CME/CEU OFFERING: Sirolimus-Eluting Stents: A Leap Forward in the Prevention of Restenosis After Percutaneous Coronary Interve

A new era in cardiovascular care may soon be upon us, with the FDA aproval of drug-eluting stents fast approaching. This new type of therapy has many in the medical industry buzzing over potential clinical outcomes and overall reduction in repeat revascularizations. There is no doubt that the combination of pharmaceuticals and medical devices will have a lasting impact in the cardiology arena. With the support of an educational grant from Cordis, a Johnson & Johnson company, Cath Lab Digest is pleased to provide you with a series of in-depth articles and patient case studies on this advanced new technology. Launching this in-depth focus on drug-eluting stents is an article written by Jeffrey J. Popma, MD, of the Department of Internal Medicine of the Brigham and Women’s Hospital in Boston, Massachussetts. One of the country’s leading interventionalists, Dr. Popma has been closely involved in the clinical trials for drug-eluting stents and is a recognized expert on this topic. Upcoming articles in our drug-eluting stent series will include a discussion of the financial impact of this new technology and in-depth case reports. Cath Lab Digest welcomes your comments. Please contact us at: cathlabdigest@aol.com ___________________________________________________________ Topic: Sirolimus-Eluting Stents: A Leap Forward in the Prevention of Restenosis After Percutaneous Coronary Intervention Faculty/Credentials: Jeffrey J. Popma, MD, Director of Interventional Cardiology, Katherine Klein, BS, RCIS, Lead Cardiovascular Technologist, Robert Medico, Jr., BS, RT(R)(CV), Lead Radiology Technologist, Cardiac Catheterization Laboratory and Department of Internal Medicine (Cardiovascular Division), Brigham and Women’s Hospital, Boston, Massachusetts Learning Objectives. At the conclusion of this activity, the participant should be able to: 1. Describe the basic processes that contribute to restenosis after coronary stent placement. 2. Outline the mechanism of action of sirolimus for the prevention of stent restenosis. 3. Review the clinical results associated with the use of sirolimus-eluting stents for the prevention of restenosis. 4. Discuss techniques for obtaining an optimal late result with the use of the sirolimus-eluting stent. 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: March 31, 2003 Expiration date: March 31, 2004. 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 HMP Communications. Physicians: HMP Communications, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC 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: 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 HMP Communications are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Dr. Popma has disclosed that he receives research grant support from Cordis, Guidant, Boston Scientific, Medtronic, Abbott Vascular, Inc., Radiant Medical, Pharmasonics, Pharmacylics, Embolic Protection, Inc, and MedNova. He is on the advisory board for Pfizer and Cordis, and a member of the speakers bureau for Pfizer, Cor-Millenium, Schering-Plough, and Boston-Scientific. Katherine Klein and Robert Medico, Jr. have no conflicts of interest to disclose. ___________________________________________________________ Nearly one million percutaneous coronary interventions will be performed in the United States this year. The vast majority (>85%) of these procedures will involve the use of one or more coronary stents. Randomized trials have shown the clinical benefits of coronary stenting over balloon angioplasty in patients with native vessel coronary artery disease^1,2 but the long-term outcome after coronary stenting is limited by the occurrence of binary restenosis (> 50% follow-up diameter stenosis) in approximately 20-25% of patients. ^3-6 Restenosis results from intimal hyperplasia within the stent and occurs more often in patients with longer stents, smaller vessels, and diabetes mellitus. ⁷ To date, systemic drug administration has failed to reduce restenosis after stenting in any consistent fashion. Drug-eluting stents have been developed to provide sustained local delivery of agents aimed at reducing the degree of tissue growth after stent placement. A number of drug-eluting systems have been tested, and it is now apparent that some drug-eluting system systems are effective in preventing restenosis, e.g.: Sirolimus; Everolimus; Polymer-delivered paclitaxel. Others have no or limited effect, e.g.: Batimastat; Dexamethasone; Stent-based paclitaxel. Finally, some are clinically detrimental, e.g.: Actinomycin D; QP-2, a Taxane derivative. These studies have demonstrated the important interaction between the stent design, the presence (or absence) of a polymeric coating used to deliver the drug, and the types of agents that are delivered to the vessel wall. Extensive clinical evaluation has been performed with the sirolimus-eluting Bx-velocity stent (CYPHER, Cordis, A Johnson and Johnson, Company, Warren, NJ) and this drug-eluting stent is now available in most parts of the world in patients to prevent restenosis after stent placement. This review will provide an overview of the sirolimus-eluting coronary stent, including: (1) Discussions of the proposed mechanism of action of sirolimus; (2) Pre-clinical and clinical results; (3) Insights into optimal deployment strategies meant to optimize the late angiographic results; (4) Potential clinical concerns associated with the use of the sirolimus-eluting stents system in clinical practice. Sirolimus (Rapamycin) Restenosis after stent placement is a complex process that begins with arterial injury, platelet deposition, and the stimulation of inflammation within the vessel wall, leading to the release of growth factors and cytokines that activate smooth muscle cells (Figure 1). Smooth muscle cells migrate to the intimal surface, divide and produce a collagenous matrix that results in intimal hyperplasia within the stent. When the intimal hyperplasia is excessive and lumen compromise results, clinical symptoms then recur. What is sirolimus? The generic reference for the stent-based delivery of rapamycin, sirolimus is a naturally occurring antimicrobial that was first identified on Easter Island8 (Figure 2). Sirolimus has potent immunosuppressive activity, and was first developed and marketed as Rapamune® (Wyeth Research, Radnor, Pennsylvania) for the prevention of renal transplantation rejection. Sirolimus’ mechanism of action. A polymeric coating on the stent results in a sustained release of sirolimus over 30 days after arterial injury (Figure 3). Cell cycle replication occurs in several distinct phases (Figure 4). Sirolimus results in cytostatic inhibition of growth factor- and cytokine-stimulated cell proliferation in the G1 phase (where the cell enlarges and makes new proteins), prior to the final mechanistic commitment to cell cycle completion8 (Figure 4). The mechanism of action is as follows: 1. Sirolimus enters the cytoplasm and combines with its cytosolic receptor, FKBP. 2. The combined complex inhibits a cytoplasmic protein called the target of rapamycin (TOR)9 (Figure 5). 3. Inhibition of TOR prevents a reduction in the p27 level, a key regulatory protein inhibitor that prevents nuclear replication. ^10,11 4. With inhibition of the cell cycle prior to nuclear replication in the S phase (DNA replication), the cell returns from the G1 phase to its resting G0 state, thereby preventing smooth muscle cell migration and proliferation. ¹² Pre-clinical Results Experimental studies have shown a dose-dependent reduction in intimal hyperplasia after arterial injury following systemic and local sirolimus use. Intramuscular sirolimus prevented intimal hyperplasia 4 weeks after balloon injury in a porcine model. ¹³ Sirolimus use was associated with a significant reduction in the lumen diameter stenosis and increase in luminal area 4 weeks after balloon injury. Similar reductions in intimal hyperplasia were found after sirolimus-eluting Crossflex stent (Cordis) placement in a rabbit iliac model. ¹⁴ Treatment with low-dose sirolimus was associated with a 23% reduction in neointimal area, whereas treatment with high-dose sirolimus was associated with a 45% reduction in intimal hyperplasia. ¹⁴ Sustained drug release from the stent and prolonged intramural arterial deposition occurred up to 28 days. No detectable sirolimus was found in the blood after 2 days. ¹⁴ Additional studies have confirmed these initial experimental studies with reduction of intimal hyperplasia by up to 50% with 185 microgram sirolimus eluted from a nonerodable polymer coating. ¹⁵ These findings demonstrated a dose-response reduction in intimal hyperplasia associated with the use of sirolimus-eluting stents. There were minimal elevations of systemic levels of sirolimus for up to 48 hours after stent implantation. Higher levels of sirolimus failed to demonstrate significant toxicity or evidence of inflammation. First-In-Man Studies Over three years ago, sirolimus-eluting stents were first implanted in 45 patients with focal native vessel disease at two centers.16 Thirty patients with de novo coronary disease were treated with a single sirolimus-eluting Bx Velocity stent in Sao Paulo, Brazil16 and another 15 patients were treated in Rotterdam, The Netherlands. ^17,18 The Sao Paulo patients were treated with 18 mm sirolimus-eluting stents loaded with a 140 µg sirolimus/cm2 metal surface area available with two different sirolimus release kinetics a fast release (N=15) or slow release (N=15) formulation. ¹⁶ Angiographic and volumetric intravascular ultrasound (IVUS) was obtained 4, 12, and 24 months later^16,19 (Figure 6). At 4 and 12 Months. In-stent minimal lumen diameter and percent diameter stenosis was essentially unchanged in both groups from the post-procedural to the 12-month follow-up study. ¹⁶ No patient approached the >50% diameter stenosis within the stent, and no edge restenosis was observed. Intravascular ultrasound (IVUS)-detected neointimal hyperplasia was virtually absent at 12 months in both the fast- and slow-release groups. ¹⁶ Although there were no cases of subacute stent thrombosis, one patient developed an acute myocardial infarction 14 months after the procedure due to a plaque rupture just proximal to the stent. At 24 months. Twenty-eight patients underwent 2-year angiographic and IVUS follow-up and a persistent reduction in intimal hyperplasia was found. ¹⁹ Although no patient had in-stent restenosis, target-vessel revascularization was needed in 3 (10%) patients by two years, including one patient who had a 52% diameter stenosis at the margin of the stent that required repeat revascularization. The second cohort of 15 patients were treated in Rotterdam with the same 140 µg sirolimus/cm2 metal surface area, but only with the slow release formulation. Angiographic and IVUS follow-up was obtained at 6 months and 18 months after stent implantation. ^17,18,20 Sirolimus-eluting stent implantation was successful in all 15 patients, but during the hospital course, one patient died of cerebral hemorrhage after peri-procedural administration of abciximab, and one patient underwent repeat stenting after 2 hours because of edge dissection that led to acute occlusion. ¹⁷ To 24 months. No additional events occurred over the next two years of follow-up. ¹⁷ Late quantitative angiographic analysis revealed no significant change in stent minimal lumen diameter or % diameter stenosis at follow-up. Three-dimensional IVUS showed no significant deterioration in lumen volume. ¹⁷ Randomized Clinical Trials in Native Coronary Arteries Following the dramatic effects on restenosis in the first-in-man studies, sirolimus-eluting stents were then evaluated in patients with symptomatic native vessel coronary artery disease in three multi-center randomized trials and one international registry (Table 1). These trials included both patients with focal lesions treatable with one stent (RAVEL) and more complex, longer length lesions located in smaller vessels (SIRIUS, E-SIRIUS, and C-SIRIUS). RAVEL. The RAVEL trial compared the sirolimus-eluting and bare metal stent in a randomized trial of 238 patients with single, primary lesions located in native coronary arteries. ²¹ In-stent late luminal loss, defined as the difference between the minimal luminal diameter immediately after the procedure and the diameter at six months, was the primary study endpoint. ²¹ The degree of late lumen loss at 6 months was significantly lower in the sirolimus-stent group (-0.01±0.33 mm) than in the standard-stent group (0.80±0.53 mm) (P21 There were no episodes of stent thrombosis. During a follow-up period of up to one year, the overall rate of major cardiac events was 5.8 percent in the sirolimus-stent group and 28.8 percent in the standard-stent group (P21 Patient subset. Motorized IVUS pullback was performed at a 6-month follow-up in a subset of 95 patients in the RAVEL trial. ²² Stent volumes, total vessel volumes, and plaque-behind-stent volumes were comparable in the two groups at 6 months. However, there were significant differences in: Neointimal hyperplasia (2±5 mm3 in sirolimus stent patients versus 37±28 mm3 in bare-metal stent patients; P22 There was also no evidence of intrastent thrombosis or persisting dissection at the stent edges. ²² Although there was a higher incidence of incomplete stent apposition (an IVUS-detected phenomenon occurring when one or more of the stent struts fails to fully expand against the vessel wall) in the sirolimus group compared with the uncoated stent group (P22 SIRIUS. The SIRIUS Trial was subsequently designed to evaluate sirolimus-eluting stents in patients with more complex coronary artery disease. ²³ Patients were included in SIRIUS if there was a single treatable lesion that was not totally occluded, with a lesion length between 15 and 30 mm and a reference diameter between 2.5 mm and 3.5 mm. ²³ A total of 1,058 patients from 53 centers in the United States were enrolled in this blinded, randomized trial that assigned patients to treatment with a sirolimus-eluting stent or a bare metal stent. ²³ Patients were at increased risk for restenosis with frequent (26%) diabetes mellitus, longer lesions (14.4 mm), and smaller vessels (2.8 mm). ²³ Preliminary results of this study were presented by the Principal Investigators of the study, Dr. Jeffrey Moses and Dr. Martin Leon (Lenox Hill Hospital, NY) at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington, D.C., September, 2002. The results of this presentation are summarized below. Compared with patients treated within bare-metal stents, patients treated with sirolimus-eluting stents had lower rates of binary angiographic restenosis within: The treated segment (36.3% with bare-metal stents versus 8.9% with sirolimus-eluting stents; p 23 There were also trends toward reduced restenosis at the edges in patients treated with sirolimus-eluting stents. Late lumen loss was reduced from 1.0 mm in patients treated with bare metal stents, to 0.17 mm in patients treated with sirolimus-eluting stents (Figure 7). The frequency of late aneurysms was similar in the two groups. The angiographic pattern of restenosis showed a shift to more frequent margin restenosis than central restenosis in patients treated with the sirolimus-eluting stent. The primary clinical endpoint in the SIRIUS trial was 8-month target-vessel failure, defined as target vessel revascularization, death, or myocardial infarction. Target vessel failure was reduced from 21.0% in patients treated with bare metal stents to 8.6% in patients with sirolimus-eluting stents (p23 Target lesion revascularization was reduced from 16.6% in bare metal stents to 4.1% in patients treated with sirolimus-eluting stents (p 23 These relative reductions in clinical events were similar in patients with left anterior descending artery disease, large and small vessels, short and long lesions, and in patients with diabetes mellitus. ²³ Expanded Lesion Subsets Randomized clinical trials have shown marked benefits to sirolimus-eluting stents in patients with native coronary vessels between 2.5 mm and 3.5 mm in size and with lesions In-Stent Restenosis. Brachytherapy has provided a major advance for patients with restenosis following stent implantation, particularly in patients with diffuse in-stent restenosis. The hope behind the following two studies was that drug-eluting stents would provide an alternative to brachytherapy in patients with in-stent restenosis. Twenty-five patients with in-stent restenosis were successfully treated in Sao Paulo, Brazil with the implantation of one or two sirolimus-eluting Bx Velocity stents.24 Angiographic and volumetric intravascular ultrasound (IVUS) follow-up were obtained 4 and 12 months later. ²⁴ Angiographic late loss averaged: At 4 months: 0.07±0.2 mm within the stent -0.05±0.3 mm within the lesion At 12 months: 0.36±0.46 mm within the stent 0.16±0.42 mm within the lesion. ²⁴ Only one patient developed in-stent restenosis at one-year follow-up. These encouraging results support the potential use of sirolimus-eluting stents in patients with non-complex in-stent restenosis. Sixteen patients with severe, recurrent in-stent restenosis in native coronary arteries (average lesion length 18.4 mm) were treated in Rotterdam, The Netherlands with one or more 18 mm Bx Velocity sirolimus-eluting stents. ²⁵ Four patients had recurrent restenosis following brachytherapy, and three patients had totally occluded vessels before the procedure.25 At four months follow-up, one patient had died and three patients had angiographic evidence of restenosis (one in-stent and two in-lesion). ²⁵ Although there was a minimal amount of in-stent late lumen loss (averaging) 0.21 mm), three patients had experienced four major adverse cardiac events by nine months (two deaths and one acute myocardial infarction necessitating repeat target vessel angioplasty). ²⁵ These results suggested that the sirolimus-eluting stent was effective at reducing intimal hyperplasia within the stent in patients with severe in-stent restenosis, but long-term therapy with the anti-platelet agent clopidogrel may be indicated. ²⁵ The results of both the Sao Paulo and Rotterdam studies suggest that a sirolimus-eluting stent may be useful for the treatment of recurrent in-stent restenosis, but more studies are needed. Direct comparisons with radiation brachytherapy are planned (Table 1). In the event that sirolimus-eluting stents are used for the treatment of complex in-stent restenosis, extended treatment with aspirin and clopidogrel is recommended. Multivessel Disease. Determining what impact the availability of the drug-eluting stent will have on referrals for coronary artery bypass surgery (CABG) is a major clinical question. Two trials will compare the value of the sirolimus-eluting stent compared with coronary artery bypass graft surgery in patients with multivessel coronary artery disease. 1.The ARTS-II Registry is a registry of patients with multivessel disease who undergo stenting with sirolimus-eluting stents. The late outcomes will be compared with the CABG group in the ARTS-I Trial. ²⁶ 2. The second planned trial is the FREEDOM Trial, a planned study with 2300 diabetic patients who will be randomly assigned to multi-vessel sirolimus-eluting stent treatment or to CABG with a left internal mammary artery placed to the left anterior descending artery. The primary endpoint will be 5-year mortality. Insights Into Optimal Deployment Strategies A number of differences in baseline characteristics and operator techniques were noted in patients enrolled in the RAVEL and SIRIUS studies (Table 2). In RAVEL, restenosis was essentially eliminated in patients with focal lesions, but occurred infrequently within the stent (3.2%) and within the stent and its 5mm margins (8.9%) in more complex patients after use of the sirolimus-eluting stent. Given that the pattern of restenosis shifted to the margins in patients treated with the sirolimus-eluting stent, a number of operator techniques may have contributed to the occurrence of so-called peri-stent restenosis. 1. One of these factors is that balloon injury proximal and distal to the stent occurred during pre- or post-dilation and may have caused injury to the vessel wall that was not sufficiently covered by sirolimus. Pre-dilation with a slightly undersized balloon may be recommended, with careful attention to use a balloon shorter than the implanted stent length. 2. Longer stent lengths should be used to make certain that there are adequate margins proximal and distal to the lesion and that the stent completely covers the lesion length. 3. The stent should not be pulled back after deployment at nominal pressures and then inflated to higher pressures to expand the proximal edge of the stent. This technique will cause proximal edge injury without adequate sirolimus coverage. 4. Finally, the stents should be expanded at moderately high pressure (12 to 16 atmospheres) to ensure complete apposition of the stent struts again the arterial wall. A shorter post-dilatation balloon should be used when high pressures are needed to expand the stent. 5. Direct stenting may be useful, provided that the proximal and distal margins of the lesion are clearly defined. 6. IVUS may be useful in questionable cases to assess lesion length and vessel size. The development of a sirolimus-eluting coronary stent represents a major advance for patients undergoing percutaneous revascularization, reducing the occurrence of clinical and angiographic restenosis by at least 75%. The absolute benefit is most pronounced in patients with small vessels, long lesions, and those with diabetes mellitus. Optimization of operator technique may reduce the injury at the edges of the stent and reduce the occurrence of margin restenosis. Further studies are ongoing that will address the value of the sirolimus-eluting stent in other lesion subsets. FOR CME/CEU QUESTIONS AND EVALUATION FORMS, PLEASE DOWNLOAD PDF NEXT TO ARTICLE TITLE.

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