<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/NCT03026283</url>
  </required_header>
  <id_info>
    <org_study_id>16-765-LHH</org_study_id>
    <nct_id>NCT03026283</nct_id>
  </id_info>
  <brief_title>The Value of CT Fractional Flow Reserve</brief_title>
  <acronym>VFFRCTA</acronym>
  <official_title>The Value of Fractional Flow Reserve Derived From Coronary CTA and in the Triage of Low to Intermediate Risk Chest Pain Patients: Design: Single Center Prospective Clinical Trial; Target Disease: Coronary Artery Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwell Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>HeartFlow, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Northwell Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Coronary Computed Tomography Angiogram (CCTA) is a non-invasive imaging modality that has&#xD;
      high sensitivity and negative predictive value for the detection of coronary artery disease&#xD;
      (CAD). The main limitations of CCTA are its poor specificity and positive predictive value,&#xD;
      as well as its inherent lack of physiologically relevant data on hemodynamic significance of&#xD;
      coronary stenosis, a data that is provided either by non-invasive stress tests such as&#xD;
      myocardial perfusion imaging (MPI) or invasively by measurement of the Fractional Flow&#xD;
      Reserve (FFR). Recent advances in computational fluid dynamic techniques applied to standard&#xD;
      CCTA are now emerging as powerful tools for virtual measurement of FFR from CCTA imaging&#xD;
      (CT-FFR). These techniques correlate well with invasively measured FFR [1-4]. The primary&#xD;
      purpose of this study is to evaluate the incremental benefit CT-FFR as compared to CCTA in&#xD;
      triaging chest pain patients in outpatient settings who are found to have obstructive CAD&#xD;
      upon CCTA (&gt; 30% and &lt; 90% stenosis). Invasive FFR and short term clinical outcomes (90 days)&#xD;
      will be correlated with each diagnostic modality in order to evaluate positive and negative&#xD;
      predictive value of each when used incrementally with CCTA.&#xD;
&#xD;
      This will be an observational trial in which patients will undergo a CCTA, as part of routine&#xD;
      care. If the patient consents to participate in the study and is found to have coronary&#xD;
      stenosis of 30% to 90%, based on the cardiologist's reading, the CCTA study will be sent to&#xD;
      HeartFlow, a vendor that will provide a computerized FFR reading, based on the CCTA study. If&#xD;
      the noninvasive FFR diagnosis indicates obstructive disease, the patient will be recommended&#xD;
      to undergo cardiac catheterization with invasive FFR.&#xD;
&#xD;
      As CCTA utilization increases, the need to train additional imaging specialists will&#xD;
      increase. This study will assess the capability of FFR-CT to enhance performance on both&#xD;
      negative and positive predictive value for less experienced readers by providing feedback&#xD;
      based on CT-FFR evaluation. CCTA readers will be grouped in two categories: those with more&#xD;
      than 10 years reading experience and those with less than 10 years reading experience. Each&#xD;
      CCTA will be read by a less experienced and a more experienced reader. Results from each&#xD;
      reader will be correlated with each other and with the CT-FFR and invasive FFR results.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      CCTA is increasingly becoming a preferred non-invasive imaging modality because of its high&#xD;
      sensitivity and negative predictive value for the detection of CAD. It has been shown to be a&#xD;
      robust imaging modality for evaluation of chest pain, and is associated with decreased&#xD;
      unnecessary hospital admission, length of stay, major adverse cardiovascular event rates,&#xD;
      recidivism rates, and downstream resource utilization compared to standard evaluation [5].&#xD;
      While findings so far are highly suggestive of CCTA's significance as a gatekeeper for&#xD;
      Invasive Coronary Angiography (ICA) by ruling out obstructive CAD, fewer than half of&#xD;
      obstructive stenosis identified by CCTA are ischemia-causing, signifying its poor positive&#xD;
      predictive value and inherent lack of physiological information [6-8]. Consequently,&#xD;
      utilization of CCTA has not entirely averted need for downstream testing for functional&#xD;
      assessment of CCTA-detected obstructive lesions either by stress testing or ICA. Recently a&#xD;
      major treatment modality, associated with the use of CCTA, has become available that offers&#xD;
      promise for improving positive predictive value and physiological relevant hemodynamic data.&#xD;
      Advances in computational fluid dynamic techniques applied to standard CCTA are now emerging&#xD;
      as a powerful tool for virtual measurement of FFR from CCTA imaging (CT-FFR). This techniques&#xD;
      correlate well with invasively measured FFR [1-4]. CT-FFR is not an investigational agent,&#xD;
      having been approved by FDA in November, 2014. However, more work is necessary to delineate&#xD;
      the patient population that could derive maximal benefit from this new technology.&#xD;
&#xD;
      While few publications regarding the use of CT-FFR specifically address the cost of&#xD;
      diagnostic work-up for obstructive disease, it is clear that the cost structure resulting&#xD;
      from changes in diagnostic testing will also change. Deferral or avoidance of cardiac&#xD;
      catheterization and nuclear stress testing will likely yield significant reductions in the&#xD;
      cost of the diagnostic testing.&#xD;
&#xD;
      From 1/1/2009 to 3/31/2015 our team introduced and operated a CCTA Chest Pain triage program&#xD;
      for low to intermediate risk patients at Stony Brook University Hospital ED and non-emergency&#xD;
      outpatient services, the only tertiary care hospital in Suffolk County. Concurrently, we&#xD;
      established a registry to monitor patient outcomes for all patients receiving CCTA at Stony&#xD;
      Brook Medicine. Our registry contained nearly 15,000 patient CCTA procedures. Our major&#xD;
      registry study established the effectiveness of CCTA as an imaging modality for evaluating&#xD;
      Emergency Department chest pain in a cost efficient manner with a false negative rate less&#xD;
      than 1% [5]. However, our registry reflects the poorer positive predictive values documented&#xD;
      by other industry studies [6-8].&#xD;
&#xD;
      False positive workup results in the necessity of performing cardiac catheterization on&#xD;
      patients at risk for obstructive disease based on assessment with current standard of care&#xD;
      (combined screening with CCTA and stress MPI). Reduction in the rate of false positive&#xD;
      testing would lead to reduction in risk from invasive procedures and radiation exposure to&#xD;
      patients and reduced cost to the health care system.&#xD;
&#xD;
      Several medical institutions currently use HeartFlow CT-FFR as standard of care for&#xD;
      evaluating obstructive disease. Generally, the standard of care at these institutions is to&#xD;
      refer patients who are 30 to 90 percent obstructed by CCTA and who have reduction of flow &lt;=&#xD;
      to 0.8 that is deemed to be medical significant by the attending cardiologist to Invasive&#xD;
      FFR. HeartFlow has reported to us confidentially that this routine use of CT-FFR has resulted&#xD;
      in a 54% reduction in false positive rate as compared to use of CCTA alone.&#xD;
&#xD;
      The purpose of this study is to evaluate the incremental benefit of Fractional Flow Reserve&#xD;
      derived from CCTA (FFR-CT) compared invasive FFR as the gold standard for patients with&#xD;
      obstructive disease (&gt; 30% and &lt; 90% stenosis). This study will also assess the capability of&#xD;
      CT-FFR to enhance performance on both negative and positive predictive value for less&#xD;
      experienced readers by providing feedback based on CT-FFR evaluation.&#xD;
&#xD;
      This will be a prospective observational clinical trial designed to evaluate the incremental&#xD;
      benefit of virtual FFR measured from CCTA, compared to invasive FFR and CCTA for the&#xD;
      detection of flow-limiting coronary stenosis, as defined by invasive FFR &lt;0.8 and vessel&#xD;
      diameter of &gt;=2mm.&#xD;
&#xD;
      572 consecutive patients who present to Lenox Hill Hospital Outpatient Clinics for CCTA due&#xD;
      to chest pain or stable angina over a ten month period and meeting the study inclusion&#xD;
      criteria are eligible for the study (Figure 1). Our team will employ CCTA-appropriateness&#xD;
      criteria to ensure proper selection of patients, derived from the Appropriate Use Criteria&#xD;
      for Cardiac Computed Tomography published in 2010 and jointly authored by multiple societies&#xD;
      including American College of Cardiology Foundation (ACCF), Society for Cardiovascular&#xD;
      Computed Tomography (SCCT), and American College of Radiology (ACR) [10]. FFR-CT measurements&#xD;
      will be performed by a core laboratory in a blinded fashion. All eligible patients will&#xD;
      undergo 64-slice or greater multi detector CCTA and CT-FFR measurements. The severity of the&#xD;
      stenosis will be determined on site by level III CCTA readers. Patients with obstructive&#xD;
      lesions of (30% to 90% stenosis) will be referred for Stress-MPI, per SOC protocol, and&#xD;
      CT-FFR. Patients with positive Stress-Myocardial Perfusion Imaging (MPI) and CCTA (50% -&#xD;
      70%%) or positive CCTA (71% to 90%) will be referred for undergo ICA with invasive FFR&#xD;
      measurement in accordance to accepted guidelines and established practice standard. They will&#xD;
      also received CT-FFR. Those patients with invasively measured FFR&lt;0.8 and with vessel&#xD;
      diameter of &gt;= 2mm, or those who require revascularizations based on invasively estimated&#xD;
      stenosis severity will be considered to have flow-limiting obstructive CAD, while the rest&#xD;
      will be considered to have non-flow limiting obstructive CAD (if also &gt;50% stenosis on ICA).&#xD;
      If stenosis severity turns out to be &lt; 50% after ICA (the gold standard), we will conclude&#xD;
      that these patients have non-obstructive CAD. (Figure 1). Patients with 30% to 49%&#xD;
      obstructive disease, according to CCTA, will be referred to optimal follow up care only. Any&#xD;
      in this group who have positive CT-FFR will return for ICA with invasive FFR measurement, and&#xD;
      follow the protocol for those with 50% to 90% obstruction.&#xD;
&#xD;
      Defining an event as performance of ICA when no intervention is necessary, we expect to&#xD;
      compare event rates for patients treated with CCTA and FFR-CT, using t-tests and a&#xD;
      multivariate, risk adjusted 90 day hazard model with 95% confidence interval. Our null&#xD;
      hypothesis is that outcomes will not vary regardless of which testing is used to assess&#xD;
      obstructive disease. Our alternative hypothesis is that evaluation with FFR-CT as oppose to&#xD;
      CTTA will change the event rate. We will also correlate noninvasive and invasive FFR studies.&#xD;
&#xD;
      We will assess inter-observer reliability of the two reader cohorts' (&gt; 10 years experience&#xD;
      and less than 10 years experience) readings for CCTA and CT-FFR.. We will also assess the&#xD;
      nondiagnostic rate for CT-FFR exams as compared to independent quality ratings of CCTA scans&#xD;
      by the scan reader. Scans will be rated as excellent, good, adequate, or non-diagnostic.&#xD;
      Non-diagnostic exams will not be sent to CT-FFR. For those sent to CT-FFR we will compare the&#xD;
      percentage of non-diagnostic exams to the percentage of non-diagnostic for CT-FFR, and we&#xD;
      will also correlate exam results by level of obstruction.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Actual">September 2018</completion_date>
  <primary_completion_date type="Actual">June 2018</primary_completion_date>
  <study_type>Observational</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>
  <primary_outcome>
    <measure>Comparison of CCTA Alone to FFR-CT After CCTA</measure>
    <time_frame>Up to 1 year from the study initiation will be required to enroll all study patients and obstain invasive and noninvasive FFR.</time_frame>
    <description>To evaluate sensitivity, specificity, positive and negative predictive value for FFR-CT after CCTA vs. CCTA alone, using invasive FFR as the gold standard.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inter-observer Reliability: Assessment of All Cases</measure>
    <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
    <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience. CCTA results were documented by the official reader, all of whom had less than 9 years experience reading CCTA. Independently the exams were reviewed by a second reader with more than 10 years experience reading CCTA. Due to an operational error, for 5 of the 572 cases that received CCTA, the detailed data was removed from the server before the second read. Therefore these cases were excluded from this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inter - Observer Reliability: Assessment of at Least Mild Disease (30% Stenosis or More)</measure>
    <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
    <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading identified at least mild disease. Mild disease is defined as cases with 30% or more stenosis documented on CCTA reading. CCTA cases that cannot be read are treated as severe.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inter - Observer Reliability: Assessment of at Least Moderate Disease (50% Stenosis or More on CCTA)</measure>
    <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
    <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading is at least moderate (50% stenosis on CCTA. CCTA cases that cannot be read are treated as severe.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inter - Observer Reliability: Assessment of Severe Disease is Diagnosesed on Official Read (70% or Greater)</measure>
    <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
    <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases with suspected severe disease on the official reading. (CCTAs that cannot be read are treated as severe).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Return Visits</measure>
    <time_frame>Up to 15 months will be required to collect 90 day follow up information on all study participants.</time_frame>
    <description>To identify factors influencing return visits within 90 days for all patients enrolled who received CCTA. While we are not aware of any documented incremental risks for adding FFR-CT to the evaluation process of coronary artery disease, this safety measure was designed to identify and evaluate all unplanned return events to ensure that they were not related to FFR-CT or to flaws in study design or operations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Return Visits -- Reasons for Return</measure>
    <time_frame>Up to 15 months will be required to collect 90 day follow up information on all study participants.</time_frame>
    <description>To identify factors influencing return visits within 90 days. All patient's who returned to the ED within 90 days of their initial visit were contacted for follow up. All their medical records were reviewed.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">586</enrollment>
  <condition>Angina, Stable Chest Pain</condition>
  <arm_group>
    <arm_group_label>1: HeartFlow CT-FFR Arm</arm_group_label>
    <description>All patients who consent will receive HeartFlow CT-FFR and medically acceptable care based on the study protocol, commonly accepted standards of care, and the patients condition.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>HeartFLow CT-FFR</intervention_name>
    <description>Patients receiving CCTA to diagnose stable chest pain or stable angina will receive CT-FFR to estimate rate of flow through the coronary arteries. The rate of flow will be compared to the rate found on Invasive FFR (the gold standard) if the subject receives invasive FFR.</description>
    <arm_group_label>1: HeartFlow CT-FFR Arm</arm_group_label>
    <other_name>Noninvasive CT-FFR, FFR-CT, Noninvasive FFR-CT</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        We reviewed a patient registry of 7,001 Stony Brook Medicine CCTA from 2011 to 2014,(work&#xD;
        from our team members' prior research). About one third of the subjects were stable chest&#xD;
        pain patients.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        1. Inclusion Criteria:&#xD;
&#xD;
          2. Capable of giving informed consent.&#xD;
&#xD;
          3. Able to cooperate with the technician performing the procedure.&#xD;
&#xD;
          4. Patient must have Body Mass Index (BMI) &lt;= 50.&#xD;
&#xD;
          5. Patients must have non-ST Elevation Myocardial Infarction (STEMI) Electrocardiogram&#xD;
             (EKG) without acute changes.&#xD;
&#xD;
          6. Patients must present to Research Institution with medically necessary appointment for&#xD;
             CCTA for the purpose of evaluation of coronary stenosis for the provisional diagnoses&#xD;
             of chest pain or angina or angina equivalent.&#xD;
&#xD;
          7. Patients must be able to take nitroglycerin and beta blockers. -&#xD;
&#xD;
          8. Patients must be 18 years of age or older.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients must not have a history of coronary stenting or coronary artery bypass graft.&#xD;
&#xD;
          2. Patients must not have severe or end stage renal disease as diagnosed as estimated&#xD;
             glomerular filtration rate (eGFR)&lt;50.&#xD;
&#xD;
          3. Patients must not have a BMI&gt;50.&#xD;
&#xD;
             -&#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>Michael Poon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwell Health</affiliation>
  </overall_official>
  <link>
    <url>https://www.nhlbi.nih.gov/health-topics/cardiac-catheterization</url>
    <description>NIH National heart, Lung and Blood Institute, What are the risks of cardiac catheterization</description>
  </link>
  <reference>
    <citation>Koo BK, Erglis A, Doh JH, Daniels DV, Jegere S, Kim HS, Dunning A, DeFrance T, Lansky A, Leipsic J, Min JK. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol. 2011 Nov 1;58(19):1989-97. doi: 10.1016/j.jacc.2011.06.066.</citation>
    <PMID>22032711</PMID>
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    <citation>Min JK, Leipsic J, Pencina MJ, Berman DS, Koo BK, van Mieghem C, Erglis A, Lin FY, Dunning AM, Apruzzese P, Budoff MJ, Cole JH, Jaffer FA, Leon MB, Malpeso J, Mancini GB, Park SJ, Schwartz RS, Shaw LJ, Mauri L. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA. 2012 Sep 26;308(12):1237-45. doi: 10.1001/2012.jama.11274.</citation>
    <PMID>22922562</PMID>
  </reference>
  <reference>
    <citation>Norgaard BL, Leipsic J, Gaur S, Seneviratne S, Ko BS, Ito H, Jensen JM, Mauri L, De Bruyne B, Bezerra H, Osawa K, Marwan M, Naber C, Erglis A, Park SJ, Christiansen EH, Kaltoft A, Lassen JF, Botker HE, Achenbach S; NXT Trial Study Group. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol. 2014 Apr 1;63(12):1145-1155. doi: 10.1016/j.jacc.2013.11.043. Epub 2014 Jan 30.</citation>
    <PMID>24486266</PMID>
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  <reference>
    <citation>Liu HY, Chen JR, Hung HC, Hsiao SY, Huang ST, Chen HS. Urinary fluoride concentration in children with disabilities following long-term fluoride tablet ingestion. Res Dev Disabil. 2011 Nov-Dec;32(6):2441-8. doi: 10.1016/j.ridd.2011.07.016. Epub 2011 Aug 5.</citation>
    <PMID>21820860</PMID>
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  <reference>
    <citation>Niska R, Bhuiya F, Xu J. National Hospital Ambulatory Medical Care Survey: 2007 emergency department summary. Natl Health Stat Report. 2010 Aug 6;(26):1-31.</citation>
    <PMID>20726217</PMID>
  </reference>
  <reference>
    <citation>Poon M, Cortegiano M, Abramowicz AJ, Hines M, Singer AJ, Henry MC, Viccellio P, Hellinger JC, Ferraro S, Poon A, Raff GL, Voros S, Farkouh ME, Noack P. Associations between routine coronary computed tomographic angiography and reduced unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the emergency department triage of chest pain. J Am Coll Cardiol. 2013 Aug 6;62(6):543-52. doi: 10.1016/j.jacc.2013.04.040. Epub 2013 May 15.</citation>
    <PMID>23684682</PMID>
  </reference>
  <reference>
    <citation>Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008 Nov 18;52(21):1724-32. doi: 10.1016/j.jacc.2008.07.031.</citation>
    <PMID>19007693</PMID>
  </reference>
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    <citation>Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem CA, Nieman K, van Werkhoven JM, Pundziute G, Weustink AC, de Vos AM, Pugliese F, Rensing B, Jukema JW, Bax JJ, Prokop M, Doevendans PA, Hunink MG, Krestin GP, de Feyter PJ. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol. 2008 Dec 16;52(25):2135-44. doi: 10.1016/j.jacc.2008.08.058.</citation>
    <PMID>19095130</PMID>
  </reference>
  <reference>
    <citation>Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, de Roos A, Cox C, Brinker J, Lima JA. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008 Nov 27;359(22):2324-36. doi: 10.1056/NEJMoa0806576.</citation>
    <PMID>19038879</PMID>
  </reference>
  <reference>
    <citation>Taylor AJ, Cerqueira M, Hodgson JM, Mark D, Min J, O'Gara P, Rubin GD; American College of Cardiology Foundation Appropriate Use Criteria Task Force; Society of Cardiovascular Computed Tomography; American College of Radiology; American Heart Association; American Society of Echocardiography; American Society of Nuclear Cardiology; North American Society for Cardiovascular Imaging; Society for Cardiovascular Angiography and Interventions; Society for Cardiovascular Magnetic Resonance; Kramer CM, Berman D, Brown A, Chaudhry FA, Cury RC, Desai MY, Einstein AJ, Gomes AS, Harrington R, Hoffmann U, Khare R, Lesser J, McGann C, Rosenberg A, Schwartz R, Shelton M, Smetana GW, Smith SC Jr. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol. 2010 Nov 23;56(22):1864-94. doi: 10.1016/j.jacc.2010.07.005.</citation>
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  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 17, 2017</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <results_first_submitted>March 6, 2020</results_first_submitted>
  <results_first_submitted_qc>May 22, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">June 5, 2020</results_first_posted>
  <last_update_submitted>May 25, 2023</last_update_submitted>
  <last_update_submitted_qc>May 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angina, Stable</mesh_term>
    <mesh_term>Chest Pain</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 21, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT03026283/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>From 1/24/2017 to 6/13/2018 patients seen in the Cardiology ambulatory care service for CCTA to be evaluated for the diagnosis of obstructive disease, and who were evaluated as low to intermediate risk for obstructive disease, and who were symptomatic were offered the opportunity to participate in the study.</recruitment_details>
      <pre_assignment_details>To participate, patients were required to complete the CCTA, and on exam have no Cardiac stenting or bypasses as determined by medical history provided by the patient and review of CCTA scan.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Initial CCTA</title>
          <description>All patients who consent will receive CCTA and medically acceptable care based on commonly accepted standards of care, and the patient's condition. The results of the CCTA will determine whether the patient receives FFR-CT or optimal medical care.</description>
        </group>
        <group group_id="P2">
          <title>Optimal Medical Care After CCTA</title>
          <description>Patients who receive a CCTA and for whom the results are normal or less than 30% obstructive disease, will be recommended for optimal medical care. This care is the commonly accepted standard of care as recommended by the patient's referring physician. (The referring physician will make all treatment decisions, and may not follow the recommendation provided by the study team).</description>
        </group>
        <group group_id="P3">
          <title>FFR-CT After CCTA</title>
          <description>Patients for whom CCTA results show 30% of more obstructive disease will be referred for FFR-CT. (The referring physician will make all treatment decisions, and may not follow the recommendation provided by the study team).</description>
        </group>
        <group group_id="P4">
          <title>Optimal Medical Care After FFR-CT</title>
          <description>Patients with negative FFR-CT and CCTA results showing 30 to 49% obstructive disease will be recommended for optimal medical care with their Cardiologist, and patients with positive FFR-CT and CCTA results showing 30 to 49% obstructive disease will be recommended for stress testing. (The referring physician will make all treatment decisions, and may not follow the recommendation provided by the study team).</description>
        </group>
        <group group_id="P5">
          <title>Stress Testing After FFR-CT</title>
          <description>Patients with 50% to 69% obstructive disease on CCTA and negative FFR-CT will be recommended for stress testing. (The referring physician will make all treatment decisions, and may not follow the recommendation provided by the study team).</description>
        </group>
        <group group_id="P6">
          <title>ICA/Diagnostic Catheterization After FFR-CT</title>
          <description>Patients with 50 to 69% obstructive disease and positive FFR-CT will be referred for diagnostic catheterization and patients with 70% obstructive disease or greater by CCTA will be referred for diagnostic catheterization. (The referring physician will make all treatment decisions, and may not follow the recommendation provided by the study team).</description>
        </group>
        <group group_id="P7">
          <title>Optimal Care After Stress Test</title>
          <description>Patients who undergo stress testing will be referred to optimal medical care if the results are negative. (The referring physician will make all treatment decisions, and may not follow the recommendation provided by the study team).</description>
        </group>
        <group group_id="P8">
          <title>ICA/Diagnostic Catheterization After Stress Test</title>
          <description>Patients who undergo stress testing will be referred to diagnostic catheterization if the result is positive.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>CCTA Diagnosis</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="586"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="572"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>CCTA not performed as planned</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Optimal Medical Care/FFR-CT Diagnosis</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="289"/>
                <participants group_id="P3" count="280"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="286"/>
                <participants group_id="P3" count="265"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="15"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Screen Failure: Enrollment Criteria</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>FFRCT Nondiagnostic</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="15"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Optimal Care/Stress Test/ICA</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="128"/>
                <participants group_id="P5" count="52"/>
                <participants group_id="P6" count="101"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="108"/>
                <participants group_id="P5" count="14"/>
                <participants group_id="P6" count="73"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="20"/>
                <participants group_id="P5" count="38"/>
                <participants group_id="P6" count="28"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Referring MD ordered diagnostic cath</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="8"/>
                <participants group_id="P5" count="11"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="9"/>
                <participants group_id="P5" count="2"/>
                <participants group_id="P6" count="2"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Referring MD ordered stress test</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="7"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Referring MD used only optimal med care</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="25"/>
                <participants group_id="P6" count="19"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Optimal Care/ICA Diagnostic Cath</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="21"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="21"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
                <participants group_id="P8" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The initial enrollment number was 586. However, 14 patients did not receive CCTA, and three additional patients became screen failures, due to medical conditions revealed on the CCTA screen. Therefore the total reported is 569.</population>
      <group_list>
        <group group_id="B1">
          <title>1: HeartFlow CT-FFR Arm</title>
          <description>All patients who consent will receive HeartFlow CT-FFR and medically acceptable care based on the study protocol, commonly accepted standards of care, and the patients condition.&#xD;
HeartFLow CT-FFR: Patients receiving CCTA to diagnose stable chest pain or stable angina will receive CT-FFR to estimate rate of flow through the coronary arteries. The rate of flow will be compared to the rate found on Invasive FFR (the gold standard) if the subject receives invasive FFR.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="569"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="569"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62.2" spread="12.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="569"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="289"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="280"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="569"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="72"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="497"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="569"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="59"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="79"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="295"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="136"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Indication</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="569"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Angina (Typical)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="62"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Angina (Atypical)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="284"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Noncardiac Chest Pain</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Dyspnea</title>
                  <measurement_list>
                    <measurement group_id="B1" value="170"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Angina Status Unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Angina Status None</title>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (BMI)</title>
          <description>Participants height and weight were recorded upon enrollment and BMI was calculated.</description>
          <population>Height and weight data was not recorded on enrollment for one participant.</population>
          <units>kg per meters squared</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="568"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28.23" spread="6.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Diabetes</title>
          <description>Participants who reported having diabetes</description>
          <population>Three study participants did not respond when asked if they were diabetic.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="566"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="117"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hypertension</title>
          <description>Participants were asked upon enrollment if they had been diagnosed with hypertension that required treatment.</description>
          <population>Two participants were unable to report whether they had been diagnosed and were being treated for hypertension,</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="567"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="337"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hyperlipidemia</title>
          <description>Participants were asked upon enrollment whether they had be diagnosed with hyperipidemia requiring medical treatment.</description>
          <population>Five study participants were unable to report upon enrollment whether they had been diagnosed with hyperlipidemia.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="564"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="312"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking History</title>
          <description>Participants were asked if they were a current smoker, had smoke in the past but quit, or had never smoked.</description>
          <population>9 Participants did not disclosed their smoking history.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Never Smoked</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="560"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="364"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Former Smoker</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="560"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="157"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Current Smoker</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="560"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Comparison of CCTA Alone to FFR-CT After CCTA</title>
        <description>To evaluate sensitivity, specificity, positive and negative predictive value for FFR-CT after CCTA vs. CCTA alone, using invasive FFR as the gold standard.</description>
        <time_frame>Up to 1 year from the study initiation will be required to enroll all study patients and obstain invasive and noninvasive FFR.</time_frame>
        <population>All patients who received FFR-CT and Diagnostic Catheterization.</population>
        <group_list>
          <group group_id="O1">
            <title>CCTA</title>
            <description>.CCTA Alone</description>
          </group>
          <group group_id="O2">
            <title>FFR-CT After CCTA</title>
            <description>FFR-CT After CCTA</description>
          </group>
        </group_list>
        <measure>
          <title>Comparison of CCTA Alone to FFR-CT After CCTA</title>
          <description>To evaluate sensitivity, specificity, positive and negative predictive value for FFR-CT after CCTA vs. CCTA alone, using invasive FFR as the gold standard.</description>
          <population>All patients who received FFR-CT and Diagnostic Catheterization.</population>
          <units>percent</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="97"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Sensitivity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="90.97" lower_limit="79.70" upper_limit="96.62"/>
                    <measurement group_id="O2" value="92.73" lower_limit="82.41" upper_limit="97.98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Specifcity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.86" lower_limit="10.42" upper_limit="40.14"/>
                    <measurement group_id="O2" value="69.71" lower_limit="46.49" upper_limit="80.25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive Predictive Value</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="64.47" lower_limit="52.66" upper_limit="75.12"/>
                    <measurement group_id="O2" value="80.95" lower_limit="69.09" upper_limit="89.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Negative Predictive Value</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.67" lower_limit="49.75" upper_limit="70.87"/>
                    <measurement group_id="O2" value="84.62" lower_limit="65.13" upper_limit="95.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Reference test is positive (test of sensitivity).</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>1.00</p_value>
            <p_value_desc>In order to evaluate the significance of sensitivity and specificity findings, we implement McNemar's test comparing sensitivity and specificity for CCTA alone and FFR-CT, assuming conditional dependence.</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Reference test is Negative</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0047</p_value>
            <p_value_desc>In order to evaluate the significance of sensitivity and specificity findings, we implement Mcnemar's test comparing sensitive and pscificity for CCTA and FFR-CT assuming dependence.</p_value_desc>
            <method>Chi-squared</method>
            <method_desc>McNemar's chi-squared = 8.00</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Inter-observer Reliability: Assessment of All Cases</title>
        <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience. CCTA results were documented by the official reader, all of whom had less than 9 years experience reading CCTA. Independently the exams were reviewed by a second reader with more than 10 years experience reading CCTA. Due to an operational error, for 5 of the 572 cases that received CCTA, the detailed data was removed from the server before the second read. Therefore these cases were excluded from this analysis.</description>
        <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
        <population>All patients who received CCTA, for whom scans were available for clinical review and review by the study's expert reader.</population>
        <group_list>
          <group group_id="O1">
            <title>CCTA Reading: Less Experienced Reader Vs. More Experience</title>
            <description>All CCTA results were read by readers with fewer than10 years experience and who spent at least one full time day per week reading CCTA and FFR-CT. These are the official results performed during the course of care. We tested agreement with expert reader with more than 10 years experience, who supervised the practice and did not routinely perform daily clinical reads.&#xD;
The arm initially had 572 subjects who completed CCTA exams. However, detailed scan results for 5 patients were inadvertently removed from the server before the second reader could review, and therefore, could not be included in the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Inter-observer Reliability: Assessment of All Cases</title>
          <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience. CCTA results were documented by the official reader, all of whom had less than 9 years experience reading CCTA. Independently the exams were reviewed by a second reader with more than 10 years experience reading CCTA. Due to an operational error, for 5 of the 572 cases that received CCTA, the detailed data was removed from the server before the second read. Therefore these cases were excluded from this analysis.</description>
          <population>All patients who received CCTA, for whom scans were available for clinical review and review by the study's expert reader.</population>
          <units>percent agreement</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <units_analyzed>CCTA Scans</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="567"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>CCTA Scans</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="567"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67.72" spread="0.0247"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Inter - Observer Reliability: Assessment of at Least Mild Disease (30% Stenosis or More)</title>
        <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading identified at least mild disease. Mild disease is defined as cases with 30% or more stenosis documented on CCTA reading. CCTA cases that cannot be read are treated as severe.)</description>
        <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
        <population>The less experienced reader read 271 of the CCTA scan as having Mild disease -- 30% obstructive disease or more. We compared these reading to the expert reader's assessment for the same cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Less Experienced Reader Vs. More Experience</title>
            <description>CCTA and FFR-CT results read by readers with fewer than10 years experience and who spent at least one full time day per week reading CCTA and FFR-CT. These are the official results performed during the course of care. We tested agreement with expert reader with more than 10 years experience.</description>
          </group>
        </group_list>
        <measure>
          <title>Inter - Observer Reliability: Assessment of at Least Mild Disease (30% Stenosis or More)</title>
          <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading identified at least mild disease. Mild disease is defined as cases with 30% or more stenosis documented on CCTA reading. CCTA cases that cannot be read are treated as severe.)</description>
          <population>The less experienced reader read 271 of the CCTA scan as having Mild disease -- 30% obstructive disease or more. We compared these reading to the expert reader's assessment for the same cases.</population>
          <units>percent agreement</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="271"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.79" spread="0.0262"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Inter - Observer Reliability: Assessment of at Least Moderate Disease (50% Stenosis or More on CCTA)</title>
        <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading is at least moderate (50% stenosis on CCTA. CCTA cases that cannot be read are treated as severe.</description>
        <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
        <population>The less experienced reader called moderate stenosis or higher (50% or more stenosis) on 159 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Less Experienced Reader Vs. More Experience</title>
            <description>CCTA and FFR-CT results read by readers with fewer than10 years experience and who spent at least one full time day per week reading CCTA and FFR-CT. These are the official results performed during the course of care. We tested agreement with expert reader with more than 10 years experience.</description>
          </group>
        </group_list>
        <measure>
          <title>Inter - Observer Reliability: Assessment of at Least Moderate Disease (50% Stenosis or More on CCTA)</title>
          <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading is at least moderate (50% stenosis on CCTA. CCTA cases that cannot be read are treated as severe.</description>
          <population>The less experienced reader called moderate stenosis or higher (50% or more stenosis) on 159 cases.</population>
          <units>percent agreement</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="159"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.88" spread="0.0385"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Inter - Observer Reliability: Assessment of Severe Disease is Diagnosesed on Official Read (70% or Greater)</title>
        <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases with suspected severe disease on the official reading. (CCTAs that cannot be read are treated as severe).</description>
        <time_frame>Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.</time_frame>
        <population>The population of patients expected to have severe of more (70% obstructive disease or more) on CCTA by less experienced reader interpretation.</population>
        <group_list>
          <group group_id="O1">
            <title>Less Experienced Reader Vs. More Experience</title>
            <description>CCTA and FFR-CT results read by readers with fewer than10 years experience and who spent at least one full time day per week reading CCTA and FFR-CT. These are the official results performed during the course of care. We tested agreement with expert reader with more than 10 years experience.</description>
          </group>
        </group_list>
        <measure>
          <title>Inter - Observer Reliability: Assessment of Severe Disease is Diagnosesed on Official Read (70% or Greater)</title>
          <description>To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases with suspected severe disease on the official reading. (CCTAs that cannot be read are treated as severe).</description>
          <population>The population of patients expected to have severe of more (70% obstructive disease or more) on CCTA by less experienced reader interpretation.</population>
          <units>percent agreement</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="83"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.81" spread="0.0422"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Return Visits</title>
        <description>To identify factors influencing return visits within 90 days for all patients enrolled who received CCTA. While we are not aware of any documented incremental risks for adding FFR-CT to the evaluation process of coronary artery disease, this safety measure was designed to identify and evaluate all unplanned return events to ensure that they were not related to FFR-CT or to flaws in study design or operations.</description>
        <time_frame>Up to 15 months will be required to collect 90 day follow up information on all study participants.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>This is a safety measure to assess urgent and emergency returns for services within 90 days of the initial encounter. Emergency returns for Acute Myocardial Infarction or urgent need for revascularization, were evaluated by the study safety committee to determine whether participation in the study had contributed to major adverse event.</description>
          </group>
        </group_list>
        <measure>
          <title>Return Visits</title>
          <description>To identify factors influencing return visits within 90 days for all patients enrolled who received CCTA. While we are not aware of any documented incremental risks for adding FFR-CT to the evaluation process of coronary artery disease, this safety measure was designed to identify and evaluate all unplanned return events to ensure that they were not related to FFR-CT or to flaws in study design or operations.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="572"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Direct Admit from CCTA</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Urgent/Unplanned return within 90 days</title>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No Unplanned/Urgent returns in 90 days</title>
                  <measurement_list>
                    <measurement group_id="O1" value="557"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Return Visits -- Reasons for Return</title>
        <description>To identify factors influencing return visits within 90 days. All patient's who returned to the ED within 90 days of their initial visit were contacted for follow up. All their medical records were reviewed.</description>
        <time_frame>Up to 15 months will be required to collect 90 day follow up information on all study participants.</time_frame>
        <population>Overall 15/572 (2.6%) patients returned for emergent visits. All outcomes may be viewed as being consistent with the diagnoses provided with CCTA and FFR-CT.</population>
        <group_list>
          <group group_id="O1">
            <title>Patients Initially Referred for Cardiac Cath</title>
            <description>These patients were referred for diagnostic Cath, because their CCTA was positive and their FFR-CT was positive.</description>
          </group>
          <group group_id="O2">
            <title>Patients Initially Referred for Stress Tesintg</title>
            <description>These patients had Moderate (50 to 69% stenoisis) finding on CCTA with Negative FFR-CT. They were referred to stress testing by protocol. One patient underwent a negative diagnostic cardiac cath. One patient was treated and released fro the ED for chest pain.</description>
          </group>
          <group group_id="O3">
            <title>Referred for Optimla Medical Care After CCTA</title>
            <description>These patients were referred to optimal medical care after CCTA. They returned to the Emergency Department with Chest Pain and were discharged after evaluation and noninvasive treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Return Visits -- Reasons for Return</title>
          <description>To identify factors influencing return visits within 90 days. All patient's who returned to the ED within 90 days of their initial visit were contacted for follow up. All their medical records were reviewed.</description>
          <population>Overall 15/572 (2.6%) patients returned for emergent visits. All outcomes may be viewed as being consistent with the diagnoses provided with CCTA and FFR-CT.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Severe Disease Received Intervention</title>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Nonobstructive Disease Went to Cardiac Cath</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Nonobstructive Disease Discharged from ED</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>90 days from the imaging encounter.</time_frame>
      <desc>Serious adverse events were major cardiac events (Acute Myocardial Infarction, death or emergency cardiac intervention). Other adverse events unnecessary exposure to invasive testing or higher risk health care environment, such as return to ED or unexpected referrals to diagnostic cardiac cath.</desc>
      <group_list>
        <group group_id="E1">
          <title>Patients Referred for Cardiac Intervention</title>
          <description>Patients for whom Cardiac Catheterization was recommended after protocol testing.</description>
        </group>
        <group group_id="E2">
          <title>Patients Referred for Stress Tesing</title>
          <description>Patients for whom stress testing was recommended after FFR-CT</description>
        </group>
        <group group_id="E3">
          <title>Patients Referred for Optimal Medical Care</title>
          <description>Patients for whom optimal medical care was recommended after protocol testing.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>Study Protocol</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="101"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="73"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="398"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="101"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="73"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="398"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Percutaneous Coronary Intevention</sub_title>
                <description>Patients diagnosed with acute disease recommended to follow up with their referring physicians had chest pain and sent to ED by physician's recommendation before treatment was completed on an ambulatory basis. Received PCI and discharged home.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="101"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="73"/>
                <counts group_id="E3" subjects_at_risk="398"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>Study Protocol</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="101"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="73"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="398"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Diagnostic Catheterization</sub_title>
                <description>A patient with findings of mild nonobstructive disease was recommended for optimal medical care. However, after consultation with referring physician has negative diagnostic catheterization. Classified as unnecessary risk exposure adverse event.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="101"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="73"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="398"/>
              </event>
              <event>
                <sub_title>Return to ED for Chest Pain</sub_title>
                <description>3 patients experience chest pain and came to ED. Patients were discharged home after treatment. Classified as unnecessary risk exposure adverse event.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="101"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="73"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="398"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>This is an observational trial. The study team made recommendations to referring physicians after diagnostic work-up with CCTA and FFR-CT we performed. However, it was up to the referring physician as to whether to follow them.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Pamela Noack</name_or_title>
      <organization>Northwell Health</organization>
      <phone>212 434 4926</phone>
      <email>pnoack@northwell.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03026283
org study id: 16-765-LHH
nct id: NCT03026283
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated device: Yes
is us export: No
Coronary Computed Tomography Angiogram (CCTA) is a non-invasive imaging modality that has
      high sensitivity and negative predictive value for the detection of coronary artery disease
      (CAD). The main limitations of CCTA are its poor specificity and positive predictive value,
      as well as its inherent lack of physiologically relevant data on hemodynamic significance of
      coronary stenosis, a data that is provided either by non-invasive stress tests such as
      myocardial perfusion imaging (MPI) or invasively by measurement of the Fractional Flow
      Reserve (FFR). Recent advances in computational fluid dynamic techniques applied to standard
      CCTA are now emerging as powerful tools for virtual measurement of FFR from CCTA imaging
      (CT-FFR). These techniques correlate well with invasively measured FFR [1-4]. The primary
      purpose of this study is to evaluate the incremental benefit CT-FFR as compared to CCTA in
      triaging chest pain patients in outpatient settings who are found to have obstructive CAD
      upon CCTA (> 30% and < 90% stenosis). Invasive FFR and short term clinical outcomes (90 days)
      will be correlated with each diagnostic modality in order to evaluate positive and negative
      predictive value of each when used incrementally with CCTA.

      This will be an observational trial in which patients will undergo a CCTA, as part of routine
      care. If the patient consents to participate in the study and is found to have coronary
      stenosis of 30% to 90%, based on the cardiologist's reading, the CCTA study will be sent to
      HeartFlow, a vendor that will provide a computerized FFR reading, based on the CCTA study. If
      the noninvasive FFR diagnosis indicates obstructive disease, the patient will be recommended
      to undergo cardiac catheterization with invasive FFR.

      As CCTA utilization increases, the need to train additional imaging specialists will
      increase. This study will assess the capability of FFR-CT to enhance performance on both
      negative and positive predictive value for less experienced readers by providing feedback
      based on CT-FFR evaluation. CCTA readers will be grouped in two categories: those with more
      than 10 years reading experience and those with less than 10 years reading experience. Each
      CCTA will be read by a less experienced and a more experienced reader. Results from each
      reader will be correlated with each other and with the CT-FFR and invasive FFR results.
CCTA is increasingly becoming a preferred non-invasive imaging modality because of its high
      sensitivity and negative predictive value for the detection of CAD. It has been shown to be a
      robust imaging modality for evaluation of chest pain, and is associated with decreased
      unnecessary hospital admission, length of stay, major adverse cardiovascular event rates,
      recidivism rates, and downstream resource utilization compared to standard evaluation [5].
      While findings so far are highly suggestive of CCTA's significance as a gatekeeper for
      Invasive Coronary Angiography (ICA) by ruling out obstructive CAD, fewer than half of
      obstructive stenosis identified by CCTA are ischemia-causing, signifying its poor positive
      predictive value and inherent lack of physiological information [6-8]. Consequently,
      utilization of CCTA has not entirely averted need for downstream testing for functional
      assessment of CCTA-detected obstructive lesions either by stress testing or ICA. Recently a
      major treatment modality, associated with the use of CCTA, has become available that offers
      promise for improving positive predictive value and physiological relevant hemodynamic data.
      Advances in computational fluid dynamic techniques applied to standard CCTA are now emerging
      as a powerful tool for virtual measurement of FFR from CCTA imaging (CT-FFR). This techniques
      correlate well with invasively measured FFR [1-4]. CT-FFR is not an investigational agent,
      having been approved by FDA in November, 2014. However, more work is necessary to delineate
      the patient population that could derive maximal benefit from this new technology.

      While few publications regarding the use of CT-FFR specifically address the cost of
      diagnostic work-up for obstructive disease, it is clear that the cost structure resulting
      from changes in diagnostic testing will also change. Deferral or avoidance of cardiac
      catheterization and nuclear stress testing will likely yield significant reductions in the
      cost of the diagnostic testing.

      From 1/1/2009 to 3/31/2015 our team introduced and operated a CCTA Chest Pain triage program
      for low to intermediate risk patients at Stony Brook University Hospital ED and non-emergency
      outpatient services, the only tertiary care hospital in Suffolk County. Concurrently, we
      established a registry to monitor patient outcomes for all patients receiving CCTA at Stony
      Brook Medicine. Our registry contained nearly 15,000 patient CCTA procedures. Our major
      registry study established the effectiveness of CCTA as an imaging modality for evaluating
      Emergency Department chest pain in a cost efficient manner with a false negative rate less
      than 1% [5]. However, our registry reflects the poorer positive predictive values documented
      by other industry studies [6-8].

      False positive workup results in the necessity of performing cardiac catheterization on
      patients at risk for obstructive disease based on assessment with current standard of care
      (combined screening with CCTA and stress MPI). Reduction in the rate of false positive
      testing would lead to reduction in risk from invasive procedures and radiation exposure to
      patients and reduced cost to the health care system.

      Several medical institutions currently use HeartFlow CT-FFR as standard of care for
      evaluating obstructive disease. Generally, the standard of care at these institutions is to
      refer patients who are 30 to 90 percent obstructed by CCTA and who have reduction of flow <=
      to 0.8 that is deemed to be medical significant by the attending cardiologist to Invasive
      FFR. HeartFlow has reported to us confidentially that this routine use of CT-FFR has resulted
      in a 54% reduction in false positive rate as compared to use of CCTA alone.

      The purpose of this study is to evaluate the incremental benefit of Fractional Flow Reserve
      derived from CCTA (FFR-CT) compared invasive FFR as the gold standard for patients with
      obstructive disease (> 30% and < 90% stenosis). This study will also assess the capability of
      CT-FFR to enhance performance on both negative and positive predictive value for less
      experienced readers by providing feedback based on CT-FFR evaluation.

      This will be a prospective observational clinical trial designed to evaluate the incremental
      benefit of virtual FFR measured from CCTA, compared to invasive FFR and CCTA for the
      detection of flow-limiting coronary stenosis, as defined by invasive FFR <0.8 and vessel
      diameter of >=2mm.

      572 consecutive patients who present to Lenox Hill Hospital Outpatient Clinics for CCTA due
      to chest pain or stable angina over a ten month period and meeting the study inclusion
      criteria are eligible for the study (Figure 1). Our team will employ CCTA-appropriateness
      criteria to ensure proper selection of patients, derived from the Appropriate Use Criteria
      for Cardiac Computed Tomography published in 2010 and jointly authored by multiple societies
      including American College of Cardiology Foundation (ACCF), Society for Cardiovascular
      Computed Tomography (SCCT), and American College of Radiology (ACR) [10]. FFR-CT measurements
      will be performed by a core laboratory in a blinded fashion. All eligible patients will
      undergo 64-slice or greater multi detector CCTA and CT-FFR measurements. The severity of the
      stenosis will be determined on site by level III CCTA readers. Patients with obstructive
      lesions of (30% to 90% stenosis) will be referred for Stress-MPI, per SOC protocol, and
      CT-FFR. Patients with positive Stress-Myocardial Perfusion Imaging (MPI) and CCTA (50% -
      70%%) or positive CCTA (71% to 90%) will be referred for undergo ICA with invasive FFR
      measurement in accordance to accepted guidelines and established practice standard. They will
      also received CT-FFR. Those patients with invasively measured FFR<0.8 and with vessel
      diameter of >= 2mm, or those who require revascularizations based on invasively estimated
      stenosis severity will be considered to have flow-limiting obstructive CAD, while the rest
      will be considered to have non-flow limiting obstructive CAD (if also >50% stenosis on ICA).
      If stenosis severity turns out to be < 50% after ICA (the gold standard), we will conclude
      that these patients have non-obstructive CAD. (Figure 1). Patients with 30% to 49%
      obstructive disease, according to CCTA, will be referred to optimal follow up care only. Any
      in this group who have positive CT-FFR will return for ICA with invasive FFR measurement, and
      follow the protocol for those with 50% to 90% obstruction.

      Defining an event as performance of ICA when no intervention is necessary, we expect to
      compare event rates for patients treated with CCTA and FFR-CT, using t-tests and a
      multivariate, risk adjusted 90 day hazard model with 95% confidence interval. Our null
      hypothesis is that outcomes will not vary regardless of which testing is used to assess
      obstructive disease. Our alternative hypothesis is that evaluation with FFR-CT as oppose to
      CTTA will change the event rate. We will also correlate noninvasive and invasive FFR studies.

      We will assess inter-observer reliability of the two reader cohorts' (> 10 years experience
      and less than 10 years experience) readings for CCTA and CT-FFR.. We will also assess the
      nondiagnostic rate for CT-FFR exams as compared to independent quality ratings of CCTA scans
      by the scan reader. Scans will be rated as excellent, good, adequate, or non-diagnostic.
      Non-diagnostic exams will not be sent to CT-FFR. For those sent to CT-FFR we will compare the
      percentage of non-diagnostic exams to the percentage of non-diagnostic for CT-FFR, and we
      will also correlate exam results by level of obstruction.
observational model: Cohort
time perspective: Prospective
measure: Comparison of CCTA Alone to FFR-CT After CCTA
time frame: Up to 1 year from the study initiation will be required to enroll all study patients and obstain invasive and noninvasive FFR.
description: To evaluate sensitivity, specificity, positive and negative predictive value for FFR-CT after CCTA vs. CCTA alone, using invasive FFR as the gold standard.
measure: Inter-observer Reliability: Assessment of All Cases
time frame: Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.
description: To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience. CCTA results were documented by the official reader, all of whom had less than 9 years experience reading CCTA. Independently the exams were reviewed by a second reader with more than 10 years experience reading CCTA. Due to an operational error, for 5 of the 572 cases that received CCTA, the detailed data was removed from the server before the second read. Therefore these cases were excluded from this analysis.
measure: Inter - Observer Reliability: Assessment of at Least Mild Disease (30% Stenosis or More)
time frame: Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.
description: To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading identified at least mild disease. Mild disease is defined as cases with 30% or more stenosis documented on CCTA reading. CCTA cases that cannot be read are treated as severe.)
measure: Inter - Observer Reliability: Assessment of at Least Moderate Disease (50% Stenosis or More on CCTA)
time frame: Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.
description: To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases on which the official reading is at least moderate (50% stenosis on CCTA. CCTA cases that cannot be read are treated as severe.
measure: Inter - Observer Reliability: Assessment of Severe Disease is Diagnosesed on Official Read (70% or Greater)
time frame: Up to 1 year will be required to obtain all reader evaluations for the study in order to asses inter-observer reliability.
description: To evaluate differences in performance of readers of CCTA and CT-FFR based on years of experience when assessing cases with suspected severe disease on the official reading. (CCTAs that cannot be read are treated as severe).
measure: Return Visits
time frame: Up to 15 months will be required to collect 90 day follow up information on all study participants.
description: To identify factors influencing return visits within 90 days for all patients enrolled who received CCTA. While we are not aware of any documented incremental risks for adding FFR-CT to the evaluation process of coronary artery disease, this safety measure was designed to identify and evaluate all unplanned return events to ensure that they were not related to FFR-CT or to flaws in study design or operations.
measure: Return Visits -- Reasons for Return
time frame: Up to 15 months will be required to collect 90 day follow up information on all study participants.
description: To identify factors influencing return visits within 90 days. All patient's who returned to the ED within 90 days of their initial visit were contacted for follow up. All their medical records were reviewed.
arm group label: 1: HeartFlow CT-FFR Arm
description: All patients who consent will receive HeartFlow CT-FFR and medically acceptable care based on the study protocol, commonly accepted standards of care, and the patients condition.
intervention type: Device
intervention name: HeartFLow CT-FFR
description: Patients receiving CCTA to diagnose stable chest pain or stable angina will receive CT-FFR to estimate rate of flow through the coronary arteries. The rate of flow will be compared to the rate found on Invasive FFR (the gold standard) if the subject receives invasive FFR.
arm group label: 1: HeartFlow CT-FFR Arm
other name: Noninvasive CT-FFR, FFR-CT, Noninvasive FFR-CT
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Poon, MD
role: Principal Investigator
affiliation: Northwell Health
url: https://www.nhlbi.nih.gov/health-topics/cardiac-catheterization
description: NIH National heart, Lung and Blood Institute, What are the risks of cardiac catheterization
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responsible party type: Sponsor
mesh term: Angina, Stable
mesh term: Chest Pain
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This is an observational trial. The study team made recommendations to referring physicians after diagnostic work-up with CCTA and FFR-CT we performed. However, it was up to the referring physician as to whether to follow them.
point of contact: 