Ricardo Petraco

First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study.

BACKGROUND Sympathetic overactivation, is reduced by renal denervation in drug-resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. METHOD 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mmHg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May-July 2011. Patients were admitted for pre-procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. RESULTS No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Δsystolic -7.1 ± 6.9 mmHg, p=0.35; Δdiastolic -0.6 ± 4.0 mmHg, p=0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Δcreatinine -5.7 ± 8.4 μmol/l, p=0.52 and Δurea -1.0 ± 1.0 mmol/l, p=0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Δ=27.1 ± 9.7 m, p=0.03), with each patient showing an increase. CONCLUSIONS This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham-controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe. ClinicalTrial.gov NCT01584700

Fractional Flow Reserve–Guided Revascularization: Practical Implications of a Diagnostic Gray Zone and Measurement Variability on Clinical Decisions

OBJECTIVES This study sought to evaluate the effects of fractional flow reserve (FFR) measurement variability on FFR-guided treatment strategy. BACKGROUND Current appropriateness guidelines recommend the utilization of FFR to guide coronary revascularization based on a fixed cut-off of 0.8. This rigid approach does not take into account the intrinsic biological variability of a single FFR result and the clinical judgment of experienced interventional cardiologists. [corrected]. METHODS FFR reproducibility data from the landmark Deferral Versus Performance of PTCA in Patients Without Documented Ischemia (DEFER) trial was analyzed (two repeated FFR measurements in the same lesion, 10 min apart) and the standard deviation of the difference (SDD) between repeated measurements was calculated. The measurement certainty (probability that the FFR-guided revascularization strategy will not change if the test is repeated 10 min later) was subsequently established across the whole range of FFR values, from 0.2 to 1. RESULTS Outside the [0.75 to 0.85] FFR range, measurement certainty of a single FFR result is >95%. However, closer to its cut-off, certainty falls to less than 80% within 0.77 to 0.83, reaching a nadir of 50% around 0.8. In clinical practice, that means that each time a single FFR value falls between 0.75 and 0.85, there is a chance that the FFR-derived revascularization recommendation will change if the measurement is repeated 10 min later, with this chance increasing the closer the FFR result is to 0.8. CONCLUSIONS A measurement FFR gray-zone is found between 0.75 and 0.85]. Therefore, clinicians should make revascularization decisions based on broadened clinical judgment when a single FFR result falls within this uncertainty zone, particularly between 0.77 and 0.83, when measurement certainty falls to less than 80%.

Disturbed Coronary Hemodynamics in Vessels with Intermediate Stenoses Evaluated with Fractional Flow Reserve: A Combined Analysis of Epicardial and Microcirculatory Involvement in Ischemic Heart Disease

Background— In chronic ischemic heart disease, focal stenosis, diffuse atherosclerotic narrowings, and microcirculatory dysfunction (MCD) contribute to limit myocardial flow. The prevalence of these ischemic heart disease levels in fractional flow reserve (FFR) interrogated vessels remains largely unknown. Methods and Results— Using intracoronary measurements, 91 coronaries (78 patients) with intermediate stenoses were classified in 4 FFR and coronary flow reserve (CFR) agreement groups, using FFR>0.80 and CFR<2 as cutoffs. Index of microcirculatory resistance (IMR) and atherosclerotic burden (Gensini score) were also assessed. MCD was assumed when IMR≥29.1 (75th percentile). Fifty-four (59.3%) vessels had normal FFR, from which only 20 (37%) presented both normal CFR and IMR. Among vessels with FFR>0.80, most (63%) presented disturbed hemodynamics: abnormal CFR in 28 (52%) and MCD in 18 (33%). Vessels with FFR>0.80 presented higher IMR [adjusted mean 27.6 (95% confidence interval, 23.4–31.8)] than those with FFR⩽0.80 [17.3 (95% confidence interval, 13.0–21.7), p=0.001]. Atherosclerotic burden was inversely correlated with CFR (r=−0.207, P=0.055), and in vessels with FFR>0.80 and CFR<2 (n=28, 39%), IMR had a wide dispersion (7–72.7 U), suggesting a combination of diffuse atherosclerotic narrowings and MCD. Vessels with FFR⩽0.80 and normal CFR presented the lowest IMR, suggesting a preserved microcirculation. Conclusions— A substantial number of coronary arteries with stenoses showing an FFR>0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.

Maximal expansion capacity with current DES platforms: a critical factor for stent selection in the treatment of left main bifurcations?

AIMS Left main stenting is increasingly performed and often involves deployment of a single stent across vessels with marked disparity in diameters. Knowing stent expansion capacity is critical to ensure adequate strut apposition after post-dilatation of the stent has been performed. Coronary stents are usually manufactured in only two or three different model designs with each design having a different maximal expansion capacity. Information about the different workhorse designs and their maximal achievable diameter is not commonly provided by manufacturers but, in the absence of this critically important information, stents implanted in segments with major changes in vessel diameter have the potential to become grossly overstretched and to remain incompletely apposed. METHODS AND RESULTS We examined the differences in workhorse designs of six commercially available drug-eluting stents (DES): the PROMUS Element, Taxus Liberté, XIENCE Prime, Resolute Integrity, BioMatrix Flex and Cypher Select stents. Using micro-computed tomography, we tested oversizing capabilities above nominal pressures for the different workhorse designs of the six DES using 4.0, 5.0 and 6.0 mm post-dilatation balloons inflated to 14 atmospheres. MLD could be increased significantly in all stents, only restricted by workhorse design limitations. Minimal inner lumen diameter (MLD) achieved after two successive 6.0 mm post-dilatations of the largest design (4.0 mm stent) was 5.7 mm for the Element, 5.6 mm for the XIENCE Prime, 6.0 mm for the Taxus, 5.4 mm for the Resolute Integrity, 5.9 mm for the BioMatrix and 5.8 mm for the Cypher stent. Significant deformations were observed during stent oversizing with large changes in terms of cell opening and crowns expansion. These are affected by design structure and reveal important differences among all stents tested. Such extensive deformations may alter the functional ability of an individual stent to scaffold a lesion and prevent restenosis. CONCLUSIONS Stent selection based on stent model design may be critical, particularly for treatment of large artery and left main bifurcations where overexpansion is normally required to optimise results and ensure full expansion of the stent.

Real-time use of instantaneous wave–free ratio: Results of the ADVISE in-practice: An international, multicenter evaluation of instantaneous wave–free ratio in clinical practice

Objectives To evaluate the first experience of real-time instantaneous wave–free ratio (iFR) measurement by clinicians. Background The iFR is a new vasodilator-free index of coronary stenosis severity, calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, when distal resistance is lowest and stable. Because all previous studies have calculated iFR offline, the feasibility of real-time iFR measurement has never been assessed. Methods Three hundred ninety-two stenoses with angiographically intermediate stenoses were included in this multicenter international analysis. Instantaneous wave–free ratio and fractional flow reserve (FFR) were performed in real time on commercially available consoles. The classification agreement of coronary stenoses between iFR and FFR was calculated. Results Instantaneous wave–free ratio and FFR maintain a close level of diagnostic agreement when both are measured by clinicians in real time (for a clinical 0.80 FFR cutoff: area under the receiver operating characteristic curve [ROCAUC] 0.87, classification match 80%, and optimal iFR cutoff 0.90; for a ischemic 0.75 FFR cutoff: iFR ROCAUC 0.90, classification match 88%, and optimal iFR cutoff 0.85; if the FFR 0.75-0.80 gray zone is accounted for: ROCAUC 0.93, classification match 92%). When iFR and FFR are evaluated together in a hybrid decision-making strategy, 61% of the population is spared from vasodilator while maintaining a 94% overall agreement with FFR lesion classification. Conclusion When measured in real time, iFR maintains the close relationship to FFR reported in offline studies. These findings confirm the feasibility and reliability of real-time iFR calculation by clinicians.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease: Physiology-Stratified Analysis of ORBITA

Background: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. Methods: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. Results: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], –4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70–1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and decreasing iFR (Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96–2.80; P=0.072) with no detectable evidence of interaction with FFR (Pinteraction=0.849) or iFR (Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P=0.006) but neither FFR (Pinteraction=0.693) nor iFR (Pinteraction=0.761) modified this effect. Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

Effects of disease severity distribution on the performance of quantitative diagnostic methods and proposal of a novel ‘V-plot’ methodology to display accuracy values

Background Diagnostic accuracy is widely accepted by researchers and clinicians as an optimal expression of a test’s performance. The aim of this study was to evaluate the effects of disease severity distribution on values of diagnostic accuracy as well as propose a sample-independent methodology to calculate and display accuracy of diagnostic tests. Methods and findings We evaluated the diagnostic relationship between two hypothetical methods to measure serum cholesterol (Cholrapid and Cholgold) by generating samples with statistical software and (1) keeping the numerical relationship between methods unchanged and (2) changing the distribution of cholesterol values. Metrics of categorical agreement were calculated (accuracy, sensitivity and specificity). Finally, a novel methodology to display and calculate accuracy values was presented (the V-plot of accuracies). Conclusion No single value of diagnostic accuracy can be used to describe the relationship between tests, as accuracy is a metric heavily affected by the underlying sample distribution. Our novel proposed methodology, the V-plot of accuracies, can be used as a sample-independent measure of a test performance against a reference gold standard.

019 Development and validation of a novel pressure-only intra-coronary index of coronary stenosis severity

Background Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimised. This is usually achieved by administration of pharmacological agents such as adenosine, which adds to the cost of the procedure and cannot be administered to all patients. In this study we determine (1) if there is a time when resistance is naturally minimised at rest and (2) assess the diagnostic efficiency, compared to FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time. Methods 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 pharmacological vasodilatation with adenosine. Results Wave intensity analysis identified a wave-free period where 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 curve of 93%, at FFR<0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85% and 91%, respectively. Conclusion Intra-coronary resistance is naturally constant and minimised during a diastolic wave-free period. The instantaneous wave-Free Ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. Adoption of instantaneous wave-Free Ratio would enable the benefits of physiologically guided angioplasty to be applicable to a larger patient population.