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					                                   CHU
                                   CAEN




            EVA-3S
Inferences and future directions

         Jacques Theron, MD
          Martial Hamon, MD
Potential tittles                                                    CHU
                                                                     CAEN




           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
                 EVA-3S
Endarterectomy versus stenting in patients
                                                                        CHU
 with symptomatic severe carotid stenosis                               CAEN



            872 initially planned*
  Inclusion criteria : Symptomatic stroke


  ASA Clopidogrel recommended

                 Randomization

   CAS                                       CAE
           Primary endpoint
    Efficacy : death, stroke @ day 30

              *Non inferiority design
     Hypothesis (stroke+death): 4% CS vs 5.6% CEA
         ARR<2% (beta risk 20%, alpha risk 5%)


                                                    N Engl J Med 2006
          Endpoint Measures at day 30                                                   CHU
                                                                                         CAEN


                   Carotid Stenting vs Endarterectomy
                   Relative Risk           CEA   Stenting    RR (95% CI)
   Endpoint                                                                    p-value
                     ± 95% CI            (n=259) (n=261)      unadjusted



      Death                                1.2%    0.8%     0.7 (0.1-3.9)        0.68


     Stroke                                2.7%    8.8%     3.3 (1.4-7.5)       0.004


Death/Stroke                               3.9%    9.6%     2.5 (1.2-5.1)        0.01



               0    1   2   3   4    5        Primary endpoint EVA-3S
        Stenting        CEA better
          better

                                                          Mas JL et al. N Engl J Med 2006
   Stroke or death among centers                                                CHU
           according to number of patients enrolled                              CAEN




 Stroke or Death           Relative Risk              RR (95% CI)      p-value
         Day 30              ± 95% CI                  unadjusted        int.



    <21 patients                                     1.9 (0.6-6.2)


21 to 40 patients                                    3.3 (0.7-15.2)      0.83


    >40 patients                                     2.7 (0.9-8.1)

                                              Low volume operators overall?
                                              1.7 cases/year/center enrolled
                     0 1 2 3 4 5 6 7 8 9 10
                                               for carotid stenting in EVA-3S
         Stenting better      CEA better

                                                  Mas JL et al. N Engl J Med 2006
Type of carotid stent                              CHU
                                                   CAEN




 EVA-3S
                    2%
                  2%
            11%

                                    Wallstent
                                    Acculink
                                    PreciseRX
      29%                     56%   WallatentOTW
                                    Zilver




             Up to 5 stents
Cerebral protection devices                                        CHU
                                                                   CAEN




                 Before recommendation: used in 58/74 (78.4%)
 EVA-3S
                 After recommendation: used in 169/173 (97.7%)
                 Overall cerebral protection use: 227/247 (92%)

                    8% 2%
                                  30%          GuardWire
              9%
                                               FilterWire
                                               SpiderRX
           11%                                 Emboshield
                                               Angioguard
                                               Spider
              13%                              Accunet
                              27%
     20 patients without protection leading to 5 stroke: 20%
Heterogeneity in protection devices with low volume operators+++
           Carotid Stenting with and without
        cerebral protection: a systematic review                                     CHU
                                                                                        CAEN


                          Endpoint Measures at day 30
                                  With     Without
                 Relative Risk
    Endpoint                   Protection Protection RR (95% CI)            p-value
                   ± 95% CI
                                (n=896) (n=2537)


       Death                          0.89%     0.71% 0.8 (0.4-1.9)           0.67


      Stroke                          0.89%     4.8%     5.4 (2.6-10.9)      <0.001


Death/Stroke                          1.8%      5.5%     3.1 (1.8-5.1)       <0.001


                                             20 patients without protection
               0 1 2 3 4 5 6 7 8
           Without    With                   Leading to 5 stroke in EVA-3S
  Protection better   Protection better

                                              Kastrup A et al. Stroke 2003;34:813-819
Antiplatelet agents in EVA-3S                                                        CHU
                                                                                     CAEN




                                       100
      % of oral antiplatelets agents

                                              82,9            85,4
                                       80

                                       60
                                                                            Dual
                                                                            Single
                                       40

                                                     17,1            14,6
                                       20

                                        0
                                             Preprocedure   Postprocedure

  Dual antiplatelet treatment only recommended in EVA-3S
  Mandatory in Sapphire trial
Emerging importance of effective
blockade of platelet aggregation                                                                     CHU
                                                                                                     CAEN




 24 patients
 Recent stroke with MES rate > 6/h on TCD
 Treated with Tirofiban (GPIIb/IIIa inhibitor)


                                40
         Microembolic signals




                                35
                                30
                                25
                                20
                                15
                                10
                                5
                                0
                                        iTCD          TCD-I        TCD-II    TCD=Transcranial doppler
                                            <24 hrs                          GPI=Glycoprotein inhibitor
                                      GPI                     >2 hrs         UFH=Unfractionated heparin
                                     UFH

                                                  Junghans U et al. Circulation 2003;107:2717-2721
Heparin and air filters reduce embolic events caused by
intra-arterial cerebral angiography                                                             CHU
                                                                                                CAEN
A prospective randomized trial

                                            Heparin missing in 2.4% procedures
 150 patients                                           in EVA-3S
 Randomized in 3 groups

                       70
                       60
    Number of events




                       50
                       40                                       Single MES
                       30                                       MES Shower
                                                                DW-MRI+
                       20
                       10
                       0
                            Control   Heparin Air Filter

                                             Bendszus M et al. Circulation 2004;110:2110-2115
Learning curve in carotid stenting    CHU
                                      CAEN




 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
Room for improvement: 4 levels                                               CHU
                                                                             CAEN




  Patient                         Pharmacological environment
  -Selection*                     -Anticoagulation monitorring
  -Anatomy, prior DW-MRI          -New antithtrombin, antiplatetets agents
  -preparation                    -prior and post procedural dual
  -loading dose of                antiplatelets treatment
  thienopyridine                  -Statin therapy


  Procedural details               Operators
  -Stents                          -Training, simulators
  -Protective devices              -Credentialling
  -Manifold with BP control        -Cerification program
  - Heparin                        -Prerandomization run-in procedures
  -Air filters                     -On-site visit of relevant committee

 * High risk features in EVA-3S
How we Falled into an ambush or a trap ?
                                                                        CHU
                                                                        CAEN




 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
Future Directions                                          CHU
                                                           CAEN




 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)
Meta-analysis of randomized trials                        CHU
                                                          CAEN


       Protected Carotid-Stenting versus Endarterectomy
                   Death & stroke at day 30




              CAS better          CEA better
Meta-analysis of randomized trials                        CHU
                                                          CAEN


       Protected Carotid-Stenting versus Endarterectomy
                   Death & stroke at day 30
Meta-analysis of randomized trials                        CHU
                                                          CAEN


       Protected Carotid-Stenting versus Endarterectomy
                        Death at day 30




                 CAS better          CEA better

				
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posted:10/11/2012
language:English
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