Division of Cardiology, Department of Internal Medicine, Faculty of Medicine , University of Indonesia,

Jakarta , Indonesia

Prof. Idrus Alwi MD, PhD, FINASIM, FACP, FACC, FESC, FAPSIC

NOAC Evidence in AFBridging the Gap Between Scientific Knowledge and Clinical Experience

Workshop objective

• Balancing safety benefit and efficacy in vulnerable patient for SPAF• Elderly

• Renal impairment

• Prior stroke

• With ACS/CAD after PCI

• Selecting NOAC based on trial results and real world evidence in Asian patient

Case illustration

• Female, 78 years old, 70 kg

• Creatinine clearance 45 mL/min

• Hypertension for 12 years (blood pressure 165/85 mmHg)

• Diagnosis of AF (asymptomatic) 5 years ago

• Now admitted to the hospital with a minor ischaemic stroke

• Current Medications• Enalapril 10 mg +

Hydrochlorothiazide 12.5 mg

• Aspirin 100 mg

AF, atrial fibrillation

CHADS2 = ...... points; CHA2DS2-VASc = ..... points; annual stroke risk ≈ ......

#1

Case illustration

• Female, 78 years old, 70 kg

• Creatinine clearance 45 mL/min

• Hypertension for 12 years (blood pressure 165/85 mmHg)

• Diagnosis of AF (asymptomatic) 5 years ago

• Now admitted to the hospital with a minor ischaemic stroke

• Current Medications• Enalapril 10 mg +

Hydrochlorothiazide 12.5 mg

• Aspirin 100 mg

AF, atrial fibrillation

CHADS2 = 4 points; CHA2DS2-VASc = 6 points; annual stroke risk ≈ 10%

#1

European Society of Cardiology Guidelines2

1. Lip GY et al, Chest. 2010;137(2):263-72; 2. Camm AJ et al, Eur Heart J. 2010;31:2369–2429

0%

3%

6%

9%

12%

15%

18%

0.0%

1.3%2.2%

3.2%4.0%

6.7%

9.8% 9.6%

6.7%

15.2%

0 1 2 3 4 5 6 7 8 9

Annual Risk of Stroke

CHA2DS2VASc Score

Ris

k o

f St

roke

CHA2DS2 – VASc risk criteria Score

Cardiac failure 1

Hypertension 1

Age >75 yrs 2

Diabetes mellitus 1

Prior Stroke or TIA 2

Vascular disease (MI, PAD, aortic atherosclerosis)

1

Age 65-74 yrs 1

Sex category (female) 1

Newer Stroke Risk Scoring System In AF: CHA2DS2VASc Score

2016 ESC Guidelines Added Edoxaban among NOACs for Stroke Prevention in Patients with AF1:

AF = atrial fibrillation; ESC = European Society of Cardiology; NOACs = novel oral anticoagulants; VKA = vitamin K antagonist; INR = international normalized ratio

1. Kirchhof P et al. Eur Heart J. 2016 Oct 7;37(38):2893-2962

Edoxaban

Apixaban

Dabigatran

Rivaroxaban

Considering this high bleeding risk patient, what would you recommend to prevent the 2nd stroke?

A. Stay with Aspirin and combine with Clopidogrel (DAPT)

B. Change to Warfarin (INR 2-3)

C. Change to NOAC

D. Change to parenteral anticoagulant first, then OAC

#1

HASBLED risk criteria Score

Hypertension 1

Abnormal renal or liver function (1 point each)

1 or 2

Stroke 1

Bleeding 1

Labile INR’s 1

Elderly (> 65 yrs old) 2

Drugs or alcohol (1 point each)

1 or 2

Bleeding Risk Assessment With HASBLED

Risk Factors/Score N

Number of Bleeds

Bleeds per 100 Patient-Years

0 798 9 1.13

1 1286 13 1.02

2 744 14 1.88

3† 187 7 3.74

4 46 4 8.70

5 8 1 12.50

Any score 3071 48 1.56

P value for trend .007

Camm AJ, et al. Eur Heart J. 2010;31(19):2369-429. Pisters R. Chest. 2010;138:1093-100. Lip GY, et al. Am J Med. 2010;123(6):484-8.

Risk of major bleeding in patients with AF in the Euro Heart Survey

†Score of ≥3 indicates ‘high risk,’

Unfortunately, a high CHADS score often correlates with a high HAS-BLED score & these patients do not receive anticoagulation due to the high bleeding risk

Singapore

Thailand Malaysia East Asia Myanmar Global VietnamTimor-Leste

LaosCambodi

aSEA Indonesia

Philippines

Incident -49.6% -18.3% -16.8% 4.9% -16.9% -8.1% -21.1% -7.9% -13.1% -13.0% -7.1% 8.8% 15.0%

Deaths -73.8% -51.5% -46.0% -42.3% -36.8% -36.2% -33.0% -32.2% -27.6% -24.4% -22.0% 6.3% 14.1%

Disability (DALYS) -74.5% -47.3% -46.5% -41.0% -38.9% -34.2% -34.6% -36.9% -32.2% -28.4% -20.1% 6.0% 15.7%

Singapore

Thailand

Malaysia

East Asia

Myanmar

Global

Vietnam

Timor-Leste

Laos

Cambodia ASEAN

Indonesia

Philippines

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

% Change since 1990 to 2016Incident Deaths Disability (DALYS)

Unlike the rest of the world, stroke burden in Indonesia keep increasing in

last 26 years

(ie. incidence, mortality, and morbidity), second to Phillipines in Southeast Asia region

Lancet Neurol. 2019 Mar 11;16(11):877–97.

Steinberg BA. Am Heart J 017;194:132-40

In real world, the use of NOAC is increasing

But, there is still significant percentage (20-30%) of patient that received

antiplatelet only or no anticoagulation at all

Since 1993, Aspirin doesn’t have proven efficacy for secondary

prevention of ischaemic stroke in patients with AF

EAFT: 1007 patients with non-rheumatic AF and recent TIA or minor ischemic stroke (mean follow-up 2.3 years)

EAFT Study Group. Lancet 1993;342:1255–62

AF, atrial fibrillation; OAC, oral anticoagulant; INR, international normalised ratio;

TIA, transient ischaemic attack

P=0.31

66

14

0

10

20

30

40

50

60

70

Str

ok

e r

isk

re

du

cti

on

vs

. p

lac

eb

o (

%)

Warfarin (INR 2.5–4.0)

Aspirin (300 mg/day)

P<0.001

12

6 Trials of Warfarin vs. Placebo

1989-1993

RE-LY

(Dabigatran)

2009

ROCKET AF

(Rivaroxaban)

2010

ARISTOTLE

(Apixaban)

2011

ENGAGE AF-TIMI 48

(Edoxaban)

2013

Warfarin vs. Placebo

2,900 Patients

NOACs vs. Warfarin

71,683 Patients

Pivotal Trials for Stroke Prevention in AF

Hart RG. Ann Intern Med 2007;146:857-867 Ruff CT. Lancet 2014;383:955-962

Warfarin is a good anticoagulant, but NOAC is better

1414

Risk factors for intracranial haemorrhage under warfarin

● Intensity of oral anticoagulation

●History of TIA or stroke

●Age (≥75 years)

●Hypertension (especially systolic BP >160 mmHg)

●Concomitant use of aspirin

Hart RG et al. Stroke 2005;36:1588-93

Hart RG et al. Stroke 2012;43:1511-17.BP, blood pressure; TIA, transient ischaemic attack

Physician tends to treat patient with subtherapeutic INR (<2)

1515

Out of range INR will cost more than in range INR, and the highest cost is associated with suboptimal INR (<2).

Schein et al. Thrombosis Journal (2016) 14:14

Major Bleeding per Year in the 4 Major SPAF trials on NOACs vs VKA

Not only efficacy, some NOACs offer better safety!

What we already know about Edoxaban?

• Edoxaban, the new kid on the block, in SPAF management, have several unique features – Once daily dosing that has been proven, safer than BID dosing– Highly selective for and potently inhibits Factor Xa– Rapidly absorbed with good bioavailability after oral dosing– Is not highly dependent on renal elimination– Does not induce CYP450 isozymes – Can be taken with or without food– Is affected by P-gp inhibition and body weight– Safe to be use with low dose ASA

• Edoxaban have clear guidance for dose reduction (60 to 30 mg)– CrCl <50 ml/min– BW <60 kg– Concomitant with strong PgP Inh

ENGAGE AF: Summary of key outcomes – Edoxaban 60/30 mg QD

Edoxaban 60 mg QD

Edoxaban better Warfarin better

0.50 1.50

Stroke, SEE, major bleed, death: ITT0.89

Cardiovascular death: ITT0.86

Death: ITT0.92

CRNM bleed: safety cohort0.86

Major bleed: safety cohort0.80

Stroke and SEE: ITT0.87

Stroke and SEE: mITT on-treatment0.79

1.00Ischaemic stroke: ITT

Hemorrhagic stroke: ITT0.54

1.000.00

Giugliano RP et al. N Engl J Med 2013;363:2093-104.

CRNM, clinically relevant non-major bleed; ITT, intention to treat;

mITT, modified ITT; QD, once daily; SEE, systemic embolic event

If this patient have mild mitral regurgitation, which anticoagulant will you choose?A. Warfarin

B. NOAC

#1

In real world, acceptance of NOAC is low in Asian

(GLORIA-AF Registry)

Mazurek M. Thromb Haemost 2017;117:2376–2388

NOAC has been dominating for SPAF treatment, except for Asia

Remaining question

Was it because more valvular AF than “non valvular”?

Why the acceptance for NOAC is still low in Asian countries?

Clinicians were often confused with “Valvular” term in SPAF trials

Valvular Atrial Fibrillation: Changing Definitions in Guidelines

ACC/AHA/ESC 2001: Non Valvular means absence of rheumatic mitral stenosis or a prosthetic heart valve.

ACC/AHA/ESC 2006: absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair.’

ESC 2012: Valvular AF includes rheumatic valvular disease and prosthetic valves

ESC 2016 / ACC/AHA 2019: Non valvular means absence of mechanical prosthetic heart valves and moderate to severe mitral stenosis.

• Other valvular problems is defined as ‘non-valvular’

• Biological valves or after valve repair included in some trials on ‘non-valvular AF’, including Edoxaban

Definition of “Valvular AF” in all NOACs trials

RELY ROCKET-AF ARISTOTLE ENGAGE-AF

Total Sample size 18,113 14,264 18,201 21,105

Exclusion criteria

regarding VHD

1. Prosthetic valve

2. Hemodynamically

relevant valve

disease

1. Hemodynamically

significant mitral

valve stenosis

2. Prosthetic heart

valve

1. Valvular disease

requiring surgery

2. Prosthetic

mechanical heart

valve,

3. Moderate or severe

mitral stenosis

1. Moderate or severe

mitral stenosis,

2. Unresected atrial

myxoma,

3. A mechanical heart

valve

Patients with VHD,

n (%)

3,950 (22%) 2,003 (14%) 4,808 (26%) 2,824 (13%)

De Caterina R. et al. JACC 2017

NOACs efficacy and safety were remain consistent in VHD, except in ROCKET trial

Question for the audience

If you were to treat the patient with a NOAC, which NOAC would you choose and at what dose?

A. Edoxaban 60mg once daily

B. Edoxaban 30mg once daily

C. Rivaroxaban 15mg once daily with food

D. Apixaban 5mg twice daily

E. Apixaban 2.5mg twice daily

F. Dabigatran 150mg twice daily

G. Dabigatran 110mg twice daily

NOAC, non vitamin-K antagonist oral anticoagulant

Female 78 years old 70 kg

Creatinine clearance 45

mL/minHypertension

Ischaemic stroke

#1

Treatment

choice

Age

Comorbidity

Renal

Function

Efficacy

Real clinical

practice

Safety

NOAC, non vitamin-K antagonist oral anticoagulant

Which NOAC should I select for my patient?

Safety in Elderly Population

28Ref) Kato ET, et al.：J Am Heart Assoc 2016 (doi：10.1161/JAHA.116.003432)

4.6

6.2

0

2

4

6

8

10

12

4.0 4.8

0

2

4

6

8

10

12

5.0

8.8

0

2

4

6

8

10

12

■ Edoxaban 60/30 mg ■ Warfarin (TTR=69.6% in >75 years, 69.5% in >80 years, 68.4% in >85 years)

>80 years (n=3,591)〔60mg⇒30mg in 53%〕

> 85years (n=899)〔60mg⇒30mg in 67%〕

Inci

den

ce r

ate

of

Maj

or

Ble

edin

g (%

/yea

r)

>75 years (n=8,474)〔60mg⇒30mg in 41%〕

HR=0.7595% CI [0.58-0.98]

HR=0.5895% CI [0.35-0.94]

HR=0.8395% CI [0.70-0.99]

“Edoxaban reduced major bleeding compared to warfarin in elderly patients over 75 years old, 80 years old, or even 85 years old.”

Korean real world evidence –

Edoxaban vs Warfarin outcome by renal function

Yu TH et al. Stroke. 2018;49:2421-9

In real-world practice, edoxaban 60 mg were associated with reduced risks for S/SE, major bleeding, and mortality compared with warfarin.

The first head-to-head comparison of the effectiveness and safety between

the two once-daily NOAC regimens (rivaroxaban, edoxaban) in a nationwide

Asian cohort with NVAF.

Lee S, et al. Sci Rep 2019;9:6690

Edoxaban vs Rivaroxaban in real world setting

after introduction of edoxaban to Asian market

Among patients with available CrCl value and body weight information, 93% on rivaroxaban and 44% on

edoxaban received inappropriate dose reduction.

Lee S, et al. Sci Rep 2019;9:6690

Lee S et al. Stroke. 2019;50:00-00. DOI: 10.1161/STROKEAHA.119.025536

Patient case

• 83 year old man, permanent AF

• Receiving stable oral anticoagulation

• Warfarin: Aiming at an INR 2.0–3.0

• Admitted with a non-ST-segment elevation myocardial Infarction

• Hypertension • Treated with an ACE inhibitor +

calcium antagonist

• Hypercholesterolemia • Treated with a statin

• Former smoker

• Chronic renal failure: eGFR 52 ml/kg/1.73m² (at admission)

• Haemoglobin level: 10.8g/dl

• White blood cell count 7.2*109/L

AF, atrial fibrillation; INR, international normalised ratio; ACE, angiotensin-converting enzyme; AF, atrial fibrillation; eGFR, etimated glomerular filtration rate

#2

What’s this patient profile?

A. High stroke risk, low bleeding risk

B. High ischemic risk, low bleeding risk

C. High stroke risk, ischemic risk, and bleeding risk

D. Low stroke risk, high ischemic and bleeding risk

#2

Risk stratification

• Adjusted stroke rate (%/year): 4.8% (Moderate-High)

CHA2DS2-VASc:

4

• Bleeds / 100 patient years: 8.7 (High)

HAS-BLED:

3

• TIMI major or minor bleeding (12 months): >4.14% (High)

Precise-DAPT:

39

83 y.o man with a history of permanent atrial fibrillation on

stable oral anticoagulation (‘warfarin’ aiming at an INR 2.0–

3.0) admitted with a NSTEMI. Hypertension and Moderate

Renal Impairment.

Patient underwent PCI with Single stent technique (bifurcation Medina 1-0-1), Endeavour

resolute stent 3.0*18 mm (DES)

CABG, coronary artery bypass graft; DAPT, dual antiplatelet therapy; INR, international normalised ratio; PCI, percutaneous coronary intervention; TIMI, thrombosis in myocardial infarction; Precise-DAPT, PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy

European Society of Cardiology Guidelines2

1. Lip GY et al, Chest. 2010;137(2):263-72; 2. Camm AJ et al, Eur Heart J. 2010;31:2369–2429

0%

3%

6%

9%

12%

15%

18%

0.0%

1.3%2.2%

3.2%4.0%

6.7%

9.8% 9.6%

6.7%

15.2%

0 1 2 3 4 5 6 7 8 9

Annual Risk of Stroke

CHA2DS2VASc Score

Ris

k o

f St

roke

CHA2DS2 – VASc risk criteria Score

Cardiac failure 1

Hypertension 1

Age >75 yrs 2

Diabetes mellitus 1

Prior Stroke or TIA 2

Vascular disease (MI, PAD, aortic atherosclerosis)

1

Age 65-74 yrs 1

Sex category (female) 1

Newer Stroke Risk Scoring System In AF: CHA2DS2VASc Score

HASBLED risk criteria Score

Hypertension 1

Abnormal renal or liver function (1 point each)

1 or 2

Stroke 1

Bleeding 1

Labile INR’s 1

Elderly (> 65 yrs old) 2

Drugs or alcohol (1 point each)

1 or 2

Bleeding Risk Assessment With HASBLED

Risk Factors/Score N

Number of Bleeds

Bleeds per 100 Patient-Years

0 798 9 1.13

1 1286 13 1.02

2 744 14 1.88

3† 187 7 3.74

4 46 4 8.70

5 8 1 12.50

Any score 3071 48 1.56

P value for trend .007

Camm AJ, et al. Eur Heart J. 2010;31(19):2369-429. Pisters R. Chest. 2010;138:1093-100. Lip GY, et al. Am J Med. 2010;123(6):484-8.

Risk of major bleeding in patients with AF in the Euro Heart Survey

†Score of ≥3 indicates ‘high risk,’

Unfortunately, a high CHADS score often correlates with a high HAS-BLED score & these patients do not receive anticoagulation due to the high bleeding risk

Precise DAPT score

Bleeding score

Points

Hb

WBC

Age

Cr CI

Prior bleed

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

≥12 11.5 ≤1011 10.5

≥5 8 ≤2012 1610 14 18

≥50 ≤9060 70 80

≥100 080 60 40 20

NoYes

Web score calculator: http://www.precisedaptscore.com/predapt/webcalculator.html CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; Hb, haemoglobin;

TIMI, thrombolysis in myocardial infarction; WBC, white blood cell count;

10.8 9

7.2 2

83 16

52 12

Precise DAPT score

Effect of Long (12-24 months) vs. short (3-6 months) DAPT

Absolu

te r

isk d

iffe

rence

(%

)

4

3

2

1

0

1

2

3

4

Very low Low Moderate High

Harm

Benefit

NET BENEFIT OF LONG DAPTIschemia= −1.53% p=0.007 NNT=65

Bleeding= +0.14% p=0.45

Ischemia= +1.41% p=0.48

Bleeding= +2.59% p=0.005 NNT=38NET HARM

LONG DAPT

PRECISE DAPT <25 >25

DAPT, dual antiplatelet therapy; MI,

myocardial infarction; TIMI, thrombolysis in

myocardial infarction; TVR, target vessel

revascularisation

Web score calculator: http://www.precisedaptscore.com/predapt/webcalculator.html

Ischemic (MI, Def. ST, stroke, TVR)

Bleeding (TIMI major or minor)

Net Effect

Question for audience

After successful PCI, how would you treat this patient?

A. DAPT only

B. OAC only

C. OAC plus DAPT for 12 months

D. OAC plus DAPT for 1 month followed by OAC and clopidogrel

E. Other

DAPT, dual antiplatelet therapy; OAC, oral anticoagulation

#2

Wang TY et al. Am Heart J. 2008;155(2):361-8.

42Capodanno D, Huber K, Mehran R, et al. Management of Antithrombotic Therapy in Atrial Fibrillation

Patients Undergoing PCI: JACC State-of-the-Art Review. J Am Coll Cardiol 2019; 74(1): 83-99.

Approximately 15% of patients with AF

may require PCI with stent placement to

treat obstructive coronary artery disease.

Anti-coagulant therapy

Thrombus in the left atrium

Low shear stress

Antiplatelet therapy (additive benefit

oral anticoagulant?)

Thrombus,platelet mediated in the

coronary artery

High shear stress

43

TF/VIIa

IX*

IXaVIIIa

X*

Xa

II*

IIa

Fibrinogen Fibrin

Thrombus

Platelet Aggregation

Conformational Activation of GPIIb/IIIa

Collagen

Thromboxane A2

ADP

Aspirin

ClopidogrelPrasugrelTicagrelor

Initiation

Propagation

Fibrin Formation

RivaroxabanApixabanEdoxaban

Dabigatran Etexilate

VII*

Anticoagulants and their targets in the

coagulation pathway

Weitz JI, et al. J Thromb Haemost 2005;3:1843–53.

44

Bleeding is bad…

CI, confidence interval; HR, hazard ratio

44.4%

19.4%

WOEST trial - Combined antiplatelet and NOAC therapy after

acute coronary syndrome: Three is a crowd!

DeWilde et al. Lancet. 2013;381:1107–15

NOAC in AF after PCI and/or ACS (1)

PIONEER-AF PCI• VKA+DAPT vs

• Rivaroxaban 2.5 mg* BID + DAPT vs

• Rivaroxaban 15 mg* QD + P2Y12

RE-DUAL PCI

• VKA+DAPT vs

• Dabigatran 110 mg BID + P2Y12

• Dabigatran 150 mg BID + P2Y12

*Rivaroxaban dose is not designed for adequate SPAF in pivotal trial

NOAC in AF after PCI and/or ACS (2)

ClinicalTrials.gov Identifier: NCT02415400

AUGUSTUS

Overall, the PIONEER-AF, RE-DUAL PCI and AUGUSTUS study validated with greater power the WOEST hypothesis (i.e.

less bleeding with the drop of ASA)

and cumulatively add strength to the concept that abandoning ASA might improve safety towards bleeding in stented patients on DAPT with a NOAC and a P2Y12 inhibitor.

PIONEER-AF PCI

RE-DUAL PCIAUGUSTUS

Patients with AF Undergoing PCIMeta Analysis –

3 NOACs vs VKA

Better safety with similar efficacy

signal?

Edoxaban- vs vitamin-K-antagonist-based anti-thrombotic regimen after successful coronary stenting

in patients with atrial fibrillation (ENTRUST-AF PCI): A randomised, open-label, phase 3b trial

Andreas Goette, Marco Valgimigli, Lars Eckardt, Jan Tijssen, Thorsten Lewalter, Giuseppe Gargiulo, Valerii Batushkin, Gianluca Campo, Zoreslava Lysak, Igor Vakaliuk, Krzysztof Milewski, Petra Laeis, Paul-Egbert Reimitz, Rüdiger Smolnik, Wolfgang Zierhut, Pascal Vranckx

ENTRUST-AF PCI: Study design

ClinicalTrials.gov Identifier: NCT02866175

*** VKA pre-defined by country, target INR 2–3

****ASA 100 mg OD for 1–12 months guided by

clinical presentation (ACS or stable CAD),

CHA2DS2-VASc and HAS-BLED

4 hours – 5 days

after sheath removal

Inclusion criteria:

• OAC indication

for AF for at

least 12 months

• Successful PCI

with stent

placement

(goal of at least

25% ACS)

**Clopidogrel 75 mg OD or if

documented need prasugrel

5 or 10 mg OD or ticagrelor

90 mg BID

Declared at randomisation

P2Y12 antagonist** (without ASA)

Edoxaban 60 mg QD*

P2Y12 antagonist (ASA 1 - 12 months)****

Vitamin K Antagonist***

*Edoxaban dose reduction to

30 mg QD if:

• CrCL ≤50 ml/min

• BW ≤60 kg

• Certain concomitant P-gp

inhibitors• Primary outcome: ISTH major and clinically relevant non-major

bleeding

AF, atrial fibrillation; ACS, acute coronary syndrome; ASA, aspirin; BID, twice daily; BW, body weight; CAD, coronary artery

disease; CrCl, creatinine clearance; INR, international normalised ratio; ISTH, International Society on Thrombosis and

Haemostasis; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; QD, once-daily; .VKA, vitamin K antagonist

R12 months: end

of treatment

N=1500

Key differentiation features of

ENTRUST-AF-PCI (Based on Study Design)

Relative to RE-DUAL, ENTRUST-AF PCI study allows greater flexibility in aspirin use in the comparator arm of 1 to 12 months (based on investigator’s decision and according to ESC guidelines)

The endpoint for AUGUSTUS is 6 months; ENTRUST-AF PCI assesses bleeding events over a 12-month period

The doses of rivaroxaban used in PIONEER-AF PCI are 25% and 75% lower than the approved 20 mg QD dose for stroke prevention in patients with AF; the doses used in ENTRUST-AF PCI were assessed globally in large, prospective, randomized trials

Primary Study EndpointITT Analysis (N=1506), overall study period

Cu

mu

lati

ve in

cid

ence

in o

utc

om

es

0.25

0.20

0.15

0.10

0.05

0.00

0

Days from randomization

360

Number at risk

330300270240210180150120906030

751 506

755 485

Edoxaban

VKA

565575584590600609618629646665688

538543552561568578588603625648678

Number of events:Edoxaban: 128/751VKA: 152/755

HR (95% CI): 0.83 (0.65; 1.05)P-value (noninferiority): 0.0010P-value (superiority); 0.1154

Post Hoc Landmark Kaplan Meier Analysis Primary Study Endpoint

Cu

mu

lati

ve r

ate

of

even

ts

0.25

0.00

0

Days from randomization

360

Number at risk

751 506

755 485

Edoxaban

VKA0.20

0.15

0.10

0.05

14 30 60 90 120 150 180 210 240 270 300 330

565575584590600609618629646665688

538543552561568578588603625648678

707

721

Phase 1 (≤day 14) HR (95% CI): 2.42 (1.27; 4.63)Phase 2 (>day 14) HR (95% CI): 0.68 (0.53; 0.88)Interaction P-value: <0.0001

Time from PCI toRandomisation: • shortest – 0.2 h• median – 45 h

94%

69%

42%37% 37% 39%

5%

23%

34% 40% 44% 44%

1%

8%

24% 22% 19% 17%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

≤Day 1 Day 2 to 7 Day 8 to 14 Day 15 to 21 Day 22 to 28 Day 29 to 35

Mean INR <2 Mean INR 2–3 Mean INR > 3

INR in VKA regimen in first 5 weeksOverall study period: median TTR = 63.1%

Should we abandon aspirin completely for AF patient after PCI?

Yes No

#2

Goette A. et al. ESC Congress 2019. FP 6044; Vrancks P. et al. Lancet. 2019. pii:S0140-6736(19)31872-0

Key takeaways for AF after PCI

Since all NOAC have published data for AF after PCI, which NOAC will you choose?A. Dabigatran

B. Rivaroxaban

C. Apixaban

D. Edoxaban

#2

Selecting NOACs in AF

after PCI

CYP450 PgP Inh

c

c

Take home message

NOACs are clearly more beneficial compare to VKA or antiplatelet in SPAF, including for vulnerable patients

Real world evidence for Asian patient strengthen the safety benefit and convenience of Edoxaban relative to VKA and other NOACs

There is no one drug fits all!

• In AF patient after successful PCI, only Dabigatran and Edoxaban have enough evidence for 12 months treatment using approved full dose for SPAF

• The use of aspirin after PCI in AF patient is still beneficial in the first 14 days due to high risk for stent thrombosis, before switching to OAC+P2Y12

• ENTRUST-AF PCI adds to the evidence of NOACs in post PCI AF patients that dual antithrombotic therapy with edoxaban plus a P2Y12 antagonist, is an alternative to VKA plus a P2Y12 antagonist, and aspirin (ASA) risk based for 1 month or more (triple therapy)