Clinical trial NCT03772743: Functional Assessment in Elderly MI Patients with Multivessel Disease
Official title: Functional Versus Culprit-only Revascularization in Elderly Patients with Myocardial Infarction and Multivessel Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Myocardial Infarction
Keywords: older adults
multivessel coronary disease
intracoronary physiology
functional assessment
Lead sponsor: Consorzio Futuro in Ricerca
Sponsor class: OTHER
First posted: 2018-12-11
Enrollment: 1445
Sex: ALL
Minimum age (years): 75
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All comers, prospective, randomized, multicenter, open-label trial with blinded adjudicated evaluation of outcomes (PROBE).
Primary purpose: TREATMENT

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)

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.

Eligibility 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

Primary outcomes:
measure: Patient oriented cardiac events
timeFrame: 1-year
Secondary outcomes:
measure: Patient oriented cardiac events
timeFrame: 3-year
measure: Patient oriented cardiac events
timeFrame: 5-year
measure: Device oriented composite endpoint
timeFrame: 1-year
measure: Device oriented composite endpoint
timeFrame: 3-year
measure: Device oriented composite endpoint
timeFrame: 5-year
measure: Cardiovascular Death or MI
timeFrame: 1-year
measure: Cardiovascular Death or MI
timeFrame: 3-year
measure: Cardiovascular Death or MI
timeFrame: 5-year
measure: All-cause death or MI
timeFrame: 1-year
measure: All-cause death or MI
timeFrame: 3-year
measure: All-cause death or MI
timeFrame: 5-year
measure: All-cause death
timeFrame: 1-year
measure: All-cause death
timeFrame: 3-year
measure: All-cause death
timeFrame: 5-year
measure: MI
timeFrame: 1-year
measure: MI
timeFrame: 3-year
measure: MI
timeFrame: 5-year
measure: Any revascularization
timeFrame: 1-year
measure: Any revascularization
timeFrame: 3-year
measure: Any revascularization
timeFrame: 5-year
measure: Ischemic Adverse Events in patients interrupting DAPT
timeFrame: 1-year
measure: Ischemic Adverse Events in patients disrupting DAPT
timeFrame: 1-year
measure: Contrast-Induced Acute Kidney Injury
timeFrame: 1 month
Other outcomes:
measure: Target Lesion Failure
timeFrame: 1-year
measure: Target Lesion Failure
timeFrame: 3-year
measure: Target Lesion Failure
timeFrame: 5-year
measure: Ischemia-driven Revascularization
timeFrame: 1-year
measure: Ischemia-driven Revascularization
timeFrame: 3-year
measure: Ischemia-driven Revascularization
timeFrame: 5-year
measure: EQ-5D scale
timeFrame: 1-year
measure: EQ-5D scale
timeFrame: 3-year
measure: EQ-5D scale
timeFrame: 5-year
measure: Short Physical Performance Battery
timeFrame: 1-year
measure: Short Physical Performance Battery
timeFrame: 3-year
measure: Short Physical Performance Battery
timeFrame: 5-year
measure: Seattle Angina Questionnarie
timeFrame: 1-year
measure: Seattle Angina Questionnarie
timeFrame: 3-year
measure: Seattle Angina Questionnarie
timeFrame: 5-year
Locations:
city: Cotignola
country: Italy
facility: Maria Cecilia Hospital
state: Ravenna
city: Agrigento
country: Italy
facility: ASP Agrigento
city: Bologna
country: Italy
facility: Ospedale Maggiore
city: Caserta
country: Italy
facility: AOU Sant'Anna e San Sebastiano
city: Caserta
country: Italy
facility: Casa di Cura San Michele Maddaloni
city: Catania
country: Italy
facility: AO Cannizzaro
city: Ferrara
country: Italy
facility: AOU Ferrara
city: Grosseto
country: Italy
facility: Ospedale della Misericordia
city: La Spezia
country: Italy
facility: Ospedale Sant.Andrea
city: Messina
country: Italy
facility: AOU Gaetano Martino
city: Mestre
country: Italy
facility: Ospedale dell'Angelo
city: Modena
country: Italy
facility: Ospedale Civile di Baggiovara
city: Moncalieri
country: Italy
facility: Ospedale Santa Croce
city: Palermo
country: Italy
facility: AOU Giaccone
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova
city: Rimini
country: Italy
facility: Ospedale Infermi
city: Roma
country: Italy
facility: AOU Sant'Andrea
city: Savigliano
country: Italy
facility: Ospedale SS Annunziata
city: Siracusa
country: Italy
facility: Ospedale Umberto I
city: Torino
country: Italy
facility: Ospedale di Rivoli
city: Verona
country: Italy
facility: AOU Integrata di Verona
city: Krosno
country: Poland
facility: Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii
city: Nowy Sącz
country: Poland
facility: Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii
city: Oświęcim
country: Poland
facility: Centrum Kardiologii Inwazyjnej Elektroterapii i Angiologii
city: Pińczów
country: Poland
facility: Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii
city: Sanok
country: Poland
facility: Podkarpackie Centrum Interwencji Sercowo-Naczyniowych
city: Ciudad Real
country: Spain
facility: Hospital General Universitario de Ciudad Real
city: La Coruña
country: Spain
facility: Complejo Hospitalario de La Coruna
city: Lugo
country: Spain
facility: Hospital Universitario Lucus Augusti
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Valencia
country: Spain
facility: Hospital Universitario La FE
city: Valladolid
country: Spain
facility: Hospital Clinico Universitario
city: Vigo
country: Spain
facility: Hospital Alvaro Conqueiro de Vigo
Study officials:
References:
citation: 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.