Efficacy and Safety of Stents in ST-Segment Elevation Myocardial Infarction

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 longterm 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 Contemporary 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.

Listen to this manuscript’s audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

From the aHeart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; bCardiology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; cDepartment of Internal Medicine, Cardiology Division, University of Campinas (UNICAMP), Campinas, Brazil; dCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium; eErasmus Medical Center, Rotterdam, the Netherlands; fOLVG Hospital, Amsterdam, the Netherlands; gDepartment of Cardiology, Gachon University Gil Medical Center, Incheon, South Korea; hDepartment of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; iInterventional Cardiology Unit-San Camillo Hospital, Rome, Italy; jUnidad de Hemodinámica y Cardiología Intervencionista, Hospital Universitario Virgen del Rocío, Seville, Spain; kSeoul National University Bundang Hospital, Seongnam, South Korea; lDepartment of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands;

m

Cardiology Depart-

ment, European Hospital Georges Pompidou-Assistance Publique Hôpitaux de Paris, Sudden Death Expert Center, INSERM U 970,

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2019.09.038

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JACC VOL. 74, NO. 21, 2019 NOVEMBER 26, 2019:2572–84

P

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Stents in STEMI: Patient-Level Network Meta-Analysis

rimary percutaneous coronary intervention is

developed to reduce the increased risk of

considered the preferred treatment in patients

stent

with ST-segment elevation myocardial infarc-

generation DES. Randomized trials evalu-

thrombosis

observed

biodegradable

with

polymer

first-

tion (STEMI) (1). Patients presenting with STEMI carry

ating

biolimus-

the highest risk of early and late adverse events after

eluting stents (BP-BES) demonstrated favor-

ABBREVIATIONS AND ACRONYMS BMS = bare-metal stent(s) BP-BES = biodegradable 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

vessel, which result in high rates of uncovered stent

DES (5–7). In the STEMI population, BP-BES

struts and stent malapposition (3). As a consequence,

has

the risk of stent thrombosis in STEMI patients is the

compared with BMS and first-generation

highest among coronary artery disease patients (2,4).

sirolimus-eluting

shown

improved

clinical

stents

outcomes

(8,9).

The

COMFORTABLE AMI (Comparison of Bio-

SEE PAGE 2585

limus Eluted From an Erodible Stent Coating

Although current guidelines for management of

With Bare Metal Stents in Acute ST-Elevation

STEMI patients indicate the preference of new-

Myocardial Infarction) trial reported that use

generation drug-eluting stents (DES) compared with

of BP-BES resulted in a lower rate of major

bare-metal stents (BMS) (Class of Recommendation I,

adverse cardiac events at 1 year compared

Level of Evidence: A), relatively little is known

with BMS (8). In the LEADERS (Limus Eluted

regarding the comparative safety and efficacy profiles

From A Durable Versus ERodable Stent

of

Coating) trial, BES significantly improved

DES

with

different

polymer

durability

or

EES = everolimus-eluting stent(s)

PES = paclitaxel-eluting stent(s)

SES = sirolimus-eluting stent(s)

STEMI = ST-segment elevation myocardial infarction

TLR = target lesion revascularization

TVR = target vessel revascularization

ZES = zotarolimus-eluting stent(s)

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

5-year follow-up compared with sirolimus-eluting

polymers

or

biodegradable

polymers

were

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 Publishing, 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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Stents in STEMI: Patient-Level Network Meta-Analysis

stents (9). In this regard, the high lipophilicity of

target lesion revascularization (TLR). Secondary out-

biolimus may facilitate rapid distribution of drug and

comes were the composite of all-cause death, rein-

potentiate local drug effects in lipidic lesion in pa-

farction, or target vessel revascularization (TVR);

tients with STEMI (10). Conversely, the safety of

individual components of the composite endpoints;

biodegradable polymer DES compared with durable

and definite or probable stent thrombosis. The

polymer DES has been questioned in several meta-

endpoint definitions from each trial were used.

analyses (11,12).

STATISTICAL ANALYSIS. Continuous variables are

Therefore, we sought, by means of an individual

presented as mean
SD or median (interquartile

patient data network meta-analysis of randomized

range). Categorical variables are presented as count

controlled trials in STEMI, to investigate the safety and

and percentages. Individual patient data from iden-

efficacy of different generations of stents in patients

tified studies obtained from the investigators were

undergoing percutaneous coronary intervention.

combined in a single dataset. All outcomes were analyzed using time-to-event analysis. The longest

METHODS

available follow-up was used for the analysis of the

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 metaanalysis (14).

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

ELIGIBILITY CRITERIA. Eligible studies were dedi-

in covariables, multivariable Cox regression analysis

cated

comparing

was performed using the following variables: age,

different stents in adult patients with STEMI under-

sex, diabetes, previous myocardial infarction, previ-

going percutaneous coronary intervention. Eligible

ous percutaneous coronary intervention, previous

studies must have at least 12 months of clinical

coronary artery bypass graft surgery and time from

follow-up. We excluded studies comparing devices

symptom onset to balloon. As a sensitivity analysis, a

other than coronary stents, such as drug-eluting bal-

frequentist 2-stage network meta-analysis was per-

loons or distal protection devices.

formed with a random effect model (R netmeta

SEARCH, STUDY SELECTION, QUALITY ASSESSMENT, AND

package) (17) using a log hazard ratio and standard

DATA COLLECTION PROCESS. We searched PubMed,

error obtained from the individual patient data of

Embase, and the Cochrane Central Register of

individual studies. Because individual patient data

Controlled trials for relevant studies without restric-

were not available in 4 of 19 studies, as an additional

tion on language or publication period. The full list of

analysis we performed a 2-stage random-effect

search terms is provided in the appendix. The titles

network meta-analysis in a Bayesian framework

and abstracts were reviewed for inclusion indepen-

combining the extracted data (binary data or hazard

dently by 2 authors (C.C. and E.T.). In case of

ratio) from the published studies on which individual

disagreement, full studies were reviewed and final

patient data were not available with the HRs from the

decision was made by consensus. Risk of bias was

studies with available individual patient data (18).

randomized

controlled

trials

appraised using the Cochrane risk of bias tool (15).

A total of 6 different stent types with respect to

Publication bias was assessed using the comparison-

the type of drug and coating were identified including

adjusted funnel plot (16).

BMS, durable polymer (DP) paclitaxel-eluting stents

Pre-specified variables and outcomes for individual

(PES) (Taxus Express, Taxus Express 2 or Taxus Lib-

patient data were requested from the investigators of

erte, Boston Scientific, Natick, Massachusetts), DP

each included study. The data were checked, and the

sirolimus-eluting stents (SES) (Cypher or Cypher

queries were sent to the investigators for clarifica-

select, Cordis, Miami Lakes, Florida), DP fast-release

tions in case of inconsistency. Each study was

zotarolimus-eluting stents (ZES) (Endeavor, Med-

approved by the local ethics committee, and all pa-

tronic, Minneapolis, Minnesota), DP everolimus-

tients provided written informed consent.

eluting stents (EES) (Xience V, Abbott Vascular,

OUTCOMES

AND

EFFECT

MEASURES. The

pre-

Santa Clara, California), and biodegradable polymer

specified primary outcome for this meta-analysis

biolimus-eluting

was the composite of cardiac death, reinfarction, or

Biosensors, Morges, Switzerland). DP-PES, -SES, and

stents

(BP-BES)

(BioMatrix,

Chichareon et al.

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Stents in STEMI: Patient-Level Network Meta-Analysis

-ZES were considered first-generation DES while

lower risk of TVR. The difference was not statistically

DP-EES

significant between patients treated with DP-ZES

and

BP-BES

were

considered

second-

generation DES. All p values were 2-sided, and p values <0.05 were

and BMS. Treatment with DP-EES was associated with a

considered to be statistically significant. Statistical

significantly

analysis was performed with R (R Foundation for

compared with BMS (unadjusted HR: 0.71; 95% CI:

Statistical Computing, Vienna, Austria) and Open-

0.53 to 0.94). However, the difference was not sig-

BUGS (MRC Biostatistics Unit, Cambridge University,

nificant in the adjusted Cox model (adjusted HR:

United Kingdom).

0.78; 95% CI: 0.56 to 1.08). The risk of all-cause

RESULTS Details of literature search, study exclusion, and selection are shown in Figure 1. Nineteen studies were eligible for the analysis. Study characteristics, definitions 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

lower

risk

of

all-cause

mortality

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 BPBES 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.

characteristics stratified by treatment arm are pre-

SENSITIVITY ANALYSES. The 1-stage fixed effect

sented in Table 1. Details of the stent types in each

network meta-analysis showed similar results to the

study are provided in the Online Appendix (Online

main analysis (Online Figure 3). The results of the

Tables 5 and 6).

2-stage random effect network meta-analysis were

PRIMARY OUTCOME. Patients treated with DP-PES,

consistent with the main analysis, with the exception

DP-SES, and DP-EES and BP-BES had significantly

that the risk of definite or probable stent thrombosis

lower risk of the primary composite endpoint of car-

with DP-EES compared with -SES did not reach sta-

diac death, reinfarction, or TLR compared with BMS

tistical significance (HR: 0.59; 95% CI: 0.35 to 1.01)

(Figure 3). The difference was driven by a significantly

(Online Figure 4). The results from the main analysis

lower risk of TLR associated with DES. The difference

were not altered after combining the individual pa-

in the risk of the primary outcome was not significant

tient data with the extracted data from the 4 studies

between patients treated with BMS and DP-ZES.

without individual patient data in the Bayesian

Among patients treated with DES, no significant dif-

network meta-analysis (Online Figure 5).

ference in the risk of the primary outcome was

COMPARISON

demonstrated. Similar findings were observed in the

BETWEEN

BMS

AND

FIRST-

AND

SECOND-GENERATION DES. Treatment with first- or

adjusted Cox models (Figure 3).

second-generation

SECONDARY OUTCOMES. The risk of the secondary

significantly lower risk of the composite primary

composite outcome of all-cause death, reinfarction,

outcome compared with BMS in both unadjusted and

or TVR was significantly lower in patients treated

adjusted models (first-generation DES vs. BMS: un-

with DP-PES, -SES, and -EES and BP-BES compared

adjusted HR: 0.70 [95% CI: 0.61 to 0.80], adjusted

with BMS in both unadjusted and adjusted models

HR: 0.72 [95% CI: 0.62 to 0.83], second-generation

(Figure 3). The differences were mainly driven by the

DES vs. BMS: unadjusted HR: 0.69 [95% CI: 0.57 to

DES

were

associated

with

a

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Stents in STEMI: Patient-Level Network Meta-Analysis

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])

generation DES vs. BMS: unadjusted HR: 0.52

(Figure 4, Online Figures 6 and 7). The difference was

[95% CI: 0.39 to 0.69], adjusted HR: 0.52 [95% CI:

driven by the lower risk of TLR associated with first-

0.39 to 0.71]). The risks of all-cause death and cardiac

and second-generation DES (first-generation DES vs.

death after adjustment were not different among the

BMS: unadjusted HR: 0.54 [95% CI: 0.45 to 0.64],

3 groups. The risk of reinfarction was not signifi-

adjusted HR: 0.53 [95% CI: 0.44 to 0.65], second-

cantly different among the BMS and first- and

Chichareon et al.

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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 (n = 575)

3,011

EXAMINATION

BMS vs. DP-EES

1,498

COMFORTABLE MI

BMS vs. BP-BES

1,157

DEBATER

BMS vs. DP-PES

619

DP-PES vs. DP-SES vs. DP-ZES

611

PASSION KOMER TYPHOON

BMS vs. DP-SES

501

RACES-MI

DP-SES vs. DP-EES

500

Juwana et al.

DP-PES vs. DP-SES

397

ZEST-AMI

DP-PES vs. DP-SES vs. DP-ZES

328

SESAMI

BMS vs. DP-SES

320

PASEO

BMS vs. DP-PES vs. DP-SES

270

SEZE

DP-SES vs. DP-ZES

121

BMS vs. DP-SES

114

Diaz de la Llera et al.

ies

tud 5s

dy 1 stu

625

ies

907

tud 2s

BMS vs. DP-SES DP-SES vs. DP-EES

XAMI

y

DP-ZES (n = 373)

s

BMS vs. DP-PES

die

HORIZONS AMI

1s tud

3s tu

Number Of Patients

3 studies

Comparison

Study

BMS (n = 3,409)

2 studies

4

DP-SES (n = 2,044)

stu d

ies

DP-EES (n = 1,405)

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

composite outcome of cardiac death, reinfarction, or

lower risk of reinfarction in patients treated with

TLR, the efficacy of DES compared with BMS in STEMI

second-generation DES than with first-generation

patients was confirmed at long-term follow-up; 2) no

DES,

not

significant differences in ischemic and safety out-

reached. The risk of definite or probable stent

although

statistical

significance

was

comes were observed between the various types of

thrombosis was significantly lower in patients treated

DES; and 3) however, second-generation DES were

with second-generation DES compared with BMS or

associated with a significant reduction in the risk of

first-generation DES (second-generation DES vs.

stent thrombosis compared with first-generation DES

BMS: unadjusted HR: 0.62 [95% CI: 0.40 to 0.97],

and BMS (Central Illustration).

adjusted HR: 0.61 [95% CI: 0.42 to 0.89], second-

DP-EES OR BP-BES IN STEMI PATIENTS. Results

generation DES vs. first-generation DES: unadjusted

from study-level network meta-analyses in patients

HR: 0.55 [95% CI: 0.34 to 0.91], adjusted HR: 0.56

with coronary artery disease treated with percuta-

[95% CI: 0.36 to 0.88]). A similar risk of definite or

neous coronary intervention have raised concerns

probable stent thrombosis was observed between

regarding the safety of BP-DES when compared with

BMS and first-generation DES.

DP-EES. Bangalore et al. (11) reported that use of BP-

DISCUSSION

DES was associated with higher mortality after 1 year than DP-EES (rate ratio: 1.52; 95% credibility in-

The major findings of this network meta-analysis can

terval: 1.02 to 2.22). A subsequent network meta-

be summarized as follows: 1) for the primary

analysis by Palmerini et al. (12) reported a higher

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Stents in STEMI: Patient-Level Network Meta-Analysis

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

Bare-Metal Stents (n ¼ 3,409)

Age, yrs

Paclitaxel-Eluting Stents (n ¼ 3,173)

Sirolimus-Eluting Stents (n ¼ 2,044)

Zotarolimus-Eluting Stents (n ¼ 373)

Everolimus-Eluting Stents (n ¼ 1,405)

Biolimus-Eluting Stents (n ¼ 575)

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 Previous PCI Previous CABG Killip class

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)

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)

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)

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 Right coronary artery

3,389

3,155

2,031

373

1,405

575

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)

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)

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)

Left anterior descending artery

GP IIb/IIIa receptor inhibitors 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.

Chichareon et al.

JACC VOL. 74, NO. 21, 2019 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 BP-BES

Cardiac Death, Reinfarction, or Target Lesion Revascularization BP-BES

0.95 (0.65-1.38)

DP-EES

0.75 (0.42-1.34)

0.80 (0.47-1.35)

DP-ZES

1.03 (0.71-1.49)

1.09 (0.84-1.41)

1.36 (0.84-2.21)

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

0.64 (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

0.94 (0.63-1.40)

DP-EES

0.79 (0.44-1.41)

0.84 (0.49-1.42)

DP-ZES

1.01 (0.68-1.52)

1.08 (0.81-1.43)

1.29 (0.79-2.09)

DP-SES

0.88 (0.63-1.24)

0.94 (0.69-1.27)

1.12 (0.68-1.84)

0.87 (0.65-1.17)

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)

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

BMS

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

1.20 (0.86-1.66)

DP-EES

0.83 (0.45-1.55)

0.70 (0.39-1.26)

DP-ZES

1.06 (0.77-1.46)

0.89 (0.71-1.12)

1.27 (0.73-2.21)

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

0.75 (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)

1.12 (0.79-1.58)

BMS

DP-EES DP-ZES

0.86 (0.46-1.61)

0.77 (0.43-1.39)

0.99 (0.68-1.43)

0.88 (0.68-1.15)

1.15 (0.66-2.00)

DP-SES

0.98 (0.73-1.33)

0.88 (0.67-1.16)

1.15 (0.65-2.04)

1.00 (0.75-1.32)

0.76 (0.59-0.98)

0.68 (0.54-0.86) 0.89 (0.50-1.58) 0.77 (0.59-1.01)

All-Cause Death

DP-PES 0.77 (0.66-0.91)

BMS

All-Cause Death

BP-BES

BP-BES

1.34 (0.83-2.17)

DP-EES

0.79 (0.34-1.85)

0.59 (0.27-1.30)

DP-ZES

1.10 (0.67-1.81)

0.82 (0.57-1.18)

1.39 (0.66-2.92)

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

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

1.26 (0.76-2.09)

DP-EES

0.85 (0.36-2.03)

0.68 (0.30-1.52)

DP-ZES

1.07 (0.62-1.86)

0.85 (0.57-1.29)

1.26 (0.59-2.65)

DP-SES

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

0.97 (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)

Cardiac Death

BMS

Cardiac Death

BP-BES

BP-BES

1.09 (0.59-2.04)

DP-EES

0.96 (0.30-3.09)

0.87 (0.30-2.59)

DP-ZES

1.02 (0.53-1.95)

0.93 (0.60-1.44)

1.06 (0.38-3.00)

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

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

1.12 (0.58-2.15)

DP-EES

1.00 (0.30-3.26)

0.89 (0.30-2.67)

DP-ZES

1.02 (0.50-2.07)

0.91 (0.56-1.48)

1.02 (0.36-2.90)

DP-SES

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

0.90 (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)

Reinfarction

BMS

Reinfarction

BP-BES 0.76 (0.41-1.40)

DP-PES

BP-BES DP-EES

2.20 (0.46-10.46) 2.91 (0.62-13.60)

DP-ZES

0.65 (0.38-1.11)

0.86 (0.56-1.31)

0.29 (0.07-1.31)

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

0.68 (0.45-1.03)

0.90 (0.57-1.41)

0.31 (0.07-1.38)

1.10 (0.84-1.45)

DP-SES 1.05 (0.74-1.47)

BMS

0.63 (0.32-1.22)

DP-EES

2.13 (0.44-10.27)

3.40 (0.72-15.93)

DP-ZES

0.57 (0.31-1.08)

0.91 (0.58-1.44)

0.27 (0.06-1.20)

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

0.69 (0.46-1.05)

1.10 (0.66-1.84)

0.32 (0.07-1.48)

1.14 (0.86-1.51)

Target Lesion Revascularization

DP-SES 1.21 (0.76-1.92)

BMS

Target Lesion Revascularization

BP-BES

BP-BES

0.83 (0.46-1.50)

DP-EES

0.47 (0.22-1.02)

0.57 (0.27-1.19)

DP-ZES

1.07 (0.63-1.82)

1.30 (0.83-2.02)

2.28 (1.21-4.28)

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

0.45 (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)

0.87 (0.46-1.63)

BMS

DP-EES DP-ZES

0.56 (0.25-1.23)

0.64 (0.30-1.37)

1.33 (0.71-2.51)

1.54 (0.91-2.60)

2.40 (1.25-4.62)

DP-SES

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 (0.29-0.70)

0.52 (0.33-0.81)

0.81 (0.42-1.56)

0.34 (0.21-0.53)

0.58 (0.47-0.72)

Target Vessel Revascularization

BMS

Target Vessel Revascularization

BP-BES

BP-BES

1.07 (0.64-1.77)

DP-EES

0.67 (0.31-1.43)

0.63 (0.31-1.29)

DP-ZES

1.03 (0.65-1.64)

0.97 (0.67-1.41)

1.54 (0.81-2.91)

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)

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)

1.04 (0.61-1.77)

DP-PES BMS

DP-EES DP-ZES

0.75 (0.34-1.64)

0.72 (0.35-1.50)

1.13 (0.66-1.95)

1.09 (0.70-1.70)

1.51 (0.80-2.87)

0.86 (0.56-1.32)

0.83 (0.55-1.24)

1.15 (0.59-2.25)

0.76 (0.51-1.13)

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)

Definite or Probable Stent Thrombosis

DP-SES DP-PES BMS

Definite or Probable Stent Thrombosis

BP-BES

BP-BES

1.12 (0.54-2.34)

DP-EES

1.58 (0.40-6.24)

1.40 (0.37-5.35)

DP-ZES

0.64 (0.33-1.22)

0.57 (0.34-0.95)

0.40 (0.11-1.43)

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

0.67 (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)

1.24 (0.56-2.73)

BMS

DP-EES DP-ZES

1.67 (0.41-6.77)

1.34 (0.35-5.18)

0.63 (0.29-1.36)

0.50 (0.28-0.90) 0.38 (0.11-1.34)

DP-SES

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

0.69 (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.

2579

2580

Chichareon et al.

JACC VOL. 74, NO. 21, 2019 NOVEMBER 26, 2019:2572–84

Stents in STEMI: Patient-Level Network Meta-Analysis

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

Comparator vs. Reference

Unadjusted HR (95% CI) Comparator/Reference

Adjusted HR (95% CI) Comparator/Reference

Cardiac death, reinfarction or TLR

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

0.70 (0.61-0.80) 0.69 (0.57-0.82) 0.98 (0.80-1.20)

0.72 (0.62-0.83) 0.70 (0.58-0.84) 0.98 (0.79-1.21)

All-cause death, reinfarction or TVR

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

0.77 (0.68-0.88) 0.69 (0.59-0.80) 0.89 (0.74-1.06)

0.78 (0.68-0.90) 0.72 (0.61-0.84) 0.92 (0.75-1.12)

All-cause death

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

0.83 (0.68-1.03) 0.77 (0.62-0.97) 0.93 (0.70-1.23)

0.84 (0.67-1.06) 0.83 (0.65-1.06) 0.99 (0.73-1.35)

Cardiac death

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

0.83 (0.64-1.07) 0.81 (0.61-1.08) 0.99 (0.70-1.39)

0.84 (0.64-1.12) 0.82 (0.61-1.12) 0.98 (0.68-1.41)

Reinfarction

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

1.05 (0.84-1.32) 0.79 (0.58-1.06) 0.75 (0.54-1.03)

1.09 (0.85-1.41) 0.85 (0.62-1.15) 0.77 (0.55-1.09)

Target lesion revascularization

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

0.54 (0.45-0.64) 0.52 (0.39-0.69) 0.96 (0.70-1.33)

0.53 (0.44-0.65) 0.52 (0.39-0.71) 0.99 (0.70-1.39)

Target vessel revascularization

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

0.64 (0.54-0.75) 0.55 (0.43-0.71) 0.87 (0.66-1.15)

0.62 (0.52-0.75) 0.57 (0.44-0.74) 0.91 (0.68-1.23)

Definite or probable stent thrombosis

First generation DES vs. BMS Second generation DES vs. BMS Second vs. First generation DES

1.12 (0.83-1.50) 0.62 (0.40-0.97) 0.55 (0.34-0.91)

1.08 (0.77-1.52) 0.61 (0.42-0.89) 0.56 (0.36-0.88)

Outcomes

0.5

1.0

Favors Comparator

2.0

0.5

Favors Reference

Favors Comparator

1.0

2.0 Favors 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

STEMI (risk ratio: 1.06; 95% CI: 0.82 to 1.37;

polymer DES than DP-EES at 1 year (HR: 2.44; 95% CI:

p interaction ¼ 0.04) (20). In the present individual pa-

1.30 to 4.76) and long-term follow-up (HR: 1.92;

tient data network meta-analysis, STEMI patients

95% CI: 1.02 to 3.45). Although BP-DES has shown

treated with BP-BES and DP-EES showed a similar

comparable efficacy and safety to DP-EES at 10-year

long-term risk of adverse outcomes. Therefore, our

follow-up in the ISAR-TEST 4 (Intracoronary Stent-

analysis does not support the findings of safety con-

ing and Angiographic Results: Test Efficacy of 3

cerns of BP-DES compared with second-generation

Limus-Eluting Stents) study, these results should be

DES. However, the hypothesis that lipophilic bio-

interpreted with caution due to reduced power and

limus might result in greater effectiveness than

incomplete late ascertainment (19).

everolimus in STEMI was not confirmed.

In the 5-year report from the COMPARE II (Ablu-

COMPARISON

BETWEEN

AND

SECOND-GENERATION

Versus Durable Polymer Everolimus-Eluting Stent)

analysis showed no difference in efficacy and safety

trial, a subgroup analysis showed that STEMI patients

outcomes among specific types of DES in STEMI pa-

treated with BP-BES had a significantly higher risk of

tients. The majority of individual patient data stem-

TVR than patients treated with DP-EES (risk ratio:

med from patients treated with BMS, DP-SES, and DP-

2.97; 95% CI: 1.16 to 7.56), whereas the risk of TVR was

PES and the number of patients treated with BP-BES

similar

was substantially smaller than the other groups.

between

2

stents

in

patients

without

DES. Our

FIRST-

minal Biodegradable Polymer Biolimus-Eluting Stent

network

meta-

Chichareon et al.

JACC VOL. 74, NO. 21, 2019 NOVEMBER 26, 2019:2572–84

2581

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) Cardiac Death, Reinfarction, or TLR

BMS as a Reference

Comparator vs. Reference

Durable polymer paclitaxel-eluting stents

1st generation DES vs. BMS

Durable polymer sirolimus-eluting stents

2nd generation DES vs. BMS 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

Favors Drug-Eluting Stents (DES)

1.5

0.5

Favors Bare-Metal Stents (BMS)

Favors Comparator

1.0

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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 everolimuseluting 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

this study in that the risks of TLR and TVR were

generation to increase the power of the analysis. The

significantly lower in patients treated with first-

phosphorylcholine-based fast-release Endeavor ZES

generation DES than BMS. However, in the study by

in the present meta-analysis is substantially different

De Luca et al. (21), very late reinfarction and stent

from

BioLinx-polymer-based

thrombosis was increased in patients treated with

slow-release Resolute ZES; the findings from this

first-generation DES at long-term follow-up, whereas

the

new-generation

meta-analysis may not be extrapolated to the

our study showed a similar risk of definite or probable

currently available Resolute ZES. We classified the

stent thrombosis between first-generation DES and

Endeavor

ZES

as

a

first-generation

DES

from

BMS.

the chronological order of its commercial availability.

In the present study, even after statistical adjust-

However, the findings did not change when the DP-

ment for baseline characteristics, second-generation

ZES was regarded as a second-generation DES in

DES had better efficacy than BMS in terms of a

sensitivity analysis (Online Figure 8).

lower risk of revascularization. In addition, the

In an earlier, smaller, patient-level pooled meta-

second-generation was safer than the first-generation

analysis of STEMI patients by De Luca et al. (21),

DES due to the lower risk of definite or probable stent

treatment with first-generation DES was associated

thrombosis. This finding is in line with the long-term

with a lower risk of TVR than treatment with BMS at

follow-up results of the LEADERS trial (5). In contrast

long-term follow-up. Our findings are consistent with

to the previous study-level network meta-analysis

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JACC VOL. 74, NO. 21, 2019 NOVEMBER 26, 2019:2572–84

Stents in STEMI: Patient-Level Network Meta-Analysis

(22–24), no difference in myocardial infarction be-

even discouraged, so that the reinterventions were

tween second-generation DES and BMS was observed

performed and justified by spontaneous angina

in the present study.

complaint leading to an angiographic investigation

STRENGTHS OF THE INDIVIDUAL PATIENT DATA

possibly coupled with a noninvasive demonstration of

NETWORK META-ANALYSIS. To our knowledge, the

ischemia. However, in most of the included studies,

present study is the first individual patient data

the lack of blinding of treating physician to the study

network meta-analysis assessing the outcomes of

devices may have introduced a potential risk of bias to

coronary stents in more than 10,000 STEMI patients.

this component of the primary endpoint. Fourth, all

Our network meta-analysis allows the indirect com-

BMS included in this analysis were considered to be

parison between different treatments for which head-

comparable and regarded as a single stent type.

to-head comparative study was not available. Prior

Perhaps more importantly, BP-BES was used in only 1

evidence comparing stent outcomes in STEMI has

study comparing BP-BES with BMS in STEMI patients.

been based on individual randomized controlled tri-

Therefore, the BP-BES had limited sample size, and the

als (which have limited power) and aggregate data

comparison between BP-BES and other DES came from

meta-analyses, which also have well-known draw-

indirect evidence only. In addition, the platform of BP-

backs. Specifically, differences in patient character-

BES in our study was stainless steel and relatively

istics often results in heterogeneity between included

thick (120 m m). Due to the lack of evidence from ran-

studies. Second, the outcomes—in particular, the

domized controlled trials in STEMI, newer-generation

composite

between

DES (e.g., ultrathin DES, and so on) were not included.

studies, which may create bias and uncertainty on the

Fifth, most of the patients included in the randomized

treatment effect estimation. Third, the temporal

controlled trials in our meta-analysis received clopi-

relationship in outcomes is not easily examined, nor

dogrel. The impact that the more potent P2Y 12 in-

can subgroup outcomes be evaluated. Meta-analysis

hibitors ticagrelor and prasugrel might have on the

using individual patient data may overcome many

outcomes between the different stent types is uncer-

of these limitations, homogenize the data, and pro-

tain. Last, the U.S. guideline for the management of

duce reliable results (25).

STEMI restricts the use of DES to patients without high

ischemic

endpoints—varied

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

bleeding risk who can tolerate a prolonged dual antiplatelet 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 conclusion about the discrepancy between the 2 guidelines, and the appropriate stent in high bleeding risk patients with STEMI remains uncertain.

CONCLUSIONS

effect, instead of absolute estimation. Third, in 7 of the was

In this large-scale individual patient data network

requested and repeat interventions on the target

meta-analysis in STEMI patients, DES was superior to

lesion were adjudicated as clinically-indicated by in-

BMS with respect to long-term efficacy. No difference

dependent clinical event committees using criteria

in long-term efficacy and safety was observed be-

recommended by the U.S. regulatory body of the U.S.

tween specific types of DES. Second-generation DES

Food and Drug Administration following the report of

were better than first-generation DES in reducing

the RAVEL (Randomized Study with the Sirolimus-

stent thrombosis.

15

included

trials,

angiographic

follow-up

Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary

ADDRESS FOR CORRESPONDENCE: Prof. Patrick W.

Artery Lesions) trial (26). These recommendations

Serruys, P.O. Box 2125, 3000 CC, Rotterdam, the

were implemented to avoid reintervention relying on

Netherlands. E-mail: [email protected].

the so-called “occulostenotic reflex” (27) not sub-

OR Dr. Yoshinobu Onuma, ThoraxCenter, Erasmus

stantiated by symptoms, ischemia, and/or quantita-

Medical Center, P.O. Box 2125, 3000 CC, Rotterdam, the

tive angiography. In 8 of the 15 included trials,

Netherlands.

angiographic follow-up was not mandated and was

Twitter: @chichareon, @R_Modolo.

E-mail:

[email protected].

Chichareon et al.

JACC VOL. 74, NO. 21, 2019 NOVEMBER 26, 2019:2572–84

Stents in STEMI: Patient-Level Network Meta-Analysis

PERSPECTIVES COMPETENCY IN PATIENT CARE AND

TRANSLATIONAL OUTLOOK: Randomized trials

PROCEDURAL SKILLS: Network meta-analysis of data

should compare the safety and efficacy of newer DES

on stent thrombosis from individual patients with STEMI

models, such as those with ultrathin struts or drug

favors DES over BMS and second- over first-generation

coating stents, in patients with STEMI.

DES. The various types of second-generation DES are associated with comparable efficacy.

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A PPE NDI X For supplemental tables and figures, please see the online version of this paper.