Seguridad y eficacia de nuevos modelos de stents liberadores de sirolimus con polímero biodegradable en el modelo preclínico / Safety and efficacy of new biodegradable polymer-based sirolimus-eluting stents in a preclinical model

Introducción y objetivos: Los nuevos stents farmacoactivos (SFA), diseñados para solventar las limitaciones de los existentes, han de someterse inicialmente al análisis preclínico. El objetivo es analizar la eficacia y la seguridad de nuevos SFA con polímero biodegradable en comparación con stents convencionales (SC) y SFA comercializados en el modelo de arteria coronaria sana porcina. Métodos: Se implantaron aleatoriamente 101 stents (SC y stents liberadores de sirolimus con polímero biodegradable: 3 formulaciones test [BD1, BD2 y BD3], Orsiro, Biomime y Biomatrix) en las arterias coronarias de 34 cerdos domésticos. Se completó estudio angiográfico e histomorfométrico al mes (n = 83) y a los 3 meses (n = 18). Resultados: Los stents se implantaron en proporción stent/arteria de 1,31 ± 0,21, sin diferencias entre grupos. Al mes, los nuevos stents (BD1, BD2 y BD3) mostraron menos pérdida tardía y reestenosis angiográfica, así como menor área neointimal y reestenosis histológica (p < 0,0005) que los SC. No se observaron diferencias significativas entre los nuevos stents y los SC en endotelización, daño vascular o inflamación; solo se encontró mayor persistencia de fibrina en los nuevos (p = 0,0006). A los 3 meses, todas estas diferencias desaparecieron, excepto una menor área neointimal con el nuevo stent BD1 (p = 0,027). No hubo diferencias en ningún parámetro al mes ni a los 3 meses entre los nuevos stents y los comercializados. Conclusiones: En este modelo preclínico, los nuevos SFA con polímero biodegradable estudiados presentan menos reestenosis que los SC, sin diferencias significativas en seguridad y eficacia respecto a SFA comercializados (AU)

Introduction and objectives New drug-eluting stents (DES) designed to overcome the limitations of existing devices should initially be tested in preclinical studies. Our objective was to analyze the safety and efficacy of new biodegradable polymer-based DES compared with bare-metal stents (BMS) and commercially available DES in a model of normal porcine coronary arteries. Methods: We randomly implanted 101 stents (BMS and biodegradable polymer-based sirolimus-eluting stents: 3 test stent iterations [BD1, BD2, and BD3], Orsiro, Biomime and Biomatrix) in the coronary arteries of 34 domestic pigs. Angiographic and histomorphometric studies were conducted 1 month (n = 83) and 3 months (n = 18) later. Results: The stents were implanted at a stent/artery ratio of 1.31 ± 0.21, with no significant differences between groups. At 1 month, the new test stents (BD1, BD2 and BD3) showed less late loss and angiographic restenosis, as well as lower histologic restenosis and neointimal area (P < .0005), than the BMS. There were no differences in endothelialization, vascular injury, or inflammation between the new test stents and BMS, although the new stents showed higher fibrin deposition (P = .0006). At 3 months, all these differences disappeared, except for a lower neointimal area with the new BD1 stent (P = .027). No differences at any time point were observed between the new test stents and commercially available controls. Conclusions: In this preclinical model, the new biodegradable polymer-based DES studied showed less restenosis than BMS and no significant differences in safety or efficacy vs commercially available DES (AU)

Safety and Efficacy of New Biodegradable Polymer-based Sirolimus-Eluting Stents in a Preclinical Model.

INTRODUCTION AND OBJECTIVES: New drug-eluting stents (DES) designed to overcome the limitations of existing devices should initially be tested in preclinical studies. Our objective was to analyze the safety and efficacy of new biodegradable polymer-based DES compared with bare-metal stents (BMS) and commercially available DES in a model of normal porcine coronary arteries. METHODS: We randomly implanted 101 stents (BMS and biodegradable polymer-based sirolimus-eluting stents: 3 test stent iterations [BD1, BD2, and BD3], Orsiro, Biomime and Biomatrix) in the coronary arteries of 34 domestic pigs. Angiographic and histomorphometric studies were conducted 1 month (n = 83) and 3 months (n = 18) later. RESULTS: The stents were implanted at a stent/artery ratio of 1.31 ± 0.21, with no significant differences between groups. At 1 month, the new test stents (BD1, BD2 and BD3) showed less late loss and angiographic restenosis, as well as lower histologic restenosis and neointimal area (P < .0005), than the BMS. There were no differences in endothelialization, vascular injury, or inflammation between the new test stents and BMS, although the new stents showed higher fibrin deposition (P = .0006). At 3 months, all these differences disappeared, except for a lower neointimal area with the new BD1 stent (P = .027). No differences at any time point were observed between the new test stents and commercially available controls. CONCLUSIONS: In this preclinical model, the new biodegradable polymer-based DES studied showed less restenosis than BMS and no significant differences in safety or efficacy vs commercially available DES.

Seguridad y eficacia de nuevos modelos de stents liberadores de sirolimus en el modelo preclínico / Safety and efficacy of new sirolimus-eluting stent models in a preclinical study

Introducción y objetivos: En el proceso de mejora de los polímeros, las plataformas y los sistemas de liberación de fármacos en los nuevos diseños de stents farmacoactivos, el análisis preclínico inicial es obligatorio. El objetivo es analizar la eficacia y la seguridad de nuevos modelos de stentsfarmacoactivos en comparación con un stent convencional y stents farmacoactivos comercializados en el modelo experimental de arteria coronaria sana porcina. Métodos: Se implantaron aleatoriamente 60 stents (stent convencional, nuevos stents liberadores de sirolimus: stents liberadores de fármaco 1, 2 y 3; Cypher® y Xience®) en las arterias coronarias de 20 cerdos domésticos raza Large White. Se realizó estudio angiográfico e histomorfométrico a los 28 días. Resultados: Los stents se implantaron en proporción stent/arteria de 1,34 ± 0,15, sin diferencias significativas entre grupos. Los nuevos stents mostraron menos pérdida tardía y restenosis angiográfica que los convencionales (p = 0,006 y p < 0,001 respectivamente). Todas las nuevas plataformas presentaron menos área neointimal y restenosis histológica que losstents convencionales (p < 0,001 para cada variable), sin diferencias con los farmacoactivos comercializados. En cuanto a la seguridad, todos los stents farmacoactivos mostraron menos endotelización que los convencionales, salvo el stent liberador de fármaco 3 (p = 0,084). Asimismo, la inflamación observada fue menor con el stent liberador de fármaco 3 que con los demás. Conclusiones: Las nuevas plataformas de stents farmacoactivos estudiadas se asocian con menos restenosis que los convencionales, sin diferencias significativas en seguridad y eficacia respecto a los stents farmacoactivos comercializados (AU)

Introduction and objectives: Initial preclinical studies are required during the process of improving polymers, platforms, and drug-eluting systems for new coronary stent designs. Our objective was to analyze the efficacy and safety of new drug-eluting stent models compared with a conventional stent and commercialized drug-eluting stents in an experimental model with healthy porcine coronary arteries. Methods: Sixty stents (conventional stent, new sirolimus-eluting stents: drug-eluting stents 1, 2 and 3; Cypher® and Xience®) were randomly placed in the coronary arteries of 20 Large White domestic pigs. Angiographic and histomorphometric studies were done 28 days later. Results: The stents were implanted at a stent/artery ratio of 1.34 ± 0.15, with no significant differences between groups. The new stents showed less late loss and angiographic restenosis than conventional stents (P = .006 and P < .001, respectively). Histologically, restenosis and neointimal area were lower with all the new platforms than with the conventional stents (P < .001 for each variable), and no differences were found vs the drug-eluting stents on the market. Safety data showed that endothelialization was lower with drug-eluting stents than with conventional stents, except for drug-eluting stent 3 (P = .084). Likewise, inflammation was lower with drug-eluting stent 3 than with other stents. Conclusions: The new drug-eluting stent platforms studied are associated with less restenosis than conventional stents and showed no significant differences in safety or efficacy vs commercialized drug-eluting stents (AU)

Safety and Efficacy of New Sirolimus-eluting Stent Models in a Preclinical Study.

INTRODUCTION AND OBJECTIVES: Initial preclinical studies are required during the process of improving polymers, platforms, and drug-eluting systems for new coronary stent designs. Our objective was to analyze the efficacy and safety of new drug-eluting stent models compared with a conventional stent and commercialized drug-eluting stents in an experimental model with healthy porcine coronary arteries. METHODS: Sixty stents (conventional stent, new sirolimus-eluting stents: drug-eluting stents 1, 2 and 3; Cypher(®) and Xience(®)) were randomly placed in the coronary arteries of 20 Large White domestic pigs. Angiographic and histomorphometric studies were done 28 days later. RESULTS: The stents were implanted at a stent/artery ratio of 1.34±0.15, with no significant differences between groups. The new stents showed less late loss and angiographic restenosis than conventional stents (P=.006 and P<.001, respectively). Histologically, restenosis and neointimal area were lower with all the new platforms than with the conventional stents (P<.001 for each variable), and no differences were found vs the drug-eluting stents on the market. Safety data showed that endothelialization was lower with drug-eluting stents than with conventional stents, except for drug-eluting stent 3 (P=.084). Likewise, inflammation was lower with drug-eluting stent 3 than with other stents. CONCLUSIONS: The new drug-eluting stent platforms studied are associated with less restenosis than conventional stents and showed no significant differences in safety or efficacy vs commercialized drug-eluting stents.

Análisis de la eficacia y la seguridad de distintos balones liberadores de paclitaxel en un modelo animal / Safety and Efficacy of Different Paclitaxel-eluting Balloons in a Porcine Model

Introducción y objetivos Los balones liberadores de paclitaxel tienen demostrada eficacia en el tratamiento y la prevención de la restenosis. Sin embargo, no todos los dispositivos comercializados son igualmente efectivos; por ello es importante comparar los resultados en un modelo preclínico. Nuestro objetivo es analizar la seguridad y la eficacia preclínicas de distintos dispositivos. Métodos En 17 cerdos domésticos (25 ± 3 kg) se implantaron 51 stents metálicos (Architect®, iVascular), uno en cada rama coronaria principal, y se sobredilataron con distintos balones de control (n = 10) o liberadores de paclitaxel: balón liberador de paclitaxel 1 (iVascular) (n = 15); balón liberador de paclitaxel 2 (iVascular) (n = 16) e In. Pact Falcon® (Medtronic) (n = 10). Tras 28 días, se analizaron los resultados de restenosis (angiografía e histomorfometría) y de reparación vascular: daño vascular, endotelización, persistencia de fibrina e inflamación. Resultados Los distintos balones liberadores de paclitaxel mostraron valores similares de estenosis en el seguimiento significativamente menores que los controles: angiografía, el 9 ± 12% frente al 34 ± 18% (p < 0,0001); histomorfometría, el 22 ± 8% frente al 51 ± 18% (p < 0,0001). Los grados de daño vascular (0,6 ± 0,5) e inflamación (0,8 ± 0,3) fueron bajos, sin diferencias entre los grupos. Los marcadores del efecto farmacológico fueron significativamente distintos entre los dispositivos liberadores de paclitaxel (sin diferencias entre ellos) y los controles: superficie endotelizada, el 87 ± 10% frente al 99 ± 2% (p = 0,0007); grado de fibrina, 2,1 ± 0,7 frente a 0,4 ± 0,5 (p < 0,0001). No hubo diferencias entre los distintos balones liberadores de paclitaxel. Conclusiones: En este modelo preclínico, los balones liberadores de paclitaxel analizados mostraron una reducción significativa de la restenosis. Aunque no se observaron datos de daño vascular o inflamación persistentes, sí se apreciaron los efectos de la acción farmacológica en forma de endotelización retrasada y acumulación de fibrina

Introduction and objectives Paclitaxel-eluting balloons have shown high antiproliferative efficacy in the treatment and prevention of restenosis. Nevertheless, not all available devices are equally effective, which makes it interesting to compare results in a preclinical model. Our objective was to assess the preclinical efficacy and safety of different devices. Methods We implanted 51 metallic stents (Architect®, iVascular) in 17 domestic swine (mean, 25 [3] kg), inserting 1 stent per major coronary artery. Stent postdilatation was performed with different control balloons (n = 10) or paclitaxel-eluting balloons: paclitaxel-eluting balloon 1 (iVascular) (n = 15); paclitaxel-eluting balloon 2 (iVascular) (n = 16) and In.Pact Falcon®(Medtronic) (n = 10). The restenosis rate (using angiography and histomorphometry) and vascular healing parameters (balloon-related vascular injury score, endothelialization rate, and fibrin and inflammation scores) were analyzed at 28 days. Results The distinct paclitaxel-eluting balloons showed a similar degree of stenosis at follow-up, which was significantly lower than that in the control group: diameter stenosis was 9% (12%) vs 34% (18%) by angiography (P < .0001) and was 22% (8%) vs 51% (18%) by histomorphometry (P < .0001). Scores for vascular injury (mean, 0.6 [0.5]) and inflammation (mean, 0.8 [0.3]) were uniformly low across all groups. Drug effect markers differed significantly between the paclitaxel-eluting balloons and control groups, with lower endothelialization rates (87% [10%] vs 99% [2%]; P = .0007) and higher fibrin scores (2.1 [0.7] vs 0.4 [0.5]; P < .0001) in the paclitaxel-eluting balloons groups. There were no differences between the different paclitaxel-eluting balloons. Conclusions: In this preclinical model, the paclitaxel-eluting balloons studied significantly reduced in-stent restenosis compared with the control balloons. Although there were no findings of persistent vascular injury or inflammation, delayed endothelialization and fibrin aggregate suggest a drug deposition response

Safety and efficacy of different paclitaxel-eluting balloons in a porcine model.

INTRODUCTION AND OBJECTIVES: Paclitaxel-eluting balloons have shown high antiproliferative efficacy in the treatment and prevention of restenosis. Nevertheless, not all available devices are equally effective, which makes it interesting to compare results in a preclinical model. Our objective was to assess the preclinical efficacy and safety of different devices. METHODS: We implanted 51 metallic stents (Architect(®), iVascular) in 17 domestic swine (mean, 25 [3] kg), inserting 1 stent per major coronary artery. Stent postdilatation was performed with different control balloons (n=10) or paclitaxel-eluting balloons: paclitaxel-eluting balloon 1 (iVascular) (n=15); paclitaxel-eluting balloon 2 (iVascular) (n=16) and In.Pact Falcon(®) (Medtronic) (n=10). The restenosis rate (using angiography and histomorphometry) and vascular healing parameters (balloon-related vascular injury score, endothelialization rate, and fibrin and inflammation scores) were analyzed at 28 days. RESULTS: The distinct paclitaxel-eluting balloons showed a similar degree of stenosis at follow-up, which was significantly lower than that in the control group: diameter stenosis was 9% (12%) vs 34% (18%) by angiography (P<.0001) and was 22% (8%) vs 51% (18%) by histomorphometry (P<.0001). Scores for vascular injury (mean, 0.6 [0.5]) and inflammation (mean, 0.8 [0.3]) were uniformly low across all groups. Drug effect markers differed significantly between the paclitaxel-eluting balloons and control groups, with lower endothelialization rates (87% [10%] vs 99% [2%]; P=.0007) and higher fibrin scores (2.1 [0.7] vs 0.4 [0.5]; P<.0001) in the paclitaxel-eluting balloons groups. There were no differences between the different paclitaxel-eluting balloons. CONCLUSIONS: In this preclinical model, the paclitaxel-eluting balloons studied significantly reduced in-stent restenosis compared with the control balloons. Although there were no findings of persistent vascular injury or inflammation, delayed endothelialization and fibrin aggregate suggest a drug deposition response.