Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

Подождите немного. Документ загружается.



CARDIAC PROBLEMS IN CRITICAL CARE

497

Sotalol

Sotalol is a class II (β-adrenergic blocker) and class III antiar-

rhythmic drug that is excreted renally and therefore must be

monitored carefully in patients with changing renal function.

It is an effective agent for atrial and ventricular arrhythmias,

but—like most antiarrhythmic agents—it has proarrhythmic

effects, occurring particularly while therapy is being initiated.

It can cause significant bradycardia and heart block when used

in conjunction with digoxin or calcium channel blockers.



Calcium Channel Blockers

These drugs can be categorized into three subclasses:

verapamil-like drugs, diltiazem-like drugs, and nifedipine-like

drugs. Some of the toxic effects are the logical result of their

therapeutic mechanisms and may be beneficial in certain set-

tings. For example, slowing of the heart rate in patients with

ischemia is a desirable effect of some of the calcium channel

blockers. However, verapamil and diltiazem also can slow AV

nodal and sinus node conduction excessively, resulting in

bradyarrhythmias and hypotension. Because they are myocar-

dial depressants, these drugs may precipitate or exacerbate

congestive heart failure. The bradycardiac effects of diltiazem

and verapamil can be augmented by concomitant use of β-

adrenergic blockers or digoxin. In contrast, nifedipine and

other drugs in its dihydropyridene class of calcium channel

blockers have no effect on the AV node but can cause reflex

tachycardia and hypotension from vasodilation. Calcium

administered intravenously may reverse some of the toxic

effects of the calcium channel blockers, at least temporarily.



Beta-Adrenergic Blockers

Beta-adrenergic blockers are extremely useful drugs for con-

trolling hypertension, treating atrial arrhythmias, and allevi-

ating myocardial ischemia. In a patient with myocardial

dysfunction, β-adrenergic blockers can precipitate profound

heart failure and block the normal tachycardiac response to

hypotension and low cardiac output. Despite this, however,

these drugs have been shown to improve long-term survival

in patients with chronic congestive heart failure, including in

patients with class III to IV heart failure.

These drugs are myocardial depressants, block the AV

node, and by blocking the action of catecholamines,

decrease the sinus nodal rate. In patients with conduction

system disease, β-adrenergic blockers may cause profound

bradycardia. The effects of Beta-adrenergic blockers and cal-

cium channel blockers on the myocardium, the sinus node,

and the AV node can be additive, resulting in severe

hypotension and heart block. Beta-adrenergic agonists may

be used to counteract the excessive depressant effects of β-

adrenergic blockers.



ACE Inhibitors

ACE inhibitors (eg, captopril, enalapril, benazepril, lisinopril)

are commonly used vasodilators valuable in the treatment of

congestive heart failure and hypertension. These drugs can

cause hyperkalemia even in patients without overt renal dis-

ease. Therefore, potassium levels must be observed carefully

when initiating or maintaining therapy with ACE inhibitors.

Rapidly developing renal failure may occur in patients with

renal artery stenosis when ACE inhibitors are started.

Angioedema is a significant and concerning side effect that

should result in terminating this entire class of drug from the

patient’s medical regimen. Cough is another side effect that

patient’s may find bothersome with this class of medica-

tions. In fact, the cough may be confused with the cough

owing to heart failure but responds fairly quickly to removal

of the drug. Angiotensin-receptor blockers have effects simi-

lar to those of ACE inhibitors and may be substituted for

management of the cough complaint. As with other antihy-

pertensive agents, profound hypotension may develop when

starting ACE inhibitors, particularly in patients who are

hypovolemic. In critically ill patients, the benefits and side

effects of these drugs need to be considered carefully.

Darbar D, Roden DM: Future of antiarrhythmic drugs. Curr Opin

Cardiol 2006;21:361–7. [PMID: 16755206]

Gheorghiade M et al: Digoxin in the management of cardiovascu-

lar disorders. Circulation 2004;109:2959–64. [PMID: 16735690]

Kowey PR et al: Classification and pharmacology of antiarrhyth-

mic drugs. Am Heart J 2000;140:12–20. [PMID: 10874257]

Zimetbaum P: Amiodarone for atrial fibrillation. N Engl J Med

2007;356:935–41. [PMID: 17329700]

Zipes DP, Jalife J (eds): Cardiac Electrophysiology from Cell to

Bedside, 4th ed. Philadelphia: Saunders, 2004.



498

Atherosclerotic coronary artery disease is the leading cause of

death in the United States. Each year approximately 1.5 million

patients experience a myocardial infarction. Approximately

20% of these individuals die before they reach the hospital,

and an additional 7–15% die during hospitalization. This

chapter will consider the major coronary artery disease

syndromes: angina pectoris, acute coronary syndromes

(unstable angina and non-ST-segment-elevation myocar-

dial infarction), and acute ST-segment-elevation myocardial

infarction.



Physiologic Considerations

Coronary Anatomy

The right and left coronary arteries arise from ostia in the

right and left sinuses of Valsalva. Their function is to deliver

oxygen and nutrients and to remove toxic metabolites. The

origin of the left coronary artery is called the left main coro-

nary artery and divides into the left anterior descending coro-

nary artery, which feeds the anterior wall of the left ventricle

and the left ventricular septum, and the left circumflex artery,

which supplies the lateral and posterior walls of the left ven-

tricle. The right coronary artery supplies the right ventricular

free wall and in 90% of cases gives off the posterior descending

artery, which, in turn, provides the blood supply for the pos-

terior right ventricle as well as the inferior left ventricular wall

and septum. The coronary artery that gives rise to the poste-

rior descending artery is referred to as dominant. Thus 90% of

people have a right-dominant circulation. The remaining 10%

have a posterior descending artery that originates from the

left circumflex coronary artery. Coronary collateral vessels

span the area between the right and left coronary artery terri-

tories. These vessels are very small and difficult to demon-

strate even during cardiac catheterization. However, as

coronary stenoses develop in the major epicardial coronary

arteries, collateral vessels may increase in size and number

and provide a protective effect by allowing increased blood

supply from the opposite coronary circulation.

Coronary Blood Flow

Coronary blood flow at rest is ordinarily 70–100 mL/min per

100 g of heart tissue. Approximately 80% of the coronary flow

occurs during diastole. As a consequence, coronary blood

flow is highly dependent on diastolic blood pressure and

resistance to coronary flow within the coronary circulation.

In the absence of disease and with a constant myocardial

oxygen requirement (M

), coronary blood flow is kept con-

stant by autoregulation of the coronary vasculature by both

myogenic and metabolic factors. Diastolic perfusion pressure

provides the driving pressure for coronary blood flow.

Metabolic factors, particularly adenosine, affect regional

myocardial blood flow. As tissue oxygen decreases, ADP is

converted to AMP and then to adenosine by the enzyme 5′-

nucleotidase. Adenosine then diffuses out of the cell and

causes relaxation of local vascular smooth muscle. This action

of adenosine is terminated by its deamination to inosine.

Myocardial Oxygen Consumption

Over 90% of the heart’s energy is derived from aerobic

metabolism, primarily from oxidation of fatty acids. The

absence of oxygen forces a transition to anaerobic metabo-

lism of glucose and glycogen. Myocardial O

requirements

are multiple: 20% of the M

is used to support the basal

metabolism of the heart, less than 5% is used to support elec-

trical activity, and approximately 15% is used to move cal-

cium into the sarcoplasmic reticulum. The most important

determinant of M

is myocardial contractility, accounting

for 60% of M

A. Heart Rate and Systolic Blood Pressure—An impor-

tant concept about coronary artery disease is the relation of

to the heart rate (HR) and systolic blood pressure

(SBP). HR × SBP is commonly referred to as the double prod-

uct. The double product is proportional to M

and can be

used as a measure of myocardial work and thus myocardial

consumption. The inotropic state of the myocardium is

another important determinant of M

and myocardial

Coronary Heart Disease

Kenneth A. Narahara, MD



CORONARY HEART DISEASE

499

work. However, it is somewhat difficult to measure clinically;

fortunately, the heart rate and systolic blood pressure usually

provide sufficient information for clinical decision making.

B. Balance of Oxygen Demand and Supply—Myocardial

ischemia represents an imbalance between myocardial oxy-

gen demand and myocardial blood supply. A fixed coronary

artery stenosis will limit coronary blood supply. In this cir-

cumstance, demand for coronary blood flow may increase,

but the stenosis will limit the available blood flow. Hence

demand will exceed supply, and myocardial ischemia will

result. The ability of the coronary artery to respond to sym-

pathetic stimulation and other local factors also can result in

an inadequate blood supply through coronary artery spasm.

However, coronary artery spasm (ie, variant angina and

Prinzmetal’s angina) is seldom the sole cause of inadequate

coronary blood flow. More often, fixed coronary artery

stenoses exist in combination with some degree of coronary

spasm or vasoconstriction to cause a myocardial O

demand-

supply imbalance.



Myocardial Ischemia (Angina Pectoris)

ESSENTIALS OF DIAGNOSIS



Complaint of heavy, pressure-like or viselike discomfort;

sometimes choking, a constricting feeling in the throat,

or a sensation of strangling; discomfort located diffusely

in substernal region, left arm, jaw, or neck—rarely local-

ized to a single point.



Discomfort lasts 30 seconds to 15 minutes.



May be provoked by exertion, emotional distress, eat-

ing, and cold.



Should decrease with rest and may be relieved in 1–2

minutes after sublingual nitroglycerin.

General Considerations

Resistance to blood flow in the coronary arteries becomes

significant when there is sufficient narrowing of the coronary

artery diameter by atherosclerotic plaques (diameter

decreased by more than 50%). The physiologic consequence

is that coronary artery blood flow becomes fixed at some

value rather than increasing to meet increased myocardial

demands. Coronary blood flow may be adequate to supply

the myocardium at rest but becomes insufficient during

exertion when the myocardial oxygen demand increases.

This explains why, in patients with stable angina pectoris,

symptoms are seen with exercise and disappear with rest.

Clinical Features

The diagnosis of angina pectoris is typically a clinical one.

Pain with the qualities described below should be considered

the primary diagnostic criterion—that is, the history is the

most important diagnostic clue to ischemic heart disease and

myocardial ischemia (angina pectoris).

A. Symptoms—There are six major features of the clinical

manifestations of myocardial ischemia (angina pectoris): the

quality of the discomfort (patients do not always complain of

“pain”), the location, the duration, provoking factors,

sources of relief, and actions taken by the patient during the

episode.

1. Quality of discomfort—Patients with myocardial

ischemia frequently describe the discomfort as a heavy,

pressure-like, or viselike sensation. They may describe chok-

ing or a constricting feeling in the throat. Indigestion or a sen-

sation of strangling is also frequently described. The patient

should be asked about “discomfort” because many patients do

not perceive angina or myocardial ischemia as “pain.”

2. Location of discomfort—The discomfort of myocar-

dial ischemia usually is located in the substernal region but

also may be located in the arms (the left more often than the

right), the jaw, the neck, the left interscapular region, or

occasionally, the epigastrium. It is often useful to ask the

patient to define the extent of the pain with one finger. The

pain of myocardial ischemia is not likely to be localized to a

single point.

3. Duration of discomfort—Angina pectoris usually lasts

30 seconds to 15 minutes. Longer episodes of ischemic pain

are associated with unstable angina or myocardial infarction.

4. Provocation of discomfort—Exertion, emotional dis-

tress, eating, cold weather, and sexual activity are frequent

initiating events.

5. Relief of discomfort—Pain from myocardial ischemia

should decrease with rest or a reduction in exertion.

Sublingual nitroglycerin should relieve angina within 1–2

minutes, and this feature can be used both for diagnosis and

for treatment.

6. Actions taken by the patient—Angina pectoris is not

relieved by inspiration or movement of the upper extremities

or torso nor by antacids or food. Pain relief achieved in this

way should make one think of other disorders.

B. Physical Findings—During an episode of angina, an S

gallop, pulmonary rales, or the murmur of mitral regurgita-

tion may appear. However, these findings are more likely to

be noted during stress testing, when the patient’s chest pain

is provoked with a physician present.

C. Electrocardiography—

1. Resting ECG—If ST-segment and T-wave changes (ie, ST-

segment depression, T-wave inversion, or both) are present

during an episode of pain and return to normal with spon-

taneous relief of pain or after administration of nitroglyc-

erin, the diagnosis of myocardial ischemia is confirmed.



CHAPTER 22

500

2. Exercise stress ECG—The resting ECG frequently is

normal in patients with myocardial ischemia owing to coro-

nary artery disease or coronary artery spasm because the

pain usually has subsided by the time the patient reaches

medical attention. For this reason, stress testing during bicy-

cle or treadmill exercise is frequently employed to reproduce

the supply and demand imbalance that triggers myocardial

ischemia. The patient is asked to walk on a treadmill or pedal

on a bicycle as the work load is increased progressively.

Continuous electrocardiographic monitoring permits detec-

tion of ST-segment depression. Exercise causes an increase in

heart rate and blood pressure (an increase in the double

product); thus patients with a fixed (and inadequate)

myocardial blood supply owing to coronary artery disease

frequently will experience angina with ST-segment depres-

sion as myocardial work exceeds a fixed O

supply.

D. Imaging Studies

1. Stress testing—Specialized forms of exercise stress test-

ing, including thallium scintigraphy and stress ventriculog-

raphy, have been introduced to diagnose myocardial

ischemia in patients who have resting ECGs that would make

the diagnosis of myocardial ischemia difficult on the basis of

exercise electrocardiography. For example, patients with rest-

ing ST-segment and T-wave abnormalities owing to left ven-

tricular hypertrophy, from administration of digitalis

glycosides, or from prior myocardial infarction may have a

stress ECG that is difficult or impossible to interpret with

precision. In these circumstances, the use of myocardial per-

fusion scanning with thallium-201 or technetium-99m ses-

tamibi may be useful. These perfusion agents are taken up by

viable myocardium in proportion to coronary blood flow. As

coronary blood flow requirements increase (such as during

exercise), myocardium supplied by normal coronary vessels

will have a normal uptake of the tracer. Conversely, areas of

myocardium served by stenotic coronary arteries will have

reduced coronary blood flow during exercise. As a conse-

quence, the reduced uptake of the perfusion agent will

appear as a “cold spot.”

Exercise ventriculography using echocardiography, cine-

CT scanning, or radionuclide angiography can identify the

presence of myocardial ischemia by the development of a

new or worsened wall motion abnormality during stress. As

myocardial O

requirements outstrip the available supply,

regional wall motion abnormalities will develop as nutrient

flow to the myocardium remains fixed in the face of an

increasing metabolic demand. Initially, a localized wall

motion abnormality will appear or will worsen (if a previous

infarction is present). Next, the global left ventricular ejec-

tion fraction will fall. Although these tests are substantially

more expensive than the standard electrocardiographic stress

test, they may provide a definitive noninvasive means of

diagnosing myocardial ischemia.

2. Coronary angiography—Anatomic diagnosis of coro-

nary atherosclerosis is made by injection of radiopaque

contrast material directly into the coronary arteries. Patients

are taken to the catheterization laboratory, where careful

hemodynamic monitoring can be performed. Significant

atherosclerotic lesions are seen as a reduction in the diame-

ter of the coronary artery, and the anatomic information can

be used to decide whether medical therapy or interventional

procedures such as coronary angioplasty or coronary artery

bypass surgery might be useful.

Differential Diagnosis

Other causes of chest pain that may have features suggestive

of angina pectoris include pericarditis (pain is often posi-

tional and related to respiration); esophageal spasm (related

to meals and swallowing); chest wall pain (often reproduced

by applying pressure to the chest wall); aortic dissection

(classically “tearing” in quality and radiating to the back;

pulses in the arms may be unequal); GI pain from esophagi-

tis, gastritis, cholecystitis, and cholelithiasis (often associated

with meals and, for esophagitis and gastritis, relieved by

antacids); and hyperventilation.

Treatment

The treatment of myocardial ischemia is directed at both

reducing myocardial O

consumption (myocardial O

demand and double product) and increasing myocardial

blood supply. Initially, medical therapy is used in an attempt

to reduce myocardial O

consumption (eg, use of beta block-

ade to reduce heart rate and blood pressure) or to increase

myocardial O

supply by using coronary vasodilators such as

calcium channel blocking agents or either short-acting (sub-

lingual nitroglycerin) or long-acting nitrates (isosorbide

dinitrate).

More aggressive therapy, such as percutaneous translumi-

nal coronary angioplasty and coronary artery bypass surgery,

increase coronary blood supply directly. While effective in

reaching this goal, as well as in relieving angina, these strate-

gies are invasive and cause a variable degree of morbidity. To

date, with the exception of patients with left main coronary

artery disease or three-vessel coronary artery disease in the

presence of left ventricular dysfunction, neither coronary

angioplasty nor coronary bypass surgery will reduce the

mortality rate from coronary artery disease. The high cost

and stress on the health care network of these procedures

would suggest that the management of myocardial ischemia

with medical therapy is a reasonable first step.

A. Long-Acting Nitrates—Nitrates are the oldest form of

anti-ischemic therapy. Their continued use is a testament to

their efficacy as well as their safety. Therapy with long-acting

nitrates aims to improve coronary blood flow. Twenty mil-

ligrams of isosorbide dinitrate three times a day is a typical

starting dose. Although lower doses may be used, they usu-

ally have little more than a placebo effect in patients with

coronary artery disease. After initial dosing with 20 mg three

times daily for 3–5 days, the dose can be increased to either



40 or 60 mg three times daily. A target dose of at least 40 mg

three times daily would be a reasonable therapeutic goal,

assuming that the patient does not suffer from headaches or

symptoms of hypotension. Alternatively, extended-release

isosorbide mononitrate in a dose of 30–120 mg once or twice

daily may enhance compliance.

“Nitrate headaches” occur frequently during the first few

days of therapy with isosorbide dinitrate. The patient should

be encouraged to continue the medication (perhaps with

administration of acetaminophen) because the headaches fre-

quently subside with time and the antianginal efficacy of the

long-acting nitrates persists. Doses of isosorbide dinitrate

larger than 60 mg three times daily generally are not necessary

for therapy of angina pectoris and produce a smaller incre-

mental improvement in symptoms compared with the

increase from 20 to 40 or 60 mg three times daily. However, in

the treatment of unstable angina or for patients who have

severe angina pectoris that is not amenable to revasculariza-

tion, such high doses of long-acting nitrates may be useful in

providing an asymptomatic or moderately symptomatic state.

B. Beta-Adrenergic Blockade—β-adrenergic blockers are

particularly effective in the treatment of patients who have

coexisting angina and hypertension. Likewise, the combina-

tion of β-blocker therapy with a long-acting nitrate may be

hemodynamically desirable because the long-acting nitrates

tend to produce a modest reflex tachycardia that can be

blunted or eliminated by beta blockade. In the treatment of

exertional angina, beta blockade can be particularly advanta-

geous because it will block catecholamine-induced increases

(from exercise or emotional stress) in heart rate and blood

pressure.

Initial therapy with β-blockers can commence with meto-

prolol, 50 mg twice daily (or 50–100 mg of sustained-release

metoprolol daily); atenolol, 50 mg once daily; or betaxolol,

10 mg once daily. In the elderly patient, these initial doses

should be reduced at the initiation of therapy. Titration of

the dose upward can commence after four to five half-lives

have elapsed, that is, 2–3 days for metoprolol, 3–4 days for

atenolol, and 5–7 days for betaxolol or extended-release

metoprolol (eg, Toprol XL). Upward titration of the dose of

β-blocker should be considered if the resting heart rate or

blood pressure are not affected by the initial dose of therapy.

As a general rule, patients who may be operating machin-

ery or driving automobiles should be warned of the possibil-

ity of drowsiness or lethargy when taking β-blockers.

Frequently, the administration of longer-acting agents such

as extended-release forms of metoprolol or betaxolol at bed-

time can be useful in reducing symptoms of fatigue and

reduced attentiveness during the daytime.

Concern is frequently raised about the use of beta block-

ade in patients with diabetes. However, if the patient does not

suffer from episodes of hypoglycemia, judicious therapy with

beta blockade is often rewarded by substantial reduction in

angina pectoris. In addition, β-blocker use in diabetic

patients with coronary artery disease is associated with a

reduction in mortality. The major concern regarding the

coadministration of beta blockade with hypoglycemic agents

is blunting of the symptoms of hypoglycemia. However, this

effect is related primarily to a reduction of tachycardia;

diaphoresis and hunger are not blunted by β-blocker ther-

apy. Of course, β-blockers should be avoided in the brittle

type 1 diabetic or in diabetics with a history of ketoacidosis.

C. Calcium Channel Blocking Agents—

1. Dihydropyridines—This class of calcium antagonists is

characterized by both a systemic and coronary vasodilator

effect. The dihydropyridines have no effect on sinoatrial (SA)

or atrioventricular (AV) nodal function. Therefore, coad-

ministration of a dihydropyridine with β-blockers for the

combined therapy of angina and hypertension is fre-

quently highly effective. Both agents tend to lower blood

pressure, and the bradycardic effect of beta blockade will

prevent any reflex tachycardia that may be engendered by the

dihydropyridine.

Nifedipine, the first-generation dihydropyridine, had a

relatively short half-life and frequently caused symptoms of

vasodilation, including flushing, headaches, and peripheral

edema. Sustained-release nifedipine is still used for refrac-

tory hypertension in doses of 30–90 mg/day or more.

However, for the treatment of coronary artery disease,

nifedipine and the second-generation dihydropyridines have

been superseded.

Amlodipine and felodipine are “long acting” dihydropyri-

dine calcium channel antagonists. Amlodipine has an inher-

ently long half-life of over 30 hours, whereas felodipine gains

its once-a-day dosing from an enteric coating that results in

the gradual release of the agent. Amlodipine is approved for

both angina and hypertension; felodipine is approved for

hypertension only.

Amlodipine is the only calcium channel blocking agent

that can be used safely in patients with impaired left ventric-

ular function. Hence the agent can be used for antianginal

treatment in addition to nitrates and β-blockers, particularly

when coexisting hypertension is present. The starting dose

for amlodipine is 2.5–5 mg/day with a recommended maxi-

mum of 10 mg/day. Higher doses of amlodipine may afford

additional antianginal and antihypertensive effects, but side

effects such as peripheral edema become more pronounced.

Given the long half-life of amlodipine, the dose of this agent

should not be increased more than once weekly.

2. Verapamil—Verapamil is a vasodilating calcium channel

blocking agent that, in addition to causing coronary artery

vasodilation, has a negative chronotropic effect. Conduction

through both the SA node and the AV node can be slowed by

this agent. Verapamil has a side-effect profile similar to that

of nifedipine. In addition, verapamil causes constipation,

and the patient’s bowel habits should be evaluated carefully.

Many clinicians will start patients on stool softeners or pro-

phylactic milk of magnesia when commencing therapy with

verapamil.

CORONARY HEART DISEASE

501



CHAPTER 22

502

Verapamil is a fairly potent peripheral vasodilator and

therefore is an effective antihypertensive agent. Additionally,

with its bradycardic effect, it may be particularly useful in

patients with ischemic heart disease who are intolerant of

β-blockers, such as those with asthma or type 1 diabetes. It

should be recalled that, on balance, verapamil exerts the

greatest negative inotropic effect of the currently available

calcium channel blockers and should be avoided in patients

with a history of congestive heart failure or a known reduc-

tion in ejection fraction. Short-acting verapamil typically is

administered in a dosage of 80–120 mg every 8 hours.

However, the long-acting verapamil preparations generally

are preferred for the sake of compliance and convenience.

Long-acting verapamil should be initiated at a dosage of

180 mg once daily with upward titration to 240 mg/day.

Titration can occur at weekly intervals for symptoms of

angina or control of hypertension. Patients should be

warned to avoid chewing or crushing the long-acting

preparations of verapamil because the entire daily dose may

be released rapidly. Long-acting verapamil should be initi-

ated at a dosage of 120 mg/day in the elderly or in under-

weight patients.

3. Diltiazem—Diltiazem has a modest effect on heart rate

and blood pressure in normotensive patients. Like all cal-

cium channel blocking agents, it exerts a coronary vasodi-

lating effect. Diltiazem’s antianginal properties are the

result of both coronary vasodilation and a reduction in the

product of heart rate and systolic blood pressure.

Diltiazem has a favorable side-effect profile characterized

by minor occurrences of dyspepsia, rash, and edema.

Because diltiazem depresses SA and AV nodal function, con-

comitant administration of β-blockers warrants careful

attention to the heart rate.

Starting dosages for diltiazem are 60 mg every 8 hours,

and this can be increased to 120 mg every 6–8 hours. Long-

acting preparations of diltiazem have been introduced.

Therapy with these sustained-release preparations can be

initiated at a dosage determined by therapy with the short-

acting preparation (eg, patients who tolerate 60 mg every

8 hours can be converted directly to 180 mg/day of the long-

acting preparation). Frequently, clinicians initiate therapy

with 180 mg of the sustained-release compound and

increase the dose weekly up to 360 mg/day. For elderly and

underweight patients, a starting dose of 120 mg/day may be

preferable.

Like all calcium channel blocking agents currently mar-

keted (with the exception of amlodipine), diltiazem should

be avoided in patients with reduced left ventricular func-

tion. A large multicenter trial demonstrated that the

administration of diltiazem to patients with left ventric-

ular ejection fractions of less than 0.40 or with pul-

monary congestion after acute myocardial infarction is

associated with an approximately 1.4-fold increase in car-

diovascular death. Similar results have been seen in trials

with verapamil.

Ben-Dor I, Battler A: Treatment of stable angina. Heart

2007;93:868–74. [PMID: 17569815]

Fox K et al: Guidelines on the management of stable angina pec-

toris: Executive summary. The Task Force on the Management

of Stable Angina Pectoris of the European Society of

Cardiology. Eur Heart J 2006;27:1341–81. [PMID: 16735367]

Gibbons RJ et al: ACC/AHA 2002 guideline update for the manage-

ment of patients with chronic stable angina: Summary article. A

report of the American College of Cardiology/American Heart

Association Task Force on Practice Guidelines (Committee on

the Management of Patients with Chronic Stable Angina).

Circulation 2003;107:149–58. [PMID: 12515758]

Hemingway H et al: Incidence and prognostic implications of sta-

ble angina pectoris among women and men. JAMA

2006;295:1404–11. [PMID: 16551712]



Acute Coronary Syndromes: Unstable

Angina and Non-ST-Segment-Elevation

Myocardial Infarction

ESSENTIALS OF DIAGNOSIS



Increase in the frequency, severity, or duration of stable

angina or angina occurring at a lower threshold (unsta-

ble angina with low-risk characteristics).



Prolonged (>20 minutes) angina at rest now resolved,

plus diabetes, age over 65, deep T-wave inversions in

more than three leads, angina on walking one to two

blocks on the level or climbing one flight of stairs at a

normal pace in the past 2 weeks, nocturnal angina, or

pathologic Q waves (unstable angina with intermediate-

risk characteristics).



Ongoing (>20 minutes) chest pain, ST-segment depression

= 1 mm or more, angina plus heart failure, or angina plus

hypotension (unstable angina with high-risk characteristics).



Any of the preceding plus cardiac enzyme markers of

myocardial necrosis (troponin I, troponin T, or CK-MB)

(non-ST-segment-elevation myocardial infarction).

General Considerations

Patients with non-ST-segment-elevation (non-Q-wave)

myocardial infarctions represent the severe end of the spec-

trum of the pathology associated with unstable angina.

Fissuring or rupture of an atherosclerotic plaque precedes

unstable angina. If the plaque disruption can be stabilized

spontaneously or through medical intervention, unstable

angina develops. If not, then non-ST-segment-elevation

myocardial infarction may occur.

The American College of Cardiology/American Heart

Association (ACC/AHA) has issued guidelines for the manage-

ment of unstable angina pectoris and non-ST-segment-

elevation myocardial infarction (non-STEMI). The intensity



CORONARY HEART DISEASE

503

of medical therapy and interventional procedures, as well as

the urgency of starting treatment, should be guided by both

symptoms and objective findings.

Clinical Features

A. Symptoms and Signs—The signs and symptoms of

unstable angina and non-STEMI are the same as those of sta-

ble angina pectoris. The distinction between stable angina

and unstable angina or non-STEMI is in the longer duration

of the pain episodes, the reduced amount of exertion

required to produce angina (including pain at rest), and the

increased frequency of chest discomfort.

B. Diagnostic Testing—As in stable angina, patients with

unstable angina frequently have normal ECGs. However, the

presence of new ST-segment depression, T-wave inversion,

or both that resolve spontaneously or with the administra-

tion of sublingual nitroglycerin identifies a category of

patients at high risk for subsequent cardiac events, including

myocardial infarction or death. Chest pain with ST-segment

depression now can be managed by specific therapy defined

by large randomized clinical trials.

A non-STEMI is diagnosed when markers of myocardial

necrosis (ie, elevated levels of troponins or CK-MB) are pres-

ent in the absence of ST-segment elevation on the ECG.

C. Evaluation of the Stabilized Patient—In patients

whose symptoms become well controlled on antianginal

therapy after an episode of unstable angina pectoris, three

approaches may be followed: (1) Perform coronary arteriog-

raphy with the anticipation of elective coronary artery angio-

plasty or coronary artery bypass surgery. If catheterization

and revascularization can be accomplished within 48 hours

of presentation, this approach can reduce morbidity and

mortality in patients with troponin-positive non-STEMIs

and in patients with unstable angina with 1 mm or more of

labile ST-segment depression on presentation. (2) Treat the

patient conservatively with increased doses of antianginal

medications. (3) Perform a functional test to select patients

most likely to benefit from more invasive therapies.

A “low level” stress test can be used in ACC/AHA low-

and intermediate-risk unstable angina patients to identify

those who are at high or low risk for development of subse-

quent myocardial infarction, further unstable angina, and

death after an initial episode of unstable angina. These exer-

cise stress tests, which are limited either by workload (5–7

mets [ie, five to seven times the resting metabolic rate]) or

heart rate (<120 beats/min or less than 65% of predicted

maximum heart rate), are used to determine whether

ischemia is present at levels of exercise likely to be encoun-

tered in ordinary daily activities. Safety is the primary reason

for limiting the test to a lower target workload or heart rate

than might be the goal for diagnosis of angina in a patient

with chest pain. Furthermore, it makes little sense intuitively

to challenge with a conventional stress test a patient who has

recently had symptoms with minimal exertion.

A negative low-level stress test is associated with a rela-

tively good outcome, with over 70% of patients with a nega-

tive study having no or mild angina pectoris in the ensuing

6 months to 1 year. Conversely, a positive low-level stress test,

with development of ST-segment depression or chest pain, is

associated with a greater than 80% incidence of subsequent

undesirable outcomes (eg, recurrent unstable angina,

myocardial infarction, or death). Thus the low-level stress

test can be used to identify patients at high risk and therefore

more likely to benefit from early aggressive management of

ischemic heart disease.

Treatment

Patients who experience an increase in the frequency or

duration of angina pectoris or a marked decline in the

amount of exertion required to provoke chest pain are can-

didates for hospitalization. This will both reduce the work of

the heart (hospitalization itself) and initiate or intensify

pharmacologic therapy for ischemic heart disease.

A. Aspirin—Over two decades ago, two major studies

attested to the importance of aspirin in the therapy of unsta-

ble angina pectoris. Both the Veterans Administration and

the Canadian Cooperative trials demonstrated a 50% reduc-

tion in deaths and myocardial infarctions in patients with

unstable angina who take one to four 325-mg aspirin tablets

a day. The observation that patients with unstable angina or

non-STEMI have large amounts of thrombus in patent but

atherosclerotic coronary arteries at the time of coronary

angioscopy or coronary arteriography provides the patho-

physiologic basis for this remarkably successful and inexpen-

sive form of therapy. Patients with true allergies to aspirin

can substitute clopidogrel, 75 mg/day.

B. Beta-Blockers—The prevention of the ischemia that

underlies unstable angina pectoris and non-STEMI is accom-

plished most easily by reducing the work of the heart. By low-

ering both the heart rate and blood pressure, β-blockers

perform this task efficiently and inexpensively. In patients with

high-risk characteristics of unstable angina or evidence of a

non-STEMI, intravenous administration of β-blocking agents

followed by oral β-blockers is appropriate and desirable.

Metoprolol should be administered intravenously in 5-mg

increments more than 2 minutes apart to a total dose of 15 mg

(or more if better control of the heart rate is desired). Following

intravenous loading of β-blockers, oral metoprolol, 50 mg twice

daily, or oral atenolol, 50 mg once daily, should be initiated.

For patients with contraindications to beta blockade (eg,

bronchospastic lung disease), calcium channel blocking

agents may be substituted. Calcium channel blockers,

angiotensin-converting enzyme (ACE) inhibitors, or

angiotensin II receptor blockers may be added to beta block-

ade if additional antihypertensive therapy is required.

C. Nitrates—Oral nitrates may be initiated as 20-mg isosor-

bide dinitrate three times per day with a target dose of 40–60 mg



CHAPTER 22

504

three times per day. Long-acting isosorbide mononitrate can

be initiated at a dosage of 20 mg/day with a target dosage of

60–120 mg/day. These agents usually are administered to

low- and intermediate-risk patients who need additional

anti-ischemic therapy after β-blockers.

Intravenous nitrate therapy may be particularly useful in

the patient with high-risk unstable angina pectoris who has

ongoing pain or the non-STEMI patient with hypertension

that is difficult to control. Patients receiving intravenous

nitroglycerin should be monitored closely, and the rate of

infusion should be titrated to relieve pain as well as to meet

blood pressure goals while avoiding hypotension.

D. Thrombolytic Therapy—There is no role for throm-

bolytic therapy in unstable angina or non-STEMI. Trials

designed to test the efficacy of thrombolytic therapy in these

settings are negative (thrombolytics increased morbidity and

mortality).

E. Clopidogrel—The thienopyridine clopidogrel is an

antiplatelet agent that inhibits platelet aggregation induced by

adenosine diphosphate (ADP), whereas aspirin blocks the

thromboxane-mediated payway. The CURE trial randomized

12,562 patients with acute coronary syndromes to clopidogrel

75 mg/day (after a 300-mg oral loading dose) or a placebo.

Clopidogrel therapy was associated with a substantial reduc-

tion in the composite endpoint of death from cardiovascular

causes, nonfatal myocardial infarction, or stroke. Although

approved for all forms of acute coronary syndromes, the ben-

efit of this agent was demonstrated only in patients with

unstable angina and ST-segment depression and patients with

non-STEMIs.

F. Anticoagulation—The ESSENCE and TIMI 11B trials

have provided convincing evidence supporting the use of the

low-molecular-weight heparin enoxaparin in high-risk

unstable angina pectoris and non-STEMI patients. While

also approved for use in intermediate-risk unstable angina, a

close look at the data suggests that the greatest benefit from

this agent occurs in patients with pain at rest and 1 mm or

more of ST-segment depression or who have elevated tro-

ponins or CK-MB. The dose of enoxaparin is 1 mg/kg subcu-

taneously every 12 hours for 48–72 hours.

Intravenous unfractionated heparin can be given for non-

STEMI as well as for intermediate- and high-risk unstable

angina. However, given the advantages of low-molecular-

weight heparin, unfractionated heparin seems most useful as

an adjunct to the glycoprotein IIb/IIIa inhibitors or in renal

failure, where enoxaparin is not desired because it is cleared

by the kidneys.

Recently, the synthetic pentasaccharide fondaparinux,

which also binds to activated factor Xa, has been shown to

reduce ischemic events in acute coronary syndromes much

the same as enoxaparin. Fewer bleeding events were observed.

G. Glycoprotein IIb/IIIa Receptor Inhibitors—This class

of drugs blocks the affinity of the glycoprotein IIb/IIIa recep-

tor for fibrinogen on platelets activated by products released

from plaque rupture. In this manner, platelet plugging and

clot formation in atherosclerotic lesions are retarded or

inhibited.

Like enoxaparin, the glycoprotein IIb/IIIa receptor

antagonists (ie, eptifibatide and tirofiban) are indicated for

the treatment of intermediate- and high-risk unstable

angina and for non-STEMI patients. Eptifibatide is

approved for use in preventing complications of percuta-

neous revascularization. Both agents are administered with

unfractionated heparin at a dose titrated to result in a

twofold increase in the partial thromboplastin time.

Eptifibatide is initiated with an intravenous bolus of 180

μg/kg, followed by an infusion of 2 μg/kg per minute for

72–96 hours. Tirofiban is given as an intravenous loading

dose of 0.4 μg/kg per minute for 30 minutes, followed by an

infusion of 0.1 μg/kg per minute for 48–96 hours.

Both glycoprotein IIb/IIIa receptor antagonists reduce the

combined endpoint of death or myocardial infarction or the

need for urgent revascularization. Like enoxaparin, the great-

est benefit from these agents appears to be conferred on the

more ill patients (ie, those with prolonged chest pain, 1 mm

or more of ST-segment depression, or elevated troponins or

cardiac enzymes). The decision to use these costly agents may

hinge on the likelihood of side effects of bleeding.

H. Coronary Angioplasty and Coronary Artery Bypass

Grafting—Debate continues regarding the advantages of

conservative compared with aggressive management of

these patients. The clinician may elect to initiate or enhance

the therapy of patients with low-risk unstable angina and

simply follow the patient symptomatically with or without

hospitalization. This option is based on the observation

that low-risk patients have a risk of serious events (eg,

death and myocardial infarction) that is similar to that

borne by patients with stable angina. Even intermediate-

risk unstable angina pectoris patients who stabilize their

symptoms on medical therapy are at risk only for an

increased rate of recurrent unstable angina during the

ensuing year. Hence, for stabilized patients, watchful wait-

ing appears to carry little risk and may avoid unneeded

revascularization procedures.

Recurrent ischemic pain despite adequate medical ther-

apy should prompt urgent coronary angiography in anticipa-

tion of coronary bypass grafting or coronary angioplasty.

This recommendation also applies to patients with recurrent

pain during treatment of non-STEMI.

Data from TACTICS and TIMI 18 suggest that patients

with rest pain plus ST-segment depression or those who have

a non-STEMI may benefit from an early (but not emergent)

cardiac catheterization in anticipation of expeditious coro-

nary revascularization.

Table 22–1 outlines basic evidence-based treatment

strategies for acute coronary syndromes. The terms low,

intermediate, and high risk refer to ACC/AHA guideline esti-

mates of risk for adverse outcome (eg, recurrent unstable

angina, myocardial infarction, and death).



CORONARY HEART DISEASE

505

Allen LA et al: Comparison of long-term mortality across the spec-

trum of acute coronary syndromes. Am Heart J 2006;151:

1072–8. [PMID: 16644337]

Ayala TH, Schulman SP: Pathogenesis and early management of

non-ST-segment-elevation acute coronary syndromes. Cardiol

Clin 2006;24:19–35. [PMID: 16326254]

Braunwald E et al: ACC/AHA 2002 guideline update for the man-

agement of patients with unstable angina and non-ST-segment-

elevation myocardial infarction. A report of the American

College of Cardiology/American Heart Association Task Force

on Practice Guidelines (Committee on the Management of

Patients with Unstable Angina). Circulation 2002;106:

1893–900. [PMID: 12356647]

Cannon CP: Acute coronary syndromes: Risk stratification and ini-

tial management. Cardiol Clin 2005;23:401–9. [PMID 16278114]

Cannon CP et al, for the TACTICS-TIMI 18 Investigators:

Comparison of early invasive and conservative strategies in

patients with unstable coronary syndromes treated with the gly-

coprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:

1879–87. [PMID: 11419424]

The CURE Trial Investigators: Effects of clopidogrel in addition to

aspirin in patients with acute coronary syndromes without ST-

segment elevation. N Engl J Med 2001;345:494–502. [PMID:

11519503]

de Winter RJ et al: Early invasive versus selectively invasive man-

agement for acute coronary syndromes. N Engl J Med

2005;353:1095–104. [PMID: 16162880]

Fitchett DH et al: Randomized evaluation of the efficacy of enoxa-

parin versus unfractionated heparin in high-risk patients with

non-ST-segment-elevation acute coronary syndromes receiving

the glycoprotein IIb/IIIa inhibitor eptifibatide: Long-term

results of the Integrilin and Enoxaparin Randomized

Assessment of Acute Coronary Syndrome Treatment (INTER-

ACT) trial. Am Heart J 2006;151:373–9. [PMID: 16442903]

Tricoci P et al: Clopidogrel to treat patients with non-ST-segment-

elevation acute coronary syndromes after hospital discharge.

Arch Intern Med 2006;166:806–11. [PMID: 16606819]

Yusuf S et al: Comparison of fondaparinux and enoxaparin in

acute coronary syndromes. N Engl J Med 2006;354:1464–76.

[PMID: 16537663]



Acute Myocardial Infarction with ST-

Segment Elevation

ESSENTIALS OF DIAGNOSIS



Precordial chest pain with or without radiation to the

left arm, shoulder, or jaw.



Pain may be identical in quality and description to that

of angina pectoris but may last from 10 minutes to sev-

eral hours.



Greater than 1 mm ST-segment elevation in two con-

tiguous leads with or without Q-wave formation.



Confirmation by serial changes in ECGs plus elevation of

cardiac enzymes (ie, CK-MB, troponin I, or troponin T).



Complications may include arrhythmias, pulmonary

edema, hypotension and shock, ventricular rupture, and

pericarditis.

Non-STEMI

(Elevated Troponin)

High-Risk UAP (Chest

Pain and ≥ 1 mm ST-

Segment Depression

High-Risk UAP (<1 mm

ST-Segment Depression)

Intermediate-

Risk UAP

Low-Risk UAP

Aspirin + + + + +

β-Adrenergic blockers + + + + +

Clopidogrel +

∗

Low-molecular-weight

heparin (enoxaparin)

†,‡

IIb-IIIa inhibitor and

unfractionated heparin

Consider cardiac catheteri-

zation and revasculariza-

tion within 48 hours

+ +

Note: Recurrent chest pain in the hospital is an indication for expeditious catheterization and intervention.

∗

For 30 days.

†

Avoid if creatinine ≥ 2.5 mg/dL.

‡

Substitute IIb-IIIa inhibitor + unfractionated heparin if urgent catheterization is planned.

Avoid if creatinine ≥ 4 mg/dL; adjust dose if creatinine ≥ 2.

Table 22-1. Treatment of unstable angina pectoris (UAP) or non-ST-segment-elevation myocardial infarction (non-STEMI)



CHAPTER 22

506

General Considerations

Coronary thrombosis is the immediate cause of acute

myocardial infarction in over 90% of patients with this syn-

drome of acute myocardial infarction with ST-segment ele-

vation (STEMI). Although early autopsy investigations

suggested a variety of other causes of acute myocardial

infarction—including coronary vasospasm and emboli—

over 86% of those with acute myocardial infarction had

coronary artery thrombi when coronary angiography was

performed within 4 hours of the onset of symptoms.

Current concepts of acute myocardial infarction support

the view that the nidus for thrombosis is an atherosclerotic

plaque in a coronary artery. The plaque itself may or may not

result in stenosis of the artery severe enough to cause symp-

toms, although more severe atherosclerotic stenoses may be

associated with exertional angina. The pathophysiologic

sequence of events then probably includes plaque rupture

with exposure of the subintimal components of the plaque to

coronary blood flow. Platelet activation occurs as the con-

tents of the atherosclerotic plaque (including cholesterol and

calcium) interact with circulating blood components.

Platelet activation releases thromboxane A

, a vasoconstric-

tive substance that may lead to localized vasospasm, which

further impedes coronary artery blood flow. The net result of

these events is interruption of coronary blood flow by

thrombus formation followed by myocardial necrosis if ther-

apy is not effective.

New information regarding the treatment of unstable

angina and non-STEMI appears almost weekly. The thera-

pies of unstable angina, non-STEMI, and STEMI are now

driven by large clinical trials that define current pharmaco-

logic and revascularization strategies.

Clinical Features

A. Symptoms—Acute myocardial infarction is classically

associated with precordial chest pain with or without radia-

tion to the left arm, shoulder, or jaw. The pain is identical to

that described in the section on angina pectoris but often

more severe. The only deviation is duration. The chest pain

of myocardial infarction lasts from 10–15 minutes to several

hours. The pain is poorly responsive to nitroglycerin and

may require morphine for relief. Diaphoresis, syncope, and

lightheadedness may be present. Dyspnea and orthopnea

may be associated with acute congestive heart failure and

pulmonary edema.

B. Signs—During myocardial infarction, an S

gallop, pul-

monary rales, or the murmur of mitral regurgitation may

appear. Myocardial infarction may be associated with

decreased intensity of S

and S

. Patients should be examined

carefully for murmurs of mitral regurgitation and for the pres-

ence of pericardial friction rubs. Rales and wheezes may indi-

cate acute pulmonary edema from congestive heart failure.

C. Laboratory Findings—Venous blood should be obtained

routinely to measure the cardiac-specific CK-MB and

troponin I or troponin T on admission to hospital and every

6–8 hours thereafter for the first 24 hours. Daily CK-MB and

troponin levels may be useful during the balance of the

patient’s hospital stay to detect silent recurrent myocardial

necrosis. A partial thromboplastin time should be obtained

on admission and repeated if unfractionated heparin therapy

is indicated. Arterial blood gases should be measured if

hypoxemia is suspected from physical findings, chest x-ray,

or pulse oximetry.

D. Electrocardiography—By definition, acute STEMI is

associated with specific electrocardiographic findings.

However, with modern management, the classic electrocar-

diographic changes of ST-segment elevation followed by T-

wave inversion with development of Q waves may be

retarded or even abolished. A substantial proportion of

patients with myocardial infarction will not develop Q waves

after initial ST-segment elevation and may demonstrate only

T-wave changes or no changes in their ECGs. The develop-

ment of Q waves portends a worse prognosis.

E. Imaging Studies—Imaging studies should not delay

prompt management of acute myocardial infarction.

1. Chest x-ray—The chest x-ray should be reviewed for car-

diomegaly, pulmonary edema, and pleural effusions. In

upright chest x-rays, fullness and congestion of vessels lead-

ing to the upper lung fields sometimes is taken as evidence of

mild pulmonary edema from heart failure.

2. Echocardiography—Echocardiography is useful in

defining coexisting heart disease—especially valvular or con-

genital disease—identifying pericardial effusion, evaluating

unexplained tachycardia, and assessing ventricular function.

Patients with acute myocardial infarction should have an

echocardiogram if there is hypotension or shock. Other indi-

cations for echocardiography include suspicion of ventricu-

lar septal rupture or severe mitral regurgitation (both

potentially requiring surgery), a large myocardial infarction

as judged from CK-MB or troponin elevation, suspected

pericardial effusion, or left ventricular dysfunction that may

be worsened by β-adrenergic blockade or calcium channel

antagonists.

An evaluation of left ventricular function by echocardio-

graphy or radionuclide ventriculography should be per-

formed in almost all patients after an acute myocardial

infarction to help define prognosis and guide appropriate

prophylactic therapy. ACE inhibitors given after myocardial

infarction will prolong survival, and the greater the degree

of reduction in ejection fraction or severity of heart failure

as defined by New York Heart Association (NYHA) func-

tional class, the greater is the benefit from the routine use of

these agents. Similar statements can be made for the β-

blocker carvedilol in patients with NYHA class II and class III

symptoms.

3. Pulmonary artery catheterization (right-sided

heart catheterization)—Right-sided heart catheteriza-

tion allows the determination of right atrial, right ventricular,