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EJMINT Original Article, 2012: 1236000072 (4th September 2012)

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Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR - Part II: methodology of future trials
Jens Fiehler, Michael Söderman, Francis Turjman, et al
EJMINT Original Article, 2012: 1236000072 (4th September 2012)

Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR - Part II: methodology of future trials

EJMINT Original Article, 2012: 1236000072 (4th September 2012)
Jens Fiehler, Michael Söderman, Francis Turjman, Philip M White, Søren Jacob Bakke, Salvatore Mangiafico, Rüdiger von Kummer, Mario Muto, Christophe Cognard, Jan Gralla

Abstract

Based on current data and experience, the joint working group of the European Society of Minimally Invasive Neurological Therapy (ESMINT) and the European Society of Neuroradiology (ESNR) make suggestions on trial design and conduct aimed to investigate therapeutic effects of mechanical thrombectomy (MT). We anticipate that this roadmap will facilitate the setting up and conduct of successful trials in close collaboration with our neighbouring disciplines.

Abbreviations

ASPECTS
Alberta Stroke Program Early CT
BCO
Balloon guiding catheter occlusion
BMT
Best medical therapy
CAS
carotid stenting
CBF
Cerebral blood flow
CBV
Cerebral blood volume
CCA
Common carotid artery
CEA
Carotid endarterectomy
CS
Conscious sedation
CTA
CT-angiography
CTP
CT-perfusion
DSA
Digital subtraction angiography
DWI
Diffusion weighted imaging
EIC
Early ischemic signs
ESMINT
European Society of Minimally Invasive Neurological Therapy
ESNR
European Society of Neuroradiology
ESO
European Stroke Organisation
FU
Follow up
GA
General anaesthesia
ICA
Internal carotid artery
IMS III
Interventional Management of Stroke III Trial
IVT
Intravenous thrombolytical therapy
MCA
Middle cerebral artery
mRS
Modified rankin scale
MT
Mechanical thrombectomy
NE-CT
Non-enhanced CT
NIH-SS
National Institute of Health Stroke Scale
PI
Perfusion MRI
RCT
Randomised control trial
sICH
symptomatic intracranial haemorrhage
stent-triever
self-expanding stents

Randomized Controlled Trials

ECASS
European Cooperative Acute Stroke Study
ICSS
International Carotid Stenting Study
IMS
Interventional Management of Stroke
MC CLEAN
Multicenter Randomized CLinical trial of endovascular treatment for acute ischemic stroke in The Netherlands.
NINDS
National Institute of Neurological Disorders and Stroke
TREVO
Thrombectomy REvascularization of Large Vessel Occlusions in Acute Ischemic Stroke
THRACE
Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke
THERAPY
The Randomized, Concurrent Controlled Trial to Assess the Penumbra System’s Safety and Effectiveness in the Treatment of Acute Stroke
PISTE
Pragmatic ischaemic stroke thrombectomy evaluation
REVASCAT
RandomizEd trial of reVascularizAtion with Solitaire FR® device vs. best mediCal therapy in the treatment of Acute stroke due to anTerior circulation large vessel occlusion presenting within 8 h of symptom onset
RIVER
Reperfuse Ischemic Vessels with Endovascular Recanalization
SPACE
Stent-Protected Angioplasty vs. Carotid Endarterectomy
SYNTHESIS EXP
SYNTHESIS Expansion
SWIFT
SOLITAIRE FR With the Intention For Thrombectomy

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Use of clinical endpoints

A pragmatic study approach enables “hard” and established primary clinical endpoints to be used. Clinical examinations (by an independent practitioner) should be scheduled at day 90 for all study subjects preferably at the investigational site (alternatively by telephone interview). The proportion of subjects with “good” clinical outcomes as measured by Modified Rankin Scale (mRS) at 90 days post treatment should be compared between two treatment groups (Table 1). A good clinical outcome will be defined as a mRS of 0-2. Superiority of MT must be the design goal as it is more invasive and, perhaps, more expensive. Formal cost effectiveness analyses of MT are required using robust randomised controlled trial (RCT) data. As patients with proximal artery occlusions have a poorer prognosis, an improvement from mRS 5 to mRS 3 (where the patients can still walk) could be considered a success. Nevertheless, such “sub-radar-success” would be considered as poor outcome and the benefit would escape a conventional study design. In comparison to a standard fixed dichotomous approach (mRS 0-2), stroke trial power and interpretation can be substantially enhanced by full ordinal and sliding dichotomy analysis [1]1. Saver JL; Optimal end points for acute stroke therapy trials: best ways to measure treatment effects of drugs and devices; Stroke 2011; 42:2356–2362 [PubMed]. An analysis of 47 trials testing treatments with likely biological benefit or harm found that shift analysis was positive in 26 %, whereas dichotomised analysis was positive in only 9 % [2]2. Barclay-Goddard R, Epstein JD, Mayo NE; Response shift: a brief overview and proposed research priorities; Qual Life Res 2009; 18:335–346 [PubMed]. We suggest incorporating this analysis as pre-defined clinical secondary endpoint, as is the case in PISTE. Other suggested clinical secondary clinical endpoints suggested are: mortality; improvement in acute to 24 h National Institute of Health Stroke Scale (NIH-SS) score; the rate of subjects with NIH-SS of 0 or 1 or improvement in NIH-SS score defined as an 8 point improvement at 24 h post treatment; full neurological recovery (Rankin 0-1 vs. 2-6) and days spent at home from admission after onset to 90 days post stroke.

Table 1 Key endpoints

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Imaging based patient selection and endpoints

The classical intravenous thrombolytical therapy (IVT) studies (e.g. NINDS, ECASS I-III) used non-enhanced CT (NE-CT) as sole imaging method. The lower therapy efficacy of IVT beyond 3 h after symptom onset has been attributed in part to the scarce imaging information from NE-CT, and in particular to the missed potential to accurately detect the site of arterial occlusion or spontaneous recanalisation. To overcome this drawback, NE-CT has been completed by CT-angiography (CTA) and CT-perfusion (CTP) to obtain information on the micro- and macrovascular level or has been completely replaced by MRI as primary imaging method in acute ischemic stroke in many centres [3]3. Eckert B, Kusel T, Leppien A, Michels P, Muller-Jensen A, Fiehler J; Clinical outcome and imaging follow-up in acute stroke patients with normal perfusion CT and normal CT angiography; Neuroradiology 2011; 53:79–88 [PubMed]. To set up an imaging protocol for multicentre RCT, a balance is required between optimal patient selection and feasibility for multi-centric approach even for severely affected patients. Several authors believe that study patients should be imaged by MRI before treatment: MRA, axial T2w and T2*w, FLAIR, diffusion weighted imaging (DWI) and perfusion MRI (PI) completing image evaluation. Using DWI/PI to assess possible areas at risk might change the indication for MT [4]4. Mlynash M, Lansberg MG, De Silva DA, et al.; Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set; Stroke 2011; 42:1270–1275 [PubMed]. MRI and CTP would also facilitate the diagnosis of reperfusion, haemorrhage and the prediction of malignant stroke progression [5, 6]5. Thomalla G, Hartmann F, Juettler E, et al.; Prediction of malignant middle cerebral artery infarction by magnetic resonance imaging within 6 hours of symptom onset: a prospective multicenter observational study; Ann Neurol 2010; 68:435–445 [PubMed]6. Minnerup J, Wersching H, Ringelstein EB, et al.; Prediction of malignant middle cerebral artery infarction using computed tomography-based intracranial volume reserve measurements; Stroke 2011; 42:3403–3409 [PubMed] and probably enhance trial safety. It has been shown in several studies that multivariate CT including CTP can also achieve a reasonable diagnostic accuracy [7]7. Coutts SB, Modi J, Patel SK, Demchuk AM, Goyal M, Hill MD; CT/CT angiography and MRI findings predict recurrent stroke after transient ischemic attack and minor stroke: results of the prospective CATCH study; Stroke 2012; 43:1013–1017 [PubMed]. To identify potential study participants who are most likely to benefit from MT, an appropriate vessel occlusion needs to be demonstrated and the volume of non-salvageable tissue needs to be compared to the volume of tissue at risk. In this section we discuss the major significance of using imaging protocols.

Imaging based patient selection

Non-enhanced CT

The ECASS I pioneered the importance of assessing the volume of early ischemic signs (EIC) heralding irreversible tissue damage in NE-CT to predict benefit from thrombolysis and introduced the “one-third” rule [8]8. von Kummer R, Allen KL, Holle R, et al.; Acute stroke: usefulness of early CT findings before thrombolytic therapy; Radiology 1997; 205:327–333 [PubMed]. In particular for non-fully trained neuroradiologists, the Alberta Stroke Program Early CT (ASPECTS) score has been developed as a systematic approach to assessing EIC on NE-CT [9–11]. Patients benefit the most with early mechanical recanalisation with an ASPECTS score >7 on baseline NE-CT [12]12. Goyal M, Menon BK, Coutts SB, Hill MD, Demchuk AM; Effect of baseline CT scan appearance and time to recanalization on clinical outcomes in endovascular thrombectomy of acute ischemic strokes; Stroke 2011; 42:93–97 [PubMed].

A recent study employing thrombus length measurements showed that in acute middle cerebral artery stroke, IVT has almost no potential to recanalise occluded vessels if thrombus length exceeds 8 mm [13, 14]13. Riedel CH, Jensen U, Rohr A, et al.; Assessment of thrombus in acute middle cerebral artery occlusion using thin-slice nonenhanced Computed Tomography reconstructions; Stroke 2010; 41:1659–1664 [PubMed]14. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O; The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length; Stroke 2011; 42:1775–1777 [PubMed]. Although not confirmed in an independent study, this finding is already in use as selection criterion for the THERAPY study.

Diffusion weighted MRI

The most accurate yet practical way to determine infarct core with strong level 1 evidence is with DWI [15]15. Lev MH; Acute stroke imaging: what is sufficient for triage to endovascular therapies? Ajnr Am J Neuroradiol 2012; 33:790–792 [PubMed]. However, DWI does not necessarily reflect later infarctions as subsequent normalisations of the hyperintensities can occur, especially in a very early phase and after recanalisation [16, 17]16. Fiehler J, Foth M, Kucinski T, et al.; Severe ADC decreases do not predict irreversible tissue damage in humans; Stroke 2002; 33:79–8617. Fiehler J, Knudsen K, Kucinski T, et al.; Predictors of apparent diffusion coefficient normalization in stroke patients; Stroke 2004; 35:514–519 [PubMed]. Final infarct volumes of >100 mL are rarely associated with a good outcome [18]18. Yoo AJ, Chaudhry ZA, Nogueira RG, et al.; Infarct volume is a pivotal biomarker after intra-arterial stroke therapy; Stroke 2012; 43:1323–1330 [PubMed].

CT/MR-angiography

The demonstration of occlusion pattern prior to randomisation is essential. Proximal occlusions generally pose a larger thrombus burden and worse clinical outcome and should be excluded from primary studies. The most proximal occlusion site should be the intracranial ICA bifurcation (occlusion of the “Carotid-T”) or the sphenoidal part of the middle cerebral artery (MCA). Prior to the publication of clot length measurements in NE-CT, a clot burden score was suggested based on CTA [19]19. Puetz V, Dzialowski I, Hill MD, et al.; Intracranial thrombus extent predicts clinical outcome, final infarct size and hemorrhagic transformation in ischemic stroke: the clot burden score; Int J Stroke 2008; 3:230–236 [PubMed] that predicts the response to IVT and thereby potentially identifies candidates for a RCT. The scale is limited because it does not take into account residual flow at the site of arterial occlusion or vessel retrograde filling [10]10. Menon BK, Puetz V, Kochar P, Demchuk AM; ASPECTS and other neuroimaging scores in the triage and prediction of outcome in acute stroke patients; Neuroimaging Clin N Am 2011; 21:407–423, xii. CTA should include at least the bifurcation of the common carotid artery (CCA) and the origin of the internal carotid artery (ICA) to identify a long vessel occlusion. Although not very responsive to IVT, this condition introduces variance and reduces the power of the study. For MRA we suggest including a contrast-enhanced MRA for evaluation of the supra-aortic vessels if possible so as to evaluate arterial access to the lesion [20]20. Alfke K, Jensen U, Pool C, et al.; Contrast-enhanced magnetic resonance angiography in stroke diagnostics: additional information compared with time-of-flight magnetic resonance angiography? Clin Neuroradiol 2011; 21:5–10 [PubMed].

CT/MR-perfusion

In general, the region with cerebral blood volume (CBV) decrease is considered the infarct core (“irreversibly damaged”) and cerebral blood flow (CBF) deficit the tissue-at-risk (often used synonymously with “penumbra”) [21]21. Wintermark M, Sincic R, Sridhar D, Chien JD; Cerebral perfusion CT: technique and clinical applications; J Neuroradiol 2008; 35:253–260 [PubMed]. However, for individuals, this concept does not necessarily hold true. Perfusion CT (as well as perfusion MRI) is notoriously non-standardised [22]22. Dani KA, Thomas RG, Chappell FM, et al.; Computed tomography and magnetic resonance perfusion imaging in ischemic stroke: definitions and thresholds; Ann Neurol 2011; 70:384–401 [PubMed] and the mismatch-concepts in their present form are often based on secondary volumetric analyses that are not applicable in the acute situation. Therefore, we do not consider CTP and PI feasible as a patient selection criterion for larger scale RCTs. The technique heavily depends on arbitrary thresholds, acquisition peculiarities, the post-processing software and the vendor [23]23. Pulli B, Schaefer PW, Hakimelahi R, et al.; Acute ischemic stroke: infarct core estimation on CT angiography source images depends on CT angiography protocol; Radiology 2012; 262:593–604 [PubMed]. Therefore, we suggest a simple approach: to enrol patients with EIC (NE-CT) less than the expected territory of the occluded artery (CTA). We suggest using CTP without thresholding as control instrument to detect deviations from this hypothesis and exclude these patients (e.g. to prove that the occlusion is more distal than diagnosed on CTA, thus violating the hypothesis of a proximal occlusion).

Digital subtraction angiography (DSA)

A complete 4-artery-DSA should not be stipulated by the protocol because of time-limitations. However, a complete examination should be encouraged if it is achievable within <5 minutes. DSA should confirm the most proximal occlusion site. Collateral scores could be used for secondary analysis but not as patient selection criterion.

Imaging endpoints

The primary target of acute stroke therapy is to avoid disability and death by limiting the tissue damage and to avoid infarct expansion. Heterogeneity of clinical outcome is dependent on infarct localisation [24]24. Rosso C, Colliot O, Valabregue R, et al.; Tissue at risk in the deep middle cerebral artery territory is critical to stroke outcome; Neuroradiology 2011; 53:763–771 [PubMed], leading to the need for large sample sizes. However, final infarct volume is a critical determinant of 3-month functional outcome and appears suitable as a surrogate biomarker in proof-of-concept intra-arterial therapy trials [18]18. Yoo AJ, Chaudhry ZA, Nogueira RG, et al.; Infarct volume is a pivotal biomarker after intra-arterial stroke therapy; Stroke 2012; 43:1323–1330 [PubMed].

Non-enhanced CT

Hypodensity in NE-CT is a highly specific marker for irreversible tissue damage. The volumetric analysis of infarct volume (mL) is an imaging endpoint with high reliability [18]18. Yoo AJ, Chaudhry ZA, Nogueira RG, et al.; Infarct volume is a pivotal biomarker after intra-arterial stroke therapy; Stroke 2012; 43:1323–1330 [PubMed]. Possible time points for this analysis would be 24 h, 48 h, 5-7 days and 90 days. Correcting this volume in follow up (FU) imaging for the initial infarct volume and monitoring the infarct growth would increase study power. However, while EIC can be reliably detected, a clear volumetric analysis of EIC cannot be reached by manual delineation even if supported by post-processing algorithms. A possible solution would be to evaluate the changes of ASPECTS score from before treatment to follow up.

CT/MR-angiography

To detect recanalisation in both arms (MT and IVT) only CTA/MRA could be used at the first FU. As data on recanalisation rates are already available, we consider this desirable.

CT/MR-perfusion

Although too inaccurate to serve as patient selection criteria, thresholded CTP and MRP maps could be used as imaging outcome criteria to detect reperfusion in both arms (MT and IVT); however, only CTA/MRA can be used at the first FU. Given the difficulties with volumetric analysis of EIC, it is conceivable to use CTP parameters such as CBV as primary marker of severe ischemia and NE-CT at FU as a marker of final infarct. Based on a central core lab analysis, more advanced analysis tools such as multivariate prediction algorithms could be employed that could potentially permit subgroup analyses even with limited sample sizes (below 50) [25, 26]25. Wu O, Christensen S, Hjort N, et al.; Characterizing physiological heterogeneity of infarction risk in acute human ischaemic stroke using MRI; Brain 2006; 129:2384–2393 [PubMed]26. Willats L, Connelly A, Christensen S, Donnan GA, Davis SM, Calamante F; The role of bolus delay and dispersion in predictor models for stroke; Stroke 2012; [PubMed].

Digital subtraction angiography

The DSA endpoints can be applied only in the MT cohort. Among several grading schemes, TICI appears to be most reliably and closely related to clinical outcome in patients with acute ischemic stroke. A dichotomisation in patients with TICI 2b or better should be predefined as an end result of the DSA procedure. However, TICI 2b covers a wide range of perfusion conditions that do not necessarily have uniform implications on lesion growth and prognosis. Additionally, the time from arterial puncture to initial restoration of flow to TICI 2b, the number of device deployments and the rate of embolisation in the vasculature proximal and distal to the target occlusion and their influence on the collateralisation should be measured. In an IV/MT study, the recanalisation success of IVT can be estimated in the MT arm. All DSA endpoints need to be determined by an independent core lab.

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Qualification requirements for interventionalists and centres

Operator experience

Every operative therapy is dependent on the technical ability and experience of the local operators, the materials used and their preparation [27]27. Solomon MJ, McLeod RS; Should we be performing more randomized controlled trials evaluating surgical operations? Surgery 1995; 118:459–467 [PubMed]. When studying a comparably new procedure, within-study-learning should be avoided as far as practical. The neuro-interventional community has learned this lesson the hard way from the trials comparing carotid stenting (CAS) vs. carotid endarterectomy (CEA).

MT in stroke should not be considered a trivial procedure because it not only requires technical handling of an ICA and/or MCA occlusion, but also treatment of complications (e.g. vessel perforation, dissection) and sometimes collateral procedures (e.g. carotid stenting). Moreover, compared to pharmacological trials there is a greater potential for variability in the compliance and performance of surgical operations because of differences in technology, surgeon skill and experience [28]28. Fiehler J, Bakke SJ, Clifton A, et al.; Plea of the defence-critical comments on the interpretation of EVA3S, SPACE and ICSS; Neuroradiology 2010; 52:601–610 [PubMed]. The magnitude of the association linking case volume to outcome varied greatly in a large systematic review [29]29. Halm EA, Lee C, Chassin MR; Is volume related to outcome in health care? A systematic review and methodologic critique of the literature; Ann Intern Med 2002; 137:511–520.

It is well accepted that surgical skill and experience affect outcomes of comparative surgical treatments profoundly [30]30. van der Linden W; Pitfalls in randomized surgical trials; Surgery 1980; 87:258–262 [PubMed] and it has also been shown that complication rates at individual centres decrease with increasing patient numbers [31]31. Verzini F, De Rango P, Parlani G, Panuccio G, Cao P; Carotid artery stenting: technical issues and role of operators' experience; Perspect Vasc Surg Endovasc Ther 2008; 20:247–257 [PubMed]. The proportion of patients being discharged home after endovascular therapy of unruptured aneurysms when treated by physicians coiling ≤5 unruptured aneurysms per year was half the rate in physicians treating at least 45 [32]32. Brinjikji W, Cloft HJ, Fiorella D, Lanzino G, Kallmes DF; Estimating the proportion of intracranial aneurysms likely to be amenable to treatment with the pipeline embolization device; J Neurointerv Surg 2011.. Data on CAS suggest the existence of a learning curve that involves a caseload larger than that generally accepted for credentialing [33]33. Verzini F, Cao P, De Rango P, et al.; Appropriateness of learning curve for carotid artery stenting: an analysis of periprocedural complications; J Vasc Surg 2006; 44:1205–1211, discussion 1211-1202. In contrast, in the CAS group in EVA3S, the 30-day risk of stroke or death was 12.2 % in patients treated by interventional physicians who had experience of >50 carotid-stenting procedures, 11.0 % in patients treated by physicians who had done 50 or fewer procedures and 7.1 % in patients treated by physicians who were still in procedural training (p = 0.49) [34]34. Mas JL, Chatellier G; Carotid angioplasty and stenting; Stroke 2008; 39:e19–e20 [PubMed]. A similarly confusing observation has been made in the ICSS study where supervised centres had a 7.1 % complication rate while experienced centres had 11.0 % (interventionalist with ≥50 CAS) [35]35. Ederle J, Dobson J, Featherstone RL, et al.; Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial; Lancet 2010; 375:985–997 [PubMed]. Such observations might be biased by the association of patient risk factors with experience level, with the less experienced physicians treating fewer high risk patients [36]36. Kadkhodayan Y, Cross DT 3rd, Derdeyn CP, Moran CJ; Carotid angioplasty and stenting in the elderly; Neuroradiology 2007; 49:933–938 [PubMed]. Assessing the individual performance of a surgeon is notoriously difficult as it requires at least 200 procedures so that 95 % CIs are sufficiently tight [37]37. Rothwell PM, Warlow CP, European Carotid Surgery Trialists' Collaborative Group; Interpretation of operative risks of individual surgeons; Lancet 1999; 353:1325 [PubMed]. The determination of the individual ability will be hampered by a learning curve that occurs while acquiring this number.

Centre experience

Several medical specialities are involved in MT of acute stroke and need to work in coordination and under time pressure (e.g. neuroradiologists, anaesthesiologists, neurologists, intensive care specialists). A recent editorial underlined the necessity of a systems approach to the MT of acute ischemic stroke, with focus on the overall sequence and workflow of a neurointerventional procedure rather than individual steps [38]38. Menon BK, Goyal M; A systems approach towards intra-arterial management of acute ischemic stroke: need for novel outcome measures and a focus on sequence rather than steps; Interv Neuroradiol 2011; 17:296–298 [PubMed]. This emphasises that a highly experienced interventional neuroradiologist is an important - but not the only factor - that influences patient outcome. Despite highly standardised study protocols, variability will persist between centres in specific treatment aspects that may escape parameterisation (e.g. peculiarities of intensive care or anaesthesia).

In the SPACE study, the heterogeneity of CAS complication rates among centres became obvious in a secondary analysis where a within-study learning in the CAS arm but not for CEA arm was observed when a long established therapy was applied [39]39. Fiehler J, Jansen O, Berger J, Eckstein HH, Ringleb PA, Stingele R; Differences in complication rates among the centres in the SPACE study; Neuroradiology 2008; 50:1049–1053 [PubMed]. In centres with higher enrolment numbers, there was even a trend towards lower complication rates in CAS vs. CEA. The relation of complications vs. centre recruitment rate of ICSS was easier to interpret: 8.7 % in low-recruiting centres vs. 6.9 % in high-recruiting centres [35]35. Ederle J, Dobson J, Featherstone RL, et al.; Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial; Lancet 2010; 375:985–997 [PubMed]. In a recent analysis of endovascular therapy of unruptured aneurysms, a highly significant association was noted between hospital volume and outcome [40]40. Brinjikji W, Rabinstein AA, Lanzino G, Kallmes DF, Cloft HJ; Patient outcomes are better for unruptured cerebral aneurysms treated at centers that preferentially treat with endovascular coiling: a study of the national inpatient sample 2001-2007; Ajnr Am J Neuroradiol 2011; 32:1065–1070. A reasonable threshold seems to be somewhere between 20 and 40 UIA coiled per year. Ruptured aneurysms need to be added to the calculation of experience, which also should certainly not be below 20, with perhaps 40 to 50 total aneurysms per year as a minimum experience level.

Based on the current suggestion to the UEMS for training institutions, the INR centre caseload of endovascular interventions should be at least 150–200 cases/year. We propose not going below this minimum requirement for centres wishing to participate in the MT vs. IVT studies.

Training background

At present, there is no evidence that it is necessary or even feasible to train non-neurointerventional physicians in stroke MT [41]41. Heck DV; Do no harm: the rush to abbreviated training of stroke interventionalists is premature and ill advised; J Neurointerv Surg 2012; 4:3–6 [PubMed]. The primary reason behind this observation is that physicians with interventional experience in other vascular territories do not become competent in this demanding field as quickly. More importantly, there is no obligation to provide the unproven treatment without experienced stroke neurointerventionalist input and the time sensitivity of the condition does not favour decentralisation.

For the CREST study, a comprehensive training and credentialing process was required prior to assembling a competent team of interventionalists with low periprocedural event rates. Interventionalists submitted cases to a multidisciplinary Interventional Management Committee [42]42. Hopkins LN, Roubin GS, Chakhtoura EY, et al.; The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of lead-in phase; J Stroke Cerebrovasc Dis 2010; 19:153–162 [PubMed]. During the subsequent lead-in phase there were differences among training background with an OR (95 % CI) of outcome events of 0.40 (0.14–1.18) for Neuroradiology and 2.09 (1.21–3.61) for Vascular Surgery (other specialities were in between) [42]42. Hopkins LN, Roubin GS, Chakhtoura EY, et al.; The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of lead-in phase; J Stroke Cerebrovasc Dis 2010; 19:153–162 [PubMed]. The authors stated that duration and intensity of training in catheter-based diagnosis and treatment were substantial for Interventional Cardiology and INR specialists. Because no formal qualification for INR exists, a number of interventions need to be employed in order to define the abilities of a given interventionalist. This has been done in previous CAS vs. CEA studies [28]28. Fiehler J, Bakke SJ, Clifton A, et al.; Plea of the defence-critical comments on the interpretation of EVA3S, SPACE and ICSS; Neuroradiology 2010; 52:601–610 [PubMed] as well as in SAMMPRIS [43]43. Chimowitz MI, Lynn MJ, Derdeyn CP, et al.; Stenting versus aggressive medical therapy for intracranial arterial stenosis; N Engl J Med 2011; 365:993–1003 [PubMed]. For SAMMPRIS, each operator’s last 20 intracranial stenting procedures were reviewed by a board of INR specialists. These 20 cases included a minimum of 3 patients treated with the particular study device (Wingspan) in whom the interventionalist personally inserted a stent, performed intracranial angioplasty for intracranial stenosis or used a Neuroform stent for an intracranial aneurysm.

Proposal

For pragmatic reasons, there needs to be an [arbitrary] cut-off for the qualification of the individual operator since objective measures do not and will not exist. The qualification criteria need to be balanced between the optimal qualification standards (as these might determine the study outcome) and a high number of putative study centres able to enrol patients. In general, we consider these trials to be rather exploratory, reflecting the reality of management as MT cannot be considered a standard therapy at present. Therefore, we suggest the criteria as detailed in Table 2. The operator requirements for MT in acute stroke of the AAN, AANS, SNIS, SVIN and particularly the SIR have been designed for clinical application of the procedure and are easier to fulfil [41]41. Heck DV; Do no harm: the rush to abbreviated training of stroke interventionalists is premature and ill advised; J Neurointerv Surg 2012; 4:3–6 [PubMed]. In essence, the requirements have been chosen to facilitate a greater number of physicians to perform MT in a clinical environment.

Table 2 Minimal requirements for study participation

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Periprocedural aspects

Periprocedural anaesthesia

The role of anaesthesia during endovascular stroke treatment is still subject to debate and there are no guidelines about whether thrombectomy should be performed under general anaesthesia (GA) or conscious sedation (CS) with local anaesthesia. The possible advantages and disadvantages of one or the other method are obvious. CS is fast to apply but intervention might be more difficult and presumably more dangerous to perform in non-compliant patients [44]44. Abou-Chebl A, Lin R, Hussain MS, et al.; Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study; Stroke 2010; 41:1175–1179 [PubMed].

GA eliminates movement and potentially improves procedural safety and efficacy [45]45. McDonagh DL, Olson DM, Kalia JS, Gupta R, Abou-Chebl A, Zaidat OO; Anesthesia and sedation practices among neurointerventionalists during acute ischemic stroke endovascular therapy; Front Neurol 2010; 1:118 [PubMed]. However, time delay, intubation and risk of hypotension have negative impact on neurological outcome [46]46. Davis MJ, Menon BK, Baghirzada LB, et al.; Anesthetic management and outcome in patients during endovascular therapy for acute stroke; Anesthesiology 2012; 116:396–405 [PubMed]. Various retrospective studies have investigated the influence of GA on neurological outcome and mortality after endovascular stroke treatment. Most studies illustrated a significantly worse neurological outcome and higher mortality rates for patients under GA [44, 46-48]44. Abou-Chebl A, Lin R, Hussain MS, et al.; Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study; Stroke 2010; 41:1175–1179 [PubMed]46. Davis MJ, Menon BK, Baghirzada LB, et al.; Anesthetic management and outcome in patients during endovascular therapy for acute stroke; Anesthesiology 2012; 116:396–405 [PubMed]47. Jumaa MA, Zhang F, Ruiz-Ares G, et al.; Comparison of safety and clinical and radiographic outcomes in endovascular acute stroke therapy for proximal middle cerebral artery occlusion with intubation and general anesthesia versus the nonintubated state; Stroke 2010; 41:1180–1184 [PubMed]48. Nichols C, Carrozzella J, Yeatts S, Tomsick T, Broderick J, Khatri P; Is periprocedural sedation during acute stroke therapy associated with poorer functional outcomes? J Neurointerv Surg 2010; 2:67–70 [PubMed]. In patients treated under GA, there was a higher incidence of post-procedural pneumonia [48]48. Nichols C, Carrozzella J, Yeatts S, Tomsick T, Broderick J, Khatri P; Is periprocedural sedation during acute stroke therapy associated with poorer functional outcomes? J Neurointerv Surg 2010; 2:67–70 [PubMed]. With a higher incidence of proximal vessel occlusion (e.g. ICA terminus) and correspondingly higher NIHSS before intervention in the GA-arm, a possible selection bias towards more complicated patients can be postulated in some studies [44]44. Abou-Chebl A, Lin R, Hussain MS, et al.; Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study; Stroke 2010; 41:1175–1179 [PubMed]. This possible bias might explain the surprisingly lower recanalisation rate [48]48. Nichols C, Carrozzella J, Yeatts S, Tomsick T, Broderick J, Khatri P; Is periprocedural sedation during acute stroke therapy associated with poorer functional outcomes? J Neurointerv Surg 2010; 2:67–70 [PubMed] and higher rate of complications [44, 48]44. Abou-Chebl A, Lin R, Hussain MS, et al.; Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study; Stroke 2010; 41:1175–1179 [PubMed]48. Nichols C, Carrozzella J, Yeatts S, Tomsick T, Broderick J, Khatri P; Is periprocedural sedation during acute stroke therapy associated with poorer functional outcomes? J Neurointerv Surg 2010; 2:67–70 [PubMed] found in the GA-arm. However, a separate analysis for patients presenting with isolated M1-MCA occlusion and balanced NIHSS in both subgroups confirmed these findings [44]44. Abou-Chebl A, Lin R, Hussain MS, et al.; Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study; Stroke 2010; 41:1175–1179 [PubMed].

Proposal

Anaesthesia likely contributes significant variability to the periprocedural protocol of patients undergoing MT. Considering the possible selection bias of retrospective data, a prospective RCT on this aspect is needed. To date, general agreement on the optimal protocol is lacking; however, CS can be recommended in all clinical settings for compliant patients. A study design on MT is needed to further address this issue, either by providing a standardised protocol for all patients or by providing subgroup analysis for GA and CS; blood pressure protocols should also be recorded.

Proximal balloon occlusion catheter

All MT techniques are accompanied by the risk of thrombus dislocation. This may either occur into the distal territory of the affected vessel or during proximal thrombus retrieval into previously unaffected vessel territories. It is well established that manual suction through a balloon guide catheter is a useful and feasible technique that facilitates thrombectomy of large burden cerebral clots [49]49. Eesa M, Almekhlafi MA, Mitha AP, Wong JH, Goyal M; Manual aspiration thrombectomy through balloon-tipped guide catheter for rapid clot burden reduction in endovascular therapy for ICA L/T occlusion; Neuroradiology 2012; [PubMed]. The presence of distal emboli during recanalisation of the target vessel is often difficult to prove as this territory has typically not been fully illustrated before recanalisation. The clinical sequelae of distal emboli mainly depends on localisation and size of vessel occlusion. Reasonable precautions and further intervention should be considered to prevent and treat distal emboli (see also rescue therapy). Nevertheless, since recanalisation of the larger proximal target vessel is achieved, improvement of brain perfusion can be assumed in the majority of cases.

Collateral infarction due to thrombus dislocation into previously unaffected vessel territories (e.g. from MCA to ACA territory) represents a major complication during MT [50, 51]50. The Penumbra Pivotal Stroke Trial Investigators; The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease; Stroke 2009; 40:2761-2768 [PubMed]51. Costalat V, Machi P, Lobotesis K, et al.; Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: a prospective 50-patient single-center study: timing, safety, and efficacy; Stroke 2011; 42:1929–1935 [PubMed]. It involves ischemia in a new brain territory with the risk of new neurological deficits. Furthermore, pial collateral flow to the territory affected initially will decrease and presumably reduce salvageable tissue. For most stent-trievers and distal thrombectomy devices, proximal 8F balloon guiding catheter occlusion (BCO) and aspiration during thrombus retrieval is recommended (e.g. Trevo/Concentric, Solitaire/Covidien, ReVive/Cordis). Little data on the efficacy of BCO is available. In-vivo studies have illustrated a significant reduction of collateral infarction using distal devices when BCO is applied [52]52. Gralla J, Schroth G, Remonda L, Nedeltchev K, Slotboom J, Brekenfeld C; Mechanical thrombectomy for acute ischemic stroke: thrombus-device interaction, efficiency, and complications in vivo; Stroke 2006; 37:3019–3024 [PubMed]. The largest core lab controlled study on the clinical use of stent-trievers documented a significantly lower incidence of collateral infarction when BCO was used [53]53. Davalos Aea; ; Stroke 2012; (in press). Other approaches to reduce risk of collateral infarction such as aspiration via an intermediate/distal access catheter might be applied in complicated anatomical settings; however, their efficacy is unknown.

Proposal

There is evidence that BCO reduces collateral infarction using distal devices and stent-trievers. Although clinical data is sparse, the use of BCO is recommended, especially in a RCT setting. However, only patients with an anatomical setting and occlusion pattern favourable for the application of a BCO should be considered for trial inclusion.

Adjunctive thrombolytic and antithrombotic agents

The preprocedural and intraprocedural role of fibrinolytic, anticoagulation and antiplatelet agents in endovascular stroke treatment is unclear [54]54. Lazzaro MA, Zaidat OO; Multimodal endovascular reperfusion therapies: adjunctive antithrombotic agents in acute stroke; Neurology 2012; 78:501–506 [PubMed].

IVT and bridging therapy

Theoretically, preprocedural application of IVT might reduce thrombus burden, soften the thrombus or disintegrate distal emboli. Yet, the additional use of thrombolytic agents carries the potential increased risk of symptomatic intracranial haemorrhage (sICH). The influence of preprocedural IVT on neurological outcome and rate of sICH of patients undergoing MT has not yet been addressed in a randomised study. However, the Multi-MERCI trial which allowed prior treatment with IV rtPA and MT found a higher recanalisation rate (69.5 %) in conjunction with other treatment modalities compared to the use of the retriever alone (57.3 %) [55]55. Smith WS, Sung G, Saver J, et al; Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial; Stroke 2008; 39:1205–1212 [PubMed]. The subgroup receiving IVT prior to MT did not show differences in rates of intracranial haemorrhage or clinically significant procedural complications [55]55. Smith WS, Sung G, Saver J, et al; Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial; Stroke 2008; 39:1205–1212 [PubMed]. More recent retrospective data on the use of the Solitaire stent on 141 patients suggests a positive impact of IVT on clinical outcome after MT. One subgroup received IVT prior to MT, either following bridging IVT (BIVT) or after failed IVT. The second subgroup did not receive any IVT either because of contraindications or due to direct MT. No significant difference in age, initial NIHSS and time to groin puncture was found. However, a higher recanalisation rate and significantly better neurological outcome (mRS 0-2, 66.2 % vs. 41.8 %) in the IVT group was found without increase in sICH rate [53]53. Davalos Aea; ; Stroke 2012; (in press).

Heparin

Heparin has been used inconsistently during studies of endovascular stroke treatment [54]54. Lazzaro MA, Zaidat OO; Multimodal endovascular reperfusion therapies: adjunctive antithrombotic agents in acute stroke; Neurology 2012; 78:501–506 [PubMed]. In the IMS [56]56. The IMS II Trial Investigators; The Interventional Management of Stroke (IMS) II Study; Stroke 2007; 38:2127-2135 [PubMed] and PROACT [57]57. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M; PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism; Stroke 1998; 29:4–11 [PubMed] trials, 2,000 units of IV heparin were administered at the beginning of the procedure followed by 450 units per hour during the procedure. Additional administration of heparin to IA rpro-UK has been shown to enhance recanalisation in conjunction with a nonsignificant trend towards a higher rate of sICH [57]57. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M; PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism; Stroke 1998; 29:4–11 [PubMed]. A subgroup analysis of the multi MERCI trial showed no increase in the rate of sICH or mortality among the group who received periprocedural heparin (median dose of 3,000 units) during multimodal revascularisation therapy compared to those who did not [58]58. Nahab F, Walker GA, Dion JE, Smith WS; Safety of Periprocedural Heparin in Acute Ischemic Stroke Endovascular Therapy: The Multi MERCI Trial; J Stroke Cerebrovasc Dis 2011..

Antiplatelet agents

Periprocedural antiplatelet therapy is often applied after deployment of implants to reduce the risk of acute and delayed stent thrombosis. There is no consensus on safety, dosage or drug combination [54]54. Lazzaro MA, Zaidat OO; Multimodal endovascular reperfusion therapies: adjunctive antithrombotic agents in acute stroke; Neurology 2012; 78:501–506 [PubMed].

Aspirin and thienopyridinem

The most commonly used agents are aspirin and thienopyridinem (e.g. Clopidogrel) derivatives. Oral antiplatelet therapy is routinely withheld following IVT or MCT for 12-24 h for potential risk of increasing the incidence of sICH. Both are typically used for secondary stroke prevention.

Abciximab

Initial studies indicated administration of abciximab was safe in stroke treatment up to 24 h from symptom onset [59, 60]59. The Abciximab in Ischemic Stroke Investigators; Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose-escalation study; Stroke 2000; 31:601-60960. Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators; Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial; Stroke 2005; 36:880-890 [PubMed]. The AbESTT-II trial, however, was terminated prematurely due to an increased risk of sICH [61]61. Adams HP Jr, Effron MB, Torner J, et al.; Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II); Stroke 2008; 39:87–99 [PubMed]. Few case series have reported on its use in variable interventions [62–64] with no definite conclusion on the use of abciximab during MT. The role of Abciximab in endovascular stroke treatment remains unclear.

Other GP IIb/IIIa inhibitors

Due to their shorter half-life, GP IIb/IIIa inhibitors such as tirofiban and epitifibatide are frequently used during or after endovascular stroke treatment [54, 65, 66]54. Lazzaro MA, Zaidat OO; Multimodal endovascular reperfusion therapies: adjunctive antithrombotic agents in acute stroke; Neurology 2012; 78:501–506 [PubMed]65. Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D; Intravenous glycoprotein IIb/IIIa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke; AJNR Am J Neuroradiol 2005; 26:2595–2601 [PubMed]66. Kwon JH, Shin SH, Weon YC, Hwang JC, Baik SK; Intra-arterial adjuvant tirofiban after unsuccessful intra-arterial thrombolysis of acute ischemic stroke: preliminary experience in 16 patients; Neuroradiology 2011; 53:779–785 [PubMed]. The SaTIS trial, a randomised, placebo-controlled trial, demonstrated the safety of Tirofiban and demonstrated no significant increase in bleeding risk (Stroke Trials Registry. Available at: http://www.strokecenter.org/trials/TrialDetail.aspx?tid593). A review of various endovascular reperfusion therapies in combination with GP IIb/IIIa inhibitors and MT suggested that the inhibitors are an independent predictor of recanalisation [67]67. Gupta R, Vora NA, Horowitz MB, et al.; Multimodal reperfusion therapy for acute ischemic stroke: factors predicting vessel recanalization; Stroke 2006; 37:986–990 [PubMed].

Proposal

RCT trials of MT should record the use of thrombolytic and antithrombotic agents, and subgroup analyses should be used to explore associations with sICH. The adjuvant use of IVT prior to MT is likely to be a significant variable. The sparse data available suggests a possible impact of tPA prior to MT on clinical outcome without increasing the rate of sICH. However, a prospective RCT on this aspect is needed. With regard to time span most centres need to begin the procedure, BIVT or even IVT can be applied without delaying MT. For the time being, preprocedural BIVT might be advocated for eligible patients in trials on MT. The standard procedural protocol might include heparin dosage up to 5,000 units throughout the intervention. Current data does not support the routine intraprocedural administration of antiplatelet agents unless a stent is implanted. In cases of in-stent thrombosis, rescue therapy using parental GP IIb/IIIa inhibitors appears to be beneficial.

Number of passes

In the study by Costalat et al. only one pass was sufficient to obtain a TICI2b/TICI3 recanalisation in 22 patients (44 %) [51]51. Costalat V, Machi P, Lobotesis K, et al.; Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: a prospective 50-patient single-center study: timing, safety, and efficacy; Stroke 2011; 42:1929–1935 [PubMed]. These results are supported by other recent Solitaire FR device studies. Castaño et al. also demonstrated a recanalisation rate of 90 % (TICI 2B/TICI3) in 18 of the 20 patients using the Solitaire device in MCA occlusions. The mean number of passes were 2.9, 2 and 1.4 as reported by Shi [68]68. Shi ZS, Loh Y, Walker G, Duckwiler GR; Endovascular thrombectomy for acute ischemic stroke in failed intravenous tissue plasminogen activator versus non-intravenous tissue plasminogen activator patients: revascularization and outcomes stratified by the site of arterial occlusions; Stroke 2010; 41:1185–1192 [PubMed], Castaño et al. [69]69. Castano C, Dorado L, Guerrero C, et al.; Mechanical thrombectomy with the Solitaire AB device in large artery occlusions of the anterior circulation: a pilot study; Stroke 2010; 41:1836–1840 [PubMed] and Machi et al. [70]70. Machi P, Costalat V, Lobotesis K, et al.; Solitaire FR thrombectomy system: immediate results in 56 consecutive acute ischemic stroke patients; J Neurointerv Surg 2012; 4:62–66 [PubMed] respectively. Optimal number of passes results from a trade-off between increasing efficiency and safety concerns. Loh reported a series of patients treated using MERCI in which up to 3 retrieval attempts correlated with good revascularisation, and when ≥4 attempts were performed, the end result was more often failed revascularisation and procedural complications [71]71. Loh Y, Kim D, Shi ZS, et al.; Higher rates of mortality but not morbidity follow intracranial mechanical thrombectomy in the elderly; AJNR Am J Neuroradiol 2010; 31:1181–1185. More passes carry the risk of damaging the endothelium. Yin et al. [72]72. Yin NS, Benavides S, Starkman S, et al.; Autopsy findings after intracranial thrombectomy for acute ischemic stroke: a clinicopathologic study of 5 patients; Stroke 2010; 41:938–947 [PubMed] reported endothelium alterations after MERCI thrombectomy. This data should be considered with caution since the purpose of preserving the endothelium of an occluded vessel is dubious. What’s more, one has to take into consideration company recommendations about the number of passes with a given device, although the use of another device during the same procedure goes beyond this limitation. Iterative passes may also prolong the procedure duration beyond a safe time window.

Proposal

A suggested cut off time for thrombectomy is 8 h (as in SWIFT, THERAPY, PISTE and IMS III) or a 1 h delay to achieve the procedure (SYNTHESIS EXP), and a maximum number of passes (5 being an accepted number) beyond which the benefit of additional passes is unlikely.

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Conclusion

Neurointerventional care is growing, with an increasing number of procedures and increasing number of centres where procedures are performed [73]73. Jansen O; Neurovascular centers–a need for a change; Clin Neuroradiol 2011; 21:51. These developments present new possibilities for performing clinical trials that could allow Interventional Neuroradiology to progress from a discipline predominantly resting on experience-based decision making into a medical specialty underpinned by clinical trial evidence [74]74. Fiehler J, Stapf C.; ARUBA–beating natural history in unruptured brain AVMs by intervention; Neuroradiology 2008; 50:465–467 [PubMed]. At present, the field of MT in patients with acute ischemic stroke is the most dynamic development in Interventional Neuroradiology and provides the greatest chance for successful trials. We sincerely hope that this first roadmap might help in designing and conducting successful trials in close collaboration with our neighbouring disciplines.

Conflict of interest

JF consults for Stryker and Codman, and gives presentations to Covidien, Boehringer Ingelheim, Philips and Siemens MS has a Consultant agreement with Mindframe (now owned by Covidien) and is PI for the Rapid Medical study. FT consults for Stryker and Codman, is on the Codman Board, and has a proctoring agreement and holds workshops for Covidien. RVK receives personal compensation for serving on the Advisory Board of Lundbeck AC, serves as Co-Chair on the Steering Committee of the DIAS-3 and -4 trials, serves on the image adjudication committee for these trials and consults for Synarc; he is Section Editor, Interventional Neuroradiology, of the journal Neuroradiology. MM is a consultant for Synthes, AB Medica/Italy, gives presentations for Johnson & Johnson and has research support from ActiveO. CC consults for Covidien, Stryker, Codman and Microvention. JG is PI of the STAR Study (Covidien).

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