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2021 AHA:ACC:ASE:CHEST:SAEM: SCCT:SCMR Guideline For The Evaluation and Diagnosis of Chest Pain
2021 AHA:ACC:ASE:CHEST:SAEM: SCCT:SCMR Guideline For The Evaluation and Diagnosis of Chest Pain
-, 2021
ª 2021 BY THE AMERICAN HEART ASSOCIATION, INC.,
AND THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION.
PUBLISHED BY ELSEVIER
2021 AHA/ACC/ASE/CHEST/SAEM/
SCCT/SCMR Guideline for the
Evaluation and Diagnosis of Chest Pain
A Report of the American College of Cardiology/American Heart Association
Joint Committee on Clinical Practice Guidelines
Writing Martha Gulati, MD, MS, FACC, FAHA, Chairy José A. Joglar, MD, FAHA, FACCz
Committee Phillip D. Levy, MD, MPH, FACC, FAHA, Vice Chairy David A. Morrow, MD, MPH, FACC, FAHAy
Members* Debabrata Mukherjee, MD, MS, FACC, FAHA, Vice Chairy Robert E. O’Connor, MD, MPH, FAHAy
Michael A. Ross, MD, FACCy
Ezra Amsterdam, MD, FACCy Leslee J. Shaw, PHD, FACC, FAHA, MSCCTy
Deepak L. Bhatt, MD, MPH, FACC, FAHAy
Kim K. Birtcher, MS, PHARMD, AACCz
*Writing committee members are required to recuse themselves from
Ron Blankstein, MD, FACC, MSCCTx
voting on sections to which their specific relationships with industry may
Jack Boyd, MDy apply; see Appendix 1 for detailed information.
Renee P. Bullock-Palmer, MD, FACC, FAHA, FASE, FSCCTy yACC/AHA Representative.
Theresa Conejo, RN, BSN, FAHAk zACC/AHA Joint Committee on Clinical Practice Guidelines Liaison.
xSociety of Cardiovascular Computed Tomography Representative.
Deborah B. Diercks, MD, MSC, FACC{
kLay Patient Representative.
Federico Gentile, MD, FACC# {Society for Academic Emergency Medicine Representative.
John P. Greenwood, MBCHB, PHD, FSCMR, FACC** #Former ACC/AHA Joint Committee member; current member during the
Erik P. Hess, MD, MSCy writing effort.
**Society for Cardiovascular Magnetic Resonance Representative.
Steven M. Hollenberg, MD, FACC, FAHA, FCCPyy
yyAmerican College of Chest Physicians Representative.
Wael A. Jaber, MD, FACC, FASEzz zzAmerican Society of Echocardiography Representative.
Hani Jneid, MD, FACC, FAHAxx xxTask Force on Performance Measures, Liaison.
This document was approved by the American College of Cardiology Clinical Policy Approval Committee in May 2021, the American Heart Association
Science Advisory and Coordinating Committee in May 2021, the Society of Cardiovascular Computed Tomography in July 2021, the Society for Academic
Emergency Medicine in June 2021, the Society for Cardiovascular Magnetic Resonance in June 2021, the American College of Chest Physicians in June
2021, the American Society of Echocardiography in June 2021, the American Heart Association Executive Committee in July 2021, and the American
College of Cardiology Science and Quality Committee in July 2021.
The American College of Cardiology requests that this document be cited as follows: Gulati M, Levy PD, Mukherjee D, Amsterdam E, Bhatt DL, Birtcher
KK, Blankstein R, Boyd J, Bullock-Palmer RP, Conejo T, Diercks DB, Gentile F, Greenwood JP, Hess EP, Hollenberg SM, Jaber WA, Jneid H, Joglar JA,
Morrow DA, O’Connor RE, Ross MA, Shaw LJ. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a
report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol.
2021;CC:CCCC–CCCC.
This article has been copublished in Circulation.
Copies: This document is available on the websites of the American College of Cardiology (www.acc.org) and the American Heart Association
(professional.heart.org). For copies of this document, please contact the Elsevier Inc. Reprint Department via fax (212-633-3820) or e-mail (reprints@
elsevier.com).
Permissions: Multiple copies, modification, 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/about/policies/
author-agreement/obtaining-permission).
ACC/AHA Joint Patrick T. O’Gara, MD, MACC, FAHA, Chair Mark A. Hlatky, MD, FACC, FAHA#
Committee Joshua A. Beckman, MD, MS, FAHA, FACC, John S. Ikonomidis, MD, PhD, FAHA#
Members Chair-Elect José A. Joglar, MD, FAHA, FACC
Glenn N. Levine, MD, FACC, FAHA, Immediate W. Schuyler Jones, MD, FACC
Past Chair# Joseph E. Marine, MD, FACC#
Daniel B. Mark, MD, MPH, FACC
Sana M. Al-Khatib, MD, MHS, FACC, FAHA# Debabrata Mukherjee, MD, MS, FACC, FAHA
Anastasia L. Armbruster, PharmD, FACC Latha P. Palaniappan, MD, MS, FAHA, FACC
Kim K. Birtcher, MS, PharmD, AACC# Mariann R. Piano, RN, PhD, FAHA
Ralph G. Brindis, MD, MPH, MACC# Tanveer Rab, MD, FACC
Joaquin E. Cigarroa, MD, FACC# Barbara Riegel, PhD, RN, FAHA#
Lisa de las Fuentes, MD, MS, FASE, FAHA Erica S. Spatz, MD, MHS, FACC
Anita Deswal, MD, MPH, FACC, FAHA Jacqueline E. Tamis-Holland, MD, FACC
Dave L. Dixon, PharmD, FACC# Duminda N. Wijeysundera, MD, PhD#
Lee A. Fleisher, MD, FACC, FAHA# Y. Joseph Woo, MD, FAHA, FACC
Federico Gentile, MD, FACC#
Zachary D. Goldberger, MD, MS, FACC, FAHA#
Bulent Gorenek, MD, FACC
#Former ACC/AHA Joint Committee member; current member
Norrisa Haynes, MD during the writing effort.
Adrian F. Hernandez, MD
ABSTRACT
AIM This clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for
clinicians to assess and diagnose chest pain in adult patients.
METHODS A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing randomized
and nonrandomized trials, observational studies, registries, reviews, and other evidence conducted on human subjects that were
published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and
other relevant databases. Additional relevant studies, published through April 2021, were also considered.
STRUCTURE Chest pain is a frequent cause for emergency department visits in the United States. The “2021 AHA/ACC/ASE/CHEST/
SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain” provides recommendations based on contemporary
evidence on the assessment and evaluation of chest pain. This guideline presents an evidence-based approach to risk stratification
and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated,
and shared decision-making with patients is recommended.
CONTENTS
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . -
2.1.1. A Focus on the Uniqueness of Chest Pain
in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . -
1.1. Methodology and Evidence Review . . . . . . . . . . . . -
2.1.2. Considerations for Older Patients With
1.2. Organization of the Writing Committee . . . . . . . . . -
Chest Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . -
CENTRIC ALGORITHMS FOR ACUTE CHEST PAIN . . - 5.2.1. Patients With Obstructive CAD Who Present
With Stable Chest Pain . . . . . . . . . . . . . . . . . . -
4.1. Patients With Acute Chest Pain and Suspected ACS 5.2.1.1. Patients With Prior Coronary Artery
(Not Including STEMI) . . . . . . . . . . . . . . . . . . . . . . . - Bypass Surgery With Stable
4.1.1. Low-Risk Patients With Acute Chest Pain . . - Chest Pain . . . . . . . . . . . . . . . . . . . . . . -
4.1.1.1. Cost-Value Considerations in the Eval- 5.2.2. Patients With Known Nonobstructive CAD
uation of Low-Risk Patients . . . . . . . . . - Presenting With Stable Chest Pain . . . . . . . . -
4.1.2. Intermediate-Risk Patients With Acute 5.2.3. Patients With Suspected Ischemia and
Chest Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . - No Obstructive CAD (INOCA) . . . . . . . . . . . . . -
4.1.2.1. Intermediate-Risk Patients With Acute
Chest Pain and No Known CAD . . . . . . - 5.3. Cost-Value Considerations in Diagnostic Testing . . -
4.1.4. Acute Chest Pain in Patients With Prior 5.3.3. Stress Echocardiographic Cost-Value
Coronary Artery Bypass Graft (CABG) Considerations . . . . . . . . . . . . . . . . . . . . . . . . -
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 5.3.4. Stress Nuclear MPI Cost-Value
4.1.5. Evaluation of Patients With Acute Chest Considerations . . . . . . . . . . . . . . . . . . . . . . . . -
Pain Receiving Dialysis . . . . . . . . . . . . . . . . . - 5.3.5. Stress CMR Cost-Value Considerations . . . . . -
4.1.6. Evaluation of Acute Chest Pain in Patients
With Cocaine and Methamphetamine Use . . -
6. EVIDENCE GAPS AND FUTURE RESEARCH . . . . . . . -
4.1.7. Shared Decision-Making in Patients With
Acute Chest Pain . . . . . . . . . . . . . . . . . . . . . . -
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . -
4.2.1. Acute Chest Pain With Suspected Acute Author Relationships With Industry and Other Entities
Aortic Syndrome . . . . . . . . . . . . . . . . . . . . . . - (Relevant) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . -
e4 Gulati et al. JACC VOL. -, NO. -, 2021
2021 Chest Pain Guideline -, 2021:-–-
1. Chest Pain Means More Than Pain in the Chest. Pain, Since 1980, the American College of Cardiology (ACC) and
pressure, tightness, or discomfort in the chest, American Heart Association (AHA) have translated scien-
shoulders, arms, neck, back, upper abdomen, or jaw, tific evidence into clinical practice guidelines with rec-
as well as shortness of breath and fatigue should all be ommendations to improve cardiovascular health. These
considered anginal equivalents. guidelines, which are based on systematic methods to
2. High-Sensitivity Troponins Preferred. High- evaluate and classify evidence, provide a foundation for
sensitivity cardiac troponins are the preferred stan- the delivery of quality cardiovascular care. The ACC and
dard for establishing a biomarker diagnosis of acute AHA sponsor the development and publication of clinical
myocardial infarction, allowing for more accurate practice guidelines without commercial support, and
detection and exclusion of myocardial injury. members volunteer their time to the writing and review
3. Early Care for Acute Symptoms. Patients with acute efforts. Guidelines are official policy of the ACC and AHA.
chest pain or chest pain equivalent symptoms should For some guidelines, the ACC and AHA partner with other
seek medical care immediately by calling 9-1-1. organizations.
Although most patients will not have a cardiac cause,
the evaluation of all patients should focus on the early Intended Use
identification or exclusion of life-threatening causes. Clinical practice guidelines provide recommendations
4. Share the Decision-Making. Clinically stable patients applicable to patients with or at risk of developing car-
presenting with chest pain should be included in diovascular disease. The focus is on medical practice in
decision-making; information about risk of adverse the United States, but these guidelines are relevant to
events, radiation exposure, costs, and alternative patients throughout the world. Although guidelines may
options should be provided to facilitate the be used to inform regulatory or payer decisions, the intent
discussion. is to improve quality of care and align with patients’ in-
5. Testing Not Needed Routinely for Low-Risk Patients. terests. Guidelines are intended to define practices
For patients with acute or stable chest pain deter- meeting the needs of patients in most, but not all, cir-
mined to be low risk, urgent diagnostic testing for cumstances and should not replace clinical judgment.
suspected coronary artery disease is not needed.
6. Pathways. Clinical decision pathways for chest pain in Clinical Implementation
the emergency department and outpatient settings Management, in accordance with guideline recommen-
should be used routinely. dations, is effective only when followed by both prac-
7. Accompanying Symptoms. Chest pain is the dominant titioners and patients. Adherence to recommendations
and most frequent symptom for both men and women can be enhanced by shared decision-making between
ultimately diagnosed with acute coronary syndrome. clinicians and patients, with patient engagement in
Women may be more likely to present with accom- selecting interventions on the basis of individual
panying symptoms such as nausea and shortness of values, preferences, and associated conditions and
breath. comorbidities.
8. Identify Patients Most Likely to Benefit From Further
Testing. Patients with acute or stable chest pain who Methodology and Modernization
are at intermediate risk or intermediate to high pre- The ACC/AHA Joint Committee on Clinical Practice
test risk of obstructive coronary artery disease, Guidelines (Joint Committee) continuously reviews, up-
respectively, will benefit the most from cardiac im- dates, and modifies guideline methodology on the basis of
aging and testing. published standards from organizations, including the
9. Noncardiac Is In. Atypical Is Out. “Noncardiac” Institute of Medicine (1,2), and on the basis of internal
should be used if heart disease is not suspected. reevaluation. Similarly, presentation and delivery of
“Atypical” is a misleading descriptor of chest pain, guidelines are reevaluated and modified in response to
and its use is discouraged. evolving technologies and other factors to optimally
10. Structured Risk Assessment Should Be Used. For pa- facilitate dissemination of information to healthcare
tients presenting with acute or stable chest pain, risk professionals at the point of care.
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Numerous modifications to the guidelines have To ensure that guideline recommendations remain
been implemented to make them shorter and enhance current, new data will be reviewed on an ongoing basis by
“user friendliness.” Guidelines are written and pre- the writing committee and staff. Going forward, targeted
sented in a modular, “knowledge chunk” format, in sections/knowledge chunks will be revised dynamically
which each chunk includes a table of recommenda- after publication and timely peer review of potentially
tions, a brief synopsis, recommendation-specific sup- practice-changing science. The previous designations of
portive text and, when appropriate, flow diagrams or “full revision” and “focused update” will be phased out.
additional tables. Hyperlinked references are provided For additional information and policies on guideline
for each modular knowledge chunk to facilitate quick development, readers may consult the ACC/AHA guide-
access and review. line methodology manual (4) and other methodology ar-
In recognition of the importance of cost–value consid- ticles (5-7). The Class of Recommendation (COR) indicates
erations, in certain guidelines, when appropriate and the strength of recommendation, encompassing the esti-
feasible, an analysis of value for a drug, device, or inter- mated magnitude and certainty of benefit in proportion to
vention may be performed in accordance with the ACC/ risk. The Level of Evidence (LOE) rates the quality of
AHA methodology (3). scientific evidence supporting the intervention on the
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2021 Chest Pain Guideline -, 2021:-–-
basis of the type, quantity, and consistency of data from both pharmacological and procedural treatments. For
clinical trials and other sources (Table 1) (8). these and all recommended drug treatment regimens, the
reader should confirm dosage with product insert mate-
Selection of Writing Committee Members
rial and evaluate for contraindications and interactions.
The Joint Committee strives to ensure that the guideline Recommendations are limited to drugs, devices, and
writing committee contains requisite content expertise treatments approved for clinical use in the United States.
and is representative of the broader cardiovascular com- Patrick T. O’Gara, MD, MACC, FAHA
munity by selection of experts across a spectrum of Chair, ACC/AHA Joint Committee on
backgrounds, representing different geographic regions, Clinical Practice Guidelines
sexes, races, ethnicities, intellectual perspectives/biases,
and clinical practice settings. Organizations and profes- 1. INTRODUCTION
sional societies with related interests and expertise are
invited to participate as partners or collaborators. 1.1. Methodology and Evidence Review
Relationships With Industry and Other Entities The recommendations listed in this guideline are, when-
The ACC and AHA have rigorous policies and methods to ever possible, evidence based. An initial extensive evi-
ensure that documents are developed without bias or dence review, which included literature derived from
improper influence. The complete policy on relationships research involving human subjects, published in English,
with industry and other entities (RWI) can be found online. and indexed in MEDLINE (through PubMed), EMBASE, the
Appendix 1 of the guideline lists writing committee mem- Cochrane Library, the Agency for Healthcare Research and
bers’ relevant RWI; for the purposes of full transparency, Quality, and other selected databases relevant to this
their comprehensive disclosure information is available in guideline, was conducted from November 11, 2017, to May
the Supplemental Appendix. Comprehensive disclosure 1, 2020. Key search words included but were not limited to
information for the Joint Committee is also available the following: acute coronary syndrome, angina, angina
Applying ACC/AHA Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or
TABLE 1
Diagnostic Testing in Patient Care (Updated May 2019)*
Medicine (SAEM), Society of Cardiovascular Computed Cardiology, CHEST, SAEM, SCCT, and SCMR, and 39 indi-
Tomography (SCCT), and Society for Cardiovascular vidual content reviewers. Reviewers’ RWI information was
Magnetic Resonance (SCMR). Appendix 1 lists writing distributed to the writing committee and is published in
committee members’ relevant RWI. For the purposes of this document (Appendix 2).
full transparency, the writing committee members’ This document was approved for publication by the
comprehensive disclosure information is available in the governing bodies of the ACC and the AHA and was
Supplemental Appendix. endorsed by the ASE, CHEST, SAEM, SCCT, and SCMR.
settings, with an emphasis on the diagnosis on ischemic the Evaluation and Diagnosis of Chest Pain,” the writing
causes. This guideline will not provide recommenda- committee first reviewed previous published guidelines
tions on whether revascularization is appropriate or and related statements. Table 2 contains a list of
what modality is indicated. Such recommendations can these publications deemed pertinent to this writing
be found in the forthcoming ACC/AHA coronary artery effort and is intended for use as a resource, thus
revascularization guideline. In developing the “2021 obviating the need to repeat existing guideline
AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for recommendations.
Publication Year
Title Organization (Reference)
Guidelines
Ventricular arrhythmias and the prevention of sudden cardiac death AHA/ACC/HRS 2017 (12)
Secondary prevention and risk reduction therapy for patients with coronary and other AHA/ACC 2011 (17)
atherosclerotic vascular disease
Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care—part 9: AHA 2010 (18)*
postcardiac arrest care 2019 (19)
Prevention, detection, evaluation, and management of high blood pressure in adults ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ 2017 (20)
NMA/PCNA
Statements
Testing of low-risk patients presenting to the emergency department with chest pain AHA 2010 (21)
Prevention of cardiovascular disease in adults with type 2 diabetes mellitus AHA/ADA 2015 (22)
Prevention and control of seasonal influenza with vaccines CDC 2018 (23)
1.4.1. Scope of the Problem remains the leading cause of death for men and women,
Synopsis accounting for >365,000 deaths annually (3). Dis-
After injuries, chest pain is the second most common tinguishing between serious and benign causes of chest
reason for adults to present to the emergency department pain is imperative. The lifetime prevalence of chest pain
(ED) in the United States and accounts for >6.5 million in the United States is 20% to 40% (4), and women
visits, which is 4.7% of all ED visits (1). Chest pain also experience this symptom more often than men (5). Of all
leads to nearly 4 million outpatient visits annually in the ED patients with chest pain, only 5.1% will have an acute
United States (2). Chest pain remains a diagnostic chal- coronary syndrome (ACS), and more than half will ulti-
lenge in the ED and outpatient setting and requires mately be found to have a noncardiac cause (6). None-
thorough clinical evaluation. Although the cause of chest theless, chest pain is the most common symptom of CAD
pain is often noncardiac, coronary artery disease (CAD) in both men and women.
affects >18.2 million adults in the United States and 1.4.2. Defining Chest Pain
1. An initial assessment of chest pain is recommended to triage patients effectively on the basis of the
1 B-NR likelihood that symptoms may be attributable to myocardial ischemia (1-7).
2. Chest pain should not be described as atypical, because it is not helpful in determining the cause and can
1 C-LD be misinterpreted as benign in nature. Instead, chest pain should be described as cardiac, possibly
cardiac, or noncardiac because these terms are more specific to the potential underlying diagnosis.
F I G U R E 2 Index of Suspicion That Chest “Pain” Is Ischemic in Origin on the Basis of Commonly Used Descriptors
more likely it is to be of cardiac ischemic origin. Atyp- GDMT guideline-directed medical therapy
ical chest pain is a problematic term. Although it was hs-cTn high-sensitivity cardiac troponin
intended to indicate angina without typical chest ICA invasive coronary angiography
symptoms, it is more often used to state that the INOCA ischemia and no obstructive coronary artery disease
symptom is noncardiac in origin. As such, we MACE major adverse cardiovascular events
discourage the use of atypical chest pain. Emphasis is MBFR myocardial blood flow reserve
more constructively placed on specific aspects of METs metabolic equivalents
symptoms that suggest their origin in terms of probable
MINOCA myocardial infarction and nonobstructive coronary arteries
ischemia. Of note, chest pain is broadly defined to also
MPI myocardial perfusion imaging
include referred pain in the shoulders, arms, jaw, neck,
NSTE-ACS non–ST-segment–elevation acute coronary syndrome
and upper abdomen. To diminish ambiguity, use “car-
PCI percutaneous coronary intervention
diac,” “possible cardiac,” and “noncardiac” to describe
PE pulmonary embolism
the suspected cause of chest pain is encouraged.
PET positron emission tomography
1.5. Abbreviations SIHD stable ischemic heart disease
2. INITIAL EVALUATION
2.1. History
1. In patients with chest pain, a focused history that includes characteristics and duration of symptoms
1 C-LD relative to presentation as well as associated features, and cardiovascular risk factor assessment should
be obtained.
Created using data from Hsia RY, et al. (3). ED indicates emergency department.
e12 Gulati et al. JACC VOL. -, NO. -, 2021
2021 Chest Pain Guideline -, 2021:-–-
Nature
Anginal symptoms are perceived as retrosternal chest discomfort (e.g., pain, discomfort, heaviness, tightness, pressure, constriction, squeezing) (Section 1.4.2,
Defining Chest Pain).
Sharp chest pain that increases with inspiration and lying supine is unlikely related to ischemic heart disease (e.g., these symptoms usually occur with acute
pericarditis).
Sudden onset of ripping chest pain (with radiation to the upper or lower back) is unlikely to be anginal and is suspicious of an acute aortic syndrome.
Fleeting chest pain—of few seconds’ duration—is unlikely to be related to ischemic heart disease.
Pain that can be localized to a very limited area and pain radiating to below the umbilicus or hip are unlikely related to myocardial ischemia.
Severity
Ripping chest pain (“worse chest pain of my life”), especially when sudden in onset and occurring in a hypertensive patient, or with a known bicuspid aortic valve or
aortic dilation, is suspicious of an acute aortic syndrome (e.g., aortic dissection).
Precipitating factors
Occurrence at rest or with minimal exertion associated with anginal symptoms usually indicates ACS.
Relieving factors
Relief with nitroglycerin is not necessarily diagnostic of myocardial ischemia and should not be used as a diagnostic criterion.
Associated symptoms
Common symptoms associated with myocardial ischemia include, but are not limited to, dyspnea, palpitations, diaphoresis, lightheadedness, presyncope or syncope,
upper abdominal pain, or heartburn unrelated to meals and nausea or vomiting.
Symptoms on the left or right side of the chest, stabbing, sharp pain, or discomfort in the throat or abdomen may occur in patients with diabetes, women, and elderly
patients.
arm, neck, jaw) and its associated symptoms (e.g., lightheadedness, confusion, presyncope or syncope, or
dyspnea, nausea, lightheadedness). When actively vague abdominal symptoms are more frequent among
treated or spontaneously resolving, it dissipates over a patients with diabetes, women, and the elderly. A
few minutes. Relief with nitroglycerin is not neces- detailed assessment of cardiovascular risk factors, re-
sarily diagnostic of myocardial ischemia and should not view of systems, past medical history, and family and
be used as a diagnostic criterion, especially because social history should complement the assessment of
other entities demonstrate comparable response (e.g., presenting symptoms.
esophageal spasm) (1,5). Associated symptoms such as
shortness of breath, nausea or vomiting, 2.1.1. A Focus on the Uniqueness of Chest Pain in Women
1. Women who present with chest pain are at risk for underdiagnosis, and potential cardiac causes should
1 B-NR always be considered (1-7).
2. In women presenting with chest pain, it is recommended to obtain a history that emphasizes accompa-
1 B-NR nying symptoms that are more common in women with ACS (1-7).
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1. In patients with chest pain who are >75 years of age, ACS should be considered when accompanying
1 C-LD symptoms such as shortness of breath, syncope, or acute delirium are present, or when an unexplained
fall has occurred (1).
result was associated with increased risk of cardio- abdominal pain, or experienced an unexplained fall.
vascular death or MI (4). The physician should have a heightened awareness to
understand that these symptoms may be associated
Recommendation-Specific Supportive Text with ACS, in addition to chest pain (1).
1. Patients >75 years of age may have symptoms of 2.1.3. Considerations for Diverse Patient Populations With
shortness of breath, syncope, mental impairment, or Chest Pain
Recommendations for Considerations for Diverse Patient Populations With Chest Pain
1. Cultural competency training is recommended to help achieve the best outcomes in patients of diverse
1 C-LD racial and ethnic backgrounds who present with chest pain.
2. Among patients of diverse race and ethnicity presenting with chest pain in whom English may not be their
1 C-LD primary language, addressing language barriers with the use of formal translation services is
recommended.
1. In patients with acute chest pain, it is recommended that 9-1-1 be activated by patients or bystanders to
1 C-LD initiate transport to the closest ED by emergency medical services (EMS) (1).
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1. In patients presenting with chest pain, a focused cardiovascular examination should be performed initially
1 C-EO to aid in the diagnosis of ACS or other potentially serious causes of chest pain (e.g., aortic dissection, PE,
or esophageal rupture) and to identify complications.
Emergency
ACS Diaphoresis, tachypnea, tachycardia, hypotension, crackles, S3, MR murmur (2); examination may be normal in
uncomplicated cases
Aortic dissection Connective tissue disorders (e.g., Marfan syndrome), extremity pulse differential (30% of patients, type A>B) (8)
Severe pain, abrupt onset þ pulse differential þ widened mediastinum on CXR >80% probability of dissection (9)
Frequency of syncope >10% (8), AR 40%–75% (type A) (10)
Esophageal rupture Emesis, subcutaneous emphysema, pneumothorax (20% patients), unilateral decreased or absent breath sounds
Other
Noncoronary cardiac: AS, AR, HCM AS: Characteristic systolic murmur, tardus or parvus carotid pulse
AR: Diastolic murmur at right of sternum, rapid carotid upstroke
HCM: Increased or displaced left ventricular impulse, prominent a wave in jugular venous pressure, systolic murmur
Pericarditis Fever, pleuritic chest pain, increased in supine position, friction rub
Pneumonia Fever, localized chest pain, may be pleuritic, friction rub may be present, regional dullness to percussion, egophony
Herpes zoster Pain in dermatomal distribution, triggered by touch; characteristic rash (unilateral and dermatomal distribution)
ACS indicates acute coronary syndrome; AR, aortic regurgitation; AS, aortic stenosis; CXR, chest x-ray; LR, likelihood ratio; HCM, hypertrophic cardiomyopathy; MR, mitral regurgi-
tation; PE, pulmonary embolism; and PUD, peptic ulcer disease.
1. Unless a noncardiac cause is evident, an ECG should be performed for patients seen in the office setting
1 B-NR with stable chest pain; if an ECG is unavailable the patient should be referred to the ED so one can be
obtained (1-5).
2. Patients with clinical evidence of ACS or other life-threatening causes of acute chest pain seen in the
1 C-LD office setting should be transported urgently to the ED, ideally by EMS (1-9).
3. In all patients who present with acute chest pain regardless of the setting, an ECG should be acquired and
1 C-LD reviewed for STEMI within 10 minutes of arrival (1-3,6,7,10).
4. In all patients presenting to the ED with acute chest pain and suspected ACS, cTn should be measured as
1 C-LD soon as possible after presentation (8,9).
5. For patients with acute chest pain and suspected ACS initially evaluated in the office setting, delayed
3: Harm C-LD transfer to the ED for cTn or other diagnostic testing should be avoided.
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1. In patients with chest pain in which an initial ECG is nondiagnostic, serial ECGs to detect potential
1 C-EO ischemic changes should be performed, especially when clinical suspicion of ACS is high, symptoms are
persistent, or the clinical condition deteriorates (1).
2. Patients with chest pain in whom the initial ECG is consistent with an ACS should be treated according to
1 C-EO STEMI and NSTE-ACS guidelines (1,2).
3. In patients with chest pain and intermediate-to-high clinical suspicion for ACS in whom the initial ECG is
2a B-NR nondiagnostic, supplemental electrocardiographic leads V7 to V9 are reasonable to rule out posterior MI
(3-5).
ECG indicates electrocardiogram; NSTE-ACS, non–ST-segment–elevation acute coronary syndrome; MI, myocardial infarction; and STEMI, ST-segment–
elevation myocardial infarction.
ruling out ACS (8-10). Thus, decision-making should pain recurs or a change in clinical condition develops
not be based solely on a single normal or nondiagnostic (21).
ECG. Left ventricular hypertrophy, bundle branch 2. When ST-elevation is present on the initial ECG, man-
blocks, and ventricular pacing may mask signs of agement should follow the prescribed STEMI treatment
ischemia or injury (11). Up to 6% of patients with algorithms in associated guidelines (2,22). Further-
evolving ACS are discharged from the ED with a normal more, if ST depression is identified on the initial ECG,
ECG (12-17). In patients where the initial ECG is normal management should follow the NSTE-ACS guidelines
or is without ST elevation, hyperacute T waves, left (1).
bundle branch block, or ST depression, serial ECGs 3. A normal ECG may be associated with left circumflex or
should be performed and management should be right coronary artery occlusions and posterior wall
guided by new electrocardiographic changes or other ischemia, which is often “electrically silent”; therefore,
diagnostic testing (see Section 2.3.4 on Biomarkers, right-sided ECG leads should be considered when such
Section 3.1 on Anatomic Testing, or Section 3.2 on lesions are suspected (2-5).
Stress Testing) (7,18-20). The timing for repeat ECG
should also be guided by symptoms, especially if chest 2.3.3. Chest Radiography
1. In patients presenting with acute chest pain, a chest radiograph is useful to evaluate for other potential
1 C-EO cardiac, pulmonary, and thoracic causes of symptoms.
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1. In patients presenting with acute chest pain, serial cTn I or T levels are useful to identify abnormal values
1 B-NR and a rising or falling pattern indicative of acute myocardial injury (1-21).
2. In patients presenting with acute chest pain, high-sensitivity cTn is the preferred biomarker because it
1 B-NR enables more rapid detection or exclusion of myocardial injury and increases diagnostic accuracy
(17,21-25).
3. Clinicians should be familiar with the analytical performance and the 99th percentile upper reference
1 C-EO limit that defines myocardial injury for the cTn assay used at their institution (23,26).
4. With availability of cTn, creatine kinase myocardial (CK-MB) isoenzyme and myoglobin are not useful for
3: No benefit B-NR diagnosis of acute myocardial injury (27-32).
upper reference limit, which is assay-dependent, is an hs-cTnI). To appropriately apply a cTn assay, clinicians
indicator of myocardial injury (1,9,21). The coefficient must be familiar with these analytical performance
of variation at the 99th percentile upper reference limit properties for the assay(s) that they use in their prac-
for each assay should be #10% (8,21). tice (21).
2. There is ample evidence for the superiority of hs-cTn 4. Comparative studies have confirmed the superiority of
assays over conventional cTn assays in multiple as- cTn over CK-MB and myoglobin for diagnosis and
pects of evaluation for patients presenting with chest prognosis of AMI (27-32). The addition of CK-MB or
pain with and without AMI (17,21,24,25,33). The sensi- myoglobin to cTn for evaluation of patients presenting
tivity and negative predictive values are greater with with chest pain is not beneficial.
hs-cTn compared with previous generation assays
(17,21,24,25). In addition, the time interval from onset
of chest pain to a detectable concentration at patient 3. CARDIAC TESTING GENERAL
presentation is shorter with hs-cTn, affording more CONSIDERATIONS
rapid rule-in and rule-out algorithms (22). Although it
is sometimes challenging to diagnostically discrimi- For acute and stable chest pain, noninvasive and invasive
nate among these causes of myocardial injury, irre- diagnostic testing is a core component of the evaluation
spective of the final diagnosis, the presence of underpinning its importance. Over the past decade, the
myocardial injury is associated with a higher risk of quality of evidence supporting clinical indications for
adverse outcomes among patients with chest pain (35). noninvasive testing has grown dramatically. The
3. The level of detection, 99th percentile upper reference approach outlined in this guideline focuses on selective
limit, analytical precision, and criteria for a significant use of testing, optimization of lower cost evaluations,
delta are assay-specific, including among the many reducing layered testing, and deferring or eliminating
different manufacturers of the same analyte (e.g., testing when the diagnostic yield is low (Figure 5).
The choice of imaging depends on the clinical question of importance, to either a) ascertain the diagnosis of CAD and define coronary anatomy or b) assess ischemia
severity among patients with an expected higher likelihood of ischemia with an abnormal resting ECG or those incapable of performing maximal exercise. ACS indicates
acute coronary syndrome; CAC, coronary artery calcium; CAD, coronary artery disease; and ECG, electrocardiogram. Please refer to Section 4.1. For risk assessment in
acute chest pain, see Figure 9. For risk assessment in stable chest pain, see Figure 11.
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Reducing unnecessary testing can provide a means to Current radiation dosimetry is low for CCTA, with effec-
exert cost savings within the diagnostic evaluation tive doses for most patients in the 3 to 5 mSv range (10).
of populations (1). In the same manner, elimination of CCTA contraindications are reported in Table 5 Although
testing where evidence is lacking and the reduction in in select situations imaging protocols that evaluate the
testing among low-risk patients for whom deferred coronary arteries, aorta, and pulmonary arteries may be
testing is appropriate are emphasized in this guideline. useful, the general approach should be to use imaging
Testing choice will be influenced by site expertise and protocols tailored to the most likely diagnosis, rather than
availability, but knowledge regarding which test may be a “triple rule out” approach (Figure 6).
preferable is useful when selecting between different
modalities. Cost should also be considered, when known 3.1.2. Invasive Coronary Angiography
by the ordering clinician and there is equipoise between
Invasive coronary angiography (ICA) defines the presence
available modalities (2). The exercise ECG is the lowest
and severity of a luminal obstruction of an epicardial
cost procedure used in the diagnostic evaluation when
coronary artery, including its location, length, and diam-
compared with stress imaging or anatomic procedures,
eter, as well as coronary blood flow (1,2). For ICA, the
with the exception of coronary artery calcium (CAC)
primary goal is the characterization and detection of a
scoring (Figure 6). For all imaging procedures, costs vary
high-grade obstructive stenosis to define feasibility and
by payer and site of services.
necessity of percutaneous or surgical revascularization.
The following sections provide a brief overview of the
The use of physiologic indices (IFR and FFR) provides
various noninvasive tests available for use in the eval-
complementary functional information (1). Radiation
uation of symptomatic patients. Previously, the term
exposure to the patient during an interventional proced-
known as CAD had been used to define those with a
ure averages 4 to 10 mSv and is dependent on procedural
significant obstructive stenosis (i.e., $50%). In this
duration and complexity (3,4).
guideline, we revise the term known CAD to include
ICA has a spatial resolution of 0.3 mm; as such, it is
patients with prior anatomic testing (invasive angiog-
impossible to visualize arterioles (diameter of 0.1 mm)
raphy or coronary computed tomographic angiography
that regulate myocardial blood flow (5). Coronary vascular
[CCTA]) with identified nonobstructive atherosclerotic
functional studies can be performed during coronary
plaque and obstructive CAD. We recognize this is a de-
angiography. Normal angiography does not exclude
parture from convention, but our intent was to ensure
abnormal coronary vascular function, and it is possible to
that those with lesser degrees of stenosis who do not
assess coronary microcirculation and coronary vaso-
require coronary intervention but would benefit from
motion. Coronary function testing may assist in manage-
optimized preventive therapy do not get overlooked.
ment of the underlying condition, in addition to
However, throughout the document, the term “obstruc-
providing prognostic information (6-8).
tive”, consistent with convention, will be used to indi-
cate CAD with $50% stenosis and nonobstructive CAD
3.2. Diagnostic Testing
will be used to indicate CAD <50% stenosis. In addition,
3.2.1. Exercise ECG
the term “high risk CAD” is used to denote patients with
obstructive stenosis who have left main stenosis $50% Symptom-limited exercise ECG involves graded exercise
or anatomically significant 3-vessel disease ($70% until physical fatigue, limiting chest pain (or discomfort),
stenosis). marked ischemia, or a drop in blood pressure occurs (1).
Candidates for exercise ECG are those: a) without
disabling comorbidity (e.g., frailty, marked obesity [body
mass index >40 kg/m 2], peripheral artery disease, chronic
3.1. Anatomic Testing
obstructive pulmonary disease, or orthopedic limitations)
3.1.1. Coronary Computed Tomography Angiography and capable of performing activities of daily living or able
CCTA can visualize and help to diagnose the extent and to achieve $5 metabolic equivalents of exercise (METs)
severity of nonobstructive and obstructive CAD, as well as (2); and b) without rest ST-T abnormalities (e.g., >0.5-mm
atherosclerotic plaque composition and high-risk features ST depression, left ventricular hypertrophy, paced
(e.g., positive remodeling, low attenuation plaque) (1-8). rhythm, left bundle branch block, Wolff-Parkinson-White
Calculation of fractional flow reserve with CT (FFR-CT) pattern, or digitalis use). Exercise electrocardiographic
provides an estimation of lesion-specific ischemia (9). contraindications are reported in Table 5.
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ASCVD indicates atherosclerotic cardiovascular disease; CAD, coronary artery disease; CAC, coronary artery calcium; CCTA, coronary computed tomography angiog-
raphy; CMR, cardiovascular magnetic resonance; ETT, exercise tolerance test; LV, left ventricular; MPI, myocardial perfusion imaging; PET, positron emission to-
mography and SPECT, single-photon emission computed tomography.
making. Performance of TTE at the bedside is ideal for abnormalities, measures of left ventricular function, and
patients with acute chest pain and can be done using high-risk findings, such as transient ischemic dilation (1-
point-of-care or handheld devices in institutions where 8). For PET, calculation of myocardial blood flow reserve
such capabilities are available. (MBFR, the ratio of peak hyperemia to resting myocar-
After ACS has been ruled out, stress echocardiography dial blood flow) adds diagnostic and prognostic infor-
can be used to define ischemia severity and for risk mation over MPI data (9-14). Radiation exposure, as
stratification purposes. For TTE and stress echocardiog- reported by an average effective dose, is w3 mSv for
raphy, ultrasound-enhancing agents are helpful for left rest/stress PET with Rb-82 and w10 mSv for Tc-99m
ventricular opacification when $2 contiguous segments SPECT; dual- isotope SPECT using thallium is not rec-
or a coronary territory is poorly visualized (3). Coronary ommended (15-17). SPECT/PET contraindications are and
flow velocity reserve in the mid-distal left anterior contraindications to type of stress test (exercise versus
descending coronary artery has been shown to improve pharmacologic) are reported in Table 5.
risk stratification and may be helpful in the select patient
with known CAD, including nonobstructive CAD (4-6). 3.2.4. Cardiovascular Magnetic Resonance Imaging
Contraindications to stress type (exercise versus phar- Cardiovascular magnetic resonance (CMR) imaging
macologic) and stress echocardiography are reported in has the capability to accurately assess global and
Table 5. regional left and right ventricular function, detect
and localize myocardial ischemia and infarction, and
3.2.3. Stress Nuclear (PET or SPECT) Myocardial Perfusion determine myocardial viability. CMR can also detect
Imaging myocardial edema and microvascular obstruction,
After ACS has been ruled out, rest/stress positron emis- which can help differentiate acute versus chronic MI,
sion tomography (PET) or single-photon emission as well as other causes of acute chest pain, including
computed tomography (SPECT) myocardial perfusion myocarditis. CMR contraindications are reported in
imaging (MPI) allows for detection of perfusion Table 5.
Exercise ECG Stress Nuclear (1)* Stress Echocardiography (2-5) Stress CMR (6) CCTA (7)*
n Abnormal ST changes on resting n High-risk unstable n Limited acoustic windows n Reduced GFR (<30 n Allergy to iodinated contrast
ECG, digoxin, left bundle branch angina, complicated ACS (e.g., in COPD patients) mL/min/1.73 m 2 ) n Inability to cooperate with scan
block, Wolff-Parkinson-White or AMI (<2 d) n Inability to reach target heart n Contraindications acquisition and/or breath-hold
pattern, ventricular paced rhythm n Contraindications to rate to vasodilator instructions
(unless test is performed to vasodilator administration
n Uncontrolled heart failure n Clinical instability (e.g., acute
establish exercise capacity and not administration
n High-risk unstable angina, n Implanted devices respiratory distress, severe hy-
for diagnosis of ischemia)
n Significant arrhyth- not safe for CMR or potension, unstable arrhythmia)
active ACS or AMI (<2 d)
n Unable to achieve $5 METs or un- mias (e.g., VT, sec- producing artifact
n Serious ventricular arrhythmia n Renal impairment as defined by
safe to exercise ond- or third-degree limiting scan qual-
or high risk for arrhythmias local protocols
n High-risk unstable angina or AMI (<2 d) atrioventricular ity/interpretation
attributable to QT n Contraindication to beta
i.e., active ACS block) or sinus n Significant
prolongation blockade in the presence of an
n Uncontrolled heart failure bradycardia <45 bpm claustrophobia
n Respiratory failure elevated heart rate and no
n n Significant hypoten- n Caffeine use within
Significant cardiac arrhythmias alternative medications available
n Severe COPD, acute pulmo-
(e.g., VT, complete atrioventricular sion (SBP <90 past 12 h for achieving target heart rate
mm Hg) nary emboli, severe pulmo-
block) or high risk for arrhythmias n Heart rate variability and
nary hypertension
caused by QT prolongation n Known or suspected
arrhythmia
n Contraindications to dobut-
n Severe symptomatic aortic stenosis bronchoconstrictive
n Contraindication to nitroglycerin
or bronchospastic amine (if pharmacologic stress
n Severe systemic arterial hyperten- (if indicated)
disease test needed)
sion (e.g., $200/110 mm Hg)
TABLE 5 Continued
Exercise ECG Stress Nuclear (1)* Stress Echocardiography (2-5) Stress CMR (6) CCTA (7)*
n Acute illness (e.g., acute PE, acute n Recent use of dipyr- n Atrioventricular block, un-
myocarditis/pericarditis, acute idamole or controlled atrial
aortic dissection) dipyridamole- fibrillation
containing n Critical aortic stenosis†
medications
n Acute illness (e.g., acute
n Use of methylxan- PE, acute myocarditis/
thines (e.g., pericarditis, acute aortic
aminophylline, dissection)
caffeine) within 12 h
n Hemodynamically signifi-
n Known hypersensi- cant LV outflow tract
tivity to adenosine, obstruction
regadenoson
n Contraindications to atro-
n Severe systemic arterial pine use:
hypertension
n Narrow-angle
(e.g., $200/110 mm Hg)
glaucoma
n Myasthenia gravis
n Obstructive
uropathy
n Obstructive gastro
intestinal disorders
n Severe systemic arterial hy-
pertension (e.g., $200/110
mm Hg)
Use of Contrast Contraindicated in:
n Hypersensitivity to perflutren
n
Hypersensitivity to blood,
blood products, or albumin
(for Optison only)
For all the imaging modalities, inability to achieve high-quality images should be considered, in particular for obese patients
Readers should also review each imaging society’s guidelines for more details on test contraindications (1-14).
*Screening for potential pregnancy by history and/or pregnancy testing should be performed according to the local imaging facilities policies for undertaking radiological examinations that involve
ionizing radiation in women of child-bearing age.
†Low-dose dobutamine may be useful for assessing for low-gradient AS.
ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; AS, aortic stenosis; CCTA, coronary computed tomography angiography; CMR, cardiovascular magnetic resonance
imaging; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; LV, left ventricular; MET, metabolic equivalent; MRI, magnetic resonance imaging; PE, pulmonary embolism;
SBP, systolic blood pressure; and VT, ventricular tachycardia.
3.3. Cardiac Testing Considerations for Women Who Are excreted into the breast milk and absorbed into the in-
Pregnant, Postpartum, or of Child-Bearing Age fant’s gastrointestinal tract (6).
This guideline focuses on elective and urgent cardiac
testing and, in both circumstances, imaging using 4. CHOOSING THE RIGHT PATHWAY WITH
ionizing radiation during pregnancy or postpartum while PATIENT-CENTRIC ALGORITHMS FOR
breast feeding should generally be avoided. When imag- ACUTE CHEST PAIN
ing is necessary to guide management, the risks and
benefits of invasive angiography, SPECT, PET, or CCTA After initial evaluation, the next step is determining
should be discussed with the patient. In all cases for a test whether further diagnostic testing is needed to establish a
deemed clinically necessary, the lowest effective dose of diagnosis or formulate a disposition plan. In some cases,
ionizing radiation should be used, including consider- there is clearly minimal risk of a serious medical condition
ations for tests with no radiation exposure (e.g., echo- although, in others, uncertainty may remain. We provide
cardiography, CMR imaging) (1). Radiation risk to the guidance to help clinicians make this determination within
fetus is very small. Iodinated contrast enters the fetal the context of acute and stable chest pain presentations.
circulation through the placenta and should be used with The initial assessment of patients presenting with acute
caution in a pregnant woman. The use of gadolinium chest pain is focused on the rapid identification of patients
contrast with CMR should be discouraged and used only with immediately life-threatening conditions such that
when necessary to guide clinical management and is ex- appropriate medical interventions can be initiated.
pected to improve fetal or maternal outcome (2-5). If Included among the potentially life-threatening (emer-
contrast is needed for a postpartum woman, breastfeed- gency) causes of chest pain are ACS (Section 4.1), acute
ing may continue because <1% of iodinated contrast is aortic syndromes (Section 4.2.1), and PE (Section 4.2.2).
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Myopericarditis is heterogeneous in its manifestations but gastrointestinal causes, are discussed in Section 4.3. Such
can include fulminant myocarditis, which carries a high nonemergency causes predominate among patients pre-
mortality rate (Section 4.2.3). A subset of noncardiovascular senting with acute chest pain; therefore, strategies that
syndromes are also immediately life-threatening, including incorporate routine, liberal use of testing carry the potential
esophageal rupture (Section 4.3.1), tension pneumothorax, for adverse effects of unnecessary investigations and un-
and sickle cell chest crisis. Nonemergency causes of chest necessary cost. Figure 7 provides an overview of this
pain, such as costochondritis and other musculoskeletal, or approach.
Recommendations for Patients With Acute Chest Pain and Suspected ACS (Not Including STEMI)
Referenced studies that support the recommendations are summarized in Online Data Supplements 8 and 9.
1. In patients presenting with acute chest pain and suspected ACS, clinical decision pathways (CDPs) should
1 B-NR categorize patients into low-, intermediate-, and high-risk strata to facilitate disposition and subsequent
diagnostic evaluation (1-14).
2. In the evaluation of patients presenting with acute chest pain and suspected ACS for whom serial troponins
1 B-NR are indicated to exclude myocardial injury, recommended time intervals after the initial troponin sample
collection (time zero) for repeat measurements are: 1 to 3 hours for high-sensitivity troponin and 3 to 6
hours for conventional troponin assays (15-17).
3. To standardize the detection and differentiation of myocardial injury in patients presenting with acute
1 C-LD chest pain and suspected ACS, institutions should implement a CDP that includes a protocol for troponin
sampling based on their particular assay (18,19)
4. In patients with acute chest pain and suspected ACS, previous testing when available should be considered
1 C-LD and incorporated into CDPs (20-24).
5. For patients with acute chest pain, a normal ECG, and symptoms suggestive of ACS that began at least
2a B-NR 3 hours before ED arrival, a single hs-cTn concentration that is below the limit of detection on initial
measurement (time zero) is reasonable to exclude myocardial injury (13,25-29).
ACS indicates acute coronary syndrome; CDP, clinical decision pathway; and ECG, electrocardiogram.
HEART Pathway EDACS ADAPT (mADAPT) NOTR 2020 ESC/hs-cTn* 2016 ESC/GRACE
(31) (44) (45) (34) (46,47) (11,38)
Target population Suspected ACS Suspected ACS, CP >5 min, Suspected ACS, CP >5 Suspected ACS, ECG, Suspected ACS, stable Suspected ACS,
planned serial troponin min, planned troponin ordered planned serial
observation troponin
Target outcome [ ED discharge without [ ED discharge rate without [ ED discharge rate [ Low-risk classification Early detection of AMI; Early detection of AMI
increasing missed increasing missed without increasing without increasing 30-d MACE
30-d or 1-y MACE 30-d MACE missed 30-d MACE missed 30-d MACE
TABLE 6 Continued
HEART Pathway EDACS ADAPT (mADAPT) NOTR 2020 ESC/hs-cTn* 2016 ESC/GRACE
(31) (44) (45) (34) (46,47) (11,38)
Variables used History Age TIMI score 0-1 Age History Age
ECG Sex No ischemic ECG Risk factors ECG HR, SBP
Age Risk factors changes Previous AMI or CAD hs-cTn (0, 1 or 2 h) Serum Cr
Risk factors History Troponin (0, 2 h) Troponin (0, 2 h) Cardiac arrest
Troponin (0, 3 h) Troponin (0, 2 h) ECG
Cardiac biomarker
Killip class
Risk thresholds:
n Low risk HEART score <3 EDACS score <16 TIMI score 0 (or <1 Age <50 y n Initial hs-cTn is Chest pain free,
Neg 0, 3-h cTn Neg 0, 2 h hs-cTn for mADAPT) <3 risk factors “very low” and Sx GRACE <140
Neg 0, 2-h hs-cTn No ischemic ECG D n Neg 0, 2-h Previous AMI or CAD onset >3 h ago n Sx <6 h - hs-cTn
cTn or hs-cTn Neg cTn or hs-cTn Or <ULN (0, 3 h)
(0, 2 h)
n No ischemic n Initial hs-cTn “low” n Sx >6 h - hs-cTn
ECG D and 1– or 2-h hs- <ULN (arrival)
cTn D is “low”
n High risk HEART score 7-10 NA TIMI score 5-7 (49) NA n Initial hs-cTn is n T0 hs-cTn >52
(48,49) “high” ng/L
Or Or
n 1- or 2-h hs-cTn D n D 1 h >5 ng/L
is high
Performance [ ED discharges by 21% More patients identified as ADAPT: More 30-d MACE AMI sensitivity >99% AMI sensitivity >99%
(40% versus 18%) low risk versus ADAPT discharged #6 h sensitivity ¼100% 62% Ruled out 30-d MACE not
Y 30-d objective testing (42% versus 31%) (19% versus 11%) 28% eligible for ED (0.2% 30-d MACE) studied
by 12% (69% versus discharge 25% Observe
57%) 13% Rule in
Y length of stay by 12 h
(9.9 versus 21.9 h)
hs-cTn accuracy: 95 92 93 99 99 –
30-d MACE
sensitivity, %
ED discharge, % 40 49 19 (ADAPT) 28 – –
39 (mADAPT)
*The terms “very low,” “low,” “high,” “1 h D,” and “2 h D” refer to hs-cTn assay-specific thresholds published in the ESC guideline (46,47).
ACS indicates acute coronary syndrome; ADAPT, Accelerated Diagnostic protocol to Assess chest Pain using Troponins; AMI, acute myocardial infarction; CP, chest pain or equivalent;
Cr, creatinine; cTn, cardiac troponin; hs-cTn, high-sensitivity cardiac troponin; ECG, electrocardiogram; ED, emergency department; EDACS, emergency department ACS; ESC, European Society of
Cardiology; GRACE, Global Registry of Acute Coronary Events; HEART, history, ECG, age, risk factors, troponin; HR, heart rate; hs, high sensitivity; MACE, major adverse cardiovascular events;
mADAPT, modified (including TIMI scores of 1) ADAPT; NA, not applicable; neg, negative; NICE, National Institute for Health and Clinical Excellence; NOTR, No Objective Testing Rule; SBP, systolic
blood pressure; SSACS, symptoms suggestive of ACS; Sx, symptoms; and ULN, upper limit of normal.
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CDP should be based on assay-specific performance testing may still have significant plaque and a higher
thresholds (4,5). CDPs are more likely to be successful event rate (20-22). The warranty period for a normal
when they incorporate multidisciplinary teams. stress-rest SPECT is highly variable because it is pri-
2. There are important differences in the performance of marily determined by the type of stress, the patient’s
highly sensitive and conventional cTn assays. hs-cTn clinical characteristics, and left ventricular ejection
assays may be used to guide disposition by repeat fraction (52).
sampling at 1, 2, or 3 hours from ED arrival using the 5. To use cTn properly, an understanding of the assay
pattern of rise or fall (i.e., delta) and the repeat value used (high sensitivity or conventional) and the timing
itself, based on assay-specific diagnostic thresholds of chest pain onset relative to ED arrival is critical
(37-43). When using conventional cTn assays, the (17,38,39). CDPs that emphasize rapid rule-out based
sampling timeframe is extended to 3 to 6 hours from on single hs-cTn concentrations below the limit of
ED arrival (36). detection should be limited to patients whose symp-
3. CDPs that include risk scores all perform well toms started at least 3 hours before ED arrival
overall, with 99% to 100% sensitivity for index- (2,5,6,11,14,16,25,40-43,53-55). Unlike high-sensitivity
visit AMI and 30-day MACE and have been shown assays, clinical decision-making based on single mea-
to decrease advanced testing to varying degrees surement of conventional cTn has not been validated
and should be used particularly with conventional (36). If the clinical presentation is still suspicious for
cTn (2,13,30-35). However, because sex-specific ACS or diagnostic uncertainty remains after serial cTn
considerations are not included in all scoring sys- measurement, it may be reasonable to repeat cTn
tems, their effectiveness in men and women may assay later (i.e., beyond 3 hours for high-sensitivity
not be equal (51). and beyond 6 hours for conventional assays)
4. Previous test results should always be considered in (23,40,41).
the evaluation of patients with acute chest pain once
TABLE 7 Warranty Period for Prior Cardiac Testing
ACS has been ruled out. In those with recent cardiac
testing and normal findings who do not have Test Modality Result Warranty Period
biomarker evidence of acute myocardial injury, further Anatomic Normal coronary angiogram 2y
CCTA with no stenosis or plaque
testing is of limited value, provided that adequate ex-
ercise levels were achieved or pharmacologic stress Stress testing Normal stress test (given adequate stress) 1y
was performed, imaging was of sufficient quality, and Table 8 provides a definition used for low-risk chest pain patients.
there are no changes in symptom frequency or stability CCTA indicates coronary computed tomographic angiography.
1. Patients with acute chest pain and a 30-day risk of death or MACE <1% should be designated as low risk
1 B-NR (1-11).
2. In patients with acute chest pain and suspected ACS who are deemed low-risk (<1% 30-day risk of death
2a B-R or MACE), it is reasonable to discharge home without admission or urgent cardiac testing (12-16).
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hs-cTn Based
T-0 T-0 hs-cTn below the assay limit of detection or “very low” threshold if symptoms present for at least 3 h
T-0 and 1- or 2-h Delta T-0 hs-cTn and 1- or 2-h delta are both below the assay “low” thresholds (>99% NPV for 30-d MACE)
HEART Pathway (20) HEART score #3, initial and serial cTn/hs-cTn < assay 99th percentile
EDACS (14) EDACS score #16; initial and serial cTn/hs-cTn < assay 99th percentile
ADAPT (21) TIMI score 0, initial and serial cTn/hs-cTn < assay 99th percentile
mADAPT TIMI score 0/1, initial and serial cTn/hs-cTn < assay 99th percentile
ADAPT indicates 2-hour Accelerated Diagnostic Protocol to Access Patients with Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarkers; cTn, cardiac troponin;
EDACS, Emergency Department Acute Coronary Syndrome; HEART Pathway, History, ECG, Age, Risk Factors, Troponin; hs-cTn, high-sensitivity cardiac troponin; MACE, major adverse
cardiovascular events; mADAPT, modified 2-hour Accelerated Diagnostic Protocol to Access Patients with Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarkers;
NOTR, No Objective Testing Rule; NPV, negative predictive value; and TIMI, Thrombolysis in Myocardial Infarction.
HEART Pathway, a modest 30-day cost savings of $216 per ated diagnostic pathway and resulted in a total cost
patient (p¼0.04) was observed (6). However, the overall reduction of $13.5 million (Australian) (7). Thus, improved
reductions in hospital admission and length of stay process efficiency and discharge of low-risk patients
impacted population estimates for cost savings from 1 ED largely results in overall cost reductions.
registry of 30,769 patients presenting before and 23,699
4.1.2. Intermediate-Risk Patients With Acute Chest Pain
patients presenting after implementation of an acceler-
1. For intermediate-risk patients with acute chest pain, TTE is recommended as a rapid, bedside test to
1 C-EO establish baseline ventricular and valvular function, evaluate for wall motion abnormalities, and to assess
for pericardial effusion.
2. For intermediate-risk patients with acute chest pain, management in an observation unit is reasonable to
2a A shorten length of stay and lower cost relative to an inpatient admission (1-7).
Anatomic Testing
1. For intermediate-risk patients with acute chest pain and no known CAD eligible for diagnostic testing
1 A after a negative or inconclusive evaluation for ACS, CCTA is useful for exclusion of atherosclerotic plaque
and obstructive CAD (1-11).
2. For intermediate-risk patients with acute chest pain, moderate-severe ischemia on current or prior (£1
1 C-EO year) stress testing, and no known CAD established by prior anatomic testing, ICA is recommended.
3. For intermediate-risk patients with acute chest pain with evidence of previous mildly abnormal stress test
2a C-LD results (£1 year), CCTA is reasonable for diagnosing obstructive CAD (12,13).
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(Continued)
Stress Testing
4. For intermediate-risk patients with acute chest pain and no known CAD who are eligible for cardiac
1 B-NR testing, either exercise ECG, stress echocardiography, stress PET/SPECT MPI, or stress CMR is useful for
the diagnosis of myocardial ischemia (1,4,10,14-36).
5. For intermediate-risk patients with acute chest pain and no known CAD, with a coronary artery stenosis of
2a B-NR 40% to 90% in a proximal or middle coronary artery on CCTA, FFR-CT can be useful for the diagnosis of
vessel-specific ischemia and to guide decision-making regarding the use of coronary revascularization
(37-43).
6. For intermediate-risk patients with acute chest pain and no known CAD, as well as an inconclusive prior
2a C-EO stress test, CCTA can be useful for excluding the presence of atherosclerotic plaque and obstructive CAD.
7. For intermediate-risk patients with acute chest pain and no known CAD, with an inconclusive CCTA, stress
2a C-EO imaging (with echocardiography, PET/SPECT MPI, or CMR) can be useful for the diagnosis of myocardial
ischemia.
F I G U R E 9 Evaluation Algorithm for Patients With Suspected ACS at Intermediate Risk With No Known CAD
Test choice should be guided by local availability and expertise. *Recent negative test: normal CCTA #2 years (no plaque/no stenosis) OR negative stress test #1 year,
given adequate stress. †High-risk CAD means left main stenosis $ 50%; anatomically significant 3-vessel disease ( $ 70% stenosis). ‡For FFR-CT, turnaround times may
impact prompt clinical care decisions. However, the use of FFR-CT does not require additional testing, as would be the case when adding stress testing. CAD indicates
coronary artery disease; CCTA, coronary CT angiography; CMR, cardiovascular magnetic resonance imaging; CT, computed tomography; FFR-CT, fractional flow reserve
with CT; GDMT, guideline-directed medical therapy; ICA, invasive coronary angiography; INOCA, ischemia and no obstructive coronary artery disease; PET, positron
emission tomography; and SPECT, single-photon emission CT.
Stress Testing referred for rest-stress MPI with mildly abnormal hs-cTn
values reported no adverse events related to the tests
4. Among patients evaluated in the ED who need further and a modest 13.6% yield for ischemic studies (55).
testing, exercise ECG is safe with most patients having Single-center, small (n¼105) randomized trial evidence
negative studies and a low risk of ACS (1,4,10,14-31, 54). suggests that stress CMR is safe without a near-term (90-
Stress echocardiography is safe and effective for triage day) increase in hospital readmission or additional
and prompt discharge of patients and is associated with testing (32-34). From a single-center registry (n¼135),
few events among those with normal or low-risk findings stress CMR was associated with a high sensitivity (100%)
over near-term follow-up of up to 6 months (17,18,36). and specificity (93%) for the detection of obstructive CAD
Prompt stress echocardiography resulted in a reduction or cardiovascular events at 1 year (35).
in ED and hospital length of stay, compared with CCTA,
with similar 2-year MACE rates (p¼0.47) (29). In the ED Sequential or Add-on Testing
evaluation of patients with acute chest pain, a nuclear 5. Patients with coronary artery stenosis of 40% to 90% in a
MPI strategy is similarly safe when compared with CCTA proximal or middle coronary segment on CCTA may
with no difference in MACE (death, ACS, or stroke) over benefit from measurement of FFR-CT (37-43). In a large
follow-up of 6 to 12 months. Longer-term follow-up data registry of 555 patients, the addition of FFR-CT was safe
from the PROSPECT trial (10) supported that at w3.5 with no difference in 90-day MACE compared with CCTA
years, the rate of MACE was similar between MPI and alone (42). No deaths or MI occurred among patients with
CCTA (p¼0.29) (10). Compared with CCTA, use of stress a negative FFR-CT when revascularization was deferred.
MPI delayed the time to diagnosis by >50% (1,4). 6. CCTA is highly effective at ruling out the presence of
Furthermore, recent observation from 213 patients plaque or stenosis and may help to clarify risk
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assessment and subsequent management decisions in ED (p<0.0001) (3). The CT-STAT (Systematic Triage of
patients with no known CAD who have inconclusive Acute Chest Pain Patients to Treatment) trial reported on
stress test results. the use of CCTA (n¼361 patients) compared with stress
7. Patients with acute chest pain who have indeterminate MPI (n¼338 patients) in the acute evaluation of chest pain
stenosis on CCTA may benefit from having a stress test with in the ED (4). In the CT-STAT trial, the time to diagnosis
imaging to evaluate for myocardial ischemia (37-43). was 2.9 hours in the CCTA arm and 6.2 hours in the stress
MPI arm (p<0.0001). Accordingly, median adjusted ED
4.1.2.1.1. Cost-Value Considerations charges were nearly 40% lower for CCTA, compared with
Economic evaluations have explored the value of stress stress MPI ($2,137 for CCTA versus $3,458 for stress MPI;
echocardiography, CCTA, and stress nuclear imaging. p<0.001). Overall, CCTA resulted in improved efficiency
Several observational series report that prompt stress with a reduction in length of stay and prompt discharge
echocardiography in the ED for the evaluation of acute (5,6), resulting in cost savings from 15% to 38% when
chest pain is associated with significantly lower costs, compared with standard care strategies (4,7) and a
with no adverse sequelae after early discharge (1,2). In a weighted cost savings of $680 (8).
single-center randomized trial of 400 patients, prompt
stress echocardiography was associated with a reduced 4.1.2.2. Intermediate-Risk Patients With Acute Chest Pain and
rate of hospitalization (p¼0.026) and length of stay in the Known CAD
Recommendations for Intermediate-Risk Patients With Acute Chest Pain and Known CAD
Referenced studies that support the recommendations are summarized in Online Data Supplements 16 and 17.
1. For intermediate-risk patients with acute chest pain who have known CAD and present with new onset or
1 A worsening symptoms, GDMT should be optimized before additional cardiac testing is performed (1,2).
2. For intermediate-risk patients with acute chest pain who have worsening frequency of symptoms with
1 A significant left main, proximal left anterior descending stenosis, or multivessel CAD on prior anatomic
testing or history of prior coronary revascularization, ICA is recommended (3-8).
3. For intermediate-risk patients with acute chest pain and known nonobstructive CAD, CCTA can be useful
2a B-NR to determine progression of atherosclerotic plaque and obstructive CAD (9-11).
4. For intermediate-risk patients with acute chest pain and coronary artery stenosis of 40% to 90% in a
2a B-NR proximal or middle segment on CCTA, FFR-CT is reasonable for diagnosis of vessel-specific ischemia and
to guide decision-making regarding the use of coronary revascularization (12-17).
5. For intermediate-risk patients with acute chest pain and known CAD who have new onset or worsening
2a B-NR symptoms, stress imaging (PET/SPECT MPI, CMR, or stress echocardiography) is reasonable (18-21).
F I G U R E 1 0 Evaluation Algorithm for Patients With Suspected ACS at Intermediate Risk With Known CAD
Test choice should be guided by local availability and expertise. *Known CAD is prior MI, revascularization, known obstructive or nonobstructive CAD on invasive or
CCTA. †If extensive plaque is present a high-quality CCTA is unlikely to be achieved, and stress testing is preferred ‡Obstructive CAD includes prior coronary artery
bypass graft/percutaneous coronary intervention. §High-risk CAD means left main stenosis $50%; anatomically significant 3-vessel disease ($70% stenosis). kFFR-CT
turnaround times may impact prompt clinical care decisions. ACS indicates acute coronary syndrome; CAD, coronary artery disease; CCTA, coronary CT angiography;
CMR, cardiovascular magnetic resonance; CT, computed tomography; FFR-CT, fractional flow reserve with CT; GDMT, guideline-directed medical therapy; ICA, invasive
coronary angiography; INOCA, ischemia and no obstructive coronary artery disease; PET, positron emission tomography; and SPECT, single-photon emission CT.
include those patients with a previous CAC scan (or stenosis is proximal or mid-coronary artery (12-17,25).
those for whom coronary artery calcification was noted From 1 large clinical registry, the deferral of coronary
as an incidental finding on chest CT) who present to an revascularization with a normal FFR-CT was safe, with
ED for evaluation of chest pain where concern exists no difference in MACE at 90 days (16).
with regard to the extent of noncalcified plaque and 5. Most randomized trials that examined the role of
potential for underlying obstructive stenosis. Howev- stress testing in the ED enrolled patients with no
er, for patients with extensive plaque, a stress test is known CAD, with few including patients with
preferred. obstructive CAD (range: 7%–15%) (18-20). Despite
4. Patients with acute chest pain who have coronary ar- this, assessing the functional significance of
tery stenosis from 40% to 90% on CCTA may benefit obstructive CAD is an important part of ischemia-
from measurement of FFR-CT, especially when the guided management (26).
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Recommendations for High-Risk Patients, Including Those With High-Risk Findings on CCTA or Stress Testing
1. For patients with acute chest pain and suspected ACS who have new ischemic changes on electrocardi-
1 B-NR ography, troponin-confirmed acute myocardial injury, new-onset left ventricular systolic dysfunction
(ejection fraction <40%), newly diagnosed moderate-severe ischemia on stress testing, hemodynamic
instability, and/or a high clinical decision pathway (CDP) risk score should be designated as high risk for
short-term MACE (1-3).
2. For patients with acute chest pain and suspected ACS who are designated as high risk, ICA is recom-
1 C-EO mended (4-7).
3. For high-risk patients with acute chest pain who are troponin positive in whom obstructive CAD has been
2a B-NR excluded by CCTA or ICA, CMR or echocardiography can be effective in establishing alternative diagnoses
(8-12).
Recommendations for Acute Chest Pain in Patients With Prior CABG Surgery
1. In patients with prior CABG surgery presenting with acute chest pain who do not have ACS, performing
1 C-LD stress imaging is effective to evaluate for myocardial ischemia or CCTA for graft stenosis or occlusion (1-7).
2. In patients with prior CABG surgery presenting with acute chest pain, who do not have ACS (8-14) or who
1 C-LD have an indeterminate/nondiagnostic stress test, ICA is useful (8).
imaging may be as a result of patient’s body habitus, reasonable when the angiographic findings have a high
inadequate or suboptimal heart rate, arrhythmias such likelihood of impacting therapeutic decisions (8).
as atrial fibrillation, left bundle branch block, or patient
4.1.5. Evaluation of Patients With Acute Chest Pain Receiving
motion. In these patients, performing an ICA is
Dialysis
Recommendation for Evaluation of Patients With Acute Chest Pain Receiving Dialysis
Referenced studies that support the recommendation are summarized in Online Data Supplement 20.
1. In patients who experience acute unremitting chest pain while undergoing dialysis, transfer by EMS to an
1 B-NR acute care setting is recommended (1-5).
Synopsis Unusual but serious causes of chest pain during dialysis are
In 2015, there were nearly 500,000 people in the United embolism (6) and vessel perforation by catheter (4,5). When
States who received maintenance dialysis to treat end-stage indicated, cardiac testing for patients on dialysis should be the
renal disease (1). Chest pain occurs during hemodialysis in same as those who are not on dialysis.
2% to 5% of patients (6,7). Causes are numerous and related to
the high prevalence of severe cardiovascular disease in this Recommendation-Specific Supportive Text
population and the dialysis procedure itself. Causes include
AMI or ACS, pericarditis, PE, pleuritis, hemolysis, gastro- 1. Because the risk of CAD is relatively high in patients
esophageal reflux, subclavian steal, and musculoskeletal dis- undergoing dialysis, when acute unremitting chest pain
orders (7). Myocardial ischemia is the most frequent serious occurs during dialysis, a 12-lead ECG should be per-
cause and can be induced by hypotension (6,7) or tachyar- formed and the patient should be urgently transferred
rhythmias (2) occurring during dialysis in patients with CAD. by EMS to an acute care setting for evaluation for cause
AMI in patients undergoing dialysis is less frequently associ- of symptoms and further clinical engagement (3).
ated with chest pain than in patients who are not on dialysis, 4.1.6. Evaluation of Acute Chest Pain in Patients With Cocaine
but warning signs may include diaphoresis or dyspnea (3). and Methamphetamine Use
Recommendation for Evaluation of Acute Chest Pain in Patients With Cocaine and Methamphetamine Use
Referenced studies that support the recommendation are summarized in Online Data Supplement 21.
1. In patients presenting with acute chest pain, it is reasonable to consider cocaine and methamphetamine
2a B-NR use as a cause of their symptoms (1-3).
1. For patients with acute chest pain and suspected ACS who are deemed low risk by a CDP, patient decision
1 B-R aids are beneficial to improve understanding and effectively facilitate risk communication (1,2).
2. For patients with acute chest pain and suspected ACS who are deemed intermediate risk by a CDP, shared
1 B-R decision-making between the clinician and patient regarding the need for admission, for observation,
discharge, or further evaluation in an outpatient setting is recommended for improving patient under-
standing and reducing low-value testing (1,2).
Recommendation for Evaluation of Acute Chest Pain With Nonischemic Cardiac Pathologies
1. In patients with acute chest pain in whom other potentially life-threatening nonischemic cardiac condi-
1 C-EO tions are suspected (e.g., aortic pathology, pericardial effusion, endocarditis), TTE is recommended for
diagnosis.
Recommendations for Acute Chest Pain With Suspected Acute Aortic Syndrome
1. In patients with acute chest pain where there is clinical concern for aortic dissection, computed to-
1 C-EO mography angiography (CTA) of the chest, abdomen, and pelvis is recommended for diagnosis and
treatment planning.
2. In patients with acute chest pain where there is clinical concern for aortic dissection, TEE or CMR should
1 C-EO be performed to make the diagnosis if CT is contraindicated or unavailable.
1. In stable patients with acute chest pain with high clinical suspicion for PE, CTA using a PE protocol is
1 B-NR recommended (1-4).
2. For patients with acute chest pain and possible PE, need for further testing should be guided by pretest
1 C-EO probability.
1. In patients with acute chest pain and myocardial injury who have nonobstructive coronary arteries on
1 B-NR anatomic testing, CMR with gadolinium contrast is effective to distinguish myopericarditis from other
causes, including myocardial infarction and nonobstructive coronary arteries (MINOCA) (1-6).
2. In patients with acute chest pain with suspected acute myopericarditis, CMR is useful if there is diagnostic
1 B-NR uncertainty, or to determine the presence and extent of myocardial and pericardial inflammation and
fibrosis (7-12).
3. In patients with acute chest pain and suspected myopericarditis, TTE is effective to determine the
1 C-EO presence of ventricular wall motion abnormalities, pericardial effusion, valvular abnormalities, or
restrictive physiology.
4. In patients with acute chest pain with suspected acute pericarditis, noncontrast or contrast cardiac CT
2b C-LD scanning may be reasonable to determine the presence and degree of pericardial thickening (7,8,13).
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1. In patients presenting with acute chest pain with suspected or known history of VHD, TTE is useful in
1 C-EO determining the presence, severity, and cause of VHD.
2. In patients presenting with acute chest pain with suspected or known VHD in whom TTE diagnostic
1 C-EO quality is inadequate, TEE (with 3D imaging if available) is useful in determining the severity and cause of
VHD.
3. In patients presenting with acute chest pain with known or suspected VHD, CMR imaging is reasonable as
2a C-EO an alternative to TTE and/or TEE is nondiagnostic.
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Recommendation for Evaluation of Acute Chest Pain With Suspected Noncardiac Causes
1. Patients with acute chest pain should be evaluated for noncardiac causes if they have persistent or
1 C-EO recurring symptoms despite a negative stress test or anatomic cardiac evaluation, or a low-risk desig-
nation by a CDP.
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Psychological
Panic disorder
Anxiety
Clinical depression
Somatization disorder
Hypochondria
Other
Hyperventilation syndrome
Sarcoidosis
Lead poisoning
Recommendation for Evaluation of Acute Chest Pain With Suspected Gastrointestinal Syndromes
1. In patients with recurrent acute chest pain without evidence of a cardiac or pulmonary cause, evaluation
2a C-LD for gastrointestinal causes is reasonable.
1. The first step in evaluation of potential esophageal 4.3.2. Evaluation of Acute Chest Pain With Suspected Anxiety
chest pain is a careful history. Although the clinical and Other Psychosomatic Considerations
Recommendation for Evaluation of Acute Chest Pain With Suspected Anxiety and Other Psychosomatic Considerations
Referenced studies that support the recommendation are summarized in Online Data Supplement 25.
1. For patients with recurrent, similar presentations for acute chest pain with no evidence of a physiological
2a B-R cause on prior diagnostic evaluation including a negative workup for myocardial ischemia, referral to a
cognitive-behavioral therapist is reasonable (1-14).
such as anxiety, panic attack, depression, somatoform ded CAD by almost 10-fold (7). Additionally, care of
disorder, and cardiophobia suggests that there may be a these patients often includes multiple tests, high cost,
psychogenic origin in many patients. These factors have and avoidable radiation exposure (5.0 mSv) (6). A low
also raised consideration of mechanisms for noncardiac rate (<10%) of clinician inquiry, documentation, or
chest pain such as central nervous system-visceral in- referral has also been noted for psychological factors,
teractions, low pain thresholds, hyperbody vigilance, even in chest pain patients with self-reported anxiety
sympathetic activation, as well as anxiety, depression, (6,7). A systematic review of therapy for patients with
and panic disorder (6,7,9,14,23-30). It has been reported chest pain, no evidence of cardiac disease, and psy-
that these patients undergo extensive and repetitive chological disorders revealed that antidepressants and
cardiac testing and have low referral to cognitive- anxiolytics had mixed evidence for efficacy (10), but a
behavioral therapists, suggesting a lost opportunity for Cochrane database of psychotherapy (17 RCTs) for such
pharmacologic or cognitive-behavioral therapy (6). patients revealed a 32% reduction in chest pain fre-
quency (11) for a 3-month interval. Approaches using
Recommendation-Specific Supportive Text cognitive-behavioral methods were most effective (11).
1. Most low-risk patients presenting to the ED or office These results were limited by small study cohorts
setting with chest pain do not have life-threatening and patient heterogeneity; however, they do suggest
conditions. Diagnoses may include psychological en- benefit from consideration of psychogenic factors in
tities such as somatization or noncardiac chest pain (1- patients who continue to seek evaluation for chest pain
13). It has been reported that in low-risk chest pain pa- despite previous definitive, negative workups.
tients without evidence of cardiac disease, depression, 4.3.3. Evaluation of Acute Chest Pain in Patients With
anxiety, and gastroesophageal syndromes each excee- Sickle Cell Disease
Recommendations for Evaluation of Acute Chest Pain in Patients With Sickle Cell Disease
Referenced studies that support the recommendations are summarized in Online Data Supplement 26.
1. In patients with sickle cell disease who report acute chest pain, emergency transfer by EMS to an acute
1 B-NR care setting is recommended (1-5).
2. In patients with sickle cell disease who report acute chest pain, ACS should be excluded (3-5).
1 C-LD
F I G U R E 1 1 Pretest Probabilities of Obstructive CAD in Symptomatic Patients According to Age, Sex, and Symptoms
Modified from Juarez-Orozco et al. (1) and Winther et al. (2). 1) The pretest probability shown is for patients with anginal symptoms. Patients with lower-risk
symptoms would be expected to have lower pretest probability. 2) The darker green- and orange-shaded regions denote the groups in which noninvasive
testing is most beneficial (pretest probability >15%). The light green–shaded regions denote the groups with pretest probability of CAD #15% in which the
testing for diagnosis may be considered based on clinical judgment (1). 3) If CAC is available, it can also be used to estimate the pretest probability based on
CAC score (2). CAC indicates coronary artery calcium; and CAD, coronary artery disease.
5.1.1. Pretest Risk Probability to Guide Need for Stress and have symptoms that have a low likelihood of representing
Anatomic Tests ischemia (Section 5.1.2). When available, information on
In the evaluation of symptomatic patients with suspected the presence and amount of CAC may be useful for
CAD, use of validated scores to predict the pretest prob- enhancing the pretest probability of obstructive CAD, as
ability of obstructive CAD may be useful to identify low- shown in Figure 11 (2). This information can be obtained
risk patients for whom testing may be deferred. It is from performing a CAC scan or, when available, from a
preferable to use contemporary estimates such as those visual estimation of CAC based on prior noncardiac chest
published in the past 10 years, such as the pretest prob- CT. Among the remaining patients classified as
ability proposed by Juarez-Orozco et al. (1) in preference intermediate-high risk, selective testing may improve
to scores from historical patient series, which may over- diagnosis of CAD and for risk stratification purposes (1-5).
estimate the frequency of obstructive CAD. Alternatively,
low-risk patients may be those <40 years of age or who 5.1.2. Low-Risk Patients With Stable Chest Pain and No Known CAD
Recommendations for Low-Risk Patients With Stable Chest Pain and No Known CAD
Referenced studies that support the recommendations are summarized in Online Data Supplements 27 and 28.
1. For patients with stable chest pain and no known CAD presenting to the outpatient clinic, a model to
1 B-NR estimate pretest probability of obstructive CAD is effective to identify patients at low risk for obstructive
CAD and favorable prognosis in whom additional diagnostic testing can be deferred (1-5).
2. For patients with stable chest pain and no known CAD categorized as low risk, CAC testing is reasonable as a first-line
2a B-R test for excluding calcified plaque and identifying patients with a low likelihood of obstructive CAD (6-9).
3. For patients with stable chest pain and no known CAD categorized as low risk, exercise testing without
2a B-NR imaging is reasonable as a first-line test for excluding myocardial ischemia and determining functional
capacity in patients with an interpretable ECG (10).
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Recommendations for Intermediate-High Risk Patients With Stable Chest Pain and No Known CAD
Referenced studies that support the recommendations are summarized in Online Data Supplements 29 and 30.
Anatomic Testing
1. For intermediate-high risk patients with stable chest pain and no known CAD, CCTA is effective for
1 A diagnosis of CAD, for risk stratification, and for guiding treatment decisions (1-12).
Stress Testing
2. For intermediate-high risk patients with stable chest pain and no known CAD, stress imaging (stress
1 B-R echocardiography, PET/SPECT MPI or CMR) is effective for diagnosis of myocardial ischemia and for
estimating risk of MACE (8,13-35).
3. For intermediate-high risk patients with stable chest pain and no known CAD for whom rest/stress nu-
2a B-R clear MPI is selected, PET is reasonable in preference to SPECT, if available to improve diagnostic ac-
curacy and decrease the rate of nondiagnostic test results (36-39).
4. For intermediate-high risk patients with stable chest pain and no known CAD with an interpretable ECG
2a B-R and ability to achieve maximal levels of exercise (‡5 METs), exercise electrocardiography is reasonable
(8,13,15,40-45).
5. In intermediate-high risk patients with stable chest pain selected for stress MPI using SPECT, the use of
2b B-NR attenuation correction or prone imaging may be reasonable to decrease the rate of false-positive findings
(46-51).
6. In intermediate-high risk patients with stable chest pain who have pathological Q waves, symptoms or
1 B-NR signs suggestive of heart failure, complex ventricular arrhythmias, or a heart murmur with unclear
diagnosis, use of TTE is effective for diagnosis of resting left ventricular systolic and diastolic ventricular
function and detection of myocardial, valvular, and pericardial abnormalities (13,14,52).
Sequential or Add-on Testing: What to Do if Index Test Results are Positive or Inconclusive
7. For intermediate-high risk patients with stable chest pain and known coronary stenosis of 40% to 90% in
2a B-NR a proximal or middle coronary segment on CCTA, FFR-CT can be useful for diagnosis of vessel-specific
ischemia and to guide decision-making regarding the use of coronary revascularization (12,53-58).
8. For intermediate-high risk patients with stable chest pain after an inconclusive or abnormal exercise ECG
2a B-NR or stress imaging study, CCTA is reasonable (5,59-63).
9. For intermediate-high risk patients with stable chest pain and no known CAD undergoing stress testing,
2a B-NR the addition of CAC testing can be useful (64-70).
10. For intermediate-high risk patients with stable chest pain after inconclusive CCTA, stress imaging is
2a B-NR reasonable (13,14,20-23, 40,71-76).
11. For intermediate-high risk patients with stable chest pain after a negative stress test but with high
2b C-EO clinical suspicion of CAD, CCTA or ICA may be reasonable.
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3. Although PET and SPECT are grouped together, PET Sequential or Add-on Testing
has improved diagnostic and prognostic perfor-
6. The use of FFR-CT is supported by several studies
mance, especially when quantitative assessment of
(56,57,104), including one reporting improved diag-
MBF can be performed (36-39). A recent clinical
nostic accuracy with FFR-CT versus coronary CT alone
trial (n¼475) reported a higher diagnostic accuracy
when applying invasive FFR as the gold standard (56).
with stress PET MPI compared with other stress test
Several multinational registries have examined the
modalities (38).
utility of FFR-CT with regards to guiding clinical
4. Diagnostic accuracy of the exercise ECG is lower (i.e.,
decision-making and the safety of deferring coronary
sensitivity and specificity range, 60%–77%) than
revascularization in patients with a negative FFR-CT
stress imaging, but prognostication remains a useful
(12,26,53,54). In the ADVANCE registry, FFR-CT
goal (13,41). In the WOMEN trial including 824
changed treatment recommendations in two-thirds
symptomatic women, exercise ECG was equally
of 5,083 patients, and there were no MACE at 90
effective when compared with exercise SPECT MPI,
days for patients with a negative FFR-CT (54). FFR-CT
with similar 2-year CAD event rates (2.0% versus
is most beneficial when measured in a coronary ste-
2.3%; p¼0.59) (40). Failure to complete the first stage
nosis of 40% to 90% severity located in a proximal or
of the Bruce protocol (or <5 METs) or to achieve 85%
mid-coronary artery segment (54,106,107).
of age-predicted fitness level increases CAD event
7. Use of CCTA after stress testing can diagnose or
risk (13,41-45). Patients exercising to Bruce stage III
exclude obstructive CAD and identify patients who
or >10 METs with a negative ECG have a low risk of
may benefit from referral to ICA (5,59-61,63). The
CAD events. In patients with submaximal exercise or
ISCHEMIA trial used CCTA after site-determined
for those with an ischemic ECG $1.0 mm ST
moderate-severe ischemia to exclude patients with
depression, additional stress imaging may improve
nonobstructive CAD and identifying those with sig-
risk detection and guide clinical management (41).
nificant left main stenosis who benefit from prompt
Marked ischemia (e.g., $2.0 mm at reduced work-
referral to ICA (63,108). Half of the screen failures for
loads) or high Duke or Lauer scores signify increased
the ISCHEMIA trial were identified by CCTA including
risk among women and men (13,41,42,44); such pa-
those with nonobstructive CAD or unprotected left
tients may benefit from additional testing (anatomic
main CAD.
or stress testing).
8. Observational registry data suggest that adding CAC
5. Use of attenuation correction algorithms and prone
can improve risk assessment, reduce diagnostic un-
imaging can reduce MPI artifacts (46-51).
certainty, help detect atherosclerotic plaque, and
guide preventive management (64-70,94,109,110).
Assessment of Left Ventricular Function
9. After an initial exercise ECG, data support an
6. Clinical practice guidelines and appropriate use criteria improved diagnostic accuracy and improved risk
support use of TTE as appropriate for the assessment of stratification with further stress imaging, such as with
regional and global left ventricular function (13,14). stress echocardiography (13,14,71,72), nuclear MPI (20-
The likelihood of abnormal findings increases when 23,40,73-76), or CMR (35,111-113).
TTE is performed selectively among higher risk pa- 10. For the symptomatic patients with negative stress test
tients, such as those with electrocardiographic Q waves findings, selective use of CCTA or invasive coronary
or heart failure symptoms, complex ventricular ar- angiography can help detect obstructive CAD and
rhythmias, or a heart murmur (52). atherosclerotic plaque and reduce diagnostic certainty.
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F I G U R E 1 2 Clinical Decision Pathway for Patients With Stable Chest Pain and No Known CAD
Test choice should be guided by local availability and expertise. *Test choice guided by patient’s exercise capacity, resting electrocardiographic abnormalities; CCTA
preferable in those <65 years of age and not on optimal preventive therapies; stress testing favored in those $65 years of age (with a higher likelihood of ischemia).
†High-risk CAD means left main stenosis $50%; anatomically significant 3-vessel disease ($70% stenosis). CAD indicates coronary artery disease; CCTA, coronary CT
angiography; CMR, cardiovascular magnetic resonance imaging; CT, computed tomography; FFR-CT, fractional flow reserve with CT; GDMT, guideline-directed medical
therapy; INOCA, ischemia and no obstructive CAD; PET, positron emission tomography; and SPECT, single-photon emission CT.
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5.2. Patients With Known CAD Presenting With Stable Chest Pain
Recommendations for Patients With Known CAD Presenting With Stable Chest Pain
Referenced studies that support the recommendations are summarized in Online Data Supplement 31.
1. For patients with obstructive CAD and stable chest pain, it is recommended to optimize GDMT (1-3).
1 A
2. For patients with known nonobstructive CAD and stable chest pain, it is recommended to optimize
1 C-EO preventive therapies (4,5).
Recommendation-Specific Supportive Text 5.2.1. Patients With Obstructive CAD Who Present With Stable
1. ACC/AHA clinical practice guidelines for treatment of Chest Pain
patients with stable CAD recommend optimization of
Recommendations for Patients With Obstructive CAD Who Present With Stable Chest Pain
Referenced studies that support the recommendations are summarized in Online Data Supplements 32 and 33.
Anatomic Testing
1. For patients with obstructive CAD who have stable chest pain despite GDMT and moderate-severe
1 A ischemia, ICA is recommended for guiding therapeutic decision-making (1-4).
2. For patients with obstructive CAD who have stable chest pain despite optimal GDMT, those referred for
1 A ICA without prior stress testing benefit from FFR or instantaneous wave free ratio (3,5-7).
3. For symptomatic patients with obstructive CAD who have stable chest pain with CCTA-defined ‡50%
1 B-R stenosis in the left main coronary artery, obstructive CAD with FFR with CT £0.80, or severe stenosis
(‡70%) in all 3 main vessels, ICA is effective for guiding therapeutic decision-making (4,8).
4. For patients who have stable chest pain with previous coronary revascularization, CCTA is reasonable to
2a B-NR evaluate bypass graft or stent patency (for stents ‡3 mm) (9-13).
Stress Testing
5. For patients with obstructive CAD who have stable chest pain despite optimal GDMT, stress PET/SPECT
1 B-NR MPI, CMR, or echocardiography is recommended for diagnosis of myocardial ischemia, estimating risk of
MACE, and guiding therapeutic decision-making (14-36).
6. For patients with obstructive CAD who have stable chest pain despite optimal GDMT, when selected for
2a B-R rest/stress nuclear MPI, PET is reasonable in preference to SPECT, if available, to improve diagnostic
accuracy and decrease the rate of nondiagnostic test results (37).
7. For patients with obstructive CAD who have stable chest pain despite GDMT, exercise treadmill testing can
2a B-NR be useful to determine if the symptoms are consistent with angina pectoris, assess the severity of symp-
toms, evaluate functional capacity and select management, including cardiac rehabilitation (4,38-40).
8. For patients with obstructive CAD who have stable chest pain symptoms undergoing stress PET MPI or stress CMR,
2a B-NR the addition of MBFR is useful to improve diagnosis accuracy and enhance risk stratification (31-36).
e54 Gulati et al. JACC VOL. -, NO. -, 2021
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F I G U R E 1 3 Clinical Decision Pathway for Patients With Stable Chest Pain (or Equivalent) Symptoms With Prior MI, Prior Revascularization, or Known CAD on
Invasive Coronary Angiography or CCTA, Including Those With Nonobstructive CAD
Test choice should be guided by local availability and expertise. *Known CAD means prior MI, revascularization, known obstructive CAD, nonobstructive CAD. †High-risk
CAD means left main stenosis $50%; or obstructive CAD with FFR-CT #0.80. ‡Test choice guided by the patient’s exercise capacity, resting electrocardiographic
abnormalities. §Patients with prior CABG or stents >3.0 mm. Follow-up Testing and Intensification of GDMT Guided by Initial Test Results and Persistence / Worsening /
Frequency of Symptoms and Shared Decision Making. CABG indicates coronary artery bypass graft; CAD, coronary artery disease; CCTA, coronary CT angiography; CMR,
cardiovascular magnetic resonance imaging; CT, computed tomography; ECG, electrocardiogram; FFR-CT, fractional flow reserve with CT; GDMT, guideline-directed
medical therapy; ICA, invasive coronary angiography; iFR, instant wave-free ratio; INOCA, ischemia and no obstructive coronary artery disease; MI, myocardial infarction;
MPI, myocardial perfusion imaging; PET, positron emission tomography; SIHD, stable ischemic heart disease; and SPECT, single-photon emission CT.
JACC VOL. -, NO. -, 2021 Gulati et al. e55
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symptoms to graded stress testing, thereby helping to risk of major CAD events. This can be effectively
confirm the diagnosis of angina pectoris; assessing accomplished using PET (31,70,71) or CMR (28). Normal
symptom severity; and selecting appropriate manage- MBFR may be helpful in excluding high risk anatomy,
ment: medical therapy, revascularization, and/or car- although reduced levels may provide a better estimate
diac rehabilitation (4,38-40). of disease extent and severity. In the presence of
nonobstructive CAD, reduced MBFR may signify coro-
Secondary Diagnostic Testing: For the Assessment of nary microvascular dysfunction, especially among
Vascular Territory Flow or Vessel-Specific Ischemia women (70).
8. Measurement of MBFR, when reduced, reflects abnor- 5.2.1.1. Patients With Prior CABG Surgery With Stable
malities of flow within the epicardial coronary arteries Chest Pain
and/or microvasculature and independently predicts
Recommendations for Patients With Prior CABG Surgery With Stable Chest Pain
1. In patients who have had prior CABG surgery presenting with stable chest pain whose noninvasive stress
1 C-LD test results show moderate-to-severe ischemia (1-7), or in those suspected to have myocardial ischemia
with indeterminate/nondiagnostic stress test, ICA is recommended for guiding therapeutic decision-
making (1).
2. In patients who have had prior CABG surgery presenting with stable chest pain who are suspected to have
2a C-LD myocardial ischemia, it is reasonable to perform stress imaging or CCTA to evaluate for myocardial
ischemia or graft stenosis or occlusion (8-15).
evaluation of bypass grafts in 93% to 100% of patients (15). stenosis in this population because of high degree of non-
In patients who have stable chest pain and are previously diagnostic segments (8-15).
known to have borderline graft stenosis or are suspected to
have new graft stenosis, CCTA is useful for assessing graft 5.2.2. Patients With Known Nonobstructive CAD Presenting With
patency but less robust for assessing native coronary vessel Stable Chest Pain
Recommendations for Patients With Known Nonobstructive CAD Presenting With Stable Chest Pain
Referenced studies that support the recommendations are summarized in Online Data Supplements 34 and 35.
Anatomic Testing
1. For symptomatic patients with known nonobstructive CAD who have stable chest pain, CCTA is reasonable
2a B-NR for determining atherosclerotic plaque burden and progression to obstructive CAD, and guiding thera-
peutic decision-making (1-7).
2. For patients with known coronary stenosis from 40% to 90% on CCTA, FFR can be useful for diagnosis of
2a B-NR vessel-specific ischemia and to guide decision-making regarding the use of ICA (8-14).
Stress Testing
3. For patients with known extensive nonobstructive CAD with stable chest pain symptoms, stress imaging
2a C-LD (PET/SPECT, CMR, or echocardiography) is reasonable for the diagnosis of myocardial ischemia (15-24).
recommendations and selection of vessels for revas- intermediate coronary stenosis as it provides insight
cularization were guided by FFR-CT in w20% of into the patient’s presenting symptoms and can help
patients. guide clinical management.
Stress Testing
5.2.3. Patients With Suspected Ischemia and No Obstructive CAD
3. Approximately 20% to 30% of patients with non-
(INOCA)
obstructive CAD will demonstrate ischemia (15-24).
Patients who experience ischemia with non- Recommendations for myocardial blood flow measure-
obstructive CAD (INOCA - see section 5.2.3) benefit ments using PET, echocardiography, and CMR are found
in Section 5.2.2.
from assessment of functional significance of an
1. For patients with persistent stable chest pain and nonobstructive CAD and at least mild myocardial
2a B-NR ischemia on imaging, it is reasonable to consider invasive coronary function testing to improve the
diagnosis of coronary microvascular dysfunction and to enhance risk stratification (1-4).
2. For patients with persistent stable chest pain and nonobstructive CAD, stress PET MPI with MBFR is
2a B-NR reasonable to diagnose microvascular dysfunction and enhance risk stratification (5-11).
3. For patients with persistent stable chest pain and nonobstructive CAD, stress CMR with the addition of
2a B-NR MBFR measurement is reasonable to improve diagnosis of coronary myocardial dysfunction and for
estimating risk of MACE (12-14).
4. For patients with persistent stable chest pain and nonobstructive CAD, stress echocardiography with the
2b C-EO addition of coronary flow velocity reserve measurement may be reasonable to improve diagnosis of
coronary myocardial dysfunction and for estimating risk of MACE.
Test choice should be guided by local availability and expertise. *Ford T, et al. (16). †Cannot exclude microvascular vasospasm. ACh indicates acetylcholine; CAD,
coronary artery disease; CFR, coronary flow reserve; CFVR, coronary flow velocity reserve; CMD, coronary microvascular dysfunction; CV, cardiovascular; FFR, fractional
flow reserve; GDMT, guideline-directed medical therapy; IMR, index of microcirculatory restriction; INOCA, ischemia and no obstructive CAD; MACE, major adverse
cardiovascular events; and MBFR, myocardial blood flow reserve.
within the epicardial coronary arteries and microvas- flow reserve improves prognostication (12-14). Stress
culature and independently predicts risk of major CAD CMR studies of MBFR have shown reasonable agree-
events (5-7,17). PET measurement of MBFR improves ment with PET (n¼21) (20).
risk stratification, including for patients with non- 4. Stress echocardiography assessing coronary flow ve-
obstructive CAD, especially women, for whom coro- locity reserve in the left anterior descending artery
nary microvascular dysfunction is suspected (18). with Doppler can currently be combined with wall
3. CMR has been used to evaluate MBFR. When validated motion analysis during vasodilator stress echocardi-
against invasive coronary physiology measures, pixel- ography. Limited data have shown that abnormal cor-
wise quantitative myocardial perfusion mapping by onary flow velocity reserve (#2) adds incremental
CMR was able to identify coronary microvascular value to the prognostic stratification achieved with
dysfunction in a small study that included 23 patients clinical and angiographic data for events such as death
with nonobstructive CAD (19). The addition of coronary and nonfatal MI in patients with angiographically
e60 Gulati et al. JACC VOL. -, NO. -, 2021
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normal or near-normal coronary arteries and preserved were lowest for the exercise ECG when compared with
at-rest regional and global left ventricular function at stress echocardiography, MPI, or CCTA (3). Randomized
baseline and during stress (21). trial data on cost are available and from the PROMISE trial
initial test costs were $174 for exercise ECG, >50% lower
5.3. Cost-Value Considerations in Diagnostic Testing than that of other imaging procedures (4). At 3-years of
A general concept regarding cost is that layered testing follow-up, the mean cost difference was $1,731 higher for
(i.e., when a test is followed by more tests) leads to higher CCTA (n¼4818) when compared with the exercise ECG
costs. To minimize the potential needs for downstream (n¼858); however, the 95% CIs for cost differences was
testing, clinicians should select the test that is most likely wide ($2 to $3,519), and there was no overall difference by
to answer a particular question. randomization (4). Overall, results from the PROMISE trial
showed that stress testing was associated with similar
5.3.1. CCTA and CAC Scanning Cost-Value Considerations costs and CAD outcomes over w3 years of follow-up (4,5).
In the outpatient setting, long-term costs were generally In a randomized trial of 824 symptomatic women, cu-
similar between CCTA and stress testing strategies (1). mulative procedural costs were nearly 50% lower for ex-
Higher invasive angiography rates after CCTA are ercise ECG versus MPI SPECT (p<0.0001), with no
matched by a greater use of downstream stress testing difference in 2-year event-free survival (p¼0.59) (6).
after initial stress testing, resulting in minimal differences
5.3.3. Stress Echocardiographic Cost-Value Considerations
in cost at 2 to 3 years of follow-up (1,2). From the
CONSERVE (Coronary Computed Tomographic Angiog- Several cost-effectiveness models have reported an
raphy for Selective Cardiac Catheterization) trial, 823 pa- increased incremental cost-effectiveness ratio for stress
tients were randomized to a selective versus direct echocardiography, compared with exercise ECG and other
referral strategy to ICA. Enrollment was limited to pa- diagnostic procedures (1-4). In these models, cost-
tients with nonemergent indications for ICA (3). The se- effectiveness was influenced by an improved diagnostic
lective referral arm included CCTA-guided use of ICA. accuracy for stress echocardiography, which led to longer
Cumulative diagnostic costs were $1,183 for the selective life expectancy (1). In a recent systematic review, the
arm and $2,755 for the direct referral arm of the evidence supports that stress echocardiography or stress
CONSERVE trial (57% lower costs). In the CCTA-guided MPI are cost-effective for those patients at intermediate
arm, follow-up stress testing was applied and contrib- pretest risk (5). The improved CAD detection for exercise
uted to reduced referrals to ICA. echocardiography resulted in fewer office and ED visits
A recent tiered testing strategy was evaluated in both and hospital days, yielding a 20% cost savings when
the CRESCENT I and II trials (2,4). From the CRESCENT I compared with the exercise ECG (6). There were 2,204
trial, CAC was used as the index test, with follow-up patients that underwent stress echocardiography in the
CCTA used only in patients with detectable CAC or for PROMISE trial, and 3-year mean costs were similar to that
those with a high pretest risk (2). In this trial, nearly of CCTA (CCTA – stress echocardiography mean cost dif-
40% of patients did not undergo CCTA, which reduced ference: –$363; 95% CI: –$1,562 to $818) (7).
diagnostic evaluation costs; no events were reported in
5.3.4. Stress Nuclear MPI Cost-Value Considerations
this subgroup. By comparison, nearly half of those ran-
domized to the exercise ECG had additional confirma- Among intermediate-risk patients, evidence synthesis
tory diagnostic testing. Overall, 1-year costs were supports that stress MPI is a cost-effective test option (1).
significantly lower in the CAC tiered testing protocol From the SPARC (Study of Myocardial Perfusion and
(16% cost savings; p<0.0001) (2). Moreover, 1-year Coronary Anatomy Imaging Roles in Coronary Artery
MACE-free survival was higher in the CAC-guided Disease) registry, observed 2-year mortality rate was
testing arm (97%) compared with exercise ECG (90%; highest for PET MPI (5.5%) compared with CCTA (0.7%) or
HR: 0.32; p¼0.011). SPECT MPI (1.6%), with 2-year cost highest for patients
undergoing PET (2). In the PROMISE trial, nearly two-
5.3.2. Exercise Electrocardiographic Cost-Value Considerations thirds of patients underwent stress MPI, and the mean
The economic evidence for the exercise ECG supports that cost was similar when compared with CCTA (3). Mean
tiered testing may offset its reduced diagnostic accuracy costs were also similar in a randomized trial of 457 pa-
(1,2). In a decision model, tiered testing of exercise ECG tients comparing stress MPI with exercise ECG (p>0.05)
followed by selective stress echocardiography resulted in (4). Among higher-likelihood patients in the UK enrolled
improved diagnostic accuracy and favorable cost- in the CECaT (Cost Effectiveness of Noninvasive Cardiac
effective ratios when compared with other testing stra- Testing) trial, MPI SPECT was the most cost-effective
tegies (2). In a Medicare cohort, observed 180-day costs approach (5).
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5.3.5. Stress CMR Cost-Value Considerations setting, is symptom classification. Methods to elicit
A synthesis of this cost evidence reveals a pattern symptoms and clusters of symptoms that provide
whereby CMR perfusion and scar imaging is associated improved pretest probabilities of symptomatic CAD
with a favorable incremental cost-effectiveness ratio may be aided with machine-learning algorithms. It is
of <$50,000 per quality-adjusted life years saved (1,2). already clear that some common dogma about chest
From a single report, a CMR strategy informed by the CE- pain descriptions, such as differences between men
MARC trial was more cost-effective than stress MPI, and women, may not be as prevalent as has been re-
largely because of the higher diagnostic accuracy for CMR ported (7) and may impede care of both sexes if they do
(2). However, the most cost-effective strategy was that of not fit preconceived notions of the clinical significance
initial exercise ECG followed by selective stress CMR and of their symptoms. However, reducing the differences
invasive angiography; for this tiered testing approach, in both sex and racial differences in treatment and
additional testing was deemed appropriate in the setting outcomes are important future goals of research and
of abnormal or inconclusive findings. In a decision model clinical care.
for intermediate pretest risk patients, a strategy of CMR 4. Clinical risk stratification and decision tools will likely
followed by selective ICA had projected reduced costs by continue to grow in popularity because they are
w25% when compared with direct referral to ICA (2,3). incorporated into electronic health records, but it
From the Stress CMR Perfusion Imaging in the United would be useful to test them in large randomized trials
States registry (4), patients with negative findings for to rigorously determine their benefit in terms of
ischemia and scar had low downstream costs (5). improved outcomes or lower costs before widespread
implementation (1). hs-cTn assays are now the global
6. EVIDENCE GAPS AND FUTURE RESEARCH standard of care for identifying myocardial injury,
although questions remain about whether minimal el-
Chest pain is one of the most common symptoms for evations, which carry prognostic value, are actionable
which a person seeks medical care, and it should there- in a manner that improves outcomes. Trials evaluating
fore be the target of substantial research investigation. various medical and procedural strategies would be
useful including diagnostic and therapeutic algorithms
1. For patients with ACS, considerable success has been
for MINOCA. The number of potential questions that
achieved in reducing door-to-balloon times for STEMI,
could be addressed will demand innovative trial de-
but little progress has been made in reducing the
signs to use resources efficiently and meaningfully.
important delays from symptom onset to presentation.
5. Increasingly, randomized trials will be performed to
Further research is needed to develop approaches to
determine which diagnostic tests can be eliminated
shorten this interval including studies of other
from initial and follow-up care, both to streamline
methods of evaluating patients with chest pain using
management algorithms and to decrease health care
technologies that permit acquisition and transmission
costs. In part, this approach will encompass evaluation
of ECGs from home and remote evaluations (e.g., tel-
of where patients with chest pain should be initially
ehealth) for those with acute symptoms (1,2).
evaluated and monitored. Comparison of the various
2. An important, increasing patient population includes
imaging modalities in randomized trials should help
women and men with angina and ACS associated with
refine test selection and use (8).
angiographically normal or nonobstructive coronary
arteries (3,4). Prognosis is not benign, pathophysiology Thus, the diagnosis and management of chest pain will
has not been clarified, and optimal therapy is unclear remain a fertile area of investigation, with randomized
in these heterogeneous groups, which are now evaluations complementing insights provided by regis-
considered in terms of INOCA (5) and MINOCA (6). tries of patients presenting with chest pain (9-12). In the
Adequately identifying patients with INOCA, and future, registries will more frequently serve as platforms
completing an evaluation to make such a diagnosis, is within which to conduct randomized trials. Accreditation
necessary but often not done, regardless of whether activities coupled with registry participation will also
chest pain is assessed in the ED, inpatient, or outpa- need to be evaluated to determine if they not only
tient setting. Further investigation to clarify disease improve processes of care but also affect clinical end-
mechanisms in these challenging syndromes is needed points (12). Assessment of long-term outcomes, patient-
to provide the basis for therapeutic advances. centered metrics, and cost will be integrated into these
3. One of the initial challenges in the evaluation of pa- studies to enhance the evidence base for care of patients
tients with chest pain, either in the emergency or office presenting with chest pain with greater precision.
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4. Mark DB, Federspiel JJ, Cowper PA, et al. Economic stress SPECT myocardial perfusion imaging as an initial
18. Murthy VL, Bateman TM, Beanlands RS, et al.
outcomes with anatomical versus functional diagnostic
Clinical quantification of myocardial blood flow using diagnostic strategy in stable patients with chest pain
testing for coronary artery disease. Ann Intern Med. and suspected CAD: cost analysis. J Nucl Cardiol.
PET: joint position paper of the SNMMI cardiovascular
2016;165:94–102. 2007;14:174–186.
council and the ASNC. J Nucl Cardiol. 2018;25:269–
297. 5. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes 5. Thom H, West NE, Hughes V, et al. Cost-effectiveness
19. Kotecha T, Martinez-Naharro A, Boldrini M, et al. of anatomical versus functional testing for coronary of initial stress cardiovascular MR, stress SPECT or stress
Automated pixel-wise quantitative myocardial perfu- artery disease. N Engl J Med. 2015;372:1291–1300. echocardiography as a gate-keeper test, compared with
sion mapping by CMR to detect obstructive coronary upfront invasive coronary angiography in the investiga-
6. Shaw LJ, Mieres JH, Hendel RH, et al. Comparative
artery disease and coronary microvascular dysfunction: tion and management of patients with stable chest pain:
effectiveness of exercise electrocardiography with or
validation against invasive coronary physiology. J Am mid-term outcomes from the CECaT randomised
without myocardial perfusion single photon emission
Coll Cardiol Img. 2019;12:1958–1969. controlled trial. BMJ Open. 2014;4:e003419.
computed tomography in women with suspected cor-
20. Engblom H, Xue H, Akil S, et al. Fully quantitative onary artery disease: results from the What Is the
5.3.5. Stress CMR Cost-Value Considerations
cardiovascular magnetic resonance myocardial perfu- Optimal Method for Ischemia Evaluation in Women
sion ready for clinical use: a comparison between (WOMEN) trial. Circulation. 2011;124:1239–1249. 1. Pletscher M, Walker S, Moschetti K, et al. Cost-
cardiovascular magnetic resonance imaging and posi- effectiveness of functional cardiac imaging in the
5.3.3. Stress Echocardiographic Cost-Value
tron emission tomography. J Cardiovasc Magn Reson. diagnostic work-up of coronary heart disease. Eur
Considerations
2017;19:78. Heart J Qual Care Clin Outcomes. 2016;2:201–207.
21. Sicari R, Rigo F, Cortigiani L, et al. Additive 1. Marwick TH, Shaw L, Case C, et al. Clinical and 2. Walker S, Girardin F, McKenna C, et al. Cost-effec-
prognostic value of coronary flow reserve in economic impact of exercise electrocardiography and tiveness of cardiovascular magnetic resonance in the
e86 Gulati et al. JACC VOL. -, NO. -, 2021
2021 Chest Pain Guideline -, 2021:-–-
diagnosis of coronary heart disease: an economic 2. Roux S, Bhatt DL. Self-treatment for acute cor- 9. Bhatt DL. Advancing the care of cardiac patients
evaluation using data from the CE-MARC study. Heart. onary syndrome: why not? Eur Heart J. 2020;41: using registry data: going where randomized clinical
2013;99:873–881. 2144–2145. trials dare not. JAMA. 2010;303:2188–2189.
3. Moschetti K, Muzzarelli S, Pinget C, et al. Cost 3. Tamis-Holland JE, Jneid H, Reynolds HR, et al. 10. Ellrodt AG, Fonarow GC, Schwamm LH, et al. Syn-
evaluation of cardiovascular magnetic resonance Contemporary diagnosis and management of patients thesizing lessons learned from get with the guidelines:
versus coronary angiography for the diagnostic work- with myocardial infarction in the absence of obstruc- the value of disease-based registries in improving
up of coronary artery disease: application of the Eu- tive coronary artery disease: a scientific statement quality and outcomes. Circulation. 2013;128:2447–2460.
ropean Cardiovascular Magnetic Resonance registry from the American Heart Association. Circulation.
11. Bhatt DL, Drozda JP Jr, Shahian DM, et al. ACC/
data to the German, United Kingdom, Swiss, and 2019;139:e891–e908.
AHA/STS statement on the future of registries and the
United States health care systems. J Cardiovasc Magn
4. Gulati M, Shaw LJ. Bairey Merz CN. Myocardial performance measurement enterprise: a report of the
Reson. 2012;14:35.
ischemia in women: lessons from the NHLBI WISE American College of Cardiology/American Heart As-
4. Kwong RY, Ge Y, Steel K, et al. Cardiac magnetic study. Clin Cardiol. 2012;35:141–148. sociation Task Force on Performance Measures and
resonance stress perfusion imaging for evaluation of The Society of Thoracic Surgeons. J Am Coll Cardiol.
5. Herscovici R, Sedlak T, Wei J, et al. Ischemia and no
patients with chest pain. J Am Coll Cardiol. 2019;74: 2015;66:2230–2245.
obstructive coronary artery disease (INOCA): what is
1741–1755.
the risk? J Am Heart Assoc. 2018;7:e008868. 12. Winchester DE, Osborne A, Peacock WF, et al.
5. Ge Y, Pandya A, Steel K, et al. Cost- Closing gaps in essential chest pain care through
6. Mukherjee D. Myocardial infarction with non-
effectiveness analysis of stress cardiovascular accreditation. J Am Coll Cardiol. 2020;75:2478–2482.
obstructive coronary arteries: a call for individualized
magnetic resonance imaging for stable chest pain
treatment. J Am Heart Assoc. 2019;8:e013361.
syndromes. J Am Coll Cardiol Img. 2020;13:1505–
1517. 7. Kreatsoulas C, Dinakar D, Mehta S, et al. Machine KEY WORDS ACC/AHA Clinical Practice
learning to evaluate gender differences in typical and Guidelines, chest pain, angina, coronary artery
atypical angina among patients with obstructive coro- disease, acute coronary syndrome, myocardial
6. EVIDENCE GAPS AND FUTURE nary artery disease. ESC Congress 2019. Paris, France. ischemia, myocardial infarction, myocardial
RESEARCH 2019. injury, noncardiac, accelerated diagnostic
8. Bhatt DL, Taqueti VR. Out with the old rule-out: pathway, clinical decision pathway, sex
1. Wang X, Bhatt DL. COVID-19: an unintended force raising the bar for acute chest pain evaluation with differences, troponins, chest pain syndromes,
for medical revolution? J Invasive Cardiol. 2020;32: randomized trials of cardiac imaging. J Am Coll Cardiol biomarkers, shared decision-making, noncardiac
E81–E82. Img. 2017;10:350–353. chest pain, cardiac imaging
JACC VOL. -, NO. -, 2021 Gulati et al. e87
-, 2021:-–- 2021 Chest Pain Guideline
Institutional,
Ownership/ Organizational, or
Committee Speakers Partnership/ Personal Other Financial Expert
Member Employment Consultant Bureau Principal Research Benefit Witness
Martha Gulati The University of Arizona None None None None None None
(Chair) Phoenix—Professor of Medicine &
Chief of Cardiology
Phillip D. Levy Wayne State University— n Apex Innovation* None n Carbon Life- n Amgen* n Amgen* None
(Vice Chair) Professor and Associate Chair for form
n AstraZeneca n Bristol-Myers n Edwards*
Research, Department of Innovations†
n AstraZeneca, Squibb* n E.R. Squibb &
Emergency Medicine; Assistant
n Mespere† n Cardiorentis*
Vice President for Translational Hospital Quality Sons, L.L.C.
Science and Clinical Research Foundation n Edwards n Janssen
Innovation n Beckman Coulter Lifesciences* Pharmaceuticals
n Boehringer n Gilead Sciences* n Roche
Ingelheim n Novartis*
n Bristol-Myers n Pfizer*
Squibb
n Roche*
n Cardiorentis
n Shire*
n Novartis*
n Trevena
n Ortho
Diagnostics*
n Pfizer
n Roche*
n Sciex
n Shire*
n Siemens*
n The Medicines
Company
n Trevena
n ZS Pharma
Debabrata Texas Tech University Health None None None None None None
Mukherjee Sciences Center El Paso—
(Vice Chair) Chairman, Department of
Medicine
Ezra Amsterdam UC Davis Medical Center— None None None None None None
Professor, Department of
Internal Medicine
Deepak L. Bhatt Brigham and Women’s Hospital n Daiichi Sankyo None None n Abbott* n Amarin Pharma None
Heart & Vascular Center— Inc.*
n Pfizer* n Amarin*
Executive Director of
n n AstraZeneca*
Interventional Cardiovascular Amgen*
n n Biotronik‡
Programs; Harvard Medical AstraZeneca*
School—Professor of Medicine n n Boehringer
Bayer*
Ingelheim*
n Boehringer
n Boston
Ingelheim*
Scientific‡
n Bristol-Myers
n Cardax†
Squibb*
n n Merck†
Cardax*
n n Novartis
Chiesi*
n n PhaseBio†
Eisai*
n n PLx Pharma†
Eli Lilly*
n n Regado
Ethicon*
Biosciences†
n FlowCo†
n Sanofi-aventis*
n Forest Laboratories*
n St. Jude
n Idorsia*
Medical‡
n Ironwood*
n Svelte‡
n Ischemix*
n Medtronic*
n Merck*
n Pfizer*
APPENDIX 1. CONTINUED
Institutional,
Ownership/ Organizational, or
Committee Speakers Partnership/ Personal Other Financial Expert
Member Employment Consultant Bureau Principal Research Benefit Witness
n PhaseBio*
n PLx Pharma*
n Regeneron*
n Roche*
n Sanofi-aventis*
n Synaptic*
n Takeda†
n The Medicines
Company*
Kim K. Birtcher University of Houston College of None None None None None None
Pharmacy—Clinical Professor
Ron Blankstein Harvard Medical School— n Amgen None None n Amgen† n Sanofi US None
Associate Professor of Medicine Services*
n Astellas Inc n Astellas Pharma†
and Radiology, Co-Director,
Cardiovascular Imaging Training n EKOS Corp. n Gilead Sciences†
Program; n Sanofi-aventis†
Brigham and Women’s Hospital—
Associate Physician, Preventive
Cardiology; Director, Cardiac
Computed Tomography
Jack Boyd Stanford University—Clinical n Esculon/Centese None None None None None
Assistant Professor, Department
n Sorin
of Cardiothoracic Surgery
Renee P. Deborah Heart & Lung Center— None None None None None None
Bullock- Director, Women’s Heart Center;
Palmer Director, Non-Invasive Cardiac
Imaging
Theresa Conejo Nazareth Hospital—Heart Failure None None None None None None
Coordinator
Deborah B. UT Southwestern—Professor and n ETHealthcare None None n Abbott* n E.R. Squibb & None
Diercks Chair, Department of Emergency Sons, L.L.C.*
n Janssen n Bristol-Myers
Medicine
Pharmaceuticals Squibb† n Konica Minolta
n Novartis* n Ortho Clinical† Healthcare
Americans, Inc.
n Roche*
n Siemens
Federico Gentile Centro Cardiologico Gentile, None None None None None None
Naples, Italy—Director
John P. Leeds Institute of Cardiovascular None None None None None None
Greenwood and Metabolic Medicine—
Mautner Chair of Cardiology,
Division of Biomedical Imaging
Erik P. Hess University of Alabama at n Gilead None None n Gilead None None
Birmingham—Professor of Sciences* Sciences*
Emergency Medicine and Vice
Chair for Research, Department
of Emergency Medicine
Steven M. Cooper Medical School of Rowan None None None None None None
Hollenberg University—Professor of
Medicine;
Cooper University Hospital—
Director, Coronary Care Unit
Wael A. Jaber Cleveland Clinic Lerner College None None None None None None
of Medicine—Professor of
Medicine, Department of
Cardiovascular Medicine and
Fuad Jubran Endowed Chair in
Cardiovascular Medicine, Heart
and Vascular Institute
APPENDIX 1. CONTINUED
Institutional,
Ownership/ Organizational, or
Committee Speakers Partnership/ Personal Other Financial Expert
Member Employment Consultant Bureau Principal Research Benefit Witness
Hani Jneid Baylor College of Medicine— None None None None None None
Associate Professor of Medicine;
The Michael DeBakey VA Medical
Center—Director of
Interventional Cardiology
Research
José A. Joglar University of Texas Southwestern None None None None None None
Medical Center—Professor of
Internal Medicine, Fellowship
Program Director, Clinical Cardiac
Electrophysiology, Elizabeth
Thaxton Page and Ellis Batten
Page, Professorship in Clinical
Cardiac Electrophysiology
Research
David A. Morrow Brigham and Women’s Hospital— n Abbott None None n Abbott* n Roche* None
Director, Levine Cardiac Intensive
n Aralez n Amgen*
Care Unit; Harvard Medical
Pharmaceuticals* n AstraZeneca*
School—Professor of Medicine,
n AstraZeneca* n
Cardiovascular Division BRAHMS*
n Bayer* n Daiichi-Sankyo*
n Daiichi Sankyo n Eisai Corporation*
n diaDexus n GlaxoSmithKline*
n Gilead Sciences n Johnson & Johnson*
n GlaxoSmithKline* n Medicines Company*
n Merck* n Merck*
n Novartis* n Novartis*
n Pfizer* n Pfizer*
n Roche* n Regeneron*
n Verseon n Roche*
n Singulex*
n Takeda
Pharmaceuticals*
Michael A. Ross Emory University School of None None None None None None
Medicine—Professor, Department
of Emergency Medicine;
Emory Healthcare—Chief of
Service, Observation Medicine;
Emory University Hospital Chest
Pain Center— Medical Director
Leslee J. Shaw Icahn School of Medicine, Mount None None None None n None
Covanos,
Sinai—Professor
Inc– Scientific
Advisory Board†
This table represents the relationships of committee 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 committee during the document development process. The table does not necessarily
reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting
stock or share of the business entity, or ownership of $$5,000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of
the person’s gross income for the previous year. Relationships that exist with no financial benefit 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 person’s household, has a reasonable potential for financial, professional or other personal gain or loss as
a result of the issues/content addressed in the document. Writing committee members are required to recuse themselves from voting on sections to which their specific relationships
with industry and other entities may apply.
*Significant relationship.
†No financial benefit.
‡This disclosure was entered under the Clinical Trial Enroller category in the ACC’s disclosure system. To appear in this category, the author acknowledges that there is no direct or
institutional relationship with the trial sponsor as defined in the ACC/AHA Disclosure Policy for Writing Committees.
ACC indicates American College of Cardiology; AHA, American Heart Association; ASE, American Society of Echocardiography; CHEST, American College of Chest Physicians; SAEM,
Society for Academic Emergency Medicine; SCCT, Society of Cardiovascular Computed Tomography; SCMR, Society for Cardiovascular Magnetic Resonance; UC, University of California;
UT, University of Texas; and VA, Veterans Affairs.
e90
APPENDIX 2. REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (COMPREHENSIVE)—2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/
SCMR GUIDELINE FOR THE EVALUATION AND DIAGNOSIS OF CHEST PAIN
Sana M. Al- Content Reviewer—AHA Duke University Medical n Medtronic None None n Abbott n Abbott None
Khatib Center
n Milestone n Medtronic* n AHA*
Pharmaceuticals n NHLBI* n Bristol-Myers Squibb
n PCORI* n Medtronic
n U.S. Food and n Pfizer
Drug
Administration*
Mouaz Al-Mallah Official Reviewer—American Houston Methodist n Pfizer None None n Siemens† n Amgen None
Society of Nuclear Cardiology
n GE Healthcare‡*
n Pfizer
n Siemens
Jayashri R. Official Reviewer—American West Roxbury VA Hospital, None None None None None None
Aragam Society of Echocardiography Harvard Medical School
Ragavendra Content Reviewer—ACC/AHA Ohio State University None None None None n Baliga’s Textbook of Internal Medi- None
Baliga Hospital cine with 1480 MCQs, Editor-in-
Chief†
n Elsevier, Deputy Editor†
n Lippincott Williams & Wilkins
n McGraw-Hill Cardiology Textbook,
Editor-in-Chief
n Oxford University Press & Prze-
wodnik praktyczny jak stosowac
statyny, Termedia Wydawnictwa
Medyczne, Editor
n Oxford University Press, Series
Editor
n Springer, Co Editor-in-Chief
n W.B. Saunders/Elsevier, 250 Cases
in Clinical Medicine, Third Edition
Joshua A. Content Reviewer—ACC/AHA Vanderbilt University n Amgen None n EMX† n Bayer (DSMB) n Amgen None
Beckman Joint Committee on Clinical Medical Center
n GlaxoSmithKline* n JanaCare† n Novartis (DSMB) n GlaxoSmithKline
Practice Guidelines
n JanOne n Vascular Interventional Advances*
n Janssen
JACC VOL.
n Pharmaceuticals*
n Sanofi-aventis*
-, NO. -, 2021
-, 2021:-–-
APPENDIX 2. CONTINUED
-, 2021:-–-
JACC VOL.
Institutional,
Ownership/ Organizational,
-, NO. -, 2021
Speakers Partnership/ or Other Expert
Reviewer Representation Employment Consultant Bureau Principal Personal Research Financial Benefit Witness
Daniel S. Berman Official Reviewer—AHA Cedars-Sinai Medical Center n Bayer* None None None n Amgen* None
n Cedars-Sinai n Bayer
Medical Center* n Cedars-Sinai Medical Center
n General Electric n GE Healthcare*
Kelley Branch Content Reviewer—Society of University of Washington n Bayer* None None n Bayer* n AstraZeneca None
Cardiovascular Computed
n Janssen n Locke Founda- n Bayer*
Tomography
Pharmaceuticals* tion Grant* n Janssen Pharmaceuticals
n Novartis‡ n Novartis
n Sanofi-aventis
Andrew Choi Official Reviewer—Society of The George Washington None None n Cleerly, Inc.* None None None
Cardiovascular Computed University School of
Tomography Medicine
Melissa A. Official Reviewer—AHA Duke University Medical None None None None n 4D Molecular None
Daubert Center Contrafect
n Heartflow
n NIH
n Roche
n Verliy
Lisa de las Content Reviewer—ACC/AHA Washington University n Acceleron n Bayer* None n Acceleron* n ACC† None
Fuentes Joint Committee on Clinical
n Altavant n Simply n Altavant* n AHA†
Practice Guidelines
n Arena Speaking* n Bayer n Circulation Journals
n Bayer n Complexa* n Pulmonary Hypertension
n Express Scripts n Johnson & Association*
n Gilead Sciences Johnson*
n n Liquidia*
Johnson &
Johnson n Medtronic*
n Mentor Planning n NIH*
and Consulting n Reata
n Phase Bio n Trio Analytics*
n V-wave n United
n WebMD* Therapeutics*
n University of
Kentucky (DSMB)
Gulati et al.
e91
e92
APPENDIX 2. CONTINUED
Institutional,
Anita Deswal Content Reviewer—ACC/AHA UT MD Anderson Cancer None None None None n ACC None
Joint Committee on Clinical Center
n AHA
Practice Guidelines
n HFSA†
Dave L. Dixon Content Reviewer—ACC/AHA Virginia Commonwealth American Pharmacists None None n Centers for Dis- n Accreditation Council for Clinical None
Joint Committee on Clinical University School of Association ease Control and Lipidology†
Practice Guidelines Pharmacy Prevention* n American College of Pharmacy
n Community Cardiology Practice Research
Pharmacy Network†
Foundation* n American Pharmacists Association
n National Lipid Association†
John U. Doherty Official Reviewer—ACC Jefferson University None None None None None None
Hospitals
Maros Ferencik Content Reviewer—Society of Oregon Health & Science n Biograph* None n AHA, Fellow to n NIH* n HeartFlow‡ None
Cardiovascular Computed University Faculty Award*
Tomography
Lee A. Fleisher Content Reviewer—ACC/AHA Centers for Medicare & None None None n NIH None None
Joint Committee on Clinical Medicaid Services (CMS)
Practice Guidelines
Mario Garcia Content Reviewer—AHA/ACC Montefiore Medical None None None None n Abiomed None
Center
n Medtronic Vascular, Inc.
n Novartis
n Philips
Seth Gemme Official Reviewer—American Baystate Medical Center n Roche None None None None None
College of Emergency Diagnostics
Physicians
Zachary D. Content Reviewer—ACC/AHA University of Wisconsin None None None None None None
Goldberger Joint Committee on Clinical School of Medicine and
Practice Guidelines Public Health
Bulent Gorenek Content Reviewer—ACC/AHA Eskisehir Osmangazi n AstraZeneca None None None None None
Joint Committee on Clinical University
n Sandoz
Practice Guidelines
Norrisa Haynes Content Reviewer—ACC/AHA University of Pennsylvania None None None None None None
Joint Committee on Clinical
Practice Guidelines
JACC VOL.
-, NO. -, 2021
-, 2021:-–-
APPENDIX 2. CONTINUED
-, 2021:-–-
JACC VOL.
Institutional,
Ownership/ Organizational,
-, NO. -, 2021
Speakers Partnership/ or Other Expert
Reviewer Representation Employment Consultant Bureau Principal Personal Research Financial Benefit Witness
Adrian F. Content Reviewer—ACC/AHA Duke University n Amgen None None n American Regent n AHA† n Defendant,
Hernandez Joint Committee on Clinical Patent
n AstraZeneca* n AstraZeneca* n AstraZeneca
Practice Guidelines Dispute,
n Bayer n Eidos (DSMB) n Boston Scientific
2019
n Biofourmis n Genentech n CSL Behring
n Boehringer n GlaxoSmithKline* n Janssen Pharmaceuticals*
Ingelheim n Janssen n Merck
n Boston Pharmaceuticals n Novartis
Scientific* n Merck n Genentech*
n Cytokinetics n NIH† n Relypsa
n Daiichi Sankyo n Novartis* n Sanofi-aventis
n Eli Lilly n PCORI†
n Merck* n Verily*
n Myokardia
n Novartis*
n Pfizer
n Relypsa
n Sanofi-aventis*
n Xogenex
Mark A. Hlatky Content Reviewer—ACC/AHA Stanford University n ACC, Global None None n HeartFlow* n George Institute† None
Joint Committee on Clinical School of Medicine Advisory n NHLBI (DSMB)
Practice Guidelines Committee
n St. Jude
n Blue Cross Blue
Shield Center for
Effectiveness
Evaluation*
n The Medicines
Company
Stephen Hoole Content Reviewer—ACC Royal Papworth n Abbott* n AstraZeneca None n Abbott* None None
Hospital, UK
n Bayer n Bayer n AstraZeneca*
n Boston Scientific n Novo
Nordisk
W. Schuyler Content Reviewer—ACC/AHA Duke University n Amgen None None n Bristol-Myers n Abbott* None
Jones Joint Committee on Clinical Squibb
n Bayer* n Amgen
Practice Guidelines
n n Janssen n
Janssen AstraZeneca
Gulati et al.
Continued on the next page
e93
e94
APPENDIX 2. CONTINUED
Institutional,
Michael Kontos Content Reviewer—ACC Virginia Commonwealth None None None None n ACC* None
University Health
n NIH‡
n Society for Academic Emergency
Medicine†
n VCSQUI†
n VHAC†
Raymond Kwong Official Reviewer—Society for Brigham and Women’s None None None n Alnylam, Inc* n Bayer None
Cardiovascular Magnetic Hospital
n MyoKardia* n Siemens
Resonance
n NIH n Society for Cardiovascular Magnetic
Resonance†
Glenn N. Levine Content Reviewer—Former Baylor College of Medicine None None None None None n Defendant,
Chair of the ACC/AHA Task In-hospital
Force on Clinical Practice death, 2020
Guidelines
n Defendant,
In-hospital
death, 2019*
Jonathan Official Reviewer—American Oregon Health & Science None None None n Bracco† n Lantheus Medical Imaging, Inc. None
Lindner Society of Echocardiography University
n GE Healthcare
n GE Lifesciences†
n Pfizer†
G.B. John Content Reviewer—ACC Vancouver Hospital n Amgen n Amgen None n Novo Nordisk None None
Mancini Research Pavillion, Professor
n AstraZeneca n HLS n NovartisPle
of Medicine
n Bayer Therapeutics
n n Sanofi-
Boehringer
Ingelheim aventis
n Eli Lilly
n Esperion
n HLS Therapeutics
n Merck
n Pfizer
n Regeneron
n Sanofi-aventis
Daniel B. Mark Content Reviewer—ACC/AHA Duke University None None None None n HeartFlow* None
Joint Committee on Clinical
n Merck*
Practice Guidelines
JACC VOL.
Jim McCord Content Reviewer—ACC/AHA Henry Ford Health System n Beckman None None n Abbott* n ACC Accreditation Services, Board None
n Roche* n Beckman Member†
n Siemens* Diagnostics*
-, NO. -, 2021
n
-, 2021:-–-
Roche*
n Siemens
-, 2021:-–-
JACC VOL.
Institutional,
Ownership/ Organizational,
-, NO. -, 2021
Speakers Partnership/ or Other Expert
Reviewer Representation Employment Consultant Bureau Principal Personal Research Financial Benefit Witness
C. Noel Bairey Content Reviewer—ACC/AHA Cedars-Sinai Heart Institute n Med Intelligence None None n California Insti- n Bayer, Advisory Board None
Merz tute for Precision n iRhythm*
Medicine*
n DOD Warrior*
n NIH-NIA*
n Sanofi-aventis*
n WISE pre-HFpEF*
Nicholas L. Mills Content Reviewer—ACC BHF Centre for n Abbott None None None None None
Cardiovascular Science,
n Laboratories
University of Edinburgh,
n LumiraDx
Edinburgh, Scotland
n Roche
Diagnostics
n Siemens
Healthineers
James Min Content Reviewer—ACC/AHA n Cleerly, Inc. None None n Cleerly, Inc. n NIH n Ablative Solutions None
n Arineta
n Memphis Meats
L. Kristin Newby Content Reviewer—ACC Duke University n Beckman-Coulter None None n Boehringer n AHA† None
n BioKier Ingelheim n ACC, Oregon Chapter
n n David H. Murdock n AstraZeneca†
Bristol-Myers
Squibb Institute for
n Boehringer Ingelheim
Business and
n CSL n David H. Murdock Research
Culture
n Medtronic Institute†
n NIH
n NHLBI n JACC, Deputy Editor*
n North Carolina
n Quidel n Roche Diagnostics
DHHS
n Roche
Diagnostics
Patrick T. O’Gara Content Reviewer—ACC/AHA Brigham and Women’s None None None None n Edwards Lifesciences† None
Joint Committee on Clinical Hospital
n JAMA Cardiology*
Practice Guidelines
n NIH*
n Medtrace†
n Medtronic†
n Medtronic Vascular, Inc.
Gulati et al.
e95
e96
APPENDIX 2. CONTINUED
Institutional,
Kevin O’Neil Content Reviewer—American Wilmington Health, PLLC None None None None n American Board of Internal None
College of Chest Physicians Medicine
n Astellas Pharma
n Commission on Accreditation for
Respiratory Care†
n Genentech
n Genzyme
n GlaxoSmith Kline
n Insmed
n Otsuka
n America Pharmaceuticals
n Philips
n Resmed Corp
n Sunovion Pharmaceuticals
W. Frank Content Reviewer—AHA Baylor College of n Abbott None n Comprehensive n Roche* n Abbott None
Peacock Medicine Research
n AstraZeneca n Aseptiscope*
Associates*
n Instrumentation n Astellas Pharma
n Emergencies in
Laboratories n AstraZeneca
Medicine†
n Janssen n Beckman Coulter, Inc.*
Pharmaceuticals*
n Boehringer Ingelheim*
n Medicure
n DiaSorin S.P.A.*
n Pharma Inc.
n E.R. Squibb & Sons, L.L.C.*
n Quidel
n Instrumentation Laboratory
n Relypsa Company*
n Siemens n Janssen Pharmaceuticals*
n Medicure Pharma Inc.
n Quidel
n Relypsa
n Roche*
n Salix Pharmaceutical Division of
Bausch Health US, LLC
n Siemens*
JACC VOL.
-, NO. -, 2021
-, 2021:-–-
APPENDIX 2. CONTINUED
-, 2021:-–-
JACC VOL.
Institutional,
Ownership/ Organizational,
-, NO. -, 2021
Speakers Partnership/ or Other Expert
Reviewer Representation Employment Consultant Bureau Principal Personal Research Financial Benefit Witness
Carl Pepine Content Reviewer—ACC/AHA University of Florida n Caladrius None None n Biocardia* None None
n Biosciences n Brigham and
n Elsevier Women’s
Hospital*
n Slack Inc.*
n CSL Behring*
n Verily
n Cytori
n XyloCor
Therapeutics*‡
n DCRI*
n GE Healthcare
n InVentive Health
Clinical, LLC‡
n Mesoblast*
n NIH‡
n NIH/NHLBI*
n Pfizer
n Sanofi-aventis‡
n U.S. Department
of Defense*
Andrea L. Price Content Reviewer—ACC Indiana University Health None None n Quality Infor- n ACC, Accredita- None None
matics Syn- tion Foundation
ergies, LLC Board*
Susan B. Promes Official Reviewer—American Penn State Health Milton S. None None None None None None
College of Emergency Hershey Medical Center
Physicians
Tanveer Rab Content Reviewer—ACC Emory University None None None None None None
Harish Content Reviewer—ACC Mayo Clinic None None None None None None
Ramakrishna
Basmah Safdar Official Reviewer—Society for Yale School of Medicine None None None None n OrthoClinical* None
Academic Emergency Medicine
n Roche*
Michael Salerno Content Reviewer—Society for University of Virginia None None None n NIH* n Heartflow n Defendant,
Cardiovascular Magnetic SPECT Cam-
n Siemens
Resonance era Malfunc-
tion, 2020
Ada Stefanescu Content Reviewer—ACC University of Toronto; None None None None None None
Gulati et al.
n Pfizer n Pfizer
e97
e98
APPENDIX 2. CONTINUED
Institutional,
Jacqueline Content Reviewer—ACC/AHA Mount Sinai Morningside None None None n Internal-Minne- n Abbott† None
Tamis- Joint Committee on Clinical Hospital apolis Heart n AHA†
Holland Practice Guidelines Institute†
n Bronx Lebanon Hospital, Cardiology
n The NGS Predict Fellowship Program Director†
Study‡
n Medscape/Heart.org
n NIH†‡
n NYS†
James Thomas Content Reviewer—ACC/AHA Northwestern Medicine n Abbott None None n Abbott n Abbott None
n Caption Health* n Caption Health n Caption Health*
n Edwards n General Electric n Edwards Lifesciences*
Lifesciences* n Medtronic Vascular, Inc.
n General Electric n Shire North American Group Inc.
n Shire North
American Group
Inc.*
Todd Villines Official Reviewer—Society of University of Virginia Health None None None None None None
Cardiovascular Computed System
Tomography and ACC
Andrew R. Official Reviewer—ACC Penn State Health None n Amarin* None None n Abbott None
Waxler
n Regeneron* n Amarin*
n Sanofi- n Amgen
aventis* n Boehringer Ingelheim
n DalCor Pharmaceuticals
n Janssen Pharmaceuticals
n Novartis
n Penn State-St. Joseph Medical
Center Foundation, Board Member†
n Penn State—St. Joseph Medical
Center Pharmacy and Therapeutics,
Committee Member†
n Portola
n Regeneron
n Sanofi-aventis
n The Medicines Company
n ZOLL Medical
JACC VOL.
Continued on the next page
-, NO. -, 2021
-, 2021:-–-
APPENDIX 2. CONTINUED
-, 2021:-–-
JACC VOL.
Institutional,
Ownership/ Organizational,
-, NO. -, 2021
Speakers Partnership/ or Other Expert
Reviewer Representation Employment Consultant Bureau Principal Personal Research Financial Benefit Witness
Nanette K. Content Reviewer—AHA Emory University n Amarin Pharma, None None n AstraZeneca† None None
Wenger Inc. n Boehringer
n AstraZeneca Ingelheim
n Janssen n U.S. Department
Pharmaceuticals of Defense
n Duke Clinical
Research
Institute†
n NHLBI†
n ZOLL Medical†
Joseph Woo Content Reviewer—ACC/AHA Stanford University School None None None None n NIH* None
Joint Committee on Clinical of Medicine
Practice Guidelines
Sammy Zakaria Official Reviewer—American Johns Hopkins University None None None None None None
College of Chest Physicians School of Medicine
Mark J. Zucker Official Reviewer—American Newark Beth Israel Medical None None None None None None
College of Chest Physicians Center
This table represents all relationships of reviewers with industry and other entities that were reported at the time of peer review, including those not deemed to be relevant to this document, at the time this document was under review. The table does not
necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting stock or share of the business entity, or ownership
of $$5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit 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. Please refer to https://www.acc.org/guidelines/about-guidelines-and-clinical-documents/
relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees.
*Significant relationship.
†No financial benefit.
‡This disclosure was entered under the Clinical Trial Enroller category in the ACC’s disclosure system. To appear in this category, the author acknowledges that there is no direct or institutional relationship with the trial sponsor as defined in the (ACCF or
AHA/ACC) Disclosure Policy for Writing Committees.
ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; ASE, American Society of Echocardiography; ASNC, American Society of Nuclear Cardiology; CHEST, American College
of Chest Physicians; DCRI, Duke Clinical Research Institute; DHHS, Department of Health and Human Services; DOD, Department of Defense; DSMB, data and safety monitoring board; HFSA, Heart Failure Society of America; JACC, Journal of the American
College of Cardiology; NHLBI, National Heart, Lung, and Blood Institute; NIA, National Institute on Aging; NIH, National Institutes of Health; NYS, New York state; PCORI, Patient-Centered Outcomes Research Institute; SAEM, Society for Academic
Emergency Medicine; SCCT, Society of Cardiovascular Computed Tomography; SCMR, Society for Cardiovascular Magnetic Resonance; UT, University of Texas; VCSQI, Virginia Cardiac Services Quality Initiative; VA, Veterans Affairs; and VHAC, Virginia
Heart Attack Coalition.