Vascular Pathology of Drug-Eluting Stents

Polymer-based sirolimus- (Cypher) and paclitaxel-eluting stents (Taxus), so-called drug-eluting stents (DES), have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary revascularization (PCI). While these stents have reduced rates of restenosis and late lumen loss compared to bare-metal stents (BMS), late thrombosis, a life-threatening complication of this technology, has emerged as a major concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that the DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared to BMS. This so-called delayed healing is "identified as" the primary substrate of an underlying cause of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis include penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions. These represent additional barriers to healing and should be avoided if DES are to be used in order to minimize the late thrombotic risks of these devices. Since the time course of complete healing with DES is unknown, the optimal duration of antiplatelet treatment remains to be determined.     

Stent thrombosis of drug eluting stent: pathological perspective

Although, the first-generation drug eluting stents (DES) have significantly reduced rates of restenosis compared to bare metal stents (BMS), an increased risk of late stent thrombosis (LST) has emerged as a major concern. Pathologic studies of patients dying from late DES thrombosis demonstrates delayed arterial healing characterized by persistent fibrin deposition and poor endothelialization as the primary substrate. However, recent thorough investigations revealed additional mechanisms of stent thrombosis such as hypersensitivity reaction, excessive fibrin deposit with malapposition, or neoatherosclerosis, which are associated with device-specific components and the majority of very late stent thrombosis is likely associated with these abnormal vascular responses. Therefore, although the incidence of stent thrombosis following DES implantation is similar in each period, the underlying mechanisms of this complication may vary. In the current review, the mechanisms of stent thrombosis in the DES era will be discussed using the data from autopsy studies that have been published.     

Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk.

OBJECTIVES: This study examined human drug-eluting stents (DES) to determine the long-term effects of these stents on coronary arterial healing and identified mechanisms underlying late stent thrombosis (LST). BACKGROUND: Although DES reduce the need for repeat revascularization compared with bare-metal stents (BMS), data suggest the window of thrombotic risk for Cypher (Cordis Corp., Miami Lakes, Florida) and Taxus (Boston Scientific Corp., Natick, Massachusetts) DES extends far beyond that for BMS. METHODS: From a registry of 40 autopsies of DES (68 stents), 23 DES cases of >30 days duration were compared with 25 matched autopsies of BMS implantation. Late stent thrombosis was defined as an acute thrombus within a stent >30 days old. RESULTS: Of 23 patients with DES >30 days old, 14 had evidence of LST. Cypher and Taxus DES showed greater delayed healing characterized by persistent fibrin deposition (fibrin score 2.3 +/- 1.1 vs. 0.9 +/- 0.8, p = 0.0001) and poorer endothelialization (55.8 +/- 26.5%) compared with BMS (89.8 +/- 20.9, p = 0.0001). Moreover, DES with LST showed more delayed healing compared with patent DES. In 5 of 14 patients suffering LST, antiplatelet therapy had been withdrawn. Additional procedural and pathologic risk factors for LST were: 1) local hypersensitivity reaction; 2) ostial and/or bifurcation stenting; 3) malapposition/incomplete apposition; 4) restenosis; and 5) strut penetration into a necrotic core. CONCLUSIONS: The Cypher and Taxus DES result in delayed arterial healing when compared with BMS of similar implant duration. The cause of DES LST is multifactorial with delayed healing in combination with other clinical and procedural risk factors playing a role.     

Late DES thrombosis: A lot of smoke,very little fire?

Recent studies and editorials have stirred controversy and generated tremendous publicity in the lay press related to the safety of drug-eluting stents (DES) for the treatment of coronary artery disease. Questions have been raised regarding the risks of late, or very late stent thrombosis with DES. The purpose of this editorial and review of stent thrombosis is to illuminate some counterpoints to some of the attention surrounding the issues of late DES thrombosis. The risks of DES stent thrombosis versus BMS may have been overstated by flawed studies. Late stent thrombosis does occur with both BMS and DES, and may or may not be modestly higher with DES. The time course of very late "DES thrombosis," suggests that persistent plaque ruptures and disease progression in the target vessel may cause some, or many of these events. There is still much to be learned about the biology of DES. Although there is a small risk of late thrombosis with DES, there is little question that this technology provides benefit to the vast majority of patients compared with prior revascularization strategies, using balloon angioplasty, BMS, or bypass surgery. Substantial resources should be devoted to creating more biocompatible DES systems, and to minimizing the risks of both early and late stent thrombosis.     

血管内超声在冠状动脉药物洗脱支架晚期血栓研究中的应用

药物洗脱支架与金属裸支架相比,减少了再狭窄的发生率,但其长期安全性却引起了人们的注意。支架置入30 d以后出现的晚期支架内血栓问题成为目前介入心脏病学的研究热点。晚期支架内血栓发生率低,但一旦发生后果严重。有研究显示其发生的原因可能包括动脉的延迟愈合、动脉瘤形成及支架贴壁不良等。现就血管内超声在冠状动脉药物洗脱支架晚期血栓研究中的应用进展做一评述。     

Percutaneous coronary intervention for unprotected left main disease in very high risk patients: safety of drug-eluting stents

Percutaneous treatment of unprotected left main coronary artery (ULMCA) stenosis using drug-eluting stents (DES) has been suggested as the best approach for patients who are poor surgical candidates. Some concerns have recently been raised regarding the risk of stent thrombosis following DES implantation. This study was performed in order to evaluate the safety of DES, as compared to bare metal stents (BMS), for ULMCA stenosis treatment in very high risk patients with a high likelihood of stent thrombosis. Forty-two consecutive patients were treated with either BMS (20) or DES (22) for ULMCA critical stenosis. Inclusion criteria were: ST elevation myocardial infarction, non-ST elevation myocardial infarction, cardiogenic shock, or logistic European System for Cardiac Operative Risk Evaluation ≥ 13%. At 1 year, one case of late thrombosis and three cases of restenosis were reported in the BMS group and none in the DES group, leading to a significantly inferior rate of target lesion revascularization (20.0 vs. 0%, p = 0.048) and major adverse cardiac events (65.0 vs. 19%, p = 0.004). DES placement for ULMCA stenosis also appears to be a safe therapeutic choice in very high-risk patients, as it provides the benefit of a reduction in restenosis without increasing the risk of early or late stent thrombosis.     

Die Stentthrombose im Fokus von Drug-eluting Stents

Coronary stent thrombosis is frequently associated with death or myocardial infarction (MI). New definitions according to the Academic Research Consortium (ARC) were proposed to serve as standard criteria for stent thrombosis. According to these definitions, stent thrombosis was classified as acute (within 24 h post implantation), subacute (1-30 days), late (31 days to 1 year), and very late (later than 1 year). Furthermore, stent thrombosis was differentiated in definite with angiographic or autoptic verification, probable, and possible. In meta-analyses using the ARC criteria, the occurrence of subacute stent thrombosis did not differ between drug-eluting stents (DES; Cypher, Taxus) or bare-metal stents (BMS) with < 1%. Very late stent thrombosis occurred 0.4-0.6% more frequently with DES compared to BMS. Available follow-up periods are limited to 4 years. The occurrence of death and MI did not differ between DES and BMS within the total follow-up period. In the meta-analysis of the Taxus studies, the event rates (death and MI) were initially lower with DES compared to BMS based on the reduced need for target vessel revascularization. Nevertheless, this was compensated in the following period by a higher event rate due to very late stent thrombosis. In real-world registries, the event rates are higher than in the first randomized studies. With DES implantation as a routine strategy, the occurrence of angiographically documented stent thrombosis was 2.9% within a period of 3 years. Classic predictors for stent thrombosis with BMS remain relevant also in the DES era. The delayed endothelialization with DES in combination with suboptimally implanted DES takes the patients to a higher and longer risk for stent thrombosis. Several guidelines recommend dual antiplatelet therapy for 12 months after DES implantation in noncomplex lesions. In complex lesions combined antiplatelet treatment should be prescribed 24 months or longer (e.g., DES after brachytherapy). Patients scheduled for surgical procedures or patients with reduced compliance should not be treated with DES.     

Drug-Eluting Coronary Stent Very Late Thrombosis Revisited

Compared to bare-metal stents (BMS), drug-eluting stents (DES) provide a significant additional reduction in restenosis rates and the need for coronary reinterventions. However, compared to BMS, the risk of very late stent thrombosis (ST) appears to be marginally higher accounting for 0.2-0.6% annual incidence for up to 3 years and possibly even longer following implantation. Risk reduction strategies include meticulous implantation technique, identification of patients with increased thrombotic risk, exclusion of patients scheduled in short term for major elective surgeries, and extended dual antithrombotic treatment for a minimum of 12 months. Future risk avoidance strategies are briefly reviewed and commented.     

Recurrent coronary stent thromboses and myocardial infarctions

Although stent thrombosis is a recognized complication of coronary intervention, recurrent stent thrombosis is rarely reported. We present a patient who suffered 3 ST-segment elevation myocardial infarctions associated with repeated stent thromboses within a month and a half. Although a potentially mechanical cause of thrombosis was identified in the only baremetal stent implanted in this case, no predisposing factors were seen for the 2 drug-eluting stents (DES). While recent worrisome data have suggested a slight increase in the incidence of late angiographic stent thrombosis (defined as occurring beyond 30 days) with drug-eluting stents (DES), their risk of subacute thrombosis (from 1 to 30 days) is reported to be equivalent to that of BMS. Therefore, this rare occurrence serves as a sobering reminder of the risks of subacute thrombosis with both BMS and DES. Marked neointimal inhibition, allergic reactions, as well as thienopyridine resistance, may all contribute to the pathophysiology of DES thrombosis. The Food and Drug Administration advisory panel has concluded that when these devices are used for "on-label" indications, the counterbalance of dramatic target lesion revascularization reduction versus rare incidence of late angiographic stent thrombosis results in no overall increase in DES myocardial infarction or mortality risk. Furthermore, a minimum of 1 year of dual antiplatelet therapy is recommended for all recipients of DES at low risk of bleeding.     

Late and very late thrombosis of drug-eluting stents: evolving concepts and perspectives

Coronary stents are the mainstay of percutaneous coronary revascularization procedures and have significantly decreased the rates of acute vessel closure and restenosis. Stent thrombosis (ST) after percutaneous coronary intervention is an uncommon and potentially catastrophic event that might manifest as myocardial infarction and sudden death. Optimization of stent implantation and dual antiplatelet therapy have markedly reduced the occurrence of this complication. Bare-metal stent (BMS) thrombosis occurs in <1% of the cases, usually within the first month after implantation. The advent of drug-eluting stents (DES) has raised concerns regarding later occurrence of ST, beyond the traditional 1-month timeframe, especially in complex lesion subsets that were excluded from randomized trials that compared BMS to DES. There is widespread controversy regarding the actual incremental risk associated with DES. Recent studies suggest a 0.5% increased long-term thrombosis risk with DES; however, the clinical significance of these events remains under debate. The degree of protection achieved by dual antiplatelet therapy and optimal duration of treatment are under investigation. Novel stent designs might potentially decrease the incidence of this event. In this review, we will describe the current knowledge of the pathophysiology of late DES thrombosis, although many aspects remain incompletely understood.     

Late and very late thrombosis of drug-eluting stents: evolving concepts and perspectives.

Coronary stents are the mainstay of percutaneous coronary revascularization procedures and have significantly decreased the rates of acute vessel closure and restenosis. Stent thrombosis (ST) after percutaneous coronary intervention is an uncommon and potentially catastrophic event that might manifest as myocardial infarction and sudden death. Optimization of stent implantation and dual antiplatelet therapy have markedly reduced the occurrence of this complication. Bare-metal stent (BMS) thrombosis occurs in <1% of the cases, usually within the first month after implantation. The advent of drug-eluting stents (DES) has raised concerns regarding later occurrence of ST, beyond the traditional 1-month timeframe, especially in complex lesion subsets that were excluded from randomized trials that compared BMS to DES. There is widespread controversy regarding the actual incremental risk associated with DES. Recent studies suggest a 0.5% increased long-term thrombosis risk with DES; however, the clinical significance of these events remains under debate. The degree of protection achieved by dual antiplatelet therapy and optimal duration of treatment are under investigation. Novel stent designs might potentially decrease the incidence of this event. In this review, we will describe the current knowledge of the pathophysiology of late DES thrombosis, although many aspects remain incompletely understood.     

Drug-eluting stents: What is the balance of risks and benefits?

Restenosis following bare metal stent (BMS) implantation has been the Achilles heel of percutaneous coronary intervention. When randomized trials showed dramatic reductions in restenosis and target-lesion revascularization in favor of drug-eluting stents (DES), they were widely embraced and soon used in 80% of percutaneous coronary interventions in the United States and some European centers. Consequently, the indications for stenting were pushed into uncharted territories. DES confirmed significant improvements in short-and mid-term outcomes as compared with BMS in real world registries. As the penetration of DES continued into patient and lesion subsets not formally tested in randomized trials, an entity characterized by sudden occlusion of the DES with an associated acute clinical syndrome was occasionally detected. The term late stent thrombosis was introduced to define this relatively new phenomenon, sometimes described with BMS as well. The absolute risk of stent thrombosis appears to be less than 2% throughout the first 3 years after stent implantation. DES thrombosis has provided a moment for pause to reconsider how to best use these new devices and what to expect from future ones.     

Stent thrombosis and drug-eluting stents

Coronary stents have been used for the treatment of patients with coronary artery disease (CAD), and significantly improved procedural safety and are associated with a lower rate of restenosis compared with balloon angioplasty alone. Drug-eluting stents (DES) have been dominant for the treatment of CAD with efficacy in significantly reducing both restenosis and target lesion revascularization. However, late and very late stent thrombosis have become a major concern in DES-implanted arteries compared with those treated with bare-metal stents (BMS). This review focuses on the feature of DES thrombosis and pathological examination and dual antiplatelet therapy for prevention of stent thrombosis.Currently, the incidence of stent thrombosis associated with first-generation and second-generation DES remains unclear in data from real-world cohort registry studies. Further studies of larger multicenter trials would give us insight into the specific mechanisms of stent thrombosis among different generations of DES.     

Second- and third-generation drug-eluting coronary stents: progress and safety

Drug-eluting stents (DES) have revolutionized the treatment of coronary artery disease by reducing the rate of in-stent restenosis from 20-40% with bare-metal stent (BMS) to 6-8% with DES. However, with widespread use of DES, safety concerns have risen due to the observation of late stent thrombosis. With this in mind and better understanding of mechanism and pathophysiology of stent thrombosis, the technological platform, especially innovative anti-restenotic agents, polymeric coatings, and stent platforms, improved with newer DES. Two second-generation DES, the Endeavor zotarolimus-eluting stent (ZES) and the Xience-V everolimus-eluting stent (EES), have provided promising results in both randomized controlled trials (SPIRIT and ENDEAVOR) and registries (E-Five, COMPARE) compared with bare-metal stents (BMS) and first-generation DES. Newer third-generation stent technology, especially biodegradable polymers, polymer-free stents, and biodegradable stents on the basis of poly-L-lactide (PLLA) or magnesium, has been evaluated in preclinical and initial clinical trials. However, despite encouraging initial results, long-term data of large-scale randomized trials as well as registries comparing them to currently approved first- and second-generation DES are still lacking.     

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.     

Stent thrombosis in the era of drug eluting stents

Despite a marked reduction in restenosis and the need for repeat revascularization procedures with the use of drug-eluting stents (DES), the risk for stent thrombosis remains of serious concern. Although the safety profiles of DES dose not seem to differ from those of bare metal stent (BMS) in the acute and subacute phases following coronary intervention, recent data suggest a potential increase of thrombotic events late after DES deployment. The main factors associated with late stent thrombosis remain elusive. Delayed re-endothelialization, hypersensitivity reaction, technical and mechanical factors and hypercoagulability have all been proposed as contributing factors. It is unlikely that any of these variables alone can cause stent thrombosis, as the incidence of each factor is much higher than the currently known rates of DES thrombosis. Further, temporal appearances of the thrombotic events represent a challenge to our understanding of re-endothelialization, as one would expect that endothelial coverage would be higher in the later phases after treatment. New expanded definitions of stent thrombosis, which also include events secondary to repeat revascularization, have been proposed to provide a better comparative endpoint between BMS and DES. Such clinical attempt to characterize stent thrombosis is valuable, but does not provide much insight into the pathophysiology and intrinsic thrombotic risk of each device. A true progress in this field will only be possible after we improve our understanding of the patho-physiology of very late stent thromboses, which may differ from events occurring earlier after treatment. The incidence of stent thrombosis remains rare, but its potential catastrophic consequences should remind clinicians and scientists to make every effort to develop strategies and technologies for its prevention. The topic of stent thrombosis in the era of DES will be reviewed in this article.     

OCT评估可降解聚合物DES术后血管修复研究进展

与裸金属支架相比,第1代药物洗脱支架（drug-eluting stent,DES）显著提高了治疗的有效性,但其永久聚合物涂层使得支架植入后内皮化延迟、血管修复受损,导致晚期支架内血栓的发生率明显升高。在此基础上新一代DES应运而生,可降解聚合物DES作为其典型代表,通过优化设计等明显改善了其植入后血管修复的进程。光学相干断层成像（OCT）作为目前分辨率最高的血管腔内影像学技术,可用于评估支架植入后内皮覆盖程度,判断血管修复情况,预测血栓性事件发生风险。本文将主要对OCT评估可降解聚合物DES植入术后血管修复及再内皮化做一综述。     

Second- and third-generation drug-eluting coronary stents

Drug-eluting stents (DES) have revolutionized the treatment of coronary artery disease by reducing the rate of in-stent restenosis from 20?C40% with bare-metal stent (BMS) to 6?C8% with DES. However, with widespread use of DES, safety concerns have risen due to the observation of late stent thrombosis. With this in mind and better understanding of mechanism and pathophysiology of stent thrombosis, the technological platform, especially innovative anti-restenotic agents, polymeric coatings, and stent platforms, improved with newer DES. Two second-generation DES, the Endeavor zotarolimus-eluting stent (ZES) and the Xience-V everolimus-eluting stent (EES), have provided promising results in both randomized controlled trials (SPIRIT and ENDEAVOR) and registries (E-Five, COMPARE) compared with bare-metal stents (BMS) and first-generation DES. Newer third-generation stent technology, especially biodegradable polymers, polymer-free stents, and biodegradable stents on the basis of poly-L-lactide (PLLA) or magnesium, has been evaluated in preclinical and initial clinical trials. However, despite encouraging initial results, long-term data of large-scale randomized trials as well as registries comparing them to currently approved first- and second-generation DES are still lacking.     

Antiplatelet therapy in the era of late stent thrombosis

Opinion statement Drug-eluting stents (DES) are the treatment of choice for obstructive coronary artery disease when percutaneous intervention is feasible. Although there are concerns regarding increased incidence of stent thrombosis, subsequent myocardial infarction, and death in patients receiving DES, careful analysis of large randomized trials has shown that risk of stent thrombosis with both bare metal stents (BMS) and DES is small. However, late stent thrombosis seems to occur more frequently with DES and seems to be closely associated with the discontinuation of dual antiplatelet therapy with aspirin and a thienopyridine derivative (usually clopidogrel). Before placing a DES in a patient, the interventional cardiologist must ensure that there are no conditions under which a patient or physician may have to discontinue dual antiplatelet therapy within a year after stent placement. If the cardiologist anticipates premature discontinuation of thienopyridine and aspirin therapy, his or her alternative is to place a BMS or recommend bypass surgery. If a situation arises in which dual antiplatelet therapy may have to be interrupted (eg, emergency or semi-elective surgery), it is strongly recommended that the treating physician consult a cardiologist and follow published guidelines.     

Evolving management of patients treated by drug-eluting stent: Prevention of late events

SummaryDrug eluting stents (DES) were introduced in clinical practice to overcome the problem of in-stent restenosis (ISR) that limited the overall efficacy of percutaneous coronary revascularization with bare metal stent (BMS). Long-term outcome data confirm a sustained benefit of DES as compared with BMS. However, this benefit is mainly evident in the first year of follow-up. Indeed, DES-related events may extend over this time, due to late events (late ISR and/or very late stent thrombosis). Prevention of late failure of DES may become a specific therapeutic target.