Prospective, Randomized Comparison of Heparin Plus IIb/IIIa by SNz207M

VIEWS: 11 PAGES: 22

									   Prospective, Randomized Comparison
    of Heparin Plus IIb/IIIa Inhibition and
Bivalirudin With or Without IIb/IIIa Inhibition
in Patients with Acute Coronary Syndromes
              Gregg W. Stone MD
        for the ACUITY Investigators
Background: Current Management of ACS
         Early invasive strategy if moderate-high risk1,2
            Median time to cath 21 hours3
         Revascularization with PCI or CABG1,2
            55% PCI, 12% CABG, 33% medical mgt3
         Triple anti-platelet therapy1,2
            Aspirin
            Clopidogrel (initiated pre or post angiography)
            GP IIb/IIIa inhibitors
              - started upstream in all pts or in the CCL for PCI
         Unfractionated or LMW heparin1,2,4
1 Braunwaldet al JACC 2002; 2 Bertrand et al. EHJ 2002;
3www.crusade.org; 4SYNERGY. JAMA 2004;292:45-54
Bivalirudin as an Alternative to UFH/LMWH
   Advantages of the direct thrombin inhibitor bivalirudin
      No requirement for anti-thrombin III
      Effective on clot-bound thrombin
      Inhibits thrombin-mediated platelet activation
      No interactions with PF-4
      Plasma half-life 25 minutes
      No requirement for anticoagulant monitoring
   Clinical results with bivalirudin in PCI
      Similar protection from ischemic events as UFH +
        GP IIb/IIIa inhibitors, with markedly reduced bleeding1
   Not previously tested in contemporary ACS patients


REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863
      Bivalirudin in ACS: Hypotheses
 In moderate-high risk patients with ACS
 undergoing an invasive strategy, compared
 to UFH or LMWH + GP IIb/IIIa inhibitors:
  • Bivalirudin + GP IIb/IIIa inhibitors will result in
   less adverse ischemic events and less bleeding

  • Bivalirudin alone will result in similar rates of
   ischemic events and markedly reduced bleeding
     Study Design – First Randomization
    Moderate-high risk unstable angina or NSTEMI
     undergoing an invasive strategy (N = 13,800)

                                 UFH or                                               Medical




                                                           Angiography within 72h
                               Enoxaparin                                           management
                               + GP IIb/IIIa

      Moderate-
                                Bivalirudin
      high risk         R*
                                + GP IIb/IIIa                                          PCI
        ACS

     Aspirin in all
      Clopidogrel               Bivalirudin
   dosing and timing              Alone                                               CABG
   per local practice


*Stratified by pre-angiography thienopyridine use or administration

 ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
        Study Design – Second Randomization
      Moderate-high risk unstable angina or NSTEMI
       undergoing an invasive strategy (N = 13,800)
                               UFH or Enoxaparin
                               Routine upstream
                                                                                Medical




                                                     Angiography within 72h
                                 GPI in all pts
                              R GPI started in                                management
                               CCL for PCI only
                                  Bivalirudin
        Moderate-              Routine upstream
                                 GPI in all pts
        high risk             R GPI started in
                                                                                 PCI
          ACS                  CCL for PCI only


        Aspirin in all
         Clopidogrel            Bivalirudin
      dosing and timing           Alone                                         CABG
      per local practice




ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
                          Major Entry Criteria
      Moderate-high risk unstable angina or NSTEMI
          Inclusion Criteria                             Exclusion Criteria
     Age ≥18 years                                   No angiography within 72h
     Chest pain ≥10’ within 24h                      Acute STEMI or shock
     At least one of:                                Bleeding diathesis or major
        New ST depression or                          bleed within 2 weeks
         transient ST elevation ≥1 mm
                                                      Platelet count ≤100,000/mm3
        Troponin I, T, or CKMB
                                                      INR >1.5 control
        Documented CAD
        All other 4 TIMI risk criteria               CrCl ≤30 ml/min
          - Age ≥65 years                             Abcx or ≥2 prior LMWH doses
          - Aspirin within 7 days                        Prior UFH, LMWH (1 dose),
          - ≥2 angina episodes w/i 24h                    eptifibatide and tirofiban
          - ≥3 cardiac risk factors                       were allowed
     Written informed consent                        Allergy to drugs, contrast


ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
                           Study Medications
 Anti-thrombin agents (started pre angiography)

                          UF Heparin               Enoxaparin                   Bivalirudin
                             U/Kg                    mg/Kg                        mg/kg
    Bolus                       60                  1.0 sc bid                     0.1 iv
    Infusion/h                  121                                                0.25 iv
                              ACT                 0.30 iv bolus2              0.50 bolus iv
    PCI
                            200-250s              0.75 iv bolus3           1.75/h infusion iv4
    CABG                Per institution          Per institution             Per institution5
    Medical mgt               None6                    None6                       None6

1 Target aPTT 50-75 seconds
2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose
4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used
5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before
6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion
      3 Primary Endpoints (at 30 Days)
          1. Composite net clinical benefit =
                  2. Ischemic composite
                              or
                      3. Major bleeding

 Death from any cause
 Myocardial infarction
 - During medical Rx: Any biomarker elevation >ULN
 - Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves
 - Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves
 Unplanned revascularization for ischemia
    3 Primary Endpoints (at 30 Days)
        1. Composite net clinical benefit =
                2. Ischemic composite
                            or
                    3. Major bleeding
                   Non CABG related bleeding
         - Intracranial bleeding or intraocular bleeding
                     - Retroperitoneal bleeding
       -Access site bleed requiring intervention/surgery
                         - Hematoma ≥5 cm
- Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source
                   - Blood product transfusion
                     Reoperation for bleeding
                                  Statistical Plan
     Anticipated event rates on UFH/Enox + GP IIb/IIIa
        Ischemic composite: 6.5%
        Major bleeding: 9.0%
        Net clinical outcome: 12.4%

     Significance testing
        Sequential non-inferiority and superiority tests
        Non-inferiority tests: One-sided a=0.025; =25%
        Superiority tests: Two sided a=0.05
        Hochberg procedure1 used to control type I error

      Sample size estimate = 13,800 patients
1Benjamini   & Hochberg. J R Stat Soc 1995
     Event Rates and Power Calculations
                   UFH/Enox +
                    GP IIb/IIIa
      Predicted       Rate
  Endpoint
  Net clinical
                      12.4%
  outcome
  Ischemic
                      6.5%
  events
  Major
                      9.0%
  bleeding


NI = non-inferiority; Sup = superiority
     Event Rates and Power Calculations
                   UFH/Enox +        Bivalirudin +
                    GP IIb/IIIa       GP IIb/IIIa
      Predicted       Rate        Rate      Power
  Endpoint                                NI    Sup
  Net clinical
                      12.4%       10.3% 99%     88%
  outcome
  Ischemic
                      6.5%        5.3%    99%   67%
  events
  Major
                      9.0%        7.5%    99%   73%
  bleeding


NI = non-inferiority; Sup = superiority
     Event Rates and Power Calculations
                   UFH/Enox +        Bivalirudin +       Bivalirudin
                    GP IIb/IIIa       GP IIb/IIIa          alone
      Predicted       Rate        Rate      Power     Rate     Power
  Endpoint                                NI    Sup           NI    Sup
  Net clinical
                      12.4%       10.3% 99%     88%   10.5%   99% 81%
  outcome
  Ischemic
                      6.5%        5.3%    99%   67%   6.5%    87%      -
  events
  Major
                      9.0%        7.5%    99%   73%   6.0%    99% 99%
  bleeding


NI = non-inferiority; Sup = superiority
               Study Organization
Principal Investigator   Gregg W. Stone
                          Columbia University, NYC, NY

Executive Committee      Michel Bertrand
                          Hosp. Cardiologique, Lambersart, France
                         A. Michael Lincoff
                          Cleveland Clinic, Cleveland, Ohio
                         Jeffrey W. Moses
                          Columbia University, NYC, NY
                         Magnus Ohman
                          Duke University, Durham, NC
                         Harvey D. White
                          Green Lane Hosp., Auckland, NZ
                Study Organization
                  Steering Committee
Frederick Feit (Chair)                Angel Cequier
    New York University                   Ciutat Sanitària Belvitge
    NYC, NY                               Barcelona, Spain
Antonio Columbo (EU Chair)            Walter Desmet
    Ospedael San Raphael                  University Hospital, Gasthuisberg
    Milano, Italy                         Leuven, Belgium
Ramin Ebrahimi                        Harold Darius
    VA Medical Ctr West Los Angeles       Krankenhaus Neukölln
    Los Angelas, CA                       Berlin, Germany
Lars Hvilsted Rasmussen               Martial Hamon
    Alborg Sygehus, Afdeling Syd          University Hospital
    Alborg, Denmark                       Caen Cedex, France
Hans-Jürgen Rupprecht                 James Hoekstra
    Gpr Klinikum Rüsselsheim              Wake Forest University
    Rüsselsheim, Germany                  Lewisville, NC
Phil Aylward                          Charles V. Pollack
    Flinders Medical Centre               Pennsylvania Hospital
    Bedford Park, Australia               Philadelphia, PA
               Study Organization
Statistical Committee       Stuart Pocock
                             London School of Hygiene and Tropical
                             Medicine, London, UK
                            Jim Ware
                             Harvard University, Boston, Mass.

Data Monitoring             The Medicines Company/Nycomed
Data Management             eTrials/The Medicines Company
Clinical Events Committee   Roxana Mehran, Director
                             Cardiovascular Research Foundation, NY

Angio. Core Laboratory      Alexandra Lansky, Director
                             Cardiovascular Research Foundation, NY

Health Economics and        David J. Cohen (Chair)
Cost-Effectiveness           Beth Israel Deaconess, Boston, Mass.
             Study Organization
Biomarker Substudy     George Dangas (Chair)
                         Columbia University, NYC, NY
                       W. Craig Hooper
                         CDC, Atlanta, GA
                       Steven R. Steinhubl
                         University of Kentucky, Lexington, KY
Data Safety and        Bernard J. Gersh (Chair)
Monitoring Committee     Mayo Clinic, Rochester, Minn
                       David Faxon
                         Brigham & Women’s Hosp., Boston, Mass.
                       Spencer King
                         Fuqua Heart Center, Atlanta, GA
                       Stuart Pocock
                         London, UK
                       Hartzell Schaff
                         Mayo Clinic, Rochester, Minn
                       David O. Williams
                        Rhode Island Hosp., Providence, RI
                ACUITY Enrollment
13,819 pts randomized at 448 centers in 17 countries
                          (4) Norway Sweden (6)
                     (5) Denmark
              (4) Netherlands           Finland (3)
    Canada (26) (5) Belgium            Poland (1)
                   (12) UK             Germany (66)
    USA (246)    (8) France          Austria (4)
                        (25) Spain Italy (15)




                                                        (4) New Zealand


                                                      (17) Australia
                       ACUITY Enrollment
 13,819 pts randomized at 448 centers in 17 countries
                              89 (0.6%) Norway Sweden 175 (1.3%)
                         150 (1.1%) Denmark
                  132 (1.0%) Netherlands           Finland 51 (0.4%)
 438 (3.2%) Canada 198 (1.4%) Belgium             Poland 14 (0.1%)
                         162 (1.2%) UK            Germany 2561 (18.5%)
7851 (56.8%) USA    155 (1.1%) France           Austria 356 (2.6%)
                           547 (4.0%) Spain   Italy 238 (1.7%)




                                                                 203 (1.5%)   New Zealand


                                                               499 (3.6%)   Australia
                            Top 20 Enrollers
B. McLaurin, MD                   R.H. Strasser, MD                S. Konstantinides, MD
  Anderson Area Medical             Technische Universitt            George-August-Universitt
  Center, Anderson, SC              Dresden, Dresden, Germany        Gttingen Goettingen,
D. Cox, MD                        T. Stuckey, MD                     Germany
  Mid Carolina Cardiology,          Lebauer CV Research            K. E. Hauptmann, MD
  Charlotte, NC                     Foundation, Greensboro, NC       Krankenhaus der
M. Zubair Jafar, MD               I. H. Lieber, MD                   Barmherzigen Bruder
  Hudson Valley Heart               North Houston Heart Center,      Medizinische Klinkill,
  Center, Poughkeepsie, NY          Kingwood, TX                     Trier, Germany
H. Chandna, MD                    R. Zelman, MD                    E. Mostel, MD
  Victoria Heart and Vascular       Cape Cod Research Institute,     Palm Beach Gardens
  Center, Victoria, TX              Hyannis, MA                      Medical Center/Palm
                                                                     Beach Cardiology,
F. Harmann, MD                    J. Neuzner, MD                     Palm Beach Gardens, FL
  Universittsklilnik Schleswig-     Klinikum Kassel GmbH,
  Holstein Campus Lbeck,            Kassel, GA                     A. Cequier, MD
  Lbeck, Germany                                                     Ciutat Santaria Bellvitge,
                                  K. Huber, MD                       Barcelona, Spain
F. Leisch, MD                       Welhelminespital der Stadt
  Allgemeines ffentl.               Wien, Vienna, Austria          M. Mockel, MD
  Krankenhaus der                                                    Charite Universitatsmedizin
                                  H. White, MD                       Berlin, Germany
  Landershauptstadt Linz,           Auckland City Hospital,
  Linz, Austria                     Auckland, New Zealand
M. Desaga, MD                     M. Buerke, MD
  Klinikum Dachu der                Klinikum der Martin-Luther-
  Landeshaupstadt Linz,             Universitt Halle-Wittenber,
  Linz, Germany                     Halle, Germany
                 Study Design – Patient Flow
       Moderate-high risk unstable angina or NSTEMI
             undergoing an invasive strategy

                                     UFH/Enox              GPI upstream (N=2294)
                                    + GP IIb/IIIa
                                      (N=4,603)            GPI CCL for PCI (N=2309)


          Moderate-                 Bivalirudin            GPI upstream (N=2311)
          high risk          R*     + GP IIb/IIIa
            ACS                       (N=4,604)            GPI CCL for PCI (N=2293)

          Aspirin in all            Bivalirudin
           Clopidogrel                Alone
        dosing and timing
                                      (N=4,612)
        per local practice


*Stratified by pre-angiography thienopyridine use or administration

								
To top