Table of Contents
OPINION
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 5-12

Insights into the role of fractional flow reserve in clinical practice


Singapore Heart, Stroke and Cancer Center, Singapore

Date of Submission14-Mar-2020
Date of Acceptance16-Mar-2020
Date of Web Publication4-Apr-2020

Correspondence Address:
Prof. Michael Chun-Leng Lim
Singapore Heart, Stroke and Cancer Centre
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cp.cp_7_20

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  Abstract 


The early trials of fractional flow reserve (FFR), such as the Deferral versus Performance of Percutaneous Transluminal Coronary Angioplasty in Patients Without Documented Ischaemia, FFR versus angiography for multivessel evaluation (FAME), and FAME 2 trials, established the role of FFR in the practice of interventional cardiology. These trials led proponents of FFR to propose making FFR a routine procedure before percutaneous coronary intervention (PCI) and to give preference to PCI over optimal medical therapy (OMT) in those with FFR-positive coronary stenoses. Follow-up results of these trials have given more insights. Some of the benefits of FFR-guided strategy over angiography-guided strategy disappeared over time, and beyond revascularization, the FFR strategy did not show benefit over OMT when considering death and myocardial infarction as endpoints. The FUnctional Testing Underlying Coronary REvascularization trial did not demonstrate the superiority of the FFR-guided strategy over angiography-guided strategy. The ORBITA and the ISHEMIA trials gave strength to the lifestyle modification and OMT approach in stable ischemic heart disease patients with moderate-to-severe ischemia. The role of FFR has to be defined in light of the evolving clinical advances in medicine and new evidence. An in-depth review of all current evidence provides no compelling evidence for the routine use of FFR in cardiac interventions. However, FFR can play a role in coronary stenoses where there is uncertainty in the hemodynamic impact of the lesions.

Keywords: Coronary angiography, fractional flow reserve, optimal medical therapy, percutaneous coronary intervention, stable angina


How to cite this article:
Lim MC. Insights into the role of fractional flow reserve in clinical practice. Cardiol Plus 2020;5:5-12

How to cite this URL:
Lim MC. Insights into the role of fractional flow reserve in clinical practice. Cardiol Plus [serial online] 2020 [cited 2020 Sep 26];5:5-12. Available from: http://www.cardiologyplus.org/text.asp?2020/5/1/5/281943




  Introduction Top


The use of fractional flow reserve (FFR) stemmed from a desire to identify which stenoses were hemodynamically significant and were most likely to benefit from intervention. FFR is the ratio of maximum blood flow distal to a stenotic lesion to normal maximum flow in the same vessel. The concept of using FFR wasfirst studied in patients with single coronary artery stenosis using three different noninvasive stress tests (exercise test, thallium scan, and stress echocardiogram), which led to the proposal of a cutoff FFR value of 0.75 as a threshold for discrimination between ischemia-inducible and ischemia-noninducible lesions.[1] This concept wasfirst tested in the Deferral versus Performance of Percutaneous Transluminal Coronary Angioplasty in Patients Without Documented Ischaemia (DEFER) trial. The DEFER trial demonstrated the importance of assessing the significance of hemodynamic changes in the vessel beyond the angiographic severity.[2],[3] Subsequent trials such as the FFR Versus Angiography for Multivessel Evaluation (FAME) and FFR-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Versus Optimal Medical Treatment Alone in Patients with Stable Coronary Artery Disease (FAME 2) trials were performed to compare FFR-guided revascularization and conventional practice.[4],[5],[6],[7],[8],[9],[10],[11]

The results of these trials anchored the role of FFR in interventional cardiology. Subsequent trials such as the FUnctional Testing Underlying Coronary REvascularization (FUTURE) trial, the Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial, and the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial provided different perspectives to the role of FFR. In this article, the role of FFR is reexamined in light of data from more recent trials.[12],[13],[14],[15],[16],[17],[18],[19],[20]


  DEFER Trial Top


In the DEFER study, a total of 325 patients with coronary stenosis of >50% were randomized to either the percutaneous coronary intervention (PCI) group or PCI-deferral group.[3] The study examined the safety and outcomes of deferring stenting in angiographic (FFR>0.75) stenoses. FFR was measured just before the planned intervention. If FFR was ≥0.75, patients were randomly assigned to deferral (Defer group; n = 91) or PCI (Perform group; n = 90). If FFR was <0.75, PCI was performed as planned (reference group; n = 144). Clinical follow-up was 5 years. Event-free survival (freedom from all-cause mortality, myocardial infarction [MI], coronary artery bypass graft surgery [CABG], and PCI) was not different between the Defer and Perform groups (80% and 73%, respectively; P = 0.52), but was significantly worse in the Reference group (63%). The composite rate of cardiac death and acute MI in the Defer, Perform, and Reference groups was 3.3%, 7.9%, and 15.7%, respectively (P = 0.21 for Defer vs. Perform group; P = 0.003 for the reference vs. both other groups). Angina free on follow-up was similar for the Defer and Performed groups. The authors concluded that the 5-year outcome after deferral of PCI of intermediate coronary stenosis based on FFR ≥0.75 was excellent, and the risk of cardiac death or MI related to this stenosis was <1% per year and was not decreased by PCI. At 15-year follow-up, the all-cause mortality and repeat revascularization were similar for all the three groups, although there was a higher incidence of myocardial infarction for Perform and Reference groups as compared to the Defer group (Defer 2.2%, Perform 10%, and Reference 12.5% vs. P = 0.03 for defer vs. perform).[2]

The DEFER trial demonstrated that for a stenosis with an FFR >0.75, PCI did not confer an advantage over optimal medical therapy (OMT) for a follow-up period of up to 15 years and was associated with a higher risk of MI as compared to OMT. The main limitation of this trial was that it was performed during the era of thick strut bare-metal stents and at which time medical therapy was limited, and hence outcomes may not be representative of the current practice.


  FAME Trial Top


After the DEFER trial, the FAME trial was conducted to compare FFR-guided revascularization with conventional angiography-guided revascularization.[4] The FAME study, a landmark trial on the use of FFR, concluded that routine measurement of FFR in patients with multivessel coronary artery disease who are undergoing PCI with drug-eluting stents significantly reduces the rate of the composite endpoint of death, nonfatal MI, and repeat revascularization at 1 year. In this study, patients were included in the study if they had multivessel coronary artery disease, which was defined as coronary artery stenoses of at least 50% of the vessel diameter in at least two of the three major epicardial coronary arteries, and if PCI was indicated. A total of 1005 patients were randomized: 509 to FFR-guided PCI and 496 to angiography-guided PCI. The mean Syntax score in both the FFR and angiography groups was 14.5. In the FFR group, stenting was only performed for those lesions with an FFR ≤0.8.

There was a statistically significant difference in the primary endpoint (major adverse cardiovascular events [MACEs] which is a composite of death, MI, and repeat revascularization) between the FFR-guided group (67 patients) and the angiography-guided group (91 patients) at 1 year (13.2% vs. 18.3%, P = 0.02). The study reported 1-year all-cause mortality of 3.0% (15 deaths, 10 of which had cardiac causes) in the angiography group and 1.8% (9 deaths, 7 of which had cardiac causes) in the FFR group (P = 0.19). MI occurred in 43 patients (8.7%) in the angiography group and in 29 (5.7%) in the FFR group (P = 0.07). A total of 47 patients (9.5%) in the angiography group and 33 (6.5%) in the FFR group required repeat revascularization (P = 0.08). Nearly 67.6% of the patients in the angiography group and 73.0% in the FFR group did not have an event and were free from angina at 1 year (P = 0.07). After 5 years, comparing the FFR group with the angiography group, the MACEs occurred in 28% versus 31% (P = 0.31), the mortality was 9% versus 10% (P = 0.5), the MI was 9% versus 12% (P = 0.2), and repeat revascularization was 15% versus 17% (P = 0.49).[5]

At the end of 1 year, there was a statistically significant difference in the MACEs between the FFR-guided and the angiography-guided groups. There was no statistically significant difference in the mortality, MI, repeat revascularization, angina free, and quality of life (measured by the EuroQOL-5D) between the FFR-guided group and the angiography-guided group. However, at the end of 5 years, this “advantage” was lost, and there was no statistically significant difference in the MACEs, mortality, MI, and repeat revascularization between the FFR-guided group and the angiography-guided group.[5]

The FAME results also showed that 89.6% of the patients in the FFR-guided group had at least one stenotic lesion that had an FFR <0.80, indicating ischemia, and 63.0% of all lesions that were measured had an FFR <0.80. Hence, in the more than a third of “significant” angiographic stenoses deemed as having no significant ischemia (using the criteria of FFR >0.8), OMT instead of PCI was not associated with a higher incidence of MI, mortality, or revascularization in the FFR-guided group.


  FAME 2 Trial Top


In the FAME 2 study, 888 patients who had at least one stenosis of at least 50% diameter reduction in at least one major native epicardial coronary artery with a diameter of at least 2.5 mm and supplying viable myocardium were randomized to PCI and OMT and OMT alone.[10] Patients who had at least one stenosis in a major coronary artery with an FFR <0.80 were randomly assigned. The primary MACEs endpoint (death, MI, and urgent revascularization) was statistically significantly lower in the PCI + OMT arm compared with the OMT arm (4.3% vs. 12.7%; P < 0.001). This was driven predominantly by a statistically significant reduction in the need for urgent revascularization (1.6% vs. 11.1%, P < 0.001). The rates of death (0.2% vs. 0.7%) and MI (3.4% vs. 3.2%) were similar. In the PCI + OMT group versus the OMT group, there were 1 cardiac death (0.2%) versus 1 cardiac death and 2 noncardiac deaths (3 deaths = 0.7%), 15 MI (3.4%) versus 14 MI (3.2%), and 7 urgent revascularization versus 49 urgent revascularization.

At 2 years, the primary MACE endpoint (death, MI, and urgent revascularization) continued to be statistically significantly lower in the PCI + OMT arm compared with the OMT arm (8.1% vs. 19.5%, P < 0.001). In addition, the revascularization rates were statistically significantly lower in the PCI arm (8.1% vs. 40.6%, P < 0.001). There was no statistically significant difference in death (1.3% vs. 1.8%, P = 0.58), MI (5.8% vs. 6.8%, P = 0.56), and death/MI (6.5% vs. 8.2%, P = 0.35).[9]

Results for the primary MACE endpoint were sustained at 5 years of follow-up for PCI + OMT (62 patients) vs. OMT (119 patients) (13.9% vs. 27.0%; P < 0.001). Death (23 deaths each; 5.1% vs. 5.2%) and MI (8.1% vs. 12.0%) were similar.[6] Deaths from cardiac causes were higher in the PCI-OMT group (11 deaths; 2.5%) versus the OMT group (7 deaths; 1.6%). The number of deaths from the registry group was 3 (1.8%). The FAME 2 investigators concluded that the stenoses with demonstrable ischemia represented by an FFR <0.8 should be revascularized rather than being managed solely with OMT. One of the major limitations of the study was early termination of the study and a mandated mean follow-up of approximately 7 months.


  FUTURE Trial Top


The FUTURE trial's objective was to compare the clinical outcomes and cost-effectiveness of coronary angiographic guidance to coronary angiography with FFR in patients with multivessel coronary artery disease.[12] The FUTURE trial, sponsored by the French government, enrolled 864 patients with three-vessel or two-vessel disease, including the left anterior descending artery. About 50% of the patients had three-vessel disease and a SYNTAX score of about 18. For patients who underwent FFR, only 2% experienced complications. The mean FFR was 0.77, and 43% of lesions had FFR >0.8. The angiography-guided group had a higher PCI rate (79%), with 12% undergoing CABG and 9% solely on OMT. The FFR-guided group had a lower PCI rate (71%), identical CABG rate (12%), and higher optimal medical rate (17%).

The FUTURE trial was stopped early because of an excess in all-cause mortality in the FFR group. The study showed that there was no significant difference in the primary outcome (all-cause death, MI, or stroke) between the FFR-guided revascularization and angiography-guided revascularization in patients with ≥2 coronary stenoses (≥50%) at 1 year (14.4% vs. 14.6%, P = 0.94). However, the risk of death was statistically significantly higher in the FFR group compared with angiography group (3.7% vs. 1.5%; P = 0.036).

The lead investigator, Dr. Rioufol, hypothesized that the higher death rates in the FFR group could be due to the lower-than-expected rate of CABG in these patients with multivessel disease, the higher rate of PCI in severe patients with a SYNTAX score over 32, and the high rate of ad hoc PCI. However, the rate of CABG was identical in both groups and the incidence of ad hoc PCI was about 90% in both groups. Although not statistically significant, there was a higher incidence of worse outcome in FFR-guided patients with a SYNTAX score >32. He also noted that the FFR patients had more severe disease with more three-vessel disease and very high SYNTAX score.

The FUTURE trial brings more questions into the role of FFR in stable angina. In the FAME study, at the end of 1 year, there was a statistically significant difference in the MACE between the FFR-guided and the angiography-guided groups, but when the components of MACE are examined individually, the results were similar in both groups. In comparison, the FUTURE trial showed similar MACE rates, but there was a significant twofold elevation in the risk of death in the FFR group. This was despite the fact that the angiography group had a higher PCI rate (79%), as compared to the FFR group (71%). Hence, contrary to the FAME data which suggested that FFR-guided strategy was superior to angiography-guided strategy in outcomes, the FUTURE data showed no superiority of FFR-guided PCI over angiography-guided PCI.


  ORBITA Trial Top


The Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial demonstrated that in stable angina patients with functionally significant stenoses on FFR, PCI when compared to a sham procedure with OMT did not improve exercise parameters or anginal frequency.[14],[16] The aim of the trial was to assess the efficacy of PCI as compared with a sham placebo procedure for angina relief among patients with stable angina. The ORBITA trial enrolled 230 patients, of which 103 patients underwent PCI and 93 underwent the sham placebo procedure. The mean FFR was 0.69 (75% of patients had FFR <0.80) and instantaneous wave-free ratio (iFR) of 0.76, and both were almost identical in both groups. Almost all the patients (97%) had one or more positive tests for ischemia. There was no significant difference in the primary endpoint of exercise time increment between groups. There were no deaths, but there were a few serious adverse events which 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. The PCI group did show more effective reduction of ischemia as ascertained by stress echocardiography. There was a correlation between lower baseline FFR values and larger improvements in stress echocardiography post-PCI. In this study, the authors were not able to demonstrate that functional tests were better able to identify the patients who would benefit from PCI. In a subsequent analysis, the authors reported that patient-reported freedom from angina was higher after PCI than after a sham procedure, but functional testing (FFR nor iFR) did not modify that effect. There was no relationship seen between pre-PCI functional test results and anginal frequency at 6 weeks. In addition to the results of FUTURE trial, the results of the ORBITA trial will make it difficult to justify the routine use of FFR in stable angina.


  ISCHEMIA Trial Top


The ISCHEMIA trial was designed to evaluate routine invasive therapy (coronary angiography and revascularization) compared with OMT among patients with stable ischemic heart disease and moderate-to-severe myocardial ischemia on noninvasive stress testing.[18],[19],[20] This was the largest randomized trial of an invasive versus conservative strategy for patients with stable ischemic heart disease, enrolling a total of 5179 with a median follow-up period of 3.3 years. Patients that were included had an objective demonstration of moderate-to-severe ischemia on noninvasive evaluation including ≥10% ischemia on nuclear perfusion scans, ≥3 segments of ischemia on stress echocardiography, ≥12% ischemia and/or ≥3 segments with ischemia on cardiac magnetic resonance perfusion scan, or ≥1.5 mm ST depression in ≥2 leads or ≥2 mm ST depression in a single lead at <7 METs with angina exercise treadmill test. The primary endpoint (MACE) was a composite of cardiovascular death, nonfatal MI, resuscitated cardiac arrest, hospitalization for unstable angina, or heart failure. The major secondary endpoints were cardiovascular death and MI. All randomized patients received lifestyle and OMT interventions. Those who were randomized to the invasive strategy underwent coronary angiography, followed by revascularization with PCI or CABG surgery. Those randomized to the OMT underwent coronary angiography only for failure of OMT. Nearly 75% of the enrolled patients had undergone coronary computed tomography angiography, of which 79% had multivessel coronary artery disease, 87% had left anterior descending stenosis (proximal in 47%), and 46% had triple-vessel coronary artery disease. Ischemia was severe in 54% of the patients.

By year 2, the event rate for the study endpoints was similar between both groups (9% vs. 9.5%). By 4 years, the MACE event rate was 2.2% lower in the invasive group as compared to the OMT group (13.3% vs. 15.5%), but this was not statistically significant. The main causal factor for this is the higher rate of procedural MI but a lower rate of spontaneous MI in the invasive group. Similarly, the major secondary endpoint of cardiovascular death or MI (11.7% in an invasive group versus 13.9% OMT group) was also not statistically significant. Despite the ischemic burden and the extensive coronary artery disease, the all-cause mortality was low in both groups (6.5% with the invasive group and 6.4% with the OMT group).

The ISCHEMIA trial found that an invasive approach as compared to lifestyle and OMT did not demonstrate a reduction in MACEs in stable patients with moderate-to-severe ischemia over a median period of 3.3 years. There was no significant reduction in both the primary endpoint and the major secondary endpoint.

An interesting finding in the ISCHEMIA trial was that the overall cardiac event rate during the study was lower than what was projected by the investigators 10 years ago. The investigators attributed this to advances in OMT and revascularization techniques. They recommended that all patients with stable ischemic heart disease should have lifestyle modification and OMT as the initial strategy, and if they still have angina despite OMT, an invasive heart procedure may provide a more lasting improvement in the quality of life.


  Fractional Flow Reserve and the Current Practice of Medicine Top


At present, the European Society of Cardiology (ESC) guidelines recommend the use of FFR to identify hemodynamically relevant coronary lesion(s) in stable patients when evidence of ischemia is not available (Class I recommendation, Level of Evidence A) and the use of FFR-guided PCI in patients with multivessel disease (Class IIa recommendation, Level of Evidence B).[21] The US Guidelines recommend that it is reasonable to use FFR to assess angiographic intermediate coronary lesions (50%–70% diameter stenosis) and can be useful for guiding revascularization decisions in patients with stable ischemic heart disease (Class IIa recommendation, Level of Evidence A).[22] As these guidelines were issued several years ago and did not take into account subsequent trial data, it is important to examine the relevance of these recommendations in light of newer data.


  Fractional Flow Reserve as the Imperfect Surrogate for Coronary Flow Top


FFR is used as a surrogate for assessing coronary blood flow. FFR is calculated by measuring the mean pressure distal to the narrowed segment, as compared to the mean aortic pressure during pharmacologically induced maximal coronary vasodilation. Currently, intracoronary adenosine is routinely used during FFR measurements. The theoretical basis for the use of FFR is based on the assumption that the relationship between coronary pressure and flow is both linear and proportional during maximal hyperemia. In this hypothetical model, the coronary pressure distal to the stenosis will represent coronary flow in the coronary segment distal to the stenosis, and the mean aortic pressure will be the base reference pressure, representing the coronary flow in the absence of stenosis. Using this hypothetical model, the FFR will represent the proportion of blood flow available to the myocardium distal to the stenosis relative to what will have been available in the absence of any coronary stenosis.

The coronary vessels adapt to changes in myocardial functional demand by the process of coronary autoregulation, which involves adaptive vasodilation or vasoconstriction to maintain adequate coronary flow. During rest, the coronary flow is generally independent of perfusion pressure at the normal clinical range of pressures. With an increase in myocardial demand, coronary autoregulation ensures that there is adequate coronary flow. Hence, in normal physiological resting conditions, there is no direct relationship between coronary pressure and flow. For coronary pressure to be used as a surrogate for impairment of coronary blood flow, coronary autoregulation must be completely abolished.

Without coronary autoregulation, compensatory mechanisms are absent and therefore, coronary flow becomes dependent on perfusion pressure. While the FFR formula assumes a linear and proportional relationship between coronary pressure and flow, in reality, it is not proportional. Hence, while FFR is used as a surrogate for assessing coronary flow and inducible myocardial ischemia, it does not always accurately reflect the true coronary flow. Furthermore, the use of adenosine to achieve complete hyperemia during FFR measurements assumes that adenosine will abolish all vasoconstrictor tones. This does not happen, and the amount of residual vasoconstrictor tone left is dependent on many other factors including medication, comorbid conditions (including obesity, chronic obstructive pulmonary disease, and renal failure), smoking, and consumption of caffeine.

In addition, one should be aware that in the experimental validation of the FFR concept, calculation of FFR considered other factors such as correction for the central venous pressure. Clinical FFR measurement uses a simplified model which assumes that the central venous pressure is normal and is negligible when compared to aortic pressure. Hence, an increase in central venous pressure can lead to an underestimation of true FFR, whereas an increase in left ventricular end-diastolic pressure can cause an increase in FFR. These factors have to be taken into consideration when interpreting FFR. Therefore, there can be a discordance between FFR values and measured coronary flow reserve in about one-third of stenoses.[23],[24],[25]


  Fractional Flow Reserve Unable to Better Identify Those Who Are More Likely to Benefit from Percutaneous Coronary Intervention Top


The findings from the ORBITA and ISCHEMIA trials demonstrate that for stable angina patients with significant coronary artery disease and moderate-to-severe ischemia, it is appropriate to consider lifestyle changes and OMT as the initial strategy.[13],[14],[15],[16],[17],[18],[19] The DEFER trial showed that OMT is also an appropriate option for those with intermediate stenosis in the coronary arteries.[2],[3] In the FAME study, in the FFR guided group, there was more than a third of “significant” angiographic stenoses (based on inclusion criteria of ≥ 50% diameter stenosis) deemed as having no significant ischemia (using the criteria of FFR >0.8), and in this cohort of patients, OMT instead of PCI was not associated with a higher incidence of MI, mortality, or revascularization.[4],[5] In FAME 2, at 2 years, although the primary MACE endpoint (death, MI, and urgent revascularization) continued to be significantly lower in the PCI + OMT arm compared with the OMT arm, this was driven primarily by the significantly lower revascularization rates in the PCI arm. The rate of death, MI, and death/MI events were similar in both groups. This trend continued at 5 years of follow-up and although the death rates were similar for both groups, deaths from cardiac causes were higher in the PCI-OMT group as compared to the OMT group. This also concurred with the findings of the ISCHEMIA trial, where the 2-year all-cause mortality was similar for both the PCI group and the OMT group. Even in those with significant FFR values as in the ORBITA trial where the mean FFR was 0.69 and the iFR was 0.76 (almost identical in both groups), the authors were not able to demonstrate that functional FFR tests were better able to identify the patients who would benefit from PCI. Hence, in practical terms, stable angina patients with demonstrable ischemia can be treated medically with no increased risk of all-cause mortality as compared to a PCI strategy. When the patient has angina despite OMT, an invasive strategy can be considered. However, the current evidence does not demonstrate a correlation between the FFR value and angina. Hence, while PCI of an FFR-positive patient with angina may relieve ischemia, it may not relieve angina.


  Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Is Unable to Demonstrate Better Outcomes Than Computed Tomography-Guided Percutaneous Coronary Intervention Top


In computed tomography (CT)-guided PCI, a CT coronary angiogram is performed instead of an invasive diagnostic coronary angiogram, and only when the patient has significant coronary artery disease on CT coronary angiogram will an invasive coronary angiogram be performed. The CT coronary angiogram is reviewed in both the cross-sectional views and longitudinal views for distribution of plaque, density of plaque, distribution of calcium, and potential plaque shift at bifurcations where there are significant bifurcation stenoses. The PCI is preplanned as to the techniques that will be used, including the use of guiding catheters, choice of guidewires, types of devices to manage significant vessel calcification, and preferred stents for vessel anatomy in order to achieve safe and better outcomes. In our experience, CT-guided PCI has resulted in far-superior outcomes compared to data published in FFR trials.[26] A total of 134 consecutive patients selected for PCI based on the results of CT coronary angiogram were entered into the study and followed up over a 4-year period (2005–2008). Significant coronary stenoses were determined independently on invasive coronary angiography. Coronary angiographic inclusion criteria were de novo lesions, 50%–100% diameter stenosis, and vessel diameter ≥2.25 mm. Complications such as MACEs, stroke, and CABG were evaluated. Out of the 134 patients, 131 (97.8%) proceeded to PCI: 45 single-vessel diseases, 41 double-vessel diseases, and 45 triple-vessel diseases. Three patients did not proceed to PCI as the stenosis seen on the invasive coronary angiogram was deemed not significant enough to warrant a PCI. There were 335 coronary artery segments with significant stenoses which met the angiographic inclusion criteria and underwent PCI. On a per-patient basis, the mean number of coronary segments that underwent PCI was 2.56 segments. The mean number of stents implanted per patient was 2.4 ± 1.4. Post-PCI, 130 patients remained on follow-up (mean follow-up period of 23 ± 11 months). Of these 130 patients, 77 underwent cardiac computed tomography angiography (CCTA), 11 had treadmill testing, and 42 had clinical follow-up only. None of the patients had angina or an abnormal treadmill test. There were no episodes of death, Q-wave MI, stroke, and CABG. Of the 77 patients who had CCTA post-PCI, none had significant in-stent restenosis, but there were five nonstented segments which developed significant stenosis (>50%), of which two were subsequently treated with PCI and the remaining three were managed with OMT. Hence, on a per-patient basis, 1.5% (2/130) of the patients underwent another PCI during the period of study. In the study, CT-guided PCI was associated with a good long-term outcome, even for complex triple-vessel disease. During the study period, there were no episodes of death, Q-wave MI, CABG, and target vessel revascularization for the stented segments. It was associated with a low incidence (1.5%) of recurrent PCI for de novo plaque progression. Hence, in terms of providing better outcomes, FFR is not superior to CT-guided PCI.


  Current Role of Fractional Flow Reserve Top


While the FAME and FAME 2 studies demonstrate that FFR has an important role in helping the physicians in the decision-making process by providing objective assessment of the significance of ischemia caused by the coronary stenosis, given the data from subsequent and more recent trials, it is debatable whether it is necessary to do this routinely before PCI. The reasons for this are as follows:

Fractional flow reserve not superior in individual endpoints

Careful analysis of the FAME study showed that there was no difference in the individual MACE components (death, MI, and repeat revascularization) between the FFR group and the angiography group and only when the composite MACE endpoint was used, there was a statistically demonstrable benefit of the FFR group over the angiography group. However, at the end of 5-year follow-up, even this benefit was not observed, and there was no statistically significant difference in the composite primary endpoint or its individual components between the FFR group and the angiography group.

Fractional flow reserve-positive stenoses may not need percutaneous coronary intervention

In the FAME 2 study, more than 80% of the FFR-positive stenoses managed with OMT did not experience MACE, and up to 60% of these patients did not require revascularization over a 2-year period. In addition, more than 10% of vessels from patients in the reference group with normal FFR values, which were treated by OMT alone, experienced MACE within thefirst 2 years of follow-up. In focusing on the conclusions of FAME 2, most readers have not taken note that the majority of FFR-positive vessels did not require revascularization, nor did they result in MACE, whereas a significant minority of FFR-negative vessels suffered from MACE within thefirst 2 years of follow-up. Hence, these facts challenge the notion in the current guidelines that FFR-positive stenoses should be considered for revascularization, and this begets the question as to whether FFR can accurately identify those stenoses that will require revascularization. The reason for this is that while FFR is used as a surrogate for coronary flow reserve, the relationship between pressure and flow is not proportional (whereas the FFR hypothetical model assumes that the relationship is linear and proportional).

Fractional flow reserve not superior in real-world data

Contrary to the FAME trial which was an industry-sponsored trial, the all-comers FUTURE trial which was sponsored by the Health Ministry of France showed that in the real-world practice, there was no significant difference in the primary outcome (all-cause death, MI, or stroke) between the FFR group and the angiography group at 1 year. Moreover, there was more than the twofold increased risk of death in the FFR group as compared with the angiography group. This was despite a higher PCI rate in the angiography group as compared to the FFR group. Being an all-comers study, the FUTURE trial was a better reflection of the real-world practice. In addition, as compared to CT-guided PCI, the outcomes for FFR-guided PCI are inferior.

Fractional flow reserve unable to better identify those who will benefit from percutaneous coronary intervention

In the ORBITA study, the authors were not able to demonstrate that functional tests (FFR nor iFR) were better able to identify the patients who would benefit from PCI even though the mean FFR was 0.69 and the iFR was 0.76 (almost identical in both groups). In addition, although patient-reported freedom from angina was higher after PCI than after a sham procedure, functional testing (FFR nor iFR) did not modify that effect.

Hence, we currently do not have unquestionable evidence to justify the routine use of FFR when performing PCI.


  Conclusions Top


The current data show that FFR is an imperfect surrogate for coronary flow, FFR is affected by limitations to the assumptions used in the hypothetical model, FFR differs from coronary flow reserve in about one-third of stenoses, the majority of FFR-positive stenosis on OMT have good outcomes, a significant minority of FFR-negative stenoses develop MACE, FFR does not correlate with angina, and recent trials show that OMT is the preferred initial therapy in a stable coronary artery.

The role of FFR has to be defined in light of the evolving clinical advances in medicine and new evidence. In summary, there is no compelling evidence for the routine use of FFR in cardiac interventions. Given the current data, there is no necessity for routine FFR in stable coronary artery patients with documented myocardial ischemia and in patients with multivessel disease. Furthermore, other techniques such as CT-guided PCI can provide far-superior outcomes to FFR-guided PCI. The most useful role of FFR, based on current data, is embodied in the current US guidelines, which considers it a reasonable option to use FFR to assess the significance of angiographic intermediate coronary lesions (50%–70% diameter stenosis), and even then the US guidelines do not make it a recommendation that FFR should be used routinely in such situations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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  In this article
Abstract
Introduction
Fractional Flow ...
Fractional Flow ...
Fractional Flow ...
Fractional Flow ...
Current Role of ...
Conclusions
DEFER Trial
FAME Trial
FAME 2 Trial
FUTURE Trial
ORBITA Trial
ISCHEMIA Trial
References

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