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.     

Choice of DES: A European Clinician's Perspective

The introduction of the first generation of drug-eluting stents (DES) in 2002 revolutionized interventional cardiology by minimizing restenosis. Reports of increased late stent thrombosis with these stents compared with bare metal stents, probably due to delayed endothelialization, emerged late in 2006. These studies contained serious methodological flaws, however. Subsequent meta-analyses clearly showed only a small incremental risk of late stent thrombosis across all patient groups. Importantly, a significant and sustained benefit of DES due to reduced restenosis and thus repeat revascularization was also shown. Several "real-world" registries have confirmed these results, as well as suggesting that use in more complex situations is not associated with adverse outcomes. Stent thrombosis is a multifactorial problem, in which the stent is only one element. Further research is required to determine optimal procedural technique and antiplatelet regimes.
Second-generation DES, with different antiproliferative drugs and more biocompatible polymers, have shown promising results in comparative studies with the first generation. Current follow-up data for these stents is only up to 3 years, however.
DES are safe and effective in the long term, though intensive research continues into ways to reduce the risk of stent thrombosis in the next generation.     

Drug eluting stents for ST-elevation myocardial infarction: risk and benefit

Drug-eluting stents have been a major advance in percutaneous coronary revascularization. Widespread use of these stents has been spurred by substantial reductions in restenosis rates when compared with bare metal stents. The use of drugeluting stents during ST-segment elevation myocardial infarction has been a common practice and is associated with lower revascularization rates in various studies. Unfortunately, significant concerns regarding the occurrence of late stent thrombosis with this technology persist. A clinical dilemma exists as to whether the benefits of reduced repeat revascularization with DES outweigh the harm caused by a possible increased occurrence of the infrequent but devastating complication of late stent thrombosis. This review with discuss the theoretical risks and benefits of DES for STEMI, the available data regarding their use, and the areas where future studies are needed.     

Coexistent in-stent restenosis, late incomplete stent apposition and mural thrombus in a zotarolimus-eluting stent

Drug-eluting stents (DES) have been demonstrated to dramatically reduce the rate of in-stent restenosis (ISR). However, some studies found an increased rate of late incomplete stent apposition (ISA) and late stent thrombosis (ST) in DES compared to traditional bare-metal stents (BMS). Endeavor stent, a new cobalt-alloy DES coated with phosphorylcholine and zotarolimus, has been reported to have a very favorable safety profile with few documented late-acquired ISA and late ST. In the present report, we described an interesting case with coexistent ISR, late ISA and mural thrombus in an Endeavor zotarolimus-eluting stent 8 months after primary percutaneous coronary intervention.     

Estrogen-Eluting Stents

Coronary stenting is routinely utilized to treat symptomatic obstructive coronary artery disease. However, the efficacy of bare metal coronary stents has been historically limited by restenosis, which is primarily due to excessive neointima formation. Drug-eluting stents (DES) are composed of a stainless steel backbone encompassed by a polymer in which a variety of drugs that inhibit smooth muscle cell proliferation and excessive neointima formation are incorporated. DES have significantly reduced the incidence of restenosis but are also associated with a small (~0.5% per year) but significant risk of late stent thrombosis. In that regard, estrogen-eluting stents have also undergone clinical evaluation in reducing restenosis with the additional potential benefit of enhancing reendothelialization of the stent surface to reduce stent thrombosis. Estrogen directly promotes vasodilatation, enhances endothelial healing, and prevents smooth muscle cell migration and proliferation. Due to these mechanisms, estrogen has been postulated to reduce neointimal hyperplasia without delaying endothelial healing. In animal studies, estrogen treatment was effective in decreasing neointimal hyperplasia after both balloon angioplasty and stenting regardless of the method of drug delivery. The first uncontrolled human study using estrogen-coated stents demonstrated acceptable efficacy in reducing late lumen loss. However, subsequent randomized clinical trials did not show superiority of estrogen-eluting stents over bare metal stents or DES. Further studies are required to determine optimal dose and method of estrogen delivery with coronary stenting and whether this approach will be a viable alternative to the current DES armamentarium.     

Late acute thrombosis after implantation of sirolimus‐eluting stent to treat in‐stent restenosis

Drug‐eluting stents (DES) have significantly reduced the incidence of in‐stent restenosis (ISR) compared to bare metal stents (BMS). However, recent randomized trials comparing DES with BMS reported few cases of late DES thrombosis. We report the case of late sirolimus‐eluting stent thrombosis occurring 22 months after its elective implantation in a restenotic BMS and soon after the interruption of combined anti‐platelet therapy with aspirin and Clopidogrel.     

Ex vivo and preclinical assessment of an endothelial progenitor cell capturing bioengineered stent

Although drug-eluting stents (DES) have significantly reduced the rates of restenosis as compared to bare metal stents, late stent thrombosis remains a major drawback, especially for "off-label" use. Delayed arterial healing, characterized by persistent fibrin deposition and poor endothelialization, has been shown to correlate with late DES thrombosis. To overcome these limitations, a "pro-healing" approach has been developed to capture circulating endothelial progenitor cells (EPC) to enhance endothelialization of the stent surface. EPC have the ability to migrate to sites of vascular injury and aid the regeneration of damaged and dysfunctional endothelium. Clinically, the safety of EPC-capture stent has been proven in numerous clinical trials with low incidence of late stent thrombosis. The focus of this review is to demonstrate the efficacy of the Genous stent in preclinical studies, specifically to show the effectiveness of the anti-CD34+ coating in promoting endothelialization and reducing thrombogenicity.     

Late acute thrombosis after implantation of sirolimus-eluting stent to treat in-stent restenosis

Drug-eluting stents (DES) have significantly reduced the incidence of in-stent restenosis (ISR) compared to bare metal stents (BMS). However, recent randomized trials comparing DES with BMS reported few cases of late DES thrombosis. We report the case of late sirolimus-eluting stent thrombosis occurring 22 months after its elective implantation in a restenotic BMS and soon after the interruption of combined anti-platelet therapy with aspirin and Clopidogrel.     

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.     

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.     

Drug-eluting stents: towards new endpoints

Drug-eluting stents (DES) have significantly reduced the rates of in-stent restenosis (ISR). As previously observed with bare-metal stents (BMS), either patient's clinical characteristics and lesion morphology may influence the risk of recurrence even with DES. In this review we will focus on the most recent available data on clinical settings where DES efficacy on long-term outcomes are largely unknown. In particular, we report on very complex lesions (bifurcations, small vessels, chronic total occlusions, in-stent restenosis) myocardial infarction, multivessel disease, treatment of bypass graft and of unprotected left main disease. Several issues are still open on DES routinary use for these indications, mainly as far as stent thrombosis is concerned. Recent pathological studies show that DES are characterized by chronic inflammatory infiltrates and delayed endothelialization. Therefore, this effect could translate in a 'vulnerable period' for thromboses longer than with BMS. Even though large meta-analysis have excluded higher rates of stent thrombosis with DES rather than with BMS, few cases of unusual very late stent thrombosis have been described, pointing out that this problem seems to be still unsolved. Although DES provide better angiographic outcomes in each clinical setting, further randomized studies are running to assess their safety and efficacy on currently off-label indications.     

Vascular responses to drug eluting stents: importance of delayed healing

Polymer-based sirolimus- (Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI). Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety 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 both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis. Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined.     

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.     

Passive and Active Polymer Coatings for Intracoronary Stents: Novel Devices to Promote Arterial Healing

Coronary stent implantation is the second great advance in the treatment of obstructive coronary artery disease since the introduction of balloon catheter angioplasty. However, in-stent restenosis (ISR) caused by neointimal hyperplasia has been a major limitation of stents, occurring in up to 30% of cases. Advances in coronary stent technology both in terms of stent design and function and especially drug-eluting stents (DES) have significantly improved the safety and efficacy of percutaneous coronary intervention (PCI) with stenting, including marked reduction in ISR. This has led to use of DES for increasingly challenging clinical and lesional subsets, with potential for increased risk of stent-associated complications, especially late stent thrombosis (LST). Because restenosis and stent thrombosis are caused by multiple and often interrelated factors, ideal agents for stent coatings should inhibit thrombus formation, inflammatory reaction, and cellular proliferation, while supporting reendothelialization. To avoid undesirable effects of currently applied (durable) polymers, biocompatible, and bioabsorbable polymers as well as DES delivery systems that minimize polymer burden have been produced and tested. Bioabsorbable stents, both polymeric and metallic, have been developed to decrease potential late complications after stent implantation. Novel strategies to address some of these challenges are in various stages of research and development. In this article we outline developments in the field of passive and active stent coatings and evaluate the ongoing role of such coatings in the contemporary era of DES.     

The risks and benefits of drug-eluting stents in the setting of STEMI

Primary percutaneous coronary intervention (PCI) represents the treatment of choice in patients with ST-segment elevation myocardial infarction (STEMI). In randomized trials excluding STEMI patients, using drug-eluting stents (DES) significantly reduced angiographic restenosis and target vessel revascularization compared with bare metal stents (BMS); however, concerns exist regarding an increased follow-up incidence of stent thrombosis after DES implantation. This complication, which is associated with higher mortality and morbidity rates, may be more frequent among STEMI patients receiving DES versus BMS. Various registries, randomized trials, and two recent meta-analyses on patients undergoing primary PCI have shown that using DES is safe and is associated with significantly reduced rates of restenosis and repeat intervention without an increased risk of myocardial infarction or stent thrombosis at intermediate-term follow-up. However, large trials with hard clinical end points and longer follow-up are needed before routine DES use can be recommended in patients undergoing primary PCI.     

Titanium-nitride-oxide-coated Titan-2 bioactive coronary stent: a new breakthrough in interventional cardiology

The introduction of drug-eluting stents (DES) has revolutionized the field of interventional cardiology, since it has reduced the incidence of restenosis by 50% to 70%. However, recent worrisome data from registries and meta-analyses emphasized higher rates of late and very late stent thrombosis associated with DES. The recently introduced titanium-nitride-oxide-coated stent bioactive stent (Titan-2) was manufactured by a proprietary process to coat titanium-nitride-oxide on the surface of the stainless steel stent, based on a plasma technology using the nano-synthesis of gas and metal. This late-breaking stent has demonstrated an excellent biocompatibility, as reflected by lower rates of platelet aggregation and fibrin deposition, and better endothelialization. Preclinical and clinical trials and registries involving real-life unselected populations have shown a low rate of major adverse cardiac events at long-term follow-up. Restenosis rates were comparable with those of DES, with very rare stent thrombosis. Equally favorable results have been obtained in patients at high-risk of in-stent restenosis, such as diabetics and those with small coronary arteries. Results in patients presenting with acute coronary syndrome have been again comparable to those of DES, with tendency to lower rates of myocardial infarction and stent thrombosis. Comparisons with second generation drug-eluting stents have also been promising.     

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.     

Late Stent Thrombosis: The Last Remaining Obstacle in Coronary Interventional Therapy

Drug-eluting stents (DES) represent an outstanding improvement in the interventional cardiology field. DES have markedly decreased stent restenosis and the clinical need for repeat revascularization, without increasing mortality, compared to bare-metal stents (BMS). However, the widespread use of DES has raised concerns regarding the occurrence of late stent thrombosis (ST), beyond the traditional 1-month timeframe in which thrombotic events were found to occur after BMS implantation. While early ST (events occurring within 1?month after stent placement) has been shown to be similar between DES and BMS, late (events occurring after 1?month following stent implantation) and very late (events occurring more than 1?year following stent implantation) ST have emerged as distinct major pitfalls of DES implantation. In this review we describe the current knowledge regarding late and very late ST after DES implantation.