Natural History of Coronary Atherosclerosis in Real-World Stable Chest Pain Patients Underwent Computed Tomography Angiography in Comparison With Invasive Multimodality Imaging

In a prospective international multicenter observational study, 1080 stable chest pain patients (REALITY Advanced registry of CCTA patients) with the suspected chronic coronary syndrome will be enrolled. All of them will undergo computed tomography angiography, CMR and/ or SPECT, and Echo. One of the cohorts will be examined with multimodality invasive imaging including quantitative coronary angiography, FFR, QFR with or without further percutaneous coronary intervention, OCT, and some of them - with IVUS, VH-IVUS. The plaque size and relevant stenosis, a composition of the atherosclerotic lesion, major adverse cardiovascular events (all-cause death, death from cardiac causes, myocardial infarction, or rehospitalization due to unstable or progressive angina, ischemia-driven revascularization) will be judged to be related to either originally treated (culprit) lesions or untreated (non-culprit) lesions. Moreover, the clinical potential of both non-invasive and invasive imaging, as well as anatomical vs functional modalities in two real-world patient flows, will be estimated with the special focus on the natural progression of atherosclerosis, clinical outcomes, and safety (contrast-induced nephropathy, radiocontrast-induced thyroid dysfunction, and radiation dose). The diagnostic accuracy will be analyzed.

The follow-up period will achieve 12 months prospectively with collected clinical events and imaging outcomes which will be determined at the baseline and 12-month follow-up.

The independent ethics expertise will be provided by the Ural State Medical University (Yekaterinburg, Russia) and Central Clinical Hospital of the Russian Academy of Sciences (Moscow, Russia). The monitoring of the clinical data with imaging as well as further CoreLab expertise (expert-level post-processing multimodal imaging software of Medis Imaging B.V., Leiden, The Netherlands) will be provided by De Haar Research Task Force, Amsterdam-Rotterdam, the Netherlands. FFR-CT is scheduled to be assessed by the ElucidVivo Research Edition software from Elucid Bio, Boston, MA, U.S.A.

The REALITY project is a part of the JHWH (Jahweh) International Advanced Cardiovascular Imaging Consortium. The main objective of the Consortium that is uniting international efforts of both Academia and Industry is a synergistic development of the advanced machine-learning imaging software in order to integrate benefits of both non-invasive and invasive imaging providing the daily clinical practice with the robust tool for the anatomical and functional examination of coronary atherosclerosis, PCI-related arterial remodeling, and relevant myocardial function.

Invasive coronary angiography with fractional flow reserve (FFR) is considered as the reference standard of daily clinical practice. This invasive approach is associated with potentially life-threatening complications, high expenditures, relatively high radiation exposure, and some patient discomfort. Noninvasive cardiac computed tomography angiography (CCTA) becomes a robust alternative to the invasive approach, especially when supported by other functional and anatomical noninvasive imaging modalities such as cardiac magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and echocardiography (Echo). Notwithstanding, their invasive counterpart, particularly a multimodal intravascular imaging (including fractional flow reserve/ FFR, quantitative flow reserve/ QFR, optical coherence tomography/ OCT, intravascular ultrasound/ IVUS, VH-IVUS) is able to rule out the high-risk, vulnerable and obstructive atherosclerosis dramatically optimizing clinical outcomes. The clinical value of these techniques remains questionable, especially if compared between noninvasive and invasive imaging methods.

The modern-day imaging modalities allow clinical cardiology to study the natural history of atherosclerosis that can predict certain clinical outcomes paving the way for a reduction of cardiovascular mortality. The retrospective studies have shown that most atherosclerotic plaques responsible for future acute coronary syndromes are angiographically mild, and the lesion-related risk factors for major adverse cardiovascular events (MACE) are poorly understood. Pathological studies have shown that thrombotic coronary occlusion after rupture of a lipid-rich atheroma with only a thin fibrous layer of intimal tissue covering the necrotic core (a thin-cap fibroatheroma) is the most common cause of myocardial infarction and death from cardiac causes. However, the prospective identification of thin-cap fibroatheromas has not been achieved, in part because the imaging tools to identify them in vivo did not exist until recently (Stone GW, et al, 2011; DOI: 10.1056/NEJMoa1002358). Both CCTA and quantitative coronary angiography (QCA) provide us with the potential of the advanced imaging of atherosclerotic lesions, but accuracy and safety remain the keystone limitations of these approaches. CCTA has the unique advantage over detecting non-calcifying plaques in addition to calcifying lesions, thus allowing for direct visualization of early atherosclerosis stages such as lipid and fibrous atheroma, which are risk factors for future coronary events. Long-term studies report an increased risk of the adverse outcomes associated with vulnerable fibroatheroma, whereas calcifying lesions tend to remain rather stable. Studies investigating the accuracy, outcome, and, thus, the diagnostic benefit of coronary CCTA in chest pain patients are scarce (Plank F, et al, 2014; doi:10.1136/openhrt-2014-000096). The accuracy of some advanced imaging modalities has recently developed to overcome existing limitations, however, the accuracy and precision of those measurements in the different stage lesions have not been established (Kan J, et al, 2014).

In a prospective international multicenter observational study, 1080 stable chest pain patients (REALITY Advanced registry of CCTA patients) with the suspected chronic coronary syndrome will be enrolled. All of them will undergo computed tomography angiography, CMR, and/ or SPECT, and Echo. One of the cohorts will be examined with multimodality invasive imaging including quantitative coronary angiography with or without further percutaneous coronary intervention, FFR, QFR, OCT, and some of them - with IVUS, VH-IVUS. The plaque size and relevant stenosis, a composition of the atherosclerotic lesion, major adverse cardiovascular events (all-cause death, death from cardiac causes, myocardial infarction, or rehospitalization due to unstable or progressive angina, ischemia-driven revascularization) will be judged to be related to either originally treated (culprit) lesions or untreated (non-culprit) lesions. Moreover, the clinical potential of both non-invasive and invasive imaging, as well as anatomical vs functional modalities in two real-world patient flows, will be estimated with the special focus on the natural progression of atherosclerosis, clinical outcomes, and safety (contrast-induced nephropathy, radiocontrast-induced thyroid dysfunction, and radiation dose). The diagnostic accuracy will be analyzed.

The follow-up period will achieve 12 months prospectively with collected clinical events and imaging outcomes which will be determined at the baseline and 12-month follow-up.

The independent ethics expertise will be provided by the Ural State Medical University (Yekaterinburg, Russia) and Central Clinical Hospital of the Russian Academy of Sciences (Moscow, Russia). The monitoring of the clinical data with imaging as well as further CoreLab expertise (expert-level post-processing multimodal imaging software of Medis Imaging B.V., Leiden, The Netherlands) will be provided by De Haar Research Task Force, Amsterdam-Rotterdam, the Netherlands.

The clinical data of the REALITY Advanced Registry include information of the complex examination with a 64-128-slice CT, two interviews with the risk factor modification recommendations, lab screening (serum fasting glucose, asparagine transaminase, alanine transaminase, total bilirubin, carbamide/ urea, creatinine, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, VLDL cholesterol), markers of the myocardium damage (myoglobin, troponin I, creatine kinase, creatine kinase-MB, brain natriuretic peptide - NT-proBNP), complete blood count, ECG, and Echo. The Registry patients will be tested with HeartAge, SCORE, Duke ACC/ AHA, Duke - DCS, Diamond-Forrester - DFM, The Seattle Angina Questionnaire - SAQ, Duke Activity Status Index -DASI, and EQ-5D-5L. Patients will be screened for the major risk factors and their modification: unhealthy blood cholesterol levels, high blood pressure, smoking, insulin resistance, diabetes, overweight or obesity, lack of physical activity, unhealthy diet (elements of Mediterranean and so-called 'Russian' diet), older age, genetic or lifestyle factors, family history of early heart disease. Moreover, such factors as CRP, sleep apnea, stress, and alcohol consumption will be assessed.

The eligibility criteria which the candidates must have fulfilled will be verified and the optimal clinical strategy will be estimated by the Heart Team, the Data Safety, and Monitoring Board. The clinical outcomes will be examined by the independent clinical endpoint adjudication committee.

The CCTA will be undergone in accordance with the 2016 SCCT (Society of Cardiovascular Computed Tomography) guidelines for the performance and acquisition of coronary computed tomographic angiography (Journal of Cardiovascular Computed Tomography/JCCT 2016;10:435e449). The results of the CCTA will be interpreted taking into account the 2020 SCCT Expert Consensus Document on Coronary CT Imaging of Atherosclerotic Plaque (JCCT 2020) and the 2021 SCCT Expert Consensus Document on Coronary Computed Tomographic Angiography (JCCT 2021). All non-invasive and invasive imaging procedures will be performed in accordance with local site practice, national, international, and societal guidelines including Society for Cardiovascular Magnetic Resonance (SCMR), American Society of Echocardiography (ASE), European Association of Percutaneous Cardiovascular Interventions (EuroPCR/ EAPCI), Society for Cardiovascular Angiography and Interventions (SCAI).

The imaging data from non-invasive (CCTA, FFR-CT, CMR, SPECT, Echo) and invasive (QCA, FFR, QFR, OCT, IVUS, VH-IVUS) methods will be handled and analyzed with the expert-level post-processing imaging software (Medis Suite Solutions: MR, XA, QFR, CT, Intravascular, Ultrasound) from Medis Medical Imaging Systems B.V. (Leiden, The Netherlands), if applicable. Raw imaging data will be transferred to the independent CoreLab (De Haar Research Task Force, Rotterdam-Amsterdam, The Netherlands) and analyzed by two experienced readers, blinded to the patient's information. The interobserver disagreements will be resolved by a third reader. FFR-CT is scheduled to be assessed by the ElucidVivo Research Edition software from Elucid Bio, Boston, MA, U.S.A.

The REALITY project is a part of the JHWH (Jahweh) International Advanced Cardiovascular Imaging Consortium. The main objective of the Consortium that is uniting international efforts of both Academia and Industry is a synergistic development of the advanced machine-learning imaging software in order to integrate benefits of both non-invasive and invasive imaging providing the daily clinical practice with the robust tool for the anatomical and functional examination of coronary atherosclerosis, PCI-related arterial remodeling, and relevant myocardial function.

The main aim of the REALITY Advanced trial is to evaluate the natural history of atherosclerosis within the concept of the Glagovian arterial remodeling in stable chest pain patients with the assessment of the clinical potential/ prognostic value and safety of the different noninvasive and invasive imaging tools as CCTA (and/ or CMR, SPECT, Echo), QCA, FFR, QFR, and applicable intravascular imaging (OCT, IVUS, VH-IVUS) handled with the advanced post-processing imaging software. Some preventive and therapeutic strategies will be examined, focusing on the place in routine clinical practice of such noninvasive imaging approach as CCTA vs relevant invasive imaging. The currently developed noninvasive imaging tools, including 64-128-320-slice CCTA processed with the high-accuracy machine-learning imaging software, can upgrade the noninvasive imaging's clinical value in contrary to the invasive approach, evaluating the significance of coronary atherosclerosis with related high-risk features of the arterial remodeling, predicting clinical outcomes, and avoiding unnecessary invasive intravascular interventions. The optimization of the diagnostic strategy and associated interventional approach can pave the way for dramatic improvement of clinical outcomes and cost-effectiveness of coronary artery disease (CAD) clinical management and, therefore, for substantial cardiovascular mortality reduction.

The REALITY Advanced trial pursued several objectives as follows:

1. To compare anatomical methods of noninvasive (CCTA, CMR) vs. invasive (QCA, OCT, IVUS, VH-IVUS) imaging with a focus on the options such as:

   1. High-risk and vulnerable features of lesions, including plaque composition with particular attention to the size of the necrotic core, the thickness and histological condition of the cap, signs of erosion, rupture, local thrombosis,
   2. Arterial remodeling,
   3. Significance of a 40% plaque burden as a keystone threshold for progression of atherosclerosis and clinical outcomes,
   4. Perivascular inflammation,
   5. Culprit vs. non-culprit lesions,
   6. Assessment of the blood flow physiological patterns, including invasively measured vs. calculated fractional flow reserve, wall shear stress (if applicable) derived from both noninvasive and invasive imaging and handled by the advanced post-processing imaging software,
   7. Diagnostic accuracy in comparison between various imaging modalities.
2. To match noninvasive and invasive anatomical (CCTA, QCA, OCT, IVUS, VH-IVUS) vs. functional (Echo, CMR, SPECT, MSCT) imaging, particularly if the anatomical significance of coronary atherosclerosis compared to the time trajectory of the cardiac function with a focus on:

   1. Ischemia (assessed by stress testing with CMR, SPECT, MSCT, Echo),
   2. Strain (both regional and global with different imaging modalities),
   3. Inflammation, including edema, fibrosis, particularly with CMR (hyperemia with EGE/ early gadolinium enhancement, edema with T2 weighted imaging, and scar/necrosis or fibrosis with LGE/ late gadolinium enhancement),
   4. Local coronary hemodynamics,
   5. Diagnostic accuracy in comparison between various imaging modalities.
3. To calculate the predictive value (with some risk stratification models) of different noninvasive and invasive imaging modalities amid various therapeutic strategies and invasive interventions. The performance of each strategy will be examined for sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operator characteristic (ROC) curve.
4. To conduct epidemiological analysis of the involved population and evaluate the cost-effectiveness of the different noninvasive and invasive strategies in stable chest pain patients, including:

   1. Direct effects: cost of imaging test, cost of complications due to imaging testing, effects of radiation, effects of contrast material, other complications of noninvasive and invasive imaging, psychological effects of the imaging test,
   2. Indirect effects: cost of the treatment, cost of complications of treatment, cost of health outcome, medical pathway, and health outcome depending on a medical decision based on the image test result, psychological effects of the test result.

Eligibility Criteria:
Inclusion Criteria:

* all stable chest pain comers with chronic coronary syndrome or angina equivalent consistent with the manifestation of the stable coronary artery disease (by the 2019 Guidelines on Chronic Coronary Syndrome);
* age between 40 and 79 years old;
* patient must have one or two-vessel disease in a native coronary vessel requiring or not requiring PCI without indications for immediate bypass surgery with any SYNTAX score;
* lesions may be either de novo or restenotic;
* successful, uncomplicated PCI could be performed in the culprit vessels and all culprit lesions, but there should be no events or complications between the procedures of PCI in the past and six months before admission to the Chest Pain Center;
* the non-culprit vessel should have no flow-limiting lesions (but any plaque burden) and be available for imaging. The non-culprit vessel must be considered safe for imaging evaluation;

Exclusion Criteria:

* any acute comorbidities;
* patient has had a documented ST-elevation acute myocardial infarction within the 24 hours or acute coronary syndrome (unstable angina, myocardial infarction) during four weeks before admission to the Chest Pain Center;
* patient has had a recent PCI (last 6 months before admission to the Chest Pain Center) unless the patient is undergoing a staged procedure for dual vessel treatment;
* unprotected left main lesion location;
* imaging evidence of severe calcification (CCTA calcium scoring with a CAC\>1000) or marked tortuosity of the vessel;
* culprit lesion is located within or distal to an arterial or saphenous vein graft;
* untreated, significant coronary lesion with a \>50-75% diameter stenosis remaining in the culprit vessel after the planned intervention (branch stenosis is permitted) unless allowed by the Heart Team, or the Institutional Review Board (IRB), or the Data Safety and Monitoring Board (DSMB);
* lesion or vessel contains visible thrombus within the imaging procedure;
* patient has an additional lesion that requires intervention within 180 days after the initial hospitalization unless allowed by the Heart Team, or the IRB, or the DSMB;
* any diameter stenosis more than 75% in the non-culprit vessel;
* indications for immediate bypass surgery within one year of enrollment with the SYNTAX above 34 (including multi-vessel disease requiring intervention in all three major coronary arteries);
* decompensated hypotension or heart failure requiring intubation, inotropes, intravenous diuretics, or intra-aortic balloon counterpulsation (including the presence of cardiogenic shock);
* patient has a known left ventricular ejection fraction \<40% or history of decompensated congestive heart failure;
* uncontrolled tachycardia or refractory ventricular arrhythmia;
* presence of cardiac implants;
* acute conduction system disease requiring a pacemaker;
* uncontrolled hypokalemia or digitalis intoxication;
* uncontrolled arterial hypertension;
* moderate or severe pulmonary hypertension with pulmonary artery systolic pressure \>35 mmHg;
* severe disorders of blood coagulation system/ coagulopathy;
* fever; active infective endocarditis; active COVID-19 infection; any active or severe chronic viral infections; sepsis;
* HIV infection: CDC acute retroviral syndrome/ acute HIV infection, CDC stage 3/ WHO stage 4 (AIDS; the CD4+ cell count is less than 200 or the percent of CD4+ cells is less than 15% of all lymphocytes); however, the subjects of the HIVE trial (NCT04810364) are allowed, but with chronic HIV infection (CDC stages 1, 2/ WHO stages 1, 2, 3) only;
* tuberculosis;
* creatinine clearance with GFR of \<45 mL/min/1.73 m2 (severe CKD, G3b-G4-G5) by CKD-EPI (2009) or \<45 mL/min by Cockroft-Gault (1976); a few reasons are there for these limitations, a) many medications are contraindicated and/ or dosages must be decreased in patients with severe CKD, b) already-in-use metformin with eGFR ≥45 mL/min/1.73 m2 is not an exclusion criterion, and metformin must be not stopped at the time of or before studies with IV contrast or withheld for 48 hours after the procedure, c) to reduce contrast material and radiation dose and therefore to prevent contrast-associated acute kidney injury, all the procedures with intravascular contrast (CCTA, CMR, SPECT, coronary angiography and any related invasive intravascular procedures) cannot be performed altogether subsequently during 24-48 hours, but it must undergo within two weeks with the recommended minimum break time between procedures of 48 hours and proper preventive hydration of the recruited patients.
* need for dialysis;
* liver cirrhosis;
* severe endocrine disorders (diabetes is permitted) including pre-existing thyroid diseases unless allowed by the Heart Team, or the IRB, or the DSMB;
* patient has a known hypersensitivity, allergy, or contraindication to any of the following: aspirin, heparin, clopidogrel, and ticlopidine, or to contrast (including iodine and gadolinium) that cannot be adequately pre-medicated;
* severe asthma or chronic obstructive pulmonary disease with FEV-1 below 50%;
* patient has other severe medical illness or recent history of substance abuse that may cause non-compliance; confound the data interpretation or is associated with an anticipated limited life expectancy of less than one year;
* stage IV cancer;
* patient on the transplant waiting list;
* moderate and severe anemia with hemoglobin below 11.0 g/dL, any severe blood diseases;
* acute or recent history of gastrointestinal bleeding;
* pregnancy;
* stroke or CVA within three months before admission to the Chest Pain Center;
* mental diseases, claustrophobia, inability for patient cooperation;
* prior participation in this study or patient is currently enrolled in another investigational use device, imaging, or drug study that has not been reached its primary endpoint.