SHA24/006003

Stroke Prevention: using a new anticoagulant in everyday clinical practice Ahmad Hersi, MBBS, MSc, FRCPC Associate Professor of Cardiac Sciences

Outlines • • • • •

Warfarin efficacy and safety ASA new safety data Risk stratification schemas New anticoagulant Agents Real life experience with Dabigatran

AF is an independent risk factor for stroke and the attributable risk increases with age

Stroke Risk Attributableto AF

Framingham Significant increase with age p<0.01

% 25

23.5%

20 15 9.9% 10 5

1.5%

2.8%

0 50-59

60-69

70-79

80-89

Age (years)

Wolf et al. Stroke 1991;22:983-988.

3

Increased risk of death after stroke in patients with AF persists for up to 8 years

Mortality Annual mortality rate, %

60

50

Patients with AF Patients without AF

40 30 20

10 0 1

2

3

4

Years post-stroke Population-based study of 3530 patients with ischaemic stroke Marini C et al. Stroke 2005;36:1115â&#x20AC;&#x201C;9

5

6

7

8

Stroke survivors with AF have poorer outcomes Outcome measure

Patients with AF

Patients without AF

Initial stroke severity, SSS score*

30

38

Initial disability, BI score*

35

52

Length of hospital stay, d

50

40

In hospital mortality, %

33

17

Discharged to nursing home, %

19

14

Neurological outcome, SSS score*

46

50

Functional outcome, BI score*

67

78

*Lower scores are associated with a poorer prognosis SSS = Scandinavian Neurological Stroke Score; BI = Barthel Index

Jorgensen HS et al. Stroke 1996;27:1765â&#x20AC;&#x201C;9

Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Warfarin Better

Control Better

AFASAK SPAF BAATAF CAFA SPINAF EAFT

Aggregate 100% Hart R, et al. Ann Intern Med 2007;146:857.

50%

0

-50%

-100%

Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions Treatment Better

Treatment Worse

Warfarin vs.

Placebo/Control

6 Trials n = 2,900

Warfarin vs.

No anticoagulation

Patients Age >65 years n = 23,657

100%

Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 1070â&#x20AC;&#x201C;1074

50%

0

-50%

RE-LY Registry Oral anticoagulation use CHADS2 ≥ 2 North Am

OAC use (CHADS 65.1% 2 ≥ 2) % INR (2-3)

53.5

South Am

West Eur

44.8%* 63.5%

43.5

66.9

East Eur

Middle East

Africa

India

China

Asia

38.7%* 55.8%* 36.9%* 39.9%* 10.5 %* 43.6%*

59.1

46.8

39.5

33.9

ecardio.org, congress report 2011

36.1

38.4

ACTIVE-W outcomes by INR control Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range

“Bad” INR control

“Good” INR control

ASA + Clopidogrel

Warfarin

Stroke Outcome; TTR= time in therapeutic range Connolly et al. Circulation 2008; 118:2029-37

ACTIVE W:Major Bleeding and INR Control

RR = 0.68

0.04

0.04

RR = 1.55

P = 0.08

0.03

0.03

P = 0.027

OAC

0.02

0.02

C+A

0.01

C+A

0.0

0.01

OAC

0.0

Cumulative Hazard Rates

<65% INR in Range

0.05

Interaction P = 0.0006

0.05

ď&#x201A;ł 65% INR in Range

0.0

0.5

ACTIVE Writing Group: Lancet 2006;367:1903-1912

1.0

1.5

0.0

Years

0.5

1.0

1.5

Risk of bleeding with ASA vs OAC

Friberg l Eu Heart J Jan 2012

Risk of bleeding with ASA vs OAC

Friberg l Eu Heart J Jan 2012

Effect of ASA on Vascular and nonvascular outcomes : Meta-analysis of RCT

Seshasai 2012, Arch Inter Med

Effect of ASA on Vascular and nonvascular outcomes : Meta-analysis of RCT

Seshasai 2012, Arch Inter Med

The CHADS2 Index Score (points)

Prevalence (%)*

Congestive Heart failure Hypertension Age >75 years Diabetes mellitus Stroke or TIA

1 1 1 1 2

32 65 28 18 10

Moderate-High risk Low risk

>2 0-1

50-60 40-50

VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

The CHA2DS2VASc Index Weight (points) Congestive heart failure or LVEF < 35% Hypertension Age >75 years Diabetes mellitus Stroke/TIA/systemic embolism Vascular Disease (MI/PAD/Aortic plaque) Age 65-74 years Sex category (female)

1 1 2 1 2 1 1 1

Moderate-High risk Low risk

>2 0-1

Lip GYH, Halperin JL. Am J Med 2010; 123: 484.

The CHA2DS2VASc Index

Summary • Warfarin losses 50% of its efficacy in real world setting.

• 50% of eligible patients for Warfarin are not on the drug.

• INR is sub-therapeutic in 50% of patients on Warfarin • ASA has similar bleeding risk as OAC

New Anticoagulant Agents

Novel Oral Anticoagulants in Advanced Development Pharmacological Properties

Feature

Dabigatran

Rivaroxaban

Apixaban

Target

IIa

Xa

Xa

Prodrug

Yes

No

No

Time to peak (h)

2

3

3

Half-life (h)

12-17

9-13

9-14

Renal excretion (%)

80

65

25

Antidote

None

None

None

WeitzJI. ACC Scientific Sessions, March 13, 2010.

Gibson M. ESC Scientific Sessions, August 2011.

Novel Anticoagulants for SPAF • Dabigatran: RE-LY – N = 18,113 (951 centers, 44 countries) – Funding/Coordination: BI, PHRI – Enrollment 12/2005-12/2007, NEJM 9/2009 • Rivaroxaban: ROCKET-AF – N = 14,246 (1178 centers, 45 countries) – Funding/Coordination: J&J/Bayer, DCRI – Enrollment 12/2006-6/2009, NEJM 9/2011 • Apixaban: ARISTOTLE – N = 18,201 (1034 centers, 39 countries) – Funding/Coordination: Pfizer/BMS, DCRI – Enrollment 12/2006-4/2010, NEJM 9/2011

Study Conduct • Dabigatran: RE-LY – FU = 2 Years – Complete FU = 99.9% – TTR = 64%

• Rivaroxaban: ROCKET-AF – FU = 1.9 Years – Complete FU = 99.9% – TTR = 55%

• Apixaban: ARISTOTLE – FU = 1.8 Years – Complete FU = 97.9% – TTR = 62%

RE-LY Trial Randomized Evaluation of Long-term Anticoagulant Therapy with Dabigatran Etexilate Non-valvular AF + >1 stroke risk factor Open-label

Warfarin (INR 2.0-3.0) n = 6,022

n = 18,113

Blinded

Dabigatran 110 mg bid n = 6,015

Dabigatran 150 mg bid n = 6,076

Primary objective: noninferiority vs. warfarin Observation period: minimum 1, mean 2, maximum 3 years Primary endpoint: all stroke + systemic embolism Safety measure: bleeding during treatment Connolly SJ et al. N Engl J Med 2009; 361: 1139.

RE-LY Trial Primary Events All Strokes and Systemic Embolic Events

Event Rate (%/year)

p <0.001 (Superiority)

4 p <0.001 (Noninferiority)

3 2

1.69

1.53

1 0

Connolly SJ et al. N Engl J Med 2009; 361: 1139.

1.11

Warfarin Dabigatran 110 mg bid Dabigatran 150 mg bid

RE-LY Trial All Major Bleeding Hgb ď&#x20AC;¤ >2 g/dl or Transfusion >2 units or Critical Site

Event Rate (%/year)

p = NS p = 0.002

Connolly SJ et al. N Engl J Med 2009; 361: 1139.

p = 0.04

RE-LY Trial Hemorrhagic Stroke Events Intracerebral hemorrhages Warfarin Dabigatran 110 mg bid Dabigatran 150 mg bid

Event Rate (%/year)

p <0.001

1 0.8 0.6 0.4

p <0.001

0.38

0.2 0

Connolly SJ et al. N Engl J Med 2009; 361: 1139.

0.10

0.12

RE-LY Trial All-Cause Mortality p = 0.047

Warfarin Dabigatran 110 mg bid Dabigatran 150 mg bid

Event Rate (%/year)

p = NS

5

4.13

4 3 2 1 0

Connolly SJ et al. N Engl J Med 2009; 361: 1139.

3.74

3.63

ROCKET-AF

Risk Factors

• CHF • Hypertension At least 2 or 3 required* • Age  75 • Diabetes OR • Stroke, TIA or Systemic embolus

Atrial Fibrillation Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 ml/min

Randomize Double Blind / Double Dummy (n ~ 14,000)

Warfarin INR target - 2.5 (2.0-3.0 inclusive)

Monthly Monitoring Adherence to standard of care guidelines

Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Mahaffey K N Engl J Med 2011

ROCKET-AF: Stroke/ SE HR 0.79 (95% CI 0.66-0.96) P<0.001

Mahaffey K N Engl J Med 2011

ROCKET-A F: Major Bleed

Mahaffey K N Engl J Med 2011

ROCKET AF: ICH

Mahaffey K N Engl J Med 2011

ARISTOTLE

ARISTOTLE

Risk Factors

• CHF • Hypertension • Age  75 • Diabetes OR • Stroke, TIA or Systemic embolus

Atrial Fibrillation Apixaban 5 mg BID

Randomize Double Blind / Double Dummy (n ~ 18201)

Warfarin INR target - 2.5 (2.0-3.0 inclusive)

Monthly Monitoring Adherence to standard of care guidelines

Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

At least 1 required*

ARISTOTLE: Stroke/SE HR 0.79 (0.66-0.95) P<0.01

Granger et al N Engl J Med , Sep 2011

ARISTOTLE: Stroke Ischemic P=0.42 Hemorrhagic P <0.001

ARISTOTLE: Major Bleed

Rates of Ischemic Stroke Comparisons to Warfarin RE-LY

Event Rate (%/year)

HR

p (ITT Analysis)

Dabigatran, 110 mg bid

1.34

1.20

0.35

Dabigatran, 150 mg bid

0.92

0.76

0.03

Warfarin

1.20

ROCKET-AF

Event Rate (%/year)

HR

p (ITT Analysis)

Rivaroxaban, 20 mg qd

1.62

0.99

0.92

Warfarin

1.64

ARISTOTLE

Event Rate (%/year)

HR

p (ITT Analysis)

Apixaban, 5 mg bid

0.97

0.92

0.42

Warfarin

1.05

Rates of Major Bleeding Comparisons to Warfarin RE-LY

Event Rate (%/year)

HR

p (ITT Analysis)

Dabigatran, 110 mg bid

2.71

0.80

0.003

Dabigatran, 150 mg bid

3.11

0.93

0.31

Warfarin

3.36

ROCKET-AF

Event Rate (%/year)

HR

p (OT Analysis)

Rivaroxaban, 20 mg qd

3.60

0.92

0.58

Warfarin

3.45

ARISTOTLE

Event Rate (%/year)

HR

p (ITT Analysis)

Apixaban, 5 mg bid

2.13

0.69

0.001

Warfarin

3.09

All-Cause Mortality Rates Comparisons to Warfarin RE-LY

Event Rate (%/year)

HR

p (ITT Analysis)

Dabigatran, 110 mg bid

3.75

0.91

0.35

Dabigatran, 150 mg bid

3.64

0.88

0.051

Warfarin

4.13

ROCKET-AF

Event Rate (%/year)

HR

p (ITT Analysis)

Rivaroxaban, 20 mg qd

4.52

0.92

0.152

Warfarin

4.91

ARISTOTLE

Event Rate (%/year)

HR

p (ITT Analysis)

Apixaban, 5 mg bid

3.52

0.89

0.01

Warfarin

3.94

Rates of ICH Event

HR

P-value

Dabigatran 110 150 Warfarin

0.23 0.32 0.74

0.31 0.40

0.001 0.001

Rivaroxabn Warfarin

0.5 0.7

0.67

0.02

Apixaban Warfarin

0.33 0.8

0.42

<0.001

Meta-anlaysis of new oral anticoagulants Am J Cardio 2012;April 24 Miller C et al

STROKE/SE

ISCHEMIC STROKE

HEMORRHAGIC STROKE

Meta-anlaysis of new oral anticoagulants Am J Cardio 2012;April 24 Miller C et al

Major bleeding

ICH

GI bleeding

â&#x20AC;˘ Clinical Practice Guidelines

European CPG 2012

European CPG 2012

European CPG 2012

Canadian Cardiovascular Society AF Guidelines Recommendations 2012 UPDATE â&#x20AC;˘ We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (e.g., CHADS2) and for the risk of bleeding (e.g., HAS-BLED), and that most patients should receive either an oral anticoagulant or ASA. (Strong Recommendation, High Quality Evidence)

â&#x20AC;˘ We suggest, that when OAC therapy is indicated, most patients should receive dabigatran or rivaroxaban or apixaban* in preference to warfarin.

(Conditional Recommendation, High Quality Evidence) *Once approved by Health Canada.

Canadian Cardiovascular Society AF Guidelines Recommendations 2012 UPDATE

â&#x20AC;˘ Values and Preferences: This recommendation places a relatively high value on comparisons to warfarin showing that dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention; dabigatran and rivaroxaban no more major bleeding and apixaban has less; dabigatran, rivaroxaban, and apixaban have less intracranial haemorrhage; and all three new OACs are much simpler to use.

Canadian Cardiovascular Society AF Guidelines Recommendations 2012 UPDATE

â&#x20AC;˘ The recommendation places less value on these features of warfarin: long experience with clinical use, availability of a specific antidote and a simple and standardized test for intensity of anticoagulant effect. The preference for one of the new OACs over warfarin is less marked among patients already receiving warfarin with stable INRs and no bleeding complications.

Conclusions • ASA has a bleeding risk similar to OAC • Female < 65 years with no other risk factor should not receive OAC • Dabigatran and Apxiban have a greater efficacy than Warfarin.

• Rivaroxaban has similar efficacy to warfarin

Thank you