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									                      The SYNTAX Trial:
             SYNergy between PCI with TAXUS and
                       cardiac surgery
                                       Trial Design and Philosophy



                                       Friedrich W. Mohr, MD, PhD
                                   On behalf of the SYNTAX investigators


SYNTAX: Trial Design and Philosophy • Serruys                              TCT • 14 October 2008 • Slide 1
      Disclosures


                  None




                 Study and Presentation Supported by Boston Scientific Corporation




SYNTAX: Trial Design and Philosophy • Serruys                           TCT • 14 October 2008 • Slide 2
      Evolution of CABG
                                                                                                                          2003
                                                                                                                       Shrivastava
                                                                                                                       et al
                                                                                                                       publish
                                         1953                                                                          ThoraCAB
                       1910        Gibbon                                                     1968                     technique
                                                                           1958                              1999
                  Carrell presents performs 1st                                         Favaloro 1st
                                                                     Sones discovers                   Diegler et al
                  a paper          successful open
       1818                                                          the diagnostic     surgeon to     publish OPCAB
                  describing       heart surgery
                                                                     coronary           perform bypass technique
 Heberden coins coronary artery using a cardio-
                                                                     angiogram          surgery (SVG)
 the term “angina bypass           pulmonary
 pectoris”                         bypass machine



               1876
                                                                                        1962                      2000
        Hammer                                                       1957/8
        diagnoses the                                                              Sabiston                 Falk et al
                                                     1950      Bailey/Longmire     attempts to
        first cardiac                                                                                       publish TECAB
        infarct in a                            Vineburg       report successful   suture an SVG            technique
        living human                            reroutes IMA   coronary            into coronary
                                                into heart     revascularization   circulation       1996                    2005
                                                muscle         on a beating                    Greenspun et al         Updated
                                                               heart                                                   ACC/AHA/SCAI
                                                                                               and Benetti et al
                                                                                               publish MIDCAB          guidelines:
                                                                                               technique               CABG remains
                                                                                                                       the standard of
                                                                                                                       care for 3VD/LM
                                                                                                                       disease

SYNTAX: Trial Design and Philosophy • Serruys                                                                      TCT • 14 October 2008 • Slide 3
      Evolution of PCI
                                                                                                                      Today
                                                                                                                 Increasing real-
                                                                                                                 world use of PCI
                                                                                                1994             in LM and 3VD
                                    1958                    1964                          1stcoronary
        1844
                               Sones discovers          Dotter               1977         stent approved
  Bernard coins                the diagnostic           introduces                        by the FDA
                                                                        Gruentzig                            2003
  the term                     coronary                 transluminal
  “cardiac                                                              peforms the 1st                FDA approval of
                               angiogram                angioplasty
  catheterization”                                                      PTCA                           1st DES




                                                 1962
                                                                                                          2002
                 1929                      Ricketts and                              1986
                                                                                                     CE Mark on 1st
                                           Abrams use the                       Sigwart and Puel
            Forssmann                                             1967                               DES
                                           percutaneous                         implant the 1st
            peforms the 1st                                 Judkins perfects
                                           approach in                          coronary stent
            human cardiac                                   the transfemoral
                                           coronary
            catheterization                                 approach
                                           arteries
                                                                                                                     2006
                                                                                                                FDA panel on
                                                                                                                the safety of
                                                                                                                DES



SYNTAX: Trial Design and Philosophy • Serruys                                                               TCT • 14 October 2008 • Slide 4
      Historical Pros & Cons



      +    Angina relief                                 +   Initially cost effective
      +    Reduced reintervention                        +   Fast recovery
      +    Complex anatomy                               +   Reduced acute complications
      +    Complete                                      +   Least invasive
           revascularization
      +    Mortality benefit in selected                 -   Increased restenosis
           patient groups                                -   Repeat revascularization

      -    Potential high costs
      -    Invasive

                   CABG                                                PCI

                        CABG is standard of care in patients
                        with left main & multivessel disease
SYNTAX: Trial Design and Philosophy • Serruys                              TCT • 14 October 2008 • Slide 5
      Eras of Comparative CABG Trials

                                                Plain Balloon Angioplasty
                                                      POBA vs CABG

                                                    Bare Metal Stents
                                                      BMS vs CABG

                                                   Drug Eluting Stents
                                                      DES vs CABG


                                                   Drug Eluting Stents
                                                DES vs CABG (randomized)


SYNTAX: Trial Design and Philosophy • Serruys                               TCT • 14 October 2008 • Slide 6
      Complexity of PCI-treated Patients
      is Increasing

                                                          Left Main

                                                            CTO

                                                         Bifurcation
                                                                                  CABG
                                                       Multiple Vessels
                                                                                  PCI
                               Complexity




                                                        Small Vessels
                                                         Long Lesion

                                                        Single Vessel

                                                Time                      Today

SYNTAX: Trial Design and Philosophy • Serruys                                     TCT • 14 October 2008 • Slide 7
      CABG Versus PCI
      Reported Literature                                                   CABG Better         PCI Better           No difference
                                                      Clinical Parameters
                    Trial                                                        Repeat            Stroke          Cost Assessment
                                     Mortality & MI     Angina Relief
                                                                            Revascularization
              GABI                              PCI          PCI                                    n/a                      n/a
              EAST                                                                              No difference                PCI
    No RITA                                                                                          na                      n/a
  stents                             No difference          CABG
   used ERACI                                                                                       n/a                      PCI
         CABRI                                                                                       na
                                                                                                                             n/a
              BARI                                                                              No difference
                                                             n/a
              MASS-2                    CABG (MI)                                                    na               No difference
              AWESOME                No difference      No difference            CABG           No difference                n/a
   BMS
   used ERACI-2                                 PCI          n/a                                    n/a               No difference
        SoS                        CABG (Mortality)         CABG                                    n/a                      n/a
              ARTSI
                                                                                                No difference                PCI
              ARTSII
                                                             n/a
   DES MAIN-                         No difference
   Used COMPARE                                                                                     n/a                      n/a

              LE MANS                                   No difference                           No difference                n/a



SYNTAX: Trial Design and Philosophy • Serruys                                                                   TCT • 14 October 2008 • Slide 8
       Evolution of Revascularization



  +    Off pump technique                                ?
  +    Less invasive approach                    How does modern          +   Improved technique
  +    Increased arterial                       CABG compare to PCI       +   Improved stent design
       revascularization                        in high-risk patients     +   DES
       Optimal perioperative                                                  Improved guidewires
                                                   eligible for both
  +                                                                       +

       care
                                                     techniques ?

                                                 Randomized Trial
                    CABG
      Which patient group continues
      to be solely eligible for CABG?                                            PCI
                                                                        What characterizes complex
                                                                         patients not eligible for
                                                                                  CABG?

                    CABG Registry                                               PCI Registry
SYNTAX: Trial Design and Philosophy • Serruys                                         TCT • 14 October 2008 • Slide 9
      In 2003/04.....


            Existing (and ongoing) trials did not address
             real-world questions and were:
                 Limited to highly selected patient subpopulations
                 Lacking an active control (registries)
                 Not utilizing current, standard techniques for
                 CABG and PCI

                  There were no contemporary, randomized
                    data available comparing CABG and PCI

SYNTAX: Trial Design and Philosophy • Serruys              TCT • 14 October 2008 • Slide 10
      SYNTAX: Intended All-Comers
      Design with Nested Registries




           Intended all-comers study design instead of a
           highly selected patient population
           Consensus physician agreement (surgeon &
           cardiologist) instead of inclusion & exclusion criteria
           And, nested registries for CABG only and PCI only
           to define patient characteristics and outcomes of
           these two unique treatment options


SYNTAX: Trial Design and Philosophy • Serruys            TCT • 14 October 2008 • Slide 11
      Open Inclusion Criteria


                  3-vessel disease and/or left main disease
                  Total occlusion without time limitation
                  Previous cerebrovascular accident >1 month
                  Renal and respiratory insufficiency
                  Decreased pump function
                  Myocardial ischemia (unstable-silent-stable)
                  Patients with comorbidity




                        Real world patient population
SYNTAX: Trial Design and Philosophy • Serruys              TCT • 14 October 2008 • Slide 12
      SYNTAX Eligible Patients

                                                   De novo disease


                                                Limited Exclusion Criteria
                                                 Previous interventions
                                                 Acute MI with CPK>2x
                                                 Concomitant cardiac surgery


                 Left Main Disease                                        3 Vessel Disease
    (isolated, +1, +2 or +3 vessels)                             (revasc all 3 vascular territories)




SYNTAX: Trial Design and Philosophy • Serruys                                          TCT • 14 October 2008 • Slide 13
      SYNTAX Trial Design
                   Heart Team (surgeon & interventional cardiologist)




               Novel approach - close collaboration between
               cardiac surgeons and interventional cardiologists
                    If both felt that the patient could be revascularized equally
                    by CABG or PCI, then the patient was randomized
                    If suitable for only 1 treatment option, then enrolled in a
                    registry
                    If not suitable to either treatment, not enrolled in SYNTAX


                    Amenable for both                  Amenable for only one
                    treatment options                   treatment approach
SYNTAX: Trial Design and Philosophy • Serruys                          TCT • 14 October 2008 • Slide 14
      SYNTAX Trial Design
                                                62 EU Sites +          23 US Sites

                                 Heart Team (surgeon & interventionalist)

                    Amenable for both                                Amenable for only one
                    treatment options                                 treatment approach
                                                         Stratification:
                                                        LM and Diabetes
                 Randomized Arms                                     Two Registry Arms
                                 N=1800                                     N=1275

         CABG                                     TAXUS*            CABG              PCI
                                        vs
         n=897                                    n=903            n=1077            n=198
      3VD   LM                                   3VD      LM     5yr f/u no f/u
     66.3% 33.7%                                65.4%    34.6%   n=649 n=428                   *
                                                                                                TAXUS Express
SYNTAX: Trial Design and Philosophy • Serruys                                        TCT • 14 October 2008 • Slide 15
      SYNTAX Score: A New Anatomic
      Score
                                                            Number &
                                                  Dominance location of
                                                              lesions

                                                                             Left Main
                               Calcification

                                                        SYNTAX
                             Thrombus                    score                  3 Vessel



                                                                             Total
                                                Bifurcation                Occlusion

                                                              Tortuosity
                                                                                       EuroInterv 2005;1:219-227
SYNTAX: Trial Design and Philosophy • Serruys                                              TCT • 14 October 2008 • Slide 16
   There is „3-vessel disease‟ and
   „3-vessel disease‟
     LCx 70-90%
                                                Patient 1   LM 99%                      Patient 2



                                                                           LAD 99%

     LAD 70-90%
                                                            LCx 100%


        SYNTAX SCORE 21                                     SYNTAX SCORE 52
                                                Patient 1                                 Patient 2

                              RCA2 70-90%

                           RCA3 70-90%



                                                                RCA 100%

SYNTAX: Trial Design and Philosophy • Serruys                                        TCT • 14 October 2008 • Slide 17
      Ultimate Goal of the SYNTAX Score


                  Angiographic tool to grade complexity of coronary
                  disease
                          A semi-quantitative, visual score will help interventional
                          cardiologists and surgeons be aware of the anatomical
                          complexity to anticipate procedural difficulties

                  Obtain evidence-based guidelines for selecting
                  revascularization technique (surgery or PCI)
                    The SYNTAX Score will be retroactively weighted
                    based on MACCE at 1 and 5 years to optimize its
                                   prognostic value


SYNTAX: Trial Design and Philosophy • Serruys                             TCT • 14 October 2008 • Slide 18
       SYNTAX Primary Endpoint
       Randomized trial

          The primary clinical endpoint is the 12-month Major
              Cardiovascular or Cerebrovascular event rate
                                 (MACCE*)
              MACCE is defined as:
                      All cause death
                      Cerebrovascular accident (CVA/Stroke)
                      Documented myocardial infarction
                      Any repeat revascularization (PCI and/or CABG)

              All events were CEC adjudicated


                                                     *ARTS   I: Serruys et al, NEJM 2001; 344: 1117-1124
SYNTAX: Trial Design and Philosophy • Serruys                                    TCT • 14 October 2008 • Slide 19
      Follow-up and Data Collection
                 Randomized Arms                             Two Registry Arms
                                 N=1800                               N=1275

         CABG                                   TAXUS*     CABG                 PCI
                                        vs
         n=897                                  n=903     n=1077               n=198
                                                            5yr f/u
                                                            n=649



     All RCT patients followed for                       649 CABG patients followed for
     5 years                                             5 years
     100% source data verification                       All PCI patients followed for
     Quality of life and Health                          5 years
     economic data captured up to                        20% source data verification
     5 years
                                                                                         *
                                                                                          TAXUS Express
SYNTAX: Trial Design and Philosophy • Serruys                                  TCT • 14 October 2008 • Slide 20
      SYNTAX Chronology

        AHA
       Concept                                                              1st patient
       Meeting                                                             March 2005
      November                         2004                        2005
        2003
                                                                          2006
                                                2007

             Enrollment
              complete
             April 2007
                                                       2008


                                                                1 year
                                                              follow-up
                                                              complete
SYNTAX: Trial Design and Philosophy • Serruys                                    TCT • 14 October 2008 • Slide 21
      SYNTAX Enrollment
                                                                                                 1800
1800


                                                                                                 1275
1200




  600


                                                                                                 85
       0

  1st Patient                                                                          Enrollment
     N 05




     N 06
     D 05

      Ja 5




     D 06

      Ja 6
     Ap 5




     Ap 6




     Ap 7
     Au 05




     Au 06
     Fe 06




     Fe 07
     Se 05




     Se 06
      Ju 5




      Ju 6
     M 05




     M 06




            07
       Ju 5




       Ju 6
      O 5




     M 6




      O 6




     M 07
           -0




           -0
            0




            0
           -0




           -0
           -0




           -0




           -0
            0




            0




            0
           -




           -
           -




           -
          l-




          l-
         n-




         n-
         g-




         g-
         r-




         r-




         r-
         n-




         n-
         p-




         b-




         p-




         b-
        ct




        ct
       ov




       ov
        ay




        ay
        ar




        ar




        ar
       ec




       ec
   Enrolled                                                                             Complete
   M




                                    Randomized Pts X X Registry Pts   Enrolling Ctrs

       2005                                                                                2007
       March                                                                               April

SYNTAX: Trial Design and Philosophy • Serruys                                          TCT • 14 October 2008 • Slide 22
      SYNTAX Enrollment:
      3,075 Patients at 85 Sites in 17 Countries




SYNTAX: Trial Design and Philosophy • Serruys      TCT • 14 October 2008 • Slide 23
      Top 30 Enrolling Centers: I
                                                CABG Investigator        PCI Investigator
           Austria                              Paul Simon               Dietmar Glogar
           Czech Rep                            Jan Tosovsky             Michael Aschermann
           Denmark                              Per Nielsen Hostrup      Leif Thuesen
           France                               Gerard Fournial          Didier Carrie
                                                Arnaud Farge             Marie-Claude Morice
                                                Jean-Paul Bessou         Jacques Berland
                                                Patrick Soula            Jean Marco
           Germany                              Friedrich Mohr           Gerhard Schuler
                                                Bruno Reichart           Peter Boekstegers
                                                Hermann Reichenspurner   Thomas Meinertz
           Hungary                              Lajos Papp               Ivan G. Horvath
                                                Ferenc Tarr              Istvan Preda
           Italy                                Paolo Ferrazzi           Giulio Guagliumi
                                                Andrea d‟Armini          Ezio Bramucci
                                                Lucia Torracca           Antonio Colombo

SYNTAX: Trial Design and Philosophy • Serruys                                           TCT • 14 October 2008 • Slide 24
      Top 30 Enrolling Centers: II
                                                CABG Investigator     PCI Investigator
           Italy                                Mattia Glauber        Sergio Berti
           Latvia                               Romans Lacis          Andrejs Erglis
           Netherlands                          Pieter Kappetein      Patrick Serruys
                                                Jacques Schonberger   Jacques Koolen
           Poland                               Andrejs Bochenek      Janus Drzewiecki
           Sweden                               Elisabeth Ståhle      Stefan James
           UK                                   Stephen Westaby       Adrian Banning
                                                Geoff Berg            Keith G. Oldroyd
                                                Steven Livesey        Keith D. Dawkins
                                                Jatin Desai           Martyn Thomas
                                                Tomasz Spyt           Anthony H. Gershlick
                                                Andrew Forsyth        Adam De Belder
                                                Graham Venn           Simon Redwood
           US                                   William Killinger     Tift Mann
                                                Michael Mack          David L. Brown

SYNTAX: Trial Design and Philosophy • Serruys                                        TCT • 14 October 2008 • Slide 25
      Objectives of SYNTAX


                  SYNTAX is an important, landmark study that aims
                  to provide evidence-based, contemporary,
                  objective randomized data about revascularization
                  of 3VD and LM patients
                  SYNTAX registry data will define outcomes in those
                  patients for whom either CABG or PCI was decided
                  to be the only treatment option
                  Development and validation of the SYNTAX score
                  may better characterize coronary vasculature
                  leading to better outcomes for patients


SYNTAX: Trial Design and Philosophy • Serruys              TCT • 14 October 2008 • Slide 26
      Considerations


                  What will the results mean for interventional
                  cardiologists? Cardiac surgeons?
                  Do the results of SYNTAX support current practice?
                  Will the results change revascularization
                  guidelines?




SYNTAX: Trial Design and Philosophy • Serruys                 TCT • 14 October 2008 • Slide 27

								
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