Hemodynamic Assessment of Stable, Intermediate Lesions in the Catheterization Laboratory Using FFR or iFR
Since its introduction, coronary angiography has been uniformly accepted as the gold standard for assessing the presence and extent of coronary artery disease. Coronary anatomy described by angiography is the main and often only piece of evidence leading to revascularization decisions.
In particular, 50% diameter stenosis has been identified as the threshold value to justify revascularization, to serve as an endpoint in studies on revascularization strategies, and to validate noninvasive techniques.1 Early animal experiments showed that hyperemic myocardial flow reserve started to decline below 4.0 when diameter stenosis was ≥50% or below 3.0 when diameter stenosis was ≥70%.2 In humans with proven atherosclerosis, this relationship between diameter stenosis and myocardial blood flow is substantially diminished by a very large scatter3 or even absent,4 with scarce relation to ischemia, left ventricular function, or clinical outcomes.
Recent studies have further shown that the relationship between diameter stenosis and functional relevance, as investigated by fractional flow reserve (FFR), is modest at best, with significant discordance in at least one third of the cases that may lead to inappropriate decisions regarding revascularization strategy.5,6 The latter emphasizes the need for proper functional evaluation as justification of performing or deferring revascularization, regardless of angiographic severity.1
FFR is the most studied index to determine the hemodynamic significance of a given epicardial coronary stenosis. It can be defined as the ratio of maximal achievable blood flow in a myocardial bed in the presence of an epicardial stenosis to the theoretical normal maximal flow in the same myocardial distribution.7 Thus, FFR represents what percentage of normal maximal flow is still achievable despite the resistance offered by a coronary stenosis. For instance, an FFR of 0.7 means that in a given coronary artery with a stenosis, it is possible to reach only 70% of the maximal blood flow had the artery been free of atherosclerotic lesions. Similarly, FFR value estimates to what extent revascularization can increase hyperemic myocardial flow if physiologic conditions are fully restored and a post- percutaneous coronary intervention (PCI) FFR value of 1.0 is reached. In other words, with an FFR of 0.7, a relative 43% or absolute 30% increase in blood flow can be expected after revascularization.
According to Darcy's law, flow equals driving pressure divided by resistance. Under maximal hyperemia, resistance is constant and minimal, and so a linear relationship between flow and pressure is established. FFR exploits this physiological phenomenon and the irrelevance of coronary venous pressure to allow calculating a ratio of two flows by simply calculating the ratio between the pressure distal to the coronary stenosis and the aortic pressure (Pd/Pa) (Figure 1).8
FFR has many useful features. First, a unique and validated cut-off value set at 0.8. Coronary stenoses with FFR > 0.8 are not associated with ischemia at noninvasive stress tests, and FFR values ≤ 0.8 are almost exclusively found in ischemic myocardial territories.7 Second, the hyperemic response of the microcirculation is very reliable once maximal hyperemia is induced, making FFR measurement highly reproducible. Third, FFR is completely independent of all the changes in hemodynamic condition that can occur during the measurement, such as changes in blood pressure, heart rate, and contractility.9 Fourth, FFR has an unsurpassed spatial resolution, being able to detect the functional significance of a stenosis at almost millimeter level.
Equipment needed for FFR measurement consists of regular PCI material (i.e., guiding catheter and Y-connector). Anticoagulation should be performed as per any routine intracoronary procedure. FFR is mainly measured by a sensor-tipped 0.014-inch pressure guidewire, where the sensor is located 30 mm back from its tip, at the junction of the radiopaque and non-radiopaque part of the wire. The wire-based system is offered by various manufacturers. Another system for FFR measurement is a dedicated maximally 0.036-inch rapid-exchange sensored microcatheter, used over any regular guidewires.
In practice, FFR measurement starts with calibration of the sensor outside of the patient to zero pressure. Second, once the sensor has left the guiding catheter, the two pressuresnamely the one measured by the pressure-sensored device (later indicated as Pd) and the one measured through the guiding catheter (later indicated as Pa)must be equalized. Then it is possible to advance the sensor optimally to the most distal point of the index coronary artery but at least distally to the investigated coronary lesion. At this point, it is important to induce a steady-state maximal hyperemic state. To do so, it is necessary to get rid of any possible epicardial coronary spasm by administering an intracoronary bolus of nitrates (200 mcg intracoronary bolus). Subsequently, microcirculatory vasodilation is induced by either an intracoronary bolus (100 mcg in the right coronary artery or 200 mcg in the left coronary artery) or an intravenous infusion (140 mcg/kg/min) of adenosine.10 Intracoronary injection should be performed briskly so as not to miss the short-lasting hyperemic effect, reaching its maximum around 10-25 seconds after injection. Intracoronary administration is quicker and allows multiple FFR measurements without significantly prolonging procedure time. On the other hand, intravenous infusion is more time-demanding because the peak hyperemic response usually occurs after 1 minute, although it allows pullback pressure measurements that are particularly useful in case of diffuse disease or multiple lesions in a single coronary artery. The lowest Pd/Pa value registered during the hyperemic state is automatically identified by the system as the value of FFR.
It has been validated versus a true gold standard using a sequential Bayesian approach against three noninvasive tests to detect myocardial ischemia: dobutamine stress echocardiography (contractile index of ischemia), exercise testing (electrical index of ischemia), and thallium scintigraphy (perfusion index of ischemia). The sensitivity of FFR < 0.75 in identifying reversible ischemia was 88%, and specificity was 100% with a stunning accuracy of 93%.7
The clinical use of FFR has also been investigated in many studies, the most iconic among which are undoubtedly the DEFER (Deferral Vs. Performance of Percutaneous Coronary Intervention of Functionally Non-Significant Coronary Stenosis) study, the FAME (Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention) trial, and the FAME 2 (Fractional Flow ReserveGuided PCI versus Medical Therapy in Stable Coronary Disease) trial.11-13
The DEFER study was the first randomized trial to investigate the appropriateness of leaving untreated coronary lesions with a non-significant FFR value. Recently, a 15-year follow-up has been published showing the safety of leaving functionally non-significant stenosis non-revascularized regardless of their angiographic appearance. Despite the similar number of deaths, a higher number of myocardial infarctions was reported when stenting such lesions.11
The FAME trial investigated patients with multivessel disease and demonstrated the superiority of an FFR-guided strategy over an angiography-guided strategy in terms of clinical outcome. In addition, it confirmed the very low rate of events in functionally non-significant lesions when left non-revascularized.12
Subsequently, the FAME 2 trial compared the clinical outcome of patients with at least one functionally significant stenosis treated either with PCI on top of medical therapy or with medical therapy alone. Patients in the PCI group had a clinical benefit driven mainly by urgent revascularization. However, in a landmark analysis, from the eighth day to 2 years after enrollment, a better outcome in terms of death and myocardial infarction was also observed, favoring PCI compared with medical therapy alone.13
Resting and Non-Maximal Hyperemic Indices
During the last few years, there has been an effort in researching functional indices of ischemia that do not necessitate maximal hyperemia and, thus, adenosine administration. The reasons for such struggle are various and include
- economic considerations,
- potential contraindications to the use of adenosine in some patients,
- the uneasiness caused in some operators by transient atrio-ventricular blocks, and
- avoidance of chest discomfort associated with the administration of the drug.
The most frequently used non-hyperemic index is undoubtedly instantaneous wave-free ratio (iFR). This index is based on the identification, through wave intensity analysis, of a wave-free diastolic period, during which resistance is considered to be naturally minimized. The value of iFR is automatically calculated by a vendor-specific software as the ratio of the mean pressure distal to the stenosis to the mean aortic pressure during the aforementioned time interval.14 Various studies assessed the accuracy of iFR in predicting FFR and reported values ranging 60-90%, with an average accuracy of 80% and a cut-off value around 0.9. Some studies, such as the ADVISE II (Adenosine Vasodilator Independent Stenosis Evaluation II) trial, advocate the use of iFR in a hybrid approach with FFR. A treatment iFR value ≤0.85, a deferral iFR value ≥0.94, and the use of FFR within the 0.86 and 0.93 iFR values ("adenosine zone") resulted in an overall 94.2% classification agreement with a lone-FFR strategy but obviated the need for vasodilators in 65% of patients.15-18
Recently, the results of two large, randomized clinical trials, iFR-SWEDEHEART (Instantaneous Wave-Free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndromes)19 and DEFINE-FLAIR (Functional Lesion Assessment of Indeterminant Stenosis to Guide Revascularization),20 have confirmed the clinical value of iFR. Both trials randomized patients with angiographically intermediate stenoses either to FFR- or iFR-guided strategy and showed non-inferiority of the latter regarding clinical outcome at 1-year follow-up.
Resting Pd/Pa ratio deserves an important mention within non-hyperemic indices. This index is particularly interesting because it can be calculated with any pressure-monitoring device. A recently published post-hoc analysis of the CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?) trial showed equivalent diagnostic performance of Pd/Pa and iFR both in stable and unstable patients, suggesting that it could be applied clinically in a similar fashion.21 Still, clinical outcome data supporting the use of resting Pd/Pa are lacking.
Being a potent but still not maximal hyperemic agent,22 contrast media by itself also allows an adenosine-free alternative to FFR, called contrast FFR. An international multicenter study by Johnson et al. reported an accuracy of 85% in predicting FFR.23 Contrast FFR could therefore be an affordable and easy-to-perform alternative to FFR, which, being adenosine-free, could partially overcome the limits of resting indices while maintaining cost-effectiveness and absence of adenosine-related side-effects.
Based on fundamental clinical data,24 it is clearly declared in the recent revascularization guidelines that coronary revascularization can provide clinical benefit only when it targets relevant myocardial ischemia. Because coronary angiography suffers marked limitations in terms of detecting coronary stenoses' functional significance, additional assessment is needed if noninvasive proof of ischemia is not available. Thanks to extensive validation work in most clinical settings, FFR is considered the gold standard of invasive macrovascular ischemia assessment. Recent clinical data suggest that non-hyperemic indices might offer reliable alternatives as well.
- Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003.
- Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol 1974;34:48-55.
- Uren NG, Melin JA, De Bruyne B, Wijns W, Baudhuin T, Camici PG. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med 1994;330:1782-8.
- White CW, Wright CB, Doty DB, et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984;310:819-24.
- Tonino PA, Fearon WF, De Bruyne B, 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;55:2816-21.
- Toth G, Hamilos M, Pyxaras S, et al. Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses. Eur Heart J 2014;35:2831-8.
- Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703-8.
- Toth GG, De Bruyne B, Rusinaru D, et al. Impact of Right Atrial Pressure on Fractional Flow Reserve Measurements: Comparison of Fractional Flow Reserve and Myocardial Fractional Flow Reserve in 1,600 Coronary Stenoses. JACC Cardiovasc Interv 2016;9:453-9.
- De Bruyne B, Bartunek J, Sys SU, Pijls NH, Heyndrickx GR, Wijns W. Simultaneous coronary pressure and flow velocity measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation 1996;94:1842-9.
- Adjedj J, Toth GG, Johnson NP, et al. Intracoronary Adenosine: Dose-Response Relationship With Hyperemia. JACC Cardiovasc Interv 2015;8:1422-30.
- Zimmermann FM, Ferrara A, Johnson NP, 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;36:3182-8.
- van Nunen LX, Zimmermann FM, Tonino PA, 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;386:1853-60.
- De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371:1208-17.
- Sen S, Escaned J, Malik IS, et al. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol 2012;59:1392-402.
- Berry C, van 't Veer M, Witt N, et al. VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): a multicenter study in consecutive patients. J Am Coll Cardiol 2013;61:1421-7.
- Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry. EuroIntervention 2013;9:91-101.
- Jeremias A, Maehara A, Généreux P, 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;63:1253-61.
- Escaned J, Echavarría-Pinto M, Garcia-Garcia HM, et al. Prospective Assessment of the Diagnostic Accuracy of Instantaneous Wave-Free Ratio to Assess Coronary Stenosis Relevance: Results of ADVISE II International, Multicenter Study (ADenosine Vasodilator Independent Stenosis Evaluation II). JACC Cardiovasc Interv 2015;8:824-33.
- Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI. N Engl J Med 2017;376:1813-23.
- Davies JE, Sen S, Dehbi HM, et al. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med 2017;376:1824-34.
- Kobayashi Y, Johnson NP, Zimmermann FM, et al. Agreement of the Resting Distal to Aortic Coronary Pressure With the Instantaneous Wave-Free Ratio. J Am Coll Cardiol 2017;70:2105-13.
- Guzman SV, West JW. Cardiac effects of intracoronary arterial injections of various roentgenographic contrast media. Am Heart J 1959;58:597-607.
- Johnson NP, Jeremias A, Zimmermann FM, et al. Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment. JACC Cardiovasc Interv 2016;9:757-67.
- Hachamovitch R, Kang X, Amanullah AM, et al. Prognostic implications of myocardial perfusion single-photon emission computed tomography in the elderly. Circulation 2009;120:2197-206.
Clinical Topics: Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Echocardiography/Ultrasound, Nuclear Imaging, Chronic Angina
Keywords: Angina, Stable, Coronary Angiography, Hyperemia, Arterial Pressure, Ventricular Function, Left, Constriction, Pathologic, Coronary Artery Disease, Coronary Stenosis, Percutaneous Coronary Intervention, Venous Pressure, Atherosclerosis, Microcirculation, Echocardiography, Stress, Exercise Test, Blood Pressure, Bayes Theorem, Myocardial Ischemia, Percutaneous Coronary Intervention
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