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EJMINT Original Article, 2012: 1236000070 (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 I: Current situation and major research questions
Jens Fiehler, Michael Söderman, Francis Turjman, et al
EJMINT Original Article, 2012: 1236000070 (4th September 2012)

Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR - Part I: Current situation and major research questions

EJMINT Original Article, 2012: 1236000070 (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

A new era of stroke treatment may have begun with mechanical thrombectomy (MT) by fully deployed closed-cell self-expanding stents (stent-triever). Multiple case series and the first randomised controlled trials (RCTs) have now been published. More studies are under way involving large numbers of patients, which in turn has resulted in less strict “pragmatic” study protocols. Problems with current trials include a lack of standardisation in the conduct of the recanalisation procedure, the definition of primary endpoints such as the grade of arterial recanalisation and tissue reperfusion, and the post-surgical care provided. In Part 1 of this two part series, we outline the current situation and the major research questions.

Randomised 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

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

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Current status and outline of the problem

MT therapy for acute ischemic stroke started with Hermann Zeumer’s IA thrombolysis in 1981 [1]1. Zeumer H, Hacke W, Kolmann HL, Poeck K; Local fibrinolysis in basilar artery thrombosis (author’s transl); Dtsch Med Wochenschr 1982;107:728–731 [PubMed], and has been performed for many years with several devices without a widespread use of any of specific method. In recent years, the MERCI device has been used; based on Phase-I -data [2]2. Gobin YP, Starkman S, Duckwiler GR, et al; MERCI 1: a phase 1 study of mechanical embolus removal in cerebral ischemia; Stroke 2004; 35:2848–2854 [PubMed] and data from the MERCI trial [3]3. Smith WS, Sung G, Starkman S, et al.; Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial; Stroke 2005; 36:1432–1438 [PubMed], the device received FDA-approval to “remove blood clots from the brain in patients experiencing an ischemic stroke” [4]4. Becker KJ, Brott TG; Approval of the MERCI clot retriever: a critical view; Stroke 2005; 36:400–403 [PubMed]. Data on the MERCI device have been pooled [5]5. Flint AC, Duckwiler GR, Budzik RF, Liebeskind DS, Smith WS; Mechanical thrombectomy of intracranial internal carotid occlusion: pooled results of the MERCI and Multi MERCI Part I trials; Stroke 2007; 38:1274–1280 [PubMed] and analysed together with the Multi MERCI trial [6]6. 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], particularly to characterise possible target populations for mechanical recanalisation [7, 8]7. Nogueira RG, Smith WS; Safety and efficacy of endovascular thrombectomy in patients with abnormal hemostasis: pooled analysis of the MERCI and multi MERCI trials; Stroke 2009; 40:516–522 [PubMed]8. Flint AC, Cullen SP, Faigeles BS, Rao VA; Predicting long-term outcome after endovascular stroke treatment: the totaled health risks in vascular events score; AJNR Am J Neuroradiol 2010; 31:1192–1196 [PubMed], the relation of recanalisation and outcome [9]9. Fields JD, Lutsep HL, Smith WS; Higher degrees of recanalization after mechanical thrombectomy for acute stroke are associated with improved outcome and decreased mortality: pooled analysis of the MERCI and Multi MERCI trials; AJNR Am J Neuroradiol 2011; 32:2170–2174 [PubMed] and the relation of recanalisation to the vessel occlusion site [10]10. Shi ZS, Loh Y, Walker G, Duckwiler GR; Clinical outcomes in middle cerebral artery trunk occlusions versus secondary division occlusions after mechanical thrombectomy: pooled analysis of the mechanical embolus removal in cerebral ischemia (MERCI) and Multi MERCI trials; Stroke 2010; 41:953–960 [PubMed]. The Penumbra thrombo-aspiration device has been studied within a registry that showed a remarkable discrepancy between recanalisation rate and clinical outcome [11]11. 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], primarily attributed to patient selection [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].

Introduction of retrievable stents

A new era began with the first reports of permanent placement of open-cell self-expanding stents to recanalise embolic intracranial artery occlusions by compression of the occluding thrombus [13-16]13. Sauvageau E, Levy EI; Self-expanding stent-assisted middle cerebral artery recanalization: technical note; Neuroradiology 2006; 48:405–408 [PubMed]14. Levy EI, Mehta R, Gupta R, et al.; Self-expanding stents for recanalization of acute cerebrovascular occlusions; AJNR Am J Neuroradiol 2007; 28:816–822 [PubMed]15. Brekenfeld C, Schroth G, Mattle HP, et al.; Stent placement in acute cerebral artery occlusion: use of a self-expandable intracranial stent for acute stroke treatment; Stroke 2009; 40:847–852 [PubMed]16. Kim SM, Lee DH, Kwon SU, Choi CG, Kim SJ, Suh DC; Treatment of acute ischemic stroke: feasibility of primary or secondary use of a self-expanding stent (Neuroform) during local intra-arterial thrombolysis; Neuroradiology 2012; 54:35–41 [PubMed]. This technique claimed to provide fast and efficient recanalisation. At about the same time, retrieval of an incompletely deployed closed-cell self-expanding stent [17]17. Kelly ME, Furlan AJ, Fiorella D; Recanalization of an acute middle cerebral artery occlusion using a self-expanding, reconstrainable, intracranial microstent as a temporary endovascular bypass; Stroke 2008; 39:1770–1773 [PubMed] used as a temporary intravascular bypass that was then also used as an thrombectomy device was reported [18]18. Suh SH, Lee KY, Hong CK, et al.; Temporary stenting and retrieval of the self-expandable, intracranial stent in acute middle cerebral artery occlusion; Neuroradiology 2009; 51:541–544 [PubMed]. In addition, the first thrombectomy by a fully deployed closed-cell self-expanding stent had already been performed successfully [19]19. Pérez MA, Miloslavski E, Fischer S, Bäzner H, Henkes H; Intracranial thrombectomy using the Solitaire stent: a historical vignette; J Neurointerv Surg. 2011; doi:10.1136/neurintsurg-2011-010149. Multiple retrospective case series (mainly small) reporting the results of these so called “stent-trievers” have been published [20–38], most from European centres. In general, recanalisation rates are high and overall clinical outcomes are comparable or superior to those reported in the IV fibrinolysis trials, despite the fact that in general the patients had more severe symptoms (higher NIHSS) and were treated at later time-points. However, the clinical outcome data were usually not externally assessed and monitored.

Recent prospective registries and RCTs

Several prospective registries and RCTs are under way. A number of them are designed to gain FDA-approval for a particular device. Others address the question of clinical outcome of MT vs. IV fibrinolysis (Tables 1 and 2). For some physicians, available clinical data are so convincing that participation in a RCT is ethically impossible. This has changed slightly with the Interventional Management of Stroke III Trial (IMS III). Following enrolment of 587 of the planned 900 patients at over 50 sites worldwide, IMS III enrolment was suspended in April 2012 because of equipoise. IMS III is a RCT aiming to examine whether an IV and IA approach is superior to standard IV tPA alone (<3 h after stroke onset). Three thrombectomy devices were approved during the study period: MERCI (cleared in 2004), Penumbra (cleared 2007) and Solitaire (cleared March 2012). Stopping enrolment at the time of the approval of the first stent-triever is a very sensible decision in order to avoid discrediting stent-trievers as a concept. However, it is now up to the MT-users to demonstrate the efficacy of stent-triever in a RCT.

Table 1 Selection of current publicly-funded RCTs of MT in acute stroke patients

Table 2 Selection of current company-driven RCTs of MT in acute stroke patients (information either from http://clinicaltrials.gov/ or from company officials)

The challenges

  • Stroke heterogeneity: Acute ischemic stroke is a syndrome with heterogeneous aetiologies, arterial and tissue pathologies. The heterogeneity mainly originates from type, size and location of the arterial obstruction, and the collateral blood circulation of the brain and volume of tissue that is already infarcted. To address this heterogeneity, a large number of patients have to be randomised, which in turn results in a less strict “pragmatic” study protocol allowing the use of several mechanical devices; this has been shown in several studies, namely IMS III, THRACE, PISTE and MR CLEAN.
  • Methodological heterogeneity: Apart from the different devices, there is no standardisation in the conduct of the recanalisation procedure, the definition of primary endpoints such as the grade of arterial recanalisation and tissue reperfusion, post-surgical care and so forth. Not even the single-device THERAPY trial (Table 2) will answer all questions regarding the efficacy of mechanical recanalisation since studies generally enrol patients who are eligible for IV tPA within an early time window, i.e. best medical therapy (BMT) and thrombectomy versus best medical treatment. Additionally, it is likely that as MT becomes more established it will become difficult to recruit patients into RCTs.

Proposal

We suggest a European “family” of interventional stroke trials with the least possible overlap. In this article we outline the key research questions and trial design issues for MT which are generally supported by the authors and the respective Societies. To allow for a consensus paper that covers a broad spectrum of the current problems, we acknowledge that a few statements do not have explicit support of all authors.

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What are the major research questions?

Is IVT/MT more effective than IVT?

Study objectives

To establish whether IVT and MT is superior to IVT only in the subgroup of patients with large vessel occlusions in the anterior circulation.

Ethical appraisal

Given the good results of previous studies and upcoming registries, such a study had been already deemed unethical by some. However, clinical equipoise may be present as MT has its own inherent risks [39]39. Tomsick TA, Khatri P, Jovin T, et al.; Equipoise among recanalization strategies; Neurology 2010; 74:1069–1076 [PubMed]. Moreover, registry data in which outcome is self-reported is not necessarily reliable. This phenomenon has been shown elegantly for carotid surgery and carotid stenting [40, 41]40. Rothwell P, Warlow C; Is self-audit reliable? Lancet 1995; 346:1623 [PubMed]41. Fiehler J; On limitations of studies and limitations of therapy options for carotid stenosis: why play golf with only a sand wedge? Neuroradiology 2010; 52:597–599 [PubMed]. Intracranial intervention has also seen similar reports with the SAMMPRIS RCT identifying higher than expected (from registry studies) complication rates in endovascular arm and lower than expected event rate in medical arm; the trial was stopped early at request of the NINDS [42]42. 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].

Ethically, it is most appropriate to test the group of patients who are eligible to receive IVT under the European Stroke Organisation (ESO) Guidelines. The trial would be conducted with a randomisation of an IV group (control) versus an IV treatment plus additional MT (experimental). A trial comparing IVT and MT (without IVT first) would deprive patients in the experimental arm of standard treatment. Such a trial could be undertaken subsequently if the IV + MT vs. IV showed benefit for MT. There is rationale for examining anterior and posterior circulation strokes separately.

Clinical patient selection

Three key variables determine whether and where in the outcome spectrum clustering will occur in stroke patients: onset to treatment time, symptoms at time of treatment and type of treatment [43]43. 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]. The time window for this study is determined by the IVT studies that showed a clinical benefit (<4.5 h) [44-46]44. Hacke W, Kaste M, Bluhmki E, et al.; Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke; N Engl J Med 2008; 359:1317–1329 [PubMed]45. Wahlgren N, Ahmed N, Davalos A, et al.; Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study; Lancet 2008; 372:1303–130946. Lees KR, Bluhmki E, von Kummer R, et al.; Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials; Lancet 2010; 375:1695–1703 [PubMed]. When IST3 data are added to other trials, benefit of IVT given at 3–6 h was not demonstrated [47]47. Wardlaw JM, Murray V, Berge E, et al.; Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis; Lancet 2012; 379(9834):2364–2372 [PubMed].

Outcomes after IVT are significantly better than in untreated comparators across baseline NIHSS 5 to 24 [48]48. Mishra NK, Lyden P, Grotta JC, Lees KR; Thrombolysis is associated with consistent functional improvement across baseline stroke severity: a comparison of outcomes in patients from the virtual international stroke trials archive (VISTA); Stroke 2010; 41:2612–2617 [PubMed]. However, the efficacy of IVT is heterogeneous with lesser or even no benefit in the most severely affected patients [49]49. Saver JL, Yafeh B; Confirmation of tPA treatment effect by baseline severity-adjusted end point reanalysis of the NINDS-tPA stroke trials; Stroke 2007; 38:414–416 [PubMed] and in patients with proximal artery occlusions [50]50. Bhatia R, Hill MD, Shobha N, et al.; Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action; Stroke 2010; 41:2254–2258 [PubMed]. The classical CT-based IVT studies together with EPITHET enrolled patients with a mean NIHSS score of 11 (interquartile range: 7–16) [46]46. Lees KR, Bluhmki E, von Kummer R, et al.; Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials; Lancet 2010; 375:1695–1703 [PubMed]. In an ad-hoc secondary analysis of published data [51]51. Thomalla G, Schwark C, Sobesky J, et al.; Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients: comparison of a German multicenter study with the pooled data of ATLANTIS, ECASS, and NINDS tPA trials; Stroke 2006; 37:852–858 [PubMed] for this manuscript, we found that in IVT patients the outcome of worse than mRS 0–2 (day 90) was predicted with a sensitivity of 89 % and a specificity of 48 % with NIHSS score of >10. Moreover, this threshold has been found to be a good predictor for a proximal vessel occlusion [52]52. Fischer U, Arnold M, Nedeltchev K, et al.; NIHSS score and arteriographic findings in acute ischemic stroke; Stroke 2005; 36:2121–2125 [PubMed]. Imaging could compensate for the lower specificity (see below). An upper NIHSS threshold is not required but will be introduced by patient selection criteria (Table 3).

Table 3 Key patient selection criteria for suggested studies

Based on the MERCI data, futile MT was often observed in elderly patients [8, 53]8. Flint AC, Cullen SP, Faigeles BS, Rao VA; Predicting long-term outcome after endovascular stroke treatment: the totaled health risks in vascular events score; AJNR Am J Neuroradiol 2010; 31:1192–1196 [PubMed]53. Hussein HM, Georgiadis AL, Vazquez G, et al.; Occurrence and predictors of futile recanalization following endovascular treatment among patients with acute ischemic stroke: a multicenter study; Ajnr Am J Neuroradiol 2010; 31:454–458 [PubMed]. Among patients undergoing MT for acute cerebrovascular occlusions with the MERCI device, increased age conveys a higher rate of stroke-related death, but disability at discharge in this group is similar to that of younger survivors [54]54. 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. Nevertheless, we suggest limiting the age of the included patients from 18 to 80 as in the large IVT studies though there seems to be no clear age cut-off for benefit [48, 55]48. Mishra NK, Lyden P, Grotta JC, Lees KR; Thrombolysis is associated with consistent functional improvement across baseline stroke severity: a comparison of outcomes in patients from the virtual international stroke trials archive (VISTA); Stroke 2010; 41:2612–2617 [PubMed]55. Berrouschot J, Rother J, Glahn J, Kucinski T, Fiehler J, Thomalla G; Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (> or =80 years) stroke patients; Stroke 2005; 36:2421–2425 [PubMed]. Although the IST-3 trial has confirmed the benefit of IVT beyond 80 years, the benefit in the older group seems particularly confined to IVT within 3 h and as yet there is no licence change to the use of rtPA [56]56. Sandercock P, Wardlaw JM, Lindley RI, et al.; The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial; Lancet 2012; 379:2352–2363.

Estimation of sample size

All estimations of sample sizes are profoundly dependent on specific design features of the RCT. Thus, non-randomised data indicate approximately 20 % absolute benefit for MT added to IVT but are based on self assessed data in most cases. Ongoing superiority trials for MT in Europe are THRACE, PISTE and MRCLEAN (Table 1). The design and powering of these trials indicate they are likely to be positive (at 1 % significance level) if the real absolute benefit of MT added to IVT is nearer 15 %. In fact, on the basis of a pre-planned meta-analysis of PISTE/MR CLEAN, an absolute benefit of as little as 8 % could be statistically confirmed (at 5 % significance level and 80 % power).

Pre-specified subgroup analyses

there are a number of important subgroup analyses to be included. These should be pre-specified. We suggest:

  • Time of start of thrombectomy: <3 h versus 3–4.5 h versus >4.5 h
  • Age (<60 versus 60–80)
  • NIHSS at presentation (e.g. <12 versus 12–20 versus >20)
  • Time to recanalisation (<45 min versus greater) from stroke onset, admission, groin puncture
  • Centre volume (e.g. >12 p.a. versus 12 or fewer p.a.) differences in final infarct volume

Is MT more effective than current best medical treatment in patients ineligible for IVT?

Study objectives

To establish whether MT is superior to BMT in patients ineligible for IVT.

Ethical appraisal

Altogether, this is ethically much more difficult as patients in the control arm would be managed with best BMT (as many are currently) whereas patients in the MT arm would receive state of the art intra-arterial intervention. This type of study is explicitly not supported by all co-authors of this manuscript.

A multicentre RCT designed to compare intra-arterial fibrinolysis therapy vs. control in the posterior circulation was stopped after enrolment of only 16 patients in more than 7 years. The authors stated: “[…] one reason for poor recruitment to the trial may have been a growing belief in the efficacy of intra-arterial thrombolysis […] resulting in patients receiving open-label treatment” [57]57. Macleod MR, Davis SM, Mitchell PJ, et al.; Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke; Cerebrovasc Dis 2005; 20:12–17 [PubMed]. Given the poor prognosis in the natural course and the different pathophysiology in the posterior circulation (more local stenoses), we believe that a trial without fibrinolysis therapy in one of the study arms might be unethical in this particular patient group.

On the other hand, as discussed above, MT might not improve or might even worsen the outcome [39]39. Tomsick TA, Khatri P, Jovin T, et al.; Equipoise among recanalization strategies; Neurology 2010; 74:1069–1076 [PubMed]. Some information will be obtained from current trials (e.g. SYNTHESIS EXP and IMS III) but may be limited by highly heterogeneous patient groups; for example, in the case of IMS III, many interventions use devices that are not be regarded as “state of the art” in Europe. Therefore, a formal RCT of MT vs. standard medical therapy in patients ineligible for IVT would be extremely valuable.

Other patient groups ineligible for IVT such as patients with recent surgery and patients with abnormal haemostasis probably have a very different safety profile and thus need to be investigated in separate analysis that will not be further discussed within this manuscript. Finally, a RCT comparing MT versus BMT in patients with failed IVT is conceivable. The alternative to RCTs is a large European Registry to collect large volumes of non-randomised data instead very quickly, possibly developed on the back of existing IV Thrombolysis Registries.

Clinical patient selection

An RCT targeting patients ineligible for IVT should be considered primarily in those presenting later than 3 h. We suggest considering >3 h rather than >4.5 h. Although IVT data shows benefit concentrated <3 h, the benefit for IVT 3–4.5 h is much weaker and even more so with higher NIHSS. Pragmatically, it would likely prove extremely hard to recruit into MT vs. standard medical therapy <3 h as it is more clinically desirable to perform active treatment in such cases. Pre-specified time window subgroups could be assessed easily e.g. 3–4.5 h, 4.5–6 h, 6–8 h. The maximum symptom duration is more controversial as there might be some patients revealing a penumbra for as long as 48 h [58]58. Heiss WD, Huber M, Fink GR, et al.; Progressive derangement of periinfarct viable tissue in ischemic stroke; J Cereb Blood Flow Metab 1992; 12:193–203 [PubMed] who may still benefit from MT. It has been shown that late endovascular revascularisation of carefully selected patients is safe and potentially improves the clinical outcome [59]59. Natarajan SK, Snyder KV, Siddiqui AH, Ionita CC, Hopkins LN, Levy EI; Safety and effectiveness of endovascular therapy after 8 hours of acute ischemic stroke onset and wake-up strokes; Stroke 2009; 40:3269–3274 [PubMed]. However, the time limit of <8 h did not show unequivocally good outcomes despite comparably good recanalisation rates [11]11. 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]. Unsurprisingly, it has been found secondarily for the Penumbra pivotal stroke trial that fast recanalisation may benefit patients with a favourable image on the baseline CT scan (ASPECTS score >7) [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]. This underlines the particular importance of imaging selection criteria for this type of study. For feasibility reasons we suggest the time window of <8 h. There would be no difference in key variables in comparison the IA + IV vs. IV study (as described above).

Estimation of sample size

Because the natural history of a major occlusive stroke where IVT cannot be given is so poor (20–25 % or less have positive outcome at 90 days), relatively small trial(s) of MT – dependent on the design with fewer than 300 subjects - could show significant differences.

Superiority of a device over another and role of current or novel drugs

Recently, two RCTs have been completed in the US that compared one particular stent-triever with the MERCI (TREVO2-study/Trevo/Concentric [60]60. Nogueira RG, Lutsep H, Gupta R, et al.; Results from the TREVO 2 study (thrombectomy revascularization of large vessel occlusions in acute ischemic stroke): randomized data comparing Trevo with Merci for thrombectomy in acute stroke; In: European Stroke Conference. Lisbon, 2012 and SWIFT-study/Solitaire/Covidien [61]61. Saver J, Jahan R, Clark W, et al.; Primary results of the solitaireTM FR with the intention for thrombectomy (SWIFT) multicenter, randomized clinical trial; In: International Stroke Conference. Los Angeles, USA, 2012; Presentation Number CT P40). Each study revealed clear superiority of the stent-triever versus the MERCI both in recanalisation rate and clinical outcome. Such device trials are less important than those assessing proof of concept of a novel therapy approach (namely MT); however, they do have a role and are important to ensure the momentum of development of better devices is maintained. Therefore, it is in everyone’s interest to encourage the technical development. Nevertheless, these devices must be proven to be safe and at least as efficacious as those they are intended to replace. Almost inevitably, most funding for device trials will need to come from industry partners. It is here that interventionists have a key role to play. On practical grounds of size of study, feasibility and so on, frequently surrogate or non-clinical outcomes will need to be used as endpoints in such trials. This imaging-based approach is overdue to be trialled in IA therapy either in isolation or more sensibly in addition to MT (especially once the benefit of MT is confirmed by the current cohort of ongoing RCTs). We thus suggest advanced prediction analyses of tissue outcome [62-64]62. 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]63. Lansberg MG, Lee J, Christensen S, et al.; RAPID automated patient selection for reperfusion therapy: a pooled analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study; Stroke 2011; 42:1608–1614 [PubMed]64. 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; 43(4):1025–1031 [PubMed].

The absolute benefit of IA thrombolysis over IVT is modest at best – around 2 % in the 2009 Cochrane Systematic Review. To date, trials on agents intended to replace rtPA such as Gp IIb/IIIa antagonists, desmoteplase and plasmin have been largely disappointing. However, a recent small Phase II trial of tenecteplase versus alteplase (in a highly selected population using CTA and CTP criteria) looks more promising up to 6 h with significantly more patients showing major neurologic improvement at 24 h in the tenecteplase arm, though the increased beneficial clinical outcome at 90 days did not reach statistical significance [65]65. Parsons M, Spratt N, Bivard A, et al.; A randomized trial of tenecteplase versus alteplase for acute ischemic stroke; N Engl J Med 2012; 366:1099–1107 [PubMed].

Further research questions

Many more questions are conceivable. At minimum, future studies should address the following issues:

  • How are patients who are likely to benefit from MT best characterised?
  • What is the clinical benefit of MT in patients with good collaterals?
  • What is the clinical benefit of IVT vs. MT in acute stroke patients with basilar artery occlusions?
  • What is the benefit of perfusion imaging (regardless of local protocol)?

Other issues that may be addressed include:

  • IVT versus MT in patients with acute stroke caused by ICA occlusion (with and without concomitant MCA occlusion)?
  • IVT versus MT in acute stroke patients with acute isolated MCA occlusion?
  • IVT versus MT in acute stroke patients with M2-occlusions?
  • Availability of IVT and MT for acute stroke patients and its impact on public health?
  • Mechanical thrombectomy with and without pre-treatment with IA thrombolytics
  • The effect of IA thrombolytics after mechanical thrombectomy?
  • The effect of neuroprotection (pharmacological, hypothermia) before MT?
  • Relevance of pre-existing infarct volume for the effect of MT?

In all likelihood further questions will arise based on the analysis of the IMS III study and other recent data.

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Conclusion

Based on current data and current experience, the key research questions are the comparisons of MT + IVT and IVT in patients both eligible and ineligible for IVT. Many more questions are conceivable and will arise based on the analysis recent data. In Part II, the joint working group of ESMINT and ESNR will make recommendations on trial design and conduct to investigate therapy effects of MT.

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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