药物涂层支架的前景及展望

目的:根据近年冠状动脉支架治疗冠状动脉硬化性心脏病的近况,认识药物涂层支架在心肌梗死治疗的最新研究与应用情况。资料来源:应用计算机检索PubMed2000-01/2006-04相关药物涂层支架的文献,检索词“drug-elutingstents,coronaryheartdisease”,并限定文献语言种类为英语。资料选择:对资料进行初审,选取包括药物涂层支架的相关文献,开始查找全文。纳入标准:药物支架治疗冠状动脉硬化性心脏病。排除标准:重复研究,综述文献,Meta分析类文章。资料提炼:纳入30篇符合标准的文献进行探讨。资料综合:药物涂层支架是将药物直接或者通过适当的载体涂布于支架表面,使支架成为一个局部药物释放系统,既可以增加治疗药物的局部浓度及作用时间,又可以避免全身用药带来的毒副作用。目前常用的支架为雷帕霉素涂层支架,紫杉醇支架,Driver支架等。它们都很好的减少了再狭窄,以至目前介入治疗的90%～95%都包括了支架植入术。结论:药物涂层支架是介入心脏病学的一项重要突破,使介入心脏病学进入了一个新的时代。     

Long-term safety of drug-eluting stents

Stent implantation in coronary stenosis has revolutionized the treatment of coronary artery disease. The introduction of antirestenotic drug coatings further improved their efficacy in reducing target vessel revascularizations. With increasing use of drug-eluting stents (DES), stent thrombosis (ST) rose as potentially fatal major complication. Initially, the incidence of ST late after stent implantation seemed to be similar for DES and bare metal stents until several studies proved otherwise in first-generation DES. Since then, the design and components of DES have been changed and new polymers, drugs and different combinations of platelet inhibitors have been introduced to further improve the safety of DES. In this review, the authors focus on the relationship between DES, lesion anatomy, implantation technique and pharmacology to avoid the occurrence of ST. Furthermore, the relationship between dual antiplatelet therapy, bleeding rate and its significant impact on patient outcome is discussed. Finally, some promising future concepts are highlighted.     

Update on drug-eluting stents.

Coronary artery disease is the number 1 killer of Americans. There are many efforts underway to prevent and treat this life-threatening disease. One such treatment is the placement of drug-eluting stents. However, recent reports that show an increased risk of potentially life-threatening complications associated with drug-eluting stents have surfaced. This article provides a brief overview of research performed concerning the risks of drug-eluting stents.     

Off-label use of stents: bare-metal versus drug-eluting stents

Drug-eluting stents (DES) became the default strategy for percutaneous revascularization due to their improved intermediate-term outcomes when compared with bare-metal stents (BMS) in the pivotal randomized, controlled trials. The excellent results of DES in on-label or US FDA-approved indications led to extrapolation of the results to more complex situations that were excluded from initial pivotal trials; such as off-label indications. Safety concerns began to grow after reports of increased late thrombosis and possibly associated increased death and myocardial infarction with DES, especially in the off-label situations. Recently, however, several important published registries have calmed some of those uncertainties and reassured the cardiology community of the safety and efficacy of DES compared with BMS. There is an overall poorer outcome with off-label use of any stent (BMS or DES) compared with standard or on-label use. This difference in outcome is most likely related to patient or specific coronary lesion characteristics or comorbidities that predispose an individual to adverse outcomes regardless of the stent type used. It is accepted now that DES use does result in a small increased risk of late thrombosis, but that risk is offset by a significant reduction in restenosis. Overall, the current data suggest that the use of DES in most lesion subsets is at least as safe as and clearly more efficacious than use of BMS in similar situations.     

Update on drug-eluting coronary stents

The introduction of drug-eluting stents (DES) to interventional cardiology practice has resulted in a significant improvement in the long-term efficacy of percutaneous coronary interventions. DES successfully combine mechanical benefits of bare-metal stents and stabilizing the lumen, with direct delivery and the controlled elution of a pharmacologic agent to the injured vessel wall to suppress further neointimal proliferation. The dramatic reduction in restenosis has resulted in the implementation of DES in clinical practice, and has rapidly expanded the whole spectrum of successfully treatable coronary conditions, particularly in high-risk patients and complex lesions. In this review the authors present current data on DES. Currently, two types of DES are available in the USA: sirolimus-eluting stents (SES) CYPHER? (Cordis Corp., FL, USA) and paclitaxel-eluting stents (PES) TAXUS?(Boston Scientific, MA, USA), and many more are on the way to approval. In addition to sirolimus and paclitaxel, several other drugs have been successfully used in DES. Everolimus and ABT-578 are both analogs of sirolimus that also have immunosuppressive and antiproliferative properties. Another approach in the development of DES is to use drugs that can accelerate re-endothelialization and restore normal endothelial function following vascular injury. Recent advances in vascular gene transfer have also demonstrated potential new treatment modalities for cardiovascular disease, particularly in the treatment of vascular restenosis.     

Off-label use of stents: bare-metal versus drug-eluting stents

Drug-eluting stents (DES) became the default strategy for percutaneous revascularization due to their improved intermediate-term outcomes when compared with bare-metal stents (BMS) in the pivotal randomized, controlled trials. The excellent results of DES in on-label or US FDA-approved indications led to extrapolation of the results to more complex situations that were excluded from initial pivotal trials; such as off-label indications. Safety concerns began to grow after reports of increased late thrombosis and possibly associated increased death and myocardial infarction with DES, especially in the off-label situations. Recently, however, several important published registries have calmed some of those uncertainties and reassured the cardiology community of the safety and efficacy of DES compared with BMS. There is an overall poorer outcome with off-label use of any stent (BMS or DES) compared with standard or on-label use. This difference in outcome is most likely related to patient or specific coronary lesion characteristics or comorbidities that predispose an individual to adverse outcomes regardless of the stent type used. It is accepted now that DES use does result in a small increased risk of late thrombosis, but that risk is offset by a significant reduction in restenosis. Overall, the current data suggest that the use of DES in most lesion subsets is at least as safe as and clearly more efficacious than use of BMS in similar situations.     

Update on drug-eluting coronary stents

The introduction of drug-eluting stents (DES) to interventional cardiology practice has resulted in a significant improvement in the long-term efficacy of percutaneous coronary interventions. DES successfully combine mechanical benefits of bare-metal stents and stabilizing the lumen, with direct delivery and the controlled elution of a pharmacologic agent to the injured vessel wall to suppress further neointimal proliferation. The dramatic reduction in restenosis has resulted in the implementation of DES in clinical practice, and has rapidly expanded the whole spectrum of successfully treatable coronary conditions, particularly in high-risk patients and complex lesions. In this review the authors present current data on DES. Currently, two types of DES are available in the USA: sirolimus-eluting stents (SES) CYPHER (Cordis Corp., FL, USA) and paclitaxel-eluting stents (PES) TAXUS (Boston Scientific, MA, USA), and many more are on the way to approval. In addition to sirolimus and paclitaxel, several other drugs have been successfully used in DES. Everolimus and ABT-578 are both analogs of sirolimus that also have immunosuppressive and antiproliferative properties. Another approach in the development of DES is to use drugs that can accelerate re-endothelialization and restore normal endothelial function following vascular injury. Recent advances in vascular gene transfer have also demonstrated potential new treatment modalities for cardiovascular disease, particularly in the treatment of vascular restenosis.     

药物洗脱支架的应用现状和展望

学术背景:最新研究发现,内皮修复延迟可导致支架内血栓形成,目前一种既具有良好的抗再狭窄功效同时又具有血栓不易形成安全性的药物支架是人们研究的目标.目的:综述药物洗脱支架新近的研究进展,以及最新的临床应用试验,同时展望其未来的发展趋势和方向.检索策略:由该论文的研究人员应用计算机检索PUBMED2002-01/2007-04期间相关文献,检索词为“drug eluting stents,percutaneous coronary intervention,coronary disease“,并限定文章语言种类为English.同时检索2005-01/2007-06因特网最新的相关国际会议报道.共检索到15篇文献,对资料进行初审,纳入标准:①有关药物支架的最新报道.②药物支架的最新研制进展.③药物支架的最新临床应用进展.排除标准:相关性低及重复性文章.文献评价:共收集到264篇药物洗脱支架研究和应用的文献,纳入42篇,同时纳入5篇相关性和时效性较强的会议报道.资料综合:理想的药物洗脱支架由支架平台,药物载体及药物三者协调构成.随着支架材料学和新型药物的开发,更加有效的支架应用于临床治疗中.最近,大量临床研究数据鼓励临床工作者将其应用于更多的挑战性冠脉病例,如慢性完全闭塞病变,多支血管病变等.然而,部分临床研究的结果使药物支架引起的晚期血栓而造成的支架安全性问题更加受到关注和重视.因此在药物支架的开发和应用中力求做到安全性和有效性的平衡.在新型的药物支架中,可降解支架,促进内皮愈合涂层支架更具发展前景.结论:药物洗脱支架是心脏介入治疗中的重大进展,它给冠心病的治疗带来了很多益处尤其是减少了再狭窄和再次血运重建,但随着对其远期疗效和安全性的重视,药物支架的研制将朝向高效低危发展.     

Understanding and minimizing late thrombosis of drug-eluting stents

Although the safety profiles of drug-eluting stents are similar to those of bare metal stents in the short term, concern has arisen about their potential for late thrombosis (occurring > 30 days after implantation). Stent thrombosis is rare but potentially devastating and can result in ST-segment elevation myocardial infarction or death. The aim of this article is to review the incidence, predictors, pathology, and prevention of late thrombosis of drug-eluting stents.     

生物可吸收涂层和永久涂层药物支架治疗冠状动脉粥样硬化性心脏病的Meta分析

背景:生物可吸收涂层药物支架和永久涂层药物支架均广泛应用于冠状动脉粥样硬化性心脏病介入治疗中,由于支架架构、支架药物、药物载体上的差异,多个研究对两种支架疗效和安全性的比较结果不完全一致.目的:比较生物可吸收涂层药物支架和永久涂层药物支架在冠状动脉粥样硬化性心脏病介入治疗的临床结果,评价两类支架在疗效和安全性上的差异.方法:检索Medline(1966-01/2010-07)、Embase(1980-01/2010-07)、Cochrane library(2010-07)、中国生物医学文献数据库(CBM,1990-01/2010-07)及相关参考文献,收集比较生物可吸收涂层药物支架与永久涂层药物支架的对照研究,采用Cochrane的随机方法学评价文献质量,应用RevMan5.0软件进行Meta分析.结果与结论:纳入10个对照研究,共纳入4391例患者,其中生物可吸收涂层药物支架组2429例,永久涂层药物支架组1962例.Meta分析结果显示,生物可吸收涂层物支架用于冠状动脉粥样硬化性心脏病患者,支架置入后6～12个月内心脏主要不良事件、靶血管血运重建、心脏性死亡、再发心肌梗死、支架内血栓形成和支架内再狭窄与永久涂层药物支架组差异无显著性意义.但生物可吸收涂层药物支架内晚期管腔丢失明显小于永久涂层药物支架组(P＜0.05).提示生物可吸收涂层物支架用于治疗冠状动脉粥硬化性心脏病安全、有效,并不劣于永久涂层药物支架,且可能在减轻冠状动脉支架置入治疗后内膜过度增生方面更具优势.     

药物缓释涂层支架的材料学特点及其生物相容性

目的:阐述药物涂层支架的材料学特点,分析其生物相容性.方法:检索PubMed数据库和中国期刊全文数据库有关药物缓释涂层支架材料学特点及生物相容性的文献,以"心血管,药物缓释,雷帕霉素,紫杉醇,冠状动脉,生物相容性,支架材料"为检索词,对资料进行初审,并查看文献后的引文文献.排除重复研究或Meta分析类文章.结果:①心血管支架中药物涂层支架材料的改进更新均以改善生物相容性和生物力学性能为目标.②心血管支架的生物相容性是一个复杂的连锁过程,血液相容性和组织相容性是评定生物相容性的两项基本内容.③利用有限元分析心血管支架材料的力学特性可为未来支架的优化设计提供有益的帮助.结论:药物涂层支架的研究涉及药物学、生物学、材料学多学科交叉,研究药物缓释载体的控释机制,寻找血液相容性更好的药物缓释载体,加强缓释载体与机体的结合强度是当前支架药物缓释载体研究所要解决的问题.     

可降解与不可降解药物涂层支架及裸金属支架置入治疗急性心肌梗死

背景：大量随机对照临床试验显示药物涂层支架较金属裸支架的支架再狭窄率低,但药物涂层支架并不降低主要心血管事件和死亡发生率,而且长期随访的临床注册研究显示其可能会增加支架晚期血栓事件。目的：评价可降解、不可降解药物涂层支架及裸金属支架置入治疗心肌梗死后患者心血管狭窄的发生率及不良反应。方法：回顾性分析236例急性心肌梗死患者的临床资料,其中79例采用生物可降解雷帕霉素洗脱支架置入治疗,83例采用不可降解雷帕霉素洗脱支架置入治疗,74例采用金属裸支架置入治疗。对比3组支架置入12个月内晚期管腔丢失和支架再狭窄,以及24个月时的主要不良心脏反应。结果与结论：置入12个月时,裸支架组支架内晚期管腔丢失多于可降解和不可降降解雷帕霉素洗脱支架组（P 〈0.05）,3组间支架再狭窄率比较差异无显著性意义（P 〉0.05）。置入24个月时,3组死亡、心因性死亡、再发心肌梗死、靶血管血运重建、靶病变血运重建、主要不良心脏事件发生率及支架内血栓形成事件比较差异无显著性意义。3种支架在直接经皮冠状动脉介入治疗急性ST段抬高型心肌梗死中的长期疗效和安全性有待进一步随访。     

Assessment of drug-eluting stents and bioresorbable stents by grayscale IVUS and IVUS-based imaging modalities

Grayscale IVUS and IVUS-based imaging modalities during the last years have become useful in the assessment not only of drug eluting stent, but also of new bioresorbable vascular scaffolds. Although IVUS resolution is not sufficient for determining stent coverage (optical coherence tomography is the gold standard), serial IVUS can measure intimal hyperplasia, assess acute and late incomplete stent apposition, detect the presence and persistence of edge dissections, study edge effects and look for causes of restenosis and thrombosis. In addition other IVUS-based imaging modalities, such as IVUS-VH, iMAP or palpography, can be used to study the serial compositional and mechanical changes of the plaque behind stent struts and also to follow the bioresorption of the new bioresorbable scaffolds, analyzing the backscattering signal coming from the polymeric struts. This review details and evaluates grayscale IVUS and IVUS-based techniques findings in clinical trials, highlighting the usefulness of these imaging modalities in the study of drug eluting stents and bioresorbable vascular scaffold.     

Release profiles in drug-eluting stents: Issues and uncertainties

This review presents the current data on drug release from drug-eluting stents and the effects of the release profiles on animal and human data for coronary stenosis. Data for the two most important drugs, sirolimus (rapamycin) and paclitaxel, are presented, the polymers used are described and the observed release profiles are discussed for various polymer carriers. The current literature on the tissue compatibility of the polymers commonly used in drug-eluting stents is also discussed.

The range of release rates from stents studied to date is limited for sirolimus, but somewhat broader for paclitaxel. Animal and human data comparing the different release profiles are limited to about 6 months for animals and 2–4 years for humans. From the data available, it appears that for both sirolimus and paclitaxel, a slow-releasing drug-eluting stent leads to slightly more favorable angiographic outcomes than more rapid release.

Most of the complications arising from the use of drug-eluting stents are attributed to incomplete healing; one possible clinical consequence of this delay in healing is that anti-platelet therapy needs to be maintained over a much longer period than is the case for bare metal stents.     

Benefits of and safety concerns associated with drug-eluting coronary stents

Drug-eluting coronary stents are being used with increasing frequency in patients undergoing percutaneous coronary intervention. Although these stents have shown remarkably low rates of restenosis compared with their predecessors, there have been increasing concerns lately regarding their safety. Extensive data have been published that demonstrate a higher risk of very late stent thrombosis with drug-eluting stents; however, this has not had any impact on long-term mortality or the risk of myocardial infarction when compared with bare-metal stents. Their overall net clinical benefit therefore still favors their use. Recent research has led to a greater understanding of the multifactorial cause of stent thrombosis, which has enabled measures to be taken to reduce an individual patient’s risk. In the future, new stent designs and new antiplatelet agents may help to reduce this risk further.     

Development of biodegradable zein-based bilayer coatings for drug-eluting stents

Drug-eluting stents (DES) have been widely used for the treatment of cardiovascular diseases. Nevertheless, chronic inflammation and delayed re-endothelialization still represent challenges for their clinical use. In the present work, we developed novel bilayer coatings for stent applications that could overcome these limitations, exclusively using biodegradable plant-based drugs and polymers. In particular, stainless steel surfaces were coated with rutin-loaded zein (the active layer) and cross-linked alginate (the sacrificial layer) via facile dip and spray coating methods. Various mechanical tests and analysis tools, such as infrared spectroscopy, water contact angle measurements, and scanning electron microscopy were used to characterize the coated surfaces. Degradation and release studies of the films were extensively carried out and compared. The release rate of rutin from the bilayer coating reached 66.1 ± 3.2% within 24 hours of incubation (initial burst period), while the rest of the drug was released over 21 days in a sustained manner. Antioxidant assays confirmed that rutin retained its free radical scavenging ability after being eluted in phosphate buffer at 37 °C. In vitro results with human fibroblasts and endothelial cells suggested that the coating materials and their degradation products are highly biocompatible. In conclusion, our novel drug-eluting coatings, fabricated with natural biodegradable polymers, are promising materials for DES applications, allowing a sustained drug delivery and improving the biocompatibility of cardiovascular implanted devices.

Zein-based biodegradable bilayer coatings were successfully prepared and characterized. Release profiles, antioxidant potential, and biocompatibility were investigated, aiming for more sustainable coatings for drug-eluting stents.     

Early experiences and clinical implications of drug-eluting stents: part 1

OBJECTIVE: To review the pathogenesis of in-stent restenosis and the evolution of drug-eluting stents (DES). DATA SOURCES: Using the search terms sirolimus, paclitaxel, and drug-eluting stents, a literature review was conducted to identify peer-reviewed articles and abstracts in MEDLINE (1966-June 2003). Recent meeting abstracts were accessed through the American Heart Association and the American College of Cardiology Web sites. Citations from available articles were also reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Published reviews and studies showing the effects of in-stent restenosis and drug-coated and -eluting stents were evaluated and reviewed. DATA SYNTHESIS: Coronary stent implantation is a common form of percutaneous coronary interventions. Approximately 20-30% of patients undergoing stent placement develop restenosis 6 months after the procedure. The primary cause of in-stent restenosis is neointimal proliferation and subsequent accumulation of extracellular matrix, collagen, and macrophages. Eluting stents with an antimitotic agent may reduce the extent of restenosis. Research is ongoing in terms of finding the ideal combination of antimitotic agent, stent, and eluting medium to create the perfect stent. CONCLUSIONS: Research over the last decade has led to a better understanding of the pathogenesis of in-stent restenosis and ways to prevent restenosis. DES are being developed as one of the strategies to prevent restenosis.     

Clinical benefits of drug-eluting stents: results from RAVEL and beyond

Drug-eluting stents have revolutionized interventional cardiology by incorporating drug and device therapy to reduce rates of restenosis. Early trials have addressed the safety and efficacy of drug-eluting stents. Recent studies have evaluated the use of drug-eluting stents in high-risk populations that were not initially randomized in the early trials. These stents have shown promising outcomes in diabetes, in-stent restenosis, and multivessel disease. The clinical benefits of these stents have been systematically quantified across multiple trials; however, there is a growing debate regarding restenosis and late-stent thrombosis after implantation. Given the expanding indications for drug-eluting stents, the American Heart Association identified it as one of the Top 10 Research Advances for 2005. The purpose of this article is to summarize the current debate surrounding late-stent thrombosis, examine the evidence from leading stent trials, and outline the clinical benefits of drug-eluting stents.