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

2. 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: [1]; Hellwig T, et al. Ann Pharmacother. 2013;47: [2]

3. 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]

4. 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: [4]; b. Bauersachs R, et al. N Engl J Med. 2010;363: [5]; c. Büller HR, et al. N Engl J Med. 2012;366: [6]; d. Agnelli G, et al. N Engl J Med. 2013;369: [7]; e. Büller HR, et al. N Engl J Med. 2013;369: [8]

5. 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: [4]

6. 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: [4]

7. 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: [5]; Büller HR, et al. N Engl J Med. 2012;366: [6]

8. 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 Abstract 20.[10]

9. 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 Abstract 20.[10]

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 ( ) --
Overall
2.1
2.3
0.89 ( )
< .001
Major bleeding
1.3
4.5
0.27 ( )
1.0
1.7
0.54 ( )
.002
Büller HR, et al. ASH Abstract 20.[10]

11. 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: [7]

12. 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: [7]

13. 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, )
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: [11]

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

15. 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 ( )
Placebo, %
RE-SONATEa
0.4
5.6
0.08 ( )
EINSTEIN-EXTb
Rivaroxaban
7.1
0.18 ( )
AMPLIFY-EXTc
Apixaban 2.5 mg
1.7
8.8
0.19 ( )
Apixaban 5 mg
0.20 ( )
a. Schulman S, et al. N Engl J Med. 2013;368: [12]; b. Bauersachs R, et al. N Engl J Med. 2010;363: [5]; c. Agnelli G, et al. N Engl J Med. 2013;368: [13]

16. 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 ( )
Placebo, %
RE-SONATEa
0.3
Not estimable
EINSTEIN-EXTb
Rivaroxaban
0.7
AMPLIFY-EXTc
Apixaban 2.5 mg
0.2
0.5
0.49 ( )
Apixaban 5 mg
0.1
0.25 ( )
a. Schulman S, et al. N Engl J Med. 2013;368: [12]; b. EINSTEIN Investigators. N Engl J Med. 2010;363: [5]; c. Agnelli G, et al. N Engl J Med. 2013;368: [13]

17. RE-MEDY Study Design Treatment period Anticoagulant therapy
Warfarin (INR, )
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: [12]

18. 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: [12]

19. 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: [12]

20. 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: Trial ID: NCT 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: [5]

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

22. 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: [13]

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

24. 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: [14] ; b. Ginsberg JS, et al. J Arthroplasty. 2009;24:1-9[15]; c. Eriksson BI, et al. Lancet. 2007;370: [16]; d. Eriksson BI, et al. Thromb Haemost. 2011;105: [17] 24

25. 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: [18]

26. 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: [19]; b. Lassen MR, et al. Lancet 2010;375: [20]; c. Lassen MR, et al. N Engl J Med 2010;363: [21] 26

27. 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: [22]

28. 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: [23]; b. Kakkar AK, et al. Lancet. 2008;372:31-39[24] ; c. Lassen MR, et al. N Engl J Med. 2008;358: [25]; d. Turpie AG, et al. Lancet. 2009;373: [26] 28

29. 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 ( )
.001
Symptomatic VTE
0.39
0.84
0.46 ( ) -- PE
0.11
0.26
0.44 ( )
All-cause mortality
0.10
0.16
0.60 ( )
Bleeding Events
Major bleeding
0.3
0.2
1.62 ( )
.23
Major + CRNM bleeding
2.8
2.5
1.17 ( )
.19
Any bleeding
6.6
6.2
1.07 ( )
.38
Turpie AG. et al. Thromb Haemost. 2011;105: [27]

30. 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

31. 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

32. 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: 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: 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: Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363: 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:

33. 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: 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: 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: 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 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: 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: Agnelli G, Büller HR, Cohen A, et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:

34. 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: 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: 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: 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: 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: 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:

35. 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: 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: 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: 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: 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: 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:

36. 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: 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: