The baseline instantaneous wave-free ratio as an index of coronary disease severity: relationship with fractional flow reserve and coronary flow reserve

Over the last 30 years the development of invasive methods to directly measure the haemodynamic impact of individual coronary stenoses on blood flow has enabled the identification of vessel-specific and lesion-specific ischaemia. Fractional flow reserve (FFR) is the most commonly used technique, largely due to the simplification brought by its pressure-only methodology. Despite the evidence accumulated demonstrating the benefits of FFR-guided decisions, its adoption remains low worldwide (6-8%) and a large proportion of patients with coronary artery disease (CAD) still undergo percutaneous interventions without any objective evidence of myocardial ischaemia. This is partly due to FFR’s reliance on the induction of coronary hyperaemia, a methodological step which adds time, cost and inconvenience for patients and clinicians. Recently, our group presented a novel invasive pressure-only methodology, the instantaneous wave-free ratio (iFR), which differs from FFR as it can be calculated at baseline, without the need for vasodilator administration. In its initial validation studies, iFR demonstrated a close diagnostic agreement with FFR and with invasive coronary flow. In this thesis, I will present a series of studies which aim to further evaluate the utility of iFR as an index coronary stenosis severity. Firstly, I will explore its diagnostic relationship with FFR in details and present a novel methodology to measure classification agreement between methods of clinical measurement. Secondly, I will evaluate the merits of utilising iFR and FFR in a common diagnostic pathway and quantify the potential benefits of such a strategy to spare patients from the need for vasodilator administration. Finally, I will investigate the relationship between pressure-only indices (iFR and FFR) and coronary flow reserve, an extensively validated marker of prognosis in coronary disease.Open Acces

Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis.

AIMS: This meta-analysis aims to quantify the association of reduced coronary flow with all-cause mortality and major adverse cardiovascular events (MACE) across a broad range of patient groups and pathologies. METHODS AND RESULTS: We systematically identified all studies between 1 January 2000 and 1 August 2020, where coronary flow was measured and clinical outcomes were reported. The endpoints were all-cause mortality and MACE. Estimates of effect were calculated from published hazard ratios (HRs) using a random-effects model. Seventy-nine studies with a total of 59 740 subjects were included. Abnormal coronary flow reserve (CFR) was associated with a higher incidence of all-cause mortality [HR: 3.78, 95% confidence interval (CI): 2.39-5.97] and a higher incidence of MACE (HR 3.42, 95% CI: 2.92-3.99). Each 0.1 unit reduction in CFR was associated with a proportional increase in mortality (per 0.1 CFR unit HR: 1.16, 95% CI: 1.04-1.29) and MACE (per 0.1 CFR unit HR: 1.08, 95% CI: 1.04-1.11). In patients with isolated coronary microvascular dysfunction, an abnormal CFR was associated with a higher incidence of mortality (HR: 5.44, 95% CI: 3.78-7.83) and MACE (HR: 3.56, 95% CI: 2.14-5.90). Abnormal CFR was also associated with a higher incidence of MACE in patients with acute coronary syndromes (HR: 3.76, 95% CI: 2.35-6.00), heart failure (HR: 6.38, 95% CI: 1.95-20.90), heart transplant (HR: 3.32, 95% CI: 2.34-4.71), and diabetes mellitus (HR: 7.47, 95% CI: 3.37-16.55). CONCLUSION: Reduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes. This finding supports recent recommendations that coronary flow should be measured more routinely in clinical practice, to target aggressive vascular risk modification for individuals at higher risk

Invasive coronary physiology in patients with angina and non-obstructive coronary artery disease: a consensus document from the coronary microvascular dysfunction workstream of the British Heart Foundation/National Institute for Health Research Partnership

Nearly half of all patients with angina have non-obstructive coronary artery disease (ANOCA); this is an umbrella term comprising heterogeneous vascular disorders, each with disparate pathophysiology and prognosis. Approximately two-thirds of patients with ANOCA have coronary microvascular disease (CMD). CMD can be secondary to architectural changes within the microcirculation or secondary to vasomotor dysfunction. An inability of the coronary vasculature to augment blood flow in response to heightened myocardial demand is defined as an impaired coronary flow reserve (CFR), which can be measured non-invasively, using imaging, or invasively during cardiac catheterisation. Impaired CFR is associated with myocardial ischaemia and adverse cardiovascular outcomes. The CMD workstream is part of the cardiovascular partnership between the British Heart Foundation and The National Institute for Health Research in the UK and comprises specialist cardiac centres with expertise in coronary physiology assessment. This document outlines the two main modalities (thermodilution and Doppler techniques) for estimation of coronary flow, vasomotor testing using acetylcholine, and outlines a standard operating procedure that could be considered for adoption by national networks. Accurate and timely disease characterisation of patients with ANOCA will enable clinicians to tailor therapy according to their patients’ coronary physiology. This has been shown to improve patients’ quality of life and may lead to improved cardiovascular outcomes in the long term

Fractional Flow Reserve/ Instantaneous Wave-Free Ratio Discordance in Angiographically Intermediate Coronary Stenoses: An Analysis Using Doppler-Derived Coronary Flow Measurements

OBJECTIVES The study sought to determine the coronary flow characteristics of angiographically intermediate stenoses classified as discordant by fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR). BACKGROUND Discordance between FFR and iFR occurs in up to 20% of cases. No comparisons have been reported between the coronary flow characteristics of FFR/iFR discordant and angiographically unobstructed vessels. METHODS Baseline and hyperemic coronary flow velocity and coronary flow reserve (CFR) were compared across 5 vessel groups: FFRþ/iFRþ (108 vessels, n 1�4 91), FFR–/iFRþ (28 vessels, n 1�4 24), FFRþ/iFR– (22 vessels, n 1�4 22), FFR–/iFR– (208 vessels, n 1�4 154), and an unobstructed vessel group (201 vessels, n 1�4 153), in a post hoc analysis of the largest combined pressure and Doppler flow velocity registry (IDEAL [Iberian-Dutch-English] collaborators study). RESULTS FFRdisagreedwithiFRin14%(50of366).Baselineflowvelocitywassimilaracrossall5vesselgroups,includingthe unobstructed vessel group (p 1�4 0.34 for variance). In FFRþ/iFR– discordants, hyperemic flow velocity and CFR were similar to both FFR–/iFR– and unobstructed groups; 37.6 (interquartile range [IQR]: 26.1 to 50.4) cm/s vs. 40.0 [IQR: 29.7 to 52.3] cm/s and 42.2 [IQR: 33.8 to 53.2] cm/s and CFR 2.36 [IQR: 1.93 to 2.81] vs. 2.41 [IQR: 1.84 to 2.94] and 2.50 [IQR: 2.11 to 3.17], respectively (p > 0.05 for all). In FFR–/iFRþ discordants, hyperemic flow velocity, and CFR were similar to the FFRþ/iFRþ group; 28.2 (IQR: 20.5 to 39.7) cm/s versus 23.5 (IQR: 16.4 to 34.9) cm/s and CFR 1.44 (IQR: 1.29 to 1.85) versus 1.39 (IQR: 1.06 to 1.88), respectively (p > 0.05 for all). CONCLUSIONS FFR/iFR disagreement was explained by differences in hyperemic coronary flow velocity. Furthermore, coronary stenoses classified as FFRþ/iFR– demonstrated similar coronary flow characteristics to angiographically unobstructed vessels

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

Background: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. Methods: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. Findings: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI −8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. Interpretation: In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy

The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually

Background: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. Aims: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. Methods: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. Results: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. Conclusion: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease

Achieving Optimal Medical Therapy: Insights From the ORBITA Trial

Background: In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo-controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline-directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results: After enrollment into the ORBITA trial, all 200 patients entered a 6-week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2-4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0-1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions: In the 12-week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer-term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02062593

Clinical Events After Deferral of LAD Revascularization Following Physiological Coronary Assessment

BACKGROUND Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR). OBJECTIVES The purpose of this study was to establish the safety of deferring treatment in the LAD using FFR or iFR within the DEFINE-FLAIR trial. METHODS MACE rates at 1 year were compared between groups (iFR and FFR) in patients whose physiological assessment led to LAD lesions being deferred. MACE was defined as a composite of cardiovascular death, myocardial infarction (MI), and unplanned revascularization at 1 year. Patients, and staff performing follow-up, were blinded to whether the decision was made with FFR or iFR. Outcomes were adjusted for age and sex. RESULTS A total of 872 patients had lesions deferred in the LAD (421 guided by FFR, 451 guided by iFR). The event rate with iFR was significantly lower than with FFR (2.44% vs. 5.26%; adjusted HR: 0.46; 95% confidence interval [CI]: 0.22 to 0.95; p = 0.04). This was driven by significantly lower unplanned revascularization with iFR and numerically lower MI (unplanned revascularization: 2.22% iFR vs. 4.99% FFR; adjusted HR: 0.44; 95% CI: 0.21 to 0.93; p = 0.03; MI: 0.44% iFR vs. 2.14% FFR; adjusted HR: 0.23; 95% CI: 0.05 to 1.07; p = 0.06). CONCLUSIONS iFR-guided deferral appears to be safe for patients with LAD lesions. Patients in whom iFR-guided deferral was performed had statistically significantly lower event rates than those with FFR-guided deferral. (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe