Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 3 (Dan-NICAD 3)

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 Overview

• Status: Unknown
• Conditions: Myocardial Ischemia; Coronary Artery Disease; Atherosclerosis; Angina Pectoris
• Intervention / Treatment: Diagnostic test: Head to head comparison: Rubidium vs 15O-water PET

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.

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

Study Locations

• Denmark
  • Herning, Denmark, 7400
    • Recruiting
    • Gødstrup Hospital
    • Contact: Simon Winther, MD, PhD; Email: simwin@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with an indication for CCTA.

Description

- 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).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Cohort; 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; Head to head comparison with invasive FFR as reference. Adjustment for abnormal microcirculation

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Simon Winther, MD, PhD, Hospital Unit West, Herning, Denmark

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2021
• Primary Completion (Anticipated): July 5, 2022
• Study Completion (Anticipated): January 5, 2023

Study Registration Dates

• First Submitted: January 11, 2021
• First Submitted That Met QC Criteria: January 11, 2021
• First Posted (Actual): January 13, 2021

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 26, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Positron Emission Tomography; Fractional flow reserve; Coronary Computed Tomography Angiography; Rubidium; 15O water
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ischemia; Atherosclerosis; Angina Pectoris
• Other Study ID Numbers: Dan-NICAD 3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No