Clinical Relevance of Poststent Fractional Flow Reserve After Drug-Eluting Stent Implantation

Abstract: Background. The prognostic value of poststent fractional flow reserve (FFR) has not been clearly defined in patients with drug-eluting stent (DES) implantation. This study sought to evaluate the association between FFR and clinical outcomes after DES implantation with intravascular ultrasound (IVUS) assistance. Methods. A total of 115 lesions (107 patients) with FFR measurement after IVUS-assisted DES implantation were enrolled. Poststent angiographic and IVUS parameters were compared with FFR values. Clinical outcomes were assessed by target vessel failure (TVF), defined as a composite of target vessel revascularization, death, or non-fatal myocardial infarction attributed to the target vessel. Results. Mean poststent FFR was 0.92 ± 0.04. Minimal stent area by IVUS had a positive correlation with poststent FFR (r = 0.36; P<.01). Poststent FFR ≥0.89 was a physiologic cut-off value for 1-year TVF-free survival. The best cut-off value of minimal stent area to define poststent FFR ≥0.89 was >5.4 mm² (sensitivity, 63.2%; specificity, 90.0%). At 3-year follow-up, lesions with poststent FFR ≥0.89 had a better TVF-free survival rate than those with poststent FFR <0.89 (89.3% vs 61.1%, P =.03). Conclusion. Poststent FFR can be a useful predictor for long-term clinical outcomes after DES implantation and relevant to IVUS minimal stent area. 

J INVASIVE CARDIOL 2015;27(8):346-351

Key words: DES implantation, fractional flow reserve, intravascular ultrasound, restenosis

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Fractional flow reserve (FFR) is an invasive physiologic index to define the functional significance of a coronary artery stenosis.¹ A previous randomized study demonstrated that FFR-guided revascularization was better than angiography-guided revascularization in patients with multivessel disease.² Furthermore, medical treatment for functionally significant stenosis resulted in worse outcomes than revascularization with drug-eluting stent (DES) implantation.³ Therefore, FFR is more commonly used in daily practice.⁴ 

In addition to lesion assessment before intervention, FFR can be used to determine the outcomes after percutaneous coronary intervention (PCI). In the era of bare-metal stent implantation, poststent FFR ≥0.95 was suggested as the cut-off value to define optimal revascularization; this value was also validated in several intravascular ultrasound (IVUS) studies.^5-10 Recent studies on the prognostic value of FFR after DES implantation have included a small number of patients, and their results were controversial.^11-14 Therefore, it is not clearly defined whether the previous cut-off value of poststent FFR can be applied to patients treated with DES, especially in those with IVUS-guided DES implantation.^11,12 Thus, this study was performed to investigate the association between poststent FFR and clinical outcomes, and to evaluate the relationship between minimal stent area and poststent FFR in patients with DES implantation assisted by IVUS assessment.

Methods

Patient population. Patients with obstructive coronary artery disease (CAD) who underwent IVUS-guided DES implantation and FFR measurement at the end of index PCI procedure were selected from the single-center prospective FFR registry. Patients with the following criteria were excluded: culprit vessel of acute coronary syndrome with regional wall-motion abnormality by echocardiography; visible thrombus of target vessel segment; Thrombolysis in Myocardial Infarction (TIMI) flow <3 after PCI; additional stenosis (>30% by visual estimation) in the target vessel; left ventricular ejection fraction <30%; primary myocardial or valvular heart disease; and reference vessel diameter <2.5 mm by visual estimation. The study protocol was approved by the Institutional Review Board (NCT01667757; www.clinicaltrials.gov). 

Invasive coronary angiography with PCI, IVUS, and FFR procedures. The target coronary artery was engaged using a 5-7 Fr guiding catheter. Angiographic images were acquired after intracoronary administration of 100-200 µg nitroglycerin.¹⁵ IVUS was performed in a standard fashion using an automated, motorized pullback system (0.5 mm/s) with commercially available imaging catheters (Boston Scientific/Scimed or Volcano Corporation). FFR was measured using a 0.014˝ pressure-sensor tipped guidewire (PressureWire; St. Jude Medical Systems) as previously described.¹⁶ Hyperemia was induced with intracoronary bolus administration adenosine (80 µg in left coronary artery, 40 µg in right coronary artery) or intravenous continuous infusion adenosine (140 µg/kg/min).¹⁷ Intracoronary nitroglycerin (200 µg) was administered before an IVUS run or FFR measurement. PCI was performed by operator’s revascularization strategy according to guidelines with commercially available first- or second-generation DESs.^18-20Successful DES implantation was defined as TIMI-3 flow with angiographic residual stenosis <10% by visual estimation.⁹ Incomplete stent apposition or stent underexpansion (as assessed by IVUS) was treated with additional balloon angioplasty.⁷ No evidence of stent edge dissection was confirmed by IVUS examination before poststent FFR measurement. 

Quantitative coronary angiography and IVUS analysis. Both quantitative coronary angiography (QCA) and IVUS analysis were performed at an independent core laboratory (Seoul National University Cardiovascular Center). QCA was performed by a single experienced observer who was blinded to the FFR value and IVUS findings. Using the guiding catheter for calibration and an edge-detection system (CAAS 5.7 QCA system; Pie Medical), the reference diameter, minimal lumen diameter, and lesion length were measured and the percent diameter stenosis was calculated. Lesion location was determined according to the American Heart Association classification.²⁰ IVUS analysis was performed by a single independent experienced observer blinded to the FFR and QCA information. Quantitative analyses of IVUS data were performed using computerized planimetry software (echoPlaque 3.0; Indec Systems, Inc) as previously described.²¹Percent area expansion was defined as the minimal stent area (MSA) divided by the average of the proximal and distal reference areas.

Follow-up and outcome analysis. Clinical follow-up data were obtained from electronic medical records of the hospital or from telephone contact, if needed. All patients were treated with usual standard medical therapy, including aspirin, clopidogrel, statins, calcium-channel blockers, beta-blockers, and nitrates based upon their clinical needs during the follow-up period.^18,19 Clinical outcomes, including all-cause death, cardiac death, myocardial infarction (MI), target lesion and target vessel revascularization, and any revascularization, were obtained. The primary endpoint was target vessel failure (TVF), defined as a composite of death, target vessel revascularization, and non-fatal MI attributed to the target vessel. Any death was considered target-vessel related cardiac death unless there was a clear non-cardiac cause or documented non-target vessel related cardiac death. Non-fatal MI was defined as an elevated cardiac enzyme with or without ischemic symptoms or new pathologic Q-waves on electrocardiogram. 

Statistical analyses. Continuous variables were presented as mean ± standard deviations and categorical variables as frequencies and percentages. Student’s t-test was performed to test the difference of continuous variables between the two groups. Analysis of discrete variables was performed using the chi-square test. Receiver operating curve analysis was performed to define the best cut-off value of MSA. The best cut-off value was determined by the maximum sum of sensitivity and specificity. Pearson’s correlation coefficients were calculated to determine the relationship between FFR and angiographic and IVUS parameters. The cut-off value of poststent FFR predicting 1-year TVF-free survival was determined by Youden index criterion. The time-to-event data were presented as Kaplan-Meier estimates and the comparisons between groups were performed by the log-rank test. A P-value of <.05 was considered statistically significant. All P-values and confidence intervals were two-sided. All analyses were performed using SPSS16.0 (IBM Corporation) and MedCalc, version 12.3.0 (MedCalc Software BVBA). 

Results

From March 2007 to Feb 2012, a total of 115 lesions (107 patients) that met the inclusion criteria were selected and included in this study. Baseline patient and lesion characteristics are shown in Tables 1 and 2. Among 137 DES implantations, 54 stents (39.5%) were second-generation DESs. Mean number of stents per lesion was 1.2 ± 0.5 and 87 lesions (75.7%) were located at the left anterior descending coronary artery. Mean percent area expansion assessed by IVUS of 137 implanted stents was 77.4 ± 21.4%. 

Relationship between poststent FFR and angiographic and IVUS parameters. Mean poststent FFR was 0.92 ± 0.04, and the distribution of poststent FFR is shown in Figure 1. There was a positive correlation between poststent FFR and MSA by IVUS (r = 0.36; 95% confidence interval [CI], 0.19-0.51). However, no correlation was found between poststent angiographic percent diameter stenosis and poststent FFR (r = -0.13; 95% CI, -0.30-0.05) (Figure 2). 

Poststent FFR and 1-year clinical outcomes. During 1-year follow-up, a total of 7 TVF cases occurred (6.6%). There were 2 cases of non-fatal MI and 5 cases of TVR. By Youden index criterion analysis, poststent FFR ≥0.89 was the physiologic cut-off value to predict 1-year TVF-free survival. The best cut-off value of MSA defining poststent FFR ≥0.89 was >5.4 mm² (sensitivity, 63.2%; specificity, 90.0%; positive predictive value, 96.4%; negative predictive value, 34.0%; accuracy, 67.8%) (Figure 3). When lesions were divided into two groups according to this cut-off value, high FFR (poststent FFR ≥0.89) was achieved in 95 lesions (82.6%). Compared with high poststent FFR lesions, low FFR lesions (poststent FFR<0.89) had more severe lesion characteristics (Table 2). After stent implantation, there was no difference in angiographic percent diameter stenosis. However, minimal lumen diameter and MSA were smaller in low-FFR lesions than in high-FFR lesions (Table 2).

Influence of poststent FFR on long-term clinical outcomes. During a 3-year follow up (median, 23.0 months), a total of 13 TVF cases occurred. Three cases of non-fatal MI and 2 cases of TVR occurred in low-FFR lesions (5 of 20 cases), and 8 cases of TVR occurred in high-FFR lesions (8 of 95 cases). There were 2 cases of non-target vessel revascularization and 3 cases of non-cardiac death (2 due to cancer and 1 due to sepsis). High-FFR lesions had better TVF-free survival rate compared with low-FFR lesions (89.3% vs 61.1%, respectively; P=.03) (Figure 4).

Discussion 

The main findings of this study were: (1) MSA by IVUS had a positive correlation with poststent FFR, but angiographic poststent percent diameter stenosis had no correlation with poststent FFR; (2) FFR ≥0.89 was associated with favorable long-term clinical outcomes after DES implantation; and (3) MSA by IVUS to define poststent FFR ≥0.89 was >5.4 mm². These results suggest that FFR measurement after stent implantation can provide useful prognostic information in patients treated with DES by IVUS assistance.

In the era of bare-metal stents, poststent FFR was a predictor associated with clinical outcomes and a range of 0.90-0.95 was suggested as a cut-off value.^5-10 Because DES implantation can reduce restenosis and target lesion revascularization, patient and lesion characteristics have changed from those in the bare-metal stent era. Therefore, an adequate cut-off value and the prognostic implications of poststent FFR should be reevaluated in patients with DES implantation. However, studies on poststent FFR after DES implantation have been limited, with a small number of patients and short follow-up duration.^11-14 Leesar et al investigated 2-year outcomes of 66 patients (DES, 38 patients) with poststent FFR measurement and found that patients with poststent FFR ≥0.96 had lower event rates than those with FFR <0.96.¹² Nam et al suggested poststent FFR of 0.90 as a cut-off value to predict 1-year outcomes after DES implantation.¹⁴ However, poststent FFR was not a predictor for target lesion revascularization after DES implantation in a study by Matsuo et al.¹¹ In this study, poststent FFR ≥0.89 was the physiologic cut-off value to predict TVF-free survival. These different results may be due to differences in baseline lesion and patient characteristics among those studies. In a study by Leesar et al, mean stent length was only 16 mm.¹² The study population had angiographic and patient characteristics similar to those in general DES registries.^21-25 Mean lesion length and stent length were 22.1 ± 11.1 mm and 30.7 ± 14.5 mm, respectively, and 72% of the lesions were B2/C lesions. The cut-off value of poststent FFR was lower in our study than in the BMS era. This might be due to the fact that less well-deployed BMS implantation has a higher potential for clinical events than DES use, where the antiproliferative effect of the drug can attenuate the effect of suboptimal expansion.

For the determination of procedural success, angiographic residual percent diameter stenosis has been commonly used in clinical practice, but its limitation is also well known.^26-28 There was no correlation between angiographic residual stenosis and poststent FFR, and there was no difference in poststent percent diameter stenosis between high-FFR and low-FFR groups in this study. Furthermore, despite the mean angiographic residual stenosis of 10.24 ± 6.34%, a total of 20 out of 115 lesions (17.4%) could not achieve poststent FFR ≥0.89. These findings illustrate the limitation of angiographic evaluation after stent implantation. IVUS can provide better quantitative and qualitative information on PCI procedures than angiographic evaluation.^21-24 In this study, there was a positive correlation between poststent FFR and MSA and the best MSA cut-off value to define the physiologic cut-off of FFR ≥0.89 was >5.4 mm². This finding matched well with the results of previous studies, which showed that an IVUS-derived MSA of 5.0-5.7 mm² could predict DES failure.^21-24 The results of the present study suggest that even though IVUS can provide better information for procedural optimization than angiography, inherent limitations of imaging technology require FFR for physiologic interpretation of anatomical findings.

Recent studies demonstrated that FFR-guided or IVUS-guided DES implantation improved outcomes compared with angiography-guided procedures. However, the benefit of adjunctive utilization of IVUS to FFR has not been proven in large clinical studies.^2-4,29 Park et al showed that the routine use of FFR in addition to IVUS before stent implantation reduced the number of stents and improved the outcomes.⁴ The present study demonstrated that poststent FFR still has additive prognostic implication in patients with DES implantation by IVUS assistance. Moreover, in this study, lesions with poststent FFR ≥0.89 had a better TVF-free survival rate than those with poststent FFR <0.89. The prognosis of patients with CAD is determined by total plaque burden as well as the severity of local stenosis. FFR measured after stent implantation represents the status of both stented and non-stented segments and may better indicate patient outcomes versus other evaluation tools. Future technical development may facilitate the use of IVUS and FFR together without further procedural risk, and improve PCI outcomes.

Study limitations. This study has several limitations. First, study subjects were recruited from a single center and the number was relatively small. Second, despite the exclusion of additional stenosis in a target vessel by angiography and IVUS-guided adjustment of stent segments, the mechanism of low FFR (such as the presence of plaque in proximal or distal diseased portion to the stented segment and/or DES underexpansion related to intrastent pressure gradient) cannot be determined as the pullback pressure tracing in all patients. Third, although both intracoronary bolus injection and intravenous infusion of adenosine are established hyperemia-inducing methods,¹⁷ the different hyperemic effect of two methods in some patients might have influenced our study results. Considering these inherent limitations to this study, a future multicenter study in a larger population is needed to confirm the findings of this study. 

Conclusion

Poststent FFR can be a useful predictor for long-term clinical outcomes in patients with DES implantation by IVUS assistance. Poststent FFR ≥0.89 was a physiologic cut-off value and this value matched with an IVUS-derived MSA >5.4 mm². 

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From the ¹Department of Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea; ²Clinical Research Center of Ilsan-Paik Hospital, Goyang, Korea; ³Department of Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea; and the ⁴Department of Medicine, Seoul National University Hospital, Seoul, Korea. 

Funding: This work was supported by a grant from the Korean Society of Interventional Cardiology in 2011 and a grant from Inje University in 2005.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Koo reports lecture honoraria and research grants from St. Jude Medical. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted May 27, 2014, provisional acceptance given September 8, 2014, final version accepted October 24, 2014.

Address for correspondence: Bon-Kwon Koo, MD, PhD, Associate Professor of Medicine/Cardiology, Seoul National University College of Medicine, 101 Daehang-ro, Chongno-gu, Seoul 110-744, Korea. Email: bkkoo@snu.ac.kr or bkk1214@gmail.com