Stephen E. Kimmel, MD, MSCE on behalf of the COAG Investigators American Heart Association

1. C O Clarification of Optimal Anticoagulation through Genetics A G 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 Association November 19, 2013

2. Background • 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

3. The 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)

4. Inclusion/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 Am Heart J 2013;166:435-41

5. Intervention Period (Days 1-5) Dose Initiation Gage et al., CPT 2008 Dose Revision Lenzini et al., CPT 2010 Am Heart J 2013;166:435-41

6. Methods – 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 Am Heart J 2013;166:435-41

7. Endpoints Trials 2010;11:108. Clinical Trials 2010;7:597-604 • 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)

8. Sample 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 Am Heart J 2013;166:435-41

9. Study Flow 1015 randomized* 501 assigned clinically guided 514 assignedgenotype-guided 29 withdrew - 2 SAE - 13 provider discretion - 14 patient decision 1 became ineligible 29 withdrew - 1 SAE - 13 provider discretion - 15 patient decision 1 lost to follow-up Included in analysis - Primary: 471 ** - Safety: 501 Included in analysis - Primary: 484 ** - Safety: 514 First patient enrolled: September 2009 Last patient enrolled: April 2013 All follow-up completed: July 2013 * Stratified by race and center ** INRs available on or after day 4/5

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

11. Warfarin Initiation and Indication † = Variable in used in pharmacogenetic and/or clinical dose-initiation and/or dose-revision algorithm)

12. Genotype Withdrew prior to genotyping: 1% PGx and <1% Clinical

13. Maintenance Dose Prediction • PGx demonstrated better maintenance dose prediction the clinical algorithm • Dose prediction as expected based on prior studies

14. Primary Outcome - PTTR at 4 Weeks • 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

15. Pre-Specified Subgroups: PTTR 4 Weeks * Interaction P value to evaluate equality of mean difference between subgroups

16. Pre-Specified Subgroups Primary Outcome

17. INR Over Time, By Race

18. Time to 1st Therapeutic INR

19. Adverse Events at 4 Weeks * Principal secondary outcome ** Odds ratio

20. Conclusions 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

21. Conclusions • 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

22. COAG Clinical Centers

23. COAG PIs and Sites

24. COAG PIs and Sites

25. Acknowledgments • Funded by the NHLBI • Additional support • Bristol-Meyers Squibb • GenMark Diagnostics • AutoGenomicsInc.