New Horizons in Anticoagulation: The Way of the Future Gloria Grice Pharm.D., BCPS St. Louis College of Pharmacy & Barnes-Jewish Hospital Anticoagulation Service Disclosure The speaker has nothing to disclose in relation to this presentation Outline How polymorphisms in cytochrome P450 2C9 (CYP2C9) affect warfarin metabolism How polymorphisms in vitamin K epoxide reductase (VKORC1) affect warfarin sensitivity Retrospective and prospective studies for warfarin initiation and refinement Advantages and disadvantages to pharmacogenetic testing New anticoagulants in development
Challenges of Warfarin Management Narrow therapeutic index Adverse effect profile Black box warning for bleeding 2 nd highest drug causing adverse events among outpatients Wide dose variability Long time to achieving therapeutic INR Clinical Predictors of Warfarin Response Age Drug interactions Alcohol Diet Hepatic dysfunction Gender BMI Ethnicity/Race Fever Changes in thyroid status Decompensated heart failure Multiple medical conditions Nutritional status Blood Loss Genotype Warfarin CYP1A1 CYP1A2 CYP3A4 R-warfarin Vitamin K Reductase S-warfarin CYP2C9 Oxidized Vitamin K Reduced Vitamin K Hypofunctional F. II, VII, IX, X Protein C, S, Z CO 2 O 2 Calumenin γ-glutamyl carboxylase Functional F. II, VII, IX, X Proteins C, S, Z
Cytochrome P450 2C9 (CYP2C9) 12+ polymorphisms in the CYP2C9 gene have been identified The two most common alleles (*2 and *3) decrease the clearance of S-warfarin 17% to 37% 2-3 fold elevated risk of adverse events during initiation Vitamin K Epoxide Reductase (VKORC1) Determines sensitivity of warfarin Several polymorphisms have been identified Low-dose (haplotype 1-2, haplotype A, AA, TT ) High-dose (haplotype 7-9, haplotype B, GG, CC ) Effect of Genotype on Dose CYP2C9 M ean warfarin dose, m g /d 7 6 5 4 3 2 1 0 5.1 4.7 3.9 4.0 3.4 2.0 1.5 *1/*1 *1/*2 *1/*3 *1/*5 *2/*2 *2/*3 *3/*3 VKORC1 1173 Genotype VKORC1 Warfarin Dose (mg/d) GG (37%) 6.2 AG (47%) 4.8 AA (16%) 3.5 Gage et al. Thromb Haemost 2004;91:87-94 D Andrea et al. Blood 2005;105(2):645-9
Incidence of CYP2C9 & VKORC1 SNPs (%) Caucasian African- American Other Asian CYP2C9 *2 13.1 5.2 10.4 0 CYP2C9 *3 6 1 4.2 4 VKORC1 Group A 36.6 9.5 41.7 85 VKORC1 Group B 63.4 90.5 58.3 14 Gage et al. Clin Pharmacol Ther 2008 in press Marsh et al. J Thromb Haemost 2006; 4: 473 4 Predicted Dosing vs. Actual Dosing Clinical Refinement Initial R 2 R= 2 = 17-22% 53% Geneti c Refinement Initial R 2 R= 2 = 47-61% 70% Lenzini et al. J Thromb Haemost 2008 (in press) INR as Surrogate Endpoint EAFT Study Group, NEJM 1995;333:5-10
Time to Anticoagulation-Related Outcomes Proportion w/out Stable Dose 1.0 0.8 0.6 0.4 Less Stable 2 χ =8.30; P=0.004 1 0.2 CYP2C9 variant Wild type 0.0 0 100 200 300 400 500 600 700 800 900 1000 N=185 Follow-up, d No. at Risk Variant 58 33 17 6 6 3 2 2 2 Wild Type 127 39 19 10 6 3 3 2 2 Higashi et al JAMA. 2002;287:1690-1698 Bleed-free Survival More Bleeding 1.0 χ 2=6.21; P=0.01 1 0.8 Wild type 0.6 0.4 CYP2C9 variant 0.2 0.0 0 400 1200 2000 2800 3600 Follow-up, d 58 23 16 9 9 6 4 3 127 71 54 34 22 10 6 0 Randomized Trials: Anderson et al. End Point PG Group (n=101) STD Group (n=99) P-value Out-of-range INRs 30.7 33.1 0.47 (%) # of dosing 3.0 3.6 0.035 adjustments # of INRs drawn 7.2 8.1 0.06 Total AEs 34 42 0.26 Genetic-guided doses were more accurate than standard dosing (p<0.001) = Fewer dosing changes and INR monitoring Anderson et al. Circulation 2007;116:2563-70 Randomized Trials: Caraco et al. End Point PG Group (n=92) STD Group P-value (n=93) Time to first 4.8 7.5 <0.001 therapeutic INR (days) Days below 2.01 8.00 <0.001 therapeutic range Time in therapeutic 80.4 63.4 <0.001 range (%) # of INRs drawn 4.9 10.7 <0.001 Bleeding events (minor) 3.2 12.5 <0.02 Caraco et al. Clin Pharmacol Ther 2008;83:460-70
Outcomes in Orthopedic Patients Lenzini et al. J Thromb Haemost 2008 (in press) Outcomes in Orthopedic Patients Outcome Variable Clinical (N=90) Genetic (N=70) P-value for cohort difference Mean PTTR in 30 days (SD) 56% (20.5%) 62% (19.1%) 0.066 Frequency INR > (Target INR + 1.5) within 30 days 17 (19) 2 (3) 0.002 Symptomatic adverse events within 30 days (%) 5 (6) 3 (4) 0.51 Lenzini et al. J Thromb Haemost 2008 (in press) Orthopedic Patients with Adverse Events Lenzini et al. J Thromb Haemost 2008 (in press)
Case 1 22 yo WF with a CVA Weight: 204 Height: 66 Non-smoker, nondrinker (no liver dz) No interacting meds CYP2C9:pending VKORC1: pending Day of INR Dose Warfarin 0 1.02 7 1. 4 2. 4 3 1.3? Case 1 22 yo WF with a CVA Weight: 204 Height: 66 Non-smoker, nondrinker (no liver dz) No interacting meds CYP2C9: *1/*3 VKORC1: AG Day of INR Dose Warfarin 0 1.02 7 1. 4 2. 4 3 1.3 4 10 2.2 4 20 2.7 4.25mg average Case 2 No genetics at initiation Estimated Dose 3.5 mg/day www.warfarindosing.org Caution: Liver Disease
Case 2 No genetics at initiation Days after INR Dose (mg) warfarin 0 1.05 3 1. 3 2. 3 3 1.5 3 4 2.3? After Pharmacogenetics Very slow metabolizer Warfarin sensitive Case 2 Very slow metabolizer; sensitive Days after warfarin INR Dose (mg) 0 1.05 3 1. 3 2. 3 3 1.5 3 4 2.3 0 5. 0 6. 0.5 7 2.1 1 21 2.5 ~0.6/day Grice G et al. J Thromb Haemost. 2008;6:207-9
Clinical Pearls Patients with SNPs in CYP2C9 Lower than expected maintenance doses INRs rise slowly if start with maintenance dose Require loading dose (or 2?) Consideration of genotype needed throughout therapy High INRs treated more aggressively May need to load again after sub-therapeutic INR Patients with SNPs in VKORC1 Lower or higher than expected maintenance dose Initiate with expected maintenance dose Genotype effect limited once therapeutic Advantages of PG More Predictable/Less Variability ( personalized medicine ) Easier for Clinician Management Fewer surprises Website, dosing algorithms available Additional variable Genetic platforms available Patient acceptance high FDA Advisory Improves Patient Outcomes? Barriers to PG No multi-centered RCT - (NIH has funding- to begin this spring) Unknown benefit in some patient populations Cost Availability Clinician knowledge Potential delay in warfarin initiation
Role for Pharmacogenetic Testing Thacker et al. J Thromb Haemost 2008 (in press) The Pipeline Certoparin Novartis Apixaban [BMS562247] BMS [TTP889] TransTech Pharma Idraparinux [SR34006] Sanofi-Avents Odiparcil [SB-424323]) GSK Dabigatran (Pradaxa ) Boehringer Ingelheim Rivaroxaban (Xarelto ) Ortho McNeil Statins Dabigatran Direct Thrombin Inhibitor For the short-term prevention of venous thromboembolism (VTE) after orthopedic surgery, long-term VTE prophylaxis, stroke prophylaxis in patients with atrial fibrillation, and the acute treatment of VTE RE-VOLUTION, RE-MODEL, RE- MOBILIZE, RE-NOVATE, RE-COVER, RE-MEDY
Dabigatran Pharmacokinetic Comparison Dabigat ran Warfari n Loveno x Prodrug Yes No No Time to 2-3 hrs 4 days 3-5 hrs peak Bioavail 6.5% 100% 92% Half-life 2.5 days 20-60 4.5 hrs hrs Renal Yes No Yes Hepatic No Yes No Proteinbinding 25-30% 99.5% 80% Gold Standard, Inc. Clinical Pharmacology, [Dabigatran]. http://clinicalpharmacology.com Eriksson B, et al. The Lancet 2007; 370: 949-955. Outcome Data Dabigat ran 150mg Total VTE + death DVT +/- PE Major bleeds ALT >3x ULN Dabigat ran 220mg Loveno x 40 mg 40.5% 36.4% 37.7% 3.8% 2.6% 3.5% 1.3% 1.5% 1.3% 3.7% 2.8% 4.0% Rivaroxaban Factor Xa Inhibitor For stroke prevention in atrial fibrillation and in the treatment and longterm secondary prevention of VTE. RECORD 1-4 Recommended for approval by the FDA advisory committee on March 24, 2009 Pharmacokinetic Comparison Rivarox aban Warfarin Lovenox Prodrug Yes No No Time to 2-3 hrs 4 days 3-5 hrs peak Bioavail 6.5% 100% 92% Half-life 2.5 days 20-60 4.5 hrs hrs Renal Yes No Yes Hepatic No Yes No Proteinbinding 25-30% 99.5% 80% Gold Standard, Inc. Clinical Pharmacology [Rivaroxaban]. http://clinicalpharmacology.com Rivaroxaban Trial Patients Enoxapari n Rivaroxab an DVT/PE/de ath (%) RRR (%) RECORD 1 (n=4541) RECORD 2 (n=2509) RECORD 3 (n=2531) Hip arthroplasty Hip arthroplasty Knee arthroplasty 40 mg qd 35 days 40 mg qd 10-14 days 40 mg qd 10-14 days 10 mg qd 35 days 10 mg qd 31-39 days 10 mg qd 10-14 days 3.7 vs 1.1 70 9.3 vs 2.0 79 18.9 vs 9.6 49 RECORD 4 (n=3148) Knee arthroplasty 30 mg bid 10-14 days 10 mg qd 10-14 days 10.1 vs. 6.9 31 Eriksson BI, Borris LC, Friedman RJ, et al. N Engl J Med 2008; 358:2765-2775
Statins Anti-inflammatory Inhibit isoprenylation of signaling proteins Increase the effect of thrombomodulin Increase the bioavailability of nitric oxide JUPITER Trial End point Patients with events, rosuvasta tin (n=8901) Patients with events, placebo (n=8901) Hazard ratio Total VTE 34 60 0.57 (0.37-0.86) Provoked 19 31 0.61 (0.35-1.09) Unprovoked 15 29 0.52 (0.28-0.96) PE 17 22 0.77 (0.41-1.45) DVT 17 38 0.45 (0.25-0.79) Glynn RJ et al. N Engl J Med 2009; DOI:10.1056./oa0900241 New Horizons in Anticoagulation: The Way of the Future Gloria Grice Pharm.D., BCPS St. Louis College of Pharmacy & Barnes-Jewish Hospital Anticoagulation Service
New Horizons in Anticoagulation: The Way of the Future 121-000-09-010-L01-P Post Test 1. Which of the following statements best describes the role of pharmacogenetics in warfarin management? A. Genotype is a useful variable to consider along with other clinical variables when selecting the first warfarin dose and refining the first several doses. B. Genotype is most helpful after one week of therapy in patients with low risk of bleeding. C. Genotype should be considered in patients who have taken warfarin previously. D. Genotype should not be considered when initiating and refining warfarin doses. 2. Which of the following drugs have demonstrated potential for venous thromboembolism prophylaxis? A. Rosuvastatin B. Darbigatran C. Rivaroxaban D. All of the above