Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 3

Overview

Brief Summary: In a cohort of symptomatic patients referred to coronary computed tomography angiography (CCTA), the investigators aim is: 1. To investigate and compare the diagnostic precision of Rubidium Positron Emission Tomography (Rb PET) and 15O-water PET (15O-water PET) in patients where CCTA does not exclude obstructive coronary artery disease (CAD) using invasive coronary angiography with fractional flow reserve (ICA-FFR) as reference standard. 2. To study the diagnostic accuracy and prognostic value of computed tomography fractional flow reserve (CT-FFR) in patients where CCTA does not exclude obstructive CAD with ICA-FFR as reference standard. 3. To validated a pre-test probability model including genetic and circulating biomarkers. 4. To identify and characterize genetic risk variants´ and circulating biomarkers importance in developing CAD. 5. To evaluate the bone mineral density in the hip and spine and correlate this to the degree of vascular calcification.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: July 5, 2022

Detailed Description

CCTA has become the preferred diagnostic modality for symptomatic patients with low to intermediate risk of CAD. Of the patients examined, CCTA exclude cardiovascular disease in 70-80% with an excellent negative predictive value of more than 95%. Having a low positive predictive value, however, CCTA often overestimates the severity of CAD, especially in patients with moderate to severe coronary calcification. Following CCTA, patients are hence unnecessarily tested using golden standard ICA-FFR. These ICAs often show no obstructive coronary stenosis and are therefore not followed by revascularization. The issues outlined raises the question of whether it is possible (1) to make a more precise risk stratification and consequently better selection of patients prior to CCTA and (2) to reduce the number of patients referred for unnecessary ICAs following CCTA. In patients with suspicion of coronary stenosis detected by CCTA, current guidelines recommend verification of myocardial ischemia. In Dan-NICAD 3, we intend to investigate the diagnostic accuracy of advanced non-invasive myocardial perfusion imaging tests; Rb PET and 15O-water PET. These examinations have shown a high diagnostic accuracy in symptomatic patients with high risk of ischemic heart disease. However, the diagnostic accuracy is not investigated in patients as follow-up after CCTA. In addition, microcirculation may impact the correlation between PET and FFR which this study will investigate further. An alternative way to increase the diagnostic accuracy of CCTA and thus avoid unnecessary downstream testing using ICA is to utilize the ability to extract physiological information from the anatomical CCTA images. CT-FFR has in previous studies shown promising results. In addition, calculated estimation of microcirculation is under development and this study will validated these algorithm. Furthermore, to validated the prognostic value of CT-FFR in a pooled analysis including Dan-NICAD 1, 2 and 3. Obtained during ICA, QFR is a novel wire-free approach for fast computation of FFR with potential to increase the global use of physiological lesion assessment. QFR is superior to traditional assessment of intermediate coronary lesions (ICA-QCA diameter stenosis). However, disagreement between FFR and QFR has been identified in up to 20% of all measurements.

Interventions

  • Diagnostic Test: Head to head comparison: Rubidium vs 15O-water PET
    • Head to head comparison with invasive FFR as reference. Adjustment for abnormal microcirculation

Arms, Groups and Cohorts

  • Cohort
    • Participants consenting to the study will undergo: a1) An interview a2) Blood samples withdrawals a3) ECG a4) Non-enhanced CT a5) Coronary CTA a6) Follow-up for > 10 years Patients with suspicion of coronary stenosis detected by CCTA will after the coroanry CTA undergo: b1) Rb PET b2) 15O-water PET b3) Invasive coronary angiography with 3 vessel measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microvascular resistance (IMR)

Clinical Trial Outcome Measures

Primary Measures

  • Diagnostic accuracy of Rb PET and 15-O PET
    • Time Frame: ICA: 4 weeks after inclusion
    • Head-to-head comparison using ICA-FFR as reference standard stratified for CFR

Secondary Measures

  • Diagnostic accuracy of QFR vs. ICA-FFR
    • Time Frame: ICA: 4 weeks after inclusion
    • Head-to-head comparison using ICA-FFR as reference standard
  • Pre-test probability model of CAD
    • Time Frame: ICA: 4 weeks after inclusion
    • Advanced pre-test probability model of CAD included clinical information, genetic and circulating biomarkers
  • Diagnostic accuracy of QFR
    • Time Frame: ICA: 4 weeks after inclusion
    • Head-to-head comparison using ICA-FFR as reference standard
  • Diagnostic accuracy of CT-FFR
    • Time Frame: ICA: 4 weeks after inclusion
    • Head-to-head comparison with PET using ICA-FFR as reference standard
  • Effect of reduced myocardial perfusion defect on symptoms of angina pectoris
    • Time Frame: Re-PET: 12 months after inclusion
    • 12 months re-PET investigation will by used for estimation of reduction of myocardial perfusion defect size which will be correlated with symptoms of angina pectoris 3 and 12 mdr. after ICA
  • Prognostic value of clinical, biomarker, genetic information
    • Time Frame: Follow-up: 3+5+10 years after inclusion
  • Prognostic value of coronary CTA, Rb PET, 15O-water PET, CT-FFR and QFR
    • Time Frame: Follow-up: 3+5+10 years after inclusion

Participating in This Clinical Trial

Inclusion Criteria

Patients with an indication for CCTA. Qualified patients who have signed a written informed consent form. Exclusion Criteria:

  • Demography and co-existing cardiac morbidity specific: Age below 30 years. Patients having a donor heart, a mechanic heart, or mechanical heart pump. Suspicion acute coronary syndrome Previous revascularization. – CCTA: Pregnant women, including women who are potentially pregnant or lactating. Reduced kidney function, with an estimated glomerular filtration rate (eGFR) < 40 mL/min. Allergy to X-ray contrast medium. PET: Contra-indication for adenosine (severe asthma, advanced AV block, or critical aorta stenosis).

Gender Eligibility: All

Minimum Age: 30 Years

Maximum Age: 100 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Aarhus
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Simon Winther, MD, PhD, Principal Investigator, Hospital Unit West, Herning, Denmark
  • Overall Contact(s)
    • Simon Winther, MD, PhD, 78430000, simwin@rm.dk

References

Nissen L, Winther S, Isaksen C, Ejlersen JA, Brix L, Urbonaviciene G, Frost L, Madsen LH, Knudsen LL, Schmidt SE, Holm NR, Maeng M, Nyegaard M, Bøtker HE, Bøttcher M. Danish study of Non-Invasive testing in Coronary Artery Disease (Dan-NICAD): study protocol for a randomised controlled trial. Trials. 2016 May 26;17(1):262. doi: 10.1186/s13063-016-1388-z.

Rasmussen LD, Winther S, Westra J, Isaksen C, Ejlersen JA, Brix L, Kirk J, Urbonaviciene G, Søndergaard HM, Hammid O, Schmidt SE, Knudsen LL, Madsen LH, Frost L, Petersen SE, Gormsen LC, Christiansen EH, Eftekhari A, Holm NR, Nyegaard M, Chiribiri A, Bøtker HE, Böttcher M. Danish study of Non-Invasive testing in Coronary Artery Disease 2 (Dan-NICAD 2): Study design for a controlled study of diagnostic accuracy. Am Heart J. 2019 Sep;215:114-128. doi: 10.1016/j.ahj.2019.03.016. Epub 2019 May 1.

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