Utility of the fractional flow reserve in the evaluation of angiographically moderate in-stent restenosis

Ramon Lopez-Palop*, Eduardo Pinar, Íñigo Lozano, Daniel Saura, Francisco Picó and Mariano Valdés

Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain

Received April 6, 2004; revised June 13, 2004; accepted July 8, 2004 * Corresponding author. Correspondence address: C/Ricardo Gill No. 20, 3 Dcha. 30002, Murcia, Spain. Tel./fax: +34 968369558 (E-mail: mlopezs{at}meditex.es).

See page 1970 for the editorial comment on this article (doi:10.1016/j.ehj.2004.09.005)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
AIMS: The evaluation of in-stent restenosis (ISR) is usually based on angiographic quantification. This evaluation is sometimes difficult and it has not an accurate clinical correlation. Fractional flow reserve (FFR) measured by intracoronary pressure wire has demonstrated its value in determining the functional repercussion of coronary stenosis. The aim of this study was to evaluate the relation between quantitative angiography-FFR in borderline in-stent restenotic lesions and the accuracy of FFR in deciding the treatment of ISR.

METHODS AND RESULTS: Quantitative angiographic values of 65 lesions in 62 patients with angiographically moderate ISR are compared with the FFR value obtained by pressure wire. An FFR value<0.75 was considered significant. Patients with non-revascularized ISR (FFR ⩾0.75) were clinically followed during a year. An FFR value ⩾0.75 was obtained in 41 lesions (63%), 21 of them with stenosis ⩾50%. The co-efficient of correlation between parameters of quantitative angiography and FFR value was <0.5. No events related to the non-treated lesions were observed.

CONCLUSIONS: A poor correlation between angiographic quantification and FFR of moderate ISR was found. Conservative management of moderate 40–70% in-stent restenotic lesions with FFR value ⩾0.75 is safe avoiding unnecessary revascularizations based solely on the angiography.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
The effectiveness of coronary stents in reducing the rate of restenosis1–3 and acute complications during coronary interventions4 has motivated its use in approximately 90% of interventional procedures.4,5 Its main limitation has been in-stent restenosis (ISR).6 Between 8% and 80% of intracoronary stents, in the first 6–8 months after implantation, develop exaggerated vascular neointimal proliferation resulting in restenosis,7 and frequently repeated interventions. Systematic angiographic revision of implanted stents has been given up in most laboratories. However, many patients with previous revascularization undergo catheterization in order to rule out ISR. Many of them present unspecific symptoms, and non-invasive tests are either inconclusive or not performed. A percentage diameter stenosis equal or superior to 50% in an angiography performed during the follow-up has been the criterion used to define ISR in most of the studies that have analysed the long-term results of coronary stents.1–3 In clinical practice, the sole presence of angiographic restenosis frequently motivates new intervention in these patients without clear demonstration of myocardial ischaemia. Myocardial fractional flow reserve (FFR) obtained by means of an intracoronary pressure wire has demonstrated its utility in the evaluation of de novo angiographically intermediate lesions.8 The FFR cut-off value of 0.75 has an excellent correlation with non-invasive ischaemia tests8–10 and the ability to predict clinical events in this setting.8,11,12 The study of functional significance assessed by pressure wire-measured FFR of angiographically intermediate ISR may help to identify patients that could benefit from new revascularization in the long-term, thus avoiding repeated procedures, which are almost always complex, and have a high rate of long-term failure. The aims of our study were (1) to determine the correlation between the quantitative angiography and the functional significance (valued by means of coronary pressure-derived FFR) of the lesions with visually moderate ISR (between 40% and 70% of the reference diameter), and (2) to determine whether FFR is a useful tool for deciding whether either to perform or to avoid new revascularizations in ISR of intermediate angiographic severity.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
Design of the study
Observational study of an historic cohort of patients.

Patients
We included all consecutive patients studied in our catheterization laboratory by coronary pressure-derived FFR, between 01/01/2000 and 07/31/2002, to assess the functional significance of a moderate ISR (visual percentage diameter stenosis between 40% and 70% in-stent, or 5mm adjacent to either of the two edges). Patients in whom angiographic study was scheduled in an investigational protocol were excluded. ISR lesions in vessels with percentage stenosis >40% in a segment proximal or distal to the zone where the ISR was located were also excluded. All patients gave written informed consent to participate in the investigation.

Procedures
The standard protocol of our laboratory for intracoronary pressure wire-derived FFR measurements was performed. After changing diagnostic by a 6F or 7F guiding catheter, 10,000 IU of intravenous heparin were administered. The projection where a greater severity had been more clearly observed in the diagnostic study was repeated after 200–300 μg of intracoronary nitroglycerin administration.

Coronary pressure measurement was performed with two different 0.014-in. pressure wires (Pressure Wire, Radi Medical Systems, Uppsala, Sweden and WaveWire Cardiometrics 0.014, Endosonics Cordova Farm, CA). The pressure wire system was selected according to criteria of the operator. The FFR calculation has been previously described.8,9,13–15 The wire was externally calibrated, and then advanced to the distal tip of the guiding catheter. After verifying that both the catheter and the pressure wire recorded equal pressures in the aortic root, the wire was advanced into the coronary artery and the sensor of the wire placed at least 10 mm beyond the target lesion. After a new 200–300 μg of intracoronary nitroglycerin dose administration, maximal hyperaemia was achieved by means of a ⩾100 μg bolus of intracoronary adenosine. FFR was determined by the ratio Pd/Pa, in the situation of maximal hyperaemia, where Pd represents mean coronary pressure distal to the stenotic segment studied measured by pressure wire, after intracoronary adenosine dose injection, and Pa represents mean aortic pressure simultaneously measured by the guiding catheter.8,9,13–15 Lesions with an FFR value <0.75 were considered as functionally significant and treated by mechanical revascularization. The lesions with an FFR value ⩾0.75 did not receive a new revascularization.

Angiographic analysis
The quantitative coronary analysis of the lesions was performed off-line by two experienced interventionists using an automated edge detection algorithm (CAAS II, Pie Medical Data, Maastricht, the Netherlands). For the calculation of the intra- and inter-observer agreement, the totality of the lesions was measured in three occasions: two by an experienced interventionist with an interval of 3 months between both measurements and one by a second experienced interventionist. Both observers were blinded to the FFR results and previously obtained angiographic measurements. Minimum luminal diameter (MLD), diameter of reference, length of lesion and percentage of diameter stenosis were measured in all cases. The average value of three angiographic measurements obtained for each lesion was considered for FFR correlation study.

Follow-up and definition of events
All patients were clinically followed by means of a personal interview at 1, 6 and 12 months. The primary endpoint was the combination of death by any cause, non-fatal myocardial infarction, and the revascularization of the evaluated lesion. Secondary endpoints were the previous isolated events, a new hospital admission for any cardiac cause, and the presence of symptoms compatible with angina.

Statistical analysis
Qualitative variables are presented as frequency and percentage. Comparisons between qualitative variables were performed using the {chi}2 test. Continuous variables are presented as means±SD. Student's t-test was used to compare continuous variables. Times since stent implant, with an asymmetrical distribution, are presented as median (25–75 percentiles) and comparisons were performed using the non-parametric Mann–Whitney U test. The intra- and inter-observer agreement analyses between quantitative variables were performed using the intraclass correlation co-efficient, and using the κ index for the qualitative ones. A p-value of less than 0.05 was considered significant. For the events during the follow-up, the corresponding curves of Kaplan–Meier were performed. Comparisons between survival curves were performed using Log Rank test. Statistical software package SPSS 11.0 was used.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
Characteristics of the patients and procedures
Sixty-five lesions in 62 patients were studied. In the study period, 295 patients with ⩾40% visual stenosis ISR underwent angiography. Revascularization without FFR study was performed in 19 patients with between 40% and 70% angiographic visual ISR: six of these after intracoronary ultrasound study; three patients included in other investigational studies; four patients with significant lesions in the same vessel of ISR; and six patients according to operator criteria. Baseline characteristics of the 62 included patients are shown in Table 1. Fifty-eight percent of the patients were sent to the catheterization laboratory without a previous non-invasive test for ischaemia detection. In 15 patients (23%), the indication of the new coronariography was atypical chest pain. Ten of these patients had presented a positive non-invasive ischaemia test (four treadmill exercise tests, four exercise echocardiography, one dobutamine echocardiography and one stress SPECT study). Fourteen patients (64%) with a positive non-invasive ischaemia test had an FFR value ⩾0.75. In 21 patients (34%) the pressure wire-studied lesion was treated alone or with other lesions. In 10 patients (16%) percutaneous coronary intervention (PCI) was performed only for lesions different from the pressure wire-studied lesion. Revascularization was not performed in 30 patients (48%). Twenty-four ISR lesions in 22 patients with FFR<0.75 were treated by balloon angioplasty (nine lesions, 37.5%), cutting balloon (seven lesions, 29.2%), brachytherapy (two lesions, 8.3%) bare in-stent stenting (five lesions, 20.8%). A significant functional ISR lesion in a patient with three-vessel disease received surgical revascularization. No complications related to the use of the pressure wire were observed.


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Table 1. Baseline characteristics of patients (N=62)
 
Results of quantitative angiography
Characteristics of the studied lesions are shown in Table 2. Studied lesions had mean values of reference diameter: 2.8±0.51 mm; minimum luminal diameter: 1.3±0.29 mm; length: 16.7±6 mm and percent diameter stenosis: 54±9%. The values of intra- and inter-observer intraclass correlation co-efficient in all measured parameters were inferior to 0.75 (Table 3). Disagreement was marked in the measurement of percent diameter stenosis (intraclass correlation co-efficients 0.48 and 0.50). Discordance in classifying the ISR as angiographically significant was 33% intra-observer (κ coefficient 0.21) and of 39% inter-observer (κ co-efficient 0.18).


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Table 2. Angiographic characteristics of the lesions according to FFR result (N=65)
 

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Table 3. Quantitative analysis of lesions: intra- and inter-observer variability
 
Correlation between quantitative angiography and FFR
Although the lesions with FFR<0.75 showed a significantly smaller MLD, and greater length and percent of diameter stenosis, very poor linear correlation was observed between the values of quantitative angiography and functional repercussion of the lesions evaluated by means of FFR (Fig. 1). Twenty-one (51.2%) of 41 lesions with diameter stenosis equal or superior to 50% presented an FFR value ⩾0.75. The superposition of the percent diameter stenosis values obtained by quantitative angiography in lesions with and without functional meaning was evident (Fig. 2). An FFR value ⩾0.75 was obtained in 41 lesions (63%) in 40 patients, none of these were revascularized.



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Fig. 1 Correlation between quantitative analysis measures (reference diameter, minimal lumen diameter (MLD), lesion length and percent diameter stenosis) and fractional flow reserve (FFR) value. r2: Correlation co-efficient.

 


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Fig. 2 Distribution of lesions according to percentage of diameter stenosis and significance of fractional flow reserve. (Shaded circles: re-revascularized lesions. White circles: medically treated lesions.)

 
Follow-up
The 62 patients included in the study were clinically followed during a one-year period (Fig. 3). No patient was missed during the follow-up period and no death and no acute infarction associated with the deferred lesion occurred. Two patients died early in the deferred group, the first (an 81-year old man) died three days after the procedure due to cardiogenic shock secondary to a complication (no-reflow) in a dominant circumflex artery treated in the same procedure in which the calculation of the FFR in the anterior descending artery was performed. The second patient (a 75-year old man) died 25 days after the functional coronary study due to a acute renal failure after a programmed complex percutaneous bilateral revascularization in both the iliac and femoral arteries. Only one of the 41 deferred lesions (2%) needed to be revascularized during follow-up (progression of a lesion in the proximal anastomoses of a saphenous vein graft to a left anterior descending artery). Three patients (13.6%) in the revascularized group suffered a non-fatal acute myocardial infarction in the follow-up (two non-Q myocardial infarctions and one anterior myocardial infarction).



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Fig. 3 Twelve-months follow-up: Kaplan–Meier curves for primary objectives of follow-up. FFR: fractional flow reserve. Solid line: patients with non-treated lesions (FFR⩾0.75). Broken line: patients with treated lesions (FFR<0.75).

 
Nine patients (22.5%) in the deferral group and nine patients (41%) in the revascularized group had a new admission for angina or chest pain (p=0.01). Four patients in each group (10.0% vs. 18.2% p=0.36) received revascularization in a different coronary artery from the one previously evaluated. Bypass surgery was performed in three patients (13.6%) in the revascularized group. In the deferral group, one year after the procedure, 33 patients (82.5%) were asymptomatic and the resting five patients felt clearly better than before the procedure. Free-events survival was significantly better in the deferral group for treatment of the studied lesion and myocardial infarction during follow-up.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
The results of the present study demonstrate that: (1) quantitative angiography is of no value in discriminating functional significance of visual ISR<70%. In our study, 51% of lesions with a percent diameter stenosis equal or superior to 50% did not show functional repercussion. (2) Deferral of revascularization on an ISR in case of FFR ⩾0.75 is safe, as is the case for native stenosis in coronary arteries. Of the patients in whom mechanical treatment of the in-stent restenosis was deferred, no death or acute myocardial infarction associated with that deferred lesion occurred and only one of the 41 deferred lesions (2%) needed to be revascularized during follow-up.

Angiographic quantification of the ISR
Angiographic stenosis ⩾50% of the reference diameter during the follow-up has been considered as indicative of ISR, and, according to the clinical situation of the patient, an indication for new revascularization. In spite of its utility and generalized use, angiographic quantification presents important limitations in establishing the clinical meaning of stenosis in ISR, particularly if the rank of intermediate severity. Angiographic quantification of ISR adds to the difficulties common with other type of lesions (superposition of branches or challenges determining the diameter of reference), the problems derived from the presence of stent. According to its radiopacity, the stent can be difficult to see and it may even become impossible to determine the correct delineation of the edges of the restenotic lesion. The stents with ISR studied in this work were third generation stents (stainless steel stents) with similar radiopacity characteristics and similar quantitative analysis problems. Although observed average differences between the different measurements were small (Table 3), agreement indices were low and disagreement in the angiographic significance of the ISR was higher than 30%.

Assessment of ISR clinical significance
It is well-known that a high percentage of angiographically intermediate lesions are revascularized without a clear evidence of ischaemia16. Non-invasive ischaemia tests frequently reflect inconclusive or contradictory results in angiographic moderate lesions, or they are even not performed before the coronariography. This last setting is more frequent in patients with ISR. The importance of deciding which lesions are clinically relevant and actually benefit from revascularization is paramount in ISR where the treatment is frequently complex and long-term unsuccessful. In our study, 58% of patients had not been studied previously by means of a non-invasive diagnostic test, and the result had been inconclusive in an additional 6%.

The FFR obtained with the intracoronary pressure wire with its cut-off point set at 0.75 has demonstrated, in de novo lesions, a better correlation with clinical significance than angiography,17 an excellent association with reversible myocardial ischaemia in intermediate lesions, and its utility deciding the treatment of these lesions.8,9 The present study demonstrates a poor correlation between the angiographic parameters usually employed in ISR and the functional repercussion of the lesion (Fig. 1). Although lesions with FFR<0.75 had a significant higher percentage diameter stenosis, in our study, coronary pressure-derived FFR showed a very poor correlation with angiographic parameters. Patients with non-treated lesions according to observed FFR values, instead of percentage stenosis, had minimal events in the one year follow-up. In moderate ISR, higher grade stenosis could be clinically more relevant but angiographic parameters are not good makers of functional significance of this kind of lesions.

Clinical implications
Rate of recurrent restenosis after the first treatment of an ISR can reach up to 80% according to clinical and angiographic characteristics.18,19 The appearance of ISR during the patient's follow-up means the failure of initial intervention in most cases, leading to complex treatments with a high cost or risk for the patient (atherectomy, brachytherapy, surgical revascularization). In our series, 51% of lesions with a percent diameter stenosis ⩾50% showed an FFR⩾0.75 and they were not revascularized. Based on FFR results, it was possible to save the potential cost of revascularization without additional risk to the patient. Two of the 40 patients with non-treated ISR died during the hospitalization. In both cases, the cause of death cannot be related to the non-revascularized lesion. During a one-year follow-up, 37 of the 38 discharged patients (97%) remained free of events. Only one patient needed revascularization of the studied lesion, suggesting that following angiographic criteria, an indeterminate number of these lesions could be improperly revascularized with an unfavourable cost-benefit relation. The use of FFR in patients with moderate ISR can safely avoid new complex and expensive revascularization procedures that an have often unsatisfactory long-term results. The best way to prevent such unfortunate course in a patient is probably not to treat a non-significant in-stent restenosis.

Drug-eluting stents and assessment of ISR
Drug-eluting stents reduce the main limitation of coronary stent, the neointimal proliferation. Although their use is associated with very important reductions in the rate of restenosis,20 in lesions of greater complexity it has not confirmed the disappearance of the ISR showed in the first studies21–23 and myocardial infarction and mortality related to the treated artery is still in the range of about 3.5% within the nine months follow-up.24 In our study, deferred ISR lesions were associated with a much better prognosis emphasizing the importance of not treating non-ischaemic lesions in spite of drug-eluting stent use.

On the other hand, at present, drug-eluting stent restenosis is an unsolved problem. The use of FFR in the evaluation of moderate restenosis of drug-eluting stents could determine the long-term results, either in clinical practice or clinical investigation, more accurately than angiography and may help to decide the necessity of new revascularization.


    Limitations
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
This is an observational study and includes a limited number of patients. The decision to perform recatheterization and functional evaluation was not based on a previously designed protocol. An important number of patients were recatheterized without non-invasive functional evaluation. However, we think that this study reproduces the habitual selection of patients and daily clinical practice in the majority of catheterization laboratories.

In the first months after implantation, the ISR is a dynamic process. The observation of an FFR ⩾0.75 in a moderate ISR in the first 2–3 months after stenting does not exclude progression of intimal proliferation in the following months, increasing lesion stenosis and its functional significance. In our series, 30% of stents with FFR ⩾0.75 had been implanted in the six previous months to the evaluation, and only 12% (five stents) in the 3 first months. None of these patients presented events during the follow-up. In our study the number of stents with less than 3 months from implant is reduced, being expected that in longer series a percentage of these lesions will need revascularization in continuing the follow-up and the degree of intimal proliferation.


    Conclusions
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
The angiographic quantification of moderate ISR has a poor correlation with its functional repercussion assessed by intracoronary pressure wire-derived FFR. The decision of revascularization in this type of lesion would have to be based on different parameters from currently used criteria, particularly the percent diameter stenosis >50%. Coronary pressure-derived FFR should therefore be considered as the optimum tool in the catheterization laboratory to decide upon the necessity of reintervention on the one hand or deferral of intervention on the other in ISR of moderate severity. Decision making in this way is safe, indicates where reintervention is necessary, and avoids unnecessary interventions which only increase risk for the patient without benefit.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 

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