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Background: We assessed whether combinations of cardiometabolic risk factors independently predict coronary plaque progression (PP) and major adverse cardiovascular events in patients with stable coronary artery disease., Methods: Patients with known or suspected stable coronary artery disease (60.9±9.3 years, 55.4% male) undergoing serial coronary computed tomography angiographies (≥2 years apart), with clinical characterization and follow-up (N=1200), were analyzed from the PARADIGM study (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging). Plaque volumes measured in coronary segments (≥2 mm in diameter) were summed to provide whole heart plaque volume (mm 3 ) and percent atheroma volume (plaque volume/vessel volume×100; %) per patient at baseline and follow-up. Rapid PP was defined as a percent atheroma volume increase of ≥1.0%/y. Major adverse cardiovascular events included nonfatal myocardial infarction, death, and unplanned coronary revascularization., Results: In an interscan period of 3.2 years (interquartile range, 1.9), rapid PP occurred in 341 patients (28%). At multivariable analysis, the combination of cardiometabolic risk factors defined as metabolic syndrome predicted rapid PP (odds ratio, 1.51 [95% CI, 1.12-2.03]; P =0.007) together with older age, smoking habits, and baseline percent atheroma volume. Among single cardiometabolic variables, high fasting plasma glucose (diabetes or fasting plasma glucose >100 mg/dL) and low HDL-C (high-density lipoprotein cholesterol; <40 mg/dL in males and <50 mg/dL in females) were independently associated with rapid PP, in particular when combined (odds ratio, 2.37 [95% CI, 1.56-3.61]; P <0.001). In a follow-up of 8.23 years (interquartile range, 5.92-9.53), major adverse cardiovascular events occurred in 201 patients (17%). At multivariable Cox analysis, the combination of high fasting plasma glucose with high systemic blood pressure (treated hypertension or systemic blood pressure >130/85 mm Hg) was an independent predictor of events (hazard ratio, 1.79 [95% CI, 1.10-2.90]; P =0.018) together with family history, baseline percent atheroma volume, and rapid PP., Conclusions: In patients with stable coronary artery disease, the combination of hyperglycemia with low HDL-C is associated with rapid PP independently of other risk factors, baseline plaque burden, and treatment. The combination of hyperglycemia with high systemic blood pressure independently predicts the worse outcome beyond PP., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02803411., Competing Interests: Dr Chang receives funding from the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (grant No. 2012027176). Dr Min receives funding from GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr Min also has an equity interest in and is an employee of Cleerly Inc. The other authors report no conflicts.

Background: Radiomics is expected to identify imaging features beyond the human eye. We investigated whether radiomics can identify coronary segments that will develop new atherosclerotic plaques on coronary computed tomography angiography (CCTA)., Methods: From a prospective multinational registry of patients with serial CCTA studies at ≥ 2-year intervals, segments without identifiable coronary plaque at baseline were selected and radiomic features were extracted. Cox models using clinical risk factors (Model 1), radiomic features (Model 2) and both clinical risk factors and radiomic features (Model 3) were constructed to predict the development of a coronary plaque, defined as total PV ​≥ ​1 ​mm 3 , at follow-up CCTA in each segment., Results: In total, 9583 normal coronary segments were identified from 1162 patients (60.3 ​± ​9.2 years, 55.7% male) and divided 8:2 into training and test sets. At follow-up CCTA, 9.8% of the segments developed new coronary plaque. The predictive power of Models 1 and 2 was not different in both the training and test sets (C-index [95% confidence interval (CI)] of Model 1 vs. Model 2: 0.701 [0.690-0.712] vs. 0.699 [0.0.688-0.710] and 0.696 [0.671-0.725] vs. 0.0.691 [0.667-0.715], respectively, all p ​> ​0.05). The addition of radiomic features to clinical risk factors improved the predictive power of the Cox model in both the training and test sets (C-index [95% CI] of Model 3: 0.772 [0.762-0.781] and 0.767 [0.751-0.787], respectively, all p ​< ​00.0001 compared to Models 1 and 2)., Conclusion: Radiomic features can improve the identification of segments that would develop new coronary atherosclerotic plaque., Clinical Trial Registration: ClinicalTrials.gov NCT0280341., Competing Interests: Declaration of competing interest Dr. Chang receives funding from the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT) (Grant No. 2012027176). Dr. James K. Min receives funding from GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr. Min also has an equity interest in and is an employee of Cleerly, Inc. The remaining authors have no relevant disclosures., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

BACKGROUND . Dose reduction strategies for coronary CTA (CCTA) have been underused in clinical practice given concern that the strategies may lower image quality. OBJECTIVE . The purpose of this study was to explore associations between dose reduction strategies and CCTA image quality in real-world clinical practice. METHODS . This subanalysis of the international Prospective Multicenter Registry on Radiation Dose Estimates of Cardiac CT Angiography in Daily Practice in 2017 (PROTECTION VI) study included 3725 patients (2109 men, 1616 women; median age, 59 years) who underwent CCTA for coronary artery evaluation performed at 55 sites in 32 countries. CCTA image sets were reviewed at a core laboratory. A range of patient and scan characteristics, including use of three dose reduction strategies (prospective ECG triggering, low tube potential, and iterative image reconstruction) and image dose, were recorded. A single core laboratory member reviewed all examinations for quantitative image quality measures, including signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), and reviewed 50% of examinations to assign a qualitative CCTA image quality score and a semiquantitative coronary calcification measure. Multivariable logistic regression models were used to identify predictors of image quality. A second core laboratory member repeated quantitative measures for 100 examinations and the qualitative measure for 383 (approximately 20%) examinations to assess interreader agreement. RESULTS . Independent predictors ( p < .05) of SNR were female sex (effect size, 2.70), lower body mass index (0.38 per 1-unit decrease), stable sinus rhythm (1.71), and scanner manufacturer (variable effect across manufacturers). These factors were also the only independent predictors of CNR. Independent predictors ( p < .05) of CCTA image quality were heart rate (0.17 per 10 beats/min reduction) and coronary calcification (0.15 per coronary calcification grade). None of the three dose-saving strategies or dose-length product was an independent predictor of any image quality measure. Interreader agreement analysis showed intraclass correlation coefficients of 0.874 for SNR and 0.891 for CNR and a kappa value of 0.812 for the qualitative score. CONCLUSION . This large international multicenter study shows that three dose reduction strategies were not associated with decreased CCTA image quality. CLINICAL IMPACT . The dose reduction strategies should be routinely implemented in clinical CCTA.

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm 3 ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized β = 0.24; 95% CI: 0.16, 0.32; P < .001) and both calcified (β = 0.26; 95% CI: 0.18, 0.34; P < .001) and noncalcified (β = 0.17; 95% CI: 0.08, 0.25; P < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (β = 0.13; 95% CI: 0.03, 0.22; P = .01), driven solely by calcified plaque volume (β = 0.24; 95% CI: 0.14, 0.34; P < .001) but not noncalcified plaque volumes (β = -0.06; 95% CI: -0.14, 0.03; P = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.

Background: Although sex- and age-specific differences in coronary plaque features detected by coronary computed tomography angiography (CCTA) are known, insufficient information regarding the long-term prognostic value of these findings exists., Methods: A total of 1615 patients with suspected but not previously diagnosed coronary artery disease (CAD) were examined by CCTA and coronary plaque features were assessed. The median follow-up period was 10.5 (IQR 9.2-11.4) years. Cox proportional-hazards analysis was used for the combined endpoint of cardiac death or nonfatal myocardial infarction., Results: The endpoint occurred more often in patients older than 65 years (5.66% vs. 2.05%; p = 0.00029) but similarly between female (3.34%) and male (3.07%) patients (p = 0.76). Both sexes displayed a similar prevalence for noncalcified (female vs. male: 0.77 ± 1.38 vs. 0.89 ± 1.41; p = 0.098) and low-attenuation (female vs. male: 2.6% vs. 4.37%; p = 0.096) plaques. As assessed by p for interaction CADRADS (p for interaction = 0.013), noncalcified plaques (p for interaction = 0.022) and low-attenuation plaques (p for interaction = 0.045) had a better primary endpoint association in women than in men. Concerning age, no difference in outcome association was apparent as evaluated by p for interaction., Conclusion: CCTA demonstrates excellent long-term prognostic value irrespective of sex and age and independent from the higher prevalence of atherosclerotic plaques in men and patients older than 65 years. Although similarly prevalent in both sexes, noncalcified and low-attenuation plaques exhibit a better prognostic value in women., Competing Interests: Declaration of competing interest Dr. Martinoff reports receiving unrestricted research grants from Siemens Healthineers. All other authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Inc.)

To determine whether the assessment of individual plaques is superior in predicting the progression to obstructive coronary artery disease (CAD) on serial coronary computed tomography angiography (CCTA) than per-patient assessment. From a multinational registry of 2252 patients who underwent serial CCTA at a ≥ 2-year inter-scan interval, patients with only non-obstructive lesions at baseline were enrolled. CCTA was quantitatively analyzed at both the per-patient and per-lesion level. Models predicting the development of an obstructive lesion at follow up using either the per-patient or per-lesion level CCTA measures were constructed and compared. From 1297 patients (mean age 60 ± 9 years, 43% men) enrolled, a total of 3218 non-obstructive lesions were identified at baseline. At follow-up (inter-scan interval: 3.8 ± 1.6 years), 76 lesions (2.4%, 60 patients) became obstructive, defined as > 50% diameter stenosis. The C-statistics of Model 1, adjusted only by clinical risk factors, was 0.684. The addition of per-patient level total plaque volume (PV) and the presence of high-risk plaque (HRP) features to Model 1 improved the C-statistics to 0.825 [95% confidence interval (CI) 0.823-0.827]. When per-lesion level PV and the presence of HRP were added to Model 1, the predictive value of the model improved the C-statistics to 0.895 [95% CI 0.893-0.897]. The model utilizing per-lesion level CCTA measures was superior to the model utilizing per-patient level CCTA measures in predicting the development of an obstructive lesion (p < 0.001). Lesion-level analysis of coronary atherosclerotic plaques with CCTA yielded better predictive power for the development of obstructive CAD than the simple quantification of total coronary atherosclerotic burden at a per-patient level.Clinical Trial Registration: ClinicalTrials.gov NCT0280341.

Background and Aims: Different methodologies to report whole-heart atherosclerotic plaque on coronary computed tomography angiography (CCTA) have been utilized. We examined which of the three commonly used plaque burden definitions was least affected by differences in body surface area (BSA) and sex., Methods: The PARADIGM study includes symptomatic patients with suspected coronary atherosclerosis who underwent serial CCTA >2 years apart. Coronary lumen, vessel, and plaque were quantified from the coronary tree on a 0.5 mm cross-sectional basis by a core-lab, and summed to per-patient. Three quantitative methods of plaque burden were employed: (1) total plaque volume (PV) in mm 3 , (2) percent atheroma volume (PAV) in % [which equaled: PV/vessel volume * 100%], and (3) normalized total atheroma volume (TAV norm ) in mm 3 [which equaled: PV/vessel length * mean population vessel length]. Only data from the baseline CCTA were used. PV, PAV, and TAV norm were compared between patients in the top quartile of BSA vs the remaining, and between sexes. Associations between vessel volume, BSA, and the three plaque burden methodologies were assessed., Results: The study population comprised 1479 patients (age 60.7 ± 9.3 years, 58.4% male) who underwent CCTA. A total of 17,649 coronary artery segments were evaluated with a median of 12 (IQR 11-13) segments per-patient (from a 16-segment coronary tree). Patients with a large BSA (top quartile), compared with the remaining patients, had a larger PV and TAV norm , but similar PAV. The relation between larger BSA and larger absolute plaque volume (PV and TAV norm ) was mediated by the coronary vessel volume. Independent from the atherosclerotic cardiovascular disease risk (ASCVD) score, vessel volume correlated with PV (P < 0.001), and TAV norm (P = 0.003), but not with PAV (P = 0.201). The three plaque burden methods were equally affected by sex., Conclusions: PAV was less affected by patient's body surface area then PV and TAV norm and may be the preferred method to report coronary atherosclerotic burden., Competing Interests: Declaration of competing interest Dr. James K. Min receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare. Dr. Min serves on the scientific advisory board of Arineta and GE Healthcare, and has an equity interest in Cleerly. Dr. Habib Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic. Dr. Kavitha Chinnaiyan is a non-compensated medical advisory board member of Heartflow Inc. The remaining authors have no relevant disclosures., (Copyright © 2020. Published by Elsevier Inc.)

Background: The association between triglyceride glucose (TyG) index and coronary atherosclerotic change remains unclear. We aimed to evaluate the association between TyG index and coronary plaque progression (PP) using serial coronary computed tomography angiography (CCTA)., Methods: A total of 1143 subjects (aged 60.7 ± 9.3 years, 54.6% male) who underwent serial CCTA with available data on TyG index and diabetic status were analyzed from The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. PP was defined as plaque volume (PV) (mm 3 ) at follow-up minus PV at index > 0. Annual change of PV (mm 3 /year) was defined as PV change divided by inter-scan period. Rapid PP was defined as the progression of percent atheroma volume (PV divided by vessel volume multiplied by 100) ≥ 1.0%/year., Results: The median inter-scan period was 3.2 (range 2.6-4.4) years. All participants were stratified into three groups based on TyG index tertiles. The overall incidence of PP was 77.3%. Baseline total PV (group I [lowest]: 30.8 (0.0-117.7), group II: 47.2 (6.2-160.4), and group III [highest]: 57.5 (8.4-154.3); P < 0.001) and the annual change of total PV (group I: 5.7 (0.0-20.2), group II: 7.6 (0.5-23.5), and group III: 9.4 (1.4-27.7); P = 0.010) were different among all groups. The risk of PP (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.167-2.327; P = 0.005) and rapid PP (OR 1.777; 95% CI 1.288-2.451; P < 0.001) was increased in group III compared to that in group I. TyG index had a positive and significant association with an increased risk of PP and rapid PP after adjusting for confounding factors., Conclusion: TyG index is an independent predictive marker for the progression of coronary atherosclerosis. Clinical registration ClinicalTrials.gov NCT02803411.

Objectives: This study explored whether the pattern of nonobstructive lesion progression into obstructive lesions would differ according to the presence of high-risk plaque (HRP)., Background: It is still debatable whether HRP simply represents a certain phase during the natural history of coronary atherosclerotic plaques or if disease progression would differ according to the presence of HRP., Methods: Patients with nonobstructive coronary artery disease, defined as percent diameter stenosis (%DS) <50%, were enrolled from a prospective, multinational registry of consecutive patients who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. HRP was defined as lesions with ≥2 features of positive remodeling, spotty calcification, or low-attenuation plaque. Quantitative total and compositional percent atheroma volume (PAV) at baseline and annualized PAV change were compared between non-HRP and HRP lesions., Results: A total of 3,049 nonobstructive lesions were identified from 1,297 patients (mean age 60.3 ± 9.3 years; 56.8% men). There were 2,624 non-HRP and 425 HRP lesions. HRP lesions had a greater total PAV and all noncalcified components of PAV and %DS at baseline compared with non-HRP lesions. However, the annualized total PAV changes were greater in non-HRP lesions than in HRP lesions. On multivariate analysis adjusted for clinical risk factors, drug use, change in lipid level, total PAV, %DS, and HRP, only the baseline total PAV and %DS independently predicted the development of obstructive lesions (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02 to 1.07, and HR: 1.07; 95% CI: 1.04 to 1.10, respectively, all p < 0.05), whereas the presence of HRP did not (p > 0.05)., Conclusions: The pattern of individual coronary atherosclerotic plaque progression differed according to the presence of HRP. Baseline PAV, not the presence of HRP features, was the most important predictor of lesions developing into obstructive lesions. (Progression of Atherosclerotic Plaque Determined By Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: We aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders., Methods: Out of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability., Results: A total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265)., Conclusion: Coronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone., Competing Interests: Declaration of competing interest Dr. James K. Min receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare. Dr. Min serves on the scientific advisory board of Arineta and GE Healthcare, and has an equity interest in Cleerly. The Department of Cardiology of the Leiden University Medical Center received research grants from Biotronik, Medtronic, Boston Scientific and Edwards Lifesciences. Arthur J.H.A. Scholte received consulting fees from GE Healthcare and Canon., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background Rapid coronary plaque progression (RPP) is associated with incident cardiovascular events. To date, no method exists for the identification of individuals at risk of RPP at a single point in time. This study integrated coronary computed tomography angiography-determined qualitative and quantitative plaque features within a machine learning (ML) framework to determine its performance for predicting RPP. Methods and Results Qualitative and quantitative coronary computed tomography angiography plaque characterization was performed in 1083 patients who underwent serial coronary computed tomography angiography from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry. RPP was defined as an annual progression of percentage atheroma volume ≥1.0%. We employed the following ML models: model 1, clinical variables; model 2, model 1 plus qualitative plaque features; model 3, model 2 plus quantitative plaque features. ML models were compared with the atherosclerotic cardiovascular disease risk score, Duke coronary artery disease score, and a logistic regression statistical model. 224 patients (21%) were identified as RPP. Feature selection in ML identifies that quantitative computed tomography variables were higher-ranking features, followed by qualitative computed tomography variables and clinical/laboratory variables. ML model 3 exhibited the highest discriminatory performance to identify individuals who would experience RPP when compared with atherosclerotic cardiovascular disease risk score, the other ML models, and the statistical model (area under the receiver operating characteristic curve in ML model 3, 0.83 [95% CI 0.78-0.89], versus atherosclerotic cardiovascular disease risk score, 0.60 [0.52-0.67]; Duke coronary artery disease score, 0.74 [0.68-0.79]; ML model 1, 0.62 [0.55-0.69]; ML model 2, 0.73 [0.67-0.80]; all P <0.001; statistical model, 0.81 [0.75-0.87], P =0.128). Conclusions Based on a ML framework, quantitative atherosclerosis characterization has been shown to be the most important feature when compared with clinical, laboratory, and qualitative measures in identifying patients at risk of RPP.

Objectives: The aim of this study was to assess the use of low tube potentials for coronary computed tomography angiography (CCTA) in worldwide clinical practice and its influence on radiation exposure, contrast agent volume, and image quality., Background: CCTA is frequently used in clinical practice. Lowering of tube potential is a potent method to reduce radiation exposure and to economize contrast agent volume., Methods: CCTAs of 4,006 patients from 61 international study sites were analyzed regarding very-low (≤80 kVp), low (90 to 100 kVp), conventional (110 to 120 kVp), and high (≥130 kVp) tube potentials. The impact on dose-length product (DLP) and contrast agent volume was analyzed. Image quality was determined by evaluation of the diagnostic applicability and assessment of the objective image parameters signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR)., Results: When compared with conventional tube potentials, low tube potentials were used in 56% of CCTAs (≤80 kVp: 9%; 90 to 100 kVp: 47%), which varied among sites from 0% to 100%. Tube potential reduction was associated with low-cardiovascular risk profile, low body mass index (BMI), and new-generation scanners. Median radiation exposure was lowered by 68% or 50% and median contrast agent volume by 25% or 13% for tube potential protocols of ≤80 kVp or 90 to 100 kVp when compared with conventional tube potentials, respectively (all p < 0.001). With the use of lower tube potentials, the frequency of diagnostic scans was maintained (p = 0.41), whereas SNR and CNR significantly improved (both p < 0.001). Considering BMI eligibility criteria, 58% (n = 946) of conventionally scanned patients would have been suitable for low tube potential protocols, and 44% (n = 831) of patients scanned with 90 to 100 kVp would have been eligible for very-low tube potential CCTA imaging of ≤80 kVp., Conclusions: This large international registry confirms the feasibility of tube potential reduction in clinical practice leading to lower radiation exposure and lower contrast volumes. The current registry also demonstrates that this strategy is still underused in daily practice. (PROspective multicenter registry on radiaTion dose Estimates of cardiac CT angIOgraphy iN daily practice in 2017 [PROTECTION-VI]; NCT02996903)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: The rationale of this study was to identify patients with fast progression of coronary plaque volume PV and characterize changes in PV and plaque components over time., Method: Total PV (TPV) was measured in 350 patients undergoing serial coronary computed tomography angiography (median scan interval 3.6 years) using semi-automated software. Plaque morphology was assessed based on attenuation values and stratified into calcified, fibrous, fibrous-fatty and low-attenuation PV for volumetric measurements. Every plaque was additionally classified as either calcified, partially calcified or non-calcified., Results: In total, 812 and 955 plaques were detected in the first and second scan. Mean TPV increase was 20 % on a per-patient base (51.3 mm³ [interquartile range (IQR): 14.4, 126.7] vs. 61.6 mm³ [IQR: 16.7, 170.0]). TPV increase was driven by calcified PV (first scan: 7.6 mm³ [IQR: 0.2, 33.6] vs. second scan: 16.6 mm³ [IQR: 1.8, 62.1], p < 0.01). Forty-two patients showed fast progression of TPV, defined as >1.3 mm 3 increase of TPV per month. Male sex (odds ratio 3.1, p = 0.02) and typical angina (odds ratio 3.95, p = 0.03) were identified as risk factors for fast TPV progression, while high-density lipoprotein cholesterol had a protective effect (odds ratio per 10 mg/dl increase of HDL cholesterol: 0.72, p < 0.01). Progression to >50 % stenosis at follow-up was observed in 34 of 327 (10.4 %) calcified plaques, in 13 of 401 (3.2 %) partially calcified plaques and 2 of 221 (0.9 %) non-calcified plaques (p < 0.01)., Conclusion: Fast plaque progression was observed in male patients and patients with typical angina. High HDL cholesterol showed a protective effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Symptom-based pretest probability scores that estimate the likelihood of obstructive coronary artery disease (CAD) in stable chest pain have moderate accuracy. We sought to develop a machine learning (ML) model, utilizing clinical factors and the coronary artery calcium score (CACS), to predict the presence of obstructive CAD on coronary computed tomography angiography (CCTA)., Methods and Results: The study screened 35 281 participants enrolled in the CONFIRM registry, who underwent ≥64 detector row CCTA evaluation because of either suspected or previously established CAD. A boosted ensemble algorithm (XGBoost) was used, with data split into a training set (80%) on which 10-fold cross-validation was done and a test set (20%). Performance was assessed of the (1) ML model (using 25 clinical and demographic features), (2) ML + CACS, (3) CAD consortium clinical score, (4) CAD consortium clinical score + CACS, and (5) updated Diamond-Forrester (UDF) score. The study population comprised of 13 054 patients, of whom 2380 (18.2%) had obstructive CAD (≥50% stenosis). Machine learning with CACS produced the best performance [area under the curve (AUC) of 0.881] compared with ML alone (AUC of 0.773), CAD consortium clinical score (AUC of 0.734), and with CACS (AUC of 0.866) and UDF (AUC of 0.682), P < 0.05 for all comparisons. CACS, age, and gender were the highest ranking features., Conclusion: A ML model incorporating clinical features in addition to CACS can accurately estimate the pretest likelihood of obstructive CAD on CCTA. In clinical practice, the utilization of such an approach could improve risk stratification and help guide downstream management., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends risk enhancers in the borderline-risk and statin recommended/intermediate-risk groups. We determined the risk reclassification by the presence and severity of coronary computed tomography angiography (CCTA)-visualized coronary artery disease (CAD) according to statin eligibility groups. Of 35,281 individuals who underwent CCTA, 1,303 asymptomatic patients (age 59, 65% male) were identified. Patients were categorized as low risk, borderline risk, statin recommended/intermediate risk or statin recommended/high risk according to the guideline. CCTA-visualized CAD was categorized as no CAD, nonobstructive, or obstructive. Major adverse cardiovascular events (MACE) were defined as a composite outcome of all-cause mortality, nonfatal myocardial infarction, and late coronary revascularization (>90 days). We tested a reclassification wherein no CAD reclassifies downward, and the presence of any CAD reclassifies upward. During a median follow-up of 2.9 years, 93 MACE events (7.1%) were observed. Among the borderline-risk and statin-recommended/intermediate-risk groups eligible for risk enhancers, the presence or absence of any CCTA-visualized CAD led to a net increase of 2.3% of cases and 22.4% of controls correctly classified (net reclassification index [NRI] 0.27, 95% CI 0.13 to 0.41, p = 0.0002). The NRI was not significant among low- or statin-recommended/high-risk patients (all p >0.05). The presence or absence of CCTA-visualized CAD, including both obstructive and nonobstructive CAD, significantly improves reclassification in patients eligible for risk enhancers in 2018 ACC/AHA guidelines. Patients in low- and high-risk groups derive no significant improvement in risk reclassification from CCTA., (Copyright © 2019. Published by Elsevier Inc.)

Aims: Coronary artery calcium score (CACS) is a strong predictor of major adverse cardiac events (MACE). Conversely, statins, which markedly reduce MACE risk, increase CACS. We explored whether CACS progression represents compositional plaque volume (PV) progression differently according to statin use., Methods and Results: From a prospective multinational registry of consecutive patients (n = 2252) who underwent serial coronary computed tomography angiography (CCTA) at a ≥ 2-year interval, 654 patients (61 ± 10 years, 56% men, inter-scan interval 3.9 ± 1.5 years) with information regarding the use of statins and having a serial CACS were included. Patients were divided into non-statin (n = 246) and statin-taking (n = 408) groups. Coronary PVs (total, calcified, and non-calcified; sum of fibrous, fibro-fatty, and lipid-rich) were quantitatively analysed, and CACS was measured from both CCTAs. Multivariate linear regression models were constructed for both statin-taking and non-statin group to assess the association between compositional PV change and change in CACS. In multivariate linear regression analysis, in the non-statin group, CACS increase was positively associated with both non-calcified (β = 0.369, P = 0.004) and calcified PV increase (β = 1.579, P < 0.001). However, in the statin-taking group, CACS increase was positively associated with calcified PV change (β = 0.756, P < 0.001) but was negatively associated with non-calcified PV change (β = -0.194, P = 0.026)., Conclusion: In the non-statin group, CACS progression indicates the progression of both non-calcified and calcified PV progression. However, under the effect of statins, CACS progression indicates only calcified PV progression, but not non-calcified PV progression. Thus, the result of serial CACS should be differently interpreted according to the use of statins., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: The long-term prognostic value of coronary computed tomography angiography (CCTA)-identified coronary artery disease (CAD) has not been evaluated in elderly patients (≥70 years). We compared the ability of coronary CCTA to predict 5-year mortality in older vs. younger populations., Methods and Results: From the prospective CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, we analysed CCTA results according to age <70 years (n = 7198) vs. ≥70 years (n = 1786). The severity of CAD was classified according to: (i) maximal stenosis degree per vessel: none, non-obstructive (1-49%), or obstructive (>50%); (ii) segment involvement score (SIS): number of segments with plaque. Cox-proportional hazard models assessed the relationship between CCTA findings and time to mortality. At a mean 5.6 ± 1.1 year follow-up, CCTA-identified CAD predicted increased mortality compared with patients with a normal CCTA in both <70 years [non-obstructive hazard ratio (HR) confidence interval (CI): 1.70 (1.19-2.41); one-vessel: 1.65 (1.03-2.67); two-vessel: 2.24 (1.21-4.15); three-vessel/left main: 4.12 (2.27-7.46), P < 0.001] and ≥70 years [non-obstructive: 1.84 (1.15-2.95); one-vessel: HR (CI): 2.28 (1.37-3.81); two-vessel: 2.36 (1.33-4.19); three-vessel/left main: 2.41 (1.33-4.36), P = 0.014]. Similarly, SIS was predictive of mortality in both <70 years [SIS 1-3: 1.57 (1.10-2.24); SIS ≥4: 2.42 (1.65-3.57), P < 0.001] and ≥70 years [SIS 1-3: 1.73 (1.07-2.79); SIS ≥4: 2.45 (1.52-3.93), P < 0.001]. CCTA findings similarly predicted long-term major adverse cardiovascular outcomes (MACE) (all-cause mortality, myocardial infarction, and late revascularization) in both groups compared with patients with no CAD., Conclusion: The presence and extent of CAD is a meaningful stratifier of long-term mortality and MACE in patients aged <70 years and ≥70 years old. The presence of obstructive and non-obstructive disease and the burden of atherosclerosis determined by SIS remain important predictors of prognosis in older populations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study was designed to assess the prognostic value of a new comprehensive coronary computed tomography angiography (CTA) score compared with the stenosis severity component of the Coronary Artery Disease-Reporting and Data System (CAD-RADS)., Background: Current risk assessment with coronary CTA is mainly focused on maximal stenosis severity. Integration of plaque extent, location, and composition in a comprehensive model may improve risk stratification., Methods: A total of 2,134 patients with suspected but without known CAD were included. The predictive value of the comprehensive CTA score (ranging from 0 to 42 and divided into 3 groups: 0 to 5, 6 to 20, and >20) was compared with the CAD-RADS combined into 3 groups (0% to 30%, 30% to 70% and ≥70% stenosis). Its predictive performance was internally and externally validated (using the 5-year follow-up dataset of the CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry], n = 1,971)., Results: The mean age of patients was 55 ± 13 years, mean follow-up 3.6 ± 2.8 years, and 130 events (myocardial infarction or death) occurred. The new, comprehensive CTA score showed strong and independent predictive value using the Cox proportional hazard analysis. A model including clinical variables plus comprehensive CTA score showed better discrimination of events compared with a model consisting of clinical variables plus CAD-RADS (0.768 vs. 0.742, p = 0.001). Also, the comprehensive CTA score correctly reclassified a significant proportion of patients compared with the CAD-RADS (net reclassification improvement 12.4%, p < 0.001). Good predictive accuracy was reproduced in the external validation cohort., Conclusions: The new comprehensive CTA score provides better discrimination and reclassification of events compared with the CAD-RADS score based on stenosis severity only. The score retained similar prognostic accuracy when externally validated. Anatomic risk scores can be improved with the addition of extent, location, and compositional measures of atherosclerotic plaque. (Comprehensive CTA risk score calculator is available at: http://18.224.14.19/calcApp/)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine the long-term prognostic power of coronary computed tomography angiography (CTA) to predict cardiac death and nonfatal myocardial infarction., Background: Prognostic usefulness of coronary CTA has been confirmed for short- and intermediate-term follow-up. However, long-term data for prognostic usefulness is still lacking, but is paramount because of the slowly progressing nature of coronary artery disease (CAD)., Methods: A total of 2,011 patients with suspected but not previously diagnosed CAD were examined by coronary CTA. Mean follow-up was 10.0 years (interquartile range [IQR]: 8.1 to 11.2 years). Cox proportional hazards analysis was used for the composite endpoint of cardiac death and nonfatal myocardial infarction. Event-free survival, which was defined as the years it took to reach a cumulative 1% risk for the composite endpoint and reclassification from clinical risk, was calculated., Results: The study endpoint was reached in 58 patients (42 cardiac deaths, 16 nonfatal myocardial infarctions). Coronary CTA-assessed CAD severity (normal, nonobstructive, or obstructive) showed the best correlation with the endpoint, with an adjusted c-index of 0.704, compared with a univariate c-index of 0.622 for the clinical risk model (Morise score) alone. The annual event rate for patients with normal coronary arteries on baseline coronary CTA was 0.04%, which translated to an event-free survival period of 10 years. The highest annual event rate of 1.33% was found in patients with 3-vessel obstructive CAD. Reclassification from clinical risk (Morise score) was possible in approximately two-thirds of all patients (68%; p < 0.0001), which led to a substantial reduction of the intermediate-risk group (reduction from 74% to 15%) in favor of the low-risk group (increase from 20% to 83%)., Conclusions: Patients with normal coronary CTA results benefitted from an event-free survival period of 10 years against cardiac death and nonfatal myocardial infarction. Risk stratification according to coronary CTA results allowed for the delineation of clearly diverging prognostic groups and reclassified approximately two-thirds of all patients from clinical risk groups., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives of the study were to examine the long-term prognostic power of coronary computed tomography angiography (CCTA) to predict death or myocardial infarction in patients with diabetes mellitus (DM). The prognostic value of CCTA in diabetic patients has been confirmed for short- and intermediate follow-up durations. The slowly progressing nature of coronary artery disease (CAD), however, underlines the necessity to validate CCTA for longer observation periods in this high-risk population. A total of 132 patients with DM and 1781 without DM were examined by CCTA and followed for a median duration of 9.7 (IQR 6.9, 11.2) and 9.9 (IQR 6.9, 11.1) years, respectively. Cox proportional hazards analysis was used for the composite endpoint of death and myocardial infarction. Warranty period was defined as the number of years that an individual stays in a low-risk group with a cumulative probability for the endpoint below 1% and calculated for patients with/without DM and rising degrees of CAD. The study endpoint was reached in 12 (9.1%) patients with and 87 (4.9%) patients without DM (p = 0.024). Quantification of coronary stenosis by CADRADS or CAD severity (normal/non-obstructive/obstructive) was incremental for endpoint prediction with a multivariate (+Morise) χ 2 of 3.90 and 3.85, respectively. The lowest annual event rate of 0.19% was noted in non-diabetic patients with no CAD, translating to a warranty period of 5.26 years. The highest annual event rate of 1.73% was found in diabetic patients with obstructive CAD, corresponding to a warranty period of 0.58 years. Compared to patients with no DM and no CAD, the risk of death or myocardial infarction in diabetic patients increased with rising levels of coronary obstruction at multivariate hazard ratios (HR) of 3.28 [95% CI 2.32, 4.64 (p < 0.001)], 3.02 [95% CI 2.19, 4.17 (p < 0.001)] and 9.40 [95% CI 4.90, 18.03 (p < 0.001)] for normal coronary arteries, non-obstructive CAD and obstructive CAD. This study validates the long-term prognostic utility of CCTA-assessed CAD for predicting death or myocardial infarction in a population of patients with DM. The rates of death or myocardial infarction rise with CAD severity in diabetic and non-diabetic patients, identifying the highest risk group of patients with DM and obstructive CAD.

The prognostic performance of coronary artery calcium score (CACS) for predicting adverse outcomes in patients with decreased renal function remains unclear. We aimed to examine whether CACS improves risk stratification by demonstrating incremental value beyond a traditional risk score according to renal function status. 9,563 individuals without known coronary artery disease were enrolled. Estimated glomerular filtration rate (eGFR, ml/min/1.73 m 2 ) was ascertained using the modified Modification of Diet in Renal Disease formula, and was categorized as: ≥90, 60 to 89, and <60. CACS was categorized as 0, 1 to 100, 101 to 400, and >400. Multivariable Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for major adverse cardiac events (MACE), comprising all-cause mortality, myocardial infarction, and late revascularization (>90 days). Mean age was 55.8 ± 11.5 years (52.8% male). In total, 261 (2.7%) patients experienced MACE over a median follow-up of 24.5 months (interquartile range: 16.9 to 41.1). Incident MACE increased with higher CACS across each eGFR category, with the highest rate observed among patients with CACS >400 and eGFR <60 (95.1 per 1,000 person-years). A CACS >400 increased MACE risk with HR 4.46 (95% CI 1.68 to 11.85), 6.63 (95% CI 4.03 to 10.92), and 6.14 (95% CI 2.85 to 13.21) for eGFR ≥90, 60 to 89, and <60, respectively, as compared with CACS 0. Further, CACS improved discrimination and reclassification beyond Framingham 10-year risk score (FRS) (AUC: 0.70 vs 0.64; category free-NRI: 0.51, all p <0.001) for predicting MACE in patients with impaired renal function (eGFR < 90). In conclusion, CACS improved risk stratification and provided incremental value beyond FRS for predicting MACE, irrespective of eGFR status., (Published by Elsevier Inc.)

Introduction: Non-statin therapy (NST) is used as second-line treatment when statin monotherapy is inadequate or poorly tolerated., Objective: To determine the association of NST with plaque composition, alone or in combination with statins, in patients undergoing coronary computed tomography angiography (coronary CTA)., Methods: From the multicenter CONFIRM registry, we analyzed individuals who underwent coronary CTA with known lipid-lowering therapy status and without prior coronary artery disease at baseline. We created a propensity score for being on NST, followed by stepwise multivariate linear regression, adjusting for the propensity score as well as risk factors, to determine the association between NST and the number of coronary artery segments with each plaque type (non-calcified (NCP), partially calcified (PCP) or calcified (CP)) and segment stenosis score (SSS)., Results: Of the 27,125 subjects in CONFIRM, 4,945 met the inclusion criteria; 371 (7.5%) took NST. At baseline, patients on NST had more prevalent risk factors and were more likely to be on concomitant cardiac medications. After multivariate and propensity score adjustment, NST was not associated with plaque composition: NCP (0.07 increase, 95% CI: -0.05, 0.20; p = 0.26), PCP (0.10 increase, 95% CI: -0.10, 0.31; p = 0.33), CP (0.18 increase, 95% CI: -0.10, 0.46; p = 0.21) or SSS (0.45 increase, 95% CI: -0.02,0.93; p = 0.06). The absence of an effect of NST on plaque type was not modified by statin use (p for interaction > 0.05 for all)., Conclusion: In this cross-sectional study, non-statin therapy was not associated with differences in plaque composition as assessed by coronary CTA., (Copyright © 2019. Published by Elsevier Inc.)

Background: Data on the impact of glycemic status on coronary plaque progression have been limited. This study evaluated the association between glycemic status and coronary plaque volume change (PVC) using coronary computed tomography angiography (CCTA)., Methods: A total of 1296 subjects (61 ± 9, 56.9% male) who underwent serial CCTA with available glycemic status were enrolled and analyzed from the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. The median inter-scan period was 3.2 (2.6-4.4) years. Quantitative assessment of coronary plaques was performed at both scans. All participants were categorized into the following groups according to glycemic status: normal, pre-diabetes (pre-DM), and diabetes mellitus (DM)., Results: During the follow-up, significant differences in PVC (normal: 51.3 ± 83.3 mm 3 vs. pre-DM: 51.0 ± 84.3 mm 3 vs. DM: 72.6 ± 95.0 mm 3 ; p < 0.001) and annualized PVC (normal: 14.9 ± 24.9 mm 3 vs. pre-DM: 15.7 ± 23.8 mm 3 vs. DM: 21.0 ± 27.7 mm 3 ; p = 0.001) were observed among the 3 groups. Compared with normal individuals, individuals with pre-DM showed no significant differences in the adjusted odds ratio (OR) for plaque progression (PP) (1.338, 95% confidence interval [CI] 0.967-1.853; p = 0.079). However, the adjusted OR for PP was higher in DM individuals than in normal individuals (1.635, 95% CI 1.126-2.375; p = 0.010)., Conclusion: DM had an incremental impact on coronary PP, but pre-DM appeared to have no significant association with an increased risk of coronary PP after adjusting for confounding factors., Clinical Trial Registration: ClinicalTrials.govNCT02803411., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Data describing clinical relevance of chronic total occlusion (CTO) identified by coronary CT angiography (CCTA) have not been reported to date. We investigated the prognosis of CTO on CCTA., Methods: We identified 22 828 patients without prior known coronary artery disease (CAD), who were followed for a median of 26 months. Based on CCTA, coronary lesions were graded as normal (no atherosclerosis), non-obstructive (1%-49%), moderate-to-severe (50%-99%) or totally occluded (100%). All-cause mortality, and major adverse cardiac events defined as mortality, non-fatal myocardial infarction and late coronary revascularisation (≥90 days after CCTA) were assessed., Results: The distribution of patients with normal coronaries, non-obstructive CAD, moderate-to-severe CAD and CTO was 10 034 (44%), 7965 (34.9%), 4598 (20.1%) and 231 (1%), respectively. The mortality rate per 1000 person-years of CTO patients was non-significantly different from patients with moderate-to-severe CAD (22.95; 95% CI 12.71 to 41.45 vs 14.46; 95% CI 12.34 to 16.94; p=0.163), and significantly higher than of those with normal coronaries and non-obstructive CAD (p<0.001 for both). Among 14 382 individuals with follow-up for the composite end point, patients with CTO had a higher rate of events than those with moderate-to-severe CAD (106.56; 95% CI 76.51 to 148.42 vs 65.45; 95% CI 58.01 to 73.84, p=0.009). This difference was primarily driven by an increase in late revascularisations in CTO patients (27 of 35 events). After multivariable adjustment, compared with individuals with normal coronaries, the presence of CTO conferred the highest risk for adverse cardiac events (14.54; 95% CI 9.11 to 23.20, p<0.001)., Conclusions: The detection of CTO on non-invasive CCTA is associated with increased rate of late revascularisation but similar 2-year mortality as compared with moderate-to-severe CAD., Trial Registration Number: NCT01443637., Competing Interests: Competing interests: Dr JKM receives funding from the Dalio Foundation, National Institutes of Health and GE Healthcare. Dr JKM serves on the scientific advisory board of Arineta and GE Healthcare, and has an equity interest in Cleerly. All other coauthors have no relevant disclosures., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To investigate the impact of diabetes on coronary artery total plaque volume (TPV) and adverse events in long-term follow-up., Methods: One-hundred-and-eight diabetic patients were matched to 324 non-diabetic patients, with respect to age, sex, body-mass index, hypertension, smoking habits, LDL and HDL cholesterol, family history for CAD as well as aspirin and statin medication. In all patients, TPV was quantified from coronary CT angiographies (CTA) using dedicated software. All-cause mortality, acute coronary syndrome and late revascularisation (>90 days) served as combined endpoint., Results: Patients were followed for 5.6 years. The endpoint occurred in 18 (16.7%) diabetic and 26 (8.0%) non-diabetic patients (odds ratio 2.3, p = 0.03). Diabetic patients had significantly higher TPV than non-diabetic patients (55.1 mm³ [IQR: 6.2 and 220.4 mm³] vs. 24.9 mm³ [IQR: 0 and 166.7 mm³], p = 0.02). A TPV threshold of 110.5 mm³ provided good separation of diabetic and non-diabetic patients at higher and lower risk for adverse events. Noteworthy, diabetic and non-diabetic patients with a TPV<110.5 mm³ had comparable outcome (hazard ratio: 1.3, p = 0.59), while diabetic patients with TPV>110.5 mm³ had significantly higher incidence of adverse events (hazard ratio 2.3, p = 0.03) compared to non-diabetic patients with TPV>110.5 mm³. There was incremental prognostic value in diabetic and non-diabetic patients over the Framingham Risk Score (Integrated Discrimination Improvement: 0.052 and 0.012, p for both <0.05)., Conclusion: Diabetes is associated with significantly higher TPV, which is independent of other CAD risk factors. Quantification of TPV improves the identification of diabetic patients at higher risk for future adverse events., (Copyright © 2019 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Extent of coronary atherosclerotic disease (CAD) burden on coronary computed tomography angiography (CCTA) as measured by segment involvement score (SIS) has a prognostic value. We sought to investigate the incremental prognostic value of 'age adjusted SIS' (aSIS), which may be a marker of premature atherosclerosis and vascular age. Consecutive patients were prospectively enrolled into the CONFIRM (Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicentre) multinational observational study. Patients were followed for the outcome of all-cause death. aSIS was calculated on CCTA for each patient, and its incremental prognostic value was evaluated. A total of 22,211 patients [mean age 58.5 ± 12.7 years, 55.8% male) with a median follow-up of 27.3 months (IQR 17.8, 35.4)] were identified. After adjustment for clinical factors and presence of obstructive CAD, higher aSIS was associated with increased death on multivariable analysis, with hazard ratio (HR) 2.40 (1.83-3.16, p < 0.001), C-statistic 0.723 (0.700-0.756), net reclassification improvement (NRI) 0.36 (0.26-0.47, p < 0.001), and relative integrated discrimination improvement (IDI) 0.33 (p = 0.009). aSIS had HR 3.48 (2.33-5.18, p < 0.001) for mortality in those without obstructive CAD, compared to HR 1.79 (1.25-2.58, p = 0.02) in those with obstructive CAD. In conclusion, aSIS has an incremental prognostic value to traditional risk factors and obstructive CAD, and may enhance CCTA risk stratification.

Aims: Advances of cardiac computed tomography angiography (CTA) have been developed for dose reduction, but their efficacy in clinical practice is largely unknown. This study was designed to evaluate radiation dose exposure and utilization of dose-saving strategies for contrast-enhanced cardiac CTA in daily practice., Methods and Results: Sixty one hospitals from 32 countries prospectively enrolled 4502 patients undergoing cardiac CTA during one calendar month in 2017. Computed tomography angiography scan data and images were analysed in a central core lab and compared with a similar dose survey performed in 2007. Linear regression analysis was performed to identify independent predictors associated with dose. The most frequent indication for cardiac CTA was the evaluation of coronary artery disease in 89% of patients. The median dose-length product (DLP) of coronary CTA was 195 mGy*cm (interquartile range 110-338 mGy*cm). When compared with 2007, the DLP was reduced by 78% (P < 0.001) without an increase in non-diagnostic coronary CTAs (1.7% in 2007 vs. 1.9% in 2017 surveys, P = 0.55). A 37-fold variability in median DLP was observed between the hospitals with lowest and highest DLP (range of median DLP 57-2090 mGy*cm). Independent predictors for radiation dose of coronary CTA were: body weight, heart rate, sinus rhythm, tube voltage, iterative image reconstruction, and the selection of scan protocols., Conclusion: This large international radiation dose survey demonstrates considerable reduction of radiation exposure in coronary CTA during the last decade. However, the large inter-site variability in radiation exposure underlines the need for further site-specific training and adaptation of contemporary cardiac scan protocols.

Objectives: This study aimed to determine the rate and extent of plaque progression (PP), changes in plaque features, and clinical predictors of PP in patients with diabetes mellitus (DM)., Background: The natural history of coronary PP in patients with DM is not well established., Methods: A total of 1,602 patients (age 61.3 ± 9.0 years; 60.3% men; median scan interval 3.8 years) who underwent serial coronary computed tomography angiography over a period of at least 24 months were enrolled and analyzed from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) trial. Study endpoints were changes in plaque features in diabetics with PP and risk factors for PP by serial coronary computed tomography angiography between patients with and without DM. PP was defined if plaque volume at follow-up minus plaque volume at baseline was >0., Results: DM was an independent risk factor for PP (84.6%; 276 of 326 patients with PP) in multivariate analysis (odds ratio [OR]: 1.526; 95% confidence interval [CI]: 1.100 to 2.118; p = 0.011). Independent risk factors for PP in patients with DM were male sex (OR: 1.485; 95% CI: 1.003 to 2.199; p = 0.048) and mean plaque burden at baseline ≥75% (OR: 3.121; 95% CI: 1.701 to 5.725; p ≤0.001). After propensity matching, percent changes in overall plaque volume (30.3 ± 36.9% in patients without DM and 36.0 ± 29.7% in those with DM; p = 0.032) and necrotic core volume (-7.0 ± 35.8% in patients without DM and 21.5 ± 90.5% in those with DM; p = 0.007) were significantly greater in those with DM. The frequency of spotty calcification, positive remodeling, and burden of low-attenuation plaque were significantly greater in patients with DM., Conclusions: People with DM experience greater PP, particularly significantly greater progression in adverse plaque, than those without DM. Male sex and mean plaque burden >75% at baseline were identified as independent risk factors for PP., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Diagnosis of coronary artery disease and management strategies have relied solely on the presence of diameter stenosis ≥50%. We assessed whether direct quantification of plaque burden (PB) and plaque characteristics assessed by coronary computed tomography angiography could provide additional value in terms of predicting rapid plaque progression., Methods and Results: From a 13-center, 7-country prospective observational registry, 1345 patients (60.4±9.4 years old; 57.1% male) who underwent repeated coronary computed tomography angiography >2 years apart were enrolled. For conventional angiographic analysis, the presence of stenosis ≥50%, number of vessel involved, segment involvement score, and the presence of high-risk plaque feature were determined. For quantitative analyses, PB and annual change in PB (△PB/y) in the entire coronary tree were assessed. Clinical outcomes (cardiac death, nonfatal myocardial infarction, and coronary revascularization) were recorded. Rapid progressors, defined as a patient with ≥median value of △PB/y (0.33%/y), were older, more frequently male, and had more clinical risk factors than nonrapid progressors (all P <0.05). After risk adjustment, addition of baseline PB improved prediction of rapid progression to each angiographic assessment of coronary artery disease, and the presence of high-risk plaque further improved the predictive performance (all P <0.001). For prediction of adverse outcomes, adding both baseline PB and △PB/y showed best predictive performance (C statistics, 0.763; P <0.001)., Conclusions: Direct quantification of atherosclerotic PB in addition to conventional angiographic assessment of coronary artery disease might be beneficial for improving risk stratification of coronary artery disease., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02803411., (© 2018 American Heart Association, Inc.)

Our objective was to assess the prognostic value of symptom typicality in patients without obstructive coronary artery disease (CAD), determined by coronary computed tomographic angiography (CCTA). We identified 4215 patients without prior history of CAD and without obstructive CAD (<50% CCTA stenosis). CAD severity was categorized as nonobstructive (1%-49%) and none (0%). Based upon the Diamond-Forrester criteria for angina pectoris, symptom typicality was classified as asymptomatic, nonanginal, atypical, and typical. Multivariable Cox proportional hazards models were used to assess the risk of major adverse cardiac events (MACE), comprising all-cause mortality, myocardial infarction, unstable angina, and late revascularization, according to symptom typicality. Mean patient age was 57.0 ±12.0 years (54.9% male). During a median follow-up of 5.3 years (interquartile range, 4.6-5.9 years), MACE were reported in 312 (7.4%) patients. Among patients with nonobstructive CAD, there was an association between symptom typicality and MACE (P for interaction = 0.05), driven by increased risk of MACE among those with typical angina and nonobstructive CAD (hazard ratio: 1.62, 95% confidence interval: 1.06-2.48, P = 0.03). No consistent relationship was found between symptom typicality and MACE among patients without any CAD (hazard ratio: 0.73, 95% confidence interval: 0.34-1.57, P = 0.08). In the CONFIRM registry, patients who presented with concomitant typical angina and nonobstructive CAD had a higher rate of MACE than did asymptomatic patients with nonobstructive CAD. However, the presence of typical angina did not appear to portend worse prognosis in patients with no CAD., (© 2018 Wiley Periodicals, Inc.)

Background: The aim of the study is examine the impact of non-obstructive (<50%stenosis) left main (LM) disease on the natural history of coronary artery disease using serial coronary computed tomography angiography (CTA)., Methods: CTAs from the PARADIGM (Progression of atherosclerotic plaque determined by computed tomographic angiography imaging) study, a prospective multinational registry of patients who underwent serial CTA at a ≥2 year interval were analyzed. Those without evidence of CAD on their baseline scan were excluded, as were those with obstructive left main disease. Coronary artery vessels and their branches underwent quantification of: plaque volume and composition; diameter stenosis; presence of high-risk plaque., Results: Of 944 (62 ± 9 years, 60% male) who had evidence of CAD at baseline, 444 (47%) had LM disease. Those with LM disease had a higher baseline plaque volume (194.8 ± 221mm3 versus 72.9 ± 84.3mm3, p < 0.001) and a higher prevalence of high-risk plaque (17.5% versus 13%, p < 0.001) than those without LM disease. On multivariable general linear model, patients with LM disease had greater annual rates of progression of total (26.5 ± 31.4mm3/yr versus 14.9 ± 20.1mm3/yr, p < 0.001) and calcified plaque volume (17 ± 24mm3/yr versus 7 ± 11mm3/yr, p < 0.001), with no difference in fibrous, fibrofatty or necrotic core plaque components., Conclusion: The presence of non-obstructive LM disease is associated with greater rates of plaque progression and a higher prevalence of high-risk plaque throughout the entire coronary artery tree compared to CAD without LM involvement. Our data suggests that non-obstructive LM disease may be a marker for an aggressive phenotype of CAD that may benefit from more intensive treatment strategies., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Machine learning (ML) is a field in computer science that demonstrated to effectively integrate clinical and imaging data for the creation of prognostic scores. The current study investigated whether a ML score, incorporating only the 16 segment coronary tree information derived from coronary computed tomography angiography (CCTA), provides enhanced risk stratification compared with current CCTA based risk scores., Methods: From the multi-center CONFIRM registry, patients were included with complete CCTA risk score information and ≥3 year follow-up for myocardial infarction and death (primary endpoint). Patients with prior coronary artery disease were excluded. Conventional CCTA risk scores (conventional CCTA approach, segment involvement score, duke prognostic index, segment stenosis score, and the Leaman risk score) and a score created using ML were compared for the area under the receiver operating characteristic curve (AUC). Only 16 segment based coronary stenosis (0%, 1-24%, 25-49%, 50-69%, 70-99% and 100%) and composition (calcified, mixed and non-calcified plaque) were provided to the ML model. A boosted ensemble algorithm (extreme gradient boosting; XGBoost) was used and the entire data was randomly split into a training set (80%) and testing set (20%). First, tuned hyperparameters were used to generate a trained model from the training data set (80% of data). Second, the performance of this trained model was independently tested on the unseen test set (20% of data)., Results: In total, 8844 patients (mean age 58.0 ± 11.5 years, 57.7% male) were included. During a mean follow-up time of 4.6 ± 1.5 years, 609 events occurred (6.9%). No CAD was observed in 48.7% (3.5% event), non-obstructive CAD in 31.8% (6.8% event), and obstructive CAD in 19.5% (15.6% event). Discrimination of events as expressed by AUC was significantly better for the ML based approach (0.771) vs the other scores (ranging from 0.685 to 0.701), P < 0.001. Net reclassification improvement analysis showed that the improved risk stratification was the result of down-classification of risk among patients that did not experience events (non-events)., Conclusion: A risk score created by a ML based algorithm, that utilizes standard 16 coronary segment stenosis and composition information derived from detailed CCTA reading, has greater prognostic accuracy than current CCTA integrated risk scores. These findings indicate that a ML based algorithm can improve the integration of CCTA derived plaque information to improve risk stratification., (Published by Elsevier Inc.)

Aim: The long-term prognostic benefit of coronary computed tomographic angiography (CCTA) findings of coronary artery disease (CAD) in asymptomatic populations is unknown., Methods and Results: From the prospective multicentre international CONFIRM long-term study, we evaluated asymptomatic subjects without known CAD who underwent both coronary artery calcium scoring (CACS) and CCTA (n = 1226). Coronary computed tomographic angiography findings included the severity of coronary artery stenosis, plaque composition, and coronary segment location. Using the C-statistic and likelihood ratio tests, we evaluated the incremental prognostic utility of CCTA findings over a base model that included a panel of traditional risk factors (RFs) as well as CACS to predict long-term all-cause mortality. During a mean follow-up of 5.9 ± 1.2 years, 78 deaths occurred. Compared with the traditional RF alone (C-statistic 0.64), CCTA findings including coronary stenosis severity, plaque composition, and coronary segment location demonstrated improved incremental prognostic utility beyond traditional RF alone (C-statistics range 0.71-0.73, all P < 0.05; incremental χ2 range 20.7-25.5, all P < 0.001). However, no added prognostic benefit was offered by CCTA findings when added to a base model containing both traditional RF and CACS (C-statistics P > 0.05, for all)., Conclusions: Coronary computed tomographic angiography improved prognostication of 6-year all-cause mortality beyond a set of conventional RF alone, although, no further incremental value was offered by CCTA when CCTA findings were added to a model incorporating RF and CACS.

Background: To investigate the incremental prognostic value of low-attenuation plaque volume (LAPV) from coronary CT angiography datasets., Methods: Quantification of LAPV was performed using dedicated software equipped with an adaptive plaque tissue algorithm in 1577 patients with suspected CAD. A combination of death and acute coronary syndrome was defined as primary endpoint. To assess the incremental prognostic value of LAPV, parameters were added to a baseline model including clinical risk and obstructive coronary artery disease (CAD), a baseline model including clinical risk and calcium scoring (CACS) and a baseline model including clinical risk and segment involvement score (SIS)., Results: Patients were followed for 5.5 years either by telephone contact, mail or clinical visits. The primary endpoint occurred in 30 patients. Quantified LAPV provided incremental prognostic information beyond clinical risk and obstructive CAD (c-index 0.701 vs. 0.767, p < .001), clinical risk and CACS (c-index 0.722 vs. 0.771, p < .01) and clinical risk and SIS (c-index 0.735 vs. 0.771, p < .01. A combined approach using quantified LAPV and clinical risk significantly improved the stratification of patients into different risk categories compared to clinical risk alone (categorical net reclassification index 0.69 with 95% CI 0.27 and 0.96, p < .001). The combined approach classified 846 (53.6%) patients as low risk (annual event rate 0.04%), 439 (27.8%) patients as intermediate risk (annual event rate 0.5%) and 292 (18.5%) patients as high risk (annual event rate 0.99%)., Conclusion: Quantification of LAPV provides incremental prognostic information beyond established CT risk patterns and permits improved stratification of patients into different risk categories., (Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac computed tomography angiography (cardiac CTA) is an increasingly used versatile imaging method to evaluate coronary and cardiac morphology. Owing to improvements in technology, image quality has continuously improved over the last 10-20 years. At the same time, numerous non-randomized and randomized studies have been performed to reduce the associated radiation exposure. Currently, it is unclear if the advances in technology and knowledge about radiation reduction translated into reduced levels of cardiac CTA radiation dose in daily clinical practice as well as a wide utilization of dose-saving strategies., Methods: The PROTECTION VI study is a multicenter, prospective, worldwide registry designed to evaluate radiation dose exposure, utilization of dose-saving strategies and diagnostic image quality during cardiac CTA in current daily practice. Assessment of image quality will be addressed by the evaluation of diagnostic image quality at the local study site and the calculation of quantitative image quality parameters in an imaging core laboratory. Above 4000 patients will be enrolled from approximately 70 sites in Europe, North America, South America, Asia and Australia. The study will analyze median radiation dose levels, image quality, frequency of use and efficacy of algorithms for dose reduction, and patient and study-related predictors associated with radiation dose., Conclusions: The PROTECTION VI study is designed to provide a reliable estimate of current radiation dose for cardiac CTA and to assess the potential for additional dose reductions., (Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess clinical outcomes associated with the novel Coronary Artery Disease-Reporting and Data System (CAD-RADS) scores used to standardize coronary computed tomography angiography (CTA) reporting and their potential utility in guiding post-coronary CTA care., Background: Clinical decision support is a major focus of health care policies aimed at improving guideline-directed care. Recently, CAD-RADS was developed to standardize coronary CTA reporting and includes clinical recommendations to facilitate patient management after coronary CTA., Methods: In the multinational CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, 5,039 patients without known coronary artery disease (CAD) underwent coronary CTA and were stratified by CAD-RADS scores, which rank CAD stenosis severity as 0 (0%), 1 (1% to 24%), 2 (25% to 49%), 3 (50% to 69%), 4A (70% to 99% in 1 to 2 vessels), 4B (70% to 99% in 3 vessels or ≥50% left main), or 5 (100%). Kaplan-Meier and multivariable Cox models were used to estimate all-cause mortality or myocardial infarction (MI). Receiver-operating characteristic (ROC) curves were used to compare CAD-RADS to the Duke CAD Index and traditional CAD classification. Referrals to invasive coronary angiography (ICA) after coronary CTA were also assessed., Results: Cumulative 5-year event-free survival ranged from 95.2% to 69.3% for CAD-RADS 0 to 5 (p < 0.0001). Higher scores were associated with elevations in event risk (hazard ratio: 2.46 to 6.09; p < 0.0001). The ROC curve for prediction of death or MI was 0.7052 for CAD-RADS, which was noninferior to the Duke Index (0.7073; p = 0.893) and traditional CAD classification (0.7095; p = 0.783). ICA rates were 13% for CAD-RADS 0 to 2, 66% for CAD-RADS 3, and 84% for CAD-RADS ≥4A. For CAD-RADS 3, 58% of all catheterizations occurred within the first 30 days of follow-up. In a patient subset with available medication data, 57% of CAD-RADS 3 patients who received 30-day ICA were either asymptomatic or not receiving antianginal therapy at baseline, whereas only 32% had angina and were receiving medical therapy., Conclusions: CAD-RADS effectively identified patients at risk for adverse events. Frequent ICA use was observed among patients without severe CAD, many of whom were asymptomatic or not taking antianginal drugs. Incorporating CAD-RADS into coronary CTA reports may provide a novel opportunity to promote evidence-based care post-coronary CTA., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular (LV) volumetric and functional parameters measured with cardiac computed tomography (cardiac CT) augment risk prediction and discrimination for future mortality. Gender- and age-specific standard values for LV dimensions and systolic function obtained by 64-slice cardiac CT are lacking., Methods and Results: 1155 patients from the Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry (54.5% males, mean age 53.1 ± 12.4 years, range: 18-92 years) without known coronary artery disease (CAD), structural heart disease, diabetes, or hypertension who underwent cardiac CT for various indications were categorized according to age and sex. A cardiac CT data acquisition protocol was used that allowed volumetric measuring of LV function. Image interpretation was performed at each site. Patients with significant CAD (>50% stenosis) on cardiac CT were excluded from the analysis. Overall, mean left ventricular ejection fraction (LVEF) was higher in women when compared with men (66.6 ± 7.7% vs. 64.6 ± 8.1%, P < 0.001). This gender-difference in overall LVEF was caused by a significantly higher LVEF in women ≥70 years when compared with men ≥70 years (69.95 ± 8.89% vs. 65.50 ± 9.42%, P = 0.004). Accordingly, a significant increase in LVEF was observed with age (P = 0.005 for males and P < 0.001 for females), which was more pronounced in females (5.21%) than in males (2.6%). LV end-diastolic volume decreased in females from 122.48 ± 27.87 (<40 years) to 95.56 ± 23.17 (>70 years; P < 0.001) and in males from 155.22 ± 35.07 (<40 years) to 130.26 ± 27.18 (>70 years; P < 0.001)., Conclusion: Our findings indicate that the LV undergoes a lifelong remodelling and highlight the need for age and gender adjusted reference values., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Patients with obstructive (≥50% stenosis) left main (LM) coronary artery disease (CAD) are at high risk for adverse events; prior studies have also documented worse outcomes among women than men with severe multivessel/LM CAD. However, the prognostic significance of nonobstructive (1%-49% stenosis) LM CAD, including sex-specific differences, has not been previously examined., Methods and Results: In the long-term CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) registry, patients underwent elective coronary computed tomographic angiography for suspected CAD and were followed for 5 years. After excluding those with obstructive LM CAD, 5166 patients were categorized as having normal LM or nonobstructive LM (18% of cohort). Cumulative 5-year incidence of death, myocardial infarction, or revascularization was higher among patients with nonobstructive LM than normal LM in both women and men: women (34.3% versus 15.4%; P <0.0001); men (24.6% versus 18.2%; P <0.0001). A significant interaction existed between sex and LM status for the composite outcome ( P =0.001). In multivariable Cox regression, the presence of nonobstructive LM plaque increased the risk for the composite outcome in women (adjusted hazard ratio, 1.48; P =0.005) but not in men (adjusted hazard ratio, 0.98, P =0.806). In subgroup analysis, women with nonobstructive LM CAD had a nearly 80% higher risk for events than men with nonobstructive LM CAD (adjusted hazard ratio, 1.78; P =0.017); sex-specific interactions were not observed across other patterns (eg, location or extent) of nonobstructive plaque., Conclusion: Nonobstructive LM CAD was frequently detected on coronary computed tomographic angiography and strongly associated with adverse events among women. Recognizing the sex-specific prognostic significance of nonobstructive LM plaque may augment risk stratification efforts., (© 2017 American Heart Association, Inc.)

Hypertension is an atherosclerosis factor and is associated with cardiovascular risk. We investigated the relationship between hypertension and the presence, extent, and severity of coronary atherosclerosis in coronary computed tomographic angiography and cardiac events risk. Of 17 181 patients enrolled in the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) who underwent ≥64-detector row coronary computed tomographic angiography, we identified 14 803 patients without known coronary artery disease. Of these, 1434 hypertensive patients were matched to 1434 patients without hypertension. Major adverse cardiac events risk of hypertension and non-hypertensive patients was evaluated with Cox proportional hazards models. The prognostic associations between hypertension and no-hypertension with increasing degree of coronary stenosis severity (nonobstructive or obstructive ≥50%) and extent of coronary artery disease (segment involvement score of 1-5, >5) was also assessed. Hypertension patients less commonly had no coronary atherosclerosis and more commonly had nonobstructive and 1-, 2-, and 3-vessel disease than the no-hypertension group. During a mean follow-up of 5.2±1.2 years, 180 patients experienced cardiac events, with 104 (2.0%) occurring in the hypertension group and 76 (1.5%) occurring in the no-hypertension group (hazard ratios, 1.4; 95% confidence intervals, 1.0-1.9). Compared with no-hypertension patients without coronary atherosclerosis, hypertension patients with no coronary atherosclerosis and obstructive coronary disease tended to have higher risk of cardiac events. Similar trends were observed with respect to extent of coronary artery disease. Compared with no-hypertension patients, hypertensive patients have increased presence, extent, and severity of coronary atherosclerosis and tend to have an increase in major adverse cardiac events., (© 2017 American Heart Association, Inc.)

Aims: To identify the effect of early revascularization on 5-year survival in patients with CAD diagnosed by coronary-computed tomographic angiography (CCTA)., Methods and Results: We examined 5544 stable patients with suspected CAD undergoing CCTA who were followed a median of 5.5 years in a large international registry. Patients were categorized as having low-, intermediate-, or high-risk CAD based on CCTA findings. Two treatment groups were defined: early revascularization within 90 days of CCTA (n = 1171) and medical therapy (n = 4373). To account for the non-randomized referral to revascularization, we developed a propensity score by logistic regression. This score was incorporated into Cox proportional hazard models to calculate the effect of revascularization on all-cause mortality. Death occurred in 363 (6.6%) patients and was more frequent in medical therapy. In multivariable models, when compared with medical therapy, the mortality benefit of revascularization varied significantly over time and by CAD risk (P for interaction 0.04). In high-risk CAD, revascularization was significantly associated with lower mortality at 1 year (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.11-0.47) and 5 years (HR 0.31, 95% CI 0.18-0.54). For intermediate-risk CAD, revascularization was associated with reduced mortality at 1 year (HR 0.45, 95% CI 0.22-0.93) but not 5 years (HR 0.63, 95% CI 0.33-1.20). For low-risk CAD, there was no survival benefit at either time point., Conclusions: Early revascularization was associated with reduced 1-year mortality in intermediate- and high-risk CAD detected by CCTA, but this association only persisted for 5-year mortality in high-risk CAD., (© The Author 2017 Published on behalf of the European Society of Cardiology.)

Background: Non-obstructive coronary artery disease (CAD) identified by coronary computed tomography angiography (CCTA) demonstrated prognostic value. CT-adapted Leaman score (CT-LeSc) showed to improve the prognostic stratification. Aim of the study was to evaluate the capability of CT-LeSc to assess long-term prognosis of patients with non-obstructive (CAD)., Methods: From 17 centers, we enrolled 2402 patients without prior CAD history who underwent CCTA that showed non-obstructive CAD and provided complete information on plaque composition. Patients were divided into a group without CAD and a group with non-obstructive CAD (<50% stenosis). Segment-involvement score (SIS) and CT-LeSc were calculated. Outcomes were non-fatal myocardial infarction (MI) and the combined end-point of MI and all-cause mortality., Results: Patient mean age was 56±12years. At follow-up (mean 59.8±13.9months), 183 events occurred (53 MI, 99 all-cause deaths and 31 late revascularizations). CT-LeSc was the only multivariate predictor of MI (HRs 2.84 and 2.98 in two models with Framingham and risk factors, respectively) and of MI plus all-cause mortality (HR 2.48 and 1.94 in two models with Framingham and risk factors, respectively). This was confirmed by a net reclassification analysis confirming that the CT-LeSc was able to correctly reclassify a significant proportion of patients (cNRI 0.28 and 0.23 for MI and MI plus all-cause mortality, respectively) vs. baseline model, whereas SIS did not., Conclusion: CT-LeSc is an independent predictor of major acute cardiac events, improving prognostic stratification of patients with non-obstructive CAD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: To investigate the long-term performance of the CONFIRM score for prediction of all-cause mortality in a large patient cohort undergoing coronary computed tomography angiography (CCTA)., Methods and Results: Patients with a 5-year follow-up from the international multicentre CONFIRM registry were included. The primary endpoint was all-cause mortality. The predictive value of the CONFIRM score over clinical risk scores (Morise, Framingham, and NCEP ATP III score) was studied in the entire patient population as well as in subgroups. Improvement in risk prediction and patient reclassification were assessed using categorical net reclassification index (NRI) and integrated discrimination improvement (IDI). During a median follow-up period of 5.3 years, 982 (6.5%) of 15 219 patients died. The CONFIRM score outperformed the prognostic value of the studied three clinical risk scores (c-indices: CONFIRM score 0.696, NCEP ATP III score 0.675, Framingham score 0.610, Morise score 0.606; c-index for improvement CONFIRM score vs. NCEP ATP III score 0.650, P < 0.0001). Application of the CONFIRM score allowed reclassification of 34% of patients when compared with the NCEP ATP III score, which was the best clinical risk score. Reclassification was significant as revealed by categorical NRI (0.06 with 95% CI 0.02 and 0.10, P = 0.005) and IDI (0.013 with 95% CI 0.01 and 0.015, P < 0.001). Subgroup analysis revealed a comparable performance in a variety of patient subgroups., Conclusions: The CONFIRM score permits a significantly improved prediction of mortality over clinical risk scores for >5 years after CCTA. These findings are consistent in a large variety of patient subgroups., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Age-adjusted coronary artery disease (CAD) burden identified on coronary computed tomography angiography predicts major adverse cardiovascular event (MACE) risk; however, it seldom contributes to clinical decision making because of a lack of nomographic data. We aimed to develop clinically pragmatic age- and sex-specific nomograms of CAD burden using coronary computed tomography angiography and to validate their prognostic use., Methods and Results: Patients prospectively enrolled in phase I of the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes) were included (derivation cohort: n=21,132; 46% female) to develop CAD nomograms based on age-sex percentiles of segment involvement score (SIS) at each year of life (40-79 years). The relationship between SIS age-sex percentiles (SIS%) and MACE (all-cause death, myocardial infarction, unstable angina, and late revascularization) was tested in a nonoverlapping validation cohort (phase II, CONFIRM registry; n=3030, 44% female) by stratifying patients into 3 SIS% groups (≤50th, 51-75th, and >75th) and comparing annualized MACE rates and time to MACE using multivariable Cox proportional hazards models adjusting for Framingham risk and chest pain typicality. Age-sex percentiles were well fitted to second-order polynomial curves (men: R 2 =0.86±0.12; women: R 2 =0.86±0.14). Using the nomograms, there were 1576, 965, and 489 patients, respectively, in the ≤50th, 51-75th, and >75th SIS% groups. Annualized event rates were higher among patients with greater CAD burden (2.1% [95% confidence interval: 1.7%-2.7%], 3.9% [95% confidence interval: 3.0%-5.1%], and 7.2% [95% confidence interval: 5.4%-9.6%] in ≤50th, 51-75th, and >75th SIS% groups, respectively; P <0.001). Adjusted MACE risk was significantly increased among patients in SIS% groups above the median compared with patients below the median (hazard ratio [95% confidence interval]: 1.9 [1.3-2.8] for 51-75th SIS% group and 3.4 [2.3-5.0] for >75th SIS% group; P <0.01 for both)., Conclusions: We have developed clinically pragmatic age- and sex-specific nomograms of CAD prevalence using coronary computed tomography angiography findings. Global plaque burden measured using SIS% is predictive of cardiac events independent of traditional risk assessment., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01443637., (© 2017 American Heart Association, Inc.)

Objectives: The goal of this study was to determine the long-term prognostic value of coronary computed tomography angiography (CTA) among patients with diabetes mellitus (DM) compared with nondiabetic subjects., Background: The long-term prognostic value of coronary CTA in patients with DM is not well established., Methods: Patients enrolled in the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry with 5-year follow-up data were identified. The extent and severity of coronary artery disease (CAD) were analyzed at baseline coronary CTA and in relation to outcomes between diabetic and nondiabetic patients. CAD according to coronary CTA was defined as none (0% stenosis), nonobstructive (1% to 49% stenosis), or obstructive (≥50% stenosis). Time to death (and in a subgroup, time to major adverse cardiovascular event) was estimated by using multivariable Cox proportional hazards models., Results: A total of 1,823 patients were identified as having DM with 5-year clinical follow-up and were propensity-matched to 1,823 patients without DM (mean age 61.8 ± 10.9 years; 54.4% male). Patients with DM did not exhibit a heightened risk of death compared with the propensity-matched nondiabetic subjects in the absence of CAD on coronary CTA (risk-adjusted hazard ratio [HR] of DM: 1.32; 95% confidence interval [CI]: 0.78 to 2.24; p = 0.296). Patients with DM were at increased risk of dying compared with nondiabetic subjects in the setting of nonobstructive CAD (in the propensity-matched cohort: HR, 2.10; 95% CI: 1.43 to 3.09; p < 0.001) with a mortality risk greater than nondiabetic subjects with obstructive disease (p < 0.001). In a risk-adjusted hazard analysis among patients with DM, both per-patient obstructive CAD and nonobstructive CAD conferred an increase in all-cause mortality risk compared with patients without atherosclerosis on coronary CTA (nonobstructive disease-HR: 2.07; 95% CI: 1.33 to 3.24; p = 0.001; obstructive disease-HR: 2.22; 95% CI: 1.47 to 3.36; p < 0.001)., Conclusions: Among patients with DM, nonobstructive and obstructive CAD according to coronary CTA were associated with higher rates of all-cause mortality and major adverse cardiovascular events at 5 years, and this risk was significantly higher than in nondiabetic subjects. Importantly, patients with DM without CAD according to coronary CTA were at a risk comparable to that of nondiabetic subjects., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary computed tomographic angiography (CTA) plus estimation of fractional flow reserve using CTA (FFRCT) safely and effectively guides initial care over 90 days in patients with stable chest pain. Longer-term outcomes are unknown., Objectives: The study sought to determine the 1-year clinical, economic, and quality-of-life (QOL) outcomes of using FFRCT instead of usual care., Methods: Consecutive patients with stable, new onset chest pain were managed by either usual testing (n = 287) or CTA (n = 297) with selective FFRCT (submitted in 201, analyzed in 177); 581 of 584 (99.5%) completed 1-year follow-up. Endpoints were adjudicated major adverse cardiac events (MACE) (death, myocardial infarction, unplanned revascularization), total medical costs, and QOL., Results: Patients averaged 61 years of age with a mean 49% pre-test probability of coronary artery disease. At 1 year, MACE events were infrequent, with 2 in each arm of the planned invasive group and 1 in the planned noninvasive cohort (usual care strategy). In the planned invasive stratum, mean costs were 33% lower with CTA and selective FFRCT ($8,127 vs. $12,145 usual care; p < 0.0001); in the planned noninvasive stratum, mean costs did not differ when using an FFRCT cost weight of zero ($3,049 FFRCT vs. $2,579; p = 0.82), but were higher when using an FFRCT cost weight equal to CTA. QOL scores improved overall at 1 year (p < 0.001), with similar improvements in both groups, apart from the 5-item EuroQOL scale scores in the noninvasive stratum (mean change of 0.12 for FFRCT vs. 0.07 for usual care; p = 0.02)., Conclusions: In patients with stable chest pain and planned invasive coronary angiography, care guided by CTA and selective FFRCT was associated with equivalent clinical outcomes and QOL, and lower costs, compared with usual care over 1-year follow-up. (The PLATFORM Study: Prospective LongitudinAl Trial of FFRct: Outcome and Resource IMpacts [PLATFORM]; NCT01943903)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: We sought to assess the incremental prognostic value of quantitative plaque characterization beyond established CT risk scores., Background: Several plaque characteristics detectable by coronary computed tomographic angiography (coronary CTA) are thought to be indicative of vulnerable plaques and subsequent cardiac events, particularly low attenuation plaque volume (LAPV), positive remodeling and the napkin-ring sign which is high density vascular adhesion with a small center of low density. It is unknown how quantitative plaque assessment can contribute to the long-term prediction of cardiovascular events in relation to established CT risk scores such as the calcium score or Segment Stenosis Score (SSS)., Methods: In 1168 consecutive patients with suspected coronary artery disease (CAD), calcium score measurement and coronary plaque characterization was performed comprising the presence of calcified, non-calcified, and partially calcified plaques on a per-segment basis. In all non-calcified or partially calcified plaques, semi-automated plaque analysis was performed to quantify low attenuation plaque volume (density <30 HU), total non-calcified plaque volume (<150 HU, TNCPV) and remodeling index. The presence of the napkin-ring sign was assessed visually. The study endpoint was the occurrence of major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction and coronary revascularization more than 90 days after coronary CTA., Results: During a clinical follow up of 5.7 years, MACE was observed in 46 patients (3.9%). All plaque characteristics were associated with MACE. The strongest association was observed for LAPV (HR 1.12, p < 0.0001). LAPV showed incremental prognostic value in a stepwise multivariable model including the Morise Score for clinical risk, calcium score and SSS (p = 0.036)., Conclusion: LAPV, TPV, PR and presence of the napkin-ring sign are predictors of MACE independently of clinical risk presentation. LAPV carries slight additional prognostic information beyond the calcium score and conventional coronary CTA analysis. It may therefore improve risk prediction after CT imaging., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Prevalence of coronary artery disease (CAD) is high in diabetic patients while diagnosis of early stage of CAD remains demanding. This study evaluates prognostic value of coronary computed tomography angiography (CCTA) for long-term outcome to predict cardiac events in oligosymptomatic diabetic patients. A cohort of 108 consecutive diabetic patients without angina pectoris or known CAD, undergoing CCTA was included. 1379 consecutive patients without diabetes were defined as a control group. Coronary artery calcium score (CACS), segment involvement score (SIS) and the segment stenosis score (SSS) were documented. The end point was a composite of cardiac events defined as all-cause death, nonfatal myocardial infarction, or unstable angina requiring hospitalization. Follow up period was 66.0 ± 14.2 month. 98% of initially enrolled patient were followed. During follow-up period 10 cardiac events within the diabetic cohort and 48 within the non-diabetic cohort were observed. Annual event rate in diabetic and non-diabetic patients was 1.74 and 0.64% respectively. In diabetic patients a multivariate analysis showed significant prognostic value over Framingham Score for SIS with a hazard ratio (HR) of 2.98 (95% CI 1.02, 8.72; p = 0.047) and SSS (HR 4.47, 95% CI 1.21, 16.49; p = 0.025), while CACS did not add prognostic value in this cohort. Annual event rate was 0% in diabetic patients with SIS = 0 and 3.9% in diabetic patients with SIS ≥ 8. CCTA allows for improved risk prediction for subsequent cardiac events in oligosymptomatic diabetic patients.

Background: Coronary computed tomography angiography (coronary CTA) can prognosticate outcomes in patients without modifiable risk factors over medium term follow-up. This ability was driven by major adverse cardiovascular events (MACE)., Objective: Determine if coronary CTA could discriminate risk of mortality with longer term follow-up. In addition we sought to determine the long-term relationship to MACE., Methods: From 12 centers, 1884 patients undergoing coronary CTA without prior coronary artery disease (CAD) or any modifiable CAD risk factors were identified. The presence of CAD was classified as none (0% stenosis), mild (1% to 49% stenosis) and obstructive (≥50% stenosis severity). The primary endpoint was all-cause mortality and the secondary endpoint was MACE. MACE was defined as the combination of death, nonfatal myocardial infarction, unstable angina, and late target vessel revascularization (>90 days)., Results: Mean age was 55.6 ± 14.5 years. At mean 5.6 ± 1.3 years follow-up, 145(7.7%) deaths occurred. All-cause mortality demonstrated a dose-response relationship to the severity and number of coronary vessels exhibiting CAD. Increased mortality was observed for >1 segment non-obstructive CAD (hazard ratio [HR]:1.73; 95% confidence interval [CI]: 1.07-2.79; p = 0.025), obstructive 1&2 vessel CAD (HR: 1.70; 95% CI: 1.08-2.71; p = 0.023) and 3-vessel or left main CAD (HR: 2.87; 95% CI: 1.57-5.23; p = 0.001). Both obstructive CAD (HR: 6.63; 95% CI: 3.91-11.26; p < 0.001) and non-obstructive CAD (HR: 2.20; 95% CI: 1.31-3.67; p = 0.003) predicted MACE with increased hazard associated with increasing CAD severity; 5.60% in no CAD, 13.24% in non-obstructive and 36.28% in obstructive CAD, p < 0.001 for trend., Conclusions: In individuals being assessed for CAD with no modifiable risk factors, all-cause mortality in the long term (>5 years) was predicted by the presence of more than 1 segment of non-obstructive plaque, obstructive 1- or 2-vessel CAD and 3 vessel/left main CAD. Any CAD, whether non-obstructive or obstructive, predicted MACE over the same time period., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)