Superior Risk Stratification With Coronary Computed Tomography Angiography Using a Comprehensive Atherosclerotic Risk Score.

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/).

Prognostic value of chronic total occlusions detected on coronary computed tomographic angiography.

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.

Prognostic value of age adjusted segment involvement score as measured by coronary computed tomography: a potential marker of vascular age.

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.

Influence of symptom typicality for predicting MACE in patients without obstructive coronary artery disease: From the CONFIRM Registry (Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry).

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.

The Coronary Artery Disease-Reporting and Data System (CAD-RADS): Prognostic and Clinical Implications Associated With Standardized Coronary Computed Tomography Angiography Reporting.

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.

Incremental prognostic value of coronary computed tomography angiography over coronary calcium scoring for major adverse cardiac events in elderly asymptomatic individuals.

Aims: Coronary computed tomography angiography (CCTA) and coronary artery calcium score (CACS) have prognostic value for coronary artery disease (CAD) events beyond traditional risk assessment. Age is a risk factor with very high weight and little is known regarding the incremental value of CCTA over CAC for predicting cardiac events in older adults. Methods and results: Of 27 125 individuals undergoing CCTA, a total of 3145 asymptomatic adults were identified. This study sample was categorized according to tertiles of age (cut-off points: 52 and 62 years). CAD severity was classified as 0, 1-49, and ≥50% maximal stenosis in CCTA, and further categorized according to number of vessels ≥50% stenosis. The Framingham 10-year risk score (FRS) and CACS were employed as major covariates. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause death or non-fatal MI. During a median follow-up of 26 months (interquartile range: 18-41 months), 59 (1.9%) MACE occurred. For patients in the top age tertile, CCTA improved discrimination beyond a model included FRS and CACS (C-statistic: 0.75 vs. 0.70, P-value = 0.015). Likewise, the addition of CCTA improved category-free net reclassification (cNRI) of MACE in patients within the highest age tertile (e.g. cNRI = 0.75; proportion of events/non-events reclassified were 50 and 25%, respectively; P-value <0.05, all). CCTA displayed no incremental benefit beyond FRS and CACS for prediction of MACE in the lower age tertiles. Conclusion: CCTA provides added prognostic value beyond cardiac risk factors and CACS for the prediction of MACE in asymptomatic older adults.

Relationship of Hypertension to Coronary Atherosclerosis and Cardiac Events in Patients With Coronary Computed Tomographic Angiography.

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.

Long-term prognostic impact of CT-Leaman score in patients with non-obstructive CAD: Results from the COronary CT Angiography EvaluatioN For Clinical Outcomes InteRnational Multicenter (CONFIRM) study.

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.

Machine learning for prediction of all-cause mortality in patients with suspected coronary artery disease: a 5-year multicentre prospective registry analysis.

AIMS: Traditional prognostic risk assessment in patients undergoing non-invasive imaging is based upon a limited selection of clinical and imaging findings. Machine learning (ML) can consider a greater number and complexity of variables. Therefore, we investigated the feasibility and accuracy of ML to predict 5-year all-cause mortality (ACM) in patients undergoing coronary computed tomographic angiography (CCTA), and compared the performance to existing clinical or CCTA metrics. METHODS AND RESULTS: The analysis included 10 030 patients with suspected coronary artery disease and 5-year follow-up from the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry. All patients underwent CCTA as their standard of care. Twenty-five clinical and 44 CCTA parameters were evaluated, including segment stenosis score (SSS), segment involvement score (SIS), modified Duke index (DI), number of segments with non-calcified, mixed or calcified plaques, age, sex, gender, standard cardiovascular risk factors, and Framingham risk score (FRS). Machine learning involved automated feature selection by information gain ranking, model building with a boosted ensemble algorithm, and 10-fold stratified cross-validation. Seven hundred and forty-five patients died during 5-year follow-up. Machine learning exhibited a higher area-under-curve compared with the FRS or CCTA severity scores alone (SSS, SIS, DI) for predicting all-cause mortality (ML: 0.79 vs. FRS: 0.61, SSS: 0.64, SIS: 0.64, DI: 0.62; P< 0.001). CONCLUSIONS: Machine learning combining clinical and CCTA data was found to predict 5-year ACM significantly better than existing clinical or CCTA metrics alone.

Rationale and Design of the CREDENCE Trial: computed TomogRaphic evaluation of atherosclerotic DEtermiNants of myocardial IsChEmia.

BACKGROUND: Coronary computed tomography angiography (CCTA) allows for non-invasive assessment of obstructive coronary artery disease (CAD) beyond measures of stenosis severity alone. This assessment includes atherosclerotic plaque characteristics (APCs) and calculation of fractional flow reserve (FFR) from CCTA (FFRCT). Similarly, stress imaging by myocardial perfusion scintigraphy (MPS) provides vital information. To date, the diagnostic performance of integrated CCTA assessment versus integrated MPS assessment for diagnosis of vessel-specific ischemia remains underexplored. METHODS: CREDENCE will enroll adult individuals with symptoms suspicious of CAD referred for non-emergent invasive coronary angiography (ICA), but without known CAD. All participants will undergo CCTA, MPS, ICA and FFR. FFR will be performed for lesions identified at the time of ICA to be ≥40 and <90 % stenosis, or those clinically indicated for evaluation. Study analyses will focus on diagnostic performance of CCTA versus MPS against invasive FFR reference standard. An integrated stenosis-APC-FFRCT metric by CCTA for vessel-specific ischemia will be developed from derivation cohort and tested against a validation cohort. Similarly, integrated metric by MPS for vessel-specific ischemia will be developed, validated and compared. An FFR value of ≤0.80 will be considered as ischemia causing. The primary endpoint will be the diagnostic accuracy of vessel territory-specific ischemia of integrated stenosis-APC-FFRCT measure by CCTA, compared with perfusion or perfusion-myocardial blood flow stress imaging testing, against invasive FFR. DISCUSSION: CREDENCE will determine the performance of integrated CCTA metric compared to integrated MPS measure for diagnosis of vessel-specific ischemia. If proven successful, this study may reduce the number of missed diagnoses and help to optimally predict ischemia-causing lesions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02173275 . Registered on June 23, 2014.

Diagnostic Accuracy, Image Quality, and Patient Comfort for Coronary CT Angiography Performed Using Iso-Osmolar versus Low-Osmolar Iodinated Contrast: A Prospective International Multicenter Randomized Controlled Trial.

RATIONALE AND OBJECTIVES: The impact of iso-osmolar versus low-osmolar iodinated contrast on diagnostic accuracy for coronary computed tomography angiography (CCTA), against the reference standard of invasive coronary angiography (ICA), has not been determined. We sought to compare in an international multicenter randomized controlled trial the impact of iso-osmolar iodixanol versus low-osmolar iopamidol on diagnostic accuracy, image quality, patient symptoms, and heart rate variability. MATERIALS AND METHODS: Adult patients who were clinically referred for ICA were randomly assigned to receive either iodixanol (n = 133) or iopamidol (n = 133) with an investigational CCTA. CCTA stenosis and image quality were scored by consensus of independent blinded core laboratory readers. Degree of stenosis by ICA was evaluated using quantitative coronary angiography and used to calculate diagnostic accuracy. Heart rate variability and patient-reported symptom questionnaires were compared between the two groups. RESULTS: A total of 266 subjects underwent both CCTA and ICA (57 ± 11 years, 58% male). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detecting coronary artery disease were 86.8%, 93.7%, 84.6%, 94.7%, and 91.7% for iodixanol and 94.7%, 88.4%, 76.6%, 97.7%, and 90.2% for iopamidol, respectively, on a per-patient level. These values were not significantly different between the two groups. There was no significant difference in image quality and heart rate increase or variability. The majority of patients reported symptoms (59.4%), with no differences in the overall or individual rate of any or moderate to severe symptoms between the two groups. Patients receiving iodixanol reported lower incidence of moderate to severe flushing (3.0% vs. 12.8%, P = .005). Lower rates of moderate to severe symptoms were particularly evident for patients with ≥55 years receiving iodixanol versus iopamidol (8.5% vs. 24.6%, P = .01). CONCLUSIONS: Diagnostic performance and image quality were similar for CCTA performed with iso-osmolar versus low-osmolar iodinated contrast. Indices of patient comfort were improved with iso-osmolar iodinated contrast.

Effectiveness of a low contrast load CT angiography protocol in octogenarians and nonagenarians being evaluated for transcatheter aortic valve replacement.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) typically requires computed tomographic angiography (CTA) for aortoiliofemoral assessment to determine feasibility of a transfemoral approach, although many candidates being considered for TAVR are at increased risk of contrast-induced nephropathy (CIN). OBJECTIVE: To determine the feasibility and safety of a load contrast load CTA protocol in octogenarians and nonagenarians at risk of CIN. APPROACH: We evaluated 54 consecutive octogenarians and nonagenarians considered for TAVR who underwent CTA using a standard contrast protocol (n=21) versus a protocol incorporating low-dose contrast in patients at risk of CIN (n=33). We compared clinical characteristics, CTA image quality (score 1-4) and interpretability, and clinical outcomes, including CIN and vascular complications. RESULTS: The mean age was 88.5±4.0 years, 37% were male, and chronic renal insufficiency was common in both the standard and low-dose contrast cohorts (57% vs. 70%, P=.39). The low-dose contrast protocol was associated with a significantly less contrast volume compared to standard contrast protocol (127±18 ml vs 76±55 ml, P<.001). Individuals imaged using low-dose (n=16) versus standard (n=17) contrast protocols received 80% less contrast volume (23±10 vs. 125±23 ml, P<.001). There was similar graded image quality (3.8±0.4 vs. 3.9±0.3, P=.76) and interpretability (100% for each, P=1.0) between standard and low-dose contrast protocol groups. There was no significant difference in rates of CIN after CTA between standard and low-dose contrast protocol groups (10% vs. 3%, P=.55), with no CIN events in those imaged by low-dose CTA. There were no major vascular injuries associated with TAVR or pigtail insertion, no major bleeding for CTA, and no noninterpretable studies in all patients. CONCLUSION: In this proof-of-principle study, a low-dose contrast protocol appears feasible and safe in octogenarians and nonagenarians undergoing screening for TAVR, and results in significant reduction in contrast load as compared to a standard contrast protocol without observed differences in image quality or safety.

Is metabolic syndrome predictive of prevalence, extent, and risk of coronary artery disease beyond its components? Results from the multinational coronary CT angiography evaluation for clinical outcome: an international multicenter registry (CONFIRM).

Although metabolic syndrome is associated with increased risk of cardiovascular disease and events, its added prognostic value beyond its components remains unknown. This study compared the prevalence, severity of coronary artery disease (CAD), and prognosis of patients with metabolic syndrome to those with individual metabolic syndrome components. The study cohort consisted of 27125 consecutive individuals who underwent ≥ 64-detector row coronary CT angiography (CCTA) at 12 centers from 2003 to 2009. Metabolic syndrome was defined as per NCEP/ATP III criteria. Metabolic syndrome patients (n = 690) were matched 1:1:1 to those with 1 component (n = 690) and 2 components (n = 690) of metabolic syndrome for age, sex, smoking status, and family history of premature CAD using propensity scoring. Major adverse cardiac events (MACE) were defined by a composite of myocardial infarction (MI), acute coronary syndrome, mortality and late target vessel revascularization. Patients with 1 component of metabolic syndrome manifested lower rates of obstructive 1-, 2-, and 3-vessel/left main disease compared to metabolic syndrome patients (9.4% vs 13.8%, 2.6% vs 4.5%, and 1.0% vs 2.3%, respectively; p < 0.05), while those with 2 components did not (10.5% vs 13.8%, 2.8% vs 4.5% and 1.3% vs 2.3%, respectively; p > 0.05). At 2.5 years, metabolic syndrome patients experienced a higher rate of MACE compared to patients with 1 component (4.4% vs 1.6%; p = 0.002), while no difference observed compared to individuals with 2 components (4.4% vs 3.2% p = 0.25) of metabolic syndrome. In conclusion, Metabolic syndrome patients have significantly greater prevalence, severity, and prognosis of CAD compared to patients with 1 but not 2 components of metabolic syndrome.

Coronary dominance and prognosis in patients undergoing coronary computed tomographic angiography: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry.

AIMS: Coronary computed tomographic angiography (CCTA) has become an important tool for non-invasive diagnosis of coronary artery disease (CAD). Coronary dominance can be assessed by CCTA; however, the predictive value of coronary dominance is controversially discussed. The aim of this study was to evaluate the prevalence and prognosis of coronary dominance in a large prospective, international multicentre cohort of patients undergoing CCTA. METHODS AND RESULTS: The study population consisted of 6382 patients with or without CAD (47% females, 53% males, mean age 56.9 ± 12.3 years) who underwent CCTA and were followed over a period of 60 months. Right or left coronary dominance was determined. Right dominance was present in 91% (n = 5817) and left in 9% (n = 565) of the study population. At the end of follow-up, outcome in patients with obstructive CAD (>50% luminal stenosis) and right dominance was similar compared with patients with left dominance [hazard ratio (HR) 0.46, 95% CI 0.16-1.32, P = 0.15]. Furthermore, no differences were observed for the type of coronary dominance in patients with non-obstructive CAD (HR 0.95, 95% CI 0.41-2.21, P = 0.8962) or normal coronary arteries (HR 1.04, 95% CI 0.68-1.59, P = 0.9). Subgroup analysis in patients with left main disease revealed an elevated hazard of the combined endpoint for left dominance (HR 6.45, 95% CI 1.66-25.0, P = 0.007), but not for right dominance. CONCLUSION: In our study population, survival after 5 years of follow-up did not differ significantly between patients with left or right coronary dominance. Thus, assessment of coronary vessel dominance by CCTA may not enhance risk stratification in patients with normal coronary arteries or obstructive CAD, but may add prognostic information for specific subpopulations.

Sex-based prognostic implications of nonobstructive coronary artery disease: results from the international multicenter CONFIRM study.

PURPOSE: To determine the clinical outcomes of women and men with nonobstructive coronary artery disease ( CAD coronary artery disease ) with coronary computed tomographic (CT) angiography data in patients who were similar in terms of CAD coronary artery disease risk factors, angina typicality, and CAD coronary artery disease extent and distribution. MATERIALS AND METHODS: Institutional review board approval was obtained for all participating sites, with either informed consent or waiver of informed consent. In a prospective international multicenter cohort study of 27 125 patients undergoing coronary CT angiography at 12 centers, 18 158 patients with no CAD coronary artery disease or nonobstructive (<50% stenosis) CAD coronary artery disease were examined. Men and women were propensity matched for age, CAD coronary artery disease risk factors, angina typicality, and CAD coronary artery disease extent and distribution, which resulted in a final cohort of 11 462 subjects. Nonobstructive CAD coronary artery disease presence and extent were related to incident major adverse cardiovascular events ( MACE major adverse cardiovascular events ), which were inclusive of death and myocardial infarction and were estimated by using multivariable Cox proportional hazards models. RESULTS: At a mean follow-up ± standard deviation of 2.3 years ± 1.1, MACE major adverse cardiovascular events occurred in 164 patients (0.6% annual event rate). After matching, women and men experienced identical annualized rates of myocardial infarction (0.2% vs 0.2%, P = .72), death (0.5% vs 0.5%, P = .98), and MACE major adverse cardiovascular events (0.6% vs 0.6%, P = .94). In multivariable analysis, nonobstructive CAD coronary artery disease was associated with similarly increased MACE major adverse cardiovascular events for both women (hazard ratio: 1.96 [95% confidence interval { CI confidence interval }: 1.17, 3.28], P = .01) and men (hazard ratio: 1.77 [95% CI confidence interval : 1.07, 2.93], P = .03). CONCLUSION: When matched for age, CAD coronary artery disease risk factors, angina typicality, and nonobstructive CAD coronary artery disease extent, women and men experience comparable rates of incident mortality and myocardial infarction.

Prognostic significance of calcified plaque among symptomatic patients with nonobstructive coronary artery disease.

BACKGROUND: Coronary artery calcium (CAC) is a well-established predictor of clinical outcomes for population screening. Limited evidence is available as to its predictive value in symptomatic patients without obstructive coronary artery disease (CAD). The aim of the current study was to assess the prognostic value of CAC scores among symptomatic patients with nonobstructive CAD. METHODS: From the COronary Computed Tomographic Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 7,200 symptomatic patients with nonobstructive CAD (<50% coronary stenosis) on coronary-computed tomographic angiography were prospectively enrolled and followed for a median of 2.1 years. Patients were categorized as without (0% stenosis) or with (>0% but <50% coronary stenosis) a luminal stenosis. CAC scores were calculated using the Agatston method. Univariable and multivariable Cox proportional hazard models were employed to estimate all-cause mortality and/or myocardial infarction (MI). Four-year death and death or MI rates were 1.9% and 3.3%. RESULTS: Of the 4,380 patients with no luminal stenosis, 86% had CAC scores of <10 while those with a luminal stenosis had more prevalent and extensive CAC with 31.9% having a CAC score of ≥100. Among patients with no luminal stenosis, CAC was not predictive of all-cause mortality (P = .44). However, among patients with a luminal stenosis, 4-year mortality rates ranged from 0.8% to 9.8% for CAC scores of 0 to ≥400 (P < .0001). The mortality hazard was 6.0 (P = .004) and 13.3 (P < .0001) for patients with a CAC score of 100-399 and ≥400. In patients with a luminal stenosis, CAC remained independently predictive in all-cause mortality (P < .0001) and death or MI (P < .0001) in multivariable models containing CAD risk factors and presenting symptoms. CONCLUSIONS: CAC allows for the identification of those at an increased hazard for death or MI in symptomatic patients with nonobstructive disease. From the CONFIRM registry, the extent of CAC was an independent estimator of long-term prognosis among symptomatic patients with luminal stenosis and may further define risk and guide preventive strategies in patients with nonobstructive CAD.

Incremental prognostic value of coronary computed tomographic angiography over coronary artery calcium score for risk prediction of major adverse cardiac events in asymptomatic diabetic individuals.

BACKGROUND: Coronary artery disease (CAD) diagnosis by coronary computed tomographic angiography (CCTA) is useful for identification of symptomatic diabetic individuals at heightened risk for death. Whether CCTA-detected CAD enables improved risk assessment of asymptomatic diabetic individuals beyond clinical risk factors and coronary artery calcium scoring (CACS) remains unexplored. METHODS: From a prospective 12-center international registry of 27,125 individuals undergoing CCTA, we identified 400 asymptomatic diabetic individuals without known CAD. Coronary stenosis by CCTA was graded as 0%, 1-49%, 50-69%, and ≥70%. CAD was judged on a per-patient, per-vessel and per-segment basis as maximal stenosis severity, number of vessels with ≥50% stenosis, and coronary segments weighted for stenosis severity (segment stenosis score), respectively. We assessed major adverse cardiovascular events (MACE) - inclusive of mortality, nonfatal myocardial infarction (MI), and late target vessel revascularization ≥90 days (REV) - and evaluated the incremental utility of CCTA for risk prediction, discrimination and reclassification. RESULTS: Mean age was 60.4 ± 9.9 years; 65.0% were male. At a mean follow-up 2.4 ± 1.1 years, 33 MACE occurred (13 deaths, 8 MI, 12 REV) [8.25%; annualized rate 3.4%]. By univariate analysis, per-patient maximal stenosis [hazards ratio (HR) 2.24 per stenosis grade, 95% confidence interval (CI) 1.61-3.10, p < 0.001], increasing numbers of obstructive vessels (HR 2.30 per vessel, 95% CI 1.75-3.03, p < 0.001) and segment stenosis score (HR 1.14 per segment, 95% CI 1.09-1.19, p < 0.001) were associated with increased MACE. After adjustment for CAD risk factors and CACS, maximal stenosis (HR 1.80 per grade, 95% CI 1.18-2.75, p = 0.006), number of obstructive vessels (HR 1.85 per vessel, 95% CI 1.29-2.65, p < 0.001) and segment stenosis score (HR 1.11 per segment, 95% CI 1.05-1.18, p < 0.001) were associated with increased risk of MACE. Beyond age, gender and CACS (C-index 0.64), CCTA improved discrimination by maximal stenosis, number of obstructive vessels and segment stenosis score (C-index 0.77, 0.77 and 0.78, respectively). Similarly, CCTA findings improved risk reclassification by per-patient maximal stenosis [integrated discrimination improvement (IDI) index 0.03, p = 0.03] and number of obstructive vessels (IDI index 0.06, p = 0.002), and by trend for segment stenosis score (IDI 0.03, p = 0.06). CONCLUSION: For asymptomatic diabetic individuals, CCTA measures of CAD severity confer incremental risk prediction, discrimination and reclassification on a per-patient, per-vessel and per-segment basis.

Does coronary CT angiography improve risk stratification over coronary calcium scoring in symptomatic patients with suspected coronary artery disease? Results from the prospective multicenter international CONFIRM registry.

AIMS: The prognostic value of coronary artery calcium (CAC) scoring is well established and has been suggested for use to exclude significant coronary artery disease (CAD) for symptomatic individuals with CAD. Contrast-enhanced coronary computed tomographic angiography (CCTA) is an alternative modality that enables direct visualization of coronary stenosis severity, extent, and distribution. Whether CCTA findings of CAD add an incremental prognostic value over CAC in symptomatic individuals has not been extensively studied. METHODS AND RESULTS: We prospectively identified symptomatic patients with suspected but without known CAD who underwent both CAC and CCTA. Symptoms were defined by the presence of chest pain or dyspnoea, and pre-test likelihood of obstructive CAD was assessed by the method of Diamond and Forrester (D-F). CAC was measured by the method of Agatston. CCTAs were graded for obstructive CAD (>70% stenosis); and CAD plaque burden, distribution, and location. Plaque burden was determined by a segment stenosis score (SSS), which reflects the number of coronary segments with plaque, weighted for stenosis severity. Plaque distribution was established by a segment-involvement score (SIS), which reflects the number of segments with plaque irrespective of stenosis severity. Finally, a modified Duke prognostic index-accounting for stenosis severity, plaque distribution, and plaque location-was calculated. Nested Cox proportional hazard models for a composite endpoint of all-cause mortality and non-fatal myocardial infarction (D/MI) were employed to assess the incremental prognostic value of CCTA over CAC. A total of 8627 symptomatic patients (50% men, age 56 ± 12 years) followed for 25 months (interquartile range 17-40 months) comprised the study cohort. By CAC, 4860 (56%) and 713 (8.3%) patients had no evident calcium or a score of >400, respectively. By CCTA, 4294 (49.8%) and 749 (8.7%) had normal coronary arteries or obstructive CAD, respectively. At follow-up, 150 patients experienced D/MI. CAC improved discrimination beyond D-F and clinical variables (area under the receiver-operator characteristic curve 0.781 vs. 0.788, P = 0.004). When added sequentially to D-F, clinical variables, and CAC, all CCTA measures of CAD improved discrimination of patients at risk for D/MI: obstructive CAD (0.82, P < 0.001), SSS (0.81, P < 0.001), SIS (0.81, P = 0.003), and Duke CAD prognostic index (0.82, P < 0.0001). CONCLUSION: In symptomatic patients with suspected CAD, CCTA adds incremental discriminatory power over CAC for discrimination of individuals at risk of death or MI.

Extent and severity of coronary artery disease by coronary CT angiography is associated with elevated left ventricular diastolic pressures and worsening diastolic function.

BACKGROUND: Patients with flow-limiting coronary stenoses exhibit elevated left ventricular end-diastolic pressure (LVEDP) and abnormal left ventricular (LV) relaxation. OBJECTIVE: We investigated the relationship of extent and severity of coronary artery disease (CAD) by coronary CT angiography (CTA) to LVEDP and measures of LV diastolic dysfunction. METHODS: We identified consecutive patients undergoing coronary CTA and transthoracic echocardiography who were assessed for diastolic function. CAD was evaluated on a per-patient, per-vessel, and per-segment basis for intraluminal diameter stenosis by using an 18-segment model (0 = none, 1 = 1%-49%, 2 = 50%-69%, and 3 = 70%-100%) and summed over segments to obtain overall coronary plaque burden (segment stenosis score [SSS]; maximum = 54). Transthoracic echocardiography evaluated mitral inflow E wave-to-A wave ratio, tissue Doppler early mitral annual tissue velocity axial excursion, stage of diastolic dysfunction, and LV dimensions and estimated LVEDP from the ratio of mitral inflow velocity to early mitral annular (medial) tissue velocity. RESULTS: Four hundred seventy-eight patients (57% women; mean age, 57.9 ± 14.6 years; 24.9% prior CAD) comprised the study population. Increasing per-patient maximal coronary stenosis, number of vessels with obstructive stenosis, and SSS were associated with increased LVEDP. The prevalence of advanced diastolic dysfunction increased with greater number of obstructive vessels. In multivariable analyses, SSS was associated with increased LVEDP (0.8 mm Hg per tertile increase in SSS, 0.5-1.1; P < .001); reduced E' axial excursion (-0.3; 95% confidence interval [CI], -0.5 to -0.1; P = .001), increased LV mass index (1.6 g/m(2) per tertile increase in SSS; P = .04), and increased relative wall thickness (0.005; 95% CI, 0.004-0.009; P = .03), with consistent relationships persisting even among persons with per-patient maximal stenosis <50% and LV ejection fraction ≥ 55%. CONCLUSIONS: Extent and severity of obstructive as well as nonobstructive CAD by coronary CTA are associated with increased LVEDP and measures of diastolic dysfunction.

Rationale and design of the ViCTORY (Validation of an Intracycle CT Motion CORrection Algorithm for Diagnostic AccuracY) trial.

BACKGROUND: Coronary CT angiography (CTA) has emerged as an effective noninvasive method for direct visualization of the coronary arteries, with high diagnostic performance compared with invasive coronary angiography (ICA). However, coronary CTA is prone to artifacts, including coronary motion, which may reduce its diagnostic performance. Intracycle motion compensation algorithms (MCAs) from a combination of software and hardware techniques now allow for correction of coronary motion, but the diagnostic performance of MCAs compared with traditional coronary CTA reconstruction methods remains unexplored. METHODS: ViCTORY (Validation of an Intracycle CT Motion CORrection Algorithm for Diagnostic AccuracY) is a prospective international multicenter trial of 218 patients which is designed to evaluate the performance of MCAs for the diagnosis of anatomically obstructive coronary artery disease (CAD) compared with an ICA reference standard, on a per-patient, per-vessel, and per-segment basis. Patients enrolled into ViCTORY will undergo investigational coronary CTA and clinically indicated ICA and will not receive heart rate-lowering medications before coronary CTA. Coronary CTA images will be reconstructed by conventional standard methods as well as by MCAs. Blinded core laboratory interpretation will be performed for coronary CTA and ICA in an intent-to-diagnose fashion. RESULTS: The primary end point of ViCTORY is the per-patient diagnostic accuracy of MCAs for the diagnosis of anatomically obstructive CAD compared with ICA. Secondary end points will include other per-patient, per-vessel, and per-segment diagnostic performance characteristics, including accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. Other key secondary end points will include diagnostic interpretability, image quality, the upper heart rate threshold of utility of MCAs, and the additive value of MCAs to traditionally reconstructed coronary CTA. CONCLUSION: ViCTORY will determine whether MCAs improve the diagnosis of obstructive CAD in patients undergoing coronary CTA who are not receiving heart rate-lowering medications.