Functional Assessment in Elderly MI Patients With Multivessel Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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Functional Versus Culprit-only Revascularization in Elderly Patients With Myocardial Infarction and Multivessel Disease

Conditions
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Myocardial Infarction

Intervention / Treatment
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* Other: Culprit-only revascularization
* Other: Complete functionally-guided revascularization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥75 years AND MI (ST-segment elevation or not ST.segment elevation MI) with indication to invasive management AND 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 Successful treatment of culprit lesion Exclusion Criteria: 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 Impossibility to identify a clear culprit lesion Non culprit lesion located in the left main

Ages Eligible for Study
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Minimum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All comers, prospective, randomized, multicenter, open-label trial with blinded adjudicated evaluation of outcomes (PROBE).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Culprit-only revascularization<br>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<br>* 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<br>|
| Other: Complete functionally-guided revascularization<br>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<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient oriented cardiac events | cumulative occurrence of all-cause death, any MI, any stroke, any revascularization | 1-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient oriented cardiac events | cumulative occurrence of all-cause death, any MI, any stroke, any revascularization | 3-year | 
| Patient oriented cardiac events | cumulative occurrence of all-cause death, any MI, any stroke, any revascularization | 5-year | 
| Device oriented composite endpoint | cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization | 1-year | 
| Device oriented composite endpoint | cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization | 3-year | 
| Device oriented composite endpoint | cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization | 5-year | 
| Cardiovascular Death or MI | cumulative occurrence of Cardiovascular Death or MI | 1-year | 
| Cardiovascular Death or MI | cumulative occurrence of Cardiovascular Death or MI | 3-year | 
| Cardiovascular Death or MI | cumulative occurrence of Cardiovascular Death or MI | 5-year | 
| All-cause death or MI | cumulative occurrence of All-cause Death or MI | 1-year | 
| All-cause death or MI | cumulative occurrence of All-cause Death or MI | 3-year | 
| All-cause death or MI | cumulative occurrence of All-cause Death or MI | 5-year | 
| All-cause death | cumulative occurrence of All-cause Death | 1-year | 
| All-cause death | cumulative occurrence of All-cause Death | 3-year | 
| All-cause death | cumulative occurrence of All-cause Death | 5-year | 
| MI | cumulative occurrence of MI | 1-year | 
| MI | cumulative occurrence of MI | 3-year | 
| MI | cumulative occurrence of MI | 5-year | 
| Any revascularization | cumulative occurrence of revascularization | 1-year | 
| Any revascularization | cumulative occurrence of revascularization | 3-year | 
| Any revascularization | cumulative occurrence of revascularization | 5-year | 
| Ischemic Adverse Events in patients interrupting DAPT | cumulative occurrence of CV death, MI, stroke and revascularization in patients interrupting DAPT | 1-year | 
| Ischemic Adverse Events in patients disrupting DAPT | cumulative occurrence of CV death, MI, stroke and revascularization in patients disrupting DAPT | 1-year | 
| Contrast-Induced Acute Kidney Injury | cumulative occurrence of Contrast-Induced Acute Kidney Injury | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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older adults, multivessel coronary disease, intracoronary physiology, functional assessment