Danish study of Non-Invasive testing in Coronary Artery Disease (Dan-NICAD): study protocol for a randomised controlled trial

Nissen et al. Trials (2016) 17:262 DOI 10.1186/s13063-016-1388-z STUDY PROTOCOL Open Access Danish study of Non-Invasive testing in Coronary Artery Disease (Dan-NICAD): study protocol for a randomised controlled trial Louise Nissen1*, Simon Winther1,2, Christin Isaksen4, June Anita Ejlersen3, Lau Brix4, Grazina Urbonaviciene5, Lars Frost5, Lene Helleskov Madsen1, Lars Lyhne Knudsen1, Samuel Emil Schmidt6, Niels Ramsing Holm2, Michael Maeng2, Mette Nyegaard7, Hans Erik Bøtker2 and Morten Bøttcher1 Abstract Background: Coronary computed tomography angiography (CCTA) is an established method for ruling out coronary artery disease (CAD). Most patients referred for CCTA do not have CAD and only approximately 20–30 % of patients are subsequently referred to further testing by invasive coronary angiography (ICA) or non-invasive perfusion evaluation due to suspected obstructive CAD. In cases with severe calcifications, a discrepancy between CCTA and ICA often occurs, leading to the well-described, low-diagnostic specificity of CCTA. As ICA is cost consuming and involves a risk of complications, an optimized algorithm would be valuable and could decrease the number of ICAs that do not lead to revascularization. The primary objective of the Dan-NICAD study is to determine the diagnostic accuracy of cardiac magnetic resonance imaging (CMRI) and myocardial perfusion scintigraphy (MPS) as secondary tests after a primary CCTA where CAD could not be ruled out. The secondary objective includes an evaluation of the diagnostic precision of an acoustic technology that analyses the sound of coronary blood flow. It may potentially provide better stratification prior to CCTA than clinical risk stratification scores alone. Methods/design: Dan-NICAD is a multi-centre, randomised, cross-sectional trial, which will include approximately 2,000 patients without known CAD, who were referred to CCTA due to a history of symptoms suggestive of CAD and a low-risk to intermediate-risk profile, as evaluated by a cardiologist. Patient interview, sound recordings, and blood samples are obtained in connection with the CCTA. All patients with suspected obstructive CAD by CCTA are randomised to either stress CMRI or stress MPS, followed by ICA with fractional flow reserve (FFR) measurements. Obstructive CAD is defined as an FFR below 0.80 or as high-grade stenosis (>90 % diameter stenosis) by visual assessment. Diagnostic performance is evaluated as sensitivity, specificity, predictive values, likelihood ratios, and C statistics. Enrolment commenced in September 2014 and is expected to be complete in May 2016. Discussion: Dan-NICAD is designed to assess whether a secondary perfusion examination after CCTA could safely reduce the number of ICAs where revascularization is not required. The results are expected to add knowledge about the optimal algorithm for diagnosing CAD. Trial registration: Clinicaltrials.gov identifier, NCT02264717. Registered on 26 September 2014. Keywords: Coronary artery disease, Coronary computed tomography angiography, Myocardial perfusion scintigraphy, Cardiac magnetic resonance imaging, Coronary angiography, Fractional flow reserve * Correspondence: 1 Department of Internal Medicine, Hospital Unit West, Gl.landevej 61, 7400 Herning, Denmark Full list of author information is available at the end of the article © 2016 Nissen et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nissen et al. Trials (2016) 17:262 Background An increasing number of patients are referred for evaluation of coronary artery disease (CAD) based on atypical symptoms. No unequivocal diagnostic strategy has been established for diagnosing CAD in patients presenting with symptoms suggestive of stable angina pectoris, and for that reason, clinical practice varies around the world. The gold standard for detecting hemodynamic obstructive CAD is invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurement [1–3]. However, ICA is costly and involves a small risk of complications and death [4]. Coronary computed tomography angiography (CCTA) has become an established procedure to examine patients with a low to intermediate risk of CAD [5–11]. Due to high negative predictive value, obstructive CAD can be excluded by CCTA in approximately 70–80 % of these patients [11], depending on the risk of the referred population. However, CCTA has consistently proven to have a low positive predictive value, often resulting in an overestimation of the severity of CAD [12], especially in patients with moderate to severe coronary calcification. Consequently, the introduction of CCTA has not led to a substantial decrease in the number of annually performed ICAs or increased the frequency of revascularisation procedures following ICA [13]. The above-mentioned issues raise 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 after CCTA. European guidelines recommend conducting a myocardium perfusion examination after CCTA to reduce the number of ICAs when no revascularization is performed [14], although disagreement still exists regarding which perfusion examination to use. Cardiac magnetic resonance imaging (CMRI) offers many advantages such as no radiation exposure and high image resolution [15–20]. A lack of scanner capacity and expertise are often mentioned as limitations. Myocardial perfusion scintigraphy (MPS) is an established perfusion test; however, disadvantages such as radiation and low sensitivity are reported as well as a balanced reduction in blood flow to the myocardium in three-vessel disease [21–24]. Many studies assessing the diagnostic accuracy of CMRI and MPS have used ICA diameter stenosis as a reference standard [16, 18[20, 22], which has been shown to be inaccurate in assessing the functional significance of a coronary stenosis compared to ICA-FFR [3]. A meta-analysis on MPS found an average sensitivity of 84 % for women and 89 % for men and a specificity of 78 % for women and 71 % for men using invasive coronary angiography– quantitative coronary angiography (ICA-QCA) as a reference standard [25]. For CMRI, a Page 2 of 11 meta-analysis of studies performed with ICA-FFR as the reference found an average sensitivity of 90 % and a specificity of 87 % [17]. The CADScor System (Acarix A/S, Denm (...truncated)