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

 -  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; HIV infection, stage
 3 (AIDS); any active or severe chronic viral infections; sepsis;

 -  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.