Fig. 22.1
Schematic model representing the coronary circulation. AO aorta, Pa arterial pressure, Pd distal coronary pressure, Pv venous pressure, Q blood flow through the myocardial vascular bed, Qc collateral blood flow, Qs blood flow through the supplying epicardial coronary artery, R resistance of the myocardial vascular bed, Rc resistance of the collateral circulation, Rs resistance of the stenosis in the supplying epicardial coronary artery, RA right atrium. Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation. 1993; 86:1354–67
The first validation study in human was performed by De Bruyne in 1994 [2]. In 22 patients, myocardial and coronary fractional flow reserve was calculated from mean aortic, distal coronary, and right atrial pressures which was recorded during maximal vasodilation. Additionally, relative myocardial flow reserve, defined as the ratio of absolute myocardial perfusion during maximal vasodilation in the stenotic area to the absolute myocardial perfusion during maximal vasodilation (adenosine 140 μg/kg/min intravenously during 4 min) in the contralateral normally perfused area, was assessed by 15O–labeled water and positron emission tomography (PET). Fractional flow reserve derived from pressure measurements correlated closely to the relative flow reserve derived from PET (Fig. 22.2). Furthermore, they also showed that the correlation between relative flow reserve obtained by PET and percentile stenosis measured from quantitative coronary angiography were markedly weaker.
Fig. 22.2
(a) Plot shows relation between the relative myocardial flow reserve of the anterior region as determined by positron emission tomography (PET) and the coronary fractional flow reserve of the stenosis in the proximal left anterior descending coronary artery. (b) Plot of the difference between the relative flow reserve and the coronary fractional flow reserve [RFR-FFR(cor)l values. Solid line represents mean difference; dashed lines represent 2 SD from this mean. De Bruyne B, Baudhuin T, Melin JA, Pijls NH, Sys SU, Bol A, et al. Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography. Circulation. 1994; 89:1013–22
22.3 Cutoff Value of 0.75 or 0.80
One of the specific features that make FFR particularly useful is that it has a normal value of 1 for every patient and every artery. Furthermore, any decrease in FFR has a direct clinical implication: For example, FFR of 0.60 means maximum blood flow to the myocardial distribution of the respective artery only reaches 60% of what it would be if that artery were completely normal [3]. However, for clinical decision-making such as whether to perform revascularization or not, we need a specific cutoff value of this continuous variable. The ischemic threshold of 0.75 was first proposed by Pijls et al. in 1995 [4]. In the report, they confirmed that normal FFR equals to 1.0 in five patients with normal coronary arteries. By utilizing FFR data of patients with stable angina, single-vessel disease, normal left ventricular function, and a positive exercise test before PTCA which normalized after angiographically successful PTCA, they showed that with the cutoff point of 0.74, there was only a minimal overlap between normal and pathological values (Fig. 22.3).
Fig. 22.3
Scatterplot showing values of FFRmyo before and after PTCA. Those values associated with proven ischemia are indicated by solid circles, and those values definitely not associated with ischemia are indicated by open circles.
Subsequent clinical studies validated the diagnostic accuracy of FFR compared with other methods to evaluate myocardial ischemia. The specificity was reported as 82 ~ 100% and sensitivity as 68 ~ 88% with cutoff value of 0.66–0.78 (Table 22.1). In the FAME study, the investigators decided to choose 0.80 as a cutoff value based on the fact that many interventional cardiologists elect to perform PCI when the FFR value is between 0.75 and 0.80 if the clinical scenario is suggestive of myocardial ischemia [10]. Recently, many clinicians use FFR ≤ 0.80 as a cutoff value to guide revascularization, and current guidelines also recommend its clinical use based on FFR ≤ 0.80 [11, 12]. Because there is a gray zone in FFR value, which is between 0.76 and 0.80, sometimes clinicians feel confused. Repeating the measurement may not be helpful because there was a report that in this gray zone, even agreement among each measurement falls, reaching nadir of approximately 50% around FFR value of 0.80 [13] (Fig. 22.4). Therefore, many experts recommend that decision-making should be based on sound clinical judgment, typicality of symptoms, presence of other test results, and technical issues related to the measurement of FFR [3].
Table 22.1
Summary of cutoff fractional flow reserve values which suggest myocardial ischemia
Authors | Year | Patients | Number | Comparator | Value | Specificity | Sensitivity | Reference |
|---|---|---|---|---|---|---|---|---|
De Bruyne | 1995 | Single vessel | 60 | Bicycle ET | 0.66 | 87% | 87% | De Bruyne et al. [5] |
Pijls | 1996 | Single vessel | 45 | ET + SPECT + DSE | 0.75 | 100% | 88% | Pijls et al. [6] |
Abe | 2000 | Single vessel | 46 | SPECT | 0.75 | 100% | 83% | Abe et al. [7] |
Chamuleau | 2001 | Multivessel | 152 | SPECT | 0.74 | 82% | 68% | Chamuleau et al. [8] |
De Bruyne | 2001 | Infarct > 5 days | 50 | SPECT | 0.78 | 88% | 88% | De Bruyne et al. [9] |
Fig. 22.4
Biological variability of FFR. Test-retest reproducibility of two repeated measurements of fractional flow reserve (FFR) taken 10 min apart is shown as a scatterplot (a, gray dashed envelope demarcates 99% of the data points from 0.5 to 1 and dotted lines show the 0.8 cutoffs). The classification certainty of a single FFR measurement is presented for FFR values from 0.70 to 0.90 (b, right vertical axis). Outside the 0.75 to 0.85 range, measurement certainty is higher than 95%. However, closer to its cut point, this certainty falls, reaching a nadir of approximately 50% around 0.8. In clinical practice, that means each time a single FFR value falls between 0.75 and 0.85, there is a chance that the dichotomous classification of a stenosis (and therefore the FFR-guided revascularization decision) will change if the test is repeated 10 min later. Within 0.77 to 0.83, this measurement certainty falls to <80%. The FFR diagnostic gray zone (0.75 to 0.85) is also displayed in (b) for comparison. FFR reproducibility data are from the landmark study DEFER, and data were obtained and digitized, from Kern et al. Classification certainty (b, right vertical axis) was calculated using the standard formula: 
with x representing each FFR value. Constant e is the base of the natural logarithm and equals 2.718. 0.8 is the currently established cutoff for FFR, and 0.032 is the standard deviation of the difference (SDD) between repeated FFR measurements, obtained from the digitized DEFER (Deferral Versus Performance of PTCA in Patients Without Documented Ischemia) reproducibility data. As this analysis was performed using the SDD of the overall population, it could be applied to any FFR cutoff. The chosen FFR cutoff of 0.8 follows current recommendations from clinical guidelines and is in line with the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) and FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2) trials. Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, Davies JE. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv. 2013; 6:222–5
with x representing each FFR value. Constant e is the base of the natural logarithm and equals 2.718. 0.8 is the currently established cutoff for FFR, and 0.032 is the standard deviation of the difference (SDD) between repeated FFR measurements, obtained from the digitized DEFER (Deferral Versus Performance of PTCA in Patients Without Documented Ischemia) reproducibility data. As this analysis was performed using the SDD of the overall population, it could be applied to any FFR cutoff. The chosen FFR cutoff of 0.8 follows current recommendations from clinical guidelines and is in line with the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) and FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2) trials. Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, Davies JE. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv. 2013; 6:222–522.4 Validation Study of Outcomes
Over the last two decades, the favorable outcomes of FFR-guided PCI have been reported in many subsets of patients including intermediate stenosis, complex multivessel disease, stable coronary artery disease, left main disease, and bifurcation lesion.
22.4.1 DEFER Study
Initially, the FFR was used to decide upon the need for revascularization in patients with intermediate coronary artery stenosis. In the DEFER study , 325 patients for whom PCI was planned (>50% diameter stenosis by visual assessment) and who did not have documented ischemia, FFR of the stenotic lesion was measured. If FFR was >0.75, patients were randomly assigned to deferral (deferral group; n = 91) or performance (performance group; n = 90) of PCI. If FFR was <0.75, PCI was performed as planned (reference group; n = 144). Five-year outcome after deferral of PCI of an intermediate coronary stenosis was excellent. The incidence rate of death and acute myocardial infarction in the deferral group was only 3.3%. For angina-free symptom, there was no difference between deferral and performance group [14] (Fig. 22.5).
Fig. 22.5
Survival and adverse events. (Top) Kaplan-Meier survival curves for freedom from adverse cardiac events during 5-year follow-up for the three groups. (Middle) Cardiac death and acute myocardial infarction rate in the three groups after a follow-up of 5 years. (Bottom) Percentage of patients free from chest pain in the three groups at baseline and during follow-up. *p = 0.028; **p = <0.001; ***p = 0.021. MI myocardial infarction, DEFER deferral of percutaneous coronary intervention, FFR fractional flow reserve, PCI percutaneous coronary intervention, PERFORM performance of percutaneous coronary intervention, REFERENCE percutaneous coronary intervention anyway because of ischemic fractional flow reserve. Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, Bär F, Hoorntje J, Koolen J, Wijns W, de Bruyne B. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007; 49:2105–11
22.4.2 FAME 1 Study
In recent years, angiography of the majority of patients shows multivessel disease, confusing which lesion is responsible for symptom. In these patients, FFR can discriminate functionally significant lesion from nonsignificant lesion to be indicated for revascularization. In the FAME study, 1005 patients with multivessel coronary artery disease were randomly assigned to angiography-guided PCI group or FFR-guided PCI group. For FFR-guided PCI group, stenting was undergone if FFR was ≤0.80, whereas in angiography-guided PCI group, the investigator underwent stenting as planned before the randomization. At 1-year follow-up, FFR-guided group had a lower rate of primary outcome end points which was a composite of death, nonfatal MI, and repeat revascularization (13.2% vs. 18.4%, P = 0.02) as compared with angiography-guided group even with fewer stents per patients (1.9 ± 1.3 vs. 2.7 ± 1.2, P < 0.001) [15]. After measurement of FFR, strategy of revascularization has been changed in ~35% of all stenotic lesions in the FAME study [16]. Similarly, there is a report that 32% of the coronary artery lesions and 48% of patients would have received a different treatment if the decision had been based on angiography only [17]. In multivessel disease, using FFR is cost-saving, saves contrast, and does not prolong the interventional procedure [18].
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