (FDA) has approved magnetic resonance imaging (MRI) conditional labelling for its Evoke system, which the company claims is “the first and only” precision, dose-control spinal cord stimulation (SCS) therapy powered by SmartLoop technology. This approval applies to all commercially implanted Evoke system patients in the USA as well as patients formerly enrolled in the ECAP study, a Saluda press release notes.

Evoke’s MRI labelling is “one of the most comprehensive in the SCS space”, the release further states, providing patients implanted with the system the ability to undergo 1.5 or 3.0T head and extremity and 1.5T full-body MRI scans across “the most implant locations in the industry”. Imaging can be done in both prone and supine positions, according to Saluda. Specific scan conditions and safety information are provided in the Evoke SCS system MRI guidelines manual.

The Evoke system provides physiologic, evoked compound action potential (ECAP)-controlled, closedloop SCS therapy, and is indicated as an aid in the management of chronic intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with failed back surgery syndrome, intractable low back pain, and leg pain.

Nalu announces positive results from spinal cord stimulation nPower US clinical study

Nalu Medical has announced the publication of the spinal cord stimulation (SCS) nPower US clinical study in the Pain Physician Journal, reporting on clinical outcomes related to the use of the Nalu SCS system to treat patients suffering from chronic intractable pain of the trunk and/or limbs, including unilateral or bilateral pain.

The SCS nPower US clinical study was a prospective, post-market observational study conducted at 15 comprehensive pain centres in the USA. The Nalu neurostimulation system was evaluated in 35 subjects with chronic low back and leg pain from baseline to three months.

Highlights of the results include 86% of subjects being “responders” (≥50% pain relief) in the low back and leg(s); 54% of subjects in the low back and 49% in the leg(s) being “high responders” (≥80% pain relief); 75% average pain reduction in the low back and 76% in the leg(s); Nalu’s wearable therapy disc reported by all patients as being comfortable and easy to use; and secondary endpoints regarding sleep, mood, functional disability and quality of life all demonstrating statistically significant outcomes at three months compared with baseline.

December 2023 | Issue 52

36 Market Watch

Clinical News

Tenzing 7 catheter

Route 92 announces positive clinical findings with Tenzing 7 delivery catheter

Route 92 Medical has announced new results from a multicentre clinical study evaluating the efficacy, safety and efficiency of the Tenzing 7 delivery catheter as a means for delivering therapeutic devices for mechanical thrombectomy in acute ischaemic stroke.

The results—now published in Stroke: Vascular and Interventional Neurology—demonstrate a 95.9% success rate in delivering large-bore reperfusion catheters to the clot face without needing a stent retriever to anchor.

In addition, 94.9% of cases achieved successful recanalisation, and 54.2% of cases achieved successful firstpass reperfusion with a 0.068-inch (inner diameter) aspiration catheter.

According to Route 92, this compares favourably with the best stent-retriever data, including with the use of “cumbersome” balloon guides.

Patients also experienced a significant median National Institutes of Health stroke scale (NIHSS) improvement of 10 at hospital discharge, while 41% of patients achieved a good 90-day functional outcome in the study.

“Early clinical and invitro experiences have always shown the potential of the Tenzing 7 delivery catheter,” said Dan Tonetti (Cooper University Health Care, Camden, USA), one of the lead contributors to the study. “These multicentre results support its position as a gamechanger in the field of neurointervention.”

Route 92 also recently announced it had raised more than US$31 million in a Series F financing round to accelerate the commercial adoption of a neurovascular intervention portfolio focused on acute ischaemic stroke. The oversubscribed capital raise was led by existing venture capital investors US Venture Partners, Norwest Venture Partners, InnovaHealth Partners, and The Vertical Group, according to a company press release.

Perfuze enrols first stroke patient in MARRS pivotal trial of Millipede system

Perfuze has announced commencement of enrolment in its pivotal MARRS study—a multicentre trial set to evaluate the performance of aspiration thrombectomy with the company’s Millipede system for revascularisation in acute ischaemic stroke. The first

patient was enrolled at Stony Brook University Hospital in Stony Brook, USA. “I am delighted to begin enrolment in the MARRS pivotal study,” said David Fiorella (Stony Brook Cerebrovascular Center, Stony Brook, USA). “It is an exciting opportunity to evaluate the next wave of thrombectomy technology with the possibility of improving interventional stroke treatment. I anticipate the results of this study will benefit future stroke patients.”

MARRS is an interventional, open-label, single-arm, prospective pivotal study that will enrol up to 220 patients at 25 sites across the USA and Europe. The study will evaluate the performance and safety of the Millipede system in patients with acute ischaemic stroke, and its results are intended to provide clinical evidence to support an application for US Food and Drug Administration (FDA) clearance, according to Perfuze.

Ameer Hassan (Valley Baptist Medical Center, Harlingen, USA) and Marc Ribó (Vall d’Hebron Hospital, Barcelona, Spain) are the principal investigators of the study.

“Super-bore aspiration has the potential to significantly improve reperfusion in stroke patients, and the Millipede system represents an elegant approach to treatment,” said Hassan.

The Perfuze Millipede 088 access catheter received US FDA 510(k) clearance for neurovascular access in 2022, and a CE mark for firstline aspiration thrombectomy in the European Union in 2021, a press release from the company notes.

Rapid announces high treatmentsuccess rate in ICAD stroke patients with Tigertriever device

Rapid Medical has announced new data demonstrating “excellent” firstpass treatment success using the Tigertriever device in complex ischaemic stroke patients with underlying intracranial atherosclerotic disease (ICAD). The complication rates were also negligible, as reported at the Society of Vascular and Interventional Neurology (SVIN) annual meeting (16–18 November 2023, Miami, USA).

“Patients with ICAD experiencing a stroke are very challenging to treat and often need rescue therapy, such as stenting,” stated Edgar Samaniego (University of Iowa, Iowa City, USA), lead author of this research, which has since been published in the Journal of NeuroInterventional Surgery. “We achieved very high treatment success and lasting results with Tigertriever alone that we have not seen with other devices. We attribute this to Tigertriever’s unique ability to open and dilate these blocked vessels—a new term we call ‘stentplasty’.”

This subanalysis of the prospective TIGER trial showed that 78% of ICAD patients achieved successful

reperfusion without further intervention, and 47% achieved recanalisation on the first procedural pass, Rapid claims in a press release. These results are “significantly better” than studies utilising other devices in this unique patient population, the company also says, adding that Tigertriever in ICAD rivals results only thought possible in nonICAD patients.

Another benefit of the high firstpass success rates was “very fast” procedure times; a median groin-torevascularisation time of 22 minutes is “the fastest reported in any prospective, randomised trial”, according to Rapid.

Some 50% of these patients also had a good clinical outcome defined as a modified Rankin scale (mRS) score of 0–2 at 90 days.

Rapid further claims that, unlike conventional stent retrievers, the Tigertriever device offers the “distinctive capability” to control radial expansion after it is positioned in a brain artery, providing exclusive advantages for ICAD patients. In addition to successful reperfusion in the present subanalysis, Tigertriever significantly dilated the artery such that no patient required permanent stenting.

Patients included in the study did not suffer symptomatic intracranial haemorrhage (sICH), vessel dissection, or embolic complications—which are typically more frequent in these ICAD patients. Rapid attributes these successes to the fact the device can be contracted to minimise disruption to the plaque and arteries during removal.

“Tigertriever provides a higher rate of successful reperfusion, reduced complications, and a needed angioplasty-like effect compared with historical studies that utilised other mechanical thrombectomy devices,” Samaniego concluded.

Raul Nogueira

Synchron completes enrolment in US COMMAND trial of endovascular brain-computer interface

Synchron has announced completion of patient enrolment in the USAbased COMMAND trial assessing the company’s endovascular braincomputer interface (BCI) technology.

“Giving patients the option to receive a BCI device without the need for open brain surgery could open up a new frontier in BCI,” said Raul Nogueira (University of Pittsburgh Medical Center [UPMC] Stroke Institute, Pittsburgh, USA). “We look forward to analysing the results of the study and potentially bringing this technology to those in need in the future.”

The COMMAND trial enrolled a total of six patients and is

being conducted under the first investigational device exemption (IDE) awarded by the US Food and Drug Administration (FDA) to a company assessing a permanently implanted BCI, according to Synchron.

The early feasibility study is evaluating safety while also assessing quantified efficacy measures of the Synchron Switch motor neuroprosthesis in patients with severe paralysis.

The primary goal of the study is to adjudge if the device can be safely implanted into the blood vessels of the brain using neurointerventional procedures, but it has also been designed to evaluate how the BCI may enable the use of patients’ thoughts to control digital devices for daily tasks like texting, emailing, online shopping and telehealth services.

The COMMAND study is being conducted at three US clinical sites: Mount Sinai Health System in New York City; University at Buffalo Neurosurgery in Buffalo; and UPMC— in collaboration with Carnegie Mellon University College of Engineering—in Pittsburgh. The study is being carried out with support from the National Institutes of Health (NIH) BRAIN initiative.

Robocath completes CARE clinical trial evaluating robotic carotid stenting

Robocath has announced the results of its CARE clinical trial focusing on robotic carotid stenting—the first phase of a research programme launched in July 2021 by Robocath and Rennes University Hospital (Rennes, France), which, in the long term, is aiming to enhance current and future generations of robots used in the treatment of neurovascular diseases.

The prospective, single-arm, nonrandomised CARE trial, launched in November 2021, saw François Eugène and Quentin Alias (both Rennes University Hospital, Rennes, France) perform a total of seven robotic procedures using ROne, an innovative robotic platform developed and marketed by Robocath. This firstgeneration robot is designed to improve treatments by enhancing physicians’ hand gestures through increased precision, as well as drastically reducing medical staff’s exposure to X-rays.

According to Robocath, all procedures in the CARE trial were performed without any medical complications, giving R-One a 100% clinical success rate. From a technical standpoint, only one of the procedures required a complete manual conversion.

“I am honoured to have been part of this clinical trial, which marks an important first step on the road to making robotic procedures routine practice for the treatment of strokes,” said Eugène. “The success of these procedures is down to two key factors: accuracy and speed of patient care. Just like human hands, Robocath’s robot can move with millimetre precision and ensure the instruments remain in a fixed

Issue 52 | December 2023 position for the entire duration of the procedure. Moreover, the technology opens up the possibility of longdistance treatment for stroke patients.

“In our line of work, precision is key to the success of each intervention,” Alias added. “I am impressed by the pinpoint accuracy of the robot’s movements. The use of robotics could become, in time, the go-to treatment option for vascular diseases.”

Athersys announces ‘disappointing’ results from MASTERS-2 interim analysis

Athersys has announced that the independent data safety monitoring board (DSMB) has completed a preplanned interim analysis of the company’s ongoing, phase three MASTERS-2 pivotal clinical trial evaluating MultiStem (invimestrocel) for the treatment of moderate-to-severe acute ischaemic stroke. The DSMB concluded that the current sample size of 300 patients is insufficiently powered to achieve the primary endpoint analysis of modified Rankin scale (mRS) shift at day 365.

There were no safety issues identified, according to Athersys, and—because the sample size required to achieve statistical significance is considerably larger—the company is intending to conduct additional data analysis with independent statisticians.

A press release states that Athersys plans to pause enrolment of new patients while this analysis is being conducted.

Separately, Athersys has announced that it has entered into a memorandum of understanding (MOU) granting Healios global rights to develop and commercialise MultiStem for the treatment of acute respiratory distress syndrome (ARDS). Under the terms of the MOU, Athersys will receive between US$1.5 million and US$4.5 million in near-term payments, with up to US$150 million in potential development and sales milestones, and additional royalties.

Athersys also expects to receive revenue from the sale of existing clinical doses of MultiStem for Healios to use in its phase three clinical trial in ARDS. These doses were manufactured in accordance with the company’s 3D bioreactor process that, earlier this year, received approval from Japan’s Pharmaceuticals and Medical Devices Agency (PMDA).

Vesalio presents positive CLEAR study results at ESMINT 2023

Vesalio has announced the recent presentation of key findings from the CLEAR study—a prospective, multicentre, open-label, single-arm, US Food and Drug Administration (FDA)-regulated investigational device exemption (IDE) trial evaluating the safety and effectiveness of the company’s Neva thrombectomy device, which is intended to facilitate retrieval of all clot types in large vessel occlusion (LVO) stroke.

Primary results from CLEAR were

Market Watch 37

Neva stent retriever

delivered at the 2023 European Society of Minimally Invasive Neurological Therapy (ESMINT) congress (4–6 September, Marseille, France)

by Serdar Geyik (Istanbul Aydın University, Istanbul, Turkey).

A Vesalio press release notes that, since the Neva launch across CEregulated markets in 2018, several academic publications have highlighted the device’s safety and its association with high first-pass recanalisation rates—widely accepted as a consistent predictor of positive patient outcomes.

And, now, the results of the CLEAR study have affirmed the safety and effectiveness of Neva, demonstrating promising first-pass rates and patient outcomes in line with previous publications. According to Vesalio, the CLEAR study showed excellent clinical outcomes, with nearly two out of three patients treated being functionally independent at 90-day follow-up. Safety results indicated that trial participants experienced low complication rates and mortality as well.

“The prospective CLEAR study confirms the value and differentiation of the Neva device compared to other stent retrievers for achieving rapid and effective revascularisation,” said Geyik.

“The results represent a step forward for improving patient outcomes after thrombectomy.”

The CLEAR study has been submitted to the FDA for clearance of the Neva device, which is now pending with the US regulator. The Neva device has been available throughout Europe and other international markets for five years, where it is indicated in LVO stroke, the release also states.

InspireMD presents positive 30-day follow-up results from C-GUARDIANS clinical trial

InspireMD recently presented 30-day results from the C-GUARDIANS US investigational device exemption (IDE) clinical trial evaluating its CGuard embolic prevention stent (EPS) system for stroke prevention at the annual Vascular Interventional Advances (VIVA) meeting (30 October–2 November 2023, Las Vegas, USA). The late-breaking abstract presentation was delivered by Chris Metzger (OhioHealth, Columbus, USA), principal investigator of the C-GUARDIANS trial.

C-GUARDIANS is a pivotal trial designed to evaluate the safety and efficacy of the CGuard carotid stent system when used to treat symptomatic and asymptomatic carotid artery

stenosis in patients undergoing carotid artery stenting (CAS) and at a high risk for carotid endarterectomy (CEA).

From July 2021 to June 2023, 316 patients were prospectively enrolled in this single-arm carotid artery stenting study, performed at 24 sites in the USA and Europe. The primary endpoint was a composite of either: incidence of major adverse events including death (all-cause mortality), any stroke or myocardial infarction (DSMI) through 30 days post-index procedure; or ipsilateral stroke from day 31 to day 365 post-procedure.

Stenting with the CGuard carotid stent system in patients with carotid artery stenosis and at high risk for CEA had a DSMI rate of 0.95%, from procedure through 30 days of followup, as per an InspireMD press release.

InspireMD now anticipates reporting primary endpoint results from C-GUARDIANS—which may support a premarket approval (PMA) application—in the second half of 2024.

Contego announces low one-year stroke rates in PERFORMANCE II carotid stent trial

Contego Medical has announced the presentation of late-breaking clinical results from the PERFORMANCE II carotid stent trial at the annual Vascular Interventional Advances (VIVA) meeting (30 October–2 November 2023, Las Vegas, USA).

PERFORMANCE II is a prospective, multicentre study evaluating the safety and effectiveness of the Neuroguard integrated embolic protection (IEP) system in 305 patients at 40 clinical sites.

“The one-year event rates in the PERFORMANCE II study are the lowest ever reported in any adequately powered, prospective, multicentre study of any type of carotid artery revascularisation, regardless of patient risk,” said William Gray (Main Line Health, Philadelphia, USA), conational principal investigator of the PERFORMANCE II trial. “These results can elevate the standard of care for patients with severe carotid artery disease who are deemed appropriate for intervention by delivering demonstrated best-in-class stroke protection.”

In the PERFORMANCE II study, the reported 30-day stroke rate was 1.31% in the intention-to-treat analysis and 0.98% in a per-protocol analysis, with no major strokes or contralateral strokes, and all patients returning to baseline neurologically within 30 days, according to a Contego press release.

At one-year follow-up (all stroke within 30 days, and ipsilateral stroke between day 31 and 12 months), the reported stroke rate was 1.68% in the intention-to-treat analysis and 1.35% in a per-protocol analysis. No major strokes or neurological deaths occurred in the study.

In addition to the PERFORMANCE II study—in which Neuroguard was placed via transfemoral or transradial access—the PERFORMANCE III

study is currently enrolling patients to evaluate the same stent placed via direct transcarotid access. The first patient was enrolled in this prospective, multicentre trial in October 2023.

Cerevasc announces presentation of initial eShunt data and NPH trial expansion Cerevasc has announced that findings from a clinical study examining the use of its eShunt system to treat communicating hydrocephalus were recently presented at the 2023 European Society of Minimally Invasive Neurological Therapy (ESMINT) congress (4–6 September, Marseille, France).

Trial data reporting the investigational use of the eShunt system in patients with hydrocephalus secondary to subarachnoid haemorrhage were delivered by Ivan Lylyk (Clínica La Sagrada Familia, Buenos Aires, Argentina)—one of the lead investigators for a study that represents the first ever treatment with the eShunt system and the world’s first endovascular treatment of communicating hydrocephalus, according to Cerevasc.

Lylyk’s presentation described the short-term impact of the eShunt system in patients with persistent communicating hydrocephalus and

Ivan Lylyk and Pedro Lylyk

elevated intracranial pressure in lieu of the invasive, surgical placement of a conventional shunt.

“We are excited by the initial data demonstrating the potential to provide patients a minimally invasive treatment for communicating hydrocephalus,” said Pedro Lylyk (Clínica La Sagrada Familia, Buenos Aires, Argentina), who is leading the study. “Transformational innovation in the management of hydrocephalus is long overdue. These results provide confidence that it may finally be on the horizon.”

In addition to this, Cerevasc also recently announced that the US Food and Drug Administration (FDA) has approved an investigational device exemption (IDE) supplement to permit the expansion of a study of its eShunt system in patients with normal-pressure hydrocephalus (NPH) to additional study participants and clinical sites.

This IDE supplement approval also allows for use of the nextgeneration eShunt system in the NPH study. According to a company press release, the Gen2 eShunt system has been designed to simplify the device preparation process, and enhance the system’s overall ease of use, while maintaining eShunt implant performance.

December 2023 | Issue 52

38 Market Watch

Product News RapidAI receives US FDA clearance of AI module for detecting hemispheric SDH

RapidAI has announced that it has received US Food and Drug Administration (FDA) clearance for Rapid SDH, its artificial intelligence (AI)-powered module for the detection and notification of suspected hemispheric acute and chronic subdural haematoma (SDH).

Together with Rapid ICH and Rapid Hyperdensity, both of which are intended for use in the detection of intracranial haemorrhage (ICH), Rapid SDH comprises RapidAI’s “unique and industry-best haemorrhagic and trauma care AI solution”, designed to help teams on the front lines of patient assessment streamline decision-making and expedite patient care.

That is according to a company press release.

Rapid SDH leverages AI and the intelligence gained from analysing hundreds of patient scans to help neurocritical care teams identify suspected hemispheric subdural haemorrhage faster and with a higher degree of accuracy than traditional methods.

And, with the advanced Rapid mobile app, Rapid SDH automatically sends results to the entire trauma team across the hospital system or treatment network, enabling clinicians to make more timely and informed transfer, and treatment decisions, for patients with traumatic brain injury or haemorrhagic stroke, the company claims.

Surmodics launches Preside hydrophilic coatings for neurovascular, coronary and peripheral applications

Surmodics has announced the commercial launch of its most advanced hydrophilic medical device coating technology, the Preside hydrophilic coatings.

As per a company press release, Preside hydrophilic coatings complement Surmodics’ existing Serene hydrophilic coatings by providing customers with a unique, low-friction and lowparticulate generation coating to further enhance distal access for neurovascular applications, as well as improve crossing for challenging coronary lesions or chronic total occlusions.

Preside hydrophilic coatings are “specifically formulated to meet the challenge of achieving the right balance of enhanced lubricity (reduction in friction) and excellent coating durability—resulting in low particulates—for the next generation of neurovascular, coronary and peripheral vascular devices”, the release adds.

Surmodics’ Preside hydrophilic coatings allow customers to leverage their existing coating processes, resulting in easy implementation in a

manufacturing environment, according to the company.

Microvention enters transradial access market with US FDA clearance of Sofia EX catheter

Microvention, a wholly owned subsidiary of Terumo Corporation, announced recently that the Sofia EX 5Fr 115cm intracranial support catheter received US Food and Drug Administration (FDA) 510(k) clearance on 15 September 2023 for use in transradial access in addition to transfemoral access.

The unique design of the Sofia EX 5Fr catheter allows for great trackability, and its large inside lumen provides fast and effective tracking to intracranial locations in patients as

Sofia EX catheter

well, according to a company press release. It also offers support and kink resistance due to being reinforced with a nitinol coil and stainless-steel braid, and the device has an inner polytetrafluoroethylene (PTFE) liner throughout its entire length with 12 transition zones optimised for pushability, Microvention further claims.

Sofia EX 5Fr radial access clearance marks Microvention’s first product intended for use in transradial access—whereby the neurovasculature is accessed via the radial artery in the wrist, as opposed to the femoral artery in the groin—and signifies the company’s “commitment to innovation”.

In its recent release, Microvention says it “believes providers should have the ability to feel confident in our Sofia EX 5Fr in either the transradial or transfemoral access approach”.

Anaconda Biomed granted additional European and US patents for novel stroke thrombectomy technology

Anaconda Biomed has announced that the European Patent Office has granted the company a European patent for “A device and a thrombectomy apparatus for extraction of thrombus from a blood vessel”, published as patent number EP 3866708 B1 on 27 September 2023. In addition, patent number US 11,771,446 B2 was also granted to the company on 3 October 2023 for a method to improve the efficacy of removing cerebral vascular thrombi.

The newly granted patents join a list of 17 issued patents for Anaconda, including “Thrombectomy device

and system for extraction of vascular thrombi from a blood vessel” in the USA with patent number US 11,013,523 B2, among other key territories, such as recently granted ones in Canada and South Korea, as well as Japan, China, Brazil, Taiwan and Australia.

The focal point of Anaconda’s product portfolio is the ANA5 advanced neurovascular access thrombectomy device, which is specifically designed for use in the anterior and posterior neurovascular vessels and comprises an aspiration funnel catheter featuring variable stiffness sections to be used in conjunction with a stent retriever.

According to Anaconda, ANA5 is currently an investigational device, and is not available for sale in the USA or the European Union.

Brainomix targets US expansion following launch of 360 platform at SVIN 2023

Brainomix has heralded its continued US expansion with the launch of a full suite of US Food and Drug Administration (FDA)-cleared modules in its Brainomix 360 platform for stroke care.

The US launch—which included the company’s previously announced, FDA-cleared e-ASPECTS module— represents a comprehensive platform designed to support clinicians and their imaging-based treatment decisions at all points across the stroke pathway, from simple to more advanced imaging.

According to a press release, the Brainomix 360 platform is powered by state-of-the-art artificial intelligence (AI) algorithms that provide real-time interpretation of brain scans to aid treatment and transfer decisions for stroke patients, with an aim towards enabling more patients to receive the right treatment, in the right place, at the right time.

The launch included Brainomix exhibiting at the Society of Vascular and Interventional Neurology (SVIN) annual meeting (16–18 November 2023, Miami, USA), with Waleed Brinjikji (Mayo Clinic, Rochester, USA) providing a keynote presentation on his experience with the Brainomix 360 platform.

Brinjikji reported findings from a recent study validating the performance of the e-ASPECTS module, demonstrating improved physician accuracy across disciplines and levels of experience regarding Alberta stroke programme early computed tomography (ASPECT) scoring.

MindRhythm receives US FDA breakthrough designation for Harmony headset

MindRhythm has announced that the US Food and Drug Administration (FDA) has awarded a Breakthrough Device designation to its Harmony headset embedded with HeadPulse technology.

This designation highlights that Harmony is “truly breakthrough”, and

Harmony device

“acknowledges the importance of this product for patients” as well as “the likelihood that MindRhythm’s pivotal trial will be successful,” according to MindRhythm’s co-founder and chair of the company’s scientific advisory board Wade Smith (University of California San Francisco, USA).

MindRhythm chose to pursue breakthrough designation in advance of its submission for FDA clearance with the belief that Harmony meets all primary and secondary criteria for the programme, including the fact that device availability is in the best interest of patients.

The function of the Harmony device is to aid in the assessment of suspected stroke patients in the prehospital setting to determine whether the patient may have a large vessel occlusion (LVO) stroke. It is designed to help emergency medical services (EMS) professionals determine the presence or absence of LVO stroke.

As per a press release from MindRhythm, there is currently no device available that can easily and accurately identify LVO before a patient arrives at a hospital.

EOSolutions receives US FDA clearance for Thinline introducer sheath

EOSolutions Corporation has announced that the US Food and Drug Administration (FDA) has cleared its Thinline introducer sheath—an approval that swiftly follows the successful launch of the company’s “revolutionary” Dr Banner balloon guide catheter (BGC) in the USA. The Thinline sheath has been “meticulously engineered” to complement the Dr Banner BGC device, offering an innovative solution to the challenges associated with largebore BGCs, as per an EOSolutions press release.

“I really enjoy using the Dr Banner balloon guide catheter,” said Italo Linfante (Florida International University, Miami, USA). “It is very supportive and its large ID [inner diameter] provides significant aspiration. Most important is the very soft, compliant balloon. It immediately conforms to the vessel wall, confirming vessel occlusion. With the clearance of the Thinline introducer sheath, I now have the option to choose an 8Fr closure system, if needed.”

According to EOSolutions, the Dr Banner BGC sets “a new standard” in the industry, with its 0.091-inch ID providing the largest BGC lumen available, translating to superior flow when aspirating and enhanced visualisation during contrast runs.

Issue 52 | December 2023

Market Watch 39

Industry News UK MHRA adds capacity for medical device certification

The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has designated three new approved bodies to increase the country’s capacity to certify medical devices.

TÜV SÜD, Intertek, and TÜV Rheinland UK join the four current UK approved bodies, almost doubling current capacity for the certification of medical devices in the UK, the MHRA says in a press release.

TÜV SÜD and Intertek have been designated as UK approved bodies to assess and certify general medical devices in accordance with Part II of the Medical Devices Regulations 2002.

TÜV Rheinland UK has also been designated to assess and certify general medical devices as well as in-vitro diagnostics in accordance with Part IV. With the exception of the very lowest risk devices, manufacturers must apply to a UK approved body for UK Conformity Assessment (CA) certification. Products can only be placed on the market in England, Wales and Scotland after they have achieved certification.

Laura Squire, MHRA chief healthcare quality and access officer,

said: “By almost doubling capacity for medical device assessment in the UK, we are supporting patients to access the safe and effective products they need to protect their health. Approved bodies play a critical role in the supply of medical devices and expanding capacity has been a key priority for us to support manufacturers to bring their products to the UK.”

Mahesh Jayaraman becomes Society of NeuroInterventional Surgery president

Mahesh Jayaraman, an interventional neuroradiologist at Rhode Island Hospital in Providence, USA—who has led national efforts to improve stroke systems of care in the USA—has been named the 28th president of the Society of NeuroInterventional Surgery (SNIS).

As president, he will lead the SNIS in all its endeavours to enhance the field, a press release details.

“SNIS and its members dedicate themselves to pursuing excellence in the growing specialty of neurointervention,” Jayaraman said.

“I am honoured to collaborate with neurointerventionists around the globe to learn and innovate, all to ensure our patients receive the best treatment

and outcomes. We look forward to an exciting year of partnership and opportunity.”

Jayaraman is a professor of Diagnostic Imaging, Neurology and Neurosurgery at the Warren Alpert Medical School of Brown University (Providence, USA), and the director of the Neurovascular Center at Rhode Island Hospital. His work has been published in more than 150 peerreviewed journal articles, books and book chapters. His clinical and research interests include improving outcomes of stroke patients—especially those with emergent large vessel occlusion.

Brain Aneurysm Foundation launches ‘Stop the Pop’ campaign

The Brain Aneurysm Foundation (BAF) has announced the launch of ‘Stop the Pop’—a new campaign intended to increase awareness of the prevalence and impact of brain aneurysms, and the need for ongoing investment to fund new innovations, screening, and treatment.

The Stop the Pop campaign aims to build awareness of symptoms, and genetic and environmental risk factors, and to increase research funding to better understand the underlying causes of the condition and to advance new treatments. The campaign includes social media, online and physical advertising, as well as upcoming events

in US cities including Boston, New York, Chicago and St Louis.

“A feeling that something has ‘popped’ is what we hear most from patients who have experienced a rupture,” said Christopher Ogilvy (Beth Israel Deaconess Medical Center, Boston, USA), who leads the BAF medical advisory board. “Many write it off as an intense headache, but it also comes with an array of other symptoms [including] blurred vision, nausea, or even seizure, and it is critical people recognise the seriousness of what they may be experiencing and immediately seek treatment. Our focus is to help individuals at risk, and the first responders and physicians who treat them, to better recognise aneurysms and initiate earlier interventions in order to reduce the number of people afflicted by this often-treatable condition.”

The majority of funds raised by the BAF are used to provide grants to academic researchers studying the underlying biology of aneurysms or developing new treatment methods. Currently, as a result of the foundation’s own fundraising initiatives, there are dozens of ongoing research efforts at academic institutions across the USA. The BAF also recently announced 17 new grants at its annual research grant symposium (21 September, Charleston, USA).

Conference calendar 14–19 January ABC WIN Seminar Val d’Isère, France

www.abcwin-seminar.com

18–21 January North American Neuromodulation Society (NANS) Annual Meeting Las Vegas, USA

www.neuromodulation.org/annualmeeting

30 January–2 February 11th ESO-ESMINT-ESNR Stroke Winter School Bern, Switzerland

www.eso-stroke.org/meetings/ winter-school

1–3 February Sun Valley Cerebrovascular Conference Sun Valley, USA www.sunvalley cerebrovascular conference.org

7–9 February International Stroke Conference (ISC) Phoenix, USA

www.professional.heart.org/en/ meetings/international-strokeconference

10–13 February Pan Arab Interventional Radiology Society (PAIRS) Neuro Dubai, United Arab Emirates www.pairscongress.com/neuro

22–23 February LINNC Seminar - Americas Edition Miami, USA

www.linnc.com/Course-information/ LINNC-Seminar-2024-AmericasEdition

26 February–1 March The European Stroke Course in Minimally Invasive Neurological Therapy (EXMINT) 6.2 Prague, Czech Republic

www.esmint.eu/training-education/ exmint

21–23 March 18th World Congress on Controversies in Neurology (CONy) London, UK www.cony.comtecmed.com

13–18 April American Academy of Neurology (AAN) Annual Meeting Denver, USA

www.aan.com/events/annualmeeting

NeuroNews is a trusted, independent source of news and opinion in the neurointerventional and neurosurgical world.

Sign up for a free print subscription* and e-newsletter subscription** www.neuronewsinternational.com *Available for US and EU readers only ** Available worldwide

TIME

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™

Fastest Aspiration System in Stroke Care a

a. Tests performed and data on file at Penumbra, Inc. Testing performed evaluated 2 variables: 1. Device unpackaging and preparation time and 2. Aspiration catheter tracking time. Bench results may not be indicative of clinical performance. Physicians’ treatment and technique decisions will vary based on their medical judgment. Individual results may vary depending on patient-specific attributes and other factors. The aspiration system includes the respective manufacturer’s commercially available guide catheter, delivery or intermediate catheter, and large-bore aspiration catheter. Systems tested include the Stryker ® AXS Vecta ® Aspiration System, Imperative Care™ Zoom™ Aspiration System, and the Penumbra RED 72 with SENDit Aspiration System.

Photograph taken by and on file at Penumbra, Inc. Caution: Federal (USA) law restricts these devices to sale by or on the order of a physician. Prior to use, please refer to the Instructions for Use (IFU) for complete product indications, contraindications, warnings, precautions, potential adverse events, and detailed instructions for use. For the complete Penumbra IFU Summary Statements, please visit: peninc.info/risk. Please contact your local Penumbra representative for more information.

Copyright ©2023 Penumbra, Inc. All rights reserved. The Penumbra P logo, RED, and SENDit are registered trademarks or trademarks of Penumbra, Inc. in the USA and other countries. All other trademarks are the property of their respective owners. 28370, Rev. A 10/23 USA

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