MR CLEAN Multicenter Randomized CLinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands C.B. Majoie, Y.B. Roos, A. van der Lugt, R. van Oostenbrugge, W. van Zwam, D.W. Dippel, Depts of Radiology and Neurology, AMC Amsterdam, MUMC Maastricht and EMC Rotterdam, The Netherlands

MR CLEAN Trial Representative cases Rationale Purpose Design Trial organisation

36-y-o W, aphasia, R arm paresis

After stent retrieval: TICI 3 stent deployed

Good outcome 6d FU MRI

49 -Y-O M: L hemiparesis Pre IATPost IAT: TICI 3 Complete recanalization

Poor outcome CT 8hrs postprocedure

Rationale IAT increases likelihood of recanalization in patients with acute ischemic stroke, BUT..... Overall effect on functional outcome of IAT as compared to no IAT is unknown at present

Needed: a pragmatic clinical trial Intervention contrast should be closely matched to current evidence based practise (incl IVT hrs) No restrictions in type of treatment unless strictly necessary Clinical inclusion criteria (stroke severity, time since onset) as broad as possible

Purpose To assess the effect of IAT on functional outcome after acute ischemic stroke of ≤ 6 hour onset, in patients with a symptomatic proximal intracranial arterial occlusion

Hypothesis 10% absolute increase in the cumulative proportion of patients with mRS 0-2 in the intervention group, compared to control group

Design Pragmatic phase III multicenter clinical trial with blinded outcome assessment Intervention contrast is IAT* versus no IAT against a background of best medical management (incl IVT within 4.5 hrs) *IA thrombolysis and/or mechanical thrombectomy at discretion of neurointerventionalist, treatment guidelines provided by executive committee

Inclusion Criteria A clinical diagnosis of acute stroke –Deficit on NIHSS ≥ 2 (1,2) CT (or MRI) scan ruling out intracranial hemorrhage Proximal intracranial arterial occlusion on CTA –distal ICA; M1,M2; A1, A2 The possibility to start treatment ≤ 6 hours from onset Informed consent Age ≥ 18 Y 1.Derex Cerebrovasc Dis 2002; 2.Fisher Stroke 2006.

Patient Subgroups Patients –not responding to IV thrombolysis –who can be treated within 6 hours, but do not meet time window requirements for IVT –with contraindications for IV or IA thrombolytic treatment (thrombectomy only)

Design: outcomes Primary –mRS at 90 days Secondary –Imaging parameters TICI (DSA) Recanalization at 24 hours (CTA) Infarct size at 5-7 days (CT) Occurrence of major bleeding –Clinical parameters Mortality at 1 week and 90 days NIHSS score at hours and 1 week ALD (Academic Linear Disability) scale, EQ5D and Barthel index at 90 days

Subgroup analyses Treatment modality –Urokinase or rtPA dose –Mechanical thrombectomy Pretreatment with iv rt-PA Early vs late treatment Stroke severity (NIHSS)

Radiological Predictors of Improved Outcome CT/CTA Source: ASPECTS (Barber PA et al, Lancet 2000) CTA: Clot Burden Score (Puetz Int J Stroke 2008) CTA: Collateral score (Tan IYL, Ann Neurol 2007) CTP: Infarct size/Penumbra Index

Center Eligibility Experience: –in acute stroke trials –with endovascular interventions –specific: with IA thrombolysis and mechanical thrombecomy at least 5 cases in the preceding year (treatment and device-specific e.g. 5 cases treated with a retrievable stent)

Planning and logistics 500 patients 4 year inclusion period 13 actively participating centers: –10 patients per year per center

Conclusions MR CLEAN will provide insight into –Clinical and radiological predictors of good outcome –Clinical and radiological criteria that improve safety –Implementation strategies for best practises of endovascular treatment –Data for cost-effectiveness analyses

Probability of finding a prox art occlusion according to day 0 NIHSS (Derex L, Cerebrovasc Dis 2002)

Low initial NIHSS score and proximal occlusion Acute stroke patients with a low NIHSS score on admission should not be excluded from early imaging. Indeed, stroke in the hyperacute stage is a dynamic process with a potential for neurologic deterioration, even in patients with an initial mild stroke severity. Some of these patients with mild symptoms on admission may actually suffer from a large vessel occlusion and the clinical course of their stroke remains open, depending on many factors such as severity of the perfusion deficit, the adequacy of collateral circulation and the presence or absence of early recanalization Derex L Cerebrovasc Dis 2002;13:

Statistical Analysis Effect of treatment estimated by means of ordinal logistic regression (shift analysis), which considers whole range of mRS Sliding dichotomy: definition of good outcome customized to each patient’s baseline condition Murray GD et al. Design and analysis of phase III trials with ordered outcome scales: the concept of sliding dichotomy.J Neurotrauma 2005;22:511-17

Ordered outcome scales: concept of sliding dichotomy Murray et al (J Neurotrauma 2005) In stead of taking a single definition of “good outcome” for all patients (e.g.mRS ≤ 2), the definition is tailored to each patient’s baseline prognosis on entry of the trial. –For a patient with very severe injury survival alone might be regarded as good outcome –For a patient with a mild injury, only full recovery would be regarded as a good outcome Patients at the prognostic extremes have the potential to contribute to the estimation of treatment effect

Sliding Dichotomy Patients are grouped to a number of bands according to baseline prognosis Each band has a customized dichotomy of the outcome scale to differentiate between “good” and “bad” outcome The total number of good outcomes in the intervention group will be compared with the corresponding number of outcomes in the intervention group Murray et al (J Neurotrauma 2005)

Recanalization  Good outcome