Refat Jabara

Impact of the Definition Utilized on the Rate of Contrast-Induced Nephropathy in Percutaneous Coronary Intervention

Several definitions have been used to assess rates of contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI). Whether the definition influences observed rates of CIN is unclear. The Oxilan Registry was the first-ever prospective analysis of the efficacy and safety of ioxilan (low-osmolar and low-viscosity contrast medium), including rates of CIN assessed by multiple definitions, in PCI. From July 2006 to June 2007, consecutive patients undergoing PCI using ioxilan were enrolled. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were assessed at baseline and 3 to 5 days after PCI. CIN was defined as SCr increase >or=0.5 mg/dl, eGFR decrease >or=25%, SCr increase >or=25%, or the composite. Of 400 patients (age 62 +/- 11 years), 19% were women, 37% were diabetic, 22% were anemic, and 8% had a history of congestive heart failure. Baseline SCr was 1.12 +/- 0.3 mg/dl and 24% had an eGFR <60 ml/min. CIN rates were 3.3% (SCr increase >or=0.5 mg/dl), 7.6% (eGFR decrease >or=25%), 10.2% (SCr increase >or=25%), and 10.5% (composite). Hospitalization was prolonged in 3.4% of patients with CIN and none required dialysis. There were no deaths or severe allergic reactions. Non-ST-elevation myocardial infarction and repeat revascularization each occurred in 0.8%. In conclusion, in this unselected population undergoing PCI, CIN ranged in frequency from 3.3% to 10.5% depending on the definition used and was not associated with in-hospital mortality or substantial morbidity, such as dialysis. The wide variation in CIN and its lack of association with adverse outcomes underscore the need for a standardized, clinically relevant definition.

Novel bioabsorbable salicylate-based polymer as a drug-eluting stent coating

Background: Permanent polymers used in current drug‐eluting stents (DES) can trigger chronic inflammation and hypersensitivity reactions, which may contribute to the increased risk of late thrombosis and rebound restenosis. Therefore, optimal polymer selection and the use of completely absorbable but biocompatible polymers are expected to minimize these risks. Objectives: We sought to evaluate a novel, potentially innately anti‐inflammatory, bioabsorbable salicylate‐based polymer as a DES coating, in a clinically relevant animal model. Methods: Four types of stents were implanted in pig coronary arteries using QCA to optimize stent apposition: bare metal stents (BMS); salicylic acid/adipic acid bioabsorbable polymer‐only coated metal stents (SA/AA); biostable polymeric sirolimus‐eluting stents (Cypher™); and metal stents coated with salicylic acid/adipic acid bioabsorbable polymer containing sirolimus (SA/AA + S). The dose density of sirolimus was 8.3 μg/mm of stent length (similar to Cypher™) with in vitro studies demonstrating elution over 30 days and complete polymer degradation in 37 days. Animals underwent angiographic restudy and were terminated at 1 month for complete histopathologic and histomorphometric analyses. Results: Both SA/AA + S and Cypher™ stents had significantly lower angiographic % stenosis when compared with BMS and SA/AA polymer‐only groups (6 ± 4% and 5 ± 4% vs. 15 ± 7% and 16 ± 5%, respectively, P < 0.001). Intimal thickness was lower for SA/AA + S and Cypher™ than for BMS (0.14 ± 0.06 and 0.13 ± 0.04 mm vs. 0.23 ± 0.05 mm, respectively, P < 0.001). Histologic % area stenosis was also lower for SA/AA + S and Cypher™ when compared with BMS (22 ± 7% and 23 ± 6% vs. 33 ± 5%, respectively, P < 0.001). There was a strong trend toward reduced inflammatory response in the SA/AA and SA/AA + S when compared with BMS and Cypher™ groups (P = 0.072). Conclusions: This study shows favorable vascular compatibility and efficacy for a novel bioabsorbable salicylate‐based polymer as a DES coating, and supports further research and development of this unique class of polymer materials for applications in cardiovascular devices.

Drug-Eluting Stents: Present and Future

In-stent restenosis (ISR) caused by neointimal hyperplasia is the major drawback after percutaneous coronary intervention (PCI) for obstructive coronary disease, occurring in up to 40% of lesions. Recently, one of the most intriguing new therapies developed is drug-eluting stents (DES) that target the central phenomenon of cellular proliferation that causes ISR. The benefits of stent-based drug delivery include maximizing the local tissue levels of therapeutic agents while minimizing systemic toxicity. Numerous DES using different thin-film polymeric drug carrier have been developed and tested, those eluting either antimitotic or antimicrotublar agents such as sirolimus and paclitaxel have been shown effective in clinical trials. Two DES, the J&J Cypher (sirolimus-eluting) and the Boston Scientific Taxus (paclitaxel-eluting) stents, are commercially available in the U.S. after a number of randomized trials demonstrated reductions in late lumen loss, binary restenosis rate, and need for repeat revascularization compared with bare-metal stents (BMS). Because ISR is multifactorial, ideal agents for DES should inhibit thrombus formation, inflammation and cellular proliferation as well as enhance re-endothelialization. The next generation of DES currently undergoing preclinical studies includes new technology, new stent designs and materials, biological polymers, bioabsorbable stents coated with new drugs including stent based gene, as well as cell delivery. The current paper will review and discuss the current and future status of DES.

Abnormal Vasomotor Function of Porcine Coronary Arteries Distal to Sirolimus-Eluting Stents

OBJECTIVES This study sought to determine vasomotor functional responses of conduit coronary artery distal to bare-metal stents (BMS), polymer-only stents (POLY), and sirolimus-eluting stents (SES) in a clinically relevant animal model. BACKGROUND Drug-eluting stents (DES) reduce in-stent restenosis, and also affect neointima formation and vascular remodeling in downstream coronary segments. Whether distal artery vasomotor function is also influenced by DES has not been determined. METHODS Pigs (n = 12) received coronary stent implants, and hearts were harvested at 1 month. Arterial segments >or=15 mm distal to stents were excised and studied in an organ-chamber apparatus. Endothelium-dependent and endothelium-independent relaxation and contraction to classical agonists were measured. RESULTS The SES showed increased lumen area and reduced neointima; abnormal vasomotor function of conduit arteries distal to SES also was observed. Contraction to endothelin-1 was significantly enhanced for SES compared with both BMS and POLY. Endothelium-dependent relaxation to a maximal dose of substance P was attenuated for SES compared with both BMS and POLY (46 +/- 6% vs. 71 +/- 3% and 78 +/- 3%, respectively, p < 0.001). Endothelium-independent relaxation to sodium nitroprusside was potentiated for SES, compared with BMS and POLY (100 +/- 5% vs. 69 +/- 7% and 77 +/- 5%, respectively, p = 0.02). CONCLUSIONS Stent-based local delivery of sirolimus profoundly inhibited neointima formation but caused vasomotor dysfunction in distal conduit vessel segments. These observations suggest that distal coronary vasospasm may be more readily evoked in the presence of DES and contribute to pathophysiological sequela.

Evaluation of a Novel Slow-Release Paclitaxel-Eluting Stent With a Bioabsorbable Polymeric Surface Coating

OBJECTIVES We sought to evaluate a new second-generation drug-eluting stent (DES), comprising a slow-release biodegradable polylactide coglycolide (PLGA) polymer and low-dose paclitaxel on a thin-strut cobalt chromium stent platform, in a clinically relevant animal model. BACKGROUND Our previous work demonstrated subacute vascular toxicity and necrosis triggering late excess neointima in pig coronaries, with a moderate paclitaxel dose eluted from an erodible polymer. The use of slower-releasing absorbable polymers with lower doses of paclitaxel is expected to minimize such adverse outcomes. METHODS Three types of stents were implanted in pig coronary arteries using quantitative coronary angiography to optimize stent apposition: bare-metal stents (BMS); absorbable, slow-release polymer-coated-only stents (POLY); and absorbable polymer-based paclitaxel-eluting stents (PACL). The dose density of paclitaxel was 0.15 microg/mm(2) with in vitro studies demonstrating a gradual elution over the course of 12 to 16 weeks. Animals underwent angiographic restudy and were terminated at 1 and 3 months for complete histopathologic and histomorphometric analyses. RESULTS At 1 month, intimal thickness varied significantly according to stent type, with the lowest level for the PACL group compared with the BMS and POLY groups (0.06 +/- 0.02 mm vs. 0.17 +/- 0.07 mm, 0.17 +/- 0.08 mm, respectively, p < 0.001); histological percent area stenosis was 18 +/- 4% for PACL compared with 27 +/- 7% for BMS and 30 +/- 12% for POLY, respectively (p = 0.001). At 3 months, PACL showed similar neointimal thickness as BMS and POLY (0.09 +/- 0.05 mm vs. 0.13 +/- 0.10 mm and 0.11 +/- 0.03 mm respectively, p = 0.582). Histological percent area stenosis was 23 +/- 8% for PACL versus 23 +/- 11% for BMS and 23 +/- 2% for POLY, respectively (p = 1.000). CONCLUSIONS This study shows favorable vascular compatibility and efficacy for a novel DES that elutes paclitaxel in porcine coronary arteries. These results support the notion that slowing the release rate and lowering the dose of paclitaxel favorably influences the vascular biological response to DES implant, decreasing early toxicity and promoting stable healing while still suppressing neointima formation.

A third generation ultra-thin strut cobalt chromium stent: histopathological evaluation in porcine coronary arteries

AIMS The present study was designed to evaluate a novel third generation bare-metal stent (BMS) comprised of an ultra-thin-strut, cobalt-chromium platform with fixed geometry, uniform cell size, and superior surface finish in a porcine coronary artery model. METHODS AND RESULTS A total of 47 BMS of two types were implanted in pig coronary arteries using QCA to optimise stent apposition: a commercially available cobalt alloy thin-strut stent (91 microm) as control (Driver; n=17), and an ultra-thin-strut (65 microm) cobalt-chromium stent (Protea; n=18). Animals underwent angiographic restudy and termination one week and one month post-implant for coronary artery histology. In addition, 12 overlapping Protea stents were analysed at one month. At one week, comparable thin neointima and mild inflammation were observed in both groups. At one month, Protea demonstrated significantly lower angiographic % stenosis (2+/-1% vs. 17+/-5%, p=0.006), intimal thickness (0.11+/-0.01 mm vs. 0.23+/-0.03 mm, p=0.003), and histologic % area stenosis (19+/-2% vs. 32+/-3%, p=0.003). Mean stent strut injury scores were low and similar between groups. Angiographic % stenosis, intimal thickness, and histologic % area stenosis of overlapping Protea stents were 3+/-1%, 0.13+/-0.01 mm, and 22+/-2%, respectively, and similar to the single Protea group. Stable fibrocellular neointimal incorporation, with complete endothelialisation and minimal inflammation, were observed at one month in all stents, including overlapped Protea segments. CONCLUSIONS When compared to a commercially available cobalt alloy BMS, the new third generation Protea stent demonstrated favourable coronary arterial response with significant reduction of neointimal formation in the porcine model. Our results showed how seemingly trivial improvements to the BMS technology can result in substantial biological responses. Future, long-term investigations are needed to ascertain the clinical applicability and implications of these findings.

High Incidence of Intramural Thrombus After Overlapping Paclitaxel-Eluting Stent Implantation Angioscopic and Histopathologic Analysis in Porcine Coronary Arteries

Background—Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results—Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P=0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS (P<0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P=0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P=0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P=0.34). Conclusions—In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity.Background— Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results— Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P =0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS ( P <0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P =0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P =0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P =0.34). Conclusions— In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity. Received January 30, 2008; accepted April 24, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Low-dose paclitaxel elution by novel bioerodible sol-gel coating on stents inhibits neointima with low toxicity in porcine coronary arteries

OBJECTIVES The present study was designed to evaluate a novel bioerodible sol-gel film coated paclitaxel-eluting stent (sol-gel-PES, 3 microg per stent) in a porcine coronary artery model. BACKGROUND Although current polymer-based PES decrease restenosis, the permanent polymer and bound drug have raised concerns regarding delayed vessel healing and late stent thrombosis. METHODS Polymer-based PES (poly-PES, n = 8), sol-gel-PES (n = 15), bare metal (BMS, n = 14), and sol-gel film only (sham, n = 12), stents were implanted in 17 juvenile pigs. Animals were terminated 28 days post-implant for angiographic restudy and complete histopathologic and histomorphometric analyses. RESULTS Angiographic late loss was equally reduced for both poly-PES and sol-gel-PES (0.51 +/- 0.64 and 0.61 +/- 0.52 mm, respectively) compared to both BMS and sham (0.98 +/- 0.74 and 1.25 +/- 0.72 mm, p < 0.05). Similarly beneficial results were observed for histomorphometric parameters of neointimal thickness and area, yielding reductions of in-stent stenosis by 43% and 48% for poly-PES, as well as 31% and 37% for sol-gel-PES, vs. BMS and sham, respectively (p < 0.05). Re-endothelialization was complete in all groups. Although the inflammatory cell infiltration and intramural thrombus scores were no different between poly- and sol-gel-PES, medial necrosis was increased for poly-PES (p < 0.05 vs. all others). CONCLUSIONS A novel bioerodible sol-gel film coated with low-dose paclitaxel demonstrates less toxicity to the coronary tunica media, while retaining effective inhibition of neointimal formation at 28 days.

Clinical and Angiographic Features of Small Vessel Stenting in the Drug-Eluting Stent Era

This study was designed to investigate the clinical and angiographic features and procedural outcomes of small‐vessel stenting in a real‐world experience during the transition era between drug‐eluting stents (DES) and bare‐metal stents (BMS).

High Incidence of Intramural Thrombus After Overlapping Paclitaxel-Eluting Stent ImplantationCLINICAL PERSPECTIVE

Background—Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results—Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P=0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS (P<0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P=0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P=0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P=0.34). Conclusions—In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity.Background— Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results— Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P =0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS ( P <0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P =0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P =0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P =0.34). Conclusions— In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity. Received January 30, 2008; accepted April 24, 2008. # CLINICAL PERSPECTIVE {#article-title-2}