CAT 2

CAT2 Valvular Diseases

After completing your assigned readings, can anyone answer the following questions related to the diagnosis and treatment of valvular diseases?

What are the key factors that determine when to proceed to aortic valve replacement for patients with aortic stenosis? What guided decision making relating to aortic surgery for acute and chronic aortic regurgitation?

Which patients with aortic stenosis should be considered for transcatheter therapies such as valvuloplasty or transcatheter aortic valve replacement?

What are the indications for surgery in patients with mitral stenosis? What are the goals of medical therapy for mitral regurgitation and when should patients be considered for mitral valve repair or replacement?

When should patients with mitral regurgitations be considered for transcatheter mitral valve procedures?

What are the objectives of treatment of pulmonic valve disease? When should patients be referred for surgery or transcatheter valve replacement?

What are the factors that determine medical versus surgical treatment of tricuspid stenosis or tricuspid regurgitation?

REPLY

AM

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SECTION 1
Cardiovascular Medicine

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CHAPTER 128
Acute Coronary Syndromes

Michael McDaniel, MD, FSCAI

Key Clinical Questions

What is the optimal care and management of patients with ST-segment elevation
myocardial infarction?

What is the optimal care and management of patients with non-ST segment
elevation acute coronary syndrome?

INTRODUCTION

The term acute coronary syndrome (ACS) refers to the spectrum clinical presentations
related to acute myocardial ischemia or infarction due to the abrupt reduction in coronary
blood flow. ACS is divided into ST-segment elevation myocardial infarctions (STEMIs) and
non-ST segment elevation acute coronary syndromes (NSTE-ACSs). The NSTE-ACS is
further subdivided on the basis of elevated cardiac biomarkers of myocardial necrosis.
Patients with elevated cardiac biomarkers are defined as non-ST segment elevation
myocardial infarction (NSTEMI) and those without elevated biomarkers are termed
unstable angina (UA).

This chapter will focus on the diagnosis, risk stratification, and treatment of patients
with ACS based on the American College of Cardiology Foundation and American Heart
Association (ACCF/AHA) practice guidelines for STEMI and NSTE-ACS. All guideline
recommendations will be cited in this chapter and referenced according the American

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College of Cardiology Foundation/American Heart Association classification scheme
(Table 128-1).

TABLE 128-1 ACCF/AHA Classification of Recommendations and Level of Evidence

Class I Class IIa Class IIb Class III
Benefit >>>
Risk
Procedure/Treatment
SHOULD be
performed/administered

Benefit >> Risk
Additional studies
with focused
objectives needed
IT IS REASONABLE
to perform
procedure/administer
treatment

Benefit ≥ Risk
Additional studies
with broad objectives
needed; Additional
registry data would
be helpful
Procedure/Treatment
MAY BE
CONSIDERED

Risk ≥ Benefit
No additional studies
needed
Procedure/Treatment
should NOT be
performed/administered
SINCE IT IS NOT
HELPFUL AND MAY BE
HARMFUL

Level A: Recommendation based on evidence from multiple randomized trials or meta-analyses
Level B: Recommendation based on evidence from a single randomized trial or non-
randomized studies
Level C: Recommendation based on expert opinion, case studies, or standard of care

From O’Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction:
executive summary: a report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol.2013;61(4):485-510.

EPIDEMIOLOGY & PATHOPHYSIOLOGY

ACS is common, with over 780,000 patients experiencing an ACS event every year in the
United States. Of these events, approximately 70% are classified as NSTE-ACS. ACS is
related to an acute imbalance of myocardial oxygen consumption and demand, usually
related to a sudden coronary artery obstruction. Autopsy studies suggest that most ACS
events are related to acute coronary thrombosis, with acute plaque rupture being the most
common etiology. The atherosclerosis at sites of plaque rupture is characterized by large
lipid-laden necrotic cores overlying a disrupted thin fibrous cap. The second most
common cause of acute coronary thrombosis is plaque erosion, characterized by
thrombus formation at an area of denuded endothelium. These plaques are characterized
by smaller plaques with less lipid necrotic core and thicker fibrous caps compared to
plaque rupture sites. Plaque erosion is actually the most common etiology of acute
coronary thrombosis in younger female patients, especially those who smoke tobacco.
More rare causes of coronary thrombosis are due to the calcified nodule which is not well
characterized and is mostly seen in the elderly, and cardioembolic etiologies which are
usually noted in distal coronary locations. Nonthrombotic sudden progressions in
coronary arteries may be related to acute intraplaque hemorrhage without thrombosis.
Rarely, acute coronary insufficiency may be caused by vasospasm, coronary arteritis, or
spontaneous dissection.

HISTORY AND PHYSICAL

The most common clinical presentation of ACS is new onset pressure-like chest pain that
occurs at rest (>10-20 minutes in duration) or with minimal activity. The pain is often

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retrosternal and can radiate to the arm (likelihood ratio [LR] 2.7), neck, or jaw and may be
associated with diaphoresis (LR 2.0), dyspnea, or nausea (LR 1.9). However, chest pain
can be absent in one-third of patients. Less common presentations of ACS include
syncope, abdominal pain, hypotension, pulmonary edema, or unexplained fatigue. While
older women and patients with diabetes most commonly present with typical symptoms
of ACS, atypical ACS presentations are most common in these patients. Symptoms that
are not characteristic of myocardial ischemia included pleuritic pain (LR 0.2), sharp or
stabbing pain localized to a single location (LR 0.3), pain reproduced by palpitation (LR
0.2-0.4), or brief episodes lasting only seconds. Risk factors for ACS include older age,
male sex, family history of coronary artery disease (CAD), peripheral arterial disease,
diabetes mellitus, renal insufficiency, and prior CAD. The differential diagnosis for ACS is
listed in Table 128-2.

TABLE 128-2 Differential Diagnosis for NSTE-ACS

Nonischemic Cardiovascular
• Aortic dissection
• Expanding aortic aneurysm
• Myocarditis
• Pericarditis
• Hypertrophic cardiomyopathy
• Pulmonary embolism
Pulmonary
• Pneumonia
• Pleuritis
• Pulmonary hypertension
• COPD
• Pneumothorax
Gastrointestinal
• Gastroesophageal reflux
• Esophageal spasm
• Esophagitis
• Esophageal hypersensitivity
• Peptic ulcer
• Pancreatitis
• Biliary obstruction
Musculoskeletal
• Cervical disk radiculopathy
• Costochondritis
• Rheumatic disease
• Trauma
Other etiologies
• Sickle cell crisis
• Herpes zoster

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• Depression and anxiety
• Drug intoxication
• Pheochromocytoma

Reprinted from Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the
Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol. 2014;64(24):e139-228 with permission from Elsevier, Inc.

The physical examination may be completely normal in many patients with ACS. Signs
and symptoms of new congestive heart failure, mitral regurgitation, and/or shock suggest
higher risk and usually require more emergent triage, treatment, and often invasive
therapies. Signs of low cardiac output may be suggested by tachycardia, cool extremities,
diaphoresis, confusion, and/or reduced urine output. Signs of congestive heart failure
include elevated jugular venous distension, pulmonary edema, audible S3, and/or lower
extremity edema.

ELECTROCARDIOGRAM

To rapidly identify STEMI, an electrocardiogram (ECG) should be performed within 10
minutes of arrival to the emergency department (ED) in all patients with signs and
symptoms of ACS (Class I, Level of Evidence [LOE] C). In addition, Emergency Medical
Service (EMS) personnel should perform a 12-lead ECG on site in all patients with
suspected ACS and transport patients with STEMI to percutaneous coronary intervention
(PCI)-capable facilities, where available.

STEMI is defined on ECG by new ST-elevation in at least two contiguous leads ≥2 mm
in leads V2-V3 or ≥1 mm in the other chest leads or limb leads. Abnormalities alone on the
EKG are insufficient to make a diagnosis of STEMI and the ECG must be interpreted in the
appropriate clinical context. While new left bundle branch block (LBBB) was once
considered as an STEMI equivalent, guidelines now recommend the LBBB in isolation
should not be considered diagnostic of acute myocardial infarction (AMI) and specific
ECG criteria have been proposed to diagnose STEMI in LBBB (Table 128-3). In addition,
ST depressions in V1-V4 may indicate posterior injury (Figure 128-1) and isolated ST-
elevation in aVR and/or V1 with diffuse ST depression may suggest acute left main or
proximal left anterior descending artery occlusion (Figure 128-2). Rarely, hyperacute T-
waves can be seen early in patients with STEMI. When the initial ECG is nondiagnostic
and the patient remains symptomatic, serial ECGs should be performed at 15 to 30 minute
intervals during the first hour or if symptoms recur (Class I, LOE C).

TABLE 128-3 ECG Criteria for Diagnosis of STEMI in the Setting of Left Bundle Branch
Block (Sgarbossa Criteria)

Criterion Odds Ratio (95% CI) Score
ST-elevation ≥1 mm and concordant with
QRS complex

25.2 (11.6-54.7) 5

ST-segment depression >1 mm in leads V1,
V2, or V3

6.0 (1.9-19.3) 3

ST-elevation >5 mm and discordant with
QRS complex

4.3 (1.8-10.6) 2

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A score >3 had a 98% specificity for acute myocardial infarction, but a score of 0 does
not rule out STEMI.

From O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-
elevation myocardial infarction: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 29;61(4):e78-140.
Reprinted with permission from Elsevier, Inc.

Figure 128-1 EKG with and ST-depression in V1-V3 suggestive of acute posterior injury.
(Reproduced, by permission, from Knoop KE, et al eds. The Atlas of Emergency Medicine,
3rd ed. New York, NY: McGraw-Hill; 2010. ECG contributor: Ian D. Jones, MD.)

Figure 128-2 ST-elevation in aVR with diffuse ST depression consistent with acute left
main or very proximal left anterior descending artery occlusion.

The 12-lead ECG may suggest a diagnosis of NSTE-ACS, but is not required to make
the diagnosis. Horizontal or downsloping dynamic ST-segment depression is highly
suggestive of NSTE-ACS. In addition, significant deep precordial T-wave inversion (Wellen’s
sign) may suggest critical left anterior descending stenosis (Figure 128-3). More
nonspecific ST-T changes are less diagnostic. Significant Q-waves can suggest a prior
myocardial infarction (MI), but do not suggest ACS.

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Figure 128-3 Deep T-wave inversion in the precordial leads suggestive of ischemia in the
left anterior descending coronary artery (Wellen’s sign).

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION (STEMI)

MANAGEMENT OF STEMI AT PCI-CAPABLE HOSPITALS

All hospitals should develop coordinated regional approaches to STEMI care and
participation in programs such as Mission:Lifeline (American Heart Association’s Mission:
Lifeline: http://www.heart.org) and the D2B Alliance is recommended (Class I, LOE B).
These initiatives promote prehospital ECG to diagnose STEMI, EMS and ED activation of
cardiac catheterization labs (“cath labs”), single calls to central paging operator to
activate the cath team, cath lab staff arrival within 20 to 30 minutes of notification, and
timely data feedback to all members of the STEMI team.

Once the diagnosis of STEMI is made, the most important therapy for patients is
emergent revascularization within 90 minutes of first medical contact (FMC) (Class I, LOE
A). As such, it is preferred for patients to bypass the ED and present directly via EMS to the
cath lab when possible to optimize reperfusion times (Figure 128-4). Most patients
arriving by EMS with ACS will receive aspirin 325 mg by EMS personnel (Class I, LOE A).
Patients should also receive an unfractionated heparin (UFH) bolus (50-70 units/kg, max
5000 units) as soon as possible upon hospital arrival (Class I, LOE C). In addition, all
patients presenting with STEMI should receive a loading dose of an oral antiplatelet
P2Y12 antagonist as early as possible (Class I, LOE B). Presently, there are three options of
the oral antiplatelet P2Y12 antagonists: clopidogrel 600 mg, prasugrel 60 mg, and
ticagrelor 180 mg. Choosing between these agents will be discussed later in the Dual
Antiplatelet Therapy Section of Late Hospital & Hospital Discharge part of the chapter.

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Figure 128-4 Algorithm for evaluation and management of acute coronary syndrome for
PCI-capable hospitals. ACS, acute coronary syndromes; ASA, aspirin; CCU, coronary care
unit; CP, chest pain; ECG, electrocardiogram; Non-STE ACS, Non-ST segment elevation
acute coronary syndrome; NTG, nitroglycerin; PCI, percutaneous coronary intervention; PO,
Per Os; SL, sublingual; STEMI, ST-segment elevation myocardial infarction.

There is little benefit to intravenous (IV) glycoprotein IIb/IIIa inhibitors (GPIs) prior to
angiography in STEMI (Class IIb, B). However, GPIs are indicated in many patients during
and after PCI for STEMI as it blocks the final common pathway of platelet activation. While
a comprehensive review of the GPI trials is beyond the scope of this chapter, a few general
principals regarding GPIs deserve mention. GPIs provide very rapid inhibition of platelets,
much greater and faster than oral P2Y12 inhibitors. In addition, pooled studies suggest
that GPIs reduce recurrent 30-day unplanned revascularization and mortality in STEMI. In
a meta-analysis of 7414 patients from multiple randomized trials, patients undergoing PCI
for STEMI receiving GPIs have about a 25% relative decrease in mortality compared to no
GPI. However, GPIs are clearly associated with about a 50% relative increase in bleeding

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complications, especially with femoral access. This bleeding is attenuated but not
eliminated by radial access. Currently, there are three GPI agents available for clinical use.
There are two small molecule agents, eptifibatide and tirofiban, and one large molecule
agent abciximab. Randomized trials, registries, and meta-analyses suggest that the large
and small molecule GPI agents have similar efficacy and safety in patients undergoing
primary PCI. As such, the choice of GPI may be driven more by cost considerations.

Bivalirudin is a direct thrombin inhibitor that has been studied extensively in primary
PCI in STEMI, but its use is controversial given conflicting recent studies. In both the 3602
patient Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial
Infarction (HORIZONS AMI) and the 2218 patient European Ambulance Acute Coronory
Syndrome angiography study (EUROMAX) trials, there were significantly less bleeding
complications in patients randomized to bivalirudin compared to the combination of UFH
and planned or provisional GPI. However, there was also significant more acute stent
thrombosis, and the bleeding reduction was attenuated in patients with radial access.
More recently, the benefits of bivalirudin compared to UFH alone have been questioned. In
the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT PPCI) trial, 1812
patients with STEMI were randomized to bivalirudin or UFH, both with provisional use of
GPI. In this trial, there was no reduction of bleeding with the use of bivalirudin and actually
higher major cardiac events with bivalirudin. It should be noted however that the use of
provisional GPI was low and similar in both groups and most patients underwent PCI
using the radial approach. Given the significantly higher cost compared to UFH, it is
controversial if bivalirudin provides value compared to UFH, and further studies are
warranted to best define the optimal role of bivalirudin in STEMI.

The radial access is increasingly utilized in STEMI as this strategy decreases access-
site complications compared to PCI via femoral access (Class IIa, LOE A). In the 1001
patient Radial versus Femoral Randomized Investigation in ST Elevation Acute Coronary
Syndrome trial, patients randomized to radial access had lower bleeding at 30 days (7.8%
vs 12.2%, number needed to treat [NNT]23, P = 0.026) and cardiac mortality (5.2% vs 9.2%,
NNT25, P = 0.02) compared with patients randomized to femoral access. Similar findings
were noted in a meta-analysis of 5055 patients from 11 randomized trials in STEMI.

MANAGEMENT OF STEMI AT NON-PCI-CAPABLE HOSPITALS

Not all patients with STEMI present to hospitals that can perform primary PCI. These
patients should be transferred to a PCI-capable hospital for primary PCI if this transport
can occur rapidly and achieve revascularization at the receiving hospital with FMC-to-
device time less than120 minutes (Class I, LOE B). If this time goal cannot be met,
fibrinolytic therapy is recommended in the absence of contraindications within 30 minutes
of hospital arrival (Class I, LOE B). Fibrin-specific agents (Tenecteplase, Reteplase, and
Alteplase) are preferred over non-fibrin-specific agents (Streptokinase). Absolute and
relative contraindications to fibrinolytic therapy are listed in Table 128-4. In addition,
patients presenting with cardiogenic shock, high bleeding risk, or presentations >3 to 4
hours after symptom onset should usually be transported to a PCI-capable hospital
regardless of transport times.

TABLE 128-4 Contraindications to Fibrinolysis in STEMI

Absolute Contraindications
• Prior intracranial hemorrhage

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• Structural cerebral vascular lesions
• Malignant intracranial neoplasm
• Ischemic stroke within 3 mo
• Suspected aortic dissection
• Active bleeding
• Significant closed-head or facial trauma within 3 mo
• Intracranial or intraspinal surgery within 2 mo
• Severe uncontrolled hypertensions unresponsive to therapy
Relative Contraindications
• Significant hypertension (SBP >180 mm Hg or DBP >110 mm Hg)
• History of ischemic stroke >3 mo
• Dementia
• Prolonged CPR >10 min
• Major surgery within 3 wk
• Recent internal bleeding within 2-4 wk
• Noncompressible vascular punctures
• Pregnancy
• Active peptic ulcer
• Oral anticoagulant therapy

All patients who receive fibrinolysis should also receive aspirin 325 mg PO loading
dose, clopidogrel 300 mg PO loading dose, and unfractionated heparin bolus and infusion.
In addition, all patients should be transferred emergently to a PCI-capable hospital for
urgent/emergent angiography as part of either a rescue PCI strategy (for failed lysis) or a
pharmocoinvasive strategy as both strategies have been shown to improve outcomes
compared to conservative management strategies.

COMATOSE PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST

Comatose patients with out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation
(VF) or pulseless ventricular tachycardia (VT) with return of spontaneous circulation
(ROSC) deserve special mention. These patients have about a 10-fold increase in mortality
compared to STEMI patients without cardiac arrest. Survival is optimized when CPR and
defibrillation are initiated early. Importantly, the neurologic exam should not be used in the
acute setting to predict future neurologic recovery or survival. While patients with longer
pulseless times, unwitnessed arrests, and longer CPR durations have worse neurologic
outcomes, there are no absolute predictors in the acute setting of neurologic recovery with
intervention. As such, the neurologic status should not solely be used to guide decisions
about invasive procedures in the acute setting.

Immediate angiography and PCI should be strongly considered for all comatose
patients with OHCA and ROSC with STEMI on initial ECG (Class I, LOE B). In addition,
targeted temperature management (TTM) should be started as soon as possible to target
32°C to 34°C for 12 to 24 hours (Class I, LOE B). Two randomized trials have reported
improved neurologic survival when TTM was initiated before or at the time of PCI, and the
combination of early angiography/intervention and TTM is associated with the highest
survival and neurologic recovery. More recently, other randomized clinical trials of TTM in

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postresuscitated patients have found equally impressive survival rates, whether cooled to
33°C versus 36°C or whether initiated in the field or after arrival at the hospital. Several
methods for hypothermia are available, but there are insufficient data to recommend one
technique over another and local expertise should guide decisions between external
cooling pads, intravascular cooling, cooling blankets, and ice packs. Of note, iced saline
should rarely be used as the volume may precipitate pulmonary edema in patients at risk
for heart failure and this can lead to more rapid fluctuations in body temperature.

While there is not a consensus to the optimal management of patients with OHCA due
to VF/VT with ROSC without ST-elevations on ECG, most of the studies also support early
angiography, PCI, and TTM for these patients as up to 25% to 30% of these patients will
have culprit lesions at angiography despite a normal ECG. However, given the greater
heterogeneity of these patients, consultation should be undertaken with interventional
cardiology prior to cath lab activation for these patients.

PRACTICE POINT

STEMI
Rapid ECG with interpretation is recommended prehospital by EMS or within 10
minutes of arrival to the hospital to rapidly identify patients with STEMI and optimize
reperfusion times.
When the initial ECG is nondiagnostic and the patient remains symptomatic, serial
ECGs should be performed at 15- to 30-minute intervals during the first hour or if
symptoms recur.
Left Bundle Branch Block in isolation should not be considered diagnostic of acute
myocardial infarction and specific ECG criteria have been proposed to diagnose
STEMI in LBBB (Table 128-3).
All patients with STEMI should receive an aspirin loading dose (325 mg),
unfractionated heparin bolus (50-70 units/kg, max 5000 units), and a P2Y12 inhibitor
loading dose prior to or at the time of angiography.
Primary PCI is recommended within 90 minutes of first medical contact for PCI-
capable hospitals.
Transfer for primary PCI from a non-PCI-capable hospital is recommended when the
first medical contract to device time (balloon or aspiration catheter) can be
accomplished within 120 minutes. When this is not possible, fibrinolysis is preferred
within 30 minutes of hospital arrival.
The optimal use of glycoprotein IIb/IIIa inhibitors and Bivalirudin in STEMI remains
controversial. When GPIs are used, they should usually be deferred until angiography
is performed.
Most comatose patients with out-of-hospital cardiac arrest due to VT/VF and return of
spontaneous circulation should undergo emergent angiography and targeted
temperature management.

NON-ST SEGMENT ELEVATION ACUTE CORONARY SYNDROMES (NSTE-ACS)
MORPHINE, OXYGEN, NITROGLYCERIN, AND ASPIRIN

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“MONA” (Morphine, Oxygen, Nitroglycerin, and Aspirin) has been part of the classic
teaching for patients with ACS for decades. However, aside from aspirin, there are now
reasons to caution the routine use of these other agents in ACS.

Morphine should probably be avoided in most patients with active angina as it can
mask ongoing ischemia or infarction in patients who may benefit from emergent
revascularization, and its use has been downgraded in recent guidelines (Class IIb, LOE B)
based on observational studies suggesting an association with adverse events and
morphine use in ACS. While this may be related to the fact that sicker patients get
morphine, morphine may mask the pain of ongoing infarction resulting in delays in
revascularization and larger infarctions. Furthermore, morphine may impair the absorption
of the oral antiplatelet agents. For most patients with active angina despite IV
nitroglycerin, urgent coronary angiography should be considered instead of morphine.

Supplemental oxygen therapy is recommended only in patients with ACS and arterial
oxygen saturation less than 90% or in respiratory distress (Class I, LOE C). The benefits of
routine oxygen use without hypoxia have never been demonstrated, and some studies
suggest that oxygen therapy may actually increase vascular resistance, reduce coronary
flow, and result in larger infarctions. Furthermore, in a pooled Cochrane analysis of 430
patients from four randomized trials demonstrated a twofold higher risk of death in
patients with AMI treated with oxygen. Taken together, routine oxygen therapy is probably
not necessary in most patients with ACS unless hypoxia is present.

Nitrates are endothelium-independent vasodilators that relieve angina by decreasing
cardiac preload and reducing ventricular wall tension. Sublingual (SL) nitroglycerin is
recommended for patients with active angina (Class I, LOE C). If the angina continues
despite 3 SL nitroglycerin, IV nitroglycerin should be given and titrated until chest pain free
or limited by side effects such as hypotension or headache (Class I, LOE B). While
nitroglycerin is effective at reducing the symptoms of angina, randomized trials have
never demonstrated improved morbidity or mortality outcomes with nitrates. In addition,
nitroglycerin should be avoided in patients with hypotension, right ventricular infarctions,
and recent phosphodiesterase inhibitor-5 (sildenafil, vardenafil, or tadalafil) use due to risk
of significant hypotension (Class III, LOE B).

All patients with ACS should receive nonenteric-coated ASA of 325 mg as soon as
possible followed by 81 mg daily maintenance dose (Class I, LOE A). Aspirin is a mainstay
of ACS therapy, results in thromboxane A2 inhibition via irreversible COX-inhibition, and
results in approximately 30% to 45% relative reductions in death and recurrent myocardial
infarction across a large spectrum of ACS. Enteric-coated aspirin should be avoided in the
early setting of ACS due to delayed absorption.

SERIAL TROPONIN ANALYSIS

Increasingly, a troponin-only biomarker strategy (without ordering creatine kinase [CK] and
creatine kinase myocardial enzyme [CK-MB] fraction) is used for the evaluation of AMI in
NSTE-ACS. Although damaged cardiac myocytes release several biomarkers, troponins are
preferred based on their superior sensitivity and specificity. Cardiac troponin will rise
within 2 to 4 hours of symptom onset and will remain elevated for several days. Shorter
intervals of serial troponin measurements (such as 0, 3, and 6 hours) more rapidly
diagnose and/or rule out AMI (Class I, LOE A). Contemporary sensitive troponin assays
now permit earlier serial sampling (in 3 hours vs previous 8 hours) for earlier detection and
treatment of AMI. Furthermore, a negative troponin value 6 hours from presentation
essentially excludes the diagnosis of AMI (unless recurrent symptoms), leading to earlier
diagnostic testing or hospital discharge. It is important for physicians to be aware of the

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troponin assay used in their local hospital, as troponin measures >6 hours from onset may
be required with less sensitive older assays. In addition, testing at longer intervals is
required (up to 24 hours) if information about infarct size is required.

There is very little value to using other cardiac biomarkers in addition to troponin, as
they are both less sensitive and less specific. Furthermore, moderate-sized registries
suggest that the addition of CK-MB adds no additional diagnostic information compared
to troponin alone. With contemporary troponin assays, CK-MB and myoglobin are not
useful in the diagnosis of ACS and the current guidelines recommend against their use
(Class III, LOE A). Importantly, elevated troponin values alone are insufficient to make a
diagnosis of NSTEMI and should be evaluated in the appropriate clinical context. There
are many reasons other than ACS for elevated troponin values (Table 128-5).

TABLE 128-5 Causes of Elevated Cardiac Troponin Values Due to Myocardial Injury

Injury related to primary myocardial ischemia
Plaque rupture
Intraluminal coronary artery thrombus formation
Injury related to supply/demand imbalance
Tachy-/bradyarrhythmias
Aortic dissection or severe aortic valve disease
Hypertrophic cardiomyopathy
Cardiogenic, hypovolemic, or septic shock
Severe respiratory failure
Severe anemia
Hypertension
Coronary spasm
Coronary embolism or vasculitis
Coronary endothelial dysfunction
Injury not related to myocardial ischemia
Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks
Rhabdomyolysis with cardiac involvement
Myocarditis
Cardiotoxic agents, like anthracyclines
Multifactorial or indeterminate myocardial injury
Heart failure stress (Takotsubo)
Pulmonary embolism or pulmonary hypertension
Sepsis
Renal failure
Severe acute neurological diseases, such as stroke or subarachnoid hemorrhage
Infiltrative diseases, like amyloidosis or sarcoidosis
Strenuous exercise

Modified by permission from Thygesen K. Third Universal Definition of Myocardial Infarction. JACC.
2012;60(16):1586 (table 1). Elsevier Inc.

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EARLY HOSPITAL TRIAGE IN NSTE-ACS

Patients with possible or definite NSTE-ACS represent a broad population with various
levels of risk. Of patients presenting to the ED with possible ACS, less than 25% will be
diagnosed with UA or AMI. However, on the opposite end, up to 5% of patients with ACS
are inappropriately discharged from the hospital without appropriate diagnostic workup.
To address these conflicting issues, observation units have been developed in many
hospitals and are recommended for low-risk patients with possible ACS. These units have
been associated with lower rates of missed acute MI, lower costs, improved patient
satisfaction, and decreased admissions for chest pain. While there are several tools used
to risk stratify patients for observation units, many hospitals use modifications of the
Goldman’s prediction rule as these criteria predict MACE within 72 hours of presentation
(Figure 128-4). The modified rule uses four criteria: (1) positive troponin or new acute ST
depression ≥1 mm or T-wave inversion in ≥2 contiguous leads in the setting of ACS; (2)
ongoing chest pain that is likely ischemic; (3) worsening of previously stable angina,
angina after revascularization procedure, or pain that is the same as that associated with
a prior MI; (4) rales above both bases or systolic blood pressure <100 (Figure 128-4). The absence of these four factor identifies patients at very low risk of subsequent cardiac events and appropriate for the observation unit (Figure 128-5). In observation units, dual antiplatelet therapy and anticoagulation is usually avoided. Patients undergo serial troponin evaluation, cardiac monitoring, and repeated ECGs. For patients with normal serial troponins and ECGs, stress testing before discharge or within 72 hours of discharge should be considered (Class IIa, LOE B). If patients have recurrent chest pain suggestive of ischemia, increased cardiac biomarkers, or dynamic ECG changes, they are then admitted to the hospital and managed according to inpatient pathways described below.

Figure 128-5 Observation unit low-risk acute coronary syndrome (ACS) protocol.

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ANTIPLATELET THERAPY AT ADMISSION

Patients who are not low risk and/or patients with recurrent symptoms, ECG changes, or
positive troponin values are admitted to the hospital for inpatient management (Figure
128-4). In addition to aspirin, dual antiplatelet therapy is recommended as soon as
possible after admission to the hospital. There are two oral P2Y12 inhibitor options for
upstream management in NSTE-ACS: clopidogrel (600 mg loading dose followed by 75
mg a day) and ticagrelor (180 mg loading dose followed by 90 mg twice a day). Both of
these agents are options for both the invasive (Class I, LOE B) and ischemia-guided (Class
I, LOE A) strategies. Choice between these agents will be discussed later in the Dual
Antiplatelet Therapy Section of Late Hospital & Hospital Discharge part of the chapter.

The early benefit of clopidogrel was first noted in the Clopidogrel in Unstable Angina to
Prevent Recurrent Events (CURE) trial, where there was a 34% relative reduction in major
cardiac events in first 24 hours in patients randomized to clopidogrel and aspirin
compared to aspirin alone. Furthermore, in a large meta-analysis of 37,814 patients
undergoing PCI from six randomized control trials and nine observational studies showed
a significant reduction in major adverse cardiac events (9.8% vs 12.3%, NNT = 40, p < 0.001) and trends toward improve mortality (1.5% vs 2.0%, p = 0.17) with dual antiplatelet therapy pretreatment compared to aspirin alone. The downside to routine upstream clopidogrel is increased bleeding in patients who require coronary artery bypass graft (CABG) surgery. However, CABG is only required in approximately 11% of patients with ACS, and if not emergent, surgery can be delayed 5 days until the antiplatelet effects have reversed.

The oral P2Y12 inhibitor prasugrel is not recommended prior to cardiac catheterization
in patients with NSTE-ACS, based on the results of the ACCOST (A Comparison of
Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the
Time of Diagnosis in Patients With Non–ST-Elevation Myocardial Infarction) trial where
4033 patients with non-STE ACS were randomized to upstream or intraprocedural
prasugrel. In this trial, there was no reduction in major adverse events but only increased
bleeding complications in patients pretreated with prasugrel. It has been suggested that
the lack of efficacy in this trial may relate to short time interval from pretreatment to
catheterization and the rapid onset of action of the drug in the cardiac cath lab.

Upstream (prior to the cath lab) GPIs are usually not necessary for most patients with
ACS in the setting of upstream oral dual antiplatelet therapy. Two randomized studies in
NSTE-ACS have noted similar efficacy with a deferred GPI strategy (given at the time of
PCI) compared with a routine upstream strategy. In the 10,500 patient Early Glycoprotein
IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome
trial, there were similar major adverse events (9.3% vs 10%, p = 0.23) with more bleeding in
the routine upstream GPI use. Similar findings were noted in the Acute Catheterization and
Urgent Intervention Triage strategY Timing Trial.

ANTICOAGULANT THERAPY AT ADMISSION

All patients admitted to the hospital with NSTE-ACS should receive IV anticoagulation
prior to cardiac catheterization as well as during PCI. While the optimal anticoagulation
strategy in patients with NSTE-ACS is unknown, the most widely used agent is UFH 60
units/kg bolus (maximum 4000 units) followed by an initial infusion of 12 units/kg/h
(maximum 1000 units/h) adjusted per activated partial thromboplastin time to maintain
therapeutic anticoagulation (Class I, LOE B). UFH does not break down existing thrombus,
but does prevent further thrombus formation. While large studies investigating UFH in ACS

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are lacking, meta-analysis suggest about a 33% reduction (relative risk 0.67 [0.44-1.02],
NNT = 40) in recurrent ischemia and infarction with the addition of UFH to aspirin. While
low molecular weight heparins (LMWHs) offer an alternate option (to UFH) in NSTE-ACS
(Class I, LOE A), large randomized trials and meta-analyses suggest essentially similar
clinical efficacy and safety compared to unfractionated heparin. However, LMWH must be
dose adjusted in patients with low glomerular filtration rates and can significantly delay
the sheath removal in the cath lab due to longer durations of action. For these reasons,
many interventional cardiologists prefer UFH to LMWH in the cardiac cath lab for patients
with NSTE-ACS.

The factor X inhibitor fondaparinux is a synthetic pentasaccharide that indirectly
inhibits factor Xa. While lower bleeding complications were noted with fondaprinux
compared to LMWH in the OASIS (Organization to Assess Strategies in Ischemic
Syndromes)-5 trial, its use should only be considered in a ischemia-guided strategy where
invasive procedures are unlikely due to increased rates of catheter thrombosis in patients
undergoing PCI. Additional anticoagulation with either unfractionated heparin or
bivalirudin is recommended when PCI is warranted with fondaparinux (Class I, LOE B).
Furthermore, fondaparinux is contraindicated in patients with GFR < 30 mL/min and the long half-life (17 hours) can delay sheath removal in the cath lab when manual closure is performed. For these reasons, this drug is not ideal for patient with NSTE-ACS in patients with an invasive strategy.

Bivalirudin is an intravenous direct thrombin inhibitor that has been widely studied in
patients with NSTE-ACS undergoing an invasive management strategy (Class I, LOE B).
Several studies have demonstrated similar efficacy and reduced bleeding complications
with bivalirudin compared to routine heparin and GPI use in NSTE-ACS. In the 13,819
patient ACUITY trial, there was a similar composite ischemic endpoint (7.8% vs 7.3%, p =
0.32) but significantly lower major bleeding complications (3.0% vs 5.7%, p < 0.001) with bivalirudin compared to UFH and GPI. Similar findings were noted in ISAR-REACT 4 trial. However, the benefits of bivalirudin over UFH in patients with NSTE-ACS undergoing PCI using the radial access are unknown.

EARLY INVASIVE STRATEGY VERSUS ISCHEMIA-GUIDED STRATEGY

All NSTE-ACS patients with refractory angina, electrical instability (eg, ventricular
fibrillation or ventricular tachycardia), and/or cardiogenic shock should undergo
immediate angiography within 2 hours of hospital presentation no matter the ECG
findings (Class I, LOE A). However, for patients that are hemodynamically and electrically
stable without ongoing angina, clinicians must select between an early invasive strategy
or an ischemia-guided strategy.

An early invasive strategy is defined as angiography within 72 hours of admission to
risk stratify patients based on coronary anatomy. The advantages to an early invasive
strategy include rapid evaluation, early revascularizaton, and earlier discharge. An early
invasive strategy is indicated for initially stabilized patients with NSTE-ACS without
contraindications to angiography and elevated risk of recurrent events (Table 128-6).
Multiple studies and meta-analyses suggests that an early invasive strategy is preferred to
an ischemia-guided strategy in higher-risk patients with NSTE-ACS as it is associated with
lower rates of repeat hospitalization, myocardial infarction, and mortality. In a combined
analysis of multiple randomized trials, there was an 11.1% absolute reduction (NNT9) in
death and myocardial infarction in the highest risk NSTE-ACS by 5-year follow-up. An early
invasive strategy is also associated with less angina and improved quality of life. It should
be remembered that these are strategy trials, and not a comparisons of revascularization

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and medical therapy. Patients undergo revascularization with CABG or PCI
revascularization in about 70% of patients randomized to an early invasive strategy and in
40% to 50% of patients randomized to an ischemia-guided strategy.

TABLE 128-6 Intermediate or High Risk Non–ST-Elevation Acute Coronary Syndrome
(NSTE-ACS) Criteria

Intermediate or High risk NSTE-ACS is defined by one or more of the following:
1. Recurrent angina/ischemia at rest with low-level activities despite intensive medical

therapy
2. Elevated troponin
3. New/dynamic ST-segment depression
4. Signs/symptoms of heart failure or new/worsening mitral regurgitation
5. High-risk findings from noninvasive testing
6. Hemodynamic instability
7. Sustained ventricular tachycardia (>30 s and/or hemodynamic instability)
8. PCI within 6 mo
9. TIMI risk score ≥3

10. Newly reduced left ve

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/or cardiogenic shock should undergo immediate angiography within 2 hours of hospital
presentation no matter the ECG findings (Class I, LOE A). However, for patients that are
hemodynamically and electrically stable without ongoing angina, clinicians must select
between an early invasive strategy or an ischemia-guided strategy.

An early invasive strategy is defined as angiography within 72 hours of admission to
risk stratify patients based on coronary anatomy. The advantages to an early invasive
strategy include rapid evaluation, early revascularizaton, and earlier discharge. An early
invasive strategy is indicated for initially stabilized patients with NSTE-ACS without
contraindications to angiography and elevated risk of recurrent events (Table 128-6).
Multiple studies and meta-analyses suggests that an early invasive strategy is preferred to
an ischemia-guided strategy in higher-risk patients with NSTE-ACS as it is associated with
lower rates of repeat hospitalization, myocardial infarction, and mortality. In a combined
analysis of multiple randomized trials, there was an 11.1% absolute reduction (NNT9) in
death and myocardial infarction in the highest risk NSTE-ACS by 5-year follow-up. An early
invasive strategy is also associated with less angina and improved quality of life. It should
be remembered that these are strategy trials, and not a comparisons of revascularization
and medical therapy. Patients undergo revascularization with CABG or PCI
revascularization in about 70% of patients randomized to an early invasive strategy and in
40% to 50% of patients randomized to an ischemia-guided strategy.

TABLE 128-6 Intermediate or High Risk Non–ST-Elevation Acute Coronary Syndrome
(NSTE-ACS) Criteria

Intermediate or High risk NSTE-ACS is defined by one or more of the following:
1. Recurrent angina/ischemia at rest with low-level activities despite intensive medical

therapy
2. Elevated troponin
3. New/dynamic ST-segment depression
4. Signs/symptoms of heart failure or new/worsening mitral regurgitation
5. High-risk findings from noninvasive testing
6. Hemodynamic instability
7. Sustained ventricular tachycardia (>30 s and/or hemodynamic instability)
8. PCI within 6 mo
9. TIMI risk score ≥3

10. Newly reduced left ventricular function (LVEF < 40%)

In contrast, an ischemia-guided strategy aims to avoid routine angiography unless
patients experience refractory or recurrent angina, hemodynamic instability, or objective
evidence of severe ischemia. An ischemia-guided strategy is preferred in patients at low
risk for recurrent events, especially in troponin negative NSTE-ACS with low TIMI risk
scores (≤2) (Table 128-7). Patients undergoing an ischemia-guided strategy should
undergo noninvasive testing prior to discharge (Class I, LOE B). The optimal test depends

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on the patient’s baseline ECG, available technologies, and local expertise. Due to low costs
and simplicity, the exercise treadmill testing is preferred in patients when the baseline ECG
is free of ST changes or LBBB (Class I, LOE C). If there are abnormal ST changes on the
baseline ECG, then imaging (Single Photon Emission Computed Tomography or
Echocardiogram) can be added to the exercise test (Class I, LOE B). Pharmacologic stress
testing with imaging is recommended for patients unable to exercise due to physical
limitations (Class I, LOE C).

TABLE 128-7 Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Non–ST-
Elevation Acute Coronary Syndrome (NSTE-ACS)

TIMI Risk Score
14-day Risk of Mortality, Recurrent MI, or Severe
Ischemia Requiring Revascularization

0-1 4.7%
2 8.3%
3 13.2%
4 19.9%
5 26.2%
6-7 40.9%

TIMI risk score is determined by presence of seven variables on admission and one point given to each
of the following: age ≥ 65 y, ≥3 cardiac risk factors, prior CAD defined as stenosis ≥50%, ST deviation
on ECG, ≥2 anginal events in 24 h, use of aspirin in prior 7 d, and elevated cardiac troponin.

PRACTICE POINT

NSTE-ACS
Low-risk patients with possible ACS do not need admission to the hospital and can be
safely monitored in an observation unit.
All patients admitted to the hospital should receive the following on admission: aspirin
325 mg followed by 81 mg a day, an oral P2Y12 antagonist (clopidogrel or ticagrelor)
loading dose followed by maintenance therapy, and anticoagulation (unfractionated
heparin preferred if invasive management possible).
Morphine and oxygen should be avoided in most patients.
Nitroglycerin should be avoided in patients with right ventricular infarctions,
hypotension, and/or recent phosphodiesterase-5 inhibitor use.
Upstream glycoprotein IIb/IIIa inhibitors are not indicated in patients with NSTE-ACS
when upstream dual antiplatelet therapy (aspirin + oral P2Y12 antagonist) is used.
Serial troponin-only testing at 0, 3, and 6 hours can be used to diagnose or rule out
myocardial infarction. There is little role for other cardiac biomarkers (CK, CKMB, or
myoglobin).
Patients with refractory angina or cardiogenic shock should undergo emergent
angiography within 2 hours of admission, even if there is no evidence of ST-elevations

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on ECG.
Initially stabilized patients at intermediate or high risk should undergo an angiography
with intent to perform intervention within 72 hours of admission. Patients at low risk
should undergo an ischemia-guided strategy with noninvasive stress testing.

LATE HOSPITAL CARE & HOSPITAL DISCHARGE
DUAL ANTIPLATELET THERAPY

All patients with ACS should receive aspirin therapy indefinitely. Regardless if medically
managed or revascularized with PCI or surgery, patients should receive low dose 81 mg
daily as it appears to be equally efficacious as higher doses but with lower bleeding
complications. In addition to aspirin, all patients with ACS should receive a P2Y12
antagonist for 1 year regardless if treated with a bare metal stent or a drug eluting stent or
without PCI. There are three options for patients who undergo PCI for ACS: clopidogrel,
prasugrel, or ticagrelor. There are two options for patients who are medically managed
without PCI: clopidogrel or ticagrelor. There is no consensus to the optimal P2Y12
antagonist in ACS at present.

The benefits of 1 year of dual antiplatelet therapy was established from the CURE trial,
where dual antiplatelet therapy (clopidogrel and aspirin) resulted in a 20% reduction (NNT
= 48) in cardiovascular death, myocardial infarction, or cerebrovascular accident
compared with aspirin alone in 12,562 patients with ACS. This benefit was noted in
patients who were managed both conservatively and invasively with PCI. Now that
clopidogrel is generic, the low cost makes it an attractive option in ACS.

Prasugrel is a P2Y12 antagonist that is more efficiently metabolized to its active
metabolite with greater potency and more rapid onset of action than clopidogrel. In 13,608
patients with ACS in the TRITON TIMI 38 trial, there were lower composite of death,
myocardial infarction, and stroke in patients randomized to prasugrel compared to
clopidogrel (9.9% vs 12.1%, NNT45, p < 0.001). However, there was significantly more major bleeding with prasugrel (2.4% vs 1.8%, NNH167, p = 0.03). Furthermore, patients over 75 years of age, body weight less than 60 pounds, and a history of stroke or transient ischemic attack had worse outcomes with prasugrel and there is a black box warning to avoid prasugrel in these patients. Despite the warning, up to 18% of patients in real word practice receive received prasugrel with these contraindications. In addition, there is little benefit to prasugrel in patients medically managed for ACS without PCI. In the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, prasugrel failed to reduce cardiac event rates compared to clopidogrel in patients with ACS undergoing medical therapy.

Ticagrelor is a direct acting P2Y12 antagonist that does not require metabolic
activation. In 18,624 patients with ACS in the PLATO trial, ticagrelor reduced the composite
of death, myocardial infarction, and stroke compared to clopidogrel (9.8% vs 11.7%,
NNT53, p = 0.003). This benefit was noted in patients undergoing PCI and those medically
managed without PCI. Using the same bleeding definition used in TRITON TIMI 38 (non-
CABG TIMI major bleeding), there was again more major bleeding with tiacagrelor
compared to clopidogrel (2.8% vs 2.2%, NNH167, p = 0.03). Interestingly, patients
randomized in the United States and Canada did not derive a benefit with ticagrelor and
trended toward harm. While this finding may be due to chance, interactions with the higher

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aspirin dose may also explain this finding. Therefore, in the United States ticagrelor is
approved for use only with the lower aspirin dose (81 mg) with a warning against the use
with the higher aspirin dose.

How is one to choose between these three P2Y12 antagonist agents: clopidogrel,
prasugrel, and ticagrelor? All three agents have a similar recommendation in the
ACCF/AHA guidelines (Class I, LOE B). However, these medications have very different
costs, efficacy, and safety considerations. While both ticagrelor and prasugrel were shown
to be superior to clopidogrel in large randomized trials, the benefits of these medications
over clopidogrel seem to be most pronounced in patients with abnormalities in clopidogrel
metabolism. Clopidogrel is a prodrug that requires two-step metabolism into an active
metabolite. Patients with abnormalities in the CYP2C19 allele have impaired metabolism,
higher on-treatment platelet reactivity, and worse outcomes with clopidogrel. Up to 30% of
the US population has abnormalities in this CYP2C19 allele, and clopidogrel carries a
warning of reduced efficacy in these patients. In the genetic subgroup analysis of the
TRITON TIMI 38 trial, prasugrel and clopidogrel had similar outcomes in patients with
normal CYP2C19 alleles. In contrast, the benefit of prasugrel was much greater in patients
with abnormal CYP2C19 alleles (NNT16) compared to overall trial (NNT50). A similar
trend was noted for ticagrelor in the genetic subgroup analysis of the PLATO trial. Taken
together, these trials suggest that the benefits of prasugrel and ticagrelor are most
pronounced in patients with abnormal CYP2C19 alleles with clopidogrel. However, for the
remaining 65% to 75% of the ACS population, clopidogrel may be as effective, safer, easier
to use, and more cost effective. Whether a tailored strategy based on genotype or platelet
function testing is safe and effective with improved value is unknown and randomized
trials are warranted.

BETA BLOCKERS

Oral β-blockers are recommended within 24 hours of presentation for patients with STEMI
(Class I, LOE B) and NSTE-ACS (Class I, LOE A) and should be continued at discharge. β-
Blockers decrease heart rate, contractility, blood pressure, and myocardial oxygen
consumption. While early β-blockers do not reduce short-term mortality in patients with
ACS, they decrease ischemia, reinfarction, and ventricular arrhythmia. Furthermore, β-
blockers improve long-term survival in patients with MI complicated by heart failure and
ventricular arrhythmia. The long-term duration of routine β-blocker therapy after
myocardial infarction without heart failure or hypertension has not been prospectively
addressed, but guidelines recommend a 3-year treatment course then reassess the clinical
need for the medication. Meta-analysis from the reperfusion era suggests β-blockers can
reduce MI (RR 0.72 [95% CI, 0.62-0.83], NNT = 209) and angina (RR 0.80 [95% CI, 0.65-
0.98], NNT = 26) at the expense of increased heart failure (RR 1.1 [95% CI, 1.05-1.16], NNH
= 79) and increased cardiogenic shock (RR 1.29 [95% CI, 1.18-1.41], NNH = 90)with no
significant impact on mortality. While oral β-blockers are an important part of ACS
management, IV β-blockers should usually be avoided as they increase the risk for shock
(Class III, LOE B). In addition, oral β-blockers are contraindicated in patients with signs of
acute heart failure, evidence of low-output state, increased risk for cardiogenic shock,
second- or third-degree heart block, and active asthma. When β-blockers are
contraindicated due to asthma exacerbation, then nondihyophyidine calcium channel
blockers could be considered as long there are no contraindications (Class I, LOE B).

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RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITORS

Angiotensin Converting Enzyme (ACE) inhibitors have been shown to lower mortality in
patients with recent myocardial infarction and reduced left ventricular ejection fractions
(LVEF) less than 40% (Class I, LOE A). Furthermore, ACE inhibitors should be strongly
considered in patients with diabetes mellitus and stable chronic kidney disease (Class I,
LOE A). In patients who are intolerant to ACE inhibitors, angiotensin receptor blockers
(ARBs) should be considered. While meta-analyses suggest a small (0.48% absolute, NNT
= 208) reduction in 30-day mortality with ACE inhibitors in ACS, the clinical significance of
this finding is unclear and ACE inhibitor should be used with caution without the above
indications given the risk for renal dysfunction and hypotension.

Aldosterone antagonists (eg, eplerenone, spironolactone) are recommended for
patients with AMI and LVEF less than or equal to 40% (Class I, LOE B). In the EPHESUS
(Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival) study,
demonstrated significantly reduced rates of death from cardiovascular causes or
hospitalization for cardiovascular events (relative risk, 0.87; 95% CI, 0.79-0.95; P = 0.002,
NNT = 30) in patients with eplerenone initiated within days of admission.

HIGH-INTENSITY STATIN THERAPY

High-intensity statin therapy should be given to all patients with ACS without
contraindications (Class I, LOE A). Statins should be started at moderate to high doses as
soon as possible on admission and continued indefinitely. The benefits of statin therapy
are well known in the primary prevention for high-risk patients and in secondary prevention
for patients with CAD. There may also be an early acute benefit in patients with NSTE-ACS.
Several studies have demonstrated reduced rates of periprocedural MI with high-dose
statin loading before PCI; therefore, a statin is recommended before PCI when possible
(Class IIa, LOE A for statin naive).

ANTICOAGULATION USE WITH ANTIPLATELET THERAPY IN ACS

The choice of stent, P2Y12 antagonist, duration of dual antiplatelet therapy, and
anticoagulant is important for patients that require anticoagulation after ACS. This
includes patients with atrial fibrillation, venous thromboembolism, mechanical heart
valves, and left ventricular thrombus. When anticoagulation is warranted, warfarin is the
most common anticoagulant agent and clopidogrel and aspirin the most common
antiplatelet agents used. Very little data support the safety of the novel anticoagulants
and P2Y12 inhibitors in this setting. In addition, patients with a history of gastrointestinal
bleeding who require anticoagulation and antiplatelet therapy should also receive proton
pump inhibitors (PPIs) (Class I, LOE C). A PPI can also be considered in patients without
history of gastrointestinal bleeding when anticoagulation and antiplatelet therapy are
warranted (Class IIa, LOE C). While there were early concerns over potential interactions
with certain PPIs and clopidogrel metabolism, more recent registry and randomized trials
suggest reductions in bleeding complications without increased cardiac events with the
combination of PPIs and clopidogrel.

Triple therapy (aspirin, clopidogrel, and warfarin) after PCI is associated with two- to
fivefold greater risk of major bleeding compared to dual antiplatelet therapy. Recent
studies suggest that aspirin can often be omitted when anticoagulation is warranted after
PCI. In the 573 patient randomized WOEST trial, omission of aspirin decreased major

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bleeding complications (44.4% vs 19.4%, NNH [by adding aspirin] 4, p < 0.0001) without any increase in ischemic events. Similar findings were noted in a meta-analysis of 1263 patients from six randomized trials as well as a larger real world registry of 12,165 patients undergoing PCI requiring anticoagulation.

Left ventricular (LV) mural thrombus is found in 3% to 15% of anterior MIs treated with
percutaneous coronary revascularization. Pooled studies have noted a fivefold increased
risk for systemic embolism with LV thrombus after anterior MI, and anticoagulation
therapy decreases this embolic risk. Thus, anticoagulation is recommended for patients
with acute MI and asymptomatic LV mural thrombus (Class IIa, LOE C). Anticoagulation
after anterior MI without mural thrombus formation is controversial. Currently, the
guidelines suggest that anticoagulation therapy may be considered for patients with
STEMI and anterior apical akinesis or dyskinesis (IIb, LOE C). However, in a recent
retrospective analysis of 460 undergoing PCI for anterior MI without LV thrombus,
anticoagulation was actually associated with an increased incidence of stroke (3.1% vs
0.3%, p = 0.02), major bleeding (8.5% vs 1.8%, p < 0.0001), mortality (5.4% vs 1.5%, p = 0.04), length of stay, and readmissions. Furthermore, after propensity matching, anticoagulation was still associated with a fourfold greater incidence of net adverse cardiac events. These findings certainly question the routine use of triple therapy in this population without LV thrombus. Until larger randomized trials are conducted, if anticoagulation is used in this setting, clinicians should probably omit aspirin, add proton pump inhibitors, target lower INR ranges, shorten the anticoagulation course (3 months), and use radial access when possible.

SECONDARY PREVENTION

All patients with ACS should be referred to a comprehensive cardiovascular rehabilitation
program (Class I, LOE B). These programs provide patient education, regular exercise,
monitor risk factors, and address lifestyle modification. The pneuomococcal vaccine is
recommended for patients 65 years and older and high-risk patients with cardiovascular
disease (Class I, LOE B). In addition, annual influenza vaccination is recommended for all
patients with ACS (Class I, LOE C), and based on randomized controlled trial data has been
shown to reduce MACE (NNT = 17) and hospitalization for ACS (NNT = 31). NSAIDs have
been associated with increased cardiovascular risk and should largely be avoided in
patients with ACS (Class III, LOE B). For patients with chronic musculoskeletal pain,
acetaminophen, nonacetylated salicylates, tramadol, or low dose narcotics should be used
as required (Class I, LOE C). If NSAIDs are required when these therapies are insufficient,
then the nonselective naproxen is preferred over other NSAIDS (Class IIa, LOE C).

PRACTICE POINT

Late Hospital ACS Care and Hospital Discharge
All patients with ACS should be discharged with dual antiplatelet therapy.

Options for P2Y12 antagonists include clopidogrel, prasugrel, and ticagrelor after
PCI.
Options for P2Y12 antagonists include clopidogrel and ticagrelor with medical
management without PCI.

All patients with ACS should receive high-intensity statin therapy.

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All patients with MI should receive oral β-blocker therapy for at least 3 years after
myocardial infarction and indefinitely for patients with congestive heart failure and/or
hypertension.
All patients with reduced LVEF ≤ 40% should receive an ACEI or ARB and aldosterone
antagonist unless contraindications.
When anticoagulation is warranted in patients with PCI for ACS, warfarin is preferred
and aspirin can usually be omitted.
All patients should be counseled about smoking cessation, diet, and exercise.
All patients should be referred to cardiac rehabilitation programs at discharge.

Discharge checklist

Dual antiplatelet therapy
High-intensity statin
Referral to cardiac rehabilitation
Smoking cessation education
β-Blocker if myocardial infarction and no contraindications
ACE inhibitor (or ARB) if diabetic, chronic renal failure, or LVEF≤40% and no
contraindications
Aldosterone inhibitor if LVEF≤40% and no contraindications

SUGGESTED READINGS
American Heart Association’s Mission: Lifeline:

http://www.heart.org/HEARTORG/HealthcareResearch/MissionLifelineHomePage/Missi
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Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American
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Bangalore S, Makani H, Radford M. Clinical outcomes with β-blockers for myocardial
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Dewilde WJ, Oirbans T, Verheugh FW, et al. Use of clopidogrel with or without aspirin in
patients taking oral anticoagulant therapy and undergoing percutaneous coronary
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Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography
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Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute
myocardial infarction. N Engl J Med. 2009;361(9):868-877.

McDaniel M, Ross M, Rab ST, et al. A comprehensive acute coronary syndrome algorithm
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