CME Offering: The Impact of Sirolimus-Eluting Stents on Patients at High Risk for Restenosis with Bare Metal Stenting

This presentation contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither the North American Center for Continuing Medical Education nor Cordis Corporation recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. Topics: The Impact of Sirolimus-Eluting Stents on Patients at High Risk for Restenosis with Bare Metal Stenting Faculty/Credentials: Atul Sharma, MD and S.Chiu Wong, MD, Maurice R. and Corinne P. Greenberg, Division of Cardiology, Department of Medicine, The New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York Learning Objectives. On completion of this activity, participants will be able to: 1. Identify the subgroups of patients at increased risk for in-stent restenosis with bare metal stents; 2. Describe the major trials demonstrating improved efficacy in treating these high risk populations with sirolimus-eluting stents. Activity instructions. Successful completion of this activity entails reading the article, answering the test questions and obtaining a score of over 70%, and submitting the test and completed evaluation form to the address listed on the form. Tests will be accepted until the expiration date listed below. A certificate of completion will be mailed to you within 60 days. Estimated time to complete this activity: 1 hour Initial release date: June 31, 2004 Expiration date: June 31, 2005. Target audience. This educational activity is designed for physicians, nurses and cardiology technologists who treat patients with coronary artery disease. Accreditation statements. This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). Physicians: The North American Center for Continuing Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMA PRA category1 credit. The North American Center for Continuing Medical Education designates this continuing medical education activity for a maximum of 1 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Nurses: The North American Center for Continuing Medical Education is an approved provider of continuing nursing education by the Pennsylvania State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. This continuing nursing education activity was approved for 1 contact hour(s). Provider approved by the California Board of Registered Nursing, Provider Number 13255 for 1 contact hour. Radiologic Technologists: Activities approved by the American Medical Association (AMA Category 1) are eligible for ARRT Category B credit as long as they are relevant to the radiologic sciences. Radiologic Technologists, registered by the ARRT, may claim up to 12 Category B credits per biennium. SICP: Society of Invasive Cardiovascular Professionals (SICP) approved for 1 CEU. Commercial support disclosure. This educational activity has been supported by an educational grant from Cordis Corporation. Faculty disclosure information. All faculty participating in Continuing Education programs presented by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Dr. Sharma has nothing to disclose. Dr. Wong discloses he is a consultant and advisory board member for Cordis Corporation, a Johnson & Johnson company.

---

In 1964, Dotter and Judkins proposed the concept of implanting intravascular stents to support the arterial wall following coronary angioplasty.¹ Since that time, predictable angiographic results, improved safety, and proven reductions in target lesion revascularization compared with balloon angioplasty have led to explosive growth in the field of percutaneous coronary stenting. In 1994, less than 1% of the 270,000 angioplasty procedures performed in the US utilized stents.² Since its approval in 1995 by the FDA for elective procedures, the use of stents has increased dramatically. Coronary stenting provides a mechanical solution to control coronary dissections, prevent acute elastic recoil, and reduce restenosis by routinely increasing target-lesion lumens.³ Initial results of randomized controlled trials demonstrated 25 to 30% reductions in binary restenosis compared with balloon angioplasty.^4-5 Subsequent improvements in stent design, flexibility, and deliverability have led to a further decrease in restenosis rates as low as 20% in some studies.⁶ However, the success of coronary stenting has led to its widespread application in more challenging coronary lesions, and with that, a resultant rise in restenosis rates. Sirolimus-eluting stents (SES) were developed to combat the process of neointimal hyperplasia that ultimately leads to in-stent restenosis, and data from multiple trials have demonstrated large, marked reductions in the rates of target vessel revascularization and angiographic binary restenosis. This review focuses on the impact of sirolimus-eluting stent placement in patients and lesions with traditionally high rates of restenosis with bare metal stenting: patients with diabetes mellitus, small coronary vessels, and long lesions. Diabetic Patients Diabetes mellitus has been shown to be an important risk factor for poor outcomes following percutaneous transluminal coronary angioplasty.⁷ Coronary stents have attenuated both the risk of acute vessel closure and of restenosis compared to balloon angioplasty⁸ however, the presence of diabetes remains a strong independent risk factor for in-stent restenosis.⁹ A retrospective observational study by Elezi and colleagues, comparing 715 diabetic patients with 2839 nondiabetic patients, demonstrated increased rates of restenosis (diabetics 37.5% versus nondiabetics 28.3%, p10 A greater degree of neointimal hyperplasia is thought to be the mechanism behind the increased restenosis rates, as evidenced by increased late loss and smaller minimum luminal diameter documented on angiographic and intravascular ultrasound follow-up.¹¹ The routine use of abciximab in diabetic patients undergoing percutaneous coronary revascularization with a stent in the EPISTENT trial resulted in a greater than 50% reduction in the need for TVR compared with patients receiving a stent without abciximab (6-month TVR rate of 16.6% in the stent-placebo group versus 8.1% in the stent-abciximab group).¹² However, restenosis rates have remained high in other studies involving glycoprotein IIb/IIIa inhibitors and patients with diabetes.¹³ In a recent trial of 11,500 patients, angiographic restenosis was seen in approximately 33% of all patients treated with bare-metal stents.¹⁴ Given that SES aggressively inhibits neointimal hyperplasia,¹⁵ there is great optimism that these devices will dramatically impact the rate of restenosis in this high-risk patient subgroup. The RAVEL (Randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization) trial, published in June of 2002, was a double-blind, placebo-controlled trial comparing the two types of stents for revascularization of single, primary lesions in native coronary arteries.¹⁶ The study enrolled 238 patients, and the primary end point was in-stent late lumen loss at 6 months. The percentage of in-stent stenosis of the luminal diameter, rare of binary restenosis, and a composite clinical end point of death, MI, and revascularization (either percutaneous or surgical) was also evaluated. Patients were eligible for the study if they had a single primary lesion 2.5-3.5mm in diameter that could be covered with an 18mm stent. Average lesion length was 9.6mm, with mean vessel size noted as 2.6mm. The SES treatment group demonstrated essentially no late-lumen loss (-0.01±0.33mm) and no episodes of binary restenosis at 6 months. In comparison, the standard-stent group had a late-lumen loss of 0.80±0.53mm and 26.6% restenosis both highly significant reductions. One-year MACE rates were 5.8% in the SES group compared to 28.8% in the bare-metal stent group (p17 In this study, 6 month in-stent late-lumen loss was low for diabetic patients treated with SES, (0.07±0.2mm) in comparison to the bare-metal stent group (0.82±0.5mm, p19 The above data demonstrate that SES inhibition of neointimal proliferation has a significant impact on the rate of restenosis among diabetics who fulfill enrollment criteria delineated for these two studies. But what about diabetics with even more complex disease real world diabetics? A recently published, non-randomized, consecutive series of patients comprising the RESEARCH registry (Rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital) sheds some light on this question. In this registry, 508 consecutive patients at Rotterdam hospital received SES as the default stent strategy and were compared to 450 patients receiving bare-metal stents in the time period prior to SES availability. Of these patients, 18% of the SES treatment group, or 91 patients, had diabetes, and were compared to 68 diabetic patients (15%) in the pre-SES group. In this small treatment population, there was a trend towards less TVR at 1 year in the diabetic cohort receiving SES (hazard ratio 0.72, 95% CI 0.30-1.77) which did not reach statistical significance (p=0.50). Diabetes mellitus itself remained a strong predictor of both MACE (hazard ratio 1.62, 95% CI 1.02-2.43, p=0.02) and of TVR itself (hazard ratio 1.81, 95% CI 1.10-2.99, p=0.02).20 These results have been corroborated in other registry data.²¹ In the future, the FREEDOM trial will compare clinical outcomes of diabetic patients with multi-vessel coronary artery disease, following treatment with either percutaneous coronary intervention using SES or coronary artery bypass surgery. The study is a multi-center, prospective, randomized trial with the primary endpoint of all-cause mortality at 5 years. Enrollment of some 2300 patients is scheduled to begin in the fall of 2004. Small Vessels and Long Lesions Numerous studies have documented the impact of vessel size on short- and long-term outcomes following coronary stenting.^22,23 Smaller stent volumes are associated with increased neointimal proliferation²⁴ as well as a lower degree of acute gain with comparable amounts of late loss.²⁵ As a result, vessel size (as measured by the surrogate of in-stent minimal area) has been shown to be inversely related to in-stent restenosis.²⁶ In one study among 2602 patients undergoing successful stent implantation, angiographic restenosis was significantly higher in the group of patients with vessel diameter of 23,27 The combination of vessel size and lesion length is a powerful predictor of neointimal hyperplasia for bare-metal stents.²⁶ Both lesion length and stent length have been shown to be independent predictors of in-stent restenosis, with rates as high as 70% for patients with small vessels and very long (>60mm) total stent length.^26,28,29 This increased risk is independent of the number of stents used, though there is some suggestion that different stent designs may contribute to an increased risk of abrupt vessel closure.³⁰ Two recent randomized, controlled trials have been performed evaluating the use of SES in patients with small (31 A total of 352 patients were enrolled, and a single coronary lesion in a vessel 2.5-3.0mm in diameter with a lesion length of 15-32mm was required for entry. Exclusion criteria included an evolving MI, ostial or calcified lesions, bifurcation lesions, and ejection fraction 32 Inclusion and exclusion criteria were similar to E-SIRIUS. Primary and secondary endpoints were similar. Average reference vessel diameter was 2.65±0.30mm and mean lesion length was 14.5±6.3mm. One hundred total patients were enrolled. Again, there was a statistically significant increase in minimum luminal diameter comparing patients treated with SES and those treated with bare-metal stents (2.46mm versus 1.49mm, p19 Furthermore, data from the RESEARCH registry on 96 patients with long lesions (>36mm stented segments) treated with SES demonstrated an 11.9% binary restenosis rate at 6-month angiographic follow-up (available in 71% of patients), with an in-stent late loss of 0.13±0.47mm.³³ MACE rates at 6 months remained low (8.3%), and the authors conclude that in a real world population of patients requiring multiple stents over very long vessel segments, SES implantation appears safe and effective. Recently published RESEARCH registry data evaluated the use of 2.25mm SES in real world patients. SES were placed in 91 patients with a total of 112 lesions, and continued minimal late-lumen loss (0.07±0.48mm) at an average follow-up of 7.1±1.3 months was demonstrated.³⁴ Binary restenosis rates in these vessels are approximately 10.7%, with 12-month TLR of 5.5%, demonstrating low rates of clinical and angiographic restenosis/ complications. Finally, preliminary 8-month results from the SES-SMART, a multi-center, non-randomized trial designed to assess the efficacy of 2.25mm SES in de novo coronary lesions, reveal a 9.3% in-segment binary restenosis for the SES treatment group compared with 53.1% for the bare metal stent group (p35 Conclusions Sirolimus-eluting stents inhibit neointimal proliferation and thereby dramatically reduce rates of in-stent restenosis, even in patients previously considered high risk for such events. Randomized, controlled trials demonstrate a 70-80% reduction in restenosis rates among patients with diabetes mellitus, patients with small coronary arteries, and those with long lesions. The results of ongoing and planned studies will serve to further clarify the role of sirolimus-eluting stents in coronary revascularization.

<small>1. Dotter CT, Judkins MR. Transluminal treatment of arteriosclerotic obstructions. Circ. 1964;30:654.</small><p>2. Heart Disease and Stroke Statistics. American Heart Association, Dallas, Texas. </p><p>3. Kuntz RE, Gibson CM, Noboyoshi M et al. Generalized model of restenosis after conventional balloon angioplasty, stenting, and directional atherectomy. J Am Coll Cardiol. 1993;21:15-25. </p><p>4. Fischman DL, Leon MB, Baim D et al, for the STRESS Trial Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496-501. </p><p>5. Serruys PW, de Jaegere P, Kiemeneij F et al, for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994.331:489-495. </p><p>6. Cutlip DE, Chauhan MS, Baim DS et al. Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials. J Am Coll Cardiol. 2002;40:2082-2089. </p><p>7. Stein B, Weintraub WS, Gebhart SP et al. Influence of diabetes mellitus on early and late ouctome after percutaneous transluminal coronary angioplasty. Circ. 1995;91:979-989. </p><p>8. Van Belle E, Perle M, Braune D et al. Effects of coronary stenting on vessel patency and long-term clinical outcome after percutanueous coronary revascularization in diabetic patients. J Am Coll Cardiol. 2002;40:410-417. </p><p>9. Abizaid A, Kornowski R, Mintz GS et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol. 1998;32:548-549. </p><p>10. Elezi S, Kastrati A, Pache J et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol. 1998;32:1866-1873. </p><p>11. Marso SP, Mak KH, Topol EJ. Daibetes mellitus: biological determinants of atherosclerosis and restenosis. Semin Interv Cardiol. 1999;4:129-143. </p><p>12. Marso SP, Lincoff AM, Ellis SG et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial) diabetic substudy. Circ. 1999;100:2477-2484. </p><p>13. O’Shea JC, Hafley GE, Greenberg S et al. Platelet Glycoprotein Iib/IIIa integrin blockade with eptifibitide in coronary stent intervention: the ESPIRIT trial: a randomized controlled trial. JAMA. 2001;285:2468-2473. </p><p>14. Holmes DR Jr, Savage M, LaBlanche JM et al. Results of prevention of restenosis with tranilast and its outcomes (PRESTO) trial. Circ. 2002;106:1243-1250. </p><p>15. 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. Circ. 2001;104:2007-2011. </p><p>16. Morice MC, Serruys PW, Sousa JE et al, 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. </p><p>17. Abizaid A, Costa MA, Blanchard D et al. Sirolimus-eluting stents inhibit neointimal hyperplasia in diabetic patients: insights from the RAVEL study. Eur Heart J. 2004;25:107-112. </p><p>18. Moses JW, Leon MB, Popma JJ et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323. </p><p>19. Holmes DR Jr, Leon MB, Moses JW et al. Analysis of 1-year clinical outcomes in the SIRIUS trial : a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circ. 2004;109:634-640. </p><p>20. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the real world: the rapamycin-eluting stent evaluated at rotterdam cardiology hospital registry. Circ. 2004;109:190-195. </p><p>21. Orlic D, Bonizzoni E, Stankovic G et al. Treatment of multivessel coronary artery disease with sirolimus-eluting stent implantation: immediate and mid-term results. J Am Coll Cardiol. 2004;43:1154-1160. </p><p>22. Zaida KM, Kapadia SP, Belli G et al. Prognostic value of absolute versus relative measures of the procedural result after successful coronary stenting: importance of vessel size in predicting long-term freedom from target vessel revascularization. Am Heart J. 2001;141:823-831. </p><p>23. Elezi S, Kastrati A, Neumann FJ et al. Vessel size and long-term outcome after coronary stent placement. Circ. 1998;98:1875-1880. </p><p>24. Dussaillant GR, Mintz GS, Pichard AD et al: Small stent size and intimal hyperplasia contribute to restenosis: a volumentric intravascular ultrasound analysis. J Am Coll Cardiol. 1995;26:720-724. </p><p>25. Akiyama T, Moussa I, Reimers B et al: Angiographic and clinical outcome following coronary stenting of small vessels: a comparison with coronary stenting of large vessels. J Am Coll Cardiol. 1998;32:1610-1618. </p><p>26. de Feyter PJ, Kay P, Disco C, Serruys PW. Reference chart derived from post-stent implantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography. Circ. 1999;100:1777-1783. </p><p>27. Kleinman N, Califf R: Results of the late breaking clinical trials ssession at ACC 2000, J Am Coll Cardiol. 2000;36:310-325. </p><p>28. Hirshfeld JW Jr, Schwartz JS, Jugo R et al. Restenosis after coronary angioplasty: a multivariate statistical model to relate lesion and procedural variables to restenosis: the M-HEART investigators. J Am Coll Cardiol. 1001;18:647-656</p><p>29. Kastari A, Elezi S, Dirschinger J et al. Influence of lesion length on restenosis after coronary stent placement. Am J Cardiol. 1999;83:1617-1622. </p><p>30. Mathew V, Hasdai D, Holmes DR Jr et al. Clinical outcome of patients undergoing endoluminal coronary artery reconstruction with three or more coronary stents. J Am Coll Cardiol. 1997;30:676-681. </p><p>31. Schofer J, Schulter M, Gerschlick AH, et al. Sirolimus-eluting stents for the treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS). Lancet. 2003;362:1093-1099. </p><p>32. Schampert E, Cohen EA, Schluter M et al. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol. 2004;43:1110-1117. </p><p>33. Degertekin M, Arampatzis CA, Lemos PA et al. Very long sirolimus-eluting stent implantation for de novo coronary lesions. Am J Cardiol. 2004;93:826-829. </p><p>34. Lemos PA, Arampatzis CA, Saia F et al. Treatment of very small vessels with 2.25-mm diameter sirolimus-eluting stents (from the RESEARCH registry). Am J Cardiol. 2004;93:633-636. </p><p>35. Ardissino D, Moses J, Stone GW. SES-SMART study. Presented at the American College of Cardiology 53rd Annual Scientific Sessions, March 7-10, 2004. New Orleans.</p>