new england

The
journal of medicine
established in 1812 April 9, 2020 vol. 382 no. 15

Initial Invasive or Conservative Strategy for Stable Coronary Disease

D.J. Maron, J.S. Hochman, H.R. Reynolds, S. Bangalore, S.M. O’Brien, W.E. Boden, B.R. Chaitman, R. Senior,
J. López‑Sendón, K.P. Alexander, R.D. Lopes, L.J. Shaw, J.S. Berger, J.D. Newman, M.S. Sidhu, S.G. Goodman,
W. Ruzyllo, G. Gosselin, A.P. Maggioni, H.D. White, B. Bhargava, J.K. Min, G.B.J. Mancini, D.S. Berman, M.H. Picard,
R.Y. Kwong, Z.A. Ali, D.B. Mark, J.A. Spertus, M.N. Krishnan, A. Elghamaz, N. Moorthy, W.A. Hueb, M. Demkow,
K. Mavromatis, O. Bockeria, J. Peteiro, T.D. Miller, H. Szwed, R. Doerr, M. Keltai, J.B. Selvanayagam, P.G. Steg, C. Held,
S. Kohsaka, S. Mavromichalis, R. Kirby, N.O. Jeffries, F.E. Harrell, Jr., F.W. Rockhold, S. Broderick, T.B. Ferguson, Jr.,
D.O. Williams, R.A. Harrington, G.W. Stone, and Y. Rosenberg, for the ISCHEMIA Research Group*​​

a bs t r ac t

BACKGROUND
Among patients with stable coronary disease and moderate or severe ischemia, The authors’ full names, academic de‑
whether clinical outcomes are better in those who receive an invasive intervention grees, and affiliations are listed in the Ap‑
pendix. Address reprint requests to Dr.
plus medical therapy than in those who receive medical therapy alone is uncertain. Maron at the Department of Medicine,
Stanford University School of Medicine,
METHODS 1265 Welch Rd., Medical School Office
We randomly assigned 5179 patients with moderate or severe ischemia to an initial Bldg. x314, Stanford, CA 94305, or at
invasive strategy (angiography and revascularization when feasible) and medical ­david​.­maron@​­stanford​.­edu; or to Dr.
Hochman at the New York University
therapy or to an initial conservative strategy of medical therapy alone and angiog- Grossman School of Medicine–New York
raphy if medical therapy failed. The primary outcome was a composite of death University Langone Health, 530 First
from cardiovascular causes, myocardial infarction, or hospitalization for unstable Ave., Skirball 9R, New York, NY 10016, or
at ­judith​.­hochman@​­nyumc​.­org.
angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was
death from cardiovascular causes or myocardial infarction. *A full list of ISCHEMIA Research Group
members is provided in the Supplemen‑
RESULTS tary Appendix, available at NEJM.org.
Over a median of 3.2 years, 318 primary outcome events occurred in the invasive- Drs. Maron and Hochman contributed
strategy group and 352 occurred in the conservative-strategy group. At 6 months, equally to this article.
the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the This article was published on March 30,
conservative-strategy group (difference, 1.9 percentage points; 95% confidence 2020, at NEJM.org.
interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, N Engl J Med 2020;382:1395-407.
respectively (difference, −1.8 percentage points; 95% CI, −4.7 to 1.0). Results were DOI: 10.1056/NEJMoa1915922
similar with respect to the key secondary outcome. The incidence of the primary Copyright © 2020 Massachusetts Medical Society.

outcome was sensitive to the definition of myocardial infarction; a secondary

analysis yielded more procedural myocardial infarctions of uncertain clinical im-
portance. There were 145 deaths in the invasive-strategy group and 144 deaths in
the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).
CONCLUSIONS
Among patients with stable coronary disease and moderate or severe ischemia, we
did not find evidence that an initial invasive strategy, as compared with an initial
conservative strategy, reduced the risk of ischemic cardiovascular events or death
from any cause over a median of 3.2 years. The trial findings were sensitive to the
definition of myocardial infarction that was used. (Funded by the National Heart,
Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number,
NCT01471522.)
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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

T
he goals of treating patients with with stable coronary disease were enrolled at clini-
stable coronary disease are to reduce their cal sites that met certain quality metrics (see the
risk of death and ischemic events and to Methods section in the Supplementary Appen-
improve their quality of life. All patients with dix, available with the full text of this article at
coronary disease should be treated with guide- NEJM.org) after clinically indicated stress testing
A Quick Take is
available at line-based medical therapy (hereafter, medical showed moderate or severe reversible ischemia on
NEJM.org therapy) to achieve these objectives.1,2 Before the imaging tests or severe ischemia on exercise tests
widespread availability of drug-eluting stents, without imaging (Fig. S1 and S2 in the Supple-
strategy trials that tested the incremental effect mentary Appendix). The option of exercise-stress
of revascularization added to medical therapy did testing without imaging was added as a protocol
not show a reduction in the incidence of death addendum in 2014 to improve recruitment and
or myocardial infarction.3,4 In one trial, fractional generalizability of the trial results.11 Key exclusion
flow reserve–guided percutaneous coronary in- criteria were an estimated glomerular filtration
tervention (PCI) with drug-eluting stents, added rate below 30 ml per minute per 1.73 m2 of body-
to medical therapy, decreased the incidence of surface area, a recent acute coronary syndrome,
urgent revascularization but not the incidence of unprotected left main stenosis of at least 50%, a
death from any cause or myocardial infarction at left ventricular ejection fraction of less than 35%,
a mean of 7 months,5 whereas the 5-year follow- New York Heart Association class III or IV heart
up showed marginal evidence of a decrease in failure, and unacceptable angina despite the use
the incidence of myocardial infarction.6 of medical therapy at maximum acceptable doses.
Several theories have been advanced to explain Most enrolled trial patients underwent coro-
why previous strategy trials involving patients with nary computed tomographic (CT) angiography to
stable coronary disease have not shown a decrease rule out left main coronary disease and nonob-
in death or myocardial infarction with revascu- structive coronary disease. The primary exceptions
larization. In trials requiring angiographic evi- to the use of CT angiography were renal dysfunc-
dence of obstructive coronary disease, patients tion that would preclude such testing or known
with high-risk anatomical features may have been coronary anatomy. Patients underwent random-
excluded and knowledge of the anatomy may have ization if protocol-indicated clinical, ischemia-
led to revascularization in patients who were ran- based, and anatomical eligibility criteria (based on
domly assigned to a conservative strategy. Previ- blinded CT angiography) had been met (Tables S1
ous studies allowed the enrollment of patients with and S2). Although sites determined whether stress-
any level of ischemia, which resulted in a minority testing results met eligibility criteria for ischemia
of patients with moderate or severe ischemia for severity, all stress tests were reviewed by indepen-
whom an invasive strategy might have been most dent core laboratories.
beneficial. In a single-center observational study
involving 10,627 patients, the incidence of death Treatment Strategies
from cardiac causes was lower among those with Eligible patients were randomly assigned, in a 1:1
at least 10% ischemia on myocardial perfusion ratio, to an initial invasive strategy of medical
imaging who underwent early revascularization therapy, angiography, and revascularization when
than among those who did not undergo revascu- feasible or to an initial conservative strategy of
larization.7 We designed the International Study medical therapy alone, with angiography reserved
of Comparative Health Effectiveness with Medical for failure of medical therapy. Randomization was
and Invasive Approaches (ISCHEMIA) to determine performed with an interactive voice–response or
the effect of adding cardiac catheterization (here- Web-based response system with the use of ran-
after, angiography) and revascularization when domly permuted blocks of varying sizes, with
feasible to medical therapy in patients with stable stratification according to enrollment site.
coronary disease and moderate or severe ischemia.8,9 Patients who were assigned to the invasive strat-
egy were to undergo angiography within 30 days
after randomization and complete revasculariza-
Me thods
tion of all ischemic territories if feasible. Sites were
Trial Population provided with guidelines for performing revascu-
The trial design and baseline characteristics of the larization, including the use of fractional flow
patients have been described previously.8,10 Patients reserve measurements when available and appro-

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 Invasive or Conservative Str ategy for Coronary Disease

priate (Fig. S3a and S3b and the Supplementary dinating center) and by the institutional review
Methods section). Decisions about the type of re- board and ethics committee at each participating
vascularization — PCI or coronary-artery bypass site (see the Supplementary Appendix). All the pa-
grafting (CABG) — were deferred to the local tients provided written informed consent.
heart team. An independent angiographic core The industry sponsors did not have access to
laboratory analyzed all protocol-assigned angio- the data during the trial and did not participate
graphic and PCI procedures. Medical therapy con- in the trial design, data analysis, or manuscript
sisted of intensive secondary prevention with life- preparation. The statistical and data coordinating
style and pharmacologic interventions applied center at Duke Clinical Research Institute moni-
equally in both groups with the use of treat-to- tored data collection and quality and performed
target algorithms (Table S3). Patients were fol- statistical analyses. The first author prepared the
lowed at 1.5, 3, 6, and 12 months after random- first draft of the manuscript. The first and second
ization and every 6 months thereafter. authors had full access to the data and were re-
sponsible for editing subsequent drafts as well as
Outcome Assessment for the decision to submit the final manuscript for
The primary outcome was the composite of death publication. All the authors vouch for the accuracy
from cardiovascular causes, myocardial infarction, and completeness of the data and adherence of the
or hospitalization for unstable angina, heart fail- trial to the protocol.
ure, or resuscitated cardiac arrest. The key sec-
ondary outcomes were the composite of death Statistical Analysis
from cardiovascular causes or myocardial infarc- The original trial design specified that 8000 pa-
tion and angina-related quality of life. Clinical tients would undergo randomization with 4 years
outcomes were adjudicated by an independent of follow-up for the five-component primary com-
clinical-event committee whose members were posite outcome reported in this article.15 Before
unaware of the trial-group assignments. the trial launch, the National Heart, Lung, and
The primary definition of nonprocedural in- Blood Institute and the data and safety monitoring
farction was based on the Third Universal Defi- board approved changing the primary outcome to
nition of Myocardial Infarction types 1, 2, 4b, and a composite of death from cardiovascular causes
4c.12 For procedural infarctions, we required higher or myocardial infarction, with a protocol-defined
biomarker thresholds for confirmation8 because procedure to revert to the five-component primary
data showed that this more stringent definition outcome if needed to preserve statistical power.
carried greater prognostic significance than the Slow recruitment and lower-than-expected aggre-
universal definition types 4a and 5.13,14 We devel- gated event rates triggered this prespecified con-
oped a secondary definition for procedural in- tingency plan and other changes, as described
farctions that used biomarker thresholds that were previously.8,11
similar to those of the universal definition but Power calculations performed in 2015 deter-
with additional criteria based on elevations of bio- mined that a trial with 5000 patients would have
marker levels alone without additional findings. at least 83% power to detect an 18% relative re-
Definitions of all trial outcomes, including both duction in the 4-year rate of the primary outcome,
the primary and the secondary definitions of pro- assuming a 4-year rate of 20% in the conservative-
cedural infarction, are provided in the Supplemen- strategy group. When power was reestimated with
tary Methods section. the use of updated event-rate assumptions derived
from blinded trial data in 2018, the final sample
Trial Organization and Oversight size was estimated to provide at least 83% power
The trial was designed by the executive committee to detect an 18.5% relative reduction in the pri-
and sponsored by the National Heart, Lung, and mary outcome, assuming average follow-up of ap-
Blood Institute, with additional support from in- proximately 3 years and an aggregate 4-year cu-
dustry sponsors (Table S4). An independent data mulative incidence of 14%.
and safety monitoring board approved the trial Detailed statistical methods are provided in
protocol (available at NEJM.org) and monitored the Supplementary Methods section. Group com-
patient safety. The protocol was approved by the parisons were performed according to the inten-
institutional review board at New York University tion-to-treat principle based on time-to-first-event
Grossman School of Medicine (the clinical coor- analyses. Cumulative event probabilities were es-

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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

timated with the use of the Kaplan–Meier method underwent randomization at 320 sites in 37 coun-
for outcomes that were not subject to competing tries (Section II in the Supplementary Appendix
risks (e.g., death from any cause) and by a non- and Fig. 1). The baseline characteristics of the pa-
parametric cumulative-incidence function estima- tients were well balanced between the two groups
tor for outcomes that were subject to competing (Table 1 and Table S5). Baseline risk-factor con-
risks (e.g., the primary outcome, for which death trol and medication use were similar in the groups
from noncardiovascular causes is a competing (Table S6). The median low-density lipoprotein
risk).16 The prespecified primary analysis was a cholesterol level was 83 mg per deciliter (2.2 mmol
covariate-adjusted Cox proportional-hazards mod- per liter) at baseline and 64 mg per deciliter
el. However, the proportional-hazards assumption (1.7 mmol per liter) at the last visit. Medication
underlying the Cox model was not met for the use at baseline and during follow-up is shown in
primary outcome (P<0.001 for time-by-treatment Figures S4 and S5.
interaction) and several secondary outcomes. We
report these results for the primary outcome and Use of Invasive Procedures and Follow-up
do not report them for any other outcomes that Among patients in the invasive-strategy group,
show nonproportionality. 96% underwent angiography and 79% underwent
The statistical analysis plan specified that pre- revascularization (PCI in 74% and CABG in 26%)
sentation of the results would emphasize non- (Table S7a and Fig. S6). Angiographic character-
parametric cumulative event-rate estimates if the istics of patients in the invasive-strategy group
proportional-hazards assumption was violated. and procedural data are provided in Table S8. In
Differences in these estimates for the invasive- the conservative-strategy group, 26% of the pa-
strategy group as compared with the conservative- tients underwent angiography and 21% underwent
strategy group at 6 months and at yearly time revascularization; 19% underwent angiography
points were tabulated and presented with 95% and 15% underwent revascularization before the
confidence intervals. The confidence intervals occurrence of a primary outcome event. The total
have not been adjusted for multiple comparisons, numbers of invasive procedures, including repeat
so these intervals should not be used to infer de- procedures, that were performed in each group
finitive treatment effects. In a post hoc analysis, were 5337 in the invasive-strategy group and 1506
we used kernel smoothing to estimate hazard-rate in the conservative-strategy group (Table S9). Pa-
functions over time for the two treatment groups.17 tients were followed until June 30, 2019; the me-
We also estimated the difference in restricted dian duration of follow-up was 3.2 years.
mean event-free time over 5 years.18,19 This quan-
tity is derived from the nonparametric cumulative Primary Outcome
event-rate curves and is interpreted as the average
The primary outcome occurred in 318 patients
number of event-free days per patient over the pe-
in the invasive-strategy group and in 352 patients
riod between randomization and 5 years. Support-in the conservative-strategy group (Table 2 and
ing analyses using a Bayesian statistical frame-Fig. 2). In prespecified covariate-adjusted Cox
work were prespecified to permit the primary model analysis, the estimated hazard ratio with
clinical results to be expressed in terms of thethe invasive strategy as compared with the conser-
posterior (post-trial) probability of a small orvative strategy was 0.93 (95% confidence interval
large effect size in light of the current trial data.
[CI], 0.80 to 1.08; P = 0.34). However, the under-
We implemented the Bayesian approach using a lying proportional-hazards assumption was vio-
flexible piecewise-exponential nonproportional- lated. At 6 months, the estimated cumulative event
hazards model (see the Supplementary Methods rate was 5.3% in the invasive-strategy group and
section). Analyses were performed with the use of
3.4% in the conservative-strategy group (differ-
SAS software (version 9.4), WinBUGS software ence, 1.9 percentage points; 95% CI, 0.8 to 3.0).
(version 1.4), and R software (version 3.6). At 5 years, the estimated cumulative event rate was
16.4% in the invasive-strategy group and 18.2%
in the conservative-strategy group (difference, −1.8
R e sult s
percentage points; 95% CI, −4.7 to 1.0). The esti-
Baseline Characteristics and Medical Therapy mated hazard rates over time are shown in Figure
From July 26, 2012, through January 31, 2018, S7. We did not find evidence of a difference in the
a total of 8518 patients were enrolled and 5179 5-year restricted mean event-free time between

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 Invasive or Conservative Str ategy for Coronary Disease

the groups (9.5 days longer in the invasive-strategy

group; 95% CI, −17.8 to 36.9).
8518 Patients were enrolled

Secondary Outcomes
There were 276 deaths from cardiovascular causes 3339 Were excluded
or myocardial infarctions in the invasive-strategy 1350 Did not have moderate or
severe ischemia, according
group and 314 in the conservative-strategy group to stress core laboratory
(Table 2 and Fig. 2). At 6 months, the estimated 1218 Did not have obstructive CAD
434 Had unprotected LMCA
event rate was 4.8% in the invasive-strategy group disease
and 2.9% the conservative-strategy group (differ-
ence, 1.9 percentage points; 95% CI, 0.9 to 3.0).
5179 Underwent randomization
At 5 years, the estimated cumulative event rate 3783 (73.0%) Underwent trial CCTA
was 14.2% in the invasive-strategy group and 1396 (27.0%) Did not undergo trial CCTA
575 Had low eGFR
16.5% in the conservative-strategy group (differ- 700 Had known coronary anatomy
ence, −2.3 percentage points; 95% CI, −5.0 to 0.4). 121 Had other reason

The restricted mean time free from death from

cardiovascular causes or infarction over 5 years
was similar in the two groups (9.4 days longer in
the invasive-strategy group; 95% CI, −16.5 to 35.2). 2588 Were assigned to invasive 2591 Were assigned to conservative
Other outcomes according to treatment group are strategy strategy
shown in Table 2, Table S10, and Figure S8. There
were more hospitalizations for heart failure and
fewer hospitalizations for unstable angina with the Median follow-up, 3.2 yr Median follow-up, 3.2 yr
(IQR, 2.1 to 4.3) (IQR, 2.2 to 4.3)
invasive strategy. There were 145 deaths in the in- 99.4% of projected follow-up 99.7% of projected follow-up
vasive-strategy group and 144 deaths in the conser- was completed was completed
28 (1.1%) Withdrew 22 (0.8%) Withdrew
vative-strategy group (hazard ratio, 1.05; 95% CI, 36 (1.4%) Were lost to follow-up 26 (1.0%) Were lost to follow-up
0.83 to 1.32). 2475 (95.6%) Underwent angio- 667 (25.7%) Underwent angio-
graphy graphy
The early increased risk of the primary and 2054 (79.4%) Underwent revas- 544 (21.0%) Underwent revas-
major secondary outcomes in the invasive-strategy cularization cularization
group was attributable to more procedural infarc-
tions in early follow-up. This early hazard differ- Figure 1. Enrollment, Randomization, and Follow-up.
ence was increased when the secondary definition Unprotected left main coronary artery (LMCA) disease was defined as 50%
of infarction, which increased the number of adju- or greater LMCA stenosis without a bypass graft to the left coronary artery.
To maximize information about baseline coronary anatomy, available coro‑
dicated procedural infarctions, was used. With the
nary computed tomographic angiographic (CCTA) images obtained less
use of the secondary definition of myocardial in- than 1 year before enrollment in 130 patients were subsequently collected
farction, the estimated cumulative event rate at for CCTA core laboratory review. The percentage of projected follow-up
6 months for the primary outcome was 10.2% in completed was calculated with the number of patient-years of observed fol‑
the invasive-strategy group and 3.7% in the con- low-up as the numerator and the number of patient-years of expected fol‑
low-up as the denominator. The percentages of patients who underwent
servative-strategy group (difference, 6.5 percentage
angiography and revascularization differ from the cumulative incidence
points; 95% CI, 5.2 to 7.9), and the estimated cu- function rates, which account for censoring. The percentage of patients
mulative event rate at 5 years was 21.2% in the who underwent angiography includes a small number of patients in the in‑
invasive-strategy group and 19.0% in the conser- vasive-strategy group who underwent angiography before randomization
vative-strategy group (difference, 2.2 percentage and did not undergo repeat angiography after randomization and before
bypass surgery. A total of 15% of the patients in the conservative-strategy
points; 95% CI, −0.7 to 5.2). The greater number
group underwent revascularization before a primary outcome event oc‑
of procedural infarctions according to the second- curred. CAD denotes coronary artery disease, eGFR estimated glomerular
ary definition is reflected in all composite outcomes filtration rate, and IQR interquartile range.
that include infarctions (Table S11 and Fig. S9).

Heterogeneity of Treatment Effect treatment effect on the primary outcome with re-
No evidence of a differential treatment effect on spect to other baseline characteristics, including
the primary outcome was found for five prespeci- the type of stress test, baseline left ventricular
fied covariates or the degree of ischemia (Fig. 3). ejection fraction, estimated glomerular filtration
Likewise, there was no evidence of a differential rate, and age.

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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

Bayesian Analysis conservative strategy; results were similar for the

In the Bayesian analysis, the post-trial probability key secondary outcome (Fig. S10 and Table S12).
that the difference in group-specific 5-year cumula- The probability that the difference in the 5-year rate
tive rates of the primary outcome is greater than of death from any cause is greater than 1 absolute
3 absolute percentage points was estimated to be percentage point was estimated to be 10.7% for a
24.5% for a difference favoring the invasive strategy difference favoring the invasive strategy and 32.1%
and less than 0.1% for a difference favoring the for a difference favoring the conservative strategy.

Table 1. Baseline Characteristics of the Patients.*

Invasive Strategy Conservative Strategy Total

Characteristic (N = 2588) (N = 2591) (N = 5179)
Median age (IQR) — yr 64 (58–70) 64 (58–70) 64 (58–70)
Male sex — no. (%) 1982 (76.6) 2029 (78.3) 4011 (77.4)
Race or ethnic group — no./total no. (%)†
White 1706/2569 (66.4) 1697/2560 (66.3) 3403/5129 (66.3)
Black 96/2569 (3.7) 108/2560 (4.2) 204/5129 (4.0)
Asian 747/2569 (29.1) 738/2560 (28.8) 1485/5129 (29.0)
Hispanic or Latino 372/2402 (15.5) 391/2413 (16.2) 4815 (15.8)
Other or multiple ethnic groups 20/2569 (0.8) 17/2560 (0.7) 37/5129 (0.7)
Hypertension — no./total no. (%) 1894/2579 (73.4) 1895/2582 (73.4) 3789/5161 (73.4)
Diabetes — no. (%) 1071 (41.4) 1093 (42.2) 2164 (41.8)
Use of insulin — no. (%) 239 (9.2) 253 (9.8) 492 (9.5)
Cigarette smoking — no./total no. (%)
Never smoked 1119/2587 (43.3) 1089/2587 (42.1) 2208/5174 (42.7)
Former smoker 1149/2587 (44.4) 1177/2587 (45.5) 2326/5174 (45.0)
Current smoker 319/2587 (12.3) 321/2587 (12.4) 640/5174 (12.4)
Family history of premature coronary artery disease — no./ 578/2228 (25.9) 592/2262 (26.2) 1170/4490 (26.1)
total no. (%)
Previous myocardial infarction — no./total no. (%) 495/2580 (19.2) 496/2582 (19.2) 991/5162 (19.2)
Previous PCI — no./total no. (%) 551/2586 (21.3) 499/2589 (19.3) 1050/5175 (20.3)
Previous CABG — no./total no. (%) 110/2588 (4.3) 93/2591 (3.6) 203/5179 (3.9)
Cardiac catheterization — no./total no. (%)
Before enrollment 979/2588 (37.8) 925/2591 (35.7) 1904/5179 (36.8)
Before enrollment and ≤12 mo before randomization 338/2504 (13.5) 329/2503 (13.1) 667/5007 (13.3)
CCTA — no./total no. (%)
Before enrollment 178/2585 (6.9) 175/2588 (6.8) 353/5173 (6.8)
Before enrollment and ≤12 mo before randomization 127/2573 (4.9) 126/2576 (4.9) 253/5149 (4.9)
Heart failure — no. (%)
History 112 (4.3) 94 (3.6) 206 (4.0)
Previous hospitalization 27 (1.0) 30 (1.2) 57 (1.1)
Median ejection fraction (IQR) — % 60 (55–65) 60 (55–65) 60 (55–65)
History of atrial fibrillation or atrial flutter — no./total no. 128/2587 (4.9) 93/2586 (3.6) 221/5173 (4.3)
(%)
Previous stroke — no./total no. (%) 83/2587 (3.2) 68/2591 (2.6) 151/5178 (2.9)
History of cerebrovascular disease — no./total no. (%)‡ 201/2582 (7.8) 176/2583 (6.8) 377/5165 (7.3)
History of peripheral-artery disease — no./total no. (%) 116/2585 (4.5) 88/2583 (3.4) 204/5168 (3.9)

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 Invasive or Conservative Str ategy for Coronary Disease

Table 1. (Continued.)

Invasive Strategy Conservative Strategy Total

Characteristic (N = 2588) (N = 2591) (N = 5179)
Angina
History — no./total no. (%) 2329/2588 (90.0) 2312/2591 (89.2) 4641/5179 (89.6)
Began or became more frequent within previous 3 mo 680/2584 (26.3) 675/2583 (26.1) 1355/5167 (26.2)
— no./total no. (%)
New onset within previous 3 mo — no./total no. (%) 415/2452 (16.9) 440/2466 (17.8) 855/4918 (17.4)
SAQ Angina Frequency score§ 80.7±20.0 82.1±19.2 81.4±19.6
Daily or weekly angina — no./total no. (%)§ 502/2314 (21.7) 442/2333 (18.9) 944/4647 (20.3)
Angina several times per mo — no./total no. (%)§ 1018/2314 (44.0) 1039/2333 (44.5) 2057/4647 (44.3)
No angina in previous 4 wk — no./total no. (%)§ 794/2314 (34.3) 852/2333 (36.5) 1646/4647 (35.4)

* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. CCTA denotes coronary computed tomographic
angiography, and IQR interquartile range.
† Race or ethnic group was reported by the patient.
‡ Previous cerebrovascular disease is defined as a previous carotid artery surgery or stent placement, a previous stroke, or a previous tran‑
sient ischemic attack.
§ The Seattle Angina Questionnaire (SAQ) captures the frequency of angina and the disease-specific effect of angina on patients’ physical
function and quality of life; the subscales are averaged to define the SAQ summary score. SAQ scores range from 0 to 100, with higher
scores indicating less frequent angina, better function, and greater quality of life. For the SAQ Angina Frequency scale, scores of 0 to 30,
31 to 60, 61 to 99, and 100 have been shown to validly reflect angina that occurs daily, weekly, monthly, and no angina, respectively, as as‑
sessed with daily diaries. Data were excluded from five sites (481 patients) because of improper completion of forms.

Discussion of myocardial infarction was used, the primary

outcome occurred more frequently in the invasive-
Over a median of 3.2 years of follow-up, among strategy group than in the conservative-strategy
patients with stable coronary disease who had group throughout the 5-year follow-up period.
moderate or severe ischemia on stress testing, A preliminary analysis of ISCHEMIA data pro-
an initial invasive strategy, as compared with an vides support for previous studies showing that
initial conservative strategy, did not reduce the spontaneous infarctions confer a higher risk of
rates of the primary or key secondary composite subsequent death than procedural infarctions.13,14
outcomes. Patients in the invasive-strategy group Despite pronounced differences in the frequency
had more procedural infarctions, and they had and timing of myocardial infarctions, there was
fewer nonprocedural infarctions during follow- no difference between the groups with respect to
up. The incidence of death from any cause was mortality. Longer-term follow-up with assessment
low and similar in the two groups. of mortality is needed to fully understand the
The opposing trends in procedural and non- prognostic implications of more procedural and
procedural infarctions drove the lack of propor- fewer nonprocedural infarctions with an invasive
tionality for the primary and key secondary strategy.
outcomes. The rate of early cardiovascular events The results of ISCHEMIA should be interpret-
was higher and the rate of late cardiovascular ed in the context of certain limitations. Power
events was lower among patients in the invasive- was decreased by reducing the sample size from
strategy group than among those in the conser- 8000 to 5179 patients, event rates were lower than
vative-strategy group. Differences in event rates expected, and the period of follow-up was modest.
between the groups in early follow-up were greater With a 3.2-year median follow-up, event-rate esti-
when the secondary definition of procedural in- mates past the median are subject to progressively
farction was used; this showed the sensitivity of greater uncertainty. The primary outcome was
rates of procedural infarctions to the definition expanded, as prespecified, owing to slow recruit-
used. The invasive strategy was associated with ment, yet there was no difference between the
fewer nonprocedural infarctions when either def- results for the primary and key secondary out-
inition was used. When the secondary definition comes. The findings do not apply to patients with

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Table 2. Estimated Differences between Treatment Groups in Cumulative Event Rates.*

Invasive Strategy Conservative Strategy Estimated Difference Hazard Ratio

Variable (N = 2588) (N = 2591) (95% CI) (95% CI)†
Primary composite outcome‡
No. of patients with events 318 352
Cumulative event rate — % 0.93 (0.80 to 1.08)
At 6 mo 5.3 3.4 1.9 (0.8 to 3.0)
At 1 yr 7.0 5.4 1.5 (0.2 to 2.9)
At 2 yr 9.0 9.5 −0.5 (−2.1 to 1.1)
At 3 yr 11.3 12.7 −1.3 (−3.2 to 0.6)
At 4 yr 13.3 15.5 −2.2 (−4.4 to 0)
At 5 yr 16.4 18.2 −1.8 (−4.7 to 1.0)
Restricted mean event-free time 4.5 yr 4.5 yr 9.5 days (−17.8 to 36.9)
Death from cardiovascular causes
or myocardial infarction
No. of patients with events 276 314
Cumulative event rate — %
At 6 mo 4.8 2.9 1.9 (0.9 to 3.0)
At 1 yr 6.2 4.6 1.6 (0.4 to 2.8)
At 2 yr 7.9 8.2 −0.3 (−1.8 to 1.2)
At 3 yr 9.7 11.0 −1.3 (−3.1 to 0.5)
At 4 yr 11.7 13.9 −2.2 (−4.4 to −0.1)
At 5 yr 14.2 16.5 −2.3 (−5.0 to 0.4)
Restricted mean event-free time 4.6 yr 4.5 yr 9.4 days (−16.5 to 35.2)
Death from any cause
No. of patients with events 145 144
Cumulative event rate — % 1.05 (0.83 to 1.32)
At 6 mo 0.8 0.4 0.4 (−0 to 0.8)
At 1 yr 1.7 1.0 0.7 (0 to 1.3)
At 2 yr 2.8 2.9 −0.1 (−1.0 to 0.9)
At 3 yr 4.3 4.3 0 (−1.2 to 1.2)
At 4 yr 6.5 6.4 0.1 (−1.5 to 1.8)
At 5 yr 9.0 8.3 0.7 (-1.6 to 3.1)
Restricted mean event-free time 4.8 yr 4.8 yr −3.0 days (−19.6 to 13.6)
Myocardial infarction
No. of patients with events 210 233
Cumulative event rate — %
At 6 mo 4.3 2.6 1.8 (0.8 to 2.8)
At 1 yr 5.3 3.8 1.5 (0.3 to 2.6)
At 2 yr 6.3 6.5 −0.1 (−1.5 to 1.2)
At 3 yr 7.7 8.5 −0.7 (−2.3 to 0.8)
At 4 yr 8.9 10.1 −1.2 (−3.0 to 0.6)
At 5 yr 10.3 11.9 −1.6 (−3.9 to 0.7)
Restricted mean event-free time 4.6 yr 4.6 yr 3.2 days (−20.3 to 26.7)

* CI denotes confidence interval.

† The hazard ratio for the invasive strategy as compared with the conservative strategy is shown, with adjustment for age, sex, estimated glo‑
merular filtration rate, ejection fraction, and diabetes. The prespecified primary analysis was a covariate-adjusted Cox proportional-hazards
model. Hazard ratios are presented for the primary outcome and for death from any cause; the latter is an outcome that appears to satisfy
the proportional-hazards assumption. The 95% confidence intervals have not been adjusted for multiple comparisons, and therefore these
intervals should not be used to infer definitive treatment effects.
‡ The primary composite outcome was death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart
failure, or resuscitated cardiac arrest.

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 Invasive or Conservative Str ategy for Coronary Disease

A Primary Composite Outcome B Death from Cardiovascular Causes or Myocardial Infarction

100 25 100 25
90 90
20 Conservative strategy 20
Conservative strategy

Cumulative Incidence (%)

Cumulative Incidence (%)

80 80
70 15 70 15

60 10 Invasive strategy 60 10
Invasive strategy
50 50
5 5
40 40
30 0 30 0
0 1 2 3 4 5 0 1 2 3 4 5
20 20
10 10
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Years since Randomization Years since Randomization
No. at Risk No. at Risk
Conservative strategy 2591 2431 1907 1300 733 293 Conservative strategy 2591 2453 1933 1325 746 298
Invasive strategy 2588 2364 1908 1291 730 271 Invasive strategy 2588 2383 1933 1314 742 282

C Death from Any Cause D Myocardial Infarction

100 25 100 25
90 90
20 20
Cumulative Incidence (%)

Cumulative Incidence (%)

80 80
70 15 70 15
Conservative strategy
60 10 Invasive strategy 60 10
50 50 Invasive strategy
5 5
40 40
Conservative strategy
30 0 30 0
0 1 2 3 4 5 0 1 2 3 4 5
20 20
10 10
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Years since Randomization Years since Randomization
No. at Risk No. at Risk
Conservative strategy 2591 2548 2065 1445 844 349 Conservative strategy 2591 2452 1931 1321 747 298
Invasive strategy 2588 2518 2061 1431 827 317 Invasive strategy 2588 2379 1931 1313 742 283

Figure 2. Time-to-Event Curves for the Primary Composite Outcome and Other Outcomes.
Panel A shows the cumulative incidence of the primary composite outcome of death from cardiovascular causes, myocardial infarction,
or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest in the conservative-strategy group and the invasive-
strategy group. Panel B shows the cumulative incidence of death from cardiovascular causes or myocardial infarction. Panel C shows the
cumulative incidence of death from any cause, and Panel D shows the cumulative incidence of myocardial infarction. In each panel, the
inset shows the same data on an enlarged y axis.

acute coronary syndromes,18,19 clinically signifi- by core laboratories had no effect on the trial
cant left main coronary artery disease,20,21 low findings. We have not yet analyzed the effect of
ejection fraction,22 class III or IV heart failure, or the completeness23 or method24 of revasculariza-
those who are very symptomatic despite the use tion on outcomes. The clinical outcomes should
of medical therapy at maximum acceptable be interpreted in the context of quality-of-life
doses. Although the stress core laboratories did outcomes, which represent a different dimension
not confirm that the degree of ischemia was suf- of treatment effectiveness and are reported sepa-
ficient to qualify for the trial in 14% of the pa- rately.25
tients who underwent randomization, a sub- In conclusion, we compared an initial inva-
group analysis showed that inclusion of patients sive strategy with an initial conservative strategy
with less than moderate ischemia as determined in patients with coronary disease and moderate

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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

Difference in Event Rate,

Percent of Invasive Strategy Minus Conservative Strategy
Subgroup Patients Estimated 5-Yr Event Rate (95% CI)
Invasive Conservative
Strategy Strategy
%
Met ischemia eligibility criteria, according to
core laboratory
No 13.8 24.4 16.3 8.1 (−11.0 to 27.3)
Yes 86.2 16.0 18.2 −2.2 (−5.2 to 0.8)
Degree of baseline ischemia, according to core laboratory
None or mild 11.9 24.7 16.9 7.9 (−11.3 to 27.1)
Moderate 33.3 18.2 20.0 −1.8 (−6.9 to 3.2)
Severe 54.8 14.6 17.1 −2.6 (−6.3 to 1.2)
Diabetes
No 58.2 14.5 15.7 −1.2 (−4.8 to 2.4)
Yes 41.8 18.8 21.6 −2.8 (−7.5 to 2.0)
New or more frequent angina ≤3 mo
No 73.8 16.0 19.1 −3.1 (−6.6 to 0.3)
Yes 26.2 17.6 15.9 1.7 (−3.6 to 6.9)
Guideline-based medical therapy at baseline
No 80.3 17.0 18.7 −1.6 (−5.1 to 1.8)
Yes 19.7 12.7 16.0 −3.3 (−9.1 to 2.5)
CAD severity based on 50% stenosis
One vessel 23.3 9.6 8.2 1.4 (−4.2 to 7.1)
Two vessel 31.4 10.2 11.9 −1.8 (−6.7 to 3.2)
Three or more vessels 45.1 20.7 23.9 −3.2 (−9.5 to 3.2)
Stenosis of the proximal LAD coronary artery (≥50%)
No 53.2 13.4 13.3 0.1 (−3.9 to 4.1)
Yes 46.8 15.5 18.1 −2.6 (−7.5 to 2.3)
−20 −10 0 10 20 30

Invasive Conservative
Strategy Strategy
Better Better

Figure 3. Analyses of Heterogeneity of Treatment Effect for the Primary Outcome.

Only the first event per patient was counted in these analyses. Ischemia severity was based on core-laboratory interpretation. A total of
1266 patients did not undergo core-laboratory–interpreted computed tomographic (CT) angiography for the trial and did not have an
available previous CT angiogram within 1 year before the trial for core-laboratory interpretation, and 923 patients had a CT angiography
core-laboratory interpretation in which the number of diseased vessels could not be evaluated. When trial images could be interpreted
for this variable, the number of diseased vessels on CT angiography was based on a 50% stenosis threshold. Data on CAD severity
based on 50% stenosis exclude 4 patients with no diseased vessels. Stenosis of the proximal left anterior descending (LAD) coronary
artery was reported when the proximal LAD segment could be evaluated on CT angiography. Patients were considered to have high at‑
tainment of guideline-based medical therapy at baseline if they met all the following criteria: low-density lipoprotein cholesterol level of
less than 70 mg per deciliter (1.8 mmol per liter) and receipt of any statin, systolic blood pressure of less than 140 mm Hg, receipt of
aspirin or other antiplatelet or anticoagulant agent, and no smoking. Patients who were determined by the core laboratory to have mod‑
erate ischemia on a nonimaging exercise-stress test did not meet ischemia eligibility, yet some such patients underwent randomization.
This explains the discrepancy between the “no” category under ischemia eligibility (13.8%) and the “none or mild” category for the “de‑
gree of baseline ischemia” subgroup (11.9%).

or severe ischemia. We did not find evidence that tional Heart, Lung, and Blood Institute, the National Institutes
of Health, or the Department of Health and Human Services.
the initial invasive strategy reduced the risk of A data sharing statement provided by the authors is available
ischemic cardiovascular events or death from any with the full text of this article at NEJM.org.
cause. The trial findings were sensitive to the Supported by grants (U01HL105907, U01HL105462,
U01HL105561, and U01HL105565) from the National Heart,
definition of myocardial infarction used. Lung, and Blood Institute, by Arbor Pharmaceuticals and Astra-
The views expressed in this article are solely those of the Zeneca Pharmaceuticals, and in part by Clinical and Transla-
authors and do not necessarily represent official views of the tional Science Awards (11UL1 TR001445 and UL1 TR002243)
National Center for Advancing Translational Sciences, the Na- from the National Center for Advancing Translational Sciences.

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 Invasive or Conservative Str ategy for Coronary Disease

Devices or medications were provided by Abbott Vascular, tis; Dr. Min, receiving grant support and advisory board fees
Medtronic, St. Jude Medical, Volcano, Amgen, Arbor Pharma- from GE Healthcare, holding equity in Cleerly, and receiving
ceuticals, AstraZeneca Pharmaceuticals, Espero Pharmaceuti- advisory board fees from Arineta; Dr. Mancini, receiving grant
cals, Merck Sharp & Dohme, Omron Healthcare, and Sunovion support, advisory board fees, and lecture fees from Amgen,
Pharmaceuticals. Sanofi, Boehringer Ingelheim, AstraZeneca Pharmaceuticals,
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Vascular and BioTelemetry; Dr. Bangalore, receiving grant sup- support from Novartis; Dr. Berman, receiving consulting fees
port and advisory board fees from Abbott Vascular and advisory from GE Healthcare and Bayer and grant support from Heart-
board fees from Biotronik, Pfizer, Amgen, and Reata Pharma- Flow; Dr. Ali, receiving grant support, paid to his institution,
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Amarin, grant support and lecture fees from Amgen, and lecture and advisory board fees from Cardiovascular Systems, lecture
fees from Janssen Pharmaceuticals; Dr. Chaitman, receiving fees from Amgen, fees for serving on a speakers’ bureau from
fees for serving on a clinical-event committee from Merck, Novo AstraZeneca Pharmaceuticals, advisory board fees from Abiomed
Nordisk, Lilly, Johnson & Johnson, Daiichi Sankyo, Imbria Phar- and Acist Medical, advisory board fees and lecture fees from
maceuticals, and XyloCor Therapeutics, and fees for serving on Boston Scientific and Cardinal Health, advisory board fees and
a data and safety monitoring board from Sanofi, Tricida, and consulting fees from Opsens Medical, and holding equity in
Relypsa; Dr. López-Sendón, receiving grant support from Bayer, Shockwave Medical; Dr. Mark, receiving grant support from
Merck, and Amgen, trial support and personal fees from Pfizer HeartFlow, Merck, Tenax Therapeutics, Eli Lilly, AstraZeneca
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ichi Sankyo, Merck, and Portola Pharmaceuticals, and grant Pharmaceuticals, Amgen, and UnitedHealthcare, fees for serv-
support and consulting fees from Bristol Myers Squibb, Glaxo­ ing on a steering committee from Novartis, and fees for serving
SmithKline, Medtronic, Pfizer, and Sanofi; Dr. Berger, receiving as principal investigator from Janssen Pharmaceuticals; Dr.
grant support from AstraZeneca Pharmaceuticals, research Demkow, receiving fees for proctoring, honoraria, consulting
support from Janssen Pharmaceuticals, and advisory board fees fees, and lecture fees from Abbott Vascular, Medtronic, and
from Amgen; Dr. Sidhu, receiving advisory board fees from As- Boston Scientific; Dr. Mavromatis, receiving grant support from
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Goodman, receiving grant support, fees for serving on a steer- cals, AstraZeneca Pharmaceuticals, Novartis, and Regeneron;
ing committee, lecture fees, consulting fees, and advisory board Dr. Steg, receiving grant support and fees for serving on a steer-
fees from Amgen, grant support, fees for serving as study chair, ing committee from Bayer–Janssen Pharmaceuticals, grant sup-
lecture fees, consulting fees, and advisory board fees from Astra­ port and lecture fees from Merck, grant support, fees for serving
Zeneca Pharmaceuticals and Bayer, lecture fees, consulting fees, as co-chair, consulting fees, and lecture fees from Sanofi, grant
and advisory board fees from Boehringer Ingelheim/Eli Lilly and support, fees for serving on a steering committee, and consult-
Servier, grant support, fees for serving on an executive steering ing fees from Amarin, consulting fees and lecture fees from
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ing fees, and advisory board fees from Bristol Myers Sqiubb– for serving on a critical-event committee from Bristol Myers
Pfizer, grant support, fees for serving on an executive steering Squibb, fees for serving on an executive steering committee
committee, and salary support from CSL Behring–PERFUSE from Boehringer Ingelheim, fees for serving on a critical-event
Research Institute, grant support, fees for serving on a data and committee from Pfizer, fees for serving on an executive steering
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Sankyo–American Regent–Duke Clinical Research Institute, from Regeneron and Eli Lilly, fees for serving as co-chair and
fees for serving on a steering committee from Esperion Thera- consulting fees from AstraZeneca Pharmaceuticals, grant sup-
peutics–C5Research, fees for serving on a steering committee, port, fees for serving as chair of a data and safety monitoring
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ceuticals, fees for serving on a data and safety monitoring com- vier, and fees for serving on a steering committee from Idorsia;
mittee and travel support from GlaxoSmithKline and Novo Dr. Kohsaka, receiving grant support and lecture fees from
Nordisk, consulting fees and advisory board fees from HLS Bayer, grant support from Daiichi Sankyo, and lecture fees from
Therapeutics, advisory board fees from Merck, grant support, Bristol Myers Squibb, Pfizer Japan, and AstraZeneca Pharmaceu-
fees for serving as a subinvestigator, lecture fees, and advisory ticals; Dr. Rockhold, receiving grant support and consulting
board fees from Novartis, grant support, fees for serving on an fees from Janssen Pharmaceuticals, consulting fees from Merck
executive steering committee, fees for serving as Canadian na- Healthcare, fees for serving on a data and safety monitoring
tional coordinator, salary support, lecture fees, consulting fees, board from Merck Research Laboratories, Novo Nordisk,
advisory board fees, and travel support from Sanofi and Regen- KLSMC Stem Cells, Aldeyra Therapeutics, Rhythm Pharmaceuti-
eron, and lecture fees, consulting fees, and advisory board fees cals, and Complexa, grant support and fees for serving on a data
from Servier; Dr. Maggioni, receiving fees for serving on study and safety monitoring board from AstraZeneca Pharmaceuticals,
committees from Bayer, Fresenius Medical Care, and Novartis; grant support and fees for trial design from Eidos Therapeutics,
Dr. White, receiving grant support and fees for serving on a fees for serving on an advisory board and holding equity in
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Pfizer USA, Eisai, DalCor Pharma UK, and American Regent, GlaxoSmithKline, and fees for study design from Phathom
advisory board fees from Sirtex Medical, Acetelion, and Genen- Pharmaceuticals; Dr. Ferguson, fees for serving as founder and
tech, grant support, fees for serving on a steering committee, chief medical officer of RFPi; Dr. Harrington, receiving grant
and advisory board fees from CSL Behring, grant support, fees support from CSL Behring, Sanofi–Aventis, AstraZeneca Phar-
for serving on a steering committee, fees for serving as cochair, maceuticals, Janssen Pharmaceuticals, Bristol Myers Squibb,
sponsorship, and travel support from Sanofi–Aventis Australia, Novartis, and The Medicines Company, consulting fees from
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imbursement of meeting expenses from Esperion Therapeutics, holding equity in Element Science, and advisory board fees from
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Shockwave Medical, TherOx, Reva, Vascular Dynamics, Robo- holding stock options in Qool Therapeutics and Orchestra
cath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor BioMed, and holding equity and stock options in Cagent Vascu-
Medical, Neovasc, V-Wave, Abiomed, Claret Medical, Sirtex lar, Applied Therapeutics, Biostar, MedFocus, Aria CV, and Car-
Medical, MAIA Pharmaceuticals, and Vectorious Medical Tech- diac Success. No other potential conflict of interest relevant to
nologies, consulting fees and holding equity in VALFIX Medical this article was reported.
and SpectraWAVE, consulting fees, holding equity, and holding Disclosure forms provided by the authors are available with
stock options in Ancora, personal fees, holding equity, and the full text of this article at NEJM.org.

Appendix
The authors’ full names and academic degrees are as follows: David J. Maron, M.D., Judith S. Hochman, M.D., Harmony R. Reynolds,
M.D., Sripal Bangalore, M.D., M.H.A., Sean M. O’Brien, Ph.D., William E. Boden, M.D., Bernard R. Chaitman, M.D., Roxy Senior,
M.D., D.M., Jose López‑Sendón, M.D., Karen P. Alexander, M.D., Renato D. Lopes, M.D., Ph.D., Leslee J. Shaw, Ph.D., Jeffrey S.
Berger, M.D., Jonathan D. Newman, M.D., M.P.H., Mandeep S. Sidhu, M.D., M.B.A., Shaun G. Goodman, M.D., Witold Ruzyllo, M.D.,
Ph.D., Gilbert Gosselin, M.D., Aldo P. Maggioni, M.D., Harvey D. White, D.Sc., Balram Bhargava, M.D., D.M., James K. Min,
M.D., G.B. John Mancini, M.D., Daniel S. Berman, M.D., Michael H. Picard, M.D., Raymond Y. Kwong, M.D., M.P.H., Ziad A. Ali, M.D.,
D.Phil., Daniel B. Mark, M.D., M.P.H., John A. Spertus, M.D., M.P.H., Mangalath N. Krishnan, D.M., Ahmed Elghamaz, M.D., Naga-
raja Moorthy, M.D., D.M., Whady A. Hueb, M.D., Marcin Demkow, M.D., Kreton Mavromatis, M.D., Olga Bockeria, M.D., Ph.D., Jesus
Peteiro, M.D., Ph.D., Todd D. Miller, M.D., Hanna Szwed, M.D., Ph.D., Rolf Doerr, M.D., Matyas Keltai, M.D., Ph.D., D.Sc., Joseph B.
Selvanayagam, M.B., B.S., D.Phil., P. Gabriel Steg, M.D., Claes Held, M.D., Ph.D., Shun Kohsaka, M.D., Stavroula Mavromichalis, M.S.,
Ruth Kirby, R.N., Neal O. Jeffries, Ph.D., Frank E. Harrell, Jr., Ph.D., Frank W. Rockhold, Ph.D., Samuel Broderick, M.S., T. Bruce
Ferguson, Jr., M.D., David O. Williams, M.D., Robert A. Harrington, M.D., Gregg W. Stone, M.D., and Yves Rosenberg, M.D., M.P.H.
The authors’ affiliations are as follows: the Department of Medicine, Stanford University School of Medicine, Stanford (D.J.M.,
R.A.H.), and Cedars–Sinai Medical Center, Los Angeles (D.S.B.) — both in California; New York University Grossman School of
Medicine (J.S.H., H.R.R., S. Bangalore, J.S.B., J.D.N., S.M.), Weill Cornell Medicine/New York–Presbyterian Hospital (L.J.S.), Cleerly
(J.K.M.), the Cardiovascular Research Foundation (Z.A.A., G.W.S.), Columbia University Irving Medical Center/New York–Presbyterian
Hospital (Z.A.A.), and Icahn School of Medicine at Mount Sinai (G.W.S.), New York, Albany Medical College and Albany Medical Cen-
ter, Albany (M.S.S.), and St. Francis Hospital, Roslyn (Z.A.A.) — all in New York; Duke Clinical Research Institute, Durham (S.M.O.,
K.P.A., R.D.L., D.B.M., F.W.R., S. Broderick), and Brody School of Medicine, East Carolina University, Greenville (T.B.F.) — both in
North Carolina; Veterans Affairs (VA) New England Healthcare System and Boston University School of Medicine (W.E.B.), Massachu-
setts General Hospital and Harvard Medical School (M.H.P.), and Brigham and Women’s Hospital (R.Y.K., D.O.W.) — all in Boston;
Saint Louis University School of Medicine, St. Louis (B.R.C.), and the Saint Luke’s Mid America Heart Institute and the University of
Missouri–Kansas City School of Medicine, Kansas City (J.A.S.); Northwick Park Hospital (R.S., A.E.) and Imperial College London and
Royal Brompton Hospital (R.S.) — all in London; Hospital Universitario La Paz, Instituto de Investigación de La Paz, Centro de Inves-
tigación Biomédica en Red Cardiovascular, Madrid (J.L.-S.), and Complejo Hospitalario Universitario A Coruna, Centro de Investigación
Biomédica en Red Cardiovascular, A Coruna (J.P.) — all in Spain; Canadian Heart Research Centre and St. Michael’s Hospital, Univer-
sity of Toronto, Toronto (S.G.G.), Montreal Heart Institute Research Center, Montreal (G.G.), and the University of British Columbia,
Vancouver (G.B.J.M.) — all in Canada; the Department of Coronary and Structural Heart Diseases (M.D.), National Institute of Cardiol-
ogy (W.R., M.D., H.S.), Warsaw, Poland; Associazione Nazionale Medici Cardiologi Ospedalieri, Florence, Italy (A.P.M.); Auckland
Hospital Green Lane Cardiovascular Services, Auckland, New Zealand (H.D.W.); All India Institute of Medical Sciences, New Delhi
(B.B.), Government Medical College Kozhikode, Kerala (M.N.K.), and Sri Jayadeva Institute of Cardiovascular Sciences and Research,
Bangalore (N.M.) — all in India; Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo,
Faculdade de Medicina, Universidade de São Paulo, São Paulo (W.A.H.); Emory University School of Medicine–Atlanta VA Medical
Center, Decatur, Georgia (K.M.); the National Research Center for Cardiovascular Surgery, Moscow (O.B.); Mayo Clinic, Rochester, MN
(T.D.M.); Praxisklinik Herz und Gefaesse, Dresden, Germany (R.D.); Semmelweis University, Budapest, Hungary (M.K.); Flinders
University, Flinders Medical Centre, Adelaide, SA, Australia (J.B.S.); Université de Paris, Assistance Publique–Hôpitaux de Paris, and
INSERM Unité 1148, Paris (P.G.S.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala Uni-
versity, Uppsala, Sweden (C.H.); Keio University School of Medicine, Shinjuku, Tokyo (S.K.); the National Institutes of Health, Bethesda,
MD (R.K., N.O.J., Y.R.); and Vanderbilt University School of Medicine, Nashville (F.E.H.).

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