7 stable ischemic hd

7/27/2019 7 Stable Ischemic Hd

1/166

7: Stable Ischemic Heart Disease

Overview

This chapter reviews the evaluation and management of stable ischemic heart disease . Risk stratification and application of

guideline directed medical therapy are emphasized before consideration of the indications for revascularization. The choice

between PCI and CABG surgery is reviewed in light of the SYNTAX trial. There is additional review of the pathophysiology and

assessment of myocardial viability and its role in decision-making, as recently reported in the STICH trial. The asymptomatic

patient and the approach to microvascular angina are also addressed.

Authors

Patrick T. O'Gara, MD, FACC

Editor-in-Chief

Thomas M. Bashore, MD, FACC

Associate Editor

James C. Fang, MD, FACC

Associate Editor

Glenn A. Hirsch, MD, MHS, FACC

Associate Editor

Julia H. Indik, MD, PhD, FACC

Associate Editor

Donna M. Polk, MD, MPH, FACC

Associate Editor

Sunil V. Rao, MD, FACC

Associate Editor


2/166

7.1: Risk Stratification

Author(s):

Benjamin M. Scirica, MD, MPH, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Recognize the importance of risk stratification in patients with stable ischemic heart disease (SIHD).

2. Appropriately choose and prioritize the various risk stratification modalities in order to efficiently and cost-effectively

manage a patient with SIHD.3. Integrate the results of multiple clinical tests when risk stratifying a patient with SIHD.

4. Recognize the appropriate, and inappropriate, use of different risk stratification techniques.


3/166

Introduction

The diagnosis of SIHD, also termed chronic coronary artery disease (CAD), encompasses a heterogeneous population

that varies in terms of comorbidities, symptoms, and risk of future cardiovascular (CV) events. SIHD includes any

condition that results in a chronic or repetitive mismatch between myocardial oxygen supply and demand. Typically, SIHD

is due to atherosclerotic obstruction of the epicardial coronary arteries however, it may also arise from microvascular

disease and vasospasm, or more rarely, congenital anomalies or nonatherosclerotic vascular injury. Angina, or ischemic

chest discomfort, is the classic symptom of SIHD however, patients may present with dyspnea, heart failure, or

arrhythmias as their only symptomatic manifestation. Moreover, many patients with SIHD are free of symptoms, either at

the time of diagnosis of SIHD, or after successful medical therapy or revascularization.

Due to the diverse nature of SIHD and differences in definitions, estimates vary regarding the actual number of affected

people. However, it is estimated that 16.3 million people in the United States alone have CAD, with approximately 9

million reporting symptomatic chest pain and 8 million reporting a prior myocardial infarction (MI).1 The prevalence of

SIHD is increasing worldwide as the burden of risk factorssmoking, obesity, diabetes, and hypertensionincreases in

the large populations of developing nations.

Given the variability in this patient population, the evaluation of patients with known or suspected SIHD must incorporate

information from multiple clinical modalities to risk stratify effectively, and thereby, deliver appropriate and timely therapy.

In general, the goal is to identify patients at the highest risk who will benefit from the most intense therapy, while

reassuring and sparing invasive procedures in patients at a lower risk. Many of the tests or techniques reviewed in this

chapter are also central to the initial diagnosis of SIHD. This module will review current methods to improve risk

stratification among patients with documented SIHD. Diagnosis of SIHD and the risk stratification of asymptomaticpatients and of patients with acute coronary syndromes are covered in the module onAsymptomatic CAD in this chapter,

Patient Assessment in Chapter 3, and in the module on Initial Management, Risk Assessment, and Risk Stratification of

ACS in Chapter 6, respectively.


4/166

Spectrum of Risk for Future Cardiovascular Disease in PatientsWith Stable Ischemic Heart Disease

In primary prevention (patients without SIHD), risk stratification is typically based on

a 10-year risk of MI or coronary heart disease death, where a 10-year risk is

considered low at


5/166

Noninvasive Risk Stratification

Table 1

LV = left ventricle LVEF = left ventricular ejection fraction.

aAlthough 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


6/166

Overview of Risk Stratification Techniques for Patients WithStable Ischemic Heart Disease(1 of 3)

The goal of evaluating a patient with SIHD should be to systematically and efficiently

utilize the multiple modalities to maximize the identification of high-risk features

without overtesting, but to ensure that critical data that would identify high-risk

patients is not missed. There are four broad categories of risk stratification that

should be considered

5

:

1. Clinical evaluation and assessment of comorbidities

2. Functional capacity/stress test

3. Ventricular function

4. Coronary anatomy

Every patient does not require each of these modalities to be evaluated. Nor do they

need to be assessed in sequence. A low-risk patient may only require a clinical

evaluation and a stress test or echocardiogram, while a high-risk patient may

proceed directly from the clinical evaluation to cardiac catheterization.

Risk Stratification Based on Clinical Evaluation

Clinical History and Physical Examination

The clinical history and physical examination remain cornerstones in the evaluation

of patients with SIHD. In general, poorly controlled traditional cardiac risk factors

hypertension, dyslipidemia, smoking, and diabetesare associated with worse

prognosis in patients with SIHD, and given that the overall risk of CV events is higher

in patients with SIHD, the absolute risk associated with the presence of diabetes, for

example, is even greater than in primary prevention.

A history of heart failure, regardless of left ventricular (LV) ejection function, is also a

marker of significantly increased risk in almost all SIHD patients. The physical

examination should support the history and identify patients with evidence of right-

sided or left-sided overload or stigmata of noncoronary atherosclerosis.

Prior Cardiovascular History

A history of a documented severe ischemic event, such as a MI or stroke,

substantially increases the risk of subsequent events compared to patients with

SIHD who have never had a major ischemic event. In the REACH (Reduction of

Atherothrombosis for Continued Health) Registry, patients with a history of MI or

stroke (n = 21,890) had a higher 4-year rate of CV death, MI, or stroke (18.3%)

compared to patients with stable vascular disease but no history of MI or stroke (n =

15,264) (12.2%, p < 0.001) (Figure 1).6 Moreover, the detection of vascular disease

in other arterial beds is also important to document as patients with polyvascular

disease (concomitant disease of the cerebrovascular or peripheral arterial beds)

are at an even higher risk.

According to the REACH Registry, the 1-year risk of CV death, MI, stroke, or

hospitalization for a CV event ranged from 12.6% for patients with an one-arterial

bed involvement, 21.1% for patients with a two-arterial bed involvement, and 26.3%

for patients with a three-arterial bed involvement (p < 0.001 for trend). 7

Assessing Functional Status and Symptoms of Stable Ischemic Heart Disease

All patients with SIHD should be closely questioned regarding their functional status

and whether their activities are limited by any potential ischemic symptoms. Simple

questions regarding the patient's usual level of activity, such as walking, climbing

stairs, carrying grocery bags, or yard work offers invaluable insight into the patient's

physical limitations. A careful understanding of the nature of the limiting symptom in

patients with low activity may offer insights into potential ischemic burden. Many

patients reduce their activities to prevent symptoms of angina and may report a

reduction in their pain when it is actually just self-limiting activity.

Figure 1

Table 2


7/166

Ischemic chest discomfort, or angina, is the classic symptom of SIHD. The

diagnosis of angina begins with a careful assessment of clinical symptoms. While

there is significant variability in the quality of angina symptoms, angina typically is a

thoracic discomfort, often centered in the midsternum that radiates to the neck, jaw,

or arm, although some describe it as more epigastric than substernal. It is most

commonly described as a pressure, squeezing, or tightness, rather than a sharp

pain. Associated symptoms are common and include diaphoresis, dyspnea,

nausea, or intense fatigue. In some patients, and, in particular, in women and the

elderly, dyspnea or diaphoresis alone, without the "typical" symptoms of substernal

pressure, are present and are often ascribed to other causes, delaying diagnosis.

The pattern of angina is critical to defining a chronic versus unstable ischemicsyndrome. Patients with chronic angina experience symptoms that are predictable,

repetitive, and inducible with exertion. Symptoms are typically stable over weeks and

months. While exertion (e.g., walking, climbing stairs, cleaning) is the most common

precipitant, anxiety and stress can also elicit angina attacks. Chronic angina always

resolves with rest or the use of sublingual nitroglycerin. Many patients report the

slow onset of angina with exertion that requires them to diminish their level of

exertion or even stop. Often, after this initial episode subsides, patients can continue

their activities without symptoms.

Careful questioning of patients with suspected angina is necessary to determine

how their quality of life is affected. Any change in a chronic angina pattern, with either

onset at rest or angina with progressively less exertion, requires a more urgent

evaluation, as it may indicate a conversion to an unstable ischemic syndrome.

Patients can then be appropriately categorized in a different Canadian

Cardiovascular Society classification group (Table 2).8 More detailed and sensitive

classification can be obtained using more sensitive, patient-based surveys, such as

the Seattle Angina Questionnaire.

Prevalence and Risk Associated With Angina

The reported incidence and prevalence of symptomatic angina is directly related to

the population being studied. In population-based studies, the incidence of angina

is closely associated with age and gender. Men between 65-85 years old are at the

highest risk, with an incidence of >10 cases per 1,000 patient-years. The risk was

approximately one-half in younger men and women of a similar age.1 Among

patients with established CAD in the REACH registry, 30% reported a history of

stable angina.

By design, clinical trial populations are variably enriched for patients with a history of

angina, to the extent that the prevalence of a history of angina ranges from 22% in

the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial

to approximately 55% in the HOPE (Heart Outcomes Prevention Evaluation Study)

trial, and to 70% in the PEACE trial. Even among patients who undergo

revascularization, angina is common. Almost one-third of the patients in the

COURAGE trial9 assigned to percutaneous coronary intervention (PCI), and one-half

of the patients assigned to revascularization in the BARI-2D trial,10 had angina at 1

year after randomization. A large clinical database found that 30% of patients who

had a PCI still reported angina 1 year later.11

Surprisingly, there is little contemporary data to indicate whether the presence of

angina carries any increase in risk compared to patients with no angina, especiallywhen accounting for other comorbidities and LV function. In the Heart and Soul Study

of patients with SIHD, 129 patients (14%) had stable angina, but angina alone was

not associated with an increased 4-year risk of CHD.12


8/166

Four-Year Risk of Cardiovascular Death, Myocardial Infarction, or Stroke in the REACH Registry

Figure 1

Four-year risk of cardiovascular death, myocardial infarction, or stroke in the REACH Registry according to whether patients had a prior

documented ischemic event, stable atherosclerosis, or risk factors only.

CV = cardiovascular MI = myocardial infarction mo = month No. = number REACH Registry = Reduction of Atherothrombosis for Continued

Health Registry.

Reproduced withpermission from Bhatt DL, Eagle KA, Ohman EM, et al, and the REACH Registry Investigators. Comparative determinants of 4-

year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010304:1350-7.


9/166

Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System

Table 2

Reproduced withpermission from the Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca.

Accessed 02/27/2012.


10/166


Resting 12-Lead Electrocardiogram

All patients with SIHD should receive baseline and regular 12-lead

electrocardiograms (ECGs). The presence of pathologic Q waves may indicate an

old infarct, therefore identifying a patient at increased risk of future ischemic events

or heart failure. Even in the absence of a known MI, pathologic Q waves in the

absence of a clear history of MI are common and offer important prognostic

information. Silent MI, identified by new Q waves, accounted for 10% and 36.8% of

the total number of MIs observed in two recent clinical trials of diabetic patients and

were associated with worse outcomes.13,14 Other ECG findings such as atrial

fibrillation, fascicular and bundle-branch blocks, and LV hypertrophy have also been

associated with worse outcomes in patients with SIHD. 15 Smaller infarcts that do

not result in persistent Q waves can be identified on a 12-lead ECG by analyzing

altered RSR' patterns (fragmented QRS), which is associated with increased CV

risk.16,17

Established Biomarkers

Patients with SIHD should have regular measurements of lipids, fasting bloodglucose, glycated hemoglobin, and renal function to ensure that the traditional risk

factors are closely monitored at goal levels. Treatment of these risk factors is

covered in the module on Prevention in Chapter 4 and the Medical Therapymodule

in this chapter.

Other Biomarkers

Many biomarkers, including those that assess myocardial necrosis, inflammation,

neurohormonal activation, metabolism, renal function, coagulation, and lipid-

trafficking have been evaluated with the hope of gaining greater insight into the

pathogenesis of atherosclerosis and SIHD. Many biomarkers are elevated in

patients with SIHD, and some of them add incremental improvements to other

clinical features in terms of discriminating between lower-risk and higher-risk

patients. No biomarker, though, has been shown to provide any clear treatmentimplications in SIHD. For example, an elevated level of B-type natriuretic peptide

(BNP) identifies a patient at an increased risk however, there are no known

treatment therapies that will reduce that risk. The lack of treatment implications has

limited the incorporation of biomarkers into current treatment algorithms.

The older generations of troponin assays were not sensitive enough to detect

elevation in patients with stable cardiac disease. The introduction of more sensitive

cardiac troponin assays alters the traditional paradigm of troponin by detecting lower

levels of circulating troponin, which are commonly found in patients with SIHD. For

example, circulating troponin was detected in >97% of patients in the PEACE trial by

using a new high-sensitivity assay, and was greater than the 99th percentile, the

standard cutpoint for diagnosis of MI, in 11.1% of patients.18 There was a graded

stepwise increase in the risk of CV death and heart failure over the 5-year follow-up

period that was independent of baseline characteristics, even though these levels

are much lower than the older, conventional troponin assays could detect ( Figure

2a). Newer troponin assays with even higher sensitivity that can detect small

increases during stress tests are now available in some countries, but their role in

the evaluation of SIHD remains very much an area of debate.

Multiple studies examining the levels of natriuretic peptides in patients with SIHD

confirm that elevated levels of hemodynamic stress are independently associated

with an increased risk of CV death and heart failure. In one long-term population-

based study of >1,000 patients with documented CAD, patients in the highest

quartile of NT-proBNP were at a >2-fold increased risk of CV death compared to the

lowest quartile (Figure 2b).19 These observations were confirmed in both the HOPE

trial and the PEACE trial populations.20,21 In the analyses from the HOPE trial, NT-

Figure 2a

Figure 2b

Figure 3


11/166

proBNP was the only biomarker that improved the discrimination for the risk of CV

death beyond that provided by traditional risk factors. Other studies that evaluated

multiple novel biomarkers found that NT-proBNP, GDF-15, cystatin C, mid-regional-

pro-adrenomedullin (MR-proADM), and mid-regional-pro-atrial natriuretic peptide

(MR-proANP) were most strongly related to CV outcomes, although incremental

improvement over established risk factors was small, even after combining

markers.22

Based on the evidence that biomarkers can offer improved risk stratification, current

clinical guidelines give a Class IIa recommendation for the more established

markers, such as high-sensitivity C-reactive protein,23 and Class IIb

recommendation for natriuretic peptides in patients with stable CAD.5 The

widespread incorporation of these biomarkers is unlikely to occur until there

become clear treatment implications, which will require prospective clinical trials.

Clinical Risk Scores

In contrast to primary prevention and acute coronary syndromes, there are few well

validated and accepted integrated clinical risk scores for patients with documented,

but stable, CAD. Several scores, including one based on 11 clinical characteristics

and another with just five variablesmale, presence of typical angina, evidence of

an old MI on ECG, diabetes, and insulin usewere shown to be associated with the

severity of CAD detected on angiography.15

Another clinical score developed in patients treated with a statin as part of a clinical

trial found that a weighted scoring system including age, sex, tobacco use, prior MI,

revascularization, hypertension, total cholesterol, and low-density lipoprotein

cholesterol categorizes patients into a low (3%) 1-year risk of death or MI.24 It is important to note that none of these scores

included either exercise tolerance test or LV function, two of the most powerful risk

stratification techniques.

Assessment of Risk With Functional or Stress Tests

Stress testing, both by exercise or pharmacologic stress, provides an enormous

amount of prognostic information, and unless contraindicated, should be performed

in all patients with suspected or known SIHD to evaluate the presence and burden of

ischemia.25 Stress testing should not be performed when urgent catheterization is

indicated, or in other tenuous hemodynamic scenarios such as severe aorticstenosis or unstable arrhythmias. Whenever possible, exercise stress testing is

preferred to pharmacologic stress testing because exercise capacity and recovery

provide significant incremental prognostic information beyond the assessment of

ischemia, and because it is the more cost-efficient option.

It is important to remember that while stress tests provide an overall assessment of

cardiopulmonary health, they will only identify hemodynamically significant coronary

lesions. The understanding that many acute lesions arise from nonobstructive

lesions explains why a patient with a "negative" stress test may subsequently

present with an acute coronary syndrome. Disease-modifying therapy, such as

blood pressure control, lipid-lowering therapy, and antiplatelet drugs, should

therefore be based on the overall risk assessment and not just the stress tests

results.

Exercise Stress Tests

Exercise stress testing has been extensively validated in many clinical situations for

a variety of indications. One common indicationthe diagnosis of CAD in patients

without known SIHDis covered in the module onAsymptomatic CAD in this

chapter and in Chapter 3 on Patient Assessment. In general, among patients with

known SIHD, the presence of ischemia, as detected by ST segment deviation on

exercise testing, may be less important per se than the physiologic parameters

assessed during the test. Maximal exercise duration, total exercise capacity, time to

symptoms or ST-segment deviation, heart rate and blood pressure response to

exercise and recovery, and the degree of symptoms are all related to prognosis.

Exercise duration and maximal exercise capacity are two of the great integrators of

overall health.26 Excellent exercise capacity, even in the presence of documented


12/166

ischemia, carries a good prognosis, while poor capacity, with or without ischemia,

identifies a patient at a higher risk of death.

There are several integrated risk scores that combine different exercise test

parameters. The Duke Treadmill Score (DTS), which includes exercise duration,

maximal ST depression, and the presence and severity of angina, is one of the most

well-validated and utilized scoring tests (Figure 3). Patients are categorized as low

risk (score of >5) with a 1-year mortality rate of 0.25%, intermediate risk (score 4 to -

10) with a 1-year mortality rate of 1.25%, and high risk (score < -11) with a 1-year

mortality rate of 5.25%.27,28 Other metrics, such as abnormal heart rate recovery

pattern, prolonged ST segment depression (>8 minutes into recovery), or abnormal

blood pressure response offer further pathophysiologic insight into the overall CV

status and identify high-risk patients.25,29

Based on the strength of evidence, cost, and ease, stress testing should, in most

cases, be the first-line test for functional capacity among patients who can exercise

and have interpretable ECG testing. The indications for additional imaging are

reviewed in the next section, but even when imaging is obtained, exercise stress,

rather than pharmacologic stress, is preferred whenever possible to obtain

functional information.

Troponin T and NT-proBNP in Stable Ischemic Heart Disease (1 of 2)

Figure 2a

Elevated levels of high-sensitivity troponin T

Reproduced withpermission from Omland T, de Lemos JA, Sabatine MS, et al, and the Prevention of Events with Angiotensin Converting Enzyme

Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009361:2538-47,

and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B-Type natriuretic peptides in patients with

stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 200750:205-14.


13/166

Troponin T and NT-proBNP in Stable Ischemic Heart Disease (2 of 2)

Figure 2b

NT-proBNP are shown to be associated with increasing risk of overall mortality in the PEACE trial of patients with documented but stable

coronary artery disease.

Reproduced withpermission from Omland T, de Lemos JA, Sabatine MS, et al, and the Prevention of Events with Angiotensin Converting Enzyme

Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009361:2538-47,

and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B-Type natriuretic peptides in patients with

stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 200750:205-14.


14/166

Duke Treadmill Score

Figure 3

The Duke Treadmill Score is the most well-validated stress testing score that accurately classifies patients into low, intermediate, and high risk

based on the time of exercise, extent of ST depressions, and severity of symptoms. In the example, a patient exercises 8 minutes, has a 1 mm

ST-segment depression, and has nonlimiting angina, which gives a score of -1, placing her in the intermediate-risk category. The same

calculations can be performed using a nomogram by drawing a line between 1) ST-segment deviation during exercise and Angina during

exercise, and 2) Ischemia-reading line and Duration of exercise to estimate the 1-year and 5-year mortality risk.

Max = maximum MET = metabolic equivalent MI = myocardial infarction min = minutes


15/166


Myocardial Imaging Techniques to Assess Ischemia

The presence of ischemia can be detected by radionuclide, echocardiographic, or

magnetic resonance imaging (MRI) techniques, and in certain scenarios, is

indicated as part of the initial stress test or as a follow-up test to prior noninvasive

studies. The two most clinically relevant parameters obtained from these techniques

are: 1) the overall burden and pattern of ischemia, and 2) an assessment of LV

function. Consensus practice guidelines recommend that myocardial imaging is

appropriate in the following scenarios among patients with known SIHD30:

To clarify an equivocal, borderline, or discordant prior stress test where

obstructive CAD remains a concern.

To evaluate new or worsening symptoms in a patient with known abnormal

coronary angiography or prior stress images.

To evaluate the physiologic consequence of a coronary stenosis or anatomic

abnormality of uncertain significance.

For further evaluation of patients with an intermediate or high DTS.

The appropriateness of imaging an asymptomaticorstable patient with a history of

abnormal coronary angiography or abnormal stress imaging is uncertain if the last

stress test was >2 years prior, and inappropriate if the last stress test was within the

last 2 years. Repeat radionuclide imaging is considered appropriate in the setting of

incomplete revascularization to assess residual ischemia and for recurrent

symptoms after revascularization (Figure 4).30

Several findings on stress imaging are important in risk stratification. Evidence of

reduced LV function (3% annual mortality rate). Moderate LV

function (35-49%), moderate stress-induced perfusion defects or wall-motion

abnormalities identify intermediate-risk patients (1-3% annual mortality). Low-risk

patients (


16/166

disease. The current appropriate use criteria for echocardiography related to the

evaluation of patients with SIHD recommend echocardiography in patients with

symptoms or conditions related to suspected cardiac etiology, including chest pain.

Routine surveillance with repeated echocardiography in patients with known CAD,

but no change in symptoms or new signs of any progression is not indicated,

however.32

Much of the evidence linking LV function and outcomes comes from older studies

such as the CASS (Coronary Artery Surgery Study) trial where over two-thirds of the

deaths at 5 years were observed in the roughly one-third of patients with reduced LV

function. Integration of LV function and the degree of CAD further refines risk

stratification. Regardless of the degree of atherosclerosis, worsening ventricular

function is associated with increased risk of death (Figures 5a, b, c, d).33

Assessment of Risk According to Coronary Anatomy

The decision to define coronary anatomy is one of the key decision-branch points in

the evaluation of patients with SIHD. The decision to proceed to coronary

angiography should be based on the results of clinical history and noninvasive risk

stratification tools. Many low- to intermediate-risk patients with SIHD may not require

coronary angiography to appropriately treat their SIHD, while in other patients,

catheterization may be the first diagnostic test after the initial clinical evaluation.

Defining the coronary anatomy should also be considered as an important tool for

risk stratification, and not simply as a diagnostic tool to identify potential lesions for

revascularization. It is also important to remember that while coronary angiographyis the "gold-standard" for identifying flow-limiting intraluminal obstructions, it is not

sensitive to identifying "vulnerable" nonobstructive coronary plaques that may rapidly

progress to acute thrombotic lesions.

Despite the limitation in identifying the actual lesion that may precipitate an acute

coronary syndrome, the extent and burden of atherosclerosis detected on

angiography clearly identifies the "vulnerable patient" who is at a higher risk of CV

complications. The most simple and widely used classification for risk stratification

is based on the number of diseased arteries (i.e., left main or single-, double-, or

triple-vessel disease). The prognostic value of this straightforward classification

was most clearly demonstrated in the CASS registry, where there was a stepwise

decrease in overall survival according to the number of diseased arteries ( Figures

5a, b, c, d).33

This relationship of overall survival to the number of diseased arteries has been

confirmed in more recent experiences. In the COURAGE trial, the rate of death or MI

after a 4.6-year follow-up period was 12.5% in patients with zero- or one-vessel

disease, approximately 18% in patients with two-vessel disease, and approximately

25% in patients with three-vessel disease.34 More detailed assessments of the

complexity of coronary disease, as calculated by techniques such as the SYNTAX

Score, may provide a more complete assessment of atherosclerotic burden and

give insight into actual treatment decisions, however, they are not typically calculated

in clinical practice. In one study of approximately 1,400 patients with CAD

undergoing PCI, the 1-year risk of death increased almost twofold with each tertile of

SYNTAX score (1.5% vs. 2.1% vs. 5.6% p = 0.002) (Figures 6, 7).10,35

The American Heart Association/American College of Cardiology Foundation(AHA/ACCF) indications for coronary angiography in patients with SIHD are

presented in Table 3.15 Even though they are somewhat dated, these indications

remain relevant and are consistent with the recommendations of other professional

societies.5

Cardiac Computed Tomography

Computed tomography angiography (CTA) has a limited role in the evaluation of

patients with known SIHD or in patients with a high-suspicion for CAD.36 In these

cases, CTA will potentially delay coronary angiography and expose patients to

increased contrast and radiation. However, similar to coronary angiography, the

degree of atherosclerosis identified by CTA is associated with worse outcomes.

Patients with any luminal abnormalities detected on CTA (who therefore have some

Figure 8

Figure 9


17/166

degree of atherosclerotic burden) are at a higher risk than patients with no evidence

of any luminal obstruction. The risk increases in patients with actual obstructive

lesions and, in particular, among patients with left main or left anterior descending

artery disease.37

Similar to angiography, the number of diseased arteries identified by CTA is closely

associated with CV complications, with the highest risk in patients with left main

artery disease (Figure 8).38 CT calcium scanning has no role in the management of

patients with SIHD, as these patients are known to have atherosclerosis, and the

degree of calcification does not correlate with the degree of stenosis.35

An Integrated Risk Stratification Algorithm

Risk stratification in patients with SIHD should proceed in a stepwise and logical

progression. The process begins with the clinical history and examination, and the

decisions about subsequent testing should build on each additional piece of

information (Figure 9). Rarely will one test drive a decision for therapy, but rather the

integration of the data from several risk stratification modalities will provide the most

complete assessment and, therefore, the most appropriately guided therapeutic

decisions.

: Appropriate Use Criteria for Cardiac Radionuclide Imaging for Patients With Ischemic Symptoms or Prior Revascularization

Figure 4

ACS = acute coronary syndrome CABG = coronary artery bypass graft ECG = electrocardiogram PCI = percutaneous coronary intervention.

Reproduced withpermission from Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use

criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the

American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of


18/166


19/166

Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (1 of 4)

Figure 5a

Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients.

Panel A: Patients with one-, two-, or three-vessel disease by ejection fraction.

EJECFR = ejection fraction.

Reproduced withpermission from Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery

Surgery Study (CASS) Registry. Circulation 199490:2645-57.


20/166


21/166


Figure 5c


Panel C: Patients with two-vessel disease by ejection fraction.





22/166


Figure 5d


Panel D: Patients with three-vessel disease by ejection fraction.





23/166

Rate of Death or MI by Number of Disease Vessels

Figure 6

The rate of death or myocardial infarction (MI) according to the number of diseased arteries among patients with stable ischemic heart disease

treated with percutaneous coronary intervention (PCI) or optimal medical therapy (OMT).

Adapted withpermissi on from Dagenais GR, Lu J, Faxon DP, et al, and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI

2D) Study Group. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations

in patients with type 2 diabetes mellitus and stable ischemic heart disease. Circulation 2011123:1492-500.


24/166

Rate of Death or MI by SYNTAX Score

Figure 7

The rate of death or myocardial infarction (MI) according to the tertile of SYNTAX Score, which quantifies the overall burden and complexity of

the disease.

Adapted withpermissi on from Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the all-comers

population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. J Am Coll Cardiol

201056:272-7.


25/166

Recommendations for Coronary Angiography for Risk Stratification in Patients With Chronic Stable Angina

Table 3

Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients withchronic stable angina-executive summary and recommendations: a report of the American College of Cardiology/American Heart Association

Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 199999:2829-48.


26/166

Overall Survival by Number of Diseased Arteries

Figure 8

Overall survival according to the number of diseased arteries detected by computed tomography angiography.

Reproduced withpermission from Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic

angiography for prediction of all-cause mortality. J Am Coll Cardiol 200750:1161-70.


27/166

Initial Evaluation of Patients With Clinical Symptoms of Angina

Figure 9

Algorithm for the initial evaluation of patients with clinical symptoms of angina.

ACS = acute coronary syndrome CABG = coronary artery bypass graft CAD = coronary artery disease CV = cardiovascular CXR = chest X-

ray DM = diabetes mellitus ECG = electrocardiogram MI = myocardial infarction MRI = magnetic resonance imaging PCI = percutaneous

coronary intervention.

Reproduced withpermission from Fox K, Garcia MA, Ardissino D, et al. 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 200627:1341-81.


28/166

Future Directions

Continued research into novel biomarkers such as high-sensitivity troponin assays, may further improve the ability

to identify patients at the highest risk. The routine incorporation of novel biomarkers into clinical care is unlikely

though, until specific treatments based on the results of the tests are identified in clinical trials.

Advances in imaging may provide greater insight into which patient may benefit from more intense therapy,

including revascularization. For example, more detailed assessments of viability, as detected by cardiac MRI or

positron emission tomography (PET) scans may better identify which patients will benefit from revascularization.

Advanced imaging techniques are also being evaluated to identify atherosclerotic lesions that are most likely to

become unstable prior to becoming symptomatic.


29/166

Key Points

SIHD, also termed CAD, encompasses a heterogeneous population, which varies in terms of comorbidities,

symptoms, and risk of future CV events.

Risk stratification in patients with SIHD should proceed in a step-wise and logical progression.

Categorization of patients into low-, intermediate-, and high-risk categories should be a primary goal in the

evaluation of patients with SIHD. Patients with an annual mortality rate of 3% as high risk.

Four broad categories of risk stratification should be considered: 1) clinical evaluation and assessment of

comorbidities, 2) functional capacity/stress rest, 3) ventricular function, and 4) coronary anatomy. Most patients will

not need all four domains tested.

Based on the strength of evidence, cost, and ease, stress testing should be in most cases the first-line test for

functional capacity among patients who can exercise and have an interpretable ECG. Some patients may have an

indication for additional imaging, but even when imaging is obtained, exercise stress, rather than pharmacologic,

is preferred whenever possible to obtain functional information.

Regardless of the clinical situation, LV function is not only one of the most powerful predictors of short- and long-

term outcomes, but also carries therapeutic implications regarding appropriate medical, revascularization, and

device-based therapies. LV function, therefore, should be assessed in all patients with SIHD, even without any

signs or symptoms of heart failure.

Coronary angiography should be performed based on the results of clinical history and noninvasive risk

stratification tools. Many low- to intermediate-risk patients with SIHD may not require coronary angiography,

whereas in other patients, catheterization may be the first diagnostic test after the initial clinical evaluation.

Defining the coronary anatomy, though, should be considered an important tool for risk stratification, and notsimply as a diagnostic tool to identify potential lesions for revascularization.


30/166

References

1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011 update: a report from the

American Heart Association. Circulation 2011123:e18-e209.

2. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery

disease. N Engl J Med 2004351:2058-68.

3. Boden WE, O'Rourke RA, Teo KK, et al., on behalf of the COURAGE Trial Research Group. Optimal medical

therapy with or without PCI for stable coronary disease. N Engl J Med 2007356:1503-16.

4. Frye RL, August P, Brooks MM, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2

Diabetes (BARI 2D) Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease.

N Engl J Med 2009360:2503-15.

5. Fox K, Garcia MA, Ardissino D, et al. 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 200627:1341-81.

6. Bhatt DL, Eagle KA, Ohman EM, et al., on behalf of the REACH Registry Investigators. Comparative determinants

of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA

2010304:1350-7.

7. Steg PG, Bhatt DL, Wilson PW, et al., on behalf of the REACH Registry Investigators. One-year cardiovascular

event rates in outpatients with atherothrombosis. JAMA 2007297:1197-206.

8. Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca. Accessed

02/27/2012.

9. Weintraub WS, Spertus JA, Kolm P, et al., on behalf of the COURAGE Trial Research Group. Effect of PCI on

quality of life in patients with stable coronary disease. N Engl J Med 2008359:677-87.10. Dagenais GR, Lu J, Faxon DP, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2

Diabetes (BARI 2D) Study Group. Effects of optimal medical treatment with or without coronary revascularization

on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart

disease. Circulation 2011123:1492-500.

11. Alexander KP, Cowper PA, Kempf JA, Lytle BL, Peterson ED. Profile of chronic and recurrent angina pectoris in a

referral population. Am J Cardiol 2008102:1301-6.

12. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the risk of recurrent cardiovascular events

in outpatients with stable coronary heart disease: the Heart And Soul Study. Arch Intern Med 2008168:1423-8.

13. Burgess DC, Hunt D, Li L, et al. Incidence and predictors of silent myocardial infarction in type 2 diabetes and the

effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

Eur Heart J 201031:92-9.

14. Chaitman BR, Hardison RM, Adler D, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2

Diabetes (BARI 2D) Study Group. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized

trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact oftreatment strategy on cardiac mortality and myocardial infarction. Circulation 2009120:2529-40.

15. Gibbons RJ, Abrams J, Chatterjee K, et al. 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 200341:159-68.

16. Das MK, Saha C, El Masry H, et al. Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events

in patients with coronary artery disease. Heart Rhythm 20074:1385-92.

17. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex versus a Q wave

in patients with coronary artery disease. Circulation 2006113:2495-501.

18. Omland T, de Lemos JA, Sabatine MS, et al., on behalf of the Prevention of Events with Angiotensin Converting

Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery


19. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death fromcardiovascular causes. N Engl J Med 2008358:2107-16.

20. Blankenberg S, McQueen MJ, Smieja M, et al., on behalf of the HOPE Study Investigators. Comparative impact of

multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the

prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study.

Circulation 2006114:201-8.

21. Omland T, Sabatine MS, Jablonski KA, et al., on behalf of the PEACE Investigators. Prognostic value of B-Type

natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol

200750:205-14.

22. Schnabel RB, Schulz A, Messow CM, et al. Multiple marker approach to risk stratification in patients with stable

coronary artery disease. Eur Heart J 201031:3024-31.

23. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to

clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control

and Prevention and the American Heart Association. Circulation 2003107:499-511.


31/166

24. Marschner IC, Colquhoun D, Simes RJ, et al., on behalf of the LIPID Study Investigators. Long-term risk

stratification for survivors of acute coronary syndromes. Results from the Long-term Intervention with Pravastatin

in Ischemic Disease (LIPID) Study. J Am Coll Cardiol 200138:56-63.

25. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A

report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

(Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol 200240:1531-40.

26. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men

referred for exercise testing. N Engl J Med 2002346:793-801.

27. Mark DB, Hlatky MA, Harrell FE Jr, Lee KL, Califf RM, Pryor DB. Exercise treadmill score for predicting prognosis in

coronary artery disease. Ann Intern Med 1987106:793-800.

28. Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected

coronary artery disease. N Engl J Med 1991325:849-53.29. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a

predictor of mortality. N Engl J Med 1999341:1351-7.

30. Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use

criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate

Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the

American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed

Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll

Cardiol 200953:2201-29.

31. Davis RC, Hobbs FD, Kenkre JE, et al. Prevalence of left ventricular systolic dysfunction and heart failure in high

risk patients: community based epidemiological study. BMJ 2002325:1156.

32. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011

Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation

Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association,

American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for

Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular

Computed Tomography, and Society for Cardiovascular Magnetic Resonance. Endorsed by the American College

of Chest Physicians. J Am Coll Cardiol 201157:1126-66.

33. Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery

Study (CASS) Registry. Circulation 199490:2645-57.

34. Mancini GB, Bates ER, Maron DJ, et al., on behalf of the COURAGE Trial Investigators. Quantitative results of

baseline angiography and percutaneous coronary intervention in the COURAGE trial. Circ Cardiovasc Qual

Outcomes 20092:320-7.

35. Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the all-comers

population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent

coating) trial. J Am Coll Cardiol 201056:272-7.

36. Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate

use criteria for cardiac computed tomography. A report of the American College of Cardiology FoundationAppropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College

of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of

Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular

Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol

201056:1864-94.

37. Pundziute G, Schuijf JD, Jukema JW, et al. Prognostic value of multislice computed tomography coronary

angiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol 200749:62-70.

38. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic

angiography for prediction of all-cause mortality. J Am Coll Cardiol 200750:1161-70.


32/166

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.


33/166

7.2: Medical Therapy

Author(s):

Richard A. Lange, MD, FACC

Learner Objectives


1. Apply appropriate secondary prevention measures of coronary heart disease (CHD).

2. Identify antianginal drugs that prevent reinfarction and improve survival in post-myocardial infarction (MI) patients.

3. Identify patients who benefit from angiotensin-converting enzyme (ACE) inhibitors.4. Describe the goal serum low-density lipoprotein cholesterol (LDL-C) concentration for patients with stable CHD.


34/166

Introduction

In the patient with chronic coronary artery disease (CAD), the goals of medical therapy are to ameliorate angina and/or

prevent recurrent major cardiovascular (CV) events (secondary prevention). The initial approach to all patients should be

focused upon eliminating unhealthy behaviors such as smoking and effectively promoting lifestyle changes that reduce

CV risk such as maintaining a healthy weight, engaging in physical activity, and adopting a healthy diet.

In addition, medical therapies that retard progression (or promote regression) of atherosclerosis, stabilize

atherosclerotic plaques, or prevent thrombosis should be administered to decrease the risk of MI and death. Such

therapies include antiplatelet agents, ACE inhibitors, and lipid-lowering therapy. In the patient with diabetes, tightglycemic control was assumed to be important in secondary CV prevention, but recent studies show that this approach

increases the risk of CV death and complications.1


35/166

Antiplatelet Therapy

Platelet aggregation is a key element of the thrombotic response to plaque disruption. Hence, platelet inhibition is

recommended in all patients with chronic CAD unless contraindicated. Aspirin (acetylsalicylic acid) irreversibly acetylates

platelet cyclooxygenase, which is required for the production of thromboxane A 2, a powerful promoter of platelet

aggregation. By inhibiting thromboxane production and subsequent platelet aggregation, aspirin reduces the risk of

thrombotic vascular events.

Among 2,920 patients with chronic CAD, theAntiplatelet Trialists' Collaboration meta-analysis showed that aspirin

treatment was associated with a 33% reduction in the risk of serious vascular events (nonfatal MI, nonfatal stroke, and

vascular death). Over the course of a couple of years of treatment, aspirin would be expected to prevent about 10-15

vascular events for every 1,000 people treated.2

Aspirin dose of 75-162 mg daily is equally as effective as 325 mg in secondary prevention, but with a lower risk of

bleeding. Doses


36/166

Clopidogrel

Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation via irreversible inhibition of the adenosine

diphosphate P2Y12 receptor. In the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial,

which enrolled 19,185 patients with a history of MI, stroke, or peripheral vascular disease, patients who received

clopidogrel had 10% fewer serious vascular events than aspirin-treated patients. 4 Since the magnitude of the difference

was small and no additional trials comparing aspirin and clopidogrel in patients with stable CAD have been conducted,

clopidogrel is recommended in patients with CAD who are allergic to or cannot tolerate aspirin.

The use of dual platelet therapy with aspirin and clopidogrel was no more effective than aspirin alone in reducing

vascular events in 15,603 asymptomatic patients with high risk for or with established atherothrombotic disease,

including stable CAD, in the CHARISMA (Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization,

Management, and Avoidance) study.5 A post-hoc analysis showed that patients with documented prior MI, ischemic

stroke, or symptomatic peripheral arterial disease appeared to derive significant benefit from dual antiplatelet therapy

with clopidogrel plus aspirin.6 Thus, treatment with aspirin 75-162 mg daily and clopidogrel 75 mg daily may be

reasonable in certain high-risk patients with chronic CAD.


37/166

Beta-Blockers

Beta-blockers are the only antianginal drugs proven to prevent reinfarction and

improve survival in patients who have had an MI. Such benefits have not been

demonstrated in patients with chronic ischemic heart disease without previous

infarction. Nevertheless, beta-blockers remain first-line therapy in the treatment of

chronic ischemic heart disease, particularly effort-induced angina, with the goal to

reduce the frequency and severity of angina and to improve exercise capacity.

Despite the fact that they differ with regard to cardioselectivity, presence of intrinsic

sympathomimetic activity or vasodilating properties, and relative lipid solubility, all

beta-blockers appear to be equally efficacious in stable ischemic heart disease. 7-11

Beta-blocker dosing should be adjusted to limit the heart rate to 55-60 bpm at rest

and to not exceed 75% of the exercise heart rate response at the onset of ischemia.

Beta-blockers improve survival, prevent CV hospitalizations, and improve symptoms

and exercise tolerance in patients with ischemic cardiomyopathy already receiving

treatment with conventional therapy (i.e., diuretics, digoxin, and ACE inhibitors).

The CIBIS II (Cardiac Insufficiency Bisoprolol Study II), MERIT-HF (Metoprolol CR/XL

Randomized Intervention Trial in Congestive Heart Failure), and COPERNICUS

(Effect of Carvedilol on Survival in Severe Chronic Heart Failure) trials demonstrated

an approximately 35% mortality reduction with bisoprolol, metoprolol, and carvedilol,

respectively (Figure 1).12-14 This does not appear to be a class effect that extends to

all beta-blockers because the BEST (Beta-Blocker Evaluation of Survival Trial) studydid not show a reduction in mortality with bucindolol. 15

Beta-blocker therapy should be initiated and continued indefinitely in all patients with

prior MI or left ventricular (LV) dysfunctionwith or without heart failure symptoms

unless contraindicated.3 Some of the mechanisms responsible for the benefits of

beta-blockers in these patients include increased myocardial beta-adrenergic

receptor density and sensitivity, and a switch in myocardial substrate utilization from

free fatty acids to glucose, which increases myocardial energy efficiency.

Although generally well tolerated, beta-blockers have several notable side effects.

Because of their negative inotropic effects, beta-blocker therapy should be advanced

cautiously in patients with impaired LV systolic function. Beta-blockers may

exacerbate coronary vasospasm in patients with variant angina, bronchospasm in

patients with reactive airway disease, and limb or digit ischemia in patients with

severe peripheral vascular disease or Raynaud's phenomenon. Impotence may

also occur with their use. Chronic beta-blocker therapy leads to an increase in beta-

receptor density. This can be clinically important, as sudden withdrawal of beta-

blocker therapy may result in increased sensitivity to endogenous catecholamines,

with precipitation of angina pectoris, MI, or death.

Figure 1


38/166

Mortality Benefit of Beta-Blockers in Congestive Heart Failure

Figure 1

Annual mortality in four studies of patients with congestive heart failure--most of whom had an ischemic cardiomyopathy--treated with a)

placebo or b) beta-blockers in addition to conventional therapy. Those treated with bisoprolol, metoprolol, or carvedilol had improved survival,

whereas those treated with bucindolol did not.

References:

1. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999353:9-13.

2. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being

in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study

Group. JAMA 2000283:1295-302.

3. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001344:1651-8.

4. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001344:1659-67.


39/166

Calcium Channel Blockers

Calcium channel blockers may be used as effective antianginal agents and for the treatment of hypertension (see

Chapter 5: Hypertension), but do not have a direct role for secondary prevention in patients with stable CHD.


40/166

Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors reduce mortality and morbidity from CV events in patients who have

heart failure due to LV systolic dysfunction, and in those who have acute MI. In

addition, "high-risk" patients with CAD or other vascular disease may benefit from an

ACE inhibitor in the absence of LV dysfunction or previous MI.

In patients with atherosclerotic vascular disease or diabetes and at least one other

CAD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study showed

that, compared to placebo, ramipril significantly decreased the primary composite

endpoint of CV death, MI, and stroke by 22% over 4.5 years of follow-up.16 Based on

these results, the Food and Drug Administration (FDA) approved the use of ramipril

for the reduction of MI, stroke, and death in high-risk patients. Similarly, in

the EUROPA (European Trial on Reduction of Cardiac Events With Perindopril in

Stable Coronary Artery Disease) study, perindopril reduced CV events (CV death, MI,

or cardiac arrest) by 20% over 4.2 years of follow-up in a lower-risk population with

stable CHD and no apparent heart failure.17

Conversely, in the PEACE (Prevention of Events With Angiotensin-Converting

Enzyme Inhibition) trial, which enrolled >8,000 low-risk patients with stable CHD and

preserved LV function who were receiving intensive current standard therapy, the

addition of trandolapril did not reduce CV death, MI, or coronary revascularization

(Figure 2).18 The lack of benefit from ACE inhibition in the PEACE trial has beenattributed to the fact that the study population was lower risk and more likely to be

intensively treated with coronary revascularization and lipid-lowering therapy than the

patients in the previous studies.

Similarly, in the QUIET (Quinapril Ischemic Event Trial)19 and IMAGINE (Ischemia

Management With Accupril Post-Bypass Graft via Inhibition of the Converting

Enzyme)20 studies of low-risk (LV ejection fraction [EF] >0.40) patients who had

undergone percutaneous coronary intervention (PCI) or coronary artery bypass

grafting (CABG), quinapril did not reduce ischemic events.

Based on these studies, the 2007 Chronic Angina Focused Update of the ACC/AHA

2002 Guidelines for the Management of Patients With Chronic Stable Angina

recommend that ACE inhibitors be started and continued indefinitely in all patients

with LVEF 0.40 and in those with hypertension, diabetes, or chronic kidney disease

unless contraindicated.3 Their use is also recommended in patients who are not

lower risk (lower risk is defined as those with normal LVEF in whom CV risk factors

are well controlled and revascularization has been performed). Finally, it is

considered reasonable to use ACE inhibitors among lower-risk patients with mildly

reduced or normal LVEF in whom CV risk factors are well controlled and

revascularization has been performed.

Figure 2


41/166

Lack of Benefit of ACE Inhibitor in "Low-Risk" Stable CAD Patients

Figure 2

Composite outcome of cardiovascular death, myocardial infarction, or coronary revascularization in low-risk patients with stable coronary

artery disease (CAD) and preserved left ventricular function treated with placebo or trandolapril in the PEACE study. Over the 4.8-year follow-

up, the addition of trandolapril to current standard therapy was not beneficial in reducing cardiovascular events.

ACE inhibitor = angiotensin-converting enzyme inhibitor.

Reproduced with permission from Massachusets Medical Society. The PEACE Trial Investigators. Angiotensin-Converting-Enzyme Inhibition in

Stable Coronary Artery Disease. N Engl J Med 2004351:2058-68. Copyright 2000, Massachusetts Medical Society. All rights reserved.


42/166

Angiotensin-Receptor Blockers

Angiotensin-receptor blockers (ARBs) are recommended for individuals who have indications for an ACE inhibitor (post-

MI, heart failure due to LV systolic function, or depressed LVEF), but are intolerant of it. The ONTARGET (ONgoing

Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) showed that telmisartan was noninferior to

ramipril for reducing mortality and CV morbidity over more than 4 years of follow-up in patients with vascular disease or

high-risk diabetes mellitus.21 However, the combination of telmisartan and ramipril was associated with an increased

incidence of adverse events without a detectable incremental benefit above either agent alone.


43/166

Influenza Vaccine

An ACC/AHA science advisory recommends annual vaccination with inactivated vaccine (administered intramuscularly)

against seasonal influenza to prevent all-cause mortality and morbidity in patients with underlying CV conditions.22 A

recent cohort study in 1,340 elderly (i.e., 65 years of age or older) patients with congestive heart failure or CAD showed

that annual influenza vaccinations reduced the winter period mortality by 37% the number needed to treat to decrease

one death during influenza period is 122 annual vaccinations. 23


44/166

Low-Density Lipoprotein Cholesterol Lowering Therapy(1 of 2)

CV death rates increase with higher serum concentrations of total and LDL

cholesterol, and the impact of elevated lipid levels is significantly greater in subjects

with pre-existing CHD than those without (Figure 3). Even modest elevations in

serum cholesterol increase the risk of a cardiac event in patients with CHD or a

recent MI. For example, the CARE (Cholesterol and Recurrent Events) trial evaluated

the role of pravastatin therapy after MI in patients with average levels of total and LDL

cholesterol (209 mg/dl and 139 mg/dl, respectively). In the placebo group, each 25

mg/dl increment in LDL-C increased the risk of a cardiac event (death or nonfatal MI)

by 28%.24 Accordingly, patients with known CHD or a CHD equivalent (i.e., diabetes

mellitus, symptomatic carotid artery disease, peripheral arterial disease, abdominal

aortic aneurysm, chronic renal insufficiency, or Framingham 10-year risk of CHD

>20%) merit aggressive lipid management.

The goal serum LDL-C concentration for patients with stable CHD or a CHD

equivalent is 130 mg/dl with low HDL-C [


45/166

with CV disease receiving background statin therapy reported no overall benefit for

fenofibrate.26

Bile acid sequestrants are effective in patients with mild to moderate elevations of

serum LDL-C. They may be used in combination with statins or nicotinic acid in

patients with markedly elevated serum levels of LDL-C. The use of a bile acid

sequestrant is often limited by gastrointestinal side effects.

Nicotinic acid is effective in patients with hypercholesterolemia and in combined

hyperlipidemia associated with normal or low-serum HDL-C levels

(hypoalphalipoproteinemia). It raises serum HDL levels with dosages as low as 1-

1.5 g/day, but higher doses (>3 g/day) are typically needed to lower serum very LDL(VLDL) and LDL cholesterol. The use of nicotinic acid is often limited by poor

tolerability, which can be minimized by taking aspirin beforehand or using a long-

acting nicotinic acid preparation. In CHD patients who are at increased risk for CV

events despite a well-controlled LDL-C on statin therapy (i.e., those with low HDL-C

and high triglyceride levels), the addition of high-dose, extended-release niacin to

statin therapy does not reduce the risk of CV events. 27

Probucol modestly lowers LDL-C, but more prominently reduces HDL-C. At present,

the use of probucol should be limited to patients with refractory

hypercholesterolemia or those with familial hypercholesterolemia and xanthomas.

Cholesterol and Death Rate in Patients With and Without CHD

Figure 3

Relation between baseline plasma cholesterol measurement and 10-year cardiovascular death rate in patients without and with coronary heart

disease in the Lipid Research Council Study. Death rates are increased at higher serum cholesterol concentrations in both groups, but the effect

is more pronounced in subjects with coronary heart disease.

CHD = coronary heart disease


46/166

Reproduced with permission from Massachusetts Medical Society. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular

disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990322:1700-7. Copyright

1990, Massachusetts Medical Society. All rights reserved.

Lipid-Lowering Drug Therapy

Table 1

Conventional dosing regimens and typical changes in the lipid profile with drug therapy.

HDL = high-density lipoprotein LDL = low-density lipoprotein.


47/166

Common Side Effects of Lipid-Lowering Drug Therapy (1 of 2)

Table 2a


48/166

Common Side Effects of Lipid-Lowering Drug Therapy (2 of 2)

Table 2b


49/166

Low-Density Lipoprotein Cholesterol Lowering Therapy(2 of 2)

Ezetimibe reduces LDL-C by inhibiting absorption of cholesterol by the small

intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver.

This causes a reduction of hepatic cholesterol stores and an increase in the

clearance of cholesterol from the blood. This mechanism is complementary to that

of the statins. Hence, ezetimibe is typically used in combination with a statin when

cholesterol is not reduced sufficiently by statin therapy alone or it is necessary to

reduce the statin dose because of side effects. To date, no long-term clinical

outcome studies have been performed with ezetimibe.

Several large trials have demonstrated that lipid lowering is beneficial in patients

with CHD. There is also ample evidence that elderly patients with CHD who do not

have life-limiting comorbid conditions benefit from lipid-lowering therapy.28 A meta-

analysis of 38 primary and secondary prevention trials found that for each 10%

reduction in serum cholesterol, CHD mortality was reduced by 15% and total

mortality risk by 11%.29

In addition to the reduction in clinical events, serial angiographic and intravascular

ultrasound studies have shown that cholesterol lowering can retard the progression

and, in many cases, induce regression of coronary atherosclerosis.30,31 This

benefit is most prominent when serum LDL-C levels are reduced below 100 mg/dl.

The mechanisms of benefit seen with lipid lowering are not completely understood.

Regression of coronary atherosclerosis is modest. Furthermore, the magnitude of

clinical benefits is disproportionate to the modest degree of regression, and they are

seen before significant regression of atherosclerosis could occur. Other factors that

may account for the beneficial effects of lipid-lowering agents include plaque

stabilization, reversal of endothelial dysfunction, antioxidant effects, decreased

thrombogenicity, and anti-inflammatory effects.

CV benefits of cholesterol lowering with statins have been demonstrated in patients

with CHD, with or without hyperlipidemia. The 4S (Scandinavian Simvastatin Survival

Study) trial of patients with hyperlipidemia (baseline serum total cholesterol levels

between 212 and 309 mg/dl) found that simvastatin therapy versus placebo for 5.4

years resulted in statistically significant reductions in total mortality (33% reduction),major coronary events (32% reduction), CV deaths (42% reduction),

revascularization procedures (37% reduction), and cerebrovascular events (37%

reduction).32 These benefits persisted at the 8-year follow-up period.33 The

reduction in major cardiac events was highly correlated with on-treatment serum

total cholesterol and LDL concentrations and with changes from baseline. Each

additional 1% reduction in LDL-C reduced the risk of major cardiac events by

1.7%.34

The LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease Trial) study

showed that patients with CHD and a broad range of serum cholesterol

concentrations benefit from statin therapy.35 The study randomized patients with

serum cholesterol concentrations of 155-270 mg/dl to therapy with pravastatin or

placebo. After a mean follow-up of 60 months, the study was terminated prematurelybecause, compared with placebo, pravastatin therapy lowered morbidity and

mortality from CV disease, as well as all-cause mortality (Figure 4). The benefit of

pravastatin was seen in all predefined subgroups, including those of any age and at

any level of total cholesterol, LDL-C, HDL-C, or triglycerides.

The CARE trial showed that statin therapy was beneficial in CHD patients with high-

normal levels of serum cholesterol.36 In this study, patients with average cholesterol

levels (mean serum total cholesterol concentration of 209 mg/dl) were treated with

pravastatin (40 mg) or placebo. At 5 years, benefits with pravastatin compared with

placebo included significant reductions in the combined incidence of coronary death

and nonfatal MI (31% reduction), the need for revascularization (25% reduction), and

the frequency of stroke (32% reduction). The benefits were seen only in patients with

LDL-C levels above 125 mg/dl.

Figure 4


50/166

The Heart Protection Study (HPS) questioned whether a target LDL goal 20,000 patients with

established CV disease, diabetes, or hypertension, simvastatin (40 mg/day)

reduced mortality (13%), cardiovascular mortality (18%), major CV events (24%), and

ischemic stroke (25%) compared to placebo over the 5.5-year follow-up. Importantly,

subgroup analysis suggested that simvastatin therapy produced similar reductions

in relative risk regardless of the baseline levels of LDL-C, including subgroups with

baseline LDL-C levels >135 mg/dl,


51/166

Key Points

Unless contraindicated, all patients with evidence of CAD should receive aspirin to prevent MI.

Beta-blockers are the only antianginal drugs proven to prevent reinfarction and improve survival in patients who

have had an MI.

Stable CAD patients receiving intensive medical therapy who are at low risk for a CV event do not benefit from ACE

inhibitor therapy. Conversely, ACE inhibitors reduce CV mortality and morbidity in "high-risk" patients with vascular

disease (i.e., those with poorly controlled risk factors or diabetes and other CV risk factors).

Statins are the most effective drugs for lowering serum LDL-C. The goal serum LDL-C concentration for patients

with stable CHD or a CHD equivalent is


52/166

References

1. Gerstein HC, Miller ME, Genuth S, et al., on behalf of the ACCORD Study Group. Long-term effects of intensive

glucose lowering on cardiovascular outcomes. N Engl J Med 2011364:818-28.

2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for

prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002324:71-86.

3. 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 200750:2264-74.

4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of

ischaemic events (CAPRIE). Lancet 1996348:1329-39.

5. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of

atherothrombotic events. N Engl J Med 2006354:1706-17.

6. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral

arterial disease in the CHARISMA trial. J Am Coll Cardiol 200749:1982-8.

7. Frishman WH, Heiman M, Soberman J, Greenberg S, Eff J. Comparison of celiprolol and propranolol in stable

angina pectoris. Celiprolol International Angina Study Group. Am J Cardiol 199167:665-70.

8. Hauf-Zachariou U, Blackwood RA, Gunawardena KA, O'Donnell JG, Garnham S, Pfarr E. Carvedilol versus

verapamil in chronic stable angina: a multicentre trial. Eur J Clin Pharmacol 199752:95-100.

9. Kardas P. Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-

daily betaxolol versus twice daily metoprolol: a randomized controlled trial. Vasc Health Risk Manag 20073:235-42.

10. Narahara KA. Double-blind comparison of once daily betaxolol versus propranolol four times daily in stable

angina pectoris. Betaxolol Investigators Group. Am J Cardiol 199065:577-82.

11. Raftery EB. The preventative effects of vasodilating beta-blockers in cardiovascular disease. Eur Heart J 199617

Suppl B:30-8.

12. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.

Lancet 1999353:9-13.

13. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality,

hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial

in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000283:1295-302.

14. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med

2001344:1651-8.

15. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with

advanced chronic heart failure. N Engl J Med 2001344:1659-67.16. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme

inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study

Investigators. N Engl J Med 2000342:145-53.

17. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery

disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet

2003362:782-8.

18. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery


19. Pitt B, O'Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor

therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol

200187:1058-63.

20. Rouleau JL, Warnica WJ, Baillot R, et al. Effects of angiotensin-converting enzyme inhibition in low-risk patients

early after coronary artery bypass surgery. Circulation 2008117:24-31.21. Yusuf S, Teo KK, Pogue J, et al., on behalf of the ONTARGET Investigators. Telmisartan, ramipril, or both in

patients at high risk for vascular events. N Engl J Med 2008358:1547-59.

22. Davis MM, Taubert K, Benin AL, et al. Influenza vaccination as secondary prevention for cardiovascular disease: a

science advisory from the American Heart Association/American College of Cardiology. Circulation

2006114:1549-53.

23. de Diego C, Vila-Corcoles A, Ochoa O, et al. Effects of annual influenza vaccination on winter mortality in elderly

people with chronic heart disease. Eur Heart J 200930:209-16.

24. Pfeffer MA, Sacks FM, Moye LA, et al. Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial.

Cholesterol And Recurrent Events. J Am Coll Cardiol 199933:125-30.

25. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education

Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 200444:720-32.

26. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J

Med 2010362:1563-74.


53/166

27. Boden WE, Probstfield JL, Anderson T, et al., on behalf of the AIM-HIGH Investigators. Niacin in patients with low

HDL cholesterol levels receiving intensive statin therapy. N Engl J Med365:2255-67.

28. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER):

a randomised controlled trial. Lancet 2002360:1623-30.

29. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit:

impact of statin trials. Circulation 199897:946-52.

30. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary

atherosclerosis: the ASTEROID trial. JAMA 2006295:1556-65.

31. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on

progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004291:1071-80.

32. [No authors listed]. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the

Scandinavian Simvastatin Survival Study (4S). Lancet 1994344:1383-9.33. Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow-up study of patients randomized in the Scandinavian

simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 200086:257-62.

34. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major

coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 199897:1453-60.

35. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of

cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of

initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.

N Engl J Med 1998339:1349-57.

36. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in

patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med

1996335:1001-9.

37. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with

simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002360:7-22.


54/166

Printable PDF

This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item.


55/166

7.3: Indications for Revascularization

Author(s):

John McPherson, MD, FACC

Learner Objectives


1. Utilize appropriate medical therapy in the management of patients with symptomatic obstructive coronary artery disease

(CAD).

2. Refer appropriate patients with significant left main or multivessel CAD for surgical or percutaneous revascularization.3. Compare and contrast t

7 stable ischemic hd

Documents