1. Effect of Genotyping Warfarin Patients on Outcomes: Results from The National Community-based Medco-Mayo Warfarin Effectiveness Study (MM-WES) Robert S Epstein MD MS, Thomas P. Moyer PhD, Ronald E. Aubert PhD, Dennis J. O’Kane PhD, Fang Xia PhD, Robert R. Verbrugge PhD, Brian F. Gage MD MS, J. Russell Teagarden DMH, RPh Medco Health Solutions, Franklin Lakes, NJ; Mayo Clinic, Rochester, MN; Washington University, St Louis MO Funding sources: Medco Health Solutions, Mayo Clinic Center for Individualized Therapy Manuscript is “in press” in Journal of American College of Cardiology

3. Study question: Does use of CYP2C9/VKORC1 testing reduce the risk of hospitalization during the first 6 months of warfarin treatment?

4. Study design: Comparative effectiveness 6 month follow-up on all patients initiating warfarin in all groups 23 benefit plan sponsors Primary comparison Comparison of general trends in practice July 2006 – June 2007 n=2688 Historical control July 2007 – February 2009 n=896 Intervention group 56 benefit plan sponsors July 2006 – June 2007 n=2688 External historical control July 2007 – February 2009 n=2688 External concurrent control Medco-Mayo Warfarin Effectiveness Study

6. Flow of the genotyping arm Mayo completed lab test – supplied report to physician and results to Medco Medco identified ‘new starts’ to warfarin on any given day of the week Medco contacted ‘new starts’ to solicit verbal informed consent Medco contacted physician for clinical information and consent for patient to receive genotype test First half of enrollment – Medco arranged for home blood draw – received written informed consent, sent blood to Mayo

8. Participants were from 49 US states

9. Results: Baseline characteristics P-value Intervention group (n= 896) Historical control (n=2688) Characteristic 0.469 24.8% 23.6% Bleeding or thromboembolism 0.405 52.8% 54.4% Any cause Prior hospitalizations (%) 0.007 11.6% 15.3% Diabetes <0.001 54.2% 47.0% Hypertension 0.489 25.8% 24.6% Deep vein thrombosis 0.501 11.8% 11.0% Pulmonary embolism 0.709 41.1% 40.4% Atrial fibrillation 0.539 4.0% 3.6% GI bleed Conditions (%) 0.354 13.6% 12.4% Steroids 0.574 10.2% 10.8% Clopidogrel 0.865 19.9% 19.6% NSAID 0.803 2.6% 2.4% Fluconazole 0.268 5.2% 4.4% Sulfamethoxazole 0.071 16.9% 14.5% Statins 0.313 3.2% 4.0% Amiodarone Medications (%) 1.000 60.5% 60.5% Male(%) 0.921 65.2 (8.3) 65.2 (8.0) Mean age, yrs (SD)

10. Results: (n=424) Warfarin Rxs within 21 days post-genotyping <0.01 -17.33 mg (4.54) 2.4% Very high 0.04 -10.14 mg (3.18) 4.0% High <0.01 -3.65 mg (1.56) 25.0% Moderate 0.21 +3.21 mg (3.41) 11.6% Mild 0.50 +1.10 mg (1.40) 28.1% Normal <0.01 +6.65 mg (1.98) 29.0% < Normal P-value Mean weekly dose change (SE) % patients Warfarin sensitivity

11. Results: Six month hospitalization rates >=1 hospitalization per 100 patients/6months Genotyping associated with 28% decrease in all-cause hospitalizations and 27% decrease in bleed or thrombo-emboli All cause Bleed or thromboembolism p-value <0.001 0.039 Intention to treat (ITT) Intervention group (n=896) Historical control (n=2688)

12. Results: All-cause hospitalization rate Intention-to-treat analyses All cause HR: 0.69 (CI: 0.58, 0.82) P<0.001 Controlled for age, comorbid conditions, drugs, propensity score, indications, prior GI bleed or VTE, history of prior hospitalization

13. Results: Hospitalization rate for bleed / thrombo-embolism. Intention-to-treat analysis. Bleed or thromboembolism HR: 0.72 (CI: 0.53, 0.97) P=0.029 Controlled for age, comorbid conditions, drugs, propensity score, indications, prior GI bleed or VTE, history of prior hospitalization