Routine Pressure-Derived Fractional Flow Reserve Guidance:
From Diagnostic to Everyday Practice

Coronary angiography remains the most widely used means of assessing the severity of coronary stenosis. Despite its universal acceptance, coronary angiography is simply luminography, and is inherently limited in determining the physiological significance of coronary stenoses.^1,2 During recent years, the pressure-derived myocardial fractional flow reserve (FFR) index, once used only as a research tool, has gained wide acceptance for determining the physiological significance of a coronary stenosis. FFR is defined as the ratio of the maximal blood flow achievable in a stenotic vessel to the normal maximal flow in the same vessel, which represents the fraction of maximum flow that can still be maintained despite the presence of the stenosis. The development of a pressure sensor-tipped angioplasty guidewire,³ which permits measurement of coronary pressure distal to coronary obstructions, has proven clinically practical and has been accepted as a valuable adjunct to coronary angiography in the catheterization laboratory. FFR is a lesion-specific index of the functional severity of coronary stenosis and has a clearly-defined cutoff value that correlates well with the findings from a variety of noninvasive stress tests.⁴ In patients with intermediate coronary lesions, a FFR value 5 This review outlines the theoretical background of FFR and its clinical applicability in the catheterization laboratory. Theory of Fractional Flow Reserve (click on image below) Instrumentation and Coronary Pressure Measurement Currently, three pressure-sensing guidewire systems are commercially available (Table 1): (1) SmartMap™ and (2) ComboMap™ systems (Volcano Corporation, Rancho Cordova, California); and the (3) RadiAnalyzer™ (Radi Medical Systems, Inc., Wilmington, Mass.). All three are based on a high-fidelity 0.014 inch guidewire in which a pressure sensor is located 3 cm proximal to the tip. The steerability and torqueability of these pressure sensor-tipped guidewires are very similar to a conventional guidewire. A 6 Fr or 7 Fr guiding catheter via the femoral approach is generally recommended for FFR assessment; however, the results of a recent study¹¹ show that it is also safe and reliable to use a conventional 4 Fr diagnostic catheter for this measurement. Before advancing the pressure-sensing guidewire, nitroglycerin and heparin are administered according to the standard protocol. Next, the pressure-sensing guidewire is zeroed externally and then advanced to the distal end of the guiding catheter. After equal pressures are confirmed at this location, the wire is advanced and placed at least 2 cm beyond the stenosis. Maximal coronary hyperemia is achieved by means of either intracoronary (IC) bolus administration or continuous intravenous (IV) infusion of a vasodilator, and FFR is then determined. Hyperemic Pharmacological Agents In order to obtain a reliable FFR measurement, achievement of maximal vasodilatation is critical, otherwise the pressure gradient across a stenosis will be underestimated, resulting in an underestimation of stenosis severity. In clinical practice, maximal coronary hyperemia can be achieved with a vasodilator either through IC bolus administration or continuous IV infusion. The most widely used agents (Table 2) are adenosine,¹² adenosine 5’-triphosphate (ATP),^13–15 papaverine,¹⁶ dipyridamole¹⁷ and dobutamine.¹⁸ Recently, studies by Parham et al.¹⁹ showed that sodium nitroprusside can also be used as an effective and safe hyperemic agent for physiological assessment. Compared to IC adenosine, IC sodium nitroprusside produces an equivalent but more sustained hyperemic response. From a practical standpoint, an ideal hyperemic agent should fulfill the following criteria: low cost, rapid action, short duration, ease-of-use and lack of significant side effects. Thus, in view of cost effectiveness, high safety profile, simplicity and facility, IC bolus administration of ATP or adenosine are the most frequently used agents for FFR measurement. In a recent study of 39 patients, De Bruyne et al.²⁰ examined the differences in FFR among adenosine, ATP, papaverine and contrast medium. They demonstrated that, at a sufficient dosage, adenosine, ATP and papaverine were all able to cause maximal hyperemia while contrast medium did not. Besides, IC adenosine and ATP at 20–40 mcg induced similar degrees of hyperemia as an IC bolus of 20 mg papaverine. However, only IV adenosine or ATP and IC papaverine were able to induce complete, true, steady-state hyperemia for a pressure pullback maneuver, which provided clear information on the exact location and severity of the stenosis in the presence of diffuse disease and multiple stenosis. According to the standard protocol for IC adenosine or ATP administration, the recommended dosage is 15–20 mcg in the right coronary artery (RCA) and 20–40 mcg in the left coronary artery (LCA). However, recent evidence suggests that the traditionally recommended dose of adenosine or ATP is not sufficient to induce maximal hyperemia in some patients, and higher doses are needed. Murtagh et al.²¹ demonstrated that in most of their patients, an IC bolus administration of a single 42 mcg high dose of adenosine was sufficient to cause maximum hyperemia in both the RCA and LCA systems. However, for patients with FFR in the borderline range of 0.75–0.80, a higher dose of adenosine was needed to ensure maximal hyperemia, otherwise lesion severity would be underestimated and subsequent treatment would be inappropriate. Furthermore, a recent study by Casella et al.²² demonstrated that high doses of IC adenosine up to 150 mcg were needed to ensure maximal hyperemia in some patients, and administration of such high doses was safe and associated with few adverse systemic effects in comparison with the standard dose. They also suggested that IV adenosine infusion of 140 mcg/kg/minute should be the method of choice for FFR assessment, since it induced a more pronounced hyperemia in most patients than did IC adenosine. Application of FFR A. Diagnostic Application a. Intermediate coronary lesion. FFR assessment is an accurate diagnostic tool for determining the physiological significance of an intermediate coronary lesion and distinguishes ischemia-producing lesions from those that do not. In a landmark study published in 1996,⁴ Pijls and colleagues demonstrated that in 45 patients with stable angina and single-vessel disease, a FFR of b. Diabetes mellitus (DM). In patients with DM, structural abnormalities in the microvascular system may blunt the maximal hyperemic response to potent hyperemic agents, and as a result, the FFR may not reliably reflect the degree of ischemia in this patient group. However, recently, a research team in Japan provided data that the cutoff value of 0.75 for FFR can also reliably detect myocardial ischemia in patients with DM. Yanagisawa et al.²⁴ compared the pressure-derived FFR for detecting inducible ischemia with SPECT imaging in diabetic patients with a mean hemoglobin A1c of 7.3%. The FFR cutoff value of 0.75 was still applicable and reliable in patients with DM, with a sensitivity of 83% and a specificity of 75%. c. Unstable angina. For patients with unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), it is believed that maximal hyperemic flow can be lower than that in patients with stable angina, so it may not be valid to apply the FFR 0.75 cutoff value obtained from patients with the latter condition. Recently, studies by Leesar et al.²⁵ showed that the 0.75 cutoff value was also valid in this patient group. Decision making based on the 0.75 FFR assessment criteria was superior to that based on stress perfusion scintigraphy and markedly reduced the duration and therefore the cost of hospitalization. Also, these benefits were not associated with an increase in procedure time, radiation exposure time or clinical event rates. d. Myocardial infarction (MI). The FFR cutoff value of 0.75 was originally estimated from data obtained from patients with single-vessel disease and without previous MI. However, in patients with prior MI, the mass of viable myocardium is smaller, and the impairment of resistance vessels may blunt the pharmacologically-induced maximal hyperemic response, making the FFR 0.75 cutoff value inapplicable. Conversely, it is also argued that if both the decrease of viable myocardium and impairment of coronary resistance vessels are matched in the infarcted area, pressure-derived FFR measurement remains a reliable indicator to predict inducible ischemia. However, in the acute phase of MI, ECG and clinical symptoms of the patient should be used to guide the treatment strategies, and FFR measurement can only be useful after at least 6 days. Claeys et al.²⁶ have shown that FFR is minimally affected (+ 5%) in patients with severe microvascular dysfunction and can be reliably applied to patients with recent MI. Two other recent studies have addressed the same issue. In patients with recent MI, De Bruyne et al.²⁷ compared the FFR with the method of myocardial perfusion single photon emission scintigraphy imaging for detecting inducible ischemia. Their results suggested that the 0.75 cutoff value for FFR was also valid in detecting reversible ischemia in patients at least 6 days after an MI. In cases of prior MI, the FFR value of 0.75 was still applicable and reliable for distinguishing between patients with positive from those with negative myocardial scintigraphy, with a sensitivity of 82% and a specificity of 87%. Usui and coworkers²⁸ compared FFR with thallium-201 myocardial imaging for detecting inducible ischemia in patients with previous MI. They also showed that FFR measurement was reliable in assessing coronary artery stenosis in patients with previous MI, with a sensitivity of 79% and a specificity of 79%. B. Prognostic Benefits a. FFR-guided balloon angioplasty. It has been shown that a high post-BA FFR is associated with a favorable long-term outcome, so the technique of FFR assessment is used to guide BA. A study on the usefulness of pressure-derived FFR to guide optimum BA intervention was conducted by Bech and colleagues.²⁹ The results of the study showed that for patients with post-BA FFR > 0.90 and a residual diameter stenosis of 0.90, the restenosis rates at 6, 12 and 24 months were 11%, 12% and 15% compared with 29%, 32% and 42% in patients with post-BA FFR b. FFR-guided stenting. It is believed that after optimal coronary stent implantation, no hyperemic gradient should persist across the stented segment and the FFR should be close to its normal value of 1.0. Thus, the pressure-derived FFR index can also be used to evaluate the result of stent implantation. A multicenter registry study on coronary pressure measurement after stenting showed that post-stenting FFR is a strong independent predictor of outcome at 6 months; the higher the post-stenting FFR, the lower the event rate. For patients with a post-stenting FFR > 0.95, the event rate was 4.9%; for values between 0.90 and 0.95, it was 6.2%; for values between 0.80 and 0.90, it was 20.3%; and for post-stenting FFR 30 In addition, studies conducted by Hanekamp et al.31 demonstrated that a post-stenting FFR > 0.94 corresponded very well with IVUS results. On the other hand, a recent study conducted by Fearon et al.³² comparing stent implantation guidance with FFR showed that a post-stenting FFR 0.96 did not reliably predict an optimal result based on validated IVUS criteria. Although the question of whether post-stenting FFR is reliable in guiding optimal stent implantation is still a controversial issue, it is generally accepted that the higher the post-stenting FFR value, the lower the event rate and the better the long-term outcome. C. FFR and Intravascular Ultrasound In order to understand whether IVUS has clinical potential to assess the functional severity of coronary stenosis, Takagi and colleagues³³ evaluated the relationship between IVUS parameters and the FFR index in 41 patients. Their results showed that the combination of both minimal lumen area of 60% by IVUS reliably predicted a FFR below 0.75, with a sensitivity of 92% and a specificity of 89%. Briguori et al.³⁴ also compared IVUS with FFR in patients with intermediate coronary stenosis. They found that a minimal lumen diameter of 70%, a minimal lumen cross-sectional area of 10 mm were the best cutoff values for FFR 0.75. However, only 50% of lesions with an area of stenosis > 70% had FFR values D. FFR and Complex Coronary Intervention a. Left main coronary artery disease (LMCA). Coronary pressure-derived FFR measurement has also been used in deciding whether bypass surgery should be performed in patients with intermediate LMCA disease. If the result of the FFR measurement is greater than or equal to 0.75, surgical treatment is not needed, and medical treatment can be used instead. Bech and colleagues³⁵ studied 54 patients with 40–60% LMCA disease. In 24 patients whose FFRs were greater than or equal to 0.75, bypass surgery was not performed and medical treatment was employed, while in the rest of the patients, CABG was carried out. The results showed that survival among patients at 3 years’ follow up in the medical and surgical groups were 100% and 97%, respectively. Event-free survival was 76% in the medical treatment group and 83% in the surgical group. These findings support the notion that coronary pressure-derived FFR is a reliable and lesion-specific index to quantify reversible ischemia caused by intermediate LMCA disease, and deferral of surgical treatment is safe if the measured FFR value exceeds 0.75. Recently, Jasti et al. ³⁶ provided data showing that IVUS also has clinical potential to assess the functional severity of LMCA disease. IVUS determined that a minimal lumen diameter of 2.8 mm and minimal lumen area of 5.9 mm2 were the best cutoff values for predicting a FFR b. Multivessel disease. In patients with multivessel disease, it is attractive to have techniques that can help interventionists to determine which particular culprit lesion is physiologically significant and is responsible for reversible ischemia. Since FFR is a reliable and lesion-specific index of stenosis severity, it can also be used as a tool for identifying one or more culprit lesions in such patients, when catheter-based treatment can be performed and surgical revascularization can be avoided. Also, if acceptable physiological assessment criteria are met for all the lesions, no further revascularization is needed, and the patient can safely undergo medical treatment. Thus, pressure-derived FFR measurement is a very useful technique in identifying multivessel disease patients who may benefit from surgical treatment and those who may not. In one study, Chamuleau and colleagues³⁷ showed that deferring BA for an intermediate stenosis was safe when based on FFR criteria, and FFR was more useful than SPECT for clinical decision making and risk stratification in multivessel disease patients. Further, a recent study by Botman and co-workers³⁸ also demonstrated that in patients with multivessel disease, intervention undertaken in those patients with one or two physiologically-significant lesions identified by FFR c. Transplant vasculopathy. Cardiac allograft vasculopathy (CAV) is the major cause of morbidity and mortality after the first year of transplantation.³⁹ Although several options are available for revascularization therapy such as repeat cardiac transplantation, PCI and CABG are available, the long-term results are poor. As a matter of fact, techniques that can be used for online decision making to justify intervention procedures in stable CAV patients on the one hand, and to avoid unnecessary intervention on the other hand, would be of clear benefit. In one case report,⁴⁰ coronary pressure measurement was used to guide BA in a CAV patient. Once an acceptable physiological assessment criterion was achieved, no further intervention was performed, and the results seemed very promising. Recently, Fearon and colleagues⁴¹ reported on their use of physiological assessment techniques in cardiac transplant patients. They further demonstrated that it was feasible to use such techniques for screening asymptomatic cardiac transplant recipients for angiographically inapparent transplant arteriopathy. However, more studies on the feasibility and safety of using coronary pressure-derived FFR measurement in cardiac transplant patients are still needed. d. Diffuse and long lesions. De Bruyne et al.⁴² suggested that in diffusely atherosclerotic coronary arteries at angiography, coronary pressure measurement is useful in quantifying the severity of the lesion. By withdrawing the pressure-sensing guidewire from distal to proximal during a steady-state of maximal hyperemia under fluoroscopy, they demonstrated a gradual subtle decrement in the pressure gradient that was not seen in normal arteries. Furthermore, they also showed that a marked pressure drop may sometimes occur between the distal and proximal part of an artery, and this observation was believed to reflect the hemodynamic effects of a flow-limiting lesion. Thus, in order to quantify lesion severity in a diffusely affected coronary vessel, maneuvers to obtain a pressure pullback curve during steady-state maximal hyperemia are needed. This curve represents the pressure gradient over the entire length of the artery and provides a clear demonstration of the exact location and severity of the stenosis in the presence of diffuse disease or multiple lesions, and thus is helpful in guiding spot-stenting in arteries with long and diffuse diseases. e. In-stent restenosis (ISR). Despite improved late outcome as compared with balloon angioplasty, ISR is a major limitation of coronary stenting. Although several treatment options for ISR are available,⁴³ long-term benefits are hampered by the recurrence of restenosis. ISR is mainly the result of neointimal hyperplasia within the stented lumen and is generally defined as 50% or more angiographic narrowing within a previously placed stent.⁴⁴ However, if the newly “created” stenosis within the stented lumen is not flow-limiting and is not responsible for ischemia, revascularization may not be necessary, and medical treatment can be used instead. Recently, Lopez-Palop and colleagues⁴⁵ evaluated the applicability of using FFR measurements in deciding the treatment of ISR. Based on 62 patients, they showed that deferral of treatment based on 0.75 FFR assessment criteria on angiographically moderate ISR lesions was safe and avoided unnecessary revascularization treatment indicated by the angiography alone. f. Tandem lesions. In vessels with tandem lesions, the FFR of each individual lesion cannot be simply calculated by the classical equation (Pd/Pa) for a single lesion, since the hemodynamic significance of each lesion is influenced by the presence of the other one. Therefore, a more complex analysis technique is required. De Bruyne and coworkers have developed a method (Figure 2) to determine the true FFR of each lesion separately in the case of tandem lesions, and this has been experimentally validated both in animals46 and humans.⁴⁷ Limitations of FFR Generally speaking, FFR assessment is a helpful technique for interventionists when making decisions regarding revascularization in patients undergoing angiography. A 0.75 cutoff value discriminates between lesions with and without ischemic potential, and assists in deciding whether surgical treatment should be undertaken in patients with complex coronary diseases. However, it has two major drawbacks. First, in managing patients with left ventricular hypertrophy, FFR values greater than or equal to 0.75 should not be used to rule out inducible ischemia,⁶ as their response to pharmacologic hyperemic agents is very poor,⁴⁸ thus the FFR values may be overestimated. Second, FFR measurement only assesses the epicardial coronary stenosis and does not provide any information on the microvascular system. As the increase of epicardial blood flow during maximal hyperemia is limited in patients with microvascular dysfunction, the FFR value might be overestimated. Thus, in managing such patients, it is best to perform simultaneous CFR and FFR assessments. A low FFR and a low CFR indicate significant epicardial disease, whereas a a high FFR and a low CFR indicate significant microvascular abnormality. With technological advances, two new devices are now available. The first is a 0.014 inch guidewire equipped with both pressure and temperature sensors. The pressure sensor measures FFR based on the conventional method, and the temperature sensor allows calculation of CFR by the thermodilution method.⁴⁹ The other device is also a dual-sensor guidewire with a Doppler sensor at the distal end and a pressure sensor located 3 cm proximal to it. The pressure sensor measures FFR and the Doppler sensor allows CFR measurement based on the conventional and well validated flow velocity method.⁵⁰ Conclusions Recent advances in the development of drug-eluting stents (DES) have emerged as a promising technology to reduce the incidence of stenosis. However, due to the high cost of these stents, decision making based on a more cost-effective strategy is needed, especially for patients with multivessel disease. With the aid of the pressure-derived FFR assessment technique, it is possible to determine which lesion is responsible for ischemia and should be treated with PCI, and which should be left alone. The ability to identify those lesions where stenting is necessary, thereby allowing the appropriate use of costly DES, prevents the increased cost of overstenting, and reduces overall medical expenditures. In addition, this strategy is safe and avoids unnecessary revascularization, which may pose an increased risk for the patient without offering benefit. In conclusion, FFR is a simple and reliable index of the functional severity of coronary artery disease. Decision making based on physiological assessment criteria is safe. If a lesion is not hemodynamically significant, patients do not derive benefit from revascularization, and medical treatment can be used instead, which is safer and results in a better outcome. As more clinical data become available, there is no question that the FFR assessment technique will become a clinically important adjunct to coronary angiography in the modern catheterization laboratory.

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