CHU C A E N EVA-3S Inferences and future directions Jacques Theron, MD Martial Hamon, MD

CHU C A E N How to organise a trap to kill a technique? Organising an embush for neuro-interventionalists? A fantastic opportunity for (French) Cardiologists? “Murders between friends” Radiologists, Vascular surgeons, Neurologists Emerging importance of training and credentialling in carotid stenting: EVA-3S EVA-3S A Carotid stenting learning curve evaluation: A trial that never should have been started in this setting Potential tittles

CHU C A E N EVA-3S Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis 872 initially planned* Inclusion criteria : Symptomatic stroke CAS Randomization CAE Primary endpoint Efficacy : death, day 30 ASA Clopidogrel recommended N Engl J Med 2006 *Non inferiority design Hypothesis (stroke+death): 4% CS vs 5.6% CEA ARR<2% (beta risk 20%, alpha risk 5%)

CHU C A E N Endpoint Measures at day 30 Carotid Stenting vs Endarterectomy 0.8%1.2%0.7 ( )0.68 Relative Risk ± 95% CI Relative Risk ± 95% CI Endpoint Death Stroke Death/Stroke Stenting better Stenting better CEA better CEA(n=259) Stenting(n=261) RR (95% CI) unadjusted p-value 8.8%2.7%3.3 ( ) % 3.9%2.5 ( )0.01 Mas JL et al. N Engl J Med 2006 Primary endpoint EVA-3S

CHU C A E N Stroke or death among centers 1.9 ( ) Relative Risk ± 95% CI Relative Risk ± 95% CI Stroke or Death Day 30 <21 patients 21 to 40 patients >40 patients RR (95% CI) unadjusted p-valueint. 3.3 ( ) 2.7 ( ) 0.83 Mas JL et al. N Engl J Med 2006 according to number of patients enrolled Stenting better CEA better Low volume operators overall? 1.7 cases/year/center enrolled for carotid stenting in EVA-3S

CHU C A E N Type of carotid stent 2% Up to 5 stents EVA-3S

CHU C A E N Cerebral protection devices EVA-3S Before recommendation: used in 58/74 (78.4%) After recommendation: used in 169/173 (97.7%) Overall cerebral protection use: 227/247 (92%) 20 patients without protection leading to 5 stroke: 20% Heterogeneity in protection devices with low volume operators+++

CHU C A E N Endpoint Measures at day 30 Carotid Stenting with and without cerebral protection: a systematic review Carotid Stenting with and without cerebral protection: a systematic review 0.71%0.89%0.8 ( )0.67 Relative Risk ± 95% CI Relative Risk ± 95% CI Endpoint Death Stroke Death/Stroke Without Protection better Without Protection better With Protection better With Protection better With Protection (n=896) WithoutProtection(n=2537) RR (95% CI) p-value 4.8%0.89%5.4 ( ) < % 1.8%3.1 ( )<0.001 Kastrup A et al. Stroke 2003;34: patients without protection Leading to 5 stroke in EVA-3S

CHU C A E N Antiplatelet agents in EVA-3S % of oral antiplatelets agents Dual antiplatelet treatment only recommended in EVA-3S Mandatory in Sapphire trial

CHU C A E N Emerging importance of effective blockade of platelet aggregation Junghans U et al. Circulation 2003;107: patients Recent stroke with MES rate > 6/h on TCD Treated with Tirofiban (GPIIb/IIIa inhibitor) GPI UFH TCD=Transcranial doppler GPI=Glycoprotein inhibitor UFH=Unfractionated heparin <24 hrs >2 hrs Microembolic signals

CHU C A E N Heparin and air filters reduce embolic events caused by intra-arterial cerebral angiography A prospective randomized trial Bendszus M et al. Circulation 2004;110: Number of events Heparin missing in 2.4% procedures in EVA-3S 150 patients Randomized in 3 groups

CHU C A E N Learning curve in carotid stenting  Training (proctorship, simulator)  Credentialing requirements Largely underestimated in EVA-3S 0 to 12 Carotid stenting??? Median of 64 in Sapphire trial >25 for CAE in EVA-3S

CHU C A E N Room for improvement: 4 levels Procedural details -Stents -Protective devices -Manifold with BP control - Heparin -Air filters Patient -Selection* -Anatomy, prior DW-MRI -preparation -loading dose of thienopyridine Pharmacological environment - Anticoagulation monitorring -New antithtrombin, antiplatetets agents -prior and post procedural dual antiplatelets treatment -Statin therapy Operators -Training, simulators -Credentialling -Cerification program -Prerandomization run-in procedures -On-site visit of relevant committee * High risk features in EVA-3S

CHU C A E N How we Falled into an ambush or a trap ?  stents, distal protection devices  Anti-thrombotic agents (before, during, after procedures)  Experience of the operators  Non-inferiority design and early stop (25 vs 10 events, p=0.01) EVA-3S design or failure of CAS announced: Be sure to include some low volume centers Organize the trial during learning curve of the operators Include patients treated during training sessions of investigators Be sure to select in your control group skilled surgeons Don’t control for material homogeneity (Stents, distal protection) Don’t control for medications (anticoagulation, antiplatelets agents) Use stastistical design, with spurious or debattable assumptions

CHU C A E N Future Directions  EVA-3S are valid for conditions tested+++ Several issues emerge and require improvements  Importance of credentialling, training  Pivotal trial need to be contolled+++(homogeneous materials, drugs, on site certification,...)  Caution for patient selection (DW-MRI, high-risk features)  Importance of anithrombotic regimens (anticoagulation, antiplatelet agents)  Technical details (MES and TCD monitorring, DW-MRI)

CHU C A E N Meta-analysis of randomized trials Protected Carotid-Stenting versus Endarterectomy Death & stroke at day 30 CAS betterCEA better

CHU C A E N Meta-analysis of randomized trials Protected Carotid-Stenting versus Endarterectomy Death & stroke at day 30

CHU C A E N Meta-analysis of randomized trials Protected Carotid-Stenting versus Endarterectomy Death at day 30 CAS betterCEA better