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Acute Coronary Syndrome
Dr.A.S.Mannoun
dasmannoun.com
Worldwide Statistics
Each year:
• > 4 million patients are admitted with unstable angina and acute MI
• > 900,000 patients undergo PTCA with or without stent
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Myocardial Ischemia
• Spectrum of presentation– silent ischemia– exertion-induced angina– unstable angina– acute myocardial infarction
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Cumulative 6-month mortality from ischemic heart disease
0 1 2 3 4 5 6
5
10
0
15
20
25
Months after hospital admission
Dea
ths
/ 100
pts
/ m
onth
Acute MIUnstable anginaStable angina
Duke Cardiovascular Database
N = 21,761; 1985-1992Diagnosis on adm to hosp
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Ischemic Heart Diseaseevaluation
• Based on the patient’s– history / physical exam– electrocardiogram
• Patients are categorized into 3 groups– non-cardiac chest pain– unstable angina– myocardial infarction
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Acute Coronary Syndrome
Ischemic DiscomfortUnstable Symptoms
No ST-segmentelevation
ST-segmentelevation
Unstable Non-Q Q-Waveangina AMI AMI
ECG
AcuteReperfusion
HistoryPhysical Exam
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Acute Coronary Syndrome
• The spectrum of clinical conditions ranging from:– unstable angina– non-Q wave MI– Q-wave MI
• characterized by the common pathophysiology of a disrupted atheroslerotic plaque
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Unstable Angina - Definition
• angina at rest (> 20 minutes)
• new-onset (< 2 months) exertional angina (at least CCSC III in severity)
• recent (< 2 months) acceleration of angina (increase in severity of at least one CCSC class to at least CCSC class III)
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Unstable AnginaLikelihood of CAD
• Previous history of CAD
• presence of risk factors
• older age
• ST-T wave ischemic ECG changes
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Unstable Anginaprecipitating factors
• Inappropriate tachycardia– anemia, fever, hypoxia, tachyarrhythmias,
thyrotoxicosis• High afterload
– aortic valve stenosis, LVH• High preload
– high cardiac output, chamber dilatation• Inotropic state
– sympathomimetic drugs, cocaine intoxication
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Unstable Anginaprognostic indicators
• Presence of ST-T-wave changes with pain• Hemodynamic deterioration
– pulmonary edema, new mitral regurgitation,– 3rd heart sound, hypotension
• Other predictors– left ventricular dysfunction, extensive CAD,
age, comorbid conditions (diabetes mellitus, obstructive pulmonary disease, renal failure, malignancy)
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Unstable Anginapathogenesis
• Plaque disruption
• Acute thrombosis
• Vasoconstriction
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Unstable Anginapathogenesis
• Plaque disruption– Passive plaque disruption
soft plaque with high concentration of cholesteryl esters and a thin fibrous cap
– Active plaque disruptionmacrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture
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Unstable Anginapathogenesis
• Acute Thrombosis– Vulnerable plaque
• disrupted plaque with ulceration• occurring in 2/3 of unstable patients• the exposed lipid-rich core abundant in
cholesteryl ester is highly thrombogenic
– Systemic Hypercoagulable State• disrupted plaque with erosion• occurring in 1/3 of unstable patients
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Unstable Anginapathogenesis
• Vasoconstriction– the culprit lesion in response to deep
arterial damage or plaque disruption– area of dysfunctional endothelium near
the culprit lesion– platelet-dependent and thrombin-
dependent vasoconstriction, mediated by serotonin and thromboxane A2
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Acute Coronary Syndrome
• Process of resolution– spontaneous thrombolysis– vasoconstriction resolution– presence of collateral circulation
• Delayed or absence of resolution may lead to non-Q-wave or Q-wave myocardial infarction
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Non-Q-Wave MIclues to diagnosis
• Prolonged chest pain
• Associated symptoms from the autonomic nervous system– nausea, vomiting, diaphoresis
• Persistent ST-segment depression after resolution of chest pain
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Prinzmetal’s Anginaclues to diagnosis
• Transient ST-segment elevation during chest pain
• Intermittent chest pain– often repetitive– usually at rest– typically in the early morning hours– rapidly relieved by nitroglycerine
• Syncope (rare), Raynaud’s, migrainedasmannoun.com
Unstable AnginaRisk Stratification
Low Risk• new-onset exertional angina• minor chest pain during exercise• pain relieved promptly by nitroglycerine
Management• can be managed safely as an outpatient
(assuming close follow-up and rapid investigation)
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Unstable AnginaRisk Stratification
Intermediate Risk• prolonged chest pain• diagnosis of rule-out MI
Management• observe in the ER or Chest Pain Unit• monitor clinical status and ECG• obtain cardiac enzymes (troponin T or I)
every 8 to 12 hours
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Unstable AnginaRisk Stratification
High Risk• recurrent chest pain• ST-segment change• hemodynamic compromise• elevation in cardiac enzymes
Management• monitor in the Coronary Care Unit
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Risk Stratification by ECG
The risk of death or MI at 30 days is strongly related to the ECG at the time of chest pain.
• ST depression 10%• T-wave inversion 5%• No ECG changes 1-2%
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Unstable AnginaTherapeutic Goals
Therapeutic Goals• Reduce myocardial ischemia • Control of symptoms • Prevention of MI and death
Medical Management• Anti-ischemic therapy• Anti-thrombotic therapy
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Unstable AnginaMedical Therapy
• Anti-ischemic therapy– nitrates, beta blockers, calcium antagonists
• Anti-thrombotic therapy– Anti-platelet therapy
• aspirin, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors
– Anti-coagulant therapy
• heparin, low molecular weight heparin (LMWH), warfarin, hirudin, hirulog
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Unstable AnginaAnti-ischemic Therapy
• restrict activities• morphine• oxygen• nitroglycerine
– pain relief, prevent silent ischemia, control hypertension, improve ventricular dysfunction
– nitrate free period recommended after the first 24-48 hours
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Unstable AnginaAnti-ischemic Therapy
• beta-blockers– lowering angina threshold– prevent ischemia and death after MI– particularly useful during high sympathetic tone
• calcium antagonists– particularly the rate-limiting agents– nifedipine is not recommended without
concomitant ß-blockade
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Unstable AnginaAnti-thrombotic Therapy
• Thrombolytics are not indicated• “lytic agents may stimulate the
thrombogenic process and result in paradoxical aggravation of ischemia and myocardial infarction”
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Platelets in Acute Coronary Syndromes
• Platelets play a key role in ACS• Sources of platelet activation (triggers)
– thromboxane A2 (TXA2)
– ADP– epinephrine– collagen– thrombin
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Unstable AnginaAnti-platelet Therapy
• aspirin is the “gold standard”– irreversible inhibition of the cyclooxygenase
pathway in platelets, blocking formation of thromboxane A2, and platelet aggregation
– in AMI, ASA reduced the risk of death by 20-25%– in UA, ASA reduced the risk of fatal or nonfatal
MI by 71% during the acute phase, 60% at 3 months, and 52% at 2 years
– bolus dose of 160-325 mg, followed by maintenance dose of 80-160 mg/d
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GP IIb/IIIa ReceptorFinal Pathway to Platelet Aggregation
• Platelet activation and aggregation are early events in the development of coronary thrombosis
• GP IIb/IIIa receptors on activated platelets undergo a conformational change allowing recognition and binding of fibrinogen
• Fibrinogen “acts like glue”, bridging GP IIb/IIIa receptors on adjacent platelets, leading to platelet aggregation
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GP IIb/IIIa ReceptorKVGFFGR
• There are approximately 50,000 GP IIb/IIIa receptors on each platelet
• KVGFFGR is a specific region within GP IIb/IIIa receptor that is thought to be involved in platelet activation
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Incidence of Ischemic Events
0
2
4
6
8
10
12
14
16
No aspirin(early 1980s)
Aspirin
16%
12%
9%
Incidence of death and MI
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Unstable AnginaAnti-platelet Therapy
• Thienopyridines– ticlopidine (Ticlid; Hoffmann-La Roche)– clopidogrel (Plavix; Bristol-Myers Squibb)
block platelet aggregation induced by ADP and the transformation of GP IIb/IIIa into its high affinity state
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Unstable AnginaAnti-platelet Therapy
• Ticlopidine– in an open-label, randomized study in patients
with unstable angina– ticlopidine 250 mg bid vs. placebo reduced the
risk of fatal or nonfatal MI by 46% at 6 months– benefit not seen at 7 days, but became apparent
after 10 days of therapy (the time required for full antiplatelet activity)
– an alternative for patient with aspirin intolerance
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Unstable AnginaAnti-platelet Therapy
• Clopidogrel– CAPRIE (Clopidogrel versus Aspirin in Patients
at Risk of Ischemic Events)– 19,000 patients randomly assigned to
clopidogrel (75 mg/d) or to aspirin (325 mg/d)– there was an 8.7% reduction in the combined
incidence of stroke, MI, or death (P=.043)– patients with MI did better with aspirin– patients with PVD or stroke did better with
clopidogrel
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Unstable AnginaAnti-platelet Therapy
• GP IIb/IIIa inhibitors– abciximab (monoclonal antibody)– eptifibatide (peptidic inhibitor)– lamifiban and tirofiban (non-peptides)
direct occupancy of the GP IIb/IIIa receptor by a monoclonal antibody or by synthetic compounds mimicking the RGD sequence for fibrinogen binding prevents platelet aggregation
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Unstable AnginaAnti-platelet Therapy
• Abciximab (Reo-Pro)– EPIC Trial
effective in preventing death, MI, and abrupt closure associated with coronary angioplasty (see also EPIC slides)
– EPISTENT Trial(unpublished - see MedSlides News)
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Unstable AnginaAnti-platelet Therapy
• Abciximab (Reo-Pro)– CAPTURE (Chimeric 7E3 Antiplatelet in
Unstable Angina Refractory to Standard Treatment)
– 1,000 patients with angiographically documented unstable angina, not responding to ASA, nitrates, heparin,and other anti-anginals, received either abciximab or placebo within 18-24 hours
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Unstable AnginaAnti-platelet Therapy
• Abciximab (ReoPro; Centocor)– CAPTURE – At 30 days, there was a 29% reduction in the
primary composite endpoint of death, MI, or urgent revascularization in the abciximab group
– At 6 months, this benefit was not evident
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Unstable AnginaAnti-platelet Therapy
• Lamifiban– PARAGON (Platelet IIb/IIIa Antagonist for
the Reduction of Acute Coronary Syndrome Events in a Global Organization Network)
– 2000 patients received two different doses of lamifiban compared with placebo + heparin
– at 6 months, there was a lower event rate (12.6% vs 17.9%) with low dose lamifiban
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Unstable AnginaAnti-platelet Therapy
• Tirofiban (Aggrastat; Merk & Co.)– PRISM (Platelet Receptor Inhibition for
Ischemic Syndrome Management)– 3,200 patients with unstable angina were
treated with either heparin or tirofiban– At 48 hours, there was significant risk
reduction (5.9% to 3.6%) in the rate of death, MI, or refractory ischemia. The benefit was lost at 30 days.
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Unstable AnginaAnti-platelet Therapy
• Tirofiban– PRISM -PLUS (Platelet Receptor Inhibition
for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms)
– randomized 1,915 patients with UA and non-Q-MI to tirofiban alone, heparin alone, or a combination of the two (all received aspirin)
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Unstable AnginaAnti-platelet Therapy
• Tirofiban– PRISM -PLUS – angiography was performed after 48 hr of
initial medical therapy – combination therapy (tirofiban, aspirin, and
heparin) reduced the risk of death and MI at 48 hr from 2.6% to 0.9%, and at 30 days from 11.9% to 8.7%
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Unstable AnginaAnti-platelet Therapy
• Tirofiban– RESTORE (Randomized Efficacy Study of
Tirfiban for Outcomes and Restenosis) – evaluate the impact of tirofiban on
angioplasty for acute coronary syndromes– tirofiban reduced the frequency of events
associated with intervention in ACS
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Unstable AnginaAnti-platelet Therapy
• Eptifibatide (Integrilin; Cor/Schering)– PURSUIT (Platelet IIb/IIIa Underpinning the
Receptor for Suppression of Unstable Ischemia Trial)
– ~11,000 patients admitted with unstable angina or non-Q-wave myocardial infarction
– a broad-based trial encompassing a variety of clinical practices and practice styles
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Unstable AnginaAnti-platelet Therapy
• Eptifibatide (Integrilin; Cor/Schering)PURSUIT– randomized to eptifibatide or placebo; all
patients received aspirin and heparin – significantly reduced the risk of death and MI
at 30 days from 15.7% to 14.2%, a 9% risk reduction
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Platelet Inhibition and Bleeding Time
IMPACT II PURSUIT
135 / 0.5 180 / 2.0
Inhibition of platelet aggregation
15 minutes after bolus 69% 84%
at steady state 40-50% >90%
4h after infusion discontinuation <30% <50%
Bleeding-time prolongation
at steady state <5x <5x
6h after infusion discontinuation 1x 1.4x
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Fibanincidence of intracranial bleeding
Treatment (%)
Study Compound Placebo Active Heparin
RESTORE Tirofiban 0.3 0.1
EPIC Abciximab 0.3 0.1
0.4
EPILOG Abciximab 0.0 0.1
IMPACT II Integrelin 0.07 0.07 0.15
Bolus
Low dose
High dose
Bolus + Infusion
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Unstable AnginaAnti-platelet Therapy
• Summary – the four “P trials” (PRISM, PRISM-PLUS,
PARAGON, PURSUIT)– all show reduction of death rate between
1.3% and 3.4% - in addition to the benefit of aspirin
– useful in the management of patients with unstable angina and MI without ST elevation
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Unstable AnginaAnti-platelet Therapy
• Summary
The question is no longer“Is there a reason to use GP IIb/IIIa inhibitors?” but “Is there a reason not to use them?”
Eric Topol, MD
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Unstable AnginaAnti-coagulant Therapy
• Heparin– recommendation is based on documented
efficacy in many trials of moderate size– meta-analyses (1,2) of six trials showed a
33% risk reduction in MI and death, but with a two fold increase in major bleeding
– titrate PTT to 2x the upper limits of normal
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Unstable AnginaAnti-coagulant Therapy
• Low-molecular-weight heparinadvantages over heparin:– better bio-availability– higher ratio (3:1) of anti-Xa to anti-IIa activity– longer anti-Xa activity, avoid rebound– induces less platelet activation– ease of use (subcutaneous - qd or bid)– no need for monitoring
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Unstable Angina Anti-coagulant Therapy
• Low-molecular-weight heparin– ESSENCE Trial (Efficacy and Safety of
Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study)
– at 30days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared to standard heparin
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ESSENCE Trialincidence of death, MI, or recurrent angina
0
5
10
15
20
25
0
5
10
15
20
25
heparin Lovenox heparin Lovenox
n=1564 n=1607 n=1564 n=1607
19.8%
16.6%P=0.019
23.3%
19.8%P=0.016
Day 14 Day 30
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Unstable Angina Coronary Interventions
• TIMI 3B – early intervention vs conservative strategy
(coronary angiography within 24-48 hrs, followed by angioplasty or bypass surgery)
– 1473 patients with UA or non-Q-wave MI were randomized, there were no difference between the groups in the rates of death or MI at 1 year
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Unstable Angina Coronary Interventions
• VANQWISH (Veteran Affairs non-Q-Wave Infarction Strategies in Hospital)– better outcome with initial conservative
therapy with lower rates of death and MI
medical invasiveHosp discharge 3% 8%One year 18.5% 24%
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Unstable Angina role of non-ionic contrast
• Ionic contrast media seem to perform better in ACS
• prospective, randomized control trial of 211 patient
• a much greater need for CABG was seen in the non-ionic contrast medium group
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Trials Underway
• GUSTO-IV (abciximab vs placebo)
• EXCITE ( Eval of Oral Xemilofiban in Controlling Thrombotic Events)
• OPUS (Orofiban in Patients with Unstable Coronary Syndromes)
• SYMPHONY (Sibrafiban vs Aspirin to Yield Maximum Protection from Ischemic Events Post ACS)
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