Diagnostic Imaging Strategies for Patients With Stable Chest Pain and Intermediate Risk of Coronary Artery Disease

Likelihood of receiving coronary intervention and extent of Coronary Artery Disease (CAD) in dependence of socioeconomic status and the likelihood of receiving further intervention within two months after the initial intervention in different European countries.

Composite outcome: Rates of Percutaneous Coronary Intervention (PCI) and use of intracoronary techniques such as Fractional Flow Reserve (FFR), Optical Coherence Tomography (OCT), Intravascular Ultrasound (IVUS) within two months after the initial intervention in different European countries.

Recommended and actually performed management based on Computed Tomographic Angiography (CTA) and Invasive Coronary Angiography (ICA) results in different countries adjusted for the extent of ischemia within two month after the initial test randomised to.

Composite outcome: Adherence to follow-up in different countries and according to prevalence of CAD as well as risk factors and socioeconomic status and most likely way of conduct of follow-up data gathering in different countries (phone interviews, letter reply, email).

European differences in occurrence and extent of Coronary Artery Disease in regards to city versus rural lifestyle

European and local differences in patient consent of sites

Occurrence of minor adverse cardiovascular events (MICE): coronary revascularisation, peripheral artery revascularisation, hospitalisation for angina pectoris, emergency department visit for angina pectoris, transient ischemic attack, congestive heart failure.

Composite outcome: Rates of Percutaneous Coronary Intervention and Coronary Artery Bypass Graft (CABG) performed within 2 months following Computed Tomography Angiography and Invasive Coronary Angiography (defined as: related to these tests) and more than 2 months after CTA and ICA until follow-up (unrelated to these tests).

Comparison in the CTA and ICA group: Rates of patients on dialysis

Composite outcome: Rate of coronary artery anomalies (benign and malignant) and rate of myocardial bridging seen on CTA and ICA and the clinical implications of these at follow-up as well as influence on Major Adverse Cardiovascular Events (MACE) and MICE

Composite outcome: Rates of patients undergoing further cardiac diagnostics, such as additional CT or ICA, Electrocardiography (ECG), Exercise ECG, Echo, Stress Echo, Magnetic Resonance Imaging (MRI) within 2 months following CT and invasive coronary angiography (defined as: related to these tests) and more than 2 months after CT and invasive coronary angiography until follow-up (unrelated to these tests).

Rates of coronary interventions within 2 months following CT and ICA (defined as: related to these tests) and more than 2 months after CT and ICA until follow-up and recurrent angina leading to hospitalisation.

Analysis of influence of prior CT on ICA and PCI in terms of duration, radiation exposure, amount of contrast agent used for ICA.

Comparison of cumulative contrast agent amount in the two arms

Composite outcome: Compared with ICA, CTA will be associated with a lower rate of coronary revascularisation, but on a per-procedure basis, revascularisation will be more complete. Performance of revascularisation will differ between the randomised groups.

Comparison in the CTA and ICA group: Distribution in the mode of revascularisation: PCI vs. CABG.

Comparison of Quality of Life between the following treatment regimens using adherence to therapy recommendation as covariate: optimal medical therapy in general in combination with risk factor modification vs. oral statin intake in combination with risk factor modification.

Geographical distribution of risk factors for MACE and MICE, cardiovascular events and cardiac events (cardiac and non-cardiac death, stroke, myocardial infarction, unstable angina pectoris, re-revascularisation and first revascularisation) in the European Union (EU) and comparison of European countries.

Extent of CAD in dependence of patients' socioeconomic status (income, education, occupation, job situation, gender)

Time from randomisation to Invasive Coronary Angiography in both groups.

Time from randomisation to first coronary revascularisation in both groups

Completeness of revascularisation (i.e. no. of vessels treated vs. number of vessels affected by > 50% stenosis); for Percutaneous Coronary Intervention single vessel vs multivessel Percutaneous Coronary Intervention and Coronary Artery Bypass Graft; stent use (bare metal vs drug eluting).

Information on surgical procedures i.e. isolated Coronary Artery Bypass Graft, Coronary Artery Bypass graft with valve replacement, Coronary Artery Bypass Graft with aortic surgery.

Comparison in the Computer Tomography angiography and Invasive Coronary Angiography group: procedures and outcomes in relation to age.

Comparison in the Computer Tomography Angiography and Invasive Coronary Angiography group: procedures and outcomes in relation to body mass index and obesity.

Composite outcome: Reduction of angina pectoris intensity (measured on a 0-10 scale, at baseline, first and final follow up, max 4 years) in the two arms and in the subgroup of a) patients with significant stenosis (on CTA or ICA) and with or without relevant myocardial ischemia that was or was not revascularised by PCI or CABG; b) patients without significant stenosis (on CT or ICA) and with or without non-coronary or non-cardiac finding potentially explaining the chest discomfort; in patients who underwent PCI versus patients who received optimal medical therapy and risk factor modification alone (matched analysis for the extent of CAD and imaging ischemia).

Composite outcome: Validation of the Rose Angina questionnaire including pain scale and the InterHeart Risk Score (IHRS) to predict MACE and MICE in both arms.

Composite outcome: Adverse events due to nitroglycerin, beta-blockers, contrast agent and other medication applied during CTA and ICA (allergic reactions, hypotension, headache, hyperthyroidism).

Composite outcome: Adverse events related to venous or arterial puncture: skin tissue and nerve injuries, bleedings: due to puncture of vessel, due to use of anticoagulants, at site of puncture (hematoma), extravasate.

Occurrence of cardiac arrhythmia

Rates of contrast-induced nephropathy (CIN) adjusted for the frequency of creatinine follow-up testing performed in the two groups.

Infections

Correlation of the experience (in years) of the CT and ICA examiner with procedural events, duration of the exams (in min), contrast agent amount (in ml) used for diagnosis and intervention (if done), and exposure of radiation (in mSv).

Composite outcome: Comparison of a) outpatient vs inpatient ICA for procedural complication rates after adjusting for risk factors for such events,b) femoral vs radial approach ICA, and c) different closure devices vs. manual compression and of frequency of interventions, results, patients acceptance and d) procedural differences, for instance bed rest time after intervention, and influence on procedural events.

Composite outcome: Complications related to ICA: Femoral arterial occlusion (or arterial access vessel) or dissection, Cardiac arrhythmia, closure or injury of vessels, injury of the heart (e.g. valve or myocardium) , twisting or rupture of the catheter or parts of the catheter consecutive surgical removal, development of arteria-venous fistulas, development of a pseudo aneurysm at puncture site, permanent edemas, embolisation of central or peripheral vessels due to thromboembolism.

Complications during or after revascularisation, for instance acute closure of coronary vessels, angina pectoris, stent migration, loss of stent and consecutive closure of vessels, stent infection.

Composite outcome: Occurrence of other adverse events (AEs) and serious adverse events (SAEs) such as heart failure, cardiogenic shock, cerebrovascular accident (CVA)/Stroke, hemorrhagic stroke, new requirement for dialysis, deep vein thrombosis/pulmonary embolism, cardiac tamponade, perforation, retroperitoneal bleeding, gastrointestinal bleeding, genital-urinary bleeding, major bleeding, red blood cell (RBC)/Whole blood transfusion, other equipment mishaps (e.g. retained foreign body guidewire fracture), wrong patient or wrong procedure

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).

Influence of non-coronary cardiac and non-cardiac findings on MACE, non-cardiac events and Quality of Life (QoL).

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

Accuracy of the parsimonious lung cancer risk prediction tool by McWilliams et al. for probability assessment of malignancy in lung nodules found in comparison to the above combined reference standard

Rate of death from cancer in both groups

Composite outcome: Rates of unnecessary follow-up procedures such as examinations, biopsies, or surgeries done based on non-coronary findings in the CTA and ICA group

Analysis of interobserver variability (site vs. core lab) of reading for coronary stenosis and plaques on CTA and for coronary stenosis on ICA

Percent diameter stenosis correlation and agreement by Computed Tomography Angiography and Invasive Coronary Angiography in patients who underwent Invasive Coronary Angiography in the Computed Tomography Angiography group after positive or non-diagnostic findings.

Composite outcome: Non-diagnostic CTA and ICA: comparison of prevalence and patient as well as technical factors leading to such uninterpretable findings or exams that could not be conducted or completed.

Correlation between percent diameter stenosis by Computed Tomography with invasive Fractional Flow Reserve in patients who had Computed Tomography and Invasive Coronary Angiography done and correlation of non-invasively estimated Fractional Flow Reserve by Computed Tomography with invasive Fractional Flow Reserve after Computed Tomography/Invasive Coronary Angiography.

Prevalence of sinus node artery being a side branch of Left Coronary Artery (LCX) or Right Coronary Artery RCA by core lab reading and the risk of CAD on CT and ICA as well as MICE and MACE.

Prevalence of left, intermediate, and right coronary distribution type by core lab and site reading and the risk of CAD (as significant) on CT and ICA at baseline and MICE and MACE.

Improvement of selection of distal coronary segments used for Coronary Artery Bypass Surgery-anastomosis by Computed Tomography in comparison to Invasive Coronary Angiography alone (especially heavy calcification detection) as assessed by the cardiac surgeons.

Relation of plaque characterisation and quantification by core lab and MACE and MICE at the two follow-up results.

Image quality of CT by core lab read and flow and concentration of contrast agent used intravenously

Coronary artery dimensions in patients in whom contraindications prevented the use of nitroglycerin for CTA versus patients who received nitroglycerin (measured as the diameter of the Left Marginal Artery (LMA), proximal Left Anterior descending artery (LAD), LCX and RCA), adjusted for gender and Body Surface Area (BSA).

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

Factors that influence the image quality of CTA ( Body Mass Index (BMI), gender, origin of patient, 80, 100, 120, 135, 140 kV, different mA settings, number of detector rows, heart rate (maximum, minimum, and average during CT acquisition), and acquisition type.

Evaluation of the 10-step guide to cardiac CT

Composite outcome: intensity, noise, signal to noise, contrast and signal to noise in some regions of interest (ROIs) (LV, RV segments 1,2,5,6,11 and levocardiography effect).

Composite outcome: levocardiography effect (scale 1 to 3) and LV, RV and segments 1,2,5,6,11 (scale 1 to 4).

Heart rate reduction achieved in Computed Tomography by the DISCHARGE betablocker protocol

Composite outcome: Heart rate reduction achieved in subgroups of patients with contraindication to betablockers or no adherence to protocol where other doses or medications such as ivabradine or calcium channel blockers were used and in different patient groups (e.g., male versus female patients, >65 years and up to 65 years of age).

Heart rate reduction achieved with conscious sedation, if used, for CT.

Composite outcome: Analysis of prevalence and extent of CAD in correlation to a high calcium score (CS), and exclusion of any CAD in correlation to a zero CS, potential of defining a threshold.

The characterisation of plaques (type and composition) by CT core lab in relation to cardiac risk factors.

Composite outcome: Differences in plaque characteristics (type and composition) and analysis of potential influence by geographical origin of the patient, after adjustment for other cardiac risk factors.

Composite outcome: Correlation and agreement for plaque characterisation and quantification by CT in comparison to intracoronary techniques such as OCT and Intravascular ultrasound (IVUS) in patients who had both tests done.

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

Correlation of effective dose and the diagnostic portion of Invasive Coronary Angiography with weight and body-mass index of the patient.

Correlation of effective dose of and contrast agent amount used for Invasive Coronary Angiography with severity of Coronary Artery Disease.

Rate of follow-up Invasive Coronary Angiographies and Percutaneous Coronary Interventions more than 2 months after initial Computed Tomography/Invasive Coronary Angiography and up to first and last follow-up

Correlation of the number of projections for the right and left coronary artery with effective dose of Invasive Coronary Angiography

Rates of left ventriculography performed

Rates of planned cross-over from CT to ICA after positive findings in CT within 2 month past initial procedure in accordance to management flow chart.

Comparison of cross-over patients (from Computed Tomography to Invasive Coronary Angiography) to non-cross-over-patients.

Composite outcome: Correlation of CTA and/or ICA results with the results of imaging ischemia tests (stress echo, stress Single Photon Emission Computed Tomography (SPECT), stress Positron Emission Tomography (PET), MRI \& stress MRI).

Correlation between imaging ischemia tests and invasive Fractional Flow Reserve if done.

Rates of imaging ischemia tests recommended

Comparison of diagnostic accuracy of imaging ischemia tests (stress echocardiography, SPECT, stress MRI, and PET) for the detection of CTA- or ICA-defined CAD (up to 48h after final procedure related to the randomised test).

Comparison of imaging ischemia results with Computed Tomography Angiography and Invasive Coronary Angiography results for prediction of Major and Minor Cardiac Adverse Events.

Correlation between imaging ischemia results and coronary stenosis as well as plaque composition and characterisation findings by Computed Tomography Angiography.

13.2.1 Rate of PCI / CABG recommended and performed after CTA and positive or negative imaging ischemia tests in comparison to the ICA arm within two month after the initial test.

Correlation of the results of study- CTA, recommended imaging ischemia test and ICA in patients with respective study course

Occurrence of procedural events in imaging ischemia testing.

Correlation of intensity and reduction of Angina Pectoris (measured on a 0-10 scale, baseline, first and final follow up, max 4 years) with positive, unequivocal, and negative imaging ischemia test results in patients in both study arms; sub-study in patients with imaging ischemia follow-up examinations with an analysis of the correlation between changes in angina intensity and ischemia extent.

Analysis of patient acceptance ("preference questionnaire") of CTA and ICA (and in those patients, who received both, which one was the preferred) as well as in the following subgroups: gender, patients without significant stenosis seen on the initial test randomised to, patients with significant stenosis seen on CTA and a) ICA not recommended or done e.g., because of imaging ischemia results or b) ICA done.

Patient acceptance of informed consent, preparation, procedural aspects of the tests performed including an assessment of maximum pain during procedures measured using a pain scale and patient acceptance of the management recommendations in the two groups.

Effective radiation dose (measures as dose length product and dose area product during CT [for coronary artery calcium score (CACS) and CTA] and ICA, respectively) used for CT and ICA and cumulative radiation dose in the two arms at different time points.

Reduction of radiation exposure by using CACS information about the coronary artery position along the Z-axis to reduce the Z-axis coverage of the subsequent CTA according to the 10 Steps Guide to Success in Cardiac CT.

Comparison of radiation dose in ICA and CT: pilot study versus non-study patients

Validation of the coronary artery disease DISCHARGE and COME-CCT pre-test probability calculators and comparison with other calculators (Diamond and Forrester, DiCAD, Duke clinical score) versus the reference standards (CTA or ICA) in the pilot study of DISCHARGE and the randomised trial.

Comparison of the ability of the DISCHARGE and COME-CCT pre-test probability calculators to predict CAD in men and women equally well in comparison to previous calculators.

Ability of the DISCHARGE and COME-CCT pre-test probability calculators to predict CAD in patients without or with coronary artery calcium on CT using CTA or ICA as the reference standard in comparison to previous calculators.

Potential advantage of the DISCHARGE and COME-CCT calculators in combination with the NIH chest discomfort guidelines to triage patients most effectively based on pretest probability in comparison to the DISCHARGE approach of CT including calcium scoring and CTA for management decision making about risk factor modification and revascularisation, respectively.

Predictive value of the DISCHARGE calculator in patients with a very low pre-test probability (<10%) who could not be randomised but were sent with an indication for ICA that these patients, who are in a screening log of the study, actually have no CAD on ICA.

Predictive value of the DISCHARGE calculator in patients with a high pre-test probability (>60%) who could not be randomised but were sent with an indication for ICA that these patients, who are in a screening log of the study, actually have a high risk of CAD on subsequent ICA.

Composite outcome: Development and validation of a novel pre-test probability calculator based on age, gender, symptoms, and cardiac risk factors and/or exercise ECG or imaging ischemia results of patients in DISCHARGE with CT and/or ICA results being the reference standard for the definition of CAD for this novel calculator; comparison of this novel calculator with the simple DISCHARGE pre-test probability calculator.

Ability of the DISCHARGE and COME-CCT (Collaborative Meta-analysis in Cardiac CT) calculators (used in the study and developed based on the study results) to predict MACE and MICE at both follow-up will be analysed.

In addition to the costs of CTA and ICA, we assess costs induced by complications caused by these diagnostic procedures. Those costs split up into costs for additional diagnostics and additional treatments necessary due to the occurrence of major cardiovascular adverse events. Therefore, number, type and severity of adverse events, caused by CTA and ICA will be evaluated as well as the type of treatment and if the treatment is conducted in an ambulant setting or requires hospitalisation.

Comparison of the costs of an additional quality adjusted life year (QALY) gained by a correct diagnosis gained by using CTA or ICA.

All analyses including costs will be conducted separately for each country with a study center to enable us to conduct comparative analyses on an international level.

Adverse events might lead to sick leave in patients, which is an important cost factor from the societal perspective. There will be an assessment of differences in sick leave in patients by clinical site.

Adverse events might lead to hospitalisation in patients. In addition to days off work, this is an important cost factor from the societal perspective. There will be an assessment of differences in hospitalisation in patients by clinical site.

Differences in adverse events might lead to a different use of diagnostic tests during the follow-up phase. Therefore, data about cost-effective differences in examinations, not being mandatory according to the study protocol, will be collected.

Differences in adverse events might lead to a different necessity of treatments during the follow-up phase. Therefore, data about cost-effective differences in treatments, not mandatory by study protocol, will be collected.

A pragmatic Case Report Form (CRF) for the assessment of staff involvement time and use of material was developed for the pilot study. The completion of questionnaires in different clinical sites will be assessed to evaluate this approach.

Differences in staff involvement time in different clinical sites will be assessed. Staff involvement time is one of the major cost drivers in health care systems.

Different consumption of materials in different clinical sites will be assessed. Therefore we will use standardised prices for inter-site comparisons.

The pilot study is not a prospective randomised trial. Inclusion of patients with a pretest-likelihood greater than 60% was allowed due to retrospective calculation of pretest likelihood. Thus, the population in the pilot study differs from the population being included in the DISCHARGE main trial.

As cost-effectiveness data will be calculated using data from the pilot study, controlling for age, gender, pretest-likelihood, and quality of live related parameters and others is essential. The prevalence of coronary artery disease will be assessed by site.

Previous cardiac examination results will be assessed in the pilot study, reflecting the routinely performed tests before referral to Computed Tomography Angiography and Invasive Coronary Angiography. The correlation of these previous tests with the CTA or ICA results will be analysed.

Due to differences in clinical practice and recommendations throughout Europe, patients may be hospitalized after Invasive Coronary Angiography. Analysis will be conducted to assess this cost factor.

Non-diagnostic segments can occur in Computed Tomography Angiography and Invasive Coronary Angiography. This might lead to subsequent examinations, thus indicating an important cost factor.

Occurrence of major cardiovascular adverse events within 48 hours after examination will be analyzed. As major cardiovascular adverse events may lead to subsequent examinations they represent a major cost factor.

Composite outcome: Group (CTA vs ICA) differences in health-related QoL instruments (SF-12 self-rated health item, SF-12 physical component summary score, EuroQol 5d-3L and Hospital Anxiety and Depression Scale). Hypothesis: There will be no group differences in QoL at 1 year and final follow-up. We will analyse sociodemographic, lifestyle and clinical predictors of changes in QoL (SF-12 physical component and VAS) between baseline and 1 year / final follow-up, separately for men and women. Important clinical predictors include significant CAD findings during the course of the study, changes in chest pain severity (Angina class), occurrence of MICE / MACE as well as baseline risk factor status (BMI, diabetes, smoking, physical inactivity, excessive alcohol intake).

Acceptance of time trade-off question in the pilot study

Comparison of the QoL questionnaires used in the pilot and in the main study (SF-12, EuroQoL 5d-3L, Hospital Anxiety and Depression Scale, and the MacNew).

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

Differences in radiation exposure and gender.

Differences regarding QoL, lifestyle and socioeconomic status at baseline as well as in regards to changes of these factors seen at the two follow-up time points in the two randomised groups and in male and female patients with and without CAD on testing.

Comparison of the examination results (rate of coronary artery disease, PCI rate adjusted for CAD prevalence, occurrence of adverse events, stress tests used, patient acceptance) in all genders.

Gender differences of coronary plaque characteristics determined by CT including parameters like coronary plaque assessment, including calcified, mixed and non-calcified plaques, remodeling index, ring-sign, spotty calcification.

Gender differences of myocardial resting blood flow / tissue characteristics determined by cardiac CT using parameters such as regional and global TPR, AD, PI, perfusion defects, myocardial calcification, myocardial fatty infiltration, myocardial thinning.

Diagnostic value of CT in men vs women - frequency of true positive findings in patients referred for ICA - i.e. frequency of revascularization in patients referred for ICA based on CT with and without ischemia testing, CT findings, Ischemia testing findings, ICA findings and revascularization in patients of the CT group referred to ICA as a consequence of index evaluation, radiation dose.

Composite outcome: Gender differences of pulmonary findings of cardiac CT a) signs of pulmonary congestion: Ground-Glass Opacification (GGO), Pleural effusions, interlobular transudate high density pulmonary attenuation index b) pulmonary emphysema (with/without CAD), low density pulmonary attenuation index c) Pulmonary embolism (major, minor).

Gender differences of structural cardiac CT findings including parameters such as LV-mass, volumes and dimensions of Left Ventricle (LV), Left Atrium (LA), Right Ventricle (RV), Right Atrium (RA) and blood pressure.

Composite outcome: Analysis of occurrence in MACE as a secondary outcome in following subgroups:

Angina classification groups CT plaque characteristic groups: high risk versus other plaques versus no plaques Gender: male versus female Age: occurrence of MACE in patient a) under 45 years, b) between 45 and 65 years and c) over 65 years QoL: patients with significant QoL reductions versus patients with no changes in QoL BMI: Patients with BMI a) under 25, b) between 25 and 30 and c) over 30

Composite outcome: definition of MACE as a) vascular death or Myocardial Infarction (MI), b) cardiac death or MI.

Occurrence of myocardial infarction and stroke