Treating angina

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To stent or not to stent? Treating angina after
ISCHEMIA—introduction
Thomas F. Lüscher 1
* and Filippo Crea2,3
1
Royal Brompton & Harefield Hospitals, Heart Division and Imperial College, National Heart & Lung Institute, London, UK; 2
Department of Cardiovascular Medicine, Fondazione
Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; and 3
Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
The problem
In 1772, the English physician William Heberden gave a talk at the
Royal Society in London on some account of a disorder of the breast
as he called it. He described it in a seminal fashion that remains valid
today: ‘Those who are afflicted with it, are seized while they are walk-
ing (more especially if it be up hill, and soon after eating) with a painful
and most disagreeable sensation in the breast, which seems as if it
would extinguish life. . .; but the moment they stand still, all this un-
easiness vanishes. . . .The pain is sometimes situated in the upper
part, sometimes in the middle, sometimes at the bottom of the os
sterni, and often more inclined to the left than to the right side. It like-
wise very frequently extends from the breast to the middle of the left
arm. The seat of it and sense of strangling and anxiety with which it is
attended may make it not improper to be called angina pectoris’.1
Heberden meticulously described a symptom, but he did not
understand the disease. Edward Jenner noticed thickened coronary
arteries at autopsy of his colleague John Hunter who had died sud-
denly after an angina attack in 1793,2
but it took decades for a first
remedy for angina pectoris and even longer for a true understanding
of the underlying disease.
The remedies
Thomas Lauder Brunton was the first to describe the effects of amyl
nitrite in angina pectoris in the Lancet in 1867.3
Twelve years later,
Thomas Murrell introduced what we still prescribe today: nitrogly-
cerine.4
For the decades to follow, however, no progress occurred
until 30 October 1958 when Mason Sones by mistake performed the
first coronary angiography in a 26-year-old gentleman with rheumatic
heart disease.5
Ever since, it was possible to visualize the narrowings
of epicardial coronary arteries that were and still are considered the
major cause of angina pectoris. Sir James Whyte Black, Nobel
Laureate in 1988, then discovered the beta-blocker propranolol in
1964.6
At the same time, calcium channel blockers such as verapamil,
diltiazem and nifedipine were developed.7
These three classes of
drugs remain the cornerstones of optimal medical therapy (OMT) of
angina pectoris today. More recently, nicorandil, a hybrid of nitrate
and a potassium channel opener,8
ranolazine that blocks late inward
sodium currents in cardiomyocytes,9
and finally, ivabradine, an If-
channel blocker in the sinus node,10
were added to the medical arma-
mentarium but with less evidence of efficacy.
In 1967, the Argentinian cardiac surgeon René Favaloro, working
at the Cleveland Clinic, used a saphenous vein of the lower limb and
sewed it in reverse order to the ascending aorta and distal to the nar-
rowing into a diseased coronary artery—and coronary artery bypass
grafting (CABG) was born.11
Indeed, CABG showed a marked im-
provement of symptoms in patients with coronary artery disease and
was ever since increasingly used in such patients. Twenty years later,
Andreas Grüntzig, working at the University Hospital Zurich, intro-
duced percutaneous transluminal coronary angioplasty (PTCA) and
opened the door for interventional cardiology.12
PTCA, later
renamed percutaneous coronary intervention (PCI) with the intro-
duction of stents, became one of the most commonly performed
medical procedures around the globe.
The controversy
In spite of all the success of CABG and PCI, debates and doubts on
their effectiveness continued. Specifically, the following questions
were again and again asked: do revascularization procedures such as
CABG and PCI really improve symptoms of angina pectoris? Do
these procedures improve outcomes as well, i.e. do they prevent
myocardial infarction and premature death?
The initial enthusiasm for PCI was dampened by the COURAGE
trial,13
showing no benefit of percutaneous revascularization over
OMT. However, the trial was criticized as it recruited only a small
proportion of patients treated in the participating centres and as bare
metal stents had been used. It was argued that, with the new drug-
eluting stents, things would be completely different. Then came
* Corresponding author. Tel: þ41 7502 008 487, Email: cardio@tomluescher.ch
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
European Heart Journal (2021) 42, 1387–1400 SPECIAL ARTICLE
doi:10.1093/eurheartj/ehab069 Ischaemic heart disease
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ORBITA,14
comparing OMT with PCI using drug-eluting stents in a
sham-controlled design and was again neutral. This again was
criticized as the trial was very small, and although symptoms and ex-
ercise tolerance only showed a trend, regional wall motion improved
significantly in the stress echocardiograms.15
Thus, this uncertainty
called for a large definitive trial. The ISCHEMIA trial presented at the
American Heart Association Scientific Sessions in November 2019
and later published in the New England Journal of Medicine16
tried to
fulfil this gap.
What, when, and for whom?
The data are the backbone of a trial, but their interpretation is often
not so straight forward. In this article, therefore, the editors of the
European Heart Journal present two different, but complementary
views by highly respected experts in the field. While Bernard Gersh
and Deepak Bhatt in their contribution ‘The Impact of the ISCHEMIA
Trial on the Indications for Angiography and Revascularization in
Patients with Stable Coronary Artery Disease’ lean more towards an
interventional reading of the data, William Boden and Peter Stone
present in their contribution ‘Why a Conservative Approach with
Optimal Medical Therapy is the Preferred Initial Management
Strategy for Chronic Coronary Syndromes’ the more conservative
view.
Conflict of interest: none declared.
References
1. Heberden W. Some account of a disorder of the breast. Med Trans R Coll Phys
Lond 1772;2:59–67.
2. Osler W. Lectures on Angina Pectoris and Allied States: New York: D. Appleton;
1897.
3. Brunton TL. On the use of nitrite of amyl in angina pectoris. Lancet 1867;90:
97–98.
4. Murrell W. Nitro-glycerine as a remedy for angina pectoris. Lancet 1879;113:
225–227.
5. Hall RJ. In memoriam: F. Mason Sones, Jr. M.D. Tex Heart Inst J 1985;12:
356–358.
6. Quirke V. Putting theory into practice: James Black, receptor theory and the de-
velopment of the beta-blockers at ICI, 1958-1978. Med Hist 2006;50:69–92.
7. Godfraind T. Discovery and development of calcium channel blockers. Front
Pharmacol 2017;8:286.
8. Kukovetz WR, Holzmann S, Pöch G. Molecular mechanism of action of nicoran-
dil. J Cardiovasc Pharmacol 1992;20: S1–7.
9. Siddiqui MAA, Keam SJ. Ranolazine. Drugs 2006;66:693–710.
10. Giavarini A, de Silva R. The role of ivabradine in the management of angina pec-
toris. Cardiovasc Drugs Ther 2016;30:407–417.
11. Favaloro RG. Landmarks in the development of coronary artery bypass surgery.
Circulation 1998;98:466–478.
12. Meier B, Bachmann D, Lüscher TF. 25 years of coronary angioplasty: almost a
fairy tale. Lancet 2003;361:527.
13. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ,
Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin
G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA,
Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group.
Optimal medical therapy with or without PCI for stable coronary disease. N Engl
J Med 2007;356:1503–1516.
14. Al-Lamee R, Thompson D, Dehbi H-M, Sen S, Tang K, Davies J, Keeble T,
Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y,
Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel
R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP, Al-Lamee R,
Thompson D, Sen S, Tang K, Davies J, Keeble T, Kaprielian R, Malik IS, Nijjer SS,
Petraco R, Cook C, Ahmad Y, Howard J, Shun-Shin M, Sethi A, Baker C, Sharp
A, Ramrakha P, Gerber R, Talwar S, Assomull R, Foale R, Mayet J, Wensel R,
Thom SA, Davies JE, Francis DP, Khamis R, Hadjiloizou N, Khan M, Kooner J,
Bellamy M, Mikhail G, Clifford P, O’Kane P, Levy T, Swallow R, Francis DP;
ORBITA investigators. Percutaneous coronary intervention in stable angina
(ORBITA): a double-blind, randomised controlled trial. Lancet 2018;391:31–40.
15. Chaitman BR, Mori Brooks M, Fox K, Lüscher TF. ORBITA revisited: what it real-
ly means and what it does not? Eur Heart J 2018;39:963–965.
16. Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE,
Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ,
Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G,
Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard
MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A,
Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller
TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S,
Mavromichalis S, Kirby R, Jeffries NO, Harrell FE, Rockhold FW, Broderick S,
Ferguson TB, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA
Research Group. Initial invasive or conservative strategy for stable coronary dis-
ease. N Engl J Med 2020;382:1395–1407.
1388 T. F. Lüscher and F. Crea
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ISCHEMIA—the impact of the ISCHEMIA trial
on the indications for angiography and
revascularization in patients with stable
coronary artery disease
Bernard J. Gersh 1
* and Deepak L. Bhatt 2
1
Department of Cardiovascular Medicine, Mayo College of Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA; and 2
Department of Cardiovascular
Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
• The ISCHEMIA trial is a large, multinational trial sponsored by the
National Heart, Lung, and Blood Institute, which has recently been
published.1
The main trial compares coronary revascularization
and optimal medical therapy (OMT) vs. OMT alone in 5179
patients enrolled after stress testing, in addition to two ancillary
studies in patients with chronic kidney disease (777 patients)2
and
a quality of life sub-study in the main ISCHEMIA trial, which
enrolled 4617 patients.3
• Crucial to placing the results of this important trial into perspec-
tive is a review of where we stood prior to the publication of
ISCHEMIA, in regard to the indications for coronary revasculariza-
tion vs. OMT in patients with chronic stable angina, more recently
referred to as chronic coronary syndromes.4
Trials of the indications for revascularization have a long history dat-
ing back to the publication of the Veterans Affairs (VA) cooperative
study of surgical vs. medical therapy for left main coronary disease.5
Since that time, a considerable body of evidence has been acquired,
albeit far from perfect, but notwithstanding, this has been the basis
for most of our societal guidelines on the management of stable an-
gina. Nonetheless, it is relevant to highlight the strengths and the limi-
tations of what evidence we have and to clarify the gaps in our
knowledge base that were the impetus and, in fact, the rationale for
the ISCHEMIA trial.
Indications for revascularization:
prior trials
The early trials of coronary bypass surgery vs. medical therapy in
patients with stable coronary artery disease had major limitations in
terms of their relatively small sample size, lack of use of the internal
mammary artery in the majority, and all of these preceded the con-
temporary era of aggressive secondary prevention, which is the
cornerstone of OMT.6
Nonetheless, these trials established the
superiority of coronary bypass over medical therapy in the short to
intermediate term for the relief of symptoms and in regard to sur-
vival; the ‘sicker the patient’, the greater the benefit of revasculariza-
tion.6
Mortality benefits were demonstrated in patients with
multivessel disease and left ventricular dysfunction (CASS trial); in
patients with severe angina and multivessel disease, including prox-
imal left anterior descending coronary disease (ECSS); and in patients
with left main coronary disease (VA trial).5–8
It is sobering to realize
that among patients undergoing angiography, the guideline-based
indications for revascularization with the objective of prolonging sur-
vival are driven by the categorization of disease severity and left ven-
tricular function established by the three original trials of bypass
surgery vs. medical therapy 30years ago.
Subsequently, there were multiple trials of percutaneous translu-
minal coronary angioplasty (PTCA) vs. medical therapy, percutan-
eous coronary intervention (PCI) with stenting vs. medical therapy,
followed by several large meta-analyses of 8–12 PCI trials.6,9
For the
most part, these trials did not show any benefit of PTCA/PCI on
death and myocardial infarction (MI) in stable patients with coronary
artery disease. Four trials provided exceptions: (i) the Asymptomatic
Cardiac Ischemia Pilot study of angina-guided vs. Holter-guided med-
ical therapy in 558 patients demonstrated a benefit on death and MI
at 2 years in a subset treated with bypass surgery10
; (ii) in the TIME
trial of patients aged 75years or older with severe angina on medical
therapy, the invasive arm demonstrated a reduction in admissions for
acute coronary syndromes at 6 months and a trend towards a reduc-
tion in non-fatal MI at 6 months but these differences were not sus-
tained during the 4-year follow-up of 1-year survivors11,12
; (iii) in the
SWISSI II trial of 201 asymptomatic patients post MI with a positive
stress test, PCI significantly reduced the incidence of cardiac death
(P 0.01) and non-fatal MI (P 0.002) at a mean follow-up of
10.2 years13
; and (iv) in the FAME II trial of 888 patients, PCI demon-
strated a significant reduction in the need for urgent early revasculari-
zation at 12months, and at 5 years there was also a significant
reduction in late MI.14
A recent meta-analysis of the FAME 2 trial and
* Corresponding author. Tel: þ1 507 284 4441, Fax: þ1 507 266 0228, Email: gersh.bernard@mayo.edu
To stent or not to stent? 1389
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two other trials of stable patients in which PCI was based upon frac-
tional flow reserve (FFR) measurements demonstrated a reduction in
death and late MI.15
In the BARI 2D trial of patients with diabetes,
coronary artery bypass graft (CABG) surgery was associated with a
reduction in non-fatal MI16
and an additional analysis of the BARI 2D
demonstrated a benefit with CABG on death, MI, and stroke but not
from PCI in a high-risk subgroup as defined by both clinical and angio-
graphic risk scores.17
In terms of angina relief, revascularization is superior to medical
therapy, but recurrence of angina after PCI has been disturbingly high
in the PTCA and bare metal stent era. In the COURAGE trial at
3 years, differences between the PCI vs. OMT group were non-signifi-
cant.18
The primary endpoint (namely exercise duration on a tread-
mill) of the small ORBITA trial also failed to show a significant benefit
of PCI in stable angina,19
although there was greater relief of angina in
a subset of patients with a reduced FFR and instantaneous wave-free
ratio (iFR) in the PCI arm.20
The role of microvascular dysfunction
causing recurrent symptoms warrants further investigation.21
In addition, most (but not all) prior studies suggested that the ex-
tent and severity of ischaemia identified patients at higher risk for
death and MI and whose prognosis would be improved by revascula-
rization.8,22,23
In a large observational number of patients and mean
follow-up (13 919 and 8.7 years in the original manuscript).22
Results
from the COURAGE and BARI 2D trials were, however, contradict-
ory in regard to the relationship between the extent of ischaemia and
subsequent death and MI and by implication the putative benefit of
coronary revascularization.24,25
Furthermore, the role of revasculari-
zation in the setting of acute coronary syndromes is not up for
debate.
Summary of the most recent
trials of percutaneous coronary
intervention: COURAGE, BARI
2D, and FAME II
In angiographically selected patients with chronic stable angina and
preserved left ventricular function, there is no benefit from coronary
revascularization upon the endpoints of death or MI. The only two
exceptions were the high-risk subset from the BARI 2D and FAME II
trials discussed earlier. The outstanding issue, therefore, was how to
extrapolate these data to the population at large who have not
undergone angiography and the role of stress testing in identifying
suitable candidates for revascularization. What is the role of revascu-
larization in patients with moderate-to-severe ischaemia and mild to
moderate angina? This brings us to the eagerly anticipated ISCHEMIA
trial.
ISCHEMIA trial
ISCHEMIA is the largest trial of an invasive vs. conservative strategy
for patients with stable heart disease.26
The conclusions are as fol-
lows. Overall, an initial invasive strategy implemented after coronary
computed tomography (CT) angiography to exclude high-risk coron-
ary anatomy did not reduce risk over a median of 3.2 years for the
primary endpoint of cardiovascular death, MI, hospitalization for un-
stable angina, heart failure, or resuscitated cardiac arrest.1
There was
also no difference in the secondary endpoint of death or MI.
Moreover, these data are fully consistent with prior trials of revascu-
larization vs. medical therapy in stable patients. Similar findings were
noted in the ISCHEMIA-CKD study.2
In patients with angina occur-
ring on a daily, weekly, or monthly basis, revascularization resulted in
an impressive and durable improvement in angina control and in the
quality of life.3
This benefit was not observed in patients without an-
gina (and interestingly, was not seen in the ISCHEMIA-CKD cohort
either). There was a trend towards an increasing rate of spontaneous
MIs in the conservatively treated group over time, which points to
the critical need for longer-term follow-up.
Like all important trials, these results provide answers but also gen-
erate new questions. Criticisms of the trial based upon a change in
the primary endpoint in response to slow enrolment were convin-
cingly refuted, and this issue does not warrant further discussion.27
The challenge is to place this trial into a clinical perspective, to under-
stand the gaps in knowledge that have been filled, and to gauge the
potential impact of these trials upon guidelines.
ISCHEMIA—clinical perspective
Patient population
Other than the presence of ischaemia, which was severe in 44.8%
and moderate in 41% based upon stress imaging studies and judged
as severe in 83% of patients undergoing stress testing without imag-
ing, overall the randomized population was a group at low risk of
mortality. Patients were clinically stable, Canadian Cardiovascular
Society angina class was 1–2 in 92% and the median ejection fraction
was 60%.
Exclusion criteria included an acute coronary syndrome within the
preceding 2 months and documented unprotected left main coronary
disease on CT angiography (5.1%), a left ventricular ejection fraction
of 35%, unacceptable angina symptoms on medical therapy, or cor-
onary anatomy unsuitable for either PCI or CABG. Another criterion
for exclusion as stated in the design paper was ‘a patient who in the
judgement of the patient’s physician is likely to have significant unpro-
tected left main disease’.26
What is unclear are those factors, presum-
ably based upon stress test findings, underlying this specific
exclusionary criterion, and in the baseline paper, the proportion of
patients who were excluded for this reason is not provided.28
Implications on the indications for
angiography and revascularization
in patients with multivessel
disease
It is well accepted that in the presence of severe symptoms on medic-
al therapy, angiography and revascularization are indicated to im-
prove the quality of life. The presence of multivessel disease with left
ventricular dysfunction is another strong indication to improve prog-
nosis (Figure 1). It is generally accepted that severe ischaemia on imag-
ing and other adverse prognostic factors on stress testing are
1390 B. J. Gersh and D. L. Bhatt
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indications for angiography with a view to improving prognosis. The
ISCHEMIA trial, however, would strongly suggest that the presence
of moderate-to-severe ischaemia on imaging alone without other
high-risk features may not be an indication for early angiography and
that such patients could be treated initially with OMT.
In patients who have already undergone angiography, the indica-
tions for revascularization are based upon the use of prior established
anatomic-based guidelines4,29
and the hemodynamic assessment of
lesion significance (FFR or iFR) (Figure 1).30
Of note,30
in the post-ST-
elevation MI setting in the COMPLETE trial, PCI of severe angio-
graphic non-culprit lesions without preceding non-invasive assess-
ment of ischaemia produced a large and significant reduction in
spontaneous MI, with continued accrual of benefit with the longer
duration of follow-up.31
Implications for the guidelines on
angiography and revascularization
The 2018 ESC guidelines on coronary revascularization provide a
class 1B recommendation for patients with a ‘large area of ischaemia,
greater than or equal to 10% of the left ventricle’.32
The recent ESC
guidelines on chronic coronary syndromes state that in patients with-
out angina symptoms but documented ischaemia in whom ‘a large
area of ischaemia of 10% or more of the left ventricle’ is present, the
recommendation is to ‘consider revascularization on top of medical
therapy’ (Class I).4
The 2012 ACCF/AHA guidelines on stable angina
and the 2014 focused update do not specifically address the extent of
ischaemia directly but recommend angiography in patients ‘whose
clinical characteristics and results of non-invasive testing suggest ‘a
high likelihood of severe ischaemic heart disease’.29,33
The
ISCHEMIA trial suggests that it would be appropriate to reassess the
role of ischaemia alone on non-invasive testing as an indication for
coronary angiography in future reiterations of the guidelines (Figure
1). In patients with continued limiting angina on OMT, the results of
the ISCHEMIA trial strongly support angiography with a view to
revascularization to improve the quality of life.
In one respect, the results of the ISCHEMIA trial are surprising,
given prior evidence (albeit observational)22
and more recent data
using positron emission tomography,34
that moderate-to-severe is-
chaemia identifies a group at high risk who would benefit from revas-
cularization. One explanation lies in the differences between
observational data and randomized trials, and it has long been estab-
lished that patients in trials always do better than historical con-
trols.35
Another potential explanation is that the large observational
studies included many patients at higher risk based upon a number of
other prognostic factors in addition to the extent of ischaemia alone
and that many such patients were excluded from the ISCHEMIA trial.
In the ISCHEMIA trial, although the extent of anatomical coronary
disease was a prognostic predictor, this was not the case in patients
stratified by the severity of ischaemia (Reynolds H, Maron D, unpub-
lished data). The lack of difference between the invasive vs. conserva-
tive strategies was seen in both groups. Nonetheless, the observation
that the event rate was lower in patients with more severe degrees
of ischaemia is puzzling and raises the question whether patients who
were more symptomatic and considered at higher risk were
excluded, particularly in countries with a low threshold for revascula-
rization.36
Viewed in this context, the presence of ischaemia is just
one of many potential risk factors which in isolation may not confer
high enough risk to benefit from revascularization.
Implications for non-invasive stress
testing
The use of a blinded CT angiography in the ISCHEMIA trial has pro-
vided useful but somewhat disturbing information. A total of 14.3%
of patients with a positive stress test for ischaemia or significant is-
chaemia had no obstructive disease, and significant left main coronary
artery disease was identified in 5.1% of patients. It is possible that the
use of non-invasive stress testing, particularly in patients with a lower
likelihood of obstructive coronary disease, will decline in favour of an
increase in use of CT angiography.4,37,38
Conclusions
We need to accept the limitations of published trials of revasculariza-
tion which largely antedate the use of third generation stents,
improved antithrombotic therapy, use of FFR and iFR, the radial ar-
tery approach, multiple arterial grafting, and newer medical therapies
such as the sodium-glucose co-transporter 2 inhibitors, and
glucagon-like peptide-1 agonists. All trials that take place against a
backdrop of rapid changes in technologies and medical therapies are
to some extent obsolete once completed, but they are the best data
that we have and sufficient to provide a consensus underlying the
guideline recommendations and appropriate use criteria. Interpreting
data in trials and registries is complex and although randomized trials
that mandate equipoise are restrictive and have ‘entry bias’,39
all
registries and non-randomized studies are subject to confounders.
The clinical assessment of the patient for revascularization needs to
integrate multiple dimensions including age, comorbidities and frailty,
procedural stroke risk, coronary anatomy and physiology, psycho-
logical and social characteristics, patient preferences, and operator
Implications of ISCHEMIA Trial
Indications for angiography and revascularization
* ISCHEMIA trial would not support this as an indication for angiography
y Severe symptoms - Ç quality of life
y Severe ischemia (imaging plus other high-risk
stress test features) - Ç survival
y Severe ischemia (imaging alone) - Ç survival ?*
y LV dysfunction - Ç survival
y Use prior anatomic-based guidelines
y Hemodynamic lesion assessment (FFR or iwFR)
In patients who have undergone angiography
Figure 1 Indications for angiography and revascularization: im-
pact of the ISCHEMIA trial. FFR, fractional flow reserve; iwFR, in-
stantaneous wave-free ratio; LV, left ventricular.
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proficiency. The ISCHEMIA trial greatly adds to our existing data on
the management of patients with chronic coronary syndromes by
identifying a subset of patients previously considered at high risk, as a
lower risk subgroup who can be initially managed safely with
guideline-based OMT with the knowledge that an invasive approach
is effective in achieving symptom relief in those with continued limit-
ing angina. It would be convenient if a well-conducted trial like
ISCHEMIA would eliminate ambiguity but the interpretation of the
results is more nuanced and reinforces the role of shared-decision
making when applying the data in clinical practice.
Conflict of interest: Dr. Deepak L. Bhatt discloses the following
relationships - Advisory Board: Cardax, CellProthera, Cereno
Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape
Cardiology, MyoKardia, PhaseBio, PLx Pharma, Regado Biosciences;
Board of Directors: Boston VA Research Institute, Society of
Cardiovascular Patient Care, TobeSoft; Chair: American Heart
Association Quality Oversight Committee; Data Monitoring
Committees: Baim Institute for Clinical Research (formerly Harvard
Clinical Research Institute, for the PORTICO trial, funded by St. Jude
Medical, now Abbott), Cleveland Clinic (including for the ExCEED
trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE
2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School
of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo),
Population Health Research Institute; Honoraria: American College
of Cardiology (Senior Associate Editor, Clinical Trials and News,
ACC.org; Vice-Chair, ACC Accreditation Committee), Baim
Institute for Clinical Research (formerly Harvard Clinical Research
Institute; RE-DUAL PCI clinical trial steering committee funded by
Boehringer Ingelheim; AEGIS-II executive committee funded by CSL
Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter),
Canadian Medical and Surgical Knowledge Translation Research
Group (clinical trial steering committees), Duke Clinical Research
Institute (clinical trial steering committees, including for the
PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP
Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the
American College of Cardiology (Guest Editor; Associate Editor),
K2P (Co-Chair, interdisciplinary curriculum), Level Ex,
Medtelligence/ReachMD (CME steering committees), MJH Life
Sciences, Population Health Research Institute (for the COMPASS
operations committee, publications committee, steering committee,
and USA national co-leader, funded by Bayer), Slack Publications
(Chief Medical Editor, Cardiology Today’s Intervention), Society of
Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME
steering committees); Other: Clinical Cardiology (Deputy Editor),
NCDR-ACTION Registry Steering Committee (Chair), VA CART
Research and Publications Committee (Chair); Research Funding:
Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer
Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai,
Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS
Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic,
MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche,
Sanofi, Synaptic, The Medicines Company; Royalties: Elsevier (Editor,
Cardiovascular Intervention: A Companion to Braunwald’s Heart
Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St.
Jude Medical (now Abbott), Svelte; Trustee: American College of
Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk,
Takeda.
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Am Coll Cardiol 2019;74:1734–1736.
35. Sacks H, Chalmers TC, Smith H. Randomized versus historical controls for clinic-
al trials. Am J Med 1982;72:233–240.
36. Antman EM, Braunwald E. Managing stable ischemic heart disease. N Engl J Med
2020;382:1468–1470.
37. Blankstein R, Bittencourt MS, Bhatt DL. Coronary CTA in the evaluation of sta-
ble chest pain: clear benefits, but not for all. J Am Coll Cardiol 2017;69:
1771–1773.
38. Lowenstern A, Alexander KP, Hill CL, Alhanti B, Pellikka PA, Nanna MG, Mehta
RH, Cooper LS, Bullock-Palmer RP, Hoffmann U, Douglas PS. Age-related differ-
ences in the noninvasive evaluation for possible coronary artery disease: insights
from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain
(PROMISE) trial. JAMA Cardiol 2020;5:193–201.
39. Brown ML, Gersh BJ, Holmes DR, Bailey KR, Sundt TM 3rd. From randomized
trials to registry studies: translating data into clinical information. Nat Clin Pract
Cardiovasc Med 2008;5:613–620.
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ISCHEMIA—why a conservative approach with
optimal medical therapy is the preferred initial
management strategy for chronic coronary
syndromes: insights from the ISCHEMIA trial
William E. Boden1
* and Peter H. Stone2
1
VA New England Healthcare System, Boston University School of Medicine, VA Boston Campus, 150 S. Huntington Avenue, Boston, MA 02130, USA; and 2
Division of
Cardiovascular Medicine, Brigham Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Introduction
Whether percutaneous coronary intervention (PCI) when added to
optimal medical therapy (OMT) improves clinical outcomes in
patients with chronic coronary syndromes (CCS) has been a continu-
ing area of investigation for more than two decades. While myocar-
dial revascularization, principally with PCI, has been the standard of
care for patients with acute coronary syndromes because it improves
survival and reduces recurrent myocardial infarction (MI),1,2
its role
in patients with CCS is less clear.2,3
Although several randomized
clinical trials (RCTs) and meta-analyses indicate that OMT with PCI
more effectively relieves angina, decreases the use of anti-anginal
medications, and improves functional status and quality of life com-
pared to OMT alone, none of these trials have demonstrated convin-
cingly that an initial strategy of OMT þ PCI improves ‘hard’
outcomes, including all-cause and cardiovascular mortality and MI
during long-term follow-up.4–12
The recently reported results of the
ISCHEMIA trial,13,14
the largest prospective trial of OMT with or
without myocardial revascularization, provide unique insight con-
cerning the incremental benefit of revascularization in chronic coron-
ary artery disease (CAD) patients with moderate-to-severe
ischaemia and inform the selection of optimal management strategy.
The evidence base for an initial
conservative approach to stable
coronary artery disease
management prior to the
ISCHEMIA trial
In the early CCS era, registry studies indicated that patients with
higher-risk coronary anatomy (greater number of arteries diseased,
presence of 95% proximal obstructions, and involvement of the left
anterior descending coronary artery) had improved survival when
treated with coronary artery bypass graft (CABG) surgery compared
to medical therapy and, in addition, that patients who exhibited pro-
gressively higher-risk coronary anatomic features experienced pro-
gressively improved survival when treated with CABG compared to
the first-generation PCI.15
An early registry study demonstrated that
patients with ischaemic myocardium 10% on radionuclide stress
imaging had substantially lower mortality when they were treated
with a revascularization procedure compared to medical therapy.16
These observations led to the formulation of guidelines recommend-
ing revascularization procedures for mortality benefit for patients
with proximal left anterior descending coronary artery obstruction
50% (class of recommendation IA), for a proven large area of is-
chaemia 10% (class of recommendation IB) and for stenoses with
fractional flow reserve (FFR) 0.80 in patients with angina or a posi-
tive stress test.17–20
Since 2000, which is generally regarded as the era of contemporary
OMT that includes both disease-modifying therapeutic interventions
(statins, inhibitors of the renin-angiotensin system, in addition to
newer P2Y12 inhibitors, anti-diabetic drugs, and agents to further
lower dyslipidemic risk) along with lifestyle interventions that include
diet, regular exercise, and smoking cessation, there have been three
pivotal, prospective RCTs that have rigorously examined the role of
OMT with or without revascularization (principally PCI) in patients
with chronic angina and CCS:6,8,9
the COURAGE trial showed that in
2287 patients with CCS and objective evidence of ischaemia and/or
angina, who were randomized after coronary angiography to OMT
alone or to OMT plus PCI with largely bare metal stents, there was
no difference in the primary composite endpoint of all-cause mortal-
ity or non-fatal MI between the two management strategies after a
mean follow-up of 4.6years,6
nor was there a reduction in mortality
during extended follow-up (median 11.9 years).21
While PCI was
associated with a reduction in angina compared to OMT alone initial-
ly, this benefit attenuated after 2 years of follow-up. The BARI 2D trial
of 2368 patients with CCS and Type 2 diabetes mellitus8
was likewise
randomized after coronary angiography and stratified into those
* Corresponding author. Tel: þ1 857 364 5613, Fax: þ1 857 364 4424, Email: william.boden@va.gov
1394 W. E. Boden and P. H. Stone
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most anatomically suitable for revascularization with PCI or CABG
surgery with patients in each stratum then randomized to either
revascularization or OMT. Despite this higher-risk clinical profile,
there was no significant difference in all-cause mortality (the co-
primary endpoint) between the OMT or revascularization groups
over a mean 5-year follow-up, though there was a significant reduc-
tion in the pre-specified composite secondary endpoint of mortality,
non-fatal MI, and stroke in the CABG-treated (but not the PCI-
treated) patients—driven entirely by a reduction in MI—as com-
pared with OMT alone.8
The smaller FAME 2 was a trial of 888
patients with multivessel CAD and FFR 0.80 who were randomized
to FFR-guided PCI vs. medical therapy in patients with FFR þ lesions.9
FAME 2 showed that the primary endpoint of death, MI or urgent
revascularization was significantly reduced with PCI, but this differ-
ence was driven solely by urgent revascularization, the most preva-
lent component of the composite, but prone to bias due to the
open-label design of the trial, but, like COURAGE and BARI 2D,
there was no benefit from PCI vs. OMT on the ‘hard’ outcomes of
death or MI at a median follow-up of 7 months, as well as at both
2 years22
and 5 years.23
At 5 years, there was a trend towards
reduced spontaneous MI in the PCI group, but this did not reach stat-
istical significance, while a recent meta-analysis of FAME 2, DANAMI-
3-PRIMULTI, and Compare-Acute indicated a significant reduction in
MI at a median 35-month Follow-up.24
Moreover, several meta-analyses of CCS were performed,10–12
including one with 5286 patients who had documented myocardial is-
chaemia, of whom over 75% underwent stenting and 50% received
statins, yet there was no significant reduction in death, non-fatal MI,
unplanned revascularization, or a durable reduction in angina with
PCI on the top of OMT, as compared with OMT alone.12
Nevertheless, there were several limitations and criticisms of these
three trials in that all CCS subjects were randomized only after diag-
nostic coronary angiography was performed, which may have intro-
duced a selection bias against the PCI arm of the trial by excluding
higher-risk patients who may have most benefitted from revasculari-
zation.25
In addition, none of these RCTs stipulated a pre-defined
threshold of baseline myocardial ischaemia as an inclusion criterion
prior to randomization. Thus, there was a prevalent belief that those
CCS patients with moderate-to-severe ischaemia in whom one might
reasonably expect a proportionately greater clinical benefit (and car-
diac event reduction) with myocardial revascularization were system-
atically excluded—a perspective that had been fuelled for decades by
observational data in over 10 000 CCS patients showing that ischae-
mia 10% of the left ventricular myocardium was associated with a
significant prognostic improvement with myocardial revasculariza-
tion.16
This ‘ischaemia hypothesis’ was the fundamental premise for
undertaking the ISCHEMIA trial, which was designed explicitly to ad-
dress the methodological shortcomings of prior RCTs,26
including
randomization prior to coronary angiography, the broad-based util-
ization of newer generation drug-eluting stents, the more widespread
use of FFR to guide revascularization and a therapeutic goal to
achieve more complete revascularization—all important features
that were incorporated into the trial.
Lastly, none of these trials (including ISCHEMIA) were sham-
controlled, so the possibility of a long-suspected ‘placebo effect’ of
PCI on anginal symptoms could not be excluded with certainty, a de-
sign feature unique to the small ORBITA trial27
of 200 stable angina
patients that compared PCI vs. sham control on a background of
OMT in subjects with stable, high-grade single-vessel CAD. The pri-
mary endpoint of placebo-adjusted increment in exercise time and
several secondary endpoints were not significantly different between
the treatment groups at 6 weeks of follow-up.27
These results under-
scored, for the very first time, the possibility of a placebo effect con-
tributing to angina relief with PCI.27,28
The ISCHEMIA trial
The recently published ISCHEMIA trial13,14
is the largest comparative
effectiveness trial (n= 5179) of an invasive vs. conservative manage-
ment strategy in patients with CCS8,9
and addressed key limitations
of previous trials by: (i) enrolling high-risk patients with at least mod-
erate inducible myocardial ischaemia at baseline; (ii) randomizing
patients prior to diagnostic coronary angiogram to reduce both re-
ferral and selection bias; (iii) incorporating state-of the-art revascula-
rization techniques including FFR-guided PCI and newer generation
drug-eluting stents at high-volume interventional sites who were pre-
selected for their skill and proficiency in revascularization; and (iv) uti-
lizing algorithm-based OMT and guidance for escalating therapies in
both arms of the trial.26
The primary outcome was a five-component
composite endpoint comprising cardiovascular death, non-fatal MI,
hospitalization for unstable angina, hospitalization for heart failure,
and resuscitated cardiac arrest, while the major secondary endpoints
were time to cardiovascular death or non-fatal MI, and anginal symp-
toms and quality of life as assessed by the Seattle Angina
Questionnaire-7 tool.
Blinded coronary computed tomography angiography (CCTA)
was performed prior to enrolment to exclude the presence of left
main CAD and the absence of obstructive CAD. Over a median 3.2-
year follow-up, 318 primary outcome events were observed; the
adjusted hazard ratio (HR) for the invasive strategy as compared with
the conservative strategy was 0.93 [95% confidence interval (CI)
0.80, 1.08, P = 0.34].14
At 6 months, the cumulative event rate was
5.3% in the invasive strategy group and 3.4% in the conservative strat-
egy group (1.9 percentage points, 95% CI 0.8, 3.0), and at 5 years, the
cumulative event rate was 16.4% and 18.2%, respectively (-1.8 per-
centage point difference, 95% CI- 4.7, 1.0).14
There was no hetero-
geneity of treatment effect based on a broad range of pre-specified
subgroups, including the presence of diabetes mellitus, new or more
frequent angina, high rate of OMT attainment, CAD severity based
on 50% stenosis (i.e. single, double, or triple vessel disease), and the
presence of proximal left anterior descending coronary stenosis
50%, or degree of baseline ischaemia. There was no difference in
total death in the invasive strategy group vs. the conservative strategy
group (HR 1.05, 95% CI 0.83, 1.32) or in cardiovascular death (HR
0.87, 95% CI 0.66, 1.15). There was also no difference in the rate of
overall MI between the two treatment strategies (adjusted HR 0.92,
95% CI 0.76, 1.11), although there were more procedural infarctions
in the invasive strategy group in early follow-up, and more spontan-
eous MIs in the conservative strategy group in the late follow-up
period.14
There were significant and durable improvements in angina
control and quality of life metrics with an invasive strategy in those
patients who had significant angina [daily/weekly (20% of patients)],
but more modest improvements in patients with monthly angina
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(44% of patients), while there was no improvement in patients with
less frequent or no angina (35% of patients).29
The most controversial finding of ISCHEMIA was the incidence of
MI, which was sensitive to the particular biomarker definition used,
and which impacted the primary and some secondary outcomes. The
primary MI definition was based on the 3rd Universal Definition of
MI, except for more rigorous biomarker criteria for peri-procedural
MI after PCI or CABG. The secondary definition of MI was based on
the 3rd Universal MI definition alone and utilized the biomarker 99%
upper reference limit from the assay manufacturer, resulting in more
procedural (Type 4A and Type 5) MI events, though these may be of
uncertain clinical importance. Using the secondary definition of MI,
the estimated cumulative event rate at 6 months for the primary out-
come was three-fold higher (10.2% in the invasive strategy group and
3.7% in the conservative strategy group), a statistically significant dif-
ference of 6.5 percentage points (95% CI 5.2, 7.9), while the esti-
mated cumulative event rate at 5 years was 21.2% in the invasive
strategy group and 19.0% in the conservative strategy group (differ-
ence, 2.2 percentage points; 95% CI- 0.7, 5.2) that was not significant-
ly different.14
There were significantly fewer spontaneous (Type 1)
MI events at 4 years in the invasive strategy, though these events
were not significantly different at 3 and 5 years. Thus, it is difficult to
interpret the clinical significance of the observed late reduction in
spontaneous MI in the invasive strategy. While it is plausible that
revascularization with CABG can lower spontaneous MI (as
observed in the BARI 2D trial) because CABG bypasses both stenot-
ic epicardial segments and non-obstructive rupture-prone vulnerable
plaques,30
it is more difficult to explain why this would be true for
PCI, as the majority of spontaneous MI events post-PCI occur as a
consequence of progression of atherosclerotic disease in non-flow-
limiting (or non-instrumented) coronary segments remote from the
stented target lesion(s). Furthermore, the difference in spontaneous
MI rates might be confounded by an imbalance in the use of dual anti-
platelet therapy, which was significantly higher in the invasive strategy
and thus favored the invasive strategy for much of the first 2 years of
follow-up. It is also noteworthy that the reduction in spontaneous MI
was observed even in those randomized to the invasive strategy who
did not undergo revascularization (21% of the invasive cohort),
which suggests strongly that this benefit cannot be attributed solely
to revascularization. Perhaps most importantly, the late 2.2% reduc-
tion in spontaneous MI observed with the invasive strategy did not
translate into a reduction in either cardiovascular or all-cause mortal-
ity at 3.2years, which challenges the interpretation that there is a
greater prognostic significance of these spontaneous MI events com-
pared with procedural MIs.
A recent updated meta-analysis of RCTs of 14 877 patients with
CCS randomized to routine revascularization strategy (primarily
PCI) vs. initial conservative strategy (of which ISCHEMIA and
ISCHEMIA-CKD were the largest trials) demonstrated that, although
there was no difference in mortality or total MI between the
Management of Patients with Stable CAD
Infrequent or acceptable angina
(~80% of patients )
Exclude CHF NYHA III/IV, recent ACS or revascularization
Exclude LMCAD: Consider CCTA; stress test
Exclude LVEF 35%: Transthoracic Echocardiography
Identify non-obstructive CAD or
microvascular ischemia: CCTA, PET-CT perfusion scan
Continue conservative strategy of OMT
If LMCAD suspected or confirmed
Invasive strategy of coronary angiography
and revascularization as indicated
Daily/weekly angina or unacceptable QoL
(~20% of patients)
Determine if patient fits entry criteria of ISCHEMIA:
Initiate or continue conservative strategy of OMT
and lifestyle modification
Maintain clinical surveillance to assess therapeutic response to treatment. If deterioration of sx or QoL,
then invasive strategy
Figure 1 Management of patients with stable coronary artery disease. ACS, acute coronary syndrome; CCTA, coronary computed tomography
angiography; CHF, congestive heart failure; CT, computed tomography; LMCAD, left main coronary artery disease; LVEF, left ventricular ejection
fraction; NYHA, New York Heart Association; OMT, optimal medical therapy; PET, positron emission tomography; QoL, quality of life; sx,
symptoms.
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treatment strategies, revascularization was associated with a reduced
risk of non-procedural MI [relative risk (RR) 0.75, 95% CI 0.67, 0.85]
and unstable angina (RR 0.64, 95% CI 0.45, 0.92), but an increased
risk of procedural MI (RR 2.48, 95% CI 1.86, 3.31).31
In the companion ISCHEMIA trial study (ISCHEMIA-CKD) of
patients with advanced kidney disease (defined as estimated glomeru-
lar filtration rate 30mL/min/body surface area), with the same entry
criteria and randomized treatment strategies, there was likewise no
difference in outcome between invasive vs. conservative groups for
the primary or secondary endpoints, although the invasive strategy
was associated with a higher incidence of stroke than the conserva-
tive strategy (HR 3.76, 95% CI 1.52, 9.32, P = 0.004) and higher inci-
dence of death or initiation of dialysis (HR 1.48, 95% CI 1.04, 2.11,
P = 0.03).32
There was no substantial or sustained benefits with re-
gard to angina-related health status between the two groups.33
A small sub-study of 212 patients with Changes in ischaemia and
Angina over One year, known as CIAO-ISCHEMIA, is designed to as-
sess these patients who were enrolled but not randomized into
ISCHEMIA because they had no obstructive CAD on CCTA. This
study seeks to assess clinical outcomes in this important subgroup
during long-term follow-up.
It is acknowledged that ISCHEMIA follow-up is limited (3.2 years)
and it cannot be excluded that differences between the groups may
emerge at longer-term follow-up.
How do we explain the results of
ISCHEMIA and earlier
randomized clinical trials?
Mechanistic implications for
understanding prognosis in
patients with chronic coronary
syndromes
The results of the ISCHEMIA trial underscore the fundamental vascu-
lar biology of coronary atherosclerosis and, consequently, the impli-
cations for prognosis and management, i.e. a severe luminal
obstruction and the resultant ischaemia, even severe ischaemia, are
neither an appropriate rationale nor justification for revascularization
procedures targeted to prevent death or MI in the CCS patient.
These trial results support the observation, in virtually every natural
history outcome study based on the detailed characterization of the
coronary atherosclerotic plaque, that the vast majority of severe
flow-limiting plaques remain quiescent and do not destabilize to
cause increased cardiovascular events (e.g. 87% in FAME-29
78% in
an international observational study of 697 patients followed for me-
dian of 3.4 years34
). As the results of COURAGE demonstrated,
disease-modifying vasculoprotective therapy including lifestyle modi-
fication, directed at the entire length of the atherosclerotic plaque, is
where the therapeutic benefit of preventing plaque destabilization is
found, thereby reducing death and MI. It is worth emphasizing, also
consistent with all previous natural history studies, that adverse event
rates in ISCHEMIA were indeed related to the extent of CAD based
on
_ 50% luminal diameter obstruction: 8% in one-vessel disease,
10% in two-vessel disease, and 18% in three or more vessel disease;
there was simply no demonstrable benefit from revascularization of
the ischaemia-causing lesions in those stable, albeit flow-limiting, pla-
ques compared to OMT alone.2
It is most likely that the metric of
‘number of arteries with a significant luminal obstruction’ is a surro-
gate marker for the sum of the extent or length of atherosclerotic
‘burden’ along all of the coronary arteries of an individual patient.
Within each plaque, whether it is obstructive or non-obstructive,
there are heterogeneous plaque areas that may be at risk to destabil-
ize, but most of these plaque areas are not severely obstructive,35
and hence not suitable targets for revascularization. A therapeutic
mechanical intervention directed at the ischaemia-producing minimal
lumen area alone would leave behind adjacent high-risk plaque areas
at risk of destabilization and the potential for a new adverse cardiac
event. Thus, it is essential to recognize that pathobiologically high-risk
plaque areas prone to cause an adverse event may exist alone as a
non-obstructing lesion that does not cause ischaemia or angina, or
may coexist up- or downstream from a severely obstructive area of
the plaque that does cause angina and ischaemia, but is itself a low-
risk area for destabilization since it is typically characterized by a thick
fibrous cap and small lipid core. The therapeutic goal is to reduce the
risk features of the plaque areas prone to destabilize, regardless of
whether they exist alone or are adjacent to a severe flow-limiting
lesion.
While PCI would be expected to leave behind plaque areas at risk
for future destabilization, CABG would be anticipated to bypass
more extensive areas of plaque and therefore be associated with a
reduced risk of subsequent spontaneous MI.30
Future ISCHEMIA
sub-studies will be necessary to determine whether surgical bypass
of greater length of high-risk plaque is associated with the reduction
of MI, as was observed in BARI 2D.
Where do we go from here in
applying these results to current
practice?
Because ISCHEMIA showed that there was no significant difference
between the two initial management strategies in the rate of death
from cardiovascular causes, MI, or hospitalization for unstable angina,
heart failure, or resuscitated cardiac arrest (the ISCHEMIA primary
endpoint) or in the rate of death from any cause or MI (the primary
endpoint in ISCHEMIA-CKD), these findings underscore the benefits
of disease-modifying OMT for CCS patients, and this must remain
our most important focus. While revascularization will always have
an important role in symptom relief and improving quality of life, our
overarching goal should be to reduce incident cardiovascular events
by deploying proven therapies that stabilize vulnerable coronary pla-
ques and enhance event-free survival.
The ISCHEMIA trial fundamentally disrupts many of our prior
beliefs concerning management strategies for patients with stable
CAD. The central and most important implication of ISCHEMIA is
that if a patient fits the entry criteria of the ISCHEMIA trial and has lit-
tle or no angina and an acceptable quality of life, which likely com-
prises a majority of patients with stable CAD, then there is no
indication for proceeding with an initial revascularization procedure
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instead of OMT. Moreover, the results of ISCHEMIA suggest that
there is little to no value in pursuing strategies to identify the severity
of an epicardial coronary obstruction or to quantify the magnitude of
ischaemia. The invasive strategy remains of evidence-based value for
those patients with, or who develop, frequent or unacceptable angina
despite OMT that limits quality of life.
A schema of proposed diagnostic and management strategies for
stable CAD patients is illustrated in Figure 1. The first consideration
would be confirmation by careful history that the patient is indeed
stable (and without unstable angina), that angina is not severe, fre-
quent, or limits the quality of life, or that heart failure (New York
Heart Association class III/IV) is not present. Diagnostic testing would
be primarily directed at determining that objective characteristics of
high risk, which served as exclusion criteria in ISCHEMIA, are not
present. The potentially most ominous high-risk characteristic is the
presence of left main CAD, which was present in 7–10% of patients
screened for ISCHEMIA. CCTA is the only non-invasive imaging mo-
dality that can identify the presence of left main CAD, and current
methods are associated with low radiation exposure,36
but wide-
spread screening with CCTA to identify the small subset of patients
with left main CAD may not be cost-effective. Stress testing, whether
exercise-based or pharmacological, primarily serves to identify the
presence and severity of inducible ischaemia, but it is now clear that
such information would not be helpful in selecting an invasive instead
of a conservative management strategy. Non-obstructive CAD, and
perhaps associated microvascular disease, that may nevertheless be
associated with an increased risk of adverse cardiac events, is identifi-
able with CCTA or positron emission tomography perfusion scan
and would justify continued management with a conservative strat-
egy. Transthoracic echocardiography would be indicated to exclude
the presence of left ventricular ejection fraction 35%. For patients
who do not satisfy these high-risk criteria, the principal goal of man-
agement would be to further optimize OMT, including lifestyle inter-
vention, and escalate anti-anginal medications as needed to control
angina and ischaemia symptoms, if present.
It would also be important to maintain adequate clinical surveil-
lance during follow-up to ensure timely reassessments of the thera-
peutic response to treatment. Patients who become asymptomatic
or only minimally symptomatic would continue with the conservative
strategy with periodic monitoring at appropriate intervals. By con-
trast, patients who either remain persistently symptomatic or whose
quality of life deteriorates would be considered appropriate candi-
dates for comprehensive clinical re-assessment with either CCTA or
invasive angiography and revascularization, if feasible, based on ana-
tomic findings.
Finally, for those patients who present initially with angina that is
frequent, severe, or limits lifestyle, an invasive strategy would be indi-
cated to identify coronary artery anatomy and, if appropriate, pro-
ceed to coronary revascularization with PCI or CABG, as indicated.
Conclusion
In many respects, both the results and the implications of the
ISCHEMIA trial are counter-intuitive to our decades-old beliefs and
practices of identifying the subset of high-risk patients based on the
severity and extent of myocardial ischaemia, and then performing
revascularization of flow-limiting obstructions to ameliorate that high
risk. Yet, while the ISCHEMIA trial findings support prior observations
that adverse cardiac outcomes are indeed more frequent in the setting
of more extensive coronary atherosclerosis, the results very clearly in-
dicate that revascularization of ischaemia-producing lesions does not
favourably alter that high risk in terms of cardiovascular event reduc-
tion. Disease-modifying medications and lifestyle interventions that re-
duce the pro-atherosclerotic, pro-inflammatory, and pro-thrombotic
manifestations of atherosclerotic disease and plaque burden, and
thereby reduce the proclivity for plaque destabilization, serve as the
mainstay foundation for treating CAD and, in particular, should remain
our principal focus of management for the stable CAD patient, with
myocardial revascularization reserved for those whose anginal symp-
toms and quality of life fail to improve, or worsen, despite OMT.
Conflict of interest: none declared.
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