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