Journal of the American College of Cardiology
© 2007 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 50, No. 16, 2007
ISSN 0735-1097/07/$32.00
doi:10.1016/j.jacc.2007.08.010
Commentary
COURAGE Under Fire
On the Management of Stable Coronary Disease
George A. Diamond, MD, FACC, Sanjay Kaul, MD, FACC
Los Angeles, California
The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial showed that
coronary interventional procedures added little to optimal medical therapy with respect to the long-term outcome of patients with stable coronary disease when used as initial therapy. Detractors opine that: 1) the trial
was unrealistic in design and the findings were not unexpected; 2) the use of coronary interventional procedures
was suboptimal; and 3) the results of COURAGE are not applicable to current clinical practice. We herein reevaluate the evidence with regard to each of these points, and conclude that COURAGE indeed provides relevant
new information to assist the practitioner in the appropriate management of patients with stable coronary
disease (J Am Coll Cardiol 2007;50:1604–9) © 2007 by the American College of Cardiology Foundation
According to Schopenhauer (1), truth passes through 3
stages: “First, it is ridiculed. Second, it is violently opposed.
Third, it is accepted as being self-evident.” Kereiakes et al.
(2) reverse this journey in their review of the COURAGE
(Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its conclusion that
percutaneous coronary intervention (PCI) adds little to
optimal medical therapy (OMT) in the management of
stable coronary disease (3). In the present counterpoint, we
revisit each signpost and proffer a more optimistic view of
the landscape.
Stage 3: “it is. . .self-evident”
Point. Kereiakes et al. (2) claim that the COURAGE trial
was “neither surprising nor new” compared with previous
studies (4). Given what was already known, “COURAGE
set an unrealistic goal” by enrolling a small select group of
relatively low-risk patients and seeking to detect a large
reduction in death or myocardial infarction (MI). Instead, “a noninferiority trial design may have been more
appropriate” (2).
Counterpoint. In fact, enrollment criteria in the COURAGE trial were entirely conventional. Clinical equipoise
and the usual desiderata of trial design necessitated exclusions at both extremes of risk (serious comorbidity and New
York Heart Association (NYHA) functional class IV angina
at the high end versus undocumented ischemia and ⬍70%
stenosis at the low end), thereby assuring a homogeneous,
albeit small, study population (6.4% of 35,539 candidates in
From the Division of Cardiology, Cedars-Sinai Medical Center, and the David
Geffen School of Medicine, University of California, Los Angeles, California.
Manuscript received August 9, 2007; revised manuscript received August 17, 2007,
accepted August 27, 2007.
the COURAGE trial versus 2.9% of 20,769 candidates in
the MASS [Medicine, Angioplasty, or Surgery Study]-II
trial [5]).
The COURAGE trial was conceived in 1996, and at the
time of its design in 1999, 6 trials comprising 1,872 patients
with stable coronary disease had already been published (4).
The rate of death or MI was 7.2% for medical therapy versus
8.6% for PCI (20% more) over 6 to 57 months. The
COURAGE trial relied instead on a consensus that PCI
would perform as well in stable coronary disease as it was
thought to do in acute coronary syndromes (W.S. Weintraub, personal communication, June 29, 2007), and its
consequent expectation of a 22% risk reduction over 3 years
(6) was indeed “unrealistic” (2). Two contemporary
meta-analyses (7,8) confirm the benefit of PCI in acute
coronary syndromes (Table 1), although a similar metaanalysis (exclusive of the COURAGE trial) shows no
comparable benefit in stable coronary disease (Table 2). In
this context, the findings in the COURAGE trial are
indeed not “new” (2).
But there is more to the story. Table 3 updates Table 2
with the data from the COURAGE trial relative to the
hypothesis that PCI⫹OMT improves death or MI better
than OMT in stable coronary disease, thereby circumventing any post hoc considerations of statistical power and
assessing the actual observations without regard for what
might have been observed (9). Independent of any “unrealistic” expectations, OMT is favored by a ratio of nearly 7:1.
Nevertheless, because the lay public is unlikely to distinguish between unstable and stable disease, most patients
undergoing elective PCI often do so under the belief that it
indeed prolongs their life or prevents a heart attack. The fact
that most (10,11) of these procedures are performed electively— often in stable patients immediately following ad
Diamond and Kaul
On the Management of Stable Coronary Disease
JACC Vol. 50, No. 16, 2007
October 16, 2007:1604–9
hoc diagnostic angiography (12)— only serves to reinforce
this belief. At the very least, then, physicians and patients
clearly act as if they believe PCI prevents death and MI in
stable coronary disease.
If, as Kereiakes et al. (2) claim, the principal benefit of
PCI in stable disease lies in “the relief of symptoms and
improvement in quality of life,” why then are these procedures being performed in asymptomatic patients (13)? And
why are some of us so enthusiastically recommending
screening tests to identify asymptomatic patients for coronary revascularization (14 –16)?
Current guidelines actually encourage such practice by
endorsing PCI as “reasonable” (Class IIa) in asymptomatic
patients with suitable anatomy, viable myocardium, and
demonstrable ischemia on noninvasive testing (17) on the
specious assumption that silent ischemia is a surrogate for
angina. In symptomatic patients, the guidelines properly
restrict PCI to those “who have not been successfully treated
by medical therapy,” saying that “the goal of treatment
should be complete, or nearly complete, elimination of
anginal chest pain” (18).
If so, PCI comes up short. Only 66% of PCI patients in
the COURAGE trial were angina free at 1 year versus 58%
for OMT (12% started out that way), and its statistical
superiority lasted for only 3 years (3), after which restenosis
or atherosclerotic progression very likely intervened. The
probability that PCI⫹OMT improves angina-free status
better than OMT by more than 10% is only 58% at 1 year,
25% at 3 years, and 4% at 5 years (Table 4). This less than
stellar performance is arguably the most “novel” contribution of the COURAGE trial. Percutaneous coronary intervention performed somewhat better in the smaller
MASS-II trial (5,19), largely because medical therapy was
not as aggressive as in the COURAGE trial (angina-free
status for PCI vs. medical therapy was 52% vs. 36% at 1 year
and 77% vs. 55% at 5 years). If these findings were to cause
us to rethink our expectations of antianginal therapy, that
alone would be “surprising [and] new” (2).
Should the COURAGE trial have been a noninferiority
trial (2)? Using our 7.2% event rate (4) for the active control
baseline and a noninferiority margin of 1.4% (a 20%
difference), such a trial (20) requires 12,242 patients—5
times that in the COURAGE trial (6). But suppose there
were sufficient resources and resolve to perform this daunting trial. There are 2 possible outcomes: either PCI⫹OMT
meets criteria for noninferiority or it does not. If not, it must
be slightly inferior (having a hazard ratio of 1.05 accord-
ing to the COURAGE trial),
thereby making OMT the preferred option. But if PCI⫹OMT
were adjudged noninferior to
OMT, on what basis could one
then say it should be preferred?
Does PCI make OMT safer?
Less costly? More convenient?
More practical? More accessible?
1605
Abbreviations
and Acronyms
DES ⴝ drug-eluting stent(s)
MI ⴝ myocardial infarction
NYHA ⴝ New York Heart
Association
OMT ⴝ optimal medical
therapy
PCI ⴝ percutaneous
coronary intervention
Stage 2: “it is violently
opposed”
Point. Kereiakes et al. (2) contend that PCI was not
optimally performed in the COURAGE trial. They argue
that if: 1) a core laboratory had assessed the angiographic
findings; 2) more patients had been treated in non-Veterans
Affairs (VA) hospitals; 3) crossovers had been less; 4) the
study had been limited to high-risk patients; 5) the definition of periprocedural MI had been more forgiving; and 6)
drug-eluting stents (DES) had been used more freely—then
the outcomes and conclusions would have been different.
Let us take up each of these points in turn.
Counterpoint. By all accounts, the standard of performance in COURAGE was high. The 21% rate of “additional revascularization” (3) is actually less than in ARTS
(Arterial Revascularization Therapies Study; 23%) and the
MASS-II trial (32%) over comparable follow-up (5,21), and
its median of 10 months indicates that about one-half these
events occurred in the first year. If, as is likely, this is a
consequence of restenosis, it is less than that of bare-metal
stenting (22). Moreover, although only one-half of the
patients with multivessel disease received multiple stents,
this too is comparable to the MASS-II trial (5) and higher
than in the New York State Angioplasty Registry (23).
Finally, although bypass surgery clearly provides more
complete revascularization than PCI, it does not prevent
more death or MI (5,21,24).
The design of the COURAGE trial specifically calls for
all angiograms being “read centrally by a core angiographic
laboratory” (6). Even if it had not, it is hard to imagine how
this would impact angiographic or clinical outcomes as
implied (2). For obvious reasons, physicians responsible for
day-to-day care cannot wait for post hoc readings. But if
this were necessary to the effectiveness of PCI, what would
be the implications for the typical hospital performing these
procedures on an ad hoc basis (12)?
Meta-Analyses of PCI in Acute Coronary Syndromes
Table 1
Meta-Analyses of PCI in Acute Coronary Syndromes
Bavry et al. (7)
End Point
Mehta et al. (8)
OR (95% CI)
p Value
OR (95% CI)
Death
0.75 (0.63–0.90)
0.001
0.92 (0.77–1.09)
0.33
Nonfatal MI
0.83 (0.72–0.96)
0.012
0.75 (0.65–0.88)
0.001
Rehospitalization
0.69 (0.65–0.74)
0.0001
0.66 (0.60–0.72)
0.001
CI ⫽ confidence interval; MI ⫽ myocardial infarction; OR ⫽ odds ratio; PCI ⫽ percutaneous coronary intervention.
p Value
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Diamond and Kaul
On the Management of Stable Coronary Disease
JACC Vol. 50, No. 16, 2007
October 16, 2007:1604–9
Meta-Analysis of PCI in Stable Coronary Disease
Table 2
Meta-Analysis of PCI in Stable Coronary Disease
OR (95% CI)
p Value
Death
End Point
0.95 (0.72–1.23)
0.68
Nonfatal MI
1.32 (0.97–1.79)
0.08
Death or nonfatal MI
1.16 (0.91–1.48)
0.24
Data from Katritsis and Ioannidis (4).
Abbreviations as in Table 1.
Although sample size restrictions limit the reliability of
subgroup analyses, there are no significant differences in
outcome between VA and non-VA systems (p ⫽ 0.19). There
is therefore no reason to believe that the observed site-to-site
variability differs from that in actual community practice.
Crossover in the COURAGE trial was similar to other
revascularization trials. In the surgery trials, crossover
ranged from 24% to 30% over 5 to 11 years (25–27) versus
35% over 7 years in RITA (Randomized Intervention Trial
of Angina)-2 (28) and 24% over 5 years in the MASS-II
trial (5). These high rates are simply a manifestation of the
progressive nature of the disease, and very likely represent
the exercise of good clinical judgment. In any event,
intention-to-treat analysis, by maintaining the advantages
of randomization, is unaffected by crossover (29).
Kereiakes et al. (2) imagine that the skewed distribution of
anginal frequency in the COURAGE trial “implies. . .2 patient populations” (1 at high risk and 1 at low risk), which
biased the conclusions against PCI (30,31). In fact, there is
nothing suspicious about this pattern. If anginal frequency is
log normally distributed (32), a single population fully accounts
for these observations (Fig. 1). Thus, subgroup analyses reveal
no treatment differences between NYHA functional class 0 to
I angina versus NYHA functional class II to III angina.
The contrary “premise” that the COURAGE trial comprised a low-risk population, based solely on a cardiac
mortality of 0.4% per year (subject to ascertainment error),
is contradicted by the magnitude of comorbidity, frequency
of inducible ischemia, and prevalence of multivessel disease.
In fact, the all-cause mortality of nearly 8% is similar to that
in the ARTS trial (21), and death or MI at 5 years is
virtually identical to that in acute coronary syndrome trials
(33,34). This is not a low-risk population.
The supposition that the definition of myocardial enzyme
elevation “no doubt, disadvantaged PCI” compared with
OMT (2) is unsupported by the evidence. Only 26 periprocedural MIs occurred using this definition, and a censored
Integrated Trial
COURAGE
Analysis
(Death
of the
or MI)
Integrated Analysis of the
Table 3
COURAGE Trial (Death or MI)
Prior OR
(95% CI)
COURAGE OR
(95% CI)
Posterior OR
(95% CI)
Pr(PCI)>0%*
1.16 (0.91–1.48)
1.05 (0.87–1.27)
1.09 (0.94–1.27)
0.13
*Pr(PCI)⬎0% ⫽ probability that the frequency of the primary outcome with PCI ⫹ optimal medical
therapy is better than with optimal medical therapy alone, the ratio of benefit to harm being given
by the odds transformation of this probability (1 ⫺ Pr)/Pr. The prior estimate is based on a
meta-analysis of previous trials of PCI versus medical therapy (4).
Abbreviations as in Table 1.
Figure 1
Simulated Distribution of Anginal
Frequency in the COURAGE Trial
Simulated anginal frequency (episodes per week) for 1,000 hypothetical
patients. If anginal frequency (f ) is log normally distributed, with mean ␮ and
median m, then log(f ) is unimodal with mean log(m) and variance 2log(␮/m)
(32). Given ␮ ⫽ 10 and m ⫽ 3, (as reported in the COURAGE trial [3,30]),
12.2% of patients are angina free (0 episodes per week) and 27.7% manifest
more than daily angina (⬎7 episodes per week). In the COURAGE trial, 12.4%
were angina free and 21.1% manifested New York Heart Association functional
class III angina at baseline. The COURAGE investigators recently corrected the
mean value from ␮ ⫽ 10 to ␮ ⫽ 6 (31). Because the mean of the log transformed distribution depends only on the median of the untransformed distribution, this correction has little effect on the simulation. Using ␮ ⫽ 6 and m ⫽
3, 16.6% are angina-free and 20.3% manifest more than daily angina.
analysis that excluded these events did not shift the results
in favor of PCI, with a hazard ratio of 0.90 (95% confidence
interval 0.73 to 1.10; p ⫽ 0.29).
Finally, because DES were used infrequently in the COURAGE trial, Kereiakes et al. (2) say this too biased the outcomes
against PCI. To explore this possibility, we performed a
putative placebo analysis (20). The resultant risk ratio for
PCI⫹OMT versus OMT increased nonsignificantly (Fig. 2),
indicating that greater use of DES, if anything, would have
been associated with a slightly greater risk of death or MI. The
claim that DES would have improved angina-free status and
quality of life (albeit likely) remains conjectural.
Stage 1: “it is ridiculed”
Point. Kereiakes et al. (2) question the relevance of the
COURAGE trial to clinical practice, because “the vast
majority of Americans [already] receive medical therapy for
their coronary artery disease.” However, they then note that
the quality of medical therapy in the COURAGE trial is
not achievable in the real world. Although the COURAGE
trial excluded 10,000 patients without reference to coronary
anatomy (5,100 without ischemia and 4,900 with an inadequate ejection fraction) (3), they stipulate that “coronary
angiography . . . should not be denied to patients with stable
angina pectoris,” because the “choice of therapy(s) for each
individual patient must be made based on coronary anatomic suitability” (2).
Diamond and Kaul
On the Management of Stable Coronary Disease
JACC Vol. 50, No. 16, 2007
October 16, 2007:1604–9
1607
Integrated Analysis of the COURAGE Trial (Angina-Free Status)
Table 4
Integrated Analysis of the COURAGE Trial (Angina-Free Status)
COURAGE RR (95% CI)
Pr(PCI) >0%
Pr(PCI) >5%
Pr(PCI) >10%
Pr(PCI) >15%*
1 yr
0.89 (0.83–0.96)
1.00
0.96
0.58
0.10
3 yrs
0.92 (0.87–0.98)
0.99
0.81
0.25
0.02
5 yrs
0.98 (0.90–1.06)
0.72
0.27
0.04
0.00
*Pr(PCI) ⬎X% ⫽ probability that angina-free status with PCI ⫹ optimal medical therapy is at least x% better than with optimal medical therapy alone using a uniform prior distribution.
RR ⫽ risk ratio; other abbreviations as in Table 1.
Counterpoint. The contention that most patients already
receive medical therapy is highly suspect. While the actual
numbers are open to debate, the simple fact is that many
patients with stable angina (and an additional number of
asymptomatic patients) are undergoing PCI without having
received sufficient medical therapy. On the conservative
assumption that 1 million procedures are being performed
each year, at least 30% of them in stable patients who could
otherwise be treated medically (2), that is 300,000 procedures that might be deferred. Even if one-third of them
eventually cross over to revascularization, that is still
200,000 fewer procedures—at a saving of at least $6 billion
annually at current levels of reimbursement. Formal assessments of cost-effectiveness and quality of life are unlikely to
contravene these projections (35).
Nevertheless, the suboptimal quality of medical therapy
outside of the COURAGE trial remains a problem. Many
patients are not treated at all, and those who are do not
adhere to treatment for very long (36). But, the recommendation of unconditional coronary angiography is no solution
and might encourage unnecessary revascularizations. Bad
behavior by some cannot justify equally bad behavior by
others. The preferable solution would be better medical
treatment rather than more intervention.
The COURAGE trial itself provides the best justification
for improving the quality of medical therapy, and payers are
Figure 2
beginning to take note. Aetna (among others) is now
offering proven preventive medications such as those in the
COURAGE trial free of charge to patients with known
heart disease or diabetes (37). It is trials such as the
COURAGE trial that encourage such innovations.
Implications
In the end, the inference in the COURAGE trial is not that
OMT is better than PCI, but that an initial recommendation of PCI⫹OMT offers no important advantage over an
initial recommendation of OMT alone (38). Percutaneous
coronary intervention can be reserved for a later time with
little risk that an unfavorable event will intervene. As was
true in the CASS (Coronary Artery Surgery Study), a
wait-and-see strategy is justified.
Why will so many of us resist this rational and prudent
conclusion (13)? Some will point to the personal, professional, and political capital that is at stake, but there are
deeper reasons. In his landmark sociologic dissection of the
medical profession, Eliot Freidson identifies 5 traits that
characterize the typical clinician (39):
We believe in what we are doing. When things go right,
we take the credit.
Imputed Effect of Drug-Eluting Stents in the COURAGE Trial
Imputed effect of drug-eluting stents in the COURAGE trial by which the risk ratio (RR) for drug-eluting stents (DES) versus optimal medical therapy (OMT) was imputed
from the RR for bare-metal stents (BMS) versus OMT in the COURAGE trial multiplied by the RR for DES versus BMS from a meta-analysis of historical trials in the medical literature (22). PCI ⫽ percutaneous coronary intervention; PES ⫽ paclitaxal-eluting stent (Taxus, Boston Scientific, Natick, Massachusetts); SES ⫽ sirolimus eluting
stent (Cypher, Cordis Corp., Miami Lakes, Florida). Squares represent mean RR, and horizontal rules represent 95% confidence interval (CI).
1608
Diamond and Kaul
On the Management of Stable Coronary Disease
We prefer action to inaction. Even action with little
chance of success is preferred over no action at all.
We are pragmatic. We see apparent cause-effect relationships even in the absence of any theoretic foundation.
We are highly subjective. We depend more on “gut
feelings” than on “book knowledge.”
We emphasize uncertainty in our defense. When things
go wrong, it is not our fault. Because we deal with
individuals rather than groups, we cannot rely on
epidemiologic concepts or probabilities derived from
population statistics.
Although these traits usually serve us well, they invite
intellectual gerrymandering. Thus, when the evidence conflicts with our judgment we tend to resist it, but when the
evidence is consistent with our judgment we tend to
embrace it. As a result, if there is even a 1% chance that
some technologic advance is marginally better than the
status quo (think tissue plasminogen activator versus streptokinase or bivalirudin versus heparin), we act as if it is a
certainty and discount the downside.
The Centers for Disease Control, however, report that
coronary heart disease deaths in the U.S. fell not 1% but
more than 40% from 1980 to 2000 (40). Nearly one-half of
this drop was attributable to treatment of conventional risk
factors and only 7% to revascularization. According to the
study’s senior author, “There has been a huge amount of
money spent on angioplasty and [bypass surgery], with the
prevailing understanding that it prevents deaths, but this is
the flashy stuff and it doesn’t make a great deal of difference”
(41).
It takes COURAGE to say that.
Reprint requests and correspondence: Dr. George A. Diamond,
2408 Wild Oak Drive, Los Angeles, California 90068. E-mail:
[email protected].
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