Abstract
Background
The correlation between fractional flow reserve (FFR) and intravascular ultrasound (IVUS) metrics including minimal lumen area (MLA), plaque burden and morphology remain a matter of debate.
Methods
Between June 2008 and May 2013, 132 intermediate stenoses in 109 patients were assessed by FFR, IVUS and quantitative angiography. Receiver-operating characteristic (ROC) curve analyses were used to identify MLA/lesion length/plaque burden cut-off values predictive of FFR < 0.80.
Results
FFR < 0.80 was observed in 39 lesions. In the entire cohort, MLA value < 2.70 mm 2 had 79.5% sensitivity, 76.3% specificity, 0.822 area under curve (AUC), 58.5% positive predictive value, 89.9% negative predictive value and 77.3% accuracy in predicting a positive FFR. In lesions with reference diameter vessel (RVD) ≥ 3.0 mm, the MLA cut-off value was 2.84 mm 2 (sensitivity 72.2%, specificity 83.0%, AUC 0.842) whereas in lesions with RVD < 3.0 mm, 2.59 mm 2 (sensitivity 90.5%, specificity 69.6%, AUC 0.823). A moderate correlation was observed between MLA and FFR (r = 0.429, p < 0.001). The cut-off lesion length predictive of FFR < 0.80 was 11.0 mm with a weak correlation between the two (r = − 0.348, p < 0.001). Plaque morphology did not significantly affect FFR (p = 0.485). On multivariable analysis, MLA (OR: 0.15; 95% CI: 0.05–0.40; p < 0.001) and plaque burden (OR: 1.11; 95% CI: 1.04–1.20; p < 0.003) were independent predictors of FFR < 0.80.
Conclusion
A modest, yet significant correlation was observed between MLA and FFR. The high negative predictive value of large MLAs (using afore-mentioned cut-off values) may provide some degree of confidence that the lesion in question is not functionally significant.
1
Introduction
The benefits of percutaneous coronary intervention (PCI) for stable coronary artery disease are debated and questioned, especially without the demonstration of significant reversible ischemia. Fractional flow reserve (FFR) has already been validated in the physiological assessment of coronary artery stenoses with an FFR value of ≤ 0.80 currently proposed as the cut-off to indicate functional significance , rather than < 0.75 which was initially identified as the optimal cut-off point . On the other hand, intravascular ultrasound (IVUS) is widely used for the quantitative and qualitative assessment of coronary artery disease. IVUS use has been reported to improve clinical outcomes as compared to angiography-guided PCI alone . Although the correlation between these complementary tools is still debated, various cut-off points for minimum lumen area (MLA) as assessed by IVUS have been proposed for positive FFR . Furthermore, the impact of plaque morphology on FFR has yet to be fully evaluated. In the FIRST (Fractional Flow Reserve and Intravascular Ultrasound Relationship) study, no correlation between plaque morphology and FFR as assessed by virtual histology IVUS was identified . The aim of this study was to further assess the correlation between quantitative coronary angiography (QCA), FFR, quantitative and qualitative IVUS.
2
Methods
2.1
Study population
Between June 2008 and May 2013, the severity of 132 intermediate stenoses (40–70% on visual estimation) in 109 patients was assessed using FFR, IVUS and QCA at 2 centers: San Raffaele Scientific Institute and EMO-GVM Centro Cuore Columbus, Milan, Italy. Exclusion criteria in this study were multiple stenoses (> 40% of diameter stenosis [DS] on visual estimation) within the target vessel, infarct-related vessel of previous myocardial infarction, left main disease, acute myocardial infarction, bypass graft disease, concomitant chronic total occlusion and contraindication to adenosine administration.
2.2
FFR assessment
Intracoronary nitroglycerin (100–200 μg) was administered before angiographic injection. The procedure was undertaken utilizing the following pressure guide wires: PrimeWire® family (Volcano, San Diego, California) and PressureWire™ Certus (St. Jude Medical, Minnesota). Equalization, wire positioning, recording duration were all undertaken as per manufacturers’ guidelines. Hyperemia was induced by the intravenous continuous infusion (140 μg/kg/min) of adenosine. Lesions with FFR < 0.80 were considered functionally significant.
2.3
IVUS assessment
IVUS studies were performed with the 40 MHz IVUS catheter (Boston Scientific, Natick, Mass) after administration of intracoronary nitroglycerin (100–200 μg). In all cases, the transducer was pulled back automatically at a speed of 0.5 mm/s up to the guiding catheter with the use of a validated motorized device. IVUS images were analyzed by 2 trained independent physicians in our laboratory. The lesion was considered to be at the site of MLA. Calcium deposits were defined as bright echoes with acoustic shadows. The arc of calcium can be measured (in degrees) by using an electronic protractor centered on the lumen. Other IVUS findings are reported according to the validated IVUS guidelines .
2.4
Quantitative Coronary Angiography
QCA data were analyzed using the Clinical Measurements Solutions system (QCA-CMS, version 5.1; MEDIS Imaging Systems, Leiden, the Netherlands) by trained physicians. The % DS at end-diastole, minimal lumen diameter, reference diameter vessel (RVD), and lesion length were measured.
2.5
Statistical Analysis
Values are presented as mean ± standard deviation or median (interquartile range [IQR]) for continuous variables or as counts and percentages for categorical variables. Clinical, echocardiographic, angiographic or procedure-related characteristics of patients were compared using Student-t test or Wilcoxon rank-sum test (continuous variables), or chi-square or Fisher’s exact test (categorical variables), as appropriate. The relationship and variability between FFR and IVUS or QCA parameters were analyzed by Pearson correlation analysis to define correlation coefficients between FFR and IVUS or QCA of lesion severity. Receiver-operating characteristic (ROC) curve analyses were performed to establish the cut-off values of MLA, plaque burden and lesion length most predictive of FFR < 0.80. Specifically, the optimal cut-off values were calculated using the Youden index. Multivariable analysis was performed to determine the independent predictors of FFR < 0.80. In the model we included variables associated with FFR < 0.80 in univariable analysis (p-value < 0.2) and those judged to be of clinical importance from previous published literature. Values of p < 0.05 were regarded as statistically significant. Analyses were carried out using SPSS for Windows, version 19.0 (SPSS Inc., Chicago, Illinois).
2
Methods
2.1
Study population
Between June 2008 and May 2013, the severity of 132 intermediate stenoses (40–70% on visual estimation) in 109 patients was assessed using FFR, IVUS and QCA at 2 centers: San Raffaele Scientific Institute and EMO-GVM Centro Cuore Columbus, Milan, Italy. Exclusion criteria in this study were multiple stenoses (> 40% of diameter stenosis [DS] on visual estimation) within the target vessel, infarct-related vessel of previous myocardial infarction, left main disease, acute myocardial infarction, bypass graft disease, concomitant chronic total occlusion and contraindication to adenosine administration.
2.2
FFR assessment
Intracoronary nitroglycerin (100–200 μg) was administered before angiographic injection. The procedure was undertaken utilizing the following pressure guide wires: PrimeWire® family (Volcano, San Diego, California) and PressureWire™ Certus (St. Jude Medical, Minnesota). Equalization, wire positioning, recording duration were all undertaken as per manufacturers’ guidelines. Hyperemia was induced by the intravenous continuous infusion (140 μg/kg/min) of adenosine. Lesions with FFR < 0.80 were considered functionally significant.
2.3
IVUS assessment
IVUS studies were performed with the 40 MHz IVUS catheter (Boston Scientific, Natick, Mass) after administration of intracoronary nitroglycerin (100–200 μg). In all cases, the transducer was pulled back automatically at a speed of 0.5 mm/s up to the guiding catheter with the use of a validated motorized device. IVUS images were analyzed by 2 trained independent physicians in our laboratory. The lesion was considered to be at the site of MLA. Calcium deposits were defined as bright echoes with acoustic shadows. The arc of calcium can be measured (in degrees) by using an electronic protractor centered on the lumen. Other IVUS findings are reported according to the validated IVUS guidelines .
2.4
Quantitative Coronary Angiography
QCA data were analyzed using the Clinical Measurements Solutions system (QCA-CMS, version 5.1; MEDIS Imaging Systems, Leiden, the Netherlands) by trained physicians. The % DS at end-diastole, minimal lumen diameter, reference diameter vessel (RVD), and lesion length were measured.
2.5
Statistical Analysis
Values are presented as mean ± standard deviation or median (interquartile range [IQR]) for continuous variables or as counts and percentages for categorical variables. Clinical, echocardiographic, angiographic or procedure-related characteristics of patients were compared using Student-t test or Wilcoxon rank-sum test (continuous variables), or chi-square or Fisher’s exact test (categorical variables), as appropriate. The relationship and variability between FFR and IVUS or QCA parameters were analyzed by Pearson correlation analysis to define correlation coefficients between FFR and IVUS or QCA of lesion severity. Receiver-operating characteristic (ROC) curve analyses were performed to establish the cut-off values of MLA, plaque burden and lesion length most predictive of FFR < 0.80. Specifically, the optimal cut-off values were calculated using the Youden index. Multivariable analysis was performed to determine the independent predictors of FFR < 0.80. In the model we included variables associated with FFR < 0.80 in univariable analysis (p-value < 0.2) and those judged to be of clinical importance from previous published literature. Values of p < 0.05 were regarded as statistically significant. Analyses were carried out using SPSS for Windows, version 19.0 (SPSS Inc., Chicago, Illinois).
3
Results
Baseline clinical characteristics are shown in Table 1 . FFR < 0.80 was observed in 39 (29.5%) lesions. Angiographic and IVUS parameters for FFR < 0.80 and FFR ≥ 0.80 are shown in Table 2 . There was no difference in RVD (2.87 ± 0.48 mm vs. 2.95 ± 0.50 mm, p = 0.407) as assessed by QCA between the FFR positive and FFR negative groups. The FFR positive group had significantly lower MLD (1.27 ± 0.42 mm vs. 1.50 ± 0.46 mm, p = 0.007), higher % DS (54.7 ± 15.2% vs. 49.1 ± 12.7%, p = 0.033) and longer lesion length (14.9 ± 9.3 mm vs. 10.8 ± 6.9 mm, p = 0.006), as compared to the FFR negative group. According to IVUS, the FFR positive group had smaller MLA (2.4 ± 0.5 mm 2 vs. 3.2 ± 0.8 mm 2 , p < 0.001) and more plaque burden (75.5 ± 7.3% vs. 67.9 ± 10.4%, p < 0.001). Importantly, there were no differences between the FFR positive and FFR negative groups with regards to vessel area at the proximal reference, lesion and distal reference sities. No significant differences were noted between the two groups with regards to plaque morphology (p = 0.485) and calcification arc (p = 0.810).
| Patient number = 109 (%) | |
|---|---|
| Age, yrs | 68.0 ± 9.3 |
| Male gender | 97 (89.0) |
| Diabetes mellitus | 27 (24.8) |
| Insulin | 3 (2.8) |
| Dyslipidemia | 64 (58.7) |
| Hypertension | 57 (52.3) |
| Current smokers | 13 (11.9) |
| LVEF, % | 55.6 ± 8.3 |
| Previous PCI | 69 (63.3) |
| Previous CABG | 7 (6.4) |
| Family history of CAD | 48 (44.0) |
| Positive stress test | 43 (39.4) |
| Multivessel disease | 77 (70.6) |
| Angina type | |
| Stable angina/asymptomatic | 99 (90.8) |
| Unstable angina | 10 (9.2) |
| Entire lesion cohort (n = 132) | FFR < 0.80 (n = 39) | FFR ≥ 0.80 (n = 93) | p value | |
|---|---|---|---|---|
| Target vessel | 0.621 | |||
| LAD | 67 (50.8) | 21 (53.8) | 46 (49.5) | |
| LCx | 37 (28.0) | 9 (23.1) | 28 (30.1) | |
| RCA | 28 (21.2) | 9 (23.1) | 19 (20.4) | |
| Proximal lesion | 67 (50.8) | 19 (48.7) | 48 (51.6) | 0.945 |
| Proximal LAD | 29 (22.0) | 8 (20.5) | 21 (22.6) | 0.793 |
| Angiographic parameters | ||||
| RVD, mm | 2.93 ± 0.50 | 2.87 ± 0.48 | 2.95 ± 0.50 | 0.407 |
| RVD ≥ 3.0 mm | 65 (49.2) | 18 (46.2) | 47 (50.5) | 0.646 |
| MLD, mm | 1.44 ± 0.46 | 1.27 ± 0.42 | 1.50 ± 0.46 | 0.007 |
| % DS | 50.7 ± 13.7 | 54.7 ± 15.2 | 49.1 ± 12.7 | 0.033 |
| Lesion length, mm | 12.0 ± 7.9 | 14.9 ± 9.3 | 10.8 ± 6.9 | 0.006 |
| IVUS parameters | ||||
| Lesion lumen area, mm 2 | 3.0 ± 0.8 | 2.4 ± 0.5 | 3.2 ± 0.8 | < 0.001 |
| Lesion lumen diameter, mm | 1.9 ± 0.3 | 1.8 ± 0.4 | 2.0 ± 0.3 | < 0.001 |
| Lesion vessel area, mm 2 | 10.9 ± 4.2 | 11.1 ± 5.2 | 10.9 ± 3.6 | 0.804 |
| Lesion vessel diameter, mm | 3.7 ± 0.7 | 3.7 ± 0.9 | 3.7 ± 0.6 | 0.997 |
| Lesion plaque area, mm 2 | 7.9 ± 4.0 | 8.7 ± 5.0 | 7.6 ± 3.4 | 0.182 |
| Lesion plaque burden, % | 70.2 ± 10.2 | 75.5 ± 7.3 | 67.9 ± 10.4 | < 0.001 |
| Plaque morphology | 0.523 | |||
| Fibrous plaque | 74 (56.1) | 18 (46.2) | 56 (60.2) | |
| Calcified plaque | 36 (27.3) | 13 (33.3) | 23 (24.7) | |
| Mixed plaque | 17 (12.9) | 6 (15.4) | 11 (11.8) | |
| Soft plaque | 5 (3.8) | 2 (5.1) | 3 (3.2) | |
| Calcification arc, degree | 86.6 ± 76.2 | 89.9 ± 76.4 | 86.1 ± 76.0 | 0.810 |
| Superficial calcification | 87 (65.9) | 23 (59.0) | 64 (68.8) | 0.648 |
| Proximal vessel area, mm 2 | 13.1 ± 4.2 | 13.0 ± 5.1 | 13.1 ± 3.8 | 0.907 |
| Proximal lumen area, mm 2 | 7.1 ± 2.7 | 7.1 ± 3.6 | 7.1 ± 2.1 | 0.936 |
| Distal vessel area, mm 2 | 11.0 ± 4.5 | 10.1 ± 4.4 | 11.5 ± 4.5 | 0.111 |
| Distal lumen area, mm | 6.2 ± 2.3 | 5.8 ± 2.3 | 6.3 ± 2.3 | 0.222 |
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