Abstract
Objective
We aimed to compare neointimal tissue characteristics between bare-metal stents (BMS) and drug-eluting stents (DES) at long-term follow-up using optical coherence tomography (OCT) and virtual histology intravascular ultrasound (VH-IVUS).
Background
Neoatherosclerosis in neointima has been reported in BMS and in DES.
Methods
Thirty patients with 36 stented lesions [BMS (n = 17) or DES (n = 19)] > 3 years after implantation were prospectively enrolled. OCT and VH-IVUS were performed and analyzed independently. Stents with ≥ 70% diameter stenosis were excluded.
Results
The median duration from implantation was 126.0 months in the BMS group and 60.0 months in the DES group (p < 0.001). Lipid-laden intima (58.8% vs. 42.1%, p = 0.317), thrombus (17.6% vs. 5.3%, p = 0.326), and calcification (35.3% vs. 26.3%, p = 0.559) did not show significant differences between BMS and DES. When divided into 3 time periods, the cumulative incidence of lipid-laden neointima from > 3 years to < 9 years was similar between BMS and DES (42.9% vs. 42.1%, p = 1.000). Furthermore, it continued to gradually increase over time in both groups. OCT-derived thin-cap fibroatheroma (TCFA) was observed in 17.6% of BMS- and 5.3% of DES-treated lesions (p = 0.326). No stents had evidence of intimal disruption. The percentage volume of necrotic core (16.1% [9.7, 20.3] vs. 9.7% [7.0, 16.5], p = 0.062) and dense calcium (9.5% [3.8, 13.6] vs. 2.7% [0.4, 4.9], p = 0.080) in neointima tended to be greater in BMS-treated lesions. Intra-stent VH-TCFA (BMS vs. DES 45.5% vs. 18.2%, p = 0.361) did not differ significantly.
Conclusion
At long-term follow-up beyond 3 years after implantation, the intra-stent neointimal tissue characteristics appeared similar for both BMS and DES.
1
Introduction
Coronary stenting has emerged as an effective strategy to attenuate the mechanical problems seen with balloon angioplasty. Over the last decade, compared to bare-metal stents (BMS), the introduction of drug-eluting stents (DES) has markedly reduced restenosis and has improved clinical outcomes among patients who underwent percutaneous coronary intervention . Nevertheless, late stent-related complications, such as in-stent restenosis and late stent thrombosis, remain major concerns in both stent types . Recently, the development of neoatherosclerosis within neointimal tissues has been reported as one of the mechanisms of late stent failure after BMS and DES implantation . Although this phenomenon occurs earlier in DES than in BMS, which suggests the more pronounced inflammation related to drug and durable polymer, and progresses over time , there are limited data comparing BMS with DES in neointimal tissue characteristics at the very late phase . The exact incidence of neoatherosclerosis inside BMS and DES remains unknown. The aim of this study was therefore to compare the morphological characteristics of neointimal tissue within the stents at long-term follow-up (> 3 years after implantation) using optical coherence tomography (OCT) and virtual histology intravascular ultrasound (VH-IVUS).
2
Methods
2.1
Study Population
From July 2012 to June 2013, a total of 32 nonconsecutive patients with BMS (17 lesions) or DES (22 lesions) > 3 years after implantation were prospectively enrolled in this study. Exclusion criteria were as follows: 1) Patients requires emergency catheterization; 2) Acute myocardial infarction; 3) Target stents with ≥ 70% stenosis on angiogram by visual estimation; 4) Cardiogenic shock; 5) Angiographically apparent thrombus-containing lesions; 6) Extremely tortuous or calcified vessels where we expected difficulty in advancing the intracoronary imaging catheter; and 7) Renal insufficiency with baseline serum creatinine > 1.5 mg/dL. In addition, patients who had undergone target lesion revascularization due to in-stent restenosis before the current admission were excluded in order to assess the natural healing process of the initially implanted BMS or DES. Also excluded were patients with heterogeneous overlapping stents.
Clinical demographic data and medical history were collected from patient hospital charts, reviewed by qualified personnel blinded to the objectives of the study, and entered prospectively into the database. Systemic hypertension included ≥ 1 of the following: Antihypertensive medication use, systolic blood pressure ≥ 140 mmHg, or diastolic blood pressure ≥ 90 mmHg. Dyslipidemia included ≥ 1 of the following: Treatment with medication, total cholesterol ≥ 220 mg/dL, low-density lipoprotein cholesterol ≥ 140 mg/dL, high-density lipoprotein cholesterol < 40 mg/dL, or triglycerides ≥ 150 mg/dL. Diabetes mellitus included ≥ 1 of the following: Oral hypoglycemic agent, insulin treatment, or hemoglobin A1c > 6.5%.
The study protocol was approved by our local institutional review board. Written, informed consent was obtained from all patients before cardiac catheterization. The study was conducted according to the principles of the Declaration of Helsinki.
2.2
Quantitative Coronary Angiography
Coronary angiography was performed after intracoronary nitroglycerin administration of 100 or 200 μg. Coronary angiograms were analyzed by an independent investigator blinded to OCT and IVUS findings derived from quantitative coronary angiography using the CAAS System (CAAS 5.9, Pie Medical Imaging BV, Maastricht, The Netherlands). The reference diameter, minimal lumen diameter, diameter stenosis, and lesion length were calculated. ISR was defined as a ≥ 50% diameter stenosis.
2.3
OCT Protocol and Data Analysis
After coronary angiography, to observe the targeted stent segment, OCT imaging was performed using a 5 or 6 F guiding catheter. OCT images were acquired using a non-occlusive technique with a frequency-domain system, 2.7 F OCT catheter (C7 Dragonfly, LightLab Imaging, Westford, MA, USA) at 100 frames/s and a pullback speed of 20 mm/s. OCT images were calibrated by adjusting the Z-offset before image acquisition to obtain accurate measurements. After the OCT catheter was positioned so that its imaging lens was at least 10 mm distal to the stent, contrast media iohexol (Omnipaque 350, GE Healthcare, Cork, Ireland) warmed at 37 °C was infused at a rate of 4 mL/s for the left coronary artery or 3 mL/s for the right coronary artery by mechanical power injector (ACIST CVi, ACIST Medical Systems, Eden Prairie, MN, USA). OCT images were digitally recorded for offline analysis and analyzed using proprietary software (St. Jude Console, St. Jude Medical, St. Paul, MN, USA). Analyses were done at each 0.2-mm longitudinal interval within the stented segment by independent investigators blinded to stent type and age (time interval from implantation to intracoronary imaging) and IVUS findings.
The tissue inside the stent was categorized as previously described ( Fig. 1 ) In brief, normal neointima was defined as a signal-rich band without signal attenuation; calcium-containing neointima was defined as a well-delineated, signal-poor region with sharp border; and lipid-laden neointima was defined as a signal-poor region with a diffuse border and marked signal attenuation. In stented lesions with lipid-laden neointima, percent lipid-rich plaque was calculated as follows: number of cross-sections with lipid-laden neointima divided by total number of analyzed cross-sections × 100 . The maximum lipid arc and thinnest fibrous cap thickness in lipid-laden intima were also measured. Neovascularization was defined as small vesicular or tubular structures (≤ 300 μm in diameter) and was divided into peri-strut (attached to stent struts or located within the deepest 50% of the neointimal thickness between struts and lumen) or intra-intima (located within the most shallow 50% of the neointimal thickness) according to the location . Intracoronary thrombus was defined as a mass that protrudes into the lumen; the presence or absence of intimal disruption was also evaluated. When the lipid arc was ≥ 180° and fibrous cap thickness was ≤ 65 μm, the neointima was defined as a thin-cap fibroatheroma-like neointima . Furthermore, the minimum lumen area was determined in each stented lesion.
2.4
IVUS Protocol and Data Analysis
As an optional investigation, IVUS images were acquired after OCT image acquisition using a phased-array, 20-MHz, 3.2 F IVUS catheter (Eagle Eye Platinum, Volcano Corporation, Rancho Cordova, CA, USA). Image acquisition was performed from a point at least 10 mm distal to the stent to the aorto-ostial junction at a rate of 0.5 or 1.0 mm/s with a motorized transducer pullback device. During pullback, grayscale IVUS was recorded and raw radiofrequency data were captured at the top of the R wave; reconstruction of the VH-IVUS color-coded map was performed by a data recorder (In-Vision Gold, Volcano Corporation). The grayscale IVUS and captured radiofrequency data were written onto a DVD-R for offline analysis. Using echoPlaque 4.0 software (INDEC Medical System, Santa Clara, CA, USA), quantitative grayscale IVUS measurements and VH-IVUS analysis were performed by experienced individuals who were unaware of stent type, age, and OCT findings.
Cross-sectional analysis was done at every recorded frame within the stent, thereby allowing volumetric measurement of stent, lumen, and neointimal hyperplasia (NIH) and its components. The grayscale IVUS analysis was performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies . As reported previously , the outer VH-IVUS contour was drawn just outside the stent to exclude stent struts and their artifacts, but minimize loss of NIH tissue. The inner VH-IVUS contour was at the lumen interface ( Fig. 2 A ). The components of NIH were classified into fibrotic tissue, fibro-fatty, dense calcium, and necrotic core, and reported as percentages of NIH area and volume. In-stent VH thin-cap fibroatheroma was defined as NIH > 40% of stent area, necrotic core > 20% of NIH area, and necrotic core abutting the lumen in ≥ 2 consecutive frames ( Fig. 2 B).
2.5
Statistical Analysis
All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, NC). Continuous variables were presented as median with interquartile range. Comparison of values was performed with non-parametric Mann Whitney U test. Categorical variables were presented as number (%) and compared with Fisher’s exact test or chi square test, as appropriate. Statistical significance was defined as a two-sided p value < 0.05.
2
Methods
2.1
Study Population
From July 2012 to June 2013, a total of 32 nonconsecutive patients with BMS (17 lesions) or DES (22 lesions) > 3 years after implantation were prospectively enrolled in this study. Exclusion criteria were as follows: 1) Patients requires emergency catheterization; 2) Acute myocardial infarction; 3) Target stents with ≥ 70% stenosis on angiogram by visual estimation; 4) Cardiogenic shock; 5) Angiographically apparent thrombus-containing lesions; 6) Extremely tortuous or calcified vessels where we expected difficulty in advancing the intracoronary imaging catheter; and 7) Renal insufficiency with baseline serum creatinine > 1.5 mg/dL. In addition, patients who had undergone target lesion revascularization due to in-stent restenosis before the current admission were excluded in order to assess the natural healing process of the initially implanted BMS or DES. Also excluded were patients with heterogeneous overlapping stents.
Clinical demographic data and medical history were collected from patient hospital charts, reviewed by qualified personnel blinded to the objectives of the study, and entered prospectively into the database. Systemic hypertension included ≥ 1 of the following: Antihypertensive medication use, systolic blood pressure ≥ 140 mmHg, or diastolic blood pressure ≥ 90 mmHg. Dyslipidemia included ≥ 1 of the following: Treatment with medication, total cholesterol ≥ 220 mg/dL, low-density lipoprotein cholesterol ≥ 140 mg/dL, high-density lipoprotein cholesterol < 40 mg/dL, or triglycerides ≥ 150 mg/dL. Diabetes mellitus included ≥ 1 of the following: Oral hypoglycemic agent, insulin treatment, or hemoglobin A1c > 6.5%.
The study protocol was approved by our local institutional review board. Written, informed consent was obtained from all patients before cardiac catheterization. The study was conducted according to the principles of the Declaration of Helsinki.
2.2
Quantitative Coronary Angiography
Coronary angiography was performed after intracoronary nitroglycerin administration of 100 or 200 μg. Coronary angiograms were analyzed by an independent investigator blinded to OCT and IVUS findings derived from quantitative coronary angiography using the CAAS System (CAAS 5.9, Pie Medical Imaging BV, Maastricht, The Netherlands). The reference diameter, minimal lumen diameter, diameter stenosis, and lesion length were calculated. ISR was defined as a ≥ 50% diameter stenosis.
2.3
OCT Protocol and Data Analysis
After coronary angiography, to observe the targeted stent segment, OCT imaging was performed using a 5 or 6 F guiding catheter. OCT images were acquired using a non-occlusive technique with a frequency-domain system, 2.7 F OCT catheter (C7 Dragonfly, LightLab Imaging, Westford, MA, USA) at 100 frames/s and a pullback speed of 20 mm/s. OCT images were calibrated by adjusting the Z-offset before image acquisition to obtain accurate measurements. After the OCT catheter was positioned so that its imaging lens was at least 10 mm distal to the stent, contrast media iohexol (Omnipaque 350, GE Healthcare, Cork, Ireland) warmed at 37 °C was infused at a rate of 4 mL/s for the left coronary artery or 3 mL/s for the right coronary artery by mechanical power injector (ACIST CVi, ACIST Medical Systems, Eden Prairie, MN, USA). OCT images were digitally recorded for offline analysis and analyzed using proprietary software (St. Jude Console, St. Jude Medical, St. Paul, MN, USA). Analyses were done at each 0.2-mm longitudinal interval within the stented segment by independent investigators blinded to stent type and age (time interval from implantation to intracoronary imaging) and IVUS findings.
The tissue inside the stent was categorized as previously described ( Fig. 1 ) In brief, normal neointima was defined as a signal-rich band without signal attenuation; calcium-containing neointima was defined as a well-delineated, signal-poor region with sharp border; and lipid-laden neointima was defined as a signal-poor region with a diffuse border and marked signal attenuation. In stented lesions with lipid-laden neointima, percent lipid-rich plaque was calculated as follows: number of cross-sections with lipid-laden neointima divided by total number of analyzed cross-sections × 100 . The maximum lipid arc and thinnest fibrous cap thickness in lipid-laden intima were also measured. Neovascularization was defined as small vesicular or tubular structures (≤ 300 μm in diameter) and was divided into peri-strut (attached to stent struts or located within the deepest 50% of the neointimal thickness between struts and lumen) or intra-intima (located within the most shallow 50% of the neointimal thickness) according to the location . Intracoronary thrombus was defined as a mass that protrudes into the lumen; the presence or absence of intimal disruption was also evaluated. When the lipid arc was ≥ 180° and fibrous cap thickness was ≤ 65 μm, the neointima was defined as a thin-cap fibroatheroma-like neointima . Furthermore, the minimum lumen area was determined in each stented lesion.
2.4
IVUS Protocol and Data Analysis
As an optional investigation, IVUS images were acquired after OCT image acquisition using a phased-array, 20-MHz, 3.2 F IVUS catheter (Eagle Eye Platinum, Volcano Corporation, Rancho Cordova, CA, USA). Image acquisition was performed from a point at least 10 mm distal to the stent to the aorto-ostial junction at a rate of 0.5 or 1.0 mm/s with a motorized transducer pullback device. During pullback, grayscale IVUS was recorded and raw radiofrequency data were captured at the top of the R wave; reconstruction of the VH-IVUS color-coded map was performed by a data recorder (In-Vision Gold, Volcano Corporation). The grayscale IVUS and captured radiofrequency data were written onto a DVD-R for offline analysis. Using echoPlaque 4.0 software (INDEC Medical System, Santa Clara, CA, USA), quantitative grayscale IVUS measurements and VH-IVUS analysis were performed by experienced individuals who were unaware of stent type, age, and OCT findings.
Cross-sectional analysis was done at every recorded frame within the stent, thereby allowing volumetric measurement of stent, lumen, and neointimal hyperplasia (NIH) and its components. The grayscale IVUS analysis was performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies . As reported previously , the outer VH-IVUS contour was drawn just outside the stent to exclude stent struts and their artifacts, but minimize loss of NIH tissue. The inner VH-IVUS contour was at the lumen interface ( Fig. 2 A ). The components of NIH were classified into fibrotic tissue, fibro-fatty, dense calcium, and necrotic core, and reported as percentages of NIH area and volume. In-stent VH thin-cap fibroatheroma was defined as NIH > 40% of stent area, necrotic core > 20% of NIH area, and necrotic core abutting the lumen in ≥ 2 consecutive frames ( Fig. 2 B).
2.5
Statistical Analysis
All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, NC). Continuous variables were presented as median with interquartile range. Comparison of values was performed with non-parametric Mann Whitney U test. Categorical variables were presented as number (%) and compared with Fisher’s exact test or chi square test, as appropriate. Statistical significance was defined as a two-sided p value < 0.05.
3
Results
3.1
Patient Characteristics
The study cohort included 30 patients with 36 stented lesions (BMS, n = 17; DES, n = 19) after exclusion of 3 stents from 2 patients who did not have ≥ 3 consecutive cross-sections with a mean neointimal thickness > 100 μm as identified by OCT. Table 1 shows patient characteristics. There were no significant differences with regard to age, gender, coronary risk factors, and prior history of myocardial infarction between the 2 groups. Although medical treatment on admission, including statin use and antiplatelet therapy, was similar between groups, low-density lipoprotein cholesterol levels were numerically higher in the BMS group (84.0 mg/dL [66.0, 93.0] vs. 59.5 mg/dL [44.0, 72.0], p = 0.075).
