Landmark Clinical Trials Evaluating NOACS in SPAF - Iqanda-CME

Report
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
History of Warfarin
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
Preventable Strokes
AF Patients with Stroke with no Known
Contraindication to Anticoagulation
No warfarin
61%
INR in range
10%
Subtherapeutic INR
29%
Gladston, DJ, et al. Stroke
2009;40:235-40
Properties of an Ideal
Anticoagulant
Properties
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
Comparative PK/PD of NOACs
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
IIa (thrombin)
Xa
Xa
Xa
Hours to Cmax
1-3
2-4
3-4
1-2
Half-life, hours
12-17
5-13
12
10-14
80
33*
27
50
Transporters
P-gp
P-gp
P-gp
P-gp
CYP Metabolism, %
None
32
<32
<4
Target
Renal Clearance, %
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]
NOAC SPAF Trials
Drug
# Randomized
Dose (mg)
Frequency
Dose Adjustment
At Baseline
After Randomization
Target INR (Warfarin)
Design
RE-LY
ROCKET-AF
ARISTOTLE
ENGAGE AF
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
18,113
14,266
18,201
21,105
150, 110
20
5
60, 30
Twice Daily
Once Daily
Twice Daily
Once Daily
No
20 → 15
5 → 2.5
60 → 30
30 → 15
0
21
5
25
No
No
No
>9%
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
PROBE*
2x blind
2x blind
2x blind
*PROBE = prospective, randomized, open-label, blinded end point evaluation
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
Patel MR, et al. N Engl J Med 2011;365:883-891
Granger CB, et al. N Engl J Med 2011;365:981-992
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
Ruff CT, et al. Lancet 2013 [in-press]
Pivotal Warfarin-Controlled Trials
Stroke Prevention in AF
Warfarin vs. Placebo
2,900 Patients
NOACs vs. Warfarin
71,683 Patients
ROCKET AF
(Rivaroxaban)
2010
6 Trial of Warfarin vs. Placebo
1989-1993
RE-LY
(Dabigatran)
2009
ENGAGE AF-TIMI 48
(Edoxaban)
2013
ARISTOTLE
(Apixaban)
2011
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
38
43
41
Aspirin Use
40
36
31
29
CHADS2
0-1
2
3-6
13
33 32
35
87
30
34
53
47
36
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
Patel MR, et al. N Engl J Med 2011;365:883-891
Granger CB, et al. N Engl J Med 2011;365:981-992
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
Ruff CT, et al. Lancet 2013 [in-press]
Trial 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
66
68
Lost to Follow-Up, N
20
32
90
1
Metrics
*TTR, time in therapeutic range
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
Patel MR, et al. N Engl J Med 2011;365:883-891
Granger CB, et al. N Engl J Med 2011;365:981-992
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
Ruff CT, et al. Lancet 2013 [in-press]
RE-LY Efficacy - Dabigatran
Stroke/Systemic Embolic Event
Non-inferiority Superiority
P-value
P-value
Dabigatran 110 vs Warfarin
< 0.001
Dabigatran 150 vs Warfarin
< 0.001
0.34
< 0.001
Margin = 1.46
Connolly, et al. N Engl J
Med 2009;361:1139-51
0.50
0.75
HR
1.00
1.25
(95% CI)
1.50
RE-LY Efficacy
Dabigatran 110 mg
Dabigatran 150 mg
Stroke/SEE
0.91 (0.74-1.11)
0.66 (0.53-0.82)
Ischemic Stroke
1.11 (0.89-1.40)
0.76 (0.60-0.98)
Hemorrhagic Stroke
0.31 (0.17-0.56)
0.26 (0.14-0.49)
Connolly, et al. N Engl J Med 2009;361:1139-51
0.1
0.3
0.5
Dabigatran Better
1.0
2.0
Warfarin Better
RE-LY Safety Results
Dabigatran 110 mg
Dabigatran 150 mg
Major Bleed
ICH
GI Bleed
MI
0.80 (0.69-0.93)
0.93 (0.81-1.07)
0.31 (0.20-0.47)
0.40 (0.27-0.60)
1.10 (0.86-1.41)
1.50 (1.19-1.89)
1.29 (0.96-1.75)
1.27 (0.94-1.71)
Connolly, et al. N Engl J Med 2009;361:1139-51
0.1
0.3
0.5
Dabigatran Better
1.0
2.0
Warfarin Better
Dabigatran
►
150 mg twice daily if CrCL > 30 mL/min
►
75 mg twice daily if CrCL 15-30 mL/min
ROCKET AF Efficacy - Rivaroxaban
Stroke/Systemic Embolic Event
Rivaroxaban Warfarin
On
Treatment
Event
Rate
Event
Rate
HR
(95% CI)
P-value
1.70
2.15
0.79
(0.65, 0.95)
0.015
2.12
2.42
0.88
(0.74, 1.03)
0.117
N = 14,143
ITT
N = 14,171
0.5
1
Rivaroxaban
better
2
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);883-891
ROCKET AF Key Secondary Efficacy
Rivaroxaban
(%/yr)
Warfarin
(%/yr)
Hazard Ratio
(95% CI)
Pvalue
Ischemic Stroke
1.34
1.42
0.94 (0.75-1.17)
0.581
Hemorrhagic Stroke
0.26
0.44
0.59 (0.37-0.93)
0.024
MI
0.91
1.12
0.81 (0.63-1.06)
0.121
Total Mortality
1.87
2.21
0.85 (0.70-1.02)
0.073
Vascular Mortality
1.53
1.71
0.89 (0.73-1.10)
0.289
Event
Patel, et al. N Engl J Med 2011; 365(10);883-891
ROCKET AF Safety
Rivaroxaban
(%/yr)
Warfarin
(%/yr)
Hazard Ratio
(95% CI)
Pvalue
Major and Clinically
Relevant Bleed
14.9
14.5
1.03 (0.96-1.11)
0.44
Major Bleed
3.6
3.4
1.04 (0.90-1.20)
0.58
Fatal Bleed
0.2
0.5
0.50 (0.31-0.79)
0.003
ICH
0.5
0.7
0.67 (0.47-0.93)
0.02
Event
Patel, et al. N Engl J Med 2011; 365(10);883-891
Rivaroxaban
►
20 mg if CrCl > 50 mL/min
►
15 mg if CrCL 15-50 mL/min
ARISTOTLE Efficacy - Apixaban
HR 0.79 (0.66–0.95)
(1.60 %/yr)
21% RRR
(1.27 %/yr )
P (non-inferiority) < 0.001
P (superiority) = 0.011
Granger CB, et al. NEJM 2011; 365:981-992
ARISTOTLE Efficacy Outcomes
Apixaban
(N = 9120)
Outcome
Stroke or systemic embolism*
Warfarin
(N = 9081)
Event
Event Rate
Rate
(%/yr)
(%/yr)
HR (95% CI)
P Value
1.27
1.60
0.79 (0.66, 0.95)
0.011
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
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
Stroke
Systemic embolism (SE)
Granger CB, et al. NEJM 2011; 365:981-992
ARISTOTLE Safety End Points
Apixaban
(%/yr)
Warfarin
(%/yr)
Hazard Ratio
(95% CI)
Pvalue
ISTH Major Bleeding
2.13
3.09
0.69 (0.60-0.80)
<
0.001
ICH
0.33
0.80
0.42 (0.30-0.58)
<
0.001
GUSTO Severe
0.52
1.13
0.46 (0.35-0.60)
<
0.001
Gastrointestinal
0.76
0.86
0.89 (0.70-1.15)
0.37
Event
Granger CB, et al. NEJM 2011; 365:981-992
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
Primary Endpoint: Stroke / SEE
(2.8 years median f/u)
Noninferiority Analysis (mITT, On Treatment)
Hazard ratio (97.5% CI)
Warfarin TTR 68.4%
0.79
Edoxaban 60* mg QD
vs warfarin
P Values
Non-inferiority Superiority
P<0.0001 P=0.017
1.07
P=0.005
Edoxaban 30* mg QD
vs warfarin
0.50
1.00
1.38
P=0.44
2.0
edoxaban noninferior
Superiority Analysis (ITT, Overall)
Hazard ratio (97.5% CI)
0.87
Edoxaban 60* mg QD
vs warfarin
P=0.08
1.13
Edoxaban 30* mg QD
vs warfarin
P=0.10
0.50
*Dose reduced by
50% in selected pts
P Value for Superiority
1.00
2.0
edoxaban superior edoxaban inferior
Key Secondary Outcomes
Edoxaban 60* mg QD
vs warfarin
Edoxaban 30* mg QD
vs warfarin
0.33
Hem. Stroke
Warfarin TTR 68.4% HR (95% CI)
P vs
warfarin
E-60
0.54
E-30
<0.001
<0.001
1.00
1.41
Ischemic Stroke
0.87
0.95
2° EP: Stroke, SEE, CV
death
Death or ICH
0.92
0.87
CV death
0.86
0.85
Myocardial infarction
<0.001
0.005
0.32
0.004
0.87
0.82
All-cause mortality
0.97
<0.001
0.08
0.006
0.013
0.008
0.60
0.94
0.13
1.19
*Dose reduced by 50%
in selected pts
0.25
0.5
edoxaban superior
1.00
2.0
edoxaban inferior
Main Safety Results
- Safety Cohort on Treatment Edoxaban 60* mg QD
vs warfarin
Edoxaban 30* mg QD
vs warfarin
Warfarin TTR 68.4%
ISTH Major Bleeding
Hazard ratio (95% CI)
0.80
0.47
P<0.001
P<0.001
0.55
Fatal Bleeding
P=0.006
P<0.001
0.35
0.47
Intracranial
Hemorrhage
0.25
*Dose reduced by
50% in selected pts
P<0.001
P<0.001
0.30
1.23
Gastrointestinal Bleeding
P Value
vs warfarin
0.67
0.5
edoxaban superior
1.0
P=0.03
P<0.001
2.0
edoxaban inferior
Safety cohort=all patients who received at least 1 dose by treatment actually received
All NOACS: Stroke or SEE
Risk Ratio (95% CI)
0.66 (0.53 - 0.82)
RE-LY
[150 mg]
ROCKET AF
0.88 (0.75 - 1.03)
ARISTOTLE
0.80 (0.67 - 0.95)
ENGAGE AF-TIMI 48
0.88 (0.75 - 1.02)
[60 mg]
Combined
0.81 (0.73 - 0.91)
[Random Effects Model]
N=58,541
0.5
Heterogeneity p=0.13
p=<0.0001
Favors NOAC
1
Favors Warfarin
2
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
Secondary Efficacy Outcomes
Risk Ratio (95% CI)
Ischemic Stroke
0.92 (0.83 - 1.02)
p=0.10
Hemorrhagic Stroke
0.49 (0.38 - 0.64)
p<0.0001
MI
0.97 (0.78 - 1.20)
p=0.77
All-Cause Mortality
0.90 (0.85 - 0.95)
p=0.0003
0.2
0.5
Favors NOAC
1
2
Favors Warfarin
Heterogeneity p=NS for all outcomes
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
All NOACS: Major Bleeding
Risk Ratio (95% CI)
0.94 (0.82 - 1.07)
RE-LY
[150 mg]
ROCKET AF
1.03 (0.90 - 1.18)
ARISTOTLE
0.71 (0.61 - 0.81)
ENGAGE AF-TIMI 48
0.80 (0.71 - 0.90)
[60 mg]
Combined
0.86 (0.73 - 1.00)
[Random Effects Model]
p=0.06
N=58,498
0.5
Heterogeneity p=0.001
Favors NOAC
1
Favors Warfarin
2
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
Secondary Safety Outcomes
Risk Ratio (95% CI)
0.48 (0.39 - 0.59)
ICH
p<0.0001
1.25 (1.01 - 1.55)
GI Bleeding
0.2
p=0.043
0.5
Favors NOAC
1
2
Favors Warfarin
Heterogeneity
ICH, p=0.22
GI Bleeding, p=0.009
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
Subgroups: Stroke or SEE
Age
Gender
Diabetes
Prior Stroke or TIA
CrCl
CHADS2 Score
VKA Status
Center-Based TTR
Risk Ratio (95% CI)
P-Interaction
<75
0.85 (0.73 - 0.99)
p=0.38
≥75
0.78 (0.68 - 0.88)
Female
0.78 (0.65 - 0.94)
Male
0.84 (0.75 - 0.94)
No
0.83 (0.74 - 0.93)
Yes
0.80 (0.69 - 0.93)
No
0.78 (0.66 - 0.91)
Yes
0.86 (0.76 - 0.98)
<50
0.79 (0.65 - 0.96)
50-80
0.75 (0.66 - 0.85)
>80
0.98 (0.79 - 1.22)
0-1
0.75 (0.54 - 1.04)
2
0.86 (0.70 - 1.05)
3-6
0.80 (0.72 - 0.89)
Naive
0.75 (0.66 - 0.86)
Experienced
0.85 (0.70 - 1.03)
<66%
0.77 (0.65 - 0.92)
≥66%
0.82 (0.71 - 0.95)
0.5
1
Favors NOAC
p=0.52
p=0.73
p=0.30
p=0.12
p=0.76
p=0.31
p=0.60
2
Favors Warfarin
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
Subgroups: Major Bleeding
Age
Gender
Diabetes
Prior Stroke or TIA
CrCl
CHADS2 Score
VKA Status
Center-Based TTR
0.2
Risk Ratio (95% CI)
P-Interaction
<75
0.79 (0.67 - 0.94)
p=0.28
≥75
0.93 (0.74 - 1.17)
Female
0.75 (0.58 - 0.97)
Male
0.90 (0.72 - 1.12)
No
0.71 (0.54 – 0.93)
Yes
0.90 (0.78 - 1.04)
No
0.85 (0.72 - 1.01)
Yes
0.89 (0.77 - 1.02)
<50
0.74 (0.52 - 1.05)
50-80
0.91 (0.76 - 1.08)
>80
0.85 (0.66 - 1.10)
0-1
0.60 (0.45 - 0.80)
2
0.88 (0.65 - 1.20)
3-6
0.86 (0.71 - 1.04)
Naive
0.84 (0.76 - 0.93)
Experienced
0.87 (0.70 - 1.08)
<66%
0.69 (0.59 - 0.81)
≥66%
0.93 (0.76 - 1.13)
0.5
Favors NOAC
1
p=0.29
p=0.12
p=0.70
p=0.57
p=0.09
p=0.78
p=0.022
2
Favors Warfarin
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
ACTIVE-W: Stroke or SEE
TTR ≥ 65%
TTR < 65%
0.10
RR = 1.83
RR = 1.11
P = 0.47
0.08
P < 0.0001
0.06
0.04
Clopi + ASA
C+A
OAC
VKA
0.02
0.02
0.04
0.06
Clopi + ASA
C+A
OAC
0.0
VKA
0.0
Event Rate (%)
0.08
0.10
P-interaction = 0.013
0.0
0.5
1.0
Years
Connolly SJ, et al. Circulation 2008;118:2029-2037
1.5
0.0
0.5
1.0
Years
1.5
ACTIVE-W: Major Bleeding
TTR ≥ 65%
TTR < 65%
RR = 0.68
P = 0.08
0.03
0.03
0.04
P = 0.027
OAC
OAC
C+A
0.02
0.02
C+A
0.01
C+A
C+A
0.0
0.01
OACOAC
0.0
Event Rate (%)
0.05
RR = 1.55
0.04
0.05
P-interaction = 0.0006
0.0
0.5
1.0
Years
Connolly SJ, et al. Circulation 2008;118:2029-2037
1.5
0.0
0.5
1.0
Years
1.5
Low Dose Regimens
Efficacy & Safety Outcomes
Dabigatran 110 mg & Edoxaban 30 mg
Risk Ratio (95% CI)
1.03 (0.84 - 1.27)
Stroke or SEE
p=0.74
1.28 (1.02 - 1.60)
Ischemic Stroke
p=0.045
0.33 (0.23 - 0.46)
Hemorrhagic Stroke
p<0.0001
MI
1.25 (1.04 - 1.50)
p=0.019
0.89 (0.83 - 0.96)
All-Cause Mortality
p=0.003
0.65 (0.43 - 1.00)
Major Bleeding
p=0.05
0.31 (0.24 - 0.41)
ICH
p<0.0001
0.89 (0.57 - 1.37)
GI Bleeding
p=0.58
N=26,107
Heterogeneity
P=NS for outcomes except:
Major Bleeding, p=<0.001
GI Bleeding, p=0.01
0.2
0.5
Favors Low Dose NOAC
1
2
Favors Warfarin
Ruff CT, et al. Lancet 2013. Published online December 4, 2013
Cardioversion
RE-LY
%
(N=647)
(N=672)
Nagarakanti R, et al. Circulation 2011;123:131-136
(N=664)
Cardioversion & Catheter Ablation
ROCKET AF
%
Piccini JP, et al. JACC 2013;61:1998-2006
%
Catheter Ablation with NOACs
Case-control: 763 consecutive patients undergoing AF ablation
P=0.85
P=0.81
P=1.0
P=1.0
Kim JS, et al. Heart Rhythm 2013; 10:483-489
Periprocedural Major Bleeding
RE-LY
%
Healey JS, et al. Circulation 2012; 126:343-348
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 Low risk High risk Low risk High risk Low risk High risk
CrCl ≥80
ml/min
≥24h
≥48h
≥24h
≥48h
no data no data
≥24h
≥48h
CrCl 50-80
ml/min
≥36h
≥72h
≥24h
≥48h
no data no data
≥24h
≥48h
CrCl 30-50
ml/min
≥48h
≥96h
≥24h
≥48h
no data no data
≥24h
≥48h
≥36h
≥48h
no data no data
≥36h
≥48h
not
not
CrCl 15-30
indicated indicated
ml/min
CrCl <15
ml/min
no official indication for use
www.NOACfor AF.eu
Heidbuchel H, et al. Eurospace 2013;15:625-651.
Dabigatran (FIIa) Monitoring
aPTT
Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127
Hemoclot Test
Rivaroxaban (Fxa) Monitoring
PT
Rotachrom Anti-Xa
Prothrombin time (s)
40
30
20
10
0
0
100
200
300
400
Rivaroxaban (µg L-1)
500
600
Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127
Managing Bleeding with NOACs
www.NOACfor AF.eu
Heidbuchel H, et al. Eurospace 2013;15:625-651.
ARISTOTLE
Apixaban: Increased Events at End of Trial
Stroke or systemic embolism
(n)
25
20
Apixaban to VKA Group
Warfarin to VKA Group
Apixaban to VKA Total Events
Warfarin to VKA Total Events
21
15
10
5
5
0
1-2
3-7
8-14
15-30
Days after last dose
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):685-686
ROCKET AF
Rivaroxaban: Increased Events at End of Trial
81.3
# Primary Events
Warfarin
P=
0.008
48.8
Rivaroxaban
Rivaroxaban
Warfarin
# Primary Events during first 30 days of transition
Patel MR, et al. NEJM 2011; 365:883-891
Patel MR, et al. JACC 2013;61:651-658
Safety/Days 3 to 30 after the last dose
Key Transition Plan Components
Double-Blind
Phase
Transition
Period
Duration of Anticoagulant Effect
Warfarin
Long
NOAC
INCREASED RISK
OF STROKE
INCREASED RISK
OF STROKE
Short
Solution =
Transition Plan
Components:
1. Open-Label OAC
2. Transition Kit
3. Frequent INRs
4. VKA Algorithm
All Patients: Stroke or SEE
30 Day Transition Period
Warfarin
# Patients with Stroke or SEE
8
Edoxaban High-Dose
7
Edoxaban Low-Dose
6
5
4
3
Warfarin
Edoxaban HD
Edoxaban LD
7 Strokes (6 Isch, 1 Hem)
7 Strokes (6 Isch, 1 Hem)
7 Strokes (6 Isch, 1 Hem)
2
1
0
Days after End of Trial Visit
HR 1.00 p=0.99
HR 0.98 p=0.96
All Patients: Major Bleeding
30 Day Transition Period
Warfarin
# Patients with Major Bleed
20
Edoxaban High-Dose
18
Edoxaban Low-Dose
16
14
12
10
8
6
4
2
Warfarin
11 Major Bleeds
Edoxaban HD
10 Major Bleeds
Warfarin
Bleeds
Edoxaban LD 6 Major
18 Major
Bleeds
Edoxaban HD
4 Major Bleeds
Edoxaban LD
5 Major Bleeds
HR 0.90 p=0.82
HR 1.60 p=0.22
Transition Kit
0
Days after End of Trial Visit
RELY-ABLE
Stroke or SEE
Dabigatran 150 mg: 1.46 % / year
Dabigatran 110 mg: 1.60 % / year
HR 0.91 (0.69-1.20)
Connolly SJ, et al. Circulation 2013;128:237-243
Major Bleeding
Dabigatran 150 mg: 3.74% / year
Dabigatran 110 mg: 2.99% / year
HR 1.26 (1.04-1.53)
Postmarketing Reports of
Bleeding with Dabigatran
Southworth MR, et al. N Engl J Med 2013; 368(14):1272-1274
Outcomes of Major Bleeding with
Dabigatran or Warfarin
5 phase III AF and VTE trials: 1,034 individuals
Adjusted OR 0.66 (95% CI 0.46-1.00)
13.0%
p=0.05
9.1%
Patients with bleed on dabigatran:
RBC transfusion
Plasma & Shorter ICU Stay
Majeed A, et al. Circulation 2013 [published online September 30, 2013]
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.

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