Danish study of Non-Invasive testing in Coronary Artery Disease 2 (Dan-NICAD 2): study design for a controlled study of diagnostic accuracy

Abstract Background Coronary computed tomography angiography (CTA) is the preferred primary diagnostic modality when examining patients with low to intermediate pre-test probability of coronary artery disease (CAD). Only 20-30% of these have potentially obstructive CAD. Because of the relatively poor positive predictive value of coronary CTA, unnecessary invasive coronary angiographies (ICA) are conducted with the costs and risks associated with the procedure. Hence, an optimized diagnostic CAD algorithm may reduce the numbers of ICAs not followed by revascularization. The Dan-NICAD 2 study has three equivalent main aims: 1) to examine the diagnostic precision of a sound based diagnostic algorithm, The CADScor®System (Acarix A/S, Denmark), in patients with a low to intermediate pre-test risk of CAD referred to a primary examination by coronary CTA. We hypothesize that the CADScor®System provides better stratification prior to coronary CTA than clinical risk stratification scores alone. 2) to compare the diagnostic accuracy of 3 Tesla cardiac magnetic resonance imaging (3T CMRI), 82 Rubidium positron emission tomography ( 82 Rb-PET) and CT-derived fractional flow reserve (FFR CT ) in patients where obstructive CAD cannot be ruled out by coronary CTA using ICA fractional flow reserve (FFR) as reference standard. 3) to compare the diagnostic performance of quantitative flow ratio (QFR) and ICA-FFR in patients with low to intermediate pre-test probability of CAD using 82 Rb-PET as reference standard. Methods/design Dan-NICAD 2 is a prospective, multicenter, cross-sectional study including approximately 2,000 patients with low to intermediate pre-test probability of CAD and without previous history of CAD. Patients are referred to CTA because of symptoms suggestive of CAD, as evaluated by a cardiologist. Patient interviews, sound recordings, and blood samples are obtained in connection with the coronary CTA. If coronary CTA does not rule-out obstructive CAD, patients will be examined by both 3T CMRI, 82 Rb-PET, FFR CT , ICA and FFR. Reference standard is ICA-FFR. Obstructive CAD is defined as an FFR ≤0.80 or as high-grade stenosis (>90 % diameter stenosis) by visual assessment. Diagnostic performance will be evaluated as sensitivity, specificity, predictive values, likelihood ratios, calibration, and discrimination. Enrolment started January 2018 and is expected to be completed by June 2020. Patients are followed for 10 years after inclusion. Discussion The results of the Dan-NICAD 2 study are expected to contribute to the improvement of diagnostic strategies for patients suspected of CAD in three different steps; risk-stratification prior to coronary CTA, diagnostic strategy after coronary CTA and invasive wireless QFR analysis as an alternative to ICA-FFR. Study registration Clinicaltrials.gov identifier, NCT03481712. Registered on January 25 th 2018.