Histopathological comparison of biodegradable polymer and permanent polymer based sirolimus eluting stents in a porcine model of coronary stent implantation

Summary

Biodegradable stent coatings were recently introduced as a potential solution to overcome sustained inflammatory responses observed with permanent polymer-based drug-eluting stents. In a preliminary study, selected biodegradable or permanent polymer-based sirolimus-eluting stent (SES) formulations were screened for effectiveness in comparison to bare metal stents (BMS) at 28 days. Subsequently, the most favourable SES formulation was compared to commercially available SES (Cypher^TM) at 28,90 and 180 days to investigate the histopathologic response as well as tissue, blood and organ pharmacokinetics. Overlapping SES implantation was conducted to evaluate vascular healing at 28 days in this particular setting. SES with biodegradable poly (L-lactide) polymer (PLLA) or poly(lactide-co-glycolide) showed the most favourable outcome with regards to reductions in neointimal area in comparison to BMS at 28 days. The PLLA SES showed a similar reduction in neointimal area compared to Cypher^TM at 28 days, with significant greater reductions at 90 and 180 days (1.7 ± 0.7 mm² vs. 3.1 ± 1.5 mm², p=0.03 and 1.8 ± 1.2 mm² vs. 3.0 ± 1.5 mm², p=0.01, respectively). Sirolimus vascular tissue concentrations were detectable up to 90 days following implantation. Overlapping stented segments showed favourable histopathologic results with respect to fibrin deposition and endothelialisation at 28 days. In conclusion, the use of PLLA as drugeluting matrix resulted in mild inflammatory responses in the presence of effective sirolimus tissue concentrations. The greater efficacy observed at long-term follow-up in PLLA SES compared to Cypher^TM may be a multifactorial result of stent design, polymer biocompatibility and improved release kinetics.

Keywords

Porcine model - sirolimus-eluting stents - restenosis

^* These authors contributed equally to this manuscript.

• References

• 1 Joner M, Finn AV, Farb A. et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48: 193-202.
• 2 Moses JW, Leon MB, Popma JJ. et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349: 1315-1323.
• 3 Stone GW, Ellis SG, Cox DA. et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004; 350: 221-231.
• 4 Virmani R, Kolodgie FD, Farb A. Drug-eluting stents: are they really safe?. Am Heart Hosp J 2004; 2: 85-88.
• 5 Akin I, Schneider H, Ince H. et al. Second- and third-generation drug-eluting coronary stents: progress and safety. Herz 2011; 36: 190-196.
• 6 de Waha A, Dibra A, Byrne RA. et al. Everolimus-eluting versus sirolimus-eluting stents: a meta-analysis of randomized trials. Circ Cardiovasc Interv 2011; 4: 371-377.
• 7 Stone GW, Rizvi A, Newman W. et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010; 362: 1663-1674.
• 8 Waseda K, Miyazawa A, Ako J. et al. Intravascular ultrasound results from the ENDEAVOR IV trial: randomized comparison between zotarolimus- and paclitaxel-eluting stents in patients with coronary artery disease. JACC Cardiovasc Interv 2009; 2: 779-784.
• 9 Byrne RA, Joner M, Kastrati A. Polymer coatings and delayed arterial healing following drug-eluting stent implantation. Minerva Cardioangiol 2009; 57: 567-584.
• 10 Nebeker JR, Virmani R, Bennett CL. et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 2006; 47: 175-181.
• 11 Potnis PA, Tesfamariam B, Wood SC. Induction of nicotinamide-adenine dinu-cleotide phosphate oxidase and apoptosis by biodegradable polymers in macrophages: implications for stents. J Cardiovasc Pharmacol 2011; 57: 712-720.
• 12 Windecker S, Serruys PW, Wandel S. et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008; 372: 1163-1173.
• 13 Committee NRC. Guide for the Care and Use of Laboratory Animals. National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Natl Acad Press 2011; 8: 1-220.
• 14 Heublein B, Ozbek C, Pethig K. Silicon carbide-coated stents: clinical experience in coronary lesions with increased thrombotic risk. J Endovasc Surg 1998; 5: 32-36.
• 15 Farb A, Tang AL, Shroff S. et al. Neointimal responses 3 months after (32)P beta-emitting stent placement. Int J Radiat Oncol Biol Phys 2000; 48: 889-898.
• 16 Joner M, Byrne RA, Lapointe JM. et al. Comparative assessment of drug-eluting balloons in an advanced porcine model of coronary restenosis. Thromb Haemost 2011; 105: 864-872.
• 17 Schwartz RS, Huber KC, Murphy JG. et al. Restenosis and the proportional neointimal response to coronary artery injury: Results in a porcine model. Journal of the American College of Cardiology 1992; 19: 267-274.
• 18 Venkatraman S, Boey F. Release profiles in drug-eluting stents: issues and uncertainties. J Control Release 2007; 120: 149-160.
• 19 Finn AV, Nakazawa G, Joner M. et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007; 27: 1500-1510.
• 20 Nakazawa G, Finn AV, Joner M. et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation 2008; 118: 1138-1145.
• 21 Nakazawa G, Finn AV, Vorpahl M. et al. Coronary responses and differential mechanisms of late stent thrombosis attributed to first-generation sirolimus- and paclitaxeleluting stents. J Am Coll Cardiol 57: 390-398.
• 22 Pilgrim T, Windecker S. Drug-eluting stent thrombosis. Minerva Cardioangiol 2009; 57: 611-620.
• 23 Nakazawa G, Ladich E, Finn AV. et al. Pathophysiology of vascular healing and stent mediated arterial injury. EuroIntervention 2008; 4 Suppl C C7-10.
• 24 Vorpahl M, Yazdani SK, Nakano M. et al. Pathobiology of stent thrombosis after drug-eluting stent implantation. Curr Pharm Des 2010; 16: 4064-4071.
• 25 Caixeta A, Lansky AJ, Serruys PW. et al. Clinical follow-up 3 years after everolimus- and paclitaxel-eluting stents: a pooled analysis from the SPIRIT II (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) and SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) randomized trials. JACC Cardiovasc Interv 2011; 3: 1220-1228.
• 26 Kandzari DE, Mauri L, Popma JJ. et al. Lateterm clinical outcomes with zotarolimus- and sirolimus-eluting stents. 5-year follow-up of the ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv 2011; 4: 543-550.
• 27 Simmons A, Padsalgikar AD, Ferris LM. et al. Biostability and biological performance of a PDMS-based polyurethane for controlled drug release. Biomaterials 2008; 29: 2987-2995.
• 28 Wilson GJ, Nakazawa G, Schwartz RS. et al. Comparison of inflammatory response after implantation of sirolimus- and paclitaxel-eluting stents in porcine coronary arteries. Circulation 2009; 120: 141-149.
• 29 De Scheerder IK, Wilczek KL, Verbeken EV. et al. Biocompatibility of biodegradable and nonbiodegradable polymer-coated stents implanted in porcine peripheral arteries. Cardiovasc Intervent Radiol 1995; 18: 227-232.
• 30 Lockwood NA, Hergenrother RW, Patrick LM. et al. In vitro and in vivo characterization of novel biodegradable polymers for application as drug-eluting stent coatings. J Biomater Sci Polym Ed 2010; 21: 529-552.
• 31 Bruggeman JP, de Bruin BJ, Bettinger CJ. et al. Biodegradable poly(polyol sebacate) polymers. Biomaterials 2008; 29: 4726-4735.
• 32 Pan C-J, Tang J-J, Weng Y-J. et al. Preparation and in vitro release profiles of drugeluting controlled biodegradable polymer coating stents. Colloids Surfaces B: Biointerfaces 2009; 73: 199-206.
• 33 Ahmed TA, Bergheanu SC, Stijnen T. et al. Clinical performance of drug-eluting stents with biodegradable polymeric coating: a meta-analysis and systematic review. EuroIntervention 2011; 7: 505-516.
• 34 Klauss V, Serruys PW, Pilgrim T. et al. 2-year clinical follow-up from the randomized comparison of biolimus-eluting stents with biodegradable polymer and sirolimus-eluting stents with durable polymer in routine clinical practice. JACC Cardiovasc Interv 2011; 4: 887-895.
• 35 Kufner S, Massberg S, Dommasch M. et al. Angiographic outcomes with biodegradable polymer and permanent polymer drug-eluting stents. Catheter Cardiovasc Interv 2011; 78: 161-166.
• 36 Wykrzykowska JJ, Garg S, Onuma Y. et al. Implantation of the biodegradable polymer biolimus-eluting stent in patient s with high SYNTAX score is associated with decreased cardiac mortality compared to a permanent polymer sirolimus-eluting stent: two year follow-up results from the ”all-comers“ LEADERS trial. EuroIntervention 7: 605-613.
• 37 Zamiri P, Kuang Y, Sharma U. et al. The biocompatibility of rapidly degrading polymeric stents in porcine carotid arteries. Biomaterials 2010; 31: 7847-7855.
• 38 Sharkawi T, Cornhill F, Lafont A. et al. Intravascular bioresorbable polymeric stents: a potential alternative to current drug eluting metal stents. J Pharm Sci 2007; 96: 2829-2837.
• 39 Kim WH, Hong MK, Virmani R. et al. Histopathologic analysis of in-stent neointimal regression in a porcine coronary model. Coron Artery Dis 2000; 11: 273-277.
• 40 Joner M, Nakazawa G, Finn AV. et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008; 52: 333-342.
• 41 Pache J, Kastrati A, Mehilli J. et al. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol 2003; 41: 1283-1288.
• 42 Finn AV, Kolodgie FD, Harnek J. et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005; 112: 270-278.
• 43 Balakrishnan B, Tzafriri AR, Seifert P. et al. Strut position, blood flow, and drug deposition: implications for single and overlapping drug-eluting stents. Circulation 2005; 111: 2958-2965.
• 44 Granada JF, Inami S, Aboodi MS. et al. Development of a novel prohealing stent designed to deliver sirolimus from a biodegradable abluminal matrix. Circ Cardiovasc Interv 2010; 3: 257-266.
• 45 Schampaert E, Moses JW, Schofer J. et al. Sirolimus-eluting stents at two years: a pooled analysis of SIRIUS, E-SIRIUS, and C-SIRIUS with emphasis on late revascularizations and stent thromboses. Am J Cardiol 2006; 98: 36-41.
• 46 Caixeta A, Leon MB, Lansky AJ. et al. 5-year clinical outcomes after sirolimus-eluting stent implantation insights from a patient-level pooled analysis of 4 randomized trials comparing sirolimus-eluting stents with bare-metal stents. J Am Coll Cardiol 2009; 54: 894-902.
• 47 Alfonso F, Perez-Vizcayno MJ, Hernandez R. et al. Sirolimus-eluting stents versus bare-metal stents in patients with in-stent restenosis: results of a pooled analysis of two randomized studies. Catheter Cardiovasc Interv 2008; 72: 459-467.
• 48 Spaulding C, Daemen J, Boersma E. et al. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356: 989-997.
• 49 Garg S, Sarno G, Serruys PW. et al. The twelve-month outcomes of a biolimus eluting stent with a biodegradable polymer compared with a sirolimus eluting stent with a durable polymer. EuroIntervention 2010; 6: 233-239.
• 50 Barlis P, Regar E, Serruys PW. et al. An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: a LEADERS trial sub-study. Eur Heart J 2010; 31: 165-176.