Computed Tomography Angiography including coronary calcium scoring and coronary computed tomography angiography

Coronary Artery Disease

Clinical management/treatment decisions based on cardiac computed tomography including coronary calcium scoring and coronary computed tomography angiography

Computed tomography angiography (cardiac CT)

Clinical management/treatment decisions based on invasive coronary angiography

Invasive coronary angiography (ICA)

Medizinische Universitaet Innsbruck

Fakultni Nemocnice V Motole

Region Hovedstaden

Charité - Universitätsmedizin Berlin

Alb Fils Kliniken Gmbh

Universitaet Leipzig

Semmelweis Egyetem

University College Dublin, National University of Ireland

Universita Degli Studi Di Cagliari

Universita Degli Studi Di Roma La Sapienza

Paula Stradina Kliniska Universitates Slimnica As

Lietuvos Sveikatos Mokslu Universitetas

Wojewodzki Szpital Specjalistyczny We Wroclawiu

Centro Hospitalar de Vila Nova de Gaia/Espinho Epe

Cardio Med Srl

Institut Za Kardiovaskularne Bolesti Vojvodine

Institut Catala de La Salut

South Eastern Health and Social Care Trust Nhs

University of Glasgow

Aintree University Hospital Nhs Foundation Trust

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

Diagnostic Imaging Strategies for Patients With Stable Chest Pain and Intermediate Risk of Coronary Artery Disease: Comparative Effectiveness Research of Existing Technologies) - A Pragmatic Randomised Controlled Trial of CT Versus ICA

Composite endpoint: major adverse cardiovascular event (MACE); defined as at least one of the following: cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

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.

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

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

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 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.

cardiac tamponade/headache

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

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