1. Allyson Sarigianis, Pharm.D. October 19, 2013

2.  Review current practice recommendations for prevention of stroke/systemic embolism in atrial fibrillation  Compare and contrast pharmacology between warfarin and target specific oral anticoagulants (TSOACs)  Summarize the efficacy and safety of TSOACs for atrial fibrillation  Examine the differences between warfarin and TSOACs for atrial fibrillation  Identify future clinical implication for new era in anticoagulation management based on AT9 2012 Chest Guidelines

3. Current FDA Approved Indications Warfarin Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE) Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events Dabigatran Stroke prevention in patients with non-valvular atrial fibrillation Rivaroxaban Stroke prevention in patients with non-valvular atrial fibrillation Prevention of VTE in patients undergoing hip or knee replacement Acute treatment of DVT/PE Secondary prevention of DVT/PE Apixaban Stroke prevention in patients with non-valvular atrial fibrillation

6. Kinetics AbsorptionOral: Rapid, complete Distribution0.14 L/kg MetabolismHepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4 ExcretionUrine (92%, primarily as metabolites) Half-life20-60 hours

7.  Onset of action:  5-7 days  May requiring bridging  Antidote:  Vitamin K, FFP, PRBC  Interactions:  Foods with high vitamin K content

8.  Medications  Amiodarone  Antiplatelets  Azole antifungals (fluconazole)  2 nd /3 rd- gen Cephalosporins  Fluoroquinolones (ciprofloxacin)  Griseofulvin  Isoniazid  Macrolides (clarithromycin)  Metronidazole  NSAIDs  Penicillins (nafcillin)  Prednisone  Rifampin  SSRIs  Sulfonamides (Bactrim)  Tetracyclines (Doxycycline )  Herbals  Ginger  Gingko  Fenugreek  Chamomile  St. John’s Wort

9.  ADRs  Bleeding/Hemorrhage/Hematuria  Vasculitis  Dermatitis, pruritus, urticaria  Abdominal pain, N/V/D  Anemia  Skin necrosis, gangrene, “purple toes” syndrome

11.  MOA: direct thrombin inhibitor which inhibits:  Both free and fibrin-bound thrombin  Cleavage of fibrinogen to fibrin  Activation of factors V, VIII, XI, and XIII  Thrombin-induced platelet aggregation

12. Kinetics AbsorptionRapid; initially slow postoperatively DistributionV d : 50-70 L MetabolismHepatic; rapidly and completely hydrolyzed to active form by plasma and hepatic esterases ExcretionRenal (80%) Half-life12-17 hours

13.  Monitoring  PPT  Onset: 1 hour, delayed by food  Antidote: None  ADRs  Bleeding (8% to 33%; major ≤ 6%)  Dyspepsia (11%)

14.  Contraindications  Hypersensitivity to dabigatran or any component  Active bleeding  Warnings/Precautions  Bleeding  Renal impairment  Anticoagulants  Invasive/surgical invasions  P-gp inducers/inhibitors

15.  Drug interactions  Category X: P-Gp inducers  Category D: Amiodarone, P-Gp inhibitors, quinidine, St. john’s Wort, verapamil  Category C: antacids, anticoagulants, antiplatelet agents, atorvastatin, dasantinib, ibritumonmab, NSAIDs, prostacyclin analogs, PPIs, salicylates, thrombolytic agents

16.  FDA Bleeding Risk: [12-7-2011]  Evaluating post-marketing reports of serious bleeding  “Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies.”

17.  ISMP Medication Safety Alert: Quarter Watch [01-12-12]  932 serious adverse events for 1 st quarter of 2011  120 deaths  25 cases of permanent disability  543 cases requiring hospitalization  505 cases involved hemorrhage: elderly patients (Median age of 80) ▪ 120 cases of hemorrhagic stroke

18.  FDA Drug Safety Communication: [11‐02‐2012]  “… FDA investigated the actual rates of gastrointestinal bleeding and intracranial hemorrhage for new users of [dabigatran] compared to new users of warfarin. The results of this Mini‐Sentinel assessment indicate that bleeding rates associated with new use of [dabigatran] do not appear to be higher than bleeding rates associated with new use of warfarin ….” 18

19.  FDA Drug Safety Communication: [12-19-2012]  “A clinical trial in Europe (the RE-ALIGN trial) was recently stopped because [dabigatran] users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin. There was also more bleeding after valve surgery in the [dabigatran] users than in the warfarin users [dabigatran] is not approved for patients with AF caused by heart valve problems. “ 19

20. May be appropriateMAY NOT be appropriateNOT appropriate Ability to comply with twice daily drug regimen History of non-adherenceSevere renal impairment (CrCl <30 ml/min) Unstable INRs on warfarin (unrelated to adherence) Stable INRs on warfarinHistory of GI bleeding or recent ulcers Difficulty obtaining regular INRs on warfarin Advanced age (75-80 yrs and older; consider benefits and risks) Active liver disease Complicated interacting drug regimens on warfarin Pregnancy, at risk of pregnancy, or lactating High risk of intracranial bleedNeed for concomitant treatment with P-gp inducer (e.g,. rifampin, St. John’s Wort) Medication regimen does not include drugs that interact with dabigatran Moderate renal impairment (CrCl 30- 50 ml/min) and the need for concomitant treatment with the P-gp inhibitors dronedarone or systemic ketoconazole Good renal function No history of GI bleeding or recent ulcers

22.  MOA: selective/reversible direct inhibitor of factor Xa  Prevents the conversion of prothrombin to thrombin  Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin

23. Creatine Clearance (mL/min) >5050-3029-15<15 or HD Atrial fibrillation20 mg po daily15 mg po dailyAvoid use Postoperative thromboprophylaxis 10 mg po daily Knee: 12-14 days Hip: 35 days 10 mg po daily, use with caution Avoid use Treatment of PE/VTE15 mg twice daily x21 days, then 20 mg po daily Use with caution Avoid use Secondary Prophaxis for PE/VTE 20 mg po dailyUse with caution Avoid use

24. Kinetics AbsorptionRapid DistributionV dss : ~50 L MetabolismHepatic (33%) via CYP3A4/5 and CYP2J2 ExcretionRenal (66% primarily via active tubular secretion); feces (28%) Half-life5-9 hours

25.  Monitoring  Prothrombin time (PT)  CBC with differential  Renal/hepatic function  Onset: 2-4 hours  Antidote: None

26.  ADRs  Pruritus (2%)  Bleeding ▪ DVT prophylaxis: 6% [major: <1%] ▪ Atrial fibrillation: 21% [major: 6%]  Thrombocytopenia (3%)  Increase in liver enzymes (7%-3%)

27.  Contraindications  Hypersensitivity to rivaroxaban or any component  Active bleeding  Drug Interactions  Category X: P-Gp or 3A4 inhibitors/inducers  Category C: anticoagulants, antiplatelet agents, NSAIDs, salicylates

28.  ISMP Medication Safety Alert: 10/4/2012  Primary event: Thrombus  158 cases, 44.4% of the total  Hemorrhage  121 cases, 34% of the total

30.  MOA: oral direct Xa inhibitor  Dose: 5mg twice daily  Dose reduction to 2.5mg twice daily if 2+ of the following: ▪ Age ≥80 years ▪ Body weight ≤60kg ▪ Scr ≥1.5mg/dl  AVOID in CrCl <15 ml/min

31. Kinetics AbsorptionRapid; Intestines DistributionV d : 21 L Metabolism15% liver metabolism CYP3A4/5 P-gp ExcretionPrimarily Biliary/Fecal (46-56%) Renal (27%) unchanged Half-life8 to 15 hours

32.  Monitoring  Minimal impact on the PT, INR, or aPTT  Factor Xa inhibition  Onset: 3-4 hours  Antidote: None

34. RE-LYROCKET-AFARISTOTLE Dabigatran 150mg BID vs. warfarin Rivaroxaban 20mg daily vs. warfarin Apixaban5mg BID vs. warfarin Study Design Trial design RCT Open blinded assessment RCT DB DD Sample size (n)18,000+14,000+18,000+ Inclusion criteria AF and selected risk factor(s) for embolization AF and CHADS2 ≥2 AF or flutter and CHADS2 ≥1 Key exclusion criteria Valvular AF Use of ASA ≥100 mg/day CrCl <30 ml/min Valvular AF; Use of ASA >100 mg/day CrCl <30 ml/min Valvular AF Need for ASA >165 mg/day SCr >2.5mg/dL or CrCl <25ml/min Follow-up (mean) 2 yr1.9 yr1.8 yr Outcome Definitions Primary EfficacyComposite of systemic embolism and stroke (ischemic or hemorrhagic) Major BleedingISTH: fatal/critical organ bleed; decrease ≥ 2g/dL Hbg or transfusion of ≥2U blood MortalityAll causes Baseline Characteristics Age (years)71 (mean)73 (median)70 (median) Female (%)36.4%39.7%35.2 % CHADS2 (mean)2.13.52.1 Previous embolic episode (%) 20% (stroke or TIA only) 55% (stroke,TIA, systemic embolism) 19% (stroke, TIA, systemic embolism ) TTR (%) (Standard 60-65%) 64%55%62%

35. Comparison of Efficacy Results RE-LYROCKETAFARISTOTLE Outcome (%/year) Dabigatran 150mg BID vs. warfarin p Value Rivaroxaban 20mg daily vs. warfarin p Value Apixaban 5mg BID vs. warfarin p Value Primary Outcome Stroke or systemic embolism 1.1 vs. 1.7% p<0.001 NNT 88 2.1 vs. 2.4%p=0.121.3 vs. 1.6% p=0.01 NNT 167 Stroke1.0 vs. 1.6% p<0.001 NNT 88 1.65 vs. 1.96%p=0.091.2 vs. 1.5% p=0.01 NNT 175 Ischemic stroke0.9 vs. 1.3% p=0.03 NNT 132 1.3 vs. 1.4p=0.580.97 vs. 1.05%p=0.42 Hemorrhagic stroke0.1vs0.4% p<0.001 NNT 182 0.26 vs. 0.44% p=0.02 NNT 333 0.24 vs. 0.47% p<0.001 NNT 238 All cause death3.6 vs. 4.1%p=0.0514.5 vs. 4.9%p=0.153.5 vs. 3.9 p=0.047 NNT 132 MI/ACS0.7 vs. 0.5% p=0.048 NNH 239 0.9 vs. 1.1%p=0.120.5 vs. 0.6%p=0.37

36. Comparison of Safety Results RE-LY ROCKETAFARISTOTLE Major bleed3.1 vs. 3.36%p=0.313.6 vs. 3.4%p=0.582.1 vs. 3.1% p<0.001 NNT 67 Intracranial bleed 0.3 vs. 0.74% p<0.001 NNT 116 0.5 vs. 0.7% p=0.02 NNT 250 0.3 vs. 0.8% p<0.001 NNT 128 GI bleed1.5 vs. 1.0% p<0.001 NNH 100 3.2 vs. 2.2%** p=0.001 NNH 100 0.76 vs. 0.86% 0.37

38.  Focused update recommendation:  Dabigatran is a useful alternative to warfarin for the prevention of stroke and systemic embolism in patients with paroxysmal to permanent AF and risk factors for stroke and systemic embolism  Do not have a prosthetic heart valve, hemodynamically significant valve disease, severe renal failure (CrCl < 15mL/min), or impaired liver disease  Alternative to warfarin for moderate-high risk patients: ▪ Difficulty achieving therapeutic INRs ▪ Inability obtaining regular bloodwork monitoring ▪ Low risk for GI bleeding ▪ Low risk for cardiovascular events

39.  2.1.8  CHADS = 0  No therapy rather than antithrombotic therapy (Grade 2B)  2.1.9  CHADS = 1  Oral anticoagulation rather than no therapy (Grade 1B)

40.  2.1.10  CHADS =2+  Oral anticoagulation rather than no therapy (Grade 1A)  2.1.11  Dabigatran 150 mg twice daily rather than adjusted-dose VKA therapy (target INR range, 2.0-3.0) (Grade 2B)

44. DabigatranRivaroxabanApixaban TargetFactor IIaFactor Xa FDA IndicationsNonvalvular AF Ortho VTE Proph Acute Treatment VTE Nonvalvular AF ProdrugYesNo DosingTwice dailyDaily, with foodTwice daily Onset1-2 hrs2-4 hrs3-4 hrs Half-life (h)14–177–118–14 Renal Adjustment ↓ 15-29ml/min Avoid < 15 ml/min Avoid < 30 ml/minAvoid < 15 ml/min Drug InteractionsP-gpCYP3A4/P-gp

45.  Efficacy  superiority vs non- inferiority  ADRs  ACS / MI risk  Cost  Clinical guidelines

46. References  Antibiotic/Antifungal Drug Interactions and Warfarin. Pharmacist's Letter 2012; 28(1):280102.  Connolly SJ, Ezekowitz MD, Yusuf S, et al. RELY Trial: Dabigatran versus warfarin in patients with atrial fibrillation. NEJM.2009; 361(12): 1139-51.  Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376: 975-83.  Reversing Dabigatran and Rivaroxaban. Pharmacist's Letter 2011; 27(9):270912.  Weitz JI. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62–70.  Institute of Safe Medication Practices. ISMP Medication Safety Alert, January 12, 2012.  “Outpatient Anticoagulation Management” VA Medical Center: MCM 11-20. Updated August 2011.  Dabigatran (Pradaxa®) National Drug Monograph, VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives, April 2011.  “Dabigatran etexilate: drug information.” www.uptodate.com. Accessed 20 January, 2012.  Rivaroxaban. Monograph. Medscape. Accessed 24 January, 2012. http://reference.medscape.com/drug/xarelto-rivaroxaban- 999670#10  Patel MA, Mahaffey KE, Garg JY, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Eng J Med. 2011.  Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604.  Lopes RD, Alexander JH, Al-Khatib SM, et al; ARISTOTLE Investigators. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159:331-9.  Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010;159:348-53.  Comparison of Oral Antithrombotics. Pharmacist's Letter. 2012; 28(1):280102.  Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126:2381.  Guyatt GH, Akl EA, Crowther M, et al. Antithrombotic Therapy and Prevention of Thrombosis.. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 2012; 141:7S-47S