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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OBackground

¨ 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 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/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)

Consent Patient

Genotype-guided Dosing Arm

Clinical-guided Dosing Arm

Day

PGx-algorithm Based Dose w/o CYP2C9

Clinical-algorithm Based Dose

1

2

3

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 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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OEndpoints

¨ 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 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 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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ODemographics

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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 57Female (%) 47 51African American (%)† 27 27Diabetes (%)† 23 24Current smoker (%)† 15 14Stroke (%)† 7 6BSA, m2, median † 2.01 2.03Amiodarone use (%) † 3 2Fluvastatin use (%) † <1 <1

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OWarfarin Initiation and Indication

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PGx-guided(n=514)

Clinical-guided(n=501)

Inpatient initiation (%) 68 66Indication for warfarin therapy (%)    DVT or PE only† 56 60Atrial fibrillation/flutter only 23 21Other indication only 11 11Multiple indications 10 8No indication given 1 1

† = Variable in used in pharmacogenetic and/or clinical dose-initiation and/or dose-revision algorithm)

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OGenotype

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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 47Heterozygous (AG or GA) 39 40Homozygous (AA) 11 12

Withdrew prior to genotyping: 1% PGx and <1% Clinical

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OMaintenance Dose Prediction

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  Pharmacogenetic-guided

Clinical-guided

 

Dose-initiation algorithm R2 0.48 0.27Dose-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 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

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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 Outcome

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OINR Over Time, By Race

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OTime to 1st Therapeutic INR

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OAdverse 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) 0.93Any INR≥4 100 (19) 92 (18) 1.1 (0.81, 1.4) 0.59Major bleeding 4 (1) 10 (2) 0.41 (0.13, 1.3) 0.13Thromboembolism 5 (1) 4 (1) 1.3 (0.34, 4.7) 0.72Clinically relevant non-major bleed 13 (3) 20 (4) 0.62 (0.30, 1.3)** 0.18All-cause death 2 (<1) 1 (<1) 2.1 (0.19, 23) 0.55* Principal secondary outcome** Odds ratio

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OConclusions

¨ 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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OConclusions

¨ 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 Centers

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OCOAG PIs and Sites

Principal Investigator: Site:

Thomas L. Ortel, MD, PhD Duke University Medical CenterJaspal Gujral, MBBS,FACP,FRCP Georgia Regents Medical CenterVinay Shah, MD Henry Ford HospitalEmile R. Mohler III, MD Hospital of the University of PennsylvaniaScott M. Stevens, MD Intermountain Medical CenterSteven Yale, MD, FACP Marshfield Clinic Research FoundationRobert D. McBane, MD Mayo Clinic College of MedicineHenny H. Billett MD, MSc Montefiore Medical CenterRobert J. Desnick, MD, PhD Mount Sinai School of MedicinePatrice Delafontaine, MD Tulane UniversityNita A. Limdi, PharmD, PhD, MSPH University of Alabama at Birmingham

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OCOAG PIs and Sites

Principal Investigator: Site:

Margaret C. Fang, MD, MPH University of California, San FranciscoJulie A. Johnson, PharmD University of FloridaRichard 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 CareJames A. S. Muldowney III, MD, FAAC Vanderbilt UniversityBrian F. Gage, MD, MSc Washington University School of MedicineDirector: Central Lab:Charles S. Eby, MD, PhD Washington University School of MedicineDirector: Investigational Drug Service:Kenneth Rockwell, Pharm D University of Pennsylvania

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OAcknowledgments

¨ Funded by the NHLBI¨ Additional support

• Bristol-Meyers Squibb• GenMark Diagnostics • AutoGenomics Inc.

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