Epstein Mmws


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Epstein Mmws

  1. 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
  2. 2. Background <ul><li>Warfarin exhibits large inter-individual dosing requirements </li></ul><ul><li>Warfarin is a leading cause of morbidity and mortality </li></ul><ul><li>Two genes account for ~33% of variance in dosing </li></ul><ul><ul><li>Cytochrome P450 2C9 (CYP2C9) – pharmacokinetics </li></ul></ul><ul><ul><li>VKORC1 – pharmacodynamics </li></ul></ul><ul><li>Meta-analysis of 3 clinical trials of warfarin genotyping showed a 32% decrease in major bleeding (RR 0.68, CI 0.22-2.06)* </li></ul>*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.
  3. 3. Study question: Does use of CYP2C9/VKORC1 testing reduce the risk of hospitalization during the first 6 months of warfarin treatment?
  4. 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
  5. 5. Statistical Methods of Outcomes Comparisons <ul><li>Unadjusted comparisons – Kaplan-Meier and log-rank tests </li></ul><ul><li>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. </li></ul><ul><li>ANALYSES </li></ul><ul><li>Intention-to-treat – all outcomes even if adverse event preceded genotype </li></ul><ul><li>Per-protocol – only those outcomes counted if post-genotype </li></ul>
  6. 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
  7. 7. Sample Mayo Clinic Laboratory Report <ul><li>Sample Lab Report: Warfarin Genotype Results </li></ul><ul><li>Medco Health Solutions Accession #: A1234567 </li></ul><ul><li>Mayo/Medco Warfarin Protocol Patient Name: DOE, JANE </li></ul><ul><li>Attn: Accounts Payable Birth Date: 09/13/1942 Age:65 Gender:F </li></ul><ul><li>100 Parsons Pond Drive Medical Rec #: 1234 </li></ul><ul><li>Franklin Lakes, NJ 07417 Client Accn #: 123456789 </li></ul><ul><li>Ordering Phys: SMITH, JOHN </li></ul><ul><li>Collect Date: 11/07/2007 10:40 AM </li></ul><ul><li>Received Date: 11/08/2007 7:19 AM </li></ul><ul><li>--------------------------------------------------------------------------------------------------------------- </li></ul><ul><li>Test Requested Result Units Ref Range Perform Site * </li></ul><ul><li>-------------- ------ ----- --------- ------- </li></ul><ul><li>Rapid DNA Extraction </li></ul><ul><li>Comment Genomic DNA was extracted. MCR </li></ul><ul><li>============================================================================ </li></ul><ul><li>CYP2C9 + VKORC1 Genotype, Warfarin </li></ul><ul><li>CYP2C9 430C>T(*2) C/T MCR </li></ul><ul><li>CYP2C9 1075A>C(*3) A/C MCR </li></ul><ul><li>CYP2C9 1076T>C(*4) T/T MCR </li></ul><ul><li>CYP2C9 1080C>G(*5) C/C MCR </li></ul><ul><li>CYP2C9 818delA(*6) A/A MCR </li></ul><ul><li>VKORC1 -1639G>A A/A MCR </li></ul><ul><li>Interpretation MCR </li></ul><ul><li>This genotype is rare and has very high sensitivity to warfarin. Warfarin dose decrease and frequent INR monitoring should be considered. </li></ul>
  8. 8. Participants were from 49 US states
  9. 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. 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. 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. 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. 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
  14. 14. Results: Same time frames External control group comparison – pre vs. post <ul><li>Hospitalization rates (unadjusted) </li></ul><ul><ul><li>Any cause 22.8% vs. 22.7% </li></ul></ul><ul><ul><li>Bleeds/thromboemboli 7.8% vs. 7.2% </li></ul></ul><ul><li>Hospitalization rates (adjusted) H.R. (95% CI) </li></ul><ul><ul><li>Any cause HR 0.98 (0.88-1.1) </li></ul></ul><ul><ul><li>Bleeding or thromboemboli HR 0.92 (0.76-1.1) </li></ul></ul>No difference in hospitalization rates over the same 2 time periods in the external controls
  15. 15. Limitations <ul><li>Non-randomized trial design </li></ul><ul><ul><li>Entire population comparison before and after population intervened upon (quasi-experiment) </li></ul></ul><ul><ul><li>Intention-to-treat biased against genotyping by including events that occurred before genotype conducted </li></ul></ul><ul><ul><li>Participation rate high – by both participants and physicians </li></ul></ul><ul><li>Hawthorne effect </li></ul><ul><ul><li>Kept the intervention to a minimum </li></ul></ul><ul><ul><li>No payment to providers who participated </li></ul></ul><ul><li>Administrative Claims Data for endpoints </li></ul><ul><ul><li>Peer-reviewed literature for algorithm with ICD-9 codes </li></ul></ul>
  16. 16. Conclusions <ul><li>Genotyping warfarin patients resulted in ~30% risk reduction in hospitalizations for all-cause and for bleeds/thromboemboli </li></ul><ul><li>Having genotyping closer to therapy initiation was even better </li></ul><ul><li>Physicians changed warfarin prescriptions in the direction suggested by the Mayo genotype laboratory report </li></ul><ul><li>Physicians were very willing (75% agreement) to order the genotype tests </li></ul>
  17. 17. Future Suggestions <ul><li>Further research warranted to confirm and extend our findings </li></ul><ul><ul><li>Elderly vs. non-elderly </li></ul></ul><ul><ul><li>Role of genotyping to prevent bleeds or thromboemboli as individual endpoints </li></ul></ul><ul><ul><li>Impact of genotyping on INR measurements </li></ul></ul><ul><ul><li>Economic evaluation of genotyping vs. usual care </li></ul></ul>