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Angiographic Pattern of Restenosis Following Implantation of Overlapping Sirolimus-Eluting (Cypher) Stents
Angiographic Pattern of Restenosis Following Implantation of Overlapping Sirolimus-Eluting (Cypher) Stents Robert M. Minutello, MD*, Sherrita Bhagan, MD, Dmitriy Feldman, MD, Atul Sharma, MD, Mun K. Hong, MD, and S. Chiu Wong, MD Sirolimus-eluting stents (Cypher) have been shown to reduce the frequency of neointimal hyperplasia and restenosis compared with bare metal stents. However, the clinical implication of overlapping stents with regard to the pattern of restenosis is unclear. All patients who underwent angiography at our institution from May 2003 to March 2005 who had previously received 2 overlapping Cypher stents in native coronary lesions and had binary restenosis were included in our study. Quantitative coronary analysis was performed to determine the degree and location of the restenotic lesion with respect to the overlapping stented segment. The primary end point was to determine how often restenotic lesions occurred at the overlapped segment versus the nonoverlapped stented segments. During the study, 11 patients fit the inclusion criteria for our study; 91% were men and 55% had diabetes mellitus. The mean total stent length was 33.7 ⴞ 8.2 mm. The mean length of the overlapped segment was 5.9 ⴞ 3.8 mm, equating to 19 ⴞ 16% of the total stented area. The average time to follow-up angiography was 277 ⴞ 126 days. All 11 lesions exhibited type 1 (focal) restenosis. Of these 11 lesions, 10 had focal restenosis at the overlapped segment (p ⴝ 0.01, binomial test). The single case involving in-stent restenosis in the nonoverlapped segment occurred at the proximal stent edge. In conclusion, the pattern of restenosis observed in our study suggests a higher relative incidence of binary restenosis in the overlapped stented segment in patients who receive 2 overlapping Cypher stents. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006; 97:499 –501) Recent studies with sirolimus-eluting coronary stents (Cypher, Cordis, Johnson & Johnson, Warren, New Jersey) have shown markedly lower rates of restenosis compared with conventional bare metal stents.1,2 Sirolimus (rapamycin), a macrocyclic lactone with anti-inflammatory and antiproliferative properties,3,4 has been shown to reduce the frequency of neointimal hyperplasia when delivered locally using a polymer stent system.5 The theoretical advantage of sirolimus as an antiproliferative agent includes a large therapeutic window,6 which would suggest safety in “double dosing” of sirolimus locally, such as in the case of overlapping stents. We sought to determine whether the incidence of restenosis is higher at the overlapped stented segment (OSS) compared with the nonoverlapped stented segments (NOS) in patients who received 2 overlapping Cypher stents and had binary restenosis on repeat angiography. •••
All patients who underwent coronary angiography at our institution from May 2003 to March 2005 who had previously received 2 overlapping Cypher stents in native coronary lesions and had binary restenosis were included in our Weill Cornell Medical College, New York, New York. Manuscript received May 26, 2005; revised manuscript received and accepted September 2, 2005. * Corresponding author: Tel: 212-746-2157; fax: 212-746-8295. E-mail address: [email protected] (R.M. Minutello). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.09.082
study. Patients who presented with acute myocardial infarction and/or presented with stent thrombosis were excluded. Patients were eligible only if the stents had been placed sequentially and longitudinally, and the area of overlap of the 2 Cypher stents was visible on angiography. Patients who had Cypher stents placed within previously placed stents and patients who had undergone bifurcation stenting were excluded. Quantitative coronary analysis was performed on all angiograms using dedicated software (QCA-CMS, version 4.0, Medis, Leiden, The Netherlands). In-stent measurements were made within the stented segment, and in-segment measurements were made within the entire stented segment plus 5 mm proximal to the proximal stent and 5 mm distal to the distal stent. The OSS corresponded to the area of stent overlap as visualized by angiography. The NOS included the in-segment area at the proximal and distal edges. The length of the OSS is a calculated value derived from the known stents lengths and the quantitative coronary angiography measured OSS/NOS length ratio, excluding the nonstented proximal and distal segments. Binary restenosis was defined as a stenosis diameter of ⱖ50%. The minimal lumen diameter and degree of stenosis were measured in the OSS and NOS. The length and percentage of the stented segment that overlapped were measured. The primary end point determined how often binary restenosis occurred at the OSS compared with the NOS in www.AJConline.org
500
The American Journal of Cardiology (www.AJConline.org)
3 of the 11 lesions. In no cases were second Cypher stents placed for edge dissection of the first stent. The area of stent overlap was clearly demarcated on follow-up angiography for all 11 lesions. The average time to follow-up angiography was 277 ⫾ 126 days. The mean reference vessel diameter was 2.69 ⫾ 0.69 mm, with an average minimal luminal diameter of 0.81 ⫾ 0.39 mm, corresponding to a mean degree of obstruction of 71 ⫾ 8%. The average lesion length was 5.5 ⫾ 2.4 mm. All 11 lesions exhibited type 1 (focal ⬍10 mm) restenosis. Of these 11 lesions, 10 had focal restenosis at the OSS (p ⫽ 0.01, binomial test). In these 10 cases, on average, 82 ⫾ 26% of the total restenotic tissue was located within the OSS. The single case involving in-stent restenosis in the NOS occurred at the proximal stent edge. Figure 1 shows 1 patient with type 1 restenosis at the OSS. •••
Figure 1. Two cine still frames from identical angle before and during coronary contrast injection in patient with angiographic in-stent restenosis at the site of Cypher overlap (arrows).
patients with binary restenosis at follow-up. That is, was the frequency of significant neointimal hyperplasia in the OSS greater than the NOS at angiographic follow-up in patients with restenosis. If the minimal lumen diameter of the restenotic lesion occurred in the OSS, was focal (⬍10 mm), and extended into the NOS, it was considered to be at the OSS. Consideration was also made that the NOS would likely occupy a longer length on average compared with the OSS, which in general would be relatively short. Given that our null hypothesis assumed equal frequencies of binary restenosis at the NOS and OSS, we accepted the possibility of a type 2 error, given that on average the area of NOS is likely to be significantly greater than the area of the OSS. A 2-tailed binomial test was performed using the previously mentioned distribution assumption. During the study, 11 patients who underwent angiography at our institution fit the inclusion criteria for our study. Of these patients, 10 were men and 55% had diabetes. Of the 11 lesions, 8 were in the left anterior descending artery, 2 in the right coronary artery, and 1 in the left circumflex artery. The mean total stent length (i.e., the NOS plus the OSS) was 33.7 ⫾ 8.2 mm. The mean length of the OSS was 5.9 ⫾ 3.8 mm, which equates to 19 ⫾ 16% of the total stented area. During their initial percutaneous coronary intervention (PCI), the mean maximum balloon/stent inflation pressure was 14.5 ⫾ 3.6 atm. The immediate post-PCI angiogram revealed ⬍10% residual stenosis in all 11 lesions by quantitative coronary angiography. The OSS was anatomically positioned at the location of the minimal luminal diameter of the lesion on the original, pre-PCI angiogram in
The results from large multicenter randomized clinical trials, most notably the Randomized Study with the SirolimusCoated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) and the US Multicenter, Randomized Double-Blind Study of the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS), have clearly shown the benefit of the sirolimus-eluting stent (Cypher) versus bare metal stents in reducing rates of in-stent restenosis and target lesion revascularization.1,2 In the SIRIUS trial, 28% of all patients had overlapping stents, with a target lesion revascularization rate in the sirolimus arm of 4.5% at 9 months and 5.7% at 1 year.2 Moreover, most restenosis observed in the Cypher stents was type 1 (focal).7,8 The assumption for the apparent efficacy of overlapping drug-eluting stents is the large therapeutic window of sirolimus in its cellular pharmacologic actions. Commercially available Cypher stents contain sirolimus at a dosage of 140 g/cm2,9 and ⱕ1,200 g/stent has been used in models without demonstrating local toxicity.5 These drugspecific pharmacokinetics make “double-dose delivery” in the case of overlapping stents potentially safe with respect to cellular toxicity and injury. However, the effect of having twice the drug and polymer locally in a coronary artery on neointimal proliferation is less clear, although some small studies that have examined cases of overlapping Cypher stents have shown no detrimental effect.10 Reports have shown that nearly all biocompatible polymers are associated with some degree of inflammatory reaction.11 It has been postulated that the inflammatory reaction in the endothelium of coronary arteries implanted with Cypher stents seen at autopsy may have been due to the polymer coating and not necessarily the metal or drug.12,13 Data from porcine models have demonstrated a more severe, persistent endothelial inflammatory response after polymer stent implantation, with a high polymer mass versus low polymer mass.14 These data suggest a possible dose response with respect to tissue inflammation and polymer amount, which would be
Coronary Artery Disease/Restenosis in Overlapping Cypher Stents
relevant in cases of Cypher overlap, because inflammation is known to be a potent stimulus for neointimal thickening.15,16 Moreover, others have postulated a possible delayed vascular inflammatory response to the stent polymer, as is seen in porcine models.12,17,18 This delayed inflammatory response may first manifest itself as neointimal growth at the OSS, given the higher polymer burden. The mean time to repeat angiogram in our study was 277 days, longer than the protocol-driven mandatory follow-up angiogram in the SIRIUS trial (240 days). Other possible explanations for the higher incidence of restenosis observed at the OSS include uneven distribution of drug release and suboptimal stent geometry in the case of overlap, which can potentially influence drug delivery.19 Moreover, stent expansion may have been suboptimal at the area of stent overlap, because the vessel cross-sectional area has been shown to be predictive of in-stent restenosis in Cypher stents.20 1. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R, for the RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 2. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE, for the SIRIUS Investigators. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 3. Gallo R, Padurean A, Jayaraman T, Marx S, Roque M, Adelman S, Chesebro J, Fallon J, Fuster V, Marks A, Badimon JJ. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999;99: 2164 –2170. 4. Marx SO, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001;104:852– 855. 5. Sousa JE, Costa MA, Abizaid A, Abizaid AS, Feres F, Pinto IM, Seixas AC, Staico R, Mattos LA, Sousa AG, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and threedimensional intravascular ultrasound study. Circulation 2001; 103:192–195. 6. Kopia GA, Snead D, Palotico R, Laver M, Fischell T, Devries J, Carter AJ, Tio F, Hulsebos L, Turck P, Snodgrass J, Dooley J. Pharmacokinetics and pharmacodynamics of sirolimus-eluting stents. Am J Cardiol 2002;90(suppl):117H.
501
7. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE, for the SIRIUS Investigators. Quantitative assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation 2004;110:3773–3780. 8. Colombo A, Orlic D, Stankovic G, Corvaja N, Spanos V, Montorfano M, Liistro F, Carlino M, Airoldi F, Chieffo A, Di Mario C. Preliminary observations regarding angiographic pattern of restenosis after rapamycin-eluting stent implantation. Circulation 2003;107:2178 –2180. 9. McKeage K, Murdoch D, Goa KL. The sirolimus-eluting stent: a review of its use in the treatment of coronary artery disease. Am J Cardiovasc Drugs 2003;3:211–230. 10. Munoz JS, Abizaid A, Mintz GS, Albertal M, Abizaid AS, Feres F, Centemero M, Staico R, Mattos LA, Pinto I, Sousa A, Sousa JE. Intravascular ultrasound study of effects of overlapping sirolimuseluting stents. Am J Cardiol 2004;93:470 – 473. 11. van der Giessen WJ, Lincoff AM, Schwartz RS, van Beusekom HM, Serruys PW, Holmes DR Jr, Ellis SG, Topol EJ. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation 1996;94:1690 –1697. 12. Virmani R, Farb A, Guagliumi G, Kolodgie FD. Drug-eluting stents: caution and concerns for long-term outcome. Coron Artery Dis 2004; 15:313–318. 13. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimuseluting stent: should we be cautious? Circulation 2004;109:701–705. 14. Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou G, Narayan P, Leon MB, et al. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001;104:1188 –1193. 15. Kornowski R, Hong MK, Tio FO, Bramwell O, Wu H, Leon MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998;31: 224 –230. 16. Schwartz RS, Chronos NA, Virmani R. Preclinical restenosis models and drug-eluting stents: still important, still much to learn. J Am Coll Cardiol 2004;44:1373–1385. 17. Carter AJ, Aggarwal M, Kopia GA, Tio F, Tsao PS, Kolata R, Yeung AC, Llanos G, Dooley J, Falotico R. Long-term effects of polymerbased, slow-release, sirolimus-eluting stents in a porcine coronary model. Cardiovasc Res 2004;63:617– 624. 18. Lafont A. The Cypher stent: no longer efficacious at three months in the porcine model? Cardiovasc Res 2004;63:575–576. 19. Colombo A, Stankovic G, Moses JW. Selection of coronary stents. J Am Coll Cardiol 2002;40:1021–1033. 20. Takebayashi H, Kobayashi Y, Mintz GS, Carlier SG, Fujii K, Yasuda T, Moussa I, Mehran R, Dangas GD, Collins MB, et al. Intravascular ultrasound assessment of lesions with target vessel failure after sirolimus-eluting stent implantation. Am J Cardiol 2005;95:498 –502.
All patients who underwent coronary angiography at our institution from May 2003 to March 2005 who had previously received 2 overlapping Cypher stents in native coronary lesions and had binary restenosis were included in our Weill Cornell Medical College, New York, New York. Manuscript received May 26, 2005; revised manuscript received and accepted September 2, 2005. * Corresponding author: Tel: 212-746-2157; fax: 212-746-8295. E-mail address: [email protected] (R.M. Minutello). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.09.082
study. Patients who presented with acute myocardial infarction and/or presented with stent thrombosis were excluded. Patients were eligible only if the stents had been placed sequentially and longitudinally, and the area of overlap of the 2 Cypher stents was visible on angiography. Patients who had Cypher stents placed within previously placed stents and patients who had undergone bifurcation stenting were excluded. Quantitative coronary analysis was performed on all angiograms using dedicated software (QCA-CMS, version 4.0, Medis, Leiden, The Netherlands). In-stent measurements were made within the stented segment, and in-segment measurements were made within the entire stented segment plus 5 mm proximal to the proximal stent and 5 mm distal to the distal stent. The OSS corresponded to the area of stent overlap as visualized by angiography. The NOS included the in-segment area at the proximal and distal edges. The length of the OSS is a calculated value derived from the known stents lengths and the quantitative coronary angiography measured OSS/NOS length ratio, excluding the nonstented proximal and distal segments. Binary restenosis was defined as a stenosis diameter of ⱖ50%. The minimal lumen diameter and degree of stenosis were measured in the OSS and NOS. The length and percentage of the stented segment that overlapped were measured. The primary end point determined how often binary restenosis occurred at the OSS compared with the NOS in www.AJConline.org
500
The American Journal of Cardiology (www.AJConline.org)
3 of the 11 lesions. In no cases were second Cypher stents placed for edge dissection of the first stent. The area of stent overlap was clearly demarcated on follow-up angiography for all 11 lesions. The average time to follow-up angiography was 277 ⫾ 126 days. The mean reference vessel diameter was 2.69 ⫾ 0.69 mm, with an average minimal luminal diameter of 0.81 ⫾ 0.39 mm, corresponding to a mean degree of obstruction of 71 ⫾ 8%. The average lesion length was 5.5 ⫾ 2.4 mm. All 11 lesions exhibited type 1 (focal ⬍10 mm) restenosis. Of these 11 lesions, 10 had focal restenosis at the OSS (p ⫽ 0.01, binomial test). In these 10 cases, on average, 82 ⫾ 26% of the total restenotic tissue was located within the OSS. The single case involving in-stent restenosis in the NOS occurred at the proximal stent edge. Figure 1 shows 1 patient with type 1 restenosis at the OSS. •••
Figure 1. Two cine still frames from identical angle before and during coronary contrast injection in patient with angiographic in-stent restenosis at the site of Cypher overlap (arrows).
patients with binary restenosis at follow-up. That is, was the frequency of significant neointimal hyperplasia in the OSS greater than the NOS at angiographic follow-up in patients with restenosis. If the minimal lumen diameter of the restenotic lesion occurred in the OSS, was focal (⬍10 mm), and extended into the NOS, it was considered to be at the OSS. Consideration was also made that the NOS would likely occupy a longer length on average compared with the OSS, which in general would be relatively short. Given that our null hypothesis assumed equal frequencies of binary restenosis at the NOS and OSS, we accepted the possibility of a type 2 error, given that on average the area of NOS is likely to be significantly greater than the area of the OSS. A 2-tailed binomial test was performed using the previously mentioned distribution assumption. During the study, 11 patients who underwent angiography at our institution fit the inclusion criteria for our study. Of these patients, 10 were men and 55% had diabetes. Of the 11 lesions, 8 were in the left anterior descending artery, 2 in the right coronary artery, and 1 in the left circumflex artery. The mean total stent length (i.e., the NOS plus the OSS) was 33.7 ⫾ 8.2 mm. The mean length of the OSS was 5.9 ⫾ 3.8 mm, which equates to 19 ⫾ 16% of the total stented area. During their initial percutaneous coronary intervention (PCI), the mean maximum balloon/stent inflation pressure was 14.5 ⫾ 3.6 atm. The immediate post-PCI angiogram revealed ⬍10% residual stenosis in all 11 lesions by quantitative coronary angiography. The OSS was anatomically positioned at the location of the minimal luminal diameter of the lesion on the original, pre-PCI angiogram in
The results from large multicenter randomized clinical trials, most notably the Randomized Study with the SirolimusCoated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) and the US Multicenter, Randomized Double-Blind Study of the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS), have clearly shown the benefit of the sirolimus-eluting stent (Cypher) versus bare metal stents in reducing rates of in-stent restenosis and target lesion revascularization.1,2 In the SIRIUS trial, 28% of all patients had overlapping stents, with a target lesion revascularization rate in the sirolimus arm of 4.5% at 9 months and 5.7% at 1 year.2 Moreover, most restenosis observed in the Cypher stents was type 1 (focal).7,8 The assumption for the apparent efficacy of overlapping drug-eluting stents is the large therapeutic window of sirolimus in its cellular pharmacologic actions. Commercially available Cypher stents contain sirolimus at a dosage of 140 g/cm2,9 and ⱕ1,200 g/stent has been used in models without demonstrating local toxicity.5 These drugspecific pharmacokinetics make “double-dose delivery” in the case of overlapping stents potentially safe with respect to cellular toxicity and injury. However, the effect of having twice the drug and polymer locally in a coronary artery on neointimal proliferation is less clear, although some small studies that have examined cases of overlapping Cypher stents have shown no detrimental effect.10 Reports have shown that nearly all biocompatible polymers are associated with some degree of inflammatory reaction.11 It has been postulated that the inflammatory reaction in the endothelium of coronary arteries implanted with Cypher stents seen at autopsy may have been due to the polymer coating and not necessarily the metal or drug.12,13 Data from porcine models have demonstrated a more severe, persistent endothelial inflammatory response after polymer stent implantation, with a high polymer mass versus low polymer mass.14 These data suggest a possible dose response with respect to tissue inflammation and polymer amount, which would be
Coronary Artery Disease/Restenosis in Overlapping Cypher Stents
relevant in cases of Cypher overlap, because inflammation is known to be a potent stimulus for neointimal thickening.15,16 Moreover, others have postulated a possible delayed vascular inflammatory response to the stent polymer, as is seen in porcine models.12,17,18 This delayed inflammatory response may first manifest itself as neointimal growth at the OSS, given the higher polymer burden. The mean time to repeat angiogram in our study was 277 days, longer than the protocol-driven mandatory follow-up angiogram in the SIRIUS trial (240 days). Other possible explanations for the higher incidence of restenosis observed at the OSS include uneven distribution of drug release and suboptimal stent geometry in the case of overlap, which can potentially influence drug delivery.19 Moreover, stent expansion may have been suboptimal at the area of stent overlap, because the vessel cross-sectional area has been shown to be predictive of in-stent restenosis in Cypher stents.20 1. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R, for the RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 2. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE, for the SIRIUS Investigators. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 3. Gallo R, Padurean A, Jayaraman T, Marx S, Roque M, Adelman S, Chesebro J, Fallon J, Fuster V, Marks A, Badimon JJ. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999;99: 2164 –2170. 4. Marx SO, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001;104:852– 855. 5. Sousa JE, Costa MA, Abizaid A, Abizaid AS, Feres F, Pinto IM, Seixas AC, Staico R, Mattos LA, Sousa AG, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and threedimensional intravascular ultrasound study. Circulation 2001; 103:192–195. 6. Kopia GA, Snead D, Palotico R, Laver M, Fischell T, Devries J, Carter AJ, Tio F, Hulsebos L, Turck P, Snodgrass J, Dooley J. Pharmacokinetics and pharmacodynamics of sirolimus-eluting stents. Am J Cardiol 2002;90(suppl):117H.
501
7. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE, for the SIRIUS Investigators. Quantitative assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation 2004;110:3773–3780. 8. Colombo A, Orlic D, Stankovic G, Corvaja N, Spanos V, Montorfano M, Liistro F, Carlino M, Airoldi F, Chieffo A, Di Mario C. Preliminary observations regarding angiographic pattern of restenosis after rapamycin-eluting stent implantation. Circulation 2003;107:2178 –2180. 9. McKeage K, Murdoch D, Goa KL. The sirolimus-eluting stent: a review of its use in the treatment of coronary artery disease. Am J Cardiovasc Drugs 2003;3:211–230. 10. Munoz JS, Abizaid A, Mintz GS, Albertal M, Abizaid AS, Feres F, Centemero M, Staico R, Mattos LA, Pinto I, Sousa A, Sousa JE. Intravascular ultrasound study of effects of overlapping sirolimuseluting stents. Am J Cardiol 2004;93:470 – 473. 11. van der Giessen WJ, Lincoff AM, Schwartz RS, van Beusekom HM, Serruys PW, Holmes DR Jr, Ellis SG, Topol EJ. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation 1996;94:1690 –1697. 12. Virmani R, Farb A, Guagliumi G, Kolodgie FD. Drug-eluting stents: caution and concerns for long-term outcome. Coron Artery Dis 2004; 15:313–318. 13. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimuseluting stent: should we be cautious? Circulation 2004;109:701–705. 14. Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou G, Narayan P, Leon MB, et al. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001;104:1188 –1193. 15. Kornowski R, Hong MK, Tio FO, Bramwell O, Wu H, Leon MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998;31: 224 –230. 16. Schwartz RS, Chronos NA, Virmani R. Preclinical restenosis models and drug-eluting stents: still important, still much to learn. J Am Coll Cardiol 2004;44:1373–1385. 17. Carter AJ, Aggarwal M, Kopia GA, Tio F, Tsao PS, Kolata R, Yeung AC, Llanos G, Dooley J, Falotico R. Long-term effects of polymerbased, slow-release, sirolimus-eluting stents in a porcine coronary model. Cardiovasc Res 2004;63:617– 624. 18. Lafont A. The Cypher stent: no longer efficacious at three months in the porcine model? Cardiovasc Res 2004;63:575–576. 19. Colombo A, Stankovic G, Moses JW. Selection of coronary stents. J Am Coll Cardiol 2002;40:1021–1033. 20. Takebayashi H, Kobayashi Y, Mintz GS, Carlier SG, Fujii K, Yasuda T, Moussa I, Mehran R, Dangas GD, Collins MB, et al. Intravascular ultrasound assessment of lesions with target vessel failure after sirolimus-eluting stent implantation. Am J Cardiol 2005;95:498 –502.