CHAPTER 14

CHRONIC STABLE ANGINA

Glenn N. Levine, MD, FACC, FAHA

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1. What is the most common cause of angina?

Angina is the sensation of discomfort experienced during periods of myocardial ischemia or
myocardial infarction. It may occur when myocardial oxygen demand exceeds myocardial
oxygen supply. Myocardial ischemia and angina are most commonly the result of significant
stenosis of one or more coronary arteries. Typically, coronary artery stenosis that is 70% or
more of the coronary artery diameter is flow restricting and may cause angina. In patients with
chronic stable angina, myocardial ischemia results when myocardial oxygen demand increases,
such as during physical exertion. Coronary vasoconstriction, particularly at the site of a
preexisting stenosis, can also contribute to myocardial ischemia and produce angina.
2. What other conditions can cause anginal pain?
& Aortic stenosis
& Hypertrophic cardiomyopathy
& Hypertensive crisis
& Tachyarrhythmias and tachycardia (such as caused by hyperthyroidism)
& Coronary artery anomaly
& Severe anemia (as a result of decreased oxygen-carrying capacity of the blood)
& Severe hypoxemia
& Coronary vasospasm (Prinzmetals angina or cocaine induced)
& Cardiac syndrome X
3. How is chronic stable angina classified or graded?
The most commonly used system is the Canadian Cardiovascular Society system, in which
angina is graded on a scale of I to IV. These grades and this system are described in Box 14-1.
4. What are the three primary antianginal medications used for the treatment of
chronic stable angina?
& Beta-blockers
& Nitrates
& Calcium channel blockers
5. What are the principal issues regarding the use of beta-blockers?
The most commonly used beta-blockers are metoprolol and atenolol, although many others are
used. Both generic and brand names are available for many of these agents. Beta-blockers
principal effects are negative chronotropic (slow heart rate) and, to a variable extent, negative
inotropic (decrease cardiac contractility). Both these actions serve to decrease cardiac oxygen
demand. Beta-blockers are usually started at a low dose, then titrated upward as tolerated.
Primary side effects include excessive bradycardia, prolongation of the PR interval and heart
block, exacerbation of congestive heart failure, and exacerbation of severe reactive airway
disease. Thus, generally they are not initiated in patients with baseline bradycardia, significantly
prolonged PR interval (more than 220240 msec), acute decompensated heart failure as a result
of systolic dysfunction, and severe reactive airway disease. In general, the dose is titrated to
control of symptoms or resting heart rate in the 60s (beats/min).

102

CHAPTER 14 CHRONIC STABLE ANGINA 103

BOX 14-1. GRADING OF ANGINA PECTORIS BY THE CANADIAN

CARDIOVASCULAR SOCIETY CLASSIFICATION SYSTEM
Class I
Ordinary physical activity, such as walking and climbing stairs, does not cause angina.
Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation.
Class II
Slight limitation of ordinary activity. Angina occurs on walking or climbing stairs rapidly,
walking uphill, walking or stair climbing after meals, in cold, in wind, under emotional
stress, or only during the few hours after awakening. Angina occurs on walking more
than two blocks on level ground and climbing more than one flight of ordinary stairs at a
normal pace and in normal condition.
Class III

Class IV

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Marked limitations of ordinary physical activity. Angina occurs on walking one to two
blocks on level ground and climbing one flight of stairs in normal conditions and at a
normal pace.

Inability to carry on any physical activity without discomfortanginal symptoms may

be present at rest.
Modified from Ferri FF: Ferris clinical advisor, 2008, Philadelphia, 2008, Mosby.

6. When should one primarily use a peripherally acting calcium channel blocker
(amlodipine or felodipine), and when should one use a calcium channel blocker
that has effects on both the heart and the periphery (verapamil, diltiazem)?
Amlodipine and felodipine are used primarily as second- or third-line antianginal agents in patients
already on beta-blockers (and often, also long-acting nitrates). They act mainly as vasodilators,
lowering blood pressure and likely having some coronary vasodilating effects. Verapamil and
diltiazem, in addition to having vasodilating effects, also have negative chronotropic and negative
inotropic effects and can block atrioventricular (AV) conduction. Thus, they may be used
instead of beta-blockers in patients with severe reactive airway disease. Generally they are not
used in patients already on beta-blockers and are contraindicated in patients with depressed
ejection fractions (less than 40%) because of their negative inotropic effects and because studies
in the 1980s suggested a worse outcome with their use in such patients.
7. When does one prescribe a long-acting nitrate?
Long-acting nitrates are often prescribed along with beta-blockers as the initial treatments in
patients with chronic stable angina (Table 14-1). A nitrate-free interval, usually overnight,
is necessary to prevent the development of tolerance to these agents. Once-a-day, long-acting
nitrate preparations are ideal in terms of avoidance of nitrate tolerance and patient compliance.
8. When should one consider using ranolazine?
Ranolazine is a newer antianginal agent unlike previous agents. It does not work by affecting
heart rate or blood pressure or by coronary artery vasodilation. Its mechanism of action is still
not completely understood. In clinical trials (MARISA, CARISA, ERICA), it leads to a modest

104 CHAPTER 14 CHRONIC STABLE ANGINA

TABLE 14-1. A N T I A N G I N A L C L A S S E S , E F F E C T S , S I D E E F F E C T S , A N D
CONTRAINDICATIONS
Class

Effects

Beta-blockers

&

&

Negative
chronotropy
Negative
inotropy

Side Effects
&

&

&

&

&

Long-acting
nitrates

Coronary
vasodilation

AV node block
and PR
prolongation
Exacerbation of
acute heart failure
Bronchospasm

&

&

&

&

&

Resting bradycardia
Prolonged PR interval
(>220240 msec)
Acute decompensated
heart failure
Severe reactive airway
disease
Baseline hypotension

Blood pressure
reduction

&

Headache

&

Venous pooling

&

Use of erectile
dysfunction
medications

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&

Extreme
bradycardia

Contraindications

&

Calcium-channel
blockers:
verapamil and
diltiazem

&

&

&

&

Venodilation
Peripheral
vasodilation
Coronary
vasodilation

Negative
chronotropy
Negative
inotropy

&

&

&

&

Extreme
bradycardia

&

&

AV node block and

PR prolongation

&

Blood pressure
reduction

&

Exacerbation of
chronic and acute
heart failure

&

&

Calcium-channel
blockers:
amlodipine and
felodipine

&

&

&

&

Peripheral
vasodilation
Coronary
vasodilation
Coronary
vasodilation

No net
negative
chronotropic
or inotropic
effects

&

&

Blood pressure
reduction

Peripheral edema

&

Resting bradycardia
Prolonged PR interval
(>220240 msec)
Baseline low blood
pressure
Acute decompensated
heart failure
Ejection fraction < 40%
Usually, patients already
on beta-blockers
Baseline low blood
pressure

CHAPTER 14 CHRONIC STABLE ANGINA 105

increase in exercise tolerance (approximately 30 seconds) and decreases in angina and
sublingual nitroglycerin (SL NTG) use. It is generally a third-line agent in patients with continued
significant angina despite traditional antianginal therapy. Its major side effect is QT prolongation.
Thus, it should not be used in patients with baseline QT prolongation or those on other
medications that can prolong the QT interval. Patients initiated on this drug should have their QT
duration monitored periodically with 12-lead electrocardiograms (ECGs). The usual starting
dose is 500 mg orally twice a day (PO BID), which can be increased to 1000 mg PO BID.
Generally this drug should be prescribed only by cardiologists.
9. Should everyone with chronic stable angina be prescribed sublingual
nitroglycerin (or nitroglycerin spray)?
Yes. This is the standard of care. Patients should be instructed on how to use SL NTG
generally one pill every 5 minutes up to a maximum of three tablets. Patients with chronic stable
angina should be instructed to call 911 and seek immediate medical attention if their angina
is not relieved after three pills or 15 minutes (or after one pill or 5 minutes in the case of patients
with a history of acute coronary syndrome [ACS]).

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10. Which patients with chronic stable angina should be referred for stress testing
or cardiac catheterization?
The two purposes of stress testing are diagnosis of coronary artery disease (CAD) and
prognosis in patients with presumed or known CAD. If the pretest likelihood of CAD is extremely
high (e.g., a 64-year-old man with multiple cardiac risk factors and classic exertional anginal
symptoms has a pretest probability of CAD of at least 94%), there is little diagnostic value in
stress testing, because even a negative stress test would not significantly change the true
probability that the patient has CAD. For example, in patients with a pretest probability of
having CAD of 90%, a negative exercise stress test lowers the post-test probability of CAD
to only 83%.
Many experts and the American College of Cardiology/American Heart Association (ACC/AHA)
guidelines on chronic stable angina advocate in many cases obtaining a stress test for
prognostic reasonsif the stress test reveals low-risk findings, then the patient can be
managed medically, whereas if the stress test reveals high-risk findings, the patient is referred
for cardiac catheterization. Although this latter strategy is often used, it is important to note that
percutaneous coronary intervention has never been shown to reduce the risk of myocardial
infarction (MI) or death in patients with chronic stable angina. Referral for cardiac
catheterization is appropriate if the patients symptoms cannot be adequately controlled with
antianginal medications, the patient develops unstable symptoms, or the patient has a
depressed ejection fraction (less than 40%).
Stress testing performed for diagnostic purposes is usually performed with the patient off
antianginal therapy, whereas stress testing performed for prognostic purposes may sometimes
be performed with the patient on antianginal agents.
11. What other medications, besides antianginal medications, should patients with
chronic stable angina be prescribed?
& Sublingual nitroglycerin, as described earlier
& Aspirin (75325 mg qD)
& Statin therapy to lower low-density lipoprotein (LDL) cholesterol levels to less than 70 to
100 mg/dl
& Angiotensin-converting enzyme (ACE) inhibitor if diabetic, hypertension, chronic kidney
disease, and left ventricular ejection fraction is less than 40%, unless contraindicated
& Clopidogrel after an episode of acute coronary syndrome and after bare-metal stent
implantation, usually for 1 year, and after drug-eluting stent implantation for at least 1 year.
Other newer antiplatelet agents that block the P2Y12 platelet receptor may be used instead

106 CHAPTER 14 CHRONIC STABLE ANGINA

&

of clopidogrel at the physicians discretion. The CHARISMA study, which assessed

long-term clopidogrel use (in addition to aspirin) in patients with atherosclerosis or with
high-risk features, demonstrated no overall benefit of this strategy, although it did show
a trend toward benefit in those with preexisting atherosclerosis. However, this latter
finding in this subgroup analysis was not statistically significant, and the general approach
to indefinitely treating all patients with atherosclerosis with long-term dual antiplatelet
treatment has not been embraced by most of the medical community.
Annual influenza vaccination

12. Is chelation therapy of any benefit in patients with coronary artery disease?
No.

BIBLIOGRAPHY, SUGGESTED READINGS, AND WEBSITES

1. Alaeddini J: Angina Pectoris: http://www.emedicine.com
2. Warnica JW: Angina Pectoris: http://www.merck.com/mmpe

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3. 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients with
Chronic Stable Angina: http://www.my.americanheart.org
4. ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina: http://www.my.
americanheart.org
5. Kannam JP, Aroesty JM, Gersh JB: Overview of the Management of Stable Angina Pectoris: http://www.
utdol.com
6. Abrams J: Chronic stable angina, N Engl J Med 352;2524 2533, 2005.

7. Bhatt DL, Fox KA, Hacke W, et al: Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events, N Engl J Med 354:1706 1717, 2006.
8. Chaitman BR, Pepine CJ, Parker JO, et al: Effects of ranolazine with atenolol, amlodipine, or diltiazem on
exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial,
JAMA 21:291:309 316, 2004.
9. Fox K, Garcia MAA, Ardissino D, et al: Guidelines on the management of stable angina pectoris, Eur Heart J
27:1341 1381, 2006.