Should new oral anticoagulants be used as first

Should New Oral Anticoagulants
be used as First Line Therapy in All
Patients?
Matt Wright MRCP PhD FHRS
Consultant Cardiologist and Electrophysiologist
St. Thomas’ Hospital
Atrial Fibrillation
Why we Anticoagulate
Atrial Fibrillation
The Challenges- Minimise Stroke Risk
Cardio-embolic strokes: higher mortality
!
Bedridden state: With AF- 41.2% / Without AF 23.7%
Odds ratio for bedridden state following stroke due to AF: 2.23
Dulli et al. Neuroepidemiology. 2003;22:118-123
Stroke
• Mean rate of stroke 5% / yr in patients with nonvalvular AF
• 2-7x increased risk compared to age-matched
controls
• 17x increased risk in patients with valvular AF
compared to age-matched controls
Stroke Rate (%/year)
Stroke Rates by Age in Patients With
AF in Untreated Control Groups
9
8
7
6
5
4
3
2
1
0
<65
65-75
Age (years)
>75
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
Severity of Stroke With AF
1061 patients admitted with acute ischemic stroke
-20.2% had AF
!
Bedridden state
41.2%
-With AF
23.7%
-Without AF
!
Odds ratio for bedridden state following stroke due to AF: 2.23 (95% CI, 1.87-2.59; P<.0005)
Dulli et al. Neuroepidemiology. 2003;22:118-123
Effect of Intensity of Oral
Anticoagulation on Stroke Severity
INR<2
9%
6%
44%
INR≥2
1%
4%
38%
Total
59%
43%
Minor (independent)
No neurologic sequelae
38%
3%
55% 2%
Total
41%
57%
Fatal stroke
Severe (total dependence)
Major (not independent)
!
!
!
N=596 patients with AF and ischaemic
stroke
Hylek et al. N Engl J Med. 2003;349:1019-1026
Should New Oral Anticoagulants
be used as First Line Therapy in All
Patients?
Atrial Fibrillation
The Challenges- Minimise Stroke Risk
• CHADS2 and CHA2DS2VASc underutilised
• GRASP-AF under utilised
• Formal Anticoagulation
– Warfarin
– Dabigatran
– Rivoroxaban
• Atrial Appendage Closure devices
Use and Adequacy of Anticoagulation in AF
Patients in Primary Care Practice
INR above target 6%
No warfarin 65%
INR in target range 15%
Subtherapeutic INR 13%
N=660
Samsa et al. Arch Intern Med. 2000;160:967-973.
Physician Concerns About Warfarin
for Stroke Prevention in AF
Risk vs benefit of warfarin
! 47% benefit greatly outweigh risk
! 34% risk slightly outweigh benefit
! 19% risk outweigh benefit
80
Percent
60
40
20
0
Risk of
Fall
History of GI Bleed
Frequently Cited Contraindications
History of Non-CNS
Bleed
History of
CV
Hemorrhage
Monette et al. J Am Geriatr Soc. 1997;45:1060-1065.
Patient Concerns About AF
100
91%
Percent
75
50
38%
25
13%
0
Stroke
Death
9%
2%
Major Minor Side Cost
Bleeding Effects
5%
Inconvenience
Man-Son-Hing et al. Arch Intern Med. 1996;156:1841-1848.
Use and Adequacy of Anticoagulation in AF Patients on Hospital Admission
No warfarin 65%
Supratherapeutic INR 19%
Therapeutic INR 37%
Warfarin 35%
Subtherapeutic INR 45%
Bungard et al. Pharmacotherapy. 2000;20:1060-1065.
Falls
• Markov decision analytic model was used to
determine the preferred treatment strategy in
patients > 65 yrs/old
• Patients need to fall >295x/ year for risk to
outweigh benefit
• Mean number of falls/ year of elderly people
who fall1.8
Man-Son-Hing et al Arch Intern Med. 1999;159:677-685
Stroke Reduction
Atrial Fibrillation
The Challenges- Minimise Stroke Risk
Atrial Fibrillation
CHA2DS2VASc Score Considerations
Female Sex
- Risk Factor only in combination
with others
!
Heart Failure
- Documented Systolic
Dysfunction
- Recent hospitilisation with
heart failure irrespective of EF
Atrial Fibrillation
CHA2DS2VASc Score Considerations
Annual Stroke Risk
•
•
•
•
•
CHADS2 0 CHA2DS2VASc 0 CHA2DS2VASc 1
CHA2DS2VASc 2 CHA2DS2VASc 3
-
0.84% - 3.2%
0.84%
1.75%
2.69%
- 3.2%
Atrial Fibrillation
CHA2DS2VASc Score Considerations
If CHADS2 + 0 or 1 Assess using CHA2DS2VASc
Atrial Fibrillation
HAS BLED
Clinical Characterisitic
Score
H
Hypertension (>160mmHg)
A
Abnormal renal or liver (Cr >200; LFTs 3 x ULN)
S
Stroke
1
B
Bleeding
1
L
Labile INR (TTR < 60%)
1
E
Elderly age (>65 years)
1
D
Drugs or Alcohol (1 each)
Maximum Score
1
1 or 2
1 or 2
9
Atrial Fibrillation
The Challenges- Minimise Stroke Risk
Aspirin has no role in the
management of AF
CHADSVASc > 1 default
position is formal
anticoagulation
HASBLED score reflects
modifiable risk factors
ESC Guidelines 2012
Narrow therapeutic range with VKA
Target INR
(2.0-3.0)
20
Odds ratio
15
Stroke
10
Intracranial bleed
5
1
0
1
2
3
4
5
6
International Normalized Ratio (INR)
Fuster V et al. Circulation 2006;114:e257 –e354
7
8
Atrial Fibrillation
NOAC Trials
Atrial Fibrillation
Mechanism of Action
NOACs
Drug Interactions
SPAF trials versus warfarin
Dabigatran
Rivaroxaban
Apixaban
Study
RE-LY
ROCKET-AF
ARISTOTLE
Design
PROBE
Double Blind
Double Blind
Follow up
2 yrs
1.5 yrs
1.5 yrs
Population size
>18,000
>14,000
>18,000
Inclusion
Nonvalvular AF + 1 risk
factor
Nonvalvular AF + 1 risk
factor
Inclusion (CHADS)
2.1
Nonvalvular AF + 2 risk
factors (i.e. moderate to
high risk)
3.5
Primary Endpoint
Stroke and systemic
embolism
64%
Stroke and systemic
embolism
55%
Stroke and systemic
embolism
62%
Warfarin comparator
INR control (mean
TTR)
2.1
1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4.
Rocket Investigators. Am Heart J 2010;159:340-347; 5. Patel MR et al. NEJM 2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med
2011;365:981-92.
New agents: Stroke, systemic
embolism vs warfarin
SSE vs warfarin (ITT
population)
%/yr
Warfarin
HR
%/yr (95% CI)
Dabigatran 150 mg
1.11
1.71
0.65 (0.52-0.81)
Dabigatran 110 mg
1.54
1.71
0.90 (0.74-1.10)
Rivaroxaban
2.1
2.4
0.88 (0.75-1.03)
Apixaban
1.27
1.60
0.79 (0.66-0.95)
SSE = stroke and systemic embolism
NNT=167
NNT=303
0.5
1
Favours new orals
Favours warfarin
1.5
New agents: Ischaemic stroke vs
warfarin
Ischaemic stroke vs
warfarin
%/yr
Dabigatran 150 mg
Warfarin
HR
%/yr
(95% CI)
0.86
1.14
0.75 (0.58-0.97)
Dabigatran 110 mg
1.28
1.14
1.13 (0.89-1.42)
Rivaroxaban
1.34
1.42
0.94 (0.75-1.17)
Apixaban*
0.97
1.05
0.92 (0.74-1.13)
*Ischaemic or uncertain type of stroke
NNT=357
0.5
1.5
1
Favours new orals
Favours warfarin
New agents: Haemorrhagic stroke vs
warfarin
Haemorrhagic stroke %/yr
vs warfarin
Warfarin
HR
%/yr (95% CI)
Dabigatran 150 mg
0.10
0.38
0.26 (0.14-0.49)
NNT=357
Dabigatran 110 mg
0.12
0.38
0.31 (0.17-0.56)
NNT=384
Rivaroxaban
0.26
0.44
0.59 (0.37-0.93)
NNT=555
Apixaban
0.24
0.47
0.51 (0.35-0.75)
NNT=434
0
1
Favours new orals
2.0
Favours warfarin
New agents: Any bleeding vs
warfarin
Any bleeding vs
warfarin
%/yr
Warfarin
HR
%/yr (95% CI)
Dabigatran 150 mg
16.56
18.37
0.91 (0.85-0.96)
Dabigatran 110 mg
14.74
18.37
0.78 (0.73-0.83)
Rivaroxaban*
14.9
14.5
1.03 (0.96-1.11)
Apixaban
18.1
25.8
0.71 (0.68-0.75)
* major and nonmajor clinically relevant bleeding (excludes
minimal bleeding)
NNT=55
NNT=28
NNT=13
0.5
Favours new orals
1.5
1
Favours warfarin
New agents: Major bleeding vs
warfarin
Major bleeding vs
warfarin
%/yr
Warfari HR
n
(95% CI)
%/yr
Dabigatran 150 mg
3.32
3.57
0.93 (0.81-1.07)
Dabigatran 110 mg
2.87
3.57
0.80 (0.70-0.93)
Rivaroxaban
3.6
3.4
1.04 (0.90-1.20
Apixaban
2.13
3.09
0.69 (0.60-0.80)
NNT=166
NNT=104
0.5
1.5
1
Favours new orals
Favours warfarin
New agents: Intracranial bleeding
vs warfarin
Intracranial bleeding
vs warfarin
%/yr
Warfarin
HR
%/yr
(95% CI)
Dabigatran 150 mg
0.32
0.76
0.41 (0.28-0.60)
NNT=227
Dabigatran 110 mg
0.23
0.76
0.30 (0.19-0.45)
NNT=188
Rivaroxaban
0.5
0.7
0.67 (0.47-0.93)
NNT=500
Apixaban
0.33
0.80
NNT=212
0.42 (0.30-0.58)
1
0
Favours new orals
2.0
Favours warfarin
AVERROES Primary end point: Stroke or systemic
Hazard ratio with apixaban, 0.45 (95% CI, 0.32–0.62)
p<0.001
0.05
Aspirin
Cumulative Hazard
0.04
0.03
0.02
Apixaban
0.01
0.00
0
3
6
9
12
Time (months)
Adapted from Connolly SJ et al. N Engl J Med 2011;364:806–817
18
23
Clinical Implications of NOACs–TTR
Outcome events rate (per 100 patient years, %)
8
Major haemorrhage
7
Thromboembolic
Linear (major haemorrhage)
6
Linear (thromboembolic)
5
4
3
2
1
0
0
40
50
60
TTR (%)
70
80
90
Adapted from Wan et al (2008)
1. Heneghan et al (2006). Lancet 367:404-411
2. Bloomfield et al (2011). Ann Int Med 154:472-482
3. Wan et al (2008). Circulation 1:87-91
• PST improve quality of
oral anticoagulation
management
-‐ 55% reduction in
thromboembolic events1
-‐ Reduction in major
hemorrhage1
-‐ Reduction in mortality2
-‐ Frequent warfarin
monitoring increases
TTR – weekly 85%
(monthly 50%)1
Anticoagulation: How to Choose?
www.NOACforAF.eu
Atrial Fibrillation
Summary
Aspirin has no role in the
management of AF
!
CHA2DS2VASc >1 then
Oral Anticoagulation
!
HASBLED > 3 Take care
!
www.NOACforAF.eu
http://www.afibmatters.org
ESC Guidelines 2012
Acknowledgements
!
!
St. Thomas’
EP Group
Imaging Sciences
Biomedical Engineering
!
Contact:
[email protected]
!
Arrhythmia Nurses
[email protected]
[email protected] !
Philips Research
Biosense Webster
Boston Scientific
MRC BHF

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