Pathology of First-generation Drug-eluting Stents in Humans

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First-generation sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) have dramatically reduced restenosis, although concern still exists about the long-term safety of this technology since observational studies have shown a steady increase in the rate of late stent thrombosis (LST), an infrequent but catastrophic complication. Although the mechanisms of LST are multifactorial, our laboratory has demonstrated that delayed arterial healing accompanied by poor endothelialisation is the primary pathogical substrate underlying this event. Delayed arterial healing is associated with penetration of necrotic core, long/overlapping stents and bifurcation stenting, especially in flow divider (high shear) regions. Grade V stent fracture is also associated with adverse pathogical findings including LST and restenosis. Moreover, localised hypersensitivity reaction is exclusive to SES as an underlying mechanism of LST, while malapposition secondary to excessive fibrin deposition is associated with PES. Uncovered struts are still identified in both SES and PES with implant duration beyond 12 months, particularly in stents placed for 'off-label' indications. In conclusion, the first generation of drug-eluting stents (DES) certainly reduce neointimal growth but this comes at the price of delayed healing.

Acknowledgement: CVPath Institute, Inc., Gaithersburg, Maryland, provided full support for this work.

Renu Virmani receives research support from Medtronic AVE, Abbott Vascular, Atrium Medical, OrbusNeich Medical, Terumo Corporation, Cordis Corporation, BioSensors International, Biotronik and Alchimedics, and is a consultant for Medtronic AVE, Abbott Vascular, WL Gore, Atrium Medical and Lutonix. The remaining authors have no conflicts of interest to declare.
Renu Virmani, CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, US. E:
Received date
29 January 2011
Accepted date
14 February 2011
  1. Serruys PW, de Jaegere P, Kiemeneij F, et al., A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group, N Engl J Med, 1994;331:489-95.
  2. Morice MC, Serruys PW, Sousa JE, et al., A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization, N Engl J Med, 2002;346:1773-80.
  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;350:221-31.
  4. Stettler C, Wandel S, Allemann S, et al., Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis, Lancet, 2007;370:937-48.
  5. Doyle B, Rihal CS, O'Sullivan CJ, et al., Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents, Circulation, 2007;116:2391-8.
  6. Daemen J, Wenaweser P, Tsuchida K, et al., Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxeleluting stents in routine clinical practice: data from a large two-institutional cohort study, Lancet, 2007;369:667-78.
  7. Lagerqvist B, Carlsson J, Frobert O, et al., Stent thrombosis in Sweden: a report from the Swedish Coronary Angiography and Angioplasty Registry, Circ Cardiovasc Interv, 2009;2:401-8.
  8. Finn AV, Joner M, Nakazawa G, et al., Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization, Circulation, 2007;115:2435-41.
  9. Marx SO, Jayaraman T, Go LO, Marks AR, Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells, Circ Res, 1995;76:412-7.
  10. Poon M, Marx SO, Gallo R, et al., Rapamycin inhibits vascular smooth muscle cell migration, J Clin Invest, 1996;98:2277-83.
  11. Wiskirchen J, Schober W, Schart N, et al., The effects of paclitaxel on the three phases of restenosis: smooth muscle cell proliferation, migration, and matrix formation: an in vitro study, Invest Radiol, 2004;39:565-71.
  12. Farb A, Burke AP, Kolodgie FD, Virmani R, Pathological mechanisms of fatal late coronary stent thrombosis in humans, Circulation, 2003;108:1701-6.
  13. Hwang CW, Wu D, Edelman ER, Physiological transport forces govern drug distribution for stent-based delivery, Circulation, 2001;104:600-5.
  14. Levin AD, Vukmirovic N, Hwang CW, Edelman ER, Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel, Proc Natl Acad Sci U S A, 2004;101:9463-7.
  15. Basalus MW, Ankone MJ, van Houwelingen GK, de Man FH, von Birgelen C, Coating irregularities of durable polymerbased drug-eluting stents as assessed by scanning electron microscopy, EuroIntervention, 2009;5:157-65.
  16. 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;112:270-8.
  17. Bavry AA, Kumbhani DJ, Quiroz R, et al., Invasive therapy along with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in non-ST-segment elevation acute coronary syndromes: a meta-analysis and review of the literature, Am J Cardiol, 2004;93:830-5.
  18. Keeley EC, Boura JA, Grines CL, Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials, Lancet, 2003;361:13-20.
  19. 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;118:1138-45.
  20. Virmani R, Kolodgie FD, Burke AP, et al., Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions, Arterioscler Thromb Vasc Biol, 2000;20:1262-75.
  21. Hwang CW, Levin AD, Jonas M, et al., Thrombosis modulates arterial drug distribution for drug-eluting stents, Circulation, 2005;111:1619-26.
  22. Di Lorenzo E, Sauro R, Varricchio A, et al., Long-term outcome of drug-eluting stents compared with bare metal stents in ST-segment elevation myocardial infarction: results of the paclitaxel- or sirolimus-eluting stent versus bare metal stent in Primary Angioplasty (PASEO) Randomized Trial, Circulation, 2009;120:964-72.
  23. Tebaldi M, Arcozzi C, Campo G, et al., The 5-year clinical outcomes after a randomized comparison of sirolimuseluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction, J Am Coll Cardiol, 2009;54:1900-1.
  24. Kaltoft A, Kelbaek H, Thuesen L, et al., Long-term outcome after drug-eluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction: 3-year follow-up of the randomized DEDICATION (Drug Elution and Distal Protection in Acute Myocardial Infarction) Trial, J Am Coll Cardiol, 2010;56:641-5.
  25. Violini R, Musto C, De Felice F, et al., Maintenance of long-term clinical benefit with sirolimus-eluting stents in patients with ST-segment elevation myocardial infarction 3-year results of the SESAMI (sirolimus-eluting stent versus bare-metal stent in acute myocardial infarction) trial, J Am Coll Cardiol, 2010;55:810-4.
  26. Atary JZ, van der Hoeven BL, Liem SS, et al., Three-year outcome of sirolimus-eluting versus bare-metal stents for the treatment of ST-segment elevation myocardial infarction (from the MISSION! Intervention Study), Am J Cardiol, 2010;106:4-12.
  27. Spaulding C, Teiger E, Commeau P, et al., Four-year follow-up of TYPHOON (Trial to Assess the Use of the CYPHer Sirolimus-Eluting Coronary Stent in Acute Myocardial Infarction Treated With BallOON Angioplasty), JACC Cardiovasc Interv, 2011;4:14-23.
  28. Vink MA, Dirksen MT, Suttorp MJ, et al., 5-Year follow-up after primary percutaneous coronary intervention with a paclitaxel-eluting stent versus a bare-metal stent in acute STsegment elevation myocardial infarction: a follow-up study of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction With ST-Segment Elevation) trial, JACC Cardiovasc Interv, 2011;4:24-9.
  29. Brodie B, Pokharel Y, Fleishman N, et al., Very late stent thrombosis after primary percutaneous coronary intervention with bare-metal and drug-eluting stents for ST-segment elevation myocardial infarction. A 15-year single-center experience, JACC Cardiovasc Interv, 2011;4:30-8.
  30. Kukreja N, Onuma Y, Garcia-Garcia H, et al., Primary percutaneous coronary intervention for acute myocardial infarction: long-term outcome after bare metal and drugeluting stent implantation, Circ Cardiovasc Interv, 2008;1:103-10.
  31. Leibundgut G, Nietlispach F, Pittl U, et al., Stent thrombosis up to 3 years after stenting for ST-segment elevation myocardial infarction versus for stable anginaÔÇöcomparison of the effects of drug-eluting versus bare-metal stents, Am Heart J, 2009;158:271-6.
  32. Ku DN, Giddens DP, Zarins CK, Glagov S, Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress, Arteriosclerosis, 1985;5:293-302.
  33. Friedman MH, Bargeron CB, Deters OJ, Hutchins GM, Mark FF, Correlation between wall shear and intimal thickness at a coronary artery branch, Atherosclerosis, 1987;68:27-33.
  34. Prosi M, Perktold K, Ding Z, Friedman MH, Influence of curvature dynamics on pulsatile coronary artery flow in a realistic bifurcation model, J Biomech, 2004;37:1767-75.
  35. Nakazawa G, Yazdani SK, Finn AV, et al., Pathological findings at bifurcation lesions: the impact of flow distribution on atherosclerosis and arterial healing after stent implantation, J Am Coll Cardiol, 2010;55:1679-87.
  36. Iakovou I, Schmidt T, Bonizzoni E, et al., Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents, JAMA, 2005;293:2126-30.
  37. Richter Y, Groothuis A, Seifert P, Edelman ER, Dynamic flow alterations dictate leukocyte adhesion and response to endovascular interventions, J Clin Invest, 2004;113:1607-14.
  38. Aoki J, Nakazawa G, Tanabe K, et al., Incidence and clinical impact of coronary stent fracture after sirolimus-eluting stent implantation, Catheter Cardiovasc Interv, 2007;69:380-6.
  39. Lee MS, Jurewitz D, Aragon J, et al., Stent fracture associated with drug-eluting stents: clinical characteristics and implications, Catheter Cardiovasc Interv, 2007;69:387-94.
  40. Shaikh F, Maddikunta R, Djelmami-Hani M, et al., Stent fracture, an incidental finding or a significant marker of clinical in-stent restenosis? Catheter Cardiovasc Interv, 2008;71:614-8.
  41. Leong DP, Dundon BK, Puri R, Yeend RA, Very late stent fracture associated with a sirolimus-eluting stent, Heart Lung Circ, 2008;17:426-8.
  42. Shite J, Matsumoto D, Yokoyama M, Sirolimus-eluting stent fracture with thrombus, visualization by optical coherence tomography, Eur Heart J, 2006;27:1389.
  43. Lee SH, Park JS, Shin DG, et al., Frequency of stent fracture as a cause of coronary restenosis after sirolimus-eluting stent implantation, Am J Cardiol, 2007;100:627-30.
  44. Nakazawa G, Finn AV, Vorpahl M, et al., Incidence and predictors of drug-eluting stent fracture in human coronary artery a pathologic analysis, J Am Coll Cardiol, 2009;54:1924-31.
  45. Yang TH, Kim DI, Park SG, et al., Clinical characteristics of stent fracture after sirolimus-eluting stent implantation, Int J Cardiol, 2009;131:212-6.
  46. Windecker S, Remondino A, Eberli FR, et al., Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization, N Engl J Med, 2005;353:653-62.
  47. Nakazawa G, Finn AV, Vorpahl M, et al., Coronary responses and differential mechanisms of late stent thrombosis attributed to first-generation sirolimus- and Paclitaxel-eluting stents, J Am Coll Cardiol, 2011;57:390-8.
  48. Marroquin OC, Selzer F, Mulukutla SR, et al., A comparison of bare-metal and drug-eluting stents for off-label indications, N Engl J Med, 2008;358:342-52.
  49. 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.
  50. 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.
  51. Nakazawa G, Finn AV, Ladich E, et al., Drug-eluting stent safety: findings from preclinical studies, Expert Rev Cardiovasc Ther, 2008;6:1379-91.
  52. Farb A, Heller PF, Shroff S, et al., Pathological analysis of local delivery of paclitaxel via a polymer-coated stent, Circulation, 2001;104:473-9.
  53. Heldman AW, Cheng L, Jenkins GM, et al., Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis, Circulation, 2001;103:2289-95.
  54. Ishida T, Tanaka K, Effects of fibrin and fibrinogendegradation products on the growth of rabbit aortic smooth muscle cells in culture, Atherosclerosis, 1982;44:161-74.
  55. Naito M, Stirk CM, Smith EB, Thompson WD, Smooth muscle cell outgrowth stimulated by fibrin degradation products. The potential role of fibrin fragment E in restenosis and atherogenesis, Thromb Res, 2000;98:165-74.
  56. 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;120:141-9, 1-2.
  57. Morice MC, Serruys PW, Barragan P, et al., Long-term clinical outcomes with sirolimus-eluting coronary stents: five-year results of the RAVEL trial, J Am Coll Cardiol, 2007;50:1299-304.
  58. Nakagawa Y, Kimura T, Morimoto T, et al., Incidence and risk factors of late target lesion revascularization after sirolimuseluting stent implantation (3-year follow-up of the j-Cypher Registry), Am J Cardiol, 2010;106:329-36.
  59. Ellis SG, Stone GW, Cox DA, et al., Long-term safety and efficacy with paclitaxel-eluting stents: 5-year final results of the TAXUS IV clinical trial (TAXUS IV-SR: Treatment of De Novo Coronary Disease Using a Single Paclitaxel-Eluting Stent), JACC Cardiovasc Interv, 2009;2:1248-59.