1. The Changing Landscape of Anticoagulation William D. Cahoon, Jr., PharmD, BCPS Cardiology Clinical Pharmacist VCU Health System April 12, 2012

2. Objectives Review dabigatran post-marketing safety data Evaluate cardiovascular data for novel oral anticoagulants Identify advantages and limitations of available agents Discuss the practical management of oral anticoagulation

3. Dabigatran

4. Oral, direct thrombin inhibitor Activation: Hydrolysis T max : 1 hour T 1/2 : 12-17 hours Metabolism: Hydrolysis Renal excretion: 80% Dosing: Fixed, twice daily Monitoring: None required Annu Rev Med 2011;62:41-57

5. Dabigatran – The First Non-Warfarin Oral direct thrombin inhibitor with no monitoring FDA approved October 2010 RE-LY Trial demonstrated: –Dabigatran superior to warfarin for stroke prevention –Equivalent rates of major bleeding By August 2011 dabigatran prescribed to 250,000 U.S. atrial fibrillation patients (~10%)

6. Dabigatran Dosage and Administration Approved Dosage Forms75 mg & 150 mg capsules Nonvalvular Atrial Fibrillation Normal Renal Function (CrCl > 30 ml/min) 150 mg twice daily Moderate Renal Impairment (CrCl 15 – 30 ml/min) 75 mg twice daily Severe Renal Impairment (CrCl < 15 ml/min) Not recommended Pradaxa  Package Insert Note: Capsules cannot be opened, crushed, or chewed

7. ISMP Safety Alert - Dabigatran 932 serious adverse events reported with dabigatran in the 1 st quarter of 2011 505 cases involved hemorrhage Hemorrhage in elderly (median age 80) “FDA and manufacturer should reevaluate dosing in the elderly”

8. Dabigatran Post-Marketing FDA investigating post-marketing reports of serious bleeding 260 fatal bleeding events worldwide Prompted safety advisories in several countries Labeling changes in US and Europe

9. Dabigatran Labeling Changes Pradaxa  Package Insert – Updated 1/2012

10. New Zealand Dabigatran Experience 7000 patients started treatment in first 2 months Audit revealed 78 bleeding episodes; 12 major Four contributing factors identified: –Prescriber error –Impaired renal function –Patient age –Lack of reversal agent N Engl J Med 2012;366(9):864-6

11. Dabigatran and MI Signal Meta-analysis revealed a significant 33% relative risk increase in MI or ACS (p=0.03) Absolute risk increase was only 0.27% RE-LY investigators found non-significant increase in MI with dabigatran Risk may be due to warfarin comparator Arch Intern Med 2012; Published Online Circulation 2012;125:669-76.

12. Warfarin Following MI OASIS and WARIS II Meta-analysis of warfarin plus aspirin –Associated with reduced risk of MI, stroke –Increase in major bleeding Thienopyridines decreased uptake of warfarin for secondary ACS prevention Ann Intern Med 2005;143:241-50

13. RE-DEEM Purpose: Select the dabigatran dose that balances effectiveness and bleeding risk Methods: Randomized, placebo-controlled trial of patients post myocardial infarction (MI) Intervention: –Dabigatran 50, 75, 110, or 150 mg twice daily or placebo Primary Outcome: Major or clinically relevant minor bleed Secondary Outcome: Incidence of cardiovascular events Eur Heart J 2011;32:2781-9

14. RE-DEEM Outcomes Placebo (n=371) Dabigatran 50 mg (n=369) Dabigatran 75 mg (n=368) Dabigatran 110 mg (n=406) Dabigatran 150 mg (n=347) Major or clinically relevant minor bleed (%) 2.43.54.37.97.8 Major bleed (%)0.50.80.32.01.2 CV death, nonfatal MI, stroke (%) 3.84.64.93.03.5 Eur Heart J 2011;32:2781-9

15. D-Fine Study Eur Soc Cardiol Congress 2011 Purpose: Test a short course of dabigatran prior to PCI Methods: Randomized, open-label trial of 50 patients Intervention: –Dabigatran 110 or 150 mg twice daily or heparin (UFH) Outcome: –5 dabigatran patients required anticoagulation bail-out –UFH provided greater level of anticoagulation protection Conclusion: Dabigatran may not provide sufficient anticoagulation to allow for elective PCI

16. Dabigatran Prior to PCI Renal Function Procedural Bleed Risk Standard RiskHigh Risk Normal or Mild Impairment (CrCl > 50 ml/min) Hold for 24 hoursHold for 48-96 hours Moderate Impairment (CrCl 30-50 ml/min) Hold for 48 hoursHold for 96 hours Severe Impairment (CrCl < 30 ml/min) Hold for 24-120 hoursHold > 120 hours Thromb Haemost 2010;103:1116-1127 BOEHRINGER INGELHEIM PHARMACEUTICALS, INC DRUG INFORMATION UNIT Percutaneous Coronary Intervention (PCI): During PCI, the activated clotting time (ACT) was to be measured and heparin administered as needed according to usual practice Reference: Data on file. Boehringer Ingelheim, Ridgefield, CT. Clinical Trial Report 1160.26.

17. Dabigatran Post Procedure Standard RiskHigh Risk Resume Dabigatran24 hours post48 hours post Curr Pharm Des 2010;16:3436-3441 Bridge therapy for AF patients typically unnecessary Use of monitored anticoagulant (i.e. heparin) may be indicated in patients following major surgery

18. Dabigatran Considerations No hepatic dose adjustment needed Close renal function monitoring required Caution in the elderly, low body weight Questionable signal of MI risk NOT on VCUHS patient assistance program (PAP); ~$152/mo, insurance coverage varies

19. Novel Anticoagulants FibrinogenFibrin IIa II Xa Direct Thrombin Inhibitors Ximelagatran Dabigatran AZD-0837 Factor Xa Inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban Eribaxaban Idraparinux (SQ) LY517717 YM150 TAK-442 TF/VIIa XIX IXa VIIIa Warfarin Sites of Action II VII IX X

20. Rivaroxaban

21. Oral factor Xa inhibitor Activation: None T max : 2-4 hours T 1/2 : 5-9 hours Metabolism: Hepatic,CYP3A4 Renal excretion: 66% Dosing: Fixed, once daily Monitoring: None required Annu Rev Med 2011;62:41-57

22. Rivaroxaban Dosage and Administration Approved Dosage Forms10, 15, & 20 mg tablets Nonvalvular Atrial Fibrillation Dosing Normal Renal Function (CrCl > 50 ml/min) 20 mg once daily* Moderate Renal Impairment (CrCl 15 – 50 ml/min) 15 mg once daily* Severe Renal Impairment (CrCl < 15 ml/min) Avoid use Prophylaxis of DVT 10 mg once daily with or without food Xarelto  Package Insert *Administer with evening meal

23. ROCKET AF Purpose: Compare rivaroxaban with warfarin for the prevention of stroke in nonvalvular atrial fibrillation (AF) Methods: Double-blind, double-dummy non-inferiority (superiority) trial of moderate to high risk patients Intervention: –Rivaroxaban 20 mg daily -or- –Warfarin (Target INR 2.5) Primary Efficacy Outcome: Stroke or systemic embolism Primary Safety Outcome: Major bleeding N Engl J Med 2011;365(10):883-91

24. ROCKET AF Outcomes Rivaroxaban (n=7081) Warfarin (n=7090) Hazard Ratio (95% CI) P-value Stroke or systemic embolic event (non-inferiority) 1.712.160.79 (0.66-0.96)<0.001 Stroke or systemic embolic event (superiority) 1.702.150.79 (0.65-0.95)0.015 Stroke or systemic embolic event (ITT superiority) 2.122.420.88 (0.74-1.03)0.117 Major bleeding 3.603.451.04 (0.90-1.20)0.576 Major and clinically relevant bleeding 14.9114.521.03 (0.96-1.11)0.442 N Engl J Med 2011;365(10):883-91

25. ATLAS ACS 2-TIMI 51 Purpose: Evaluate rivaroxaban as adjunctive therapy following recent ACS Methods: Double-blind, placebo-controlled study of patients within 7 days post ACS Intervention: –Rivaroxaban 2.5 mg twice daily –Rivaroxaban 5 mg twice daily –Placebo Primary Outcome: Composite of death, MI, stroke N Engl J Med 2012;366(1):9-19

26. ATLAS ACS 2-TIMI 51 Primary Endpoint: Rivaroxaban 2.5 mg 9.1% vs. placebo 10.7% (HR 0.84, p=0.02) Primary Endpoint: Rivaroxaban 5 mg 8.8% vs. placebo 10.7% (HR 0.85, p=0.03) N Engl J Med 2012;366(1):9-19

27. ATLAS ACS 2-TIMI 51 March 2012 - FDA granted priority review for the additional indication of reducing CV events post ACS N Engl J Med 2012;366(1):9-19 Safety Rivaroxaban 2.5 mg (n=5114) Rivaroxaban 5 mg (n=5115) Placebo (n=5113) P-value (combined) TIMI major bleeding 1.82.40.6<0.001 TIMI minor bleeding 0.91.60.50.003 Bleeding requiring medical attention 12.916.27.5<0.001 Intracranial bleed 0.40.70.20.009

28. X-PLORER Purpose: Compare rivaroxaban with UFH as the primary anticoagulant in elective PCI Intervention (Estimated enrollment 105 pts): –UFH 70-100 IU/kg bolus, ACT goal 250-300 sec –Rivaroxaban 10 mg single dose –Rivaroxaban 20 mg single dose –Rivaroxaban 10 mg plus UFH 50 IU/kg bolus Primary Outcome: Thrombosis and ischemic events Estimated study completion April 2012 www.clinicaltrials.gov accessed 3/2012

29. Rivaroxaban Prior to PCI Half-life 5-9 hours; once daily dosing Activity does not correlate with aPTT or ACT Procedural Bleed Risk Standard RiskHigh Risk Hold for 24 hoursHold for 24-48 hours *Consider longer drug free interval in renal impairment

30. Rivaroxaban Post Procedure Standard RiskHigh Risk Resume Rivaroxaban24 hours post48 hours post Xarelto  Package Insert Should be restarted as soon as adequate hemostasis established If oral medication cannot be taken following procedure consider administering a parenteral anticoagulant

31. Rivaroxaban Considerations Avoid in moderate-severe hepatic impairment Renal dose adjustment required Once daily dosing may improve compliance Potential “benefit” in ACS patients On VCUHS PAP program; ~$151/mo, insurance coverage varies

32. Apixaban

33. Oral, factor Xa inhibitor Activation: None T max : 3-3.5 hours T 1/2 : 9-14 hours Metabolism: Hepatic,CYP3A4 Renal excretion: 25% Dosing: Fixed, twice daily Monitoring: None required Annu Rev Med 2011;62:41-57

34. ARISTOTLE Purpose: Compare apixaban with warfarin for the prevention of stroke or systemic embolism Methods: Randomized, double-blind trial of patients with at least 1 risk factor for stroke Intervention: –Apixaban 5 mg twice daily -or- –Warfarin (Target INR 2.0 - 3.0) Primary Efficacy Outcome: Stroke or systemic embolism Primary Safety Outcome: Major bleeding N Engl J Med 2011;365(11):981-92

35. ARISTOTLE Outcomes Apixaban (n=9120) Warfarin (n=9081) Hazard Ratio P-value Stroke or systemic embolic event 1.271.60.790.01 Death from any cause 3.523.940.890.047 Major bleeding 2.133.090.69<0.001 Any bleeding 18.125.80.71<0.001 Stroke, systemic embolism, major bleed 3.174.110.77<0.001 FDA to review apixaban on June 28, 2012 N Engl J Med 2011;365(11):981-92

36. APPRAISE-2 Purpose: Evaluate the role of apixaban in patients with recent acute coronary syndromes (ACS) Methods: Double-blind, parallel group trial of high risk ACS patients with mono or dual antiplatelet therapy Intervention: –Apixaban 5 mg twice daily -or- –Placebo Primary Outcome: Composite of cardiovascular death, MI, and ischemic stroke N Engl J Med 2011;365(8):699-708

37. APPRAISE-2 Stopped early by data safety monitoring board Increase in major bleed events without reduction in recurrent ischemic events Outcomes Apixaban (n=3705) Placebo (n=3687) Hazard RatioP-value CV death, MI, stroke 7.57.90.950.51 TIMI major bleeding 1.30.52.590.001 GUSTO major bleeding 1.00.33.050.001 Intracranial bleed 0.30.14.060.03 CV death, MI, stroke, fatal bleeding 8.08.10.980.80 N Engl J Med 2011;365(8):699-708

38. Apixaban Considerations NOT FDA approved Hepatic dose adjustment may be necessary Renal dose adjustment unlikely Decreased bleed rates compared with warfarin Risk-benefit neutral in ACS

39. Choice of Agent

40. Atrial Fibrillation Trial Comparison Variables RE-LY (n=18,113) ROCKET-AF (n=14,264) ARISTOTLE (n=18,201) Study drug Dabigatran 150 mg BID Rivaroxaban 20 mg daily Apixaban 5 mg BID ComparatorWarfarin INR 2-3 TTR (mean)64%55%62.2% Mean Age71 yo73 yo70 yo CHADS 2 score2.23.52.1 Primary Outcome 1.11% vs. 1.69% (p<0.001) 2.12% vs. 2.42% (p=0.117) 1.27% vs. 1.6% (p<0.001) Major bleeding 3.11% vs. 3.36% (p=0.31) 3.60% vs. 3.46% (p=0.576) 2.13% vs. 3.09% (p<0.001)

41. Characteristics of Novel Agents VariablesDabigatranRivaroxabanApixaban FDA approvedOctober 2010November 2011N/A Drug ClassDTIFactor Xa Inhibitor T max (hrs)1-32-41-3 Half-life (hrs)14-175-98-15 Dose IntervalTwice dailyOnce dailyTwice daily Renal80%36%25% Renal Dose Adj.Yes Unlikely Hepatic ImpairmentNo adjustmentAvoid UseCaution / Avoid Use Other AEsDyspepsiaN/A Possible MonitoringpTT, ACTPT, anti-Xa

42. Patient Selection Novel anticoagulants may be most appropriate for: –Unstable INRs on warfarin –Difficulty or hardship with INR monitoring –CrCl > 30 ml/min –History of good medication compliance –Patients < 75 years old Novel anticoagulants probably not the best choice for: –Consistently therapeutic INRs on warfarin –Renal dysfunction (dabigatran and rivaroxaban) –History of significant GI disease or GI bleeding –Medication non-compliance –No prescription insurance / unable to afford co-pay

43. Management of Bleeding Bleeding on Therapy MildModerate-SevereLife-Threatening Delay next dose or discontinue Symptomatic Treatment Compression Surgical intervention Fluid replacement Blood transfusion Charcoal (overdose) Dialysis (dabigatran) Consider rFVIIa or PCC Thromb Haemost 2010;103:1116-1127

44. Bleeding Reversal No reversal agents or antidotes exist Vitamin K and protamine should be avoided Clotting factor concentrates may be an option –Prothrombin Complex Concentrate 50 units/kg –FEIBA 50-100 units/kg –Factor VIIa 90 mcg/kg Monitor for signs of clinical improvement

45. Other Potential Indications Post-operative prophylaxis (orthopedic) –Each agent has been evaluated in clinical trials –Only rivaroxaban FDA approved for this indication DVT prophylaxis in medically ill Acute venous thromboembolism treatment Pharmacotherapy 2011;31(12):1175-91

46. Notable Agents in Development Edoxaban –Oral factor Xa inhibitor in phase III trials –ENGAGE AF TIMI 48 Trial Otamixaban –IV, short-acting factor Xa inhibitor –Phase III TAO trial in early invasive ACS plasma derived (pd)-factor Xa antidote –Potential antidote for factor Xa inhibitors –Preliminary trials showed dose dependent reversal Pharmacotherapy 2011;31(10):975-1016 Am J Hematol 2012; e-pub ahead of print

47. Remaining Questions Real world effectiveness vs. clinical trial efficacy Market uptake of multiple novel oral anticoagulants Safety of triple antithrombotic therapy Safety with concomitant prasugrel or ticagrelor therapy Management of bleeding and identification of antidote

48. Summary: Oral Anticoagulants Dabigatran associated with post-marketing bleed events Rivaroxaban the first oral, factor Xa inhibitor to market Clinical trials evaluating use in other cardiovascular indications (ACS, PCI) in addition to AF Management of bleeding difficult as no antidote exists Agent-specific characteristics to guide drug selection

49. Questions?