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CME/CE Released: 05/07/2009; Valid for credit through 05/07/2010

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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.

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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.

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]

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

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 III

Marked limitation of ordinary physical activity(Angina on walking 1 or 2 blocks on the level or 1 flight of stairs at a normal pace under normal conditions)

Class IV

Inability to carry out any physical activity without discomfort or angina at rest

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

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 (definite)

(1) Substernal chest discomfort with a characteristic quality and duration that are (2) provoked by exertion or emotional stress, and (3) relieved by rest or nitroglycerin

Atypical (probable)

Meets 2 of the above characteristics

Noncardiac chest pain

Meets 1 or none of the typical anginal characteristics

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]

Table 4. Alternative Diagnoses to Angina for Patients With Chest Pain

Nonischemic Cardiovascular Pulmonary Gastrointestinal Chest Wall Psychiatric

Aortic dissection Pericarditis

Pulmonary embolusPneumothoraxPneumonia Pleuritis

Esophageal Esophagitis Spasm RefluxBiliary Colic Cholecystitis Choledocholithiasis CholangitisPeptic ulcer Pancreatitis

Costochondritis Fibrositis Rib fracture Sternoclavicular arthritis Herpes zoster (before the rash)

Anxiety disorders Hyperventilation Panic disorder Primary anxietyAffective disorders (eg, depression) Somatoform disordersThought disorders (eg, fixed delusions)

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 examECG: 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.

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 the Bruce protocol and Duke treadmill score)

Symptomatic patients with intermediate-to-high probability of CAD who are able to exercise and not taking digoxin (LOE: B)

After significant change in anginal pattern (LOE: C)

Baseline ECG abnormalities (Wolff-Parkinson-White syndrome, electronically paced ventricular rhythm, > 1 mm ST depression at rest, LVH, or complete LBBB) (LOE: B)

Established diagnosis of CAD (prior MI, angiography) (LOE: B)

Cardiac stress imaging (able to exercise) -- exercise MPI or exercise

Patients with intermediate pretest probability of CAD with abnormal results on resting ECG or are

Patients with LBBB or cardiac pacing device (LOE: B)

echocardiography using digoxin (LOE: B)

Cardiac stress imaging (unable to exercise) -- adenosine or dipyridamole MPI or dobutamine echocardiography

Patients with an intermediate pretest probability of CAD (LOE: B) or in patients with prior revascularization (LOE: B), but do not have LBBB or a cardiac pacing device

Dobutamine echocardiography not recommended in patients with LBBB or cardiac pacing device (LOE: B)

Cardiac stress imaging -- adenosine or dipyridamole MPI

Patients with LBBB or with cardiac pacing device (regardless of 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]

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)

• 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

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 control

< 140/90 mm Hg or < 130/80 mm Hg if patient has diabetes or chronic kidney disease

Lipid management

- LDL-C < 100 mg/dL; reduction of LDL-C < 70 mg/dL or high-dose statin therapy is 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 management

Body mass index: 18.5-24.9 kg/m2 Waist circumference:- Men: < 40 in- Women: < 35 in

Diabetes management

HbA1c < 7%

Antiplatelet agents

Aspirin should be started at 75-162 mg/day and continued indefinitely in all patients 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%

Aldosterone blockade

Use in patients post MI, without significant renal dysfunction or hyperkalemia, who 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 vaccination

An annual influenza vaccination is recommended for patients with cardiovascular 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

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

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.

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

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

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).

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]

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

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.

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.

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.

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-

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

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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.