SECTION​ ​2

​ ISOR
CARDIOVASCULAR​ D
DERS

Edited​ b
​ y​ T
​ erry​ L​ .​ S
​ chwing
hammer

Acute​ ​Coronary​ ​Syndromes

• ​Acute​ ​coronary​ ​syndromes​ ​ ​(ACSs) ​ ​include ​ ​all ​ ​syndromes ​ ​compatible ​ ​with ​ ​acute
myocardial ischemia resulting from imbalance between myocardial oxygen demand
and supply.
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.

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 A​2​ 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.
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.
tion and reduced pumping function, leading to cardiac failure.
tion, ​ ​arrhythmias, ​ ​pericarditis, ​ ​stroke ​ ​secondary ​ t​ o ​ l​ eft ​ v​ entricular (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.
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 ​ c​ oronary ​ ​artery ​ ​disease ​ ​(CAD)

should be assessed.
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.

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 ​ o​ n ​ ​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.
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.
• ​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.
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) ​ n​ itroglycerin ​ ​(NTG), (3) ​ ​aspirin,
(4) a P2Y​12​ platelet inhibitor, (5) and anticoagulation with bivalirudin, unfractionated
heparin (UFH), or enoxaparin.
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 ​ i​ n ​ p​ atients ​ ​who ​ ​have ​ ​either
anterior wall MI or LVEF of 40% or less and no contraindications.
38

​ HAPTER​ 5​
Acute​ ​Coronary​ ​Syndromes|​ C
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​ ​stratification​a​;​ ​multilead​ ​continuous​ S ​ T-segment
candidates​ ​(fibrinolysis​ ​or​ ​primary​ ​PCI) monitoring;​ ​obtain​ s​ erial​ ​troponin​ a​ nd​ ​CK​ ​MB​b,c

Obtain​ ​serial​ ​troponin​ ​and​ ​CK​ ​MB​ ​as Initiate​ ​pharmacotherapy​ ​for​ ​non-ST-segment
confirmatory;​ ​results​ ​not​ ​needed​ ​before elevation​ A
​ CS​ b
​ ased​ o
​ n​ ​patient​ ​risk
reperfusion​ ​therapy​ ​is​ ​initiated;​ ​multilead
continuous​ ​ST-segment​ ​monitoring

Low-risk Moderate- and high-risk

Initiate​ ​adjunctive​ ​ST-segment​ ​elevation Stress​ ​test​ ​to​ e

​ valuate​ ​likelihood​ ​of​ ​CAD
ACS​ ​pharmacotherapy

Negative​ ​stress​ ​te Positive​ ​stress​ t​ est

st

Coronary​ ​angiography​ ​with

Diagnosis​ ​of​ ​noncardiac
revascularization​ ​(PCI​ ​or​ ​CABG)
chest​ ​pain​ ​syndro
me
FIGURE​ ​5–1.​ ​Evaluation​ ​of​ ​the​ ​acute​ ​coronary​ ​syndrome​ ​patient.​ a​​ As​ ​described
in​ ​textbook​ ​Table​ ​7-1.​ b​​ “Positive”:​ ​Above​ ​the​ ​myocardial​ ​infarction​ ​decision​ ​limit.
c
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​ S ​ elf-Assessment​ ​Program.​ B ​ ook​ ​1:​ C
​ ardiology,​ 7​ th​ ​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.
fibrinolytic therapy.
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​ ​O​2​ ​saturation​ ​<90%)

SL​ ​NTG,​ a ​ spirin,​ ​morphine
sulfate​d​,​ ​IV​ ​NTG​d
Symptoms​ ​≤​ ​to​ ​12​ ​h Symptoms​ ​>1
​ 2​ ​h

Reperfusion therapy

Secondary​ ​PCI​ ​or​ ​CABG​ ​or​ ​fibrinolysis

for​ ​select​ p
​ atients;​ ​for​ ​secondary
High-intensity​ ​statin PCI​ ​during​ ​hospitalization,​ ​administer
bivalirudine​e​ ​alone​ ​or​ ​UFH​ o
​ r
enoxaparin​c​ ​or​ f​ ondaparinux
Fibrinolysis
(plus​ ​UFH)​ ​with​ o​ ptional​ ​GP
Primary​ ​PCI
​ f​ ​PCI​f
llb/Illa​ ​inhibitor​ ​at​ ​time​ o

Clopidogrel,​ ​prasugrel,

Bivalirudin​e​ ​alone​ ​or IV​ ​UFH​a​ ​or​ I​ V​ a

​ nd​ S
​ C
unfractionated​ ​heparin enoxaparin​b,c
with​ ​GP​ ​llb/Illa (preferred;​ s​ elected​ ​patients)
receptor​ ​inhibitor
or​ ​IV​ ​and​ ​SC​ f​ ondaparinux​d

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

FIGURE​ ​5–2.​ ​Initial​ ​pharmacotherapy​ ​for​ ​ST-segment​ ​elevation​ ​myocardial
infarction.​ ​a​For​ ​at​ ​least​ ​48​ ​hours.​ ​b​See​ ​textbook​ ​Table​ ​24–2​ ​for​ ​dosing​ ​and​ ​specific
types​ ​of​ ​patients​ ​who​ ​should​ ​not​ ​receive​ ​enoxaparin.​ c​​ For​ ​the​ ​duration​ ​of​ ​hospitaliza-
tion,​ ​up​ ​to​ ​8​ ​days.​ d​​ For​ ​select​ ​patients,​ ​see​ ​textbook​ ​Table​ ​24–2.​ e​​ If​ ​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:​ C
​ ardiology​.​ ​Lenexa,
KS:​ ​American​ ​College​ ​of​ ​Clinical​ ​Pharmacy;​ ​2010.)
40

Acute​ ​Coronary​ ​Syndromes ​ HAPTER​ 5​

|​ C

suspected aortic dissection, and (7) significant closed head or facial trauma within 3
months. Primary PCI is preferred in these situations.
non–fibrin-specific agent streptokinase.
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

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.
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 ​ n​ ot ​ p​ reviously ​ ​taking ​ ​aspirin
should receive 325 mg non–enteric-coated aspirin.
continued indefinitely. Because of increased bleeding risk in patients receiving aspi-
 rin plus a P2Y​12​ inhibitor, low-dose aspirin (81 mg daily) is preferred following PCI.
(COX-2) selective inhibitors at the time of STE MI due to increased risk of death,
reinfarction, HF, and myocardial rupture.
patients about the risk of GI bleeding.

Platelet​ ​P2Y​12​ ​Inhibitors

• ​Clopidogrel​, ​prasugrel​, and ​ticagrelor​ block a subtype of ADP receptor (the P2Y​12
receptor) ​ ​on ​ ​platelets, ​ ​preventing ​ ​binding ​ ​of ​ A
​ DP ​ t​ o ​ t​ he ​ ​receptor ​ ​and ​ ​subsequent
expression of platelet GP IIb/IIIa receptors, reducing platelet aggregation.
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.
STE MI or NSTE ACS) is at least 12 months for patients receiving either a bare metal
or drug-eluting stent.
prasugrel at least 7 days, to reduce risk of postoperative bleeding, unless the need for
revascularization outweighs the bleeding risk.
ing ​ ​a ​ ​fibrinolytic ​ ​or ​ ​who ​ ​do ​ ​not ​ ​receive ​ ​reperfusion ​ t​ herapy. ​ ​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.

orally twice daily.

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.
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.
mary PCI or fibrinolysis, clopidogrel is the preferred P2Y​12​ 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.
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.
lowed by 0.125 mcg/kg/min (maximum 10 mcg/min) for 12 hours.
2 mcg/kg/min for 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 ​ b​ ivalirudin ​ ​because ​ ​of ​ ​increased
bleeding risk.
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.
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).
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.
[Cl​cr​] ≥30 mL/min) or 24 hours if impaired renal function (Cl​cr​ 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 ​ HAPTER​ 5​

|​ C

75 years and older, give enoxaparin 0.75 mg/kg SC every 12 hours. Continue enoxa-
parin throughout hospitalization or up to 8 days.
 kg/h infusion. Discontinue at the end of PCI or continue at 0.25 mg/kg/h if prolonged
anticoagulation is necessary.
hospital day 2.
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.
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.
lar arrhythmias.
✓​ ​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.
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.

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.
5 minutes for up to three doses to relieve chest pain and myocardial ischemia.
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.

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.
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​).
IIIa inhibitor (optional with either UFH or enoxaparin but should be avoided with
bivalirudin).
• ​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​.
ization), enoxaparin, UFH, or low-dose ​fondaparinux​ is recommended.
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.
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.
P2Y​12​ ​Inhibitors
• ​When ​ ​an ​ ​initial invasive strategy ​ ​is selected, ​ ​there are two initial ​ ​options for dual
antiplatelet therapy depending on choice of P2Y​12​ 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])​ ​As
pirin,
a
Early​ ​conservative​ ​strategy
Medical​ ​management​ ​only​ ​planned
Optional​ ​initiate​ ​GP​ ​IIb/IIIa​ ​inhibitor IV​ ​UFH,​ ​Subcut​ ​enoxaparin,​ ​Subcut​ ​fondaparin
or​ ​switch​ ​anticoagulant​ ​to​ ​bivalirudin; ux​b
administer​ ​additional​ ​loading​ d ​ ose​ ​of
clopidogrel/ticagrelor​ ​prior​ ​to​ P ​ CI

E
arly​ ​Inva
sive​ ​Stra
tegy
E
arly​ ​coro
nary​ ​angi
ography​
planned
less​ ​than​ ​or​ ​equal​ ​to​ ​12–24​ ​hours​ ​from​ ​hospital​
presentat
ion

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d
r​ ​c r​ ​o
plus​ ​UFH​ ​administered​ ​at​ ​time​ ​of​ ​P l r​ ​(
C o b
I p )​ ​G
High-intensity​ ​statin Recurrent​ ​ischemia, Clopidogrel​ ​300​ m
​ g​ ​or​ ​ticagrelor
prior​ ​to​ ​PCI heart​ ​failure,​ ​or
Urgent arrhythmias
angiography No​ ​recurrent​ ​ischemia,​ ​heart​ ​failure,
​or​ ​arrhythmias

®​-blocker,​ ​statin,​ A
​ CE​ ​inhibitor
High-intensity​ ​statin Nonurgent​ ​angiography
(or​ ​ARB);​ ​Discontinue​ ​IV​ ​NTG
Angiograph and​ ​anticoagulant​f
y
P
CI

P No​ ​or​ ​noncritical​ ​CAD; CABG;​ ​continue/ No​ ​or​ ​noncritical​ ​CAD;​ T ​ reat​ Stress​ ​test
CI;​ ​c discontinue change​ ​anticoagulant CHD Positivefindings​ N ​ egative​ ​fin
onsid anticoagulant;​ ​treat to​ ​UFH;​ ​discontinue r
dings
er​ ​pra CHD​ ​risk​ ​factors;​ ​if clopidogrel/ticagrelor isk​ ​factors;​ ​Continue​ c ​ lopido
sugre CAD,​ ​continue​ ​P2Y​12 and​ ​GP​ ​IIb/IIIa​ ​inhibitor grel/ for​ ​ischemia​ ​for​ ​ischemia
l​e​ ​if inhibitor,​ ​aspirin,​ ​and prior​ ​to​ ​surgery t Treat​ ​C
cl statin;​ ​add​ ​®-​ blocker icagrelor,​ a​ spirin​ i​ f​ ​CAD HD
opido and​ ​ACE​ ​inhibitor​ ​(or​ ​ARB) Continue​ c ​ lopidogrel/tica risk​ ​facto
grel/ti grelor;​ ​discontinue rs
cagre anticoagulant;​ ​continue​ ​GP
lor​ ​no ​IIb/IIIa​ ​inhibitor​ ​per
t guidelines;​ ​discontinue​ ​NT
pre G;​ ​continue​ ​statin​ ​and
viousl aspirin;​ ​add​ ® ​ -​ blocker​ ​and​ ​A
y​ ​give CE​ ​inhibitor​ (​ or​ A
​ RB)
n;​ ​dis
conti
nue
ant
icoag
ulant;
​conti
nue​
GP
IIb/III
a​ ​inhi
bitor​
per​ ​g
uideli
nes;
dis
conti
nue​
NTG;​
conti
nue
statin​ ​and​ ​aspirin,​ ​add​ ​®​-blo
cker
an
d​ ​AC
E​ ​inhi
bitor​ ​(
or​ ​AR
B)

FIGURE​ ​5–3.​ ​Initial​ ​pharmacotherapy​ ​for​ ​non–ST-segment​ ​elevation​ ​ACS.​ a​​ For​ ​selected​ ​patients.​ b​​ Preferr
ed​ ​in​ ​patients​ ​at​ ​high​ ​risk​ ​for​ ​bleeding.​ ​c​If​ ​pretreated
with​ ​UFH,​ ​stop​ ​UFH​ ​infusion​ ​for​ ​30​ ​minutes​ ​prior​ ​to​ ​administration​ ​of​ ​bivalirudin​ ​bolus​ ​plus​ ​infusion.​ d​
May​ ​require​ ​IV​ ​supplemental​ ​dose​ ​of​ ​enoxaparin.​ e​​ Do
not​ ​use​ ​if​ ​prior​ ​history​ ​of​ ​stroke/TIA,​ ​age​ ​older​ ​than​ ​75​ ​years,​ ​or​ ​body​ ​weight​ ​60​ ​kg​ ​or​ ​less.​ f​​ SC​ ​enoxap
arin​ ​or​ ​UFH​ ​can​ ​be​ ​continued​ ​at​ ​a​ ​lower​ ​dose​ ​for​ ​venous
thromboembolism​ ​prophylaxis.​ ​(ACS,​ ​acute​ ​coronary​ ​syndrome;​ ​ACE,​ ​angiotensin-converting​ ​enzym
e;​ ​ARB,​ ​angiotensin​ ​receptor​ ​blocker;​ ​CABG,​ ​coronary​ ​artery
bypass​ ​graft;​ ​CAD,​ ​coronary​ ​artery​ ​disease;​ ​CHD,​ ​coronary​ ​heart​ ​disease;​ ​GP,​ ​glycoprotein;​ ​IV,​ ​intrave
nous;​ ​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​ ​synd
romes.​ ​In:​ ​Chisholm-Burns​ ​M,​ ​Wells​ ​BG,​ ​Schwinghammer​ ​TL,
​ harmacotherapy​ P
Malone​ ​PM,​ ​Kolesar​ ​JM,​ ​DiPiro​ ​JT,​ ​eds.​ P ​ rinciples​ a
​ nd​ ​Practice​.​ ​3rd​ ​ed.​ ​New​ ​York,​ ​N
Y:​ ​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.

ticagrelor can be started within 1 hour after PCI and the P2Y​12​ inhibitor continued
with low-dose aspirin. Following PCI, continue dual oral antiplatelet therapy for at
least 12 months.

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 P2Y​12​ inhibitors are
used earlier, and bivalirudin is often selected as the anticoagulant.
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.
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. ​ C
​ ontinue ​ I​ V ​ ​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.
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 ​ d​ eath, ​ ​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.
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.
tality, decrease reinfarction, and prevent HF. Most patients with CAD (not just those

46

Acute​ ​Coronary​ ​Syndromes ​ HAPTER​ 5​

|​ C

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
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
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.

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.
 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
priate targets based on current practice guidelines.
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.
(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.
used. In general, the most common adverse reactions from ACS therapies include
hypotension and bleeding.

See​ C
​ hapter​ ​7,​ ​Acute​ ​Coronary​ ​Syndromes,​ a ​ uthored​ b
​ y​ S
​ arah​ ​A.​ ​Spinler​ a
​ nd​ ​Simon​ D
​ e
Denus,​ ​for​ a
​ ​m
​ ore​ ​detailed​ ​discussion​ ​of​ ​this​ t​ opic.
47