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

Study Overview
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Brief Summary
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In a cohort of symptomatic patients referred to coronary computed tomography angiography (CCTA), the investigators aim is: 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. 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. To validated a pre-test probability model including genetic and circulating biomarkers. To identify and characterize genetic risk variants and circulating biomarkers importance in developing CAD. To evaluate the bone mineral density in the hip and spine and correlate this to the degree of vascular calcification.

Detailed Description
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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. Dan-NICAD 3 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 ICA-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 microcirculatiory function is under development and this study will validated these algorithms. Furthermore, the prognostic value of CT-FFR is unknown and will be tested in the pooled cohort of Dan-NICAD 1, 2 and 3. Obtained during ICA, quantitative flow ratio (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 based on quantitative coronary analysis of ICA. However, disagreement between ICA-FFR and QFR has been identified in up to 20% of all measurements. QFR will be validated compared to PET and ICA-FFR.

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

Conditions
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Angina Pectoris, Atherosclerosis, Coronary Artery Disease, Myocardial Ischemia

Intervention / Treatment
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* Diagnostic Test: Head to head comparison: Rubidium vs 15O-water PET


Participation Criteria
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Eligibility Criteria
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- 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 or 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 or allergy to X-ray contrast medium. PET: contra-indication for adenosine (severe asthma, advanced atrioventricular block, or critical aorta stenosis).

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort<br>Participants consenting to the study will undergo: a1) An interview a2) Blood samples withdrawals a3) ECG a4) Non-enhanced CT a5) CCTA a6) Follow-up for > 10 years Patients with suspicion of coronary stenosis detected by CCTA will after 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) | Diagnostic Test: Head to head comparison: Rubidium vs 15O-water PET<br>* Head to head comparison with invasive FFR as reference. Adjustment for abnormal microcirculation<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic accuracy of QFR vs. ICA-FFR | Head-to-head comparison using ICA-FFR as reference standard | ICA: 4 weeks after inclusion | 
| Pre-test probability model of CAD | Advanced pre-test probability model of CAD included clinical information, genetic and circulating biomarkers | ICA: 4 weeks after inclusion | 
| Diagnostic accuracy of QFR | Head-to-head comparison using ICA-FFR as reference standard | ICA: 4 weeks after inclusion | 
| Diagnostic accuracy of CT-FFR | Head-to-head comparison with PET using ICA-FFR as reference standard | ICA: 4 weeks after inclusion | 
| Effect of reduced myocardial perfusion defect on symptoms of angina pectoris | 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 | Re-PET: 12 months after inclusion | 
| Prognostic value of clinical, biomarker, genetic information | Prognotic models will be developed based on machine learning algorithms | Follow-up: Myocardial infarction and mortality rates after 3+5+10 years | 
| Prognostic value of clinical markers, CCTA, Rb PET, 15O-water PET, CT-FFR and QFR | Prognotic models will be developed based on machine learning algorithms | Follow-up: Myocardial infarction and mortality rates after 3+5+10 years | 
| Predictive models of obstructive CAD | Development of pre-test probability models of obstructive CAD at ICA | ICA: 4 weeks after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Positron Emission Tomography, Coronary Computed Tomography Angiography, Rubidium, 15O water, Fractional flow reserve