Use of Fractional Flow Reserve in ACS

Case Presentation

A 64-year-old man was admitted with a 2-week history of unstable angina. One week before presentation, he had a cardiac catheterization at another facility showing isolated moderate disease in the first diagonal branch (50%) and normal left ventricular systolic function. No intervention was performed at that time. The patient was started on antianginal therapy but continued to be symptomatic both at rest and with exertion.

The admission electrocardiogram showed no ischemic changes. High-sensitivity troponin I remained normal on serial testing. Myocardial perfusion imaging showed large reversible defects in the anterior and anterolateral walls. The angiogram showed the 50% stenosis in the diagonal as previously reported (Figure 1).

Figure 1

Figure 1

Given the patient's symptoms and stress test results, fractional flow reserve (FFR) was used to assess the diagonal lesion. Baseline Pd/Pa ratio was 0.52 and dropped to 0.47 with intravenous adenosine (Figure 2A). A 2.5 x 18 mm drug-eluting stent was deployed at the lesion site with excellent angiographic results (Figure 3). Post-percutaneous coronary intervention (PCI) FFR showed baseline Pd/Pa of 0.9 and FFR of 0.76 (Figure 2B).

Figure 2

Figure 2

Figure 3

Figure 3

Due to persistent ischemic FFR, intracoronary optical coherence tomography (OCT) evaluated the stent site. The stent was well-expanded and well-apposed, but there was a red thrombus proximal to the stent near the ostium of the vessel with decreased minimal lumen area (2.7 mm2) that was not appreciated angiographically (Figures 4A-B).

Figure 4

Figure 4

A 2.5 x 8 mm drug-eluting stent was deployed with excellent angiographic results (Figure 5). A final FFR measurement was attempted but could not be obtained due to pressure wire damage. At 4-week follow-up, the patient was free of chest pain.

Figure 5

Figure 5

FFR of the Culprit Lesion in ACS

Acute coronary syndromes (ACS) constitute the highest risk subset of all coronary artery disease presentations. Of approximately half a million PCIs performed in the United States 2009-2010 in the National Cardiovascular Data Registry, 71% were performed for an ACS.1 Although studies have suggested that FFR has a role in evaluating ischemia in non-culprit lesions in ST-segment elevation myocardial infarction (STEMI), possibly preventing unnecessary PCI,2,3 a real concern regarding the safety of deferring PCI in culprit lesions with non-ischemic FFR values in patients with non-ST-segment elevation myocardial infarction (NSTEMI) has been raised for multiple reasons. First, there is an inability of FFR to detect plaques with unstable features without significant flow limitation, which may provoke further ischemia and myocardial damage. Stated in another way, if FFR is measured after spontaneous partial thrombus dissolution, the stenosis might become less flow-limiting, resulting in an FFR in the non-ischemic range. Second, accurate FFR assessment is based on the pivotal assumption of a stable microvasculature; it is known that ACS patients manifest varying degrees of transient microvascular dysfunction, particularly in the culprit vessel, due to plaque rupture, embolization, or inflammation and can consequently have a falsely normal FFR.4,5

A post-hoc analysis of ACS patients from the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that ACS patients who underwent angiography-guided PCI had higher event rates versus ASC patients who underwent angiography-guided plus FFR-guided PCI (26 vs. 21%) with a similar difference observed in patients with stable ischemic heart disease (SIHD). Further, the investigators found that none of the subsequent myocardial infarctions in the FFR group were at lesion sites deferred from stenting as a result of a non-ischemic FFR.6 In the FAMOUS-NSTEMI (Fractional Flow Reserve Versus Angiographically Guided Management to Optimise Outcomes in Unstable Coronary Syndromes) trial, FFR-guided PCI was studied prospectively in 350 patients with NSTEMI. The authors reported that FFR guidance led to a change in treatment decision in 20% of patients and was associated with an overall reduction in revascularization rate with no difference in major adverse cardiovascular events (MACE) at 12-month follow-up.2 However, most of the FFR-guided patients in both treatment arms received at least one stent, presumably to the culprit vessel. Therefore, these data may support the safety and effectiveness of deferring PCI in lesions with FFR > 0.80 in non-culprit vessels in patients with NSTEMI, but the use of FFR in the culprit lesion remains less clear. Caution should therefore be taken before drawing any conclusions from this study regarding the safety of deferral of culprit lesions.

We have recently demonstrated in a large cohort of patients that FFR-guided deferral in ACS patients using the FFR value established for SIHD is associated with a significantly higher risk of MACE compared with SIHD after propensity matching. NSTEMI presentation had the highest risk, with unstable angina being worse than SIHD but lower risk than NSTEMI.7 The same study showed that ACS presentation was an independent predictor of adverse events at extended follow-up compared with patients with SIHD. ACS patients had a threefold higher risk of subsequent myocardial infarction and target vessel failure.7 Another recent retrospective multicenter study has supported these findings and reported increased target vessel failure in deferred lesions in ACS patients within a median time interval of 15 months from the index FFR measurement.8 Thus, the safety of deferring intervention of the culprit lesion in ACS patients is uncertain based on existing data.

FFR is not commonly used in current clinical practice in ACS patients. In fact, an expert consensus statement on FFR use recommends that FFR measurement of the culprit vessel of a patient with ACS should not be performed.9 If used in lesions in which the culprit is uncertain, interpretation of results should be made cautiously. If a normal FFR occurs but the suspicion is that the lesion is, in fact, the culprit, the use of imaging as was performed in this case is reasonable for clinical decision-making.

FFR in Non-Culprit Vessel in STEMI

Two recent trials have supported revascularization of the non-infarct-related artery with FFR guidance in STEMI patients. DANAMI-3-PRIMULTI (The Third Danish Study of Optimal Acute Treatment of Patients With STEMI: Primary PCI in Multivessel Disease) and the Compare-Acute (Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction) trial both demonstrated improved 1-year outcomes among patients undergoing FFR-guided complete revascularization versus culprit-only PCI.10,11 In both studies, the primary endpoint was driven predominantly by a reduction in repeat revascularization, with no significant differences in death and myocardial infarction. On the other hand, previous angiographically-driven studies of complete revascularization of patient presenting with acute myocardial infarction have shown a reduction in death and myocardial infarction.12,13 One can argue that FFR in the acute setting is misleading because there may be other unstable non-culprit lesions that cannot be detected by FFR (false negative) and that might benefit from revascularization.14,15 This hypothesis could account for superior outcomes in the previously noted angiography-guided studies compared with the FFR-guided studies.

Use of Post-PCI FFR

Despite optimal angiographic results after PCI, approximately one-fifth of lesions show persistent ischemia under maximal hyperemia.16 Several studies have shown that lower post-PCI FFR is associated with increased risk of MACE.10-14 What has been less clear is whether further improvement in FFR can be achieved in vessels that have an angiographically optimized result. We recently demonstrated that FFR can, in fact, be improved by post-dilatation or further stenting, potentially improving long-term outcomes.16

We have also shown that ACS patients who achieved final FFR values >0.91 had a significantly lower adverse event rate compared with a final FFR of ≤0.91 (19 vs. 30%; p = 0.03).17 In fact, patients with ACS who achieved final FFR of >0.91 had similar outcomes to SIHD patients (19 vs. 16%; p = 0.51), and ACS was no longer a significant predictor of MACE.17


Deferring PCI on the basis of non-ischemic FFR in patients with ACS is associated with significantly worse outcomes compared with patients with SIHD and should be used with caution in this population. This is especially true for lesions that are clearly culprit lesions. Often, the culprit lesion is not clear, and a hybrid evaluation using physiology (FFR) and imaging (OCT and intravascular ultrasound [IVUS]) may be extremely valuable in clinical decision-making. We have provided a proposed algorithm for FFR and imaging in the ACS setting (Figure 6).

Figure 6: Algorithm for the Use of FFR in ACS

Figure 6


  1. Chan PS, Patel MR, Klein LW, et al. Appropriateness of percutaneous coronary intervention. JAMA 2011;306:53-61.
  2. Layland J, Oldroyd KG, Curzen N, et al. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial. Eur Heart J 2015;36:100-11.
  3. Layland J, Carrick D, McEntegart M, et al. Vasodilatory capacity of the coronary microcirculation is preserved in selected patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2013;6:231-6.
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  6. Sels JW, Tonino PA, Siebert U, et al. Fractional flow reserve in unstable angina and non-ST-segment elevation myocardial infarction experience from the FAME (Fractional flow reserve versus Angiography for Multivessel Evaluation) study. JACC Cardiovasc Interv 2011;4:1183-9.
  7. Hakeem A, Edupuganti MM, Almomani A, et al. Long-Term Prognosis of Deferred Acute Coronary Syndrome Lesions Based on Nonischemic Fractional Flow Reserve. J Am Coll Cardiol 2016;68:1181-91.
  8. Picchi A, Leone AM, Zilio F, et al. Outcome of coronary lesions with deferred revascularization due to negative fractional flow reserve in subjects with acute coronary syndrome. Int J Cardiol 2017;230:335-8.
  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.
  10. Engstrøm T, Kelbæk H, Helqvist S, 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;386:665-71.
  11. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med 2017;376:1234-44.
  12. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115-23.
  13. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015;65:963-72.
  14. Vergallo R, Uemura S, Soeda T, et al. Prevalence and Predictors of Multiple Coronary Plaque Ruptures: In Vivo 3-Vessel Optical Coherence Tomography Imaging Study. Arterioscler Thromb Vasc Biol 2016;36:2229-38.
  15. Lee SG, Lee CW, Hong MK, Kim JJ, Park SW, Park SJ. Change of multiple complex coronary plaques in patients with acute myocardial infarction: a study with coronary angiography. Am Heart J 2004;147:281-6.
  16. Agarwal SK, Kasula S, Hacioglu Y, Ahmed Z, Uretsky BF, Hakeem A. Utilizing Post-Intervention Fractional Flow Reserve to Optimize Acute Results and the Relationship to Long-Term Outcomes. JACC Cardiovasc Interv 2016;9:1022-31.
  17. Kasula S, Agarwal SK, Hacioglu Y, et al. Clinical and prognostic value of poststenting fractional flow reserve in acute coronary syndromes. Heart 2016;102:1988-94.

Clinical Topics: Acute Coronary Syndromes, 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: Coronary Artery Disease, Troponin I, Drug-Eluting Stents, Acute Coronary Syndrome, Myocardial Infarction, Myocardial Perfusion Imaging, omega-Chloroacetophenone, Myocardial Perfusion Imaging, Adenosine, Tomography, Optical Coherence, Constriction, Pathologic, Hyperemia, Dilatation, Physical Exertion, Solubility, Angina, Unstable, Electrocardiography, Percutaneous Coronary Intervention, Cardiac Catheterization, Angioplasty, Thrombosis, Angiography, Microvessels, Inflammation, Algorithms

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