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

MR CLEAN Trial

• Representative cases • Rationale • Purpose• Design• Trial organisation

www.mrclean-trial.org

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 IAT Post IAT: TICI 3Complete 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 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

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)

Yes

Yes

YesYes

No

No

Yes

Yes

Yes

Clinical diagnosis of ischemic stroke?

CT/MRI ruled out hemorrhage?

Relevant proximal intracranialanterior arterial circulation

occlusion on CTA/MRA/DSA?

Tx possible within6 hours?

CI for iv or ia alteplase?

Too late for ivtreatment

No/poorresponse to iv

alteplase

Endovascular treatment No endovascular treatment

CI for mechanical treatment?

Randomize

Yes

Contra-indications for iv/ia alteplase• Cerebral infarction within the previous 6 weeks.• History of intracerebral hemorrhage.• Severe head injury the previous 4 weeks.• Major surgery, gastrointestinal bleeding or urinary tract bleeding within 2 weeks.• Arterial blood pressure > 185/110 mmHg. • Blood glucose < 2.7 or > 22.2 mmol/L.• Clinical signs of hemorrhagic diathesis or platelet count <90 x 10*9/L, APTT>50 sec or INR >1.7.• Treatment with iv alteplase in a dose exceeding 0.9 mg/kg or 90 mg.

Contra-iondications for mechanical thrombectomy• Stenosis of the symptomatic carotid artery exceeding 70% (NASCET), which cannot be stented. • Blood glucose < 2.7 or > 22.2 mmol/l.• Arterial blood pressure > 185/110 mmHg.• INR >3.0 and/or platelet count <40 x 10*9/L

NIHSS ≥ 2?

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

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

www.mrclean-trial.org

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;13:225-229

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)

RecanalizationGood outcome

RecanalizationGood outcome