Author + information
- Javier Escaned, MD, PhD∗ ( and )
- Hernán Mejía-Rentería, MD
- ↵∗Address for correspondence:
Dr. Javier Escaned, Hospital Clinico San Carlos IDISSC, Prof. Martin Lagos s/n, 28040 Madrid, Spain.
Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) play an important role as gatekeepers for appropriate coronary revascularization in stable patients. Although their use in decision-making improves patient outcomes compared with angiography alone, every FFR/iFR trial has consistently reported a given long-term percentage of cardiac events in deferred revascularization patients (1). In practical terms, an FFR >0.80 or iFR >0.89 rightly indicates that revascularization will not help the patient, but it does not imply that the patient is risk free. It is quite likely that some of these clinical events have an origin in microcirculatory dysfunction, which is not explored by pressure-derived indices.
What Do Physiological Indices Tell Us About Coronary Circulation?
The epicardial vessels play a key role in conductance and distribution of blood to the different myocardial territories. This is why relative estimates of coronary conductance, such as FFR or iFR, are so useful in anticipating the potential effect of revascularization on coronary hemodynamics. In contrast to the function of epicardial vessels, the key role of the microcirculation is matching coronary blood supply to myocardial oxygen requirements (i.e., it is a system of varying conductance). In this regard, coronary flow reserve (CFR) is the most appropriate index to appraise the functionality of the microcirculation: it is an index that explores this dynamic function.
In the field of invasive cardiology, CFR has been heavily criticized as a physiological index. The main theoretical reasons include the dependence of CFR values on resting or baseline flow measurements, the lack of a sharp FFR-like cutoff, and the inability to explore separately the epicardial and microcirculatory domains. But perhaps the most relevant reason for its virtual abandonment in the catheterization laboratory was the arrival of FFR: a simple, practical index for interventionalists, whose diagnostic and therapeutic work in coronary artery disease is largely focused on the epicardial vessels.
In this issue of JACC: Cardiovascular Interventions, Lee et al. (2) report their very interesting research on the value of CFR in the FFR era. Investigators from 5 South Korean centers pooled a total of 519 consecutive patients with stable coronary artery disease who underwent, as part of their routine clinical practice, measurements of FFR and thermodilution-based CFR in 737 vessels. The authors focused their research on patients who had revascularization was deferred, classifying them into 4 groups according to dichotomous FFR and CFR values (using 0.80 and 2.00 as cutoff values, respectively). Vessel-oriented (VOCO) and patient-oriented outcomes at 5-year follow-up were adjudicated by an independent clinical events committee, and compared between study groups.
The characteristics of the study population deserve some comment. First, only 26% of the 849 interrogated stenoses presented FFR ≤0.80: 112 treated with percutaneous coronary intervention (PCI) (excluded from subsequent analysis) and 106 deferred and followed up. Contemporary FFR trials report much higher rates of FFR ≤0.80 lesions: 77% in the FAME II (Fractional Flow Reserve (FFR) Guided Percutaneous Coronary Intervention (PCI) Plus Optimal Medical Treatment (OMT) Versus OMT) (3) and 35% in the DEFINE FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) (4) trials (the latter being more representative of real-life FFR populations). This suggests that the investigators interrogated milder obstructive disease than in published FFR studies, perhaps reflecting their proficiency in CFR and their interest in both epicardial vessel and microcirculatory status. In any case, from the perspective of obstructive disease, this could imply a lower-risk population. It also remains unclear why revascularization was deferred in 106 lesions with FFR ≤0.80. If, for example, PCI deferral was due to unfavorable lesion characteristics, this might have implications for long-term outcome.
Abnormal microcirculatory function was frequent in patients with deferred revascularization (22% of lesions presenting with abnormal CFR). Only older age and a smaller vessel lumen (probably reflecting diffuse epicardial disease) predicted which patients were most likely to have impaired CFR. Yet, a low CFR was associated with an overall 5-year event rate of 11%, a figure that must be taken seriously, given that it was similar to that of patients with FFR ≤0.80 (12%). These were not the same patients, however: a mismatch in categorical classification of FFR and CFR occurred in around one-third of patients.
Does CFR Contribute to Better Patient Risk Stratification?
The most interesting observations of the study are derived from the combined analysis of FFR and CFR. The authors found better clinical outcomes in patients with nonsignificant (FFR >0.80) stenosis and preserved microcirculation (CFR >2.00), with an outstanding 5-year VOCO rate of 2.9%. This raises the possibility of better predicting good long-term outcomes when both FFR and CFR are concordantly normal. It could be argued that such favorable outcomes in the concordantly normal group stem from the discussed low-risk profile of the study population. But this objection becomes less plausible when we consider the outcomes of patients with FFR >0.80 lesions and abnormal CFR (22% of FFR >0.80 cases), who presented a more than 3-fold increase in 5-year VOCO rate (9.8%) compared with the concordantly normal group.
What clinical events were observed in patients with FFR >0.80 according to CFR findings? The results are interesting because in these patients, vessel-specific revascularization was performed not solely based on persistence of symptoms, but rather on documented progression of obstructive disease; however, we cannot draw firm conclusions from this due to the relatively low number of events. Repeat revascularization was due to deferred lesion progression in 100% of patients (5 of 5) with concordantly normal FFR/CFR. By contrast, in patients with FFR >0.80 and abnormal CFR, repeat revascularization was caused by new obstructive disease in other coronary segments in 60% (3 of 5), and one-half of deaths (50%, 4 of 8) were due to MI or sudden death. These findings reflect the WISE (Women’s Ischemia Syndrome Evaluation) study (5), in which an abnormal CFR in the absence of obstructive disease anticipated the development of epicardial lesions.
Together, these findings suggest that CFR has an important incremental value over FFR alone in stratifying patient risk. It may contribute to identifying a high-risk phenotype of cardiovascular disease: namely, in those patients who, having obstructive epicardial atheroma, the predominant abnormality of coronary hemodynamics relates to microcirculatory dysfunction (Figure 1).
The study provides interesting data on another interesting group of FFR/CFR discordance: those with CFR >2.00 but abnormal FFR. In these patients, it has been proposed that because CFR is not significantly affected by the hemodynamic effect of the epicardial stenosis, PCI might be deferred despite an FFR ≤0.80. Although the relative VOCO rate was not significantly different from the FFR >0.80/CFR ≤2.00 discordant group, the nature of clinical events was substantially different: repeat revascularization was triggered by angina aggravation or unstable angina (i.e., without progression of obstructive disease) in 2 patients (2 of 3), and only 1 death (1 of 3) had a documented cardiac origin. This deserves further investigation: it remains plausible that clinicians opted for PCI due to persistence of angina and an FFR ≤0.80, even in the absence of documented progression of disease. Finally, the fact that the event rate was highest in patients with concordantly abnormal FFR and CFR supports the recent 5-year results of the FAME II study and the performance of coronary revascularization in these patients.
The findings made by Lee et al. (2) probably could be refined by applying additional methodological approaches, such as calculating coronary flow capacity (6) (which circumvents some of the aforementioned theoretical shortcomings of CFR) or microcirculatory resistance. Yet, the evidence gathered in this study supports the value of CFR in obtaining a more comprehensive assessment of patients with ischemic heart disease and the need for simpler and more accurate tools to measure intracoronary flow. For the time being, what we have learned from our Korean colleagues is that in the iFR/FFR era, CFR is too valuable an index to be neglected in the catheterization laboratory.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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