Utility of fractional flow reserve in moderate in-stent re-stenosis and jailed side branches and comparison of fractional flow reserve with single-photon emission computed tomography-myocardial perfusion imaging in native coronary artery stenosis

Ajitkumar Jadhav; Deepak Sadashiv Phalgune; Suhas Hardas

doi:10.4103/heartindia.heartindia_33_19

ORIGINAL ARTICLE

Year : 2020 | Volume : 8 | Issue : 1 | Page : 21-25

Utility of fractional flow reserve in moderate in-stent re-stenosis and jailed side branches and comparison of fractional flow reserve with single-photon emission computed tomography-myocardial perfusion imaging in native coronary artery stenosis

Ajitkumar Jadhav¹, Deepak Sadashiv Phalgune², Suhas Hardas³
¹ Department of Cardiology, DY Patil Medical College and Hospital, Pune, Maharashtra, India
² Poona Hospital and Research Centre, Pune, Maharashtra, India
³ Department of Cardiology, Poona Hospital and Research Centre, Pune, Maharashtra, India

Date of Submission	25-Jul-2019
Date of Decision	17-Jan-2020
Date of Acceptance	04-Feb-2020
Date of Web Publication	03-Apr-2020

Correspondence Address:
Dr. Deepak Sadashiv Phalgune
18/27, Bharat Kunj-1, Erandawane, Pune - 411 038, Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/heartindia.heartindia_33_19

Abstract

Background: Functional flow reserve (FFR) is used to determine functional significance of coronary artery stenosis. FFR demonstrated discrepancy between angiographic and functional significance of jailed side branches (JSBs) as well as moderate in-stent restenosis (ISR), with only minority of such lesions having functional significance. An attempt was made to study the utility of FFR and comparison of FFR with single-photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) in native coronary artery stenoses.
Methods: A total of 101 lesions in 79 patients with stable ischemic coronary artery disease were subjected to FFR and SPECT-MPI including native as well as ISR and JSB. Relation between FFR and perfusion imaging was analyzed quantitatively. Sensitivity, specificity, positive predictive value, and negative predictive value were used for diagnostic accuracy.
Results: FFR was ≤≤ 0.75 in majority of the lesions having >70% stenosis. Most of the lesions having reversible perfusion defect had FFR ≤≤ 0.80. There was a significant negative correlation between summed difference score (SPECT-MPI) with FFR value. As FFR value decreased, summed difference score increased. Sensitivity and specificity did not differ much when FFR cutoff was taken as 0.75 or 0.80.
Conclusion: There was a significant negative correlation between FFR and sum difference score (SPECT-MPI). Sensitivity and specificity of SPECT-MPI did not differ much when FFR value cutoff was taken as 0.75 or 0.80.

Keywords: Coronary angiography, functional flow reserve, in-stent re-stenosis, jailed side branches, single-photon emission computed tomography-myocardial perfusion imaging

How to cite this article:
Jadhav A, Phalgune DS, Hardas S. Utility of fractional flow reserve in moderate in-stent re-stenosis and jailed side branches and comparison of fractional flow reserve with single-photon emission computed tomography-myocardial perfusion imaging in native coronary artery stenosis. Heart India 2020;8:21-5

How to cite this URL:
Jadhav A, Phalgune DS, Hardas S. Utility of fractional flow reserve in moderate in-stent re-stenosis and jailed side branches and comparison of fractional flow reserve with single-photon emission computed tomography-myocardial perfusion imaging in native coronary artery stenosis. Heart India [serial online] 2020 [cited 2023 Jun 2];8:21-5. Available from: https://www.heartindia.net/text.asp?2020/8/1/21/281877

Introduction

Noninvasive diagnostic assessment of patients with coronary artery disease (CAD) being considered for myocardial revascularization comprises the assessment of ischemia and the evaluation of viability in patients with regional wall motion abnormalities or reduced ejection fraction. Functional testing to assess ischemia is critical for the assessment of stable patients with CAD. Documentation of ischemia using functional testing before elective invasive procedures for CAD is the preferred approach.^[1] In stable CAD, functional flow reserve (FFR) is applicable in virtually all pathologic conditions, such as single- and multi-vessel disease, left main disease, in-stent re-stenosis (ISR), previous myocardial infarction, and even bypass grafts with superior segmental and spatial resolution compared to any noninvasive stress tests such as single-photon emission computed tomography (SPECT)-myocardial perfusion imaging (MPI). As the decision to perform an FFR measurement is usually made when the available clinical and angiographic data leave the operator uncertain as to whether or not to revascularize a coronary lesion, many interventional cardiologists elect to perform percutaneous coronary intervention when the FFR is between 0.75 and 0.80 in order to avoid leaving ischemic lesions untreated at the cost of potentially overtreating.^[2]

The ischemic threshold of FFR has been replicated independently with different noninvasive functional tests in numerous studies including exercise electrocardiography, dobutamine stress echocardiography, and SPECT-MPI.^[2] FFR maintains its diagnostic accuracy in the assessment of patients with multi-vessel CAD. Considering the important limitations of myocardial perfusion techniques in patients with multi-vessel CAD, this group of functional tests are commonly used in conjunction with FFR to guide revascularization in patients with stable 2–3 vessel disease.^[3]

The study of functional significance assessed by pressure wire-measured FFR of angiographically intermediate ISR may help 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.^[4]

FFR has been shown to be safe and feasible in assessing jailed side branches (JSBs) and also demonstrated the discrepancy between the angiographic and functional significance of JSB. These findings have profound implications in guiding strategies of bifurcation coronary artery stenosis management. However, these studies examined a limited number of lesions and did not use a dedicated bifurcation quantitative coronary angiography (QCA) analysis. Hence, an attempt was made to study the utility of FFR in moderate ISR and JSB, and also to make comparison of FFR with SPECT-MPI in native coronary artery stenoses.

Methods

All patients of either sex attending the Outpatient Department of Cardiology or admitted in Poona Hospital and Research Centre, Pune, Maharashtra, between February 2014 and May 2015 with stable CAD and ready to participate were included in the study. Permission was obtained from the ethics committee and scientific advisory committee of the institution. Informed written consent of all the patients was obtained after explaining the details of the study and the risk involved. The study included patients with an angiographically moderate coronary stenosis (>50% diameter stenosis by QCA) in a native coronary artery (>2.5 mm), stented or JSB (ostial stenosis >50%, vessel size >2 mm, and lesion length <10 mm), and moderate ISR (>50% diameter stenosis by QCA). Exclusion criteria were patients with total occlusion of the target artery and absence or withdrawal of written informed consent.

Based on a previous study,^[5] setting an alpha error at 0.05 and power at 80%, a sample size of 79 patients was calculated by formula^[6] with 80% power and 5% probability of Type I error to reject null hypothesis for this observational study. All the patients studied were with angiographically intermediate coronary artery stenosis and were subjected to stress MPI and FFR, and the relation between FFR and perfusion imaging was analyzed quantitatively.

Coronary pressure measurement was performed with a 0.014” pressure guide wire. The wire was introduced through a 6F or 7F guiding catheter, calibrated, advanced into the coronary artery, and positioned distal to the stenosis.^[7] Adenosine (90 μg in the right or 120 μg in the left coronary artery with incremental doses if required, and a maximum up to 180 μg) was administered to induce maximum hyperemia.^[8],[9] 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 and with the help of RadiAnalyzer™ Xpress Measurement System (St. Jude Medical, St. Paul, Minnesota, USA).^[7] The measurement was performed twice, and FFR was taken as the lowest value of both measurements.

SPECT-MPI was performed by an expert with either physiological (exercise) or pharmacological stress with machine SIEMENS SYMBIA E dual-head gamma camera with cardiac automated quantification software Corridor 4DM (Siemens Medical Solutions, Malvern, PA, USA) for result analysis. Each patient underwent both the modalities of investigations within a time period of 1 week.

Statistical analysis

Data collected were entered in Excel 2007, and analysis of data was done using Statistical Package for Social Sciences version 20 (IBM Corporation Armonk, NY, USA). The comparison of qualitative variables such as percentage stenosis and reversible perfusion defect was done by using Chi-square test or Fisher's exact test. Pearson's correlation between summed difference score with FFR value was calculated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated. The confidence limit for significance was fixed at 95% level with P < 0.05.

Results

The mean age of the patients was 55.5 years with standard deviation ± 12.06. In all, 53/79 (67.1%) patients were male. In all, 75.9%, 12.7%, and 11.4% patients had single-vessel, double-vessel, and triple-vessel CAD, respectively. A total of 101 lesions were assessed in 79 patients. The distribution was as follows: left anterior descending (LAD) artery – 54/101 (53.5%), left circumflex (LCx) artery – 22/101 (21.8%), and right coronary artery (RCA) – 25/101 (24.7%). Of the 101 lesions, 78 (77.2%), 11 (10.9%), and 12 (11.9%) were native, ISR, and JSB, respectively. In all, 83.5% of the patients underwent exercise stress, whereas 16.5% of the patients underwent pharmacological stress during SPECT-MPI study.

There was a statistically significant difference between percentage stenosis by QCA with FFR in different groups. If FFR was ≤0.75, majority of the lesions (95.8%) were having >70% stenosis [Table 1]. There was a statistically significant difference in FFR and reversible perfusion defects in LAD and LCx coronary arteries [Table 2].

Table 1: Baseline percentage stenosis by quantitative coronary angiography and functional flow reserve

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Table 2: Vessel-wise functional flow reserve value with reversible perfusion defect in the respective territory of the single-photon emission computed tomography-myocardial perfusion imaging

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As evident from [Table 3], there was a statistically significant difference between FFR and reversible perfusion defects. In all, 26.1% of the patients had reversible perfusion defect with FFR >0.75, whereas 73.9% had reversible perfusion defect with an FFR ≤0.75. Only 4.3% of the patients had reversible perfusion defect with FFR >0.80, whereas 95.7% had reversible perfusion defect with FFR ≤0.80. If the cutoff value of FFR was taken as 0.75, the sensitivity and specificity were 56.7% and 91.6%, respectively, with a diagnostic accuracy of 81.2%. If the cutoff value of FFR was taken as 0.80, the sensitivity and specificity were 44.9% and 98.1%, respectively, with a diagnostic accuracy of 72.3% [Table 4].

Table 3: Functional flow reserve values with reversible perfusion defect by single-photon emission computed tomography-myocardial perfusion imaging

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Table 4: Diagnostic accuracy at vessel level calculated from with two different cutoff functional flow reserve values

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When summed difference score was plotted against FFR values, there was a statistically significant negative correlation between the summed difference score with FFR value. As FFR value decreased, the summed difference score increased (Pearson's correlation coefficient^® = −0.52 [95% confidence interval (CI): 0.33–0.70], P < 0.05).

Discussion

In the present study, FFR was ≤0.75 in majority of the lesions having >70% stenosis. Most of the lesions having reversible perfusion defect had an FFR ≤0.80. There was a negative correlation between summed difference score measured on SPECT-MPI with FFR value.

Ahn et al.^[10] and Lindstaedt et al.^[2] reported triple-vessel disease in 8.3% and 24.7% of the patients, respectively, whereas it was 11.4% in the present study. Ahn et al.^[10] reported that there was a statistically significant difference in percentage diameter stenosis and FFR groups. The present research substantiated these findings.

There was a statistically significant difference in FFR and reversible perfusion defects in LAD and LCx coronaries. This suggests that reversible perfusion defects in respective coronary territory match significantly with LAD and LCx coronary arteries, but there was no statistically significant difference in FFR and reversible perfusion defect in RCA territory probably due to elevated diaphragm attenuating inferior wall perfusion defects. Melikian et al. reported that after combining reversible and fixed perfusion defects, concordance between FFR and SPECT-MPI was observed in 135/201 (67.1%) vascular territories and discordance was observed in 66/201 (32.9%) vascular zones.^[1] Ragosta et al.^[3] reported concordance in 69% and discordance in 31%, whereas in the present study, 81.1% showed concordance and 18.9% vessels showed discordance. The major discrepancy between concordant and discordant zones was due to larger proportion of discordant zones with FFR <0.75 despite no perfusion abnormality.

In a study by Melikian et al.,^[1] on a per-vessel basis, there was a poor concordance between the ability of SPECT-MPI and FFR to detect similar abnormalities suggestive of ischemia in a given territory (Kappa = 0.28 [95% CI: 0.15–0.42]), and the level of agreement was poor. While in the present study, (Kappa = 0.52 [95% CI: 0.33–0.70]) the strength of agreement is considered to be “moderate.” While comparing the correlation between summed difference score and actual FFR value, Melikian et al.^[1] reported that there was weak negative correlation (r = −0.29, P ≤ 0.05), in the present study there was good negative correlation (r = −0.52, P ≤ 0.05).

Sensitivity, specificity, PPV, NPV, and diagnostic accuracy of various studies are compared with those of the present research [Table 5]. In the present study, the sensitivity was 56% and 44% when we used FFR threshold of <0.75 and <0.80, respectively. Yanagisawa et al.^[11] reported higher sensitivity (72%) in their study. The sensitivity of our research is comparable to the studies conducted by Ragosta et al.,^[3] Förster et al.,^[12] and Schaap et al.^[13] In the present study, the specificity was 91% and 98% when we used FFR threshold of <0.75 and <0.80, respectively. The specificity was comparable to studies conducted by Melikian et al.,^[1] Ragosta et al.,^[3] Yanagisawa et al.,^[11] Förster et al.,^[12] and Schaap et al.^[13]

Table 5: Comparison of sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy in various studies

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It was observed in various previous studies that hemodynamically significant CAD cannot be accurately ruled out by SPECT-MPI studies. Krüger et al.^[14] studied the use of FFR versus stress perfusion scintigraphy in ISR. They concluded that FFR value of <0.75 is not only valid for diagnosing significant native coronary stenosis, but also for stent restenosis.

In the studies conducted by Ahn et al.^[10] and Koo et al.,^[15] there was a negative correlation between the diameter stenosis by QCA and FFR of side branch (r = −0.21, P = 0.002, and r = −0.41, P ≤ 0.001, respectively), whereas in the present study, there was no significant negative correlation between percentage diameter stenosis and FFR value in postinterventional side branches. This can be explained on the basis of limited number of lesions included in our study, which warrants more number of such lesions to be studied for long term.

Limitations

The present study was an observational study with small sample size and follow-up of 1 year only. In SPECT-MPI, additional left ventricular parameters (regional wall motion abnormalities, transient dilatation, scars, etc.,) were not taken into consideration, which will have an impact on CAD prognosis The sample size was small in ISR and JSB; hence, studies with larger sample size and longer duration should be undertaken, especially ISR and JSB.

Conclusion

In the present study, FFR was ≤0.75 in majority of the lesions having >70% stenosis. Most of the lesions having reversible perfusion defect had FFR ≤0.80. There was a negative correlation between summed difference score with FFR value. Sensitivity and specificity of SPECT-MPI did not differ much when FFR value cutoff was taken as 0.75 or 0.80.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Melikian N, de Bondt P, Tonino P, de Winter O, Wyffels E, Bartunek J, et al. Fractional flow reserve and myocardial perfusion imaging in patients with angiographic multivessel coronary artery disease. JACC Cardiovasc Interv 2010;3:307-14.
2.	Lindstaedt M, Halilcavusogullari Y, Yazar A, Holland-Letz T, Bojara W, Mügge A, et al. Clinical outcome following conservative vs. revascularization therapy in patients with stable coronary artery disease and borderline fractional flow reserve measurements. Clin Cardiol 2010;33:77-83.
3.	Ragosta M, Bishop AH, Lipson LC, Watson DD, Gimple LW, Sarembock IJ, et al. Comparison between angiography and fractional flow reserve versus single-photon emission computed tomographic myocardial perfusion imaging for determining lesion significance in patients with multivessel coronary disease. Am J Cardiol 2007;99:896-902.
4.	Lopez-Palop R, Pinar E, Lozano I, Saura D, Picó F, Valdés M. Utility of the fractional flow reserve in the evaluation of angiographically moderate in-stent restenosis. Eur Heart J 2004;25:2040-7.
5.	Rieber J, Jung P, Erhard I, Koenig A, Hacker M, Schiele TM, et al. Comparison of pressure measurement, dobutamine contrast stress echocardiography and SPECT for the evaluation of intermediate coronary stenoses. The COMPRESS trial. Int J Cardiovasc Intervent 2004;6:142-7.
6.	Malhotra RK, Indrayan A. A simple nomogram for sample size for estimating sensitivity and specificity of medical tests. Indian J Ophthalmol 2010;58:519-22. [PUBMED] [Full text]
7.	Bech GJ, de Bruyne B, Pijls NH, de Muinck ED, Hoorntje JC, Escaned J, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: A randomized trial. Circulation 2001;103:2928-34.
8.	Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation 1990;82:1595-606.
9.	Kern MJ, Deligonul U, Tatineni S, Serota H, Aguirre F, Hilton TC. Intravenous adenosine: Continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease. J Am Coll Cardiol 1991;18:718-29.
10.	Ahn JM, Lee JY, Kang SJ, Kim YH, Song HG, Oh JH, et al. Functional assessment of jailed side branches in coronary bifurcation lesions using fractional flow reserve. JACC Cardiovasc Interv 2012;5:155-61.
11.	Yanagisawa H, Chikamori T, Tanaka N, Hatano T, Morishima T, Hida S, et al. Correlation between thallium-201 myocardial perfusion defects and the functional severity of coronary artery stenosis as assessed by pressure-derived myocardial fractional flow reserve. Circ J 2002;66:1105-9.
12.	Förster S, Rieber J, Ubleis C, Weiss M, Bartenstein P, Cumming P, et al. Tc-99m sestamibi single photon emission computed tomography for guiding percutaneous coronary intervention in patients with multivessel disease: A comparison with quantitative coronary angiography and fractional flow reserve. Int J Cardiovasc Imaging 2010;26:203-13.
13.	Schaap J, Kauling RM, Boekholdt SM, Nieman K, Meijboom WB, Post MC, et al. Incremental diagnostic accuracy of hybrid SPECT/CT coronary angiography in a population with an intermediate to high pre-test likelihood of coronary artery disease. Eur Heart J Cardiovasc Imaging 2013;14:642-9.
14.	Krüger S, Koch KC, Kaumanns I, Merx MW, Schäfer WM, Buell U, et al. Use of fractional flow reserve versus stress perfusion scintigraphy in stent restenosis. Eur J Intern Med 2005;16:429-31.
15.	Koo BK, Kang HJ, Youn TJ, Chae IH, Choi DJ, Kim HS, et al. Physiologic assessment of jailed side branch lesions using fractional flow reserve. J Am Coll Cardiol 2005;46:633-7.