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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, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA. 1.

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

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Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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, MPH

TIMI Study Group

Brigham and Women’s Hospital

Harvard Medical School

Boston, MA

1


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

1989-1993

RE-LY

(Dabigatran)

2009

ARISTOTLE

(Apixaban)

2011


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Comparative PK/PD of NOACs

CYP = cytochromeP450; P-gp= P-glycoprotein

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

Pradaxa[package insert]. Ridgefield, CT: BoehringerIngelheim 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 ClinPharmacol2010;50:743–753

Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342

Bathala, et al. Drug MetabDispos 2012;40:2250–2255


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

NOAC SPAF Trials

*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;365:883-891

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Baseline Characteristics

CHADS2

0-1

2

3-6

Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Trial Metrics

*TTR, time in therapeutic range

Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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)

0.80 (0.67 - 0.95)

ARISTOTLE

0.88 (0.75 - 1.02)

ENGAGE AF-TIMI 48

[60 mg]

Combined

0.81 (0.73 - 0.91)

[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 2013 [in-press]


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

1

2

Favors Warfarin

Favors NOAC

Heterogeneity p=NS for all outcomes

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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)

0.80 (0.71 - 0.90)

ENGAGE AF-TIMI 48

Combined

0.86 (0.73 - 1.00)

[60 mg]

Favors NOAC

Favors Warfarin

[Random Effects Model]

p=0.06

N=58,498

0.5

1

2

Heterogeneity p=0.001

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

p=0.043

0.2

0.5

1

2

Favors Warfarin

Favors NOAC

Heterogeneity

ICH, p=0.22

GI Bleeding, p=0.009

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Subgroups: Stroke or SEE

P-Interaction

Risk Ratio (95% CI)

Age

<75

0.85 (0.73 - 0.99)

p=0.38

≥75

0.78 (0.68 - 0.88)

Gender

Female

p=0.52

0.78 (0.65 - 0.94)

Male

0.84 (0.75 - 0.94)

Diabetes

No

p=0.73

0.83 (0.74 - 0.93)

Yes

0.80 (0.69 - 0.93)

Prior Stroke or TIA

No

p=0.30

0.78 (0.66 - 0.91)

Yes

0.86 (0.76 - 0.98)

CrCl

0.79 (0.65 - 0.96)

p=0.12

<50

50-80

0.75 (0.66 - 0.85)

>80

0.98 (0.79 - 1.22)

CHADS2Score

0-1

0.75 (0.54 - 1.04)

p=0.76

2

0.86 (0.70 - 1.05)

3-6

0.80 (0.72 - 0.89)

VKA Status

Naive

p=0.31

0.75 (0.66 - 0.86)

Experienced

0.85 (0.70 - 1.03)

Center-Based TTR

<66%

0.77 (0.65 - 0.92)

p=0.60

≥66%

0.82 (0.71 - 0.95)

0.5

1

2

Favors NOAC

Favors Warfarin

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Subgroups: Major Bleeding

P-Interaction

Risk Ratio (95% CI)

Age

p=0.28

0.79 (0.67 - 0.94)

<75

0.93 (0.74 - 1.17)

≥75

Gender

0.75 (0.58 - 0.97)

Female

p=0.29

0.90 (0.72 - 1.12)

Male

Diabetes

p=0.12

0.71 (0.54 – 0.93)

No

0.90 (0.78 - 1.04)

Yes

Prior Stroke or TIA

p=0.70

0.85 (0.72 - 1.01)

No

Yes

0.89 (0.77 - 1.02)

CrCl

p=0.57

0.74 (0.52 - 1.05)

<50

50-80

0.91 (0.76 - 1.08)

0.85 (0.66 - 1.10)

>80

CHADS2Score

p=0.09

0.60 (0.45 - 0.80)

0-1

2

0.88 (0.65 - 1.20)

0.86 (0.71 - 1.04)

3-6

VKA Status

p=0.78

0.84 (0.76 - 0.93)

Naive

0.87 (0.70 - 1.08)

Experienced

Center-Based TTR

p=0.022

0.69 (0.59 - 0.81)

<66%

0.93 (0.76 - 1.13)

≥66%

0.2

0.5

1

2

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

Favors NOAC

Favors Warfarin


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Low Dose Regimens

Efficacy & Safety Outcomes

Risk Ratio (95% CI)

Dabigatran 110 mg & Edoxaban 30 mg

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

0.2

0.5

1

2

Favors Low Dose NOAC

Favors Warfarin

N=26,107

Heterogeneity

P=NS for outcomes except:

Major Bleeding, p=<0.001

GI Bleeding, p=0.01

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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, MPH

TIMI Study Group

Brigham and Women’s Hospital

Harvard Medical School

Boston, MA

14


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Research Support:

Daiichi Sankyo, AstraZeneca

Consultant and Advisory Boards:

BoehringerIngelheim, Daiichi Sankyo, Bristol-Meyers Squibb

Disclosures

15


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Stroke Prevention in AF

Warfarin vs. Placebo

AFASAK-1 (671)

SPAF (421)

BAATAF (420)

CAFA (378)

SPINAF (571)

EAFT (439)

64%

All Trials (n=6)

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

Warfarin Worse

Warfarin Better

16

Hart RG, et al. Ann Intern Med 2007;146:857-867.


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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 Trials of Warfarin vs. Placebo

1989-1993

RE-LY

(Dabigatran)

2009

ARISTOTLE

(Apixaban)

2011


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

18


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Comparative PK/PD of NOACs

CYP = cytochromeP450; P-gp= P-glycoprotein

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

Pradaxa[package insert]. Ridgefield, CT: BoehringerIngelheim 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 ClinPharmacol2010;50:743–753

Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342

Bathala, et al. Drug MetabDispos 2012;40:2250–2255


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

NOAC SPAF Trials

*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;365:883-891

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Baseline Characteristics

CHADS2

0-1

2

3-6

Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Trial Metrics

*TTR, time in therapeutic range

Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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)

0.80 (0.67 - 0.95)

ARISTOTLE

0.88 (0.75 - 1.02)

ENGAGE AF-TIMI 48

[60 mg]

Combined

0.81 (0.73 - 0.91)

[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 2013 [in-press]


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

1

2

Favors Warfarin

Favors NOAC

Heterogeneity p=NS for all outcomes

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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)

0.80 (0.71 - 0.90)

ENGAGE AF-TIMI 48

Combined

0.86 (0.73 - 1.00)

[60 mg]

Favors NOAC

Favors Warfarin

[Random Effects Model]

p=0.06

N=58,498

0.5

1

2

Heterogeneity p=0.001

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

p=0.043

0.2

0.5

1

2

Favors Warfarin

Favors NOAC

Heterogeneity

ICH, p=0.22

GI Bleeding, p=0.009

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Subgroups: Stroke or SEE

P-Interaction

Risk Ratio (95% CI)

Age

<75

0.85 (0.73 - 0.99)

p=0.38

≥75

0.78 (0.68 - 0.88)

Gender

Female

p=0.52

0.78 (0.65 - 0.94)

Male

0.84 (0.75 - 0.94)

Diabetes

No

p=0.73

0.83 (0.74 - 0.93)

Yes

0.80 (0.69 - 0.93)

Prior Stroke or TIA

No

p=0.30

0.78 (0.66 - 0.91)

Yes

0.86 (0.76 - 0.98)

CrCl

0.79 (0.65 - 0.96)

p=0.12

<50

50-80

0.75 (0.66 - 0.85)

>80

0.98 (0.79 - 1.22)

CHADS2Score

0-1

0.75 (0.54 - 1.04)

p=0.76

2

0.86 (0.70 - 1.05)

3-6

0.80 (0.72 - 0.89)

VKA Status

Naive

p=0.31

0.75 (0.66 - 0.86)

Experienced

0.85 (0.70 - 1.03)

Center-Based TTR

<66%

0.77 (0.65 - 0.92)

p=0.60

≥66%

0.82 (0.71 - 0.95)

0.5

1

2

Favors NOAC

Favors Warfarin

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Subgroups: Major Bleeding

P-Interaction

Risk Ratio (95% CI)

Age

p=0.28

0.79 (0.67 - 0.94)

<75

0.93 (0.74 - 1.17)

≥75

Gender

0.75 (0.58 - 0.97)

Female

p=0.29

0.90 (0.72 - 1.12)

Male

Diabetes

p=0.12

0.71 (0.54 – 0.93)

No

0.90 (0.78 - 1.04)

Yes

Prior Stroke or TIA

p=0.70

0.85 (0.72 - 1.01)

No

Yes

0.89 (0.77 - 1.02)

CrCl

p=0.57

0.74 (0.52 - 1.05)

<50

50-80

0.91 (0.76 - 1.08)

0.85 (0.66 - 1.10)

>80

CHADS2Score

p=0.09

0.60 (0.45 - 0.80)

0-1

2

0.88 (0.65 - 1.20)

0.86 (0.71 - 1.04)

3-6

VKA Status

p=0.78

0.84 (0.76 - 0.93)

Naive

0.87 (0.70 - 1.08)

Experienced

Center-Based TTR

p=0.022

0.69 (0.59 - 0.81)

<66%

0.93 (0.76 - 1.13)

≥66%

0.2

0.5

1

2

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

Favors NOAC

Favors Warfarin


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

ACTIVE-W: Stroke or SEE

TTR ≥ 65%

TTR < 65%

P-interaction = 0.013

RR = 1.11

P = 0.47

RR = 1.83

P < 0.0001

Clopi + ASA

Clopi + ASA

Event Rate (%)

VKA

VKA

Years

Years

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

ACTIVE-W: Major Bleeding

TTR ≥ 65%

TTR < 65%

P-interaction = 0.0006

RR = 0.68

P = 0.08

RR = 1.55

P = 0.027

Event Rate (%)

Years

Years

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Low Dose Regimens

Efficacy & Safety Outcomes

Risk Ratio (95% CI)

Dabigatran 110 mg & Edoxaban 30 mg

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

0.2

0.5

1

2

Favors Low Dose NOAC

Favors Warfarin

N=26,107

Heterogeneity

P=NS for outcomes except:

Major Bleeding, p=<0.001

GI Bleeding, p=0.01

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


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

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

32


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

BACK – UP

33


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Factor Xa Inhibitors: Stroke or SEE

Risk Ratio (95% CI)

ROCKET AF

0.88 (0.75 - 1.03)

0.80 (0.67 - 0.95)

ARISTOTLE

0.88 (0.75 - 1.02)

ENGAGE AF-TIMI 48

Combined

0.86 (0.78 - 0.94)

[Random Effects Model]

p=0.0011

N=46,443

0.5

1

2

Favors NOAC

Favors Warfarin

Heterogeneity p=0.65


Comprehensive meta analysis comparing the efficacy and safety of noacs with warfarin in af

Factor Xa Inhibitors: Bleeding

Risk Ratio (95% CI)

1.03 (0.89, 1.18)

ROCKET

0.70 (0.61, 0.81)

ARISTOTLE

0.80 (0.71, 0.90)

ENGAGE AF-TIMI 48

0.83 (0.68, 1.02)

Combined

[Random Effects Model]

2

1

0.5

N=46,400

Favors NOAC

Favors Warfarin

Heterogeneity p=0.0006


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