EARLY ACS Study Design Early Eptifibatide in nonST segment elevation ACS

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EARLY ACS Study Design Early Eptifibatide in nonST segment elevation ACS Powered By Docstoc
					       EARLY ACS
Trial Rationale and Design

Robert A. Harrington, MD, FACC, FSCAI
         Professor of Medicine
   Duke Clinical Research Institute
   Duke University Medical Center
        NSTE Acute Coronary Syndromes:
                Key Issues 2005
   High-risk NSTE ACS patients
       multiple medical therapies; invasive strategy of care
       high event rates
   Platelet GP IIb/IIIa inhibitors
       Broad populations versus targeted high-risk
       Timing of initiation: “upstream” versus PCI; CABG
       Data in contemporary practice (concomitant therapies)
   Clopidogrel
       Timing of initiation
       Bleeding risk in CABG
From the 1998 Archives…

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                                                   Death or MI at 30 Days

Freedom from Death / MI

                                                                                 Hazard Ratio (95% CI)
                          0.95                                                                           1.1
                                                                            30-Day Death/MI
                                                                                  HR 0.96 (0.86-1.06)

                                     Enoxaparin                       0.8                       1                1.2
                                     UFH                                      Enoxaparin                UFH
                          0.8                                                   Better                  Better
                                 0    5    10     15   20   25   30
                                     Days from Randomization
                                          Enoxaparin      UFH
                                           (n = 4993)   (n = 4985)

              Aspirin (%)                     95           95

              Beta blocker (%)                86           86
              Ace inhibitor (%)               64           62
              Statin (%)                      69           70

              Clopidogrel (%)                 62           63

              GP IIb-IIIa inhibitor (%)       56           58
“Protein-Targeted” Treatment Strategies in ACS:
Benefit of GPIIb/IIIa Inhibitor by Troponin Status





            0.125        1             2 0.125        1         2 0.125       1         2

                    TnT-negative                 TnT-positive             Interaction
                             -Newby LK, et al. Circ 103:2891;2001
GP IIb/IIIa Blockade Before and After PCI:

                            Before PCI                                    Post-PCI

               8%                               Placebo                               8.0%
                                                GP IIb/IIIa inhibitor
 Death or MI

                        N=12,296                                                      4.9%
                        P=0.001                    4.3%
                                                    2.9%                    N=2754
               2%                                                           P=0.001

                    0      +24 h     +48 h      +72 h                      +24 h   +48 h

                                   -Boersma E, et al. Circulation, 1999
  Abciximab vs. Placebo in PCI after pretreatment
  with Clopidogrel (ISAR-REACT)

Kastrati et al. N Eng J Med 2004
Clopidogrel: Balancing Efficacy and Safety
Uncertainties Regarding Timing of Therapy

     Early treatment
         Reduced early ischemic events
         Potential for bleeding if early CABG
     Wait until catheterization
        Avoid treatment of patients pre-CABG
        Lost opportunity for early benefit
ACC/AHA 2002 Guideline Update for the
Management of Patients with UA and NSTE MI

Class I
  A platelet GP IIb/IIIa antagonist, should be administered, in addition
  to aspirin and heparin, to patients in whom catheterization and PCI
  are planned. The GP IIb/IIIa antagonist may also be administered
  just prior to PCI. (Level of Evidence: A)

 Class IIa
   A platelet GP IIb/IIIa antagonist should be administered to patients
   already receiving heparin, aspirin, and clopidogrel in whom
   catheterization and PCI are planned. The GP IIb/IIIa antagonist
   may also be administered just prior to PCI. (Level of Evidence: B)
      Acute (< 24 hrs) Anti-Platelet Therapies
             High-Risk NSTE ACS in CRUSADE

                      40%                           40%
40%     36%


20%                                   20%


      GP IIb/IIIa   Clopidogrel   GP IIb/IIIa +    Neither

                                            CRUSADE Q2 2003 data
Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment
 Elevation Acute Coronary Syndrome: A Randomized,
 Double-blind, Placebo-Controlled Trial Evaluating the
Clinical Benefits of Early Front-loaded Eptifibatide in the
 Treatment of Patients with Non-ST-segment Elevation
              Acute Coronary Syndromes
                           Trial Organization
                                                      Sponsor
                                                Schering-Plough (SPRI)
                                                      Sponsor
                                  Schering-           European Site Management
 Millennium                        Plough             Drug Distribution for sites
                                                         outside North America
                                                International Steering Committee
                      Sites                           Scientific & Clinical Leadership

                     Patients                   DCRI/ CVC
DCRI/ CVC                          ICTI/ IVRS         Scientific & Clinical Leadership
                                                      North American Site
                                                      Coordinating Center
                           CTS Durham                 Data Management
              TIMI          Pharmacy            TIMI
                                                      Scientific & Clinical Leadership
             Primary Objective

To demonstrate the superiority of early
eptifibatide compared to placebo (with
provisional use of eptifibatide in the cath lab) in
reducing the composite of death, MI, recurrent
ischemia, and thrombotic bail-out within 96
hours in patients with high-risk NSTE ACS
managed with an early invasive strategy
                         Study Design
   2 of 3 criteria:
1. Age > 60 yo          High-risk NSTE    ACS
2. + CKMB or TNT/I
3. ST  or transient ST     n = 10,500

        Eptifibatide (180/2/180)          Placebo
                    Randomize within 8 hours
     Early invasive strategy: no sooner than next calendar day

  1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout
                   2 Endpoint: 30 d Death/MI
           Concomitant Therapies

   Aspirin
   Enoxaparin or Unfractionated Heparin
       Dosing guides provided in protocol
       Lessons from SYNERGY
       Use of bivalirudin or other direct thrombin
        inhibitor is prohibited
   Clopidogrel
    300 mg load / 75 mg daily dose
       Randomization stratified by investigator’s
        intention to start clopidogrel pre-cath
        Blinded Study Drug Administration

   Duration of infusion
       Medically managed
         • Minimum = 72 hours; maximum = 96 hours
       Percutaneous coronary intervention
         • Minimum = 72 hours; maximum of 96 hours
         • Continue for 18 hours after procedure
       Coronary Artery Bypass Surgery
         • Maximum of 120 hours
         • Continue infusion until 2 hours before surgery
         Use of Eptifibatide in the Cath Lab
          (1) After Angiography and Before PCI

   Eptifibatide during PCI according to local
       PCI active treatment kits are available for use after
        the diagnostic angiogram and before PCI begins
       Kit contents are opposite of the initial study drug
        assignment at randomization
       PCI active kits are used for the bolus doses of
        eptifibatide/placebo (no charge), open label hospital
        supply of eptifibatide is used for the infusion
       Use of PCI active kits before PCI begins is not
        considered a study endpoint
        Use of Eptifibatide in the Cath Lab
                (2) After PCI Has Begun

   Once the guidewire crosses the lesion, use of
    bail-out study drug is permitted to manage
    complications of PCI, but is considered an
    endpoint event
       Decrement in TIMI flow grade or abrupt closure
       Dissection with decreased flow
       Distal embolization
       Side-branch closure
       Clinical instability due to ischemia or prolonged
        ischemia during the procedure
                  Study Endpoints

   Primary Efficacy Composite (96 hours)
       All cause mortality
       New MI*,
       Recurrent ischemia requiring urgent
       Need for thrombotic bailout with GP IIb/IIIa*
   Key Secondary Efficacy Endpoint
       Death or new MI* through 30 days
   Safety Endpoints
       Hemorrhage, transfusion, stroke*,
        thrombocytopenia, SAEs, post-operative bleeding

    *Adjudicated by independent, blinded CEC
                Statistical Methods

   Power = 85% to detect a 22.5% reduction in the
    primary quadruple composite assuming an event
    rate of 5.8% with placebo
   Power = 85% for the key secondary efficacy
    endpoint of death or MI at 30 days (15% RRR,
    placebo rate 12.7%)
   Prespecified subgroups
       Proper: Age, baseline troponin, hospital type,
        diabetes, early clopidogrel, UFH vs enoxaparin,
        TIMI Risk Score
       Improper: By management strategy (PCI, CABG,
               Biomarker Substudy

Objectives                      Local hospital lab: WBC,
 Identify high-risk NTE-        creat, FBS, Hgb A1C
  ACS patients                  Core Lab (NA only):
 Explore the ability of         inflammation, ischemia,
  eptifibatide to modulate       necrosis, hemodynamic
  cardiac biomarkers             stress, thrombosis
 Identify patients who            3 timepoints: baseline,
  benefit most from early            pre-cath, 1 day post-cath
  eptifibatide                  DNA specimen: (NA only) at
            Platelet Inhibition in NSTE ACS
                 Summary of Current Status

   NSTE ACS remains major clinical challenge
   Equipoise around best timing of initiation of GP
    IIb/IIIa inhibitors in high-risk NSTE-ACS patients in
    whom invasive strategy planned
   Uncertainties about the use of clopidogrel in high-risk
    NSTE-ACS in whom invasive strategy planned
   Optimal combination of antithrombotic Rx is uncertain

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