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Early aspirin withdrawal, also known as P2Y12-inhibitor monotherapy, following percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) can reduce bleeding without a trade-off in efficacy. Still the average daily bleeding risk is highest during the first months and it remains unclear if aspirin can be omitted immediately following PCI. The LEGACY study is an open-label, multicenter randomized controlled trial evaluating the safety and efficacy of immediate P2Y12-inhibitor monotherapy versus dual antiplatelet therapy (DAPT) for 12 months in 3,090 patients. Patients are randomized immediately following successful PCI for NSTE-ACS to 75-100 mg aspirin once daily versus no aspirin. The primary hypothesis is that immediately omitting aspirin is superior to DAPT with respect to major or minor bleeding defined as Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, while maintaining noninferiority for the composite of all-cause mortality, myocardial infarction and stroke compared to DAPT. The LEGACY study is the first randomized study that is specifically designed to evaluate the impact of immediately omitting aspirin, and thus treating patients with P2Y12-inhibitor monotherapy, as compared to DAPT for 12 months on bleeding and ischemic events within 12 months following PCI for NSTE-ACS.

Evidence supporting the use of coronary physiology as an adjunct to coronary angiography to guide percutaneous coronary interventions has accumulated over the past 25 years. The fractional flow reserve has dominated this evolving physiological guidance of coronary intervention and its use is supported by large clinical outcome trials. However, despite clinical practice guidelines advocating its use in most patients with coronary stenosis who are eligible for coronary intervention, the uptake of a physiology-guided approach remains limited. The use of non-hyperaemic coronary pressure measurements to guide coronary interventions was introduced in an attempt to simplify the routine application of coronary physiology-guided intervention in daily practice. Over the past decade, a large scientific effort has focused on the development of several non-hyperaemic pressure ratios. In this Review, we detail the basic principles of coronary physiology in non-hyperaemic conditions, the rationale for the use of non-hyperaemic coronary pressure measurements for stenosis evaluation, the current evidence base for the available non-hyperaemic coronary pressure ratios, the basis for the discordance between non-hyperaemic coronary pressure ratios and fractional flow reserve, and the potential advantages of these new parameters over fractional flow reserve.Non-hyperaemic pressure measurements have emerged as a useful tool to guide coronary interventions and are recommended as a substitute for fractional flow reserve (FFR). In this Review, van de Hoef and colleagues explain the rationale for the use of non-hyperaemic pressure ratios instead of FFR for stenosis evaluation.

Background Coronary vascular dysfunction comprises VSA and/or MVA and is more common in women than in men with angina without obstructive coronary artery disease (ANOCA). Invasive coronary function testing is considered the reference test for diagnosis, but its burden on patients is large. We aimed to investigate the potential of electrocardiography (ECG) as noninvasive marker for vasospastic angina (VSA) and microvascular angina (MVA) diagnosis. Methods We systematically screened Pubmed and EMBASE databases for studies reporting on ECG characteristics in ANOCA patients with (a suspicion of) coronary vascular dysfunction. We assessed study quality using QUADAS‐2. We extracted data on diagnostic values of different ECG characteristics and analyzed whether the studies were sex‐stratified. Results Thirty publications met our criteria, 13 reported on VSA and 17 on MVA. The majority addressed repolarization‐related ECG parameters. Only 1 of the 13 VSA papers and 4 of the 17 MVA papers showed diagnostic accuracy measures of the ECG characteristics. The presence of early repolarization, T‐wave alternans, and inverted U waves showed of predictive value for VSA diagnosis. The QTc interval was predictive for MVA diagnosis in all six studies reporting on QTc interval. Sex‐stratified results were reported in only 5 of the 30 studies and 3 of those observed sex‐based differences. Conclusions ECG features are not widely evaluated in diagnostic studies for VSA and MVA. Those features predictive for VSA and MVA diagnosis mostly point to repolarization abnormalities and may contribute to noninvasive risk stratification.

To evaluate the first experience of real-time instantaneous wave–free ratio (iFR) measurement by clinicians. 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. 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. 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. 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. [Display omitted]

The aim was threefold: 1) expound the independent physiological parameters that drive FFR, 2) elucidate contradictory conclusions between fractional flow reserve (FFR) and coronary flow reserve (CFR), and 3) highlight the need of both FFR and CFR in clinical decision making. Simple explicit theoretical models were supported by coronary data analyzed retrospectively. FFR was expressed as a function of pressure loss coefficient, aortic pressure and hyperemic coronary microvascular resistance. The FFR-CFR relationship was also demonstrated mathematically and was shown to be exclusively dependent upon the coronary microvascular resistances. The equations were validated in a first series of 199 lesions whose pressures and distal velocities were monitored. A second dataset of 75 lesions with pre- and post-PCI measures of FFR and CFR was also analyzed to investigate the clinical impact of our hemodynamic reasoning. Hyperemic coronary microvascular resistance and pressure loss coefficient had comparable impacts (45% and 49%) on FFR. There was a good concordance (y = 0.96 x - 0.02, r2 = 0.97) between measured CFR and CFR predicted by FFR and coronary resistances. In patients with CFR < 2 and CFR/FFR ≥ 2, post-PCI CFR was significantly >2 (p < 0.001), whereas it was not (p = 0.94) in patients with CFR < 2 and CFR/FFR < 2. The FFR behavior and FFR-CFR relationship are predictable from basic hemodynamics. Conflicting conclusions between FFR and CFR are explained from coronary vascular resistances. As confirmed by our results, FFR and CFR are complementary; they could jointly contribute to better PCI guidance through the CFR-to-FFR ratio in patients with coronary artery disease.

Angina with nonobstructive coronary arteries (ANOCA) is a major cause of chronic coronary syndromes, affecting nearly half of patients with anginal symptoms who undergo invasive coronary angiography. ANOCA may lead to substantial symptom burden, increased risk of adverse cardiac events, increased healthcare utilization due to ongoing symptoms, repeat hospitalizations, and invasive testing. The pathophysiology of ANOCA often involves a variety of coronary disorders, such as coronary microvascular dysfunction, epicardial or microvascular vasospasm and endothelial dysfunction. While coronary function testing (CFT) can identify each of these specific endotypes, in current practice it is used as a second- or third-line diagnostic tool, delaying diagnosis which contributes to persistent symptoms and diminished quality of life. The ILIAS ANOCA clinical trial aims to enhance understanding and management of ANOCA through early routine CFT-guided management. After exclusion of obstructive coronary artery disease, eligible patients undergo comprehensive CFT, and will be randomized to blinding of the CFT results (control group) or disclosure of the CFT results combined with a tailored medical therapy escalation plan (intervention group). The control group will be unblinded after 1 year. The primary outcome is the mean difference in the within-subject change in Seattle Angina Questionnaire (SAQ) summary score between the groups at 6 months from baseline. Secondary outcomes include differences in SAQ-summary score and additional health-status and quality of life questionnaires at 12 and 24 months from baseline. International Clinical Trials Registry Platform identifier NL-OMON20739.

Revascularization decision for intermediate stenoses necessitates consideration of their hemodynamic impact. We report the use of distal coronary pressure (Pd) above proximal aortic pressure (Pa) during the early expansion period as a visual dichotomous marker (negative expansion resistance, NER) for rapid clinical decision-making. Simultaneous pressure and velocity signals were used to calculate instantaneous wave-free ratio (iFR), fractional flow reserve (FFR), hyperemic stenosis resistance (hSR), and to identify the NER. NER was defined as the Pd > Pa during the early-expansion period, which refers to early-decompression of coronary circulation marked by pressure decay (dP/dt < 0) coinciding the time-window of reduced ejection phase of systole to early diastole. Classification performance of NER was evaluated against iFR, FFR and hSR. Out of 475 lesions with mean diameter stenosis of 61% ± 16% from 388 patients with chronic coronary syndrome (CCS), 46%(217/475) exhibited the NER-phenomenon. Of these, 96% (209/217) had an iFR above 0.89(NPV = 0.96[95%CI 93–98] PPV = 0.47[95%CI 41–54]) indicating hemodynamically non-significant lesions. 94%(204/217) of the NER( +) lesions had an hSR below 0.80(NPV = 0.94 [95%CI 90–97] PPV = 0.36[95%CI 30–42]), and 88%(191/217) had an FFR above 0.80 (NPV = 0.88[95%CI 83–92] PPV = 0.53[95%CI 46–59]), indicating non-flow limiting lesions. Of 8 lesions with NER despite an abnormal iFR, only 1 had abnormal hSR, whereas 7 had normal hSR. Of 162 lesions with abnormal FFR, iFR identified 53 (33%) as ‘normal’ whereas NER was present in 26 (16%) of these cases.NER was associated with instantaneously stronger coronary decompression wave(8.0 ± 11.2 vs 5.5 ± 10.1 10.kW.m-2.s -2 p:0.016) and higher flow acceleration(195 ± 204 vs 106 ± 182 cm.s -2 p  < 0.001). In conclusion, the NER, visually recognized by resting pressure tracings, rules out flow-limiting lesions in CCS with high certainty, offering a simple first-line evaluation for clinical decision-making, and warrants prospective clinical studies.

Fractional flow reserve is routinely used to estimate the extent of myocardial ischaemia caused by the narrowing of a coronary artery. In this Review, the physiological basis of this measurement, its limitations, and its clinical use are discussed. Documentation of inducible myocardial ischaemia, related to the coronary stenosis of interest, is of increasing importance in lesion selection for percutaneous coronary intervention (PCI). Fractional flow reserve (FFR) is an easily understood, routine diagnostic modality that has become part of daily clinical practice, and is used as a surrogate technique for noninvasive assessment of myocardial ischaemia. However, the application of a single, discrete, cut-off value for FFR-guided lesion selection for PCI, and its adoption in contemporary revascularization guidelines, has limited the requirement for a thorough understanding of the physiological basis of FFR. This limitation constitutes an obstacle for the adequate use and interpretation of this technique, and also for the understanding of new and future modalities of physiological functional intracoronary testing. In this Review, we revisit the fundamental elements of coronary physiology in the absence or presence of coronary artery disease. We provide insight into three essential characteristics of FFR as a diagnostic tool in contemporary clinical practice—the theoretical framework of FFR and its associated limitations; the characteristics and role of FFR as a surrogate for noninvasively assessed myocardial ischaemia; and the requirement and associated caveats of potent vasodilatory drugs to induce maximal vasodilatation of the coronary vascular bed. Key Points Fractional flow reserve (FFR) is an invasive technique that was introduced as a surrogate for noninvasive assessment of inducible myocardial ischaemia FFR is the physiological index of choice to evaluate functional lesion severity, because it is cost-effective and its use has unequivocal clinical benefit to patients with stable coronary artery disease The relationship between FFR and inducible myocardial ischaemia and, therefore, the accuracy of FFR to identify ischaemia-generating stenoses, as based on a single, predefined cut-off value, can differ between patients FFR is based on a simplified, theoretical framework of the coronary circulation, which has important consequences for appropriate use and interpretation that should be considered in daily clinical practice The technique to measure FFR should adhere to methods used in validation studies, especially the methods used to achieve maximal vasodilatation, to ensure appropriate lesion selection for percutaneous coronary intervention Full physiological investigation of a coronary lesion requires simultaneous assessment of intracoronary pressure and flow, thereby separating the contributions of epicardial and microvascular resistance to reduced blood flow

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

It remains uncertain if invasive coronary physiology beyond fractional flow reserve (FFR) can refine lesion selection for revascularization or provide additional prognostic value. Coronary flow reserve (CFR) equals the ratio of hyperemic to baseline flow velocity and has a wealth of invasive and noninvasive data supporting its validity. Because of fundamental physiologic relationships, binary classification of FFR and CFR disagrees in approximately 30%-40% of cases. Optimal management of these discordant cases requires further study. The aim of the study was to determine the prognostic value of combined FFR and CFR measurements to predict the 24-month rate of major adverse cardiac events. Secondary end points include repeatability of FFR and CFR, angina burden, and the percentage of successful FFR/CFR measurements which will not be excluded by the core laboratory. This prospective, nonblinded, nonrandomized, and multicenter study enrolled 455 subjects from 12 sites in Europe and Japan. Patients underwent physiologic lesion assessment using the 0.014” Philips Volcano ComboWire XT that provides simultaneous pressure and Doppler velocity sensors. Intermediate coronary lesions received only medical treatment unless both FFR (≤0.8) and CFR (<2.0) were below thresholds. The primary outcome is a 24-month composite of death from any cause, myocardial infarction, and revascularization. The DEFINE-FLOW study will determine the prognostic value of invasive CFR assessment when measured simultaneously with FFR, with a special emphasis on discordant classifications. Our hypothesis is that lesions with an intact CFR ≥ 2.0 but reduced FFR ≤ 0.8 will have a 2-year outcome with medical treatment similar to lesions with FFR> 0.80 and CFR ≥ 2.0. Enrollment has been completed, and final follow-up will occur in November 2019.