Drug-eluting Stents-Issues and Developments

Drug-eluting Stents-Issues and Developments

Alahmar Albert E
Citation: US Cardiology, 2009;6(2):87-96
Published: November 2009
download article View ebook

| More
dots

Abstract
Drug-eluting stents (DES) have demonstrated their superiority to bare-metal stents (BMS) with respect to in-stent restenosis and the need for repeat revascularization. Since DES gained the CE mark in 2002 and the US Food and Drug Administration (FDA) approved the first DES in 2003, there has been a significant increase in the use of these devices. Nevertheless, safety concerns have emerged and reports of increased risk for late stent thrombosis with its potentially devastating clinical outcome have tempered the original enthusiasm generated by the advent of these stents. New-generation DES with novel polymers, antiproliferative drugs, and improved platforms are now approved or under investigation. In this article we provide an appraisal based on published clinical data of the safety and efficacy of various DES.
Keywords
Drug-eluting stents, polymer, stent thrombosis, anti proliferative, restenosis, reservoir/

Disclosure: Albert E Alahmar, MD, MRCP, has no conflicts of interest to declare. Anthony H Gershlick, MBBS, FRCP, receives modest research grants from Cordis, Medtronic, and Boehringer Ingleheim. He also serves on the speakers’ bureau for Medtronic and Abbott Vascular.
Received: August 18, 2009 Accepted: October 2, 2009
Correspondence: Albert E Alahmar, MD, MRCP, Department of Cardiovascular Intervention, Glenfield Hospital, Leicester University Hospitals, LE3 9QQ, UK. E: ae.alahmar@googlemail.com

Drug-eluting stents (DES) have revolutionized the field of interventional cardiology. The US Food and Drug Administration (FDA) is expecting that the total number of DES implanted in 2010 will surpass 5 million worldwide. Although initial results seemedpromising, longer-term follow-up in a wider range of patients revealed some concerns. Enhanced platelet aggregation, delayed neointimal growth, a local hypersensitivity reaction against the polymer coating, and a failure of sirolimus-, paclitaxel-, and tacrolimus-eluting stents to reduce neointimal hyperplasia at 90 and 180 days in animals when the drug was completely eluted from the stent are the main concerns.1–8

A number of stents have been and are currently being tested in animal and human trials. They are coated with drugs that aim to inhibit inflammation and neointimal proliferation. However, the rocess of restenosis is a sequence of complex events that has been partly tested and understood over the last two decades.9 Locally eleased drug interferes with the various mechanisms responsible for each step in the restenotic cascade, and a wide variety of agents are currently available. Although only everolimus-eluting stents (EES), sirolimus-eluting stents (SES), and paclitaxel-eluting stents (PES) have received FDA approval to date, multiple alternative devices are attempting to find a way to achieve the same goal, namely the reduction of re-stenosis and the need for repeat interventions.

Existing and Under Investigation Drugs
Six Limus-family-related drugs are currently being studied in DES, namely sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus. Sirolimus, everolimus, biolimus A9, and zotarolimus all bind to the FKBP12-binding protein, which subsequently binds to the mammalian target of rapamycin (mTOR) and thereby blocks the cell cycle, mainly of the smooth-muscle cell from the G1 to S phase. The mechanisms of action of tacrolimus and pimecrolimus are different. Both drugs bind to FKBP506. The tacrolimus/pimecrolimus FKBP506 omplex subsequently inhibits the calcineurin receptor, which leads to decreased cytokine expression on the cell surface membrane and results in an inhibition of T-cell activation and lower smooth-muscle cell selectivity (see Figures 1 and 2). A non-Limus-family-related drug widely studied for its efficacy in coronary stents is paclitaxel. Its effect has been mainly explained by its ability to stabilize microtubules and thereby inhibit cell division in the G0/G1 and G2/M phases.

To register to view full article click here

Keywords:
Drug-eluting stents, polymer, stent thrombosis, anti proliferative, restenosis, reservoir

References:
  1. Virmani R, Guagliumi G, Farb A, et al., Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious?, Circulation, 2004;109:701–5.
  2. McFadden EP, Stabile E, Regar E, et al., Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy, Lancet, 2004;364:1519–21.
  3. 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: 175–81.
  4. Hofma SH, van der Giessen WJ, van Dalen BM, et al., Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation, Eur Heart J, 2006;27: 166–70.
  5. Babinska A, Markell MS, Salifu MO, Aet al., Enhancement ofhuman platelet aggregation and secretion induced by rapamycin, Nephrol Dial Transplant, 1998;13:3153–9.
  6. Sianos G, Hofma S, Ligthart JM, et al., Stent fracture and restenosis in the drug-eluting stent era, Catheter Cardiovasc Interv, 2004;61:111–16.
  7. Scheller B, Grandt A, Wnendt S, et al., Comparative study of tacrolimus and paclitaxel stent coating in the porcine coronary model, Z Kardiol, 2005;94:445–52.
  8. Virmani R, Not so fast: animals don’t lie: your clinical followup isn’t long enough! Paper presented at: Transcatheter Cardiovascular Therapeutics Symposium, October 17–21, 2005.
  9. Virmani R, Farb A, Pathology of in-stent restenosis, Curr Opin Lipidol, 1999;10:499–506.
  10. Marx SO, Marks AR,Bench to bedside: the development of rapamycin and its application to stent restenosis, Circulation, 2001;104:852–5.
  11. Gingras AC, Raught B, Sonenberg N, mTOR signaling to translation, Curr Top Microbiol Immunol, 2004;279: 169–97.
  12. Rensing BJ, Vos J, Smits PC, et al., Coronary restenosis elimination with a sirolimus eluting stent: first European human experience with 6-month angiographic and intravascular ultrasonic follow-up, Eur Heart J, 2001;22: 2125–30.
  13. Sousa JE, Costa MA, Abizaid AC, et al., Sustained suppression of neointimal proliferation by sirolimus-eluting stents: oneyear angiographic and intravascular ultrasound follow-up, Circulation, 2001;104:2007.
  14. Aoki J, Abizaid AC, Serruys PW, et al., Evaluation of four-year coronary artery response after sirolimus-eluting stentimplantation using serial quantitative intravascular ultrasound and computer-assisted grayscale value analysis for plaque composition in event-free patients, J Am Coll Cardiol, 2005;46:1670–76.
  15. Moses JW, Leon MB, Popma JJ, et al., Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary arter, N Engl J Med, 2003;349:1315–23.
  16. Schofer J, Schluter M, Gershlick AH, et al., Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS), Lancet, 2003;362:1093–9.
  17. Schampaert E, Cohen EA, Schluter M, et al., The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS), J Am Coll Cardiol, 2004;43:1110–15.
  18. Lemos PA, Serruys PW, van Domburg RT, et al., Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the ‘real world’: the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry, Circulation, 2004;109:190–95.
  19. Daemen J, Ong A, Stefanini G, et al., Three-year clinical followup of the unrestricted use of the sirolimus-eluting stent compared to the use of a standard bare metal stent as partof the Rapamycin-Eluting-Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry, Am J Cardiol, 2006;98:895–901.
  20. Leon BF, Moses J, Holmes DR, et al., Long-term benefit of cypher sirolimus eluting coronary stents: four-year follow-up of the SIRIUS study. Paper presented at the American College of Cardiology Conference, March 11–14, 2006.
  21. Schuler W, Sedrani R, Cottens S, et al., SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo, Transplantation, 1997;64:36–42.
  22. Serruys P, AT O, Piek JJ, et al., A randomized comparison of a durable polymer Everolimus-eluting stent with a bare metal coronary stent: the SPIRIT first trial, Euro Intervention, 2005;1: 58–65.
  23. Tsuchida K, Piek JJ, Neumann FJ, et al., One-year results of a durable polymer everolimus-eluting stent in de novo coronary narrowings (The SPIRIT FIRST Trial), Euro Intervention, 2005;1:266–72.
  24. Serruys PW, Ruygrok PJN, Piek JJ, et al., A randomized comparison of an everolimus eluting coronary stent with a paclitaxel eluting coronary stent: the SPIRIT II trial, Euro Intervention, 2006;2:286–94.
  25. Haraguchi G, Pruitt S, Brodeur A, et al., Increased expressionof eNOS by Endeavor zotarolimus-eluting stents compared to other DES in porcine coronary artery implants, Am J Cardiol, 2006;98:32–3.
  26. Meredith IT, Ormiston J, Whitbourn R, et al., First-in-human study of the Endeavor ABT-578-eluting phosphorylcholineencapsulated stent system in de novo native coronary arterylesions: Endeavor I Trial, Euro Intervention, 2005;1:157–64.
  27. Fajadet J, Wijns W, Laarman GJ, et al., Randomized, double-blind, multicenter study of the Endeavor zotarolimuseluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial, Circulation, 2006;114:798–806.
  28. Kandzari DE, Leon MB, Popma JJ, et al., Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlledtrial, J Am Coll Cardiol, 2006;48:2440–47.
  29. Chevalier B, A randomized, controlled trial to evaluate thesafety and efficacy of the ZoMaxx Drug-Eluting Coronary Stent System compared to the TAXUS Express2 Paclitaxel- Eluting Coronary Stent System in de novo coronary artery lesions. Paper presented at: Transcatheter CardiovascularTherapeutics Symposium, October 22–27, 2006.
  30. Grube E, Hauptmann K, Buellesfeld L, et al., Six-month results of a randomized study to evaluate safety and efficacy of a biolimus A9 eluting stent with a biodegradable polymer coating, Euro Intervention, 2005;1:53–7.
  31. Chevalier B, NOBORI 1: part 1: a prospective, randomized trial of Biolimus A9 and paclitaxel-eluting stents: 9-month clinical and angiographic follow-up. Paper presented at: Transcatheter Cardiovascular Therapeutics Symposium,October 22–27, 2006.
  32. Zollinger M, Waldmeier F, Hartmann S, et al., Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro, Drug Metab Dispos, 2006;34:765–74.
  33. Abizaid A.,Avantec pimecrolimus eluting stent. Paperpresented at: Transcatheter Cardiovascular Therapeutics Symposium, October 17–21, 2005.
  34. Steffel J, Latini RA, Akhmedov A, et al., Rapamycin, but not FK- 506, increases endothelial tissue factor expression: implications for drug-eluting stent design, Circulation, 2005;112:2002–11.
  35. Morice MC, Wijns W, DiMario C, et al., Direct stenting of denovo coronary stenoses with tacrolimus-eluting versus carbon-coated carbostents: the randomized JUPITER II trial, Euro Intervention, 2006;2:45–52.
  36. Colombo A, Drzewiecki J, Banning A, et al., Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions, Circulation, 2003;108:788–94.
  37. Stone GW, Ellis SG, Cox DA, et al., A polymer-based, paclitaxeleluting stent in patients with coronary artery disease, N Engl J Med, 2004;350:221–31.
  38. Stone GW, Ellis SG, Cannon L, et al., Outcomes of the polymerbased paclitaxel-eluting TAXUS stent in complex lesions: principal clinical and angiographic results from the TAXUS-V Pivotal Randomized Trial. Paper presented at: Annual ScientificSession of the American College of Cardiology, March 6–9, 2005.
  39. Stone GW, Gruberg L, TAXUS VI: Two-year results from the pivotal prospective randomized trial of the slow-release polymer-based paclitaxel-eluting stent. Paper presented at: Transcatheter Cardiovascular Therapeutics Symposium, September 27–October 1, 2004.
  40. Stone GW, Ellis SG, Cannon L, et al., Comparison of a polymerbased paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial, JAMA, 2005;294:1215–23.
  41. Turco M, Ormiston J.,TAXUS ATLAS 9-month results: evaluation of TAXUS Liberté versus TAXUS Express. Paper presented at: Congress of the EuroPCR, Paris, May 16–19, 2006.
  42. Thomas M, TAXUS Liberté in everyday practice: the TAXUS OLYMPIA post-approval registry. Paper presented at: Transcatheter Cardiovascular Therapeutics Symposium, October 22–27, 2006, Washington, DC.
  43. Vranckx P, Serruys PW, Gambhir S, et al., Biodegradablepolymer-based, paclitaxel-eluting Infinnium stent: 9-month clinical and angiographic follow-up results from the SIMPLE II Prospective Multi-Centre Study, Euro Intervention, 2006;2:310–17.
  44. Kastrati A, Schomig A, Dirschinger J, et al., Increased risk of restenosis after placement of gold-coated stents: results of a randomized trial comparing gold-coated with uncoated steel stents in patients with coronary artery disease. Circulation, 2000;101:2478–88.
  45. Iofina E, Langenberg R, Blindt R, et al., Polymer-based paclitaxel-eluting stents are superior to nonpolymer-based paclitaxel-eluting stents in the treatment of de novo coronary lesions, Am J Cardiol, 2006;98:1022–7.
  46. Gershlick A, De Scheerder I, Chevalier B, et al., Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European Evaluation of Paclitaxel Eluting Stent (ELUTES) trial, Circulation, 2004;109:487–93.
  47. Park SJ, Shim WH, Ho DS, et al., A paclitaxel-eluting stent for the prevention of coronary restenosis, N Engl J Med, 2003;348: 1537–45.
  48. Lansky AJ, Costa RA, Mintz GS, et al., Non-polymer-basedpaclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial, Circulation, 2004;109:1948–54.
  49. van der Giessen WJ, Lincoff AM, Schwartz RS, et al., Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries,Circulation, 1996;94:1690–97.
  50. Sousa JE, Costa MA, Farb A, et al., Images in cardiovascularmedicine: vascular healing 4 years after the implantation of sirolimus-eluting stent in humans: a histopathological examination, Circulation, 2004;110:e5–6.
  51. Suzuki T, Kopia G, Hayashi S, et al., Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model, Circulation, 2001;104:1188–93.
  52. Meredith IT, RESOLUTE: four-month angiographic and IVUS subset. Paper presented at: Transcatheter Cardiovascular Therapeutics Symposium, October 22–27, 2006.
  53. Rajtar A, Kaluza G, Yang Q, et al., Hydroxyapatite-coated cardiovascular stents, Euro Intervention, 2006;2:113–15.
  54. Mehilli J, Kastrati A, Wessely R, et al., Randomized trial of a nonpolymer-based rapamycin-eluting stent versus a polymerbased paclitaxel-eluting stent for the reduction of late lumen loss, Circulation, 2006;113:273–9.
  55. Gupta V, Aravamuthan BR, Baskerville S, et al., Reduction of subacute stent thrombosis (SAT) using heparin-coated stents in a large-scale, real world registry, J Invasive Cardiol, 2004;16:304-10.et al., Isolation of putative progenitor endothelial cells for angiogenesis, Science, 1997;275:964–7.
  56. Aoki J, Serruys PW, van Beusekom H, et al., Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry, J AmColl Cardiol, 2005;45:1574–9.
  57. Serruys P, The genous endothelial cell capture system finalresults from the HEALING II study. Paper presented at: Transcatheter Cardiovascular Therapeutics Symposium; October 17–21, 2005.
  58. Vasa M, Fichtlscherer S, Adler K, et al., Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease, Circulation, 2001;103:2885–90.
  59. Serruys PW, Strauss BH, Beatt KJ, et al., Angiographic follow-upafter placement of a self-expanding coronary-artery stent, NEngl J Med, 1991;324:13–17.
  60. Cutlip DE, Baim DS, Ho KK, et al., Stent thrombosis in themodern era: a pooled analysis of multicenter coronary stentclinical trials, Circulation, 2001;103:1967–71.
  61. Schuhlen H, Kastrati A, Dirschinger J, et al., Intracoronarystenting and risk for major adverse cardiac events during thefirst month, Circulation, 1998;98:104–11.
  62. Ong AT, McFadden EP, Regar E, de Jaegere PP, et al., Lateangiographic stent thrombosis (LAST) events withdrug-eluting stents, J Am Coll Cardiol, 2005;45:2088–92.
  63. Iakovou I, Schmidt T, Bonizzoni E, et al., Incidence, predictors,and outcome of thrombosis after successful implantation ofdrug-eluting stents, JAMA, 2005;293:2126–30.
  64. Rodriguez AE, Mieres J, Fernandez-Pereira C, et al., Coronarystent thrombosis in the current drug-eluting stent era: insightsfrom the ERACI III trial, J Am Coll Cardiol, 2006;47:205–7.
  65. Kuchulakanti PK, Chu WW, Torguson R, et al., Correlates andlong-term outcomes of angiographically proven stentthrombosis with sirolimus- and paclitaxel-eluting stents,Circulation, 2006;113:1108–13.
  66. Park DW, Park SW, Park KH, et al., Frequency of and risk factorsfor stent thrombosis after drug-eluting stent implantationduring long-term follow-up, Am J Cardiol, 2006;98:352–6.
  67. Urban P, Gershlick AH, Guagliumi G, et al., Safety of coronarysirolimus-eluting stents in daily clinical practice: one-yearfollow-up of the e-Cypher registry, Circulation, 2006;113:1434–41.
  68. de la Torre-Hernandez JM, Rumoroso JR, Perez de Prado A, etal., Differential predictors for subacute, late and very late drugelutingstent thrombosis: results from the multicenterESTROFA study. Presented at: Annual Scientific Sessions of theAmerican College of Cardiology, March 24–27, 2007.
  69. Daemen J, Wenaweser P, Tsuchida K, et al., Early and latecoronary stent thrombosis of sirolimus-eluting and paclitaxelelutingstents in routine clinical practice, Lancet,2007;369:667–8.
  70. Honda Y, Fitzgerald PJ, Stent thrombosis: an issue revisited in achanging world, Circulation, 2003;108:2–5.
  71. Virmani R, Guagliumi G, Farb A, et al., Localized hypersensitivityand late coronary thrombosis secondary to a sirolimus-elutingstent: should we be cautious?, Circulation, 2004;109:701–5.
  72. Nebeker JR, Virmani R, Bennett CL, et al., Hypersensitivitycases associated with drug-eluting coronary stents: a reviewof available cases from the Research on Adverse DrugEvents and Reports (RADAR) project, J Am Coll Cardiol,2006;47:175–81.
  73. Orford JL, Lennon R, Melby S, et al., Frequency and correlatesof coronary stent thrombosis in the modern era: analysis of asingle center registry, J Am Coll Cardiol, 2002;40:1567–72.
  74. Ong AT, Hoye A, Aoki J, et al., Thirty-day incidence and sixmonthclinical outcome of thrombotic stent occlusion afterbare-metal, sirolimus, or paclitaxel stent implantation, J Am CollCardiol, 2005;45:947–53.
  75. McFadden EP, Stabile E, Regar E, et al., Late thrombosis indrug-eluting coronary stents after discontinuation ofantiplatelet therapy, Lancet, 2004;364:1519–21.
  76. Cutlip D, Standardized consensus definitions for clinicalendpoints in DES studies: impact on reported event rates fromclinical trials. Available at: www.tctmd.com/csportal/ShowBinary/BEA%20Repository/TCTMD%20Portal/EPSlidePresPoolNew/2006/Nov2006/Cutlip_T06_T1310//pdfFile
  77. Mauri L, Hsieh WH, Massaro JM, et al., Stent thrombosis inrandomized clinical trials of drug-eluting stents, N Engl J Med,2007; 356:1020–29.
  78. Cutlip D, Stent thrombosis after drug-eluting stenting: impactof a new standard definition on clinical trial results. Paperpresented at: Transcatheter Cardiovascular Therapeuticsmeeting, October 22–27, 2006.
  79. Serruys PW, Kutryk MJ, Ong AT, Coronary-artery stents,N Engl J Med, 2006;354:483–95.
  80. Babapulle MN, Joseph L, Belisle P, et al., A hierarchicalBayesian meta-analysis of randomised clinical trials ofdrug-eluting stents, Lancet, 2004;364:583–91.
  81. Nordmann AJ, Briel M, Bucher HC, Mortality in randomizedcontrolled trials comparing drug-eluting versus bare metalstents in coronary artery disease: a meta-analysis, Eur Heart J,2006;27:2784–2814.
  82. Camenzind E, Do drug-eluting stent increase death?, ESC CongressNews. Barcelona, Spain, 2006.
  83. Spaulding C, Daemen J, Boersma E, et al., A pooled analysis ofdata comparing sirolimus-eluting stents with bare metalstents, N Engl J Med, 2007;356:989–997.
  84. Maeng M, Jensen LO, Kaltoft A, et al., Stent thrombosis afterimplantation of drug-eluting or bare metal coronary stents inwestern Denmark. Paper presented at: Annual ScientificSessions of the American College of Cardiology, March 24–27,2007.
  85. Williams DO, Abbott JD, Kip KE, Outcomes of 6,906 patientsundergoing percutaneous coronary intervention in the era ofdrug-eluting stents: report of the DEScover Registry, Circulation,2006;114:2154–62.
  86. Lagerqvist B, James SK, Stenestrand U, et al., Long-termoutcomes with drug-eluting stents versus bare-metal stents inSweden, N Engl J Med, 2007;356:1009–19.
  87. Tepe G, Wendel HP, Khorchidi S, et al., Thrombogenicity ofvarious endovascular stent types: an in vitro evaluation,J Vasc Interv Radiol, 2002;13:1029–35.
  88. Vogt F, Stein A, Rettemeier G, et al., Long-term assessment of anovel biodegradable paclitaxel-eluting coronary polylactidestent, Eur Heart J, 2004;25:1330–40.
  89. Tamai H, Igaki K, Kyo E, et al., Initial and 6-month results ofbiodegradable poly-l-lactic acid coronary stents in humans,Circulation, 2000;102:399–404.
  90. Heublein B, Rohde R, Kaese V, et al., Biocorrosion ofmagnesium alloys: a new principle in cardiovascular implanttechnology?, Heart, 2003;89:651–6.
  91. Di Mario C, Griffiths H, Goktekin O, et al., Drug-elutingbioabsorbable magnesium stent, J Interv Cardiol, 2004;17:391–5.
  92. Erbel R, Di Mario C, Bartunek J, et al., Temporary scaffolding ofcoronary arteries with bioabsorbable magnesium stents: aprospective, non-randomised multicentre trial, Lancet,2007;369:1869–75.
  93. Seruys PW, Ormiston AJ, Onuma Y, et al., A Bioabsorbableeverolimus-eluting coronary stent system (ABSORB): two-yearoutcomes and results from multiple imaging methods, Lancet,2009;373:897–910.

Copyright® 2004 - 2010 Business Briefings, Ltd. All rights reserved.
Touch Cardiology is for informational purposes and should not be considered medical advice, diagnosis or treatement recommendations.