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.     

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.     

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.     

Diagnosis and management challenges of in-stent restenosis in coronary arteries

Over the course of the 3 decades, percutaneous coronary intervention(PCI) with stent implantation transformed the practice of cardiology. PCI with stenting is currently the most widely performed procedure for the treatment of symptomatic coronary disease. In large trials, drugeluting stents(DES) have led to a significant reduction in in-stent restenosis(ISR) rates, one of the major limitations of bare-metal stents. Due to these favorable findings, DES was rapidly and widely adopted enabling more complex coronary interventions. Nevertheless, ISR remains a serious concern as late stent complications. ISR mainly results from aggressive neointimal proliferation and neoatherosclerosis. DES-ISR treatment continues to be challenging complications for interventional cardiologists.     

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.     

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.     

Future stent drug delivery systems

Drug-eluting stents (DES) with antiproliferative drugs attached via polymers on the stent surface have reduced in-stent restenosis and repeat revascularization compared with bare metal stent (BMS) across nearly all lesion and patient subsets. However, the small number of patients with in-stent restenosis after DES treatment still exists. Furthermore, concerns about long-term safety of DES are raised, particularly regarding the higher-than-expected late-event thrombosis. There is no doubt that the DES will continue to play a pivotal role in the treatment of coronary artery disease, yet future designs need to incorporate features that reduce thrombosis and promote endothelialization along with maintaining the efficacy. This review focuses on novel generation of DES, discussing new programs, including new antiproliferative agents, novel polymeric and non polymeric stents.     

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.     

Benefits of drug eluting stents versus bare metal stents in ST-elevation myocardial infarction: a contemporary review

The efficacy of drug-eluting stents (DES) in reducing the rates of in-stent restenosis after percutaneous coronary intervention (PCI) compared to bare metal stents (BMS) in stable coronary artery disease has been well demonstrated. Thus, the Food and Drug Administration has approved the utilization of DES for stable coronary disease. However, there is still much debate surrounding the implantation of DES for patients with ST-segment elevation myocardial infarction (STEMI) given safety concerns about the possibility of increased rates of stent thrombosis with DES. The review of the current body of evidence comparing DES with BMS is consistent with results from previous trials in stable coronary disease and reveals lower rates of revascularization with DES in STEMI patients. The ultimate decision regarding the appropriate stent during PCI needs to be individualized as patients' compliance with dual antiplatelet therapy is critical. The data suggest that PCI with DES in STEMI patients who adhere to long-term dual antiplatelet therapy is safe and effective. Randomized trials with longer-term follow-up are necessary to better elucidate the safety and efficacy of DES versus BMS in patients with STEMI.     

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.     

Antiplatelet therapy following drug-eluting stent implantation: new clinical data and recommendations

Technological developments in percutaneous coronary interventions (PCI) allow the possibility for less invasive revascularization in an increasing number of patients with atherosclerotic coronary artery disease. Bare-metal stents (BMS) have considerably improved the efficacy of PCI in addition to greatly reducing restenosis. However, even with standard stents, restenosis has remained a significant limitation of this revascularization technique. The advent of drug-eluting stents (DES) has dramatically reduced in-stent restenosis and, as a result, the need for repeat revascularization. However, their potential thrombogenicity has raised concerns about their clinical utility and long-term safety. Indeed, there is a possible higher rate of late stent thrombosis (LST) with DES compared with BMS. Antiplatelet therapy has been shown to be efficient in preventing DES thrombosis. Nevertheless, in the future, significant improvement will occur to improve the safety and efficacy of this therapy. This article will summarize the pathophysiology and the epidemiology of stent thrombosis (ST). Definitions of definite, probable and possible ST will be described. Furthermore, clinical risk factors for ST will be clearly enumerated. Then, the various antiplatelet therapeutic strategies used to prevent ST will be taken in consideration. Finally, a summary of the major recommendations about antiplatelet therapy made by some of the most prestigious learned societies will be presented.     

Drug-Eluting Versus Bare Metal Stents in Saphenous Vein Graft Intervention: An Updated Comprehensive Meta-Analysis of Randomized Trials

BackgroundDrug eluting stents (DES) are preferred over bare metal stents (BMS) for native coronary artery revascularization unless contraindicated. However, the preferred stent choice for saphenous venous graft (SVG) percutaneous coronary interventions (PCI) is unclear due to conflicting results.MethodsPubMed, Clinical trials registry and the Cochrane Center Register of Controlled Trials were searched through June 2018. Seven studies (n = 1639) comparing DES versus BMS in SVG-PCI were included. Endpoints were major adverse cardiac events (MACE), cardiovascular mortality, all-cause mortality, myocardial infarction (MI), target vessel revascularization (TVR), target lesion revascularization (TLR), in-stent thrombosis, binary in-stent restenosis, and late lumen loss (LLL).ResultsOverall, during a mean follow up of 32.1 months, there was no significant difference in the risk of MACE, cardiovascular mortality, all-cause mortality, MI, stent thrombosis, TVR and TLR between DES and BMS. However, short-term follow up (mean 11 months) showed lower rate of MACE (OR 0.66 [0.51, 0.85]; p = 0.002), TVR (OR 0.47 [0.23, 0.97]; p = 0.04) and binary in-stent restenosis (OR 0.14 [0.06, 0.37]; p < 0.0001) in DES as compared with BMS. This benefit was lost on long-term follow up with a mean follow up 35.5 months.ConclusionIn this meta-analysis of SVG-PCI, DES use was associated with similar MACE, cardiovascular mortality, all-cause mortality, MI, in-stent thrombosis, TVR and TLR compared with BMS during long-term follow up. There was high incidence of MACE noted in both DES and BMS suggesting a need for exploring novel strategies to treat SVG disease to improve clinical outcomes.     

Angiographic results of the cobalt chromium Vision and Mini-Vision stents

BACKGROUND:

Drug-eluting stents (DES) have been shown to reduce repeat revascularizations compared with their bare-metal stent (BMS) platforms. Modern BMS may be associated with better angiographic results compared with the older BMS platforms. In the Basel Stent Kosten Effektivitats Trial (BASKET), target vessel revascularization after six months was nonsignificantly different between DES and BMS with clinical follow-up.

OBJECTIVES:

To evaluate angiographic results of the cobalt chromium Vision and Mini-Vision stents (Abbott Vascular, USA).

METHODS:

A total of 247 consecutive patients with 293 de novo lesions in native coronary arteries were treated with cobalt chromium Vision (n=184; stent diameter 2.75 mm to 4.0 mm) or Mini-Vision stents (n=109; stent diameter 2.0 mm to 2.5 mm), and scheduled for six months of angiographic follow-up. The primary end point was in-stent late loss after six months.

RESULTS:

Acute coronary syndromes were present in 83.4% (n=206) of patients. The preinterventional reference diameter of Vision stents was 2.70±0.34 mm and for Mini-Vision stents, it was 2.13±0.27 mm (P<0.001). Clinical and angiographic follow-up was 98.0% and 51.2%, respectively. In the Vision group, in-stent late loss was 0.64±0.67 mm and the binary rest-enosis rate was 17.9%. In the Mini-Vision group, in-stent late loss was 0.82±0.71 mm and the restenosis rate was 45.4%. No difference in occurrence of restenosis within the segments proximal or distal to the stent was observed. The restenotic pattern was predominantly focal with a short length of 7.9±4.4 mm.

CONCLUSIONS:

The use of the cobalt chromium Vision stent for the treatment of de novo lesions was associated with a low late loss and binary angiographic restenosis rate.     

Short- and long-term benefits of drug-eluting stents compared to bare metal stents even in treatment for large coronary arteries

Although drug-eluting stents (DES) for percutaneous coronary intervention (PCI) have dramatically reduced the incidence of in-stent restenosis, their deployment for large-size coronary lesions is still controversial because of problems such as late in-stent thrombosis and late catch-up in DES. We aimed to evaluate the long-term outcome beyond 2 years of bare metal stents (BMS) as compared with DES in large vessels. Consecutive 228 patients who underwent PCI with large-size stents (>3.5 mm in diameter) in our hospital were enrolled in this study. The end points of this study are target lesion revascularization (TLR) and occurrence of major adverse cardiac events (MACE) for subject patients. We analyzed 183 patients (152 men, mean age 65.8 ± 10.5 years) whose outcome could be followed up for at least 2 years. At the first 8-month follow-up, clinically driven TLR rate was significantly higher in patients who received BMS than those who received DES (17.2 vs. 2.2 %, p < 0.05), although the rate of TLR was not different between the 2 groups beyond 8 months. Thus, overall rate of TLR was higher in BMS than in DES (22.7 vs. 5.4 %, p < 0.05). Under these conditions, the higher rate of TLR for BMS was observed in simple as well as complex lesions with or without diabetes, although there were no significant differences in MACE between BMS and DES. Multivariate analysis showed that BMS was an only independent factor of TLR at the 8 month follow-up period [p = 0.004, odds ratio 9.58, 95 % confidence interval (2.10–43.8)]. These results demonstrate that the rate of in-stent restenosis in large-size coronary lesions was transiently higher in the first 8 months for patients implanted with BMS compared with DES in which no in-stent thrombosis and TLR beyond 2 years were observed. We suggest using the DES even in large-size coronary lesions in terms of short- and long-term outcomes.     

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.     

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.     

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。     

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.     

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.     

Bare-metal stent outcomes in an unselected patient population

BACKGROUND: Randomized trials have shown that drug-eluting stents (DES) substantially reduce in-stent restenosis compared with bare-metal stents (BMS). HYPOTHESIS: Revascularization event rates related to BMS restenosis may be higher in the trials setting than in real-world experience, calling into question the extent of benefit possible with widespread DES use in regular practice. METHODS: Between December 1998 and March 2003, 17,102 patients with BMS registered in the Goodroe Healthcare Solutions Data Warehouse met the inclusion criteria for this retrospective study of catheterization laboratory data. We examined the database for evidence of diagnostic angiography or percutaneous coronary intervention (PCI) readmission within 1 year after stenting. RESULTS: Repeat PCI was documented for 2070 patients, and 232 were referred for coronary artery bypass graft surgery (CABG)-in sum, 13.5% of the cohort. Stented region revascularization was observed in 8.4%: 1350 patients underwent subsequent PCI, and 84 of the patients referred for CABG had in-stent lesion recurrence. Only 1207 (7.1%) patients required stent-related PCI after 30 days, the time frame consistent with restenosis. CONCLUSIONS: In this "real-world" series, reintervention of a stented region after the first follow-up month was documented in fewer than 8% of patients in a large cohort that had received BMS. The rate of clinical events potentially related to BMS in-stent restenosis in this large, unselected patient population is substantially lower than that in the control arms of some DES trials. The incremental benefit of widespread conversion from BMS to DES may be smaller in some patient populations than is suggested by the results of those trials.