- Email: [email protected]
Drug Eluting Stents: The Promised Land in the Periphery?
References 1. Teirstein PS, MassuIJo V, lani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl] Med 1997; 336:1697-1703. 2. Waksman R, White RL, Chan RC, et al. Intracoronary radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000; 101:2165-2171 3. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl] Med 2001; 344:250-256 4. Ajani AE and Waksman R. Beta radiation-state of the art. ] Interv Cardiol 2001; 14:601-609. 5. Waksman R, Raizner AE, Yeung AC, et al. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controIJed trial. Lancet 2002; 359:551-557. 6. Waksman R. Intracoronary gamma radiation for diffuse in-stent restenosis: a two center randomized clinical study-The Washington radiation for in-stent restenosis trial for tong lesions (LONG WRISD.] Am ColJ Cardiol 2000; 36:315-316. 7. ]aved MH, Mintz GS, Waksman R et al. Serial intravascular ultrasound assessment of the efficacy of intracoronaly ( radiation therapy for preventing recurrence of very long, diffuse, m-stent restenosis lesions. Circulation 2000; 104:856-859. 8. Yerin V, Popowski Y, deBruyne B, et al. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after baIJoon angioplasty. N Engl ] Med 2001; 344:243-249. 9. A1biero R, Nishida T, Adamian M, et al. Edge restenosis after implantation of high activity (32)P radioactive beta-emitting stents. Circulation 2000; 101: 2454-2457. 10. Kim HS, Waksman R, Cottin Y, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. ] Am Coli CardioJ 2001; 37:1026-1030. 11. Cheneau E, Yazdi H, Chan R, et al. How to fix the edge effect of catheter based radiation therapy? Circulation (in press). 12. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. ] Am Coli Cardiol 2000; 36:65-68. 13. Waksman R, Ajani AE, Wbite RL, et al. Twelve versus six montbs of clopidogrel to reduce cardiac major events in patients undergoing gamma radiation therapy for in-stent restenosis: WRIST 12 VS. WRIST PLUS. Circulation (in press). 14. Waksman R, Ajani AE, White RL, et al. lntravascular
gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl ] Med 2002; 346: 1194-1199. 15. Verin V, Urban P, Popowski Y, et al. Feasibility of intracoronaly beta-irradiation to reduce restenosis after balloon angioplasty. A cJinical pilot study. Circulation 1997; 95:1138-1144. 16. King SB III, Williams DO, Chougule P, et al. Endovascular beta-radiation to reduce restenosis after coronaly baIJoon angioplasty: results of the beta energy restenosis trial (BERD. Circulation 1998; 97: 2025-2030 17. Raizner AE, Oesterle SN, Waksman R, et al. lnhibition of restenosis with beta-emitting radiotherapy: report of the proliferation reduction with vascular energy tria l (PREVENT). Circulation 2000; 102:951958. 18. Sianos G, Kay IP, Costa MA, Regar E et al. Geographic miss during catheter based intracoronary beta radiation: incidence and implications in the BRlE study. Beta radiation in Europe. ] Am Coli Cardiol 2001; 38:415-420. 19. Liermann DD, Bottcher HD, Kollath], et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries. Cardiovasc Intervent Radiol 1994; 17: 12-16. 20. Minar E, Pokrajac B, Maca T, et al. Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty : results of a prospective randomized study. Circulation 102: 2694-2699. 21. Waksman R, Laird ]R, ]urkovitz CT, et al. lnu'avascular radiation therapy after baIJoon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARlS feasibility trial. ] Vasc lnterv Radiol 2001; 12:915-921. 8:10 a.m. Gold Medal Award Wi1UJ.er Presentation Sidney Wallace, MD M.D. Anderson Cancer Center Houston, TX
8:25 a.m. Drug Eluting Stents: The Promised Land in the Periphery? Lindsay Mac/Jan, MD University oj British Columbia Vancouver, British Columbia, Canada
Apart from infrainguinal vessels, stenting has been demonstrated to effectively reduce the rate of restenosis when compared to balloon dilatation. However, in-stent restenosis remains the major late term limitation of this technique. In-stent restenosis is considered to be the result of neointimal hyperplasia alone, which is mainly
P83
due to the proliferation of smooth muscle cells and their migration into the intima and secretion of ext.ra cellular proteoglycan matrix. Immediately after stent insertion, platelet activation and thrombus formation take place. There is also acute inflammation, granulation tissue formation, and the local release of chemotaetic and growth factors and oxygen derived free radicJes, which trigger a complex array of events that modulate matrix production and cellular migration and proliferation. Drug Eluting Stents Local drug administration using the stent itself as the delivery platform has theoretical advantages to the stent. As the drug and stent are delivered as a complex, its action begins at the time of vessel injury and additional manipulations are not needed. Creating a drug/polymer complex that will effectively adhere to the stent even with prolonged storage, after sterilisation, and with subsequent expansion is an extraOl'dinary feat. Stents that deliver drugs are complex devices with three components: the stent, the drug and the slow release polymeric coating connecting the two. The longterm outcome of treat.ments with these devices will depend on the mural response to all three components. The underlying polymer must be non-thrombogenic and preferably cause no mural reaction. Drugs that have been actively investigated include Actinomycin-D, Paclitaxel, and fulpamycin.
Actinomycin-D Actinomycin-D is an antibiotic used for its antiproliferative properties in the treatment of various malignant neoplasm. It is a protein synthesis inhibitor at the transcriptional level that blocks cellular proliferation by forming a stable complex with double-stranded DNA (via deoxyguanosine residues), thus blocking DNA-directed RNA synthesis. Its effect as a stent coating were evaJuated by Guidant in the ACTION trial, and after disappointing results, further investigation of actinomycin-D has been interrupted. Paclitaxel Paclitaxel is an antitumoral drug naturally extracted from the bark and needles of the Pacific yew trees. It is a microtubule stabiliser. Mictrotubules are formed by polymers of tubulin in a dynamie equilibrium of alpha and beta subunits and their principal function is the formation of the mitotic spindle during cellular division. Microtubules help to maintain celi shape and are intimately related to the functions of intracellular transport, signalling, protein secretion and motility. PaclitaxeJ induces abnormal polymerization of tubules fonning stable dysfunctional microtubules and therefore disrupting the cellular processes. Several clinical triais using Paclitaxel e1uting stents have or are being conducted. The Taxus trial series is a group or studies using NIR or Express stents are made by Boston Scientific Inc (Mapie Grove, MN) and coated with Paclitaxel. The Taxus-I triaI is a safety study that randomized 61 patients
P84
with de novo lesioos comparing NIR bare stents to Paclitaxel coated stents 0.6 mg/mm 2 ). The restenosis rate at 6 months was 0% in the Paclitaxel coated group versus 10.3% in the bare NIR group (P = .11). No edge effect was observed. Taxus-II is an efficacy study that enrolled 532 patients with de novo coronary lesions. Final results were expected at the end of 2002. ELUTES (the EvaLUation of pacliTaxel Eluting Stents) is a double blind efficacy study which evaluated Paclitaxel coated V-Flex coronary stents from Cook Inc (Bloomington IN) in 190 patients with de novo coronary lesioos. The drug coating of the stent was unique in that no polymeric vehicle was used so the drug was applied directly to the stent. At 6 months, the restenosis rate in the uncoated stent group was 21% versus 3% in the group receiving the highest dose of Paclitaxel (P = .055). The mean diameter stenosis was 34% in the controI group and 14% in the Paclitaxel coated group (P < .01). The ASPECT (Asian Paclitaxel Eluting Stent Clinical Tria!) included 177 patients with de novo coronary lesions treated with the Cook Supra G caronary stent and randomized to no drug ar two different doses of Paclitaxel. Restenosis at 6 months was seen in 27% of patients with uncoated stent and 4% in the highest dose stents (P < .001).
Rapamycin Rapamycin is a macrolide antibiotic with a potent immunosuppressive action produced by Streptomyces hygroscopicus. Rapamycin bJocks celi cycle progression of the Gl to S transition inhibiting cellular proliferation. Its action is mediated by binding to an intracellular receptor, the FK506 binding protein. Complex RapamycinFKBP512 then inhibits the activity of a specific kinase mTOR (mammalian target of Rapamycin). Susa repOlted 45 patients with de novo coronary lesions treated with Bx VeJocity stents (Johnson & Johnson-COl'dis, Brunswiek, NJ) comparing uncoated stents with stents treated with sirolimlls. A fast release preparation permitted drug delively for 15 days and a sJow release preparation more than 28 days. At 6 months, no restenosis was seen in the treated group. RAVEL (RAndomized study with the sirolimus-coated Bx VELocity) balloon expandable stent in the treat.ment of patients with de novo caronary artery treatments compared the outcome of 38 patients who received either bare or drug elllting stents. At 6 months, the restenosis rate in the drug-elllting group was zero, the loss in minimal luminal diameter was zero and there was no target Jesion rejntervention. SIRIUS is a prospective randomized U.S. trial of 1,100 patients with de novo coronary lesions comparing uncoated with Rapamycincoated Bx Velocity stents. Preliminary results in the first 400 patients were presented in the Paris Course on RevascuJarization 2002. In-stent restenosis at 8 months was 2% in the drug coated and 31% in the non-coated stent arm (P < .001). SIROCCO is the only tria! to date evaluating drug
eluting stents in peripheral vascular disease, prospectively randomizing patients with TASC c1ass A, B, or C SFA disease into groups receiving uncoated or Rapamycin-coated Smart stents (Cordis j and J, Miami FL). AJthough the data did not reach statistical significance, at 6 months 17.6% of 16 patients in the uncoated group demonstrated in-stent restenosis (defined as >50% narrowing within the stent) compared with 0% of the Rapamycin group. Of the 33 patients, 6 deveJoped stent fractures. Data has not been presented revealing whether there are c1inical consequences to these fractures at this time.
Brachytherapy In the celi cycle, paclitaxel interrupts passage from M to the Gl phase and Rapamycin transition from Gl to G2. Radjation acts on all stages of the cell cycle. In the coronary circulation brachytherapy has largely been investigated in the tJeatment of in-stent restenosis. Early triais were conducted comparing gamma radiation; in the SCRlPPS I trial, 46.4% of 28 patients in the control group had recurrence of theiJ in-stent restenosis compared with 21.4% of 28 patients in the treatment arm. In \V'RIST, in-stent restenosis recurred in 60.7% of 56 patients compared with 23.7% in the radiated arm. More evaluation of SFA angioplasry complimented by intravascular brachtherapy has been conducted than triais of drug coated stents in the peripheral circulation. In a nonrandomized registry, Lierman and Schappel reported on the use of Ir192 in 29 patients, achieving 80% patency at 5 years. A contral group was not available for comparison. Minar reported that the use of Ir192 in 100 nonrandomized patients resulted in a 50% reduction in restenosis at 5 years in comparison with balloon angioplasry alone. In PARlS 1,13.3% of 35 patients treated with Ir l92 had a 13.3% restenosis rate at 12 months. While all these results which are the logical early assessment of new application of a technology, are tantalizing, we will not have a significant quantification oC the benents oC radiotherapy in the periphelY until the results of PARIS II, a fully enrolled 300 patient prospective randomized tria l are presented later this year. Conclusion Both drug coated stents and brachytherapy have been evaluated more thoroughly in the coronaly circulation than in the periphery; even in that circulation insufficient data is available to assess the fuli impact of either technoJogy on restenosis rates or to allow critical comment on relative efficacies or indications for specific therapies. The earliest impression is that radiotherapy is more Iikely to be applied to in-stent restenosis, and drug eluting stents to cle novo lesions. In the peripheral ciJculation d1ere is even less data to guide us. The unique repetitive mechanical forces placed upon stents in the SFA-popIiteal segment may thwart even the most efficacious stent coating. Between the time of printing of this abstraet and the
oral presentation, considerable new data will become available and will be included in the oral presentation.
Bibliography 1. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis; c1assification and implications for long-term outcome. Circulation 1999; 100:1872-1878 2. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999; 10:499-506. 3. de Feyter Pj, Vos j. Rensing Bj. Anti-restenosis Triais. Curr Interv Cardiol Rep 2000; 2:326-331. 4. Helclman AW, Cheng L, jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasis at 4 weeks in a porcine model of coronaty restenosis. Circulation 2001; 103:2289-2295. 5. Dustin P. Microtubules. Sci Am 1980; 243:66-76. 6. Rowinsky EK, Donehower Re. Paclitaxel (taxol). N Engl j Med 1995; 332:1004-1014. 7. Schiff PB, HOIWitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 1980; 77:1561-1565. 8. jordan MA, Toso Rj, Thrawer D, Wilson L. Mechanism of mitotic block and inhibition of celi proliferation by taxol at low concentrations. Prac Nad Acad Sci USA 1993; 90:9552-9556. 9. Honda Y, Grube E, de la Fuente LM, Yock PG, Sterizer SH, Fitzgerald Pj. Novel drug-delivelY stent: intravasclllar ultrasound observations from the first human experience with the QP2-eluting polymer stent system. Circulation 2001; 104:380-383. 10. Oberholt M, Kunert W, Herdeg C, et al. Inhibitions of smooth mllscle cell proliferation after local drug delivery of the antimitotic drug paclitaxel using a porous baJloon catheter. Basic Res Cardiol 2001; 96: 275-282. 11. Hong MK, Kornowski R, Bramswll 0, Raghab AO, Leon MB. Paclitaxel coated Gianturo-Rollbin 11 (GR II) stents reduce neointimal hyperpJasia in a porcine coronary in-stent restenosis model. Coron AJtery Dis 2001; 12:513-515. 12. Kandzari DE, Kay K, O'Shea jC, et al. Highlights from the American Heart Association annual scientific sessions 2001: November 11 to 14, 2001. Am Heart j 2002; 143:217-228. 13. Park Sj. Asian Paclitaxel Eluting Stent Clinical TrialASPECT. Transcatheter cardiovacular therapeutics 2001 meeting. 14. De la Fuente LM, Miano j, Mradj, et al. Initiał results of the Qunam drug eluting stent (QuaDS-QP-2) RegiStly (BARDDS) in human sllbjects. Catheter Cardiovasc Interv 2001; 53:480-488.
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15. Grube E. SCORE trial. Paris Course of Revascularization-EROPCR 2001. 16. Sun J, Manc SO, Chen HJ, Poon M, Marks AR, Rabbani LE. Role for p27 (KipI) in Vascular Smooth Muscle Celi Migration. Circulation 2001; 103:29672972. 17. Manc SQ, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001; 104:852-855. 18. Suzuki T, Kopia G, Hayashi S, Bailey LI', Llanos G, Wilensky R, et al. Stent based delivelY of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104:1188-1193. 19. Sousa JE, Csta MA, Abizaid AC, Rensing BJ, Abizaid AS, Tanalura LF et al. Sustained suppression of neointimal proliferation by sirolimus eluting stents: oneyear angiographic and intravascular ultrasound follow up. Circulation 2001; 104:2007-2011. 20. Farb A, Heller Pe, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer coated stent. Circulation 2001; 104:473-479.
8:45 a.m. Future Direction with Drug Delivery and Stent Design Julio C. Palmaz, II1D The University oj Texas Health Science Center San Antonio, TX
As a result of attending this session the attendee should be able to: • List patient-related and stent-related causes of instent restenosis. • Give a list of stent design features Iinked to in-stent restenosis. • Name chemical elements related -to in-stent restenosis. The failure mode of contemporaly implantable vascular stents varies according to their size. Large diameter devices such as aortic stent-grafts are most susceptible to corrosion leading to degradation of mechanical integrity. Smali and medium diameter stents such as coronary and renal stents respectively, are prone to neointimal hyperplasia leading to in-stent restenosis. Because of the large num ber of coronary stent procedures performed each year in-stent restenosis is by far the most important Iimitation ofthese devices. Patency of a stent depends on a) the dinical pronie of the host; b) the characteristics of the target lesion; c) procedural factors; and d) technical features of the stent, including its design and material composition. Restenosis is the lossof the luminal diameter gain obtained at the time of initial stent placement due to neointimal hyperplasia. The timing of its occurrence is similar to other percutaneous coronary interventions. In-stent restenosis typically develops 1-3 months after stem placement (1,2), but may be progressive up to 18
P86
months (3). The late lass of the stent lumen by intimal hyperplasia was found to be a constant proportion ot' the initial luminal gain. Because stents produce the largest initial gain, compared to balloon angioplasty and atherectomy, they suffer the largest late loss (4). This nnding is consistent with the fact that a large increase in the lumen generally involves a high degree of vessel wall damage, in tum producing a propoltionally large intimal hyperplastic response. The correlation or the degree of stent-induced injury to the vessel wall, with the extent of intimal hyperplasia was demonstrated in experimental models (5). Schwartz et al demonstrated a close correlation between the degree of penetration of the stent struts into the layers of the vessel wall and intimal proliferation measured as cross sectional area. In human specimens obtained at autopsy or postoperatively, Farb et al. connrmed a relationship between injury and extent of intimai formation (6). More recently, the degree of intimal hyperplasia has been correlated with histological evidence of inflammation in the stented vessel. Acute inflammatolY innltrates of neutrophils is prevalent a few days after stent placement (6), while macrophages and Iymphocytes predominate 6 months following stenting and later (7). However, granuloma formation has been observed in the vicinity of the stent struts in stented vessels with intimal hyperplasia, independently from the degree of injury (8). AJthough inflammatory infiltrate has been identined predominantly in stented vessels with medial disruption, and penetration of stent struts in the lipid core (7), others have called attention on the role of particulate contaminants of stents producing inflammation. Whelan et al. (9), identified starch and nbers in tissues surrounding implanted stents, and Bayes-Genis et al. (10), demonstrated that pressure rinsing of stents before placement to remove particulate contaminants, results in a reduction af intimal hyperplasia. Kastrati et al. (11), recently reviewed restenosis risk factors after coronary angioplasty and stenting. Increased risk for restenosis was associated with clinical pronie variabies such as diabetes mellirus and high blood pressure. Other clinical risks for stent restenosis included the DD phenotype for tl1e angiotensin converting enzyme gene (12). Elevated fibrinogen level is Iikely to increase the risk for stent restenosis since it has been associated with increased failllre rate of vascular implants such as in lower extremity bypass procedures (13). Lesion characteristics sllch as smali diameter vessel, long lesions, ostial lesions, complex lesions, complete occlusions, high grade stenoses and previollsly stenotic lesions, are all associated with an increased risk of restenosis. Finally, procedural variabies such as placement of muItiple stents, and stent type have a strong influence on the proceduraI outcame (11). Among all of the currently known risk factors, the technical aspects of the stem are the most amenable to change. Optimization of stent design and materials hopefully will lead to improved clinical results.
gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl ] Med 2002; 346: 1194-1199. 15. Verin V, Urban P, Popowski Y, et al. Feasibility of intracoronaly beta-irradiation to reduce restenosis after balloon angioplasty. A cJinical pilot study. Circulation 1997; 95:1138-1144. 16. King SB III, Williams DO, Chougule P, et al. Endovascular beta-radiation to reduce restenosis after coronaly baIJoon angioplasty: results of the beta energy restenosis trial (BERD. Circulation 1998; 97: 2025-2030 17. Raizner AE, Oesterle SN, Waksman R, et al. lnhibition of restenosis with beta-emitting radiotherapy: report of the proliferation reduction with vascular energy tria l (PREVENT). Circulation 2000; 102:951958. 18. Sianos G, Kay IP, Costa MA, Regar E et al. Geographic miss during catheter based intracoronary beta radiation: incidence and implications in the BRlE study. Beta radiation in Europe. ] Am Coli Cardiol 2001; 38:415-420. 19. Liermann DD, Bottcher HD, Kollath], et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries. Cardiovasc Intervent Radiol 1994; 17: 12-16. 20. Minar E, Pokrajac B, Maca T, et al. Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty : results of a prospective randomized study. Circulation 102: 2694-2699. 21. Waksman R, Laird ]R, ]urkovitz CT, et al. lnu'avascular radiation therapy after baIJoon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARlS feasibility trial. ] Vasc lnterv Radiol 2001; 12:915-921. 8:10 a.m. Gold Medal Award Wi1UJ.er Presentation Sidney Wallace, MD M.D. Anderson Cancer Center Houston, TX
8:25 a.m. Drug Eluting Stents: The Promised Land in the Periphery? Lindsay Mac/Jan, MD University oj British Columbia Vancouver, British Columbia, Canada
Apart from infrainguinal vessels, stenting has been demonstrated to effectively reduce the rate of restenosis when compared to balloon dilatation. However, in-stent restenosis remains the major late term limitation of this technique. In-stent restenosis is considered to be the result of neointimal hyperplasia alone, which is mainly
P83
due to the proliferation of smooth muscle cells and their migration into the intima and secretion of ext.ra cellular proteoglycan matrix. Immediately after stent insertion, platelet activation and thrombus formation take place. There is also acute inflammation, granulation tissue formation, and the local release of chemotaetic and growth factors and oxygen derived free radicJes, which trigger a complex array of events that modulate matrix production and cellular migration and proliferation. Drug Eluting Stents Local drug administration using the stent itself as the delivery platform has theoretical advantages to the stent. As the drug and stent are delivered as a complex, its action begins at the time of vessel injury and additional manipulations are not needed. Creating a drug/polymer complex that will effectively adhere to the stent even with prolonged storage, after sterilisation, and with subsequent expansion is an extraOl'dinary feat. Stents that deliver drugs are complex devices with three components: the stent, the drug and the slow release polymeric coating connecting the two. The longterm outcome of treat.ments with these devices will depend on the mural response to all three components. The underlying polymer must be non-thrombogenic and preferably cause no mural reaction. Drugs that have been actively investigated include Actinomycin-D, Paclitaxel, and fulpamycin.
Actinomycin-D Actinomycin-D is an antibiotic used for its antiproliferative properties in the treatment of various malignant neoplasm. It is a protein synthesis inhibitor at the transcriptional level that blocks cellular proliferation by forming a stable complex with double-stranded DNA (via deoxyguanosine residues), thus blocking DNA-directed RNA synthesis. Its effect as a stent coating were evaJuated by Guidant in the ACTION trial, and after disappointing results, further investigation of actinomycin-D has been interrupted. Paclitaxel Paclitaxel is an antitumoral drug naturally extracted from the bark and needles of the Pacific yew trees. It is a microtubule stabiliser. Mictrotubules are formed by polymers of tubulin in a dynamie equilibrium of alpha and beta subunits and their principal function is the formation of the mitotic spindle during cellular division. Microtubules help to maintain celi shape and are intimately related to the functions of intracellular transport, signalling, protein secretion and motility. PaclitaxeJ induces abnormal polymerization of tubules fonning stable dysfunctional microtubules and therefore disrupting the cellular processes. Several clinical triais using Paclitaxel e1uting stents have or are being conducted. The Taxus trial series is a group or studies using NIR or Express stents are made by Boston Scientific Inc (Mapie Grove, MN) and coated with Paclitaxel. The Taxus-I triaI is a safety study that randomized 61 patients
P84
with de novo lesioos comparing NIR bare stents to Paclitaxel coated stents 0.6 mg/mm 2 ). The restenosis rate at 6 months was 0% in the Paclitaxel coated group versus 10.3% in the bare NIR group (P = .11). No edge effect was observed. Taxus-II is an efficacy study that enrolled 532 patients with de novo coronary lesions. Final results were expected at the end of 2002. ELUTES (the EvaLUation of pacliTaxel Eluting Stents) is a double blind efficacy study which evaluated Paclitaxel coated V-Flex coronary stents from Cook Inc (Bloomington IN) in 190 patients with de novo coronary lesioos. The drug coating of the stent was unique in that no polymeric vehicle was used so the drug was applied directly to the stent. At 6 months, the restenosis rate in the uncoated stent group was 21% versus 3% in the group receiving the highest dose of Paclitaxel (P = .055). The mean diameter stenosis was 34% in the controI group and 14% in the Paclitaxel coated group (P < .01). The ASPECT (Asian Paclitaxel Eluting Stent Clinical Tria!) included 177 patients with de novo coronary lesions treated with the Cook Supra G caronary stent and randomized to no drug ar two different doses of Paclitaxel. Restenosis at 6 months was seen in 27% of patients with uncoated stent and 4% in the highest dose stents (P < .001).
Rapamycin Rapamycin is a macrolide antibiotic with a potent immunosuppressive action produced by Streptomyces hygroscopicus. Rapamycin bJocks celi cycle progression of the Gl to S transition inhibiting cellular proliferation. Its action is mediated by binding to an intracellular receptor, the FK506 binding protein. Complex RapamycinFKBP512 then inhibits the activity of a specific kinase mTOR (mammalian target of Rapamycin). Susa repOlted 45 patients with de novo coronary lesions treated with Bx VeJocity stents (Johnson & Johnson-COl'dis, Brunswiek, NJ) comparing uncoated stents with stents treated with sirolimlls. A fast release preparation permitted drug delively for 15 days and a sJow release preparation more than 28 days. At 6 months, no restenosis was seen in the treated group. RAVEL (RAndomized study with the sirolimus-coated Bx VELocity) balloon expandable stent in the treat.ment of patients with de novo caronary artery treatments compared the outcome of 38 patients who received either bare or drug elllting stents. At 6 months, the restenosis rate in the drug-elllting group was zero, the loss in minimal luminal diameter was zero and there was no target Jesion rejntervention. SIRIUS is a prospective randomized U.S. trial of 1,100 patients with de novo coronary lesions comparing uncoated with Rapamycincoated Bx Velocity stents. Preliminary results in the first 400 patients were presented in the Paris Course on RevascuJarization 2002. In-stent restenosis at 8 months was 2% in the drug coated and 31% in the non-coated stent arm (P < .001). SIROCCO is the only tria! to date evaluating drug
eluting stents in peripheral vascular disease, prospectively randomizing patients with TASC c1ass A, B, or C SFA disease into groups receiving uncoated or Rapamycin-coated Smart stents (Cordis j and J, Miami FL). AJthough the data did not reach statistical significance, at 6 months 17.6% of 16 patients in the uncoated group demonstrated in-stent restenosis (defined as >50% narrowing within the stent) compared with 0% of the Rapamycin group. Of the 33 patients, 6 deveJoped stent fractures. Data has not been presented revealing whether there are c1inical consequences to these fractures at this time.
Brachytherapy In the celi cycle, paclitaxel interrupts passage from M to the Gl phase and Rapamycin transition from Gl to G2. Radjation acts on all stages of the cell cycle. In the coronary circulation brachytherapy has largely been investigated in the tJeatment of in-stent restenosis. Early triais were conducted comparing gamma radiation; in the SCRlPPS I trial, 46.4% of 28 patients in the control group had recurrence of theiJ in-stent restenosis compared with 21.4% of 28 patients in the treatment arm. In \V'RIST, in-stent restenosis recurred in 60.7% of 56 patients compared with 23.7% in the radiated arm. More evaluation of SFA angioplasry complimented by intravascular brachtherapy has been conducted than triais of drug coated stents in the peripheral circulation. In a nonrandomized registry, Lierman and Schappel reported on the use of Ir192 in 29 patients, achieving 80% patency at 5 years. A contral group was not available for comparison. Minar reported that the use of Ir192 in 100 nonrandomized patients resulted in a 50% reduction in restenosis at 5 years in comparison with balloon angioplasry alone. In PARlS 1,13.3% of 35 patients treated with Ir l92 had a 13.3% restenosis rate at 12 months. While all these results which are the logical early assessment of new application of a technology, are tantalizing, we will not have a significant quantification oC the benents oC radiotherapy in the periphelY until the results of PARIS II, a fully enrolled 300 patient prospective randomized tria l are presented later this year. Conclusion Both drug coated stents and brachytherapy have been evaluated more thoroughly in the coronaly circulation than in the periphery; even in that circulation insufficient data is available to assess the fuli impact of either technoJogy on restenosis rates or to allow critical comment on relative efficacies or indications for specific therapies. The earliest impression is that radiotherapy is more Iikely to be applied to in-stent restenosis, and drug eluting stents to cle novo lesions. In the peripheral ciJculation d1ere is even less data to guide us. The unique repetitive mechanical forces placed upon stents in the SFA-popIiteal segment may thwart even the most efficacious stent coating. Between the time of printing of this abstraet and the
oral presentation, considerable new data will become available and will be included in the oral presentation.
Bibliography 1. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis; c1assification and implications for long-term outcome. Circulation 1999; 100:1872-1878 2. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999; 10:499-506. 3. de Feyter Pj, Vos j. Rensing Bj. Anti-restenosis Triais. Curr Interv Cardiol Rep 2000; 2:326-331. 4. Helclman AW, Cheng L, jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasis at 4 weeks in a porcine model of coronaty restenosis. Circulation 2001; 103:2289-2295. 5. Dustin P. Microtubules. Sci Am 1980; 243:66-76. 6. Rowinsky EK, Donehower Re. Paclitaxel (taxol). N Engl j Med 1995; 332:1004-1014. 7. Schiff PB, HOIWitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 1980; 77:1561-1565. 8. jordan MA, Toso Rj, Thrawer D, Wilson L. Mechanism of mitotic block and inhibition of celi proliferation by taxol at low concentrations. Prac Nad Acad Sci USA 1993; 90:9552-9556. 9. Honda Y, Grube E, de la Fuente LM, Yock PG, Sterizer SH, Fitzgerald Pj. Novel drug-delivelY stent: intravasclllar ultrasound observations from the first human experience with the QP2-eluting polymer stent system. Circulation 2001; 104:380-383. 10. Oberholt M, Kunert W, Herdeg C, et al. Inhibitions of smooth mllscle cell proliferation after local drug delivery of the antimitotic drug paclitaxel using a porous baJloon catheter. Basic Res Cardiol 2001; 96: 275-282. 11. Hong MK, Kornowski R, Bramswll 0, Raghab AO, Leon MB. Paclitaxel coated Gianturo-Rollbin 11 (GR II) stents reduce neointimal hyperpJasia in a porcine coronary in-stent restenosis model. Coron AJtery Dis 2001; 12:513-515. 12. Kandzari DE, Kay K, O'Shea jC, et al. Highlights from the American Heart Association annual scientific sessions 2001: November 11 to 14, 2001. Am Heart j 2002; 143:217-228. 13. Park Sj. Asian Paclitaxel Eluting Stent Clinical TrialASPECT. Transcatheter cardiovacular therapeutics 2001 meeting. 14. De la Fuente LM, Miano j, Mradj, et al. Initiał results of the Qunam drug eluting stent (QuaDS-QP-2) RegiStly (BARDDS) in human sllbjects. Catheter Cardiovasc Interv 2001; 53:480-488.
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15. Grube E. SCORE trial. Paris Course of Revascularization-EROPCR 2001. 16. Sun J, Manc SO, Chen HJ, Poon M, Marks AR, Rabbani LE. Role for p27 (KipI) in Vascular Smooth Muscle Celi Migration. Circulation 2001; 103:29672972. 17. Manc SQ, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001; 104:852-855. 18. Suzuki T, Kopia G, Hayashi S, Bailey LI', Llanos G, Wilensky R, et al. Stent based delivelY of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104:1188-1193. 19. Sousa JE, Csta MA, Abizaid AC, Rensing BJ, Abizaid AS, Tanalura LF et al. Sustained suppression of neointimal proliferation by sirolimus eluting stents: oneyear angiographic and intravascular ultrasound follow up. Circulation 2001; 104:2007-2011. 20. Farb A, Heller Pe, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer coated stent. Circulation 2001; 104:473-479.
8:45 a.m. Future Direction with Drug Delivery and Stent Design Julio C. Palmaz, II1D The University oj Texas Health Science Center San Antonio, TX
As a result of attending this session the attendee should be able to: • List patient-related and stent-related causes of instent restenosis. • Give a list of stent design features Iinked to in-stent restenosis. • Name chemical elements related -to in-stent restenosis. The failure mode of contemporaly implantable vascular stents varies according to their size. Large diameter devices such as aortic stent-grafts are most susceptible to corrosion leading to degradation of mechanical integrity. Smali and medium diameter stents such as coronary and renal stents respectively, are prone to neointimal hyperplasia leading to in-stent restenosis. Because of the large num ber of coronary stent procedures performed each year in-stent restenosis is by far the most important Iimitation ofthese devices. Patency of a stent depends on a) the dinical pronie of the host; b) the characteristics of the target lesion; c) procedural factors; and d) technical features of the stent, including its design and material composition. Restenosis is the lossof the luminal diameter gain obtained at the time of initial stent placement due to neointimal hyperplasia. The timing of its occurrence is similar to other percutaneous coronary interventions. In-stent restenosis typically develops 1-3 months after stem placement (1,2), but may be progressive up to 18
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months (3). The late lass of the stent lumen by intimal hyperplasia was found to be a constant proportion ot' the initial luminal gain. Because stents produce the largest initial gain, compared to balloon angioplasty and atherectomy, they suffer the largest late loss (4). This nnding is consistent with the fact that a large increase in the lumen generally involves a high degree of vessel wall damage, in tum producing a propoltionally large intimal hyperplastic response. The correlation or the degree of stent-induced injury to the vessel wall, with the extent of intimal hyperplasia was demonstrated in experimental models (5). Schwartz et al demonstrated a close correlation between the degree of penetration of the stent struts into the layers of the vessel wall and intimal proliferation measured as cross sectional area. In human specimens obtained at autopsy or postoperatively, Farb et al. connrmed a relationship between injury and extent of intimai formation (6). More recently, the degree of intimal hyperplasia has been correlated with histological evidence of inflammation in the stented vessel. Acute inflammatolY innltrates of neutrophils is prevalent a few days after stent placement (6), while macrophages and Iymphocytes predominate 6 months following stenting and later (7). However, granuloma formation has been observed in the vicinity of the stent struts in stented vessels with intimal hyperplasia, independently from the degree of injury (8). AJthough inflammatory infiltrate has been identined predominantly in stented vessels with medial disruption, and penetration of stent struts in the lipid core (7), others have called attention on the role of particulate contaminants of stents producing inflammation. Whelan et al. (9), identified starch and nbers in tissues surrounding implanted stents, and Bayes-Genis et al. (10), demonstrated that pressure rinsing of stents before placement to remove particulate contaminants, results in a reduction af intimal hyperplasia. Kastrati et al. (11), recently reviewed restenosis risk factors after coronary angioplasty and stenting. Increased risk for restenosis was associated with clinical pronie variabies such as diabetes mellirus and high blood pressure. Other clinical risks for stent restenosis included the DD phenotype for tl1e angiotensin converting enzyme gene (12). Elevated fibrinogen level is Iikely to increase the risk for stent restenosis since it has been associated with increased failllre rate of vascular implants such as in lower extremity bypass procedures (13). Lesion characteristics sllch as smali diameter vessel, long lesions, ostial lesions, complex lesions, complete occlusions, high grade stenoses and previollsly stenotic lesions, are all associated with an increased risk of restenosis. Finally, procedural variabies such as placement of muItiple stents, and stent type have a strong influence on the proceduraI outcame (11). Among all of the currently known risk factors, the technical aspects of the stem are the most amenable to change. Optimization of stent design and materials hopefully will lead to improved clinical results.