Anticoagulation and Thrombosis Management A Review of Non-Vitamin K Oral Anticoagulants: Venous Thromboembolism Title Slide Layout

Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban Target IIa (thrombin) Xa Hours to maximum concentration 1-3 2-4 3-4 1-2 Half-life, h 12-17 5-13 12 9-11 Renal clearance, % 80 33* 27 50 Transporters P-gp Cytochrome P450 metabolism, % None 32 <32 <4 *33% renally cleared; 33% excreted unchanged in urine. Heidbuchel H, et al. Europace. 2013;15:625-651[1]; Hellwig T, et al. Ann Pharmacother. 2013;47:1478-1487.[2]

Treatment and Secondary Prevention Initial (acute): 0 to ~7 days Long-term (subacute): ~7 days to ~3 months Extended: ~3 months to indefinite VKA or NOAC VKA: initiated concurrently with parenteral anticoagulant; parenteral anticoagulant is continued until the INR ≥ 2.0 for 24 hours NOAC: initiated after parenteral anticoagulant (dabigatran/edoxaban) or initiated in place of parenteral anticoagulant (rivaroxaban/apixaban) and continued thereafter Parenteral: Heparin, LMWH, fondaparinux Kearon C, et al. Chest. 2012;141(2 Suppl):e419s-e494S.[3]

Acute VTE Treatment Trials RE-COVER IIa EINSTEINb,c AMPLIFYd Hokusaie Drug Dabigatran Rivaroxaban Apixaban Edoxaban N 2589 8281 5395 8240 Design 2 x blind PROBE Indication VTE DVT or PE Heparin bridge Yes No Duration, mo 6 3, 6, 12 3-12 Content Slide Layout: TEXT a. Schulman S, et al. Circulation. 2014;129:764-772[4]; b. Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510[5]; c. Büller HR, et al. N Engl J Med. 2012;366:1287-1297[6]; d. Agnelli G, et al. N Engl J Med. 2013;369:799-808[7]; e. Büller HR, et al. N Engl J Med. 2013;369:1406-1415.[8]

RE-COVER II Study Design Warfarin INR 2.0 to 3.0 Dabigatran 150 mg twice daily R 6 months of treatment Acute VTE Treatment with LMWH or UFH for 5 to 11 days N = 2589 Primary efficacy outcomes: Symptomatic recurrent VTE and related death Principal safety outcome: Major bleeding Palette Schulman S, et al. Circulation. 2014;129:764-772.[4]

RE-COVER II Results % Efficacy Safety P < .001 (for noninferiority) Dabigatran Warfarin P < .001 (for noninferiority) % Efficacy Safety Schulman S, et al. Circulation. 2014;129:764-772.[4]

EINSTEIN DVT/PE Study Designs Open-label, noninferiority study Predefined treatment period of 3, 6, or 12 months EINSTEIN-DVT: Objectively confirmed VTE without PE Day 21 Rivaroxaban 15 mg twice daily Rivaroxaban 20 mg once daily N = 3449 30-day poststudy treatment period R Enoxaparin twice daily for 5 or more days, plus VKA INR 2.0 to 3.0 EINSTEIN-PE: Objectively confirmed PE ± DVT N = 4832 Day 1 Primary efficacy outcome: Symptomatic recurrent VTE Principal safety outcome: Major or nonmajor clinically relevant bleeding Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510[5]; Büller HR, et al. N Engl J Med. 2012;366:1287-1297.[6]

EINSTEIN Pooled Data Efficacy % Age, y Weight, kg Cr Cl, mL/min Prins MH, et al. Thromb J. 2013;11:21[9]; Büller HR, et al. ASH 2012. Abstract 20.[10]

EINSTEIN Pooled Data Major Bleeding Age, y Weight, kg Cr Cl, mL/min % Prins MH et al. Thromb J. 2013;11:21[9]; Büller HR, et al. ASH 2012. Abstract 20.[10]

EINSTEIN Pooled Data Fragile Patients Elderly (>75 years) Body weight ≤ 50 kg Renal failure (Cr Cl < 50 mL/min) Outcome Rivaroxaban, % (n = 791) Enoxaparin/VKA, % (n = 782) HR (95% CI) P Value Recurrence of thromboembolism 2.7 3.8 0.68 (0.39-1.18) -- Overall 2.1 2.3 0.89 (0.66-1.19) < .001 Major bleeding 1.3 4.5 0.27 (0.13-0.54) 1.0 1.7 0.54 (0.37-0.79) .002 Büller HR, et al. ASH 2012. Abstract 20.[10]

AMPLIFY Study Design Follow-up at 6 months Apixaban 10 mg twice daily for 7 days Apixaban 5 mg twice daily Follow-up at 6 months Patients with DVT or PE ± DVT R Enoxaparin every 12 hours for 5 or more days and warfarin to INR 2.0 to 3.0 N = 5395 Palette Primary efficacy outcome: Symptomatic recurrent VTE or VTE-related death Principal safety outcome: Major bleeding Agnelli G, et al. N Engl J Med. 2013;369:799-808.[7]

AMPLIFY Results Efficacy Safety Bleeding Rate, % Recurrent VTE, % (noninferiority) P < .001 Bleeding Rate, % Recurrent VTE, % P < .001 (superiority) Agnelli G, et al. N Engl J Med. 2013;369:799-808.[7]

Maximum treatment period of 12 months Hokusai-VTE Study Design Maximum treatment period of 12 months Standard therapy LMWH/UFH (at least 5 days) + warfarin (INR, 2.0-3.0) N = 8292 Symptomatic DVT and/or PE Edoxaban LMWH/UFH (at least 5 days) + edoxaban 60 mg once daily R Day 1 Primary efficacy outcome: Symptomatic recurrent VTE or VTE-related death Principal safety outcome: Major or CRNM bleeding during treatment Raskob, G et al. J Thromb Haemost. 2013;11:1287-1294.[11]

P < .001 (noninferiority) Hokusai-VTE Results P = .004 (superiority) P < .001 (noninferiority) % Büller HR, et al. N Engl J Med. 2013;369:1406-1415.[8]

Recurrent VTE in Extension VTE Trials Incidence of Recurrent VTE Trial Agent NOAC, % Warfarin, % HR (95% CI) RE-MEDYa Dabigatran 1.8 1.3 1.44 (0.78-2.64) Placebo, % RE-SONATEa 0.4 5.6 0.08 (0.02-0.25) EINSTEIN-EXTb Rivaroxaban 7.1 0.18 (0.09-0.39) AMPLIFY-EXTc Apixaban 2.5 mg 1.7 8.8 0.19 (0.11-0.33) Apixaban 5 mg 0.20 (0.11-0.34) a. Schulman S, et al. N Engl J Med. 2013;368:709-718[12]; b. Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510[5]; c. Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]

Major Bleeding in Extension VTE Trials Incidence of Major Bleeding Trial Agent NOAC, % Warfarin, % HR (95% CI) RE-MEDYa Dabigatran 0.9 1.8 0.52 (0.27-1.02) Placebo, % RE-SONATEa 0.3 Not estimable EINSTEIN-EXTb Rivaroxaban 0.7 AMPLIFY-EXTc Apixaban 2.5 mg 0.2 0.5 0.49 (0.09-2.64) Apixaban 5 mg 0.1 0.25 (0.03-2.24) a. Schulman S, et al. N Engl J Med. 2013;368:709-718[12]; b. EINSTEIN Investigators. N Engl J Med. 2010;363:2499-2510[5]; c. Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]

RE-MEDY Study Design Treatment period Anticoagulant therapy Warfarin (INR, 2.0-3.0) Placebo Confirmed VTE Anticoagulant therapy 3 to 12 months and “increased risk of recurrence” Dabigatran etexilate 150 mg twice daily R 0 to 7 days until INR ≤ 2.3 Follow-up every 30 days to 6 months, then every 90 days to end of treatment Up to 36 months End of treatment Screening Screening/baseline Treatment period Schulman ref not in the list Schulman S, et al. N Engl J Med. 2013;368:709-718.[12]

RE-SONATE Study Design Follow-up 30 days Extended follow-up 11 months Treatment period Screening Dabigatran etexilate 150 mg twice daily Anticoagulant (VKA) therapy 6 to 18 months R Placebo 0 to 7 days until INR ≤ 2.3 18 months End of extension follow-up 6 months End of treatment 7 months End of study follow-up Confirmed VTE Screening Schulman S, et al. N Engl J Med. 2013;368:709-718.[12]

RE-MEDY, RE-SONATE Results Efficacy Safety Dabigatran Warfarin Dabigatran Placebo RE-MEDY RE-SONATE RE-MEDY RE-SONATE Schulman S, et al. N Engl J Med. 2013;368:709-718.[12]

EINSTEIN-Extension Study Design Additional 6 to 12 months of treatment Equipoise: Should treatment be continued? Patients in EINSTEIN-DVT who had completed 6 to 12 months of therapy Rivaroxaban 20 mg once daily Additional 6 to 12 months of treatment R Placebo N = 1197 PEINSTEIN PE: study design EINSTEIN PE is a randomized, open-label, active-controlled, parallel-group, non-inferiority, event­driven study. Patients (N=4,845) with confirmed acute symptomatic PE with or without symptomatic DVT. Patients randomized to receive oral rivaroxaban 15 mg bid for 3 weeks then 20 mg od, or subcutaneous enoxaparin (1 mg/kg bid for at least 5 days) and VKA, (INR 2.0–3.0) started within 48 hours, for 3, 6 or 12 months.1,2 EINSTEIN PE is still on going – estimated completion October 2011. Reference 1. EINSTEIN PE. Available at: http://clinicaltrials.gov. Trial ID: NCT00439777. Accessed August 2011 alette Primary efficacy outcome: Symptomatic recurrent VTE Principal safety outcome: Major bleeding Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510.[5]

EINSTEIN-Extension Results P < .001 P < .001 Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510.[5]

AMPLIFY-EXT Study Design Placebo N = 2482 Clinical diagnosis of DVT or PE, anticoagulation treatment 6 to 12 months, no recurrence Follow-up at 12 months Apixaban 2.5 mg twice daily Apixaban 5 mg twice daily Equipoise: Should treatment be continued? R Agnelli not in the ref list Primary endpoint: VTE recurrence or death Secondary outcome measures: Major bleeding Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]

AMPLIFY-EXT Results P < .001 Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]

Dabigatran Trials in Major Orthopedic Surgery Dabigatran (not approved by the US Food and Drug Administration for this indication) RE-MODEL: Dabigatran 150/220 mg vs enoxaparin 40 mg daily, 6 to 10 days, TKRa RE-MOBILIZE: Dabigatran 150/220 mg daily vs enoxaparin 30 mg twice a day, 12 to 15 days, TKRb RE-NOVATE: Dabigatran 150/220 mg vs enoxaparin 40 mg daily, 28 to 35 days THRc RE-NOVATE II: Dabigatran 220 mg vs enoxaparin 40 mg daily, 28 to 35 days, THRd a. Eriksson BI, et al. J Thromb Haemost. 2007;5:2178-2185[14] ; b. Ginsberg JS, et al. J Arthroplasty. 2009;24:1-9[15]; c. Eriksson BI, et al. Lancet. 2007;370:949-956[16]; d. Eriksson BI, et al. Thromb Haemost. 2011;105:721-729.[17] 24

Dabigatran Pooled Analysis Enoxaparin Dabigatran 150 mg Dabigatran 220 mg Efficacy P Value Major VTE and VTE-related mortality, % 3.3 3.8 .91 3.0 .20 Safety Major bleeding, % 1.4 1.1 .16 .61 Major + CRNM 5.0 5.6 .58 .56 Friedman RJ, et al. Thromb Res. 2010;126:175-182.[18]

Apixaban Trials in Major Orthopedic Surgery Apixaban ADVANCE-1: Apixaban 2.5 mg twice daily vs enoxaparin 30 mg every 12 hours for 10 to 14 days, TKRa ADVANCE-2: Apixaban 2.5 mg twice daily vs enoxaparin 40 mg daily for 10 to 14 days, TKRb ADVANCE-3: Apixaban 2.5 mg twice daily vs enoxaparin 40 mg daily every 24 hours for 5 weeks, THRc a. Lassen MR, et al. N Engl J Med. 2009;361:594-604[19]; b. Lassen MR, et al. Lancet 2010;375:807-815[20]; c. Lassen MR, et al. N Engl J Med 2010;363:2487-2498. [21] 26

Apixaban Pooled Results of ADVANCE-2 and ADVANCE-3 N = 8464 patients undergoing TKR (ADVANCE-2) and THR (ADVANCE-3) Efficacy Apixaban Enoxaparin Risk Difference (95% CI) P Major VTE, % 0.7 1.5 −0.8 (−1.2 to −0.3) .001 Safety Major bleeding, % 0.8 −0.02 (−0.4 to 0.4) -- CRNM bleeding, % 3.6 4.2 −0.6 (−1.4 to 0.3) Raskob GE, et al. J Bone Joint Surg Br 2012;94:257-264.[22]

Rivaroxaban Trials in Major Orthopedic Surgery Rivaroxaban RECORD1: Rivaroxaban 10 mg daily vs enoxaparin 40 mg daily for 5 weeks, THRa RECORD2: Rivaroxaban 10 mg daily for 5 weeks vs enoxaparin 40 mg daily for 10 to 14 days, THRb RECORD3: Rivaroxaban 10 mg vs enoxaparin 40 mg daily for 13 to 17 days, TKRc RECORD4: Rivaroxaban 10 mg daily vs enoxaparin 30 mg every 12 hours for 17 days, TKRd a. Eriksson BI, et al. N Engl J Med. 2008;358:2765-2775[23]; b. Kakkar AK, et al. Lancet. 2008;372:31-39[24] ; c. Lassen MR, et al. N Engl J Med. 2008;358:2776-2786[25]; d. Turpie AG, et al. Lancet. 2009;373:1673-1680.[26] 28

Rivaroxaban RECORD1-RECORD4: Pooled Analysis N = 12,729 Rivaroxaban, % Enoxaparin, % HR (95% CI) P Primary Efficacy End Point Composite of symptomatic VTE + all-cause mortality 0.5 1.0 0.48 (0.30-0.76) .001 Symptomatic VTE 0.39 0.84 0.46 (0.27-0.76) -- PE 0.11 0.26 0.44 (0.15-1.12) All-cause mortality 0.10 0.16 0.60 (0.18-1.82) Bleeding Events Major bleeding 0.3 0.2 1.62 (0.77-3.53) .23 Major + CRNM bleeding 2.8 2.5 1.17 (0.93-1.46) .19 Any bleeding 6.6 6.2 1.07 (0.92-1.24) .38 Turpie AG. et al. Thromb Haemost. 2011;105:444-453.[27]

Abbreviations 95% CI = 95% confidence interval ADVANCE-1 = Apixaban Dose Orally vs Anticoagulation with Enoxaparin ADVANCE-2 = Apixaban versus enoxaparin for thromboprophylaxis after knee replacement ADVANCE-3 = Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 3 AMPLIFY = Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy CRNM = clinically relevant nonmajor DVT = deep vein thrombosis EXT = extension HR = hazard ratio INR = international normalized ratio LMWH = low-molecular-weight heparin NOAC = non-vitamin K (novel) oral anticoagulants PE = pulmonary embolism

Abbreviations (cont) P-gp = P-glycoprotein PK/PD = pharmacokinetics/pharmacodynamics PROBE = prospective, randomized, open-label, blinded end point evaluation RECORD = Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism RE-COVER = Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism RE-LY = Randomized Evaluation of Long-Term Anticoagulation Therapy RE-SONATE = Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation THR = total hip replacement TKR = total knee replacement UFH = unfractionated heparin VKA = vitamin K antagonist VTE = venous thromboembolism

References 1. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625-651. 2. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother. 2013;47:1478-1487. 3. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S-e494S. 4. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-772. 5. Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510. 6. Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.

References (cont) 7. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808. 8. Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415. 9. Prins MH, Lensing AW, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21. 10. Büller HR, et al. Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies. ASH Annual Meeting Abstracts. 2012;120:Abstract 20. 11. Raskob G, Büller H, Prins M, et al; Hokusai-VTE Investigators. Edoxaban for the long-term treatment of venous thromboembolism: rationale and design of the Hokusai-venous thromboembolism study--methodological implications for clinical trials. J Thromb Haemost. 2013;11:1287-1294. 12. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718. 13. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.

References (cont) 14. Eriksson BI, Dahl OE, Rosencher N, et al; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185. 15. Ginsberg JS, Davidson BL, Comp PC, et al; RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9. 16. Eriksson BI, Dahl OE, Rosencher N, et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. 17. Eriksson BI, Dahl OE, Huo MH, et al; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721-729. 18. Friedman RJ, Dahl OE, Rosencher N, et al; RE-MOBILIZE, RE-MODEL, RE-NOVATE Steering Committees. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res. 2010;126:175-182. 19. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604.

References (cont) 20. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815. 21. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-2498. 22. Raskob GE, Gallus AS, Pineo GF, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br. 2012;94:257-264. 23. Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775. 24. Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31-39. 25. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786.

References (cont) 26. Turpie AG, Lassen MR, Davidson BL, et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673-1680. 27. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105:444-453.