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(Circulation. 2001;103:2928.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

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

A Randomized Trial

G. Jan Willem Bech, MD; Bernard De Bruyne, MD, PhD; Nico H.J. Pijls, MD, PhD; Ebo D. de Muinck, MD, PhD; Jan C.A. Hoorntje, MD, PhD; Javier Escaned, MD, PhD; Pieter R. Stella, MD; Eric Boersma, MSc, PhD; Jozef Bartunek, MD, PhD; Jacques J. Koolen, MD, PhD; William Wijns, MD, PhD

From the Catharina Hospital, Eindhoven, the Netherlands (G.J.W.B., N.H.J.P., E.B., J.J.K.); Cardiovascular Center, Aalst, Belgium (B.D.B, J.B., W.W.); Academic Hospital, Maastricht, the Netherlands (E.D.d.M.); Isala Clinics, Zwolle, the Netherlands (J.C.A.H.); Academic Hospital, Utrecht, the Netherlands (P.R.S.); and Hospital Universitario San Carlos, Madrid, Spain (J.E.).

Correspondence to Nico H.J. Pijls, MD, PhD, Catharina Hospital, Department of Cardiology, PO Box 1350, 5602 ZA Eindhoven, The Netherlands. E-mail Nico.Pijls{at}inter.nl.net

	Abstract

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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 addition, the percentage of patients free from angina was similar between the deferral and performance groups (49% versus 50% at 12 months and 70% versus 51% at 24 months) but was significantly higher in the reference group (67% at 12 and 80% at 24 months).

Conclusions—In patients with a coronary stenosis without evidence of ischemia, coronary pressure–derived FFR identifies those who will benefit from PTCA.

Key Words: coronary disease • angioplasty • pressure • blood flow

	Introduction

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In patients with chest pain and a coronary stenosis at angiography, revascularization is warranted if objective evidence of reversible ischemia is present and medical therapy fails.¹ Yet, PTCA is often recommended solely on the basis of the angiogram, although noninvasive testing for reversible ischemia is either negative, equivocal, or not performed at all.² In such patients, it is unclear whether the chest pain must be attributed to the coronary stenosis and whether PTCA improves event-free survival or functional class.³ Fractional flow reserve (FFR) is an invasive index of the functional severity of a stenosis determined from coronary pressure measurement during cardiac catheterization. FFR expresses maximum achievable blood flow to the myocardium supplied by a stenotic artery as a fraction of normal maximum flow. Its normal value is 1.0, and a value of 0.75 reliably identifies stenoses associated with inducible ischemia. The diagnostic accuracy of FFR for that purpose is >90%, which is higher than for any other invasive or noninvasive test.^{3 4 5 6 7}

Retrospective studies suggest that deferral of angioplasty in patients with FFR >0.75 is safe and results in an excellent clinical outcome.^{6 8} This has never been investigated, however, in a prospective study. Therefore, the present randomized study was undertaken in patients referred for PTCA without documented ischemia to investigate whether FFR discriminates patients in whom PTCA is appropriate from those in whom it is not.

	Methods

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Selection of Patients
Patients were eligible if they were referred for elective PTCA of an angiographically significant de novo stenosis (>50% diameter stenosis by visual assessment) in a native coronary artery with a reference diameter >2.5 mm and if no evidence of reversible ischemia had been documented by noninvasive testing within the previous 2 months. Noninvasive tests were either negative, inconclusive, or simply not performed. Patients with total occlusion of the target artery, Q-wave infarction, or unstable angina were excluded. Patients with small target arteries were excluded because these patients would have a favorable outcome anyway and their inclusion could bias the outcome in favor of deferral of PTCA. There were no other exclusion criteria. The study protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all patients before they entered the study.

Randomization
Figure 1 depicts the flow chart of the study. Just before the planned PTCA procedure, all patients were randomized to deferral or performance of PTCA. After intracoronary administration of 200 µg of nitroglycerin, control angiograms were made, followed by measurement of FFR (see below). If FFR was >0.75, randomization was applied. If FFR was <0.75, randomization was ignored and PTCA was performed as planned. This resulted in 3 groups of patients: (1) patients with FFR >0.75 in whom PTCA was deferred (deferral group); (2) patients with FFR >0.75 in whom PTCA was performed (performance group); and (3) patients with FFR <0.75 in whom PTCA was performed nevertheless (reference group). Randomization was performed before coronary catheterization, and thus before FFR measurement, for 2 reasons: first, to avoid selection bias by exclusion of eligible patients by the operator after FFR had been determined; and second, to account for possible complications related to the performance of the pressure measurement itself.

View larger version (19K): [in this window] [in a new window]   Figure 1. Overview of randomization schedule and formation of 3 groups.

Coronary Pressure Measurement and Calculation of FFR
Coronary pressure measurement was performed with a 0.014-in pressure guidewire (Radi Medical Systems). The wire was introduced through a 6F or 7F guiding catheter, calibrated, advanced into the coronary artery, and positioned distal to the stenosis as described previously.⁶ Adenosine was administered to induce maximum hyperemia, either intravenously (140 µg · kg^-1 · min^-1) or intracoronary (15 µg in the right or 20 µg in the left coronary artery).^{9 10} FFR was calculated as the ratio of mean hyperemic distal coronary pressure measured by the pressure wire to mean aortic pressure measured by the guiding catheter.⁶ The measurement was performed twice, and FFR was taken as the average of both measurements. Next, optimum PTCA was performed in patients in the performance and reference groups according to the local routine of participating centers. The performance of further coronary pressure measurements during the procedure was not allowed.

End Points and Follow-Up
Clinical follow-up was performed at hospital discharge and after 1, 3, 6, 12, and 24 months. The primary end point was absence of adverse cardiac events during 24 months of follow-up. Adverse cardiac events were defined as all-cause mortality, myocardial infarction, CABG, coronary angioplasty, and any procedure-related complication necessitating major intervention or prolonged hospital stay. Myocardial infarction was defined as the development of pathological Q-waves on the ECG or an increase of serum creatinine kinase levels to more than twice the normal value.^{11 12} An independent end-points committee reviewed all events, and analysis was based on the committee’s classification of events. Secondary end points included freedom from angina (Canadian Cardiovascular Society class I) at 1, 3, 6, 12, and 24 months of follow-up and the use of antianginal drugs. Repeat coronary angiography was only performed if clinically indicated. Decisions regarding additional treatment and medication during follow-up were entirely at the discretion of the referring cardiologist.

Statistical Analysis
All comparisons were made on an intention-to-treat basis. Comparisons between continuous data were tested by use of paired and unpaired t test. Categorical data were tested by use of Fisher’s exact test or ² test and McNemar’s test. Patient survival curves for absence of adverse cardiac events were constructed according to the method of Kaplan and Meier and compared by the log-rank test. A P value <0.05 was considered significant; all tests were 2-tailed. Values are presented as mean±SD.

	Results

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Baseline Characteristics and Procedural Results
Of 325 patients, 167 were randomly assigned to deferral and 158 to performance of PTCA (Figure 1). FFR was >0.75 in 181 patients, of whom 91 were randomized to deferral of PTCA and 90 to performance of PTCA. FFR was <0.75 in 144 patients. The latter group constituted the reference group, as discussed in Methods. Baseline characteristics are presented in Table 1. Stenosis severity for the individual patients in the 3 groups is plotted in Figure 2. Baseline angiographic and hemodynamic data are presented in Table 2. FFR was 0.86±0.06 in the deferral group, 0.87±0.07 in the performance group, and 0.57±0.16 in the reference group. The absolute difference between the first and second FFR measurements was 0.03±0.02. Angiographic characteristics after PTCA and the number of stents placed were similar in the performance and reference groups (Table 2).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

View larger version (24K): [in this window] [in a new window]   Figure 2. Individual values of stenosis severity at baseline as assessed by quantitative coronary angiography in 3 groups.

View this table: [in this window] [in a new window]   Table 2. Angiographic Data and FFR Results

In-Hospital Adverse Events
Table 3 shows in-hospital adverse events. None of the patients in the deferral group had an in-hospital event. In the performance group, 5 patients (5.5%) had an in-hospital event (P=0.03 for comparison with deferral group). In the reference group, 12 patients (7.6%) experienced an in-hospital event (no difference versus performance group, P=0.61; P=0.004 for comparison with deferral group).

View this table: [in this window] [in a new window]   Table 3. Outcomes1

Long-Term Follow-Up
Complete follow-up was obtained in 325 patients (100%) after 12 months and in 317 (98%) after 24 months. As presented in Figure 3, event-free survival was 89% in the deferral group and 83% in the performance group (P=0.27; 95% CI of absolute difference -15.7% to 4.6%). Event-free survival in the reference group was 78%, which was not different from the performance group (P=0.31) but was significantly lower than in the deferral group (P=0.03). Adverse events are listed in Table 3. The incidence of death was similar among the 3 groups. The incidence of myocardial infarction or revascularization was similar in the deferral and performance groups (P=0.14) but was significantly higher in the reference group (P<0.001 compared with deferral group and P<0.05 compared with performance group).

View larger version (21K): [in this window] [in a new window]   Figure 3. Kaplan-Meier survival curves for freedom from adverse cardiac events during 24 months of follow-up for 3 groups.

Angina and Medication Usage
The percentage of patients who were free from angina increased significantly in all groups and persisted throughout the study (Figure 4). The increase was similar for the deferral and performance groups after 1 year but was higher for the reference group (P<0.0001). After 2 years, this percentage was higher in the deferral group than in the performance group (P=0.02) but was still highest in the reference group (P<0.001). Use of antianginal and lipid-lowering drugs was similar in the 3 groups, both at baseline and at the end of the study (Table 4).

View larger version (62K): [in this window] [in a new window]   Figure 4. Percentage of patients free from angina in 3 groups at baseline and follow-up.

View this table: [in this window] [in a new window]   Table 4. Use of Antianginal and Lipid-Lowering Medication

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The present study indicates that in patients referred for PTCA of a coronary stenosis without objective proof of ischemia, approximately half of these stenoses are hemodynamically not significant, as indicated by FFR >0.75. Compared with medical treatment, PTCA in these patients did not reduce adverse cardiac events or the use of antianginal drugs, nor did it result in a better functional class (Canadian Cardiovascular Society class). In contrast, in patients with a coronary stenosis and FFR <0.75, which indicates hemodynamic significance, PTCA resulted in a significantly greater improvement in functional class.

The incidence of angiographically visible coronary artery disease increases with age and is 40% in a 60-year-old population.¹³ However, the prognosis in such a population is not primarily determined by the angiographic presence and severity of the stenosis but by the extent and severity of inducible ischemia.¹⁴ Therefore, it is generally accepted that when objective evidence of inducible ischemia is demonstrated and medical therapy fails, coronary revascularization is warranted.¹ In contrast, if noninvasive stress testing is either negative, inconclusive, or simply not performed, it is unclear whether PTCA should be performed. In these patients, who represent a considerable proportion of the general PTCA population, the decision to perform PTCA is often based on the coronary angiogram alone, and its benefit is unproven.^{2 15}

FFR, calculated from coronary pressure measurement, is a reliable index of the functional severity of a coronary stenosis, and a value of 0.75 discriminates stenoses associated with inducible ischemia.^{3 4 5 6} In the present study, FFR was used to divide patients within a group in which physiological significance of the stenosis was most likely (FFR <0.75) and within a group in which that was not the case (FFR >0.75). Although average angiographic severity was slightly greater in stenoses with FFR <0.75, the overlap between both groups was so large that angiography could not be used to predict the absence or presence of inducible ischemia in individual patients (Figure 2).

In the present study, the event rate at 2 years was 11% in the deferral group and 17% in the performance group (NS, P=0.27). In those patients in the deferral group with an event at follow-up, initial FFR values were evenly distributed, which indicated that the cutoff value of 0.75 was appropriate. After 2 years of follow-up, symptomatic improvement was greater in the deferral group than in the performance group (P=0.02). This means that in patients with FFR >0.75, no benefit of PTCA was present, either in terms of adverse events or in functional class. The event rate was highest (23%) in the reference group. Such an event rate is generally reported after single-vessel PTCA and is accepted because it is outweighed by the considerable symptomatic improvement, as was clearly the case in the present study (Figure 4).^{16 17} In addition, the significantly larger improvement in anginal status in the reference group also suggests that chest pain in these patients was indeed due to the target stenosis. This provides post hoc support to the decision to perform PTCA in those patients.

The present study also allowed comparison of patients who undergo PTCA of a hemodynamically significant stenosis (reference group) and of a nonsignificant stenosis (performance group). It showed that event rates were similar but that symptomatic improvement was significantly more pronounced in case of significant stenosis (Figure 4.) It is unclear why Canadian Cardiovascular Society class also improved in patients with FFR >0.75, even without revascularization. Similar observations have been made in other studies, and the reassurance of both the patient and physician that was provided by an additional method of excluding functional significance of the stenosis may have played a role.^{7 16 18 19} Similarly, it is not obvious why the number of patients with angina at 2 years of follow-up was higher in the performance group than in the deferral group. One may wonder whether this was related to the PTCA. In this respect, no difference in the use of antianginal or lipid-lowering drugs was present between the deferral and performance groups either at baseline or during 2 years of follow-up (Table 4).

Some previous studies^{20 21 22} suggested that acute ischemic events occur predominantly at the site of previously insignificant or mild stenoses. This has been extrapolated into a belief that mild stenoses would have a worse prognosis than severe stenoses and that the use of PTCA in such mild lesions would be beneficial.²³ However, our data show that PTCA of such lesions without functional significance did not improve outcome or anginal status and did not reduce the use of antianginal medication. These findings are in accordance with a recent study showing that deferral of PTCA on the basis of intravascular ultrasound analysis of stenosis resulted in a favorable outcome.²⁴ In this context, it should be emphasized that in the present study, the event rate in patients in the deferral group was 11%, which was 3 to 4 times higher than in an age-matched population without heart disease. Therefore, it is evident that the presence of a functionally nonsignificant stenosis poses an increased risk. However, the issue addressed here is that such risk cannot be reduced by performing PTCA. In such patients, modification of risk factors and adequate medical treatment are probably of greater prognostic value than a mechanical coronary intervention.^{8 15}

According to the American Heart Association/American College of Cardiology guidelines,¹ PTCA should preferably be performed after inducible ischemia has been documented. Yet, the present study also indicates that in 50% of patients without previously documented ischemia, FFR identifies a significant stenosis that warrants subsequent PTCA. The present multicenter study confirms that such measurement of coronary pressure and FFR is feasible, safe, and reproducible.

This study has several limitations. First, it does not provide any data as to the adverse cardiac event rate that would have occurred in the reference group (patients with FFR <0.75) when angioplasty would also have been deferred. Second, control angiography was not performed during follow-up except when clinically indicated. This strategy was chosen to prevent the sudden increase in re-PTCA at follow-up when systematic control angiograms are performed.²⁵ Finally, in some patients enrolled in the present study, exercise-induced spasm superimposed on a functionally nonsignificant stenosis or microvascular disease cannot be ruled out.

In conclusion, in patients with a coronary stenosis who are referred for PTCA without objective evidence of ischemia, measurement of coronary pressure just before the planned intervention identifies patients with FFR >0.75 who do not benefit from PTCA and patients with FFR <0.75 in whom PTCA is an appropriate treatment and markedly improves functional class.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Participating Centers
Netherlands
F. Bär, Academic Hospital Maastricht; H. Suryapranata, J. Schoemaker, T. Last, Hospital De Weezenlanden, Zwolle; P. de Jaegere, F. Eefting, University Medical Center, Utrecht; J. Piek, S. Chamuleau, Academisch Medisch Centrum, Amsterdam; P. Serruys, A. Wardeh, University Hospital Rotterdam Dijkzigt; H. Bonnier, K.H. Peels, Catharina Hospital Eindhoven.

Spain
C. Macaya, J. Cortés Lawrenz, University Hospital San Carlos, Madrid.

South Korea
W. Ro Lee, G. Hyeon-cheol, Samsung Medical Center, Seoul.

Belgium
V. Legrand, Center Hospitalier Universitaire Sart-Tilman, Liège; Guy Heyndrickx, F. Staelens, A. Roets, Cardiovascular Center Aalst.

Germany
C. Kühn, Center for Cardiology, Prof Mathey, Schofer und Partner, Hamburg; D. Baumgart, M. Haude, S. Vetter, Universitätsklinikum Essen.

Sweden
P. Albertsson, L. Grip, Sahlgrenska Hospital Göteborg.

Japan
A. Hirayama, K. Kodama, Osaka Police Hospital.

Received December 15, 2000; revision received March 27, 2001; accepted April 3, 2001.

	References

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