Download In Mildly Symptomatic Patients, Should an Invasive Strategy with

Controversies in
Interventional
Cardiology
In Mildly Symptomatic Patients, Should an
Invasive Strategy with Catheterization and
Revascularization Be Routinely Undertaken?
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In Mildly Symptomatic Patients, an Invasive Strategy with
Catheterization and Revascularization Should Not Be
Routinely Undertaken
David J. Maron, MD; Henry H. Ting, MD, MBA
P
an approach using patient-centered shared decision-making
(SDM) to enable clinicians and patients to discuss treatment
options and decide whether to pursue a conservative or invasive strategy, rather than a routine invasive strategy with cath
and revascularization for all such patients (Figure 1).
Eighty percent of percutaneous coronary intervention (PCI)
is performed ad hoc,1 which means that diagnostic cath and
PCI are performed at the same setting with no temporal pause
to assess alternative treatment options and patient preferences
once the coronary anatomy is known. Patient preferences and
values are paramount when alternative treatments confer equivalent clinical outcomes, as is the case in comparative effectiveness trials to date for SIHD patients with mild symptoms.
atients with mild, exertional angina and their physicians
routinely face the decision of whether to pursue a conservative strategy of guideline-directed medical therapy (GDMT)
versus an invasive strategy of diagnostic cardiac catheterization (cath) and revascularization plus GDMT. Recent randomized clinical trials with stable ischemic heart disease (SIHD)
patients comparing a conservative versus revascularization
strategy have demonstrated no difference in major clinical
events, but these trials randomized patients after performing
cath and knowing coronary anatomy.
This issue of Controversies in Interventional Cardiology
addresses the following statement: “In mildly symptomatic
patients, should an invasive strategy with catheterization and
revascularization be routinely undertaken?” The authors presenting the pro and con positions have agreed on the following assumptions: (1) the patient has been diagnosed recently
with SIHD on the basis of a stress test performed for typical symptoms; (2) the stress test did not demonstrate highrisk features to suggest significant left main disease; (3) the
diagnosis of coronary artery disease (CAD) is not in question;
(4) the symptoms are mild and do not interfere significantly
with quality of life; and (5) medical therapy has not been optimized. In this discussion, GDMT will refer to lifestyle and
pharmacological therapy for secondary prevention and for
treatment of angina. For this clinical scenario, we recommend
Review of Evidence for GDMT Versus
Revascularization+GDMT
Evidence supporting a routine invasive strategy of cath and
revascularization for patients with SIHD is outdated. In randomized controlled trials conducted in the 1970s involving
≈2600 patients with SIHD, coronary artery bypass grafting (CABG) improved survival as compared with medical
therapy in patients with high-risk anatomy, specifically left
main and 3-vessel disease.2–5 The relevance of these studies
today is speculative because they compared CABG with minimal, if any, medical therapy, and medical therapy has since
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 2 of a 2-part article.
Part 1 appears on page 107.
From the Departments of Medicine and Emergency Medicine, Vanderbilt University School of Medicine, Nashville, TN (D.J.M.); and the Knowledge
and Evaluation Research Unit, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (H.H.T.).
Correspondence to David J. Maron, MD, Vanderbilt Heart and Vascular Institute, 1215 21st Ave South, MCE 5th Floor South Tower, Nashville, TN
37232-8800. E-mail: [email protected]
(Circ Cardiovasc Interv. 2013;6:114-121.)
© 2013 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org
114
DOI: 10.1161/CIRCINTERVENTIONS.112.973438
Maron and Ting Invasive Strategy Should Not Be Routine 115
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Figure 1. Management decision point legend, illustrating common decisions faced by clinicians and
patients with stable ischemic heart disease. CABG
indicates coronary artery bypass graft; CAD, coronary artery disease; and PCI percutaneous coronary
intervention.
improved significantly. In aggregate, contemporary GDMT
can be expected to yield ≈50% relative risk reduction, reducing and potentially eclipsing any benefit from revascularization.6–9 Subsequent trials compared PCI with medical therapy
and found no reduction in death or myocardial infarction (MI)
from PCI.10
Recent Trials Comparing Revascularization
and Medical Therapy
Impact on Death or Myocardial Infarction
In the current era of GDMT, the 2 largest comparative
effectiveness trials of coronary revascularization versus
medical therapy in patients with SIHD—COURAGE (Clini­
cal Outcomes Utilizing Revascularization and Aggressive
Drug Evaluation) and BARI 2D (Bypass Angioplasty Revas­
cularization Investigation 2 Diabetes)—enrolled patients with
angiographically proven CAD with typical angina or objective
evidence of ischemia.11,12 These differed from all previous
trials in that medical therapy was comprehensive, intensive,
and applied equally to both treatment groups. COURAGE and
BARI 2D found that an invasive strategy of revascularization
(in COURAGE, PCI only) plus optimal medical therapy
(OMT) did not reduce the rate of death/MI or death,
respectively, as compared with OMT alone. The Fractional
Flow Reserve versus Angiography for Multivessel Evaluation
2 (FAME 2) trial compared fractional flow reserve–guided PCI
plus GDMT (PCI group) with GDMT alone (medical-therapy
group) in patients with stable CAD.13 The primary end point
was a composite of death, MI, or urgent revascularization.
Recruitment was halted prematurely after 888 subjects were
randomized with a mean follow-up of 7 months because of
a significant between-group difference in the primary end
point. Although fractional flow reserve–guided PCI did not
reduce the risk of death or MI, it did reduce the rate of urgent
revascularization (1.6% versus 11.1%; hazard ratio [HR],
0.13; 95% confidence interval [CI], 0.06–0.30; P<0.001).
Impact on Quality of Life
The Coronary Artery Surgery Study demonstrated that
CABG was superior to medical therapy for long-term
quality of life.14 At 1 and 5 years after entry, the frequency of angina-free patients was 66% and 63% in the
surgical group and 30% and 38% in the medical group.
In COURAGE, patients with angina at baseline had an
incremental benefit from PCI for 6 to 24 months (Figure
2A); patients with more severe angina had a greater benefit from PCI.15 By 3 years the frequency of angina-free
patients was 59% in the PCI+OMT group and 56% in the
OMT group (P=0.30). There was no significant difference
between treatment groups in mean quality of life score
after 12 months for the entire COURAGE cohort (Figure 2B). Among patients with mild-to-moderate angina
at baseline, there was no significant difference between
treatment groups in quality of life after 6 months (Figure 2C). In BARI 2D, patients in the CABG stratum randomized to revascularization had a higher rate of freedom
from angina throughout the 5-year follow-up compared
with patients randomized to medical therapy. The quality of life benefit from PCI in BARI 2D was less durable;
freedom from angina was significantly higher in the PCI
group compared with the medical therapy group only in
the first year of follow-up.16
116 Circ Cardiovasc Interv February 2013
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coronary anatomy is known. No adequately powered strategy trials have randomized patients before cath, highlighting
the lack of evidence to support a strategy of GDMT without
knowledge of coronary anatomy, even among SIHD patients
with mild symptoms. However, there is also no evidence from
randomized controlled trials that performing cath and revascularization in patients with SIHD reduces major cardiovascular
events. Another limitation is that the majority of PCI procedures performed in COURAGE and BARI 2D used bare metal
stents because drug-eluting stents had not been routinely available. Yet current evidence does not demonstrate that drugeluting stents reduce death or MI compared with bare metal
stents.10 Furthermore, fractional flow reserve–guided PCI was
not performed in COURAGE or BARI 2D. Lastly, COURAGE and BARI 2D had low enrolled-to-screened patient
ratios, calling into question their generalizability. However, a
low enrolled-to-screened ratio was also observed for the BARI
(Bypass Angioplasty Revascularization Investigation) trial,
a landmark study that compared CABG with PCI in SIHD
patients with multivessel CAD and helped to justify PCI as a
comparable alternative to CABG.17
High-Risk Subgroups That Might Benefit
From Routine Revascularization in the
GDMT Era
It is unclear whether the lack of superiority of PCI compared
with contemporary GDMT to reduce adverse cardiovascular
events in patients with SIHD is attributable to improvements
in medical therapy, less complete revascularization with PCI
as compared with CABG, patient selection (ie, high-risk
patients were not enrolled), or other unknown reasons. If there
is a benefit from revascularization in SIHD compared with
GDMT alone, it should be most evident among the highest
risk patients.
High-Risk Anatomic Features
Figure 2. A, Freedom from angina over time as assessed with
the angina-frequency scale of the Seattle Angina Questionnaire,
according to treatment group (COURAGE trial). B, Mean quality of
life score over time for entire COURAGE trial population. *P<0.01
for the difference between treatment groups. C, Percentage of
patients with mild-to-moderate angina and clinically significant
increase in quality of life score over time (COURAGE trial). *P<0.05
for the difference between treatment groups. Square denotes
PCI+OMT; circle, OMT. OMT indicates optimal medical therapy;
and PCI, percutaneous coronary intervention. Adapted with permission from Weintraub et al.15
Limitations of Previous Trials
All patients who participated in COURAGE and BARI 2D
underwent cath to define coronary anatomy before randomization. Strict interpretation of these and all previous SIHD
strategy trials is that the results apply only to patients when
COURAGE and BARI 2D included modest numbers of
patients with high-risk anatomic features, and secondary
analyses were performed to elucidate the role of revascularization in such patients. In COURAGE, there was no significant benefit from PCI in patients with 3-vessel CAD and
EF <50%, but the sample size was small (n=126, P=0.26).18
Among 406 patients with EF<50% (18% of the sample), the
hazard ratio for PCI+OMT versus OMT was 1.14 (95% CI
0.77–1.70).11 There was no anatomic feature that defined a
subset that benefited from PCI, including proximal left anterior descending artery stenosis which was present in 25% of
patients.19 In contrast, among patients in BARI 2D for whom
CABG was determined to be the most appropriate method of
revascularization, the 5-year rate of the secondary end point
(death, MI, or stroke) was lower (driven by MI events) in the
subset assigned to CABG (n=378) versus those assigned to
GDMT (n=385, 22.4% versus 30.5% [79 versus 115 events],
P=0.01).12 This was a post hoc analysis of a secondary end
point in the CABG stratum.
Maron and Ting Invasive Strategy Should Not Be Routine 117
High-Risk Clinical Features
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COURAGE investigators performed a post hoc analysis of
high-risk patients defined as onset of Canadian Cardiovascular
Society (CCS) Class III angina within 2 months or stabilized
acute coronary syndrome within 2 weeks of enrollment. They
found an initial strategy of OMT alone for these patients did
not result in increased death or MI at 4.6 years or worse angina
at 1 year, but it was associated with a high rate of crossover
to PCI in the first year (30%), whereas the overall crossover
rate was 16%.20 COURAGE patients with mild angina had
fewer events than more symptomatic patients and experienced
no reduction in events from routine PCI. This suggests there
should be equipoise between GDMT versus PCI+GDMT in
patients with mild angina.
High-Risk Ischemia
Although severity of ischemia is correlated with risk of death,
it is unknown whether revascularization to reduce ischemia
improves prognosis. It is not known whether the increased
risk of death from ischemia is attributable to inherent adverse
effects of ischemia (eg, arrhythmias), occlusion of severe
stenoses, or whether severe ischemia is simply a marker of a
larger number of nonflow-limiting vulnerable plaques prone
to rupture.21–23 Observational data suggest that revascularization is associated with lower cardiac mortality in patients with
>10% ischemia.24,25 Using paired core laboratory-measured
myocardial perfusion imaging studies, the COURAGE serial
nuclear substudy found that PCI+OMT was superior to OMT
alone in reducing ischemia.26 For both treatment groups combined, ischemia reduction was associated with a lower rate of
death or MI for 3.6 years: 16% for those with significant ischemia reduction compared with 34% for those without (adjusted
multivariate P=0.08). A subsequent COURAGE analysis of
outcomes by treatment strategy in 468 patients with moderate
or severe ischemia on baseline myocardial perfusion imaging
showed no reduction in death or MI from PCI+OMT for 4.6
years (PCI+OMT 22% versus OMT 19%, HR 1.08, 95% CI
0.71,1.65).27 Therefore, it is not known whether PCI+OMT
reduces death or MI as compared with OMT even among the
subset of patients with moderate to severe ischemia.
Practice Guidelines and Appropriate Use
Criteria for Managing Patients With SIHD
The purpose of an invasive strategy for patients with SIDH
is to improve survival or relieve symptoms. The American
College of Cardiology Foundation (ACCF)/American Heart
Association (AHA) 2011 guidelines for revascularization
provide three Class I recommendations for CABG in SIHD
to improve survival (all based on the outdated CABG
versus medical therapy studies): unprotected left main,
3-vessel disease with or without proximal left anterior des­
cending artery disease, and 2-vessel disease with pro­ximal
left anterior descending artery disease.28,29 There is one
Class I recommendation for PCI or CABG to relieve sym­
ptoms: patients with ≥1 significant stenoses amenable to
revascularization and unacceptable angina despite guidelinedirected medical therapy. SIHD guidelines recommend cath
when (1) noninvasive testing suggests high-risk coronary
lesion(s), or (2) unacceptable symptoms persist despite an
adequate trial of guideline-directed medical therapy, and (3)
revascularization is consistent with patient preferences.30 This
recommendation is not based on clinical trial evidence.
Appropriate use criteria were developed by ACCF in collaboration with other societies to provide practice standards in
use of cath and PCI, and to mitigate over- and underuse. The
2012 appropriate use criteria for cath indicate that it is appropriate to perform cath when a patient with suspected CAD has
symptoms associated with intermediate- or high-risk features
on noninvasive testing, or high-risk findings on noninvasive
testing regardless of symptom severity.31 The 2012 appropriate use criteria for revascularization prioritized the following
factors to determine the appropriateness of revascularization:
(1) clinical presentation (acute coronary syndrome or stable
angina); (2) severity of angina (asymptomatic, CCS Class I,
II, III, or IV); (3) severity of ischemia on noninvasive testing;
(4) intensity of medical therapy; and (5) extent of anatomic
disease (1-, 2-, 3-vessel disease, with or without proximal
left anterior descending artery or left main coronary disease).
For patients with CCS Class I or II angina, Figure 3 indicates
whether revascularization is appropriate (A), inappropriate (I),
or uncertain (U) as modified by severity of ischemia, intensity
of medical therapy, and extent of anatomic disease.32 Maximal
medical therapy is defined as the use of ≥2 classes of agents
to reduce angina. Low-risk stress test findings are associated
with cardiac mortality <1% per year; intermediate-risk with
1% to 3% per year; and high-risk with >3% per year. Figure
3 shows that revascularization is appropriate for all patients
with mild angina who are on maximal medical therapy and
have a high-risk stress test, whereas revascularization is either
inappropriate or uncertain (as modified by extent of anatomic
disease) for patients with mild angina who are not on maximal
medical therapy and have a low-risk stress test.
Current Practice
Registry data show that among patients with suspected CAD
who have moderately or severely abnormal noninvasive tests,
38% to 61% are not referred to cath.33 The appropriate cath
referral rate after an abnormal stress test is unknown. An
adequate trial of guideline-directed medical therapy should be
undertaken before revascularization is contemplated.30 Unfortunately, among patients with the most abnormal noninvasive
tests, 24% do not receive aspirin and 23% do not receive a
lipid-lowering agent at 90 days after the index test,33 as recommended by guidelines.30
Revascularization rates vary widely and are related closely to
rates of cath, varying by region from 16 to 77 per 1000 among
Medicare beneficiaries.34 The relationship between cath and
PCI is strong (R2=0.78), whereas the association with CABG
is modest (R2=0.41). The tighter relationship between cath and
PCI may be explained by the common practice of ad hoc PCI,1
118 Circ Cardiovasc Interv February 2013
Even before sedation, however, there is evidence that
patients are not aware of the benefits and harms of alternative
treatments for SIHD. In a survey of 153 patients with SIHD
undergoing elective cath with possible PCI, 88% believed that
PCI would reduce their risk for MI and 82% believed that PCI
would reduce their risk for death.42 In contrast, patients’ cardiologists (n=27) believed that PCI would prevent MI in 17% of
the cases and reduce mortality in 15% of the cases. This discordance highlights the need to improve patients’ knowledge
of the expected benefit of alternative treatments as well as
enhancing patients’ involvement in making decisions aligned
with their preferences, values, and goals.
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Shared Decision-Making
Figure 3. Appropriate use ratings by Canadian Cardiovascular
Society (CCS) Class I or II angina. A indicates appropriate; CTO,
chronic total occlusion; I, inappropriate; Int., intermediate; Max,
maximum; Med., medical; min, minimal; prox. LAD, proximal left
anterior descending artery; Rx, treatment; U, uncertain; and vz.,
vessel.
which is based more on visual estimation of stenosis and technical feasibility than on evidence that revascularization reduces
events.34–37 The diagnostic-therapeutic cascade34 may explain
why GDMT is not maximized before PCI, even after publication of COURAGE.38 If a routine cath is performed before optimizing medical therapy, ad hoc PCI is likely to be performed,
potentially distracting attention away from medications with
proven benefit to decrease events. On the other hand, the diagnostic cascade assumes noninvasive testing accurately identifies obstructive CAD when 59% of the time it does not.39
There are multiple forces that favor performing ad hoc
PCI when a significant stenosis is detected at diagnostic
cath.36,37,40,41 They include referring physician and patient
expectations, incremental burden and costs to the patient and
practice to schedule a second procedure, ability to improve
ischemia and angina burden quickly, avoidance of vascular
access and bleeding complications, avoidance of regret from
a perceived error of omission (ie, regretting inaction if the
patient has a bad outcome), fear of malpractice litigation, and
reimbursement policies. Unfortunately, ad hoc PCI involves
proceeding directly from a diagnostic test (cath) to a therapeutic procedure (PCI) when the patient is sedated and has
not been fully informed about the potential risks, benefits, and
alternative treatment options.
Patient-centered SDM is an approach to improve patient
knowledge and involvement in medical decisions, particularly
when alternative treatments have comparable clinical
outcomes. SDM is not appropriate for decisions when benefits
clearly outweigh risks (such as resuscitation for cardiac arrest)
and technical decisions (such as PCI coronary guide catheter
selection). In the SDM model, patient involvement begins
with the development of a partnership between clinician and
patient, and includes participation in information exchange,
deliberation, and decision-taking.43 Decision aids are tools
to facilitate information exchange, as well as integration and
understanding of the information.44 A systematic review of 55
randomized clinical trials involving decision aids found that
compared with usual care, the use of decision aids is associated
with greater patient knowledge, more realistic expectations,
lower decisional conflict, and increased proportion of patients
actively engaged in decision-making.45
For patients with SIHD, SDM aims to help clinicians and
patients choose between an initial strategy of GDMT alone
versus GDMT+cath±revascularization (Figure 1).46 An older
randomized trial compared SDM with an interactive video
presenting benefits and risks of medical therapy, PCI, and
CABG versus usual care. SDM significantly improved patient
knowledge, and fewer patients in the SDM arm decided to
have revascularization (58%) as compared with usual care
(75%).47 Ting and colleagues are conducting a randomized
trial using a decision aid for patients with SIHD considering
GDMT versus PCI+GDMT.48 (Figure 4 shows the personalized decision aid for patients with CCS Class I/II angina).
Evidence Gap in Support of an Invasive
Practice Paradigm for SIHD: Ongoing
Research
Results from COURAGE and BARI 2D underscore the need to
define the appropriate role of revascularization for SIHD in the
era of GDMT. Because these trials showed no reduction in their
primary end points from revascularization, which patients with
SIHD, if any, benefit from an invasive strategy in terms of clinical events? This is the primary question asked by the National
Heart, Lung, and Blood Institute–sponsored ISCHEMIA
(International Study of Comparative Health Effectiveness
Maron and Ting Invasive Strategy Should Not Be Routine 119
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adverse events in SIHD when added to GDMT but does
improve symptoms more rapidly than GDMT alone (the benefit from PCI is transient, the benefit from CABG more durable). Based on this evidence, we do not recommend a routine
invasive strategy in patients with mild symptoms. Rather, we
recommend routine patient-centered SDM to enable the clinician and patient to decide on a treatment that is most aligned
with the patient’s preferences, values, and goals—be it conservative or invasive.
All patients in randomized controlled strategy trials to date
underwent cath before randomization, leading to possible
selection bias by excluding higher-risk patients after knowing
the coronary anatomy. This leaves cardiologists with a knowledge gap regarding the need to perform cath in patients with
SIHD, recognizing that once cath is performed, ad hoc PCI
is likely to follow. The ISCHEMIA trial results are expected
to fill this gap. Meanwhile, in the absence of evidence that
an invasive strategy is superior to a conservative strategy,
informed and knowledgeable clinician–patient dyads should
jointly choose an initial treatment strategy.
Figure 4. Decision aid for patients with Canadian Cardiovascular
Society (CCS) Class I or II angina. Decision aid tool to help clinicians and patients with CCS Class I or II angina discuss alternative
treatment choices (PCI+OMT vs OMT) and their expected benefits.
OMT indicates optimal medical therapy; and PCI, percutaneous
coronary intervention. Reprinted with permission of Mayo Foundation for Medical Education and Research. All rights reserved.
Sources of Funding
Dr Maron receives support from National Heart, Lung, and Blood
Institute grant 1R01-HL105907-01 (ISCHEMIA Trial).
Disclosures
Dr Maron is a shareholder of Cardiovascular Care Group, Inc.
with Medical and Invasive Approaches) trial (ClinicalTrials.
gov Identifier NCT01471522), which will determine whether
an invasive strategy of routine cath and revascularization plus
GDMT in SIHD patients with at least moderate ischemia
reduces cardiovascular death or MI compared with a conservative strategy of GDMT alone, with cath reserved for patients
who fail GDMT. In contrast with COURAGE and BARI 2D,
randomization of patients will occur before cath, avoiding
potential selection bias that would exclude higher-risk patients
by knowing their coronary anatomy. The feasibility of patient
recruitment is supported by multiple imaging registries showing the rate of referral to cath for patients with at least moderate ischemia is only 35% to 65%.33,49,50 In further support that
sufficient equipoise exists to study the initial management of
patients with SIHD, a survey of 500 cardiologists found that
80% were willing to enroll SIHD patients with at least moderate ischemia into a trial with an initial noninvasive strategy
arm.51 The ACCF/AHA CABG and PCI guideline writing
committees endorse the performance of the ISCHEMIA trial,
“which will provide contemporary data on the optimal management strategy (medical therapy or revascularization with
CABG or PCI) of patients with SIHD.”29
Conclusion
In patients with mild angina (CCS Class I/II) and no high-risk
findings on stress testing, GDMT should be initiated routinely
for secondary prevention and symptom control. The weight
of evidence indicates that revascularization does not reduce
References
1. Hannan EL, Samadashvili Z, Walford G, Holmes DR, Jacobs A, Sharma
S, Katz S, King SB, 3rd. Predictors and outcomes of ad hoc versus non-ad
hoc percutaneous coronary interventions. J AM COLL CARDIOL. Cardiovasc Interv. 2009;2:350–356.
2. Coronary Artery Surgery Study (CASS): A randomized trial of coronary
artery bypass surgery. Survival data. Circulation. 1983;68:939–950.
3. Eleven-year survival in the veterans administration randomized trial of
coronary bypass surgery for stable angina. The Veterans Administration
coronary artery bypass surgery cooperative study group. N Engl J Med.
1984;311:1333–1339.
4. Varnauskas E. Twelve-year follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med. 1988;319:332–337.
5. Yusuf S, Zucker D, Peduzzi P, Fisher LD, Takaro T, Kennedy JW, Davis
K, Killip T, Passamani E, Norris R. Effect of coronary artery bypass graft
surgery on survival: overview of 10-year results from randomised trials by
the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet.
1994;344:563–570.
6. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy
AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–1592.
7. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2
diabetes. N Engl J Med. 2003;348:383–393.
8. Haskell WL, Alderman EL, Fair JM, Maron DJ, Mackey SF, Superko HR,
Williams PT, Johnstone IM, Champagne MA, Krauss RM. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical
cardiac events in men and women with coronary artery disease. The Stanford
Coronary Risk Intervention Project (SCRIP). Circulation. 1994;89:975–990.
9. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N.
Mediterranean diet, traditional risk factors, and the rate of cardiovascular
complications after myocardial infarction: final report of the Lyon Diet
Heart Study. Circulation. 1999;99:779–785.
120 Circ Cardiovasc Interv February 2013
Downloaded from http://circinterventions.ahajournals.org/ by guest on May 10, 2017
10. Trikalinos TA, Alsheikh-Ali AA, Tatsioni A, Nallamothu BK, Kent DM.
Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis. Lancet.
2009;373:911–918.
11. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ,
Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L,
Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates
ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE
Trial Research Group. Optimal medical therapy with or without PCI for
stable coronary disease. N Engl J Med. 2007;356:1503–1516.
12. Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor
JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA,
Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial
of therapies for type 2 diabetes and coronary artery disease. N Engl J Med.
2009;360:2503–2515.
13. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic
N, Möbius-Winkler S, Mobius-Winckler S, Rioufol G, Witt N, Kala P,
MacCarthy P, Engström T, Oldroyd KG, Mavromatis K, Manoharan G,
Verlee P, Frobert O, Curzen N, Johnson JB, Jüni P, Fearon WF; FAME
2 Trial Investigators. Fractional flow reserve-guided PCI versus medical
therapy in stable coronary disease. N Engl J Med. 2012;367:991–1001.
14. Rogers WJ, Coggin CJ, Gersh BJ, Fisher LD, Myers WO, Oberman A,
Sheffield LT. 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;82:1647–1658.
15. Weintraub WS, Spertus JA, Kolm P, Maron DJ, Zhang Z, Jurkovitz C, Zhang
W, Hartigan PM, Lewis C, Veledar E, Bowen J, Dunbar SB, Deaton C,
Kaufman S, O’Rourke RA, Goeree R, Barnett PG, Teo KK, Boden WE, Mancini GB; COURAGE Trial Research Group. Effect of PCI on quality of life
in patients with stable coronary disease. N Engl J Med. 2008;359:677–687.
16. Dagenais GR, Lu J, Faxon DP, Kent K, Lago RM, Lezama C, Hueb W,
Weiss M, Slater J, Frye RL; Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. Effects of optimal medical
treatment with or without coronary revascularization on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and
stable ischemic heart disease. Circulation. 2011;123:1492–1500.
17. Comparison of coronary bypass surgery with angioplasty in patients with
multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) investigators. N Engl J Med. 1996;335:217–225.
18. Mancini GBJ, Hartigan PM, Maron DJ, Shaw L, Berman D, Chaitman
B, Bates ER, Kostuk W, Knudtson M, Dada M, Teo KK, O’Rourke RA,
WE. B. Relation of angiographic patterns and ejection fraction to clinical
outcomes in the COURAGE trial. J Am Coll Cardiol. 2008;51:A244.
19. Mancini GB, Bates ER, Maron DJ, Hartigan P, Dada M, Gosselin G, Kostuk W, Sedlis SP, Shaw LJ, Berman DS, Berger PB, Spertus J, Mavromatis K, Knudtson M, Chaitman BR, O’Rourke RA, Weintraub WS, Teo K,
Boden WE; COURAGE Trial Investigators and Coordinators. Quantitative
results of baseline angiography and percutaneous coronary intervention in
the COURAGE trial. Circ Cardiovasc Qual Outcomes. 2009;2:320–327.
20. Maron DJ, Spertus JA, Mancini GB, Hartigan PM, Sedlis SP, Bates ER,
Kostuk WJ, Dada M, Berman DS, Shaw LJ, Chaitman BR, Teo KK,
O’Rourke RA, Weintraub WS, Boden WE; COURAGE Trial Research
Group. Impact of an initial strategy of medical therapy without percutaneous coronary intervention in high-risk patients from the Clinical
Outcomes Utilizing Revascularization and Aggressive DruG Evaluation
(COURAGE) trial. Am J Cardiol. 2009;104:1055–1062.
21. Fuster V, Badimon J, Chesebro JH, Fallon JT. Plaque rupture, thrombosis,
and therapeutic implications. Haemostasis. 1996;26 suppl 4:269–284.
22. Shah PK. Mechanisms of plaque vulnerability and rupture. J Am Coll Cardiol. 2003;41(4 suppl S):15S–22S.
23. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable
plaque. J Am Coll Cardiol. 2006;47(8 suppl):C13–C18.
24. Hachamovitch R, Kang X, Amanullah AM, Abidov A, Hayes SW, Friedman JD, Cohen I, Thomson LE, Germano G, Berman DS. Prognostic
implications of myocardial perfusion single-photon emission computed
tomography in the elderly. Circulation. 2009;120:2197–2206.
25. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization
compared with medical therapy in patients with no prior coronary artery
disease undergoing stress myocardial perfusion single photon emission
computed tomography. Circulation. 2003;107:2900–2907.
26. Shaw LJ, Berman DS, Maron DJ, Mancini GB, Hayes SW, Hartigan PM,
Weintraub WS, O’Rourke RA, Dada M, Spertus JA, Chaitman BR, Friedman J, Slomka P, Heller GV, Germano G, Gosselin G, Berger P, Kostuk
WJ, Schwartz RG, Knudtson M, Veledar E, Bates ER, McCallister B, Teo
KK, Boden WE; COURAGE Investigators. Optimal medical therapy with
or without percutaneous coronary intervention to reduce ischemic burden:
results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117:1283–1291.
27. Shaw LJ, Weintraub WS, Maron DJ, Hartigan PM, Hachamovitch R, Min
JK, Dada M, Mancini GB, Hayes SW, O’Rourke RA, Spertus JA, Kostuk W, Gosselin G, Chaitman BR, Knudtson M, Friedman J, Slomka P,
Germano G, Bates ER, Teo KK, Boden WE, Berman DS. Baseline stress
myocardial perfusion imaging results and outcomes in patients with stable
ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention. Am Heart J. 2012;164:243–250.
28. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG,
Cigarroa JE, Disesa VJ, Hiratzka LF, Hutter AM, Jr, Jessen ME, Keeley
EC, Lahey SJ, Lange RA, London MJ, Mack MJ, Patel MR, Puskas JD,
Sabik JF, Selnes O, Shahian DM, Trost JC, Winniford MD. 2011 ACCF/
AHA Guideline for Coronary Artery Bypass Graft Surgery: a report of the
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation. 2011;124:e652–e735.
29. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B,
Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange
RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting
HH; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular
Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for
Percutaneous Coronary Intervention. A report of the American College
of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines and the Society for Cardiovascular Angiography and
Interventions. J Am Coll Cardiol. 2011;58:e44–122.
30. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas
PS, Foody JM, Gerber TC, Hinderliter AL, King SB, 3rd, Kligfield PD,
Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger
MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR Jr, Smith
SC Jr, Spertus JA, Williams SV, Anderson JL. 2012 ACCF/AHA/ACP/
AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of
Patients With Stable Ischemic Heart Disease: A Report of the American
College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines, and the American College of Physicians, American
Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions,
and Society of Thoracic Surgeons. Circulation. 2012;126:e354–e471.
31. Patel MR, Bailey SR, Bonow RO, Chambers CE, Chan PS, Dehmer GJ,
Kirtane AJ, Wann LS, Ward RP. ACCF/SCAI/AATS/AHA/ASE/ASNC/
HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for
diagnostic catheterization: a report of the American College of Cardiology
Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, American Association for Thoracic
Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society
of America, Heart Rhythm Society, Society of Critical Care Medicine,
Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll
Cardiol. 2012;59:1995–2027.
32. Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. ACCF/SCAI/
STS/AATS/AHA/ASNC/HFSA/SCCT 2012 Appropriate use criteria for
coronary revascularization focused update: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic
Surgeons, American Association for Thoracic Surgery, American Heart Association, American Society of Nuclear Cardiology, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2012;59:857–881.
33. Hachamovitch R, Nutter B, Hlatky MA, Shaw LJ, Ridner ML, Dorbala
S, Beanlands RS, Chow BJ, Branscomb E, Chareonthaitawee P, Weigold WG, Voros S, Abbara S, Yasuda T, Jacobs JE, Lesser J, Berman DS,
Thomson LE, Raman S, Heller GV, Schussheim A, Brunken R, Williams
KA, Farkas S, Delbeke D, Schoepf UJ, Reichek N, Rabinowitz S, Sigman
SR, Patterson R, Corn CR, White R, Kazerooni E, Corbett J, Bokhari S,
Maron and Ting Invasive Strategy Should Not Be Routine 121
Downloaded from http://circinterventions.ahajournals.org/ by guest on May 10, 2017
Machac J, Guarneri E, Borges-Neto S, Millstine JW, Caldwell J, Arrighi
J, Hoffmann U, Budoff M, Lima J, Johnson JR, Johnson B, Gaber M,
Williams JA, Foster C, Hainer J, Di Carli MF; SPARC Investigators. Patient management after noninvasive cardiac imaging results from SPARC
(Study of myocardial perfusion and coronary anatomy imaging roles in
coronary artery disease). J Am Coll Cardiol. 2012;59:462–474.
34. Lucas FL, Siewers AE, Malenka DJ, Wennberg DE. Diagnostic-therapeutic cascade revisited: coronary angiography, coronary artery bypass graft
surgery, and percutaneous coronary intervention in the modern era. Circulation. 2008;118:2797–2802.
35. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The
dissociation between clinical and angiographic findings in ischemic heart
disease. Circulation. 1995;92:2333–2342.
36. Lin GA, Dudley RA, Redberg RF. Cardiologists’ use of percutaneous coronary interventions for stable coronary artery disease. Arch Intern Med.
2007;167:1604–1609.
37. Holmboe ES, Fiellin DA, Cusanelli E, Remetz M, Krumholz HM. Perceptions of benefit and risk of patients undergoing first-time elective percutaneous coronary revascularization. J Gen Intern Med. 2000;15:632–637.
38. Borden WB, Redberg RF, Mushlin AI, Dai D, Kaltenbach LA, Spertus JA.
Patterns and intensity of medical therapy in patients undergoing percutaneous coronary intervention. JAMA. 2011;305:1882–1889.
39. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV,
Brindis RG, Douglas PS. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;362:886–895.
40. Lin GA, Dudley RA, Redberg RF. Why physicians favor use of percutaneous coronary intervention to medical therapy: a focus group study. J Gen
Intern Med. 2008;23:1458–1463.
41. Lee J, Chuu K, Spertus J, O’Keefe J. Abstract 6224: Widespread patient
misconceptions regarding the benefits of elective percutaneous corornary
intervention. Circulation. 2008;118:S 1161.
42. Rothberg MB, Sivalingam SK, Ashraf J, Visintainer P, Joelson J, Kleppel
R, Vallurupalli N, Schweiger MJ. Patients’ and cardiologists’ perceptions
of the benefits of percutaneous coronary intervention for stable coronary
disease. Ann Intern Med. 2010;153:307–313.
43. Charles C, Gafni A, Whelan T. Decision-making in the physician-patient
encounter: revisiting the shared treatment decision-making model. Soc Sci
Med. 1999;49:651–661.
44.Coylewright M, Shepel K, Leblanc A, Pencille L, Hess E, Shah N,
Montori VM, Ting HH. Shared Decision Making in Patients with Stable
Coronary Artery Disease: PCI Choice. PLoS ONE. 2012;7:e49827.
45. O’Connor AM, Stacey D, Entwistle V, Llewellyn-Thomas H, Rovner D,
Holmes-Rovner M, Tait V, Tetroe J, Fiset V, Barry M, Jones J. Decision
aids for people facing health treatment or screening decisions. Cochrane
Database Syst Rev. 2003:CD001431.
46. Coylewright M, Montori V, Ting HH. Patient-centered shared decisionmaking: a public imperative. Am J Med. 2012;125:545–547.
47. Morgan MW, Deber RB, Llewellyn-Thomas HA, Gladstone P, Cusimano
RJ, O’Rourke K, Tomlinson G, Detsky AS. Randomized, controlled trial
of an interactive videodisc decision aid for patients with ischemic heart
disease. J Gen Intern Med. 2000;15:685–693.
48. Coylewright M, Shepel K, Leblanc A, Pencille L, Hess E, Shah N, Montori VM, Ting HH. Shared decision making in patients with stable coronary artery disease: PCI choice. PLoS One. 2012;7:e49827. doi:10.1371/
journal.pone.0049827.
49. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Kang X, Germano
G, Berman DS. Is there a referral bias against catheterization of patients
with reduced left ventricular ejection fraction? Influence of ejection fraction and inducible ischemia on post-single-photon emission computed
tomography management of patients without a history of coronary artery
disease. J Am Coll Cardiol. 2003;42:1286–1294.
50. Thomas GS, Miyamoto MI, Morello AP, 3rd, Majmundar H, Thomas JJ,
Sampson CH, Hachamovitch R, Shaw LJ. Technetium 99m sestamibi
myocardial perfusion imaging predicts clinical outcome in the community
outpatient setting. The Nuclear Utility in the Community (NUC) Study. J
Am Coll Cardiol. 2004;43:213–223.
51. Maron DJ, Stone GW, Berman DS, Mancini GB, Scott TA, Byrne DW,
Harrell FE Jr, Shaw LJ, Hachamovitch R, Boden WE, Weintraub WS,
­ anagement
Spertus JA. Is cardiac catheterization necessary before initial m
of patients with stable ischemic heart disease? Results from a Web-based
survey of cardiologists. Am Heart J. 2011;162:1034–1043.e13.
Key Words: angina, stable ◼ cardiac catheterization ◼ chronic ischemic
heart disease ◼ percutaneous coronary intervention
Response to Maron and Ting
Dean J. Kereiakes, MD; Gregg W. Stone, MD
Although shared decision-making between patients and physicians is essential, relying on studies such as COURAGE in
which substantial ischemia was uncommon, mortality was low, and contemporary technologies weren’t used under-estimates the potential benefits of modern revascularization. In a recent study from Ontario, Canada, adjusted 3-year rates of
death or ACS were 64% and 75% higher if revascularization was not performed in patients with Appropriate or Uncertain
AUC, respectively, emphasizing the perils of under-treatment. Moreover, the adjusted hazard ratio for Inappropriate AUC
category was 0.99, emphasizing lack of harm with PCI.
Best-in-class DES are associated with lower rates of stent thrombosis, MI, recurrent ischemia, unplanned revascularization and improved quality of life. By the time large-scale studies such as COURAGE and BARI 2D are completed, the
therapies tested are often out of date. The FAME-2 study demonstrated a 58% reduction in death and spontaneous MI with
PCI compared to medical therapy alone in hemodynamically significant lesions. Even when including peri-procedural MIs
(which have little or no prognostic significance), the hazard ratio for death and MI was 0.61 favoring PCI, a benefit not reaching statistical significance (P=0.22) as the trial was stopped early given the benefit of PCI for preventing unplanned urgent
revascularization.
Drs. Maron and Ting state that “GDMT can be expected to yield ~50% relative risk reduction, reducing and potentially
eclipsing any benefit from revascularization.” The benefits of GDMT apply to patients undergoing PCI as well. PCI and
GDMT are complementary in that PCI relieves ischemia whereas GDMT may not, as seen in the COURAGE nuclear
substudy. Conversely, GDMT prevents progression of atherosclerosis and vulnerable plaque rupture from lesions which
are mostly non-ischemia-producing. Thus, pending results of the ISCHEMIA trial, revascularization is appropriate in most
patients with mild symptoms and at least moderate ischemia.
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In Mildly Symptomatic Patients, Should an Invasive Strategy with Catheterization and
Revascularization Be Routinely Undertaken?: In Mildly Symptomatic Patients, an
Invasive Strategy with Catheterization and Revascularization Should Not Be Routinely
Undertaken
David J. Maron and Henry H. Ting
Circ Cardiovasc Interv. 2013;6:114-121
doi: 10.1161/CIRCINTERVENTIONS.112.973438
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