JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 74, NO.

21, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

Efficacy and Safety of Stents in

ST-Segment Elevation Myocardial Infarction
Ply Chichareon, MD,a,b,* Rodrigo Modolo, MD,a,c,* Carlos Collet, MD,a,d Erhan Tenekecioglu, MD,e
Maarten A. Vink, MD, PHD,f Pyung Chun Oh, MD,g Jung-Min Ahn, MD,h Carmine Musto, MD, PHD,i
Luis S. Díaz de la Llera, MD,j Young-Seok Cho, MD, PHD,k Roberto Violini, MD,i Seung-Jung Park, MD, PHD,h
Harry Suryapranata, MD, PHD,l Jan J. Piek, MD, PHD,a Robbert J. de Winter, MD, PHD,a
Joanna J. Wykrzykowska, MD, PHD,a Christian Spaulding, MD, PHD,m Woong Chol Kang, MD, PHD,g
Ton Slagboom, MD,f Sjoerd H. Hofma, MD, PHD,n Inge F. Wijnbergen, MD, PHD,o Emilio Di Lorenzo, MD, PHD,p
Nico H. Pijls, MD, PHD,o Lorenz Räber, MD, PHD,q Salvatore Brugaletta, MD, PHD,r Manel Sabaté, MD, PHD,r
Hans-Peter Stoll, MD,s Gregg W. Stone, MD,t Stephan Windecker, MD,q Yoshinobu Onuma, MD, PHD,d,u
Patrick W. Serruys, MD, PHDv

ABSTRACT

BACKGROUND To date, no specific drug-eluting stent (DES) has fully proven its superiority over others in patients with
ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention.

OBJECTIVES The purpose of this study was to compare the safety and efficacy of coronary artery stents in STEMI
patients in a patient-level network meta-analysis.

METHODS Eligible studies were dedicated randomized controlled trials comparing different stents in STEMI patients
undergoing percutaneous coronary intervention with at least 12 months of clinical follow-up. Of 19 studies identified
from the published data, individual patient data were collected in 15 studies with 10,979 patients representing 87.7% of
patients in the overall network of evidence. The primary endpoint was the composite of cardiac death, reinfarction, or
target lesion revascularization.

RESULTS Overall, 8,487 (77.3%) of 10,979 STEMI patients were male and the mean age was 60.7 years. At a median
follow-up of 3 years, compared with bare-metal stents (BMS), patients treated with paclitaxel-, sirolimus-, everolimus-,
or biolimus-eluting stents had a significantly lower risk of the primary endpoint (adjusted hazard ratios [HRs]: 0.74 [95%
confidence interval (CI): 0.63 to 0.88], 0.65 [95% CI: 0.49 to 0.85], 0.70 [95% CI: 0.53 to 0.91], and 0.66 [95% CI:
0.49 to 0.88], respectively). The risk of primary endpoint was not different between patients treated with BMS and
zotarolimus-eluting stents (adjusted HR: 0.83 [95% CI: 0.51 to 1.38]). Among patients treated with DES, no significant
difference in the risk of the primary outcome was demonstrated. Treatment with second-generation DES was associated
with significantly lower risk of definite or probable stent thrombosis compared with BMS (adjusted HR: 0.61 [95% CI:
0.42 to 0.89]) and first-generation DES (adjusted HR: 0.56 [95% CI: 0.36 to 0.88]).

CONCLUSIONS In STEMI patients, DES were superior to BMS with respect to long-term efficacy. No difference in long-
term efficacy and safety was observed among specific DES. Second-generation were superior to first-generation DES in
reducing stent thrombosis. (Clinical Outcomes After Primary Percutaneous Coronary Intervention [PCI] Using Contem-
porary Drug-Eluting Stent [DES]: Evidence From the Individual Patient Data Network Meta-Analysis; CRD42018104053)
(J Am Coll Cardiol 2019;74:2572–84) © 2019 by the American College of Cardiology Foundation.

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Campinas (UNICAMP), Campinas, Brazil; dCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium; eErasmus Medical Center,
JACC.org.
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Medical Center, Incheon, South Korea; hDepartment of Cardiology, University of Ulsan College of Medicine, Asan Medical Center,
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JACC VOL. 74, NO. 21, 2019 Chichareon et al. 2573
NOVEMBER 26, 2019:2572–84 Stents in STEMI: Patient-Level Network Meta-Analysis

P rimary percutaneous coronary intervention is developed to reduce the increased risk of ABBREVIATIONS

considered the preferred treatment in patients stent thrombosis observed with first- AND ACRONYMS

with ST-segment elevation myocardial infarc- generation DES. Randomized trials evalu-
BMS = bare-metal stent(s)
tion (STEMI) (1). Patients presenting with STEMI carry ating biodegradable polymer biolimus-
BP-BES = biodegradable
the highest risk of early and late adverse events after eluting stents (BP-BES) demonstrated favor-
polymer biolimus eluting
percutaneous coronary intervention (2). Due to pla- able clinical outcomes compared with BMS stent(s)
que vulnerability, high clot burden, and persistent and noninferior clinical outcomes compared DES = drug-eluting stent(s)
inflammation, STEMI patients are predisposed to with first-generation DES and biocompatible DP = durable polymer
delayed healing and positive remodeling of the durable polymer-coated second-generation
EES = everolimus-eluting
vessel, which result in high rates of uncovered stent DES (5–7). In the STEMI population, BP-BES stent(s)
struts and stent malapposition (3). As a consequence, has shown improved clinical outcomes PES = paclitaxel-eluting
the risk of stent thrombosis in STEMI patients is the compared with BMS and first-generation stent(s)

highest among coronary artery disease patients (2,4). sirolimus-eluting stents (8,9). The SES = sirolimus-eluting

COMFORTABLE AMI (Comparison of Bio- stent(s)

SEE PAGE 2585
limus Eluted From an Erodible Stent Coating STEMI = ST-segment elevation
myocardial infarction
Although current guidelines for management of With Bare Metal Stents in Acute ST-Elevation
TLR = target lesion
STEMI patients indicate the preference of new- Myocardial Infarction) trial reported that use
revascularization
generation drug-eluting stents (DES) compared with of BP-BES resulted in a lower rate of major
TVR = target vessel
bare-metal stents (BMS) (Class of Recommendation I, adverse cardiac events at 1 year compared revascularization
Level of Evidence: A), relatively little is known with BMS (8). In the LEADERS (Limus Eluted
ZES = zotarolimus-eluting
regarding the comparative safety and efficacy profiles From A Durable Versus ERodable Stent stent(s)
of DES with different polymer durability or Coating) trial, BES significantly improved
drug coatings in this life-threatening condition (1). safety and efficacy outcomes in patients with acute
New-generation DES with more biocompatible dura- myocardial infarction, especially those with STEMI, at
ble polymers or biodegradable polymers were 5-year follow-up compared with sirolimus-eluting

PARCC, Paris Descartes University, Paris, France; nMedisch Centrum Leeuwarden, Leeuwarden, the Netherlands; oDepartment of
Cardiology, Catharina Hospital Eindhoven, Eindhoven, the Netherlands; pCardiology Department, G. Moscati Hospital, Avellino,
Italy; qDepartment of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; rHospital Clinic,
Institut Clinic Cardiovascular, Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona,
Barcelona, Spain; sBiosensors Clinical Research, Morges, Switzerland; tNew York Presbyterian Hospital, Columbia University
Medical Center and the Cardiovascular Research Foundation, New York, New York; uCardialysis Clinical Trials Management and
Core Laboratories, Rotterdam, the Netherlands; and the vDepartment of Cardiology, Imperial College of London, London, United
Kingdom. *Drs. Chichareon and Modolo contributed equally to this work and are joint first authors. This study was funded by
Biosensors international. The sponsor was not involved in analysis, interpretation of data, writing of the report nor in the decision
to submit the paper for publication. Drs. Chichareon, Modolo, Collet, and Tenekecioglu have received a grant from Biosensors
during the conduct of the study. Dr. Collet has received grants and personal fees from Heartflow Inc.; and has received personal
fees from Philips and Abbott Vascular outside of the submitted work. Dr. Piek has received nonfinancial support from Abbott
Vascular; and has received personal fees and nonfinancial support from Philips/Volcano outside of the submitted work. Dr.
Spaulding has received grants and personal fees from Cordis, Johnson & Johnson, during the conduct of the study; has received
personal fees from Stentys, Medtronic, Abbott, and Terumo; and has received grants from Biosensors and Boston Scientific
outside of the submitted work. Dr. Hofma has received unrestricted research grants from Abbott Vascular to the Research
Department of the Division of Cardiology of the Medical Center Leeuwarden, during the conduct of the XAMI study. Dr. Pijls has
received grants from Abbott and Hexacath; has equity in Philips, ASML, General Electric, and Heart Flow; and has received
consultant fees from Boston Scientific outside of the submitted work. Dr. Räber has received grants to his institution from Abbott,
Biotronik, Boston Scientific, Heartflow, Sanofi, and Regeneron; and has received speaker fees from Abbott, Amgen, AstraZeneca,
CSL Behring, Sanofi, and Vifor. Dr. Sabaté has received personal fees from and served as a consultant for Abbott Vascular outside
of the submitted work. Dr. Stoll is a full-time employee of Biosensors International. Dr. Stone has received personal fees from
Terumo, Amaranth, Medical Development Technologies, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath,
HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-wave, Abiomed, Claret, Backbeat, Sirtex, Ancora, Qool
Therapeutics, and SpectraWave; holds equity in Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Caliber, SpectraWave,
Biostar family of funds, and MedFocus family of funds; is director of SpectraWave; and his institution, Columbia University, has
received royalties from Abbott for sale of the MitraClip. Dr. Windecker has received grants from Amgen, Abbott, Boston Scientific,
Bristol-Myers Squibb, Bayer, Biotronik, Edwards, Medtronic, Sinomed, and Polares outside of the submitted work. Dr. Onuma has
served as a member of the Advisory Board of Abbott Vascular. Dr. Serruys has received personal fees from Abbott Laboratories,
AstraZeneca, Biotronik, Cardialysis, GLG Research, Medtronic, Sino Medical Sciences Technology, Société Europa Digital Pub-
lishing, Stentys France, Svelte Medical Systems, Philips/Volcano, St. Jude Medical, Qualimed, and Xeltis outside of the submitted
work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received June 3, 2019; revised manuscript received August 9, 2019, accepted September 3, 2019.

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2574 Chichareon et al.
Stents in STEMI: Patient-Level Network Meta-Analysis
stents (9). In this regard, the high lipophilicity of
biolimus may facilitate rapid distribution of drug and
potentiate local drug effects in lipidic lesion in pa-
tients with STEMI (10). Conversely, the safety of
biodegradable polymer DES compared with durable
polymer DES has been questioned in several meta-
analyses (11,12).
Therefore, we sought, by means of an individual
patient data network meta-analysis of randomized
controlled trials in STEMI, to investigate the safety and
efficacy of different generations of stents in patients
undergoing percutaneous coronary intervention.
METHODS
PROTOCOL AND REGISTRATION. This study was
registered in the International Prospective Register of
Systematic Reviews (PROSPERO) (CRD42018104053).
We reported the study in accordance with the
Preferred Reporting Items for a Systematic Review
and Meta-analysis of Individual participant data (13)
and the extended statement on network meta-
analysis (14).
ELIGIBILITY CRITERIA. Eligible studies were dedi-
cated randomized controlled trials comparing
different stents in adult patients with STEMI under-
going percutaneous coronary intervention. Eligible
studies must have at least 12 months of clinical
follow-up. We excluded studies comparing devices
other than coronary stents, such as drug-eluting bal-
loons or distal protection devices.
SEARCH, STUDY SELECTION, QUALITY ASSESSMENT, AND
DATA COLLECTION PROCESS. We searched PubMed,
Embase, and the Cochrane Central Register of
Controlled trials for relevant studies without restric-
tion on language or publication period. The full list of
search terms is provided in the appendix. The titles
and abstracts were reviewed for inclusion indepen-
dently by 2 authors (C.C. and E.T.). In case of
disagreement, full studies were reviewed and final
decision was made by consensus. Risk of bias was
appraised using the Cochrane risk of bias tool (15).
Publication bias was assessed using the comparison-
adjusted funnel plot (16).
Pre-specified variables and outcomes for individual
patient data were requested from the investigators of
each included study. The data were checked, and the
queries were sent to the investigators for clarifica-
tions in case of inconsistency. Each study was
approved by the local ethics committee, and all pa-
tients provided written informed consent.
OUTCOMES AND EFFECT MEASURES. The pre-
specified primary outcome for this meta-analysis
was the composite of cardiac death, reinfarction, or
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JACC VOL. 74, NO. 21, 2019
NOVEMBER 26, 2019:2572–84
target lesion revascularization (TLR). Secondary out-
comes were the composite of all-cause death, rein-
farction, or target vessel revascularization (TVR);
individual components of the composite endpoints;
and definite or probable stent thrombosis. The
endpoint definitions from each trial were used.
STATISTICAL ANALYSIS. Continuous variables are
presented as mean
SD or median (interquartile
range). Categorical variables are presented as count
and percentages. Individual patient data from iden-
tified studies obtained from the investigators were
combined in a single dataset. All outcomes were
analyzed using time-to-event analysis. The longest
available follow-up was used for the analysis of the
outcomes. Primary analysis was performed using
1-stage individual patient data network meta-analysis
in the Cox proportional hazard model stratified by
study. Since heterogeneity in treatment effects from
study to study was anticipated, a random effect
model was used for the primary analysis with study as
random variable. To this end, a gamma frailty model
was used. Hazard ratios (HRs) with 95% confidence
intervals (CIs) are reported. To adjust for differences
in covariables, multivariable Cox regression analysis
was performed using the following variables: age,
sex, diabetes, previous myocardial infarction, previ-
ous percutaneous coronary intervention, previous
coronary artery bypass graft surgery and time from
symptom onset to balloon. As a sensitivity analysis, a
frequentist 2-stage network meta-analysis was per-
formed with a random effect model (R netmeta
package) (17) using a log hazard ratio and standard
error obtained from the individual patient data of
individual studies. Because individual patient data
were not available in 4 of 19 studies, as an additional
analysis we performed a 2-stage random-effect
network meta-analysis in a Bayesian framework
combining the extracted data (binary data or hazard
ratio) from the published studies on which individual
patient data were not available with the HRs from the
studies with available individual patient data (18).
A total of 6 different stent types with respect to
the type of drug and coating were identified including
BMS, durable polymer (DP) paclitaxel-eluting stents
(PES) (Taxus Express, Taxus Express 2 or Taxus Lib-
erte, Boston Scientific, Natick, Massachusetts), DP
sirolimus-eluting stents (SES) (Cypher or Cypher
select, Cordis, Miami Lakes, Florida), DP fast-release
zotarolimus-eluting stents (ZES) (Endeavor, Med-
tronic, Minneapolis, Minnesota), DP everolimus-
eluting stents (EES) (Xience V, Abbott Vascular,
Santa Clara, California), and biodegradable polymer
biolimus-eluting stents (BP-BES) (BioMatrix,
Biosensors, Morges, Switzerland). DP-PES, -SES, and
JACC VOL. 74, NO. 21, 2019
NOVEMBER 26, 2019:2572–84
-ZES were considered first-generation DES while
DP-EES and BP-BES were considered
generation DES.
All p values were 2-sided, and p values <0.05 were
considered to be statistically significant. Statistical
analysis was performed with R (R Foundation for
Statistical Computing, Vienna, Austria) and Open-
BUGS (MRC Biostatistics Unit, Cambridge University,
United Kingdom).
RESULTS
Details of literature search, study exclusion, and se-
lection are shown in Figure 1. Nineteen studies were
eligible for the analysis. Study characteristics, defi-
nitions used for the outcomes in each study, and the
risk of bias assessment are presented in the Online
Appendix (Online Tables 1 to 4, Online Figures 1
and 2). Among the 19 identified studies, individual
patient data were available in 15 studies, with 10,979
patients representing 87.7% of patients in the overall
network of evidence (Figure 2). In these patients, the
mean age was 60.7
17.9 years, 22.7% were female,
and 16.1% were diabetic. Median onset of symptoms
to balloon was 214 min (interquartile range: 149 to
334 min). Percutaneous coronary intervention was
performed with BMS in 3,409 patients in 9 trials,
DP-PES in 3,173 patients in 6 trials, DP-SES in 2,044
patients in 11 trials, DP-ZES in 373 patients in 3 trials,
DP-EES in 1,405 patients in 3 trials, and BP-BES in 575
patients in 1 trial. Median duration of follow-up was 3
years (interquartile range: 2.0 to 4.9 years). Patient
characteristics stratified by treatment arm are pre-
sented in Table 1. Details of the stent types in each
study are provided in the Online Appendix (Online
Tables 5 and 6).
PRIMARY OUTCOME. Patients treated with DP-PES,
DP-SES, and DP-EES and BP-BES had significantly
lower risk of the primary composite endpoint of car-
diac death, reinfarction, or TLR compared with BMS
(Figure 3). The difference was driven by a significantly
lower risk of TLR associated with DES. The difference
in the risk of the primary outcome was not significant
between patients treated with BMS and DP-ZES.
Among patients treated with DES, no significant dif-
ference in the risk of the primary outcome was
demonstrated. Similar findings were observed in the
adjusted Cox models (Figure 3).
SECONDARY OUTCOMES. The risk of the secondary
composite outcome of all-cause death, reinfarction,
or TVR was significantly lower in patients treated
with DP-PES, -SES, and -EES and BP-BES compared
with BMS in both unadjusted and adjusted models
(Figure 3). The differences were mainly driven by the
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Chichareon et al. 2575
Stents in STEMI: Patient-Level Network Meta-Analysis
lower risk of TVR. The difference was not statistically
second- significant between patients treated with DP-ZES
and BMS.
Treatment with DP-EES was associated with a
significantly lower risk of all-cause mortality
compared with BMS (unadjusted HR: 0.71; 95% CI:
0.53 to 0.94). However, the difference was not sig-
nificant in the adjusted Cox model (adjusted HR:
0.78; 95% CI: 0.56 to 1.08). The risk of all-cause
mortality was similar among patients treated with
BMS, DP-PES, DP-SES, DP-ZES, and BP-BES.
The risk of cardiac death or reinfarction was not
significantly different among patients treated with
BMS and different DES. Trends toward a lower risk of
reinfarction were present in patients treated with BP-
BES compared with BMS (unadjusted HR: 0.68;
95% CI: 0.45 to 1.03; adjusted HR: 0.69; 95% CI: 0.46
to 1.05), DP-PES (unadjusted HR: 0.61; 95% CI: 0.37 to
1.01; adjusted HR: 0.61; 95% CI: 0.37 to 1.01), and
DP-SES (unadjusted HR: 0.65; 95% CI: 0.38 to 1.11;
adjusted HR: 0.57; 95% CI: 0.31 to 1.08), although
these differences were not statistically significant.
Treatment with DP-EES was associated with a
significantly lower risk of definite or probable stent
thrombosis compared with BMS (unadjusted HR: 0.60;
95% CI: 0.36 to 1.00; adjusted HR: 0.55; 95% CI: 0.31 to
1.00) and DP-SES (unadjusted HR: 0.57; 95% CI: 0.34 to
0.95; adjusted HR: 0.50; 95% CI: 0.28 to 0.90). No
significant difference in the risk of definite or probable
stent thrombosis was observed among patients
treated with BMS, DP-PES, DP-ZES, and BP-BES.
SENSITIVITY ANALYSES. The 1-stage fixed effect
network meta-analysis showed similar results to the
main analysis (Online Figure 3). The results of the
2-stage random effect network meta-analysis were
consistent with the main analysis, with the exception
that the risk of definite or probable stent thrombosis
with DP-EES compared with -SES did not reach sta-
tistical significance (HR: 0.59; 95% CI: 0.35 to 1.01)
(Online Figure 4). The results from the main analysis
were not altered after combining the individual pa-
tient data with the extracted data from the 4 studies
without individual patient data in the Bayesian
network meta-analysis (Online Figure 5).
COMPARISON BETWEEN BMS AND FIRST- AND
SECOND-GENERATION DES. Treatment with first- or
second-generation DES were associated with a
significantly lower risk of the composite primary
outcome compared with BMS in both unadjusted and
adjusted models (first-generation DES vs. BMS: un-
adjusted HR: 0.70 [95% CI: 0.61 to 0.80], adjusted
HR: 0.72 [95% CI: 0.62 to 0.83], second-generation
DES vs. BMS: unadjusted HR: 0.69 [95% CI: 0.57 to
2576 Chichareon et al. JACC VOL. 74, NO. 21, 2019

Stents in STEMI: Patient-Level Network Meta-Analysis NOVEMBER 26, 2019:2572–84

F I G U R E 1 Flow Diagram of the Systematic Review

Records identified through database searching in March 2017

(PubMed, EMBASE, CENTRAL, n = 3,799)

135 duplicated records removed

Records screened by title (n = 3,664)

3,416 records excluded as not relevant

Studies assessed for eligibility (n = 248)

224 records excluded based on Abstract

24 Full-text articles assessed for eligibility

5 studies excluded
1 comparison between similar treatment coding in
the network analysis
1 subgroup analysis of RCT
1 study included bioabsorbable vascular scaffold
2 clinical follow-up less than 12 months

19 studies included in the network meta-analysis

4 studies; Individual patient data were not available

Sponsor or principal investigators declined to
participate

15 studies with individual patient data available

for the network meta-analysis

RCT ¼ randomized controlled trial.

0.82], adjusted HR: 0.70 [95% CI: 0.58 to 0.84])
(Figure 4, Online Figures 6 and 7). The difference was
driven by the lower risk of TLR associated with first-
and second-generation DES (first-generation DES vs.
BMS: unadjusted HR: 0.54 [95% CI: 0.45 to 0.64],
adjusted HR: 0.53 [95% CI: 0.44 to 0.65], second-
generation DES vs. BMS: unadjusted HR: 0.52
[95% CI: 0.39 to 0.69], adjusted HR: 0.52 [95% CI:
0.39 to 0.71]). The risks of all-cause death and cardiac
death after adjustment were not different among the
3 groups. The risk of reinfarction was not signifi-
cantly different among the BMS and first- and

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JACC VOL. 74, NO. 21, 2019 Chichareon et al. 2577
NOVEMBER 26, 2019:2572–84 Stents in STEMI: Patient-Level Network Meta-Analysis

F I G U R E 2 Network Plot and Characteristics of the Included Studies

Network Plot of 15 Studies with Available Individual Patient Data

BP-BES BMS
(n = 575) (n = 3,409)
Number Of 1s
Study Comparison Patients tud
y
HORIZONS AMI BMS vs. DP-PES 3,011 DP-ZES
(n = 373)
EXAMINATION BMS vs. DP-EES 1,498

COMFORTABLE MI BMS vs. BP-BES 1,157

DEBATER BMS vs. DP-SES 907

2s
3 studies
XAMI DP-SES vs. DP-EES 625
ies

tud
tud
5s

ies
PASSION BMS vs. DP-PES 619

1 stu
s
KOMER DP-PES vs. DP-SES vs. DP-ZES 611

die
tu

dy
TYPHOON BMS vs. DP-SES 501

3s
RACES-MI DP-SES vs. DP-EES 500 2 studies
Juwana et al. DP-PES vs. DP-SES 397

ZEST-AMI DP-PES vs. DP-SES vs. DP-ZES 328 4

stu
SESAMI BMS vs. DP-SES 320 dies
DP-SES DP-EES
PASEO BMS vs. DP-PES vs. DP-SES 270 (n = 2,044) (n = 1,405)
SEZE DP-SES vs. DP-ZES 121

Diaz de la Llera et al. BMS vs. DP-SES 114

DP-PES
(n = 3,173)

References for each study are reported in Online Table 1. Each node represents each stent type. Node size is proportional to the number of patients randomized to each
stent. The thickness of the line connecting each node is proportional to the number of direct comparisons. BMS ¼ bare-metal stent; BP-BES ¼ biodegradable polymer
biolimus-eluting stent(s); DP ¼ durable polymer; EES ¼ everolimus-eluting stent(s); PES ¼ paclitaxel-eluting stent(s); SES ¼ sirolimus-eluting stent(s);
ZES ¼ zotarolimus-eluting stent(s).

second-generation DES. There was a trend toward a
lower risk of reinfarction in patients treated with
second-generation DES than with first-generation
DES, although statistical significance
reached. The risk of definite or probable stent
thrombosis was significantly lower in patients treated
with second-generation DES compared with BMS or
first-generation DES (second-generation DES vs.
BMS: unadjusted HR: 0.62 [95% CI: 0.40 to 0.97],
adjusted HR: 0.61 [95% CI: 0.42 to 0.89], second-
generation DES vs. first-generation DES: unadjusted
HR: 0.55 [95% CI: 0.34 to 0.91], adjusted HR: 0.56
[95% CI: 0.36 to 0.88]). A similar risk of definite or
probable stent thrombosis was observed between
BMS and first-generation DES.
DISCUSSION
The major findings of this network meta-analysis can
be summarized as follows: 1) for the primary
composite outcome of cardiac death, reinfarction, or
TLR, the efficacy of DES compared with BMS in STEMI
patients was confirmed at long-term follow-up; 2) no
was not significant differences in ischemic and safety out-
comes were observed between the various types of
DES; and 3) however, second-generation DES were
associated with a significant reduction in the risk of
stent thrombosis compared with first-generation DES
and BMS (Central Illustration).
DP-EES OR BP-BES IN STEMI PATIENTS. Results
from study-level network meta-analyses in patients
with coronary artery disease treated with percuta-
neous coronary intervention have raised concerns
regarding the safety of BP-DES when compared with
DP-EES. Bangalore et al. (11) reported that use of BP-
DES was associated with higher mortality after 1
year than DP-EES (rate ratio: 1.52; 95% credibility in-
terval: 1.02 to 2.22). A subsequent network meta-
analysis by Palmerini et al. (12) reported a higher

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2578 Chichareon et al. JACC VOL. 74, NO. 21, 2019

Stents in STEMI: Patient-Level Network Meta-Analysis NOVEMBER 26, 2019:2572–84

T A B L E 1 Baseline and Procedural Characteristics According to Types of Stent

Bare-Metal Paclitaxel-Eluting Sirolimus-Eluting Zotarolimus-Eluting Everolimus-Eluting Biolimus-Eluting

Stents Stents Stents Stents Stents Stents
(n ¼ 3,409) (n ¼ 3,173) (n ¼ 2,044) (n ¼ 373) (n ¼ 1,405) (n ¼ 575)

Age, yrs 3,406 3,173 2,043 373 1,405 575

60.84
12.08 60.69
11.75 60.23
11.59 60.66
12.44 60.63
11.90 60.78
11.62
Female 3,408 3,173 2,043 373 1,405 575
756 (22.2) 743 (23.4) 489 (23.9) 84 (22.5) 307 (21.9) 112 (19.5)
Diabetes 3,403 3,172 2,041 373 1,404 575
518 (15.2) 494 (15.6) 356 (17.4) 82 (22.0) 237 (16.9) 84 (14.6)
Hypertension 3,390 3,172 2,028 371 1,404 575
1,500 (44.2) 1,491 (47.0) 745 (36.7) 161 (43.4) 571 (40.7) 279 (48.5)
Hyperlipidemia 3,291 3,080 1,931 372 1,403 572
1,335 (40.6) 1185 (38.5) 619 (32.1) 128 (34.4) 574 (40.9) 324 (56.6)
Previous MI 2,692 3,172 1,350 373 1,404 575
219 (8.1) 248 (7.8) 88 (6.5) 8 (2.1) 92 (6.6) 31 (5.4)
Previous PCI 2,888 3,171 1,543 373 1,403 575
171 (5.9) 248 (7.8) 83 (5.4) 15 (4.0) 70 (5.0) 19 (3.3)
Previous CABG 2,888 3,172 1,543 373 1,404 575
34 (1.2) 62 (2.0) 33 (2.1) 1 (0.3) 21 (1.5) 10 (1.7)
Killip class 2,482 2,913 837 262 1,153 575
I 2,281 (91.9) 2,654 (91.1) 770 (92.0) 220 (84.0) 1,046 (90.7) 535 (93.0)
II 155 (6.2) 214 (7.3) 45 (5.4) 32 (12.2) 79 (6.9) 32 (5.6)
III 23 (0.9) 16 (0.5) 10 (1.2) 5 (1.9) 13 (1.1) 3 (0.5)
IV 23 (0.9) 29 (1.0) 12 (1.4) 5 (1.9) 15 (1.3) 5 (0.9)
Time from onset of symptom to balloon, min 2,726 3,056 1,548 371 1,241 575
296.75
248.26 305.62
1,180.23 264.91
234.89 323.38
314.52 287.24
275.48 323.28
276.34
Infarct-related artery 3,389 3,155 2,031 373 1,405 575
Right coronary artery 1,411 (41.6) 1,306 (41.4) 773 (38.1) 135 (36.2) 581 (41.4) 263 (45.7)
Left main artery 7 (0.2) 5 (0.2) 11 (0.5) 2 (0.5) 7 (0.5) 2 (0.3)
Left anterior descending artery 1,449 (42.8) 1,391 (44.1) 923 (45.4) 204 (54.7) 591 (42.1) 226 (39.3)
Left circumflex artery 510 (15.0) 429 (13.6) 316 (15.6) 32 (8.6) 220 (15.7) 82 (14.3)
Saphenous vein graft 12 (0.4) 24 (0.8) 8 (0.4) 0 (0.0) 6 (0.4) 2 (0.3)
GP IIb/IIIa receptor inhibitors 3,067 3,073 1,631 313 1,403 575
1,683 (54.9) 1,604 (52.2) 656 (40.2) 75 (24.0) 610 (43.5) 276 (48.0)
Direct stenting 2,553 2,662 1,033 313 1,141 574
1,054 (41.3) 678 (25.5) 237 (22.9) 5 (1.6) 634 (55.6) 235 (40.9)
Thrombectomy 2,538 2,852 994 163 1,405 575
1,028 (40.5) 184 (6.5) 247 (24.8) 33 (20.2) 798 (56.8) 350 (60.9)
Target lesion number 2,319 2,548 565 313 751 575
1.20
0.52 1.12
0.38 1.04
0.21 1.04
0.22 1.37
0.70 1.19
0.47
Total stent number 3,287 3,098 1,712 373 1,151 575
1.35
0.68 1.46
0.78 1.20
0.48 1.23
0.47 1.37
0.64 1.50
0.74
Total stent length, mm 3,294 3,102 1,712 373 1,151 575
25.25
13.31 28.80
16.39 25.19
11.89 29.91
13.57 26.88
14.05 28.52
14.71
ACE inhibitor or ARB at discharge 2,108 2,817 1,815 373 654 568
1,589 (75.4) 2,315 (82.2) 1,269 (69.9) 308 (82.6) 432 (66.1) 445 (78.3)
Statin at discharge 2,274 2,817 1,915 313 654 568
2,046 (90.0) 2,671 (94.8) 1,620 (84.6) 263 (84.0) 616 (94.2) 558 (98.2)
Beta-blocker at discharge 2,274 2,818 1,757 373 250 568
2,027 (89.1) 2,558 (90.8) 1,564 (89.0) 279 (74.8) 232 (92.8) 490 (86.3)

Values are n, mean
SD, or n (%). All data are patient-level.

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypass grafting; GP ¼ glycoprotein; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary
intervention.

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JACC VOL. 74, NO. 21, 2019 Chichareon et al. 2579
NOVEMBER 26, 2019:2572–84 Stents in STEMI: Patient-Level Network Meta-Analysis

F I G U R E 3 League Table of the Comparison of Outcomes Between Various Stent Types Using 1-Stage Random Effects Network Meta-Analysis in
Unadjusted and Adjusted Models

Cardiac Death, Reinfarction, or Target Lesion Revascularization Cardiac Death, Reinfarction, or Target Lesion Revascularization

BP-BES BP-BES
0.95 (0.65-1.38) DP-EES 0.94 (0.63-1.40) DP-EES
0.75 (0.42-1.34) 0.80 (0.47-1.35) DP-ZES 0.79 (0.44-1.41) 0.84 (0.49-1.42) DP-ZES
1.03 (0.71-1.49) 1.09 (0.84-1.41) 1.36 (0.84-2.21) DP-SES 1.01 (0.68-1.52) 1.08 (0.81-1.43) 1.29 (0.79-2.09) DP-SES
0.86 (0.62-1.20) 0.91 (0.69-1.21) 1.14 (0.70-1.86) 0.84 (0.65-1.08) DP-PES 0.88 (0.63-1.24) 0.94 (0.69-1.27) 1.12 (0.68-1.84) 0.87 (0.65-1.17) DP-PES
0.64 (0.48-0.87) 0.68 (0.54-0.87) 0.86 (0.52-1.40) 0.63 (0.50-0.79) 0.75 (0.64-0.88) BMS 0.66 (0.49-0.88) 0.70 (0.53-0.91) 0.83 (0.51-1.38) 0.65 (0.49-0.85) 0.74 (0.63-0.88) BMS

All-Cause Death, Reinfarction, or Target Vessel Revascularization All-Cause Death, Reinfarction, or Target Vessel Revascularization

BP-BES BP-BES
1.20 (0.86-1.66) DP-EES 1.12 (0.79-1.58) DP-EES
0.83 (0.45-1.55) 0.70 (0.39-1.26) DP-ZES 0.86 (0.46-1.61) 0.77 (0.43-1.39) DP-ZES
1.06 (0.77-1.46) 0.89 (0.71-1.12) 1.27 (0.73-2.21) DP-SES 0.99 (0.68-1.43) 0.88 (0.68-1.15) 1.15 (0.66-2.00) DP-SES
0.93 (0.69-1.26) 0.78 (0.61-1.01) 1.12 (0.63-1.97) 0.88 (0.70-1.11) DP-PES 0.98 (0.73-1.33) 0.88 (0.67-1.16) 1.15 (0.65-2.04) 1.00 (0.75-1.32) DP-PES
0.75 (0.58-0.97) 0.63 (0.51-0.77) 0.90 (0.51-1.59) 0.71 (0.59-0.86) 0.81 (0.69-0.94) BMS 0.76 (0.59-0.98) 0.68 (0.54-0.86) 0.89 (0.50-1.58) 0.77 (0.59-1.01) 0.77 (0.66-0.91) BMS

All-Cause Death All-Cause Death

BP-BES BP-BES
1.34 (0.83-2.17) DP-EES 1.26 (0.76-2.09) DP-EES
0.79 (0.34-1.85) 0.59 (0.27-1.30) DP-ZES 0.85 (0.36-2.03) 0.68 (0.30-1.52) DP-ZES
1.10 (0.67-1.81) 0.82 (0.57-1.18) 1.39 (0.66-2.92) DP-SES 1.07 (0.62-1.86) 0.85 (0.57-1.29) 1.26 (0.59-2.65) DP-SES
1.18 (0.75-1.86) 0.88 (0.61-1.27) 1.49 (0.70-3.16) 1.07 (0.75-1.53) DP-PES 1.22 (0.77-1.94) 0.97 (0.65-1.45) 1.43 (0.67-3.06) 1.14 (0.75-1.73) DP-PES
0.94 (0.64-1.39) 0.71 (0.53-0.94) 1.20 (0.56-2.55) 0.86 (0.63-1.17) 0.80 (0.63-1.02) BMS 0.97 (0.66-1.43) 0.78 (0.56-1.08) 1.14 (0.53-2.47) 0.91 (0.61-1.34) 0.80 (0.62-1.03) BMS

Cardiac Death Cardiac Death

BP-BES BP-BES
1.09 (0.59-2.04) DP-EES 1.12 (0.58-2.15) DP-EES
0.96 (0.30-3.09) 0.87 (0.30-2.59) DP-ZES 1.00 (0.30-3.26) 0.89 (0.30-2.67) DP-ZES
1.02 (0.53-1.95) 0.93 (0.60-1.44) 1.06 (0.38-3.00) DP-SES 1.02 (0.50-2.07) 0.91 (0.56-1.48) 1.02 (0.36-2.90) DP-SES
1.09 (0.60-1.98) 1.00 (0.64-1.57) 1.14 (0.40-3.27) 1.07 (0.67-1.70) DP-PES 1.09 (0.59-2.00) 0.98 (0.59-1.61) 1.10 (0.38-3.17) 1.07 (0.62-1.84) DP-PES
0.87 (0.52-1.47) 0.80 (0.56-1.14) 0.92 (0.32-2.63) 0.86 (0.58-1.28) 0.80 (0.59-1.09) BMS 0.90 (0.53-1.50) 0.80 (0.54-1.20) 0.90 (0.31-2.61) 0.88 (0.54-1.43) 0.82 (0.60-1.13) BMS

Reinfarction Reinfarction

BP-BES BP-BES
0.76 (0.41-1.40) DP-EES 0.63 (0.32-1.22) DP-EES
2.20 (0.46-10.46) 2.91 (0.62-13.60) DP-ZES 2.13 (0.44-10.27) 3.40 (0.72-15.93) DP-ZES
0.65 (0.38-1.11) 0.86 (0.56-1.31) 0.29 (0.07-1.31) DP-SES 0.57 (0.31-1.08) 0.91 (0.58-1.44) 0.27 (0.06-1.20) DP-SES
0.61 (0.37-1.01) 0.81 (0.49-1.34) 0.28 (0.06-1.24) 0.95 (0.64-1.39) DP-PES 0.61 (0.37-1.01) 0.97 (0.56-1.67) 0.29 (0.06-1.28) 1.06 (0.66-1.70) DP-PES
0.68 (0.45-1.03) 0.90 (0.57-1.41) 0.31 (0.07-1.38) 1.05 (0.74-1.47) 1.10 (0.84-1.45) BMS 0.69 (0.46-1.05) 1.10 (0.66-1.84) 0.32 (0.07-1.48) 1.21 (0.76-1.92) 1.14 (0.86-1.51) BMS

Target Lesion Revascularization Target Lesion Revascularization

BP-BES BP-BES
0.83 (0.46-1.50) DP-EES 0.87 (0.46-1.63) DP-EES
0.47 (0.22-1.02) 0.57 (0.27-1.19) DP-ZES 0.56 (0.25-1.23) 0.64 (0.30-1.37) DP-ZES
1.07 (0.63-1.82) 1.30 (0.83-2.02) 2.28 (1.21-4.28) DP-SES 1.33 (0.71-2.51) 1.54 (0.91-2.60) 2.40 (1.25-4.62) DP-SES
0.73 (0.45-1.19) 0.88 (0.57-1.38) 1.55 (0.82-2.92) 0.68 (0.48-0.96) DP-PES 0.77 (0.47-1.26) 0.89 (0.55-1.46) 1.39 (0.73-2.65) 0.58 (0.36-0.93) DP-PES
0.45 (0.29-0.69) 0.54 (0.36-0.80) 0.95 (0.50-1.79) 0.41 (0.31-0.56) 0.61 (0.50-0.75) BMS 0.45 (0.29-0.70) 0.52 (0.33-0.81) 0.81 (0.42-1.56) 0.34 (0.21-0.53) 0.58 (0.47-0.72) BMS

Target Vessel Revascularization Target Vessel Revascularization

BP-BES BP-BES
1.07 (0.64-1.77) DP-EES 1.04 (0.61-1.77) DP-EES
0.67 (0.31-1.43) 0.63 (0.31-1.29) DP-ZES 0.75 (0.34-1.64) 0.72 (0.35-1.50) DP-ZES
1.03 (0.65-1.64) 0.97 (0.67-1.41) 1.54 (0.81-2.91) DP-SES 1.13 (0.66-1.95) 1.09 (0.70-1.70) 1.51 (0.80-2.87) DP-SES
0.80 (0.52-1.23) 0.75 (0.51-1.10) 1.19 (0.62-2.30) 0.77 (0.58-1.04) DP-PES 0.86 (0.56-1.32) 0.83 (0.55-1.24) 1.15 (0.59-2.25) 0.76 (0.51-1.13) DP-PES
0.56 (0.38-0.82) 0.52 (0.38-0.73) 0.83 (0.43-1.60) 0.54 (0.42-0.69) 0.70 (0.58-0.85) BMS 0.56 (0.38-0.82) 0.54 (0.37-0.78) 0.75 (0.38-1.47) 0.49 (0.34-0.73) 0.65 (0.53-0.79) BMS

Definite or Probable Stent Thrombosis Definite or Probable Stent Thrombosis

BP-BES BP-BES
1.12 (0.54-2.34) DP-EES 1.24 (0.56-2.73) DP-EES
1.58 (0.40-6.24) 1.40 (0.37-5.35) DP-ZES 1.67 (0.41-6.77) 1.34 (0.35-5.18) DP-ZES
0.64 (0.33-1.22) 0.57 (0.34-0.95) 0.40 (0.11-1.43) DP-SES 0.63 (0.29-1.36) 0.50 (0.28-0.90) 0.38 (0.11-1.34) DP-SES
0.62 (0.33-1.17) 0.55 (0.30-1.00) 0.39 (0.11-1.39) 0.97 (0.62-1.53) DP-PES 0.66 (0.35-1.26) 0.53 (0.28-1.01) 0.40 (0.11-1.42) 1.05 (0.60-1.86) DP-PES
0.67 (0.40-1.14) 0.60 (0.36-1.00) 0.43 (0.12-1.53) 1.06 (0.73-1.53) 1.09 (0.76-1.54) BMS 0.69 (0.41-1.17) 0.55 (0.31-1.00) 0.41 (0.11-1.52) 1.10 (0.62-1.94) 1.04 (0.72-1.51) BMS

(Left) Unadjusted model; (right) adjusted model. Values shown are hazard ratio and 95% confidence interval. Comparisons between treatments should be
read from left to right, and their hazard ratio is in the cell in common between the column-defining treatment and the row-defining treatment. Hazard
ratios <1 favor the column-defining treatment for the network estimates. Significant values are in red. Abbreviations as in Figure 2.

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2580 Chichareon et al. JACC VOL. 74, NO. 21, 2019

Stents in STEMI: Patient-Level Network Meta-Analysis NOVEMBER 26, 2019:2572–84

F I G U R E 4 Outcomes Between Bare-Metal Stents and First- and Second-Generation Drug-Eluting Stents in 1-Stage Random Effects Network Meta-Analysis

Unadjusted HR (95% CI) Adjusted HR (95% CI)

Outcomes Comparator vs. Reference Comparator/Reference Comparator/Reference

Cardiac death, First generation DES vs. BMS 0.70 (0.61-0.80) 0.72 (0.62-0.83)
reinfarction or TLR Second generation DES vs. BMS 0.69 (0.57-0.82) 0.70 (0.58-0.84)
Second vs. First generation DES 0.98 (0.80-1.20) 0.98 (0.79-1.21)

All-cause death, First generation DES vs. BMS 0.77 (0.68-0.88) 0.78 (0.68-0.90)
reinfarction or TVR Second generation DES vs. BMS 0.69 (0.59-0.80) 0.72 (0.61-0.84)
Second vs. First generation DES 0.89 (0.74-1.06) 0.92 (0.75-1.12)

All-cause death First generation DES vs. BMS 0.83 (0.68-1.03) 0.84 (0.67-1.06)
Second generation DES vs. BMS 0.77 (0.62-0.97) 0.83 (0.65-1.06)
Second vs. First generation DES 0.93 (0.70-1.23) 0.99 (0.73-1.35)

Cardiac death First generation DES vs. BMS 0.83 (0.64-1.07) 0.84 (0.64-1.12)
Second generation DES vs. BMS 0.81 (0.61-1.08) 0.82 (0.61-1.12)
Second vs. First generation DES 0.99 (0.70-1.39) 0.98 (0.68-1.41)

Reinfarction First generation DES vs. BMS 1.05 (0.84-1.32) 1.09 (0.85-1.41)
Second generation DES vs. BMS 0.79 (0.58-1.06) 0.85 (0.62-1.15)
Second vs. First generation DES 0.75 (0.54-1.03) 0.77 (0.55-1.09)

Target lesion First generation DES vs. BMS 0.54 (0.45-0.64) 0.53 (0.44-0.65)
revascularization Second generation DES vs. BMS 0.52 (0.39-0.69) 0.52 (0.39-0.71)
Second vs. First generation DES 0.96 (0.70-1.33) 0.99 (0.70-1.39)

Target vessel First generation DES vs. BMS 0.64 (0.54-0.75) 0.62 (0.52-0.75)
revascularization Second generation DES vs. BMS 0.55 (0.43-0.71) 0.57 (0.44-0.74)
Second vs. First generation DES 0.87 (0.66-1.15) 0.91 (0.68-1.23)

Definite or probable First generation DES vs. BMS 1.12 (0.83-1.50) 1.08 (0.77-1.52)
stent thrombosis Second generation DES vs. BMS 0.62 (0.40-0.97) 0.61 (0.42-0.89)
Second vs. First generation DES 0.55 (0.34-0.91) 0.56 (0.36-0.88)

0.5 1.0 2.0 0.5 1.0 2.0

Favors Favors Favors Favors
Comparator Reference Comparator Reference

After a median follow-up of 3 years, hazard ratios (HRs) and confidence intervals (CIs) were assessed for the risk of outcomes in unadjusted and adjusted models.
BMS ¼ bare-metal stents; CI ¼ confidence interval; DES ¼ drug-eluting stents; HR ¼ hazard ratio; MI ¼ myocardial infarction; TLR ¼ target lesion revascularization;
TVR ¼ target vessel revascularization.

rate of definite stent thrombosis in biodegradable
polymer DES than DP-EES at 1 year (HR: 2.44; 95% CI:
1.30 to 4.76) and long-term follow-up (HR: 1.92;
95% CI: 1.02 to 3.45). Although BP-DES has shown
comparable efficacy and safety to DP-EES at 10-year
follow-up in the ISAR-TEST 4 (Intracoronary Stent-
ing and Angiographic Results: Test Efficacy of 3
Limus-Eluting Stents) study, these results should be
interpreted with caution due to reduced power and
incomplete late ascertainment (19).
In the 5-year report from the COMPARE II (Ablu-
minal Biodegradable Polymer Biolimus-Eluting Stent
Versus Durable Polymer Everolimus-Eluting Stent)
trial, a subgroup analysis showed that STEMI patients
treated with BP-BES had a significantly higher risk of
TVR than patients treated with DP-EES (risk ratio:
2.97; 95% CI: 1.16 to 7.56), whereas the risk of TVR was
similar between 2 stents in patients
STEMI (risk ratio: 1.06; 95% CI: 0.82 to 1.37;
p interaction ¼ 0.04) (20). In the present individual pa-
tient data network meta-analysis, STEMI patients
treated with BP-BES and DP-EES showed a similar
long-term risk of adverse outcomes. Therefore, our
analysis does not support the findings of safety con-
cerns of BP-DES compared with second-generation
DES. However, the hypothesis that lipophilic bio-
limus might result in greater effectiveness than
everolimus in STEMI was not confirmed.
COMPARISON BETWEEN FIRST- AND
SECOND-GENERATION DES. Our network meta-
analysis showed no difference in efficacy and safety
outcomes among specific types of DES in STEMI pa-
tients. The majority of individual patient data stem-
med from patients treated with BMS, DP-SES, and DP-
PES and the number of patients treated with BP-BES
without was substantially smaller than the other groups.

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JACC VOL. 74, NO. 21, 2019 Chichareon et al. 2581
NOVEMBER 26, 2019:2572–84 Stents in STEMI: Patient-Level Network Meta-Analysis

C ENTR AL I LL U STRA T I O N Drug-Eluting Stents in ST-Segment Elevation Myocardial Infarction Patients:

Efficacy and Safety

Cardiac Death, Reinfarction, or Target Lesion Revascularization (TLR)

BMS as a Reference Cardiac Death, Reinfarction, or TLR

Durable polymer Comparator vs. Reference

paclitaxel-eluting stents
1st generation DES vs. BMS
Durable polymer 2nd generation DES vs. BMS
sirolimus-eluting stents
2nd vs. 1st generation DES
Durable polymer
zotarolimus-eluting stents Definite or Probable Stent Thrombosis
Comparator vs. Reference
Durable polymer
everolimus-eluting stents 1st generation DES vs. BMS
2nd generation DES vs. BMS
Biodegradable polymer
biolimus-eluting stents 2nd vs. 1st generation DES

0.5 1.0 1.5 0.5 1.0 2.0

Favors Drug-Eluting Favors Bare-Metal Favors Favors
Stents (DES) Stents (BMS) Comparator Reference
Chichareon, P. et al. J Am Coll Cardiol. 2019;74(21):2572–84.

(Left) Adjusted HRs and 95% CIs of various types of DES compared with BMS for the primary endpoint of cardiac death, reinfarction, or target lesion revascularization.
(Right) Adjusted HRs and 95% CIs for the comparison between first- and second-generation DES and BMS for the primary endpoint and definite or probable stent
thrombosis. Cox regression analysis stratified by trial, random effect. Adjusted for age, sex, diabetes, history of previous myocardial infarction, history of previous
coronary artery bypass graft, history of previous percutaneous coronary intervention, and time from onset to balloon. First-generation DES represented by durable
polymer paclitaxel-eluting stents, sirolimus-eluting stents, and zotarolimus-eluting stents. Second-generation DES represented by durable polymer everolimus-
eluting stents and biodegradable polymer biolimus-eluting stents. BMS ¼ bare-metal stents; CI ¼ confidence interval; DES ¼ drug-eluting stents; HR ¼ hazard ratio;
TLR ¼ target lesion revascularization.

Therefore, we stratified patients based on the stent
generation to increase the power of the analysis. The
phosphorylcholine-based fast-release Endeavor ZES
in the present meta-analysis is substantially different
from the new-generation BioLinx-polymer-based
slow-release Resolute ZES; the findings from this
meta-analysis may not be extrapolated to the
currently available Resolute ZES. We classified the
Endeavor ZES as a first-generation DES
the chronological order of its commercial availability.
However, the findings did not change when the DP-
ZES was regarded as a second-generation DES in
sensitivity analysis (Online Figure 8).
In an earlier, smaller, patient-level pooled meta-
analysis of STEMI patients by De Luca et al. (21),
treatment with first-generation DES was associated
with a lower risk of TVR than treatment with BMS at
long-term follow-up. Our findings are consistent with
this study in that the risks of TLR and TVR were
significantly lower in patients treated with first-
generation DES than BMS. However, in the study by
De Luca et al. (21), very late reinfarction and stent
thrombosis was increased in patients treated with
first-generation DES at long-term follow-up, whereas
our study showed a similar risk of definite or probable
stent thrombosis between first-generation DES and
from BMS.
In the present study, even after statistical adjust-
ment for baseline characteristics, second-generation
DES had better efficacy than BMS in terms of a
lower risk of revascularization. In addition, the
second-generation was safer than the first-generation
DES due to the lower risk of definite or probable stent
thrombosis. This finding is in line with the long-term
follow-up results of the LEADERS trial (5). In contrast
to the previous study-level network meta-analysis

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2582 Chichareon et al.
Stents in STEMI: Patient-Level Network Meta-Analysis
(22–24), no difference in myocardial infarction be-
tween second-generation DES and BMS was observed
in the present study.
STRENGTHS OF THE INDIVIDUAL PATIENT DATA
NETWORK META-ANALYSIS. To our knowledge, the
present study is the first individual patient data
network meta-analysis assessing the outcomes of
coronary stents in more than 10,000 STEMI patients.
Our network meta-analysis allows the indirect com-
parison between different treatments for which head-
to-head comparative study was not available. Prior
evidence comparing stent outcomes in STEMI has
been based on individual randomized controlled tri-
als (which have limited power) and aggregate data
meta-analyses, which also have well-known draw-
backs. Specifically, differences in patient character-
istics often results in heterogeneity between included
studies. Second, the outcomes—in particular, the
composite ischemic endpoints—varied between
studies, which may create bias and uncertainty on the
treatment effect estimation. Third, the temporal
relationship in outcomes is not easily examined, nor
can subgroup outcomes be evaluated. Meta-analysis
using individual patient data may overcome many
of these limitations, homogenize the data, and pro-
duce reliable results (25).
STUDY LIMITATIONS. First, although individual pa-
tient data were successfully obtained in 87.7% of the
total patients in the eligible STEMI randomized
controlled trials, patient-level data were unavailable
from 4 studies comprising 1,537 patients. However, the
results from the Bayesian network meta-analysis that
incorporated these trials were similar to the main
analysis. Second, the original endpoint definitions
from each trial were used, which may add some
imprecision to the results. Therefore, the network
meta-analysis model was based on relative treatment
effect, instead of absolute estimation. Third, in 7 of the
15 included trials, angiographic follow-up was
requested and repeat interventions on the target
lesion were adjudicated as clinically-indicated by in-
dependent clinical event committees using criteria
recommended by the U.S. regulatory body of the U.S.
Food and Drug Administration following the report of
the RAVEL (Randomized Study with the Sirolimus-
Coated Bx Velocity Balloon-Expandable Stent in the
Treatment of Patients with de Novo Native Coronary
Artery Lesions) trial (26). These recommendations
were implemented to avoid reintervention relying on
the so-called “occulostenotic reflex” (27) not sub-
stantiated by symptoms, ischemia, and/or quantita-
tive angiography. In 8 of the 15 included trials,
angiographic follow-up was not mandated and was
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JACC VOL. 74, NO. 21, 2019
NOVEMBER 26, 2019:2572–84
even discouraged, so that the reinterventions were
performed and justified by spontaneous angina
complaint leading to an angiographic investigation
possibly coupled with a noninvasive demonstration of
ischemia. However, in most of the included studies,
the lack of blinding of treating physician to the study
devices may have introduced a potential risk of bias to
this component of the primary endpoint. Fourth, all
BMS included in this analysis were considered to be
comparable and regarded as a single stent type.
Perhaps more importantly, BP-BES was used in only 1
study comparing BP-BES with BMS in STEMI patients.
Therefore, the BP-BES had limited sample size, and the
comparison between BP-BES and other DES came from
indirect evidence only. In addition, the platform of BP-
BES in our study was stainless steel and relatively
thick (120 m m). Due to the lack of evidence from ran-
domized controlled trials in STEMI, newer-generation
DES (e.g., ultrathin DES, and so on) were not included.
Fifth, most of the patients included in the randomized
controlled trials in our meta-analysis received clopi-
dogrel. The impact that the more potent P2Y 12 in-
hibitors ticagrelor and prasugrel might have on the
outcomes between the different stent types is uncer-
tain. Last, the U.S. guideline for the management of
STEMI restricts the use of DES to patients without high
bleeding risk who can tolerate a prolonged dual anti-
platelet therapy, whereas the European guideline
recommends DES over BMS for any percutaneous
coronary intervention regardless of the anticipated
dual antiplatelet therapy duration (1,28,29). The
absence of duration of dual antiplatelet therapy does
not allow the present study to draw a specific conclu-
sion about the discrepancy between the 2 guidelines,
and the appropriate stent in high bleeding risk patients
with STEMI remains uncertain.
CONCLUSIONS
In this large-scale individual patient data network
meta-analysis in STEMI patients, DES was superior to
BMS with respect to long-term efficacy. No difference
in long-term efficacy and safety was observed be-
tween specific types of DES. Second-generation DES
were better than first-generation DES in reducing
stent thrombosis.
ADDRESS FOR CORRESPONDENCE: Prof. Patrick W.
Serruys, P.O. Box 2125, 3000 CC, Rotterdam, the
Netherlands. E-mail: patrick.w.j.c.serruys@gmail.com.
OR Dr. Yoshinobu Onuma, ThoraxCenter, Erasmus
Medical Center, P.O. Box 2125, 3000 CC, Rotterdam, the
Netherlands. E-mail: yoshinobuonuma@gmail.com.
Twitter: @chichareon, @R_Modolo.
JACC VOL. 74, NO. 21, 2019
NOVEMBER 26, 2019:2572–84
PERSPECTIVES
COMPETENCY IN PATIENT CARE AND
PROCEDURAL SKILLS: Network meta-analysis of data
on stent thrombosis from individual patients with STEMI
favors DES over BMS and second- over first-generation
DES. The various types of second-generation DES are
associated with comparable efficacy.
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KEY WORDS bare-metal stents,
drug-eluting stents, efficacy, individual
patient data network meta-analysis, safety,
ST-segment elevation myocardial
infarction
A PPE NDI X For supplemental tables and
figures, please see the online version of this
paper.

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