1. Anticoagulation and Thrombosis Management
A Review of Non-Vitamin K Oral Anticoagulants:
Stroke Prevention in Atrial Fibrillation
Title Slide Layout

2. Comparative Pharmacology
Characteristic
Rivaroxabana
Apixabanb
Dabigatranc
Edoxaband
Target Xa
Thrombin
Time to maximum concentration, h
2-4
3-4
1-3
1-2
Renal clearance, %
33* 25 80 50
Transporters
P-gp
Cytochrome P450 metabolism, % 32
<32
None
<4
Bioavailability, %
80-100
~50
3-7 62
Dosing
Once daily
Twice daily
*33% renally cleared; 33% excreted unchanged in urine.
a. Xarelto® PI 2014[1]; b. Eliquis® PI 2014[2]; c. Pradaxa® PI 2014[3]; d. Savaysa™ PI 2015.[4]

3. Risk Score Apps HAS-BLEDa CHADS2b CHA2DS2-VAScc
a. Hefesoft. HAS-BLED Bleeding Risk Calculator for iPad[5]; b. Usquare Soft Inc. CHADS2 Application.[6]; c. Juergens D. CHA2DS2-VASc Score Application.[7]

4. NOACs for Stroke Prevention in AF
Dabigatran
RE-LY
Reported September 2009
Apixaban
ARISTOTLE
Reported September 2011    
Rivaroxaban
ROCKET AF
Reported
November 2010
Edoxaban
ENGAGE AF-TIMI 48
Reported November

5. NOAC Trials Baseline Characteristics RE-LYa (Dabigatran)
ROCKET AFb (Rivaroxaban)
ARISTOTLEc (Apixaban)
ENGAGE AF- TIMI 48d (Edoxaban)
Number randomized
18,113
14,264
18,201
21,105
Age, years (range)
72 (±9)
73 (65-78)
70 (63-76)
72 (64-78)
Female, % 37 40 35 38
Paroxysmal AF, % 32 18 15 25
VKA naive, % 50 43 41
Aspirin use, % 36 31 29
CHADS2 0 to 1 34
CHADS2 2 13 --
CHADS2 ≥3 33 87 30
≤3: 77
>4: 23
Prior heart failure, % 62 58
Content Slide Layout: TEXT
a. Connolly SJ, et al. N Engl J Med. 2009;361: [8]; b. Patel MR, et al. N Engl J Med. 2011;365: [9]; c. Granger CB, et al. N Engl J Med. 2011;365: [10]; d. Giugliano RP, et al. N Engl J Med. 2013;369: [11]

6. NOAC Trials Efficacy and Safety RE-LYa Dabigatran 110 mg P 150 mg
Warfarin
Stroke or SE, %/y
1.53
< .001
1.11
1.69
Major bleeding, %/y
2.7
.003
3.1
.31
3.4
ROCKET AFb
Rivaroxaban
1.7
2.2
Major or CRNM bleeding, %/y
14.9
14.5
.44
ARISTOTLEc
Apixaban
1.27
1.60
.01
4.07
6.01
ENGAGE AF-TIMI 48d
Edoxaban 60 mg
1.57
1.80
.08
2.75
3.43
a. Connolly SJ, et al. N Engl J Med. 2009;361: [8]; b. Patel MR, et al. N Engl J Med. 2011;365:883-91[9]; c. Granger CB, et al. N Engl J Med. 2011;365: [10]; d. Giugliano RP, et al. N Engl J Med. 2013;369: [11]

7. NOAC Trials Rates of Intracranial Bleeding RE-LYa Dabigatran 110 mg P
Warfarin
Rate/y, %
0.23
< .001
0.30
0.74
ROCKET AFb
Rivaroxaban
0.5
0.7
.02
ARISTOTLEc
Apixaban
0.33
0.80
ENGAGE AF-TIMI 48d
Edoxaban
60 mg
0.39
0.85
a. Connolly SJ, et al. N Engl J Med. 2009;361: [8]; b. Patel MR, et al. N Engl J Med. 2011;365: [9]; c. Granger CB, et al. N Engl J Med. 2011;365: [10]; d. Giugliano RP, et al. N Engl J Med. 2013;369: [11]

8. NOAC Trials Mortality ARISTOTLEa RE-LYb ROCKET AFc ENGAGE AF-TIMI 48d
Warfarin
Apixaban
RR (95% CI) P
3.94
3.52
0.89 ( )
.047
RE-LYb
Warfarin
Dabigatran 110 mg
RR (95% CI) P
Dabigatran 150 mg
4.13
3.75
0.91 ( )
.13
3.64
0.88 ( )
.51
ROCKET AFc
Warfarin
Rivaroxaban
RR (95% CI) P
As treated: 2.2
1.9
0.85 ( )
.07
ITT:
4.5
0.92 ( )
.15
ENGAGE AF-TIMI 48d
Warfarin
Edoxaban 30 mg
RR (95% CI) P
Edoxaban 60 mg
4.35
3.80
0.87 ( )
.006
3.99
0.92 ( )
.08
POOLEDe
Warfarin
NOACs
RR (95% CI) P
3.94
3.52
0.90 ( )
.0003
a. Connolly SJ, et al. N Engl J Med. 2009;361: [8]; b. Patel MR, et al. N Engl J Med. 2011;365: [9]; c. Granger CB, et al. N Engl J Med. 2011;365: [10]; d. Giugliano RP, et al. N Engl J Med. 2013;369: [11]; e. Ruff CT, et al. Lancet ;383: [12]

9. AF Registries ORBIT-AF: 10,098 patients in the United Statesa
Outpatients
PINNACLEb
AF, CAD, hypertension, and HF in the outpatient setting
Part of National Cardiovascular Data Registry suite of clinical registries
a. Cullen MW, et al. Circ Cardiovasc Qual Outcomes. 2013;6: [13]; b. PINNACLE Registry website.[14]

10. AF Registries (cont)
GLORIA-AF: 56,000 patients in nearly 50 countriesa
Patients with newly diagnosed AF
GARFIELD: 50,000 patients in 50 countriesb
Euro Heart Survey: 5333 patients in 35 countriesc
Outpatients and inpatients
RELY-AF: 15,400 patients in 46 countriesd
Patients presenting to the emergency department
a. Huisman MV, et al. Am Heart J. 2014;167: [15]; b. Kakkar AK, et al. Am Heart J. 2012;163:13-19[16]; c. Nieuwlaat R, et al. Eur Heart J. 2005;26: [17]; d. Oldgren J, et al. Circulation. 2014;129: [18]

11. X-VeRT Design Early Delayed Cardioversion 2:1 End of study treatment
(only if adequate anticoagulation or immediate transesophageal echocardiography)
Rivaroxaban
20 mg daily*
Rivaroxaban
20 mg daily* R
1-5 days
Cardioversion
42 days
2:1
VKA
VKA
OAC
Cardioversion
Strategy
End of study treatment
30-day
follow-up
Rivaroxaban
20 mg daily*
Rivaroxaban
20 mg daily*
Delayed R
≥ 21 days
(maximum 56 days)
Cardioversion
42 days
2:1
VKA
VKA
*15 mg if CrCl mL/min; VKA with INR
Ezekowitz MD, et al. Am Heart J. 2014;167: [19]

12. X-VeRT Primary Efficacy
Rivaroxaban VKA
Incidence, %
RR: 0.50
(95% CI, )
RR: 0.50
(95% CI, )
n = 5
n = 5
n = 5
n = 5
Rivaroxaban n = Rivaroxaban n = 1002
VKA n = VKA n = 502
*Excluded patients from the ITT group who were found to have atrial thrombi on transesophageal echocardiography.
Cappato R, et al. Eur Heart J. 2014;35: [20]

13. X-VeRT Safety Outcomes
RR: 0.76
(95% CI, )
Incidence, %
n = 988 n = 499
Rivaroxaban VKA
0.61
n = 6
n = 4
n = 1
n = 2
Cappato R, et al. Eur Heart J. 2014;35: [20]

14. NOACs in Renal Dysfunction
US Labeling
Dabigatran
Rivaroxaban
CrCl > 30 mL/min
150 mg × 2
CrCl > 50 mL/min
20 mg × 1
CrCl mL/min
75 mg × 2
CrCl mL/min
15 mg × 1
CrCl < 15 mL/min
Not recommended
Apixaban
Edoxaban
≥2 of the following:
age ≥ 80 years, weight ≤ 60 kg, serum Cr≥ 1.5 mg/dL
2.5 mg × 2
CrCl > 50 to ≤ 95 mL/min
60 mg × 1
30 mg × 1
Pradaxa PI[3]; Xarelto PI[1]; Eliquis PI[2]; Savaysa PI.[4]

15. Abbreviations
AF = atrial fibrillation ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation CHADS2 = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack or thromboembolism CHA2DS2-VASc = congestive heart failure/left ventricular dysfunction, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack/thromboembolism, vascular disease/coronary artery disease/myocardial infarction/peripheral artery disease/aortic plaque, age 65 to 74 years, and sex category/female CI = confidence interval CrCl = creatinine clearance CRNM = clinically relevant nonmajor bleeding ENGAGE AF-TIMI 48 = Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 GARFIELD = Global Anticoagulant Registry in the Field GLORIA-AF = Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation INR = international normalized ratio

16. Abbreviations
ITT = intention to treat LMWH = low-molecular-weight heparin NOAC = non-vitamin K (novel) oral anticoagulant ORBIT-AF = Outcomes Registry for Better Informed Treatment of Atrial Fibrillation P-gp = P-glycoprotein PK/PD = pharmacokinetics/pharmacodynamics RE-LY = Randomized Evaluation of Long-Term Anticoagulation Therapy RE-MEDY = Secondary Prevention of Venous Thrombo Embolism 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 RR = risk ratio SE = systemic embolism SPAF = Stroke Prevention in Atrial Fibrillation UFH = unfractionated heparin VKA = vitamin K antagonist X-VeRT = Explore the Efficacy and Safety of Once-Daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Patients With Non-valvular Atrial Fibrillation Scheduled for Cardioversion Trial

17. References
1. Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; Savaysa™ [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; Hefesoft. HAS-BLED Bleeding Risk Calculator for iPad. 6. Usquare Soft Inc. CHADS2 Application. 7. Juergens D. CHA2DS2-VASC Score Application. 8. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365: Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:

18. References (cont)
11. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369: Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383: Cullen MW, Kim S, Piccini JP Sr, et al; ORBIT-AF Investigators. Risks and benefits of anticoagulation in atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circ Cardiovasc Qual Outcomes. 2013;6: PINNACLE Registry. National Cardiovascular Data Registry website. Accessed January 31, Huisman MV, Lip GY, Diener HC, et al. Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: a global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation. Am Heart J. 2014;167: Kakkar AK, Mueller I, Bassand JP, et al. International longitudinal registry of patients with atrial fibrillation at risk of stroke: Global Anticoagulant Registry in the FIELD (GARFIELD). Am Heart J. 2012;163:13-19.
Reference 13 was unable to be verified or completed – please verify.

19. References (cont)
17. Nieuwlaat R, Capucci A, Camm AJ, et al; European Heart Survey Investigators. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2005;26: Oldgren J, Healey JS, Ezekowitz M, et al; RE-LY Atrial Fibrillation Registry Investigators. Variations in cause and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: the RE-LY Atrial Fibrillation Registry. Circulation. 2014;129: Ezekowitz MD, Cappato R, Klein AL, et al. Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion. Am Heart J. 2014;167: Cappato R, Ezekowitz MD, Klein AL, et al; X-VeRT Investigators. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J. 2014;35: