Research

JAMA Internal Medicine | Original Investigation

Assessment of Nonfatal Myocardial Infarction as a Surrogate

for All-Cause and Cardiovascular Mortality in Treatment
or Prevention of Coronary Artery Disease
A Meta-analysis of Randomized Clinical Trials
Kevin O’Fee, MD; Elena Deych, MS; Oriana Ciani, PhD; David L. Brown, MD

Editor's Note page 1588

IMPORTANCE Although nonfatal myocardial infarction (MI) is associated with an increased Supplemental content
risk of mortality, evidence validating nonfatal MI as a surrogate end point for all-cause or
cardiovascular (CV) mortality is lacking.

OBJECTIVE To examine whether nonfatal MI may be a surrogate for all-cause or CV mortality

in patients with or at risk for coronary artery disease.

DATA SOURCES In this meta-analysis, PubMed was searched from inception until December
31, 2020, for randomized clinical trials of interventions to treat or prevent coronary artery
disease reporting mortality and nonfatal MI published in 3 leading journals.

STUDY SELECTION Randomized clinical trials including at least 1000 patients with 24 months
of follow-up.

DATA EXTRACTION AND SYNTHESIS Trial-level correlations between nonfatal MI and all-cause
or CV mortality were assessed for surrogacy using the coefficient of determination (R2).
The criterion for surrogacy was set at 0.8. Subgroup analyses based on study subject
(primary prevention, secondary prevention, mixed primary and secondary prevention, and
revascularization), era of trial (before 2000, 2000-2009, and 2010 and after), and follow-up
duration (2.0-3.9, 4.0-5.9, and ⱖ6.0 years) were performed.

MAIN OUTCOMES AND MEASURES All-cause or CV mortality and nonfatal MI.

RESULTS A total of 144 articles randomizing 1 211 897 patients met the criteria for inclusion.
Nonfatal MI did not meet the threshold for surrogacy for all-cause (R2 = 0.02; 95% CI,
0.00-0.08) or CV (R2 = 0.11; 95% CI, 0.02-0.27) mortality. Nonfatal MI was not a surrogate
for all-cause mortality in primary (R2 = 0.01; 95% CI, 0.001-0.26), secondary (R2 = 0.03; 95%
CI, 0.00-0.20), mixed primary and secondary prevention (R2 = 0.001; 95% CI, 0.00-0.08),
or revascularization trials (R2 = 0.21; 95% CI, 0.002-0.50). For trials enrolling patients before
2000 (R2 = 0.22; 95% CI, 0.08-0.36), between 2000 and 2009 (R2 = 0.02; 95% CI,
0.00-0.17), and from 2010 and after (R2 = 0.01; 95% CI, 0.00-0.09), nonfatal MI was not
a surrogate for all-cause mortality. Nonfatal MI was not a surrogate for all-cause mortality
in randomized clinical trials with 2.0 to 3.9 (R2 = 0.004; 95% CI, 0.00-0.08), 4.0 to 5.9
(R2 = 0.06; 95% CI, 0.001-0.16), or 6.0 or more years of follow-up (R2 = 0.30; 95% CI,
0.01-0.55).
Author Affiliations: Department of
CONCLUSIONS AND RELEVANCE The findings of this meta-analysis do not appear to establish Medicine, Washington University
School of Medicine in St Louis,
nonfatal MI as a surrogate for all-cause or CV mortality in randomized clinical trials of St Louis, Missouri (O’Fee, Deych,
interventions to treat or prevent coronary artery disease. Brown); Cardiovascular Division,
Washington University School of
Medicine in St Louis, St Louis,
Missouri (Deych, Brown); Center for
Research in Health and Social Care
Management, SDA Bocconi, Milan,
Italy (Ciani); University of Exeter
College of Medicine and Health,
Exeter, United Kingdom (Ciani).
Corresponding Author: David L.
Brown, MD, Cardiovascular Division,
Washington University School of
Medicine in St Louis, 660 S Euclid
JAMA Intern Med. 2021;181(12):1575-1587. doi:10.1001/jamainternmed.2021.5726 Ave, Campus Box 8086, St Louis, MO
Published online October 25, 2021. 63110 (dlb8366@gmail.com).

(Reprinted) 1575
© 2021 American Medical Association. All rights reserved.
 Research Original Investigation Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality
I
n the 19th century, acute myocardial infarction (MI) result-
ing from coronary thrombosis was believed to be univer-
sally fatal. However, by the beginning of the next century,
it was recognized that survival from acute MI was possible al-
though still associated with significant mortality.1 However,
as mortality rates decreased with advances in acute MI man-
agement in the second half of the 20th century, the evalua-
tion of new therapies required a different standard.2 How-
ever, as mortality rates decreased with advances in acute MI
management in the second half of the 20th century, the evalu-
ation of new therapies became necessary using a different
standard.2 In the early 1990s, Braunwald and colleagues3 sug-
gested that combining mortality with nonfatal complications
might better inform the overall outcomes of experimental
therapies, accelerate the pace of evaluating proposed innova-
tions, and minimize the number of patients exposed to inef-
fective therapies. Nonfatal MI was subsequently incorpo-
rated as an end point in landmark studies of acute coronary
syndromes and ultimately in almost all studies of treatment
or prevention of coronary artery disease based on the assump-
tion that nonfatal MI was a surrogate for mortality and that pre-
venting nonfatal MI would reduce mortality—a belief that
endures.4-10 However, the use of nonfatal MI as a surrogate
for mortality has been questioned for not meeting accepted
standards for surrogacy.10-14
The assertion of surrogacy of one end point for another re-
quires 3 levels of evidence.15 First, there must be biological
plausibility. Although biological plausibility is necessary, it is
not sufficient to establish surrogacy.16 Second, observational
or epidemiologic studies demonstrating a consistent associa-
tion between the surrogate and the final outcome are re-
quired. The highest level of proof is trial-level surrogacy in
which, across many trials, treatments that improve the surro-
gate end point also improve the ultimate end point of inter-
est. Establishing trial-level surrogacy requires an analysis of
all randomized clinical trials (RCTs), with each trial serving as
a unique data point. There is abundant evidence demonstrat-
ing that the association between nonfatal MI and all-cause or
cardiovascular (CV) mortality meets the first 2 levels of evi-
dence but, to our knowledge, the third and most stringent level
of proof has never been assessed. We therefore performed an
analysis of RCTs reported over the past approximately 50 years
to test the null hypothesis that nonfatal MI is not a surrogate
for all-cause or CV mortality by assessing the correlation
between the treatment effect of an intervention on nonfatal
MI and the treatment effect of the same intervention on
all-cause or CV mortality.
Methods
PubMed was searched from inception until December 31, 2020,
for RCTs of interventions to treat or prevent the clinical mani-
festations of coronary artery disease published in The New
England Journal of Medicine, JAMA, or The Lancet that re-
ported all-cause mortality and nonfatal MI outcomes (eAp-
pendix in the Supplement). The search was limited to these
journals because trials published in the highest-impact jour-
1576 JAMA Internal Medicine December 2021 Volume 181, Number 12 (Reprinted)
© 2021 American Medical Association. All rights reserved.
Key Points
Question Can nonfatal myocardial infarction be validated as
a surrogate end point for all-cause or cardiovascular mortality
in the treatment and prevention of coronary artery disease?
Findings In this meta-analysis of 144 randomized clinical trials
with data from 1 211 897 patients, surrogacy between nonfatal
myocardial infarction and all-cause or cardiovascular mortality
was not noted.
Meaning Results of this meta-analysis suggest that treatments
that reduce nonfatal myocardial infarction cannot be assumed
to reduce all-cause or cardiovascular mortality.
nals have higher methodological quality, larger sample sizes,
and lower risk of bias.17 This report follows the Preferred
Reporting Items for Systematic Reviews and Meta-analyses
protocol (PRISMA-P) and was registered with PROSPERO
(CRD42020172341).18
Included studies required randomization to an investi-
gational treatment or treatment strategy or a placebo or
active control. Investigational treatments or strategies
included any pharmacological, imaging, revascularization,
or lifestyle intervention aimed at the primary or secondary
prevention of coronary artery disease. To maximize preci-
sion of the reported treatment effects and the number of
events, the inclusion criteria required a minimum sample
size of at least 1000 patients with at least 24 months of
follow-up.
Two independent investigators (K.O. and D.L.B.)
screened trials and determined eligibility for inclusion. Risk
of bias was also assessed using the Cochrane Collaboration
tool. Trial-level data were then extracted from primary pub-
lications. Trial-level data have been previously demon-
strated as the highest level of evidence for establishing the
validity of surrogate end points. 19,20 Extracted variables
included study subject, year of the first patient enrollment,
total number of randomized participants, intervention type,
control type, median follow-up time, and definition of
MI used for outcome adjudication. Outcomes extracted
included nonfatal MI, all-cause mortality, and CV mortality.
Nonfatal MI data reflected the number of adjudicated MI
events based on the definition of MI used in each trial. Most
trials used the World Health Organization definition or a uni-
versal definition of MI; however, trial-specific definitions
were also used.21-25 If any outcomes data or the definition of
nonfatal MI used for adjudication were unavailable in the
primary publication, associated publications, or a published
protocol, corresponding authors were contacted by email
to request the missing data. Trials with missing data and
negative response after 60 days (n = 74) were excluded.
Negative responses included refusal by investigators (n = 3),
no response to request (n = 55), or data declared no longer
available (n = 16). The definition of CV mortality was that
used in individual RCTs and was generally defined as a com-
posite of sudden cardiac death or death from acute MI, heart
failure, stroke, CV procedures, or other CV causes.
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Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality
Statistical Analysis
A meta-analysis of summary statistics from each article was
performed using Comprehensive Meta-Analysis, version 2.0
(Biostat Inc) software. Estimates of effect for all-cause mor-
tality, CV mortality, and nonfatal MI were calculated from crude
event rates with a random-effects model using inverse vari-
ance weighting, expressed as odds ratios (ORs) with 95% CIs
and presented in forest plots. Data were analyzed according
to the intention-to-treat principle. The presence of between-
study heterogeneity was determined by the I2 value (ranging
from 0% to 100%) and graded as follows: values less than 25%
(low heterogeneity), between 25% and 50% (moderate hetero-
geneity), and 50% or higher (high heterogeneity).26 Funnel
plots for mortality and nonfatal MI were constructed to as-
sess for publication bias. The Egger test was used to identify
asymmetry of funnel plots. The Egger test regresses the stan-
dardized effect sizes on their precisions; in the absence of pub-
lication bias, the regression intercept is expected to be 0.
To generate a graphic representation of the association
between nonfatal MI and all-cause or CV mortality, the log-
transformed ORs or hazard ratios (HRs) for nonfatal MI (the
putative surrogate) were graphed on the x coordinate with
the ORs and HRs for all-cause or CV mortality (the true end
point) graphed on the y coordinate, with each trial serving as
a unique data point. A horizontal line with slope = 0 indi-
cates no association; a positive slope indicates some degree
of positive association, whereas a negative slope indicates
a negative association between nonfatal MI and all-cause or
CV mortality. We attempted to determine the surrogate treat-
ment effect, defined as the maximum value of the OR for non-
fatal MI that needs to be observed in a trial to conclude a sig-
nificant effect on all-cause or CV mortality. The surrogate
treatment effect is determined by the intersection of the
upper prediction limit and the horizonal line indicating log
OR mortality = 0.
Because positive correlation does not necessarily meet the
more stringent criteria for surrogacy, trial-level surrogacy of
nonfatal MI for all-cause or CV mortality was assessed by gen-
erating a coefficient of determination, R 2 (with 95% CI),
between the natural logarithm of the ORs or HRs for nonfatal
MI and all-cause and CV mortality using a weighted linear re-
gression in which each study was weighted by the number of
observations. The R2 values (corresponding to the explained
variation) fall between 0 and 1.00, with 0 indicating the ab-
sence of surrogacy and 1.00 indicating perfect surrogacy. The
CI for R2 was obtained from bootstrap resampling. The thresh-
old for validating nonfatal MI as a surrogate for all-cause
or CV mortality was set at 0.8 with the 95% CI excluding 0.6.
This predefined threshold was arbitrary but has been used
elsewhere.27 It was determined prospectively to limit post hoc
biases. All statistical analyses other than the meta-analysis
were performed in R, version 4.0 (R Foundation for Statisti-
cal Computing).
Four prespecified subgroup analyses based on study sub-
ject, era of the trial, duration of follow-up, and type of control
group treatment were performed to investigate their associa-
tions with surrogacy. Study subjects included primary pre-
vention, secondary prevention, mixed primary and second-
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Original Investigation Research
Figure 1. Preferred Reporting Items for Systematic Review
and Meta-analysis Diagram
1025 Records identified through database searching
1025 Records after duplicates removed
1025 Records screened
727 Records excluded based on title
and abstract
298 Full-text articles assessed for eligibility
154 Full-text articles excluded
80 Inclusion criteria
74 Missing event/MI definition data
144 Studies included in qualitative synthesis
144 Studies included in quantitative synthesis
MI indicates myocardial infarction.
ary prevention, and revascularization trials. The time period
was based on the year the first patient was enrolled and di-
vided into 3 eras: before 2000, from 2000 to 2010, and after
2010, corresponding to the adoption of troponin in the uni-
versal definition of MI in 2000 and the widespread adoption
of commercially available high-sensitive troponins in 2010.22,28
Duration of follow-up was categorized as 2.0 to 3.9 years, 4.0
to 5.9 years, and 6.0 or more years. Control groups receiving
either active or placebo treatments were analyzed separately.
For sensitivity analysis, we analyzed only trials that reported
time-to-event data presented as HRs.
Results
Description of Trials
As illustrated in Figure 1, 1025 RCTs were identified for screen-
ing, with 298 meeting inclusion criteria. Data extraction was
completed for 144 RCTs reflecting 5 726 395 patient-years
of follow-up in 1 211 897 patients. 25,29-171 eTable 1 in the
Supplement presents the trial-level characteristics of the 144
studies. eTable 2 in the Supplement provides an assessment
of risk of bias, and eTable 3 in the Supplement provides the
full study names. By study subject, there were 24 primary pre-
vention, 57 mixed primary/secondary prevention, 46 second-
ary prevention, and 17 revascularization RCTs. By interven-
tion, there were 117 trials of pharmacological agents, 3 trials
of imaging strategies, 7 trials of lifestyle interventions, and
17 trials of interventional therapies. By time period, there were
62 trials with first patient enrollment before 2000, 44 trials
that began enrollment between 2000 and 2009, and 38
trials that initiated enrollment in 2010 and after. Follow-up
duration was between 2.0 and 3.9 years in 66 trials, between
4.0 and 5.9 years in 57 trials, and 6.0 or more years in 21 trials.
The earliest included trial was published in May 1972, and the
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 Research Original Investigation Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality

Figure 2. Correlations of Treatment Effects on Nonfatal Myocardial Infarction (MI) and All-Cause or Cardiovascular Mortality

A Overall analysis of 144 trials B Analysis of 112 trials

0.6 0.9

0.6
True end point treatment effect, log OR

True end point treatment effect, log OR

0.3
0.3

0 0

–0.3
–0.3
–0.6

–0.6 –0.9

–1.0 –0.5 0 0.5 1.0 –1.0 –0.5 0 0.5 1.0

Surrogate end point treatment effect, log OR Surrogate end point treatment effect, log OR

C Subgroup analysis
0.4
True end point treatment effect, log HR

0.2

–0.2

–0.4

–0.6 –0.4 –0.2 0 0.2 0.4

Surrogate end point treatment effect, log HR

A, Overall analysis of 144 trials for the association between the logarithm of the
odds ratio (log OR) for the surrogate end point of nonfatal MI and the true end
point of all-cause mortality. B, Analysis of 112 trials for the association between
the log OR for the surrogate end point of nonfatal MI and the true end point of
cardiovascular mortality. C, Subgroup analysis of trials reporting hazard ratios
(HRs) for the association between the log HR for the surrogate end point of
nonfatal MI and the true end point of all-cause mortality. The dark blue area
represents the 95% CI for the regression line (solid blue), light blue area
represents the 95% prediction interval, and circle sizes are proportionate to
the number of observations.

most recent trial was published in November 2020. Cardio- demonstrates the outcomes of randomized interventions on
vascular mortality was reported in 112 RCTs enrolling 1 023 852 nonfatal MI and mortality for the 144 RCTs grouped by study
patients. Hazard ratios were reported in 48 trials with 367 531 subject in ascending chronological order from the date of the
participants. first patient enrollment.
In the pooled analysis of the 144 trials, randomized as-
signment to an investigational treatment reduced the rate of Correlations of Treatment Effects
nonfatal MI from 4.2% to 3.7% (OR, 0.87; 95% CI, 0.85-0.90; Figure 2A illustrates the log-transformed graphical represen-
overall P < .001; I2 = 58%; P < .001) and reduced all-cause mor- tation of the OR for nonfatal MI and the OR for all-cause mor-
tality from 7.3% to 7.0% (OR, 0.95; 95% CI, 0.93-0.97; overall tality for all 144 trials. Overall, the slope of the regression line
P < .001; I2 = 53%; P < .001). Funnel plots were symmetrical was not significantly different than the horizontal (0.09;
for both end points, indicating lack of publication bias. 95% CI, −0.01 to 0.19), and the coefficient of determination
The Egger test did not identify asymmetry for the funnel plot confirmed that the trial-level treatment effect on nonfatal
for nonfatal MI (intercept, −0.16; 95% CI, −0.80 to 0.49; P = .31) MI did not predict treatment effect on all-cause mortality
or mortality (intercept, −0.44; 95% CI, −1.02 to 0.14; P = .07) (R2 = 0.02; 95% CI, 0.00-0.08) (Table). Because the upper
(eFigure 1 in the Supplement). eFigure 2 in the Supplement bound of the prediction interval never crossed the log

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Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality Original Investigation Research

Table. Overall and Subgroup Analyses of the Correlation of Treatment Effects and Coefficient of Determination
of MI for All-Cause and Cardiovascular Mortality

Analysis Trials Patients, No. Regression formula Slope (95% CI) P value R2 (95% CI)
All-cause mortality 144 1 211 897 −0.02 + 0.09 × log (OR_MI) 0.09 (−0.01 to 0.19) .07 0.02 (0.00 to 0.08)
Study subject
Primary prevention 24 352 897 0.001 + 0.12 × log (OR_MI) 0.12 (−0.05 to 0.29) .14 0.01 (0.001 to 0.26)
Primary-secondary prevention 57 461 329 −0.04 + 0.02 × log (OR_MI) 0.02 (−0.14 to 0.18) .80 0.001 (0.00 to 0.08)
Secondary prevention 46 351 823 −0.02 + 0.14 × log (OR_MI) 0.14 (−0.11 to 0.40) .27 0.03 (0.00 to 0.20)
Revascularization 17 45 848 0.04 + 0.28 × log (OR_MI) 0.28 (−0.02 to 0.60) .07 0.21 (0.002 to 0.50)
Era of first patient enrollment
<2000 62 461 103 −0.02 + 0.27 × log (OR_MI) 0.27 (0.14 to 0.41) <.001 0.22 (0.08 to 0.36)
2000-2009 44 397 766 −0.005 + −0.08 × log (OR_MI) −0.08 (−0.26 to 0.10) .38 0.02 (0.00 to 0.17)
≥2010 38 353 028 −0.05 + −0.05 × log (OR_MI) −0.05 (−0.27 to 0.17) .67 0.01 (0.00 to 0.09)
Length of follow-up, y
2.0-3.9 66 484 978 −0.02 + 0.04 × log (OR_MI) 0.04 (−0.12 to 0.20) .61 0.004 (0.00 to 0.08)
4.0-5.9 57 486 054 −0.009 + 0.14 × log (OR_MI) 0.14 (−0.01 to 0.29) .07 0.06 (0.001 to 0.16)
≥6.0 21 240 865 −0.023 + 0.466 × log (OR_MI) 0.47 (0.12 to 0.81) .01 0.30 (0.01 to 0.55)
Control arm
Placebo 86 827 461 −0.02 + 0.09 × log (OR_MI) 0.09 (−0.06 to 0.25) .23 0.02 (0.00 to 0.10)
Active 58 384 436 −0.03 + 0.10 × log (OR_MI) 0.10 (−0.04 to 0.23) .16 0.03 (0.00 to 0.13)
Studies reporting time-to-event outcomes 48 367 531 −0.02 + −0.05 × log (HR_MI) −0.05 (−0.16 to 0.26) .63 0.01 (0.00 to 0.06)
Studies reporting cardiovascular mortality 112 1 023 852 −0.03 + 0.29 × log (OR_MI) 0.29 (0.13 to 0.44) .0003 0.11 (0.02 to 0.27)

Abbreviations: HR, hazard ratio; MI, myocardial infarction; OR, odds ratio.

OR_mortality = 0 horizontal, the surrogate treatment effect
cannot be calculated, indicating there is no OR achievable
by an intervention for nonfatal MI that would predict a sig-
nificant reduction in the OR for all-cause mortality. Figure 2B
shows the log-transformed representation of the OR for non-
fatal MI and the OR for CV mortality in 112 trials. The slope
of the regression line indicates a positive correlation between
nonfatal MI and CV mortality. However, at R2 = 0.11 (95% CI,
0.02-0.27), the coefficient of determination does not vali-
date nonfatal MI as a surrogate for CV mortality (Table). Be-
cause the upper bound of the prediction interval never crosses
the log OR_mortality = 0 horizontal, the surrogate treatment
effect cannot be calculated, indicating there is no OR achiev-
able by an intervention for nonfatal MI that would predict
a significant reduction in the OR for CV mortality. Limiting
the analysis to the 48 RCTs that reported HRs, there was no
significant difference between the slope of the regression line
from the horizontal (−0.05; 95% CI, −0.27 to 0.17) and no
evidence of surrogacy (R2 = 0.005; 95% CI, 0.00 to 0.06)
(Figure 2C) (Table).
By study subject, nonfatal MI did not meet the threshold
for surrogacy of all-cause mortality in primary prevention
(R 2 = 0.01; 95% CI, 0.001-0.26), secondary prevention
(R2 = 0.03; 95% CI, 0.00-0.20), mixed primary and second-
ary prevention (R2 = 0.001; 95% CI, 0.00-0.08), and revascu-
larization trials (R2 = 0.21; 95% CI, 0.002-0.50) (Figure 3)
(Table). By time period of the RCT in trials with the first
patient enrollment before 2000, the slope of the regression
line was significantly greater than the horizontal (0.27; 95%
CI, 0.14-0.41), but despite the positive association, nonfatal MI
did not meet the threshold for surrogacy of all-cause mortal-
ity (R2 = 0.22; 95% CI, 0.08-0.36). There was no significant
difference in the regression lines from the horizontal and even
weaker evidence of surrogacy for periods 2000-2009
(R2 = 0.02; 95% CI, 0.00-0.17) and 2010 and beyond (R2 = 0.01;
95% CI, 0.00-0.09) (Figure 4) (Table).
The regression lines were not significantly different from
the horizonal line with no evidence of surrogacy of nonfatal
MI for all-cause mortality for follow-up length of 2.0 to 3.9 years
(R2 = 0.004; 95% CI, 0.00-0.08) and 4.0-5.9 years (R2 = 0.06;
95% CI, 0.001-0.16). For follow-up length of 6.0 or more years,
there was a significant difference in the slope of the regres-
sion line from the horizontal (0.47; 95% CI, 0.12-0.81), but
the coefficient of determination did not achieve the thresh-
old for surrogacy (R2 = 0.30; 95% CI, 0.01-0.55) (eFigure 3 in
the Supplement) (Table).
eFigure 4 in the Supplement shows the subgroup analy-
sis based on the type of treatment in the control group
(placebo or active therapy). In neither case was the slope of
the regression line significantly different than the horizontal,
indicating no correlation. Furthermore, R2 values were 0.02
for placebo and 0.03 for active control, indicating the ab-
sence of surrogacy of nonfatal MI for all-cause mortality (Table).
Discussion
Surrogate end points in clinical trials are biological markers or
clinical events (eg, nonfatal MI) that may be observed earlier
than the clinical end points (eg, death) that are of primary in-
terest to patients and clinicians.10 Since the earliest descrip-
tions, it has been recognized that the natural history of acute
MI includes mortality.1 It has been assumed, therefore, that
interventions to prevent nonfatal MI would reduce all-cause

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 Research Original Investigation Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality

Figure 3. Subgroup Analysis by Study Subject for the Association Between the Logarithm of the Odds Ratios (Log ORs) for the End Points

A Primary prevention B Primary-secondary prevention

0.4 0.6

0.4
True end point treatment effect, log OR

True end point treatment effect, log OR

0.2
0.2

0 0

–0.2
–0.2
–0.4

–0.4 –0.6

–0.8 –0.6 –0.4 –0.2 0 0.2 –1.2 –0.8 –0.4 0 0.4

Surrogate end point treatment effect, log OR Surrogate end point treatment effect, log OR

C Secondary prevention D Revascularization

0.4 0.8

0.6
True end point treatment effect, log OR

True end point treatment effect, log OR

0.2

0.4

0
0.2

0
–0.2

–0.2

–0.4
–0.4

–0.6 –0.6

–1.0 –0.5 0 0.5 1.0 –0.4 –0.2 0 0.2 0.4 0.6 0.8
Surrogate end point treatment effect, log OR Surrogate end point treatment effect, log OR

Surrogate end point of nonfatal myocardial infarction and the true end points blue area represents the 95% CI for the regression line (solid blue), light blue
of all-cause mortality primary prevention (A), mixed primary-secondary area represents the 95% prediction interval, and circle size is proportionate
prevention (B), secondary prevention (C), and revascularization (D). The dark to the number of observations.

or CV mortality, supporting the notion that nonfatal MI is There are at least 3 potential explanations for the lack of
a surrogate for mortality. However, in this meta-analytic trial-level surrogacy between nonfatal MI and all-cause or
assessment of nonfatal MI surrogacy including 144 RCTs that CV mortality. First, over the time course of this study, the
randomized 1.2 million patients with 5.7 million years of extent of myocardial injury required to diagnose nonfatal MI
follow-up to interventions to treat or prevent coronary artery has decreased with the introduction of progressively more
disease, we found no trial-level correlation between nonfatal sensitive biomarkers. At the same time, background primary
MI and all-cause or CV mortality. The I2 values for the 144 RCTs and secondary treatments have improved. Thus, more
included in the meta-analysis revealed significant heteroge- recently detected nonfatal MIs may be so small and second-
neity, which is an advantage in this setting because between- ary prevention treatments so successful that nonfatal MIs
trial differences provide opportunities in subgroup analyses are no longer on the causal pathway of mortality. However,
to find more specific settings in which surrogacy exists. How- even in the earliest era of RCTs prior to 2000 and before the
ever, even in subgroups divided by study subject, study era, widespread introduction of troponin assays to detect myo-
duration of follow-up, and control arm treatment, we were cardial injury, the R2 value was only 0.27, which does not
unable to detect any evidence of surrogacy. We also found meet the threshold for surrogacy. In subsequent eras, from
no evidence of surrogacy when limiting the analysis to stud- 2000 to 2010 before the introduction of high-sensitivity
ies that reported time-to-event data. troponin assays and from 2011 to 2020 after the introduction

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Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality Original Investigation Research

Figure 4. Subgroup Analysis by Era of Trial Enrollment for the Association Between the Logarithm of the Odds Ratios (OR) for End Points

A Trials with first patient enrolled before 2000 B Trials with first patient enrolled 2000-2009
0.6 0.6
True end point treatment effect, log OR

True end point treatment effect, log OR

0.3 0.3

0 0

–0.3 –0.3

–0.6 –0.6

–1.0 –0.5 0 0.5 1.0 –0.8 –0.4 0 0.4 0.8

Surrogate end point treatment effect, log OR Surrogate end point treatment effect, log OR

C Trials with first patient enrolled from 2010 and after

0.6
True end point treatment effect, log OR

0.3

–0.3

–0.6

–1.0 –0.5 0 0.5 1.0

Surrogate end point treatment effect, log OR

Surrogate end point of myocardial infarction (MI) and true end point of all-cause 95% CI for the regression line (solid blue). Light blue area represents the 95%
mortality in trials with first patient enrolled before 2000 (A) from 2000 to prediction interval. Circle size is proportionate to trial size.
2009 (B), and in 2010 and after (C). The dark blue area area represents the

of high-sensitivity troponin assays, there was no correlation
between the treatment effects on nonfatal MI and all-cause
mortality.
Second, it is plausible that the failure to demonstrate sur-
rogacy between nonfatal MI and all-cause mortality relates to
the competing risk of non-CV death that CV interventions
would not be expected to reduce. In a post hoc analysis of the
IMPROVE-IT trial (included in this analysis), the relative inci-
dence of CV and non-CV death following an acute coronary syn-
drome was investigated.172 For patients who presented with
an ST-segment-elevation MI, the incidence of CV death was
higher than non-CV death for 4 years following the index event
after which non-CV death predominated. For unstable an-
gina or non–ST-segment elevation MI, the cumulative inci-
dence of CV death remained higher than non-CV death for the
entire duration of follow-up (median, 6.0 years). Although simi-
lar data for RCTs performed in different settings are lacking,
our subgroup analysis showing no significant surrogacy at
2.0 to 3.9, 4.0 to 5.9, and 6.0 or more years suggests that an
increasing risk of non-CV death over time is not a likely expla-
nation for the overall lack of surrogacy. Furthermore, the lack
of surrogacy of nonfatal MI for CV mortality further weakens
this potential explanation.
The third potential explanation for the lack of surrogacy
of nonfatal MI for all-cause or CV mortality relates to the
heterogeneous nature of MI. Although the earliest descrip-
tions attributed all acute MIs to coronary thrombosis,
by 1939 it was recognized that there were both thrombotic
and nonthrombotic causes of acute MI.1,173 However, it was
not until 2007 that an international consensus classification
of acute MI subtypes, the universal definition of MI, was
published.23 By the time this classification was revised in
201224 and updated in 2018,174 5 clinical subtypes of acute
MI in addition to the non-MI diagnosis of acute nonischemic

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© 2021 American Medical Association. All rights reserved.

 Research Original Investigation Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality

myocardial injury were recognized, each with different Limitations

pathophysiologic mechanisms and different mortality rates
and causes.
The 2 most common MI subtypes are type 1, attributed
to atherosclerotic plaque rupture or erosion and secondary
thrombosis, and type 2, resulting from an acute imbalance
in myocardial oxygen supply and demand without throm-
bosis. The reported proportion of adjudicated type 2 MI
ranges from 2% to 58% of all MI presentations.175 Physician
accuracy in differentiating type 1 from type 2 MI is poor.176
However, distinction of the 2 categories is important
because, in addition to different pathophysiologic charac-
teristics, type 1 and type 2 MIs require different manage-
ment and have different outcomes.
For type 1 MI, treatment focuses on restoring or maintain-
ing coronary arterial patency pharmacologically or with re-
vascularization. Treatment of type 2 MI focuses on reversing
the underlying cause of supply and demand mismatch. In most
studies, both short- and long-term mortality are higher in pa-
tients with type 2 MI.176 The increased mortality in patients
with nonfatal type 2 MI is associated with their greater bur-
den of comorbidities rather than their underlying coronary dis-
ease. Thus, treatments that reduce nonfatal type 2 MI, which
is a marker for comorbidities, would not be expected to re-
duce all-cause or CV mortality and would blunt any potential
surrogacy of nonfatal type 1 MI for mortality.
Since its earliest recognition, most treatment and preven-
tion strategies have focused on type 1 MI. Although the devel-
opment of increasingly sensitive troponin assays over the past
decade has increased the diagnosis of acute MI by approxi-
mately 50% and allowed the elucidation of the various MI phe-
notypes, it is unlikely their existence is new.177 Thus, the appli-
cation of type 1 MI treatment and prevention strategies to the
other MI subtypes is likely an important contributor to the lack
of correlation between the effects of treatment for nonfatal MI
with the treatment effect for all-cause or CV mortality.
There are limitations to this analysis. First, by confining our
search strategy to 3 journals, we did not include all poten-
tially relevant RCTs. Second, not all trials identified by our
search strategy were included because of the lack of availabil-
ity of relevant data. However, unlike traditional meta-
analyses, the use of nonexhaustive sets of trials are less of a
concern as long as the included trials reflect a wide range of
heterogeneity of treatment effects.178 Third, the specific thresh-
old we used to grade the presence of surrogacy has not been
externally validated. Others have recommended a threshold
of 0.65 for coefficients of determination (R2).16 However, it
is unlikely that the overall R2 of 0.02 or even the highest R2
of 0.30 identified in studies with a follow-up of 6.0 or more
years would be interpreted as representing significant sur-
rogacy by any standard.179 Fourth, the patients enrolled in RCTs
may not be representative of the overall population of
patients with or at risk for coronary artery disease. Fifth, it is
possible that with longer follow-up, especially in primary pre-
vention trials, the R2 values may have approached the sur-
rogacy thresholds. Sixth, only 3 RCTs provided data on the MI
subtypes, which prevented us from evaluating surrogacy as
a function of MI subtype.
Conclusions
In this meta-analysis, nonfatal MI, as defined in RCTs
of treatment and prevention of coronary artery disease,
could not be validated as a surrogate end point for all-cause
or CV mortality. Thus, interventions that reduce nonfatal MI
cannot be assumed to reduce mortality. Inclusion of nonfatal
MI as an end point in RCTs may still be justified based on its
association with impaired quality of life and increased use
of health care resources, but not based on its surrogacy for
mortality.10

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Accepted for Publication: August 2, 2021. 1. Braunwald E. Evolution of the management of CIR.97.25.2502

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Author Contributions: Dr Brown had full access to
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for the integrity of the data and the accuracy of
the data analysis.
Concept and design: O'Fee, Brown.
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Administrative, technical, or material support:
O'Fee, Brown.
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REWIND Investigators. Dulaglutide and
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121-130. doi:10.1016/S0140-6736(19)31149-3
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Effect of apabetalone added to standard therapy
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 Supplementary Online Content

O’Fee K, Deych E, Ciani O, Brown DL. Assessment of nonfatal myocardial infarction as

a surrogate for all-cause and cardiovascular mortality in treatment or prevention of
coronary artery disease: a meta-analysis of randomized clinical trials. JAMA Intern Med.
Published online October 25, 2021. doi:10.1001/jamainternmed.2021.5726

eFigure 1. Funnel Plots for Nonfatal Myocardial Infarction and All-cause Mortality
eFigure 2. Treatment Effect of Myocardial Infarction (MI) and All-cause Mortality by
Study Type
eFigure 3. Subgroup Analysis by Years of Follow-up for the Association Between the
Logarithm of the Odds Ratios (OR) for Surrogate End Point of Myocardial Infarction
(MI) and True Endpoint of All-cause Mortality
eFigure 4. Subgroup Analysis by Type of Control Arm for the Association Between the
Logarithm of the Odds Ratios (OR) for Surrogate End Point of Myocardial Infarction
(MI) and True End Point of All-cause Mortality
eAppendix. Search Strategy
eTable 1. Trial Characteristics
eTable 2. Assessment of Risk of Bias
eTable 3. Trial Abbreviations, Names, and Date of Publication
eReferences

This supplementary material has been provided by the authors to give readers additional
information about their work.

© 2021 American Medical Association. All rights reserved. 1

Figure 1. Funnel plots for nonfatal myocardial infarction and all-cause mortality.
1A. Nonfatal myocardial infarction

1B. All-cause mortality

© 2021 American Medical Association. All rights reserved. 2

eFigure 2. Treatment effect of myocardial infarction (MI) and all-cause mortality by study type

2A. Revascularization

© 2021 American Medical Association. All rights reserved. 3

2B. Primary prevention

© 2021 American Medical Association. All rights reserved. 4

2C. Mixed primary/secondary prevention

© 2021 American Medical Association. All rights reserved. 5

2C. (continued)

© 2021 American Medical Association. All rights reserved. 6

2D. Secondary prevention

© 2021 American Medical Association. All rights reserved. 7

2D. (continued)

© 2021 American Medical Association. All rights reserved. 8

eFigure 3. Subgroup analysis by years of follow-up for the association between the logarithm of
the odds ratios (OR) for surrogate endpoint of myocardial infarction (MI) and true endpoint of
all-cause mortality
3A. 2-3.9 years

© 2021 American Medical Association. All rights reserved. 9

3B. 4-5.9 years

© 2021 American Medical Association. All rights reserved. 10

3C. >6 years

© 2021 American Medical Association. All rights reserved. 11

eFigure 4. Subgroup analysis by type of control arm for the association between the logarithm of

the odds ratios (OR) for surrogate endpoint of myocardial infarction (MI) and true endpoint of

all-cause mortality

4A. Placebo

© 2021 American Medical Association. All rights reserved. 12

4B. Active control

© 2021 American Medical Association. All rights reserved. 13

eAppendix. Search Strategy
Pubmed
("cardiovascular events"[All Fields] OR "cardiovascular event"[All Fields]) OR (("myocardial
infarction"[All Fields] OR "myocardial infarction"[All Fields]) AND (("death"[MeSH Terms]
OR "death"[All Fields]) OR ("death"[MeSH Terms] OR "death"[All Fields] OR "deaths"[All
Fields]) OR ("mortality"[Subheading] OR "mortality"[All Fields] OR "mortality"[MeSH Terms])
OR ("mortality"[MeSH Terms] OR "mortality"[All Fields] OR "mortalities"[All Fields]) OR
fatal[All Fields] OR fatalities[All Fields])) AND ("N Engl J Med"[Journal] OR
"Lancet"[Journal] OR "JAMA"[Journal]) AND (Randomized Controlled Trial[ptyp] AND
("1945/01/01"[PDAT] : "2020/12/31"[PDAT])) AND (Randomized Controlled Trial[ptyp] AND
("1945/01/01"[PDAT] : "2020/12/31"[PDAT]))

© 2021 American Medical Association. All rights reserved. 14

 eTable 1. Trial Characteristics
Trial name, Year of Investigational Control arm MI Investigation Contro Media
publication date First arm definition al arm, N l arm, n
Patient N follow-
Enrollmen up,
t years

Revascularization trials (N=17)

RITA-1, 1998 1988 Percutaneous Coronary artery WHO 510 501 6.5
transluminal bypass grafting definition1
coronary (CABG)
angioplasty
(PTCA)

RITA-2, 1997 1992 PTCA Optimal medical WHO 504 514 2.7
therapy (OMT) definition

RITA-3, 2005 1997 Early invasive Conservative WHO 895 915 5

strategy strategy definition

COURAGE, 2007 1999 Percutaneous OMT COURAGE 1149 1138 4.6

coronary definition2
intervention
(PCI) and OMT

OAT, 2006 2000 PCI and OMT OMT OAT 1082 1084 3
definition3

BARI 2D, 2009 2001 Revascularizatio OMT BARI 2D 1176 1192 5.3
n and OMT trial
definition4

ROOBY-FS, 2017 2002 Off pump On pump CABG Universal 1104 1099 5
CABG definition of
myocardial
infarction
(UDMI),
20075

FREEDOM, 2012 2005 PCI CABG FREEDOM 953 947 3.8

Trial
definition6

CORONARY, 2006 Off pump On pump CABG ACC 2375 2377 4.8
2016 CABG definition
clinical
outcomes
for patients
with ACS7

SORT OUT III, 2006 Zotarolimus- Sirolimus ICD-10 1162 1170 5

2014 eluting stent eluting stent Diagnosis
Code I21.9

© 2021 American Medical Association. All rights reserved. 15

EXAMINATION, 2008 Everolimus- Bare-metal stent WHO 751 747 5
2016 eluting stent extended
definition8

NORSTENT, 2016 2008 Drug-eluting Bare-metal stent Third 4504 4509 4.9
stent UDMI,
20129

EXCEL, 2019 2010 PCI CABG EXCEL trial 948 957 5

definition10

DANAMI 3- 2011 Deferred PCI Standard PCI Third 603 612 3.5
DEFER, 2016 UDMI, 2012

ISCHEMIA, 2020 2012 Early invasive OMT ISCHEMIA 2588 2591 3.2
angiography and trial
OMT definition
(modified
Third
UDMI)11

COMPLETE, 2019 2013 Complete Revascularizatio Third 2016 2025 3

revascularizatio n of culprit UDMI, 2012
n including non- lesion (s)
culprit lesion(s)

REGROUP, 2019 2014 Endoscopic Open vein-graft Third UDMI 576 574 2.8
vein-graft harvesting
harvesting CABG
CABG

Primary prevention trials (N= 24)

Hjermann et al, 1972 Smoking Standard of care WHO 604 628 5

1981 cessation and definition
dietary
consultation

LRC-CPPT, 1984 1973 Cholestyramine Placebo WHO 1906 1900 7.4

definition

Kornitzer et al, 1974 Smoking Standard of care WHO 8525 9855 5.5
1983 cessation, definition
weight loss,
exercise, and
dietary
consultation

Rose et al, 1983 1974 Smoking Standard of care WHO 9734 7617 5.5
cessation, definition
weight loss,
exercise, and
dietary
consultation

© 2021 American Medical Association. All rights reserved. 16

PHS, 1989 1981 Aspirin Placebo WHO 11037 11034 5
definition

SAPAT, 1992 1985 Aspirin and Placebo and WHO 1009 1026 4.2
sotalol sotalol definition

AFCAPS/TexCAP 1990 Lovastatin Placebo WHO 3304 3301 5.2

S, 1998 definition

WHS, 2005 1992 Aspirin Placebo WHO 19934 19942 10.1

definition

WHS, 2005 1992 Vitamin E Placebo WHO 19937 19939 10.1

definition

ALERT, 2003 1996 Fluvastatin Placebo WHO 1050 1052 5.1

definition

CARDS, 2004 1997 Atorvastatin Placebo WHO 1428 1410 3.9

definition

DIAD, 2009 2000 Myocardial Standard of care Joint 561 562 4.8
perfusion ESC/ACC
imaging definition12

JPPP, 2014 2005 Aspirin Standard of care AHA/ESC 7220 7244 5

epidemiolog
y and
clinical
research
studies
definition13

ASCEND, 2018 2005 Aspirin Placebo Joint 7740 7740 7.4

ESC/ACC
definition

ASCEND, 2018 2005 Omega-3 fatty Placebo Joint 7740 7740 7.4
acid ESC/ACC
definition

HOPE-3, 2016 2007 Rosuvastatin Placebo Third 6361 6344 5.6

UDMI, 2012

ARRIVE, 2018 2007 Aspirin Placebo WHO 6270 6276 5

definition

CSPPT, 2015 2008 Folic acid and Enalapril Joint 10348 10354 4.5
enalapril ESC/ACC
definition

PROMISE, 2015 2010 Coronary Functional stress UDMI, 2007 4996 5007 2.1
computed test
tomographic
angiography
(CCTA)

© 2021 American Medical Association. All rights reserved. 17

SCOT-HEART, 2010 CCTA Standard of care UDMI, 2007 2073 2073 4.8
2018

ASPREE, 2018 2010 Aspirin Placebo Joint 9525 9589 4.7

ESC/ACC
definition

VITAL, 2019 2011 Omega-3 fatty Placebo Third 12933 12938 5.3
acid UDMI, 2012

VITAL, 2019 2011 Vitamin D Placebo Third 12927 12944 5.3

UDMI, 2012

THEMIS, 2019 2014 Ticagrelor and Aspirin and Third 9619 9601 3.3
aspirin placebo UDMI, 2012

Mixed primary/secondary prevention (N= 57)

UKPDS 33, 1998 1977 Intensive Standard WHO 2729 1138 10

glycemic control glycemic control definition

ETDRS, 1992 1980 Aspirin Placebo WHO 1856 1855 5

definition

SALT, 1991 1984 Aspirin Placebo WHO 676 684 2.7

definition

STOP- 1985 Active Placebo WHO 812 815 4

Hypertension, 1991 antihypertensive definition
therapy

SHEP, 1991 1985 Active Placebo WHO 2365 2371 4.5

antihypertensive definition
therapy

SOLVD, 1992 1986 Enalapril Placebo WHO 3396 3401 5

definition

Indo- 1989 Dietary Standard of care WHO 499 501 2

Mediterranean Diet consultation definition
Heart Study, 2002

CAPPP, 1999 1991 Captopril Beta blocker or WHO 5492 5493 6.1
diuretic definition

NORDIL, 2000 1992 Diltiazem Beta-blocker WHO 5410 5471 4.5

and diuretic definition

ALLHAT, 2000 1994 Chlorthalidone Doxazosin WHO 15268 9067 3.3

definition

HPS, 2002 1994 Anti-oxidant Placebo WHO 10269 10267 5

vitamins definition

HPS, 2002 1994 Simvastatin Placebo WHO 10269 10267 5

definition

© 2021 American Medical Association. All rights reserved. 18

ALLHAT-LLT, 1994 Pravastatin Standard of care WHO 5170 5185 4.8
2002 definition

LIFE, 2002 1995 Losartan Atenolol WHO 660 666 4.7

definition

PROSPER, 2002 1997 Pravastatin Placebo WHO 2891 2913 3.2

definition

ESPRIT, 2006 1997 Aspirin and Aspirin WHO 1363 1376 3.5
dipyridamole definition

PHS II, 2012 1997 Multivitamin Placebo WHO 7317 7324 11.2
definition

4D, 2005 1998 Atorvastatin Placebo WHO 619 636 4

definition

FIELD, 2005 1998 Fenofibrate Placebo WHO 4895 4900 5

definition

RUTH, 2006 1998 Raloxifene Placebo WHO 5044 5057 5.6

definition

WAFACS, 2008 1998 Vitamins B6, Placebo WHO 2721 2721 7.3
B9, and B12 definition

FeAST, 2007 1999 Phlebotomy Standard of care Joint 636 641 3.5
ESC/ACC
definition

WAVE, 2007 2000 Anti-coagulation Anti-platelet WHO 1080 1081 2.9

and anti-platelet definition

VADT, 2015 2000 Intensive Standard ICD-9 837 818 9.8

glycemic control glycemic control diagnosis
code 410.x

ADVANCE, 2007 2001 Perindopril- Placebo WHO 5569 5571 4.3

indapamide definition

ADVANCE, 2008 2001 Gliclazide for Standard WHO 5571 5569 4.3
intensive glycemic control definition
glycemic control

TRANSCEND, 2001 Telmisartan Placebo ACC 2954 2972 4.6

2008 definition
clinical
outcomes
for patients
with ACS

RECORD, 2009 2001 Rosiglitazone Standard of care Joint 2220 2227 5.5
ESC/ACC
definition

© 2021 American Medical Association. All rights reserved. 19

ACCORD, 2010 2001 Intensive blood Standard blood ACCORD 2362 2371 4.7
pressure control pressure control definition14

ACCORD, 2010 2001 Fenofibrate Placebo ACCORD 2765 2753 4.7

definition

ACCORD, 2011 2001 Intensive Standard ACCORD 5128 5123 4.7

glycemic control glycemic control definition

Look AHEAD, 2001 Decreased Standard of care UDMI, 2007 2570 2575 9.6
2013 caloric intake
and increase
physical activity

CHARISMA, 2006 2002 Clopidogrel and Placebo and Joint 7802 7801 2.3
Aspirin Aspirin ESC/ACC
definition

NAVIGATOR, 2002 Valsartan Placebo UDMI, 2007 4631 4675 6.5

2010

NAVIGATOR, 2002 Nateglinide Placebo UDMI, 2007 4645 4661 6.5

2010

PRoFESS, 2008 2003 Aspirin and Clopidogrel WHO 10181 10151 2.5
dipyridamole definition

ROADMAP, 2011 2004 Olmesartan Placebo Joint 2232 2215 3.2

ESC/ACC
definition

IRIS, 2016 2005 Pioglitazone Placebo Third 1939 1937 4.8

UDMI, 2012

PERFORM, 2011 2006 Terutroban Aspirin UDMI, 2007 9556 9544 2.4

SAVOR-TIMI 53, 2010 Saxagliptin Placebo UDMI, 2007 8280 8212 2.1
2013

EMPA-REG 2010 Empagliflozin Placebo UDMI, 2007 4687 2333 3.1

OUTCOME, 2015

SPRINT, 2015 2010 Intensive blood Standard blood UDMI, 2007 4678 4683 3.3
pressure control pressure control

LEADER, 2016 2010 Liraglutide Placebo UDMI, 2007 4668 4672 3.8

SPRINT, 2016 2010 Intensive blood Standard blood UDMI, 2007 1317 1319 3.1
pressure control pressure control

EXSCEL, 2017 2010 Exenatide Placebo UDMI, 2007 7356 7396 3.2

CARES, 2018 2010 Febuxostat Allopurinol UDMI, 2007 3098 3092 2.7

Amarenco et al, 2010 Low target LDL High target LDL UDMI, 2007 1430 1430 3.5
2020

© 2021 American Medical Association. All rights reserved. 20

PolyIran, 2019 2011 Polypill tablet Non- ICD-10 3421 3417 3
pharmacologic diagnosis
intervention code I21

REDUCE-IT, 2019 2011 Icosapent ethyl Placebo UDMI, 2007 4089 4090 4.9

REWIND, 2019 2011 Dulaglutide Placebo UDMI, 2007 4949 4952 5.4

Nissen et al, 2018 2012 Naltrexone and Placebo UDMI, 2007 4455 4450 2.3
bupropion

SUSTAIN-6, 2016 2013 Semaglutide Placebo Third 1648 1649 2.1

UDMI, 2012

CARMELINA, 2013 Linagliptin Placebo UDMI, 2007 3494 3485 2.2

2019

DECLARE-TIMI 2013 Dapagliflozin Placebo Third 8582 8578 4.2

58, 2019 UDMI, 2012

PIVOTAL, 2019 2013 High-dose iron Low-dose iron Third 1093 1048 2.1
administered administered UDMI, 2012
proactively reactively

LoDoCo2, 2020 2014 Colchicine Placebo Third 2762 2760 2.4

UDMI, 2012

VOYAGER PAD, 2015 Rivaroxaban Placebo and Third 3286 3278 2.3
2020 and aspirin aspirin UDMI, 2012

Secondary prevention (N= 46)

Coronary Drug 1966 Dextrothyroxine Placebo Diseases of 1053 2618 3

Project, 1972 the Heart
and Blood
Vessels, ed
6, 1964

Taylor et al, 1982 1973 Oxprenolol Placebo WHO 632 471 4

definition

AMIS, 1980 1975 Aspirin Placebo WHO 2267 2257 3.2

definition

EPSIM, 1982 1975 Oral Aspirin WHO 652 651 2.4

anticoagulation definition
(multiple
agents)

BHAT, 1983 1978 Propranolol Placebo WHO 1916 1921 2.1

hydrochloride definition

Smith et al, 1990 1983 Warfarin Placebo WHO 607 607 3.1
definition

© 2021 American Medical Association. All rights reserved. 21

MDPIT, 1988 1983 Diltiazem Placebo WHO 1232 1234 2.1
definition

ASPECT, 1994 1986 Anti-coagulation Placebo WHO 1700 1704 3.1

(multiple definition
agents)

SAVE, 1992 1987 Captopril Placebo WHO 1115 1116 3.5

definition

4S, 1994 1988 Simvastatin Placebo WHO 2221 2223 5.4

definition

CARE, 1996 1989 Pravastatin Placebo WHO 2081 2078 5

definition

TRACE, 1995 1990 Trandolapril Placebo WHO 876 873 3.1

definition

LIPID, 1998 1990 Pravastatin Placebo WHO 4512 4502 6.1

definition

LIPID, 2000 1990 Pravastatin Placebo WHO 1633 1627 6

definition

LIPID, 2002 1990 Pravastatin Placebo WHO 3914 3766 8

definition

Rubins et al, 1999 1991 Gemfibrozil Placebo WHO 1264 1267 5.1
definition

HERS II, 2002 1994 Estrogen and Placebo WHO 1380 1383 6.8
progesterone definition
replacement

LIPS, 2002 1996 Fluvastatin Placebo WHO 844 833 3.9

definition

ESPRIT, 2002 1996 Estradiol Placebo WHO 513 504 2

valerate definition

PEACE, 2004 1996 Trandolapril Placebo ACC 4158 4132 4.8

definition
clinical
outcomes
for patients
with ACS

EUROPA, 2003 1997 Perindopril Placebo Joint 6110 6108 4.2

ESC/ACC
definition

TNT, 2005 1998 Atorvastatin Atorvastatin WHO 4995 5006 4.9

80mg daily 10mg daily definition

SEARCH, 2010 1998 Simvastatin Simvastatin WHO 6031 6033 6.7

80mg daily 20mg daily definition

© 2021 American Medical Association. All rights reserved. 22

SEARCH, 2010 1998 Vitamins B9 and Placebo WHO 6033 6031 6.7
B12 definition

IDEAL, 2005 1999 Atorvastatin Simvastatin Joint 4439 4449 4.8

ESC/ACC
definition

PROVE IT-TIMI 2000 Atorvastatin Pravastatin ACC 2099 2063 2

22, 2004 80mg daily 40mg daily definition
clinical
outcomes
for patients
with ACS

PROVE IT-TIMI 2000 Gatifloxacin Placebo ACC 2076 2086 2

22, 2005 definition
clinical
outcomes
for patients
with ACS

PROactive, 2005 2001 Pioglitazone Placebo WHO 2605 2633 2.9

definition

ARISE, 2008 2003 Succinobucol Placebo Joint 3078 3066 2

ESC/ACC
definition

AIM-HIGH, 2011 2005 Niacin Placebo WHO 1718 1696 3

definition

IMPROVE-IT, 2005 Ezetimibe and Simvastatin ACC 9067 9077 6

2015 simvastatin definition
clinical
outcomes
for patients
with ACS

HPS2-THRIVE, 2007 Niacin and Placebo UDMI, 2007 12838 12835 3.9
2014 laropiprant

dal-OUTCOMES, 2008 Dalcetrapib Placebo UDMI, 2007 7938 7933 2.6

2012

STABILITY, 2014 2008 Darapladib Placebo UDMI, 2007 7924 7904 3.7

TECOS, 2015 2008 Sitagliptin Placebo ACC 7257 7266 3

definition
clinical
outcomes
for patients
with ACS

SAVE, 2016 2008 CPAP Usual care ACC 1346 1341 3.7
definition
clinical

© 2021 American Medical Association. All rights reserved. 23

 outcomes
for patients
with ACS

SIGNIFY, 2014 2009 Ivabradine Placebo UDMI, 2007 9550 9552 2.3

AleCardio, 2014 2010 Aleglitazar Placebo UDMI, 2007 3616 3610 2

ELIXA, 2015 2010 Lixisenatide Placebo AHA/ESC 3034 3034 2

epidemiolog
y and
clinical
research
studies
definition

ODYSSEY 2012 Alirocumab Placebo Third 9462 9462 2.8

OUTCOMES, UDMI, 2012
2018

FOURIER, 2017 2013 Evolocumab Placebo Third 13784 13780 2.2

UDMI, 2012

GLOBAL 2013 Aspirin and Aspirin and Third 7980 7988 2

LEADERS, 2018 ticagrelor one ticagrelor or UDMI, 2012
month, clopidogrel for
subsequently 12 months,
ticagrelor for 23 subsequently
months aspirin for 12
months

CIRT, 2019 2013 Methotrexate Placebo Third 2391 2395 2.3

UDMI, 2012

ATPCI, 2020 2014 Trimetazidine Placebo Third 2998 3009 4

UDMI, 2012

AFIRE, 2019 2015 Rivaroxaban Rivaroxaban Third 1107 1108 2

and aspirin UDMI, 2012

BETonMACE, 2015 Apabetalone Placebo Third 1212 1206 2.2

2020 UDMI, 2012

Abbreviations: CABG, coronary artery bypass grafting; CCTA, coronary computed

tomographic angiography; MI, myocardial infarction; OMT, optimal medical
therapy; PCI, percutaneous coronary intervention; PCTA, percutaneous
transluminal coronary angioplasty; UDMI, universal definition of myocardial
infarction; WHO, World Health Organization.

© 2021 American Medical Association. All rights reserved. 24

eTable 2. Assessment of Risk of Bias
Blinding of
Random Blinding of Incomplete
Allocation participants Selective
sequence outcome outcome
concealment and Reporting Other
Trial generation assessment assessment
(selection personnel (reporting bias
(selection (detection (attrition
bias) (performance bias)
bias) bias) bias)
bias)
REGROUP - - ? - - -
AFIRE - - ? - - -
DECLARE-TIMI
- - - - - -
58
EXCEL - - ? - - -
THEMIS - - - - - -
PolyIran + + ? ? - +
CARMELINA - - - - - -
CIRT - - - - - -
COMPLETE - - ? - - -
VITAL, Omega-3
- - - - - -
fatty acid
VITAL, Vitamin D - - - - - -
PIVOTAL - - ? - - -
REWIND - - - - - -
REDUCE-IT - - - - - -
CARES - - - - - -
GLOBAL
- - ? - - -
LEADERS
SCOT-HEART - - ? ? - -
ODYSSEY
- - - - - -
OUTCOMES
ASPREE - - - - - -
ARRIVE - - - - - -
ASCEND, Aspirin - - - - - -
ASCEND, Omega-
- - - - - -
3 Fatty Acid
ROOBY-FS - - ? - - -
FOURIER - - - - - -
EXSCEL - - - - - -
HOPE-3 - - - - - -
SPRINT, 2016 - - ? - - -
EXAMINATION - - ? - - -
Nissen et al, 2016 - - - - - -
SAVE, 2016 - - ? - - -
LEADER - - - - - -
SUSTAIN-6 - - - - - -
CORONARY - - + - - -
IRIS - - - - - -

© 2021 American Medical Association. All rights reserved. 25

 DANAMI 3-
- - ? - - -
DEFER
NORSTENT - - ? - - -
EMPA-REG
- - - - - -
OUTCOME
SPRINT, 2015 - - ? - - -
ELIXA - - - - - -
CSPPT - - - - - -
VADT - - ? - ? -
TECOS - - - - - -
PROMISE - - ? - - -
IMPROVE-IT - - - - - -
STABILITY - - - - - -
SORT OUT III - - ? - - -
AleCardio ? ? - - - -
JPPP - - ? - - -
HPS2-THRIVE - - - - - -
SIGNIFY - - - - - -
SAVOR-TIMI 53 - - - - - -
Look AHEAD - - ? - - -
PHS II - ? - - - -
dal-OUTCOMES - - - - - -
FREEDOM - - ? ? - -
ROADMAP - - - - - -
PERFORM - - - - - -
AIM-HIGH - - - - - -
ACCORD, 2011 - - ? - - -
SEARCH,
- - - - ? -
Simvastatin
SEARCH, Vitamin
- - - - ? -
B9/B12
NAVIGATOR,
- - - - - -
valsartan
Navigator,
- - - - - -
nateglinide
ACCORD,
- - - - - -
fenofibrate, 2010
ACCORD, BP,
- - ? - - -
2010
DIAD - - ? - - -
RECORD - - ? - - -
BARI 2D - - ? - - -
TRANSCEND - - - - - -
ARISE - - - - - -
PRoFESS - - - - - -
WAFACS ? ? - - - -
ADVANCE, 2008 - - ? - - -
FeAST - - ? - - -
WAVE - - ? - - -

© 2021 American Medical Association. All rights reserved. 26

 ADVANCE, 2007 - - ? - - -
COURAGE - - ? - - -
OAT - - ? - - -
ESPRIT, 2006 - - ? - - -
CHARISMA - - - - - -
RUTH - - - - - -
4D - - - - - -
WHS, aspirin - - - - - -
IDEAL - - ? - - -
WHS, vitamin E - - - - - -
TNT - - - - - -
FIELD - - - - - -
RITA 3 - - ? - - -
PROactive - - - - - -
PROVE IT-TIMI
- - - - - -
22, 2005
HPS, simvastatin - - - - - -
CARDS - - - - - -
PROVE IT-TIMI
- - - - - -
22, 2004
PEACE - - - - - -
ALERT - - - - - -
EUROPA ? ? - - - -
Indo-Mediterranean
? ? ? ? - -
Diet Heart Study
PROSPER - - - - - -
LIPS - - - - - -
LIFE - - - - - -
HPS, vitamins,
- - ? - - -
2002
HPS, simvastatin,
- - ? - - -
2002
LIPID, 2002 - - ? - - -
HERS II - - ? ? - -
ESPRIT, 2002 - - ? - - -
ALLHAT-LLT - - ? ? - -
LIPID, 2000 - - - - - -
NORDIL - - ? - - -
ALLHAT - - ? ? - -
Rubins et al, 1999 - - - - - -
CAPPP - - ? - - -
LIPID, 1998 - - - - - -
RITA-1 - - ? - - -
AFCAPS/TeCAPS - - - - - -
UKPDS 33 - - - - - -
RITA-2 - - ? - - -
CARE - - - - - -
TRACE - - - - - -
ASPECT ? ? - ? - -

© 2021 American Medical Association. All rights reserved. 27

 4S - - - - - -
SOLVD - - - - - -
SAVE, 1992 - - - - - -
SAPAT ? ? - - - -
ETDRS ? ? ? ? - -
STOP-Hypertension ? ? - - - -
SALT - - ? - - -
SHEP - - - - - -
Smith et al, 1990 - - - - - -
PHS - - - - - -
MDPIT - - - - - -
LRC-CPPT - - - - - -
Rose et al, 1983 ? ? ? ? - -
Kornitzer et al,
? ? ? ? - -
1983
BHAT - - - - - -
Taylor et al, 1982 - - - - - -
EPSIM - - ? - - -
Hjermann et al,
- - ? - - -
1981
AMIS - - - - - -
Coronary Drug
- - - - - -
Project
ISCHEMIA - - ? - - -
BETonMACE - - - - - -
VOYAGER PAD - - - - - -
ATPCI - - - - - -
LoDoCo2 - - - - - -

Each domain was judged as ‘low risk of bias’ (-), ‘high risk of bias’ (+), or ‘unclear risk of bias’ (?) in each study
according to the Revised Cochrane risk-of-bias tool for randomized trials (Sterne, Jonathan A C et al. “RoB 2: a
revised tool for assessing risk of bias in randomised trials.” BMJ (Clinical research ed.) vol. 366 l4898. 28 Aug.
2019, doi:10.1136/bmj.l4898)

© 2021 American Medical Association. All rights reserved. 28

eTable 3. Trial Abbreviations, Names, and Date of Publication

Trial abbreviation Trial name Publication

date
- The Coronary Drug Project15 May 1972
AMIS Aspirin Myocardial Infarction Study16 Feb 1980
- Effect of Diet and Smoking Intervention on the Dec 1981
Incidence of Coronary Heart Disease – Oslo Study
Group17
EPSIM Controlled Comparison of Aspirin and Oral Sep 1982
Anticoagulants in Prevention of Death after
Myocardial Infarction18
- Long-Term Prevention Study with Oxprenolol in Nov 1982
Coronary Heart Disease19
- Belgian Heart Disease Prevention Project: Incidence May 1983
and Mortality Results20
- UK Heart Disease Prevention Project: Incidence and May 1983
Mortality Results21
BHAT A Randomized Trial of Propranolol in Patient with Nov 1983
Acute Myocardial Infarction22
LRC-CPPT The Lipid Research Clinics Coronary Primary Jan 1984
Prevention Trial Results23
MDPIT The Effect of Diltiazem on Mortality and Reinfarction Aug 1988
after Myocardial Infarction24
PHS Final Report on the Aspirin Component of the Jul 1989
Ongoing Physicians’ Health Study25
- The Effect of Warfarin on Mortality and Reinfarction Jul 1990
after Myocardial Infarction26

© 2021 American Medical Association. All rights reserved. 29

 SHEP Prevention of Stroke by Antihypertensive Drug Jun 1991
Treatment in Older Persons with Isolated Systolic
Hypertension27
SALT Swedish Aspirin Low-Dose Trial of 75mg Aspirin as Nov 1991
Secondary Prophylaxis after Cerebrovascular
Ischemic Events28
STOP- Morbidity and Mortality in the Swedish Trial in Old Nov 1991
Hypertension Patients with Hypertension29
SAVE Effect of Captopril on Mortality and Morbidity in Sep 1992
Patients with Left Ventricular Dysfunction after
Myocardial Infarction30
ETDRS Aspirin Effects on Mortality and Morbidity in Patients Sep 1992
with Diabetes Mellitus31
SOLVD Effect of Enalapril on Myocardial Infarction and Nov 1992
Unstable Angina in Patient with Low Ejection
Fraction32
SAPAT Double-blind Trial of Aspirin in Primary Prevention Dec 1992
of Myocardial Infarction in Patients with Stable
Chronic Angina Pectoris33
ASPECT Effect of Long-term Oral Anticoagulation Treatment Feb 1994
on Mortality and Cardiovascular Morbidity after
Myocardial Infarction34
4S Randomized Trial of Cholesterol Lowering in 4444 Nov 1994
Patients with Coronary Heart Disease: the
Scandinavian Simvastatin Survival Study35
TRACE A Clinical Trial of the Angiotensin-converting- Dec 1995
enzyme Inhibitor Trandolapril in Patients with Left
Ventricular Dysfunction after Myocardial Infarction36
CARE The Effect of Pravastatin on Coronary Events after Oct 1996
Myocardial Infarction in Patients with Average
Cholesterol Levels37
RITA-2 Coronary Angioplasty versus Medical Therapy for Aug 1997
Angina: the Second Randomized Intervention
Treatment of Angina38

© 2021 American Medical Association. All rights reserved. 30

AFCAPS/TexCAPS Primary Prevention of Acute Coronary Events with May 1998
Lovastatin in Men and Women with Average
Cholesterol Levels39
UKPDS 33 Intensive Blood-glucose Control with Sulphonylureas Sep 1998
or Insulin Compared with Conventional Treatment
and Risk of Complications in Patients with Type 2
Diabetes40
RITA-1 Long-term Results of RITA-1 Trial: Clinical and Cost Oct 1998
Comparisons of Coronary Angioplasty and Coronary-
artery Bypass Grafting41
LIPID Prevention of Cardiovascular Events and Death with Nov 1998
Pravastatin in Patients with Coronary Heart Disease
and a Broad Range of Initial Cholesterol Levels42
CAPPP Effect of Angiotensin-converting-enzyme Inhibition Feb 1999
Compared with Conventional Therapy on
Cardiovascular Morbidity and Mortality in
Hypertension43
- Gemfibrozil for the Secondary Prevention of Aug 1999
Coronary Heart Disease in Men with Low Levels of
High-density Lipoprotein Cholesterol44
ALLHAT Major Cardiovascular Events in Hypertensive Patients Apr 2000
Randomized to Doxazosin vs Chlorthalidone45
NORDIL Randomized Trial of Effects of Calcium Antagonists Jul 2000
Compared with Diuretics and Beta-blockers on
Cardiovascular Morbidity and Mortality in
Hypertension46
LIPID Effects of Pravastatin in 3260 Patients with Unstable Dec 2000
Angina47
LIPID Long-term Effectiveness and Safety of Pravastatin in Apr 2002
9014 Patients with Coronary Heart Disease and
Average Cholesterol Concentrations48
LIPS Fluvastatin for Prevention of Cardiac Events Jun 2002
following Successful First Percutaneous Coronary
Intervention49
HERS II Cardiovascular Disease Outcomes during 6.8 Years of Jul 2002
Hormone Therapy50

© 2021 American Medical Association. All rights reserved. 31

 HPS MRC/BHF Heart Protection Study of Cholesterol Jul 2002
Lowering with Simvastatin in 20,536 High-risk
Individuals: a Randomized Placebo-controlled Trial51
HPS MRC/BHF Heart Protection Study of Antioxidant Jul 2002
Vitamin Supplementation in 20,536 High-risk
Individuals: a Randomized Placebo-controlled Trial52
LIFE Effects of Losartan on Cardiovascular Morbidity and Sep 2002
Mortality in Patients with Isolated Systolic
Hypertension and Left Ventricular Hypertrophy53
Indo-Mediterranean Effect of an Indo-Mediterranean Diet on Progression Nov 2002
Diet Heart Study of Coronary Artery Disease in High Risk Patients54

PROSPER Pravastatin in Elderly Individuals at Risk of Vascular Nov 2002

Disease55
ALLHAT-LLT Major Outcomes in Moderately Dec 2002
Hypercholesterolemic, Hypertensive Patients
Randomized to Pravastatin vs. Usual Care56
ESPRIT Oestrogen Therapy for Prevention of Reinfarction in Dec 2002
Postmenopausal Women57
ALERT Effect of Fluvastatin on Cardiac Outcomes in Renal Jun 2003
Transplant Recipients58
EUROPA Efficacy of Perindopril in Reduction of Sep 2003
Cardiovascular Events among Patients with Stable
Coronary Artery Disease59
PROVE IT-TIMI Intensive Versus Moderate Lipid Lowering with Apr 2004
22 Statins after Acute Coronary Syndromes60
CARDS Primary Prevention of Cardiovascular Disease with Aug 2004
Atorvastatin in Type 2 Diabetes in the Collaborative
Atorvastatin Diabetes Study61
PEACE Angiotensin-converting-enzyme Inhibition in Stable Nov 2004
Coronary Artery Disease62
WHS A Randomized Trial of Low-dose Aspirin in the Mar 2005
Primary Prevention of Cardiovascular Disease in
Women63

© 2021 American Medical Association. All rights reserved. 32

 TNT Intensive Lipid Lowering with Atorvastatin in Apr 2005
Patients with Stable Coronary Disease64
PROVE IT-TIMI Antibiotic Treatment of Chlamydia pneumoniae after Apr 2005
22 Acute Coronary Syndrome65
WHS Vitamin E in the Primary Prevention of Jul 2005
Cardiovascular Disease and Cancer: the Women’s
Health Study66
4D Atorvastatin in Patients with Type 2 Diabetes Mellitus Jul 2005
Undergoing Hemodialysis67
RITA-3 5-year Outcome of an Interventional Strategy in Non- Sep 2005
ST-Elevation Acute Coronary Syndrome68
PROactive Secondary Prevention of Macrovascular Events in Oct 2005
Patients with Type 2 Diabetes in the PROactive
Study69
IDEAL High-dose Atorvastatin vs Usual-dose Simvastatin for Nov 2005
Secondary Prevention after Myocardial Infarction70
FIELD Effects of Long-term Fenofibrate Therapy on Nov 2005
Cardiovascular Events in 9795 people with Type 2
Diabetes Mellitus71
CHARISMA Clopidogrel and Aspirin Versus Aspirin Alone for the Apr 2006
Prevention of Atherothrombotic Events72
ESPRIT Aspirin Plus Dipyridamole Versus Aspirin Alone after May 2006
Cerebral Ischemia of Arterial Origin73
RUTH Effects of Raloxifene on Cardiovascular Events and Jul 2006
Breast Cancer in Postmenopausal Women74
OAT Coronary Intervention for Persistent Occlusion after Dec 2006
Myocardial Infarction3
FeAST Reduction of Iron Stores and Cardiovascular Feb 2007
Outcomes in Patients with Peripheral Arterial
Disease75
COURAGE Optimal Medical Therapy With or Without PCI for Apr 2007
Stable Coronary Disease2
WAVE Oral Anticoagulation and Antiplatelet Therapy and Jul 2007
Peripheral Artery Disease76

© 2021 American Medical Association. All rights reserved. 33

ADVANCE Effects of a Fixed Combination of Perindopril and Sep 2007
Indapamide on Macrovascular and Microvascular
Outcomes in Patients with Type 2 Diabetes Mellitus77
WAFACS Effect of Folic Acid and B Vitamins on Risk of May 2008
Cardiovascular Events and Total Mortality Among
Women at High Risk for Cardiovascular Disease78
ARISE Effects of Succinobucol (AGI-1067) after an Acute May 2008
Coronary Syndrome79
ADVANCE Intensive Blood Glucose Control and Vascular Jun 2008
Outcomes in Patients with Type 2 Diabetes80
PRoFESS Aspirin and Extended-release Dipyridamole versus Sep 2008
Clopidogrel for Recurrent Stroke81
TRANSCEND Effect of the Angiotensin-receptor Blocker Sep 2008
Telmisartan on Cardiovascular Events in High-risk
Patients Intolerant to Angiotensin-converting Enzyme
Inhibitors82
DIAD Cardiac Outcomes after Screening for Asymptomatic Apr 2009
Coronary Artery Disease in Patients with Type 2
Diabetes83
BARI 2D A Randomized Trial of Therapies for Type 2 Diabetes Jun 2009
and Coronary Artery Disease4
RECORD Rosiglitazone Evaluated for Cardiovascular Outcomes Jun 2009
in Oral Agent Combination Therapy for Type 2
Diabetes84
NAVIGATOR Effect of Nateglinide on the Incidence of Diabetes and Apr 2010
Cardiovascular Events85
NAVIGATOR Effect of Valsartan on the Incidence of Diabetes and Apr 2010
Cardiovascular Events86
ACCORD Effects of Intensive Blood-pressure Control in Type 2 Apr 2010
Diabetes14
ACCORD Effects of Combination Lipid Therapy in Type 2 Apr 2010
Diabetes Mellitus87
SEARCH Effects of Homocysteine-lowering with Folic Acid Jun 2010
plus Vitamin B12 vs Placebo on Mortality and Major
Morbidity in Myocardial Infarction Survivors88

© 2021 American Medical Association. All rights reserved. 34

 SEARCH Intensive Lowering of LDL Cholesterol with 80mg Jun 2010
Versus 20mg Simvastatin Daily in 12,064 Survivors
of Myocardial Infarction89
ACCORD Long-term Effects of Intensive Glucose Lowering on Mar 2011
Cardiovascular Outcomes90
ROADMAP Olmesartan for the Delay or Prevention of Mar 2011
Microalbuminuria in Type 2 Diabetes91
PERFORM Terutroban versus Aspirin in Patients with Cerebral Jun 2011
Ischaemic Events92
AIM-HIGH Niacin in Patients with Low HDL Cholesterol Levels Dec 2011
Receiving Intensive Statin Therapy93
PHS II Multivitamins in the Prevention of Cardiovascular Nov 2012
Disease in Men94
dal-OUTCOMES Effects of Dalcetrapib in Patients with a Recent Acute Nov 2012
Coronary Syndrome95
FREEDOM Strategies for Multivessel Revascularization in Dec 2012
Patients with Diabetes6
Look AHEAD Cardiovascular Effects of Intensive Lifestyle Jul 2013
Intervention in Type 2 Diabetes96
SAVOR-TIMI 53 Saxagliptin and Cardiovascular Outcomes in Patients Oct 2013
with Type 2 Diabetes Mellitus97
AleCardio Effect of Aleglitazar on Cardiovascular Outcomes Apr 2014
After Acute Coronary Syndrome in Patients with
Type 2 Diabetes Mellitus98
STABILITY Darapladib for Preventing Ischemic Events in Stable May 2014
Coronary Artery Disease99
SORT OUT III Differential Clinical Outcomes after 1 Year Versus 5 Jun 2014
Years in a Randomized Comparison of Zotarolimus-
eluting and Sirolimus-eluting Coronary Stents100
HPS2-THRIVE Effects of Extended-release Niacin with Laropiprant Jul 2014
in High-risk Patients101
SIGNIFY Ivabradine in Stable Coronary Artery Disease Without Sep 2014
Clinical Heart Failure102

© 2021 American Medical Association. All rights reserved. 35

 JPPP Low-dose Aspirin for Primary Prevention of Dec 2014
Cardiovascular Events in Japanese Patients 60 Years
or Older with Atherosclerotic Risk Factors103
PROMISE Outcomes of Anatomical Versus Functional Testing Apr 2015
for Coronary Artery Disease104
CSPPT Efficacy of Folic Acid Therapy in Primary Prevention Apr 2015
of Stroke Among Adults with Hypertension in
China105
VADT Follow-up of Glycemic Control and Cardiovascular Jun 2015
Outcomes in Type 2 Diabetes106
IMPROVE-IT Ezetimibe Added to Statin Therapy after Acute Jun 2015
Coronary Syndromes107
TECOS Effect of Sitagliptin on Cardiovascular Outcomes in Jul 2015
Type 2 Diabetes108
EMPA-REG Empagliflozin, Cardiovascular Outcomes, and Nov 2015
OUTCOME Mortality in Type 2 Diabetes109
SPRINT A Randomized Trial of Intensive Versus Standard Nov 2015
Blood-pressure Control110
ELIXA Lixisenatide in Patients with Type 2 Diabetes and Dec 2015
Acute Coronary Syndrome111
EXAMINATION Clinical Outcomes in Patients with ST-segment Jan 2016
Elevation Myocardial Infarction Treated with
Everolimus-eluting Stents Versus Bare-metal Stents112
- Effect of Naltrexone-bupropion on Major Adverse Mar 2016
Cardiovascular Events in Overweight and Obese
Patients with Cardiovascular Risk Factors113
IRIS Pioglitazone after Ischemic Stroke or Transient Apr 2016
Ischemic Attack114
HOPE-3 Cholesterol Lowering in Intermediate-Risk Persons May 2016
without Cardiovascular Disease115
DANAMI 3- Deferred Versus Conventional Stent Implantation in May 2016
DEFER Patients with ST-segment Elevation Myocardial
Infarction116

© 2021 American Medical Association. All rights reserved. 36

 SPRINT Intensive vs Standard Blood Pressure Control and Jun 2016
Cardiovascular Disease Outcomes in Adults Aged
≥75 Years117
LEADER Liraglutide and Cardiovascular Outcomes in Type 2 Jul 2016
Diabetes118
SAVE CPAP for Prevention of Cardiovascular Events in Sep 2016
Obstructive Sleep Apnea119
NORSTENT Drug-eluting or Bare-metal Stents for Coronary Sep 2016
Artery Disease120
SUSTAIN-6 Semaglutide and Cardiovascular Outcomes in Patients Nov 2016
with Type 2 Diabetes121
CORONARY Five-year Outcomes after Off-pump or On-pump Dec 2016
Coronary-artery Bypass Grafting122
FOURIER Evolocumab and Clinical Outcomes in Patients with May 2017
Cardiovascular Disease123
ROOBY-FS Five-year Outcomes after On-pump and Off-pump Aug 2017
Coronary-artery bypass124
EXSCEL Effects of Once-weekly Exenatide on Cardiovascular Sept 2017
Outcomes in Type 2 Diabetes125
CARES Cardiovascular Safety of Febuxostat or Allopurinol in Mar 2018
Patients with Gout126
SCOT-HEART Coronary CT Angiography and 5-year Risk of Sep 2018
Myocardial Infarction127
GLOBAL Ticagrelor Plus Aspirin for 1 Month, Followed by Sep 2018
LEADERS Ticagrelor Monotherapy for 23 Months vs Aspirin
Plus Clopidogrel or Ticagrelor for 12 Months,
Followed by Aspirin Monotherapy for 12 Months
After Implantation of a Drug-eluting Stent128
ARRIVE Use of Aspirin to Reduce Risk of Initial Vascular Sep 2018
Events in Patients at Moderate Risk of Cardiovascular
Disease129
ASCEND Effects of Aspirin for Primary Prevention in Persons Oct 2018
with Diabetes Mellitus130
ASCEND Effects of n-3 Fatty Acid Supplements in Diabetes Oct 2018
Mellitus131

© 2021 American Medical Association. All rights reserved. 37

 ASPREE Effect of Aspirin on Cardiovascular Events and Oct 2018
Bleeding in the Healthy Elderly132
ODYSSEY Alirocumab and Cardiovascular Outcomes after Acute Nov 2018
OUTCOMES Coronary Syndrome133
CARMELINA Effect of Linagliptin vs Placebo on Major Jan 2019
Cardiovascular Events in Adults with Type 2 Diabetes
and High Cardiovascular and Renal Risk134
REDUCE-IT Cardiovascular Risk Reduction with Icosapent Ethyl Jan 2019
for Hypertriglyceridemia135
VITAL Marine n-3 Fatty Acids and Prevention of Jan 2019
Cardiovascular Disease and Cancer136
VITAL Vitamin D Supplements and Prevention of Cancer and Jan 2019
Cardiovascular Disease137
REGROUP Randomized Trial of Endoscopic or Open Vein-graft Jan 2019
Harvesting for Coronary-artery Bypass138
DECLARE-TIMI Dapagliflozin and Cardiovascular Outcomes in Type Jan 2019
58 2 Diabetes139
PIVOTAL Intravenous Iron in Patients Undergoing Maintenance Jan 2019
Hemodialysis140
CIRT Low-dose Methotrexate for the Prevention of Feb 2019
Atherosclerotic Events141
REWIND Dulaglutide and Cardiovascular Outcomes in Type 2 July 2019
Diabetes142
PolyIran Effectiveness of Polypill for Primary and Secondary Aug 2019
Prevention of Cardiovascular Diseases143
AFIRE Antithrombotic Therapy for Atrial Fibrillation with Sep 2019
Stable Coronary Disease144
THEMIS Ticagrelor in Patients with Stable Coronary Disease Oct 2019
and Diabetes145
COMPLETE Complete Revascularization with Multivessel PCI for Oct 2019
Myocardial Infarction146
EXCEL Five-year Outcomes after PCI or CABG for Left Main Nov 2019
Coronary Disease10

© 2021 American Medical Association. All rights reserved. 38

 - A Comparison of Two LDL Cholesterol Targets after Jan 2020
Ischemic Stroke147
ISCHEMIA Initial Invasive or Conservative Strategy for Stable Apr 2020
Coronary Disease11
BETonMACE Effect of Apabetalone Added to Standard Therapy on Apr 2020
Major Adverse Cardiovascular Events in Patients with
Recent Acute Coronary Syndrome and Type 2
Diabetes148
VOYAGER PAD Rivaroxaban in Peripheral Artery Disease after May 2020
Revascularization149
ATPCI Efficacy and Safety of Trimetazidine after Sept 2020
Percutaneous Coronary Intervention150
LoDoCo2 Colchicine in Patients with Chronic Coronary Nov 2020
Disease151

© 2021 American Medical Association. All rights reserved. 39

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