Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF

1

Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with

Warfarin in AF

An Analysis Including 71,683 Patients from Four Large Randomized Clinical Trials

Christian T. Ruff, MD, MPHTIMI Study Group

Brigham and Women’s HospitalHarvard Medical School

Boston, MA

2

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

3

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 <4CYP = 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

4

NOAC SPAF TrialsRE-LY ROCKET-AF ARISTOTLE ENGAGE AF

Drug Dabigatran Rivaroxaban Apixaban Edoxaban# Randomized 18,113 14,266 18,201 21,105Dose (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 25After Randomization No No No >9%

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

RE-LY(Dabigatran)

ROCKET-AF(Rivaroxaban)

ARISTOTLE(Apixaban)

ENGAGE AF(Edoxaban)

# Randomized 18,113 14,264 18,201 21,105Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78]

Female, % 37 40 35 38Paroxysmal AF 32 18 15 25VKA naive 50 38 43 41

Aspirin Use 40 36 31 29

5

Baseline Characteristics


32

35

33 13

87

4753

34

36

30CHADS2

23-6

0-1

6

Trial Metrics

RE-LY(Dabigatran)


ARISTOTLE(Apixaban)

ENGAGE AF(Edoxaban)

Median Follow-Up, years 2.0 1.9 1.8 2.8Median TTR 66 58 66 68

Lost to Follow-Up, N 20 32 90 1


*TTR, time in therapeutic range

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 [in-press] 7

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

8

Heterogeneity p=NS for all outcomes

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

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

9


N=58,498p=0.06


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

10

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 TIAYesNoDiabetes

0.80 (0.69 - 0.93)

0.83 (0.74 - 0.93) p=0.73

Subgroups: Stroke or SEE

11Ruff CT, et al. Lancet 2013 [in-press]

Center-Based TTR

VKA Status

CHADS2 Score

CrCl

Gender

Age

Favors NOAC0.2 0.5 1 2

Favors Warfarin

Prior Stroke or TIA

DiabetesMaleFemale≥75<75

YesNo

≥66%<66%ExperiencedNaive3-620-1 >8050-80<50

YesNo

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


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

13

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 [in-press]

14

Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with

Warfarin in AF

An Analysis Including 71,683 Patients from Four Large Randomized Clinical Trials

Christian T. Ruff, MD, MPHTIMI Study Group

Brigham and Women’s HospitalHarvard Medical School

Boston, MA

15

Research Support:Daiichi Sankyo, AstraZeneca

Consultant and Advisory Boards:Boehringer Ingelheim, Daiichi Sankyo, Bristol-Meyers Squibb

Disclosures

100% 50% 0% -50% -100%

AFASAK-1 (671) SPAF (421)BAATAF (420)

CAFA (378)

SPINAF (571)

EAFT (439)

All Trials (n=6)

Warfarin Better Warfarin Worse

64%

Stroke Prevention in AF Warfarin vs. Placebo

Hart RG, et al. Ann Intern Med 2007;146:857-867.16

17

Pivotal Warfarin-Controlled TrialsStroke Prevention in AF

6 Trials 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

18

First to contain data from all 4 phase 3 warfarin-controlled trials

Robust sample size− Precision in assessing relative benefit of NOACs in key clinical

subgroups− Effects of agents on important secondary outcomes

Pooled data for FXa and thrombin inhibitors− Target key coagulation enzymes− Trials share similar design− Agents used interchangeably clinically and grouped together by Guidelines

Separate meta-analysis of low dose dabigatran and edoxaban

Comprehensive picture of the NOACs as a therapeutic option

Meta-Analysis

19

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 <4CYP = 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

20

NOAC SPAF TrialsRE-LY ROCKET-AF ARISTOTLE ENGAGE AF

Drug Dabigatran Rivaroxaban Apixaban Edoxaban# Randomized 18,113 14,266 18,201 21,105Dose (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 25After Randomization No No No >9%

Target INR (Warfarin) 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0Design PROBE* 2x blind 2x blind 2x blind

*PROBE = prospective, randomized, open-label, blinded end point evaluation


RE-LY(Dabigatran)


ARISTOTLE(Apixaban)

ENGAGE AF(Edoxaban)

# Randomized 18,113 14,264 18,201 21,105Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78]

Female, % 37 40 35 38Paroxysmal AF 32 18 15 25VKA naive 50 38 43 41

Aspirin Use 40 36 31 29

21

Baseline Characteristics


32

35

33 13

87

4753

34

36

30CHADS2

23-6

0-1

22

Trial Metrics

RE-LY(Dabigatran)


ARISTOTLE(Apixaban)

ENGAGE AF(Edoxaban)

Median Follow-Up, years 2.0 1.9 1.8 2.8Median TTR 66 58 66 68

Lost to Follow-Up, N 20 32 90 1


*TTR, time in therapeutic range

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined


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


N=58,541


[60 mg]

[150 mg]

Ruff CT, et al. Lancet 2013 [in-press] 23

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

24

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

25


N=58,498p=0.06


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

26

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


Prior Stroke or TIAYesNoDiabetes

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

DiabetesMaleFemale≥75<75

YesNo

≥66%<66%ExperiencedNaive3-620-1 >8050-80<50

YesNo

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 29

ACTIVE-W: Stroke or SEE

Years Years

Eve

nt R

ate

(%)

TTR ≥ 65% TTR < 65%

P-interaction = 0.013

RR = 1.83P < 0.0001

RR = 1.11P = 0.47

0.0

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5

OAC

C+A

0.0

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5

OAC

C+A

Clopi + ASA

VKA

Clopi + ASA

VKA

0.0

0.01

0.02

0.03

0.04

0.05

0.0 0.5 1.0 1.5

OAC

C+A

0.0

0.01

0.02

0.03

0.04

0.05

0.0 0.5 1.0 1.5

OAC

C+A

Connolly SJ, et al. Circulation 2008;118:2029-2037 30

ACTIVE-W: Major Bleeding

Years Years

Eve

nt R

ate

(%)

P-interaction = 0.0006

RR = 1.55P = 0.027

RR = 0.68P = 0.08

TTR ≥ 65% TTR < 65%

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

31

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 [in-press]

32

NOACs significantly reduce stroke (19%)− Primarily driven by reduction in hemorrhagic stroke (51%)

NOACs significantly reduce mortality (10%)

Trend toward less bleeding− Substantial reduction in ICH (52%)− Increased GI bleeding (25%)

The relative efficacy and safety of NOACs consistent across a wide spectrum of AF patients

− Even less bleeding when INR not as well controlled

Low dose NOAC regimens reduce mortality and have a very favorable bleeding profile but more ischemic events

Differences in agents, patients, and trials may not be accounted for− Heterogeneity major bleeding and GI bleeding

Conclusions

33

BACK – UP

0.5 1 2


ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

Combined

0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.86 (0.78 - 0.94)p=0.0011

Factor Xa Inhibitors: Stroke or SEE

34


N=46,443

Risk Ratio (95% CI)


Factor Xa Inhibitors: Bleeding

35

ENGAGE AF-TIMI 48

0.80 (0.71, 0.90)

ARISTOTLE

0.70 (0.61, 0.81)

ROCKET

1.03 (0.89, 1.18)

Combined

0.83 (0.68, 1.02)


N=46,400


Risk Ratio (95% CI)


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Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF

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