Transcript Slides - Clinical Trial Results

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
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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, ScheringPlough, 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, BristolMyers 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
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Patients with acute coronary syndromes (ACS) and
reduced renal function are at increased risks of both
ischemic and bleeding complications
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Platelet function and coagulation abnormalities
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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
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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
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Patients with a serum creatinine >2 mg/dl were excluded
Dosing recommendations were determined from small
clinical studies and pharmacokinetic modeling
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A reduction in dose by one half (to 1 μg/kg/min) in patients
with an eCrCl <50 ml/min
Objectives
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Using data from The Early GP IIb/IIIa Inhibition in Non–STsegment Elevation ACS (EARLY ACS) trial we aimed to:
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Describe the frequency of eptifibatide dose reduction in
patients with eCrCl <50 ml/min
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Explore the unadjusted and adjusted relationships
among treatment assignment, initial infusion dosing, risk
of bleeding and ischemic complications among high-risk
NSTE ACS patients
Methods
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
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Efficacy and Safety Endpoints
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Primary ischemic composite at 96 hours
 Death from any cause
 Myocardial infarction (MI)
 Recurrent ischemia requiring urgent revascularization (RIUR)
 Thrombotic bailout (TBO)
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Secondary ischemic composite at 30 days
 All-cause death or MI
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Safety Endpoints
 Non–coronary artery bypass graft (CABG)-related TIMI major
bleeding and GUSTO moderate/severe bleeding
 Non–CABG-related transfusion
Statistical Analysis
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Baseline characteristics, concomitant medications, and
index procedures were summarized by eCrCl (<50 ml/min
or ≥50 ml/min) and dosing group
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Rates of the efficacy and bleeding end points were
examined within eCrCl groups according to randomized
treatment
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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
Baseline Characteristics by CrCl and Dose of Study Drug
CrCl <50 ml/min
(n=1730)
CrCl ≥50 ml/min
(n=7257)
Excess dose
(n=594)
Adjusted dose
(n=1136)
Standard dose
(n=7257)
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
21.0
53.2
9.4
16.3
35.6
30.5
9.2
24.6
29.9
41.0
11.5
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
43.9
(37.3, 47.3)
38.8
(31.7, 44.9)
81.4
(66.3, 101.7)
8.6
48.1
43.3
7.9
42.8
49.3
18.4
48.2
32.4
Baseline characteristics (%)
Median age, yrs*
Baseline CrCl (ml/min)*
TIMI risk categories
0-2
3-4
>4
In-hospital Treatment 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)
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)
4.5
33.7
55.1
6.7
7.2
39.3
48.0
5.5
5.4
33.7
53.7
7.2
97/213
(45.5%)
146/516
(28.3%)
760/2752
(27.6%)
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 (%)
Any initial UFH infusion^ (n=3481)
Excess initial infusion dose
Any enoxaparin ^ (n= 5863)
Excess dose
Ischemic and Bleeding Event Rates by eCrCl Category and
Treatment Assignment
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%)
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%)
Non-CABG bleeding
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
Limitations
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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
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Subject to confounders for which multivariable adjustment
may not have accounted
Conclusions
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Initial infusion of eptifibatide was incorrectly dosed in
1/3 of NSTE ACS patients with eCrCl <50 ml/min
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In patients with reduced renal function eptifibatide
dose adjustment did not result in lower bleeding risk
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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