Clinical Review & Education

JAMA | Review

Diagnosis and Treatment of Acute Coronary Syndromes

A Review
Deepak L. Bhatt, MD, MPH; Renato D. Lopes, MD, PhD; Robert A. Harrington, MD

Multimedia
IMPORTANCE Acute coronary syndromes (ACS) are characterized by a sudden reduction in
blood supply to the heart and include ST-segment elevation myocardial infarction (STEMI),
non-STEMI (NSTEMI), and unstable angina. Each year, an estimated more than 7 million
people in the world are diagnosed with ACS, including more than 1 million patients
hospitalized in the US.

OBSERVATIONS Chest discomfort at rest is the most common presenting symptom of ACS
and affects approximately 79% of men and 74% of women presenting with ACS, although
approximately 40% of men and 48% of women present with nonspecific symptoms, such as
dyspnea, either in isolation or, more commonly, in combination with chest pain. For patients
presenting with possible ACS, electrocardiography should be performed immediately
(within 10 minutes of presentation) and can distinguish between STEMI and non–ST-segment
elevation ACS (NSTE-ACS). STEMI is caused by complete coronary artery occlusion and
accounts for approximately 30% of ACS. ACS without significant ST-segment elevation on
electrocardiography, termed NSTE-ACS, account for approximately 70% of ACS, are caused
by partial or intermittent occlusion of the artery and are associated with ST-segment
depressions (approximately 31%), T-wave inversions (approximately 12%), ST-segment
depressions combined with T-wave inversions (16%), or neither (approximately 41%). When
electrocardiography suggests STEMI, rapid reperfusion with primary percutaneous coronary
intervention (PCI) within 120 minutes reduces mortality from 9% to 7%. If PCI within 120
minutes is not possible, fibrinolytic therapy with alteplase, reteplase, or tenecteplase at full
dose should be administered for patients younger than 75 years without contraindications
and at half dose for patients 75 years or older (or streptokinase at full dose if cost is a
consideration), followed by transfer to a facility with the goal of PCI within the next 24 hours.
High-sensitivity troponin measurements are the preferred test to evaluate for NSTEMI. In Author Affiliations: Brigham and
high-risk patients with NSTE-ACS and no contraindications, prompt invasive coronary Women’s Hospital Heart and Vascular
angiography and percutaneous or surgical revascularization within 24 to 48 hours are Institute, Harvard Medical School,
Boston, Massachusetts (Bhatt);
associated with a reduction in death from 6.5% to 4.9%. Division of Cardiology, Duke Clinical
Research Institute, Duke University
CONCLUSIONS AND RELEVANCE Each year, an estimated more than 7 million people are
School of Medicine, Durham,
diagnosed with ACS worldwide. For patients with STEMI, coronary catheterization and PCI North Carolina (Lopes); Department
within 2 hours of presentation reduces mortality, with fibrinolytic therapy reserved for of Medicine, Stanford University,
patients without access to immediate PCI. For high-risk patients with NSTE-ACS without Stanford, California (Harrington).
contraindications, prompt invasive coronary angiography followed by percutaneous or Corresponding Author: Deepak L.
Bhatt, MD, MPH, 75 Francis St,
surgical revascularization is associated with lower rates of death.
Boston, MA 02115 (dlbhattmd@
post.harvard.edu).
JAMA. 2022;327(7):662-675. doi:10.1001/jama.2022.0358 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

A
cute coronary syndromes (ACS) are defined by a sudden
reduction in blood supply to the heart and include
ST-segmentelevationmyocardialinfarction(STEMI)andnon–
ST-segment elevation ACS (NSTE-ACS). NSTE-ACS consists of non–ST-
segment elevation myocardial infarction (NSTEMI) and unstable
angina.1-4 Each year, an estimated more than 7 million people are di-
agnosed with ACS worldwide, including more than 1 million patients
hospitalized in the US for ACS.5,6 Approximately 5% of patients with
ACS die before hospital discharge.2,5-7 Coronary atherosclerotic plaque
rupture with thrombus formation accounts for approximately 70% of
fatal acute MIs and sudden coronary deaths.8 This review summa-
rizes current evidence regarding epidemiology, pathophysiology, clini-
cal presentation, diagnosis, treatment, and prognosis of ACS (Box).
Methods
We searched PubMed for English-language studies of the epidemi-
ology, pathophysiology, diagnosis, treatment, and prognosis of ACS
that were published from January 1, 2000, to January 1, 2022. A total
of 1094 articles were retrieved with the search. We manually in-
spected the reference lists of selected articles for other relevant

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 Diagnosis and Treatment of Acute Coronary Syndromes
sources. Of the 109 sources included in this review, 43 were clinical
trials, 14 were reviews, 21 were meta-analyses, 22 were observa-
tional studies, 1 was an autopsy study, and 8 were guidelines, sci-
entific statements, or consensus documents.
Epidemiology
STEMI accounts for approximately 30% of ACS and NSTE-ACS
accounts for approximately 70% of ACS (Figure 1).7,9 Risk factors
associated with ACS include older age, current tobacco use, diabe-
tes, and elevated levels of lipids, blood pressure, and body mass
index.10 High-income regions, such as the US and Western Europe,
have experienced a decline in MI since approximately the
mid-1980s.11 A 25-year study (1984-2008) in Denmark found that
the standard incidence of MI per 100 000 people decreased by
37% in women (from 209 to 131) and by 48% in men (from 410 to
213).11 This is likely due, in part, to population declines in the preva-
lence of cigarette smoking. For example, in Pueblo, Colorado,
smoking cessation was associated with a 27% decrease in the inci-
dence of MI, from 257 to 187 cases per 100 000 person-years.2,12
Rates of ACS have increased in younger people. For example,
between 1995 and 2014, the percentage of acute MI admissions for
patients aged 35 to 54 years increased from 27% to 32% (21% to 31%
among women and 30% to 33% among men).13,14 When a patient
50 years or younger presents with ACS and does not have tradi-
tional risk factors, a toxicology screen should be performed be-
cause cocaine or marijuana is an instigating factor in approximately
10% of ACS among patients in this age range.15-17 The Determi-
nants of Myocardial Infarction Onset Study found that rates of ACS
were higher during the 60 minutes after marijuana use compared
with periods of nonuse; of the 124 patients with MI who smoked mari-
juana, 37 (29.8%) smoked within 24 hours of MI onset and 9 (7.3%)
within 1 hour of symptom onset.18 Patients with a history of ACS
should be advised not to smoke marijuana.
ACS is common among older people. About 85% of deaths as-
sociated with ACS occur in those 65 years or older, and patients 65
years and older account for approximately 60% of ACS hospital ad-
missions in the US.19 ACS is common in rural populations in the US.
In 2017, the age-adjusted mortality rate per 100 000 population per
year for cardiovascular disease was 251.4 in rural communities com-
pared with 208.6 for large metropolitan areas in the US.20 An esti-
mated 80% of cardiovascular deaths now occur in low- and middle-
income countries, such as Brazil, Russia, India, and China.21
Pathophysiology
Approximately 64% of ACS are due to rupture of lipid-laden plaque
that is incited by inflammation and followed by platelet-rich throm-
bosis (Figure 2).22 When thrombosis completely occludes the ves-
sel, STEMI occurs. When the thrombus is nonocclusive, NSTEMI typi-
cally occurs. It is important to recognize that complete vessel
occlusion does not always result in ST-segment elevation. In par-
ticular, vessels supplying the lateral wall of the left ventricular myo-
cardium, such as the left circumflex artery or a large diagonal branch
arising from the left anterior descending artery, may result in less
characteristic changes, such as ST-segment depression.23
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Review Clinical Review & Education
Box. Commonly Asked Questions About Acute Coronary
Syndromes (ACS)
What Are ACS?
• ACS refer to a sudden reduction in blood supply to the heart
muscle due to ST-segment elevation myocardial infarction
(STEMI), non-STEMI (NSTEMI), or unstable angina.
How Are ACS Diagnosed?
• In addition to a clinical history that most often includes sudden
onset of severe chest discomfort, prompt electrocardiography
and high-sensitivity troponin measurements are necessary to
determine whether ACS are present and the etiology of the ACS
(ie, STEMI, NSTEMI, or unstable angina), which determines the
therapeutic strategy.
What Causes ACS?
• The most common cause of ACS is rupture of atherosclerotic
plaque with thrombus formation. Other less-frequent causes
include plaque erosion, calcific nodules, coronary spasm,
spontaneous coronary artery dissection, coronary embolism, and
myocardial infarction with nonobstructive coronary arteries.
Do All Patients With ACS Need a Cardiac Catheterization?
• The majority of patients, such as those with electrocardiographic
changes, elevated troponin levels, ongoing chest pain,
hypotension, or ventricular arrhythmias, will need to undergo
cardiac catheterization and, based on their coronary anatomy,
percutaneous or surgical revascularization. Low-risk patients
without these features are most often initially treated with
medications only and noninvasive testing to stratify risk.
Alternative mechanisms such as plaque erosion (when throm-
bus forms on fibrointimal plaque rather than the necrotic core of the
plaque) may also be responsible for ACS and may be more com-
mon in women than men (Table 1). In an autopsy study of 291 pa-
tients who died of acute MI due to acute coronary thrombosis, 74
(25%) showed plaque erosion.24 Plaque erosion was more com-
mon in women than in men (37.4% vs 18.5%).24 Calcific nodules, de-
fined as a protruding nodular calcification with attached thrombus
on a lumen surface, are another potential cause of ACS. Patients with
calcific nodules may have worse cardiac outcomes after percutane-
ous coronary intervention (PCI) due to the elevated cardiac event
risk associated with coronary calcification.25 One retrospective analy-
sis of 657 patients with ACS reported that patients with calcific nod-
ules, compared with those without calcific nodules, had higher rates
of major adverse cardiovascular events (57.0% vs 8.8%), ACS reoc-
currence (37.0% vs 3.4%), and target lesion revascularization (46.0%
vs 5.3%) over a median follow-up of 1304 days.25
Additional causes of ACS include coronary spasm, coronary ar-
tery dissection, and other causes of MI with nonobstructive coro-
nary arteries (MINOCA).26-31 MINOCA is defined as acute MI asso-
ciated with a rise and fall of troponin on serial assessment with at
least 1 value above the 99th percentile upper reference limit, com-
bined with clinical evidence of infarction, nonobstructive coronary
arteries on angiography, and no alternative etiology to explain the
diagnosis. MINOCA is present in approximately 5% to 6% of pa-
tients with MI.30,31 Women are approximately 5 times more likely
than men to have MINOCA (14.9% vs 3.5%), and patients who are
“non-White” are approximately 1.5 times more likely than patients
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 Clinical Review & Education Review Diagnosis and Treatment of Acute Coronary Syndromes

Figure 1. Initial Diagnosis and Management of Acute Coronary Syndromes

Perform immediate electrocardiogram (ECG) when acute coronary syndromes (ACS) are suspected
ST-segment elevation is present on ECG ST-segment elevation is not present on ECG
ST-segment elevation myocardial infarction (STEMI)a diagnosed Non–ST-segment elevation ACS (NSTE-ACS) diagnosed

Treat with antiplatelet and anticoagulant therapy Treat with antiplatelet and anticoagulant therapy

Catheterization laboratory available within 2 h Elevated high-sensitivity troponin levels present within 3 h
YES NO YES NO

Treat with fibrinolytics NSTEMIb diagnosed Unstable angina b diagnosed

- Alteplase, reteplase, or tenecteplase
- Streptokinase (if cost is a consideration)
High-risk features present (heart failure, ECG changes,c
ongoing chest discomfort, or hemodynamic instability)
Transfer to percutaneous coronary YES NO
intervention (PCI) facility within 24 h

Medical therapy and risk factor control

Perform coronary angiography to assess presence of obstruction
Obstruction not present
Myocardial infarction with
nonobstructive coronary
arteries diagnosed
Medical therapy and risk factor control
only, no coronary revascularization
Obstruction present
Noninvasive evaluation (eg, computed
tomography angiography or stress testing)
Treat with PCI
STEMI — within 2 h if catheterization laboratory Significantly abnormal results present
is available (within 24 h if transfer to outside YES NO
facility is necessary)
NSTE-ACS — within 24-48 h if appropriate for
coronary anatomy, otherwise proceed with medical Continue medical therapy
therapy or coronary artery bypass graft surgery and risk factor control

b
Electrocardiography and serial troponin measurements form the basis of the ECG changes other than persistent ST-segment elevations may be present.
diagnosis of the exact type of acute coronary syndrome and help guide further c
ECG changes include transient ST-segment elevations, ST-segment
management. This proposed treatment algorithm has not been validated. depressions, and T-wave inversions.
a
In cases of STEMI, troponins would also likely be positive, but reacting quickly
is a priority over test results.

who are White to have MINOCA (14.9% vs 10.0%).30 These less-
common forms of MI generally require evaluation with contrast car-
diac magnetic resonance imaging or coronary vascular imaging to
establish the diagnosis.31 Tachyarrhythmias, heart failure, and myo-
carditis can cause troponin level increases that are not due to ACS,
and therefore it is important to interpret troponin levels in the con-
text of whether the clinical presentation is consistent with ische-
mic symptoms and ACS.2
Clinical Presentation
The most common symptom of ACS is chest discomfort. One sys-
tematic review and meta-analysis that included 1 226 163 patients
from 27 observational studies demonstrated presence of chest
pain in 79% of men and 74% of women with ACS.1,32 Although a
higher prevalence of “atypical” symptoms has been associated with
ACS in women, more recent evidence suggests that sex differences
in symptoms are likely due to differing descriptions and interpreta-
tions of symptoms rather than to actual major differences in
presentation.32 Therefore, symptoms in women presenting with
ACS are no longer considered “atypical.”1,32 However, symptoms
other than chest discomfort, such as dyspnea, are slightly more
common in women than in men (48% and 40%), but concomitant
chest discomfort is most often also present. Common non–chest
pain symptoms in people with ACS include pain between the
shoulder blades, neck pain, palpitations, jaw pain, nausea or vomit-
ing, fatigue, shortness of breath, indigestion, dizziness, syncope,
stomach or epigastric pain, left arm and shoulder pain, and
diaphoresis.32 Similarly, older age and diabetes are not associated
with distinct ACS presentations, although older patients and
patients with diabetes may be more likely to present with symp-
toms such as shortness of breath rather than chest pain.2 In a trial
that examined troponin concentrations in 2285 patients with
stable multivessel coronary artery disease and diabetes, 39.3% of
patients had elevated troponin (ⱖ14 ng/L) at baseline, which may
complicate the rapid diagnosis of ACS.33 This phenomenon is par-
ticularly common in patients with impaired kidney function and
especially in those with end-stage kidney disease because troponin
is excreted by the kidneys. Measurement of troponin over 2 to 3
days can help exclude ACS in patients with chronic kidney disease,
because absence of a rise and fall in troponin level reduces the like-
lihood of ACS. However, even in the absence of ACS, an elevated
troponin level is associated with a higher risk of subsequent cardio-
vascular events and warrants intensive cardiac risk factor manage-
ment, including antiplatelet and lipid-lowering therapy.33
Assessment and Diagnosis
When ACS are suspected, current clinical practice guidelines rec-
ommend performing electrocardiography within 10 minutes of pre-
sentation to an emergency department (Figure 1).1,2 If ST-segment
elevation is present, then emergent invasive coronary angiography,

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 Diagnosis and Treatment of Acute Coronary Syndromes Review Clinical Review & Education

Figure 2. Plaque Rupture and Other Etiologies of Acute Coronary Syndromes

A Coronary artery anatomy

Layers of a coronary artery

Aorta Endothelium
Left coronary artery
SMOOTH
Right ARTERY MUSCLE
VASA
coronary artery CROSS
Acute coronary VASORUM
SECTION
artery obstruction
Tunica intima

Ischemia Tunica media

or infarction
Tunica adventitia

B Types of acute coronary syndromes (ACS)

Plaque rupture (≈60% of patients with ACS) Plaque erosion (≈25% ) Calcified nodule (≈5%)
ST-segment elevation myocardial infarction STEMI or NSTEMI STEMI, NSTEMI, or unstable angina
(STEMI) or non-STEMI (NSTEMI)

Lipid-laden plaque Lipid-rich plaque

with inflammatory with diffuse
cells Denuded calcium deposits
endothelial surface
Thin fibrous cap caused by local flow Protruding eccentric
perturbation nodular calcification
Plaque rupture Constrictive
remodeling

Formation of Thrombus
Formation of fibrin- platelet-rich
and platelet-rich thrombus
thrombus

Coronary spasm (≈1%-5%) Spontaneous dissection (≈1%-4%) Embolism (≈1%-3%)

STEMI, NSTEMI, or unstable angina STEMI or NSTEMI STEMI or NSTEMI

Intimal tear

False lumen

Focal smooth True lumen Embolus

muscle spasm of cardiac or
noncardiac origin
Hematoma can occur
in vessel wall

Other characteristics of coronary spasm

• May occur independent of or in conjunction
with other types of ACS
• Can be multifocal or multivessel
• Possibility of spasm may increase with presence
of damaged endothelial cells

MI with nonobstructive coronary arteries (≈5%-6%) — See Table 1 for more information

Rupture of cholesterol-laden plaque triggered by inflammation with dissection, and coronary embolism. If there is no angiographically significant
superimposed platelet-rich thrombus formation is the predominant mechanism epicardial obstructive disease, myocardial infarction with nonobstructive
of acute coronary syndromes, but there are several other etiologies, including coronary arteries is diagnosed.
plaque erosion, calcific nodules, coronary spasm, spontaneous coronary artery

if available within 2 hours, should be performed to confirm the ACS without significant ST-segment elevations on electrocar-
diagnosis of STEMI and treat with PCI. diography are associated with ST-segment depressions (31.3%),

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 Clinical Review & Education Review
Table 1. Pathophysiology and Characteristics of Acute Coronary Syndromes (ACS)
Type of
Cause ACS Pathophysiology
Plaque rupture STEMI or Lipid-laden plaque rupture due to
NSTEMI inflammation followed by
development of platelet-rich
thrombosis
Plaque erosion STEMI or Plaque erosion occurs with local
NSTEMI flow perturbation, resulting in a
denuded endothelial surface with
formation of neutrophil
extracellular traps and propagation
of thrombus formation
Calcific nodule STEMI, A protruding nodular calcification
NSTEMI, penetrates the lumen surface with
or UA subsequent thrombus formation
Coronary spasm STEMI, Extreme vasoconstriction of an
NSTEMI, epicardial coronary artery, which
or UA causes near-total or total vessel
occlusion and sometimes
superimposed thrombosis; can also
occur in the microvasculature
Spontaneous STEMI or Obstruction to blood flow due to an
coronary artery NSTEMI intimal tear as well as separation of
dissection the medial and adventitial vascular
(SCAD) walls associated with intramural
hematoma protrusion into the
lumen; either in single or multiple
arteries; more often affects the
middle and distal portions of the
artery, most commonly the left
anterior descending artery
Coronary artery STEMI or Conditions such as atrial
embolism due to NSTEMI fibrillation, left ventricular
thrombus from thrombus, valvular thrombus, or
elsewhere in the paradoxical emboli from the
body causing venous system passing through an
obstruction atrial or ventricular septal defect
are associated with coronary artery
embolism, which leads to complete
obstruction of an epicardial
coronary artery or branch and
infarction of the myocardium
served by that vessel
Myocardial STEMI or Can occur from a variety of causes,
infarction with NSTEMI eg, plaque disruption (plaque
nonobstructive rupture or erosion and calcific
coronary nodules), epicardial coronary
arteries vasospasm, microvascular
dysfunction, spontaneous coronary
artery dissection, coronary
embolism, or coronary thrombosis,
which lead to MI despite the
absence of any severe obstructive
coronary artery stenoses, although
the specific cause often remains
undiagnosed
T-wave inversions (11.7%), both (15.7%), or neither (41.2%). 9
When a patient presents with symptoms of ACS but does not
have ST-segment elevation, rapid testing with high-sensitivity tro-
ponin, such as cardiac troponin T or I, should be performed. If the
initial high-sensitivity troponin measurement is normal, a second
normal measurement within 3 hours can reliably exclude ACS
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Diagnosis and Treatment of Acute Coronary Syndromes
Percentage
Characteristics of ACS
Most common etiology in both Approximately
sexes 60%8
More common in women than Approximately
in men 25%24
Patients with chronic kidney Approximately
disease and those receiving 5%25
dialysis have a higher
prevalence of coronary calcific
nodules; calcific nodules are
associated with a higher rate
of requiring repeated coronary
revascularization due to
growth of the calcified nodule
In patients with ACS who do Approximately
not have obstructive coronary 1%-5%26,27
artery disease on angiography,
coronary spasm can be
evaluated with provocative
testing, such as administering
acetylcholine, although it is
typically treated empirically
without such testing
Approximately 90% of patients Approximately
with SCAD are women 1%-4%28
(approximately 55% are
postmenopausal); emotional
stress reported in
approximately 50% of patients
and physical stress
in approximately 30% of
patients; fibromuscular
dysplasia, systemic
inflammatory disorders,
peripartum state, and
connective tissue disorders
predispose; best to reserve PCI
or CABG for refractory
symptoms
Evaluation with Approximately
transesophageal 1%-3%29
echocardiography and
continuous electrocardio-
graphic monitoring are useful
to evaluate for several of the
causes
More prevalent in women Approximately
(5 times higher odds) and 5%-6%30
non-White patients (1.5 times
higher odds); less likely to Abbreviations: ACS, acute coronary
have traditional cardiovascular syndromes; CABG, coronary artery
risk factors bypass grafting; NSTEMI,
non–ST-segment elevation
myocardial infarction; PCI,
percutaneous coronary intervention;
STEMI, ST-segment elevation
myocardial infarction; UA, unstable
angina.
with a negative predictive value of approximately 99%, although
algorithms that suggest testing at presentation and again 1 or 2
hours later may be preferred.2,34 Prompt evaluation with bedside
echocardiography may identify a new wall motion abnormality in
patients presenting with NSTEMI in the setting of ongoing chest
discomfort or ST-segment depression. These patients require
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 Diagnosis and Treatment of Acute Coronary Syndromes
immediate coronary angiography and revascularization when
anatomically appropriate.
Exercise stress testing with or without myocardial imaging, or
noninvasive computed tomographic (CT) coronary angiography,
can stratify risk in patients who do not have electrocardiographic
abnormalities, troponin elevation, arrhythmia, hemodynamic insta-
bility, or ongoing chest pain and determine whether they have
symptomatic coronary artery disease.35 Patients with a normal CT
angiogram (ie, no epicardial coronary artery obstructive disease)
do not require additional diagnostic testing.1 An observational
analysis of 1023 patients from the VERDICT trial (which random-
ized patients with NSTE-ACS to receive early or very early invasive
coronary angiography and obtained blinded coronary CT angio-
grams in both groups) aimed to determine whether coronary CT
angiography could exclude coronary artery stenosis greater than or
equal to 50% in patients with NSTE-ACS.36 Coronary stenosis
greater than or equal to 50% was identified in 68.9% of patients
by CT coronary angiography and in 67.4% of patients who under-
went invasive coronary angiography. The negative predictive value
of CT coronary angiography in this study was 90.9%, the positive
predictive value was 87.9%, the sensitivity was 96.5%, and the
specificity was 72.4%.36
Treatment
STEMI should be treated with immediate cardiac catheterization and
coronary angiography followed by PCI with drug-eluting stent im-
plantation (Figure 1). When the electrocardiography suggests STEMI,
rapid reperfusion with primary PCI within 120 minutes reduces mor-
tality by 2%, from 9% to 7%, compared with fibrinolytic therapy.37
A 16-year follow-up of the Danish Acute Myocardial Infarction 2
(DANAMI-2) study of 1572 patients with STEMI randomized to re-
ceive either fibrinolysis or primary PCI demonstrated significant ben-
efit of PCI compared with fibrinolysis (cardiac mortality rates of 18.3%
vs 22.7%).38 In up to 10% of patients who undergo cardiac cath-
eterization for presumed STEMI, etiologies of ST-segment eleva-
tion other than coronary artery occlusion, such as pericarditis, are
ultimately diagnosed.1,3 In approximately 1% of patients with STEMI,
cardiac surgery is indicated because of mechanical complications of
STEMI (eg, acute mitral regurgitation, ventricular septal defect, myo-
cardial free wall rupture).1,3
If PCI is not performed within approximately 120 minutes of the
initial presentation of STEMI (either at the presenting hospital or on
transfer), fibrinolytic therapy with alteplase, reteplase, or
tenecteplase should be administered at full dose for people younger
than 75 years and at half dose for patients 75 years or older if there
are no contraindications.39 Contraindications to fibrinolytic therapy
include active or recent bleeding, recent stroke, serious head trauma,
bleeding diatheses, and uncontrolled hypertension. If cost is a bar-
rier to prescribing alteplase, reteplase, or tenecteplase, such as in
certain regions of the world, streptokinase can be used for fibrino-
lysis, although it is less effective at reperfusion than currently avail-
able fibrinolytics.5 After treatment with fibrinolytic therapy, the pa-
tient should be transferred to a facility where angiography and PCI
can be performed within the next 6 to 24 hours.39
The COMPLETE trial randomized 4041 patients with STEMI
and multivessel disease to undergo either revascularization
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Review Clinical Review & Education
of every significant stenosis in all major coronary arteries or
treatment of the culprit coronary artery without additional re-
vascularization.40 Revascularizations were performed with PCI. At
a median follow-up of 3 years, death from cardiovascular causes or
new MI occurred in 7.8% of patients in the complete revasculariza-
tion group vs 10.5% of patients in the group in which only the cul-
prit lesion was treated (hazard ratio [HR], 0.74 [95% CI, 0.60-
0.91]; P = .004).40 Rates of death from cardiovascular causes,
new MI, or ischemia-driven revascularization occurred in 8.9% of
those randomized to complete revascularization and 16.7% of
those randomized to the culprit lesion–only group (HR, 0.51 [95%
CI, 0.43-0.61]; P < .001).40 Several meta-analyses of randomized
trials have reported findings consistent with results from the
COMPLETE trial.40-42 However, the optimal timing of revascular-
ization of the nonculprit coronary arteries remains uncertain and
should be determined based on patient characteristics such as the
exact coronary anatomy and kidney function. Of note, when car-
diogenic shock is present during the initial event, only the
occluded artery responsible for the STEMI should be treated
because clinical trial evidence demonstrates no advantages and
potential harms from treating multiple coronary arteries in
patients with STEMI and cardiogenic shock.43
For patients with NSTE-ACS, if the first or subsequent troponin
measurements are increased above the 99th percentile upper ref-
erence limit, then initial therapeutic options consist of either a con-
servative (medical) or invasive approach with coronary angiogra-
phy followed by revascularization, depending on the coronary
angiogram results. Typically, percutaneous treatment with drug-
eluting stents is used for patients with NSTE-ACS, with coronary
artery bypass grafting reserved for complex multivessel disease in
patients at low risk for surgical complications, such as perioperative
stroke or prolonged surgical recovery.2,3,14 Patients with previous
stroke, multiple comorbidities, or frailty are at particular risk for sur-
gical complications. Several randomized trials and meta-analyses of
randomized trials have evaluated conservative vs invasive strate-
gies, and most supported an early invasive approach for patients
who are at moderate to high risk, as determined by abnormal tro-
ponin levels, electrocardiographic changes, or risk scores. For those
at low risk, patient preferences and shared decision-making are
particularly relevant in deciding between a conservative or invasive
strategy. One meta-analysis of 7 trials including 8375 patients who
had NSTEMI showed that early invasive therapy with PCI, per-
formed within 24 to 48 hours of presentation, was associated with
lower mortality compared with conservative therapy (4.9% for
patients treated with invasive therapy compared with 6.5% for
patients treated with antiplatelet and antithrombin agents at a
mean follow-up of 2 years).44 Among patients with NSTEMI who
undergo coronary angiography, approximately 60% will receive
PCI, 10% will receive coronary artery bypass grafting during the
hospitalization for NSTEMI, and 30% initially receive medical
therapy alone.14 Nonobstructive coronary plaque is associated
with significant ischemic risk among patients who do not undergo
coronary revascularization.45-47 Approximately 11% of the 9294
patients with NSTE-ACS from the TRILOGY ACS trial of prasugrel vs
clopidogrel had another ischemic event within 30 months.46 In
patients with significant comorbid diseases, such as COVID-19,
heart failure, or kidney failure, troponin elevation is common and
may be due to etiologies other than plaque rupture (Table 1).2,48
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 Clinical Review & Education Review
Table 2. Recommended Antithrombotic Therapies for Acute Coronary Syndromes
Aspirin
Population All patients on presentation
Medication and Chew and swallow 325 mg
dose of uncoated aspirin on
presentation, followed by
81 mg daily
Efficacy rates At 5 wk, in patients with
suspected acute MI, the rate
of vascular death was 9.4%
with aspirin vs 11.8% with
placebo (P < .001); nonfatal
reinfarction (1.0% vs 2.0%)
and nonfatal stroke (0.3% vs
0.6%) were also significantly
reduced49
Mechanism of Aspirin irreversibly inhibits
action cyclooxygenase-dependent
platelet activation and
aggregation by reducing
thromboxane A2 synthesis
Contraindications Aspirin allergy—if time
allows, desensitization
should be performed in
a monitored setting
Adverse effects Major bleeding similar
(0.4%) with both aspirin and
placebo; small absolute
excess of minor bleeds
compared with placebo
(0.6%; P < .01)
Duration Lifelong, unless major
bleeding occurs; consider
proton pump inhibitor if at
increased gastrointestinal
bleeding risk55
Comment Aspirin monotherapy
remains the most commonly
used long-term antiplatelet
strategy worldwide
Abbreviations: DAPT, dual antiplatelet therapy; NOAC, non–vitamin K antagonist oral anticoagulant; PCI, percutaneous coronary intervention.
Oral antiplatelet therapies (aspirin and a P2Y12 inhibitor) and
parenteral anticoagulants (unfractionated heparin, low-molecular-
weight heparin, direct thrombin inhibitors, or Factor Xa inhibitors)
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P2Y12 receptor antagonists
All patients either after coronary
angiography or, if anticipated delay to
catheterization of more than 48 h, on initial
presentation
Clopidogrel, 600-mg loading dose followed
by 75 mg daily in patients treated medically
or undergoing PCI; prasugrel, 60-mg
loading dose followed by 10 mg daily in
patients undergoing PCI; ticagrelor, 180-mg
loading dose followed by 90 mg twice daily
in patients treated medically or undergoing
PCI
Over 12 mo, clopidogrel combined with
aspirin vs placebo combined with aspirin
reduced cardiovascular death, MI, or stroke
from 11.4% to 9.3% (P < .001)50; over
15 mo, prasugrel plus aspirin vs clopidogrel
plus aspirin reduced cardiovascular death,
MI, or stroke from 12.1% to 9.9%
(P < .001)51; over 12 mo, ticagrelor plus
aspirin vs clopidogrel plus aspirin reduced
vascular death, MI, or stroke from 11.7% to
9.8% (P < .001); vascular death was also
reduced from 5.1% to 4.0% (P = .001)52
Clopidogrel, prasugrel, and ticagrelor inhibit
platelet activation and aggregation via
antagonism of the platelet adenosine
diphosphate P2Y12 receptor; the active
metabolites of clopidogrel and prasugrel
bind irreversibly, whereas ticagrelor binds
reversibly
Active major bleeding; prasugrel should not Active major bleeding;
be used in patients with a history of stroke known heparin antibodies
or transient ischemic attack due to the risk
of intracranial hemorrhage; ticagrelor
should be used with caution in patients with
marked baseline dyspnea; it does not worsen
pulmonary function, but may make
subsequent assessment of dyspnea more
challenging
Significant increases in major bleeding for
clopidogrel vs placebo group (3.7% vs 2.7%;
P = .001); significant increases in major
bleeding with prasugrel vs clopidogrel
(2.4% vs 1.8%; P = .03) and in fatal
bleeding (0.4% vs 0.1%; P = .002);
significant increases in major bleeding not
related to coronary artery bypass grafting
with ticagrelor vs clopidogrel (4.5% vs
3.8%; P = .03), although similar overall
rates of major bleeding (11.6% vs 11.2%;
P = .43)
At least 12 mo, and if low bleeding risk and
continued high ischemic risk, consider
longer duration (if ticagrelor, reduce dose
to 60 mg twice daily after 12 mo)
Assessment of ongoing ischemic and
bleeding risks necessary to decide on DAPT
beyond 12 mo; usually not recommended if
at high bleeding risk, such as patients with a
history of anemia, thrombocytopenia, or
prior bleeding; risk scores may be helpful
are recommended therapies in the initial management of ACS, re-
gardless of whether treatment is invasive or noninvasive
(Table 2). 56,57 Bleeding is a common complication of these
Diagnosis and Treatment of Acute Coronary Syndromes
Parenteral anticoagulation
All patients on presentation
Unfractionated heparin
intravenous bolus and
infusion per institutional
dosing nomogram;
subcutaneous
low-molecular-weight
heparin
A meta-analysis of
randomized trials showed
that short-term (up to 7 d)
unfractionated heparin or
low-molecular-weight
heparin vs control was
associated with a lower rate
of death or MI (4.5% vs
7.4%; P <.001)53
Unfractionated heparin
contains a pentasaccharide
sequence that binds to
antithrombin; the resulting
complex inhibits thrombin
and various coagulation
factors, such as Factor Xa;
low-molecular-weight
heparin works similarly but
has a relatively greater
degree of activity against
Factor Xa
No significant increased risk
of major bleeding with
short-term therapy seen in
this meta-analysis
Until revascularization in
patients receiving invasive
treatment; until pain-free in
patients treated
conservatively, typically at
least 48 h
For unfractionated heparin,
a weight-based nomogram
is necessary; for
low-molecular-weight
heparin, need to be
cognizant of kidney function
Oral anticoagulation
Patients with left ventricular
thrombus or atrial fibrillation
Warfarin; NOACs (apixaban,
dabigatran, edoxaban,
rivaroxaban) preferred for
atrial fibrillation if no
contraindications
A meta-analysis of randomized
trials showed the NOACs were
associated with a lower rate of
stroke or systemic embolic
events than warfarin for atrial
fibrillation (3.1% vs 3.8%;
P < .001) over a median
follow-up ranging from 1.8
to 2.8 y54
Warfarin is a vitamin K
antagonist that competitively
inhibits the vitamin K epoxide
reductase complex 1,
preventing activation
of vitamin K, which
is a necessary cofactor for
synthesis of several coagulation
factors; dabigatran
competitively inhibits thrombin;
apixaban, edoxaban, and
rivaroxaban competitively
inhibit Factor Xa
Active major bleeding
Intracranial bleeding: 0.7%
with NOACs vs 1.5% with
warfarin (P < .001);
gastrointestinal bleeding: 2.6%
with NOACs vs 2.0% with
warfarin (P = .043)
For left ventricular thrombus,
at least 3 mo, with repeated
imaging to examine for
thrombus persistence to
determine the need for
continued anticoagulation;
potentially lifelong if left
ventricular aneurysm
For NOACs in impaired kidney
function, carefully follow the
labels because recommended
dose adjustments differ among
the agents
jama.com
 Diagnosis and Treatment of Acute Coronary Syndromes
therapies.56 Compared with treatment with aspirin and heparin,
treatment with intravenous glycoprotein IIb/IIIa inhibitors was as-
sociated with a 1% absolute reduction in 30-day MI or death in
patients with NSTE-ACS, particularly in those undergoing PCI, and
was associated with a 1% absolute increase in major bleeding.56,58
In patients with planned coronary angiography, administration of
P2Y12 inhibitors should be withheld until after the coronary anatomy
is defined to avoid exposing patients who might need cardiac sur-
gery to the bleeding risks from these medications.2,59
Among patients with NSTEMI undergoing cardiac catheteriza-
tion, current guidelines recommend access to the coronary arter-
ies via the radial artery instead of the femoral artery.3 Because the
radial artery is more easily compressed to prevent bleeding, com-
pared with the femoral artery, bleeding and vascular complica-
tions, such as retroperitoneal hemorrhage and arteriovenous fistu-
lae, are less frequent.60,61 A clinical trial randomized 8404 patients
with ACS with or without ST-segment elevation to undergo either
radial or femoral access for coronary angiography. Major bleeding
occurred in 1.6% of patients randomized to the radial access group
vs 2.3% in those in the femoral access group (P = .013).60 All-cause
mortality during a follow-up of 30 days was also lower (1.6% vs 2.2%;
P = .045).60 Currently, the most common form of major bleeding in
ACS is gastrointestinal bleeding. Among the 3761 patients receiv-
ing aspirin plus clopidogrel who were randomized to receive either
omeprazole or placebo in the COGENT trial, rates of gastrointesti-
nal bleeding were 1.1% in the omeprazole group vs 2.9% in the pla-
cebo group at 180-day follow-up (P < .001).62 In 25 086 patients with
ACS, compared with aspirin at a dose of 300 to 325 mg, low-dose
aspirin (75-100 mg daily) therapy lowered the risk of gastrointesti-
nal bleeding from 0.4% to 0.2% (P = .04) at 30 days.63
Overall, 5% to 10% of people with ACS have concomitant atrial
fibrillation. In these patients, therapeutic goals consist of reducing
ischemic event rates and reducing thromboembolic complications
of atrial fibrillation, such as stroke. Previously, standard therapy con-
sisted of dual antiplatelet therapy (DAPT) combined with oral
anticoagulation.2 However, more recent observational studies re-
ported that this triple antithrombotic therapy was associated with
a 5.5% rate of major bleeding compared with 2.5% for patients
treated with DAPT.64,65 Results of randomized clinical trials and meta-
analyses of randomized trials have demonstrated that a non–
vitamin K antagonist oral anticoagulant, such as apixaban or
rivaroxaban, combined with a P2Y12 inhibitor, such as clopidogrel
or ticagrelor, is associated with lower rates of bleeding after dis-
charge over the following year.66-70 In these studies, aspirin was also
prescribed concomitantly during hospitalization and, in some stud-
ies, up to a week after discharge or, less frequently, for a month in
patients at extremely high risk of stent thrombosis due to the com-
plexity of the coronary procedure.66-70 In the presence of left ven-
tricular thrombus or aneurysm, full-dose anticoagulation with war-
farin is typically recommended for at least 3 months. However, more
recent single-center studies suggested that non–vitamin K antago-
nist oral anticoagulants such as apixaban and rivaroxaban may pro-
vide similar efficacy without need for monitoring.71,72
High-intensity statins should be initiated at the time of presen-
tation in all patients with ACS (Table 3). In the MIRACL trial of 3086
patients randomized to receive atorvastatin (80 mg/d) or placebo
beginning 24 to 96 hours after ACS, rates of the primary end point
(death, nonfatal acute MI, cardiac arrest with resuscitation, or re-
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Review Clinical Review & Education
current objectively documented symptomatic myocardial ische-
mia requiring emergency rehospitalization) were 14.8% in those in
the atorvastatin group compared with 17.4% in patients in the pla-
cebo group (relative risk, 0.84 [95% CI, 0.70-1.00]).82 In a second-
ary analysis, atorvastatin reduced the rate of recurrent coronary is-
chemia requiring emergency hospitalization from 8.4% to 6.2%
(relative risk, 0.74 [95% CI, 0.57-0.95]).82 Long-term adherence to
statins is greater with in-hospital initiation of statins.82
Patients with ACS and left ventricular dysfunction or diabetes
should be prescribed either an angiotensin-converting enzyme in-
hibitor or an angiotensin II receptor blocker prior to discharge
(Table 3). There is no evidence that one class is superior to the other
among patients with ACS.83 The angiotensin receptor and neprily-
sin inhibitor sacubitril-valsartan may be preferred to angiotensin-
converting enzyme inhibition in patients with an ejection fraction
less than or equal to 40% when the blood pressure and creatinine
are stable after discharge. Among 8442 patients with heart failure
with reduced ejection fraction randomized to receive sacubitril-
valsartan or enalapril for a median of 27 months, sacubitril-
valsartan reduced mortality from 19.8% to 17.0% in the outpatient
setting.84 However, in the PARADISE-MI trial, 5661 patients with MI
and reduced left ventricular ejection fraction were randomized to
receive sacubitril-valsartan or ramipril for a median of 22 months,
and there was no difference between the drugs for the primary end
point of death from cardiovascular causes or incident heart failure.85
In patients with left ventricular dysfunction, β-blockers should be
prescribed, but randomized trials have not demonstrated benefit of
β-blockers in patients with normal left ventricular function and re-
vascularization of all significant coronary lesions (Table 3). Obser-
vational data show no association of chronic use of β-blockers with
benefit for these patients.86
Mineralocorticoid receptor antagonists, such as spironolactone
and eplerenone, are associated with reduced morbidity and mor-
tality in patients with ACS and left ventricular dysfunction
(Table 3).2 One clinical trial in which 2737 patients with systolic
heart failure (approximately half of whom had a history of previous
MI) were randomized to receive eplerenone or placebo demon-
strated that eplerenone reduced rates of death from cardiovascular
causes or hospitalization for heart failure compared with placebo
(18.3% vs 25.9%) over a median follow-up of 21 months.80 A meta-
analysis of 2 randomized trials in patients with heart failure with
reduced ejection fraction without ACS showed that sodium-
glucose cotransporter-2 inhibitors were associated with lower rates
of cardiovascular mortality compared with placebo (10.8% to
10.0% with empagliflozin in EMPEROR-Reduced; HR, 0.92 [95%
CI, 0.75-1.12]; 11.5% to 9.6% with dapagliflozin in DAPA-HF; HR,
0.82 [95% CI, 0.69-0.98]; meta-analysis combination HR, 0.86
[95% CI, 0.76-0.98]; P = .027).87,88
Prognosis
Recurrent ischemic events are common among patients with pre-
vious ACS. In a study of 21 890 patients with history of an ischemic
event, 18.3% had cardiovascular death, MI, or stroke within 4 years
of follow-up.89-91 Intensive lifestyle modification, such as a plant-
based diet and daily exercise, is important and should include re-
ferral to cardiac rehabilitation programs.92 Smoking cessation can
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 Clinical Review & Education Review Diagnosis and Treatment of Acute Coronary Syndromes

Table 3. Recommended Medical Therapies for Acute Coronary Syndromes

High-intensity ACE Mineralocorticoid
Category statin Ezetimibe PCSK9 inhibitor Icosapent ethyl β-Blocker inhibitor/ARB receptor antagonist
Population All patients on In patients In patients already Patients with Patients with left Patients with Patients with left
presentation already receiving maximally fasting or ventricular left ventricular ventricular
receiving tolerated statin and nonfasting dysfunction or dysfunction or dysfunction
maximally ezetimibe with LDL triglycerides significant residual diabetes
tolerated cholesterol greater ≥135 mg/dL, coronary artery
statin with LDL than or equal to despite maximally disease with
cholesterol approximately tolerated statin angina
greater than or 70 mg/dL dose
equal to
approximately
50 mg/dL
Medication and Maximally 10 mg daily Alirocumab or 2 g twice a day Several generic Several generic Aldosterone or
dose tolerated statin evolocumab with meals choices choices eplerenone
dose, such as subcutaneously
atorvastatin, every 2 wk or once
40 mg or 80 mg monthly
daily, or
rosuvastatin, 20
mg or 40 mg daily
Efficacy rates At 2 years, the When added to Over a median Over 6.2 y, Over a mean of A meta-analysis At a mean follow-up
rate of death, MI, statin therapy, follow-up of 2.8 y, icosapent ethyl vs 1.3 y, mortality of randomized of 24 mo, death
unstable angina ezetimibe vs death from coronary placebo reduced was lower with trials showed reduced from 46%
requiring placebo heart disease, MI, cardiovascular carvedilol than that ACE with placebo to 35%
rehospitalization, reduced ischemic stroke, or death, MI, stroke, placebo (12% vs inhibitors vs with spironolactone
revascularization cardiovascular unstable angina coronary 15%; P = .03)77 control were (P < .001)79; at a
(performed at death, MI, requiring revascularization, associated with median follow-up of
least 30 d after unstable hospitalization was or unstable angina lower mortality 21 mo,
randomization), angina reduced from 11.1% from 22.0% to at 30 d (7.1% cardiovascular death
or stroke was requiring to 9.5% (P < .001); 17.2% (P < .001); vs 7.6%; or hospitalization for
reduced from rehospital- mortality was cardiovascular P = .004)78 heart failure was
26.3% with ization, reduced from 4.1% death was reduced 18.3% with
low-intensity coronary to 3.5% (P = .03)75 from 5.2% to 4.3% eplerenone vs 25.9%
(pravastatin, revascular- (P = .03)76 with placebo
40 mg) to ization (P < .001)80
22.4% with (performed at
high-intensity least 30 d after
(atorvastatin, random-
80 mg) statin ization), or
therapy stroke from
(P = .005)73 34.7% to
32.7% over 7 y
(P = .016)74
Mechanism of Statins Ezetimibe PCSK9 promotes Icosapent ethyl, β-blockers are ACE inhibitors Mineralocorticoid
action competitively reduces degradation of LDL a highly purified competitive prevent the receptor antagonists
inhibit absorption of receptors, which and stable ethyl antagonists of conversion of competitively bind
3-hydroxy-3- cholesterol in reduces their ester of circulating angiotensin I to to mineralocorticoid
methyl-glutaryl- the small number on the liver eicosapentaenoic catecholamines, angiotensin II, receptors and inhibit
coenzyme A intestines by cell surface; thus, acid, lowers and thereby lower resulting in the effects of the
reductase, the blocking inhibition of PCSK9 triglyceride levels, heart rate and vasodilation steroid hormone
enzyme that Niemann-Pick increases LDL although the blood pressure and lowering of aldosterone,
converts C1-Like 1 cholesterol uptake, predominant blood pressure; resulting in diuresis
HMG-CoA to protein leading to lower mechanisms of angiotensin II and lowering of
mevalonate during plasma levels cardiovascular receptor blood pressure
cholesterol benefit likely blockers
synthesis involve effects of selectively
EPA that reduce block the
inflammation and angiotensin II
oxidation and also type 1 receptor
stabilize cell and lower
membranes blood pressure
Contra- Active liver Active liver History of a serious Known Contraindications Contraindica- Hyperkalemia; with
indications disease or disease hypersensitivity hypersensitivity common to the tions common eplerenone,
unexplained, reaction to the drug (eg, anaphylactic class include to the class potassium
persistent reaction) to the severe include a >5.5 mEq/L at
elevations in drug or its bradycardia, history of initiation; creatinine
aminotransferase components second- or angioedema clearance ≤30
levels third-degree heart with an ACE mL/min; similar for
block, sick sinus inhibitor; spironolactone
syndrome (if no hereditary or
permanent idiopathic
pacemaker), angioedema
decompensated
heart failure, and
cardiogenic shock

(continued)

reduce the relative risk of all-cause and cardiovascular mortality by time of index hospitalization, at a median of 10.2 years, patients who
70% to 80%. For example, in the YOUNG-MI registry of 1088 pa- continued to smoke had an all-cause mortality rate of 13.2% com-
tients with first-time MI who were current cigarette smokers at the pared with 4.1% in those who quit smoking.15 Patients with ACS

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 Diagnosis and Treatment of Acute Coronary Syndromes Review Clinical Review & Education

Table 3. Recommended Medical Therapies for Acute Coronary Syndromes (continued)

High-intensity ACE Mineralocorticoid
Category statin Ezetimibe PCSK9 inhibitor Icosapent ethyl β-Blocker inhibitor/ARB receptor antagonist
Adverse effects Elevations in No significant Local injection-site Hospitalization for Higher rates of the Increase in Gynecomastia or
alanine differences in reactions were atrial fibrillation following adverse hypotension breast pain in 10% of
aminotransferase elevations in increased from 2.1% or flutter effects with (17.6% vs men with
levels more than 3 alanine to 3.8% (P < .001) increased from timolol vs placebo: 9.3%; P = .01) spironolactone vs
times the upper aminotrans- 2.1% to 3.1% bradycardia and kidney 1% of men with
limit of normal ferase levels (P = .004); (5.0% vs 0.3%; dysfunction placebo (P < .001);
were 1.1% with that exceeded serious bleeding P < .001); (1.3% vs 0.6%; potassium level
pravastatin group 3 times the increased from hypotension P = .01) >5.5 mmol/L
and 3.3% with upper limit of 2.1% to 2.7% (3.1% vs 1.6%; in 11.8% with
atorvastatin normal or in (P = .06) P < .05); cold eplerenone and 7.2%
(P < .001); muscle-related hands/feet with placebo
discontinuation by adverse events (7.7% vs 0.6%; (P < .001)
the investigators P < .001);
because of bronchial
myalgias, muscle obstruction
aches, or (1.9% vs 0.7%;
elevations in P < .05); and
creatine kinase fatigue (4.8% vs
levels in 2.7% of 1.2%; P < .001)81
patients with
pravastatin vs
3.3% with
atorvastatin
(P = .23)
Duration Lifelong, unless Lifelong Lifelong Lifelong Lifelong Lifelong Lifelong
adverse effects
clearly related to
drug
Comment If intolerant, Can also be Effective even at Unknown if Benefit in patients Both ACE Monitoring of
switch statins or useful in LDL cholesterol patients with with complete inhibitors and potassium needed,
use lower doses; if patients who <100 mg/dL, but allergies to fish revascularization ARBs provide but an underutilized
that does not are truly statin and/or shellfish
cost-effectiveness is and normal left similar benefit, therapy
work, consider intolerant currently an issue are at increased ventricular although ARBs
referral to a risk of an allergic function unclear may be a bit
preventive reaction; increases better tolerated
cardiology clinic risk for
hospitalization for
atrial fibrillation,
especially in
patients with
a history
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; EPA, eicosapentaenoic acid; HMG-CoA, 3-hydroxy-3-methylglutaryl-
coenzyme A; LDL, low-density lipoprotein; MI, myocardial infarction; PCSK9, proprotein convertase subtilisin-kexin type 9.

should be treated for the rest of their lives with antithrombotic and
lipid-lowering medications (Table 2 and Table 3). DAPT with aspirin
and a P2Y12 receptor antagonist is indicated for at least 1 year if no
bleeding complications occur.2 A longer duration of DAPT further
decreased the risk of recurrent MI and ischemic stroke, but was as-
sociated with an increased rate in major bleeding.93-96 In a meta-
analysis of 24 randomized clinical trials with 79 073 patients who re-
ceived DAPT after PCI, treatment with DAPT for durations longer
than 12 months compared with a 12-month period of treatment was
associated with 3.8 fewer cases of MI per 1000 person-years and
4.9 more cases of major bleeding per 1000 person-years at a me-
dian follow-up of 18 months.93-96 Patients at increased risk of bleed-
ing, such as those with a history of bleeding, anemia, or thrombo-
cytopenia, are not good candidates for long-term therapy with DAPT.
The PRECISE-DAPT score, a risk score (C index of 0.73 for out-of-
hospital major or minor bleeding) identified patients treated with
DAPT who were at increased risk of bleeding and consists of 5 items:
age, creatinine clearance, hemoglobin, white blood cell count, and
history of spontaneous bleeding.97,98 In addition to risk scores, con-
sidering patient values and preferences is important when decid-
ing what patients are appropriate candidates for shorter or longer
durations of DAPT. Another option for long-term antithrombotic
therapy is low-dose aspirin combined with 2.5 mg of rivaroxaban
twice daily.99-104 In the COMPASS trial, 9152 patients with coro-
nary or peripheral artery disease randomized to receive 2.5 mg of
rivaroxaban twice daily and 100 mg of aspirin compared with 9126
patients randomized to receive 100 mg of aspirin alone demon-
strated that the combination therapy reduced the composite of car-
diovascular death, stroke, or MI from 5.4% to 4.1% (P < .001) and
mortality from 4.1% to 3.4% (P = .01) compared with aspirin over a
median follow-up of 23 months. Of note, the COMPASS trial ex-
cluded patients with an indication for DAPT at the time of random-
ization, although 69% of the patients with coronary artery disease
in the trial had a history of MI.99-104
Patients with ACS benefit from intensive low-density lipopro-
tein cholesterol (LDL-C) lowering to less than approximately
50 mg/dL.73-75,105 The IMPROVE-IT trial randomized 18 144 pa-
tients with ACS to receive either ezetimibe combined with statin
therapy or statin therapy alone.74 The combination of ezetimibe plus
statins reduced the rate of the primary end point of cardiovascular
death, nonfatal MI, unstable angina requiring rehospitalization, coro-
nary revascularization, or nonfatal stroke from 34.7% to 32.7%
(P = .016) at 7 years.74 The ODYSSEY trial randomized 18 924 pa-
tients with a history of ACS who were receiving the maximum tol-
erated dose of statins to receive either alirocumab subcutaneously
to attain an LDL target of 25 to 50 mg/dL or placebo.75 Alirocumab
significantly reduced the rate of the composite end point of
death due to coronary heart disease, nonfatal MI, ischemic stroke,

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 Clinical Review & Education Review Diagnosis and Treatment of Acute Coronary Syndromes

or unstable angina requiring hospitalization compared with pla-
cebo (9.5% vs 11.1%).75,105 Benefit was greater in patients who had
a baseline LDL-C of at least 100 mg/dL compared with those with a
baseline LDL-C less than 100 mg/dL (LDL-C <80 mg/dL: 8.3% vs
9.5%; LDL-C of 80-100 mg/dL: 9.2% vs 9.5%; LDL-C ⱖ100 mg/dL:
11.5% vs 14.9%).75,105,106 High-intensity statins, such as rosuvasta-
tin and atorvastatin, and ezetimibe are first-line therapy for pa-
tients with ACS. Proprotein convertase subtilisin-kexin type 9 in-
hibitors can be added to high-intensity statins and ezetimibe when
needed to reduce LDL-C by 50% to 60% to at least less than
70 mg/dL.75,105,106 Patients with ACS should receive annual influ-
enza vaccines. In patients with history of MI or high-risk stable coro-
nary heart disease, rates of all-cause mortality over the 12-month
follow-up with the influenza vaccine were 2.9%, compared with
4.9% with placebo (HR, 0.59 [95% CI, 0.39-0.89]; P = .01).107,108
An assessment of left ventricular function should be per-
formed at the time of admission for ACS. If the ejection fraction is
not normal, repeated echocardiography should be performed by ap-
proximately 3 months after optimal medical therapy is prescribed.
If the left ventricular ejection fraction is less than or equal to 35% at
that time, referral to a cardiac electrophysiologist should be consid-
ered for possible implantable cardioverter defibrillator placement
to reduce the risk of sudden cardiac death from fatal ventricular ar-
rhythmias. In 1232 patients with prior MI and an ejection fraction less
than or equal to 30% randomized to receive a defibrillator or to a
control group, the MADIT II trial reported mortality rates of 19.8%
in the control group compared with 14.2% in the defibrillator group
(HR, 0.69 [95% CI, 0.51-0.93]; P = .016) during a mean follow-up
of 20 months.109
Limitations
This review has several limitations. First, some relevant reports may
have been missed. Second, a formal quality assessment of the lit-
erature was not performed. Third, this review does not cover the ef-
fects of all risk factors for ACS, such as stimulant use, vaping, and
air pollution.
Conclusions
Each year, an estimated more than 7 million people are diagnosed
with ACS worldwide. For patients with STEMI, coronary catheter-
ization and PCI within 2 hours of presentation reduces mortality,
with fibrinolytic therapy reserved for patients without access to
immediate PCI. For high-risk patients with NSTE-ACS without con-
traindications, prompt invasive coronary angiography followed by
percutaneous or surgical revascularization is associated with lower
rates of death.

ARTICLE INFORMATION
Accepted for Publication: January 11, 2022.
Author Contributions: Drs Bhatt and Lopes had full
access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Bhatt, Lopes.
Drafting of the manuscript: Bhatt, Lopes.
Critical revision of the manuscript for important
intellectual content: All authors.
Supervision: Lopes, Harrington.
Conflict of Interest Disclosures: Dr Bhatt reported
receiving grants from Amarin, AstraZeneca, Bristol
Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi
Aventis, The Medicines Company, Pfizer, Forest
Laboratories/AstraZeneca, Ischemix, Roche, Stasys,
Amgen, Eli Lilly, Chiesi, Ironwood, Abbott,
Regeneron, Idorsia, Synaptic, Fractyl, Afimmune,
Ferring Pharmaceuticals, Lexicon, Contego Medical,
MyoKardia/BMS, Owkin, HLS Therapeutics, Garmin,
89Bio, Faraday Pharmaceuticals, Javelin, and Reid
Hoffman Foundation; personal fees from Duke
Clinical Research Institute, Mayo Clinic, Population
Health Research Institute, Belvoir Publications,
Slack Publications, WebMD, Elsevier, Cleveland
Clinic, Mount Sinai School of Medicine, HMP Global,
Harvard Clinical Research Institute (now Baim
Institute for Clinical Research), the Journal of the
American College of Cardiology, TobeSoft, Bayer,
Medtelligence/ReachMD, CSL Behring, K2P,
Canadian Medical and Surgical Knowledge
Translation Research Group, MJH Life Sciences,
Level Ex, Arnold and Porter Law Firm, Piper Sandler,
and Cowen and Company; grants and other support
from PLx Pharma, Cardax, Boston Scientific,
PhaseBio, Novo Nordisk, Cereno Scientific,
CellProthera, Janssen, Novartis, and NirvaMed;
other support from FlowCo, CSI, Takeda, Medscape
Cardiology, Regado Biosciences, Boston VA
Research Institute, Clinical Cardiology, the US
Department of Veterans Affairs, St Jude Medical
(now Abbott), Biotronik, Merck, Svelte, and Philips;
personal fees, nonfinancial support, and other
support from American College of Cardiology and
Boehringer Ingelheim; personal fees and
nonfinancial support from the Society of
Cardiovascular Patient Care; and nonfinancial
support from American Heart Association outside
the submitted work. Dr Lopes reported receiving
consulting fees from Bayer, Boehringer Ingelheim,
Daiichi Sankyo, Merck, and Portola
Pharmaceuticals; and grants and consulting fees
from Bristol Myers Squibb, GlaxoSmithKline,
Medtronic, Pfizer, and Sanofi outside the submitted
work. Dr Harrington reported receiving research
funding from Janssen and consulting fees from
Bristol Myers Squibb and Element Science outside
the submitted work.
Additional Contributions: The authors would like
to thank Sara Mercuro, BA, from Brigham and
Women’s Hospital for extensive reference searching
and formatting.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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