Docstoc

Acute Myocardial Infarction are Thrombolitics Enough miocardial infarction

Document Sample
Acute Myocardial Infarction are Thrombolitics Enough  miocardial infarction Powered By Docstoc
					Acute Myocardial
Infarction are
Thrombolitics Enough ?

       Augustin J. DeLago M.D.,F.A.C.C
       Director,Catheterization
       Laboratory
       Director,Invasive Cardiology
       The Heart Institute
       Albany Medical Center
Management Strategies in AMI
                  Early evidence of
                  reduced mortality
                     after IC SK


                   Evidence of
                  mortality benefit
                    after IV SK
                      (GISSI)

                    GUSTO-I, TIMI:
                 •Lytics, 90-min CBF
                   reduce mortality
                 •New lytics created
GUSTO-I: The Benefit of
Reperfusion       Patency ~ Mortality
                                             10
                                                             P=0.009




                      30-day mortality (%)
                                                                         P=0.08
                                                    8.9
                                             8
    The Open
                                                                   7.4
      Artery
                                             6
    Hypothesis
  • Reperfusion                              4                                     4.4
    of the IRA
    results in LV                            2
    preservation
  • Open the                                 0
                                                  TIMI 0-1       TIMI 2           TIMI 3
    artery early to                               90-minute angiography
    improve                            Ross AM et al. N Engl J Med. 1993;329:1615–1622.
    outcomes
Innovations in the Management
of AMI

    INFARCT The Mortality Ceiling With Modern
                                        Fibrinolytics
                 Survival probability
                                                    Alteplase
                                                    Tenecteplase




                                                   Percentage of survival
     ASSENT-2
     • Designed to test the superior fibrin specificity of tenecteplase vs alteplase
       (equivalence study)
     • Outcome: No difference in mortality
Innovations in the Management
of AMI


       INFARCT The Mortality Ceiling With Modern
                                     Fibrinolytics
                                     GUSTO-III Survival Curve
                                    16
                                         Alteplase
                                         Reteplase
                    mortality (%)

                                    12


                                    8

                                                     Alteplase mortality rate (11.0%)
                                    4                Reteplase mortality rate (11.21%)
                                                     P=0.6630
                                    0
                                                           days
        • Designed to test the theory that reteplase would be superior to alteplase
          because of its superior angiographic data
        • Outcome: No difference in mortality
        Ohman EM. Oral presentation, ACC 1999.
Innovations in the Management
of AMI


                Limitations of Fibrinolysis
           • Mortality ceiling (6% to 7%)
          • Successful reperfusion (45% to
        60%)
           • ICH risk (0.5% to 1.5%)
           • Approximately 40% of patients do
        not achieve TIMI-3 flow at 90 minutes
           • Critical time dependence for
        reperfusion to achieve optimal outcomes
GP IIb/IIIa Inhibitors

            Small molecule              Abciximab




                                                     Artist’s conceptio

    Competitive blockade           Steric hindrance
    Highly specific for GP IIb/IIIaNonspecific
    Mimic amino acid sequences     Binds with 3 chain on GP IIb/IIIa
                                   v3
GP IIb/IIIa Inhibitors


       Abciximab            Tirofiban      Eptifibatide


       Binding            Competitive   Competitive

       Half-life
         Plasma             ~2 h             ~2 h
                <10 min
         Biologic           ~2 h             ~2 h
                 Days

       Clearance           Renal             Renal
          Renal/Spleen
GP IIb/IIIa Inhibitors



    Benefits of GP IIb/IIIa Inhibition
                in AMI:
       Review of Clinical Trials
   EPIC: AMI Subset – Post Hoc Analysis


                                                       Placebo (n=23)        Abciximab bolus        Abciximab bolus
                                                                                (n=19)              + infusion (n=22)
                        Death/re-MI/urgent TVR (%)
                                                     100
                                                      90                                        P=0.002
                                                      80
                                                                                                                 91%
                                                      70           P=0.06
                                                      60
                                                                                   83%   47.8
                                                      50
                                                      40                                          32.3
                                                      30    26.1
                                                                    21.1
                                                      20
                                                      10                     4.5                           4.5
                                                       0
                                                                   30 days                      6 months
Lefkovits J et al. Am J Cardiol. 1996;77:1045–
1051.
TIMI 14

           TIMI 3 Flow : 90
           min
                              tPA + rPA Phases
                   Full Dose Lytic 50% Lytic+ Abx
             100

              80                      70           74          73
          %            62
          Pts 60
              40
             n = 215         87             148          88
              20

               0 tPA     rPA                tPA          rPA
               100 mg 10 + 10 U            50 mg        5+5U

                            p=0.014
TIMI 14
          Abciximab Improves ST Res-90
          min
                            tPA + rPA pooled
                        Complete (> 70%)
                           ST Res
             100
                               P<0.0005
              80
                                              58
              60
                       40
              40
              20
                           N=179       N=329
               0
                     Lytic                Lytic +
                                           Abx
                    de Lemos et al AHA 1999
                     GP IIb/IIIa Inhibitors in Primary
                     PTCA


                                      RAPPORT
                                                        End Points
                                                   • Primary: Composite of
                                                  any-cause death, recurrent
                             Objective              MI, repeat TVR within
                   Evaluate safety and efficacy            6 months
                   of abciximab as adjunctive     •Secondary: Composites of
                    therapy to primary PTCA        death, MI, urgent TVR at
                                                      7 days and 30 days


Brener SJ et al. Circulation. 1998;98:734–741.
        RAPPORT
        30-Day End Points (Intent-to-
        Treat)
                                                                                 Placebo (n=242)
                                       15
                                                  P=0.03                         Abciximab (n=241)
                                                11.2           48%
                                       10
                       % of Patients



                                                                                     P=0.006
                                                                      P=0.52
                                                                                    6.6
                                                       5.8           5.8                           74%
                                       5                                   4.6

                                                                                           1.7

                                       0
                                            Death, re-MI, or    Death or re-MI       Urgent
                                                urgent                            intervention
                                             intervention
Brener SJ et al. Circulation. 1998;98:734–741.
PCI with Adjunctive GP IIb/IIIa



                                          30-d Mortality, MI, Urgent ReV
               30
                         26.1
     Percent



                                                   Control
               20                                  Abciximab
                                                                                     15.3
                                                                      11.2
                                       9.7              9.2
               10                                                                           7.3
                                4.5                                          5.8
                                             3.6
                                                                2

                 0
               Trial      EPIC        GUSTO-III        Neumann        RAPPORT        ADMIRAL
         N:         64     392/83       200                   403            300
         Random:   No      No           Yes                   Yes            Yes
         PCI:    PTCA      PTCA         Stent                 PTCA           Stent
         P:       0.06     0.04         0.03                  <0.05          <0.05
 .
Lysis vs Primary PTCA

            15                                            30-d Mortality or Discharge
                           Lytic             PTCA                           11.9
                              *P<0.05
            10                                                                 8.7*
  Percent




                   6.5          7                         7
                                                                                      6.5
                                                              5.7 5.6 5.5
                                               4.3                                       4.4*
            5                            3.6
                       2.6
                                    1.0*

            0
                   PAMI      ZWOLLE MAYO GUSTO-IIb MITI                      CCP      Weaver
              N    395        395           103           1138    3145      20,683      2606
            Herrmann HC. Am J Cardiol. 2000;85:10C-16C.
     Reperfusion in AMI



    FIBRINOLYSIS

                                PRIMARY PTCA




•   Reduces mortality   •   Lower mortality
•   Well studied        •   Anatomic definition
•   Widely available    •   Avoids hemorrhage
  Facilitated Percutaneous
   Coronary Intervention:
Evidence for the Efficacy of a
        New Approach
Potential Benefits of
Facilitated PCI


•   May be cost-effective if combination pharmacologic therapy lessens the need for PC
•   Improves patient stability during intervention
     – Patients with open arteries have less shock, IABP, pacemaker, arrest
     – Higher technical success due to less hectic procedure, better distal vessel
       visualization
•   Fuses best aspects of fibrinolysis and primary PCI
     – Earlier and greater TIMI-3 flow rates
     – May improve myocardial tissue perfusion
    SPEED: Study Population
                                  Dose-finding             Abciximab +
  SPEED study                       (n=305)                reteplase
      (n=528)                                              Abciximab +
Primary end point                  Confirmation            reteplase (5+5 U) vs
                                     (n=223)               full-dose reteplase
   = TIMI-3 flow
                                                           (10+10 U)
                                60-90 min
                                angiogram
 Nonqualifying                   (n=466)                     No early PCI
  PCI (n=43)                                                   (n=162)


                                                       Facilitated PCI
                                                          (n=323)
 Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–
 1496.
SPEED

  TIMI Grade 3 Flow at 60-90 Min

                  Angiographic Core Lab Reading
        100
                        p = 0.06             p = 0.2

                                     62%

                48%                                     51%
        50

                                                                          29%



              n = 107              n = 103             n = 75           n = 66
         0
                r-PA           60 U Hep             40 U Hep          Abciximab
               Alone          Abciximab            Abciximab            Alone
                              + r-PA 5 + 5         + r-PA 5 + 5
                                                                  ACC 1999: Oral Prese
            SPEED: Clinical Success

                                                    Freedom From Mortality, MI, Urgent ReV at 30 days


                                                   100
                                                                                        94.4%
                                                   95
                                         Percent



                                                                      P<0.05
                                                   90
                                                                                        83.8%
                                                   85

                                                   80
                                                           0        10            20      30
                                                                           Days
Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–1496.       Early PCI          No Early PCI
Results in a Perspective
       GUSTO-1                  Meta-analysis                    SPEED
        90-min                     60-min                        60-min
100%                     100%                      100%
       p < 0.001                                                  p = 0.06

            23%                                                    14%
 75%                     75%          23%            75%
                                                                            62%
                  54%
                                                              48%
 50%                     50%                45%      50%

       31%
                         25%    22%                  25%
 25%



 0%                       0%                          0%
       SK         t-PA           SK         t-PA              r-PA Abciximab
                                                                   r-PA 5 + 5
                                              ACC 1999: Oral Presentation
GUSTO-IV AMI

   Trial Protocol (n = 16,600)
                                           ST , lytic eligible, < 6 h
                                                               ASA

                        No Abciximab                                                   Abciximab*


                2 x 10 U bolus (30’)                                         2 x 5 U bolus (30’)
                     Reteplase                                                    Reteplase

                Standard Heparin:                                                Low Dose Heparin:
         5,000 U bolus followed by either                                           60 U/kg bolus
                                                                                   followed by a
             800 U/hr (pts < 80 kg) or                                           7 U/kg/h infusion
         1,000 U/hr (pts > 80 kg) infusion


                                         1º endpoint: mortality at 30 days
                                  2º endpoint: clinical and safety events at 30 days

   * 0.25mg/kg bolus followed by 0.125 g/kg/min infusion for 12 hours
Suggested Treatment Strategy

                Abciximab
               Half Dose Lytic


               Low Dose Heparin:
                  60 U/kg bolus
                 followed by a
               7 U/kg/h infusion



    URGENT PCI IF PERSISTENT CHEST
         PAIN OR ST ELEVATION
    Future Studies
                        TNK + Tirofiban
                            Phase IIb
•   FASTER              TNK + Abciximab
                         [ Spring 2001 ]
                          TNK + heparin
•   ASSENT III           r-PA + Abciximab
                       TNK + LMW heparin
                         r-PA + heparin
•   GUSTO V - MI
                        approx 6000 pts
                           16,600 pts
                        TNK + Eptifibatide
                           Phase IIb
•   INTEGRITI                 Phase III
                          [ Spring +IIb
                        Abciximab2001 ]PCI
                           [ Spring 2001 ]]
                     Abciximab + r-PA + PCI
                             Starting now
•   FINESSE          2700 pts; starting now
Summary

  • Several aspects of combined fibrinolytic and
    GP IIb/IIIa inhibition reperfusion strategy remain
    to be clarified
  • Further reductions in mortality should be
    expected with more inclusion of platelet inhibition
    in reperfusion strategies for ST-elevation MI
  • Combined pharmacologic and catheter-based
    reperfusion approaches will offer optimal
    treatment to more patients
Evolving Questions
       • Optimal dosing of unfractionated
         heparin added to combined
         fibrinolysis and GP IIb/IIIa inhibition
       • Clinical importance of differences
         among GP IIb/IIIa antagonists in
         potency, effects on other adhesion
         molecules, and efficacy in protecting
         microvasculature
       • Validation of the safety and efficacy
         of early invasive management
         combined with potent platelet
         inhibition

				
DOCUMENT INFO