Controversies in Anticoagulation

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1 Controversies in Anticoagulation Katrina Babilonia, PharmD Pharmacy Clinical Specialist Anticoagulation University of Colorado Hospital Patient Case: DS DS 67 y/o CC: Chest Pain & Heart racing PMH: aortic valve replacement (porcine), HTN, & GERD Afib with RVR metoprolol & warfarin Day 1 Day 2 Day 3 Day 4 warfarin 5mg 5mg Held Held INR * Hct Would you have considered doing warfarin genetic testing on this patient prior to warfarin initiation? Would you do genetic testing after his GI bleed? Warfarin Sensitivity Genotyping CYP2C9 Responsible for metabolizing warfarin S-isomer Gene mutations CYP2C9*2, CYP2C9*3 Both mutations are associated with reduced warfarin dosing requirements to achieve therapeutic INR VKORC1 Gene that determines the activity of vitamin K epoxide reductase (VKOR) Gene mutations A/A, G/A, G/G increased sensitivity to warfarin These 2 gene variations account for more than 1/3 of the variance associated with stable therapeutic warfarin dosing

2 International Warfarin Pharmacogenetics Consortium* Pharmacogenetic warfarin dose algorithm was developed using patient data set (4043 pts) 21 Research groups from 9 countries and 4 continents Dose predictions from pharmacogenetic model were compared with clinical model and fixed dose model Clinical value was evaluated by % of patients whose predicted dose was within 20% of actual dose Pharmacogenetic Algorithm = Better Dose Prediction P value < for both comparisons Pharmacogenetic algorithm available at IWPC. N Eng J Med 2009;360:753-64

3 National, prospective, comparative effectiveness study comparing the 6 month incidence of hospitalization in patients receiving warfarin genotyping (896) vs historical control group (2688). A secondary analysis to rule out temporal trends with 2 external control groups Results: Compared to historical controls: Patients in the genotyped group had 31% fewer hospitalizations overall, 28% fewer hospitalizations for bleeding or thromboembolism. Limitations historical control group Where do we go from here? 8/07 FDA added info to warfarin package insert regarding lowering warfarin doses in patients with CYP 2C9 and VKORC1 SNP 08/09 CMS will not reimburse for warfarin pharmacogenomic testing unless it is part of a clinical trial Cost Effectiveness? If restricted to patients at high risk for hemorrhage Meet criteria: prevent > 32% of bleeding events, be available within 24 hours, and cost less than $200 More Studies COAG, GIFT

4 Patient Case: DM DM is a 45 female admitted for treatment of LE cellulitis PMH: HTN, Asthma, DM Type II Admitted to medicine home meds continued, started on vancomycin and unasyn, dalteparin 5000 iu daily HD #4 new painful swelling in R LE, US shows new DVT Did this patient receive adequate DVT Proph? Antifactor Xa activity & Body Weight N = 17 patients and 2 volunteers Anti-Xa levels hourly x 10 hours Enoxaparin 40 mg SC x1 dose AUC for Hour 10 Frederiksen SG, et al. Br J Surg. 2003; 90 (5): Body Weight (kg) PREVENT Trial Fixed dose dalteparin was effective in reducing VTE by 45% in medicine pts > 45 y/o. Subgroup Analysis Obesity defined as BMI > 30 for males, > 28.6 for females Primary endpoint Obese 2.8% vs 4.3%, Non-obese 2.8% vs 5.2% RRR of 36% across BMI subgroups EXCEPT pt with BMI > 40 Kucher N, et al. Arch Intern Med 2005; 165:341-5

5 Enoxaparin 30 mg BID vs 40 mg BID in Bariatric Surgery 481 pts undergoing either primary or revisional bariatric surgery (BMI = 51) Patients receiving lovenox 40 mg bid had fewer VTE events compared with 30 mg bid (2 DVT vs 1 DVT/4 PE, p < 0.01) 1 bleeding complication in each group Scholton DJ, et al. Obes Surg 2002; 12: Enoxaparin for VTE Prophylaxis in Orthopedic Surgery Dose: 40 units qd Obese: BMI > 32 kg/m2 N = 807 Incidence (%) Samama MM, et al. Thromb Haemost. 1995;73:977. VTE Where do we go from here? Recommendations Increasing VTE prophylactic doses of LMWH s MAY be appropriate in morbidly obese patients (BMI > 40 kg/m 2 ) How much do we increase VTE prophylactic doses? Enoxaparin 40 mg sq BID Dalteparin & UFH 6500 Units? 7500 Units?

6 Patient Case: JJ JJ is a 59 y/o male with CC SOB, increasing dyspnea on exertion & LEE BP 150/87, HR 85, Cr 1.6, BNP 2400 PMH: HTN (has not seen a Dr in 10 years) ECHO LVEF severely reduced with global hypokinesis Hospital Course: Diuresis and medication optimization R2 asks on rounds Shouldn t we anticoagulate him for low EF? Guideline & Consensus Recommendations for Anticoagulation in HF Organization American College of Chest Physicians Heart Failure Society of America American College of Cardiology AHA Guideline or Recommendation In pts with CHF due to nonischemic etiology, we recommend against routine use of aspirin or oral vitamin K antagonists (Grade 1B) In the absense of afib, a recent large anterior MI, or LV thrombus, warfarin anticoagulation may be considered in pts with dilated cardiomyopathy and LVEF < 35%. Careful assessment of potential risks and benefits should be undertaken. (Strength of Evidence = C) The usefulness of anticoagulation is not well established in pts with heart failure who do not have a fib or previous thromboembolic event. (Class IIb, level of evidence B) Thromboembolism Rates in HF 2 Prospective observational studies: 406 pts, EF 23%, Afib 16%, TE rate 2.7% pts, EF 27%, 24 months. Cerebral TE 1.7 events per 100 pt years 10 Post Hoc Analysis: SAVE LVEF independently ass. with stroke risk (p = 0.01), risk of TE by 18% for every 5 % in EF 11 SOLVD 6378 pt over 40 months, Overall TE events 2.4% in woman and 1.8% in men. Annual risk of stroke; mild/ mod EF 1.5%, Severe EF 4% vs 0.5% in general population 12 In more recent trials annual incidence of thromboembolic events in HF ranged from 1-3%.

7 Data Supporting Anticoagulation in HF SAVE Post Hoc 11 Oral Milrinone Post Hoc 13 SOLVD Post Hoc Cohort 12 Warfarin vs no Warfarin Multicenter trial in 1088 pts Warfarin pt (n=861) vs No Warfarin (n=5652) Warfarin ass. with an 81% RRR in stroke* Warfarin sig reduced the risk of stroke in pts with EF < 20% (0.6% risk vs 3.3%) After adjustments Warfarin ass. with reduced all cause & CV mortality (p = & p = 0.002) Data Refuting Anticoagulation in HF HELAS 14 Designed to recruit 6000 pts, only 197 enrolled WASH pts followed months (6.1% had afib) No difference in stroke, embolism, MI or reinfarction, HF exac, or death No difference in primary outcome (composite of death, MI & stroke) WATCH 16 Designed for 4500 pts followed 3.5 years, only 1587 pts followed for 23 month No difference in primary outcome (composite of all cause mortality, MI & stroke) Where do we go from here? More Studies WARCEF: Warfarin vs ASA 325 daily in 3-5 year event-free survival for composite endpoint of death and stroke with EF < 35% (no afib/ mechanical valves) Anticoagulate? YES - LVEF < 35% PLUS AFib, Recent MI & mural thrombus, Intracardiac thrombus, Mechanical Valve Evaluate case by case - LVEF < 35% and no additional risk factors Who would anticoagulate patient JJ?

8 References: 1. IWPC. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N Eng J Med 2009;360: Epstein RS, et al. Warfarin Genotyping Reduces Hospitalization Rates. JACC 2010;55(25): Eckman MH, et al. Cost Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients with Nonvalvular Atrial Fibrillation. Ann Int Med 2009;150(2): References: 4. Ginsburg GS, Noora D. The Long and Winding Road to Warfarin Pharmacogentic Testing. JACC 2010; 55(25): Frederiksen SG, et al. Enoxaparin effect depends on body weight and current doses may be inadequate in obese patients. Br. J Surg 2003;90: Kucher N, et al. Efficacy and safey of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med; 165: References: 6. Scholton DJ, et al. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002;12: Samama MM, et al. Relation between weight, obesity, and frequency of deep vein thrombosis after enoxaparin in orthopedic surgery. Thromb Haemost 1995;73: Ripley TL, Nutescu E. Anticoagulation in patients with heart failure and normal sinus rhythm. Am J Health Sys Pharm 2009;66:134-41

9 References: 9. Cioffi G, et al. Systemic thromboembolism in chronic heart failure: a prospective study in 406 patiens. Eur Heart J 1996;17: Katz SD, et al. Low incidence of stroke in ambulatory patients with heart failure: a prospective study. Am Heart J 1993;126: Loh E, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction (SAVE). N Engl J Med 1997;336: References: 12. Dries DL, et al. Ejection fraction and risk of thromboembolic events in patietns with systaolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular trial. JACC 1997;29: Falk RH, et al. for the PROMISE investigators. The effect of warfarin on prevalence of stroke in patients with severe heart failure. JACC 1993;21: Cokkinoa DV, et al. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Failure 2006;8: References: 15. Cleland JG, et al. The Warfarin/ Aspirin Study in Heart Failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148: Massie BM, et al. The warfarin and Antiplatelet therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. J Card Fail 2004;10: Nair A, et al. Anticoagulation in patients with heart failure: who, when, and why? Eur Heart J Sup 2006; 8 (E): E32-38