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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 decision-making, as recently reported in the STICH trial. The asymptomatic
patient and the approach to microvascular angina are also addressed.
Authors
Patrick T. O'Gara, MD, FACC
Editor-in-Chief
Thomas M. Bashore, MD, FACC
Associate Editor
James C. Fang, MD, FACC
Associate Editor
Glenn A. Hirsch, MD, MHS, FACC
Associate Editor
Julia H. Indik, MD, PhD, FACC
Associate Editor
Donna M. Polk, MD, MPH, FACC
Associate Editor
Sunil V. Rao, MD, FACC
Associate Editor
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7.1: Risk Stratification
Author(s):
Benjamin M. Scirica, MD, MPH, FACC
Learner Objectives
Upon completion of this module, the reader will be able to:
1. Recognize the importance of risk stratification in patients with stable ischemic heart disease (SIHD).
2. Appropriately choose and prioritize the various risk stratification modalities in order to efficiently and cost-effectively
manage a patient with SIHD.3. Integrate the results of multiple clinical tests when risk stratifying a patient with SIHD.
4. Recognize the appropriate, and inappropriate, use of different risk stratification techniques.
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Introduction
The diagnosis of SIHD, also termed chronic coronary artery disease (CAD), encompasses a heterogeneous population
that varies in terms of comorbidities, symptoms, and risk of future cardiovascular (CV) events. SIHD includes any
condition that results in a chronic or repetitive mismatch between myocardial oxygen supply and demand. Typically, SIHD
is due to atherosclerotic obstruction of the epicardial coronary arteries however, it may also arise from microvascular
disease and vasospasm, or more rarely, congenital anomalies or nonatherosclerotic vascular injury. Angina, or ischemic
chest discomfort, is the classic symptom of SIHD however, patients may present with dyspnea, heart failure, or
arrhythmias as their only symptomatic manifestation. Moreover, many patients with SIHD are free of symptoms, either at
the time of diagnosis of SIHD, or after successful medical therapy or revascularization.
Due to the diverse nature of SIHD and differences in definitions, estimates vary regarding the actual number of affected
people. However, it is estimated that 16.3 million people in the United States alone have CAD, with approximately 9
million reporting symptomatic chest pain and 8 million reporting a prior myocardial infarction (MI).1 The prevalence of
SIHD is increasing worldwide as the burden of risk factorssmoking, obesity, diabetes, and hypertensionincreases in
the large populations of developing nations.
Given the variability in this patient population, the evaluation of patients with known or suspected SIHD must incorporate
information from multiple clinical modalities to risk stratify effectively, and thereby, deliver appropriate and timely therapy.
In general, the goal is to identify patients at the highest risk who will benefit from the most intense therapy, while
reassuring and sparing invasive procedures in patients at a lower risk. Many of the tests or techniques reviewed in this
chapter are also central to the initial diagnosis of SIHD. This module will review current methods to improve risk
stratification among patients with documented SIHD. Diagnosis of SIHD and the risk stratification of asymptomaticpatients and of patients with acute coronary syndromes are covered in the module onAsymptomatic CAD in this chapter,
Patient Assessment in Chapter 3, and in the module on Initial Management, Risk Assessment, and Risk Stratification of
ACS in Chapter 6, respectively.
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Spectrum of Risk for Future Cardiovascular Disease in PatientsWith Stable Ischemic Heart Disease
In primary prevention (patients without SIHD), risk stratification is typically based on
a 10-year risk of MI or coronary heart disease death, where a 10-year risk is
considered low at
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Noninvasive Risk Stratification
Table 1
LV = left ventricle LVEF = left ventricular ejection fraction.
aAlthough the published data are limited, patients with these findings will probably not be at low risk in the presence of either a high-risk treadmill
score or severe resting LV dysfunction (LVEF
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Overview of Risk Stratification Techniques for Patients WithStable Ischemic Heart Disease(1 of 3)
The goal of evaluating a patient with SIHD should be to systematically and efficiently
utilize the multiple modalities to maximize the identification of high-risk features
without overtesting, but to ensure that critical data that would identify high-risk
patients is not missed. There are four broad categories of risk stratification that
should be considered
5
:
1. Clinical evaluation and assessment of comorbidities
2. Functional capacity/stress test
3. Ventricular function
4. Coronary anatomy
Every patient does not require each of these modalities to be evaluated. Nor do they
need to be assessed in sequence. A low-risk patient may only require a clinical
evaluation and a stress test or echocardiogram, while a high-risk patient may
proceed directly from the clinical evaluation to cardiac catheterization.
Risk Stratification Based on Clinical Evaluation
Clinical History and Physical Examination
The clinical history and physical examination remain cornerstones in the evaluation
of patients with SIHD. In general, poorly controlled traditional cardiac risk factors
hypertension, dyslipidemia, smoking, and diabetesare associated with worse
prognosis in patients with SIHD, and given that the overall risk of CV events is higher
in patients with SIHD, the absolute risk associated with the presence of diabetes, for
example, is even greater than in primary prevention.
A history of heart failure, regardless of left ventricular (LV) ejection function, is also a
marker of significantly increased risk in almost all SIHD patients. The physical
examination should support the history and identify patients with evidence of right-
sided or left-sided overload or stigmata of noncoronary atherosclerosis.
Prior Cardiovascular History
A history of a documented severe ischemic event, such as a MI or stroke,
substantially increases the risk of subsequent events compared to patients with
SIHD who have never had a major ischemic event. In the REACH (Reduction of
Atherothrombosis for Continued Health) Registry, patients with a history of MI or
stroke (n = 21,890) had a higher 4-year rate of CV death, MI, or stroke (18.3%)
compared to patients with stable vascular disease but no history of MI or stroke (n =
15,264) (12.2%, p < 0.001) (Figure 1).6 Moreover, the detection of vascular disease
in other arterial beds is also important to document as patients with polyvascular
disease (concomitant disease of the cerebrovascular or peripheral arterial beds)
are at an even higher risk.
According to the REACH Registry, the 1-year risk of CV death, MI, stroke, or
hospitalization for a CV event ranged from 12.6% for patients with an one-arterial
bed involvement, 21.1% for patients with a two-arterial bed involvement, and 26.3%
for patients with a three-arterial bed involvement (p < 0.001 for trend). 7
Assessing Functional Status and Symptoms of Stable Ischemic Heart Disease
All patients with SIHD should be closely questioned regarding their functional status
and whether their activities are limited by any potential ischemic symptoms. Simple
questions regarding the patient's usual level of activity, such as walking, climbing
stairs, carrying grocery bags, or yard work offers invaluable insight into the patient's
physical limitations. A careful understanding of the nature of the limiting symptom in
patients with low activity may offer insights into potential ischemic burden. Many
patients reduce their activities to prevent symptoms of angina and may report a
reduction in their pain when it is actually just self-limiting activity.
Figure 1
Table 2
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Ischemic chest discomfort, or angina, is the classic symptom of SIHD. The
diagnosis of angina begins with a careful assessment of clinical symptoms. While
there is significant variability in the quality of angina symptoms, angina typically is a
thoracic discomfort, often centered in the midsternum that radiates to the neck, jaw,
or arm, although some describe it as more epigastric than substernal. It is most
commonly described as a pressure, squeezing, or tightness, rather than a sharp
pain. Associated symptoms are common and include diaphoresis, dyspnea,
nausea, or intense fatigue. In some patients, and, in particular, in women and the
elderly, dyspnea or diaphoresis alone, without the "typical" symptoms of substernal
pressure, are present and are often ascribed to other causes, delaying diagnosis.
The pattern of angina is critical to defining a chronic versus unstable ischemicsyndrome. Patients with chronic angina experience symptoms that are predictable,
repetitive, and inducible with exertion. Symptoms are typically stable over weeks and
months. While exertion (e.g., walking, climbing stairs, cleaning) is the most common
precipitant, anxiety and stress can also elicit angina attacks. Chronic angina always
resolves with rest or the use of sublingual nitroglycerin. Many patients report the
slow onset of angina with exertion that requires them to diminish their level of
exertion or even stop. Often, after this initial episode subsides, patients can continue
their activities without symptoms.
Careful questioning of patients with suspected angina is necessary to determine
how their quality of life is affected. Any change in a chronic angina pattern, with either
onset at rest or angina with progressively less exertion, requires a more urgent
evaluation, as it may indicate a conversion to an unstable ischemic syndrome.
Patients can then be appropriately categorized in a different Canadian
Cardiovascular Society classification group (Table 2).8 More detailed and sensitive
classification can be obtained using more sensitive, patient-based surveys, such as
the Seattle Angina Questionnaire.
Prevalence and Risk Associated With Angina
The reported incidence and prevalence of symptomatic angina is directly related to
the population being studied. In population-based studies, the incidence of angina
is closely associated with age and gender. Men between 65-85 years old are at the
highest risk, with an incidence of >10 cases per 1,000 patient-years. The risk was
approximately one-half in younger men and women of a similar age.1 Among
patients with established CAD in the REACH registry, 30% reported a history of
stable angina.
By design, clinical trial populations are variably enriched for patients with a history of
angina, to the extent that the prevalence of a history of angina ranges from 22% in
the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial
to approximately 55% in the HOPE (Heart Outcomes Prevention Evaluation Study)
trial, and to 70% in the PEACE trial. Even among patients who undergo
revascularization, angina is common. Almost one-third of the patients in the
COURAGE trial9 assigned to percutaneous coronary intervention (PCI), and one-half
of the patients assigned to revascularization in the BARI-2D trial,10 had angina at 1
year after randomization. A large clinical database found that 30% of patients who
had a PCI still reported angina 1 year later.11
Surprisingly, there is little contemporary data to indicate whether the presence of
angina carries any increase in risk compared to patients with no angina, especiallywhen accounting for other comorbidities and LV function. In the Heart and Soul Study
of patients with SIHD, 129 patients (14%) had stable angina, but angina alone was
not associated with an increased 4-year risk of CHD.12
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Four-Year Risk of Cardiovascular Death, Myocardial Infarction, or Stroke in the REACH Registry
Figure 1
Four-year risk of cardiovascular death, myocardial infarction, or stroke in the REACH Registry according to whether patients had a prior
documented ischemic event, stable atherosclerosis, or risk factors only.
CV = cardiovascular MI = myocardial infarction mo = month No. = number REACH Registry = Reduction of Atherothrombosis for Continued
Health Registry.
Reproduced withpermission from Bhatt DL, Eagle KA, Ohman EM, et al, and the REACH Registry Investigators. Comparative determinants of 4-
year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010304:1350-7.
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Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System
Table 2
Reproduced withpermission from the Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca.
Accessed 02/27/2012.
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Overview of Risk Stratification Techniques for Patients WithStable Ischemic Heart Disease(2 of 3)
Resting 12-Lead Electrocardiogram
All patients with SIHD should receive baseline and regular 12-lead
electrocardiograms (ECGs). The presence of pathologic Q waves may indicate an
old infarct, therefore identifying a patient at increased risk of future ischemic events
or heart failure. Even in the absence of a known MI, pathologic Q waves in the
absence of a clear history of MI are common and offer important prognostic
information. Silent MI, identified by new Q waves, accounted for 10% and 36.8% of
the total number of MIs observed in two recent clinical trials of diabetic patients and
were associated with worse outcomes.13,14 Other ECG findings such as atrial
fibrillation, fascicular and bundle-branch blocks, and LV hypertrophy have also been
associated with worse outcomes in patients with SIHD. 15 Smaller infarcts that do
not result in persistent Q waves can be identified on a 12-lead ECG by analyzing
altered RSR' patterns (fragmented QRS), which is associated with increased CV
risk.16,17
Established Biomarkers
Patients with SIHD should have regular measurements of lipids, fasting bloodglucose, glycated hemoglobin, and renal function to ensure that the traditional risk
factors are closely monitored at goal levels. Treatment of these risk factors is
covered in the module on Prevention in Chapter 4 and the Medical Therapymodule
in this chapter.
Other Biomarkers
Many biomarkers, including those that assess myocardial necrosis, inflammation,
neurohormonal activation, metabolism, renal function, coagulation, and lipid-
trafficking have been evaluated with the hope of gaining greater insight into the
pathogenesis of atherosclerosis and SIHD. Many biomarkers are elevated in
patients with SIHD, and some of them add incremental improvements to other
clinical features in terms of discriminating between lower-risk and higher-risk
patients. No biomarker, though, has been shown to provide any clear treatmentimplications in SIHD. For example, an elevated level of B-type natriuretic peptide
(BNP) identifies a patient at an increased risk however, there are no known
treatment therapies that will reduce that risk. The lack of treatment implications has
limited the incorporation of biomarkers into current treatment algorithms.
The older generations of troponin assays were not sensitive enough to detect
elevation in patients with stable cardiac disease. The introduction of more sensitive
cardiac troponin assays alters the traditional paradigm of troponin by detecting lower
levels of circulating troponin, which are commonly found in patients with SIHD. For
example, circulating troponin was detected in >97% of patients in the PEACE trial by
using a new high-sensitivity assay, and was greater than the 99th percentile, the
standard cutpoint for diagnosis of MI, in 11.1% of patients.18 There was a graded
stepwise increase in the risk of CV death and heart failure over the 5-year follow-up
period that was independent of baseline characteristics, even though these levels
are much lower than the older, conventional troponin assays could detect ( Figure
2a). Newer troponin assays with even higher sensitivity that can detect small
increases during stress tests are now available in some countries, but their role in
the evaluation of SIHD remains very much an area of debate.
Multiple studies examining the levels of natriuretic peptides in patients with SIHD
confirm that elevated levels of hemodynamic stress are independently associated
with an increased risk of CV death and heart failure. In one long-term population-
based study of >1,000 patients with documented CAD, patients in the highest
quartile of NT-proBNP were at a >2-fold increased risk of CV death compared to the
lowest quartile (Figure 2b).19 These observations were confirmed in both the HOPE
trial and the PEACE trial populations.20,21 In the analyses from the HOPE trial, NT-
Figure 2a
Figure 2b
Figure 3
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proBNP was the only biomarker that improved the discrimination for the risk of CV
death beyond that provided by traditional risk factors. Other studies that evaluated
multiple novel biomarkers found that NT-proBNP, GDF-15, cystatin C, mid-regional-
pro-adrenomedullin (MR-proADM), and mid-regional-pro-atrial natriuretic peptide
(MR-proANP) were most strongly related to CV outcomes, although incremental
improvement over established risk factors was small, even after combining
markers.22
Based on the evidence that biomarkers can offer improved risk stratification, current
clinical guidelines give a Class IIa recommendation for the more established
markers, such as high-sensitivity C-reactive protein,23 and Class IIb
recommendation for natriuretic peptides in patients with stable CAD.5 The
widespread incorporation of these biomarkers is unlikely to occur until there
become clear treatment implications, which will require prospective clinical trials.
Clinical Risk Scores
In contrast to primary prevention and acute coronary syndromes, there are few well
validated and accepted integrated clinical risk scores for patients with documented,
but stable, CAD. Several scores, including one based on 11 clinical characteristics
and another with just five variablesmale, presence of typical angina, evidence of
an old MI on ECG, diabetes, and insulin usewere shown to be associated with the
severity of CAD detected on angiography.15
Another clinical score developed in patients treated with a statin as part of a clinical
trial found that a weighted scoring system including age, sex, tobacco use, prior MI,
revascularization, hypertension, total cholesterol, and low-density lipoprotein
cholesterol categorizes patients into a low (3%) 1-year risk of death or MI.24 It is important to note that none of these scores
included either exercise tolerance test or LV function, two of the most powerful risk
stratification techniques.
Assessment of Risk With Functional or Stress Tests
Stress testing, both by exercise or pharmacologic stress, provides an enormous
amount of prognostic information, and unless contraindicated, should be performed
in all patients with suspected or known SIHD to evaluate the presence and burden of
ischemia.25 Stress testing should not be performed when urgent catheterization is
indicated, or in other tenuous hemodynamic scenarios such as severe aorticstenosis or unstable arrhythmias. Whenever possible, exercise stress testing is
preferred to pharmacologic stress testing because exercise capacity and recovery
provide significant incremental prognostic information beyond the assessment of
ischemia, and because it is the more cost-efficient option.
It is important to remember that while stress tests provide an overall assessment of
cardiopulmonary health, they will only identify hemodynamically significant coronary
lesions. The understanding that many acute lesions arise from nonobstructive
lesions explains why a patient with a "negative" stress test may subsequently
present with an acute coronary syndrome. Disease-modifying therapy, such as
blood pressure control, lipid-lowering therapy, and antiplatelet drugs, should
therefore be based on the overall risk assessment and not just the stress tests
results.
Exercise Stress Tests
Exercise stress testing has been extensively validated in many clinical situations for
a variety of indications. One common indicationthe diagnosis of CAD in patients
without known SIHDis covered in the module onAsymptomatic CAD in this
chapter and in Chapter 3 on Patient Assessment. In general, among patients with
known SIHD, the presence of ischemia, as detected by ST segment deviation on
exercise testing, may be less important per se than the physiologic parameters
assessed during the test. Maximal exercise duration, total exercise capacity, time to
symptoms or ST-segment deviation, heart rate and blood pressure response to
exercise and recovery, and the degree of symptoms are all related to prognosis.
Exercise duration and maximal exercise capacity are two of the great integrators of
overall health.26 Excellent exercise capacity, even in the presence of documented
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ischemia, carries a good prognosis, while poor capacity, with or without ischemia,
identifies a patient at a higher risk of death.
There are several integrated risk scores that combine different exercise test
parameters. The Duke Treadmill Score (DTS), which includes exercise duration,
maximal ST depression, and the presence and severity of angina, is one of the most
well-validated and utilized scoring tests (Figure 3). Patients are categorized as low
risk (score of >5) with a 1-year mortality rate of 0.25%, intermediate risk (score 4 to -
10) with a 1-year mortality rate of 1.25%, and high risk (score < -11) with a 1-year
mortality rate of 5.25%.27,28 Other metrics, such as abnormal heart rate recovery
pattern, prolonged ST segment depression (>8 minutes into recovery), or abnormal
blood pressure response offer further pathophysiologic insight into the overall CV
status and identify high-risk patients.25,29
Based on the strength of evidence, cost, and ease, stress testing should, in most
cases, be the first-line test for functional capacity among patients who can exercise
and have interpretable ECG testing. The indications for additional imaging are
reviewed in the next section, but even when imaging is obtained, exercise stress,
rather than pharmacologic stress, is preferred whenever possible to obtain
functional information.
Troponin T and NT-proBNP in Stable Ischemic Heart Disease (1 of 2)
Figure 2a
Elevated levels of high-sensitivity troponin T
Reproduced withpermission from Omland T, de Lemos JA, Sabatine MS, et al, and the Prevention of Events with Angiotensin Converting Enzyme
Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009361:2538-47,
and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B-Type natriuretic peptides in patients with
stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 200750:205-14.
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Troponin T and NT-proBNP in Stable Ischemic Heart Disease (2 of 2)
Figure 2b
NT-proBNP are shown to be associated with increasing risk of overall mortality in the PEACE trial of patients with documented but stable
coronary artery disease.
Reproduced withpermission from Omland T, de Lemos JA, Sabatine MS, et al, and the Prevention of Events with Angiotensin Converting Enzyme
Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009361:2538-47,
and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of B-Type natriuretic peptides in patients with
stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 200750:205-14.
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Duke Treadmill Score
Figure 3
The Duke Treadmill Score is the most well-validated stress testing score that accurately classifies patients into low, intermediate, and high risk
based on the time of exercise, extent of ST depressions, and severity of symptoms. In the example, a patient exercises 8 minutes, has a 1 mm
ST-segment depression, and has nonlimiting angina, which gives a score of -1, placing her in the intermediate-risk category. The same
calculations can be performed using a nomogram by drawing a line between 1) ST-segment deviation during exercise and Angina during
exercise, and 2) Ischemia-reading line and Duration of exercise to estimate the 1-year and 5-year mortality risk.
Max = maximum MET = metabolic equivalent MI = myocardial infarction min = minutes
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Overview of Risk Stratification Techniques for Patients WithStable 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 follow-up test to prior noninvasive
studies. The two most clinically relevant parameters obtained from these techniques
are: 1) the overall burden and pattern of ischemia, and 2) an assessment of LV
function. Consensus practice guidelines recommend that myocardial imaging is
appropriate in the following scenarios among patients with known SIHD30:
To clarify an equivocal, borderline, or discordant prior stress test where
obstructive CAD remains a concern.
To evaluate new or worsening symptoms in a patient with known abnormal
coronary angiography or prior stress images.
To evaluate the physiologic consequence of a coronary stenosis or anatomic
abnormality of uncertain significance.
For further evaluation of patients with an intermediate or high DTS.
The appropriateness of imaging an asymptomaticorstable patient with a history of
abnormal coronary angiography or abnormal stress imaging is uncertain if the last
stress test was >2 years prior, and inappropriate if the last stress test was within the
last 2 years. Repeat radionuclide imaging is considered appropriate in the setting of
incomplete revascularization to assess residual ischemia and for recurrent
symptoms after revascularization (Figure 4).30
Several findings on stress imaging are important in risk stratification. Evidence of
reduced LV function (3% annual mortality rate). Moderate LV
function (35-49%), moderate stress-induced perfusion defects or wall-motion
abnormalities identify intermediate-risk patients (1-3% annual mortality). Low-risk
patients (
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disease. The current appropriate use criteria for echocardiography related to the
evaluation of patients with SIHD recommend echocardiography in patients with
symptoms or conditions related to suspected cardiac etiology, including chest pain.
Routine surveillance with repeated echocardiography in patients with known CAD,
but no change in symptoms or new signs of any progression is not indicated,
however.32
Much of the evidence linking LV function and outcomes comes from older studies
such as the CASS (Coronary Artery Surgery Study) trial where over two-thirds of the
deaths at 5 years were observed in the roughly one-third of patients with reduced LV
function. Integration of LV function and the degree of CAD further refines risk
stratification. Regardless of the degree of atherosclerosis, worsening ventricular
function is associated with increased risk of death (Figures 5a, b, c, d).33
Assessment of Risk According to Coronary Anatomy
The decision to define coronary anatomy is one of the key decision-branch points in
the evaluation of patients with SIHD. The decision to proceed to coronary
angiography should be based on the results of clinical history and noninvasive risk
stratification tools. Many low- to intermediate-risk patients with SIHD may not require
coronary angiography to appropriately treat their SIHD, while in other patients,
catheterization may be the first diagnostic test after the initial clinical evaluation.
Defining the coronary anatomy should also be considered as an important tool for
risk stratification, and not simply as a diagnostic tool to identify potential lesions for
revascularization. It is also important to remember that while coronary angiographyis the "gold-standard" for identifying flow-limiting intraluminal obstructions, it is not
sensitive to identifying "vulnerable" nonobstructive coronary plaques that may rapidly
progress to acute thrombotic lesions.
Despite the limitation in identifying the actual lesion that may precipitate an acute
coronary syndrome, the extent and burden of atherosclerosis detected on
angiography clearly identifies the "vulnerable patient" who is at a higher risk of CV
complications. The most simple and widely used classification for risk stratification
is based on the number of diseased arteries (i.e., left main or single-, double-, or
triple-vessel disease). The prognostic value of this straightforward classification
was most clearly demonstrated in the CASS registry, where there was a stepwise
decrease in overall survival according to the number of diseased arteries ( Figures
5a, b, c, d).33
This relationship of overall survival to the number of diseased arteries has been
confirmed in more recent experiences. In the COURAGE trial, the rate of death or MI
after a 4.6-year follow-up period was 12.5% in patients with zero- or one-vessel
disease, approximately 18% in patients with two-vessel disease, and approximately
25% in patients with three-vessel disease.34 More detailed assessments of the
complexity of coronary disease, as calculated by techniques such as the SYNTAX
Score, may provide a more complete assessment of atherosclerotic burden and
give insight into actual treatment decisions, however, they are not typically calculated
in clinical practice. In one study of approximately 1,400 patients with CAD
undergoing PCI, the 1-year risk of death increased almost twofold with each tertile of
SYNTAX score (1.5% vs. 2.1% vs. 5.6% p = 0.002) (Figures 6, 7).10,35
The American Heart Association/American College of Cardiology Foundation(AHA/ACCF) indications for coronary angiography in patients with SIHD are
presented in Table 3.15 Even though they are somewhat dated, these indications
remain relevant and are consistent with the recommendations of other professional
societies.5
Cardiac Computed Tomography
Computed tomography angiography (CTA) has a limited role in the evaluation of
patients with known SIHD or in patients with a high-suspicion for CAD.36 In these
cases, CTA will potentially delay coronary angiography and expose patients to
increased contrast and radiation. However, similar to coronary angiography, the
degree of atherosclerosis identified by CTA is associated with worse outcomes.
Patients with any luminal abnormalities detected on CTA (who therefore have some
Figure 8
Figure 9
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degree of atherosclerotic burden) are at a higher risk than patients with no evidence
of any luminal obstruction. The risk increases in patients with actual obstructive
lesions and, in particular, among patients with left main or left anterior descending
artery disease.37
Similar to angiography, the number of diseased arteries identified by CTA is closely
associated with CV complications, with the highest risk in patients with left main
artery disease (Figure 8).38 CT calcium scanning has no role in the management of
patients with SIHD, as these patients are known to have atherosclerosis, and the
degree of calcification does not correlate with the degree of stenosis.35
An Integrated Risk Stratification Algorithm
Risk stratification in patients with SIHD should proceed in a stepwise and logical
progression. The process begins with the clinical history and examination, and the
decisions about subsequent testing should build on each additional piece of
information (Figure 9). Rarely will one test drive a decision for therapy, but rather the
integration of the data from several risk stratification modalities will provide the most
complete assessment and, therefore, the most appropriately guided therapeutic
decisions.
: Appropriate Use Criteria for Cardiac Radionuclide Imaging for Patients With Ischemic Symptoms or Prior Revascularization
Figure 4
ACS = acute coronary syndrome CABG = coronary artery bypass graft ECG = electrocardiogram PCI = percutaneous coronary intervention.
Reproduced withpermission from Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use
criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the
American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of
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Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (1 of 4)
Figure 5a
Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients.
Panel A: Patients with one-, two-, or three-vessel disease by ejection fraction.
EJECFR = ejection fraction.
Reproduced withpermission from Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 199490:2645-57.
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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 two-vessel disease by ejection fraction.
EJECFR = ejection fraction.
Reproduced withpermission from Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 199490:2645-57.
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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 three-vessel disease by ejection fraction.
EJECFR = ejection fraction.
Reproduced withpermission from Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 199490:2645-57.
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Rate of Death or MI by Number of Disease Vessels
Figure 6
The rate of death or myocardial infarction (MI) according to the number of diseased arteries among patients with stable ischemic heart disease
treated with percutaneous coronary intervention (PCI) or optimal medical therapy (OMT).
Adapted withpermissi on from Dagenais GR, Lu J, Faxon DP, et al, and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI
2D) Study Group. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations
in patients with type 2 diabetes mellitus and stable ischemic heart disease. Circulation 2011123:1492-500.
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Rate of Death or MI by SYNTAX Score
Figure 7
The rate of death or myocardial infarction (MI) according to the tertile of SYNTAX Score, which quantifies the overall burden and complexity of
the disease.
Adapted withpermissi on from Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the all-comers
population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. J Am Coll Cardiol
201056:272-7.
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Recommendations for Coronary Angiography for Risk Stratification in Patients With Chronic Stable Angina
Table 3
Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients withchronic stable angina-executive summary and recommendations: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 199999:2829-48.
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Overall Survival by Number of Diseased Arteries
Figure 8
Overall survival according to the number of diseased arteries detected by computed tomography angiography.
Reproduced withpermission from Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic
angiography for prediction of all-cause mortality. J Am Coll Cardiol 200750:1161-70.
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Initial Evaluation of Patients With Clinical Symptoms of Angina
Figure 9
Algorithm for the initial evaluation of patients with clinical symptoms of angina.
ACS = acute coronary syndrome CABG = coronary artery bypass graft CAD = coronary artery disease CV = cardiovascular CXR = chest X-
ray DM = diabetes mellitus ECG = electrocardiogram MI = myocardial infarction MRI = magnetic resonance imaging PCI = percutaneous
coronary intervention.
Reproduced withpermission from Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive
summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 200627:1341-81.
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Future Directions
Continued research into novel biomarkers such as high-sensitivity troponin assays, may further improve the ability
to identify patients at the highest risk. The routine incorporation of novel biomarkers into clinical care is unlikely
though, until specific treatments based on the results of the tests are identified in clinical trials.
Advances in imaging may provide greater insight into which patient may benefit from more intense therapy,
including revascularization. For example, more detailed assessments of viability, as detected by cardiac MRI or
positron emission tomography (PET) scans may better identify which patients will benefit from revascularization.
Advanced imaging techniques are also being evaluated to identify atherosclerotic lesions that are most likely to
become unstable prior to becoming symptomatic.
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Key Points
SIHD, also termed CAD, encompasses a heterogeneous population, which varies in terms of comorbidities,
symptoms, and risk of future CV events.
Risk stratification in patients with SIHD should proceed in a step-wise and logical progression.
Categorization of patients into low-, intermediate-, and high-risk categories should be a primary goal in the
evaluation of patients with SIHD. Patients with an annual mortality rate of 3% as high risk.
Four broad categories of risk stratification should be considered: 1) clinical evaluation and assessment of
comorbidities, 2) functional capacity/stress rest, 3) ventricular function, and 4) coronary anatomy. Most patients will
not need all four domains tested.
Based on the strength of evidence, cost, and ease, stress testing should be in most cases the first-line test for
functional capacity among patients who can exercise and have an interpretable ECG. Some patients may have an
indication for additional imaging, but even when imaging is obtained, exercise stress, rather than pharmacologic,
is preferred whenever possible to obtain functional information.
Regardless of the clinical situation, LV function is not only one of the most powerful predictors of short- and long-
term outcomes, but also carries therapeutic implications regarding appropriate medical, revascularization, and
device-based therapies. LV function, therefore, should be assessed in all patients with SIHD, even without any
signs or symptoms of heart failure.
Coronary angiography should be performed based on the results of clinical history and noninvasive risk
stratification tools. Many low- to intermediate-risk patients with SIHD may not require coronary angiography,
whereas in other patients, catheterization may be the first diagnostic test after the initial clinical evaluation.
Defining the coronary anatomy, though, should be considered an important tool for risk stratification, and notsimply as a diagnostic tool to identify potential lesions for revascularization.
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References
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011 update: a report from the
American Heart Association. Circulation 2011123:e18-e209.
2. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery
disease. N Engl J Med 2004351:2058-68.
3. Boden WE, O'Rourke RA, Teo KK, et al., on behalf of the COURAGE Trial Research Group. Optimal medical
therapy with or without PCI for stable coronary disease. N Engl J Med 2007356:1503-16.
4. Frye RL, August P, Brooks MM, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2
Diabetes (BARI 2D) Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease.
N Engl J Med 2009360:2503-15.
5. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive
summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology.
Eur Heart J 200627:1341-81.
6. Bhatt DL, Eagle KA, Ohman EM, et al., on behalf of the REACH Registry Investigators. Comparative determinants
of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA
2010304:1350-7.
7. Steg PG, Bhatt DL, Wilson PW, et al., on behalf of the REACH Registry Investigators. One-year cardiovascular
event rates in outpatients with atherothrombosis. JAMA 2007297:1197-206.
8. Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca. Accessed
02/27/2012.
9. Weintraub WS, Spertus JA, Kolm P, et al., on behalf of the COURAGE Trial Research Group. Effect of PCI on
quality of life in patients with stable coronary disease. N Engl J Med 2008359:677-87.10. Dagenais GR, Lu J, Faxon DP, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2
Diabetes (BARI 2D) Study Group. Effects of optimal medical treatment with or without coronary revascularization
on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart
disease. Circulation 2011123:1492-500.
11. Alexander KP, Cowper PA, Kempf JA, Lytle BL, Peterson ED. Profile of chronic and recurrent angina pectoris in a
referral population. Am J Cardiol 2008102:1301-6.
12. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the risk of recurrent cardiovascular events
in outpatients with stable coronary heart disease: the Heart And Soul Study. Arch Intern Med 2008168:1423-8.
13. Burgess DC, Hunt D, Li L, et al. Incidence and predictors of silent myocardial infarction in type 2 diabetes and the
effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.
Eur Heart J 201031:92-9.
14. Chaitman BR, Hardison RM, Adler D, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2
Diabetes (BARI 2D) Study Group. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized
trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact oftreatment strategy on cardiac mortality and myocardial infarction. Circulation 2009120:2529-40.
15. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with
chronic stable angina--summary article: a report of the American College of Cardiology/American Heart
Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable
Angina). J Am Coll Cardiol 200341:159-68.
16. Das MK, Saha C, El Masry H, et al. Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events
in patients with coronary artery disease. Heart Rhythm 20074:1385-92.
17. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex versus a Q wave
in patients with coronary artery disease. Circulation 2006113:2495-501.
18. Omland T, de Lemos JA, Sabatine MS, et al., on behalf of the Prevention of Events with Angiotensin Converting
Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery
disease. N Engl J Med 2009361:2538-47.
19. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death fromcardiovascular causes. N Engl J Med 2008358:2107-16.
20. Blankenberg S, McQueen MJ, Smieja M, et al., on behalf of the HOPE Study Investigators. Comparative impact of
multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the
prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study.
Circulation 2006114:201-8.
21. Omland T, Sabatine MS, Jablonski KA, et al., on behalf of the PEACE Investigators. Prognostic value of B-Type
natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol
200750:205-14.
22. Schnabel RB, Schulz A, Messow CM, et al. Multiple marker approach to risk stratification in patients with stable
coronary artery disease. Eur Heart J 201031:3024-31.
23. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to
clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control
and Prevention and the American Heart Association. Circulation 2003107:499-511.
7/27/2019 7 Stable Ischemic Hd
31/166
24. Marschner IC, Colquhoun D, Simes RJ, et al., on behalf of the LIPID Study Investigators. Long-term risk
stratification for survivors of acute coronary syndromes. Results from the Long-term Intervention with Pravastatin
in Ischemic Disease (LIPID) Study. J Am Coll Cardiol 200138:56-63.
25. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A
report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
(Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol 200240:1531-40.
26. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men
referred for exercise testing. N Engl J Med 2002346:793-801.
27. Mark DB, Hlatky MA, Harrell FE Jr, Lee KL, Califf RM, Pryor DB. Exercise treadmill score for predicting prognosis in
coronary artery disease. Ann Intern Med 1987106:793-800.
28. Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected
coronary artery disease. N Engl J Med 1991325:849-53.29. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a
predictor of mortality. N Engl J Med 1999341:1351-7.
30. Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use
criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate
Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the
American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed
Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll
Cardiol 200953:2201-29.
31. Davis RC, Hobbs FD, Kenkre JE, et al. Prevalence of left ventricular systolic dysfunction and heart failure in high
risk patients: community based epidemiological study. BMJ 2002325:1156.
32. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011
Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation
Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association,
American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for
Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular
Computed Tomography, and Society for Cardiovascular Magnetic Resonance. Endorsed by the American College
of Chest Physicians. J Am Coll Cardiol 201157:1126-66.
33. Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery
Study (CASS) Registry. Circulation 199490:2645-57.
34. Mancini GB, Bates ER, Maron DJ, et al., on behalf of the COURAGE Trial Investigators. Quantitative results of
baseline angiography and percutaneous coronary intervention in the COURAGE trial. Circ Cardiovasc Qual
Outcomes 20092:320-7.
35. Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the all-comers
population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent
coating) trial. J Am Coll Cardiol 201056:272-7.
36. Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate
use criteria for cardiac computed tomography. A report of the American College of Cardiology FoundationAppropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College
of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of
Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular
Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol
201056:1864-94.
37. Pundziute G, Schuijf JD, Jukema JW, et al. Prognostic value of multislice computed tomography coronary
angiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol 200749:62-70.
38. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic
angiography for prediction of all-cause mortality. J Am Coll Cardiol 200750:1161-70.
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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. Apply appropriate secondary prevention measures of coronary heart disease (CHD).
2. Identify antianginal drugs that prevent reinfarction and improve survival in post-myocardial infarction (MI) patients.
3. Identify patients who benefit from angiotensin-converting enzyme (ACE) inhibitors.4. Describe the goal serum low-density lipoprotein cholesterol (LDL-C) concentration for patients with stable CHD.
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Introduction
In the patient with chronic coronary artery disease (CAD), the goals of medical therapy are to ameliorate angina and/or
prevent recurrent major cardiovascular (CV) events (secondary prevention). The initial approach to all patients should be
focused upon eliminating unhealthy behaviors such as smoking and effectively promoting lifestyle changes that reduce
CV risk such as maintaining a healthy weight, engaging in physical activity, and adopting a healthy diet.
In addition, medical therapies that retard progression (or promote regression) of atherosclerosis, stabilize
atherosclerotic plaques, or prevent thrombosis should be administered to decrease the risk of MI and death. Such
therapies include antiplatelet agents, ACE inhibitors, and lipid-lowering therapy. In the patient with diabetes, tightglycemic control was assumed to be important in secondary CV prevention, but recent studies show that this approach
increases the risk of CV death and complications.1
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Antiplatelet Therapy
Platelet aggregation is a key element of the thrombotic response to plaque disruption. Hence, platelet inhibition is
recommended in all patients with chronic CAD unless contraindicated. Aspirin (acetylsalicylic acid) irreversibly acetylates
platelet cyclooxygenase, which is required for the production of thromboxane A 2, a powerful promoter of platelet
aggregation. By inhibiting thromboxane production and subsequent platelet aggregation, aspirin reduces the risk of
thrombotic vascular events.
Among 2,920 patients with chronic CAD, theAntiplatelet Trialists' Collaboration meta-analysis showed that aspirin
treatment was associated with a 33% reduction in the risk of serious vascular events (nonfatal MI, nonfatal stroke, and
vascular death). Over the course of a couple of years of treatment, aspirin would be expected to prevent about 10-15
vascular events for every 1,000 people treated.2
Aspirin dose of 75-162 mg daily is equally as effective as 325 mg in secondary prevention, but with a lower risk of
bleeding. Doses
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Clopidogrel
Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation via irreversible inhibition of the adenosine
diphosphate P2Y12 receptor. In the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial,
which enrolled 19,185 patients with a history of MI, stroke, or peripheral vascular disease, patients who received
clopidogrel had 10% fewer serious vascular events than aspirin-treated patients. 4 Since the magnitude of the difference
was small and no additional trials comparing aspirin and clopidogrel in patients with stable CAD have been conducted,
clopidogrel is recommended in patients with CAD who are allergic to or cannot tolerate aspirin.
The use of dual platelet therapy with aspirin and clopidogrel was no more effective than aspirin alone in reducing
vascular events in 15,603 asymptomatic patients with high risk for or with established atherothrombotic disease,
including stable CAD, in the CHARISMA (Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization,
Management, and Avoidance) study.5 A post-hoc analysis showed that patients with documented prior MI, ischemic
stroke, or symptomatic peripheral arterial disease appeared to derive significant benefit from dual antiplatelet therapy
with clopidogrel plus aspirin.6 Thus, treatment with aspirin 75-162 mg daily and clopidogrel 75 mg daily may be
reasonable in certain high-risk patients with chronic CAD.
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Beta-Blockers
Beta-blockers are the only antianginal drugs proven to prevent reinfarction and
improve survival in patients who have had an MI. Such benefits have not been
demonstrated in patients with chronic ischemic heart disease without previous
infarction. Nevertheless, beta-blockers remain first-line therapy in the treatment of
chronic ischemic heart disease, particularly effort-induced angina, with the goal to
reduce the frequency and severity of angina and to improve exercise capacity.
Despite the fact that they differ with regard to cardioselectivity, presence of intrinsic
sympathomimetic activity or vasodilating properties, and relative lipid solubility, all
beta-blockers appear to be equally efficacious in stable ischemic heart disease. 7-11
Beta-blocker dosing should be adjusted to limit the heart rate to 55-60 bpm at rest
and to not exceed 75% of the exercise heart rate response at the onset of ischemia.
Beta-blockers improve survival, prevent CV hospitalizations, and improve symptoms
and exercise tolerance in patients with ischemic cardiomyopathy already receiving
treatment with conventional therapy (i.e., diuretics, digoxin, and ACE inhibitors).
The CIBIS II (Cardiac Insufficiency Bisoprolol Study II), MERIT-HF (Metoprolol CR/XL
Randomized Intervention Trial in Congestive Heart Failure), and COPERNICUS
(Effect of Carvedilol on Survival in Severe Chronic Heart Failure) trials demonstrated
an approximately 35% mortality reduction with bisoprolol, metoprolol, and carvedilol,
respectively (Figure 1).12-14 This does not appear to be a class effect that extends to
all beta-blockers because the BEST (Beta-Blocker Evaluation of Survival Trial) studydid not show a reduction in mortality with bucindolol. 15
Beta-blocker therapy should be initiated and continued indefinitely in all patients with
prior MI or left ventricular (LV) dysfunctionwith or without heart failure symptoms
unless contraindicated.3 Some of the mechanisms responsible for the benefits of
beta-blockers in these patients include increased myocardial beta-adrenergic
receptor density and sensitivity, and a switch in myocardial substrate utilization from
free fatty acids to glucose, which increases myocardial energy efficiency.
Although generally well tolerated, beta-blockers have several notable side effects.
Because of their negative inotropic effects, beta-blocker therapy should be advanced
cautiously in patients with impaired LV systolic function. Beta-blockers may
exacerbate coronary vasospasm in patients with variant angina, bronchospasm in
patients with reactive airway disease, and limb or digit ischemia in patients with
severe peripheral vascular disease or Raynaud's phenomenon. Impotence may
also occur with their use. Chronic beta-blocker therapy leads to an increase in beta-
receptor density. This can be clinically important, as sudden withdrawal of beta-
blocker therapy may result in increased sensitivity to endogenous catecholamines,
with precipitation of angina pectoris, MI, or death.
Figure 1
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Mortality Benefit of Beta-Blockers in Congestive Heart Failure
Figure 1
Annual mortality in four studies of patients with congestive heart failure--most of whom had an ischemic cardiomyopathy--treated with a)
placebo or b) beta-blockers in addition to conventional therapy. Those treated with bisoprolol, metoprolol, or carvedilol had improved survival,
whereas those treated with bucindolol did not.
References:
1. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999353:9-13.
2. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being
in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study
Group. JAMA 2000283:1295-302.
3. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001344:1651-8.
4. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001344:1659-67.
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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.
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Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors reduce mortality and morbidity from CV events in patients who have
heart failure due to LV systolic dysfunction, and in those who have acute MI. In
addition, "high-risk" patients with CAD or other vascular disease may benefit from an
ACE inhibitor in the absence of LV dysfunction or previous MI.
In patients with atherosclerotic vascular disease or diabetes and at least one other
CAD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study showed
that, compared to placebo, ramipril significantly decreased the primary composite
endpoint of CV death, MI, and stroke by 22% over 4.5 years of follow-up.16 Based on
these results, the Food and Drug Administration (FDA) approved the use of ramipril
for the reduction of MI, stroke, and death in high-risk patients. Similarly, in
the EUROPA (European Trial on Reduction of Cardiac Events With Perindopril in
Stable Coronary Artery Disease) study, perindopril reduced CV events (CV death, MI,
or cardiac arrest) by 20% over 4.2 years of follow-up in a lower-risk population with
stable CHD and no apparent heart failure.17
Conversely, in the PEACE (Prevention of Events With Angiotensin-Converting
Enzyme Inhibition) trial, which enrolled >8,000 low-risk patients with stable CHD and
preserved LV function who were receiving intensive current standard therapy, the
addition of trandolapril did not reduce CV death, MI, or coronary revascularization
(Figure 2).18 The lack of benefit from ACE inhibition in the PEACE trial has beenattributed to the fact that the study population was lower risk and more likely to be
intensively treated with coronary revascularization and lipid-lowering therapy than the
patients in the previous studies.
Similarly, in the QUIET (Quinapril Ischemic Event Trial)19 and IMAGINE (Ischemia
Management With Accupril Post-Bypass Graft via Inhibition of the Converting
Enzyme)20 studies of low-risk (LV ejection fraction [EF] >0.40) patients who had
undergone percutaneous coronary intervention (PCI) or coronary artery bypass
grafting (CABG), quinapril did not reduce ischemic events.
Based on these studies, the 2007 Chronic Angina Focused Update of the ACC/AHA
2002 Guidelines for the Management of Patients With Chronic Stable Angina
recommend that ACE inhibitors be started and continued indefinitely in all patients
with LVEF 0.40 and in those with hypertension, diabetes, or chronic kidney disease
unless contraindicated.3 Their use is also recommended in patients who are not
lower risk (lower risk is defined as those with normal LVEF in whom CV risk factors
are well controlled and revascularization has been performed). Finally, it is
considered reasonable to use ACE inhibitors among lower-risk patients with mildly
reduced or normal LVEF in whom CV risk factors are well controlled and
revascularization has been performed.
Figure 2
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Lack of Benefit of ACE Inhibitor in "Low-Risk" Stable CAD Patients
Figure 2
Composite outcome of cardiovascular death, myocardial infarction, or coronary revascularization in low-risk patients with stable coronary
artery disease (CAD) and preserved left ventricular function treated with placebo or trandolapril in the PEACE study. Over the 4.8-year follow-
up, the addition of trandolapril to current standard therapy was not beneficial in reducing cardiovascular events.
ACE inhibitor = angiotensin-converting enzyme inhibitor.
Reproduced with permission from Massachusets Medical Society. The PEACE Trial Investigators. Angiotensin-Converting-Enzyme Inhibition in
Stable Coronary Artery Disease. N Engl J Med 2004351:2058-68. Copyright 2000, Massachusetts Medical Society. All rights reserved.
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Angiotensin-Receptor Blockers
Angiotensin-receptor blockers (ARBs) are recommended for individuals who have indications for an ACE inhibitor (post-
MI, heart failure due to LV systolic function, or depressed LVEF), but are intolerant of it. The ONTARGET (ONgoing
Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) showed that telmisartan was noninferior to
ramipril for reducing mortality and CV morbidity over more than 4 years of follow-up in patients with vascular disease or
high-risk diabetes mellitus.21 However, the combination of telmisartan and ramipril was associated with an increased
incidence of adverse events without a detectable incremental benefit above either agent alone.
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Influenza Vaccine
An ACC/AHA science advisory recommends annual vaccination with inactivated vaccine (administered intramuscularly)
against seasonal influenza to prevent all-cause mortality and morbidity in patients with underlying CV conditions.22 A
recent cohort study in 1,340 elderly (i.e., 65 years of age or older) patients with congestive heart failure or CAD showed
that annual influenza vaccinations reduced the winter period mortality by 37% the number needed to treat to decrease
one death during influenza period is 122 annual vaccinations. 23
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Low-Density Lipoprotein Cholesterol Lowering Therapy(1 of 2)
CV death rates increase with higher serum concentrations of total and LDL
cholesterol, and the impact of elevated lipid levels is significantly greater in subjects
with pre-existing CHD than those without (Figure 3). Even modest elevations in
serum cholesterol increase the risk of a cardiac event in patients with CHD or a
recent MI. For example, the CARE (Cholesterol and Recurrent Events) trial evaluated
the role of pravastatin therapy after MI in patients with average levels of total and LDL
cholesterol (209 mg/dl and 139 mg/dl, respectively). In the placebo group, each 25
mg/dl increment in LDL-C increased the risk of a cardiac event (death or nonfatal MI)
by 28%.24 Accordingly, patients with known CHD or a CHD equivalent (i.e., diabetes
mellitus, symptomatic carotid artery disease, peripheral arterial disease, abdominal
aortic aneurysm, chronic renal insufficiency, or Framingham 10-year risk of CHD
>20%) merit aggressive lipid management.
The goal serum LDL-C concentration for patients with stable CHD or a CHD
equivalent is 130 mg/dl with low HDL-C [
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with CV disease receiving background statin therapy reported no overall benefit for
fenofibrate.26
Bile acid sequestrants are effective in patients with mild to moderate elevations of
serum LDL-C. They may be used in combination with statins or nicotinic acid in
patients with markedly elevated serum levels of LDL-C. The use of a bile acid
sequestrant is often limited by gastrointestinal side effects.
Nicotinic acid is effective in patients with hypercholesterolemia and in combined
hyperlipidemia associated with normal or low-serum HDL-C levels
(hypoalphalipoproteinemia). It raises serum HDL levels with dosages as low as 1-
1.5 g/day, but higher doses (>3 g/day) are typically needed to lower serum very LDL(VLDL) and LDL cholesterol. The use of nicotinic acid is often limited by poor
tolerability, which can be minimized by taking aspirin beforehand or using a long-
acting nicotinic acid preparation. In CHD patients who are at increased risk for CV
events despite a well-controlled LDL-C on statin therapy (i.e., those with low HDL-C
and high triglyceride levels), the addition of high-dose, extended-release niacin to
statin therapy does not reduce the risk of CV events. 27
Probucol modestly lowers LDL-C, but more prominently reduces HDL-C. At present,
the use of probucol should be limited to patients with refractory
hypercholesterolemia or those with familial hypercholesterolemia and xanthomas.
Cholesterol and Death Rate in Patients With and Without CHD
Figure 3
Relation between baseline plasma cholesterol measurement and 10-year cardiovascular death rate in patients without and with coronary heart
disease in the Lipid Research Council Study. Death rates are increased at higher serum cholesterol concentrations in both groups, but the effect
is more pronounced in subjects with coronary heart disease.
CHD = coronary heart disease
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Reproduced with permission from Massachusetts Medical Society. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular
disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990322:1700-7. Copyright
1990, Massachusetts Medical Society. All rights reserved.
Lipid-Lowering Drug Therapy
Table 1
Conventional dosing regimens and typical changes in the lipid profile with drug therapy.
HDL = high-density lipoprotein LDL = low-density lipoprotein.
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Common Side Effects of Lipid-Lowering Drug Therapy (1 of 2)
Table 2a
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Common Side Effects of Lipid-Lowering Drug Therapy (2 of 2)
Table 2b
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Low-Density Lipoprotein Cholesterol Lowering Therapy(2 of 2)
Ezetimibe reduces LDL-C by inhibiting absorption of cholesterol by the small
intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver.
This causes a reduction of hepatic cholesterol stores and an increase in the
clearance of cholesterol from the blood. This mechanism is complementary to that
of the statins. Hence, ezetimibe is typically used in combination with a statin when
cholesterol is not reduced sufficiently by statin therapy alone or it is necessary to
reduce the statin dose because of side effects. To date, no long-term clinical
outcome studies have been performed with ezetimibe.
Several large trials have demonstrated that lipid lowering is beneficial in patients
with CHD. There is also ample evidence that elderly patients with CHD who do not
have life-limiting comorbid conditions benefit from lipid-lowering therapy.28 A meta-
analysis of 38 primary and secondary prevention trials found that for each 10%
reduction in serum cholesterol, CHD mortality was reduced by 15% and total
mortality risk by 11%.29
In addition to the reduction in clinical events, serial angiographic and intravascular
ultrasound studies have shown that cholesterol lowering can retard the progression
and, in many cases, induce regression of coronary atherosclerosis.30,31 This
benefit is most prominent when serum LDL-C levels are reduced below 100 mg/dl.
The mechanisms of benefit seen with lipid lowering are not completely understood.
Regression of coronary atherosclerosis is modest. Furthermore, the magnitude of
clinical benefits is disproportionate to the modest degree of regression, and they are
seen before significant regression of atherosclerosis could occur. Other factors that
may account for the beneficial effects of lipid-lowering agents include plaque
stabilization, reversal of endothelial dysfunction, antioxidant effects, decreased
thrombogenicity, and anti-inflammatory effects.
CV benefits of cholesterol lowering with statins have been demonstrated in patients
with CHD, with or without hyperlipidemia. The 4S (Scandinavian Simvastatin Survival
Study) trial of patients with hyperlipidemia (baseline serum total cholesterol levels
between 212 and 309 mg/dl) found that simvastatin therapy versus placebo for 5.4
years resulted in statistically significant reductions in total mortality (33% reduction),major coronary events (32% reduction), CV deaths (42% reduction),
revascularization procedures (37% reduction), and cerebrovascular events (37%
reduction).32 These benefits persisted at the 8-year follow-up period.33 The
reduction in major cardiac events was highly correlated with on-treatment serum
total cholesterol and LDL concentrations and with changes from baseline. Each
additional 1% reduction in LDL-C reduced the risk of major cardiac events by
1.7%.34
The LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease Trial) study
showed that patients with CHD and a broad range of serum cholesterol
concentrations benefit from statin therapy.35 The study randomized patients with
serum cholesterol concentrations of 155-270 mg/dl to therapy with pravastatin or
placebo. After a mean follow-up of 60 months, the study was terminated prematurelybecause, compared with placebo, pravastatin therapy lowered morbidity and
mortality from CV disease, as well as all-cause mortality (Figure 4). The benefit of
pravastatin was seen in all predefined subgroups, including those of any age and at
any level of total cholesterol, LDL-C, HDL-C, or triglycerides.
The CARE trial showed that statin therapy was beneficial in CHD patients with high-
normal levels of serum cholesterol.36 In this study, patients with average cholesterol
levels (mean serum total cholesterol concentration of 209 mg/dl) were treated with
pravastatin (40 mg) or placebo. At 5 years, benefits with pravastatin compared with
placebo included significant reductions in the combined incidence of coronary death
and nonfatal MI (31% reduction), the need for revascularization (25% reduction), and
the frequency of stroke (32% reduction). The benefits were seen only in patients with
LDL-C levels above 125 mg/dl.
Figure 4
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The Heart Protection Study (HPS) questioned whether a target LDL goal 20,000 patients with
established CV disease, diabetes, or hypertension, simvastatin (40 mg/day)
reduced mortality (13%), cardiovascular mortality (18%), major CV events (24%), and
ischemic stroke (25%) compared to placebo over the 5.5-year follow-up. Importantly,
subgroup analysis suggested that simvastatin therapy produced similar reductions
in relative risk regardless of the baseline levels of LDL-C, including subgroups with
baseline LDL-C levels >135 mg/dl,
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Key Points
Unless contraindicated, all patients with evidence of CAD should receive aspirin to prevent MI.
Beta-blockers are the only antianginal drugs proven to prevent reinfarction and improve survival in patients who
have had an MI.
Stable CAD patients receiving intensive medical therapy who are at low risk for a CV event do not benefit from ACE
inhibitor therapy. Conversely, ACE inhibitors reduce CV mortality and morbidity in "high-risk" patients with vascular
disease (i.e., those with poorly controlled risk factors or diabetes and other CV risk factors).
Statins are the most effective drugs for lowering serum LDL-C. The goal serum LDL-C concentration for patients
with stable CHD or a CHD equivalent is
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References
1. Gerstein HC, Miller ME, Genuth S, et al., on behalf of the ACCORD Study Group. Long-term effects of intensive
glucose lowering on cardiovascular outcomes. N Engl J Med 2011364:818-28.
2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002324:71-86.
3. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines
for the management of patients with chronic stable angina: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused
update of the 2002 Guidelines for the management of patients with chronic stable angina. J Am Coll
Cardiol 200750:2264-74.
4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of
ischaemic events (CAPRIE). Lancet 1996348:1329-39.
5. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. N Engl J Med 2006354:1706-17.
6. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral
arterial disease in the CHARISMA trial. J Am Coll Cardiol 200749:1982-8.
7. Frishman WH, Heiman M, Soberman J, Greenberg S, Eff J. Comparison of celiprolol and propranolol in stable
angina pectoris. Celiprolol International Angina Study Group. Am J Cardiol 199167:665-70.
8. Hauf-Zachariou U, Blackwood RA, Gunawardena KA, O'Donnell JG, Garnham S, Pfarr E. Carvedilol versus
verapamil in chronic stable angina: a multicentre trial. Eur J Clin Pharmacol 199752:95-100.
9. Kardas P. Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-
daily betaxolol versus twice daily metoprolol: a randomized controlled trial. Vasc Health Risk Manag 20073:235-42.
10. Narahara KA. Double-blind comparison of once daily betaxolol versus propranolol four times daily in stable
angina pectoris. Betaxolol Investigators Group. Am J Cardiol 199065:577-82.
11. Raftery EB. The preventative effects of vasodilating beta-blockers in cardiovascular disease. Eur Heart J 199617
Suppl B:30-8.
12. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
Lancet 1999353:9-13.
13. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality,
hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial
in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000283:1295-302.
14. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med
2001344:1651-8.
15. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with
advanced chronic heart failure. N Engl J Med 2001344:1659-67.16. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme
inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000342:145-53.
17. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery
disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet
2003362:782-8.
18. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery
disease. N Engl J Med 2004351:2058-68.
19. Pitt B, O'Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor
therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol
200187:1058-63.
20. Rouleau JL, Warnica WJ, Baillot R, et al. Effects of angiotensin-converting enzyme inhibition in low-risk patients
early after coronary artery bypass surgery. Circulation 2008117:24-31.21. Yusuf S, Teo KK, Pogue J, et al., on behalf of the ONTARGET Investigators. Telmisartan, ramipril, or both in
patients at high risk for vascular events. N Engl J Med 2008358:1547-59.
22. Davis MM, Taubert K, Benin AL, et al. Influenza vaccination as secondary prevention for cardiovascular disease: a
science advisory from the American Heart Association/American College of Cardiology. Circulation
2006114:1549-53.
23. de Diego C, Vila-Corcoles A, Ochoa O, et al. Effects of annual influenza vaccination on winter mortality in elderly
people with chronic heart disease. Eur Heart J 200930:209-16.
24. Pfeffer MA, Sacks FM, Moye LA, et al. Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial.
Cholesterol And Recurrent Events. J Am Coll Cardiol 199933:125-30.
25. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education
Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 200444:720-32.
26. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J
Med 2010362:1563-74.
7/27/2019 7 Stable Ischemic Hd
53/166
27. Boden WE, Probstfield JL, Anderson T, et al., on behalf of the AIM-HIGH Investigators. Niacin in patients with low
HDL cholesterol levels receiving intensive statin therapy. N Engl J Med365:2255-67.
28. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER):
a randomised controlled trial. Lancet 2002360:1623-30.
29. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit:
impact of statin trials. Circulation 199897:946-52.
30. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary
atherosclerosis: the ASTEROID trial. JAMA 2006295:1556-65.
31. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on
progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004291:1071-80.
32. [No authors listed]. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet 1994344:1383-9.33. Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow-up study of patients randomized in the Scandinavian
simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 200086:257-62.
34. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major
coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 199897:1453-60.
35. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of
cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
N Engl J Med 1998339:1349-57.
36. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med
1996335:1001-9.
37. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002360:7-22.
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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 t