Management of acute coronary

syndromes in patients presenting

without persistent ST-segment
elevation

Recommendations of the European Society of Cardiology

Updated version –December 2002

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 Task Force on management of ACS without
persistent ST-segment elevation
• Developed by the ESC Committee for
Practice Guidelines (CPG)
• Approved by the Board of the ESC

This Task Force was entirely supported financially by the European Society of
Cardiology and was developed without any involvement of pharmaceutical companies

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 Task Force Members
M.E. Bertrand (FR), Chair

M.L. Simoons (NL) K.A.A. Fox (GB)

L.C. Wallentin (SE) C.W. Hamm (DE)

E.P. McFadden (FR) P.J. De Feyter (NL)

W. Ruzyllo (PL) G.Specchia (IT)

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NST-AMI ACS Task Force. © 2003 European Society of Cardiology
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 ACUTE CORONARY SYNDROMES

• Different clinical expressions

• Resulting from a common underlying
pathophysiological mechanism:
– Atherosclerotic plaque rupture (or erosion)
– Different degrees of superimposed
thrombosis
– Distal embolization

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 ACS with persistent ACS without persistent
ST-segment elevation ST-segment elevation

Troponin or CK-MB Troponin elevated or not

Myocardial infarction Unstable angina

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 Epidemiology
N Countries Timing STE-ACS Non
STE-ACS

EuroHeart Survey 10,484 25 Sep ‘00 42.3% 51.2%

Europe May ’01

GRACE 11,543 14 Apr ‘99 30% 63%

World Dec ‘00

Mortality and non-fatal MI at 6-month FU: 13%

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 Mechanisms β-blockers
Targeted approaches
Myocardial
Oxygen
Inflammation Supply Myoc
demand

Plaque rupture
or erosion PCI
Stent Luminal narrowing

Nitrates
Platelet aggregation Adapted from M.J Davies Ca antagonists
Vasospasm
Aspirin GpIIb/IIIa receptor inhib
Clopidogrel
Thrombosis
UH Heparin LMWH

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ACS without persistent ST-segment elevation
Treatment options

Five categories of treatment:

• Anti-ischaemic agents
• Anti-thrombin agents
• Anti-platelet agents
• (Fibrinolytics)
• Coronary revascularization

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 Levels of evidence
Level of evidence A
Level of evidence B
Level of evidence C
Data derived from multiple
randomized clinical trials or
meta-analyses
Data derived from a single
randomized trial or non-
randomized studies
Consensus opinion of the
experts

Early benefit Early benefit Sustained Additional

Prevention of Effect of Long-term
↓ ischaemia Death / MI Early benefit ↓ Death / MI

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 Anti-ischaemic agents
• Beta-blockers:
– Three DB randomized trials comparing BB to placebo
– 13 % RR reduction in progression to Acute MI
A B B A
• Nitrates
– No RDZ placebo-controlled trials C (-) (-) (-)

• Calcium channel blockers

– Small RDZ trials
– Meta-analysis on death and MI suggests that there is no
prevention of death and MI B B (-) (-)

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 Heparin (UFH or LMWH) vs. Placebo
0.67
UFH Control [95% CI]
7.9 % 10.4% 0.45-0.99
C B (-) (-)

0.34
LMWH Control [95% CI]
1.6 % 5.2% 0.20-0.58

A A A A 0.2 0.6 1 1.4

Heparin better Placebo better

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Randomized trials comparing LMWH vs. UFH
Death and non-fatal MI

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 Antiplatelets : Trials ASA vs. Placebo
Death or MI (%)
ASA vs. N ASA Placebo
Placebo
Theroux 479 2.46% 6.35%

Lewis 1266 4.9% 10.1%

Cairns 555 6.1% 12.9%

RISC 728 6.5% 17.1%

0.41
Total 3096 5.2% 11.8%

0 0.2 0.4 0.6 0.8 1 1.2

(-) A A A ASA better Pl. better

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 ADP receptor
receptor antagonists:
antagonists: Clopidogrel
Clopidogrel (CURE
(CURE trial:
trial: 12,562
12,562 pts )

End-point Clopi- Placebo P

dogrel
CV death/MI/Stroke 9.3% 11.4% 0.80 <0.001
CV death 5.1% 5.2% 0.33
0.77
MI 5.2% 6.7% 0.0004
Death/MI 30-day 3.9% 4.8% 0.007
Death/MI 9-mth 8.6% 10.5% 0.001
Refractory isch. 8.7% 9.3% 0.22
1.69
Major bleeding 3.7% 2.9% 0.001
2.12
Minor bleeding 5.1% 2.4% <0.001
NEJM 2001;345:494-502
0 0.5 1 1.5 2 2.5
B B B B Clopidogrel better Placebo better

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 Gp IIb/IIIa receptor inhibitors. Death and MI at 30-day FU
Seven Trials comparing GPIIb/IIIa vs Placebo in ACS:
Both groups received Heparin +ASA
A A A A

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 GpIIb/IIIa inhibitors and PCI:
CAPTURE, PRISM-PLUS, PURSUIT combined
N=12,296 N=2,754 N=2,736
10%
p=0.001 p=0.001 p=0.474
8% 8.0%
Placebo
6%
4.9%
4%
4.3%
IIb/IIIa blocker
2.9%
2% P 1.6%
1.3%
IIb/IIIa
0%
1 2 3 1 2 7 14 21 days
PCI

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GpIIb/IIIa vs. Placebo : Death and non fatal MI at 30 days
N patients GpIIb/IIIa Plac.
0.84
Troponin (+) 4,964 10.3% 12%
1.16
Troponin (-) 6,095 7% 6.2%
0.79
PCI/CABG 11,986 14.3% 17.3%
0.97
No PCI/CABG 19,416 10.1% 10.5%
0.88
Diabetes 6,458 13.7% 22%
0.74
Diabetes 6,458 4.6% 6.2%
(death)
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

GpIIb/IIIa better Placebo better

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 ACS without persistent ST-segment elevation
Coronary revascularization
• Indications and approach depend on the extent
and angiographic characteristics of the lesions
• Wide variation among countries
– In the use of coronary angiography: 52% in
EuroHeartSurvey
– In subsequent revascularization(EuroHeartSurvey) :
• 25.4% of PCI (73.5% with stent implantation)
• 5.4% of CABG

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 Revascularization in contemporary trials
% of revascularization
70 30.8% 28% 61% 37% 58% 37%

60 PCI
41
50
44 CABG
Percentage

40

30 24 18
25.4
20
13
20 19
10 15 13 14

0 5.4
Invasive Conservative Invasive Conservative
Eur. H. Surv CURE TACTICS FRISC-II

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 ACS without persistent ST-segment elevation
Respective Indications and Strategy
! Single VD (30-38%) Usually PCI

! LM (4-8%) or MVD (44-59%) Usually CABG

! 2VD/3VD Evaluation on an individual basis

! Invasive vs. Conservative strategy

• FRISC II: Revascularization at 4 days for PCI and 8 days for CABG
• TACTICS: Upstream Treatment with Tirofiban- Cor angio 4-48hrs
• RITA-3 : upstream enoxaparin
• At FU significant reduction of Death,or MI or Death/MI/Rec. Isch in
favour of the invasive strategy

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 TACTICS , FRISC-II (6-mths), RITA-3 (1 yr)
Invasive vs. Conservative strategy: Death and MI
16
22% p<0.03 14.1
14 Conservative
Invasive 12.1
12
10 9.5 26% p<0.05 9.4 9.4
Percentage

8.3
7.3 7.6
8
6
4
2
0
TACTICS FRISC-II UK MI definitions ACC/ESC MI
definitions
A A A A RITA-3

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Levels of evidence of the different therapeutic options

Early benefit Early benefit Sustained Additional

Reduction Prevention Effect of Long-term
ischaemia Death/MI Early benefit Death/MI
Beta-blockers A B B A
Nitrates C (-) (-) (-)
Ca Antagonists B B (-) (-)
Aspirin (-) A A A
Thienopyridines B B B B
IIb/IIIa receptor blockers A A A A
Unfractionated heparin C B (-) (-)
LWMH A A A C
Direct antithrombins (-) A A (-)
Revascularization C B B B

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 ACS Without Persistent ST-segment Elevation

Risk stratification: Two types of risk

Acute risk Long-term risk

i.e. Thrombotic risk

Underlying CAD and LV function

Inflammation

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ACS without persistent ST-segment elevation
Risk assessment

Thrombotic risk Underlying coronary artery disease

Clinical markers
Recurrent ischaemia
Age
History of prior MI, CABG
ST-segment depression
Diabetes, HF
Biological markers
Dynamic ST-segment changes
CRP, Fibrinogen, IL-6, BNP
Renal dysfunction
Elevated troponins
Angiographical markers
EF
Thrombus on angiography
Extension of vessel disease

Acute risk Long-term risk

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 ECG: Risk predictor
25

Death/MI, Ref Ang at 30days

21
20

15
10 10
10 7
5

0
ST-depression Inverted T- Normal Transient ST-
waves elevation
25
22.1 25

D e a th /M I a t 3 0 d a y s
Death & MI Death & MI
D e a th /M I a t 3 0 d a y s

19.7
20 20

15 15 12.7
9.1 9.5
10 10
6.7
5 5

0 0
No ST ST 1 mm ST > 2mm 0-2 episodes /d 2-5 episodes /d >5 epidodes /d

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 Comparison Troponin (+ ) vs. Troponin (- )
T+ T-
7.7
Death short-term 5.7% 0.9%
N=3091
9.9
Death/MI short-term 13.4% 3.0%
2.74
Death long-term 7% 3.5%
2.9 N=4273
Death/MI long-term 20.2% 9%

0 2 4 6 8 10 12 14 16 18

Ottani et al Am Heart J 2000; 140:917 x (risk if TnT +)

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 Admission Chest pain
Working Suspicion of Acute Coronary
diagnosis Syndrome

ECG Persistent No persistent Normal or atypical

ST – elevation ST – elevation ECG changes
Bio-
chemistry CK-MB Troponin Troponin
Troponin Twice negative
Risk
stratification High Risk Low Risk Probably not ACS

Treatment

Secondary
prevention

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 Patients judged to be at high risk for
progression to MI or death
Heparin
Heparin (LMWH
(LMWH or
or UFH),
UFH), ASA,
ASA, Clopidogrel,
Clopidogrel, Betablockers,
Betablockers, Nitrates
Nitrates
0 2 4 48h

Patients
Patients with
with recurrent
recurrent ischaemia
ischaemia
Recurrent
Recurrent chest
chest pain
pain
Dynamic
Dynamic ST-segment
ST-segment changes
changes GpIIb/IIIa blocker &
((ST-segment
ST-segment depression
depression or
or transient
transient Coronary angiography
ST
ST segment
segment elevation)
elevation)
Elevated
Elevated troponin
troponin levels
levels
Diabetes
Diabetes
Early
Early post
post infarction
infarction unstable
unstable angina
angina
Haemodynamic
Haemodynamic instability
instability In Emergency
Major
Major arrhythmias
arrhythmias (VF,
(VF, VT)
VT)

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Patients judged to be at low risk for progression to death or MI
Heparin
Heparin (LMWH
(LMWH or
or UFH),
UFH), ASA,
ASA, Clopidogrel,
Clopidogrel, Beta-blockers,
Beta-blockers, Nitrates
Nitrates

• No recurrence of chest pain within observational period

• No elevation of troponin or other biochemical markers of
thrombosis
• No ST-segment depression (Negative or flat T-waves,
normal ECG

Repeat troponin measurements between 6 and 12 hours

No ECG changes and second troponin measurement: negative

Heparin discontinued Oral treatment with ASA, Clopidogrel, Beta-blockers, Nitrates)

Stress
Stresstest
testto
toconfirm
confirmororto
toestablish
establishaadiagnosis
diagnosisof
ofCAD
CAD
To
Toassess
assessthe
therisk
riskof
offuture
futureevents
events

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 Clinical suspicion of ACS
Physical examination, ECG monitoring, Blood samples

Persistent
Persistent No
No persistent
persistent Undetermined
Undetermined
ST-Segment
ST-Segment elevation
elevation ST-Segment
ST-Segment elevation
elevation diagnosis
diagnosis

Thrombolysis
Thrombolysis Heparin
Heparin (LMWH
(LMWH or
or UFH),
UFH), ASA,
ASA,
PCI
PCI Clopidogrel*,
Clopidogrel*, Betablockers,
Betablockers, Nitrates
Nitrates ASA
ASA

High
High risk
risk Low
Low risk
risk

Second
Second troponin
troponin measurement
measurement
GPIIb/IIIa
GPIIb/IIIa
Cor.
Cor. Angiography
Angiography
Positive
Positive Twice
Twice negative
negative
PCI, CABG or medical management
Depending upon clinical and
angiographic features
Stress
Stress test
test
Cor.
Cor. angiography
angiography
* omit clopidogel if the patient is likely to go to CABG within 5 days

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 ACS without persistent ST-segment elevation
Long-term management
• Aggressive and extensive risk factor
modification
• Patients should quit smoking
• ASA (75-100 mg for life), Clopidogrel (9
months, possibly 12 months)
• Betablockers
• Lipid lowering drugs: HMG-CoA reductase
inhibitors HPS, 4S, CARE, LIPID,
(A to Z ongoing)
• ACE inhibitors (HOPE),
(EUROPA, PEACE ongoing)

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Guidelines: ACS without persistent ST-segment
elevation

Caveats

• Guidelines are based upon evidence resulting

from many clinical trials:
– These trials were restricted to selected populations
• Guidelines describe the current knowledge but …
– They do not give the solution for an individual patient
• Clinical science is different from Practice

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 Conclusion (1)
• Importance of risk-stratification
– To perform the triage
– To choose the best strategy
– To predict the prognosis

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 Conclusion (2)
• High-risk patients require:
– Aggressive anti-thrombotic treatment
• Antithrombin agents
• Aggressive antiplatelet treatment: blockade of the three
principal pathways
– ASA
– Clopidogrel
– GpIIb/IIIa
– Invasive strategy
• PCI prepared by upstream treatment
• Rapidly evolving field: frequent update
• Needs for implementation programme across
Europe

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 The End

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