Clinical Use of Sirolimus-Eluting Stents

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1 Cardiovascular Drug Reviews Vol. 25, No. 4, pp C 2007 The Authors Journal compilation C 2007 Blackwell Publishing Inc. Clinical Use of Sirolimus-Eluting Stents Ajay J. Kirtane and Martin B. Leon Center for Interventional Vascular Therapy, Columbia University Medical Center, New York, NY, USA Keywords: Coronary stents PCI Percutaneous coronary intervention Rapamycin Sirolimus Sirolimus stents. ABSTRACT Drug-eluting stents, or intracoronary stents that combine the local delivery of antirestenotic pharmacologic therapies while maintaining the mechanical advantage of bare metal stents over balloon angioplasty alone, are a highly complex technology that have profoundly affected the practice of percutaneous coronary intervention over the last 5 years. These devices were designed specifically to treat the neointimal hyperplasia occurring after conventional bare metal stent placement, and have been remarkably successful in this regard. However, recent concerns have been raised regarding the long-term safety of these devices, particularly when used outside of the specific patient and lesion subsets studied in the pivotal randomized trials that led to device approval by regulatory bodies within the United States and abroad. This review aims to present a brief description of the sirolimus-eluting stent device platform and its mechanism of action, followed by an overview of current data regarding efficacy and safety regarding the clinical use of sirolimus-eluting stent technology. INTRODUCTION The introduction of coronary stent technology as an adjunct to balloon angioplasty in the late 1980s dramatically impacted the scope of percutaneous coronary intervention (PCI), Address correspondence and reprint requests to: Ajay J. Kirtane, MD, SM, Assistant Professor of Clinical Medicine, Center for Interventional Vascular Therapy, Division of Cardiology, Columbia University Medical Center, New York, NY Tel.: ; Fax: ; ak189@columbia.edu Dr. Kirtane has received an honorarium from Boston Scientific and Dr. Leon is a member of the scientific advisory boards of numerous device companies. 316

2 SIROLIMUS STENTS 317 heralding a revolution in interventional cardiology. By reducing the incidence of abrupt closure and negating the recoiling force of vessels treated with angioplasty, the use of intracoronary stents has resulted in lower rates of periprocedural complications and more durable and stable results following PCI. Despite early concerns about acute and subacute stent thrombosis, the widespread use of peri- and postprocedural antiplatelet regimens in conjunction with high-pressure balloon inflations has largely mitigated this risk (Colombo et al. 1995; Leon et al. 1998), and, as a result, since the late 1990s, intracoronary stents have been used in the vast majority of PCI procedures. Until recently, the Achilles heel of stenting has been the occurrence of restenosis, or renarrowing of the treated coronary artery secondary to vascular injury, leading to a proliferation of smooth muscle cells (termed neointima ) at the site of stent placement. This mechanism of restenosis is relatively specific to stent procedures (as opposed to the predominant mechanism of restenosis following balloon angioplasty, which is related to compromise of the luminal area caused by acute recoil and negative remodeling). Restenosis, defined angiographically as a 50% or greater percentage diameter stenosis at the site of PCI, has been observed to occur in roughly 20 40% of lesions treated with conventional stents, with variation based upon patient, lesion, and technique-specific factors. Thus, despite the predictable and excellent immediate- and short-term results of PCI with stents, a sizeable proportion of patients treated with conventional bare metal stent (BMS) procedures develop angiographic restenosis, typically 6 12 months after undergoing PCI. Because some angiographic restenosis may be clinically silent, a slightly lesser proportion of patients experience clinical restenosis, defined as the recurrence of symptoms or inducible ischemia attributable to a lesion recently treated with PCI. Many studies have demonstrated that restenosis adds to patient morbidity and increased costs, as patients with restenosis frequently require repeat revascularization, and up to 35% of patients present with unstable angina or myocardial infarction (Schuhlen et al. 2004; Chen et al. 2006; Nayak et al. 2006). Drug-eluting stents (DESs), or intracoronary stents that combine the local delivery of antirestenotic pharmacologic therapies while maintaining the mechanical advantage of the BMS were designed specifically to treat the neointimal hyperplasia occurring after conventional BMS placement, and have been remarkably successful in this regard. The DES has been associated with low rates of angiographic restenosis as well as low rates of target lesion revascularization (a surrogate of clinical restenosis) in numerous studies, with 40 60% relative reductions in the incidences of these endpoints compared to BMS (Morice et al. 2002; Moses et al. 2003a). These results have been validated outside of the pivotal randomized trials that led to device approval in subsequent trials and real-world registries enrolling more complex patient and lesion subsets. The first clinical use of DES technology began with the introduction of the Cypher TM stent (Cordis, Johnson and Johnson) through initial first-in-man studies as well as in subsequent clinical trials leading to the device s approval in Europe in 2002 and the United States in This stent, the prototypical and most-studied sirolimus-eluting stent (SES) has now been implanted in over three million patients, and in the short time since its introduction, over 850 articles have been written about the stent (data from This review aims to present an overview of current data regarding efficacy and potential safety concerns regarding the clinical use of SES stent technology, following a description of the device platform and its mechanism of action. The article focuses primarily on the most

3 318 A.J. KIRTANE AND M.B. LEON widely studied SES, the Cypher TM stent, and its application in the treatment of coronary artery disease. SIROLIMUS-ELUTING STENTS (SES) Components and Mechanism of Action of the SES Drug eluting stents (DESs) comprise three major components: the stent platform (stent and delivery balloon), the drug carrier, and the drug itself. For the Cypher TM SES, the stent platform is the Bx-Velocity TM stent, a slotted-tube stent with a closed-cell design constructed from 316L stainless steel. This stent is mounted on either the Raptor TM or Raptorrail R delivery system, which allows relatively precise balloon-expandable stent delivery. Prior to mounting, the stent is coated both on its luminal as well as its abluminal surface with biostable (nonerodible) polymers consisting of poly-n-butyl methacrylate and polyethylene vinyl acetate that are loaded with sirolimus (also known as rapamycin, an agent that is used in organ transplantation to prevent rejection). The polymers, which uniformly coat the stent with a thickness of 5 10 microns, serve as a drug carrier vehicle, ensuring that the sirolimus is released into the vessel wall through programmed release. The slow-release formulation of the Cypher TM SES, used in clinical practice, uses a basecoat of blended polymers that is loaded with sirolimus as well as a topcoat of polymer alone (without sirolimus), which acts as a diffusion barrier and thereby reduces the rate of drug release from the basecoat into the vessel wall. With this formulation of polymers, the majority of sirolimus (approximately 80%) is released within the first month after stent implantation, with approximately 50% of the drug released in the first 2 weeks. Following stent implantation, sirolimus is eluted from the stent and readily diffuses into the vessel wall and into cells. Sirolimus (also known as rapamycin) is a macrolytic lactone produced by Streptomyces hygroscopicus. Its molecular formula is C 51 H 79 NO 13 and its molecular weight is It is insoluble in water and sparingly soluble in hexane and petroleum ether. Sirolimus is an immunosuppressant and is used clinically as Rapamune R, primarily for prophylaxis for organ rejection. In the pharmacokinetic studies that led to device approval, the mean dose of sirolimus delivered with single stent implantation was 161 ± 15 μg, with a maximal concentration of 0.57 ± 0.12 μg/ml at 3.90 ± 2.38 hours and a terminal half-life of 206 hours (Cypher TM stent Instructions for Use accessed at Sirolimus released systemically exists within blood and is 92% bound to plasma proteins, with primary metabolism by the liver via CYP3A4 and P-glycoprotein pathways. Of note, in pharmacokinetic studies that led to device approval, blood levels of sirolimus after SES implantation were fold lower than those observed after oral administration of sirolimus in healthy volunteers or transplant patients. While the terminal half-life of sirolimus after SES implantation is 2-to-4-fold greater than that observed in patients undergoing oral sirolimus dosing, this likely represents continued release of sirolimus from the SES rather than diminished clearance or elimination. Drug-specific toxicities related to systemic sirolimus administration are possible following SES implantation, but are less likely than those described with oral sirolimus administration given the significantly lower blood levels achieved after SES implantation.

4 SIROLIMUS STENTS 319 Within cells, sirolimus exerts both antiinflammatory and antiproliferative properties, thereby reducing smooth muscle cell proliferation in the arterial wall following stentrelated injury (Marx et al. 1995; Poon et al. 1996). The primary mechanism of action of sirolimus s inhibition of neointimal hyperplasia is thought to be related to its ability to bind to FK binding protein-12 (FKBP-12) in cells; together the Sirolimus-FKBP-12 complex binds to and inhibits activation of the mammalian target of rapamycin (mtor), preventing progression in the cell cycle form the G1 phase to the S phase (Marx and Marks 2001). The SES was demonstrated to have a marked effect on suppression of neointimal hyperplasia following implantation in initial studies using a porcine coronary model (Gallo et al. 1999; Suzuki et al. 2001), findings which have translated into the efficacy of SESs in limiting restenosis in human clinical trials. While the SES has definitively been shown to reduce the amount of neointimal hyperplasia that occurs as a result of vascular injury following stent implantation in both animal and human studies, there are also potential side effects and toxicities of both the polymer as well as the drug as it diffuses into the vessel wall. Because the SES affords the ability to deliver sirolimus locally and directly to the coronary vessel, the amount of sirolimus required to achieve therapeutic effect in the target tissue of the stented vessel has minimal systemic effects. Therefore, the toxicity of SES is related primarily to the effects of the polymer and drug in the local vessel milieu. Local infiltration of eosinophils suggesting a hypersensitivity reaction to the polymer carrier has been described following SES implantation (Virmani et al. 2004), and may also adversely affect complete healing at the site of vascular injury. From a population-level perspective, these types of events appear to be rare, and can be manifest as either local intrastent inflammation or as systemic symptoms. In an analysis of 5783 voluntary reports of adverse events related to DES (including both SES and paclitaxel-eluting stents) in the U.S. Food and Drug Administration (FDA) database, 14 events were identified and characterized as probable or certain SES-induced hypersensitivity reactions (Nebeker et al. 2006). Additional local vascular side effects have been described following SES implantation, which may impact long-term safety. Following BMS implantation, re-endothelialization of stent struts, or healing at the site of vascular injury occurs in the majority of patients within 1 month of stent implantation. Thus, during this period, patients are typically treated with dual antiplatelet therapy to mitigate any increased thrombotic risk posed by incompletely endothelialized stent struts. With SES, angioscopic and histopathologic studies in preclinical models and in humans have demonstrated a persistence of fibrin and thrombus deposition and incomplete endothelialization at the site of vascular injury in comparison to BMS (Joner et al. 2006; Kotani et al. 2006). These findings appear to be even more pronounced in patients with overlapping stents (Finn et al. 2005). As a result, additional antiplatelet therapy is recommended for at least 1 year in patients at low risk for bleeding, but definitive data regarding the optimal duration of dual antiplatelet therapy are lacking (Grines et al. 2007). Additionally, there have been reports of late stent malapposition, aneurysm formation, and abnormal vasomotor reactivity and endothelial dysfunction following SES implantation (Stabile et al. 2004; Hong et al. 2006; Maekawa et al. 2006; Siqueira et al. 2007). It is currently unclear whether these vascular responses to SES are persistent phenomena and to what extent they are associated directly with clinical sequelae in unselected patients, although a recent analysis from a histopathologic study of 81 thrombosis cases has demonstrated an association between incomplete endothelial stent coverage and late stent thrombosis (Finn et al. 2007).

5 320 A.J. KIRTANE AND M.B. LEON Clinical Studies with the SES: Efficacy in First-in-Man and Pivotal Approval Studies The first human study of the SES was a pilot study of the SES in 45 patients with coronary artery disease conducted in Sao Paulo, Brazil and Rotterdam, The Netherlands. In this study, the SES demonstrated marked suppression of neointimal hyperplasia measured by intravascular ultrasound and quantitative coronary angiography at both 4 months and 1 year (Sousa et al. 2001a; Sousa et al. 2001b). Following the success of the SES in this initial study, the landmark RAVEL trial was conducted, randomizing 238 patients outside the United States with relatively simple de novo coronary lesions 18 mm of length or less in coronary arteries mm in diameter to either the Cypher SES or its bare metal uncoated stent, the Bx-VELOCITY stent (Morice et al. 2002). In RAVEL, at 6-month angiographic follow-up, late loss (the change in minimal luminal diameter from the end of the procedure to follow-up) was markedly lower among SES-treated patients ( 0.01 mm vs mm, P < 0.001), with a corresponding reduction in the rate of restenosis (0% vs. 26%, P < 0.001). The rate of major adverse cardiac events (MACEs), a composite of death, myocardial infarction, coronary artery bypass grafting, or target vessel revascularization at 1 year was 5.8% for SES-treated patients versus 28.8% for BMS-treated patients (P < 0.001). These results have been maintained at longer term follow-up, with 3-year event rates demonstrating a significant and persistent reduction in MACE with SES compared to BMS (15.5% vs. 33.1%, P = 0.002) (Fajadet et al. 2005). The pivotal U.S. trial that led to FDA approval of SES was the SIRIUS trial, a patient randomized trial comparing the Cypher DES to its uncoated BMS in patients with vessel diameters mm and lesion lengths of mm (Moses et al. 2003b). The patient population and lesion types were in general more complex in SIRIUS compared to RAVEL, with a 26% prevalence of diabetes and a mean lesion length of 14.4 mm. The primary endpoint, the rate of target vessel failure (a composite of cardiac death, myocardial infarction, or revascularization of the target vessel) at 9 months, was markedly lower among SES-treated patients (8.6% vs. 21.0% for BMS-treated patients, P < 0.001). The rate of MACE was similarly lower with SES compared to BMS (7.1% vs. 18.9%, P < 0.001). The 60 80% relative benefit of SES versus BMS was observed in all tested subgroups in the trial, including diabetic patients, and irrespective of vessel size. Additionally, longer term follow-up from SIRIUS has also demonstrated a persistently maintained benefit of SES over BMS, with 2-year rates of MACE of 10.1% versus 24.4%, respectively (P < 0.001) (Weisz et al. 2006). Among the 703 of the 850 patients assigned to receive angiographic follow-up in the trial, angiographic restenosis was greatly reduced with the SES [(in-stent: 3.2% vs. 35.4% for BMS, P < 0.001; in-segment (including the 5 mm proximal and distal to the stent): 8.9% versus 36.3%, P < 0.001]). As expected, late loss was markedly lower with SES compared to BMS (in-stent: 0.17 mm vs mm, P < 0.001), and in the subgroup of patients receiving intravascular ultrasound, neointimal volume was much lower with SES. Even in patients experiencing restenosis events in SIRIUS, the pattern of restenosis was diffuse in only 13% of patients with SES restenosis versus 58% with BMS restenosis (P < 0.001). Diffuse restenosis is in general more difficult to treat than focal restenosis, and has been associated with adverse clinical outcomes among patients undergoing repeat PCI (Mehran et al. 1999). Thus, even in the patients with restenosis with an SES, treatment with

6 SIROLIMUS STENTS 321 repeat PCI for SES-restenosis was associated with more favorable outcomes than would be expected for BMS-restenosis patients (Moussa et al. 2006). Two additional blinded randomized trials of the Cypher SES versus BMS, C-SIRIUS and E-SIRIUS (collectively termed NEW-SIRIUS), were performed in Canada and Europe, respectively (Schofer et al. 2003a; Schampaert et al. 2004). Overall, these trials had inclusion/exclusion criteria similar to those of SIRIUS, with similar lesion lengths (mean 14.8 mm) but slightly smaller vessel sizes (mean diameter 2.61 mm). In these trials, the overall rate of angiographic restenosis was markedly lower with SES compared to BMS (in-stent: 3.1% vs. 42.7%, P < 0.001; in-segment: 5.1% vs. 44.2%, P < 0.001). Similar reductions in MACE with the use of SES compared to BMS as observed in SIRIUS were observed in C-SIRIUS and E-SIRIUS as well. A pooled analysis of SIRIUS, C-SIRIUS, and E-SIRIUS at 2-year follow-up demonstrated significant reductions in MACE (10.6% vs. 26.3%, P < 0.001) with SES compared to BMS (Schampaert et al. 2006). Efficacy Data in Specific Subgroups and Broader Patient Populations The data based upon RAVEL, SIRIUS, C-SIRIUS, and E-SIRIUS demonstrate both individually, and, in aggregate, that the use of SES in simple de novo coronary lesions results in dramatic reductions in restenosis and the need for target vessel revascularization compared to BMS. These results, which led to the worldwide approval of the Cypher SES for use, also subsequently led to widespread use of SES as the dominant stent in PCI procedures soon after device approval. However, it has been estimated that only 30% of lesions treated in general practice would have met entry/exclusion criteria for these trials (Win et al. 2007), and thus the majority of use of SES in real-world clinical practice has been for more complex lesion subsets than in the initial randomized studies as well as for a number of off-label indications. Several registry studies have examined the use of SES in real-world clinical practice. While these data are observational, the results largely parallel those from the randomized clinical trials. The first of these registries, the RESEARCH registry, is a consecutive prospective study of patients undergoing SES implantation compared to a historical control group of patients undergoing PCI with BMS implantation just before approval of SES. Despite the greater patient and lesion complexity seen in this registry compared to the randomized trials, the unrestricted use of SES has been associated with significant reductions in MACE and target vessel revascularization at up to 3 years of follow-up (Lemos et al. 2004b; Daemen et al. 2006). Similar low rates of MACE and target vessel revascularization have been observed in other real-world registries (Urban et al. 2006; Win et al. 2007). Diabetes Mellitus Patients with diabetes mellitus are at greater risk for restenosis as well as for other MACE events following PCI. Despite higher overall rates of repeat revascularization and MACE when compared to the nondiabetic subgroup in the SIRIUS trial, subgroup analyses demonstrated similar efficacy of SES compared to BMS in patients with diabetes mellitus (Moussa et al. 2004). In the randomized DIABETES trial of 160 patients undergoing

7 322 A.J. KIRTANE AND M.B. LEON stenting with SES or BMS, 9-month late loss was reduced with SES (0.06 mm vs mm, P < 0.001), and rates of target lesion revascularization and MACE were significantly lower with SES, with similar results among noninsulin-requiring and insulin-requiring patients (Sabate et al. 2005). The benefit of SES over BMS was persistent with follow-up out to 2 years (Jimenez-Quevedo et al. 2007). Similarly, data from the SES-treated arm of the ISAR-DIABETES trial demonstrated a high efficacy of SES (Dibra et al. 2005), and observational studies have also demonstrated efficacy of SES in the treatment of diabetic patients with coronary artery disease (Kuchulakanti et al. 2006), although the benefit of SES compared to BMS appeared to be mitigated over longer term follow-up in one series (Daemen et al. 2007a). Of note, attempts to increase the dose of sirolimus to counter the greater propensity for restenosis in diabetic patients have not translated into improved outcomes. In the 3D study randomizing 56 patients with diabetes mellitus to treatment with the standard dose Cypher SES versus a similar stent with twice the dose of sirolimus, there were no differences in any of the angiographic endpoints, indicating no benefit of a higher dose SES (Sousa et al. 2005). Long Lesions and Small Vessels Lesion length has been demonstrated to be a significant predictor of restenosis among PCI-treated patients. The mean lesion length in the four major randomized trials of SES versus BMS was <15 mm overall, which is shorter than the majority of lesions treated in clinical practice. Data from observational studies and prospective trials have demonstrated low overall rates of restenosis, target vessel revascularization, and MACE with SES among this complex lesion subset (Kim et al. 2006a; Kim et al. 2006c). Most recently, in the LONG DES-II study, a study of patients undergoing treatment with SES and a mean lesion length of 34 mm, the rate of 9-month angiographic restenosis was a remarkable 3.3%, and the rate of MACE was 12.0%, which compares favorably to BMS control populations. Because the amount of neointimal hyperplasia (as measured by late loss) observed following PCI with stenting is thought to be relatively independent of vessel size, the benefits of SES are potentially even greater among small vessels which are less likely to tolerate greater amounts of late loss. In a prospective registry of 100 patients undergoing treatment with a 2.25-mm SES, 6-month restenosis rates were 16.9%, but compared favorably to a propensity-matched cohort of patients undergoing stenting with BMS, in whom restenosis rates were 30.6% (Moses et al. 2006). Similarly, in SES-SMART, a 257 patient randomized trial of SES versus BMS in patients with small vessels (mean diameter 2.2 mm) including 2.25-mm, 2.5-mm, and 2.75-mm SES, treatment with SES was associated with a marked reduction in restenosis and MACE at 8 months (9.8% vs. 53.1% for binary restenosis; 9.3% vs. 31.3% for MACE, P < for both). These results have been paralleled in several observational registry studies (Elezi et al. 2006; Meier et al. 2006; Tanimoto et al. 2006). In-Stent Restenosis and Chronic Total Occlusion In-stent restenosis (ISR) has been estimated to occur in 20 40% of patients undergoing PCI with BMS, and leads to repeat revascularization, increased hospital costs, and comorbidity. Prior to the advent of DES, treatment for ISR was limited to repeat angioplasty and stenting, with or without adjunctive vascular brachytherapy. The results with vascular

8 SIROLIMUS STENTS 323 brachytherapy were improved compared to angioplasty alone, but overall rates of recurrence following brachytherapy were high. An initial comparison of SES versus vascular brachytherapy in patients with BMS ISR demonstrated favorable angiographic and clinical outcomes with SES (Feres et al. 2005). In the SISR trial, a randomized trial in 384 patients with ISR undergoing repeat PCI, treatment with SES compared to brachytherapy was associated with a significant reduction in the rate of 9-month MACE (10.0% vs. 19.2%, P = 0.02) as well as reductions in angiographic restenosis and late loss (Holmes et al. 2006). These results have been paralleled in two other prospective registry studies (Kim et al. 2006b; Zavalloni et al. 2006). Chronic total occlusions are another complex lesion subset associated with high rates of restenosis and MACE. Non-randomized data from several registry series have demonstrated excellent short-term and intermediate-term results with the use of SES in the treatment of chronic total occlusions compared to BMS controls (Lemos et al. 2004a; Ge et al. 2005; Kelbaek et al. 2006; Lotan et al. 2006). The PRISON-II study, a randomized trial of 200 patients undergoing PCI for chronic total occlusion, demonstrated lower rates of angiographic restenosis, target vessel revascularization, and MACE among patients treated with SES compared to BMS (Suttorp et al. 2006). Bifurcation Disease, Saphenous Vein Grafts, and Multivessel Disease The benefits of SES in limiting angiographic and clinical restenosis have been demonstrated in several other complex lesion subsets, including coronary bifurcation lesions, saphenous vein grafts, and multivessel disease. While to the best of our knowledge there have been no randomized trials comparing the use of SES versus BMS in patients with bifurcation disease, three studies have suggested that a provisional approach, or SES implantation in the main vessel with stand-alone angioplasty of the sidebranch with stenting only when absolutely necessary, is the favored approach for the treatment of bifurcation disease (Colombo et al. 2004; Pan et al. 2004; Steigen et al. 2006). While the overall results are favorable compared to historical data using BMS, these studies have also demonstrated that there do not appear to be reductions in the rate of restenosis with the use of two stents. With regards to the treatment of saphenous vein grafts, the RRISC trial randomized 75 patients with saphenous vein graft disease to treatment with SES or BMS, and demonstrated significant reductions at 6-month angiographic follow-up in the amount of late loss and the rate of restenosis with SES (in-stent restenosis: 11.3% vs. 30.6%, P = 0.024) (Vermeersch et al. 2006). There were no differences in rates of death or myocardial infarction between the two study arms. The treatment of multivessel coronary artery disease with PCI has been controversial, particularly given the excellent long-term clinical outcomes of patients who are surgical candidates and are treated with coronary artery bypass grafting. However, the majority of prior studies of PCI versus surgery for multivessel disease have demonstrated similar overall survival with both techniques, with a marked benefit in the need for repeat revascularization among surgically treated patients (Pocock et al. 1995; The Bypass Angioplasty Revascularization Investigation (BARI) Investigators 1996; Mercado et al. 2005; Stone et al. 2005). Thus, the use of SES, which reduces the rate of repeat revascularization, could potentially narrow the gap between PCI and surgery. While randomized trials of SES versus surgery in patients with multivessel disease are ongoing, preliminary registry data have demonstrated excellent outcomes among patients with multivessel disease undergoing PCI with DES. In

9 324 A.J. KIRTANE AND M.B. LEON the ARTS-II, a prospective registry of SES for multivessel disease, 3-year follow-up data demonstrated similar rates of mortality, myocardial infarction, and repeat revascularization among patients with multivessel disease treated with DES compared to a similar cohort of coronary angiography bypass grafting (CABG) patients from ARTS-I (unpublished data presented by P. Serruys, American Heart Association Scientific Sessions 2006). Acute Myocardial Infarction The use of SES in acute myocardial infarction has been studied in both observational registries as well as in randomized clinical trials. In registry series, the use of SES compared to BMS was associated with improved clinical outcomes at one year, primarily driven by a lower rate of target vessel revascularization (Newell et al. 2006; Percoco et al. 2006). In the TYPHOON trial, a randomized trial of SES versus BMS in 712 patients undergoing primary PCI, treatment with SES was associated with a reduction in MACE, largely driven by a lower rate of target vessel revascularization (5.6% vs. 13.4% with BMS, P < 0.001) (Spaulding et al. 2006). Angiographic follow-up at 8 months was available in 174 of these patients, and demonstrated reductions in late loss and restenosis among patients treated with SES. Of note, the rates of other adverse cardiac events (death, recurrent myocardial infarction, and stent thrombosis) were not different between patients receiving SES or BMS. In the SESAMI trial of 320 patients randomized to SES versus BMS, the rate of restenosis was reduced by SES (9.3% vs. 21.3%, P = 0.032), with similar reductions in target lesion revascularization and MACE (Menichelli et al. 2007). Potential for Adverse Late Effects of SES and Long-Term Follow-up Data As described previously, the use of SES has been associated with excellent short-term and intermediate-term clinical outcomes, with marked reductions in the rates of angiographic and clinical restenosis compared to BMS. These findings were initially demonstrated in the pivotal randomized trials that led to device approval, and have subsequently been extended to more complex lesion and patient subsets. While the use of SES in these studies has been associated with reduced MACE, the majority of clinical benefit in these studies is manifest through reductions in restenosis and target vessel revascularization. Most trials comparing SES and BMS, both individually and in aggregate in meta-analyses, have demonstrated similar overall rates of death, myocardial infarction, and other safety endpoints (Moses et al. 2003a; Katritsis et al. 2005; Nordmann et al. 2006). The difficulty in assessing differences in hard clinical endpoints in these studies is partly due to the limited sample sizes of these studies, which have typically been powered to demonstrate efficacy of SES through the use of endpoints that speak more to the mechanism of effect of SES in limiting neointimal hyperplasia and repeat revascularization, rather than to overall safety. The specific safety issue of SES that has probably generated the most scrutiny and interest is the issue of late stent thrombosis. As a result of concerns regarding delayed endothelialization and vessel healing with the possibility of an attendant late thrombosis risk with DES, the occurrence of stent thrombosis has been closely monitored within studies of SES. These studies and indeed the FDA labeling of SES have mandated a longer duration

10 SIROLIMUS STENTS 325 of dual antiplatelet therapy (3 months or greater) than is conventionally recommended with BMS. Initial data from the pivotal randomized studies have demonstrated a similar overall incidence of stent thrombosis with SES and BMS (Morice et al. 2002; Moses et al. 2003a; Schofer et al. 2003b; Schampaert et al. 2004; Schampaert et al. 2006). However, since the SES has been introduced into widespread clinical practice, there has been observational evidence specifically relating to the occurrence of late stent thrombosis, or stent thrombosis occurring greater than 30 days following stent implantation ( Kerner et al. 2003; McFadden et al. 2004; Walpoth and Hess 2004; Jeremias et al. 2004; Daemen et al. 2007b). It has been difficult to accurately assess the risk of stent thrombosis, and, in particular, late stent thrombosis, with SES for several reasons. Stent thrombosis following PCI is a rare phenomenon, occurring after less than 2% of PCI procedures. Thus, a total study size of approximately 8000 patients would be needed, for example, in order to detect a 50% relative increase (1% absolute increase) in the rate of stent thrombosis. In comparison, all four major randomized SES versus BMS trials enrolled a total of 1748 patients, and thus even with meta-analytic techniques, the available published data remain underpowered to address the comparative incidence of stent thrombosis with SES and BMS. Additionally, because of the pronounced efficacy of SES observed in the initial approval studies, use of the SES has been so widespread that it has become logistically difficult to find a comparable control group to SES or to conduct further adequately powered randomized trials comparing SES to BMS. Moreover, estimates of the incremental risk of stent thrombosis with SES compared to DES given the current available trial data are not likely applicable to the majority of patients currently treated with SES, as the clinical use of SES has expanded to a variety of off-label indications that have not been studied sufficiently, particularly with regards to safety endpoints, such as stent thrombosis. Data regarding the long-term outcomes of SES compared to BMS at 4-year follow-up in the four major randomized trials (RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS) have recently been published (Mauri et al. 2007; Spaulding et al. 2007; Stone et al. 2007). At 4 years, the rates of death or myocardial infarction were no different between SES- and BMS-treated patients (11.6% vs. 10.3%, P = 0.39), and the rate of protocol-defined stent thrombosis was similar between SES- and BMS-treated patients (1.2% vs. 0.6%, P = 0.20). However, there were more very late stent thromboses as defined according to the study protocols (those occurring >1 year following PCI) with SES compared to BMS (5 events vs. 0 events, P = 0.025). These data as well as other data from registry series and a meta-analysis of 14 trials comparing SES to BMS have indicated that SES is associated with a similar rate of early and overall stent thrombosis, but is perhaps also associated with an increased risk of late and very late stent thrombosis (Kastrati et al. 2007). There are several notable caveats to these data. First, the very limited number of overall events in these underpowered analyses increases the possibility of random variation in event rates, and greatly limits the ability to detect differences between the study groups. Additionally, the protocol definitions of stent thrombosis in the pooled analyses of randomized clinical studies censored stent thrombosis events occurring after an intervening target lesion revascularization. In other words, if a patient had a repeat PCI for a restenosis event followed by an episode of stent thrombosis, this thrombosis event was not counted in the original protocol definition, and, therefore, these events are not reflected in published analyses as well as in the pooled data above. Due to the far greater number of target lesion revascularization events in the BMS arms of these randomized trials compared to the SES arms, this represents informative censoring of events and undercounts of events occurring following

11 326 A.J. KIRTANE AND M.B. LEON index BMS implantation by intent-to-treat analyses. In fact, in analyses accounting for this censoring, six additional stent thrombosis events occurred after an intervening target lesion revascularization; all of these events occurred in the BMS arms of these trials and were not counted in the published reports of these trials (Mauri et al. 2007). This finding, in addition to the fact that the use of the SES results in a reduced rate of restenosis and repeat revascularization, may explain why the observed increased rate of stent thrombosis was not accompanied by an increased rate of late death or myocardial infarction. Nonetheless, given the findings of delayed endothelialization and vascular injury with SES based upon histopathologic data from preclinical animal studies as well as human autopsy studies, the potential of an increased risk of stent thrombosis remains, and it is unclear whether this risk can be mitigated by prolonged antiplatelet therapy, which in turn may have untoward side effects and is associated with substantial costs. It also appears that the incidence of stent thrombosis and adverse clinical events overall is higher in patients treated with off-label DES use compared to the use of these devices as studied in the pivotal randomized trials (Beohar et al. 2007; Win et al. 2007). Whether there are thus greater risks of adverse events with the use of SES compared to BMS in these off-label indications is currently unknown. While one nonrandomized registry study has demonstrated a greater risk of adverse events beyond 1 year with the use of DES compared to BMS (Lagerqvist et al. 2007), other studies have demonstrated the opposite (Simonton et al., unpublished data). In the absence of randomized data, it is extremely difficult to ascertain the long-term safety of DES in unselected patients, and, thus, several large-scale registries are ongoing in order to better assess DES safety. CONCLUSIONS In summary, the ability of the SES to focally target the restenotic process following intracoronary stent implantation has led to the widespread use of this first-generation technology and has translated into substantial reductions in restenosis and repeat revascularization among patients undergoing PCI. However, the potential side effects of this potent drug-device combination relating to delayed endothelialization and a possibly increased risk of late stent thrombosis underscores the need for further development and refinement of DES technology. The capacity of newer generation SES systems with bioabsorbable polymers and or polymer-less drug delivery systems to limit the toxicity of SES merits further study. Additionally, the further study of the mechanisms of late stent thrombosis as well as the patient-related correlates of thrombosis events could facilitate screening of at-risk populations and targeted therapy to reduce the occurrence of these events. PCI Percutaneous coronary intervention BMS Bare metal stent DES Drug-eluting stent SES Sirolimus-eluting stent ADDENDUM Abbreviations

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