Impact of Absolute Myocardial Blood Flow Quantification on the Diagnostic Performance of PET-Based Perfusion Scans Using 82Rubidium.

BACKGROUND: Guidelines propose the inclusion of quantitative measurements from 82Rubidium positron emission tomography (RbPET) to discriminate obstructive coronary artery disease (CAD). However, the effect on diagnostic accuracy is unknown. The aim was to investigate the optimal RbPET reading algorithm for improved identification of obstructive CAD. METHODS: Prospectively enrolled patients (N=400) underwent RbPET and invasive coronary angiography with fractional flow reserve and quantitative coronary angiography. Quantitative measurements (myocardial blood flow (MBF), MBF reserve, transient ischemic dilatation) by RbPET were step-wisely added to a qualitative assessment by the summed stress score based on their diagnostic accuracy of obstructive CAD by invasive coronary angiography-fractional flow reserve. Prespecified cutoffs were summed stress score ≥4, hyperemic MBF 2.00 mL/g per min, and MBF reserve 1.80, respectively. Hemodynamically obstructive CAD was defined as >90% diameter stenosis or invasive coronary angiography-fractional flow reserve ≤0.80, and sensitivity analyses included a clinically relevant reference of anatomically severe CAD (>70% diameter stenosis by invasive coronary angiography-quantitative coronary angiography). RESULTS: Hemodynamically obstructive CAD was present in 170/400 (42.5%) patients. Stand-alone summed stress score showed a sensitivity and specificity of 57% and 93%, respectively, while hyperemic MBF showed similar sensitivity (61%, P=0.57) but lower specificity (85%, P=0.008). With increased discrimination by receiver-operating characteristic curves (0.78 versus 0.85; P<0.001), combining summed stress score, MBF and MBF reserve showed the highest sensitivity of 77% but lower specificity of 74% (P<0.001 for both comparisons). Against anatomically severe CAD, all measures independently yielded high discrimination ≥0.90 with increased sensitivity and lower specificity by additional quantification. CONCLUSIONS: The inclusion of quantitative measurements to a RbPET read increases in the identification of obstructive CAD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712.

Danish study of Non-Invasive Testing in Coronary Artery Disease 3 (Dan-NICAD 3): study design of a controlled study on optimal diagnostic strategy.

INTRODUCTION: Current guideline recommend functional imaging for myocardial ischaemia if coronary CT angiography (CTA) has shown coronary artery disease (CAD) of uncertain functional significance. However, diagnostic accuracy of selective myocardial perfusion imaging after coronary CTA is currently unclear. The Danish study of Non-Invasive testing in Coronary Artery Disease 3 trial is designed to evaluate head to head the diagnostic accuracy of myocardial perfusion imaging with positron emission tomography (PET) using the tracers 82Rubidium (82Rb-PET) compared with oxygen-15 labelled water PET (15O-water-PET) in patients with symptoms of obstructive CAD and a coronary CT scan with suspected obstructive CAD. METHODS AND ANALYSIS: This prospective, multicentre, cross-sectional study will include approximately 1000 symptomatic patients without previous CAD. Patients are included after referral to coronary CTA. All patients undergo a structured interview and blood is sampled for genetic and proteomic analysis and a coronary CTA. Patients with possible obstructive CAD at coronary CTA are examined with both 82Rb-PET, 15O-water-PET and invasive coronary angiography with three-vessel fractional flow reserve and thermodilution measurements of coronary flow reserve. After enrolment, patients are followed with Seattle Angina Questionnaires and follow-up PET scans in patients with an initially abnormal PET scan and for cardiovascular events in 10 years. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish regional committee on health research ethics. Written informed consent will be provided by all study participants. Results of this study will be disseminated via articles in international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04707859.

Second-Line Myocardial Perfusion Imaging to Detect Obstructive Stenosis: Head-to-Head Comparison of CMR and PET.

BACKGROUND: Guidelines recommend verification of myocardial ischemia by selective second-line myocardial perfusion imaging (MPI) following a coronary computed tomography angiography (CTA) with suspected obstructive coronary artery disease (CAD). Head-to-head data on the diagnostic performance of different MPI modalities in this setting are sparse. OBJECTIVES: The authors sought to compare, head-to-head, the diagnostic performance of selective MPI by 3.0-T cardiac magnetic resonance (CMR) and 82rubidium positron emission tomography (RbPET) in patients with suspected obstructive stenosis at coronary CTA using invasive coronary angiography (ICA) with fractional flow reserve (FFR) as reference. METHODS: Consecutive patients (n = 1,732, mean age: 59.1 ± 9.5 years, 57.2% men) referred for coronary CTA with symptoms suggestive of obstructive CAD were included. Patients with suspected stenosis were referred for both CMR and RbPET and subsequently ICA. Obstructive CAD was defined as FFR ≤0.80 or >90% diameter stenosis by visual assessment. RESULTS: In total, 445 patients had suspected stenosis on coronary CTA. Of these, 372 patients completed both CMR, RbPET and subsequent ICA with FFR. Hemodynamically obstructive CAD was identified in 164 of 372 (44.1%) patients. Sensitivities for CMR and RbPET were 59% (95% CI: 51%-67%) and 64% (95% CI: 56%-71%); P = 0.21, respectively, and specificities 84% (95% CI: 78%-89%) and 89% (95% CI: 84%-93%]); P = 0.08, respectively. Overall accuracy was higher for RbPET compared with CMR (73% vs 78%; P = 0.03). CONCLUSIONS: In patients with suspected obstructive stenosis at coronary CTA, CMR, and RbPET show similar and moderate sensitivities but high specificities compared with ICA with FFR. This patient group represents a diagnostic challenge with frequent mismatch between advanced MPI tests and invasive measurements. (Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 [Dan-NICAD 2]; NCT03481712).

Advanced heart sound analysis as a new prognostic marker in stable coronary artery disease.

Aims: Recent technological advances enable diagnosing of obstructive coronary artery disease (CAD) from heart sound analysis with a high negative predictive value. However, the prognostic impact of this approach remains unknown. To investigate the prognostic value of heart sound analysis as two scores, the Acoustic-score and the CAD-score, in patients with suspected CAD which is treated according to standard of care. Methods and results: Consecutive patients with angina symptoms referred for coronary computed tomography angiography (CTA) were enrolled. The Acoustic-score was developed from eight acoustic CAD-related features. This score was combined with risk factors to generate the CAD-score. A cut-off score >20 was pre-specified for both scores to indicate disease. If coronary CTA raised suspicion of obstructive CAD, patients were referred to invasive angiography and revascularized when indicated. Of 1675 enrolled patients, 1464 (87.4%) were included in this substudy. The combined primary endpoint was all-cause mortality and myocardial infarction (n = 26). Follow-up was 3.1 (2.7-3.4) years. Of patients with primary endpoints, the Acoustic-score was >20 in 25 (96%); the CAD-score was >20 in 22 (85%). In an unadjusted Cox analysis of the primary endpoints, the hazard ratio for scores >20 under current standard clinical care was 12.6 (1.7-93.2) for the Acoustic-score and 5.4 (1.9-15.7) for the CAD-score. The CAD-score contained prognostic information even after adjusting for lipid-lowering therapy initiation, stenosis at CTA, and early revascularization. Conclusion: Heart sound analysis seems to carry prognostic information and may improve initial risk stratification of patients with suspected CAD. Clinicaltrialsorg ID: NCT02264717.

Validation and update of the minimal risk tool in patients suspected of chronic coronary syndrome.

Risk stratification in patients with suspected coronary artery disease (CAD) is important. Recently, the minimal-risk-tool (MRT) was developed to identify individuals with low CAD risk despite symptoms in order to avoid unnecessary testing. We aimed to validate and update the MRT-model in a contemporary cohort. The Dan-NICAD trial cohort, consisting of 1675 consecutive patients referred for coronary computed tomography angiography (CTA), was used to calculate the MRT-score based on the published fitted variable coefficients from the PROMISE and SCOT-HEART trials. Minimal risk was defined as zero calcium score, no coronary atherosclerosis at coronary CTA, and no cardiovascular events in the follow-up period. We tested an updated MRT-model by pooling the fitted variable coefficients from all three trials. A total of 1544 patients fulfilling the inclusion criteria were followed for 3.1 [2.7-3.4] years. In 710 (46%) patients, the criteria for minimal risk were fulfilled. Despite substantial coefficient variation, the MRTs based on the PROMISE, the SCOT-HEART and the updated MRT variables showed similar moderate to high discriminative performance for minimal risk estimation. Although all three models tended to underestimate minimal risk, the updated MRT had the best performance. Using a 75% minimal risk cut-off, the updated MRT showed a sensitivity of 11.6% (95% CI 9.3-14.2%) and specificity of 99.3% (95% CI 98.6-99.8%). An updated MRT model based on three large studies increased calibration compared to the existing MRT models, whereas discrimination was similar despite substantial coefficient variation. The updated MRT might supplement currently recommended pre-test probability models.

Danish study of Non-Invasive testing in Coronary Artery Disease 2 (Dan-NICAD 2): Study design for a controlled study of diagnostic accuracy.

BACKGROUND: Coronary computed tomography angiography (CTA) is the preferred primary diagnostic modality when examining patients with low to intermediate pre-test probability of coronary artery disease (CAD). Only 20-30% of these have potentially obstructive CAD. Because of the relatively poor positive predictive value of coronary CTA, unnecessary invasive coronary angiographies (ICAs) are conducted with the costs and risks associated with the procedure. Hence, an optimized diagnostic CAD algorithm may reduce the numbers of ICAs not followed by revascularization. The Dan-NICAD 2 study has 3 equivalent main aims: (1) To examine the diagnostic precision of a sound-based diagnostic algorithm, The CADScor®System (Acarix A/S, Denmark), in patients with a low to intermediate pre-test risk of CAD referred to a primary examination by coronary CTA. We hypothesize that the CADScor®System provides better stratification prior to coronary CTA than clinical risk stratification scores alone. (2) To compare the diagnostic accuracy of 3T cardiac magnetic resonance imaging (3T CMRI), 82rubidium positron emission tomography (82Rb-PET), and CT-derived fractional flow reserve (FFRCT) in patients where obstructive CAD cannot be ruled out by coronary CTA using ICA fractional flow reserve (FFR) as reference standard. (3) To compare the diagnostic performance of quantitative flow ratio (QFR) and ICA-FFR in patients with low to intermediate pre-test probability of CAD using 82Rb-PET as reference standard. METHODS: Dan-NICAD 2 is a prospective, multicenter, cross-sectional study including approximately 2,000 patients with low to intermediate pre-test probability of CAD and without previous history of CAD. Patients are referred to coronary CTA because of symptoms suggestive of CAD, as evaluated by a cardiologist. Patient interviews, sound recordings, and blood samples are obtained in connection with the coronary CTA. If coronary CTA does not rule out obstructive CAD, patients will be examined by 3T CMRI 82Rb-PET, FFRCT, ICA, and FFR. Reference standard is ICA-FFR. Obstructive CAD is defined as an FFR ≤0.80 or as high-grade stenosis (>90% diameter stenosis) by visual assessment. Diagnostic performance will be evaluated as sensitivity, specificity, predictive values, likelihood ratios, calibration, and discrimination. Enrolment started January 2018 and is expected to be completed by June 2020. Patients are followed for 10 years after inclusion. DISCUSSION: The results of the Dan-NICAD 2 study are expected to contribute to the improvement of diagnostic strategies for patients suspected of CAD in 3 different steps: risk stratification prior to coronary CTA, diagnostic strategy after coronary CTA, and invasive wireless QFR analysis as an alternative to ICA-FFR.

Pre-test probability prediction in patients with a low to intermediate probability of coronary artery disease: a prospective study with a fractional flow reserve endpoint.

AIMS: European and North American guidelines currently recommend pre-test probability (PTP) stratification based on simple probability models in patients with suspected coronary artery disease (CAD). However, no unequivocal recommendation has yet been established. We aimed to compare the ability of risk factors and different PTP stratification models to predict haemodynamically obstructive CAD with fractional flow reserve (FFR) as reference in low to intermediate probability patients. METHODS AND RESULTS: We prospectively included 1675 patients with low to intermediate risk who had been referred to coronary computed tomography angiography (CTA). Patients with coronary stenosis were subsequently investigated by invasive coronary angiography (ICA) with FFR measurement if indicated. Discrimination and calibration were assessed for four models: the updated Diamond-Forrester (UDF), the CAD Consortium Basic, the Clinical, and the Clinical + Coronary artery calcium score (CACS). At coronary CTA, 24% of patients were diagnosed with a suspected stenosis and 10% had haemodynamically obstructive CAD at the ICA. Calibration for all CAD Consortium models increased compared with the UDF score. However, all models overestimated the probability of haemodynamically obstructive CAD. Discrimination increased by area under the receiver operating curve from 67% to 86% for UDF vs. CAD Consortium Clinical + CACS. The proportion of low-probability patients (pre-test score < 15%) was for the UDF, CAD Consortium Basic, Clinical, and Clinical + CACS: 14%, 58%, 51%, and 66%, respectively. The corresponding negative predictive values were 97%, 94%, 95%, and 98%, respectively. CONCLUSION: CAD Consortium models improve PTP stratification compared with the UDF score, mainly due to superior calibration in low to intermediate probability patients. Adding the coronary calcium score to the models substantially increases discrimination. CLINICAL TRIALS. GOV IDENTIFIER: NCT02264717.

Diagnostic performance of an acoustic-based system for coronary artery disease risk stratification.

OBJECTIVE: Diagnosing coronary artery disease (CAD) continues to require substantial healthcare resources. Acoustic analysis of transcutaneous heart sounds of cardiac movement and intracoronary turbulence due to obstructive coronary disease could potentially change this. The aim of this study was thus to test the diagnostic accuracy of a new portable acoustic device for detection of CAD. METHODS: We included 1675 patients consecutively with low to intermediate likelihood of CAD who had been referred for cardiac CT angiography. If significant obstruction was suspected in any coronary segment, patients were referred to invasive angiography and fractional flow reserve (FFR) assessment. Heart sound analysis was performed in all patients. A predefined acoustic CAD-score algorithm was evaluated; subsequently, we developed and validated an updated CAD-score algorithm that included both acoustic features and clinical risk factors. Low risk is indicated by a CAD-score value ≤20. RESULTS: Haemodynamically significant CAD assessed from FFR was present in 145 (10.0%) patients. In the entire cohort, the predefined CAD-score had a sensitivity of 63% and a specificity of 44%. In total, 50% had an updated CAD-score value ≤20. At this cut-off, sensitivity was 81% (95% CI 73% to 87%), specificity 53% (95% CI 50% to 56%), positive predictive value 16% (95% CI 13% to 18%) and negative predictive value 96% (95% CI 95% to 98%) for diagnosing haemodynamically significant CAD. CONCLUSION: Sound-based detection of CAD enables risk stratification superior to clinical risk scores. With a negative predictive value of 96%, this new acoustic rule-out system could potentially supplement clinical assessment to guide decisions on the need for further diagnostic investigation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02264717; Results.

Danish study of Non-Invasive testing in Coronary Artery Disease (Dan-NICAD): study protocol for a randomised controlled trial.

BACKGROUND: Coronary computed tomography angiography (CCTA) is an established method for ruling out coronary artery disease (CAD). Most patients referred for CCTA do not have CAD and only approximately 20-30 % of patients are subsequently referred to further testing by invasive coronary angiography (ICA) or non-invasive perfusion evaluation due to suspected obstructive CAD. In cases with severe calcifications, a discrepancy between CCTA and ICA often occurs, leading to the well-described, low-diagnostic specificity of CCTA. As ICA is cost consuming and involves a risk of complications, an optimized algorithm would be valuable and could decrease the number of ICAs that do not lead to revascularization. The primary objective of the Dan-NICAD study is to determine the diagnostic accuracy of cardiac magnetic resonance imaging (CMRI) and myocardial perfusion scintigraphy (MPS) as secondary tests after a primary CCTA where CAD could not be ruled out. The secondary objective includes an evaluation of the diagnostic precision of an acoustic technology that analyses the sound of coronary blood flow. It may potentially provide better stratification prior to CCTA than clinical risk stratification scores alone. METHODS/DESIGN: Dan-NICAD is a multi-centre, randomised, cross-sectional trial, which will include approximately 2,000 patients without known CAD, who were referred to CCTA due to a history of symptoms suggestive of CAD and a low-risk to intermediate-risk profile, as evaluated by a cardiologist. Patient interview, sound recordings, and blood samples are obtained in connection with the CCTA. All patients with suspected obstructive CAD by CCTA are randomised to either stress CMRI or stress MPS, followed by ICA with fractional flow reserve (FFR) measurements. Obstructive CAD is defined as an FFR below 0.80 or as high-grade stenosis (>90 % diameter stenosis) by visual assessment. Diagnostic performance is evaluated as sensitivity, specificity, predictive values, likelihood ratios, and C statistics. Enrolment commenced in September 2014 and is expected to be complete in May 2016. DISCUSSION: Dan-NICAD is designed to assess whether a secondary perfusion examination after CCTA could safely reduce the number of ICAs where revascularization is not required. The results are expected to add knowledge about the optimal algorithm for diagnosing CAD. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02264717 . Registered on 26 September 2014.

The Western Denmark Cardiac Computed Tomography Registry: a review and validation study.

BACKGROUND: As a subregistry to the Western Denmark Heart Registry (WDHR), the Western Denmark Cardiac Computed Tomography Registry (WDHR-CCTR) is a clinical database established in 2008 to monitor and improve the quality of cardiac computed tomography (CT) in Western Denmark. OBJECTIVE: We examined the content, data quality, and research potential of the WDHR-CCTR. METHODS: We retrieved 2008-2012 data to examine the 1) content; 2) completeness of procedure registration using the Danish National Patient Registry as reference; 3) completeness of variable registration comparing observed vs expected numbers; and 4) positive predictive values as well as negative predictive values of 19 main patient and procedure variables. RESULTS: By December 31, 2012, almost 22,000 cardiac CTs with up to 40 variables for each procedure have been registered. Of these, 87% were coronary CT angiography performed in patients with symptoms indicative of coronary artery disease. Compared with the Danish National Patient Registry, the overall procedure completeness was 72%. However, an additional medical record review of 282 patients registered in the Danish National Patient Registry, but not in the WDHR-CCTR, showed that coronary CT angiographies accounted for only 23% of all nonregistered cardiac CTs, indicating >90% completeness of coronary CT angiographies in the WDHR-CCTR. The completeness of individual variables varied substantially (range: 0%-100%), but was >85% for more than 70% of all variables. Using medical record review of 250 randomly selected patients as reference standard, the positive predictive value for the 19 variables ranged from 89% to 100% (overall 97%), whereas the negative predictive value ranged from 97% to 100% (overall 99%). Stratification by center status showed consistently high positive and negative predictive values for both university (96%/99%) and nonuniversity centers (97%/99%). CONCLUSION: WDHR-CCTR provides ongoing prospective registration of all cardiac CTs performed in Western Denmark since 2008. Overall, the registry data have a high degree of completeness and validity, making it a valuable tool for clinical epidemiological research.