stroke prevention in atrial fibrillation trial data are supported by clinical experience
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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. Topics of Discussion. - PowerPoint PPT PresentationTRANSCRIPT
Dr. MUHAMMAD SYUKRI, Sp JP
PUSAT JANTUNG Regional
Stroke Prevention in Atrial Fibrillation
Trial Data are Supported by Clinical Experience
BAGIAN KARDIOLOGI DAN KEDOKTERAN VASKULAR FKUA/PUSAT JANTUNG RS. DR. M
DJAMIL, PADANG
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
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
Sinus Rhytm
Atrial Fibriillation
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 IrelandScottish 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.
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
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
Burden and Management of AF
Friberg, Rosenqvist & Lip Eur Heart J 2012
Similar safety profile of OAC and ASA
in intracranial bleeding and major bleeding
Burden and Management of AF
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
13
Is there any NEW,Better & Ideal Antithrombotic Agent?
At least as effective as warfarinPredictable responseWide therapeutic windowLow incidence and severity of adverse effectsOral fixed doseNo need for routine anticoagulation monitoringLow potential for food or drug interactionsFast onset and offset of action
Lip GY et al. EHJ Suppl. 2005;7:E21–25
Requirements ??
?
?
?
?
?
?
?
Guidelines ?
Long term safety profile ?
NOACs approved forprevention of systemic embolism or stroke in
patients with non-valvular AF
17
Dabigatran ® 150 mg twice daily is proven to provide superior Ischaemic Stroke prevention vs. Warfarin1
24% risk reduction in Ischaemic Stroke
Result of New OAC Clinical Studies RE-LY ® Results: Primary Endpoint
RRR24%
Haemorrhagic Stroke
Both dosages of Dabigatran® dramatically reduced the risk of haemorrhagic stroke compared with warfarin:1
RRR69%
RRR74%
18
RE-LY ® Results: Secondary EndpointLife-Threatening Bleeding
Rates
Intracranial Bleeding
Both doses of Dabigatran ®
Significantly reduced the riskof life threatening bleedingcompared with warfarin1
Both doses of Dabigatran ® substantially reduced the riskof intracranial bleedingcompared with warfarin1
RRR33%
RRR20%
RRR70%
RRR59%
25
Result of New OAC Clinical Studies(stroke ischemic)
The objective is to
reduce
Ischemic Stroke…
27
Result of New OAC Clinical Studies(Intracranial Hemorrhage)
… and minimizing the
risk of
Intracranial
Haemorrhage
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 2011Not head-to-head comparison – for illustrative purposes only
RE-LY® ROCKET-AFARISTOTLE
c
Results of RELY among Asian populationEfficacy outcomes (Asia vs. non-Asia)
RE-LY® Asia
Stroke or SEE Asia Non-Asia Ischemic stroke Asia Non-Asia Hemorrhagic stroke Asia Non-AsiaMyocardial infarction Asia Non-AsiaDeath from any cause Asia Non-Asia
Dabigatran 150mg bidvs. Warfarin
Dabigatran 110mg bidvs. Warfarin
Rate (%/year)
110mg bidWarfarin
Dabigatran
1.0 2.00Warfarin better
HR (95%CI)
Dabigatran better
1.391.06
1.120.81
0.170.09
0.500.86
4.013.57
3.061.48
2.020.98
0.750.32
0.580.65
5.093.96
Interactionp value
Interactionp value
0.0853
0.1977
0.7590
0.3782
0.4244
150mg bid
2.501.37
2.051.14
0.110.12
0.510.88
5.013.53
0.5597
0.5959
0.2729
0.3761
0.5929
1.0 2.00Dabigatran better Warfarin better
HR (95%CI)
Results of RELY among Asian populationSafety outcomes (Asia vs. non-Asia)
RE-LY® Asia
Major bleeding Asia Non-Asia GI major bleeding Asia Non-Asia Life threatening bleeding Asia Non-Asia Intracranial bleeding Asia Non-AsiaMinor bleeding Asia Non-AsiaMajor or minor bleeding Asia Non-Asia
Dabigatran 150mg bidvs. Warfarin
Dabigatran 110mg bidvs. Warfarin
Rate (%/year)
150mg bid 110mg bidWarfarin
Dabigatran
1.0 2.00Warfarin betterDabigatran better
HR (95%CI)Interaction
p valueInteraction
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
<0.0001
<0.0001
0.0705
0.3379
0.0738
0.4561
<0.0001
<0.0001
1.0 2.00Dabigatran better Warfarin better
HR (95%CI)
20
RELY-ABLE®
The RELY-ABLE® study: Long-term multi-centre extension of dabigatran treatment in patients with atrial fibrillationStudy design
RELY-ABLE®: Extension of RE-LY®
AF and ≥1 additional risk factor for stroke
Absence of contraindications
Warfarin (INR 2.0–3.0)
n=6022
Dabigatran etexilate
110 mg BIDn=6015
Dabigatran etexilate
150 mg BIDn=6076
Dabigatran etexilate
110 mg BIDN=2914
Dabigatran etexilate
150 mg BIDN=2937
RELY-ABLE®
RE-LY®
R
OBJECTIVE:Evaluate long-term safety of dabigatran etexilate (two doses) in patients with AF
BID = twice daily
RELY-ABLE® goals, design and summary
Goals 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®)
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®
What the Guideline Says: ESC 2012
Atrial fibrillation
Valvular AF*
Assess risk of stroke
CHA2DS2-VASc score
No antithrombotictherapy NOAC VKA
0 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
No
Yes
Recommended Optional
No room for Antiplatelet
Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
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:10.1093/eurheartj/ehs253
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:10.1093/eurheartj/ehs253
28
2012
ESC Guidelines 2012for the management of AF
29 *Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
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:•a dose-adjusted VKA (INR 2–3); or•a direct thrombin inhibitor (dabigatran); or•an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)… should be considered, based upon an assessment of the risk of bleeding complications and patient preferences
IIa A
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 : 2029-2037. 2. Connoly SJ et al. N Engl J Med 2009; 361(12): 1139-1151
34
Is there any NEW,Better & Ideal Antithrombotic Agent?
At least as effective as warfarinPredictable responseWide therapeutic windowLow incidence and severity of adverse effectsOral fixed doseNo need for routine anticoagulation monitoringLow potential for food or drug interactionsFast onset and offset of action
Lip GY et al. EHJ Suppl. 2005;7:E21–25
Requirements Dabigatran 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)
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)