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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 decision­making, 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 Editor­in­Chief
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
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 cost­effectively
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.
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 factors—smoking, obesity, diabetes, and hypertension—increases 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 asymptomatic
patients and of patients with acute coronary syndromes are covered in the module on Asymptomatic 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.
Spectrum of Risk for Future Cardiovascular Disease in Patients
With Stable Ischemic Heart Disease
In primary prevention (patients without SIHD), risk stratification is typically based on
a 10­year risk of MI or coronary heart disease death, where a 10­year risk is
considered low at <10% (or <1% per year), intermediate at 10­20%, and high at
>20%. Unfortunately, there are no similarly accepted and validated risk
categorizations for patients with SIHD, due largely to the fact that different studies
included many types of patients at varying risk for CV events.
For instance, the 1­year rate of death or MI in the PEACE (Prevention of Events With
Angiotensin­Converting Enzyme Inhibition Trial) study was <2% per year,2 whereas it
was more than twice as high among patients in the COURAGE (Clinical Outcomes
Utilizing Revascularization and Aggressive Drug Evaluation) trial3 and the BARI­2D
(Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial.4 Moreover,
many of the landmark studies of SIHD pre­date widespread utilization of stents,
statins, or dual­antiplatelet therapy, and therefore, contemporary event rates may be
substantially lower.
Despite the variability among the data, categorization of patients into low­,
intermediate­, and high­risk categories should be a primary goal in the evaluation of
patients with SIHD. Patients with an annual mortality rate of <1% are considered at
low risk, 1­3% are considered at intermediate risk, and >3% are considered at high
risk (Table 1). The analogous categories for annual CV death rate would be <1%, 1­
2%, and >2%, respectively.
Table 1
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 high­risk treadmill
score or severe resting LV dysfunction (LVEF <35%). Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP­ASIM guidelines for the management of patients with
chronic stable angina­executive 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 1999;99:2829­48.
Overview of Risk Stratification Techniques for Patients With
Stable 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 high­risk features
without overtesting, but to ensure that critical data that would identify high­risk
patients is not missed. There are four broad categories of risk stratification that
should be considered5 :
1. 2. 3. 4. Clinical evaluation and assessment of comorbidities
Functional capacity/stress test
Ventricular function
Coronary anatomy
Every patient does not require each of these modalities to be evaluated. Nor do they
need to be assessed in sequence. A low­risk patient may only require a clinical
evaluation and a stress test or echocardiogram, while a high­risk 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 diabetes—are 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 left­sided 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 4­year 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 1­year risk of CV death, MI, stroke, or
hospitalization for a CV event ranged from 12.6% for patients with an one­arterial
bed involvement, 21.1% for patients with a two­arterial bed involvement, and 26.3%
for patients with a three­arterial 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 self­limiting activity.
Figure 1
Table 2
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 ischemic
syndrome. 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, patient­based 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 population­based studies, the incidence of angina
is closely associated with age and gender. Men between 65­85 years old are at the
highest risk, with an incidence of >10 cases per 1,000 patient­years. The risk was
approximately one­half 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 one­third of the patients in the
COURAGE trial9 assigned to percutaneous coronary intervention (PCI), and one­half
of the patients assigned to revascularization in the BARI­2D 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, especially
when 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 4­year risk of CHD.12
Four­Year Risk of Cardiovascular Death, Myocardial Infarction, or Stroke in the REACH Registry
Figure 1
Four­year 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 with permission 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 2010;304:1350­7.
Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System
Table 2
Reproduced with permission from the Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca.
Accessed 02/27/2012.
Overview of Risk Stratification Techniques for Patients With
Stable Ischemic Heart Disease
(2 of 3)
Resting 12­Lead Electrocardiogram
All patients with SIHD should receive baseline and regular 12­lead
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 bundle­branch 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 12­lead 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 blood
glucose, 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 Therapy module
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 lower­risk and higher­risk
patients. No biomarker, though, has been shown to provide any clear treatment
implications in SIHD. For example, an elevated level of B­type 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 high­sensitivity 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 5­year follow­up
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 long­term population­
based study of >1,000 patients with documented CAD, patients in the highest
quartile of NT­proBNP were at a >2­fold 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
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 NT­proBNP, GDF­15, cystatin C, mid­regional­
pro­adrenomedullin (MR­proADM), and mid­regional­pro­atrial natriuretic peptide
(MR­proANP) 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 high­sensitivity C­reactive 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 variables—male, presence of typical angina, evidence of
an old MI on ECG, diabetes, and insulin use—were 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 low­density lipoprotein
cholesterol categorizes patients into a low (<1%), intermediate (1­3%), and high
(>3%) 1­year 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 aortic
stenosis 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 cost­efficient 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. Disease­modifying therapy, such as
blood pressure control, lipid­lowering 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 indication—the diagnosis of CAD in patients
without known SIHD—is covered in the module on Asymptomatic 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 ST­segment 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
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
well­validated and utilized scoring tests (Figure 3). Patients are categorized as low
risk (score of >5) with a 1­year mortality rate of 0.25%, intermediate risk (score 4 to ­
10) with a 1­year mortality rate of 1.25%, and high risk (score < ­11) with a 1­year
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 high­risk patients.25,29
Based on the strength of evidence, cost, and ease, stress testing should, in most
cases, be the first­line 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 NT­proBNP in Stable Ischemic Heart Disease (1 of 2)
Figure 2a
Elevated levels of high­sensitivity troponin T Reproduced with permission 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 2009;361:2538­47,
and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B­Type natriuretic peptides in patients with
stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:205­14.
Troponin T and NT­proBNP in Stable Ischemic Heart Disease (2 of 2)
Figure 2b
NT­proBNP 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 with permission 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 2009;361:2538­47,
and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B­Type natriuretic peptides in patients with
stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:205­14.
Duke Treadmill Score
Figure 3
The Duke Treadmill Score is the most well­validated 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
ST­segment depression, and has nonlimiting angina, which gives a score of ­1, placing her in the intermediate­risk category. The same
calculations can be performed using a nomogram by drawing a line between 1) “ST­segment deviation during exercise” and “Angina during
exercise”, and 2) “Ischemia­reading line” and “Duration of exercise” to estimate the 1­year and 5­year mortality risk. Max = maximum; MET = metabolic equivalent; MI = myocardial infarction; min = minutes
Overview of Risk Stratification Techniques for Patients With
Stable Ischemic Heart Disease
(3 of 3)
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 follow­up 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 asymptomatic or stable 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 (<35%) at rest or during stress, a large or multiple areas of
stress­induced perfusion defect (especially if anterior) or wall­motion abnormalities,
and evidence of stress­induced dilation or increased lung­update of radionuclide
tracer identify patients at highest risk (>3% annual mortality rate). Moderate LV
function (35­49%), moderate stress­induced perfusion defects or wall­motion
abnormalities identify intermediate­risk patients (1­3% annual mortality). Low­risk
patients (<1% annual mortality) include patients with small or no stress­induced
perfusion defects or wall­motion abnormalities, although it is important to integrate
the imaging results with LV function and the physiologic results from the exercise
tests (Table 1).15
Figure 4
Table 1
Figure 5a
Figure 5b
Figure 5c
Figure 5d
The indications and prognosis obtained from stress echocardiography or MRI is
similar to radionuclide imaging. The choice between the different modalities will
depend on local expertise, cost, and if there is additional information that is better
assessed with one modality compared to the other. For example, stress
echocardiography may be preferred if ischemic mitral regurgitation is suspected.
One advantage of stress echocardiography is that exercise testing can be
performed, whereas stress MRI requires pharmacologic stress.
Figure 6
Assessment of Risk by Left Ventricular Function
Regardless of the clinical situation, LV systolic function is not only one of the most
powerful predictors of short­term and long­term outcomes, but it also carries
therapeutic implications regarding appropriate medical, revascularization, and
device­based therapies. LV function therefore should be assessed in all patients
with SIHD, even without any signs or symptoms of heart failure.31
Figure 7
Echocardiography
In most cases, echocardiography will be the modality of choice for assessing LV
function, because it is easy to obtain and can also evaluate valvular or other
structural heart disease. Most radionuclide studies will also provide accurate
measurements of LV function, and if normal, would not require a follow­up
echocardiogram unless there is a clinical suspicion for structural or valvular heart
Table 3
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
Figure 8
Much of the evidence linking LV function and outcomes comes from older studies
such as the CASS (Coronary Artery Surgery Study) trial where over two­thirds of the
deaths at 5 years were observed in the roughly one­third 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
Figure 9
Assessment of Risk According to Coronary Anatomy
The decision to define coronary anatomy is one of the key decision­branch 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 intermediate­risk 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 angiography
is the "gold­standard" for identifying flow­limiting 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
triple­vessel 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 4.6­year follow­up period was 12.5% in patients with zero­ or one­vessel
disease, approximately 18% in patients with two­vessel disease, and approximately
25% in patients with three­vessel 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 1­year 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 high­suspicion 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
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 with permission 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
Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society
of Nuclear Medicine. J Am Coll Cardiol 2009;53:2201­29. 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 high­risk treadmill
score or severe resting LV dysfunction (LVEF <35%). Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP­ASIM guidelines for the management of patients with
chronic stable angina­executive 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 1999;99:2829­48. 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 three­vessel disease by ejection fraction.
EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Long­term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 1994;90:2645­57. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (2 of 4)
Figure 5b
Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients.
Panel B: Patients with one­vessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Long­term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 1994;90:2645­57. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (3 of 4)
Figure 5c
Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients.
Panel C: Patients with two­vessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Long­term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 1994;90:2645­57. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (4 of 4)
Figure 5d
Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients.
Panel D: Patients with three­vessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Long­term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 1994;90:2645­57. 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 with permission 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 2011;123:1492­500. 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 with permission from Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the all­comers
population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. J Am Coll Cardiol
2010;56:272­7. 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/ACP­ASIM guidelines for the management of patients with
chronic stable angina­executive 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 1999;99:2829­48.
Overall Survival by Number of Diseased Arteries
Figure 8
Overall survival according to the number of diseased arteries detected by computed tomography angiography. Reproduced with permission from Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic
angiography for prediction of all­cause mortality. J Am Coll Cardiol 2007;50:1161­70. 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 with permission 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 2006;27:1341­81. Future Directions
Continued research into novel biomarkers such as high­sensitivity 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.
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 step­wise and logical progression.
Categorization of patients into low­, intermediate­, and high­risk categories should be a primary goal in the
evaluation of patients with SIHD. Patients with an annual mortality rate of <1% are considered low risk, an annual
rate of 1­3% as intermediate risk, and >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 first­line 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
device­based 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 intermediate­risk 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 not
simply as a diagnostic tool to identify potential lesions for revascularization.
References
1. Roger VL, Go AS, Lloyd­Jones DM, et al. Heart disease and stroke statistics­2011 update: a report from the
American Heart Association. Circulation 2011;123:e18­e209.
2. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin­converting­enzyme inhibition in stable coronary artery
disease. N Engl J Med 2004;351:2058­68.
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 2007;356:1503­16.
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 2009;360:2503­15.
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 2006;27:1341­81.
6. Bhatt DL, Eagle KA, Ohman EM, et al., on behalf of the REACH Registry Investigators. Comparative determinants
of 4­year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA
2010;304:1350­7.
7. Steg PG, Bhatt DL, Wilson PW, et al., on behalf of the REACH Registry Investigators. One­year cardiovascular
event rates in outpatients with atherothrombosis. JAMA 2007;297:1197­206.
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 2008;359:677­87.
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 2011;123:1492­500.
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 2008;102:1301­6.
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 2008;168:1423­8.
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 2010;31:92­9.
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 of
treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009;120:2529­40.
15. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with
chronic stable angina­­summary 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;41:159­68.
16. Das MK, Saha C, El Masry H, et al. Fragmented QRS on a 12­lead ECG: a predictor of mortality and cardiac events
in patients with coronary artery disease. Heart Rhythm 2007;4:1385­92.
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 2006;113:2495­501.
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
disease. N Engl J Med 2009;361:2538­47.
19. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from
cardiovascular causes. N Engl J Med 2008;358:2107­16.
20. Blankenberg S, McQueen MJ, Smieja M, et al., on behalf of the HOPE Study Investigators. Comparative impact of
multiple biomarkers and N­Terminal pro­brain 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 2006;114:201­8.
21. Omland T, Sabatine MS, Jablonski KA, et al., on behalf of the PEACE Investigators. Prognostic value of B­Type
natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol
2007;50:205­14.
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 2010;31:3024­31.
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 2003;107:499­511.
24. Marschner IC, Colquhoun D, Simes RJ, et al., on behalf of the LIPID Study Investigators. Long­term risk
stratification for survivors of acute coronary syndromes. Results from the Long­term Intervention with Pravastatin
in Ischemic Disease (LIPID) Study. J Am Coll Cardiol 2001;38:56­63.
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 2002;40:1531­40.
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 2002;346:793­801.
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 1987;106:793­800.
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 1991;325:849­53.
29. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart­rate recovery immediately after exercise as a
predictor of mortality. N Engl J Med 1999;341:1351­7.
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 2009;53:2201­29.
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 2002;325:1156.
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 2011;57:1126­66.
33. Emond M, Mock MB, Davis KB, et al. Long­term survival of medically treated patients in the Coronary Artery Surgery
Study (CASS) Registry. Circulation 1994;90:2645­57.
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 2009;2:320­7.
35. Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the all­comers
population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent
coating) trial. J Am Coll Cardiol 2010;56:272­7.
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 Foundation
Appropriate 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
2010;56:1864­94.
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 2007;49:62­70.
38. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic
angiography for prediction of all­cause mortality. J Am Coll Cardiol 2007;50:1161­70.
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7.2: Medical Therapy
Author(s): Richard A. Lange, MD, FACC
Learner Objectives
Upon completion of this module, the reader will be able to:
1. 2. 3. 4. Apply appropriate secondary prevention measures of coronary heart disease (CHD).
Identify antianginal drugs that prevent reinfarction and improve survival in post­myocardial infarction (MI) patients.
Identify patients who benefit from angiotensin­converting enzyme (ACE) inhibitors.
Describe the goal serum low­density lipoprotein cholesterol (LDL­C) concentration for patients with stable CHD.
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 lipid­lowering therapy. In the patient with diabetes, tight
glycemic 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
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 A2 , 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, the Antiplatelet Trialists' Collaboration meta­analysis 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 10­15
vascular events for every 1,000 people treated.2
Aspirin dose of 75­162 mg daily is equally as effective as 325 mg in secondary prevention, but with a lower risk of
bleeding. Doses <75 mg have less proven benefit.2,3 The 2007 Chronic Angina Focused Update of the American College
of Cardiology/American Heart Association (ACC/AHA) 2002 Guidelines for the Management of Patients With Chronic
Stable Angina recommend that all patients with chronic stable angina or those with clinical or laboratory evidence of CAD
receive aspirin, 75­162 mg daily, indefinitely.3 Although aspirin prevents vascular events, it does not reduce anginal
episodes.
Aspirin is relatively contraindicated in patients with known allergies to nonsteroidal anti­inflammatory drugs, and in
patients with the syndrome of asthma, rhinitis, and nasal polyps.
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 aspirin­treated 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 post­hoc 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 75­162 mg daily and clopidogrel 75 mg daily may be
reasonable in certain high­risk patients with chronic CAD.
Beta­Blockers
Beta­blockers 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, beta­blockers remain first­line therapy in the treatment of
chronic ischemic heart disease, particularly effort­induced 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
beta­blockers appear to be equally efficacious in stable ischemic heart disease.7­11
Beta­blocker dosing should be adjusted to limit the heart rate to 55­60 bpm at rest
and to not exceed 75% of the exercise heart rate response at the onset of ischemia.
Beta­blockers 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), MERIT­HF (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).12­14 This does not appear to be a class effect that extends to
all beta­blockers because the BEST (Beta­Blocker Evaluation of Survival Trial) study
did not show a reduction in mortality with bucindolol.15
Beta­blocker therapy should be initiated and continued indefinitely in all patients with
prior MI or left ventricular (LV) dysfunction—with or without heart failure symptoms—
unless contraindicated.3 Some of the mechanisms responsible for the benefits of
beta­blockers in these patients include increased myocardial beta­adrenergic
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, beta­blockers have several notable side effects.
Because of their negative inotropic effects, beta­blocker therapy should be advanced
cautiously in patients with impaired LV systolic function. Beta­blockers 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 beta­blocker 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
Mortality Benefit of Beta­Blockers in Congestive Heart Failure
Figure 1
Annual mortality in four studies of patients with congestive heart failure­­most of whom had an ischemic cardiomyopathy­­treated with a)
placebo or b) beta­blockers 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 (CIBIS­II): A randomised trial. Lancet 1999;353:9­13.
2. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled­release metoprolol on total mortality, hospitalizations, and well­being
in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT­HF). MERIT­HF Study
Group. JAMA 2000;283:1295­302.
3. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651­8.
4. A trial of the beta­blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659­67.
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.
Angiotensin­Converting 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, "high­risk" 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 follow­up.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 high­risk 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 follow­up in a lower­risk population with
stable CHD and no apparent heart failure.17
Conversely, in the PEACE (Prevention of Events With Angiotensin­Converting
Enzyme Inhibition) trial, which enrolled >8,000 low­risk 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 been
attributed to the fact that the study population was lower risk and more likely to be
intensively treated with coronary revascularization and lipid­lowering therapy than the
patients in the previous studies.
Similarly, in the QUIET (Quinapril Ischemic Event Trial)19 and IMAGINE (Ischemia
Management With Accupril Post­Bypass Graft via Inhibition of the Converting
Enzyme)20 studies of low­risk (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 lower­risk patients with mildly
reduced or normal LVEF in whom CV risk factors are well controlled and
revascularization has been performed.
Figure 2
Lack of Benefit of ACE Inhibitor in "Low­Risk" Stable CAD Patients
Figure 2
Composite outcome of cardiovascular death, myocardial infarction, or coronary revascularization in “low­risk” patients with stable coronary
artery disease (CAD) and preserved left ventricular function treated with placebo or trandolapril in the PEACE study. Over the 4.8­year follow­
up, the addition of trandolapril to current standard therapy was not beneficial in reducing cardiovascular events. ACE inhibitor = angiotensin­converting enzyme inhibitor. Reproduced with permission from Massachusets Medical Society. The PEACE Trial Investigators. Angiotensin­Converting­Enzyme Inhibition in
Stable Coronary Artery Disease. N Engl J Med 2004;351:2058­68. Copyright © 2000, Massachusetts Medical Society. All rights reserved.
Angiotensin­Receptor Blockers
Angiotensin­receptor 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 follow­up in patients with vascular disease or
high­risk 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.
Influenza Vaccine
An ACC/AHA science advisory recommends annual vaccination with inactivated vaccine (administered intramuscularly)
against seasonal influenza to prevent all­cause 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
Low­Density 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 pre­existing 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 LDL­C 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 10­year risk of CHD
>20%) merit aggressive lipid management.
The goal serum LDL­C concentration for patients with stable CHD or a CHD
equivalent is <100 mg/dl.25 When LDL­lowering drug therapy is employed in high­
risk or moderately high­risk persons, it is advised that the intensity of therapy be
sufficient to achieve at least a 30­40% reduction in LDL­C levels.
For individuals considered to be at very high risk for CHD, an LDL­C goal of <70
mg/dl is a reasonable therapeutic strategy.25 This group would include individuals
with established CV disease plus one of the following: 1) multiple major risk factors
(especially diabetes), 2) severe and poorly controlled risk factors (especially
continued cigarette smoking), and 3) multiple risk factors of the metabolic syndrome
(especially high triglycerides >200 mg/dl plus non­high­density lipoprotein
cholesterol [HDL­C] >130 mg/dl with low HDL­C [<40 mg/dl]).
All patients with high serum LDL­C should undergo lifestyle modifications, such as
reducing dietary total and saturated fat (to <20% and <10% of caloric intake,
respectively), weight loss if overweight, and aerobic exercise. Such changes typically
result in <10% reduction in serum total and LDL cholesterol levels. However, in
several clinical trials, lifestyle modification alone has been associated with
angiographic evidence of slowed progression and modest regression of coronary
atherosclerosis and reduced clinical events (angina, MI, coronary revascularization,
or death). In these trials, the clinical and angiographic improvement induced by
dietary intervention was more likely to occur when it resulted in substantial
reductions in LDL­C. Unfortunately, dietary modification alone is often unsuccessful
in achieving target serum LDL­C concentrations.
Lipid­altering agents include several classes of drugs: bile acid sequestrants,
nicotinic acid, hydroxymethylglutaryl coenzyme A (HMG­CoA) reductase inhibitors
(statins), fibrates, probucol, and ezetimibe. These drugs differ with respect to
mechanism of action and to the degree and type of lipid lowering. Thus, the
indications for a particular drug are influenced by the underlying lipid abnormality.
Conventional dosing regimens and typical changes in the lipid profile with drug
therapy are listed in Table 1. Common side effects are listed in Tables 2a and b.
Cessation of therapy because of adverse effects occurs most commonly with bile
acid sequestrants and short­acting nicotinic acid, and least commonly with the
statins.
Statins are the most effective drugs for lowering serum LDL­C, with reductions in the
range of 20­60%. Additionally, they lower serum triglyceride 15­35% and raise
serum HDL­C 5­15%. Fluvastatin is the least potent, and rosuvastatin is the most
potent statin. Adverse reactions occur less frequently with the statins than with the
other classes of lipid­lowering agents, but patients taking them should be monitored
for possible liver or muscle injury.
The major effects of the fibrates are to lower serum triglyceride and raise HDL­C
levels. They are effective for the treatment of hypertriglyceridemia and combined
hyperlipidemia with or without low­serum HDL­C (hypoalphalipoproteinemia). The
benefits of fibrates in the contemporary era of statin use is questionable, since
the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial of diabetics
Figure 3
Table 1
Table 2a
Table 2b
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 LDL­C. They may be used in combination with statins or nicotinic acid in
patients with markedly elevated serum levels of LDL­C. 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 low­serum HDL­C 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 well­controlled LDL­C on statin therapy (i.e., those with low HDL­C
and high triglyceride levels), the addition of high­dose, extended­release niacin to
statin therapy does not reduce the risk of CV events.27
Probucol modestly lowers LDL­C, but more prominently reduces HDL­C. 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 10­year 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 Reproduced with permission from Massachusetts Medical Society. Pekkanen J, Linn S, Heiss G, et al. Ten­year mortality from cardiovascular
disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322:1700­7. Copyright
© 1990, Massachusetts Medical Society. All rights reserved.
Lipid­Lowering Drug Therapy
Table 1
Conventional dosing regimens and typical changes in the lipid profile with drug therapy. HDL = high­density lipoprotein; LDL = low­density lipoprotein.
Common Side Effects of Lipid­Lowering Drug Therapy (1 of 2)
Table 2a
Common Side Effects of Lipid­Lowering Drug Therapy (2 of 2)
Table 2b
Low­Density Lipoprotein Cholesterol Lowering Therapy
(2 of 2)
Ezetimibe reduces LDL­C 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 long­term 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 life­limiting comorbid conditions benefit from lipid­lowering 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 LDL­C 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 lipid­lowering agents include plaque
stabilization, reversal of endothelial dysfunction, antioxidant effects, decreased
thrombogenicity, and anti­inflammatory 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 8­year follow­up period.33 The
reduction in major cardiac events was highly correlated with on­treatment serum
total cholesterol and LDL concentrations and with changes from baseline. Each
additional 1% reduction in LDL­C reduced the risk of major cardiac events by
1.7%.34
The LIPID (Long­Term 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 155­270 mg/dl to therapy with pravastatin or
placebo. After a mean follow­up of 60 months, the study was terminated prematurely
because, compared with placebo, pravastatin therapy lowered morbidity and
mortality from CV disease, as well as all­cause 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, LDL­C, HDL­C, 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
LDL­C levels above 125 mg/dl.
Figure 4
The Heart Protection Study (HPS) questioned whether a target LDL goal <100 mg/dl
is sufficient in high­risk individuals.37 In this study of >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 5.5­year follow­up. Importantly,
subgroup analysis suggested that simvastatin therapy produced similar reductions
in relative risk regardless of the baseline levels of LDL­C, including subgroups with
baseline LDL­C levels >135 mg/dl, <116 mg/dl, or <100 mg/dl.
The PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial extends
the use of statins to the older population.28 Approximately 6,000 subjects ages 70­
82 years with a history of vascular disease or CV disease risk factors were
randomized to pravastatin (40 mg/day) or placebo and followed for 3.2 years. Major
coronary events, defined as nonfatal MI and CHD death, were reduced by 19% and
CHD mortality by 24% with pravastatin therapy.
Mortality Benefit With Statin Therapy in Patients With a Broad Range of Serum Cholesterol Concentrations
Figure 4
Kaplan­Meier estimates of mortality due to coronary heart disease in the pravastatin and placebo groups in the LIPID Study. CHD = coronary heart disease Reproduced with permission from Massachusetts Medical Society. Prevention of cardiovascular events and death with pravastatin in patients
with coronary heart disease and a broad range of initial cholesterol levels. The Long­Term Intervention with Pravastatin in Ischaemic Disease
(LIPID) Study Group. N Engl J Med 1998;339:1349­57. Copyright © 1998, Massachusetts Medical Society. All rights reserved.
Key Points
Unless contraindicated, all patients with evidence of CAD should receive aspirin to prevent MI.
Beta­blockers 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 "high­risk" 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 LDL­C. The goal serum LDL­C concentration for patients
with stable CHD or a CHD equivalent is <100 mg/dl, and for those at "very high risk" (i.e., established CHD and
multiple risk factors), the LDL­C goal is <70 mg/dl.
References
1. Gerstein HC, Miller ME, Genuth S, et al., on behalf of the ACCORD Study Group. Long­term effects of intensive
glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818­28.
2. Antithrombotic Trialists' Collaboration. Collaborative meta­analysis of randomised trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71­86.
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 2007;50:2264­74.
4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of
ischaemic events (CAPRIE). Lancet 1996;348:1329­39.
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 2006;354:1706­17.
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 2007;49:1982­8.
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 1991;67:665­70.
8. Hauf­Zachariou 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 1997;52:95­100.
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 2007;3:235­
42.
10. Narahara KA. Double­blind comparison of once daily betaxolol versus propranolol four times daily in stable
angina pectoris. Betaxolol Investigators Group. Am J Cardiol 1990;65:577­82.
11. Raftery EB. The preventative effects of vasodilating beta­blockers in cardiovascular disease. Eur Heart J 1996;17
Suppl B:30­8.
12. CIBIS­II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS­II): a randomised trial.
Lancet 1999;353:9­13.
13. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled­release metoprolol on total mortality,
hospitalizations, and well­being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial
in congestive heart failure (MERIT­HF). MERIT­HF Study Group. JAMA 2000;283:1295­302.
14. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med
2001;344:1651­8.
15. Beta­Blocker Evaluation of Survival Trial Investigators. A trial of the beta­blocker bucindolol in patients with
advanced chronic heart failure. N Engl J Med 2001;344:1659­67.
16. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin­converting­enzyme
inhibitor, ramipril, on cardiovascular events in high­risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000;342:145­53.
17. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery
disease: randomised, double­blind, placebo­controlled, multicentre trial (the EUROPA study). Lancet
2003;362:782­8.
18. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin­converting­enzyme inhibition in stable coronary artery
disease. N Engl J Med 2004;351:2058­68.
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
2001;87:1058­63.
20. Rouleau JL, Warnica WJ, Baillot R, et al. Effects of angiotensin­converting enzyme inhibition in low­risk patients
early after coronary artery bypass surgery. Circulation 2008;117:24­31.
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 2008;358:1547­59.
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
2006;114:1549­53.
23. de Diego C, Vila­Corcoles A, Ochoa O, et al. Effects of annual influenza vaccination on winter mortality in elderly
people with chronic heart disease. Eur Heart J 2009;30:209­16.
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 1999;33:125­30.
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 2004;44:720­32.
26. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J
Med 2010;362:1563­74.
27. Boden WE, Probstfield JL, Anderson T, et al., on behalf of the AIM­HIGH Investigators. Niacin in patients with low
HDL cholesterol levels receiving intensive statin therapy. N Engl J Med;365:2255­67.
28. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER):
a randomised controlled trial. Lancet 2002;360:1623­30.
29. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit:
impact of statin trials. Circulation 1998;97:946­52.
30. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high­intensity statin therapy on regression of coronary
atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556­65.
31. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid­lowering therapy on
progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071­80.
32. [No authors listed]. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383­9.
33. Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow­up study of patients randomized in the Scandinavian
simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 2000;86:257­62.
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 1998;97:1453­60.
35. The Long­Term 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 Long­Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
N Engl J Med 1998;339:1349­57.
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
1996;335:1001­9.
37. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20,536 high­risk individuals: a randomised placebo­controlled trial. Lancet 2002;360:7­22.
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7.3: Indications for Revascularization
Author(s): John McPherson, MD, FACC
Learner Objectives
Upon completion of this module, the reader will be able to:
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 the management of patients with stable ischemic heart disease (SIHD) and acute coronary
syndromes (ACS) with respect to the need for revascularization.
4. Manage asymptomatic patients with obstructive CAD according to current treatment guidelines.
Introduction
Despite many advances in the primary prevention of cardiovascular (CV) disease,
SIHD continues to be a significant cause of morbidity and disability. It is estimated
that 10 million Americans have SIHD, with 500,000 new cases of angina diagnosed
each year.1 Unlike patients with ACS, patients with SIHD are primarily managed in
the outpatient setting, with a focus on four major aspects of care: 1) identification
and treatment of associated diseases that can precipitate angina, 2) reduction of
coronary risk factors and modifying lifestyle factors, 3) administering medical therapy
(see module on Medical Therapy in this chapter), and 4) revascularization by
percutaneous coronary intervention (PCI) or by coronary artery bypass grafting
(CABG).
Through this comprehensive approach, the prevalence of major CV risk factors,
such as tobacco use, hypercholesterolemia, and hypertension, has decreased, and
with the use of evidence­based therapies (including antiplatelet agents, beta­
blockers, angiotensin­converting enzyme [ACE] inhibitors, statins, and myocardial
revascularization), mortality from CAD has decreased by nearly 50% over the past
several decades.2,3
In 1964, Garrett, Dennis, and DeBakey reported on the first CABG surgery.4 In the
following two decades, myocardial revascularization with CABG in patients with
SIHD was a major focus of investigation. Studies including the landmark CASS
(Coronary Artery Surgery Study)5 and VACS (Veterans Administration Cooperative
Study)6 demonstrated a mortality benefit with CABG in specific anatomic subsets of
patients, primarily due to the use of the left internal mammary graft to revascularize
the left anterior descending (LAD) coronary artery.7 With improvement in surgical
techniques and perioperative management, clinical outcomes following elective
CABG have continued to improve, with an approximate 2% major adverse event rate
and a 1% hospital mortality rate.8
PCI in the form of balloon angioplasty was first performed by Gruentzig in 1977 for
the treatment of proximal, noncalcified lesions involving a single coronary artery.9
Refinement of percutaneous techniques has also advanced over the past two
decades, allowing for the ability to treat a wide range of patients with significant
comorbidities and complex CAD. In addition, advances in adjunctive
pharmacological therapy with dual antiplatelet therapy, antithrombotic agents,
vascular closure devices, and radial arterial access have also led to a reduction in
periprocedural ischemic events and reduced bleeding complications.10 Data from a
high­volume PCI center on patients undergoing elective PCI from 2003­3006
demonstrated a procedural success rate of 96%, a major cardiac adverse event rate
of 0.6%, and a mortality rate of 0.1%.11
Along with refinement in revascularization techniques of the past three decades,
understanding of the pathogenesis and triggers of adverse CV events in patients
with SIHD has advanced in parallel. An important finding is that the majority of ACS
are caused by nonobstructive, clinically silent coronary plaques. Several studies,
including the COURAGE (Clinical Outcomes Utilizing Revascularization and
Aggressive Drug Evaluation) trial,12 have demonstrated that successful PCI of
severe, clinically stable coronary stenoses does not reduce the rate of death or
myocardial infarction compared with optimal medical therapy. In the COURAGE trial,
2,287 patients were randomized to PCI plus optimal medical therapy or optimal
medical therapy alone. At 4.6­year follow­up, rates of death and nonfatal myocardial
infarction were similar (19.0% and 18.5%, respectively) (Figure 1, panel A). With
some exceptions, the primary benefit of revascularization in SIHD patients, therefore,
is relief of ischemic symptoms rather than prevention of major cardiac events.
In 2009, the American College of Cardiology Foundation, the Society for
Cardiovascular Angiography and Intervention, and the Society of Thoracic Surgeons,
along with other key specialty and subspecialty societies, published
appropriateness criteria for coronary revascularization.13 These criteria and the
available evidence guiding the selection of patients who are candidates for
revascularization is discussed later in this module.
Figure 1
Kaplan­Meier Survival Curves
Figure 1
The estimated 4.6­year 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 medical­therapy group. In Panel B, the estimated 4.6­year rate of death from any cause was 7.6% in the PCI group and
8.3% in the medical­therapy group. In Panel C, the estimated 4.6­year rate of hospitalization for acute coronary syndrome (ACS) was 12.4% in
the PCI group and 11.8% in the medical­therapy group. In Panel D, the estimated 4.6­year rate of acute myocardial infarction was 13.2% in the PCI
group and 12.3% in the medical­therapy group. CI = confidence interval; PCI = percutaneous coronary intervention. Reproduced with permission from 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;356:1503­16.
Acute Coronary Syndromes
The evidence supporting revascularization as the fundamental treatment of patients with ACS and ST­segment elevation
myocardial infarction (STEMI) is discussed in detail in Chapter 6: Acute Coronary Syndromes. In patients presenting with
STEMI, revascularization for primary reperfusion is appropriate unless the presentation is >12 hours from symptom onset
and there are no ongoing ischemic symptoms or hemodynamic instability. Following thrombolytic therapy,
revascularization is indicated in patients with heart failure or ongoing ischemia and should be considered in patients with
STEMI and high­risk features, such as extensive ST­segment elevation, new left bundle branch block, anterior infarction,
and depressed left ventricular (LV) function.13 Following successful reperfusion therapy, the revascularization of
nonculprit arteries before hospital discharge should be performed only in patients with clinical instability, recurrent or
provokable ischemia, or depressed LV function. In general, revascularization should be considered in patients
presenting with unstable angina or non−ST­segment elevation myocardial infarction and high­risk features, as outlined in
Chapter 6: Acute Coronary Syndromes.
Stable Ischemic Heart Disease
There are two principal objectives of revascularization in patients with SIHD:
improvement of survival and relief of ischemic symptoms. In general, all patients
with SIHD should receive appropriate medical therapy before revascularization is
considered. The decision to refer SIHD patients for revascularization generally
should be based on five clinical factors: 1) the presence of significant left main
disease, 2) noninvasive risk stratification, 3) severity of ischemic symptoms, 4) the
anatomical severity of CAD burden, and 5) the intensity of medical therapy. For a
discussion regarding the choice of revascularization strategy (i.e., surgical vs.
percutaneous) in patients with SIHD, refer to the module on Percutaneous Coronary
Intervention versus Coronary Artery Bypass Grafting in this chapter.
Table 1
Table 2
Left Main Disease
Revascularization in patients with left main coronary stenosis ≥50% was primarily
studied in the 1970s and 1980s. Multiple studies from that era, including data from
the VACS6 and the CASS registry,5 demonstrated that CABG significantly improved
survival compared with medical therapy in patients with significant left main coronary
disease. There are currently no randomized studies comparing PCI with medical
therapy in left main disease. Based on available surgical data, revascularization is
indicated in all patients with significant left main disease, regardless of symptoms
or noninvasive findings.14,15
Table 3
Noninvasive Risk Assessment
Criteria for noninvasive risk stratification are summarized in Table 1. In patients
referred for noninvasive testing, the annual mortality risk is directly related to
exercise capacity, severity of ischemic symptoms, the amount of ischemia
demonstrated on imaging, and the degree of ventricular dysfunction.
In patients with moderate­to­severe inducible ischemia (involving ≥10% of total
myocardium), patients treated with revascularization have a significantly lower
mortality rate compared with those treated medically.16 Thus, revascularization is
recommended in nearly all patients with high­risk noninvasive findings; there is
uncertainty in asymptomatic or minimally symptomatic patients without proximal LAD
coronary disease (Table 2). In patients with intermediate risk on noninvasive testing,
nearly all patients with ischemic symptoms despite maximal medical therapy should
be referred for revascularization (Table 3). In general, patients with proximal LAD
disease or three­vessel disease regardless of therapy also benefit from
revascularization.
Intermediate­risk, asymptomatic patients with a low burden of CAD generally are
inappropriate candidates for revascularization. In patients with low­risk noninvasive
findings, only patients with ischemic symptoms despite maximal medical therapy
should be referred for revascularization. An exception to this recommendation
involves patients with severe symptoms and a large disease burden; therapeutic
uncertainty exists regarding patients with no symptoms or with only mild symptoms
(Table 4).
Severity of Ischemic Symptoms
The Canadian Cardiovascular Society (CCS) classification method is most
commonly used to evaluate the severity of ischemic symptoms (Table 5). As
expected, the severity of anginal symptoms correlates with mortality risk. In patients
with class III or IV symptoms, revascularization with CABG has been demonstrated
to improve survival compared with medical therapy.5 Although relatively little data are
available that compare PCI to medical therapy in these patients, revascularization is
recommended in nearly all patients with severe (CCS class III or IV) angina (Table
2).
In patients with SIHD who have milder symptoms (CCS class I or II), the decision to
revascularize should include consideration of the intensity of medical therapy,
noninvasive risk assessment, and the anatomical extent of CAD. Thus,
Table 4
Table 5
Table 6
revascularization is indicated in patients who have high­risk noninvasive findings,
symptoms despite maximal medical therapy, and significant disease burden
(Tables 2, 3). In general, asymptomatic patients should be considered for
revascularization only when noninvasive findings are high­risk, or for severe three­
vessel disease (Table 4).
Anatomical Coronary Artery Disease Burden
From an anatomical standpoint, it is well established that the extent of CAD predicts
outcomes in patients with SIHD. In general, CV risk is associated with the amount of
myocardium supplied by the diseased arteries (Table 6). In the CASS study, a
mortality benefit was observed with revascularization in patients with the following
conditions:
Left main coronary artery stenosis or left main equivalent disease
Three­vessel CAD, particularly with a reduced LV ejection fraction (≤40%)
Two­vessel CAD including a >75% stenosis in the proximal LAD artery
In the absence of the above conditions, the decision to revascularize a patient with
SIHD should take into account the degree of CAD in the context of the severity of
symptoms on maximal medical therapy, the degree of ischemia present on
noninvasive testing, and the amount of myocardium supplied by the diseased
vessels. Thus, there is a gradient for the appropriateness of revascularization based
on these three factors. For patients with single­vessel CAD not involving the proximal
LAD artery, revascularization is only indicated in the presence of class III/IV angina or
intermediate­to­high risk findings on noninvasive stress testing (Tables 2, 3).
Noninvasive Risk Stratification
Table 1
LV = left ventricular; LVEF = left ventricular ejection fraction. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for
coronary revascularization. J Am Coll Cardiol 2009;53:530­53.
Appropriateness Ratings by High­Risk Findings on Noninvasive Imaging Study and Severity of Angina
Table 2
CTO = chronic total occlusion; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for
coronary revascularization. J Am Coll Cardiol 2009;53:530­53.
Appropriateness Ratings by Intermediate­Risk Findings on Noninvasive Imaging Study and Severity of Angina
Table 3
CTO = chronic total occlusion; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for
coronary revascularization. J Am Coll Cardiol 2009;53:530­53.
Appropriateness Ratings by Low­Risk Findings on Noninvasive Imaging Study and Asymptomatic Patients
Table 4
CTO = chronic total occlusion; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for
coronary revascularization. J Am Coll Cardiol 2009;53:530­53.
Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System
Table 5
Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for
coronary revascularization. J Am Coll Cardiol 2009;53:530­53.
Prognosis by Extent of Anatomical Coronary Artery Disease
Table 6
*Assuming medical treatment only. CAD = coronary artery disease; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for
coronary revascularization. J Am Coll Cardiol 2009;53:530­53.
Special Patient Subsets
Previous Coronary Artery Bypass Grafting
In general, the indications for revascularization in patients with prior CABG are the same as for patients without prior
CABG; patients with high­risk noninvasive findings or those with obstructive disease subtending a large myocardial
territory are expected to derive a mortality benefit with revascularization. By contrast, patients with a patent internal
mammary graft to the LAD artery and low­risk noninvasive findings should be referred for revascularization, primarily for
symptomatic relief despite maximal medical therapy. However, with the increased level of complexity of CV disease and
limited evidence regarding repeat revascularization in these patients, the threshold for appropriateness is generally lower
than for patients without prior CABG.13
Elderly Patients
Although increasing age is known to be a strong predictor of adverse events in patients with CAD, it is also clear that
elderly patients are at higher risk for adverse events after revascularization from both CABG and PCI.17,18 In addition,
most large randomized trials of revascularization excluded elderly patients. With improvements in both surgical and
percutaneous revascularization techniques, the risks of revascularization procedures in elderly patients are declining,
and data from more recent studies indicate that selected elderly patients derive similar if not more relative benefit from
revascularization compared with younger patients.17­19
The current practice guidelines for PCI and CABG as well as the Appropriateness Criteria for Revascularization apply to
all adult patients with SIHD, regardless of age. However, careful consideration of patient­specific procedural risks and
comorbidities is of particular importance in the treatment of elderly patients.
Diabetes
Patients with diabetes who have SIHD are at increased risk for adverse CV events compared with nondiabetic patients.
However, there is no evidence that a more aggressive approach to revascularization in these patients improves
outcomes. In the BARI 2D (Bypass Angioplasty Revascularization Investigation) trial, patients with diabetes randomized to
revascularization had no improvement in 5­year death rate, myocardial infarction, or stroke compared with those treated
with optimal medical therapy.20 However, if the decision is made to revascularize a patient with diabetes, there is
evidence that outcomes are better with CABG than with PCI. In the era of bare­metal stents, a large meta­analysis
demonstrated improved long­term survival with CABG compared with PCI.21
Current data on the use of drug­eluting stents from the SYNTAX (Synergy Between Percutaneous Coronary Intervention
With Taxus and Cardiac Surgery) study found that patients with diabetes had higher rates of revascularization following
PCI than with CABG, particularly in those with more complex disease.22
Chronic Kidney Disease
CV disease is the primary cause of mortality in patients with chronic kidney disease. Although data from randomized
trials are not available, findings from observational studies suggest an improved survival rate with revascularization in
patients with multivessel CAD and chronic kidney disease.23
Left Ventricular Dysfunction
Early data from randomized trials demonstrated a survival benefit with CABG compared with medical therapy in patients
with mild­to­moderate LV systolic dysfunction.5,6 However, more recent data from the STICH (Surgical Treatment for
Ischemic Heart Failure) trial did not demonstrate an overall survival benefit with CABG in patients with ischemic
cardiomyopathy and LV ejection fraction ≤35%.24 Because multiple secondary endpoints from STICH did indicate
improved outcomes with CABG, the study follow­up has been extended to 10 years to evaluate long­term outcomes.
There are currently no randomized data on the use of PCI in this population, and current guidelines state that CABG to
improve survival is reasonable in patients with mild­to­moderate LV systolic dysfunction and significant CAD with
evidence of viable myocardium in the region of intended revascularization.14,15
Hybrid Coronary Revascularization
The rationale behind hybrid coronary revascularization is to combine the advantages of CABG (durability of the left internal
mammary artery [LIMA] graft) and PCI in patients with multivessel CAD.25 Typically, the LAD artery is surgically bypassed
using the LIMA, and PCI is performed of one or more other coronary arteries. Patients particularly suited for the hybrid
approach include those with chronic total occlusions or patent vessels unfavorable for PCI and patients with a lack of
surgical graft conduit or heavily calcified aortas in which saphenous vein grafting would be difficult. Hybrid procedures
may be performed in a suitable hybrid operative suite in one setting, or they may be staged. In a staged procedure, the
PCI usually follows the LIMA bypass to minimize perioperative bleeding from antiplatelet therapy and also so that
angiographic evaluation of the LIMA graft can be performed.
Preoperative Coronary Revascularization
In general, decisions on revascularization in patients with SIHD undergoing noncardiac surgery are consistent with those
regarding other patients with SIHD. Patients with significant left main or severe three­vessel CAD should be treated with
revascularization prior to elective noncardiac surgery. In the absence of these indications, there is no evidence that
routine preoperative revascularization improves outcomes after noncardiac surgery. If PCI is performed in a patient in
whom noncardiac surgery is likely, the operator should consider carefully the timing of the operation, the feasibility of
continuing dual antiplatelet therapy during surgery, and the type of stent used in the PCI.
Noncardiac surgery performed within 4 weeks of stent implantation is associated with high rates of stent thrombosis and
death; in this case, balloon angioplasty is recommended whenever possible. If surgery is anticipated within 1­12 months
following PCI, it recommended that bare­metal stents be used, such that dual antiplatelet therapy can be discontinued
safely before surgery. If a drug­eluting stent is placed, elective surgery should be delayed for at least 12 months, if
possible.15
Adjunctive Assessment of the Physiologic Significance of Coronary Artery Stenoses
It is well­known that angiography has limitations in the assessment of coronary stenoses, particularly in the evaluation of
intermediate (40­70% obstructive) lesions. Fractional flow reserve (FFR) has emerged as a useful tool in the
assessment of such lesions. FFR values <0.75 correlate well with ischemia on noninvasive testing, and the findings
from the DEFER (Deferral Versus Performance of Balloon Angioplasty in Patients Without Documented Ischemia) study
demonstrated that patients with angiographic lesions associated with an FFR >0.75 had better outcomes with medical
therapy compared with PCI.26
The evaluation and treatment of patients with multivessel CAD using FFR was studied in the FAME (Fractional Flow
Reserve Versus Angiography for Multivessel Evaluation) study.27 In FAME, PCI was deferred in lesions with an FFR of
>0.80. Despite lower overall use of stents and revascularization, clinical outcomes were improved in the FFR group
compared with the group treated with angiography alone. Intravascular ultrasound (IVUS) can provide significant
additional information about coronary lesions, such as luminal diameters, cross­sectional area, and plaque size and
characteristics. IVUS has been used to assist in the evaluation of angiographically indeterminate coronary lesions.
In general, in left main coronary stenoses, a minimal luminal area of <6 mm2 is believed to be consistent with a flow­
limiting lesion that may benefit from revascularization. In other coronary stenoses, the correlation between minimum
luminal area and ischemia is more problematic, as other factors including vessel size, lesion length, and the extent of
myocardium subtended by the lesion may influence the ischemic potential and choice of treatment.
Summary
SIHD is one of the most common manifestations of CV disease, and its prevalence undoubtedly will increase over time.
Treatment of patients with SIHD initially should focus on secondary prevention with medical therapy and control of
modifiable coronary risk factors. The two fundamental goals of revascularization in SIHD are to improve survival and to
provide relief of ischemic symptoms. In SIHD, patients with improved survival with revascularization include those with
significant left main disease, a large amount of ischemic myocardium, and severe anginal symptoms despite maximal
medical therapy. In stable symptomatic patients, the anatomical degree of CAD burden, the amount of ischemia on
noninvasive stress testing, the severity of symptoms, the intensity of medical therapy, and associated comorbidities are
all important considerations in determining the clinical benefits of surgical or percutaneous revascularization.
Key Points
Medical therapy with antiplatelet agents, lipid­lowering therapy, and antianginal agents is the mainstay of
treatment in patients with SIHD.
The goals of revascularization are to improve survival and to provide relief of ischemic symptoms.
Revascularization is indicated in patients with significant left main stenosis and in patients with multivessel
disease involving the proximal LAD artery, particularly with subnormal LV systolic function.
Factors influencing the decision to perform coronary revascularization include the anatomical degree of CAD
burden, the amount of provokable ischemia on noninvasive testing, the severity of symptoms, the intensity of
medical therapy, and associated comorbidities.
References
1. Lloyd­Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics­­2009 update: a report from the
American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:e21­
181.
2. Fox CS, Evans JC, Larson MG, Kannel WB, Levy D. Temporal trends in coronary heart disease mortality and
sudden cardiac death from 1950 to 1999: the Framingham Heart Study. Circulation 2004;110:522­7.
3. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980­2000. N
Engl J Med 2007;356:2388­98.
4. Garrett HE, Dennis EW, DeBakey ME. Aortocoronary bypass with saphenous vein graft. Seven­year follow­up.
JAMA 1973;223:792­4.
5. Alderman EL, Bourassa MG, Cohen LS, et al. Ten­year follow­up of survival and myocardial infarction in the
randomized Coronary Artery Surgery Study. Circulation 1990;82:1629­46.
6. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteen­year follow­up in the Veterans Affairs
Cooperative Study of Coronary Artery Bypass Surgery for stable angina. Circulation 1992;86:121­30.
7. Sabik JF 3rd, Blackstone EH, Gillinov AM, Banbury MK, Smedira NG, Lytle BW. Influence of patient characteristics
and arterial grafts on freedom from coronary reoperation. J Thorac Cardiovasc Surg 2006;131:90­8.
8. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Task Force on Myocardial
Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio­Thoracic
Surgery (EACTS). Eur Heart J 2010;31:2501­55.
9. Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary artery stenosis: percutaneous
transluminal coronary angioplasty. N Engl J Med 1979;301:61­8.
10. Marso SP, Amin AP, House JA, et al. Association between use of bleeding avoidance strategies and risk of
periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA 2010;303:2156­
64.
11. Hilliard AA, From AM, Lennon RJ, et al. Percutaneous revascularization for stable coronary artery disease.
Temporal trends and impact of drug­eluting stents. JACC Cardiovasc Interv 2010;3:172­9.
12. 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;356:1503­16.
13. Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 Appropriateness Criteria for Coronary
Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task
Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American
Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology.
Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of
Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:530­53.
14. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report
of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular
Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123­210.
15. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary
intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol
2011;58:e44­122.
16. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short­term survival benefit associated with
revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing
stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900­7.
17. Graham MM, Ghali WA, Faris PD, et al. Survival after coronary revascularization in the elderly. Circulation
2002;105:2378­84.
18. Singh M, Peterson ED, Roe MT, et al. Trends in the association between age and in­hospital mortality after
percutaneous coronary intervention: National Cardiovascular Data Registry experience. Circ Cardiovasc Interv
2009;2:20­6.
19. TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary
artery disease (TIME): a randomized trial. Lancet 2001;358:951­7.
20. Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery
disease. N Engl J Med 2009;360:2503­15.
21. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary
interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised
trials. Lancet 2009;373;1190­7.
22. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3­vessel
coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel­eluting stents. J Am Coll
Cardiol 2010;55:1067­75.
23. Hemmelgarn BR, Southern D, Culleton BF, et al. Survival after coronary revascularization among patients with
kidney disease. Circulation 2004;110:1890­5.
24. Velazquez EJ, Lee KL, Deja MA, et al. Coronary­artery bypass surgery in patients with left ventricular dysfunction. N
Eng J Med 2011;364:1607­16.
25. Zhao DX, Leacche M, Balaguer JM, et al. Routine intraoperative completion angiography after coronary artery
bypass grafting and 1­stop hybrid revascularization: results from a fully integrated hybrid catheterization
laboratory/operating room. J Am Coll Cardiol 2009;53:232­41.
26. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally
nonsignificant stenosis: 5­year follow­up of the DEFER study. J Am Coll Cardiol 2007;49:2105­11.
27. Pijls NH, Fearon WF, Tonino PA, et al., on behalf of the FAME Study Investigators. Fractional flow reserve versus
angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease:
2­year follow­up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am
Coll Cardiol 2010;56:177­84.
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7.4: Percutaneous Coronary Intervention Versus Coronary Artery Bypass
Grafting
Author(s): John McPherson, MD, FACC
Learner Objectives
Upon completion of this module, the reader will be able to:
1. Identify patients with coronary artery disease (CAD) in whom revascularization with coronary artery bypass grafting
(CABG) confers a survival benefit.
2. Compare the efficacy of percutaneous coronary intervention (PCI) with that of CABG in the treatment of patients with
multivessel CAD.
3. Identify patients with specific clinical characteristics who would benefit from surgical revascularization as opposed to
percutaneous revascularization.
4. Identify patients with specific clinical characteristics who would benefit from percutaneous revascularization as opposed
to surgical revascularization.
5. Review the rationale and possible clinical benefits of hybrid coronary revascularization.
Introduction
As mentioned in the module on Indications for Revascularization in this chapter, the management of stable ischemic
heart disease (SIHD) focuses on reduction of coronary risk factors, aggressive medical therapy, and, when appropriate,
revascularization by PCI or with CABG. This module reviews the considerations implicit in the choice of revascularization
mode in patients with SIHD.
Coronary Artery Bypass Grafting
The development of CABG for the treatment of symptomatic CAD occurred in the 1960s.1 In two decades that followed,
myocardial revascularization with CABG in patients with SIHD was a major focus of investigation, evaluated in studies
including the Coronary Artery Surgery Study (CASS) and registry,2 and the Veterans Administration Cooperative Study.3 In
these studies, the major benefit of CABG compared with medical therapy was in relief of anginal symptoms, although
there was also a demonstrable mortality benefit with CABG in specific subsets of patients, such as those with left main
coronary artery (LMCA) disease, three­vessel CAD, and those with left ventricular (LV) dysfunction.4
With improvement in surgical techniques and perioperative management, clinical outcomes following elective CABG
have continued to improve, with an approximate 2% major adverse event rate and a 1% hospital mortality rate reported in
recent studies.5 Specific refinements to CABG include the use of arterial conduits (left and right internal mammary artery,
radial artery), "off­pump" (beating heart) CABG, and sternal­sparing, minimally invasive techniques.
Percutaneous Coronary Intervention
Dr. Andreas Gruentzig first performed PCI in the form of balloon angioplasty in 1977 for the treatment of stable angina
caused by proximal, noncalcified single­vessel CAD.6 Major advances in percutaneous techniques, including the
development of bare­metal and drug­eluting coronary stents, adjunctive pharmacological therapy with dual antiplatelet
therapy and newer antithrombotic agents, vascular closure devices, and radial arterial access have enabled the use of
PCI in the treatment of a wide range of patients with significant comorbidities and complex CAD.
PCI is now performed in approximately 600,000 patients per year in the United States, in hospitals with and without
onsite cardiac surgical capabilities. As with CABG, advances in PCI have also led to a reduction in periprocedural
complications despite the treatment of older, higher­risk patients.7 Data from a high­volume PCI center on patients
undergoing elective PCI from 2003­2006 demonstrated a procedural success rate of 96%, a major cardiac adverse event
rate of 0.6%, and a mortality rate of 0.1%.8
Recently, a "hybrid" approach to revascularization has been developed, in which the benefits of CABG and PCI are
combined to provide patients with a durable, complete revascularization and a minimally invasive procedure. Although
long­term data regarding this approach are limited, initial results appear promising, and it is likely that a hybrid approach
will emerge as a reasonable therapeutic alternative to traditional CABG and PCI in patients with SIHD.9,10
Regardless of the technique used, it is now clear that coronary revascularization is only one component of a
comprehensive strategy in the optimal management of SIHD. The use of long­term antiplatelet agents, control of
hypertension and hypercholesterolemia, referral for cardiac rehabilitation, and lifestyle counseling are all important
elements in improving outcomes following revascularization. With some exceptions in patients with a high burden of
CAD, the primary benefit of revascularization in patients with SIHD is relief of ischemic symptoms rather than prevention
of major cardiac events.
Given the rapid advancements in both CABG and PCI techniques and postprocedural care, much debate surrounds the
choice of surgical versus percutaneous revascularization for any given patient. Several randomized trials comparing
CABG and PCI have attempted to answer this question, but progress in this area has been hampered by enrollment of
only a small proportion of screened patients and limited generalizability due to the rapid technological advancements in
both fields. The available evidence and current recommendations guiding the approach to revascularization in patients
with SIHD is discussed in the following sections.
Anatomical and Functional Considerations
Single­Vessel CAD
To date, no randomized trial has demonstrated a survival benefit in revascularization
of patients with stable, single­vessel CAD not involving the proximal left anterior
descending (LAD) coronary artery. Thus, the objective of either CABG or PCI in these
patients is relief of ischemic symptoms despite maximal medical therapy. In these
cases, PCI is generally the preferred approach because of its lower procedural
morbidity, particularly when a more durable internal mammary arterial conduit is not
planned or used at time of CABG. A rare exception may be a highly symptomatic,
large, chronically occluded artery in which the distal vessel is a reasonable target for
surgical grafting and the likelihood of successful PCI is low.
Several studies have suggested that CABG for isolated proximal LAD disease is
associated with improved survival compared with medical therapy.11
Revascularization for these patients is recommended in the appropriateness criteria
for coronary revascularization, published by the American College of Cardiology
Foundation (ACCF), the Society for Cardiovascular Angiography and Intervention,
and the Society of Thoracic Surgeons, along with other key specialty and
subspecialty societies.12
In a large meta­analysis of nine randomized trials, CABG and PCI for proximal LAD
disease resulted in similar rates of stroke, myocardial infarction, and 5­year survival;
CABG was associated with more relief of angina and lower rates of repeat
revascularization, whereas PCI was associated with shorter hospital stays and less
need for blood transfusion.13 Thus, either approach is considered reasonable in
this case.
Figure 1
Figure 2
Figure 3
Figure 4a
Left Main Coronary Artery Disease
Patients with disease of the LMCA (defined as a ≥50% angiographic stenosis) are at
particularly high risk of cardiovascular morbidity and mortality. Clearly, CABG for
LMCA disease improves survival compared with medical therapy,2,3,11 and
revascularization is indicated. Unlike CABG, no randomized data demonstrate a
survival benefit in patients with PCI of the LMCA, and currently PCI for LMCA disease
is considered inappropriate when CABG is a reasonable option.12,14 However, with
the advent of bare­metal and drug­eluting stents, PCI of the LMCA in patients without
prior CABG ("unprotected" LMCA) is increasingly considered a revascularization
option.
Improved outcomes with contemporary PCI and recent data comparing LMCA PCI
with CABG are challenging the standard of care in patients with LMCA disease.
Registries comparing PCI and CABG in patients with LMCA disease have shown
similar rates of survival, decreased rates of stroke, and increased rates of repeat
revascularization with PCI compared with CABG.15
In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus
and Cardiac Surgery) trial, a randomized study comparing CABG to PCI with drug­
eluting stents in patients with multivessel CAD, 40% of the patients had significant
LMCA disease.16 In this subgroup, major adverse cardiovascular event rates were
similar; the rate of repeat revascularization was significantly higher in the PCI group
(11.8% vs. 6.5%) and the stroke rate was significantly higher in the CABG group
(2.7% vs. 0.3%). Ongoing large, randomized trials comparing LMCA PCI with CABG
will inform the optimal treatment approach for these high­risk patients.
Multivessel Disease
Improvements in revascularization techniques have allowed both interventional
cardiologists and cardiac surgeons to treat effectively more patients with increasing
levels of CAD disease burden and comorbidities. Not surprisingly, revascularization
with either CABG or PCI is now technically feasible in the vast majority of these
patients. In patients with SIHD, PCI of multivessel disease has not been
demonstrated to improve survival compared with medical therapy.14 This is in
Figure 4b
contrast to much older surgical data, in which CABG was shown to improve survival
in subsets of patients with multivessel CAD, particularly in patients with three­vessel
CAD and involvement of the proximal LAD coronary artery, or with LV dysfunction.2,3
Given the significant changes in both surgical techniques and medical therapy, it is
unclear whether these results would be replicated in a contemporary setting.
With few exceptions, comparing CABG with PCI in randomized trials has been
challenging because of inherent difficulties in enrolling typical "real­world" patients,
given the necessary study inclusion/exclusion criteria and physician biases. In
addition, the data are not always applicable due to the rapid advances in both CABG
and PCI techniques (i.e., off­pump CABG, drug­eluting stents). Thus, many of the
currently available data are contained in several large registries and a few
randomized trials, with significant variations in techniques.
In the New York State Registry, treatment of multivessel CAD was compared in
22,000 patients undergoing PCI using bare­metal stents and 15,000 patients
treated with CABG.17 Lower mortality with CABG was observed in patients with more
complex CAD, including those with three­vessel CAD and proximal LAD disease.
Similar differences in mortality were reported with the use of drug­eluting stents in
the same registry.18
Although other registries have not reported differences in survival, findings of
increased repeat revascularization following PCI and increased incidence of stroke
following CABG have been consistent. In a meta­analysis of 24,000 patients with
multivessel CAD treated with drug­eluting stents or CABG, rates of myocardial
infarction and survival were similar, but rates of repeat revascularization were four
times higher in patients treated with PCI.19
In the first randomized trial of PCI versus CABG for the treatment of multivessel CAD,
the BARI (Bypass Angioplasty Revascularization Investigation) researchers
randomized 1,829 patients with multivessel CAD to balloon angioplasty or CABG.20
At 5 years, infarct­free survival was similar in the two groups (80% vs. 79%), but
patients treated with angioplasty had a much higher rate of repeat revascularization
(54% vs. 8%). Furthermore, the 5­year survival rate was significantly higher in the
subgroup of diabetic patients treated with CABG (81% vs. 66%) (Figure 1).
Several similar randomized trials compared PCI using bare­metal stents with CABG,
and Hlatky and colleagues 15 performed a large meta­analysis incorporating these
studies along with earlier data. In their analysis, although overall mortality was again
similar between the two groups, patients with diabetes and those older than 65
years had improved survival with CABG (Figure 2).
The SYNTAX trial was the first large randomized trial to compare treatment with PCI
using drug­eluting stents to CABG in patients with multivessel CAD.16 In the
SYNTAX trial, patients were also stratified according to the presence of LMCA
disease and diabetes. The investigators also introduced the "SYNTAX score"21 to
objectively evaluate in detail the complexity of CAD. At 3 years, the composite
endpoint of death, MI, stroke, and repeat revascularization was higher in the PCI arm
(28.0% vs. 20.2%), primarily driven by a difference in repeat revascularization (19.7%
vs. 10.7%). Mortality rates were similar in patients treated with CABG and PCI.
The SYNTAX study also reaffirmed the notion that clinical outcomes following PCI for
multivessel CAD are inversely proportional to the overall burden and complexity of
CAD: in patients with low SYNTAX scores (defined as 0­22) and intermediate
SYNTAX scores (23­32), event rates were similar in patients treated with PCI or
CABG; whereas patients with high SYNTAX scores (≥33) had significantly lower
adverse event rates following CABG (Figure 3).22
Previous Coronary Artery Bypass Grafting
In patients with previous CABG referred for revascularization, it is important to
consider the type and number of remaining functional grafts, the degree of viable
myocardium supplied by the diseased vessels, the complexity of the disease in the
involved vessels, and patient comorbidities. In patients with a patent internal
mammary graft to the LAD coronary artery and poor distal surgical targets, PCI is
generally preferred. By contrast, CABG is preferred in patients with extensive
disease, reasonable surgical targets, and the availability of an internal mammary
conduit to an occluded artery.14
Completeness of Revascularization
In the treatment of patients with SIHD, the ability to provide full revascularization may
affect patient outcomes. Rates of complete revascularization typically are higher in
patients undergoing CABG than in those undergoing PCI, as demonstrated in recent
studies including the SYNTAX trial.16 Following PCI, incomplete revascularization
has been associated with a slight increase in long­term mortality and increased
rates of subsequent CABG (Figures 4a, b).23
Survival Among Patients With and Without Diabetes and Multivessel CAD in the BARI Study
Figure 1
Survival among patients who were being treated for diabetes at base line (heavy lines) and all other patients (light lines). Patients assigned to CABG are indicated by solid lines, and those assigned to PTCA by dashed lines. The numbers of patients at risk are shown
below the graph at base line, three years, and five years. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; CAD = coronary artery disease; PTCA =
percutaneous transluminal coronary angioplasty. Reproduced with permission from The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary­
bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:217­25.
Mortality in Patients After CABG or Multivessel PCI According to Diabetes
Figure 2
*Number of patients available for follow­up. Data show overall unadjusted mortality rates for patients with diabetes and without diabetes. Panel A
includes patients from all ten trials. Panel B excludes patients from the BARI trial. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention. Reproduced with permission from Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous
coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomized trials. Lancet
2009;373;1190­7.
Rates of Major Adverse Cardiac or Cerebrovascular Events According to SYNTAX Score
Figure 3
CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; SYNTAX = Synergy Between Percutaneous Coronary
Intervention With Taxus and Cardiac Surgery. Reproduced with permission from Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary
intervention versus coronary­artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961­72.
Kaplan­Meier Survival Curves for Patients With Complete and Incomplete Revascularization After Coronary Stenting (1 of 2)
Figure 4a
IR = incomplete revascularization. Reproduced with permission from Wu C, Dyer AM, King SB, et al. Impact of incomplete revascularization on long­term mortality after coronary
stenting. Circ Cardiovasc Interv 2011;4:413­21.
Kaplan­Meier Survival Curves for Patients With Complete and Incomplete Revascularization After Coronary Stenting (2 of 2)
Figure 4b
IR = incomplete revascularization. Reproduced with permission from Wu C, Dyer AM, King SB, et al. Impact of incomplete revascularization on long­term mortality after coronary
stenting. Circ Cardiovasc Interv 2011;4:413­21.
Special Patient Subsets
Diabetes
Patients with diabetes and SIHD clearly are at increased risk for adverse
cardiovascular events compared with nondiabetic patients. Patients with diabetes
referred for revascularization often have more diffuse and complex CAD; achieving
complete revascularization with PCI can be more challenging. As mentioned earlier,
patients with diabetes enrolled in the BARI trial had a lower mortality rate following
CABG when compared with multivessel angioplasty (Figure 1).20
In the era of bare­metal stents, a large meta­analysis demonstrated improved long­
term survival and decreased repeat revascularization in patients with diabetes
treated with CABG compared with PCI (Figure 2).15 The most recent available data
are from the SYNTAX trial. With the use of drug­eluting stents for multivessel PCI,
patients with diabetes had higher rates of revascularization following PCI than with
CABG, particularly those with more complex disease.16 Overall, rates of death,
myocardial infarction, and stroke were similar between the two groups. However, in
the subset of diabetics with SYNTAX scores of ≥33, mortality was significantly higher
following PCI than after CABG (13.5% vs. 4.1%) (Figure 5). Thus, similar to
nondiabetic patients, the decision regarding mode of revascularization should
include consideration of CAD complexity and disease burden, which is often greater
in patients with diabetes. In patients with extensive disease, CABG is the preferred
treatment.
Left Ventricular Systolic Dysfunction
Data from CASS and other studies established that mortality is improved following
revascularization with CABG in patients with LV dysfunction and multivessel CAD.2
Data in the literature are scarce regarding outcomes after contemporary PCI in this
patient population, although some studies have demonstrated similar mortality
rates in patients treated with PCI and CABG.14 At present, decisions regarding the
approach to revascularization in these patients should also be made based on other
factors, such as disease complexity, presence of diabetes, and patient
preferences.14
Figure 1
Figure 2
Figure 5
Survival Among Patients With and Without Diabetes and Multivessel CAD in the BARI Study
Figure 1
Survival among patients who were being treated for diabetes at base line (heavy lines) and all other patients (light lines). Patients assigned to CABG are indicated by solid lines, and those assigned to PTCA by dashed lines. The numbers of patients at risk are shown
below the graph at base line, three years, and five years. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; CAD = coronary artery disease; PTCA =
percutaneous transluminal coronary angioplasty. Reproduced with permission from The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary­
bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:217­25.
Mortality in Patients After CABG or Multivessel PCI According to Diabetes
Figure 2
Number of patients available for follow­up. Data show overall unadjusted mortality rates for patients with diabetes and without diabetes. Panel A
includes patients from all ten trials. Panel B excludes patients from the BARI trial. Reproduced with permission from Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous
coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomized trials. Lancet
2009;373;1190­7.
Clinical Outcomes at 1 Year in Patients With Diabetes in the SYNTAX Study
Figure 5
CABG = coronary artery bypass grafting; CVA = cerebrovascular accident; MI = myocardial infarction; PES = paclitaxel­eluting stents; SYNTAX =
Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery. Reproduced with permission from Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3­vessel
coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel­eluting stents. J Am Coll Cardiol 2010;55:1067­75.
Hybrid Coronary Revascularization
Hybrid coronary revascularization typically is characterized by elective revascularization of the LAD coronary artery with a
left internal mammary arterial graft and PCI of one or more major epicardial vessels. Other examples include minimally
invasive valve surgery combined with PCI to coronary lesions (valve/PCI), to "convert" a high­risk valve/CABG procedure
into a lower risk, isolated, minimally invasive valve procedure.
Potential benefits of a hybrid procedure include: 1) provides a durable revascularization to the LAD coronary artery; 2)
allows for a minimally invasive surgical approach; 3) provides angiographic confirmation of bypass graft patency during
hybrid PCI; 4) enables treatment of patients with inadequate graft conduit and/or heavily calcified aortas; and 5) allows
effective treatment of patients with multiple comorbidities.14 Emerging data suggest that, in selected patients, outcomes
following hybrid coronary revascularization are similar to those following standard CABG.9,10
Depending on the capabilities of the hospital and the needs of the patient, hybrid procedures may be performed in a
hybrid operating room or as a staged procedure, with initial CABG or PCI followed by the other within 2­3 days. In staged
hybrid procedures, the CABG component is usually performed first in order to delay the necessary post­PCI dual
antiplatelet therapy until after the surgery and thus minimize bleeding risk, and also to allow for bypass graft angiography.
Heart Team Approach to Revascularization
Many patients with SIHD referred for revascularization have complex anatomical CAD and multiple clinical variables that
require careful consideration when choosing a revascularization strategy, particularly when both CABG and PCI are
technically feasible. Recent randomized trials comparing CABG with PCI, including the SYNTAX study, have mandated the
formation of a multidisciplinary Heart Team in the evaluation of patients with complex CAD.
The Heart Team, composed of an interventional cardiologist, cardiac surgeon, and occasionally a noninvasive
cardiologist, cannot only provide a comprehensive evaluation of the patient's coronary anatomy and suitability for PCI or
CABG, but also can assess the patient's comorbidities and treatment preferences. The most recent ACCF­endorsed
guidelines for both PCI and CABG have recommended a Heart Team approach to revascularization in all patients with
unprotected LMCA disease or complex CAD.11,14
Summary
Patients with stable, symptomatic CAD should be treated with a comprehensive approach focusing on reduction of
coronary risk factors and aggressive medical therapy. The primary goals of revascularization are relief of ischemic
symptoms refractory to medical therapy and improvement in survival when extensive CAD is present.
Both CABG and PCI have specific advantages: CABG generally is more durable, resulting in more relief of anginal
symptoms and fewer repeat revascularization procedures, whereas PCI is associated with less procedural morbidity,
shorter hospital stays, and faster recovery. For uncomplicated CAD, CABG and PCI have similar long­term outcomes. As
CAD complexity and burden increase, the incidence of continued angina symptoms and need for repeat revascularization
increase to a greater extent after PCI compared with CABG.
Recent studies have demonstrated similar long­term survival rates after CABG and PCI, even in patients with extensive
CAD. However, improved survival after revascularization has only been shown with CABG in these patients, and thus,
CABG is currently the preferred approach for patients with significant left main or complex three­vessel CAD. Other
factors, such as patient age, LV function and the presence of diabetes are important considerations in determining the
optimal treatment for individuals with complex CAD, and the involvement of a multidisciplinary Heart Team should be a
fundamental component of their care.
Future Directions
Recently, the National Cardiovascular Disease Registry working group of the ACC was awarded a Grand Opportunities
grant by the National Heart, Lung, and Blood Institute to study the comparative effectiveness of PCI and CABG for the
treatment of stable CAD.24 In this study, the existing ACC and Society of Thoracic Surgery databases will be used to
compare procedural outcomes; in addition, long­term outcomes will be analyzed using the Centers for Medicare &
Medicaid Services' 100% denominator file data. It is anticipated that more than 100,000 patients will be included in this
study, which undoubtedly will provide valuable information of the optimal approach to revascularization in a wide array of
patients.
Key Points
Revascularization with CABG to improve survival is indicated in patients with significant LMCA disease or severe
three­vessel CAD involving the proximal LAD coronary artery.
In patients with single­vessel CAD, long­term outcomes following successful PCI and CABG are similar.
In patients with multivessel CAD without a high level of complexity (e.g., low­to­intermediate SYNTAX score),
successful revascularization with CABG or PCI results in similar long­term outcomes.
In patients with complex multivessel CAD (high SYNTAX score), revascularization with CABG results in fewer
repeat revascularization procedures and improved long­term survival compared with multivessel PCI.
Patients with significant left main or complex multivessel CAD ideally should be evaluated by a multidisciplinary
Heart Team to determine the most appropriate method of revascularization.
References
1. Garrett HE, Dennis EW, DeBakey ME. Aortocoronary bypass with saphenous vein graft. Seven­year follow­up.
JAMA 1973; 223:792­4.
2. Alderman EL, Bourassa MG, Cohen LS, et al. Ten­year follow­up of survival and myocardial infarction in the
randomized Coronary Artery Surgery Study. Circulation 1990;82:1629­46.
3. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteen­year follow­up in the Veterans Affairs
Cooperative Study of Coronary Artery Bypass Surgery for stable angina. Circulation 1992;86:121­30.
4. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10­year
results from randomised trials by the Coronary Artery Bypass Surgery Trialists Collaboration. Lancet
1994;344:563­70.
5. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. The Task Force on Myocardial
Revascularization of the European Society of Cardiology and the European Association for Cardio­Thoracic
Surgery. Eur Heart J 2010;31:2501­55.
6. Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary artery stenosis: percutaneous
transluminal coronary angioplasty. N Engl J Med 1979;301:61­8.
7. Marso SP, Amin AP, House JA, et al. Association between use of bleeding avoidance strategies and risk of
periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA 2010;303:2156­
64.
8. Hilliard AA, From AM, Lennon RJ, et al. Percutaneous revascularization for stable coronary artery disease.
Temporal trends and impact of drug­eluting stents. JACC Cardiovasc Interv 2010;3:172­9.
9. Zhao DX, Leacche M, Balaguer JM, et al. Routine intraoperative completion angiography after coronary artery
bypass grafting and 1­stop hybrid revascularization: results from a fully integrated hybrid catheterization
laboratory/operating room. J Am Coll Cardiol 2009;53:232­41.
10. Halkos ME, Vassiliades TA, Douglas JS, et al. Hybrid coronary revascularization versus off­pump coronary after
bypass grafting for the treatment of multivessel coronary artery disease. Ann Thorac Surg 2011;92:1695­702.
11. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A
report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of
Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123­210.
12. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for
Coronary Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria
Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American
Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology.
Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of
Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:530­53.
13. Kapoor JR, Gienger AL, Ardehali R, et al. Isolated disease of the proximal left anterior descending artery:
comparing the effectiveness of percutaneous coronary interventions and coronary artery bypass surgery. JACC
Cardiovasc Interv 2008;1:483­91.
14. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary
Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol
2011;58:e44­122.
15. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary
interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised
trials. Lancet 2009;373:1190­7.
16. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3­vessel
coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel­eluting stents. J Am Coll
Cardiol 2010;55:1067­75.
17. Hannan EL, Racz MJ, Walford G, et al. Long­term outcomes of coronary­artery bypass grafting versus stent
implantation. N Engl J Med 2005;352:2174­83.
18. Hannan EL, Wu C, Walford G, et al. Drug­eluting stents vs. coronary­artery bypass grafting in multivessel coronary
disease. N Engl J Med 2008;358:331­41.
19. Benedetto U, Melina G, Angeloni E, et al. Coronary artery bypass grafting versus drug­eluting stents in multivessel
coronary artery disease: a meta­analysis on 24,268 patients. Eur J Cardiothorac Surg 2009;36:611­5.
20. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary­bypass
surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:217­25.
21. Sianos G, Morel MA, Kappetein AP, et al. The SYNTAX Score: an angiographic tool grading the complexity of
coronary artery disease. EuroIntervention 2005;1:219­27.
22. Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary
intervention versus coronary­artery bypass grafting for severe coronary artery disease. N Engl J Med
2009;360:961­72.
23. Wu C, Dyer AM, King SB 3rd, et al. Impact of incomplete revascularization on long­term mortality after coronary
stenting. Circ Cardiovasc Interv 2011;4:413­21.
24. Klein LW, Edwards FH, DeLong ER, Ritzenthaler L, Dangas GD, Weintraub WS. ASCERT: the American College of
Cardiology Foundation­­The Society of Thoracic Surgeons collaboration on the comparative effectiveness of
revascularization strategies. JACC Cardiovasc Interv 2010;3:124­6.
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7.5: Hibernation, Stunning/Viability
Author(s): Anna Lisa Crowley MD, FACC Raymond J. Kim MD, FACC
Learner Objectives
Upon completion of this module, the reader will be able to:
1. 2. 3. 4. Define myocardial hibernation, stunning, and viability.
Identify the techniques currently available to assess myocardial viability.
Describe the STICH (Surgical Treatment for Heart Disease) trial.
Examine the underlying assumptions in viability testing.
Introduction
Background
The concept that dysfunctional myocardium may be viable has been known for decades. Specific physiologic states that
can result in dysfunctional, yet viable myocardium are stunning and hibernation. "Myocardial stunning" describes the
state of post­ischemic myocardial dysfunction in the presence of relatively normal blood flow.1 On light microscopy,
stunned myocardium appears normal. However, there is decreased adenosine triphosphate and subtle ultrastructural
abnormalities.2
The mechanism underlying stunning is not completely understood. It has been proposed that stunning involves
myofilament desensitization to calcium, possibly by initial calcium overload during reperfusion, leading to troponin I
proteolysis and/or oxygen radical formation during ischemia­reperfusion damaging the contractile cell membranes. In
general, stunned myocardium has been shown to recover function within hours to days, and recovery may take longer in
cases of longer ischemic episodes prior to revascularization.3
The term "myocardial hibernation" describes the state of chronic myocardial dysfunction at rest that can be partially or
completely restored to normal either by improving blood flow and/or by reducing demand.4 This physiology was first
noted when ventricular wall­motion abnormalities improved after coronary artery bypass grafting (CABG).5­7 Biopsy
specimens from regions of dysfunctional myocardium that recovered function after CABG showed that 90% of the volume
consisted of viable cells.8,9 However, increased glycogen is seen in areas previously occupied by myofilaments, and
small mitochondria are present.10 The mechanism underlying hibernating myocardium is not completely understood, but
many investigators believe it is due to a chronic reduction in resting coronary blood flow. Others suggest that blood flow is
normal in hibernating myocardium, and that the dysfunction results from repetitive episodes of stunning.10 In contrast to
the relatively early recovery of function seen with myocardial stunning, recovery of function has been shown to take up to 1
year after revascularization in myocardial hibernation.3 Thus, myocardial stunning and hibernation both represent
myocardium that is alive (or viable), rather than dead (or nonviable).
Clinical Importance of Viability
In patients with coronary artery disease (CAD) and left ventricular (LV) systolic dysfunction, determining which patients
may benefit most from revascularization is clinically important. Guidelines for revascularization are provided by the
American College of Cardiology Foundation and the American Heart Association (ACCF/AHA), which was last updated in
201111
In patients with poor LV function, surgical revascularization is given a Class I recommendation (evidence/agreement that
treatment is useful/efficacious) for patients with the following coronary anatomy: 1) significant left main stenosis or 2)
proximal LAD stenosis with two­ or three­vessel disease.
These recommendations are based largely on data from older randomized trials that focused primarily on the
angiographic appearance of CAD and did not take other factors such as myocardial viability into consideration. While
these studies showed benefit in the overall population with severe angiographic disease, from a mechanistic point of
view, one would expect that additional information, such as the presence or absence of extensive viable myocardium,
could improve patient risk stratification for revascularization.
The potential importance of myocardial viability testing in reference to prognosis after revascularization has been
evaluated in many small, single­center studies, including a meta­analysis demonstrating decreased annual mortality in
patients with viability who were undergoing revascularization compared to those who were not undergoing
revascularization.12
Allman et al., in a meta­analysis of 24 studies, which included 3,088 patients with a mean LV ejection fraction (EF) of
32%, concluded that, in patients with significant viability (as determined by thallium perfusion imaging, F­18
fluorodeoxyglucose metabolic imaging, or dobutamine echocardiography), revascularization was associated with a
79.6% reduction in annual mortality compared with medical treatment (3.2% vs. 16%; p < 0.0001).13 Conversely, in
patients without viability, mortality rates were similar for revascularization and medical therapy (7.7% vs. 6.2%; p = not
significant).
Based on data such as these, the ACCF/AHA guidelines on the diagnosis and management of heart failure from 2009
and CABG surgery from 2011 state that CABG, in addition to those with the coronary anatomy described earlier, may be
performed in patients with poor LV function and significant CAD if there is significant viable myocardium (Class IIa
recommendation [weight of evidence/opinion is in favor of usefulness/efficacy]).11,14 In contrast, CABG is not
recommended in patients without evidence of intermittent ischemia and significant viable myocardium (Class III
recommendation [evidence/agreement that treatment is not useful/efficacious or may be harmful]).
However, the evidence for these recommendations has limitations. First, studies were small, not randomized,
observational, and retrospective, leading to potential patient selection bias. Second, the methodology and criteria for
defining viability, as well as the treatment regimens, were not standardized among the different studies. Finally, the
success and completeness of myocardial revascularization was not investigated by follow­up angiography or stress
imaging data in most studies.12 Given these flaws, meta­analyses incorporating these data are subject to the same
limitations. In part, due to these limitations, the STICH trial was undertaken.15
STICH was a randomized, multicenter, nonblinded trial funded by the National Heart, Lung, and Blood Institute.15
Patients with angiographic documentation of CAD amenable to surgical revascularization and LV systolic dysfunction (EF
≤35%) were eligible for enrollment. Exclusion criteria were left main stenosis >50%, cardiogenic shock, myocardial
infarction (MI) within 3 months, and need for aortic valve surgery. In hypothesis 1, enrolled patients were randomly
assigned to receive medical therapy alone or medical therapy plus CABG. In hypothesis 2, enrolled patients were
randomly assigned to receive medical therapy plus CABG or medical therapy plus CABG and surgical ventricular
reconstruction.
Between 2002 and 2007, 1,212 patients from 99 centers in 22 countries were enrolled in hypothesis 1. The primary
endpoint was death from any cause. In the initial design of the STICH trial, viability testing with single­photon emission
computed tomography (SPECT) was required. However, this requirement proved to be an impediment to study
enrollment. Therefore, the protocol was revised in 2004 to make viability testing optional, and the decision to perform the
test was left up to the recruiting investigators. In addition, the viability test options were expanded to include SPECT (four
separate protocols), dobutamine stress echocardiography (DSE), or both.16
Overall, there was no significant difference between patients with medical therapy alone and medical therapy plus CABG
with respect to the primary endpoint of death from any cause at a median of 5.1 years of follow­up.15 In the 601 patients
who received a viability study, there was a significant association between viability and outcome on univariate analysis,
but not on multivariate analysis. Surprisingly, the assessment of myocardial viability did not identify patients with a
differential survival benefit from CABG, as compared with medical therapy alone, in contrast with the prior literature.16
The authors point out that conclusions drawn from STICH are limited by a number of factors.16 First, slightly less than
half of the 1,212 patients enrolled in the hypothesis 1 comparison underwent viability testing. Second, patients were not
randomized to viability testing, and third, testing could have been performed prior to, on the day of, or after study
enrollment. These factors may have led to patient selection/enrollment bias and may have influenced subsequent clinical
decision making. Additionally, only a small percentage of patients were deemed not to have viable myocardium (19%),
which limited the power of the analysis to detect a differential effect of CABG, as compared to medical therapy alone, in
patients with myocardial viability as compared to those without myocardial viability. Lastly, the viability analyses were
limited to SPECT and DSE imaging. While the results were similar for SPECT and for DSE, caution should be taken to
not extrapolate these results to other imaging modalities that were not tested in STICH, such as positron emission
tomography (PET), delayed­enhancement cardiac magnetic resonance (DE­CMR), and delayed­enhancement
multidetector computed tomography (DE­MDCT).
Despite the study limitations, the STICH trial is a landmark investigation that raises an important question: Is viability
assessment important? From a pathophysiologic viewpoint, it would be difficult to interpret the STICH results as
concluding that alive myocardium is the same as dead myocardium. On the other hand, from a clinical viewpoint, the
STICH results show that using "status quo" viability methods to determine who will benefit from CABG is highly
problematic. As a result, there clearly is a need to re­assess the underlying mechanisms regarding how viability tests are
assumed to work and how they are interpreted.
The following sections will focus on the current techniques used to assess myocardial viability and their underlying
pathophysiologic basis, and explore what might constitute an "ideal" technique. Given the results from STICH, the
numerous small studies published prior to STICH relating viability imaging to functional recovery and prognosis will not
be summarized. Instead, fundamental concepts in viability assessment will be examined. Additionally, DE­CMR as a
paradigm will be used to discuss many of the underlying assumptions in viability.
Physiological Basis Of Viability Testing
Morphology
Simple morphological characteristics of the LV may provide useful information about
viability. For instance, ventricular wall thinning has been used as a marker for the
absence of viability, based on the hypothesis that a thinned region represents scar
tissue and chronic MI. Cwajg et al. studied 45 patients with stable CAD and LV
dysfunction using echocardiography. and concluded that "a simple measurement of
end­diastolic wall thickness ≤6 mm virtually excludes the potential for recovery of
function."17 Similarly, Baer et al. studied 43 patients with chronic MI and LV
dysfunction with cardiac magnetic resonance (CMR) and concluded that "the
depiction of significantly reduced end­diastolic wall thickness (<5.5 mm) excludes a
clinically relevant amount of persistent viable myocardium."18
However, there are some limitations with this approach. First, it is not intended to
examine viability in the setting of acute MI where wall thickness may be normal or
even increased by as much as 50% despite the lack of viable myocytes.19 Second,
the time required for acute myocardial necrosis to heal and turn into collagenous
scar with resultant wall thinning may be substantial and in the order of 6­8 weeks.
Third, even in the chronic setting, although it is clear that transmural infarction is
frequently associated with myocardial thinning, there are less data in the setting of
nontransmural infarction, and the transmurality of infarction that is necessary for wall
thinning is unknown.
Function
By definition, the presence of contraction or systolic wall thickening in a region
demonstrates substantial viable myocardium. However, the converse may not be
true. Absent resting contraction does not necessarily mean that the myocardium is
dead. Obvious examples of this include the phenomena of myocardial "stunning"
and "hibernation" in which contraction is absent despite preserved viability.
Clinically, dysfunctional, but viable, myocardium may be differentiated from infarction
by assessing contractile reserve, as only viable myocardium will respond to
inotropic stimulation by demonstrating enhanced contraction and systolic thickening.
Based on this principle, both DSE and CMR have been used to assess contractile
reserve and thus viability. In general, both DSE and CMR demonstrate lower
sensitivity than specificity for predicting functional improvement.18,20,21
The observation that contractile reserve may have relatively modest sensitivity for
predicting functional improvement highlights the indirect relationship between
contractile reserve and viability. Experimental studies of chronic low­flow ischemia
have shown that some viable regions are so delicately balanced between
reductions in flow and function, with exhausted coronary flow reserve, that any
inotropic stimulation merely results in ischemia and precludes the ability to enhance
contractility.22
Perfusion
Myocardial perfusion is related to myocardial viability in that chronic absence of
blood flow, of course, is incompatible with viability. However, it is important to
recognize that perfusion does not have a direct one­to­one relationship with viability.
For example, myocardial ischemia is caused by reduced perfusion, but this
pathophysiologic state, by definition, requires viable myocardium. Reperfused acute
infarction is another pathophysiologic state where perfusion and viability are
dissociated. The entire infarcted region is by definition nonviable; however, tissue
perfusion may range from nearly zero in central regions of the infarct with profound
microvascular damage to nearly normal in other regions in which the
microvasculature is intact.23
The heterogeneity of perfusion in reperfused infarction has been demonstrated in
humans using contrast echocardiography,24 and measured in animal models using
radioactive microspheres.25 Additionally, the pathophysiology of hibernating
Figure 1
myocardium itself suggests a discordance. Although there are some conflicting
data, hibernating myocardium, which represents viable tissue, is believed to be due
to chronically reduced perfusion. These discrepancies in the relationship between
perfusion and viability underscore the potential limitations in utilizing a technique
that measures perfusion for assessing viability.
Metabolism and Cell Membrane Integrity
Techniques that examine the metabolic activity or cell membrane integrity of
myocytes should provide, at least theoretically, the most direct means for
determining whether myocytes are alive or dead. Scintigraphic techniques using
PET or SPECT are examples of such methods.26 Specifically, preserved glucose
metabolism can be examined by F­18 fluorodeoxyglucose (FDG) PET, cell
membrane integrity by thallium­201 SPECT, and intact mitochondria by technetium­
99m sestamibi SPECT. For the latter two techniques, however, myocardial perfusion
probably also affects tracer activity to some degree.
Overall, radionuclide techniques demonstrate moderate to good sensitivity (81­93%)
but poor specificity (50­66%) for predicting functional improvement.20 In general,
SPECT has lower diagnostic accuracy than PET and is more prone to
underestimate viability,27 most likely because of technical limitations, such as lower
spatial resolution, use of lower energy tracers, and lack of built­in attenuation
correction. The poor specificity of both techniques may also relate to technical
limitations; however, the use of functional improvement after revascularization as the
truth standard for viability may result in an artificially low specificity.
DE­CMR is another technique that can index cell membrane integrity. Although the
gadolinium­based contrast media used for DE­CMR is inert, and active transport
processes across cell membranes such as for thallium are not present, there
appears to be a direct, but inverse relationship between gadolinium concentration
and the percentage of viable myocytes within any given region of myocardial tissue.
The mechanism is likely based on the following: 1) tissue volume in normal
myocardium is predominantly intracellular (75­80% of the water space)28; and 2)
currently available gadolinium contrast media are "extracellular" agents since they
do not cross cell membranes.29 Thus, the volume of distribution of gadolinium
contrast in normal myocardium is quite small (approximately 20% of water space),
and one can consider viable myocytes as actively excluding contrast media.30
Pathophysiologic states that result in a reduced density of viable myocytes will then
have increased volume of distribution of gadolinium and higher concentration.31
Note that this mechanism is independent of the cause or etiology for nonviable
myocardium. Whether the tissue consists of contraction­band necrosis in the setting
of acute MI, collagenous scar in chronic MI, or fibrosis in various nonischemic
cardiomyopathies, the region will have increased gadolinium concentration if there
is a reduced density of viable myocytes.30
DE­CMR has been shown to be highly effective in identifying the presence, location,
and extent of MI in both the acute and chronic settings in both animal and human
studies.31­35 Additionally, it has been used to predict reversible myocardial
dysfunction in those undergoing revascularization procedures.36­38
Recently the delayed­enhancement concept has been extended to MDCT. The
interpretation of contrast­enhancement patterns on MDCT appears quite similar to
that for DE­CMR, and is likely based on the same underlying mechanism because
the iodinated contrast media used for MDCT has nearly identical pharmacokinetics
as that of "extracellular" gadolinium contrast.39
Likewise, in animal models, DE­MDCT assessment of acute and chronic MI has
been shown to accurately reflect true infarct size and morphology as determined by
histopathology.40 Although currently there are few studies in humans,39,41 these
initial studies have demonstrated an excellent agreement between DE­MDCT and
CMR, albeit with reduced contrast­to­noise ratio and image quality for
MDCT.39 Figure 1 shows a comparison between DE­MDCT and DE­CMR in three
patients.
Delayed Enhancement Images From Cardiac Magnetic Resonance and Multidetector Computed Tomography in 3 Different Patients With Acute
Myocardial Infarctions
Figure 1
Short­axis delayed­enhancement cardiac magnetic resonance (panels a, c, e) and delayed­enhancement multidetector computed tomography
images (panels b, d, f) in three different patients with acute myocardial infarction attributable to left anterior descending artery (panels a, b), right
coronary artery (panels c, d), and left circumflex artery (panels e, f) occlusion after successful revascularization. There is excellent agreement
between hyperenhanced regions (arrows) on the two techniques. Adapted with permission from Mahnken AH, Koos R, Katoh M, et al. Assessment of myocardial viability in reperfused acute myocardial infarction
using 16­slice computed tomography in comparison to magnetic resonance imaging. J Am Coll Cardiol 2005;45:2042­7.
The "Ideal" Technique
Knowing How Much Is Alive Is Not Enough
A useful exercise is to consider what might constitute an "ideal" technique for
assessing viability. Certainly, it would be important for the technique to be fast and
safe, and to provide reproducible results. However, what might not be so apparent is
that even if a technique were available that could offer precise quantification of
viability without technical limitations (e.g., infinite spatial resolution, no artifacts), this
would still be insufficient to provide a complete characterization of viability, and thus,
would be insufficient to provide the highest accuracy in predicting wall­motion
improvement or clinical benefit after coronary revascularization.42
Certainly, there are additional factors that are not related to limitations in noninvasive
testing that could reduce accuracy in predicting functional improvement. These have
been well described and include perioperative or postoperative occult MI,43
incomplete revascularization as a result of diffuse disease,44 or tethering of regions
with extensive scarring adjacent to viable regions.45 For the purposes of this
section, these clinical factors will not be considered; instead, it will focus on issues
related to the noninvasive assessment of viability and will examine the concept that
"knowing how much is alive is not enough."
A central tenet of this concept is that a technique that offers even a perfect
assessment of what is alive (viable) has substantial and practical limitations
compared with a technique that offers both an assessment of what is alive and what
is dead (nonviable). This tenet may be counterintuitive, because it would seem that
by knowing exactly how much is alive, by deductive logic, one should know how
much is dead. However, this is an incorrect assumption, and the patient examples
in Figure 2 may be illustrative.
The left panel in the top row of Figure 3 (Patient A) shows a midventricular, short­axis
DE­CMR image of a normal heart in diastole. With DE­CMR, nonviable regions such
as infarction appear bright (hyperenhanced), whereas viable regions appear black.
First, consider only a "nonviability" or bright region assessment. A quick visual
inspection shows no evidence of myocardial bright regions; thus, one rapidly
concludes that no infarction is present. In comparison, now consider only a "viability"
or black region assessment. One can trace the endocardial and epicardial borders
of viable myocardium (center panel), and then plot the transmural extent of viability
as a function of position, starting from the anterior wall at 12:00 and moving
counterclockwise around the LV (right panel).
From the plot, it is obvious that there is marked heterogeneity in the transmural
extent of viability, with as much as 12 mm of viable myocardium in the portion of the
inferior wall adjacent to the posterior papillary muscle and as little as 7 mm in the
anteroseptal wall at the RV insertion site. Concerning this finding, it is important to
note that it has been long known that there can be significant variation in diastolic
wall thickness at different points around the LV, even if papillary muscles are
excluded and healthy volunteers are studied.46 This observation then naturally
proceeds to the conclusion that there can be significant variability in the transmural
extent of viable myocardium at different locations of the normal LV, as was found in
Patient A.
The principle that normal hearts can have significant heterogeneity in the extent of
viable myocardium has direct clinical implications. For example, in a region with
70%, the viability of the region with the maximum amount of viability may represent
either a normal region with 70% the wall thickness of the thickest region or a region
with a subendocardial MI. The images from Patient B (Figure 2) underscore this
concept. This particular patient had a clinically documented MI due to occlusion of
the right coronary artery (RCA), which was reopened during primary angioplasty.
Again, consider first only a "nonviability" assessment. From a quick visual perusal
(left panel), one can determine that there is a subendocardial bright region in the
inferoseptal wall consistent with the patient's prior MI in the RCA perfusion territory.
Next, consider only a "viability" assessment, similar to the assessment performed in
Figure 2
Figure 3
Figure 4
Figure 5
Patient A. Again, endocardial and epicardial contours are traced (center panel);
however, one difference should be noted. The endocardial contour is along the
border of viable (black) myocardium, and the infarcted region is not included. The
plot showing the extent of viable myocardium (right panel) once more shows marked
regional variability, and from this assessment, the presence and/or location of
infarction is not evident. Thus, in this patient, the intrinsic variation in the extent of
viable myocardium for noninfarcted regions is greater than the reduction in viable
myocardium for the region with subendocardial infarction. This renders the
subendocardial infarction "invisible" for any technique that can assess only viable
myocardium, even if the technique has perfect accuracy and has infinite spatial
resolution.
These two patient examples highlight the differences between techniques that can
visualize only viable myocardium, as opposed to techniques that can visualize viable
and nonviable myocardium. Additionally, it is important to recognize that the use of
different techniques often lead to differences in the way in which viability is
quantified, although the nomenclature used may be the same. For instance, when
only viable myocardium can be visualized, the percentage of viability in any given
segment is assessed indirectly and generally refers to the amount of viability in the
segment normalized to the segment with the maximum amount of viability or to data
from a gender­specific database of controls. Conversely, when both viable and
nonviable myocardium can be visualized, the percentage of viability can be
assessed directly and expressed as the amount of viability in the segment
normalized to the amount of viability plus infarction in the same segment (Figure 3).
The differences in the way in which viability is measured can alter clinical
interpretation. For the normal heart in Patient A, the indirect method would show that
there is significant regional variability in the extent of viable myocardium: 60­100% of
maximum viability; whereas, the direct method would show essentially no variability
because all of the segments would be classified as 100% viable. Likewise for
Patient B, the indirect method would not be able to identify the region of
subendocardial infarction because the extent of viable myocardium in this sector is
within the normal variation; whereas, the direct method would clearly identify the
region with subendocardial infarction because this region would be the only region
with less than 100% viable myocardium.
These patient examples also clarify the mechanism by which subendocardial
infarcts are routinely missed by techniques such as SPECT and PET (Figure 4).47­49
Although it is often reported that limited spatial resolution is the reason, it should be
evident that even infinite spatial resolution would not improve the detection of
subendocardial infarction by these or other methodologies based on assessing
only viable myocardium. Conversely, a methodology with poor spatial resolution
(e.g., a single voxel across the LV wall) would still be able to detect subendocardial
infarction if it had the ability to assess both alive and dead tissue.
Is 'Thinned' Myocardium Always Dead?
As discussed earlier in the module, prior studies report that, in patients with
coronary disease and LV dysfunction, regions with thinned myocardium represent
scar tissue and cannot improve in contractile function after revascularization.17
Some recent observations appear to refute this concept.17,50,51
Figure 5 shows CMR images of two patients (Patient C and Patient D) who have
severe CAD and chronic LV dysfunction. The left panels represent long­axis views
acquired before coronary revascularization. Two points should be noted on the cine
images. First, both patients have severe contractile dysfunction of the anterior wall.
Second, Patient D has associated thinning of the anterior wall (diastolic wall
thickness, 5.0 mm), whereas Patient C does not (diastolic wall thickness, 8.0 mm).
Based on these cine images and the existing literature, one might expect that there
is more viable myocardium in the anterior wall of Patient C than in Patient D, and, in
fact, question the need for viability testing at all in Patient D because the thinned,
akinetic anterior wall must undoubtedly be scar tissue and thus nonviable.
The DE­CMR images acquired before revascularization, however, indicate a different
clinical interpretation. In Patient C, there is a bright endocardial rim of
hyperenhancement (infarction) that measures, on average, 4.5 mm in thickness.
The remaining epicardial rim of tissue, which is black (viable), measures 3.5 mm in
thickness (total thickness, 8 mm). In Patient D, there is also an endocardial rim of
hyperenhancement; however, it measures on average only 1.5 mm in thickness. The
epicardial rim, which is viable measures 3.5 mm in thickness (total thickness, 5
mm). Note that, in both patients, the absolute amount of viable myocardium is the
same (3.5 mm), however, when the extent of viability is expressed as a percentage
of the total amount of myocardium in the segment, Patient C has less than 50%
viable myocardium (3.5 / 8 = 44%), whereas Patient D has >50% viable myocardium
(3.5 / 5 = 70%).
The right­most panels represent cine images acquired 2 months after coronary
revascularization. Patient C exhibits no improvement in contractile function in the
anterior wall and, in fact, develops diastolic wall thinning in this region. Conversely,
Patient D exhibits not only significant improvement in anterior wall contractile
function, but also recovery of diastolic wall thickness in this region (from 5 mm to 9
mm).
Three fundamental points are raised by these patient examples. First, it is apparent
that a method that can quantify only viable myocardium, even if technically flawless
(e.g., infinite spatial resolution, no artifacts), provides insufficient information to allow
a comprehensive assessment of myocardial viability. Because both patients had the
same, reduced amount of viable myocardium (3.5 mm thickness), we would have
predicted, incorrectly as it turns out, that both patients would not improve in
contractile function following revascularization.
Second, it is evident that the absolute amount of viable myocardium in a given region
is dynamic and can increase or decrease as a result of ventricular remodeling.
Whereas it is common knowledge that myocardial viability can decrease, for
example due to MI with associated wall thinning, the reverse process in which
regions of thin myocardium become thick with an absolute increase in the
transmural extent of viability (as in Patient D) has not been described.
Third, it appears that quantification of nonviable, in addition to viable, myocardium is
important in predicting contractile improvement following revascularization. For
instance, incorporating information regarding nonviable myocardium into a ratio of
viable to total myocardium (viable plus nonviable) within the same region would lead
to the conclusion that the anterior wall of Patient D has a higher percentage of viable
myocardium (70%) than Patient C (44%), and thus, is more likely to improve in
contractile function. The follow­up cine images in the figure demonstrate that this
prediction is correct. Future investigations are necessary to explore and validate
these concepts.
Regional Variation in Determining the Extent of Viable Myocardium
Figure 2
Left panels show delayed­enhancement images of a normal subject (Patient A) and a patient with a subendocardial, inferior wall myocardial
infarction (Patient B). The center panels show tracing of the borders of viable myocardium. The right panels plot the extent of viability (thickness)
as a function of left ventricular location. Note that there is significant regional variation in the extent of viable myocardium. Adapted with permission from Kim RJ, Shah DJ. Fundamental concepts in myocardial viability assessment revisited: when knowing how much is
"alive" is not enough. Heart 2004;90:137­40.
Differences Between an Indirect and Direct Method of Quantifying Regional Myocardial Viability
Figure 3
Cartoon highlighting differences between an indirect and direct method of quantifying regional viability. The indirect method is based on
assessment of viable regions only. The direct method is based on assessment of viable and nonviable regions. Viable myocardium is black, and
infarct is white. “Remote” zone represents segment with maximum amount of viability. Reproduced with permission from Fuster V, Kim RJ. Frontiers in cardiovascular magnetic resonance. Circulation 2005;112:135­44.
Short Axis Views From Three Canines With Subendocardial Myocardial Infarctions
Figure 4
Comparison of a method that indexes cell membrane integrity and detects only viable myocardium (single­photon emission computed tomography
[SPECT]) and a method that indexes cell membrane integrity and detects both viable and nonviable myocardium (delayed­enhancement cardiac
magnetic resonance [DE­CMR]) with histology in three canines with subendocardial infarcts (arrows). Note that the infarcts are not evident on
SPECT.
Adapted with permission from Wagner A, Mahrholdt H, Holly TA, et al. Contrast­enhanced MRI and routine single photon emission computed
tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 2003;361:374­9.
Cardiac Magnetic Resonance in 2 Patients Before and After Revascularization
Figure 5
Delayed­enhancement cardiac magnetic resonance (CMR) and cine images of two patients (C and D) before coronary revascularization and cine
images 2 months after revascularization. Adapted with permission from Kim RJ, Shah DJ. Fundamental concepts in myocardial viability assessment revisited: when knowing how much is
"alive" is not enough. Heart 2004;90:137­40.
Common Assumptions
Intermediate Levels of Viability
Viability testing is thought to be less helpful when intermediate levels of viability are
measured (i.e., levels of viability that result in only approximately 50% of these
regions recovering function after revascularization). This view is a result of a
common assumption regarding functional recovery. First, it is important to
distinguish between what would be desirable clinically from what can actually occur
physiologically. While we may ask for an improved technique with better predictive
value, perhaps in reality, we are asking for a different physiological relationship—an
abrupt threshold of viability, below which there is virtually no chance for functional
recovery, and above which nearly all have functional recovery. Figure 6, Panel A
demonstrates that, with an abrupt threshold, the problem of predicting an
intermediate likelihood for functional recovery is greatly minimized. Unfortunately,
this physiological relationship may not exist.
Second, it is essential to remember that functional recovery is a continuum (as is
viability itself), and not simply a binary—yes or no—function. Thus, part of the
problem with intermediate levels of viability is expecting that these regions will or will
not have functional recovery in this binary fashion. Because it more closely reflects
reality, it may be better to consider most regions with intermediate levels of viability
as having a high chance for an intermediate amount of improvement rather than
50% likely to have complete recovery and the other 50% likely to have no
improvement whatsoever.
Complicating this issue is the belief that a threshold phenomenon exists between
the transmural extent of infarction and systolic thickening. This assumption is based
primarily on results by Lieberman et al,52 who demonstrated in a canine model of
acute infarction that akinesia is expected if infarction involves ≥20% of the wall
thickness. However, the animal model involved permanent coronary ligation and
likely included effects from myocardial stunning and/or ongoing ischemia.
Evaluation in humans with chronic infarction suggests that a threshold phenomenon
does not exist.53,54 These data indicate that it is problematic to extrapolate the
results of Lieberman's study, which did not consider the effects of stunning and/or
ongoing ischemia, to humans following revascularization in whom substantial
stunning, ischemia, or hibernation may no longer be present.
The finding that two techniques can demonstrate a similar relationship between the
amount of viability and the likelihood of functional recovery does not mean that the
techniques have the same diagnostic capability. For example, both an accurate and
a less accurate technique may show that, for a given intermediate level of viability, on
average, 50% of segments recover function. However, part of the problem again is
defining functional recovery as a binomial variable. Figure 6, Panel B demonstrates
the utility of expressing functional recovery as a continuous variable (e.g., millimeters
of improvement in systolic wall thickening). Although the overall relationship is the
same, for any given level of viability, the better technique will provide a smaller
variability (smaller error bars) in the absolute amount of functional improvement than
the worse technique.
Functional Recovery as the Standard of Truth
The ideal reference standard for evaluating viability imaging techniques would be
histopathological examination. However, for the vast majority of clinical studies, this
is not feasible, and functional recovery following revascularization has become the
de facto standard. This clinical endpoint makes sense for a variety of reasons.
Because LV dysfunction portends poor prognosis, one would expect that functional
recovery would be an important and beneficial clinical outcome of revascularization.
Additionally, if a myocardial region recovers function, then one might confidently
assume that the region has a substantial amount of viable myocytes.
Indeed, this has been confirmed by histopathological examination. In 33 patients
with LAD disease, Maes et al. took transmural needle biopsies from the LV anterior
wall during CABG. The biopsies from regions that were dysfunctional prior to
Figure 6
revascularization, but recovered afterwards, showed 89% ± 6% of the volume
consisted of viable cells.8 Similarly, Dakik et al. reported that among 21 biopsied
dyssynergic myocardial segments, the 11 which recovered function after CABG had
93% ± 4% viability by volume.9 However, a common misconception is that, if a
region does not have functional improvement, then this region is nonviable. In fact,
Maes8 and Dakik9 observed that biopsy specimens from regions that did not
improve after revascularization still had 65% ± 25% and 69% ± 21% viability by
volume, respectively.
There are several reasons why regions that are predominantly viable may not
recover function following revascularization. First, revascularization may often be
incomplete in patients with extensive atherosclerosis.44 Therefore, there may be
persistent areas of hibernating myocardium. Second, viable myocardium may be
juxtaposed to regions with extensive scarring and unable to respond to
revascularization because of tethering.45 Third, the use of a single evaluation of
ventricular function soon after revascularization may lead to an underestimation of
the true rate of functional recovery. Bax and colleagues evaluated functional recovery
in 26 patients at 3 and 14 months following CABG.3 At 3 months, only 31% of
hibernating segments recovered, whereas at 14 months, an additional 61%
recovered.
Even with these limitations, one could argue that functional recovery is an
appropriate truth standard for viability because without recovery there may be no
benefit to the patient for undergoing revascularization. On this point, the results by
Samady et al. are instructive.55 Of the 104 consecutive patients who underwent pre­
and post­CABG LVEF assessment, 68 patients had improvement in LVEF (>5%
increase) and 36 patients had no significant change. Surprisingly, the two groups
had similar postoperative improvement in angina and heart failure scores, and there
was no difference in CV mortality, with a mean follow­up period of 32 months. The
authors concluded that a lack of improvement in LVEF after CABG is not associated
with poorer outcome, and speculated that many patients without improvement in
LVEF may nonetheless have substantial viable myocardium that can respond to
effective revascularization with beneficial effects on prognosis.
Thus, functional recovery is a flawed truth standard for evaluating viability imaging
techniques. The primary problem is that regions (or patients) without functional
recovery may have substantial viability that may be important to detect clinically. This
has implications for the published studies that have used functional recovery as the
standard for evaluating tests of viability. Poor specificity (for functional recovery)
should be considered less important than poor sensitivity, because for the former, a
number of "false positives" (test showed viability but there was no functional
recovery) may represent a problem with the truth standard rather than the technique.
A future STICH substudy will address whether functional recovery can predict other
clinically relevant endpoints such as death (E. Velazquez, personal communication,
2011).
The decision for revascularization is dependent on several factors besides the
amount of viability, including specifics regarding the coronary anatomy, the presence
of angina or ischemia, and patient comorbidities. Additionally, viable myocardium
can be in different states (i.e., normal, ischemic, hibernating, cardiomyopathic from a
nonischemic process, etc.), and it is likely that differentiating between these states
may be important for revascularization decisions in some patients.
Assumptions in evaluating viability techniques
Figure 6
Panel A: A technique that demonstrates a smooth linear relationship between viability and functional recovery may be considered limited in that
intermediate levels of viability predict intermediate likelihood for functional recovery. With an abrupt threshold relationship between viability and
functional recovery, the problem of predicting intermediate likelihood for functional recovery is greatly minimized. Panel B: Two techniques with different diagnostic capability may show a similar overall relationship between viability and functional improvement.
However, if functional improvement is expressed as a continuous, rather than binomial, variable, the better technique may reduce the variability
(smaller error bars) in predicting the absolute amount of functional improvement. Reproduced from Di Carli M and Kwong R (editors). Novel Techniques for Imaging the Heart: Cardiac MR and CT. 1st edition. West Sussex: Wiley­
Blackwell; 2008.
Summary
This module provided a review the pathophysiology of myocardial viability and description of its clinical importance.
Methods to assess myocardial viability are varied and may only indirectly be related to whether myocytes are alive or
dead. There are many assumptions regarding viability testing. Several arise, in part, from considering viability and/or
functional recovery as a simple binary—yes or no—function, rather than as a continuum, which better reflects reality.
Although an important clinical endpoint, functional recovery after revascularization is a flawed truth standard for evaluating
viability techniques, because myocardium that does not recover may be predominantly viable rather than nonviable.
Understanding the underlying assumptions in viability testing is important, as the results of the recent STICH trial
highlight. In contrast to earlier, smaller studies, STICH found that common clinical methods such as DSE and SPECT
have not identified patients with a differential survival benefit from CABG, as compared with medical therapy alone.16
Ultimately, the decision for revascularization still involves many factors besides the amount of viability (and nonviability).
Key Points
The term "myocardial stunning" describes the state of postischemic myocardial dysfunction in the presence of
relatively normal blood flow.
The term "myocardial hibernation" describes the state of chronic myocardial dysfunction at rest that can be
partially or completely restored to normal either by improving blood flow and/or by reducing demand.
Several noninvasive imaging methods are available that assess myocardial viability either indirectly (by
measuring morphology or contractile reserve) or directly (by measuring metabolic activity or cell membrane
integrity).
In the STICH trial, the assessment of myocardial viability with DSE and/or SPECT did not identify patients with a
differential survival benefit from CABG, as compared with medical therapy alone, in contrast with the prior
literature.
Understanding the underlying assumptions in current viability assessment methods is important.
Suggested Reading
1. Bonow RO, Maurer G, Lee KL, et al, and the STICH Trial Investigators. Myocardial viability and survival in ischemic
left ventricular dysfunction. N Engl J Med 2011;364:1617­25.
2. Schinkel AF, Bax JJ, Delgado V, Poldermans D, Rahimtoola SH. Clinical relevance of hibernating myocardium in
ischemic left ventricular dysfunction. Am J Med 2010;123:978­86.
3. Partington SL, Kwong RY, Dorbala S. Multimodality imaging in the assessment of myocardial viability. Heart Fail
Rev 2011;16:381­95.
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7.6: Microvascular Angina
Author(s): Ashish Gupta, MD, PhD
C. Noel Bairey Merz, MD, FACC
Carl J. Pepine, MD, MACC
Learner Objectives
Upon completion of this module, the reader will be able to:
1. Review new data regarding the prevalence of microvascular coronary dysfunction.
2. Discuss emerging data regarding pathophysiological mechanisms of microvascular coronary dysfunction.
3. Evaluate diagnostic strategies for microvascular coronary dysfunction.
Background and Prevalence of Microvascular Coronary
Dysfunction
The exact prevalence of microvascular coronary dysfunction as the basis for angina
and other findings suggesting ischemic heart disease (IHD) is unknown. But it is
estimated that over 9 million Americans have angina pectoris, which significantly
impacts quality of life, ability to work, and costs to society.1 Among patients
undergoing coronary angiography for evaluation of chest pain thought to represent
angina pectoris, a significant proportion has angiographically "normal" epicardial
vessels or insufficient obstructive disease to explain ischemia. The CASS (Coronary
Artery Surgery Study) registry found that among 25,000 patients undergoing coronary
angiography, 39% of females and 11% of men had what appeared to be "normal"
epicardial arteries.2
The American College of Cardiology (ACC)­National Cardiovascular Data Registry
(NCDR) database of >375,886 patients found that "nonobstructive coronary artery
disease (CAD)" was considerably more frequent than that reported from the CASS,
and the frequency was significantly higher among women (51%) versus men
(32%).3 The WISE (Women's Ischemia Syndrome Evaluation) prospective cohort
found that 62% of females referred to angiography for angina had nonobstructive
CAD,4 and approximately one­half of these patients who had coronary flow
measured had evidence of microvascular dysfunction (reduced flow reserve to
adenosine). Among patients presenting with biomarker confirmed acute coronary
syndrome in multiple clinical trials, women were found to have a higher prevalence
of nonobstructive disease versus men (Figure 1).5 Angina, in general, also appears
to be more prevalent in women than men, based on comparisons from 31 countries:
6.7% in women versus 5.6% in men.6
Historical Considerations, Definitions, and Nomenclature
In their classical report on the relationship between clinical manifestations and
pathologic findings, Blumgart and colleagues7 noted that uncomplicated angina
pectoris was usually associated with occlusions of at least two of the main
epicardial coronary arteries. With the introduction of coronary angiography, this
concept was reinforced by multiple reports. Using this background in 1967, Likoff
and colleagues8 first called attention to the "paradox of angina with unmistakable
normal coronary angiograms" in a group of 15 women with ischemic
electrocardiogram (ECG) abnormalities without diabetes or hypertension. They also
suggested the possibility of microvascular abnormalities. Referring to a group of
patients with normal coronary angiograms plus ECG and transmyocardial lactate
evidence of myocardial ischemia reported by Arbogast and Bourassa, Kemp and
colleagues coined the descriptor "syndrome X" in 1973.9,10
Cannon and colleagues11 introduced the term "microvascular angina" in 1983 after
documenting evidence for microvascular dysfunction as an inappropriate coronary
flow response to various stimuli, despite angiographically normal epicardial
vessels. However, in subsequent studies they questioned the presence of ischemia
when they could not detect left ventricular (LV) wall motion abnormalities by
echocardiography.
In 1991, Maseri and colleagues proposed that focal ischemia, in small regions
scattered throughout the myocardium caused by prearteriolar dysfunction, could
explain the absence of LV wall motion changes.12 Using cardiac magnetic
resonance imaging, which provides superior resolution to evaluate perfusion,
Panting, Pennell, and colleagues then documented a relative failure of
subendocardial perfusion to increase with adenosine infusion in these patients that
could also account for an absence of major changes in LV wall motion.13
More recently, Camici and Crea14 further refined the definition of coronary
microvascular dysfunction as "a dysregulation of coronary blood flow, not
attributable to obstructive CAD, that results from either structural or functional
mechanisms in the coronary microvasculature." They also developed a clinical
classification (Table 1), and summarized the possible pathogenetic mechanisms
based on alterations observed and their possible causes (Table 2).
Figure 1
Table 1
Table 2
Prevalence of “Normal” or Nonobstructive Coronary Arteries in Acute Coronary Syndrome Trials Reporting Results of “Early Angiography
Figure 1
Reproduced with permission from Anderson RD, Pepine CJ. How to manage angina with normal coronary arteries (update). In: Fauci A,
Braunwald E, Kasper D, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw­
Hill Professional; 2009.
Clinical Classification of Coronary Microvascular Dysfunction
Table 1
Adapted with permission from Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830­40.
Pathogenetic Mechanisms of Coronary Microvascular Dysfunction
Table 2
ACS = acute coronary syndrome. Adapted with permission from Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830­40.
Clinical Findings
Clinically, the syndrome of microvascular angina is characterized by predominantly effort or stress­related chest
symptoms (discomfort, dyspnea) that often are indistinguishable from symptoms attributable to angina pectoris
associated obstructive CAD. While microvascular angina may occur in men, most patients with this syndrome are
women. The exam is usually normal, as is the ECG, other than occasional minor ST­T wave alterations. These patients
often have some ST segment depression and/or perfusion studies suggestive of myocardial ischemia during
spontaneous or provoked angina that is not attributable to obstructive CAD. These abnormalities, however, are widely
variable in their reproducibility on repeated testing, but this finding is also not unusual for many patients with obstructive
CAD.
Although testing for epicardial coronary artery spasm is important, because it can be specifically treated, the
overwhelming majority of patients with microvascular angina have no evidence for spontaneous or provoked coronary
artery spasm or cardiac (e.g., hypertrophic or dilated cardiomyopathy, transplant vasculopathy) or systemic (e.g.,
amyloidosis) diseases known to be associated with microvascular coronary dysfunction. The WISE cohort identified a
high prevalence of atherosclerosis risk conditions (e.g., hypertension, diabetes, and obesity), and except in patients with
left bundle branch block, LV systolic function is usually normal or may even be hyperdynamic. Nevertheless, while there is
usually important functional disability, this syndrome was believed to be rarely associated with sudden death or
myocardial infarction (MI), until the more recent WISE findings discussed in the next section.
Pathophysiology
Atherosclerosis Risk Factors
Numerous small studies initially suggested that women with atherosclerosis risk
factors were usually postmenopausal, while larger consecutive cohorts, including
the WISE study, suggested that these women tend to be younger and frequently
premenopausal compared with those with obstructive CAD.4 Traditional risk factors
like hypertension, obesity, hypertriglyceridemia, and diabetes, as well as the
Framingham risk score tend to underestimate the risk for adverse outcomes.
Several conditions found only in females, including early menopause, gestational
diabetes, peripartum vascular dissection, pre­eclampsia and eclampsia, polycystic
ovarian syndrome, low birth weight children, and hypothalamic hypoestrogenemia,
carry increased risk for CAD later in life,15 but it is unknown if such conditions
portend microvascular angina before these women develop clinically manifest CAD.
Data from the WISE study demonstrated that coronary microvascular dysfunction is
present in at least 50% of women with chest pain in the absence of obstructive CAD
and cannot be completely explained by risk factors for atherosclerosis, hormone
levels, or inflammatory markers.
The diagnosis of microvascular dysfunction should be considered in patients with
chronic chest pain syndromes resembling angina, who do not have evidence of
obstructive CAD. Women also suffer disproportionately from a variety of generalized
vascular disorders that are known to be associated with CAD, as well as
microvascular disease, including systemic lupus erythematosus (SLE), rheumatoid
arthritis, migraine, Raynaud's phenomenon, and autoimmune arthritis. These
observations support the influence of lifelong, varying reproductive hormone levels
related to ovarian cycling, pregnancy, peripartum, and menopause that are likely to
influence vascular function.
The role that abnormal coronary reactivity plays in ischemia among women without
obstructive CAD has been described, but the relative importance of endothelial and
microvascular dysfunction has been insufficiently explored. An integrated working
understanding of the cascade of mechanisms and manifestations of ischemia
impacting IHD risk in women is reviewed in Figure 2.16
It has been proposed that microvascular coronary dysfunction leading to chronic
stable angina (e.g., microvascular angina) is more prevalent in women than men as
a result of risk factor clustering, vascular inflammation and remodeling, and
hormonal alterations.15­18 Abnormal coronary reactivity occurs in the setting of
atherosclerosis risk factors and is usually associated with underlying atheroma
vulnerable to clinical instability and more progressive disease states. It is for this
reason that identifying nonobstructive atheroma may provide greater risk
stratification in women. An overarching working model of this proposed female­
specific IHD pathophysiology is depicted in Figure 3.16
Although the relationship between microvascular dysfunction and epicardial
atherosclerosis is not fully understood, a leading hypothesis is that it is a single
disease process. This is based on observations from animal models documenting
that most atherosclerosis risk conditions (e.g., increased low­density lipoprotein
cholesterol [LDL­C], glucose) injure the microvessels. The response to vascular
wall injury may vary related to sex differences in vascular remodeling and vascular
reactivity.
Figure 2
Figure 3
Cascade of Mechanisms and Manifestations of Ischemia Having an Impact on Ischemic Heart Disease Risk in Women
Figure 2
Adapted with permission from Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol
2009;54:1561­75.
Overarching Model of Ischemic Heart Disease Pathophysiology in Women
Figure 3
CAD = coronary artery disease; PCOS = polycystic ovarian syndrome. Adapted with permission from Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol
2009;54:1561­75.
Regulation of the Microvascular Coronary Circulation
Various regulatory mechanisms of the microvascular coronary circulation and
experimental evidence supporting these mechanisms have been reviewed in detail
by Patel and Fisher.19 The complex interplay of these regulatory pathways is
outlined in Figure 4, and a brief synopsis of key regulatory mechanisms follows.
Metabolic Factors
Broadly speaking, coronary flow is linearly related to myocardial oxygen
requirements. An increase in myocardial metabolism must be balanced by an
increased supply of nutrients and oxygen from blood, otherwise ischemia results.
The supply increase is primarily a result of microvascular endothelium­mediated
dilation via nitric oxide, adenosine, and adenosine triphosphate sensitive K+
channels.
Myogenic Factors
Maintenance of intraluminal pressure within fine limits in the microcirculation is
necessary to ensure adequate transport of substances across the vascular lumen
to the tissues. With elevated intraluminal pressure, there is a risk of tissue damage
due to edema. In the medium sized arterioles, the main mechanism involved in
regulation of the microvascular circulation is alteration of smooth muscle tone in
response to changes in intraluminal pressure, and this is independent of
endothelial function. These myogenic responses are reduced in the
subendocardium compared with the subepicardium, which may also explain why
the subendocardium is more prone to ischemic injury, particularly given the
increased physical stresses in the subendocardium during the cardiac cycle.
Endothelial Factors
Three major mediators include nitric oxide, endothelial­derived hyperpolarizing
factor, and prostacyclin. Production and release of these mediators is triggered by
shear stress detected at the endothelial cell surface receptor. In addition,
endothelial cells are responsible for production of potent vasoconstrictors including
thromboxane A2, some prostaglandins, angiotensin II, and endothelin 1.
Maintenance of smooth muscle tone is dependent on a fine balance between
endothelial­derived vasoconstrictors and vasodilators.
Other Factors
Many other factors play a role in control of the microcirculation. These include the
autonomic nervous system and extravascular physical forces of the beating heart.
Subendocardial perfusion, in particular, is reduced by physical forces related to the
contracting heart muscle, which explains why the subendocardium is most prone to
ischemic injury.
Figure 4
Mechanisms Responsible for Regulation of Myocardial Microvascular Resistance
Figure 4
Factors involved in regulating tone of the microcirculation. Endothelial­dependent regulation, mediated by release of mediators from endothelial
cells in response to stimuli such as shear stress and platelet derived factors, is the dominant mechanism in larger arterioles. Myogenic regulation
utilizes smooth muscle cell stretch receptors in activation of membrane bound ionic channels to respond to changes in intraluminal pressure and
is dominant in medium sized microvessels. Metabolic factors (e.g., change in PCO2, pH, and adenosine) contribute to dilation in response to
increasing metabolic activity, and this is most prominent in the smallest microvessels. In addition, neurally mediated factors and extravascular
mechanical forces are involved in regulation of myocardial microvascular resistance. ACh = acetylcholine; EDHF = endothelial­derived hyperpolarizing factor; K+ATP = adenosine triphosphate sensitive K+ channel; LVEDP = left
ventricular end­diastolic pressure; NO = nitric oxide; PKC = protein kinase C; PLC = phospholipase C; RVEDP = right ventricular end­diastolic
pressure. Adapted with permission from Patel B, Fisher M. Therapeutic advances in myocardial microvascular resistance: unraveling the enigma.
Pharmacol Ther 2010;127:131­47
Pathogenetic Mechanisms of Microvascular Coronary
Dysfunction
On the basis of the clinical settings in which it occurs, microvascular coronary
dysfunction can be classified into four types: 1) dysfunction occurring in the absence
of CAD and myocardial diseases, 2) dysfunction in the presence of myocardial
diseases, 3) dysfunction in the presence of obstructive epicardial CAD, and 4)
iatrogenic dysfunction. Various clinical scenarios have been reviewed by Camici and
Crea,14 and are summarized in Table 2.
Several pathophysiologic mechanisms including structural and functional
aberrations of the coronary microvasculature, as well as the extravascular changes,
may account for microvascular coronary dysfunction.
Pathogenetic Mechanisms of Coronary Microvascular Dysfunction
Table 2
ACS = acute coronary syndrome. Adapted with permission from Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830­40.
Table 2
Assessment of Microvascular Function
As a result of the small size of the coronary microcirculation and limited resolution of
available imaging techniques, direct visualization and morphologic assessment of
human coronary microvasculature in vivo is not possible with current techniques.
Therefore, assessment is usually based on evaluating physiologic and functional
properties.20 Both noninvasive and invasive methods are available (Table 3). In
general, these techniques may be grouped into three categories: 1) techniques for
assessment of inducible myocardial ischemia (e.g., magnetic resonance imaging
[MRI] perfusion, position emission tomography [PET], single­photon emission
computed tomography [SPECT]), 2) myocardial perfusion abnormality, and 3)
assessment of coronary flow response to maximal hyperaemia.
Table 3
In the absence of obstructive CAD, inducible myocardial ischemia or myocardial
perfusion defect or impaired coronary flow reserve (CFR) may be used as indicators
of coronary microvascular dysfunction. The ability to quantify microvascular blood
flow in resting and stress states allows for the determination of CFR, the ratio of
maximal hyperemic to resting flow rates. Mild variations in a normal cutoff exist
between different quantification methods, such that a CFR <2.0 and 2.5 is generally
considered abnormal.21 CFR is typically decreased when measured in a vessel
with epicardial stenosis, but in the absence of this, decreased CFR is representative
of microvascular coronary dysfunction.
Available Methods to Assess Coronary Microvascular Function
Table 3
CFR = coronary flow reserve; CT = computed tomography; FFR = fractional flow reserve; IMR = index of microcirculatory resistance; MRI =
magnetic resonance imaging; PET = position emission tomography; SPECT = single­photon emission computed tomography; TIMI = Thrombolysis in
Myocardial Infarction. Adapted with permission from Leung DY, Leung M. Non­invasive/invasive imaging: significance and assessment of coronary microvascular
dysfunction. Heart 2011;97:587­95.
Management Considerations
Chronic angina in a patient with microvascular coronary dysfunction is associated
with diverse spectra of clinical disorders and involves multiple mechanisms with
various clinical consequences. In approaching a patient with chronic angina, the
following specific conditions need to be considered for appropriate management
after obstructive CAD and coronary spasm have been excluded with reasonable
certainty:
Insulin resistance states (e.g., diabetes, metabolic syndrome).
Associated myocardial disorders (e.g., primary cardiomyopathies [e.g.,
dilated and hypertrophic] and secondary cardiomyopathies [e.g., long­
standing hypertension, severe valvular disease]).
Inflammatory/immune/connective tissue disorder (e.g., SLE, rheumatoid
arthritis, progressive systemic sclerosis, giant cell arteritis).
Known diseases of the myocardium (e.g., myocarditis).
Early infiltrative heart disease (e.g., amyloidosis, hemochromatosis).
If none of the preceding structural mechanisms for coronary microvasculature are
likely, the patient should be considered to have a functional disorder to explain
"microvascular angina" and other manifestations of myocardial ischemia. Although
large outcome studies are needed, some treatments have been shown to be
effective in small trials for reduction of symptoms and even improvement in
microvascular coronary function. Therapeutic approaches to patients with chronic
stable angina in patients with normal epicardial coronary arteries for the
improvement of function, angina, and quality of life are outlined in Table 4.19,22
Whether these treatments modify the intermediate to long­term course or reduce the
frequency of adverse outcomes is unknown at this time.
Table 4
Therapeutic Approaches to Patients With Angina and Normal Coronary Arteries
Table 4
ACE = angiotensin­converting enzyme; ARB = angiotensin­receptor blocker; CAD = coronary artery disease; EECP = enhanced external
counterpulsation; VSMC = vascular smooth muscle cell.
Key Points
Chronic stable angina, even among patients with normal appearing coronary angiography, carries a significant
burden in terms of morbidity and overall adverse outcome.
Microvascular coronary dysfunction is an important prognostic factor in a wide range of diseases.
Microvascular coronary dysfunction may be present in the absence of overt obstructive disease in conduit and
epicardial arteries.
Microvascular coronary dysfunction can be detected in the presence of vascular risk factors and may be reversible
with lifestyle modification and treatment of risk factors.
Microvascular coronary dysfunction may lead to myocardial ischemia, as seen in patients with microvascular
angina.
Assessment of coronary microcirculation depends on evaluation of its functional aspects. Both invasive and
noninvasive methods are available to assess microvascular coronary function.
Most available methods do not assess microvascular coronary function in isolation. They assess the total impact
of both epicardial coronary disease and microvascular dysfunction on coronary flow or myocardial perfusion
reserve.
A CFR <2.5 is generally considered abnormal. Decreased CFR in the setting of normal epicardial vessels is
representative of microvascular coronary dysfunction.
Assessment of microvascular coronary function may allow early identification of at risk patients, monitoring of
treatment, or open new therapeutic intervention.
Management includes traditional antianginal drugs and novel therapies including potassium channel openers,
metabolic agents, ρ­kinase inhibitors, angiotensin­converting enzyme inhibitors, late sodium channel modifiers,
and statins.
References and Suggested Reading
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2. Camici PG. Is the chest pain in cardiac syndrome X due to subendocardial ischemia? Eur Heart J 2007;28:1539­
40.
3. Pries AR, Habazettl H, Ambrosio G, et al. A review of methods for assessment of coronary microvascular disease
in both clinical and experimental settings. Cardiovasc Res 2008;80:165­74.
4. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction. Circulation 2007;115:1285­95.
5. Pauly DF, Johnson BD, Anderson RD, et al. In women with symptoms of cardiac ischemia, nonobstructive
coronary arteries, and microvascular dysfunction, angiotensin­converting enzyme inhibition is associated with
improved microvascular function: a double­blind randomized study from the National Heart, Lung and Blood
Institute Women's Ischemia Syndrome Evaluation (WISE). Am Heart J 2011;162:678­84.
6. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease
is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2011;Sep 11:[Epub ahead
of print].
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7.7: Asymptomatic Coronary Artery Disease
Author(s): Michael S. Lauer, MD, FACC
Learner Objectives
Upon completion of this module, the reader will be able to:
1. Cite criteria for valid screening tests for chronic disease so that physicians can work with their patients to make informed
decisions about whether to undergo testing.
2. Appraise the value of novel risk markers of asymptomatic disease, appreciating that statistical independence alone is
inadequate evidence.
3. Describe assessments that should be undertaken in all asymptomatic adults, assessments that should not be
undertaken in any asymptomatic adult, and assessments that might be reasonable in intermediate­risk asymptomatic
adults.
Introduction
Perhaps no other type of medical technology better captures the public imagination than screening. “Catch it early,” the
thinking goes, because by catching it early, one can “nip it in the bud,” literally stopping potentially deadly disease in its
tracks before it even has a chance to strike. There is no question that screening for asymptomatic disease can, when
properly applied, save lives. Large­scale randomized trials have shown, for example, that screening can lower death
rates related to certain cancers (e.g., breast, colon, and lung) and related to abdominal aortic aneurysm.1 However, in
other cases, screening has not worked, and has instead led to probable harm, with many patients subject to un­needed
and in some cases dangerous downstream tests and procedures.2­5
Coronary artery disease (CAD) potentially lends itself well to screening. It has long been known that there is an extended
asymptomatic latent period, a period that can last for decades. One half of all major coronary events, including fatal
events, come without warning. Despite improvements in medical therapy and prevention, there continues to be a high
prevalence of atherosclerotic risk factors in the United States. The combination of new and potentially powerful screening
tests, along with effective treatments for risk factors, gives credence to routine CAD screening among adults deemed to
be at intermediate risk.6
Screening for Chronic Disease: General Considerations
The United States Preventive Services Task Force (USPSTF) has listed four criteria
for when screening is valuable (Table 1): two related to disease and two related to a
candidate test.7 For a disease to be worthwhile screening, it must be common and
serious, and it must have a prolonged asymptomatic phase; both of these criteria
are clearly met for CAD.
For a screening test to have value, it must have a low false­positive rate, and its use
must lead to improved clinical outcomes. When examining these two criteria,
screening tests for CAD fall short. For example, even among adults who were
enrolled in the MESA (Multi­Ethnic Study of Atherosclerosis) and who had high
coronary calcium scores, well over 90% experienced no coronary events during a
median 3.8 years of follow­up.8 To date, no randomized trials have definitively shown
a link between use of a screening test and reduced risk of myocardial infarction (MI)
or coronary death. Of note, none of the four USPSTF criteria mention prediction. The literature linking
various noninvasive tests to clinical events is extensive, but it is important to keep in
mind that prediction does not necessarily imply prevention.
It is tempting to use observational data to show that patients who undergo screening
tests have better clinical outcomes. However, it is important for clinicians to
recognize serious biases that cloud interpretation of observational analyses, and to
be able to explain them to their colleagues and patients, who may be overly
influenced by aggressive direct­to­consumer advertising.3
Three major biases in observational screening studies are9 :
1. Lead­time bias: Disease is detected at an earlier stage, but death (or a
major clinical event) occurs whenever it was destined to occur, leading to an
increase in apparent survival.
2. Length­time bias: Patients with indolent disease that occurs over a
prolonged period without manifesting symptoms are more likely to be
detected when undergoing a screening test, because aggressive disease
strikes before the test is performed. Detecting less aggressive disease by
screening tests leads to an apparent increase in survival in this group.
3. Overdiagnosis bias: This is related to length­time bias. “Disease” is detected
by screening tests, but the “disease” never would have clinically manifested
had it never been found. This is sometimes called “pseudo­disease.”
Sometimes disease regresses spontaneously; other times it progresses so
slowly that another pathological process kills the patient first.10
Table 1
United States Preventive Services Task Force Criteria for a Valid Screening Test
Table 1
Reproduced with permissino from U.S. Preventive Services Task Force. Guide to Clinical Preventive Services (2nd Edition): Report of the U.S.
Preventive Services Task Force. McLean, VA: International Medical Publishing; 2009.
Assessing the Value of Novel Prognostic Tests
In the absence of randomized trials, most data on novel prognostic tests are based
on cohort studies in which investigators have attempted to show that tests are
“independently” predictive of risk after accounting for known predictors. Typically,
investigators use regression models (e.g., Cox regression) and pronounce a test to
be independently predictive if the “adjusted” p­value is <0.05. An American Heart
Association (AHA) Scientific Statement on evaluation of novel markers of
cardiovascular risk describes more stringent criteria.11 These include the following:
Statistical independence over and above existing data (e.g., age, gender,
standard risk factors).
Discrimination: The ability to distinguish between people who develop
disease and those who do not. This is typically assessed by calculating a “c­
statistic,” or “c­index,” which is analogous to the area under a receiver
operating characteristic (ROC) curve. A value of 1.0 implies perfect
discrimination, whereas a value of 0.5 implies no discriminative ability any
better than chance.
Reclassification: The ability of a test to accurately reclassify people from one
risk category to another. For example, if a person who ultimately develops
disease is reclassified from intermediate to high risk, the test reclassifies
correctly; conversely, if a person who ultimately develops disease is
reclassified from high to intermediate risk, the test has yielded misleading
information. Measures to assess reclassification include the “Net
Reclassification Improvement.”
Other important test characteristics to consider include:
Accuracy and reproducibility: Does the test correctly measure what it claims
to measure, and will it do so in a consistent manner?
Costs: When a physician orders a test, he or she can cause the patient and
society to incur a variety of costs, including those of the test itself as well as
the costs of downstream tests, procedures, and complications.
Test impact: Beyond costs and procedures, tests can lead to lifestyle
changes and pharmacological interventions. These may be reasonable, but
only if they lead to improved clinical outcomes. In the absence of randomized
trials, one often cannot determine whether a test has a salutary impact.12 The preceding criteria and characteristics are summarized in Table 2.
Table 2
Characteristics by Which Novel Risk­Stratification Tests Are Assessed
Table 2
References:
1. Hlatky MA, Greenland P, Arnett DK, et al.; on behalf of the American Heart Association Expert Panel on Subclinical Atherosclerotic
Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific
statement from the American Heart Association. Circulation 2009;119:2408­16.
2. Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need
randomized trials? Ann Intern Med 2006;144:850­5.
Current Guidelines: General Approach and Recommendations on
Specific Tests
The American College of Cardiology Foundation and the AHA (ACCF/AHA) recently
released guidelines on assessment of cardiovascular risk in asymptomatic adults.6
The guidelines recommend the following approach.
First, clinicians should calculate a global risk score for all adults (Class IB). A variety
of risk scores are available (Table 3); all use multiple traditional cardiovascular risk
factors. The scores are useful for deriving a single quantitative estimate to classify
subjects as being low risk (<10% risk/10 years), intermediate risk (10­20%/10
years), or high risk (>20%/10 years) for experiencing major coronary events. To
further modify risk, the guidelines recommend obtaining family history for premature
atherothrombotic cardiovascular disease (Class IB). For subjects who are deemed
to be at low or high risk, no further testing is needed.
Second, clinicians can consider performing further tests in adults who, based on
global risk scores and family history, are at intermediate risk (10­20% 10­year risk). Among the tests that clinicians might consider (Class IIA) in this intermediate­risk
group are:
High­sensitivity C­reactive protein (hs­CRP): In adults who meet the inclusion
and exclusion criteria of the JUPITER (Justification for the Use of Statins in
Prevention: An Intervention Trial Evaluating Rosuvastatin) trial,13 (i.e., men
ages >50 years; women ages >60 years; low­density lipoprotein cholesterol
<130 mg/dl; not on lipid­lowering, hormone replacement, or
immunosuppressant therapy; without clinical coronary heart disease,
diabetes, chronic kidney disease, severe inflammatory conditions, or
contraindications to statins) to detect elevated levels.
Urine analysis: In adults with hypertension or diabetes, to detect
microalbuminuria.
Resting electrocardiogram (ECG): In adults with hypertension or diabetes, to
detect left ventricular hypertrophy, silent Q waves, intraventricular conduction
delays, and ST­T abnormalities.
Carotid intima­media thickness: Published recommendations on required
equipment, technical approach, and operator training and experience for
performance of the test must be carefully followed to achieve high­quality
results.
Ankle­brachial index: Reasonable for asymptomatic adults.
Coronary calcium: Reasonable for asymptomatic adults.
The guidelines list a group of tests that may be reasonable (Class IIB). These
include hs­CRP in younger adults than those enrolled in the JUPITER trial, urine
analysis in the absence of hypertension or diabetes, lipoprotein­associated
phospholipase A2, resting ECGs in the absence of hypertension or diabetes,
echocardiography in the absence of hypertension, exercise ECG (e.g., in sedentary
adults considering starting a vigorous exercise program) with particular attention to
non­ECG markers such as exercise capacity, and stress myocardial perfusion
imaging (MPI) in people with diabetes, a strong family history, and high coronary
calcium score.
Finally, the guidelines delineate tests that should NOT be done (Class III):
genotypes, lipid measures beyond those provided by a standard profile, natriuretic
peptide, arterial flow dilatation, arterial stiffness, stress echocardiography, stress
MPI (except as noted earlier), computed tomography (CT) angiography, and
magnetic resonance (MR) angiography.
Table 3
Global Risk Scores
Table 3
CHD = coronary heart disease; CVD = cardiovascular disease; HDL = high­density lipoprotein; hs­CRP = high­sensitivity C­reactive protein; LDL =
low­density lipoprotein; MI = myocardial infarction. Reproduced with permission from: Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in
asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J
Am Coll Cardiol 2010;56:e50­103.
Special Circumstances
The ACCF/AHA guidelines address specific approaches to asymptomatic adults with diabetes and approaches to
women.6 For people with diabetes, it is reasonable (Class IIA) to measure coronary calcium, while it may be considered
(Class IIB) to obtain glycosylated hemoglobin and stress MPI. It is noteworthy that investigators have performed a
randomized trial of MPI in diabetes and found that, although MPI abnormalities predicted coronary events, the use of MPI
did not reduce risk.14 This trial, known as DIAD (Detection of Ischemia in Asymptomatic Diabetics), demonstrates the
principle that prediction does not necessarily imply prevention.
The guidelines recommend that a global risk score and family history be obtained in all asymptomatic women (Class IB
for both).
Unmet Needs
It is noteworthy that the ACCF/AHA guidelines do not give any Class IA recommendation for clinicians assessing
cardiovascular risk in asymptomatic adults. This is because it is not known whether any measurement or test (including
global risk scores) improves outcomes. One might think that risk assessment and screening tests could lead to
improved adherence and motivation to interventions that treat risk factors, but at least one randomized US Army trial of
coronary artery calcium scoring was negative.15
Similarly, it is not known whether acquisition of global risk scores, family history, or findings from screening tests guide
therapy or long­term monitoring in such a way as to improve health outcomes, mainly because randomized trials on this
topic are few.12,16 The recently completed NLST (National Lung Screening Trial) serves as an example.17 Key Points
It cannot be automatically assumed that diagnosing disease in an early, asymptomatic state prevents clinical
disease or improves health.
It cannot be automatically assumed that if a test predicts clinical events, its routine use will prevent events.
Although a test may “independently” predict events by standard statistical criteria, it may fail to improve clinicians’
ability to discriminate patients who will develop disease from those who will not, and to properly reclassify
patients’ risk.
More importantly, although a test may predict events, it may not predict response to preventive interventions.
All asymptomatic adults should be checked for global risk based on standard cardiovascular risk factors, and for
family history of premature CAD.
Physicians may refer intermediate­risk patients for a number of tests, but they should inform their patients that it is
not known whether obtaining information from additional tests will lead to better health. These tests include hs­
CRP (for those meeting JUPITER criteria), urine analysis and resting ECG (in people with hypertension or
diabetes), carotid intima­media thickness, ankle­brachial index, and coronary calcium scores.
Randomized trials are needed to improve physicians’ ability to work with patients and make informed evidence­
based decisions about screening for CAD in asymptomatic adults. References
1. Ashton HA, Buxton MJ, Day NE, et al.; on behalf of the Multicentre Aneurysm Screening Study Group. The
Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality
in men: a randomised controlled trial. Lancet 2002;360:1531­9.
2. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet 2002;359:881­4.
3. Lee TH, Brennan TA. Direct­to­consumer marketing of high­technology screening tests. N Engl J Med
2002;346:529­31.
4. Lauer MS. Screening for coronary heart disease: has the time for universal imaging arrived? Cleve Clin J Med
2007;74:645­50, 653­4, 656
5. Andriole GL, Crawford ED, Grubb RL 3rd, et al.; on behalf of the PLCO Project Team. Mortality results from a
randomized prostate­cancer screening trial. N Engl J Med 2009;360:1310­9.
6. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in
asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50­103.
7. U.S. Preventive Services Task Force. Guide to Clinical Preventive Services (2nd Edition): Report of the U.S.
Preventive Services Task Force. McLean, VA: International Medical Publishing; 2009.
8. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic
groups. N Engl J Med 2008;358:1336­45.
9. Patz EF, Jr., Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med 2000;343:1627­33.
10. Black WC, Czum JM. Screening coronary CT angiography: no time soon. J Am Coll Radiol 2007;4:295­9.
11. Hlatky MA, Greenland P, Arnett DK, et al.; on behalf of the American Heart Association Expert Panel on Subclinical
Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel
markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation
2009;119:2408­16.
12. Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test,
and when do we need randomized trials? Ann Intern Med 2006;144:850­5.
13. Ridker PM, Danielson E, Fonseca FA, et al.; on behalf of the JUPITER Study Group. Rosuvastatin to prevent
vascular events in men and women with elevated C­reactive protein. N Engl J Med 2008;359:2195­207.
14. Young LH, Wackers FJ, Chyun DA, et al.; on behalf of the DIAD Investigators. Cardiac outcomes after screening for
asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled
trial. JAMA 2009;301:1547­55.
15. O'Malley PG, Feuerstein IM, Taylor AJ. Impact of electron beam tomography, with or without case management, on
motivation, behavioral change, and cardiovascular risk profile: a randomized controlled trial. JAMA 2003;289:2215­
23.
16. Bonow RO. Clinical practice. Should coronary calcium screening be used in cardiovascular prevention strategies?
N Engl J Med 2009;361:990­7.
17. The National Lung Screening Trial Research Team. Reduced lung­cancer mortality with low­dose computed
tomographic screening. N Engl J Med 2011;Jun 30:[Epub ahead of print].
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Chapter 7 Exam
Visit the online version of the product to see the correct answer and commentary.
1. A paper in a medical journal reports on a new diagnostic screening test that is a
“statistically significant independent predictor” of major cardiovascular events in
asymptomatic adults, even after accounting for standard risk factors. The authors
argue that clinicians should use the test.
Which of the following is the most important reason why the authors’ argument is
not valid?
A. Failure to account for discrimination.
B. Failure to account for impact on outcome.
C. Failure to account for reclassification.
D. Failure to account for calibration.
2.
Which of the following statements is TRUE regarding the treatment of multivessel
CAD?
A. Routine revascularization in patients with ischemic cardiomyopathy and LV
ejection fraction below 35% improves survival.
B. Percutaneous revascularization guided by FFR is associated with similar
numbers of stents per procedure but improved outcomes at 2 years compared
with revascularization guided by angiography.
C. Patients with diabetes and multivessel CAD have improved survival with
CABG compared with PCI using bare­metal stents; mortality data comparing
surgery with drug­eluting stents in patients with diabetes are inconclusive.
D. A patient with severe stenoses in the proximal LAD artery and proximal right
coronary artery should be treated with maximal medical therapy and referred for
revascularization only for relief of anginal symptoms.
3.
In which of the following situations is revascularization associated with improved
survival?
A. Chronic occlusion of a large dominant circumflex artery; intermediate risk on
noninvasive testing; class II angina.
B. Severe stenoses of the mid­LAD and proximal circumflex arteries;
intermediate risk on noninvasive testing; asymptomatic on metoprolol.
C. Chronic occlusion of a dominant right coronary artery; severe stenosis of the
mid­circumflex; class II angina on maximal medical therapy.
D. 80% stenoses of the proximal LAD and proximal circumflex arteries; normal
ventricular function; class I angina.
4.
Which of the following tests is LEAST likely to provide any incremental prognostic
information in patients with established SIHD?
A. Echocardiography.
B. Cardiac MRI.
C. NT­proBNP or BNP.
D. Computed tomography calcium score.
5.
When evaluating patients with SIHD and categorizing them into an appropriate risk
group, which of the following are the corresponding 1­year mortality rates for low,
intermediate, or high risk?
A. <5% (low), 5­8% (intermediate), >8% (high).
B. <1% (low), 1­3% (intermediate), >3% (high).
C. <3% (low), 3­4% (intermediate), >5% (high).
D. <10% (low), 10­20% (intermediate), >20% (high).
6.
Which of the following statements is TRUE regarding revascularization?
A. Compared with stenting, CABG for isolated proximal LAD disease is
associated with improved 1­year survival.
B. In patients with multivessel CAD, 1­year mortality rates are similar following
PCI with drug­eluting stents compared with CABG.
C. In patients with multivessel CAD, 1­year repeat revascularization rates are
similar following PCI with drug­eluting stents compared with CABG.
D. In the SYNTAX study, patients with significant LMCA disease had similar 1­
year rates of survival and repeat revascularization after PCI compared with
CABG.
7. A 45­year­old man with diabetes is evaluated for chronic Canadian
Cardiovascular Society class III angina despite treatment with aspirin, metoprolol,
ranolazine, and atorvastatin. On cardiac catheterization, his ventricular function is
normal, and he has focal 90% stenoses in his mid­LAD coronary artery, mid­right
coronary artery, and a large first obtuse marginal branch.
Which of the following statements is TRUE regarding this patient’s treatment?
A. Continued medical therapy with addition of a long­acting nitrate is indicated,
given his normal LV function.
B. Multivessel PCI with drug­eluting stents is associated with an increased risk
of mortality at 1 year compared with CABG, regardless of his SYNTAX score.
C. In patients with diabetes, multivessel PCI with drug­eluting stents is
associated with an increased risk of repeat revascularization at 1 year compared
with CABG.
D. The patient should be further evaluated with myocardial perfusion imaging
and undergo revascularization if moderate or high­risk findings are
demonstrated.
8. A 64­year­old man with angiographic documentation of CAD amenable to surgical
revascularization and a LVEF of 30% is being evaluated in the clinic for routine
follow­up. His most recent MI was 6 months ago. He does not have left main or
aortic valve disease and has never had cardiogenic shock. You are considering
whether or not a viability study will help you to determine if this patient will benefit
from surgical revascularization.
Which of the following statements is TRUE regarding the prognostic value of a
viability study in this patient?
A. Viability assessment by SPECT and/or DSE will identify patients with a
greater likelihood of survival, independent of other baseline prognostic variables.
B. Viability assessment by SPECT is superior to DSE in identifying patients with
a differential survival benefit from CABG.
C. Viability assessment by SPECT and/or DSE will identify patients with a
differential survival benefit from CABG.
D. Viability assessment by DSE is superior to SPECT in identifying patients with
a differential survival benefit from CABG.
E. Viability assessment by SPECT and/or DSE will not identify patients with a
differential survival benefit from CABG.
9. A 62­year­old woman presents to your office complaining of chest discomfort,
which has been increasing in frequency over the past 2 years. At first she noticed the
discomfort with extreme exertion, while running with her grandchildren. The
discomfort began in her substernal region and radiated to her back and left
shoulder, and resolved with rest. She attributed these symptoms to getting old and
being out of shape. About 9 months ago, she noticed that these episodes were
occurring about once a week and now were precipitated by either physical activity
(walking up or down the stairs, doing household chores with her arms) or emotional
stress related to her job as a teacher of autistic children.
Although these episodes continue to resolve with rest, she is concerned about
whether she should retire. She has a 50 pack­year smoking history and quit 2 years
ago when these episodes first started. She admits to poor dietary habits, history of
hypertension, and infrequent migraine both diagnosed in her late 40s and currently
treated with enalapril 10 mg daily and hydrochlorothiazide 12.5 mg daily. She has
dyslipidemia treated with lovastatin 20 mg daily for 2 years with total cholesterol of
215 mg/dl, low­density lipoprotein (LDL) of 125 mg/dl, high­density lipoprotein of 32
mg/dl, and triglycerides of 178 mg/dl. She does not have diabetes. She has never
seen a cardiologist and has never had an ECG or any other cardiovascular testing.
Her father died of a fatal myocardial infarction at the age of 62, and her mother died
of lung cancer at the age of 58. Her older brother has had coronary artery bypass
grafting, and her younger sister has dyslipidemia and diabetes.
Other than being overweight (5 feet 3 inches, 174 lbs) with a blood pressure today of
162/89 mm Hg, her exam is unremarkable.
Her cardiologist determines that she has stable angina, and that her blood pressure
and LDL need better control. Before addressing her retirement question and per
ACC/American Heart Association (AHA) guidelines, the cardiologist discusses the
need for additional noninvasive cardiac risk stratification. Her resting ECG was
normal, and enalapril was increased to 20 mg, hydrochlorothiazide to 25 mg daily,
and lovastin to 40 mg daily. After a lengthy discussion, the patient was not interested
in taking a long­acting nitrate, fearing that it would provoke her migraine. Likewise,
she did not want to take a beta­blocker or calcium antagonist because she had
experienced fatigue and edema when she had been prescribed these agents over
the previous years for hypertension.
The patient returns to the office nurse for blood pressure checks over the next 3
weeks. Then an exercise stress test was done using the Bruce protocol with Duke
treadmill scoring. Her stress test results are as follows:
Resting heart rate: 80 bpm; resting blood pressure 128/78 mm Hg.
Time on treadmill: 9 minutes and 30 seconds without chest discomfort.
Peak heart rate: 142 bpm; peak blood pressure 185/92 mm Hg.
At peak exercise, she exhibits a 1.5 mm horizontal to downsloping ST depression in
inferior leads, consistent with ischemia with fairly high workload. She did not have
any symptoms. An immediate postexercise echocardiogram reveals an ejection
fraction of 65% and no wall motion abnormalities. Her ST­segment depression
resolved completely in 1 minute.
Which of the following is NOT a primary goal of therapy for patients with chronic
stable angina?
A. Reduce coronary perfusion pressure.
B. Increase quality of life by reducing ischemia and preventing symptoms.
C. Increase quantity of life by disease modification and prevention of myocardial
infarction and death.
Please visit the online version to engage in this Exam.
1. The correct answer is B. For a screening test to be of value, its use must lead to an
improvement in clinical outcome.
2. The correct answer is C. In a large meta­analysis of studies comparing coronary artery
bypass surgery with multivessel PCI, lower mortality was observed in patients with diabetes who
were treated with surgery.1 These studies were conducted before the advent of drug­eluting
stents. The SYNTAX study compared multivessel PCI with drug­eluting stents to surgery.2 In
SYNTAX, although there was no difference in mortality in the diabetic subgroup, the patients
treated with PCI had increased rates of repeat revascularization at follow­up.
The STICH trial compared routine revascularization to optimal medical therapy in patients with
ischemic cardiomyopathy and severe LV dysfunction (defined as a LV ejection fraction below
35%).3 In STICH, overall mortality was no different between the two groups, although secondary
endpoints were improved in the surgical arm. The follow­up in STICH will be extended to
examine the effect of revascularization on long­term mortality.
In the FAME study, the use of FFR in guiding percutaneous revascularization in patients with
multivessel CAD resulted in lower rates of stent use and improved outcomes at 2 years.4
Patients with multivessel CAD including severe disease of the proximal LAD artery should be
considered for revascularization to improve survival. This recommendation is based on the CASS
study.5
References
1. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with
percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual
patient data from ten randomized trials. Lancet 1990;373;1190­7.
2. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3­
vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel­eluting
stents. J Am Coll Cardiol 2010;55:1067­75.
3. Velazquez EJ, Lee KL, Deja MA, et al. Coronary artery bypass surgery in patients with left
ventricular dysfunction. N Eng J Med 2011;364:1607­16.
4. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding
percutaneous coronary intervention in patients with multivessel coronary artery disease: 2­year
follow­up of the FAME study. J Am Coll Cardiol 2010;56:177­84.
5. Alderman EL, Bourassa MG, Cohen LS, et al. Ten­year follow­up of survival and myocardial
infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82:1629­46.
3. The correct answer is D. Data on the mortality benefit of revascularization in patients with
multivessel CAD is primarily from the studies from three decades ago comparing CABG with
medical therapy. In the CASS study,1 a mortality benefit was observed with revascularization in
patients with the following conditions:
Left main coronary artery stenosis or left main equivalent disease
Three­vessel CAD, particularly with a reduced LV ejection fraction (≤40%)
Two­vessel CAD including >75% stenosis in the proximal LAD
There is no evidence that survival is improved in patients with single­vessel CAD not involving the
proximal LAD. Patients with mild­to­moderate angina from multivessel CAD not involving the
proximal LAD may derive symptomatic relief from revascularization, but there is no evidence that
survival is improved.
References
1. Alderman EL, Bourassa MG, Cohen LS et al. Ten­year follow­up of survival and myocardial infarction
in the randomized Coronary Artery Surgery Study. Circulation 1990;82:1629­46.
4. The correct answer is D. Assessment of LV function is critical in the evaluation of patients
with SIHD, and thus, echocardiography provides important information regarding prognosis.
Cardiac MRI is also a reasonable test in patients with SIHD. In addition to providing quantifiable
data regarding LV function, it may offer insight into myocardial viability, which may help guide
therapy. NT­proBNP or BNP have been shown to identify patients at greater risk of death and
heart failure among patients with SIHD, and therefore, do add incremental prognostic
information. Calcium scoring, as assessed with CT, 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.
References
1. 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
2011;57:1126­66.
2. Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B­Type
natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol
2007;50:205­14.
3. 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 Foundation Appropriate 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 2010;56:1864­94.
5. The correct answer is B. While the risk categories in SIHD are not as well validated and
accepted as in primary prevention, in SIHD, low risk is considered a 1­year mortality rate of <1%,
intermediate risk is considered a 1­year mortality rate of 1­3%, and high risk is considered a 1­
year mortality rate of >3%. In primary prevention, the rates are much lower, with a 10­year risk of
death and MI of <10% (or <1% per year) in low­risk patients, 10­20% in intermediate­risk
patients, and >20% in high­risk patients.
References
1. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of
patients with chronic stable angina­summary 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;41:159­68.
6. The correct answer is B. The SYNTAX study was the first randomized trial to compare
treatment with PCI using drug­eluting stents with CABG in patients with multivessel CAD. Overall
rates of mortality at 12 months were similar in the two groups, whereas repeat revascularization
procedures were increased in patients treated with PCI. In SYNTAX, the 40% of patients with
significant LMCA disease were stratified at randomization to PCI or CABG. In this group, mortality
rates were similar, and repeat revascularization rates were increased following PCI.
In a large meta­analysis, CABG and PCI for proximal LAD disease resulted in similar rates of
stroke, myocardial infarction, and 5­year survival; CABG was associated with more relief of
angina and lower rates of repeat revascularization, whereas PCI was associated with shorter
hospital stays and less need for blood transfusion.
References
1. Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous
coronary intervention versus coronary­artery bypass grafting for severe coronary artery disease. N
Engl J Med 2009;360:961­72.
2. Kapoor JR, Gienger AL, Ardehali R, et al. Isolated disease of the proximal left anterior descending
artery: comparing the effectiveness of percutaneous coronary interventions and coronary artery
bypass surgery. JACC Cardiovasc Interv 2008;1:483­91.
7. The correct answer is C. The SYNTAX study was the first randomized trial to compare
treatment with PCI using drug­eluting stents versus CABG in patients with multivessel CAD. In
SYNTAX, patients with diabetes were stratified at randomization to PCI or CABG. In this group,
mortality rates were similar, whereas repeat revascularization rates were increased following
multivessel PCI. However, in the subset of patients with diabetes with SYNTAX scores of ≥33,
mortality was significantly higher following PCI than with CABG (13.5% vs. 4.1%).
Revascularization is indicated in this patient, given his severe anginal symptoms despite
medical therapy in the presence of significant CAD.
References
1. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3­
vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel­eluting
stents. J Am Coll Cardiol 2010;55:1067­75.
2. Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous
coronary intervention versus coronary­artery bypass grafting for severe coronary artery disease. N
Engl J Med 2009;360:961­72.
3. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness
Criteria for Coronary Revascularization: a report by the American College of Cardiology Foundation
Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions,
Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart
Association, and the American Society of Nuclear Cardiology. Endorsed by the American Society of
Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular
Computed Tomography. J Am Coll Cardiol 2009;53:530­53.
8. The correct answer is E. Option C is incorrect because SPECT and DSE will NOT identify
patients with a differential survival benefit from CABG, based on the STICH viability trial results.
Options B and D are incorrect because there is no significant difference between DSE and
SPECT in terms of lack of identifying patients with a differential survival benefit from CABG, based
on the STICH viability trial results. Option A is incorrect because viability status is not significantly
associated with the rate of death after adjustment for other significant baseline variables such as
LVEF, end­diastolic volume, and end­systolic volume index.1
References
1. Bonow RO, Maurer G, Lee KL, et al, and the STICH Trial Investigators. Myocardial viability and
survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364:1617­25.
9. The correct answer is A. There are two primary objectives in managing patients with chronic
stable angina: 1) increase quantity of life by disease modification to prevent myocardial infarction
and death, and 2) increase quality of life by reducing ischemia and preventing angina and related
symptoms. See the 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for
the Management of Patients With Chronic Stable Angina. Treating her high blood pressure to the
120­130 mm Hg systolic and 60­85 mm Hg diastolic level will not impair coronary perfusion, but
will reduce myocardial oxygen demand to lessen the possibility of ischemia.
References
1. Fraker TD Jr, Fihn SD; 2002 Chronic Stable Angina Writing Committee; American College of
Cardiology; American Heart Association; Gibbons RJ, Abrams J, Chatterjee K, 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;50:2264­74.