Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-Monitored, Oral Anticoagulants...

Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-

Monitored, Oral Anticoagulants (NOACs) for SPAF

New Paradigms in the Science and Medicine of Heart Disease

CHRISTIAN T. RUFF, MD, MPHAssociate Physician Cardiovascular Division

Brigham and Women's Hospital Instructor of Medicine

Harvard Medical SchoolBoston, 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

Subtherapeutic INR 29%

INR in range10%

No warfarin61%

Preventable Strokes

AF Patients with Stroke with no Known Contraindication to

Anticoagulation

Gladston, DJ, et al. Stroke 2009;40:235-40

Properties Benefit

Oral, once-daily dosing Ease of administration

Rapid onset of actionNo need for overlapping parenteral anticoagulant

Minimal food or drug interactions

Simplified dosing

Predictable anticoagulant effect

No coagulation monitoring

Extra renal clearanceSafe in patients with renal disease

Rapid offset in actionSimplifies management in case of bleeding or intervention

Antidote For emergencies

Properties of an Ideal Anticoagulant

Comparative PK/PD of NOACs

Dabigatran Rivaroxaban Apixaban Edoxaban

Target 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

Renal Clearance, % 80 33* 27 50

Transporters P-gp P-gp P-gp P-gp

CYP Metabolism, % None 32 <32 <4

CYP = cytochrome P450; P-gp = P-glycoprotein

Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011Weinz 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; abstractOgata, et al. J Clin Pharmacol 2010;50:743–753Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342Bathala, et al. Drug Metab Dispos 2012;40:2250–2255

*33% renally cleared; 33% excreted unchanged in urine

Ruff CT, et al. Lancet 2013 [in-press]

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 Twice Daily Once Daily

Dose Adjustment No 20 → 15 5 → 2.5 60 → 3030 → 15

At Baseline 0 21 5 25

After Randomization No No No >9%

Target INR (Warfarin) 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0

Design 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;361:1139-1151Patel MR, et al. N Engl J Med 2011;365:883-891Granger CB, et al. N Engl J Med 2011;365:981-992Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907


Pivotal Warfarin-Controlled TrialsStroke Prevention in AF

6 Trial of Warfarin vs. Placebo1989-1993

RE-LY(Dabigatran)

2009

ROCKET AF (Rivaroxaban)

2010

ARISTOTLE (Apixaban)

2011

ENGAGE AF-TIMI 48 (Edoxaban)

2013

Warfarin vs. Placebo2,900 Patients

NOACs vs. Warfarin71,683 Patients

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

Baseline Characteristics


32

35

33 13

87

4753

34

36

30CHADS2

23-6

0-1


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 66 68

Lost to Follow-Up, N 20 32 90 1


*TTR, time in therapeutic range


0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs Warfarin

Dabigatran 150 vs Warfarin

Non-inferiority

P-value

< 0.001

< 0.001

Superiority

P-value

0.34

< 0.001

Margin = 1.46

HR (95% CI)

RE-LY Efficacy - DabigatranStroke/Systemic Embolic Event

Connolly, et al. N Engl J Med 2009;361:1139-51

0.1 0.3 0.5 1.0 2.0

Dabigatran 110 mg

Dabigatran 150 mg

Stroke/SEE

Ischemic Stroke

Hemorrhagic Stroke

0.91 (0.74-1.11)

0.66 (0.53-0.82)

1.11 (0.89-1.40)

0.76 (0.60-0.98)

0.31 (0.17-0.56)

0.26 (0.14-0.49)

Dabigatran Better Warfarin Better

RE-LY Efficacy


0.1 0.3 0.5 1.0 2.0

Major Bleed

ICH

GI Bleed

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)

MI1.29 (0.96-

1.75)1.27 (0.94-1.71)

Dabigatran Better Warfarin Better

RE-LY Safety Results


Dabigatran 110 mg

Dabigatran 150 mg

► 150 mg twice daily if CrCL > 30 mL/min

► 75 mg twice daily if CrCL 15-30 mL/min

Dabigatran

Rivaroxaban Warfarin

Event Rate

Event Rate

HR(95% CI) P-value

On Treatment

N = 14,143

1.70 2.15 0.79 (0.65, 0.95) 0.015

ITTN = 14,171

2.12 2.42 0.88 (0.74, 1.03) 0.117

Rivaroxabanbetter

Warfarinbetter

Event Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat through

Site Notification populations

0.5 1 2

Patel, et al. N Engl J Med 2011;365(10);883-891

ROCKET AF Efficacy - RivaroxabanStroke/Systemic Embolic Event

ROCKET AF Key Secondary Efficacy

EventRivaroxaban

(%/yr)Warfarin

(%/yr)Hazard Ratio

(95% CI)P-

value

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

Patel, et al. N Engl J Med 2011; 365(10);883-891

ROCKET AF Safety

EventRivaroxaban

(%/yr)Warfarin

(%/yr)Hazard Ratio

(95% CI)P-

value

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

Patel, et al. N Engl J Med 2011; 365(10);883-891

► 20 mg if CrCl > 50 mL/min

► 15 mg if CrCL 15-50 mL/min

Rivaroxaban

ARISTOTLE Efficacy - Apixaban

Granger CB, et al. NEJM 2011; 365:981-992

HR 0.79 (0.66–0.95)

P (non-inferiority) < 0.001

21% RRR

(1.27 %/yr )

(1.60 %/yr)

P (superiority) = 0.011

ARISTOTLE Efficacy Outcomes


Outcome

Apixaban(N = 9120)

Warfarin(N = 9081)

HR (95% CI)P

ValueEvent Rate

(%/yr)

Event Rate

(%/yr)

Stroke or systemic embolism*

1.27 1.600.79 (0.66,

0.95)0.011

Stroke 1.19 1.510.79 (0.65,

0.95)0.012

Ischemic or uncertain 0.97 1.050.92 (0.74,

1.13)0.42

Hemorrhagic 0.24 0.470.51 (0.35,

0.75)<

0.001

Systemic embolism (SE) 0.09 0.100.87 (0.44,

1.75)0.70

All-cause death* 3.52 3.940.89 (0.80,

0.998)0.047

Stroke, SE, or all-cause death

4.49 5.040.89 (0.81,

0.98)0.019

Myocardial infarction 0.53 0.610.88 (0.66,

1.17)0.37

ARISTOTLE Safety End Points

EventApixaban

(%/yr)Warfarin

(%/yr)Hazard Ratio

(95% CI)P-

value

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


► 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

Apixaban

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


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

0.87P=0.08

P=0.10

Hazard ratio (97.5% CI)

1.13

0.50 1.00 2.0

P Value for Superiority



edoxaban superior edoxaban inferior

Superiority Analysis (ITT, Overall)

Warfarin TTR 68.4%

*Dose reduced by 50% in selected pts

Key Secondary Outcomes

edoxaban superior edoxaban inferior

Warfarin TTR 68.4%

*Dose reduced by 50% in selected pts

2° EP: Stroke, SEE, CV death

Death or ICH

All-cause mortality

CV death

Myocardial infarction

HR (95% CI)

Hem. Stroke

Ischemic Stroke

0.25 1.00 2.00.5



1.190.94

0.85

1.411.00

0.540.33

0.870.95

0.870.82

0.920.87

0.86

P vs warfarin

E-60 E-30

<0.001<0.001

0.97<0.001

0.0050.32

0.004<0.001

0.080.006

0.0130.008

0.600.13

Main Safety Results- Safety Cohort on Treatment -

P Value vs

warfarin

Safety cohort=all patients who received at least 1 dose by treatment actually received*Dose reduced by 50% in selected pts

Warfarin TTR 68.4% Hazard ratio (95% CI) Edoxaban 60* mg QD

vs warfarinEdoxaban 30* mg QD

vs warfarin

edoxaban superior edoxaban inferior0.25 1.00.5

P<0.001P<0.001

ISTH Major Bleeding 0.800.47

2.0

Fatal Bleeding 0.550.35

P=0.006P<0.001

Intracranial Hemorrhage

0.470.30

P<0.001P<0.001

Gastrointestinal Bleeding1.23

0.67 P=0.03P<0.001

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined

Favors NOAC Favors Warfarin

0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.66 (0.53 - 0.82)

0.81 (0.73 - 0.91)

Risk Ratio (95% CI)

p=<0.0001

0.5 1 2

All NOACS: Stroke or SEE

[Random Effects Model]

N=58,541

Heterogeneity p=0.13

[60 mg]

[150 mg]

Ruff CT, et al. Lancet 2013. Published online December 4, 2013

All-Cause Mortality

MI

Hemorrhagic Stroke

Ischemic Stroke

0.90 (0.85 - 0.95)

0.97 (0.78 - 1.20)

0.49 (0.38 - 0.64)

0.92 (0.83 - 1.02)

Risk Ratio (95% CI)

p=0.0003

p=0.77

p<0.0001

p=0.10


0.2 0.5 1 2

Secondary Efficacy Outcomes

Heterogeneity p=NS for all outcomes


ARISTOTLE

ROCKET AF

Combined


Risk Ratio (95% CI)

0.80 (0.71 - 0.90)

0.71 (0.61 - 0.81)

1.03 (0.90 - 1.18)

0.94 (0.82 - 1.07)

0.86 (0.73 - 1.00)

0.5 1 2

All NOACS: Major Bleeding

[Random Effects Model]

N=58,498p=0.06

Heterogeneity p=0.001

RE-LY[150 mg]

ENGAGE AF-TIMI 48[60 mg]


GI Bleeding

ICH

1.25 (1.01 - 1.55)

0.48 (0.39 - 0.59)

Risk Ratio (95% CI)

p=0.043

p<0.0001


0.2 0.5 1 2

Secondary Safety Outcomes

Heterogeneity ICH, p=0.22GI Bleeding, p=0.009


≥66% 0.82 (0.71 - 0.95)

<66% 0.77 (0.65 - 0.92)

Experienced 0.85 (0.70 - 1.03)

Naive 0.75 (0.66 - 0.86)

3-6 0.80 (0.72 - 0.89)

2 0.86 (0.70 - 1.05)

0-1 0.75 (0.54 - 1.04)

>80 0.98 (0.79 - 1.22)

50-80 0.75 (0.66 - 0.85)

<50 0.79 (0.65 - 0.96)

Yes 0.86 (0.76 - 0.98)

No 0.78 (0.66 - 0.91)

Male 0.84 (0.75 - 0.94)

Female 0.78 (0.65 - 0.94)

≥75 0.78 (0.68 - 0.88)

<75 0.85 (0.73 - 0.99)

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 Warfarin0.5 1 2

Prior Stroke or TIA

Yes

NoDiabetes

0.80 (0.69 - 0.93)

0.83 (0.74 - 0.93) p=0.73

Subgroups: Stroke or SEE


Center-Based TTR

VKA Status

CHADS2 Score

CrCl

Gender

Age

Favors NOAC0.2 0.5 1 2

Favors Warfarin

Prior Stroke or TIA

Diabetes

Male

Female

≥75

<75

Yes

No

≥66%

<66%

Experienced

Naive

3-6

2

0-1

>80

50-80

<50

Yes

No

p=0.022

p=0.78

p=0.09

p=0.57

p=0.70

p=0.29

p=0.28

0.93 (0.76 - 1.13)

0.69 (0.59 - 0.81)

0.87 (0.70 - 1.08)

0.84 (0.76 - 0.93)

0.86 (0.71 - 1.04)

0.88 (0.65 - 1.20)

0.60 (0.45 - 0.80)

0.85 (0.66 - 1.10)

0.91 (0.76 - 1.08)

0.74 (0.52 - 1.05)

0.89 (0.77 - 1.02)

0.85 (0.72 - 1.01)

0.90 (0.72 - 1.12)

0.75 (0.58 - 0.97)

0.93 (0.74 - 1.17)

0.79 (0.67 - 0.94)

Risk Ratio (95% CI) P-Interaction

p=0.12

0.90 (0.78 - 1.04)

0.71 (0.54 – 0.93)

Subgroups: Major Bleeding


Connolly SJ, et al. Circulation 2008;118:2029-2037

ACTIVE-W: Stroke or SEE

Years

Eve

nt R

ate

(%)

TTR ≥ 65% TTR < 65%

P-interaction = 0.013

RR = 1.83

P < 0.0001

RR = 1.11

P = 0.47

0.0

0.0

20

.04

0.0

60

.08

0.1

0

0.0 0.5 1.0 1.5

OAC

C+A

0.0

0.0

20

.04

0.0

60

.08

0.1

0

0.0 0.5 1.0 1.5

OAC

C+A

Clopi + ASA

VKA

Clopi + ASA

VKA

Years

0.0

0.0

10

.02

0.0

30

.04

0.0

5

0.0 0.5 1.0 1.5

OAC

C+A

0.0

0.0

10

.02

0.0

30

.04

0.0

5

0.0 0.5 1.0 1.5

OAC

C+A


ACTIVE-W: Major Bleeding

Years Years

Eve

nt R

ate

(%)

P-interaction = 0.0006

RR = 1.55

P = 0.027

RR = 0.68

P = 0.08

TTR ≥ 65% TTR < 65%

OAC

C+A

C+A

OAC

GI Bleeding 0.89 (0.57 - 1.37)

ICH 0.31 (0.24 - 0.41)

Major Bleeding 0.65 (0.43 - 1.00)

All-Cause Mortality 0.89 (0.83 - 0.96)

MI 1.25 (1.04 - 1.50)

Hemorrhagic Stroke 0.33 (0.23 - 0.46)

Ischemic Stroke 1.28 (1.02 - 1.60)

Stroke or SEE 1.03 (0.84 - 1.27)

Risk Ratio (95% CI)

p=0.58

p<0.0001

p=0.05

p=0.003

p=0.019

p<0.0001

p=0.045

p=0.74

Favors Low Dose NOAC Favors Warfarin0.2 0.5 1 2

Low Dose RegimensEfficacy & Safety Outcomes

N=26,107

Dabigatran 110 mg & Edoxaban 30 mg

Heterogeneity P=NS for outcomes except: Major Bleeding, p=<0.001GI Bleeding, p=0.01 Ruff CT, et al. Lancet 2013. Published online December 4, 2013

(N=647)

Cardioversion

(N=672) (N=664)Nagarakanti R, et al. Circulation 2011;123:131-136

RE-LY

%

ROCKET AF

%

Cardioversion & Catheter Ablation

Piccini JP, et al. JACC 2013;61:1998-2006

Kim JS, et al. Heart Rhythm 2013; 10:483-489

Catheter Ablation with NOACs

Case-control: 763 consecutive patients undergoing AF ablation

P=0.85

P=1.0

P=1.0

%

P=0.81

Periprocedural Major Bleeding

%

Healey JS, et al. Circulation 2012; 126:343-348

RE-LY

Discontinuing NOACs Prior to Procedures

Heidbuchel H, et al. Eurospace 2013;15:625-651.

www.NOACfor AF.eu

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


CrCl 30-50 ml/min


CrCl 15-30 ml/min

not indicate

d

not indicated

≥36h ≥48h no data no data ≥36h ≥48h

CrCl <15 ml/min

no official indication for use

Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127

Dabigatran (FIIa) Monitoring

aPTT Hemoclot Test

Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127

Rivaroxaban (Fxa) Monitoring

PT

Rivaroxaban (µg L-1)0 100 200 300 400 500 600

Pro

thro

mb

in t

ime

(s

)

0

10

20

30

40

Rotachrom Anti-Xa

Managing Bleeding with NOACs

Heidbuchel H, et al. Eurospace 2013;15:625-651.

www.NOACfor AF.eu

Granger CB, et al. European Heart Journal 2012;33 (Supplement):685-686

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).

1-2 3-7 8-14 15-300

5

10

15

20

25

21

5

Apixaban to VKA Group Warfarin to VKA Group Apixaban to VKA Total Events Warfarin to VKA Total Events

Days after last dose

Str

oke o

r syste

mic

em

bolism

(n

)

ARISTOTLEApixaban: Increased Events at End of Trial

Rivaroxaban

Warfarin

48.8

81.3

# P

rim

ary

Eve

nts P =

0.008

Patel MR, et al. NEJM 2011; 365:883-891Patel MR, et al. JACC 2013;61:651-658

Safety/Days 3 to 30 after the last dose

# Primary Events during first 30 days of transition

ROCKET AFRivaroxaban: Increased Events at End of Trial

Rivaroxaban Warfarin

Key Transition Plan Components

Warfarin

NOAC

Double-Blind Phase

Transition Period

Duration of Anticoagulant Effect

Solution =Transition Plan

Components:1. Open-Label OAC2. Transition Kit3. Frequent INRs4. VKA Algorithm

Long

Short

INCREASED RISK OF STROKE

INCREASED RISK OF STROKE

All Patients: Stroke or SEE30 Day Transition Period

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Total0

1

2

3

4

5

6

7

8Warfarin

Edoxaban High-Dose

Edoxaban Low-Dose

Days after End of Trial Visit

# P

atie

nts

wit

h S

tro

ke o

r S

EE

Warfarin 7 Strokes (6 Isch, 1 Hem)Edoxaban HD 7 Strokes (6 Isch, 1 Hem) HR 1.00 p=0.99Edoxaban LD 7 Strokes (6 Isch, 1 Hem) HR 0.98 p=0.96

All Patients: Major Bleeding30 Day Transition Period

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Total0

2

4

6

8

10

12

14

16

18

20Warfarin

Edoxaban High-Dose

Edoxaban Low-Dose

Days after End of Trial Visit

# P

atie

nts

wit

h M

ajo

r B

leed

Transition Kit

Warfarin 11 Major Bleeds Edoxaban HD 10 Major Bleeds HR 0.90 p=0.82Edoxaban LD 18 Major Bleeds HR 1.60 p=0.22Warfarin 6 Major Bleeds

Edoxaban HD 4 Major Bleeds Edoxaban LD 5 Major Bleeds

RELY-ABLE


Stroke or SEE Major Bleeding

Dabigatran 150 mg: 3.74% / year Dabigatran 110 mg: 2.99% / year

HR 1.26 (1.04-1.53)

Dabigatran 150 mg: 1.46 % / year Dabigatran 110 mg: 1.60 % / year

HR 0.91 (0.69-1.20)

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

Majeed A, et al. Circulation 2013 [published online September 30, 2013]

5 phase III AF and VTE trials: 1,034 individuals

13.0%

9.1%

Adjusted OR 0.66 (95% CI 0.46-1.00)p=0.05

Patients with bleed on dabigatran: RBC transfusion Plasma & Shorter ICU Stay

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.

Conclusions

Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-Monitored, Oral Anticoagulants...

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