Journal of the American College of Cardiology Vol. 50, No.

16, 2007
© 2007 by the American College of Cardiology Foundation ISSN 0735-1097/07/$32.00
Published by Elsevier Inc. 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 out-
come 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 reeval-
uate 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 the COURAGE trial versus 2.9% of 20,769 candidates in
stages: “First, it is ridiculed. Second, it is violently opposed. the MASS [Medicine, Angioplasty, or Surgery Study]-II
Third, it is accepted as being self-evident.” Kereiakes et al. trial [5]).
(2) reverse this journey in their review of the COURAGE The COURAGE trial was conceived in 1996, and at the
(Clinical Outcomes Utilizing Revascularization and Ag- time of its design in 1999, 6 trials comprising 1,872 patients
gressive Drug Evaluation) trial and its conclusion that with stable coronary disease had already been published (4).
percutaneous coronary intervention (PCI) adds little to The rate of death or MI was 7.2% for medical therapy versus
optimal medical therapy (OMT) in the management of 8.6% for PCI (20% more) over 6 to 57 months. The
stable coronary disease (3). In the present counterpoint, we COURAGE trial relied instead on a consensus that PCI
revisit each signpost and proffer a more optimistic view of would perform as well in stable coronary disease as it was
the landscape. thought to do in acute coronary syndromes (W.S. Wein-
traub, personal communication, June 29, 2007), and its
Stage 3: “it is. . .self-evident” consequent expectation of a 22% risk reduction over 3 years
(6) was indeed “unrealistic” (2). Two contemporary
Point. Kereiakes et al. (2) claim that the COURAGE trial
meta-analyses (7,8) confirm the benefit of PCI in acute
was “neither surprising nor new” compared with previous
studies (4). Given what was already known, “COURAGE coronary syndromes (Table 1), although a similar meta-
set an unrealistic goal” by enrolling a small select group of analysis (exclusive of the COURAGE trial) shows no
relatively low-risk patients and seeking to detect a large comparable benefit in stable coronary disease (Table 2). In
reduction in death or myocardial infarction (MI). In- this context, the findings in the COURAGE trial are
stead, “a noninferiority trial design may have been more indeed not “new” (2).
appropriate” (2). But there is more to the story. Table 3 updates Table 2
Counterpoint. In fact, enrollment criteria in the COUR- with the data from the COURAGE trial relative to the
AGE trial were entirely conventional. Clinical equipoise hypothesis that PCI⫹OMT improves death or MI better
and the usual desiderata of trial design necessitated exclu- than OMT in stable coronary disease, thereby circumvent-
sions at both extremes of risk (serious comorbidity and New ing any post hoc considerations of statistical power and
York Heart Association (NYHA) functional class IV angina assessing the actual observations without regard for what
at the high end versus undocumented ischemia and ⬍70% might have been observed (9). Independent of any “unreal-
stenosis at the low end), thereby assuring a homogeneous, istic” expectations, OMT is favored by a ratio of nearly 7:1.
albeit small, study population (6.4% of 35,539 candidates in Nevertheless, because the lay public is unlikely to distin-
guish between unstable and stable disease, most patients
undergoing elective PCI often do so under the belief that it
From the Division of Cardiology, Cedars-Sinai Medical Center, and the David indeed prolongs their life or prevents a heart attack. The fact
Geffen School of Medicine, University of California, Los Angeles, California.
Manuscript received August 9, 2007; revised manuscript received August 17, 2007, that most (10,11) of these procedures are performed elec-
accepted August 27, 2007. tively— often in stable patients immediately following ad
JACC Vol. 50, No. 16, 2007 Diamond and Kaul 1605
October 16, 2007:1604–9 On the Management of Stable Coronary Disease

hoc diagnostic angiography (12)— only serves to reinforce ing to the COURAGE trial), Abbreviations
this belief. At the very least, then, physicians and patients thereby making OMT the pre- and Acronyms
clearly act as if they believe PCI prevents death and MI in ferred option. But if PCI⫹OMT
DES ⴝ drug-eluting stent(s)
stable coronary disease. were adjudged noninferior to
MI ⴝ myocardial infarction
If, as Kereiakes et al. (2) claim, the principal benefit of OMT, on what basis could one
NYHA ⴝ New York Heart
PCI in stable disease lies in “the relief of symptoms and then say it should be preferred?
Association
improvement in quality of life,” why then are these proce- Does PCI make OMT safer?
OMT ⴝ optimal medical
dures being performed in asymptomatic patients (13)? And Less costly? More convenient? therapy
why are some of us so enthusiastically recommending More practical? More accessible?
PCI ⴝ percutaneous
screening tests to identify asymptomatic patients for coro- coronary intervention
nary revascularization (14 –16)? Stage 2: “it is violently
Current guidelines actually encourage such practice by opposed”
endorsing PCI as “reasonable” (Class IIa) in asymptomatic
Point. Kereiakes et al. (2) contend that PCI was not
patients with suitable anatomy, viable myocardium, and
optimally performed in the COURAGE trial. They argue
demonstrable ischemia on noninvasive testing (17) on the
that if: 1) a core laboratory had assessed the angiographic
specious assumption that silent ischemia is a surrogate for
findings; 2) more patients had been treated in non-Veterans
angina. In symptomatic patients, the guidelines properly
Affairs (VA) hospitals; 3) crossovers had been less; 4) the
restrict PCI to those “who have not been successfully treated
study had been limited to high-risk patients; 5) the defini-
by medical therapy,” saying that “the goal of treatment
should be complete, or nearly complete, elimination of tion of periprocedural MI had been more forgiving; and 6)
anginal chest pain” (18). drug-eluting stents (DES) had been used more freely—then
If so, PCI comes up short. Only 66% of PCI patients in the outcomes and conclusions would have been different.
the COURAGE trial were angina free at 1 year versus 58% Let us take up each of these points in turn.
for OMT (12% started out that way), and its statistical Counterpoint. By all accounts, the standard of perfor-
superiority lasted for only 3 years (3), after which restenosis mance in COURAGE was high. The 21% rate of “addi-
or atherosclerotic progression very likely intervened. The tional revascularization” (3) is actually less than in ARTS
probability that PCI⫹OMT improves angina-free status (Arterial Revascularization Therapies Study; 23%) and the
better than OMT by more than 10% is only 58% at 1 year, MASS-II trial (32%) over comparable follow-up (5,21), and
25% at 3 years, and 4% at 5 years (Table 4). This less than its median of 10 months indicates that about one-half these
stellar performance is arguably the most “novel” contribu- events occurred in the first year. If, as is likely, this is a
tion of the COURAGE trial. Percutaneous coronary inter- consequence of restenosis, it is less than that of bare-metal
vention performed somewhat better in the smaller stenting (22). Moreover, although only one-half of the
MASS-II trial (5,19), largely because medical therapy was patients with multivessel disease received multiple stents,
not as aggressive as in the COURAGE trial (angina-free this too is comparable to the MASS-II trial (5) and higher
status for PCI vs. medical therapy was 52% vs. 36% at 1 year than in the New York State Angioplasty Registry (23).
and 77% vs. 55% at 5 years). If these findings were to cause Finally, although bypass surgery clearly provides more
us to rethink our expectations of antianginal therapy, that complete revascularization than PCI, it does not prevent
alone would be “surprising [and] new” (2). more death or MI (5,21,24).
Should the COURAGE trial have been a noninferiority The design of the COURAGE trial specifically calls for
trial (2)? Using our 7.2% event rate (4) for the active control all angiograms being “read centrally by a core angiographic
baseline and a noninferiority margin of 1.4% (a 20% laboratory” (6). Even if it had not, it is hard to imagine how
difference), such a trial (20) requires 12,242 patients—5 this would impact angiographic or clinical outcomes as
times that in the COURAGE trial (6). But suppose there implied (2). For obvious reasons, physicians responsible for
were sufficient resources and resolve to perform this daunt- day-to-day care cannot wait for post hoc readings. But if
ing trial. There are 2 possible outcomes: either PCI⫹OMT this were necessary to the effectiveness of PCI, what would
meets criteria for noninferiority or it does not. If not, it must be the implications for the typical hospital performing these
be slightly inferior (having a hazard ratio of 1.05 accord- 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) Mehta et al. (8)

End Point OR (95% CI) p Value OR (95% CI) p Value

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.
1606 Diamond and Kaul JACC Vol. 50, No. 16, 2007
On the Management of Stable Coronary Disease October 16, 2007:1604–9

Meta-Analysis of PCI in Stable Coronary Disease

Table 2 Meta-Analysis of PCI in Stable Coronary Disease

End Point OR (95% CI) p Value

Death 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 Figure 1 Simulated Distribution of Anginal
Frequency in the COURAGE Trial
ranged from 24% to 30% over 5 to 11 years (25–27) versus
35% over 7 years in RITA (Randomized Intervention Trial Simulated anginal frequency (episodes per week) for 1,000 hypothetical
of Angina)-2 (28) and 24% over 5 years in the MASS-II 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)
trial (5). These high rates are simply a manifestation of the (32). Given ␮ ⫽ 10 and m ⫽ 3, (as reported in the COURAGE trial [3,30]),
progressive nature of the disease, and very likely represent 12.2% of patients are angina free (0 episodes per week) and 27.7% manifest
the exercise of good clinical judgment. In any event, 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
intention-to-treat analysis, by maintaining the advantages class III angina at baseline. The COURAGE investigators recently corrected the
of randomization, is unaffected by crossover (29). mean value from ␮ ⫽ 10 to ␮ ⫽ 6 (31). Because the mean of the log trans-
Kereiakes et al. (2) imagine that the skewed distribution of formed distribution depends only on the median of the untransformed distribu-
tion, this correction has little effect on the simulation. Using ␮ ⫽ 6 and m ⫽
anginal frequency in the COURAGE trial “implies. . .2 pa- 3, 16.6% are angina-free and 20.3% manifest more than daily angina.
tient 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 analysis that excluded these events did not shift the results
log normally distributed (32), a single population fully accounts in favor of PCI, with a hazard ratio of 0.90 (95% confidence
for these observations (Fig. 1). Thus, subgroup analyses reveal interval 0.73 to 1.10; p ⫽ 0.29).
no treatment differences between NYHA functional class 0 to Finally, because DES were used infrequently in the COUR-
I angina versus NYHA functional class II to III angina. AGE trial, Kereiakes et al. (2) say this too biased the outcomes
The contrary “premise” that the COURAGE trial com- against PCI. To explore this possibility, we performed a
prised a low-risk population, based solely on a cardiac putative placebo analysis (20). The resultant risk ratio for
mortality of 0.4% per year (subject to ascertainment error), PCI⫹OMT versus OMT increased nonsignificantly (Fig. 2),
is contradicted by the magnitude of comorbidity, frequency indicating that greater use of DES, if anything, would have
of inducible ischemia, and prevalence of multivessel disease. been associated with a slightly greater risk of death or MI. The
In fact, the all-cause mortality of nearly 8% is similar to that claim that DES would have improved angina-free status and
in the ARTS trial (21), and death or MI at 5 years is quality of life (albeit likely) remains conjectural.
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 Stage 1: “it is ridiculed”
elevation “no doubt, disadvantaged PCI” compared with Point. Kereiakes et al. (2) question the relevance of the
OMT (2) is unsupported by the evidence. Only 26 peripro- COURAGE trial to clinical practice, because “the vast
cedural MIs occurred using this definition, and a censored majority of Americans [already] receive medical therapy for
Integrated Trial
COURAGE Analysis
(Death
of the
or MI) their coronary artery disease.” However, they then note that
Integrated Analysis of the the quality of medical therapy in the COURAGE trial is
Table 3
COURAGE Trial (Death or MI) not achievable in the real world. Although the COURAGE
Prior OR COURAGE OR Posterior OR
trial excluded 10,000 patients without reference to coronary
(95% CI) (95% CI) (95% CI) Pr(PCI)>0%* anatomy (5,100 without ischemia and 4,900 with an inad-
1.16 (0.91–1.48) 1.05 (0.87–1.27) 1.09 (0.94–1.27) 0.13 equate ejection fraction) (3), they stipulate that “coronary
*Pr(PCI)⬎0% ⫽ probability that the frequency of the primary outcome with PCI ⫹ optimal medical
angiography . . . should not be denied to patients with stable
therapy is better than with optimal medical therapy alone, the ratio of benefit to harm being given angina pectoris,” because the “choice of therapy(s) for each
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).
individual patient must be made based on coronary ana-
Abbreviations as in Table 1. tomic suitability” (2).
JACC Vol. 50, No. 16, 2007 Diamond and Kaul 1607
October 16, 2007:1604–9 On the Management of Stable Coronary Disease

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 beginning to take note. Aetna (among others) is now
receive medical therapy is highly suspect. While the actual offering proven preventive medications such as those in the
numbers are open to debate, the simple fact is that many COURAGE trial free of charge to patients with known
patients with stable angina (and an additional number of heart disease or diabetes (37). It is trials such as the
asymptomatic patients) are undergoing PCI without having COURAGE trial that encourage such innovations.
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 Implications
otherwise be treated medically (2), that is 300,000 proce-
dures that might be deferred. Even if one-third of them In the end, the inference in the COURAGE trial is not that
eventually cross over to revascularization, that is still OMT is better than PCI, but that an initial recommenda-
200,000 fewer procedures—at a saving of at least $6 billion tion of PCI⫹OMT offers no important advantage over an
annually at current levels of reimbursement. Formal assess- initial recommendation of OMT alone (38). Percutaneous
ments of cost-effectiveness and quality of life are unlikely to coronary intervention can be reserved for a later time with
contravene these projections (35). little risk that an unfavorable event will intervene. As was
Nevertheless, the suboptimal quality of medical therapy true in the CASS (Coronary Artery Surgery Study), a
outside of the COURAGE trial remains a problem. Many wait-and-see strategy is justified.
patients are not treated at all, and those who are do not Why will so many of us resist this rational and prudent
adhere to treatment for very long (36). But, the recommen- conclusion (13)? Some will point to the personal, profes-
dation of unconditional coronary angiography is no solution sional, and political capital that is at stake, but there are
and might encourage unnecessary revascularizations. Bad deeper reasons. In his landmark sociologic dissection of the
behavior by some cannot justify equally bad behavior by medical profession, Eliot Freidson identifies 5 traits that
others. The preferable solution would be better medical characterize the typical clinician (39):
treatment rather than more intervention.
The COURAGE trial itself provides the best justification We believe in what we are doing. When things go right,
for improving the quality of medical therapy, and payers are we take the credit.

Figure 2 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 medi-
cal 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 JACC Vol. 50, No. 16, 2007
On the Management of Stable Coronary Disease October 16, 2007:1604–9

We prefer action to inaction. Even action with little 7. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of
early invasive therapy in acute coronary syndromes: a meta-analysis of
chance of success is preferred over no action at all. contemporary randomized clinical trials. J Am Coll Cardiol 2006;48:
We are pragmatic. We see apparent cause-effect relation- 1319 –25.
ships even in the absence of any theoretic foundation. 8. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive
strategies in patients with acute coronary syndromes: a collaborative
We are highly subjective. We depend more on “gut meta-analysis of randomized trials. JAMA 2005;293:2908 –17.
feelings” than on “book knowledge.” 9. Diamond GA, Kaul S. Prior convictions: Bayesian approaches to the
analysis and interpretation of clinical megatrials. J Am Coll Cardiol
We emphasize uncertainty in our defense. When things 2004;43:1929 –39.
go wrong, it is not our fault. Because we deal with 10. Anderson HV, Shaw RE, Brindis RG, et al. A contemporary
overview of percutaneous coronary interventions. The American
individuals rather than groups, we cannot rely on College of Cardiology-National Cardiovascular Data Registry
epidemiologic concepts or probabilities derived from (ACC-NCDR). J Am Coll Cardiol 2002;39:1096 –103.
population statistics. 11. Feldman DN, Gade CL, Slotwiner AJ, et al. Comparison of outcomes
of percutaneous coronary interventions in patients of three age groups
Although these traits usually serve us well, they invite (⬍60, 60 to 80, and ⬎80 years) (from the New York State Angioplasty
Registry). Am J Cardiol 2006;98:1334 –9.
intellectual gerrymandering. Thus, when the evidence con- 12. Krone RJ, Shaw RE, Klein LW, Blankenship JC, Weintraub WS. Ad
flicts with our judgment we tend to resist it, but when the hoc percutaneous coronary interventions in patients with stable coro-
evidence is consistent with our judgment we tend to nary artery disease—a study of prevalence, safety, and variation in use
embrace it. As a result, if there is even a 1% chance that from the American College of Cardiology National Cardiovascular
Data Registry (ACC-NCDR). Catheter Cardiovasc Interv 2006;68:
some technologic advance is marginally better than the 696 –703.
status quo (think tissue plasminogen activator versus strep- 13. Lin GA, Dudley RA, Redberg RF. Cardiologists’ use of percutaneous
tokinase or bivalirudin versus heparin), we act as if it is a coronary interventions for stable coronary artery disease. Arch Intern
Med 2007;167:1604 –9.
certainty and discount the downside. 14. Beller GA. Noninvasive screening for coronary atherosclerosis and
The Centers for Disease Control, however, report that silent ischemia in asymptomatic type 2 diabetic patients: is it appro-
coronary heart disease deaths in the U.S. fell not 1% but priate and cost-effective? J Am Coll Cardiol 2007;49:1918 –23.
15. Bax JJ, Bonow RO, Tschope D, Inzucchi SE, Barrett E, Global
more than 40% from 1980 to 2000 (40). Nearly one-half of Dialogue Group for the Evaluation of Cardiovascular Risk in Patients
this drop was attributable to treatment of conventional risk With Diabetes. The potential of myocardial perfusion scintigraphy for
factors and only 7% to revascularization. According to the risk stratification of asymptomatic patients with type 2 diabetes. J Am
study’s senior author, “There has been a huge amount of Coll Cardiol 2006;48:754 – 60.
16. DiCarli MF, Hachamovitch R. Should we screen for occult coronary
money spent on angioplasty and [bypass surgery], with the artery disease among asymptomatic patients with diabetes (review)?
prevailing understanding that it prevents deaths, but this is J Am Coll Cardiol 2005;45:50 –3.
the flashy stuff and it doesn’t make a great deal of difference” 17. Smith SC Jr., Feldman TE, Hirshfeld JW Jr., et al. ACC/AHA/
ACAI 2005 guideline update for percutaneous coronary interven-
(41). tion—summary article: a report of the American College of Cardiol-
It takes COURAGE to say that. ogy/American Heart Association Task Force on Practice Guidelines
(ACC/AHA/SCAI Writing Committee to Update the 2001 Guide-
lines for Percutaneous Coronary Intervention). Circulation 2006;113:
Reprint requests and correspondence: Dr. George A. Diamond, 156 –75.
2408 Wild Oak Drive, Los Angeles, California 90068. E-mail: 18. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline
gadiamond@pol.net. 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.
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