The Role of Anticoagulants
Keith A A Fox
Edinburgh Centre for Cardiovascular
Science
The GARFIELD Registry is funded by an unrestricted research grant
from Bayer Pharma AG
www.tri-london.ac.uk
Disclosure Statement
Keith A. A. Fox
•
President of the British Cardiovascular Society 2009-2012
•
European Society of Cardiology: ESC Programme Chair 20122014
•
–
KAA Fox member of the ESC guidelines group:
ESC Guidelines: Non-ST elevation ACS EHJ (2007) 28,
1598–1660
ESC Guidelines: ST Elevation MI EHJ (2008) 29: 2909-2945
–
•
•
•
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Co-Chair ROCKET-AF, Steering Committee
Major funding: British Heart Foundation, Medical Research
Council and the Wellcome Trust
Additional funding: Bayer, Janssen, Sanofi, Lilly, Astra Zeneca
No stock ownership
Untreated and Under-treated Patients
• Clear need to:
– Identify patients with unsuspected AF and
stroke risk
– Anticoagulate those at stroke risk
– Improve adherence to anticoagulation
– Aspirin is not an adequate therapy for stroke
prevention in AF
Lowest Effective Intensity for Warfarin Therapy
Odds Ratio
15
INR
2.0
1.7
1.5
1.3
10
5
3
1
1.0
1.5
2.0
3.0
4.0
Odds Ratio
1.0
2.0
3.3
6.0
7.0
INR
INR below 2.0 results in a higher risk of stroke
Hylek EM, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for
patients with non-rheumatic atrial fibrillation. N Engl J Med. 1996;335:540-546.
Risk of Intracranial Haemorrhage (Outpatients)
11.2
18.2
2.3
2.7
10
Odds Ratio
8
 PTR above 2.0 increases the
risk of bleeding
 The odds ratio of subdural
hemorrhage increased 7.6
fold as the PTR increased
from 2.0 to 2.5
6
4
2
0
0
1.4
1.6
1.8
2
Prothrombin Time Ratio
Hylek EM, and Singer DE. Risk factors for intracranial hemorrhage in
outpatients taking warfarin. Ann Intern Med. 1994;120:897-902.
Warfarin vs Antiplatelet Agents Systematic Overview
4.5 million people with AF in the EU
Hart RG, et al. Ann Intern Med. 2007;146:857-867.
Problems With Vitamin K-Based Oral Anticoagulation
• Risk of bleeding
– Many contra-indications
•
•
•
•
•
Narrow therapeutic window
Frequent blood testing
Many drug interactions
Discontinuations for surgery/procedures
Lifestyle restrictions
Finding the
right balance
is key!
Stroke and
ACS Risk
Bleeding
Risk
The Dutch Bypass Oral Anticoagulants Study:
Distribution of Time in Each INR Range
Time in INR Class (patient-years)
450
RANGE
50%
400
350
300
250
200
150
100
50
0
1
1.5
2
2.5
3
3.5 4
INR
4.5
5
5.5
Dutch bypass OA vs ASA. Lancet. 2000;355:346-351.
6
6.5 >6.5
Tolerability of Warfarin During First Year of Therapy
Elderly Patients in the US
Major bleeding event
Taken off therapy
Rate (per 100 personyears)
Rate (per 100 personyears)
0
3.1
15.6
1
4.3
17.1
2
2.0
12.9
3
19.5
32.6
≥4
23.4
32.1
CHADS2 score
• 58% time in therapeutic range
• Major haemorrhage 7.2%; ICH 2.5%
– Rates were 2.75× higher in patients ≥80 years
• 28% of patients discontinued warfarin at 1 year
Hylek EM, et al. Circulation. 2007;115:2689-2696.
Time in Therapeutic Range (UK)
n=2,074,928 INRs in Primary Care
http://www.4s-dawn.com/products/anticoagulation/dawn-ac-benchmarking-service/
Targets for Anticoagulants
ORAL
DIRECT
PARENTERAL
TF/VIIa
X
IX
VIIIa
IXa
Fondaparinux
Va
Rivaroxaban
Xa
Apixaban
LMWH
Edoxaban
II
Dabigatran
AZD 0837
INDIRECT
UFH
IIa
Fibrinogen
Weitz JI, Bates SM. J Thromb Haemost. 2005;3:1843-1853.
Weitz JI, et al. Chest. 2008;133:234-256.
Fibrin
12
NOACs vs Warfarin: Trial Summary
Outcome
RE-LY1
Dabigatran
150 mg
vs Warfarin
RR (95% CI)
ROCKET AF2
Rivaroxaban vs
Warfarin
RR (95% CI)
ARISTOTLE3
Apixaban vs
Warfarin
RR (95% CI)
ENGAGE AF4
Edoxaban* 60 mg
vs Warfarin
HR (95% CI)
Stroke or SE
0.65 (0.52-0.81)
P <.001
0.79 (0.66-0.96)
P <.001
0.79 (0.66-0.95)
P =01
0.79 (0.63–0.99)
P <.001
Death from
any cause
0.88 (0.77-1.00)
P =.051
0.85 (0.70, 1.02)
0.073
0.89 (0.80-0.998)
P =.047
0.92 (0.83-1.01)
P =.08
Intracranial
hemorrhage
0.40 (0.27-0.60)
P <.001
0.67 (0.47-0.93)
P =.02
0.42 (0.30-0.58)
P <.001
0.47 (0.34-0.63)
P <.001
Trial group
size
Dabig 150: 6076
W: 6022
Riva: 7131†
W: 7133
Apix: 9120
W: 9081
Edox 60mg: 7035
W: 7036
NB: trial populations differ in characteristics
Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151.[1]
Patel MR, et al. N Engl J Med. 2011;365:883-891.[2]
Granger CB, et al. N Engl J Med. 2011;365:981-992.[3]
Giugliano RP, et al. N Engl J Med. 2013;369:2093-2104.[4]
* Edoxaban is not yet approved
for stroke prevention in AF patients.
† ITT population at baseline
ESC 2012 Guidelines: All Novel OACs Preferred
Over VKAs Based on Net Clinical Benefit
Class*
Level#
I
A
IIa
A
Novel OACs in patients with VKA issues, e.g. unstable
INR, VKA-related adverse events
I
B
Novel OAC over VKA based on net clinical benefit for
most patients with non-valvular AF
IIa
A
Recommendations
CHA2DS2-VASc ≥2 : VKA or novel OACs
CHA2DS2-VASc = 1: VKA or novel OACs (except female
patients <65 years with score = 1 based on gender)
*Class of recommendation; #Level of evidence
Camm AJ, et al. Eur Heart J. 2012;33:2719-2747.
So, based on the evidence, what is the future….?
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Systematic detection of AF and stroke risk
Improved patient education for compliance
Registry programmes and quality control
Reduced stroke risk, ICH and major complications
with “NOACs”
No need to routinely monitor
Do we need antidotes? Yes, rarely
New indications – AF and ACS, post ACS
The NOACs will become the norm for anticoagulation