Author + information
- Published online December 18, 2012.
- Stephan D. Fihn, MD, MPH, Chair, Writing Committee†,
- Julius M. Gardin, MD, Vice Chair, Writing Committee⁎,‡,
- Jonathan Abrams, MD, Writing Committee Member‡,
- Kathleen Berra, MSN, ANP, Writing Committee Member⁎,§,
- James C. Blankenship, MD, Writing Committee Member⁎∥,
- Apostolos P. Dallas, MD, Writing Committee Member⁎,†,
- Pamela S. Douglas, MD, Writing Committee Member⁎,‡,
- JoAnne M. Foody, MD, Writing Committee Member⁎,‡,
- Thomas C. Gerber, MD, PhD, Writing Committee Member‡,
- Alan L. Hinderliter, MD, Writing Committee Member‡,
- Spencer B. King III, MD, Writing Committee Member⁎,‡,
- Paul D. Kligfield, MD, Writing Committee Member‡,
- Harlan M. Krumholz, MD, Writing Committee Member‡,
- Raymond Y.K. Kwong, MD, Writing Committee Member‡,
- Michael J. Lim, MD, Writing Committee Member⁎∥,
- Jane A. Linderbaum, MS, CNP-BC, Writing Committee Member¶,
- Michael J. Mack, MD, Writing Committee Member⁎,#,
- Mark A. Munger, PharmD, Writing Committee Member⁎,‡,
- Richard L. Prager, MD, Writing Committee Member#,
- Joseph F. Sabik, MD, Writing Committee Member⁎,⁎⁎,
- Leslee J. Shaw, PhD, Writing Committee Member⁎,‡,
- Joanna D. Sikkema, MSN, ANP-BC, Writing Committee Member⁎,§,
- Craig R. Smith Jr, MD, Writing Committee Member⁎⁎,
- Sidney C. Smith Jr, MD, Writing Committee Member⁎,††,
- John A. Spertus, MD, MPH, Writing Committee Member⁎,‡‡ and
- Sankey V. Williams, MD, Writing Committee Member⁎,†
- cardiovascular diagnostic techniques
- coronary artery disease
- coronary stenosis
- minimally invasive surgical procedures
- myocardial ischemia
- myocardial revascularization
- risk factors
- stable angina
ACCF/AHA Task Force Members
Jeffrey L. Anderson, MD, FACC, FAHA, Chair
Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect
Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair 2009–2011§§
Sidney C. Smith, Jr, MD, FACC, FAHA, Past Chair 2006–2008§§
Cynthia D. Adams, MSN, APRN-BC, FAHA§§
Nancy M. Albert, PhD, CCNS, CCRN, FAHA
Ralph G. Brindis, MD, MPH, MACC
Christopher E. Buller, MD, FACC§§
Mark A. Creager, MD, FACC, FAHA
David DeMets, PhD
Steven M. Ettinger, MD, FACC§§
Robert A. Guyton, MD, FACC
Judith S. Hochman, MD, FACC, FAHA
Sharon Ann Hunt, MD, FACC, FAHA§§
Richard J. Kovacs, MD, FACC, FAHA
Frederick G. Kushner, MD, FACC, FAHA§§
Bruce W. Lytle, MD, FACC, FAHA§§
Rick A. Nishimura, MD, FACC, FAHA§§
E. Magnus Ohman, MD, FACC
Richard L. Page, MD, FACC, FAHA§§
Barbara Riegel, DNSc, RN, FAHA§§
William G. Stevenson, MD, FACC, FAHA
Lynn G. Tarkington, RN§§
Clyde W. Yancy, MD, FACC, FAHA
Table of Contents
1.1 Methodology and Evidence Overview…...e49
1.2 Organization of the Writing Committee…...e50
1.3 Document Review and Approval…...e50
1.4 Scope of the Guideline…...e50
1.5 General Approach and Overlap With Other Guidelines or Statements…...e52
1.6 Magnitude of the Problem…...e53
1.7 Organization of the Guideline…...e54
1.8 Vital Importance of Involvement by an Informed Patient: Recommendation…...e56
2. Diagnosis of SIHD…...e58
2.1 Clinical Evaluation of Patients With Chest Pain…...e58
2.1.1 Clinical Evaluation in the Initial Diagnosis of SIHD in Patients With Chest Pain: Recommendations…...e58
2.1.3 Physical Examination…...e60
22.214.171.124 Resting Electrocardiography to Assess Risk: Recommendation…...e60
2.1.5 Differential Diagnosis…...e60
2.1.6 Developing the Probability Estimate…...e61
2.2 Noninvasive Testing for Diagnosis of IHD…...e62
2.2.1 Approach to the Selection of Diagnostic Tests to Diagnose SIHD…...e62
126.96.36.199 Assessing Diagnostic Test Characteristics…...e63
188.8.131.52 Safety and Other Considerations Potentially Affecting Test Selection…...e64
184.108.40.206 Exercise Versus Pharmacological Testing…...e65
220.127.116.11 Concomitant Diagnosis of SIHD and Assessment of Risk…...e65
2.2.2 Stress Testing and Advanced Imaging for Initial Diagnosis in Patients With Suspected SIHD Who Require Noninvasive Testing: Recommendations…...e66
18.104.22.168 Able to Exercise…...e66
22.214.171.124 Unable to Exercise…...e66
2.2.3 Diagnostic Accuracy of Nonimaging and Imaging Stress Testing for the Initial Diagnosis of Suspected SIHD…...e68
126.96.36.199 Exercise ECG…...e68
188.8.131.52 Exercise and Pharmacological Stress Echocardiography…...e68
184.108.40.206 Exercise and Pharmacological Stress Nuclear Myocardial Perfusion SPECT and Myocardial Perfusion PET…...e68
220.127.116.11 Pharmacological Stress CMR Wall Motion/Perfusion…...e69
18.104.22.168 Hybrid Imaging…...e69
2.2.4 Diagnostic Accuracy of Anatomic Testing for the Initial Diagnosis of SIHD…...e69
22.214.171.124 Coronary CT Angiography…...e69
126.96.36.199 CAC Scoring…...e70
188.8.131.52 CMR Angiography…...e70
3. Risk Assessment…...e70
3.1 Clinical Assessment…...e70
3.1.1 Prognosis of IHD for Death or Nonfatal MI: General Considerations…...e70
3.1.2 Risk Assessment Using Clinical Parameters…...e71
3.2 Advanced Testing: Resting and Stress Noninvasive Testing…...e72
3.2.1 Resting Imaging to Assess Cardiac Structure and Function: Recommendations…...e72
3.2.2 Stress Testing and Advanced Imaging in Patients With Known SIHD Who Require Noninvasive Testing for Risk Assessment: Recommendations…...e74
184.108.40.206 Risk Assessment in Patients Able to Exercise…...e74
220.127.116.11 Risk Assessment in Patients Unable to Exercise…...e74
18.104.22.168 Risk Assessment Regardless of Patients' Ability to Exercise…...e74
22.214.171.124 Exercise ECG…...e75
126.96.36.199 Exercise Echocardiography and Exercise Nuclear MPI…...e76
188.8.131.52 Dobutamine Stress Echocardiography and Pharmacological Stress Nuclear MPI…...e77
184.108.40.206 Pharmacological Stress CMR Imaging…...e77
220.127.116.11 Special Patient Group: Risk Assessment in Patients Who Have an Uninterpretable ECG Because of LBBB or Ventricular Pacing…...e77
3.2.3 Prognostic Accuracy of Anatomic Testing to Assess Risk in Patients With Known CAD…...e78
18.104.22.168 Coronary CT Angiography…...e78
3.3 Coronary Angiography…...e78
3.3.1 Coronary Angiography as an Initial Testing Strategy to Assess Risk: Recommendations…...e78
3.3.2 Coronary Angiography to Assess Risk After Initial Workup With Noninvasive Testing: Recommendations…...e78
4.1 Definition of Successful Treatment…...e80
4.2 General Approach to Therapy…...e82
4.2.1 Factors That Should Not Influence Treatment Decisions…...e83
4.2.2 Assessing Patients' Quality of Life…...e84
4.3 Patient Education: Recommendations…...e84
4.4 Guideline-Directed Medical Therapy…...e86
4.4.1 Risk Factor Modification: Recommendations…...e86
22.214.171.124 Lipid Management…...e86
126.96.36.199 Blood Pressure Management…...e88
188.8.131.52 Diabetes Management…...e89
184.108.40.206 Physical Activity…...e91
220.127.116.11 Weight Management…...e92
18.104.22.168 Smoking Cessation Counseling…...e92
22.214.171.124 Management of Psychological Factors…...e93
126.96.36.199 Alcohol Consumption…...e94
188.8.131.52 Avoiding Exposure to Air Pollution…...e94
4.4.2 Additional Medical Therapy to Prevent MI and Death: Recommendations…...e95
184.108.40.206 Antiplatelet Therapy…...e95
220.127.116.11 Beta-Blocker Therapy…...e96
18.104.22.168 Renin-Angiotensin-Aldosterone Blocker Therapy…...e97
22.214.171.124 Influenza Vaccination…...e98
126.96.36.199 Additional Therapy to Reduce Risk of MI and Death…...e99
4.4.3 Medical Therapy for Relief of Symptoms…...e100
188.8.131.52 Use of Anti-ischemic Medications: Recommendations…...e100
4.4.4 Alternative Therapies for Relief of Symptoms in Patients With Refractory Angina: Recommendations…...e104
184.108.40.206 Enhanced External Counterpulsation…...e104
220.127.116.11 Spinal Cord Stimulation…...e105
5. CAD Revascularization…...e106
5.1 Heart Team Approach to Revascularization Decisions: Recommendations…...e106
5.2 Revascularization to Improve Survival: Recommendations…...e108
5.3 Revascularization to Improve Symptoms: Recommendations…...e109
5.4 CABG Versus Contemporaneous Medical Therapy…...e109
5.5 PCI Versus Medical Therapy…...e110
5.6 CABG Versus PCI…...e110
5.6.1 CABG Versus Balloon Angioplasty or BMS…...e110
5.6.2 CABG Versus DES…...e111
5.7 Left Main CAD…...e111
5.7.1 CABG or PCI Versus Medical Therapy for Left Main CAD…...e111
5.7.2 Studies Comparing PCI Versus CABG for Left Main CAD…...e111
5.7.3 Revascularization Considerations for Left Main CAD…...e112
5.8 Proximal LAD Artery Disease…...e112
5.9 Clinical Factors That May Influence the Choice of Revascularization…...e113
5.9.1 Completeness of Revascularization…...e113
5.9.2 LV Systolic Dysfunction…...e113
5.9.3 Previous CABG…...e113
5.9.4 Unstable Angina/Non–ST-Elevation Myocardial Infarction…...e113
5.9.5 DAPT Compliance and Stent Thrombosis: Recommendation…...e113
5.10 Transmyocardial Revascularization…...e114
5.11 Hybrid Coronary Revascularization: Recommendations…...e114
5.12 Special Considerations…...e114
5.12.2 Older Adults…...e115
5.12.3 Diabetes Mellitus…...e116
5.12.5 Chronic Kidney Disease…...e118
5.12.6 HIV Infection and SIHD…...e118
5.12.7 Autoimmune Disorders…...e119
5.12.8 Socioeconomic Factors…...e119
5.12.9 Special Occupations…...e119
6. Patient Follow-Up: Monitoring of Symptoms and Antianginal Therapy…...e119
6.1 Clinical Evaluation, Echocardiography During Routine, Periodic Follow-Up: Recommendations…...e120
6.2 Follow-Up of Patients With SIHD…...e121
6.2.1 Focused Follow-Up Visit: Frequency…...e121
6.2.2 Focused Follow-Up Visit: Interval History and Coexisting Conditions…...e121
6.2.3 Focused Follow-Up Visit: Physical Examination…...e122
6.2.4 Focused Follow-Up Visit: Resting 12-Lead ECG…...e122
6.2.5 Focused Follow-Up Visit: Laboratory Examination…...e122
6.3 Noninvasive Testing in Known SIHD…...e122
6.3.1 Follow-Up Noninvasive Testing in Patients With Known SIHD: New, Recurrent, or Worsening Symptoms Not Consistent With Unstable Angina: Recommendations…...e122
18.104.22.168 Patients Able to Exercise…...e122
22.214.171.124 Patients Unable to Exercise…...e123
126.96.36.199 Irrespective of Ability to Exercise…...e124
6.3.2 Noninvasive Testing in Known SIHD—Asymptomatic (or Stable Symptoms): Recommendations…...e124
6.3.3 Factors Influencing the Use of Follow-Up Testing…...e124
6.3.4 Patient Risk and Testing…...e125
6.3.5 Stability of Results After Normal Stress Testing in Patients With Known SIHD…...e126
6.3.6 Utility of Repeat Stress Testing in Patients With Known CAD…...e127
6.3.7 Future Developments…...e127
Appendix 1. Author Relationships With Industry and Other Entities (Relevant)…...e159
Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant)…...e161
Appendix 3. Abbreviations List…...e163
Appendix 4. Nomogram for Estimating–Year CAD Event-Free Survival…...e164
The medical profession should play a central role in evaluating the evidence related to drugs, devices, and procedures for the detection, management, and prevention of disease. When properly applied, expert analysis of available data on the benefits and risks of these therapies and procedures can improve the quality of care, optimize patient outcomes, and favorably affect costs by focusing resources on the most effective strategies. An organized and directed approach to a thorough review of evidence has resulted in the production of clinical practice guidelines that assist physicians in selecting the best management strategy for an individual patient. Moreover, clinical practice guidelines can provide a foundation for other applications, such as performance measures, appropriate use criteria, and both quality improvement and clinical decision support tools.
The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly produced guidelines in the area of cardiovascular disease since 1980. The ACCF/AHA Task Force on Practice Guidelines (Task Force), charged with developing, updating, and revising practice guidelines for cardiovascular diseases and procedures, directs and oversees this effort. Writing committees are charged with regularly reviewing and evaluating all available evidence to develop balanced, patient-centric recommendations for clinical practice.
Experts in the subject under consideration are selected by the ACCF and AHA to examine subject-specific data and write guidelines in partnership with representatives from other medical organizations and specialty groups. Writing committees are asked to perform a literature review; weigh the strength of evidence for or against particular tests, treatments, or procedures; and include estimates of expected outcomes where such data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered. When available, information from studies on cost is considered, but data on efficacy and outcomes constitute the primary basis for the recommendations contained herein.
In analyzing the data and developing recommendations and supporting text, the writing committee uses evidence-based methodologies developed by the Task Force (1). The Class of Recommendation (COR) is an estimate of the size of the treatment effect, with consideration given to risks versus benefits as well as evidence and/or agreement that a given treatment or procedure is or is not useful/effective or in some situations may cause harm. The Level of Evidence (LOE) is an estimate of the certainty or precision of the treatment effect. The writing committee reviews and ranks evidence supporting each recommendation, with the weight of evidence ranked as LOE A, B, or C according to specific definitions that are included in Table 1. Studies are identified as observational, retrospective, prospective, or randomized as appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and are ranked as LOE C. When recommendations at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues for which sparse data are available, a survey of current practice among the clinicians on the writing committee is the basis for LOE C recommendations, and no references are cited. The schema for COR and LOE is summarized in Table 1, which also provides suggested phrases for writing recommendations within each COR. A new addition to this methodology is separation of the Class III recommendations to delineate whether the recommendation is determined to be of “no benefit” or is associated with “harm” to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment or strategy versus another have been added for COR I and IIa, LOE A or B only.
In view of the advances in medical therapy across the spectrum of cardiovascular diseases, the Task Force has designated the term guideline-directed medical therapy (GDMT) to represent optimal medical therapy as defined by ACCF/AHA guideline (primarily Class I)–recommended therapies. This new term, GDMT, will be used herein and throughout all future guidelines.
Because the ACCF/AHA practice guidelines address patient populations (and healthcare providers) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR. For studies performed in large numbers of subjects outside North America, each writing committee reviews the potential influence of different practice patterns and patient populations on the treatment effect and relevance to the ACCF/AHA target population to determine whether the findings should inform a specific recommendation.
The ACCF/AHA practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment about care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. As a result, situations may arise in which deviations from these guidelines might be appropriate. Clinical decision making should involve consideration of the quality and availability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise in which additional data are needed to inform patient care more effectively; these areas will be identified within each respective guideline when appropriate.
Prescribed courses of treatment in accordance with these recommendations are effective only if followed. Because lack of patient understanding and adherence may adversely affect outcomes, physicians and other healthcare providers should make every effort to engage the patient's active participation in prescribed medical regimens and lifestyles. In addition, patients should be informed of the risks, benefits, and alternatives to a particular treatment and should be involved in shared decision making whenever feasible, particularly for COR IIa and IIb, for which the benefit-to-risk ratio may be lower.
The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the writing committee. All writing committee members and peer reviewers of this guideline were required to disclose all such current health care-related relationships, including those existing 24 months (from 2005) before initiation of the writing effort. The writing committee chair may not have any relevant relationships with industry or other entities (RWI); however, RWI are permitted for the vice chair position. In December 2009, the ACCF and AHA implemented a new policy that requires a minimum of 50% of the writing committee to have no relevant RWI; in addition, the disclosure term was changed to 12 months before writing committee initiation. The present guideline was developed during the transition in RWI policy and occurred over an extended period of time. In the interest of transparency, we provide full information on RWI existing over the entire period of guideline development, including delineation of relationships that expired more than 24 months before the guideline was finalized. This information is included in Appendix 1. These statements are reviewed by the Task Force and all members during each conference call and meeting of the writing committee and are updated as changes occur. All guideline recommendations require a confidential vote by the writing committee and must be approved by a consensus of the voting members. Members who recused themselves from voting are indicated in the list of writing committee members, and specific section recusals are noted in Appendix 1. Authors' and peer reviewers' RWI pertinent to this guideline are disclosed in Appendixes 1 and 2, respectively. Comprehensive disclosure information for the Task Force is also available online at http://www.cardiosource.org/ACC/About-ACC/Who-We-Are/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The work of the writing committee is supported exclusively by the ACCF, AHA, American College of Physicians (ACP), American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), Society for Cardiovascular Angiography and Interventions (SCAI), and Society of Thoracic Surgeons (STS), without commercial support. Writing committee members volunteered their time for this activity.
The recommendations in this guideline are considered current until they are superseded by a focused update or the full-text guideline is revised. Guidelines are official policy of both the ACCF and AHA.
Jeffrey L. Anderson, MD, FACC, FAHA Chair, ACCF/AHA Task Force on Practice Guidelines
1.1 Methodology and Evidence Overview
The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011.
Searches were limited to studies, reviews, and other evidence in human subjects and that were published in English. Key search words included but were not limited to the following: accuracy, angina, asymptomatic patients, cardiac magnetic resonance (CMR), cardiac rehabilitation, chest pain, chronic angina, chronic coronary occlusions, chronic ischemic heart disease (IHD), chronic total occlusion, connective tissue disease, coronary artery bypass graft (CABG) versus medical therapy, coronary artery disease (CAD) and exercise, coronary calcium scanning, cardiac/coronary computed tomography angiography (CCTA), CMR angiography, CMR imaging, coronary stenosis, death, depression, detection of CAD in symptomatic patients, diabetes, diagnosis, dobutamine stress echocardiography, echocardiography, elderly, electrocardiogram (ECG) and chronic stable angina, emergency department, ethnic, exercise, exercise stress testing, follow-up testing, gender, glycemic control, hypertension, intravascular ultrasound, fractional flow reserve (FFR), invasive coronary angiography, kidney disease, low-density lipoprotein (LDL) lowering, magnetic resonance imaging (MRI), medication adherence, minority groups, mortality, myocardial infarction (MI), noninvasive testing and mortality, nuclear myocardial perfusion, nutrition, obesity, outcomes, patient follow-up, patient education, prognosis, proximal left anterior descending (LAD) disease, physical activity, reoperation, risk stratification, smoking, stable ischemic heart disease (SIHD), stable angina and reoperation, stable angina and revascularization, stress echocardiography, radionuclide stress testing, stenting versus CABG, unprotected left main, weight reduction, and women.Appendix 3 contains an list of abbreviations used in this document.
To provide clinicians with a comprehensive set of data, the absolute risk difference and number needed to treat or harm, if they were published and their inclusion was deemed appropriate, are provided in the guideline, along with confidence intervals (CIs) and data related to the relative treatment effects, such as odds ratio (OR), relative risk (RR), hazard ratio, or incidence rate ratio.
1.2 Organization of the Writing Committee
The writing committee was composed of physicians, cardiovascular interventionalists, surgeons, general internists, imagers, nurses, and pharmacists. The writing committee included representatives from the ACP, AATS, PCNA, SCAI, and STS.
1.3 Document Review and Approval
This document was reviewed by 2 external reviewers nominated by both the ACCF and the AHA; 2 reviewers nominated by the ACP, AATS, PCNA, SCAI, and STS; and 19 content reviewers, including members of the ACCF Imaging Council, ACCF Interventional Scientific Council, and the AHA Council on Clinical Cardiology. Reviewers' RWI information was collected and distributed to the writing committee and is published in this document (Appendix 2). Because extensive peer review comments resulted in substantial revision, the guideline was subjected to a second peer review by all official and organizational reviewers. Lastly, the imaging sections were peer reviewed separately, after an update to that evidence base.
This document was approved for publication by the governing bodies of the ACCF, AHA, ACP, AATS, PCNA, SCAI, and STS.
1.4 Scope of the Guideline
These guidelines are intended to apply to adult patients with stable known or suspected IHD, including new-onset chest pain (i.e., low-risk unstable angina [UA]), or to adult patients with stable pain syndromes (Figure 1). Patients who have “ischemic equivalents,” such as dyspnea or arm pain with exertion, are included in the latter group. Many patients with IHD can become asymptomatic with appropriate therapy. Accordingly, the follow-up sections of this guideline pertain to patients who were previously symptomatic, including those who have undergone percutaneous coronary intervention (PCI) or CABG.
This guideline also addresses the initial diagnostic approach to patients who present with symptoms that suggest IHD, such as anginal-type chest pain, but who are not known to have IHD. In this circumstance, it is essential that the practitioner ascertain whether such symptoms represent the initial clinical recognition of chronic stable angina, reflecting gradual progression of obstructive CAD or an increase in supply/demand mismatch precipitated by a change in activity or concurrent illness (e.g., anemia or infection), or whether they represent an acute coronary syndrome (ACS), most likely due to an unstable plaque causing acute thrombosis. For patients with newly diagnosed stable angina, this guideline should be used. Patients with ACS have either acute myocardial infarction (AMI) or UA. For patients with AMI, the reader is referred to the “ACCF/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction” (STEMI) (2,3). Similarly, for patients with UA that is believed to be due to an acute change in clinical status attributable to an unstable plaque or an abrupt change in supply (e.g., coronary occlusion with myocardial supply through collaterals), the reader is referred to the “ACCF/AHA Guidelines for the Management of Patients With Unstable Angina/non–ST-Elevation Myocardial Infarction” (UA/NSTEMI) (4,4a). There are, however, patients with UA who can be categorized as low risk and are addressed in this guideline (Table 2).
A key premise of this guideline is that once a diagnosis of IHD is established, it is necessary in most patients to assess their risk of subsequent complications, such as AMI or death. Because the approach to diagnosis of suspected IHD and the assessment of risk in a patient with known IHD are conceptually different and are based on different literature, the writing committee constructed this guideline to address these issues separately. It is recognized, however, that a clinician might select a procedure for a patient with a moderate to high pretest likelihood of IHD to provide information for both diagnosis and risk assessment, whereas in a patient with a low likelihood of IHD, it could be sensible to select a test simply for diagnostic purposes without regard to risk assessment. By separating the conceptual approaches to ascertaining diagnosis and prognosis, the goal of the writing committee is to promote the sensible application of appropriate testing rather than routine use of the most expensive or complex tests whether warranted or not. It is not the intent of the writing committee to promote unnecessary or duplicate testing, although in some patients this could be unavoidable.
Additionally, this guideline addresses the approach to asymptomatic patients with SIHD that has been diagnosed solely on the basis of an abnormal screening study, rather than on the basis of clinical symptoms or events such as anginal symptoms or ACS. The inclusion of such asymptomatic patients does not constitute an endorsement of such tests for the purposes of screening but is simply an acknowledgment of the clinical reality that asymptomatic patients often present for evaluation after such tests have been performed. Multiple ACCF/AHA guidelines and scientific statements have discouraged the use of ambulatory monitoring, treadmill testing, stress echocardiography, stress myocardial perfusion imaging (MPI), and computed tomography (CT) scoring of coronary calcium or coronary angiography as routine screening tests in asymptomatic individuals. The reader is referred to these documents for a detailed discussion of screening, which is beyond the scope of this guideline (Table 3).
Patients with known IHD who were previously asymptomatic or whose symptoms were stable can develop new or recurrent chest pain or other symptoms suggesting ACS. Just as in the case of patients with new-onset chest pain, the clinician must determine whether such recurrent or worsening pain is consistent with ACS or simply represents symptoms more consistent with chronic stable angina that do not require emergent attention. As indicated previously, patients with AMI or moderate- to high-risk UA fall outside of the scope of this guideline, whereas those with chronic stable angina or low-risk UA are addressed in the present guideline.
When patients with documented IHD develop recurrent chest pain, the symptoms still could be attributable to another condition. Such patients are included in this guideline if there is sufficient suspicion that their heart disease is a likely source of symptoms to warrant cardiac evaluation. If the evaluation demonstrates that IHD is unlikely to cause the symptoms, the evaluation of noncardiac causes is beyond the scope of this guideline. If the evaluation demonstrates that IHD is the likely cause of their recurrent symptoms, subsequent management of such patients does fall within this guideline.
The approach to screening and management of asymptomatic patients who are at risk for IHD but who are not known to have IHD is also beyond the scope of this guideline, but it is addressed in the “ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults” (5). Similarly, the present guideline does not apply to patients with chest pain symptoms early after revascularization by either percutaneous techniques or CABG. Although the division between “early” and “late” symptoms is arbitrary, the writing committee believed that this guideline should not be applied to patients who develop recurrent symptoms within 6 months of revascularization. Pediatric patients are beyond the scope of this guideline, because IHD is very unusual in such patients and is related primarily to the presence of coronary artery anomalies. Patients with chest pain syndromes after cardiac transplantation also are not included in this guideline.
1.5 General Approach and Overlap With Other Guidelines or Statements
This guideline overlaps with numerous clinical practice guidelines published by the ACCF/AHA Task Force on Practice Guidelines; the National Heart, Lung, and Blood Institute; and the ACP (Table 3). To maintain consistency, the writing committee worked with members of other committees to harmonize recommendations and eliminate discrepancies. Some recommendations from earlier guidelines have been updated as warranted by new evidence or a better understanding of earlier evidence, whereas others that were no longer accurate or relevant or were overlapping were modified; recommendations from previous guidelines that were similar or redundant were eliminated or consolidated when possible.
Most of the topics mentioned in the present guideline were addressed in the “ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina—Summary Article” (7), and many of the recommendations in the present guideline are consistent with those in the 2002 document. Whereas the 2002 update dealt individually with specific drugs and interventions for reducing cardiovascular risk and medical therapy of angina pectoris, the present document recommends a combination of lifestyle modifications and medications that constitute GDMT. In addition, recommendations for risk reduction have been revised to reflect new evidence and are now consistent with the “AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update” (8). Also in the present guideline, recommendations and text related to revascularization are the result of extensive collaborative discussions between the PCI and CABG writing committees, as well as key members of the SIHD and UA/NSTEMI writing committees. In a major undertaking, the PCI and CABG guidelines were written concurrently with input from the STEMI guideline writing committee and additional collaboration with the SIHD guideline writing committee, allowing greater collaboration between these writing committees on revascularization strategies in patients with CAD (including unprotected left main PCI, multivessel disease revascularization, and hybrid procedures) (9,10). Section 5 is included as published in both the PCI and CABG guidelines in its entirety.
In addition to cosponsoring practice guidelines, the ACCF has sponsored appropriate use criteria (AUC) documents for imaging testing, diagnostic catheterization, and coronary revascularization since 2005 (11–16). Practice guideline recommendations are based on evidence from clinical and observational trials and expert consensus; AUCs are complementary to practice guidelines and make every effort to be concordant with their recommendations. In general, the recommendations in this guideline and current AUCs are consistent. Apparent discrepancies usually reflect differing frameworks or imaging methodologies. Moreover, where guidelines leave “gaps” (i.e., unaddressed applications), AUCs can provide additional clinical guidance based on the best available clinical evidence and use a prospective, expert consensus methodology (16). Specifically, AUCs provide detailed indications for testing and procedures to aid clinical decision making, categorizing each indication as appropriate, uncertain, or inappropriate. Thus, ACCF AUCs provide an additional means to identify candidates for testing or procedures as well as those for whom they would be inappropriate or for whom the optimal approach is uncertain. Inappropriate candidates are those for whom compelling evidence indicates that testing is not indicated or, in some cases, results in reduced accuracy. Uncertain indications are those with either published evidence or lack of expert consensus on testing use.
AUCs also include relevant clinical scenarios not addressed by these guidelines (11), such as the issue of testing during follow-up of patients with SIHD with stress echocardiography (15), single-photon emission computed tomography (SPECT) MPI (12), CMR, and CCTA (13,14). These AUC documents address the intervals between testing for various stress imaging indications. As with all standards documents, ongoing evaluation is required to update the recommendations on the value, limitations, timing, costs, and risks of imaging as an adjunct to clinical assessment during follow-up of patients with established SIHD. Review of these AUCs is beyond the scope of the present document, and the reader is referred to the most recent AUC documents to complement the guidelines provided here.
As the scientific basis of the approach to management of cardiovascular disease has rapidly expanded, the size and scope of clinical practice guidelines have grown commensurately to a point where they have become too unwieldy for routine use by practicing clinicians. The most current national guidelines for management of hypertension (Joint National Committee VII) (17) and hyperlipidemia (Adult Treatment Panel III) (18) combined comprise nearly 400 pages. Thus, the writing committee recognized that it would be unfeasible to produce a document that would be simultaneously practical and exhaustive and, therefore, has tried to create a resource that provides a comprehensive approach to management of SIHD for which the relevant evidence is succinctly summarized and referenced. The writing committee used current and credible meta-analyses, when available, instead of conducting a systematic review of all primary literature.
1.6 Magnitude of the Problem
IHD remains a major public health problem nationally and internationally. It is estimated that 1 in 3 adults in the United States (about 81 million) has some form of cardiovascular disease, including >17 million with coronary heart disease and nearly 10 million with angina pectoris (26,27). Among persons 60 to 79 years of age, approximately 25% of men and 16% of women have coronary heart disease, and these figures rise to 37% and 23% among men and women ≥80 years of age, respectively (27).
Although the survival rate of patients with IHD has been steadily improving (28), it was still responsible for nearly 380,000 deaths in the United States during 2010, with an age-adjusted mortality rate of 113 per 100,000 population (29). Although IHD is widely known to be the number 1 cause of death in men, this is also the case for women, among whom this condition accounts for 27% of deaths (compared with 22% due to cancer) (30). IHD also accounts for the vast majority of the mortality and morbidity of cardiac disease. Each year, >1.5 million patients have an MI. Many more are hospitalized for UA and for evaluation and treatment of stable chest pain syndromes. Beyond the need for hospitalization, many patients with chronic chest pain syndromes are temporarily unable to perform normal activities for hours or days and thus experience a reduced quality of life. Among patients enrolled in the BARI (Bypass Angioplasty Revascularization Investigation) study (31), about 30% never returned to work after coronary revascularization, and 15% to 20% of patients rated their own health as “fair” or “poor” despite revascularization. Similarly, observational studies of patients recovering from an AMI demonstrated that 1 in 5 patients, even after intensive treatment at the time of their AMI, still suffered angina 1 year later (32). These data confirm the widespread clinical impression that IHD continues to be associated with considerable patient morbidity despite the decline in cardiovascular mortality rate. Patients who have had ACS, such as AMI, remain at risk for recurrent events even if they have no, or limited, symptoms and should be considered to have SIHD.
In approximately 50% of patients, angina pectoris is the initial manifestation of IHD (27). The incidence of angina rises continuously with age in women, whereas the incidence of angina in men peaks between 55 and 65 years of age before declining (27). Despite angina's clinical importance and high frequency, modern, population-based data are quite limited, and these figures likely underestimate the true prevalence of angina (33).
The annual rates per 1,000 population of new episodes of angina for nonblack men are 28.3 for ages 65 to 74 years, 36.3 for ages 75 to 84 years, and 33.0 for age ≥85 years. For nonblack women in the same age groups, the rates are 14.1, 20.0, and 22.9, respectively. For black men, the rates are 22.4, 33.8, and 39.5, and for black women, the rates are 15.3, 23.6, and 35.9, respectively (30). In a study conducted in Finland, the age-standardized, annual incidence of angina was 2.03 in men and 1.89 in women per 100 populations (33).
Further estimates of the prevalence of chronic, symptomatic IHD can be obtained by extrapolating from data on ACS and, more specifically, AMI. About one half of patients presenting to the hospital with ACS have preceding angina (27). One current estimate is that about 50% of patients who suffer an AMI each year in the United States survive until hospitalization (27). Two older population-based studies from Olmsted County, MN, and Framingham, MA, examined the annual rates of MI in patients with symptoms of angina and reported similar rates of 3% to 3.5% per year (34,35). On this basis, it can be estimated that there were 30 patients with stable angina for every patient with infarction who was hospitalized, which represents 16.5 million persons with angina in the United States. However, since the data reported in these studies were collected, it is likely that the much greater use of effective medical therapies, including antianginal medications and revascularization procedures, has reduced the proportion of patients with symptomatic angina—although there are still many patients whose symptoms are poorly controlled (36–38).
The costs of caring for patients with IHD are enormous, estimated at $156 billion in the United States for both direct and indirect costs in 2008. More than one half of direct costs are related to hospitalization. In 2003, the Medicare program alone paid $12.2 billion for hospitalizations for IHD, including $12,321 per discharge for AMI and $11,783 per discharge for admissions for coronary atherosclerosis (39).
Another major expense is for invasive procedures and related costs. In 2006 in the United States, there were 1,313,000 inpatient PCI procedures, 448,000 inpatient coronary artery bypass procedures, and 1,115,000 inpatient diagnostic cardiac catheterizations (27,40). In addition, ≥13 million outpatient visits for IHD occur in the United States annually (41). It was estimated that the costs of outpatient and emergency department visits in 2000 by patients with chronic angina were $922 million and $286 million, respectively, and prescriptions accounted for $291 million. Long-term care costs—including skilled nursing, home health, and hospice care—were $2.6 billion, which represented 30% of the total cost of care for chronic angina (42).
Although the direct costs associated with SIHD are substantial, they do not account for the significant indirect costs of lost workdays, reduced productivity, long-term medication, and associated effects. The indirect costs have been estimated to be almost as great as the direct costs (27,43) (Table 4). The magnitude of the problem can be summarized succinctly: SIHD affects many millions of Americans, with associated annual costs that are measured in tens of billions of dollars.
1.7 Organization of the Guideline
The overarching framework adopted in constructing this guideline reflects the complementary goals of treating patients with known SIHD, alleviating or improving symptoms, and prolonging life. This guideline is divided into 4 basic sections summarizing the approaches to diagnosis, risk assessment, treatment, and follow-up. Five algorithms summarize the management of stable angina: diagnosis (Figure 2), risk assessment (Figure 3), GDMT (Figure 4), and revascularization (Figures 5 and 6). We readily acknowledge, however, that in actual clinical practice, the elements comprising the 4 sections and the steps delineated in the algorithms often overlap and are not always separable. Some low-risk patients, for example, might require only clinical assessment to determine that they do not need any further evaluation or treatment. Other patients might require only clinical assessment and further adjustment of medical therapy if their preferences and comorbidities preclude revascularization, thus obviating the necessity for risk stratification. The stress testing/angiography algorithm might be applicable for diagnostic purposes in patients with symptoms that suggest SIHD or to perform risk assessment in patients with established SIHD.
1.8 Vital Importance of Involvement by an Informed Patient: Recommendation
1. Choices about diagnostic and therapeutic options should be made through a process of shared decision making involving the patient and provider, with the provider explaining information about risks, benefits, and costs to the patient. (Level of Evidence: C)
In accordance with the principle of autonomy, the healthcare provider is obliged to solicit and respect the patient's preferences about choice of therapy. Although this principle, in the setting of cardiovascular disease, has received only limited study, the concept of shared decision making increasingly is viewed as an approach that ensures that patients remain involved in key decisions. This approach leads to higher quality of care (44,45).
To ensure that the patient is able to make the most informed decisions possible, the provider must give sufficient information about the underlying disease process, along with all relevant diagnostic and therapeutic options—including anticipated outcomes, risks, and costs to the patient (46). This information should be provided in a manner that is readily comprehensible and permits the opportunity for dialog and questions.
Patients should be encouraged to seek additional information from other sources, including those on the Internet, such as those maintained by the National Institutes of Health, the Centers for Disease Control and Prevention, and the ACCF/AHA. Substantial research indicates that when informed about absolute or marginal benefit, patients often elect to postpone or forego invasive procedures. Two patients with similar pretest probabilities of IHD could prefer different approaches because of variations in personal beliefs, economic situation, or stage of life. Because of the variation in symptoms and clinical characteristics among patients, as well as their unique perceptions, expectations, and preferences, there is often no single correct approach to any given set of clinical circumstances. In assisting patients to reach an informed decision, it is essential to elicit the breadth of their knowledge, values, preferences, and concerns.
The healthcare provider has a responsibility to ensure that patients understand and consider both the upside and downside of available options, in both the near and long terms. All previous guidelines reviewed by the writing committee have recognized the crucial role that patient preferences play in the selection of a treatment strategy (9,10,47–49). It is essential that these discussions be conducted in a location and atmosphere that permits adequate time for discussion and contemplation. Initiating a discussion about the relative merits of PCI or CABG while a patient is in the midst of a procedure, for example, is not usually consistent with these principles.
In crafting a diagnostic strategy, the objective is to ascertain, as accurately as possible, whether the patient has IHD while minimizing the expense, discomfort, and potential harms of any tests or procedures. This includes avoiding procedures that are likely to yield false positive or false negative results or that are unnecessary or inappropriate. The objective for procedures intended to assess prognosis is similar.
Treatment options should be emphasized, especially in cases where there is no substantial advantage of one strategy over others. For most patients, the goal of treatment should be to simultaneously maximize survival and to achieve prompt and complete (or nearly complete) elimination of anginal chest pain with return to normal activities—in other words, a functional capacity of Canadian Cardiovascular Society (CCS) Class I angina (50). For example, for an otherwise healthy, active patient, the treatment goal is usually the complete elimination of chest pain and a return to vigorous physical activity. Conversely, an elderly patient with more severe angina and several serious coexisting medical problems might be satisfied with a reduction in symptoms that permits limited activities of daily living. Patients with anatomy that would ordinarily favor the choice of CABG could have comorbidities that make the risk of surgery unacceptable, in which case PCI or medical therapy is a more attractive option.
In counseling patients, the healthcare provider should be aware of, and help to rectify, common misperceptions. Many patients assume, for example, that opening a partially blocked artery will naturally prevent a heart attack and prolong life irrespective of other anatomic and clinical factors. When there is little expectation of an improvement in survival from revascularization, patients should be so informed. When evidence points to probable benefit from either revascularization or medical therapy, it should be quantified to the extent possible, with explicit acknowledgment of uncertainties, and should be discussed in the context of what treatment option is best for that particular patient. When possible, the relative time course of response to therapy should be described for therapeutic choices. Some patients might, for example, initially opt for PCI over medical therapy because relief of symptoms is typically more rapid. However, when informed of the immediate risk of complications of PCI, some patients could prefer conservative therapy. Similarly, many patients choose PCI over CABG because it is less invasive and provides for quicker recovery, despite the fact that repeat revascularization procedures are performed more frequently after PCI. Patients' preferences in these circumstances often are influenced by their attitudes toward risk and by the tendency to let immediate smaller benefits outweigh larger future risks, a phenomenon termed “temporal discounting” (51).
2 Diagnosis of SIHD
2.1 Clinical Evaluation of Patients With Chest Pain
2.1.1 Clinical Evaluation in the Initial Diagnosis of SIHD in Patients With Chest Pain: Recommendations
1. Patients with chest pain should receive a thorough history and physical examination to assess the probability of IHD before additional testing (52). (Level of Evidence: C)
2. Patients who present with acute angina should be categorized as stable or unstable; patients with UA should be further categorized as being at high, moderate, or low risk (4,4a). (Level of Evidence: C)
The clinical examination is the key first step in evaluating a patient with chest pain and should include a detailed assessment of symptoms, including quality, location, severity, and duration of pain; radiation; associated symptoms; provocative factors; and alleviating factors. Adjectives often used to describe anginal pain include “squeezing,” “grip-like,” “suffocating,” and “heavy,” but it is rarely sharp or stabbing and typically does not vary with position or respiration. On occasion the patient might demonstrate the classic Levine's sign by placing a clenched fist over the precordium to describe the pain. Many patients do not, however, describe angina as frank pain but as tightness, pressure, or discomfort. Other patients, in particular women and the elderly, can present with atypical symptoms such as nausea, vomiting, midepigastric discomfort, or sharp (atypical) chest pain. In the WISE (Women's Ischemic Syndrome Evaluation) study, 65% of women with ischemia presented with atypical symptoms (54).
Anginal pain caused by cardiac ischemia typically lasts minutes. The location is usually substernal, and pain can radiate to the neck, jaw, epigastrium, or arms. Pain above the mandible, below the epigastrium, or localized to a small area over the left lateral chest wall is rarely angina. Angina is often precipitated by exertion or emotional stress and relieved by rest. Sublingual nitroglycerin also usually relieves angina, within 30 seconds to several minutes. The history can be used to classify symptoms as typical, atypical, or noncardiac chest pain (6) (Table 5). The patient presenting with angina must be categorized as having stable angina or UA (4,4a). UA is defined as new onset, increasing (in frequency, intensity, or duration), or occurring at rest (50) (Table 6). However, patients presenting with UA are subdivided by their short-term risk (Table 2). Patients at high or moderate risk often have experienced rupture of coronary artery plaque and have a risk of death higher than that of patients with stable angina but not as great as that of patients with AMI. These patients should be transferred promptly to an emergency department for evaluation and treatment. The short-term prognosis of patients with low-risk UA, however, is comparable to those with stable angina, and their evaluation can be conducted safely and expeditiously in an outpatient setting.
After thorough characterization of chest pain, the presence of risk factors for IHD (55) should be determined. These include smoking, hyperlipidemia, diabetes mellitus, hypertension, obesity or metabolic syndrome, physical inactivity, and a family history of premature IHD (i.e., onset in a father, brother, or son before age 55 years or a mother, sister, or daughter before age 65 years). A history of cerebrovascular or peripheral artery disease (PAD) also increases the likelihood of IHD.
2.1.3 Physical Examination
The examination is often normal or nonspecific in patients with stable angina (56) but could reveal related conditions such as heart failure, valvular heart disease, or hypertrophic cardiomyopathy. An audible rub suggests pericardial or pleural disease. Evidence of vascular disease includes carotid or renal artery bruits, a diminished pedal pulse, or a palpable abdominal aneurysm. Elevated blood pressure (BP), xanthomas, and retinal exudates point to the presence of IHD risk factors. Pain reproduced by pressure on the chest wall suggests a musculoskeletal etiology but does not eliminate the possibility of angina due to IHD.
188.8.131.52 Resting Electrocardiography to Assess Risk: Recommendation
1. A resting ECG is recommended in patients without an obvious, noncardiac cause of chest pain (57–59). (Level of Evidence: B)
Patients with SIHD who have the following abnormalities on a resting ECG have a worse prognosis than those with normal ECGs (57–59): evidence of prior MI, especially Q waves in multiple leads or an R wave in V1 indicating a posterior infarction (60); persistent ST-T-wave inversions, particularly in leads V1 to V3 (61–64); left bundle-branch block (LBBB), bifascicular block, second- or third-degree atrioventricular (AV) block, or ventricular tachyarrhythmia (65); or left ventricular (LV) hypertrophy (62,66).
2.1.5 Differential Diagnosis
Although the symptoms of some patients might be consistent with a very high probability of IHD, in others, the etiology might be less certain, and alternative diagnoses should be considered (Table 7). However, even when angina seems likely to be related to IHD, other coexisting conditions can precipitate symptoms by inducing or exacerbating myocardial ischemia, by either increased myocardial oxygen demand or decreased myocardial oxygen supply (Table 8). When severe, these conditions can cause angina in the absence of significant anatomic coronary obstruction. Chest pain in women is less often due to IHD than in men, even when the pain is typical. Nevertheless, pain in women can be related to vascular dysfunction in the absence of epicardial CAD. Entities that cause increased oxygen demand include hyperthermia (particularly if accompanied by volume contraction) (67), hyperthyroidism, and cocaine or methamphetamine abuse. Sympathomimetic toxicity, due, for example, to cocaine intoxication, not only increases myocardial oxygen demand but also induces coronary vasospasm and can cause infarction in young patients. Long-term cocaine use can cause premature development of IHD (68,69). Severe uncontrolled hypertension increases LV wall tension, leading to increased myocardial oxygen demand and decreased subendocardial perfusion. Hypertrophic cardiomyopathy and aortic stenosis can induce even more severe LV hypertrophy and resultant wall tension. Ventricular or supraventricular tachycardias are another cause of increased myocardial oxygen demand, but when paroxysmal these are difficult to diagnose.
Anemia is the prototype for conditions that limit myocardial oxygen supply. Cardiac output rises when the hemoglobin drops to <9 g/dL, and ST-T-wave changes (depression or inversion) can occur at levels <7 g/dL.
Hypoxemia resulting from pulmonary disease (e.g., pneumonia, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial fibrosis, or obstructive sleep apnea) can also precipitate angina. Polycythemia, leukemia, thrombocytosis, and hypergammaglobulinemia are associated with increased blood viscosity that can decrease coronary artery blood flow and precipitate angina, even in patients without significant coronary stenoses.
2.1.6 Developing the Probability Estimate
When the clinical evaluation is complete, the practitioner must determine whether the probability of IHD is sufficient to recommend further testing, which is often a standard exercise test. When the probability of disease is <5%, further testing is usually not warranted because the likelihood of a false-positive test (i.e., positive test in the absence of obstructive CAD) is actually higher than that of a true positive. On the other hand, when the exercise test is negative in a patient who has a very high likelihood of IHD on the basis of the history, there is a substantial chance that in reality the result is falsely negative. Thus, further testing is most useful in patients in whom the cause of chest pain is truly uncertain (i.e., the probability of IHD is between 20% and 70%). It is necessary to note, however, that these probabilities relate solely to the presence of obstructive CAD and do not pertain to ischemia due to microvascular disease or other causes. They also do not reflect the likelihood that a nonobstructing plaque could become unstable and cause ischemia.
A landmark study (52) showed how information about the type of pain and age and sex of the patient can provide a reasonable estimate of the likelihood of IHD. For instance, a 64-year-old man with typical angina has a 94% likelihood of having significant coronary stenosis. A 32-year-old woman with nonanginal chest pain has a 1% chance of coronary stenosis (70–72). Other clinical characteristics that improved the accuracy of prediction include active or recent smoking, Q-wave or ST-T-wave changes on the ECG, hyperlipidemia (defined at the time of study as a total cholesterol level >250 mg/dL), and diabetes mellitus (defined at that time as a fasting glucose level >140 mg/dL). Of these characteristics, diabetes mellitus had the greatest influence on increasing the probability of IHD. The presence of hypertension or a family history of premature IHD did not provide additional predictive accuracy. The results of the aforementioned landmark study subsequently were replicated with data from CASS (Coronary Artery Surgery Study) (73) and were within 5% of the original estimates for 23 of 24 patient groupings. The single major exception was the category of adults who were ≤50 years of age with atypical angina, for whom the CASS estimate was 17% higher. On the basis of this high degree of concordance, the data from these studies were merged in the 2002 Chronic Stable Angina guideline (7,52,73) (Table 9).
Additional validation studies were conducted with data from the Duke Databank for Cardiovascular Disease, which also incorporated electrocardiographic findings (Q waves or ST-T changes) and information about risk factors (smoking, diabetes mellitus, hyperlipidemia) (71). Table 10 presents the Duke data for mid-decade patients (35, 45, 55, and 65 years of age). Two probabilities are given. The first is for a low-risk patient with no risk factors and a normal ECG. The second is for a high-risk patient who smokes and has diabetes mellitus and hyperlipidemia but has a normal ECG. A key contribution of the Duke Databank is the value of incorporating data about risk factors into the probability estimate.
A limitation of these predictive models, however, is that because they were developed with data from patients referred to university medical centers, they tended to overestimate the likelihood of IHD in patients at lower risk. It is possible to correct this referral (or ascertainment) bias by using the overall prevalence of IHD in the primary-care population (72), although these adjustments are themselves subject to error if the prevalence estimates are flawed.
An additional limitation of these models is that they were derived from populations of patients ≤70 years of age. Yet another drawback is that they perform less well in women, in part because the prevalence of obstructive CAD is lower in women than in men. As shown in Table 9, the Diamond-Forrester model substantially overestimates the likelihood of CAD compared with the prevalence observed in the WISE study (52,74).
After integrating data from the clinical evaluation, model predictions, and other relevant factors to develop a probability estimate, the clinician must then engage the patient in a process of shared decision making, as noted in Section 1.8, to determine whether further testing is warranted.
2.2 Noninvasive Testing for Diagnosis of IHD
2.2.1 Approach to the Selection of Diagnostic Tests to Diagnose SIHD
Functional or stress testing to detect inducible ischemia has been the “gold standard” and is the most common noninvasive test used to diagnose SIHD. All functional tests are designed to provoke cardiac ischemia by using exercise or pharmacological stress agents either to increase myocardial work and oxygen demand or to induce vasodilation-elicited heterogeneity in induced coronary flow. These techniques rely on the principles embodied within the ischemic cascade (Figure 7), in which graded ischemia of increasing severity and duration produces sequential changes in perfusion, relaxation and contraction, wall motion, repolarization, and, ultimately, symptoms, all of which can be detected by an array of cardiovascular testing modalities (75). The production of ischemia, however, depends on the severity of stress imposed (i.e., submaximal exercise can fail to produce ischemia) and the severity of the flow disturbance. Coronary stenoses <70% are often undetected by functional testing.
Because abnormalities of regional or global ventricular function occur later in the ischemic cascade, they are more likely to indicate severe stenosis and, thus, demonstrate a higher diagnostic specificity for SIHD than do perfusion defects, such as those seen on nuclear MPI. Isolated perfusion defects, on the other hand, can result from stenoses of borderline significance, raising the sensitivity of nuclear MPI for underlying CAD but lowering the specificity for more severe stenosis.
The recent availability of multislice CCTA allows for the noninvasive visualization of anatomic CAD with high-resolution images similar to invasive coronary angiography. As would be expected, CCTA and invasive angiography exhibit a high degree of concordance, as they are both anatomic tests, and CCTA is more sensitive in detecting obstructive CAD, especially at diameter stenosis ≤70%, than is nuclear MPI (76).
The accuracy of a CCTA reader in estimating coronary stenosis within a vessel is hindered by the presence of dense coronary calcification and a tendency to overestimate the severity of lesions relative to invasive angiography (77). No direct comparisons of the effectiveness of a functional approach with inducible ischemia or an anatomic approach assessing coronary stenosis have been completed in the noninvasive setting, although several randomized controlled trials (RCTs) are under way, which will directly or indirectly compare test modalities: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain; clinicaltrials.gov identifier NCT01174550), RESCUE (Randomized Evaluation of Patients With Stable Angina Comparing Diagnostic Examinations; clinicaltrials.gov identifier NCT01262625), and ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; clinicaltrials.gov identifier NCT01471522).
In 2010, the United Kingdom's National Institute for Clinical Excellence Guidance for “Chest pain of recent onset: Assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin” provide, for a healthcare system that allocates resources differently from that of the United States, recommendations for an initial assessment of CAD. This Guidance recommends beginning in people without confirmed CAD with a detailed clinical assessment and performing a 12-lead ECG in those in whom stable angina cannot be diagnosed or excluded on the basis of clinical assessment alone. The Guidance suggests that there is no need for further testing in those with an estimated likelihood <10%. In those with an estimated likelihood of CAD of 10% to 29%, the National Institute for Clinical Excellence document recommends beginning with CT coronary artery calcium (CAC) scoring as the first-line diagnostic investigation, whereas the present SIHD guideline provides a Class IIb recommendation for several reasons, as outlined in Section 184.108.40.206.
220.127.116.11 Assessing Diagnostic Test Characteristics
A hierarchy of diagnostic test evidence has been proposed by Fryback and Thornbury (78) and ranges from evidence on technical quality (level 1) through test accuracy (sensitivity and specificity associated with test interpretation), to changes in diagnostic thinking, effect on patient management, and patient outcomes, to societal costs and benefits (level 6). A similar framework has been proposed for biomarkers by Hlatky et al. (79). In practice, although knowledge of the effect of diagnostic testing on outcomes would be highly desirable, the vast majority of available evidence is on diagnostic or prognostic accuracy. Therefore, this information most commonly is used to compare test performance.
Diagnostic accuracy is commonly represented by the terms sensitivity and specificity, which are calculated by comparing test results to the “gold standard” of the results of invasive coronary angiography. The sensitivity of any noninvasive test to diagnose SIHD expresses the frequency that a patient with angiographic IHD will have a positive test result, whereas the specificity measures the frequency that a patient without IHD will have a negative result. In addition, predictive accuracy represents the frequency that a patient with a positive test does have IHD (positive predictive value) or that a patient with a negative test truly does not have IHD (negative predictive value). The predictive accuracy may be used for both diagnostic and prognostic accuracy analyses; in the latter case, the comparison is to subsequent cardiovascular events. It is important to note that apparent test performance can be altered substantially by the pretest probability of IHD (52,80,81), making the accurate assessment of pretest probability and proper patient selection essential for diagnostic interpretation statements on IHD prevalence by test results. The positive predictive value of a test declines as the disease prevalence decreases in the population under study, whereas the negative predictive accuracy increases (82). Finally, the performance of noninvasive tests also varies in certain patient populations, such as obese patients, the elderly, and women (Section 5.12), who often are underrepresented in clinical studies.
Estimates of all test characteristics are subject to workup bias, also known as verification or posttest referral bias (81,83,84). This bias occurs when the results of stress testing are used to decide which patients undergo the standard reference procedure (invasive coronary angiography) to establish a definitive diagnosis of IHD (i.e., patients with positive results on stress testing are referred for coronary angiography, whereas those with negative results are not). This bias has the effect of raising the measured sensitivity and lowering the measured specificity in relation to their true values. Mathematical corrections can be applied to estimate corrected values (84–86).
Diagnostic testing is most valuable when the pretest probability of IHD is intermediate—for example, when a 50-year-old man has atypical angina, and the probability of IHD is approximately 50% (Table 9). The precise definition of intermediate probability (i.e., between 10% and 90%, 20% and 80%, or 30% and 70%) is somewhat arbitrary. In addition to these boundaries, other factors are important in the decision to refer a patient to testing, including the degree of uncertainty acceptable to the physician and patient; the likelihood of an alternative diagnosis; the accuracy of the diagnostic test selected (i.e., sensitivity and specificity), test reliability, procedural cost, and the potential risks of further testing; and the benefits and risks of treatment in the absence of additional testing. A definition of 10% and 90%, first advocated in 1980 (87), has been applied in several studies (88,89). Although broad, this range still excludes several sizable patient groups (e.g., older men with typical angina and younger women with nonanginal pain). When the probability of IHD is high, a positive test result is merely confirmatory, whereas a negative test result might not diminish the probability of disease sufficiently to be clinically useful and could even be misleading because of the possibility that it is a false negative result. When the probability of IHD is very low, however, a negative test result is simply confirmatory, whereas a positive test result might not be clinically useful and could be misleading if falsely positive. The importance of relying on clinical judgment and refraining from testing in very low-risk populations is well illustrated by a thought experiment proposed by Diamond and Kaul in a letter to the editor of The New England Journal of Medicine:
“As an example, suppose we have a test marker with 80% sensitivity and 80% specificity (typical of cardiac stress tests). Given 100 individuals with a10% disease prevalence, there will be 8 true positives (100 × 0.1 × 0.8) and 18 false positives (100 × 0.9 × 0.2). If we refer only these 26 positive responders for angiography, the observed “diagnostic yield” is only 31% (8/26). Moreover, the test's sensitivity will appear to be 100% (all diseased subjects having a positive test), and its specificity will appear to be 0% (all non-diseased subjects also having a positive test). Hence, the more we rely on a test, the less well it appears to perform.” (90, p. 93)
The likelihood of CAD proposed above differs substantially from that in the populations from which the estimates of noninvasive test performance were derived; the overall prevalence of CAD from a meta-analysis was 60% (91). Instead, contemporary age-, sex-, and symptom-based IHD probability estimates can be gleaned from a multicenter cohort of 14,048 patients with suspected IHD undergoing CCTA (92).
18.104.22.168 Safety and Other Considerations Potentially Affecting Test Selection
All forms of noninvasive stress testing carry some risk. Maximal exercise testing is associated with a low but finite incidence of cardiac arrest, AMI, and even death. Pharmacological stress agents fall into 2 broad categories: beta-agonists such as dobutamine, which increase heart rate and inotropy, and vasodilators such as adenosine, dipyridamole, or regadenoson, which act to increase blood flow to normal arteries while decreasing perfusion to stenotic vessels. Each of these pharmacological stress agents also carries a very small risk of drug-specific adverse events (dobutamine: ventricular arrhythmias; dipyridamole/adenosine: bronchospasm in chronic obstructive pulmonary disease).
Nuclear perfusion imaging and CCTA use ionizing radiation techniques for visualizing myocardial perfusion and anatomic CAD, respectively. Risk projections are based largely on observations from atomic bomb survivors exposed to higher levels of ionizing radiation. The Linear-No-Threshold hypothesis states that any exposure could result in an increased projected cancer risk and that there is a dose–response relationship to elevated cancer risk with higher exposures. Considerable controversy exists surrounding the extrapolation of projected cancer risk to low-level exposure in medical testing, and no reported evidence links low-level exposure to observed cancer risk. Even when the Linear-No-Threshold hypothesis is used, the projected incident cancer is estimated to be very low for nuclear MPI and CCTA (93–95). Nevertheless, general agreement exists that the overriding principle of caution and safety should apply by projecting the Linear-No-Threshold hypothesis.
The principle of As Low as Reasonably Achievable (ALARA) should be applied in all patient populations. For CCTA performed with contemporary equipment in accordance with the Society of Cardiovascular Computed Tomography recommendations, average estimated radiation dose ranges from 5 to 10 mSv (96). For stress nuclear MPI, when the American Society of Nuclear Cardiology–recommended rest-stress Tc-99m SPECT or Rb-82 positron emission tomography (PET) protocol (97) is used, the estimated radiation dose is approximately 11 or 3 mSV, respectively (97,98). On the basis of American Society of Nuclear Cardiology guidelines, dual-isotope or rest-stress Tl-201 imaging is discouraged for diagnostic procedures because of its high radiation exposure. The use of new high-efficiency nuclear MPI cameras results in a similar or lower effective dose for both dual-isotope and rest-stress Tc-99m imaging (99–101). For both CT and nuclear imaging, the AHA, Society of Cardiovascular Computed Tomography, and American Society of Nuclear Cardiology recommend widespread application of dose-reduction techniques whenever possible (96–98). Clinicians should apply the concept of benefit-to-risk ratio when considering testing. When testing is used appropriately, the clinical benefit in terms of supportive diagnostic or prognostic accuracy exceeds the projected risk such that there is an advantage to testing (13,14). When it is used inappropriately or overused, the benefit of testing is low, and the risk of exposure is unacceptably high. Of note, care should be taken when exposing low-risk patients to ionizing radiation. This is particularly of concern in younger patients for whom the projected cancer risk is elevated (102).
Use of contrast agents with CCTA can cause allergic reactions. Contrast agents also can affect renal function and therefore should be avoided in patients with chronic kidney disease. CMR might be contraindicated in patients with claustrophobia or implanted devices, and use of gadolinium contrast agents is associated rarely with nephrogenic systemic fibrosis. For this reason, gadolinium is contraindicated in patients with severe renal dysfunction (estimated glomerular filtration rates <30 mL/min per 1.73 m2), and the dose should be adjusted for patients with mild to moderate dysfunction (estimated glomerular filtration rates 30 to 60 mL/min per 1.73 m2). As with all safety considerations, the potential risks need to be considered carefully in concert with the potential benefits from the added information obtained to guide care.
In addition to pretest likelihood, a variety of clinical factors influence noninvasive test selection (103–105). Chief among these are the patient's ability to exercise, body habitus, cardiac medication use, and ECG interpretability. The decision to add imaging in patients who have an interpretable ECG and are capable of vigorous exercise is important because imaging and nonimaging testing have different diagnostic accuracies, predictive values, and costs. Most, but not all, studies evaluating cohorts of patients undergoing both exercise ECG and stress imaging have shown that the addition of imaging information provides incremental benefit in terms of both diagnostic and prognostic information with an acceptable increase in cost (Section 22.214.171.124) (106–117).
Other factors affecting test choice include local availability of specific tests, local expertise in test performance and interpretation, the presence of multiple diagnostic or prognostic questions better addressed by one form of testing over another, and the existence of prior test results (especially when prior images are available for comparison). Finally, although echocardiographic, radionuclide, and CMR stress imaging can have complementary roles for estimating patient prognosis, there is rarely a reason to perform multiple tests in the same patient, unless the results of the initial imaging test are unsatisfactory for technical reasons or the findings are equivocal or require confirmation.
126.96.36.199 Exercise Versus Pharmacological Testing
When a patient is able to perform routine activities of daily living without difficulty, exercise testing to provoke ischemia is preferred because it often can provide a higher physiological stress than would be achieved by pharmacological testing. This can translate into a superior ability to detect ischemia as well as providing a correlation to a patient's daily symptom burden and physical work capacity not offered by pharmacological stress testing. In addition, exercise capacity alone is a very strong prognostic indicator (118,119).
The goal of exercise testing for suspected SIHD patients is 1) to achieve high levels of exercise (i.e., maximal exertion), which in the setting of a negative ECG generally and reliably excludes obstructive CAD, or 2) to document the extent and severity of ECG changes and angina at a given workload (i.e., demand ischemia) so as to predict the likelihood of underlying significant or severe CAD. Thus, candidates for exercise testing must possess sufficient functional capacity to attain maximal, volitional stress levels. Because there is high variability in age-predicted maximal heart rate among subjects of identical age (120), achieving 85% of age-predicted maximal heart rate might not indicate sufficient effort during exercise testing and should not be used as a criterion to terminate a stress test (121). Failure to reach peak heart rate (if beta blockers have been held as recommended) or to achieve adequate levels of exercise in the setting of a negative ECG is consistent with functional disability and results in an indeterminate estimation of CAD. Female-specific age-predicted maximal heart rate and functional capacity measurements are available (118,122).
Standard treadmill protocols initiate exercise at 3.2 to 4.7 metabolic equivalents (METs) of work and increase by several METs every 2 to 3 minutes of exercise (e.g., modified or standard Bruce protocol). Most activities of daily living require approximately 4 to 5 METs of physical work to perform. Thus, reported limitations in activities of daily living identify a patient who might be unable to perform maximal exercise. Gentler treadmill protocols, with incremental stages of 1 MET, or bicycle stress can help some patients achieve maximal exercise capacity.
Optimal candidates with sufficient physical functioning may be identified as those capable of performing at least moderate physical functioning (i.e., performing at least moderate household, yard, or recreational work and most activities of daily living) and with no disabling comorbidity (including frailty, advanced age, marked obesity, PAD, chronic obstructive pulmonary disease, or orthopedic limitations). Patients incapable of at least moderate physical functioning or with disabling comorbidity should be referred for pharmacological stress imaging. In the setting of submaximal exercise and a negative stress ECG, consideration should be given to performing additional testing with pharmacological stress imaging to evaluate for inducible ischemia.
188.8.131.52 Concomitant Diagnosis of SIHD and Assessment of Risk
Although the primary goal of testing among patients with new onset of symptoms suggesting SIHD is to diagnose or exclude obstructive CAD, the various modalities also can provide additional information about long-term risk (Section 3.3.2), and this prognostic ability may influence the selection of an initial test. Exercise capacity remains one of the strongest indicators of long-term risk (including death) for men and women with suspected and known CAD (118,123–125). In addition, information derived from treadmill exercise (e.g., Duke treadmill score (126,127) and heart rate recovery) provides incremental diagnostic and prognostic information. For this reason, it is preferable to perform exercise stress if the patient is able to achieve a maximal workload. For the exercise-capable patient with a normal baseline ECG, the decision to perform imaging with nuclear or echocardiographic techniques along with stress ECG should be based on many factors, including the likelihood of garnering substantial incremental prognostic information that is likely to alter clinical and therapeutic management.
Estimates of cost-effectiveness of various testing strategies in symptomatic patients have been used to inform responses to rising healthcare costs. However, to be of value, estimates of cost-effectiveness must use contemporary estimates of effectiveness that incorporate considerations of disease prevalence and test accuracy. Furthermore, costs must reflect not only the index test but also the episode of care and the longer-term induced costs and outcomes of diagnosed and undiagnosed SIHD. Ideally, these data would be derived from RCTs or registries designed to compare the effectiveness of testing strategies and observed associated costs. However, in the interim until such evidence is available, mixed methods and decision analytic models provide general estimates of the cost-effectiveness of various forms of testing. Mixed methods use observational evidence of index and downstream procedures, hospitalization, and drug costs and apply cost weights to estimate cumulative costs (128–130), whereas decision analytic models simulate clinical and financial data (131–137). Regardless of the approach, inherent assumptions and uncertainties with regard to the data and incomplete consideration of risks and benefits require that such calculations be considered as estimates only (138).
In most studies, stress imaging is estimated to provide a benefit over exercise ECG at a reasonable cost, commensurate with accepted values for cost effectiveness (i.e., at the threshold for economic efficiency of <$50,000 per added year of life), a result driven primarily by more frequent angiography and adverse cardiovascular events for those with a negative exercise ECG. Results of decision analytic and mixed modeling approaches comparing stress echocardiography with myocardial perfusion SPECT vary, with some favoring exercise echocardiography and others favoring exercise nuclear MPI (128,133).
The patient's pretest likelihood of CAD also influences cost-effectiveness such that exercise echocardiography is more cost-effective in lower-risk patients (with annual risk of death or MI <2%) than in higher-risk patients, in whom nuclear MPI is more cost-effective. Use of invasive coronary angiography as a first test is not cost-effective in patients with a pretest probability <75% (139,140). Finally, it is important to note that as the reimbursement for stress imaging decreases (it is now less than half the value used in older studies), the relative cost-effectiveness (dollars/quality-adjusted life-year saved) of stress imaging is more favorable than that of exercise ECG, and the comparative advantage of lower- to higher-cost imaging procedures is minimized.
The cost-efficiency of CCTA is less well studied but also depends on disease prevalence (139,140). Data conflict as to whether patients undergoing CCTA as initial imaging modality are less or more likely to undergo invasive coronary angiography or revascularization, although it appears that they have similar or lower rates of adverse cardiovascular events (128,130,141,142). As a result, CCTA performed alone or in combination with functional testing minimizes adverse cardiac events, maximizes quality-adjusted life-years (140,143), and is estimated to be cost-effective.
Although data on cost-effectiveness and patient satisfaction for CMR are limited, evidence suggests that CMR can improve patient management. The German Pilot/European Cardiovascular Magnetic Resonance (EuroCMR) registry of 11,040 consecutive patients evaluated for cardiomyopathy, ischemia, and myocardial viability found that CMR satisfied all requested imaging needs in 86% of patients so that no further imaging was required (144). In the 3,351 stress CMR cases, invasive angiography was avoided in 45%, compared with 18% in patients who underwent nuclear imaging.
2.2.2 Stress Testing and Advanced Imaging for Initial Diagnosis in Patients With Suspected SIHD Who Require Noninvasive Testing: Recommendations
See Table 11 for a summary of recommendations from this section.
184.108.40.206 Able to Exercise
1. Standard exercise ECG testing is recommended for patients with an intermediate pretest probability of IHD who have an interpretable ECG and at least moderate physical functioning or no disabling comorbidity (114,145–147). (Level of Evidence: A)
2. Exercise stress with nuclear MPI or echocardiography is recommended for patients with an intermediate to high pretest probability of IHD who have an uninterpretable ECG and at least moderate physical functioning or no disabling comorbidity (91,132,148–156). (Level of Evidence: B)
1. For patients with a low pretest probability of obstructive IHD who do require testing, standard exercise ECG testing can be useful, provided the patient has an interpretable ECG and at least moderate physical functioning or no disabling comorbidity. (Level of Evidence: C)
2. Exercise stress with nuclear MPI or echocardiography is reasonable for patients with an intermediate to high pretest probability of obstructive IHD who have an interpretable ECG and at least moderate physical functioning or no disabling comorbidity (91,132,148–156). (Level of Evidence: B)
3. Pharmacological stress with CMR can be useful for patients with an intermediate to high pretest probability of obstructive IHD who have an uninterpretable ECG and at least moderate physical functioning or no disabling comorbidity (153,157,158). (Level of Evidence: B)
1. CCTA might be reasonable for patients with an intermediate pretest probability of IHD who have at least moderate physical functioning or no disabling comorbidity (158–166). (Level of Evidence: B)
2. For patients with a low pretest probability of obstructive IHD who do require testing, standard exercise stress echocardiography might be reasonable, provided the patient has an interpretable ECG and at least moderate physical functioning or no disabling comorbidity. (Level of Evidence: C)
Class III: No Benefit
1. Pharmacological stress with nuclear MPI, echocardiography, or CMR is not recommended for patients who have an interpretable ECG and at least moderate physical functioning or no disabling comorbidity (155,167,168). (Level of Evidence: C)
2. Exercise stress with nuclear MPI is not recommended as an initial test in low-risk patients who have an interpretable ECG and at least moderate physical functioning or no disabling comorbidity. (Level of Evidence: C)
220.127.116.11 Unable to Exercise
1. Pharmacological stress with nuclear MPI or echocardiography is recommended for patients with an intermediate to high pretest probability of IHD who are incapable of at least moderate physical functioning or have disabling comorbidity (148–150,152–156). (Level of Evidence: B)
1. Pharmacological stress echocardiography is reasonable for patients with a low pretest probability of IHD who require testing and are incapable of at least moderate physical functioning or have disabling comorbidity. (Level of Evidence: C)
2. CCTA is reasonable for patients with a low to intermediate pretest probability of IHD who are incapable of at least moderate physical functioning or have disabling comorbidity (158–166). (Level of Evidence: B)
3. Pharmacological stress CMR is reasonable for patients with an intermediate to high pretest probability of IHD who are incapable of at least moderate physical functioning or have disabling comorbidity (153,157,158,169–172). (Level of Evidence: B)
Class III: No Benefit
1. Standard exercise ECG testing is not recommended for patients who have an uninterpretable ECG or are incapable of at least moderate physical functioning or have disabling comorbidity (91,132,148–156,161). (Level of Evidence: C)
1. CCTA is reasonable for patients with an intermediate pretest probability of IHD who a) have continued symptoms with prior normal test findings, or b) have inconclusive results from prior exercise or pharmacological stress testing, or c) are unable to undergo stress with nuclear MPI or echocardiography (173). (Level of Evidence: C)
1. For patients with a low to intermediate pretest probability of obstructive IHD, noncontrast cardiac CT to determine the CAC score may be considered (174). (Level of Evidence: C)
SeeOnline Data Supplement 1for additional data on diagnostic accuracy of stress testing and advanced imaging for the diagnosis of suspected SIHD.
2.2.3 Diagnostic Accuracy of Nonimaging and Imaging Stress Testing for the Initial Diagnosis of Suspected SIHD
18.104.22.168 Exercise ECG
The exercise ECG has been the cornerstone of diagnostic testing of SIHD patients for several decades. The diagnostic endpoint for an ischemic ECG is ≥1 mm horizontal or down-sloping (at 80 ms after the J point) ST-segment depression at peak exercise. ST-segment elevation (in a non–Q-wave lead and excluding aortic valve replacement) during or after exercise occurs infrequently but represents a high-risk ECG finding consistent with an ACS. The diagnostic accuracy of exertional ST-segment depression has been studied extensively in several meta-analyses, systematic reviews, large observational registries, and RCTs (114,145–147,175). The composite diagnostic sensitivity and specificity, unadjusted for referral bias, is 61% and ranges from 70% to 77%, but it is lower in women (146,147,175) and lower than that for stress imaging modalities. A similar accuracy has been reported for correlation of ECG ischemia with anatomic CAD by CCTA (176). Diagnostic accuracy is improved when consideration is given to additional non-ECG factors, such as exercise duration, chronotropic incompetence, angina, ventricular arrhythmias, heart rate recovery, and hemodynamic response to exercise (i.e., drop in systolic BP), or when combination scores such as the Duke treadmill or Lauer scores are applied (118,177–180).
Multiple factors in addition to the patient's inability to achieve maximal exercise levels influence the accuracy of the ECG during exercise testing to diagnose obstructive CAD. Resting ECG abnormalities preclude accurate interpretation of exercise-induced changes and reduce test accuracy; these include abnormalities affecting the ST segment, such as LV hypertrophy, LBBB, ventricular-paced rhythm, or any resting ST-segment depression ≥0.5 mm. Although some have proposed calculating the difference from rest to exercise of changes ≥1 mm for patients with significant resting ST-segment changes, the accuracy of this approach has been less extensively studied and validated. The interpretation of ST-segment changes in patients with right bundle-branch block can be limited, especially in the precordial leads. Certain medications, including digitalis, also influence ST-segment changes and can produce ischemic ECG changes that are frequently false positive findings. In addition, anti-ischemic therapies can reduce heart rate and myocardial workload, and therefore, a lack of ischemic ECG changes can reflect false negative findings when the test is used to diagnose SIHD. It is routine practice to withhold beta-blocker therapy for 24 to 48 hours before testing. Patients who are candidates for an exercise ECG must be able to exercise and must have an interpretable ECG, which is defined as a normal 12-lead ECG or one with minimal resting ST-T-wave abnormalities (<0.5 mm).
22.214.171.124 Exercise and Pharmacological Stress Echocardiography
The diagnostic endpoint of exercise and pharmacological stress echocardiography is new or worsening wall motion abnormalities and changes in global LV function during or immediately after stress. In addition to the detection of inducible wall motion abnormalities, most stress echocardiography includes screening images to evaluate resting ventricular function and valvular abnormalities. This information can be helpful in a symptomatic patient without a proven diagnosis.
Pharmacological stress echocardiography in the United States is performed largely by using dobutamine with an endpoint of inducible wall motion abnormalities (Table 11). Vasodilator agents such as adenosine are used rarely in the United States but are used more commonly in Europe. The diagnostic accuracy of exercise and pharmacological stress echocardiography has been studied extensively in multiple meta-analyses, systematic reviews, and large, multicenter, observational registries (91,148–152,154,175). In several contemporary meta-analyses, the diagnostic sensitivity (uncorrected for referral bias) ranged from 70% to 85% for exercise and 85% to 90% for pharmacological stress echocardiography (91,150,152,154). The uncorrected diagnostic specificity ranges from 77% to 89% and 79% to 90% for exercise and pharmacological stress echocardiography, respectively. The use of intravenous ultrasound contrast agents can improve endocardial border delineation and can result in improved diagnostic accuracy (181). Myocardial contrast echocardiography also has been examined for determination of rest and stress myocardial perfusion, with the results showing comparability to myocardial perfusion SPECT findings in small patient series (182). However, the technique is currently in limited use in the United States.
The diagnostic accuracy of all imaging modalities is influenced by technical factors that could be inherent in the technique (i.e., variable correlation between perfusion and wall motion abnormalities and CAD extent and severity) or that result from physical characteristics of the patient that reduce image quality. For echocardiography, reduced image quality, defined as reduced LV endocardial visualization, has been reported for obese individuals and those with chronic lung disease, although the use of intravenous contrast enhancement results in sizeable improvement in endocardial border delineation.
126.96.36.199 Exercise and Pharmacological Stress Nuclear Myocardial Perfusion SPECT and Myocardial Perfusion PET
Myocardial perfusion SPECT generally is performed with rest and (for exercise or pharmacological stress) with stress Tc-99m agents, with Tl-201 having limited applications (e.g., viability) because of its higher radiation exposure (97). Pharmacological stress generally is used with vasodilator agents administered as a continuous infusion (adenosine, dipyridamole) or bolus (regadenoson) injection. The diagnostic endpoint of nuclear MPI is reduction in myocardial perfusion after stress. Nonperfusion high-risk markers include a markedly abnormal ECG, extensive stress-induced wall motion abnormalities, reduced post-stress left ventricular ejection fraction (LVEF) ≥5% or global LVEF (rest or post-stress) <45%, transient ischemic LV dilation, increased lung or right ventricular uptake, or abnormal coronary flow reserve with myocardial perfusion PET (183–186).
The diagnostic accuracy for detection of obstructive CAD of exercise and pharmacological stress nuclear MPI has been studied extensively in multiple meta-analyses, systematic reviews, RCTs, and large, multicenter, observational registries (91,114,132,147,148,152,155,156,175). From these reports, the uncorrected diagnostic sensitivity ranged from 82% to 88% for exercise and 88% to 91% for pharmacological stress nuclear MPI. The uncorrected diagnostic specificity ranged from 70% to 88% and 75% to 90% for exercise and pharmacological stress nuclear MPI, respectively.
Diagnostic image quality is affected in obese patients, as well as in women and men with large breasts. Reductions in breast tissue artifact have been reported with the use of the Tc-99m agents as well as with attenuation-correction algorithms or prone imaging (187–190). For myocardial perfusion SPECT, global reductions in myocardial perfusion, such as in the setting of left main or 3-vessel CAD, can result in balanced reduction and an underestimation of ischemic burden.
Myocardial perfusion PET is characterized by high spatial resolution of the photon attenuation–corrected images with 82Rubidium or 13N-ammonia used as myocardial blood flow tracers. Although less well studied than myocardial perfusion SPECT, a meta-analysis of 19 studies suggests that PET has a slightly higher (uncorrected) sensitivity for detection of CAD (191,192), including in women and obese patients (193).
188.8.131.52 Pharmacological Stress CMR Wall Motion/Perfusion
In recent years, more centers have used pharmacological stress CMR in the diagnostic evaluation of SIHD patients. The imaging endpoint depends on the stress agent: development of a new wall motion abnormality for cine CMR with dobutamine stress or a new perfusion abnormality with vasodilator stress. From a contemporary meta-analysis of 37 studies, the uncorrected diagnostic sensitivity and specificity of dobutamine-induced CMR wall motion imaging were 83% and 86%, whereas the uncorrected diagnostic sensitivity and specificity of vasodilator stress–induced CMR MPI were 91% and 81% (153). Several small comparative series have reported accuracy data in relation to stress echocardiography and nuclear imaging. Importantly, normal CMR perfusion has a high negative predictive value for obstructive CAD (194). One multicenter study that enrolled 234 patients demonstrated similar diagnostic accuracy between CMR perfusion and SPECT MPI in detecting obstructive CAD (172). More recently, a randomized study of 752 patients directly compared pharmacological stress CMR with SPECT MPI and reported higher sensitivity by pharmacological stress CMR than SPECT MPI in the detection of angiographically significant coronary stenosis (87% versus 67%; p<0.0001) (169). With dobutamine stress, CMR wall motion had high accuracy for detection of obstructive CAD in patients with suboptimal echocardiographic acoustic window (170). CMR dobutamine wall motion imaging demonstrated higher accuracy than dobutamine echocardiography wall motion (171). Although wall motion and perfusion imaging are used to assess the presence and extent of ischemia, most experienced centers also acquire late gadolinium enhancement (LGE) imaging in the same session to delineate the extent and severity of scarred myocardium.
184.108.40.206 Hybrid Imaging
Current imaging is based largely on the use of a single modality, but combined or hybrid applications increasingly are available, which include both PET and CT or SPECT and CT, thus allowing for combined anatomic and functional testing. In addition, newer scanning techniques have allowed assessment of perfusion and FFR by CCTA alone, in addition to coronary anatomy (195–201). Notably, these combined assessments allow for a fused image in which the physiological assessment of flow is coupled with the anatomic extent and severity of CAD and also provides information on plaque composition and arterial remodeling. Limited evidence is available on hybrid imaging, although several reports have reported prognostic accuracy for cardiac events with both ischemic and anatomic markers (202–206). Other combinations of imaging modalities also are being developed, including PET/CMR, which is currently a research application. The strength of combined imaging is the added value of anatomy guiding interpretation of ischemic and scarred myocardium as well as providing information to guide therapeutic decision making. Hybrid imaging also can overcome technical limitations of myocardial perfusion SPECT or myocardial perfusion PET by providing anatomic correlates to guide interpretative accuracy (207) and can provide the functional information that an anatomic technique like CCTA or magnetic resonance angiography lacks; however, radiation dose is increased.
2.2.4 Diagnostic Accuracy of Anatomic Testing for the Initial Diagnosis of SIHD
220.127.116.11 Coronary CT Angiography
With improvements in temporal and spatial resolution as well as volume coverage, evaluation of coronary arteries with CCTA is now possible with a high degree of image quality (208). The extent and severity of angiographic CAD are 2 of the most important prognostic factors and remain essential for revascularization decision making (209). Five meta-analyses and 3 controlled clinical trials have reported the diagnostic accuracy of CCTA with 64-slice CT, yielding sensitivity values ranging from 93% to 97% and specificity values ranging from 80% to 90% (159–166) for detecting obstructive CAD on invasive coronary angiography, unadjusted for referral bias. In a small series of women, the diagnostic accuracy of CCTA was similarly high (210). Prior reports included subsets of patients who already had been referred for invasive angiography, and as such, test performance would be altered by the biases inherent in a preselected population. Factors related to diminished accuracy include image quality, the extent of coronary calcification, and body mass index (BMI) (208).
A potential advantage of CCTA over standard functional testing is its very high negative predictive value for obstructive CAD, which can reassure caregivers that providing GDMT and deferring consideration of revascularization constitute a sensible strategy. In addition to documentation of stenotic lesions, CCTA can qualitatively visualize arterial remodeling and nonobstructive plaque, including calcified, noncalcified, or mixed plaque (211–216). The presence of nonobstructive plaque has been shown to be helpful to guiding risk assessment and can aid in discerning the etiology of patient symptoms (211,215,216). CT information has been correlated with functional stress testing (203,204,215). Not every obstructive lesion produces ischemia, and ischemia can be present in the absence of a significant stenosis in epicardial vessels, which results in discordance between anatomic imaging with CCTA and functional stress testing. Several series have reported the positive predictive value of an anatomic lesion detected on CCTA to range from 29% to 44% when ischemia on a stress study is used as a reference standard (203,204). The evidence on concordance, however, remains incomplete, with current research showing the highest degree of concordance between ischemia and mixed plaque. Because the presence of significant calcification often can preclude the accurate assessment of lesion severity or cause a false positive study, CCTA should not be performed in patients who have known extensive calcification or a high risk of CAD.
18.104.22.168 CAC Scoring
CT also provides measurement of a CAC score, calculated as the product of the CAC area by maximal plaque density (in Hounsfield units) (217). The CAC score frequently has been applied for risk assessment in asymptomatic individuals (5), and it also has been used to predict the presence of high-grade coronary stenosis as the cause of chest pain in symptomatic patients. When the data from 2 large multicenter registries, including a total of 3,615 symptomatic patients, were combined, the estimated diagnostic sensitivity for the CAC score to predict obstructive CAD on invasive angiography was 85%, with a specificity of 75% (218). In a recent meta-analysis of 18 studies, which included 10,355 symptomatic patients, the presence of nonzero CAC score had a pooled sensitivity and specificity of 98% and 40%, respectively, for detection of significant CAD on invasive coronary angiography (174).
Although the diagnostic sensitivity of CAC to detect obstructive CAD is fairly high, the frequency of false negative exams (i.e., significant CAD in the absence of CAC) is not well established. In small single-center studies, perfusion defects on nuclear MPI or high-grade coronary stenosis on coronary angiography can be present in 0% to 39% of symptomatic patients with a calcium score of zero (219–223). In the recent large, multicenter, CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter Registry) registry, CCTA showed mild, nonobstructive CAD in 13%, stenosis ≥50% in 3.5%, and stenosis ≥70% in 1.4% of the 10,037 symptomatic patients without known CAD who had a CAC score of zero (214). Documentation of obstructive CAD without CAC occurs more often in younger patients in whom atherosclerotic plaque has not advanced to the stage of calcification.
Previous official documents from the AHA and ACCF (218) concluded that “patients considered to be at low risk of coronary disease by virtue of atypical cardiac symptoms may benefit from CAC testing to help in ruling out the presence of obstructive coronary disease” (218) or that “coronary calcium assessment may be reasonable for the assessment of symptomatic patients, especially in the setting of equivocal treadmill or functional testing (Class IIb, LOE: B).” The present writing committee believed that additional evidence in sufficiently large cohorts of patients establishing the uncorrected diagnostic accuracy of CAC to rule in or rule out high-grade coronary artery stenosis in symptomatic patients was needed.
22.214.171.124 CMR Angiography
Although not widely applied, CMR angiography has been performed for the detection of the extent and severity of obstructive CAD. As a result of small coronary artery size, tortuosity, and motion, the diagnostic accuracy of CMR angiography is reduced as compared with CCTA (224). A multicenter, controlled clinical trial of patients referred to invasive angiography revealed that magnetic resonance angiography had an 81% negative predictive value for excluding CAD (225). Several meta-analyses that included a total of 59 studies have reported diagnostic sensitivity and specificity ranging from 87% to 88% and 56% to 70%, respectively (158,226), with reports of a lower accuracy than that of CCTA (164). Variability in diagnostic accuracy with CMR angiography has been attributed to a lack of uniformity in pulse sequences and the application of varying analytic methods (227). Recent improvements applying 32-channel 3.0-T CMR have shown comparable abilities to detect CAD as compared with CCTA (228). No recommendations for the use of CMR angiography are included in this guideline.
3 Risk Assessment
3.1 Clinical Assessment
3.1.1 Prognosis of IHD for Death or Nonfatal MI: General Considerations
IHD is a chronic disorder with a natural history that spans multiple decades. The disease typically cycles through clinically defined phases: asymptomatic, stable angina, accelerating angina, and ACS (UA or AMI), although the progression from one state to another is not necessarily linear. The specific approach to assessing risk of subsequent adverse outcomes varies according to the patient's clinical phase, even though for those with SIHD, there is no universally accepted approach. This represents a key area for future research. The approach recommended in the present guideline is informed by the treatment goals of prolonging survival and optimizing health status and by the concept that the benefits of treatment are often proportional to the patient's underlying risk. From this perspective, it is essential to quantify the patient's prognosis as accurately as possible. Several approaches to estimating the risk of cardiovascular mortality or events are provided later in this guideline. In the absence of an established prognostic model, the following considerations are highlighted:
1. Sociodemographic characteristics: Age is the single strongest determinant of survival, whereas ethnicity and sex have conflicting and less important effects on risk. Lower socioeconomic status also is associated with worse outcomes (229).
2. Cardiovascular risk factors: Smoking, hypertension, dyslipidemia, family history of premature CAD, obesity, and sedentary lifestyle confer a greater risk of complications.
3. Coexisting medical conditions: Diabetes mellitus (230), chronic kidney disease (CKD) (231), chronic pulmonary disease, and malignancy are the most important noncardiac conditions to influence prognosis (232–234).
4. Cardiovascular comorbidities: Heart failure, PAD, and cerebrovascular diseases are strong prognostic risk factors for mortality.
5. Psychosocial characteristics: Depression repeatedly has been demonstrated to be strongly and independently associated with worse survival, and anxiety has also been implicated (235–242). Poor social support, poverty, and stress also are associated with adverse prognosis (236,243–245).
6. Health status: Patients' symptoms, functional capacity, and quality of life are associated significantly with survival and the incidence of subsequent ACS (246,247). In a large, prospective cohort of patients in the Veterans Affairs healthcare system, physical limitations due to angina were second only to age in predicting mortality (246).
7. Anginal frequency: Frequency of angina is a very strong predictor of subsequent ACS hospitalizations (246).
8. Cardiac disease severity: The degree and distribution of stenoses measured by coronary angiography, findings on exercise testing and stress imaging, and LV function measured with a variety of technologies all provide meaningful prognostic information that supplements more clinical information.
3.1.2 Risk Assessment Using Clinical Parameters
Although there are several models to predict the likelihood of complications and survival in asymptomatic, general populations and in patients with ACS, there is a relative paucity of information about models for assessing the risk of patients with known SIHD that incorporate a broad range of relevant data. Accurate risk assessment according to clinical variables is essential to determining optimal treatment strategies. Lauer and colleagues developed a risk index that incorporates variables from the history and exercise test on the basis of data from >32,000 individuals (248). They found that their index, which can be calculated by using a nomogram (Figure 8), was better able to predict individuals with a low (<3%) risk of death than was the Duke treadmill score. Daly and colleagues reported an index to estimate risk of death or nonfatal AMI derived from data on an international sample of approximately 3,000 patients who presented with angina and were followed up for 18 months (Figures 9 and 10). Obstructive CAD was documented in one third, whereas another third had negative evaluations. The c statistic for the model was 0.74, which indicates a relatively high level of accuracy (57).
Several risk-assessment schemes have been developed to assist in identifying patients with severe CAD, including left main disease, although several of these studies are up to 2 decades old. One study (70) identified 8 clinical characteristics that are important in estimating the likelihood of severe IHD: typical angina, previous MI, age, sex, duration of chest pain symptoms, risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking), carotid bruit, and chest pain frequency. A subsequent study (71) provided detailed equations to predict both severe IHD and survival on the basis of clinical parameters. One study (249) developed a simple risk score for predicting severe (left main or 3-vessel) CAD that was based on 5 clinical variables: age, sex, history of MI, presence of typical angina, and diabetes mellitus with or without insulin use. This same score was validated subsequently for prognostic purposes (250,251). This score can be easily memorized and calculated (Figure 11) and yields an integer ranging from 0 to 10 (57). The score can be applied to determine if a patient is more suitable for stress testing or possibly (in appropriate patients who are at highest risk) for proceeding directly to coronary angiography. Each curve shows the probability of severe IHD as a function of age for a given cardiac risk score. As shown on the Figure 11 graph, some patients have a high likelihood (>50%) of having severe disease for which revascularization might improve survival on the basis of clinical parameters alone. For example, a 50-year-old male patient who has diabetes mellitus, is taking insulin, and has typical angina and a history of previous MI has a likelihood of severe coronary stenosis >60% and thus might proceed directly to angiography if warranted by his preferences and other clinical factors, although in most circumstances stress testing will assist in planning further tests and treatments (87,252). Creation of valid, quantitative models on the basis of data from current registries and trials to accurately identify patients with anatomic distributions of CAD for which revascularization has been shown to improve survival, such as left main disease, should be a research priority.
Studies have suggested that addition of levels of novel biomarkers such as C-reactive protein and brain natriuretic peptide can improve prediction of mortality and cardiovascular events (5,57). Considerable controversy remains; however, as to whether these tests truly provide incremental information beyond more well-accepted risk factors, and few of the studies have focused on patients with SIHD (253–255). Inflammatory biomarkers, such as myeloperoxidase (256), biochemical markers of lipid-related atherogenic processes [lipoprotein(a), apolipoprotein B, small dense LDL, and lipoprotein-associated phospholipase A2] (257,258), and low levels of circulating troponin detected by high-sensitivity assays (259) also are under investigation as indices of risk in patients with SIHD.
3.2 Advanced Testing: Resting and Stress Noninvasive Testing
3.2.1 Resting Imaging to Assess Cardiac Structure and Function: Recommendations
1. Assessment of resting LV systolic and diastolic ventricular function and evaluation for abnormalities of myocardium, heart valves, or pericardium are recommended with the use of Doppler echocardiography in patients with known or suspected IHD and a prior MI, pathological Q waves, symptoms or signs suggestive of heart failure, complex ventricular arrhythmias, or an undiagnosed heart murmur (21,57,58,260,261). (Level of Evidence: B)
1. Assessment of cardiac structure and function with resting echocardiography may be considered in patients with hypertension or diabetes mellitus and an abnormal ECG. (Level of Evidence: C)
2. Measurement of LV function with radionuclide imaging may be considered in patients with a prior MI or pathological Q waves, provided there is no need to evaluate symptoms or signs suggestive of heart failure, complex ventricular arrhythmias, or an undiagnosed heart murmur. (Level of Evidence: C)
Class III: No Benefit
1. Echocardiography, radionuclide imaging, CMR, and cardiac CT are not recommended for routine assessment of LV function in patients with a normal ECG, no history of MI, no symptoms or signs suggestive of heart failure, and no complex ventricular arrhythmias. (Level of Evidence: C)
2. Routine reassessment (<1 year) of LV function with technologies such as echocardiography radionuclide imaging, CMR, or cardiac CT is not recommended in patients with no change in clinical status and for whom no change in therapy is contemplated. (Level of Evidence: C)
SeeOnline Data Supplement 2for additional data on using resting imaging to assess cardiac structure and function.
In the presence of signs or symptoms suggestive of heart failure, it is imperative to obtain an objective measure of LV function if a prognosis-altering change in therapy could be based on the findings. For example, a rest ejection fraction (EF) <35% is associated with an annual mortality rate >3% per year (260). Resting 2-dimensional echocardiography with Doppler echocardiography is the preferred approach because it provides a thorough assessment of all aspects of cardiac structure and function, including identifying the mechanism of heart failure and differentiating systolic LV from diastolic dysfunction.
Rest imaging also can provide valuable therapeutic guidance and prognostic information in patients without symptoms or signs of ventricular dysfunction or changing clinical status, especially in those with evidence of other forms of heart disease (e.g., hypertensive, valvular). For example, echocardiography can identify LV or left atrial dilation; identify aortic stenosis (a potential non-CAD mechanism for angina-like chest pain); measure pulmonary artery pressure; quantify mitral regurgitation; identify a LV aneurysm; identify a LV thrombus, which increases the risk of death (262); and measure LV mass and the ratio of wall thickness to chamber radius—all of which predict cardiac events and mortality (20,117,263–267).
Although nuclear imaging accurately measures EF, it does not provide additional information on valvular or pericardial disease and requires exposure to ionizing radiation (21,268). Although CMR is applied less widely, it also accurately measures LV performance and provides insight into myocardial and valvular structures (269). Use of delayed hyperenhancement techniques can identify otherwise undetected scarred as well as viable myocardium. Cardiac CT also provides high-resolution detection of cardiac structures and EF. Nevertheless, all 3 tests generally are more expensive than a resting echocardiogram. Although the amount of ionizing radiation required in cardiac CT and nuclear MPI has been lowered over the years and will continue to reduce, the use of these tests for risk assessment is discouraged in patients with low pretest probability of CAD and in young patients.
3.2.2 Stress Testing and Advanced Imaging in Patients With Known SIHD Who Require Noninvasive Testing for Risk Assessment: Recommendations
See Table 12 for a summary of recommendations from this section.
126.96.36.199 Risk Assessment in Patients Able to Exercise
1. Standard exercise ECG testing is recommended for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG (106–110,112–114,132–134). (Level of Evidence: B)
2. The addition of either nuclear MPI or echocardiography to standard exercise ECG testing is recommended for risk assessment in patients with SIHD who are able to exercise to an adequate workload but have an uninterpretable ECG not due to LBBB or ventricular pacing (7,111,264–266,270,299,300). (Level of Evidence: B)
1. The addition of either nuclear MPI or echocardiography to standard exercise ECG testing is reasonable for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG (271–279). (Level of Evidence: B)
2. CMR with pharmacological stress is reasonable for risk assessment in patients with SIHD who are able to exercise to an adequate workload but have an uninterpretable ECG (279–284). (Level of Evidence: B)
1. CCTA may be reasonable for risk assessment in patients with SIHD who are able to exercise to an adequate workload but have an uninterpretable ECG (285,286). (Level of Evidence: B)
Class III: No Benefit
1. Pharmacological stress imaging (nuclear MPI, echocardiography, or CMR) or CCTA is not recommended for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG. (Level of Evidence: C)
188.8.131.52 Risk Assessment in Patients Unable to Exercise
1. Pharmacological stress with either nuclear MPI or echocardiography is recommended for risk assessment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG (7,264–266,287–290). (Level of Evidence: B)
1. Pharmacological stress CMR is reasonable for risk assessment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG (280–284,291). (Level of Evidence: B)
2. CCTA can be useful as a first-line test for risk assessment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG (286).(Level of Evidence: C)
184.108.40.206 Risk Assessment Regardless of Patients' Ability to Exercise
1. Pharmacological stress with either nuclear MPI or echocardiography is recommended for risk assessment in patients with SIHD who have LBBB on ECG, regardless of ability to exercise to an adequate workload (287–290,292). (Level of Evidence: B)
2. Either exercise or pharmacological stress with imaging (nuclear MPI, echocardiography, or CMR) is recommended for risk assessment in patients with SIHD who are being considered for revascularization of known coronary stenosis of unclear physiological significance (266,278,293,294). (Level of Evidence: B)
1. CCTA can be useful for risk assessment in patients with SIHD who have an indeterminate result from functional testing (286). (Level of Evidence: C)
1. CCTA might be considered for risk assessment in patients with SIHD unable to undergo stress imaging or as an alternative to invasive coronary angiography when functional testing indicates a moderate- to high-risk result and knowledge of angiographic coronary anatomy is unknown. (Level of Evidence: C)
Class III: No Benefit
1. A request to perform either a) more than 1 stress imaging study or b) a stress imaging study and a CCTA at the same time is not recommended for risk assessment in patients with SIHD. (Level of Evidence: C)
SeeOnline Data Supplement 2for additional data on risk assessment.
220.127.116.11 Exercise ECG
To assess the risk of cardiovascular events in patients who are able to exercise to an adequate workload and have an interpretable resting ECG, exercise is the preferred stressor because it provides an objective assessment of functional capacity and correlative information with activities of daily living. The occurrence of ST-segment depression at a reduced workload or persisting into recovery coupled with exertional symptoms is associated with a high risk of cardiovascular mortality (302). Other risk markers for mortality include low exercise capacity (generally defined as less than stage II of the Bruce protocol or ≤20% age- and sex-predicted values) (118), failure to increase systolic BP to >120 mm Hg or a sustained >10–mm Hg decrease from resting values during exercise, complex ventricular ectopy or arrhythmias during stress or recovery, and delayed heart rate recovery (e.g., <10- or 12-beats-per-minute reduction in the first minute) (303). The Duke treadmill score and the Lauer nomogram score are validated predictive instruments that incorporate parameters from an exercise ECG test. The Duke treadmill score includes duration of exercise, severity of ST-depression or elevation, and angina (limiting and nonlimiting); has been demonstrated to be highly predictive across an array of patient populations, including women and men with suspected and known SIHD; and has been shown to provide independent risk information beyond clinical data, coronary anatomy, and LVEF (126,177). It stratifies patients into risk groups that could prove useful for patient management, as follows: no further testing for low-risk patients, consideration for invasive testing for high-risk patients, and stress imaging for the intermediate-risk patients. By comparison, the Lauer score incorporates clinical variables, which results in more effective classification of low-risk (<1% annual mortality rate) patients (248).
18.104.22.168 Exercise Echocardiography and Exercise Nuclear MPI
Evidence from thousands of patients evaluated in multiple large registries and clinical trials and meta-analyses confirm that a normal exercise echocardiogram or exercise nuclear MPI is associated with a very low risk of death due to cardiovascular causes or AMI (111,265,304). The extent and severity of inducible abnormalities in wall motion or perfusion are directly correlated with the degree of risk. For nuclear MPI, reversible perfusion defects encompassing 10% of the myocardium (determined either semiquantitatively with summed scores or quantitatively) to assess defect extent and severity are considered moderately abnormal, and reversible perfusion defects encompassing ≥15% of the myocardium are considered severely abnormal (277,305,306). Other findings also indicative of elevated risk include a reduction in reduced post-stress LVEF ≥5% or a global LVEF <45%, transient ischemic LV dilation, increased lung or right ventricular uptake, or abnormal coronary reserve (detected on myocardial perfusion PET). For echocardiography, a wall motion abnormality extending beyond 2 to 3 segments as well as the presence of change in >1 coronary territory are suggestive of higher risk. For both tests, multiple defects in different coronary territories with either moderately reduced perfusion (or ≥10% of the myocardium) or inducible wall motion abnormalities with transient ischemic dilatation are suggestive of severe CAD. Currently, the National Institutes of Health–National Heart, Lung, and Blood Institute–sponsored ISCHEMIA trial is under way and is comparing the effectiveness of a conservative versus catheterization-based initial management strategy for patients with moderate–severe ischemia.
Several large single-center and multicenter registries have demonstrated consistently that both stress nuclear MPI and stress echocardiography provide incremental prognostic value beyond that provided by a standard ECG (115,272,299,305,307–315). The addition of imaging is mandatory for patients who have an uninterpretable baseline ECG (including the presence of LBBB or ventricular pacing, LV hypertrophy, use of digitalis or electrolyte abnormalities, coexisting resting ST-segment abnormality, or preexcitation syndromes) and might be of value in patients with equivocal stress-induced (316) ECG ST changes (317) or an intermediate Duke treadmill score (316). Poornima et al., demonstrated that nuclear MPI has independent prognostic value even in patients with low-risk Duke treadmill scores, but only if there is increased clinical risk, such as a history of typical angina, MI, diabetes mellitus, and advanced age (318,319). Similarly, information from exercise echocardiography appears to provide improved prediction of mortality among patients with low-risk Duke treadmill scores (311,318). From a large registry, the extent of ischemic myocardium as quantified by summed difference score by nuclear MPI has been shown to form an effective prognostic score for the prediction of cardiac mortality (320). Results from exercise nuclear MPI and exercise stress echocardiography appear to provide accurate estimates of the likelihood of death among men and women with suspected and known SIHD and for patients from different ethnic groups (314,321,322).
From a review of large single- and multicenter registries and meta-analyses (111,115,272), the following conclusions can be made:
1. A normal exercise nuclear MPI study or a normal exercise stress echocardiogram during which the age-predicted target heart rate is achieved is associated with a very low annual risk of cardiac death and AMI (generally <1%) in both men and women.
2. Normal and mildly abnormal nuclear MPI or exercise stress echocardiography is associated with a low frequency of referral for coronary revascularization or worsening clinical status and UA admission (1.3% and 1% annually, respectively) (141).
3. Rates of cardiac ischemic events increase in proportion to the degree of abnormalities on stress nuclear MPI or echocardiography, with moderate to severe abnormalities associated with an annual risk of cardiovascular death or MI ≥5% (115,278,279,284,305,306,310,313,314,323–330).
4. For patients with mild abnormalities, coronary angiography might be considered if the patient exhibits other features that might indicate the likelihood of “high-risk” CAD, including low EF on gated nuclear MPI or echocardiographic imaging (331) or transient ischemic dilatation of the left ventricle (332).
5. Moderate to severe abnormalities, such as abnormal wall motion in ≥4 segments or multivessel abnormalities, indicate an increased risk (range: 6- to 10-fold) over that of patients with a normal stress imaging study (271).
Nonetheless, the current literature with regard to exercise nuclear MPI or exercise echocardiography should be clarified in several ways. Although a normal exercise nuclear MPI or exercise echocardiogram usually is associated with a low annual risk of cardiac death or AMI, the negative predictive value is reduced among patients with a higher pretest likelihood of CAD (111,115,279,284,305,306,310,313,314,323–328,330). Furthermore, although trials have shown that imaging is useful to detect ischemia and guide intervention in patients with SIHD and that a reduction in ischemia by stress nuclear MPI is associated with an observed (unadjusted) event-free survival (306,333), there is no trial evidence comparing the effectiveness of a strategy of imaging testing for risk stratification versus a strategy of nontesting in patients with SIHD.
22.214.171.124 Dobutamine Stress Echocardiography and Pharmacological Stress Nuclear MPI
In one third to one half of patients who undergo risk assessment, exercise stress is not recommended because of an inability to exercise or an abnormal ECG. Similar to exercise echocardiography, multiple large single-center reports have shown that dobutamine stress echocardiography accurately classifies patients into high-risk and very-low-risk groups. A normal dobutamine echocardiogram is associated with a risk of an adverse cardiac event of 1% to 2% (312,334). Classification as high risk by dobutamine stress echocardiography is most reliable when ischemia is detected in the territory of the LAD and is somewhat less reliable in patients with diabetes mellitus (335). In specialized centers, either quantification of strain rate or myocardial contrast enhancement on dobutamine echocardiography has been shown to provide information that supplements the wall motion score alone in predicting cardiac mortality (336). Dobutamine echocardiography also has been used extensively in risk-stratifying patients with SIHD undergoing noncardiac vascular surgery. Because the risk of a cardiac event in the perioperative period is quite low, the positive predictive value of dobutamine echocardiography is also low, although the negative predictive value of a normal result is very high and is associated with a very low likelihood of a perioperative event (337,338).
Similar to exercise SPECT, vasodilator stress nuclear MPI has been shown to effectively assess risk of subsequent events in patients with SIHD, with a low annualized event rate of 1.6% observed in patients with a normal adenosine SPECT versus 10.6% in patients with a severely abnormal study (summed stress score >13) (339). This event rate also was observed in elderly patients with normal pharmacological SPECT (340,341). Because of greater comorbidity in patients who cannot exercise, the annualized event rate of patients who had a normal pharmacological stress nuclear MPI increase the event rate nearly 2-fold higher than that of exercising patients who had a normal nuclear MPI, after adjustment for age and comorbidity (342). Additional nonperfusion risk markers can be derived from pharmacological stress, including an abnormal ECG, high resting heart rate, and low peak/rest heart rate ratio (276,332). To facilitate clinical risk assessment, a nomogram based on robust risk markers, including LV function and extent of myocardial ischemia by SPECT, has been developed and validated (Appendix 4) (276).
126.96.36.199 Pharmacological Stress CMR Imaging
Although clinical experience with using stress CMR for risk assessment is substantially less than with stress echocardiography and nuclear MPI, available evidence indicates that stress CMR can provide highly accurate prognostic information. On the basis of 16 single-site studies providing data from 7,200 patients (283) (8 of these studies used vasodilator stress perfusion imaging, 6 dobutamine stress CMR cine imaging, and 2 combined stress perfusion and cine imaging), the following general conclusions can be drawn:
1. A normal stress CMR study with either vasodilator myocardial perfusion or inotropic stress cine imaging is associated with a low annual rate of cardiac death or MI, ranging from 0.01% to 0.6% (280,283), and provides accurate risk assessment in patients of either sex (281,343).
2. Detection of myocardial ischemia (by either perfusion or cine imaging) and LGE imaging of infarction appear to provide complementary information.
3. An abnormal stress CMR with evidence of ischemia is associated with elevated likelihood of cardiac death or MI, with hazard ratios ranging from 2.2 to 12 (279,282).
The current evidence related to CMR for risk assessment of patients is limited by the predominance of data collection from tertiary care centers with high experience in CMR, heterogeneity of imaging techniques and equipment, and evolution of interpretative standards.
188.8.131.52 Special Patient Group: Risk Assessment in Patients Who Have an Uninterpretable ECG Because of LBBB or Ventricular Pacing
Isolated “false-positive” reversible perfusion defects of the septum on nuclear MPI due to abnormal septal motion causing a reduction in diastolic filling time have been reported in patients with LBBB without significant coronary stenosis. Compared to patients without LBBB, use of exercise stress in patients with LBBB or ventricular pacing substantially reduced diagnostic specificity (289,292). Although a normal nuclear perfusion scan in this clinical setting is highly accurate in indicating the absence of a significant coronary stenosis and a low risk of subsequent cardiac events (288), an abnormal study can be nondiagnostic (148,287). In patients with LBBB on a rest ECG, dobutamine stress echocardiography is less sensitive but more specific than nuclear MPI in detecting coronary stenosis and provides prognostic information that is incremental to clinical findings (344). One meta-analysis demonstrated that abnormal stress nuclear MPI and stress echocardiography each confer an up to 7-fold increased risk of adverse cardiovascular events (148).
3.2.3 Prognostic Accuracy of Anatomic Testing to Assess Risk in Patients With Known CAD
184.108.40.206 Coronary CT Angiography
Given the high accuracy in detecting angiographically significant coronary stenosis, estimates of cardiovascular risk according to the Duke CAD index with data obtained via CCTA appear to be as accurate as those obtained from cardiac catheterization. However, the actual event rates in patients undergoing CCTA have been substantially lower because of differences in the underlying risk profiles of patient groups that have been referred for these 2 procedures (345). Furthermore, data from CONFIRM suggest that the finding of nonobstructive CAD on CCTA supplements clinical information in predicting risk of mortality (286). For example, 20% to 25% of patients with an intermediate pretest likelihood of risk (1% to 3% annual mortality rate) based on clinical information (without EF) were reassigned to a different risk category according to information from CCTA. Given that failed bypass grafts can result in unprotected CAD, which confers a higher risk, the assessment of the extent of graft patency by CCTA is also of prognostic value (346,347). Although exercise stress testing in general is preferred in risk assessment, for patients unlikely to achieve conclusive results, consensus opinion suggests that it is reasonable to proceed with a CCTA for risk-assessment purposes.
Several ongoing trials are comparing the prognostic values of CCTA and functional imaging modalities such as nuclear MPI and stress echocardiography (348). At present, there are no prospectively gathered trial data demonstrating that CCTA leads to better patient selection for medical or invasive intervention or to better clinical outcomes.
3.3 Coronary Angiography
3.3.1 Coronary Angiography as an Initial Testing Strategy to Assess Risk: Recommendations
1. Patients with SIHD who have survived sudden cardiac death or potentially life-threatening ventricular arrhythmia should undergo coronary angiography to assess cardiac risk (349–351). (Level of Evidence: B)
2. Patients with SIHD who develop symptoms and signs of heart failure should be evaluated to determine whether coronary angiography should be performed for risk assessment (352–355). (Level of Evidence: B)
3.3.2 Coronary Angiography to Assess Risk After Initial Workup With Noninvasive Testing: Recommendations
1. Coronary arteriography is recommended for patients with SIHD whose clinical characteristics and results of noninvasive testing indicate a high likelihood of severe IHD and when the benefits are deemed to exceed risk (59,126,260,310,356–362). (Level of Evidence: C)
1. Coronary angiography is reasonable to further assess risk in patients with SIHD who have depressed LV function (EF <50%) and moderate risk criteria on noninvasive testing with demonstrable ischemia (363–365). (Level of Evidence: C)
2. Coronary angiography is reasonable to further assess risk in patients with SIHD and inconclusive prognostic information after noninvasive testing or in patients for whom noninvasive testing is contraindicated or inadequate. (Level of Evidence: C)
3. Coronary angiography for risk assessment is reasonable for patients with SIHD who have unsatisfactory quality of life due to angina, have preserved LV function (EF >50%), and have intermediate risk criteria on noninvasive testing (306,366). (Level of Evidence: C)
Class III: No Benefit
1. Coronary angiography for risk assessment is not recommended in patients with SIHD who elect not to undergo revascularization or who are not candidates for revascularization because of comorbidities or individual preferences (306,366). (Level of Evidence: B)
2. Coronary angiography is not recommended to further assess risk in patients with SIHD who have preserved LV function (EF >50%) and low-risk criteria on noninvasive testing (306,366). (Level of Evidence: B)
3. Coronary angiography is not recommended to assess risk in patients who are at low risk according to clinical criteria and who have not undergone noninvasive risk testing. (Level of Evidence: C)
4. Coronary angiography is not recommended to assess risk in asymptomatic patients with no evidence of ischemia on noninvasive testing. (Level of Evidence: C)
Coronary angiography defines coronary anatomy, including the location, length, diameter, and contour of the epicardial coronary arteries; the presence and severity of coronary luminal obstruction(s); the nature of the obstruction; the presence and extent of angiographically visible collateral flow; and coronary blood flow. Despite the ability of newer noninvasive imaging modalities such as CT angiography to visualize and characterize the coronary tree, invasive coronary angiography currently remains the “gold standard.” Coronary angiography has 2 clinical goals: 1) to assess a patient's risk of death and future cardiovascular events through characterization of the presence and extent of obstructive CAD and 2) to ascertain the feasibility of percutaneous or surgical revascularization. The likelihood that revascularization might decrease angina and improve a patient's quality of life should be considered when a patient deems his or her quality of life unsatisfactory despite a conscientious program of evidence-based medical therapy.
The most commonly used nomenclature for defining coronary anatomy is that which was developed for CASS (367) and further modified by the BARI study group (368). This scheme is based on the assumption that there are 3 major coronary arteries: the LAD, the circumflex, and the right coronary artery, with a right-dominant, left-dominant, or codominant circulation. The extent of disease is defined as 1-vessel, 2-vessel, 3-vessel, or left main disease, with a significant stenosis ≥70% diameter reduction. Left main disease, however, also has been defined as a stenosis ≥50%.
Despite being recognized as the traditional “gold standard” for clinical assessment of coronary atherosclerosis, coronary angiography is not without limitations. First, the technical quality of angiograms in many settings can make accurate interpretation difficult or impossible. In a random sample of >300 coronary angiograms performed in New York State during the 1990s, 4% were of unacceptable quality, and 48% exhibited technical deficiencies that could interfere with accurate interpretation (369). Although more modern techniques and equipment likely have eliminated some of these deficiencies, few studies have addressed this issue, particularly in patients who present technical challenges, such as those who are obese. Second, problems also exist with interobserver reliability. These investigators also found only 70% overall agreement among readers with regard to the severity of stenosis, and this was reduced to 51% when restricted to coronary vessels rated as having some stenosis by any reader. Third, angiography in isolation provides only anatomic data and is not a reliable indicator of the functional significance of a given coronary stenosis unless a technique such as FFR (discussed below) is used to provide information about the physiological significance of an anatomic stenosis. Lastly, coronary angiography does not distinguish between a vulnerable plaque, with a large lipid core, thin fibrous cap, and increased macrophages, and a stable plaque that does not exhibit these features. Serial angiographic studies performed before and after acute events and early after MI suggest that plaques resulting in UA and MI commonly were found to be <50% obstructive before the acute event and were therefore angiographically “silent” (370,371). Diagnostic testing to determine vulnerable plaque, and therefore the subsequent risk for MI, remains intensely studied, but no “gold standard” yet has emerged (372). Despite these limitations of coronary angiography, the extent and severity of CAD remain very significant predictors of long-term patient outcomes (Table 13) (55,70,71,373,374).
For patients who are found to be at high risk of coronary events or death on the basis of clinical data and noninvasive testing, coronary angiography is often warranted to provide a more complete risk assessment even though cardiac symptoms might not be severe. Certain clinical characteristics, though relatively infrequent in patients with IHD, have been associated with a high likelihood of severe disease, including the following: chest pain leading to pulmonary edema, chest pain associated with lightheadedness, syncope or hypotension, exertional syncope, and an exercise-induced gallop sound on cardiac auscultation. In addition to clinical signs and symptoms, findings on noninvasive studies could also suggest that certain patients are at high risk of serious cardiac events. These findings include abnormal physiological response to exercise or imaging studies that suggest extensive myocardial ischemia (Table 14). Some examples from Table 14 (high-risk category) which may suggest somewhat less extensive myocardial ischemia: CCTA 2-vessel disease, CAC score >400 Agatston units, severe resting LV dysfunction (LVEF <35%) not readily explained by noncoronary causes, stress defects at 10% level, 2 coronary beds wall motion abnormality on stress echocardiography but only 2 segments.
Coronary angiography helps to quantify risk on the basis of an anatomic prognostic index; the simplest and most widely used is the classification of disease into 1-, 2-, or 3-vessel or left main CAD (358,375–377). In the CASS registry (364) of medically treated patients, the 12-year survival rate of patients with normal coronary arteries was 91%, compared with 74% for those with 1-vessel disease, 59% for those with 2-vessel disease, and 40% for those with 3-vessel disease. The probability of survival declines progressively with the number of coronary arteries that are occluded. The presence of severe proximal LAD artery disease significantly reduces the survival rate. The 5-year survival rate with 3-vessel disease plus >95% proximal LAD stenosis was reported to be 59%, as compared with a rate of 79% for 3-vessel disease without LAD stenosis (Table 13).
With the use of data accumulated in the 1980s, a nomogram was developed to predict 5-year survival rate on the basis of clinical history, physical examination, coronary angiography, and LVEF (Figure 12). The importance of considering clinical factors and especially LV function in estimating the risk of a given coronary angiographic finding is illustrated by comparing the predicted 5-year survival rate of a 65-year-old man with stable angina, 3-vessel disease, and normal ventricular function with that of a 65-year-old man with stable angina, 3-vessel disease, heart failure, and an EF of 30%. The 5-year survival rate for the former was estimated to be 93%, whereas patients with the same characteristics but with heart failure and reduced EF had a predicted survival rate of only 58%. Because of advances in treatment, it is almost certain that the survival rate has improved since these studies were conducted, but the relative differences in survival likely persist.
The development of symptomatic LV failure in a patient with SIHD is often an indication of severe, obstructive CAD and demands expeditious evaluation for the presence of active ischemia. Depending on the acuity and severity of symptoms, angiography or evaluation for ischemia with noninvasive testing is warranted.
An additional, but less quantifiable, benefit of coronary angiography and LV function assessment derives from the ability of experienced angiographers to integrate the findings on coronary angiography and left ventriculography to estimate the potential benefit of revascularization strategies discussed below. The characteristics of coronary lesions (e.g., stenosis severity, length, complexity, and presence of thrombus), the number of lesions posing jeopardy to regions of contracting myocardium, the possible role of collaterals, and the mass of jeopardized viable myocardium also can afford some insight into the consequences of subsequent vessel occlusion. For example, a patient with a noncontracting inferior or lateral wall and severe proximal stenosis of a very large LAD artery is presumably at substantial risk of developing cardiogenic shock if the LAD artery were to become occluded.
In view of the importance of proximal versus distal coronary stenoses, a “jeopardy score” has been developed, which takes the prognostic significance of a lesion's location into consideration (378). Angiographic studies indicate that a direct correlation also exists between the angiographic severity of CAD and the amount of angiographically insignificant plaque buildup elsewhere in the coronary tree. These studies suggest that the higher mortality rate of patients with multivessel disease could occur because they have more mildly stenotic or nonstenotic plaques that are potential sites for acute coronary events than do patients with 1-vessel disease (379).
For many years, it has been known that patients with severe stenosis of the left main coronary artery have a poor prognosis when treated medically. A gradation of worsening risk also has been found with increasing degrees of stenosis of the left main in medically managed patients (380–382). Angiographic determination of the significance of left main disease can be difficult, with suboptimal intraobserver agreement with regard to the degree of severity of any given stenosis (381,383,384). However, multiple other modalities are available to the angiographer to assist in accurately determining the significance of a left main lesion (i.e., FFR and intravascular ultrasound). Despite the challenges posed by angiographic determination of left main disease, it remains the best option for the diagnosis and reevaluation of left main disease if concern exists about progression of previously diagnosed disease because of the inability to consistently detect and evaluate this condition with noninvasive testing or clinical assessment (385–390).
4.1 Definition of Successful Treatment
The paramount goals of treating patients with SIHD are to minimize the likelihood of death while maximizing health and function. The more specific objectives are to:
• Reduce premature cardiovascular death;
• Prevent complications of SIHD that directly or indirectly impair patients' functional well-being, including nonfatal AMI and heart failure;
• Maintain or restore a level of activity, functional capacity, and quality of life that is satisfactory to the patient;
• Completely, or nearly completely, eliminate ischemic symptoms; and
• Minimize costs of health care, in particular by eliminating avoidable adverse effects of tests and treatments, by preventing hospital admissions, and by eliminating unnecessary tests and treatments.
These goals are pursued with 5 fundamental, complementary, and overlapping strategies:
1. Educate patients about the etiology, clinical manifestations, treatment options, and prognosis of IHD, to support active participation of patients in their treatment decisions.
2. Identify and treat conditions that contribute to, worsen, or complicate IHD.
3. Effectively modify risk factors for IHD by both pharmacological and nonpharmacological methods.
4. Use evidence-based pharmacological treatments to improve patients' health status and survival, with attention to avoiding drug interactions and side effects.
5. Use revascularization by percutaneous catheter-based techniques or CABG when there is clear evidence of the potential to improve patients' health status and survival.
4.2 General Approach to Therapy
The writing committee has constructed these guidelines from the perspective that when making decisions about diagnostic tests and therapeutic interventions, their potential effects on improving survival and health status should be considered independently. Although treatment choices often are intended to achieve both goals simultaneously, circumstances exist in which a treatment is administered in pursuit of only one of these goals. For example, when pharmacotherapy such as aspirin or angiotensin-converting enzyme (ACE) inhibitors is prescribed, the goal is to improve survival but not necessarily quality of life. Similarly, revascularization can be performed to improve symptoms, even when there is no expectation of improved survival. Occasionally, treatment recommendations related to achieving these goals can be at odds, such as when a patient is encouraged to take a medication that significantly reduces the risk of death even though it causes mild or moderate adverse side effects.
It might also be the case that a patient expresses a preference for a treatment approach (e.g., PCI) when the practitioner believes another approach (e.g., GDMT) would be preferable. Although practitioners always should engage patients in a detailed discussion about their individual goals and values in order to tailor therapy, this is particularly important when therapeutic goals or the patient's or provider's preferences are not aligned. It is essential that these discussions be conducted in a location and atmosphere that permits adequate time for discussion and contemplation. Initiating a discussion about the relative merits of medical therapy versus revascularization while a patient is in the midst of procedure, for example, is not usually consistent with these principles.
Reducing the risk of mortality should be pursued as intensively as is sensible for all patients with SIHD. It has been estimated that nearly half of the dramatic decline in cardiovascular mortality observed during the past 40 years is attributable to interventions directed at modifying risk factors. Of this change, 47% can be attributed to treatments, including risk factor reduction after AMI, other guideline-based treatments for UA and heart failure, and revascularization for chronic angina (391). An additional 44% reduction in age-adjusted death is attributed to population-based changes in risk factors (391). Unfortunately, these changes have been offset somewhat by increases in BMI and type 2 diabetes mellitus, which result in an increased number of deaths (391).
The 2011 secondary prevention and risk reduction therapy statement (8) summarizes the key interventions known to improve survival and prevent subsequent cardiac events. Worldwide, it has been estimated that 90% of the risk of MI is attributable to 9 measureable risk factors, including smoking, diabetes mellitus, hypertension, obesity, impaired psychological well-being, poor diet, lack of exercise, alcohol consumption, and dyslipidemia (392). The initial approach to all patients should be focused on eliminating unhealthy behaviors such as smoking and effectively promoting lifestyle changes (e.g., maintaining a healthy weight, engaging in physical activity, adopting a healthy diet [Figure 4]). In addition, for most patients, an evidence-based set of pharmacological interventions is indicated to reduce the risk of future events. The presumed mechanism by which these interventions work is stabilization of the coronary plaque to prevent rupture and thrombosis (8). These include antiplatelet agents (393), statins (394–401), and beta blockers, along with other agents if indicated, to control hypertension (402,403). ACE inhibitors are indicated in many patients with SIHD, especially those with diabetes mellitus or LV dysfunction (296,301,404). Similarly, tight glycemic control not only has not been shown to reduce the risk of macrovascular complications in patients with type 2 diabetes mellitus, it also appears to increase the risk of cardiovascular death and complications. Nonetheless, weight loss, aerobic exercise, an AHA Step II diet, and ACE inhibitors in patients with diabetes mellitus with proteinuria all can improve patients' risks of microvascular complications and, potentially, cardiac events.
For the purposes of this guideline, the writing committee elected to retain the classification for risk of cardiovascular events that has been accepted by consensus over the past 2 decades. Patients with a predicted annual cardiac mortality rate of <1% per year are considered to be at low risk, those with a predicted rate of 1% to 3% per year are considered to be at intermediate risk, and those with a predicted average >3% per year are considered to be at high risk.
For patients at high risk of mortality, the prevalence of severe CAD (e.g., left main coronary occlusion) is higher, and coronary angiography can define the coronary anatomy and help to plan further therapy beyond standard GDMT (Figure 5). If the patient is at low or intermediate risk for mortality, therapeutic decisions should be directed toward improving symptoms and function, and catheterization may be deferred if symptoms can be controlled with medical therapy alone. For patients in whom angiography is performed and who are determined to be at low or intermediate risk, evidence reaffirms that it is safe to defer revascularization and institute a program of evidence-based medical therapy, because neither survival nor adverse cardiac events are averted by proceeding immediately to revascularization (366,397,405–409). If a patient in this category has symptoms that are completely or almost completely relieved with medical therapy, it is usually prudent to continue with medical therapy without proceeding to revascularization. If symptoms persist, however, then a discussion with the patient to elicit his or her preferences and goals is necessary, along with a frank discussion of the benefits and risks of PCI and CABG, to ascertain whether the symptoms have been ameliorated sufficiently to warrant simply continuing with medical therapy alone (Figures 4 and 5).
Coronary revascularization generally improves survival among certain subgroups of patients, particularly those with severe left main coronary stenosis. When revascularization is being considered on an elective basis solely for reducing the risk of death, the healthcare provider should engage the patient in an explicit consideration of the estimated improvement in survival relative to the potential risks and costs of the procedure and related interventions. Because reliable estimates of benefit, such as absolute risk reduction, are frequently unavailable for many specific subgroups, the risk for death can be estimated before treatment and the anticipated absolute risk reduction calculated (obtained by multiplying the RR reduction by the pretreatment risk). In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, in which 1,212 patients with an LVEF ≤35% and CAD amenable to revascularization were randomized to CABG or medical therapy, there was no significant difference in overall mortality rate, but during a median follow-up of 56 months, 28% of those assigned to CABG died of a cardiovascular cause, compared with 33% of those receiving medical therapy (410). This information can be converted to a more interpretable framework, such as the average reduction in risk of events or number needed to treat. In this example, the average reduction in cardiovascular events was 19%, and it would be necessary to perform bypass surgery on about 5 patients with LV dysfunction to prevent 1 cardiovascular death at 5 years (i.e., number needed to treat = 5, calculated as 1 ÷ absolute risk reduction, or 1/0.19 [although there would be no effect on overall mortality rate]). This process complies with the Institute of Medicine's goals for transparently sharing evidence with patients so that they can control (or more actively participate in) their own decisions (411). In general, a beneficial effect of revascularization on survival has been demonstrated most clearly among patients with the highest cardiovascular risk (412). Although traditional methods of risk stratification have relied on coronary anatomy and LV function, other strategies described in this guideline can be used (Figure 5).
The specific anatomic features of the patient and the likelihood of procedural success often influence the approach to a patient for whom revascularization is being considered. For example, a given patient with 1-vessel disease might have coronary anatomic features that would make the risk of PCI high enough and the likelihood of success low enough that CABG or medical therapy would be preferred. In general, complete revascularization leads to better outcomes than incomplete revascularization (413–418). In patients with chronic total occlusion, CABG could be preferable to PCI (419), but this is still controversial. Although the technology and techniques for PCI of chronic total occlusions are improving, there remains no current evidence that survival is improved after successful PCI of a chronic total occlusion. Some patients with diabetes mellitus can have such diffuse disease that neither CABG nor PCI is likely to produce sustained benefits. Other patients can have small-caliber arteries or diffuse disease that is likely to lead to early graft failure. Still others can have long, complex lesions that are very likely to undergo restenosis after PCI, although use of drug-eluting stents (DES) can reduce this risk.
The majority of patients with SIHD have clinical features indicating that revascularization is unlikely to improve life expectancy or the risk of subsequent MI. For such patients, antianginal therapy and intensive treatment for risk factors are recommended before consideration of PCI or CABG to relieve symptoms. A broad range of highly effective drugs is available, including beta blockers, calcium channel blockers, long-acting nitrates, and newer agents such as ranolazine. Comparative trials among these medications are relatively few and for the most part small (420). On the basis of the available data, however, all of the classes of agents appear to be relatively similar in antianginal efficacy, and all have very acceptable profiles of safety and tolerability. Beta blockers have been shown to improve survival in patients after AMI and in patients with hypertension; they provide 24-hour coverage and have a long history of clinical use. For these reasons, the writing committee recommends these agents as first-line drugs for treating angina. In patients who do not tolerate or adequately respond to beta blockers, calcium channel blockers and/or long-acting nitrates may be substituted or added. Ranolazine has been shown to inhibit the late sodium current in humans and has demonstrated lusitropic properties (421). Clinical trials have shown that this agent is comparable to other agents in alleviating angina. Although this agent has been approved by the U.S. Food and Drug Administration (FDA) for first-line use in patients with chronic angina, the writing committee recommends that ranolazine be considered in circumstances in which beta blockers, calcium channel blockers, and nitrates are not adequately effective or are not tolerated.
4.2.1 Factors That Should Not Influence Treatment Decisions
The 2 medical indications for revascularization are to prevent death and cardiovascular complications and to improve symptoms and quality of life. Nonetheless, the use of revascularization has risen dramatically in the past 3 decades. Much of this increase appears to be for indications for which benefits in survival or symptoms in comparison with noninvasive therapies are unlikely (422). National data suggest that about 12% of PCIs could be inappropriate because they lack evident potential to improve either survival or symptoms (423). Several reasons influence patients and physicians to prefer revascularization when the likelihood of benefit is less than the potential risk of the procedure. An ingrained preference for action (i.e., revascularization) over perceived inaction (i.e., medical therapy alone) likely often influences the decision making of both patients and physicians (252). Moreover, some healthcare professionals are unduly pessimistic about survival with conservative medical therapy and inaccurately optimistic about the survival benefits of revascularization procedures (424). As indicated earlier, patients often believe mistakenly that PCI has the potential to prevent AMI and prolong survival (423,425). In addition, the attendant expense and risk of combined antiplatelet therapy for an uncertain period of time might not be fully considered. Physicians are professionally obligated to provide accurate estimates of the risks, benefits, and costs of various therapeutic options that are based on the best available scientific data. Other factors can induce physicians to recommend revascularization. These include medicolegal concerns (often exaggerated) and feeling compelled to satisfy the expectations of patients and referring physicians (which are sometimes misinformed or unrealistic) (426). Additionally, there are well-documented regional variations in the use and appropriateness of cardiac procedures that appear to reflect local practice styles (427). This might partly reflect a mistaken belief by some physicians that “more care is better care” (428). Although successful procedures can be psychologically satisfying to the physician and the patient, this does not justify the attendant economic costs and risk of complications of procedures that offer minimal, if any, genuine benefit (429–431).
Although rarely discussed explicitly, financial incentives seem to affect the willingness of a minority of physicians and institutions to recommend certain procedures or drug therapies. Strong incentives created by the payment system encourage overutilization. Also, a small number of physicians might have financial relationships with the manufacturers of devices or drugs that might represent apparent conflicts that ought to be disclosed to patients. At a higher level, those responsible for the payment system, the manufacturers of devices and drugs, and physicians making clinical decisions must commit to supporting guideline-based interventions. Any and all conflicts of interest must be revealed to patients in the process of informed consent before any invasive or noninvasive procedure.
4.2.2 Assessing Patients' Quality of Life
In addition to interventions undertaken to improve survival and prevent cardiovascular complications, therapy also is prescribed to improve patients' health status, a general term that incorporates many facets, including severity of symptoms, functional limitations, and quality of life. Assessment of health status is often unstructured and exclusively qualitative, but efforts to standardize this assessment are recommended, beginning with a structured inventory of activity, symptoms, and quality of life, supplemented by the use of simple, semiquantitative scales such as the CCS and New York Heart Association classifications (432,433).
The CCS and New York Heart Association classifications are limited, however, because they quantify health status from the physicians' perspective, rather than directly reporting patients' experiences, and they are known to have limited reproducibility and sensitivity to important clinical changes. Furthermore, even these simple classifications of health status are recorded infrequently in health records (432,434). One approach to directly eliciting perceptions of health status from patients with IHD is to use the self-administered Seattle Angina Questionnaire (SAQ), a valid, sensitive, and prognostically important questionnaire, to quantify the symptoms, functional limitations, and quality of life of patients with SIHD (246,247,435). Although such instruments typically are used in research trials, they are readily applicable to clinical practice and can be used serially to assess and monitor the effectiveness of therapy, including antianginal medications and revascularization (434). The formal assessment of a patient's disease-specific health status, through either the CCS or the SAQ, has been endorsed as a performance measure of healthcare quality (436).
4.3 Patient Education: Recommendations
1. Patients with SIHD should have an individualized education plan to optimize care and promote wellness, including:
a. education on the importance of medication adherence for managing symptoms and retarding disease progression (437–439) (Level of Evidence: C);
b. an explanation of medication management and cardiovascular risk reduction strategies in a manner that respects the patient's level of understanding, reading comprehension, and ethnicity (8,440–444) (Level of Evidence: B);
c. a comprehensive review of all therapeutic options (8,441–444) (Level of Evidence: B);
d. a description of appropriate levels of exercise, with encouragement to maintain recommended levels of daily physical activity (8,445–448) (Level of Evidence: C);
e. introduction to self-monitoring skills (445,447,448) (Level of Evidence: C); and
f. information on how to recognize worsening cardiovascular symptoms and take appropriate action. (Level of Evidence: C)
2. Patients with SIHD should be educated about the following lifestyle elements that could influence prognosis: weight control, maintenance of a BMI of 18.5 to 24.9 kg/m2, and maintenance of a waist circumference less than 102 cm (40 inches) in men and less than 88 cm (35 inches) in women (less for certain racial groups) (8,440,449–452); lipid management (18); BP control (17,453); smoking cessation and avoidance of exposure to secondhand smoke (8,454,455); and individualized medical, nutrition, and lifestyle changes for patients with diabetes mellitus to supplement diabetes treatment goals and education (456).(Level of Evidence: C)
1. It is reasonable to educate patients with SIHD about:
a. adherence to a diet that is low in saturated fat, cholesterol, and trans fat; high in fresh fruits, whole grains, and vegetables; and reduced in sodium intake, with cultural and ethnic preferences incorporated (8,17,18,457,458) (Level of Evidence: B);
b. common symptoms of stress and depression to minimize stress-related angina symptoms (459) (Level of Evidence: C);
c. comprehensive behavioral approaches for the management of stress and depression (237,460–462) (Level of Evidence: C); and
d. evaluation and treatment of major depressive disorder when indicated (237,238,437,461,463,464,467,468). (Level of Evidence: B)
Multiple risk factors for heart disease, vascular disease, and stroke are typically present in persons with SIHD, including hypertension, smoking, dyslipidemia, diabetes mellitus, overweight, and physical inactivity (27,392). At a national level, in 2000, only 5% of individuals without IHD and 7% of those with IHD were fully adherent to recommendations for physical activity, fruit and vegetable consumption, and nonsmoking.
The approach to managing risk factors usually requires partnerships among the healthcare team, the patient, their family, and their community. The goal of this partnership is to assure an effective exchange of information, sharing of concerns, and an improved understanding of treatments, with the aim of improving quality of life and health outcomes. The American Academy of Family Physicians defines patient education as “the process of influencing patient behavior through the provision of information and counseling that is designed to produce changes in knowledge, attitudes, and skills necessary to maintain or improve health” (469). The Joint Commission mandates patient education as a principal guiding policy to improve health outcomes. Effective patient education and counseling are based on a collaborative approach that acknowledges individual patient needs through an understanding of cognitive, behavioral, and sociodemographic factors. Patients actively involved in care decisions are more likely to follow a treatment plan and engage in behaviors that can improve their health.
When educating patients, it is important to communicate an understanding of a specific disease process, the need for laboratory testing, medication management and adherence, reporting of efficacy and side effects, and behavioral lifestyle change (8). Unfortunately, the type, intensity, frequency, and duration of educational programs are not well established for individual risk factors. For example, the Ask, Advise, Assess, Assist, and Arrange algorithm for smoking cessation often is used, although supporting data from RCTs are lacking (470). In addition, who should deliver education programs and how to evaluate efficacy are not well studied. In smoking cessation, the most effective intervention continues to be a physician's recommendation for the patient “to quit.” However, quit rates for smoking are also dependent on the appropriate use of medical therapies and group support programs (442,471). In diabetes care, patient education has the potential to be as effective as or more effective than medical therapies (472). The management of hypertension, heart failure, dyslipidemia, type 2 diabetes mellitus, weight loss, and physical activity is enhanced by ongoing health education and support in addition to physician office visits.
Factors that complicate effective patient education include low literacy, adverse sociodemographic factors (e.g., poverty, social isolation, and emotional disorders such as depression), cultural beliefs and language barriers, environmental factors, advanced age, and the presence of complex comorbidities. These factors and others play an important role in the adoption of healthy lifestyles and adherence to recommended medical therapies. In addition, how to best provide cost-effective educational strategies remains a challenge in today's healthcare environment (473). The lack of payment for these activities remains an important barrier. Clinic-based education generally consists of the following:
1. Individual counseling. This educational format commonly is used in the context of a routine clinic visit. It tends to be directive and didactic, generally not interactive or behaviorally oriented, relatively brief, and sometimes supported with written materials. Follow-up to ascertain effectiveness is not commonly practiced.
2. Group education. Group care or shared office visits have been tested in multispecialty group practices. They offer the benefit of providing education to larger numbers of patients with similar diagnoses (e.g., type 2 diabetes mellitus), combined with an individualized physician visit. They tend to be behaviorally oriented with planned follow-up for effectiveness and outcomes.
3. Self-monitoring. Self-monitoring skills enhance patient education and behavior change. Examples such as home BP and blood glucose monitoring and tracking daily calories and physical activity minutes can support important lifestyle change. Review of self-monitoring logs by patient and provider at subsequent clinic visits supports the continued importance of and attention to behavior change. In some healthcare plans, these data can be entered via web portals for patients (474).
4. Internet- and computer-based education. A growing number of health plans provide health information via websites and special programs. This approach is often low in cost to the patient but requires adequate computer access and skills, higher reading levels, and self-motivation to change behavior (e.g., AHA Choose to Move) (475).
5. Hand-held computer devices, smartphones, and other portable devices. Portable devices have the potential to provide motivational reminders and prompts for lifestyle change but have not yet been thoroughly tested.
Present efforts to improve the effectiveness of patient education and lifestyle interventions integrate key constructs related to behavior change theory. A summary of the most common models is provided below:
1. Motivational interviewing, a social learning theory, promotes behavioral change through empathetic and reflective listening, encouraging patients to determine their reasons for change, helping healthcare professionals deal with resistance, and supporting self-efficacy (476).
2. Self-efficacy theory posits that the ability to change behavior depends upon one's self-confidence to perform a specific action (such as walking 30 minutes daily) and the belief that one can persist with this action. Low self-efficacy predicts poor ability to achieve a specified lifestyle change. Improving one's self-efficacy will improve the ability to change a particular lifestyle (477).
3. The Transtheoretical Model of behavior change is based on “stages of change.” The theory relies on the observation that many individuals traverse 5 distinct temporal processes in achieving permanent change. These include precontemplation, contemplation, preparation, action, and maintenance. Application of this model of change entails categorizing an individual's progress in the process of change and recognizing that cycling through phases is common in the process of achieving permanent change (478).
The interventions described above should be provided within a medical environment that provides coordinated, team-based care. Data accumulating from interventions that incorporate principles of the chronic care model (479), such as the patient-centered medical home, have demonstrated beneficial effects not only on intermediate outcomes such as glycemic and BP but also on cost, utilization, and mortality rate (480,481). This approach depends on the active participation of an engaged, informed patient, which in turn relies on the patient's understanding of his or her condition, ability to adhere safely to complex medical therapies, and willingness to communicate on a regular basis with the healthcare team. In addition to counseling about the approach to management of SIHD and risk reduction, patients often seek information about other aspects of their health, particularly issues that are often not directly addressed by healthcare providers.
One such topic that commonly arises is possible restrictions on sexual activity. Regrettably, there are relatively limited scientific data on the cardiovascular demands and potential risks of sexual activity in patients with heart disease, some of it dating back 3 or 4 decades and nearly all of it dealing with men. In general, sexual activity is equivalent to mild to moderate physical activity requiring 3 to 5 METs (i.e., the equivalent of climbing 2 flights of stairs or walking briskly) (482). The few available studies suggest that AMI within 1 to 2 hours of sexual activity is associated with an average RR of 2.7 among middle-aged men, with the greatest risk among those who are sedentary (483–486). Because the overall incidence of AMI is low in the population and periods of exposure relatively infrequent, it has been postulated that the absolute risk is exceedingly low for any individual (487). However, ECG monitoring during sexual activity in 1 study of men with IHD revealed that nearly a third developed ST depression and nearly half developed arrhythmias. It appeared, however, that these findings also were found during similarly stressful activities that did not involve sex, and the arrhythmias were largely benign. Moreover, these patients were not initially on anti-ischemic medications, and it was reported that the ischemic changes on ECG resolved when subjects took beta blockers. Thus, it seems that sexual activity should not necessarily be regarded as appreciably different from other types of physical activity that impose equivalent metabolic demands. Needless to say, patients should be treated to maximize their capacity for physical activity, as described subsequently in this guideline.
Patients often express concerns that medications given to treat symptoms or reduce cardiovascular risk could cause erectile dysfunction. Although these perceptions are often firmly and widely held, studies and reviews have not delineated a clear association between these drugs, including beta blockers, and sexual dysfunction (488–492).
A related issue that could arise is use of phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil, or tadalafil, to improve erectile function. Although, as discussed in the section on treatment of SIHD, current evidence has shown that these drugs do not raise the risk of adverse cardiovascular events in men with SIHD (493,494), there is a clear risk of serious hypotension when they are taken in conjunction with nitrates, and the combination is absolutely contraindicated. There are also potential drug–drug interactions with alpha-blockers that are sometimes used to treat hypertension (495).
4.4 Guideline-Directed Medical Therapy
4.4.1 Risk Factor Modification: Recommendations
220.127.116.11 Lipid Management
1. Lifestyle modifications, including daily physical activity and weight management, are strongly recommended for all patients with SIHD (18,496). (Level of Evidence: B)
2. Dietary therapy for all patients should include reduced intake of saturated fats (to <7% of total calories), trans fatty acids (to <1% of total calories), and cholesterol (to <200 mg/d) (18,497–500). (Level of Evidence: B)
3. In addition to therapeutic lifestyle changes, a moderate or high dose of a statin therapy should be prescribed, in the absence of contraindications or documented adverse effects. (18,398,400,458,501). (Level of Evidence: A)
Epidemiological studies have established serum cholesterol as an important coronary heart disease risk factor. The Framingham Heart Study, Multiple Risk Factor Intervention trial, and the Lipid Research Clinics trials all found a continuous, graded increase in coronary events with increasing LDL cholesterol in men and women who were initially free of IHD (502,506–508). A similar relationship has been observed among patients with SIHD (509–511). The association between LDL cholesterol and cardiovascular risk is curvilinear, or log-linear, meaning that the decrease in RR for a given 1-mg/dL decrease in LDL cholesterol seems to be the same at any level of baseline LDL cholesterol. The principal lipid modification strategy recommended by the NCEP ATP-III (National Cholesterol Education Program Adult Treatment Panel III) in patients with SIHD is the reduction of LDL cholesterol (18,24). This should start with therapeutic lifestyle changes, including dietary therapy, daily physical activity, and weight management. Most patients also will benefit from cholesterol-lowering drug therapy, preferably with a statin.
Effective dietary approaches to lowering LDL cholesterol include replacing saturated and trans fatty acids with dietary carbohydrates or unsaturated fatty acids and reducing dietary cholesterol. Although the response to dietary interventions is variable, a diet low in saturated fat and cholesterol typically lowers LDL cholesterol by 10% to 15% (497–500). Other beneficial dietary interventions can include addition of plant stanols/sterols (2 g/d), which trials suggest lower LDL cholesterol by 5% to 15%, and addition of viscous fiber (>10 g/d), which reduces LDL cholesterol by 3% to 5% (512–515). A 10-lb weight loss reduces LDL cholesterol by 5% to 8% (496). Regular physical activity is also a key component of therapeutic lifestyle modification. Although exercise does not reliably lower LDL cholesterol, it facilitates weight loss and has other beneficial effects on the lipid profile (516–518).
Controlled clinical trials of lipid-lowering drug therapy have demonstrated that lowering of LDL cholesterol is associated with a reduced risk of adverse cardiovascular events. Earlier trials used bile acid sequestrants (cholestyramine), fibric acid derivatives (gemfibrozil and clofibrate), or niacin. More contemporary studies have convincingly established the efficacy of statins in the primary and secondary prevention of coronary events (394–396,398,400,501,519–522). In a prospective meta-analysis published by the Cholesterol Treatment Trialist Collaborators in 2010 that examined data from 26 randomized trials of statin therapy (comparing higher- to lower-dose statin therapy or statin therapy to a control regimen), the mean difference in LDL cholesterol was 31 mg/dL, ranging from 12 to 68 mg/dL. Each 40-mg/dL reduction in LDL cholesterol was associated with a 10% reduction in all-cause mortality and a 20% reduction in coronary mortality, with corresponding reductions in nonfatal MI, need for coronary revascularization, and first nonfatal ischemic stroke (458). The absolute benefit of therapy was a function of an individual's absolute risk of fatal MI (458). In trials comparing higher- to lower-dose statin therapy, the average, weighted reduction in LDL cholesterol at 1 year was 20 mg/dL among those receiving higher-dose regimens. Among patients assigned to more intensive regimens, there was a 15% lower incidence of major vascular events (95% CI: 11 to 18; p<0.0001), which reflected a 13% lower risk of coronary death or nonfatal MI (95% CI: 7 to 19; p<0.0001), a 19% lower risk of undergoing coronary revascularization (95% CI: 15 to 24; p<0.0001), and a 16% lower risk of ischemic stroke (95% CI: 5 to 26; p=0.005). The reductions in serum LDL cholesterol and in cardiovascular risk were similar in magnitude to those observed in trials comparing statin therapy to a control regimen. The absolute benefit of therapy was defined chiefly by an individual's absolute risk of death due to coronary occlusion (458). Appropriate treatment goals for patients with SIHD have been informed by several trials of intensive lipid-lowering therapy. The HPS (Heart Protection Study) compared simvastatin 40 mg daily to placebo in patients with IHD, other occlusive vascular disease, or diabetes mellitus. On-treatment LDL cholesterol levels averaged 88 mg/dL in those allocated to simvastatin and 127 mg/dL in those randomized to placebo. A consistent and early benefit of therapy was demonstrated, with a 13% reduction in mortality rate and an 18% reduction in coronary death rate (398). Similar reductions in RR were observed regardless of baseline levels of LDL cholesterol, including in those with initial levels <116 mg/dL or <97 mg/dL. (Of note, LDL cholesterol levels in the HPS were not drawn with patients in the fasting state and were measured values rather than the calculated values used in clinical practice and in most trials; measured LDL cholesterol is generally about 15% higher than calculated LDL cholesterol) (398). In the TNT (Treating to New Targets) trial, patients with clinically apparent IHD and LDL cholesterol >130 mg/dL were randomly assigned to either 10 mg or 80 mg of atorvastatin per day. The mean LDL cholesterols were 77 mg/dL during treatment with 80 mg of atorvastatin and 101 mg/dL during treatment with 10 mg of atorvastatin. There was a 22% reduction in a composite cardiovascular endpoint and a 20% reduction in cardiac deaths with more intensive therapy but no reduction in all-cause mortality (400). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) study patients with a past history of MI were randomly assigned to intensive lipid-lowering therapy with atorvastatin 80 mg daily or simvastatin 20 mg daily. During treatment, mean LDL cholesterol levels were 104 mg/dL in the simvastatin group and 80 mg/dL in the atorvastatin group. The results showed a nonsignificant trend toward reduction of the primary composite endpoint of coronary death, nonfatal MI, or cardiac arrest (hazard ratio: 0.89; 95% CI: 0.78 to 1.01); significant reductions in some secondary endpoints such as nonfatal MI and coronary revascularization; and no effect on all-cause mortality (501). It should be noted that both these trials compared 2 drug regimens and did not directly test the benefit of achieving a given level of LDL cholesterol and that, to date, there is no clear evidence that treating to a specific target, as opposed to treating with a higher dose of a higher-potency statin, is beneficial. The mean achieved LDL cholesterol levels among patients treated in the high-dose atorvastatin arms of the TNT and IDEAL studies were 77 and 81 mg/dL, respectively.
These data support intensive LDL cholesterol lowering with statins in patients with SIHD. An update of the ATP-III report (18,24) recommends treatment to an LDL cholesterol level <100 mg/dL in patients with established CAD or other high-risk features, with an LDL cholesterol goal of <70 mg/dL as a therapeutic option in patients at very high risk. However, as discussed above, although the presence of data confirming the use of a specific, numeric target LDL cholesterol level for all patients with SIHD has been challenged, the benefit of therapy with moderate- to high-dose statin therapy is well established (458). For this reason, the recommendations in this guideline stress the importance of prescribing a statin in at least a moderate dose. The ATP-IV report is anticipated later in 2012 and is expected to provide guidance for the treatment of LDL cholesterol levels on the basis of the results of an extensive systematic review. Factors that identify patients at very high risk in the ATP-III update include the presence of established coronary vascular disease, plus 1) multiple major risk factors, especially diabetes mellitus; 2) severe and poorly controlled risk factors, especially continued tobacco use; and 3) multiple risk factors for the metabolic syndrome. Again, it should be acknowledged that no studies have assessed the benefits of titrating lipid-lowering drugs to achieve a specific LDL cholesterol target. In addition, trials of intensive lipid lowering for secondary prevention have used statins alone. Although the addition of other agents could lower LDL cholesterol in patients in whom a target level cannot be achieved with a statin, the utility of this approach in reducing risk of cardiovascular morbidity and mortality has not been firmly established.
A secondary target of therapy introduced by ATP-III is non–HDL cholesterol in patients with elevated triglycerides (18,24). Non–HDL cholesterol is defined as the difference between total cholesterol and HDL cholesterol. It includes all cholesterol and lipoprotein particles that are considered atherogenic, including LDL cholesterol, lipoprotein, intermediate-density lipoprotein, and very-low-density lipoprotein, and is a predictor of cardiovascular death (523). Because statins lower LDL cholesterol and non–HDL cholesterol to a similar extent, the relative benefits of lowering these 2 lipid measures cannot be distinguished from recent clinical trials. Fibrates could reduce the risk of coronary events in patients with high triglycerides and low HDL cholesterol levels and could have an adjunctive role in these patients in combination with statins (503,524). Nicotinic acid raises HDL cholesterol, and several trials support the efficacy of niacin when used alone or in combination with statins (504,505,525).
Observational studies and treatment trials suggest that consumption of omega-3 fatty acids reduces cardiovascular risk. Cohort and case–control studies have found an RR reduction of about 15% for fish consumption versus little or no fish consumption (526). In the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico) Prevention study in patients with prior MI, 1 g daily of fish oil supplement resulted in a 20% reduction in mortality at 42 months (527). Pharmacological treatment with fish oil at higher doses (2 to 4 g daily) is effective in reducing triglyceride levels (528).
18.104.22.168 Blood Pressure Management
1. All patients should be counseled about the need for lifestyle modification: weight control; increased physical activity; alcohol moderation; sodium reduction; and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products (17,529–537). (Level of Evidence: B)
2. In patients with SIHD with BP 140/90 mm Hg or higher, antihypertensive drug therapy should be instituted in addition to or after a trial of lifestyle modifications (538–543). (Level of Evidence: A)
3. The specific medications used for treatment of high BP should be based on specific patient characteristics and may include ACE inhibitors and/or beta blockers, with addition of other drugs, such as thiazide diuretics or calcium channel blockers, if needed to achieve a goal BP of less than 140/90 mm Hg (544,545). (Level of Evidence: B)
Hypertension is an important independent risk factor for ischemic cardiovascular events. Observational studies have demonstrated a continuous and graded relationship between BP and cardiovascular risk. In a collaborative meta-analysis of prospective studies of nearly 1 million adults without preexisting vascular disease, the risk of a vascular death increased linearly over the BP range of 115/75 mm Hg to 185/115 mm Hg, without a threshold effect. Each increment of 20 mm Hg in systolic BP or 10 mm Hg in diastolic BP was associated with a doubling of risk (546). RCTs indicate that treatment results in a reduction of cardiovascular risk consistent with predictions from epidemiological studies (538–543,547).
Treatment of high BP should begin with lifestyle measures. Maintenance of an appropriate body weight (BMI <25 kg/m2) is a key element of the nonpharmacological strategies recommended to improve BP control; weight loss of 10 kg typically results in a decrease in BP of 5 to 20 mm Hg (529–531,548,549). Consumption of a diet rich in fruits, vegetables, and low-fat dairy products (532,533); reduction of dietary sodium intake (529,531,533,534,550); regular physical activity (535); and moderation of alcohol consumption (536) also result in significant lowering of BP.
In many patients with SIHD, therapy with medications will be required to lower BP to the desired level. Treatment trials have definitively demonstrated a beneficial effect of antihypertensive drug therapy on cardiovascular disease risk. An overview of 17 placebo-controlled trials, most of which focused on lowering diastolic BP, showed that reducing diastolic BP 5 to 6 mm Hg (or an estimated 10 to 20 mm Hg in systolic BP) within a population was associated with a significant reduction in vascular mortality, with approximately 40% reduction in stroke and 20% reduction in coronary events (547). This benefit of treatment also has been observed in studies of older adult patients with isolated systolic hypertension (539,551,552).
Despite the plethora of clinical studies, the appropriate BP threshold for initiating medical therapy and specific treatment goals for patients with chronic IHD remain controversial. RCTs have demonstrated a benefit from antihypertensive therapy in patients with a diastolic BP >90 mm Hg (547) and also in patients with isolated systolic hypertension and a systolic BP >160 mm Hg (539,551,552). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a target BP of <140/90 mm Hg in patients with uncomplicated hypertension and of <130/80 mm Hg in patients with diabetes mellitus or CKD (17). Observations from epidemiological studies and the relatively high absolute risk of cardiovascular events in patients with vascular disease have led some to suggest that a lower BP target might also be appropriate in individuals with SIHD (553).
On the other hand, excessive reduction in diastolic BP could compromise coronary perfusion in SIHD patients, and some studies have demonstrated a J-shaped relationship between diastolic BP and coronary events (554). The ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial (555), which enrolled patients with type 2 diabetes mellitus at high risk of cardiovascular events, found no benefit of targeting a systolic BP of 120 mm Hg compared with a systolic BP of 140 mm Hg in reducing a composite endpoint of MI, stroke, or death from cardiovascular causes. In a related vein, in AASK (African-American Study of Kidney Diseases and Hypertension) (556), 1,094 black patients with hypertensive kidney disease (diastolic pressure >95 mm Hg and glomerular filtration rate of 20 to 60 mL/min) and no diabetes mellitus were randomly assigned to achieve a mean arterial pressure target ≤92 mm Hg (corresponding to 130/80 mm Hg) or to a target of 102 to 107 mm Hg (corresponding to 140/90 mm Hg). Overall, there was no advantage to more intensive BP control with regard to progression to end-stage kidney disease or death (556).
Although in patients with uncomplicated hypertension there are a variety of considerations in selecting a medication, effective BP lowering is the most important factor in preventing stroke and MI. Clinical trials have failed to convincingly demonstrate superiority of any single antihypertensive drug class in preventing cardiovascular events (544,545). In many patients with SIHD, the choice of medications is guided by compelling indications for specific classes of drugs, as discussed elsewhere in this guideline (Table 15) (557). ACE inhibitors improve outcomes in most patients with CAD, especially those with a history of MI, LV dysfunction and heart failure, or CKD or diabetes mellitus (295,296,301,558–562). Angiotensin-receptor blockers (ARBs) are beneficial in the same spectrum of patients (563–566). Beta blockers are recommended in patients with angina pectoris, a history of MI, or LV dysfunction (567–571). Aldosterone antagonists improve prognosis in patients with LV dysfunction and heart failure (572,573). Calcium antagonists are useful in the treatment of angina. Many patients with SIHD will require a combination of drugs, including a diuretic, to achieve optimal BP control.
The role of emotional stress in relationship to hypertension has yet to be fully elucidated. It might be important to acknowledge the potential relationship of stress to many of the cardiovascular risk factors, particularly hypertension, when counseling patients.
22.214.171.124 Diabetes Management
1. For selected individual patients, such as those with a short duration of diabetes mellitus and a long life expectancy, a goal hemoglobin A1c (HbA1c) of 7% or less is reasonable (574–576). (Level of Evidence: B)
2. A goal HbA1c between 7% and 9% is reasonable for certain patients according to age, history of hypoglycemia, presence of microvascular or macrovascular complications, or presence of coexisting medical conditions (577,578). (Level of Evidence: C)
1. Initiation of pharmacotherapy interventions to achieve target HbA1c might be reasonable (456,579–588). (Level of Evidence: A)
Class III: Harm
1. Therapy with rosiglitazone should not be initiated in patients with SIHD (589,590). (Level of Evidence: C)
Diabetes mellitus is an important independent risk factor for cardiovascular disease. Type 1 diabetes mellitus is associated with at least a 10-fold increase in cardiovascular events (591,592), and patients with type 2 diabetes mellitus have a risk of death from cardiovascular causes that is 2 to 6 times that of persons without diabetes mellitus (593–595). The complications of atherosclerosis account for 80% of deaths among patients with diabetes mellitus, and IHD is responsible for the majority of deaths (574,596). Diabetes mellitus is associated with a poor outcome in patients with SIHD, even after the extent of disease and other clinical characteristics are taken into account. In the CASS registry, for example, patients with diabetes mellitus had a 57% greater risk of death after adjustment for other risk factors (597).
Clinical trials have demonstrated a salutary effect of intensive glycemic control on the development of microvascular complications of diabetes mellitus, such as retinopathy, nephropathy, and peripheral and autonomic neuropathy (574,575,598), with secondary analyses suggesting a benefit extending into the normal range of HbA1c. However, the efficacy of intensive diabetes therapy in reducing cardiovascular disease is less well established. In the DCCT (Diabetes Control and Complications Trial), patients with type 1 diabetes mellitus were randomized to intensive (mean achieved HbA1c 7.4%) or conventional (mean achieved HbA1c 9.1%) therapy. During the mean 6.5 years of observation, fewer cardiovascular events occurred in the intensive-treatment group, but the number of events was small, and the difference between groups did not reach statistical significance (574). In a long-term follow-up study of this population, however, intensive therapy reduced the risk of cardiovascular events by 42% (579). Intensive glycemic controlled to a reduction in microvascular complications (primarily the need for retinal laser photocoagulation) but not cardiovascular events in the patients with type 2 diabetes mellitus who participated in the UKPDS (UK Prospective Diabetes Study) (575). In a secondary analysis, treatment with metformin seemed to confer most of the benefit, whereas treatment with a sulfonylurea was not associated with a significant improvement in any endpoint (599). Patients in UKPDS treated with metformin had a lower median HbA1c (7.4% versus 8.0%) and a 37% reduction in ≥1 diabetes endpoints compared with those in the conventional therapy (diet alone) group (580). In the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study, patients with type 2 diabetes mellitus and evidence of vascular disease were randomized to pioglitazone or placebo. HbA1c averaged 7.8% at baseline and decreased by 0.3% in the placebo group and by 0.8% in those on active therapy. There was no significant difference between treatment groups in the primary study endpoint, although pioglitazone resulted in a statistically significant 16% relative reduction in a secondary endpoint of mortality, nonfatal MI, and stroke (581).
Three studies in patients with type 2 diabetes mellitus suggest that even more intensive glucose lowering fails to reduce the incidence of cardiovascular events and could cause harm (576,578,600). The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial tested a strategy of intensive glucose control with a target HbA1c of 6.5%, with the sulfonylurea gliclazide (modified release) and other drugs used as required (576). After a media