Section 2

Cardiovascular Disorders
Edited by Terry L. Schwinghammer

5
Chapter

Acute Coronary Syndromes

• Acute coronary syndromes (ACSs) include all syndromes compatible with acute
myocardial ischemia resulting from imbalance between myocardial oxygen demand
and supply.
• ACSs are classified according to electrocardiographic (ECG) changes into (1)
ST-segment-elevation (STE) myocardial infarction (MI) or (2) non–ST-segment-
elevation (NSTE) ACS, which includes NSTE MI and unstable angina (UA).

PATHOPHYSIOLOGY
• Endothelial dysfunction, inflammation, and formation of fatty streaks contribute to
development of atherosclerotic coronary artery plaques.
• The cause of ACS in more than 90% of patients is rupture, fissuring, or erosion of an
unstable atheromatous plaque. A clot forms on top of the ruptured plaque. Exposure
of collagen and tissue factor induces platelet adhesion and activation, which promote
release of adenosine diphosphate (ADP) and thromboxane A2 from platelets produc-
ing vasoconstriction and platelet activation. A change in the conformation of the gly-
coprotein (GP) IIb/IIIa surface receptors of platelets occurs that cross-links platelets
to each other through fibrinogen bridges.
• Simultaneously, activation of the extrinsic coagulation cascade occurs as a result of
exposure of blood to the thrombogenic lipid core and endothelium, which are rich
in tissue factor. This leads to formation of a fibrin clot composed of fibrin strands,
cross-linked platelets, and trapped red blood cells.
• Ventricular remodeling occurs after MI and is characterized by left ventricular dila-
tion and reduced pumping function, leading to cardiac failure.
• Complications of MI include cardiogenic shock, heart failure (HF), valvular dysfunc-
tion, arrhythmias, pericarditis, stroke secondary to left ventricular (LV) thrombus
embolization, venous thromboembolism, and LV free-wall rupture.

CLINICAL PRESENTATION
• Predominant symptom is midline anterior chest discomfort (usually at rest), severe
new-onset angina, or increasing angina that lasts at least 20 minutes. Discomfort may
radiate to the shoulder, down the left arm, to the back, or to the jaw. Accompanying
symptoms may include nausea, vomiting, diaphoresis, and shortness of breath.
• No specific features indicate ACS on physical examination. However, patients with
ACS may present with signs of acute HF or arrhythmias.

DIAGNOSIS
• Obtain 12-lead ECG within 10 minutes of presentation. Key findings indicating
myocardial ischemia or MI are STE, ST-segment depression, and T-wave inversion.
Appearance of a new left bundle-branch block with chest discomfort is highly spe-
cific for acute MI. Some patients with myocardial ischemia have no ECG changes,
so biochemical markers and other risk factors for coronary artery disease (CAD)
should be assessed.
• Biochemical markers of myocardial cell death are important for confirming diagno-
sis of acute MI. Diagnosis is confirmed with detection of rise and/or fall of cardiac
37
SECTION 2   |   Cardiovascular Disorders

biomarkers (cardiac troponin preferred) with at least one value above the 99th per-
centile of the upper reference limit and at least one of the following: (1) symptoms
of ischemia; (2) new significant ST-segment–T-wave changes or new left bundle-
branch block; (3) pathological Q waves; or (4) imaging evidence of new loss of viable
myocardium or new regional wall motion abnormality. Typically, a blood sample is
obtained once in the emergency department, then 6 to 9 hours later.
• Patient symptoms, past medical history, ECG, and biomarkers are used to stratify
patients into low, medium, or high risk of death, MI, or likelihood of failing phar-
macotherapy and needing urgent coronary angiography and percutaneous coronary
intervention (PCI).

TREATMENT
• Goals of Treatment: Short-term goals include: (1) early restoration of blood flow to
the infarct-related artery to prevent infarct expansion (in the case of MI) or prevent
complete occlusion and MI (in UA), (2) prevention of death and other complications,
(3) prevention of coronary artery reocclusion, (4) relief of ischemic chest discomfort,
and (5) resolution of ST-segment and T-wave changes on ECG. Long-term goals
include control of cardiovascular (CV) risk factors, prevention of additional CV
events, and improvement in quality of life.
GENERAL APPROACH
• General measures include hospital admission, oxygen if saturation is low, continuous
multilead ST-segment monitoring for arrhythmias and ischemia, frequent measure-
ment of vital signs, bedrest for 12 hours in hemodynamically stable patients, use of
stool softeners to avoid Valsalva maneuver, and pain relief.
• Obtain serum potassium, magnesium, glucose, and creatinine; baseline complete
blood cell count (CBC) and coagulation tests; and fasting lipid panel. Draw lipid
panel within the first 24 hours of hospitalization because values for cholesterol (an
acute phase reactant) may be falsely low after that period.
• It is important to triage and treat patients according to their risk category (Fig. 5–1).
• Patients with STE MI are at high risk of death, so initiate immediate efforts to rees-
tablish coronary perfusion and adjunctive pharmacotherapy.
NONPHARMACOLOGIC THERAPY
• For patients with STE MI presenting within 12 hours of symptom onset, the reperfu-
sion treatment of choice is early reperfusion with primary PCI of the infarct artery
within 90 minutes of first medical contact.
• For patients with NSTE ACS, practice guidelines recommend coronary angiography
with either PCI or coronary artery bypass graft (CABG) surgery revascularization as
early treatment for high-risk patients; such an approach may also be considered for
patients not at high risk.
EARLY PHARMACOTHERAPY FOR STE MI (Fig. 5–2)
• In addition to reperfusion therapy, American College of Cardiology Foundation/
American Heart Association (ACCF/AHA) guidelines recommend that all patients
with STE MI and without contraindications should receive within the first day of
hospitalization and preferably in the emergency department: (1) intranasal oxygen
(if oxygen saturation is low), (2) sublingual (SL) nitroglycerin (NTG), (3) aspirin,
(4) a P2Y12 platelet inhibitor, (5) and anticoagulation with bivalirudin, unfractionated
heparin (UFH), or enoxaparin.
• Administer a GP IIb/IIIa inhibitor with UFH to patients undergoing primary PCI.
Give IV β-blockers and IV NTG to select patients. Initiate oral β-blockers the first day
in patients without cardiogenic shock. Administer morphine to patients with refrac-
tory angina as an analgesic and venodilator that lowers preload. Start an angiotensin-
converting enzyme (ACE) inhibitor within 24 hours in patients who have either
anterior wall MI or LVEF of 40% or less and no contraindications.
38
 Acute Coronary Syndromes   |  CHAPTER 5

Ischemic chest discomfort symptoms, lasting at least 20 min;

suspect acute coronary syndrome

Obtain and interpret a 12-lead ECG within 10 min

ST-segment elevation No ST-segment elevation

ST-segment depression T-wave inversion No ECG changes

Initiate reperfusion therapy in appropriate Risk stratificationa; multilead continuous ST-segment

candidates (fibrinolysis or primary PCI) monitoring; obtain serial troponin and CK MBb,c

Obtain serial troponin and CK MB as Initiate pharmacotherapy for non-ST-segment

confirmatory; results not needed before elevation ACS based on patient risk
reperfusion therapy is initiated; multilead
continuous ST-segment monitoring

Low-risk Moderate- and high-risk

Initiate adjunctive ST-segment elevation

ACS pharmacotherapy
Stress test to evaluate likelihood of CAD

Negative stress test Positive stress test

Diagnosis of noncardiac Coronary angiography with

chest pain syndrome revascularization (PCI or CABG)

Figure 5–1.  Evaluation of the acute coronary syndrome patient. aAs described
in textbook Table 7-1. b“Positive”: Above the myocardial infarction decision limit.
c
“Negative”: Below the myocardial infarction decision limit. (ACS, acute coronary
syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CK MB,
creatine kinase myocardial band; ECG, electrocardiogram; PCI, percutaneous coronary
intervention. (Modified with permission from Spinler SA. Evolution of antithrombotic
therapy used in acute coronary syndromes. In: Richardson MM, Chant C, Cheng JWM, et
al, eds. Pharmacotherapy Self-Assessment Program. Book 1: Cardiology, 7th ed. Lenexa, KS:
American College of Clinical Pharmacy; 2010.)

Fibrinolytic Therapy
• A fibrinolytic agent is indicated in patients with STE MI presenting within 12 hours
of the onset of chest discomfort who have at least 1 mm of STE in two or more con-
tiguous ECG leads and are unable to undergo primary PCI within 120 minutes of
medical contact. Limit use of fibrinolytics between 12 and 24 hours after symptom
onset to patients with ongoing ischemia.
• It is not necessary to obtain the results of biochemical markers before initiating
fibrinolytic therapy.
• Absolute contraindications to fibrinolytic therapy include: (1) history of hemorrhagic
stroke (at any time), (2) ischemic stroke within 3 months, (3) active internal bleeding,
(4) known intracranial neoplasm, (5) known structural cerebrovascular lesion, (6)
39
SECTION 2   |   Cardiovascular Disorders

ST-segment elevation myocardial infarction

Oxygen (if O2 saturation <90%)

SL NTG, aspirin, morphine
sulfated, IV NTGd

Symptoms ≤ to 12 h Symptoms >12 h

Reperfusion therapy

Secondary PCI or CABG or fibrinolysis

for select patients; for secondary
High-intensity statin PCI during hospitalization, administer
bivalirudinee alone or UFH or
enoxaparinc or fondaparinux
(plus UFH) with optional GP
llb/Illa inhibitor at time of PCIf
Primary PCI Fibrinolysis

Clopidogrel, prasugrel,
Clopidogrel, statin
or ticagrelor

Bivalirudine alone or IV UFHa or IV and SC

unfractionated heparin enoxaparinb,c
with GP llb/Illa (preferred; selected patients)
receptor inhibitor or IV and SC fondaparinuxd

β-Blocker, ACE inhibitor (or ARB), eplerenone (or spironolactone)d

Figure 5–2.  Initial pharmacotherapy for ST-segment elevation myocardial

infarction. aFor at least 48 hours. bSee textbook Table 24–2 for dosing and specific
types of patients who should not receive enoxaparin. cFor the duration of hospitaliza-
tion, up to 8 days. dFor select patients, see textbook Table 24–2. eIf pretreated with
UFH, stop UFH infusion for 30 minutes prior to administration of bivalirudin (bolus plus
infusion). f Increased risk of major bleeding and ICH if a GP IIb/IIIa inhibitor is added to
an anticoagulant for PCI following fibrinolysis, especially in the elderly; weigh risk ver-
sus benefit (ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker;
CABG, coronary artery bypass graft surgery; GP, glycoprotein; NTG, nitroglycerin; PCI,
percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; UFH, unfraction-
ated heparin.) (Modified with permission from Spinler SA. Evolution of antithrombotic
therapy used in acute coronary syndromes. In: Richardson MM, Chant C. Cheng JWM,
et al, eds. Pharmacotherapy Self-Assessment Program. 7th ed. Book 1: Cardiology. Lenexa,
KS: American College of Clinical Pharmacy; 2010.)

40
 Acute Coronary Syndromes   |  CHAPTER 5

suspected aortic dissection, and (7) significant closed head or facial trauma within 3
months. Primary PCI is preferred in these situations.
• A fibrin-specific agent (alteplase, reteplase, or tenecteplase) is preferred over the
non–fibrin-specific agent streptokinase.
• Treat eligible patients as soon as possible, but preferably within 30 minutes from the
time they present to the emergency department, with one of the following regimens:
✓ Alteplase: 15 mg IV bolus followed by 0.75 mg/kg infusion (maximum 50 mg) over
30 minutes, followed by 0.5 mg/kg infusion (maximum 35 mg) over 60 minutes
(maximum dose 100 mg)
✓ Reteplase: 10 units IV over 2 minutes, followed 30 minutes later with another
10 units IV over 2 minutes
✓ Tenecteplase: A single IV bolus dose given over 5 seconds based on patient
weight: 30 mg if less than 60 kg; 35 mg if 60 to 69.9 kg; 40 mg if 70 to 79.9 kg;
45 mg if 80 to 89.9 kg; and 50 mg if 90 kg or greater
✓ Streptokinase: 1.5 million units in 50 mL of normal saline or 5% dextrose in water
IV over 60 minutes
• Intracranial hemorrhage (ICH) and major bleeding are the most serious side
effects. The risk of ICH is higher with fibrin-specific agents than with streptokinase.
However, the risk of systemic bleeding other than ICH is higher with streptokinase
than with fibrin-specific agents.
Aspirin
• Administer aspirin to all patients without contraindications within 24 hours before
or after hospital arrival. It provides additional mortality benefit in patients with STE
ACS when given with fibrinolytic therapy.
• In patients experiencing an ACS, non–enteric-coated aspirin, 160 to 325 mg, should
be chewed and swallowed as soon as possible after the onset of symptoms or imme-
diately after presentation to the emergency department regardless of the reperfusion
strategy being considered. Patients undergoing PCI not previously taking aspirin
should receive 325 mg non–enteric-coated aspirin.
• A daily maintenance dose of 75 to 162 mg is recommended thereafter and should be
continued indefinitely. Because of increased bleeding risk in patients receiving aspi-
rin plus a P2Y12 inhibitor, low-dose aspirin (81 mg daily) is preferred following PCI.
• Discontinue other nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2
(COX-2) selective inhibitors at the time of STE MI due to increased risk of death,
reinfarction, HF, and myocardial rupture.
• The most frequent side effects of aspirin include dyspepsia and nausea. Inform
patients about the risk of GI bleeding.
Platelet P2Y12 Inhibitors
• Clopidogrel, prasugrel, and ticagrelor block a subtype of ADP receptor (the P2Y12
receptor) on platelets, preventing binding of ADP to the receptor and subsequent
expression of platelet GP IIb/IIIa receptors, reducing platelet aggregation.
• A P2Y12 receptor inhibitor in addition to aspirin is recommended for all patients
with STE MI. For patients undergoing primary PCI, give clopidogrel, prasugrel, or
ticagrelor, in addition to aspirin, to prevent subacute stent thrombosis and longer-
term CV events.
• The recommended duration of P2Y12 inhibitors for a patient undergoing PCI (either
STE MI or NSTE ACS) is at least 12 months for patients receiving either a bare metal
or drug-eluting stent.
• If CABG surgery is planned, withhold clopidogrel and ticagrelor for 5 days, and
prasugrel at least 7 days, to reduce risk of postoperative bleeding, unless the need for
revascularization outweighs the bleeding risk.
• Clopidogrel: 300 mg oral loading dose followed by 75 mg orally daily in patients receiv-
ing a fibrinolytic or who do not receive reperfusion therapy. Avoid loading dose in
patients aged 75 years or more. A 600-mg oral loading dose is recommended before pri-
mary PCI, except that 300 mg should be given if within 24 hours of fibrinolytic therapy.
41
SECTION 2   |   Cardiovascular Disorders

• Prasugrel: 60 mg oral loading dose followed by 10 mg orally once daily for patients
weighing 60 kg (132 lb) or more.
• Ticagrelor: 180 mg oral loading dose in patients undergoing PCI, followed by 90 mg
orally twice daily.
• The most frequent side effects of clopidogrel and prasugrel include nausea, vomiting,
and diarrhea, (2%–5% of patients). Thrombotic thrombocytopenic purpura (TTP)
has been reported rarely with clopidogrel. Ticagrelor is associated with nausea (4%),
diarrhea (3%), dyspnea (14%), and, rarely, ventricular pauses and bradyarrhythmias.
• In patients with STE MI receiving fibrinolysis, early therapy with clopidogrel 75 mg
once daily during hospitalization and up to 28 days reduces mortality and reinfarc-
tion without increasing risk of major bleeding. In adults younger than 75 years receiv-
ing fibrinolytics, the first dose of clopidogrel can be a 300-mg loading dose.
• For patients with STE MI who do not undergo reperfusion therapy with either pri-
mary PCI or fibrinolysis, clopidogrel is the preferred P2Y12 inhibitor added to aspirin
and should be continued for at least 14 days (and up to 1 year). Ticagrelor may also
be an option in medically managed patients with ACS.

Glycoprotein IIb/IIIa Receptor Inhibitors

• GP IIb/IIIa receptor inhibitors block the final common pathway of platelet aggrega-
tion, namely cross-linking of platelets by fibrinogen bridges between the GP IIb and
IIIa receptors on the platelet surface.
• Abciximab (IV or intracoronary administration), eptifibatide, or tirofiban may be
administered in patients with STE MI undergoing primary PCI who are treated with
UFH. Do not administer GP IIb/IIIa inhibitors to patients with STE MI who will not
be undergoing PCI.
• Abciximab: 0.25 mg/kg IV bolus given 10 to 60 minutes before the start of PCI, fol-
lowed by 0.125 mcg/kg/min (maximum 10 mcg/min) for 12 hours.
• Eptifibatide: 180 mcg/kg IV bolus, repeated in 10 minutes, followed by infusion of
2 mcg/kg/min for 18 to 24 hours after PCI.
• Tirofiban: 25 mcg/kg IV bolus, then 0.15 mcg/kg/min up to 18 to 24 hours after PCI.
• Routine use of a GP IIb/IIIa receptor inhibitor is not recommended in patients who
have received fibrinolytics or in those receiving bivalirudin because of increased
bleeding risk.
• Bleeding is the most significant adverse effect. Do not use GP IIb/IIIa inhibitors in
patients with a history of hemorrhagic stroke or recent ischemic stroke. Risk of bleed-
ing is increased in patients with chronic kidney disease; reduce the dose of eptifiba-
tide and tirofiban in renal impairment. An immune-mediated thrombocytopenia
occurs in approximately 5% of patients with abciximab and fewer than 1% of patients
receiving eptifibatide or tirofiban.

Anticoagulants
• Either UFH or bivalirudin is preferred for patients undergoing primary PCI,
whereas for fibrinolysis, either UFH, enoxaparin, or fondaparinux may be used.
• UFH initial dose for primary PCI is 50 to 70 units/kg IV bolus if a GP IIb/IIIa inhibi-
tor is planned and 70 to 100 U/kg IV bolus if no GP IIb/IIIa inhibitor is planned; give
supplemental IV bolus doses to maintain the target activated clotting time (ACT).
• UFH initial dose with fibrinolytics is 60 U/kg IV bolus (maximum 4000 units), fol-
lowed by constant IV infusion of 12 U/kg/h (maximum 1000 U/h). Adjust the UFH
infusion dose frequently to maintain a target activated partial thromboplastin time
(aPTT) of 1.5 to 2 times control (50–70 seconds). Measure the first aPTT at 3 hours
in patients with STE ACS who are treated with fibrinolytics and at 4 to 6 hours in
patients not receiving thrombolytics or undergoing primary PCI.
• Enoxaparin dose is 1 mg/kg subcutaneous (SC) every 12 hours (creatinine clearance
[Clcr] ≥30 mL/min) or 24 hours if impaired renal function (Clcr 15–29 mL/min). For
patients with STE MI receiving fibrinolytics, enoxaparin 30 mg IV bolus is followed
immediately by 1 mg/kg SC every 12 hours if younger than 75 years. In patients

42
 Acute Coronary Syndromes   |  CHAPTER 5

75 years and older, give enoxaparin 0.75 mg/kg SC every 12 hours. Continue enoxa-
parin throughout hospitalization or up to 8 days.
• Bivalirudin dose for PCI in STE MI is 0.75 mg/kg IV bolus, followed by 1.75 mg/
kg/h infusion. Discontinue at the end of PCI or continue at 0.25 mg/kg/h if prolonged
anticoagulation is necessary.
• Fondaparinux dose is 2.5 mg IV bolus followed by 2.5 mg SC once daily starting on
hospital day 2.
• For patients undergoing PCI, discontinue anticoagulation immediately after the
procedure. In patients receiving an anticoagulant plus a fibrinolytic, continue UFH
for a minimum of 48 hours and enoxaparin and fondaparinux for the duration of
hospitalization, up to 8 days. In patients who do not undergo reperfusion therapy,
anticoagulant therapy may be administered for up to 48 hours for UFH or for the
duration of hospitalization for enoxaparin or fondaparinux.
β-Adrenergic Blockers
• If no contraindications, administer a β-blocker early (within the first 24 hours) and
continue indefinitely.
• Benefits result from blockade of β1 receptors in the myocardium, which reduces
heart rate, myocardial contractility, and BP, thereby decreasing myocardial oxygen
demand. Reduced heart rate increases diastolic time, thus improving ventricular fill-
ing and coronary artery perfusion.
• β-Blockers reduce risk for recurrent ischemia, infarct size, reinfarction, and ventricu-
lar arrhythmias.
• Usual doses of β-blockers, with target resting heart rate of 50 to 60 beats/min:
✓ Metoprolol: 5 mg by slow (over 1–2 minutes) IV bolus, repeated every 5 minutes
for total initial dose of 15 mg. If a conservative regimen is desired, reduce initial
doses to 1 to 2 mg. Follow in 1 to 2 hours by 25 to 50 mg orally every 6 hours. If
appropriate, initial IV therapy may be omitted.
✓ Propranolol: 0.5 to 1 mg slow IV push, followed in 1 to 2 hours by 40 to 80 mg
orally every 6 to 8 hours. If appropriate, the initial IV therapy may be omitted.
✓ Atenolol: 5 mg IV dose, followed 5 minutes later by a second 5 mg IV dose, then
50 to 100 mg orally once daily beginning 1 to 2 hours after the IV dose. The initial
IV therapy may be omitted.
• The most serious side effects early in ACS include hypotension, acute HF, brady-
cardia, and heart block. Initial acute administration of β-blockers is not appropriate
for patients presenting with acute HF but may be attempted in most patients before
discharge after treatment of acute HF.
• Continue β-blockers for at least 3 years in patients with normal LV function and
indefinitely in patients with LV systolic dysfunction and LVEF of 40% or less.
Statins
• Administer a high-intensity statin, either atorvastatin 80 mg or rosuvastatin 40 mg,
to all patients prior to PCI (regardless of prior lipid-lowering therapy) to reduce the
frequency of periprocedural MI following PCI.
Nitrates
• NTG causes venodilation, which lowers preload and myocardial oxygen demand. In
addition, arterial vasodilation may lower BP, thereby reducing myocardial oxygen
demand. Arterial dilation also relieves coronary artery vasospasm and improves
myocardial blood flow and oxygenation.
• Immediately upon presentation, administer one SL NTG tablet (0.4 mg) every
5 minutes for up to three doses to relieve chest pain and myocardial ischemia.
• Intravenous NTG is indicated for patients with an ACS who do not have a contrain-
dication and who have persistent ischemia, HF, or uncontrolled high BP. The usual
dose is 5 to 10 mcg/min by continuous infusion, titrated up to 100 mcg/min until
relief of symptoms or limiting side effects (eg, headache or hypotension). Continue
treatment for approximately 24 hours after ischemia is relieved.

43
SECTION 2   |   Cardiovascular Disorders

• Oral nitrates play a limited role in ACS because clinical trials have failed to show a
mortality benefit for IV followed by oral nitrate therapy in acute MI.
• The most significant adverse effects of nitrates include tachycardia, flushing, head-
ache, and hypotension. Nitrates are contraindicated in patients who have taken the
oral phosphodiesterase-5 inhibitors sildenafil or vardenafil within the prior 24 hours
or tadalafil within the prior 48 hours.
Calcium Channel Blockers
• After STE MI, calcium channel blockers (CCBs) are used for relief of ischemic
symptoms in patients who have contraindications to β-blockers. There is little clini-
cal benefit beyond symptom relief, so avoid CCBs in acute management of all ACSs
unless there is a clear symptomatic need or contraindication to β-blockers.
• A CCB that lowers heart rate (diltiazem or verapamil) is preferred unless the patient
has LV systolic dysfunction, bradycardia, or heart block. In those cases, either amlo-
dipine or felodipine is preferred. Avoid nifedipine because it causes reflex sympa-
thetic activation, tachycardia, and worsened myocardial ischemia.
✓ Diltiazem: 120 to 360 mg sustained release orally once daily
✓ Verapamil: 180 to 480 mg sustained release orally once daily
✓ Amlodipine: 5 to 10 mg orally once daily
EARLY PHARMACOTHERAPY FOR NSTE ACS (Fig. 5–3)
• Early pharmacotherapy for NSTE ACS is similar to that for STE ACS.
• In absence of contraindications, treat all patients in the emergency department with
intranasal oxygen (if oxygen saturation is low), SL NTG, aspirin, and an anticoagu-
lant (UFH, enoxaparin, fondaparinux, or bivalirudin).
• High-risk patients should proceed to early angiography and may receive a GP IIb/
IIIa inhibitor (optional with either UFH or enoxaparin but should be avoided with
bivalirudin).
• Administer a P2Y12 inhibitor to all patients.
• Give IV β-blockers and IV NTG to select patients.
• Initiate oral β-blockers within the first 24 hours in patients without cardiogenic shock.
• Give morphine to patients with refractory angina, as described previously.
• Fibrinolytic therapy is never administered in NSTE ACS.
Aspirin
• Aspirin reduces risk of death or MI by approximately 50% compared with no anti-
platelet therapy in patients with NSTE ACS. Dosing of aspirin is the same as for STE
ACS, and aspirin is continued indefinitely.
Anticoagulants
• For patients treated by an early invasive approach with early coronary angiography
and PCI, administer UFH, enoxaparin, or bivalirudin.
• If an initial conservative strategy is planned (no coronary angiography or revascular-
ization), enoxaparin, UFH, or low-dose fondaparinux is recommended.
• Continue therapy for at least 48 hours for UFH, until the patient is discharged from
the hospital (or 8 days, whichever is shorter) for either enoxaparin or fondaparinux,
and until the end of the PCI or angiography procedure (or up to 72 hours after PCI)
for bivalirudin.
• For NSTE ACS, the dose of UFH is 60 U/kg IV bolus (maximum 4000 units), fol-
lowed by a continuous IV infusion of 12 U/kg/h (maximum 1000 U/h). Titrate the
dose to maintain aPTT between 1.5 and 2 times control.
P2Y12 Inhibitors
• When an initial invasive strategy is selected, there are two initial options for dual
antiplatelet therapy depending on choice of P2Y12 inhibitor:
1. Aspirin plus early use of clopidogrel or ticagrelor (in the emergency department)
2. Aspirin plus double-bolus dose eptifibatide plus an eptifibatide infusion or high-
dose tirofiban bolus plus infusion administered at the time of PCI.
44
 Non–ST-segment elevation ACS

Oxygen (if O2 saturation less than 90%[0.90]) Aspirin,

a a
SL NTG, IV NTG Morphine sulfate

Optional initiate GP IIb/IIIa inhibitor Early conservative strategy

Early Invasive Strategy
or switch anticoagulant to bivalirudin; Medical management only planned
Early coronary angiography planned
administer additional loading dose of
less than or equal to 12–24 hours from hospital presentation
clopidogrel/ticagrelor prior to PCI
IV UFH, Subcut enoxaparin, Subcut fondaparinuxb
IV UFH, bivalirudinc, Subcut
d
enoxaparin , or Subcut fondaparinux High-intensity statin Recurrent ischemia,
prior to PCI heart failure, or Clopidogrel 300 mg or ticagrelor
plus UFH administered at time of PCI
arrhythmias
One of two options:
Urgent
(a) Either clopidogrel 600 mg or
angiography No recurrent ischemia, heart failure, or arrhythmias
ticagrelor or (b) GP IIb/IIIa inhibitor
High-intensity statin Nonurgent angiography
β-blocker, statin, ACE inhibitor
Angiography (or ARB); Discontinue IV NTG
and anticoagulantf

Acute Coronary Syndromes   |  CHAPTER 5

PCI; consider prasugrele if
clopidogrel/ticagrelor not
previously given; discontinue
anticoagulant; continue GP
IIb/IIIa inhibitor per guidelines;
discontinue NTG; continue
statin and aspirin, add β-blocker
and ACE inhibitor (or ARB)
No or noncritical CAD;
discontinue
anticoagulant; treat
CHD risk factors; if
CAD, continue P2Y12
inhibitor, aspirin, and
statin; add β-blocker
and ACE inhibitor (or ARB)
PCI
CABG; continue/ No or noncritical CAD; Treat CHD Stress test
change anticoagulant risk factors; Continue clopidogrel/
to UFH; discontinue ticagrelor, aspirin if CAD
clopidogrel/ticagrelor Positive findings Negative findings
and GP IIb/IIIa inhibitor Continue clopidogrel/ticagrelor; discontinue for ischemia for ischemia
prior to surgery anticoagulant; continue GP IIb/IIIa inhibitor per
guidelines; discontinue NTG; continue statin and Treat CHD
aspirin; add β-blocker and ACE inhibitor (or ARB) risk factors

FIGURE 5–3.  Initial pharmacotherapy for non–ST-segment elevation ACS. aFor selected patients. bPreferred in patients at high risk for bleeding. cIf pretreated
with UFH, stop UFH infusion for 30 minutes prior to administration of bivalirudin bolus plus infusion. dMay require IV supplemental dose of enoxaparin. eDo
not use if prior history of stroke/TIA, age older than 75 years, or body weight 60 kg or less. fSC enoxaparin or UFH can be continued at a lower dose for venous
thromboembolism prophylaxis. (ACS, acute coronary syndrome; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CABG, coronary artery
bypass graft; CAD, coronary artery disease; CHD, coronary heart disease; GP, glycoprotein; IV, intravenous; NSTE, non–ST-segment elevation; NTG, nitroglycerin; PCI,
percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; STE MI, ST-segment-elevation myocardial infarction; TIA, transient ischemic attack; UFH,
unfractionated heparin.) (Modified with permission from Spinler SA, de Denus S. Acute coronary syndromes. In: Chisholm-Burns M, Wells BG, Schwinghammer TL,
45

Malone PM, Kolesar JM, DiPiro JT, eds. Pharmacotherapy Principles and Practice. 3rd ed. New York, NY: McGraw-Hill; 2013:133–167.)
SECTION 2   |   Cardiovascular Disorders

• For subsequent antiplatelet therapy in patients undergoing PCI initially treated with
regimen 1 above, a GP IIb/IIIa inhibitor (abciximab, eptifibatide, or high-dose tirofi-
ban) can be added, and then clopidogrel continued with low-dose ASA.
• For patients undergoing PCI initially treated with option 2, clopidogrel, prasugrel, or
ticagrelor can be started within 1 hour after PCI and the P2Y12 inhibitor continued
with low-dose aspirin. Following PCI, continue dual oral antiplatelet therapy for at
least 12 months.
• For patients receiving an initial conservative strategy, either clopidogrel or ticagrelor
can be administered in addition to aspirin. Continue dual antiplatelet therapy for at
least 12 months.
Glycoprotein IIb/IIIa Receptor Inhibitors
• The role of GP IIb/IIIa inhibitors in NSTE ACS is diminishing as P2Y12 inhibitors are
used earlier, and bivalirudin is often selected as the anticoagulant.
• Routine administration of eptifibatide (added to aspirin and clopidogrel) prior to
angiography and PCI in NSTE ACS does not reduce ischemic events and increases
bleeding risk. Therefore, the two antiplatelet initial therapy options described in the
previous section are preferred.
• For low-risk patients and a conservative management strategy, there is no role for
routine GP IIb/IIIa inhibitors because bleeding risk exceeds the benefit.

Nitrates
• Administer SL NTG followed by IV NTG to patients with NSTE ACS and ongo-
ing ischemia, HF, or uncontrolled high BP. Continue IV NTG for approximately
24 hours after ischemia relief.

β-Blockers
• In the absence of contraindications, administer oral β-blockers to all patients with
NSTE ACS within 24 hours of hospital admission. Benefits are assumed to be similar
to those seen in patients with STE MI.
• Continue β-blockers indefinitely in patients with LVEF of 40% or less and for at least
3 years in patients with normal LV function.

Calcium Channel Blockers

• As described previously for STE ACS, CCBs should not be administered to most
patients with ACS.

SECONDARY PREVENTION FOLLOWING MI

• Goals of Treatment: The long-term goals after MI are to: (1) control modifiable
coronary heart disease (CHD) risk factors; (2) prevent development of systolic HF;
(3) prevent recurrent MI and stroke; (4) prevent death, including sudden cardiac
death; and (5) prevent stent thrombosis after PCI.

PHARMACOTHERAPY
• Start pharmacotherapy that has been proven to decrease mortality, HF, reinfarction
or stroke, and stent thrombosis prior to hospital discharge for secondary prevention.
• After MI from either STE MI or NSTE ACS, all patients (in the absence of contrain-
dications) should receive indefinite treatment with aspirin (or clopidogrel if aspirin
contraindications), an ACE inhibitor, and a “high-intensity” statin for secondary
prevention of death, stroke, or recurrent infarction.
• Start ACE inhibitors and continue indefinitely in all patients after MI to reduce mor-
tality, decrease reinfarction, and prevent HF. Most patients with CAD (not just those

46
 Acute Coronary Syndromes   |  CHAPTER 5

with ACS or HF) benefit from an ACE inhibitor. The dose should be low initially and
titrated to the dose used in clinical trials if tolerated, for example:
✓ Captopril: 6.25 to 12.5 mg initially; target dose 50 mg two or three times daily
✓ Enalapril: 2.5 to 5 mg initially; target dose 10 mg twice daily
✓ Lisinopril: 2.5 to 5 mg initially; target dose 10 to 20 mg once daily
✓ Ramipril: 1.25 to 2.5 mg initially; target dose 5 mg twice daily or 10 mg once daily
✓ Trandolapril: 1 mg initially; target dose 4 mg once daily
• An angiotensin receptor blocker may be prescribed for patients with ACE inhibitor
cough and a low LVEF and HF after MI:
✓ Candesartan: 4 to 8 mg initially; target dose 32 mg once daily
✓ Valsartan: 40 mg initially; target dose 160 mg twice daily
• Continue a β-blocker for at least 3 years in patients without HF or an ejection frac-
tion of 40% or less and indefinitely in patients with LV systolic dysfunction or HF
symptoms. A CCB can be used to prevent anginal symptoms in patients who cannot
tolerate or have contraindications to β-blockers but should not be used routinely in
the absence of such findings.
• Continue a P2Y12 inhibitor for at least 12 months for patients undergoing PCI and for
patients with NSTE ACS receiving a medical management strategy. Continue clopi-
dogrel for at least 14 days in patients with STE MI not undergoing PCI.
• To reduce mortality, consider a mineralocorticoid receptor antagonist (eplerenone
or spironolactone) within the first 7 days after MI in all patients already receiving an
ACE inhibitor (or ARB) and a β-blocker and have an LVEF of 40% or less and either
HF symptoms or diabetes mellitus. The drugs are continued indefinitely.
✓ Eplerenone: 25 mg initially; target dose 50 mg once daily
✓ Spironolactone: 12.5 mg initially; target dose 25 to 50 mg once daily
• All patients with CAD should receive dietary counseling and a statin to reach appro-
priate targets based on current practice guidelines.
• Prescribe a short-acting SL NTG or lingual NTG spray for all patients to relieve angi-
nal symptoms when necessary. Chronic long-acting nitrates have not been shown to
reduce CHD events after MI and are not used in ACS patients who have undergone
revascularization unless the patient has chronic stable angina or significant coronary
stenosis that was not revascularized.
• For all ACS patients, treat and control modifiable risk factors such as hypertension
(HTN), dyslipidemia, obesity, smoking, and DM.

EVALUATION OF THERAPEUTIC OUTCOMES

• Monitoring parameters for efficacy for both STE and NSTE ACS include: (1) relief
of ischemic discomfort, (2) return of ECG changes to baseline, and (3) absence or
resolution of HF signs and symptoms.
• Monitoring parameters for adverse effects are dependent on the individual drugs
used. In general, the most common adverse reactions from ACS therapies include
hypotension and bleeding.

See Chapter 7, Acute Coronary Syndromes, authored by Sarah A. Spinler and Simon De
Denus, for a more detailed discussion of this topic.

47