Low- vs High-Iodine–Concentration Contrast Media for Coronary CT Angiography and Dynamic Stress CT Perfusion: A Prospective, Randomized Noninferiority Trial with Secondary Diagnostic Validation Using Invasive Coronary Angiography and Fractional Flow Reserve

Low- vs High-Iodine–Concentration Contrast Media for Coronary CT Angiography and Dynamic Stress CT Perfusion: A Prospective, Randomized Noninferiority Trial with Secondary Diagnostic Validation Using Invasive Coronary Angiography and Fractional Flow Reserve | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Low- vs High-Iodine–Concentration Contrast Media for Coronary CT Angiography and Dynamic Stress CT Perfusion: A Prospective, Randomized Noninferiority Trial with Secondary Diagnostic Validation Using Invasive Coronary Angiography and Fractional Flow Reserve Sung-Jin Cha, Pil-Hyun Jeon, Dong-Hee Kho, Hyosung Cho, Sung Min Ko This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9275618/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background This prospective randomized trial is designed to determine whether low–iodine-concentration contrast media will be noninferior to high–iodine-concentration contrast media for (i) coronary enhancement and image quality on coronary CT angiography (CCTA) and (ii) whether it yields comparable and preserved absolute myocardial blood flow (MBF) quantification on dynamic stress CT perfusion (CTP). A secondary objective is to evaluate diagnostic performance in clinically relevant subcohorts by comparing (a) CCTA stenosis assessment with invasive coronary angiography (ICA) and (b) dynamic stress CTP ischemia assessment with invasive fractional flow reserve (FFR). Methods The trial plans to enroll 258 adults (≥ 40 years) with known or suspected coronary artery disease referred for clinically indicated cardiac CT (CCTA with planned dynamic stress CTP). Participants will be randomized 1:1 to receive low–iodine-concentration contrast media (270 mg I/mL) or high–iodine-concentration contrast media (350 mg I/mL). The co-primary endpoints will be objective coronary enhancement on CCTA and absolute MBF in predefined non-ischemic myocardial segments. For secondary diagnostic validation, ICA will be used as the reference for ≥ 50% anatomic stenosis when performed as part of routine care, and FFR (≤ 0.80) will be used as the reference for lesion-specific ischemia when obtained. The CCTA co-primary endpoint will be analyzed using linear mixed-effects models with a prespecified noninferiority margin, whereas the MBF co-primary endpoint will be evaluated for comparability using a standard two-sided test without a margin. Diagnostic accuracy will be summarized using sensitivity, specificity, predictive values, and receiver-operating-characteristic analyses with methods that account for within-patient correlation across vessels. Results This study is designed to demonstrate noninferior coronary enhancement, preserved CCTA diagnostic performance, and comparable MBF measurements and ischemia detection using low–iodine-concentration contrast media under standardized acquisition and reconstruction protocols. Conclusions Low–iodine-concentration contrast media are expected to provide noninferior image quality and diagnostic performance for both anatomic and functional cardiac CT, supporting iodine-reduction strategies without compromising clinical diagnostic validity. Trial registration KCT0011418. Registered on 07 January 2026. Coronary CT angiography Dynamic CT perfusion Iodinated contrast media Noninferiority trial Invasive coronary angiography Figures Figure 1 Figure 2 Figure 3 Introduction Coronary computed tomography angiography (CCTA) has become a first-line noninvasive test for evaluating coronary artery disease (CAD), providing high diagnostic accuracy for detecting luminal stenosis and characterizing atherosclerotic plaque [ 1 – 3 ]. Nevertheless, CCTA has important inherent limitations. It offers a predominantly anatomic assessment of the coronary lumen and does not directly quantify the hemodynamic significance of individual lesions; consequently, the correlation between anatomic stenosis severity and functionally significant ischemia is at best modest [ 4 ]. Image quality and diagnostic performance may also be substantially degraded in patients with heavy coronary calcification or prior stents, where blooming artifacts can overestimate stenosis and increase false-positive rates [ 5 , 6 ]. Dynamic stress CT perfusion (CTP) is a functional imaging technique that quantifies the hemodynamic significance of coronary stenosis by measuring myocardial blood flow (MBF) under pharmacologic stress. When combined with CCTA in a single one-stop-shop examination, CTP adds functional data to anatomic information, enabling a more comprehensive characterization of CAD than either modality alone and potentially improving diagnostic accuracy and clinical decision-making [ 7 – 9 ]. This comprehensive strategy poses a dilemma in contrast use. Although high-concentration iodinated media have been favored to maximize opacification and diagnostic confidence, they also increase the total iodine load—the most important modifiable risk factor for contrast-associated acute kidney injury (CA-AKI)—an issue that is particularly critical in patients with renal impairment, diabetes, or cardiovascular comorbidities [ 10 – 12 ]. Recent advances in CT hardware and software have challenged the traditional linkage between iodine concentration and image quality. In particular, low tube-voltage techniques augment iodine attenuation and may allow diagnostically adequate enhancement with lower iodine concentration while reducing radiation exposure [ 13 – 16 ]. However, for a protocol intended for registration and for clinical translation, technical noninferiority alone is not sufficient. It is also important to predefine and prospectively evaluate whether iodine reduction preserves downstream diagnostic validity in real-world pathways, including referral to invasive coronary angiography (ICA) and physiology assessment with fractional flow reserve (FFR). Methods/Design Trial Design This study is designed as a prospective, single-institution, randomized, double-blind noninferiority trial (Fig. 1 ). The trial will evaluate whether a low–iodine-concentration iodinated contrast media protocol is noninferior to a high–iodine-concentration protocol for (1) coronary enhancement on CCTA (anatomic co-primary endpoint) and whether it yields comparable and preserved (2) absolute MBF on dynamic stress CTP in non-ischemic territories (functional co-primary endpoint). In addition, prespecified secondary analyses will evaluate diagnostic accuracy of CCTA and dynamic stress CTP against invasive reference standards (ICA and FFR) in the subset of participants who undergo invasive testing as part of standard care. Ethics and Registration The protocol has been approved by the Institutional Review Board of Wonju Severance Christian Hospital (IRB number: CR122087). The trial will be conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. Written informed consent will be obtained from all participants before any study procedures. The trial was registered at the Clinical Research Information Service (CRIS), Republic of Korea (Trial registration: KCT0011418). Population and Setting The trial plans to enroll 258 adults with known or suspected CAD referred for clinically indicated cardiac CT (CCTA with planned dynamic stress CTP). Eligible participants will be ≥ 40 years of age, will have electrocardiography (ECG)-gated imaging feasibility, and will have adequate renal function (e.g., estimated glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m²). Exclusion criteria will include suspected acute myocardial infarction or unstable angina; complex congenital heart disease; significant renal dysfunction or acute kidney injury (e.g., serum creatinine ≥ 1.5 mg/dL or eGFR < 45 mL/min/1.73 m²); history of coronary artery bypass grafting (percutaneous coronary intervention/stents permitted and recorded); pregnancy or lactation; history of severe hypersensitivity to iodinated contrast media or vasodilator stress agents; contraindications to nitroglycerin; contraindications to adenosine triphosphate (ATP); and uncontrolled arrhythmia precluding diagnostic acquisition. Sample Size The sample size is based on the co-primary noninferiority endpoint for CCTA enhancement. Based on prior data indicating approximately a 10.77% reduction in ascending aortic attenuation with low- versus high-concentration contrast, the noninferiority margin is set at 11% (approximately 50 HU) [14. 15]. Assuming a standard deviation of 119 HU, one-sided α = 0.025 and 90% power, 117 participants per group are required. Allowing for 10% attrition, the target enrollment is 129 participants per group (n = 258 total). Secondary diagnostic accuracy analyses (against ICA and FFR) will be considered exploratory/prespecified and will be interpreted in light of the number of participants undergoing clinically indicated invasive testing. Randomization, Allocation Concealment, and Blinding Participants will be allocated 1:1 to the low-concentration or high-concentration contrast group by sequentially applying a pre-generated randomized list as consecutive eligible patients are referred for examination. The allocation sequence will be computer-generated in SAS. Allocation concealment will be ensured using a secure electronic assignment module. CT technologists and coordinators may be unblinded for injection preparation; however, image readers and the primary outcome assessors will remain blinded to treatment assignment and contrast concentration. Images will be presented in randomized order to minimize recall and expectation bias. Contrast Media and Injection Protocols Participants will receive either high-concentration contrast (Xenetix 350, iobitridol 350 mg I/mL) or low-concentration contrast (Iobrix 270, iohexol 270 mg I/mL). Dynamic stress CTP will use a fixed volume (40 mL) injected at 5 mL/s followed by a 30 mL saline chaser. CCTA will use a tri-phasic protocol at 4.5 mL/s: 0.9 mL/kg of assigned contrast, followed by 45 mL of a 70:30 contrast–saline mixture, and a final 30 mL saline chaser. Two intravenous lines will be secured for contrast media injection and adenosine triphosphate infusion. All injections will be performed with a dual-head power injector (Dual Shot GX7; Nemoto Kyorindo, Tokyo, Japan). Weight-based dosing and fixed scan timing are intended to standardize iodine delivery conditions across participants. Patient Preparation and Stress Protocol Participants will be instructed to abstain from caffeine for 24 hours prior to imaging and to withhold theophylline on the day of the examination. In the absence of contraindications, sublingual nitroglycerin will be administered immediately before CCTA to promote coronary vasodilation. For heart-rate control, if baseline heart rate is ≥ 60 beats per minute, oral ivabradine (5 mg or 7.5 mg) will be administered per protocol. Heart rate will be measured every 10 minutes for 40 minutes; scanning will typically commence at approximately 60 minutes once adequate rate reduction is achieved. Dynamic stress CTP will be performed during intravenous adenosine triphosphate infusion at 140 µg/kg/min for 3 minutes. CT Acquisition Protocol All examinations will be performed on a third-generation dual-source CT scanner (SOMATOM Force, Siemens Healthineers, Forchheim, Germany) and will comprise coronary calcium scoring, dynamic stress CTP, and CCTA (Fig. 2 ). For dynamic stress CTP, acquisition will begin 4 seconds after contrast initiation and proceed in shuttle mode (z-axis coverage 105 mm) over a fixed 32-second interval, yielding approximately 10–15 time frames depending on heart rate. Images will be acquired in end-systole using collimation 96 × 0.6 mm, rotation time 250 ms, automated tube-voltage and tube-current modulation(CARE Dose4D and CARE kV, Siemens Healthineers, Forchheim, Germany). Physiologic data (baseline heart rate, peak heart rate at CTP, and heart-rate increment) will be recorded prospectively. Following completion of CTP, CCTA will be acquired after a standardized inter-exam interval of approximately 10 minutes. Immediately before CCTA, 0.6 mg sublingual nitroglycerin will be administered. Prospective ECG-triggered axial scanning will be used for heart rate < 65 bpm, whereas retrospective ECG-gated acquisition with ECG-based tube-current modulation will be used for heart rate ≥ 65 bpm. CT Reconstruction and Post-Processing Dynamic stress CTP datasets will be reconstructed in the axial plane (slice thickness 3 mm, 2 mm overlap) using a medium-sharp quantitative kernel (Qr40) to preserve linearity of iodine attenuation. Post-processing will be performed on workstation (Syngo.via VB10, Siemens Healthineers, Forchheim, Germany) using commercial perfusion software. MBF (mL/100 mL/min) will be derived by parametric deconvolution based on a two-compartment tracer-kinetic model applied to time–attenuation curves. The arterial input function will be placed in the ascending aorta or left ventricular cavity using standardized ROIs. The left ventricle will be segmented according to the AHA 17-segment model and polar maps generated for territorial and segmental analyses. CCTA datasets will be reconstructed with a medium–soft vascular kernel (Bv40) and iterative reconstruction (ADMIRE, strength 3). Images will be transferred to offline workstation, for post-processing, and optimal phases (mid-diastolic and/or end-systolic) will be selected for evaluation. Radiation Dose Assessment For each examination, CTDIvol and dose–length product will be recorded for each scan component (calcium scoring, dynamic stress CTP, and CCTA). Effective dose will be estimated as DLP × 0.014 mSv/mGy·cm, and total study dose will be calculated as the sum across components. Image Analysis Quantitative CCTA image quality will be evaluated using ROIs in proximal and distal segments of each major coronary artery (left anterior descending coronary artery [LAD], left circumflex artery [LCX], right coronary artery [RCA]) to obtain mean attenuation (HU) (Fig. 3 A-C). Image noise will be defined as the standard deviation of attenuation in a homogeneous ascending aortic ROI (Fig. 3 D). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) will be calculated as SNR = HU_coronary / SD_aorta and CNR = (HU_coronary − HU_myocardium) / SD_aorta, where HU_myocardium is measured from a mid-ventricular septal ROI (Fig. 3 E). Measurements will be performed on the optimal phase and averaged for per-vessel and per-patient analyses. Dynamic stress CTP MBF will be quantified on voxel-wise MBF maps. For segmental analysis, ROIs will be drawn on short-axis MBF maps using the AHA 17-segment model, positioned ≥ 2 mm from endocardial and epicardial borders (Fig. 3 F). For the co-primary MBF endpoint, the primary analysis set will include only predefined non-ischemic segments (e.g., visually normal segments with MBF ≥ 100 mL/100 mL/min). Segments with MBF < 100 mL/100 mL/min will be excluded from the primary analysis and evaluated in prespecified sensitivity and diagnostic-performance analyses. Qualitative Image Quality Assessment All CCTA and dynamic stress CTP datasets will be independently reviewed by two board-certified cardiovascular radiologists (> 10 years’ experience) blinded to clinical information and contrast group. CCTA diagnostic quality will be graded on a 5-point Likert scale (5 excellent to 1 nondiagnostic). Dynamic stress CTP interpretability will be graded using an analogous 5-point Likert scale. Readers will also record diagnostic acceptability (acceptable vs non-acceptable) and diagnostic confidence (high/medium/low). Discrepancies will be resolved by consensus after independent review. Secondary Diagnostic Validation: ICA and FFR Secondary diagnostic validation will be performed in participants who undergo invasive testing as part of routine care. The decision to perform ICA and/or FFR will be made by treating cardiologists based on clinical assessment and standard practice, independent of study participation. ICA will be interpreted by experienced interventional cardiologists. Anatomic stenosis severity will be recorded per vessel using standard quantitative or visual assessment; ≥50% luminal narrowing will define significant stenosis for CCTA diagnostic-performance analyses. For physiology, when FFR is measured, FFR ≤ 0.80 will define functionally significant ischemia in the interrogated vessel. For CCTA diagnostic performance, analyses will compare CCTA-derived stenosis categories against ICA on a per-vessel and per-patient basis. For dynamic stress CTP diagnostic performance, analyses will compare CTP ischemia (territorial/segmental defects or low MBF) against vessel-level FFR where available, with mapping of myocardial territories to corresponding coronary vessels using standardized AHA territorial assignments and clinical correlation. Statistical Methods All statistical analyses will be performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Baseline characteristics will be summarized by group. Standardized mean differences (SMD) will be used to assess baseline balance; variables with absolute SMD ≥ 0.25 will be considered imbalanced and included as covariates in sensitivity analyses. Quantitative endpoints with repeated measures (HU, SNR, CNR, MBF) will be analyzed using linear mixed-effects models (LMMs) with random intercepts for patients (nested within the contrast group) to account for intra-individual correlation across vessels or myocardial segments in independent patient cohorts. Fixed effects will include contrast group, measurement location, and group×location interaction. Noninferiority will be assessed using the estimated between-group difference (low minus high) and its two-sided 95% confidence interval. For CCTA, noninferiority will be concluded if the lower bound of the 95% confidence interval for Δ (HU) is greater than − 50 HU, and if diagnostic adequacy criteria (e.g., mean HU threshold) are met. For MBF (the functional co-primary endpoint), noninferiority margins will not be applied. Instead, the comparability of MBF between the two contrast groups will be evaluated using standard two-sided hypotheses testing (α = 0.05) within the linear mixed-effects model framework to confirm that absolute quantitative values are statistically preserved. Qualitative image-quality endpoints (Likert scores) will be compared using Mann–Whitney U tests, with proportional-odds models as sensitivity analyses. Interobserver agreement will be assessed using weighted κ for ordinal scales and Cohen’s κ for binary acceptability. Secondary diagnostic accuracy analyses will be conducted in the subset undergoing ICA and/or FFR. For coronary CT angiography using invasive coronary angiography as the reference standard, sensitivity, specificity, positive predictive value, and negative predictive value will be calculated for the detection of ≥ 50% coronary artery stenosis. Overall diagnostic performance will be quantified using receiver-operating-characteristic (ROC) curve analysis and the area under the ROC curve (AUC). For CTP versus FFR, similar metrics will be calculated for detecting FFR-defined ischemia (≤ 0.80). Because multiple vessels may be contributed by a single participant, analyses will account for within-patient clustering (e.g., using generalized estimating equations for binary endpoints and cluster-robust variance estimators for AUC and confidence intervals). Prespecified sensitivity analyses will evaluate the impact of verification bias (invasive testing performed based on clinical indication) using approaches such as restricting to clinically comparable subgroups and/or statistical correction methods, as feasible given sample size. Missing data will be described and handled using appropriate methods for the endpoint (e.g., mixed models under missing at random assumptions, with sensitivity analyses if missingness is substantial). Data Management and Safety Monitoring A centralized data-coordinating center will oversee data capture and quality control. Study data will be entered into a secure electronic system. Monitoring will include periodic audits of completeness, protocol adherence, and adverse-event reporting. Endpoints are imaging-based and do not mandate repeat imaging. Clinical management decisions, including invasive testing, will be determined by treating physicians according to standard care. No interim efficacy analysis is planned. Discussion This prospective, randomized noninferiority trial is designed to address a clinically important question in contemporary cardiac CT: whether reduction of iodine concentration in contrast media can be achieved without compromising the diagnostic performance of CCTA for detecting anatomically significant coronary artery disease, nor the quantitative and diagnostic performance of dynamic stress CTP for identifying myocardial ischemia, within an integrated anatomic–functional imaging workflow. CCTA is widely used as a first-line noninvasive test for suspected CAD because of its high sensitivity and negative predictive value [ 16 , 20 ]. However, false-positive findings remain a concern, particularly in patients with heavy coronary calcification, diffuse atherosclerosis, or prior percutaneous coronary intervention [ 5 , 6 ]. In these settings, maintaining robust diagnostic performance—rather than image quality alone—is essential. Dynamic stress CTP provides complementary functional information by enabling quantitative assessment of myocardial blood flow and ischemia, thereby addressing one of the key limitations of anatomic imaging [ 7 – 9 ]. The integration of CCTA and dynamic stress CTP into a single examination offers a comprehensive evaluation of both coronary anatomy and myocardial perfusion. However, this approach increases total iodine exposure, which remains the most important modifiable risk factor for CA-AKI [ 11 , 12 ]. With the aging population and increasing prevalence of chronic kidney disease and cardiometabolic comorbidities, strategies to reduce iodine load have become increasingly relevant. Recent advances in CT technology, including low tube-voltage acquisition and advanced reconstruction algorithms, have challenged the traditional reliance on high–iodine-concentration contrast media [ 13 , 15 ]. While prior studies have suggested that iodine reduction may preserve image quality for CCTA, evidence remains limited regarding its impact on quantitative MBF and, more importantly, on diagnostic performance against invasive reference standards[ 15 , 17 – 19 ]. The present trial addresses this gap by combining a rigorous noninferiority framework for technical endpoints with prespecified diagnostic accuracy analyses using ICA and FFR when performed as part of routine clinical care. If noninferiority is demonstrated for coronary enhancement and myocardial blood flow, and if diagnostic performance of both CCTA and dynamic stress CTP is preserved in the invasive validation cohorts, the findings would support broader adoption of iodine-reduction strategies in integrated cardiac CT protocols. Such an approach could facilitate safer use of combined anatomic–functional CT imaging, particularly in patients at increased risk for contrast-associated kidney injury, while maintaining confidence in downstream invasive decision-making. Several limitations warrant consideration. This is a single-center study, and generalizability may depend on scanner technology and local expertise. In addition, ICA and FFR are performed based on clinical indication rather than mandated by the protocol, introducing the potential for verification bias. To mitigate this, the study prespecifies sensitivity analyses and statistical methods that account for clustered data and clinically driven testing. Finally, the study focuses on imaging-based endpoints and does not evaluate clinical outcomes; therefore, the results will inform technical and diagnostic validity rather than outcome equivalence. Conclusion This prospective, randomized noninferiority trial is designed to evaluate whether low–iodine-concentration contrast media can be used without compromising image quality or diagnostic performance of CCTA, nor quantitative MBF assessment and ischemia detection on dynamic stress CTP. By addressing both anatomic and functional diagnostic performance within a unified cardiac CT workflow, this study is expected to provide evidence supporting a more patient-centered and resource-conscious approach to contrast media optimization in modern cardiac CT. Declarations Conflicts of Interest: This study is supported by Taejoon Pharmaceutical Co., Ltd. The sponsor had no role in study design, data collection, data analysis, interpretation, or manuscript preparation. The authors declare no other conflicts of interest. Author Contribution S.M.K. and S.-J.C. conceptualized the study and designed the overall trial. S.M.K., S.-J.C., H.C., and P.-H.J. established the methodology and study protocol. S.-J.C., P.-H.J., and D.-H.K. planned the CT image acquisition, reconstruction, and quantitative post-processing workflows. S.-J.C., H.C., and P.-H.J. developed the statistical analysis plan. S.M.K. administered the project and supervised the research framework. S.-J.C. developed the protocol visualizations and wrote the original draft. S.M.K., H.C., P.-H.J., and D.-H.K. critically reviewed and edited the manuscript. All authors reviewed the manuscript and approved the final version. Acknowledgements This study is supported by Taejoon Pharmaceutical Co., Ltd. (Seoul, Republic of Korea). The sponsor had no role in the study design, data collection, data analysis, interpretation of the results, or the decision to submit the manuscript. References Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain. Circulation 2021;144:e368-e454. Pontone G, Guaricci AI, Palmer SC, et al. Diagnostic performance of non-invasive imaging for stable coronary artery disease: a meta-analysis. Int J Cardiol 2020;300:276–81. Pontone G, Baggiano A, Andreini D, et al. Stress computed tomography perfusion versus fractional flow reserve CT-derived in suspected coronary artery disease: the PERFECTION study. JACC Cardiovasc Imaging 2019;12:1487–97. Kwan AC, Gransar H, Tzolos E, et al. The accuracy of coronary CT angiography in patients with coronary calcium score above 1000 Agatston units: comparison with quantitative coronary angiography. J Cardiovasc Comput Tomogr 2021;15:412–8. Dahdal J, Jukema RA, Remmelzwaal S, et al. Diagnostic performance of CCTA and CTP for clinically suspected in-stent restenosis: a meta-analysis. J Cardiovasc Comput Tomogr 2025;19:183–90. Yang J, Dou G, He B, et al. Stress myocardial blood flow ratio by dynamic CT perfusion identifies hemodynamically significant CAD. JACC Cardiovasc Imaging 2020;13:966–76. Andreini D, Mushtaq S, Trabattoni D, et al. Diagnostic accuracy of dynamic stress myocardial CT perfusion compared with invasive physiology in patients with stents: the ADVANTAGE 2 study. Radiology 2024;313:e232225. Ko SM, Cha SJ, Kim H, et al. Diagnostic performance of dynamic myocardial perfusion imaging using third-generation dual-source computed tomography in patients with intermediate pretest probability of coronary artery disease. J Cardiovasc Dev Dis 2025;12:264. Lee YC, Hsieh CC, Chang TT, Li CY. Contrast-induced acute kidney injury among patients with chronic kidney disease undergoing imaging studies: a meta-analysis. AJR Am J Roentgenol 2019;213:728–35. Werner S, Bez C, Hinterleitner C, Horger M. Incidence of contrast-induced acute kidney injury in high-risk oncology patients undergoing contrast-enhanced CT with a reduced dose of the iso-osmolar iodinated contrast medium iodixanol. PLoS One 2020;15:e0233433. Nie Z, Liu Y, Wang C, Sun G, Chen G, Lu Z. Safe limits of contrast media for contrast-induced nephropathy: a prospective cohort study. Front Med (Lausanne) 2021;8:701062. Nagayama Y, Tanoue S, Tsuji A, et al. Application of 80-kVp scan and raw data-based iterative reconstruction for reduced iodine load abdominal-pelvic CT in patients at risk of contrast-induced nephropathy: effects on radiation dose, image quality and renal function. Br J Radiol 2018;91:20170632. Im DJ, Kim YH, Choo KS, et al. Comparison of coronary computed tomography angiography image quality with high- and low-concentration contrast agents (CONCENTRATE): study protocol for a randomized controlled trial. Trials 2016;17:315. Cha MJ, Kim SM, Ahn TR, Choe YH. Comparing feasibility of low-tube-voltage with low-iodine contrast vs high-voltage with high-iodine contrast in coronary CTA. PLoS One 2020;15:e0236108. Yoshida K, Tanabe Y, Hosokawa T, et al. Coronary CT angiography for clinical practice. Jpn J Radiol 2024;42:555–80. Mihl C, Kok M, Wildberger JE, et al. Coronary CT angiography using low concentrated contrast media injected with high flow rates: feasible in clinical practice. Eur J Radiol 2015;84:2155–60. Wang S, Sun Z, Zeng Y, et al. Feasibility study of “triple-low” technique for coronary CT angiography. Sci Rep 2024;14:32110. Zhang M, Hao P, Jiang C, et al. Personalized application of three different iodine concentrations in coronary CT angiography. J Cell Mol Med 2020;24:5446–53. Alwaheidi D, Ehtesham A, Azizi S, et al. Meta-analysis of the diagnostic accuracy of CCTA vs invasive angiography in preoperative cardiac surgery planning. Open Heart 2025;12:e003768. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 04 May, 2026 Reviews received at journal 04 May, 2026 Reviewers agreed at journal 29 Apr, 2026 Reviews received at journal 24 Apr, 2026 Reviewers agreed at journal 09 Apr, 2026 Reviewers invited by journal 09 Apr, 2026 Editor assigned by journal 07 Apr, 2026 Submission checks completed at journal 07 Apr, 2026 First submitted to journal 31 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9275618","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620612382,"identity":"f3ce0652-34cb-44b7-ab1e-1b3532e8451c","order_by":0,"name":"Sung-Jin Cha","email":"","orcid":"","institution":"Yonsei University","correspondingAuthor":false,"prefix":"","firstName":"Sung-Jin","middleName":"","lastName":"Cha","suffix":""},{"id":620612385,"identity":"8cef8f8d-adc7-443f-9aa6-5ecf0bf50aa4","order_by":1,"name":"Pil-Hyun Jeon","email":"","orcid":"","institution":"Dawon University","correspondingAuthor":false,"prefix":"","firstName":"Pil-Hyun","middleName":"","lastName":"Jeon","suffix":""},{"id":620612395,"identity":"72e1f943-2b05-4aa7-8bff-ac42a6afa412","order_by":2,"name":"Dong-Hee Kho","email":"","orcid":"","institution":"Wonju Severance Christian Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dong-Hee","middleName":"","lastName":"Kho","suffix":""},{"id":620612400,"identity":"23ef48f8-f08d-4868-991f-038277ccda40","order_by":3,"name":"Hyosung Cho","email":"","orcid":"","institution":"Yonsei University","correspondingAuthor":false,"prefix":"","firstName":"Hyosung","middleName":"","lastName":"Cho","suffix":""},{"id":620612406,"identity":"8bd19233-fdfb-403d-bcc5-cecf0607f6e0","order_by":4,"name":"Sung Min Ko","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYBACCQYGxsd/KmrkGBh4oEI8eDWAtTAb8Jw5ZkySFjYJ3jbmxAaitUj2n06TkGBjS99w/OzBBx8Y7OQYeM4+wKtFWiJ3s4UBj0zuhjN5yYYzGJKNGXjbDfBqkZPg3XgjQYItd8OBHDNpHoYDiQ38bPgdJsd/doPEAQPmdIPzb4jUIs2Qu0myIYE5weAGzBbeNvxaJGfkbjZmOHDMcOaNN8aGMwySjdl4juHXInH+7MbHjP9q5PnO5xg++FBhJ8fPk4ZfCxwoHACRwLAi4BMkIN9AtNJRMApGwSgYaQAAl4A/hVIkqZ4AAAAASUVORK5CYII=","orcid":"","institution":"Wonju Severance Christian Hospital","correspondingAuthor":true,"prefix":"","firstName":"Sung","middleName":"Min","lastName":"Ko","suffix":""}],"badges":[],"createdAt":"2026-03-31 06:53:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9275618/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9275618/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107257201,"identity":"3119dc42-1f52-453c-a707-dc8e61eab1f3","added_by":"auto","created_at":"2026-04-19 12:27:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64256,"visible":true,"origin":"","legend":"\u003cp\u003eStudy workflow and design. CT, computed tomography; CCTA, Coronary CT Angiography; CTP, CT Perfusion; MBF, Myocardial Blood Flow; ICA, Invasive Coronary Angiography; FFR, Fractional Flow Reserve.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9275618/v1/03792fa88bba278c72669749.png"},{"id":107482480,"identity":"749a977d-9cc5-42fc-82e7-ee7f5ad474db","added_by":"auto","created_at":"2026-04-22 02:23:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":206151,"visible":true,"origin":"","legend":"\u003cp\u003eIntegrating anatomical and functional assessment of coronary artery disease using dynamic CT-MPI and CCTA. After patient preparation and monitoring, non-contrast prospective electrocardiography-guided axial CT for calcium scoring was obtained. Stress CT-MPI is acquired in ECG-triggered axial shuttle mode via intravenous adenosine infusion lasting at least 3 min. An optional 5 min delayed CT scan can be added while waiting 10 min after stress CT-MPI. CCTA is performed using prospective ECG-triggered or retrospective ECG-gated scanning with ECG pulsing based on HR. CT-MPI, computed tomography-myocardial perfusion imaging; IV, intravenous; BP, blood pressure; HR, heart rate; ECG, electrocardiography; CM, contrast media.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9275618/v1/a3dafe30af63c7736dbb8613.png"},{"id":107257203,"identity":"74bbfd6d-5902-48d8-b28e-538bd52cc993","added_by":"auto","created_at":"2026-04-19 12:27:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":440222,"visible":true,"origin":"","legend":"\u003cp\u003eQuantitative assessment of CCTA image quality and myocardial perfusion using dynamic stress CT perfusion (CTP).\u003c/p\u003e\n\u003cp\u003e(A–C) Curved multiplanar reformations of the three major coronary arteries—right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex artery (LCX)—show the regions of interest (ROIs) placed in proximal and distal segments for measurement of coronary attenuation (HU).\u003cbr\u003e\n(D) A homogeneous ROI in the ascending aorta was used to define image noise as the standard deviation of attenuation (SD_aorta).\u003cbr\u003e\n(E) A mid-ventricular septal myocardial ROI was used to obtain myocardial attenuation (HU_myocardium) for contrast-to-noise ratio (CNR) calculation.\u003cbr\u003e\n(F) Voxel-wise myocardial blood flow (MBF) map obtained from dynamic stress CTP, with segmental ROIs placed on a short-axis view according to the AHA 17-segment model for MBF quantification.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9275618/v1/2997aee429b01e3eaa9ebb65.png"},{"id":107485464,"identity":"31f7f18c-dc86-4cbe-9829-69cebc793ba2","added_by":"auto","created_at":"2026-04-22 02:35:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":948284,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9275618/v1/dacf6a1e-336c-442e-a60c-d5908a9e186d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLow- vs High-Iodine–Concentration Contrast Media for Coronary CT Angiography and Dynamic Stress CT Perfusion: A Prospective, Randomized Noninferiority Trial with Secondary Diagnostic Validation Using Invasive Coronary Angiography and Fractional Flow Reserve\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCoronary computed tomography angiography (CCTA) has become a first-line noninvasive test for evaluating coronary artery disease (CAD), providing high diagnostic accuracy for detecting luminal stenosis and characterizing atherosclerotic plaque [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nevertheless, CCTA has important inherent limitations. It offers a predominantly anatomic assessment of the coronary lumen and does not directly quantify the hemodynamic significance of individual lesions; consequently, the correlation between anatomic stenosis severity and functionally significant ischemia is at best modest [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Image quality and diagnostic performance may also be substantially degraded in patients with heavy coronary calcification or prior stents, where blooming artifacts can overestimate stenosis and increase false-positive rates [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDynamic stress CT perfusion (CTP) is a functional imaging technique that quantifies the hemodynamic significance of coronary stenosis by measuring myocardial blood flow (MBF) under pharmacologic stress. When combined with CCTA in a single one-stop-shop examination, CTP adds functional data to anatomic information, enabling a more comprehensive characterization of CAD than either modality alone and potentially improving diagnostic accuracy and clinical decision-making [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis comprehensive strategy poses a dilemma in contrast use. Although high-concentration iodinated media have been favored to maximize opacification and diagnostic confidence, they also increase the total iodine load\u0026mdash;the most important modifiable risk factor for contrast-associated acute kidney injury (CA-AKI)\u0026mdash;an issue that is particularly critical in patients with renal impairment, diabetes, or cardiovascular comorbidities [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent advances in CT hardware and software have challenged the traditional linkage between iodine concentration and image quality. In particular, low tube-voltage techniques augment iodine attenuation and may allow diagnostically adequate enhancement with lower iodine concentration while reducing radiation exposure [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, for a protocol intended for registration and for clinical translation, technical noninferiority alone is not sufficient. It is also important to predefine and prospectively evaluate whether iodine reduction preserves downstream diagnostic validity in real-world pathways, including referral to invasive coronary angiography (ICA) and physiology assessment with fractional flow reserve (FFR).\u003c/p\u003e"},{"header":"Methods/Design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial Design\u003c/h2\u003e \u003cp\u003eThis study is designed as a prospective, single-institution, randomized, double-blind noninferiority trial (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The trial will evaluate whether a low\u0026ndash;iodine-concentration iodinated contrast media protocol is noninferior to a high\u0026ndash;iodine-concentration protocol for (1) coronary enhancement on CCTA (anatomic co-primary endpoint) and whether it yields comparable and preserved (2) absolute MBF on dynamic stress CTP in non-ischemic territories (functional co-primary endpoint). In addition, prespecified secondary analyses will evaluate diagnostic accuracy of CCTA and dynamic stress CTP against invasive reference standards (ICA and FFR) in the subset of participants who undergo invasive testing as part of standard care.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics and Registration\u003c/h3\u003e\n\u003cp\u003e The protocol has been approved by the Institutional Review Board of Wonju Severance Christian Hospital (IRB number: CR122087). The trial will be conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. Written informed consent will be obtained from all participants before any study procedures. The trial was registered at the Clinical Research Information Service (CRIS), Republic of Korea (Trial registration: KCT0011418).\u003c/p\u003e\n\u003ch3\u003ePopulation and Setting\u003c/h3\u003e\n\u003cp\u003eThe trial plans to enroll 258 adults with known or suspected CAD referred for clinically indicated cardiac CT (CCTA with planned dynamic stress CTP). Eligible participants will be \u0026ge;\u0026thinsp;40 years of age, will have electrocardiography (ECG)-gated imaging feasibility, and will have adequate renal function (e.g., estimated glomerular filtration rate [eGFR]\u0026thinsp;\u0026ge;\u0026thinsp;45 mL/min/1.73 m\u0026sup2;). Exclusion criteria will include suspected acute myocardial infarction or unstable angina; complex congenital heart disease; significant renal dysfunction or acute kidney injury (e.g., serum creatinine\u0026thinsp;\u0026ge;\u0026thinsp;1.5 mg/dL or eGFR\u0026thinsp;\u0026lt;\u0026thinsp;45 mL/min/1.73 m\u0026sup2;); history of coronary artery bypass grafting (percutaneous coronary intervention/stents permitted and recorded); pregnancy or lactation; history of severe hypersensitivity to iodinated contrast media or vasodilator stress agents; contraindications to nitroglycerin; contraindications to adenosine triphosphate (ATP); and uncontrolled arrhythmia precluding diagnostic acquisition.\u003c/p\u003e\n\u003ch3\u003eSample Size\u003c/h3\u003e\n\u003cp\u003eThe sample size is based on the co-primary noninferiority endpoint for CCTA enhancement. Based on prior data indicating approximately a 10.77% reduction in ascending aortic attenuation with low- versus high-concentration contrast, the noninferiority margin is set at 11% (approximately 50 HU) [14. 15]. Assuming a standard deviation of 119 HU, one-sided α\u0026thinsp;=\u0026thinsp;0.025 and 90% power, 117 participants per group are required. Allowing for 10% attrition, the target enrollment is 129 participants per group (n\u0026thinsp;=\u0026thinsp;258 total). Secondary diagnostic accuracy analyses (against ICA and FFR) will be considered exploratory/prespecified and will be interpreted in light of the number of participants undergoing clinically indicated invasive testing.\u003c/p\u003e\n\u003ch3\u003eRandomization, Allocation Concealment, and Blinding\u003c/h3\u003e\n\u003cp\u003eParticipants will be allocated 1:1 to the low-concentration or high-concentration contrast group by sequentially applying a pre-generated randomized list as consecutive eligible patients are referred for examination. The allocation sequence will be computer-generated in SAS. Allocation concealment will be ensured using a secure electronic assignment module. CT technologists and coordinators may be unblinded for injection preparation; however, image readers and the primary outcome assessors will remain blinded to treatment assignment and contrast concentration. Images will be presented in randomized order to minimize recall and expectation bias.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eContrast Media and Injection Protocols\u003c/h2\u003e \u003cp\u003eParticipants will receive either high-concentration contrast (Xenetix 350, iobitridol 350 mg I/mL) or low-concentration contrast (Iobrix 270, iohexol 270 mg I/mL). Dynamic stress CTP will use a fixed volume (40 mL) injected at 5 mL/s followed by a 30 mL saline chaser. CCTA will use a tri-phasic protocol at 4.5 mL/s: 0.9 mL/kg of assigned contrast, followed by 45 mL of a 70:30 contrast\u0026ndash;saline mixture, and a final 30 mL saline chaser. Two intravenous lines will be secured for contrast media injection and adenosine triphosphate infusion. All injections will be performed with a dual-head power injector (Dual Shot GX7; Nemoto Kyorindo, Tokyo, Japan). Weight-based dosing and fixed scan timing are intended to standardize iodine delivery conditions across participants.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient Preparation and Stress Protocol\u003c/h3\u003e\n\u003cp\u003eParticipants will be instructed to abstain from caffeine for 24 hours prior to imaging and to withhold theophylline on the day of the examination. In the absence of contraindications, sublingual nitroglycerin will be administered immediately before CCTA to promote coronary vasodilation. For heart-rate control, if baseline heart rate is \u0026ge;\u0026thinsp;60 beats per minute, oral ivabradine (5 mg or 7.5 mg) will be administered per protocol. Heart rate will be measured every 10 minutes for 40 minutes; scanning will typically commence at approximately 60 minutes once adequate rate reduction is achieved. Dynamic stress CTP will be performed during intravenous adenosine triphosphate infusion at 140 \u0026micro;g/kg/min for 3 minutes.\u003c/p\u003e\n\u003ch3\u003eCT Acquisition Protocol\u003c/h3\u003e\n\u003cp\u003eAll examinations will be performed on a third-generation dual-source CT scanner (SOMATOM Force, Siemens Healthineers, Forchheim, Germany) and will comprise coronary calcium scoring, dynamic stress CTP, and CCTA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). For dynamic stress CTP, acquisition will begin 4 seconds after contrast initiation and proceed in shuttle mode (z-axis coverage 105 mm) over a fixed 32-second interval, yielding approximately 10\u0026ndash;15 time frames depending on heart rate. Images will be acquired in end-systole using collimation 96 \u0026times; 0.6 mm, rotation time 250 ms, automated tube-voltage and tube-current modulation(CARE Dose4D and CARE kV, Siemens Healthineers, Forchheim, Germany). Physiologic data (baseline heart rate, peak heart rate at CTP, and heart-rate increment) will be recorded prospectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFollowing completion of CTP, CCTA will be acquired after a standardized inter-exam interval of approximately 10 minutes. Immediately before CCTA, 0.6 mg sublingual nitroglycerin will be administered. Prospective ECG-triggered axial scanning will be used for heart rate\u0026thinsp;\u0026lt;\u0026thinsp;65 bpm, whereas retrospective ECG-gated acquisition with ECG-based tube-current modulation will be used for heart rate\u0026thinsp;\u0026ge;\u0026thinsp;65 bpm.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCT Reconstruction and Post-Processing\u003c/h2\u003e \u003cp\u003eDynamic stress CTP datasets will be reconstructed in the axial plane (slice thickness 3 mm, 2 mm overlap) using a medium-sharp quantitative kernel (Qr40) to preserve linearity of iodine attenuation. Post-processing will be performed on workstation (Syngo.via VB10, Siemens Healthineers, Forchheim, Germany) using commercial perfusion software. MBF (mL/100 mL/min) will be derived by parametric deconvolution based on a two-compartment tracer-kinetic model applied to time\u0026ndash;attenuation curves. The arterial input function will be placed in the ascending aorta or left ventricular cavity using standardized ROIs. The left ventricle will be segmented according to the AHA 17-segment model and polar maps generated for territorial and segmental analyses.\u003c/p\u003e \u003cp\u003eCCTA datasets will be reconstructed with a medium\u0026ndash;soft vascular kernel (Bv40) and iterative reconstruction (ADMIRE, strength 3). Images will be transferred to offline workstation, for post-processing, and optimal phases (mid-diastolic and/or end-systolic) will be selected for evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRadiation Dose Assessment\u003c/h2\u003e \u003cp\u003eFor each examination, CTDIvol and dose\u0026ndash;length product will be recorded for each scan component (calcium scoring, dynamic stress CTP, and CCTA). Effective dose will be estimated as DLP \u0026times; 0.014 mSv/mGy\u0026middot;cm, and total study dose will be calculated as the sum across components.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eImage Analysis\u003c/h2\u003e \u003cp\u003eQuantitative CCTA image quality will be evaluated using ROIs in proximal and distal segments of each major coronary artery (left anterior descending coronary artery [LAD], left circumflex artery [LCX], right coronary artery [RCA]) to obtain mean attenuation (HU) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-C). Image noise will be defined as the standard deviation of attenuation in a homogeneous ascending aortic ROI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) will be calculated as SNR\u0026thinsp;=\u0026thinsp;HU_coronary / SD_aorta and CNR = (HU_coronary\u0026thinsp;\u0026minus;\u0026thinsp;HU_myocardium) / SD_aorta, where HU_myocardium is measured from a mid-ventricular septal ROI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE). Measurements will be performed on the optimal phase and averaged for per-vessel and per-patient analyses.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDynamic stress CTP MBF will be quantified on voxel-wise MBF maps. For segmental analysis, ROIs will be drawn on short-axis MBF maps using the AHA 17-segment model, positioned\u0026thinsp;\u0026ge;\u0026thinsp;2 mm from endocardial and epicardial borders (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). For the co-primary MBF endpoint, the primary analysis set will include only predefined non-ischemic segments (e.g., visually normal segments with MBF\u0026thinsp;\u0026ge;\u0026thinsp;100 mL/100 mL/min). Segments with MBF\u0026thinsp;\u0026lt;\u0026thinsp;100 mL/100 mL/min will be excluded from the primary analysis and evaluated in prespecified sensitivity and diagnostic-performance analyses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eQualitative Image Quality Assessment\u003c/h2\u003e \u003cp\u003eAll CCTA and dynamic stress CTP datasets will be independently reviewed by two board-certified cardiovascular radiologists (\u0026gt;\u0026thinsp;10 years\u0026rsquo; experience) blinded to clinical information and contrast group. CCTA diagnostic quality will be graded on a 5-point Likert scale (5 excellent to 1 nondiagnostic). Dynamic stress CTP interpretability will be graded using an analogous 5-point Likert scale. Readers will also record diagnostic acceptability (acceptable vs non-acceptable) and diagnostic confidence (high/medium/low). Discrepancies will be resolved by consensus after independent review.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Diagnostic Validation: ICA and FFR\u003c/h2\u003e \u003cp\u003eSecondary diagnostic validation will be performed in participants who undergo invasive testing as part of routine care. The decision to perform ICA and/or FFR will be made by treating cardiologists based on clinical assessment and standard practice, independent of study participation. ICA will be interpreted by experienced interventional cardiologists. Anatomic stenosis severity will be recorded per vessel using standard quantitative or visual assessment; \u0026ge;50% luminal narrowing will define significant stenosis for CCTA diagnostic-performance analyses. For physiology, when FFR is measured, FFR\u0026thinsp;\u0026le;\u0026thinsp;0.80 will define functionally significant ischemia in the interrogated vessel.\u003c/p\u003e \u003cp\u003eFor CCTA diagnostic performance, analyses will compare CCTA-derived stenosis categories against ICA on a per-vessel and per-patient basis. For dynamic stress CTP diagnostic performance, analyses will compare CTP ischemia (territorial/segmental defects or low MBF) against vessel-level FFR where available, with mapping of myocardial territories to corresponding coronary vessels using standardized AHA territorial assignments and clinical correlation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Methods\u003c/h2\u003e \u003cp\u003eAll statistical analyses will be performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Baseline characteristics will be summarized by group. Standardized mean differences (SMD) will be used to assess baseline balance; variables with absolute SMD\u0026thinsp;\u0026ge;\u0026thinsp;0.25 will be considered imbalanced and included as covariates in sensitivity analyses.\u003c/p\u003e \u003cp\u003eQuantitative endpoints with repeated measures (HU, SNR, CNR, MBF) will be analyzed using linear mixed-effects models (LMMs) with random intercepts for patients (nested within the contrast group) to account for intra-individual correlation across vessels or myocardial segments in independent patient cohorts. Fixed effects will include contrast group, measurement location, and group\u0026times;location interaction. Noninferiority will be assessed using the estimated between-group difference (low minus high) and its two-sided 95% confidence interval. For CCTA, noninferiority will be concluded if the lower bound of the 95% confidence interval for Δ (HU) is greater than \u0026minus;\u0026thinsp;50 HU, and if diagnostic adequacy criteria (e.g., mean HU threshold) are met. For MBF (the functional co-primary endpoint), noninferiority margins will not be applied. Instead, the comparability of MBF between the two contrast groups will be evaluated using standard two-sided hypotheses testing (α\u0026thinsp;=\u0026thinsp;0.05) within the linear mixed-effects model framework to confirm that absolute quantitative values are statistically preserved.\u003c/p\u003e \u003cp\u003eQualitative image-quality endpoints (Likert scores) will be compared using Mann\u0026ndash;Whitney U tests, with proportional-odds models as sensitivity analyses. Interobserver agreement will be assessed using weighted κ for ordinal scales and Cohen\u0026rsquo;s κ for binary acceptability.\u003c/p\u003e \u003cp\u003eSecondary diagnostic accuracy analyses will be conducted in the subset undergoing ICA and/or FFR. For coronary CT angiography using invasive coronary angiography as the reference standard, sensitivity, specificity, positive predictive value, and negative predictive value will be calculated for the detection of \u0026ge;\u0026thinsp;50% coronary artery stenosis. Overall diagnostic performance will be quantified using receiver-operating-characteristic (ROC) curve analysis and the area under the ROC curve (AUC). For CTP versus FFR, similar metrics will be calculated for detecting FFR-defined ischemia (\u0026le;\u0026thinsp;0.80). Because multiple vessels may be contributed by a single participant, analyses will account for within-patient clustering (e.g., using generalized estimating equations for binary endpoints and cluster-robust variance estimators for AUC and confidence intervals). Prespecified sensitivity analyses will evaluate the impact of verification bias (invasive testing performed based on clinical indication) using approaches such as restricting to clinically comparable subgroups and/or statistical correction methods, as feasible given sample size. Missing data will be described and handled using appropriate methods for the endpoint (e.g., mixed models under missing at random assumptions, with sensitivity analyses if missingness is substantial).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eData Management and Safety Monitoring\u003c/h2\u003e \u003cp\u003eA centralized data-coordinating center will oversee data capture and quality control. Study data will be entered into a secure electronic system. Monitoring will include periodic audits of completeness, protocol adherence, and adverse-event reporting. Endpoints are imaging-based and do not mandate repeat imaging. Clinical management decisions, including invasive testing, will be determined by treating physicians according to standard care. No interim efficacy analysis is planned.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective, randomized noninferiority trial is designed to address a clinically important question in contemporary cardiac CT: whether reduction of iodine concentration in contrast media can be achieved without compromising the diagnostic performance of CCTA for detecting anatomically significant coronary artery disease, nor the quantitative and diagnostic performance of dynamic stress CTP for identifying myocardial ischemia, within an integrated anatomic\u0026ndash;functional imaging workflow.\u003c/p\u003e \u003cp\u003eCCTA is widely used as a first-line noninvasive test for suspected CAD because of its high sensitivity and negative predictive value [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, false-positive findings remain a concern, particularly in patients with heavy coronary calcification, diffuse atherosclerosis, or prior percutaneous coronary intervention [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In these settings, maintaining robust diagnostic performance\u0026mdash;rather than image quality alone\u0026mdash;is essential. Dynamic stress CTP provides complementary functional information by enabling quantitative assessment of myocardial blood flow and ischemia, thereby addressing one of the key limitations of anatomic imaging [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe integration of CCTA and dynamic stress CTP into a single examination offers a comprehensive evaluation of both coronary anatomy and myocardial perfusion. However, this approach increases total iodine exposure, which remains the most important modifiable risk factor for CA-AKI [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. With the aging population and increasing prevalence of chronic kidney disease and cardiometabolic comorbidities, strategies to reduce iodine load have become increasingly relevant.\u003c/p\u003e \u003cp\u003eRecent advances in CT technology, including low tube-voltage acquisition and advanced reconstruction algorithms, have challenged the traditional reliance on high\u0026ndash;iodine-concentration contrast media [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. While prior studies have suggested that iodine reduction may preserve image quality for CCTA, evidence remains limited regarding its impact on quantitative MBF and, more importantly, on diagnostic performance against invasive reference standards[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The present trial addresses this gap by combining a rigorous noninferiority framework for technical endpoints with prespecified diagnostic accuracy analyses using ICA and FFR when performed as part of routine clinical care.\u003c/p\u003e \u003cp\u003eIf noninferiority is demonstrated for coronary enhancement and myocardial blood flow, and if diagnostic performance of both CCTA and dynamic stress CTP is preserved in the invasive validation cohorts, the findings would support broader adoption of iodine-reduction strategies in integrated cardiac CT protocols. Such an approach could facilitate safer use of combined anatomic\u0026ndash;functional CT imaging, particularly in patients at increased risk for contrast-associated kidney injury, while maintaining confidence in downstream invasive decision-making.\u003c/p\u003e \u003cp\u003eSeveral limitations warrant consideration. This is a single-center study, and generalizability may depend on scanner technology and local expertise. In addition, ICA and FFR are performed based on clinical indication rather than mandated by the protocol, introducing the potential for verification bias. To mitigate this, the study prespecifies sensitivity analyses and statistical methods that account for clustered data and clinically driven testing. Finally, the study focuses on imaging-based endpoints and does not evaluate clinical outcomes; therefore, the results will inform technical and diagnostic validity rather than outcome equivalence.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis prospective, randomized noninferiority trial is designed to evaluate whether low\u0026ndash;iodine-concentration contrast media can be used without compromising image quality or diagnostic performance of CCTA, nor quantitative MBF assessment and ischemia detection on dynamic stress CTP. By addressing both anatomic and functional diagnostic performance within a unified cardiac CT workflow, this study is expected to provide evidence supporting a more patient-centered and resource-conscious approach to contrast media optimization in modern cardiac CT.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of Interest:\u003c/h2\u003e \u003cp\u003eThis study is supported by Taejoon Pharmaceutical Co., Ltd. The sponsor had no role in study design, data collection, data analysis, interpretation, or manuscript preparation. The authors declare no other conflicts of interest.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eS.M.K. and S.-J.C. conceptualized the study and designed the overall trial. S.M.K., S.-J.C., H.C., and P.-H.J. established the methodology and study protocol. S.-J.C., P.-H.J., and D.-H.K. planned the CT image acquisition, reconstruction, and quantitative post-processing workflows. S.-J.C., H.C., and P.-H.J. developed the statistical analysis plan. S.M.K. administered the project and supervised the research framework. S.-J.C. developed the protocol visualizations and wrote the original draft. S.M.K., H.C., P.-H.J., and D.-H.K. critically reviewed and edited the manuscript. All authors reviewed the manuscript and approved the final version.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis study is supported by Taejoon Pharmaceutical Co., Ltd. (Seoul, Republic of Korea). The sponsor had no role in the study design, data collection, data analysis, interpretation of the results, or the decision to submit the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKnuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain. Circulation 2021;144:e368-e454.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePontone G, Guaricci AI, Palmer SC, et al. Diagnostic performance of non-invasive imaging for stable coronary artery disease: a meta-analysis. Int J Cardiol 2020;300:276\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePontone G, Baggiano A, Andreini D, et al. Stress computed tomography perfusion versus fractional flow reserve CT-derived in suspected coronary artery disease: the PERFECTION study. JACC Cardiovasc Imaging 2019;12:1487\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwan AC, Gransar H, Tzolos E, et al. The accuracy of coronary CT angiography in patients with coronary calcium score above 1000 Agatston units: comparison with quantitative coronary angiography. J Cardiovasc Comput Tomogr 2021;15:412\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDahdal J, Jukema RA, Remmelzwaal S, et al. Diagnostic performance of CCTA and CTP for clinically suspected in-stent restenosis: a meta-analysis. J Cardiovasc Comput Tomogr 2025;19:183\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang J, Dou G, He B, et al. Stress myocardial blood flow ratio by dynamic CT perfusion identifies hemodynamically significant CAD. JACC Cardiovasc Imaging 2020;13:966\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndreini D, Mushtaq S, Trabattoni D, et al. Diagnostic accuracy of dynamic stress myocardial CT perfusion compared with invasive physiology in patients with stents: the ADVANTAGE 2 study. Radiology 2024;313:e232225.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKo SM, Cha SJ, Kim H, et al. Diagnostic performance of dynamic myocardial perfusion imaging using third-generation dual-source computed tomography in patients with intermediate pretest probability of coronary artery disease. J Cardiovasc Dev Dis 2025;12:264.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee YC, Hsieh CC, Chang TT, Li CY. Contrast-induced acute kidney injury among patients with chronic kidney disease undergoing imaging studies: a meta-analysis. AJR Am J Roentgenol 2019;213:728\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWerner S, Bez C, Hinterleitner C, Horger M. Incidence of contrast-induced acute kidney injury in high-risk oncology patients undergoing contrast-enhanced CT with a reduced dose of the iso-osmolar iodinated contrast medium iodixanol. PLoS One 2020;15:e0233433.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNie Z, Liu Y, Wang C, Sun G, Chen G, Lu Z. Safe limits of contrast media for contrast-induced nephropathy: a prospective cohort study. Front Med (Lausanne) 2021;8:701062.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagayama Y, Tanoue S, Tsuji A, et al. Application of 80-kVp scan and raw data-based iterative reconstruction for reduced iodine load abdominal-pelvic CT in patients at risk of contrast-induced nephropathy: effects on radiation dose, image quality and renal function. Br J Radiol 2018;91:20170632.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIm DJ, Kim YH, Choo KS, et al. Comparison of coronary computed tomography angiography image quality with high- and low-concentration contrast agents (CONCENTRATE): study protocol for a randomized controlled trial. Trials 2016;17:315.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCha MJ, Kim SM, Ahn TR, Choe YH. Comparing feasibility of low-tube-voltage with low-iodine contrast vs high-voltage with high-iodine contrast in coronary CTA. PLoS One 2020;15:e0236108.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida K, Tanabe Y, Hosokawa T, et al. Coronary CT angiography for clinical practice. Jpn J Radiol 2024;42:555\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMihl C, Kok M, Wildberger JE, et al. Coronary CT angiography using low concentrated contrast media injected with high flow rates: feasible in clinical practice. Eur J Radiol 2015;84:2155\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang S, Sun Z, Zeng Y, et al. Feasibility study of \u0026ldquo;triple-low\u0026rdquo; technique for coronary CT angiography. Sci Rep 2024;14:32110.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang M, Hao P, Jiang C, et al. Personalized application of three different iodine concentrations in coronary CT angiography. J Cell Mol Med 2020;24:5446\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlwaheidi D, Ehtesham A, Azizi S, et al. Meta-analysis of the diagnostic accuracy of CCTA vs invasive angiography in preoperative cardiac surgery planning. Open Heart 2025;12:e003768.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiovascular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Cardiovascular Imaging](https://jcvi.biomedcentral.com/)","snPcode":"44348","submissionUrl":"https://submission.springernature.com/new-submission/44348/3","title":"Journal of Cardiovascular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Coronary CT angiography, Dynamic CT perfusion, Iodinated contrast media, Noninferiority trial, Invasive coronary angiography","lastPublishedDoi":"10.21203/rs.3.rs-9275618/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9275618/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis prospective randomized trial is designed to determine whether low\u0026ndash;iodine-concentration contrast media will be noninferior to high\u0026ndash;iodine-concentration contrast media for (i) coronary enhancement and image quality on coronary CT angiography (CCTA) and (ii) whether it yields comparable and preserved absolute myocardial blood flow (MBF) quantification on dynamic stress CT perfusion (CTP). A secondary objective is to evaluate diagnostic performance in clinically relevant subcohorts by comparing (a) CCTA stenosis assessment with invasive coronary angiography (ICA) and (b) dynamic stress CTP ischemia assessment with invasive fractional flow reserve (FFR).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe trial plans to enroll 258 adults (\u0026ge;\u0026thinsp;40 years) with known or suspected coronary artery disease referred for clinically indicated cardiac CT (CCTA with planned dynamic stress CTP). Participants will be randomized 1:1 to receive low\u0026ndash;iodine-concentration contrast media (270 mg I/mL) or high\u0026ndash;iodine-concentration contrast media (350 mg I/mL). The co-primary endpoints will be objective coronary enhancement on CCTA and absolute MBF in predefined non-ischemic myocardial segments. For secondary diagnostic validation, ICA will be used as the reference for \u0026ge;\u0026thinsp;50% anatomic stenosis when performed as part of routine care, and FFR (\u0026le;\u0026thinsp;0.80) will be used as the reference for lesion-specific ischemia when obtained. The CCTA co-primary endpoint will be analyzed using linear mixed-effects models with a prespecified noninferiority margin, whereas the MBF co-primary endpoint will be evaluated for comparability using a standard two-sided test without a margin. Diagnostic accuracy will be summarized using sensitivity, specificity, predictive values, and receiver-operating-characteristic analyses with methods that account for within-patient correlation across vessels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis study is designed to demonstrate noninferior coronary enhancement, preserved CCTA diagnostic performance, and comparable MBF measurements and ischemia detection using low\u0026ndash;iodine-concentration contrast media under standardized acquisition and reconstruction protocols.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLow\u0026ndash;iodine-concentration contrast media are expected to provide noninferior image quality and diagnostic performance for both anatomic and functional cardiac CT, supporting iodine-reduction strategies without compromising clinical diagnostic validity.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eKCT0011418. Registered on 07 January 2026.\u003c/p\u003e","manuscriptTitle":"Low- vs High-Iodine–Concentration Contrast Media for Coronary CT Angiography and Dynamic Stress CT Perfusion: A Prospective, Randomized Noninferiority Trial with Secondary Diagnostic Validation Using Invasive Coronary Angiography and Fractional Flow Reserve","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:27:05","doi":"10.21203/rs.3.rs-9275618/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-04T15:00:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T14:57:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134954068483019383390093472052000143598","date":"2026-04-29T04:50:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-25T01:11:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268883924699984553832731595886265780511","date":"2026-04-10T01:18:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-10T00:40:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-07T06:01:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-07T06:01:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiovascular Imaging","date":"2026-03-31T06:46:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiovascular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Cardiovascular Imaging](https://jcvi.biomedcentral.com/)","snPcode":"44348","submissionUrl":"https://submission.springernature.com/new-submission/44348/3","title":"Journal of Cardiovascular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c1971fd2-d0f5-41d5-aee4-e23a8ff1abb5","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-04T15:00:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T14:57:16+00:00","index":15,"fulltext":""},{"type":"reviewerAgreed","content":"134954068483019383390093472052000143598","date":"2026-04-29T04:50:06+00:00","index":14,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T15:09:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:27:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9275618","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9275618","identity":"rs-9275618","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}