1. cme.medscape.com
CME/CE Information
CME/CE Released: 05/07/2009; Valid for credit through 05/07/2010
This activity has expired.
The accredited provider can no longer issue certificates for this activity. Medscape cannot attest to
the timeliness of expired CME activities.
Target Audience
This activity is intended for cardiologists, internists, family medicine and primary care physicians, and
other healthcare professionals who manage patients with chronic stable angina.
Goal
The goal of this activity is to provide guideline-based recommendations for the diagnosis and
treatment of patients presenting with symptoms suggestive of chronic stable angina.
Learning Objectives
Upon completion of this activity, participants will be able to:
• Describe the pathophysiology of chronic stable angina
• Tailor diagnostic and treatment decisions in patients with an increased likelihood of coronary
artery disease
• Select appropriate diagnostic testing according to patient presentation
• Identify treatment options for chronic stable angina, including the role of nontraditional
agents and percutaneous coronary intervention
Credits Available
Physicians - maximum of 1.50 AMA PRA Category 1 Credit(s)™
Pharmacists - 1.50 application-based ACPE (0.150 CEUs)
All other healthcare professionals completing continuing education credit for this activity will be
issued a certificate of participation.
Physicians should only claim credit commensurate with the extent of their participation in the activity.
Accreditation Statements
For Physicians
MedscapeCME is accredited by the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians.

2. MedscapeCME designates this educational activity for a maximum of 1.5 AMA PRA Category 1
Credit(s)™ . Physicians should only claim credit commensurate with the extent of their participation
in the activity.
Contact This Provider
For Pharmacists
Medscape, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of
continuing pharmacy education.
Medscape designates this continuing education activity for 1.5 contact hour(s) (0.15 CEUs)
(Universal Program Number 461-000-09-064-H01-P).
Contact this provider
For questions regarding the content of this activity, contact the accredited provider for this CME/CE
activity noted above. For technical assistance, contact CME@medscape.net
Instructions for Participation and Credit
There are no fees for participating in or receiving credit for this online educational activity. For
information on applicability and acceptance of continuing education credit for this activity, please
consult your professional licensing board.
This activity is designed to be completed within the time designated on the title page; physicians
should claim only those credits that reflect the time actually spent in the activity. To successfully earn
credit, participants must complete the activity online during the valid credit period that is noted on the
title page.
Follow these steps to earn CME/CE credit*:
1. Read the target audience, learning objectives, and author disclosures.
2. Study the educational content online or printed out.
3. Online, choose the best answer to each test question. To receive a certificate, you must
receive a passing score as designated at the top of the test. Medscape encourages you to
complete the Activity Evaluation to provide feedback for future programming.
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate
but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 5 years; at any
point within this time period you can print out the tally as well as the certificates by accessing "Edit
Your Profile" at the top of your Medscape homepage.
*The credit that you receive is based on your user profile.
Hardware/Software Requirements
Medscape requires version 4.x browsers or higher from Microsoft or Netscape. Certain educational
activities may require additional software to view multimedia, presentation or printable versions of
their content. These activities will be marked as such and will provide links to the required software.
That software may be: Macromedia Flash, Apple Quicktime, Adobe Acrobat, Microsoft Powerpoint,
Windows Media Player, and Real Networks Real One Player.

3. Case Presentation
The following test-and-teach case is an educational activity modeled on the interactive grand rounds
approach. The questions within the activity are designed to test your current knowledge. After each
question, you will be able to see whether you answered correctly and will then read evidence-based
information that supports the most appropriate answer choice. Please note that these questions are
designed to challenge you; you will not be penalized for answering the questions incorrectly. At the
end of the case, there will be a short post-test assessment based on material covered in the activity.
Patient History
SW presents to her primary care physician with complaints of
episodes of chest discomfort. She is a 62-year-old divorced mother
of two who has been suffering from increasing chest discomfort for
the past 1-2 years. At first she only noticed the discomfort when
she experienced extreme exertion, such as running for the bus, and
these symptoms always promptly resolved when she stopped or
slowed down. She attributed this to no more than "getting old" and
"being out of shape." About 6-9 months ago, she noted that the
chest pain episodes had become more frequent, occurring perhaps
once or twice per week and precipitated by stress, either physical
(walking up and down stairs at home with the laundry) or mental
(especially after a day's work at her job in a government office), but again always resolved with rest.
When the chest discomfort episodes began to occur more than once per week, she was persuaded
to visit her primary care physician.
Medical History
SW is overweight (5'5" height; 174 lb) and smoked cigarettes 1 pack/day for 15 years, although she
managed to taper off and completely stopped about 5 years ago. She drinks a "very occasional"
glass of wine. She admits to having a "poor diet" consisting of high-salt, high-fat foods, with few fresh
vegetables or fruits, but reports that she takes multivitamins to compensate for her poor diet.

4. She has a history of hypertension (blood pressure, 160/92 mm Hg), which was diagnosed in her late
40s, and she has been relatively adherent to a prescription of enalapril 10 mg and "a diuretic" for the
last 10+ years.
Dyslipidemia (total cholesterol, 215 mg/dL; LDL, 138 mg/dL; HDL, 35 mg/dL) was diagnosed during a
clinic visit 2 years ago; she takes lovastatin 10 mg daily "when she remembers."
The patient has never been seen by a cardiologist or had an echocardiogram.
Family History
SW's father had a fatal myocardial infarction (MI) at age 64, and her mother died at age 68 of lung
disease, which motivated the patient to stop smoking. She has a younger sister, age 58, who is also
overweight and taking medications for hypertension and abnormal blood cholesterol.
Which of the following statements is the most accurate as it relates to chronic stable
angina?
Episodes typically last longer than 20 minutes
It can be caused by acute pericarditis
It only occurs in patients with clinical atherosclerosis
It occurs when the myocardial oxygen demand exceeds the oxygen supply
Burden of Chronic Stable Angina
Hardly a day goes by in a busy clinician's office when he or she is not confronted with a patient
complaining of chest discomfort. Was it something the patient ate, or is it a life-threatening cardiac
emergency -- or is it something in-between? Angina recognition and management are age-old and
increasingly prevalent obstacles for clinicians. Because of the spectrum of medical conditions that
nonspecialists are called on to treat, a case study that reviews the basics of how to diagnose and
manage a presentation of "chest pain" is warranted.
Angina pectoris is a clinical syndrome that occurs when the myocardial oxygen demand exceeds the
oxygen supply. It usually occurs in patients with a buildup (= 70% stenotic occlusion) of
atherosclerotic plaque in 1 or more coronary arteries.[1] However, angina can also occur in persons
with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension; it can also
be present in patients with normal coronary arteries and myocardial ischemia related to vasospasm
or endothelial dysfunction, resulting in impaired coronary flow reserve -- a disorder that is believed to
involve the smaller nutrient arterioles of the subendocardium.[2]

5. Ischemic heart disease (IHD) is the leading cause of death worldwide and can vary substantially in its
clinical presentation.[3] The clinical spectrum of IHD ranges from complete blockage of at least 1
coronary artery, which causes an abrupt interruption of blood flow to the heart muscle resulting in an
acute MI, to various lesser degrees of blockage or narrowings, which typically represent less
emergent presentations.[2] An example of the latter is chronic stable angina, which manifests as
discomfort in the chest, neck, arms, and jaw that generally lasts for 10-15 minutes. It is precipitated
typically by physical activity or emotional stress and is relieved by rest or nitroglycerin.
With an estimated 16 million Americans affected,[2] chronic stable angina is the most common
manifestation of IHD, and its prevalence is greater in women than in men.[4] Anginal symptoms
significantly impair quality of life and functional status, making routine activities of daily living
burdensome and painful.[2,5] Of importance, the burden of the condition not only stems from its
morbidity, but more so because of its increased risk for death.[6,7] The economic toll of treatment is
also worth mentioning with aggregate direct and indirect costs approximating $165 billion each year.[8]
Chronic stable angina has historically been managed with pharmacologic therapies aimed at
reducing vasoconstrictive actions that occur as part of the cellular cascade of events associated with
ischemia: vasodilation, reduced blood pressure, and reduced heart rate.[2] However, the
demonstrated results from traditional therapies, either alone or in conjunction with revascularization,
have shown that many patients still do not achieve the American College of Cardiology/American
Heart Association (ACC/AHA) treatment goal of freedom from exertional angina.[2,9,10] In addition,
registries and healthcare initiatives document significant underutilization of appropriate therapies.[9,11,12]
Given its current status and because of 2 recent developments -- a major trial establishing the best
evidence-based approach to treating stable IHD and the first new pharmaceutical agent approved for
treating stable angina in over 20 years -- the goal of this program is to describe the diagnosis and
management of a patient presenting with symptoms secondary to chronic IHD, ie, stable angina.
Case Narrative
SW's physician asks the nurse to run a standard electrocardiogram (ECG), and he then asks her
several questions about the exact nature and quality of her chest discomfort, exactly where it is,
when it occurs, and whether she has experienced any associated symptoms.
According to the ACC/AHA 2002 guidelines for the management of chronic stable angina,
which of the following is considered the most important step in the evaluation of a patient
with chest pain?
Assessment of risk factors for coronary artery disease (CAD)
Determination of likelihood of CAD
Symptom severity
Symptom location

6. Predicting the Likelihood of CAD and Ischemic Risk
According to the ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic
Stable Angina, the most important first step in the evaluation of a patient who presents with chest
pain is the clinical history.[2]
When properly conducted, the clinical history allows the clinician to estimate the likelihood of
clinically significant CAD with a high degree of accuracy.[2] The significance of determining the
likelihood of CAD cannot be overstated. As noted in the guidelines, an accurate estimate of the
likelihood of CAD "is necessary for interpretation of further test results and good clinical decision
making about therapy."
The first step, a detailed description of the symptom complex, enables the clinician to characterize
between cardiac vs noncardiac etiologies.[13] Five components are typically considered:
• Symptom characterization;
• Site and distribution;
• Provocation;
• Duration; and
• Factors that relieve the discomfort.
As described above, classic (typical) angina is usually characterized by a feeling of discomfort
(pressure, squeezing, tightness, heaviness, etc) in the chest, or discomfort in the jaw, shoulder, back,
or arm, which usually lasts up to 10 minutes.[2] It is typically aggravated by exertion or emotional
stress, and confirmed for a clinician when it is relieved rapidly by rest or by sublingual nitroglycerin.[2]
The severity of symptoms does not correlate with the severity of CAD,[2] but should be assessed to
facilitate diagnosis and treatment decisions (Table 1).
Table 1. Classification of Angina Severity According to the Canadian Cardiovascular Society
Class Level of Symptoms
Class I Ordinary activity does not cause angina
(Angina with strenuous, rapid, or prolonged exertion only)
Class II Slight limitation of ordinary activity
(Angina on walking or climbing stairs rapidly, walking uphill, or exertion after meals, in cold
weather, when under emotional stress, or only during the first few hours after awakening)
Class Marked limitation of ordinary physical activity
III (Angina on walking 1 or 2 blocks on the level or 1 flight of stairs at a normal pace under
normal conditions)
Class Inability to carry out any physical activity without discomfort or angina at rest
IV
Anginal equivalents, such as exertional dyspnea, sweating, excessive fatigue, and fainting, are
common in women and in the elderly.[14] Women frequently present with atypical complaints; women

7. may report variable pain thresholds, inframammary pain, palpitations, or sharp stabbing pain.[14] Such
atypical presentations have unfortunately led to frequent underdiagnoses and undertreatment in this
vulnerable population.[15-17]
Symptom history can be used to clinically classify the pain as typical angina, atypical angina, or
noncardiac chest pain (Table 2).[2,13,18] Of note, the probabilities for noncardiac chest pain and atypical
angina are significantly more likely in primary care practice.[13] Patients with noncardiac chest pain are
generally at lower risk for IHD.[2]
Table 2. Clinical Classification of Chest Pain
Type Characteristics
Typical angina (1) Substernal chest discomfort with a characteristic quality and duration that are (2)
(definite) provoked by exertion or emotional stress, and (3) relieved by rest or nitroglycerin
Atypical Meets 2 of the above characteristics
(probable)
Noncardiac chest Meets 1 or none of the typical anginal characteristics
pain
When used in combination with age and sex, this simple approach to categorize pain type serves for
secondary stratification to determine the likelihood that symptoms are secondary to CAD (Table 3).
[2,18]
This model, however, was established on university-based studies, and caution should be
exercised when applying it in a primary care setting for patients who present for the first time with
chest pain complaints.[2]
Table 3. Pretest Likelihood of Coronary Artery Disease in Symptomatic Patients, According to
Age and Sex
Age (yrs) Nonanginal Chest Pain Atypical Angina Typical Angina
Men Women Men Women Men Women
%
30-39 4 2 34 12 76 26
40-49 13 3 51 22 87 55
50-59 20 7 65 31 93 73
60-69 27 14 72 51 94 86
Each value represents the percentage of patients with significant coronary artery disease on
catheterization.
In addition to symptom history, estimating the likelihood of CAD should also include assessment of
traditional coronary risk factors.[2,13] However, risk factors should not be the primary contributor to
determining the likelihood that symptoms are secondary to CAD. The guidelines recommend that
differential diagnoses be considered in patients with risk factors for CAD but who otherwise have a
low probability of a history of angina (Table 4).[2]

8. Table 4. Alternative Diagnoses to Angina for Patients With Chest Pain
Nonischemic
Cardiovascular Pulmonary Gastrointestinal Chest Wall Psychiatric
Aortic dissection Pulmonary Esophageal Costochondritis Anxiety disorders
Pericarditis embolus Esophagitis Fibrositis Hyperventilation
Pneumothorax Spasm Rib fracture Panic disorder
Pneumonia Reflux Sternoclavicular Primary anxiety
Pleuritis Biliary arthritis Affective disorders
Colic Herpes zoster (eg, depression)
Cholecystitis (before the rash) Somatoform disorders
Choledocholithiasis Thought disorders
Cholangitis (eg, fixed delusions)
Peptic ulcer
Pancreatitis
The ACC/AHA guidelines stipulate that a resting ECG should also be performed in all patients with
symptoms suggestive of angina.[2] However, the ECG will be normal or not diagnostic in
approximately 50% of patients with chronic stable angina.[2] A normal rest ECG should not exclude
severe CAD.[2,18]
Case Narrative (Continued)
Table 5 shows SW's lab results.
Table 5. Laboratory Values
Laboratory Values
LDL-C (mg/dL) 110
HDL-C (mg/dL) 38
Total-C (mg/dL) 220
TG (mg/dL) 180
Creatinine 1.1
Fasting glucose (mg/dL) 103
A1c (%) 5.8
Other observations:
No evidence of heart failure in physical exam
ECG: normal
On the basis of the patient's presenting complaints, SW's physician categorizes her symptoms as
typical angina. Coupled with her age and sex, she is believed to be at intermediate risk for CAD. The
patient is stable, not currently symptomatic, and is able to exercise. SW's physician now has to
assess how her chest pain translates into a level of CAD risk for a future coronary event and the
most effective testing to help determine that risk.

9. According to the ACC/AHA guidelines, which of the following should be the initial testing
modality for this patient with an intermediate probability of CAD?
Exercise ECG stress test (without imaging)
Exercise stress test with imaging
Myocardial perfusion imaging (MPI) with thallium
Dobutamine echocardiography
Coronary angiography
Determining Ischemic Risk
Once the clinician has determined that the patient's chest pain is likely due to ischemia, the next step
is to obtain a definitive diagnosis of CAD. The ACC/AHA guidelines underline the importance of
matching the intensity of evaluation method against a patient's estimated probability of CAD.[2] (For
patients with chest discomfort suggestive of CAD but a low probability of events, the decision to
pursue further testing should be based on a shared discussion between the patient and the clinician.)
Patients who are estimated to have an intermediate or high likelihood of CAD (> 10%-20%
probability; Table 4) should undergo further risk stratification testing with noninvasive and/or invasive
strategies, as indicated. Noninvasive testing can include exercise ECG stress testing, MPI with
sestamibi or thallium, and stress echocardiography. Invasive evaluation includes coronary
angiography.
Generally, all patients with an intermediate-to-high probability of CAD should undergo stress testing,
with exercise as the preferred form of stress. (Of note, the inability to exercise is in itself a negative
prognostic factor.[13]) The choice of test will depend on several variables: For example, can the patient
exercise on a treadmill or bicycle to a level high enough for exertion? Is the baseline ECG normal or
abnormal? Is the patient taking digoxin? Has the patient previously undergone revascularization?
These considerations will dictate whether a standard exercise treadmill stress test, MPI, or possibly
coronary angiography should be performed (Table 6).[2,13]
Table 6. Recommendations for Initial Noninvasive Test for Risk Stratification
Test Recommended Not Recommended
Exercise ECG testing (using Symptomatic patients with Baseline ECG abnormalities (Wolff-
the Bruce protocol and Duke intermediate-to-high probability of Parkinson-White syndrome,
treadmill score) CAD who are able to exercise and electronically paced ventricular
not taking digoxin (LOE: B) rhythm, > 1 mm ST depression at
rest, LVH, or complete LBBB) (LOE:
After significant change in anginal B)
pattern (LOE: C)
Established diagnosis of CAD (prior
MI, angiography) (LOE: B)
Cardiac stress imaging (able Patients with intermediate pretest Patients with LBBB or cardiac
to exercise) -- exercise MPI probability of CAD with abnormal pacing device (LOE: B)
or exercise results on resting ECG or are

10. echocardiography using digoxin (LOE: B)
Cardiac stress imaging Patients with an intermediate Dobutamine echocardiography not
(unable to exercise) -- pretest probability of CAD (LOE: recommended in patients with LBBB
adenosine or dipyridamole B) or in patients with prior or cardiac pacing device (LOE: B)
MPI or dobutamine revascularization (LOE: B), but do
echocardiography not have LBBB or a cardiac
pacing device
Cardiac stress imaging -- Patients with LBBB or with cardiac
adenosine or dipyridamole pacing device (regardless of
MPI ability to exercise) (LOE: B)
CAD = coronary artery disease; ECG = electrocardiographic; LBBB = left bundle branch block; LOE
= level of evidence; LVH = left ventricular hypertrophy; MPI = myocardial perfusion imaging
ECG exercise stress testing is the most commonly employed test for risk stratification in stable IHD.
When performed in patients with an intermediate pretest probability of CAD, ECG exercise testing
has the largest effect on post-test probability and, in turn, on clinical decision making (Class I, level of
evidence [LOE]: B).[2] Although less useful for a diagnosis in patients with a high pretest probability,
the test results can be used to determine a patient's risk and prognosis.[18] Interpretation of the
exercise test should include symptomatic response, exercise capacity (duration and intensity),
hemodynamic response, and changes in ECG during or after testing. Positive exercise stress testing
is most commonly defined as ST-segment depression (= 1 mm of horizontal or downsloping) or ST
elevation (= 60-80 msec after the end of the QRS complex).[2,18]
Coronary angiography is typically recommended for patients in whom there is a strong suspicion that
there is significant (or extensive) CAD and in whom noninvasive testing is contraindicated or unlikely
to have reliable results.[2] The decision to move forward with coronary angiography can also be
guided by the performance of noninvasive tests. For example, a patient with a high-risk treadmill
stress test is likely indicated for coronary angiography. Similarly, coronary angiography may be
appropriate in a patient with abnormal, but not definitely diagnostic noninvasive test results who
would benefit from a more certain diagnosis (Class IIa, LOE: C).[2]
Diagnostic Modalities for CAD in Women
The utility of ECG stress testing in women is a topic of debate. The rate of false positives has been
shown to be higher in women than men, and may be attributed to differences in criteria for defining
coronary disease, prevalence of multivessel disease and prior MI, type and intensity of exercise,
prevalence of nonobstructive CAD, and hormonal differences.[2,19] Exercise imaging modalities are
known to have a greater diagnostic accuracy than standard exercise stress tests in both men and
women, leading some to suggest that imaging exercise testing be the preferred test to diagnose CAD
in women.[20] However, the ACC/AHA guidelines note that there are insufficient data to support such a
recommendation.[2] In addition, diagnostic angiography is equally effective in women and men, yet
studies have documented lower rates of referral for angiography in women despite positive stress
tests.[2]

11. Ultimately, the type of test to employ should be based on a comprehensive assessment of likelihood
of CAD while considering the specificity and sensitivity of the testing modality, as well as patient
preference and comorbidities.[2]
Determining Ischemic Risk Based on Diagnostic Studies
A patient's ischemic risk is usually related to 4 variables: (1) left ventricular (LV) function, (2)
anatomic extent and severity of atherosclerosis, (3) evidence of a recent coronary plaque rupture,
and (4) patient's general health and noncoronary comorbidity.[2]
For patients with stable angina, the presence of diabetes, hypertension, dyslipidemia (increased
LDL-C and/or decreased HDL-C), current smoking, metabolic syndrome, and peripheral arterial
disease have been shown to be predictive of increased risk.[2] Such factors suggest a greater
progression of atherosclerosis with the potential for repeated coronary plaque events. Increasing age
is an important factor to consider, as are prior MI, symptoms and signs of heart failure, the pattern of
occurrence (recent onset or progressive), and severity of angina -- particularly if unresponsive to
therapy.
Whereas noninvasive testing modalities can be used for risk stratification, the guidelines note that
risk stratification with coronary angiography may be limited by the fact that the testing cannot
determine which plaques are likely to lead to subsequent rupture.[2] The ACC/AHA guidelines
recommend the use of coronary angiography for risk stratification in patients with disabling chronic
stable angina despite chronic therapy (Class I, LOE: B), in patients with high-risk criteria on
noninvasive testing (Class I, LOE: B; Table 7), and in those with signs and symptoms of congestive
heart failure (Class I, LOE: C) or clinical characteristics that indicate a high likelihood of severe CAD
(Class I, LOE: C).
Table 7. Noninvasive Risk Stratification[2]
High-Risk (> 3% annual mortality rate)
• Severe resting left ventricular dysfunction (LVEF < 35%)
• High-risk treadmill score (score = -11)
• Severe exercise left ventricular dysfunction (exercise LVEF < 35%)
• Stress-induced large perfusion defect (particularly if anterior)
• Stress-induced multiple perfusion defects of moderate size
• Large, fixed perfusion defect with LV dilation or increased lung uptake (thallium-201)
• Stress-induced moderate perfusion defect with LV dilation or increased lung uptake (thallium-201)
• Echocardiographic wall motion abnormality (involving > 2 segments) developing at low dose of
dobutamine (= 10 mg/kg/min) or at a low heart rate (< 120 beats/min)
• Stress echocardiographic evidence of extensive ischemia
Intermediate-Risk (1%-3% annual mortality rate)
• Mild/moderate resting left ventricular dysfunction (LVEF = 35%-49%)
• Intermediate-risk treadmill score (-11 < score < 5)
• Stress-induced moderate perfusion defect without LV dilation or increased lung intake (thallium-201)
• Limited stress echocardiographic ischemia with a wall motion abnormality only at higher doses of
dobutamine involving = 2 segments
Low-Risk ( < 1% annual mortality rate)

12. • Low-risk treadmill score (score = 5)
• Normal or small myocardial perfusion defect at rest or with stress*
• Normal stress echocardiographic wall motion or no change of limited resting wall motion
abnormalities during stress*
LV = left ventricular; LVEF = left ventricular ejection fraction
*Although the published data are limited, patients with these findings will probably not be at low risk
in the presence of either a high-risk treadmill score or severe resting LV dysfunction (LVEF < 35%).
Case Narrative
SW's physician concludes that her angina is stable, and she is not really at imminent risk for a
coronary event. He, therefore, decides that she does not need to be admitted or referred for a
coronary angiogram. He discusses this conclusion with her, per guidelines, but advises additional
noninvasive testing in order to get a better idea of the severity of her chest pain (ie, when, how
quickly, and how acutely), and whether there is objective evidence of inducible myocardial ischemia.
She agrees, and he sends her for exercise ECG testing, using the Bruce protocol and Duke treadmill
score as a means of quantifying her response to graded exercise.
SW's stress testing results come back and confirm a diagnosis of CAD:
Resting heart rate: 80 bpm
Exercise heart rate: 142 bpm
Time on treadmill: 9 min 30 sec
Blood pressure: 185/92 mm Hg
At peak exercise, she exhibits 1.5 mm horizontal ST-segment depression in leads II, III, and aVF
consistent with inferior wall subendocardial ischemia at a fairly high external workload.
Which of the following is not a primary goal of therapy for patients with chronic stable CAD?
Increase blood oxygen supply
Increase quantity of life by disease modification and prevention of MI and death
Improve quality of life by reducing ischemia and relieving anginal symptoms
Treatment of Chronic Stable Angina
There are 2 primary objectives in managing the patient with stable IHD. The first is to increase the
quantity of life by reducing the risk for ischemic events with lifestyle modification and

13. vasculoprotective therapies. The second goal is to improve the quality of life by reducing the burden
of symptoms through the use of anti-anginal and anti-ischemic agents.
Vasculoprotective Therapies
Instituting a treatment protocol aimed at directly treating the pathophysiology of stable IHD is a
critical step in the management of the patient with stable IHD. Vasculoprotective therapy includes
lifestyle changes (eg, cigarette smoking cessation, appropriate diet, weight reduction/maintenance,
regular exercise, etc) and pharmacologic therapy with aspirin, angiotensin-converting enzyme (ACE)
inhibitors, and statins, which -- in the aggregate -- reduce progression of atherosclerosis, stabilize
atherosclerotic plaque, and decrease the risk for plaque rupture and superimposed total or subtotal
thrombotic occlusions in patients with chronic stable angina.[21] The ACC/AHA guideline
recommendations for cardiovascular risk reduction in patients with stable CAD are shown in Table 8.
[21]
Table 8. ACC/AHA Guideline Recommendations for Cardiovascular Risk Reduction in Patients
With Stable Coronary Artery Disease
Risk Factor Recommendations
Smoking Complete cessation; no exposure to environmental tobacco smoke
Blood pressure < 140/90 mm Hg or < 130/80 mm Hg if patient has diabetes or chronic kidney
control disease
Lipid - LDL-C < 100 mg/dL; reduction of LDL-C < 70 mg/dL or high-dose statin therapy is
management reasonable/desirable in high-risk patients
- If baseline LDL-C = 100 mg/dL, LDL-lowering drug therapy should be initiated in
addition to therapeutic lifestyle changes
- If on-treatment LDL-C is = 100 mg/dL, LDL-lowering drug therapy should be
intensified (may require combination therapy)
- If triglycerides are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL (therapeutic
options for reducing non-HDL-C include niacin or fibrate therapy)
- If triglycerides are = 500 mg/dL, therapeutic options to lower levels to reduce the
risk for pancreatitis are fibrate or niacin; these should be initiated before LDL-C-
lowering therapy. The goal is to achieve non-HDL-C < 130 mg/dL, if possible
Physical activity - 30-60 min, 7 days/wk (minimum, 5 days/wk)
- Moderate-intensity aerobic activity should be encouraged on all days of the week,
supplemented by an increase in daily activities
Weight Body mass index: 18.5-24.9 kg/m2
management Waist circumference:
- Men: < 40 in
- Women: < 35 in
Diabetes HbA1c < 7%
management
Antiplatelet Aspirin should be started at 75-162 mg/day and continued indefinitely in all patients
agents unless contraindicated
ACE inhibitors ACE inhibitors should be started and continued indefinitely in all patients with left
ventricular ejection fraction ≤ 40% and in those with hypertension, diabetes, or
chronic kidney disease, unless contraindicated
ARBs Use in patients who are intolerant of ACE inhibitors and have heart failure or have
had a myocardial infarction with left ventricular ejection fraction ≤ 40%

14. Aldosterone Use in patients post MI, without significant renal dysfunction or hyperkalemia, who
blockade are already receiving therapeutic doses of an ACE inhibitor and beta-blocker, have a
left ventricular ejection fraction ≤ 40%, and have either diabetes or heart failure
Influenza An annual influenza vaccination is recommended for patients with cardiovascular
vaccination disease
ACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; HbA1c = glycated
hemoglobin (A1c); MI = myocardial infarction
Traditional Anti-anginal and Anti-ischemic Therapies in Stable Angina
In addition to the importance of reducing ischemic risk with lifestyle modification and appropriate
therapies, the second major objective in the management of stable IHD is to reduce the burden of
angina (symptom intensity and frequency). Traditional therapies include nitrates, beta-blockers,
calcium channel blockers (CCBs), and combinations thereof.
Nitrates
Nitroglycerin was the first medication to be used for angina more than a century ago. Nitrates reduce
myocardial oxygen demand by increasing venous capacitance, thus reducing LV volume (preload).
Nitrates dilate coronary arteries and favorably enhance subendocardial perfusion.[22] Sublingual
nitroglycerin has been used to treat the acute onset of anginal symptoms as well as prophylactically
to minimize or prevent anginal symptoms when these agents are administered in advance of the
known offending activity.
Isosorbide dinitrate and its active metabolite, isosorbide mononitrate, are used as an oral preparation
for the treatment of angina.[23] Extended-release preparations offer the convenience of once-daily
regimens. None of the nitrate regimens provide 24-hour anti-anginal prophylaxis due to the
development of nitrate tolerance.[24] Prevention of tolerance requires an intermittent dosing strategy
with a nitrate-free interval of 8-12 hours. Nitrates are generally well tolerated, with facial flushing and
headache being the most common side effects. Severe hypotension may occur if nitrates are used
within 24 hours of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil).[2,25]
Beta-blockers
In the setting of stable IHD, beta-blockers are recommended as initial therapy for patients with prior
MI (Class I, LOE: A) or without prior MI (Class I, LOE: B).[2] Beta-blockers reduce heart rate and
contractility and reduce myocardial oxygen demand. Reduction in heart rate increases the diastolic
filling time during which nutritive coronary flow occurs, enhancing myocardial tissue perfusion. Beta-
blockers limit increases in heart rate during exercise and are particularly effective in exercise-induced
angina.
All beta-blockers are equally effective in alleviating angina pectoris, although optimal doses may
vary. The doses of beta-blockers must be titrated to increase exercise tolerance and reduce
symptoms of angina while avoiding unwanted side effects. Prominent side effects include

15. bradycardia, bronchoconstriction, fatigue, depression, impotence, and worsening of peripheral
vascular disease. Despite concerns about their side effects, beta-blockers can be safely used in
many patients with chronic obstructive pulmonary disease or peripheral arterial disease.
Calcium Channel Blockers
A variety of CCBs have been studied in the long-term treatment of chronic stable angina. CCBs block
the entry of calcium into the myocardial and vascular smooth muscle cells and promote both
coronary and peripheral vasodilation.
Calcium antagonists include 2 general subclasses of agents: dihydropyridines and
nondihydropyridines. Dihydropyridines (eg, nifedipine, amlodipine, and nicardipine) have a
proportionately greater effect on vascular smooth muscle and are particularly effective in reducing
systemic arterial blood pressure. Results of a prior meta-analysis indicated that the use of these
drugs for hypertension does not increase morbidity and mortality.[26] Dihydropyridines reduce the
frequency of anginal episodes, improve exercise duration, and reduce the need for nitroglycerin.
Nondihydropyridines (verapamil and diltiazem) affect conduction through the AV node and have a
negative chronotropic action. Verapamil, diltiazem, and short-acting nifedipine are effective in
vasospastic (Prinzmetal's) angina.[27] However, short-acting nifedipine is associated with an increased
incidence of cardiovascular events and is not recommended for patients with unstable angina or
acute coronary syndrome.[28] On the other hand, verapamil, diltiazem, and long-acting dihyropyridines
(eg, amlodipine, extended-release nifedipine) have been shown to be safe and effective in treating
stable angina.
Combination Therapy
Combinations of anti-anginal drugs may be used if symptoms persist. Beta-blockers and nitrates may
be more effective than nitrates or beta-blockers alone.[29] Similarly, the combination of beta-blockers
with dihydropyridine CCBs has been shown to be more effective for improving exercise duration and
is better tolerated than either class of drug used alone.[30] No data exist, however, on the efficacy of
using more than 2 drugs. Certain drug combinations should be avoided because of the potential for
adverse effects, including hypotension or bradycardia. Newer agents may offer additional
pharmacologic benefit in combination with traditional anti-anginal medications.
Case Narrative
At this point, SW's noninvasive stress testing confirms a degree of ischemia, but not of sufficient
degree to mandate further invasive testing to identify the location and degree of coronary obstruction.
Her ischemia seems stable, and therefore it is appropriate to prescribe a full course of optimal
medical treatment, per treatment guidelines.
Looking over her chart, the physician notes that she admits to a poor diet, plus quasi-adherence to a
regimen of 10 mg enalapril plus a diuretic as well as a low-dose, low-potency statin. The physician
strongly advises SW to improve her diet, and asks his nursing staff to follow up with further advice

16. and some information handouts. Because she doesn't exhibit signs of heart failure, and he believes
that it may be affecting her overall adherence, he cancels the diuretic. He now switches the ACE
inhibitor therapy to ramipril 10 mg/day and adds amlodipine 5 mg/day plus aspirin 162 mg/day. He
tells SW that this therapy should help her reach a target blood pressure of 120/80 mm Hg and a
target total/LDL cholesterol of 175/100 mg/dL, and he explains the importance of remaining adherent
to her regimen to protect her against future events ("heart attack") as she grows older.
Which of the following statements about nontraditional (ie, ranolazine, ivabradine, and
nicorandil, trimetazidine, and fasudil) anti-anginal agents is most accurate?
Mechanisms of action complement the anti-ischemic properties of traditional agents
They reduce the risk for mortality compared with traditional agents
They are more effective as single- vs combination-drug therapy
They are similarly effective in patients with stable and unstable angina
Novel Anti-anginal Therapies
Novel Anti-anginal Therapies
Despite intensive escalation of anti-anginal therapy, including combinations of beta-blockers, long-
acting nitrates, and CCBs, a fair number of patients continue to experience persistent or refractory
angina.[9] A greater understanding of the pathophysiologic pathways associated with chronic stable
angina has led to the development of novel agents that target those specific pathways. Of note, the
mechanisms of action of these newer drugs are complementary to those of the traditional anti-
anginal agents. Such agents include ranolazine, ivabradine, and nicorandil, trimetazidine, and
fasudil.
Ranolazine
Ranolazine is a late sodium (Na+) current inhibitor that has anti-anginal and anti-ischemic effects
without eliciting any change in the heart rate, blood pressure, or rate-pressure (double) product.[31]
Myocardial ischemia causes an exaggerated, enhanced late inward Na+ current, which leads to
intracellular sodium overload, which, in turn, leads to intracellular calcium overload, resulting in
increased diastolic LV stiffness as well as electrical instability. By inhibiting the abnormal increase in
the late inward sodium current, the agent prevents the "downstream" consequences of ischemic LV
stiffness and compression of intramyocardial blood vessels, which reduces myocardial ischemia.[31]
The results from 4 randomized trials (in over 8000 randomized patients) showed a convincing benefit
of ranolazine as either monotherapy or as add-on therapy.[32-35] The cumulative effect of these 4 trials
is a consistent clinical benefit on angina relief, reduced exercise-induced ischemia, a significant
reduction in recurrent ischemia, and a reduction in the need for additional anti-anginal medication.

17. The largest of these studies, the Metabolic Efficiency with Ranolazine for Less Ischemia in NSTE
ACS (MERLIN-TIMI 36)[35] trial, randomized 6560 patients with moderate- to high-risk NSTEMI (a
more clinically unstable population) to either ranolazine or placebo in addition to standard care and
followed them for a median of 1 year. The primary efficacy endpoint was a composite of
cardiovascular death, MI, or recurrent ischemia through the end of the study. Similar to the use of
traditional agents, such as nitrates and CCBs, use of ranolazine was not associated with a reduction
in the trial's primary composite endpoint of death, MI, or recurrent myocardial ischemia. However,
ranolazine was shown to significantly reduce the secondary endpoint of recurrent myocardial
ischemia compared with traditionally treated patients.
As a result of its multiple effects on transmembrane ion currents, ranolazine slightly prolongs the QT
interval, although this has not been shown to increase the risk for torsades de pointes.[36] Ranolazine
is approved by the US Food and Drug Administration for the treatment of stable angina alone or in
combination with other anti-anginal therapies. Dosing should be initiated at 500 mg twice daily and
increased to maximum dose of 1000 mg twice daily on the basis of clinical symptoms. Dizziness and
nausea are the most commonly reported side effects. The drug should not be used in combination
with strong inhibitors or inducers of CYP3A or in patients with clinically significant hepatic
impairment.
Ivabradine
The If current ("f" is for "funny," as the current is still poorly understood) is an inward Na+/K+ current
that activates pacemaker cells of the sinoatrial (SA) node.[37] Ivabradine is a novel, specific heart rate-
lowering agent that acts on SA-node cells by selectively inhibiting pacemaker If current in a dose-
dependent manner. It slows the diastolic depolarization slope of the SA-node cells and reduces heart
rate during rest and exercise. In patients with chronic stable angina, ivabradine monotherapy (7.5 mg
twice daily and 10 mg twice daily) has been shown to be noninferior to atenolol[38] or amlodipine[39] in
all tested exercise parameters. More recently, the ASSOCIATE trial[40] demonstrated that ivabradine
in combination with atenolol significantly improved exercise parameters after 4 months of therapy
compared with atenolol alone. The most common side effect reported with ivabradine is sinus
bradycardia; other side effects include luminous phenomena (phosphenes), which are described as a
transient enhanced visual brightness, headaches, and blurred vision.[38-41]
Nicorandil
Nicorandil activates the adenosine triphosphate (ATP)-sensitive K+ channels, which play an important
role in ischemic preconditioning and promote dilation of the coronary resistance arterioles. Its nitrate
moiety dilates epicardial coronary vessels and systemic veins. In the Impact Of Nicorandil in Angina
(IONA)[42] trial, the addition of nicorandil to standard anti-anginal therapy was associated with a
significant (17%) reduction in the primary endpoint of coronary heart disease, death, nonfatal MI, or
unplanned hospitalization for cardiac chest pain compared with placebo, suggesting that the drug
may have cardioprotective properties.
Trimetazidine

18. Trimetazidine is a metabolic modulator and partial fatty acid oxygenation inhibitor that has been
proven to be beneficial for combination therapy in patients with stable angina. Oxygen requirements
of glucose pathways are lower than the free fatty acid pathway. During ischemia, oxidized free fatty
acid levels rise, which blunt the glucose pathway. Trimetazidine inhibits beta-oxidation and shifts the
equilibrium toward increased use of glucose, thus improving oxygen utilization. In the Trimetazidine
in Angina Combination Therapy (TACT) trial, trimetazidine in combination with long-acting nitrates or
beta-blockers was shown to significantly improve exercise performance as well as reduce the
number of anginal attacks per week compared with placebo.[43]
Fasudil
Rho kinase in the myocardial cell triggers vasoconstriction through accumulation of phosphorylated
myosin. Animal models of coronary artery spasm have shown that Rho kinase inhibitors effectively
suppress vasoconstriction. Fasudil, an orally available Rho kinase inhibitor, increased the time to > 1
mm ST-segment depression and improved exercise duration.[44] Fasudil did not affect the heart rate
or blood pressure and was well tolerated.
The results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug
Evaluation (COURAGE) trial most closely support which of the following statements as it
relates to patients with stable chronic CAD?
Optimal medical therapy (OMT) should be the strategy of choice in all patients with stable
CAD
Percutaneous coronary intervention (PCI) should not play a major role in secondary
prevention in patients with stable CAD
PCI is associated with significant reductions in death and MI compared with OMT alone
Objective evidence of inducible myocardial ischemia on noninvasive testing is not
necessary before PCI
PCI for Chronic Stable Angina
In addition to medical management, the ACC/AHA guidelines recommend revascularization with
coronary artery bypass graft surgery or PCI in some patients with chronic stable angina.[2] The
decision to proceed with revascularization requires a careful balance of many factors, namely, patient
preference and physician judgment. Of note, it entails a careful balance ensuring that the patient
would have a significantly better prognosis with revascularization than with medical therapy.
Despite ACC/AHA recommendations that reserve PCI for patients who remain symptomatic despite
OMT or for those with high-risk criteria on noninvasive testing (Table 9), the practice of simply

19. referring a stable angina patient for angiography (before noninvasive testing) or for PCI (before initial
course of medical therapy) is an all too frequent occurrence for many clinicians.
Table 9. ACC/AHA Class I Recommendations for PCI in Stable Chronic Angina[2]
Class I Recommendation
Patients with 2- or 3-vessel disease with significant proximal LAD CAD, who have anatomy suitable for
catheter-based therapy and normal LV function who do not have treated diabetes (LOE: B)
Patients with 1- or 2-vessel CAD without significant proximal LAD CAD, but with a large area of viable
myocardium and high-risk criteria on noninvasive testing (LOE: B)
Patients with prior PCI with either recurrent stenosis or high-risk criteria on noninvasive testing (LOE:
C)
Patients who have not been successfully treated by medical therapy and can undergo
revascularization with acceptable risk (LOE: B)
CAD = coronary artery disease; LAD = left anterior descending; LOE = level of evidence; LV = left
ventricular; PCI = percutaneous coronary intervention
A challenge today in the United States is how to address the huge increase in the number of PCI
procedures being performed every year. In 2006, more than 1.31 million PCI procedures were
performed, roughly 3 times the number of procedures being performed 10 years earlier, and 3
important statistics stand out.[8] Roughly half of these procedures were in persons > 65 years of age
and roughly half were elective.[45] In addition, the total cost of these procedures to Medicare in 2005
was estimated to be about $20 billion. The fact that almost half of PCIs are elective raises the
question: Were they medically necessary? According to the New York State PCI Registry, 85% of the
PCI procedures in 2006 were elective, almost one third of those in patients with chronic stable
angina, and these rates are mirrored in the US national data.[46] However, according to data from a
Medicare claims database, only 44% of patients who presented with stable CAD or chronic angina in
2004 underwent a noninvasive study, such as an ECG stress test, to assess the degree of ischemia
before they were referred for an elective PCI procedure.[47] From these statistics it is evident that
many patients who presented with chronic stable angina were being referred to the cath lab and
emerging having been treated with a PCI procedure. The empirical question was whether these
patients with stable angina, when they have not been first diagnosed with objective evidence of
inducible myocardial ischemia or treated intensively with OMT, really needed, or benefited from, PCI.
COURAGE
This hypothesis was tested in the COURAGE trial,[48] which enrolled 2287 patients who had objective
evidence of myocardial ischemia and significant CAD at 50 US and Canadian centers. Between 1999
and 2004, 2287 patients who had objective evidence of myocardial ischemia and significant CAD
were randomized to undergo PCI with OMT (PCI group; n = 1149) or to receive OMT alone (OMT
group; n = 1138). The primary outcome was death from any cause and nonfatal MI during follow-up
(mean follow-up of 4.6 years).

20. All patients received the standard course of anti-anginal therapy. Patients undergoing PCI received
aspirin and clopidogrel, in accordance with accepted treatment guidelines and established practice
standards. Medical anti-ischemic therapy in both groups included long-acting metoprolol, amlodipine,
and isosorbide mononitrate, alone or in combination, along with either lisinopril or losartan as
standard secondary prevention. All patients received aggressive therapy to lower LDL-C levels with a
target level of 60-85 mg/dL. After the LDL-C target was achieved, an attempt was made to raise
HDL-C to > 40 mg/dL and to lower triglycerides to < 150 mg/dL with exercise and extended-release
niacin or fibrates, alone or in combination. In patients undergoing PCI, target lesion revascularization
was always attempted, and complete revascularization was performed as clinically appropriate.
Success after PCI as seen on angiography was defined as normal coronary artery flow and < 50%
stenosis in the luminal diameter after balloon angioplasty and < 20% after coronary stent
implantation. Clinical success was defined as angiographic success plus the absence of in-hospital
MI, emergency coronary artery bypass graft, or death. Drug-eluting stents were not approved for
clinical use until the final 6 months of the study; therefore, few patients received these intracoronary
devices.
The study found that as an initial management strategy in patients with stable IHD, the addition of
PCI to OMT did not reduce the cumulative rates of MI and death (19.0% vs 18.5%) or in all-cause
death (7.6% vs 8.3%) compared with OMT alone (Figure). Subsequent analyses demonstrated that
the addition of PCI to OMT was not cost-effective[49] and had only a small (significant) incremental
benefit in quality of life that did not extend beyond 36 months.[50]

21. Figure. Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE):
Kaplan-Meier survival curves.[48]
In Panel A, the estimated 4.6-year rate of the composite primary outcome of death from any cause
and nonfatal myocardial infarction was 19.0% in the PCI group and 18.5% in the medical-therapy
group. In Panel B, the estimated 4.6-year rate of death from any cause was 7.6% in the PCI group
and 8.3% in the medical-therapy group. In Panel C, the estimated 4.6-year rate of hospitalization for
acute coronary syndrome (ACS) was 12.4% in the PCI group and 11.8% in the medical-therapy
group. In Panel D, the estimated 4.6-year rate of acute myocardial infarction was 13.2% in the PCI
group and 12.3% in the medical-therapy group.
In addition to generating considerable discussion and debate, the COURAGE trial should also lead to
changes in the treatment of patients with stable CAD, with expected substantial healthcare savings.
PCI has an established place in treating angina but is not superior to intensive medical therapy to
prevent MI and death in symptomatic or asymptomatic patients, such as those enrolled in the
COURAGE trial. Secondary prevention has proved its worth, with lipid-modulating therapy, lifestyle
modification, and the use of aspirin, beta-blockers, and ACE inhibitors. Patients who are clinically
unstable, who have left main CAD, or in whom OMT has failed to control symptoms remain
candidates for revascularization. However, PCI should not play a major role as part of a secondary
prevention strategy.
Case Conclusion
SW has returned for her 6-month follow-up visit and reports "substantial improvement" in her
symptoms on an increased regimen of a beta-blocker, amlodipine, and ramipril. The nurse, following
standard procedure in this primary care practice, had already "casually" asked her about her
adherence to the doctor's orders. Had she modified her diet? Was she taking all her medicines?
Were there any of the medicines that she didn't like or thought caused her problems? When the
physician sees her, he questions her carefully about her symptoms and then asks her again about
her adherence to the treatment regimen. On the basis of her answers and what the nurse has told
him, he believes that SW is being a relatively "good" patient. He can see, however, that her pain has
not entirely resolved, and he expresses concern that her persistent symptoms may potentially require
revascularization for full symptom relief. Her physician discusses the potential benefit and value of
coronary revascularization, but the patient expresses a strong sentiment for a more conservative
approach.
SW was prescribed ranolazine 500 mg twice daily and, after 4 weeks of therapy, experienced a
significant improvement in her anginal symptoms. In view of her clinical response, both she and her
physician believed that her symptomatic improvement and quality of life were such that she should
continue with this management approach.
Conclusion

22. Not all patients will respond to medical therapy, as in the case above, so it is essential not to view
medical therapy and myocardial revascularization as competing or mutually exclusive therapeutic
approaches. Clinical decision making must include a careful and thoughtful application of evidence-
based data derived from clinical trials, but must also recognize and respect individual patient
preference, physician judgment and preference, and a synthesis of both subjective and objective
parameters in configuring "the best approach" for a given patient. Both myocardial revascularization
and OMT have well-defined therapeutic roles, and the challenge providers face is integrating this
scientific information in a way that promotes the best individualized treatment that meets the needs
and welfare of the patient.
This activity is supported by an independent educational grant from Gilead.
References
1. Maseri A, Crea F, Kaski JC, Davies G. Mechanisms and significance of cardiac ischemic
pain. Prog Cardiovasc Dis. 1992;35:1-18.
2. Gibbons RJ, Abrams J, Chatterjee K, et al; American College of Cardiology; American Heart
Association Task Force on Practice Guidelines (Committee on the Management of Patients
With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management 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). J Am Coll Cardiol.
2003;41:159-168.
3. Dunder K, Lind L, Lagerqvist B, Zethelius B, Vessby B, Lithell H. Cardiovascular risk factors
for stable angina pectoris versus unheralded myocardial infarction. Am Heart J.
2004;147:502-508.
4. Hemingway H, Langenberg C, Damant J, et al. Prevalence of angina in women versus men:
a systematic review and meta-analysis of international variations across 31 countries.
Circulation. 2008;117:1526-1536.
5. Pocock S, Henderson R, Seed P, et al. Quality of life, employment status, and anginal
symptoms after coronary angioplasty or bypass surgery. 3-year follow-up in the Randomized
Intervention Treatment of Angina (RITA) Trial. Circulation. 1996;94:135-142.
6. Hemingway H, McCallum A, Shipley M, Manderbacka K, Martikainen P, Keskimaki I.
Incidence and prognostic implications of stable angina pectoris among women and men.
JAMA. 2006;295:1404-1411.
7. Buckley B, Murphy AW. Do patients with angina alone have a more benign prognosis than
patients with a history of acute myocardial infarction, revascularisation or both? Findings
from a community cohort study. Heart. 2009;95:461-467.
8. Lloyd-Jones D, Adams R, Carnethon M, et al; American Heart Association Statistics
Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics -- 2009
update: a report from the American Heart Association Statistics Committee and Stroke
Statistics Subcommittee. Circulation. 2009;119:e21-e181.

23. 9. Steg P, Himberg D. Unmet medical needs and therapeutic opportunities in stable angina.
Eur Heart J. 2005;7:H7-H15.
10. Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina;
report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J.
2002;23:355-370.
11. Daly CA, Clemens F, Lopez Sendon JL, et al; on behalf of the Euro Heart Survey
Investigators. The initial management of stable angina in Europe, from the Euro Heart
Survey. A description of pharmacological management and revascularization strategies
initiated within the first month of presentation to a cardiologist in the Euro Heart Survey of
Stable Angina. Eur Heart J. 2005;26:1011-1022.
12. Mensah GA, Mokdad AH, Ford ES, Greenlund KJ, Croft JB. State of disparities in
cardiovascular health in the United States. Circulation. 2005;111:1233-1241.
13. Snow V, Barry P, Fihn SD, et al; ACC Chronic Stable Angina Panel. Evaluation of primary
care patients with chronic stable angina: guidelines from the American College of
Physicians. Ann Intern Med. 2004;141:57-64.
14. Abrams J. Chronic stable angina. N Engl J Med. 2005;352:2524-2533.
15. Blomkalns AL, Chen AY, Hochman JS, et al; CRUSADE Investigators. Gender disparities in
the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-
scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina
Patients Suppress Adverse Outcomes With Early Implementation of the American College of
Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative.
J Am Coll Cardiol. 2005;45:832-837.
16. Chou AF, Wong L, Weisman CS, et al. Gender disparities in cardiovascular disease care
among commercial and medicare managed care plans. Womens Health Issues.
2007;17:139-149.
17. Lansky AJ, Hochman JS, Ward PA, et al; American College of Cardiology Foundation;
American Heart Association. Percutaneous coronary intervention and adjunctive
pharmacotherapy in women: a statement for healthcare professionals from the American
Heart Association. Circulation. 2005;111:940-953.
18. Fox K, Garcia MA, Ardissino D, et al; Task Force on the Management of Stable Angina
Pectoris of the European Society of Cardiology; ESC Committee for Practice Guidelines
(CPG). Guidelines on the management of stable angina pectoris: executive summary: the
Task Force on the Management of Stable Angina Pectoris of the European Society of
Cardiology. Eur Heart J. 2006;27:1341-1381.
19. Shaw LJ, Merz CN, Pepine CJ, et al; for the WISE investigators. Insights from the NHLBI-
sponsored Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol.
2006;47(suppl):S4-S20.
20. Mieres HJ, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of
women with suspected coronary artery disease: Consensus statement from the Cardiac
Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and
Intervention Committee, Council on Cardiovascular Radiology and Intervention, American
Heart Association. Circulation. 2005;111:682-696.

24. 21. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the
ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a
report of the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for
the management of patients with chronic stable angina. J Am Coll Cardiol. 2007;50:2264.
22. Kaski JC, Plaza LR, Meran DO, Araujo L, Chierchia S, Maseri A. Improved coronary supply:
prevailing mechanism of action of nitrates in chronic stable angina. Am Heart J.
1985;110(pt2):238-245.
23. Abrams J. Nitroglycerin and long-acting nitrates in clinical practice. Am J Med.
1983;74:85-94.
24. Thadani U. Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris,
unstable angina, and heart failure. Cardiovasc Drugs Ther. 1997;10:735-742.
25. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of
sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol.
1999;33:273-282.
26. Alderman MH, Cohen H, Roque R, et al. Effect of long-acting and short-acting calcium
antagonists on cardiovascular outcomes in hypertensive patients. Lancet.
1997;349:594-598.
27. Chahine RA, Feldman RL, Giles TD, et al. Randomized placebo-controlled trial of
amlodipine in vasospastic angina. Amlodipine Study 160 Group. J Am Coll Cardiol.
1993;21:1365-1370.
28. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients
with coronary heart disease. Circulation. 1995;92:1326-1331.
29. Waysbort J, Meshulam N, Brunner D. Isosorbide-5-mononitrate and atenolol in the treatment
of stable exertional angina. Cardiology. 1991;79(suppl2):19-26.
30. Leon MB, Rosing DR, Bonow RO, Epstein SE. Combination therapy with calcium-channel
blockers and beta blockers for chronic stable angina pectoris. Am J Cardiol.
1985;55:69B-80B.
31. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential
cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart.
2006;92(suppl4):iv6-iv14.
32. Chaitman BR, Pepine CJ, Parker JO, et al; Combination Assessment of Ranolazine In
Stable Angina (CARISA) Investigators. 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. 2004;291:309-316.
33. Stone PH, Gratsiansky NA, Blokhin A, et al. Antianginal efficacy of ranolazine when added
to maximal treatment with a conventional therapy: the efficacy of ranolazine in chronic
angina (ERICA) trial. J Am Coll Cardiol. 2006;48:566-575.
34. Chaitman BR, Skettino SL, Parker JO, et al; the MARISA Investigators. Anti-ischemic effects
and long-term survival during ranolazine monotherapy in patients with chronic severe
angina. J Am Coll Cardiol. 2004;43:1375-1382.

25. 35. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel
electrophysiological properties, on the incidence of arrhythmias in patients with non ST-
segment elevation acute coronary syndrome: results from the Metabolic Efficiency With
Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis
in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation.
2007;116:1647-1652.
36. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine,
a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110:904-910.
37. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of
selective blockers. Pharmacol Res. 2006;53:399-406.
38. Tardif JC, Ford I, Tendera M, et al; INITIATIVE Investigators. Efficacy of ivabradine, a new
selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur
Heart J. 2005;26:2529-2536.
39. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine
compared with amlodipine in patients with stable effort angina pectoris: a 3-month
randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67:393-405.
40. Tardif JC, Ponikowski P, Kahan T; for the ASSOCIATE Study Investigators. Efficacy of the If
current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker
therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.
41. Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and
antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-
blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
42. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina:
the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002;359:1269-1275.
43. Chazov EI, Lepakchin VK, Zharova EA, et al. Trimetazidine in Angina Combination Therapy
-- the TACT study: trimetazidine versus conventional treatment in patients with stable angina
pectoris in a randomized, placebo-controlled, multicenter study. Am J Ther. 2005;12:35-42.
44. Vicari RM, Chaitman B, Keefe D, et al; Fasudil Study Group. Efficacy and safety of fasudil in
patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J Am Coll
Cardiol. 2005;46:1803-1811.
45. Kirtane AJ, Cohen DJ. When is better not good enough?: Insights from the COURAGE
economic study. Circ Cardiovasc Qual Outcomes. 2008;1:4-6.
46. Feldman DN, Gade CL, Slotwiner AJ, et al. Comparison of outcomes of percutaneous
coronary interventions in patients of three age groups (<60, 60 to 80, and >80 years) (from
the New York State Angioplasty Registry) Am J Cardiol. 2006;98:1334-1339.
47. Lin GA, Dudley RA, Lucas FL, Malenka DJ, Vittinghoff E, Redberg RF. Frequency of stress
testing to document ischemia prior to elective percutaneous coronary intervention. JAMA.
2008;300:1765-1773.
48. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for
stable coronary disease. N Engl J Med. 2007;356:1503-1516.
49. Weintraub WS, Boden WE, Zhang Z, et al; the Department of Veterans Affairs Cooperative
Studies Program No. 424 (COURAGE Trial) Investigators and Study Coordinators. Cost-

26. effectiveness of percutaneous coronary intervention in optimally treated stable coronary
patients. Circ Cardiovasc Qual Outcomes. 2008;1:12-20.
50. Weintraub WS, Spertus JA, Kolm P, et al; the COURAGE Trial Research Group. Effect of
PCI on quality of life in patients with stable coronary disease. N Engl J Med.
2008;359:677-687.
Authors and Disclosures
As an organization accredited by the ACCME, MedscapeCME requires everyone who is in a position
to control the content of an education activity to disclose all relevant financial relationships with any
commercial interest. The ACCME defines "relevant financial relationships" as financial relationships
in any amount, occurring within the past 12 months, including financial relationships of a spouse or
life partner, that could create a conflict of interest.
MedscapeCME encourages Authors to identify investigational products or off-label uses of products
regulated by the US Food and Drug Administration, at first mention and where appropriate in the
content.
Author(s)
William E. Boden, MD
Professor and Associate Chair, Department of Medicine, SUNY Health Science
Center, and Chief, Medical Service, VA Medical Center, Syracuse, N.Y.
Disclosure: William E. Boden, MD, FACC, FAHA, has disclosed that he has
received grants for clinical research from Abbott Laboratories, Merck & Co., Inc.,
Pfizer Inc., and sanofi-aventis. Dr. Boden has also disclosed that he served as an
advisor or consultant for Abbott Laboratories, CV Therapeutics, and sanofi-
aventis, and has served on the speaker's bureau of Abbott Laboratories, CV
Therapeutics, Merck & Co., Inc., Pfizer Inc., and sanofi-aventis.
Writer(s)
Linda Brookes, MSc
freelance medical writer based in London and New York
Disclosure: Linda Brookes, MSc, has disclosed no relevant financial relationships.
Editor(s)
Ariana Del Negro
Scientific Director, MedscapeCME
Disclosure: Ariana Del Negro has disclosed no relevant financial relationships.