5.1 Stroke Prevention in AF - Dr. Samuel Sp.jp

8/18/2019 5.1 Stroke Prevention in AF - Dr. Samuel Sp.jp

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Stroke Prevention in Atrial Fibrillation

Optimizing the use of NOAC in Clinical Practice

Dr Samuel Sudanawidjaja, SpJP

Dr M Soewandhie Hospital


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Topics of Discussion

• Burden and Management of AF

• Challenges and limitation of ASA and VKA

• What the Guideline Says

• The goal of OAC therapy

• Results of the studies with NOACs

• Results of RELY among Asian population

• Dabigatran data in Real-World Setting

• Summary


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Burden and Management of AF

Chowdhury P, et al. Cleve Clin J Med. 2009;76:543 –550

Thrombus (clot)

Affectedportion of the brain

Atrial fibrillation is a supraventricular arrhythmia

characterized by chaotic and uncoordinated

contraction of the atrium


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The Stroke Association: www.stroke.org.uk. Base on: Office of National Statistics Health Statistics

Quarterly, Winter 2001 "Stroke incidence and risk factors in a population based cohort study“.The Stroke Association estimate that 5,000 people per year have a stroke in Northern Ireland

Scottish Stroke Care Audit 2005/2006.

David Bloom's silent killer.David Bloom was an American

television journalist covering

Iraq war who died suddenly in

2003 after a pulmonary

embolism.


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Prevention of complications,

including thromboembolism

(particularly ischaemic

stroke) and heart failure

Relief of symptoms

Choice of antithrombotic therapy should be tailored to the patient based on:

Risk of thromboembolism Risk of bleeding

ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369 –429;

ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101 –9


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Superior Efficacy Profile of OAC vs ASA

to Prevent Stroke in Patients With

Nonvalvular AF

Hart et al, Ann Intern Med 2007;146:857 –867


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Challenges and limitations of ASA and VKA

Camm AJ et al. Eur Heart J 2012;33:2719 –47; Aspirin Tablets BP 300 mg: SmPC, 2013; Ansell J et al.

Chest 2008;133;160S –198S; Nutescu EA et al. Cardiol Clin 2008;26:169 –87; Umer Ushman MH et al.J Interv Card Electrophysiol 2008;22:129 –37


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What the Guideline Says:

ESC 2012

Atrial fibrillation

Valvular AF*

Assess risk of strokeCHA2DS2-VASc score

No antithrombotic

therapyNOAC VKA

0 1

No (i.e. nonvalvular)

Yes

≥2

Oral anticoagulant therapy


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What the Guideline Says: ESC 2012

(Risk of stroke)•

Update strongly recommendsa practice shift towards

identification of ‘truly low

risk’ patients with AF (i.e. age


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What the Guideline Says: ESC 2012

(Risk of bleeding)HAS-BLED score:• allows clinicians to make

informed assessment of

bleeding risk

• makes clinicians think of the

correctable risk factors for

bleeding

• has been validated in severalindependent cohorts

• correlates well with ICH risk

High HAS-BLED score per se

should not be used to exclude

patients from OAC therapy

Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253


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Most strokes associated with AF are ischaemic

Based on data collected in the Danish National Indicator Project for 39 484 patients hospitalized for stroke

(including 6294 patients with AF)

Andersen KK et al. Stroke 2009;40:2068 –72 13

Types of stroke in patients with AF

Ischaemic(92%)

Ischaemic stroke

(n=5810)

Haemorrhagic stroke

(n=484)

Haemorrhagic

(8%)


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Survival times after ischaemic stroke

are worse with AF

• By 1 year after ischaemic stroke, two-thirds of patients with AF have died,compared with one-third of those without AF

Follow-up of 501 patients with ischaemic stroke in the Framingham study

Lin HJ et al. Stroke 1996;27:1760 –4 14

1.0

0 60

Days after stroke

P r o b a b i l i t y

Survival

0.8

0.6

0.4

0.2

0120 180 240 300 360

Patients with AF (n=103)

P


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The goal of OAC therapy

“I need to

maximize risk

reduction at the

same time asminimizing harmto the patient… “

- PCP CPA Study

1. Circulation. 2008; 118 : 2029-2037. 2. Connoly SJ et al. N Engl J Med 2009; 361(12): 1139-1151


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Results of the studies with NOACs

(Ischaemic stroke)

140 (1.54) 136 (1.50)

149 (1.34) 161 (1.42)

0.5 1.0

Favours NOAC Favours warfarin

0.89 –1.291.02

0.75 –1.170.94

152 (1.28) 134 (1.14)Dabi 110

(ITT)

0.89 –1.421.13

1.50.0

Riva(Safety AT)

Apixaban**

(ITT)

103 (0.86) 134 (1.14)Dabi 150

(ITT)

0.58 –0.970.75

2.0

NOAC Warfarin HR 95% CINo. of events (%/yr)

162 (0.97) 175 (1.05) 0.74 –1.130.92Apixaban*

(ITT)

1. Connolly SJ et al. N Engl J Med 2009;361:1139 –51; 2. Connolly SJ et al. N Engl J Med

2010;363:1875 –6; 3. Patel MR et al. N Engl J Med 2011;365:883 –91; 4. Granger C et al. N Engl JMed 2011;365:981 –92; 5. Lopes R et al. Lancet 2012; 380:1749 –58

Not head-to-head comparison – for illustrative purposes only – adapted from references 1 –5

* Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group.

Among the patients with ischaemic strokes, haemorrhagic transformation occurred in 12 patients with apixaban and 20 patients with warfarin

** Revised data; re-categorized following original publication

Dabigatran 150mg is THE ONLY NOAC

that has significant benefit in preventing

ischaemic stroke


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(Intracranial bleeding)

1. Connolly SJ et al. N Engl J Med 2009;361:1139 –51; 2. Connolly SJ et al. N Engl J Med

2010;363:1875 –6; 3. Patel MR et al. N Engl J Med 2011;365:883 –91; 4. Granger C et al. N Engl JMed 2011;365:981 –92; 5. Lopes R et al. Lancet 2012; 380:1749 –58

52 (0.33) 122 (0.80)

55 (0.5) 84 (0.7)

0.5 1.0

Favors NOAC Favors warfarin

HR 95% CI

0.30 –0.580.42

0.47 –0.930.67

27 (0.23) 90 (0.76)Dabi 110

(ITT)

0.19 –0.450.30

1.50.0

Riva

(safety AT)

Apixaban

(ITT)

38 (0.32) 90 (0.76)Dabi 150

(ITT)

0.28 –0.600.41

2.0

NOAC WarfarinNo. of events (%/yr)

Both Dabigatran 110mg and 150mg has significant

benefit for reduction of intracranial bleeding


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(CV Mortality)

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

RE-LY® ROCKET-AF ARISTOTLE

c

Only Dabigatran 150mg BID has superior reduction inCARDIOVASCULAR MORTALITY


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Results of RELY among Asian population

Efficacy outcomes (Asia vs. non-Asia)

RE-LY® Asia

Stroke or SEE

Asia

Non-Asia

Ischemic stroke

Asia

Non-Asia

Hemorrhagic stroke

Asia

Non-Asia

Myocardial infarction

Asia

Non-AsiaDeath from any cause

Asia

Non-Asia

Dabigatran 150mg bidvs. Warfarin


Rate (%/year)

110mg bid

WarfarinDabigatran

1.0 2.00

Warfarin better

HR (95%CI)

Dabigatran better

1.39

1.06

1.12

0.81

0.17

0.09

0.50

0.86

4.01

3.57

3.06

1.48

2.02

0.98

0.75

0.32

0.58

0.65

5.09

3.96

Interaction

p value

Interaction

p value

0.0853

0.1977

0.7590

0.3782

0.4244

150mg bid

2.50

1.37

2.05

1.14

0.11

0.12

0.51

0.88

5.01

3.53

0.5597

0.5959

0.2729

0.3761

0.5929

1.0 2.00

Dabigatran better Warfarin better

HR (95%CI)


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Results of RELY among Asian population

Safety outcomes (Asia vs. non-Asia)

RE-LY® Asia

Major bleedingAsiaNon-AsiaGI major bleedingAsiaNon-AsiaLife threatening bleedingAsiaNon-AsiaIntracranial bleedingAsiaNon-AsiaMinor bleedingAsiaNon-AsiaMajor or minor bleedingAsiaNon-Asia



Rate (%/year)

150mg bid 110mg bid

WarfarinDabigatran

1.0 2.00

Warfarin betterDabigatran better

HR (95%CI)

Interaction

p value

Interaction

p value

2.173.52

0.961.69

1.281.52

0.450.29

12.4315.27

13.9917.02

3.823.53

1.411.01

2.201.79

1.100.71

19.6615.81

22.0317.74

2.222.99

1.151.14

0.911.29

0.230.23

10.1213.69

11.7215.27

0.0079

0.0089

0.1749

0.9509


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US FDA analysis of 134,000 Medicare

patients comparing dabigatran and warfarin

Primary findings for dabigatran are based on analysis of both 75 mg and 150 mgtogether without stratification by dose. Warfarin is the reference group. CI =

confidence interval; HR = hazard ratio; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)

Incidence rateper 1000 person-years Adjusted HR

(95% CI)Dabigatran Warfarin

Ischaemicstroke

11.3 13.9 0.80 (0.67-0.96)

Intracranialhaemorrhage

3.3 9.6 0.34 (0.26-0.46)

Death 32.6 37.8 0.86 (0.77-0.96)

AMI 15.7 16.9 0.92 (0.78-1.08)

Major GIbleeding

34.2 26.5 1.28 (1.14-1.44)

Compared to warfarin, dabigatran has lower risks of• ischaemic stroke• intracranial haemorrhage• DeathWith no increased risk of MI

New users of dabigatran andwarfarin with recently diagnosedwith AF patients, aged ≥65years

P R A / 0

2 4 / F E B 1 6 / A Y


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Is Dabigatran trial supported

with real world data?

22

Randomized Controlled Trial vs Real World Data


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Malaysian registry study supports

the positive efficacy and safety profile of dabigatran in Asia

Yap LB et al. J Thromb Thrombolysis. 2014;38:39 –4423

• Observational cohort study

• National Health Institute in

Malaysia

• 510 dabigatran users

– 31% switched from warfarin – 60% taking 150 mg BID dose – 315 days of follow-up

(average)

“The rate of occurrences of adverse effects and bleeding

were lower than those seen in the RE-LY® trial”

OBSERVATION

• 1 haemorrhagic stroke

• 0 ischaemic strokes

• 2 major bleeding (GI)• Dyspepsia 4%

• Withdrawal 18%

Malaysian AF Registry


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Lower incidence of ischemic stroke

Dabigatran compared to No Tx, Aspirin, and Warfarin

10,38

7,957,34

5,95

4,39

3,1

2,24

7,74

0

1

2

3

4

5

6

7

8

9

1011

No Tx Aspirin Q1 Q2 Q3 Q4 Dabigatran Overall

Ischemic Stroke

% /

y e a r

Ho CW et al. Stroke published online November 18, 2014;

Warfarin

Total Patients: 8754Dabigatran Pts: 393Mean follow up: 3 yrs

TTR quartilesQ1: 56.2%)

Hongkong AF Registry


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Independent FDA study of >134.000 Medicare patients mirrors thefavourable benefit-risk profile of dabigatran from RE-LY®

In the USA, the licensed doses for Pradaxa ® are: 150 mg BID and

75 mg BID for the prevention of stroke and systemic embolism in

adult patients with NVAF. RE-LY ® was a PROBE (prospective,randomized, open-label with blinded endpoint evaluation) study

*Primary findings for dabigatran are based on analysis ofboth 75 mg & 150 mg together without stratification bydose. 1. Graham et al. Circulation 2014; 2. Connolly et al.NEJM 2009; 3. Connolly et al. NEJM 2010; 4. Pradaxa®:

Local Product Information. 2015.; 5. Connolly S et al.NEJM 2014

MORTALITY

RE-LY®2 –5

Warfarin

D150 BID

MEDICARE*1Warfarin

D150 & D75 BID

combined

E V E N T R A T E ( % P

E R Y E A

R )

I N C I D E

N C E R A T E P E R

1 0 0 P E R S O N - Y E A R S

ISCHAEMIC

STROKEICH MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76

P=0.04

HR: 0.80P=0.02

RR: 0.41

P


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Summary

• AF confers an increased risk of stroke, which is dependant upon the presence of

various stroke risk factors

• All NVAF patient with ≥ 1 risk of stroke should receive anticoagulation - ASA is not

an alternative, availability of NOACs has led to revisions in treatment guidelines

• The net clinical benefit balancing ischaemic stroke vs intracranial bleeding favors

Dabigatran

• Superior efficacy of dabigatran for prevention of stroke/SE was consistent

between Asian and non-Asian patients, greater reductions in major bleeding with

dabigatran in Asian patients compared with warfarin

•

Give right dose for the right patient (150mg or 110mg): Age, HASBLED, renalfunction and drug interactions

• Dabigatran is THE ONLY NOAC with long-term safety data in this setting (RELY-

ABLE, PMS EMA, FDA and ASIAN Registry Data)


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THANK YOU VERY MUCH


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5.1 Stroke Prevention in AF - Dr. Samuel Sp.jp

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