<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03772743</url>
  </required_header>
  <id_info>
    <org_study_id>56/2019/Sper/AOUFe</org_study_id>
    <nct_id>NCT03772743</nct_id>
  </id_info>
  <brief_title>Functional Assessment in Elderly MI Patients With Multivessel Disease</brief_title>
  <acronym>FIRE</acronym>
  <official_title>Functional Versus Culprit-only Revascularization in Elderly Patients With Myocardial Infarction and Multivessel Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Consorzio Futuro in Ricerca</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Consorzio Futuro in Ricerca</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Elderly patients presenting with myocardial infarction (MI) and multivessel disease are the&#xD;
      highest risk population with the worst prognosis. No trial has ever been designed to optimize&#xD;
      their outcome. The actual real-life standard of care is, in the best of the cases, culprit&#xD;
      only revascularization. However, real-life registries show that outcome of MI elderly&#xD;
      patients treated with this strategy is far from being optimal with at least a 15% rate of&#xD;
      cardiac death or myocardial infarction at 1 year. To date, studies on this population have&#xD;
      been focused on devices (bare metal stent vs biodegradable drug eluting stent) or on dual&#xD;
      antiplatelet regimen (long vs short) and no study was focused on evaluating if complete&#xD;
      revascularization is able to improve the prognosis in these patients. The contemporary&#xD;
      complete revascularization is represented by a functionally-driven revascularization that&#xD;
      recently showed to significantly reduce myocardial infarction rate and outperformed an&#xD;
      angio-complete revascularization. Thus, our hypothesis is that a functionally-driven complete&#xD;
      revascularization in elderly patients with MI and multivessel disease may improve prognosis&#xD;
      compared to the actual standard of care in these patients, namely culprit only&#xD;
      revascularization. Being a &quot;strategy&quot; trial, we identified the patient-oriented composite&#xD;
      endpoint (POCE) as primary outcome of interest (all cause death, any MI, any stroke, any&#xD;
      revascularization).&#xD;
&#xD;
      Several pre-specified substudies have been planned. A detailed list of the substudies is&#xD;
      available in the website of the trial (http://www.thefiretrial.com)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND OF THE STUDY&#xD;
&#xD;
      Acute myocardial infarction (AMI) is the most frequent clinical presentation in older adults&#xD;
      (≥75 years). Registry data shows that up to 65% of patients ≥75 years with AMI has&#xD;
      multivessel disease, namely at least one lesion beyond the culprit one with diameter stenosis&#xD;
      &gt;50% and located in a coronary artery different from the culprit vessel. Presence of&#xD;
      multivessel disease is a marker of worse prognosis. The rate of adverse events, such as death&#xD;
      and MI is 3-fold higher in multivessel disease patients if compared to single vessel disease&#xD;
      patients. During a 3-5 years follow-up, the number of adverse events related to non-culprit&#xD;
      lesions is double than the one related to culprit lesions (data from SWEDEHEART registry and&#xD;
      PROSPECT trial). These adverse events are even more frequent in older adults reaching a&#xD;
      15-30% incidence at 1 year. Several studies were focused on older adults with AMI in order to&#xD;
      optimize their treatment. The main focus of those studies were: optimal dual antiplatelet&#xD;
      therapy (DAPT) duration and type of stent. As for DAPT, data is in favour of a short regimen&#xD;
      (1-6 months) as it represents the best balance between ischemic protection and reduction of&#xD;
      bleeding events. In both LEADERS FREE and ZEUS trials, age was the main criteria for&#xD;
      enrollment and it was considered as a marker of high risk of bleeding event. In the ongoing&#xD;
      XIENCE 28 study, age ≥75 years is considered a sufficient criteria to prescribe 28 days of&#xD;
      DAPT after stent implantation.&#xD;
&#xD;
      As for stent type, the recent SENIOR trial showed that biodegradable polymer second&#xD;
      generation drug eluting stents (DES) are the gold standard in older adults receiving&#xD;
      percutaneous coronary interventions (PCI). These stents clearly outperformed bare metal&#xD;
      stents with a low event rate in presence of a short DAPT regimen. Thus, at the present time,&#xD;
      we have sufficient data to consider biodegradable polymer DES and short DAPT as cornerstones&#xD;
      of the treatment in older adults with MI. On the contrary, we have no scientific evidence&#xD;
      regarding the best treatment strategy to apply in multivessel disease patients. It is not&#xD;
      clear whether to prefer a culprit only strategy or if revascularization of non-culprit&#xD;
      lesions is associated to a reduction of adverse events.&#xD;
&#xD;
      Culprit lesion treatment with PCI and stent implantation in MI setting is universally agreed&#xD;
      as gold standard since it reduces morbidity and mortality. In the last 10 years, several&#xD;
      studies were focused on the treatment of non-culprit lesions. PRAMI, CULPRIT, DANAMI 3&#xD;
      PRIMULTI, COMPARE ACUTE trial tried to assess if a systematic treatment of non-culprit&#xD;
      lesions was associated with an improved prognosis if compared to a culprit only strategy. All&#xD;
      these studies showed that complete revascularization clearly reduce the risk of repeated&#xD;
      revascularizations. However, no study showed a significant impact on death or MI. When pooled&#xD;
      in a meta-analysis, we can observe a trend in favour of MI reduction but data cannot be&#xD;
      considered as conclusive. In 2019, COMPLETE trial results will be disclosed. In COMPLETE&#xD;
      trial, more than 4000 patients were enrolled with consequent power to detect a difference in&#xD;
      terms of death and MI. The limits of all the above mentioned studies are that the mean age&#xD;
      was around 60 years and that only ST-segment elevated MI (STEMI) patients were included. No&#xD;
      study included a relevant portion of patients ≥75 years nor included no-STEMI (NSTEMI)&#xD;
      patients. However, a culprit lesion is identifiable in more than 90% of NSTEMI patients and&#xD;
      the issue on their management is similar to the one of the STEMI patients. In addiction, in&#xD;
      older adults, clinical presentation is as NSTEMI in more than 70% of the cases. Consequently,&#xD;
      it is mandatory to generate solid data on the correct treatment strategy in these patients.&#xD;
&#xD;
      In younger adults (&lt;65 years), in concordance with the solid scientific evidences, it is&#xD;
      widespread a complete revascularization strategy. In older adults (≥75 years), also&#xD;
      guidelines, in absence of clear data, suggest a case-by-case decision and suggest to consider&#xD;
      age as one of the determinants of the final decision (Class IIa level of evidence C, ESC&#xD;
      NSTEMI guidelines). Both European and American registry data shows clearly that the most&#xD;
      frequently applied strategy is the culprit only one, both in STEMI and NSTEMI patients. Also&#xD;
      in the LEADERS FREE trial, patients ≥75 years had multivessel disease in 65% of the cases,&#xD;
      but in more than 80% of them, treatment was limited to the culprit lesion. In conclusion, the&#xD;
      actual gold standard of treatment in older adults with MI and multivessel disease is the&#xD;
      culprit-only strategy. The traditional concept of complete revascularization was based on&#xD;
      angiography. Operator visually identified the lesions &gt;50% and decided to treat or not each&#xD;
      one of them. Contemporary data on fractional flow reserve and instantaneous free-wave ratio&#xD;
      demonstrated that an angio-guided strategy is similar to a coin toss in terms of detection of&#xD;
      lesions causing ischemia. This leads to unnecessary PCIs or avoided necessary PCIs in more&#xD;
      than 50% of the cases. Studies on angio-complete revascularization probably failed to show an&#xD;
      MI reduction because of this reason. In addition, long-term follow-up data of lesions&#xD;
      functionally deferred shows that the rate of death and MI at 5 years is below 3%. As a&#xD;
      consequence, functional revascularization should be considered as contemporary strategy to&#xD;
      achieve a real complete revascularization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 15, 2019</start_date>
  <completion_date type="Anticipated">October 3, 2026</completion_date>
  <primary_completion_date type="Actual">October 30, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>All comers, prospective, randomized, multicenter, open-label trial with blinded adjudicated evaluation of outcomes (PROBE).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Patient oriented cardiac events</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of all-cause death, any MI, any stroke, any revascularization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patient oriented cardiac events</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of all-cause death, any MI, any stroke, any revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient oriented cardiac events</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of all-cause death, any MI, any stroke, any revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Device oriented composite endpoint</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Device oriented composite endpoint</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Device oriented composite endpoint</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiovascular Death or MI</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of Cardiovascular Death or MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiovascular Death or MI</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of Cardiovascular Death or MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiovascular Death or MI</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of Cardiovascular Death or MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause death or MI</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of All-cause Death or MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause death or MI</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of All-cause Death or MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause death or MI</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of All-cause Death or MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause death</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of All-cause Death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause death</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of All-cause Death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause death</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of All-cause Death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MI</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MI</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MI</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Any revascularization</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Any revascularization</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Any revascularization</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of revascularization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ischemic Adverse Events in patients interrupting DAPT</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of CV death, MI, stroke and revascularization in patients interrupting DAPT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ischemic Adverse Events in patients disrupting DAPT</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of CV death, MI, stroke and revascularization in patients disrupting DAPT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Contrast-Induced Acute Kidney Injury</measure>
    <time_frame>1 month</time_frame>
    <description>cumulative occurrence of Contrast-Induced Acute Kidney Injury</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Target Lesion Failure</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of Target Lesion Failure</description>
  </other_outcome>
  <other_outcome>
    <measure>Target Lesion Failure</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of Target Lesion Failure</description>
  </other_outcome>
  <other_outcome>
    <measure>Target Lesion Failure</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of Target Lesion Failure</description>
  </other_outcome>
  <other_outcome>
    <measure>Ischemia-driven Revascularization</measure>
    <time_frame>1-year</time_frame>
    <description>cumulative occurrence of ischemia-driven revascularization</description>
  </other_outcome>
  <other_outcome>
    <measure>Ischemia-driven Revascularization</measure>
    <time_frame>3-year</time_frame>
    <description>cumulative occurrence of ischemia-driven revascularization</description>
  </other_outcome>
  <other_outcome>
    <measure>Ischemia-driven Revascularization</measure>
    <time_frame>5-year</time_frame>
    <description>cumulative occurrence of ischemia-driven revascularization</description>
  </other_outcome>
  <other_outcome>
    <measure>EQ-5D scale</measure>
    <time_frame>1-year</time_frame>
    <description>quality of life as assessed by EQ-5D scale</description>
  </other_outcome>
  <other_outcome>
    <measure>EQ-5D scale</measure>
    <time_frame>3-year</time_frame>
    <description>quality of life as assessed by EQ-5D scale</description>
  </other_outcome>
  <other_outcome>
    <measure>EQ-5D scale</measure>
    <time_frame>5-year</time_frame>
    <description>quality of life as assessed by EQ-5D scale</description>
  </other_outcome>
  <other_outcome>
    <measure>Short Physical Performance Battery</measure>
    <time_frame>1-year</time_frame>
    <description>Physical Performance as assessed by Short Physical Performance Battery</description>
  </other_outcome>
  <other_outcome>
    <measure>Short Physical Performance Battery</measure>
    <time_frame>3-year</time_frame>
    <description>Physical Performance as assessed by Short Physical Performance Battery</description>
  </other_outcome>
  <other_outcome>
    <measure>Short Physical Performance Battery</measure>
    <time_frame>5-year</time_frame>
    <description>Physical Performance as assessed by Short Physical Performance Battery</description>
  </other_outcome>
  <other_outcome>
    <measure>Seattle Angina Questionnarie</measure>
    <time_frame>1-year</time_frame>
    <description>angina symptoms control as assessed by Seattle Angina Questionnarie</description>
  </other_outcome>
  <other_outcome>
    <measure>Seattle Angina Questionnarie</measure>
    <time_frame>3-year</time_frame>
    <description>angina symptoms control as assessed by Seattle Angina Questionnarie</description>
  </other_outcome>
  <other_outcome>
    <measure>Seattle Angina Questionnarie</measure>
    <time_frame>5-year</time_frame>
    <description>angina symptoms control as assessed by Seattle Angina Questionnarie</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1445</enrollment>
  <condition>Myocardial Infarction</condition>
  <arm_group>
    <arm_group_label>Culprit-only revascularization</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Complete functionally-guided revascularization</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Culprit-only revascularization</intervention_name>
    <description>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</description>
    <arm_group_label>Culprit-only revascularization</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Complete functionally-guided revascularization</intervention_name>
    <description>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</description>
    <arm_group_label>Complete functionally-guided revascularization</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients ≥75 years AND&#xD;
&#xD;
          2. MI (ST-segment elevation or not ST.segment elevation MI) with indication to invasive&#xD;
             management AND&#xD;
&#xD;
          3. Multi-vessel disease defined as at least 1 non-culprit coronary artery lesion at least&#xD;
             2.5 mm in diameter deemed at visual estimation with a diameter stenosis % ranging from&#xD;
             50 to 99% amenable to successful treatment with PCI AND&#xD;
&#xD;
          4. Successful treatment of culprit lesion&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Planned surgical revascularization&#xD;
&#xD;
          2. Non-cardiovascular co-morbidity reducing life expectancy to &lt; 1 year&#xD;
&#xD;
          3. Any factor precluding 1-year follow-up&#xD;
&#xD;
          4. Prior Coronary Artery Bypass Graft (CABG) Surgery&#xD;
&#xD;
          5. Impossibility to identify a clear culprit lesion&#xD;
&#xD;
          6. Non culprit lesion located in the left main&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>75 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Maria Cecilia Hospital</name>
      <address>
        <city>Cotignola</city>
        <state>Ravenna</state>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASP Agrigento</name>
      <address>
        <city>Agrigento</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Maggiore</name>
      <address>
        <city>Bologna</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Sant'Anna e San Sebastiano</name>
      <address>
        <city>Caserta</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Casa di Cura San Michele Maddaloni</name>
      <address>
        <city>Caserta</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AO Cannizzaro</name>
      <address>
        <city>Catania</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Ferrara</name>
      <address>
        <city>Ferrara</city>
        <zip>44124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale della Misericordia</name>
      <address>
        <city>Grosseto</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Sant.Andrea</name>
      <address>
        <city>La Spezia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Gaetano Martino</name>
      <address>
        <city>Messina</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale dell'Angelo</name>
      <address>
        <city>Mestre</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Civile di Baggiovara</name>
      <address>
        <city>Modena</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Santa Croce</name>
      <address>
        <city>Moncalieri</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Giaccone</name>
      <address>
        <city>Palermo</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Santa Maria delle Croci</name>
      <address>
        <city>Ravenna</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Arcispedale Santa Maria Nuova</name>
      <address>
        <city>Reggio Emilia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Infermi</name>
      <address>
        <city>Rimini</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Sant'Andrea</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale SS Annunziata</name>
      <address>
        <city>Savigliano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Umberto I</name>
      <address>
        <city>Siracusa</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale di Rivoli</name>
      <address>
        <city>Torino</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Integrata di Verona</name>
      <address>
        <city>Verona</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii</name>
      <address>
        <city>Krosno</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii</name>
      <address>
        <city>Nowy Sącz</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Kardiologii Inwazyjnej Elektroterapii i Angiologii</name>
      <address>
        <city>Oświęcim</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii</name>
      <address>
        <city>Pińczów</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Podkarpackie Centrum Interwencji Sercowo-Naczyniowych</name>
      <address>
        <city>Sanok</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital General Universitario de Ciudad Real</name>
      <address>
        <city>Ciudad Real</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario de La Coruna</name>
      <address>
        <city>La Coruña</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Lucus Augusti</name>
      <address>
        <city>Lugo</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinico San Carlos</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital General Universitario Gregorio Maranon</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La Paz</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario Universitario de Santiago</name>
      <address>
        <city>Santiago De Compostela</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La FE</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinico Universitario</name>
      <address>
        <city>Valladolid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Alvaro Conqueiro de Vigo</name>
      <address>
        <city>Vigo</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
    <country>Poland</country>
    <country>Spain</country>
  </location_countries>
  <reference>
    <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.</citation>
    <PMID>32822656</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>December 9, 2018</study_first_submitted>
  <study_first_submitted_qc>December 9, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>March 29, 2023</last_update_submitted>
  <last_update_submitted_qc>March 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>older adults</keyword>
  <keyword>multivessel coronary disease</keyword>
  <keyword>intracoronary physiology</keyword>
  <keyword>functional assessment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myocardial Infarction</mesh_term>
    <mesh_term>Infarction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_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</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>After the publication of the manuscripts reporting the primary outcome and the prespecified substudies</ipd_time_frame>
    <ipd_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</ipd_access_criteria>
    <ipd_url>http://thefiretrial.com</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03772743
org study id: 56/2019/Sper/AOUFe
nct id: NCT03772743
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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)
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: All comers, prospective, randomized, multicenter, open-label trial with blinded adjudicated evaluation of outcomes (PROBE).
primary purpose: Treatment
masking: None (Open Label)
measure: Patient oriented cardiac events
time frame: 1-year
description: cumulative occurrence of all-cause death, any MI, any stroke, any revascularization
measure: Patient oriented cardiac events
time frame: 3-year
description: cumulative occurrence of all-cause death, any MI, any stroke, any revascularization
measure: Patient oriented cardiac events
time frame: 5-year
description: cumulative occurrence of all-cause death, any MI, any stroke, any revascularization
measure: Device oriented composite endpoint
time frame: 1-year
description: cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization
measure: Device oriented composite endpoint
time frame: 3-year
description: cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization
measure: Device oriented composite endpoint
time frame: 5-year
description: cumulative occurrence of Cardiovascular Death, MI or non-culprit target vessel revascularization
measure: Cardiovascular Death or MI
time frame: 1-year
description: cumulative occurrence of Cardiovascular Death or MI
measure: Cardiovascular Death or MI
time frame: 3-year
description: cumulative occurrence of Cardiovascular Death or MI
measure: Cardiovascular Death or MI
time frame: 5-year
description: cumulative occurrence of Cardiovascular Death or MI
measure: All-cause death or MI
time frame: 1-year
description: cumulative occurrence of All-cause Death or MI
measure: All-cause death or MI
time frame: 3-year
description: cumulative occurrence of All-cause Death or MI
measure: All-cause death or MI
time frame: 5-year
description: cumulative occurrence of All-cause Death or MI
measure: All-cause death
time frame: 1-year
description: cumulative occurrence of All-cause Death
measure: All-cause death
time frame: 3-year
description: cumulative occurrence of All-cause Death
measure: All-cause death
time frame: 5-year
description: cumulative occurrence of All-cause Death
measure: MI
time frame: 1-year
description: cumulative occurrence of MI
measure: MI
time frame: 3-year
description: cumulative occurrence of MI
measure: MI
time frame: 5-year
description: cumulative occurrence of MI
measure: Any revascularization
time frame: 1-year
description: cumulative occurrence of revascularization
measure: Any revascularization
time frame: 3-year
description: cumulative occurrence of revascularization
measure: Any revascularization
time frame: 5-year
description: cumulative occurrence of revascularization
measure: Ischemic Adverse Events in patients interrupting DAPT
time frame: 1-year
description: cumulative occurrence of CV death, MI, stroke and revascularization in patients interrupting DAPT
measure: Ischemic Adverse Events in patients disrupting DAPT
time frame: 1-year
description: cumulative occurrence of CV death, MI, stroke and revascularization in patients disrupting DAPT
measure: Contrast-Induced Acute Kidney Injury
time frame: 1 month
description: cumulative occurrence of Contrast-Induced Acute Kidney Injury
measure: Target Lesion Failure
time frame: 1-year
description: cumulative occurrence of Target Lesion Failure
measure: Target Lesion Failure
time frame: 3-year
description: cumulative occurrence of Target Lesion Failure
measure: Target Lesion Failure
time frame: 5-year
description: cumulative occurrence of Target Lesion Failure
measure: Ischemia-driven Revascularization
time frame: 1-year
description: cumulative occurrence of ischemia-driven revascularization
measure: Ischemia-driven Revascularization
time frame: 3-year
description: cumulative occurrence of ischemia-driven revascularization
measure: Ischemia-driven Revascularization
time frame: 5-year
description: cumulative occurrence of ischemia-driven revascularization
measure: EQ-5D scale
time frame: 1-year
description: quality of life as assessed by EQ-5D scale
measure: EQ-5D scale
time frame: 3-year
description: quality of life as assessed by EQ-5D scale
measure: EQ-5D scale
time frame: 5-year
description: quality of life as assessed by EQ-5D scale
measure: Short Physical Performance Battery
time frame: 1-year
description: Physical Performance as assessed by Short Physical Performance Battery
measure: Short Physical Performance Battery
time frame: 3-year
description: Physical Performance as assessed by Short Physical Performance Battery
measure: Short Physical Performance Battery
time frame: 5-year
description: Physical Performance as assessed by Short Physical Performance Battery
measure: Seattle Angina Questionnarie
time frame: 1-year
description: angina symptoms control as assessed by Seattle Angina Questionnarie
measure: Seattle Angina Questionnarie
time frame: 3-year
description: angina symptoms control as assessed by Seattle Angina Questionnarie
measure: Seattle Angina Questionnarie
time frame: 5-year
description: angina symptoms control as assessed by Seattle Angina Questionnarie
arm group label: Culprit-only revascularization
arm group type: Other
description: 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.
arm group label: Complete functionally-guided revascularization
arm group type: Other
description: 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.
intervention type: Other
intervention name: Culprit-only revascularization
description: 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
arm group label: Culprit-only revascularization
intervention type: Other
intervention name: Complete functionally-guided revascularization
description: 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
arm group label: Complete functionally-guided revascularization
criteria: 
gender: All
minimum age: 75 Years
maximum age: N/A
healthy volunteers: No
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country: Italy
country: Poland
country: Spain
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.
PMID: 32822656
responsible party type: Sponsor
mesh term: Myocardial Infarction
mesh term: Infarction
sharing ipd: Yes
ipd 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
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: After the publication of the manuscripts reporting the primary outcome and the prespecified substudies
ipd 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
ipd url: http://thefiretrial.com