Percutaneous coronary intervention and stent thrombosis

Despite improved stent implantation technologies and effective antiplatelet regimens, stent thrombosis has been one of the most important problem in percutaneous coronary intervention. Stent thrombosis is a rare but usually catastrophic event, frequently associated with large MI or death. Stent thrombosis is generally categorized according to the timing of the event as early (0 to 30 days), late (31 days to 1 year), very late (> 1 year). Late and very late stent thrombosis after stent implantation has not yet been adequately characterized, mainly because of its low incidence. And the optimal duration of dual antiplatelet therapy remains uncertain for patients receiving drug-eluting stents.     

Expectation for new-generation drug eluting stents

Drug eluting stent (DES) dramatically reduced the instent restenosis(ISR). However, very late stent thrombosis appeared as another significant problem especially after the termination of dual antiplatelet therapy. The next-generation DESs are characterized by either biodegradable polymer, controlled drug delivery or biodegradable stent. By the introduction of these DESs, it is expected to reduce any long-term sequels while ensuring the reduction of ISR.     

Prolonged dual antiplatelet therapy after drug-eluting stent implantation improves long-term prognosis for acute coronary syndrome: five-year results from a large cohort study

BACKGROUND: To investigate the most appropriate dual antiplatelet therapy(DAPT) duration for patients with acute coronary syndrome(ACS) after drug-eluting stent(DES) implantation in the largest cardiovascular center of China.METHODS: We enrolled 5,187 consecutive patients with ACS who received DES from January to December 2013. Patients were divided into four groups based on DAPT duration: standard DAPT group(11–13 months, n=1,568) and prolonged DAPT groups(13–18 months [n=308], 18–24 months [n=...     

Study design of the influence of SErotonin inhibition on patients with RENAl impairment or diabetes undergoing drug-eluting stent implantation (SERENADE) study: A multicenter,open-label,prospective, randomized study

BackgroundThe rates of stent failure after percutaneous coronary intervention have decreased since the introduction of the drug-eluting stent (DES). However, chronic kidney disease (CKD) and diabetes mellitus (DM) remain strong clinical predictors of poor prognosis despite DES implantation. Sarpogrelate, a selective serotonin (5-hydroxytryptamine (HT)2a [5-HT2A]) receptor antagonist, has antiproliferative effects, reducing neointimal hyperplasia and smooth muscle cell proliferation, as well as potent antiplatelet action, inhibiting 5-HT-induced platelet aggregation. However, efficacy and safety data for sarpogrelate in patients with CKD or DM are limited. We aim to determine whether sarpogrelate has beneficial effects in patients with CDK or DM treated with DES implantation.Methods/designThe SERENADE trial is a multicenter, open-label, prospective, randomized study that will test the superiority of triple anti-platelet therapy (TAT; aspirin, clopidogrel, and sarpogrelate) to conventional dual antiplatelet therapy (DAT; aspirin and clopidogrel) in preventing late lumen loss 9 months after the index procedure in patients with CKD or DM. A total of 220 patients diagnosed with coronary artery disease with DM or CKD will be randomized to the TAT or DAT groups (1:1 ratio) after DES implantation. The primary endpoint is late lumen loss at 9 months assessed by quantitative coronary angiography. Secondary efficacy endpoints are composites of major adverse cardiovascular events including cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Secondary safety endpoints are major bleeding events and hepatic or renal impairment.DiscussionThe SERENADE trial will provide insight on the efficacy of adjunctive therapy with sarpogrelate after DES implantation for patients with high-risk profiles such as CKD or DM.Trial registrationNational Institutes of Health Clinical Trials Registry (ClinicalTrials.gov NCT02294643).     

Is late stent thrombosis in drug-eluting stents a real clinical issue?

Summary Background Randomized studies have not found an increased rate of late stent thrombosis (LAST) in drug-eluting stents (DES) compared with bare metal stents (BMS) but those studies were statistically not powered to show such a difference. At the same time there is an increasing number of reports of LAST in DES patients in the current literature. Patients and methods We tried to describe the incidence of LAST in an unselected DES and BMS patient population. All patients who underwent stenting in our hospital between October 2003 and March 2006 were included in the study (n=1377). A total of 424 (30.1%) patients were treated with only BMS stents, 520 (37.8%) with paclitaxel-eluting stents (PES), 384 (27.9%) with sirolimus-eluting stents (SES) and 49 (3.6%) with BMS and DES. Long-term follow-up of all patients was used to determine the incidence of LAST as defined by angiographically proven stent thrombosis associated with acute symptoms more than 30 days after stent implantation. Followup was between 1 month and 2 years 7 months (mean 12 months). Patients treated with DES were younger (66±11 years) than BMS patients (72±10 years; p<0.001) and more often had diabetes (24.2% vs 17.4%; p < 0.001). A previous PCI had been performed in 27.1% of DES patients vs 13.9% of BMS patients (p < 0.001). Results There were 9 cases of LAST: 2 with SES (at 6 and 11 months after implantation), 6 with PES (at 6, 9 (2×), 10, 16 and 26 months), and one with BMS (at 22 months). All patients with LAST presented with STEMI and without an angina history that suggested restenosis. Two cases were related to complete cessation of antiplatelet therapy, one because of patient non-compliance (SES), one after aspirin was stopped for orthopedic surgery (BMS). Two cases occurred within 1 month of cessation of clopidogrel therapy and while these patients were on aspirin therapy. Five cases occurred on aspirin monotherapy 2, 3, 4, 10 and 20 months, respectively after planned cessation of clopidogrel. None of the cases occurred under dual antiplatelet therapy. All patients underwent primary PCI; none died. Conclusion Angiografically proven LAST occurred in our unselected patient population with an incidence of 0.84% in patients treated with DES and 0.21% in BMS patients within a mean follow-up of 12 months (p = 0.36). LAST may indeed occur in clinically stable patients while on aspirin monotherapy. Since LAST led in all patients to STEMI it seems to be a serious clinical issue that prompts further investigation and discussion of length of dual platelet therapy.     

Long-term safety of drug-eluting stents

Stent implantation in coronary stenosis has revolutionized the treatment of coronary artery disease. The introduction of antirestenotic drug coatings further improved their efficacy in reducing target vessel revascularizations. With increasing use of drug-eluting stents (DES), stent thrombosis (ST) rose as potentially fatal major complication. Initially, the incidence of ST late after stent implantation seemed to be similar for DES and bare metal stents until several studies proved otherwise in first-generation DES. Since then, the design and components of DES have been changed and new polymers, drugs and different combinations of platelet inhibitors have been introduced to further improve the safety of DES. In this review, the authors focus on the relationship between DES, lesion anatomy, implantation technique and pharmacology to avoid the occurrence of ST. Furthermore, the relationship between dual antiplatelet therapy, bleeding rate and its significant impact on patient outcome is discussed. Finally, some promising future concepts are highlighted.     

Very early tissue coverage after drug-eluting stent implantation: an optical coherence tomography study

The aim of this study was to evaluate neointimal coverage in the very early phase after second-generation drug-eluting stent (DES) implantation using optical coherence tomography (OCT). Patients who underwent staged percutaneous coronary intervention within 30 days after DES implantation were enrolled. OCT was performed to observe DES previously implanted. The median time interval from implantation to OCT examination was 21.5 days. A total of 10,625 struts of 54 stents (52 everolimus-eluting stents and 2 zotarolimus-eluting stents) in 42 lesions were analyzed. Strut tissue coverage was observed in 71.1?±?19.2?% of the struts, malapposed struts in 2.56?±?3.37?%, strut tissue coverage at the side branch orifice in 10.6?±?17.2?%, and struts with protrusion in 0.95?±?3.46?%. Mean tissue thickness on the covered struts was 39.8?±?14.2 µm. The percentage of stent coverage was significantly lower in the overlapping segments than in the non-overlapping segments (48.4?±?17.5?% vs. 74.4?±?20.2?%, P?<?0.05). Most of the stent struts were covered by tissue within 30 days after second-generation DES implantation. However, the percentage of strut coverage was lower in the overlapping segments than in the non-overlapping segments, suggesting that very early interruption of dual antiplatelet therapy might result in increased risk of stent thrombosis, even in second-generation DES.     

Biolimus-eluting stent with biodegradable polymer (Nobori®): an overview of recent clinical results,SORT OUT V and COMPARE II trials

Evaluation of: Christiansen E, Jensen L, Thayssen P et al. Biolimus eluting biodegradable polymer coated stent vs durable polymer coated sirolimus eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomized non inferiority trial. Lancet 381, 661–669 (2013); Smits P, Hofma S, Togni M et al. Abluminal biodegradable polymer biolimus-eluting stent vs durable polymer everolimus eluting stent (COMPARE II): a randomized, controlled, non inferiority trial. Lancet 381, 651–660 (2013).

Since their apparition, first generation drug-eluting stents (DESs) have raised concerns regarding the risk of late and very late stent thrombosis as compared to bare metal stents and require prolonged dual antiplatelet therapy. Aside from delayed strut endothelialisation, positive vessel remodelling and late stent mal-apposition due to chronic inflammation may be a leading cause for these stent thromboses. In fact, the persistence of the durable polymer after complete drug release is responsible for local hypersensitivity and inflammatory reactions. Third generation DESs with biocompatible or biodegradable polymer have subsequently been developed to address this issue. In this article, we evaluate and discuss the results of two recent publications investigating safety and efficacy of a third generation DES with biodegradable polymer as compared to first and second generation DESs with durable polymer.     

Optical coherence tomography endpoints in stent clinical investigations: strut coverage

Late stent thrombosis (LST) and very LST (VLST) are infrequent complications after drug-eluting stent (DES) implantation, but they carry a significant risk for patients. Delayed healing, which may be represented by incomplete stent coverage, has been observed in necropsy vessel specimens treated with DES. As a result, in vivo assessment of stent coverage, as well as stent apposition using optical coherence tomography (OCT), have been recently used as surrogate safety endpoints in clinical trials testing DES platforms. By adopting strut coverage assessed by OCT, one can assess the safety profile of the new generation of DES in preregistration studies. This article focuses on stent strut coverage as a central predictor of late DES thrombosis from the histopathological point of view, discusses the limitations of the current imaging modalities and presents the technical characteristics of OCT for the detection of neointimal coverage after stent implantation. We also review the preclinical and clinical investigations using this novel imaging modality.     

Antiplatelet therapy in the era of drug-eluting stents: current and future perspectives

The use of drug-eluting stents (DESs) dramatically reduced in-stent restenosis. However, the increasing use of these stents has raised concern about their potential thrombogenicity. Indeed, the particularity of DES thrombosis compared with bare metal stent thrombosis is a high rate of late thrombosis. Antiplatelet therapy is efficient in preventing DES thrombosis. However, this therapy could be optimized and may be improved in the future. This article will review the mechanisms and the epidemiology of stent thrombosis. Then, we will summarize the antiplatelet therapeutic strategies used to prevent stent thrombosis and especially DES-associated thrombosis. Finally, we will present some data with regard to potential advantages and pitfalls in DES thrombosis prevention using novel antiplatelet agents currently under development, as well as future stent designs with improved healing properties.     

Antiplatelet therapy in the era of drug-eluting stents: current and future perspectives

The use of drug-eluting stents (DESs) dramatically reduced in-stent restenosis. However, the increasing use of these stents has raised concern about their potential thrombogenicity. Indeed, the particularity of DES thrombosis compared with bare metal stent thrombosis is a high rate of late thrombosis. Antiplatelet therapy is efficient in preventing DES thrombosis. However, this therapy could be optimized and may be improved in the future. This article will review the mechanisms and the epidemiology of stent thrombosis. Then, we will summarize the antiplatelet therapeutic strategies used to prevent stent thrombosis and especially DES-associated thrombosis. Finally, we will present some data with regard to potential advantages and pitfalls in DES thrombosis prevention using novel antiplatelet agents currently under development, as well as future stent designs with improved healing properties.     

A novel approach to define risk of stent thrombosis after percutaneous coronary intervention with drug-eluting stents: the DERIVATION score

Recent studies of drug-eluting stents (DES) use in routine clinical practice have led to concern regarding their long-term safety and to questions about the adequacy of current antiplatelet therapy guidelines. This study sought to derivate a risk score for predicting stent thrombosis after drug-eluting stenting. The large single center DES Real-world Incremental Value in the erA of percutaneous revascularizaTION (DERIVATION) database, collecting data about 1,377 patients of any age undergoing PCI with DES as treatment for symptomatic coronary artery disease, was use for this purpose. Logistic regression and bootstrap procedure were used to select correlates of stent thrombosis that were subsequently weighted and integrated into an integer scoring system. Five variables selected from the initial multivariate model were weighted proportionally to their respective odds ratio for stent thrombosis [baseline left ventricular ejection fraction <50% (4 points), angioplasty in the setting of acute coronary syndromes (3 points), bifurcation lesion (2 points), left anterior descending as target vessel (2 points), multiple stenting (2 points)]. Three strata of risk were defined (low risk, 0–2; intermediate risk, 3–6; high risk ≥7) with good prognostic accuracy for early, late and very late thrombosis (c statistic = 0.75, 0.65 and 0.73, respectively) in the derivation set. In conclusion, the DERIVATION score may be used as a simple clinical tool for the identification of a sizable cohort in whom close monitoring and aggressive therapy may be beneficial.     

Restenosis of a drug eluting stent on the previous bioresorbable vascular scaffold successfully treated with a drug-coated balloon: A case report

BACKGROUNDThe in-stent restenosis (ISR) rates are reportedly inconsistent despite the increased use of second-generation drug eluting stent (DES). Although bioresorbable vascular scaffold (BVS) have substantial advantages with respect to vascular restoration, the rate of scaffold thrombosis is higher with BVS than with DES. Optimal treatment strategies have not been established for DES-ISR to date.CASE SUMMARYWe report on a case of a 60-year-old man patient with acute coronary syndrome. He had a history of ST-segment elevation myocardial infarction associated with very late scaffold thrombosis and treated with a DES. Coronary angiography revealed significant stenosis, suggesting DES-ISR on the previous BVS. Optical coherence tomography (OCT) identified a plaque rupture and a disrupted scaffold strut in the neointimal proliferation of DES. To treat the DES-ISR on the previous BVS, we opted for a drug-coated balloon (DCB) after a balloon angioplasty using a semi-compliant and non-compliant balloon. The patient did not experience adverse cardiovascular events on using a DCB following the use of intensive dual antiplatelet therapy and statin for 24 mo. CONCLUSIONThis case highlights the importance of OCT as an imaging modality for characterizing the mechanism of target lesion failure. The use of a DCB following the administration of optimal pharmacologic therapy may be an optimal strategy for the treatment and prevention of recurrent BVS thrombosis and DES-ISR.     

Drug-eluting stents: trading restenosis for thrombosis?

Summary.  Within the last 6 years, it has been demonstrated that drug-eluting stents (DES) reduce significantly angiographic and clinical restenosis after percutaneous coronary interventions. These results are consistent across several clinical randomized controlled trials comparing these new devices with bare metallic stents (BMS), which themselves have already markedly improved the results obtained with balloon angioplasty in the early days of this method of myocardial revascularization. Nevertheless, some concerns have been raised regarding a delayed endothelialization of the coated prostheses leading to late stent thrombosis occurring mainly when antiplatelet therapy is discontinued in the follow-up. The most recent data show that, in comparison with BMS, there is a small excess of late (> 1 year) stent thrombosis but this is not associated with an increased risk of death or myocardial infarction or all cause mortality. These concerns do not outweigh the strong benefits of DES in preventing restenosis but require a number of measures concerning a longer dual antiplatelet treatment (than initially expected), to control patient treatment compliance and to provide a complete education of patients and physicians. Future devices dealing with the two issues (antiproliferative properties with rapid controlled endothelialization preventing thrombosis) would be the next major advance in this rapidly evolving field.     

替罗非班应用在药物涂层支架植入术后老年患者实行非心脏手术的可行性和安全性

目的:明确替罗非班是否可以在药物涂层支架植入老年患者实行非心脏手术围手术期替代口服双联抗血小板药物而发挥预防支架内血栓的作用,同时不增加外科手术的出血。方法:入选入院前1年内曾因冠心病植入药物涂层支架服用双联抗血小板药物而后无缺血性胸痛症状,因外科疾病保守治疗无效需手术治疗的12例患者配对分组,手术前5d停用口服双联抗血小板药物,治疗组6例患者应用替罗非班0.1μg/(kg·min)持续静脉微量泵泵入,对照组6例患者应用低分子肝素依诺肝素1mg/kg皮下注射(每天2次),手术结束后在重症监护室中继续术前应用方法,根据外科情况允许,停用替罗非班及低分子肝素,尽早恢复口服双联抗血小板药物使用,分析围手术期两组新发心血管事件以及严重出血事件。结果:两组患者围手术期均未发生缺血性室性恶性心律失常、心绞痛、心肌梗死、心源性猝死,未发生大量出血而导致输血或需二次手术止血等出血事件。结论:替罗非班应用在药物涂层支架植入术后患者实行非心脏手术替代口服双联抗血小板药物预防围手术期支架内血栓的治疗作用不亚于低分子肝素,没有严重的出血并发症,而且有半衰期短的特点,其优势需要大样本随机对照试验以进一步证实。     

A case–control study on platelet reactivity in patients with coronary stent thrombosis

Summary. Background: The pathophysiology of stent thrombosis (ST) has evolved from the identification of single causative factors to a complex multifactorial model. Objectives: The aim of the present study was to investigate whether patients with a history of ST exhibit heightened platelet reactivity to clopidogrel and aspirin. Patients/methods: Pretreatment and on‐treatment platelet reactivity to clopidogrel and aspirin, as well as dual antiplatelet therapy resistance, was determined in 84 patients with a history of definite ST (cases: 41 early ST; 43 late ST) and in 103 control patients with a previously implanted coronary stent but no ST after the index procedure. Platelet function was evaluated with optical aggregometry, the VerifyNow P2Y12 and aspirin assays, the PFA‐100 Innovance P2Y* cartridge, the flow cytometric vasodilator‐stimulated phosphoprotein assay and urine 11‐dehydrothromboxane B₂ measurement before and after the administration of a 600‐mg loading dose of clopidogrel and 100 mg of aspirin. The study was registered at ClinicalTrials.gov, number NCT01012544. Results: Patients with a history of early ST clearly demonstrated higher on‐clopidogrel platelet reactivity than controls. Patients with both early and late ST exhibited heightened on‐aspirin platelet reactivity status, and dual antiplatelet therapy resistance was more frequent. Conclusions: Patients with a history of early ST exhibit a poor response to clopidogrel. Furthermore, both early and late ST are strongly and independently associated with heightened on‐aspirin platelet reactivity, and dual antiplatelet therapy resistance is more frequent.     

Is stent thrombosis the new Achilles heel of interventional cardiology? State of the Art clinical trials, causes and approaches for prevention

Coronary stents are the mainstay of percutaneous coronary intervention. Stent thrombosis is a potentially catastrophic and often life-threatening complication. If it occurs it presents in up to 80% as myocardial infarction, about half of the affected patients die from this complication. The dual antiplatelet therapy has markedly reduced its occurrence. Today, stent thrombosis occurs in <1%, usually as a delayed event; but compared to bare metal stents the overall incidence has not increased in meta-analyses of randomized trials. The advent of drug-eluting stents (DES) has raised concerns regarding the occurrence of delayed stent thrombosis. Delayed arterial wall healing as well as prothrombotic characteristics of the drug eluting stent itself may contribute to stent thrombosis. In order to prevent stent thrombosis a standardized fixed dose antiplatelet therapy with ASA and clopidogrel is recommended. But, their efficacy depends on patient's individual characteristics such drug metabolism. Therefore, individual determination of platelet function in each patient undergoing stent implantation may help to avoid prothrombotic as well as bleeding complications.     

紫杉醇药物洗脱支架置入后并发症:6个月随访

背景:紫杉醇药物洗脱支架临床应用的安全性和有效性已经国际临床试验研究证实,在适当放宽病变的入选标准情况下,其再狭窄发生率仍明显低于金属裸支架.目的:通过对应用紫杉醇药物洗脱支架的患者进行冠状动脉造影随访,观察该支架再狭窄发生情况和支架对局部血管的作用,探讨支架材料与宿主的生物相容性.设计:随访观察.单位:解放军总医院心内科.对象:选择2003-05/2005-05解放军总医院心血管内科有冠状动脉介入治疗指征,且行紫杉醇药物洗脱支架置入的冠心病患者297例,男265例,女32例,年龄36～76岁.患者均对治疗和实验知情同意;该实验经医院伦理委员会批准.方法:全部患者置入美国Boston Scientific生产的紫杉醇药物洗脱支架.患者支架术后6和12个月回院复查,并于术后6个月行冠状动脉造影,测量数据包括:靶血管参考管径、最小管腔直径,计算直径狭窄率、晚期管腔丢失情况.主要观察指标:紫杉醇药物洗脱支架置入后6个月冠状动脉造影结果,随访支架材料与宿主的生物相容性.结果:①冠状动脉造影定量分析结果:冠状动脉造影随访时,晚期管腔支架内丢失显著高于支架近端边缘及支架远端边缘,差异有显著性意义(P＜0.05).②支架再狭窄的随访:6个月时冠动脉造影有14例发生再狭窄,再狭窄发生率为10.4%(14/134).再狭窄的类型以支架内弥漫性再狭窄7例.再血管化率为6.7%.③支架动脉瘤形成:冠状动脉造影随访时显示支架部位有小动脉瘤形成1例,动脉瘤发生率为0.75%(1/134).④心血管不良事件:支架置入后1例4个月发生猝死,猝死发生率为0.34%(1/297).支架置入后5d发生支架内亚急性血栓形成1例,发生率0.34%(1/297).术后12个月晚期血栓形成2例,总心血管不良事件发生率为1.35%.结论:①紫杉醇药物洗脱支架的管腔丢失主要在支架内,置入后再狭窄以支架内弥漫性多见,心血管不良事件发生率较低.②紫杉醇药物洗脱支架可导致靶病变血管局部小的瘤样扩张.术后及随访结果总体数据显示紫杉醇药物洗脱支架与患者的生物相容性较好.     

Dual antiplatelet therapy following drug-eluting stent implantation: how long is long enough?

A period of dual antiplatelet therapy (DAPT) is mandatory after drug-eluting stent (DES) implantation to reduce the risk of stent thrombosis as a consequence of inflammation during the healing process. DAPT is also claimed to be associated with other benefits beyond this, including a reduction in ischemic events and improvements in clinical outcomes. A number of studies have investigated the feasibility of shortened DAPT in a bid to maximize benefits, while reducing adverse events; however, there are recent data to suggest that prolongation of DAPT may be associated with additional benefits at the risk of increased bleeding complications. On the basis of currently available evidence, we believe that all patients should be treated with DAPT for a minimum of 6 months after drug-eluting stent (DES) implantation. However, the decision to prolong therapy beyond this should be made on an individual basis, taking into account the potential benefits against specific risk factors for subsequent adverse events.