Transcript Document
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 2012 2014 • • • • • – – KAA Fox member of the ESC guidelines group:
ESC Guidelines: Non-ST elevation ACS
1598 –1660 EHJ (2007) 28,
ESC Guidelines: ST Elevation MI
EHJ (2008) 29: 2909-2945 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
15 10 INR Odds Ratio
2.0
1.0
1.7
1.5
1.3
2.0
3.3
6.0
5 3 1 1.0
1.5
2.0
INR 3.0
4.0
7.0
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)
10 8 6 4 2 0 0 11.2
18.2
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
1.4
1.6
1.8
2 Prothrombin Time Ratio 2.3
2.7
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
Stroke and ACS Risk Bleeding Risk
Finding the right balance is key!
The Dutch Bypass Oral Anticoagulants Study: Distribution of Time in Each INR Range 450 400 RANGE 50% 350 300 250 200 150 100 50 0 1 1.5 2 2.5 3 3.5 4 INR 4.5 5 5.5 6 6.5 >6.5
Dutch bypass OA vs ASA.
Lancet.
2000;355:346-351.
Tolerability of Warfarin During First Year of Therapy Elderly Patients in the US
CHADS 2
0 1 2 3 ≥4
score
• • •
Major bleeding event Rate (per 100 person years)
3.1
4.3
2.0
19.5
23.4
Taken off therapy Rate (per 100 person years)
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 15.6
17.1
12.9
32.6
32.1
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
TF/VIIa X IX Rivaroxaban Apixaban Edoxaban VIIIa IXa Va Xa II Dabigatran AZD 0837 Fibrinogen
Weitz JI, Bates SM.
J Thromb Haemost.
2005;3:1843-1853.
Weitz JI,
et al. Chest.
2008;133:234-256.
IIa Fibrin
PARENTERAL INDIRECT
Fondaparinux LMWH UFH
12
NOACs vs Warfarin:
Trial Summary
Outcome RE-LY 1 Dabigatran 150 mg vs Warfarin RR (95% CI)
Stroke or SE Death from any cause Intracranial hemorrhage 0.65 (0.52-0.81)
P
<.001
0.88 (0.77-1.00)
P
=.051
0.40 (0.27-0.60)
P
<.001
Trial group size Dabig 150: 6076 W: 6022
ROCKET AF 2 Rivaroxaban vs Warfarin RR (95% CI)
0.79 (0.66-0.96)
P
<.001
0.85 (0.70, 1.02) 0.073
0.67 (0.47-0.93)
P
=.02
Riva: 7131 † W: 7133
ARISTOTLE Apixaban vs Warfarin RR (95% CI) 3
0.79 (0.66-0.95)
P
=01 0.89 (0.80-0.998)
P
=.047
0.42 (0.30-0.58)
P
<.001
Apix: 9120 W: 9081
ENGAGE AF 4 Edoxaban * 60 mg vs Warfarin HR (95% CI)
0.79 (0.63
–0.99)
P
<.001
0.92 (0.83-1.01)
P
=.08
0.47 (0.34-0.63)
P
<.001
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
Recommendations
CHA 2 DS 2 VASc ≥2 : VKA or novel OACs CHA 2 DS 2 -VASc = 1: VKA or novel OACs (except female patients <65 years with score = 1 based on gender) Novel OACs in patients with VKA issues, e.g. unstable INR, VKA-related adverse events Novel OAC over VKA based on net clinical benefit for most patients with non-valvular AF
Class* Level #
I A IIa I IIa A B A *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….?
• 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