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The ACST-2 MRI substudy

The ACST-2 MRI substudy Rationale , design and update on enrolment ACST-2 Investigators’ Meeting Oxford, 5 April 2013 Leo Bonati Department of Neurology and Stroke Unit University Hospital Basel. Conflicts of interest ?. International Carotid Stenting Study (ICSS)

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The ACST-2 MRI substudy

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  1. The ACST-2 MRI substudy Rationale, design and update on enrolmentACST-2 Investigators’ MeetingOxford, 5 April 2013Leo BonatiDepartment of Neurology and Stroke UnitUniversity Hospital Basel

  2. Conflictsofinterest? • International Carotid Stenting Study (ICSS) • European Carotid Surgery Trial 2 (ECST-2)

  3. Conflictsofinterest? • International Carotid Stenting Study (ICSS) • European Carotid Surgery Trial 2 (ECST-2)

  4. Overview • MRI in carotiddiseasetrials– experiencefromtheICSS-MRI substudy • Rationale forusing MRI in ACST-2 • The unstablecarotidplaque • Design ofthe ACST-2-MRI substudy and update on enrollment

  5. MRI-basedoutcomeassessment in carotidtrials

  6. 12 12 10 10 8 8 Proportion with event (%) Proportion with event (%) 6 6 4 4 2 2 0 0 0 30 60 90 120 0 30 60 90 120 Time from randomisation in days Time from randomisation in days CAS CEA 12 10 8 Proportion with event (%) 6 4 2 0 0 30 60 90 120 Time from randomisation in days Carotid Stenting Trialists Collaboration: pooled analysis of EVA-3S, SPACE, ICSS (n=3433 symptomatic patients). Events within 120 days of randomisation Any stroke or death Disabling stroke or death RR 1.53 (1.20-1.95)p=0.0006 RR 1.27 (0.92-1.74)n.s. 8.9% 4.8% 5.8% 3.7% All-cause death Any stroke RR 1.66 (1.28-2.15)p=0.0001 RR 1.44 (0.84-2.47)n.s. 12 8.2% 10 8 Proportion with event (%) 6 4.9% 4 1.9% 2 CSTC. Bonati et al., Lancet 2010; 376: 1062–73 1.3% 0 0 30 60 90 120 Time from randomisation in days

  7. International CarotidStenting Study (ICSS) Long-term follow-upto 10 years Peri-procedural stroke or death or ipsilateral stroke during follow-up CAS CEA European Stroke Conference 2012, Lisbon

  8. ICSS-MRI substudy: New ischaemic brain lesions after treatment Bonati et al., Lancet Neurol 2010; 9: 353–62

  9. ICSS-MRI substudy: Total DWI lesionvolumeandsymptoms (bothtreatmentgroupscombined) Hemispheric ischaemic stroke No focal deficit Higher total lesionsvolumes in patientswithstrokethan in thosewithsilentlesions (p<0.001) Bonati et al., Lancet Neurol 2010; 9: 353–62

  10. 100 Lesion count(log) 10 1 0 Stenting (124 pts.) Median (IQR) 0.5 (0-3) Endarterectomy(107 pts.) 0 (0-0) ICSS-MRI substudy: Total DWI lesion number (lesion count) • Risk ratio 8.8 (4.4-17.5)for a higher lesion count with CAS than CEA • negative binomial regression p<0.001 Gensicke et al., Stroke. 2013;44:80-6

  11. Lesion count (negative binomial regression) New lesions yes/no(logistic regression) 97% 91% 100 76% 95% 80 87% 60 65% Power (%) 40 20 0 75 50 100 150 200 250 Sample size (n patients) ICSS-MRI substudy: Statistical power Gensicke et al., Stroke. 2013;44:80-6

  12. Why use brain MRI in ACST-2?

  13. Whyusebrain MRI in ACST-2? • NOT TO…. • Replaceclinicalendpoints

  14. Whyusebrain MRI in ACST-2? • NOT TO…. • Replaceclinicalendpoints • Reducethenumberofpatientsenrolled in thetrial

  15. Whyusebrain MRI in ACST-2? • NOT TO…. • Replaceclinicalendpoints • Reducethenumberofpatientsenrolled in thetrial • Publishdatabeforepublicationoftheclinicalmainresults

  16. Rationale for MRI substudy in ACST-2 • Diffusion-weighted MRI (DWI) ishighly sensitive in detectingsmall, silentembolitothebrain after carotid revascularisation

  17. Rationale for MRI substudy in ACST-2 • Diffusion-weighted MRI (DWI) ishighly sensitive in detectingsmall, silentembolitothebrain after carotid revascularisation • MRI canbeassessedblindedtotheallocatedtreatment – avoidanceofascertainmentbias

  18. Rationale for MRI substudy in ACST-2 • Diffusion-weighted MRI (DWI) ishighly sensitive in detectingsmall, silentembolitothebrain after carotid revascularisation • MRI canbeassessedblindedtotheallocatedtreatment – avoidanceofascertainmentbias • High statistical power: treatmenteffectsandsubgroupinteractionsarevisible in small sample sizes

  19. Rationale for MRI substudy in ACST-2 • Diffusion-weighted MRI (DWI) ishighly sensitive in detectingsmall, silentembolitothebrain after carotid revascularisation • MRI canbeassessedblindedtotheallocatedtreatment – avoidanceofascertainmentbias • High statistical power: treatmenteffectsandsubgroupinteractionsarevisible in small sample sizes • Usein substudiesaddressingadditional researchquestionswhichare not feasibletoanswer in themaintrial • Biomarkers • Plaque imaging • Archimaging

  20. Rationale for MRI substudy in ACST-2 • Diffusion-weighted MRI (DWI) ishighly sensitive in detectingsmall, silentembolitothebrain after carotid revascularisation • MRI canbeassessedblindedtotheallocatedtreatment – avoidanceofascertainmentbias • High statistical power: treatmenteffectsandsubgroupinteractionsarevisible in small sample sizes • Usein substudiesaddressingadditional researchquestionswhichare not feasibletoanswer in themaintrial • Biomarkers • Plaque imaging • Archimaging

  21. Markers forplaqueinstability

  22. CREST: Death oranystrokewithin 30 daysoftreatment • Symptomatic stenosisn= 1’321 • Stent: 6.0% +/- 0.9% vs • CEA: 3.2% +/- 0.7% HR = 1.89 95%CI: 1.11- 3.21 p= 0.019 • Asymptomatic stenosis n=1’181 • Stent: 2.5% +/- 0.6% vs • CEA: 1.4% +/- 0.5% HR = 1.88 95%CI: 0.79 – 4.42 p= 0.15 Brott et al., N Engl J Med 010;363:11-23

  23. CREST: Death oranystrokewithin 30 daysoftreatment • Symptomaticstenosisn= 1’321≈ unstable plaque • Stent: 6.0% +/- 0.9% vs • CEA: 3.2% +/- 0.7% HR = 1.89 95%CI: 1.11- 3.21 p= 0.019 • Asymptomaticstenosisn=1’181≈ stable plaque • Stent: 2.5% +/- 0.6% vs • CEA: 1.4% +/- 0.5% HR = 1.88 95%CI: 0.79 – 4.42 p= 0.15 Brott et al., N Engl J Med 010;363:11-23

  24. Biomarkers:Atherogenesis, inflammation, andplaquerupture Peter Libby, Nature 2002

  25. Imaging markers: Plaque echolucency on carotidultrasound

  26. Rationale foridentifyingunstableplaques in ACST-2 • Assessment of serum biomarkers of plaque activation, platelet activation and inflammation, as well as quantitative ultrasound (and MRI) of the carotid plaque may identify biological and structural correlates of plaque instability • Patients with unstable carotid plaques may be at increased risk for cerebral embolism during treatment • Plaque instability may favour CEA over CAS

  27. The ACST-2-MRI substudy

  28. ACST-MRI substudy: Objectives • Tocomparetheincidenceofsymptomaticandsilentcerebral ischaemia between CAS and CEA using MRI asblinded, surrogateoutcomeassessment

  29. ACST-MRI substudy: Objectives • Tocomparetheincidenceofsymptomaticandsilentcerebral ischaemia between CAS and CEA using MRI asblinded, surrogateoutcomeassessment • Toinvestigatewhetherserumbiomarkers, plaqueultrasound (orplaque MRI) predictcerebral ischaemia in CAS or CEA

  30. ACST-MRI substudy: Objectives • Tocomparetheincidenceofsymptomaticandsilentcerebral ischaemia between CAS and CEA using MRI asblinded, surrogateoutcomeassessment • Toinvestigatewhetherserumbiomarkers, plaqueultrasound (orplaque MRI) predictcerebral ischaemia in CAS or CEA • Totestwhethertheseparametersmodifythe relative riskofcerebral ischaemia betweentreatments

  31. Study flow chart Randomisation in ACST-2 Randomised to CAS Randomised to CEA 1-7 d beforetreatment Treatment Treatment After treatment 1-3 days after treatment 1 month after treatment CAS: carotidartery stenting, CEA: carotid endarterectomy, MRI: magneticresonanceimaging

  32. Study flow chart Randomisation in ACST-2 MRI Randomised to CAS Randomised to CEA 1-7 d beforetreatment Treatment Treatment Module 1: Brain MRI After treatment MRI 1-3 days after treatment 1 month after treatment CAS: carotidartery stenting, CEA: carotid endarterectomy, MRI: magneticresonanceimaging

  33. Study flow chart Randomisation in ACST-2 MRI Randomised to CAS Randomised to CEA Ultrasound 1-7 d beforetreatment Treatment Treatment Module 1: Brain MRI Module 2: Ultrasound After treatment MRI 1-3 days after treatment 1 month after treatment CAS: carotidartery stenting, CEA: carotid endarterectomy, MRI: magneticresonanceimaging

  34. Study flow chart Randomisation in ACST-2 MRI Randomised to CAS Randomised to CEA Ultrasound Biomarkers 1-7 d beforetreatment Treatment Treatment Biomarkers Module 1: Brain MRI Module 2: Ultrasound Module 3: Biomarkers After treatment MRI 1-3 days after treatment Biomarkers 1 month after treatment CAS: carotidartery stenting, CEA: carotid endarterectomy, MRI: magneticresonanceimaging

  35. Imaging • Multimodal MRI • Brain: FLAIR, T2, DWI, T2* (mandatory) • Carotid plaqueimaging (onlybeforetreatment) • Carotid Duplex ultrasound (1-7 daysbeforetreatment): • Offline quantitative greyscaleanalysis (PlaqueAnalyzer®) • MRI and grey-scale ultrasound will be analysedcentrally, blinded to treatment allocation and clinical outcomes

  36. Serum biomarkeranalysis • Markers of platelet activation: P-selectin, E-selectin, PMP activity • Markers of endothelial activation: vWF, VCAM-1, ICAM-1, E-selectin and thrombomodulin • Inflammatory markers: hs-CRP, SAA, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, MBL, MMP-1,2,3,9,10, TIMP-1 • PMP, vWF and MBL will be analysed with single enzyme-linked immunosorbent assays (ELISA) • other biomarkers will be analysed with multiplex electrochemilluminescent immunosorbent assays (Meso Scale Discovery, Maryland 20877, U.S.A.).

  37. Participating centres • Target: n=240 • Currentlyenrolled: n=16 • Active centres: • Unversity Hospital Basel • UMC Utrecht • Serbian Clinical Centre Belgrade

  38. Participating centres • Target: n=240 • Currentlyenrolled: n=16 • Active centres: • Unversity Hospital Basel • UMC Utrecht • Serbian Clinical Centre Belgrade • WeneedmoreACST-2 centres withgoodaccesstoMRI

  39. Interested in joining? • Please send me an email: • leo.bonati@windowslive.com • Manythanks!

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