Outcomes of patients with moderate-to-severe Ischemia excluded from the ischemia trial.

BACKGROUND: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial showed no difference in outcomes between medical therapy vs coronary revascularization in the management of patients with stable coronary artery disease. We aimed to determine the percentage of patients with at least moderate ischemia that would have been eligible for enrollment and evaluate the outcomes of those who would not. METHODS: Consecutive patients who underwent cardiac single-photon emission computed tomography (SPECT) between April 2016 and September 2019 were identified and all-cause mortality was determined. RESULTS: There were a total of 1508 patients (mean age 67 ± 11.6 years, 69.5% males) with any perfusion defect on SPECT. Patients had a high prevalence of cardiac risk factors (73.4% with hypertension and 54.4% with diabetes mellitus.) Nearly half (709, 47%) had moderate-to-severe ischemia but over two-thirds (479/709, 66.3%) had at least one ISCHEMIA trial exclusion criteria. Patients meeting ISCHEMIA enrollment criteria had a significantly lower all-cause mortality than those who would have been excluded (3.91% vs. 11.3%, respectively, P < .001). CONCLUSION: Our results show that ISCHEMIA selected a relatively small subset of lower risk patients among the larger higher risk group of patients with moderate-to-severe ischemia typical to most cardiology centers.

Left ventricular mass on positron emission tomography: Validation against cardiovascular magnetic resonance.

BACKGROUND: Left ventricular hypertrophy (LVH) is an important clinical finding that is independently associated with mortality and cardiovascular events. We aimed to assess the interstudy variability of LV mass quantitation between PET and CMR. METHODS: Patients who underwent both PET and CMR within 1 year were identified from prospective institutional registries. LV mass on PET was compared against LV mass on CMR using several statistical measures of agreement. RESULTS: A total of 105 patients (mean age 60 ± 14 years, 67.6% male) were included. The median (interquartile range, IQR) duration between CMR and PET was 47 (11-154) days. The median (IQR) LV mass values were 168.0 g (126.0-202.0) on CMR and 174.0 g (150.0-212.0) with PET (absolute mean difference 29.42 ± 25.3). There was a good correlation (Spearman ρ = 0.81, P < 0.001; Intraclass Correlation Coefficient 0.78, 95% CI 0.70-0.85, P < 0.001) with moderate limits of agreement (95% limits of agreement - 63.78 to 83.7.) Results were consistent, albeit with moderate correlation, in subgroups of patients with LVH, in patients with myocardial infarction, in patients with LV ejection fraction < 50%, and those with limited image quality. LV mass on PET tended to be underestimated at high values compared to CMR. CONCLUSION: We demonstrate good correlation and reproducibility of LV mass quantitation by PET against the reference standard of CMR across a wide range of normal and diseased hearts with a tendency of PET to underestimate mass at higher mass values.

A tale of two technologies: Can nuclear cardiology survive the emergence of cardiac CT the seventeenth annual Mario S. Verani lectureship.

The Mario S. Verani Lectureship has traditionally been an opportunity for presenters to reflect on the state of nuclear cardiology in clinical practice and expound on new innovations in the field. Mario Verani was a visionary who embraced change and, as a cardiologist, sought to define where other cardiac imaging techniques might complement nuclear cardiology for improving patient care. Over the last decade, nuclear cardiology and cardiac computed tomography (CT) have developed in parallel with both expanding beyond the evaluation of coronary artery disease. However, many consider cardiac CT a formidable threat to nuclear cardiology due to pivotal technical innovations and its subsequent exponential growth in recent years. It is only fitting that this year's lectureship explore the relative value of both techniques in evaluating and managing cardiac disease, their relative strengths and weaknesses, and the potential value of combining nuclear cardiology and cardiac CT imaging for enhancing patient management. To Mario, my mentor, colleague for over 20 years and friend, this lectureship is truly in honor and remembrance of you.

Nuclear Cardiology Practice in Asia: Analysis of Radiation Exposure and Best Practice for Myocardial Perfusion Imaging　- Results From the IAEA Nuclear Cardiology Protocols Cross-Sectional Study (INCAPS).

BACKGROUND: This paper examines the current status of radiation exposure to patients in myocardial perfusion imaging (MPI) in Asia.Methods and Results:Laboratories voluntarily provided information on MPI performed over a 1-week period. Eight best practice criteria regarding MPI were predefined by an expert panel. Implementation of ≥6 best practices (quality index [QI] ≥6) was pre-specified as a desirable goal for keeping radiation exposure at a low level. Radiation effective dose (ED) in 1,469 patients and QI of 69 laboratories in Asia were compared against data from 239 laboratories in the rest of the world (RoW). Mean ED was significantly higher in Asia (11.4 vs. 9.6 mSv; P<0.0001), with significantly lower doses in South-East vs. East Asia (9.7 vs. 12.7 mSv; P<0.0001). QI in Asia was lower than in RoW. In comparison with RoW, Asian laboratories used thallium more frequently, used weight-based technetium dosing less frequently, and trended towards a lower rate of stress-only imaging. CONCLUSIONS: MPI radiation dose in Asia is higher than that in the RoW and linked to less consistent use of laboratory best practices such as avoidance of thallium, weight-based dosing, and use of stress-only imaging. Given that MPI is performed in Asia within a diverse array of medical contexts, laboratory-specific adoption of best practices offers numerous opportunities to improve quality of care.

Nuclear Cardiology Practices and Radiation Exposure in the Oceania Region: Results From the IAEA Nuclear Cardiology Protocols Study (INCAPS).

BACKGROUND: There is concern about radiation exposure with radionuclide myocardial perfusion imaging (MPI). This sub-study of the International Atomic Energy Agency (IAEA) Nuclear Cardiology Protocols Study reports radiation doses from MPI, and use of dose-optimisation protocols in Australia and New Zealand (ANZ), and compares them with data from the rest of the world. METHODS: Data were collected from 7911 MPI studies performed in 308 laboratories worldwide in one week in 2013, including 439 MPI studies from 34 ANZ laboratories. For each laboratory, effective radiation dose (ED) and a quality index (QI) score (out of 8) based on pre-specified "best practices" was determined. RESULTS: In ANZ patients, ED ranged from 0.9-17.9 milliSievert (mSv). Median ED was similar in ANZ compared with the rest of the world (10.0 (IQR: 6.5-11.7) vs. 10.0 (IQR 6.4-12.6, P=0.15), as were mean QI scores (5.5±0.7 vs. 5.4±1.3, P=0.84). Use of stress-only imaging (17.6% vs. 31.8% of labs, P=0.09) and weight-based dosing of technetium-99m (14.7% vs. 30.3%, P=0.07) was lower in ANZ compared with the rest of the world but this difference was not statistically significant. Median ED was significantly lower in metropolitan versus non-metropolitan laboratories (10.1 mSv vs. 11.6 mSv, P<0.01), although mean QI scores were similar (5.4±0.8 vs. 5.5±0.7, P=0.75). CONCLUSION: Across ANZ, there is variability in ED from MPI, and use of radiation safety practices, particularly between metropolitan and non-metropolitan laboratories. Overall, ANZ laboratories have a similar median ED to laboratories in the rest of the world.

Nuclear cardiology practice and associated radiation doses in Europe: results of the IAEA Nuclear Cardiology Protocols Study (INCAPS) for the 27 European countries.

PURPOSE: Nuclear cardiology is widely used to diagnose coronary artery disease and to guide patient management, but data on current practices, radiation dose-related best practices, and radiation doses are scarce. To address these issues, the IAEA conducted a worldwide study of nuclear cardiology practice. We present the European subanalysis. METHODS: In March 2013, the IAEA invited laboratories across the world to document all SPECT and PET studies performed in one week. The data included age, gender, weight, radiopharmaceuticals, injected activities, camera type, positioning, hardware and software. Radiation effective dose was calculated for each patient. A quality score was defined for each laboratory as the number followed of eight predefined best practices with a bearing on radiation exposure (range of quality score 0 - 8). The participating European countries were assigned to regions (North, East, South, and West). Comparisons were performed between the four European regions and between Europe and the rest-of-the-world (RoW). RESULTS: Data on 2,381 European patients undergoing nuclear cardiology procedures in 102 laboratories in 27 countries were collected. A cardiac SPECT study was performed in 97.9 % of the patients, and a PET study in 2.1 %. The average effective dose of SPECT was 8.0 ± 3.4 mSv (RoW 11.4 ± 4.3 mSv; P < 0.001) and of PET was 2.6 ± 1.5 mSv (RoW 3.8 ± 2.5 mSv; P < 0.001). The mean effective doses of SPECT and PET differed between European regions (P < 0.001 and P = 0.002, respectively). The mean quality score was 6.2 ± 1.2, which was higher than the RoW score (5.0 ± 1.1; P < 0.001). Adherence to best practices did not differ significantly among the European regions (range 6 to 6.4; P = 0.73). Of the best practices, stress-only imaging and weight-adjusted dosing were the least commonly used. CONCLUSION: In Europe, the mean effective dose from nuclear cardiology is lower and the average quality score is higher than in the RoW. There is regional variation in effective dose in relation to the best practice quality score. A possible reason for the differences between Europe and the RoW could be the safety culture fostered by actions under the Euratom directives and the implementation of diagnostic reference levels. Stress-only imaging and weight-adjusted activity might be targets for optimization of European nuclear cardiology practice.

Prognostic Value of Coronary Artery Calcium Score in Acute Chest Pain Patients Without Known Coronary Artery Disease: Systematic Review and Meta-analysis.

STUDY OBJECTIVE: Coronary artery calcium score (CACS) is a well-established test for risk stratifying asymptomatic patients. Recent studies also indicate that CACS may accurately risk stratify stable patients presenting to the emergency department (ED) with acute chest pain; however, many were underpowered. The purpose of this systematic review and meta-analysis is to evaluate the prognostic value and accuracy of a zero (normal) CACS for identifying patients at acceptable low risk for future cardiovascular events who might be safely discharged home from the ED. METHODS: We searched multiple databases for longitudinal studies of CACS in symptomatic patients without known coronary artery disease that reported major adverse cardiovascular events (MACEs), including death and myocardial infarction. Pooled risk ratios, sensitivity, specificity, and likelihood ratios were analyzed. RESULTS: Eight studies evaluated 3,556 patients, with a median follow-up of 10.5 months. Pooled prevalence of zero CACS was 60%. Patients with CACS=0 had a significantly lower risk of cardiovascular events compared with those with CACS greater than 0 (MACEs: relative risk 0.06, 95% confidence interval 0.04 to 0.11, I2=0%; death/myocardial infarction: relative risk 0.19; 95% confidence interval 0.08 to 0.47, I2=0%). The pooled event rates for CACS=0 (MACEs 0.8%/year; death/myocardial infarction 0.5%/year) were significantly lower than for CACS greater than 0 (MACEs 14.6%/year; death/myocardial infarction 3.5%/year). Analysis of summary testing parameters showed a sensitivity of 96%, specificity of 60%, positive likelihood ratio of 2.36, and negative likelihood ratio of 0.07. CONCLUSION: Acute chest pain patients without history of coronary artery disease, ischemic ECG changes, or increased cardiac enzyme levels commonly have a CACS of zero, with a very low subsequent risk of MACEs or death or myocardial infarction. This meta-analysis proffers the potential role of initial CACS testing for avoiding unnecessary hospitalization and further cardiac testing in acute chest pain patients with a CACS of zero.

Clinical Utility of Multidetector Computed Tomography in Redo Valve Procedures.

BACKGROUND: Transesophageal echocardiography (TEE) is recommended for diagnosis in patients suspected of prosthetic valve dysfunction, but could be limited in its ability to identify the etiology of these dysfunctions and to assess extracardiac structures. Our objective is to examine the usefulness of multidetector computed tomography (MDCT) in establishing the etiology of the dysfunctions and its clinical utility in preoperative assessment in these patients. METHODS: Twenty-two prosthetic heart valves from 20 consecutive patients who had a preoperative MDCT and underwent redo prosthetic valve procedures from December 2008 to February 2013 were examined retrospectively. Results from MDCT and TEE were compared to intraoperative findings. Extravalvular MDCT findings including coronary artery/bypass graft, high-risk features for reoperative cardiac surgery, and extracardiac findings were also assessed. RESULTS: MDCT correctly identified 15 valve regurgitation and seven valve obstructions compared to intraoperative findings. Both TEE and MDCT were able to correctly identify the etiologies in 93% (14/15) of regurgitant valves. However, MDCT was better able to identify the etiology of obstructive valves than TEE (86% [6/7] vs. 43% [3/7]) compared to intraoperative findings. In patients who had preoperative invasive angiography, MDCT correctly identified two patients with significant coronary artery disease (CAD) and ruled out 11 without significant CAD. Furthermore, MDCT detected five high-risk features for postoperative complications and eight clinically relevant extracardiac findings. CONCLUSIONS: MDCT displayed comparable or better diagnostic performance than TEE for identifying the type of dysfunction and its etiology, as well as providing additional coronary and other extravalvular evaluations useful for preoperative planning.

Current worldwide nuclear cardiology practices and radiation exposure: results from the 65 country IAEA Nuclear Cardiology Protocols Cross-Sectional Study (INCAPS).

AIMS: To characterize patient radiation doses from nuclear myocardial perfusion imaging (MPI) and the use of radiation-optimizing 'best practices' worldwide, and to evaluate the relationship between laboratory use of best practices and patient radiation dose. METHODS AND RESULTS: We conducted an observational cross-sectional study of protocols used for all 7911 MPI studies performed in 308 nuclear cardiology laboratories in 65 countries for a single week in March-April 2013. Eight 'best practices' relating to radiation exposure were identified a priori by an expert committee, and a radiation-related quality index (QI) devised indicating the number of best practices used by a laboratory. Patient radiation effective dose (ED) ranged between 0.8 and 35.6 mSv (median 10.0 mSv). Average laboratory ED ranged from 2.2 to 24.4 mSv (median 10.4 mSv); only 91 (30%) laboratories achieved the median ED ≤ 9 mSv recommended by guidelines. Laboratory QIs ranged from 2 to 8 (median 5). Both ED and QI differed significantly between laboratories, countries, and world regions. The lowest median ED (8.0 mSv), in Europe, coincided with high best-practice adherence (mean laboratory QI 6.2). The highest doses (median 12.1 mSv) and low QI (4.9) occurred in Latin America. In hierarchical regression modelling, patients undergoing MPI at laboratories following more 'best practices' had lower EDs. CONCLUSION: Marked worldwide variation exists in radiation safety practices pertaining to MPI, with targeted EDs currently achieved in a minority of laboratories. The significant relationship between best-practice implementation and lower doses indicates numerous opportunities to reduce radiation exposure from MPI globally.

Regadenoson provides perfusion results comparable to adenosine in heterogeneous patient populations: a quantitative analysis from the ADVANCE MPI trials.

BACKGROUND: Total and reversible left ventricular (LV) perfusion defect size (PDS) predict patient outcome. Limited data exist as to whether regadenoson induces similar perfusion abnormalities as observed with adenosine. We sought to determine whether regadenoson induces a similar LV PDS as seen with adenosine across varying patient populations. METHODS AND RESULTS: ADVANCE MPI were prospective, double-blind randomized trials comparing regadenoson to standard adenosine myocardial perfusion tomography (SPECT). Following an initial adenosine SPECT, patients were randomized to either regadenoson (N = 1284) or a second adenosine study (N = 660). SPECT quantification was performed blinded to randomization and image sequence. Propensity analysis was used to define comparability of regadenoson and adenosine perfusion results. Baseline clinical and SPECT results were similar in the two randomized groups. There was a close correlation between adenosine and regadenoson-induced total (r (2) = 0.98, P < .001) and reversible (r (2) = 0.92, P < .001) PDS. Serial differences in total (0.00 ± 3.51 vs -0.11 ± 3.46, P = .51) and reversible (0.15 ± 3.79 vs 0.07 ± 3.33, P = .65) PDS were also comparable in patients randomized to regadenoson vs adenosine, respectively, and irrespective of age, gender, diabetic status, body mass index, or prior cardiovascular history. By propensity analysis, regadenoson-induced total PDS was significantly larger than observed with adenosine. CONCLUSION: This is the first study to show that regadenoson induces similar, if not larger, perfusion defects than those observed with adenosine across different patient populations and demonstrates the value of quantitative analysis for defining serial changes in SPECT perfusion results. Regadenoson should provide comparable diagnostic and prognostic SPECT information to that obtained with adenosine.

Is regadenoson an appropriate stressor for MPI in patients with left bundle branch block or pacemakers?

BACKGROUND: Patients with LBBB or ventricular pacemaker undergoing MPI are at risk for false positive MPI results in the setting of an elevated heart rate (HR) with exercise or dobutamine stress. The areas of increased apparent ischemia are typically the LAD and septal territories. METHODS: In a subanalysis of the ADVANCE MPI 1 and 2 studies, perfusion on an initial adenosine and a second MPI study with regadenoson or adenosine was compared by visual and quantitative analysis. Among 2,015 patients, 64 had LBBB and 93 had pacemakers. The hemodynamic response during the second scan was compared in those with and without LBBB and PM. RESULTS: Following regadenoson, peak HR in the LBBB group increased by a mean of 25.4 compared to 15.3 bpm following adenosine (P = .0083). In the pacemaker group HR was blunted, 11.8 and 8.1 following regadenoson and adenosine, respectively (P = .1262). However, the visually assessed summed difference score and the quantitatively assessed extent of ischemia for the LAD and septal territories and the entire LV did not differ between the initial adenosine and subsequent regadenoson scans. CONCLUSIONS: The significant increase in HR observed with regadenoson compared to adenosine did not translate into greater perfusion defects in the LAD or septal territories in patients undergoing regadenoson stress.

Incremental prognostic value of digital positron emission tomography derived myocardial flow reserve: A prospective cohort study.

BACKGROUND: Positron Emission Tomography (PET) Myocardial Perfusion Imaging (MPI) is a robust diagnostic and prognostic test in patients with suspected or known coronary artery disease (CAD). We aimed to assess the incremental prognostic value of myocardial flow reserve (MFR) using the latest generation of digital PET scanners. METHODS: Consecutive patients with clinically indicated PET MPI for suspected or known CAD were included. Myocardial blood flow (MBF) in ml/min/g was obtained from dynamic images at rest and peak hyperemia, and the myocardial flow reserve (MFR) was calculated as the ratio of stress to rest MBF. Patients were followed from the date of PET imaging for the occurrence of the primary outcome (composite of all-cause death, myocardial infarction, and Percutaneous Coronary Intervention or Coronary Artery Bypass Graft occurring >90 days after imaging). Nested multivariable Cox regression models were used to assess the incremental prognostic role of MFR over traditional risk factors and PET relative perfusion parameters. RESULTS: The final cohort consisted of 3534 patients (mean age 67 ± 12 years, 48% female, 67% Caucasian, 53% obese, 55% hypertension, 32% diabetes, 42% dyslipidemia). During a median follow-up of 8.5 (3.0-15.4) months, 229 patients (6.5%, 6.4 per 1000 person-years) experienced the primary outcome. In nested multivariable Cox models, impaired MFR (MFR < 2) was significantly associated with the primary outcome (HR 2.9, 95% CI 2.0-4.1, p < 0.001) and significantly improved discrimination (Harrell's C 0.77, p = 0.002). CONCLUSION: MFR derived from digital PET scanners has an independent and incremental prognostic role in patients with suspected or known CAD.

Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis.

AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with endothelial dysfunction. We aimed to determine the effects of prior coronavirus disease 2019 (COVID-19) on the coronary microvasculature accounting for time from COVID-19, disease severity, SARS-CoV-2 variants, and in subgroups of patients with diabetes and those with no known coronary artery disease. METHODS AND RESULTS: Cases consisted of patients with previous COVID-19 who had clinically indicated positron emission tomography (PET) imaging and were matched 1:3 on clinical and cardiovascular risk factors to controls having no prior infection. Myocardial flow reserve (MFR) was calculated as the ratio of stress to rest myocardial blood flow (MBF) in mL/min/g of the left ventricle. Comparisons between cases and controls were made for the odds and prevalence of impaired MFR (MFR < 2). We included 271 cases matched to 815 controls (mean ± SD age 65 ± 12 years, 52% men). The median (inter-quartile range) number of days between COVID-19 infection and PET imaging was 174 (58-338) days. Patients with prior COVID-19 had a statistically significant higher odds of MFR <2 (adjusted odds ratio 3.1, 95% confidence interval 2.8-4.25 P < 0.001). Results were similar in clinically meaningful subgroups. The proportion of cases with MFR <2 peaked 6-9 months from imaging with a statistically non-significant downtrend afterwards and was comparable across SARS-CoV-2 variants but increased with increasing severity of infection. CONCLUSION: The prevalence of impaired MFR is similar by duration of time from infection up to 1 year and SARS-CoV-2 variants, but significantly differs by severity of infection.

Assessing risk in acute chest pain: The value of stress myocardial perfusion imaging in patients admitted through the emergency department.

BACKGROUND: To prospectively assess the clinical value of stress-gated myocardial single photon emission computed tomography (SPECT) for triaging patients admitted through the emergency department (ED) with acute chest pain (ACP). METHODS: Prospective, observational cohort study in 1,576 consecutive patients who were evaluated for ACP over a 29-month period. Stress SPECT was performed within 24 hours of admission from the ED. Analysis included quantification of total and ischemic left ventricular perfusion defect size (PDS). Cardiac events were defined as an acute coronary syndrome during the index hospitalization or in follow-up over 7.3 ± 2.8 months. RESULTS: Eighty-five cardiac events occurred in 77 patients (4.9%). SPECT was abnormal in 135 patients (8.6%) of whom 83 (61.5%) had a reversible defect. Event rates were significantly higher in patients with an abnormal (40%) versus a normal (1.6%) SPECT (P < .0001); and in those with a (1) large (>15%) versus small (≤15%) PDS (50.0% vs 33.7%, P = .05) and (2) large (>10%) versus small (≤10%) ischemic PDS (87.5% vs 42.4%, P < .0001, respectively). SPECT best predicted cardiac events by multivariate analysis. The addition of SPECT to clinical variables significantly improved overall risk prediction (global χ(2) 103.6 vs 207.1, P < .001). CONCLUSIONS: Stress SPECT can accurately assess risk in a heterogeneous group of patients with ACP of unclear cardiac etiology, and beyond that provided by a clinical risk assessment alone. Our results support the use of stress SPECT for identifying very low-risk ACP patients with normal study results who can be safely discharged home.

Sex differences in machine learning computed tomography-derived fractional flow reserve.

Coronary computed tomography angiography (CCTA) derived machine learning fractional flow reserve (ML-FFRCT) can assess the hemodynamic significance of coronary artery stenoses. We aimed to assess sex differences in the association of ML-FFRCT and incident cardiovascular outcomes. We studied a retrospective cohort of consecutive patients who underwent clinically indicated CCTA and single photon emission computed tomography (SPECT). Obstructive stenosis was defined as ≥ 70% stenosis severity in non-left main vessels or ≥ 50% in the left main coronary. ML-FFRCT was computed using a machine learning algorithm with significant stenosis defined as ML-FFRCT < 0.8. The primary outcome was a composite of death or non-fatal myocardial infarction (D/MI). Our study population consisted of 471 patients with mean (SD) age 65 (13) years, 53% men, and multiple comorbidities (78% hypertension, 66% diabetes, 81% dyslipidemia). Compared to men, women were less likely to have obstructive stenosis by CCTA (9% vs. 18%; p = 0.006), less multivessel CAD (4% vs. 6%; p = 0.25), lower prevalence of ML-FFRCT < 0.8 (39% vs. 44%; p = 0.23) and higher median (IQR) ML-FFRCT (0.76 (0.53-0.86) vs. 0.71 (0.47-0.84); p = 0.047). In multivariable adjusted models, there was no significant association between ML-FFRCT < 0.8 and D/MI [Hazard Ratio 0.82, 95% confidence interval (0.30, 2.20); p = 0.25 for interaction with sex.]. In a high-risk cohort of symptomatic patients who underwent CCTA and SPECT testing, ML-FFRCT was higher in women than men. There was no significant association between ML-FFRCT and incident mortality or MI and no evidence that the prognostic value of ML-FFRCT differs by sex.

Prognostic Value of Computed Tomography-Derived Fractional Flow Reserve Comparison With Myocardial Perfusion Imaging.

OBJECTIVES: The aim of this study was to compare the incremental prognostic value of coronary computed tomography (CT) angiography (CCTA)-derived machine learning fractional flow reserve CT (ML-FFRct) versus that of ischemia detected on single-photon emission-computed tomography (SPECT) myocardial perfusion imaging (MPI) on incident cardiovascular outcomes. BACKGROUND: SPECT MPI and ML-FFRct are noninvasive tools that can assess the hemodynamic significance of coronary atherosclerotic disease. METHODS: We studied a retrospective cohort of consecutive patients who underwent clinically indicated CCTA and SPECT MPI. ML-FFRct was computed using a ML prototype. The primary outcome was all-cause mortality and nonfatal myocardial infarction (D/MI), and the secondary outcome was D/MI and unplanned revascularization, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) occurring more than 90 days postimaging. Multiple nested multivariate cox regression was used to model a scenario wherein an initial anatomical assessment was followed by a functional assessment. RESULTS: A total of 471 patients (mean age: 64 ± 13 year; 53% males) were included. Comorbidities were prevalent (78% hypertension, 66% diabetes, 81% dyslipidemia). ML-FFRct was <0.8 in at least 1 proximal/midsegment was present in 41.6% of patients, and ischemia on MPI was present in 13.8%. After a median follow-up of 18 months, 7% of patients (n = 33) experienced D/MI. On multivariate Cox proportional analysis, the presence of ischemia on MPI but not ML-FFRct significantly predicted D/MI (HR: 2.3; 95% CI: 1.0-5.0; P = 0.047; or HR: 0.7; 95% CI: 0.3-1.4; P = 0.306 respectively) when added to CCTA obstructive stenosis. Furthermore, the model with SPECT ischemia had higher global chi-square result and significantly improved reclassification. Results were similar using the secondary outcome and on several sensitivity analyses. CONCLUSIONS: In a high-risk patient cohort, SPECT MPI but not ML-FFRct adds independent and incremental prognostic information to CCTA-based anatomical assessment and clinical risk factors in predicting incident outcomes.