Medco is a registered trademark of Medco Health Solutions, Inc. 2010 Medco Health Solutions, Inc. All rights reserved. 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. OKane 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 Manuscript is in press in Journal of American College of Cardiology 2010 Medco Health Solutions, Inc. All rights reserved. 2 Disclosures for Robert Epstein MD Financial disclosures: None Honoraria: None Support: Medco and Mayo Clinic Center for Individualized Therapy 2010 Medco Health Solutions, Inc. All rights reserved. 3 Background Warfarin exhibits large inter-individual dosing requirements Warfarin is a leading cause of morbidity and mortality Two genes account for ~33% of variance in dosing Cytochrome P450 2C9 (CYP2C9) pharmacokinetics VKORC1 pharmacodynamics Meta-analysis of 3 clinical trials of warfarin genotyping showed a 32% decrease in major bleeding (RR 0.68, CI )* *Eckman MH, Rosand J, Geenberg SM, Gage BF: Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Int Med 2009;150(2):73-83. 2010 Medco Health Solutions, Inc. All rights reserved. 4 Study hypothesis & design: Hypothesis: The use of CYP2C9/VKORC1 testing will reduce the risk of hospitalization during the first 6 months of warfarin treatment Design: Prospective observational cohort study with national community based sampling (quasi-experimental) 2010 Medco Health Solutions, Inc. All rights reserved. 5 Inclusion/exclusion criteria Inclusion Criteria: Males, females year of age New starts to warfarin Physician approval & Patient informed consent Exclusion Criteria: Known hypersensitivity reaction to warfarin Patients residing in Olmsted County MN Recent hospital stay >7 days in length Short-term use of warfarin 2010 Medco Health Solutions, Inc. All rights reserved. 6 Primary Comparison 23 Benefit Plan Sponsors56 Benefit Plan Sponsors July 2006 June 2007 n=2688 Historical control July 2007 February 2009 n=896 Intervention group Comparison of External Controls July 2006 June 2007 n=2688 External historical control July 2007 February 2009 n=2688 External concurrent control Medco-Mayo Warfarin Effectiveness Study Study groups* *6 month follow-up on all patients initiating warfarin in all groups 2010 Medco Health Solutions, Inc. All rights reserved. 7 Methods for Outcomes Comparisons Unadjusted comparisons Kaplan-Meier and log-rank tests Adjusted comparisons propensity scores to handle participant/non-participant differences, indications for therapy, specific concomitant drugs, medical conditions, prior history of hospitalization or history of bleed/thromboemboli. ANALYSES Intention-to-treat all outcomes even if adverse event preceded genotype Per-protocol only those outcomes counted if post-genotype 2010 Medco Health Solutions, Inc. All rights reserved. 8 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 2010 Medco Health Solutions, Inc. All rights reserved. 9 Sample Mayo Clinic Laboratory Report Sample Lab Report: Warfarin Genotype Results Medco Health SolutionsAccession #: A Mayo/Medco Warfarin ProtocolPatient Name: DOE, JANE Attn: Accounts PayableBirth Date:09/13/1942 Age:65 Gender:F 100 Parsons Pond DriveMedical Rec #: 1234 Franklin Lakes, NJ 07417Client Accn #: Ordering Phys: SMITH, JOHN Collect Date: 11/07/ :40 AM Received Date: 11/08/2007 7:19 AM Test RequestedResultUnitsRef Range Perform Site * Rapid DNA Extraction Comment Genomic DNA was extracted. MCR ============================================================================ CYP2C9 + VKORC1 Genotype, Warfarin CYP2C9 430C>T(*2)C/T MCR CYP2C9 1075A>C(*3)A/C MCR CYP2C9 1076T>C(*4)T/T MCR CYP2C9 1080C>G(*5)C/C MCR CYP2C9 818delA(*6)A/A MCR VKORC G>AA/A MCR ============================================================================ Interpretation: This genotype is rare and has very high sensitivity to warfarin. Warfarin dose decrease and frequent INR monitoring should be considered. 2010 Medco Health Solutions, Inc. All rights reserved. 10 Participants from 49 US states 2010 Medco Health Solutions, Inc. All rights reserved. 11 Results: Baseline characteristics Characteristic Historical control (n=2688) Intervention group (n= 896)P-value Mean age, yrs (SD)65.2 (8.0)65.2 (8.3)0.921 Male(%)60.5% Medications (%) Amiodarone4.0%3.2%0.313 Statins14.5%16.9%0.071 Sulfamethoxazole4.4%5.2%0.268 Fluconazole2.4%2.6%0.803 NSAID19.6%19.9%0.865 Clopidogrel10.8%10.2%0.574 Steroids12.4%13.6%0.354 Conditions (%) GI bleed3.6%4.0%0.539 Atrial fibrillation40.4%41.1%0.709 Pulmonary embolism11.0%11.8%0.501 Deep vein thrombosis24.6%25.8%0.489 Hypertension47.0%54.2%