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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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Burden and Management of AF
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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Burden and Management of AF
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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Burden and Management of AF
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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Results of the studies with NOACs
(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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Results of the studies with NOACs
(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
Dabigatran 110mg 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
Dabigatran 150mg bidvs. Warfarin
Dabigatran 110mg bidvs. Warfarin
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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