<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/NCT04430400</url>
  </required_header>
  <id_info>
    <org_study_id>11005</org_study_id>
    <nct_id>NCT04430400</nct_id>
  </id_info>
  <brief_title>Integrated Diagnostic Algorithm for Acute Aortic Syndromes</brief_title>
  <acronym>PROFUNDUS</acronym>
  <official_title>Integration of Pre-test PRObability, Focused Cardiac UltrasouNd and D-dimer for Diagnosis of acUte Aortic Syndromes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliero-Universitaria Careggi</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Ospedaliero-Universitaria Careggi</source>
  <oversight_info>
    <has_dmc>No</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>
      Observational, prospective, multicentre, international, non-profit, investigator-driven,&#xD;
      outcome and diagnostic accuracy study performed in Emergency Departments. The study will&#xD;
      evaluate the performance of diagnostic algorithms integrating pre-test probability assessment&#xD;
      with a risk score, focus cardiac ultrasound and D-dimer, to rule-in/out acute aortic&#xD;
      syndromes. For each patient, the outcome will be established after review of hospital and&#xD;
      30-day follow-up data.&#xD;
&#xD;
      In participating centers, an acute aortic syndrome will be considered to be ruled out without&#xD;
      advanced imaging by a D-dimer level lower than 500 ng per milliliter, in patients with a low&#xD;
      clinical pre-test probability assessed using the aortic dissection detection (ADD) risk&#xD;
      score. Using outcome data, the study will primarily assess the accuracy and efficiency of&#xD;
      this diagnostic rule-out protocol (prospective management study). The study will also&#xD;
      evaluate the performance of alternative rule out strategies based on a different clinical&#xD;
      score and on a D-dimer cutoff adjusted on patient's age.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and rationale. Acute aortic syndromes (AASs) are deadly and difficult to diagnose&#xD;
      cardiovascular emergencies. AASs include acute aortic dissection, intramural aortic hematoma,&#xD;
      penetrating aortic ulcer and spontaneous aortic rupture. A conclusive diagnosis of AASs&#xD;
      requires an advanced imaging exam, such as computed tomographic angiography (CTA),&#xD;
      transoesophageal echocardiography (TEE) or magnetic resonance imaging. These exams are&#xD;
      time-consuming, costly and frequently require transfer of patients to specialized clinical&#xD;
      centres. CTA, the most frequently used advanced imaging exam for suspected AASs in the&#xD;
      Emergency Department (ED), exposes patients to significant ionizing radiations and to&#xD;
      contrast medium, carrying inherent risks of anaphylaxis and contrast nephropathy. Selection&#xD;
      of patients necessitating an advanced aortic imaging exam is therefore worrisome. There is a&#xD;
      need for standardized diagnostic management of AAS workup, and in particular for a validated&#xD;
      diagnostic algorithm incorporating evidence-based decision rules allowing:&#xD;
&#xD;
        1. rapid identification of patients necessitating urgent CTA;&#xD;
&#xD;
        2. safe rule-out of patients not requiring CTA. Based on available guidelines and further&#xD;
           evidence, standardized decision rules for rule-in and rule-out of AASs can effectively&#xD;
           based on integration of: (1) standardized pre-test probability assessment, (2) bedside&#xD;
           imaging of the aorta with focus cardiac ultrasound (FoCUS), and (3) biomarker testing&#xD;
           (D-dimer assay).&#xD;
&#xD;
      Aim of the study. The aim of the present study is to evaluate the performance of integrated&#xD;
      diagnostic algorithms for standardized diagnostic workup (rule-in/out) of AASs. Primary&#xD;
      outcome will be the occurrence of AASs in patients at low clinical pre-test probability&#xD;
      presenting a negative D-dimer test result.&#xD;
&#xD;
      Setting. The study will be performed in several international EDs. Participating EDs will&#xD;
      satisfy the following criteria for 24 hours / 7 days, in their routine clinical practice: (1)&#xD;
      experienced use of bedside FoCUS, (2) local access to urgent D-dimer (DD) assay, (3) local&#xD;
      access to urgent CTA. Both hub and spoke centers will be allowed to participate in the study,&#xD;
      if local census is &gt;30.000 visits/years.&#xD;
&#xD;
      Study design. This will be an observational, prospective, multicentre, international,&#xD;
      non-profit, investigator-driven, outcome and diagnostic accuracy study. The study protocol&#xD;
      does not imply any modification in the routine diagnostic and therapeutic approach to&#xD;
      patients with suspected AASs. The only difference from standard care will be:&#xD;
&#xD;
        1. registration of selected demographic and clinical data of study patients, obtained&#xD;
           during the index ED visit;&#xD;
&#xD;
        2. follow-up (by telephone or clinical visit) of patients after 1 month from the index ED&#xD;
           visit, for collection of selected clinical data.&#xD;
&#xD;
      Study population. The study will be performed on adult outpatients evaluated in the ED for&#xD;
      AAS-compatible symptoms (chest/abdominal/back pain, syncope, neurological deficit, limb&#xD;
      ischemia), in whom AASs are considered in differential diagnosis by the attending&#xD;
      physician(s). Eligibility will be defined during or after medical evaluation in the ED and&#xD;
      always before establishment of a final diagnosis. In each centre, patient recruitment will&#xD;
      start after obtaining approval from the local Ethic Committee.&#xD;
&#xD;
      Study methods and organization. Patients will be evaluated in the ED by an authorized&#xD;
      physician practicing Emergency Medicine and will be managed in accordance with international&#xD;
      guidelines. The recommended standard of care for diagnosis and treatment of patients with&#xD;
      suspected AAS will be as indicated by the European Society of Cardiology 2014 guidelines (see&#xD;
      diagnostic management protocol section). However, attending physicians will be allowed to&#xD;
      derogate from guideline indications based on the clinical scenario, irrespective of patient's&#xD;
      participation to the present study. After medical evaluation, a clinical suspicion of AAS&#xD;
      will prompt to possible enrolment in the study. The attending physician or an authorized&#xD;
      study research investigator or collaborator will then acquire patient (or next of kin, if&#xD;
      deemed necessary) consent to participate to the study and will fill a standardized clinical&#xD;
      form registering the relevant clinical data.&#xD;
&#xD;
      Pre-test probability assessment. During the index visit, physicians will collect relevant&#xD;
      clinical data and evaluate the presence/absence of pre-specified clinical variables. The&#xD;
      pre-test probability of AAS will be assessed using the aortic detection dissection risk score&#xD;
      (ADDs). The ADDs, recommended by the AHA 2010 and the ESC 2014 guidelines, is based on 12&#xD;
      variables organized in 3 categories. Patients are classified at low probability if ADDs is ≤1&#xD;
      (i.e. satisfying criteria in 0 or 1 risk category), or at high probability if ADDs is ≥2&#xD;
      (i.e. satisfying criteria 2 or 3 risk categories). During data analysis, the pre-test&#xD;
      probability of AAS will be assessed also with the AORTA score (AORTAs). The AORTAs, developed&#xD;
      and validated by the Study Coordinators, is a simplified score based on only 6 ADDs&#xD;
      variables. Patients are classified at low probability if AORTAs is ≤1, or at high probability&#xD;
      if AORTAs is ≥2. AORTAs based classification will be used in data analysis, and not for&#xD;
      clinical decision.&#xD;
&#xD;
      D-dimer. D-dimer levels will be analysed in the hospital laboratory on venous samples with an&#xD;
      automated test. Diagnostic tests will be site-specific. In the study centers, the D-dimer&#xD;
      test results will be interpreted by clinicians using a fixed cutoff of 500 ng/mL (Fibrinogen&#xD;
      Equivalent Unit, FEU). Data analysis will also evaluate the performance of an age-adjusted&#xD;
      cutoff, calculated in each patient as: age (years) x 10, with a minimum of 500 ng/mL.&#xD;
&#xD;
      Focused cardiac ultrasound. The attending physician, a cardiologist or an authorized study&#xD;
      research investigator expert in bedside emergency ultrasonography will perform a FoCUS on&#xD;
      study patients during ED evaluation, before advanced aortic imaging tests or surgery.&#xD;
      Evaluation of the heart and aorta will be performed with the patient in the supine or left&#xD;
      lateral decubitus positions, using the following views: (1) left parasternal (long-axis) and&#xD;
      (2) suprasternal notch view. Additional views including apical, subcostal, right parasternal,&#xD;
      abdominal and neck for carotid arteries will be decided by the attending physician.&#xD;
&#xD;
      The following will be considered as direct sonographic signs of AASs:&#xD;
&#xD;
        1. presence of an intimal flap separating two aortic lumens;&#xD;
&#xD;
        2. presence of an intramural aortic thickening (circular or crescentic thickening of the&#xD;
           aortic wall &gt;5 mm);&#xD;
&#xD;
        3. presence of a crater-like outpouching with jagged edges in the aortic wall.&#xD;
&#xD;
      The following signs will also be researched, as potential indirect sonographic signs of AASs:&#xD;
&#xD;
        1. thoracic aorta dilatation (diameter ≥4 cm);&#xD;
&#xD;
        2. pericardial effusion or tamponade&#xD;
&#xD;
        3. aortic valve regurgitation at colour Doppler (at least moderate), based on subjective&#xD;
           evaluation.&#xD;
&#xD;
      Integrated diagnostic strategies. In study centers, AAS will be considered to be ruled out&#xD;
      without advanced imaging by a D-dimer level &lt;500 ng/mL, in patients with a low clinical&#xD;
      pre-test probability assessed with the ADDs. The study will also assess and compare&#xD;
      alternative diagnostic strategies integrating pre-test probability assessment, FoCUS and&#xD;
      D-dimer (DD). Data analysis will evaluate all possible integrations of these tools. Based on&#xD;
      available evidence, key rule-out strategies will be: ADDs/DD 500 ng/mL, ADDs/DD age-adjusted,&#xD;
      AORTAs/DD 500 ng/mL, AORTAs/DD age-adjusted. FoCUS results will be variably combined to&#xD;
      optimize diagnostic performance.&#xD;
&#xD;
      Advanced Aortic imaging. The advanced aortic imaging exam used to confirm or refuse a&#xD;
      diagnosis of AASs will be CTA, TEE or magnetic resonance angiography, performed by physicians&#xD;
      not involved in the present study, according to local procedures. Patient enrolment in the&#xD;
      study will not change standard patient management and will not affect medical decision to&#xD;
      perform aortic imaging. Instruments used for imaging will be site-specific. These exams will&#xD;
      be performed and interpreted by specialized radiologists, cardiologists or surgeons not&#xD;
      involved in the present study.&#xD;
&#xD;
      Diagnostic management protocol. In participating centers, patient care will be managed&#xD;
      according to the European Society of Cardiology (ESC 2014) algorithm. Clinically stable&#xD;
      patients at low clinical pre-test probability (defined by ADD score ≤1) and a D-dimer level&#xD;
      &lt;500 ng/mL FEU, will be considered suitable for diagnostic rule-out (i.e. exclusion of AAS&#xD;
      without perfoming advanced aortic imaging). All other patients, including patients at high&#xD;
      clinical pre-test probability (defined by ADD score ≥1) and patients at low clinical pre-test&#xD;
      probability with D-dimer ≥500 ng/mL FEU, will be subjected to advanced aortic imaging. This&#xD;
      protocol will be considered as standard of care in the participating centers. However,&#xD;
      attending physicians will be allowed to derogate from protocol indications based on the&#xD;
      clinical scenario, and irrespective of patient's participation to the present study.&#xD;
&#xD;
      Follow-up data. AASs are difficult to diagnose disease entities. Given the severity of AASs&#xD;
      in untreated patients, investigators assume that individuals with an undiagnosed AAS would&#xD;
      experience major clinical events leading to conclusive diagnosis within 30 days from the ED&#xD;
      visit. Therefore, all study patients will enter a 30-day clinical follow-up to allow accurate&#xD;
      case adjudication.&#xD;
&#xD;
      Final diagnosis. The final diagnosis will be established in each centre dichotomically&#xD;
      (presence or absence of an AAS) by two senior investigators, who will review all available&#xD;
      clinical data (including aortic imaging studies, medical, surgical, autopsy records if&#xD;
      applicable). Reviewers will be blinded to pre-test probability assessment, FoCUS findings and&#xD;
      D-dimer levels. The reviewers will judge on presence or absence of an AAS, and define the AAS&#xD;
      type (acute aortic dissection, aortic intramural hematoma, penetrating aortic ulcer or&#xD;
      spontaneous aortic rupture), and Stanford classification. In patients without AAS, a&#xD;
      prevalent alternative diagnosis will be defined.&#xD;
&#xD;
      Analysis and statistical methods. Dichotomous data will be expressed as proportions with&#xD;
      their 95% confident interval (95% CI) and continuous data as mean and standard deviation&#xD;
      (SD). The chi square test will be used for the comparison of dichotomous data, and the&#xD;
      unpaired Student's t-test will be used to compare normally distributed data. The diagnostic&#xD;
      performance of diagnostic tests and strategies will be assessed by computing sensitivity,&#xD;
      specificity, negative/positive predictive values and negative/positive likelihood ratios. The&#xD;
      failure rate (or false negative proportion) will be calculated as the number of patients with&#xD;
      a final diagnosis of AAS divided by the number of patients satisfying rule-out criteria. The&#xD;
      rule-out efficiency will be calculated as the number of patients satisfying the rule-out&#xD;
      criteria divided by the number of all included patients. The rule-in efficiency will be&#xD;
      calculated as the number of patients satisfying the rule-in criteria (i.e. proceeding to&#xD;
      advanced aortic imaging) divided by the number of all included patients. P-values will be&#xD;
      two-sided, and a P-value lower than 0.05 will be considered as statistically significant.&#xD;
      Analysis will be performed with the Statistical Package for the Social Sciences (SPSS)&#xD;
      statistical package (version 17.0, SPSS Inc., Chicago, Illinois).&#xD;
&#xD;
      Sample size. The study will be sized to test the null hypothesis that the failure rate of the&#xD;
      integrated rule-out diagnostic strategy (low probability/DD-) exceeds 2%. Investigators&#xD;
      assume, based on literature data, that the punctual failure rate is 0.5%. With a type I error&#xD;
      (alpha) of 0.05 and a type II error (beta) of 0.2, approximately 496 patients at low&#xD;
      probability with a negative DD will have to be enrolled, to reject the null hypothesis.&#xD;
      Assuming that such patients are 30% of enrolled subjects, approximately 1653 patients should&#xD;
      be analysed. Assuming a 10% rate of patients lost at follow-up, at least 1837 patients should&#xD;
      be enrolled.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2019</start_date>
  <completion_date type="Actual">January 4, 2023</completion_date>
  <primary_completion_date type="Actual">January 4, 2023</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>30 Days</target_duration>
  <primary_outcome>
    <measure>Diagnostic performance of integrated diagnostic strategies for acute aortic syndromes</measure>
    <time_frame>1 mont after the end of recruitment</time_frame>
    <description>The diagnostic performance of each diagnostic strategy will be assessed by computing sensitivity, specificity, negative/positive predictive values and negative/positive likelihood ratios with their 95% confident interval (95% CI).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Failure rate of integrated diagnostic strategies for rule-out of acute aortic syndromes</measure>
    <time_frame>1 mont after the end of recruitment</time_frame>
    <description>The failure rate (or false negative proportion) of each diagnostic strategy will be calculated as the number of patients with a final diagnosis of AAS divided by the number of patients satisfying rule-out criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficiency of integrated diagnostic strategies for rule-out of acute aortic syndromes</measure>
    <time_frame>1 mont after the end of recruitment</time_frame>
    <description>The rule-out efficiency of each diagnostic strategy will be calculated as the number of patients satisfying the rule-out criteria divided by the number of all included patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficiency of integrated diagnostic strategies for rule-in of acute aortic syndromes</measure>
    <time_frame>1 month after the end of recruitment</time_frame>
    <description>The rule-in efficiency of each diagnostic strategy will be calculated as the number of patients satisfying the rule-in criteria (i.e. proceeding to advanced aortic imaging) divided by the number of all included patients.</description>
  </secondary_outcome>
  <enrollment type="Actual">3023</enrollment>
  <condition>Acute Aortic Syndrome</condition>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>integrated diagnostic algorithm</intervention_name>
    <description>Diagnostic management was as follows. An acute aortic syndrome will be considered to be ruled out without advanced aortic imaging, in clinically stable patients at low clinical pre-test probability (defined by ADD score ≤1) and a D-dimer level &lt;500 ng/mL FEU. The other patients will be subjected to advanced aortic imaging for conclusive diagnosis.&#xD;
Attending physicians will be allowed to derogate from protocol indications based on the clinical scenario and clinal gestalt, irrespective of patient's participation to the present study.</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The study will be performed on adult outpatients evaluated for specified symptoms in the&#xD;
        ED, in whom AASs are considered in differential diagnosis by the attending physician(s).&#xD;
        Eligibility will be defined during or after medical evaluation in the ED and always before&#xD;
        establishment of a final diagnosis. In each centre, patient recruitment will start after&#xD;
        obtaining approval from the local Ethic Committee&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Presence of ≥1 of the following symptoms, dating ≤14 days: neck pain, truncal&#xD;
             (thoracic/back/abdominal) pain, syncope, organ perfusion deficit (focal neurologic&#xD;
             deficit, limb ischemia);&#xD;
&#xD;
          -  AAS considered as meaningful diagnostic concern based on clinical judgement of the&#xD;
             attending physician.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt;18 years;&#xD;
&#xD;
          -  Evident alternative diagnoses to acute aortic syndromes (e.g. herpes zoster, skeletal&#xD;
             pain);&#xD;
&#xD;
          -  Primary trauma;&#xD;
&#xD;
          -  History of previous acute aortic syndrome;&#xD;
&#xD;
          -  Patient's refusal to participate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Fulvio Morello, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Azienda Ospedaliero Universitaria Città della Salute e della Scienza</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Heart Institute, University of Sao Paolo</name>
      <address>
        <city>São Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charitè Universitätsmedizin</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Jena, Unit Zentrale Notaufnahme</name>
      <address>
        <city>Jena</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>A.O.U. Città della Salute e della Scienza di Torino, Ospedale Molinette, S.C. Medicina d'Urgenza U (MECAU)</name>
      <address>
        <city>Torino</city>
        <state>Piemonte</state>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emergency Department Azienda Ospedaliera Universitaria Careggi</name>
      <address>
        <city>Firenze</city>
        <state>Tuscany</state>
        <zip>50134</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda USL Toscana Centro, Medicina d'Urgenza e Dipartimento Emergenza e Area Critica</name>
      <address>
        <city>Empoli</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Maggiore Policlinico, U.O.C Pronto Soccorso e Medicina D'Urgenza</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Niguarda, Medicina d'Urgenza e Pronto Soccorso</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOUP - Azienda Ospedaliera Università Pisana-Cisanello, Dipartimento di Emergenza</name>
      <address>
        <city>Pisa</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico Gemelli, Medicina d'Urgenza e Pronto Soccorso</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Permaisuri Bainun Hospital, Jalan Raja Ashman (Jalan Hospital)</name>
      <address>
        <city>Ipoh</city>
        <state>Perak</state>
        <zip>30400</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsspital Basel</name>
      <address>
        <city>Basel</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Malaysia</country>
    <country>Switzerland</country>
  </location_countries>
  <results_reference>
    <citation>Nazerian P, Mueller C, Soeiro AM, Leidel BA, Salvadeo SAT, Giachino F, Vanni S, Grimm K, Oliveira MT Jr, Pivetta E, Lupia E, Grifoni S, Morello F; ADvISED Investigators. Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study. Circulation. 2018 Jan 16;137(3):250-258. doi: 10.1161/CIRCULATIONAHA.117.029457. Epub 2017 Oct 13.</citation>
    <PMID>29030346</PMID>
  </results_reference>
  <results_reference>
    <citation>Morello F, Mueller C, Soeiro AM, Leidel BA, Salvadeo SAT, Nazerian P; ADvISED Investigators. Response by Morello et al to Letters Regarding Article, &quot;Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study&quot;. Circulation. 2018 Jul 24;138(4):448-449. doi: 10.1161/CIRCULATIONAHA.118.034861. No abstract available.</citation>
    <PMID>30571366</PMID>
  </results_reference>
  <results_reference>
    <citation>Nazerian P, Pivetta E, Veglia S, Cavigli E, Mueller C, de Matos Soeiro A, Leidel BA, Lupia E, Rutigliano C, Wussler D, Grifoni S, Morello F; ADvISED Investigators. Integrated Use of Conventional Chest Radiography Cannot Rule Out Acute Aortic Syndromes in Emergency Department Patients at Low Clinical Probability. Acad Emerg Med. 2019 Nov;26(11):1255-1265. doi: 10.1111/acem.13819. Epub 2019 Jul 22.</citation>
    <PMID>31220387</PMID>
  </results_reference>
  <results_reference>
    <citation>Nazerian P, Mueller C, Vanni S, Soeiro AM, Leidel BA, Cerini G, Lupia E, Palazzo A, Grifoni S, Morello F. Integration of transthoracic focused cardiac ultrasound in the diagnostic algorithm for suspected acute aortic syndromes. Eur Heart J. 2019 Jun 21;40(24):1952-1960. doi: 10.1093/eurheartj/ehz207.</citation>
    <PMID>31226214</PMID>
  </results_reference>
  <results_reference>
    <citation>Bima P, Pivetta E, Nazerian P, Toyofuku M, Gorla R, Bossone E, Erbel R, Lupia E, Morello F. Systematic Review of Aortic Dissection Detection Risk Score Plus D-dimer for Diagnostic Rule-out Of Suspected Acute Aortic Syndromes. Acad Emerg Med. 2020 Oct;27(10):1013-1027. doi: 10.1111/acem.13969. Epub 2020 Apr 21.</citation>
    <PMID>32187432</PMID>
  </results_reference>
  <results_reference>
    <citation>Morello F, Santoro M, Fargion AT, Grifoni S, Nazerian P. Diagnosis and management of acute aortic syndromes in the emergency department. Intern Emerg Med. 2021 Jan;16(1):171-181. doi: 10.1007/s11739-020-02354-8. Epub 2020 May 1.</citation>
    <PMID>32358680</PMID>
  </results_reference>
  <results_reference>
    <citation>Morello F, Bima P, Pivetta E, Santoro M, Catini E, Casanova B, Leidel BA, de Matos Soeiro A, Nestelberger T, Mueller C, Grifoni S, Lupia E, Nazerian P. Development and Validation of a Simplified Probability Assessment Score Integrated With Age-Adjusted d-Dimer for Diagnosis of Acute Aortic Syndromes. J Am Heart Assoc. 2021 Feb 2;10(3):e018425. doi: 10.1161/JAHA.120.018425. Epub 2021 Jan 21.</citation>
    <PMID>33474974</PMID>
  </results_reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Ospedaliero-Universitaria Careggi</investigator_affiliation>
    <investigator_full_name>Peiman Nazerian</investigator_full_name>
    <investigator_title>Vice Director Emergency Department</investigator_title>
  </responsible_party>
  <keyword>acute aortic syndrome</keyword>
  <keyword>aortic dissection</keyword>
  <keyword>d-dimer</keyword>
  <keyword>echocardiography</keyword>
  <keyword>emergency department</keyword>
  <keyword>diagnosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Aortic Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <!-- 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/NCT04430400
org study id: 11005
nct id: NCT04430400
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Observational, prospective, multicentre, international, non-profit, investigator-driven,
      outcome and diagnostic accuracy study performed in Emergency Departments. The study will
      evaluate the performance of diagnostic algorithms integrating pre-test probability assessment
      with a risk score, focus cardiac ultrasound and D-dimer, to rule-in/out acute aortic
      syndromes. For each patient, the outcome will be established after review of hospital and
      30-day follow-up data.

      In participating centers, an acute aortic syndrome will be considered to be ruled out without
      advanced imaging by a D-dimer level lower than 500 ng per milliliter, in patients with a low
      clinical pre-test probability assessed using the aortic dissection detection (ADD) risk
      score. Using outcome data, the study will primarily assess the accuracy and efficiency of
      this diagnostic rule-out protocol (prospective management study). The study will also
      evaluate the performance of alternative rule out strategies based on a different clinical
      score and on a D-dimer cutoff adjusted on patient's age.
Background and rationale. Acute aortic syndromes (AASs) are deadly and difficult to diagnose
      cardiovascular emergencies. AASs include acute aortic dissection, intramural aortic hematoma,
      penetrating aortic ulcer and spontaneous aortic rupture. A conclusive diagnosis of AASs
      requires an advanced imaging exam, such as computed tomographic angiography (CTA),
      transoesophageal echocardiography (TEE) or magnetic resonance imaging. These exams are
      time-consuming, costly and frequently require transfer of patients to specialized clinical
      centres. CTA, the most frequently used advanced imaging exam for suspected AASs in the
      Emergency Department (ED), exposes patients to significant ionizing radiations and to
      contrast medium, carrying inherent risks of anaphylaxis and contrast nephropathy. Selection
      of patients necessitating an advanced aortic imaging exam is therefore worrisome. There is a
      need for standardized diagnostic management of AAS workup, and in particular for a validated
      diagnostic algorithm incorporating evidence-based decision rules allowing:

        1. rapid identification of patients necessitating urgent CTA;

        2. safe rule-out of patients not requiring CTA. Based on available guidelines and further
           evidence, standardized decision rules for rule-in and rule-out of AASs can effectively
           based on integration of: (1) standardized pre-test probability assessment, (2) bedside
           imaging of the aorta with focus cardiac ultrasound (FoCUS), and (3) biomarker testing
           (D-dimer assay).

      Aim of the study. The aim of the present study is to evaluate the performance of integrated
      diagnostic algorithms for standardized diagnostic workup (rule-in/out) of AASs. Primary
      outcome will be the occurrence of AASs in patients at low clinical pre-test probability
      presenting a negative D-dimer test result.

      Setting. The study will be performed in several international EDs. Participating EDs will
      satisfy the following criteria for 24 hours / 7 days, in their routine clinical practice: (1)
      experienced use of bedside FoCUS, (2) local access to urgent D-dimer (DD) assay, (3) local
      access to urgent CTA. Both hub and spoke centers will be allowed to participate in the study,
      if local census is >30.000 visits/years.

      Study design. This will be an observational, prospective, multicentre, international,
      non-profit, investigator-driven, outcome and diagnostic accuracy study. The study protocol
      does not imply any modification in the routine diagnostic and therapeutic approach to
      patients with suspected AASs. The only difference from standard care will be:

        1. registration of selected demographic and clinical data of study patients, obtained
           during the index ED visit;

        2. follow-up (by telephone or clinical visit) of patients after 1 month from the index ED
           visit, for collection of selected clinical data.

      Study population. The study will be performed on adult outpatients evaluated in the ED for
      AAS-compatible symptoms (chest/abdominal/back pain, syncope, neurological deficit, limb
      ischemia), in whom AASs are considered in differential diagnosis by the attending
      physician(s). Eligibility will be defined during or after medical evaluation in the ED and
      always before establishment of a final diagnosis. In each centre, patient recruitment will
      start after obtaining approval from the local Ethic Committee.

      Study methods and organization. Patients will be evaluated in the ED by an authorized
      physician practicing Emergency Medicine and will be managed in accordance with international
      guidelines. The recommended standard of care for diagnosis and treatment of patients with
      suspected AAS will be as indicated by the European Society of Cardiology 2014 guidelines (see
      diagnostic management protocol section). However, attending physicians will be allowed to
      derogate from guideline indications based on the clinical scenario, irrespective of patient's
      participation to the present study. After medical evaluation, a clinical suspicion of AAS
      will prompt to possible enrolment in the study. The attending physician or an authorized
      study research investigator or collaborator will then acquire patient (or next of kin, if
      deemed necessary) consent to participate to the study and will fill a standardized clinical
      form registering the relevant clinical data.

      Pre-test probability assessment. During the index visit, physicians will collect relevant
      clinical data and evaluate the presence/absence of pre-specified clinical variables. The
      pre-test probability of AAS will be assessed using the aortic detection dissection risk score
      (ADDs). The ADDs, recommended by the AHA 2010 and the ESC 2014 guidelines, is based on 12
      variables organized in 3 categories. Patients are classified at low probability if ADDs is ≤1
      (i.e. satisfying criteria in 0 or 1 risk category), or at high probability if ADDs is ≥2
      (i.e. satisfying criteria 2 or 3 risk categories). During data analysis, the pre-test
      probability of AAS will be assessed also with the AORTA score (AORTAs). The AORTAs, developed
      and validated by the Study Coordinators, is a simplified score based on only 6 ADDs
      variables. Patients are classified at low probability if AORTAs is ≤1, or at high probability
      if AORTAs is ≥2. AORTAs based classification will be used in data analysis, and not for
      clinical decision.

      D-dimer. D-dimer levels will be analysed in the hospital laboratory on venous samples with an
      automated test. Diagnostic tests will be site-specific. In the study centers, the D-dimer
      test results will be interpreted by clinicians using a fixed cutoff of 500 ng/mL (Fibrinogen
      Equivalent Unit, FEU). Data analysis will also evaluate the performance of an age-adjusted
      cutoff, calculated in each patient as: age (years) x 10, with a minimum of 500 ng/mL.

      Focused cardiac ultrasound. The attending physician, a cardiologist or an authorized study
      research investigator expert in bedside emergency ultrasonography will perform a FoCUS on
      study patients during ED evaluation, before advanced aortic imaging tests or surgery.
      Evaluation of the heart and aorta will be performed with the patient in the supine or left
      lateral decubitus positions, using the following views: (1) left parasternal (long-axis) and
      (2) suprasternal notch view. Additional views including apical, subcostal, right parasternal,
      abdominal and neck for carotid arteries will be decided by the attending physician.

      The following will be considered as direct sonographic signs of AASs:

        1. presence of an intimal flap separating two aortic lumens;

        2. presence of an intramural aortic thickening (circular or crescentic thickening of the
           aortic wall >5 mm);

        3. presence of a crater-like outpouching with jagged edges in the aortic wall.

      The following signs will also be researched, as potential indirect sonographic signs of AASs:

        1. thoracic aorta dilatation (diameter ≥4 cm);

        2. pericardial effusion or tamponade

        3. aortic valve regurgitation at colour Doppler (at least moderate), based on subjective
           evaluation.

      Integrated diagnostic strategies. In study centers, AAS will be considered to be ruled out
      without advanced imaging by a D-dimer level <500 ng/mL, in patients with a low clinical
      pre-test probability assessed with the ADDs. The study will also assess and compare
      alternative diagnostic strategies integrating pre-test probability assessment, FoCUS and
      D-dimer (DD). Data analysis will evaluate all possible integrations of these tools. Based on
      available evidence, key rule-out strategies will be: ADDs/DD 500 ng/mL, ADDs/DD age-adjusted,
      AORTAs/DD 500 ng/mL, AORTAs/DD age-adjusted. FoCUS results will be variably combined to
      optimize diagnostic performance.

      Advanced Aortic imaging. The advanced aortic imaging exam used to confirm or refuse a
      diagnosis of AASs will be CTA, TEE or magnetic resonance angiography, performed by physicians
      not involved in the present study, according to local procedures. Patient enrolment in the
      study will not change standard patient management and will not affect medical decision to
      perform aortic imaging. Instruments used for imaging will be site-specific. These exams will
      be performed and interpreted by specialized radiologists, cardiologists or surgeons not
      involved in the present study.

      Diagnostic management protocol. In participating centers, patient care will be managed
      according to the European Society of Cardiology (ESC 2014) algorithm. Clinically stable
      patients at low clinical pre-test probability (defined by ADD score ≤1) and a D-dimer level
      <500 ng/mL FEU, will be considered suitable for diagnostic rule-out (i.e. exclusion of AAS
      without perfoming advanced aortic imaging). All other patients, including patients at high
      clinical pre-test probability (defined by ADD score ≥1) and patients at low clinical pre-test
      probability with D-dimer ≥500 ng/mL FEU, will be subjected to advanced aortic imaging. This
      protocol will be considered as standard of care in the participating centers. However,
      attending physicians will be allowed to derogate from protocol indications based on the
      clinical scenario, and irrespective of patient's participation to the present study.

      Follow-up data. AASs are difficult to diagnose disease entities. Given the severity of AASs
      in untreated patients, investigators assume that individuals with an undiagnosed AAS would
      experience major clinical events leading to conclusive diagnosis within 30 days from the ED
      visit. Therefore, all study patients will enter a 30-day clinical follow-up to allow accurate
      case adjudication.

      Final diagnosis. The final diagnosis will be established in each centre dichotomically
      (presence or absence of an AAS) by two senior investigators, who will review all available
      clinical data (including aortic imaging studies, medical, surgical, autopsy records if
      applicable). Reviewers will be blinded to pre-test probability assessment, FoCUS findings and
      D-dimer levels. The reviewers will judge on presence or absence of an AAS, and define the AAS
      type (acute aortic dissection, aortic intramural hematoma, penetrating aortic ulcer or
      spontaneous aortic rupture), and Stanford classification. In patients without AAS, a
      prevalent alternative diagnosis will be defined.

      Analysis and statistical methods. Dichotomous data will be expressed as proportions with
      their 95% confident interval (95% CI) and continuous data as mean and standard deviation
      (SD). The chi square test will be used for the comparison of dichotomous data, and the
      unpaired Student's t-test will be used to compare normally distributed data. The diagnostic
      performance of diagnostic tests and strategies will be assessed by computing sensitivity,
      specificity, negative/positive predictive values and negative/positive likelihood ratios. The
      failure rate (or false negative proportion) will be calculated as the number of patients with
      a final diagnosis of AAS divided by the number of patients satisfying rule-out criteria. The
      rule-out efficiency will be calculated as the number of patients satisfying the rule-out
      criteria divided by the number of all included patients. The rule-in efficiency will be
      calculated as the number of patients satisfying the rule-in criteria (i.e. proceeding to
      advanced aortic imaging) divided by the number of all included patients. P-values will be
      two-sided, and a P-value lower than 0.05 will be considered as statistically significant.
      Analysis will be performed with the Statistical Package for the Social Sciences (SPSS)
      statistical package (version 17.0, SPSS Inc., Chicago, Illinois).

      Sample size. The study will be sized to test the null hypothesis that the failure rate of the
      integrated rule-out diagnostic strategy (low probability/DD-) exceeds 2%. Investigators
      assume, based on literature data, that the punctual failure rate is 0.5%. With a type I error
      (alpha) of 0.05 and a type II error (beta) of 0.2, approximately 496 patients at low
      probability with a negative DD will have to be enrolled, to reject the null hypothesis.
      Assuming that such patients are 30% of enrolled subjects, approximately 1653 patients should
      be analysed. Assuming a 10% rate of patients lost at follow-up, at least 1837 patients should
      be enrolled.
observational model: Cohort
time perspective: Prospective
measure: Diagnostic performance of integrated diagnostic strategies for acute aortic syndromes
time frame: 1 mont after the end of recruitment
description: The diagnostic performance of each diagnostic strategy will be assessed by computing sensitivity, specificity, negative/positive predictive values and negative/positive likelihood ratios with their 95% confident interval (95% CI).
measure: Failure rate of integrated diagnostic strategies for rule-out of acute aortic syndromes
time frame: 1 mont after the end of recruitment
description: The failure rate (or false negative proportion) of each diagnostic strategy will be calculated as the number of patients with a final diagnosis of AAS divided by the number of patients satisfying rule-out criteria.
measure: Efficiency of integrated diagnostic strategies for rule-out of acute aortic syndromes
time frame: 1 mont after the end of recruitment
description: The rule-out efficiency of each diagnostic strategy will be calculated as the number of patients satisfying the rule-out criteria divided by the number of all included patients.
measure: Efficiency of integrated diagnostic strategies for rule-in of acute aortic syndromes
time frame: 1 month after the end of recruitment
description: The rule-in efficiency of each diagnostic strategy will be calculated as the number of patients satisfying the rule-in criteria (i.e. proceeding to advanced aortic imaging) divided by the number of all included patients.
intervention type: Diagnostic Test
intervention name: integrated diagnostic algorithm
description: Diagnostic management was as follows. An acute aortic syndrome will be considered to be ruled out without advanced aortic imaging, in clinically stable patients at low clinical pre-test probability (defined by ADD score ≤1) and a D-dimer level <500 ng/mL FEU. The other patients will be subjected to advanced aortic imaging for conclusive diagnosis.
Attending physicians will be allowed to derogate from protocol indications based on the clinical scenario and clinal gestalt, irrespective of patient's participation to the present study.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Fulvio Morello, MD, PhD
role: Principal Investigator
affiliation: Azienda Ospedaliero Universitaria Città della Salute e della Scienza
facility: 
facility: 
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country: Brazil
country: Germany
country: Italy
country: Malaysia
country: Switzerland
citation: Nazerian P, Mueller C, Soeiro AM, Leidel BA, Salvadeo SAT, Giachino F, Vanni S, Grimm K, Oliveira MT Jr, Pivetta E, Lupia E, Grifoni S, Morello F; ADvISED Investigators. Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study. Circulation. 2018 Jan 16;137(3):250-258. doi: 10.1161/CIRCULATIONAHA.117.029457. Epub 2017 Oct 13.
PMID: 29030346
citation: Morello F, Mueller C, Soeiro AM, Leidel BA, Salvadeo SAT, Nazerian P; ADvISED Investigators. Response by Morello et al to Letters Regarding Article, "Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study". Circulation. 2018 Jul 24;138(4):448-449. doi: 10.1161/CIRCULATIONAHA.118.034861. No abstract available.
PMID: 30571366
citation: Nazerian P, Pivetta E, Veglia S, Cavigli E, Mueller C, de Matos Soeiro A, Leidel BA, Lupia E, Rutigliano C, Wussler D, Grifoni S, Morello F; ADvISED Investigators. Integrated Use of Conventional Chest Radiography Cannot Rule Out Acute Aortic Syndromes in Emergency Department Patients at Low Clinical Probability. Acad Emerg Med. 2019 Nov;26(11):1255-1265. doi: 10.1111/acem.13819. Epub 2019 Jul 22.
PMID: 31220387
citation: Nazerian P, Mueller C, Vanni S, Soeiro AM, Leidel BA, Cerini G, Lupia E, Palazzo A, Grifoni S, Morello F. Integration of transthoracic focused cardiac ultrasound in the diagnostic algorithm for suspected acute aortic syndromes. Eur Heart J. 2019 Jun 21;40(24):1952-1960. doi: 10.1093/eurheartj/ehz207.
PMID: 31226214
citation: Bima P, Pivetta E, Nazerian P, Toyofuku M, Gorla R, Bossone E, Erbel R, Lupia E, Morello F. Systematic Review of Aortic Dissection Detection Risk Score Plus D-dimer for Diagnostic Rule-out Of Suspected Acute Aortic Syndromes. Acad Emerg Med. 2020 Oct;27(10):1013-1027. doi: 10.1111/acem.13969. Epub 2020 Apr 21.
PMID: 32187432
citation: Morello F, Santoro M, Fargion AT, Grifoni S, Nazerian P. Diagnosis and management of acute aortic syndromes in the emergency department. Intern Emerg Med. 2021 Jan;16(1):171-181. doi: 10.1007/s11739-020-02354-8. Epub 2020 May 1.
PMID: 32358680
citation: Morello F, Bima P, Pivetta E, Santoro M, Catini E, Casanova B, Leidel BA, de Matos Soeiro A, Nestelberger T, Mueller C, Grifoni S, Lupia E, Nazerian P. Development and Validation of a Simplified Probability Assessment Score Integrated With Age-Adjusted d-Dimer for Diagnosis of Acute Aortic Syndromes. J Am Heart Assoc. 2021 Feb 2;10(3):e018425. doi: 10.1161/JAHA.120.018425. Epub 2021 Jan 21.
PMID: 33474974
responsible party type: Principal Investigator
investigator affiliation: Azienda Ospedaliero-Universitaria Careggi
investigator full name: Peiman Nazerian
investigator title: Vice Director Emergency Department
mesh term: Acute Aortic Syndrome
mesh term: Syndrome