International Journal of Cardiology and Cardiovascular Medicine

ISSN 2517-570X

Fractional Flow Reserve: Should be the Gold Standard for Therapeutic Definition of Coronary Artery Disease?

Costantini CR1, Macedo RM 1, Denk MA1, Costantini CO1, Tarbine SG1, Santos MF1, Folador JC1, Folador JC1 , Jose Antonio F Ramires2*,

1 Department of Cardiology Hospital Cardiologico Costantini- Curitiba _Parana.

2 Department of Cardiology Heart Institute-INCOR, USP- Sao Paulo, Brazil

Corresponding author

Jose Antonio F Ramires
Department of Cardiology Heart Institute-INCOR
USP- Sao Paulo

  • Received Date:February 01, 2018
  • Accepted Date: March 01, 2018
  • Published Date: March 07, 2018

DOI:   10.31021/ijccm.20181111

Article Type:  Editorial

Manuscript ID:   IJCCM-1-111

Publisher:   Boffin Access Limited.

Volume:   1.2

Journal Type:   Open Access

Copyright:  © 2018 Ramires JAF, et al.
Creative Commons Attribution 4.0


Ramires JAF, Costantini CR, MacedoRM, Denk MA, Costantini CO, et al. Fractional flow reserve: Should be the Gold Standard for therapeutic definition of coronary artery disease? Int J Cardiol Cardiovasc Med. 2018 Mar;1(2):111

The ideal Coronary Artery Disease (CAD) treatment strategy should be defined based on the results from functional and anatomical examinations according to current guidelines [1]. However, this concept is apparently being overlooked by some centers, where percutaneous coronary intervention (PCI) is used to treat coronary lesions with ≤50% diameter stenosis, regardless of their functional repercussion [2-8].

Concern about the unnecessary revascularization of the myocardium motivated some cardiologists to develop the concept of functional PCI, where through the measurement of coronary fractional flow reserve (FFR) the therapeutic decision can be made [9].

Validated for clinical use in 1996 by Nico Pijls [10], FFR has gained popularity in interventional cardiology since then. It is important to note that its indications were strengthened by three studies with a small number of patients (1375 in total) and using different methods: the pioneering study by Nico Pijls the DEFER trial, and the FAME 1 trial [10-12]. Several maximal coronary hyperemia induction methods and cut- off values were used along these studies. Thus, this editorial aims to provoke a reflection to consider if FFR with all this fragility of measurement methodology should be considered gold standard to define a percutaneous treatment.

The FAME 1 trial showed that routine application of FFR to therapeutic decision-making in patients requiring multiple stents with a 0.80 cut-off resulted in a significant decrease in adverse events and hospital costs compared with the strategy guided only by angiography [12]. Such evidence had already been reported in the DEFER trial, wherein the event-free survival of patients with non-ischemia-causing lesions (FFR>0.80) was high after one and 5-year follow-up, and was similar between groups that performed or did not perform PCI (92 vs 89% and 80 vs 73%, respectively) [11].

The 0.75 value of FFR has high sensitivity and specificity for positive and negative results in identifying ischemia in intermediate coronary stenoses when compared with three noninvasive functional methods [bicycle exercise testing, myocardial perfusion scintigraphy (MPC), and stress echocardiography (ECHO stress)], using intravenous injection of adenosine at the dose of 140 μg/kg/min as an inducer of maximal hyperemia, according to Pijls et al. [10].

Adenosine-induced maximal coronary hyperemia has been widely discussed, with no apparent consensus as to the best way to perform this method, as shown in the DEFER II trial (026 test), which evaluated 325 patients using the FFR with a cut-off value of 0.75. Adenosine-induced maximal coronary hyperemia was performed differently from that proposed by Pijls et al. [10]., through an intravenous injection of 140 μg/kg/min combined with 15 μg doses in the right coronary artery and 20 μg in the left coronary artery during intracoronary (IC) infusion. The FAME [12] trial proposed adenosine-induced maximal coronary hyperemia at a dose of 140 μg/kg/min infused into the femoral vein (central access) and using 0.80 as cut-off value [13,14].

The hyperemia induction method for FFR measurement has not yet been carefully standardized (Intravenous (IV), Continuous (CI), Peripheral (PI), or Central Infusion (CI), combined doses, duplicate doses). Lastly, which is the FFR reference value for defining the treatment of a disease as aggressive as CAD?

What is the optimal (FFR) cut-off point for ischemia detection?
According to Pijls et al [10], the cut-off point for ischemia detection with 93% accuracy is 0.75, showing that values assessed by FFR measurement lower than 0.75 are always virtually associated with myocardial ischemia, whereas values higher than 0.75 are almost never associated with ischemia. Shal and cols [15] analyzed 18 studies that used noninvasive, functional tests (Bicycle exercise testing + MPC + ECHO stress), comparing the results assessed by FFR measurement, and the cut-off values ranging from 0.67 to 0.75 were best associated with ischemic areas. However, the cut-off point was set at 0.80 to increase ischemia detection sensitivity to almost 100%, based on the FAME trial [12].

It should be noted that FFR was validated as class IA in guidelines [16] using two cut-off points, 0.75 and 0.80, creating a dichotomy, and the concept termed the grey zone. Thus, stenoses with FFR values within this range are ultimately interpreted as dubious among the interventionist community. Consequently, keeping patients on conservative treatment under these circumstances is known to have a worse prognosis [17].

Petraco et al [18]. suggested that the grey zone of the FFR measurement ranges from 0.75 to 0.85. In clinical practice, this means that each time a single FFR measurement falls within these two values, the recommendation for revascularization guided by this method might change if the measurement is repeated 10 minutes later. The closer to 0.80 the FFR result is, the higher this likelihood will be. Furthermore, in 2013, Tarkin et al. [19] published a study showing that FFR measurements should only be performed when a stable hyperemia state is reached for ≥ 60 seconds during intravenous adenosine infusion. This study assessed that changes in systemic Blood Pressure (BP) caused by intravenous adenosine may lead to changes in the classification of the lesion based on the FFR measurement, affecting the clinical decision. Such changes were observed in 9% of cases, with differences when performing the measurements at peak values and under stable hyperemic conditions,using the threshold of 0.80 and in 5.2% of cases using the threshold of 0.75. This method was used in the DEFER and FAME trials, according to the authors [11,12]. However, there is no reference to microcirculation, nor to changes in peripheral resistance and compliance with changes in coronary perfusion pressure, nor to the FFR measurement at different time points in the aforementioned studies methodology. As an example, the DEFER trial [11] used two adenosine infusion methods, IV and CI. It should be noted that such situations are not included in the current guidelines [16].

Another key issue that was ignored or overlooked in the main protocols is the caffeine regimen for FFR measurement. Caffeine is known to attenuate the effects of adenosine, and its use should be contraindicated prior to these measurements [20-25]. Sparv et al showed that using caffeine 6 hours before FFR measurement by adenosine-induced maximal coronary hyperemia might significantly affect the results.

For reflection
This editorial note discussed the use of FFR measurement as the gold standard method for defining the treatment of coronary artery disease. This is motivated by the concern regarding an unfavorable outlook of percutaneous treatment for CAD, considering the fact that many patients are no longer being treated based on the information provided by FFR measurement, which remains less reproducible, either because the hyperemia induction method is still not standardized, or because of the lack of an objective definition of a cut-off point. These issues must be discussed along with the need for conducting studies with a direct comparison between FFR measurements and noninvasive functional methods in patients with moderate and severe coronary disease. There is a risk of an exponential increase in the number of cardiac adverse events, which could be avoided through improved evaluation, having them great impact on health care. Finally, should we forgot the results of ischemia detected by non-invasive methods and just accept those detected by FFR?


  1. Smith SC Jr, Feldman TE, Hirshfeld JW J, Jacobs AK, Kern MJ, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention-summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol .2006;47:216-235.(Ref.)
  2. Gould KL. Does coronary flow trump coronary anatomy? J Am Coll Cardiol Img. 2009;2:1009-1023.(Ref.)
  3. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, et al. The syntax score: An angiographic tool grading the complexity of coronary artery disease. Euro Interv. 2005;1:219-227. (Ref.)
  4. Brandt PWT, Partridge JB, Wattie WJ. Coronary arteriography: Method of presentation of the arteriogram report and a scoring system. Clin Radiol. 1977;28:361-65 (Ref.)
  5. Reardon MFPD, Nestel PJMD, Craig IHMD, Harper RWMD. Lipoprotein predictors of the severity of coronary artery disease in men and women. Circulation. 1985;71:881-888. (Ref.)
  6. Friesinger GC, Page EE, Ross RS. Prognostic significance of coronary arteriography. Transactions of the Association of American Physicians. 1970;83:78-92. (Ref.)
  7. Lin GA, Dudley RA, Lucas FL, Malenka DJ, Vittinghoff E, et al. Frequency of stress testing to document ischemia prior to elective percutaneous coronary intervention. JAMA. 2008;300:1765-1773. (Ref.)
  8. Dehmer GJ, Weaver D, Roe MT, Milford-Beland S, Fitzgerald S, et al. A Contemporary View of Diagnostic Cardiac Catheterization and Percutaneous Coronary Intervention in the United States: A Report From the Cath PCI Registry of the National Cardiovascular Data Registry, 2010 Through June 2011. J Am Coll Cardiol 2012;60(20):2017-31. (Ref.)
  9. Moses JW, Stone GW, Nikolsky E, Mintz GS, Dangas G, et al. Drug-eluting stents in the treatment of intermediate le-sions: pooled analysis from four randomized trials. J Am Coll Cardiol. 2006;47:2164-2171. (Ref.)
  10. Pijls NHJ, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334(26):1703-1708. (Ref.)
  11. Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007;49(21):2105-2111.(Ref.)
  12. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, et al. FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. (Ref.)
  13. Chamuleau SA, Meuwissen M, Koch KT, van Eck-Smit BL, Tio RA ,et al. Usefulness of fractional flow reserve for risk stratification of patients with multivessel coronary artery disease and an intermediate stenosis. Am J Cardiol 2002;89:377-380. (Ref.)
  14. De Bruyne B, Pijls NH, Bartunek J, Kemal Kulecki, Jan-Willem Bech ,et al. Fractional flow reserve inpatients with prior myocardial infarction. Circulation. 2001;104:157-162. (Ref.)
  15. Mohdnazri SR, Keeble TR, Sharp ASP. Fractional Flow Reserve: Does a Cut-off Value add Value? Interventional Cardiology Review. 2016;11(1):17-26. (Ref.)
  16. Windecker S, Kolh P, Alfonso F, Kolh P, Alfonso F, et al. 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). Eur Heart J. 2014 Oct 1 35(37):2541-2619 (Ref.)
  17. Adjedj J, De Bruyne B, Floré V, Giuseppe Di Gioia, Angela Ferrara, et al. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation. 2016;133:502-508 (Ref.)
  18. Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, et al. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv. 2013;6(3):222-5. Erratum in: JACC Cardiovasc Interv. 2013;6(4):431. (Ref.)
  19. Tarkin JM, Nijjer S, Sen S, Petraco R, Echavarria-Pinto M, et al. Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study. Circ Cardiovasc Interv. 2013;6(6):654-661. (Ref.)
  20. Aqel RA, Zoghbi GJ, Trimm JR, Baldwin SA, Iskandrian AE. Effect of caffeine administered intravenously on intracoronaryadministered adenosine induced coronary hemodynamics in patients with coronary artery disease. Am J Cardiol. 2004;93(3):343-346. (Ref.)
  21. Fredholm BB. Adenosine actions and adenosine receptors after 1 week treatment with caffeine. Acta Physiol Scand. 1982;115(2):283-286. (Ref.)
  22. Choi OH, Shamim MT, Padgett WL, Daly JW. Caffeine and theophyllineanalogues: correlation of behavioral effects with activity as adenosine receptorantagonists and as phosphodiesterase inhibitors. Life Sci. 1988;43(5):387–398. (Ref.)
  23. Salcedo J, Kern MJ. Effects of caffeine and theophylline on coronary hyperemia induced by adenosine or dipyridamole. Catheter CardiovascInterv. 2009;74(4):598-605. (Ref.)
  24. Biaggioni I, Paul S, Puckett A, Arzubiaga C. Caffeine and theophyllineas adenosine receptor antagonists in humans. J Pharmacol Exp Ther.1991;258(2):588–593. (Ref.)
  25. Hendel RC, Berman DS, Di Carli MF, Heidenreich PA, Henkin RE, et al. American College of Cardiology Foundation Appropriate Use Criteria Task F, American Society of Nuclear C, et al. ACCF/ASNC/ ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. Circulation. 2009;119(22):e561–587. (Ref.)