MR CLEAN M ulticenter R andomized CL inical Trial of E ndovascular Treatment of A cute Ischemic Stroke in the N eth

1. MR CLEANMulticenter 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

2. MR CLEAN Trial • Representative cases • Rationale • Purpose • Design • Trial organisation www.mrclean-trial.org

3. 36-y-o W, aphasia, R arm paresis

4. stent deployed After stent retrieval: TICI 3

5. Good outcome 6d FU MRI

6. 49 -Y-O M: L hemiparesis Pre IAT Post IAT: TICI 3 Complete recanalization

7. Poor outcome CT 8hrs postprocedure

8. 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

9. Needed: a pragmatic clinical trial • Intervention contrast should be closely matched to current evidence based practise (incl IVT 0-4.5 hrs) • No restrictions in type of treatment unless strictly necessary • Clinical inclusion criteria (stroke severity, time since onset) as broad as possible

10. 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

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

12. 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

13. 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 • Derex Cerebrovasc Dis 2002; • Fisher Stroke 2006.

14. 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)

16. 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 24-48 hours and 1 week • ALD (Academic Linear Disability) scale, EQ5D and Barthel index at 90 days

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

18. 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

19. 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)

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

21. 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 www.mrclean-trial.org

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

24. 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 remainsopen, 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;13:225-229

26. 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

27. Ordered outcome scales: concept of sliding dichotomyMurray 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

28. 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)

30. RecanalizationGood outcome

31. RecanalizationGood outcome