CME/CEU Offering

The following activity is supported by an unrestricted educational grant from Cordis Corporation. This presentation contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither HMP Communications 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: An Update on Percutaneous Coronary Intervention in 2003: Are There Important Implications for Diabetics in the Era of the Drug-Eluting Stent? Faculty/Credentials: Andrew J. Carter DO, FACC, Medical Director, Cardiovascular Research, Providence Health System, Providence St. Vincent’s Medical Center, Portland, Oregon Learning Objectives. At the conclusion of this activity, the participant should be able to: 1. Describe the clinical outcomes of drug-eluting stents from large multicenter randomized clinical trials (RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS) and registry studies (e-Cypher); 2. Identify key elements of diabetic syndromes that contribute to an increased probability of restenosis in patients with diabetes; 3. Describe aspects of operator technique to optimize acute and long-term clinical outcomes with drug-eluting stents in patients with diabetes. 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: October 31, 2003 Expiration date: October 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 is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications 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. Carter disclosed that he is the recipient of research grants from Boston Scientific, Cordis Corporation, Guidant Corporation and Medtronic, Inc. An Update on Percutaneous Coronary Intervention in 2003: Are There Important Implications for Diabetics in the Era of the Drug-Eluting Stent? Andrew J. Carter DO, FACC, Medical Director, Cardiovascular Research Providence Health System, Providence St. Vincent’s Medical Center, Portland, Oregon In April 2003, the FDA approved Cypher (Cordis Corporation, a Johnson and Johnson Co.), the first sirolimus-based drug-eluting stent (DES) for the prevention of restenosis in patients with de novo native coronary arterial lesions 15 to 30 mm length, in vessels 2.5 to 3.5 mm diameter. Scientific organizations such as the American Heart Association and experts in the field of cardiovascular medicine have touted the sirolimus-eluting stent (SES) as the single most important innovation since the inception of percutaneous coronary interventional procedures in the late 1970’s. The SES introduces the first legitimate therapy for the prevention of restenosis, described as the Achilles’ heel of balloon angioplasty and stenting. The sirolimus-eluting stent is the most widely tested DES, with an excess of 10,000 patients treated in randomized clinical trials (FIM, RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS) and post market surveillance registries (e-Cypher) (Table 1). To date, this evidence documents a 75% reduction in clinical and angiographic restenosis for patients with focal de novo coronary arterial lesions treated with the SES in several international randomized trials. Despite the massive body-evidence in favor of a broad clinical application of a SES, several important questions and problem areas remain. In critical patient subsets, such as acute myocardial infarction, only early (30-day) outcome data are available that indicates adequate safety of an SES in this population. ¹ Limited data exists for the treatment of failed bypass grafts, in-stent restenosis and vascular brachytherapy failures, although registries (SECURE) and a randomized clinical trial (SISR) are in progress to address these unique and challenging lesion subsets. Diabetic patients have posed a particularly notable challenge even for the DES. Despite the overwhelming effects of the SES in patients with focal de novo coronary arterial lesions, this benefit was less profound in the diabetic subset of the SIRIUS study. The frequency of angiographic restenosis was in excess of 20% at 8 months for diabetic patients with reference vessel dimensions less than 2.5 mm diameter in comparison to > 50% for the BX Velocity group. In particular, the insulin-requiring diabetic patients appeared to have the least treatment effect, with two-fold greater angiographic late lumen loss relative to non-diabetic patients 8-months after SES placement.² The data from the SIRIUS trial, which documents a similar relative reduction in target lesion revascularization (TLR) (75%) in diabetic and non-diabetic subsets for the SES in comparison with bare metal stents, affirms the tenacity of restenosis in the diabetic patient. The issue of restenosis in the diabetic patient is complicated by the atherosclerotic burden vessel wall mechanics, and numerous biologic aberrations induced by hyperglycemia dyslipidemia, and insulin on clotting factors, platelet function, fibrinolytic system, cytokines and growth factors promoting excessive neointimal hyperplasia following coronary stent placement. ³ Diabetes results in increased circulating serum glucose levels. Hyperglycemia is potentially related to many steps in the process of restenosis; however, no consistent data implicate hyperglycemia and restenosis. ⁴ Insulin has several biological properties, which may be related to the process of restenosis. In fact, some argue that insulin-resistance, rather than diabetes, is a more important predictor of restenosis. ⁵ In the era of the drug-eluting stent, perhaps a more careful look at operator technique, device selection and adjunctive therapy can provide important insight to enable maximal efficacy of stent-based delivery of sirolimus and other drugs for the prevention of restenosis in patients with diabetes. The case example and general guidelines provided in Figures 1 and 2 are intended to highlight some of the key elements to optimal utilization of the SES. The rationale for stent-based sirolimus therapy for the prevention of restenosis is based on the physical properties, the mechanism of action and experimental data documenting efficacy for this drug-eluting stent in the porcine coronary model. ^6,7 Sirolimus (MW 914, Rapamune, Wyeth-Ayerst) is a hydrophobic drug that has low solubility in aqueous solutions. The agent is lipophilic, which allows the drug to easily pass though cell membranes, enabling intramural distribution and arterial tissue retention. In addition, cellular uptake occurs by binding to the cytosolic receptor, FKBP-12, which also may enhance chronic tissue retention of sirolimus (Figure 3). The SES utilizes a non-erodable methacrylate co-polymer matrix for controlled endovascular delivery of the drug to the arterial tissue. The drug, sirolimus, is blended with the polymer to create a 30% drug to polymer ratio by weight. A thin (5 to 10 microns) coating is applied to the surface of the stent (BX Velocity, Cordis, a Johnson and Johnson Co.). The quantity of sirolimus loaded onto each stent is approximately 140 mg/cm2. The release of the agent is prolonged by the application of thin layer of non-drug polymer over the drug and polymer basecoat. This stent-based drug delivery system provides controlled release of sirolimus over a period of approximately 12 weeks. ⁸ The selection and deployment of drug-eluting stents (DES) requires the operator to understand all of the technical specifications of the SES. When handling DES in the cath lab, meticulous attention is necessary to avoid manual contact with the stent before deployment. Excessive operator manipulation or direct hand contact may disrupt the integrity of the surface coating or introduce foreign material that could adversely affect drug delivery and biocompatibility. Sirolimus is a lipophilic and hydrophobic compound. Thus, there is very little tendency for sirolimus to leak from the stent during deployment. Sirolimus elution is controlled by principles of diffusion, from areas of high concentration on the surface of the stent to areas of low concentration in the tissue and blood. Sirolimus release is also mediated by the presence of a drug-free topcoat which delays the elution profiles. Stent diameter sizing should be based upon careful visual angiographic estimates and in some cases online QCA or quantitative IVUS measurements. Ideally, the angiographic stent balloon to reference vessel diameter should be in a range of 1.1:1. The use of IVUS to guide stent diameter selection should be based on a mid-wall proximal reference diameter, or the average of proximal and distal reference diameters, if significant vessel tapering is present. The 6- and 7-cell platform of the SES can be over-expanded by approximately 1.00 mm in diameter. Specifically, a 2.5 mm diameter 6-cell stent can be safely expanded up to 3.75 mm diameter. A 3.5 mm diameter 7-cell stent can be safely expanded up to 4.75 mm diameter. The selection of stent length should be based upon the length of the diseased zone of the artery and not the >50% stenosis zone traditionally used with bare metal stents in order to provide full lesion coverage. The data from E-Sirius supports the concept to stent from disease free to disease free (or proximal to distal normal reference) in order to reduce the probability of peri-stent restenosis, which was more commonly observed in the SIRIUS trial (Table 1). Operators should choose a safe landing zone, 3-5 mm outside the shoulders of the lesion, to position the stent edges, thus providing lesion scaffolding and drug to the region of vessel injury. In current practice of DES, the overall stent lengths will be 5-10 mm longer than with previous bare metal stent techniques. Typically, a stent to lesion length will be in a range of greater than 1.5 to 1, in order to reduce the risk for peri-stent restenosis. If undecided between two stent lengths, always choose to size up to the longer stent length or confirm the minimal required stent length using other techniques (marker wire, online QCA, IVUS). IVUS with automatic pullback and marker guidewires can be helpful tools to select optimal stent length, for angulated coronary segments in particular. IVUS can also be helpful to document the anatomic extent of disease in order to identify optimal SES placement in the vessel. In cases of multiple DES, it is essential to overlap stents 3 to 4 mm to avoid gaps, which will eliminate areas of geographic miss that are prone to restenosis. Lesion preparation is necessary in order to facilitate delivery of DES and to minimize risk for disruption of the surface coating. A non-aggressive strategy is employed to avoid deep wall injury, dissections, and damage to adjacent normal reference vessel zones. It is advisable to minimize vessel injury by under-sizing the pre-dilation balloon (by 0.5-1.0 mm), using shorter length balloons focusing on the areas of worst stenosis and always shorter than the anticipated length of the subsequent DES. Low-pressure balloon inflations (2 To date, the phenomena of late strut malapposition has not been linked to any clinical events such as late thrombosis. Although clinical trial and early post market surveillance data indicates a similar low risk for stent thrombosis with SES versus bare metal stents (9 Pre-treatment with clopidogrel > 6 hrs prior to procedure is recommended in order to achieve sufficient antiplatelet effects for elective stenting. The selected use of IIb/IIIa platelet inhibitor may be a consideration in stable or low risk patients, with high dose (600 mg) clopidogrel loading prior to procedure and conventional heparin dosing or bivalirudin in particular. ¹⁰ The problem of restenosis in the diabetic population remains formidable even in the era of the drug-eluting stent. Experimental and clinical research is necessary to determine the optimal treatment for the prevention of restenosis in the diabetic patient. The data from the planned studies with the sirolimus-eluting stent in diabetics with single-vessel disease (South American sirolimus diabetic dose escalation clinical trial) and multi-vessel disease (FREEDOM Trial, CABG versus multi-vessel/ lesion sirolimus-eluting stent) will provide a better understanding of drug and dose response effects in a larger series of patients, as well as comparison with present revascularization therapies. Similar efficacy and dose response trials must be conducted with other DES, like the paclitaxel-eluting stent (Taxus, Boston Scientific, Maple Grove, MN). In the treatment of more complex patients and lesion subsets, operators will need advanced techniques to optimize delivery and deployment of DES, particularly with longer length stents. The selection of proper pre-treatment strategy, optimal DES length to cover the lesion and areas of injury, sufficient deployment to enable complete apposition and full expansion may require more frequent use of IVUS guidance. Careful diligence to peri-procedural and post-procedural adjunctive antiplatelet therapy will be necessary to reduce unanticipated thrombotic events. Ultimately, a combination of systemic (i.e., glycoprotein IIb/IIIa inhibitors, thiazolidinediones, statins or other) and local therapy with DES will likely prove more effective by targeting the biologic effects of hyperglycemia or insulin, as well as local device biocompatibility. The selection of diabetic patients for PCI with DES should follow published ACC/AHA guidelines for PCI in the pre-DES era. ¹¹ In diabetic patients suitable for PCI with DES, meticulous attention to operator technique and implementation of effective adjunctive anti-platelet therapies is essential to optimize acute and long-term clinical outcomes. To obtain credit, please download, fill out, and return attached PDF for the required evaluation and questions.

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