Analysis of revascularisation in ischaemic stroke with EmboTrap (ARISE I study) and meta-analysis of thrombectomy

Abstract

Background and purpose

The goal of the analysis of revascularisation in ischaemic stroke with EmboTrap study (ARISE I) was to demonstrate the effectiveness of EmboTrap.

Methods

ARISE I was an open label, single arm, multicentre, prospective study for the treatment of acute stroke due to large vessel occlusion. The primary outcome was revascularisation of the target vessel as measured by the modified thrombolysis in cerebrovascular infarction (mTICI) score of at least 2b following thrombectomy with EmboTrap. For comparison of the ARISE I results a meta-analysis of eight randomised controlled trials was performed.

Results

ARISE I enrolled 40 patients. Their baseline characteristics that are predictors of stroke outcome and procedure timings in ARISE I were similar to those reported in recent randomised controlled trials. The primary outcome, good revascularisation rates (mTICI 2b/3 scores) after three or fewer passes with EmboTrap were 75% (95% confidence interval (CI) 62–88%), which is the same as 74% found in randomised controlled trials (difference of 0.8%, P = 0.95). After additional EmboTrap passes or the use of another device mTICI 2b/3 scores rose to 85% (95% CI 74–96%), which was also similar to the randomised controlled trials (difference 11%, P = 0.38). The high revascularisation rates in ARISE I converted into 64% good clinical outcomes (modified Rankin scale ≤2) compared to 50% in randomised controlled trials (difference 14%; 95% CI –13.7–41.7%; P = 0.32).

Conclusions

ARISE I demonstrates that thrombectomy using the EmboTrap stent retriever yields similar results to devices that were used in recent randomised controlled trials for the treatment of stroke due to large vessel occlusions.

ClinicalTrials.gov identifier NCT02190552

Introduction

Thrombectomy using stent retrievers or contact aspiration brought a significant advance in the treatment of acute ischaemic stroke. Randomised controlled trials (RCTs) showed the benefit of thrombectomy, mostly with preceding intravenous recombinant tissue plasminogen activator (IV rt-PA) versus IV rt-PA alone in large vessel occlusions of the anterior circulation.^1–6 Two additional trials of thrombectomy or thrombus aspiration that were halted prematurely because of the accumulated positive evidence showed trends in the same direction.^7,8 Nevertheless, the proportion of good revascularisation, usually defined as a modified thrombolysis in cerebrovascular infarction (mTICI) score of at least 2b, was on average only 75% in these trials, and the rates of good outcome, defined as a modified Rankin scale (mRS) score of 0–2, only 51%. This indicates that the fate of too many patients is still bleak, and further progress in stroke treatment is needed.

EmboTrap is a novel CE marked mechanical revascularisation device intended to clear large vessel occlusions. It was designed for use in the anterior and posterior cerebral circulation in vessels of 1.5–5 mm diameter and it differs from other stent retrievers. EmboTrap contains a central canal that opens a small channel for blood to flow immediately after insertion into the occluded artery and before retrieving the clot. This provides blood flow to the ischaemic tissue even before retraction of the clot, breaks the pressure gradient at the occlusion site and might eventually turn into saving more tissue at risk and better clinical outcomes. In this pilot study we report the performance of EmboTrap in acute ischaemic stroke.

Methods

The analysis of revascularisation in ischaemic stroke with EmboTrap (ARISE I study) is an open label, single arm, multicentre, prospective observational study to examine the efficacy of EmboTrap to treat acute ischaemic stroke resulting from large vessel occlusions (see Appendix 1 for a list of the ARISE I trial investigators).

Inclusion criteria for ARISE I were patient's age between 18 and 80 years, informed consent by the patient or legal representative, acute focal cerebral ischaemia, a National Institutes of Health stroke scale (NIHSS) score of 8 or greater and 25 or less, and a pre-ictal mRS score of 0–1. Patients with more than 5 hours' symptom duration or unknown time of onset were eligible for ARISE I if the stroke volume was less than 30 mL on magnetic resonance imaging (MRI) (diffusion restriction) or computed tomography (CT) (low cerebral blood volume) and perfusion reduction indicated mismatch. Exclusion criteria are listed in the study protocol (see the Supplementary files). The plan was to include 100 patients.

The study protocol recommended use of the EmboTrap device as described in the operating manual. The use of a balloon guide catheter for flow arrest, a distal access catheter or both to support clot retrieval was considered optional.

The primary endpoint was revascularisation as measured by a mTICI score of at least 2b following the use of EmboTrap.⁹

Secondary endpoints were time to revascularisation defined as time from groin puncture to final angiographic result, the number of passes to achieve mTICI 2b or greater flow, mortality, serious device-related adverse effects such as vessel perforation or dissection, symptomatic intracerebral haemorrhage and clinical outcome at 90 (±14) days. A good clinical outcome was judged as an mRS score of 2 or less. Symptomatic haemorrhage was defined as intracerebral haematoma in over 30% of the infarcted area with substantial space-occupying effect or as any haemorrhage outside the infarct (intraparenchymal haemorrhage type 2) at post-treatment scan combined with neurological deterioration leading to an increase of 4 points or more on the NIHSS. Symptomatic subarachnoid haemorrhage was also assessed.

Endpoints, adverse events and clinical outcomes were assessed and reported by the local investigators. A data and safety monitoring board with neurologists and neurointerventionists adjudicated whether adverse events were deemed attributable to the procedure, to the EmboTrap system, adjuvant therapy (intra-arterial thrombolysis, thrombectomy), or resulting from the natural course of the initial stroke. The study was approved by the ethics committees of all participating centres.

Neuravi, the sponsor, initiated and set up the study according to good clinical practice, and an external contract research organisation performed the monitoring. Data were analysed by two independent statisticians. The principal investigators had full access to all the data.

Statistical analysis of ARISE I data

The baseline characteristics of the ARISE I patients are specified as continuous variables or as binary responses. The primary outcome of the mTICI score and the key secondary response of the mRS score at 90 days are categorical, while further secondary responses are continuous (time of various stages of the operation process) or binary (symptomatic intracranial haemorrhage). Table 1 provides means and standard deviations (SDs) for continuous and counts for categorical responses, along with the sample sizes.

Table 1.

Baseline characteristics of ARISE I plus that in combination with characteristics of mechancial thrombectomy arm patients in previous RCTs.

	ARISE I			All studies			Comparison of ARISE I and all studies
	Sample size and patients with characteristic where appropriate	Estimated proportion or mean	95% CI	Sample size and patients with characteristic where appropriate	Estimated proportion or mean	95% CI	Estimated difference between ARISE I and random effects model	95% CI (non-zero denoted)	P value*
Age (years)	40	64	(59.6, 68.4)	966	66.4	(64.9, 67.9)	–2.6	(–8.3, 3.2)	0.38
Men	25/40	0.62	(0.47, 0.78)	528/966	0.55	(0.51, 0.58)	0.08	(–0.08, 0.25)	0.31
Atrial fibrillation	6/40	0.15	(0.04, 0.26)	248/762	0.32	(0.27, 0.37)	–0.19	(–0.31, –0.06)*	<0.01
Diabetes	6/40	0.15	(0.04, 0.26)	154/964	0.17	(0.11, 0.22)	–0.02	(–0.22, 0.18)	0.85
Dyslipidemia	9/40	0.22	(0.10, 0.35)	306/871	0.35	(0.27, 0.44)	–0.15	(–0.41, 0.12)	0.27
Hypertension	19/40	0.47	(0.32, 0.63)	526/961	0.58	(0.50, 0.65)	–0.11	(–0.38, 0.16)	0.43
Smoking	5/40	0.12	(0.02, 0.23)	346/931	0.34	(0.24, 0.45)	–0.25	(–0.56, 0.07)	0.12
Previous stroke/TIA	5/40	0.12	(0.02. 0.23)	74/763	0.09	(0.06, 0.13)	0.04	(–0.10, 0.17)	0.59
Previous MI, CAD	2/40	0.05	(0.01, 0.18)	99/654	0.14	(0.07, 0.22)	–0.11	(–0.31, 0.08)	0.25
ICA occlusion	6/40	0.15	(0.04, 0.26)	211/951	0.22	(0.17, 0.27)	–0.08	(–0.25, –0.10)	0.39
M1 occlusions	29/40	0.72	(0.59, 0.86)	671/951	0.69	(0.62, 0.76)	0.04	(–0.20, 0.28)	0.75
M2 occlusions	5/40	0.12	(0.02, 0.23)	65/951	0.08	(0.04, 0.11)	0.05	(–0.09, 0.19)	0.47
Systolic blood pressure (mmHg)	40	144.4	(137.7, 151.2)	931	145.2	(143.0, 147.5)	–0.88	(–9.6, 7.9)	0.84
Diastolic blood pressure (mmHg)	40	81.1	(76.7, 85.5)	176	78.4	(76.5, 80.4)	3.25	(–1.6, 8.1)	0.19
NIHSS	40	15.5	(14.1, 16.9)	966	17	(16.5, 17.6)	–1.7	(–3.5, 0.04)	0.06
IVT before thrombectomy	31/40	0.78	(0.65, 0.90)	845/966	0.89	(0.81, 0.98)	–0.13	(–0.42, 0.15)	0.37

The sample size along with estimated mean/proportion and 95% confidence intervals (CIs) are provided. The estimated difference in the mean/proportion between the ARISE I patients and all patients included in previous randomised controlled trials (RCTs) is also provided along with a 95% CI for the difference and P value for the Z-test.

For the baseline characteristics the small numbers of missing patient records are assumed missing completely at random and no imputation is carried out. The primary response of the mTICI score is available for all patients. However, the secondary response of mRS scores at 90 days were unavailable for some patients and were imputed as follows:

• no imputation, in which missing data were ignored;

• carry forward imputation, in which the last available mRS score was carried forward or set to 6 if none were available; or

• worst case imputation, in which missing mRS scores were set to 6.

The ARISE I results are compared to thrombectomy RCTs using a meta-analysis, based on the reported statistics from these RCTs which are detailed in the next section. A random effects model fitted using restricted maximum likelihood estimation is used for the meta-analysis using the metafor package version 1.9-9 in the statistical software package R version 3.4.0.^10,11 A Z-test of the null hypothesis of no difference was employed to assess whether the ARISE I performance was the same or different from the RCTs. If the two-sided 95% confidence interval included zero difference or equivalently, the P value was larger than 0.05, the ARISE I procedure was considered consistent with the RCTs.

Meta-analysis of RCTs

The individual patient records for the thrombectomy RCTs were not available for this meta-analysis, so the summary statistics reported in the original study papers and supplementary materials are utilised instead. The ARISE I patients were included in the meta-analysis to supplement the evidence of the treatment effect. As ARISE I is a relatively small study the estimates changed very little and the same conclusions are obtained when the ARISE I patients were excluded from the meta-analysis.

For all the continuous variables of interest the sample mean and SD from each study arm were extracted to compare with those calculated from the individual patient data from the ARISE I trial. If the sample mean and SDs were not reported the median and interquartile range were used to estimate them, and if these were not available the median and range were used instead.^12,13 If none of these statistics were reported the values were defined as missing.

Results

From 19 November 2014 to 27 May 2016, 40 patients at six European study sites in France, Germany, Ireland, Spain and Sweden were included in ARISE I. The study was terminated early in favour of ARISE II, a similar multicentre study launched by the sponsor in North America and Europe (ClinicalTrials.gov Identifier: NCT02190552).¹⁴

Six of the 40 included patients failed to meet the inclusion criteria as defined in the protocol, because EmboTrap was not used as the first device (one), pre-ictal mRS was not assessed (two), pre-ictal mRS with 4 points was too high and stroke onset was unknown (one) and age was more than 80 years (two). A per-protocol analysis excluding the patients who breached the inclusion criteria did not change the following conclusions.

Baseline characteristics of the ARISE I patients and all RCT patients within the mechancial thrombectomy arms are shown in Table 1. As a few baseline characteristics were not reported by the RCTs the number of patients with observations from the meta-analysis varies.

The final columns of Table 1 provide the difference between the estimated mean/proportion for the ARISE I trial and that obtained when combined with all RCT thrombectomy arms. There was no significant difference for any baseline characteristic at the 95% confidence level, except for a previous history of atrial fibrillation.

Table 2 reports the primary and secondary outcomes of the ARISE I trial and then combined with the RCT mechancial thrombectomy arms. The treatment process time (time from groin puncture to final angiogram) was not reported in any RCT so a meta-analysis is not possible. The time from stroke onset to end of the procedure was only reported by EXTEND IA, REVASCAT, PISTE and THRACE, hence the low sample size in the meta-analysis. The mortality at 90 days (mRS 6) was low for the ARISE I cohort when analysing only patients with a recorded score. However, when the carry forward and worst case imputation schemes were applied the mortality increased to the same level as observed in the RCTs. The results of the carry forward and worst case imputation schemes were the same when estimating the proportion of patients with good clinical outcomes (mRS ≤ 2) so these are combined in Table 2.

Table 2.

Treatment times, primary and secondary outcomes of ARISE I and that in combination with RCT patients in the mechancial thrombectomy arm of previous RCTs.

	ARISE I			All studies			Comparison of ARISE I and all studies
	Sample size and patients with characteristic where appropriate	Estimated proportion or mean	95% CI	Sample size and patients with characteristic where appropriate	Estimated proportion or mean	95% CI	Estimated difference between ARISE I and random effects model	95% CI (non-zero denoted)	P value*
Process time (minutes)	40	75.5	(59.7, 91.4)	NA	NA		NA	NA	NA
Onset of symptoms to end of procedure (minutes)	37	275.4	(217.2, 333.6)	412	285.1	(244.9, 325.3)	–11.4	(–133.8, 110.9)	0.85
Onset of symptoms to groin puncture (minutes)	38	249.3	(191.8, 306.8)	899	237.4	(221.0, 253.7)	12.67	(–61.2, 86.6)	0.74
Onset of symptoms to IVT (minutes)	29	118.6	(99.9, 137.2)	923	117.6	(106.1, 129.2)	1.0	(–40.3, 42.3)	0.96
mRS6 (ignore missing)	1/36	0.03	(0.00, 0.17)	134/952	0.12	(0.08, 0.16)	–0.11	(–0.21, –0.77)*	0.03
mRS6 (carry forward imputation)	2/40	0.05	(0.01, 0.18)	135/956	0.13	(0.09, 0.16)	0.09	(–0.19, 0.02)	0.12
mRS6 (worst case imputation)	5/40	0.12	(0.02, 0.23)	138/956	0.13	(0.10, 0.17)	–0.01	(–0.14, 0.12)	0.88
mRS≤2 (ignore missing)	23/36	0.64	(0.48, 0.80)	457/952	0.51	(0.43, 0.59)	0.14	(–0.14, 0.42)	0.32
mRS≤2 (carry forward and worst case imputation)	23/40	0.57	(0.42, 0.73)	457/956	0.51	(0.43, 0.58)	0.08	(–0.20, 0.35)	0.59
mTICI2 b/3 after ≤ 3 EmboTrap passes	30/40	0.75	(0.62, 0.88)	574/817	0.74	(0.67, 0.81)	0.01	(–0.24, 0.26)	0.95
mTICI2 b/3 after ≤ 3 EmboTrap® passes and rescue therapy if needed	34/40	0.85	(0.74, 0.96)	578/817	0.75	(0.68, 0.83)	0.11	(–0.13, 0.35)	0.38
Symptomatic ICH	0/40	0.00	(0.00, 0.17)	34/935	0.03	(0.01, 0.04	0.02	(–0.07, 0.04)	0.57

Note that the treatment process times were frequently unreported. The sample size along with estimated mean/proportion and 95% confidence intervals (CIs) are provided. The estimated difference in the mean/proportion between the ARISE I patients and the patients of the previous randomised controlled trials (RCTs) is also provided along with a 95% CI for the difference and P value for the Z-test.

Nine patients experienced a total of 11 serious adverse events during the ARISE I study. Three were device or procedure related (one subarachnoid haemorrhage and two vessel perforations), two were procedure related (two access site complications) and six were disease or stroke related (one embolism in the cerebral artery, one occlusion of the internal carotid artery, two atrial fibrillations and two haemorrhagic transformations of stroke). No patient experienced any symptomatic intracranial haemorrhage.

Figure 1(a) shows the primary study outcome of good revascularisation as measured by a mTICI 2b/3 score within three passes with EmboTrap, with a more detailed and visual summary of the individual RCT results that underpinned the meta-analysis presented in Table 2. The mean and median numbers of passes until good revascularisation were two, one pass in 17 patients, two passes in 10 and three in 13.

Figure 1.

(a) The primary outcome of good revascularisation as measured by a modified thrombolysis in cerebrovascular infarction (mTICI) 2b/3 score within three or fewer passes with EmboTrap. The proportion of patients with previous intravenous thrombolysis was the same in ARISE I and the randomised controlled trials. ARISE40 designates the 40 ARISE I patients. (b) The rate of mTICI 2b/3, if after three passes additional rescue therapy procedures were used. ARISE40 designates the 40 ARISE I patients (see also Supplementary Figure 1).

If revascularisation was less than mTICI 2b/3 after three EmboTrap passes rescue therapy was used if deemed necessary. Nine patients received rescue therapy with EmboTrap or other devices. The median number of passes remained two, but the mean increased to 2.65 with a range of one to eight. After rescue therapy the revascularisation rate of mTICI 2b/3 rose from 30 (75%) to 34 (85%) patients (Figure 1(b)).

Figure 2 provides a direct comparison of good clinical outcome defined as mRS of 2 or less between the ARISE I and the RCT thrombectomy arms, a secondary study outcome.

Figure 2.

Direct comparison of a good clinical outcome (modified Rankin scale ≤ 2) between ARISE I and the mechanical thrombectomy arms of previous randomised controlled trials. The similar and numerically (but not significantly) more positive performance of the ARISE I procedure is visually obvious. ARISE40 designates the 40 ARISE I patients (see also Supplementary Figure 2).

Figure 3 shows the clinical outcome at 90 days after thrombectomy, with or without prior intravenous thrombolysis, compared with the best medical treatment in all the RCTs. Best medical treatment included mostly intravenous thrombolysis, and outcomes of mRS of 2 or less were considered favourable. The ARISE I study had no best medical treatment arm so is not included in the meta-analysis.

Figure 3.

Good clinical outcome (modified Rankin scale ≤ 2) at 90 days after mechanical thrombectomy, with or without prior intravenous thrombolysis, compared to best medical treatment for previous randomised controlled trials. Direct comparison using the log relative risk. Values higher than zero indicate a beneficial effect of mechanical thrombectomy.

Discussion

The main purpose and primary outcome of ARISE I was to demonstrate that revascularisation procedures using the EmboTrap device achieve equal or better revascularisation rates in stroke due to large vessel occlusion than other devices that had been used in recent RCTs. This goal was reached.

The primary outcome of ARISE I, i.e. mTICI 2b/3 after three or fewer passes with the EmboTrap was achieved in 75% of patients. This is consistent with mTICI 2b/3 rates of 74% and an estimated difference of 0.8% (P = 0.44; Table 2 and Figure 1(a)). If the interventionalist in ARISE I considered revascularisation inadequate after three EmboTrap passes, rescue therapy with further EmboTrap passes or another device was permitted. After rescue therapy mTICI 2b/3 revascularisation rates rose to 85%, with a positive estimated difference of 11% compared to the RCTs. This difference is numerically better but not significant (P = 0.38; Table 2 and Figure 1(b)).

The high revascularisation rate achieved in ARISE I converted into a high rate of good clinical outcome (mRS ≤ 2) as shown in Table 2 and Figure 2. The clinical outcomes in ARISE I were consistently similar to the outcomes in the RCTs, with a non-significant estimated improvement of 14% (P = 0.32). Even if imputation with the worst case scenario is performed, the similar performance of the ARISE I procedure is maintained.

The baseline characteristics of the ARISE I patients were similar to the RCT patients. The NIHSS scores of ARISE I patients were numerically lower on average than in RCT patients, but the difference was statistically not significant.There is only one significant difference in baseline characteristics, as fewer patients in ARISE I experienced atrial fibrillation. However, this imbalance is unlikely to have influenced outcomes as the much larger MR CLEAN study did not show any different endovascular treatment effect between patients with and without atrial fibrillation.¹⁵

The intervention procedure times in ARISE I were also the same as in the RCTs. Imaging was not used for the majority of patients to select them for ARISE I. Imaging selection was applied for only five patients who entered the study more than 5 hours after symptom onset. Therefore, the similar and somewhat favourable ARISE I results are unlikely to be due to an imbalance of baseline characteristics or due to a bias of treating only better patients.

When ARISE I was started the positive results of the MR CLEAN study had already been presented. Therefore a control group with best medical treatment for comparison with thrombectomy in ARISE I would have been unethical. However, indirect comparisons of ARISE I with best medical treatment of RCTs are feasible. As EmboTrap in ARISE I performed equally well as endovascular treatment in the RCTs (Figure 2), its effectiveness in thrombectomy is likely to be superior to best medical treatment as well. Figure 3 serves to demonstrate this indirect comparison. It shows the proportion of good clinical outcomes (mRS ≤ 2) after thrombectomy compared to best medical treatment in previous RCTs with a highly significant difference (P = 7.0 × 10⁻¹⁰). The ARISE I results as illustrated in Figures 1–3 indicate that thrombectomy with EmboTrap was as effective as thrombectomy performed with other devices in the previous RCTs of stroke due to large vessel occlusion.

Nine patients in ARISE I experienced serious adverse events, but none of them caused any acute or persistent neurological deficits. In addition, no patient experienced any symptomatic intracranial haemorrhage. Therefore, the use of EmboTrap in ARISE I was safe.

The ARISE I study was stopped before the planned sample size was reached in favour of ARISE II. This is the main limitation of this study as it reduces statistical power. Results in ARISE I were reported by the investigators. A missing core laboratory in ARISE I represents another limitation. However, the performance of EmboTrap in ARISE I was similar to the performance in the much larger ARISE II study that used a core laboratory for assessment.¹⁴ Revascularisation of mTICI 2b/3 in ARISE II was achieved in 182 of 227 patients (80.2%) after three or fewer passes with EmboTrap, and 146 of them (67.3%) recovered to mRS 0–2 at 90 days.

Furthermore, ARISE I was a non-randomised study, which allows only indirect comparisons with best medical treatment from previous RCTs. Nevertheless, the results of single arm studies should be published and if not reported a bias will occur in systematic reviews.

In conclusion, ARISE I shows that thrombectomy using the EmboTrap stent retriever yields similar results to the devices that were used in previous RCTs for the treatment of stroke due to large vessel occlusions.

Appendix 1

The ARISE I trial investigators are:

Trial principal investigators: Tommy Andersson (Co-PI), Heinrich P Mattle (Co-PI)

Data safety monitoring board: Mayank Goyal, Werner Hacke and Laurent Pierot

Statisticians: John Newell, Carl Scarrott

Enrolling sites:

Department of Radiology, Beaumont Hospital, Dublin, Ireland

Site PI: John Thornton

Study coordinators: Ailbhe Cullen, Patricia Daly, Lorna Hutchinson

Other site investigators: Paul Brennan, Seamus Looby, Paul O Brien, Alan O Hare, David William

Hospital Clinic de Barcelona, Barcelona, Spain

Site PI: Juan Macho

Study coordinator: Antonio Lopez

Other site investigators: Jordi Blasco, Luis SanRoman

Department of Radiology and Neuroradiology, Universitätsklinikum Schleswig-Holstein UKSH, Kiel Campus, Germany

Site PI: Christian Riedel

Study coordinators: Sabine Krieter, Susanne Becke

Other site investigators: Fritz Wodarg, Naomi Larsen, Olav Jansen

Karolinska University Hospital, Stockholm, Sweden

Site PI: Tommy Andersson

Study coordinators: Åke Holmberg

Other site investigators: Michael Söderman, Patrick Brouwer

CHU Montpellier, Hôpital Gui de Chauliac, Montpellier, France

Site PI: Alain Bonafé

Study coordinator: M Moynier

Other site investigators: V Costalat, C Riquelme, O Eker, G Gascou

Hôpital Rothschild, Paris, France

Site PI: Michel Piotin

Study coordinator: Marie Abrivard

Other site investigators: Hocine Redjem, Gabriele Cicco, Stanislas Smajda

Author contribution

Heinrich P Mattle designed the study, interpreted the data, drafted and finalised the manuscript, and is responsible for the integrity of the work.

Carl Scarrott performed the meta-analysis including data extraction and revised the manuscript critically for important intellectual content.

Mairsil Claffey designed the study, interpreted the data and revised the manuscript critically for important intellectual content.

John Thornton, Juan Macho, Christian Riedel, Michael Söderman, Alain Bonafé and Michel Piotin acquired data and revised the manuscript critically for important intellectual content.

John Newell performed the meta-analysis including data extraction and revised the manuscript critically for important intellectual content.

Tommy Andersson designed the study, interpreted the data and revised the manuscript critically for important intellectual content.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HPM, JT and TA report consultancy for Neuravi, MS reports consultancy for Neuravi – Cerenovus, Medtronic and Neurvana, and AB reports consultancy for Medtronic, Stryker and Microvention. The remaining authors report no conflicts of interest.

Funding

The authors disclosed receipt of the following financial support for the research authorship, and/or publication of this article: the study was funded by Neuravi Ltd., Galway, Ireland.