Intravascular brachytherapy versus drug-eluting stents for the treatment of patients with drug-eluting stent restenosis

Drug-eluting stents (DESs), although promising technology, still are associated with restenosis; therefore, we evaluated the safety and efficacy of intravascular radiation therapy for the treatment of DES in-stent restenosis (ISR). Treatment of DES ISR has not been established, although intravascular radiation therapy is an effective treatment for patients with ISR of bare metal stents. Other modalities are conventional percutaneous coronary intervention (PCI), including restenting with DES. Radiation for Eluting Stents in Coronary FailUrE (RESCUE) is an international, Internet-based registry of 61 patients who presented with ISR of a DES and were assigned to intravascular radiation therapy with commercially available systems after PCI. Outcomes of these patients were compared with those of a consecutive series of 50 patients who presented with ISR of a DES and were assigned to repeat DES (r-DES) treatment. Baseline clinical and angiographic characteristics were similar between groups, except for more Cypher stents as the initial DES that restenosed in the r-DES group than in the intravascular radiation therapy group (88.5% vs 69%, p = 0.01). At 8 months there were fewer overall major adverse cardiac events in the intravascular radiation therapy group compared with the r-DES group (9.8% vs 24%, p = 0.044). The need for target vessel and target lesion revascularizations was similar in the 2 groups at 8 months. There has been no report of subacute thrombosis in either group. In conclusion, intravascular radiation therapy as adjunct therapy to PCI for patients presenting with ISR of a DES is safe and should be considered an alternative therapeutic option for this difficult subset of patients.     

Management of drug-eluting stent restenosis

In-stent restenosis has been a longstanding problem after percutaneous coronary intervention. The introduction of the drug-eluting stent (DES) successfully reduced the rate of restenosis; however, it is not completely diminished. Although restenosis occurs less frequently compared to the bare-metal stent (BMS), DES restenosis remains a familiar problem due to the increasing total number of implanted DESs as well as the targeting of more complex lesions. In addition, worse outcomes after repeat revascularization compared to BMS restenosis are reported in DES restenosis. Management of DES restenosis is an emerging issue, which requires careful evaluation of the restenosed lesion, together with cautious determination of therapeutic strategy. In this review, available repeat revascularization procedures for DES restenosis as well as possible impacting factors on the outcomes are discussed.     

同种和不同种药物洗脱支架治疗冠状动脉药物洗脱支架内再狭窄有效性的系统评价

目的评价同种药物洗脱支架和不同种药物洗脱支架治疗冠状动脉药物洗脱支架内再狭窄的有效性。方法计算机检索Pub Med、OVID、Embase、Cochrane图书馆、万方数据库、中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库(CBM)、维普数据库(VIP),收集同种和不同种药物洗脱支架治疗冠状动脉药物洗脱支架内再狭窄的临床资料,共纳入10项研究,1680名患者,使用Rev Man5.2软件进行系统评价。检索时间为各大数据库建库至2015年10月。结果在治疗冠状动脉药物洗脱支架内再狭窄时,采用不同药物洗脱支架可降低靶病变血运重建率(OR=0.73,95%CI为0.55~0.96,P=0.02)和主要不良心血管事件发生率(OR=0.72,95%CI为0.54~0.96,P=0.03)。两组间的病死率(OR=1.03,95%CI为0.49~2.16,P=0.95)和心肌梗死发生率(OR=0.59,95%CI为0.24~1.41,P=0.23)无统计学差异。结论对于药物洗脱支架内再狭窄患者,再次植入不同药物洗脱支架比植入同种支架更获益。     

Coronary restenosis after implantation of drug-eluting stents

Randomized trials comparing drug-eluting stents (DES) with bare-metal stents have shown that the former significantly reduce the incidence of angiographic and clinical restenosis into an unprecedented low, one-digit, range. However, post-DES restenosis is not zero. Next to incomplete coverage with DES of the vessel segment injured by balloon angioplasty, factors such as stent underexpansion, stent overexpansion, and nonuniform distribution of stent struts have been associated with post-DES restenosis. Current evidence suggests that inadequate, though predominantly focal, delivery of the antiproliferative agent (sirolimus or paclitaxel) into the vessel wall is likely the common cause of post-DES restenosis. There is no consensus at present on how to treat post-DES restenosis. Long-term results reported to date on small numbers of patients undergoing interventional treatment for post-DES restenosis appear to be worse than outcomes observed after the index intervention, regardless of whether another DES was implanted or not, and warrant further study.     

In-stent restenosis in the drug-eluting stent era

The introduction of the drug-eluting stent (DES) proved to be an important step forward in reducing rates of restenosis and target lesion revascularization after percutaneous coronary intervention. However, the rapid implementation of DES in standard practice and expansion of the indications for percutaneous coronary intervention to high-risk patients and complex lesions also introduced a new problem: DES in-stent restenosis (ISR), which occurs in 3% to 20% of patients, depending on patient and lesion characteristics and DES type. The clinical presentation of DES ISR is usually recurrent angina, but some patients present with acute coronary syndrome. Mechanisms of DES ISR can be biological, mechanical, and technical, and its pattern is predominantly focal. Intravascular imaging can assist in defining the mechanism and selecting treatment modalities. Based upon the current available evidence, an algorithm for the treatment approaches to DES restenosis is proposed.     

How to approach drug-eluting stent restenosis

Drug-eluting stents (DES) have been a major advance in percutaneous coronary intervention reducing restenosis and repeat revascularization. The application of DES to the treatment of complex lesion and patient subsets has resulted in significant rates of DES restenosis or failure. Though predominantly focal, substantial rates of non-focal DES restenosis are being observed. Non-focal disease most likely represents a resistant process that will remain a therapeutic challenge. An understanding of the causative mechanical and biological factors is essential for the prevention and treatment of DES restenosis. Robust data relating to the treatment efficacy for this problem is lacking. At present, repeat DES or vascular brachytherapy appear to the best available options. Evidence from randomized controlled trials and large registries is required to establish a formal treatment approach. We provide guidelines based on current available evidence.     

药物洗脱支架置人术后断裂导致支架内再狭窄的临床分析

目的 探讨药物洗脱支架(DES)置入术后支架断裂与再狭窄的关系及支架断裂的特点.方法 回顾性分析冠状动脉支架置人术后行冠状动脉造影复查的536例患者,实验分为DES组(N=397)和裸金属支架(BMS)组(n=139).分析支架置入术前、术后及复查时的冠状动脉造影图像,找出支架内再狭窄和支架断裂的病例,分析支架断裂和再狭窄的关系以及支架断裂的病变特征及形态特征.结果 DES组和BMS组再狭窄分别为31例和30例(P＜0.01),其中5例发生支架断裂,断裂的支架均为DES,BMS组未见支架断裂,两组差异有统计学意义(P＜0.05).发生支架断裂的5例靶病变均为扭曲病变,支架断裂均发生在血管扭曲成角处.结论 支架断裂是DES置入术后发生再狭窄的原因之一,扭曲病变置入长的DES后可能容易发生支架断裂.     

Update on drug-eluting stents for prevention of restenosis

Despite the success of coronary stent implantations in the last decade, in-stent restenosis due to neointimal hyperplasia remains a problem to overcome. Neointimal hyperplasia is a vascular response to stent injury and mainly consists of proliferation of smooth muscle cells and deposition of extracellular matrix. Recently, local drug delivery has been advocated as a potential strategy to prevent in-stent restenosis. Unprecedented results have been obtained in early clinical studies on sirolimus-eluting and paclitaxel-eluting stents. Trials using various pharmaceutical coatings on different coronary stents are ongoing. More types of drug-eluting stents are expected on the market in the near future. Meanwhile, the evaluation of drug-eluting stents is entering the second phase in which the safety and efficacy in more complex lesion subsets and different clinical presentations are being investigated. Results including cost-benefit analyses are expected to have a tremendous impact on the practice of interventional cardiology in the next decade.     

关于药物洗脱支架再狭窄研究的进展

支架内再狭窄是介入治疗技术中面临的重要医学难题,药物洗脱支架明显降低支架内再狭窄率,然而在抑制血管平滑肌细胞过度增殖的同时,也抑制了支架处内皮功能和生长,其内皮化延迟可导致晚期再狭窄及延迟血栓的形成。本文就药物洗脱支架再狭窄现状、影响因素、发生机制和各种治疗方法的研究进展做一综述。     

Variable histological and ultrasonic characteristics of restenosis after drug-eluting stents

Bare-metal stents have undergone intense pathological and clinical examination, but histological characterization of drug-eluting stent (DES) restenosis (ISR) remains unknown. We report a series of cases (n = 6) with intravascular ultrasound (IVUS) and pathological examinations over 8 months after DES deployment. Tissue samples were obtained using atherectomy devices in 5 cases and a thrombectomy catheter in 1 case. Histology revealed not only smooth muscle cell proliferation, which correlated with homogeneous hypoechoic tissue by IVUS in one case, but also demonstrated delayed healing features such as organized fibrin deposition in 3 cases (one with homogeneous echolucent tissue by IVUS), macrophage and T-lymphocyte infiltration in others. IVUS appearance of ISR components varied from echolucent to echodense images. This report suggests a variable histological and IVUS pattern of ISR after DES implantation. Further investigations are necessary to define the potentially pro-thrombotic histological features of ISR after DES implantation, and the relationship between the molecular mechanisms of thrombosis and DES restenosis.     

Vascular brachytherapy for patients with drug-eluting stent restenosis

Background: The rate of drug‐eluting stent (DES) in‐stent restenosis (ISR) exceeds 10% in complex subsets of patients and lesions. The optimal management of DES ISR remains undetermined. Vascular brachytherapy (VBT) is proven to be effective for the treatment of bare metal stent ISR but its outcome for DES ISR has not been established. Methods: Ninety‐nine consecutive patients who presented with ISR following DES implantation in 122 lesions were subjected to conventional percutaneous coronary intervention with adjunct VBT using either beta radiation (Beta Rail in 74 patients [82.2%] and the Galileo system in 13 patients [14.4%]) or gamma radiation (Checkmate system in 3 patients [3.3%]). Patients were followed clinically for major adverse cardiac events (MACE) during 1‐year follow‐up. Results: A high proportion of patients in this cohort presented with complex ISR; 31.1% had recurrences of ISR to the same site, 55% had diffuse or proliferate pattern of restenosis, and 23 lesions (18.9%) were located in a saphenous vein graft. Procedural success and uneventful in‐hospital course were documented in all patients post VBT. At 12 months' follow‐up, the target lesion revascularization (TLR) rate was 11% and the overall MACE rate was 26%. Patients with multiple episodes of ISR to the same site had a TLR of 16% and MACE rate of 35.5%. Conclusions: VBT for the treatment of DES ISR was found to be effective and safe and should be considered for the treatment of DES ISR, in particular in complex patients with multiple recurrences.     

Biological aspects of radiation and drug-eluting stents for the prevention of restenosis

Based on recent advances, this article aims to review the biological basis for the use of either radiation or drug-eluting stents for the prevention of restenosis, and to elucidate the complementary role that they may play in the future. Vascular restenosis is a multifactorial process primarily driven by the remodeling of the arterial wall, as well as by the hyperproliferation of smooth muscle cells (SMC). These pathophysiological features are the target of therapeutic strategies aimed at inhibiting constrictive remodeling as well as inhibiting SMC proliferation. The success of radiation as well as anti-proliferative drugs such as paclitaxel and sirolimus lies in the primary and/or multifactorial inhibition of cell proliferation. Radiation has the additional feature of preventing constrictive remodeling while sirolimus has the potential property of being anti-inflammatory, which may be a desirable feature. The effects of radiation are not reliant on any uptake and "metabolism" by the target cells, as in the case with drugs, and thus radiation potentially may be more effective as a result of its more-direct action. However, radiation does have some significant drawbacks compared to drug-eluting stents, including a much delayed re-endothelialization resulting in the need for prolonged anti-platelet therapy. Based on recent clinical data, drug-eluting stents have been shown to markedly reduce the likelihood of restenosis, which actually favors this approach for the prevention of restenosis. From a biological perspective, drug-eluting stents and radiation have certain differences, which are reviewed in this article.     

药物洗脱球囊与第二代药物洗脱支架治疗药物支架内再狭窄的观察性研究

目的:对中国汉族人群中药物洗脱球囊(DEB)和第二代药物洗脱支架(DES)内再狭窄(ISR)的疗效进行非劣效性比较。方法:连续入选2014年9月至2015年8月,因DES-ISR而接受DEB或第二代DES治疗的患者,根据所接受的治疗策略将患者分别纳入DEB组和第二代DES组。记录两组患者住院期间主要不良心血管事件(MACE)发生率,并于术后12个月通过电话或门诊进行临床随访。结果:共纳入DES-ISR患者183例,包括DEB组74例,DES组109例;根据Mehran分型,非点状病变患者147例。住院期间两组患者均未发生MACE;(12.4±2.9)个月临床随访发现,DEB组共发生MACE 8例,包括心源性死亡1例、非致死性心肌梗死(MI)2例和靶血管血运重建(TVR)6例;第二代DES组MACE 3例,均为TVR。DEB组的MACE发生率高于第二代DES组(11.0%vs.2.8%,P=0.03),并且DEB组的无事件生存率劣于第二代DES组(89.0%vs.97.2%,P非劣效=0.94),而在非点状病变患者中,DEB组患者的无事件生存率仍劣于第二代DES组患者(87.9%vs.96.6%,P非劣效=0.92)。结论:药物洗脱球囊在中国汉族人群中治疗药物洗脱支架内再狭窄的疗效劣于第二代药物洗脱支架,且在非点状病变患者中仍劣于第二代药物洗脱支架。