Recovery of platelet reactivity following cessation of either aspirin or ticagrelor in patients treated with dual antiplatelet therapy following percutaneous coronary intervention: a GLOBAL LEADERS substudy.

Cessation of one component of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has been associated with increased risk of ischemic events but it is uncertain whether discontinuation of aspirin is preferable to discontinuation of the oral P2Y12 inhibitor. The GLOBAL LEADERS study compared two antiplatelet strategies following PCI, cessation of aspirin at 1 month with continued ticagrelor monotherapy for 23 months versus standard DAPT for 12 months followed by aspirin monotherapy for a further 12 months. We assessed recovery of platelet reactivity after withdrawal of either aspirin or ticagrelor at 1 month and 12 months, respectively, in this study. Platelet aggregation (PA) was assessed before cessation of DAPT ('baseline') and after 2, 7, and 14 days post-cessation using Multiplate whole-blood aggregometry with collagen, thrombin-receptor-activating peptide (TRAP), adenosine diphosphate (ADP) and arachidonic acid (AA) as agonists. Following cessation of aspirin at 1 month, there was marked recovery of PA induced by AA (baseline [mean ± SD]: 11.1 ± 7.4 U vs. 14 days: 64.9 ± 19.6 U, p < .0001) and collagen (37.4 ± 22.9 U vs. 79.8 ± 13.8 U, p < .0001), whereas PA induced by ADP (18.6 ± 6.6 vs. 69.1 ± 20.5, p < .0001) and collagen (34.4 ± 18.7 U vs. 43.0 ± 21.0, p = .0018) recovered following cessation of ticagrelor at 12 months. There were no significant changes in TRAP-induced PA in either group. In conclusion, cessation of either component of DAPT leads to substantial increase in platelet reactivity with differential effects on different pathways of platelet activation when aspirin or the P2Y12 inhibitor is stopped. Further work is required to determine which patients receive net benefit from long-term continuation of DAPT.

Diastolic pressure ratio: new approach and validation vs. the instantaneous wave-free ratio.

AIMS: The instantaneous wave-free ratio (iFR) and whole-cycle Pd/Pa investigate coronary physiology during non-hyperaemic conditions. To test for unique physiologic properties of the wave-free period when making resting coronary pressure measurements, we compared post hoc a diastolic pressure ratio (dPR) and Pd/Pa against iFR for numerical similarity and test/retest repeatability. METHODS AND RESULTS: Eight hundred and ninety-three lesions from 833 subjects were included from the VERIFY 2 and CONTRAST studies. Diastolic pressure ratio and a linear transform of Pd/Pa were compared against iFR for diagnostic performance. Mean difference between dPR and iFR [Δ = -0.006 ± 0.011, r2 = 0.993, area under receiver operating characteristic (ROC) curve (AUC) = 0.997] mirrored the difference of two iFR measurements repeated immediately (Δ = <0.001 ± 0.004, r2 = 0.998, AUC = 1.00). Minor variations in the definition of dPR changed its value by <1-2% over a broad range of the cardiac cycle. A linear transform of Pd/Pa showed very good diagnostic performance (Δ = -0.012 ± 0.031, r2 = 0.927, AUC = 0.979). Post hoc iFR values were validated against real-time iFR values and matched almost exactly (average Δ = <0.001 ± 0.004, 99.6% within ±0.01). CONCLUSIONS: Our dPR offers numerical equivalency to iFR. Despite different technical approaches for identifying the relevant period of diastole, the agreement between dPR and iFR and the insensitivity of dPR to minor variations in its definition further confirm numerical equivalency among resting metrics.

Predictive factors of discordance between the instantaneous wave-free ratio and fractional flow reserve.

OBJECTIVES: To identify clinical, angiographic and hemodynamic predictors of discordance between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR). BACKGROUND: The iFR was found to be non-inferior to the gold-standard FFR for guiding coronary revascularization, although it is discordant with FFR in 20% of cases. A better understanding of the causes of discordance may enhance application of these indices. METHODS: Both FFR and iFR were measured in the prospective multicenter CONTRAST study. Clinical, angiographic and hemodynamic variables were compared between patients with concordant values of FFR and iFR (cutoff ≤0.80 and ≤0.89, respectively). RESULTS: Out of the 587 patients included, in 466 patients (79.4%) FFR and iFR agreed: both negative, n = 244 (41.6%), or positive, n = 222 (37.8%). Compared with FFR, iFR was negative discordant (FFR+/iFR-) in 69 (11.8%) patients and positive discordant (FFR-/iFR+) in 52 (8.9%) patients. On multivariate regression, stenosis location (left main or proximal left anterior descending) (OR: 3.30[1.68;6.47]), more severe stenosis (OR: 1.77[1.35;2.30]), younger age (OR: 0.93[0.90;0.97]), and slower heart rate (OR: 0.59[0.42;0.75]) were predictors of a negative discordant iFR. Absence of a beta-blocker (OR: 0.41[0.22;0.78]), older age (OR: 1.04[1.00;1.07]), and less severe stenosis (OR: 0.69[0.53;0.89]) were predictors of a positive discordant iFR. CONCLUSIONS: During iFR acquisition, stenosis location, stenosis degree, heart rate, age and use of beta blockers influence concordance with FFR and should be taken into account when interpreting iFR.

Diabetes does not impact the diagnostic performance of contrast-based fractional flow reserve: insights from the CONTRAST study.

BACKGROUND: Adenosine-free coronary pressure wire metrics have been proposed to test the functional significance of coronary artery lesions, but it is unexplored whether their diagnostic performance might be altered in patients with diabetes. METHODS: We performed a post-hoc analysis of the CONTRAST study, which prospectively enrolled an international cohort of patients undergoing routine fractional flow reserve (FFR) assessment for standard indications. Paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, contrast-based FFR, and FFR) were made. A central core laboratory analyzed blinded pressure tracings in a standardized fashion. RESULTS: Of 763 subjects enrolled at 12 international centers, 219 (29%) had diabetes. The two groups were well-balanced for age, clinical presentation (stable or unstable), coronary vessel studied, volume and type of intracoronary contrast, and volume of intracoronary adenosine. A binary threshold of cFFR ≤ 0.83 produced an accuracy superior to both Pd/Pa and iFR when compared with FFR ≤ 0.80 in the absence of significant interaction with diabetes status; indeed, accuracy in subgroups of patients with or without diabetes was similar for cFFR (86.7 vs 85.4% respectively; p = 0.76), iFR (84.2 vs 80.0%, p = 0.29) and Pd/Pa (81.3 vs 78.9%, p = 0.55). There was no significant heterogeneity between patients with or without diabetes in terms of sensitivity and specificity of all metrics. The area under the receiver operating characteristic (ROC) curve was largest for cFFR compared with Pd/Pa and iFR which were equivalent (cFFR 0.961 and 0.928; Pd/Pa 0.916 and 0.870; iFR 0.911 and 0.861 in diabetic and non-diabetic patients respectively). CONCLUSIONS: cFFR provides superior diagnostic performance compared with Pd/Pa or iFR for predicting FFR irrespective of diabetes (clinicaltrials.gov identifier NCT02184117).

Fractional flow reserve-guided management in stable coronary disease and acute myocardial infarction: recent developments.

Coronary artery disease (CAD) is a leading global cause of morbidity and mortality, and improvements in the diagnosis and treatment of CAD can reduce the health and economic burden of this condition. Fractional flow reserve (FFR) is an evidence-based diagnostic test of the physiological significance of a coronary artery stenosis. Fractional flow reserve is a pressure-derived index of the maximal achievable myocardial blood flow in the presence of an epicardial coronary stenosis as a ratio to maximum achievable flow if that artery were normal. When compared with standard angiography-guided management, FFR disclosure is impactful on the decision for revascularization and clinical outcomes. In this article, we review recent developments with FFR in patients with stable CAD and recent myocardial infarction. Specifically, we review novel developments in our understanding of CAD pathophysiology, diagnostic applications, prognostic studies, clinical trials, and clinical guidelines.

Validation of a new non-hyperemic physiological index: the constant-resistance ratio (cRR).

OBJECTIVES: The instantaneous wave-free ratio (iwFR) has limited availability. A new resting index called the constant-resistance ratio (cRR), which dynamically identifies cardiac intervals with constant and minimum resistance, has been developed; however, its diagnostic performance is unknown. The aim of this study was to validate the cRR by retrospectively calculating the cRR values from raw pressure waveforms of 2 publicly available datasets and compare them with those of the iwFR. METHODS: Waveform data from the CONTRAST and VERIFY 2 studies were used. The primary endpoint was Bland-Altman bias between cRR and iwFR. Secondary endpoints included diagnostic agreement, correlation, receiver operating characteristic (ROC) analysis, and success rates of cRR and iwFR. RESULTS: Among the 1036 waveforms, 871 were successful in determining paired cRR and iwFR values, while cRR was 6% more successful than iwFR (P less than .0001). The mean bias between cRR and iwFR was 0.003, with 95% limits of agreement [-0.021,0.028]. These 2 indices were highly correlated (r = 0.991; P less than .0001). Using an iwFR of 0.89 or less as the reference standard, the optimal cRR cutoff was 0.89, with an area under the ROC curve of 0.991 (P less than .001) and a diagnostic accuracy of 96.9% (95% CI [96%, 98%]). CONCLUSIONS: The cRR, a new resting index for identifying dynamic cardiac intervals with constant and minimum resistance, demonstrated high numerical agreement, diagnostic consistency, and a higher success rate than the iwFR based on the 2 publicly available datasets.

Use of a Pressure Wire for Automatically Correcting Artifacts in Phasic Pressure Tracings From a Fluid-Filled Catheter.

BACKGROUND/PURPOSE: Matching phasic pressure tracings between a fluid-filled catheter and high-fidelity pressure wire has received limited attention, although each part contributes half of the information to clinical decisions. We aimed to study the impact of a novel and automated method for improving the phasic calibration of a fluid-filled catheter by accounting for its oscillatory behavior. METHODS/MATERIALS: Retrospective analysis of drift check tracings was performed using our algorithm that corrects for mean difference (offset), temporal delays (timing), differential sensitivity of the manifold transducer and pressure wire sensor (gain), and the oscillatory behavior of the fluid-filled catheter described by its resonant frequency and damping factor (how quickly oscillations disappear after a change in pressure). RESULTS: Among 2886 cases, correcting for oscillations showed a large improvement in 28 % and a medium improvement in 41 % (decrease in root mean square error >0.5 mmHg to <1 or 1-2 mmHg, respectively). 96 % of oscillators were underdamped with median damping factor 0.27 and frequency 10.6 Hz. Fractional flow reserve or baseline Pd/Pa demonstrated no clinically important bias when ignoring oscillations. However, uncorrected subcycle non-hyperemic pressure ratios (NHPR) displayed both bias and scatter. CONCLUSIONS: By automatically accounting for the oscillatory behavior of a fluid-filled catheter system, phasic matching against a high-fidelity pressure wire can be improved compared to standard equalization methods. The majority of tracings contain artifacts, mainly due to underdamped oscillations, and neglecting them leads to biased estimates of equalization parameters. No clinically important bias exists for whole-cycle metrics, in contrast to significant effects on subcycle NHPR.

Deep learning for prediction of fractional flow reserve from resting coronary pressure curves.

BACKGROUND: It would be ideal for a non-hyperaemic index to predict fractional flow reserve (FFR) more accurately, given FFR's extensive validation in a multitude of clinical settings. AIMS: The aim of this study was to derive a novel non-hyperaemic algorithm based on deep learning and to validate it in an internal validation cohort against FFR. METHODS: The ARTIST study is a post hoc analysis of three previously published studies. In a derivation cohort (random 80% sample of the total cohort) a deep neural network was trained (deep learning) with paired examples of resting coronary pressure curves and their FFR values. The resulting algorithm was validated against unseen resting pressure curves from a random 20% sample of the total cohort. The primary endpoint was diagnostic accuracy of the deep learning-derived algorithms against binary FFR ≤0.8. To reduce the variance in the precision, we used a fivefold cross-validation procedure. RESULTS: A total of 1,666 patients with 1,718 coronary lesions and 2,928 coronary pressure tracings were included. The diagnostic accuracy of our convolutional neural network (CNN) and recurrent neural networks (RNN) against binary FFR ≤0.80 was 79.6±1.9% and 77.6±2.3%, respectively. There was no statistically significant difference between the accuracy of our neural networks to predict binary FFR and the most accurate non-hyperaemic pressure ratio (NHPR). CONCLUSIONS: Compared to standard derivation of resting pressure ratios, we did not find a significant improvement in FFR prediction when resting data are analysed using artificial intelligence approaches. Our findings strongly suggest that a larger class of hidden information within resting pressure traces is not the main cause of the known disagreement between resting indices and FFR. Therefore, if clinicians want to use FFR for clinical decision making, hyperaemia induction should remain the standard practice.

Coronary lithotripsy: a novel approach to intra-coronary calcification with 'cracking' results?

Coronary lithotripsy is a novel approach to percutaneous coronary intervention (PCI). It is based on well-established technology dating back to 1980 when lithotripsy was first used to treat renal calculi. Its application in cardiovascular medicine is a more recent development that involves using a low-pressure lithotripsy balloon to deliver unfocused acoustic pulse waves in a circumferential mechanical energy distribution. This causes fracturing of calcification within the surrounding vasculature, facilitating optimal stent deployment. This article aims to review recent clinical experience and the published data regarding intravascular lithotripsy (IVL). All relevant articles were identified via PubMed using keywords including "intravascular lithotripsy", "shockwave" and "coronary". All studies that contained published datasets regarding IVL with patient numbers >50 were included for review. There were 116 results found. After reviewing all the publications, articles were then tabulated and 17 were found to be relevant, including only four clinical studies. In this review we found that intracoronary lithotripsy for heavily calcified arteries appears to be a safe, effective, easy-to-use method of dealing with an otherwise technically-challenging and high-risk scenario. It appears to carry low risk, uses low pressures, and exerts its effects on both superficial and deep intravascular calcium. Further prospective data with long-term follow-up will be required to explore both the off-label uses of IVL (such as post-stent dilatation), and the long-term patency of these vessels.

Clinical cases illustrating the efficacy of intra-coronary lithotripsy.

We provide the details of three cases utilising intravascular lithotripsy, a novel approach to percutaneous coronary intervention (PCI).

Percutaneous coronary intervention versus medical therapy in patients with angina and grey-zone fractional flow reserve values: a randomised clinical trial.

INTRODUCTION: There is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75-0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in GZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control. METHODS: We enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ). RESULTS: 104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the target GZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve <2.0 in the target GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months. CONCLUSIONS: Non-invasive evidence of major ischaemia is uncommon in patients with GZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months. TRIAL REGISTRATION NUMBER: NCT02425969.

Single- Versus 2-Stent Strategies for Coronary Bifurcation Lesions: A Systematic Review and Meta-Analysis of Randomized Trials With Long-Term Follow-up.

BACKGROUND: The majority of coronary bifurcation lesions are treated with a provisional single-stent strategy rather than an up-front 2-stent strategy. This approach is supported by multiple randomized controlled clinical trials with short- to medium-term follow-up; however, long-term follow-up data is evolving from many data sets. METHODS AND RESULTS: Meta-analysis of randomized controlled trials evaluating long-term outcomes (≥1 year) according to treatment strategy for coronary bifurcation lesions. Nine randomized controlled trials with 3265 patients reported long-term clinical outcomes at mean weighted follow-up of 3.1±1.8 years. Provisional single stenting was associated with lower all-cause mortality (2.94% versus 4.23%; risk ratio: 0.69; 95% confidence interval, 0.48-1.00; P=0.049; I2=0). There was no difference in major adverse cardiac events (15.8% versus 15.4%; P=0.79), myocardial infarction (4.8% versus 5.5%; P=0.51), target lesion revascularization (9.3% versus 7.6%; P=0.19), or stent thrombosis (1.8% versus 1.6%; P=0.28) between the groups. Prespecified sensitivity analysis of long-term mortality at a mean of 4.7 years of follow-up showed that the provisional single-stent strategy was associated with reduced all-cause mortality (3.9% versus 6.2%; risk ratio: 0.63; 95% confidence interval, 0.42-0.97; P=0.036; I2=0). CONCLUSIONS: Coronary bifurcation percutaneous coronary intervention using a provisional single-stent strategy is associated with a reduction in all-cause mortality at long-term follow-up.

Validation of a novel non-hyperaemic index of coronary artery stenosis severity: the Resting Full-cycle Ratio (VALIDATE RFR) study.

AIMS: Randomised controlled trials have reported instantaneous wave-free ratio (iFR) to be non-inferior to fractional flow reserve (FFR) for major adverse cardiovascular events at one year; however, iFR is limited by sensitive landmarking of the pressure waveform, and the assumption that maximal flow and minimal resistance occur during a fixed period of diastole. We sought to validate the resting full-cycle ratio (RFR), a novel non-hyperaemic index of coronary stenosis severity based on unbiased identification of the lowest distal coronary pressure to aortic pressure ratio (Pd/Pa), independent of the ECG, landmark identification, and timing within the cardiac cycle. METHODS AND RESULTS: VALIDATE-RFR was a retrospective study designed to derive and validate the RFR. The primary endpoint was the agreement between RFR and iFR. RFR was retrospectively determined in 651 waveforms in which iFR was measured using a proprietary Philips/Volcano wire. RFR was highly correlated to iFR (R2=0.99, p<0.001), with a mean bias of -0.002 (95% limits of agreement -0.023 to 0.020). The diagnostic performance of RFR versus iFR was diagnostic accuracy 97.4%, sensitivity 98.2%, specificity 96.9%, positive predictive value 94.5%, negative predictive value 99.0%, area under the receiver operating characteristic curve of 0.996, and diagnostically equivalent within 1% (mean difference -0.002; 95% CI: -0.009 to 0.006, p=0.03). The RFR was detected outside diastole in 12.2% (341/2,790) of all cardiac cycles and 32.4% (167/516) of cardiac cycles in the right coronary artery where the sensitivity of iFR compared to FFR was lowest (40.6%). CONCLUSIONS: RFR is diagnostically equivalent to iFR but unbiased in its ability to detect the lowest Pd/Pa during the full cardiac cycle, potentially unmasking physiologically significant coronary stenoses that would be missed by assessment dedicated to specific segments of the cardiac cycle.

Fractional flow reserve: a clinical perspective.

Fractional flow reserve (FFR) is a reference invasive diagnostic test to assess the physiological significance of an epicardial coronary artery stenosis. FFR-guided percutaneous coronary intervention in stable coronary artery disease has been assessed in three seminal clinical trials and the indications for FFR assessment are expanding into other clinical scenarios. In this article we review the theoretical, experimental and clinical basis for FFR measurement. We place FFR measurement in the context of the comprehensive invasive assessment of coronary physiology in patients presenting with known or suspected angina pectoris in daily clinical practice, and review the recent developments in FFR assessment.

Validation of the "smart" minimum FFR Algorithm in an unselected all comer population of patients with intermediate coronary stenoses.

Using data from a commercial pressure wire system (St. Jude Medical) we previously developed an automated "smart" algorithm to determine a reproducible value for minimum FFR (smFFR) and confirmed that it correlated very closely with measurements made off-line by experienced coronary physiology core laboratories. In this study we used the same "smart" minimum algorithm to analyze data derived from a different, commercial pressure wire system (Philips Volcano) and compared the values obtained to both operator-defined steady state FFR and the online automated minimum FFR reported by the pressure wire analyser. For this analysis, we used the data collected during the VERIFY 2 study (Hennigan et al. in Circ Cardiovasc Interv, doi: 10.1161/CIRCINTERVENTIONS.116.004016 ) in which we measured FFR in 257 intermediate coronary stenoses (mean DS 48%) in 197 patients. Maximal hyperaemia was induced using intravenous adenosine (140 mcg/kg/min). We recorded both the online minimum FFR generated by the analyser and the operator-reported steady state FFR. Subsequently, the raw pressure tracings were coded, anonymised and 256/257 were subjected to further off-line analysis using the smart minimum FFR (smFFR) algorithm. The operator-defined steady state FFR correlated well with smFFR: r = 0.988 (p < 0.001), average bias 0.008 (SD 0.014), 95% limits of agreement -0.020 to 0.036. The online automated minimum FFR also correlated well with the smFFR: r = 0.998 (p < 0.001), average bias 0.004 (SD 0.006), 95% limits of agreement -0.016 to 0.008. Finally, the online automated minimum FFR correlated well the operator-reported steady state FFR: r = 0.988 (p < 0.001), average bias 0.012 (SD 0.014), 95% limits of agreement -0.039 to 0.015. In 95% of lesions studied (244/256), the operator reported steady-state FFR, smFFR, and online automated minimum FFR agreed with each other to within 0.04, which is within the previously reported test/retest limits of agreement of FFR reported by an experienced core lab. Disagreements >0.05 among methods were rare but in these cases the two automated algorithms almost always agreed with each other rather than with the operator-reported value. Within the VERIFY 2 dataset, experienced operators reported a similar FFR value to both an online automated minimum (Philips Volcano) and off-line "smart" minimum computer algorithm. Thus, treatment decisions and clinical studies using either method will produce nearly identical results.

Comparison of Different Diastolic Resting Indexes to iFR: Are They All Equal?

BACKGROUND: Pressure measurement for the duration of the wave-free period (WFP) is considered essential for resting-state physiological assessment of coronary stenosis severity using the instantaneous wave-free ratio (iFR). OBJECTIVES: The aim of this study was to compare other diastolic resting indexes to iFR. METHODS: In the population of the VERIFY2 (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography) study, iFR calculated by proprietary software (Volcano Harvest, Volcano Corporation, Rancho Cordova, California) was compared with the ratio of resting distal coronary pressure and aortic pressure during the complete duration of diastole (dPR), 25% to 75% of diastole (dPR25-75), and midpoint of diastole (dPRmid), along with Matlab calculated iFR (iFRmatlab) and iFR-like indexes shortening the length of the WFP by 50 and 100 ms (iFR-50ms and iFR-100ms), respectively. Mutual differences, Spearman correlations, area under the curve values from receiver-operating characteristic analyses, and diagnostic performance with respect to iFR and fractional flow reserve (FFR) were calculated for all indexes. RESULTS: Median iFR in 197 patients with 257 vessels was 0.91 with an interquartile range of 0.87 to 0.95. The mutual differences (± SD) with iFR were 0.006 ± 0.011 (dPR), 0.001 ± 0.007 (dPR25-75), 0.001 ± 0.008 (dPRmid), 0.005 ± 0.009 (iFRmatlab), 0.003 ± 0.008 (iFR-50ms), and 0.001 ± 0.009 (iFR-100ms). Correlations for all indexes with iFR were >0.99 (p < 0.001 for all). Area under the curve values for predicting iFR were >0.99 for all indexes as well. Diagnostic accuracy compared with FFR was 76% to 77% for all indexes including iFR. CONCLUSIONS: All diastolic resting indexes tested were identical to iFR, both numerically and with respect to their agreement with FFR. A numerically equal value to iFR can be determined without restriction to the WFP. Cutoff values, guidelines, and clinical recommendations for iFR can therefore be extended to these other indexes. (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography [VERIFY2]; NCT02377310).

Discordance Between Resting and Hyperemic Indices of Coronary Stenosis Severity: The VERIFY 2 Study (A Comparative Study of Resting Coronary Pressure Gradient, Instantaneous Wave-Free Ratio and Fractional Flow Reserve in an Unselected Population Referred for Invasive Angiography).

BACKGROUND: Distal coronary to aortic pressure ratio (Pd/Pa) and instantaneous wave-free ratio (iFR) are indices of functional significance of a coronary stenosis measured without hyperemia. It has been suggested that iFR has superior diagnostic accuracy to Pd/Pa when compared with fractional flow reserve (FFR).We hypothesized that in comparison with FFR, revascularization decisions based on either binary cutoff values for iFR and Pd/Pa or hybrid strategies incorporating iFR or Pd/Pa will result in similar levels of disagreement. METHODS AND RESULTS: This is a prospective study in consecutive patients undergoing FFR for clinical indications using proprietary software to calculate iFR. We measured Pd/Pa, iFR, FFR, and hyperemic iFR. Diagnostic accuracy versus FFR ≤0.80 was calculated using binary cutoff values of ≤0.90 for iFR and ≤0.92 for Pd/Pa, and adenosine zones for iFR of 0.86 to 0.93 and Pd/Pa of 0.87 to 0.94 in the hybrid strategy. One hundred ninety-seven patients with 257 stenoses (mean diameter stenosis 48%) were studied. Using binary cutoffs, diagnostic accuracy was similar for iFR and resting Pd/Pa with misclassification rates of 21% versus 20.2% (P=0.85). In the hybrid analysis, 54% of iFR cases and 53% of Pd/Pa cases were outside the adenosine zone and rates of misclassification were 9.4% versus 11.9% (P=0.55). CONCLUSIONS: Binary cutoff values for iFR and Pd/Pa result in misclassification of 1 in 5 lesions. Using a hybrid strategy, approximately half of the patients do not receive adenosine, but 1 in 10 lesions are still misclassified. The use of nonhyperemic indices of stenosis severity cannot be recommended for decision making in the catheterization laboratory. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02377310.

Infarct size and left ventricular remodelling after preventive percutaneous coronary intervention.

OBJECTIVE: We hypothesised that, compared with culprit-only primary percutaneous coronary intervention (PCI), additional preventive PCI in selected patients with ST-elevation myocardial infarction with multivessel disease would not be associated with iatrogenic myocardial infarction, and would be associated with reductions in left ventricular (LV) volumes in the longer term. METHODS: In the preventive angioplasty in myocardial infarction trial (PRAMI; ISRCTN73028481), cardiac magnetic resonance (CMR) was prespecified in two centres and performed (median, IQR) 3 (1, 5) and 209 (189, 957) days after primary PCI. RESULTS: From 219 enrolled patients in two sites, 84% underwent CMR. 42 (50%) were randomised to culprit-artery-only PCI and 42 (50%) were randomised to preventive PCI. Follow-up CMR scans were available in 72 (86%) patients. There were two (4.8%) cases of procedure-related myocardial infarction in the preventive PCI group. The culprit-artery-only group had a higher proportion of anterior myocardial infarctions (MIs) (55% vs 24%). Infarct sizes (% LV mass) at baseline and follow-up were similar. At follow-up, there was no difference in LV ejection fraction (%, median (IQR), (culprit-artery-only PCI vs preventive PCI) 51.7 (42.9, 60.2) vs 54.4 (49.3, 62.8), p=0.23), LV end-diastolic volume (mL/m2, 69.3 (59.4, 79.9) vs 66.1 (54.7, 73.7), p=0.48) and LV end-systolic volume (mL/m2, 31.8 (24.4, 43.0) vs 30.7 (23.0, 36.3), p=0.20). Non-culprit angiographic lesions had low-risk Syntax scores and 47% had non-complex characteristics. CONCLUSIONS: Compared with culprit-only PCI, non-infarct-artery MI in the preventive PCI strategy was uncommon and LV volumes and ejection fraction were similar.

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment.

OBJECTIVES: This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). BACKGROUND: FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. METHODS: We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. RESULTS: A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. CONCLUSIONS: cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement.

Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

Fractional flow reserve (FFR) requires the use of maximal hyperaemia as described in the original preclinical and clinical validation studies and subsequent practice changing randomized controlled trials. A perception that the need for hyperaemia (usually induced with adenosine) was one of the obstacles to more widespread adoption of FFR has led to interest in the use of resting non-hyperaemic indices to assess the functional significance of coronary stenoses. We examine the current evidence base and conclude that resting indices agree with FFR in only 80 % of lesions when a binary cut-off is employed but closer to 90 % when hybrid strategies utilising both resting indices and FFR are utilised. It seems counter intuitive to sacrifice diagnostic accuracy when in most patients and healthcare systems the induction of hyperaemia with adenosine is safe and emminently affordable.