In-stent neoatherosclerosis: a final common pathway of late stent failure

Percutaneous coronary intervention with stenting is the most widely performed procedure for the treatment of symptomatic coronary disease, and drug-eluting stents (DES) have minimized the limitations of bare-metal stents (BMS). Nevertheless, there remain serious concerns about late complications such as in-stent restenosis and late stent thrombosis. Although in-stent restenosis of BMS was considered as a stable condition with an early peak of intimal hyperplasia, followed by a regression period beyond 1 year, recent studies have reported that one-third of patients with in-stent restenosis of BMS presented with acute coronary syndrome that is not regarded as clinically benign. Furthermore, both clinical and histologic studies of DES have demonstrated evidence of continuous neointimal growth during long-term follow-up, which is designated as "late catch-up" phenomenon. Here, we present emerging evidence of de novo neoatherosclerosis based on histology, angioscopy, and intravascular images that provide a new insight for the mechanism of late stent failure. In-stent neoatherosclerosis is an important substrate for late stent failure for both BMS and DES, especially in the extended phase. In light of the rapid progression in DES, early detection of neoatherosclerosis may be beneficial to improving long-term outcome of patients with DES implants.     

Focal in-stent restenosis and in-stent thrombosis within the same bare-metal stent 5 years after deployment in a saphenous vein graft

Complications of percutaneous coronary intervention include in-stent restenosis (ISR) and in-stent thrombosis (IST) which have different underlying pathophysiological processes and different treatment strategies. ISR is primarily due to excessive neointimal growth and occurs in 20-30% of bare-metal stents (BMS). Drug-eluting stents (DES) have decreased the rates of ISR (< 10%), but are potentially associated with increased IST related to delayed arterial healing and stent strut exposure. ISR of BMS typically occurs within 6 months of stent deployment. IST usually occurs within 12 months of DES deployment. We present a case of focal ISR and IST within the same BMS, confirmed with intravascular ultrasound, 5 years after deployment in a saphenous vein graft.     

The union of anti-CD34 antibody can improve the performance of drug-eluting stents

Objectives : The authors investigate whether the combination of anti‐CD34 antibody with DES is win–win cooperation. Background : DES may reduce the risk of restenosis compared to bare‐metal stents (BMS), but they were found to inhibit the healing process of intima. Methods : Fifteen BMS, 17 DES, and 16 combined anti‐CD34 antibody and DES were randomly implanted in the coronary arteries of 22 minipigs. Ten minipigs were followed up to 2 weeks. The stenting coronary segments were examined by histological examination and scanning electron microscopy after in vivo coronary angiography and intracoronary optical coherence tomography (OCT) examinations. The other 12 minipigs were followed up to 3 months. Coronary angiography and intracoronary OCT examination were performed in vivo and histological examination was performed on the stenting coronary segments. Results : After 2 weeks, the neointimal covering level of the DES was lower than that in BMS, but the covering level of the combined stents was even better than the BMS. After 3 months, neointimal hyperplasia was significant in the BMS, but not in the other two types of stents. The in‐stent late lumen loss of the combined stents even showed a decreasing tendency when compared with the DES. Conclusion : The combination of anti‐CD34 antibody and DES can not only well offset the short‐term inhibitory effect on re‐endothelialization but also slightly enhance the long‐term antiproliferative effect. © 2011 Wiley Periodicals, Inc.     

New developments in drug-eluting stents

Although the use of balloon catheters or stents for the treatment of coronary artery lesions shows good short-term results, long-term prognosis due to the occurrence of restenosis in 20%-30% of patients is less promising. Thus new techniques and mechanical improvements to balloons and stents are always necessary in order to achieve the best possible results from percutaneous coronary intervention. Drug-eluting stents (DES) have improved the principles of bare metal stents (BMS) by neointimal growth inhibition due to local drug release. DES can significantly reduce the incidence of in-stent restenosis. These benefits and lower costs compared to surgical treatment make the DES a more attractive alternative for the treatment of coronary heart disease. Currently, the CYPHER Sirolimus-eluting stent (SES) by Cordis (approved by the FDA on 24th April 2003), the TAXUS Express and the LIBERTE Paclitaxel-eluting stent (PES) by Boston Scientific (approved by the FDA on 4th March 2004 and October 10, 2008), the Endeavor Zotarolimus-eluting stent (ZES) by Medtronic (approved by the FDA on 1st February 2008) and the Xience V Everolimus-eluting stent (EES) by Abbott Vascular (approved by the FDA on 2nd July 2008) are approved in the US. Following approval of the Cypher and Taxus stents, the clinical data indicated a slightly higher incidence of stent thrombosis (ST) as compared to the pure BMS after implantation. The present article discusses the main clinical trials and design developments in DES currently available and takes a prospective look at future technologies in the field of DES.     

Neue Entwicklungen bei medikamentenfreisetzenden Stents

Although the use of balloon catheters or stents for the treatment of coronary artery lesions shows good short-term results, long-term prognosis due to the occurrence of restenosis in 20%?C30% of patients is less promising. Thus new techniques and mechanical improvements to balloons and stents are always necessary in order to achieve the best possible results from percutaneous coronary intervention. Drug-eluting stents (DES) have improved the principles of bare metal stents (BMS) by neointimal growth inhibition due to local drug release. DES can significantly reduce the incidence of in-stent restenosis. These benefits and lower costs compared to surgical treatment make the DES a more attractive alternative for the treatment of coronary heart disease. Currently, the CYPHER Sirolimus-eluting stent (SES) by Cordis (approved by the FDA on 24th April 2003), the TAXUS Express and the LIBERTE Paclitaxel-eluting stent (PES) by Boston Scientific (approved by the FDA on 4th March 2004 and October 10, 2008), the Endeavor Zotarolimus-eluting stent (ZES) by Medtronic (approved by the FDA on 1st February 2008) and the Xience V Everolimus-eluting stent (EES) by Abbott Vascular (approved by the FDA on 2nd July 2008) are approved in the US. Following approval of the Cypher and Taxus stents, the clinical data indicated a slightly higher incidence of stent thrombosis (ST) as compared to the pure BMS after implantation. The present article discusses the main clinical trials and design developments in DES currently available and takes a prospective look at future technologies in the field of DES.     

Effectiveness of statin-eluting stent on early inflammatory response and neointimal thickness in a porcine coronary model.

BACKGROUND: Drug-eluting stent (DES) implantation is routine during coronary revascularization because DES significantly reduce rates of restenosis and target lesion revascularization compared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosis because of delayed healing with poorer endothelialization and persistent local inflammation. Statins can inhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverse effects on endothelial function, and to inhibit neointimal hyperplasia in a porcine coronary model. METHODS AND RESULTS: Pigs were randomized into groups in which the coronary arteries (9 pigs, 18 coronaries in each group) had either a cerivastatin-eluting stent (CES) or a BMS. All animals survived without any adverse effects. Inflammatory cell infiltration evaluated using scanning electron microscopy on day 3 after stenting was significantly decreased in the treated vessels (inflammation score: 1.15+/-0.12 vs 2.43+/-0.34, p<0.0001). At day 28, endothelial function with intracoronary infusion of bradykinin was preserved in both the CES and BMS groups. Volumetric intravascular ultrasound images revealed decreased intimal volume in the CES group (28.3+/-5.4 vs 75.9+/-4.2 mm3, p<0.0001). Histomorphometric analysis showed reduced neointimal area (1.74+/-0.45 vs 3.83+/-0.51 mm2, p<0.0001) in the CES group despite similar injury scores (1.77+/-0.30 vs 1.77+/-0.22, p=0.97). CONCLUSION: In porcine coronary arteries CES significantly decreased neointimal hyperplasia with a decreased early inflammatory response and without endothelial dysfunction.     

光学相干断层成像评价不同类型药物洗脱支架置入术后的内膜覆盖

目的 应用光学相干断层成像(OCT)对比不同类型药物洗脱支架(DES)置入后的内膜覆盖情况.方法 入选62例在我院置入DES(15.3±5.7)个月后行OCT检查的患者,依据置入支架类型分为Cypher支架组(病例数=26,支架数=57)、Endeavor支架组(病例数=17,支架数=23)和Firebird支架组(病...     

Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings.

OBJECTIVES: The goal of this study was to use angioscopy to investigate the amount of neointimal coverage after sirolimus-eluting stent (SES) implantation. BACKGROUND: Sirolimus-eluting stents reduce intimal hyperplasia. METHODS: We used angioscopy to evaluate 37 consecutive stented coronary artery lesions (15 SES and 22 bare-metal stents [BMS]) in 25 patients (18 men, 7 women) at 3 to 6 months after stent implantation. Angioscopic evaluation focused on: 1) neointimal coverage of stent struts, and 2) the existence of thrombi. The degree of neointimal coverage was classified as grade 0 when there was no neointimal coverage (similar to immediately after the implantation); grade 1 when stent struts bulged into the lumen, but were covered and still translucently visible; grade 2 when stent struts were visible but not clearly seen (not translucent); and grade 3 when stent struts were not visible because they were embedded in the neointima. RESULTS: Thrombi were identified in eight stented segments, tended to be more common with SES (p = 0.14), but were not seen on angiography. Three of the 15 SES (20%) had grade 0 neointimal coverage, and only 2 SES (13.3%) had complete coverage (grades 2/3). In contrast, all 22 BMS showed complete intimal coverage (grades 2/3). Thrombi were more common in stents with incomplete neointimal coverage (p = 0.09). CONCLUSIONS: The SES had incomplete neointimal coverage three to six months after implantation, and this was associated with subclinical thrombus formation.     

Acute myocardial infarction late following stent implantation: Incidence, mechanisms and clinical presentation

Acute myocardial infarction (AMI) can occur late following stent implantation with an incidence up to > 6% at 3-4 years, with no difference between DES and BMS. AMI can originate either from the stented site or from disease progression at nonstented sites. Restenosis, against previous thoughts, can lead to AMI. Stent thrombosis occurs with similar overall frequency following DES and BMS implantations, although a higher very late stent thrombosis with DES has been observed. Dissimilar mechanisms between BMS and DES thrombosis are very likely, with impaired neointimal healing being the rule for DES but the exemption for BMS. The use of invasive imaging techniques is useful in elucidating the involved mechanism. Disease progression is a particularly important cause of AMI late post stenting. The angiographic study depicted stent failure and disease progression equally implicated in the AMI late post stenting. When the AMI underlying mechanism is stent thrombosis, it usually occurs earlier and more frequently presented as STEMI compared to the other causes of AMI. The AMI caused by restenosis is more often presented as nonSTEMI, while disease progression leads to AMI later than the other causes. Further research should address equally not only the stent related inadequacies but also disease progression as causes of the future AMI. Angiographic follow-up and intracoronary imaging seem the most appropriate methods to define the exact pathophysiologic mechanism responsible for the AMI post stenting.     

Drug-eluting stent-supported percutaneous coronary intervention for chronic total coronary occlusion.

OBJECTIVES: This study sought to determine the clinical and angiographic outcomes after drug-eluting stent (DES)-supported percutaneous coronary intervention (PCI) for chronic total coronary occlusion (CTO). BACKGROUND: There are few data about the efficacy of DES-supported PCI for CTO. METHODS: All consecutive patients who had a sirolimus-eluting stent or a paclitaxel-eluting stent implanted for CTO from December 2003 to December 2004 were analyzed. Clinical and angiographic outcomes of patients treated with DES were compared with a case-matched control group of patients treated with bare metal stents (BMS) in the 12 months before the routine use of DES. RESULTS: Successful DES-supported PCI was performed in 92 patients and 104 CTO. The case-matched control group consisted of 26 patients and 27 CTO successfully treated with BMS. There were no differences between groups in baseline clinical and angiographic characteristics. Stent length in the DES group was higher as compared with that of BMS group (51+/-28 mm vs. 40+/-19 mm, P=0.073). The 6-month major adverse cardiac event (MACE) rate was lower in the DES group as compared with that of BMS group (9.8% vs. 23%, P=0.072). The angiographic follow-rate was 80% in the DES group and 81% in the BMS group. The 6-month restenosis rate was 19% in the DES group and 45% in the BMS group (P<0.001). By multivariate analysis, it was found that in the DES group, the only predictors of restenosis were stented segment length (OR 1.031, 95% CI 1.01-1.06, P=0.009) and a target vessel reference diameter<2.5 mm (OR 6.48, 95% CI 1.51-27.83, P=0.012), while the only predictor of MACE was stent length (OR 1.04, 95% CI 1.01-1.08, P=0.006). CONCLUSIONS: DES implantation for CTO decreases the risk of mid-term restenosis and MACE. Small vessels and diffuse disease requiring the implantation of multiple stents and very long stents for full coverage of the target lesion are still associated with a relatively high risk of restenosis.     

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.     

Difference in neointimal coverage at chronic stage between bare metal stent and sirolimus-eluting stent evaluated at stent-strut level by optical coherence tomography

Compared with the bare metal stent (BMS), suppression of neointimal growth in the sirolimus-eluting stent (SES) reduced restenosis at the cost of more exposed struts that could impose the risk of stent thrombosis. The present study was conducted to analyze neointimal coverage patterns of stents at a strut-level after implantation of BMS or SES with the use of optical coherence tomography (OCT). We enrolled 35 patients and analyzed neointimal coverage of every strut from 41 stents (BMS: n = 8, SES: n = 33) by using OCT at follow-up of the stent implantation. All of the 371 struts from eight BMSs were covered with ≥100 μm of neointima, while 19.8 and 3.5 % of 3,478 struts from 33 SESs were uncovered (neointimal thickness of <10 μm) and malapposed, respectively. The histogram of neointimal thickness showed basically normal distribution in BMS but skewed in SES. No regional difference in neointimal thickness was observed in BMS (proximal, 535.7 ± 25.2 μm; body, 532.4 ± 17.0 μm; distal, 485.8 ± 27.0 μm). In SES, however, the body segment showed thinner neointima [median 40 μm (interquartile range (IQR) 10–90 μm)] than proximal [60 μm (IQR 10–140 μm), p < 0.001] or distal [50 μm (IQR 10–110 μm), p < 0.001] segment, while uncovered and malapposed struts were more frequent in the proximal and body segments. In conclusion, SES, compared with BMS, showed more suppressed neointimal growth with regional variation: neointimal thickness was the least in the body part while the ratio of exposed and malapposed struts was minimal in the distal segment. OCT was useful for a strut-level analysis of neointimal coverage over the whole stent.     

Economic analysis of the use of drug-eluting stents from the perspective of Belgian health care

OBJECTIVE: Recent evidence shows that drug-eluting stent devices (DES) substantially reduce the risk of in-stent restenosis compared with classic bare metal stent devices (BMS). In Belgium, however, the use of BMS is still standard procedure due to the higher prices of the newer DES. Although the use of DES is more expensive in the short term it might be beneficial in the long term due to the avoidance of revascularization costs.The primary objective of this study is to compare the net cost of DES and BMS from the perspective of Belgian health care. METHODS AND RESULTS: Cost differences between DES and BMS are determined by the difference in stent price and the difference in the rate of re-intervention. The cost of revascularization of patients with in-stent restenosis was estimated based on data gathered at the Antwerp University hospital (UZA). Data on effectiveness were obtained from a literature meta-analysis. Because of some important study limitations, a sensitivity analysis was included in this study. In general, the use of DES was cost saving as compared with BMS, with savings amounting to E 165 for Cypher stent devices and Euro 128 for Taxus stent devices in the base case scenario. For patients with a high risk of restenosis net savings persist in almost all sensitivity analyses. CONCLUSION: The use of DES in patients with a high in-stent restenosis risk is cost saving. Price evolutions in the stent device market predict that the use of DES, if not yet cost saving, will become cost saving in the near future for all types of patients. Recent evidence, however, casts some doubt on the long-term effectiveness of DES.     

Strut fracture of DES: An increasing problem?

Drug-eluting stents (DES) have greatly reduced the possibility of in-stent restenosis by inhibiting neointimal growth. But recently stent fracture has emerged as a complication. Stent fracture may cause restenosis, even occlusion. Here we report a case of stent fracture after percutaneous coronary intervention with DES without restenosis.     

Recent advances in coronary angioscopy

Angioscopy enables macroscopic pathological diagnosis of cardiovascular diseases from the inside. This imaging modality has been intensively directed to characterizing vulnerable coronary plaques. Scoring of plaque color was developed, and based on prospective studies; dark yellow or glistening yellow plaques were proposed as vulnerable ones. Colorimetry apparatus was developed to assess the yellow color of the plaques quantitatively. The effects of lipid-lowering therapies on coronary plaques were confirmed by angioscopy. However, since observation is limited to surface color and morphology, pitfalls of this imaging technology became evident. Dye-staining angioscopy and near-infrared fluorescence angioscopy were developed for molecular imaging, and the latter method was successfully applied to patients. Color fluorescence angioscopy was also established for molecular and chemical basis characterization of vulnerable coronary plaques in both in vitro and in vivo. Drug-eluting stents (DES) reduce coronary restenosis significantly, however, late stent thrombosis (LST) occurs, which requires long-term antiplatelet therapy. Angioscopic grading of neointimal coverage of coronary stent struts was established, and it was revealed that neointimal formation is incomplete and prevalence of LST is higher in DES when compared to bare-metal stent. Many new stents were devised and they are now under experimental or clinical investigations to overcome the shortcomings of the stents that have been employed clinically. Endothelial cells are highly anti-thrombotic. Neoendothelial cell damage is considered to be caused by friction between the cells and stent struts due to the thin neointima between them that might act as a cushion. Therefore, development of a DES that causes an appropriate thickness (around 100 μm) of the neointima is a potential option with which to prevent neoendothelial cell damage and consequent LST while preventing restenosis.     

冠状动脉支架置入术后不同类型支架再狭窄形式分析

目的通过分析冠状动脉支架置入后造影复查的影像资料,寻找不同支架再狭窄的特点。方法入选行冠状动脉病变介入治疗后造影复查的846处病变,对再狭窄病变行再狭窄形式分析。结果裸支架和药物支架再狭窄中支架近端局限性再狭窄分别占5.69%和33.67%(P=0.000),而支架内弥漫性再狭窄分别占29.27%和9.18%(P=0.000),弥漫性狭窄累及支架两端的分别为20.33%和6.12%(P=0.003),闭塞性再狭窄发生率分别为9.76%和10.20%(P=0.912)。雷帕霉素及其衍生物释放支架和紫杉醇释放支架再狭窄支架边缘局限性再狭窄分别为47.06%和25.00%(P=0.037),支架内弥漫性狭窄分别为1.96%和16.67%(P=0.018)。结论药物支架改变了支架再狭窄模式,弥漫型转为局限型;闭塞性再狭窄时药物支架以支架近端闭塞为主,裸支架以支架内闭塞为主;紫杉醇药物释放支架弥漫性再狭窄发生率较雷帕霉素释放支架有所增加。     

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.     

Intravascular ultrasound-guided high-pressure balloon predilatation for optimal drug-eluting stent deployment in restenosis of a stent implanted 7 years earlier. Do we know the right technique for in-stent restenosis restenting?

Although off-label, drug-eluting stent (DES) implantation is a preferred intervention for in-bare metal stent restenosis (BMS ISR). Off-label DES implantation appears to be associated with a higher risk of stent thrombosis and lesion recurrence. Accordingly, routine BMS ISR restenting with DES is associated with more frequent subsequent thrombosis. Intravascular ultrasound (IVUS) studies point to stent underexpansion as the major mechanism of late DES failure. We report a case of a patient with BMS ISR in whom IVUS clarified initial BMS expansion; consequently, high-pressure predilatation with an angiographically oversized conventional balloon was applied prior to DES deployment; and finally, IVUS verified the stent expansion.     

Neointimal regression‐induced incomplete coverage of a bare‐metal stent in the left main trunk: Serial angiographic and angioscopic evidence obtained by 5‐year follow‐up

Very late stent thrombosis (VLST), a rare complication of stenting, has been reported to develop more frequently at later than 1 year after the deployment of the drug‐eluting stent (DES) compared with the bare‐metal stent (BMS). However, the causes for the difference in the incidence remain unknown. Serial angioscopy on 1,591 and 1,952 days after BMS deployment in a Japanese male patient with acute myocardial infarction revealed incomplete neointimal coverage (INC) without the development of cardiovascular event. Therefore, the potential development of VLST remains undeniable in BMS‐deployed patients who had INC. © 2009 Wiley‐Liss, Inc.     

Single-center randomized evaluation of paclitaxel-eluting versus conventional stent in acute myocardial infarction (SELECTION)

OBJECTIVES: To evaluate the superiority of the paclitaxel-eluting stent (PES) in reducing neointimal hyperplasia (NIH) over its corresponding bare metal stent (BMS) during primary percutaneous coronary intervention (PCI). BACKGROUND: Primary PCI with stent implantation is the repercussion strategy of choice for ST-elevation myocardial infarction (STEMI); nonetheless restenosis rate is still high. Drug-eluting stents have been proven to reduce restenosis rate in many settings, but their use during primary PCI is still controversial. METHODS: Consecutive patients with STEMI <12 hours were randomized to receive PES or BMS. The primary end-point was the percentage of the stent volume obstructed by neointimal proliferation (NIH) measured by intravascular ultrasound (IVUS) at a 7-month angiographic follow-up. Secondary end-points were binary restenosis rate and major adverse cardiac events (MACE, i.e., death, nonfatal myocardial infarction, and target lesion revascularization). RESULTS: Eighty patients with STEMI were randomized into the PES or BMS group. Patients were well matched for baseline characteristics and the index procedure was always successful. In-hospital and 1-month MACE were 2.5% per group. NIH at 7 months was 4.6% versus 20% (P< 0.01), late lumen loss 0.1 versus 1.01 mm (P = 0.01). MACE were 7.5% versus 42.5% (P = 0.001) with no difference in death and recurrent myocardial infarction rates. Late-acquired incomplete stent apposition (ISA) rate was 5.1% versus 2.7% (P = 0.65). One subacute stent thrombosis was reported in each group. CONCLUSIONS: PES was superior to its corresponding BMS in reducing NIH in the STEMI setting without any increase in early and long-term clinical adverse events.