Revascularization in stable ischemic heart disease (SIHD) is indicated in patients on optimal medical therapy with angina and/or demonstrable ischemia and a significant stenosis in one or more epicardial coronary arteries.

Angiography alone, however, often cannot accurately determine the hemodynamic significance of coronary lesions, particularly those of intermediate stenosis severity. A lesion may appear significant on coronary angiography but may not have functional significance. PCI of functionally insignificant coronary artery lesions may have serious consequences; therefore, judicious decision-making in the cardiac catheterization laboratory is indicated.

For this reason, it is becoming increasingly important to show that a stenosis is capable of inducing myocardial ischemia prior to intervention. Fractional flow reserve (FFR) is a well-validated evidence-based tool to objectively measure the physiologic significance of epicardial coronary arterial stenosis.

As such, this article will briefly discuss the principles of FFR, current evidence and rationale supporting its use, and comparison with other modalities like instantaneous wave-free ratio (iFR) and diastolic hyperemia-free ratio (DFR).

Traditionally, visually estimated coronary stenosis has been used to guide PCI. However, the advent of technologies such as FFR, iFR and DFR has turned the tide.

Principles of FFR

FFR is a ratio of pressures related to two flows: the maximum myocardial flow in the stenotic territory divided by the maximum blood flow if the same artery was theoretically normal. The measurement is obtained using a coronary pressure wire or catheter advanced distal to the coronary stenosis of interest (Pd) and dividing that pressure by the mean aortic pressure (Pa) measured through the guiding catheter during maximum coronary hyperemia. In the absence of an epicardial stenosis, no pressure drop will occur along the vessel and FFR will thus be normal, i.e., 1.0.

Three major prospective randomized trials have demonstrated the clinical utility of FFR: DEFER, FAME and FAME 2.^1-3

Quantification of the impact of individual stenoses within a diffusely diseased vessel or a vessel with tandem stenosis and assessing the magnitude of the contribution of different stenoses to the overall disease burden of the vessel is not possible with current hyperemic measures.

Resting flow overcomes difficulties encountered with a hyperemic state; it aids with prediction of the physiological effect of treating a particular stenosis within the vessel and permitting intervention according to the likely physiological gain.

iFR: Principles and Data

iFR is the ratio of Pd to Pa measured during a select portion of diastole, the wave-free period, when the microvascular resistance is theoretically constant and minimal. Like FFR, iFR is performed with high-fidelity pressure wires that are passed distal to the coronary stenosis.

The enhancement over FFR obviates the need for adenosine, a step that can be time-consuming and costly for cath labs that is utilized infrequently and is contraindicated in some patients. iFR isolates the wave-free period. During this time, competing forces that affect coronary flow are quiescent, and pressure and flow (Pd and Pa) are linearly related as compared with all other periods in the cardiac cycle.

When a stenosis is flow limiting, Pd and Pa pressures over the wave-free period diverge, with iFR values below 0.89 suggesting flow restriction (normal value is 1.0). Theoretically, iFR can be calculated using a single heartbeat, but is typically averaged over five beats for normalization. iFR is measured at rest, without the need for pharmacological stressors. Measuring pullbacks in different areas can be accomplished quickly and easily without the need for adenosine.

iFR-pullback permits assessment of the hemodynamic impact of an individual stenosis in vessels with tandem lesions. It can predict the impact of removing the stenosis on coronary hemodynamics. With co-registration, the pressure wire pullback can be integrated with the angiographic findings to enhance understanding of the data.

Regarding prognosis and periprocedural complications, the noninferiority of iFR to FFR was demonstrated in the iFR-SWEDEHEART and DEFINE-FLAIR trials.^4,5

In iFR-SWEDEHEART, which included patients with SIHD or an acute coronary syndrome, iFR was used as a measure of severity of coronary artery stenosis and was shown to be noninferior to FFR in terms of the composite endpoint of all-cause death, nonfatal myocardial infarction (MI) and unplanned revascularization within a year of the index PCI (6.7 percent vs. 6.1 percent; hazard ratio [HR], 1.12; 95 percent confidence interval [CI], 0.79-1.58; p=0.007 for noninferiority).

Between the two groups, there was no significant difference for the rate of MI, target lesion revascularization, restenosis and stent thrombosis. Periprocedural chest discomfort was reported by significantly more patients in the FFR group than in the iFR group (68.3 percent vs. 3.0 percent; p<0.001).

DEFINE-FLAIR showed that the one-year risk of all-cause death, nonfatal MI or unplanned revascularization was 6.8 percent for iFR vs. 7.0 percent for FFR (HR, 0.95; 95 percent CI, 0.68-1.33; p<0.001 for noninferiority).

In DEFINE-FLAIR, fewer patients in the iFR group compared with the FFR group had adverse procedural symptoms and clinical signs (39 patients [3.1 percent] vs. 385 patients [30.8 percent]; p<0.001). The median procedural time was significantly shorter with iFR than with FFR (40.5 minutes vs. 45.0 minutes; p=0.001).

The term iFR is now often replaced with the phrase "ratio of distal coronary to aortic pressure without hyperemia."

Diastolic Hyperemia-Free Ratio

The introduction of the resting, diastolic wave-free period has led to both physiologic and practical controversy. Physiologically, what is unclear is whether the wave-free period possesses unique properties when making pressure-only measurements in the coronary arteries.

There is debate over whether clinical findings apply narrowly to the wave-free period, or to a broad range of diastolic metrics. There is some evidence that resting metrics would demonstrate numerical equivalency despite differing physiologic and technical details, thereby making resting physiology more universally accessible.

DFR calculates a diastolic portion of the cardiac cycle at rest and uses a cutoff of 0.89. The DFR window uses two criteria: Pa < mean Pa and a downsloping Pa. Selecting the wave-free period Is not necessary to obtain results.

In a recent report, DFR and iFR were shown to be numerically identical using a pooled analysis of data from the VERIFY 2 and CONTRAST studies that included 893 waveform tracings from 833 patients.⁶

According to data presented by Jung-Min Ahn, MD, and colleagues at TCT 2018, equivalent prognostic performance with DFR and iFR was demonstrated using data from the IRIS-FFR registry. The investigators retrospectively evaluated 1,102 deferred lesions in 926 patients using five nonhyperemic pressure ratios, including DFR.

Implementing Physiologic Measurement

Revascularization of noninfarct-related coronary arteries at the time of an acute MI remains a topic of debate where physiological measurements of the culprit vessel may not be valid due to microvascular dysfunction. FFR-guided revascularization strategy can be safely applied to patients with left main coronary artery stenosis.⁷

Among the advantages of iFR are a drug-free approach, as well as the ability to reach a higher flow velocity during the measurement, which allows for better discrimination of hemodynamically significant stenoses.

A class effect among nonhyperemic pressure ratios, i.e., iFR and DFR, is based on a single cutoff and similar clinical equivalence where indices of 0.89 or less generated by iFR are equivalent to the common limit of 0.80 or less in FFR.⁶

According to the ACC/AHA guideline on PCI, FFR is reasonable for the assessment of angiographic intermediate-severe coronary stenosis (50-90 percent) and can be useful for guiding revascularization decisions in patients with coronary artery disease (Class IIa, Level A).⁸

Appropriate use criteria on coronary revascularization endorses the use of both FFR and iFR for functional lesion assessment in single and multivessel coronary artery disease.⁹

In summary, physiology-guided decision-making adds objective evidence on the functional significance of a coronary lesion in SIHD. There is need for innovation that refines the available technology to aid clinical decision-making, especially in diffuse coronary artery disease and vessels with tandem lesions.

References

1. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105-11.
2. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24.
3. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991-1001.
4. Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med 2017;376:1813-23.
5. Davies JE, Sen S, Dehbi HM, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med 2017;376:1824-1834.
6. Johnson NP, Li W, Chen X, et al. Diastolic pressure ratio: new approach and validation vs. the instantaneous wave-free ratio. Eur Heart J 2019;40:2585-94.
7. Hamilos M, Muller O, Cuisset T, et al. Long‐term clinical outcome after fractional flow reserve‐guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation 2009;120:1505–1512.
8. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
9. Lotfi A, Jeremias A, Fearon WF, et al. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: a consensus statement of the Society of Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2014;83:509-18.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging

Keywords: ACC Publications, Cardiology Magazine, Acute Coronary Syndrome, Adenosine, Angina Pectoris, Cardiac Catheterization, Confidence Intervals, Constriction, Pathologic, Arterial Pressure, Coronary Angiography, Coronary Artery Disease, Decision Making, Coronary Stenosis, Diastole, Myocardial Infarction, Hyperemia, Percutaneous Coronary Intervention, Percutaneous Coronary Intervention, Prospective Studies, Prognosis, Registries, Research Personnel, Reference Values, Retrospective Studies, Stents, Thrombosis

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