1. Anticoagulation and Thrombosis Management
A Review of Non-Vitamin K Oral Anticoagulants:
Other Uses
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* 25 50
Transporters
P-gp
Cytochrome P450 metabolism, %
None
<32
~50
<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. Rationale for the Use of Oral Anticoagulation Post MI
WARISa
Warfarin, n = 607
Placebo, n = 607 P
Death, %
15.5
20.3
.0267
Reinfarction, %
13.5
20.4
.0007
Major bleeding
1.3 --
WARIS-IIb
Warfarin,
n = 1216
Aspirin,
n = 1206
W + A,
n = 1208
W vs A
W vs W + A
A vs W + A
Death, nonfatal reinfarction or stroke, %
16.7 20 15
.03 NS
.001
Major bleeding, %/y
0.68
0.17
0.57
Smith P, et al. N Engl J Med. 1990;323: [3]; b. Hurlen M, et al. N Engl J Med. 2002;347: [4]

4. APPRAISE-2 Efficacy and Safety Results
Trial terminated November 2011 because of excess clinically important bleeding events in the apixaban group without counterbalancing reduction in ischemic events
Outcome
Apixaban 5 mg twice daily, %
Placebo, %
HR (95% CI) P
Efficacy
n = 3705
n = 3687
Cardiovascular death, myocardial infarction, or ischemic stroke
7.5
7.9
0.95 ( )
.51
Death
4.2
3.9
1.08 ( )
Cardiovascular death
2.8
3.0
0.96 ( )
.76
Safety: bleeding
n = 3673
n = 3642
TIMI criteria: major bleeding
1.3
0.5
2.59 ( )
.001
Fatal bleeding
0.1 NA
Intracranial bleeding
0.3
4.06 ( )
.03
Any bleeding
18.5
8.4
2.36 ( )
< .001
Alexander JH, et al. N Engl J Med. 2011;365: [5]

5. Rivaroxaban in ACS: ATLAS ACS 2—TIMI 51
Trial dose of rivaroxaban was 2.5 mg and 5 mg twice daily vs 20 mg daily in patients with atrial fibrillation
P = .02
Rivaroxaban 2.5 mg twice daily
Rivaroxaban 5 mg twice daily
Placebo
P = .002 %
P = .03
P = .66
Mega JL, et al. N Engl J Med. 2012;366:9-19.[6]

6. Kaplan-Meier Event Rate, %
ATLAS-2
Reduction in Stent Thrombosis (Definite/Probable)
Rivaroxaban 2.5 mg twice daily
Rivaroxaban 5 mg twice daily
Placebo
P values = mITT
Kaplan-Meier Event Rate, %
P = .023
P = .089
Gibson CM, et al. J Am Coll Cardiol. 2013;62: [7]

7. ATLAS-2
Mortality Benefit With Very Low-dose Rivaroxaban in Patients With STEMI
P = .008
P = .007
P = .006
N = 7727
Mega JL, et al. J Am Coll Cardiol. 2013;61: [8]

8. Patients With Active Cancer Clinically Relevant Bleeding
NOAC Trials Outcomes in Patients With Cancer: Prespecified Subgroup Analyses
NOAC Trial
Patients With Active Cancer
Recurrent VTE
Clinically Relevant Bleeding
EINSTEIN-DVT
Rivaroxaban = 6.8%
VKA = 5.2%
Rivaroxaban = 3.4%
VKA = 5.6%
Rivaroxaban = 14.4%
VKA =15.9%
EINSTEIN-PE
Rivaroxaban = 4.7%
VKA = 4.5%
Rivaroxaban = 1.8%
VKA = 2.8%
Rivaroxaban = 12.3% VKA = 9.3%
EINSTEIN-Extension
Rivaroxaban = 4.5%
Placebo = 4.4% NR
AMPLIFY
Apixaban = 2.5%
AMPLIFY-EXT
Placebo = 2.2%
2.5 mg apixaban =1.8%
5 mg apixaban =1.1%
RE-COVER
Dabigatran = 5%
VKA =4.5%
Dabigatran = 3.1%
VKA = 5.3%
RE-MEDY
Dabigatran = 4.2%
VKA = 4.1%
Dabigatran = 3.3%
VKA = 1.7%
Hokusai-VTE
Edoxaban = 2.6%
VKA = 2.4%
Edoxaban = 3.7%
VKA = 7.1%
Edoxaban = 18.3%
VKA = 25.3%
Bauersachs R, et al. N Engl J Med. 2010;363: [9]; Büller HR, et al. N Engl J Med. 2012;366: [10]; Agnelli G, et al. N Engl J Med. 2013;369: [11]; Agnelli G, et al. N Engl J Med. 2013;368: [12]; Schulman S, et al. N Engl J Med. 2009;361: [13]; Schulman S, et al. N Engl J Med. 2013;368: [14]; Büller HR, et al. N Engl J Med. 2013;369: [15]; Raskob GE, et al. ASH Abstract 211.[16]

9. SELECT-D Study Design Placebo
Rivaroxaban
15 mg orally twice daily × 3 weeks
20 mg once daily × 6 months
Dalteparin
200 IU/kg daily subcutaneously × 1 month
150 IU/kg months 2 to 6
Primary efficacy: incidence of recurrent VTE
Secondary outcomes: safety, acceptability, biomarker identification, and health economics
Residual vein thrombosis-positive patients
20 mg once daily
6 months vs 12 months
of treatment
Placebo
Prospective, randomized, open-label, multicenter, pilot trial in selected patients with cancer at risk for VTE recurrence
Estimated enrollment: 530 patients
Young A, et al. ASCO Abstract TPS9661.[17]

10. Abbreviations
95% CI = 95% confidence interval ACS = acute coronary syndrome AMPLIFY = Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy APPRAISE = Apixaban for Prevention of Acute Ischemic Safety Events ATLAS ACS 2—TIMI 51 = Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 DVT = deep vein thrombosis EXT = extension HR = hazard ratio ITT = intention to treat MITT = modified intention to treat NOAC = non-vitamin K (novel) oral anticoagulant NR = not reported

11. Abbreviations (cont)
PE = pulmonary embolism P-gp = P-glycoprotein PK/PD = pharmacokinetics/pharmacodynamics RE-COVER = Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism RE-MEDY = Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism SELECT-D = Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism STEMI = ST-segment-elevation myocardial infarction VKA = vitamin K antagonist VTE = venous thromboembolism WARIS = Warfarin Re-Infarction Study WARIS-II = Warfarin, Aspirin, Re-Infarction Study

12. 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: Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med. 1990;323: Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347: Alexander JH, Lopes RD, James S, et al; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365: Mega JL, Braunwald E, Wiviott SD, et al; ATLAS-ACS 2 TIMI 51. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366: Gibson CM, Chakrabarti AK, Mega J, et al; ATLAS-ACS 2 TIMI 51 Investigators. Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51. J Am Coll Cardiol. 2013;62:

13. References (cont)
8. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51). J Am Coll Cardiol. 2013;61:
9. Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:
10. 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:
11. 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:
12. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:
13. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:
14. 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:

14. References (cont)
15. 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: Raskob GE, Büller HR, Angchaisuksiri P, et al. Edoxaban for long-term treatment of venous thromboembolism in cancer patients. Presented at: 55th ASH Annual Meeting and Exposition; December 9; 2013; New Orleans, LA. Abstract Young A, Dunn J, Chapman O, et al. SELECT-D: Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract TPS9661.