LA GESTION DU TRAITEMENT

PAR NOAC

CHEZ LE PATIENT

AVEC UNE CARDIOPATHIE

ISCHÉMIQUEProfesseur Cedric HERMANS, MD, PhD, MRCP (Lon), FRCP (Lon, Edin)

Haemostasis and Thrombosis Unit

Haemophilia Clinic

Division of Haematology

Cliniques Universitaires Saint-Luc

Catholic University of Louvain

1200 Brussels, Belgium

Cedric.hermans@uclouvain.be Bruxelles Novembre 2014

OLD VERSUS NEW ANTICOAGULANTS :MULTIPLE- VERSUS SINGLE-FACTOR INHIBITION

VKAs LMWHs Anti-XaAnti-IIa

Mode of action Interference with Vit K recycling

Potentiation of antithrombin

Direct inhibition

Targets FII, FVII, FIX, FXReduced synthesis

Indirect inhibition of FXa and FIIa

Selective inhibition of FXa or FIIa

Efficacy Universal anticoagulants including Mechanical CardiacValve

Universal anticoagulants

Acute phase of PE

Prevention and treatmentof VTE

Prevention of stroke in AF

…

LES NOUVEAUX ANTICOAGULANTS ORAUX (DIRECTS)INHIBITION DIRECTE ET CIBLÉE DU FXA OU DU FIIA (THROMBINE)

Fibrinogène Fibrine

IIaProthrombine

Xa + Va

X

Tissue Factor-VIIa

IXaIX

VIIIaRivaroxaban (Xarelto) (Bayer)

Apixaban (Eliquis) (BMS / PFIZER)

Edoxaban (Lixiana) (Daiichi Sankyo)

Dabigatran Etexilate (Pradaxa)

(Boehringer-Ingelheim)

Pradaxa / Dabigatran : anti-thrombine

E Liqui S : E pour equilibrium - Liqui pour liquid and S pour Stability

Xarelto : Xa, RELiable, Treatment, Oral Cedric HERMANS UCL 2014

COMPARAISON DES NOUVEAUX ANTICOAGULANTS ORAUX

ApixabanELIQUIS

RivaroxabanXARELTO

DabigatranPRADAXA

Mécanisme d’action Inhibition directe FXa Inhibition directe FXa Inhibition directe FIIa

Biodisponibilité orale ~50 % 80 % 6.5 %

Voie d’administration orale orale orale

Posologie 2x/jour1x/jour (FA, MTEV)

1x/jour (prévention MTEV)

2x/jour (MTEV, FA)

Pro-drogue Non Non Oui

Interférence alimentaire Non Non Non

Elimination rénale ~27 % 36 % 85 %

Demi-vie (T1/2) ~12h 7–11 h 14–17 h

Tmax 3 h 2–4 h 0.5–2 h

Interférencesmédicamenteuses

Inhibiteurs CYP 3A4 et P-gp

Inducteurs CYP 3A4

Inhibiteurs CYP 3A4 et P-gp

Inducteurs CYP 3A4

Inhibiteurs P-gpInducteurs P-gp

PROPRIÉTÉS DES NOUVEAUX

ANTICOAGULANTS ORAUX (NACOS)

• Administration orale

• Rapidité de l’effet anticoagulant

• Inhibition directe et ciblée des facteurs Xa ou IIa

• Demi-vie courte (12h)

• Effet prévisible

• Pas d’interférence alimentaire et peu

d’interférences médicamenteuses

• Plus facile à manipuler

• Elimination rénale

DEVELOPMENT AND VALIDATION OF NOACS

DVT/VTEProphylaxisOrthopaedic

Surgery

DVT/VTETreatment

AF/Stroke

Prevention

DVT/VTEProphylaxis

Medicalpatients

Acute coronary syndrome

Cedric HERMANS UCL 2014

NOACS AND ATRIAL FIBRILLATION

09/2009

09/2011

09/2011

Cedric HERMANS 2014

EFFICACITÉ DES NOACS PAR RAPPORT AUX AVKS

CHEZ LES PATIENTS EN FA

Pradaxa110 mgx2

Pradaxa150 mgx2

Xarelto20 mg

Apixaban5 (2.5) mgx2

Prévention AVC +embole systémique

Pradaxa = AVK Pradaxa meilleur Xarelto = AVK *> AVK **

Apixaban meilleur

Prévention AVC ischémique

Pradaxa = AVK Pradaxa meilleur Xarelto = AVK Apixaban = AVK

AVC hémorragique Pradaxa meilleur Pradaxa meilleur Xarelto meilleur Apixaban meilleur

Hémorragie majeure

Pradaxa meilleur Pradaxa = AVK Xarelto = AVK Apixaban meilleur

Hémorragie digestive majeure

Pradaxa = AVK Pradaxa moins bon

Xarelto moins bon

Apixaban = AVK

Hémorragie cérébrale

Pradaxa meilleur Pradaxa meilleur Xarelto meilleur Apixaban =meilleur

* Analyse ITT ** Analyse On-Treatment

Age: 73

Presentation:

• ACS diagnosed in ED

• Underlying paroxysmal NVAF

identified

• Transferred to cardiac

catheterization lab for diagnostic

coronary angiography & PCI with

DES

Additional information:

• CHA2DS2-VASc = 3

• HAS-BLED = 2

Current medications:

• ASA

Maria has arrived at the emergency department with severe chest pain

Atrial fibrillationand coronary artery disease

• New onset AF in a patient with a history of coronary heart disease

– Recent ACS (< 1 year)

– Remote ACS (> 1 year)

• ACS in an AF patient (on NOAC)

CARDIOVASCULAR BENEFITS OF NOACS IN

PATIENTS WITH AF AND CONCOMITANT USE OF

ANTIPLATELET AGENT(S)

1. Dans AL et al. Circulation 2013;127:634–40; 2. Patel MR et al. N Engl J Med 2011;365:883–91;

3. Goodman SG et al. J Am Coll Cardiol 2014;63:891–900; 4. Granger CB et al. N Engl J Med 2011;365:981–92

Concomitant use antiplatelet agents in patients with AF

treated with NOACs

ROCKET-AF (rivaroxaban)

• 36% of patients received concomitant ASA; clopidogrel contraindicated2

• Prior ASA independently associated with increased risk of major bleeding3

RE-LY® (dabigatran)

• 38.4% of patients received antiplatelets, including ASA alone (32.0%), clopidogrel

alone (1.9%), or both (4.5%)

• Benefits of dabigatran vs warfarin consistent irrespective of concomitant antiplatelets1

ARISTOTLE (apixaban)

• 31% of patients received concomitant ASA; clopidogrel contraindicated4

• Benefits of apixaban vs warfarin consistent irrespective of concomitant ASA4

NOACS + ANTI-PLAQUETTAIRES

RISQUE HÉMORRAGIQUE

06 March 2015 13Circulation. 2013 Feb 5;127(5):634-40.

NOAC + Antiplatelets

06 March 2015 14Circulation. 2013 Feb 5;127(5):634-40.

Dans AL et al. Circulation 2013;127:634–40

Benefits of dabigatran at both dosages vs warfarin

consistent irrespective of concomitant antiplatelet use

No antiplatelet Antiplatelet Antiplatelet

1.251.000.50 1.75

Dabigatran 110 mg BID

vs warfarin

0.25

Favours dabigatran Favours warfarin Favours dabigatran Favours warfarin

0.75 1.501.251.000.50 1.750.25 0.75 1.50

Stroke/SE

All stroke

Ischaemic stroke

CV death

Major bleed

Minor bleed

All bleed

Intracranial

Extracranial

P(inter)

0.74

0.72

0.67

0.67

0.79

0.51

0.85

0.37

0.84

P(inter)

0.06

0.04

0.08

0.36

0.87

0.39

0.50

0.53

0.64

Dabigatran 150 mg BID

vs warfarin

APIXABAN VS WARFARIN WITH CONCOMITANT AAS

John H. Alexander at al, European Heart Journal 2013

MYOCARDIAL INFARCTION

NO INCREASED RISK OF MI WITH DABIGATRAN

06 March 2015 19

Feb 2014

RE-LY® myocardial ischaemic eventssubanalysis (2012): cardiac outcomes (1)

Numerical imbalance in rate of MI: not statistically significant for either dose of dabigatran compared with warfarin

– No imbalance for silent MI or fatal MI

HR = hazard ratio

Hohnloser SH et al. Circulation 2012;125:669–7620

Event rate (%/yr) D110 vs warfarin D150 vs warfarin

D110 D150 W HR (95% CI) P value HR (95% CI) P value

Total MI 0.82 0.81 0.64 1.29 (0.96–1.75) 0.09 1.27 (0.94–1.71) 0.12

Clinical MI 0.73 0.74 0.56 1.30 (0.95–1.80) 0.10 1.32 (0.96–1.81) 0.09

Silent MI 0.09 0.07 0.08 1.22 (0.50–2.93) 0.66 0.87 (0.34–2.27) 0.72

Fatal MI 0.13 0.11 0.10 1.32 (0.63–2.80) 0.46 1.06 (0.49–2.33) 0.88

AF – warfarin comparator

2013 RELY-ABLE®: Long-term Benefits

Long Term Multi-Center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation

Patients taking dabigatran etexilatewere followed for up to a further 4.3yrs after completion of the RE-LY® trial

Patients continued to receive the same blinded dose of dabigatran etexilate as in the RE-LY® trial

1. Connolly SJ. et al. Circulation .2013;128:237–43.

DOSES BLINDED

RE-LY® & RELY-ABLE® : Benefits maintained long-term

In the combined RE-LY®/RELY-ABLE® analysis, there were :

• Lower rates of ischaemic and haemorrhagic stroke/SE on dabigatran 150 mg twice

daily versus 110mg twice daily

• Low rates of hemorrhagic stroke on both dosages

• Rates of major bleeding consistent to data from RE-LY®

• Very low rates of intracranial bleeding

• No new safety signals

Data from the RELY-ABLE® analysis is consistent with the findings from RE-LY®

The combined data validate that both doses of dabigatran etexilate are clinically effective for long-term stroke prevention for patients with non-valvular AF, with a

favourable safety profile sustained during up to 6.7 years of ongoing treatment

1. Connolly SJ. et al. Circulation .2013;128:237–43.

Benefit–risk profile of dabigatran confirmed in FDA study of >134 000 Medicare patients

Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)

Incidence rate per 1000 person-yearsAdjusted HR

(95% CI)Dabigatran Warfarin

Ischaemic stroke 11.3 13.9 0.80 (0.67-0.96)

Intracranial haemorrhage 3.3 9.6 0.34 (0.26-0.46)

Major gastrointestinal bleeding

34.2 26.5 1.28 (1.14-1.44)

Acute myocardial infarction 15.7 16.9 0.92 (0.78-1.08)

Mortality 32.6 37.8 0.86 (0.77-0.96)

Dabigatran was associated with a lower risk of ischaemic stroke,intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin.

2014

RE-LY®2–4 >18 000 patients

0.41

1. www.fda.gov/Drugs/DrugSafety/ucm396470.htm.

2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med. 2010;363:1875–6; 4. Pradaxa®: EU SPC 2014

Favourable benefit-risk profile of dabigatran confirmed

in independent FDA study of >134 000 patients

Medicare1 >134 000 patients

0.86 1.28

0.920.80

0.34

0.88

1.48

1.270.75

In the USA, the licensed doses for dabigatran etexilate are 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF

Numbers on bars denote hazard ratios vs warfarin

110 mg BID, indicated for certain patients, was shown to be as effective as warfarin in preventing stroke or systemic embolism in RE-LY®, which was a

PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial

CABG, coronary artery bypass graft; UA, unstable angina

Hohnloser SH et al. Circulation 2012;125:669–76

Benefits of dabigatran vs warfarin consistent in patients

with or without prior MI or CAD

1.51.00.5 1.51.00.52.0 2.0

P(inter)

0.28

0.72

0.49

0.85

0.66

0.45

0.95

0.91

0.35

0.61

P(inter)Dabigatran 110 mg BID

vs warfarin

Dabigatran 150 mg BID

vs warfarin

Stroke/SE

MI

MI, UA, PCI,

CABG, CV arrest,

cardiac death

Major bleeding

Net clinical benefit

No prior CAD/MI Prior CAD/MI Prior CAD/MI

0.0 0.0

Favours dabigatran Favours warfarin Favours dabigatran Favours warfarin

For medical non-promotional reactive use only

APIXABAN IN PATIENTS WITH

ATRIAL FIBRILLATION AND

PRIOR CORONARY ARTERY

DISEASE

Insights from the ARISTOTLE Trial

Bahit et al. Circulation 2012;126:A13026

27For medical non-promotional reactive use only

Results of the subpopulation with prior CAD

Of the total study patient population, 36.5% of patients

(n=6639) had prior CAD

Patients with prior CAD were more often male and had

prior stroke, diabetes mellitus and hypertension compared

with patients without prior CAD

Patients with prior CAD were more likely to be on aspirin

at baseline (42.2% vs 24.5%; p<0.001) when compared

with patients without prior CAD

Bahit et al. Circulation 2012;126:A13026 CAD, coronary artery disease.

28For medical non-promotional reactive use only

Adapted from Bahit et al. Circulation 2012;126:A13026

Prior CAD

All-cause death

4.21 4.40 0.96 (0.81–1.13)

No prior CAD 3.11 3.68 0.85 (0.73–0.98)

Prior CAD

Intracranial bleeding

0.27 0.73 0.36 (0.20–0.66)

No prior CAD 0.37 0.85 0.44 (0.30–0.65)

Prior CAD

ISTH major bleeding

2.39 3.05 0.78 (0.62–0.98)

No prior CAD 1.99 3.12 0.64 (0.53–0.76)

Prior CAD

Myocardial infarction

0.95 1.00 0.95 (0.66–1.35)

No prior CAD 0.29 0.39 0.75 (0.47–1.20)

Prior CAD

Stroke or SE

1.47 1.55 0.95 (0.71–1.27)

No prior CAD 1.15 1.63 0.70 (0.56–0.89)

Rate (%/yr) HR 95% CI p value for

interaction

0.2786

0.5867

0.1724

0.4491

0.1148

0.2 0.5 1 2

Favours apixaban Favours warfarin

Results

Apixaban Warfarin

CAD, coronary artery disease; CI, confidence interval;

HR, hazard ratio; SE, systemic embolism.

29For medical non-promotional reactive use only

Conclusions

In patients with atrial fibrillation, apixaban reduces stroke

or systemic embolism and causes less bleeding and

death compared with warfarin

These treatment effects were consistent in patients with

and without a history of coronary artery disease

Bahit et al. Circulation 2012;126:A13026

NOAC AND ACUTE

CORONARY SYNDROME

Lip GY et al. Thromb Haemost 2010;103:13–28

AF + ACS requires treatment with both anticoagulant and

antiplatelet therapy

31

~30% of patients with AF and an indication for continuous OAC have

co-existing CAD and may require PCI

An estimated 1–2 million anticoagulated patients in Europe are

candidates for PCI procedures

Long-term anticoagulant therapy is essential for prevention of recurrent

ischaemic events

Initial antiplatelet therapy is essential for

prevention of stent thrombosis following PCI

573 patients receiving OAC and undergoing PCI in open-label, randomized WOEST trial

TVR, target vessel revascularisation; ST, stent thrombosis; TIMI, thrombolysis in myocardial infarction bleeding criteria

Dewilde WJ et al. Lancet 2013;381:1107–15

WOEST: exclusion of ASA from combination therapy is

associated with improved outcomes vs triple therapy

OAC + clopidogrel associated with significant reduction in major bleeding and no

increase in thrombotic events vs triple therapy with OAC + clopidogrel + ASA

Total number of TIMI bleeding events Death, MI, TVR, stroke, ST

Time (days)

100

80

60

40

30

0

30 60 120 180 270 365

Cu

mu

lati

ve

in

cid

en

ce

(%

)

19.4%

44.4%

HR: 0.36 (95% CI: 0.26‒0.50) P<0.0001

17.6%

11.1%

HR: 0.60 (95% CI: 0.38‒0.94) P=0.025

90

70

50

10

20

0 90

Triple-therapy group

Double-therapy group

100

80

60

40

30

0

30 60 120 180 270 365

90

70

50

10

20

0 90

Time (days)

Triple-therapy group

Double-therapy group

210

253

194

244

181

241

173

236

159

226

140

208

284

279

186

241

272

276

270

273

261

266

252

263

242

258

223

234

284

279

266

270

Triple therapy

Double therapy

Number at risk

Cu

mu

lati

ve

in

cid

en

ce

(%

)

Syndrome coronarien aigu et NOACs

• PRADAXA

– Etude Re-Deem

• APIXABAN

– Etude « Appraise-2 » interrompue pour excès de saignements

• XARELTO

– ATLAS ACS 2-TIMI 51 trial

XARELTO AND ACS

Indication Dose and regimen

Duration of therapy Patient population

Prevention of atherothrombotic events in patients with elevated cardiac biomarkers after an ACS in combination with antiplatelet therapy

2.5 mg bid co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine

Extension of treatment >12 months should be done on an individual patient basis (limited experience up to 24 months)

Patients after an ACS with elevated cardiac biomarkers

*Moderate renal impairment = CrCl: 30–49 ml/min; severe renal impairment = CrCl: 15–29 ml/min

Bayer Pharma AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2013. Available at: http://www.xarelto.com/en/information-on-xarelto/summary-of-product-characteristics/ [accessed 24 January 2014].

Feb 2014

EXPERIENCE WITH DABIGATRAN IN ACS :

RE-DEEM™

• Dose-escalation Phase II trial in patients with recent ACS

Randomized to placebo or dabigatran (50 mg, 75 mg, 110 mg or 150 mg, all BID)

At baseline, >99% of patients were also receiving dual antiplatelet therapy

• Overall, a low number of patients experienced cardiac events

Minor differences between treatment groups

In the composite outcome, there were fewer events at higher vs lower doses of dabigatran

ACS = acute coronary syndromes; BID = twice daily; CV = cardiovascular; D110 = dabigatran 110 mg twice daily;D150 = dabigatran 150 mg twice daily

Oldgren J et al. Eur Heart J 2011;32:2781–9 39

Placebo Dabigatran

Outcome, n (%)(n=371)

50 mg BID(n=369)

75 mg BID(n=368)

110 mg BID(n=406)

150 mg BID(n=347)

CV death, non-fatal MI, or non-haemorrhagic stroke

14 (3.8) 17 (4.6) 18 (4.9) 12 (3.0) 12 (3.5)

CV death 9 (2.4) 8 (2.2) 9 (2.4) 5 (1.2) 4 (1.2)

Non-fatal MI 4 (1.1) 9 (2.4) 8 (2.2) 7 (1.7) 8 (2.3)

Non-haemorrhagic stroke 3 (0.8) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0)

Severe recurrent ischaemia 9 (2.4) 9 (2.4) 11 (3.0) 9 (2.2) 11 (3.2)

All-cause death 14 (3.8) 8 (2.2) 10 (2.7) 7 (1.7) 7 (2.0)

ACS – placebo comparator

Feb 2014

EXPERIENCE WITH DABIGATRAN IN ACS :

RE-DEEM™

• Dose-escalation Phase II trial in patients with recent ACS

Randomized to placebo or dabigatran (50 mg, 75 mg, 110 mg or 150 mg, all BID)

At baseline, >99% of patients were also receiving dual antiplatelet therapy

• Overall, a low number of patients experienced cardiac events

Minor differences between treatment groups

In the composite outcome, there were fewer events at higher vs lower doses of dabigatran

ACS = acute coronary syndromes; BID = twice daily; CV = cardiovascular; D110 = dabigatran 110 mg twice daily;D150 = dabigatran 150 mg twice daily

Oldgren J et al. Eur Heart J 2011;32:2781–9 40

Placebo Dabigatran

Outcome, n (%)(n=371)

50 mg BID(n=369)

75 mg BID(n=368)

110 mg BID(n=406)

150 mg BID(n=347)

CV death, non-fatal MI, or non-haemorrhagic stroke

14 (3.8) 17 (4.6) 18 (4.9) 12 (3.0) 12 (3.5)

CV death 9 (2.4) 8 (2.2) 9 (2.4) 5 (1.2) 4 (1.2)

Non-fatal MI 4 (1.1) 9 (2.4) 8 (2.2) 7 (1.7) 8 (2.3)

Non-haemorrhagic stroke 3 (0.8) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0)

Severe recurrent ischaemia 9 (2.4) 9 (2.4) 11 (3.0) 9 (2.2) 11 (3.2)

All-cause death 14 (3.8) 8 (2.2) 10 (2.7) 7 (1.7) 7 (2.0)

ACS – placebo comparator

In this high-risk patient population, no negative effect of dabigatran on myocardial ischaemic events was reported

Feb 2014

EXPERIENCE WITH DABIGATRAN IN ACS :

RE-DEEM™

• Dose-escalation Phase II trial in patients with recent ACS

Randomized to placebo or dabigatran (50 mg, 75 mg, 110 mg or 150 mg, all BID)

At baseline, >99% of patients were also receiving dual antiplatelet therapy

• Overall, a low number of patients experienced cardiac events

Minor differences between treatment groups

In the composite outcome, there were fewer events at higher vs lower doses of dabigatran

ACS = acute coronary syndromes; BID = twice daily; CV = cardiovascular; D110 = dabigatran 110 mg twice daily;D150 = dabigatran 150 mg twice daily

Oldgren J et al. Eur Heart J 2011;32:2781–9 41

Placebo Dabigatran

Outcome, n (%)(n=371)

50 mg BID(n=369)

75 mg BID(n=368)

110 mg BID(n=406)

150 mg BID(n=347)

CV death, non-fatal MI, or non-haemorrhagic stroke

14 (3.8) 17 (4.6) 18 (4.9) 12 (3.0) 12 (3.5)

CV death 9 (2.4) 8 (2.2) 9 (2.4) 5 (1.2) 4 (1.2)

Non-fatal MI 4 (1.1) 9 (2.4) 8 (2.2) 7 (1.7) 8 (2.3)

Non-haemorrhagic stroke 3 (0.8) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0)

Severe recurrent ischaemia 9 (2.4) 9 (2.4) 11 (3.0) 9 (2.2) 11 (3.2)

All-cause death 14 (3.8) 8 (2.2) 10 (2.7) 7 (1.7) 7 (2.0)

ACS – placebo comparator

Although it was not the primary endpoint or objective of the study, there was a trend towards fewer events with D110 and D150 than with placebo

Feb 2014

EXPERIENCE WITH DABIGATRAN IN ORTHOPAEDIC SURGERY

• ACS events were centrally adjudicated in three Phase III trials of VTE prevention in orthopaedic surgery RE-MODEL™, RE-NOVATE®, RE-MOBILIZE® (total >8000 patients)

• Rates of ACS (definite/likely) events were low and similar for patients treated with dabigatran (150 mg or 220 mg OD combined) and enoxaparin

OD = once daily

Eriksson BI et al. Thromb Res 2012;130:396–402; Clemens A et al. Vasc Health Risk Manag 2013;9:599–615 42

Adjudicated ACS events, n (%)Dabigatran(n=5419)

Enoxaparin(n=2716)

Definite/likely 42 (0.8) 20 (0.7)

Definite 28 (0.5) 17 (0.6)

Primary VTE prevention – enoxaparin comparator

Feb 2014

EXPERIENCE WITH DABIGATRAN IN ORTHOPAEDIC SURGERY

• ACS events were centrally adjudicated in three Phase III trials of VTE prevention in orthopaedic surgery RE-MODEL™, RE-NOVATE®, RE-MOBILIZE® (total >8000 patients)

• Rates of ACS (definite/likely) events were low and similar for patients treated with dabigatran (150 mg or 220 mg OD combined) and enoxaparin

OD = once daily

Eriksson BI et al. Thromb Res 2012;130:396–402; Clemens A et al. Vasc Health Risk Manag 2013;9:599–61543

Adjudicated ACS events, n (%)Dabigatran(n=5419)

Enoxaparin(n=2716)

Definite/likely 42 (0.8) 20 (0.7)

Definite 28 (0.5) 17 (0.6)

Primary VTE prevention – enoxaparin comparator

No negative effect of dabigatran on myocardial ischaemic events was reported

APIXABAN

1. The APPRAISE-2 study was a Phase III clinical trial in patients

with recent acute coronary syndrome treated with apixaban 5 mg

twice daily or placebo in addition to mono or dual antiplatelet

therapy.

2. This study was stopped early due to an increase in bleeding which

was not offset by clinically meaningful reductions in ischaemic

events.1

Alexander JH, et al; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute

coronary syndrome. N Engl J Med 2011;365:699-708.

AF (NOAC) + ACS/PCI

Aug 2014

ESC Working Group consensus

Antithrombotic treatment following coronary artery stenting in AF patients at moderate to high risk of TE (in whom OAC is required)

46

New antiplatelets such as prasugrel and ticagrelor have not yet been evaluated with OACsBMS = bare metal stent; DES = drug-eluting stent; ESC = European Society of Cardiology;RCT = randomized controlled trial; TE = thromboembolism1. Lip GYH et al. Thromb Haemost 2010;103:13–28; 2. Heidbuchel H et al. Europace 2013;15:625–51

Short-term

• Triple therapy: warfarin + ASA + clopidogrel • Duration varies from 2–4 weeks (high haemorrhagic risk, elective

PCI and BMS) to 6 months (low/intermediate haemorrhagic risk, ACS, BMS/DES)

• Followed by warfarin + either clopidogrel or ASA for up to 12 months in some patient groups (ACS or DES)

Lifelong

• Warfarin alone

Aug 2014

ESC Working Group consensus

Antithrombotic treatment following coronary artery stenting in AF patients at moderate to high risk of TE (in whom OAC is required)

47

New antiplatelets such as prasugrel and ticagrelor have not yet been evaluated with OACs4

BMS = bare metal stent; DES = drug-eluting stent; ESC = European Society of Cardiology;RCT = randomized controlled trial; TE = thromboembolism1. Lip GYH et al. Thromb Haemost 2010;103:13-28; 2. Heidbuchel H et al. Europace 2013;15:625–51

Short-term

• Triple therapy: warfarin + ASA + clopidogrel • Duration varies from 2–4 weeks (high haemorrhagic risk, elective

PCI and BMS) to 6 months (low/intermediate haemorrhagic risk, ACS, BMS/DES)

• Followed by warfarin + either clopidogrel or ASA for up to 12 months in some patient groups (ACS or DES)

Lifelong

• Warfarin alone

These recommendations are based on OAC being indicated for patients with AF

and stroke risk factors, and dual antiplatelet therapy being indicated after

ACS or PCI

Lip GYH et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu298

Latest guidance for combination therapy in patients with

NVAF and ACS/PCI

In general, the period of triple therapy should be as short as

possible, followed by OAC plus a single antiplatelet therapy

(preferably clopidogrel 75 mg/d, or as an alternative, ASA

75–100 mg/d)

B

Level

I

Class

Long-term antithrombotic therapy with OAC (beyond 12

months) is recommended in all patients

Recommendation

CIIb

Where a NOAC is used in combination with clopidogrel and/or

low-dose ASA, the lower tested dose for stroke prevention in

AF (dabigatran 110 mg BID, rivaroxaban 15 mg OD, or

apixaban 2.5 mg BID) may be considered

General

recommendation

*Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients; **ASA as an alternative to

clopidogrel may be considered in patients on dual therapy (i.e. oral anticoagulation plus single antiplatelet); ***Dual therapy

with oral anticoagulation and an antiplatelet agent (ASA or clopidogrel) may be considered in patients at very high risk of

coronary events. DAPT, dual antiplatelet therapy; Lip et al Eur Heart J 2014 doi:10.1093/eurheartj/ehu298

Latest guidance for combination therapy in patients with

NVAF and ACS/PCI (2)

STEP 1 – Stroke risk

STEP 2 – Bleeding risk

STEP 3 – Clinical setting

STEP 4 –

Antithrombotic

therapy

Nonvalvular atrial fibrillation

CHA2DS2-VASc = 1 CHA2DS2-VASc ≥ 2

Low to intermediate(e.g. HAS-BLED = 0–2)

High(e.g. HAS-BLED ≥ 3)

Low to intermediate(e.g. HAS-BLED = 0–2)

High(e.g. HAS-BLED ≥ 3)

Stable CAD ACS Stable CAD ACS Stable CAD ACS Stable CAD ACS

Triple or dual therapy*

or DAPT

TripletherapyO A C

A C

O A CDual

therapy

or DAPT

O C

Triple or dual therapy*

O A CTriple

or dual therapy*

O A C

Tripletherapy

O A C

O A COral anticoagulation ASA 75–100 mg daily Clopidogrel 75 mg daily

If PCI is performed

If PCI is performed

If PCI is performed

If PCI is performed

Time from PCI/ACS

Lifelong

12 months

6 months

4 weeks

0

Dual therapy**

Dual therapy**

or DAPTO A or C

A C

O A or C

A CDual

therapy**

O A or C

Triple ordual

therapy*

O A C

Triple or dual therapy*

O A C

Triple or dual therapy*

O A C

Dual therapy**

Dual therapy**

O A or C O A or C

Monotherapy***O

Dual therapy**

O A or C

Monotherapy***O

Not head-to-head comparison; no clinical conclusions can be drawn

A2.5 = apixaban 2.5 mg BID; D110 = dabigatran etexilate 110 mg BID; R15 = rivaroxaban 15 mg OD

Lip GYH et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu298

Use of low dose NOAC in recent AF trials

50% of

dabigatran group

received D110

n=6015

21% of

rivaroxaban group

received R15

n=1474

4.7% of

apixaban group

received A2.5

n=428

Tested among all eligible

patients in RE-LY®

May be considered on its

own merits

Prescribed only to a minority subset of patients in

clinical trials

May not necessarily provide adequate

antithrombotic protection for AF in patients without

the clinical features used for dose adjustment

TRIPLE THERAPY WITH A NOAC : KEY MESSAGES

54

• Oral anticoagulation with VKA OR NOAC

• No preference within class of NOACs

• Use lower tested dose

• Dabigatran 110 mg is the only

lower dose with proven efficacy in

randomised patients

• Other measures to limit

bleeding risk during thriple

therapy:• 1. Use of clopidogrel (Plavix)

instead of ticagrelor (Brilique), prasugrel (Efient)

• 2. Low dose aspirin <100 mg OD• 3. Radial access• 4. Consider intiating PPI

ONGOING TRIALS IN PATIENTS WITH AF

UNDERGOING A PCI WITH STENTING

55

Studies Interventions

PIONEER AF-PCI Safety of two rivaroxaban regimens vs VKA

RE-DUAL PCI Efficacy and safety of dual therapy with

dabigatran vs. triple therapy with VKA

www.clinicaltrials.gov

1160.186 - RE-DUAL PCI

A prospective Randomised, open label, blinded endpoint

(PROBE) study to Evaluate DUAL antithrombotic therapy with

dabigatran etexilate (110mg and 150mg b.i.d.) plus clopidogrel

or ticagrelor vs. triple therapy strategy with warfarin (INR 2.0 –

3.0) plus clopidogrel or ticagrelor and aspirin in patients with

non valvular Atrial Fibrillation (NVAF) that have undergone a

percutaneous coronary intervention (PCI) with stenting.

*Warfarin arm: 1 month after bare metal stent or 3 months after drug-eluting stent

Adapted from Cannon C. AHA 2013; and Boehringer Ingelheim data on file

RE-DUAL PCI™: two new approaches to improving care

for patients with AF undergoing PCI

Dual primary endpoints: Death, MI, stroke/SE and major bleeding

Patients with AF

undergoing PCI (n=8520)

R

Dabigatran 150 mg BID

+ clopidogrel/ticagrelor

Screening

0–72 hours

after PCI

Dabigatran 110 mg BID

+ clopidogrel/ticagrelor

Warfarin (INR 2.0–3.0)

+ clopidogrel/ticagrelor*

n=2840 patients per arm

Minimum treatment duration: 6 months

PIONEER AF-PCI : OVERVIEW

PCI STUDY

Primary endpoint

Composite of TIMI major bleeding events, minor bleeding events and bleeding events requiring medical attention

Key inclusion criteria

History of paroxysmal, persistent or permanent non-valvular AF

Undergone PCI (with stent placement) for primary atherosclerotic disease

Key exclusion criteria

High bleeding risk or contraindication to anticoagulation

Prior stroke/TIA

CrCl <30 ml/min

Hepatic disease

www.clinicaltrials.gov/ct2/show/NCT01830543 Back to programme overview

59

PIONEER AF-PCI: OVERVIEW

PCI STUDY

Rivaroxaban 15 mg od#‡ + clopidogrel*

Objective: safety of two rivaroxaban regimens vs VKA after PCI (with stent placement) in non-valvular AF

End of

treatment

(12 months)

Rivaroxaban 2.5 mg bid‡

+ DAPT**

VKA (INR 2.0–3.0)§

+ DAPT*

Rivaroxaban 15 mg od#

+ low-dose ASA

VKA + low-dose

ASA

N=2100

1:1:1 Intended DAPT duration

of 1, 6 or 12 months

Population: Paroxysmal, persistent or permanent AF, undergoing PCI (with stent placement)

R

* alternative use of prasugrel or ticagrelor allowed, but capped at 15%

** ASA (75–100 mg daily) + clopidogrel (75 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 15%); #CrCl

30–49 ml/min: 10 mg od; ‡First dose 72–96 hours after sheath removal; §First dose 12–72 hours after sheath removal

www.clinicaltrials.gov

Conclusions

• Management of NVAF patients with IHD is complex

• Need for robust data on new antithrombotic strategies (trials ongoing) (RE-DUAL PCI)

• Recent consensus recommendations are useful

New onset AF / Recent ACS (< 1 year)Low – moderate atherothromboticrisk

VKA monotherapy after 1-6 months

NOAC (low-dose) = good alternative to VKA

High atherothrombotic risk VKA + Clopidogrel

NOAC (low-dose) = good alternative to VKA

Low CHA2DS2-VASC score and high atherothrombotic risk

AAS + Clopidogrel

New onset AF / Remote ACS (> 1 year)VKA alone is superior to Aspirin post-ACS > no antiplatelet needed for most patients with AF and stable CAD

Advantages of NOCAs over VKAs are preserved in stable CAD patients with AF, NOACs provide safe and effective alternatives to VKAs

*Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients; **ASA as an alternative to

clopidogrel may be considered in patients on dual therapy (i.e. oral anticoagulation plus single antiplatelet); ***Dual therapy

with oral anticoagulation and an antiplatelet agent (ASA or clopidogrel) may be considered in patients at very high risk of

coronary events. DAPT, dual antiplatelet therapy; Lip et al Eur Heart J 2014 doi:10.1093/eurheartj/ehu298

Latest guidance for combination therapy in patients with

NVAF and ACS/PCI (2)

STEP 1 – Stroke risk

STEP 2 – Bleeding risk

STEP 3 – Clinical setting

STEP 4 –

Antithrombotic

therapy

Nonvalvular atrial fibrillation

CHA2DS2-VASc = 1 CHA2DS2-VASc ≥ 2

Low to intermediate(e.g. HAS-BLED = 0–2)

High(e.g. HAS-BLED ≥ 3)

Low to intermediate(e.g. HAS-BLED = 0–2)

High(e.g. HAS-BLED ≥ 3)

Stable CAD ACS Stable CAD ACS Stable CAD ACS Stable CAD ACS

Triple or dual therapy*

or DAPT

TripletherapyO A C

A C

O A CDual

therapy

or DAPT

O C

Triple or dual therapy*

O A CTriple

or dual therapy*

O A C

Tripletherapy

O A C

O A COral anticoagulation ASA 75–100 mg daily Clopidogrel 75 mg daily

If PCI is performed

If PCI is performed

If PCI is performed

If PCI is performed

Time from PCI/ACS

Lifelong

12 months

6 months

4 weeks

0

Dual therapy**

Dual therapy**

or DAPTO A or C

A C

O A or C

A CDual

therapy**

O A or C

Triple ordual

therapy*

O A C

Triple or dual therapy*

O A C

Triple or dual therapy*

O A C

Dual therapy**

Dual therapy**

O A or C O A or C

Monotherapy***O

Dual therapy**

O A or C

Monotherapy***O