Functional Assessment in Elderly MI Patients With Multivessel Disease (FIRE)

• ClinicalTrials.gov Identifier: NCT03772743
• Recruitment Status: Active, not recruiting
• First Posted: December 11, 2018
• Last Update Posted: March 31, 2023
• Sponsor: Consorzio Futuro in Ricerca
• Information provided by (Responsible Party): Consorzio Futuro in Ricerca

Study Description

Brief Summary:

Elderly patients presenting with myocardial infarction (MI) and multivessel disease are the highest risk population with the worst prognosis. No trial has ever been designed to optimize their outcome. The actual real-life standard of care is, in the best of the cases, culprit only revascularization. However, real-life registries show that outcome of MI elderly patients treated with this strategy is far from being optimal with at least a 15% rate of cardiac death or myocardial infarction at 1 year. To date, studies on this population have been focused on devices (bare metal stent vs biodegradable drug eluting stent) or on dual antiplatelet regimen (long vs short) and no study was focused on evaluating if complete revascularization is able to improve the prognosis in these patients. The contemporary complete revascularization is represented by a functionally-driven revascularization that recently showed to significantly reduce myocardial infarction rate and outperformed an angio-complete revascularization. Thus, our hypothesis is that a functionally-driven complete revascularization in elderly patients with MI and multivessel disease may improve prognosis compared to the actual standard of care in these patients, namely culprit only revascularization. Being a "strategy" trial, we identified the patient-oriented composite endpoint (POCE) as primary outcome of interest (all cause death, any MI, any stroke, any revascularization).

Several pre-specified substudies have been planned. A detailed list of the substudies is available in the website of the trial (http://www.thefiretrial.com)

Condition or disease	Intervention/treatment	Phase
Myocardial Infarction	Other: Culprit-only revascularization; Other: Complete functionally-guided revascularization	Not Applicable

Detailed Description:

BACKGROUND OF THE STUDY

Acute myocardial infarction (AMI) is the most frequent clinical presentation in older adults (≥75 years). Registry data shows that up to 65% of patients ≥75 years with AMI has multivessel disease, namely at least one lesion beyond the culprit one with diameter stenosis >50% and located in a coronary artery different from the culprit vessel. Presence of multivessel disease is a marker of worse prognosis. The rate of adverse events, such as death and MI is 3-fold higher in multivessel disease patients if compared to single vessel disease patients. During a 3-5 years follow-up, the number of adverse events related to non-culprit lesions is double than the one related to culprit lesions (data from SWEDEHEART registry and PROSPECT trial). These adverse events are even more frequent in older adults reaching a 15-30% incidence at 1 year. Several studies were focused on older adults with AMI in order to optimize their treatment. The main focus of those studies were: optimal dual antiplatelet therapy (DAPT) duration and type of stent. As for DAPT, data is in favour of a short regimen (1-6 months) as it represents the best balance between ischemic protection and reduction of bleeding events. In both LEADERS FREE and ZEUS trials, age was the main criteria for enrollment and it was considered as a marker of high risk of bleeding event. In the ongoing XIENCE 28 study, age ≥75 years is considered a sufficient criteria to prescribe 28 days of DAPT after stent implantation.

As for stent type, the recent SENIOR trial showed that biodegradable polymer second generation drug eluting stents (DES) are the gold standard in older adults receiving percutaneous coronary interventions (PCI). These stents clearly outperformed bare metal stents with a low event rate in presence of a short DAPT regimen. Thus, at the present time, we have sufficient data to consider biodegradable polymer DES and short DAPT as cornerstones of the treatment in older adults with MI. On the contrary, we have no scientific evidence regarding the best treatment strategy to apply in multivessel disease patients. It is not clear whether to prefer a culprit only strategy or if revascularization of non-culprit lesions is associated to a reduction of adverse events.

Culprit lesion treatment with PCI and stent implantation in MI setting is universally agreed as gold standard since it reduces morbidity and mortality. In the last 10 years, several studies were focused on the treatment of non-culprit lesions. PRAMI, CULPRIT, DANAMI 3 PRIMULTI, COMPARE ACUTE trial tried to assess if a systematic treatment of non-culprit lesions was associated with an improved prognosis if compared to a culprit only strategy. All these studies showed that complete revascularization clearly reduce the risk of repeated revascularizations. However, no study showed a significant impact on death or MI. When pooled in a meta-analysis, we can observe a trend in favour of MI reduction but data cannot be considered as conclusive. In 2019, COMPLETE trial results will be disclosed. In COMPLETE trial, more than 4000 patients were enrolled with consequent power to detect a difference in terms of death and MI. The limits of all the above mentioned studies are that the mean age was around 60 years and that only ST-segment elevated MI (STEMI) patients were included. No study included a relevant portion of patients ≥75 years nor included no-STEMI (NSTEMI) patients. However, a culprit lesion is identifiable in more than 90% of NSTEMI patients and the issue on their management is similar to the one of the STEMI patients. In addiction, in older adults, clinical presentation is as NSTEMI in more than 70% of the cases. Consequently, it is mandatory to generate solid data on the correct treatment strategy in these patients.

In younger adults (<65 years), in concordance with the solid scientific evidences, it is widespread a complete revascularization strategy. In older adults (≥75 years), also guidelines, in absence of clear data, suggest a case-by-case decision and suggest to consider age as one of the determinants of the final decision (Class IIa level of evidence C, ESC NSTEMI guidelines). Both European and American registry data shows clearly that the most frequently applied strategy is the culprit only one, both in STEMI and NSTEMI patients. Also in the LEADERS FREE trial, patients ≥75 years had multivessel disease in 65% of the cases, but in more than 80% of them, treatment was limited to the culprit lesion. In conclusion, the actual gold standard of treatment in older adults with MI and multivessel disease is the culprit-only strategy. The traditional concept of complete revascularization was based on angiography. Operator visually identified the lesions >50% and decided to treat or not each one of them. Contemporary data on fractional flow reserve and instantaneous free-wave ratio demonstrated that an angio-guided strategy is similar to a coin toss in terms of detection of lesions causing ischemia. This leads to unnecessary PCIs or avoided necessary PCIs in more than 50% of the cases. Studies on angio-complete revascularization probably failed to show an MI reduction because of this reason. In addition, long-term follow-up data of lesions functionally deferred shows that the rate of death and MI at 5 years is below 3%. As a consequence, functional revascularization should be considered as contemporary strategy to achieve a real complete revascularization.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1445 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: All comers, prospective, randomized, multicenter, open-label trial with blinded adjudicated evaluation of outcomes (PROBE).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Functional Versus Culprit-only Revascularization in Elderly Patients With Myocardial Infarction and Multivessel Disease
• Actual Study Start Date: July 15, 2019
• Actual Primary Completion Date: October 30, 2022
• Estimated Study Completion Date: October 3, 2026

Arms and Interventions

Arm	Intervention/treatment
Culprit-only revascularization; All patients randomized to culprit only revascularization must not undergo percutaneous coronary intervention (PCI) any lesion except from the culprit lesion already treated at the moment of the randomization. Staged procedures are considered protocol violation.	Other: Culprit-only revascularization; Implantation of drug eluting stents with biodegradable polymer with struts ≤65 μ in the culprit lesion of the MI. Each patient should receive revascularization with Supraflex stent or its newer versions
Complete functionally-guided revascularization; Patients who are randomized to this strategy will receive revascularization of the culprit lesion and guided by functional assessment on all non-culprit lesions. Functional evaluation is mandatory for all stenosis with diameter stenosis % between 50 and 90% at visual estimation. Revascularization must be guided by functional assessment on all vessels. The system utilized to obtain functional evaluation is left to Operator's discretion. PCI is allowed only if functional evaluation is positive according to the threshold of the chosen functional system. It is suggested to achieve functional complete revascularization within the index procedure, while it is mandatory to obtain it within the index hospitalization.	Other: Complete functionally-guided revascularization; Implantation of drug eluting stents with biodegradable polymer with struts ≤65 μ in the culprit lesion of the MI and in all non culprit lesions with positive functional assessment. Each patient should receive revascularization with Supraflex stent or its newer versions

Outcome Measures

Primary Outcome Measures :

1. Patient oriented cardiac events [ Time Frame: 1-year ]
   cumulative occurrence of all-cause death, any MI, any stroke, any revascularization

Secondary Outcome Measures :

1. Patient oriented cardiac events [ Time Frame: 3-year ]
   cumulative occurrence of all-cause death, any MI, any stroke, any revascularization
2. Patient oriented cardiac events [ Time Frame: 5-year ]
   cumulative occurrence of all-cause death, any MI, any stroke, any revascularization
3. Device oriented composite endpoint [ Time Frame: 1-year ]
   cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization
4. Device oriented composite endpoint [ Time Frame: 3-year ]
   cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization
5. Device oriented composite endpoint [ Time Frame: 5-year ]
   cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization
6. Cardiovascular Death or MI [ Time Frame: 1-year ]
   cumulative occurrence of Cardiovascular Death or MI
7. Cardiovascular Death or MI [ Time Frame: 3-year ]
   cumulative occurrence of Cardiovascular Death or MI
8. Cardiovascular Death or MI [ Time Frame: 5-year ]
   cumulative occurrence of Cardiovascular Death or MI
9. All-cause death or MI [ Time Frame: 1-year ]
   cumulative occurrence of All-cause Death or MI
10. All-cause death or MI [ Time Frame: 3-year ]
    cumulative occurrence of All-cause Death or MI
11. All-cause death or MI [ Time Frame: 5-year ]
    cumulative occurrence of All-cause Death or MI
12. All-cause death [ Time Frame: 1-year ]
    cumulative occurrence of All-cause Death
13. All-cause death [ Time Frame: 3-year ]
    cumulative occurrence of All-cause Death
14. All-cause death [ Time Frame: 5-year ]
    cumulative occurrence of All-cause Death
15. MI [ Time Frame: 1-year ]
    cumulative occurrence of MI
16. MI [ Time Frame: 3-year ]
    cumulative occurrence of MI
17. MI [ Time Frame: 5-year ]
    cumulative occurrence of MI
18. Any revascularization [ Time Frame: 1-year ]
    cumulative occurrence of revascularization
19. Any revascularization [ Time Frame: 3-year ]
    cumulative occurrence of revascularization
20. Any revascularization [ Time Frame: 5-year ]
    cumulative occurrence of revascularization
21. Ischemic Adverse Events in patients interrupting DAPT [ Time Frame: 1-year ]
    cumulative occurrence of CV death, MI, stroke and revascularization in patients interrupting DAPT
22. Ischemic Adverse Events in patients disrupting DAPT [ Time Frame: 1-year ]
    cumulative occurrence of CV death, MI, stroke and revascularization in patients disrupting DAPT
23. Contrast-Induced Acute Kidney Injury [ Time Frame: 1 month ]
    cumulative occurrence of Contrast-Induced Acute Kidney Injury

Other Outcome Measures:

1. Target Lesion Failure [ Time Frame: 1-year ]
   cumulative occurrence of Target Lesion Failure
2. Target Lesion Failure [ Time Frame: 3-year ]
   cumulative occurrence of Target Lesion Failure
3. Target Lesion Failure [ Time Frame: 5-year ]
   cumulative occurrence of Target Lesion Failure
4. Ischemia-driven Revascularization [ Time Frame: 1-year ]
   cumulative occurrence of ischemia-driven revascularization
5. Ischemia-driven Revascularization [ Time Frame: 3-year ]
   cumulative occurrence of ischemia-driven revascularization
6. Ischemia-driven Revascularization [ Time Frame: 5-year ]
   cumulative occurrence of ischemia-driven revascularization
7. EQ-5D scale [ Time Frame: 1-year ]
   quality of life as assessed by EQ-5D scale
8. EQ-5D scale [ Time Frame: 3-year ]
   quality of life as assessed by EQ-5D scale
9. EQ-5D scale [ Time Frame: 5-year ]
   quality of life as assessed by EQ-5D scale
10. Short Physical Performance Battery [ Time Frame: 1-year ]
    Physical Performance as assessed by Short Physical Performance Battery
11. Short Physical Performance Battery [ Time Frame: 3-year ]
    Physical Performance as assessed by Short Physical Performance Battery
12. Short Physical Performance Battery [ Time Frame: 5-year ]
    Physical Performance as assessed by Short Physical Performance Battery
13. Seattle Angina Questionnarie [ Time Frame: 1-year ]
    angina symptoms control as assessed by Seattle Angina Questionnarie
14. Seattle Angina Questionnarie [ Time Frame: 3-year ]
    angina symptoms control as assessed by Seattle Angina Questionnarie
15. Seattle Angina Questionnarie [ Time Frame: 5-year ]
    angina symptoms control as assessed by Seattle Angina Questionnarie

Eligibility Criteria

• Ages Eligible for Study: 75 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients ≥75 years AND
2. MI (ST-segment elevation or not ST.segment elevation MI) with indication to invasive management AND
3. Multi-vessel disease defined as at least 1 non-culprit coronary artery lesion at least 2.5 mm in diameter deemed at visual estimation with a diameter stenosis % ranging from 50 to 99% amenable to successful treatment with PCI AND
4. Successful treatment of culprit lesion

Exclusion Criteria:

1. Planned surgical revascularization
2. Non-cardiovascular co-morbidity reducing life expectancy to < 1 year
3. Any factor precluding 1-year follow-up
4. Prior Coronary Artery Bypass Graft (CABG) Surgery
5. Impossibility to identify a clear culprit lesion
6. Non culprit lesion located in the left main

Contacts and Locations

Locations

Italy

Maria Cecilia Hospital

Cotignola, Ravenna, Italy

ASP Agrigento

Agrigento, Italy

Ospedale Maggiore

Bologna, Italy

AOU Sant'Anna e San Sebastiano

Caserta, Italy

Casa di Cura San Michele Maddaloni

Caserta, Italy

AO Cannizzaro

Catania, Italy

AOU Ferrara

Ferrara, Italy, 44124

Ospedale della Misericordia

Grosseto, Italy

Ospedale Sant.Andrea

La Spezia, Italy

AOU Gaetano Martino

Messina, Italy

Ospedale dell'Angelo

Mestre, Italy

Ospedale Civile di Baggiovara

Modena, Italy

Ospedale Santa Croce

Moncalieri, Italy

AOU Giaccone

Palermo, Italy

Ospedale Santa Maria delle Croci

Ravenna, Italy

Arcispedale Santa Maria Nuova

Reggio Emilia, Italy

Ospedale Infermi

Rimini, Italy

AOU Sant'Andrea

Roma, Italy

Ospedale SS Annunziata

Savigliano, Italy

Ospedale Umberto I

Siracusa, Italy

Ospedale di Rivoli

Torino, Italy

AOU Integrata di Verona

Verona, Italy

Poland

Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii

Krosno, Poland

Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii

Nowy Sącz, Poland

Centrum Kardiologii Inwazyjnej Elektroterapii i Angiologii

Oświęcim, Poland

Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii

Pińczów, Poland

Podkarpackie Centrum Interwencji Sercowo-Naczyniowych

Sanok, Poland

Spain

Hospital General Universitario de Ciudad Real

Ciudad Real, Spain

Complejo Hospitalario de La Coruna

La Coruña, Spain

Hospital Universitario Lucus Augusti

Lugo, Spain

Hospital Clinico San Carlos

Madrid, Spain

Hospital General Universitario Gregorio Maranon

Madrid, Spain

Hospital Universitario La Paz

Madrid, Spain

Complejo Hospitalario Universitario de Santiago

Santiago De Compostela, Spain

Hospital Universitario La FE

Valencia, Spain

Hospital Clinico Universitario

Valladolid, Spain

Hospital Alvaro Conqueiro de Vigo

Vigo, Spain

Sponsors and Collaborators

Consorzio Futuro in Ricerca

More Information

Publications:

Biscaglia S, Guiducci V, Santarelli A, Amat Santos I, Fernandez-Aviles F, Lanzilotti V, Varbella F, Fileti L, Moreno R, Giannini F, Colaiori I, Menozzi M, Redondo A, Ruozzi M, Gutierrez Ibanes E, Diez Gil JL, Maietti E, Biondi Zoccai G, Escaned J, Tebaldi M, Barbato E, Dudek D, Colombo A, Campo G. Physiology-guided revascularization versus optimal medical therapy of nonculprit lesions in elderly patients with myocardial infarction: Rationale and design of the FIRE trial. Am Heart J. 2020 Nov;229:100-109. doi: 10.1016/j.ahj.2020.08.007. Epub 2020 Aug 18.

• Responsible Party: Consorzio Futuro in Ricerca
• ClinicalTrials.gov Identifier: NCT03772743
• Other Study ID Numbers: 56/2019/Sper/AOUFe
• First Posted: December 11, 2018
• Last Update Posted: March 31, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data will be available after motivated request to the Executive Committee of the study. All requests will be evaluated for acceptance. Positive evaluation by the Executive Committee is mandatory before data release
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: After the publication of the manuscripts reporting the primary outcome and the prespecified substudies
• Access Criteria: Data will be available after motivated request to the Executive Committee of the study. All requests will be evaluated for acceptance. Positive evaluation by the Executive Committee is mandatory before data release
• URL: http://thefiretrial.com

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Consorzio Futuro in Ricerca:

older adults; multivessel coronary disease; intracoronary physiology; functional assessment

Additional relevant MeSH terms:

Myocardial Infarction; Infarction; Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases