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NON-ST SEGMENT ELEVATION MYOCARDIAL INFARCTION
25
and pulmonary congestion resulting from a large ante-
rior wall infarction.
The differential diagnosis for patients presenting with
a suspected ACS encompasses the spectrum of cardio-
vascular, pulmonary, gastrointestinal, and musculosk-
eletal disorders, among many others (see Table 2-1).
The most important goal of an emergency physician
is to consider those causes that are acutely life threat-
ening. This consideration is most commonly accom-
plished through interventions such as the history of
the event, physical examination, 12-lead electrocar-
diography, chest roentgenography, and routine blood
tests. There are several etiologies of coronary isch-
emia, which represent a perfusion imbalance between
myocardial oxygen supply and demand.
16
The AHA/
ACC recognizes fi ve types of myocardial ischemia or
infarction (see Table 2-2 on page 26). Acute coronary
syndromes are the most common cause of life-threat-
ening myocardial ischemia, and encompass several
disorders that represent a common pathology. The
primary event in these disorders is the acute rupture
of an intra-coronary atherosclerotic plaque result-
ing in platelet aggregation and subsequent thrombus
formation.
17
The subtypes of an ACS exist on a con-
tinuum of severity and include: unstable angina (UA),
non-ST-elevation myocardial infarction (NSTEMI),
and ST-elevation myocardial infarction (STEMI). The
fi rst two subtypes result from the subtotal occlusion
of a coronary artery; the only difference is positive
coronary syndrome, with reported positive likelihood
ratios greater than two.
6,9,11
The severity, duration,
and size distribution of the chest pain are not help-
ful predictors, nor is the patient’s response to nitro-
glycerin or a “GI cocktail.”
6,11–13
Other elements of
the history, such as nausea, diaphoresis, and dyspnea,
do occur frequently in patients with acute coronary
syndromes, but they generally play little role in differ-
entiating such syndromes from other common causes
of chest pain.
6,9–11
Traditional risk factors are important long-term
predictors for CAD, but their value in diagnosing
acute ischemic syndromes in an ED setting is less cer-
tain if of any value at all.
14
One retrospective study
fi nds that, for patients younger than age 40, the pres-
ence of traditional risk factors for CAD is additive
and quite helpful, with positive likelihood ratios of
approximately 3 and 7 for the presence of 2–3 and
3–5 risk factors, respectively. However, the pres-
ence of such risk factors are only modestly helpful in
patients age 40–65, and not helpful at all in patients
older than 65.
15
One study evaluating the predictive
value of various combinations of elements of the his-
tory in patients with suspected ACS fi nds that of those
patients who do not have a known history of CAD,
and present with sharp or stabbing pain that is pleu-
ritic, positional, or reproducible in nature, none are
diagnosed with ischemic heart disease.
4
Thus, certain
elements of the history are only minimally helpful in
diagnosing an ACS, and while the combination of
pertinent features is more helpful, history alone does
not allow for safe triage of such patients.
The physical examination of patients present-
ing with a suspected ACS should focus initially on
stability of the patient. Pertinent vital signs, such as
heart rate, blood pressure, and oxygenation status
should be closely monitored and corrected accord-
ingly. Features of potential decompensation, such as
elevated jugular venous pressure and auscultation of
mitral regurgitation, rales, or an S3, are noteworthy
when present, but the ability of clinicians to reliably
and accurately ascertain these items is variable and not
always possible during a rapid assessment in a noisy
ED.
9
Pulmonary and abdominal examinations may
provide clues to an alternative diagnosis. Largely, the
physical examination of the ACS patient is either nor-
mal or nonspecifi cally abnormal; obvious abnormali-
ties, if present, most often result from complications
of ACS, rather than the event itself—e.g., hypotension
Table 2-1. Differential diagnosis for nontraumatic
chest pain.
Life Threatening Non-life Threatening
Cardiac Cardiac
Acute coronary syndrome Pericarditis
Aortic dissection Stable angina
Noncardiac Noncardiac
Pulmonary embolism GERD
Pneumothorax Peptic ulcer disease
Esophageal rupture Pancreatitis
Pneumonia Cholecystitis
Esophageal spasm
Costochondritis
Cervical/thoracic spine
disease
Shingles
Anxiety
CHAPTER 2
26
The diagnostic value of the initial EKG in patients
presenting with a suspected ACS has been the subject
of numerous studies. Unfortunately, these studies dif-
fer with respect to the patient population, the method
for diagnosing an ACS, the defi nition of an abnormal
EKG, and the experience of the interpreting physi-
cian. Commonly reported sensitivities range from
40–81% yet may be as low as 20%.
19–22,6
However,
the sensitivity is proportional to the degree of isch-
emia, and is thus much higher for STEMI than it is
for UA/NSTEMI,
23
and is also higher when performed
during an episode of chest pain.
24
The specifi city also
ranges widely, but it is much higher for more defi ni-
tive fi ndings such as ST-elevation (as high as 95%)
than for ST-depression or nonspecifi c T wave changes
(as low as 35%).
2,20
While the presence of ischemic changes on the EKG
is certainly helpful in diagnosis, the absence of such
changes does not safely rule out ACS as the cause of
chest pain. The number of patients with a fi nal diag-
nosis of an ACS whose initial EKG is read as normal
ranges from 1–37%, while those with only nonspe-
cifi c EKG changes upon presentation range from
3–46%.
1,4,20,25–28
Confounding this problem is the fact
that 24–63% of patients who do not receive a fi nal
diagnosis of an ACS will have an initial EKG that is
not completely normal.
4,10
While a single EKG is rarely diagnostic, the value
of electrocardiography is directly proportional to
the number of EKGs performed.
2,26
Obtaining both
prehospital and in-hospital EKGs has been shown to
improve sensitivity, with a slight drop in specifi city.
22
Furthermore, the use of continuous EKG monitoring
with serial 12-lead EKGs has been shown to signifi -
cantly improve sensitivity for the diagnosis of both an
ACS and a myocardial infarction with little reduction
in specifi city.
29
The prognostic value of the initial EKG in patients
with an ACS has also been extensively studied. Severe
outcomes are fortunately quite low in patients whose
initial EKG is read as normal or nonspecifi c: 0–1% and
0.6–6% for death and life-threatening complications,
respectively.
23,25–27
Not surprisingly, the outcomes
for those patients whose initial EKGs show changes
suspicious for ischemia are worse.
23,27
Furthermore,
these risks appear to correlate with the type of isch-
emic changes present. One study reveals that the risk
of death or MI at 30 days is 5.5%, 10.5%, 9.4%,
and 12.5% for patients whose initial EKGs revealed
evidence of myocardial necrosis in NSTEMI, while
STEMI results from the total occlusion of a coro-
nary artery and produces transmural infarction with
ST-segment elevation on the standard 12-lead EKG.
17
Because both UA and NSTEMI result from identical
coronary pathophysiology, they are thus assessed and
managed in similar fashion.
Beyond the focused history and physical examina-
tion, the 12-lead EKG is the most important bed-
side test in the initial evaluation of patient with a
suspected ACS, and it should be performed without
delay upon patient arrival. When possible, this EKG
should be compared to a prior EKG to assess for
ischemic changes. An observational study of 63,478
patients with a suspected ACS fi nds a median time
of 15 minutes from arrival to initial EKG, but the
delay is greater than 10 minutes in 65% of patients.
Risk factors for such a delay are female gender, non-
Caucasian ethnicity, active tobacco use, prior percu-
taneous transluminal coronary angioplasty, lack of
medical insurance, and an off-hour presentation to a
teaching hospital. Although there was also an associ-
ated delay in therapy in these patients, there was no
difference in mortality or infarction rate.
18
Table 2-2. Clinical classifi cation of myocardial
infarction.
14
Type 1
Spontaneous myocardial infarction related to ischemia
due to a primary coronary event such as plaque rupture
(ACS) or dissection
Type 2
Myocardial infarction secondary to ischemia due to either
increased oxygen demand or decreased supply; examples
include coronary artery spasm, coronary embolism, severe
anemia, tachydysrhythmias, hypertension, and hypotension
(demand ischemia)
Type 3
Sudden unexpected cardiac death, including cardiac
arrest, due to a primary coronary event but before routine
diagnostic tests can be obtained
Type 4a
Myocardial infarction associated with PCI
Type 4b
Myocardial infarction associated with stent thrombosis
Type 5
Myocardial infarction associated with CABG
NON-ST SEGMENT ELEVATION MYOCARDIAL INFARCTION
27
have a defi nite or probable ACS, can be transferred
to a fl oor bed with continuous telemetry monitor-
ing. Patients in whom an ACS is considered unlikely
can safely be discharged for outpatient noninva-
sive testing after ED evaluation. For patients whose
diagnoses remain uncertain, chest pain centers have
been shown to decrease hospital costs and lengths
of stay, as opposed to inpatient evaluations, when
further investigation is required.
2
Regardless of the
disposition, patients with an ACS often receive ini-
tial therapy while in the ED. As opposed to patients
with STEMI, where the goal is to open the occluded
artery either medically with fi brinolysis or mechani-
cally with PCI, those with UA/NSTEMI are usually
treated medically, at least initially; fi brinolytic therapy
is contraindicated and is of no benefi t or even harm-
ful in this patient population.
36–38
Thus, the goal is to
restore a proper perfusion balance by decreasing oxy-
gen demand through a reduction in myocardial work-
load, and increasing oxygen supply by halting ongoing
thrombus formation (see Table 2-3). As discussed in
detail below, all patients with suspected ACS should
receive continuous oxygen therapy via nasal cannula,
chewable aspirin, and nitroglycerin unless contraindi-
cated, with further therapy once a defi nitive diagnosis
is obtained.
Medical therapies that decrease myocardial oxygen
demand include nitroglycerin, beta-blockers, and mor-
phine. Nitroglycerin primarily works through decreas-
ing venous return and thus cardiac preload, and to a
lesser extent through coronary artery vasodilatation.
39
It is most commonly given in a dissolving sublingual
form, but can also be given topically or intravenously.
Nitroglycerin has been shown to signifi cantly decrease
the severity and number of chest pain episodes.
39,40
A
isolated T-wave inversions, isolated ST-depressions,
isolated ST-elevations, and both ST-depressions and
elevations, respectively. A similar trend is seen at
6 months.
30
In addition to an appropriate symptom and EKG
abnormality, the diagnosis of myocardial infarction
requires the elevation of one or more cardiac-specifi c
biomarkers.
16
The most commonly used indicators
are the cardiac-specifi c troponins I and T (TnI and
TnT). Troponin molecules associate with tropomyo-
sin within muscle fi bers and thus regulate myocar-
dial contraction via their interaction with the actin/
myosin complex.
17
The cardiac-specifi c troponins
have near 100% specifi city for myocardial events,
and are thus preferred over CK-MB for the diagnosis
of myocardial infarction.
16
Elevated cardiac troponins
imply myocardial necrosis, and thus will be present
in STEMI and NSTEMI, but not in UA or stable
angina. The sensitivities of TnT and TnI for NSTEMI
have been reported at 94% and 100%, respective-
ly.
21
Because such elevations can take 4–6 hours after
an event to show, all patients with a suspected ACS
should have serial troponins checked with at least one
level collected 6 hours after the onset of symptoms.
2,21
Elevated cardiac-specifi c troponins indicate myocar-
dial necrosis, which is not limited to primary coronary
ischemia. Alternative causes range from non-urgent
causes, including demand ischemia, extreme exertion,
renal failure, pericarditis, and infi ltrative or infl am-
matory myocardial processes, to potentially life-
threatening etiologies, such as severe congestive heart
failure, pulmonary embolism, sepsis, cardiac contu-
sion, Takotsubo cardiomyopathy, and subarachnoid
hemorrhage.
16,31,32
Perhaps an equally important quality of cardiac-
specifi c troponins is their prognostic value. Elevated
levels are associated with a higher risk of death or
MI at 48 hours, 14 days, and 30 days.
33
In one trial,
the 42-day mortality of patients with UA/NSTEMI is
directly related to the initial TnI value: 1%, 3.7%, and
7.5% for TnI ⬍0.4 ng/ml, ⬎0.4 ng/ml, and ⬎9 ng/ml,
respectively.
34
Furthermore, the 72-hour troponin value
directly correlates to the extent of myocardial necro-
sis.
35
Thus, cardiac-specifi c troponins are an important
diagnostic and prognostic tool.
While the diagnostic evaluation is ongoing, the cli-
nician must determine the appropriate level of care for
the patient. Unstable patients obviously require ICU
admission, while those who are clinically stable, but
Table 2-3. Therapy for UA/NSTEMI.
Anti-Anginal Anti-Ischemic
Antiplatelet Antithrombotic
Oxygen Aspirin Unfractionated
heparin
Nitrates Clopidogrel Low molecular
weight heparins
Beta-blockers Glycoprotein IIb/IIIa
inhibitors
Direct thrombin
inhibitors
Morphine sulfate Fondaparinux
CHAPTER 2
28
intravenous beta-blocker therapy has merit. No
mortality benefi t exists, yet the beta-blocker group
noted a small reduction in infarct size and a slight
decrease in the incidence of ventricular fi brillation.
Unfortunately, this group also had a higher rate of
cardiogenic shock, particularly in elderly patients as
well as those with borderline perfusion; tachycardia;
and mild acute pulmonary congestion. These same
patients also developed bradycardia, hypotension,
and pulmonary congestion more frequently than the
non-beta-blocker treatment group. Thus, this study
suggests that the use of intravenous beta-blockers
early in the patient’s ACS is potentially problematic.
48
We must also realize that the potential physiologic
benefi ts of beta-blocker therapy can be achieved with
oral administration within the fi rst 24 hours of pre-
sentation. As such, the best course of treatment is to
evaluate the patient, determine the physiologic sta-
tus over a period of observation, and then offer the
appropriate beta-blocker therapy.
Antiplatelet therapy is a key feature in the man-
agement of UA/NSTEMI. For more than 25 years,
aspirin, an irreversible inhibitor of intracellular
thromboxane A2 production, has been the antiplatelet
drug of choice.
59
Numerous studies demonstrate ben-
efi ts of early aspirin administration for UA/NSTEMI,
in doses ranging from 75 mg once daily to 324 mg
four times daily, which include both short- and long-
term signifi cant reductions in myocardial infarction
and death.
60–66
The thienopyridines, clopidogrel and
ticlopidine, antagonize the cell surface ADP-receptors
that contribute to platelet aggregation.
59
Clopidogrel
is generally preferred over ticlopidine because of its
more favorable side effect profi le, and early admin-
istration has been shown to improve short-term and
long-term outcomes in patients with UA/NSTEMI.
66–71
Clopidogrel’s benefi t has been observed versus pla-
cebo, as well as in combination with aspirin versus
aspirin alone and its benefi cial qualities have been
demonstrated in patients treated with both primary
medical and interventional strategies.
66,67,69-73
For
patients undergoing early PCI, studies evaluating
the optimal dose and timing of clopidogrel admin-
istration report that a high loading dose of 600 mg
requires only 2 hours to attain an adequate platelet
inhibitory effect, while a lower loading dose of 300 mg
may require up to 15 hours for maximal effi cacy.
72,74,75
Because bleeding, including CABG-related bleeding
(but not non-CABG-related life-threatening bleeding)
pooled analysis of more than 2000 patients with acute
MI who were given nitrates (either nitroglycerin or
nitroprusside) reveals a signifi cant decrease in mor-
tality versus placebo, with the benefi t occurring early
during hospitalization.
41
Long-term studies evaluating
the use of intravenous, followed by oral, nitrates fails
to show a long-term mortality benefi t, but they verify
that nitrates are safe to use in the initial phases of an
ACS.
42,43
However, nitrate use requires caution in cer-
tain conditions, such as right ventricular infarction,
cardiogenic shock, or co-existent aortic stenosis.
Beta-blockers are another cornerstone of ACS
therapy. By reducing heart rate, blood pressure, and
contractility through interfering with adrenergic stim-
ulation, they reduce cardiac oxygen demand.
44
Many
studies have evaluated their early (within 12 hours)
use in an ACS with overall favorable results. The
short-term benefi ts of early beta-blocker use include a
reduction in chest pain, infarct size, re-infarction rate,
cardiogenic shock, life-threatening dysrhythmias, and
cardiac free-wall rupture.
44–51
There also seems to be
a short-term mortality benefi t to the early adminis-
tration of beta-blockers, although there are mixed
results from several studies, many of them were pre-
1990 and were conducted on a heterogeneous patient
population with mixed coronary syndromes.
44,48,49,51,52
Long-term follow-up confi rms a mortality benefi t
of early beta-blocker administration after an ACS,
and is primarily due to a reduction in cardiovascu-
lar death.
51,53–56
There are obvious safety concerns
to administering beta-blockers to certain patient
populations. It is best to avoid beta-blocker therapy
in patients with bradycardia, hypotension, or signs
of acute heart failure.
48,51,56
Studies show that beta-
blockers are safe to administer to patients with a his-
tory of chronic obstructive pulmonary disease, even if
it is severe, although one should only use cardioselec-
tive beta-blockers, and their use should be avoided in
patients who may be having an acute exacerbation
of the lung disease.
57,58
Should beta-blockers be con-
traindicated for pulmonary reasons, non-dihydropyri-
dine calcium-channel blockers may be used instead.
5
Morphine sulfate is recommended for patients with
persistent chest pain despite nitroglycerin and beta-
blocker therapy because of its anxiolytic and mild
venodilatatory properties.
5
In 2005, the ClOpidogrel and Metoprolol in
Myocardial Infarction Trial (COMMIT) was pub-
lished, and casts serious doubt on whether early
NON-ST SEGMENT ELEVATION MYOCARDIAL INFARCTION
29
to a routine upstream versus deferred selective (at the
time of PCI) approach, but this subject has not been
intensively investigated.
101,102
Despite the proven ben-
efi t of these agents, retrospective data suggest that
they are underused, which may be due to the fact that
most trials have invariably demonstrated an increase
in bleeding complications, mostly minor but in some
cases major.
95,103
Thus, the ideal form of anti-platelet
therapy must weigh individual risks and benefi ts, but the
fact that a small percentage of patients are resistant
to the effects of one class of antiplatelet medication
underscores the importance of having multiple avail-
able options.
Antithrombotic therapy is an important adjunct to
antiplatelet therapy in patients with UA/NSTEMI, as
the downstream effect of platelet aggregation is acti-
vation of the coagulation cascade. Unfractionated
heparin (UFH) inhibits factor Xa and soluble factor
IIa via antithrombin III activation in an approxi-
mately equal ratio.
104
Although individual trials have
slight differences with regards to the timing, dos-
ing, and route of administration of UFH, standard
bolus and pTT-guided continuous infusion therapy
are of overall short-term benefi t in patients with UA/
NSTEMI.
62,64,105–107
Although signifi cantly improved
outcomes have been demonstrated with isolation
therapy, the largest benefi t is seen in those patients
treated with concomitant aspirin, as they act via com-
plimentary mechanisms, and there seems to be some
risk of rebound ischemia after the discontinuation of
UFH in patients without aspirin protection.
105,108–110
The low molecular weight heparins (LMWH) selec-
tively inhibit factor Xa to a greater extent than factor
IIa, and have the advantage of more reliable pharma-
cokinetics, which eliminates the need for pTT-guided
dose adjustments.
104
Three LMWH, nadroparin,
dalteparin, and enoxaparin, have been studied as
alternatives to UFH, and there are pharmacological
and clinical differences between these three agents.
111
Enoxaparin has demonstrated superiority to standard
UFH therapy with regards to effi cacy, while dalteparin
and nadroparin have shown more mixed results, but
are acceptable alternatives.
104,111–119
Furthermore,
only enoxaparin has a sustained benefi t at long-
term follow-up.
120
However, most trials revealing
the superiority of enoxaparin were performed in the
era prior to the routine use of stents and glycopro-
tein inhibitors. Later trials comparing UFH versus
enoxaparin in the presence of glycoprotein inhibitors
is signifi cantly increased by co-administration of aspi-
rin and clopidogrel, it is recommended that clopi-
dogrel be withheld if urgent CABG is considered
likely.
68,69,72,73,76
The issue of clopidogrel therapy in the
ED is unresolved with regards to the most appropri-
ate patient for such therapy, as well as the time and
location of administration.
Glycoprotein IIb/IIIa inhibitors, the third class of
antiplatelet medications, work by inhibiting the gly-
coprotein IIb/IIIa receptor found on platelet cell mem-
branes.
59
The benefi ts of abciximab and eptifi batide
were initially observed in patients undergoing either
urgent or elective PCI, including patients with UA/
NSTEMI, where they signifi cantly decrease important
short-term cardiac outcomes.
77–85
Abciximab has since
shown a long-term mortality benefi t for this indication,
but no advantage is seen when it is used as primary
medical treatment for patients with UA/NSTEMI who
are not undergoing revascularization.
86,87
Tirofi ban
and eptifi batide provide signifi cant benefi t in patients
with UA/NSTEMI, either prior to PCI or as part of a
noninvasive approach.
88–92
Lamifi ban has more mixed
results in this patient population.
93,94
A meta-analysis
of all patients with UA/NSTEMI reveals signifi cantly
improved outcomes with glycoprotein inhibition, and
particular benefi t has been demonstrated in certain
high-risk patients, such as those with elevated tro-
ponins, diabetes, and a TIMI score greater than three
(Table 2-4).
59,73,95–99
In patients managed invasively,
the benefi t occurs both prior to and after PCI.
100
Trials
investigating the optimal timing of glycoprotein inhib-
itor administration have shown possible superiority
Table 2-4. TIMI risk score for UA/NSTEMI.
Age ⱖ 65
Known coronary stenosis ⱖ 50%
ST-segment depression on initial ECG
ⱖ 2 episodes of angina in the past 24 hours
Use of aspirin in the past 7 days
Elevated cardiac biomarkers
ⱖ 3 risk factors for CAD*
* Family history of CAD, hypertension, hypercholester-
olemia, diabetes, current smoking
Adapted from: Sabatine MS, Antman EM. The thrombol-
ysis in myocardial infarction risk score in unstable angina/
non-ST-segment elevation myocardial infarction. J Am
Coll Cardiol. 2003;41:89S–95S.
CHAPTER 2
30
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show less clear benefi t, but have maintained its sta-
tus as superior to UFH.
121–126
There is no benefi t to
long-term administration of any heparin agent, and
one should not switch between individual heparins
during acute treatment due to dosing differences that
compromise effi cacy or safety.
104,107,121
Minor bleed-
ing is signifi cantly increased with all LMWH versus
UFH, with a possibility of increased major bleeding,
but this risk must be balanced against the ease of
administration of LMWH and the proven superior
effi cacy of enoxaparin.
104,111,127
LMWH are contrain-
dicated in patients with renal failure or body weight
extremes.
Direct thrombin inhibitors (DTI) act independently
of antithrombin III to inactivate both soluble and
fi brin-bound factor IIa.
128
The two most studied DTI,
hirudin and bivalirudin, have equivalence or slight ben-
efi t with regards to effi cacy versus UFH in patients with
UA/NSTEMI, but most of these trials were performed
prior to the routine use of stents and glycoprotein IIb/
IIIa inhibitors, and primarily involved patients under-
going an early invasive strategy.
128–141
Furthermore,
heterogeneity exists with regards to safety, as hirudin
is associated with a signifi cantly higher rate of major
bleeding, while bivalirudin is associated with a signifi -
cantly lower rate.
138
The addition of either upstream or
downstream glycoprotein IIb/IIIa inhibitors to bivaliru-
din does increase the bleeding rate to approximate that
of patients treated similarly with UFH, and while less
bleeding has been observed with bivalirudin alone, there
may be a loss of effi cacy with bivalirudin in the absence
of a glycoprotein inhibitor.
139,140,142–144
Fondaparinux, a
direct factor Xa inhibitor, has recently been shown to
have equivalent effi cacy versus enoxaparin with a sig-
nifi cant reduction in major bleeding for UA/NSTEMI
patients.
145,146
As more therapies become available, the
potential number of combinations of antiplatelet and
antithrombotic agents is multiplying. Although this
will hopefully improve anti-ischemic management,
the potential for bleeding complications must always
be carefully assessed, as supratherapeutic dosing does
occur in the nonclinical trial-based world of everyday
practice, and is associated with increased mortality and
lengths of hospital stay.
147
Section IV: Decision making
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