key: cord-0783751-nxax0vfp
authors: Biscaglia, Simone; Guiducci, Vincenzo; Santarelli, Andrea; Santos, Ignacio Amat; Fernandez-Aviles, Francisco; Lanzilotti, Valerio; Varbella, Ferdinando; Fileti, Luca; Moreno, Raul; Giannini, Francesco; Colaiori, Iginio; Menozzi, Mila; Redondo, Alfredo; Ruozzi, Marco; Ibañes, Enrique Gutiérrez; Gil, José Luis Díez; Maietti, Elisa; Zoccai, Giuseppe Biondi; Escaned, Javier; Tebaldi, Matteo; Barbato, Emanuele; Dudek, Dariusz; Colombo, Antonio; Campo, Gianluca
title: Physiology-guided revascularization versus optimal medical therapy of non-culprit lesions in elderly patients with myocardial infarction: Rationale and design of the FIRE trial()
date: 2020-08-18
journal: Am Heart J
DOI: 10.1016/j.ahj.2020.08.007
sha: 107837a44b8db037d5999edad80362f21d1a4155
doc_id: 783751
cord_uid: nxax0vfp

BACKGROUND: Myocardial infarction (MI) in elderly patients is associated with unfavorable prognosis, and it is becoming an increasingly prevalent condition. The prognosis of elderly patients is equally impaired in ST-segment elevation (STE) or non-STE (NSTE), and it is markedly worsened by the common presence of multivessel disease (MVD). Given the limited evidence available for elderly patients, it has not yet been established whether, as for younger patients, a complete revascularization strategy in MI patients with MVD should be advocated. We present the design of a dedicated study that will address this research gap. METHODS AND DESIGN: The FIRE trial is a prospective, randomized, international, multicenter, open-label study with blinded adjudicated evaluation of outcomes. Patients aged 75 years and older, with MI (either STE or NSTE), MVD at coronary artery angiography and a clear culprit lesion will be randomized to culprit-only treatment or to physiology-guided complete revascularization. The primary endpoint will be the patient-oriented composite endpoint (POCE) of all cause death, any MI, any stroke, any revascularization at one year. The key secondary endpoint will be the composite of cardiovascular death and MI. Quality of life and physical performance will be evaluated as well. All components of the primary and key secondary outcome will be tested also at 3 and 5 years. The sample size for the study is 1400 patients. IMPLICATIONS: The FIRE trial will provide evidence on whether a specific revascularization strategy should be applied to elderly patients presenting MI and MVD in order to improve their clinical outcomes.

As a result of shifting demographics and increased life expectancy, it is estimated that the number of elderly adults will increase by 44% from 2017 to 2030 1 . Since the prevalence of coronary artery disease (CAD) is linked to aging, healthcare systems and professionals will have to deal with an increasing number of old patients presenting with acute and chronic presentation of ischaemic heart disease. It is estimated that 15-20% of subjects over 75 years old develop MI 2 . The challenge of dealing with an increasing number of elderly patients with MI goes beyond a mere statistical increase. While cardiovascular (CV) death is slowly declining in the general population, it remains unchanged in elderly MI patients because they 2, 32, 3 are at higher risk of both ischemic and bleeding complications 2, 4-6 . Advanced age is associated with functional impairment and comorbidities, resulting in a more severe clinical presentation and complications due to invasive procedures and medical treatments and consequent worsening prognosis 2, [4] [5] [6] In addition, elderly patients with acute coronary syndrome (ACS) usually receive optimal medical therapy, but are more conservatively treated in terms of coronary artery angiography (CAA) and are the ones with the worst prognosis 7 .

Multivessel disease (MVD) is associated with a worse outcome in patients with CAD. Elderly patients undergoing CAA present MVD in 55% of the cases 2, 8 . In the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial, the mean number of diseased vessels increased with age and was related to a worsening prognosis 9 . By multivariable analysis, the presence of triple-vessel disease was the strongest predictor of 1-year death (HR=2.60, p=0.009), death and re-infarction (HR=1.88, p=0.03), and major adverse cardiac events (MACE) (HR=1.80, p=0.0009) 9 . Comparable results were found in the Western Denmark Heart Registry 10 High Risk of Bleeding) trial, MVD was reported in 62% of patients and it was the most important correlate for the 2-year ischemic endpoint (HR 1.66, 95% CI 1.27-2.18, p<0.001) 4 . However, only 22% of patients received a multivessel revascularization.

Reperfusion of the culprit lesion through primary PCI is the standard of care in STEMI patients, regardless of their age 11 . Registry data show that 51% of elderly STEMI patients present MVD and the majority of them (54%) receive culprit-only lesion treatment, while complete revascularization is achieved in only 31% of MVD patients 8 . The management of non-culprit lesions in STEMI patients with MVD has been the focus of several randomized clinical trials (RCT) comparing culprit-only vs. complete revascularization strategies [12] [13] [14] [15] [16] . The results of the largest RCT on the topic have been recently published 17 like in all the other RCTs evaluating the best treatment strategy for MVD ( Table 1 ). The rate of adverse events was extremely low, being CV death around 3% at a median follow-up of 3 years. In addition, a recent subanalysis of the DANAMI-PRIMULTI-3 trial questioned the "one size fits all" approach in terms of revascularization strategy in STEMI patients with MVD, showing that in patients ≥75 years randomized to culprit-only or FFR-guided complete revascularization, there were no significant differences in the incidence of the primary endpoint (9 (15%) versus 11 (22%); HR 1.49 (95% CI 0.57-4.65); log-rank p =0.19; p for interaction versus patients <75 years <0.001). 18 J o u r n a l P r e -p r o o f Besides, less than 30% of elderly ACS patients present ST-segment elevation at hospital admission 2 .

Non-ST segment-elevation myocardial infarction (NSTEMI) is considered a heterogeneous disease and, for this reason, it is more complex to approach in the design of RCTs. Consequently, all the studies focusing on a strategy to pursue in MVD in an ACS setting have been conducted only in a STEMI setting. However, NSTEMI is the most frequent clinical presentation in elderly patients 2, 3, 19-21 . The management of STEMI and NSTEMI patients in terms of interventional and pharmacological strategies is similar 22, 23 . In particular, being the pathophysiology in common, namely the disruption of a vulnerable atherosclerotic plaque or erosion of the coronary artery endothelium, the main goal is in both settings is to restore flow or avoid occlusion of the culprit vessel although with different time frames 22, 23 . In addition, mortality in elderly patients after NSTEMI seems to be higher than the one after STEMI 24 . Therefore, NSTEMI patients were included in a trial focused on identifying which revascularization strategy to pursue in elderly patients. In elderly NSTEMI patients, not only is the management of MVD unclear, but even the need for an invasive treatment is object of an ongoing RCT (NCT03052036). In the FAST-MI (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) registry, 76% of the patients not receiving CAA were aged ≥75 years 25 .

For what concerns the management of MVD, data are lacking. In the FAST-MI registry, 5-year allcause mortality in patients with NSTEMI medically managed and with MVD was 54.2% 25 27 . There is no randomized comparison between culprit-only and complete revascularization in NSTEMI with MVD, with hard clinical endpoint to date. A recent Scientific Statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society pointed out that additional studies are needed to define the risks and benefits of conservative versus invasive care in elderly patients with acute coronary syndrome (ACS) 28 .

In most RCTs investigating the benefit of complete revascularization, the decision to proceed or not with revascularization was angiography-guided. In the recent COMPLETE trial, the use of intracoronary physiology was negligible (<1%) 17 .

There are several reasons to utilize physiology in elderly MI patients. First, functional guided revascularization can have the same benefit of angio-guided revascularization in terms of MI reduction, and at the same time the number of treated vessels is significantly reduced 14, 15, 29, 30 . Second; the presence of residual "anatomic" CAD after functionally complete revascularization has no impact on prognosis 31 . Third, the occurrence of procedural complications, especially those impacting the prognosis such as peri-procedural MI and CI-AKI, is directly proportional both to age and number of treated vessels [32] [33] [34] [35] [36] [37] . Fourth, periprocedural complications are associated with a worse prognostic impact in elderly patients [32] [33] [34] [35] [36] [37] . Finally, the number of treated vessels is a major driver of prolonged dual antiplatelet therapy (DAPT) duration, which is associated with major bleeding and all-cause mortality in elderly patients 4, 6 .

Elderly patients with MI and MVD have the worst prognosis among CAD patients. No trial has ever been designed to optimize their strategy and consequently their outcome. The main presentation of elderly MI patients is as NSTEMI, and their current real-life standard of care is, at best, the culprit only revascularization. However, real-life registries show that their outcome is far from being optimal 24 . To date, studies on elderly patients have been focused on devices (bare metal vs. drugeluting stent) 4, 5, 38, 39 . In NSTEMI elderly patients, an ongoing trial is sought to understand what is better between a "selective" or a "routinely" invasive approach. However, when in elderly MI patients an invasive approach is selected and MVD is detected, there are no RCTs showing what is the best strategy to improve the prognosis. Our hypothesis is that functionally-guided complete revascularization in elderly patients with MI and multivessel disease, compared to the culprit only revascularization, may reduce the occurrence of the composite patient-oriented endpoint of all cause death, MI, stroke, and ischemia-driven revascularization.

The Functional versus Culprit-only Revascularization in Elderly Patients with Myocardial Infarction and Multivessel Disease (FIRE) trial is an all-comers, prospective, randomized, international, multicenter, open-label study with blinded adjudicated evaluation of outcomes (PROBE). The study flow chart is reported in Figure 1 . The Sponsor of the study is the Italian nonprofit organization Consorzio Futuro in Ricerca (www.ciefferre.it). Institutional review boards in all participating centers have approved the protocol. Patients will be included if they meet all the following inclusion criteria: i) age ≥ 75 years; ii) MI (STE or NSTE) with indication to invasive management; iii) MVD defined as clearly identifiable culprit lesion amenable for PCI and stenting and at least one lesion in a non-culprit coronary artery different from the culprit one, showing at least 2.5 mm in diameter deemed at visual estimation with a diameter stenosis % ranging from 50 to J o u r n a l P r e -p r o o f 99% in two perpendicular angiographic views and amenable to successful treatment with PCI; iv) successful treatment of culprit lesion. The main exclusion criteria are planned surgical revascularization; non-cardiovascular co-morbidity reducing life expectancy to < 1 year; any factor precluding 1-year follow-up; prior coronary artery bypass graft (CABG) surgery; left main as nonculprit lesion; inability to identify a clear culprit lesion (Figure 1 ). In the NSTEMI setting, culprit lesion identification should rely on ECG, echocardiography, and conventional angiography. In addition, invasive (intravascular ultrasoundnear-infrared spectroscopy and/or optical coherence tomography) and non-invasive imaging tools (cardiac magnetic resonance and/or speckle tracking) should be utilized to identify the culprit lesion when the conventional assessment is not conclusive (see Supplementary Materials).

All patients undergoing CAA because of MI must be screened for eligibility. Every month during the enrollment phase, the study team will check via a screening logthe number of elibigle patients not enrolledin order to eventually reduce the selection bias. Written informed consent must be obtained prior to randomization. The informed consent can be signed before CAA, but the patient's eligibility can be confirmed only after the evidence of MVD amenable for PCI and after the successful culprit lesion treatment. Culprit lesion PCI is defined as successful by the operator based on final flow (Thrombolysis In Myocardial Infarction flow 3), residual stenosis (<30%), and absence of clinical, angiographic or electrocardiographic signs of complications. It also has to be assessed with two perpendicular angiographic views. Patients with MI and MVD receiving only culprit lesion treatment in the index procedure can be considered eligible and then randomized within 48 hours after the end of the procedure. Key baseline patient characteristics (i.e., inclusion/exclusion criteria, demographics, medical history, details of cardiovascular anatomy, ECG and laboratory test results) will be recorded on the electronic Case Report Forms (eCRF, J o u r n a l P r e -p r o o f https://trials-ice.advicepharma.com/firetrial/). All CAA from the initial qualifying PCI as well as all functional assessments will be collected and forwarded to an angiographic core lab for central blinded assessment.

Randomization will be performed after CAA and culprit lesion treatment using an internet-based system. The patient identification number (Patient ID) and the treatment allocation will be assigned by the central randomization system. Treatment allocation will be assigned according to a computer-generated randomization list stratified by center. Randomization will also be stratified by sex and clinical presentation (STE-vs. NSTE-MI). All patients who are randomized are irrevocably included in the study, whether or not they are subsequently found to be eligible, or actually receiving the allocated treatment. Therefore, all patients must be followed until the pre-specified study end date.

Drug-eluting stents with biodegradable polymer with thin struts should be implanted 38 . In order to standardize the treatment, it is strongly suggested to utilize Supraflex Cruz (SMT Pvt Ltd, Surat, India). Supraflex Cruz is an ultra-thin (60 µm for all diameters and lengths) stent, with a biodegradable polymer eluting sirolimus. Supraflex has been demonstrated to be non-inferior to the actual best in class (Xience, Abbott) in terms of device-oriented endpoint (DOCE) with a very low rate of MI (2.5%) and definite or probable stent thrombosis (0.8%). Interestingly, in the perprotocol analysis, Supraflex showed a significant 61% reduction of clinical indicated TLR (3.1 vs.

1.2%, p=0.02) 40 Patients who are randomized to functionally-guided complete strategy will receive revascularization of the non-culprit lesions guided by functional assessment. Functional evaluation is mandatory for all stenosis with diameter stenosis % between 50% and 90% at visual estimation, while it is suggested but not mandatory for all stenosis between 91% and 99% 41 . The system utilized to obtain functional evaluation is left to the operator's discretion. FFR, instantaneous free-wave ratio (iFR), resting full-cycle ratio (RFR), diastolic hyperemia-free ratio (DFR), diastolic pressure ratio (DPR), contrast FFR (cFFR) and quantitative flow ratio (QFR) are all allowed. PCI is allowed only if functional evaluation is positive according to the threshold of the chosen functional system. PCI of vessel with negative functional evaluation is considered a protocol violation. Routine stress testing and repeat angiography are not indicated in patients whose symptoms are stable. It is suggested to achieve functional complete revascularization within the index procedure, while it is mandatory to obtain it within the index hospitalization.

All patients, regardless of their randomization group, will receive OMT. Unless there is an absolute contraindication, all patients will receive standard secondary prevention according to current guidelines 42 . In the presence of typical or atypical effort angina (or equivalent symptoms), betablockers, nitrates, ranolazine, and ivabradine should be titrated before suggesting a new CAA.

Patients at high bleeding risk (HBR) according to BARC criteria 43 should be treated with a short DAPT regimen (1 month) as per prespecified substudy (www.thefiretrial.com/news FIRE-HDR substudy).

After initial hospital discharge, routine clinic follow-up will occur at 1 month ± 14 days (telephone contact or clinic visit, according to the local practice), 1 year (clinic visit) and yearly clinic visits thereafter up to 5 years. At each visit, the general status, compliance with medical therapy, and J o u r n a l P r e -p r o o f adverse events will be assessed. Low-density lipoprotein, blood pressure and glycemic targets, angina status (SAQ), quality of life (EQ-5D), frailty (Rockwood Clinical Frailty Scale) and physical performance (SPBB) will be assessed at the 1-, 3-and 5-year visit.

Being a strategy trial, we identified the patient-oriented composite endpoint (POCE) as the primary outcome of interest (all-cause death, any MI, any stroke, any revascularization) 44 . The primary outcome will be assessed at 1 year. The key secondary outcome will be the composite of CV death and new-MI at 1 year ( Figure 2 ). MI will be defined according to the Fourth Universal Definition (see study protocol) 45 . All components of the primary outcome will be tested also at 3 and 5 years.

A committee consisting of clinicians who are blinded to treatment allocation (Clinical Event Committee) will review and adjudicate all adverse events based on source documents. Adjudication results will be binding for the final analysis. To minimize potential bias related to open-label design, only the revascularizations fully respecting the below reported criteria will be considered.

Revascularization will be considered ischemia-driven and, consequently, appropriate if it is performed in presence of: hospitalization for recurrent MI; hospitalization for hemodynamic instability or refractory ischemic heart failure (defined as Killip class ≥3); intractable angina (CCS Class 3 or 4 symptoms) despite OMT and positive functional assessment or objective, proven and documented evidence of ischemia in the territory of one or more vessels (e.g.: myocardial perfusion scintigraphy with ischemic territory greater than 10% of overall left ventricular mass). Other secondary outcomes will include: major bleedings according to Bleeding Academic Consortium (BARC) classification; EuroQol-5 Dimension (EQ-5D) quality of life; short physical performance battery (SPBB), and Seattle Angina Questionnaire (SAQ) Frequency scale at 1, 3 and 5 years.

All statistical analyses will be performed by the Clinic and Epidemiology Research Center of the University of Ferrara. The analysis will be performed on an Intention to Treat (ITT) set, defined as all intentionally randomized patients, by randomization treatment. Supportive per-protocol analyses will be performed on the primary and key secondary endpoints. A detailed statistical analysis plan will be completed before the end of the study and uploaded on the trial website. In brief, continuous variables will be tested for normal distribution with the Kolmogorov-Smirnov test and with a visual estimate of the Q-Q plot. Normally distributed variables will be presented as mean±SD and compared by t-test and 1-way ANOVA. Otherwise, median [interquartile range], Mann-Whitney U, and Kruskal-Wallis tests will be used. Categorical variables will be summarized in terms of absolute and relative frequencies (percentages) and compared by using the χ2 test. Two-sided tests will be carried out in order to check the superiority of functionally-driven complete revascularization. Statistical significance will be set at α=0.05 level. Formal type-I error control will be ensured for the primary and the key secondary endpoint by a sequential procedure where significance for the key secondary endpoint is accepted only if the primary endpoint is positive.

Kaplan-Meyer curves will be plotted to describe survival free from adverse events, and the difference between groups will be tested with the log-rank test. Cox regression models will test any confounding factor. Variables with a p-value <0.1 at univariate analysis will be entered into a multivariable analysis to identify the independent predictors. When appropriate, 95% CI will be calculated. In addition, we will assess the composite primary outcome POCE with the use of the Finkelstein-Schoenfeld method, which is based on the principle that each patient in the clinical trial is compared with every other patient in a pairwise manner. This method focuses primarily on allcause mortality. The pairwise comparison proceeds in hierarchical fashion, using all-cause mortality, followed by frequency of MI when patients cannot be differentiated based on mortality and so on for the other endpoints. We will apply the Finkelstein-Schoenfeld method to the patients stratified according to clinical presentation (STE vs NSTE) and the number of diseased vessels (2 J o u r n a l P r e -p r o o f vs 3), yielding four stratification pools. All analyses will be performed with STATA 13 (StataCorp, College Station, TX).

Data are lacking regarding death, MI, stroke and revascularization at 1 year in patients ≥75 years with MI and MVD treated with culprit only revascularization. Taking into account available (Table   1 ) and recently published data 46, 47 , we estimated a conservative 15% rate of the primary endpoint (POCE) at 1 year in the culprit-only strategy group. We hypothesize that the functional assessment should reduce the primary endpoint by at least 30% (Table 2) . Therefore, the sample size required to have an 80% chance to achieve this result is of 1358 patients, considering as significant the 5% level (computation by log-rank test). Taking into account a 2% attrition rate, the final sample size is inflated to 1385 patients. After at least 900 patients have completed the 30-day follow-up, the assumption of the sample size calculation will be checked by estimating the Kaplan-Meier 1-year risk of having reached the primary endpoint. Unadjudicated data will be used for this purpose. No randomization information will be available and all the evaluation on the sample size will be performed in a blinded fashion. If the pooled event rate will be significantly lower than expected, at 0.01 significance level, the sample size may be increased.

The FIRE trial program includes several prespecified substudies. The synopsis of all prespecified substudies will be uploaded on the website (www.thefiretrial.com) and will be freely downloadable.

It is important to mention the four substudies that have been generated to solve specific issues and to fill the evidence gaps. The first focuses on the occurrence of adverse events in patients with high dual risk (HDR) (ischemic and bleeding according to BARC-HBR classification 43 The fourth will be the cost-effectiveness analysis in the study population.

The FIRE trial is ongoing in sites in Italy, Spain, and Poland. Any additional site participating in the trial will be reported on the website in the dedicated area. The Executive Committee of the Study is 

The FIRE trial is an investigator-initiated study. The Sponsor received unrestricted grants for the trial conduction from SMT, Medis, and Siemens (see https://www.thefiretrial.com/supporters/ for updates). The authors are solely responsible for the design and conduct of this study, all study analyses and drafting and editing of the paper.

A central core lab located in the University of Ferrara will review, blinded to patient outcomes, all the angiographies from the enrolling centers, the evaluation of the culprit lesion, its successful treatment, the % diameter stenosis, and the functional evaluation of all the stenosis with the evaluation of the functional pitfalls. The core lab will also have the task of safeguarding the quality of the angiograms obtained at each participating center. Whenever relevant pitfalls in the functional evaluation are present in more than three cases in the same center, detailed retraining on functional J o u r n a l P r e -p r o o f evaluation will be performed. If the center will fail to perform a proper functional evaluation even after the functional retraining, any patient enrollment at the site will be stopped. The coordinator of the corelab (Professor Emanuele Barbato) and all the rest of the team are not directly involved in the enrollment of patients.

The study was registered on December 11, 2018 with the ClinicalTrials.gov Identifier 

The idea beyond the conduction of the FIRE trial is to ensure that patients and physicians have access to transparent and interactive interfaces to be able to check the study status and the news day-by-day. To this end, a website is available (www.thefiretrial.com) with dedicated sections for physicians and patients. The website has also educational purposes with a dedicated section (tips) with a PowerPoint presentation of several clinical topics related to the study. In addition, the FIRE trial is on twitter (@theFIRE_trial) in order to amplify the study and the investigators' visibility as well as to share clinical issues related to the topic of the study with colleagues around the world. Percutaneous Coronary Intervention (SAFE-STEMI for Seniors) trial will be focused on older STEMI patients with MVD and will randomize them to iFR-guided or culprit-only revascularization 48 . It will include around 500 patients aged 60 and over. The SENIOR-RITA randomizes patients aged 75 and over to invasive (CAA±PCI) versus conservative management (NCT03052036). The FIRE trial includes patients≥75 years with both STEMI and NSTEMI, utilizing a strategy able to reduce peri-procedural complications (functional-guided complete revascularization).

Altogether, findings from these studies will be helpful to improve the management of a growing subgroup of patients admitted to hospitals.

We are aware that the FIRE trial has some limitations. First, the focus is on the management of elderly patients with MI and MV disease. Consequently, the randomization occurs after CAA (within 48 hours after PCI of the culprit lesion) and the study results will only be applicable to patients who underwent invasive management, thus excluding those treated conservatively (either not receiving CAA or PCI). For the same reason, the presence of selection bias cannot be ruled out, although strategies aimed at its minimization have been utilized (e.g.: monthly screening log).

Second, complete revascularization has to be obtained within index hospitalization, while, after the J o u r n a l P r e -p r o o f recent publication of a COMPLETE subanalysis 49 , a broader time frame could have also been possible. However, when the FIRE trial was designed, the available evidence at the time suggested that achieving complete revascularization within the same procedure 12, 13, 50 or at least within index hospitalization 14 , could be the best strategy. Third, there are no randomized data on physiologyguided complete revascularization in NSTEMI, and this may have affected the sample size calculation. Fourth, the inclusion of STEMI and NSTEMI may complicate the interpretation of the results, even though randomization is stratified according to clinical presentation. Fifth, after the publication of the COMPLETE trial 17 , a primary endpoint including CV death and MI might have been more suitable. However, all published and ongoing studies regarding complete revascularization, including COMPLETE, had ischemia-driven revascularization in the primary endpoint. Sixth, the inclusion of patients with CTO is aimed at the inclusion of a real-life population, but it may add a potential confounder. Finally, randomization is performed only on the basis of age, while comorbidities and frailty should also be considered as important determinants of the overall patient's status 46 . J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

Viale Randi 5, Ravenna 48121, Italy 11. Instituto de Investigación Hospital La Paz (IDIPAZ)

GVM Care & Research, Via Corriera 1

Calle del Prof Martin Lagos s/n, Madrid 28040

Conceptualization, Funding acquisition, Methodology, Project Administration, Investigation, Supervision, Writing -Original Draft. Vincenzo Guiducci: Investigation, Writingreview & editing. Andrea Santarelli: Investigation, Writing -review & editing. Ignacio Amat Santos: Investigation, Writing -review & editing. Francisco Fernandez-Aviles: Investigation, Writing -review & editing. Valerio Lanzilotti: Investigation, Writing -review & editing

Ferdinando Varbella: Investigation, Writing -review & editing. Luca Fileti: Investigation, Writing -review & editing. Raul Moreno: Methodology, Investigation, Supervision, Project Administration, Writing -review & editing. Francesco Giannini: Investigation, Writing -review & editing. Iginio Colaiori: Investigation, Writing -review & editing. Mila Menozzi: Investigation, Writing -review & editing. Alfredo Redondo: Investigation, Writing -review & editing

Conceptualization, Methodology, Investigation, Supervision, Project Administration, Writingreview & editing. Marco Ruozzi: Investigation, Writing -review & editing. Enrique Gutiérrez Ibañes: Investigation, Writing -review & editing., José Luis Díez Gil: Investigation, Writingreview & editing. Elisa Maietti: Methodology, Supervision

Writing -review & editing. Emanuele Barbato: Conceptualization, Methodology, Supervision, Project Administration, Writing -review & editing. Dariusz Dudek: Conceptualization, Investigation, Supervision, Project Administration, Writing -review & editing

Writing -review & editing. Gianluca Campo: Conceptualization, Funding acquisition, Methodology, Project Administration, References

Association Between Aging of the US Population and Heart Disease Mortality From

Coronary Artery Disease in Patients >/=80 Years of Age

Population trends in the incidence and outcomes of acute myocardial infarction

2-Year Outcomes of High Bleeding Risk Patients After Polymer-Free Drug-Coated Stents

Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk

Mortality Following Cardiovascular and Bleeding Events Occurring Beyond 1 Year After Coronary Stenting: A Secondary Analysis of the Dual Antiplatelet Therapy (DAPT) Study

Combinations of bleeding and ischemic risk and their association with clinical outcomes in acute coronary syndrome

Multivessel disease in patients over 75years old with ST elevated myocardial infarction. Current management strategies and related clinical outcomes in the ESTROFA MI+75 nation-wide registry

Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction

Influence of multivessel disease with or without additional revascularization on mortality in patients with STsegment elevation myocardial infarction

ESC Guidelines for the management of acute myocardial infarction in patients presenting with STsegment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)

Randomized trial of preventive angioplasty in myocardial infarction

Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial

Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction

A randomised trial of target-vessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up

Complete Revascularization with Multivessel PCI for Myocardial Infarction

The benefit of complete revascularization after primary PCI for STEMI is attenuated by increasing age: Results from the DANAMI-3-PRIMULTI randomized study

Elderly patients with non-ST-elevation acute coronary syndromes: a call for action

Effect of an invasive strategy on in-hospital outcome in elderly patients with non-ST-elevation myocardial infarction

Age, clinical presentation, and outcome of acute coronary syndromes in the Euroheart acute coronary syndrome survey

Acute myocardial infarction

ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC)

Statistics on mortality following acute myocardial infarction in 842 897 Europeans

Editor's Choice-Medically managed patients with non-ST-elevation acute myocardial infarction have heterogeneous outcomes, based on performance of angiography and extent of coronary artery disease

Complete Versus Culprit-Only Lesion Intervention in Patients With Acute Coronary Syndromes

Multivessel versus Single Vessel Angioplasty in Non-ST Elevation Acute Coronary Syndromes: A Systematic Review and Metaanalysis

Knowledge Gaps in Cardiovascular Care of the Older Adult Population: A Scientific Statement From the American Heart Association

Five-Year Outcomes with PCI Guided by Fractional Flow Reserve

Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data

Prognostic Value of the Residual SYNTAX Score After Functionally Complete Revascularization in ACS

Comparison of In-Hospital Mortality, Length of Stay, Postprocedural Complications, and Cost of Single-Vessel Versus Multivessel Percutaneous Coronary Intervention in Hemodynamically Stable Patients With ST-Segment Elevation Myocardial Infarction (from Nationwide Inpatient Sample

Periprocedural myocardial infarction and injury in elective coronary stenting

Impact of Contrast-Induced Acute Kidney Injury After Percutaneous Coronary Intervention on Short-and Long-Term Outcomes: Pooled Analysis From the HORIZONS-AMI and ACUITY Trials

Contrast-Induced Acute Kidney Injury

Impact of large periprocedural myocardial infarction on mortality after percutaneous coronary intervention and coronary artery bypass grafting for left main disease: an analysis from the EXCEL trial

Multivessel vs culprit-only percutaneous coronary intervention among patients 65 years or older with acute myocardial infarction

Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial

Zotarolimuseluting versus bare-metal stents in uncertain drug-eluting stent candidates

Safety and efficacy of a sirolimus-eluting coronary stent with ultra-thin strut for treatment of atherosclerotic lesions (TALENT): a prospective multicentre randomised controlled trial

Fractional Flow Reserve-Guided Complete Revascularization Improves the Prognosis in Patients With ST-Segment-Elevation Myocardial Infarction and Severe Nonculprit Disease: A DANAMI 3-PRIMULTI Substudy (Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization)

ESC Guidelines for the diagnosis and management of chronic coronary syndromes

Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk

Standardized End Point Definitions for Coronary Intervention Trials: The Academic Research Consortium-2 Consensus Document

The assessment of scales of frailty and physical performance improves prediction of major adverse cardiac events in older adults with acute coronary syndrome

Prognostic impact of percutaneous coronary intervention in octogenarians with non-ST elevation myocardial infarction: A report from SWEDEHEART

Opportunities for enhancing the care of older patients with ST-elevation myocardial infarction presenting for primary percutaneous coronary intervention: Rationale and design of the SAFE-STEMI for Seniors trial

Timing of Staged Nonculprit Artery Revascularization in Patients With ST-Segment Elevation Myocardial Infarction: COMPLETE Trial

Single-Staged Compared With Multi-Staged PCI in Multivessel NSTEMI Patients: The SMILE Trial

Non-culprit lesions detected during primary PCI: treat invasively or follow the guidelines?

A Randomized Trial of Complete Versus Culprit-Only Revascularization During Primary Percutaneous Coronary Intervention in Diabetic Patients With Acute ST Elevation Myocardial Infarction and Multi Vessel Disease

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