Optimal diagnostic approach for using CT-derived quantitative flow ratio in patients with stenosis on coronary computed tomography angiography.

BACKGROUND: Coronary computed tomography angiography (CCTA)-derived quantitative flow ratio (CT-QFR) is an on-site non-invasive technique estimating invasive fractional flow reserve (FFR). This study assesses the diagnostic performance of using most distal CT-QFR versus lesion-specific CT-QFR approach for identifying hemodynamically obstructive coronary artery disease (CAD). METHODS: Prospectively enrolled de novo chest pain patients (n â€‹= â€‹445) with ≥50 â€‹% visual diameter stenosis on CCTA were referred for invasive evaluation. On-site CT-QFR was analyzed post-hoc blinded to angiographic data and obtained as both most distal (MD-QFR) and lesion-specific CT-QFR (LS-QFR). Abnormal CT-QFR was defined as ≤0.80. Hemodynamically obstructive CAD was defined as invasive FFR ≤0.80 or ≥70 â€‹% diameter stenosis by 3D-quantitative coronary angiography. RESULTS: In total 404/445 patients had paired CT-QFR and invasive analyses of whom 149/404 (37 â€‹%) had hemodynamically obstructive CAD. MD-QFR and LS-QFR classified 188 (47 â€‹%) and 165 (41 â€‹%) patients as abnormal, respectively. Areas under the receiver-operating characteristic curve for MD-QFR was 0.83 vs. 0.85 for LS-QFR, p â€‹= â€‹0.01. Sensitivities for MD-QFR and LS-QFR were 80 â€‹% (95%CI: 73-86) vs. 77 â€‹% (95%CI: 69-83), p â€‹= â€‹0.03, respectively, and specificities were 73 â€‹% (95%CI: 67-78) vs. 80 â€‹% (95%CI: 75-85), p â€‹< â€‹0.01, respectively. Positive predictive values for MD-QFR and LS-QFR were 63 â€‹% vs. 69 â€‹%, p â€‹< â€‹0.01, respectively, and negative predictive values for MD-QFR and LS-QFR were 86 â€‹% vs. 85 â€‹%, p â€‹= â€‹0.39, respectively). CONCLUSION: Using a lesion-specific CT-QFR approach has superior discrimination of hemodynamically obstructive CAD compared to a most distal CT-QFR approach. CT-QFR identified most cases of hemodynamically obstructive CAD while a normal CT-QFR excluded hemodynamically obstructive CAD in the majority of patients.

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.

Instantaneous wave free ratio vs. fractional flow reserve and 5-year mortality: iFR SWEDEHEART and DEFINE FLAIR.

BACKGROUND AND AIMS: Guidelines recommend revascularization of intermediate epicardial artery stenosis to be guided by evidence of ischaemia. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are equally recommended. Individual 5-year results of two major randomized trials comparing FFR with iFR-guided revascularization suggested increased all-cause mortality following iFR-guided revascularization. The aim of this study was a study-level meta-analysis of the 5-year outcome data in iFR-SWEDEHEART (NCT02166736) and DEFINE-FLAIR (NCT02053038). METHODS: Composite of major adverse cardiovascular events (MACE) and its individual components [all-cause death, myocardial infarction (MI), and unplanned revascularisation] were analysed. Raw Kaplan-Meier estimates, numbers at risk, and number of events were extracted at 5-year follow-up and analysed using the ipdfc package (Stata version 18, StataCorp, College Station, TX, USA). RESULTS: In total, iFR and FFR-guided revascularization was performed in 2254 and 2257 patients, respectively. Revascularization was more often deferred in the iFR group [n = 1128 (50.0%)] vs. the FFR group [n = 1021 (45.2%); P = .001]. In the iFR-guided group, the number of deaths, MACE, unplanned revascularization, and MI was 188 (8.3%), 484 (21.5%), 235 (10.4%), and 123 (5.5%) vs. 143 (6.3%), 420 (18.6%), 241 (10.7%), and 123 (5.4%) in the FFR group. Hazard ratio [95% confidence interval (CI)] estimates for MACE were 1.18 [1.04; 1.34], all-cause mortality 1.34 [1.08; 1.67], unplanned revascularization 0.99 [0.83; 1.19], and MI 1.02 [0.80; 1.32]. CONCLUSIONS: Five-year all-cause mortality and MACE rates were increased with revascularization guided by iFR compared to FFR. Rates of unplanned revascularization and MI were equal in the two groups.

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.

Coronary Artery Stenosis Evaluation by Angiography-Derived FFR: Validation by Positron Emission Tomography and Invasive Thermodilution.

BACKGROUND: Fractional flow reserve (FFR) derived from invasive coronary angiography (QFR) is promising for evaluation of intermediate coronary artery stenosis. OBJECTIVES: The authors aimed to compare the diagnostic performance of QFR and the guideline-recommended invasive FFR using 82Rubidium positron emission tomography (82Rb-PET) myocardial perfusion imaging as reference standard. METHODS: This is a prospective, observational study of symptomatic patients with suspected obstructive coronary artery disease on coronary computed tomography angiography (≥50% diameter stenosis in ≥1 vessel). All patients were referred to 82Rb-PET and invasive coronary angiography with FFR and QFR assessment of all intermediate (30%-90% diameter stenosis) stenoses. Main analyses included a comparison of the ability of QFR and FFR to identify reduced myocardial blood flow (<2 mL/g/min) during vasodilation and/or relative perfusion abnormalities (summed stress score ≥4 in ≥2 adjacent segments). RESULTS: A total of 250 patients (320 vessels) with indication for invasive physiological assessment were included. The continuous relationship of 82Rb-PET stress myocardial blood flow per 0.10 increase in FFR was +0.14 mL/g/min (95% CI: 0.07-0.21 mL/g/min) and +0.08 mL/g/min (95% CI: 0.02-0.14 mL/g/min) per 0.10 QFR increase. Using 82Rb-PET as reference, QFR and FFR had similar diagnostic performance on both a per-patient level (accuracy: 73%; 95% CI: 67%-79%; vs accuracy: 71%; 95% CI: 64%-78%) and per-vessel level (accuracy: 70%; 95% CI: 64%-75%; vs accuracy: 68%; 95% CI: 62%-73%). The per-vessel feasibility was 84% (95% CI: 80%-88%) for QFR and 88% (95% CI: 85%-92%) for FFR by intention-to-diagnose analysis. CONCLUSIONS: With 82Rb-PET as reference modality, the wire-free QFR solution showed similar diagnostic accuracy as invasive FFR in evaluation of intermediate coronary stenosis. (DAN-NICAD - Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease; NCT02264717).

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).

Likelihood reclassification by an acoustic-based score in suspected coronary artery disease.

OBJECTIVE: Validation studies of the 2019 European Society of Cardiology pretest probability model (ESC-PTP) for coronary artery disease (CAD) report that 35%-40% of patients have low pretest probability (ESC-PTP 5% to <15%). Acoustic detection of coronary stenoses could potentially improve clinical likelihood stratification. Aims were to (1) investigate the diagnostic performance of an acoustic-based CAD score and (2) study the reclassification potential of a dual likelihood strategy by the ESC-PTP and a CAD score. METHODS: Consecutive patients (n=1683) with stable angina symptoms referred for coronary CT angiography (CTA) underwent heart sound analyses by an acoustic CAD-score device. All patients with ≥50% luminal stenosis in any coronary segment at coronary CTA were referred to investigation with invasive coronary angiography (ICA) with fractional flow reserve (FFR).A predefined CAD-score cut-off ≤20 was used to rule out obstructive CAD. RESULTS: In total, 439 patients (26%) had ≥50% luminal stenosis on coronary CTA. The subsequent ICA with FFR showed obstructive CAD in 199 patients (11.8%). Using the ≤20 CAD-score cut-off for obstructive CAD rule-out, sensitivity was 85.4% (95% CI 79.7 to 90.0), specificity 40.4% (95% CI 37.9 to 42.9), positive predictive value 16.1% (95% CI 13.9 to 18.5) and negative predictive value 95.4% (95% CI 93.4 to 96.9) in all patients. Applying the cut-off in ESC-PTP 5% to <15% patients, 316 patients (48%) were down-classified to very-low likelihood. The obstructive CAD prevalence was 3.5% in this group. CONCLUSION: In a large contemporary cohort of patients with low CAD likelihood, the additional use of an acoustic rule-out device showed a clear potential to downgrade likelihood and could supplement current strategies for likelihood assessment to avoid unnecessary testing. TRIAL REGISTRATION NUMBER: NCT03481712.

Diagnostic accuracy of optical flow ratio: an individual patient-data meta-analysis.

BACKGROUND: Optical flow ratio (OFR) is a novel method for the fast computation of fractional flow reserve (FFR) from optical coherence tomography. AIMS: We aimed to evaluate the diagnostic accuracy of OFR in assessing intermediate coronary stenosis using wire-based FFR as the reference. METHODS: We performed an individual patient-level meta-analysis of all available studies with paired OFR and FFR assessments. The primary outcome was vessel-level diagnostic concordance of the OFR and FFR, using a cut-off of ≤0.80 to define ischaemia and ≤0.90 to define suboptimal post-percutaneous coronary intervention (PCI) physiology. This meta-analysis was registered in PROSPERO (CRD42021287726). RESULTS: Five studies were finally included, providing 574 patients and 626 vessels (404 pre-PCI and 222 post-PCI) with paired OFR and FFR from 9 international centres. Vessel-level diagnostic concordance of the OFR and FFR was 91% (95% confidence interval [CI]: 88%-94%), 87% (95% CI: 82%-91%), and 90% (95% CI: 87%-92%) in pre-PCI, post-PCI, and overall, respectively. The overall sensitivity, specificity, and positive and negative predictive values were 84% (95% CI: 79%-88%), 94% (95% CI: 92%-96%), 90% (95% CI: 86%-93%), and 89% (95% CI: 86%-92%), respectively. Multivariate logistic regression indicated that a low pullback speed (odds ratio [OR] 7.02, 95% CI: 1.68-29.43; p=0.008) was associated with a higher risk of obtaining OFR values at least 0.10 higher than FFR. Increasing the minimal lumen area was associated with a lower risk of obtaining an OFR at least 0.10 lower than FFR (OR 0.39, 95% CI: 0.18-0.82; p=0.013). CONCLUSIONS: This individual patient data meta-analysis demonstrated a high diagnostic accuracy of OFR. OFR has the potential to provide an improved integration of intracoronary imaging and physiological assessment for the accurate evaluation of coronary artery disease.

Quantitative flow ratio versus fractional flow reserve for guiding percutaneous coronary intervention: design and rationale of the randomised FAVOR III Europe Japan trial.

Quantitative flow ratio (QFR) is a computation of fractional flow reserve (FFR) based on invasive coronary angiographic images. Calculating QFR is less invasive than measuring FFR and may be associated with lower costs. Current evidence supports the call for an adequately powered randomised comparison of QFR and FFR for the evaluation of intermediate coronary stenosis. The aim of the FAVOR III Europe Japan trial is to investigate if a QFR-based diagnostic strategy yields a non-inferior 12-month clinical outcome compared with a standard FFR-guided strategy in the evaluation of patients with intermediary coronary stenosis. FAVOR III Europe Japan is an investigator-initiated, randomised, clinical outcome, non-inferiority trial scheduled to randomise 2,000 patients with either 1) stable angina pectoris and intermediate coronary stenosis, or 2) indications for functional assessment of at least 1 non-culprit lesion after acute myocardial infarction. Up to 40 international centres will randomise patients to either a QFR-based or a standard FFR-based diagnostic strategy. The primary endpoint of major adverse cardiovascular events is a composite of all-cause mortality, any myocardial infarction, and any unplanned coronary revascularisation at 12 months. QFR could emerge as an adenosine- and wire-free alternative to FFR, making the functional evaluation of intermediary coronary stenosis less invasive and more cost-effective.

Predictive value of post-percutaneous coronary intervention fractional flow reserve: a systematic review and meta-analysis.

AIMS: We aimed to investigate the relationship between post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) and clinical outcome using a systematic review with a study-level meta-analysis. METHODS AND RESULTS: MEDLINE, Embase, and CENTRAL were systematically searched for articles with clinical follow-up reporting mean or median final post-PCI FFR. The main outcome was a composite of major adverse cardiac events (MACE) including all-cause death, myocardial infarction (MI), and target vessel revascularization (TVR). Meta-regression analyses were performed on mean post-PCI FFR values. A total of 62 studies with 12 340 patients and 12 923 stented vessels were included, with follow-ups ranging from 1 to 89 months. Post-PCI FFR was not continuously associated with the rate of 1-year MACE or 1-year TVR using meta-regression models accounting for heterogeneous follow-up lengths. For studies comparing high vs. low post-PCI FFR, low post-PCI FFR was associated with high risk ratio for MACE {1.97 [95% confidence interval (CI):1.45-2.67]}, all-cause death [1.59 (95% CI: 1.08-2.34)], MI [3.18 (95% CI: 1.84-5.50)], TVR [2.08 (95% CI: 1.63-2.65)] and angina status [2.50 (95% CI: 1.53-4.06)] using different optimal cut-off values spanning from 0.80 to 0.95. CONCLUSION: We found no clear continuous association between post-PCI FFR and clinical outcomes in this systematic study-level meta-analysis. In a subset of studies investigating binary classification, high post-PCI FFR was associated with a better clinical outcome than low post-PCI FFR.We investigated the relationship between post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) and rate of major adverse cardiac events (MACE), including all-cause death, myocardial infarction (MI), and target vessel revascularization (TVR), using a systematic review and study-level meta-analysis, pooling 12 340 patients from 62 studies. Mean post-PCI FFR was not continuously associated with a 1-year MACE rate accounting for heterogenous follow-up lengths. Still, the risk ratio favoured high post-PCI FFR for reduced MACE, all-cause death, MI, TVR, and better angina status using different cut-offs.

Three-Dimensional Angiographic Characteristics versus Functional Stenosis Severity in Fractional and Coronary Flow Reserve Discordance: A DEFINE FLOW Sub Study.

BACKGROUND: Coronary angiography alone is insufficient to identify lesions associated with myocardial ischemia that may benefit from revascularization. Coronary physiology parameters may improve clinical decision making in addition to coronary angiography, but the association between 2D and 3D qualitative coronary angiography (QCA) and invasive pressure and flow measurements is yet to be elucidated. METHODS: We associated invasive fractional flow reserve (FFR), coronary flow reserve (CFR) and coronary flow capacity (CFC) with 2D- and 3D-QCA in 430 intermediate lesions of 366 patients. RESULTS: Overall, 2D-QCA analysis resulted in less severe stenosis severity compared with 3D-QCA analysis. FFR+/CFR- lesions had similar 3D-QCA characteristics as FFR+/CFR+ lesions. In contrast, vessels with FFR-/CFR+ discordance had 3D-QCA characteristics similar to those of vessels with concordant FFR-/CFR-. Contrarily, FFR+/CFR- lesions had CFC similar to that of as FFR-/CFR- lesions. CONCLUSIONS: Non-flow-limiting lesions (FFR+/CFR-) have 3D-QCA characteristics similar to those of FFR+/CFR+, but the majority are not associated with inducible myocardial ischemia as determined by invasive CFC. FFR-/CFR+ lesions have 3D-QCA characteristics similar to those of FFR-/CFR- lesions but are more frequently associated with a moderately to severely reduced CFC, illustrating the angiographic-functional mismatch in discordant lesions.

Impact of coronary plaque morphology on the precision of computational fractional flow reserve derived from optical coherence tomography imaging.

Background: Computational fractional flow reserve (FFR) was recently developed to expand the use of physiology-guided percutaneous coronary intervention (PCI). Nevertheless, current methods do not account for plaque composition. It remains unknown whether the numerical precision of computational FFR is impacted by the plaque composition in the interrogated vessels. Methods: This study is an observational, retrospective, cross-sectional study. Patients who underwent both optical coherence tomography (OCT) and FFR prior to intervention between August 2011 and October 2018 at Wakayama Medical University Hospital were included. All frames from OCT pullbacks were analyzed using a deep learning algorithm to obtain coronary plaque morphology including thin-cap fibroatheroma (TCFA), lipidic plaque volume (LPV), fibrous plaque volume (FPV), and calcific plaque volume (CPV). The interrogated vessels were stratified into three subgroups: the overestimation group with the numerical difference between the optical flow ratio (OFR) and FFR >0.05, the reference group with the difference ≥-0.05 and ≤0.05, and the underestimation group with the difference <-0.05. Results: In total 230 vessels with intermediate coronary artery stenosis from 193 patients were analyzed. The mean FFR was 0.82±0.10. Among them, 21, 179, and 30 vessels were in the overestimation, the reference, and the underestimation group, respectively. TCFA was higher in the underestimation group (60%) compared with reference (36.3%) and overestimation group (19%). Besides, it was not associated with numerical difference between OFR and FFR (NDOF) after multilevel linear regression. LPV was associated with NDOF as OFR underestimated FFR with -0.028 [95% confidence interval (CI): -0.047, -0.009] for every 100 mm3 increase in LPV. Conclusions: High lipid burden underestimates FFR when OFR is used to assess the hemodynamic importance of intermediate coronary artery stenosis. TCFA, FPV, and CPV were not independent predictors of NDOF.

Prognostic value of microvascular resistance and its association to fractional flow reserve: a DEFINE-FLOW substudy.

OBJECTIVE: This study aimed to evaluate the prognostic value of hyperemic microvascular resistance (HMR) and its relationship with hyperemic stenosis resistance (HSR) index and fractional flow reserve (FFR) in stable coronary artery disease. METHODS: This is a substudy of the DEFINE-FLOW cohort (NCT02328820), which evaluated the prognosis of lesions (n=456) after combined FFR and coronary flow reserve (CFR) assessment in a prospective, non-blinded, non-randomised, multicentre study in 12 centres in Europe and Japan. Participants (n=430) were evaluated by wire-based measurement of coronary pressure, flow and vascular resistance (ComboWire XT, Phillips Volcano, San Diego, California, USA). RESULTS: Mean FFR and CFR were 0.82±0.10 and 2.2±0.6, respectively. When divided according to FFR and CFR thresholds (above and below 0.80 and 2.0, respectively), HMR was highest in lesions with FFR>0.80 and CFR<2.0 (n=99) compared with lesions with FFR≤0.80 and CFR≥2.0 (n=68) (2.92±1.2 vs 1.91±0.64 mm Hg/cm/s, p<0.001). The FFR value was proportional to the ratio between HMR and the HMR+HSR (total resistance), 95% limits of agreement (-0.032; 0.019), bias (-0.003±0.02) and correlation (r2=0.98, p<0.0001). Cox regression model using HMR as continuous parameter for target vessel failure showed an HR of 1.51, 95% CI (0.9 to 2.4), p=0.10. CONCLUSIONS: Increased HMR was not associated with a higher rate of adverse clinical events, in this population of mainly stable patients. FFR can be equally well expressed as HMR/HMR+HSR, thereby providing an alternative conceptual formulation linking epicardial severity with microvascular resistance. TRIAL REGISTRATION NUMBER: NCT02328820.

Characterization of quantitative flow ratio and fractional flow reserve discordance using doppler flow and clinical follow-up.

The physiological mechanisms of quantitative flow ratio and fractional flow reserve disagreement are not fully understood. We aimed to characterize the coronary flow and resistance profile of intermediate stenosed epicardial coronary arteries with concordant and discordant FFR and QFR. Post-hoc analysis of the DEFINE-FLOW study. Anatomical and Doppler-derived physiological parameters were compared for lesions with FFR+QFR- (n = 18) vs. FFR+QFR+ (n = 43) and for FFR-QFR+ (n = 34) vs. FFR-QFR- (n = 139). The association of QFR results with the two-year rate of target vessel failure was assessed in the proportion of vessels (n = 195) that did not undergo revascularization. Coronary flow reserve was higher [2.3 (IQR: 2.1-2.7) vs. 1.9 (IQR: 1.5-2.4)], hyperemic microvascular resistance lower [1.72 (IQR: 1.48-2.31) vs. 2.26 (IQR: 1.79-2.87)] and anatomical lesion severity less severe [% diameter stenosis 45.5 (IQR: 41.5-52.5) vs. 58.5 (IQR: 53.1-64.0)] for FFR+QFR- lesions compared with FFR+QFR+ lesions. In comparison of FFR-QFR+ vs. FFR-QFR- lesions, lesion severity was more severe [% diameter stenosis 55.2 (IQR: 51.7-61.3) vs. 43.4 (IQR: 35.0-50.6)] while coronary flow reserve [2.2 (IQR: 1.9-2.9) vs. 2.2 (IQR: 1.9-2.6)] and hyperemic microvascular resistance [2.34 (IQR: 1.85-2.81) vs. 2.57 (IQR: 2.01-3.22)] did not differ. The agreement and diagnostic performance of FFR using hyperemic stenosis resistance (> 0.80) as reference standard was higher compared with QFR and coronary flow reserve. Disagreement between FFR and QFR is partly explained by physiological and anatomical factors. Clinical Trials Registration https://www.clinicaltrials.gov ; Unique identifier: NCT01813435. Changes in central physiological and anatomical parameters according to FFR and QFR match/mismatch quadrants.

Reproducibility of quantitative flow ratio: the QREP study.

BACKGROUND: Quantitative flow ratio (QFR) is a tool for physiological lesion assessment based on invasive coronary angiography. AIMS: We aimed to assess the reproducibility of QFR computed from the same angiograms as assessed by multiple observers from different, international sites. METHODS: We included 50 patients previously enrolled in dedicated QFR studies. QFR was computed twice, one month apart by five blinded observers. The main analysis was the coefficient of variation (CV) as a measure of intra- and inter-observer reproducibility. Key secondary analysis was the identification of clinical and procedural characteristics predicting reproducibility. RESULTS: The intra-observer CV ranged from 2.3% (1.5-2.8) to 10.2% (6.6-12.0) among the observers. The inter-observer CV was 9.4% (8.0-10.5). The QFR observer, low angiographic quality, and low fractional flow reserve (FFR) were independent predictors of a large absolute difference between repeated QFR measurements defined as a difference larger than the median difference (>0.03). CONCLUSIONS: The inter- and intra-observer reproducibility for QFR computed from the same angiograms ranged from high to poor among multiple observers from different sites with an average agreement of 0.01±0.08 for repeated measurements. The reproducibility was dependent on the observer, angiographic quality and the coronary artery stenosis severity as assessed by FFR.

Performance of quantitative flow ratio in patients with aortic stenosis undergoing transcatheter aortic valve implantation.

OBJECTIVES: This study aims to evaluate the diagnostic performance of quantitative flow ratio (QFR) pre transcatheter aortic valve implantation (TAVI) in patients with aortic valve stenosis (AS) and coronary artery disease (CAD). Post-TAVI fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) was used as reference. BACKGROUND: CAD is prevalent in patients with AS, but the hemodynamics of AS confounds evaluation using pressure wire-based assessments. QFR might be less sensitive to the presence of AS thereby allowing for CAD evaluation before aortic valve replacement. Further, QFR does not require the use of pressure wire and therefore has the potential for reducing costs and complications related to insertion of a coronary pressure wire. METHODS: The diagnostic performance of QFR in coronary angiograms from 28 patients undergoing TAVI was evaluated. In all patients, both FFR and iFR were measured pre- and immediately post-TAVI while QFR was measured pre-TAVI. RESULTS: Using post-TAVI FFR and iFR as reference the diagnostic accuracy of pre-TAVI QFR were 83% (95%CI; 68-97) and 52% (95%CI; 30-74) p = .008, respectively. CONCLUSIONS: Pre-TAVI QFR showed a good diagnostic performance using post-TAVI FFR as reference. QFR could become a wire-free, safe, and quick way of evaluating CAD in patients with severe AS undergoing TAVI.

Polygenic Risk Score-Enhanced Risk Stratification of Coronary Artery Disease in Patients With Stable Chest Pain.

BACKGROUND: Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography on a suspicion of obstructive CAD. METHODS: In this prespecified diagnostic substudy of the Dan-NICAD trial (Danish study of Non-Invasive testing in Coronary Artery Disease), we included 1617 consecutive patients with stable chest symptoms and no history of CAD referred for coronary computed tomography angiography. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped, and their PRSs were calculated. All patients underwent coronary computed tomography angiography. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography with fractional flow reserve. A combined end point of obstructive CAD was defined as a visual invasive coronary angiography stenosis >90%, fractional flow reserve <0.80, or a quantitative coronary analysis stenosis >50% if fractional flow reserve measurements were not feasible. RESULTS: The PRS was associated with obstructive CAD independent of CRFs (adjusted odds ratio, 1.8 [95% CI, 1.5-2.2] per SD). The PRS had an area under the curve of 0.63 (0.59-0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with area under the curve of 0.75 (0.71-0.79), which was 0.04 more than the CRF model (P=0.0029). By using pretest probability (pretest probability) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1×10-4) was obtained, with a down-classification of risk in 24% of patients (211 of 862) in whom the pretest probability was 5% to 15% based on CRFs alone. CONCLUSIONS: Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02264717.

Immediate post-procedural functional assessment of percutaneous coronary intervention: current evidence and future directions.

Percutaneous coronary intervention (PCI) guided by coronary physiology provides symptomatic benefit and improves patient outcomes. Nevertheless, over one-fourth of patients still experience recurrent angina or major adverse cardiac events following the index procedure. Coronary angiography, the current workhorse for evaluating PCI efficacy, has limited ability to identify suboptimal PCI results. Accumulating evidence supports the usefulness of immediate post-procedural functional assessment. This review discusses the incidence and possible mechanisms behind a suboptimal physiology immediately after PCI. Furthermore, we summarize the current evidence base supporting the usefulness of immediate post-PCI functional assessment for evaluating PCI effectiveness, guiding PCI optimization, and predicting clinical outcomes. Multiple observational studies and post hoc analyses of datasets from randomized trials demonstrated that higher post-PCI functional results are associated with better clinical outcomes as well as a reduced rate of residual angina and repeat revascularization. As such, post-PCI functional assessment is anticipated to impact patient management, secondary prevention, and resource utilization. Pre-PCI physiological guidance has been shown to improve clinical outcomes and reduce health care costs. Whether similar benefits can be achieved using post-PCI physiological assessment requires evaluation in randomized clinical outcome trials.

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.