Pathology of Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus- and Paclitaxel-Eluting Stents in Humans

Initial trials comparing stenting with balloon angioplasty demonstrated improved angiographic and clinical outcomes with the former.1–3 The main clinical problem with bare metal stents (BMS) became the development of in-stent restenosis.4–6 Early data suggested that drug-eluting stents (DES) could mitigate, if not abolish, this problem.7–9 Since the approval of DES, these devices have become the predominant stents used in percutaneous coronary interventions, regardless of indication. As of September 2007, the Cypher sirolimus-eluting stent (SES) (Cordis Johnson & Johnson, Miami Lakes, Fla) had been deployed in >3 million patients worldwide,10 and the millionth Taxus paclitaxel-eluting stent (PES) (Boston Scientific, Natick, Mass) was implanted as of January 2005.11 Over the past 2 years, numerous reports of very late stent thrombosis (ST) with first-generation DES have surfaced. This highly morbid complication and data suggesting that death and myocardial infarction (MI) may be more common with DES12,13 have altered the focus of trials and registries working to determine optimal DES use. There is a hope that second-generation DES will be less prone to ST as a result of differences in drug, stent design, and polymer. Medtronic, Inc (Minneapolis, Minn) presented safety and efficacy data to a public meeting of the US Food and Drug Administration (FDA) Circulatory System Devices Panel (CSDP) in October 2007 on its Endeavor zotarolimus-eluting stent (ZES), seeking approval for the indication of treating de novo native coronary lesions ≤27 mm with reference vessel diameters of 2.5 to 3.5 mm. The FDA asked the CSDP to determine whether the data presented demonstrated a reasonable level of safety and effectiveness, with clinical benefits clearly outweighing short- and long-term risks of ZES use. Important efficacy end points included ischemia-driven target lesion revascularization (TLR) or target vessel revascularization (TVR); safety end points included death, MI, and ST. The …

Drug-eluting Stents at a Crossroads: the good, the Bad and the Ugly

Coronary Responses and Differential Mechanisms of Late Stent Thrombosis Attributed to First-Generation Sirolimus- and Paclitaxel-Eluting Stents

Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial FibrillationAtrial fibrillation (AF) is the most common arrhythmia in clinical practice.There is substantial information available about cellular electrophysiological abnormalities in patients with long-standing persistent AF, but the atrial-cellular pathophysiology in patients with paroxysmal AF (pAF) is largely unknown.Here, we used simultaneous measurements of intracellular [Ca 2+ ] and membrane current/potential in atrial cardiomyocytes from sinus rhythm and pAF patients (last AF episode a median of 10-20 days preoperatively), together with biochemistry and computational modeling, to define the cellular and molecular mechanisms promoting atrial arrhythmogenesis in pAF.L-type Ca 2+ currents and action potential durations were unaltered in pAF patients, indicating the absence of typical AF-associated remodeling.However, cardiomyocytes from pAF patients had enhanced diastolic sarcoplasmic reticulum (SR) Ca 2+ leak and increased susceptibility to spontaneous diastolic SR Ca 2+release events, causing delayed after-depolarizations/triggered activities that promote atrial ectopic (focal) activity.Pharmacological and biochemical studies indicated that the susceptibility to spontaneous cellular activity in pAF was attributable to enhanced SR Ca 2+ uptake, resulting from phospholamban hyperphosphorylation (removing phospholamban-induced inhibition of SR uptake), and ryanodine receptor (SR Ca 2+ release) channel dysregulation, including enhanced ryanodine receptor expression and increased single-channel open probability.Simulation studies indicated that both increased SR Ca 2+ leak and enhanced SR Ca 2+ uptake likely contribute to aberrant diastolic SR Ca 2+-release events.Our findings constitute the first direct evidence for an important role of Ca 2+-dependent ectopic activity in atrial arrhythmogenesis of pAF patients and provide insights into underlying mechanisms.The cellular and molecular mechanisms underlying abnormal Ca 2+ handling in pAF are distinct from those of long-standing persistent AF patients, suggesting possible opportunities to develop tailored therapeutic approaches for pAF.See p 145.

Four legs good, two legs better. — —George Orwell, Animal Farm, 1945 Since the earliest use of coronary stents for treating symptomatic coronary stenosis, maintaining patent arteries after treatment has remained an elusive goal. Although the first bare metal stents opened stenotic arteries, they injured the arterial wall. The buildup of intimal scar tissue caused restenosis, a frustrating problem for prevention or treatment. After a dozen years of research, however, drug-eluting stents were developed; armed with polymer coating and paclitaxel or sirolimus, they prevented restenosis and were hailed as a major therapeutic breakthrough. Article see p 141 Not long afterward, however, questions about the safety and efficacy of drug-eluting stents surfaced as reports of late stent thrombosis began to appear.1,2 Cardiologists wondered if prevention of restenosis was always a good thing. If no protective cellular layer formed over the struts of the drug-eluting stent—even months or years after implantation—would thrombus develop on the exposed metal scaffolding or other damaged or inflamed areas on the blood vessel wall? Over months or years, would progressive inflammation or late “catchup” tissue growth cause drug-eluting stents to lose their early advantage over bare metal stents? The pendulum in this debate has swung back and forth as clinical trials first raised concern about increased thrombosis and then later quelled our fears as our understanding of how drug-eluting stents work in real life has matured. An important issue has been the increased use of stents in patients with more complex coronary and other disorders, raising the question of whether the established standards of safety and efficacy still apply. Answers for these challenging questions have come from 2 worlds: clinical studies of patients with stents …

Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis

In this second part of the article, we will complete the review of drug-eluting stent technologies (Table 1) and discuss methodological and technical aspects of drug-eluting stents. View this table: TABLE 1. Drug-Eluting Stent Platforms Under Investigation ### Biological Agents (Continued) #### (1) Stents Eluting Antiproliferative Agents A number of antineoplastic medications have been considered for the prevention of restenosis. Paclitaxel and its derivatives have been the most investigated compounds of this group. ##### (a) Paclitaxel-Eluting Stents Paclitaxel (Taxol; Bristol-Myers Squibb) is a microtubule-stabilizing agent with potent antitumor activity.1 Many different platforms that use polymer coating or surface modifications to adhere paclitaxel onto the stents have been utilized over the past 2 years. ###### Preclinical Data Unlike other antimitotic agents, paclitaxel shifts the cytoskeleton equilibrium toward assembly, leading to reduced vascular cell proliferation, migration, and signal transduction.2 Paclitaxel is highly lipophilic, resulting in a rapid cellular uptake and a long-lasting effect in the cell.3 NIR stents (Boston Scientific Corp) coated with poly(lactide-co-Σ-caprolactone) copolymer and paclitaxel (200 μg/stent) were placed in porcine coronary arteries. Paclitaxel-eluting stents showed a marked reduction in neointimal and medial cell proliferation at all time points (7, 28, 56, and 180 days).4 However, arteries treated with paclitaxel showed incomplete healing, late persistence of a large number of macrophages, and fibrin deposition. Similar findings were observed with a stent platform coated with cross-linked biodegradable polymer (chondroitin sulfate and gelatin) and 42.0, 20.2, 8.6, or 1.5 μg of paclitaxel in rabbit iliac arteries.5 These studies indicate the need for a more controlled drug release of paclitaxel due to the narrow toxic-therapeutic window and high hydrophobic character of this compound. ###### Clinical Data: De Novo Lesions The QuaDS drug-eluting stent (Quanam Medical Corp) was the first drug-eluting stent implanted in human coronary arteries. This slotted tube stent has 50% of its surface area covered by multiple nonbiodegradable polyacrylate sleeves that release 7-hexanoyltaxol (called QP2 or taxane). Approximately 800 μg of the …

Primary percutaneous coronary intervention (P-PCI) is the preferred reperfusion strategy for patients with ST-segment elevation myocardial infarction if it can be performed rapidly by an experienced team.1 Compared with balloon angioplasty, routine bare-metal stent (BMS) implantation decreases risk for target vessel revascularization (TVR) and possibly reduces myocardial reinfarction rates but does not reduce mortality rates.2,3 Therefore, BMS has become the dominant P-PCI strategy, despite initial concern about increased stent thrombosis rates from delayed healing or inadequate late stent apposition due to initial thrombus trapping. Less established is the role of drug-eluting stents (DES) in P-PCI. DES have the potential to further decrease TVR rates but may increase risk for stent thrombosis. In fact, the risk of stent thrombosis might even be higher in P-PCI than in electively treated patients because of the combination of increased platelet activation, delayed healing, lack of endothelialization, and the proinflammatory and prothrombotic environment in the infarct artery.4 Article see p 103 Several relatively small randomized clinical trials have shown inconsistent efficacy for DES over BMS for P-PCI. Three meta-analyses of these trials have concluded that there is no difference in death or myocardial infarction rates, but TVR rates are decreased.5–7 Variably included were 12 studies that differed in trial design, inclusion criteria, end-point definitions, stent types, duration of clopidogrel treatment, and type of follow-up (angiographic versus clinical). They were limited by sample size and duration of follow-up and usually required angiographic documentation of stent thrombosis, which may have underestimated its true incidence. In this issue of Circulation: Cardiovascular Interventions , Kukreja et al8 report a single-center registry study that is an expanded version of a previous publication.9 Again including the 185 ST-segment elevation myocardial infarction patients treated with Sirolimus-eluting stents (SES) from April 2002 to February 2003, they compare …

The publication in January 2001 of the first-in-man results showing zero restenosis after sirolimus-eluting stent implantation produced enormous excitement in the cardiological community.1 The long-awaited tool—a safe, restenosis-proof, easy-to-use stent—had been found. It was not too long thereafter that paclitaxel-eluting stents also demonstrated their capability to decrease restenosis. Today, both sirolimus- and paclitaxel-eluting stents have been shown in randomized trials to reduce restenosis as compared with conventional metallic stents (Figure 1).2–6 Most of these studies have been recently released in the form of abstracts during medical meetings and are still unpublished.3,5,6 In addition to sirolimus and paclitaxel, other agents have shown promising early results in recent studies, enlarging the body of evidence demonstrating the potential benefits of what are known as drug-eluting stents.7 Regulatory agencies have been very active in evaluating some of these devices in the United States, Europe, South America, and Asia. The sirolimus-eluting stent has been available for routine use in Europe, South America, and Asia since the first half of 2002 and received approval from the US Food and Drug Administration to be marketed in April 2003. Paclitaxel-eluting stents have also received CE (Conformite Europeenne) marking for commercialization in Europe and are now beginning to be commercialized. Figure 1. Randomized trials showing reduction of binary restenosis with drug-eluting stents.2–6 The case seemed to be closed. Restenosis, the Achilles’ heel of percutaneous revascularization, appeared defeated. However, since the sirolimus-eluting stents became available, very little has changed in the everyday life of almost all interventional laboratories in Europe. Why? Has the new treatment presented any undesirable effect? Was the desire to defeat restenosis not as great as supposed? The answer is none of the above. The limitation currently impeding more widespread use of the new technology is nontechnical, nonmedical, and nonbiological. The …

Sirolimus-Eluting Stents vs Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease: Meta-analysis of Randomized Trials

Placement of sirolimus-eluting stents or paclitaxel-eluting stents has emerged as the predominant percutaneous treatment strategy in patients with coronary artery disease (CAD). Whether there are any differences in efficacy and safety between these 2 drug-eluting stents is unclear. To compare outcomes of sirolimus-eluting and paclitaxel-eluting coronary stents on the basis of data generated by randomized head-to-head clinical trials. PubMed and the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to April 2005. Randomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with CAD reporting the outcomes of interest (target lesion revascularization, angiographic restenosis, stent thrombosis, myocardial infarction [MI], death, and the composite of death or MI) during a follow-up of at least 6 months. Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest. Six trials, including 3669 patients, met the selection criteria. No significant heterogeneity was found across trials. Target lesion revascularization, the primary outcome of interest, was less frequently performed in patients who were treated with the sirolimus-eluting stent (5.1%) vs the paclitaxel-eluting stent (7.8%) (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.49-0.84; P = .001). Similarly, angiographic restenosis was less frequently observed among patients assigned to the sirolimus-eluting stent (9.3%) vs the paclitaxel-eluting stent (13.1%) (OR, 0.68; 95% CI, 0.55-0.86; P = .001). Event rates for sirolimus-eluting vs paclitaxel-eluting stents were 0.9% and 1.1%, respectively, for stent thrombosis (P = .62); 1.4% and 1.6%, respectively, for death (P = .56); and 4.9% and 5.8%, respectively, for the composite of death or MI (P = .23). Patients receiving sirolimus-eluting stents had a significantly lower risk of restenosis and target vessel revascularization compared with those receiving paclitaxel-eluting stents. Rates of death, death or MI, and stent thrombosis were similar.

A 52-year-old female presented with an acute coronary syndrome, anterior T wave inversions, and elevated cardiac markers. After cardiac catheterization, a critical mid-left anterior descending artery (LAD) stenosis involving the origin of the second diagonal branch and a critical mid-right stenosis were observed. It was felt that the “culprit” vessel was the LAD, and a successful angioplasty was performed with a drug-eluting stent (DES), Cypher (Cordis), placed in the LAD and the diagonal branch dilated with a balloon. The right coronary artery (RCA) was treated with a drug-eluting stent 3 days later (Figure 1 …

Background-This article reports the 2-year clinical, angiographic, and intravascular ultrasound outcomes of the everolimus-eluting stent (EES) compared with the paclitaxel-eluting stent (PES) in the randomized SPIRIT II trial. Methods and Results-This was a prospective, single-blind clinical trial in which a total of 300 patients with de novo native coronary artery lesions were randomized to either EES or PES in a 3:1 fashion. Clinical follow-up was planned at 2 years in all patients. A subset of 152 patients underwent serial angiographic and intravascular ultrasound analyses at 6 months and 2 years. After 2 years, target lesion failure (cardiac death, myocardial infarction, and ischemia-driven target lesion revascularization) rates were 6.6% and 11% in EES and PES, respectively (P0.31). At 6 months, a significant reduction in angiographic in-stent late loss and percentage volume obstruction measured by intravascular ultrasound was observed in the EES group. However, at 2-year follow-up, a late increased intimal hyperplasia growth after implantation of an EES was observed. There were no significant differences between EES and PES for in-stent late loss (EES, 0.330.37 mm versus PES, 0.340.34 mm; P0.84) and percentage volume obstruction (EES, 5.186.22% versus PES, 5.806.31%; P0.65) at 2 years. The incidence of stent thrombosis was low and comparable in both groups (EES, 0.9%; PES, 1.4%). Conclusions-Although the previously reported angiographic and clinical superiority of the EES has vanished over time, this report confirms and extends the previously demonstrated noninferiority in terms of in-stent late loss of the EES when compared with the PES up to 2-year follow-up. There were no significant differences between EES and PES in clinical, angiographic and intravascular ultrasound outcomes at 2 years. (Circ Cardiovasc Intervent. 2009;2:339-347.)

BackgroundIn-stent-restenosis (ISR) is considered to be an essential limiting factor of stenting in coronary heart disease (CHD). The development of coated stents has raised expectations on substantial lowering restenosis after stenting with decreasing the rate of restenosis and a reduction in the rate of clinical events.ObjectivesThe present analysis addresses the questions on medical effectiveness and cost-effectiveness of the use of various coated stent types in CHD.MethodsThe literature was searched in December 2004 in the most relevant medical and economic databases. The medical evaluation was conducted on the basis of published RCT. The data from the studies regarding various angiographic, sonographic and clinical endpoints were checked for methodical quality and summarised in meta-analyses.Within the scope of economic evaluation the primary studies were analysed and modelling was performed, applying clinical effect estimates from the meta-analyses of the medical evaluation and current estimates of German costs.ResultsMedical evaluationTen different stenttypes were used in the included 26 RCT. The results for heparin, silicon-carbide, carbon and PTFE coated stenttypes could not reveal any significant differences between the medical effectiveness of coated and uncoated stents. The application of sirolimus, paclitaxel, everolimus and 7-hexanoyltaxol eluting stents showed a significant lower restenosis at 6-9 months with decrease in the rate of restenosis for polymer-based sirolimus, paclitaxel and 7-hexanoyltaxol eluting stents. In contrast, the use of gold-coated and actinomycin-D eluting stents was associated with a significantly higher restenosis. The polymer-based sirolimus and paclitaxel eluting stents also showed a significant and considerable reduction in the rate of repeated percutaneous revascularisations at 6-12 months (3.5% vs. 19.7%; p<0.0001, RR=0.19 [95%CI: 0.11; 0.33] and 3.5% vs. 12.2%; p<0.0001, RR=0.30 [95%CI: 0.20; 0.43]) and an equivalent reduction in the rate of combined events. The 7-hexanoyltaxol-eluting stents caused, however, a significant increase of stent thrombosis as well as of myocardial infarctions.Economic evaluationThe allocation to polymer-based sirolimus and paclitaxel eluting stents resulted in incremental costs (compared with uncoated stents) of approximately 1,421 € and 1,234 € per patient, taking in account expected revascularisations during the first year after implantation. The mean incremental cost-effectiveness-ratios per avoided revascularisation was 8,881 € and 13,711 €, respectively. The "break-even"-prices for these stenttypes in the used model were 707 € and 551 €, and the "break-even"-risks for ISR after stenting with uncoated stent, was 76% and 65%, respectively. The use of the other evaluated coated stents seems not to be cost-effective.DiscussionThe absolute effects and cost savings for patient groups with a higher risk of restenosis could be considerably higher than for patient groups with a lower risk of restenosis. The transferability of the results from the present analysis to other (sub)-populations and technology modifications is limited. The direct comparability of the results for sirolimus and paclitaxel eluting stents is also restricted.ConclusionsFrom a medical point of view the use of polymer-based sirolimus or paclitaxel eluting stents can be recommended. The use of gold coated, 7-hexanoyltaxol and actinomycin-D eluting stents is in contrast not recommendable.From an economical point of view and on the basis of current stent prices the polymer-based eluting sirolimus and paclitaxel stents should primarily be recommended for patients with a higher risk of restenosis.

Drug-Eluting Stents and the Future of Coronary Artery Bypass Surgery: Facts and Fiction