the coag trial: a randomized trial of a pharmacogenetic versus a clinical algorithm for warfarin...
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The COAG Trial:A Randomized Trial of a Pharmacogenetic
versus a Clinical Algorithm for Warfarin Dosing
The COAG Trial:A Randomized Trial of a Pharmacogenetic
versus a Clinical Algorithm for Warfarin Dosing
Stephen E. Kimmel, MD, MSCE on behalf of the COAG Investigators
American Heart AssociationNovember 19, 2013
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A G Clarification of Optimal Anticoagulation through Genetics
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OBackgroundBackground
¨ The need for clinical trials prior to widespread adoption of pharmacogenetic-based drug dosing and selection remains widely debated
¨ Warfarin• Model for pharmacogenetics• Hypothesis: Adding genetic to
clinical information will improve anticoagulation control
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OThe COAG Clinical TrialThe COAG Clinical Trial
A multicenter, double-blinded, stratified RCT of 1,015 participants, comparing two approaches:
1) initiation of warfarin therapy based on algorithms using only clinical
information (Clinical-guided dosing arm)
2) initiation of warfarin therapy based on algorithms using clinical
information and an individual’s genotype (PGx-guided dosing arm)
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OInclusion/ExclusionInclusion/Exclusion
¨ Inclusion/Exclusion Criteria included:• New warfarin starters• Any indication for warfarin• Expected duration of treatment ≥ 1 month• Target INR 2–3• If prior warfarin use, maintenance dose unknown• Genetic variants unknown• Clinician opinion that no contraindications to
using the dosing algorithms
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OIntervention Period (Days 1-5)Intervention Period (Days 1-5)
Consent Patient
Genotype-guided Dosing Arm
Clinical-guided Dosing Arm
Day
PGx-algorithm Based Dose w/o CYP2C9
Clinical-algorithm Based Dose
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Clinical Dose Revision Algorithm
Dose
Randomize
PGx Based Dose, incl CYP2C9
Clinical-algorithm Based Dose
Clinical-algorithm Based Dose
Clinical-algorithmBased Dose
Genetic Dose Revision Algorithm
Dose
PGx Based Dose,incl CYP2C9
Genetics Available for 1st Dose
Genetics Not Available for 1st Dose
Clinical Dose Revision Algorithm
Dose
Genetic Dose Revision Algorithm
Dose
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Am Heart J 2013;166:435-41
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OMethods – Key Design ElementsMethods – Key Design Elements
¨ Randomization stratified by site and race• African American vs non-African American
¨ Blinded to dose• To maintain blinding to study arm• Isolate effects of genotyping from other
post-randomization effects¨ Genotyped all participants at randomization
• To maintain blinding¨ Pre-specified Subgroups
• Race• Sex• Number of allelic variants
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OEndpointsEndpoints
¨ Primary Outcome• Percent time in therapeutic INR range (PTTR)
at 28 days• Co-primary analyses of PTTR
– In entire study population– In those with ≥1.0 mg/day absolute difference in
initiation dose by the 2 algorithms
¨ Principal secondary outcome• INR ≥4 or serious clinical event (TE/Bleed)
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Trials 2010;11:108.Clinical Trials 2010;7:597-604
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OSample Size and PowerSample Size and Power
¨ Target sample size 1,022 to ensure >80% power
– 5.5% absolute difference in PTTR with a type-1 error rate of 0.04 among all participants
– 9% difference among the co-primary subgroup with a type-1 error rate of 0.01
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OStudy FlowStudy Flow
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1015 randomized*
514 assignedgenotype-guided
501 assignedclinically guided
Included in analysis- Primary: 484 **- Safety: 514
29 withdrew - 1 SAE - 13 provider discretion - 15 patient decision 1 lost to follow-up
29 withdrew - 2 SAE - 13 provider discretion - 14 patient decision1 became ineligible
First patient enrolled: September 2009Last patient enrolled: April 2013All follow-up completed: July 2013
Included in analysis- Primary: 471 **- Safety: 501
* Stratified by race and center** INRs available on or after day 4/5
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ODemographicsDemographics
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† = Variable used in pharmacogenetic and/or clinical dose-initiation and/or dose-revision algorithm)
PGx-Guided(n=514)
Clinical-guided(n=501)
Age, years, median† 59 57
Female (%) 47 51
African American (%)† 27 27
Diabetes (%)† 23 24
Current smoker (%)† 15 14
Stroke (%)† 7 6
BSA, m2, median † 2.01 2.03
Amiodarone use (%) † 3 2
Fluvastatin use (%) † <1 <1
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OWarfarin Initiation and IndicationWarfarin Initiation and Indication
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PGx-guided(n=514)
Clinical-guided(n=501)
Inpatient initiation (%) 68 66
Indication for warfarin therapy (%)
DVT or PE only† 56 60
Atrial fibrillation/flutter only 23 21
Other indication only 11 11
Multiple indications 10 8
No indication given 1 1
† = Variable in used in pharmacogenetic and/or clinical dose-initiation and/or dose-revision algorithm)
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OGenotypeGenotype
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Genetic variantsPGx-Guided
(n=514)Clinical-guided
(n=501)CYP2C9*2 (%)† No variants 81 84Heterozygous 18 14Homozygous 1 1
CYP2C9*3 (%)† No variants 92 90Heterozygous 7 10Homozygous <1 0
VKORC1 (%)† No variants (GG) 49 47
Heterozygous (AG or GA) 39 40Homozygous (AA) 11 12
Withdrew prior to genotyping: 1% PGx and <1% Clinical
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OMaintenance Dose PredictionMaintenance Dose Prediction
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Pharmacogenetic-guided
Clinical-guided
Dose-initiation algorithm R2 0.48 0.27
Dose-revisionalgorithm R2 0.69 0.54
• PGx demonstrated better maintenance dose prediction the clinical algorithm
• Dose prediction as expected based on prior studies
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OPrimary Outcome - PTTR at 4 WeeksPrimary Outcome - PTTR at 4 Weeks
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Genotype-
guided dosingClinical-guided
dosingMean difference
(95% CI) * P-value Mean (SD) Mean (SD)
PTTR All participants (n=955) 45.2 (26.6) 45.4 (25.8) -0.18 (-3.4, 3.1) 0.91
Algorithms’ Difference 0.63**≥ 1mg/d (n=392) 45.1 (25.5) 46.5 (27.1) -1.1 (-6.2, 4.0) 0.67< 1 mg/d (n=563) 45.2 (27.4) 44.7 (24.8) 0.52 (-3.7, 4.8) 0.81
* Mean difference in PTTR between genotype-guided and clinical-guided dosing groups, estimated from multivariable linear regression models that adjusted for race and clinical center
**Interaction P value to evaluate equality of mean difference between subgroups
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OPre-Specified Subgroups: PTTR 4 Weeks Pre-Specified Subgroups: PTTR 4 Weeks
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Genotype-guided dosing
Clinical-guided dosing
Mean difference (95% CI) P-value
Race 0.003 *AA(n=255) 35.2 (26.0) 43.5 (26.5) -8.3 (-15, -2.0) 0.010Non AA(n=700) 48.8 (25.9) 46.1 (25.5) 2.8 (-1.0, 6.6) 0.15
Sex 0.71 *Male(486) 44.9 (26.9) 45.5 (25.4) 0.44 (-4.2, 5.1) 0.85Female(n=469) 45.4 (26.3) 45.3 (26.2) -0.81 (-5.5, 3.9) 0.73
Total # variants 0.21 *1 variant (n=343) 48.1 (26.5) 45.0 (23.7) 2.6 (-2.9, 8.1) 0.350 or >1 variant (n=612) 43.6 (26.5) 45.7 (27.0) -1.7 (-5.8, 2.4) 0.41
* Interaction P value to evaluate equality of mean difference between subgroups
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OPre-Specified Subgroups Primary OutcomePre-Specified Subgroups Primary Outcome
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OINR Over Time, By RaceINR Over Time, By Race
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OTime to 1st Therapeutic INRTime to 1st Therapeutic INR
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OAdverse Events at 4 WeeksAdverse Events at 4 Weeks
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Outcome
PGx-Guided (n=514)
Clinical-guided (n=501)
Hazard ratio (95% CI) P-value
n (%) n (%)
Any INR≥4, major bleeding, or TE* 105 (20) 103 (21) 1.0 (0.77, 1.3) 0.93
Any INR≥4 100 (19) 92 (18) 1.1 (0.81, 1.4) 0.59
Major bleeding 4 (1) 10 (2) 0.41 (0.13, 1.3) 0.13
Thromboembolism 5 (1) 4 (1) 1.3 (0.34, 4.7) 0.72
Clinically relevant non-major bleed 13 (3) 20 (4) 0.62 (0.30, 1.3)** 0.18
All-cause death 2 (<1) 1 (<1) 2.1 (0.19, 23) 0.55
* Principal secondary outcome** Odds ratio
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OConclusionsConclusions
¨ COAG trial does not support the hypothesis that adding genetic information to determine dosing for the first five days of warfarin therapy improves anticoagulation control compared to initiating warfarin using only clinical information
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OConclusionsConclusions
¨ No effect of pharmacogenetic-based dosing in those expected to have benefit based on predicted dose differences
¨ Effects varied by race• Clinical-based dosing may be better than PGx-
based dosing in African Americans
¨ COAG highlights the importance of performing randomized trials for pharmacogenetics, particularly for complex medicine regimens such as warfarin
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OCOAG Clinical CentersCOAG Clinical Centers
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OCOAG PIs and SitesCOAG PIs and Sites
Principal Investigator: Site:
Thomas L. Ortel, MD, PhD Duke University Medical Center
Jaspal Gujral, MBBS,FACP,FRCP Georgia Regents Medical Center
Vinay Shah, MD Henry Ford Hospital
Emile R. Mohler III, MD Hospital of the University of Pennsylvania
Scott M. Stevens, MD Intermountain Medical Center
Steven Yale, MD, FACP Marshfield Clinic Research Foundation
Robert D. McBane, MD Mayo Clinic College of Medicine
Henny H. Billett MD, MSc Montefiore Medical Center
Robert J. Desnick, MD, PhD Mount Sinai School of Medicine
Patrice Delafontaine, MD Tulane University
Nita A. Limdi, PharmD, PhD, MSPH University of Alabama at Birmingham23
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OCOAG PIs and SitesCOAG PIs and Sites
Principal Investigator: Site:
Margaret C. Fang, MD, MPH University of California, San Francisco
Julie A. Johnson, PharmD University of Florida
Richard B. Horenstein, MD University of Maryland School of Medicine
Sherif Z. Abdel-Rahman, PhDUniversity of Texas Medical Branch at Galveston
Robert C. Pendleton, MD University of Utah Health Care
James A. S. Muldowney III, MD, FAAC Vanderbilt University
Brian F. Gage, MD, MSc Washington University School of Medicine
Director: Central Lab:
Charles S. Eby, MD, PhD Washington University School of Medicine
Director: Investigational Drug Service:
Kenneth Rockwell, Pharm D University of Pennsylvania
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OAcknowledgmentsAcknowledgments
¨ Funded by the NHLBI¨ Additional support
• Bristol-Meyers Squibb• GenMark Diagnostics • AutoGenomics Inc.
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