Analytic Review

Journal of Intensive Care Medicine

2015, Vol. 30(4) 186-200
Acute Coronary Syndrome ª The Author(s) 2013
Reprints and permission:
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DOI: 10.1177/0885066613503294
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Nader Makki, MD1, Theresa M. Brennan, MD2,

and Saket Girotra, MD, SM2

Abstract
Acute coronary syndrome (ACS) is a major health care and economic burden in the United States and accounts for more than
1 million hospitalizations annually. The morbidity and mortality due to ACS are substantial—nearly half of all deaths due to
coronary heart disease occur following an ACS. This review provides an up-to-date summary of the pathophysiology, diagnosis,
and treatment of ACS. We also provide an overview of the management of common hemodynamic disturbances and myocardial
infarction complications that physicians often encounter in an intensive care setting.

Keywords
acute coronary syndrome, unstable angina, myocardial infarction, management

Introduction with either pharmacological or catheter-based approaches in

Each year approximately 635 000 Americans have a new epi-
sode of acute coronary syndrome (ACS), and approximately
280 000 have a recurrent event.1 Although mortality from ACS
has declined substantially,2 it is still estimated that 40% of the
patients who experience a coronary event will die within 5
years with the risk of death being 5 to 6 times higher in individ-
uals who experience a recurrent event.3,4 The economic burden
due to ACS is also quite substantial; annual cost per patient is
estimated to be US$22 528 to US$32 345 with the majority
being due to hospitalizations.5 Direct costs (physician, hospital
services, and prescribed medications) and indirect costs
(decreased productivity) were estimated to be at US$310 bil-
lion in 2009.1 Given the high prevalence of ACS, its deleterious
impact on health, and its economic consequences, improving
outcomes in patients with ACS through the use of evidence-
based treatments, can have significant societal benefits.
Pathophysiology
Rupture of an atherosclerotic plaque that results in partial or
complete occlusion of an epicardial coronary artery is the most
common mechanism responsible for ACS. Plaque disruption
exposes subendothelial collagen, which results in activation
of platelets and the coagulation cascade, leading to thrombus
formation.6 Reduction in blood flow due to coronary occlusion
and/or distal embolization of thrombus into coronary microcir-
culation results in symptoms of ischemic chest discomfort.
Thrombus may be completely or partially occlusive. Patients
with complete occlusion generally present with ST-segment
elevation myocardial infarction (STEMI). If the occlusion is
unresolved in a timely manner, it may result in transmural
infarction.7 This provides the rationale for early reperfusion
patients with STEMI. Patients with partially occluded coronary
arteries generally lack ST-segment elevation but may have
other changes suggestive of ischemia (eg, ST-segment depres-
sion, T wave inversions).7 These patients are classified as hav-
ing unstable angina (UA) or non-STEMI (NSTEMI),
depending on whether they have evidence of myocardial injury
(elevation in troponin).
Certain anatomic characteristics of the atherosclerotic pla-
que make it more likely to rupture and lead to ACS. These
include presence of a thin fibrous cap, a large lipid core popu-
lated by numerous inflammatory cells, abundant production of
matrix metalloproteinases, and relative lack of smooth muscle
cells.6,7 Also referred to as vulnerable plaque, such plaques can
evade angiographic detection, as they may not be anatomically
obstructive, and may remain silent until they trigger thrombo-
sis.8,9 In addition, several patient factors may increase the like-
lihood of plaque rupture resulting in ACS and sudden death.
Systemic inflammatory changes, changes in local shear stress,
platelet hyperreactivity, and prothrombotic states (transient
hypercoagulability from smoking, dehydration, infection,
1
Department of Internal Medicine, University of Iowa Hospitals and Clinics,
Iowa City, IA, USA
2
Division of Cardiovascular Diseases, Department of Internal Medicine,
University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Received April 10, 2013, and in revised form May 31, 2013. Accepted for
publication June 11, 2013.
Corresponding Author:
Saket Girotra, Division of Cardiovascular Diseases, Department of Internal
Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Ste 4430
RCP, Iowa City, IA 52242, USA.
Email: saket-girotra@uiowa.edu
Makki et al 187

Table 1. New Classification Scheme for Acute Myocardial Infarction (AMI).

Type 1 Spontaneous MI related to ischemia secondary to a primary coronary event like plaque rupture, erosion, or dissection.
Type 2 MI secondary to ischemia due to increased demand or decreased oxygen supply, for example, coronary artery spasm, anemia, sepsis in a
patient with coronary artery disease, arrhythmias, hypotension, and hypertension.
Type 3 Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia, accompanied by
presumably new ST-segment elevation, new left bundle branch block, or evidence of fresh thrombus in a coronary artery by
angiography and/or at autopsy, but death occurring before blood samples could be obtained or at a time before the appearance of
cardiac biomarkers in the blood.
Type 4 (4a) MI associated with percutaneous coronary intervention.
(4b) MI associated with stent thrombosis as documented by angiography or at autopsy.
Type 5 Myocardial infarction related to coronary artery bypass grafting (CABG).
Abbreviation: MI, myocardial infarction.

cocaine, malignancy, etc) facilitate this process.7,10 Myocardial
ischemia and/or infarction may also result from coronary artery
spasm, emboli, or dissection in the absence of atherosclerotic
coronary artery disease.11 Finally, instrumentation of the cor-
onary vessels during percutaneous coronary intervention (PCI)
or coronary artery bypass surgery (CABG) may result in myo-
cardial necrosis.
New Definition
Given the diverse mechanisms that may lead to myocardial
ischemia, a clinical classification system has been developed
to ensure consistency between clinical reports of myocardial
infarction (MI). This classification, which is based on clinical,
pathological, and prognostic differences, is shown in Table 1.12
Type 1 is due to plaque rupture with thrombosis, whereas
type 2 is secondary to an imbalance between myocardial oxy-
gen demand and supply with fixed atherosclerotic obstruction,
vasospasm, or endothelial dysfunction playing a permissive
role. Type 3 includes patients with sudden death having fatal
MI even though cardiac biomarker evidence is lacking. Finally,
types 4 and 5 include patients with MI associated with PCI and
CABG, respectively.
Clinical Features
Most patients with ACS describe chest discomfort that is deep,
poorly localized, and potentially radiating into the left arm,
jaw, or neck. The discomfort is usually prolonged (>20 min-
utes) and may be unrelieved by rest and/or nitroglycerin. For
those with prior episodes of stable angina, the discomfort asso-
ciated with ACS is usually more severe, though this is not
always a reliable marker of ACS. Patients may present with
symptoms other than chest discomfort; such ‘‘angina equiva-
lent’’ symptoms include dyspnea (most common), nausea and
vomiting, diaphoresis, and unexplained fatigue. Although most
patients with ACS may have an unremarkable physical exam-
ination, findings such as diaphoresis, cool and clammy skin,
presence of an S3 or an S4, an apical systolic murmur (due
to mitral regurgitation caused by papillary muscle dysfunc-
tion), and lung rales due to pulmonary edema suggest profound
ischemia and impending cardiogenic shock. Such patients may
seemingly appear stable, but they can deteriorate quite rapidly
and therefore should be triaged to cardiac intensive care unit
and/or, early coronary angiography.
Electrocardiogram
A 12-lead electrocardiogram (ECG) is the single most impor-
tant test in the initial evaluation of patients with ACS and
should be performed and reviewed within 10 minutes of arrival
of a patient with suspected ACS.13 Presence of ST-segment ele-
vation in 2 or more contiguous leads or a new left bundle
branch block (LBBB) in the appropriate clinical scenario iden-
tifies patients who would benefit from emergent reperfusion
therapy (Figure 1A and B). Findings such as transient ST-
segment elevation, ST-segment depression, and/or T-wave
inversions support a high likelihood of ACS. Such patients
need to be started on aggressive medical therapy and need to
be evaluated for early coronary angiography. While a normal
ECG reduces the likelihood of ACS, it should be remembered
that the posterior (Figure 2A and B) and lateral walls (Figure
3A and B) are not adequately represented on the ECG and
therefore may not completely exclude ischemia in those
territories.
Cardiac Biomarkers
In patients with clinical syndrome that is consistent with ACS,
elevation in cardiac biomarkers signifies MI. Cardiac troponins
T and I are the most sensitive and specific markers of myocar-
dial necrosis and have largely replaced other biomarkers. An
elevation in cardiac troponin above the 99th percentile of the
normal range for the specified assay constitutes an abnormal
test. Since it may take up to 6 hours following onset of myo-
cardial necrosis for troponin to become elevated, an initial
negative test should prompt a repeat test 6 to 9 hours later.
Importantly, reperfusion therapy should not be delayed in
patients with suspected STEMI until troponin elevation is
documented. In patients without ST-segment elevation but sus-
pected ACS, 2 negative tests 6 to 9 hours apart usually exclude
NSTEMI, but not UA, which by definition represents ACS
without myocardial necrosis. Although troponin assays have
greatly enhanced the ability to diagnose acute infarction, diag-
nosis of reinfarction using troponin may be difficult, given that
the levels may remain elevated up to 2 weeks following the
188 Journal of Intensive Care Medicine 30(4)

Figure 1. A, A 12-lead ECG representing anterior ST-segment elevation myocardial infarction (STEMI). This ECG was performed on a 56-year-old
man with previous history of drug eluting stent to proximal left anterior descending (LAD) artery who presented with several hours of chest pain
and diaphoresis. The ECG shows marked ST-segment elevation in all precordial leads. B, Angiographic still frame showing occluded LAD. The
patient had an occluded proximal LAD due to thrombosis of the old LAD stent. The patient had stopped taking his aspirin for a GI procedure. He
underwent successful primary percutaneous coronary intervention (PCI) with balloon angioplasty only. ECG indicates electrocardiogram.

Figure 2. A. A 12-lead ECG representing posterior infarct. This ECG was obtained on a 52-year-old woman with chest tightness and left neck
pain who presented within 30 minutes of onset. The patient became hemodynamically unstable shortly after presentation. Significant ST-segment
depressions are noted in the anterior precordial leads signifying a true posterior infarct along with subtle inferior ST-segment elevation. B,
Angiographic still frame showing an occluded proximal RCA. This patient had an occluded proximal RCA. The patient underwent successful
primary percutaneous coronary intervention (PCI) with a bare metal stent with immediate resolution of ST-segment elevation. The patient had
an uneventful recovery. Echocardiogram prior to discharge showed intact left ventricular function with mild hypokinesis involving the inferior
wall. ECG indicates electrocardiogram; RCA, right coronary artery.

initial injury. Creatinine kinase (CK), especially the MB frac-
tion, has a shorter half-life (3-5 days) and may be used in that
situation. Recently, introduction of highly sensitive troponin
assays into clinical practice has further improved the sensitivity
and specificity of diagnosing ACS, especially early in the clin-
ical course when traditional troponin assays may remain nega-
tive. In a recent study of 1818 patients with suspected ACS, a
single-sensitive troponin I assay at the time of admission sub-
stantially improved diagnostic accuracy (area under the curve
0.96) compared to traditional troponin assay.14 This could
potentially allow earlier detection of MI in patients with sus-
pected ACS.
It is important to emphasize that elevation in cardiac tropo-
nins identifies myocardial injury, regardless of the mechanism
of injury. This mechanism could be myocardial ischemia due to
ACS (most patients) or due to alternative etiologies that are
unrelated to ischemia (eg, decompensated heart failure, myo-
pericarditis, pulmonary embolism, trauma, etc). Therefore, ele-
vation in troponins should be interpreted in the appropriate
clinical context.
Makki et al 189

Figure 3. A, A 12-lead ECG representing lateral wall ischemia. This ECG was obtained on a 71-year old man with chest and jaw pain. There is
subtle ST-segment elevation in I, aVL, V5, and V6 and reciprocal changes most prominent in V1 and V2. Coronary angiography showed 99%
thrombotic lesion in a large diagonal artery. B. Angiographic still frame showing an occluded diagonal artery. The angiographic still frame for the
above patient showed an occluded large diagonal branch of the LAD. This was successfully treated with a drug-eluting stent. The procedure was
uneventful and the patient had complete resolution of chest discomfort. ECG indicates electrocardiogram; LAD, left anterior descending.

Diagnosing ACS in Critically Ill Patients
Although most patients with ACS are identified in the emer-
gency room, some patients experience ACS while hospitalized
for other indications (eg, postoperative patients in surgical
units, critically ill patients). Diagnosing ACS in such patients
may be challenging due to difficulty in obtaining clinical his-
tory due to concurrent illness or sedation, and presence of coex-
isting conditions that may produce ECG changes suggestive of
ischemia (eg, hyperkalemia). As a result, a heightened degree
of clinical suspicion is required which may be complemented
with interviewing family members, comparing recent ECG
with previous tracings, and using alternative diagnostic modal-
ities like bedside echocardiography for new wall motion
abnormalities indicative of ischemia. Managing ACS in this
population is rarely straightforward (eg, bleeding risk with anti-
platelet and antithrombotic treatments in postoperative
patients, risk of contrast-induced nephropathy in patients with
borderline renal function, etc), and therefore requires close col-
laboration with the primary medical and/or surgical team in
devising appropriate treatment plans. It is clear that critically
ill patients who have troponin elevation even in the absence
of ACS have a markedly worse prognosis.15
Reperfusion Therapy for Patients With STEMI
Emergent reperfusion therapy to establish flow in the infarct-
related coronary artery reduces infarct size and mortality in
patients with STEMI.13 Reperfusion may be achieved using
either pharmacological (eg, thrombolytics) or mechanical
means (eg, primary PCI). Achieving prompt reperfusion treat-
ment is the cornerstone of STEMI treatment and is regarded as
an important goal for health care systems delivering STEMI
care. If a thrombolytic strategy is chosen, it is recommended
that treatment be started within 30 minutes of patient arrival
(door-to-needle time). If a mechanical reperfusion strategy is
chosen (primary PCI), it is recommended that balloon inflation
in the infarct-related artery occurs within 90 minutes of patient
arrival (door-to-balloon time). Both these measures are
included as core measures of quality of STEMI care, under-
scoring the importance of timely reperfusion in these patients.
The choice of reperfusion treatment depends on the availability
of PCI capability and patient factors.
Primary PCI
Primary PCI is more effective in restoring coronary blood flow
compared to thrombolytics. A number of studies, including a
large meta-analysis have shown that when both are available,
primary PCI is superior to thrombolytics in reducing mortality,
recurrent MI, and stroke and is associated with lower risk of
bleeding, making it the reperfusion treatment of choice in
patients with STEMI (Figure 4).16 Very few patients are con-
sidered ineligible for primary PCI (eg, patients with poor arter-
ial access).
A major limitation of primary PCI is that it is not available at
all hospitals (only 25% of US hospitals have PCI capability).17
Treatment options for patients who present to hospitals without
PCI capability include administration of thrombolytics or
transfer to a center capable of performing primary PCI, a
choice that is governed by the rapidity with which transfer can
be achieved and patient factors. Studies have shown that the
incremental benefit of primary PCI over thrombolytics in
reducing mortality is completely lost when PCI-related delay
(door-to-balloon minus door-to-needle time) is more than 60
minutes.18 Others have suggested that this relationship may
be modified by patient factors (eg, age, infarct location, and ini-
tial delay in presentation) with lower tolerance for PCI-related
190
Figure 4. Short-term and long-term outcomes in patients with acute coronary syndrome (ACS) treated with thrombolytics versus percuta-
neous transluminal angioplasty. Adapted with permission from Keeley et al.16
delay in younger patients, those with anterior infarction, or
those presenting within 120 minutes of symptom onset.19
Real-world studies have also documented significant delays
in achieving timely reperfusion in patients with STEMI that
present to hospital without PCI capability and get transferred
to a PCI-capable center (median door to balloon time of 120
minutes, <20% of transferred patients achieved overall door
to balloon time under 90 minutes).20 Given that most of the
transferred patients were eligible for thrombolytics, it appears
that immediate on-site thrombolytics may be underutilized in
the real world. Current guidelines recommend that on-site
thrombolysis is preferred for eligible patients with STEMI in
whom transfer to a PCI-capable center cannot be achieved
within 90 minutes of patient arrival.13
Thrombolytics
An analysis of all randomized trials of thrombolytic agents,
which included at least 1000 patients, showed that thrombolytics
were associated with a 25% overall reduction in short-term mor-
tality in patients with ST-segment elevation or new LBBB.21
The absolute mortality reduction was 30 per 1000 for patients
Journal of Intensive Care Medicine 30(4)
presenting within 0 to 6 hours and 20 per 1000 for patients pre-
senting between 7 and 12 hours. Beyond 12 hours, the benefit
was uncertain although is still recommended in patients younger
than 65 years who have evidence of ongoing symptoms and per-
sistent ST-segment elevation. In older patients, the modest clin-
ical benefit of thrombolysis in late presenters may be offset by
increased risk of complications. Compared to patients who were
treated later, mortality benefit was much larger in patients who
were treated within 2 hours of onset of STEMI where it
approached the benefit afforded by primary PCI.22
A number of thrombolytic agents have been studied in STEMI
which include fibrin nonspecific agents (eg, streptokinase)23 or
fibrin-specific agents (eg, tissue plasminogen activator [t-PA],
reteplase, and tenecteplase).24-26 Due to its lack of fibrin specifi-
city and antigenicity, streptokinase is not commonly used in the
United States for patients with STEMI. On the other hand, t-PA
is fibrin specific and requires a bolus dose followed by an infusion
over 90 minutes. Modification of t-PA using recombinant tech-
nology has led to the development of third-generation agents
(tenecteplase, reteplase), which have more sustained plasma
half-life allowing them to be administered as a bolus dose only,
thereby simplifying treatment algorithms. Table 2 lists the
Makki et al 191

Table 2. Absolute and Relative Contraindication to Thrombolytic Therapy.

Absolute Contraindications Relative Contraindications

Any previous history of hemorrhagic stroke Oral anticoagulant therapy

History of stroke, dementia, or central nervous system Acute pancreatitis
damage within 1 year Pregnancy or within 1 week postpartum
Head trauma or brain surgery within 6 months Active peptic ulceration
Known intracranial neoplasm Transient ischemic attack within 6 months
Suspected aortic dissection Dementia
Internal bleeding within 6 weeks Infective endocarditis
Active bleeding or known bleeding disorder Active cavitating pulmonary tuberculosis
Major surgery, trauma, or bleeding within 6 weeks Advanced liver disease
Intracardiac thrombi
Uncontrolled hypertension (systolic blood pressure >180 mm Hg, diastolic blood
pressure >110 mm Hg)
Puncture of noncompressible blood vessel within 2 weeks
Previous streptokinase therapy
Traumatic cardiopulmonary resuscitation within 3 weeks

Table 3. List of Available Thrombolytic Agents.

Agent Dose Fibrin Specific Comments

Streptokinase 1.5 million units for 30-60 minutes No Lower cost

Neutralizing antibodies may limit
subsequent use
Risk of hypersensitivity
Less effective compared to fibrin-specific agents
Tissue plasminogen activator 15 mg bolus ! 0.75 mg/kg over Yes More effective than streptokinase.
(t-PA, altepase) 30 min ! 0.5 mg/kg over 60 minutes Costly
Short half-life, requires continuous infusion
Reteplase Two boluses 10 units each Yes Outcomes similar to alteplase
30 minutes apart Short half-life, allows bolus dosing
Tenecteplase Single bolus Yes As effective as alteplase
<60 kg: 30 mg Can be administered as a bolus due to
60-69 kg: 35 mg longer half-life.
70-79 kg: 40 mg
80-89 kg: 45 mg
>90 kg: 50 mg
Abbreviation: t-PA, tissue plasminogen activator.

absolute and relative contraindications of thrombolytics, and
Table 3 lists the available thrombolytic agents that are approved
for use in patients with STEMI in the United States. It is estimated
that nearly 40% of the patients treated with thrombolytic agents
may not achieve reperfusion in the infarct-related artery as
evidenced by ongoing symptoms, and/or persistent ST-segment
elevation on the ECG, and another 10% may develop recurrent
symptoms while in hospital after initial successful reperfu-
sion.27,28 Such patients are best managed with PCI (rescue PCI).
Given the potential need for rescue PCI, we recommend that all
patients with STEMI, following treatment with thrombolytics,
should be transferred to a PCI-capable hospital.
Revascularization in Patients With NSTEMI
of high-risk patients (patients with angina that is refractory to
medical therapy, ventricular tachycardia or other life-
threatening arrhythmias, cardiogenic shock, etc). There is no
role for thrombolytics in this group of patients (class III recom-
mendation). Patients with UA/NSTEMI should be admitted to
telemetry or intensive care unit depending upon their clinical
situation and undergo a period of medical stabilization as out-
lined below prior to undergoing coronary risk stratification.
Patients at high risk of short-term mortality should undergo
coronary angiography within 24 to 48 hours with the intent
to revascularize, whereas patients at low risk may undergo non-
invasive evaluation. A number of risk stratification schemes
are available, of which the most widely used is the Thromboly-
sis in Myocardial Infarction (TIMI) risk score.

In contrast to STEMI, the majority of patients with NSTEMI

and UA can be initially stabilized with medical therapy. Emer- Risk Stratification. The TIMI risk score is a 7-point scoring sys-
gent coronary angiography may be necessary in a small group tem that includes age (65), aspirin use in the last 7 days,
192 Journal of Intensive Care Medicine 30(4)

Table 4. Guidelines for PCI and CABG in Patients With UA/NSTEMI.

Recommendations for PCI

Early invasive strategy with angiography and PCI within 12–24 hours of admission (class I)
Early invasive PCI strategy in high-risk patients without serious comorbidity and who have amenable lesions for PCI (class I)
PCI or CABG in patients with 1 or 2 vessel CAD with or without proximal LAD but with a large viable at-risk territory (class I)
Recommendations for CABG
Significant left main CAD (>50%; class I)
Three vessel CAD, especially patients with LVEF less than 50% (class I)
Two vessel CAD with significant proximal LAD stenosis and either LVEF less than 50% or ischemia on stress testing (class I)
Poor or no options for PCI who have ongoing ischemia refractory to medical therapy (class I)
Abbreviations: CABG, coronary artery bypass surgery; LAD, left anterior descending; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percuta-
neous coronary intervention; UA, unstable angina.

severe angina (2 episodes in the last 24 hours), ST-segment
changes (0.5 mm), cardiac marker elevation, history of cor-
onary artery disease (CAD; 50% stenosis), and at least 3 risk
factors for CAD (hypertension, hypercholesterolemia, diabetes,
family history of CAD, and current smoker).29 This score
assess an individual’s 30-day risk of all-cause mortality, MI,
and recurrent ischemia. Studies have shown that patients with
higher scores are more likely to benefit from an early invasive
strategy.30 The tool is simple and easy to apply at the patient’s
bedside. The Global Registry of Acute Cardiac Events
(GRACE) risk score is an alternative method of risk stratifica-
tion. Although, it is more complex, it may be better at predict-
ing long-term events (eg, 6-month and 1-year mortality).31
Early Invasive Versus Conservative Strategy. An early invasive
strategy (diagnostic angiography with intent to revascularize)
is recommended in high-risk groups within 24 to 48 hours.
These include patients with high TIMI score, patients with
refractory angina, elevated cardiac biomarkers, hemodynamic
instability, and prior CABG and PCI within the last 6 months.
Early invasive strategy has been shown to reduce the risk of MI
(odds ratio [OR] 0.75, 95% confidence interval [CI] 0.65-0.88,
P < .05), severe angina (OR 0.77, 95% CI 0.68-0.87, P < .05)
and rehospitalization (OR 0.66, 95% CI 0.60-0.72, P < .05)
when compared to a conservative strategy in such patients.32
For low-risk patients or patients with significant comorbid-
ities (eg, advanced cancer, advanced Alzheimer’s disease, or
other noncardiac life-threatening conditions), an initial conser-
vative strategy is recommended. This strategy includes initial
medical stabilization followed by noninvasive evaluation with
echocardiography and a stress test (eg, exercise treadmill, or
adenosine myocardial perfusion scan, or dobutamine echocar-
diography) following initial medical stabilization. Presence of
high-risk findings on noninvasive evaluation (eg, large area
of ischemia, EF < 40%) should prompt coronary angiography
and revascularization as indicated. Table 4 lists the American
College of Cardiology/American Heart Association guidelines
for revascularization in patients with UA/NSTEMI.33
Medical Therapy
Administration of agents that increase myocardial oxygen sup-
ply or reduce myocardial oxygen demand may limit infarct
size. This is achieved through administration of supplemental
oxygen (class IIa recommendation), especially if patients are
hypoxemic. Nitroglycerin increases oxygen supply by dilating
coronary arteries and reduces myocardial oxygen demand by
reducing preload and afterload. It can be administered as a sub-
lingual tablet (0.3–0.6 mg up to 3 times), spray, or intravenous
drip (5–10 mg/min which may be up titrated to 200 mg/min, as
needed). Morphine also provides relief in chest discomfort; it
also helps to reduce preload and allay anxiety.
b-Blockers reduce myocardial oxygen demand by decreas-
ing heart rate, blood pressure, and contractility. Although they
are clearly beneficial in alleviating angina, acute b-blocker
therapy may precipitate cardiogenic shock in some high-risk
patients (eg, age greater than 70, systolic blood pressure less
than 120 mm Hg, heart rate greater than 110 bpm or less than
60 bpm and increased time since onset of symptoms of
STEMI). Caution is advised in using b-blockers in this set-
ting.34,35 Other relative contraindications to b-blocker therapy
include (PR interval greater than 0.24 seconds, second or third
degree heart block or reactive airway disease).
Oral preparations are acceptable and can be switched to
intravenous if patients are unstable. Goal of therapy is to reduce
heart rate to 60 beats/minute with a systolic blood pressure of
90 to 100 mm Hg. Calcium channel blockers are third-line
agents and are usually recommended in cocaine-induced and
vasospastic angina; only diltiazem and verapamil (both of
which act selectively on the heart muscle) have been shown
to reduce recurrent MI and death.36,37 b-Blockers and nitrates
are contraindicated in patients with right ventricular infarction
(evidence of ST-segment elevation on right sided EKGs) as
they may lead to dangerous hypotension.
Antiplatelet Agents. Antiplatelet agents form the cornerstone of
medical therapy in patients with ACS. Aspirin irreversibly
blocks the platelet enzyme cyclooxygenase 1 and prevents
collagen-induced platelet activation as well as the synthesis and
release of thromboxane A2, a potent platelet activator. Com-
pared with placebo, 160 mg of aspirin daily reduces the risk
of short-term (ie, 35-day) death by 23% in patients with
STEMI.23 A loading dose of 162 to 325 mg should be given
immediately followed by a maintenance dose of 75 to 100
mg; higher maintenance doses are associated with increased
bleeding risk without any mortality benefit.38
Makki et al
Clopidogrel is a thienopyridine that causes irreversible inhi-
bition of the P2Y12 receptor—the platelet surface ADP recep-
tor thereby preventing ADP-induced platelet aggregation. It is
a prodrug that requires metabolic activation by cytochrome
P450s to its active metabolite. There is overwhelming evidence
that clopidogrel reduces ischemic end points in all subsets of
patients with ACS (STEMI, NSTEMI, and UA).39-41 A loading
dose of 300 mg followed by a maintenance dose of 75 mg daily
is recommended; for patients who are planned for early PCI, a
loading dose of 600 mg achieves earlier platelet inhibition than
the 300 mg loading dose. Risk of major bleeding is increased in
patients treated with clopidogrel, which may be of particular
concern in patients referred for bypass surgery. It is recom-
mended that clopidogrel be discontinued at least 5 days before
planned/elective surgery if possible. After bypass surgery, clo-
pidogrel should be resumed whenever feasible and continued
for a period of up to 1 year.
Clopidogrel Resistance. There is significant interindividual
variability in the antiplatelet response to clopidogrel in popula-
tions.42 Several factors account for this interindividual variabil-
ity (also termed clopidogrel resistance)—diabetes, smoking,
ACS, potential drug interactions, and genetic polymorphisms
in the cytochrome P450 enzymes. In fact, polymorphism
involving the CYP2C19 enzyme, the major enzyme involved
in clopidogrel activation has received considerable attention
in the past few years. The wild-type allele is referred to as the
*1 allele and codes for an enzyme with normal activity. The *2
and *3 alleles code for a defective enzyme with little or no
metabolic activity, whereas the *17 allele codes for an enzyme
with enhanced activity. The reduced function CYP2C19 alleles
(*2 and *3) are relatively common (30% of whites, 40% of
blacks, and over 55% of East Asians).43 Patients with 1 (or
more) reduced function alleles have reduced (or absent) ability
to activate clopidogrel and therefore have lower platelet inhibi-
tion while receiving clopidogrel.44,45 These patients are at
increased risk of adverse cardiovascular events including stent
thrombosis, and this effect appears to be limited only to
patients who receive coronary stents.46 Prasugrel, which is less
dependent on CYP2C19 enzymes and ticagrelor, which does
not require metabolic activation are alternative therapies for
patients with recurrent events despite receiving clopidogrel.
Future studies will clarify whether tailoring antiplatelet therapy
based on genetic testing is beneficial in reducing cardiovascu-
lar events.47
Prasugrel is an alternative thienopyridine with a mechanism
of action similar to clopidogrel. However, it is much more
potent compared to clopidogrel and is less dependent on cyto-
chrome P450s for its enzymatic activation. As a result, patients
receiving prasugrel achieve more rapid (within 30 minutes fol-
lowing a loading dose of 60 mg) and complete platelet inhibi-
tion with significantly less interindividual variability in its
response.48 Clinical studies have confirmed that prasugrel is
much more effective in reducing ischemic events compared
to clopidogrel in patients with ACS.49 In addition, it is also an
alternative to clopidogrel in patients who may have recurrent
193
events (eg, stent thrombosis) while receiving clopidogrel (ie,
patients with clopidogrel resistance). The greater potency of pra-
sugrel is partly counterbalanced by an increased risk of bleeding.
It is contraindicated in patients with a previous stroke or transi-
ent ischemic attack, patients 75 years or older, or weighing less
than 60 kg.
Ticagrelor is a nonthienopyridine and a reversible ADP
receptor antagonist that does not require metabolic activation.
It is administered as a loading dose of 180 mg followed by a
maintenance dose of 90 mg twice a day. It is more potent than
clopidogrel and is also another alternative for patients with clo-
pidogrel resistance. In a large clinical trial involving 18 624
patients with ACS, ticagrelor was associated with a 16% reduc-
tion in cardiovascular events, and a 22% reduction in total mor-
tality compared to clopidogrel; rates of non-CABG major
bleeding and fatal intracranial bleeding were slightly
increased.50
Glycoprotein IIb/IIIa Inhibitors. Glycoprotein IIb/IIIa agents—
abciximab, eptifibatide, and tirofiban block the final common
pathway of platelet aggregation—the fibrinogen-mediated
cross-linkage of platelets through the GP IIb/IIIa receptor. With
the advent of oral dual antiplatelet therapy, these agents are
used much less commonly in patients with ACS. Current indi-
cations for use of glycoprotein IIb/IIIa inhibitors include
patients with UA/NSTEMI with refractory angina despite dual
antiplatelet therapy, patients not pretreated with dual antiplate-
let therapy prior to PCI or patients with a large clot burden dur-
ing PCI.51
Antithrombotic Drugs. Anticoagulant drugs are the cornerstone of
medical treatment of ACS. The choice of anticoagulation may
depend upon the reperfusion strategy, but full systemic anticoa-
gulation should be administered to all patients without contra-
indications. Table 5 provides details regarding individual
anticoagulation agents. For patients with STEMI and UA/
NSTEMI treated with invasive strategy, unfractionated
heparin, or bivaluridin is preferred.52-54 For patients treated
with conservative strategy, enoxaparin or fondaparinux are pre-
ferred agents.55,56Anticoagulation may be discontinued in
patients following PCI unless there are alternative indications
(eg, intra-aortic balloon pump, mechanical valve). However,
it should be continued for at least 48 hours in patients treated
with thrombolysis, or medically managed patients with UA/
NSTEMI.
Statins. Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-
coenzyme A reductase, an enzyme essential for cholesterol
production in hepatocytes. As a result, they increase the surface
expression of low-density lipoprotein (LDL) receptor and
increase clearance of LDL-cholesterol from the plasma. Given
the central role played by LDL-cholesterol in plaque formation,
lowering of LDL-cholesterol by statins has been shown to sig-
nificantly decrease the risk of recurrent coronary events and
mortality over long term.57 Guidelines recommend that LDL-
cholesterol target should be less than 100 mg/dL in patients
194 Journal of Intensive Care Medicine 30(4)

Table 5. List of Recommended Anticoagulation Agents in Patients With ACS.

Agent Mechanism Dose Comments

Unfractionated Binds antithrombin, which
heparin inactivates thrombin (IIa),
and activated factor Xa.
Enoxaparin Similar to UFH except greater 1mg/kg twice a day
specificity for Xa, and
reduced anti-IIa activity
Bivalirudin Direct thrombin inhibitor
Fondaparinux Factor Xa inhibitor
Abbreviations: ACS, acute coronary syndrome; ACT, activated clotting time; aPTT, activated partial thromboplastin time; PCI, percutaneous coronary interven-
tion; STEMI, ST-segment elevation myocardial infarction.
Bolus: 60-70 units/kg
Maintenance: 12-15 units/kg/hr
Prior to PCI: administer 0.3 mg/kg
bolus if last dose of enoxaparin was
more than 8 hours ago
Initial: bolus 0.1 mg/kg followed by
0.25 mg/kg/hr
Prior to PCI: additional bolus of 0.5 Anticoagulant activity can be monitored using ACT
mg/kg followed by 1.75 mg/kg/hr
2.5 mg once daily
Widely used, inexpensive
Anticoagulant activity can be easily monitored using
ACT or aPTT, which makes it attractive for use in
catheterization laboratory.
Risk of heparin-induced thrombocytopenia (HIT)
More predictable anticoagulant activity (doesn’t
require routine monitoring). Anti-Xa levels can be
used to monitor, however not widely available.
Dose response unpredictable in obese patients
Contraindicated in patients with advanced renal fail-
ure or dialysis
Lower risk of HIT
STEMI: not commonly used especially in patients
undergoing PCI due to difficulty in monitoring
anticoagulant activity.
NSTEMI: may be used as an alternative to heparin
especially in patients treated with an initial con-
servative strategy
Superior to heparin or enoxaparin due to lower risk
of bleeding
Can be used in patients with HIT
No anti-dote available
Expensive
Should not be used in patients treated with a con-
servative strategy (not studied)
Low risk of bleeding
Can be used in patients with HIT
Not recommended in patients undergoing invasive
treatment due to higher rates of guide catheter
thrombosis

with established CAD (post-ACS), with newer evidence sug-
gesting incremental benefit with even more aggressive targets
(LDL less than 70 mg/dL).58 However, statins have additional
pleiotropic effects, which include reducing inflammation, and
plaque stabilization that makes them beneficial even in the
short term (before significant LDL-cholesterol reduction is
achieved). High-dose atorvastatin 80 mg/d started within 1 to
3 days in patients with UA/NSTEMI was found to reduce the
risk of recurrent ischemia and rehospitalization within a few
weeks.59 Therefore, we recommend that statins be initiated
regardless of baseline cholesterol levels in all patients with
ACS within the first 24 hours of admission.
Inhibitors of Renin–Angiotensin–Aldosterone Axis. Angiotensin-
converting enzyme inhibitors (ACE-I) especially lisinopril and
captopril have been shown to decrease mortality in patients
with ACS who present with pulmonary congestion or reduced
ejection fraction (LVEF <40%; class I).60 Mortality benefit
with ACE-I was noted as early as 24 hours and has been attrib-
uted to its effects on ventricular remodeling.61 In patients who
cannot tolerate ACE-I, angiotensin receptor blockers (ARB; eg,
valsartan) may be used as alternative agents. The combination
of ACE-I and ARBs agents was found to be harmful in these
patients.62 Hyperkalemia and renal failure are common side
effects of these medications. The Eplerenone Post-Acute Myo-
cardial Infarction Heart Failure Efficacy and Survival (EPHE-
SUS) study found that the selective aldosterone receptor
blocker—eplerenone reduced mortality and rate of sudden car-
diac death in patients with MI complicated by LV dysfunction
and/or heart failure.63 Patients should be closely monitored for
development of hyperkalemia, especially in the setting of renal
failure.
Hemodynamic Compromise in Patients With ACS
Mortality in patients with ACS is commonly a result of circu-
latory failure due to severe LV dysfunction, or as a result of
complications. Most complications manifest themselves as
hemodynamic compromise. Common hemodynamic distur-
bances include cardiogenic shock, hypovolemia secondary to
hemorrhage, and arrhythmias.
Cardiogenic Shock. Cardiogenic shock is one of the dreaded
complications of ACS and is associated with a high mortality
Makki et al
(>50%).64 The incidence of cardiogenic shock in patients with
ACS ranges from 5% to 10%. Extensive myocardial damage
that results in severe LV dysfunction is the most common etiol-
ogy of cardiogenic shock. Patients with ACS and cardiogenic
shock usually have severe 3-vessel disease and involvement
of left anterior descending (LAD) is common. In addition,
patients with extensive right ventricular infarction (usually
seen in combination with inferior STEMI) can also have pro-
found hypotension and cardiogenic shock due to impaired fill-
ing of the LV. Less commonly, cardiogenic shock may result
due to the development of a mechanical complication (eg, rup-
ture of the interventricular septum resulting in ventricular sep-
tal defect, papillary muscle rupture resulting in acute mitral
regurgitation, and free wall rupture resulting in cardiac tampo-
nade). Mechanical complications have become less common in
the era of reperfusion therapy but still continue to occur, espe-
cially when reperfusion is delayed.
Clinically, patients may have respiratory distress, diaphor-
esis, and cool extremities in addition to other signs and symp-
toms of ACS. Altered mental status may result due to cerebral
hypoperfusion. On physical examination, patients usually have
tachycardia (heart rate >100/min), hypotension (SBP < 90 mm
Hg), hypoxemia, and cool extremities. An S3 gallop rhythm
may be present on cardiac auscultation. A holosystolic murmur
at the lower left sternal border signifies development of a ven-
tricular septal defect (VSD); an apical systolic murmur may be
heard in patients with acute mitral regurgitation. The ECG
changes are consistent with extensive ischemia. Development
of profound hypotension following administration of nitrogly-
cerin may indicate right ventricular infarction. Laboratory stud-
ies may show lactic acidosis and evidence of end-organ failure
(renal, hepatic, etc).
Hemodynamic criteria for cardiogenic shock include sus-
tained hypotension (systolic blood pressure <90 mm Hg for
at least 30 minutes), reduced cardiac index (<2.2 L/min/m2)
and an elevated pulmonary capillary wedge pressure (PCWP
>15 mm Hg); the latter can be assessed during a right heart
catheterization. Echocardiogram is especially helpful when
there is suspicion for mechanical complications (free wall rup-
ture, ventricular septal rupture, and papillary muscle rupture).
Invasive blood pressure monitoring is also recommended in
titrating vasopressor and/or ionotropes.
In addition to standard pharmacological support for ACS
(antithrombotics, antiplatelets that were previously discussed),
vasopressors, and/or inotropes are important in optimizing
myocardial performance, improving tissue perfusion and stabi-
lizing the patient. b-Adrenergic agonists (dopamine, dobuta-
mine) are helpful in improving myocardial contractility;
dobutamine may also lower afterload and improve end-organ
perfusion. Patients with right ventricular infarction should be
given a trial of plasma volume expansion before initiation of
inotropes. b-Blockers are contraindicated in patients with car-
diogenic shock. If severe hypotension (SBP < 70 mm Hg)
develops, vasopressors like norepinephrine may be needed
(Figure 5). Placement of an intra-aortic balloon pump (IABP)
can be valuable in this situation as it helps improve myocardial
195
performance by reducing afterload, improving coronary per-
fusion and increasing cardiac output. Thus, IABP may help
stabilize patients as definitive treatment is planned (eg,
revascularization, surgery for papillary muscle rupture, etc).
Although recent evidence has called into question the utility
of intra-aortic balloon in patients with cardiogenic shock,65
we believe they are still useful in stabilizing patients. Other
mechanical support devices like Impella, Tandem heart provid-
ing more robust LV support have been recently introduced, but
may not be as widely available.
Emergent revascularization is indicated in patients in car-
diogenic shock due to severe myocardial ischemia (class I) and
has been shown to reduce mortality, especially in patients less
than 75 years of age.66 At hospitals with PCI capability,
patients should promptly undergo coronary angiography and
PCI as indicated; CABG is used less often due to high operative
mortality. At hospitals without PCI capability, immediate
transfer to a PCI capable hospital should be considered after
stabilizing the patient. Although subgroup analyses of lytic
trials suggested a lack of benefit in patients with cardiogenic
shock, thrombolysis should be considered in patients with
STEMI who cannot be transferred to a PCI-capable center in
a timely fashion. Patients with cardiogenic shock due to
mechanical complications should be promptly evaluated by a
cardiac surgeon. Unless prompt surgery can be performed,
mortality in these patients is very high. Reducing afterload with
an intra-aortic balloon pump can be extremely beneficial in sta-
bilizing patients with a VSD or papillary muscle rupture prior
to surgery.
Bleeding
Given the central role of antiplatelet and antithrombotic treat-
ments in ACS treatment, bleeding is predictably a common
complication in patients with ACS. Bleeding should be consid-
ered in patients who become hypotensive. In patients under-
going PCI, access site bleeding accounts for a majority of
bleeding episodes. In post-PCI patients, hemopericardium due
to guidewire-induced coronary artery perforation is another
potential procedural cause of bleeding and should be consid-
ered as etiology of hypotension. Most bleeding episodes can
be managed with local control, and interruption of anticoagula-
tion. Hemopericardium post-PCI warrants urgent pericardio-
centesis as well as treatment of coronary perforation with
balloons/covered stents.
Several studies have shown that bleeding including minor
bleeding is associated with an increase in the risk of death,
MI, and stroke in patients with ACS.67 Treatments that lower
bleeding (eg, bivalirudin) also lower mortality in patients with
ACS.53,54 The causal mechanisms of the adverse impact of
bleeding on clinical outcomes remain unclear but may be
related to interruption of antiplatelet and antithrombotic regi-
mens, hypotension, anemia with reduction in oxygen delivery,
and potentially worsening myocardial ischemia.
Until recently, transfusion practices in patients with ACS
were based on liberal thresholds (<10 g/dL); recent evidence
196
Figure 5. Choice of pressors in patients with cardiogenic shock. Adapted with permission from Antman et al.13
has challenged this notion. Mortality is increased with blood
transfusion in patients who are hemodynamically stable, and
hematocrit as low as 25% may be well tolerated.60,68 Potential
explanations include platelet activation and aggregation,
impaired oxygen and nitric oxide delivery, all of which can
promote thrombosis and worsen degree of ischemia. As a
result, recent guidelines have recommended a more restrictive
transfusion threshold (hematocrit < 25%).
Arrhythmias
Patients with ACS are at risk of a variety of brady- and tachy-
arrhythmias. Here, we focus on atrioventricular (AV) block and
ventricular arrhythmias—the 2 common arrhythmias associ-
ated with ACS.
The mechanisms of AV block in patients with ACS include
ischemia or infarction of the conduction tissue, or increased
parasympathetic activity. First-degree and second-degree AV
blocks (Mobitz type I) are usually due to ischemia of the AV
node often seen in patients with involvement of the right coron-
ary artery. Bradycardia in these patients is usually self-limited
and does not require treatment, even when it progresses to com-
plete heart block because the escape rhythm (junctional
rhythm) is usually stable. Temporary pacing is rarely neces-
sary, and complete recovery of AV block occurs in a majority
of these patients. On the other hand, ischemia to the His-
Journal of Intensive Care Medicine 30(4)
Purkinje system (associated with extensive anterior infarction)
may be associated with second-degree Mobitz type II block
and/ or complete heart block. Escape rhythms in such patients
are unstable or they may progress to frank asystole. Therefore,
these patients frequently require temporary and even perma-
nent pacemaker.
While premature ventricular complexes or short runs of non-
sustained ventricular tachycardia (VT) are common in patients
with ACS, they are usually well tolerated and do not require
specific antiarrhythmic therapy (other than b-blockers).69 More
prolonged episodes can be accompanied by hypotension or
degenerate into ventricular fibrillation (VF). Treatment with
intravenous lidocaine (loading dosage: 1-1.5 mg/kg of intrave-
nous lidocaine followed by an infusion 1-3 mg/min) or intrave-
nous amiodarone (loading dose: 150-300 mg, followed by
infusion 0.5-1 mg/kg/min) is recommended. Defibrillation is
necessary in unstable patients or patients with VF.
Future Therapeutic Approaches
Although mechanical or pharmacological reperfusion in
patients with ACS has led to improved outcomes, some patients
do not achieve myocardial reperfusion despite restoration of
coronary flow (‘‘no-reflow’’). This is due to a combination of
distal embolization leading to microcirculatory occlusion,
ischemia, and reperfusion injury.70 For patients with a high
Makki et al
thrombus burden, manual aspiration has been shown to reduce
infarct size and mortality in patients with STEMI.71,72 Based on
an improved understanding of the pathogenetic mechanisms of
‘‘no-reflow,’’ a number of newer drugs (eg, endothelin receptor
antagonists) as well as old drugs (eg, nitroprusside, adenosine)
have been suggested to reduce the likelihood of ‘‘no-reflow’’;
these need to be evaluated in prospective randomized trials.
Another major advance during the past decade has been in the
field of intracoronary imaging using intravascular ultrasound,
and optical coherence tomography. These tools have greatly
enhanced tissue characterization of coronary plaques and made
it possible to reliably detect vulnerable plaques—plaques that
have a high risk of rupture.9 Although the technology is pro-
mising, clinical application is currently limited due to lack of
specificity of the available imaging techniques. Moreover, it
remains unclear whether specific interventions targeted at
patients with high burden of vulnerable plaques (eg, preemp-
tive stenting, escalation of pharmacotherapy, etc) will prevent
MI and reduce sudden cardiac death. Finally, the potential of
improving left ventricular function and remodeling using stem
cells that have been studied in a number of preclinical and early
clinical studies carries significant promise for the future.73,74
Conclusion
Patients with ACS account for a significant proportion of hos-
pitalization and health care costs in the United States. Over the
past 25 years, there has been significant improvement in our
understanding of the biology of atherosclerosis and the
mechanisms that lead to ACS. At the same time, important
breakthroughs in the development of newer drugs and treat-
ment protocols have led to improved outcomes. Diagnosis of
ACS hinges on careful history, physical examination, and ECG
and may be challenging in critically ill patients. Emergent
revascularization is indicated in patients with STEMI and those
with hemodynamic compromise due to ischemia (eg, cardio-
genic shock). Patients with UA and NSTEMI who are stable
on presentation can undergo a period of medical stabilization
with further management dictated by their underlying risk.
Close collaboration between internists, hospitalists, intensive
care physicians, cardiologists, and cardiac surgeons is of para-
mount importance.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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