Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 (Dan-NICAD 2)

In a cohort of symptomatic patients referred to coronary computed tomography angiography (CCTA), the investigators aim:

1. To investigate and compare the diagnostic precision of Rubidium Positron Emission Tomography (Rb PET) and 3 Tesla Cardiac Magnetic Resonance imaging (3T CMRI) in patients where CCTA does not exclude significant coronary artery disease (CAD) using invasive coronary angiography with fractional flow reserve (ICA-FFR) as reference standard.
2. To evaluate the diagnostic precision of quantitative flow ratio (QFR) and ICA-FFR in patients where CCTA does not exclude significant CAD using Rb PET and 3T CMRI as reference standard.
3. To show superiority for the CADScor®System compared to the Diamond-Forrester score in detection of CAD with CCTA and ICA quantitative coronary angiography (ICA-QCA) as reference standard.
4. To study the diagnostic accuracy of computed tomography fractional flow reserve (CT-FFR) in patients where CCTA does not exclude significant CAD with ICA-FFR as reference standard.
5. To identify and characterize genetic risk variants´ and circulating biomarkers´ importance in developing CAD.
6. To evaluate the bone mineral density in the hip and spine and correlate this to the degree of vascular calcification.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia; Coronary Artery Disease; Atherosclerosis; Angina Pectoris
• Intervention / Treatment: Diagnostic test: Diagnostic tests

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 2, we intend to investigate the diagnostic accuracy of advanced non-invasive myocardial perfusion imaging tests; Rb PET and 3T CMRI. 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.

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. CT-FFR has not been head to head compared against Rb PET and 3T CMRI.

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.

Acoustic detections of coronary stenosis from automatically recorded and analyzed heart sounds is a newly developed technology potentially useful for pre-test risk stratification before e.g. CCTA. One of these devices, the CADScor®System, has previously shown an area under the receiver operating characteristic curve (AUC of ROC) of 70-80% compared to conventional ICA-QCA. This indicates that the CADScor®System could potentially supplement clinical assessment of CAD and be used for risk stratification prior to CCTA.

The investigators aim to obtain blood samples for biobank purposes and record heart sounds with the CADScor®System in 2000 patients that by clinical evaluation undergo CCTA. In approximately 400 patients (20%), CCTA does not exclude significant CAD. These patients are all examined using Rb PET, 3T CMRI, and ICA with QCA. In patients with a coronary diameter stenosis of 30-90% determined during the ICA examination, FFR, coronary flow reserve (CFR) and QFR is performed.

• Study Type: Observational
• Enrollment (Actual): 1732

Contacts and Locations

Study Locations

• Denmark
  • Randers, Denmark, 8900
    • Regional Hospital of Randers
  • Viborg, Denmark, 8800
    • Regional Hospital of Viborg
  • Region Midtjylland
    • Aarhus, Region Midtjylland, Denmark, 8200
      • Aarhus University Hospital
    • Herning, Region Midtjylland, Denmark, 7400
      • Regional Hospital of Herning
    • Silkeborg, Region Midtjylland, Denmark, 8600
      • Regional Hospital of Silkeborg

Participation Criteria

Eligibility Criteria

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

• Sampling Method: 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:

CADScor specific

• Fragile or compromised skin in the area for application of the CADScor®Patch.
• Known allergy to polyacrylate adhesives.
• Significant operation scars or abnormal body shape in left IC4 (4th Inter Costal region).
• Use of vasodilating agents at the same day and prior to CAD-score measurements.

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.

Scan specific

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.

CMRI and PET:

• Contra-indication for adenosine (severe asthma, advanced AV block, or critical aorta stenosis).
• Contra-indications for MRI (implanted medicinal pumps or nerve stimulators, magnetic foreign objects in sensitive areas, i.e. the eye).
• Patients having an ICD or pacemaker, a cochlea implant, or metal clips evaluated by the including doctor.

General:

- Patients not able to breath-hold (COPD/asthma).

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy of 3T CMRI vs. Rb PET.	Head-to-head comparison using ICA-FFR as reference standard. Diagnostic accuracy is measured using specificity, sensitivity, positive and negative predictive value and likelihood ratios.	4 weeks after inclusion.
Diagnostic accuracy of QFR vs. ICA-FFR.	Head-to-head comparison using myocardial perfusion examinations as reference standard. Diagnostic accuracy is measured using specificity, sensitivity, positive and negative predictive values, likelihood ratios and area under receiving operating curves (AUC-ROC).	4 weeks after inclusion.
Diagnostic accuracy of CADScor vs. Diamond-Foster Score.	AUC-ROC for CAD-score and Diamond-Forrester score in detection of CAD with CCTA and ICA-QCA as reference in patients ≥40 years.	4 weeks after inclusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genome-wide Associations.	The primary analysis will be a genome-wide association analysis, to determine candidate genes and markers underlying coronary artery disease and bone mineralization.	4 weeks after inclusion.
Bone mineral density.	To study the bone mineral density in this cohort and its relation to vascular calcification.	1 day after inclusion.
Coronary flow measurement´s impact on diagnostic accuracy of myocardial perfusion imaging (MPI).	Impact of coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) on myocardial perfusion imaging (MPI) diagnostic accuracy using specificity, sensitivity, positive and negative predictive values.	4 weeks after inclusion.
Diagnostic accuracy of quantitative CMRI analysis.	Diagnostic accuracy of quantitative CMRI analysis compared to ICA with FFR-CFR.	4 weeks after inclusion.
Absolute measurements of coronary flow with quantitative CMRI analysis.	Correlation analysis between flow measurements estimated by quantitative CMRI vs. Rb PET.	4 weeks after inclusion.
Diagnostic accuracy of CADScor vs. Diamond-Foster Score.	AUC-ROCs for CAD-score and Diamond-Forrester score in detection of CAD with CCTA and ICA-QCA as reference in total population.	4 weeks after inclusion.
Diagnostic accuracy of CADScor vs. Diamond-Forrester Score.	Sensitivity, specificity, negative and positive predictive value of CAD-score and Diamond-Forrester score with CCTA and ICA-QCA as reference standard. For the CADScor®System specifically, the following criteria are applicable: Sensitivity >79%; Negative predictive value maximum 3% lower than the anticipated negative predictive value; Rule-out proportion ≥30%	4 weeks after inclusion.
CADScor.	AUC-ROCs, sensitivity, specificity, negative and positive predictive value of CAD-score with ICA-FFR as reference standard.	4 weeks after inclusion.
QFR FFR mismatch.	A subgroup analysis is performed for patients with mismatch between QFR and FFR using CFR and IMR as reference standard.	4 weeks after inclusion.
Diagnostic accuracy of CT-FFR.	To evaluate the diagnostic accuracy of CT-FFR using ICA-FFR as reference standard.	4 weeks after inclusion.
Effect of revascularisation on symptoms of angina pectoris.	Evaluation of coronary revascularissation to reduce symptoms of angina pectoris 3 and 12 mdr. after ICA.	3+12 months after ICA
Prognostic value of clinical, biomarker, and genetic information.	To validate the 3, 5 and 10 yr. prognostic value of a pre-test probability score including clinical, biomarker and genitic information in patients with symptoms suggestive of CAD referred for coronary CTA.	3+5+10 years after inclusion.
Prognostic value of heart sound analysis and CAD-score.	To investigate the 3, 5 and 10 yr. prognostic value of pre-specified heart sound analysis and CAD-score in patients with symptoms suggestive of CAD referred for coronary CTA.	3+5+10 years after inclusion.
Prognostic value of coronary CTA, RbPET, 3T CMR, CT-FFR and QFR	To investigate the 3, 5 and 10 yr. prognostic value of the study's imaging techniques in patients with symptoms suggestive of CAD referred for coronary CTA.	3+5+10 years after inclusion.

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Morten Böttcher, MD, Ph.D, Regional Hospital of Herning, department of cardiology

Publications and helpful links

General Publications

• 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 24, 2018
• Primary Completion (Actual): December 3, 2020
• Study Completion (Actual): December 3, 2020

Study Registration Dates

• First Submitted: January 25, 2018
• First Submitted That Met QC Criteria: March 21, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Actual): January 20, 2021
• Last Update Submitted That Met QC Criteria: January 19, 2021
• Last Verified: December 1, 2020

More Information

Terms related to this study

• 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: 000-0001

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