Download Coronary Revascularization in Patients with Stable

courage trial
Coronary Revascularization in Patients with
Stable or Asymptomatic Coronary Artery Disease:
A Review of the Courage Trial
Michael C. Reed, MD, and Hitinder S. Gurm, MD
Abstract
• Objective: To review the COURAGE trial and other
data related to revascularization of patients with asymptomatic or stable coronary artery disease.
• Methods: Literature review.
• Results: The goals of therapy in patients with stable
angina are to alleviate symptoms, prevent future
events, and improve survival. This is achieved by a
combination of antiplatelet therapy, risk factor modification, antianginal medications, and revascularization with percutaneous coronary intervention (PCI)
or coronary artery bypass grafting. The COurage
trial compared optimal medical therapy plus PCI
with bare-metal stenting with optimal medical therapy alone. No significant difference was seen in the
rate of death or MI; patients in the PCI group had
less angina and 1 and 3 years but not at 5 years
and had fewer new revascularizations.
• Conclusion: Revascularization in asymptomatic or
stable CAD is reasonable in patients who continue
to have symptoms despite optimal medical therapy
and in patients in whom revascularization may
change survival. Patient preferences should be included in decision making.
C
oronary revascularization with percutaneous coronary intervention (PCI) reduces death and myocardial infarction in acute coronary syndrome [1–5]. It is
also effective in the relief of angina and in the improvement
of short-term exercise tolerance in patients with chronic ischemic heart disease [6–8]. However, there is no clear evidence
that PCI as secondary prevention of stable coronary artery
disease improves survival. The recently published Clinical
Outcomes Utilizing Revascularization and Aggressive Drug
Evaluation (COURAGE) trial is the first to compare contemporary medical therapy with contemporary revascularization techniques [9]. In this article, we review the COURAGE
trial and other data related to revascularization of patients
with asymptomatic or stable coronary artery disease.
344 JCOM July 2008 Vol. 15, No. 7
Clinical Context
Epidemiology
Ischemic heart disease is the leading cause of death in
the United States [10]. It is responsible for 1 out of every
4.8 deaths [11,12]. More than 1 million people per year suffer
a myocardial infarction, and even more require hospitalization and lifestyle limitations as a result of their disease.
Even after revascularization, up to 20% of patients do not
return to work [13]. Approximately one half of patients with
ischemic heart disease initially present with chronic stable
angina, a symptom that likely affects more than 6 million
people in the United States [14,15]. Left untreated, coronary
artery disease can progress to increased myocardial ischemia, myocardial infarction, left ventricular dysfunction,
and death. Appropriate management of chronic stable angina is crucial to minimization of morbidity and mortality
in coronary heart disease.
Pathogenesis
Myocardial ischemia occurs from an imbalance between
myocardial oxygen supply and demand. The vast majority
of chronic ischemic heart disease in industrialized nations is
related to coronary atherosclerosis. Plaque and remodeling
from the coronary atherosclerotic process forms obstruction
within the lumen of coronary arteries and disrupts normal
endothelial function. The resulting decrease in myocardial
oxygen supply may not be enough to produce symptoms at
rest, but activities that increase myocardial oxygen demand
may lead to myocardial ischemia and symptoms of angina.
Major independent risk factors for coronary heart disease include advanced age, smoking, diabetes mellitus,
hyperlipidemia, hypertension, and family history of premature coronary artery disease [16]. Less common potential
etiologies of epicardial coronary artery obstruction include
coronary vasospasm, congenital abnormalities, vasculitis,
From the Division of Cardiovascular Medicine, University of Michigan, Ann
Arbor, MI.
www.turner-white.com
clinical review
mechanical compression from masses or aortic dissection
flap, scarring from trauma or radiation, coronary embolism,
and thrombus in situ.
Clinical Findings
The major symptom of coronary heart disease is angina
pectoris. Angina typically manifests as a deep visceral pressure, as opposed to a sharp or stabbing pain. The pain usually has a substernal component and may radiate to the jaw
or the left arm, especially the ulnar surface of the left arm.
Angina is usually preceded by events that increase myocardial oxygen demand, such as exertion, emotional stress,
rapid tachyarrhythmias, or extreme hypertension. The pain
is transient, lasting between 2 and 20 minutes. It is relieved
by cessation of the event that increased myocardial oxygen
demand or by administration of sublingual nitroglycerin.
Some patients do not manifest typical symptoms of angina. Rather, they may present with symptoms that reflect
underlying myocardial ischemia. Transient left ventricular
myocardial dysfunction may lead to dyspnea disproportionate to the degree of exercise or activity. Palpitations,
syncope, or sudden cardiac death may occur from ventricular arrhythmias due to myocardial ischemia, but these are
uncommon. Patients with chronic myocardial ischemia and
left ventricular dysfunction may present with symptoms of
heart failure. Patients may also initially present with symptoms of claudication or transient cerebral ischemia related to
atherosclerosis in other vascular locations.
A resting or ambulatory electrocardiogram or a noninvasive stress test in a patient with symptoms suggestive
of coronary ischemia typically diagnoses coronary heart
disease. A number of patients undergo stress testing as part
of annual physical evaluation or as part of a preoperative
workup and are diagnosed with coronary artery disease
although they may not have any symptoms attributable to
coronary artery disease.
Several clinical factors impact prognosis in chronic
ischemic heart disease. The Canadian Cardiovascular Society’s (CCS) angina functional class system is closely tied
to prognosis: the higher the Canadian class, the worse
the prognosis [17]. Impaired left ventricular function is a
powerful predictor of a poor prognosis [18]. In addition,
high-risk features on noninvasive stress testing portend
to a worse outcome. These high-risk features include low
exercise capacity, a high-risk Duke Treadmill score, severe
left ventricular dysfunction with exercise, stress-induced
large anterior or multiple perfusion defects on nuclear imaging, stress-induced left ventricular dilation, or extensive
ischemia on stress echocardiogram [19–22].
The extent and severity of angiographic coronary artery
disease is a powerful predictor of long-term outcome with
www.turner-white.com
prognosis worsening with multivessel disease. Patients with
left main and proximal left anterior descending coronary
artery disease with a large amount of myocardium at risk
also have a worse survival. These observations have formed
the anatomic rationale for revascularization in patients with
chronic ischemic heart disease [23,24].
Treatment
The goals of treatment in coronary artery disease are to
relieve symptoms, prevent future events, and improve
sur­vival. This is achieved by a combination of antiplatelet
therapy, risk factor modification, antianginal medications,
and coronary artery revascularization.
Medical Management
All patients with coronary artery disease should have optimal medical management, regardless of whether or not they
are revascularized. Medical management is aimed at ways
to limit progression of disease while prolonging quantity
and improving quality of life. The mainstays of optimal
medical management are antiplatelet therapy, risk factor
reduction, and antianginal therapy.
Antiplatelet therapy is one of the cornerstones to the
management of coronary artery disease. The risk of adverse
cardiovascular events was reduced by an average of 33%
with aspirin in a study of more than 3000 patients with
stable angina [25,26]. In addition, aspirin decreases both the
short- and long-term risk of fatal and nonfatal myocardial
infarction in patients with unstable angina [27,28]. It is not
clear that a dose of 325 mg per day is superior to 81 mg
per day. However, doses less than 75 mg per day have less
benefit [29]. Clopidogrel also is beneficial in the secondary
prevention of combined myocardial infarction, vascular
death, or ischemic stroke, and is an alternative in patients
intolerant to aspirin [30].
Aggressive cholesterol lowering also improves survival in
patients with stable coronary artery disease. Multiple secondary prevention trials have demonstrated marked mortality
benefit with the addition of HMG-CoA reductase inhibitors
(statins) [31–33]. The 4S trial reduced total and low-density
lipoprotein (LDL) cholesterol while raising high-density lipoprotein cholesterol and demonstrated a reduction of 30%
to 35% in 5-year mortality and major coronary events. In the
largest cholesterol-lowering trial, the Heart Protection Study,
20,000 patients with coronary disease, other vascular disease,
diabetes and/or hypertension were randomized to simva­
statin versus placebo. After a mean of 5 years, mortality was
reduced by 25% even in patients with a baseline LDL cholesterol less than 100 mg/dL [34]. The mechanism of this benefit
likely involves plaque stabilization and possibly regression.
Smoking cessation, control of hypertension, management
Vol. 15, No. 7 July 2008 JCOM 345
courage trial
of diabetes, exercise, and weight reduction in obese patients
with hypertension, hyperlipidemia, or diabetes are established
interventions in the management of chronic ischemic heart
disease. With regard to hypertension, angiotensin-converting
enzyme (ACE) inhibitors should be used in all patients with
diabetes or impaired left ventricular function [35,36]. The data
are mixed as to whether all patients with coronary artery
disease benefit from an ACE inhibitor even if they do not have
diabetes or left ventricular dysfunction [37,38].
While the goals of antiplatelet therapy and risk factor
reduction in stable coronary artery disease are to prolong
survival, the primary goal of antianginal therapy is to
relieve symptoms and thereby improve quality of life.
b Blockers, calcium channel blockers, and nitrates are the
most effective agents for relieving angina. They can be used
alone or in combination. A detailed discussion of the antianginal medicines will not be presented here.
Revascularization
Revascularization of stenotic coronary arteries makes anatomic sense. Stable coronary artery disease creates symptoms by reducing coronary blood flow and creating an imbalance between myocardial oxygen supply and demand. It
therefore seems intuitive that restoration of coronary blood
flow and improvement in myocardial oxygen supply would
benefit patients over the short and long term. In addition,
coronary artery disease is a diffuse process, and prognosis
in chronic ischemic heart disease is closely related to the
degree and severity of atherosclerotic plaque [23]. Theoretically, revascularization of stenotic lesions and thus stabilization of this atherosclerotic plaque seems important in the
prevention of future coronary events.
However, there is no definitive proof that revascularization of symptomatic angiographically severe stenosis
reduces the risk of myocardial infarction compared with
medical therapy in all patients with chronic ischemic heart
disease. Most myocardial infarctions occur as the result
of angiographically moderate stenosis that does not cause
symptoms prior to plaque rupture and infarction [39,40].
Further, revascularization itself is not without risk of myocardial infarction and death.
It is out of this context that the first trials comparing
medical therapy to coronary artery bypass grafting (CABG)
or PCI developed. These trials sought to answer whether revascularization and restoration of coronary blood flow would
improve outcome in patients with stable coronary artery
disease. As revascularization techniques improve and optimal medical therapy has been more refined, the early trials
become more difficult to interpret. This led to the COURAGE
trial, which sought to definitively test if current revascularization techniques provided any benefit beyond contemporary
medical therapy.
346 JCOM July 2008 Vol. 15, No. 7
Revascularization with PCI
Since 1977, PCI has been a therapeutic strategy to treat coronary artery stenosis. Percutaneous transluminal coronary
angioplasty (PTCA), the original method of intervention,
involves inflation of a balloon at the tip of a catheter across
the stenotic lesion. The risk of acute closure of coronary lesions was unacceptably high in the early days of PTCA, but
this risk has been abated substantially with the introduction
of intracoronary stents, improved antiplatelet therapy, and
improved selection of appropriate lesions. Both PTCA and
stenting are effective in improving symptoms of angina.
The advantages of PCI are the low morbidity and mortality,
early hospital discharge, and convenience to the patient.
Some patients do not have anatomy suitable for effective
PCI, and the risk of short- and long-term restenosis is not
insignificant [41,42].
Early Trials of Medical Therapy Versus PCI
The initial trials comparing PCI with medical therapy were
limited for a number of reasons. Most of these trials primarily compared medical therapy with PTCA, a technique that
is clearly inferior to currently practiced stent placement.
In early studies that did include stents in the PCI group,
current antiplatelet therapies known to improve post-PCI
vessel patency, such as clopidogrel and glycoprotein IIb/
IIIa inhibition, were not used. In addition, none of the early
comparison trials used current optimal medical therapy.
Finally, the early trials predominantly involved patients
who were at low risk of mortality, such as patients with
1-vessel disease.
Early trials comparing PTCA with medical therapy
consistently showed improved angina control but no clear
mortality benefit with PTCA [43–46]. In fact, in the Randomized Intervention Treatment of Angina (RITA-2) trial,
the PTCA group had a slightly higher risk of death or
myocardial infarction at 2.7 years, but this was primarily
related to periprocedure cardiac enzyme elevations [44].
In the Atorvastatin Versus Revascularization Treatment
(AVERT) trial, PTCA was superior to medical therapy in
relief of angina but had a significantly higher incidence of
the combined endpoint of ischemic events, hospitalization,
and repeat intervention compared with medical therapy
(21% vs. 13%, respectively) [45]. However, LDL cholesterol
was reduced much more in the medical therapy arm and
this may explain some of the results.
COURAGE Trial
The COURAGE trial was the first to compare optimal medical therapy with optimal medical therapy plus contemporary
PCI with stenting in patients with chronic stable angina [9].
This study randomized 2287 patients to current aggressive
medical therapy versus current aggressive medical therapy
www.turner-white.com
clinical review
plus bare-metal stenting. The mean age of these patients was
62 years, 87% of them were symptomatic, and 58% of them
had CCS class II and class III angina [17].
All included patients needed to have objective evidence
of myocardial ischemia and angiographically significant
disease in at least 1 vessel. In fact, 70% of patients had 2- or
3-vessel disease. Patients were excluded if they had CCS
class IV angina, 50% or greater left main coronary artery
disease, a markedly positive exercise treadmill test, or an
ejection fraction of less than 30%. Patients considered unsuitable for PCI for technical reasons were also excluded.
All patients received antiplatelet therapy with aspirin
or clopidogrel. All patients received aggressive cholesterol
lowering with simvastatin plus or minus ezetimibe therapy
(median LDL achieved, 72 mg/dL). The medical compliance
in this study was impressive: at 5 years, 93% of patients were
on a statin and 94% were on aspirin. Exercise was encouraged
to improve lipid profiles when appropriate. ACE inhibitors
and angiotensin receptor blockers were added as standard
secondary prevention. Finally, all patients were placed on
antianginal therapy as tolerated with b blockers, calcium
channel blockers, or nitrates.
There was no significant difference between the 2 groups
in the primary endpoint of the study (a composite of death
from any cause and nonfatal myocardial infarction) at
4.6 years (18.5% in the PCI group vs. 19% in the medical
group [95% confidence interval, 0.87–1.27]; P = 0.62). There
was also no difference in the rates of hospitalization for
patients with acute coronary syndrome (approximately 12%
in both groups). However, patients in the PCI group had
significantly less angina at 1 and 3 years, but not at 5 years.
There were also significantly fewer new revascularizations
in the PCI group (21.1% vs. 33%; hazard ratio, 0.60 [95%
confidence interval, 0.51–0.71]; P < 0.001) during the course
of the study. Interestingly, 33% of patients in the medical
therapy arm ultimately required revascularization.
It is worth noting that the COURAGE trial excluded
patients known to have a survival benefit from revascularization: those with acute coronary syndromes, left main
coronary artery disease, low ejection fraction, and markedly
positive stress testing. The results of this trial should not be
extrapolated to this population.
There are some limitations to the COURAGE trial. Of
the 35,539 patients who underwent assessment, 32,468 were
excluded, raising the question of whether those included are
truly representative of the population at large. Further, 85%
of the patients were male, and 86% of the patients were white.
In addition, among the patients who underwent PCI, 14.5%
of the lesions were treated with PTCA rather than with stenting. Of those stented, only 15% received drug-eluting stents.
Although there is no proven mortality difference between
bare-metal stents and drug-eluting stents, drug-eluting stents
www.turner-white.com
reduce the chance of in-stent restenosis and repeat revascularization [47–51]. Finally, patient preference was not a factor
in the study. In real-world practice, patient preference plays
an important role in clinical decision making regarding the
timing of when to pursue revascularization.
Despite its limitations, the COURAGE trial does provide clinicians with the best head-to-head comparison of
contemporary medical management and PCI and suggests
that medical management alone is an appropriate initial
management strategy for selected patients with chronic
stable angina.
The lack of survival benefit in the revascularized patients
in both early and contemporary trials may be explained by
differences between stable and vulnerable atherosclerotic
plaque. The plaque of patients with chronic stable angina detected on positive stress testing or as significant angiographic
stenosis tends to have a thick fibrous cap, a small lipid core,
more smooth muscle cells, and fewer inflammatory cells
[52]. This plaque may remodel in an inward fashion, which
gradually narrows the coronary lumen, reduces myocardial
blood flow, and increases ischemia, but does not necessarily
rupture and lead to an acute coronary syndrome. The characteristics of stable atherosclerotic plaque are much different
than those found in vulnerable plaque, which tends to have
a thin fibrous cap, a large lipid core, and more inflammatory
cells. Vulnerable or unstable plaque tends to remodel in an
extraluminal fashion. It may or may not encroach on the
coronary vessel lumen and may or may not be detected on a
stress test or even on coronary angiography. It may, however,
be more likely to rupture and lead to an occluded vessel and
an acute coronary syndrome [53–56].
Revascularization with CABG
In selected patients with chronic stable angina, CABG
provides symptomatic relief and survival benefit when
compared with medical management. The early CABG versus medical management trials helped identify subsets of
patients who are at high risk of death without surgery. This
includes patients with left main coronary artery disease, left
main coronary artery equivalent disease such as significant
stenosis in both the proximal left anterior descending and
the left circumflex artery, 3-vessel coronary artery disease
with a reduced left ventricular ejection fraction, 2-vessel
coronary artery disease with a greater than 75% proximal
left anterior descending, and an impaired left ventricular
ejection fraction with 1- and 2-vessel disease and viable
myocardium distal to the coronary blockages [19,57–59].
In addition to survival benefit observed in selected
patients in the original trials, patients receiving CABG had
marked improvement in angina at 5 years compared with
the medical therapy arm [60,61]. This symptomatic benefit
was less at 10 years, in part because of crossover from the
Vol. 15, No. 7 July 2008 JCOM 347
courage trial
medical arm to the surgery arm and in part because of failure in the vein graft bypasses.
The early large multicenter trials comparing CABG with
medical management are limited because contemporary
optimal medical management was not employed. In addition, many of the earlier trials used only saphenous vein
grafting and did not include the more superior left internal
mammary grafting. There are no current randomized trials
comparing contemporary medical therapy with contemporary CABG techniques in patients with chronic stable
angina, preserved left ventricular function, and lack of left
main disease. To what extent the results of the COURAGE
trial can be extrapolated to revascularization with CABG is
not entirely certain.
CABG Versus PCI in Multivessel Disease
Several trials have compared PTCA and CABG in patients
with multivessel disease. The largest trials comparing PTCA
with CABG in the United States are the Bypass Angioplasty
Revascularization Investigation (BARI) and the Emory Angioplasty Surgery Trial (EAST) [62,63]. Repeat intervention
was much more common with PTCA, but neither trial found
a difference in mortality up to 8 years. An exception is in the
subgroup of diabetic patients with multiple severe lesions;
these patients had a mortality benefit with CABG in 1 major
trial [62]. Meta-analyses of the early trials comparing PTCA
and CABG for patients with multivessel disease have also
found no difference in all-cause mortality at 2.7 years but
did show an increase in repeat intervention in the PTCA
groups (33.7% vs. 3.3%) at 1 year. In addition, patients in the
CABG groups have more freedom from angina compared
with those in the PTCA groups [62,63].
The earliest trials comparing CABG and PCI for revascularization of patients with chronic stable angina were limited
because they did not all involve internal mammary grafting,
which improves both long-term graft patency and survival
compared with saphenous vein grafting. In addition, these
trials did not involve the use of stents, which reduce restenosis and repeat intervention in patients with multivessel
disease. Further, they did not use glycoprotein IIb/IIIa inhibitors or aggressive lipid lowering. Finally, both BARI and
EAST involved patients with normal left ventricular function
and 2-vessel rather than 3-vessel disease. In short, these trials
did not evaluate many high-risk patients known to have a
mortality benefit from CABG.
Two large trials have compared bare-metal stenting
with CABG with internal mammary grafting in this patient
population. The ARTS I study revealed no difference in
mortality between these methods at 1, 3, and 5 years [64].
However, the stent group had a lower rate of event-free survival than the CABG group (73.8% vs. 87.8%, respectively)
due to an increase in repeat intervention, particularly in
348 JCOM July 2008 Vol. 15, No. 7
diabetic patients and those with initial incomplete revascularization. The Stent or Surgery (SoS) trial likewise found
a significantly higher incidence of repeat revascularization
compared with CABG in management of patients with multivessel disease [65]. Combined meta-analysis of published
studies comparing stenting with CABG for patients with
multivessel disease essentially corroborate the results of the
larger trials, finding no significant difference in mortality at
1 and 3 years but higher rates of repeat intervention in the
stent groups [66].
Drug-eluting stents reduce the rate of restenosis and
repeat revascularization when compared with bare-metal
stents. The ARTS II registry compared patients with sirolimus drug-eluting stents to historical CABG patients and
historical bare-metal stent patients from the ARTS I trial. At
1 year, the rate of major adverse cardiac and cerebrovascular
events were similar in the drug-eluting stent and the CABG
groups and were significantly lower than the bare-metal
stent group (10.4%, 11.6%, and 26.5%, respectively). The rate
of repeat intervention in the drug-eluting stent group was
8.5%, as compared with 4.1% in the CABG group and 21.3%
in the bare-metal stent group. These findings are clearly limited in that they were observational and nonrandomized.
A recent observational study compared drug-eluting
stents and CABG in 17,400 patients in New York State. The
major findings of the study were that CABG had significantly lower adjusted rates of death and of death or myocardial infarction compared with drug-eluting stents. This was
an observational study and thus is subject to potential bias,
and the degree of survival benefit in this analysis was more
extreme than that observed in the original trials comparing
CABG and medical therapy.
To summarize, PCI appears to be similar to CABG with
no difference in survival in selected patient populations
with chronic stable angina, multivessel disease, and preserved left ventricular function. Compared with CABG, PCI
leads to increased early rates of repeat revascularization.
This revascularization may occur at the target lesion or
because of progressive coronary artery disease at other sites.
The rate of restenosis and repeat revascularization after PCI
has been significantly decreased with the advent of baremetal and drug-eluting stents. It is worth pointing out that
patients who receive drug-eluting stents and are unable or
unwilling to continue dual antiplatelet therapy with aspirin
and clopidogrel are at high risk of subacute or even late stent
thrombosis.
Asymptomatic Coronary Artery Disease
Asymptomatic coronary artery disease may be detected
when stress testing, computed tomography angiography, or
coronary angiography is obtained in patients without symptoms. Although the randomized controlled trials in stable
www.turner-white.com
clinical review
ischemic heart disease have been primarily performed in
symptomatic patients, asymptomatic disease is associated
with an adverse prognosis and should be treated [67–70].
The goals of treatment are to reduce cardiac events and to
improve survival.
Risk factor modification and antiplatelet therapy are mainstays of therapy in patients with asymptomatic coronary artery disease. Despite the lack of symptoms of angina in these
patients, b blockers, calcium channel blockers, and nitrates,
either alone or in combination, may be a useful therapeutic
addition as well. b Blockers have been shown in small studies
to reduce adverse outcomes, reduce left ventricular dysfunction, and reduce asymptomatic ischemia detected on exercise
treadmill testing [70,71]. Calcium channel blockers reduce
ischemic episodes and duration but have minimal if any
impact on improving adverse outcomes [72,73].
Revascularization has been compared with medical therapy in patients with asymptomatic coronary artery disease.
In the ACIP (Asymptomatic Coronary Ischemia Pilot) trial,
558 patients either free of angina or with well-controlled
angina were randomly assigned to medical therapy guided
by angina relief, medical therapy guided by ischemia-free
Holter monitoring, or revascularization with PTCA or CABG
[70]. Mortality at 1 to 2 years was better in either revascularization group compared with the medical management
group. Similar results were found in trials from the early
1990s comparing medical therapy with PTCA in postmyocardial infarction silent ischemia [74,75]. In the SWISSI II trial,
201 patients with silent ischemia detected on exercise stress
testing in the first 3 months postmyocardial infarction and
documented 1- or 2-vessel coronary artery disease suitable
for PCI were randomized to PTCA or medical management.
At a mean follow-up of 10.2 years, cardiac death, nonfatal
myocardial infarction, and symptom-driven revascularization was 3.2% in the PTCA group as compared with 9.5% in
the medical management group.
It is important to emphasize that both the medical and
invasive therapy were suboptimal in the trials above. As
such, it is difficult to draw firm conclusions at this time that
revascularization of asymptomatic coronary artery disease
is superior to optimal medical therapy. Approximately 13%
of the patients included in the COURAGE trial were classified as asymptomatic, but the study was not powered to
accurately state whether the overall results apply to this
sub­group as well.
Although the available data are less robust for asymptomatic patients, the same recommendations for revascularization in symptomatic patients apply to asymptomatic patients. That is, patients with asymptomatic coronary artery
disease should receive antiplatelet therapy and aggressive
risk factor reduction. In addition, conditions associated with
a higher mortality, such as significant left main coronary
www.turner-white.com
artery disease, should be considered for revascularization
even in the absence of symptoms.
Recommendations
In light of the existing data, revascularization in asymptomatic or stable coronary artery disease is a reasonable approach in patients who continue to have symptoms despite
optimal medical therapy and in patients in whom revascularization may change survival. The following guide may be
useful adjunct to clinical decision making:
1. Patients with asymptomatic or symptomatic but
stable disease should undergo an assessment of their
left ventricular function and risk stratification with
stress testing.
2. Patients with impaired left ventricular function or
with high-risk features on their stress testing should
undergo left heart catheterization and coronary angiography.
3. In the setting of normal left ventricular function and
a low-risk stress test, it is reasonable to pursue anti­
platelet therapy and aggressive risk factor modification. Should these patients have symptoms refractory
to medical management, then left heart catheterization and coronary angiography is indicated.
4. Patients with angiographic nonobstructive disease
should continue to be managed medically and followed closely to determine need for further testing as
dictated by changes in clinical status.
5. Patients with coronary anatomy and left ventricular
function that clearly would benefit from surgical
revascularization—left main coronary artery disease
or its equivalent, 3-vessel disease with impaired left
ventricular function or diabetes, proximal left anterior
descending with 2-vessel disease and a large area of
myocardial ischemia detected on stress imaging—
should be referred for CABG.
6. Patients with refractory symptoms and normal left
ventricular function and 1- or 2-vessel coronary
disease amenable to PCI could be treated with a
coronary stent. In patients with 3-vessel CAD, the
choice of revascularization would be determined by
the nature of the coronary stenosis and patient and
physician choice.
Decision making regarding whether to revascularize and
which method of revascularization to pursue may not always
be obvious or algorithmic. Most patients with asymptomatic
coronary disease or with chronic stable angina will not have
a clinical scenario in which invasive treatment would clearly
improve survival. Rather, most will be referred because of
Vol. 15, No. 7 July 2008 JCOM 349
courage trial
symptomatic management. Some patients will have complex
lesions for which PCI may carry a higher risk. Other patients
may have disease for which CABG is indicated, but they
also may have comorbid illnesses, including prior CABG,
which place them at much higher risk for surgical morbidity or mortality. Ultimately, clinical decision making in the
management of stable coronary disease is best based on the
informed preference of the patient and the practiced judgment of the physician.
Corresponding author: Hitinder S. Gurm, MD, Univ. of Michigan Cardiovascular Center, 2A394, 1500 E. Medical Center Dr., Ann Arbor, MI
48109, [email protected].
References
1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA
guidelines for the management of patients with ST-elevation
myocardial infarction—executive summary: a report of the
American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients with
Acute Myocardial Infarction). Circulation 2004;110:588–636.
2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial
infarction: a quantitative review of 23 randomised trials.
Lancet 2003;361:13–20.
3. Invasive compared with non-invasive treatment in unstable
coronary-artery disease: FRISC II prospective randomised
multicentre study. FRagmin and Fast Revascularisation
during InStability in Coronary artery disease Investigators.
Lancet 1999;354:708–15.
4. Cannon CP, Weintraub WS, Demopoulos LA, et al; TACTICS
(Treat Angina with Aggrastat and Determine Cost of Therapy
with an Invasive or Conservative Strategy)—Thrombolysis in
Myocardial Infarction 18 Investigators. Comparison of early
invasive and conservative strategies in patients with unstable
coronary syndromes treated with the glycoprotein IIb/IIIa
inhibitor tirofiban. N Engl J Med 2001;344:1879–87.
5. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable
angina or non-ST-elevation myocardial infarction: the British
Heart Foundation RITA 3 randomised trial: Randomized Intervention Trial of unstable Angina. Lancet 2002;360:743–51.
6. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel
coronary artery disease. N Engl J Med 1992;326:10–6.
7. Coronary angioplasty versus medical therapy for angina:
the second Randomised Intervention Treatment of Angina
(RITA-2) trial. Lancet 1997;350:461–8.
8. Henderson RA, Pocock SJ, Clayton TC, et al; Second Randomized Intervention Treatment of Angina (RITA-2) Trial Participants. Seven-year outcome in the RITA-2 trial: coronary
angioplasty versus medical therapy. J Am Coll Cardiol 2003;
42:1161–70.
9. Boden WE, O’Rourke RA, Teo KK, et al; COURAGE Trial Research Group. Optimal medical therapy with or without PCI
350 JCOM July 2008 Vol. 15, No. 7
for stable coronary disease. N Engl J Med 2007;356:1503–16.
10. American Heart Association. Biostatistical fact sheets. Dallas: American Heart Association; 1997:1–29.
11. American Heart Association. 1999 Heart and stroke statistical
update. Dallas: American Heart Association; 1999.
12. 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 2003;
41:159–68.
13. Hlatky MA, Boothroyd D, Horine S, et al. Employment after
coronary angioplasty or coronary bypass surgery in patients
employed at the time of revascularization. Ann Intern Med
1998;129:543–7.
14. Elveback LR, Connolly DC, Melton LJ 3rd. Coronary heart
disease in residents of Rochester, Minnesota. VII. Incidence,
1950 through 1982. Mayo Clin Proc 1986;61:896–900.
15. Kannel WB, Feinleib M. Natural history of angina pectoris
in the Framingham study. Prognosis and survival. Am J
Cardiol 1972;29:154–63.
16. 27th Bethesda Conference. Matching the intensity of risk factor management with the hazard for coronary disease events.
September 14–15, 1995. J Am Coll Cardiol 1996;27:957–1047.
17. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/
SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the
2001 Guidelines for Percutaneous Coronary Intervention).
J Am Coll Cardiol 2006;47:e1–121.
18. Harris PJ, Harrell FE Jr, Lee KL, et al. Survival in medically
treated coronary artery disease. Circulation 1979;60:1259–69.
19. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically
treated patients in the coronary artery surgery study (CASS)
registry. Circulation 1982;66:562–8.
20. Mark DB, Shaw L, Harrell FE, et al. Prognostic value of a
treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991;325:849–53.
21. Beller GA. Radionuclide perfusion imaging techniques for
evaluation of patients with known or suspected coronary
artery disease. Adv Intern Med 1997;42:139–201.
22. Marwick TH. Use of stress echocardiography for the prognostic assessment of patients with stable chronic coronary
artery disease. Eur Heart J 1997;18 Suppl D:D97–101.
23. Ringqvist I, Fisher LD, Mock M, et al. Prognostic value of angiographic indices of coronary artery disease from the Coronary
Artery Surgery Study (CASS). J Clin Invest 1983;71:1854–66.
24. Eleven year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina.
The Veterans Administration Coronary Artery Bypass Cooperative Study Group. N Engl J Med 1984;311:1333–9.
25. Ridker PM, Manson JE, Gaziano JM, et al. Low-dose aspirin
therapy for chronic stable angina. A randomized, placebocontrolled clinical trial. Ann Intern Med 1991;114:835–9.
26. Collaborative overview of randomised trials of antiplatelet
www.turner-white.com
clinical review
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
therapy—I: Prevention of death, myocardial infarction, and
stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists Collaboration. BMJ 1994;
308:81–106.
Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects
of aspirin against acute myocardial infarction and death in
men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983;309:396–403.
Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or
both in unstable angina. Results of a Canadian multicenter
trial. N Engl J Med 1985;313:1369–75.
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;324:71–86.
A randomised, blinded, trial of clopidogrel versus aspirin
in patients at risk of ischaemic events (CAPRIE). CAPRIE
Steering Committee. Lancet 1996;348:1329–39.
Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: the Scandinavian Simvastatin
Survival Study (4S). Lancet 1994;344:1383–9.
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;335:1001–9.
Prevention of cardiovascular events and death with prava­
statin 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 1998;339:1349–57.
Heart Protection Study Collaborative Group. MRC/BHF
Heart Protection Study of cholesterol lowering with simva­
statin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7–22.
Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril
on mortality and morbidity in patients with left ventricular
dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669–77.
Effect of enalapril on mortality and the development of heart
failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators [published
erratum appears in N Engl J Med 1992;327:1768]. N Engl J
Med 1992;327:685–91.
Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. The Heart Outcomes Prevention
Evaluation Study Investigators. N Engl J Med 2000;342:145–
53.
Braunwald E, Domanski MJ, Fowler SE, et al; PEACE Trial
Investigators. Angiotensin-converting-enzyme inhibition in
stable coronary artery disease. N Engl J Med 2004;351:2058–
68.
Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;
12:56–62.
www.turner-white.com
40. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary
artery disease? Circulation 1988;78(5 Pt 1):1157–66.
41. Topol EJ, Leya F, Pinkerton CA, et al. A comparison of directional atherectomy with coronary angioplasty in patients with
coronary artery disease. The CAVEAT Study Group. N Engl J
Med 1993;329:221–7.
42. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty
in the treatment of coronary artery disease. Stent Restenosis
Study Investigators. N Engl J Med 1994;331:496–501.
43. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel
coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992;326:10–6.
44. Coronary angioplasty versus medical therapy for angina: the
second Randomised Intervention Treatment of Angina (RITA-2)
trial. RITA-2 Trial Participants. Lancet 1997;350:461–8.
45. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering
therapy compared with angioplasty in stable coronary artery
disease. Atorvastatin versus Revascularization Treatment In­
vestigators. N Engl J Med 1999;341:70–6.
46. Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of
randomized controlled trials. BMJ 2000;321:73–7.
47. Spaulding C, Daemen J, Boersma E, et al. A pooled analysis
of data comparing sirolimus-eluting stents with bare-metal
stents. N Engl J Med 2007;356:989–97.
48. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of
sirolimus- and paclitaxel-eluting coronary stents. N Engl J
Med 2007;356:998–1008.
49. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl
J Med 2007;356:1030–9.
50. Lagerqvist B, James SK, Stenestrand U, et al; SCAAR Study
Group. Long-term outcomes with drug-eluting stents versus
bare-metal stents in Sweden. N Engl J Med 2007;356:1009–19.
51. Mauri L, Hsieh W, Massaro JM, et al. Stent thrombosis in
randomized clinical trials of drug-eluting stents. N Engl J
Med 2007;356:1020–9.
52. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to
vulnerable patient: a call for new definitions and risk assessment strategies. Circulation 2003;108:1664–72.
53. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92:657–71.
54. Mann JM, Davies MJ. Vulnerable plaque. Relation of characteristics to degree of stenosis in human coronary arteries.
Circulation 1996;94:928–31.
55. Libby P. Molecular bases of the acute coronary syndromes.
Circulation 1995;91:2844–50.
56. Fuster V, Fallon JT, Nemerson Y. Coronary thrombosis. Lancet 1996;348 Suppl 1:S7–10.
57. Eighteen-year follow-up in the Veterans Affairs Cooperative
Study of Coronary Artery Bypass Surgery for stable angina.
The VA Coronary Artery Bypass Surgery Cooperative Study
Vol. 15, No. 7 July 2008 JCOM 351
courage trial
Group. Circulation 1992;86:121–30.
58. Varnauskas E. Twelve-year follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med
1988;319:332–7.
59. Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized
trial of coronary artery bypass surgery. Survival of patients
with a low ejection fraction. N Engl J Med 1985;312:1665–71.
60. Myers WO, Schaff HV, Gersh BJ, et al. Improved survival of
surgically treated patients with triple vessel coronary artery
disease and severe angina pectoris. A report from the Coronary Artery Surgery Study (CASS) registry. J Thorac Cardiovasc Surg 1989;97:487–95.
61. Rogers WJ, Coggin CJ, Gersh BJ, et al. Ten-year follow-up
of quality of life in patients randomized to receive medical therapy or coronary artery bypass graft surgery. The
Coronary Artery Surgery Study (CASS). Circulation 1990;82:
1647–58.
62. Comparison of coronary bypass surgery with angioplasty in
patients with multivessel disease. The Bypass Angioplasty
Revascularization Investigation (BARI) Investigators [published erratum appears in N Engl J Med 1997;336:147]. N Engl
J Med 1996;335:217–25.
63. King SB 3rd, Lembo NJ, Weintraub WS, et al. A randomized
trial comparing coronary angioplasty with coronary bypass
surgery. Emory Angioplasty versus Surgery Trial (EAST).
N Engl J Med 1994;331:1044–50.
64. Serruys PW, Unger F, Sousa JE, et al; Arterial Revascularization Therapies Study Group. Comparison of coronary-artery
bypass surgery and stenting for the treatment of multivessel
disease. N Engl J Med 2001;344:1117–24.
65. SoS Investigators. Coronary artery bypass surgery versus
percutaneous coronary intervention with stent implantation
in patients with multivessel coronary artery disease (the Stent
or Surgery trial): a randomised controlled trial. Lancet 2002;
360:965–70.
66. Hannan EL, Wu C, Walford G, et al. Drug-eluting stents
vs. coronary-artery bypass grafting in multivessel coronary
disease. N Engl J Med 2008;358:331–41.
67. Exercise electrocardiogram and coronary heart disease mortality in the Multiple Risk Factor Intervention Trial. Multiple
68.
69.
70.
71.
72.
73.
74.
75.
Risk Factor Intervention Trial Research Group. Am J Cardiol
1985;55:16–24.
Gibbons LW, Mitchell TL, Wei M, et al. Maximal exercise
test as a predictor of risk for mortality from coronary heart
disease in asymptomatic men. Am J Cardiol 2000;86:53–8.
Forslund L, Hjemdahl P, Held C, et al. Prognostic implications of ambulatory myocardial ischemia and arrhythmias
and relations to ischemia on exercise in chronic stable angina
pectoris (the Angina Prognosis Study in Stockholm [APSIS]).
Am J Cardiol 1999;84:1151–7.
Pepine CJ, Sharaf B, Andrews TC, et al. Relation between
clinical, angiographic and ischemic findings at baseline and
ischemic-related adverse outcomes at 1 year in the Asymptomatic Cardiac Ischemic Pilot study. ACIP Study Group.
J Am Coll Cardiol 1997;29:1483–9.
Knatterud G, Bourassa MG, Pepine CJ, et al. Effects of treatment strategies to suppress ischemia in patients with coronary artery disease: 12-week results of the Asymptomatic
Cardiac Ischemia Pilot (ACIP) study [published erratum
appears in J Am Coll Cardiol 1995;26:842]. J Am Coll Cardiol
1994;24:11–20.
Pepine CJ, Cohn PF, Deedwania PC, et al. Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life. The Atenolol Silent Ischemia Study
(ASIST). Circulation 1994;90:762–8.
Stone PH, Gibson RS, Glasser SP, et al. Comparison of propranolol, diltiazem and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential
effects on ambulatory ischemia, exercise performance, and
anginal symptoms. The ASIS Study Group. Circulation 1990;
82:1962–72.
Madsen JK, Grande P, Saunamaki K, et al. Danish multicenter
randomized study of invasive versus conservative treatment
in patients with inducible ischemia after thrombolysis in
acute myocardial infarction (DANAMI). DANish trial in
Acute Myocardial Infarction. Circulation 1997;96:748–55.
Erne P, Schoenenberger AW, Burckhardt D, et al. Effects of
percutaneous coronary interventions in silent ischemia after
myocardial infarction: the SWISSI II randomized controlled
trial. JAMA 2007;297:1985–91.
Copyright 2008 by Turner White Communications Inc., Wayne, PA. All rights reserved.
352 JCOM July 2008 Vol. 15, No. 7
www.turner-white.com