Acute Coronary Syndrome
Dr.A.S.Mannoun
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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
Deaths / 100 pts / month
25
N = 21,761; 1985-1992
Diagnosis on adm to hosp
20
15
Acute MI
Unstable angina
Stable angina
10
5
0
0
1
2
3
4
5
Months after hospital admission
Duke Cardiovascular Database
6
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Ischemic Heart Disease
evaluation
• 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 Discomfort
Unstable Symptoms
No ST-segment
elevation
Unstable
angina
History
Physical Exam
ST-segment
elevation
Non-Q
AMI
Q-Wave
AMI
ECG
Acute
Reperfusion
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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 Angina
Likelihood of CAD
•
•
•
•
Previous history of CAD
presence of risk factors
older age
ST-T wave ischemic ECG changes
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Unstable Angina
precipitating 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 Angina
prognostic 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 Angina
pathogenesis
• Plaque disruption
• Acute thrombosis
• Vasoconstriction
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Unstable Angina
pathogenesis
• Plaque disruption
– Passive plaque disruption
soft plaque with high concentration of
cholesteryl esters and a thin fibrous cap
– Active plaque disruption
macrophage-rich area with enzymes
that may degrade and weaken the
fibrous cap; predisposing it to rupture
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Unstable Angina
pathogenesis
• 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 Angina
pathogenesis
• Vasoconstriction
– the culprit lesion in response to deep
arterial damage or plaque disruption
– area of dysfunctional endothelium near
the culprit lesion
– platelet-dependent and thrombindependent 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 MI
clues 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 Angina
clues 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, migraine
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Unstable Angina
Risk 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 Angina
Risk 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 Angina
Risk 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 Angina
Therapeutic 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 Angina
Medical 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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Receptor
Final 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 Receptor
KVGFFGR
• 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
Incidence of death and MI
16
14
16%
12
12%
10
8
9%
6
4
2
0
No aspirin
(early 1980s)
Aspirin
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Unstable Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 nonQ-MI to tirofiban alone, heparin alone, or a
combination of the two (all received aspirin)
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Unstable Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-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
135 / 0.5
Inhibition of platelet aggregation
15 minutes after bolus
at steady state
4h after infusion discontinuation
Bleeding-time prolongation
at steady state
6h after infusion discontinuation
69%
40-50%
<30%
<5x
1x
PURSUIT
180 / 2.0
84%
>90%
<50%
<5x
1.4x
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Fiban
incidence of intracranial bleeding
Study
Compound
Treatment (%)
Placebo Active
RESTORE
EPIC
Tirofiban
Abciximab
0.3
0.3
EPILOG
IMPACT II
Abciximab
Integrelin
0.0
0.07
0.1
0.1
0.4
0.1
0.07
0.15
Heparin
Bolus
Bolus + Infusion
Low dose
High dose
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Unstable Angina
Anti-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 Angina
Anti-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 Angina
Anti-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 Angina
Anti-coagulant Therapy
• Low-molecular-weight heparin
advantages 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 Trial
incidence of death, MI, or recurrent angina
Day 14
25
Day 30
25
20
20
19.8%
15
23.3%
19.8%
16.6%
15
P=0.016
P=0.019
10
10
5
5
n=1564 n=1607
n=1564 n=1607
0
0
heparin Lovenox
heparin Lovenox
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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-QWave Infarction Strategies in Hospital)
– better outcome with initial conservative
therapy with lower rates of death and MI
Hosp discharge
One year
medical
3%
18.5%
invasive
8%
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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