Abstract
Background
A fractional flow reserve (FFR) of <0.8 is currently used to guide revascularization in lesions with intermediate coronary stenosis. Whether there is an intravascular ultrasound (IVUS) measurement or a cutoff value that can reliably determine which of these intermediate lesions requires intervention is unclear.
Aims
We assessed IVUS measurement accuracy in defining functional ischemia by FFR.
Methods
The analysis included 205 intermediate lesions (185 patients) located in vessel diameters >2.5 mm. Positive FFR was considered present at <0.8. IVUS measurements were correlated to the FFR findings in intermediate lesions with 40%–70% stenosis. Fifty-four (26.3%) lesions had FFR<0.8.
Results
There was moderate correlation between FFR and IVUS measurements, including minimum lumen area (MLA) ( r =0.36, P <.001), minimum lumen diameter (MLD) ( r =0.25, P =<.001), lesion length ( r =−0.43, P <.001), and area stenosis ( r =−0.33, P =.01). A receiver operating characteristic curve (ROC) identified MLA<3.09 mm 2 (sensitivity 69.2%, specificity 79.5%) as the best threshold value for FFR<0.8. The correlation between FFR and IVUS was better for large vessels compared to small vessels. ROC analysis identified the best threshold value for FFR<0.8 of MLA<2.4 mm 2 [area under curve (AUC)=0.74] in lesions with reference vessel diameters of 2.5–3 mm, MLA<2.7 mm 2 (AUC=0.77) in lesions with reference vessel diameters of 3–3.5 mm, and MLA<3.6 mm 2 (AUC=0.70) in lesions with reference vessel diameters >3.5 mm.
Conclusion
Anatomic measurements of intermediate coronary lesions obtained by IVUS show a moderate correlation to FFR values. The correlation was better for larger-diameter vessels. Vessel size should always be taken into account when determining the MLA associated with functional ischemia.
1
Introduction
The management of intermediate coronary lesions, defined by a diameter stenosis of 40%–70%, continues to be a therapeutic dilemma regarding the appropriate criteria for undertaking revascularization. Measurement of the degree of stenosis with visual estimation from the angiogram or by quantitative coronary angiography (QCA) is imprecise and is reported to have high inter- and intraobserver variability . Both intravascular ultrasound (IVUS) and fractional flow reserve (FFR) are currently used to define the severity of such lesions by providing accurate anatomical and physiological data, respectively. Clinical decisions based on FFR of intermediate coronary stenosis is safe and is based on large, multicenter, randomized trials demonstrating that postponing revascularization of intermediate severity lesions on angiography with FFR>0.75 is safe and results in an excellent clinical outcome , and FFR-guided coronary intervention is associated with reduced major adverse cardiac events (MACE) in patients with multivessel coronary artery disease .
Data identifying IVUS parameter thresholds for potential ischemia are less robust. A retrospective, single-center analysis determined that minimum lumen cross-sectional area (MLA)>4 mm 2 in intermediate native coronary artery lesion correlates with a low event rate ; while the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial reported MLA<4 mm 2 to be one of the correlates of non-culprit-lesion-related events . We previously reported a moderate correlation between IVUS anatomical parameter and FFR, and MLA<4 mm 2 does not always imply functional ischemia. This study was undertaken in a large cohort of patients in order to evaluate the correlation between IVUS parameters and FFR values in patients with intermediate coronary stenosis and to determine IVUS anatomical criteria associated with functional significance (FFR<0.8) of intermediate coronary stenosis in different reference vessel size diameters.
2
Methods
This was a single-center, prospective registry of patients who underwent elective coronary angiography and had intermediate coronary stenosis defined as a stenosis of 40%–70% by visual estimation at ≥1 major epicardial coronary artery. Patients were assessed by QCA, IVUS, and FFR. From July 2007 to January 2011, 205 intermediate lesions in major epicardial coronary vessels of 185 patients were studied. Patients with acute myocardial infarction (MI), saphenous vein graft lesions, lesions in small vessels defined as <2.5 mm reference vessel diameter, or with >1 lesion in the studied vessel were excluded. Written, informed consent for all procedures was obtained from each patient. Clinical data regarding cardiac risk factors, left ventricular function, and prior noninvasive studies were also collected.
QCA analysis was performed by an independent technologist blinded to the results of both IVUS and FFR. A computer-assisted, automatic contour detection technique (CAAS Quantitative Coronary Angiography for Research, Pie Medical Imaging BV, Maastricht, the Netherlands) was employed. The outer diameter of the contrast-filled catheter served as the calibration standard. After selection of the optimal projection displaying the most severe stenosis, the percent diameter stenosis at end diastole, minimum lumen diameter (MLD), reference vessel diameter, and lesion length were measured. Lesion length was calculated as the distance between the proximal and distal shoulder in the projection demonstrating the stenosis with the least foreshortening.
IVUS studies were performed using one of two commercially available systems. The Boston Scientific (Natick, MA, USA) system incorporated a 40-MHz single-element beveled transducer (Atlantis SR) rotating at 1800 rpm coupled with Clear View (CVIS, Sunnyvale, CA, USA) or Galaxy (Boston Scientific) consoles. The Volcano Therapeutics system (Rancho Cordova, CA, USA) incorporated a phased-array immobile set of crystals arranged circularly around the catheter and was activated sequentially at 20 MHz. All IVUS images were recorded after administration of intracoronary nitroglycerin 200 μg. The transducer was pulled back from the distal coronary artery through the target stenosis and to the proximal portion at 0.5 or 1.0 mm/s. Images were recorded on videotapes or compact discs for offline analysis. Quantitative analysis of the IVUS images was performed by a skilled interpreter using computerized planimetry with TapeMeasure 4.2.16C (INDEC Systems, Inc., Mountain View, CA, USA). Lumen cross sections were measured at the most stenotic site with the smallest lumen. The reference vessel cross-sectional area was measured by tracing the leading edge of the adventitia with the most visually normal cross section (largest lumen with the least plaque) within 10 mm proximal and distal to the lesion. A distal reference was used for ostial lesions. The area stenosis was calculated as reference lumen area minus MLA, divided by reference lumen area.
To assess FFR, a 0.014-in. pressure guide wire (Radi Medical System, Uppsala, Sweden) was employed. Distal pressure was measured immediately distal to the stenosis during a period of maximum hyperemia induced by intravenous adenosine (140 μg/kg/min for the right coronary artery and 180 μg/kg/min for the left coronary artery). Aortic pressure was measured through the guiding catheter (6 or 7 Fr). FFR was calculated as the ratio of the coronary pressure distal to the lesion measured by the pressure wire to the mean aortic pressure measured by the guiding catheter. Based on results of these three methods, we correlated the IVUS and QCA parameters with FFR results. The decision to treat any lesion was made by the operator.
Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, NC, USA). Continuous variables are expressed as mean±standard deviation, and categorical variables are expressed as frequency and percentages. Differences between continuous variables were assessed with Student’s t test. Categorical variables were compared with the χ 2 test or Fisher’s Exact Test when appropriate. Significance was set at P <.05. The relationship and variability between FFR and the IVUS or QCA parameters were analyzed by Pearson correlation analysis to define correlation coefficients between FFR and IVUS or QCA index of lesion severity. Logistic regression and receiver operating characteristic curve analysis was performed to establish the value of IVUS indices that were most predictive of FFR<0.8.
2
Methods
This was a single-center, prospective registry of patients who underwent elective coronary angiography and had intermediate coronary stenosis defined as a stenosis of 40%–70% by visual estimation at ≥1 major epicardial coronary artery. Patients were assessed by QCA, IVUS, and FFR. From July 2007 to January 2011, 205 intermediate lesions in major epicardial coronary vessels of 185 patients were studied. Patients with acute myocardial infarction (MI), saphenous vein graft lesions, lesions in small vessels defined as <2.5 mm reference vessel diameter, or with >1 lesion in the studied vessel were excluded. Written, informed consent for all procedures was obtained from each patient. Clinical data regarding cardiac risk factors, left ventricular function, and prior noninvasive studies were also collected.
QCA analysis was performed by an independent technologist blinded to the results of both IVUS and FFR. A computer-assisted, automatic contour detection technique (CAAS Quantitative Coronary Angiography for Research, Pie Medical Imaging BV, Maastricht, the Netherlands) was employed. The outer diameter of the contrast-filled catheter served as the calibration standard. After selection of the optimal projection displaying the most severe stenosis, the percent diameter stenosis at end diastole, minimum lumen diameter (MLD), reference vessel diameter, and lesion length were measured. Lesion length was calculated as the distance between the proximal and distal shoulder in the projection demonstrating the stenosis with the least foreshortening.
IVUS studies were performed using one of two commercially available systems. The Boston Scientific (Natick, MA, USA) system incorporated a 40-MHz single-element beveled transducer (Atlantis SR) rotating at 1800 rpm coupled with Clear View (CVIS, Sunnyvale, CA, USA) or Galaxy (Boston Scientific) consoles. The Volcano Therapeutics system (Rancho Cordova, CA, USA) incorporated a phased-array immobile set of crystals arranged circularly around the catheter and was activated sequentially at 20 MHz. All IVUS images were recorded after administration of intracoronary nitroglycerin 200 μg. The transducer was pulled back from the distal coronary artery through the target stenosis and to the proximal portion at 0.5 or 1.0 mm/s. Images were recorded on videotapes or compact discs for offline analysis. Quantitative analysis of the IVUS images was performed by a skilled interpreter using computerized planimetry with TapeMeasure 4.2.16C (INDEC Systems, Inc., Mountain View, CA, USA). Lumen cross sections were measured at the most stenotic site with the smallest lumen. The reference vessel cross-sectional area was measured by tracing the leading edge of the adventitia with the most visually normal cross section (largest lumen with the least plaque) within 10 mm proximal and distal to the lesion. A distal reference was used for ostial lesions. The area stenosis was calculated as reference lumen area minus MLA, divided by reference lumen area.
To assess FFR, a 0.014-in. pressure guide wire (Radi Medical System, Uppsala, Sweden) was employed. Distal pressure was measured immediately distal to the stenosis during a period of maximum hyperemia induced by intravenous adenosine (140 μg/kg/min for the right coronary artery and 180 μg/kg/min for the left coronary artery). Aortic pressure was measured through the guiding catheter (6 or 7 Fr). FFR was calculated as the ratio of the coronary pressure distal to the lesion measured by the pressure wire to the mean aortic pressure measured by the guiding catheter. Based on results of these three methods, we correlated the IVUS and QCA parameters with FFR results. The decision to treat any lesion was made by the operator.
Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, NC, USA). Continuous variables are expressed as mean±standard deviation, and categorical variables are expressed as frequency and percentages. Differences between continuous variables were assessed with Student’s t test. Categorical variables were compared with the χ 2 test or Fisher’s Exact Test when appropriate. Significance was set at P <.05. The relationship and variability between FFR and the IVUS or QCA parameters were analyzed by Pearson correlation analysis to define correlation coefficients between FFR and IVUS or QCA index of lesion severity. Logistic regression and receiver operating characteristic curve analysis was performed to establish the value of IVUS indices that were most predictive of FFR<0.8.
3
Results
Two hundred and five intermediate coronary lesions in 185 patients were analyzed. The baseline clinical characteristics and lesion-specific characteristics are presented in Table 1 . The mean age was 64.5±11.5 years, and 123 patients (66.4%) were male. One hundred and fifteen lesions (56.1%) were located in the left anterior descending artery (LAD) territory. In 54 stenoses (26.3%), the FFR was <0.8.
| Patient characteristics, n (%) | |
|---|---|
| Age (years) | 64.5±11.5 |
| Male | 123 (66.4%) |
| Hypertension | 152 (82.1%) |
| Hyperlipidemia | 149 (80.5%) |
| Smoker | 39 (21%) |
| Family history of coronary artery disease | 62 (33.5%) |
| Diabetes | 47 (25.4%) |
| Previous PCI | 79 (42.7%) |
| Previous coronary artery bypass graft | 19 (10.2%) |
| Previous MI | 40 (21.6%) |
| Ejection fraction (%) | 54.7±12.7 |
| Lesion characteristics | |
| Left main artery | 12 (5.8%) |
| Left anterior descending/diagonal artery | 115 (56.1%) |
| Circumflex artery | 31 (15.1%) |
| Right coronary artery | 47 (22.9%) |
| Reference vessel diameter | |
| 2.5–3 mm | 50 (24.4%) |
| 3–3.5 mm | 76 (37.1%) |
| >3.5 mm | 79 (38.5%) |
| Quantitative coronary analysis | |
| Diameter stenosis (%) | 48.3±9.4 |
| Minimal luminal diameter (mm) | 1.7±0.48 |
| Reference diameter (mm) | 3.3±0.7 |
| Lesion length (mm) | 11.4±6.2 |
| FFR | |
| Mean FFR | 0.84±0.08 |
| FFR<0.8 | 54 (26.3%) |
| Intravascular ultrasound | |
| Minimal luminal area (mm 2 ) | 3.5±1.3 |
| Minimal luminal diameter (mm) | 1.8±0.5 |
| Lesion length (mm) | 12.7±7.3 |
| Reference luminal area (mm 2 ) | 8.6±3.2 |
| Area stenosis (%) | 57.3±14.5 |
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