www.tri-london.ac.uk

The GARFIELD Registry is funded by an unrestricted research grant from Bayer Pharma AG

The Role of AnticoagulantsKeith A A Fox

Edinburgh Centre for Cardiovascular Science

Disclosure StatementKeith 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 EHJ (2007) 28, 1598–1660– 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

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.

INR below 2.0 results in a higher risk of stroke

INR Odds Ratio 2.0 1.01.7 2.01.5 3.31.3 6.0

1.0 1.5 3.0 4.0 7.0

135

10

15

2.0

Odd

s R

atio

INR

Lowest Effective Intensity for Warfarin Therapy

Hylek EM, and Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120:897-902.

1.6

1.40 1.8 2 2.3 2.7Prothrombin Time Ratio

0

2

4

6

8

1018.211.2

Odd

s R

atio

Risk of Intracranial Haemorrhage (Outpatients)

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

Warfarin vs Antiplatelet Agents Systematic Overview

Hart RG, et al. Ann Intern Med. 2007;146:857-867.

4.5 million people with AF in the EU

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

Bleeding Risk

Stroke and ACS Risk

Finding the

right balance

is key!

Dutch bypass OA vs ASA. Lancet. 2000;355:346-351.

The Dutch Bypass Oral Anticoagulants Study: Distribution of Time in Each INR Range

0

50

100

150

200

250

300

350

400

450

1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 >6.5

RANGE50%

Tim

e in

IN

R C

lass

(p

ati

en

t-years

)

INR

Tolerability of Warfarin During First Year of TherapyElderly Patients in the US

• 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

Major bleeding event Taken off therapy

CHADS2 score Rate (per 100 person-years)

Rate (per 100 person-years)

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

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/

12

UFH

Targets for Anticoagulants

ORAL

DIRECT

PARENTERAL

INDIRECT

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Rivaroxaban

Apixaban

Edoxaban

LMWH

Fondaparinux

Weitz JI, Bates SM. J Thromb Haemost. 2005;3:1843-1853.Weitz JI, et al. Chest. 2008;133:234-256.

Dabigatran

AZD 0837

NOACs vs Warfarin: Trial Summary

Outcome

RE-LY1 Dabigatran

150 mg vs WarfarinRR (95% CI)

ROCKET AF2 Rivaroxaban vs

WarfarinRR (95% CI)

ARISTOTLE3 Apixaban vs

WarfarinRR (95% CI)

ENGAGE AF4

Edoxaban* 60 mgvs WarfarinHR (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: 6076W: 6022

Riva: 7131†

W: 7133Apix: 9120W: 9081

Edox 60mg: 7035W: 7036

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 approvedfor stroke prevention in AF patients.† ITT population at baseline

NB: trial populations differ in characteristics

ESC 2012 Guidelines: All Novel OACs Preferred Over VKAs Based on Net Clinical Benefit

Recommendations Class* Level#

CHA2DS2-VASc ≥2 : VKA or novel OACs I A

CHA2DS2-VASc = 1: VKA or novel OACs (except female patients <65 years with score = 1 based on gender)

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

*Class of recommendation; #Level of evidenceCamm 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