2. Dr. MUHAMMAD SYUKRI, Sp JP
PUSAT
JANTUNG
Regional
Stroke Prevention in Atrial Fibrillation Trial Data are Supported by Clinical Experience
Dr. MUHAMMAD SYUKRI, Sp JP
BAGIAN KARDIOLOGI DAN KEDOKTERAN VASKULAR FKUA/PUSAT JANTUNG RS. DR. M DJAMIL, PADANG

3. Topics of Discussion Burden and Management of AF
Challenges and limitation of ASA and VKA
New Oral Anti Coagulants ( NOACs)
Results of the studies with NOACs, RELY and RELY-ABLE
Results of RELY among Asian population
What the Guideline Says
The goal of OAC therapy
Summary

4. Burden and Management of AF
Affected portion of the brain
Sinus Rhytm
Atrial Fibriillation
Thrombus (clot)
Atrial fibrillation is a supraventricular arrhythmia characterized by chaotic and uncoordinated contraction of the atrium
Chowdhury P, et al. Cleve Clin J Med. 2009;76:543–550

5. Burden and Management of AF
David Bloom's silent killer.
David Bloom was an American television journalist covering Iraq war who died suddenly in 2003 after a pulmonary embolism.
The Stroke Association: 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.

6. 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

7. Burden and Management of AF
Superior Efficacy Profile of OAC vs ASA to Prevent Stroke in Patients With
Non Valvuler AF
Hart et al, Ann Intern Med 2007;146:857–867

8. Burden and Management of AF
Similar safety profile of OAC and ASA in intracranial bleeding and major bleeding
Friberg, Rosenqvist & Lip Eur Heart J 2012

9. 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

10. Is there any NEW, Better & Ideal Antithrombotic Agent?
Requirements ?
At least as effective as warfarin
Predictable response
Wide therapeutic window
Low incidence and severity of adverse effects
Oral fixed dose
No need for routine anticoagulation monitoring
Low potential for food or drug interactions
Fast onset and offset of action ? ? ? ? ? ? ? ? ?
Guidelines
Long term safety profile ? 13
Lip GY et al. EHJ Suppl. 2005;7:E21–25

11. prevention of systemic embolism or stroke in
NOACs approved for
prevention of systemic embolism or stroke in
patients with non-valvular AF

14. Result of New OAC Clinical Studies RE-LY ® Results: Primary Endpoint
Dabigatran ® 150 mg twice daily is proven to provide superior Ischaemic Stroke prevention vs. Warfarin1
24% risk reduction in
Ischaemic Stroke
RRR
24%
Haemorrhagic Stroke
AF is the most common heart rhythm disturbance1
It is estimated that 1 in 4 individuals aged 40 years or older will develop AF1
In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain, France and the UK were living with diagnosed AF2
Due to the aging population, this number is expected to double within 30 years3
1. Lloyd-Jones DM, et al. Circulation 2004;110: Decision Resources. Atrial Fibrillation Report. Dec 2008.
3. Go AS, et al. JAMA 2001;285:
RRR
74%
RRR
69%
Both dosages of Dabigatran® dramatically reduced the risk of haemorrhagic stroke compared with warfarin:1 17

15. RE-LY ® Results: Secondary Endpoint
Life-Threatening Bleeding Rates
RRR
20%
RRR
33%
Both doses of Dabigatran ®
Significantly reduced the risk
of life threatening bleeding
compared with warfarin1
Intracranial Bleeding
AF is the most common heart rhythm disturbance1
It is estimated that 1 in 4 individuals aged 40 years or older will develop AF1
In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain, France and the UK were living with diagnosed AF2
Due to the aging population, this number is expected to double within 30 years3
1. Lloyd-Jones DM, et al. Circulation 2004;110: Decision Resources. Atrial Fibrillation Report. Dec 2008.
3. Go AS, et al. JAMA 2001;285:
RRR
59%
RRR
70%
Both doses of Dabigatran ®
substantially reduced the risk
of intracranial bleeding
compared with warfarin1 18

16. Result of New OAC Clinical Studies (stroke ischemic)
The objective is to reduce
Ischemic Stroke… 25

17. Result of New OAC Clinical Studies (Intracranial Hemorrhage)
… and minimizing the risk of
Intracranial Haemorrhage 27

18. Results of the studies with NOACs (CV Mortality)
RE-LY®
ROCKET-AF
ARISTOTLE c
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011
Not head-to-head comparison – for illustrative purposes only

19. Results of RELY among Asian population Efficacy outcomes (Asia vs
Results of RELY among Asian population Efficacy outcomes (Asia vs. non-Asia)
Rate (%/year)
Dabigatran 150mg bid
vs. Warfarin
Dabigatran 110mg bid
vs. Warfarin
Dabigatran
Warfarin
Interaction
p value
Interaction
p value
150mg bid
110mg bid
HR (95%CI)
HR (95%CI)
Stroke or SEE
Asia
Non-Asia
Ischemic stroke
Hemorrhagic stroke
Myocardial infarction
Death from any cause
1.39
1.06
1.12
0.81
0.17
0.09
0.50
0.86
4.01
3.57
2.50
1.37
2.05
1.14
0.11
0.12
0.51
0.88
5.01
3.53
3.06
1.48
2.02
0.98
0.75
0.32
0.58
0.65
5.09
3.96
0.0853
0.1977
0.7590
0.3782
0.4244
0.5597
0.5959
0.2729
0.3761
0.5929
1.0
2.0
1.0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
RE-LY® Asia

20. Results of RELY among Asian population Safety outcomes (Asia vs
Results of RELY among Asian population Safety outcomes (Asia vs. non-Asia)
Rate (%/year)
Dabigatran 150mg bid
vs. Warfarin
Dabigatran 110mg bid
vs. Warfarin
Dabigatran
Warfarin
Interaction
p value
Interaction
p value
HR (95%CI)
HR (95%CI)
150mg bid
110mg bid
Major bleeding
Asia
Non-Asia
GI major bleeding
Life threatening bleeding
Intracranial bleeding
Minor bleeding
Major or minor bleeding
2.17
3.52
0.96
1.69
1.28
1.52
0.45
0.29
12.43
15.27
13.99
17.02
2.22
2.99
1.15
1.14
0.91
1.29
0.23
10.12
13.69
11.72
15.27
3.82
3.53
1.41
1.01
2.20
1.79
1.10
0.71
19.66
15.81
22.03
17.74
0.0079
0.0089
0.1749
0.9509
<0.0001
0.0705
0.3379
0.0738
0.4561
<0.0001
1.0
2.0
1.0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
RE-LY® Asia

21. RELY-ABLE®
The RELY-ABLE® study: Long-term multi-centre extension of dabigatran treatment in patients with atrial fibrillation
Study design
RE-LY® – Trial conduct
The RE-LY® study was conducted to very high standards.
Follow-up was completed for 99.9% of the patients who participated in the study, with only 20 of the 18,113 patients lost to follow-up.1
The quality of INR control for patients in the warfarin treatment arm was also high.1
The time-in-therapeutic-range (TTR) in RE-LY® was 67% for VKA-experienced and 61% for VKA-naïve patients.1
The higher TTR in VKA-experienced patients is not surprising given they had previous experience with dealing with the challenges of VKA treatment and so would be expected to achieve better INR control.
The quality of INR control achieved in RE-LY® was considerably better than is typically achieved in routine clinical practice.
In the meta-analysis of studies of INR control in the community setting presented earlier, the average TTR was only 51%.2
Therefore, warfarin is likely to have performed better in RE-LY® than is typical of routine clinical practice and any benefits demonstrated with dabigatran etexilate compared with warfarin in RE-LY® might be enhanced in the real-life as compared with the clinical trial setting.
References
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.
Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009;15:244–252. 20

22. RELY-ABLE®: Extension of RE-LY®
OBJECTIVE:
Evaluate long-term safety of dabigatran etexilate (two doses) in patients with AF
RE-LY®
AF and ≥1 additional risk factor for stroke
Absence of contraindications R
Warfarin
(INR 2.0–3.0)
n=6022
Dabigatran etexilate
110 mg BID
n=6015
Dabigatran etexilate
150 mg BID
n=6076
RELY-ABLE®
Dabigatran etexilate
110 mg BID
N=2914
Dabigatran etexilate
150 mg BID
N=2937
BID = twice daily

23. RELY-ABLE® goals, design and summary
To describe the long-term efficacy and safety of ongoing dabigatran therapy following RE-LY®
Methods
Patients eligible at completion of RE-LY® study if:
Alive and still receiving study dabigatran
Being followed at centre participating in RELY-ABLE®
Dabigatran blinded dose continued in RELY-ABLE® for 2.3 years
Analysis
Two follow-up periods described
RELY-ABLE® (post-RE-LY®)
RE-LY® + RELY-ABLE® (beginning of RE-LY® to end of RELY-ABLE®)

24. RELY-ABLE® goals, design and summary
In patients who continued treatment on dabigatran after RE-LY®, the rates of stroke and major bleeding remain low
There were no new safety signal observed during this extended follow up period
The results from RELY-ABLE® are highly consistent with those observed in RE-LY®

25. What the Guideline Says: ESC 2012
Atrial fibrillation
Valvular AF*
Assess risk of stroke CHA2DS2-VASc score
No antithrombotic therapy
NOAC
VKA 1
No (i.e. nonvalvular)
Yes ≥2
Oral anticoagulant therapy
<65 years and lone AF (including females)
Assess bleeding risk (HAS-BLED score) Consider patient values and preferences  to choose right dose
Yes No
No room for Antiplatelet
AHA/ ASA 5 points:
CHADS2  CHA2DS2-VASc
No room for ASA
NOAC = VKA
Ablation
Future research for CHA2DS2-VASc 0-1
Recommended
Optional
Camm AJ et al. Eur Heart J doi: /eurheartj/ehs253

26. What the Guideline Says: ESC 2012 (Risk of stroke)
Update strongly recommends a practice shift towards identification of ‘truly low risk’ patients with AF (i.e. age <65 years and lone AF) who do not need antithrombotic therapy
CHADS2 does not reliably identify ‘truly low risk’ patients
CHA2DS2-VASc:
inclusive of the most common stroke risk factors
validated in multiple cohorts
better than CHADS2 at identifying ‘truly low risk’ patients
As good as CHADS2 in identifying patients who develop stroke and thromboembolism
Camm AJ et al. Eur Heart J doi: /eurheartj/ehs253

27. 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 several independent 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: /eurheartj/ehs253

28. 2012 28

29. ESC Guidelines 2012 for the management of AF
Recommendation
Class
Level
In patients with CHA2DS2-VASc score ≥2, OAC therapy with:
a dose-adjusted VKA (INR 2–3); or
a direct thrombin inhibitor (dabigatran); or
an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)
… is recommended unless contraindicated I A
In patients with CHA2DS2-VASc score 1, OAC therapy with:
… should be considered, based upon an assessment of the risk of bleeding complications and patient preferences
IIa 29
*Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J doi: /eurheartj/ehs253

30. THE GOAL of OAC therapy
“I need to maximize risk reduction at the same time as minimizing harm to the patient… “
- PCP CPA Study
1. Circulation. 2008; 118 : Connoly SJ et al. N Engl J Med 2009; 361(12):

31. Is there any NEW, Better & Ideal Antithrombotic Agent?
Requirements
Dabigatran
At least as effective as warfarin
Predictable response
Wide therapeutic window
Low incidence and severity of adverse effects
Oral fixed dose
No need for routine anticoagulation monitoring
Low potential for food or drug interactions
Fast onset and offset of action
SUPERIOR
YES
YES
YES
YES
YES
YES
YES
Guidelines
ACCP, ESC, AHA/ASA,
NICE, CCS, PERDOSSI
Long term safety profile
RELY-ABLE, PMS
(FDA and EMA) 34
Lip GY et al. EHJ Suppl. 2005;7:E21–25

32. 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 from RE-LY®
Net clinical benefit was consistently in favor of DE for both doses compared with warfarin, in both Asians and non-Asians
Give right dose for the right patient (150mg or 110mg): Age, HASBLED, renal function and drug interactions
Dabigatran provides long-term safety data in this setting (RELY-ABLE, PMS EMA and FDA)

33. Terima Kasih