Two-year longitudinal evaluation of a second-generation thin-strut sirolimus-eluting bioresorbable coronary scaffold with hybrid cell design in porcine coronary arteries.

BACKGROUND: The first commercially available bioresorbable scaffold (BRS) had a strut thickness of 156 microns. As such, it had the potential for delivery challenges and higher thrombogenicity. The aim herein, is to evaluate biomechanical performance, pharmacokinetics and vascular healing of a novel thin strut (100 µm) sirolimus eluting BRS (MeRes-100, Meril Life Sciences, Gujarat, India) against the once clinically used BRS (Absorb BVS, Abbott, Santa Clara, CA) in porcine coronary arteries. METHODS: Following device implantation, angiographic and optical coherence tomography (OCT) evaluation were performed at 45, 90, 180 days, 1 year and 2 years. Histological evaluation was per-formed at 30, 90 and 180 days. RESULTS: At 2 years, both lumen (MeRes-100 7.07 ± 1.82 mm² vs. Absorb BVS 7.57 ± 1.39 mm2, p = NS) and scaffold areas (MeRes-100 9.73 ± 1.80 mm² vs. Absorb BVS 9.67 ± 1.25 mm², p = NS) were comparable between tested and control scaffolds. Also, the late lumen area gain at 2 years was similar in both groups tested (MeRes-100 1.03 ± 1.98 mm² vs. Absorb BVS 0.85 ± 1.56 mm², p = NS). Histologic examination up to 6 months showed comparable healing and inflammation profiles for both devices. CONCLUSIONS: The novel sirolimus-eluting BRS with thinner struts and hybrid cell design showed similar biomechanical durability and equivalent inhibition of neointimal proliferation when compared to the first-ever Absorb BVS up to 2 years in normal porcine coronary arteries.

Peri-strut low-intensity areas in optical coherence tomography correlate with peri-strut inflammation and neointimal proliferation: an in-vivo correlation study in the familial hypercholesterolemic coronary swine model of in-stent restenosis.

BACKGROUND: Peri-strut low-intensity area (PLI) is a common imaging finding during the evaluation of in-stent neointima using optical coherence tomography (OCT). We aimed to determine the biological significance of PLI by comparing in-vivo OCT images with the corresponding histological sections obtained from the familial hypercholesterolemic swine model of coronary stenosis. METHODS: A total of 26 coronary vessels of nine familial hypercholesterolemic swine were injured with 30% balloon overstretch and then immediately followed by everolimus eluting or bare metal stent placement at 20% overstretch. At 30 days, all stented vessels were subjected to in-vivo OCT analysis and were harvested for histological evaluation. For OCT analysis, stent cross-sections (three per stent) were categorized into presence (PLI+) or absence (PLI-) of PLI. In histology, inflammation and fibrin deposition were scored semiquantitatively from 0 (none) to 3 (severe). RESULTS: PLI was found in 64.9% of stent sections. Peri-strut inflammation was more frequently observed in OCT sections PLI (+) compared with PLI (-) (56.0 vs. 7.4%, P=0.01). In contrast, peri-strut fibrin deposits was similar in both groups (PLI+=58.0% vs. PLI-=59.3%, P=0.94). Histological neointimal thickness was significantly higher in PLI (+) sections (mean±SE: 0.68±0.06 vs. 0.34±0.02 mm; P<0.01), yielding a higher percent area stenosis compared with PLI (-) (mean±SE: 59.0±4.4 vs. 34.1±2.2%, P<0.01). The PLI diagnostic sensitivity and specificity for inflammation were 80 and 76.1%, respectively (>56% PLI, area under the curve=0.86, P<0.01), whereas for fibrin deposition, the sensitivity and specificity were 42.2 and 76.1%, respectively (area under the curve=0.56, P=NS). Area under the receiver operating characteristic curve was significantly higher for identifying inflammation than fibrin (0.86 vs. 0.56, P<0.01). The severity of PLI correlated with the neointimal thickness when assessed by OCT (R=0.79, P<0.001). CONCLUSION: The presence of PLI in OCT correlates with neointimal thickness and appears to have a diagnostic value in the recognition of peri-strut inflammation, therefore possibly serving as a surrogate for in-vivo assessment of stent efficacy.

Tissue uptake, distribution, and healing response after delivery of paclitaxel via second-generation iopromide-based balloon coating: a comparison with the first-generation technology in the iliofemoral porcine model.

OBJECTIVES: This study sought to evaluate vascular drug uptake, distribution and response of second-generation paclitaxel coated balloon (PCB) (Cotavance, MEDRAD Interventional, Indianola, Pennsylvania) and compare it with first-generation technology, containing identical excipient and drug concentration. BACKGROUND: Original PCB technologies displayed a heterogeneous deposition of crystalline paclitaxel-iopromide inside the balloon folds, whereas second-generation PCBs consisted of more homogeneous, circumferential coatings. METHODS: Paclitaxel tissue uptake was assessed in 20 iliofemoral arteries of a domestic swine. Vascular healing response was assessed in the familial hypercholesterolemic model of iliofemoral in-stent restenosis. Three weeks after bare-metal stent implantation, vascular segments were randomly revascularized with first-generation PCBs (n = 6), second-generation PCBs (n = 6), or plain balloon angioplasty (PBA) (n = 6). At 28 days, angiographic and histological evaluation was performed in all treated segments. RESULTS: One-hour paclitaxel tissue uptake was 42% higher in the second-generation PCBs (p = 0.03) and resulted in more homogeneous segment-to-segment distribution compared with first-generation PCBs. Both angiography (percentage of diameter stenosis: second-generation 11.5 ± 11% vs. first-generation 21.9 ± 11% vs. PBA 46.5 ± 10%; p < 0.01) and histology (percentage of area stenosis: second-generation 50.5 ± 7% vs. first-generation 54.8 ± 18% vs. PBA 78.2 ± 9%; p < 0.01) showed a decrease in neointimal proliferation in both PCB groups. Histological variance of the percentage of area stenosis was lower in second-generation compared with first-generation PCBs (51.7 vs. 328.3; p = 0.05). The presence of peristrut fibrin deposits (0.5 vs. 2.4; p < 0.01) and medial smooth muscle cell loss (0 vs. 1.7; p < 0.01) were lower in the second-generation compared with first-generation PCBs. CONCLUSIONS: In the experimental setting, second-generation PCB showed a comparable efficacy profile and more favorable vascular healing response when compared to first-generation PCB. The clinical implications of these findings require further investigation.

Stent healing response following delivery of paclitaxel via durable polymeric matrix versus iopromide-based balloon coating in the familial hypercholesterolaemic swine model of coronary injury.

AIMS: The routine use of paclitaxel-coated balloons (PCB) in combination with bare metal stents (BMS) in de novo coronary lesions has been questioned. In this study, we aimed to compare the vascular response of BMS implanted using a second-generation PCB (BMS+PCB) with the TAXUS stent (PES) and a BMS control (BMS) in the familial hypercholesterolaemic swine (FHS) model of coronary injury. METHODS AND RESULTS: A total of 17 stents (PES=6, BMS+PCB=6, and BMS=5) were implanted in the coronary territory of 10 FHS using a 20% overstretch injury ratio. Imaging evaluation (QCA and IVUS) was conducted in all animals at baseline and 28 days following stent implantation. Following terminal imaging all animals were euthanised and stented coronary segments harvested for histological evaluation. At 28 days, the lowest degree of percentage diameter stenosis by QCA was achieved by the PES (2.9 ± 9%) followed by the BMS+PCB (9.5 ± 16.4%) and the BMS group (25.65 ± 18.7%, p<0.05). In histology, percentage area of stenosis (BMS+PCB=29.6 ± 6.4% vs. PES=21.5 ± 3.3% vs. BMS=55.2 ± 12.9%; p<0.01) and neointimal thickness (BMS+PCB=0.26 ± 0.1 mm vs. PES=0.21 ± 0.1 mm vs. BMS=0.59 ± 0.2 mm; p<0.01) were significantly reduced in both paclitaxel groups in comparison to BMS controls. Both BMS+PCB and BMS groups had higher endothelialisation scores (PES=1.50 ± 0.9 vs. BMS+PCB=2.73 ± 0.4 vs. BMS=3.00; p<0.05) and lower peri-strut inflammatory scores (PES=0.83 ± 0.4 vs. BMS+PCB=0.20 ± 0.2 vs. BMS=0.43 ± 0.6, p<0.05) when compared to PES. Neointima maturity (PCB+BMS: 2.00 [2-2.4] vs. PES: 1.00 [0.3-1] vs. BMS: 3.00, p<0.05) and fibrin deposition (PCB+BMS: 1.40 ± 0.3 vs. PES: 2.17 ± 0.7 vs. BMS: 0.27 ± 0.3, p<0.05) scores in PCB+BMS appeared to fall between the PES and the BMS ranges. CONCLUSIONS: In the FHS coronary injury model, BMS implantation using a PCB yields a degree of neointimal inhibition comparable to the PES. The BMS+PCB combination presented lower degrees of inflammation and fibrin deposition; however, signs of delayed healing were still present.

Evaluation of efficacy and dose response of different paclitaxel-coated balloon formulations in a novel swine model of iliofemoral in-stent restenosis.

OBJECTIVES: The authors aimed to validate a novel iliofemoral in-stent restenosis (ISR) model for the efficacy evaluation of paclitaxel-coated balloons (PCB) using the familial hypercholesterolemic swine (FHS). BACKGROUND: Most of the validation work regarding PCB technologies has been performed in the coronary territory of juvenile domestic swine. Although invaluable for safety evaluation, this model is not suited for the evaluation of the efficacy of peripheral PCB technologies. METHODS: Twenty-four iliofemoral segments in 12 FHS underwent balloon injury and self-expanding stent placement. After 21 days, the resulting ISR lesions were treated with either 1 µg/mm(2) dose (n = 8), or 3 µg/mm(2) dose (n = 8) PCB (Cotavance, Bayer Pharma AG/MEDRAD, Indianola, Pennsylvania), or with an identical uncoated control balloon (n = 8). RESULTS: At termination (28 days after treatment), the percent diameter stenosis by quantitative vascular analysis in the control group was higher (31.2 ± 13.7%) compared with the 1 µg/mm(2) (19.3 ± 14.0%, 38% reduction) and 3 µg/mm(2) (8.6 ± 10.7%, 72% reduction) PCB groups. Intravascular ultrasound analysis showed 36% (1 µg/mm(2) dose, p = 0.04) and 55% (3 µg/mm(2) dose, p < 0.01) reductions in neointimal volume stenosis. In the histological analysis, the control group showed the highest degree of percent area stenosis (65 ± 14.3%). The reductions in percent area stenosis was 13.2% (p = 0.5) and 26% (p = 0.04) in the 1 µg/mm(2) and 3 µg/mm(2) dose groups, respectively. CONCLUSIONS: The FHS model of iliofemoral ISR demonstrated a dose-dependent effect on the inhibition of neointimal proliferation of a clinically validated PCB technology. This model represents a positive step toward the efficacy evaluation of PCB in the peripheral vascular territory.

Paclitaxel-iopromide coated balloon followed by "bail-out" bare metal stent in porcine iliofemoral arteries: first report on biological effects in peripheral circulation.

AIMS: Despite recent abundance of data on drug-coated balloon technology, the biological effects of paclitaxel coated balloon (PCB) treatment followed by bare metal stent (BMS) implantation in peripheral arteries (simulating bail-out stenting, a common clinical scenario), have not been published. METHODS AND RESULTS: PCB technology containing a paclitaxel-iopromide coating and identical iopromide-coated controls (without paclitaxel) were used in 16 porcine ilio-femoral arteries. The biological effects of inflating one (PCBx1) or two sequential (PCBx2) paclitaxel coated balloons before BMS implantation were compared to the single application of a control balloon (CCBx1; contrast coated balloons). At 30 days PCBx2 displayed significantly reduced late lumen loss by angiography (58% reduction vs. CCBx1; p=0.04) and neointimal area by histomorphometry (35% reduction vs. CCBx1 and 30% vs. PCBx1; p=0.02). Similarly, percent area stenosis in the PCBx2 group was reduced by 45% as compared to CCBx1 and PCBx1 (p=0.04). At this time, all parameters of vessel wall healing (including injury score, inflammation, and endothelialisation) following drug coated balloon treatment were comparable to the control group. CONCLUSIONS: Paclitaxel delivery to porcine ilio-femorals using PCB followed by BMS implantation effectively decreased neointimal proliferation. More extensive and prolonged proliferative response of the vessel after stenting (necessitating higher drug dose) could potentially explain the undetectable effect of PEBx1 relative to CCBx1 in this pilot study. Histological analysis confirmed the safety and biocompatibility of PCB technology.

Coronary bare metal stent implantation in homozygous LDL receptor deficient swine induces a neointimal formation pattern similar to humans.

INTRODUCTION: To date, most of all new developments in stent technologies are tested in normal animals. Although invaluable in the evaluation of device safety, the juvenile domestic swine (DS) do not follow the biological healing response occurring in humans following coronary stent implantation. By using a novel swine breed afflicted with familial hypercholesterolemia (FHS), we aimed to analyse the vascular response occurring following bare metal stent (BMS) implantation by comparing in vivo endovascular imaging and histological data. METHODS: A total of 26 swine were included in this study (12 FHS and 14 DS). Sixty eight BMS (FHS=28 versus DS=40) were implanted using a 10% overstretch ratio. Imaging evaluation (IVUS and OCT) was conducted in all animals at 30 (n=14) or 90 (n=12) days following stent implantation. After imaging, the stented coronary segments were harvested for histological evaluation. RESULTS: At 30 days, the degree of neointimal formation analysed by OCT (%AS=DS 21.9 ± 10% versus FHS 25.4 ± 12%; p=0.18) and histology (DS 24.6 ± 10% versus FHS 23.58 ± 10%; p=0.8) was similar between both animal groups. At 90 days, the degree of neointimal formation in the DS group decreased in all analysed variables (-40% in IVUS neointimal volume, -57% in OCT %AS, and -30% in %AS by histology) compared to the progression of neointimal formation observed in the FHS group (+29% in IVUS neointimal volume, +27% in OCT %AS and +43% in %AS by histology). CONCLUSION: The pattern of neointimal formation following BMS implantation in the FHS follows a progressive course that does not occur in the DS. Therefore, by providing a progressive neointimal biological response to BMS implantation, the FHS could serve as an ideal efficacy model for the validation of drug eluting stent technologies.

In vivo intravascular ultrasound analysis of the absorption rate of the Angio-Seal vascular closure device in the porcine femoral artery.

AIMS: Device-based arterial closure is currently used to achieve haemostasis following percutaneous intervention. Little is known about the in vivo patterns of device absorption. We aimed to characterise the absorption dynamics following implantation of the Angio-Seal VIP closure device (AVCD) (St. Jude Medical, St. Paul, MN, USA) by using serial intravascular ultrasound (IVUS) and histology. METHODS AND RESULTS: Eleven AVCD were implanted following 6 Fr femoral arterial sheath in six pigs. Using carotid access, angiograms and IVUS were performed at baseline, 3, 5, 7, 14, 30 and 42 days following deployment. At termination, arteries were processed for histology at 14 (n=3), 30(n=4) and 42 days (n=4). By IVUS, following implantation the intravascular component (IC) area remained unchanged up to 14 days and decreased by 50% at 30 days and 95% by 42 days. By histology, there was a progressive decline in the IC area at 14 days and decrease by 30% at 30 days and 77% by 42 days. Histology demonstrated almost complete absorption of the IC and no signs of severe chronic granulomatous inflammation. CONCLUSIONS: IVUS serial imaging demonstrated almost complete absorption of the IC by 42 days in normal porcine femoral arteries. There was no evidence of severe chronic granulomatous vascular inflammation demonstrated by histology.