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

Reduced Renal Function

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.

Disclosures Disclosures 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 http://www.dcri.duke.edu/research/coi.jsp.

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 projects.

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 http://www.dcri.duke.edu/research/coi.jsp.

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 www.dcri.duke.edu/research/coi.jsp.

Background Background

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)

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)

Background Background

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

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

Objectives Objectives

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

MethodsMethods

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 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

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 AnalysisStatistical 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 treatment

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 comparisons

CrCl <50 ml/min (n=1730)

CrCl ≥50 ml/min(n=7257)

Excess dose

(n=594)

Adjusted dose

(n=1136)

Standard dose

(n=7257)

Baseline characteristics (%)

Median age, yrs* 77.5(72.0, 81.7)

78.0(72.0, 82.5)

65.1(58.4, 71.9)

Female sex 56.4 46.3 27.1

Region of enrollment North America Western Europe Eastern Europe Middle East, Africa, Asia

21.053.29.4

16.3

35.630.59.2

24.6

29.941.011.517.5

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(37.3, 47.3)

38.8(31.7, 44.9)

81.4(66.3, 101.7)

TIMI risk categories 0-2 3-4 >4

8.648.143.3

7.942.849.3

18.448.232.4

Baseline Characteristics by CrCl and Dose of Study Drug

CrCl <50 ml/min CrCl ≥50 ml/min

Excess dose

(n=594)

Adjusted dose

(n=1136)

Standard dose

(n=7257)

In-hospital treatment (%)

Aspirin 97.0 96.5 97.6

UFH or Enoxaparin None (n=498) UFH only (n=3093) Enoxaparin only (n=4767) Both UFH/enoxaparin (n=629)

4.533.755.16.7

7.239.348.05.5

5.433.753.77.2

Any initial UFH infusion^ (n=3481)

Excess initial infusion dose 97/213(45.5%)

146/516(28.3%)

760/2752(27.6%)

Any enoxaparin ^ (n= 5863)

Excess dose

72/425

(16.9%)

115/684

(16.8%)

515/4754

(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

In-hospital Treatment by CrCl and Dose of Study Drug

CrCl <50 ml/min CrCl ≥50 ml/min

Early

eptifibatide

Delayed

eptifibatide

Early

eptifibatide

Delayed

eptifibatide

Death/MI/RIUR/TBO

within 96 hrs

106/867

(12.2%)

101/863

(11.7%)

313/3640

(8.6%)

351/3617

(9.7%)

Death or MI at 30 days 132/867

(15.2%)

132/863

(15.3%)

367/3640

(10.1%)

420/3617

(11.6%)

Non-CABG bleeding

GUSTO moderate/severe 82/842

(9.7%)

55/846

(6.5%)

144/3591

(4.0%)

64/3580

(1.8%)

TIMI major 21/852

(2.5%)

7/850

(0.8%)

48/3598

(1.3%)

29/3584

(0.8%)

Transfusion 92/867

(10.6%)

71/863

(8.2%)

123/3640

(3.4%)

71/3617

(2.0%)

Ischemic and Bleeding Event Rates by eCrCl Category and Treatment Assignment

Adjusted ORs for the Efficacy End Point Comparisons According to Renal Function and Dosing Categories

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

Adjusted ORs for non-CABG TIMI major, GUSTO moderate/severe Bleeding According to CrCl and Dosing Categories

Limitations Limitations

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

ConclusionsConclusions

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