Acute Coronary Syndromes

Paul F. Frey, MD, MPH; and Richard Lange, MD

FAST FACTS

Acute coronary syndrome (ACS) consists of the signs and symptoms

compatible with progressive or acute nonexertional myocardial
ischemia and is divided into nonST segment elevation ACS and ST
segment elevation ACS.
Risk stratification is important in guiding therapy for patients with
nonST segment elevation ACS.
The electrocardiographic (ECG) diagnosis of ST segment elevation
ACS is defined by more than 1 mm of ST segment elevation in
two limb leads, more than 2 mm of ST segment elevation in two
contiguous precordial leads, or a new or presumed new left bundle
branch block.
In the patient with ST segment elevation ACS, prompt reperfusion of
the infarct-related artery (IRA) is essential.
Aggressive risk factor modification and secondary prevention therapy
should be applied to all patients with ACS.

1. Cardiovascular disease is the leading cause of death in the United

States, accounting for more than 1 of every 5 deaths. Each year,
approximately 1.7 million patients are hospitalized in the United States
with ACS.1
2. ACS consists of the signs and symptoms of myocardial ischemia that
occur at rest or with minimal exertion and usually is caused by rupture
of a coronary atherosclerotic plaque, with subsequent platelet
aggregation and coronary thrombosis.
3. The management of ACS depends on ECG findings. Patients
with ST segment elevation probably have total occlusion of an
epicardial coronary artery and should receive prompt reperfusion
of the IRA, whereas patients with ACS and without ST segment
elevation probably have subtotal occlusion of an epicardial coronary
artery and should receive intense antiplatelet and anticoagulant
therapy. Cardiac catheterization should be performed in those at
high risk for myocardial infarction (MI) or death on the basis of risk
stratification.
I. CLINICAL PRESENTATION
The history, physical examination, ECG findings, and cardiac biomarkers
are used to determine whether the patient with chest pain has ACS
(Table 8-1). Important historical features include the following:
86

Normal

T wave flattening or inversion in leads with

dominant R waves
Normal electrocardiogram

Chest discomfort reproduced by palpation

TO CAD
Low Likelihood (absence of high- or
intermediate-likelihood features but may
have the following)
Probable ischemic symptoms in absence of
any of the intermediate-likelihood
characteristics
Recent cocaine use

ACUTE CORONARY SYNDROMES

Modified from Braunwald E, Mark DB, Jones RH et al: Unstable angina: diagnosis and management, Rockville, Md, 1994, Agency for Health Care Policy and Research and the
National Heart, Lung, and Blood Institute, U.S. Public Health Service, U.S. Department of Health and Human Services; AHCPR Publication No. 94-0602.
CAD, coronary artery disease.

TABLE 8-1
LIKELIHOOD THAT SIGNS AND SYMPTOMS REPRESENT ACUTE CORONARY SYNDROME SECONDARY
Intermediate Likelihood (absence of
high-likelihood features and presence
High Likelihood (any of the following)
of any of the following)
History
Chest or left arm pain or discomfort
Chest or left arm pain or discomfort
as chief symptom reproducing
as chief symptom
prior documented angina
Age <70 yr
Known history of CAD, including
Male sex
myocardial infarction
Diabetes mellitus
Examination
Transient mitral regurgitation,
Extracardiac vascular disease
hypotension, diaphoresis,
pulmonary edema, or rales
Electrocardiogram
New, or presumably new, transient ST
Fixed Q waves
segment deviation (>0.05 mV) or
Abnormal ST segments or T
T wave inversion (>0.2 mV) with
waves not documented to be new
symptoms
Cardiac markers
Elevated cardiac troponin I, troponin
Normal
T, or creatine kinase myocardial
band

Acute Coronary Syndromes 87

88 Cardiology

1. Quality and frequency of chest discomfort. Chest discomfort more

severe than the patients usual chest pain or occurring more frequently
suggests ACS.
2. Rest pain. Chest discomfort occurring at rest or with minimal activity
suggests ACS.
3. Duration of chest pain. Stable angina rarely causes chest discomfort
longer than 10 minutes. Chest pain lasting longer is more likely to
indicate ACS.
4. Prior cardiac history. Patients with chest pain within 2 months of an
MI or coronary revascularization have ACS until proven otherwise.
5. Associated symptoms. Diaphoresis, shortness of breath, palpitations,
and nausea often accompany chest pain caused by ACS.
II. DIAGNOSIS
All patients being evaluated for ACS should be placed on a cardiac
monitor, and a 12-lead electrocardiogram should be obtained within 10
minutes of presentation and repeated if the chest discomfort changes.
A careful physical examination (including assessment of blood pressure
in both arms) should be performed and a chest film obtained. A blood
sample should be sent for analysis of the comprehensive metabolic panel,
troponin level, fractionated creatine kinase (CK) concentration, complete
blood cell count, and prothrombin and activated partial thromboplastin
times. Risk stratification of the patient should then be used.
A. ELECTROCARDIOGRAM
1. A 12-lead electrocardiogram should be obtained immediately for every
patient with signs or symptoms suggestive of ACS and compared with a
previous electrocardiogram if available.
2. The electrocardiogram differentiates ST segment elevation ACS from
nonST segment elevation ACS. This distinction is vital because
treatment differs greatly between the two syndromes.
3. The current ECG criteria for the diagnosis of ST elevation ACS require
more than 1 mm ST elevation in two or more anatomically contiguous
limb leads, more than 2 mm ST elevation in two or more anatomically
contiguous precordial leads, or a new or presumed new left bundle
branch block.
4. Serial ECG analysis is essential because a suspected nonST segment
elevation ACS may evolve into an ST segment elevation ACS.
5. A right-sided electrocardiogram should be obtained in all patients with
ST segment elevations in the inferior leads to determine whether right
ventricular MI is present. ST segment elevation in V4 of the right-sided
leads suggests a right ventricular infarction.
6. When the electrocardiogram meets ST segment elevation ACS criteria,
the patient becomes eligible for acute reperfusion therapy. The current
recommendations are to administer thrombolytic therapy within 30
minutes or perform percutaneous coronary intervention (PCI) within
90 minutes of diagnosis.

Acute Coronary Syndromes 89

III. MANAGEMENT: NONST SEGMENT ELEVATION ACS

A. RISK STRATIFICATION
Risk stratification is integral in the management of a nonST segment
elevation ACS because not all patients with ACS are equally likely to have
adverse cardiac events (i.e., death, MI, or urgent revascularization).
Patients are classified as being at high, intermediate, or low risk of having
an adverse cardiac event, and therapy is tailored to the patients risk
profile. The following clinical tools help risk stratify patients:

8
ACUTE CORONARY SYNDROMES

7. Patients with nonST segment elevation ACS may initially have a

normal electrocardiogram or nonspecific ST-T wave changes. Thus a
normal electrocardiogram does not exclude this diagnosis. ST segment
depressions of more than 1 mm in two or more contiguous limb leads
(or more than 2 mm in two or more contiguous precordial leads) may
be present and predict adverse cardiac events.
B. CARDIAC BIOMARKERS
1. In patients with a nonST segment elevation ACS, serum biomarkers
(e.g., cardiac enzymes) indicative of myocardial necrosis are helpful in
stratifying risk and differentiating ischemia from infarction. It takes
several hours from the time myocardial injury occurs until biomarkers
are detectable in the serum, so the patient with a nonST segment
elevation ACS may have normal values initially at presentation.
Therefore blood samples should be obtained at the time of presentation
and again 6 to 12 hours later.
2. Traditional biomarkers included CK, troponin I or T, and myoglobin.
Based on current guidelines, the cardiac-specific troponins such as
troponin T and troponin I are the preferred markers. Troponin T is
detectable in the serum within 4 hours after myocardial injury, with
elevated serum levels for 7 to 10 days. Troponin I is typically detectable
within 6 hours of myocardial injury, and the serum levels remain
elevated for 7 to 10 days. Troponin I is less likely to be associated with
false elevations than troponin T in patients with renal insufficiency.
3. CK exists in three isoforms (MM, MB, BB), of which CK-MB is cardiacspecific. CK-MB serum levels typically increase 3 to 6 hours after
myocardial injury, peak at 12 to 24 hours, and return to normal within
3 days. CK-MB is less cardiospecific than troponin, and serum levels
may be elevated in the patient with trauma, surgery, rhabdomyolysis,
sepsis, hypothyroidism, or renal dysfunction.
4. Myoglobin is a highly sensitive and early marker of myocardial damage.
Serum myoglobin levels begin to increase within 2 hours of myocardial
injury and peak at 24 hours. However, serum myoglobin has very low
specificity because myoglobin increases with skeletal muscle injury,
trauma, intramuscular injections, alcohol abuse, renal dysfunction, and
hypothermia or hyperthermia. Therefore a negative myoglobin within
8 hours of the onset of chest pain may be useful to help rule out
myocardial ischemia.

90 Cardiology

1. Electrocardiogram and cardiac biomarkers. ST segment depression and

elevated cardiac biomarkers are associated with a higher risk of adverse
outcomes. Patients with only one of the two are at intermediate risk,
and those with neither are at low risk.
2. A list of historical and physical findings the American Heart Association
has adopted in assisting with risk stratification is provided in Table 8-2.
3. Thrombolysis in Myocardial Infarction (TIMI) risk score assessment.
The TIMI risk factor score predicts the probability of adverse cardiac
outcomes in patients with nonST segment elevation ACS based on
data available at the bedside.2 Seven variables are assessed (Box 8-1),
with the likelihood of an adverse cardiac event predicted by the number
of variables present. Patients with a score of less than 3 are at low risk,
those with a score of 3 or 4 are at intermediate risk, and those with a
score of 5 or higher are at high risk for having a cardiac event over the
next 30 days.
B. INTERVENTION: PHARMACOLOGIC AND NONPHARMACOLOGIC
1. The management of nonST segment elevation ACS is based on risk
stratification. All patients initially are treated with aspirin, beta-blockers,
nitrates, and anticoagulation unless contraindicated. Once these
therapies are initiated, the first decision is whether the patient should
undergo early invasive or noninvasive management. The next decision
is whether the patient should receive clopidogrel or a glycoprotein (GP)
IIb/IIIa inhibitor.

BOX 8-1
THROMBOLYSIS IN MYOCARDIAL INFARCTION RISK FACTOR SCORE
RISK FACTORS
Age >65 years
Three or more risk factors for coronary artery disease
Prior coronary stenosis 50%
Two or more anginal events in past 24 hr
Aspirin use in past 7 d
ST segment changes
Positive cardiac markers
30-DAY RISK OF ADVERSE CARDIAC EVENT*
Number of Risk Factors
Risk (%)
0-1
4.7
2
8.3
3
13.2
4
19.9
5
26.2
6-7
41.0
Data from Antman E et al: JAMA 284:835, 2000.
*Defined as myocardial infarction, cardiac-related death, or persistent ischemia. Low risk, score
0-2; intermediate risk, score 3-4; high risk, score 5-7.

ACUTE CORONARY SYNDROMES

Modified from Braunwald E, Mark DB, Jones RH et al: Unstable angina: diagnosis and management, Rockville, Md, 1994, Agency for Health Care Policy and Research and the
National Heart, Lung, and Blood Institute, U.S. Public Health Service, U.S. Department of Health and Human Services; AHCPR Publication No. 94-0602.
CAD, coronary artery disease; MI, myocardial infarction.
*Estimation of the short-term risks of death and nonfatal cardiac ischemic events in unstable angina is a complex multivariable problem that cannot be fully specified in a table
such as this; therefore this table is meant to offer general guidance and illustration rather than rigid algorithms.

TABLE 8-2
SHORT-TERM RISK OF DEATH OR NONFATAL MYOCARDIAL INFARCTION IN PATIENTS WITH UNSTABLE ANGINA*
Low Risk (no high- or intermediate-risk
High Risk (at least 1 of the following
Intermediate Risk (no high-risk feature
feature but may have any of the
features must be present)
but must have 1 of the following)
following features)
History
Accelerating tempo of ischemic
Prior MI, peripheral or cerebrovascular
symptoms in preceding 48 hr
disease, or coronary artery bypass
graft; prior aspirin use
Character of pain
Prolonged (>20 min) rest pain
Prolonged (>20 min) rest angina, now
New-onset Canadian Cardiovascular
resolved, with moderate or high
Society Class III or IV angina in
likelihood of CAD; rest angina
the past 2 wk without prolonged
(<20 min) or relieved with rest or
(<20 min) rest pain but with moderate
sublingual nitroglycerin
or high likelihood of CAD
Clinical findings
Pulmonary edema, probably due to
Age >70 years
ischemia; new or worsening mitral
regurgitation murmur; S3; or new or
worsening rales
Hypotension
Bradycardia or tachycardia
Age >75 years
Electrocardiogram
Angina at rest with transient ST
T wave inversions > 0.2 mV
Normal or unchanged electrocardiogram
segment changes >0.05 mV
Pathological Q waves
during an episode of chest discomfort
Bundle branch block, new or
presumed new
Sustained ventricular tachycardia
Cardiac markers
Markedly elevated (e.g., troponin T or
Slightly elevated (e.g., troponin T
Normal
troponin I > 0.1 ng/ml)
> 0.01 but < 0.1 ng/ml)

Acute Coronary Syndromes 91

92 Cardiology

2. Aspirin. Platelet activation and aggregation play an important role

in the pathophysiology of ACS. Aspirin inhibits the production of
thromboxane, which is a potent mediator of platelet activation. As soon
as ACS is suspected, 325 mg of nonenteric-coated aspirin should
be administered. Patients with aspirin allergy can be given clopidogrel.
Ticlopidine should not be used in lieu of clopidogrel because of its slow
(3 to 5 days) onset of action.
3. Beta-adrenergic blockers reduce myocardial oxygen demand by exerting
negative inotropic and chronotropic effects and protect against cardiac
arrhythmias. Metoprolol is the preferred beta-adrenergic blocker because
of its b1-selective activity. It is initially given as a 5-mg intravenous (IV)
bolus. If tolerated, the 5-mg dose is repeated twice at 10-minute
intervals for a maximum dosage of 15 mg. The patient is then started
on orally administered metoprolol. The dosage is titrated to achieve a
mean systemic arterial pressure of 60 to 70 mmHg and a heart rate of
60 beats/min. If these hemodynamic goals are not tolerated, the lowest
tolerated mean arterial pressure and pulse should be targeted.
4. Nitrates reduce myocardial oxygen demand (by reducing preload)
and increase myocardial blood flow (by dilating coronary vessels).
Sublingual nitroglycerin tablets or spray should be used initially if the
patient is not hypotensive and has no other contraindications to these
agents, such as sildenafil use in the previous 24 hours. If the patients
chest discomfort does not resolve after three 0.4-mg nitroglycerin
tablets given 5 minutes apart, a continuous nitroglycerin IV infusion
can be initiated at 10 g/min and titrated upward by 10 g every 3 to
5 minutes until the patients discomfort resolves, the mean systemic
arterial blood pressure drops below 25% of initial values in an initially
hypertensive patient, or the systolic blood pressure drops below
110 mmHg in a normotensive patient. Common side effects include
hypotension and headaches. Tachyphylaxis may occur with prolonged
use. A reflex tachycardia can also occur in patients not receiving a betaadrenergic blocker or other negative chronotropic therapy.
5. Anticoagulation. Plaque rupture exposes tissue factor, which initiates
the clotting cascade and coronary thrombosis. Patients with a nonST
segment elevation ACS should receive anticoagulation unless a
major contraindication exists. Two forms of heparin are approved
for use in these patients: unfractionated heparin and lowmolecularweight heparin. For the patient with a history of heparin-induced
thrombocytopenia who needs anticoagulation, lepirudin, a direct
thrombin inhibitor, can be administered as a 0.4-mg/kg bolus followed
by a 0.15-mg/kg/hr (maximum 16.5 mg/hr) infusion with a targeted
activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times the
upper limit of normal.
a. Unfractionated heparin is initiated as an IV bolus followed by a
continuous infusion. The American Heart Association recommends
a weight-based dosage regimen consisting of a 60- to 70-U/kg

Acute Coronary Syndromes 93

8
ACUTE CORONARY SYNDROMES

(maximum 5000-U) bolus followed by a maintenance infusion of 12 to

15 U/kg/hr. The aPTT should be measured 6 hours after every dosage
adjustment and the infusion adjusted to reach an aPTT of 2 to 2.5
times the upper limit of normal. If the patient is receiving a GP IIb/IIIa
inhibitor, the target aPTT is lower (1.8 to 2 times the upper end of
normal) in order to minimize the risk of bleeding.
b. Lowmolecular-weight heparin is also approved for use in the patient
with a nonST segment elevation ACS. Enoxaparin is administered
initially as a 30-mg IV bolus, and then 1 mg/kg is administered
subcutaneously twice daily. It has several advantages over heparin: It is
easier to administer, does not necessitate aPTT monitoring, and is less
likely to cause heparin-induced thrombocytopenia. Conversely, it is
more expensive than heparin, it has a long half life, and its therapeutic
effects cannot be reversed completely with protamine. Thus concerns
have been raised regarding its use in patients referred for coronary
revascularization. The dosage is reduced in the patient with renal failure
or obesity (weight > 120 kg), and the patient with a history of heparininduced thrombocytopenia should not receive lowmolecular-weight
heparin.
c. Two double-blind randomized trialsEfficacy and Safety of
Subcutaneous Enoxaparin in NonQ Wave Coronary Events (ESSENCE)
and TIMI 11Bcompared enoxaparin and unfractionated heparin
therapy in 7081 patients with nonST segment elevation ACS and
demonstrated a significant reduction in the incidence of MI and
urgent revascularization for recurrent angina with enoxaparin.3,4 In
these studies, patients were referred for catheterization if they had
spontaneous or provocable ischemia (known as an ischemia-guided
management strategy). The recent Superior Yield of the New Strategy
of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors
(SYNERGY) study compared lowmolecular-weight heparin and
unfractionated heparin therapy in 10,027 patients with nonST
segment elevation ACS who were treated with a GP IIb/IIIa inhibitor and
an early invasive strategy.5 The primary endpoint (incidence of death or
MI at 30 days) was similar for the two treatments; however, patients
receiving lowmolecular-weight heparin had a higher rate of bleeding.
6. Clopidogrel is a thienopyridine antiplatelet agent that inhibits adenosine
diphosphatemediated activation of platelets. Clopidogrel has a quick
onset of action when administered as a loading dose, and its benefits
in nonST segment elevation ACS have been demonstrated in several
large-scale trials.
a. In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic
Events (CURE) trial, 12,562 patients with ACS were randomized to
receive placebo or clopidogrel, 300 mg loading dose and then 75 mg
daily.6 All participants received daily aspirin and were followed for 3 to
12 months. The clopidogrel-treated patients were less likely to suffer a
major adverse cardiovascular event (9.4% vs. 11.3%) but more likely

94 Cardiology

to have major bleeding (3.7% vs. 2.7%, p = .001). Those who

received clopidogrel within 5 days of coronary artery bypass surgery
had a significantly higher risk of bleeding and need for transfusions
perioperatively. For this reason, many surgeons delay cardiac surgery
if the patient has received clopidogrel within 5 days of the planned
procedure.
b. Two other studies address the use of clopidogrel in the setting of PCI
and revascularization: the PCI CURE study7 and the Clopidogrel for the
Reduction of Events During Observation (CREDO) study.8 The PCI
CURE study, a subset of the CURE trial, evaluated the 2658 patients
undergoing PCI who were pretreated with clopidogrel and received
study drug or placebo for 4 weeks after the procedure. Compared with
those in the placebo group, the clopidogrel-treated patients experienced
a lower rate of the combined endpoint of cardiovascular death, MI, or
urgent revascularization at 30 days (6.4% and 4.5%, respectively;
p = .03). The CREDO trial randomly assigned 2116 patients to
placebo or clopidogrel 3 to 24 hours before PCI and for up to 12
months afterward. The clopidogrel-treated patients were less likely to
have an adverse ischemic event in the year after PCI. Thus prolonged
therapy with clopidogrel after successful PCI reduces the risk of
subsequent ischemic events.
c. Current American College of Cardiology and American Heart Association
(ACC/AHA) recommendations for the use of clopidogrel include all
patients not at high risk for bleeding in whom a noninterventional
approach is planned. A 300-mg oral dose is administered initially, and
then 75 mg is given daily for at least 1 month. Clopidogrel should
also be used in patients in whom PCI is planned.9 In these patients, a
300- to 600-mg oral loading dose should be given 4 to 6 hours before
the procedure and 75 mg administered daily for up to 12 months
afterward. Because clopidogrel therapy should be discontinued at least
5 to 7 days before elective coronary artery bypass grafting, many
cardiologists avoid giving clopidogrel to the patient with ACS in whom
cardiac catheterization and a determination regarding the need for
coronary artery bypass grafting can be performed expeditiously (within
24 to 36 hours of presentation).
7. Glycoprotein IIb/IIIa receptor inhibitors. The final pathway in platelet
aggregation is activation of the GP IIb/IIIa receptor, which allows
platelets to bind to fibrinogen and von Willebrand factor. Three GP
IIb/IIIa inhibitors are available: abciximab, a monoclonal antibody
against the IIb/IIIa receptor; tirofiban, a peptidomimetic inhibitor; and
eptifibatide, a cyclic peptide inhibitor. Several studies have shown the
clinical efficacy of eptifibatide and tirofiban in the setting of ACS.10-12
Subgroup analysis of the data in these studies shows that the greatest
clinical benefit occurs in high- and intermediate-risk patients. Current
data support the use of eptifibatide or tirofiban in high-risk patients,
especially those with an elevated serum troponin in whom coronary

Acute Coronary Syndromes 95

Modified from Braunwald E et al: Circulation 106:1893, 2002.

angiography is likely. An IV bolus of eptifibatide or tirofiban is followed

by continuous IV infusion of the drug for 48 to 72 hours. If PCI is
performed, the infusion is continued for 12 to 24 hours after the
procedure. Abciximab is beneficial only in patients undergoing PCI,13 in
which case the IV infusion is initiated in the cardiac catheterization
laboratory and continued for 12 hours after PCI.
8. Early percutaneous coronary angiography compared with an ischemiaguided approach. Three randomized, prospective studies have shown
that an early invasive strategy in conjunction with aggressive medical
management is superior to an ischemia-guided approach, in which
angiography and PCI are reserved for patients with spontaneous or
provocable ischemia.14-16 Subgroup analysis has shown that high- and
intermediate-risk patients benefit the most from an early invasive
strategy. The current ACC/AHA recommendations include an early
invasive strategy for any patient with high-risk features (Box 8-2). For
intermediate- and low-risk patients without evidence of myocardial
necrosis (elevation in cardiac biomarkers) a noninvasive stress test is a
reasonable approach, with catheterization reserved for those with
inducible ischemia. For patients with evidence of myocardial necrosis,
most cardiologists would recommend early cardiac catheterization.
IV. MANAGEMENT: ST SEGMENT ELEVATION ACS
A. RISK STRATIFICATION
1. As with all forms of ACS, risk stratification is crucial to patient
management. A classification scheme developed in the late 1960s by

8
ACUTE CORONARY SYNDROMES

BOX 8-2
CLASS I RECOMMENDATIONS FOR AN EARLY INVASIVE STRATEGY
FOR UNSTABLE ANGINA AND NONST SEGMENT ELEVATION
MYOCARDIAL INFARCTION
Recurrent angina or ischemia at rest or with low-level activities despite intensive
antiischemic therapy
Elevated troponin T or troponin I
New or presumably new ST segment depression
Recurrent angina or ischemia with congestive heart failure symptoms, S3 gallop,
pulmonary edema, worsening rales, or new mitral regurgitation
High-risk findings on noninvasive stress testing
Depressed left ventricular systolic function (e.g., ejection fraction < 0.4 on
noninvasive testing)
Hemodynamic instability
Sustained ventricular tachycardia
Percutaneous coronary intervention within 6 mo
Prior coronary artery bypass graft

96 Cardiology

Killip and Kimball correlates heart failure signs and outcome17

(Table 8-3). Many studies have confirmed that the Killip classification
predicts short- and long-term mortality after MI.
2. The TIMI study group developed a simple bedside stratification tool for
patients with ST segment elevation ACS18 (Table 8-4), assigning points
for clinical risk indicators on the basis of patient history, physical
examination, and features on presentation. When applied to the 84,029
patients in the National Registry of Myocardial Infarction 3 database,
the scoring system reveals a graded risk in 30-day mortality ranging
from 1.1% to 30% for scores ranging from 0 to more than 8,
respectively.19

TABLE 8-3
RISK STRATIFICATION BASED ON KILLIP CLASS IN THE GISSI-1 TRIAL OF
STREPTOKINASE AND PLACEBO IN ACUTE MYOCARDIAL INFARCTION
GISSI-1 (% of patients)
Killip Class
Definition
Incidence
Control Mortality
Lytic Mortality
I
No congestive
71
7.3
5.9
heart failure
II
S3 gallop or
23
19.9
16.1
basilar rales
III
Pulmonary edema
4
39
33
(rales more than
halfway up)
IV
Cardiogenic shock
2
70.1
69.9
(systolic blood
pressure <90)

TABLE 8-4
THROMBOLYSIS IN MYOCARDIAL INFARCTION RISK SCORE FOR ST SEGMENT
ELEVATION MYOCARDIAL INFARCTION
Clinical Risk Indicators
Points
HISTORY
Age 75 yr
3
Age 65-74 yr
2
History of diabetes, hypertension, or angina
1
EXAMINATION
Systolic blood pressure < 100 mmHg
3
Heart rate >100 beats/min
2
Killip class II-IV
2
Weight < 67 kg
1
PRESENTATION
Anterior ST elevation or left bundle branch block
1
Time to reperfusion > 4 hr
1
Total possible points
14
Data from Morrow DA et al: JAMA 286:1356, 2001.

Acute Coronary Syndromes 97

TABLE 8-5
TIMI ANGIOGRAPHIC GRADING SYSTEM: ANGIOGRAPHIC ASSESSMENT OF
RESTORATION OF FLOW TO THE IRA
TIMI Grade
Definition
0
Complete occlusion of the IRA
1
Some flow beyond the obstruction but none distally (e.g., penetration
of blood without perfusion)
2
Reperfusion of the entire IRA but flow is delayed and slower than
normal
3
Normal flow in the IRA
Modified from TIMI Study Group: N Engl J Med 312:932, 1985.
IRA, infarct-related artery; TIMI, Thrombolysis in Myocardial Infarction.

8
ACUTE CORONARY SYNDROMES

B. INTERVENTION: PHARMACOLOGIC AND NONPHARMACOLOGIC

1. Patients should be treated with an antiischemic drug regimen consisting
of aspirin, beta-blockers, and nitroglycerin and considered for acute
reperfusion therapy via administration of a thrombolytic agent or
primary PCI. Early flow restoration in the infarct-related artery salvages
myocardium and improves survival. The adequacy of coronary blood
flow after reperfusion therapy can be assessed angiographically using
the TIMI grading system (Table 8-5).
2. Early recognition of ischemia and rapid reperfusion salvage
myocardium and improve survival. Initiation of thrombolytic therapy
within 30 minutes of symptom onset can abort infarction. Although
patients derive survival benefit if treated with a thrombolytic agent
within 12 hours of symptom onset,24 maximum benefit is obtained if a
thrombolytic agent is administered within 2 hours of symptom onset.20
With primary PCI, mortality rates increase significantly when door-toballoon time exceeds 90 minutes.21 Based on these data, current
ACC/AHA recommendations are to administer thrombolytic therapy
within 30 minutes or perform PCI within 90 minutes of arrival, with an
overall goal of total ischemic time (from symptom onset to intervention)
less than 120 minutes.22
3. Thrombolytics (fibrinolytic agents) act by converting plasminogen to
plasmin, which digests fibrin and enhances thrombus dissolution.
Large randomized controlled trials have demonstrated relative mortality
benefits on the order of 20% to 30% when thrombolytic therapy is
administered in a timely manner.
a. Multiple thrombolytic agents are available in the United States. When
choosing an agent, one must consider factors such as efficacy, side
effect profile, ease of administration, and cost. Several of the major
thrombolysis trials are reviewed in Table 8-6.
b. Before a thrombolytic agent is administered, the patient must be
screened for potential contraindications that increase the risk of
intracranial hemorrhage and bleeding (Box 8-3).

98 Cardiology

TABLE 8-6
SELECT THROMBOLYTIC STUDIES
Study
Year
Findings
ISIS-2
1988
This placebo-controlled, randomized trial of 17,187 patients
demonstrated lower 30-day mortality with streptokinase
(9.2%) or aspirin (9.4%) treatment than placebo (13.2%)
(p < .00001) and lowest mortality when aspirin and
streptokinase were combined (8%) (p < .00001).23
GUSTO-1

1993

In this 41,021 patient study, patients treated with t-PA and

intravenous heparin had higher coronary patency rates and
better 30-day survival (6.4%) than patients treated with
streptokinase and subcutaneous or intravenous heparin
(7.4%) or a combination of reduced-dose t-PA and
streptokinase (7.2%).24

GUSTO-3

1997

This trial of 15,059 patients compared reteplase with

alteplase. The 30-day mortality rates were similar for the two
groups, as were the nonfatal stroke rates.25

ASSENT-2

1999

This trial of 16,949 patients compared tenecteplase and

alteplase. Mortality at 30 days was equivalent (6.18% vs.
6.15%, respectively); however, the tenecteplase-treated group
had fewer noncerebral bleeding events (26.4% vs. 28.9%,
p = .0003) and transfusions (4.2% vs. 5.5%, p = .0002).26

t-PA, tissue plasminogen activator.

c. Efficacy of thrombolytic therapy. Patients with complete resolution of

ST segment elevation at 90 minutes have a 93% likelihood of infarctrelated artery patency and a nearly 80% probability of TIMI 3 flow.27
Patients (approximately 20% to 30% of those receiving thrombolytic
agents) who do not have improvement or resolution of chest discomfort
or at least a 50% reduction in the degree of ST elevation within
60 minutes of thrombolytic administration should be considered for
immediate coronary angiography.28
d. Current recommendations of the ACC and AHA regarding thrombolytic
therapy are shown in Box 8-4.29
4. PCI. Primary PCI requires the immediate availability of a catheterization
laboratory and skilled staff. High-volume (49 or more procedures per
year) and intermediate-volume (17 to 48 procedures per year) centers
have lower mortality rates than low-volume centers.30 Despite these
limitations, primary PCI is the preferred therapy for ST segment
elevation MI when performed in a timely fashion and by skilled
practitioners. Thrombolytic therapy restores normal blood flow to the
infarct-related artery in 50% to 60% of patients,31 and primary PCI
does so in more than 90%.32 A meta-analysis of 23 trials showed
better outcomes for PCI than for thrombolytic therapy, with lower rates
of short-term death (7% vs. 9%, p = .0004), nonfatal reinfarction
(3% vs. 7%, p < .0001), stroke (1% vs. 2%, p = .0004), and the

Acute Coronary Syndromes 99

Modified from Antman EM et al: Circulation 110:588-636, 2004. Available at www.acc.org.

BOX 8-4
RECOMMENDATIONS OF THE AMERICAN COLLEGE OF CARDIOLOGY AND
AMERICAN HEART ASSOCIATION FOR THROMBOLYTIC THERAPY
CLASS I
ST elevation (>0.1 mm in 2 or more contiguous leads), time to therapy 12 hr
New or presumably new left bundle branch block within past 12 hr
CLASS IIA
12-lead electrocardiographic findings consistent with a true posterior MI within
12 hr of symptom onset
Patients with symptoms beginning within the past 12 to 24 hr with continued ST
elevation (>0.1 mm in 2 or more contiguous leads) and ischemic symptoms
CLASS III
ST elevation with time to therapy >24 hr
ST segment depression unless true posterior MI suspected
Data from Antman EM et al: Circulation 110:588-636, 2004. Available at www.acc.org.
MI, myocardial infarction.

8
ACUTE CORONARY SYNDROMES

BOX 8-3
ABSOLUTE AND RELATIVE CONTRAINDICATIONS TO THROMBOLYTIC
THERAPY FOR MYOCARDIAL INFARCTION
ABSOLUTE CONTRAINDICATIONS
Any prior intracranial hemorrhage
Known structural cerebral vascular lesion (e.g., arteriovenous malformation)
Known malignant intracranial neoplasm (primary or metastatic)
Ischemic stroke within 3 mo except acute ischemic stroke within 3 hr
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed head or facial trauma within 3 mo
RELATIVE CONTRAINDICATIONS
History of chronic, severe, poorly controlled hypertension
Severe uncontrolled hypertension on presentation (>180/110 mmHg)
History of prior ischemic stroke > 3 mo before, dementia, or known intracranial
disorder not covered in contraindications
Traumatic or prolonged (> 10 min) cardiopulmonary resuscitation or major surgery
(within 3 wk)
Noncompressible vascular punctures
Internal bleeding within 4 weeks
For streptokinase or anistreplase, prior exposure (especially within 2 yr) or prior
allergic reaction
Pregnancy
Active peptic ulcer
Current use of anticoagulants (the higher the international normalized ratio, the
higher the risk of bleeding)

100 Cardiology

combined endpoint of death, nonfatal reinfarction, and stroke (8% vs.

14%, p < .0001).33 Primary PCI is also associated with a significantly
lower rate of long-term (5-year) mortality than streptokinase (13% vs.
24%, p = .01).34
a. Transport to PCI sites. Recognition of the advantages of PCI over
thrombolytics has led investigators to explore whether the patient with
acute MI who presents to a hospital without catheterization facilities
should be transferred emergently to a site where PCI is available. If the
triage and transport time is short (90 minutes), then transfer of the
patient to a center with catheterization facilities may be preferable. In
the recent Danish Trial in Acute Myocardial Infarction (DANAMI-2)
study, patients treated in this manner had a lower incidence of
reinfarction than patients treated with thrombolysis.35 A recent
metaanalysis of 21 studies comparing PCI with thrombolytic therapy
showed equivalence of the two reperfusion strategies with respect to
30-day mortality when the delay to PCI was 62 minutes or more and
equivalence for the two strategies for composite endpoints of death,
reinfarction, or stroke when the delay to PCI was 93 minutes or more.36
Thus for institutions where timely administration of PCI is not practical,
thrombolytics remain the treatment of choice for ST segment elevation
ACS.
b. Current ACC/AHA recommendations for primary PCI are summarized in
Box 8-5.
5. GP IIb/IIIa receptor inhibitors. The role of GP IIb/IIIa receptor inhibitors
in ST segment elevation ACS is still being defined.
a. Many believe that administration of a GP IIb/IIIa receptor inhibitor
in conjunction with reduced-dose thrombolytic therapy provides
more complete macrovascular and microvascular reperfusion than
thrombolytic monotherapy. Several small trials in which a thrombolytic
agent and GP IIb/IIIa receptor inhibitor were given concomitantly
showed improvements in early angiographic IRA patency and ST
segment resolution.37-39 Larger trials, such as ASSENT 3 (tenecteplase
plus abciximab vs. tenecteplase)40 and Global Use of Strategies to Open
Occluded Arteries (GUSTO) V (reteplase plus abciximab vs. reteplase),41
have shown that survival after therapy with a GP IIb/IIIa inhibitor and
thrombolytic agent is no different than after a thrombolytic agent
is given alone. However, the combination is associated with a higher
incidence of bleeding complications and intracranial hemorrhage,
particularly in older adults. Therefore combination therapy is not
justified at this time.
b. When coupled with primary PCI, GP IIb/IIIa receptor inhibition
reduces the composite endpoint of death, MI, and the need for urgent
revascularization. The ADMIRAL trial (n = 300) demonstrated a
significant reduction in the combined endpoint of death, reinfarction,
and need for urgent repeat revascularization with abciximab in
patients undergoing PCI for ST segment elevation ACS (6.0% vs.

Acute Coronary Syndromes 101

Data from Antman EM et al: Circulation 110:588-636, 2004. Available at www.acc.org.

CHF, congestive heart failure; DTBT, door-to-balloon time; LBBB, left bundle branch block; MI,
myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST segment elevation
myocardial infarction.

8
ACUTE CORONARY SYNDROMES

BOX 8-5
RECOMMENDATIONS FOR PRIMARY PCI
CLASS I
As an alternative to thrombolytic therapy in patients with acute MI and ST segment
elevation or new or presumed new LBBB who can undergo angioplasty of the
infarct-related artery within 12 hr of onset of symptoms if performed in a timely
fashion (balloon inflation within 90 min of presentation) by people skilled in the
procedure and supported by experienced personnel in an appropriate laboratory
environment.
Specific Considerations
PCI should be performed as quickly as possible, with a DTBT goal <90 min.
If symptom duration is <3 hr and the expected DTBT minus door-to-needle time is
<1 hr, PCI is preferred; if DTBT minus door-to-needle time is >1 hr, fibrinolytic
therapy is preferred.
If symptom duration is >3 hr, PCI is preferred, with goal DTBT <90 min.
PCI should be considered, if clinically suitable, for patients <75 yr old with STEMI
or LBBB who develop shock within 36 hr of MI and can be revascularized
within 18 hr of shock.
PCI should be performed in patients with severe CHF or pulmonary edema (Killip
class III) and onset of symptoms within 12 hr, with DTBT as short as possible
(i.e., goal <90 min).
CLASS IIA
PCI is reasonable for patients with good functional status who are 75 yr or older
with STEMI or LBBB or who develop shock within 36 hr of MI and are suitable
for revascularization that can be performed within 18 hr of shock.
It is reasonable to perform PCI with symptom onset in the past 12-24 hours when
CHF or hemodynamic or electrical instability is present.
CLASS IIB
The benefit of primary PCI for patients with STEMI who are eligible for fibrinolysis
is not well established when performed by operators with fewer than 75 PCI
procedures per year.
CLASS III
PCI should not be performed in a noninfarcted artery at the time of primary PCI in
patients without hemodynamic compromise.
Primary PCI should not be performed in asymptomatic patients more than 12 hr
after onset of STEMI if they are hemodynamically and electrically stable.

102 Cardiology

14.6%, p = .01).42 The largest study of GP IIb/IIIa receptor inhibition

during primary PCI for ST segment elevation ACS, the CADILLAC study,
enrolled 2082 patients and demonstrated a significant benefit when
abciximab was used with PCI (with or without stenting). Major adverse
events occurred in 20% of patients in the primary PCI group, 16.5%
with primary PCI plus abciximab, 11.5% with stenting alone, and
10.2% with stenting plus abciximab (p < .001). The majority of benefit
seen with abciximab plus stenting was related to a lower risk of repeat
revascularization procedures.43 Nonetheless, as interventional techniques
evolve, GP IIb/IIIa receptor inhibitors continue to demonstrate consistent
benefits for patients treated with PCI reperfusion.
V. POST-ACS TREATMENT
A. COMPLICATIONS
Approximately 80% of in-hospital deaths after ST segment elevation ACS
are caused by severe left ventricular pump failure. The remaining 20%
of in-hospital deaths are caused by post-MI mechanical complications
(Table 8-7), including mitral regurgitation from a ruptured papillary
muscle, left ventricular free wall rupture, and acute ventricular septal
defect.44 Prompt clinical evaluation and bedside echocardiography of the
patient with circulatory collapse are important in establishing the diagnosis
and directing therapy.
Reperfusion arrhythmias are common after antegrade blood flow is
successfully reestablished in the IRA. Premature ventricular contractions,
nonsustained ventricular tachycardia, accelerated idioventricular rhythm,
and heart block are common after successful reperfusion. In addition, the
patient with an inferior infarct may have sinus bradycardia and transient
hypotension (Bezold-Jarisch reflex).
B. SECONDARY PREVENTION
Once stabilized, patients with ACS should undergo risk factor assessment
followed by the initiation of medications and lifestyle interventions for

TABLE 8-7
COMPLICATIONS OF MI

Papillary rupture causing

severe mitral regurgitation
Left ventricular rupture
Acute ventricular septal defect
Severe left ventricular
dysfunction and shock

Incidence (%)

Time to Onset
After MI

Percentage of
MI-Associated
Mortality

<1
2
7

2-7 d
5-14 d
Any time

5
10
5

Any time

80

Modified from Reeder GS: Mayo Clin Proc 70:880, 1995.

MI, myocardial infarction.

Acute Coronary Syndromes 103

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