Contents

 Perspectives of Drug Eluting Stents
The Next Revolution

Jeffrey W. Moses, Nicholas Kipshidze and Martin B. Leon
Lenox Hill Heart and Vascular Institute of New York
and Cardiovascular Research Foundation, New York, USA

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%) ofrestenosis 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 ofnonsurgical revascularization accounting for about 80% of all ((Author: ?percutaneous or invasive cardiac))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 ofrestenosis.
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 angioplasty ((Author: ?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 (he 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.

 

Literature:
1.Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation 1998; 98: 1802-20
2.Fischman Dl, Leon MB, Baim 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
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
4. Topol EJ. Coronary-artery stents: gauging, gorging, and gouging. N Engl J Med 1998; 339: 1702-4
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
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
7. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stenrs to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987; 316: 701-6
8. El-Omar MM, Dangas G, Iakovou I, et al. Update on in-stent restenosis. Curr Interv Cardiol Rep 2001; 3: 296-305
9. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stent. N Engl J Med 1997; 336: 1697-703
10. Malhorta S, Teirstein PS. The SCRIPPS trial: catheter-based radiotherapy to inhibit coronary restenosis. J Invasive Cardiol 2000; 12 (6) 330-2
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
12. teirstein PS, Kuntz RE. New frontiers in interventional cardiology: intravascular radiation to prevent restenosis. Circulation 2001 Nov. 20; 104 (21): 2620-6
13. Wiletz JR, Sanborn TA, Haudenschild CC, et al. Platelet accumulation in experimental angioplasty: time course and relation to vascular injury. Circulation 1987; (3): 636-42
14. Wilensky RI, March KL, Gradus-Pizlo I, et al. Vascular injury, repair, and restenosis after percutaneous transluminal angioplasty in the atherosclerosit rabbit. Circulation 1995; 92 (10): 2995-3005
15. Stoltenberg RL, Geraghty J, Steele DM, et al. Inhibition of intimal hyperplazia in rat aortic allografts with cyclosporine. Tranplantation 1995; 60 (9): 993-8
16. Glagov S. Intimal hypeplasia, vascular modeling, and the restenosis problem. Circulation 1994; 89:2888-91
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
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
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
20. Moses PRL, Campbell GR, Wang ZL, et al. Smooth muscle phenotypic expression in human arteries. Lab Invest 1985; 53: 556-62
21. Austin GE, Ratliff NB, Hollman J, et al. Intimal 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
22. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury. Lab Invest 1983; 49: 327-33
23. Schwartz SM, deBlois D, O’Brien ERM. The intima: soil for atherosclerosis and restenosis. Circ Res 1995; 77: 445-65
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 Nat Acad Sci USA 1993; 90: 8474-8
25. Sirois MG, Simons M, Edelman BR, et al. Platelet release of platelet derived growth factor is required for intimal hyperplasia in rate vascular injury model [abstract] . Circulation 1994; 90 Suppl. 1:I-511
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
27. Edelman ER, Rogers C. Pathologic responses to stenting. Am J Cardiol 1998; 81: 4E-6E
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
29. Kornowsky R, Hong MK, Tiio FO, et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998; 31:224-30
30. Jawien A, Bowen-Pope DF, Lindner V, et al. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest 1992; 89: 507-11
31. Sriram V, Patterson C. Cell cycle in vasculoproliferative diseases-potential interventions and routes of delivery. Circulation 2001; 103: 2414-9
32. Koster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact allergies in patients with coronaty in-stent restenosis. Lancet 2000; 356: 1895-7
33. Kipshidze N, Moses J, Shankar LR, et al. Perspectives on antisense therapy for the prevention of restenosis. Curr Opin Molecular Ther 2001, 227
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
35. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary areteries by targeting regulators of the cell cycle. Circulation 1999; 99:2164-70
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
37. Marx SO, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001; 104:852-5
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
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
40. Bailey S. Local drug delivery during percutaneous coronary intervention. Curr Interv Cardiol Rep 2000; 2 (4): 349-57
41. 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
42. Ettenson DS, Edelman ER. Local drug delivery: an emerging approach in the treatment of restenosis. Vasc Med 2000; 5 (2): 97-102
43. Hofma SH, van Beusekom HM, Serruys PW, et al. Recent developments in coated stents. Curr Interv Cardiol 2001 Feb; 3 (1): 2836
44. Xiaoshun L, Huang Y, De Scheeder I. Study of antirestenosis with the biodivysiodexamethasone eluting stent (STRIDE): a multicenter trial. 51 Annual Scientific Session, Atlanta, GA. J Am Coll Cardiol 2002 Mar 17-20; 19, 5 Suppl A. 15A: 1052-7
45. 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
46. Sousa JE, Costa MA, Abizaid A, et al. Sustained supression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104 (17): 2007-11
47. 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
48. 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 Mar 17-20; 39 (5 Suppl A): 58A
49. 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
50. 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
51. 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
52.Chevalier B, De Scheeder 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
53. 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
54. 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
55. Chao-Wei H, Wu D, Edelman E. physiological transport forces govern drug distribution for stent-based delivery. Circulation 2001; 104:600-5
56. 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
57. Liistro F, Colombo A. Late acute thrombosis after Paclitaxel eluting stent implantation. Heart 2001 Sep; 86 (3): 262-4
58. Degertekin M, Regar E, Tanabe K, et al. Incidence of incomplete stent apposition at six-month follow-up in the multicenter RAVEL trial [abstract no. 823-5]. J Am Coll Cardiol 2002 Mar 17-20; 39 (5 Suppl A): 38A
59. 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
60. De la Fuente LM, Miano J, Mrad J, et al. Initial results of the Quanam drug-eluting stent (QuaDS-QR-2): registry (BARDDS) in human subjects. Catheter Cardiovasc Interv 2001 Aug; 53 (4): 480-8

Contents