FFR: Fractional Flow Reserve

Fractional flow reserve (FFR) is a diagnostic cardiac catheterization technique used to measure blood flow and pressure in an isolated segment of the coronary artery. FFR is the current standard of care for the evaluation of lesions in intermediate-grade stenosis. It is more precise than non-invasive techniques in determining the functional significance and ischemic potential of the observed lesion.^1,2

FFR Definition & Description

FFR is defined as ratio of pressure measured in coronary segment distal to stenosis (Pd) and pressure measured proximal to stenosis, usually aortic pressure (Pa) or pressure measured in healthy proximal coronary segment. Fractional flow reserve formula is FFR = Pd/Pa.³ FFR is measured using guidewires equipped with micromanometer pressure sensors.² The coronary guidewires are inserted via transradial or transfemoral catheterization.⁴

FFR was originally defined as the ratio of proximal and distal blood flow across the coronary stenosis. The blood flow is related to pressure through coronary arterial resistance (R = pressure/flow). Under the condition of minimal distal resistance, the relationship between pressure and flow becomes linearized, and the pressure, which is easier to measure, can be used as a proxy for the blood flow across the coronary stenosis.^2,5

For measurement accuracy, it is necessary to achieve stable pressure under hyperemia, a physiological state of maximal coronary blood flow and minimal vascular resistance.⁶ This is achieved by administration of adenosine by intravenous continuous infusion (140 mcg/kg/min) or intracoronary bolus (50 to 100 mcg into the right coronary artery, 100 to 200 mcg into left coronary artery). In a healthy coronary artery with normal blood flow, the FFR value equals 1, indicating no obstruction to blood flow present. The presence of coronary stenosis lowers Pd/Pa ratio. An FFR of 0.8 or lower identifies coronary stenosis that induces ischemia with 90% accuracy.^6,7

FFR Indication

FFR is indicated in patients with stable coronary artery disease (CAD) to determine ischemic potential of intermediate coronary stenosis observed on invasive coronary angiograms (ICA).^7,8 ICAs alone cannot reliably identify hemodynamically significant stenosis.⁹ FFR can overcome this limitation. When noninvasive tests are inconclusive in patients that present with persistent chest pain and moderate coronary stenosis, FFR reliably indicates functionally significant coronary stenosis and guides revascularization decision avoiding unnecessary interventions.⁷

Several large-scale clinical trials have evaluated FFR for use in assessment of coronary stenosis severity and guidance for revascularization.^4,10 The DEFER trial demonstrated safety and efficacy on deferral of percutaneous coronary intervention (PCI) in patients with FFR of 0.75 or higher.¹¹ The FAME trial showed a reduction in major adverse cardiac events (MACE – death, myocardial infarction and revascularization) and in revascularization in patients with multivessel disease undergoing FFR-guided PCI compared to PCI alone.¹²

The FAMEII trial demonstrated that FFR-guided PCI in stable CAD patients with FFR of 0.8 or lower, combined with optimal medical therapy, decreased the incidence of MACE relative to optimal medical therapy alone.¹³ The efficacy of FFR-guided PCI was confirmed at 3 and 5 years follow-up in the FAMEII trial.^14,15 Based on the results of clinical trials, FFR was given class I, level A recommendation by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery for identification of hemodynamically relevant stenosis and to guide PCI in patients with multivessel disease.¹

The American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Intervention (SCAI) designated FFR as reasonable for the evaluation of intermediate stenosis and helpful in guiding revascularization decisions in patients with stable ischemic heart disease (class IIa, level A).¹⁶ A recent SCAI consensus statement recommends expanded use of FFR when non-invasive imaging is unavailable or inconclusive.¹⁷

Other Indications

FFR has been evaluated in the following special clinical scenarios:⁶

• Acute coronary syndrome to assess non-culprit artery lesions
• Left main coronary artery stenosis
• Multivessel disease
• Assessment prior to coronary artery bypass grafting (CABG)
• Diffuse atherosclerosis
• Sequential stenosis
• Bifurcation and ostial branch stenosis

Relevant Metrics

Table 1. Main hyperemic and non-hyperemic indices for assessment of coronary lesions:²

INDEX	ISCHEMIA CUT-OFF
FFR	≤ 0.80
Pd/Pa (whole cycle)	≤ 0.91
C(contrast)FFR	≤ 0.83
iFR	≤ 0.89
RFR	≤ 0.89
DFR	≤ 0.89
DPR	≤ 0.89
QFR	≤ 0.80

FFR Complications & Contraindications

There are no absolute contraindications for FFR tests.³ Second and third degree atrioventricular blocks, sick sinus syndrome without pacemaker, prolong QT- interval, severe hypotension, heart failure and obstructive pulmonary disease are relative contraindications for intravenous administration of adenosine. Generally, invasive diagnostic procedures should not be attempted if invasive therapeutic options don’t exist.

FFR test measurements have limitations in patients with small-vessel disease, diffuse coronary artery disease and left ventricular hypertrophy.¹⁸ These conditions may lead to underestimation of severity of coronary stenosis due to the restriction in blood flow after pharmacological vasodilation and corresponding decrease in distal coronary blood pressure.

Several comorbidities can influence performance and safety of FFR tests.³ The accuracy of FFR tests may be affected in older patients due to the age-associated changes in microvasculature, leading to higher observed FFR values independent of degree of stenosis. Similarly, patients with diabetes mellitus can have falsely elevated FFR values due to microvasculature pathology and impaired response to vasodilators administered during the test. This could lead to reduced treatment of elderly and diabetic patients when FFR values are used as guidelines.

Although the true effect of the diseased microvasculature on FFR values is still debated, it has been shown that PCI interventions guided by FFR are equally beneficial in patients older than 65 years of age with multivessel disease as in younger patients with the same disease and in patients with and without diabetes, compared to angiography-guided PCI.

References

1. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2018;40(2):87-165.

2. Okutucu S, Cilingiroglu M, Feldman MD. Physiologic Assessment of Coronary Stenosis: Current Status and Future Directions. Curr Cardiol Rep. 2021;23(7):88.

3. Peper J, Becker LM, Kuijk JP van, Leiner T, Swaans MJ. Fractional Flow Reserve: Patient Selection and Perspectives. Vasc Heal Risk Management. 2021;17:817-831.

4. Achenbach S, Germany D of C Friedrich Alexander University (FAU) Erlangen Nuremberg, Rudolph T, et al. Performing and Interpreting Fractional Flow Reserve Measurements in Clinical Practice: An Expert Consensus Document. Interventional Cardiol Rev. 2017;12(02):97.

5. Pijls NH, Son JA van, Kirkeeide RL, Bruyne BD, Gould KL. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation. 1993;87(4):1354-1367.

6. Chowdhury M, Osborn EA. Physiological Assessment of Coronary Lesions in 2020. Curr Treat Options Cardiovasc Medicine. 2020;22(1):2.

7. Pijls NHJ, Bruyne B de, Peels K, et al. Measurement of Fractional Flow Reserve to Assess the Functional Severity of Coronary-Artery Stenoses. New Engl J Medicine.1996;334(26):1703-1708.

8. Bruyne BD, Fearon WF, Pijls NHJ, et al. Fractional Flow Reserve–Guided PCI for Stable Coronary Artery Disease. New Engl J Medicine. 2014;371(13):1208-1217.

9. Tonino PAL, Fearon WF, Bruyne BD, et al. Angiographic Versus Functional Severity of Coronary Artery Stenoses in the FAME Study Fractional Flow Reserve Versus Angiography in Multivessel Evaluation. J Am Coll Cardiol. 2010;55(25):2816-2821.

10. Bertolone DT, Gallinoro E, Esposito G, et al. Contemporary Management of Stable Coronary Artery Disease. High Blood Press Cardiovasc Prev. 2022;29(3):207-219.

11. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J. 2015;36(45):3182-3188.

12. Pijls NHJ, Fearon WF, Tonino PAL, et al. Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease 2-Year Follow-Up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) Study. J Am Coll Cardiol. 2010;56(3):177-184.

13. Bruyne BD, Pijls NHJ, Kalesan B, et al. Fractional Flow Reserve–Guided PCI versus Medical Therapy in Stable Coronary Disease. New Engl J Medicine. 2012;367(11):991-1001.

14. Fearon WF, Nishi T, Bruyne BD, et al. Clinical Outcomes and Cost-Effectiveness of Fractional Flow Reserve–Guided Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease. Circulation. 2018;137(5):480-487.

15. Nunen LX van, Zimmermann FM, Tonino PAL, et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial. Lancet. 2015;386(10006):1853-1860.

16. Members WC, Levine GN, Bates ER, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. Circulation. 2011;124(23):e574-e651.

17. Patel MR, Calhoon JH, Dehmer GJ, et al. 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 Surgeons. J Am Coll Cardiol. 2017;69(17):2212-2241.

18. Pijls NHJ, Bruyne B de, Peels K, et al. Measurement of Fractional Flow Reserve to Assess the Functional Severity of Coronary-Artery Stenoses. New Engl J Medicine.1996;334(26):1703-1708.

Author Bio

Ivana Celic, PhD, is a biomedical scientist and freelance medical and scientific writer. Her research interests include genome plasticity, cancer, aging, neurodegenerative disease, and infertility. She actively participates in laboratory research and scientific writing and presentations.