Dabigatran - Cardiology Update FK UNAND

Report
PUSAT
JANTUNG
Regional
Dr. MUHAMMAD
SYUKRI, Sp JP
BAGIAN KARDIOLOGI DAN
KEDOKTERAN VASKULAR FKUA/PUSAT
JANTUNG RS. DR. M DJAMIL, PADANG
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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
Sinus Rhytm
Affected
portion of the brain
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
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: 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.
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
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
Similar safety profile of OAC and ASA
in intracranial bleeding and major bleeding
Friberg, Rosenqvist & Lip Eur Heart J 2012
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
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
?
Lip GY et al. EHJ Suppl. 2005;7:E21–25
13
NOACs approved for
prevention of systemic embolism or stroke in
patients with non-valvular AF
RRR
24%
Dabigatran ® 150 mg twice daily
is proven to provide superior
Ischaemic Stroke prevention vs.
Warfarin1
 24% risk reduction in
Ischaemic Stroke
Haemorrhagic Stroke
RRR
74%
RRR
69%
Both dosages of Dabigatran®
dramatically reduced the risk of
haemorrhagic stroke compared
with warfarin:1
17
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
RRR
59%
RRR
70%
Both doses of Dabigatran ®
substantially reduced the risk
of intracranial bleeding
compared with warfarin1
18
25
27
RE-LY®
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
ROCKET-AFARISTOTLE
Rate (%/year)
Dabigatran
Warfarin
150mg bid 110mg bid
Stroke or SEE
Asia
Non-Asia
Ischemic stroke
Asia
Non-Asia
Hemorrhagic stroke
Asia
Non-Asia
Myocardial infarction
Asia
Non-Asia
Death from any cause
Asia
Non-Asia
Dabigatran 150mg bid
vs. Warfarin
Dabigatran 110mg bid
vs. Warfarin
HR (95%CI)
HR (95%CI)
Interaction
p value
Interaction
p value
1.39
1.06
2.50
1.37
3.06
1.48
0.0853
0.5597
1.12
0.81
2.05
1.14
2.02
0.98
0.1977
0.5959
0.17
0.09
0.11
0.12
0.75
0.32
0.7590
0.2729
0.50
0.86
0.51
0.88
0.58
0.65
0.3782
0.3761
4.01
3.57
5.01
3.53
5.09
3.96
0.4244
0.5929
0
1.0
2.0
Dabigatran better Warfarin better
RE-LY® Asia
0
1.0
2.0
Dabigatran better Warfarin better
Rate (%/year)
Dabigatran
Warfarin
150mg bid 110mg bid
Major bleeding
Asia
Non-Asia
GI major bleeding
Asia
Non-Asia
Life threatening bleeding
Asia
Non-Asia
Intracranial bleeding
Asia
Non-Asia
Minor bleeding
Asia
Non-Asia
Major or minor bleeding
Asia
Non-Asia
Dabigatran 150mg bid
vs. Warfarin
Dabigatran 110mg bid
vs. Warfarin
HR (95%CI)
HR (95%CI)
Interaction
p value
Interaction
p value
2.17
3.52
2.22
2.99
3.82
3.53
0.0079
0.0705
0.96
1.69
1.15
1.14
1.41
1.01
0.0089
0.3379
1.28
1.52
0.91
1.29
2.20
1.79
0.1749
0.0738
0.45
0.29
0.23
0.23
1.10
0.71
0.9509
0.4561
12.43
15.27
10.12
13.69
19.66
15.81
<0.0001
<0.0001
13.99
17.02
11.72
15.27
22.03
17.74
<0.0001
<0.0001
0
1.0
2.0
0
1.0
Dabigatran better Warfarin better Dabigatran better
RE-LY® Asia
2.0
Warfarin better
The RELY-ABLE® study: Long-term multicentre extension of dabigatran treatment in
patients with atrial fibrillation
Study design
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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
Dabigatran etexilate
110 mg BID
N=2914
Dabigatran etexilate
150 mg BID
N=2937
RELY-ABLE®
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BID = twice daily
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Goals
 To describe the long-term efficacy and safety of ongoing
dabigatran therapy following RE-LY®
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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
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Analysis
 Two follow-up periods described
▪ RELY-ABLE® (post-RE-LY®)
▪ RE-LY® + RELY-ABLE® (beginning of RE-LY® to end of RELY-ABLE®)
In patients who continued treatment on dabigatran after RELY®, 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®
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Atrial fibrillation
Yes
Valvular AF*
No (i.e. nonvalvular)
Yes
<65 years and lone AF (including females)
No
Assess risk of stroke
CHA2DS2-VASc score
No room for
Antiplatelet
0
1
≥2
Oral anticoagulant therapy
Assess bleeding risk
(HAS-BLED score)
Consider patient values and preferences  to
choose right dose
No antithrombotic
therapy
NOAC
Recommended
Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
VKA
Optional
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Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
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
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
2012
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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
29
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*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
“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
Requirements
At least as effective as warfarin
Dabigatran
SUPERIOR
Predictable response
YES
Wide therapeutic window
YES
Low incidence and severity of adverse effects
YES
Oral fixed dose
YES
No need for routine anticoagulation monitoring
YES
Low potential for food or drug interactions
YES
Fast onset and offset of action
YES
Guidelines
Long term safety profile
ACCP, ESC, AHA/ASA,
NICE, CCS, PERDOSSI
RELY-ABLE, PMS
(FDA and EMA)
34
Lip GY et al. EHJ Suppl. 2005;7:E21–25
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 nonAsians
 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)
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