Biolimus-eluting stent with biodegradable polymer (Nobori®): an overview of recent clinical results,SORT OUT V and COMPARE II trials

Evaluation of: Christiansen E, Jensen L, Thayssen P et al. Biolimus eluting biodegradable polymer coated stent vs durable polymer coated sirolimus eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomized non inferiority trial. Lancet 381, 661–669 (2013); Smits P, Hofma S, Togni M et al. Abluminal biodegradable polymer biolimus-eluting stent vs durable polymer everolimus eluting stent (COMPARE II): a randomized, controlled, non inferiority trial. Lancet 381, 651–660 (2013).

Since their apparition, first generation drug-eluting stents (DESs) have raised concerns regarding the risk of late and very late stent thrombosis as compared to bare metal stents and require prolonged dual antiplatelet therapy. Aside from delayed strut endothelialisation, positive vessel remodelling and late stent mal-apposition due to chronic inflammation may be a leading cause for these stent thromboses. In fact, the persistence of the durable polymer after complete drug release is responsible for local hypersensitivity and inflammatory reactions. Third generation DESs with biocompatible or biodegradable polymer have subsequently been developed to address this issue. In this article, we evaluate and discuss the results of two recent publications investigating safety and efficacy of a third generation DES with biodegradable polymer as compared to first and second generation DESs with durable polymer.     

No country for old stents? Improving long-term patient outcomes with biodegradable polymer drug-eluting stents

Biodegradable polymer-coated drug-eluting stents (DESs) represent an attractive approach to improve vascular healing after coronary intervention. The proof-of-concept chain of investigation includes preclinical safety assessment, surrogate end point clinical efficacy studies and large-scale clinical outcome studies, in which noninferiority against benchmark devices is assessed at 12 months, with adjudication of hypothesized clinical advantage at long-term follow-up. The 4-year outcome data from large-scale trials such as the LEADERS study represents a final link in this process. Data from this trial show maintenance of noninferiority and an overall improvement in the composite of death, myocardial infarction and revascularization with biodegradable polymer DESs versus durable polymer sirolimus-eluting stents that is statistically significant and perhaps also clinically important (risk ratio: 0.81; 95% CI: 0.66-1.00; p-value for superiority = 0.05). Furthermore, although reductions in the incidence of stent thrombosis with biodegradable polymer stents at 4 years did not reach statistical significance, in keeping with the hypothesized mechanism of benefit, the observed risk differences seemed to be driven by a reduction in very late events beyond 1 year after intervention. These findings are backed up by those from a pooled analysis of the three largest biodegradable polymer DES randomized trials. With the availability of high-quality biodegradable polymer devices and the phasing out of earlier generation devices, the next 5 years will see increasing uptake of this therapy in routine practice. Whether improvements in outcomes with biodegradable polymer DESs can also be demonstrated against second-generation durable polymer stents is the subject of a number of ongoing clinical trials.     

药物洗脱支架治疗冠状动脉支架内再狭窄的长期疗效观察

目的：评价药物洗脱支架治疗支架内再狭窄的长期疗效。方法：经药物洗脱支架治疗的支架内狭窄患者63例,平均随访22个月,观察有无主要心脏不良事件发生。结果：63例患者中,主要心脏不良事件的发生率为46．5％,未发生支架内血栓形成及心肌梗死事件。药物洗脱支架治疗药物洗脱支架术后支架内再狭窄疗效优于金属裸支架术后支架内再狭窄。Logistic多因素分析显示,药物洗脱支架治疗支架内再狭窄的疗效与年龄、性别、病变严重程度、病变直径、原支架种类及药物支架涂层材料无显著相关。结论：药物洗脱支架治疗支架内再狭窄安全、有效。     

Coronary in-stent restenosis: predisposing clinical and stent-related factors,diagnostic performance and analyses of inaccuracies in 320-row computed tomography angiography

The aim of this study was to identify predisposing factors for coronary in-stent restenosis (ISR) and assess its detection by 320-row computed tomography angiography (CTA) using invasive coronary angiography (ICA) as a gold standard. A total of 189 patients (aged 35–79, mean age 56.6, 169 males) with 318 stents underwent ICA within 4 days after CTA. ISR was found in 19 (10.0?%) patients and 25 (7.9?%) stents. At the patient level, the presence of ISR was significantly related to the number of deployed stents (P?=?0.026) and body mass index (P?=?0.030). At the stent level, stents with diameter <3 mm were more likely to have ISR than those with diameter ≥3 mm (53.8?% vs. 28.9?%, P?=?0.016). Bare metal stents were significantly more likely to have ISR than drug-eluting stents (15.2?% vs. 6?%, P?=?0.022). ISR was not significantly related to stent length (P?=?0.097) and stent placement in coronary arteries at the vessel level (P?=?0.059). False-positive or false-negative results of CTA were not related to stent location, diameter, length, and strut thickness (P?>?0.05). At the patient level, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CTA for detecting ISR were 90, 96, 74, 99, and 96?%, respectively. At the stent level, the corresponding figures were 92, 96, 67, 99, and 96?%. The high negative predictive value of 99?% suggests that 320-row CTA is helpful for excluding ISR.     

320排容积CT检查对冠脉支架植入术后患者支架内再狭窄的评价

目的 探讨320排容积CT对冠脉内支架植入术后忠者支架内再狄窄的评估价值.方法 对81例冠心病经皮冠脉介入治疗术后患者的临床资料进行观察分析,以冠脉造影结果为金标准,计算320排容积CT对诊断支架内再狭窄的灵敏度、特异度、阳性预测值、阴性预测值.结果 320排容积CT对支架内再狭窄诊断的灵敏度、特异度、阳性预测值、阴性预测值分别为94.87%、98.1%、92.5%、98.73%.结论 320排容积CT对支架内再狭窄的诊断有较高的阳性预测值,可以用于冠状动脉支架植入术后对冠脉支架的随访.     

血清ECP水平与药物洗脱支架晚期支架内再狭窄的相关性

目的:探讨嗜酸性粒细胞阳离子蛋白(eosinophil cationic protein, ECP)与药物洗脱支架(drug eluting stent, DES)晚期支架内再狭窄(in-stent restenosis, ISR)的相关性。方法:选取2014年12月至2016年7月在复旦大学附属中山医院植入DES并超过1年后返院复查造影患者202例,根据复查造影结果分为ISR组(100例)和无ISR组(102例),应用夹心酶联免疫吸附(ELISA)法测定血清ECP水平并比较其在2组间差异。在ISR组和无ISR组,根据支架载药涂层,进一步分为永久涂层-DES组(DP-DES亚组)及可降解涂层-DES组(BP-DES亚组),分析血清ECP水平与载药涂层的关系。结果:ISR组血清ECP水平明显高于无ISR组(P=0.003)。手术年龄和ECP水平是晚期ISR形成的独立危险因素。ISR组DP-DES亚组血清ECP水平高于无ISR组DP-DES亚组(P=0.002)。结论:血清ECP水平在晚期ISR患者中显著升高,可能与支架药物涂层有关。     

Types and characteristic features of drug-eluting stents

Types and characteristics of current-available drug-eluting stents(DES) are introduced in this review. Currently, DESs with agents of "limus family" are mainly used because of their efficacy and safety. Two representative performances, angiographic late loss and incidence of late acquired incomplete stent apposition, are compared between these DESs. Furthermore, patient-to-patient variation in amount of neointimal hyperplasia, which is chiefly associated with clinical outcomes, tends to be larger for the DES with larger average angiographic late loss. Thrombotic complications are unexpectedly more frequent in the DES with larger late loss within first one year according to the randomized clinical trials, however, persistent influences to vascular wall become dominant factors stent thrombosis at very late phases.     

血管内超声分析重复支架术有或无联合冠脉内放疗对患者支架内再狭窄复发的作用

目的　系列血管内超声 (IVUS)分析重复支架术 (RS)有或无联合冠脉内的放射治疗 (IRT)对支架内再狭窄 (ISR)患者再狭窄复发的作用。方法　 99例 ISR的患者经 RS治疗后随机分为 1 92 Ir放疗组 (n=5 7)和对照组 (n=4 2 ) ,行系列冠脉造影和 IVUS检查 ,分别测量支架、管腔及增生内膜的面积和容积。结果　随访 6月 ,冠脉造影显示放疗组较对照组再狭窄复发率低。两组基线和随访的支架最小面积、平均面积和容积均无变化。两组在随访 6月支架最小腔内面积、平均腔内面积和管腔容积均减小 ,平均增生内膜面积和增生内膜容积均增加 ,但对照组比放疗组的变化更明显。结论　系列 IVUS证实 :IRT抑制新生的内膜形成 ,RS联合 IRT较 RS不联合 IRT更有效减少患者的 ISR复发     

Optical coherence tomography findings of very late stent thrombosis after drug-eluting stent implantation

Previous optical coherence tomography (OCT) studies in patients with drug-eluting stents (DESs)-related very late stent thrombosis (VLST) were scarce. Therefore, we investigated OCT findings of VLST after implantation of DESs. Using OCT, we analyzed the status of stent struts and neointimal characteristics in 18?patients who developed VLST after DES implantation. These results were compared to those in 57?patients with neointimal hyperplasia causing?>40% diameter stenosis. Lipid-laden neointima was defined as a region with marked signal attenuation and a diffuse border. Four (22.2%) of 18 patients with VLST had ruptured and lipid-laden neointima inside DESs without uncovered or malapposed stent struts. In the remaining 14 patients who developed VLST without neointimal rupture, uncovered and malapposed struts were observed in nine and seven patients, respectively, and lipid-laden neointima in four patients. Lipid-laden neointima was more frequently observed in four patients with neointimal rupture than in 14 patients without neointimal rupture (100% vs. 28.6%, respectively, P?=?0.023). Of 57 patients with neointimal hyperplasia, eight (14.0%) had lipid-laden neointima. Time to OCT study after DES implantation was significantly longer in the eight patients with lipid-laden neointima than in 49 patients without lipid-laden neointima (45.5?±?17.7?months vs. 11.7?±?7.2?months, respectively, P?<?0.001). Lipid-laden neointima was detected in some patients with neointimal hyperplasia?>?1?year after DES implantation. In addition to uncovered or malapposed struts, rupture of lipid-laden neointima inside DESs was identified in some patients with DES-related VLST.     

Comparison of in-stent neoatherosclerosis and tissue characteristics between early and late in-stent restenosis in second-generation drug-eluting stents: an optical coherence tomography study

Optical frequency domain imaging (OFDI) was utilized to compare the prevalence of neoatherosclerosis (NA) and morphological characteristics of the neointimal tissue in second generation drug eluting stent (G2-DES)-treated lesions between early (<1 year, E-ISR) and late (>1 year, L-ISR) in-stent restenotic phases. Data comparing NA and in vivo tissue characteristics between early and late in-stent restenosis (ISR) after implantation of G2-DES is limited. An OFDI analysis was performed in 50 G2-DESs {35 everolimus-eluting stent [22 cobalt-chromium (CoCr), 13 platinum-chromium (PtCr)], and 15 biolimus-eluting stent [BES]} ISR lesions (46 consecutive patients) undergoing target lesion revascularization, classified as E-ISR (n?=?22 lesion) and L-ISR (n?=?28 lesion). NA, defined as a neointima formation containing lipids or calcification was observed in fewer than half (24/50) of all ISR lesions with no significant difference between E-ISR and L-ISR lesions (50 vs. 46.4%, p?=?0.8). There were also no significant differences in the morphological appearance and tissue characteristics between E-ISR and L-ISR lesions. ISR was more likely to occur earlier [median 8.6 (8.3–8.9) months] after PtCr-EES implantations (12 lesions vs. 1, p < 0.001), while 3/4 of the BES ISR lesions and more than 2/3 of the CoCr-EES ISR lesions were observed after 1 year of implantation [median 21.3 (20.7–27.5) months, p < 0.001]. Acknowledging some limitations, our observations may suggest that the prevalence of neoatherosclerosis and the morphological appearance, and tissue characteristics of G2-DESs restenotic lesions are similar between the early and late restenotic phases. Certain platforms (PtCr-EESs) may have preferentially presented with early ISR.     

Predictive value of plasma plasminogen activator inhibitor-1 for coronary restenosis: dependence on stent implantation and antithrombotic medication.

BACKGROUND: The plasmin activation system is involved in the development of restenosis after percutaneous coronary interventions (PCI). Conflicting data exist concerning the role of plasminogen activator inhibitor-1 (PAI-1) and its predictive value for restenosis. OBJECTIVES: To evaluate the fibrinolytic response to injury after PCI with or without stent implantation on different antithrombotic medications and its relation to late restenosis. PATIENTS AND METHODS: Eighty consecutive patients with successful PCI without (balloon only; n = 37) or with stent implantation (stent; n = 43) on different antithrombotic regimes (balloon only, aspirin; stent, aspirin/coumadin/dipyridamole vs. aspirin/ticlopidine). Blood samples were taken at baseline and up to 7 days after PCI and PAI-1 active antigen and tissue plasminogen activator (t-PA) antigen were determined. Restenosis was angiographically determined after 6 months. RESULTS: PCI increased both t-PA and PAI-1 levels (P < 0.001), with a significant prolonged and pronounced increase in stent vs. balloon-only patients (P < 0.05). Restenosis (stent 26%; balloon 38%) was significantly correlated to an attenuated PAI-1 increase after 24 h in the ticlopidine group (P = 0.007; restenosis, relative Delta PAI-1 + 50 +/- 28%; non-restenosis, + 139 +/- 50%), but not in the coumadin group. In the balloon-only group late restenosis (ISR) was associated with a trend for an augmented PAI-1 increase after 24 h. CONCLUSIONS: Coronary stent implantation significantly increases t-PA and PAI-1 plasma levels up to 1 week compared with balloon angioplasty alone. ISR in ticlopidine-treated patients was associated with an attenuated early PAI-1 active antigen increase. A less than 50% increase 24 h after stent implantation under ticlopidine treatment may identify patients at risk for the development of ISR.     

Coronary Stent Assessment with 64-Slice Multislice Computed Tomography: A Literature Review

Coronary in-stent restenosis (ISR) and thrombosis cause recurrent cardiac ischemia, require repeat investigations, and have significant clinical and financial implications. As coronary stenting becomes widespread, the number of patients with recurrent ischemia is increasing. ISR and thrombosis occur in up to 10 and 0.8%, respectively, of patients with drug-eluting stents. A noninvasive investigation for symptomatic stented patients is required to identify stent thrombosis, ISR, and de novo lesions in native coronary arteries. The difficulties in using computed tomography to image high-density materials adjacent to moving calcified vessels have been reduced with advances in spatial and temporal resolution and reconstruction software. This review examines the advantages and disadvantages of 64-slice multislice computed tomography for coronary stent evaluation, explaining the diagnostic difficulties and outlining techniques to optimize diagnostic accuracy.     

心肌内双层多孔生物可降解性药物缓释支架的制备

目的：制备心肌内双层多孔生物可降解性药物缓释支架,评估其对透室壁性心肌血管重建术后心肌孔道的作用效果。方法：以聚己内酯为材料,以牛血清白蛋白为模型药物,以聚乳酸-聚乙醇酸共聚物为药物载体,制备成生物可降解性药物缓释支架。采用考马斯亮蓝试剂法对支架上牛血清白蛋白含量及体外释放量进行测定,万能材料测定仪测定支架的力学性能。制备猪慢性心肌局部缺血模型,体内评估该支架在透室壁性心肌血管重建术后对心肌孔道的作用效果。结果：该支架牛血清白蛋白携带量为每支架10mg,30d后牛血清白蛋白释放量达80%,支架压缩80%时承受的应力为1.2MPa,在透室壁性心肌血管重建后可保持心肌孔道通畅。结论：成功制备心肌内双层多孔生物可降解性药物缓释支架,能承受心肌压力并达到缓慢控制释放药物的效果,可维持透室壁性心肌血管重建后的心肌孔道通畅。     

新型可完全降解材料聚外消旋乳酸-三亚甲基碳酸酯聚合物体内降解行为和组织相容性

背景:目前应用于临床的金属裸支架、金属药物洗脱支架、合金支架等置入心血管后会导致局部血管内膜增生、血栓形成,增加心血管不良事件发生率。因此,应用高分子聚合物材料研发和制备完全生物可降解血管支架逐渐成为研究热点。目的:观察新型完全生物可降解材料聚外消旋乳酸-三亚甲基碳酸酯(PDLLA/TMC)(50/50)聚合物在机体内的降解行为和组织相容性。方法:以课题组前期合成并研究的聚合物PDLLA/TMC(50/50)为实验对象,聚左旋乳酸-三亚甲基碳酸酯(PLLA/TMC)(50/50)和聚乳酸(PLLA)为对照,分别将其薄膜片植入144只6月龄Wistar大鼠,在不同的时间点,采用体积排除色谱、凝胶渗透色谱、核磁共振、环境扫描电镜研究其体内降解行为,并通过光镜下镜检及周围炎性细胞计数量化评价其组织相容性。结果与结论:在植入机体前60d,3组材料的失重率并没有太大的区别,降解速率均相对平稳缓慢,PDLLA/TMC的降解速率略快于其他两组聚合物材料,60d后PDLLA/TMC的降解速率明显加快,其失重率显著高于另外两种聚合物材料,180d后PDLLA/TMC大部分被降解,其余两种聚合物降解很少。3种聚合物材料包埋于生物体内即开始出现相对分子质量下降,初期下降速率较快,而后逐渐趋缓。3种材料的表面结构随着降解时间的延长,由初期的较为光滑整齐变为后期的皱褶、扭曲、紊乱、凹陷和孔洞,且PDLLA/TMC材料表面变化较明显。PDLLA/TMC和PLLA/TMC与PLLA比较,各个时间点均有相对较低的炎症细胞计数,差异均有显著性意义(P<0.05);而PDLLA/TMC与PLLA/TMC比较,各个时间节点上的炎性细胞计数差异均无显著性意义(P>0.05)。证实PDLLA/TMC聚合物是一种新型的完全生物可降解材料,具有良好的降解性能和组织相容性。     

冠状动脉CTA斑块特征评价支架内再狭窄风险

目的 探讨冠状动脉CTA斑块特征评估植入支架后发生支架内再狭窄（ISR）的风险。方法 对166例患者于支架植入前行冠状动脉CTA检查,观察血管狭窄程度和斑块特征,并于植入支架后6~18个月内复查冠状动脉造影;根据有无ISR,将其分为ISR组（n=16）与无ISR组（n=150）,比较两组间的差异;采用多因素Logistic回归分析获得ISR的危险因素,以ROC曲线评价各因素诊断ISR的效能。结果 ISR组病变长度,非钙化斑块、点状钙化、正性重构比例和正性重构指数均大于无ISR组（P均<0.05）。多因素Logistic回归分析结果显示,非钙化斑块[回归系数（B）=1.89,优势比（OR）=6.63,P=0.01]、点状钙化（B=1.28,OR=3.59,P=0.01）、正性重构（B=2.17,OR=8.71,P<0.01）、病变长度（B=0.05,OR=1.05,P=0.04）是导致ISR的危险因素。病变长度及正性重构指数诊断ISR的ROC曲线下面积（AUC）分别为0.70和0.82（P均<0.01）,联合上述斑块特征预判ISR的AUC为0.87（P<0.01）。结论 病变长度、正性重构、非钙化斑块、点状钙化可用于评估冠状动脉支架植入后发生ISR的风险。     

生物可降解心血管支架与人体相容性的系统评价

背景：冠状动脉支架置入后的再狭窄等并发症越来越引起关注。目的：系统评价生物可降解心血管支架材料与人体相容性的研究。方法：计算机检索EMbase（1980/2011-08）、MEDLINE（1966/2011-08）和中国生物医学文献数据库（CBM,1978/2011-08）、中文学术期刊全文数据库（CNKI）,筛查相关文章的参考文献收集发表的生物可降解心血管支架生物相容性的动物实验和临床实验中文献,对可降解心血管支架材料生物相容性的总结。结果与结论：当血管内皮化完成之后,生物可降解支架如期降解,从而克服了支架本身作为异物的血栓源性,抑制早期血栓形成及晚期新生内膜增生,具有良好的生物相容性,有效降低了再狭窄的发生率。同时,生物可降解支架还可作为药物局部投放的载体,达到有效防止支架置入后血管急性闭塞和降低再狭窄发生率。     

Antiplatelet therapy in the era of drug-eluting stents: current and future perspectives

The use of drug-eluting stents (DESs) dramatically reduced in-stent restenosis. However, the increasing use of these stents has raised concern about their potential thrombogenicity. Indeed, the particularity of DES thrombosis compared with bare metal stent thrombosis is a high rate of late thrombosis. Antiplatelet therapy is efficient in preventing DES thrombosis. However, this therapy could be optimized and may be improved in the future. This article will review the mechanisms and the epidemiology of stent thrombosis. Then, we will summarize the antiplatelet therapeutic strategies used to prevent stent thrombosis and especially DES-associated thrombosis. Finally, we will present some data with regard to potential advantages and pitfalls in DES thrombosis prevention using novel antiplatelet agents currently under development, as well as future stent designs with improved healing properties.     

Utility of coronary orbital atherectomy with guide‐extension system for distally located undilatable in‐stent restenosis: A case report

Orbital atherectomy (OA) may be effective in managing undilatable in‐stent restenosis (ISR) despite off‐label indications. We demonstrated that optical frequency domain imaging (OFDI)‐guided OA, with a guide‐extension system was effective even in distally located, undilatable ISR. However, OFDI revealed that inter‐struts calcified neoatherosclerosis remained a challenging issue.     

Antiplatelet therapy in the era of drug-eluting stents: current and future perspectives

The use of drug-eluting stents (DESs) dramatically reduced in-stent restenosis. However, the increasing use of these stents has raised concern about their potential thrombogenicity. Indeed, the particularity of DES thrombosis compared with bare metal stent thrombosis is a high rate of late thrombosis. Antiplatelet therapy is efficient in preventing DES thrombosis. However, this therapy could be optimized and may be improved in the future. This article will review the mechanisms and the epidemiology of stent thrombosis. Then, we will summarize the antiplatelet therapeutic strategies used to prevent stent thrombosis and especially DES-associated thrombosis. Finally, we will present some data with regard to potential advantages and pitfalls in DES thrombosis prevention using novel antiplatelet agents currently under development, as well as future stent designs with improved healing properties.     

生物可降解心血管支架与人体相容性的系统评价

背景:冠状动脉支架置入后的再狭窄等并发症越来越引起关注.目的:系统评价生物可降解心血管支架材料与人体相容性的研究.方法:计算机检索 Embase(1980/2011-08)、MEDLINE(1966/2011-08)和中国生物医学文献数据库(CBM,1978/2011-08)、中文学术期刊全文数据库(CNKI),筛查相关文章的参考文献收集发表的生物可降解心血管支架生物相容性的动物实验和临床实验中文献,对可降解心血管支架材料生物相容性的总结.结果与结论:当血管内皮化完成之后,生物可降解支架如期降解,从而克服了支架本身作为异物的血栓源性,抑制早期血栓形成及晚期新生内膜增生,具有良好的生物相容性,有效降低了再狭窄的发生率.同时,生物可降解支架还可作为药物局部投放的载体,达到有效防止支架置入后血管急性闭塞和降低再狭窄发生率.