Ten-year Follow-up of the Clinical Evaluation of Everolimus-Eluting Coronary Stents in the Treatment of Patients With ST-segment Elevation Myocardial Infarction: EXAMINATION-EXTEND Trial
Conditions: Myocardial Infarction, ST Elevation Myocardial Infarction, Infarction, Necrosis, Heart Disease, Cardiovascular Diseases, Vascular Diseases
Sponsor: Hospital Clinic of Barcelona

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
1 
 
EXAMINATION EXTEND — HCB/2018/0906 
Complete study protocol version 1.0. September 12, 2018 
(NCT04462315) 
Study Design 
 
1. Title Research 
Very long-term clinical outcomes of Everolimus-Eluting Stent versus Bare-Metal Stent 
in ST-segment Elevation Myocardial Infarction. The EXAMINATION EXTEND trial. 
 
2. Investigator Names and sites 
EXAMINATION EXTEND principal investigators 
dr. Salvatore Brugaletta, MD, PhD, Hospital Clínic de Barcelona 
dr. Josep Gómez-Lara, MD, PhD, Hospital Universitari de Bellvitge 
dr. Luis Ortega-Paz, MD, PhD, Hospital Clínic de Barcelona 
Prof. Manel Sabaté, MD, PhD, Hospital Clínic de Barcelona 
 
3. Department & name head of the Department 
Interventional cardiology unit, Department of cardiology, Cardiovascular institute, 
Hospital Clinic of Barcelona, Barcelona Spain. Institut d'Investigacions Biomèdiques 
August Pi i Sunyer (IDIBAPS). Prof. Manel Sabaté. 
 
4. Research category 
The EXAMINATION trial was originally a multicenter, randomized, controlled, 
superiority clinical trial to the second-generation everolimus-eluting stent (EES) with 
the cobalt-chromium balloon-expandable bare-metal stent (BMS) in patients undergoing 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
2 
percutaneous coronary intervention (PCI) for ST-segment elevation myocardial 
infarction, up to 5- year follow-up. The EXAMINATION EXTEND is a retrospective, 
multicenter, international study to compare the 10-year follow-up clinical outcomes of 
primary PCI with EES versus BMS. The EXAMINATION EXTEND is an investigator-
driven study with limited funding; the Spanish Heart Foundation has committed 50.000 
Euro. 
 
5. Background 
Percutaneous coronary intervention (PCI) is the standard of treatment in ST-elevation 
myocardial infarction (STEMI) when performed in experienced Institutions within 
adequate time delay after the symptoms onset. 1 ST-segment elevation myocardial 
infarction (STEMI) represents the paradigm of a thrombotic milieu and a challenging 
clinical scenario to test new intracoronary devices. 2 In this clinical setting, first 
generation drug-eluting stents (DES) have demonstrated to reduce clinical and 
angiographic restenosis compared to BMS. 3-9 Conversely, these benefits were 
counterbalanced by an increased risk of very late stent thrombosis. 10-13 These safety 
concerns were confirmed by autopsy and intravascular imaging studies, showing 
evidence of incomplete endothelialization, delayed arterial healing, and vessel 
remodeling due to chronic inflammation in patients with very late stent thrombosis. 14-19 
Development of neotherosclerosis has been identified as an important player in the 
pathophysiology of the occurrence of very late events.  
Second generation everolimus-eluting stent (EES; Xience™ V; Abbott Vascular, Santa 
Clara, CA) has been designed with a thin (7.8 μm) non-adhesive, durable, 
biocompatible acrylic polymers and fluorinated copolymer. 20 As compared with first 
generation DES, the Xience™ V stent was able to reduce both the restenosis and the 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
3 
thrombosis rates in randomised controlled trials and meta-analyses. 21,22 The 
EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial 
INfArcTION) all-comers trial was designed to compare clinical outcomes between EES 
and BMS in STEMI patients. At 5-year follow-up it demonstrated clinical superiority of 
EES over a BMS in patients with STEMI requiring primary percutaneous coronary 
intervention. 23 
Currently available data on clinical outcome beyond 5 years are scant, especially in an 
important clinical scenario such as STEMI. It is therefore unknown if advantages of 
second-generation DES are maintained at very long-term follow-up, when incidence of 
neotherosclerosis is high and it may play an important role in the pathophysiology of 
the occurrence of very late events. 
We herein sought to compare 10-year clinical outcomes of EES vs. BMS in the 
EXAMINATION trial, focusing on differential effects between the first 5 years and 
subsequent years. 
 
6. Objectives 
The EXAMINATION EXTEND study aims to examine patient and device-oriented 
endpoints after ten years of follow-up in STEMI patients randomly assigned to EES or 
BMS in the EXAMINATION trial focusing on the differences between 5 and 10 years 
of follow-up. 
 
7. Methods 
The EXAMINATION TRIAL is a multicentre, multinational, prospective, randomised, 
two-arm, single-blind, controlled trial performed in patients with STEMI 
(clinicaltrials.gov number: NCT00828087). It has randomized 1.498 patients to receive 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
4 
either an EES (751 patients) or a BMS (747 patients). At 5 years, complete clinical 
follow-up was obtained in 97.3% in both arms. 
A total of 12 centers in 3 countries were involved in the trial. All these centers have 
been contacted to prolong follow-up up to 10 years. Nine Institutions agreed to 
participate in this project for a total of 1.450 patients expected at 10-year follow-up. 
An excel sheet was sent to all the centers to be fulfilled with 10-year follow-up of the 
patients included, collecting all-cause death, any myocardial infarction and any 
revascularization occurred between 5 and 10 years.  
The primary endpoint of the study is the patient-oriented combined endpoint of all-
cause death, any myocardial infarction or any revascularization at 10 year according to 
the Academic Research Consortium (ARC). 24 The secondary endpoint of the study is 
the device-oriented combined endpoint of cardiac death, target vessel myocardial 
infarction or target lesion revascularization at 10-year. 24 In addition, stent thrombosis 
(according to the ARC definitions24) will be collected.  
A clinical event committee, whose members are masked to the assigned stent, will 
independently adjudicate all deaths, potential myocardial infarctions, stent thrombosis, 
and revascularization procedures. We expect a 40% incidence of events for a total of 
400 events to be adjudicated. 
 
8. Inclusion and exclusion criteria 
There are no relevant inclusion and exclusion criteria for the current extended study 
since this pertains to a follow-up of patients already enrolled in the main 
EXAMINATION trial. 
 
 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
5 
9. Population 
The population was the patients enrolled in the EXAMINATION trial. The study had 
broad inclusion and few exclusion criteria. Any patient presenting with STEMI with the 
following electrocardiogram criteria: at least 1 mm in two or more standard leads or at 
least 2 mm in two or more contiguous precordial leads or left bundle-branch block that 
was not known to be old, within the first 48 h after the symptoms onset requiring 
emergent percutaneous coronary intervention with a vessel size ranging between 2·25 
mm and 4·0 mm without other anatomical restrictions could be included. Exclusion 
criteria were age younger than 18 years, pregnancy, patients with known intolerance to 
aspirin, clopidogrel, heparin, stainless steel, everolimus or contrast material, and 
patients on chronic treatment anti-vitamin K agents, and STEMI secondary to stent 
thrombosis. The patients were enrolled at 11 sites in 3 countries. 
 
10. Endpoints 
The prespecified primary endpoint of the EXAMINATION EXTEND study are the 
patient-oriented combined endpoint of all-cause death, any myocardial infarction, or 
any revascularization at 10 year according to the Academic Research Consortium 
(ARC) definition. 24 Secondary endpoints included the device-oriented combined 
endpoint of cardiac death, target vessel myocardial infarction (MI), or target lesion 
revascularization (TLR) 24; all-cause and cardiac death; target vessel revascularization 
(TVR); and, stent thrombosis (according to ARC definitions). 24 Detailed descriptions 
of the study endpoints and definitions have been reported previously. 25  
Vital status will be verified in all patients. Independent study monitors (ADKNOMA, 
Barcelona, Spain) will verify the adequacy of the extended follow-up in 50% of all the 
patients included, together with all the reported events on-site. All events will be 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
6 
adjudicated and classified by an independent event adjudication committee blinded to 
the treatment groups (Barcicore Lab, Barcelona, Spain). 
 
11. Data collection 
The EXAMINATION trial protocol was approved by the institutional review board of 
all 85 sites and is consistent with the International Conference on Harmonisation 
Guidance of Industry E6 Good Clinical Practice, the Declaration of Helsinki local 
regulations. Written consent was obtained from all participating patients when enrolled 
at baseline, for the duration of 5-years of follow-up. 
Data collection for the entire cohort of patients will be performed via principal 
investigators at participating centers. Each center will be contacted by email to gather 
long-term results for the patients at that particular center. Teleconference calls will be 
performed for the site training and clarify issues. 
The ethical committee will approve the protocol of the coordinating center (Ethics 
Committee for Drug Research, Hospital Clínic of Barcelona, Spain). After that, the 
study protocol approval by each site medical ethics committee approval will be 
requested. Once obtained, survival 
status and clinical outcomes will be retrospectively collected. Patient records at 
hospitals will be checked to assess survival status. If survival is unclear from the patient 
record, national death registries will be consulted to complete information on death and 
the specific date. In case a patient has died, the cause of death will be determined from 
medical records. 
 
 
 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
7 
12. Data base information 
An anonymous database of patients enrolled in the EXAMINATION trial is already 
available with baseline characteristics, procedural characteristics, and outcome data. All 
patients included in the database have been assigned a unique study number. Patient 
information of the patient assigned this study number is only available at individual 
sites. Local principal investigators will send anonymous data identifiable per unique 
study number to the study coordinator and principal investigator (dr. Salvatore 
Brugaletta). A central database will be stored at the Institut d'Investigacions 
Biomèdiques August Pi i Sunyer (IDIBAPS). In comparison to the already existing 
database, this database will be edited only by changing the duration of follow-up, date 
of death if this occurred, and the cause of death. 
 
13. Statistics 
A specific statistical plan analysis document will be provided. All analyses will be 
performed according to the intention-to-treat principle. Patients with missing follow-up 
data will be included in the analysis and censored at the time they are lost to follow-up 
or at 5-year if their recruiting hospital did not participate in the 10-year follow-up. We 
will analyze the primary endpoint of 10-year patient-oriented composite endpoint using 
Kaplan-Meier curves, with a log-rank p-value to test between-groups differences. We 
will use Cox proportional hazards models to estimate hazard ratios (HRs) with 95% 
confidence intervals (CI) comparing EES with BMS. We will do landmark analyses in 
the overall population, setting the landmark points at 1 and 5 years to distinguish the 
EXAMINATION trial results from the extended follow-up of the EXAMINATION 
EXTEND study. The same will be done for the device-oriented composite endpoint and 
the other secondary endpoints.  Subgroup analyses will include the following specified 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
8 
variables: gender, age>75, presence of diabetes, post-PCI TIMI <3, multivessel disease, 
ejection fraction <30%, Killip class >I, ST-segment resolution >70%, use of aspiration 
thrombectomy catheters, primary PCI (STEMI<12h), and left anterior descending as the 
infarct-related artery. 
 
14. Time Schedule 
 
 
15. Administrative aspects and publication 
Confidentiality and handling and storage of data and documents 
Data will be stored on the Hospital Clínic local network drive with automatic overnight 
back-up. Stored data regarding patients and personnel included in this study can only be 
accessed by the investigators and the Ethics Committee for Drug Research of the 
Hospital Clínic (including Hospital Clínic auditors and monitors, if necessary). The 
processing, communication, and transfer of personal data of all participants will comply 
with EU Regulation 2016/679 of the European Parliament and of the Council of 27 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
9 
April 2016 on the protection of individuals concerning the processing of personal data 
and the free movement of data, which must be complied with from 25 May 2018. If 
published in scientific journals or presented at scientific meetings, any information from 
this study will not reveal patient identity. Data will be stored for a maximum of 25 years 
after ending the study. Collected data will be secured against unauthorized access and 
stored and secured by the Hospital Clínic of Barcelona. 
 
 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
10 
16. Relevant articles 
1. 
Wijns W, Kolh P, Danchin N et al. Guidelines on myocardial revascularization: 
The Task Force on Myocardial Revascularization of the European Society of 
Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery 
(EACTS). Eur Heart J 2010;31:2501-55. 
2. 
Steg PG, Fox KA, Eagle KA et al. Mortality following placement of drug-
eluting and bare-metal stents for ST-segment elevation acute myocardial infarction in 
the Global Registry of Acute Coronary Events. Eur Heart J 2009;30:321-9. 
3. 
Kastrati A, Dibra A, Spaulding C et al. Meta-analysis of randomized trials on 
drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. 
European heart journal 2007;28:2706-13. 
4. 
Daemen J, Tanimoto S, Garcia-Garcia HM et al. Comparison of three-year 
clinical outcome of sirolimus- and paclitaxel-eluting stents versus bare metal stents in 
patients with ST-segment elevation myocardial infarction (from the RESEARCH and T-
SEARCH Registries). The American journal of cardiology 2007;99:1027-32. 
5. 
Spaulding C, Henry P, Teiger E et al. Sirolimus-eluting versus uncoated stents in 
acute myocardial infarction. N Engl J Med 2006;355:1093-104. 
6. 
Spaulding C, Teiger E, Commeau P et al. Four-year follow-up of TYPHOON 
(trial to assess the use of the CYPHer sirolimus-eluting coronary stent in acute 
myocardial infarction treated with BallOON angioplasty). JACC Cardiovasc 
Interv;4:14-23. 
7. 
Valgimigli M, Campo G, Arcozzi C et al. Two-year clinical follow-up after 
sirolimus-eluting versus bare-metal stent implantation assisted by systematic 
glycoprotein IIb/IIIa Inhibitor Infusion in patients with myocardial infarction: results 
from the STRATEGY study. Journal of the American College of Cardiology 
2007;50:138-45. 
8. 
Stone GW, Witzenbichler B, Guagliumi G et al. Heparin plus a glycoprotein 
IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus 
bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results 
from a multicentre, randomised controlled trial. Lancet 2011;377:2193-204. 
9. 
Stone GW, Witzenbichler B, Guagliumi G et al. Bivalirudin during primary PCI 
in acute myocardial infarction. N Engl J Med 2008;358:2218-30. 
10. 
Wenaweser P, Daemen J, Zwahlen M et al. Incidence and correlates of drug-
eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-
institutional cohort study. Journal of the American College of Cardiology 
2008;52:1134-40. 
11. 
Kastrati A, Mehilli J, Pache J et al. Analysis of 14 trials comparing sirolimus-
eluting stents with bare-metal stents. N Engl J Med 2007;356:1030-9. 
12. 
Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis 
of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 
2007;356:989-97. 
13. 
Stone GW, Moses JW, Ellis SG et al. Safety and efficacy of sirolimus- and 
paclitaxel-eluting coronary stents. The New England journal of medicine 2007;356:998-
1008. 
14. 
Nakazawa G, Finn AV, Joner M et al. Delayed arterial healing and increased late 
stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial 
infarction patients: an autopsy study. Circulation 2008;118:1138-45. 
15. 
Finn AV, Nakazawa G, Joner M et al. Vascular responses to drug eluting stents: 
importance of delayed healing. Arterioscler Thromb Vasc Biol 2007;27:1500-10. 

EXAMINATION EXTEND - HCB/2018/0906 (NCT04462315). Protocol version 1.0. September 12, 2018 
11 
16. 
Cook S, Ladich E, Nakazawa G et al. Correlation of intravascular ultrasound 
findings with histopathological analysis of thrombus aspirates in patients with very late 
drug-eluting stent thrombosis. Circulation 2009;120:391-9. 
17. 
Joner M, Finn AV, Farb A et al. Pathology of drug-eluting stents in humans: 
delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202. 
18. 
Wilson GJ, Nakazawa G, Schwartz RS et al. Comparison of inflammatory 
response after implantation of sirolimus- and paclitaxel-eluting stents in porcine 
coronary arteries. Circulation 2009;120:141-9, 1-2. 
19. 
Carter AJ, Aggarwal M, Kopia GA et al. Long-term effects of polymer-based, 
slow-release, sirolimus-eluting stents in a porcine coronary model. Cardiovasc Res 
2004;63:617-24. 
20. 
Sheiban I, Villata G, Bollati M, Sillano D, Lotrionte M, Biondi-Zoccai G. Next-
generation drug-eluting stents in coronary artery disease: focus on everolimus-eluting 
stent (Xience V). Vasc Health Risk Manag 2008;4:31-8. 
21. 
Serruys PW, Ruygrok P, Neuzner J et al. A randomised comparison of an 
everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent:the SPIRIT II 
trial. EuroIntervention 2006;2:286-94. 
22. 
Planer D, Smits PC, Kereiakes DJ et al. Comparison of everolimus- and 
paclitaxel-eluting stents in patients with acute and stable coronary syndromes: pooled 
results from the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting 
Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and 
Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) Trials. 
JACC Cardiovascular interventions 2011;4:1104-15. 
23. 
Sabate M, Brugaletta S, Cequier A et al. Clinical outcomes in patients with ST-
segment elevation myocardial infarction treated with everolimus-eluting stents versus 
bare-metal stents (EXAMINATION): 5-year results of a randomised trial. Lancet 
2016;387:357-366. 
24. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent 
trials: a case for standardized definitions. Circulation 2007; 115(17): 2344-51. 
25. Sabate M, Cequier A, Iniguez A, et al. Rationale and design of the EXAMINATION 
trial: a randomised comparison between everolimus-eluting stents and cobalt-chromium 
bare-metal stents in ST-elevation myocardial infarction. EuroIntervention : journal of 
EuroPCR in collaboration with the Working Group on Interventional Cardiology of the 
European Society of Cardiology 2011; 7(8): 977-84.