Clinical trial NCT04707859: Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 3
Official title: Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 3
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Angina Pectoris
Atherosclerosis
Coronary Artery Disease
Myocardial Ischemia
Keywords: Positron Emission Tomography
Coronary Computed Tomography Angiography
Rubidium
15O water
Fractional flow reserve
Lead sponsor: University of Aarhus
Sponsor class: OTHER
First posted: 2021-01-13
Enrollment: 1000
Sex: ALL
Minimum age (years): 30
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with an indication for CCTA.

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.

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. 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.

Eligibility criteria: - 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).

Primary outcomes:
measure: Diagnostic accuracy of Rb PET and 15-O PET
timeFrame: ICA: 4 weeks after inclusion
Secondary outcomes:
measure: Diagnostic accuracy of QFR vs. ICA-FFR
timeFrame: ICA: 4 weeks after inclusion
measure: Pre-test probability model of CAD
timeFrame: ICA: 4 weeks after inclusion
measure: Diagnostic accuracy of QFR
timeFrame: ICA: 4 weeks after inclusion
measure: Diagnostic accuracy of CT-FFR
timeFrame: ICA: 4 weeks after inclusion
measure: Effect of reduced myocardial perfusion defect on symptoms of angina pectoris
timeFrame: Re-PET: 12 months after inclusion
measure: Prognostic value of clinical, biomarker, genetic information
timeFrame: Follow-up: Myocardial infarction and mortality rates after 3+5+10 years
measure: Prognostic value of clinical markers, CCTA, Rb PET, 15O-water PET, CT-FFR and QFR
timeFrame: Follow-up: Myocardial infarction and mortality rates after 3+5+10 years
measure: Predictive models of obstructive CAD
timeFrame: ICA: 4 weeks after inclusion
Other outcomes:
Locations:
city: Herning
country: Denmark
facility: Gødstrup Hospital
Study officials:
affiliation: Hospital Unit West, Herning, Denmark
name: Simon Winther, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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, Botker HE, Bottcher 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.
citation: Rasmussen LD, Winther S, Westra J, Isaksen C, Ejlersen JA, Brix L, Kirk J, Urbonaviciene G, Sondergaard 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, Botker HE, Bottcher 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.