1. New Paradigms in the
Science and Medicine of Heart Disease
Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-Monitored, Oral Anticoagulants (NOACs) for SPAF
CHRISTIAN T. RUFF, MD, MPH
Associate Physician Cardiovascular Division
Brigham and Women's Hospital
Instructor of Medicine
Harvard Medical School
Boston, MA 1

2. History of Warfarin
The history of warfarin dates to the 1920s. A veterinary pathologist determined that an outbreak of a severe and frequently fatal hemorrhagic disease in cattle in the northern United States and Canada was due to the ingestion of moldy silage made from sweet clover.1 The potent anticoagulant effect was linked to the lack of functioning prothrombin, a critical component at the terminus of the coagulation cascasde. It took another 20 years until chemists at the University of Wisconsin synthesized a compound that they named dicumarol and confirmed that it was identical to the naturally occurring substance, coumarin, present in spoiled hay. The group at Wisconsin continued to develop more potent iterations of the compound for use as a rodenticide, resulting in the patent for warfarin (the acronym WARF stands for Wisconsin Alumni Research Foundation with the addition of ‘‘arin’’ derived from coumarin) in It was not developed as a therapeutic anticoagulant in humans until the 1950s after an inductee in the US army unsuccessfully attempted suicide by ingesting warfarin.4 In 1954, it was approved for medical use in humans.
Karl Paul Link: Wisconsin

3. Limitations of Warfarin
Delayed onset/offset
Multiple food and drug interactions
Genetic variability in metabolism (VKORC1 and CYP2C9)
Requires frequent monitoring of INR due to limited therapeutic index

4. Gladston, DJ, et al. Stroke 2009;40:235-40
Preventable Strokes
AF Patients with Stroke with no Known Contraindication to Anticoagulation
No warfarin 61%
INR in range 10%
Analyzed 597 patients with a first ischemic stroke who had known atrial fibrillation, were classified as high risk for stroke, and who had no known contraindications to anticoagulation
Subtherapeutic INR 29%
Gladston, DJ, et al. Stroke 2009;40:235-40

5. Properties of an Ideal Anticoagulant
Benefit
Oral, once-daily dosing
Ease of administration
Rapid onset of action
No need for overlapping parenteral anticoagulant
Minimal food or drug interactions
Simplified dosing
Predictable anticoagulant effect
No coagulation monitoring
Extra renal clearance
Safe in patients with renal disease
Rapid offset in action
Simplifies management in case of bleeding or intervention
Antidote
For emergencies 5

6. Comparative PK/PD of NOACs
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Target
IIa (thrombin) Xa
Hours to Cmax
1-3
2-4
3-4
1-2
Half-life, hours
12-17
5-13 12
10-14
Renal Clearance, % 80
33* 27 50
Transporters
P-gp
CYP Metabolism, %
None 32
<32
<4
CYP = cytochrome P450; P-gp = P-glycoprotein
*33% renally cleared; 33% excreted unchanged in urine
Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013
Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011
Weinz et al. Drug Dispos Metab 2009;37:1056–1064
ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK
Matsushima et al. Am Assoc Pharm Sci 2011; abstract
Ogata, et al. J Clin Pharmacol 2010;50:743–753
Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342
Bathala, et al. Drug Metab Dispos 2012;40:2250–2255
Ruff CT, et al. Lancet 2013 [in-press]

7. NOAC SPAF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Drug Dabigatran
Rivaroxaban
Apixaban
Edoxaban
# Randomized
18,113
14,266
18,201
21,105
Dose (mg)
150, 110 20 5
60, 30
Frequency
Twice Daily
Once Daily
Dose Adjustment No
20 → 15
5 → 2.5
60 → → 15
At Baseline 21 25
After Randomization
>9%
Target INR (Warfarin)
Design
PROBE*
2x blind
*PROBE = prospective, randomized, open-label, blinded end point evaluation
Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365:
Granger CB, et al. N Engl J Med 2011;365:
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: /NEJMoa
Ruff CT, et al. Lancet 2013 [in-press]

8. 6 Trial of Warfarin vs. Placebo
Pivotal Warfarin-Controlled Trials
Stroke Prevention in AF
Warfarin vs. Placebo
2,900 Patients
NOACs vs. Warfarin
71,683 Patients
ROCKET AF
(Rivaroxaban)
2010
ENGAGE AF-TIMI 48
(Edoxaban)
2013
6 Trial of Warfarin vs. Placebo
RE-LY
(Dabigatran)
2009
ARISTOTLE
(Apixaban)
2011

9. ROCKET-AF (Rivaroxaban)
Baseline Characteristics
RE-LY (Dabigatran)
ROCKET-AF (Rivaroxaban)
ARISTOTLE (Apixaban)
ENGAGE AF (Edoxaban)
# Randomized
18,113
14,264
18,201
21,105
Age, years
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
0-1 2
3-6
Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365:
Granger CB, et al. N Engl J Med 2011;365:
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: /NEJMoa
Ruff CT, et al. Lancet 2013 [in-press]

10. ROCKET-AF (Rivaroxaban)
Trial Metrics
Metrics
RE-LY (Dabigatran)
ROCKET-AF (Rivaroxaban)
ARISTOTLE (Apixaban)
ENGAGE AF (Edoxaban)
Median Follow-Up, years
2.0
1.9
1.8
2.8
Median TTR 66 58 68
Lost to Follow-Up, N 20 32 90 1
*TTR, time in therapeutic range
Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365:
Granger CB, et al. N Engl J Med 2011;365:
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: /NEJMoa
Ruff CT, et al. Lancet 2013 [in-press]

11. RE-LY Efficacy - Dabigatran
Stroke/Systemic Embolic Event
0.50
0.75
1.00
1.25
1.50
Dabigatran 110 vs Warfarin
Dabigatran 150 vs Warfarin
Non-inferiority
P-value
< 0.001
Superiority
0.34
Margin = 1.46
HR (95% CI)
Connolly, et al. N Engl J Med 2009;361: 11

12. Connolly, et al. N Engl J Med 2009;361:1139-51
RE-LY Efficacy
Dabigatran 110 mg
Dabigatran 150 mg
0.91 ( )
Stroke/SEE
0.66 ( )
1.11 ( )
Ischemic Stroke
0.76 ( )
Review of the efficacy data from RE-LY: Dabigatran 150 mg twice daily was superior to warfarin in reducing the composite primary endpoint of stroke and systemic embolism. Dabigatran 110 mg twice daily was non-inferior to warfarin. These results were largely driven by the substantial reductions in hemorrhagic stroke with both dabigatran dose groups compared to warfarin. There was a more modest reduction in ischemic stroke with dabigatran 150 mg twice daily compared to warfarin and similar rates for dabigatran 110 mg twice daily compared to warfarin.
No significant difference in mortality.
0.31 ( )
Hemorrhagic Stroke
0.26 ( )
0.1
0.3
0.5
1.0
2.0
Connolly, et al. N Engl J Med 2009;361:
Dabigatran Better
Warfarin Better

13. Connolly, et al. N Engl J Med 2009;361:1139-51
RE-LY Safety Results
Dabigatran 110 mg
Dabigatran 150 mg
0.80 ( )
Major Bleed
0.93 ( )
0.31 ( )
ICH
0.40 ( )
1.10 ( )
GI Bleed
Review of the safety data from RE-LY: The risk of major bleeding was similar in the dabigatran 150 mg and warfarin groups and significantly lower in the dabigatran 110 mg group. Substantial reductions in intracranial hemorrhage (ICH) were seen for both dabigatran dose groups compared to warfarin.
The rate of gastrointestinal bleeding was significantly higher with dabigatran 150 mg twice daily compared to warfarin and numerically increased for the lower dose. Higher rates of dyspepsia: 150 mg 11.3%, 110 mg 11.8%, warfarin 5.8%
There were non-significant increases in the rates of myocardial infarction in both dabigatran dose groups compared to warfarin.
1.50 ( )
1.29 ( ) MI
1.27 ( )
Connolly, et al. N Engl J Med 2009;361:
0.1
0.3
0.5
1.0
2.0
Dabigatran Better
Warfarin Better

14. Dabigatran 150 mg twice daily if CrCL > 30 mL/min14 14

15. Event Rates are per 100 patient-years
ROCKET AF Efficacy - Rivaroxaban
Stroke/Systemic Embolic Event
Rivaroxaban
Warfarin
Event Rate
HR (95% CI)
P-value
On Treatment
N = 14,143
1.70
2.15
(0.65, 0.95)
0.015
ITT
N = 14,171
2.12
2.42
(0.74, 1.03)
0.117
Rivaroxaban
better
Warfarin better
Event Rates are per 100 patient-years
Based on Safety on Treatment or Intention-to-Treat through Site Notification populations
Patel, et al. N Engl J Med 2011;365(10);

16. ROCKET AF Key Secondary Efficacy
Event
Rivaroxaban
(%/yr)
Warfarin
Hazard Ratio
(95% CI)
P-value
Ischemic Stroke
1.34
1.42
0.94 ( )
0.581
Hemorrhagic Stroke
0.26
0.44
0.59 ( )
0.024 MI
0.91
1.12
0.81 ( )
0.121
Total Mortality
1.87
2.21
0.85 ( )
0.073
Vascular Mortality
1.53
1.71
0.89 ( )
0.289
Patel, et al. N Engl J Med 2011; 365(10); 16

17. ROCKET AF Safety Event Rivaroxaban (%/yr) Warfarin Hazard Ratio
(95% CI)
P-value
Major and Clinically Relevant Bleed
14.9
14.5
1.03 ( )
0.44
Major Bleed
3.6
3.4
1.04 ( )
0.58
Fatal Bleed
0.2
0.5
0.50 ( )
0.003
ICH
0.7
0.67 ( )
0.02
Patel, et al. N Engl J Med 2011; 365(10); 17

18. Rivaroxaban 20 mg if CrCl > 50 mL/min 15 mg if CrCL 15-50 mL/min 18

19. P (non-inferiority) < 0.001
ARISTOTLE Efficacy - Apixaban
(1.60 %/yr)
HR 0.79 (0.66–0.95)
21% RRR
(1.27 %/yr )
P (non-inferiority) < 0.001
P (superiority) = 0.011
Granger CB, et al. NEJM 2011; 365:

20. ARISTOTLE Efficacy Outcomes
Apixaban
(N = 9120)
Warfarin
(N = 9081)
HR (95% CI)
P Value
Event Rate
(%/yr)
Stroke or systemic embolism*
1.27
1.60
0.79 (0.66, 0.95)
0.011
Stroke
1.19
1.51
0.79 (0.65, 0.95)
0.012
Ischemic or uncertain
0.97
1.05
0.92 (0.74, 1.13)
0.42
Hemorrhagic
0.24
0.47
0.51 (0.35, 0.75)
< 0.001
Systemic embolism (SE)
0.09
0.10
0.87 (0.44, 1.75)
0.70
All-cause death*
3.52
3.94
0.89 (0.80, 0.998)
0.047
Stroke, SE, or all-cause death
4.49
5.04
0.89 (0.81, 0.98)
0.019
Myocardial infarction
0.53
0.61
0.88 (0.66, 1.17)
0.37
Granger CB, et al. NEJM 2011; 365:

21. ARISTOTLE Safety End Points
Event
Apixaban
(%/yr)
Warfarin
Hazard Ratio
(95% CI)
P-value
ISTH Major Bleeding
2.13
3.09
0.69 ( )
< 0.001
ICH
0.33
0.80
0.42 ( )
GUSTO Severe
0.52
1.13
0.46 ( )
Gastrointestinal
0.76
0.86
0.89 ( )
0.37
Granger CB, et al. NEJM 2011; 365: 21

22. Apixaban 5 mg twice daily
2.5 mg twice daily if at least 2 of the following:
Age ≥ 80 years
Weight ≤ 60 kg
Cr ≥ 1.5 mg/dL 22 22

23. Primary Endpoint: Stroke / SEE (2.8 years median f/u)
Noninferiority Analysis (mITT, On Treatment)
0.79
0.50
1.00
2.0
Edoxaban 60* mg QD
vs warfarin
Edoxaban 30* mg QD
P Values
Non-inferiority Superiority
P<0.0001
P=0.005
Hazard ratio (97.5% CI)
1.07
1.38
P=0.017
P=0.44
edoxaban noninferior
Warfarin TTR 68.4%
0.87
P=0.08
P=0.10
Hazard ratio (97.5% CI)
1.13
0.50
1.00
2.0
P Value for Superiority
Edoxaban 60* mg QD
vs warfarin
Edoxaban 30* mg QD
edoxaban superior
edoxaban inferior
Superiority Analysis (ITT, Overall)
*Dose reduced by 50% in selected pts

24. Key Secondary Outcomes
P vs warfarin
E-60
E-30
<0.001
0.97
0.005
0.32
0.004
0.08
0.006
0.013
0.008
0.60
0.13
Edoxaban 60* mg QD
vs warfarin
Edoxaban 30* mg QD
vs warfarin
Warfarin TTR 68.4%
HR (95% CI)
1.19
0.94
0.85
1.41
1.00
0.54
0.33
0.87
0.95
0.82
0.92
0.86
Hem. Stroke
Ischemic Stroke
2° EP: Stroke, SEE, CV death
Death or ICH
All-cause mortality
CV death
Myocardial infarction
*Dose reduced by 50% in selected pts
0.25
0.5
1.00
2.0
edoxaban superior
edoxaban inferior

25. Main Safety Results - Safety Cohort on Treatment -
Edoxaban 60* mg QD
vs warfarin
Edoxaban 30* mg QD
vs warfarin
P Value
vs warfarin
Warfarin TTR 68.4%
Hazard ratio (95% CI)
P<0.001
ISTH Major Bleeding
0.80
0.47
Fatal Bleeding
0.55
0.35
P=0.006
P<0.001
Intracranial
Hemorrhage
0.47
0.30
P<0.001
Gastrointestinal Bleeding
1.23
0.67
P=0.03
P<0.001
0.25
0.5
1.0
2.0
edoxaban superior
edoxaban inferior
*Dose reduced by 50% in selected pts
Safety cohort=all patients who received at least 1 dose by treatment actually received

26. All NOACS: Stroke or SEE
Risk Ratio (95% CI)
RE-LY
0.66 ( )
[150 mg]
ROCKET AF
0.88 ( )
ARISTOTLE
0.80 ( )
ENGAGE AF-TIMI 48
0.88 ( )
[60 mg]
Combined
0.81 ( )
[Random Effects Model]
p=<0.0001
N=58,541
0.5 1 2
Favors NOAC
Favors Warfarin
Heterogeneity p=0.13
Ruff CT, et al. Lancet Published online December 4, 2013

27. Secondary Efficacy Outcomes
Risk Ratio (95% CI)
Ischemic Stroke
0.92 ( )
p=0.10
Hemorrhagic Stroke
0.49 ( )
p<0.0001 MI
0.97 ( )
p=0.77
All-Cause Mortality
0.90 ( )
p=0.0003
0.2
0.5 1 2
Favors NOAC
Favors Warfarin
Heterogeneity p=NS for all outcomes
Ruff CT, et al. Lancet Published online December 4, 2013

28. All NOACS: Major Bleeding
ARISTOTLE
ROCKET AF
Combined
Favors NOAC
Favors Warfarin
Risk Ratio (95% CI)
0.80 ( )
0.71 ( )
1.03 ( )
0.94 ( )
0.86 ( )
RE-LY
[150 mg]
ENGAGE AF-TIMI 48
[60 mg]
[Random Effects Model]
p=0.06
N=58,498
0.5 1 2
Heterogeneity p=0.001
Ruff CT, et al. Lancet Published online December 4, 2013

29. Secondary Safety Outcomes
Risk Ratio (95% CI)
ICH
0.48 ( )
p<0.0001
1.25 ( )
GI Bleeding
p=0.043
0.2
0.5 1 2
Favors NOAC
Favors Warfarin
Heterogeneity
ICH, p=0.22
GI Bleeding, p=0.009
Ruff CT, et al. Lancet Published online December 4, 2013

30. Subgroups: Stroke or SEE
≥66%
0.82 ( )
<66%
0.77 ( )
Experienced
0.85 ( )
Naive
0.75 ( )
3-6
0.80 ( ) 2
0.86 ( )
0-1
0.75 ( )
>80
0.98 ( )
50-80
0.75 ( )
<50
0.79 ( )
Yes
0.86 ( ) No
0.78 ( )
Male
0.84 ( )
Female
0.78 ( )
≥75
0.78 ( )
<75
0.85 ( )
Center-Based TTR
VKA Status
CHADS2 Score
CrCl
Gender
Age
Risk Ratio (95% CI)
p=0.60
p=0.31
p=0.76
p=0.12
p=0.30
p=0.52
p=0.38
P-Interaction
Favors NOAC
Favors Warfarin
0.5 1
Prior Stroke or TIA
Diabetes
0.80 ( )
0.83 ( )
p=0.73
Ruff CT, et al. Lancet Published online December 4, 2013

31. Subgroups: Major Bleeding
Risk Ratio (95% CI)
P-Interaction
Age
0.2
0.5 1 2
Favors Warfarin
<75
0.79 ( )
p=0.28
≥75
0.93 ( )
Gender
Female
0.75 ( )
p=0.29
Male
0.90 ( )
Diabetes No
0.71 (0.54 – 0.93)
p=0.12
Yes
0.90 ( )
Prior Stroke or TIA No
0.85 ( )
p=0.70
Yes
0.89 ( )
CrCl
<50
0.74 ( )
p=0.57
50-80
0.91 ( )
>80
0.85 ( )
CHADS2 Score
0-1
0.60 ( )
p=0.09 2
0.88 ( )
3-6
0.86 ( )
VKA Status
Naive
0.84 ( )
p=0.78
Experienced
0.87 ( )
Center-Based TTR
<66%
0.69 ( )
p=0.022
≥66%
0.93 ( )
Favors NOAC
Ruff CT, et al. Lancet Published online December 4, 2013

32. ACTIVE-W: Stroke or SEE
TTR ≥ 65%
TTR < 65%
P-interaction = 0.013
RR = 1.83
P <
RR = 1.11
P = 0.47
Clopi + ASA
Clopi + ASA
Event Rate (%)
VKA
VKA
Years
Years
Connolly SJ, et al. Circulation 2008;118:

33. ACTIVE-W: Major Bleeding
TTR ≥ 65%
TTR < 65%
P-interaction =
RR = 1.55
P = 0.027
RR = 0.68
P = 0.08
OAC
Event Rate (%)
C+A
OAC
C+A
Years
Years
Connolly SJ, et al. Circulation 2008;118:

34. Dabigatran 110 mg & Edoxaban 30 mg
Low Dose Regimens
Efficacy & Safety Outcomes
Dabigatran 110 mg & Edoxaban 30 mg
GI Bleeding
0.89 ( )
ICH
0.31 ( )
Major Bleeding
0.65 ( )
All-Cause Mortality
0.89 ( ) MI
1.25 ( )
Hemorrhagic Stroke
0.33 ( )
Ischemic Stroke
1.28 ( )
Stroke or SEE
1.03 ( )
Risk Ratio (95% CI)
p=0.58
p<0.0001
p=0.05
p=0.003
p=0.019
p=0.045
p=0.74
Favors Low Dose NOAC
Favors Warfarin
0.2
0.5 1 2
N=26,107
Heterogeneity
P=NS for outcomes except:
Major Bleeding, p=<0.001
GI Bleeding, p=0.01
Ruff CT, et al. Lancet Published online December 4, 2013

35. Cardioversion % RE-LY (N=647) (N=672) (N=664)
# Strokes 110 : 5, 150:2, Warf: 4
Methods and Results—Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography
was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for 3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P0.71; D150 versus warfarin, P0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P0.06; D150 versus warfarin, P0.99).
Conclusions—This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in
this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion.
(N=647)
(N=672)
(N=664)
Nagarakanti R, et al. Circulation 2011;123: 35

36. Cardioversion & Catheter Ablation
ROCKET AF %
Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n 321;
1.44 [n 161] in the warfarin arm, 1.46 [n 160] in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences,
the long-term incidence of stroke or systemic embolism (hazard ratio [HR]: 1.38; 95% confidence interval [CI]: 0.61 to 3.11), cardiovascular death (HR: 1.57; 95% CI: 0.69 to 3.55), and death from all causes (HR: 1.75; 95%
CI: 0.90 to 3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR: 2.01; 95% CI: 1.51 to 2.68), but there was no evidence of a differential effect by randomized treatment (p value for interaction 0.58). The incidence of stroke or systemic embolism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-treated and warfarin-treated groups.
Conclusions Despite an increase in hospitalization, there were no differences in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation
doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion.
Piccini JP, et al. JACC 2013;61: 36

37. Catheter Ablation with NOACs
Case-control: 763 consecutive patients undergoing AF ablation
P=0.85
P=0.81 %
P=1.0
Methods and results
In this case-control analysis, 763 consecutive patients (mean age 61±10 years) underwent RFA of AF using dabigatran (N = 191) or uninterrupted warfarin (N = 572) for periprocedural anticoagulation. In all patients, anticoagulation was started≥4 weeks before RFA. Dabigatran was held after the morning dose on the day before the procedure and resumed 4 hours after vascular hemostasis was achieved. A transesophageal echocardiogram performed in all patients receiving dabigatran did not demonstrate an intracardiac thrombus. There were no thromboembolic complications in either group. The prevalence of major (4 of 191, 2.1%) and minor (5 of 191, 2.6%) bleeding complications in the dabigatran group were similar to those in the warfarin group (12 of 572, 2.1%; P = 1.0 and 19 of 572, 3.3%; P = .8, respectively). Pericardial tamponade occurred in 2 of 191 (1%) patients in the dabigatran group and in 7 of 572 (1.2%) patients in the warfarin group (P = 1.0). All patients who had a pericardial tamponade, including 2 in the dabigatran group, had uneventful recovery after perdicardiocentesis. On multivariate analysis, international normalized ratio (odds ratio [OR] 4.0; 95% confidence interval [CI] 1.1–15.0; P = .04), clopidogrel use (OR 4.2; 95% CI 1.5–12.3; P = .01), and CHA2DS2-VASc score (OR 1.4; 95% CI 1.1–1.8; P = .01) were the independent risk factors of bleeding complications only in the warfarin group.
Conclusions
When held for approximately 24 hours before the procedure and resumed 4 hours after vascular hemostasis, dabigatran appears to be as safe and effective as uninterrupted warfarin for periprocedural anticoagulation in patients undergoing RFA of AF.
P=1.0
Kim JS, et al. Heart Rhythm 2013; 10:

38. Periprocedural Major Bleeding
RE-LY %
¼ of patients required surgery or invasive procedures
Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation.
In RE-LY, nearly half of all patients treated with dabigatran had surgery within 48 hours of stopping oral anticoagulation, a rate >4 times higher than among patients receiving warfarin.
There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44.
Healey JS, et al. Circulation 2012; 126:

39. no official indication for use
Discontinuing NOACs
Prior to Procedures
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
No important bleeding risk and/or adequate local haemostasis possible: perform at trough level (i.e. ≥12h or 24h after last intake)
Low risk
High risk
CrCl ≥80 ml/min
≥24h
≥48h
no data
CrCl ml/min
≥36h
≥72h
CrCl ml/min
≥96h
CrCl ml/min
not indicated
CrCl <15 ml/min
no official indication for use
AF.eu
Heidbuchel H, et al. Eurospace 2013;15:

40. Dabigatran (FIIa) Monitoring
aPTT
Hemoclot Test
Van Ryn J, et al. Thromb Hemost. 2010; 103:

41. Rivaroxaban (Fxa) MonitoringPT
Rotachrom Anti-Xa
Rivaroxaban (µg L-1)
100
200
300
400
500
600
Prothrombin time (s) 10 20 30 40
Van Ryn J, et al. Thromb Hemost. 2010; 103:

42. www.NOACfor AF.eu Managing Bleeding with NOACs
Heidbuchel H, et al. Eurospace 2013;15:

43. Stroke or systemic embolism (n)
ARISTOTLE
Apixaban: Increased Events at End of Trial
Stroke or systemic embolism (n)
To attempt to mitigate the excess number of strokes in the transition from a Factor Xa inhibitor to open-label anticoagulation during the transition phase, the ARISTOTLE investigators utilized a 2-day transition kit that allowed for an overlap of apixaban and warfarin among subjects who had been randomized to apixaban. No similar overlap was used (or necessary) in the subjects randomized to warfarin, since they were were not exposed to a period of potential under-anticoagulation. However, despite the 2-day overlap during the start of the transition in ARISTOTLE, subjects who had been randomized to apixaban during the blinded treatment phase of the study still experienced a higher rate of stroke during the transition phase compared to those who had received blinded warfarin during the treatment phase. Indeed, the excess number of strokes (21 vs. 5) during the 30-day transition period was almost identical to the excess seen in the ROCKET-AF study, despite a 2-day overlap transition kit utilized in ARISTOTLE. When the timing of the strokes during the transition phase were analyzed by timing of occurrence, an interesting pattern emerged. In the first 2 days of the transition, there was only 1 stroke in each group. This likely reflects the success of the transition kit in subjects who were transitioning from apixaban to warfarin. These subjects received a 2-day transition kit that contained apixaban, and thus received BOTH apixaban and warfarin for the first 2 days of the transition period. However, once the transition kit was completed, an increase in the number of strokes was apparent among the subjects transitioning from apixaban to open-label VKA, compared to those transitioning from warfarin to open-label VKA. The numbers of strokes in the days 3-7, 8-14, and range for subjects transitioning from apixaban to open-label VKA were 4, 5, and 11 respectively. In contrast, only 0, 1, and 3 subjects transitioning from study-drug warfarin to open-label VKA during these same time intervals of the transition phase experienced a stroke. Of note, the ARISTOTLE investigators compared this early excess rate of stroke in the transition phase to the risk of stroke at the start of the trial among subjects who were VKA-naïve and had been randomized to warfarin. A similar excess (5.41/yr vs. 1.41%/yr) was seen at the start of the trial among those who were just starting warfarin without preceding anticoagulation. This suggests that a substantially longer period of overlap of anticoagulants (i.e., >48 hours) is needed during the transition phase to avoid an increased risk of stroke. In addition, subjects must be followed very closely with frequent INR measurements and rapid uptitration of warfarin to avoid long delays in obtaining a therapeutic INR. These features are critical elements of the ENGAGE AF-TIMI 48 End of Study Transition Plan.
Pattern mirrored the first 30 days of the trial where warfarin-naïve patients starting warfarin had a higher rate of stroke or systemic embolism (5.41%/year) than warfarin-experienced patients (1.41%/year).
Granger CB, et al. European Heart Journal 2012;33 (Supplement):

44. ROCKET AF Rivaroxaban: Increased Events at End of Trial P = 0.008
# Primary Events
81.3
Warfarin
P = 0.008
48.8
# Primary Events during first 30 days of transition
Rivaroxaban
Rivaroxaban
Warfarin
Safety/Days 3 to 30 after the last dose
Patel MR, et al. NEJM 2011; 365:
Patel MR, et al. JACC 2013;61:

45. Key Transition Plan Components
Double-Blind Phase
Transition Period
Solution = Transition Plan
Duration of Anticoagulant Effect
Long
Warfarin
INCREASED RISK OF STROKE
Components:
1. Open-Label OAC
2. Transition Kit
3. Frequent INRs
4. VKA Algorithm
NOAC
Short
INCREASED RISK OF STROKE

46. All Patients: Stroke or SEE 30 Day Transition Period
Warfarin 7 Strokes (6 Isch, 1 Hem)
Edoxaban HD 7 Strokes (6 Isch, 1 Hem) HR p=0.99
Edoxaban LD 7 Strokes (6 Isch, 1 Hem) HR p=0.96
# Patients with Stroke or SEE
Days after End of Trial Visit

47. All Patients: Major Bleeding 30 Day Transition Period
Warfarin 11 Major Bleeds
Edoxaban HD 10 Major Bleeds HR p=0.82
Edoxaban LD 18 Major Bleeds HR p=0.22
# Patients with Major Bleed
Warfarin 6 Major Bleeds
Edoxaban HD 4 Major Bleeds
Edoxaban LD 5 Major Bleeds
Transition Kit
Days after End of Trial Visit

48. Connolly SJ, et al. Circulation 2013;128:237-243
RELY-ABLE
Stroke or SEE
Major Bleeding
Dabigatran 150 mg: 1.46 % / year
Dabigatran 110 mg: 1.60 % / year
HR 0.91 ( )
Dabigatran 150 mg: 3.74% / year
Dabigatran 110 mg: 2.99% / year
HR 1.26 ( )
Background—During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses.
Methods and Results—Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE–eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69–1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04–1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80–1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y.
Conclusions—During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death.
Connolly SJ, et al. Circulation 2013;128:

49. Postmarketing Reports of Bleeding with Dabigatran
In the months following the approval of dabigatran in October 2012, the FDA received many reports of serious and fatal bleeding through the FDA Adverse Event Reporting System (FAERS). In RE-LY, similar bleeding risk between dabigatran and warfarin. Weber effect: newly marketed products, by virtue of their novelty alone, may elicit adverse-event reports at a high rate. Example of stimulated reporting.
Southworth MR, et al. N Engl J Med 2013; 368(14):

50. Outcomes of Major Bleeding with Dabigatran or Warfarin
5 phase III AF and VTE trials: 1,034 individuals
Adjusted OR 0.66 (95% CI )
13.0%
p=0.05
9.1%
Background- The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. [RELY, RECOVER 1&2, REMEDY, RESONATE]
Methods and Results- Two independent investigators reviewed bleeding reports from 1,034 individuals with 1,121 major bleeds enrolled in 5 phase III trials comparing dabigatran with
warfarin in 27,419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16,755) were older, had lower creatinine clearance and more frequently used aspirin or
non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10,002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the
warfarin group (13.0%; pooled odds ratio [OR] 0.68, 95% confidence interval [CI]: ; p=therapy, transfusions Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care and had a trend to lower mortality compared with those who had major bleeding on warfarin.
After adjustment for sex, age, weight, renal function and concomitant antithrombotic therapy, the pooled OR for 30-day mortality with dabigatran versus warfarin was 0.66 (95% CI: ; p=0.051). Major bleeds in dabigatran patients were more frequently treated with blood ransfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; p<0.001) but less
frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; p<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received
dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; p=0.01).
Conclusions- Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care and had a trend to
lower mortality compared with those who had major bleeding on warfarin.
Patients with bleed on dabigatran:
RBC transfusion
Plasma & Shorter ICU Stay
Majeed A, et al. Circulation 2013 [published online September 30, 2013]

51. Conclusions
New therapies provide the promise of providing safer and more convenient anticoagulation.
There are important differences in the half-life, metabolism, & renal elimination across the NOACs that will alter the risk/benefit profile in specific populations.
Persistent concern with lack of ability to monitor the level of anticoagulation.
Further experience and guidance needed in managing anticoagulation peri-procedure.
Desire for reversal agent and strategies to manage serious bleeding. 51 51