Improved Management of Patients With Recent-Onset Stable Chest Pain

Composite endpoint: Major Adverse Cardiovascular Events (MACE) including cardiovascular death, myocardial infarction, stroke, and procedure-related complications from diagnostic testing and subsequent management/therapy in the two randomization groups. Procedure-related complications (major and minor) are defined in the subsequent outcome measure and include events occurring during or within 48 hours after CT or ICA or related tests or revascularization procedures.

Rate of procedure-related complications by diagnostic imaging modality and by interventional/surgical treatments (PCI, CABG). Includes major and minor complications. Major complications: events occurring during or within 48 hours after CT or ICA or related tests or revascularization procedures, including death, nonfatal myocardial infarction, nonfatal stroke, complications prolonging hospitalization ≥24 hours, coronary/aortic dissection, cardiogenic shock, cardiac tamponade, retroperitoneal bleeding, cardiac arrhythmia (ventricular tachycardia/fibrillation), or cardiac arrest. Minor complications: events occurring during or within 48 hours after CT or ICA or related tests or revascularization procedures not meeting major criteria, including hematoma or secondary bleeding at the puncture site, bradycardia, angina pectoris without myocardial infarction, allergic reaction to contrast media, hypotension requiring treatment, infection, thrombosis, or arteriovenous fistula.

• Agreement of the diagnostic decision with the pre-test probability (PTP, below 15%, 15-50%, above 50% criterion) with the National Health Services guidelines for suspected coronary artery disease and the statistical distribution of PTP values across the scale (NVL KHK 2024), measured using the updated DISCHARGE PTP calculator in the two randomisation groups, 2) Agreement of the mean pre-test probability with the prevalence of obstructive coronary artery disease (CAD) defined as at least one at least 50% coronary artery diameter stenosis on coronary computed tomography angiography (CTA) and/or invasive coronary angiography (ICA) in the two randomisation groups.

Rate of functional tests performed during the follow-up period (stress electrocardiography (ECG), cardiac stress magnetic resonance imaging (MRI), stress echocardiography, stress myocardial perfusion single-photon emission CT (SPECT), myocardial stress perfusion positron emission tomography (PET)) in the two randomisation groups.

Rate of coronary artery revascularisations (percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)) performed during the follow-up period in the two randomisation groups.

Rate of coronary CT performed during the follow-up period in the two randomisation groups.

Rate of ICA procedures performed during the follow-up period in the two randomisation groups.

Rate of diagnostic findings on the ICA procedures performed in the two randomisation groups (obstructive or non-obstructive CAD or no signs of CAD) to assess the yield of ICA defined as the proportion of ICAs performed in both randomisation groups demonstrating obstructive CAD.

Rate of diagnostic findings on the CTA procedures performed in the two randomisation groups (obstructive or non-obstructive CAD or no signs of CAD) to assess the yield of CTA defined as the proportion of CTAs performed in both randomisation groups demonstrating obstructive CAD.

Rate of hospitalisations due to chest pain during the follow-up period in the two randomisation groups.

Rate of emergency department visits due to chest pain during the follow-up period in the two randomisation groups.

Proportion of non-diagnostic coronary CTs in the two randomisation groups.

Estimated radiation exposure of cardiac imaging tests including coronary CT, ICA, SPECT, and PET in the two randomisation groups in millisieverts (mSv).

EQ-5D-5L: validated questionnaire with five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and 5 levels (no problems, slight problems, moderate problems, severe problems and extreme problems) in the two randomisation groups.

SAQ-7 questionnaire (short version): disease-specific health status instrument for coronary artery disease (CAD) with seven items from the physical limitations, angina frequency, and quality of life domains in the two randomisation groups.

Cumulative healthcare costs that can be mapped from routine health insurance data.

Cumulative healthcare costs that can be mapped from primary data

ΔCt/ΔMACE: The calculated total costs are compared with MACE (primary endpoint). The results are presented as the incremental cost-effectiveness ratio (ICER). Data sources are routine data and patient survey distributed by the health insurers.

ΔCt/ΔMACE: The calculated total costs are compared with MACE (primary endpoint) in the two randomisation groups. The results are presented as the incremental cost-effectiveness ratio (ICER). Data source is primary health care utilisation data in the two randomisation groups.

ΔCt/ΔQALYs: The calculated total costs are compared with quality of life (secondary endpoint), measured using the standardised and validated EQ-5D-5L. The results are presented as the incremental cost-utility ratio (ICUR). Data sources are routine data and patient survey distributed by health insurers.

ΔCt/ΔQALYs: The calculated total costs are compared with quality of life (secondary endpoint), measured using the standardised and validated EQ-5D-5L. The results are presented as the incremental cost-utility ratio (ICUR). Data sources are primary data and patient quality of life survey in the two randomisation groups.

Analysis of prevalence of a) non-coronary cardiac causes of symptoms (such as aortic dissection, valve disease, pericarditis) or b) non-cardiac causes of symptoms (such as thrombus, pulmonary embolism, pleural effusion, pneumonia, hiatal hernia) on CT in the two randomisation groups.

Influence of non-coronary cardiac and non-cardiac findings on MACE, non-cardiac events and Quality of Life (QoL) measured using EQ-5D-5L in the two randomisation groups.

Rate for malignancy in pulmonary nodules seen on CT (reference standard: biopsy results in the two randomisation groups, Positron Emission Tomography (PET) findings, or progression versus no change or regression on follow-up CT).

Rate of death from cancer in both randomisation groups.

Composite outcome: Rates of unnecessary follow-up procedures such as examinations, biopsies, or surgeries performed based on non-coronary findings on CT in the two randomisation groups.

Analysis of interobserver variability (site vs. core lab and interobserver in the core lab) of reading for the presence of coronary stenosis (obstructive CAD) and plaques on CTA (types, characteristics, volumes etc.).

Association between plaque characterisation and quantification by core lab and MACE (with and without inclusion of procedure-related complications).

Image quality of coronary CT by core lab read (manual and automated): comparison of the two randomisation groups. This analysis involves also an analysis of the heart rate during CT and the use of oral and intravenous betablockers before CTA in the two randomisation groups.

Noise in CTA imaging in the two randomisation groups and the factors it depends on, for instance adherence vs. non-adherence to scan protocol.

Quantitative assessment of aortic valve calcification and fibrosis on CT to predict the occurrence of major adverse cardiovascular events (MACE) and the future need for transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). This outcome includes the following objectives: 1. To automate the measurement of fibrotic and calcified aortic valve characteristics on CT; 2. To assess the concordance between anatomical fibrocalcific aortic valve thickening and functional haemodynamics as measured by echocardiography, and to predict rapid hemodynamic progression; 3. To develop and validate an integrated patient risk score for predicting clinical outcomes.

Analysis of prevalence of MACE in correlation to a calcium score (CS) of zero: the prognostic value of a calcium score of zero.

The characterisation of plaques (type and composition) by CT core lab in relation to cardiac risk factors at baseline in all patients who underwent CT.

Risk factors for and influence of statin treatment on plaque progression or regression in patients who had follow-up cardiac CT done.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in women and men in the two randomisation groups.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in both randomisation groups in patient a) under 65 years, b) between 65 and 75 years and c) over 75 years.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in patients with and without diabetes mellitus in the two randomisation groups.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in patients with BMI a) under 25, b) between 25 and 30 and c) over 30 in the two randomisation groups.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in patients with different smoking habits (current smokers, current non-smokers, never-smokers) in the two randomisation groups.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in patients with significant QoL reductions versus patients with no changes in QoL in the two randomisation groups.

Comparison of MACE, procedural complications, and examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in pre- and post-menopausal women in the two randomisation groups.

Differences of coronary plaque characteristics determined by CT including parameters like coronary plaque assessment, including calcified, mixed and non-calcified plaques, remodelling index, ring-sign, spotty calcification in pre- and post-menopausal women.

Differences of epicardial adipose tissue characteristics determined by CT including parameters like EAT volume, EAT density, EAT radiomics (adjusted for coronary calcium score, age and body surface area) and their relation to MACE and CAD.

The MHS is a well validated and established diagnostic clinical prediction rule estimating the clinical probability of coronary heart disease in patients presenting with chest pain in primary care. However, the prognostic value has not been evaluated so far. For this secondary analysis, we will calculate the rate of coronary events (death, lethal and non-lethal myocardial infarctions), stratified by the MHS score values.

Comparison of the pretest probability between the two randomisation groups in patients receiving CTA to determine success of the intervention in regard to indication for CTA.

Recalibration of the DISCHARGE calculator based on the results of the trial. Calibration will be done nationwide across Germany and regionally. Both versions will be compared.

The DISCHARGE Calculator is based on the well validated COME-CCT Calculator and was calibrated on the DISCHARGE trial data. However, the prognostic value has not been evaluated so far. For this secondary analysis, we will calculate the rate of MACE and any subset within MACE, stratified by the DISCHARGE Calculator.

Bayesian evaluation of the different rates of major adverse cardiovascular events (MACE) and secondary outcomes in the two randomization groups. The primary analysis assesses whether the intervention reduces 12-month MACE compared with standard care in patients with suspected chronic CAD. Secondary outcomes are analysed using Bayesian methods.

Does recruitment in primary care setting versus in CT centres impact the rate of MACE within the two randomisation groups and between the two randomisation groups?

Time from first clinical presentation with stable chest pain (recruitment) to documented final diagnostic classification (obstructive CAD, non-obstructive CAD, or no signs of CAD or no need to further investigate as the chest pain is clearly noncardiac) in the two randomisation groups

Proportion of patients with documented pre-test probability assessment prior to diagnostic CT and ICA in the two randomisation groups

Proportion of patients with documented justification for the selected diagnostic strategy (e.g., CTA-first, functional testing, direct ICA) in the two randomisation groups.

Proportion of patients undergoing more than one sequential non-therapeutic diagnostic tests (e.g., CTA → stress imaging → ICA) in the two randomisation groups.

Proportion of patients in whom lipid-lowering therapy is newly initiated or escalated (dose increase or switch to high-intensity statin) following diagnostic evaluation.

Proportion of scheduled diagnostic imaging appointments (CTA or ICA) not attended by the patient without prior cancellation.

Proportion of structured quantitative CTA reports according to QCI consensus statement and the results of the ISCHEMIA trial (no CAD-RADS) in the two randomisation groups.

Proportion of CTA reports that include a standardised patient-friendly summary explaining results, cardiovascular risk implications, and recommended next steps in plain language in the two randomisation groups.

Patient acceptance of informed consent, preparation, procedural aspects of the tests performed and patient acceptance of the management recommendations.

Gender differences regarding all aspects of medical history will be collected at baseline and follow-up. Data will be analysed in regards to occurrence of MACE and MICE in all genders.

All primary, secondary, and pre-specified study outcomes will be analysed according to predefined cluster regions within the stepped-wedge design to assess regional heterogeneity of intervention effects in the two randomisation groups.

All primary, secondary, and pre-specified study outcomes will be analysed across German federal states (Bundesländer) to assess regional heterogeneity of intervention effects in the two randomisation groups.

All primary, secondary, and pre-specified study outcomes will be analysed according to aggregated cardinal regions of Germany (North (Hamburg, Kiel/Lübeck, Göttingen), South (Augsburg, Erlangen, Würzburg/Bad Neustadt, Ulm, Tübingen), East (Rostock/Greifswald, Berlin/Brandenburg, Jena, and Leipzig), and West (Düsseldorf, Wiesbaden/Frankfurt, Marburg/Gießen, Köln) to explore broad geographic variation of intervention effects in the two randomisation groups..

Questionnaire for sociodemographic and characteristics of primary care and CT centres. Interviews regarding contextual factors that shape how the intervention works; and that affect (or may be affected by) implementation, intervention mechanisms and outcomes. Causal mechanisms present within the context which act to sustain the status quo or potentiate effects by comparing the two randomisation groups.

TIDieR Checklist is used to describe the complex intervention

How is delivery achieved; training, resources, etc. Participation of at least 1 person/clinic; Positive online-evaluation (emotion, readiness to present again in the clinic, grading (as in school grades), open feedback, self-evaluated competency in the two randomisation groups.

NoMad-survey for long-term implementation (normalisation); Implementation questionnaire and interviews with Elements: Integration in every-day routine, knowledge of guideline, involvement of cardiologists in the two randomisation groups.

Multiple provenances of data and acquisition time-points to test mechanisms of impact: Questionnaire on the use of a pre-test probability calculator; Questionnaire on use of decision aids; Questionnaires on structure of radiology reports; Qualitative experiences of all involved person-groups in the two randomisation groups.

Time from first clinical presentation with stable chest pain (recruitment) to first documented diagnostic imaging procedure.

Development and/or testing of an automated coronary artery plaque quantification tool for total plaque volume, calcified plaque volume, and noncalcified plaque volume with high diagnostic accuracy and predictive value for MACE.

Development and/or testing of an automated high risk plaque (HRP) quantification tool with high diagnostic accuracy and predictive value for MACE.

Development and/or testing of an automated Total Segmentator tool for quantitative imaging biomarker extraction, aiming to achieve high diagnostic accuracy and predictive value for major adverse cardiovascular events (MACE). This includes the development and validation of a dedicated cardiac Total Segmentator for detailed segmentation of cardiac structures, as well as a complementary multi-organ segmentation model to enable integrated assessment of cardiac and extracardiac imaging biomarkers relevant to cardiovascular risk. The approach will evaluate the performance of these models in terms of segmentation accuracy, robustness, and their ability to improve prediction of MACE.

We aim to determine if the elements of the NVF have an impact on interobserver variability in CT in the intervention phase compared to the control phase by comparing the two randomisation groups.

Fully automated quantification of coronary artery calcium on CT on the vessel- and segment level, and its prognostic ability for major adverse cardiovascular events (MACE).

Are there more coronary artery bypass grafting (CABG) procedures being planned on CT (rather than ICA) in the intervention phase compared to the control phase? This will be assessed by the proportion of patients undergoing ICA after CT for planning of CABG.