Les Syndromes Coronariens Aigus : diagnostic, mise au point, therapeutique

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Les Syndromes Coronariens Aigus diagnostic,
mise au point, therapeutique

• Victor Legrand
• CHU de Liège

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Acute Coronary Syndromes (ACS)

• Patients with a presumed STEMI
• Ongoing chest discomfort
• Persistent ST-segment elevation or new LBBB

This generally reflects acute total coronary
occlusion

• Patients with chest pain without persistent ST
  segment elevation
• Permanent or transient ST-segment depression
• T wave inversion
• Flat T waves
• Pseudo normalization of T
• Non-specific ECG changes and even normal ECG

This generally reflects transient coronary
occlusion or small coronary vessel obstruction
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Clinical presentation angina pectoris
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ACS ECG changes
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ACS Angiographic pattern
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ACS Pathophysiology
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ACS Pathophysiology
Markers of myocardial damage LV dysfunction
Inflammatory markers
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ACS Biological Markers

• Markers of Inflammation
• usCRP nl lt 3
• non specific, neither diagnostic for ACS
• MPO, Il6,
• under investigation, same remarks as for us CRP

• Markers of myonecrosis LV dysfunction
• Tn it , CKmb
• High sensitivity specificity
• Important diagnostic tool
• Pro BNP
• High sensitivity for LV dysfunction
• Important prognostic tool

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Epidemiology
Mortality non fatal MI at 6 mths F-U 13
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ACS survival by diagnosis at admission
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ACS without persistent ST-segment elevation

• Clinical presentation
• Wide variety of symptoms
• Prolonged (gt 20 min.) angina pain at rest (80)
• New onset (de novo) severe (CCSC 3) or recent
  destabilization ofpreviously stable angina (20)
• Atypical presentations are not uncommon
  particularly in younger(25-40 y.o), older (gt75),
  diabetics women

• Physical examination Most often normal
• Purpose
• To exclude non-cardiac causes of chest pain,
  non-ischaemic cardiacdisorders, potential
  precipitating factors
• To detect hemodynamic instability or LV
  dysfunction

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Troponins,CKmb or myoglobin ?

• Troponins
• Highly specific of any cardiac damage (not only
  of ischemic origin)
• Release pattern similar to CKmb, but much lower
  clearance
• Kidney clearance (possible interference in CRF)
• False positive with some kits using murine a/g

• CKmb
• Somewhat less specific (smooth muscle release)
• More background for data interpretation
• No advantage over Tn for diagnosing AMI
• Less sensitive for nonSTEMI and UAP
• Myoglobin
• Earliest enzymatic release, but fastest clearance
• Not usefull in UAP/nonSTEMI
• Potential interest in early diagnosis of AMI

! Only 2 markers can be choosen
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Incidence of Death from Cardiac Cause _at_ 2
years Influence of ST depression Tn levels _at_ 24
hours
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Incidence of Death from Cardiac Cause _at_ 2
years Influence of CRP Tn levels _at_ 24 hours
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BNP and Event Rate in ACS
The Incidence of Death, New or Progressive CHF,
and New or Recurrent MI at 30 Days and 10 Months
among Patients with BNP Levels above or at or
below the Prespecified Threshold of 80 pg per
Millilitre.
de Lemos JA et al. N Engl J Med 20013451014-21
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Mortality and number of elevated Cardiac Markers
TACTICS-TIMI 18 (B)
OPUS-TIMI 16 (A)
Sabatine MS et al. Circulation 20021051760-1763
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TIMI Risk Score For UA/NSTEMI 7 Independent
Predictors
OR (95 CI) P

• Age gt 65 y
• gt 3 CAD Risk Factors
• Prior Stenosis gt 50
• ST deviation
• gt 2 Anginal events lt 24 h
• ASA in last 7 days
• Elev Cardiac Markers

1.75 (1.35-2.25) lt 0.001 1.54 (1.16-2.06)
0.003 1.70 (1.30-2.21) lt 0.001
1.51 (1.13-2.02) 0.005 1.53 (1.20-1.96)
0.001 1.74 (1.17-2.59)
0.006 1.56 (1.21-1.99) lt 0.001
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Prediction of Death/MI (Day 14) TIMI 11B
C Statistic 0.63 c2 trend P lt0.001
D/MI
Number of Risk Factors
Antman et al JAMA 284 835, 2000
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Markers of thrombotic riskAcute risk

• Recurrence of chest pain
• ST-segment depression
• Dynamic ST-segment changes
• Elevated level of cardiac troponins
• Thrombus on angiography

Evidence level A
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Markers of underlying disease Long-term risk

• Clinical markers
• Age
• History of prior MI
• History of severe angina
• Diabetes

• Biological markers
• Level of C-reactive protein
• Level of (pro)BNP

• Angiographic markers
• LV dysfunction
• Extent of coronary artery disease

Evidence level A
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Therapeutic Management of UAP / non STEMI
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Acute Coronary Syndromes Without ST ?Evidence
for Aspirin
Cairns Lewis Theroux Wallentin Pooled
0
1.0
2.0
Favors Placebo
Favors Aspirin
Relative Risk Death or MI
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Acute Coronary Syndromes without ST ? Evidence
for Heparin Use (UFH ASA versus ASA)
Relative Risk of Death or MI
Theroux (n 243) RISC (n 399) Cohen (n
69) Cohen (n 214) Holdright (n 185) Gurfinkel
(n 143) Overall (n 1353)
2.66
6.87
P 0.06
0.5
1
1.5
2
0
ASA UFH Better
ASA Better
Oler A, JAMA 1996
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LMWH vs. UFH in Non-ST ?ACSEffect on Death, MI,
Recurrent Ischemia
Trial FRIC (Dalteparin n
1,482) FRAXIS (nadroparin n 2,357) ESSENCE (eno
xaparin n 3,171) TIMI 11B (enoxaparin n
3,910)
?
?
(p 0.032)
?
(p 0.029)
?
.75 1.0 1.5
LMWH Better
UFH Better
Braunwald E, Circulation 2000
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CURE Primary Results

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11.4
Placebo ASA
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9.3
10
8
Clopidogrel ASA
Death, MI, or Stroke
20 RRR P lt 0.001 N 12,562
6
4
2
0
3
6
9
0
12
Months of Follow-Up
N Engl J Med. 2001
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CREDO Trial 1 Year Benefit of Clopidogrel
MI, Stroke, or Death
Placebo Better
Clopidogrel Better
Subgroup
RRR
95 CI
28.8 26.5 27.6 22.7 11.2
32.8 28.8 19.0 24.5 32.1
26.9
(52.4 to -6.5) (49.3 to -6.6) (47.8 to
-0.4) (53.2 to -27.6) (46.2 to -46.8) (51.6 to
6.8) (47.4 to 3.6) (57.0 to -52.6) (45.5 to
-4.6) (58.9 to -12.1) (44.3 to 3.9)
IV GP IIb/IIIa Inhibitor Use Yes (N826)
No (N1289) ACS Yes (N1407)
No (N694) Diabetes Yes (N560)
No (N1556) Stent Yes (N1616)
No (N500) Male (N1510) Female (N606) Overall (
N2116)
0.6
0.8
1.0
1.2
0.4
Hazard ratio (95 CI)
Plus ASA and other standard therapies
Steinhubl S, Berger P, Tift Mann III J et al.
JAMA. 2002Vol 288,No 192411-2420.
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CURE - Bleeding Complications
Placebo ASA(N 6303)
Clopidogrel ASA(N 6259)
P-Value

• Major bleeding
  2.7 3.7 0.001
• Life-threatening bleeding 1.8
  2.2 NS
• Non-life-threatening bleeding 0.9
  1.5 0.002
• Minor bleeding
  2.4 5.1 lt 0.001

N Engl J Med, 2001
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Hospital Care Anti-Thrombotic Therapy
CLASS 1

• Immediate aspirin
• Clopidogrel, if aspirin contraindicated
• Aspirin clopidogrel for up to 1 month, if
  medical therapy or PCI is planned
• (9 months Clopidogrel)
• Heparin (IV unfractionated, LMW) with
  antiplatelet agents listed above
• Enoxaparin preferred over UFH unless CABG is
  planned within 24 hours

ESC
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Antithrombotic therapy

• ASA
• 500 to 1000mg IV, followed by 100 to 160mg orally
• C-I active bleeding
• Heparin
• Bolus 2.500 UI, followed by IV 10-15 UI/kg/h
  (aPTT 75-90sec)
• C-I HIT
• LMWH
• Enox. 1mg/kg SC tid, Nadro. 100U/kg SC tid
• Clopidogrel (Ticlopidine)
• Loading dose (300mg 600mg?), followed by 75mg/d

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GP IIb/IIIa Inhibition for Non-ST-Elevation ACS
30-Day Death or Nonfatal MI
n
Trial
Risk Ratio 95 CI
Placebo
GP IIb/IIIa
7.1
PRISM
5.8
3,232
PRISM PLUS
11.9
10.2
1,915
PARAGON A
11.7
11.3
2,282
PURSUIT
15.7
14.2
9,461
PARAGON B
11.4
10.5
5,165
GUSTO-IV ACS
8.0
8.7
7,800
0.92 (0.86, 0.995) p 0.037
11.5
10.7
Pooled
29,855
0.5
1.0
1.5
Placebo Better
GP IIb/IIIa Better
Boersma, Lancet 2002
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Platelet GP IIb/IIIa Inhibition for Non ST ?
ACSEnhanced Benefit in Patients Undergoing
Early PCI
Placebo
GP IIb/IIIa
18.5
20
16.7
11.6
11.6
10.2
30-Day Death or MI
10
5.9
0
PRISM-PLUS
PURSUIT
PARAGON-B
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GpIIb/IIIa inhibitors and PCI CAPTURE, PRISM,
PURSUIT combined
N12,296 p0.001
N2,736 p0.474
N2,754 p0.001
10
8
8.0
Placebo
6
4.9
4.3
4
IIb/IIIa blocker
2.9
P
1.6
2
1.3
IIb/IIIa
0
PCI
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PCI patients Death, MI at 30 days
0.1
1
GP IIb/IIIa better
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Hospital Care Antithrombotic Therapy
CLASS 1 cont

• GPIIbIIIa antagonist added if planified PCI or
  just before PCI
• Eptifibatide/Tirofiban in addition to ASA and
  Heparin/LMWH if High Risk features (without
  planned invasive strategy).
• GPIIbIIIa antagonist with ASA/Anticoag and
  Clopidogrel with planned cath/PCI

CLASS 2
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Abciximab ( ReoPro)

• Allowed only before PCI if UAP, nonSTEMI, complex
  coronary stenosis with visible thrombus
• IV bolus (0.25mg/kg) in cath lab, followed by IV
  10µg/min for 12 h
• UFH dosage to keep aPTT between 50-70sec
• Monitoring of platelet count (stop if lt 50.000)

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Aggrastat (Tirofiban)

• Allowed if chest pain within the last 12 hrs and
• recurrent ST/T changes or Tn or haemodynamic
  instability or severe arrythmia or residual
  angina post STEMI
• Bolus 0,4µg/kg/min for 30min, followed by 0,1
  µg/kg/min
• If creatinine clearance lt30ml/min 50 dose
  reduction
• Catheterization should be performed within 48h
  (the earlier, the better)
• IIb/IIIa inhibitors have proven to be of value
  only when PCI is performed !

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ACS without persistent ST-segment
elevationDirect antithrombin drugs

• Combined analysis of OASIS-1 pilot,
  OASIS-2,GUSTO IIb indicates
• RR reduction 22 at 72h
• RR reduction 17 at 7days
• RR reduction 10 at 35 days

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Antithrombotic therapy

• Aggressive  cocktails  increase bleeding risks
• UFH may be preferred,
  particularly if IIb/IIIa inhib. are used or with
  clopidogrel on top (A to Z trial, Synergy)
• Alternative treatment with bivalirudin
  (Angiomax) is currently tested ( ACUITY Trial)
• Bivalirudin ASA/Clopid.
• Vs
• LMWH (UFH) IIb/IIIa inhib. ASA/Clopid.
• Role of ximelagratan (Fondaparinux) ? (PENTUA
  Sportif trials)

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ACS without persistent ST-segment
elevationFibrinolytic treatment
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Hospital Care Anti-Ischemic Therapy (1)

• ?-blocker (IV?oral) if not contraindicated
• Non-dihydropyridine Ca2 antagonist if ?-blocker
  contraindicated and no LV dysfunction, for
  recurrent ischemia
• ACE inhibitor if ? BP persists with NTG
  ?-blocker, for pts with CHF or diabetes

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Hospital Care Anti-Ischemic Therapy (2)

• Extended-release Ca2 blocker instead of
  ?-blocker
• Immediate-release Ca2 blocker with ?-blocker
• Long-acting Ca2 blocker for recurrent ischemia,
  if no contraindications and NTG ?-blocker used
  fully

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FRISC-II Mortality at One-Year Invasive Vs.
Conservative Management Strategies
.04
Non-Invasive (n 1235)
.03
Probability of Death
.02
Invasive (n 1222)
.01
Invasive Noninvasive RR (95 CI) 2.2
4.0 0.56 (0.35 - 0.89) p 0.018
0
360
180
90
30
0
Wallentin, Lancet 2000
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TACTICS-TIMI-18 Primary Endpoint Death, MI,
Rehospitalization for ACS at 6 Months
19.4 15.9
20
16
12
O.R 0.78 95 CI (0.62, 0.97) p0.025
Patients
8
4
CONS
INV
0
0
1
2
3
4
5
6
Time (months)
Cannon C, AHA 2000
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Trials of Intervention in Acute Coronary Syndromes
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Hospital Care Conservative vs. Invasive
Strategies (1)

• Early invasive strategy in high-risk patients
  with any of the following
• - Recurrent ischemia, despite meds
• - Elevated Troponin I or T
• - New ST-segment depression
• - New CHF symptoms
• - High-risk stress test findings
• - LV dysfunction (EF lt 40)
• - Hemodynamic instability, sustained VT
• - PCI within 6 months, prior CABG

ESC
Post Infarction angina
ECG precluding assessment of ST changes
ESC
ESC
Diabetes mellitus
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Hospital Care Conservative vs. Invasive
Strategies (2)

• Either strategy in low- to moderate-risk patients
  without contraindications to revascularization
• Early invasive strategy for patients with
  repeated ACS presentations, without high-risk
  features or ongoing ischemia

Invasive strategy is not rated nor recommended in
low-risk patients.
ESC
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Discharge/Post-Discharge Medications

• ASA, if not contraindicated
• Clopidogrel, when ASA contraindicated
• Aspirin Clopidogrel, for up to 9 months
• ?-blocker, if not contraindicated
• Lipid ? agents diet, if LDL gt130 mg/dL
• ACE Inhibitor CHF, EF lt 40, DM, HTN or any CAD

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Risk Factor Modification

• Smoking Cessation Counseling
• Dietary Counseling and Modification
• Cardiac Rehabilitation Referral
• HTN Control (BP lt 130/85 mm Hg)
• Tight Glycemic Control in Diabetics

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Summary
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Patients judged to be at high risk
forprogression to MI or death
Patients with recurrent ischemia Recurrent chest
pain Dynamic ST-segment changes (ST-segment
depression or transient ST segment
elevation) Early post infarction unstable
angina Elevated troponin levels Hemodynamic
instability Major arrhythmias (VF, VT)
ASA UFH or LMWH IIb/IIIa inhib.
(clopid.) Nitrates Betablockers ACE
inh. Statine Coronary angiography
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Patients judged to be at low risk forprogression
to MI or death

• No recurrence of chest pain within
  observationalperiod
• No elevation of troponin or other
  biochemicalmarkers of thrombosis
• No ST-segment depressionNegative T waves, Flat T
  waves, Normal ECG

Repeat troponin measurements between 6 and 12
hours
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Patients judged to be at low risk forprogression
to MI or death
No ECG changes Second troponin measurement
negative
Heparin discontinued Oral treatment with ASA,
Beta-blockers, nitrates, (Calcium antagonists)
Stress test To confirm or to establish a
diagnosis of CAD To assess the risk of future
events
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ACS with acute persistent ST elevation

• Q wave Myocardial Infarction

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Reperfusion Therapy
Level of evidence A
Recommendations Reperfusion therapy is
indicated in all patients with history of chest
pain/discomfort of lt12 hours and associated with
ST-segment elevation or (presumed) new
bundle-branch block on the ECG
Class I X
IIa
IIb
III
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PCI vs Lysis Timing is critical Nallamothu and
Bates, 2003
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8
Thrombolysis
6
8
Primary PCI
30d-Mortaliy ()
6
4
2
0
1
4
6
8
0
2
3
5
7
Time from Onset of Pain to First Medical Contact
adapted after Huber J Thrombos Thrombolys 2003
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Primary PCI
Level of Evidence A C A A

• Recommendations
• Preferred treatment if performed by experienced
  team lt90 min after first medical contact
• Indicated for patients in shock and those with
  contraindications to fibrinolytic therapy
• GP IIb/IIIa antagonists and primary PCI
• no stenting
• with stenting

Class I X X X
IIa X
IIb
III

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Rescue PCI
IIa X
Class I
IIb
III
Level of Evidence B

• Recommendations
• After failed thrombolysis in patients with large
  infarcts

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Pharmacological Reperfusion
Class I X
IIa
IIb
III
Level of evidence A
Recommendations In the absence of
contraindications and if primary PCI cannot be
performed within 90 min by an experienced team
pharmacological reperfusion should be initiated
as soon as possible
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Fibrinolytic Treatment
Class I
IIa X
IIb
III
Level of evidence C

• Recommendations
• Choice of fibrinolytic agent depends on
  individual assessment of benefit and risk,
  availability and cost
• In patients presenting late
• (gt4 hours after symptom onset) a more
  fibrin-specific agent such as tenecteplase or
  alteplase is preferred

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Fibrinolytic Treatment
Class I X
IIa X
IIb
III
Level of evidence B B
Recommendations Prehospital initiation of
fibrinolytic therapy if appropriate facilities
exist Re-administration of a non-immunogenic
lytic agent if evidence of reocclusion and
mechanical reperfusion not available
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• Use of Anticoagulants
• A reduced dose of UFH with earlier (3h) aPTT
  monitoring
• Enoxaparin reduction in ischemic events but
  excess of bleeding complications including ICH in
  ptsgt 75 years and therefore not (yet) recommended
• Direct Antithrombins (eg. bivalirudin) not
  recommended

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• Use of Antiplatelet Agents
• Low dose aspirin to all patients
• GPIIb/IIIa antagonists in combination with
  half-dose lytic not recommended
• No short-term or long-term mortality reduction
• Excess of bleeding complications especially in
  the elderly
• Increased cost

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Routine Prophylactic Therapiesin the Acute Phase
Recommendations Aspirin 150-325 mg (no
enteric-coated formulation) I.v. BB if no
contraindication ACEI oral formulation on first
day - to all patients if no contraindication - to
high-risk patients Nitrates Calcium
antagonists Magnesium Lidocaine
Class I X X
IIa X
IIb X X
III X X X
Level of evidence A A A A A B A B
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Secondary Prevention (1)
Class I X X X X X X
IIa X
IIb X
III
Level of evidence C B C B B A C B
Recommendations Stop smoking Optimal glycaemic
control Blood pressure control
Mediterranean-type diet Supplementation with 1
g fish oil n-3 poly-unsaturated fatty
acids Aspirin 75 to 160 mg daily If aspirin is
not tolerated - clopidogrel (75 mg daily) - oral
anticoagulant
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Secondary Prevention (2)
Recommendations Oral BB if no contraindications C
ontinuation of ACEIstarted on the first day
Statins if in spite of dietTC gt190 mg/dl
and/orLDLlt115 mg/dl Fibrates if HDL cholesterol
? 45 mg/dland TG ? 200 mg/dl Calcium antagonists
(diltiazem orverapamil) if contraindications to
BB and no heart failure Nitrates in the absence
of angina
IIa X
IIb X
III X
Level of evidence A A A A B A
Class I X X X
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Rest echo Stress echo Rest MPS Stress
MPS Rest RNV Stress ECG CAG
At presentation Diagnosis Diagnosis Prima
ry PCI
At 48 hrs LV function Thrombus High risk
Before discharge LV function Viability Ischaemia
Viability Ischaemia Alternative to echo for LV
function Viability Ischaemia
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STEMI Management Risk Assessment
Myocardial Infarction
Clinical Risk Assessment
High risk
Medium or low risk
Assess LV function ischaemia exercise
tolerance
Coronary angiogram
High risk
Medium risk
Low risk
Suitable anatomy viable myocardium
No
Yes
Medical Rx
Significant angina?
Yes
No
Revascularise
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Thank You !