Fractional flow reserve (FFR) utilizes a specialized guide wire to measure blood pressure within a coronary artery. The original description of FFR required the induction of maximal hyperemia to achieve near linear correlation between coronary pressure and blood flow.¹ The most commonly used pharmacological agent is adenosine as an intravenous infusion, although recent evidence suggests that high-dose intracoronary bolus injection may have similar efficacy (200 mcg into the left coronary artery and 100 mcg in the right coronary artery).² FFR is defined as the ratio of mean distal coronary pressure to mean aortic pressure. Incorporating stenosis severity, myocardial territory and viability, and collateral perfusion, FFR is able to fully assess the functional significance of a coronary stenosis. Multiple studies have compared FFR with noninvasive functional testing and found an acceptable overall correlation.³ Translesional functional assessment with FFR initially used a cutoff value of 0.75, indicating that coronary pressure is reduced by 25% from normal. The cutoff value, however, was increased to 0.80, improving the sensitivity of FFR, and was validated in multiple prospective, randomized trials with this threshold.⁴

Coronary physiology is an important tool that can guide management decisions for intermediate lesions and multivessel coronary artery disease (CAD), determining whether the patient would benefit from revascularization or medical therapy. Despite long-term data showing improved outcomes with FFR-guided decision-making, its use remains significantly underutilized in practice, with FFR being used in 6.1% of interventions for intermediate coronary lesions (40-70% stenosis).⁵

Resting Gradient Physiology

More recently, interest in resting gradients has emerged given the many limitations of adenosine use and hyperemia. Most notably, the instant wave-free ratio (iFR) has been introduced as an alternative to FFR. Physiologic lesion assessment with iFR offers the benefit of a drug-free index of stenosis severity with the comparable accuracy of FFR.^6,7 Objective ischemia assessment can be performed with either modality because both FFR and iFR have been demonstrated to show no significant differences in the prediction of myocardial ischemia from 13N-ammonia positron emission tomography.⁸ Additionally, iFR-guided revascularization was noninferior to FFR-guided revascularization for major adverse cardiac events (MACE) at 1-year follow-up in 2 separate, large randomized multicenter trials.^9,10

FFR Evidence

Initial prospective randomized studies utilizing FFR evaluated the safety of deferring percutaneous coronary intervention (PCI). The DEFER (Percutaneous Coronary Intervention of Functionally Nonsignificant Stenosis) study demonstrated that PCI can be safely deferred based on a nonsignificant FFR.¹¹ At 15-years follow-up, the rate of myocardial infarction was significantly lower in the defer group (2.2%) compared with patients who underwent revascularization (10%).¹²

Tonino et al. demonstrated the importance of FFR in patients with multivessel coronary disease undergoing revascularization in the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. FFR-guided PCI was associated with lower 1-year adverse events and reduced costs. In the FAME 2 (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2) study, the investigators found that FFR-guided PCI, compared with medical therapy alone, improved the outcome; patients without evidence of ischemia had favorable outcomes without PCI.^13,14 The reduction in adverse events seen with FFR in the PCI group was driven by a reduction in urgent revascularization.

Muller et al. demonstrated good prognostication by deferring revascularization with a negative FFR for the long-term clinical outcome of patients with an angiographically intermediate left anterior descending coronary artery (LAD). In this study, medical treatment of patients with a hemodynamically nonsignificant stenosis (FFR ≥0.80) in the proximal LAD was associated with an excellent long-term clinical outcome, with survival at 5 years, which is similar to a control group without known CAD (92.9% survival).¹⁵

Contrary to the large body of research supporting the safety and benefit of functional testing with FFR, the FUTURE (Functional Testing Underlying Coronary Revascularisation) study was stopped early due to increased mortality in the arm randomized to a FFR-guided treatment strategy. It is unclear from these unpublished data if this finding was incidental because the full data set is not yet available.¹⁶

A large, prospective registry, IRIS-FFR, evaluated the prognosis of deferred and revascularized lesions based on FFR value.¹⁷ This registry demonstrated that the FFR value was linearly associated with the risk of cardiac events in deferred lesions. However, deferring revascularization in favor of medical therapy in lesions with FFR ≥0.76 was a reasonable and safe treatment strategy. Additionally, the investigators found that revascularization for coronary artery stenosis with a low FFR (≤0.75) was associated with improved outcomes.

FFR in Acute Coronary Syndrome (ACS)

Although the use of FFR is most established among patients presenting with stable angina, revascularization of non-infarct-related coronary arteries at the time of an acute myocardial infarction (AMI) remains a hotly debated topic. Physiology measurements of the culprit vessel are neither practical nor valid due to microvascular obstruction, but assessment of the non-culprit artery is feasible and has theoretical appeal. Nevertheless, the concern is that patients with AMI may have multiple ruptured plaque and thus target lesions that may be underestimated by the use of FFR.¹⁸ In fact, recent evidence suggests that culprit lesions of patients presenting with a non-ST-segment elevation myocardial infarction that were deferred based on a "negative" FFR have a relatively high event rate, calling into question the use of FFR in that patient population.¹⁹

Two recent randomized trials add to the growing body of evidence supporting revascularization of the non-infarct-related artery with the guidance of FFR. The DANAMI-3-PRIMULTI (The Third Danish Study of Optimal Acute Treatment of Patients With STEMI: Primary PCI in Multivessel Disease) trial demonstrated that FFR-guided staged complete revascularization during the index admission led to significantly decreased future revascularizations at 1 year follow-up than those who received treatment for the infarct-related vessel alone.²⁰ Similarly, the Compare-Acute (Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction) trial investigators examined whether FFR-guided treatment improved outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease to evaluate the benefit of revascularization in the acute setting of non-infarct-related lesions.²¹ FFR-guided revascularization at the time of primary PCI resulted in a lower rate of a composite cardiovascular event rate at 1 year, mainly driven by decreased subsequent revascularizations. The investigators also found that approximately half the lesions in non-infarct-related arteries that were significant on angiography had an FFR value greater than 0.80 and therefore were not physiologically significant. This supports the notion that routine use of an FFR-guided strategy for complete revascularization during ACS has the potential to significantly decrease unnecessary interventions during primary PCI as well as future revascularizations. Clinical data on FFR are summarized in Table 1.

Table 1: Landmark Physiology Studies With FFR

Study Name	Year	Size	Trial Design	Clinical Presentation	FFR Cutoff	Outcomes
DEFER11	2001	325 patients at 14 medical centers	Prospective, randomized	Stable chest pain and an intermediate stenosis without objective evidence of ischemia	0.75	No benefit stenting a non-ischemic stenosis
FAME4	2009	1,005 patients at 20 medical centers	Prospective, randomized	Multivessel CAD	0.80	Routine measurement of FFR in patients with multivessel CAD who are undergoing PCI with drug-eluting stent significantly reduces MACE at 1 year
FAME 213	2012	888 patients at 28 medical centers	Prospective, randomized	Stable CAD and hemodynamically significant stenoses	0.80	FFR-guided PCI with drug-eluting stent + optimal medical therapy (OMT) vs. OMT alone decreased the rate of urgent revascularization. In FFR negative lesions, OMT alone resulted in excellent outcomes, regardless of the angiographic appearance of the stenoses
Muller et al.15	2011	730 patients at 1 Belgium center	Observational, non-randomized study	Angiographically intermediate isolated proximal LAD stenosis	0.80	Medical treatment is associated with favorable long-term clinical outcomes in angiographically equivocal lesions non-ischemic by FFR
Mayo Registry22	2013	7,358 patients at the Mayo Clinic	Retrospective registry	Patients undergoing PCI, excluding STEMI or cardiogenic shock	<0.75→PCI 0.75-0.80→Operator discretion >0.8→OMT	FFR-guided treatment strategy is associated with a favorable long-term outcome with decreased MACE
Van Belle et al.(R3F)23	2014	1,075 patients at 20 centers in France	Prospective observational study	Angiographically ambiguous lesion	0.80	FFR during diagnostic angiography is safe and associated with reclassification of the revascularization decision in about half of the patients
RIPCORD24	2014	200 patients at 10 centers in the United Kingdom	Prospective observational study	Stable angina	0.8	FFR has an important influence both on which coronary arteries have significant stenosis and on patient management
DANAMI-3-PRIMULTI20	2015	627 patients at 2 centers in Europe	Prospective randomized controlled trial	Patients with STEMI and multivessel disease who had undergone primary PCI of an infarct-related coronary artery	0.80	Complete staged revascularization during the index admission, guided by FFR reduces the risk of future events, driven by fewer repeat revascularizations
Compare-Acute21	2017	885 at 24 centers in Europe and Asia	Prospective randomized controlled trial	Patients with STEMI and multivessel disease who had undergone primary PCI of an infarct-related coronary artery	0.80	FFR-guided complete revascularization of non-infarct-related arteries in the acute setting resulted in lower MACE, driven by decreased revascularization
IRIS-FFR17	2017	5,846 patients	Prospective registry	Patients with at least one coronary lesion	0.75	FFR ≤0.75: the risk of MACE was significantly lower in revascularized lesions than in deferred lesions. Lesions with FFR ≥0.76, the risk of MACE was not significantly different between deferred and revascularized lesions.

Guidelines on the Use of Coronary Physiology

According to the American College of Cardiology (ACC) guidelines on coronary revascularization, FFR is reasonable for the assessment of angiographic intermediate coronary lesions (50-70% diameter stenosis) and can be useful for guiding revascularization decisions in patients with CAD (Class IIa, Level A).²⁵ A recent consensus document on the use of FFR has suggested to expand its use in coronary stenoses up to 90%, given that up to 20% of lesions between 70-90% stenosis are not hemodynamically significant.²⁶ Also, the most recent version of the appropriate use criteria on coronary revascularization endorses the use of both FFR and iFR for functional lesion assessment in single and multivessel CAD.²⁷ The most recent society guidelines and indications for the use of FFR are summarized in Table 2.

Table 2: Indications and Guidelines for FFR

Title	Recommendations
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 Interventions25	FFR is reasonable 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 (SIHD). (Class lla, Level of Evidence A).
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 Interventions26	In SIHD when noninvasive imaging is unavailable, nondiagnostic, or discordant, FFR should be used to assess functional significance of intermediate-severe coronary stenosis (50-90%). In SIHD, PCI of lesions with FFR <0.80 improves symptom control and decreases urgent revascularization compared to medical therapy. When FFR >0.80 in angiographically intermediate lesions with SIHD, medical therapy is indicated.
2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)28	Deferral of PCI or coronary artery bypass graft in patients with FFR >0.80 appears safe. FFR measurement is indicated for the assessment of the functional consequences of moderate coronary stenosis. FFR-guided PCI with medical therapy has been shown to decrease the need for urgent revascularization compared with the best available medical therapy alone.
ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2016 Appropriate Use Criteria for Coronary Revascularization in Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society of Thoracic Surgeons29	In the presence of an asymptomatic intermediate-severity non-culprit artery stenosis, revascularization was rated as “appropriate therapy,” provided that the FFR was ≤0.80.
ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons27	Invasive measurements (such as FFR) may be very helpful in further defining the need for revascularization and may substitute for stress test findings. FFR ≤0.80 is abnormal and is consistent with downstream inducible ischemia. Appropriate use criteria advocate for expanded use of intracoronary physiological testing.

Summary

There is strong clinical trial evidence that a strategy of ischemia-guided coronary revascularization improves long-term clinical outcomes while reducing overall cost when compared with angiographic-only guidance. Physiology-guided decision-making in conjunction with coronary angiography adds objective evidence on the functional significance of a coronary lesion in both SIHD and non-infarct-related AMI, improving clinical decision-making. We recommend an algorithmic approach to determine when to incorporate physiology into daily practice to optimize outcomes with PCI (Figure 1). Suggested treatment implementation based on iFR is presented in Figure 2.

Figure 1: Algorithm for Physiologic Lesion Assessment

Approach to physiologic lesion assessment for coronary revascularization in stable and unstable patients.

Figure 2: Treatment Implementation Based on iFR

References

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Keywords: Acute Coronary Syndrome, Adenosine, Ammonia, Angina, Stable, Angioplasty, Blood Pressure, Constriction, Pathologic, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Coronary Stenosis, Drug-Eluting Stents, Echocardiography, Hyperemia, Infusions, Intravenous, Myocardial Infarction, Myocardial Revascularization, Percutaneous Coronary Intervention, Positron-Emission Tomography, Prognosis, Prospective Studies, Registries, Shock, Cardiogenic, Surgeons, Thoracic Surgery, Tomography, Optical Coherence

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