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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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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