Fractional Flow Reserve

  • F. M. Zimmermann
  • N. H. J. Pijls
  • W. A. L. ToninoEmail author


The potential benefit of revascularization depends on the presence and extent of myocardial ischemia. Performing percutaneous coronary intervention (PCI) on ischemia-inducing coronary stenoses improves both symptoms and outcome, while performing PCI on non-ischemia-inducing stenoses has no benefit and is potentially harmful. Noninvasive testing and the coronary angiogram have limited ability to distinguish specific ischemic territories and responsible stenoses, especially in multivessel coronary disease. To overcome these shortcomings, fractional flow reserve (FFR) has been developed as a stenosis-specific index to determine whether a coronary stenosis has ischemic potential. FFR-guided PCI improves both symptoms and outcome. As such, knowledge of coronary physiology and FFR has become imperative in daily coronary decision making.


  1. 1.
    Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico JA, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation. 1998;97(6):535–43. Large SPECT study demonstrating the relationship between the extent of inducible ischemia and outcome. CrossRefPubMedGoogle Scholar
  2. 2.
    Shaw LJ, Berman DS, Maron DJ, Mancini GB, Hayes SW, Hartigan PM, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117(10):1283–91. Substudy of the COURAGE trial, which demonstrated that if ischemia is substantially reduced by PCI, the prognosis improves. CrossRefPubMedGoogle Scholar
  3. 3.
    Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van't Veer M, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol. 2007;49(21):2105–11. Key study demonstrating the excellent prognosis of hemodynamically nonsignificant stenoses without added benefit of performing PCI on these lesions. CrossRefPubMedGoogle Scholar
  4. 4.
    Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, 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):3182–8. Longest follow-up of a randomized trial using FFR. CrossRefPubMedGoogle Scholar
  5. 5.
    Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, 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):2816–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Toth GG, Johnson NP, Jeremias A, Pellicano M, Vranckx P, Fearon WF, et al. Standardization of fractional flow reserve measurements. J Am Coll Cardiol. 2016;68(7):742–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek JKJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334(26):1703–8. Key paper showing high sensitivity (90%) and specificity (100%) of FFR versus a unique gold standard.CrossRefPubMedGoogle Scholar
  8. 8.
    Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213–24. Landmark study showing superiority of FFR-guided PCI to angiography-guided PCI in patients with multivessel disease. CrossRefPubMedGoogle Scholar
  9. 9.
    van Nunen LX, Zimmermann FM, Tonino PA, Barbato E, Baumbach A, Engstrøm T, 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):1853–60.CrossRefPubMedGoogle Scholar
  10. 10.
    De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991–1001. Key study on the benefit of FFR-guided PCI versus medical therapy in patients with stable stable coronary artery disease and functionally significant stenoses. CrossRefPubMedGoogle Scholar
  11. 11.
    Li J, Elrashidi MY, Flammer AJ, Lennon RJ, Bell MR, Holmes DR, et al. Long-term outcomes of fractional flow reserve-guided vs. angiography-guided percutaneous coronary intervention in contemporary practice. Eur Heart J. 2013;34(18):1375–83.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Park SJ, Ahn JM, Park GM, Cho YR, Lee JY, Kim WJ, et al. Trends in the outcomes of percutaneous coronary intervention with the routine incorporation of fractional flow reserve in real practice. Eur Heart J. 2013;34(43):3353–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Hamilos M, Muller O, Cuisset T, Ntalianis A, Chlouverakis G, Sarno G, 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(15):1505–12. Largest study on the use of FFR to guide revascularization of equivocal left main stenosis. CrossRefPubMedGoogle Scholar
  14. 14.
    Yong AS, Daniels D, De Bruyne B, Kim HS, Ikeno F, Lyons J, et al. Fractional flow reserve assessment of left main stenosis in the presence of downstream coronary stenoses. Circ Cardiovasc Interv. 2013;6(2):161–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Koo BK, Park KW, Kang HJ, Cho YS, Chung WY, Youn TJ, et al. Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve. Eur Heart J. 2008;29(6):726–32. Study demonstrating the usefulness of FFR to guide treatment decisions in the treatment of side branches.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen SL, Ye F, Zhang JJ, Xu T, Tian NL, Liu ZZ, et al. Randomized comparison of FFR-guided and angiography-guided provisional stenting of true coronary bifurcation lesions: the DKCRUSH-VI trial (Double Kissing Crush Versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions VI). JACC Cardiovasc Interv. 2015;8(4):536–46.CrossRefPubMedGoogle Scholar
  17. 17.
    Ntalianis A, Sels JW, Davidavicius G, Tanaka N, Muller O, Trana C, et al. Fractional flow reserve for the assessment of nonculprit coronary artery stenoses in patients with acute myocardial infarction. JACC Cardiovasc Interv. 2010;3(12):1274–81. Paper demonstrating that FFR of non-culprit stenoses at the time of myocardial infarction is reliable. CrossRefPubMedGoogle Scholar
  18. 18.
    Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang L, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386(9994):665–71.CrossRefPubMedGoogle Scholar
  19. 19.
    Botman CJ, Schonberger J, Koolen S, Penn O, Botman H, Dib N, et al. Does stenosis severity of native vessels influence bypass graft patency? A prospective fractional flow reserve-guided study. Ann Thorac Surg. 2007;83(6):2093–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Pellicano M, De Bruyne B, Toth GG, Casselman F, Wijns W, Barbato E. Fractional flow reserve to guide and to assess coronary artery bypass grafting. Eur Heart J. 2016;pii:ehw505. [Epub ahead of print]CrossRefGoogle Scholar
  21. 21.
    Pijls NH, Klauss V, Siebert U, Powers E, Takazawa K, Fearon WF, et al. Coronary pressure measurement after stenting predicts adverse events at follow-up: a multicenter registry. Circulation. 2002;105(25):2950–4.CrossRefPubMedGoogle Scholar
  22. 22.
    Tonino PA, Johnson NP. Why is fractional flow reserve after percutaneous coronary intervention not always 1.0? JACC Cardiovasc Interv. 2016;9(10):1032–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Jeremias A, Maehara A, Généreux P, Asrress KN, Berry C, De Bruyne B, et al. Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study. J Am Coll Cardiol. 2014;63(13):1253–61. Comprehensive core laboratory analysis showing the accuracy of resting Pd/Pa and iFR to identify inducible ischemia of only 80%. CrossRefPubMedGoogle Scholar
  24. 24.
    Zimmermann FM, De Bruyne B, Pijls NH, Desai M, Oldroyd KG, Park SJ, et al. Rationale and design of the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 3 trial: a comparison of fractional flow reserve–guided percutaneous coronary intervention and coronary artery bypass graft surgery in patients with multivessel coronary artery disease. Am Heart J. 2015;170(4):619–626.e2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • F. M. Zimmermann
    • 1
  • N. H. J. Pijls
    • 1
  • W. A. L. Tonino
    • 1
    Email author
  1. 1.Catharina Hospital EindhovenEindhovenThe Netherlands

Personalised recommendations