Coronary fractional flow reserve (FFR) is a pressure- based index of the functional significance of epicardial coronary stenoses. It is defined as the ratio of the maximal flow in a stenotic artery to the flow in the same artery in the absence of stenosis. It can be easily measured using a coronary pressure wire during routine coronary angiography and is defined as the ratio of the coronary pressure distal to the lesion to the pressure in the aorta when the artery is maximally dilated. FFR has been validated in a variety of stenoses, and it has the same threshold value regardless of the type of stenosis: values < 0.8 are considered abnormal (the upper limit of normal being a value of 1) (see Coronary Lesions For Which FFR May Be Used sidebar).1 FFR is independent of heart rate, rhythm, and contractility. It is also highly reproducible, and the cut-off value of 0.8 has > 90% accuracy for identification of ischemia causing stenoses.2 These features and its ease of use make it suitable for the investigation of multiple stenoses and vessels in the same setting.

FAME: RATIONALE AND STUDY DESIGN
FFR-guided percutaneous coronary intervention (PCI) appears to yield better clinical outcomes than PCI guided by angiography alone.3 Before the publication of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study, several smaller studies had established the clinical utility of FFR-guided revascularization (percutaneous or surgical) in patients with coronary artery disease (CAD). However, data supporting the use of FFR in patients with multivessel disease treated with PCI were scarce. The FAME study was a prospective, randomized controlled trial designed to investigate the effects of FFR- versus angiography-guided PCI on clinical outcomes in a large cohort of patients.4

The FAME study was conducted in 20 centers across Europe and the United States and included 1,005 patients with multivessel (ie, two- or three-vessel) disease. Patients were randomized to undergo PCI based on either angiographic findings alone or angiography in conjunction with FFR. In the latter group, all lesions with a > 50% stenosis were investigated with FFR, and only those associated with a value < 0.8 were treated with stents (97% of which were drug-eluting stents [DES]). Patients were followed clinically for at least 1 year after the index procedure.

FAME STUDY: KEY FINDINGS
FFR-guided multivessel PCI reduced the rate of major adverse cardiac events (MACE) (death, myocardial infarction [MI], or repeat revascularization) by 30% at 1 year compared to angiography-guided PCI. The risk of death or MI was reduced by 35% in patients randomized to FFR (see Key Findings From the FAME Study sidebar). Patients treated with FFR-guided PCI received two stents compared to three stents in patients randomized to angiography- guided PCI. Despite a lower use of DES in patients in the FFR arm of the study, the number of patients who were free of angina at 1 year was similar in the FFR- and angiography-guided PCI cohorts. The procedure time and length of hospital stay were identical in the two groups, but hospital costs were lower in the FFR cohort. The 2-year follow-up data were recently published. The beneficial effects of FFR-guided PCI on death and nonfatal MI were maintained after 24 months (34% lower MACE rates in the FFR-guided group).5 The rate of repeat revascularization in the FFR-guided PCI cohort was low: only 3% of lesions initially deferred on the basis of an FFR > 0.8 required a subsequent intervention.

IMPLICATIONS FOR CONTEMPORARY PRACTICE
Optimal Treatment Strategy for Multivessel CAD: PCI Versus Surgery
Despite advances in stent technologies and interventional techniques, PCI has been unable to yield better clinical outcomes than coronary artery bypass graft surgery (CABG) in patients with multivessel CAD. In the SYNTAX study (Synergy between PCI with Taxus and Cardiac Surgery), patients with three-vessel coronary disease randomized to CABG experienced fewer cardiac events compared to patients treated with angiography-guided PCI using DES.7 Patients with higher SYNTAX scores (ie, with more complex anatomies) did better with CABG than with stents. A more complete revascularization may underlie the better longterm outcome with CABG than with PCI, particularly in patients with complex coronary anatomy (eg, bifurcation and trifurcation lesions). In the SYNTAX study, the decision to treat a particular lesion (or set of lesions) was based on traditional angiography alone. Given the findings from the FAME study, many patients in the SYNTAX trial underwent revascularization of lesions that were not hemodynamically significant. Patients treated with PCI for such lesions were thus exposed to potential complications of stents (such as restenosis, stent thrombosis, and increased contrast loads) without any benefits due to the absence of myocardial ischemia. Although this may have also occurred in patients who underwent CABG, surgical outcomes were not affected as much because graft failure in a nonischemic vessel after CABG often remains clinically silent. When comparing the 1-year clinical outcomes between patients in the SYNTAX PCI cohort and the FAME FFR-guided cohort, one may speculate that had the SYNTAX investigators used a more physiologic SYNTAX score (ie, only including lesions with an FFR value of ≤ 0.8), fewer lesions would have been revascularized, and patients randomized to PCI would have fared better. Nevertheless, a randomized study is needed to confirm this hypothesis.

Cost Benefits of FFR Utilization
The FAME study reported that the use of FFR in patients with multivessel disease was associated with a lower cost over the course of 1 year. Day-of-procedure procedure costs were lower in the FFR-guided cohort because the added cost of the pressure wire was offset by the cost of additional stents used in the angiography-guided arm (average expense per procedure was $5,332 ± 3,261 for FFR vs $6,007 ± 2,819 for angiography alone). The economic advantages of using FFR to guide therapy are not only restricted to patients with multivessel disease. One study before FAME showed that FFR-guided PCI markedly reduced hospital costs in patients with single-vessel disease who present with unstable angina or after a non-ST elevation MI.8 In this study, the information obtained by FFR measurement at the time of the index procedure obviated the need for additional stress testing and resulted in shorter hospital stays without affecting clinical outcomes. To result in substantial savings, FFR-guided PCI must be a routine practice so that it results in a significant decrease in the use of stents compared to angiography-guided PCI.

PCI Volumes
The FAME study showed that patients treated with FFRguided PCI received fewer stents than those treated using angiography alone. Although these findings underscore the clinical superiority of using an FFR-based approach in treating patients with CAD, they have also led skeptics to suggest that the routine use of FFR will cause PCI volumes to decrease and will eventually lead to lower revenues. A closer look at the angiographic data from FAME suggests that this scenario is unlikely.6 In the FFR-guided cohort, only 46% of the 509 patients actually had multivessel involvement after identification of all hemodynamically significant lesions. Many of the remaining patients were found to have single-vessel disease, making them optimal candidates for PCI in conjunction with aggressive medical therapy (Figure 1). If one uses the FAME data and applies them to all-comers referred for coronary angiography, the decrease in PCI volumes resulting from patients having angiographically significant but functionally insignificant CAD (ie, FFR values > 0.8) is likely to be counterbalanced by the number of patients with three-vessel CAD who become candidates for PCI instead of multivessel CABG because they have functional single- or two-vessel disease (Figure 2). One possible scenario is depicted in Figure 2, in which the observed angiographic severity of CAD (by number of vessels) newly diagnosed during elective cardiac catheterization is compared to the expected prevalence of functionally significant disease in the same population based on the FAME results.9

FAME 2: LOOKING AHEAD
FAME 2 is the follow-up study to FAME, and its objective is to compare the clinical effectiveness of FFR-guided PCI with optimal medical therapy (OMT) versus OMT alone in patients with one- or two-vessel CAD. The rationale behind the study is similar to that of the original FAME study: routine utilization of FFR may improve outcomes in patients with CAD by allowing judicious stent implantation. The FAME 2 study will hopefully address the issues raised by contemporary trials of OMT for stable CAD, such as COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). COURAGE reported similar outcomes with OMT and OMT with angiography-guided PCI.10 The trial will follow patients with at least one hemodynamically significant coronary lesion (ie, FFR ≤ 0.8) for at least 2 years after randomization to OMT alone or DES placement. Endpoints will include MACE (similar to the original FAME study), cost-effectiveness, and functional status. The study is being conducted at 30 centers across the United States and Europe, and the first patient was enrolled earlier this year.

OPTIMIZING OUTCOMES USING FFR
Currently, two pressure wire systems are available for commercial use in the United States. Both systems use a 0.014-inch wire with an integrated pressure sensor at the distal end. The electronic component at the proximal end is detachable, allowing the pressure wire to function as an angioplasty guidewire during coronary interventions. The PressureWire Certus system (St. Jude Medical, Inc., St. Paul, MN) allows measurement of thermodilution-derived coronary flow reserve by virtue of two temperature sensors along the distal end of the wire. The ComboWire XT system (Volcano Corporation, San Diego, CA) incorporates a Doppler wire that can also measure coronary flow reserve. The process for setting up both systems is straightforward and can be completed within minutes.

Coronary hyperemia may be induced using an intracoronary bolus of adenosine (or papaverine) or an intravenous infusion of adenosine. The FAME trial mandated use of intravenous adenosine, which has become the preferred method of measuring FFR in many catheterization labs. The hyperemia induced using intravenous adenosine is sustained and yields pressure readings that are reproducible (and more reliable). One major advantage of this technique is that it allows interrogation of multiple areas within the same vessel by means of pressure pullback. The recommended dose of intravenous adenosine is 140 µg/kg/h, preferably administered through a large vein. At the present time, there are no data to support the use of regadenoson (Lexiscan, Astellas Pharma US, Inc., North Deerfield, IL) for the induction of hyperemia. Although an FFR value < 0.8 is consistent with the presence of an obstructive stenosis, values from 0.8 to 0.9 are also abnormal and denote the presence of mild-to-moderate CAD. Of note, FFR does not delineate anatomy. Thus, intravascular ultrasound continues to be an invaluable tool for guiding PCI of complex lesions (eg, bifurcation or trifurcation lesions).

CONCLUSIONS
The FAME study showed that routine use of FFR to guide PCI in patients with multivessel CAD leads to better clinical outcomes at 2 years and does not add to the costs of the procedure. Angiography alone is inadequate to guide revascularization because it fails to identify the functional significance of the stenosis. Many patients with angiographic three-vessel CAD actually have functional one- or two-vessel disease, making them optimal candidates for PCI. FFR can be measured conveniently at the time of diagnostic angiography and does not add to procedure time or radiation exposure time compared to angiography alone. Intravenous adenosine yields the most reliable results and should be used whenever possible.

Salman A. Arain, MD, FACC, is from the Tulane University Heart and Vascular Institute in New Orleans, Louisiana. He has disclosed that he is on the Speaker's Bureau for St. Jude Medical, Inc. Dr. Arain may be reached at sarain@tulane.edu.

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