Stable angina

THE PRESENT AND FUTURE
JACC STATE-OF-THE-ART REVIEW
Evaluation and Management of
Patients With Stable Angina:
Beyond the Ischemia Paradigm
JACC State-of-the-Art Review
Richard Ferraro, MD,a,
* Jacqueline M. Latina, MD,a,
* Abdulhamied Alfaddagh, MD,a
Erin D. Michos, MD, MHS,a
Michael J. Blaha, MD, MPH,a
Steven R. Jones, MD,a
Garima Sharma, MD,a
Jeffrey C. Trost, MD,a
William E. Boden, MD,b
William S. Weintraub, MD,c
João A.C. Lima, MD, MBA,a
Roger S. Blumenthal, MD,a
Valentin Fuster, MD, PHD,d,e
Armin Arbab-Zadeh, MD, PHD, MPHa
ABSTRACT
Coronary heart disease is a chronic, systemic disease with a wide range of associated symptoms, clinical outcomes, and
health care expenditure. Adverse events from coronary heart disease can be mitigated or avoided with lifestyle and risk
factor modifications, and medical therapy. These measures are effective in slowing the progression of atherosclerotic
disease and in reducing the risk of thrombosis in the setting of plaque disruptions. With increasing effectiveness of
prevention and medical therapy, the role of coronary artery revascularization has decreased and is largely confined to
subgroups of patients with unacceptable angina, severe left ventricular systolic dysfunction, or high-risk coronary
anatomy. There is a compelling need to allocate resources appropriately to improve prevention. Herein, we review the
scientific evidence in support of medical therapy and revascularization for the management of patients with stable
coronary heart disease and discuss implications for the evaluation of patients with stable angina and public policy.
(J Am Coll Cardiol 2020;76:2252–66) © 2020 by the American College of Cardiology Foundation.
Cardiovascular disease (CVD) remains the
most frequent cause of death and disability
in the United States, with health care expen-
ditures each year exceeding $3 trillion and expected
to approach $6 trillion by 2027 (1). Coronary heart dis-
ease (CHD) accounts for the largest share of CVD,
driven by the many associated tests, hospitalizations,
and therapies (2). Approximately 5% of the US popu-
lation ages 25 to 64 years undergo stress testing
each year for evaluation of suspected angina pectoris
(3). Extrapolating these data to 220,000,000
Americans aged 25 years and older, well over
10,000,000 stress tests are performed annually in
the United States alone, costing more than $11 billion
(4). The recent publication of the ISCHEMIA (Interna-
tional Study of Comparative Health Effectiveness
with Medical and Invasive Approaches) trial results
has renewed discussions about the appropriate man-
agement of patients with stable CHD (5,6). The pur-
pose of this paper is to outline principles and
supporting evidence on contemporary evaluation
and management in this important patient group.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2020.08.078
From the a
Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
b
VA New England Healthcare System, Boston University School of Medicine, Boston, Massachusetts, c
MedStar Heart & Vascular
Institute, Washington Hospital Center, Washington, DC; d
Department of Medicine-Division of Cardiology, Mount Sinai Medical
Center, Icahn School of Medicine at Mount Sinai Medical Center, New York, New York; and the e
Centro Nacional de Inves-
tigaciones Cardiovasculares (CNIC), Madrid, Spain. *Drs. Ferraro and Latina contributed equally to this work.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the JACC author instructions page.
Manuscript received August 7, 2020; revised manuscript received August 24, 2020, accepted August 30, 2020.
Listen to this manuscript’s
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 6 , N O . 1 9 , 2 0 2 0
ª 2 0 2 0 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N
P U B L I S H E D B Y E L S E V I E R

The most common clinical manifestation of CHD
is angina pectoris and its alleviation is a vital
component in the management of patients with
CHD. Stable angina is defined here as symptoms that
may be ascribed to myocardial ischemia, for
example, chest discomfort, but lack the duration and
severity that one may associate with acute myocar-
dial infarction. Stable angina, therefore, is typically
managed in the outpatient setting. The severity and
frequency of angina in patients with stable CHD
enrolled in clinical trials and observational studies
are listed in Tables 1 and 2. Patients with severe or
unacceptable angina have frequently been excluded
from clinical trials. In the COURAGE (Clinical Out-
comes Utilizing Revascularization and Aggressive
Drug Evaluation) trial, most (two-thirds) had Cana-
dian Cardiovascular Society (CCS) I or II angina and
21% class III angina (patients with class IV were
excluded) (7). The FAME 2 (Fractional Flow Reserve
versus Angiography for Multivessel Evaluation 2)
study enrolled patients with all CCS classes,
including 7% of patients with CCS IV angina (8). In
the ISCHEMIA trial, 95.4% of patients had CCS II or
less severe angina despite most (86%) having mod-
erate or severe inducible myocardial ischemia (pa-
tients with unacceptable angina were excluded) (9).
The Seattle Angina Questionnaire (SAQ) allows for
more detailed assessment of angina frequency re-
ported by patients, its associated physical limitations,
and quality of life. The SAQ Frequency Score ranges
from on a scale from 0 to 100, with 100 being best
(free of angina). Average SAQ Frequency Score was
68.5 in COURAGE and 81.5 in ISCHEMIA at baseline
(Table 2). Although women were noted to have
somewhat more frequent angina than men in
ISCHEMIA, daily angina was rare (<3%)
among both women and men (10).
Given the typically stringent entry criteria
for clinical trials, observational studies may
provide a more realistic assessment of angina
severity/frequency in the community.
Among 5,558 patients surveyed at 6 Veterans
Affairs General Medicine Clinics, 83% re-
ported minimal or mild angina (11). The
APPEAR (Provider Evaluation of Angina Re-
lief) study prospectively assessed 25 U.S.
outpatient cardiology clinics for angina fre-
quency (12). The mean SAQ Angina Fre-
quency Score of 1,257 patients with stable
CHD was 92, with just 7.6% reporting weekly
or daily angina. Notably, 67% of patients had
no angina. These data were very similar to
another outpatient clinic sample obtained in
the Heart & Soul study (Table 2) (13). In the
international CLARIFY (Prospective Obser-
vational Longitudinal Registry of Patients
with Stable Coronary Artery Disease) study,
80% of 20,291 patients reported no angina
(14). Overall, patients with stable CHD have
no or only mild angina, although some pa-
tients do have severe or frequent symptoms
with substantial reduction of quality of life.
GOALS OF ASSESSMENT IN PATIENTS WITH
STABLE ANGINA
The risk of major adverse cardiovascular events
(MACE) is relatively low in most patients without a
history of CHD presenting with stable chest pain (15).
As such, risks, costs, and downstream utilization with
testing must be carefully considered. Given concerns
for patient safety, costs, and resource restrictions, it
is desirable to avoid unnecessary testing. Diagnostic
choices should be geared toward guidance of avail-
able management options, which range from a sole
focus on risk factor modification, varying intensity of
medical therapy, to coronary artery revascularization.
Management goals in patients with stable CHD are
centered on: 1) improving event-free survival; and 2)
symptomatic improvement (both in physical function
and quality of life). A simple algorithm may
adequately guide the selection of diagnostic and
therapeutic options in most cases.
TREATMENT OPTIONS
The principal management strategy remains lifestyle
intervention and intensive pharmacologic secondary
HIGHLIGHTS
Results from large clinical trials support
medical therapy rather than revasculari-
zation as an initial management strategy
for most patients with stable ischemic
heart disease.
Available data support revascularization
only for specific patient subgroups, in
contrast to prevalent practice patterns.
Further efforts are needed to align in-
centives, resource allocation, and patient
expectations with evidence to promote
application of medical management and
preventive care as the initial strategy for
patients with stable CHD.
A B B R E V I A T I O N S
A N D A C R O N Y M S
ACS = acute coronary
syndrome
CABG = coronary artery bypass
grafting
CCS = Canadian Cardiovascular
Society
CHD = coronary heart disease
CT = computed tomography
CVD = cardiovascular disease
DAPT = dual antiplatelet
therapy
FFR = fractional flow reserve
LDL = low-density lipoprotein
MACE = major adverse
cardiovascular event
MRI = magnetic resonance
imaging
NCDR = National
Cardiovascular Data Registry
OMT = optimal medical therapy
PCI = percutaneous coronary
intervention
PCSK-9 = proprotein
convertase subtilisin/kexin
type 9
SAQ = Seattle Angina
Questionnaire
J A C C V O L . 7 6 , N O . 1 9 , 2 0 2 0 Ferraro et al.
N O V E M B E R 1 0 , 2 0 2 0 : 2 2 5 2 – 6 6 Evaluation and Management of Stable Angina
2253

prevention—together often referred to as optimal
medical therapy (OMT), with coronary artery revas-
cularization in addition if medical therapy alone is
ineffective. Patients with CHD benefit from regular
exercise, a healthy diet, abstinence from tobacco or
excessive alcohol use, and control of serum lipids,
hypertension, and blood glucose (16). Strong evi-
dence supports the effectiveness of these in-
terventions for improving outcomes and they remain
the foundation for managing patients with CHD (16).
Coronary artery revascularization may be per-
formed by percutaneous coronary intervention (PCI)
or coronary artery bypass grafting (CABG) with the
intent to improve symptoms and, in selected pa-
tients, event-free survival. The number of revascu-
larization procedures in patients with stable CHD
performed each year in the United States is difficult to
estimate because many patients are being referred
with the indication of unstable angina; a syndrome
that is poorly defined, and perhaps even an obsolete
diagnosis (17). In response to stricter eligibility
criteria to perform PCI in patients with stable angina,
a sharp increase of PCI referrals for unstable angina
was noted over the past years suggesting it is pref-
erentially diagnosed over stable angina (“upcoded”)
to justify referral to and reimbursement for revascu-
larization (18,19).
According to estimates from the American Heart
Association, there were 954,000 PCI and 397,000
CABG procedures performed in the United States in
2010 (20), not including outpatient PCI. Applying a
breakdown of indications from the NCDR (National
Cardiovascular Data Registry) (21), approximately
one-third of revascularization procedures are being
performed for acute ST-segment elevation and non-
ST-segment elevation myocardial infarction for
which there is broad consensus for the benefit of
intervention. The indications for the remaining two-
thirds of cases are for stable symptoms or for “un-
stable angina” without evidence of myocardial
infarction (21). Thus, approximately 900,000 revas-
cularization procedures are being performed for non–
myocardial infarction indications each year, with the
number of cases performed in truly stable patients
being unknown given difficulties distinguishing be-
tween unstable and stable angina.
REVASCULARIZATION VERSUS MEDICAL
THERAPY FOR ANGINA CONTROL
Most patients with stable CHD have mild, infrequent
chest discomfort or no symptoms (Table 2). In most
patients, symptoms will lessen or even resolve with
either medical therapy or revascularization. Data
from COURAGE in selected patients with stable CHD
considered for revascularization revealed improve-
ment over time with high quality-of-life scores during
follow-up with either OMT alone or with PCI in
addition to OMT (22). Although patients assigned to
PCI derived a small incremental benefit over OMT,
this difference disappeared by 24 to 36 months for
most domains of the SAQ. ISCHEMIA also confirmed
an improvement in angina frequency with the inva-
sive strategy over OMT, which was sustained at
36 months (mean SAQ 88.6 vs. 86.3) (23). The benefit
of revascularization was larger with more frequent
angina at baseline (35% of patients had no angina),
especially with daily or weekly angina (5.3-point dif-
ference at 36 months).
An important caveat in both trials, however, is the
unblinded treatment allocation that may have influ-
enced results. The sham-controlled ORBITA (Objec-
tive Randomised Blinded Investigation with Optimal
Medical Therapy of Angioplasty in Stable Angina)
study did not find significant differences in angina
severity or quality of life measures in patients with
stable, single-vessel CHD assigned to OMT or PCI (24),
although more patients became symptom-free with
PCI (25). An analysis of FAME 2 revealed a 77%
reduction in angina severity within 30 days after pa-
tients were told they had no flow-limiting disease
(26). Thus, it remains unclear if the symptomatic
improvement with revascularization noted in
COURAGE and ISCHEMIA is due to treatment or may
be at least partly attributed to a placebo effect.
Patients with severe symptoms may be more likely
to derive symptom improvement with PCI but
10% of patients have CCS III or IV angina even in
selected clinical trial populations such as ISCHEMIA
or BARI-2D (Bypass Angioplasty Revascularization
TABLE 1 Baseline Angina Severity by CCS Angina Score in
Selected Major Trials
BARI-2D* COURAGE FAME 2 ISCHEMIA
No angina 11.2 12.4 11.2 20.8
CCS Class I
42.5
29.8 20.3 28.2
CCS Class II 36.5 45.2 45.4
CCS Class III
8.6
21.1 16.3 4.6
CCS Class IV 0 (excluded) 7.0 0†
Values are %. Data were obtained from the respective publications (7–9,49).
*Angina classes I/II and III/IV were grouped. †Patients with unacceptable angina
despite medical management were excluded from enrollment.
BARI-2D ¼ Bypass Angioplasty Revascularization Investigation in Type-2 Dia-
betes; CCS ¼ Canadian Cardiovascular Society; COURAGE ¼ Clinical Outcomes
Utilizing Revascularization and Aggressive Drug Evaluation; FAME 2 ¼ Fractional
Flow Reserve versus Angiography for Multi-vessel Evaluation;
ISCHEMIA ¼ International Study of Comparative Health Effectiveness with Medical
and Invasive Approaches.
Ferraro et al. J A C C V O L . 7 6 , N O . 1 9 , 2 0 2 0
Evaluation and Management of Stable Angina N O V E M B E R 1 0 , 2 0 2 0 : 2 2 5 2 – 6 6
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Investigation in Type-2 Diabetes) (Table 1). Available
data confirm current practice guidelines, which
recommend revascularization to be reserved for cases
of unacceptable angina despite adequate OMT (16).
STRATEGIES FOR IMPROVING
EVENT-FREE SURVIVAL
GENERAL CONCEPTS. To determine the appropriate
treatment for patients with stable CHD, it is prudent
to review mechanisms leading to adverse patient
outcome. Death or morbidity in patients with stable
CHD is caused by acute coronary events and its
downstream complications (e.g., heart failure,
arrhythmia) (27). The most common mechanism
leading to an acute coronary syndrome (ACS) is
atherosclerotic plaque disruption with subsequent
thrombosis and partial or complete lumen occlusion
(27). There is an exceedingly low risk of myocardial
infarction or cardiac death in patients without evi-
dence of coronary atherosclerosis by imaging, even in
the presence of symptoms suspicious for angina (28).
Coronary artery dissection, spasm, or embolus may
occur in the absence of coronary atherosclerotic dis-
ease, but these events are uncommon.
On the other hand, the risk of adverse events cor-
relates with the anatomic extent of coronary artery
disease (29). Although most atherosclerotic plaques
remain stable and do not lead to acute coronary
events, the more plaques that are present, the greater
the risk that plaque disruptions will occur and the
greater the probability of arterial thrombosis and a
clinical event (27). The coronary atherosclerotic
burden, therefore, is the main determinant of risk
(30). In addition, rapidly progressive atherosclerosis
and a conducive hemostatic milieu increases risk of
myocardial infarction and death (27). In most pa-
tients, the convergence of prothrombotic factors in-
crease their probability of events (27). Many of these
factors enhancing the probability of a thrombosis
(e.g., diabetes mellitus, hyperlipidemia, arterial hy-
pertension, obesity) can be modified and their effects
mitigated by medical therapies or by lifestyle
modifications.
OPTIMAL MEDICAL THERAPY FOR IMPROVING
EVENT-FREE SURVIVAL. CHD is adequately add-
ressed by using a systemic approach aimed at stabi-
lizing the atherosclerotic disease process and modi-
fying the biological response to the stimulus of
thrombosis. An overview of clinical trials of medical
therapy for secondary prevention in patients with
CHD is provided in Table 3. Lipid-lowering therapy,
antithrombotic therapy, blood pressure and diabetes
control, cessation of cigarette smoking, better diets,
and more awareness of the detrimental effects of a
sedentary lifestyle have a substantial impact on
morbidity and mortality in patients with CHD (31–33).
Furthermore, even small changes in risk factor con-
trol or improved adherence to medication have a
substantial impact on patient outcome (34,35).
The 2018 American Heart Association/American
College of Cardiology Cholesterol Guideline for pa-
tients with clinical atherosclerotic cardiovascular
disease recommends maximally tolerated statin for
a goal of low-density lipoprotein cholesterol (LDL-C)
reduction of $50% (36). The guideline further rec-
ommends strong consideration of ezetimibe to
complement high-intensity statin for patients with
known CHD with LDL persistently $70 mg/dl, and
that patients with $70 mg/dl LDL despite these
measures can be considered for proprotein con-
vertase subtilisin/kexin type 9 (PCSK-9) inhibitor
use. In addition to antiplatelet therapy, typically
initiated with aspirin, selected patients benefit from
dual antiplatelet therapy (DAPT) or low-dose rivar-
oxaban plus low-dose aspirin after ACS (37,38). For
patients with diabetes mellitus, treatments with
sodium/glucose cotransporter 2 inhibitors and
glucagon-like peptide-1 receptor agonists, have been
associated with improved outcome and are now
recommended as first-line treatment in diabetes
management for the purposes of CVD prevention
(39,40). Recently, the addition of icosapent ethyl
was found to reduce MACE in patients with
elevated triglycerides on a background of standard
treatment of CVD (41,42). Last, anti-inflammatory
treatment shows promise as novel therapy for sec-
ondary prevention (43,44).
REVASCULARIZATION VERSUS MEDICAL THERAPY
FOR IMPROVING EVENT-FREE SURVIVAL. An over-
view of recent major clinical trials addressing patient
outcome after OMT, PCI, or CABG is provided in
TABLE 2 Angina Frequency and Associated Physical Limitation in Clinical Trials and
Observational Studies
HEART SOUL COURAGE ISCHEMIA APPEAR
No angina 61.9% 22.0% 35.5% 67.3%
Monthly 27.3% No data 44.3% 25.1%
Daily/weekly 10.9% No data 20.3% 7.6%
SAQ Frequency Score 89.1 68.5 81.5 91.6
SAQ Physical Limitation 76.9 66.0 79.4 71.6
Data were obtained from the respective publications (12,13,22,23). Data for treatment groups in clinical studies
were averaged. Note that the difference to Table 1 regarding patients without angina in the ISCHEMIA trial is due
to different methodology in obtaining data.
APPEAR ¼ Provider Evaluation of Angina Relief; SAQ ¼ Seattle Angina Questionnaire; other abbreviations as in
Table 1.
2255

Figure 1. The conceptual basis for the benefit of
revascularization in patients with stable CHD has
been linked to the assumption that reducing
myocardial ischemia and improving myocardial
perfusion leads to better clinical outcome (45). Direct
evidence for the benefit of revascularization in
patients with stable CHD exists for the use of CABG in
patients with left main disease, 3-vessel CHD,
2-vessel CHD including the proximal left anterior
descending coronary artery, as well as in patients
with decreased ejection fraction or diabetes and
multivessel CHD (16). Practice guidelines also support
TABLE 3 Medical Therapy for Prevention of Death, Stroke, or Myocardial Infarction in Patients With Coronary Heart Disease
Medication Study/First Author, Year (Ref. #) Outcome Hazard Ratio (95% CI)
Single antiplatelet therapy
Aspirin ISIS 2, 1988 (90) Vascular death 0.77 (0.7–0.85)*
Aspirin Antithrombotic Trialists Collaboration, 2009 (91) CHD death
Major coronary event
Stroke
0.87 (0.78–0.98)
0.80 (0.73–0.88)
0.81 (0.71–0.92)
Aspirin Udell et al., meta-analysis, 2015 (92) CV death, MI, or stroke
CV death
All-cause death
0.78 (0.67–0.90)
0.85 (0.74–0.98)
0.92 (0.83–1.03)
Aspirin Fanaroff et al. meta-analysis, 2017 (93) All-cause death 0.80 (0.73–0.87)
Clopidogrel CAPRIE, 1996 (94) Stroke, MI, or all-cause death 0.93 (0.86–1.01)
Advanced antithrombotic therapy
Clopidogrel þ ASA Fanaroff et al. meta-analysis, 2017 (93) All-cause death 0.79 (0.68–0.92)
Clopidogrel þ ASA for 30m DAPT Study, 2014 (52) Death, MI, or stroke
All-cause death
0.71 (0.59–0.85)
1.36 (1.00–1.85)
Ticagrelor þ ASA Fanaroff et al. meta-analysis, 2017 (93) All-cause death 0.68 (0.58–0.82)
Ticagrelor 60 mg BID þ ASA PEGASUS-TIMI 54 (37) CV death, MI, or stroke
Death from CHD, MI, stroke
All-cause death
0.84 (0.74–0.95)
0.83 (0.73–0.94)
0.89 (0.76–1.04)
Prasugrel þ ASA Fanaroff et al. meta-analysis, 2017 (93) All-cause death 0.74 (0.60–0.91)
Low-dose Rivaroxaban þ ASA COMPASS (95) MI, stroke, or CV death
All-cause death
0.74 (0.65–0.86)
0.77 (0.65–0.90)
ACE inhibitors/ARB
Ramipril HOPE, 2000 (96) MI, stroke, CV death
All-cause mortality
0.78 (0.70–0.86)
0.84 (0.75–0.95)
Trandolopril PEACE, 2004 (97) MI, CABG, PCI, CV death
All-cause death
0.96 (0.88–1.06)
0.89 (0.76–1.04)
Perindopril EUROPA, 2003 (98) MI, cardiac arrest, CV death
All-cause death
0.80 (0.71–0.91)
0.89 (0.77–1.02)
Telmisartan TRANSCEND, 2008 (99) MI
All-cause death
0.79 (0.62–1.01)
1.05 (0.91–1.22)
Beta-blockers
Beta-blockers after MI FAST-MI, 2016 (100) All-cause death at 30 days
All-cause death at 1 yr
All-cause death at 5 yrs
0.46 (0.26–0.82)
0.77 (0.46–1.30)
1.19 (0.65–2.18)
Lipid-lowering medications
Simvastatin 4S, 1994 (101) All-cause death 0.70 (0.58–0.85)
Pravastatin LIPID, 1998 (102) Death from CHD
All-cause death
0.76 (0.65–0.78)
0.78 (0.69–0.87)
Pravastatin CARE, 1996 (103) CV death or nonfatal MI
Death from CHD
0.76 (0.64–0.91)
0.80 (0.61–1.05)
Atorvastatin MIRACL, 2001 (104) Nonfatal MI
Death
0.90 (0.69–1.16)
0.94 (0.67–1.31)
Ezetimibe with Simvastatin IMPROVE-IT, 2015 (105) MI
Death from any cause
0.87 (0.80–0.95)
0.99 (0.91–1.07)
Evolocumab FOURIER, 2017 (106) MI
All-cause death
0.73 (0.65–0.82)
1.04 (0.91–1.19)
Alirocumab after ACS ODYSSEY, 2018 (107) Death, MI, or stroke
Death from any cause
0.86 (0.79–0.93)
0.85 (0.73–0.98)
Icosapent ethyl REDUCE-IT, 2019 (41) Fatal or nonfatal MI
CV death
All-cause death
0.69 (0.58–0.81)
0.80 (0.66–0.98)
0.87 (0.74–1.02)
*Odds ratio.
ACE ¼ angiotensin-converting enzyme; ACS ¼ acute coronary syndrome; ARB ¼ angiotensin receptor blocker; ASA ¼ aspirin; CHD ¼ coronary heart disease; CI ¼ confidence
interval; CV ¼ cardiovascular; DAPT ¼ dual antiplatelet therapy; MACE ¼ major adverse cardiovascular events compromising cardiovascular death, nonfatal MI, or nonfatal
stroke; MI ¼ myocardial infarction; SCA ¼ sudden cardiac arrest; UA ¼ unstable angina.
2256

(Class IIa recommendation) CABG for patients with
multivessel disease and extensive myocardial
ischemia on provocative testing though supporting
evidence exists predominantly from observational,
retrospective analyses (16). Most studies comparing
CABG with medical therapy date as far back as the
1980s, with medical therapy not including essential
contemporary components, such as antiplatelet or
aggressive lipid-lowering therapy, which have shown
to improve survival in patients with CHD (46).
The mechanisms by which CABG leads to improved
outcome in selected patients with high-risk features
compared with medical therapy remain poorly un-
derstood (45). Analyses of the STICH (Surgical Treat-
ment for Ischemic Heart Failure) trial found no
differences in New York Heart Association heart fail-
ure or CCS angina classifications among patients
assigned to CABG versus medical therapy at
48 months follow-up, which suggests that improved
myocardial perfusion with surgical revascularization
may not be a major factor in explaining the difference
in patient outcome (47). Numerous studies have
shown that PCI is associated with reduced ischemic
burden in patients with stable CHD without affecting
mortality or myocardial infarction risk demonstrating
that reducing inducible myocardial ischemia may not
be a factor for improving patient survival (48). Thus,
neither improving myocardial function by restoring
epicardial blood flow nor reducing myocardial
ischemia by coronary artery revascularization has
been implicated in extended survival in patients with
stable CHD.
Risk reduction for myocardial infarction has been
observed with CABG (49) but not with PCI versus
medical therapy (48). In an updated meta-analysis,
including data from ISCHEMIA, relative risk of
myocardial infarction with PCI versus OMT was
0.93 (95% confidence interval [CI]: 0.83 to 1.03)
with procedure-related and spontaneous myocardial
infarction risk offsetting each other (50). However,
more patients assigned to routine revascularization
using PCI receive DAPT, which is associated with 22%
risk reduction for myocardial infarction in patients
with CHD or similar risk profile in a meta-analysis (51).
In high-risk patients with CHD (e.g., history of PCI) a
myocardial infarction risk reduction of 53% was
observed (52). An analysis of the TRITON-TIMI 38
(Trial to Assess Improvement in Therapeutic Out-
comes by Optimizing Platelet Inhibition with
Prasugrel-Thrombolysis In Myocardial Infarction 38)
in 12,844 patients with ACS and PCI revealed more
potent antithrombotic therapy was associated with
fewer spontaneous myocardial infarctions (hazard
ratio: 0.80; 95% CI: 0.67 to 0.95), particularly in the
later phase of the study (53). Data from the PEGASUS-
TIMI 54 (Prevention of Cardiovascular Events in
FIGURE 1 Major Clinical Trials for the Management of Stable CHD in the Past 2 Decades
COURAGE (n = 2,287)
PCI + OMT vs. OMT in stable CHD
• All had evidence of ischemia
• 31% triple-vessel CHD
• 4.6 years median follow-up
• HR death/MI 1.05 (95% CI: 0.87 to 1.27)
STICH (n = 1,212)
CABG + OMT vs. OMT in ICM
• Median EF 28%
• HR death 0.86 (95% CI: 0.72 to 1.04)
FREEDOM (n = 1,900)
CABG vs PCI in diabetics patients
• MI/stroke-free survival 81% vs. 73%
(p = O.005)
ISCHEMIA (n = 5,179)
PCI or CABG vs. OMT
• 85% moderate or severe ischemia
• CV death or MI 14.2% vs. 16.5% (p = NS)
2007 2009 2011 2012 2018 2020
BARI-2D (n = 2,368)
CABG or PCI compared to OMT in diabetic patients
• 31% triple-vessel CHD; 5.3 years mean follow-up
• No difference in mortality CABG or PCI compared to OMT
• MI/stroke-free survival PCI vs. OMT 77% vs. 79% (p = 0.15)
• MI/stroke-free survival CABG vs. OMT 70% vs. 78% (p = 0.01)
FAME 2 (n = 888)
FFR guided PCI + OMT vs. OMT alone
• HR death/MI 0.61 (95% CI: 0.28 to 1.35)
• Revascularization 0.13 (95% CI: 0.06
to 0.30)
ORBITA (n = 200)
PCI vs OMT, double-blinded
• Single-vessel CHD
• Endpoint Δ exercise capacity after 6 weeks
• PCI vs. placebo 16.6 s (–8.9 to 42.0), p = 0.2
• SAQ angina frequency 93.0 vs. 84.6, p = 0.26
A synopsis is provided summarizing key findings from major clinical trials on the effectiveness of medical therapy, PCI, or CABG in patients with stable
coronary heart disease. Data were obtained from the respective publications (7–9,24,49,56,57). To allow comparison of standardized endpoints among
trials, we focused our reporting on death, myocardial infarction, or stroke, where available. CABG ¼ coronary artery bypass grafting; CHD ¼ coronary heart
disease; PCI ¼ percutaneous coronary intervention; OMT ¼ optimal medical therapy; MI ¼ myocardial infarction; NS ¼ not significant; SAQ ¼ Seattle
Angina Questionnaire.
2257

Patients with Prior Heart Attack Using Ticagrelor
Compared to Placebo on a Background of Aspirin–
Thrombolysis In Myocardial Infarction 54) confirmed
the benefit of myocardial infarction risk reduction
with DAPT in patients both with and without PCI (54).
It is clear, therefore, that more potent antithrombotic
treatment is associated with lower myocardial infarc-
tion risk and that unequal allocation of such treat-
ment, as in the case of PCI versus OMT trials, creates a
bias against OMT for the outcome of spontaneous
myocardial infarction. The role of revascularization in
the prevention of spontaneous myocardial infarction
remains an area of active discussion and future
investigation.
In contrast to PCI, CABG addresses not focal
stenoses but provides new conduits free of athero-
sclerotic disease. We speculate that CABG, bypassing
the proximal, heavily diseased coronary arterial cir-
culation with arterial conduits resistant to athero-
sclerosis (internal mammary or radial arteries),
reduces the risk of downstream vascular thrombosis
and myocardial infarction (45,55). This theory is
consistent with our understanding of risk from CHD
and may explain why CABG leads to improved patient
outcome compared with PCI (56).
Systemic treatment of patients with CHD with OMT
has been rapidly evolving and now includes the
application of high-dose statins, ezetimibe, PCSK-9
inhibitors, icosapent ethyl, DAPT, aldosterone-
antagonists in patients with severely reduced left
ventricular ejection fraction, low-dose anti-
coagulation, sodium/glucose cotransporter
2-inhibitors and glucagon-like peptide-1 receptor
agonists, and emerging anti-inflammatory treatment.
The benefit of CABG noted in the 1980s has been
difficult to replicate in trials composed of patients
treated with contemporary medical therapy. The
BARI-2D trial did not find a mortality benefit with
CABG over OMT in patients with multivessel CHD and
diabetes mellitus (49). The STICH trial failed to
demonstrate significant mortality reduction with
CABG over OMT at its specified endpoint analysis in
patients with severe CHD and severely reduced left
ventricular systolic function (57). Although a 10%
lower mortality was observed with CABG after 10
years (58), STICH did not use medical therapy, which
since then has shown to reduce risk of mortality or
myocardial infarction in this population (e.g.,
aldosterone-antagonists, DAPT, or advanced lipid
therapy).
THE ISCHEMIA TRIAL. Recently, results from the
largest randomized controlled clinical trial in patients
with stable CHD have been published (9). ISCHEMIA,
a multicenter study of 5,179 patients with stable
FIGURE 2 Cumulative 1- and 5-Year Costs for Coronary Artery Revascularization According to Indication
Costsin$Billion
0
10
20
30
40
50
60
Acute MI No MI
1-Year 5-Year
Shown are estimated cumulative costs for CABG and PCI for the indication of acute myocardial infarction and other indications according to
the estimated number of procedures in 2010, NCDR data on the breakdown of revascularization procedures for PCI, and data from the
FREEDOM trial on adjusted costs for PCI ($33,976 for year 1 and $56,860 for year 5) and CABG ($41,855 and $60,501, respectively)
(20,21,78). Of estimated 1,351,000 inpatient revascularization procedures in 2010, 397,000 (29.4%) had CABG and 954,000 had PCI.
Assuming a similar distribution among patients undergoing revascularization for acute MI versus others, approximately 133,789/321,498
underwent CABG/PCI for acute MI versus 263,211/632,502 for other indications, respectively. CABG ¼ coronary artery bypass grafting;
PCI ¼ percutaneous coronary intervention; MI ¼ myocardial infarction; NCDR ¼ National Cardiovascular Data Registry.
2258

ischemic heart disease and moderate-to-severe
ischemia on stress testing, sought to determine if an
invasive strategy of OMT plus cardiac catheterization
and coronary revascularization, if feasible, versus a
conservative strategy of OMT alone, with revascu-
larization reserved for treatment failure led to
improved prognosis for participants, with a primary
endpoint of myocardial infarction, cardiovascular
death, hospitalization for unstable angina, heart
failure, or resuscitated cardiac arrest (9).
ISCHEMIA revealed no significant difference (haz-
ard ratio of 0.93; 95% CI: 0.80 to 1.08) for the main
study outcome. No significant differences were noted
for the secondary outcomes of cardiovascular or all-
cause death, myocardial infarction, cardiac arrest, or
stroke. Hospitalization rates for unstable angina were
lower with routine revascularization but they were
greater for heart failure hospitalization.
The most notable findings were those for myocar-
dial infarction. Cumulative incidence curves revealed
an early hazard for increased myocardial infarction
with routine revascularization which was offset by a
late benefit. Accordingly, rates for periprocedural
myocardial infarction were almost 3-fold higher with
routine revascularization but the hazard of sponta-
neous myocardial infarctions was 33% lower. Inter-
pretation of these findings is hindered by unequal
allocation of DAPT among participants. Approxi-
mately one-quarter of patients in the conservative
versus one-half in the invasive arm received DAPT at
12 months (24% vs. 30% at the last study visit). That
26% of revascularizations were performed with CABG
likely further contributed to lower follow-up
myocardial infarction incidence (49). Finally, ISCHE-
MIA’s criteria for periprocedural myocardial infarc-
tion were aligned with standards by the Society of
Cardiovascular Angiography and Interventions,
which are much more stringent than those proposed
in the 4th Universal Definition of Myocardial Infarc-
tion consensus document (59). Using an alternative
definition of periprocedural myocardial infarction in
ISCHEMIA was associated with a significantly lower
5-year cumulative myocardial infarction rate in the
conservative strategy versus invasive (12.7% vs.
15.4% [95% CI for difference: 0.3% to 5.1%]), despite
the unequal allocation of DAPT which favored the
invasive strategy (9).
Average follow-up in ISCHEMIA was somewhat
shorter than in other comparable trials, for example,
COURAGE, STICH, or FREEDOM (Future Revasculari-
zation Evaluation in Patients with Diabetes Mellitus:
Optimal Management of Multivessel Disease), which
may limit its interpretation. On the other hand, there
was no separation of cumulative survival after 5 years
and with longer follow-up a difference would be un-
expected (48). In COURAGE, no difference in mor-
tality was found between the arms at 10 years (60).
Other limitations of ISCHEMIA include its stringent
entry criteria, which hindered reaching its original
enrollment goals. In the Study of Myocardial Perfu-
sion and Coronary Anatomy Imaging Roles in Coro-
nary Artery Disease (SPARC), only 8% had moderate
or severe abnormalities on nuclear stress testing (61).
Thus, most patients with stable angina have lower
risk characteristics and smaller ischemic burden than
participants in ISCHEMIA, suggesting that symptom
improvement with routine revascularization may be
less evident in the broader population of patients
with stable CHD.
Notwithstanding these limitations, the ISCHEMIA
trial substantially added to the literature by clarifying
the role of inducible ischemia for clinical manage-
ment and demonstrated that even in high-risk pa-
tients with stable CHD, a routine invasive versus
conservative strategy is not associated with improved
event-free survival. ISCHEMIA also confirmed an
invasive strategy does not reduce the risk of hospi-
talization for heart failure. In prespecified subgroup
analyses, none of the currently considered “high-
risk” criteria (e.g., multivessel disease, involvement
of the proximal left anterior descending artery, or
severe inducible ischemia) were associated with
improved patient outcome in the invasive versus
conservative arms. The lack of ischemia severity
predicting outcome in ISCHEMIA was also noted in
COURAGE (60,62). Conversely, patients with exten-
sive atherosclerosis (e.g., 3-vessel involvement) were
of greater risk of MACE versus those with 1-vessel
CHD, confirming it is the atherosclerotic burden and
not ischemia as the driver of events (29,60,62). In a
prospectively studied ISCHEMIA companion trial of
patients with severe kidney disease, a strategy of
routine revascularization was associated with higher
incidence of stroke than the conservative strategy
TABLE 4 Patient Outcome Among Patients Undergoing CTA Versus Functional Testing
for Evaluation of Stable Chest Pain in Clinical Studies
PROMISE SCOT-HEART Danish Registry
Study size, n 10,003 4,146 86,705
Median follow-up, months 25 58 43
Nonfatal MI, HR CT (95% CI) 0.77 (0.48–1.23)* 0.60 (0.41–0.87) 0.71 (0.61–0.82)
Death or MI, HR CT (95% CI) 0.88 (0.67–1.15) 0.59 (0.41–0.84)† 0.87 (0.81–0.94)
Data were obtained from the respective publications and pooled analyses (15,83–85). *Indicates odds ratio as
opposed to hazard ratio, which was not provided. †Indicates coronary heart disease–related death instead of all-
cause death.
CI ¼ confidence interval; CT ¼ computed tomography; CTA ¼ CT angiography; HR ¼ hazard ratio;
MI ¼ myocardial infarction; PROMISE ¼ Prospective Multicenter Imaging Study for Evaluation of Chest Pain;
SCOT-HEART ¼ Scottish Computed Tomography of the Heart.
2259

(hazard ratio: 3.76; 95% CI: 1.52 to 9.32) and with a
higher incidence of death or initiation of dialysis
(hazard ratio: 1.48; 95% CI: 1.04 to 2.11) (63).
RISKS AND COSTS OF MEDICAL THERAPY
AND REVASCULARIZATION
Medical therapy is itself not without risk and may
lead to a wide array of adverse effects, including
renal failure, hepatotoxicity, bleeding complica-
tions, anaphylaxis, hematologic abnormalities, and
others. With careful patient selection, however, the
benefit of medical therapy for CHD outweighs its
risk and leads to improved patient outcome. The
costs for medical therapy are considerable. Average
annualized medication costs in patients with stable
CHD enrolled in the REACH (REduction of Athero-
thrombosis for Continued Health) registry exceeded
$2,500, with lipid-lowering therapy accounting for
the largest share (64). Since the publication of
REACH, costs for medical therapy have increased
alongside novel treatment, particularly with the
introduction of PCSK-9 inhibitors (65). As novel
treatments continue to emerge, including those that
provide substantive benefit, it can be expected
these costs continue to grow in the absence of sig-
nificant structural changes to the U.S. health care
system.
Risks associated with revascularization are
considerable. Complications after PCI for all in-
dications except ST-segment elevation myocardial
infarction were noted in 4.5% of 787,980 patients
based on self-reported data in the NCDR (21). Further,
an additional 2% had bleeding or vascular complica-
tions requiring treatment (21). In a validated sample
from a multicenter U.S. consortium, 10.7% of 64,335
patients had acute renal failure, vascular complica-
tions, gastrointestinal bleeding, or MACE after PCI
using a 6-French catheter (66). Notably since then,
radial access and use of even smaller catheters have
led to reduced adverse event rates; 7.1% versus 8.8%
with femoral access in a meta-analysis (67).
In clinical trials, however, complications such as
renal failure, vascular injury, or bleeding are not al-
ways captured. Complications specifically after elec-
tive PCI were investigated among 440 patients at
CENTRAL ILLUSTRATION Contemporary Evaluation and Management of Stable Angina
Stable Angina
Initial Medical Treatment
CT Coronary Angiography
No Atherosclerosis
Limited Nonobstructive
(50% stenosis) in 1-2 Vessels
Extensive Nonobstructive
or Obstructive (≥50%*) CAD
Left Main or 3-Vessel CAD
+ DM or ICM (EF 35%)
Lifestyle Therapy
Risk Factor Modification
OMT for functional angina
Additional Moderate
Medical Therapy†
Additional Intensive
Medical Therapy‡
PCI/CABG for failed 0MT
Additional Intensive
Medical Therapy
+ Revascularization
Ferraro, R. et al. J Am Coll Cardiol. 2020;76(19):2252–66.
A proposed testing and management algorithm for patients with angina. Staging of coronary artery disease modified after Arbab-Zadeh and Fuster (29).
*Denotes stenosis assessment by quantified analysis (corresponding to approximately 70% by visual evaluation) (29). †For example, single antiplatelet
therapy, single-agent lipid-lowering therapy. ‡For example, intensified antithrombotic and/or lipid-lowering therapy, anti-inflammatory treatment.
CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; DM ¼ diabetes mellitus; EF ¼ ejection fraction; PCI ¼ percutaneous coronary
intervention.
2260

private and public hospitals in Brazil, revealing a
complication rate of 22% (68). Among complications
after PCI, the significance of peri-procedural
myocardial infarctions remains controversial. In
1,949 patients undergoing elective PCI at the Mayo
Clinic, 19.6% were found to have a post-procedural
troponin rise, indicating acute myocardial injury (69).
Although troponin elevation was an independent
predictor of long-term mortality, many subsequent
studies questioned the clinical significance of a small
troponin rise after PCI (70,71) and the threshold for
clinically meaningful post-procedural myocardial
injury is still heavily debated. As a result, studies are
using vastly different criteria for defining periproce-
dural myocardial infarction, leading to incidences
varying by 400% or more (72). The Universal Defini-
tion of Myocardial Infarction requires both biomarker
and electrocardiogram or imaging evidence of
myocardial infarction after revascularization (59).
However, biomarker, imaging, and even electrocar-
diogram data are not routinely obtained, leading to
underreporting. By magnetic resonance imaging
(MRI), evidence of irreversible myocardial injury was
found in 28% of patients after elective PCI (73).
Perhaps of even greater concern is the incidence of
post-procedural acute silent brain infarcts, which is
rarely investigated but may be detected by MRI. A
meta-analysis of brain MRI scans pre- and post-PCI
revealed evidence of silent brain infarcts in 14% of
patients (mean of 10 studies) (74). Patients undergo-
ing CABG reveal cerebral infarcts in 25% of cases
(mean of 9 studies) (74). Even if not associated with
an overt clinical stroke, silent brain infarcts are
associated with cognitive decline and depression
(75).
Resources consumed by revascularization are also
substantial. Average hospital cost among 833,344 U.S.
patients was $23,211 for PCI, which increased to
$37,524 for 9.3% of patients who had unplanned
readmission within 30 days (76). Pooled data from 11
studies performed in the United States found median
cost for CABG to be $61,445 (77). Even when using
conservative data from the FREEDOM trial published
in 2012, estimated annual cost for revascularization
accumulate to $30 billion for approximately 900,000
revascularizations performed in the United States
each year for stable or “unstable” angina (78)
(Figure 2). Costs for revascularization accounted for
more than 50% of annual expenses for hospitalization
in the REACH registry (64). A strategy of routinely
using PCI in patients with stable CHD is more costly
than an approach focused on OMT (79). Thus, the
risks and expenditure associated with PCI and CABG
must be weighed against their benefit when
considering management options in patients with
stable CHD.
THE SIGNIFICANCE OF
NONOBSTRUCTIVE DISEASE
For decades, the focus for evaluating and managing
patients with stable chest pain has been obstructive
CHD. Data from both invasive and noninvasive coro-
nary angiography, however, have since demonstrated
that nonobstructive CHD, when extensive, may be
associated with risk of myocardial infarction and
cardiac death similar to obstructive disease, consis-
tent with the concept of a risk continuum from
atherosclerosis (29,80,81).
In the PROMISE (Prospective Multicenter Imaging
Study for Evaluation of Chest Pain) trial, most car-
diovascular deaths or myocardial infarctions (67%)
occurred in patients with a normal stress test at
baseline, most of which were found to have non-
obstructive atherosclerotic disease by computed to-
mography (CT) (82). This suggests that we miss the
opportunity to implement comprehensive preventive
measures in most patients presenting with stable
chest pain by relying on stress test results. The SCOT-
HEART (Scottish Computed Tomography of the Heart)
trial revealed a 41% (95% CI: 0.41 to 0.84) lower
hazard of coronary artery disease–related death or
myocardial infarction (2.3% vs. 3.9%) in patients
assigned to an anatomic versus traditional, functional
strategy (83). This was attributed to detection of
nonobstructive coronary atherosclerosis and the
initiation of directed preventive therapy (e.g., sta-
tins). The ability to noninvasively detect non-
obstructive atherosclerotic disease by CT, therefore,
should be considered an important opportunity to
initiate prevention earlier in disease process, a strat-
egy proven effective in reducing adverse events (29).
IMPLICATIONS FOR THE EVALUATION OF
PATIENTS WITH STABLE ANGINA
The 3 central objectives in the evaluation of patients
with stable angina are: 1) establishing symptom
severity; 2) confirming the presence and extent of
CHD; and 3) identifying high-risk features which may
warrant revascularization. Most patients with CHD
have no or only mild angina that may be controlled
with medication. However, some patients, particu-
larly those who are physically very active, may derive
considerable symptomatic benefit from revasculari-
zation. A careful history is often enough to establish
the pattern and severity of symptoms. Although it
appears tempting to obtain exercise testing to verify
symptoms, neither the absence nor the presence of
2261

inducible symptoms is likely to change management,
which is based on the patient’s report on symptoms
during daily life activities.
The presence and extent of coronary artery disease
is best assessed noninvasively by CT coronary angi-
ography given its ability to detect both non-
obstructive and obstructive atherosclerotic disease.
In direct comparison to the traditional evaluation
using stress testing, CT has been shown to yield su-
perior risk stratification due to its ability to differen-
tiate risk in patients according to the presence and
extent of coronary atherosclerotic disease (82).
Importantly, CT-guided management is associated
with improved patient outcome compared with the
traditional approach using functional testing (84).
Table 4 reveals lower risk of death or nonfatal
myocardial infarction in the PROMISE and SCOT-
HEART trials and in a large Danish Registry
(15,83–85). Although the individual results from
PROMISE were not statistically significant, likely due
to insufficient statistical power, pooled analyses
revealed a 31% odds reduction for myocardial infarc-
tion with CT versus traditional testing (84).
A remaining challenge in the evaluation of patients
with stable angina is determining the need/
appropriateness for revascularization for improving
MACE-free survival. Although clinical practice
guidelines still list certain anatomic characteristics
(e.g., left main, triple-vessel disease or multivessel
CHD including the proximal left anterior descending
coronary artery) as high-risk criteria, the ISCHEMIA
trial suggests that only left main disease remains
undisputed (although not tested in this trial) for
prompting revascularization in this context. The
minimum requirement for evaluating patients with
stable angina, therefore, is the exclusion of left main
coronary artery disease, which may be performed, as
in ISCHEMIA, using CT coronary angiography.
In the setting of equipoise for hard endpoints,
future research may directly address the impact of
CT-guided management and may more strongly
consider procedural complications in the outcome
analysis of conservative and invasive management
strategies. Many other atherosclerotic plaque features
can be obtained by CT and which have been associ-
ated with increased risk of adverse events (e.g., low-
density plaque, external remodeling), although none
have been prospectively validated for effectively
guiding management. Future studies may delineate if
some of these features yield incremental value for
identifying patients who may benefit from advanced
interventions.
Functional flow reserve (FFR)-guided management
has been used for a subset of patients with stable CHD
with claims of cost-effectiveness and improved pa-
tient outcome (86,87). Conceptually, the ISCHEMIA
trial, at least partially, invalidates the concept of FFR-
guided treatment, as it is based on the idea of treating
ischemia-inducing lesions. Indeed, the FAME 2 study
did not find reduced hazard for death or myocardial
infarction among patients with stable CHD assigned
to FFR-guided revascularization versus medical
management despite advantaging the FFR arm by
allocating DAPT in a much greater proportion versus
OMT and by establishing restrictive criteria for peri-
procedural myocardial infarctions (8,88). Further-
more, cost savings and apparent outcome benefits
with FFR-guided management reported from obser-
vational studies lack true control groups without FFR
or revascularization (87). Invasive and noninvasive
FFR evaluation are costly and, at present, remain
without conclusive evidence of improved patient
outcome versus OMT. Alongside cost constraints, the
use of FFR should be confined to the few situations in
which symptoms cannot be controlled by medication
and a culprit lesion cannot be identified.
A streamlined evaluation and management algo-
rithm for patients with stable angina is provided in
the Central Illustration. Most patients will require a
single test and no revascularization. Stress testing
may be considered in cases where management is
affected (e.g., uncertainty of symptom origin or
severity), although a careful history should establish
symptom characteristics in most cases. Functional
testing may also be helpful in low risk patients or
cases of poor CT image quality (e.g., in the setting of
very severe coronary artery calcification or motion
artifacts).
Patients with significant left main disease ($50%
stenosis) have been excluded from enrollment in
recent clinical trials with a conservative treatment
strategy and thus may be identified by CT coronary
angiography and considered for revascularization. In
addition, BARI-2D and FREEDOM support CABG in
diabetic patients with extensive CHD (e.g., 3-vessel
involvement) (49,56,89). Patients with multivessel
CHD and severe left ventricular systolic dysfunction
(ejection fraction 35%) may be considered for CABG
based on the STICH trial (58). The decision to perform
revascularization in most patients with stable CHD,
however, should be symptom driven.
SUMMARY AND CONCLUSIONS
Coronary heart disease is best addressed by a
comprehensive approach aimed at halting athero-
sclerotic disease and reducing the risk of thrombosis.
Unfortunately, our success in optimal risk factor
2262

modification in patients with stable CHD remains
poor: only 41% of patients achieved all basic goals in
the recent ISCHEMIA trial, with success rates likely
even lower outside the rigorous clinical trial context.
A greater focus on achieving prevention goals in pa-
tients with CHD will have a substantial impact on
patient outcome and rates of hospitalization and
more resources and incentives should be allocated for
improved secondary prevention.
The ISCHEMIA trial suggests that even selected,
high-risk patients with extensive ischemic burden do
not benefit from revascularization barring unaccept-
able angina despite OMT. As ISCHEMIA excluded
patients with unacceptable angina, advanced heart
failure, and those with unprotected left main disease,
our evaluation may be geared to identify such pa-
tients for consideration of revascularization along-
side an initial strategy of OMT.
Atherosclerosis is a systemic disease of the arterial
circulation, with focal areas of more severe manifes-
tation. From an imaging standpoint, the paradigm of
ischemia testing may have come to an end. Recent
evidence from COURAGE, PROMISE, SCOT-HEART,
and ISCHEMIA has demonstrated that functional
testing for inducible myocardial ischemia is inferior to
anatomic assessment for risk stratifying and managing
patients with suspected or known CHD. Consistent
with a large body of evidence, risk from CHD is medi-
ated by the extent of atherosclerotic disease burden
and not by the extent of inducible ischemia. Given that
55% of patients had nonobstructive CHD by CT in
PROMISE, which was associated with 77% of cardio-
vascular deaths and myocardial infarctions at follow-
up, there is immense opportunity to impact the dis-
ease at an earlier stage in a very large population of
patients with occult CHD.
Last, to allow a greater focus on prevention, our
health care system must adjust its reimbursement
structures and incentivize prevention. Health care
systems have begun to transition to value-based
health care and pay providers for services linked to
improved patient outcome. These initiatives need to
be strengthened to support our transition from a
focus on procedures to prevention, which is needed
to decrease the burden of CVD worldwide in the 21st
century.
AUTHOR RELATIONSHIP WITH INDUSTRY
Dr. Blaha has received grant support from Amgen Foundation; and
has been on the advisory board for Amgen, Sanofi, Regeneron,
Novartis, Novo Nordisk, Bayer, Akcea, and Kowa. Dr. Arbab-Zadeh
has received grant support from Canon Medical Systems. All other
authors have reported that they have no relationships relevant to the
contents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr. Armin A.
Zadeh, Department of Medicine, Division of Cardiol-
ogy, Johns Hopkins University School of Medicine,
600 North Wolfe Street, Halsted 562, Baltimore,
Maryland 21287–0025. E-mail: azadeh1@jhmi.edu.
Twitter: @Armin_Zadeh.
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KEY WORDS atherosclerosis, coronary
artery disease, coronary heart disease,
ischemic syndrome, stable ischemic heart
disease
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