Anda di halaman 1dari 21

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO.

18, 2014
2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION AND ISSN 0735-1097/$36.00
THE AMERICAN HEART ASSOCIATION, INC. http://dx.doi.org/10.1016/j.jacc.2014.07.017
PUBLISHED BY ELSEVIER INC.

FOCUSED GUIDELINE UPDATE

2014 ACC/AHA/AATS/PCNA/SCAI/STS
Focused Update of the Guideline for the
Diagnosis and Management of Patients
With Stable Ischemic Heart Disease
A Report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

Writing Group Stephan D. Fihn, MD, MPH, Chairy Srihari S. Naidu, MD, FACC, FAHA, FSCAI{
Members* James C. Blankenship, MD, MHCM, MACC, FAHA, E. Magnus Ohman, MD, FACC*#
Vice Chair*y Peter K. Smith, MD, FACC**

Karen P. Alexander, MD, FACC, FAHA*y


*Writing group members are required to recuse themselves from voting on
John A. Bittl, MD, FACCy
sections to which their specic relationships with industry and other
John G. Byrne, MD, FACCz entities may apply; see Appendix 1 for recusal information.
Barbara J. Fletcher, RN, MN, FAHAx yACC/AHA Representative. zAmerican Association for Thoracic Surgery
Gregg C. Fonarow, MD, FACC, FAHA*k Representative. xPreventive Cardiovascular Nurses Association
Representative. kACC/AHA Task Force on Performance Measures Liaison.
Richard A. Lange, MD, FACC, FAHAy
{Society for Cardiovascular Angiography and Interventions Representative.
Glenn N. Levine, MD, FACC, FAHAy #ACC/AHA Task Force on Practice Guidelines Liaison. **Society of
Thomas M. Maddox, MD, MSC, FACC, FAHAy Thoracic Surgeons Representative.

ACC/AHA Task Jeffrey L. Anderson, MD, FACC, FAHA, Chair Judith S. Hochman, MD, FACC, FAHAyy
Force Members Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect Richard J. Kovacs, MD, FACC, FAHA
E. Magnus Ohman, MD, FACC
Nancy M. Albert, PhD, RN, FAHA Susan J. Pressler, PhD, RN, FAHA
Biykem Bozkurt, MD, PhD, FACC, FAHA Frank W. Sellke, MD, FACC, FAHA
Ralph G. Brindis, MD, MPH, MACC Win-Kuang Shen, MD, FACC, FAHA
Lesley H. Curtis, PhD, FAHA
David DeMets, PhDyy
yyFormer Task Force member; current member during the writing effort.
Robert A. Guyton, MD, FACCyy

This document was approved by the American College of Cardiology Board of Trustees, American Heart Association Science Advisory and Coordi-
nating Committee, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography
and Interventions, and Society of Thoracic Surgeons in July 2014.
The American College of Cardiology requests that this document be cited at follows: Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG,
Fletcher BJ, Fonarow GC, Lange RA, Levine GN, Maddox TM, Naidu SS, Ohman EM, Smith PK. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of
the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association,
Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:192949.
This article is copublished in Circulation and Catheterization and Cardiovascular Interventions.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and American Heart Asso-
ciation (my.americanheart.org). For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail reprints@elsevier.com.
Permissions: Modication, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the
American College of Cardiology. Requests may be completed online via the Elsevier site (http://www.elsevier.com/authors/obtainingpermission-to-re-
use-elsevier-material).
1930 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

TABLE OF CONTENTS Guidelines (Task Force) has created a focused update


process to revise the existing guideline recommenda-
PREAMBLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1930 tions that are affected by evolving data or opinion.
New evidence is reviewed in an ongoing manner to
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1933 respond quickly to important scientic and treat-
1.1. Methodology and Evidence Review . . . . . . . . . . . 1933 ment trends that could have a major impact on patient
outcomes and quality of care. Evidence is reviewed
1.2. Organization of Committee and Relationships
at least twice a year, and updates are initiated on an
With Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1933
as-needed basis and completed as quickly as possible
1.3. Review and Approval . . . . . . . . . . . . . . . . . . . . . . 1933 while maintaining the rigorous methodology that the ACC
and AHA have developed during their partnership of >20
2. DIAGNOSIS OF SIHD . . . . . . . . . . . . . . . . . . . . . . . . . 1933
years.
2.3. Invasive Testing for Diagnosis of Coronary Artery A focused update is initiated when new data that are
Disease in Patients s With Suspected SIHD: deemed potentially important for patient care are pub-
Recommendations (New Section) . . . . . . . . . . . . 1933
lished or presented at national and international meet-
4. TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1936 ings (Section 1.1, Methodology and Evidence Review).
Through a broad-based vetting process, the studies
4.4. Guideline-Directed Medical Therapy . . . . . . . . . 1936
included are identied as being important to the relevant
4.4.2. Additional Medical Therapy to Prevent patient population. The focused update is not intended to
MI and Death: Recommendation . . . . . . . 1936
be based on a complete literature review from the date of
4.4.2.5. Additional Therapy to Reduce Risk
the previous guideline publication but rather to include
of MI and Death . . . . . . . . . . . . . . . 1936
pivotal new evidence that may effect changes in current
4.4.2.5.4. Chelation Therapy . . . . . . 1936
recommendations. Specic criteria or considerations for
4.4.4. Alternative Therapies for Relief of
inclusion of new data include the following:
Symptoms in Patients With Refractory
Angina: Recommendation . . . . . . . . . . . . 1937  Publication in a peer-reviewed journal;
4.4.4.1. Enhanced External
 Large, randomized, placebo-controlled trial(s);
Counterpulsation . . . . . . . . . . . . . . . 1937
 Nonrandomized data deemed important on the basis
5. CAD REVASCULARIZATION . . . . . . . . . . . . . . . . . . 1938 of results affecting current safety and efcacy as-
sumptions, including observational studies and meta-
5.2. Revascularization to Improve Survival:
Recommendations . . . . . . . . . . . . . . . . . . . . . . . . 1938 analyses;
 Strength/weakness of research methodology and
5.6. CABG Versus PCI . . . . . . . . . . . . . . . . . . . . . . . . . 1938 ndings;
5.6.2. CABG Versus Drug-Eluting Stents . . . . . . 1938  Likelihood of additional studies inuencing current
5.7.2. Studies Comparing PCI Versus CABG ndings;
for Left Main CAD . . . . . . . . . . . . . . . . . . . 1939  Impact on current performance measures and/or likeli-
5.12. Special Considerations . . . . . . . . . . . . . . . . . . . . 1940 hood of need to develop new performance measure(s);
 Request(s) and requirement(s) for review and update
5.12.3. Diabetes Mellitus . . . . . . . . . . . . . . . . . . . 1940
from the practice community, key stakeholders, and
APPENDIX 1 other sources free of industry relationships or other
potential bias;
Author Relationships With Industry and
Other Entities (Relevant) . . . . . . . . . . . . . . . . . . . . . . . 1944  Number of previous trials showing consistent results; and
 Need for consistency with a new guideline or guideline
APPENDIX 2 updates or revisions.

Reviewer Relationships With Industry and In analyzing the data and developing recommenda-
Other Entities (Relevant) . . . . . . . . . . . . . . . . . . . . . . . 1946
tions and supporting text, a writing committee uses
evidence-based methodologies developed by the Task
PREAMBLE Force (1). The Class of Recommendation (COR) is an esti-
mate of the size of the treatment effect, with consider-
Keeping pace with emerging evidence is an ongoing ation given to risks versus benets as well as evidence
challenge to timely development of clinical practice and/or agreement that a given treatment or procedure is
guidelines. In an effort to respond promptly to new or is not useful/effective and in some situations may
evidence, the American College of Cardiology (ACC)/ cause harm. The Level of Evidence (LOE) is an estimate
American Heart Association (AHA) Task Force on Practice of the certainty or precision of the treatment effect.
JACC VOL. 64, NO. 18, 2014 Fihn et al. 1931
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

TABLE 1 Applying Classication of Recommendations and Level of Evidence

A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend
themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.
*Data available from clinical trials or registries about the usefulness/efcacy in different subpopulations, such as sex, age, history of diabetes mellitus, history of prior myocardial
infarction, history of heart failure, and prior aspirin use. For comparative-effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use
of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

The writing committee reviews and ranks evidence sup- available, a survey of current practice among the clini-
porting each recommendation, with the weight of evi- cians on the writing committee is the basis for LOE C
dence ranked as LOE A, B, or C, according to specic recommendations, and no references are cited. The
denitions that are included in Table 1. Studies are iden- schema for COR and LOE is summarized in Table 1, which
tied as observational, retrospective, prospective, or also provides suggested phrases for writing recommen-
randomized as appropriate. For certain conditions for dations within each COR. A new addition to this meth-
which inadequate data are available, recommendations odology is separation of the Class III recommendations to
are based on expert consensus and clinical experience delineate whether the recommendation is determined to
and are ranked as LOE C. When recommendations at be of no benet or is associated with harm to the
LOE C are supported by historical clinical data, appro- patient. In addition, in view of the increasing number of
priate references (including clinical reviews) are cited if comparative-effectiveness studies, comparator verbs and
available. For issues about which sparse data are suggested phrases for writing recommendations for the
1932 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

comparative effectiveness of one treatment or strategy reviewers of the guideline are required to disclose all
versus another have been added for COR I and IIa, LOE A current healthcarerelated relationships, including those
or B only. existing 12 months before initiation of the writing effort.
In view of the advances in medical therapy across the In December 2009, the ACC and AHA implemented a new
spectrum of cardiovascular diseases, the Task Force has policy for relationships with industry and other entities
designated the term guideline-directed medical therapy (RWI) that requires the writing committee chair plus a
(GDMT) to represent medical therapy that is strongly minimum of 50% of the writing committee to have no
recommended by (primarily Class I and IIa) ACC/AHA relevant RWI (Appendix 1 for the ACC/AHA denition of
guidelines. The term, GDMT, will be used herein. It is relevance). These statements are reviewed by the Task
anticipated that what currently constitutes GDMT will Force and all members during each conference call and/or
evolve over time as new therapies and evidence emerge. meeting of the writing committee and are updated as
Because the ACC/AHA practice guidelines address changes occur. All guideline recommendations require a
patient populations (and healthcare providers) residing condential vote by the writing committee and must be
in North America, drugs that are currently unavailable in approved by a consensus of the voting members. Mem-
North America are discussed in the text without a spe- bers are not permitted to draft or vote on any text or
cic COR. For studies performed in large numbers of recommendations pertaining to their RWI. Members of
subjects outside North America, a writing committee this writing group, who recused themselves from voting,
reviews the potential impact of different practice pat- are indicated, and specic section recusals are noted in
terns and patient populations on the treatment effect Appendix 1. Authors and peer reviewers RWI pertinent
and relevance to the ACC/AHA target population to to this guideline are disclosed in Appendices 1 and 2,
determine whether the ndings should inform a specic respectively. Additionally, to ensure complete trans-
recommendation. parency, this writing group members comprehensive
The ACC/AHA practice guidelines are intended to assist disclosure informationincluding RWI not pertinent to
healthcare providers in clinical decision making by this documentis available as an online supplement.
describing a range of generally acceptable approaches to Comprehensive disclosure information for the Task Force
the diagnosis, management, and prevention of specic is also available online. The work of this writing group
diseases or conditions. The guidelines are intended to is supported exclusively by the ACC, AHA, American
dene practices that meet the needs of most patients in Association for Thoracic Surgery (AATS), Preventive
most circumstances. The ultimate judgment about care of Cardiovascular Nurses Association (PCNA), Society for
a particular patient must be made by the healthcare pro- Cardiovascular Angiography and Interventions (SCAI),
vider and patient in light of all the circumstances pre- and Society of Thoracic Surgeons (STS) without commer-
sented by that patient. As a result, situations may arise in cial support. Writing group members volunteered their
which deviations from these guidelines are appropriate. time for this activity.
In clinical decision making, consideration should be given To maintain relevance at the point of care for practicing
to the quality and availability of expertise in the area physicians, the Task Force continues to oversee an
where care is provided. When these guidelines are used as ongoing process improvement initiative. As a result, in
the basis for regulatory or payer decisions, the goal should response to pilot projects, several changes to these
be improvement in quality of care. guidelines will be apparent, including limited narrative
Prescribed courses of treatment in accordance with text and a focus on summary and evidence tables (with
these recommendations are effective only if they are fol- references linked to abstracts in PubMed).
lowed. Because lack of patient understanding and In April 2011, the Institute of Medicine released 2 re-
adherence may adversely affect outcomes, physicians and ports: Finding What Works in Health Care: Standards for
other healthcare providers should engage the patients Systematic Reviews and Clinical Practice Guidelines We
active participation in prescribed medical regimens and Can Trust (2,3). It is noteworthy that the ACC/AHA prac-
lifestyles. In addition, patients should be informed of the tice guidelines were cited as being compliant with many
risks and benets of and alternatives to a particular of the standards that were proposed. A thorough review
treatment and should be involved in shared decision of these reports and our current methodology is under
making whenever feasible, particularly for COR IIa and way, with further enhancements anticipated.
IIb, for which the benet-to-risk ratio may be lower. The recommendations in this focused update are
The Task Force makes every effort to avoid actual, considered current until they are superseded in another
potential, or perceived conicts of interest that may focused update or the full-text guideline is revised.
arise as a result of industry relationships, professional Guidelines are ofcial policy of the ACC and AHA.
biases, or personal interests among the members of the Jeffrey L. Anderson, MD, FACC, FAHA
writing group. All writing committee members and peer Chair, ACC/AHA Task Force on Practice Guidelines
JACC VOL. 64, NO. 18, 2014 Fihn et al. 1933
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

1. INTRODUCTION relevant to the data under consideration. The writing


group included representatives from the ACC, AHA, AATS,
These guidelines are intended to apply to adult patients PCNA, SCAI, and STS.
with stable known or suspected ischemic heart disease
(IHD), including those with new-onset chest pain (i.e., low- 1.3 Review and Approval

risk unstable angina) or stable pain syndromes. Patients This document was reviewed by 5 ofcial reviewers from
who have ischemic equivalents, such as dyspnea or arm the ACC and the AHA, as well as 1 reviewer each from the
pain with exertion, are included in the latter group. Many AATS, PCNA, SCAI, and STS; and 33 individual content
patients with IHD may become asymptomatic with appro- reviewers, including members of the American College of
priate therapy. Accordingly, the follow-up sections of this Physicians, ACC Imaging Section Leadership Council, ACC
guideline pertain to patients who were previously symp- Interventional Section Leadership Council, ACC Preven-
tomatic, including those who have undergone percuta- tion of Cardiovascular Disease Section Leadership Coun-
neous coronary intervention (PCI) or coronary artery bypass cil, ACC Surgeons Council, AHA Council on Clinical
graft (CABG). In this document, coronary angiography is Cardiology, and the Association of International Gover-
understood to refer to invasive coronary angiography. nors. Reviewers RWI information was collected and
distributed to the writing group and is published in this
1.1 Methodology and Evidence Review document (Appendix 2).
Late-breaking clinical trials presented at the 2012 scien- This document was approved for publication by the
tic meetings of the ACC, AHA, and European Society of governing bodies of the ACC, AHA, and by other partner
Cardiology, as well as other selected data reported organizations, the AATS, PCNA, SCAI, and STS.
through October, 2013, were reviewed by the 2012 stable
ischemic heart disease (SIHD) guideline writing commit-
2. DIAGNOSIS OF SIHD
tee along with the Task Force and other experts to iden-
tify trials and other key data that might affect guideline
2.3 Invasive Testing for Diagnosis of Coronary Artery Disease
recommendations. On the basis of the criteria and con-
in Patients With Suspected SIHD: Recommendations
siderations noted previously (see Preamble), recently
(New Section)
published trial data and other clinical information were
See Online Data Supplement 1 for additional information.
considered important enough to prompt a focused update
of the 2012 SIHD guideline (4). Evidence considered for CLASS I
deliberation by the writing group was added to evidence
1. Coronary angiography is useful in patients with presumed
tables in the Data Supplement available online, although
SIHD who have unacceptable ischemic symptoms despite
it did not result in recommendation changes. Among the
GDMT and who are amenable to, and candidates for, coro-
topics considered for inclusion in the focused update was nary revascularization. (Level of Evidence: C)
the use of fractional ow reserve (FFR) for assessing in-
termediate coronary lesions, including newer data from CLASS IIA
the FAME (Fractional Flow Reserve Versus Angiography 1. Coronary angiography is reasonable to dene the extent and
for Multivessel Evaluation) 2 study (5). Although this was severity of coronary artery disease (CAD) in patients with
acknowledged to be an important new contribution to the suspected SIHD whose clinical characteristics and results of
literature, it did not alter the recommendations for FFR noninvasive testing (exclusive of stress testing) indicate a
made in the 2012 full-text guideline (4). high likelihood of severe IHD and who are amenable to, and
Consult the full-text version or the executive summary candidates for, coronary revascularization (712). (Level of
of the 2012 SIHD guideline for policy on clinical areas not Evidence: C)
covered by the focused update (4,6). The individual rec- 2. Coronary angiography is reasonable in patients with sus-
ommendations in this focused update will be incorpo- pected symptomatic SIHD who cannot undergo diagnostic
rated into future revisions or updates of the full-text stress testing, or have indeterminate or nondiagnostic stress
guideline. tests, when there is a high likelihood that the ndings will
result in important changes to therapy. (Level of Evidence: C)
1.2 Organization of Committee and Relationships With Industry
For this focused update, representative members of the CLASS IIB

2012 stable ischemic heart disease (SIHD) guideline 1. Coronary angiography might be considered in patients with
writing committee were invited to participate, and they stress test results of acceptable quality that do not suggest
were joined by additional invited members to form a new the presence of CAD when clinical suspicion of CAD remains
writing group, referred to as the 2014 focused update high and there is a high likelihood that the ndings will result
writing group. Members were required to disclose all RWI in important changes to therapy. (Level of Evidence: C)
1934 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

This section has been added to the 2014 SIHD focused update benets of the procedure have been carefully consid-
to ll a gap in the 2012 SIHD guideline (4). It specically ered and understood by the patient. Coronary angiog-
addresses the role of coronary angiography for the diagnosis raphy to assess coronary anatomy for revascularization
of CAD in patients with suspected SIHD. is appropriate only when it is determined beforehand
Coronary angiography for risk stratication has been that the patient is amenable to, and a candidate for,
addressed in Section 3.3 of the 2012 SIHD full-text percutaneous or surgical revascularization. In patients
guideline (4). Recommendations for use of coronary with abnormal, noninvasive stress testing for whom a
angiography in the following specic clinical circum- diagnosis of CAD remains in doubt, many clinicians
stances have been addressed in other guidelines or proceed to diagnostic coronary angiography. However,
statements and will not be discussed further here: in some patients, multidetector CT angiography may be
appropriate and safer than routine invasive angiog-
 Patients with heart failure and/or reduced ejection
fraction (13) raphy for this purpose. Indications and contraindica-
tions to CT angiography, including subsets of patients
 Patients who have experienced sudden cardiac death
for whom it can be considered, are also discussed in the
or sustained ventricular arrhythmia (14)
2010 expert consensus document on CT angiography
 Patients undergoing preoperative cardiovascular eval-
(18) and the 2010 appropriate use criteria for cardiac
uation for noncardiac surgery (including solid organ
CT (19).
transplantation) (15)
Although coronary angiography is considered the
 Evaluation of cardiac disease among patients who are
gold standard for the diagnosis of CAD, it has inherent
kidney or liver transplantation candidates (16,17)
limitations and shortcomings. Angiographic assessment
Note that ACC/AHA guidelines for coronary angiography of stenosis severity relies on comparison to an adjacent,
were published in 1999 but not updated, and they are now nondiseased reference segment. In diffusely diseased
superseded by the above documents. coronary arteries, lack of a normal reference segment
There are no high-quality data on which to base rec- may lead to underestimation of lesion severity by angi-
ommendations for performing diagnostic coronary angi- ography. Multiple studies have documented signicant
ography because no study has randomized patients with interobserver variability in the grading of coronary artery
SIHD to either catheterization or no catheterization. Trials stenosis (20,21), with disease severity overestimated by
in patients with SIHD comparing revascularization and visual assessment when coronary stenosis is $50%
GDMT have, to date, all required angiography, most often (21,22). Although quantitative coronary angiography
after stress testing, as a prerequisite for subsequent provides a more accurate assessment of lesion severity
revascularization. Additionally, the incremental benet than does visual assessment, it is rarely used in clinical
of detecting or excluding CAD by coronary angiography practice because it does not accurately assess the phys-
remains to be determined. The ISCHEMIA (International iological signicance of lesions (23). Many stenoses
Study of Comparative Health Effectiveness With Medical considered to be severe by visual assessment of coronary
and Invasive Approaches) trial is currently randomizing angiograms (i.e., $70% luminal narrowing) do not
patients with at least moderate ischemia on stress testing restrict coronary blood ow at rest or with maximal
to a strategy of optimal medical therapy alone (with cor- dilatation, whereas others considered to be insigni-
onary angiography reserved for failure of medical ther- cant (i.e., <70% luminal narrowing) are hemodynami-
apy) or routine cardiac catheterization followed by cally signicant (24). Coronary angiography also cannot
revascularization (when appropriate) plus optimal medi- assess whether an atherosclerotic plaque is stable or
cal therapy. Before randomization, however, patients vulnerable (i.e., likely to rupture and cause an acute
with normal renal function will undergo blinded coronary syndrome).
computed tomography (CT) angiography to exclude them Intravascular ultrasound and optical coherence to-
if signicant left main CAD or no signicant CAD is pre- mography provide more precise information about the
sent. The writing group strongly endorses the ISCHEMIA severity of stenosis and plaque morphology than does
trial, which will provide contemporary, high-quality evi- coronary angiography and, in certain cases, can be useful
dence about the optimal strategy for managing patients adjunctive tests (9). These imaging procedures are dis-
with nonleft main SIHD and moderate-to-severe ischemia. cussed in the 2011 PCI guideline (9). FFR can assess the
In the majority of patients with suspected SIHD, hemodynamic signicance of angiographically interme-
noninvasive stress testing for diagnosis and risk strati- diate or indeterminant lesions and allows one to
cation is the appropriate initial study. Importantly, decide when PCI may be benecial or safely deferred
coronary angiography is appropriate only when the in- (24,25). It has been suggested in several studies that a PCI
formation derived from the procedure will signicantly strategy guided by FFR may be superior to a strategy
inuence patient management and if the risks and guided by angiography alone (5,24,26,27).
JACC VOL. 64, NO. 18, 2014 Fihn et al. 1935
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

Invasive procedures may cause complications. Data diagnostic angiography and revascularization, instead of
from the ACCs National Cardiovascular Data Registry initial stress testing. Patients with long-standing diabetes
CathPCI Registry during the 2012 calendar year included a mellitus and end-organ damage, severe peripheral
1.5% incidence of procedural complications of diagnostic vascular disease (e.g., abdominal aortic aneurysm), or
angiography. Complications in earlier reports included previous chest (mantle) radiation therapy may have se-
death, stroke, myocardial infarction (MI), bleeding, vere CADparticularly when ischemic symptoms are
infection, contrast allergic or anaphylactoid reactions, present (2831). Patients with a combination of typical
vascular damage, contrast-induced nephropathy, ar- angina, transient heart failure, pulmonary edema, or ex-
rhythmias, and need for emergency revascularization ertional or unheralded syncope may have severe CAD.
(2832). Complications are more likely to occur in certain Noninvasive testing, such as rest echocardiography
patient groups, including those of advanced age revealing multiple regional wall motion abnormalities or
(>70 years), and those with marked functional impair- electrocardiography with diffuse ischemic changes in
ment (Canadian Cardiovascular Society class IV angina or multiple territories, may reect CAD with a large ischemic
New York Heart Association class IV heart failure), severe burden and justify diagnostic angiography without prior
left ventricular dysfunction or CAD (particularly left main stress testing. The writing group has found that creating a
disease), severe valvular disease, severe comorbid medi- recommendation governing the use of angiography for
cal conditions (e.g., renal, hepatic, or pulmonary disease), such high-risk patients remains controversial. The writing
bleeding disorders, or a history of an allergic reaction to group recognizes, however, that many clinicians believe
radiographic contrast material (2832). The risk of that prompt diagnostic angiography and revascularization,
contrast-induced nephropathy is increased in patients instead of initial stress testing, are appropriate for such
with renal insufciency or diabetes mellitus (9,33). In high-risk patients who are likely to have underlying severe
deciding whether angiography should be performed in CAD for which revascularization would confer a survival
these patients, these risks should be balanced against the advantage.
increased likelihood of nding critical CAD. The concept Coronary angiography is not routinely performed after
of informed consent requires that risks and benets of adequate stress testing has been negative for ischemia.
and alternatives to coronary angiography be explicitly Still, stress tests can be falsely negative and, in a patient
discussed with the patient before the procedure is with high pretest likelihood of CAD, Bayes theorem pre-
undertaken. dicts that a high post-test likelihood of CAD will remain as
Despite these shortcomings and potential complica- well. Therefore, when clinicians strongly suspect that a
tions, coronary angiography is useful to a) ascertain the stress test is falsely negative (e.g., a patient with typical
cause of chest pain or anginal equivalent symptoms, angina who also has multiple risk factors for CAD),
b) dene coronary anatomy in patients with high-risk diagnostic angiography may be warranted. When stress
noninvasive stress test ndings (Section 3.3 in the 2012 testing yields an ambiguous or indeterminate result in a
full-text guideline) as a requisite for revascularization, patient with a high likelihood of CAD, coronary angiog-
c) determine whether severe CAD may be the cause of raphy may be preferable to another noninvasive test and
depressed left ventricular ejection fraction, d) assess for may be the most effective means to reach a diagnosis.
possible ischemia-mediated ventricular arrhythmia, e) The frequency with which coronary angiography is
evaluate cardiovascular risk among certain recipient and performed varies across geographic regions, and in some
donor candidates for solid-organ transplantation, and areas it may be underutilized or overutilized (34). The
f) assess the suitability for revascularization of patients optimal rate of normal coronary angiography in clinical
with unacceptable ischemic symptoms (i.e., symptoms practice remains undened. In the ACCs National Cardio-
that are not controlled with medication and that limit ac- vascular Data Registry CathPCI Registry, approximately
tivity or quality of life). Coronary angiography may also be 45% of elective cardiac catheterizations performed at
helpful when initial stress testing is inconclusive or hospitals did not detect clinically signicant (dened as
yields conicting results and denitive determination of >50% luminal diameter) stenoses (29,35), although rates
whether IHD is present will result in important changes to varied markedly between hospitals (i.e., range, 0% to 77%)
therapy. The exclusion of epicardial CAD in a patient with (35). Hospitals with lower rates of signicant CAD at cath-
recurring chest pain or other potential ischemic symptoms eterization were more likely to have performed angiog-
is particularly useful when it leads to more appropriate raphy on younger patients; those with no symptoms or
treatment, including withdrawal of medications. atypical symptoms; and those with negative, equivocal, or
In a subset of patients, clinical characteristics, symp- unperformed functional status assessment (35). Even
toms, and/or results of noninvasive testing alone indi- among those with a positive result on a noninvasive test,
cating a high likelihood of multivessel or left main only 41% of patients were found to have signicant CAD
disease (e.g., large ischemic burden) may prompt (36). In a study performed within the Veterans Health
1936 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

Administration, 21% of patients undergoing elective cath- that can be excreted. Advocates maintain that this process
eterization had normal coronary arteries (dened as can result in both regression of atherosclerotic plaques
having no lesions $20%). The median proportion of normal and relief of angina and that EDTA reduces oxidative
coronary arteries was 10.8% among hospitals in the lowest stress in the vascular wall. Anecdotal reports have sug-
quartile and 30.3% among hospitals in the highest quartile gested that EDTA chelation therapy can result in relief
(37). The authors concluded that factors causing variation of angina in patients with SIHD. Studies in patients
in patient selection for coronary angiography exist in in- with intermittent claudication and SIHD have failed to
tegrated nonfee-for-service health systems as well as in demonstrate improvements in exercise measures (38,39),
fee-for-service systems. ankle-brachial index (38,39), or digital subtraction an-
Angiographically normal or near-normal coronary ar- giograms with chelation (40). A randomized controlled
teries are more common among women, who are more trial (RCT) examining the effect of chelation therapy on
likely than men to have myocardial ischemia due to SIHD studied 84 patients with stable angina and a positive
microvascular disease. The relatively high proportion of treadmill test for ischemia (41). Those randomized to
patients with ischemia and no signicant epicardial ste- active therapy received weight-adjusted disodium EDTA
noses may indicate opportunities to improve patient se- chelation therapy for 3 hours per treatment, twice weekly
lection for coronary angiography, or to consider the for 15 weeks, and then once monthly for an additional 3
possibility of syndromes caused by abnormal coronary months. There were no differences between groups in
vasoreactivity. Nevertheless, the exclusion of signicant changes in exercise time to ischemia, exercise capacity, or
epicardial CAD with a high level of condence can be quality-of-life scores. The National Center of Comple-
important for high-quality diagnosis and patient man- mentary and Alternative Medicine and the National Heart,
agement, and therefore the reported frequencies of Lung, and Blood Institute conducted TACT (Trial to
normal coronary ndings should be understood within Assess Chelation Therapy) (42), an RCT comparing che-
this context (29,3537). lation with placebo in patients who had experienced MI.
The primary composite endpoint of total mortality,
4. TREATMENT recurrent MI, stroke, coronary revascularization, or hos-
pitalization for angina occurred in 222 (26%) patients in
4.4 Guideline-Directed Medical Therapy the chelation group and 261 (30%) patients in the placebo
group (hazard ratio: 0.82; 95% CI: 0.69 to 0.99; p0.035
4.4.2 Additional Medical Therapy to Prevent MI and Death:
[because of multiple comparisons, statistical signicance
Recommendation
was considered at p values #0.036]). No individual
4.4.2.5 Additional Therapy to Reduce Risk of MI and Death endpoint differed signicantly between groups. Among
See Table 2 for the revised recommendation for chelation patients with diabetes mellitus, there was a 39% reduc-
therapy and Online Data Supplement 2 for evidence sup- tion (hazard ratio: 0.61; 95% CI: 0.45 to 0.83) in the
porting the recommendation. composite endpoint for the chelation-treated patients
relative to the placebo-treated patients (p0.02 for
4.4.2.5.4 Chelation Therapy interaction). Despite these positive ndings, the TACT
Chelation therapy, which consists of a series of intrave- investigators did not recommend the routine use of che-
nous infusions of disodium ethylene diamine tetraacetic lation therapy to reduce symptoms or cardiovascular
acid (EDTA) in combination with other substances, has complications for all patients with SIHD, given the modest
been touted as a putative noninvasive means of overall benet, high proportion of patient withdrawals
improving blood ow in atherosclerotic vessels, treating (18% lost to follow-up), absence of adequate scientic
angina, and preventing cardiac events. EDTA combines basis for the therapy, and possibility of a false positive
with polyvalent cations, such as calcium and cadmium outcome. The large proportion of withdrawals was
(a constituent of cigarette smoke that is associated with especially concerning given that 50% more patients
cardiovascular risk) (43,44), to form soluble complexes withdrew from chelation therapy than from placebo,

TABLE 2 Recommendation for Chelation Therapy

2012 Recommendation 2014 Focused Update Recommendation Comment

Class III: No Benet Class IIb


1. Chelation therapy is not recommended with 1. The usefulness of chelation therapy Modied recommendation (changed Class of
the intent of improving symptoms or reducing is uncertain for reducing cardiovascular Recommendation from III: No Benet
cardiovascular risk in patients with SIHD (3841). events in patients with SIHD (3842). to IIb and Level of Evidence from C to B).
(Level of Evidence: C) (Level of Evidence: B)

SIHD indicates stable ischemic heart disease.


JACC VOL. 64, NO. 18, 2014 Fihn et al. 1937
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

which raised important concerns about unmasking of The efcacy of EECP in treating stable angina pectoris
treatment assignments that could have inuenced key has been evaluated in 2 RCTs and several observational
outcomes (e.g., revascularization or hospitalization for registry studies. In MUST-EECP (Multicenter Study of
angina). In addition, chelation therapy is not risk free. Enhanced External Counterpulsation), 139 patients with
Disodium EDTA, particularly when infused too rapidly, angina, documented CAD, and evidence of ischemia on
may cause hypocalcemia, renal failure, and death (45,46). exercise testing were randomized to 35 hours of active
Although disodium EDTA is approved by the U.S. Food and counterpulsation or to inactive counterpulsation (with
Drug Administration for specic indications, such as iron insufcient pressure to alter blood pressure) (47). Time
overload and lead poisoning, it is not approved for use in to $1-mm ST-segment depression on stress testing
preventing or treating cardiovascular disease. Accord- increased signicantly in patients treated with active
ingly, the writing group nds that the usefulness of che- counterpulsation (from 33718 s to 37918 s) compared
lation therapy in cardiac disease is highly questionable. with placebo (from 32621 s to 33020 s; p0.01). The
groups did not differ in terms of exercise duration,
4.4.4 Alternative Therapies for Relief of Symptoms in Patients change in daily nitroglycerin use, or mean frequency of
With Refractory Angina: Recommendation angina, although the percentage reduction in frequency
See Table 3 for the recommendation on enhanced external of anginal episodes was somewhat greater among patients
counterpulsation (EECP) and Online Data Supplement 3 for who received active counterpulsation. Of patients re-
evidence supporting the recommendation. ceiving EECP, 55% reported adverse events, including leg
and back pain and skin abrasions, compared with 26% in
4.4.4.1 Enhanced External Counterpulsation the control group (relative risk: 2.13; 95% CI: 1.35 to 3.38),
Although EECP was carefully reviewed in the 2012 SIHD with approximately half of these events categorized as
guideline (4), comments received after the guidelines device related. An additional trial of EECP was conducted
publication prompted a re-examination of the existing in 42 symptomatic patients with CAD who were random-
literature, even though no truly new data have become ized (2:1 ratio) to 35 hours of either EECP (n28) or sham
available. EECP is a technique that uses inatable cuffs EECP (n14) (51). Over the 7-week study period, average
wrapped around the lower extremities to increase venous Canadian Cardiovascular Society angina class improved
return and augment diastolic blood pressure (47). The with EECP as compared with control (3.160.47 to
cuffs are inated sequentially from the calves to the thigh 1.200.40 and 2.930.26 to 2.930.26 in EECP and sham
muscles during diastole and are deated instantaneously control, respectively; p<0.001). Data from RCTs on long-
during systole. The resultant diastolic augmentation in- term outcomes are lacking.
creases coronary perfusion pressure, and the systolic cuff In a meta-analysis of 13 observational studies that
depression decreases peripheral resistance. Treatment is tracked 949 patients, Canadian Cardiovascular Society
associated with improved left ventricular diastolic lling, anginal class was improved by $1 class in 86% of EECP-
peripheral ow-mediated dilation, and endothelial func- treated patients (95% CI: 82% to 90%). There was,
tion. Other putative mechanisms for improvement in however, a high degree of heterogeneity among the
symptoms include recruitment of collaterals, attenuation studies, which lessens condence in the results of the
of oxidative stress and proinammatory cytokines, pro- meta-analysis (Q statistic p0.008) (52). The EECP Con-
motion of angiogenesis and vasculogenesis, and a pe- sortium reported results from 2,289 consecutive patients
ripheral training effect (4851). EECP was approved by the undergoing EECP therapy at 84 participating centers,
U.S. Food and Drug Administration in 1995 for the treat- including a subgroup of 175 patients from 7 centers who
ment of patients with CAD and refractory angina pectoris underwent radionuclide perfusion stress tests before and
who fail to respond to standard revascularization pro- after therapy (53). Treatment was associated with
cedures and aggressive pharmacotherapy. A treatment improved perfusion images and increased exercise dura-
course typically consists of 35 sessions of 1 hour each, tion. Similarly, the International EECP Registry reported
given 5 days a week. Contraindications include decom- improvement of $1 Canadian Cardiovascular Society
pensated heart failure, severe peripheral artery disease, angina class in 81% of patients immediately after the last
and severe aortic regurgitation. EECP treatment (54). Improvements in health-related

TABLE 3 Recommendation for EECP

2012 Recommendation 2014 Focused Update Recommendation Comment

Class IIb Class IIb


1. EECP may be considered for relief of refractory angina 1. EECP may be considered for relief of refractory angina 2012 recommendation
in patients with SIHD (47). (Level of Evidence: B) in patients with SIHD (47). (Level of Evidence: B) remains current.

EECP indicates enhanced external counterpulsation, and SIHD, stable ischemic heart disease.
1938 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

quality of life have also been reported with EECP, but there or repeat revascularization during the 3 years after
is limited evidence with which to determine the duration randomizationoccurred in 20.2% of patients who had
of the health-related benets of treatment (55,56). received CABG and 28.0% of those who had undergone
In general, existing data, largely from uncontrolled DES implantation (p<0.001). The rates of death and
studies, suggest a benet from EECP among patients with stroke were not signicantly different; however, MI
angina refractory to other therapy. Additional data from (3.6% for CABG, 7.1% for DES) and repeat revasculariza-
well-designed RCTs are needed to better dene the role of tion (10.7% for CABG, 19.7% for DES) were more likely to
this therapeutic strategy in patients with SIHD (57). On occur with DES implantation (82). At 5 years of follow-up
the basis of this re-examination of the literature, the (83), MACCE occurred in 26.9% of patients who had
recommendation about EECP remains unchanged from received CABG and 37.3% of those who had undergone
the 2012 guideline. DES implantation (p<0.0001). The combined endpoint of
death, stroke, or MI was also lower in CABG-treated
5. CAD REVASCULARIZATION
patients than in DES-treated patients (16.7% versus
20.8%; p0.03) (83).
5.2 Revascularization to Improve Survival: Recommendations
In SYNTAX, the extent of CAD was assessed using the
See Table 4 for recommendations on CAD revascularization SYNTAX score, which is based on the location, severity,
to improve survival and Online Data Supplement 4 for and extent of coronary stenoses, with a low score indi-
evidence supporting the recommendations. cating less complicated anatomic CAD. In post hoc ana-
lyses, a low score was dened as #22; intermediate, 23 to
5.6 CABG Versus PCI
32; and high, $33. The occurrence of MACCE correlated
5.6.2 CABG Versus Drug-Eluting Stents with the SYNTAX score for DES patients but not for those
See Online Data Supplement 5 for additional evidence table. who had undergone CABG. At 12-month follow-up, the
Although the results of 10 observational studies primary endpoint was similar for CABG and DES in those
comparing CABG and drug-eluting stent (DES) implanta- with a low SYNTAX score. In contrast, MACCE occurred
tion have been published (7079), most of these studies more often after DES implantation than after CABG in those
had short follow-up periods (12 to 24 months). In a meta- with an intermediate or high SYNTAX score (66). At 3 years
analysis of 24,268 patients with multivessel CAD treated of follow-up, the mortality rate was greater in subjects with
with CABG or DES (80), the incidences of death and MI 3-vessel CAD treated with DES than in those treated with
were similar for the 2 procedures, but the frequency with CABG (6.2% versus 2.9%). The differences in MACCE at 5-
which repeat revascularization was performed was year follow-up between those treated with DES or CABG
roughly 4 times higher after DES implantation. Only 1 increased with an increasing SYNTAX score (83).
large RCT comparing CABG and DES implantation has Although the utility of the SYNTAX score in everyday
been published. The SYNTAX (Synergy Between Percuta- clinical practice remains uncertain, it seems reasonable to
neous Coronary Intervention With TAXUS and Cardiac conclude from SYNTAX and other data that survival rates
Surgery) trial randomly assigned 1,800 patients (of a total of patients undergoing PCI or CABG with relatively un-
of 4,337 who were screened) to receive DES or CABG complicated and lesser degrees of CAD are comparable,
(66,81,82). Major adverse cardiac and cerebrovascular whereas for those with complex and diffuse CAD, CABG
events (MACCE)a composite of death, stroke, MI, appears to be preferable (8183).

TABLE 4 Recommendations for CAD Revascularization to Improve Survival

2012 Recommendation 2014 Focused Update Recommendations Comments

Class IIa Class I


1. CABG is probably recommended in preference 1. A Heart Team approach to revascularization is New recommendation
to PCI to improve survival in patients with recommended in patients with diabetes
multivessel CAD and diabetes mellitus, mellitus and complex multivessel CAD (66).
particularly if a LIMA graft can be (Level of Evidence: C)
anastomosed to the LAD artery (5865). 2. CABG is generally recommended in Modied recommendation (Class of
(Level of Evidence: B) preference to PCI to improve survival in Recommendation changed from IIa to I,
patients with diabetes mellitus and wording modied, additional RCT added).
multivessel CAD for which revascularization is
likely to improve survival (3-vessel CAD or
complex 2-vessel CAD involving the proximal
LAD), particularly if a LIMA graft can be
anastomosed to the LAD artery, provided
the patient is a good candidate for surgery
(58,6165,5969). (Level of Evidence: B)

CABG indicates coronary artery bypass graft; CAD, coronary artery disease; LAD, left anterior descending; LIMA, left internal mammary artery; PCI, percutaneous coronary intervention;
and RCT, randomized controlled trial.
JACC VOL. 64, NO. 18, 2014 Fihn et al. 1939
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

5.7.2 Studies Comparing PCI and CABG for Left Main CAD Angioplasty Using Sirolimus-Eluting Stent in Patients
See 2012 SIHD Guideline Data Supplement (Table 8-13) for With Left Main Coronary Artery Disease) trial of 600 pa-
informational evidence tables (4). tients with left main disease, the composite endpoint of
Of all patients undergoing coronary angiography, death, MI, or stroke at 2 years occurred in 4.4% of patients
approximately 4% are found to have left main CAD (84), treated with DES and 4.7% of patients treated with CABG,
>80% of whom also have signicant ($70% diameter) but ischemia-driven target-vessel revascularization was
stenoses in other epicardial coronary arteries. In pub- required more often in the patients treated with PCI (9.0%
lished cohort studies, it has been found that major clinical versus 4.2%) (88).
outcomes 1 year after revascularization are similar with The results from these 3 RCTs suggest (but do not
PCI or CABG and that mortality rates are similar at 1, 2, denitively prove) that major clinical outcomes in
and 5 years of follow-up; however, the risk of undergoing selected patients with left main CAD are similar with
target-vessel revascularization is signicantly higher with CABG and PCI at 1- to 2-year follow-up but that repeat
stenting than with CABG. revascularization rates are higher after PCI than after
In the SYNTAX trial, 45% of screened patients with CABG. RCTs with extended follow-up of $5 years are
unprotected left main CAD had complex disease that required to provide denitive conclusions about the
prevented randomization; 89% of those underwent CABG optimal treatment of left main CAD; 2 such studies are
(66,81). In addition, 705 of the 1,800 patients with un- under way. In a meta-analysis of 8 cohort studies and 2
protected left main CAD were randomized to either DES or RCTs (89), death, MI, and stroke occurred with similar
CABG. The majority of patients with left main CAD and a frequency in the PCI- and CABG-treated patients at 1, 2,
low SYNTAX score had isolated left main CAD or left main and 3 years of follow-up. Target-vessel revasculariza-
CAD plus 1-vessel CAD. The majority of those with an tion was performed more often in the PCI group at
intermediate score had left main CAD plus 2-vessel CAD, 1 year (OR: 4.36), 2 years (OR: 4.20), and 3 years (OR:
and most of those with a high SYNTAX score had left main 3.30).
CAD plus 3-vessel CAD. At 1 year, rates of all-cause death Additional analyses using Bayesian methods, initiated
and MACCE were similar among patients who had un- by the Task Force, have afrmed the equivalence of PCI
dergone DES and those who had undergone CABG (81). and CABG for improving survival in patients with unpro-
Repeat revascularization was performed more often in the tected left main CAD who are candidates for either
DES group than in the CABG group (11.8% versus 6.5%), strategy (12). A Bayesian cross-design and network meta-
but stroke occurred more often in the CABG group (2.7% analysis was applied to 12 studies (4 RCTs and 8 obser-
versus 0.3%). At 3 years of follow-up, the incidence of vational studies) comparing CABG with PCI (n4,574
death in those undergoing left main CAD revasculariza- patients) and to 7 studies (2 RCTs and 5 observational
tion with low or intermediate SYNTAX scores (<33) was studies) comparing CABG with medical therapy (n3,224
3.7% after DES and 9.1% after CABG (p0.03), whereas in patients). The ORs of death at 1 year after PCI compared
those with a high SYNTAX score ($33), the incidence of with CABG did not differ among RCTs (OR: 0.99; 95%
death after 3 years was 13.4% after DES and 7.6% after Bayesian credible interval 0.67 to 1.43), matched cohort
CABG (p0.10) (81). Because the primary endpoint of the studies (OR: 1.10; 95% Bayesian credible interval 0.76 to
overall SYNTAX trial was not met (i.e., noninferiority 1.73), and other types of cohort studies (OR: 0.93; 95%
comparison of CABG and DES), the results of these sub- Bayesian credible interval 0.58 to 1.35). A network meta-
group analyses need to be applied with caution. At analysis suggested that medical therapy is associated
5 years of follow-up, MACCE rates did not differ signif- with higher risk of death at 1 year than is the use of PCI for
icantly between groups of patients with low or inter- patients with unprotected left main CAD (OR: 3.22; 95%
mediate SYNTAX scores, but signicantly more patients Bayesian credible interval 1.96 to 5.30) (12). In that study,
in the DES group with high SYNTAX scores had the Bayesian method generated a credible interval that
MACCE than in the CABG group (46.5% versus 29.7%; has a high probability of containing the true OR. In other
p0.003) (86). words, the true value for the OR has a 95% probability
In the LE MANS (Study of Unprotected Left Main of lying within the interval of 0.68 to 1.45. Because the
Stenting Versus Bypass Surgery) trial (87), 105 patients value 1 is included in the credible interval, which is
with left main CAD were randomized to receive PCI or also symmetrical, the results show no evidence of a dif-
CABG. Although a low proportion of patients treated with ference between PCI and CABG for 1-year mortality
PCI received DES (35%) and a low proportion of patients rate. The possibility that PCI is associated with increased
treated with CABG received internal mammary grafts or decreased 1-year mortality over CABG is small (<2.5%
(72%), the outcomes at 30 days and 1 year were similar for a possible 45% increase or for a 32% decrease, ac-
between the groups. In the PRECOMBAT (Premier of cording to the denition of the 95% Bayesian credible
Randomized Comparison of Bypass Surgery Versus interval).
1940 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

5.12 Special Considerations trials (including FREEDOM) (68). The study of 3,131 pa-
In addition to patients coronary anatomy, left ventricular tients showed that at 5-year or longest follow-up, patients
function, and history of prior revascularization, clinical with diabetes mellitus randomized to CABG had a lower
features such as the existence of coexisting chronic con- all-cause mortality rate than did those randomized to PCI
ditions might inuence decision making. However, the with either DES or bare metal stent (relative risk 0.67; 95%
paucity of information about special subgroups is one of CI: 0.52 to 0.86; p0.002) (94).
the greatest challenges in developing evidence-based In summary, patients with SIHD and diabetes mellitus
guidelines applicable to large populations. As is the case should receive GDMT. For patients whose symptoms
for many chronic conditions, studies specically geared compromise their quality of life, revascularization should
toward answering clinical questions about the manage- be considered. CABG appears to be associated with lower
ment of SIHD in women, older adults, and persons with risk of mortality than is PCI in most patients with diabetes
chronic kidney disease are lacking. The ACCF/AHA mellitus and complex multivessel disease, although the
guidelines for the management of patients with unstable Heart Team may identify exceptions. To address the
angina/nonST-elevation myocardial infarction (90,91) important issue of deciding between PCI and CABG in
address special subgroups. The present section echoes patients with diabetes mellitus and complex multivessel
those management recommendations. Although this sec- CAD, a Heart Team approach would be benecial. This
tion will briey review some special considerations for was an integral component of the FREEDOM, SYNTAX,
diagnosis and therapy in certain groups of patients, the and BARI trials (68,66,59) and is therefore emphasized in
general approach should be to apply the recommenda- this setting. The Heart Team is a multidisciplinary team
tions in this guideline consistently among groups. composed of an interventional cardiologist and a cardiac
surgeon who jointly 1) review the patients medical con-
5.12.3 Diabetes Mellitus dition and coronary anatomy, 2) determine that PCI and/
or CABG are technically feasible and reasonable, and,
See Online Data Supplement 6 for additional evidence table.
3) discusses revascularization options with the patient
In the FREEDOM (Future Revascularization Evaluation in
before a treatment strategy is selected.
Patients With Diabetes Mellitus: Optimal Management of
Future research may be facilitated by including a eld
Multivessel Disease) trial, 1,900 patients with multivessel
in the National Cardiovascular Data PCI Registry and the
CAD were randomized to either PCI with DES or CABG (68).
STS database to identify cases turned down for the
The primary outcomea composite of death, nonfatal MI,
alternative revascularization strategy.
or nonfatal strokeoccurred less frequently in the CABG
group (p0.005), with 5-year rates of 18.7% in the CABG
group and 26.6% in the DES group. The benet of CABG PRESIDENTS AND STAFF
was related to differences in rates of both MI (p<0.001)
and death from any cause (p0.049). Stroke was more American College of Cardiology
frequent in the CABG group, with 5-year rates of 5.2% in Patrick T. OGara, MD, MACC, President
the CABG group and 2.4% in the DES group (p0.03). Shalom Jacobovitz, Chief Executive Ofcer
Other studies have provided mixed evidence, but none William J. Oetgen, MD, MBA, FACC, Executive Vice President,
has suggested a survival advantage of PCI. The 5-year Science, Education, and Quality
update from the SYNTAX trial did not show a signicant Amelia Scholtz, PhD, Publications Manager, Clinical
advantage in survival after CABG compared with survival Policy and Pathways
after DES in patients with diabetes mellitus and multi- American College of Cardiology/American Heart Association
vessel CAD (12.9% versus 19.5%; p0.065) (83). A meta- Lisa Bradeld, CAE, Director, Clinical Policy and Guidelines
analysis of 4 trials showed no signicant advantage Ezaldeen Ramadhan III, Project Management Team Leader,
in survival after CABG compared with survival after Science and Clinical Policy
PCI for patients with diabetes mellitus (7.9% versus American Heart Association
12.4%; p0.09) (92). In a pooled analysis, it was Elliott Antman, MD, FACC, FAHA, President
found that patients with diabetes mellitus assigned to Nancy Brown, Chief Executive Ofcer
CABG had improved survival (23% versus 29%; p0.008 Rose Marie Robertson, MD, FAHA, Chief Science Ofcer
for the interaction between presence of diabetes Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice
mellitus and type of revascularization procedure after President, Ofce of Science Operations
adjustment) (93). Marco Di Buono, PhD, Vice President, Science, Research,
The strongest evidence supporting the use of CABG and Professional Education, Ofce of Science Operations
over PCI for patients with diabetes mellitus and multi- Jody Hundley, Production Manager, Scientic Publi-
vessel CAD comes from a published meta-analysis of 8 cations, Ofce of Science Operations
JACC VOL. 64, NO. 18, 2014 Fihn et al. 1941
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

REFERENCES

1. American College of Cardiology/American Heart As- STS 2012 appropriate use criteria for diagnostic cath- and the Society for Cardiovascular Magnetic Resonance.
sociation: Methodology Manual and Policies From the eterization: a report of the American College of Car- J Am Coll Cardiol 2010;56:186494.
ACCF/AHA Task Force on Practice Guidelines. Available diology Foundation Appropriate Use Criteria Task
20. Leape LL, Park RE, Bashore TM, et al. Effect
at: http://assets.cardiosource.com/Methodology_ Force, Society for Cardiovascular Angiography and In-
of variability in the interpretation of coronary angio-
Manual_for_ACC_AHA_Writing_Committees.pdf. terventions, American Association for Thoracic Sur-
grams on the appropriateness of use of coronary
Accessed April 29, 2014. gery, American Heart Association, American Society of
revascularization procedures. Am Heart J 2000;139:
Echocardiography, American Society of Nuclear Cardi-
2. Institute of Medicine (U.S.). Finding What Works in 10613.
ology, Heart Failure Society of America, Heart Rhythm
Health Care: Standards for Systematic Reviews.
Society, Society of Critical Care Medicine, Society of 21. Fleming RM, Kirkeeide RL, Smalling RW, et al.
Washington, D.C.: National Academies Press, 2011.
Cardiovascular Computed Tomography, Society for Patterns in visual interpretation of coronary arterio-
3. Institute of Medicine (U.S.). Committee on Cardiovascular Magnetic Resonance, and Society of grams as detected by quantitative coronary arteriog-
Standards for Developing Trustworthy Clinical Practice Thoracic Surgeons. J Am Coll Cardiol 2012;59:1995 raphy. J Am Coll Cardiol 1991;18:94551.
Guidelines: Clinical Practice Guidelines We Can Trust. 2027.
22. Nallamothu BK, Spertus JA, Lansky AJ, et al.
Washington, D.C.: National Academies Press, 2011.
12. Bittl JA, He Y, Jacobs AK, et al. Bayesian methods Comparison of clinical interpretation with visual
4. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ afrm the use of percutaneous coronary intervention assessment and quantitative coronary angiography in
AHA/ACP/AATS/PCNA/SCAI/STS guideline for the to improve survival in patients with unprotected left patients undergoing percutaneous coronary interven-
diagnosis and management of patients with stable main coronary artery disease. Circulation 2013;127: tion in contemporary practice: the Assessing Angiog-
ischemic heart disease: a report of the American Col- 217785. raphy (A2) project. Circulation 2013;127:1793800.
lege of Cardiology Foundation/American Heart Asso-
13. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/ 23. Anderson RD, Pepine CJ. Coronary angiography: is
ciation Task Force on Practice Guidelines, and the
AHA guideline for the management of heart failure: a it time to reassess? Circulation 2013;127:17602.
American College of Physicians, American Association
report of the American College of Cardiology Founda-
for Thoracic Surgery, Preventive Cardiovascular Nurses 24. Kern MJ, Samady H. Current concepts of integrated
tion/American Heart Association Task Force on Practice
Association, Society for Cardiovascular Angiography coronary physiology in the catheterization laboratory.
Guidelines. J Am Coll Cardiol 2013;62:e147239.
and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2010;55:17385.
J Am Coll Cardiol 2012;60:e44164. 14. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/
25. Bech GJ, de Bruyne B, Pijls NH, et al. Fractional
ESC 2006 guidelines for management of patients
5. de Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional ow reserve to determine the appropriateness of an-
with ventricular arrhythmias and the prevention of
ow reserveguided PCI versus medical therapy in gioplasty in moderate coronary stenosis: a randomized
sudden cardiac death: a report of the American
stable coronary disease. N Engl J Med 2012;367: trial. Circulation 2001;103:292834.
College of Cardiology/American Heart Association
9911001.
Task Force and the European Society of Cardiology 26. Tonino PAL, de Bruyne B, Pijls NHJ, et al. Fractional
6. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ Committee for Practice Guidelines (Writing Committee ow reserve versus angiography for guiding percuta-
AHA/ACP/AATS/PCNA/SCAI/STS guideline for the to Develop Guidelines for Management of Patients neous coronary intervention. N Engl J Med 2009;360:
diagnosis and management of patients with stable With Ventricular Arrhythmias and the Prevention of 21324.
ischemic heart disease: executive summary: a report of Sudden Cardiac Death). J Am Coll Cardiol 2006;48:
the American College of Cardiology Foundation/ 27. Pijls NHJ, Fearon WF, Tonino PAL, et al. Fractional
e247346.
American Heart Association task force on practice ow reserve versus angiography for guiding percuta-
15. Fleisher LA, Fleischmann KE, Auerbach AD, et al. neous coronary intervention in patients with multi-
guidelines, and the American College of Physicians,
2014 ACC/AHA guideline on perioperative cardiovas- vessel coronary artery disease: 2-year follow-up of the
American Association for Thoracic Surgery, Preventive
cular evaluation and management of patients under- FAME (Fractional Flow Reserve Versus Angiography for
Cardiovascular Nurses Association, Society for Cardio-
going noncardiac surgery. J Am Coll Cardiol 2014 In Multivessel Evaluation) study. J Am Coll Cardiol 2010;
vascular Angiography and Interventions, and Society of
press. 56:17784.
Thoracic Surgeons. J Am Coll Cardiol 2012;60:
2564603. 16. Lentine KL, Costa SP, Weir MR, et al. Cardiac dis- 28. Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA
ease evaluation and management among kidney and guidelines for coronary angiography: a report of the
7. Hammermeister KE, DeRouen TA, Dodge HT. Vari-
liver transplantation candidates: a scientic statement American College of Cardiology/American Heart
ables predictive of survival in patients with coronary
from the American Heart Association and the American Association Task Force on practice guidelines
disease. Selection by univariate and multivariate ana-
College of Cardiology Foundation. J Am Coll Cardiol (Committee on Coronary Angiography). Developed
lyses from the clinical, electrocardiographic, exercise,
2012;60:43480. in collaboration with the Society for Cardiac Angiog-
arteriographic, and quantitative angiographic evalua-
tions. Circulation 1979;59:42130. 17. Raval Z, Harinstein ME, Skaro AI, et al. Cardiovas- raphy and Interventions. J Am Coll Cardiol 1999;33:
cular risk assessment of the liver transplant candidate. 1756824.
8. Mark DB, Hlatky MA, Harrell FE Jr., et al. Exercise
J Am Coll Cardiol 2011;58:22331.
treadmill score for predicting prognosis in coronary 29. Dehmer GJ, Weaver D, Roe MT, et al.
artery disease. Ann Intern Med 1987;106:793800. 18. Mark DB, Berman DS, Budoff MJ, et al. ACCF/ACR/ A contemporary view of diagnostic cardiac catheteri-
AHA/NASCI/SAIP/SCAI/SCCT 2010 expert consensus zation and percutaneous coronary intervention in the
9. Levine GN, Bates ER, Blankenship JC, et al. 2011
document on coronary computed tomographic angiog- United States: a report from the CathPCI Registry of
ACCF/AHA/SCAI guideline for percutaneous coronary
raphy: a report of the American College of Cardiology the National Cardiovascular Data Registry, 2010
intervention: a report of the American College of Car-
Foundation Task Force on Expert Consensus Docu- through June 2011. J Am Coll Cardiol 2012;60:201731.
diology Foundation/American Heart Association Task
ments. J Am Coll Cardiol 2010;55:266399.
Force on Practice Guidelines and the Society for Car- 30. Batyraliev T, Ayalp MR, Sercelik A, et al. Compli-
diovascular Angiography and Interventions. J Am Coll 19. Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/ cations of cardiac catheterization: a single-center
Cardiol 2011;58:e44122. SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 study. Angiology 2005;56:7580.
appropriate use criteria for cardiac computed tomog-
10. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/ 31. Chandrasekar B, Doucet S, Bilodeau L, et al. Com-
raphy: a report of the American College of Cardiology
AHA guideline for coronary artery bypass graft surgery: plications of cardiac catheterization in the current era:
Foundation Appropriate Use Criteria Task Force, the
a report of the American College of Cardiology Foun- a single-center experience. Catheter Cardiovasc Interv
Society of Cardiovascular Computed Tomography, the
dation/American Heart Association Task Force on 2001;52:28995.
American College of Radiology, the American Heart
Practice Guidelines. J Am Coll Cardiol 2011;58:
Association, the American Society of Echocardiography, 32. West R, Ellis G, Brooks N, et al. Complications of
e123210.
the American Society of Nuclear Cardiology, the North diagnostic cardiac catheterisation: results from a
11. Patel MR, Bailey SR, Bonow RO, et al. ACCF/SCAI/ American Society for Cardiovascular Imaging, the Soci- condential inquiry into cardiac catheter complica-
AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/ ety for Cardiovascular Angiography and Interventions, tions. Heart 2006;92:8104.
1942 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

33. Levine GN, Kern MJ, Berger PB, et al. Management 49. Shechter M, Matetzky S, Feinberg MS, et al. 63. Malenka DJ, Leavitt BJ, Hearne MJ, et al.
of patients undergoing percutaneous coronary revas- External counterpulsation therapy improves endothe- Comparing long-term survival of patients with multi-
cularization. Ann Intern Med 2003;139:12336. lial function in patients with refractory angina pectoris. vessel coronary disease after CABG or PCI: analysis of
J Am Coll Cardiol 2003;42:20905. BARI-like patients in northern New England. Circula-
34. Ko DT, Wang Y, Alter DA, et al. Regional variation
tion 2005;112:I3716.
in cardiac catheterization appropriateness and baseline 50. Urano H, Ikeda H, Ueno T, et al. Enhanced external
risk after acute myocardial infarction. J Am Coll Cardiol counterpulsation improves exercise tolerance, reduces 64. Niles NW, McGrath PD, Malenka D, et al. Survival
2008;51:71623. exercise-induced myocardial ischemia and improves of patients with diabetes and multivessel coronary
left ventricular diastolic lling in patients with coro- artery disease after surgical or percutaneous coronary
35. Douglas PS, Patel MR, Bailey SR, et al. Hospital
nary artery disease. J Am Coll Cardiol 2001;37:939. revascularization: results of a large regional prospec-
variability in the rate of nding obstructive coronary
tive study. Northern New England Cardiovascular Dis-
artery disease at elective, diagnostic coronary angiog- 51. Braith RW, Conti CR, Nichols WW, et al. Enhanced
ease Study Group. J Am Coll Cardiol 2001;37:100815.
raphy. J Am Coll Cardiol 2011;58:8019. external counterpulsation improves peripheral artery
ow-mediated dilation in patients with chronic angina: 65. Weintraub WS, Stein B, Kosinski A, et al. Outcome
36. Patel MR, Peterson ED, Dai D, et al. Low diagnostic
a randomized sham-controlled study. Circulation 2010; of coronary bypass surgery versus coronary angio-
yield of elective coronary angiography. N Engl J Med
122:161220. plasty in diabetic patients with multivessel coronary
2010;362:88695.
artery disease. J Am Coll Cardiol 1998;31:109.
52. Shah SA, Shapiro RJ, Mehta R, et al. Impact of
37. Bradley SM, Maddox TM, Stanislawski MA, et al.
enhanced external counterpulsation on Canadian Car- 66. Serruys PW, Morice MC, Kappetein AP, et al.
Normal coronary rates for elective angiography in the
diovascular Society angina class in patients with Percutaneous coronary intervention versus coronary-
Veterans Affairs Healthcare System: insights from the
chronic stable angina: a meta-analysis. Pharmaco- artery bypass grafting for severe coronary artery dis-
VA CART Program (Veterans Affairs Clinical Assess-
therapy 2010;30:63945. ease. N Engl J Med 2009;360:96172.
ment Reporting and Tracking). J Am Coll Cardiol 2014;
63:41726. 53. Stys TP, Lawson WE, Hui JCK, et al. Effects of 67. Deleted in press.
enhanced external counterpulsation on stress radio- 68. Farkouh ME, Domanski M, Sleeper LA, et al. Stra-
38. Guldager B, Jelnes R, Jrgensen SJ, et al. EDTA
nuclide coronary perfusion and exercise capacity in tegies for multivessel revascularization in patients with
treatment of intermittent claudicationa double-blind,
chronic stable angina pectoris. Am J Cardiol 2002;89: diabetes. N Engl J Med 2012;367:237584.
placebo-controlled study. J Intern Med 1992;231:2617.
8224.
69. Hannan EL, Racz MJ, Walford G, et al. Long-term
39. van Rij AM, Solomon C, Packer SG, et al. Chelation
54. Barsness G, Feldman AM, Holmes DRJ, et al. The outcomes of coronary-artery bypass grafting versus
therapy for intermittent claudication. A double-blind,
International EECP Patient Registry (IEPR): design, stent implantation. N Engl J Med 2005;352:217483.
randomized, controlled trial. Circulation 1994;90:
methods, baseline characteristics, and acute results.
11949. 70. Hannan EL, Wu C, Walford G, et al. Drug-eluting
Clin Cardiol 2001;24:43542.
stents vs. coronary-artery bypass grafting in multi-
40. Sloth-Nielsen J, Guldager B, Mouritzen C, et al.
55. Wu E, Mrtensson J, Brostrm A. Enhanced vessel coronary disease. N Engl J Med 2008;358:
Arteriographic ndings in EDTA chelation therapy
external counterpulsation in patients with refractory 33141.
on peripheral arteriosclerosis. Am J Surg 1991;162:
angina pectoris: a pilot study with six months follow-
1225. 71. Briguori C, Condorelli G, Airoldi F, et al. Comparison
up regarding physical capacity and health-related
of coronary drug-eluting stents versus coronary artery
41. Knudtson ML, Wyse DG, Galbraith PD, et al. Che- quality of life. Eur J Cardiovasc Nurs 2013;12:43745.
bypass grafting in patients with diabetes mellitus. Am J
lation therapy for ischemic heart disease: a randomized
56. McKenna C, McDaid C, Suekarran S, et al. Enhanced Cardiol 2007;99:77984.
controlled trial. JAMA 2002;287:4816.
external counterpulsation for the treatment of stable
72. Javaid A, Steinberg DH, Buch AN, et al. Outcomes
42. Lamas GA, Goertz C, Boineau R, et al. Effect of angina and heart failure: a systematic review and
of coronary artery bypass grafting versus percutaneous
disodium EDTA chelation regimen on cardiovascular economic analysis. Health Technol Assess 2009;13:
coronary intervention with drug-eluting stents for
events in patients with previous myocardial infarction: iiiiiv, ixxi, 190.
patients with multivessel coronary artery disease.
the TACT randomized trial. JAMA 2013;309:124150.
57. Amin F, Al Hajeri A, Civelek B, et al. Enhanced Circulation 2007;116:I2006.
43. Tellez-Plaza M, Guallar E, Howard BV, et al. Cad- external counterpulsation for chronic angina pectoris. 73. Lee MS, Jamal F, Kedia G, et al. Comparison of
mium exposure and incident cardiovascular disease. Cochrane Database Syst Rev 2010:CD007219. bypass surgery with drug-eluting stents for diabetic
Epidemiology 2013;24:4219.
58. Sorajja P, Chareonthaitawee P, Rajagopalan N, patients with multivessel disease. Int J Cardiol 2007;
44. Xun P, Liu K, Morris S, et al. Association of toenail et al. Improved survival in asymptomatic diabetic 123:3442.
cadmium levels with measures of sub-clinical athero- patients with high-risk SPECT imaging treated with 74. Park DW, Yun SC, Lee SW, et al. Long-term mor-
sclerosis: the Coronary Artery Risk Development in coronary artery bypass grafting. Circulation 2005;112: tality after percutaneous coronary intervention with
Young Adults (CARDIA) Trace Element Study. In: Ab- I3116. drug-eluting stent implantation versus coronary artery
stracts From the Epidemiology and Prevention/Phys- bypass surgery for the treatment of multivessel coro-
59. Inuence of diabetes on 5-year mortality and
ical Activity, Nutrition and Metabolism 2012 Scientic nary artery disease. Circulation 2008;117:207986.
morbidity in a randomized trial comparing CABG and
Sessions (abstr P301). Circulation 2012;125 Suppl:
PTCA in patients with multivessel disease: the Bypass 75. Tarantini G, Ramondo A, Napodano M, et al. PCI
AP 301.
Angioplasty Revascularization Investigation (BARI). versus CABG for multivessel coronary disease in di-
45. Centers for Disease Control and Prevention (CDC). Circulation 1997;96:17619. abetics. Catheter Cardiovasc Interv 2009;73:508.
Deaths associated with hypocalcemia from chelation
60. Banning AP, Westaby S, Morice MC, et al. Diabetic 76. Varani E, Balducelli M, Vecchi G, et al. Comparison
therapyTexas, Pennsylvania, and Oregon, 2003-
and nondiabetic patients with left main and/or 3-vessel of multiple drug-eluting stent percutaneous coronary
2005. MMWR Morb Mortal Wkly Rep 2006;55:2047.
coronary artery disease: comparison of outcomes with intervention and surgical revascularization in patients
46. Howland MA. Edetate calcium disodium cardiac surgery and paclitaxel-eluting stents. J Am Coll with multivessel coronary artery disease: one-year
(CaNa2EDTA). In: Nelson L, Goldfrank LR, editors. Cardiol 2010;55:106775. clinical results and total treatment costs. J Invasive
Goldfranks Toxicologic Emergencies. New York: Cardiol 2007;19:46975.
61. Hoffman SN, TenBrook JA, Wolf MP, et al. A meta-
McGraw-Hill Medical, 2011:12903.
analysis of randomized controlled trials comparing 77. Yang JH, Gwon HC, Cho SJ, et al. Comparison of
47. Arora RR, Chou TM, Jain D, et al. The multicenter coronary artery bypass graft with percutaneous trans- coronary artery bypass grafting with drug-eluting stent
study of enhanced external counterpulsation (MUST- luminal coronary angioplasty: one- to eight-year out- implantation for the treatment of multivessel coronary
EECP): effect of EECP on exercise-induced myocardial comes. J Am Coll Cardiol 2003;41:1293304. artery disease. Ann Thorac Surg 2008;85:6570.
ischemia and anginal episodes. J Am Coll Cardiol 1999;
62. Hueb W, Lopes NH, Gersh BJ, et al. Five-year 78. Yang ZK, Shen WF, Zhang RY, et al. Coronary artery
33:183340.
follow-up of the Medicine, Angioplasty, or Surgery bypass surgery versus percutaneous coronary inter-
48. Akhtar M, Wu GF, Du ZM, et al. Effect of external Study (MASS II): a randomized controlled clinical trial vention with drug-eluting stent implantation in pa-
counterpulsation on plasma nitric oxide and of 3 therapeutic strategies for multivessel coronary tients with multivessel coronary disease. J Interv
endothelin-1 levels. Am J Cardiol 2006;98:2830. artery disease. Circulation 2007;115:10829. Cardiol 2007;20:106.
JACC VOL. 64, NO. 18, 2014 Fihn et al. 1943
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

79. Weintraub WS, Grau-Sepulveda MV, Weiss JM, 85. Deleted in press. AHA 2007 guidelines for the management of patients
et al. Comparative effectiveness of revascularization with unstable angina/non-ST-elevation myocardial
86. Mohr FW, Morice MC, Kappetein AP, et al. Coro-
strategies. N Engl J Med 2012;366:146776. infarction: a report of the American College of Cardi-
nary artery bypass graft surgery versus percutaneous
ology Foundation/American Heart Association Task
80. Benedetto U, Melina G, Angeloni E, et al. Coronary coronary intervention in patients with three-vessel
Force on Practice Guidelines. J Am Coll Cardiol 2013;
artery bypass grafting versus drug-eluting stents in disease and left main coronary disease: 5-year follow-
61:e179347.
multivessel coronary disease. A meta-analysis on 24, up of the randomised, clinical SYNTAX trial. Lancet
268 patients. Eur J Cardiothorac Surg 2009;36:6115. 2013;381:62938. 92. Daemen J, Boersma E, Flather M, et al. Long-term
safety and efcacy of percutaneous coronary inter-
81. Morice MC, Serruys PW, Kappetein AP, et al. Out- 87. Buszman PE, Kiesz SR, Bochenek A, et al. Acute
vention with stenting and coronary artery bypass
comes in patients with de novo left main disease and late outcomes of unprotected left main stenting in
surgery for multivessel coronary artery disease: a
treated with either percutaneous coronary intervention comparison with surgical revascularization. J Am Coll
meta-analysis with 5-year patient-level data from the
using paclitaxel-eluting stents or coronary artery Cardiol 2008;51:53845.
ARTS, ERACI-II, MASS-II, and SoS trials. Circulation
bypass graft treatment in the Synergy Between
88. Park SJ, Kim YH, Park DW, et al. Randomized trial 2008;118:114654.
Percutaneous Coronary Intervention with TAXUS and
Cardiac Surgery (SYNTAX) trial. Circulation 2010;121: of stents versus bypass surgery for left main coronary 93. Hlatky MA, Boothroyd DB, Bravata DM, et al.
264553. artery disease. N Engl J Med 2011;364:171827. Coronary artery bypass surgery compared with percu-
89. Naik H, White AJ, Chakravarty T, et al. taneous coronary interventions for multivessel disease:
82. Kappetein AP, Feldman TE, Mack MJ, et al. Com-
A meta-analysis of 3,773 patients treated with a collaborative analysis of individual patient data from
parison of coronary bypass surgery with drug-eluting
percutaneous coronary intervention or surgery for ten randomised trials. Lancet 2009;373:11907.
stenting for the treatment of left main and/or three-
vessel disease: 3-year follow-up of the SYNTAX trial. unprotected left main coronary artery stenosis. J Am 94. Verma S, Farkouh ME, Yanagawa B. Comparison of
Eur Heart J 2011;32:212534. Coll Cardiol Intv 2009;2:73947. coronary artery bypass surgery and percutaneous cor-
90. Jneid H, Anderson JL, Wright RS, et al. 2012 onary intervention in patients with diabetes: a meta-
83. Kappetein AP, Head SJ, Morice MC, et al. Treat-
ACCF/AHA focused update of the guideline for the analysis of randomised controlled trials. The Lancet
ment of complex coronary artery disease in patients
management of patients with unstable angina/ Diabetes & Endocrinology 2013;1:31728.
with diabetes: 5-year results comparing outcomes of
bypass surgery and percutaneous coronary interven- non-ST-elevation myocardial infarction (updating the
tion in the SYNTAX trial. Eur J Cardiothorac Surg 2013; 2007 guideline and replacing the 2011 focused
KEY WORDS ACC/AHA Clinical Practice
43:100613. update): a report of the American College of Cardi-
Guidelines, cardiac catheterization,
ology Foundation/American Heart Association Task
84. Ragosta M, Dee S, Sarembock IJ, et al. Prevalence cardiovascular, chelation therapy, coronary
Force on Practice Guidelines. J Am Coll Cardiol 2012;
of unfavorable angiographic characteristics for percu- angiography, coronary artery bypass graft,
60:64581.
taneous intervention in patients with unprotected left counterpulsation, diagnostic techniques,
main coronary artery disease. Catheter Cardiovasc 91. Anderson JL, Adams CD, Antman EM, et al. 2012 focused update, myocardial ischemia,
Interv 2006;68:35762. ACCF/AHA focused update incorporated into the ACCF/ percutaneous coronary intervention
1944 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)


2014 ACC/AHA/AATS/PCNA/SCAI/STS FOCUSED UPDATE OF THE GUIDELINE FOR THE DIAGNOSIS
AND MANAGEMENT OF PATIENTS WITH STABLE ISCHEMIC HEART DISEASE

Institutional,
Ownership/ Organizational, Voting
Committee Speakers Partnership/ Personal or Other Expert Recusals by
Member Employment Consultant Bureau Principal Research Financial Benet Witness Section*

Stephan D. Fihn Department of Veterans None None None None None None None
(Chair) AffairsDirector, Ofce
of Analytics and
Business Intelligence

James C. Geisinger Medical Center None None None  AstraZeneca None None 2.2.5
Blankenship Staff Physician; Director,  Boston 4.4.2
(Vice Chair) Cardiac Catheterization Scientic 4.4.4
Laboratory  Kai 5.2
Pharmaceutical
 The Medicines
Company
 Schering-
Plough
 Volcano

Karen P. Duke University Medical None None None  Gilead  Sano- None 2.2.5
Alexander CenterAssociate aventis 4.4.2
Professor of Medicine/ 4.4.4
Cardiology 5.2

John A. Bittl Munroe Regional Medical None None None None None None None
CenterInvasive
Cardiologist

John G. Byrne Brigham and Womens None None None None None None None
HospitalChief,
Division of Cardiac
Surgery

Barbara J. University of North None None None None None None None
Fletcher FloridaClinical
Associate Professor,
School of Nursing

Gregg C. UCLA Cardiomyopathy  Boston None None None None None 2.2.5
Fonarow CenterProfessor Scientic 5.2
of Medicine  Johnson &
Johnson
 The Medicines
Company
 Medtronic

Richard A. University of Texas Health None None None None None None None
Lange Science Center, San
AntonioProfessor
of Medicine

Glenn N. Baylor College of None None None None None None None
Levine MedicineProfessor
of Medicine; Director,
Cardiac Care Unit

Thomas M. VA Eastern Colorado None None None None None None None
Maddox Health Care System
Cardiologist
Srihari S. Winthrop University None None None None None None None
Naidu HospitalDirector,
Cardiac Catheterization
Laboratory

Continued on the next page


JACC VOL. 64, NO. 18, 2014 Fihn et al. 1945
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

APPENDIX 1. CONTINUED

Institutional,
Ownership/ Organizational, Voting
Committee Speakers Partnership/ Personal or Other Expert Recusals by
Member Employment Consultant Bureau Principal Research Financial Benet Witness Section*
E. Magnus Duke Medicine  AstraZeneca  Gilead None  Daiichi- None None 2.2.5
Ohman Professor of Medicine  Bristol-Myers Sciences Sankyo 4.4.2
Squibb  Gilead 4.4.4
 Gilead Sciences 5.2
Sciences
 The Medicines
Company
 Merck
 Sano-
aventis
Peter K. Smith Duke University Medical None None None None None None None
CenterProfessor of
Surgery; Chief,
Thoracic Surgery

This table represents the relationships of writing group members with industry and other entities that were determined to be relevant to this document. These relationships were
reviewed and updated in conjunction with all meetings and/or conference calls of the writing group during the document development process. The table does not necessarily reect
relationships with industry at the time of publication. A person is deemed to have a signicant interest in a business if the interest represents ownership of $5% of the voting stock or
share of the business entity, or ownership of $$10,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the
persons gross income for the previous year. Relationships that exist with no nancial benet are also included for the purpose of transparency. Relationships in this table are modest
unless otherwise noted.
According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or
issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing
drug or device addressed in the document; or c) the person or a member of the persons household has a reasonable potential for nancial, professional, or other personal gain or loss as
a result of the issues/content addressed in the document.
*Writing group members are required to recuse themselves from voting on sections to which their specic relationships with industry and other entities may apply. Section numbers
pertain to those in the full-text guideline.
Signicant relationship.
No nancial benet.
AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiology; AHA, American Heart Association; PCNA, Preventive Cardiovascular Nurses
Association; SCAI, Society for Cardiovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; and VA, Veterans Affairs.
1946 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

APPENDIX 2. REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)


2014 ACC/AHA/AATS/PCNA/SCAI/STS FOCUSED UPDATE OF THE GUIDELINE FOR THE DIAGNOSIS
AND MANAGEMENT OF PATIENTS WITH STABLE ISCHEMIC HEART DISEASE

Institutional,
Organizational,
Speakers Personal or Other
Peer Reviewer Representation Employment Consultant Bureau Research Financial Benet

Judith S. Ofcial ReviewerACC/ New York University None None  NIH None
Hochman AHA Task Force on School of Medicine (PIISCHEMIA
Practice Guidelines Clinical Chief of trial)*
Cardiology

Bruce W. Ofcial ReviewerAHA Cleveland Clinic None None None None


Lytle Foundation
Chairman, Thoracic
and Cardiovascular
Surgery

Margo B. Ofcial ReviewerACC Cedar-Sinais Heart None None None  Gilead Sciences*
Minissian Board of Governors InstituteCardiology
Nurse Practitioner;
University of
California Los
AngelesAssistant
Clinical Professor

C. Michael Ofcial ReviewerACC Centra Lynchburg None None None None


Valentine Board of Trustees General Hospital
Director, Cardiac
Progressive Care
Unit; Centra
Stroobants Heart
CenterDirector of
Clinical Quality

Lani M. Ofcial ReviewerAHA University of Nebraska None None None None


Zimmerman Medical Center
Professor, College of
Nursing

Robert S.D. Organizational Ohio State University None None None None
Higgins ReviewerSTS Director, Division of
Cardiac Surgery

Ajay J. Organizational Columbia University None  Boston  Medtronic* None


Kirtane ReviewerSCAI Medical CenterChief Scientic*
Academic Ofcer;
Director,
Interventional
Cardiology
Fellowship Program;
and Assistant
Professor of Clinical
Medicine

Joseph D. Organizational University of Vermont None None None None


Schmoker ReviewerAATS Associate Professor
of Surgery and
Medicine; Fletcher
Allen Health Care
Director of the Center
for Thoracic Aortic
Disease

Joanna D. Organizational University of Miami None None None None


Sikkema ReviewerPCNA Adult Nurse
Practitioner, School
of Nursing and Health
Studies

Nancy M. Content Reviewer Cleveland Clinic None None None None


Albert ACC/AHA Task FoundationSenior
Force on Practice Director of Nursing
Guidelines and Research
Mohamed A. Content ReviewerAIG Alexandria University None None None None
Sobhy Aly Professor of
Cardiology, Head of
Cardiology
Department

Continued on the next page


JACC VOL. 64, NO. 18, 2014 Fihn et al. 1947
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

APPENDIX 2. CONTINUED

Institutional,
Organizational,
Speakers Personal or Other
Peer Reviewer Representation Employment Consultant Bureau Research Financial Benet

Jeffrey L. Content Reviewer Intermountain Medical  Sano-aventis None None None


Anderson ACC/AHA Task CenterAssociate
Force on Practice Chief of Cardiology
Guidelines

Eric R. Bates Content Reviewer University of Michigan  AstraZeneca None None None
Health System  Bristol-Myers
Professor, Squibb
Department of  Daiichi-Sankyo
Internal Medicine  Merck
 Sano-aventis

Ralph G. Content Reviewer University of California None None None None


Brindis ACC/AHA Task San Francisco
Force on Practice Clinical Professor
Guidelines of Medicine,
Department of
Medicine and Philip
R. Lee Institute for
Health Policy Studies

Biykem Content Michael E. None None None None


Bozkurt Reviewer DeBakey VA Medical
ACC/AHA Task CenterChief,
Force on Practice Cardiology Section;
Guidelines The Mary and Gordon
Cain Chair and
Professor of
Medicine; Director,
Winters Center for
Heart Failure
Research

Steven M. Content Reviewer VA Eastern Colorado None None None None


Bradley Health Care System
Physician

James A. Burke Content Lehigh Valley Heart None None None None
Reviewer Specialists
ACC Interventional Cardiovascular
Scientic Council Disease Doctor

John H. Content Reviewer University of Texas None None None None


Calhoon Health Science
CenterProfessor;
Chair, CT Surgery
Department

Lesley Curtis Content Duke University School None None  GE Healthcare* None
Reviewer of Medicine  Johnson &
ACC/AHA Task Associate Professor Johnson*
Force on Practice of Medicine
Guidelines

Prakash C. Content Reviewer University of California  Gilead Sciences None None None
Deedwania San FranciscoChief
of Cardiology

Gregory J. Content Reviewer Scott & White None None None None
Dehmer HealthcareDirector,
Division of
Cardiology; Texas
A&M Health Science
Center College of
MedicineProfessor
of Medicine
Linda D. Content Morristown Medical None None  Edwards  Edwards
Gillam ReviewerACC CenterProfessor Lifesciences Lifesciences
Imaging Council of Cardiology; Vice
Chair, Cardiovascular
Medicine

Continued on the next page


1948 Fihn et al. JACC VOL. 64, NO. 18, 2014

2014 Stable Ischemic Heart Disease Focused Update NOVEMBER 4, 2014:192949

APPENDIX 2. CONTINUED

Institutional,
Organizational,
Speakers Personal or Other
Peer Reviewer Representation Employment Consultant Bureau Research Financial Benet

Christopher B. Content Duke Clinical Research  AstraZeneca None  Bristol-Myers  GE Healthcare*


Granger ReviewerAHA InstituteAssociate  Bristol-Myers Squibb*  Medtronic*
Professor of Squibb  Medtronic*  Philips Medical*
Medicine; Director,  Daiichi-Sankyo  Merck*
Cardiac Care Unit  Eli Lilly  Sano-aventis*
 The Medicines  The Medicines
Company Company*

Robert A. Content Emory University School  Medtronic None None None


Guyton Reviewer of Medicine
ACC/AHA Task Professor of Surgery
Force on Practice and Chief, Division of
Guidelines Cardiothoracic
Surgery

Jonathan L. Content Mt. Sinai Medical  AstraZeneca None None None


Halperin Reviewer CenterProfessor of  Boston Scientic
ACC/AHA Task Medicine  Bristol-Myers
Force on Practice Squibb
Guidelines  Daiichi-Sankyo
 Johnson & Johnson
 Medtronic
 Sano-aventis*

Mark A. Content Reviewer Stanford University  Blue Cross/Blue None None None
Hlatky School of Medicine Shield
Professor of Health  Gilead Sciences
Research and Policy  HeartFlow*

Lloyd W. Content Reviewer Rush University Medical None None None None
Klein CenterProfessor,
Internal Medicine

Richard J. Content Krannert Institute of None None None  Cook Medical*


Kovacs Reviewer Cardiology  Eli Lilly
ACC/AHA Task Professor of Clinical
Force on Practice Medicine
Guidelines

Stephen J. Content Reviewer University of Connecticut None None None None


Lahey Health Center
Professor; Chief of
Cardiothoracic
Surgery

Michael J. Content Reviewer Baylor Health Care None None  Edwards None
Mack SystemDirector Lifesciences

Daniel B. Mark Content Reviewer Duke Clinical Research None None  AstraZeneca  Eli Lilly*
InstituteProfessor  Eli Lilly*  Medtronic*
of Medicine  Gilead Sciences
 Medtronic*

David J. Maron Content Reviewer Vanderbilt University None None  AstraZeneca* None
Medical Center  Gilead Sciences*
Director, Vanderbilt  Merck*
Chest Pain Center

Hani K. Najm Content Reviewer National Guard Health None None None None
ACC Surgeons AffairsPresident,
Scientic Council Saudi Heart
Association

L. Kristin Content Reviewer Duke University Medical  AstraZeneca None  Amylin  Bristol-Myers
Newby CenterAssociate  Daiichi-Sankyo  Eli Lilly Squibb*
Professor, Clinical  Johnson & Johnson  Merck*
Medicine  Philips Medical
 WebMD
Patrick T. Content Reviewer Brigham and Womens None None None  Lantheus Medical
OGara HospitalDirector,
Clinical Cardiology;
Harvard Medical
SchoolProfessor of
Medicine

Continued on the next page


JACC VOL. 64, NO. 18, 2014 Fihn et al. 1949
NOVEMBER 4, 2014:192949 2014 Stable Ischemic Heart Disease Focused Update

APPENDIX 2. CONTINUED

Institutional,
Organizational,
Speakers Personal or Other
Peer Reviewer Representation Employment Consultant Bureau Research Financial Benet

Joseph F. Sabik Content Reviewer Cleveland Clinic  Edwards None  Abbott None
ACC Surgeons Department Chair, Lifesciences Laboratories
Scientic Council Thoracic and  Medtronic  Edwards
Cardiovascular Lifesciences
Surgery

Vikas Saini Content Reviewer The Lown Institute None None None None
President

Frank W. Sellke Content Reviewer Brown Medical School None None  The Medicines None
ACC/AHA Task and LifespanChief Company
Force on Practice of Cardiothoracic
Guidelines Surgery

William S. Content Reviewer Christiana Care Health  Bristol-Myers None None None
Weintraub SystemSection Squibb
Chief, Cardiology  Daiichi-Sankyo
 Eli Lilly

Christopher J. Content Reviewer Ochsner Health System None None None  St. Jude
White Director, John Medical
Ochsner Heart and (DSMB)
Vascular Institute

Sankey V. Content ReviewerACP University of None None None None


Williams Pennsylvania Health
SystemProfessor of
General Medicine

Poh Shuan Content ReviewerAIG Tan Tock Seng Hospital, None None None  Boston Scientic
Daniel Yeo Department of  Merck
Cardiology  Schering-Plough
Cardiologist

No reviewer had a relevant ownership, partnership, or principal position to report. No reviewer reported acting as an expert witness in a relevant matter.
This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant to this document. It
does not necessarily reect relationships with industry at the time of publication. A person is deemed to have a signicant interest in a business if the interest represents ownership
of $5% of the voting stock or share of the business entity, or ownership of $$10 000 of the fair market value of the business entity; or if funds received by the person from the
business entity exceed 5% of the persons gross income for the previous year. A relationship is considered to be modest if it is less than signicant under the preceding denition.
Relationships that exist with no nancial benet are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in
alphabetical order within each category of review.
According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or
issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing
drug or device addressed in the document; or c) the person or a member of the persons household has a reasonable potential for nancial, professional, or other personal gain or loss as
a result of the issues/content addressed in the document.
*Signicant relationship.
No nancial benet.
AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiology; ACP, American College of Physicians; AHA, American Heart Association; AIG,
Association of International Governors; DSMB, Data Safety Monitoring Board; ISCHEMIA trial, International Study of Comparative Health Effectiveness With Medical and Invasive
Approaches trial; PCNA, Preventive Cardiovascular Nurses Association; PI, principle investigator; SCAI, Society for Cardiovascular Angiography and Interventions; and STS, Society of
Thoracic Surgeons.