The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Managing Stable Ischemic Heart Disease

Elliott M. Antman, M.D., and Eugene Braunwald, M.D.

The preferred contemporary approach to the man- The presence of moderate or severe ischemia was
agement of stable ischemic heart disease, also determined with stress imaging in the majority
referred to as chronic coronary syndrome,1 is not of patients. In ISCHEMIA, the majority of pa-
well defined. Two strategies are commonly used.2 tients also underwent coronary computed tomo-
The conservative strategy uses guideline-based graphic angiography at screening to confirm the
medical therapy, including antianginal drugs as presence of coronary obstruction and to rule out
well as disease-modifying agents, such as hypo- left main coronary artery disease; the results of
lipidemic, antithrombotic, and renin–angioten- the imaging studies were confirmed on blinded
sin blocking therapies. The invasive strategy adds review at core laboratories. Unlike in previous
coronary angiography, followed by either percu- trials, randomization to the conservative and
taneous coronary intervention or coronary-artery invasive strategies in these trials was carried out
bypass grafting, to guideline-based medical ther- before coronary angiography was performed,
apy. Important advances have occurred in both thereby reducing the likelihood of bias.
strategies, leading to equipoise as to which In ISCHEMIA, 96% of the patients in the inva-
approach is preferable for patients with stable sive-strategy group underwent coronary angiog-
ischemic heart disease.3,4 raphy, whereas only 26% of the patients in the
The International Study of Comparative Health conservative-strategy group did so, for an ische­
Effectiveness with Medical and Invasive Ap- mic event or inadequate control of symptoms.
proaches (ISCHEMIA), the results of which are The corresponding percentages in ISCHEMIA-CKD
now reported in the Journal, tested whether an were 85% and 32%. Of note, in ISCHEMIA-CKD,
initial invasive strategy would result in better half the patients in the invasive-strategy group
outcomes than a conservative strategy among did not undergo revascularization, most often
patients with stable ischemic heart disease and because they did not have obstructive coronary
moderate or severe myocardial ischemia. In the disease, despite having a positive stress test. In
main trial, 5179 patients underwent randomiza- the two trials, the power was reduced because
tion at 320 centers in 37 countries.5 Another 777 enrollments and aggregated event rates were
patients who had advanced chronic kidney dis- lower than anticipated, leading to changes in the
ease in addition to the other conditions were planned sample sizes and, in ISCHEMIA, to a
included in a separate trial (ISCHEMIA-CKD).6 change in the primary end point.10
Both trials used a patient-centric approach by There was no significant difference between
incorporating sophisticated analyses of angina- the two strategies in the rate of death from cardio-
related quality of life.7,8 vascular causes, myocardial infarction, or hospi-
These trials have a number of important talization for unstable angina, heart failure, or
positive features. More patients underwent ran- resuscitated cardiac arrest (the primary end
domization in each trial than in previous trials point in ISCHEMIA) or in the rate of death from
addressing this issue. The patients had, on aver- any cause or myocardial infarction (the primary
age, excellent control of low-density–lipoprotein end point in ISCHEMIA-CKD).5,6 In ISCHEMIA,
cholesterol and systolic blood pressure, as well rates of death from any cause were quite low, at
as glycated hemoglobin in those with diabetes.5,9 approximately 6.4% at 4 years in both groups. In

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 The n e w e ng l a n d j o u r na l of m e dic i n e

ISCHEMIA-CKD, death rates were higher, at ap- of myocardial infarctions differed, leading to
proximately 27% at 3 years, again without a differ- results that favored the conservative strategy
ence between the two groups. The most straight- throughout follow-up. Both the primary and the
forward conclusion is that, insofar as “hard” end secondary definitions of myocardial infarction
points are concerned, the two strategies seem to were complex. Analyses of the prespecified but
have been equally efficacious in the two trials. not yet reported end points of “complicated” and
In ISCHEMIA, the patients in the invasive-strategy “large” myocardial infarctions would be of inter-
group reported substantially fewer anginal symp- est and potentially informative to the clinical
toms than the patients in the conservative- community.
strategy group,7 although the magnitude of this Although there is some uncertainty regarding
benefit depended on angina frequency at base- the interpretation of the ISCHEMIA results —
line (and 35% had no angina at baseline). In given that the difference in outcomes between
ISCHEMIA-CKD, there was no benefit with re- the two strategies is driven by results for myo-
gard to angina-related health status with the cardial infarction, and those results depend on
invasive strategy.8 the definition used in the analysis — the inva-
Possible reasons for the lack of difference in sive strategy does not appear to be associated
“hard” outcomes in ISCHEMIA are the relatively with clinically meaningful differences in outcomes
low risk for clinical events among the trial patients during 4 years of follow-up. This finding under-
and the potential effect of practice patterns that scores the benefits of disease-modifying con-
may have excluded more-symptomatic patients temporary pharmacotherapy for coronary artery
from the trial in countries with a low threshold disease. Thus, provided there is strict adherence
for revascularization. Of note, in ISCHEMIA, the to guideline-based medical therapy, patients with
Kaplan–Meier curves showed a trend for a greater stable ischemic heart disease who fit the profile
number of myocardial infarctions (predomi- of those in ISCHEMIA and do not have unac-
nantly procedural) in the invasive-strategy group ceptable levels of angina can be treated with an
than in the conservative-strategy group during initial conservative strategy. However, an inva-
the first 6 months of the trial, but as the trial sive strategy, which more effectively relieves
proceeded, the curves crossed, and more myo- symptoms of angina (especially in patients with
cardial infarctions (predominantly spontaneous) frequent episodes7), is a reasonable approach at
occurred in the conservative-strategy group. At any point in time for symptom relief.
4 years, the cumulative incidence of death from Among patients with stable ischemic heart
cardiovascular causes or myocardial infarction disease who have advanced chronic kidney dis-
(based on the primary definition) was higher in ease, the risk of clinical events is more than
the conservative-strategy group than in the inva- three times as high as the risk among those
sive-strategy group (13.9% vs. 11.7%). It is pos- without chronic kidney disease, but an initial
sible that ISCHEMIA ended before a substantial invasive strategy does not appear to reduce event
difference in favor of the invasive strategy rates or relieve angina symptoms for these pa-
emerged. Since it is unlikely that ISCHEMIA will tients.6,8 Therefore, patients with stable ischemic
be repeated, it is especially important to extend heart disease and chronic kidney disease can
follow-up with the patients before contact with usually be treated with a conservative strategy.12
them is lost; additional events may enhance our Disclosure forms provided by the authors are available with
understanding of the effect of the trajectory of the the full text of this editorial at NEJM.org.
event curves and ascertain the durability of the
From the Department of Medicine, Brigham and Women’s
benefit of an invasive strategy with regard to con- Hospital, and Harvard Medical School — both in Boston.
trol of angina. It would also be helpful to develop
a risk score for the trial patients in order to de- This editorial was published on March 30, 2020, at NEJM.org.
termine the outcomes at various levels of risk.11
1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for
As pointed out by the authors of ISCHEMIA, the diagnosis and management of chronic coronary syndromes.
when myocardial infarction was analyzed accord- Eur Heart J 2020;​41:​407-77.
ing to a secondary definition (see the Supple- 2. Braunwald E. Coronary-artery surgery at the crossroads.
N Engl J Med 1977;​297:​661-3.
mentary Appendix, available with the full text of 3. Stone GW, Hochman JS, Williams DO, et al. Medical therapy
the article at NEJM.org), the number and pattern with versus without revascularization in stable patients with

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 Managing Stable Ischemic Heart Disease

moderate and severe ischemia: the case for community equi- invasive or conservative care in coronary and advanced kidney
poise. J Am Coll Cardiol 2016;​67:​81-99. disease. N Engl J Med. DOI:​10.1056/NEJMoa1916374.
4. Chacko L, Howard JP, Rajkumar C, et al. Effects of percuta- 9. Hochman JS, Reynolds HR, Bangalore S, et al. Baseline char-
neous coronary intervention on death and myocardial infarction acteristics and risk profiles of participants in the ISCHEMIA
stratified by stable and unstable coronary artery disease: a meta- randomized clinical trial. JAMA Cardiol 2019;​4:​273-86.
analysis of randomized controlled trials. Circ Cardiovasc Qual 10. ISCHEMIA Trial Research Group. International Study of
Outcomes 2020;​13(2):​e006363. Comparative Health Effectiveness with Medical and Invasive
5. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive Approaches (ISCHEMIA) trial: rationale and design. Am Heart J
or conservative strategy for stable coronary disease. N Engl J 2018;​201:​124-35.
Med. DOI:​10.1056/NEJMoa1915922. 11. Antman EM, Loscalzo J. Precision medicine in cardiology.
6. Bangalore S, Maron DJ, O’Brien SM, et al. Management of Nat Rev Cardiol 2016;​13:​591-602.
coronary disease in patients with advanced kidney disease. 12. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al.
N Engl J Med. DOI:​10.1056/NEJMoa1915925. Chronic kidney disease and cardiovascular risk: epidemiology,
7. Spertus JA, Jones PG, Maron DJ, et al. Health-status out- mechanisms, and prevention. Lancet 2013;​382:​339-52.
comes with invasive or conservative care in coronary disease.
N Engl J Med. DOI:​10.1056/NEJMoa1916370. DOI: 10.1056/NEJMe2000239
8. Spertus JA, Jones PG, Maron DJ, et al. Health status after Copyright © 2020 Massachusetts Medical Society.

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