Skip to main content
Log in

Perspectives of Drug-Eluting Stents

The Next Revolution

American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Coronary stent implantation has become a well established therapy in the management of coronary artery disease (CAD). Although the Stent Restenosis Study (STRESS) and Belgium-Netherlands Stent (BENESTENT) trials demonstrated convincingly that stenting is superior to percutaneous transluminal coronary angioplasty with respect to restenosis in de novo lesions, there is, however, still a high incidence (10 to 50%) of restenosis following stent implantation.

Improvements in stent design and implantation techniques resulted in an increase in the use of coronary stents and today, in most centers in the US and Europe, stenting has become the predominant form of nonsurgical revascularization accounting for about 80% of all percutaneous coronary intervention procedures. Coronary stents provide luminal scaffolding that virtually eliminates elastic recoil and remodelling. Stents, however, do not decrease neointimal hyperplasia and in fact lead to an increase in the proliferative comportment of restenosis.

Agents that inhibit cell-cycle progression indirectly have also been tested as inhibitors of vascular proliferation. When coated onto stents, sirolimus, a macrolide antibiotic with immunosuppressive properties, and paclitaxel and dactinomycin, both chemotherapeutic agents, induced cell-cycle arrest in smooth muscle cells (SMC) and inhibited neointimal formation in animal models.

Preliminary clinical studies with drug-eluting stents produced dramatic results eliminating restenosis in large and mid-size arteries. Quantitative coronary angiography and intravascular ultrasound demonstrated virtually complete inhibition of tissue growth at 6 and 12 months after sirolimus-eluting stent implantation. Results are also very encouraging with paclitaxel-coated stents. However, it needs to be proven that current drug-eluting stents will produce similar results in ‘real life’ interventional practice (long lesions, lesions in small vessels, in vein grafts, chronic total occlusions, and bifurcated and ostial lesions). The ongoing randomized, double-blind sirolimus-coated Bx Velocity™ balloon expandable stent in the treatment of patients with de novo coronary artery lesions (SIRIUS) trial may answer some of these concerns.

With further improvements, including the expansion of drug-loading capacity, double coatings and coatings with programmable pharmacokinetic capacity using advances in nanotechnology (which may allow for more precise and controlled release of less toxic and improved molecules), we think that in the next few years the practice of interventional cardiology may undergo major changes. A new era of dramatic improvements in the treatment of CAD may have dawned. The prospect of approval of this technology should herald a host of clinical trials to revisit basic assumptions about the place of coronary stenting in the contemporary care of obstructive (and nonobstructive) CAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Table II
Fig. 3

Notes

  1. DELIVER is not an acronym. The DELIVER trial is evaluating paclitaxel-coated stents in Europe.

References

  1. Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation 1998; 98: 1802–20

    Article  PubMed  CAS  Google Scholar 

  2. Fischman DL, Leon MB, Bairn DS, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease: Stent Restenosis Study Investigators. N Engl J Med 1994; 331: 496–501

    Article  PubMed  CAS  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. Topol EJ. Coronary-artery stents: gauging, gorging, and gouging. N Engl J Med 1998; 339: 1702–4

    Article  PubMed  CAS  Google Scholar 

  5. Serruys PW, Foley DP, Suttorp M-J, et al. A randomized comparison of the value of additional stenting after optimal balloon angioplasty for long coronary lesions. J Am Coll Cardiol 2002; 39: 393–9

    Article  PubMed  Google Scholar 

  6. Van den Brand M, Rensing J, Morel MM, et al. The effect of completeness of revascularization on event-free survival at one-year in the ARTS trial. J Am Coll Cardiol 2002; 39: 559–64

    Article  PubMed  Google Scholar 

  7. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987; 316: 701–6

    Article  PubMed  CAS  Google Scholar 

  8. El-Omar MM, Dangas G, Iakovou I, et al. Update on in-stent restenosis. Curr Interv Cardiol Rep 2001; 3: 296–305

    PubMed  Google Scholar 

  9. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336: 1697–703

    Article  PubMed  CAS  Google Scholar 

  10. Malhotra S, Teirstein PS. The SCRIPPS trial: catheter-based radiotherapy to inhibit coronary restenosis. J Invasive Cardiol 2000; 12(6): 330–2

    PubMed  CAS  Google Scholar 

  11. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001; 25; 344(4): 250–6

    Article  PubMed  CAS  Google Scholar 

  12. Teirstein PS, Kuntz RE. New frontiers in interventional cardiology: intravascular radiation to prevent restenosis. Circulation 2001 Nov. 20; 104(21): 2620–6

    Article  PubMed  CAS  Google Scholar 

  13. Wilentz JR, Sanborn TA, Haudenschild CC, et al. Platelet accumulation in experimental angioplasty: time course and relation to vascular injury. Circulation 1987; (3): 636–42

    Article  Google Scholar 

  14. Wilensky RI, March KL, Gradus-Pizlo I, et al. Vascular injury, repair, and restenosis after percutaneous transluminal angioplasty in the atherosclerotic rabbit. Circulation 1995; 92(10): 2995–3005

    Article  PubMed  CAS  Google Scholar 

  15. Stoltenberg RL, Geraghty J, Steele DM, et al. Inhibition of intimai hyperplasia in rat aortic allografts with cyclosporine. Transplantation 1995; 60(9): 993–8

    Article  PubMed  CAS  Google Scholar 

  16. Glagov S. Intimai hyperplasia, vascular modeling, and the restenosis problem. Circulation 1994; 89: 2888–91

    Article  PubMed  CAS  Google Scholar 

  17. Schwartz R, Holmes D, Topol E. The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol 1992; 20: 1284–93

    Article  PubMed  CAS  Google Scholar 

  18. Schwartz RS, Murphy JG, Edwards WD, et al. Restenosis after balloon angioplasty: a practical proliferative model in porcine coronary arteries. Circulation 1990; 82: 2190–200

    Article  PubMed  CAS  Google Scholar 

  19. Ross R, Wight TN, Strandness E, et al. Human atherosclerosis. I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol 1984; 114: 79–93

    PubMed  CAS  Google Scholar 

  20. Moses PRL, Campbell GR, Wang ZL, et al. Smooth muscle phenotypic expression in human carotid arteries. Lab Invest 1985; 53: 556–62

    Google Scholar 

  21. Austin GE, Ratliff NB, Hollman J, et al. Intimai proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1985; 6: 369–75

    Article  PubMed  CAS  Google Scholar 

  22. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury. Lab Invest 1983; 49: 327–33

    PubMed  CAS  Google Scholar 

  23. Schwartz SM, deBlois D, O’Brien ERM. The intima: soil for atherosclerosis and restenosis. Circ Res 1995; 77: 445–65

    Article  PubMed  CAS  Google Scholar 

  24. Morishita R, Gibbons GH, Ellison KE, et al. Single intraluminal delivery of antisense cdc2 kinase and proliferating -cell nuclear antigen oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc Natl Acad Sci U S A 1993; 90: 8474–8

    Article  PubMed  CAS  Google Scholar 

  25. Sirois MG, Simons M, Edelman BR, et al. Platelet release of platelet derived growth factor is required for intimai hyperplasia in rate vascular injury model [abstract]. Circulation 1994; 90 Suppl. 1: I–511

    Google Scholar 

  26. Mintz GS, Popma JJ, Hong MK, et al. Intravascular ultrasound to discern device-specific effects and mechanisms of restenosis. Am J Cardiol 1996; 78: 18–22

    Article  PubMed  CAS  Google Scholar 

  27. Edelman ER, Rogers C. Pathobiologic responses to stenting. Am J Cardiol 1998; 81: 4E–6E

    Article  PubMed  CAS  Google Scholar 

  28. Komatsu R, Ueda M, Naruko T, et al. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation 1998; 98: 224–33

    Article  PubMed  CAS  Google Scholar 

  29. Kornowski R, Hong MK, Tio FO, et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998; 31: 224–30

    Article  PubMed  CAS  Google Scholar 

  30. Jawien A, Bowen-Pope DF, Lindner V, et al. Platelet-derived growth factor promotes smooth muscle migration and intimai thickening in a rat model of balloon angioplasty. J Clin Invest 1992; 89: 507–11

    Article  PubMed  CAS  Google Scholar 

  31. Sriram V, Patterson C. Cell cycle in vasculoproliferative diseases-potential interventions and routes of delivery. Circulation 2001; 103: 2414–9

    Article  PubMed  CAS  Google Scholar 

  32. Koster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 2000; 356: 1895–7

    Article  PubMed  CAS  Google Scholar 

  33. Kipshidze N, Moses J, Shankar LR, et al. Perspectives on antisense therapy for the prevention of restenosis. Curr Opin Mol Ther 2001 Jun; 3(3): 265–77

    PubMed  CAS  Google Scholar 

  34. Herdeg C, Oberhoff M, Baumbach A, et al. Local Paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J Am Coll Cardiol 2000; 35(7): 1969–76

    Article  PubMed  CAS  Google Scholar 

  35. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimai thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999; 99: 2164–70

    Article  PubMed  CAS  Google Scholar 

  36. Suzuki T, Kopia G, Shin-ichiro H, et al. Stent-based delivery of Sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104: 1188–93

    Article  PubMed  CAS  Google Scholar 

  37. Marx SO, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001; 104: 852–5

    Article  PubMed  CAS  Google Scholar 

  38. 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 May; 103(18): 2289–95

    Article  PubMed  CAS  Google Scholar 

  39. Schink JC, Singh DK, Rademaker AW, et al. Etoposide, methotrexate, actinomycin cyclophosphamide, and vincristine in the treatment of metastatic, high-risk gestational trophoblastic disease. Obstet Gynecol 1992 Nov; 80(5): 817–20

    PubMed  CAS  Google Scholar 

  40. Ellis SG, Roubin GS, Wilentz J, et al. Effect of 18- to 24-hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. Am Heart J 1989 Apr; 117(4): 777–82

    Article  PubMed  CAS  Google Scholar 

  41. Faxon DP, Spiro TE, Minor S, et al. Low molecular weight heparin in prevention of restenosis after angioplasty: results of Enoxaparin Restenosis (ERA) Trial. Circulation 1994 Aug; 90(2): 908–14

    Article  PubMed  CAS  Google Scholar 

  42. Thornton MA, Gruentzig AR, Hollma J, et al. Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984 Aug; 69(4): 721–7

    Article  PubMed  CAS  Google Scholar 

  43. Schwartz L, Nourassa MG, Lesperance J, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. New Engl J Med 1988 Jun 30; 318(26): 1714–9

    Article  PubMed  CAS  Google Scholar 

  44. Urban P, Buller N, Fox K, et al. Lack of effect of warfarin on the restenosis rate or on clinical outcome after balloon coronary angioplasty. Br Heart J 1988 Dec; 60(6): 485–8

    Article  PubMed  CAS  Google Scholar 

  45. Serruys PW, Rutsch W, Heyndrick X, et al. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Tromboxane-Antagonism Study (CARPORT). Circulation 1991; 82(4): 1568–80

    Article  Google Scholar 

  46. Grigg LE, Kay TW, Valentine PA, et al. Determinants of restenosis and lack of effect of dietary Supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. Am Coll Cardiol 1989 Marl; 13(3): 665–72

    Article  CAS  Google Scholar 

  47. Weintraub WS, Boccuzzi SJ, Klein JL, et al. Lack of effect of lovastatin on restenosis after coronary angioplasty: Lovastatin Restenosis Trial Study Group. N Engl J Med 1994 Nov; 331(20): 1131–7

    Article  Google Scholar 

  48. Whitworth HB, Roubin GS, Hollman J, et al. Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1986 Dec; 8(6): 1271–6

    Article  PubMed  CAS  Google Scholar 

  49. Faxon DP. Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR Study, a multicenter, double-blind, placebo controlled trial of cilazapril. The Multicenter American Research Trial with Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study group. J Am Coll Cardiol 1995 Feb; 25(2): 362–9

    Article  PubMed  CAS  Google Scholar 

  50. Pepine CJ, Hirschfeld JW, Macdonald RG, et al. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. M-HEART Group. Circulation 1990 Jun; 81(6): 1753–61

    Article  PubMed  CAS  Google Scholar 

  51. Galassi AR, Tamburino C, Nicosia A, et al. A randomized comparison of trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, versus aspirin in prevention of angiographic restenosis after coronary artery Palmaz-Schatz stent implantation. Catheter Cardiovasc Interv 1999 Feb; 46(2): 162–8

    Article  PubMed  CAS  Google Scholar 

  52. Emanulesson H, Beatt KJ, Bagger JP, et al. Long-term effects of angiopeptin treament in coronary angioplasty. Reduction of clinical events but not angiographic restenosis. European Angiopeptin Study Group. Circulation 1995 Mar; 91(6): 2759–60

    Google Scholar 

  53. Bailey S. Local drug delivery during percutaneous coronary intervention. Curr Interv Cardiol Rep 2000; 2(4): 349–57

    PubMed  Google Scholar 

  54. Oberhoff M, Herdeg C, Ghobainy R, et al. Local delivery of Paclitaxel using the double-balloon perfusion catheter before stenting in the porcine coronary artery. Catheter Cardiovasc Interv 2001 Aug; 53(4): 562–8

    Article  PubMed  CAS  Google Scholar 

  55. Ettenson DS, Edelman ER. Local drug delivery: an emerging approach in the treatment of restenosis. Vasc Med 2000; 5(2): 97–102

    PubMed  CAS  Google Scholar 

  56. Hofma SH, van Beusekom HM, Serruys PW, et al. Recent developments in coated stents. Curr Interv Cardiol 2001 Feb; 3(1): 28–36

    Google Scholar 

  57. Xiaoshun L, Huang Y, De Scheerder I. Study of antirestenosis with the biodivysio dexamethasone eluting stent (STRIDE): a multicenter trial. 51st Annual Scientific Session, Atlanta, GA. J Am Coll Cardiol 2002 Mar 17–20; 19, 5 Suppl. A. 15A: 1052–7

    Google Scholar 

  58. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of Sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular study. Circulation 2001; 103(2): 192–5

    Article  PubMed  CAS  Google Scholar 

  59. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104(17): 2007–11

    Article  PubMed  CAS  Google Scholar 

  60. Sousa JE, Morice MC, Serruys PW, et al. The RAVEL Study: a randomized study with the sirolimus coated BX velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions [abstract no. 2198]. Circulation 2001 Oct; 104 Suppl. II: 17

    Google Scholar 

  61. Abizaid A, Serruys P, Abizaid A, et al. The absence of edge effect after implantation of sirolimus-eluting stents to treat in-stent restenosis: a three-dimensional intravascular ultrasound volumetric analysis [abstract no. 1174-14]. J Am Coll Cardiol 2002; 39 (5 Suppl. A): 58A

    Article  Google Scholar 

  62. Degertekin M, Tanabe K, Regar E, et al. Are sirolimus-eluting stents inducing vascular remodeling?: a subgroup analysis of 3D-intravascular ultrasound in the RAVEL trial [abstract no. 1174-18]. J Am Coll Cardiol 2002 Mar 17–20; 39 (5 Suppl. A): 59A

    Article  Google Scholar 

  63. Abizaid A, Serruys P, Sousa JE, et al. Total suppression of neointimal proliferation after implantation of sirolimus-eluting stents: volumeric intravascular ultrasound results from the randomized RAVEL trial [abstract no. 880-4]. J Am Coll Cardiol 2002; 39 Suppl. A: 71A

    Article  Google Scholar 

  64. Moses JW, Leon MB, Popma JJ, et al. The US Multicenter, randomized, double-blind study of the sirolimus-eluting stent in coronary lesions: early (30-day) safety results [abstract 2200]. Circulation 2001 Oct; Suppl. II: 104

    Google Scholar 

  65. Park SJ, Won HS, Ho DS, et al. The clinical effectiveness of paclitaxel-coated coronary stents for the reduction of restenosis in the ASPECT trial [abstract 2199]. Circulation 2001 Oct; 104 Suppl. II: 17

    Google Scholar 

  66. Chevalier B, De Scheerder I, Gershlick A, et al. Effect on restenosis with a paclitaxel eluting stent: factors associated with inhibition in the elutes clinical study [abstract no. 1174-17]. J Am Coll Cardiol 2002 Mar 17–20; 39 (5 Suppl. A): 59A

    Article  Google Scholar 

  67. Grube E, Silber SM, Hauptmann KE, et al. Taxus I: prospective, randomized, double-blind comparison of NIRx TM stents coated with paclitaxel in a polymer carrier in de-novo coronary lesions compared with uncoated controls [abstract 2197]. Circulation 2001 Oct; 104 Suppl. II: 17

    Google Scholar 

  68. Grube E, Serruys PW. Safety and performance of a paclitaxel-eluting stent for the treatment of in-stent restenosis: preliminary results of the Taxus III trial [abstract no. 1174-15]. J Am Coll Cardiol 2002 Mar 17–20; 39 (5 Suppl. A): 58A

    Article  Google Scholar 

  69. Guidant initiates new international paclitaxel eluting stent trial, dated May 2, 2002 [News release]. Available from URL: http://www.guidant.com/webapp/-emarketing/news/news.jsp?date=0502$year=2002. [Accessed 2002 May 27]

  70. Kereiakes DJ, Linnemeier TJ. Studies with actinomycin D: from ACTION to US OPEN pivotal study. Oral presentation during Transcatheter Cardiovascular Therapeutics 2001, Sep 12–16, Washington, DC. Available from URL: http://www/tctmd.com/. [ Accessed 2001 Sep 11].

  71. Chao-Wei H, Wu D, Edelman E. Physiological transport forces govern drug distribution for stent-based delivery. Circulation 2001; 104: 600–5

    Article  Google Scholar 

  72. De Scheerder I, Yanming H, Dens J, et al. Treatment of in-stent restenosis using paclitaxel eluting stents: a single centre pilot trial [abstract 3503]. Circulation 2001 Oct; 104 Suppl. II: 17

    Google Scholar 

  73. Liistro F, Colombo A. Late acute thrombosis after Paclitaxel eluting stent implantation. Heart 2001 Sep; 86(3): 262–4

    Article  PubMed  CAS  Google Scholar 

  74. Degertekin M, Regar E, Tanabe K, et al. Incidence of incomplete stent apposition at six-month follow-up in the multi center RAVEL trial [abstract no. 823-5]. J Am Coll Cardiol 2002 Mar 17-20; 39 (5 Suppl. A): 38A

    Article  Google Scholar 

  75. Serruys PW, Abizaid A, Foley D, et al. Sirolimus-eluting stents abolish neointimal hyperplasia in patients with in-stent restenosis: late angiographic and intravascular ultrasound results [abstract no. 823-1]. J Am Coll Cardiol 2002 Mar 17–20; 39 (5 Suppl. A): 37A

    Article  Google Scholar 

  76. De la Fuente LM, Miano J, Mrad J, et al. Initial results of the Quanam drug-eluting stent (QuaDS-QP-2): registry (BARDDS) in human subjects. Catheter Cardiovasc Interv 2001 Aug; 53(4): 480–8

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors owe much gratitude to John R. Petersen, MD for his review of the manuscript and to Cathy Kennedy for copy editing and manuscript preparation.

This research was supported in part by a Leon Hess Research grant at Lenox Hill Hospital (New York, NY) and Cardiovascular Research Foundation (New York, NY).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeffrey W. Moses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moses, J.W., Kipshidze, N. & Leon, M.B. Perspectives of Drug-Eluting Stents. Am J Cardiovasc Drugs 2, 163–172 (2002). https://doi.org/10.2165/00129784-200202030-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200202030-00004

Keywords

Navigation