Nico H.J. Pijls

Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses

BACKGROUND The clinical significance of coronary-artery stenoses of moderate severity can be difficult to determine. Myocardial fractional flow reserve (FFR) is a new index of the functional severity of coronary stenoses that is calculated from pressure measurements made during coronary arteriography. We compared this index with the results of noninvasive tests commonly used to detect myocardial ischemia, to determine the usefulness of the index. METHODS In 45 consecutive patients with moderate coronary stenosis and chest pain of uncertain origin, we performed bicycle exercise testing, thallium scintigraphy, stress echocardiography with dobutamine, and quantitative coronary arteriography and compared the results with measurements of FFR. RESULTS In all 21 patients with an FFR of less than 0.75, reversible myocardial ischemia was demonstrated unequivocally on at least one noninvasive test. After coronary angioplasty or bypass surgery was performed, all the positive test results reverted to normal. In contrast, 21 of the 24 patients with an FFR of 0.75 or higher tested negative for reversible myocardial ischemia on all the noninvasive tests. No revascularization procedures were performed in these patients, and none were required during 14 months of follow-up. The sensitivity of FFR in the identification of reversible ischemia was 88 percent, the specificity 100 percent, the positive predictive value 100 percent, the negative predictive value 88 percent, and the accuracy 93 percent. CONCLUSIONS In patients with coronary stenosis of moderate severity, FFR appears to be a useful index of the functional severity of the stenoses and the need for coronary revascularization.

Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study.

OBJECTIVES The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD). BACKGROUND In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up. METHODS At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was <or=0.80. RESULTS The number of indicated lesions was 2.7+/-0.9 in the angiography-guided group and 2.8+/-1.0 in the FFR-guided group (p=0.34). The number of stents used was 2.7+/-1.2 and 1.9+/-1.3, respectively (p<0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p=0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p=0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p=0.08). For lesions deferred on the basis of FFR>0.80, the rate of myocardial infarction was 0.2% and the rate of revascularization was 3.2 % after 2 years. CONCLUSIONS Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774).

Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation.

OBJECTIVES The purpose of this study was to investigate the relationship between angiographic and functional severity of coronary artery stenoses in the FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation) study. BACKGROUND It can be difficult to determine on the coronary angiogram which lesions cause ischemia. Revascularization of coronary stenoses that induce ischemia improves a patients functional status and outcome. For stenoses that do not induce ischemia, however, the benefit of revascularization is less clear. METHODS In the FAME study, routine measurement of the fractional flow reserve (FFR) was compared with angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease. The use of the FFR in addition to angiography significantly reduced the rate of all major adverse cardiac events at 1 year. Of the 1,414 lesions (509 patients) in the FFR-guided arm of the FAME study, 1,329 were successfully assessed by the FFR and are included in this analysis. RESULTS Before FFR measurement, these lesions were categorized into 50% to 70% (47% of all lesions), 71% to 90% (39% of all lesions), and 91% to 99% (15% of all lesions) diameter stenosis by visual assessment. In the category 50% to 70% stenosis, 35% were functionally significant (FFR <or=0.80) and 65% were not (FFR >0.80). In the category 71% to 90% stenosis, 80% were functionally significant and 20% were not. In the category of subtotal stenoses, 96% were functionally significant. Of all 509 patients with angiographically defined multivessel disease, only 235 (46%) had functional multivessel disease (>or=2 coronary arteries with an FFR <or=0.80). CONCLUSIONS Angiography is inaccurate in assessing the functional significance of a coronary stenosis when compared with the FFR, not only in the 50% to 70% category but also in the 70% to 90% angiographic severity category.

Fractional Flow Reserve A Useful Index to Evaluate the Influence of an Epicardial Coronary Stenosis on Myocardial Blood Flow

BACKGROUND Fractional flow reserve (FFR), defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow, is a lesion-specific index of stenosis severity that can be calculated by simultaneous measurement of mean arterial, distal coronary, and central venous pressure (Pa, Pd, and Pv, respectively), during pharmacological vasodilation. The aims of this study were to define ranges of FFR values, whether associated with inducible ischemia or not, and to investigate FFR in normal coronary arteries. METHODS AND RESULTS In 60 patients accepted for percutaneous transluminal coronary angioplasty (PTCA) of single-vessel disease, with a positive exercise test (ET) < 24 hours before PTCA, FFR was determined during adenosine-induced hyperemia just before and 15 minutes after angioplasty. Pa was measured by the guiding catheter, Pd by an 0.018-in fiber-optic pressure-monitoring wire, and Pv, by a multipurpose catheter. The ET was repeated after 5 to 7 days, and only if this second ET had reverted to normal was the pre-PTCA value of FFR definitely considered to be associated with inducible ischemia and the post-PTCA value not. Myocardial FFR (FFRmyo) increased from 0.53 +/- 0.15 before PTCA to 0.88 +/- 0.07 after PTCA. Coronary FFR increased from 0.38 +/- 0.19 to 0.83 +/- 0.12. In all patients, values of FFRmyo definitely associated with ischemia were < or = 0.74, whereas all except two values not associated with inducible ischemia exceeded 0.74. Moreover, FFRmyo in 18 coronary arteries in 5 normal patients equaled 0.98 +/- 0.03. CONCLUSIONS A value of FFRmyo of 0.74 reliably discriminates coronary stenosis, whether associated with inducible ischemia or not. Therefore, FFRmyo is a useful index to determine the functional significance of an epicardial coronary stenosis and may facilitate clinical decision making in patients with an equivocal coronary stenosis.

Clinical ResearchInterventional CardiologyFractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease: 2-Year Follow-Up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) Study

OBJECTIVES The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD). BACKGROUND In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up. METHODS At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was <or=0.80. RESULTS The number of indicated lesions was 2.7+/-0.9 in the angiography-guided group and 2.8+/-1.0 in the FFR-guided group (p=0.34). The number of stents used was 2.7+/-1.2 and 1.9+/-1.3, respectively (p<0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p=0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p=0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p=0.08). For lesions deferred on the basis of FFR>0.80, the rate of myocardial infarction was 0.2% and the rate of revascularization was 3.2 % after 2 years. CONCLUSIONS Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774).

Fractional Flow Reserve–Guided PCI for Stable Coronary Artery Disease

BACKGROUND We hypothesized that in patients with stable coronary artery disease and stenosis, percutaneous coronary intervention (PCI) performed on the basis of the fractional flow reserve (FFR) would be superior to medical therapy. METHODS In 1220 patients with stable coronary artery disease, we assessed the FFR in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years. RESULTS The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%; hazard ratio, 0.39; 95% confidence interval [CI], 0.26 to 0.57; P<0.001). This reduction was driven by a lower rate of urgent revascularization in the PCI group (4.0% vs. 16.3%; hazard ratio, 0.23; 95% CI, 0.14 to 0.38; P<0.001), with no significant between-group differences in the rates of death and myocardial infarction. Urgent revascularizations that were triggered by myocardial infarction or ischemic changes on electrocardiography were less frequent in the PCI group (3.4% vs. 7.0%, P=0.01). In a landmark analysis, the rate of death or myocardial infarction from 8 days to 2 years was lower in the PCI group than in the medical-therapy group (4.6% vs. 8.0%, P=0.04). Among registry patients, the rate of the primary end point was 9.0% at 2 years. CONCLUSIONS In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone. (Funded by St. Jude Medical; FAME 2 ClinicalTrials.gov number, NCT01132495.).

Fractional Flow Reserve to Determine the Appropriateness of Angioplasty in Moderate Coronary Stenosis

Background—PTCA of a coronary stenosis without documented ischemia at noninvasive stress testing is often performed, but its benefit is unproven. Coronary pressure–derived fractional flow reserve (FFR) is an invasive index of stenosis severity that is a reliable substitute for noninvasive stress testing. A value of 0.75 identifies stenoses with hemodynamic significance. Methods and Results—In 325 patients for whom PTCA was planned and who did not have documented ischemia, FFR of the stenosis was measured. If FFR was >0.75, patients were randomly assigned to deferral (deferral group; n=91) or performance (performance group; n=90) of PTCA. If FFR was <0.75, PTCA was performed as planned (reference group; n=144). Clinical follow-up was obtained at 1, 3, 6, 12, and 24 months. Event-free survival was similar between the deferral and performance groups (92% versus 89% at 12 months and 89% versus 83% at 24 months) but was significantly lower in the reference group (80% at 12 months and 78% at 24 months). In addi...

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

BACKGROUND To assess coronary lesion severity in the catheterization laboratory, several guide wire-based methods have been proposed. The purpose of the present study was to compare the feasibility and the reproducibility of coronary flow velocity reserve (CFVR), instantaneous hyperemic diastolic velocity-pressure slope index (IHDVPS), and pressure-derived myocardial fractional flow reserve (FFRmyo). METHODS AND RESULTS From distal coronary pressure and flow velocity signals (0.014-in guide wires), CFVR, IHDVPS, and FFRmyo were computed in 15 stenoses (13 patients) under the four following pairs of conditions: (1) twice under baseline conditions; (2) during atrial pacing at 80 and 110 bpm; (3) before and during intravenous infusion of nitroprusside; and (4) before and during intravenous infusion of dobutamine. A total of 104 measurements were obtained. Both CFVR and FFRmyo could be calculated in all cases. IHDVPS could be calculated in only 79% of cases. The mean value of CFVR did not change between the two baseline measurements and during infusion of nitroprusside but decreased from 1.85 +/- 0.41 to 1.66 +/- 0.45 (P < .05) during atrial pacing and from 1.90 +/- 0.50 to 1.41 +/- 0.28 (P < .05) during dobutamine infusion. The mean values of IHDVPS and FFRmyo remained similar, whichever the changes in hemodynamic conditions. The coefficient of variation between two consecutive measurements was significantly lower for FFRmyo (4.2%) than for CFVR (17.7%) and for IHDVPS (24.7%). CONCLUSIONS CFVR is easy to measure but sensitive to hemodynamic changes. IHDVPS can be measured only in < 80% of cases and is highly variable even without changes in hemodynamic conditions. FFRmyo is easy to measure and almost independent of hemodynamic changes.

Physiological Assessment of Coronary Artery Disease in the Cardiac Catheterization Laboratory A Scientific Statement From the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology

With advances in technology, the physiological assessment of coronary artery disease in patients in the catheterization laboratory has become increasingly important in both clinical and research applications, but this assessment has evolved without standard nomenclature or techniques of data acquisition and measurement. Some questions regarding the interpretation, application, and outcome related to the results also remain unanswered. Accordingly, this consensus statement was designed to provide the background and evidence about physiological measurements and to describe standard methods for data acquisition and interpretation. The most common uses and support data from numerous clinical studies for the physiological assessment of coronary artery disease in the cardiac catheterization laboratory are reviewed. The goal of this statement is to provide a logical approach to the use of coronary physiological measurements in the catheterization lab to assist both clinicians and investigators in improving patient care.

Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography.

BACKGROUND Experimental studies have shown that fractional flow reserve (defined as the ratio of maximal achievable flow in a stenotic area to normal maximal achievable flow) can be calculated from coronary pressure measurements only. The objectives of this study were to validate fractional flow reserve calculation in humans and to compare this information with that derived from quantitative coronary angiography. METHODS AND RESULTS Twenty-two patients with an isolated, discrete proximal or mid left anterior descending coronary artery stenosis and normal left ventricular function were studied. 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 micrograms.kg-1 x min-1 intravenously during 4 minutes) in the contralateral normally perfused area, was assessed by 15O-labeled water and positron emission tomography (PET). Myocardial and coronary fractional flow reserve were calculated from mean aortic, distal coronary, and right atrial pressures recorded during maximal vasodilation. Distal coronary pressures were measured by an ultrathin, pressure-monitoring guide wire with minimal influence on the trans-stenotic pressure gradient. Minimal obstruction area, percent area stenosis, and calculated stenosis flow reserve were assessed by quantitative coronary angiography. There was no difference in heart rate, mean aortic pressure, or rate-pressure product during maximal vasodilation during PET and during catheterization. Percent area stenosis ranged from 40% to 94% (mean, 77 +/- 13%), myocardial fractional flow reserve from 0.36 to 0.98 (mean, 0.61 +/- 0.17), and relative flow reserve from 0.27 to 1.23 (mean, 0.60 +/- 0.26). A close correlation was found between relative flow reserve obtained by PET and both myocardial fractional flow reserve (r = .87) and coronary fractional flow reserve obtained by pressure recordings (r = .86). The correlations between relative flow reserve obtained by PET and stenosis measurements derived from quantitative coronary angiography were markedly weaker (minimal obstruction area, r = .66; percent area stenosis, r = -.70; and stenosis flow reserve, r = .68). CONCLUSIONS Fractional flow reserve derived from pressure measurements correlates more closely to relative flow reserve derived from PET than angiographic parameters. This validates in humans the use of fractional flow reserve as an index of the physiological consequences of a given coronary artery stenosis.