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EARLY ACS dosing.03.12.10ppt


									Safety and Efficacy of Adjusted-Dose Eptifibatide
in Patients With Acute Coronary Syndromes and
            Reduced Renal Function

         Chiara Melloni, Stefan K. James, Jennifer A. White,
        Robert P. Giugliano, Robert A. Harrington, Kurt Huber,
       Paul W. Armstrong, Robert M. Califf, Frans Van de Werf,
                 Gilles Montalescot, L. Kristin Newby

From the Division of Cardiology and Duke Clinical Research Institute, Duke University Medical Center (C.M., J.A.W.,
R.A.H., P.T., L.K.N.), Durham, NC; Uppsala University Hospital (S.K.J), Uppsala, Sweden; TIMI Study Group, Brigham
and Women’s Hospital (R.P.G.), Boston, MA; Department of Medicine (Cardiology and Emergency Medicine),
Wilhelminenspital (K.H.), Vienna, Austria; University of Alberta (P.W.A.), Edmonton, Alberta, Canada; University
Hospital Gasthuisberg and Leuven Coordinating Center (F.V.W.), Leuven, Belgium; Institut de Cardiologie, Pitié–
Salpêtrière Hospital (G.M.), Paris, France; Duke Translational Medicine Institute, Duke University Medical Center
(R.M.C.), Durham, NC.
   Chiara Melloni: None.
   Stefan K. James: Research grants and speaker fees received from Astra Zeneca, Sanofi Aventis, BMS, Eli
    Lilly, and Schering Plough.
   Jennifer A. White: None.
   Robert P. Giugliano: Research grant support, advisory board, and honoraria for lectures, Schering-
    Plough, Inc., and Merck & Co., Inc.
   Robert A. Harrington: Research funding and consulting with Schering-Plough, now Merck. A complete
    listing of Dr. Harrington’s relationships with industry is available at
   Kurt Huber: Research grants from Bristol-Myers Squibb, Eli Lilly, Medtronic, Sanofi-Aventis; consulting
    fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Fibrex, Eli Lilly,
    Portola, Sanofi-Aventis, Schering-Plough, The Medicines Company, and Schering Plough; lecture fees from
    AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cordis / Johnson&Johnson,
    Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Aventis.
   Pierluigi Tricoci: Research grant and advisory board, Merck & Co., Inc.
   Paul W. Armstrong: Consulting or other services that generate personal income from sanofi-aventis,
    Bristol-Myers Squibb Canada, Merck Frosst Canada Ltd, Abbott Laboratories, GlaxoSmithKline, Bristol-
    Myers Squibb/Pfizer, Regado Biosciences, and F. Hoffmann-La Roche Ltd; research grant or contract from
    Boehringer Ingelheim (Canada) Ltd, sanofi-aventis Canada, Eli Lilly, Schering-Plough Research Institute,
    Scios Inc/Ortho-Biotech, GlaxoSmithKline, Portola Pharmaceutical Inc, Uppsala Clinical Research Center
    and AstraZeneca, and Merck & Company Inc., that partially supports his university salary and/or research
   Frans Van de Werf: Research grants from Schering-Plough (now Merck) and Roche; advisory board and
    speakers fee from Schering-Plough, Merck, and Roche.
   Gilles Montalescot: Research support from Schering-Plough, Inc., and Merck & Co., Inc.
   Robert M. Califf: Research funding and consulting with Schering-Plough, now Merck (all consulting funds
    donated to not for profits). A complete listing of Dr. Califf’s relationships with industry is available at
   L. Kristin Newby: Research grant from Schering Plough and Merck & Co., Inc. through the DCRI;
    consulting honoraria from Schering-Plough. A complete listing of Dr. Newby’s relationships with industry is
    available at

   Patients with acute coronary syndromes (ACS) and
    reduced renal function are at increased risks of both
    ischemic and bleeding complications
       Platelet function and coagulation abnormalities
       Improper dose adjustment of antithrombotic therapy
   Dosing strategies based on estimated renal function have
    been developed for renally eliminated antithrombotic
    agents to minimize bleeding risk while preserving
    therapeutic benefits
   Cockcroft-Gault (CG) is the recommended formula for
    estimation of creatinine clearance (eCrCl)

   Efficacy and safety of eptifibatide, a GP IIb/IIIa inhibitor,
    dosed at an infusion of 2 μg/kg/min in the setting of non–
    ST-segment elevation (NSTE) ACS were demonstrated in
    the PURSUIT trial
       Patients with a serum creatinine >2 mg/dl were excluded
   Dosing recommendations were determined from small
    clinical studies and pharmacokinetic modeling
       A reduction in dose by one half (to 1 μg/kg/min) in patients
        with an eCrCl <50 ml/min

   Using data from The Early GP IIb/IIIa Inhibition in Non–ST-
    segment Elevation ACS (EARLY ACS) trial we aimed to:
       Describe the frequency of eptifibatide dose reduction in
        patients with eCrCl <50 ml/min
       Explore the unadjusted and adjusted relationships
        among treatment assignment, initial infusion dosing, risk
        of bleeding and ischemic complications among high-risk
        NSTE ACS patients

  Study Population
8987 EARLY ACS patients with eCrCl data and study drug
   infusion rates were categorized as
Standard dose      2 μg/kg/min when eCrCl ≥50ml/min
Adjusted dose      1 μg/kg/min when eCrCl <50 ml/min
Excess dose        2 μg/kg/min when eCrCl <50 ml/min
            Efficacy and Safety Endpoints
   Primary ischemic composite at 96 hours
      Death from any cause
      Myocardial infarction (MI)
      Recurrent ischemia requiring urgent revascularization (RIUR)
      Thrombotic bailout (TBO)

   Secondary ischemic composite at 30 days
      All-cause death or MI

   Safety Endpoints
     Non–coronary artery bypass graft (CABG)-related TIMI major
      bleeding and GUSTO moderate/severe bleeding
     Non–CABG-related transfusion
                   Statistical Analysis
   Baseline characteristics, concomitant medications, and
    index procedures were summarized by eCrCl (<50 ml/min
    or ≥50 ml/min) and dosing group

   Rates of the efficacy and bleeding end points were
    examined within eCrCl groups according to randomized

   Odds ratios (OR) with 95% confidence intervals (CI) were
    generated for efficacy and bleeding comparisons by
    treatment for each dosing category
      Covariates, excluding eCrCl, from logistic regression
       models for major efficacy and safety outcomes in the
       EARLY ACS population used to adjust for differences
       in baseline characteristics within treatment
Baseline Characteristics by CrCl and Dose of Study Drug
                                          CrCl <50 ml/min           CrCl ≥50 ml/min
                                             (n=1730)                  (n=7257)
                               Excess dose         Adjusted dose    Standard dose
                                 (n=594)              (n=1136)         (n=7257)
Baseline characteristics (%)
Median age, yrs*                   77.5                 78.0             65.1
                                (72.0, 81.7)         (72.0, 82.5)     (58.4, 71.9)
Female sex                         56.4                 46.3              27.1
Region of enrollment
  North America                    21.0                 35.6              29.9
  Western Europe                   53.2                 30.5              41.0
  Eastern Europe                    9.4                  9.2              11.5
  Middle East, Africa, Asia        16.3                 24.6              17.5

Diabetes                           32.7                 40.8              28.4
Dyslipidemia                       58.8                 59.1              57.2
Hypertension                       79.6                 82.7              68.6
Prior CABG                         14.0                 19.6              12.5
Prior MI                           30.0                 35.7              26.0
Prior PCI                          28.3                 28.2              23.6
Baseline CrCl (ml/min)*            43.9                 38.8              81.4
                                (37.3, 47.3)         (31.7, 44.9)     (66.3, 101.7)
TIMI risk categories
   0-2                              8.6                  7.9              18.4
   3-4                             48.1                 42.8              48.2
   >4                              43.3                 49.3              32.4
      In-hospital Treatment by CrCl and Dose of Study Drug
                                                 CrCl <50 ml/min          CrCl ≥50 ml/min

                                     Excess dose          Adjusted dose   Standard dose
                                       (n=594)               (n=1136)        (n=7257)
In-hospital treatment (%)
Aspirin                                 97.0                   96.5            97.6

UFH or Enoxaparin
  None (n=498)                           4.5                    7.2             5.4
  UFH only (n=3093)                     33.7                   39.3            33.7
  Enoxaparin only (n=4767)              55.1                   48.0            53.7
  Both UFH/enoxaparin (n=629)            6.7                    5.5             7.2
Any initial UFH infusion^ (n=3481)
  Excess initial infusion dose          97/213               146/516         760/2752
                                       (45.5%)               (28.3%)          (27.6%)

Any enoxaparin ^ (n= 5863)              72/425                115/684        515/4754
  Excess dose                          (16.9%)                (16.8%)         (10.8%)
Clopidogrel                             90.9                   88.3            91.0
Beta-blocker                            85.5                   86.4            88.3
Statin                                  81.5                   84.8            87.4
ACE-I                                   67.5                   64.1            69.5
ARB                                     12.3                   12.1             9.2
PCI                                     54.5                   51.6            60.9
CABG                                     9.4                   12.3            13.4

Medical management only                 36.5                   36.6            26.1
     Ischemic and Bleeding Event Rates by eCrCl Category and
                      Treatment Assignment

                              CrCl <50 ml/min                CrCl ≥50 ml/min
                             Early        Delayed          Early        Delayed
                          eptifibatide   eptifibatide   eptifibatide   eptifibatide
Death/MI/RIUR/TBO           106/867        101/863       313/3640       351/3617
within 96 hrs               (12.2%)        (11.7%)        (8.6%)         (9.7%)

Death or MI at 30 days      132/867        132/863       367/3640       420/3617
                            (15.2%)        (15.3%)        (10.1%)        (11.6%)

Non-CABG bleeding
  GUSTO moderate/severe     82/842         55/846        144/3591        64/3580
                            (9.7%)         (6.5%)         (4.0%)          (1.8%)
  TIMI major                21/852           7/850        48/3598        29/3584
                            (2.5%)          (0.8%)         (1.3%)         (0.8%)

  Transfusion                92/867        71/863        123/3640        71/3617
                            (10.6%)        (8.2%)         (3.4%)          (2.0%)
Adjusted ORs for the Efficacy End Point Comparisons
 According to Renal Function and Dosing Categories
Adjusted ORs for non-CABG TIMI major, GUSTO moderate/severe
       Bleeding According to CrCl and Dosing Categories

   Bolus doses were not considered in the dosing categories
   Possible subsequent infusion dose adjustments due to
    correctly recognized errors in dosing or to changes in CrCl
    or bleeding events were not taken into account
   Secondary, non-randomized comparison of the effect of
    treatment according to dose
       Subject to confounders for which multivariable adjustment
        may not have accounted
   Initial infusion of eptifibatide was incorrectly dosed in
    1/3 of NSTE ACS patients with eCrCl <50 ml/min

   In patients with reduced renal function eptifibatide
    dose adjustment did not result in lower bleeding risk

   Because of lack of efficacy and failure to reduce
    bleeding complications, our data do not support
    routine early eptifibatide administration among NSTE
    ACS patients with reduced renal function

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