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Angina PectorisDan-NICAD 2NCT03481712

Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2

An observational study of Angina Pectoris and Atherosclerosis, run by University of Aarhus at 5 sites in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 30 years and older
What is being tested?
Diagnostic tests
How many people
1,732 participants
Where
5 sitesDenmark
Study dates
24 Jan 2018to 3 Dec 2020
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Patients with an indication for CCTA.

Who may be able to join

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

Who cannot join

  • 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
Show all 20Show fewer
  • 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).

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

Denmark5 sites

  • Aarhus University Hospital

    Aarhus, Central Jutland, 8200

  • Regional Hospital of Herning

    Herning, Central Jutland, 7400

  • Regional Hospital of Randers

    Randers, 8900

  • Regional Hospital of Silkeborg

    Silkeborg, Central Jutland, 8600

  • Regional Hospital of Viborg

    Viborg, 8800

Other trials in Denmark

About this study

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.
Read the 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.

Being tested
Diagnostic tests
Medical subject headings
Angina Pectoris, Atherosclerosis, Coronary Artery Disease, Myocardial Ischemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Diagnostic testsDiagnostic test

    Head-to-head comparison between:

    • CADScor and Diamond-Foster score
    • Rb PET and 3T CMRI
    • QFR and ICA-FFR

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 4 weeks after inclusion.

  2. 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).

    Measured: 4 weeks after inclusion.

  3. 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.

    Measured: 4 weeks after inclusion.

Secondary outcomes (14)

  1. 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.

    Measured: 4 weeks after inclusion.

  2. Bone mineral density.

    To study the bone mineral density in this cohort and its relation to vascular calcification.

    Measured: 1 day after inclusion.

  3. 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.

    Measured: 4 weeks after inclusion.

  4. Diagnostic accuracy of quantitative CMRI analysis.

    Diagnostic accuracy of quantitative CMRI analysis compared to ICA with FFR-CFR.

    Measured: 4 weeks after inclusion.

  5. Absolute measurements of coronary flow with quantitative CMRI analysis.

    Correlation analysis between flow measurements estimated by quantitative CMRI vs. Rb PET.

    Measured: 4 weeks after inclusion.

  6. 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.

    Measured: 4 weeks after inclusion.

  7. 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%

    Measured: 4 weeks after inclusion.

  8. CADScor.

    AUC-ROCs, sensitivity, specificity, negative and positive predictive value of CAD-score with ICA-FFR as reference standard.

    Measured: 4 weeks after inclusion.

  9. QFR FFR mismatch.

    A subgroup analysis is performed for patients with mismatch between QFR and FFR using CFR and IMR as reference standard.

    Measured: 4 weeks after inclusion.

  10. Diagnostic accuracy of CT-FFR.

    To evaluate the diagnostic accuracy of CT-FFR using ICA-FFR as reference standard.

    Measured: 4 weeks after inclusion.

  11. Effect of revascularisation on symptoms of angina pectoris.

    Evaluation of coronary revascularissation to reduce symptoms of angina pectoris 3 and 12 mdr. after ICA.

    Measured: 3+12 months after ICA

  12. 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.

    Measured: 3+5+10 years after inclusion.

  13. 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.

    Measured: 3+5+10 years after inclusion.

  14. 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.

    Measured: 3+5+10 years after inclusion.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Mar 2018
  2. Study start24 Jan 2018
  3. Primary completion3 Dec 2020
  4. Study completion3 Dec 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
1,732 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03481712
Sponsor's protocol ID
000-0001
Acronym
Dan-NICAD 2
Status last verified
Dec 2020
First submitted
25 Jan 2018
Last updated
20 Jan 2021
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Rasmussen LD, Hoek R, Westra J, Soby JH, Maaniitty T, Braathen AT, Saraste A, Isaksen C, Nissen L, Petersen SE, Aakhus S, Knaapen P, Gormsen LC, Christiansen EH, Knuuti JM, Bottcher M, Driessen RS, Winther S. Diagnostic yield of second-line functional imaging after an abnormal coronary computed tomography angiography: an individual patient-data meta-analysis. Eur Heart J Cardiovasc Imaging. 2026 Jun 1;27(6):1176-1189. doi: 10.1093/ehjci/jeag088.

    PubMed 41913985

  • Rasmussen LD, Sikjaer M, Soby JH, Pedersen OB, Westra J, Efthekhari A, Christiansen EH, Foldyna B, Williams MC, Dweck MR, Newby DE, Douglas PS, Bottcher M, Winther S. Dual probability approach for risk adjustment in patients with a low clinical likelihood of coronary artery disease. Eur Heart J Cardiovasc Imaging. 2025 Aug 29;26(9):1507-1517. doi: 10.1093/ehjci/jeaf193.

    PubMed 40590244

  • Brix GS, Rasmussen LD, Rohde PD, Nissen L, Nyegaard M, O'Donoghue ML, Bottcher M, Winther S. Elevated lipoprotein(a) levels are independently associated with the presence of significant coronary stenosis in de-novo patients with stable chest pain. Am Heart J. 2025 Apr;282:103-113. doi: 10.1016/j.ahj.2025.01.001. Epub 2025 Jan 7.

    PubMed 39788470

  • Karim SR, Westra JS, Rasmussen LD, Eftekhari A, Sejr-Hansen M, Winther S, Bottcher M, Christiansen EH. Effect of Guiding Catheter Extubation During Physiological Assesment of Stenosis. Catheter Cardiovasc Interv. 2025 Mar;105(4):735-744. doi: 10.1002/ccd.31370. Epub 2024 Dec 30.

    PubMed 39736151

  • Rasmussen LD, Westra J, Karim SR, Dahl JN, Soby JH, Ejlersen JA, Gormsen LC, Eftekhari A, Christiansen EH, Bottcher M, Winther S. Microvascular resistance reserve: impact on health status and myocardial perfusion after revascularization in chronic coronary syndrome. Eur Heart J. 2025 Feb 3;46(5):424-435. doi: 10.1093/eurheartj/ehae604.

    PubMed 39217607

  • Rasmussen LD, Murphy T, Milidonis X, Eftekhari A, Karim SR, Westra J, Dahl JN, Isaksen C, Brix L, Ejlersen JA, Nyegaard M, Johansen JK, Sondergaard HM, Mortensen J, Gormsen LC, Christiansen EH, Chiribiri A, Petersen SE, Bottcher M, Winther S. Myocardial Blood Flow by Magnetic Resonance in Patients With Suspected Coronary Stenosis: Comparison to PET and Invasive Physiology. Circ Cardiovasc Imaging. 2024 Jun;17(6):e016635. doi: 10.1161/CIRCIMAGING.124.016635. Epub 2024 Jun 18.

    PubMed 38889213

  • Rasmussen LD, Gormsen LC, Ejlersen JA, Karim SR, Westra J, Knudsen LL, Kirk J, Sondergaard HM, Mortensen J, Knuuti J, Christiansen EH, Eftekhari A, Bottcher M, Winther S. Impact of Absolute Myocardial Blood Flow Quantification on the Diagnostic Performance of PET-Based Perfusion Scans Using 82Rubidium. Circ Cardiovasc Imaging. 2024 Jan;17(1):e016138. doi: 10.1161/CIRCIMAGING.123.016138. Epub 2024 Jan 16.

    PubMed 38227687

  • Rasmussen LD, Winther S, Eftekhari A, Karim SR, Westra J, Isaksen C, Brix L, Ejlersen JA, Murphy T, Milidonis X, Nyegaard M, Benovoy M, Johansen JK, Sondergaard HM, Hammid O, Mortensen J, Knudsen LL, Gormsen LC, Christiansen EH, Chiribiri A, Petersen SE, Bottcher M. Second-Line Myocardial Perfusion Imaging to Detect Obstructive Stenosis: Head-to-Head Comparison of CMR and PET. JACC Cardiovasc Imaging. 2023 May;16(5):642-655. doi: 10.1016/j.jcmg.2022.11.015. Epub 2023 Feb 8.

    PubMed 36881421

  • Rasmussen LD, Winther S, Karim SR, Westra J, Kirk Johansen J, Sondergaard HM, Hammid O, Sevestre E, Onuma Y, Nyegaard M, Ejlersen JA, Hoj Christiansen E, Eftekhari A, Holm NR, Schmidt SE, Bottcher M. Likelihood reclassification by an acoustic-based score in suspected coronary artery disease. Heart. 2023 Jul 27;109(16):1223-1230. doi: 10.1136/heartjnl-2023-322357.

    PubMed 36878672

  • 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.

    PubMed 31323454

Questions about this trial

What is this clinical trial studying?

An observational study of Angina Pectoris and Atherosclerosis, run by University of Aarhus at 5 sites in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Diagnostic accuracy of 3T CMRI vs. Rb PET. (time frame: 4 weeks after inclusion.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03481712, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jan 2021.

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