Guidelines nste-acs-slides

ESC Guidelines for the Management of
Non-ST Segment Elevation Acute Coronary
Non-ST
Syndromes

Jean-Pierre Bassand, MD, FESC Christian Hamm, MD, FESC
Co-chair Co-chair
University Hospital Jean Minjoz Kerckhoff Heart Center
Besançon Bad Nauheim
France Germany

ESC Guidelines for the Management of NSTE-ACS (1)

Members of the Task Force

• Jean-Pierre Bassand, • Christian Hamm,
France Germany
Co-Chair Co-chair
• Diego Ardissino, Italy • Keith Fox, United
• Andrzej Budaj, Poland Kingdom
• Eric Boersma, • David Hasdai, Israel
Netherlands • Magnus Ohman, USA
• Francisco Fernandez- • Lars Wallentin, Sweden
Aviles, Spain • William Wijns, Belgium

European Heart Journal Advance Access published June 14, 2007


Trends and Prognosis in NSTE-ACS
NSTE-ACS
180 1975 - 1978 1990 - 1991
1981 - 1984 1993 - 1995
160 1986 - 1988 1997

140
Incidence rate (per 100,000)

120

100

80

60

40

20

0
Q-Wave Non Q-Wave
Furman MI. et al JACC 2001; 37: 1571-80


Trends and Prognosis in NSTE-ACS
NSTE-ACS
STEMI versus NSTEMI - Cumulative 1 Year Mortality
1
Survival after STEMI versus NSTEMI

0,9 NSTEMI

STEMI

0,8

0,7
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Courtesy A Gitt Months after Acute STEMI / NSTEMI


STEMI versus NSTEMI
Hospital vs 1-Year-Mortality
14 STEMI
NSTEMI
12 p<0.01 p<0.01
10,8

10 9,3
Mortakity percent

8 7,1

5,7
6

4

2

0


STEMI versus NSTEMI
Mortality after Discharge
1
Survival (MI Patients discharged alive)

0,98
STEMI

0,96

NSTEMI
0,94

0,92

0,9
0 1 2 3 4 5 6 7 8 9 10 11 12
Months after Discharge


Methods


Methods
1- Cost/benefit and cost/risk ratios in the terms of
– Number Needed to Treat

2 - Class III re-introduced in the level of recommendations
– Class III = contra-indication (it goes without saying,
but it’s better to say it !)


Randomized trials
of UFH/LMWH (dark bars ) vs Control (open bars)
Size Death or MI at end study medication Major bleeds

Theroux ’88 243

0
Cohen ’90 69 0 0
0
RISC ’90 399 0

0
Cohen ’94 214

Holdright ’94 285

0
Gurfinkel ’95 143

FRISC ’96 1506

All 2859
Heparin+ Ctrl+ Heparin+ Ctrl+ Heparin+ Ctrl+
2 2
0% 20% 40% 0.25 0.5 1 2 1 10 10 ∞ 10 10 1 0% 3% 6% 0.1 0.5 1 2 10
Incidence Odds ratio and 95% NNT and 95% CI Incidence Odds ratio and 95%
CI CI
4.7% vs 7.4% 0.55 (0.39-0.77) 31 (23-62) 1.1% vs 0.5% 2.3 (0.97-5.4)


Methods

1- Cost/benefit and cost/risk ratios in the form of
– Number Needed to Treat

2 - Class III re-introduced in the level of recommendations
– Class III = contra-indication (it goes without saying,
but it’s better in saying !)


Methods
3- Quality level of trials taken into account
– Double blind, randomised design
– Use of hard endpoints in the primary endpoint
• death and MI
• death / MI / stroke and bleeding as net clinical benefit
– Adequate sample size calculations
– Contemporary adjunctive treatments (stents, clopidogrel,
IIb/IIIa inhibitors…)
4- Efficacy / safety profile of drugs / treatments taken into
account for the gradation of recommendations


Classes of Recommendations
Class I Evidence and/or general agreement that a given treatment of
procedure is beneficial, useful, effective

Class II Conflicting evidence and/or a divergence of opinion about the
usefulness / efficacy of the given treatment or procedure

Class IIa Weight of evidence / opinion is in favour of usefulness / efficacy

Class IIb Usefulness / efficacy is less well established by evidence /
opinion
Class III Evidence or general agreement that the given treatment or
procedure is not useful / effective, and in some cases may be
harmful.


Levels of Evidence

Data derived from multiple randomized clinical
Level of Evidence A
trials or meta-analyses.

Data derived from a single randomized clinical
Level of Evidence B
trial or large non-randomized studies.

Consensus of opinion of the experts and/or
Level of Evidence C small studies, retrospective studies,
registries.


Table of Contents (1)
• Epidemiology and Natural History
• Pathophysiology
• Diagnosis & Risk Assessment
• Treatment
– Anti-ischaemic agents
– Anti-coagulants
– Anti-platelet agents
– Resistance to antiplatelet agents/drug interactions
– Withdrawal of antiplatelet agents
– Coronary revascularisation
– Long-term management and rehabilitation

Table of Contents (2)
• Complications and their management
– Bleeding
– Thrombocytopenia
• Special Conditions & Populations
– Elderly
– Diabetes
– Impact of Gender
– Anaemia
– Chronic Kidney Disease
• Management Strategy
• Performance Measures

Pathophysiology


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

Adapted from Michael Davies Adapted from Michael Davies

Troponin elevated Troponins elevated or not


Diagnosis & Risk Assessment


Admission Chest Pain
Working
Suspicion of Acute Coronary Syndrome
diagnosis

Persistent ST/T – Normal or Undetermined
ECG
ST – elevation Abnormalities ECG

Bio-
Troponin Troponin
chemistry
positive 2 x negative
Risk
stratification High Risk Low Risk

Diagnosis STEMI NSTEMI Unstable Angina

Treatment Reperfusion Invasive Non-invasive

Predictive Value of ST Depression
1
No ST-depression
0,95 1mm ST-depression
2mm ST-depression

0,9
Survival

0,85

0,8

0,75

0,7
0 30 60 90 120 180
Follow-up in days
Kaul et al. PARAGON Study. JACC 2003


Example of Release of Cardiac Markers in a Patient with NSTE-ACS
NSTE-ACS
(Shaded Area Indicates Normal Range).
4
Multiples of upper reference limit

cTnT
3

cTnl
2

Myoglobin
1

CK-MB
0
0 20 40 60 80 100
Hours after admission


Non-coronary Conditions with Troponin Elevation
Non-coronary
• Severe congestive heart failure – acute and chronic
• Aortic dissection, aortic valve disease or
hypertrophic cardiomyopathy
• Cardiac contusion, ablation, pacing, cardioversion,
or endomyocardial biopsy
• Inflammatory diseases, e.g., myocarditis, or
myocardial extension of endo-/pericarditis
• Hypertensive crisis
• Tachy- or bradyarrhythmias
• Pulmonary embolism, severe pulmonary
hypertension
• Hypothyroidism
• …/…

Non-coronary Conditions with Troponin Elevation
Non-coronary
• …/…
• Apical ballooning syndrome
• Chronic or acute renal dysfunction
• Acute neurological disease, including stroke, or
subarachnoid haemorrhage
• Infiltrative diseases, e.g., amyloidosis,
haemochromatosis, sarcoidosis, scleroderma
• Drug toxicity, e.g., adriamycin, 5-fluorouracil,
herceptin, snake venoms
• Burns, if affecting >30% of body surface area
• Rhabdomyolysis
• Critically ill patients, especially with respiratory
failure, or sepsis

Cardiac and non cardiac conditions that can
mimic NSTE-ACS
NSTE-ACS

Cardiac Pulmonary Haematological Vascular Gastro-intestinal Orthopedic

Myocarditis Pulmonary Sickle cell anaemia Aortic dissection Esophageal Cervical
Pericarditis embolism Aortic aneurysm spasm discopathy
Myopericarditis Pulmonary Aortic coarctation Esophagitis Rib fracture
Cardiomyopathy infarction Cerebrovascular Peptic ulcer Muscle injury/
Valvular disease Pneumonia disease Pancreatitis inflammation
Apical ballooning Pleuritis Cholescystitis Costochondritis
(Tako-Tsubo Pneumothorax
syndrome)


ACS
Initial Decision-making Algorithm
ECG
ST ST Neg. T normal

Troponin
Arrival & > 6-12 hours

+
STEMI High Risk Low Risk


Recommendations for Diagnosis and Risk
Stratification (1)

• Diagnosis and short-term risk stratification of
NSTE-ACS should be based on a combination of
clinical history, symptoms, ECG, biomarkers and
risk score results (I-B).


GRACE ACS Risk Model


Mortality in hospital and at 6 months in low, intermediate and
high risk categories in registry populations according to the
GRACE Risk score http://www.outcomes.org/grace
http://www.outcomes.org/grace

Risk category GRACE Risk Score In-hospital deaths (%)
(tertiles)
Low <=108 <1
Intermediate 109-140 1 -3
High >140 >3
Risk category GRACE Risk Score Post-discharge to 6
(tertiles) months deaths (%)
Low <=88 <3
Intermediate 89-118 3 -8
High >118 >8


Recommendations for Diagnosis and Risk Stratification
(2)
• The evaluation of the individual risk is a dynamic process
that is to be updated as the clinical situation evolves.

– A 12-lead ECG should be obtained within 10 minutes after first
medical contact and immediately read by an experienced
physician. (I-C) Additional leads (V3R and V4R, V7-V9) should be
recorded. ECG should be repeated in case of recurrence of
symptoms, and at 6, 24 hours and before hospital discharge (I-
C).

– Blood must be drawn promptly for troponin (cTnT or cTnI)
measurement. The result should be available within 60 minutes.
(I-C) The test should be repeated after 6-12 hours if the initial
test is negative (I-A).
– …/…

Recommendations for Diagnosis and Risk Stratification
(3)
• The evaluation of the individual risk is a dynamic
process that is to be updated as the clinical situation
evolves.
– …/…
– Established risk scores (such as GRACE) should be
implemented for initial and subsequent risk assessment (I-B)

– An echocardiogram is recommended to rule out differential
diagnoses (I-C).

– In patients without recurrence of pain, normal ECG findings,
and negative troponins tests, a non-invasive stress test for
inducible ischaemia is recommended before discharge (I-A).


Recommendations for Diagnosis and Risk stratification (4)
Long Term Risk
• The following predictors of long-term death or MI
should be considered in risk stratification (I-B):
– Clinical indicators: age, heart rate, blood pressure,
Killip class, diabetes, previous MI/CAD
– ECG markers: ST-segment depression
– Laboratory markers: troponins, GFR/ CrCl/ Cystatin C,
BNP/NT-proBNP, hsCRP
– Imaging findings: low ejection fraction, main stem
lesion, 3- vessel disease.
– Risk score result


Treatment


Therapeutic Options
• Anti-ischaemic agents
• Anti-coagulants
– UFH or LMWHs
– Fondaparinux
– Bivalirudin
• Anti-platelet agents
– ASA
– Clopidogrel
– IIbIIIa Inhibitors
• Revascularisation


Treatment
-------
Anti-ischaemic agents
Anti-ischaemic


Recommendations for Anti-ischaemic Drugs
Anti-ischaemic
• Beta-blockers are recommended in the absence of
contraindications, particularly in patients with hypertension
or tachycardia (I-B).

• Intravenous or oral nitrates are effective for symptom relief
in the acute management of anginal episodes (I-C).

• Calcium channel blockers provide symptom relief in patients
already receiving nitrates and beta-blockers; they are useful
in patients with contraindications to beta-blockade, and in
the subgroup of patients with vaso-spastic angina (I-B).

• Nifedipine, or other dihydropyridines, should not be used
(III-B), unless combined with beta-blockers (IIa-B)


Treatment
------
Anti-coagulants
Anti-coagulants


What’s New with Anti-coagulants
What’s Anti-coagulants
1 - Pharmacological Treatment
- Superior efficacy with equivalent safety of enoxaparin over UFH
(Petersen meta-analysis)
- Fondaparinux non-inferior to enoxaparin in OASIS-5
- Fondaparinux reduced bleeding rate by ~ 50% in OASIS-5
- Reduction in bleeding impacts on outcome (significant risk
reduction for death, MI and stroke)
2 - Anti-coagulants in the Setting of PCI
- Enoxaparin is not superior to UFH in SYNERGY
- Bivalirudin superior to UFH/LMWH + GPIIb/IIIA inhibitors in
ACUITY


Anticoagulants – New Comers
• Fondaparinux
– Unequivocal benefit over enoxaparin
– Significant RR of both bleeding and ischaemic risks
– Closes the loop – Shift in the paradigm
– Catheter thrombi issue
– Bleeding risk issue with UFH ‘on top’ of fonda. in PCI patients
• Bivalirudin
– Not double blind trial
– Non inferiority margin issue
– Biased comparison of the different regimens
– No impact of bleeding risk reduction on outcome at short and
long term FU


Efficacy and Bleeding Complications Among
Patients Randomized to Enox or UFH in NSTE-ACS
Death or MI at 30 Days
Events, No./Total (%)
Trial Enoxaparin UHF OR (95% CI) Favors Favor
Enoxaparin UFH

ESSENCE 94/1607 (5.8) 118/1564 (7.5) 0.76 (0.58-1.01)
TIMI 11B 145/1953 (7.4) 163/1957 (8.6) 0.88 (0.70-1.11)
ACUTE II 25/315 (7.9) 17/210 (8.1) 0.97 (0.51-1.83)
INTERACT 19/380 (5.0) 33/366 (9.0) 0.54 (0.30-0.96)
A to Z 137/1852 (7.4) 139/1768 (7.9) 0.94 (0.73-1.20)
SYNERGY 696/4992 (14.0) 722/4982 (14.5) 0.96 (0.86-1.07)
OVERALL 1116/11099 (10.1) 1192/10847 (11.0) 0.91 (0.83-0.99)
0.2 0.5 1 2
OR (95% CI)

Petersen.
Petersen. JAMA 2004;292:89–96
2004;292:89–


Enoxaparin Was Non-Inferior to UFH
Non-Inferior
in Reducing Death or MI in the SYNERGY Trial
Hazard Ratio (95% CI)
1
Enoxaparin 1 mg sc bid 30-Day Death/MI
30-Day Death/MI
UFH (aPTT 50-70 sec)
Freedom from Death / MI

0.95

0.9
HR 0.96 (0.87-1.06)

0.85

0.8
0 5 10 15 20 25 30 0.8 1 1.1 1.2
Enoxaparin UFH
Days from Randomization
better better
JAMA 2004;292:45-54 Am Heart J 2005;149:581-90


OASIS 5 Trial
Death, myocardial infarction or refractory ischemia through day 9

0.06
Fondaparinux
0.05 Enoxaparin
Cumulative Hazard

0.04

0.03

0.02

Hazard ratio, 1.01 (95% CI, 0.90 - 1.13)
0.01

0.00
0 1 2 3 4 5 6 7 8 9
NEJM 2006;354:1464
Days


OASIS 5 Trial
Major bleeding through day 9
0.04
Fondaparinux
Enoxaparin
0.03
Cumulative Hazard

0.02

0.01
Hazard ratio, 0.52 (95% CI, 0.44 - 0.61)
P<0.001
0.00
0 1 2 3 4 5 6 7 8 9
NEJM 2006;354:1464
Days


Relation Between Bleeding and Mortality in
OASIS-5
OASIS-5
Mortality: Day 30
0,04
HR 0.83
95% CI 0.71-0.97 Enoxaparin
P = 0.022
0,03
Cumulative Hazard

Fondaparinux

0,02

0,01

0
0 3 6 9 12 15 18 21 24 27 30
Days
NEJM 2006;354:1464


OASIS 5 Trial
Death through day 180
0.08
Fondaparinux
Enoxaparin
0.06
Cumulative Hazard

0.04

0.02 Hazard ratio, 0.83 Hazard ratio, 0.89
(95% CI, 0.71 – 0.97) (95% CI, 0.80 - 1.00)
P=0.02 P=0.05
0.00
0 30 60 90 120 150 180
Days
NEJM 2006;354:1464


Relation Between Bleeding and Mortality in
OASIS-5
OASIS-5
Mortality at Days 30/180 in Patients with Major Bleeds
0,2

Maj Bleed 9 days
0,15
Cumulative Hazard

0,1

No Maj Bleed 9 days
0,05

0
0 30 60 90 120 150 180
Days
NEJM 2006;354:1464


A New Concept is Born
New Concept Born
1. Bleeding carries a high risk of death, MI and stroke
2. Rate of major bleeding is as high as the rate of death at
the acute phase of NSTE-ACS
3. Prevention of bleeding is equally as important as
prevention of ischemic events and results in a
significant risk reduction for death, MI and stroke
4. Risk stratification for bleeding should be part of the
decision making process


Acuity Trial
15
Net clinical outcome composite end-point
end-point
Cumulative events percent

10

5
Estimate P
UFH/Enoxaparin + IIb/IIIa (N=4603) 11.7% (log rank)

Bivalirudin + IIb/IIIa (N=4604) 11.8% 0.89
Bivalirudin alone (N=4612) 10.1% 0.014

0
0 5 10 15 20 25 30 35

NEJM 2006;355:2203 Days from randomization


Acuity – Primary Endpoint Measures
UFH/Enoxaparin + GPI vs. Bivalirudin Alone

Primary Bival UFH/Enox RR (95% CI) P value
endpoint Risk Ratio ± 95% CI alone + IIb/IIIa (non inferior)
(superior)
0
Net clinical < 0.001
10.1 % 11.7 % 0.86 (0.77-0.97)

Upper boundary non-inferiority
outcome 0.015

Ischemic 0.02
7.8 % 7.3 % 1.08 (0.93-1.24)
composite 0.32

Major < 0.001
3.0 % 5.7 % 0.53 (0.43-0.65)
bleeding < 0.001
0 Bivalirudin
1 UFH/Enox + 2
alone better IIb/IIIa better

NEJM 2006;355:2203


Randomized trials of UFH/LMWH (dark bars ) vs Control
( open bars)

Theroux ’88 243

0
Cohen ’90 69 0 0
0
RISC ’90 399 0

0
Cohen ’94 214

Holdright ’94 285

0
Gurfinkel ’95 143

FRISC ’96 1506

All 2859
Heparin+ Ctrl+ Heparin+ Ctrl+ Heparin+ Ctrl+
2 2
0% 20% 40% 0.25 0.5 1 2 1 10 10 ∞ 10 10 1 0% 3% 6% 0.1 0.5 1 2 10
CI CI
4.7% vs 7.4% 0.55 (0.39-0.77) 31 (23-62) 1.1% vs 0.5% 2.3 (0.97-5.4)


Randomized trials
Enoxaparin (dark bars) vs UFH (open bars)
Size Death or MI at 30 days Major bleeds

ESSENCE ’97 3171

TIMI-11B ’99 3910

ACUTE-II ’02 525

INTERACT ’03 746

A to Z ’04 3620

SYNERGY ’04 9974

All 21946
LMWH+ UFH+ LMWH+ UFH+ LMWH+ UFH+
2 2
0% 10% 20% 0.5 1 2 1 10 10 ∞ 10 10 1 0% 5% 10% 0.1 0.5 1 2 10
CI CI
10.1% vs 11.0% 0.91 (0.83-0.99) 113 (61-1438) 3.9% vs 3.7% 1.1 (0.96-1.3)


Randomized trials
Direct thrombin inhibitors (DTIs) (dark bars) vs UFH/LMWH (open bars)
(DTIs)


GUSTO-2B ’95 12142

OASIS pilot ’97 909

OASIS ’99 10141

Klootwijk ’99 300

ACUITY ’06 9207

All 32699
DTI+ UFH+ DTI+ UFH+ DTI+ UFH+
2 2
0% 10% 20% 0.5 1 2 1 10 10 ∞ 10 10 1 0% 3% 6% 0.1 0.5 1 2 10
CI CI
7.7% vs 8.3% 0.93 (0.85-1.0) 176 (89-∞) 2.3% vs 2.3% 1.0 (0.89-1.2)


Recommendations for Anticoagulation (1)

• Anticoagulation is recommended for all patients in addition
to antiplatelet therapy (I-A).

• Anticoagulation should be selected according to the risk of
both ischaemic and bleeding events (I-B). Several
anticoagulants are available, namely UFH, LMWH,
fondaparinux, bivalirudin. The choice depends on the initial
strategy, urgent invasive, early invasive, or conservative
(I-B) (see section Management Strategy).

• In an urgent invasive strategy UFH (I-C), or enoxaparin (IIa-
B) or bivalirudin (I-B) should be immediately started.


• In an non-urgent situation, as long as decision between
early invasive or conservative strategy is pending :

– Fondaparinux is recommended on the basis of the most
favorable efficacy/safety profile. (I-A)

– Enoxaparin with a less favourable efficacy/safety profile than
fondaparinux should be used only if the bleeding risk is low (IIa-
B)

– As efficacy/safety profile of LMWH (other than enoxaparin) or
UFH relative to fondaparinux is unknown; these anticoagulants
cannot be recommended over fondaparinux (IIa-B)


• At PCI procedures the initial anticoagulant should be
maintained also during the procedure regardless whether
this treatment is UFH (I-C), enoxaparin (IIa-B) or
bivalirudin (I-B), while addititional UFH in standard dose
(50-100 IU/kg bolus) is necessary in case of fondaparinux
(IIa-C).

• Anticoagulation can be stopped within 24 hours after
invasive procedure (IIa-C). In a conservative strategy,
fondaparinux, enoxaparin or other LMWH may be
maintained up to hospital discharge (I-B).


Treatment
------
Anti-platelet agents
Anti-platelet


Anti-Platelet Treatment
Anti-Platelet
Pharmacological Treatment

• Loading dose 600mg vs 300mg clopidogrel : unsettled
issue
• New ADP receptor antagonists under development
(TRITON, PLATO, CHAMPION: ongoing studies)
• GP IIb/IIIa inhibitors
– Upstream or deferred
– ACUITY Timing – No unequivocal results


Four randomised trials of aspirin (dark bars) vs
control (open bars)


VA ’83 1266

Cairns ’85 555

Theroux ’88 479

RISC ’90 796 0

All 3096
Aspirin+ Ctrl+ Aspirin+ Ctrl+ Aspirin+ Ctrl+
2 2
0% 10% 20% 0.25 0.5 1 2 1 10 10 ∞ 10 10 1 0% 3% 6% 0.1 0.5 1 2 10
CI CI
6.2% vs 12.2% 0.47 (0.37-0.61) 17 (14-23) 1.2% vs 0.9% 1.4 (0.68-2.7)


CURE Trial
Early and late effects of Clopidogrel

0-30 days 31 days to 12 months
1.00 1.00

0.98 0.98
Proportion event free

Clopidogrel

Placebo Clopidogrel
0.96 0.96
Placebo

0.94 0.94

0.92 0.92
RR: 0.79 (0.67-092) RR: 0.82 (0.70-095)
p=0.003 P=0.009
0.90 0.90
0 1 2 3 4 1 4 6 8 10 12
NEJM 2001;345:494 Days Months
Circulation 2003;107:966


CURE Trial
Bleeding Within 7 Days After CABG Surgery

Drug stopped > 5 days prior to CABG
P C
OR and 95% CI
0.89
Life threatening 4.2 3.7 0.47 1.69

0.14 0.80
Other major 1.1 0.7 2.48

0.83
Life threatening or major 5.3 4.4 0.46 1.48

0.72
TIMI major 2.4 1.8 0.29 1.78

0.84
GUSTO severe/life-threatening 2.9 2.4 0.38 1.8

0 Placebo more 1 Clopidogrel more 3


Recommendations for Oral Antiplatelet Drugs (1)
• Aspirin is recommended for all patients presenting with
NSTE-ACS without contraindication at an initial loading
dose of 160 - 325mg (non-enteric) (I-A), and at a
maintenance dose of 75 to 100mg long-term (I-A).

• For all patients, immediate 300mg loading dose of
clopidogrel is recommended, followed by 75mg
clopidogrel daily (I-A). Clopidogrel should be maintained
for 12 months unless there is an excessive risk of
bleeding (I-A).

• For all patients with contraindication to aspirin,
clopidogrel should be given instead (I-B).


Recommendations for Oral Antiplatelet Drugs (2)

• In patients considered for an invasive
procedure/PCI, a loading dose of 600mg of
clopidogrel may be used to achieve more rapid
inhibition of platelet function (IIa-B).

• In patients pretreated with clopidogrel who need
to undergo CABG, surgery should be postponed
for 5 days for clopidogrel withdrawal if clinically
feasible (IIa-C).


Randomised trials of GP IIb/IIIa inhibitors (dark bars) vs
control (open bars )

PRISM ’98 3232

PRISM-PLUS 1915
’98
PARAGON-A 2282
’98
PURSUIT ’98 10948

GUSTO-IV ’01 7800

PARAGON-B 5225
’02

All 31402
GPIIb/IIIa+ Ctrl+ GPIIb/IIIa+ Ctrl+ GPIIb/IIIa+ Ctrl+
2 2
0% 10% 20% 0.5 1 2 1 10 10 ∞ 10 10 1 0% 2.5% 5% 0.1 0.5 1 2 10
CI CI
10.8% vs 11.8% 0.91 (0.85-0.98) 111 (63-549) 1.6% vs 1.0% 1.6 (1.3-2.0)


ACUITY Timing - Primary Endpoint Measures
Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

Primary Upstream Deferred RR (95% CI) P value
endpoint Risk Ratio ± 95% CI IIb/IIIa IIb/IIIa (non inferior)
(superior)
0
11.7 % 11.7 % 1.00 (0.89-1.11)

outcome 0.93
Net clinical <0.001
11.7% 11.7% 1.00 (0.89-1.11)
Ischemicoutcome 0.93
0.06
7.1 % 7.9 % 1.12 (0.97-1.29)
composite 0.13
Ischemic 0.06
composite 7.1% 7.9% 1.12 (0.97-1.29)
Major
0.80 (0.67-0.95) <0.13
0.001
6.1 % 4.9 %
bleeding 0.01
Major bleeding <0.001
6.1% 4.9% 0.80 (0.67-0.95)
0 Deferred
1 Routine
2 0.01
PCI GPI Upstream GPI
better better
JAMA 2007;297:591
JAMA 2007; 297:591


Recommendations for GP IIb/IIIa Inhibitors (1)
• In patients at intermediate to high risk, particularly
patients with elevated troponins, ST-depression, or
diabetes, either eptifibatide or tirofiban for initial early
treatment are recommended in addition to oral
antiplatelet agents (IIa-A).

• The choice of combination of antiplatelet agents and
anticoagulants should be made in relation to risk of
ischaemic and bleeding events. (I-B)

• Patients who received initial treatment with eptifibatide or
tirofiban prior to angiography, should be maintained on
the same drug during and after PCI (IIa-B)


Recommendations for GP IIb/IIIa Inhibitors (2)

• In high risk patients not pretreated with GP IIb/IIIa inhibitors and
proceeding to PCI, abciximab is recommended immediately
following angiography. (I-A) The use of eptifibatide or tirofiban in
this setting is less well established (IIa-B).

• GP IIb/IIIa inhibitors must be combined with an anticoagulant (I-A).

• Bivalirudin may be used as an alternative to GP IIb/IIIa inhibitors
plus UFH/LMWH. (IIa-B)

• When anatomy is known and PCI planned to be performed within
24 hours with GP IIb/IIIa inhibitors, most secure evidence is for
abciximab (IIa-B)


Resistance to Antiplatelet Agents &
Drug interactions


Recommendations for Resistance to
Antiplatelet Treatment/Drugs Interactions
• Routine assessment of platelet aggregation inhibition in
patients submitted to either aspirin or clopidogrel therapy,
or both, is not recommended (IIb-C).

• NSAID (selective COX 2 inhibitors and non-selective NSAID)
should not be administered in combination with either
aspirin or clopidogrel (III-C).

• Clopidogrel can be administered with all statins (I-B).

• The triple association of aspirin, clopidogrel and VKA
should only be given if compelling indication exists, in
which case, the lowest efficacious INR and shortest duration
for the triple association should be targeted (IIa-C).


Withdrawal of antiplatelet agents


Recommendations for Withdrawal of Antiplatelet
Treatment
• Temporary interruption of dual antiplatelet therapy (aspirin
and clopidogrel) within the first 12 months after the initial
episode is discouraged (I-C).

• Temporary interruption for major or life-threatening bleeding
or for surgical procedures where even minor bleeding may
result in severe consequences (brain or spinal surgery) is
mandatory (IIa-C).

• Prolonged or permanent withdrawal of aspirin, clopidogrel
or both is discouraged unless clinically indicated.
Consideration should be given to the risk of recurrence of
ischaemic events which depends (among other factors), on
initial risk, on presence and type of stent implanted, and on
time window between proposed withdrawal and index event
and/or revascularisation (I-C).

Clinical Use of Antithrombotic Therapy.
Oral Antiplatelet Therapy
• Aspirin initial dose: 160–325 mg nonenteric formulation, followed by 75–100mg daily
Clopidogrel 75 mg/d after a loading dose of 300mg (600mg when rapid onset of action is wanted)

Anticoagulants
• Fondaparinux* 2.5mg subcutaneously daily
• Enoxaparin* 1mg/kg subcutaneously every 12 h
• Dalteparin* 120 IU/kg every 12 h
• Nadroparin* 86 IU/kg every 12 h
• UFH intravenous Bolus 60–70 U/kg (maximum 5000 IU) followed by infusion of 12–15 IU/kg/h (maximum
1000 U/h) titrated to aPTT 1.5–2.5 times control
• Bivalirudin* intravenous bolus of 0.1 mg/kg and infusion of 0.25 mg/kg/hr. Additional intravenous bolus
0.5 mg/kg and infusion increased to 1.75 mg/kg/hour before PCI
GP IIb/IIIa inhibition*
• Abciximab 0.25 mg/kg intravenous bolus followed by infusion of 0.125 µg/kg/min (maximum 10 µg/min)
for 12 to 24 h
• Eptifibatide 180 µg/kg intravenous bolus (second bolus after 10 min for PCI) followed by infusion of 2.0
µg/kg/min for 72 to 96 h
• Tirofiban 0.4 µg/kg/min intravenously for 30 minutes followed by infusion of 0.10 µg/kg/min for 48 to 96 h.
A high dose regimen (bolus 25µg/kg + 0.15µg/kg/min infusion for 18 hours) is tested in clinical trials.


Treatment
------
Coronary revascularisation


Invasive vs. Conservative Strategies
1. New data coming from long-term follow-up of RITA-3,
FRISC-2 and Mehta meta-analysis show significant risk
reduction for death and death & MI at long-term follow-up
2. Early hazard shown in ICTUS trial (excess of death & MI
observed within 1st month after revascularisation in
immediate invasive group)
3. Early hazard shown in Mehta meta-analysis

ICTUS Lancet 2007;369:827 FRISC 2 Lancet 2000;356:9-16
RITA-3 Lancet 2005;366:914 Mehta JAMA 2005:293:2908


Invasive vs Conservative Strategies
Death, MI, Rehospitalization for ACS
25

RITA-3 Conservative 20.0 %
20
Cumulative percent

15

Intervention 16.6 %
10

Odds Ratio 0.78
5 95% CI 0.61-0.99
P = 0.044

0
0 1 2 3 4 5
Follow-up time (years)
Lancet 2005;366:914


Invasive vs Conservative Strategies
Death, MI, Rehospitalization for ACS
30

ICTUS
Early invasive 22.7
20 21.2
Percent

Selective invasive

10
RR 1.07
95% CI 0.87-1.33
P = 0.33

0
100 200 300 400
Time (days)
Lancet 2007;369:827


Relative Mortality Benefit with the Revascularisation vs Gradient in Rates
of Revascularisation Between both Randomisation Arms

60
GUSTO IV-ACS
Invasive vs conservative strategies percent

Databank analysis
50
FRISC II
40
Relative mortality benefit:

30
20 TIMI IIIb TACTIS
-TIMI 18
10
RITA 3
0
10 20 30 40 50 60 70 80 90
ICTUS
-10
Difference in rate of revascularization: Invasive - Conservative strategies percent
-20
-30
VANQWISH
-40

Eur Heart J 2004; 25: 1471-1472


Meta-Analysis: Invasive Therapy
Meta-Analysis:

Bavry et al. JACC 2006


Timing of Intervention

1. Few studies have shown superiority of very early intervention vs
deferred intervention.
• ISAR-COOL (small sample size) JAMA 2003;290:1593

2. Many trials, registries and meta-analysis have shown early hazard
with early intervention vs deferred intervention
• ICTUS trial NEJM 2005;353:1095

• Mehta Meta-analysis JAMA 2005;293:2908
• GRACE & CRUSADE registries Heart 2007;93:177
Arch Intern Med 2006;166:2027
3. Timing of intervention recommended on the basis of risk
stratification


Pharmacological Environment of PCI
1. Loading dose of clopidogrel
• 300 vs 600mg
• pre-treatment vs no pre-treatment
2. Anti-coagulants in the cathlab
• UFH
• Bivalirudin
• Enoxaparin if started in the ward (no cross-over)
• Fondaparinux cannot be used stand-alone
3. Triple antiplatelet therapy
• Recommended on the basis of ISAR-REACT-2
JAMA 2006;295:1531


Glycoprotein IIb/IIIa inhibitors: II B or Not II B?
• ISAR-REACT 2 : triple antiplatelet Rx superior to double
antiplatelet Rx in moderate to high risk patients submitted to PCI
• ACUITY* better net clinical outcome (death+MI+urgent
revasc+bleeding) with bivalirudin alone vs UFH/LMWH +
GPIIb/IIIa inhibitors
• BUT, trends towards higher ischemic risk with bivalirudin alone
(significant in patients not pretreated with clopidogrel)
• Beneficial effect in ACUITY* entirely driven by risk reduction for
bleeding (no impact on outcome)
• Liberal non-inferiority margin
• No impact of bleeding risk reduction on short and long term
outcome

*Randomised but not double blind study


Double vs Triple Antiplatelet Therapy in the Cathlab – ISAR-REACT-2
ISAR-REACT-2

Primary End Point
15

Placebo 11.9
Death, MI, UTVR percent

10
Abciximab 8.9

5
RR 0.75
95% CI 0.58-0.97

0
0 5 10 15 20 25 30
Days after randomization
JAMA 2006;295:1531


Double vs Triple Antiplatelet Therapy in the Cathlab – ISAR-REACT-2
ISAR-REACT-2

Troponin Level and Benefit with Abciximab
20

Troponin-Positive RR=0.71 (0.54 - 0.98)
Death, MI, UTVR percent

15

10
Abciximab vs Placebo

Troponin-Negative RR=0.99 (0.56 - 1.78)
5

0
0 5 10 15 20 25 30
Days after randomization
JAMA 2006;295:1531


Glycoprotein IIb/IIIa inhibitors: II B or Not II B?
• ISAR-REACT 2 : triple antiplatelet Rx superior to double
antiplatelet Rx in moderate to high risk patients submitted to PCI
• ACUITY* better net clinical outcome (death+MI+urgent
revasc+bleeding) with bivalirudin alone vs UFH/LMWH +
GPIIb/IIIa inhibitors
• BUT, trends towards higher ischemic risk with bivalirudin alone
(significant in patients not pretreated with clopidogrel)
• Beneficial effect in ACUITY* entirely driven by risk reduction for
bleeding (no impact on outcome)
• Wide non-inferiority margin
• No impact of bleeding risk reduction on short and long term
outcome
• ACUITY Timing – Upstream vs deferred IIB/IIIA inhibitors
equivocal results *Randomised but not double blind study


ACUITY Timing - Primary Endpoint Measures
Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

Primary Upstream Deferred RR (95% CI) P value
endpoint Risk Ratio ± 95% CI IIb/IIIa IIb/IIIa (non inferior)
(superior)
0
11.7 % 11.7 % 1.00 (0.89-1.11)

outcome 0.93
Net clinical <0.001
11.7% 11.7% 1.00 (0.89-1.11)
Ischemicoutcome 0.93
0.06
7.1 % 7.9 % 1.12 (0.97-1.29)
composite 0.13
Ischemic 0.06
composite 7.1% 7.9% 1.12 (0.97-1.29)
Major
0.80 (0.67-0.95) <0.13
0.001
6.1 % 4.9 %
bleeding 0.01
Major bleeding <0.001
6.1% 4.9% 0.80 (0.67-0.95)
0 Deferred
1 Routine
2 0.01
PCI GPI Upstream GPI
better better
JAMA 2007;297:591
JAMA 2007; 297:591


Randomised trials comparing early invasive (dark bars) vs
conservative strategy (open bars)
Size Death or MI at 1 year

FRISC-II ’00 2453

TRUCS ’00 148

TIMI-18 ’01 2220

VINO ’02 131

RITA-3 ’02 1810

ICTUS ’05 1200

All 7962
Invasive+ Cons+ Invasive+ Cons+
2 2
0% 10% 20% 30% 0.25 0.5 1 2 1 10 10 ∞ 10 10 1
Incidence Odds ratio and 95% NNT and 95% CI
CI
9.5% vs 11.1% 0.84 (0.73-0.97) 63 (36-368)


Recommendations for invasive evaluation
and revascularisation (1)
• Urgent coronary angiography is recommended in patients with
refractory or recurrent angina associated with dynamic ST
deviation, heart failure, life threatening arrhythmias or
haemodynamic instability (I - C).

• Early (< 72 hours) coronary angiography followed by
revascularisation (PCI or CABG) in patients with intermediate to
high-risk features is recommended (I - A).

• Routine invasive evaluation of patients without intermediate to
high risk features is not recommended (III-C), but non-invasive
assessment of inducible ischaemia is advised (I - C).


Recommendations for invasive evaluation
and revascularisation (2)
• PCI of non-significant lesions by angiography is not
recommended (III - C).

• After critical evaluation of the risk to benefit ratio,
and depending on known co-morbidities and
potential need for non-cardiac surgery in the
short/medium term (e.g. planned intervention or
other conditions) requiring temporary withdrawal of
dual antiplatelet therapy, consideration should be
given to the type of stent to be implanted (BMS or
DES) (I-C).


NSTE-ACS – Summary of Treatment Approaches
NSTE-ACS

Size Death or MI Major bleeds

Aspirin vs Ctrl 3096 0.47 17 1.4

Heparin vs Ctrl 2858 0.55 31 2.3

GP IIb/IIIa vs 31402 0.91 11 1.6
Ctrl 1

LMWH vs UFH 21946 0.91 11 1.1
3

DTI vs UFH 24701 0.88 10 1.3
2

Invasive vs 7962 0.84 63
Cons
Exp+ Ctrl+ Exp+ Ctrl+ Exp+ Ctrl+
2 2
0% 5% 10% 15% 0.5 1 2 1 10 10 ∞ 10 10 1 0% 2.5% 5% 0.1 0.5 1 2 10
CI CI


Treatment
Long-term management &
Long-term
rehabilitation


Recommendations for Long Term Drug
Therapy (1)
Lipid lowering therapy

• Statins are recommended for all NSTE-ACS patients
(in the absence of contraindications), irrespective of
cholesterol levels, initiated early (within 1-4 days)
after admission, in the aim of achieving LDLc levels
<100mg/dL (< 2.6 mmol/L) (I-B).

• Intensive lipid-lowering therapy with target LDLc
levels <70 mg/dL (< 1.81 mmol/L) initiated within 10
days after admission, is advisable (IIa-B).


Therapy (2)
Beta-blockers
• Beta-blockers should be given to all patients with reduced
LV function (I-A).

ACE Inhibitors
• ACE inhibitors are indicated long-term in all patients with
LVEF ≤40% and in patients with diabetes, hypertension or
CKD, unless contraindicated (I-A).

• ACE inhibitors should be considered for all other patients to
prevent recurrence of ischaemic events (IIa-B). Agents and
doses of proven efficacy are recommended (IIa-C).


Therapy (3)
Angiotensin-Receptor Blockers
• Angiotensin-Receptor Blockers should be
considered in patients who are intolerant to ACE
inhibitors and/ or who have heart failure or MI with
LVEF <40% (I-B).

Aldosterone receptor antagonists:
• Aldosterone blockade should be considered in
patients after MI who are already treated with ACE
inhibitors and beta-blockers, and who have a LVEF
<40% and either diabetes or heart failure, without
significant renal dysfunction or hyperkaleamia (I-B).


Recommendations for Rehabilitation and
Return to Physical Activity
• After NSTE-ACS, assessment of functional capacity is
recommended (I-C).

• Every patient after NSTE-ACS should undergo an ECG-
guided exercise test (if technically feasible), or an equivalent
non-invasive test for ischemia, within 4-7 weeks after
discharge (IIa-C)

• Based on cardiovascular status and on the results of
functional physical capacity assessment, patients should be
informed about the timing of resumption and the
recommended level of physical activity, including leisure,
work and sexual activities (I-C).


Complications and their management
Bleeding
Thrombocytopenia


TIMI and GUSTO Bleeding Definitions
TIMI Bleeding Classification
Major Intracranial haemorrhage or clinically overt bleeding (including
imaging) ≥ 5 g/dL decrease in the haemoglobin
concentration
Minor Clinically overt bleeding (including imaging) with 3 to < 5 g/dL
decrease in the haemoglobin concentration
Minimal Clinically overt bleeding (including imaging) with a < 3 g/dL
decrease in the haemoglobin concentration
GUSTO Bleeding Classification
Severe or life threatening Either intracranial haemorrhage or bleeding that causes
haemodynamic compromise and requires intervention
Moderate Bleeding that requires blood transfusion but does not result in
haemodynamic compromise
Mild Bleeding that does not meet criteria for either severe or
moderate bleeding


Hospital Outcome by
Final Diagnosis
10
STEMI (13,862)
8 NSTEMI (11,316)
8 UA (12,509)
Patients percent

6
5

4
4
3 3

2
2 1,3
0,9
0,5

0
Death Major Bleed Stroke
Am J Cardiol 2002; 90: 358


Multivariate Model for Major Bleeding in Patients with
NSTE-ACS
NSTE-ACS
Variable Adjusted OR 95%CI P-value

Age (per 10-year increase) 1.22 1.10-1.35 0.0002
Female sex 1.36 1.07-1.73 0.0116
History of renal insufficiency 1.53 1.13-2.08 0.0062
History of bleeding 2.18 1.14-4.08 0.014
Mean arterial pressure (per 20mmHg decrease) 1.14 1.02-1.27 0.019
Diuretics 1.91 1.46-2.49 <0.0001
LMWH only 0.68 0.50-0.92 0.012
LMWH and UFH* 0.72 0.52-0.98 0.035
GP IIb/IIIa inhibitors only 1.86 1.43-2.43 <0.0001
Thrombolytics and GP IIb/IIIa inhibitors 4.19 1.68-10.4 0.002
IV inotropic agents 1.88 1.35-2.62 0.0002
Right-heart catheterisation 2.01 1.38-2.91 0.0003
Moscucci. Eur Heart J 2003;24:1815


Multivariate Model for Major Bleeding in Patients
with NSTEMI

Variable Adjusted OR P-value
Age (per 10y increase) 1.22 0.0002
Female sex 1.36 0.0116
History of renal insufficiency 1.53 0.0062
History of bleeding 2.18 0.014

GPIIb/IIIa blockers 1.86 <0.001
Percutaneous interventions 2.24 <0.0001
Moscucci. Eur Heart J 2003;24:1815


In-Hospital Death Rates in Patients According
In-Hospital
to Major Bleeding
50
No Major Bleed
Major Bleed
40
Patients percent

30 ** p < 0.001
**
** ** 22,8

20 18,6 **
16,1 15,3

10 7
5,1 5,3
3

0
Overall STEMI NSTEMI UA

Moscucci M et al. Eur Heart J 2003;24:1815-23.
2003;24:1815-


30 Day Death According to Bleeding
OASIS Registry, OASIS-2, CURE
OASIS-2,
14

12
Bleeding
Cumulative Events, percent

10

8
5-fold ↑ risk
6

4
No Bleeding
2

0
0 5 10 15 20 25 30
Days
Eikelboom Circulation 2006;114: 774 - 782


Increased Mortality at Days 30/180 in Patients
with Major Bleeds by Day 9 in OASIS 5
0,2

May Bleed 9 days
0,15
Cumulative Hazard

0,1

No May Bleed 9 days
0,05

Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44)
0
0 30 60 90 120 150 180
Days
Budaj et al. JACC 2006;abstract 972-224


Dosage of Drugs and Major Bleeding
Dose Group
35
Underdosed
30 Recommended
Mild Excess
Major Bleeding percent

25 Major Excess

20
178

15

10
714
237 1955
2073
5 2063 922
2074 2327
3998 5879
0
UFH LMWH GP IIb/IIIa
Treatment
Alexander JAMA 2004;294:3108


30 Day Survival by Transfusion Group
GUSTO IIb, PURSUIT, PARAGON B
IIb,
( n=24,000 10% transfused )
1

0,98 No Transfusion
Survival RAtes

0,96

0,94
Transfusion
0,92

0,9
0 5 10 15 20 25 30 35
Days
Rao SV, JAMA 2004;292:1555


Recommendations for Bleeding
Complications (1)
• Assessment of bleeding risk is an important component of
the decision making process. Bleeding risk is increased with
higher or excessive doses of anti-thrombotic agents, length
of treatment, combinations of several anti-thrombotic drugs,
switch between different anticoagulant drugs, as well as
with older age, reduced renal function, low body weight,
female gender, baseline haemoglobin and invasive
procedures (I-B).

• Bleeding risk should be taken into account when deciding
for a treatment strategy. Drugs, combination of drugs and
non-pharmacological procedures (vascular access) known
to carry a reduced risk of bleeding should be preferred in
patients at high risk of bleeding (I-B)


Recommendations for Bleeding
Complications (2)
• Minor bleeding should preferably be managed without
interruption of active treatments (I-C).

• Major bleeding requires interruption and/or neutralisation
of both anticoagulant and antiplatelet therapy, unless
bleeding can be adequately controlled by specific
haemostatic intervention (I-C).

• Blood transfusion may have deleterious effects on
outcome, and should therefore be considered individually,
but withheld in haemodynamically stable patients with
haematocrit >25% or haemoglobin level > 8g/L (I-C).


Recommendations for Thrombocytopenia
• Significant thrombocytopenia (<100,000/µL or >50% drop in platelet count)
occurring during treatment with GP IIb/IIIa inhibitors and/or heparin (LMWH or
UFH) requires the immediate interruption of these drugs. (I-C)

• Severe thrombocytopenia (<10,000/µL) induced by GP IIb/IIIa inhibitors requires
platelet transfusion with or without fibrinogen supplementation with fresh
frozen plasma or cryoprecipitate in case of bleeding. (I-C)

• Interruption of heparin (UFH or LMWH) is warranted in case of documented or
suspected HIT. In case of thrombotic complications, anticoagulation can be
achieved with DTI (I-C).

• Prevention of HIT can be achieved with use of anticoagulants devoid of risk of
HIT, such as fondaparinux or bivalirudin, or by brief prescription of heparin
(UFH or LMWH) in case these compounds are chosen as anticoagulant (I-B).


Special Conditions & Populations
Elderly
Impact of Gender


Clinical Outcomes for Patients Stratified by Age
(Invasive Vs Conservative Strategies) from TACTICS–TIMI-18 Trial
TACTICS–TIMI-18

Death Nonfatal MI
Management % Management %
Age Group Cons. Inv. OR Age Group Cons. Inv. OR

≤ 55 y 1.3 1.2 0.90 ≤ 55 y 3.4 4.2 1.22

> 55-65 y 2.0 2.2 1.11 > 55-65 y 7.4 5.7 0.75

> 65-75 y 4.8 4.7 0.97 > 65-75 y 7.6 4.7 0.60

> 75 y 10.1 7.9 0.77 > 75 y 13.7 4.3 0.28*

* P = 0.010
0 0.5 1 1.5 2 0 0.5 1 1.5 2
Invasive Conservative Invasive Conservative
better better better better

Am J Cardiol 2003;91:1466


Clinical Outcomes for Patients Stratified by Age
(Invasive Vs Conservative Strategies) from TACTICS–TIMI-18 Trial
TACTICS–TIMI-18

Death or Nonfatal MI Death, MI or Rehospitalization
Management % Management %
Age Group Cons. Inv. OR Age Group Cons. Inv. OR

≤ 55 y 4.8 5.0 1.07 ≤ 55 y 16.4 13.1 0.77

> 55-65 y 9.1 7.6 0.82 > 55-65 y 19.5 18.0 0.90

> 65-75 y 10.3 7.8 0.73 > 65-75 y 18.2 14.9 0.79

> 75 y 21.6 10.8 0.44† > 75 y 30.2 20.1 0.58†
†
†
P = 0.016 P = 0.05
0 0.5 1 1.5 2 0 0.5 1 1.5 2
Invasive Conservative Invasive Conservative
better better better better

Am J Cardiol 2003;91:1466


Recommendations for Special Populations
Elderly
• Elderly patients (>75 years) often have atypical symptoms. Active screening for
NSTE-ACS should be initiated at lower levels of suspicion than among younger
(<75 years) patients (I-C).

• Treatment decisions in the elderly should be tailored according to estimated life
expectancy, patient wishes and co-morbidities to minimize risk and improve
morbidity and mortality outcomes in this frail but high-risk population. (I – C)

• Elderly patients should be considered for routine early invasive strategy, after
careful evaluation of their inherent raised risk of procedure-related
complications, especially during CABG (I – B).

Women
• Women should be evaluated and treated in the same way as men, with special
attention to co-morbidities (I-B).


Diabetes


Treatment Effect on 30-day Mortality Among Diabetic Patients
30-day
with NSTE ACS from Six Randomised Clinical Trials
Trial N Placebo % IIb/IIIa %
Odds Ratio & 95% CI

PURSUIT 2163 p = 0.33 6.1 5.1

PRISM 687 p = 0.07 4.2 1.8

PRISM-PLUS 362 p = 0.17 6.7 3.6

GUSTO IV 1677 p = 0.022 7.8 5.0
p = 0.51
PARAGON A 412 6.2 4.6
p = 0.93
PARAGON B 1157 4.8 4.9

Pooled 6458 p = 0.007 6.2 4.6
0 0.5 1 1.5 2
IIb/IIIa better Placebo better



Recommendations for Diabetes
• Tight glycaemic control to achieve normoglycaemia as soon
as possible is recommended in all diabetic patients with
NSTE-ACS in the acute phase (I-C).

• Insulin infusion may be needed to achieve normoglycaemia
in selected NSTE-ACS patients with high blood glucose
levels at admission (IIa-C)

• Early invasive strategy is recommended for diabetic patients
with NSTE-ACS (I – A).

• Diabetic patients with NSTE-ACS should receive intravenous
GP IIb/IIIa inhibitors as part of the initial medical
management which should be continued through the
completion of PCI (IIa-B).


Anaemia


Recommendations for Anaemia

• Low baseline haemoglobin is an independent marker of the
risk of ischaemic and bleeding events at 30 days. It should
be taken into consideration in assessing initial risk (I-B).

• All necessary measures should be taken during the course
of initial management to avoid worsening of anaemia by
bleeding (I-B).

• Well tolerated anaemia at baseline in patients with NSTE-
ACS should not lead to systematic blood transfusion which
should be considered only in case of compromised
haemodynamic status (I-C).


Chronic Kidney Disease


Stages of CKD, according to the National
Kidney Foundation
Stage Description GFR
(mL/min/1.73m²)
1 Kidney damage with normal or ≥90
increased GFR
2 Kidney damage with mild decrease 60-89
in GFR
3 Moderate decrease in GFR 30-59

4 Severe decrease in GFR 15-29

5 Kidney failure <15 (or dialysis)


In-hospital Mortality or Bleeding According to the Level of CrCl
In-hospital
in Patients Treated with UFH or LMWH
0,2
Estimated probability of in-hospital events

In-hospital mortality UFH
Bleeding UFH
In-hospital Mortality LMWH
0,15
Bleeding LMWH

0,1

0,05

0
30 60 90 120 150 180 210 240 270 300 330
Creatinine clereance (mL / min)
EHJ 2005;26:2285


Outcomes According to Degree of Renal Function
Impairment in NSTE-ACS Patients in GRACE Registry
NSTE-ACS
15
Severe
Moderate
** Normal / minimally impaired

10
**
Patients percent

8,5
7,9
7,3

5,9 6

5 4
3,8
*
1,8
0,9 0,9 0,9
0,4
0
Mortality MI Stroke Major bleeding
Heart 2003;89:1003


Recommendations for the Use of Drugs in Case of CKD
Drug Recommendations in case of CKD
Simvastatin*
Simvastatin* Low renal elimination. In patients with severe renal failure (CrCl <30ml/min), careful with doses >10mg
(CrCl
Ramipril*
Ramipril* Dose adaptation required if CrCl <30ml/min (initial dose 1.25mg daily). Dose must not exceed 5mg per day.
Losartan*
Losartan* Recommended for the treatment of hypertension or renal failure in diabetes type 2 with microalbuminuria 50-
in 50-
100mg per day. Regular monitoring of electrolyte balance and serum creatinine is recommended.
serum
Clopidogrel No information in patients with renal failure
Enoxaparin* In case of severe renal failure (CrCl<30mL/min), either contraindicated or dose adjustment required,
(CrCl<30mL/min),
according to country-specific labelling.
country-
Fondaparinux Contraindicated in severe renal failure (CrCl <30ml/min). However, as much lower risk of bleeding
(CrCl
complications were observed in Oasis-5 with fondaparinux as compared with enoxaparin, even in
Oasis- enoxaparin,
patients with severe renal failure, this drug might be the anticoagulant of choice in this situation.
anticoagulant
Bivalirudin If the CrCl < 30 mL/min, reduction of the infusion rate to 1.0 mg/kg/h should be considered. If a patient is on
mL/min, considered.
haemodialysis, the infusion should be reduced to 0.25 mg/kg/h. No reduction in the bolus dose is
No
needed.
Tirofiban Dose adaptation required in patients with renal failure. 50% of the dose only if CrCl <30ml/min.
Eptifibatide As 50% of eptifibatide is cleared through the kidney in patients with renal failure, precautions must be taken
in patients with impaired renal function (CrCl <50ml/min). The infusion dose should be reduced to
(CrCl
1µg/kg/min in such patients. The dose of the bolus remains unchanged at 180µg/kg. Eptifibatide is
unchanged 180µ
contra-indicated in patients with creatinine clearance <30mL/min.
contra-
Abciximab No specific recommendations for the use of abciximab, or for dose adjustment in case of renal failure. Careful
abciximab,
evaluation of haemorrhagic risk is needed before using the drug in case of renal failure.
Atenolol Half dose recommended for patients with CrCl between 15 and 35ml/min (50mg/day). Quarter dose (25mg/day)
recommended if CrCl <15ml/min.


Recommendations for Patients with CKD (1)
• CrCl and/or GFR should be calculated for every patient hospitalised
for NSTE-ACS (I-B). Elderly people, women and low body weight
patients merit special attention as near normal serum creatinine
levels may be associated with lower than expected CrCl and GFR
levels (I-B).

• Patients with CKD should receive the same first-line treatment as
any other patient, in the absence of contra-indications (I-B).

• In patients with CrCl < 30ml/min or GFR <30ml/min/1.73m², a careful
approach to the use of anticoagulants is recommended, since dose
adjustment is necessary with some, while others are
contraindicated. (I-C)


Recommendations for Patients with CKD (2)
• UFH infusion adjusted according to aPTT is recommended when
CrCl < 30ml/min or GFR <30ml/min/1.73m² (I-C).

• GP IIb/IIIa inhibitors can be used in case of renal failure. Dose
adaptation is needed with eptifibatide and tirofiban. Careful
evaluation of the bleeding risk is recommended for abciximab (I-
B).

• Patients with CKD with CrCl < 60 ml/min are at high risk of
further ischaemic events and therefore should be submitted to
invasive evaluation and revascularisation whenever possible
(IIa-B).

• Appropriate measures are advised to reduce the risk of contrast
induced nephropathy (I-B).

Management Strategy


Diagnosis and risk stratification
1st step: Initial Evaluation STRA
STRA T
Quality of chest pain
Assessment of likelihood of CAD EGY
TEGY
ECG (ST elevation or other ECG abnormalities)

2nd step: Validation & Risk Assessment
Biochemistry
Responsiveness to antianginal treatment
ECG (repeat, continuous monitoring)
Echocardiography, MRI, CT
Risk score

Treatment
3rd step: Invasive Management
Emergent
Early
No/elective
4th step: Revascularisation
5th step: Long-term management

Risk Stratification
1. Features of high risk that mandates urgent
angiography / revascularization
– Refractory angina (e.g. evolving MI without ST abnormalties)
– Recurrent angina despite intense antianginal treatment
associated with ST depression (> 2 mm) or deep negative T
waves.
– Clinical symptoms of heart failure or haemodynamic
instability (“ shock”)
– Life threatening arrhythmias (ventricular fibrillation or
ventricular tachycardia)


Risk Stratification
2 - Features of high risk that mandates early (<72 hours)
angiography / revascularization
– Elevated troponin levels
– Dynamic ST or T wave changes (symptomatic or silent) (> 0.5mm)
– Diabetes mellitus
– Reduced renal function (GFR < 60 ml/min/1.73m²)
– Depressed LVEF < 40%
– Early post MI angina
– PCI within 6 months
– Prior CABG
– Intermediate to high risk according to a risk score


GRACE ACS Risk Model


Risk Stratification
3 - No features of high risk
– No recurrence of chest pain
– No signs of heart failure
– No abnormalities in the initial ECG or a second
ECG (6 to 12 hours)
– No elevation of troponins (arrival and at 6 – 12
hours)


Primary therapeutic measures
Oxygen Insufflation (4 to 8 L/min) if oxygen saturation is < 90%
Nitrates Sublingually or intravenously (caution if systolic blood pressure < 90mmHg)
pressure

Aspirin Initial dose of 160–325mg non-enteric formulation followed by 75–100 mg/d (intravenous
160– non- 75–
administration is acceptable)
Clopidogrel Loading dose of 300mg (or 600mg for rapid onset of action) followed by 75 mg daily
followed

Anticoagulation Choice between differrent options depends on strategy:
• UFH intravenous Bolus 60–70 IU/kg (maximum 5000 IU) followed by infusion of 12–15 IU/kg/h
60– 12–
(IU/h maximum 1000) titrated to aPTT 1.5–2.5 times control
1.5–
• Fondaparinux 2.5 mg/daily subcutaneously
• Enoxaparin 1 mg/kg twice/daily subcutaneously
• Dalteparin 120 IU/kg twice/daily subcutaneously
• Nadroparin 86 IU/kg twice/daily subcutaneously
• Bivalirudin 0.1 mg/kg bolus followed by 0.25 mg/kg/h

Morphine 3 to 5 mg intravenous or subcutaneous, depending on pain severity
severity
Oral betablocker Particularly, if tachycardia or hypertension without sign of heart failure
heart

Atropine 0.5 - 1 mg intravenously, if bradycardia or vagal reaction


Management Strategy
Orientation
• Quality of chest pain and a symptom-oriented physical
examination
• Assessment of the likelihood of CAD (e.g. age, risk
factors, previous MI, CABG, PCI)
• ECG (ST deviation or other ECG abnormalities)

NST-ACS STEMI immediate
No CAD
possible reperfusion

Validation

Management Strategy
Validation
• Routine clinical chemistry, particularly troponins (on presentation and after 6 to 12 hours) and other
markers according to working diagnoses (e.g. D-dimers, BNP, NT-proBNP)
• Repeat, preferably continuous ST segment monitoring (when available)
• Echocardiogram, MRI, CT or nuclear imaging for differential diagnoses (e.g. aortic dissection,
pulmonary embolism),
• Responsiveness to antianginal treatment
• Risk score assessment
• Bleeding risk assessment

Urgent < 120 min Early < 72 hours Elective
Elevated troponin levels No recurrence of chest pain
1- Refractory angina Dynamic ST or T wave changes No signs of heart failure
2-Recurrent angina despite intense Diabetes mellitus
No abnormalities in the initial
antianginal treatment Reduced renal function
associated with ST depression (GFR < 60 ml/min/1.73m²)
ECG or a second ECG (6 to 12
(> 2 mm) or deep negative T Depressed LVEF < 40% hours)
waves. Early post MI angina No elevation of troponins
3-Clinical symptoms of heart failure PCI within 6 months (arrival and at 6 – 12 hours)
or haemodynamic instability Prior CABG
4-Life threatening arrhythmias Intermediate to high risk
(ventricular fibrillation or ( GRACE risk score )
ventricular tachycardia)


1. First Contact 2. Diagnosis/Risk Assessment 3. Invasive Strategy

Persistent or recurrent angina with/ without ST
changes (≥ 2 mm) or deep neg. T resistant to
Other diagnosis urgent
antianginal treatment
Clinical symptoms of heart failure or progressing
haemodynamic instability
Life threatening arrhythmias (VF,VT)

Initial Validation
Elevated troponin levels
Evaluation Response to antianginal treatment
Dynamic ST or T wave changes
(symptomatic or silent)
Routine biochemistry, including
Quality of chest pain Diabetes mellitus
troponins (on presentation and after
Symptom-oriented
physical examination
ACS 6 to 12 hours), poss. special early Renal dysfunction (GFR<60ml/min/1.73m² )
Reduced left ventricular function (EF <40%)
markers (e.g. D-dimers, BNP/ NT-
Likelihood of CAD possible proBNP) (< 72 hrs) Early post-infarction angina
Electrocardiogram (ST- Prior MI
Repeat or continuous ST segment
elevation or other
monitoring PCI within 6 months
abnormalities)
Risk score assessment Prior CABG
Bleeding risk assessment Intermediate to high GRACE risk score
Differential diagnosis exclusion:
echocardiogram, CT, MRI, nuclear
imaging.

No recurrence of chest pain

STEMI no/
No signs of heart failure
No new ECG changes

elective (Arrival and at 6 – 12 hours)
No elevation of troponins
(Arrival and at 6 – 12 hours)


Performance Measures


Recommendations for Performance
Measures
• Development of regional and/or national
programmes to systematically measure
performance indicators and provide feedback
to individual hospitals is strongly
encouraged (I-C).


Guidelines nste-acs-slides

More Related Content

Similar to Guidelines nste-acs-slides

More from Loveis1able Khumpuangdee

Recently uploaded

Guidelines nste-acs-slides