Estimation of coronary wave intensity analysis using noninvasive techniques and its application to exercise physiology.

Wave intensity analysis (WIA) has found particular applicability in the coronary circulation where it can quantify traveling waves that accelerate and decelerate blood flow. The most important wave for the regulation of flow is the backward-traveling decompression wave (BDW). Coronary WIA has hitherto always been calculated from invasive measures of pressure and flow. However, recently it has become feasible to obtain estimates of these waveforms noninvasively. In this study we set out to assess the agreement between invasive and noninvasive coronary WIA at rest and measure the effect of exercise. Twenty-two patients (mean age 60) with unobstructed coronaries underwent invasive WIA in the left anterior descending artery (LAD). Immediately afterwards, noninvasive LAD flow and pressure were recorded and WIA calculated from pulsed-wave Doppler coronary flow velocity and central blood pressure waveforms measured using a cuff-based technique. Nine of these patients underwent noninvasive coronary WIA assessment during exercise. A pattern of six waves were observed in both modalities. The BDW was similar between invasive and noninvasive measures [peak: 14.9 ± 7.8 vs. -13.8 ± 7.1 × 10(4) W·m(-2)·s(-2), concordance correlation coefficient (CCC): 0.73, P < 0.01; cumulative: -64.4 ± 32.8 vs. -59.4 ± 34.2 × 10(2) W·m(-2)·s(-1), CCC: 0.66, P < 0.01], but smaller waves were underestimated noninvasively. Increased left ventricular mass correlated with a decreased noninvasive BDW fraction (r = -0.48, P = 0.02). Exercise increased the BDW: at maximum exercise peak BDW was -47.0 ± 29.5 × 10(4) W·m(-2)·s(-2) (P < 0.01 vs. rest) and cumulative BDW -19.2 ± 12.6 × 10(3) W·m(-2)·s(-1) (P < 0.01 vs. rest). The BDW can be measured noninvasively with acceptable reliably potentially simplifying assessments and increasing the applicability of coronary WIA.

Resolving the paradox of randomised controlled trials and observational studies comparing multi-vessel angioplasty and culprit only angioplasty at the time of STEMI.

BACKGROUND: Patients presenting with ST-elevation myocardial infarction commonly have multi-vessel coronary artery disease. After the culprit artery is treated, the optimal treatment strategy for the residual disease is not yet defined. Large observational studies suggest that treatment of residual disease should be deferred but smaller randomised controlled trials (RCTs) suggest multi-vessel primary percutaneous coronary intervention (MV-PPCI) at the time of STEMI is safe. We examine if allocation bias of high-risk patients could explain the conflicting results between observational studies and RCTs and aim to resolve the paradox between the two. METHODS: A meta-analysis of registries comparing culprit-only PPCI to MV-PPCI was performed. We then determined if high-risk patients were more likely to be allocated to MV-PPCI. A meta-regression was performed to determine if any allocation bias of high-risk patients could explain the difference in outcomes between therapies. RESULTS: 47,717 patients (19 studies) were eligible. MV-PPCI had higher mortality than culprit-only PPCI (OR 1.59, 95% CI 1.12 to 2.24, p=0.03). However, higher risk patients were more likely to be allocated to MV-PPCI (OR 1.45, 95% CI 1.18 to 1.78, p=0.0005). When this was accounted for, there was no difference in mortality between culprit-only PPCI and MV-PPCI (OR 0.99, 95% CI 0.69 to 1.41, p=0.94). DISCUSSION: Clinicians preferentially allocate higher-risk patients to MV-PPCI at the time of STEMI, resulting in observational studies reporting higher mortality with this strategy. When this is accounted for, these large observational studies in 'real world' patients support the conclusion of the smaller RCTs in the field: MV-PPCI has equivalent mortality to a culprit-only approach.

A new method of applying randomised control study data to the individual patient: A novel quantitative patient-centred approach to interpreting composite end points.

BACKGROUND: Modern randomised controlled trials typically use composite endpoints. This is only valid if each endpoint is equally important to patients but few trials document patient preference and seek the relative importance of components of combined endpoints. If patients weigh endpoints differentially, our interpretation of trial data needs to be refined. METHODS AND RESULTS: We derive a quantitative, structured tool to determine the relative importance of each endpoint to patients. We then apply this tool to data comparing angioplasty with drug-eluting stents to bypass surgery. The survey was administered to patients undergoing cardiac catheterisation. A meta-analysis comparing coronary artery bypass grafting (CABG) to percutaneous coronary interventuin (PCI) was then performed using (a) standard MACE and (b) patient-centred MACE. Patients considered stroke worse than death (stroke 102.3 ± 19.6%, p < 0.01), and MI and repeat revascularisation less severe than death (61.9 ± 26.8% and 41.9 ± 25.4% respectively p < 0.01 for both). 7 RCTs (5251 patients) were eligible. Meta-analysis demonstrated that standard MACE occurs more frequently with PCI than surgery (OR 1.44; 95% CI 1.10 to 1.87; p = 0.007). Re-analysis using patient-centred MACE found no significant difference between PCI and CABG (OR 1.22, 95% CI 0.97 to 1.53; p = 0.10). CONCLUSIONS: Patients do not consider the constituent endpoints of MACE equal. We derive a novel patient-centred metric that recognises and quantifies the differences attributed to each endpoint. When patient preference data are applied to contemporary trial results, there is no significant difference between PCI and CABG. Responses from individual patients in clinic could be used to give individual patients a recommendation that is truly personalised.

Pre-angioplasty instantaneous wave-free ratio pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease.

OBJECTIVES: The aim of this study was to perform hemodynamic mapping of the entire vessel using motorized pullback of a pressure guidewire with continuous instantaneous wave-free ratio (iFR) measurement. BACKGROUND: Serial stenoses or diffuse vessel narrowing hamper pressure wire-guided management of coronary stenoses. Characterization of functional relevance of individual stenoses or narrowed segments constitutes an unmet need in ischemia-driven percutaneous revascularization. METHODS: The study was performed in 32 coronary arteries with tandem and/or diffusely diseased vessels. An automated iFR physiological map, integrating pullback speed and physiological information, was built using dedicated software to calculate physiological stenosis severity, length, and intensity (ΔiFR/mm). This map was used to predict the best-case post-percutaneous coronary intervention (PCI) iFR (iFRexp) according to the stented location, and this was compared with the observed iFR post-PCI (iFRobs). RESULTS: After successful PCI, the mean difference between iFRexp and iFRobs was small (mean difference: 0.016 ± 0.004) with a strong relationship between ΔiFRexp and ΔiFRobs (r = 0.97, p < 0.001). By identifying differing iFR intensities, it was possible to identify functional stenosis length and quantify the contribution of each individual stenosis or narrowed segment to overall vessel stenotic burden. Physiological lesion length was shorter than anatomic length (12.6 ± 1.5 vs. 23.3 ± 1.3, p < 0.001), and targeting regions with the highest iFR intensity predicted significant improvement post-PCI (r = 0.86, p < 0.001). CONCLUSIONS: iFR measurements during continuous resting pressure wire pullback provide a physiological map of the entire coronary vessel. Before a PCI, the iFR pullback can predict the hemodynamic consequences of stenting specific stenoses and thereby may facilitate the intervention and stenting strategy.

Improvement in coronary haemodynamics after percutaneous coronary intervention: assessment using instantaneous wave-free ratio.

OBJECTIVE: To determine whether the instantaneous wave-free ratio (iFR) can detect improvement in stenosis significance after percutaneous coronary intervention (PCI) and compare this with fractional flow reserve (FFR) and whole cycle Pd/Pa. DESIGN: A prospective observational study was undertaken in elective patients scheduled for PCI with FFR ≤ 0.80. Intracoronary pressures were measured at rest and during adenosine-mediated vasodilatation, before and after PCI. iFR, Pd/Pa and FFR values were calculated using the validated fully automated algorithms. SETTING: Coronary catheter laboratories in two UK centres and one in the USA. PATIENTS: 120 coronary stenoses in 112 patients were assessed. The mean age was 63 ± 10 years, while 84% were male; 39% smokers; 33% with diabetes. Mean diameter stenosis was 68 ± 16% by quantitative coronary angiography. RESULTS: Pre-PCI, mean FFR was 0.66 ± 0.14, mean iFR was 0.75 ± 0.21 and mean Pd/Pa 0.83 ± 0.16. PCI increased all indices significantly (FFR 0.89 ± 0.07, p<0.001; iFR 0.94 ± 0.05, p<0.001; Pd/Pa 0.96 ± 0.04, p<0.001). The change in iFR after intervention (0.20 ± 0.21) was similar to ΔFFR 0.22 ± 0.15 (p=0.25). ΔFFR and ΔiFR were significantly larger than resting ΔPd/Pa (0.13 ± 0.16, both p<0.001). Similar incremental changes occurred in patients with a higher prevalence of risk factors for microcirculatory disease such as diabetes and hypertension. CONCLUSIONS: iFR and FFR detect the changes in coronary haemodynamics elicited by PCI. FFR and iFR have a significantly larger dynamic range than resting Pd/Pa. iFR might be used to objectively document improvement in coronary haemodynamics following PCI in a similar manner to FFR.

Diagnostic classification of the instantaneous wave-free ratio is equivalent to fractional flow reserve and is not improved with adenosine administration. Results of CLARIFY (Classification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study).

OBJECTIVES: This study sought to determine if adenosine administration is required for the pressure-only assessment of coronary stenoses. BACKGROUND: The instantaneous wave-free ratio (iFR) is a vasodilator-free pressure-only measure of the hemodynamic severity of a coronary stenosis comparable to fractional flow reserve (FFR) in diagnostic categorization. In this study, we used hyperemic stenosis resistance (HSR), a combined pressure-and-flow index, as an arbiter to determine when iFR and FFR disagree which index is most representative of the hemodynamic significance of the stenosis. We then test whether administering adenosine significantly improves diagnostic performance of iFR. METHODS: In 51 vessels, intracoronary pressure and flow velocity was measured distal to the stenosis at rest and during adenosine-mediated hyperemia. The iFR (at rest and during adenosine administration [iFRa]), FFR, HSR, baseline, and hyperemic microvascular resistance were calculated using automated algorithms. RESULTS: When iFR and FFR disagreed (4 cases, or 7.7% of the study population), HSR agreed with iFR in 50% of cases and with FFR in 50% of cases. Differences in magnitude of microvascular resistance did not influence diagnostic categorization; iFR, iFRa, and FFR had equally good diagnostic agreement with HSR (receiver-operating characteristic area under the curve 0.93 iFR vs. 0.94 iFRa and 0.96 FFR, p = 0.48). CONCLUSIONS: iFR and FFR had equivalent agreement with classification of coronary stenosis severity by HSR. Further reduction in resistance by the administration of adenosine did not improve diagnostic categorization, indicating that iFR can be used as an adenosine-free alternative to FFR.

Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry.

AIMS: To evaluate the classification agreement between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) in patients with angiographic intermediate coronary stenoses. METHODS AND RESULTS: Three hundred and twelve patients (339 stenoses) with angiographically intermediate stenoses were included in this international clinical registry. The iFR was calculated using fully automated algorithms. The receiver operating characteristic (ROC) curve was used to identify the iFR optimal cut-point corresponding to FFR 0.8. The classification agreement of coronary stenoses as significant or non-significant was established between iFR and FFR and between repeated FFR measurements for each 0.05 quantile of FFR values, from 0.2 to 1. Close agreement was observed between iFR and FFR (area under ROC curve= 86%). The optimal iFR cut-off (for an FFR of 0.80) was 0.89. After adjustment for the intrinsic variability of FFR, the classification agreement (accuracy) between iFR and FFR was 94%. Amongst the stenoses classified as non-significant by iFR (>0.89) and as significant by FFR (≤0.8), 81% had associated FFR values located within the FFR "grey-zone" (0.75-0.8) and 41% within the 0.79-0.80 FFR range. CONCLUSIONS: In a population of intermediate coronary stenoses, the classification agreement between iFR and FFR is excellent and similar to that of repeated FFR measurements in the same sample. Vasodilator-independent assessment of intermediate stenosis seems applicable and may foster adoption of coronary physiology in the catheterisation laboratory.

Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation.

AIMS: Adoption of fractional flow reserve (FFR) remains low (6-8%), partly because of the time, cost and potential inconvenience associated with vasodilator administration. The instantaneous wave-Free Ratio (iFR) is a pressure-only index of stenosis severity calculated without vasodilator drugs. Before outcome trials test iFR as a sole guide to revascularisation, we evaluate the merits of a hybrid iFR-FFR decision-making strategy for universal physiological assessment. METHODS AND RESULTS: Coronary pressure traces from 577 stenoses were analysed. iFR was calculated as the ratio between Pd and Pa in the resting diastolic wave-free window. A hybrid iFR-FFR strategy was evaluated, by allowing iFR to defer some stenoses (where negative predictive value is high) and treat others (where positive predictive value is high), with adenosine being given only to patients with iFR in between those values. For the most recent fixed FFR cut-off (0.8), an iFR of <0.86 could be used to confirm treatment (PPV of 92%), whilst an iFR value of >0.93 could be used to defer revascularisation (NPV of 91%). Limiting vasodilator drugs to cases with iFR values between 0.86 to 0.93 would obviate the need for vasodilator drugs in 57% of patients, whilst maintaining 95% agreement with an FFR-only strategy. If the 0.75-0.8 FFR grey zone is accounted for, vasodilator drug requirement would decrease by 76%. CONCLUSION: A hybrid iFR-FFR decision-making strategy for revascularisation could increase adoption of physiology-guided PCI, by more than halving the need for vasodilator administration, whilst maintaining high classification agreement with an FFR-only strategy.

Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study.

OBJECTIVES: The purpose of this study was to develop an adenosine-independent, pressure-derived index of coronary stenosis severity. BACKGROUND: Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic efficiency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time. METHODS: A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measurements were made at baseline and under pharmacologic vasodilation with adenosine. RESULTS: Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 ± 0.06 and 284 ± 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 ± 0.06 and 302 ± 315 mm Hg s/m; p = NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r = 0.9, p < 0.001) with excellent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR <0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively. CONCLUSIONS: Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481).