ESC Guidelines for the management of acute

coronary syndromes in patients presenting

without persistent ST-segment elevation

Chairpersons

JeanJean--Pierre BassandPierre Bassand

Department of CardiologyDepartment of Cardiology

University Hospital Jean University Hospital Jean MinjozMinjoz

BesançonBesançon, France, France

Christian W. HammChristian W. Hamm

Medical Clinic IMedical Clinic I

University Hospital GiessenUniversity Hospital Giessen

& & KerckhoffKerckhoff Heart and Thorax CenterHeart and Thorax Center

Bad Bad NauheimNauheim, Germany, Germany

Members of the Task Force

Christian W. Hamm (Chairperson) (Germany),

Jean-Pierre Bassand (Chairperson), (France),

Stefan Agewall (Norway), Jeroen Bax (The Netherlands), Eric Boersma

(The Netherlands), Hector Bueno (Spain), Pio Caso (Italy), Dariusz Dudek (Poland), (The Netherlands), Hector Bueno (Spain), Pio Caso (Italy), Dariusz Dudek (Poland),

Stephan Gielen (Germany), Kurt Huber (Austria), Magnus Ohman (USA), Mark C.

Petrie (UK), Frank Sonntag (Germany), Miguel Sousa Uva (Portugal), Robert F.

Storey (UK), William Wijns (Belgium), Doron Zahger (Israel).

DisclosuresDisclosures

Honoraria/Consulting/Speakers bureauHonoraria/Consulting/Speakers bureau

Astra ZenecaAstra Zeneca

BayerBayer

Eli LillyEli LillyEli LillyEli Lilly

GSKGSK

IrokoIroko

MSD MSD SheringShering PloughPlough

SanofiSanofi AventisAventis

European Heart Journal Advance Access published August 26, 2011

ESC Guidelines for the Management of NSTE-ACS (6)ESC Guidelines for the Management of NSTE-ACS (6)

European Heart Journal Advance Access published June 14, 2007European Heart Journal Advance Access published June 14, 2007

What is new?• Diagnostic

• High-sensitive troponin introduced

• Echocardiography standard

• Coronary CT for rule-out in low/intermediate risk patients

• Risk Stratification

• 3-hour fast rule-out protocol• 3-hour fast rule-out protocol

• Bleeding risk score (CRUSADE)

• Medical Treatment

• Ticagrelor and prasugrel introduced

• Revascularisation

• Timing of revascularisation

Recommendations for diagnosis and risk stratification 1

Mortality in hospital and at 6 months according to the

GRACE risk score

CRUSADE score of in-Hospital major bleeding

www.crusadebleedingscore.org

Risk of major bleeding across the spectrum of CRUSADE bleeding score

Recommendations for diagnosis and risk stratification 2

Recommendations for diagnosis and risk stratification 1

Rapid rule-out of ACS with high-sensitivity troponin.

HsTroponin I HsTroponin I AssayAssay and and EarlyEarlyDiagnosisDiagnosis of MIof MI

Keller T JAMA 2011; 306:2684

Hs Troponin I assay at 99 percentile cut-off

At 3 hours:

Sensitivity is 98.2%

NPV is 99.4%

Sensitive Troponin I Assay in ACS

Mills JAMA 2011; 305:1210

Implications of lowering threshold of plasma troponinconcentration in diagnosis of myocardial infarction:

cohort study

Mills BMJ 2012;344:e1533 doi: 10.1136/bmj.e1533

Implications of lowering threshold of plasma troponinconcentration in diagnosis of myocardial infarction:

cohort study

Mills BMJ 2012;344:e1533 doi: 10.1136/bmj.e1533

Implications of lowering threshold of plasma troponinconcentration in diagnosis of myocardial infarction:

cohort study

Mills BMJ 2012;344:e1533 doi: 10.1136/bmj.e1533

Keller T N Engl J Med 2009; 361:868

Keller T N Engl J Med 2009; 361:868

Troponin elevation

Possible non-acute coronary

syndrome causes syndrome causes

Cardiac and non-cardiac conditions that can mimic ACS

What is new?• Diagnostic

• High-sensitive troponin introduced

• Echocardiography standard

• Coronary CT for rule-out in low/intermediate risk patients

• Risk Stratification

• 3-hour fast rule-out protocol• 3-hour fast rule-out protocol

• Bleeding risk score (CRUSADE)

• Medical Treatment

• Ticagrelor and prasugrel introduced

• Revascularisation

• Timing of revascularisation

AspirinAspirin

Class Level

25

P2Y12 Inhibitors

Class Level

P2YP2Y1212 inhibitor recommendations 1inhibitor recommendations 1

27

Class Level

Class Level

P2YP2Y1212 inhibitor recommendations 2inhibitor recommendations 2

28

PLATO: time to first primary efficacy PLATO: time to first primary efficacy

event (composite of CV death, MI or stroke)event (composite of CV death, MI or stroke)

12111098765

13

Cum

ula

tive incid

ence (

%)

9.8

11.7Clopidogrel

Ticagrelor

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

543210Cum

ula

tive incid

ence (

%)

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Curves are Kaplan-Meier rates, HR = hazard ratio; CI = confidence interval

6

5

4

3

7

Cu

mu

lative

in

cid

en

ce

(%

)

Clopidogrel

Ticagrelor

5.8

6.9

6

4

3

Clopidogrel

Ticagrelor

4.0

5.1

7

5

Myocardial infarction Cardiovascular death

Cu

mu

lative

in

cid

en

ce

(%

)

Secondary efficacy endpoints over time Secondary efficacy endpoints over time

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,560

8,678

8,405

8,520

8,177

Days after randomisation

6,703

6,796

5,136

5,210

4,109

4,191

0 60 120 180 240 300 360

3

2

1

0

Cu

mu

lative

in

cid

en

ce

(%

)

8,279

HR 0.84 (95% CI 0.75–0.95), p=0.005

0 60 120 180 240 300 360

3

2

1

0HR 0.79 (95% CI 0.69–0.91), p=0.001

9,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Cu

mu

lative

in

cid

en

ce

(%

)

TicagrelorTicagrelor

Class Level

31

10

15

HR 0.81(0.73-0.90)

P=0.0004

Prasugrel

Clopidogrel

En

dp

oin

t (%

)

12.1

9.9

138

events

TRITONTRITON--TIMI study TIMI study Balance of Efficacy and SafetyBalance of Efficacy and Safety

CV Death / MI / Stroke

NNT = 46

0

5

0 30 60 90 180 270 360 450

Prasugrel

Days

En

dp

oin

t (%

)

HR 1.32

(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.8

2.4

35

events TIMI Major NonCABG Bleeds

NNH = 167

PrasugrelPrasugrel

Class Level

33

ClopidogrelClopidogrel dosingdosing

Class Level

Class Level

34

Class Level

ClopidogrelClopidogrel response variabilityresponse variability

Class Level

35

Class Level

GP IIb/IIIa receptor inhibitorGP IIb/IIIa receptor inhibitor

Class Level

36

Class Level

15

20

Death/MI/UTVR, %

ISAR-REACT 2: Outcomes according to Tn level

Troponin-Positive: RR=0.71 [0.54-0.95]

0

5

10

0 5 10 15 20 25 30

Days after randomization

Abciximab vs. Placebo

Troponin-Negative: RR=0.99 [0.56-1.76]

Kastrati A et al. JAMA 2006

ACUITY TimingACUITY Timing

11,7% 11,7%

30 d

ay e

ve

nts

(%

)

Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIaRoutine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

PNI <0.0001

PSup = 0.93

PNI = 0.044

PSup = 0.13

PNI < 0.0001

PSup = 0.009

7,1%6,1%

4,9%

7,9%

Net clinical

outcome

Ischemic

composite

Major bleeding

30 d

ay e

ve

nts

(%

)

Stone, G. W. et al. JAMA 2007;297:591-602

10

15Death, MI, Death, MI, recurrent recurrent ischaemiaischaemia or thrombotic bailoutor thrombotic bailout

Pri

ma

ry e

nd

po

int

10.0%

9.3%

Delayed provisionaleptifibatide

EARLY ACSDelayed provisional vs routine early eptifibatide

0

5

0 8 16 24 32 40 48 56 64 72 80 88 96

RIUR = recurrent ischemia requiring urgent revascularization, TBO = thrombotic bailout.

Giugliano RP, et al. NEJM. 2009;360:2176-90.

Pri

ma

ry e

nd

po

int

Time Since Randomization, h

9.3%

P=0.23(stratified for intended early

clopidogrel use)

eptifibatide

Routine early

eptifibatide

PLATO: major bleeding according PLATO: major bleeding according

to use of to use of GPIIbGPIIb//IIIaIIIa antagonist during antagonist during

hospitalisationhospitalisation

40

Upstream GP IIb/IIIa receptor inhibitorUpstream GP IIb/IIIa receptor inhibitor

Class Level

Class Level

41

Class Level

Class Level

BivalirudinBivalirudin vsvs GPIIbGPIIb//IIIaIIIa antagonistsantagonists

Class Level

42

AnticoagulantsAnticoagulants

Class Level

43

Class Level

Death/MI/RI: Day 9C

um

ula

tive

Ha

za

rd

0.0

30

.04

0.0

50.0

6

Days

Cu

mu

lative

Ha

za

rd

0.0

0.0

10

.02

0.0

3

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR 1.01

95% CI 0.90-1.13

Major Bleeding: 9 DaysC

um

ula

tive H

azard 0

.03

0.0

4

HR 0.53 95% CI 0.45-0.62

P<<0.00001

Enoxaparin

Days

Cu

mu

lati

ve H

azard

0.0

0.0

10.0

2

0 1 2 3 4 5 6 7 8 9

Fondaparinux

Mortality: Day 30C

um

ula

tive H

aza

rd0.0

20.0

3

Enoxaparin

Fondaparinux

Days

Cu

mu

lati

ve H

aza

rd0.0

0.0

10.0

2

0 3 6 9 12 15 18 21 24 27 30

HR 0.83 HR 0.83

95% CI 0.7195% CI 0.71--0.970.97

P=0.022P=0.022

Outcomes to 30 days

Low dose 2.2% vs. Standard dose 1.8%, HR 1.20 (95% CI 0.64-2.23, p=0.57)

Major Bleed at 30 days

0.02

0.03

0.04

0.05

0.01

0.02

0.03

0.04

0.05Death/MI/TVR at 30 days

Low dose 4.5% vs. Standard dose 2.9%HR 1.56 (95% CI 0.98-2.48, p=0.06)

Subgroup analysis showed consistent results for primary outcome and for death/MI/TVR for pre-specified subgroups of: Age, Sex,

GP IIb/IIIa, BMI, CrCl, Arterial access site

Days

3 6 9 12 15 18 21 24 27 303 6 9 12 15 18 21 24 27 3000

0.0

0.01Standard DoseLow Dose

No. at Risk

Standard Dose

Low Dose

1002 986 981 980 980 978

1024 1002 1001 998 997 994

Days

0 3 6 9 12 15 18 21 24 27 300 3 6 9 12 15 18 21 24 27 30

0.0

0.01Standard DoseLow Dose

No. at Risk

Standard Dose

Low Dose

1002 980 975 975 974 971

1024 997 988 982 981 978

FondaparinuxFondaparinux

Class Level

48

Class Level

HeparinsHeparins

Class Level

Class Level

Use of Use of

antithrombotic drugs antithrombotic drugs

in chronic kidney in chronic kidney

diseasedisease

50

Recommendations for oral antiplatelet agents 1

PLATO

TRITON-TIMI 38

Recommendations for GP IIb/IIIa receptor inhibitorsCH9

Dia 52

CH9 Tabelle teilen, nebeneinander auf 1 SeiteProf. Dr. Christian Hamm; 21-8-2011

Recommendations for anticoagulants

Decision-making algorithm in ACS

Recommendations for invasive evaluation and revascularization

Criteria for high risk with indication for

invasive management

“Management Strategy”

of NSTE - ACSof NSTE - ACS

Management of NSTE - ACS

• Step 1: Initial evaluation

• Step 2: Diagnosis validation and

risk assessment

• Step 3: Invasive strategy• Step 3: Invasive strategy

• Step 4: Revascularisation modality

• Step 5: Hospital discharge and

post-discharge

Initial therapeutic measures

Checklist of treatments when an ACS diagnosis appears likely

Checklist of antithrombotic treatments prior to PCI

Measures checked at discharge

Take Home messages

• NSTE-ACS is a frequent cause of hospitalization

Heterogenous population as regards risk

• Diagnostics

• Clinical presentation, ECG, troponin

• High-sensitive troponin introduced

• Echocardiography for everybody

• Coronary CT for rule-out in low/intermediate risk patients

• Risk Stratification

• 3-hour fast rule-out protocol based on hs-troponin

• Ischaemic risk (GRACE score )

• Bleeding risk (CRUSADE score )

Take Home messages (continued 1)

• First line antithrombotic treatment

• Ticagrelor and prasugrel recently introduced

• Revascularisation

• Timing of revascularisation customized according to risk

– Within 72 hours anyway, but

– Within 2 hours for very high risk patients (lifethreatening symptoms)

– Within 24 hours for patients with high risk criteria (GRACE score > 140,

troponin release, ST-T changes)

• Non invasive evaluation for low risk patients

Take Home messages (continued 2)

• Special populations and situations

• Diabetes, elderly, women, CKD, anaemia.....

• Bleeding complications ...

• Long term secondary prevention

• Secondary prevention programmes

• Lifestyle

• Drug therapy

Risk of major bleeding across the spectrum of CRUSADE bleeding score

Ten Take home messages

1 - NSTE-ACS is a frequent cause of hospitalization

2 - Heterogenous population as regards risk

3 - Diagnostic• Clinical presentation

• ECG

• (High-)sensitive troponin

• Echocardiography standard for all

• Coronary CT for rule-out in low/intermediate risk patients

4 - Risk Stratification• 3-hour fast rule-out protocol based on hs-troponin

• Ischaemic risk (GRACE score )

• Bleeding risk (CRUSADE score )

5 - Antischaemic Therapy

6 - Antiplatelet treatment • Aspirin lifelong for all, plus

• Ticagrelor (12 months) or

• Prasugrel (only prior PCI)

• Clopidogrel , if ticagrelor and prasugrel not available

• Glycoprotein IIb/IIIa in high risk patients, but not

Ten Take home messages

• Glycoprotein IIb/IIIa in high risk patients, but not routinely upstream

7 - Anticoagulation• Fondaparinux best benefit/ risk profile (add UFH if PCI)

• Enoxaparin, other low molecular weight heparins or unfractionated heparin are less recommended options

• Bivalirudin in high risk bleeding as alternative to GP IIb/IIIa + UFH in patients undergoing PCI

8 - Revascularisation• Timing of revascularisation customized according to risk

– Within 72 hours all patients at risk, but

– Within 2 hours for very high risk patients (lifethreateningsymptoms)

– Within 24 hours for patients with high risk criteria (GRACE score > 140, troponin release, ST-T changes)

• Non invasive evaluation for low risk patients

Ten Take home messages

• Non invasive evaluation for low risk patients

9 - Special populations and situations• Special attention to diabetes, elderly, women, CKD,

anaemia.

• Adjust medication doses according to renal function

10 - Long term management, secondary prevention

Thank you !Thank you !