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.     

Stent thrombosis

Intense investigation continues on the pathobiology of stent thrombosis (ST) because of its morbidity and mortality. Because little advance has been made in outcomes following ST, ongoing research is focused on further understanding predictive factors as well as ST frequency and timing in various patient subsets, depending upon whether a drug-eluting stent or bare-metal stent has been implanted. Although the preventive role of antiplatelet therapies remains unchallenged, new data on genomics and variability in response to antiplatelet therapy, as well as the effects of novel therapeutic agents and duration of therapy, have become available. The goal remains identification of patients at particularly increased risk of ST so that optimal prevention strategies can be developed and employed.     

支架内血栓形成病例的临床特点分析

目的:分析支架内血栓形成病例的临床特点并探讨其原因.方法:收集自2007-04至2008-06的所有支架内血栓的患者,共12例.其中男性10例,女性2例.1例置入金属裸支架,其余11例均为药物涂层支架.分析入选病例的临床特点,冠状动脉病变特征.结果:12例患者中,亚急性血栓5例;晚期血栓4例;极晚期血栓3例.分析病变特点及血栓形成原因显示:在早期血栓形成的5例中4例为原发性支架贴壁不良、支架膨胀不良、未完全覆盖病变;1例为糖尿病、长病变、完全闭塞病变.在晚期和极晚期血栓形成的7例病例中3例因为停用了波立维;2例有支架内严重再狭窄;1例为正性重构、获得性贴壁不良;1例为糖尿病、小血管病变,且支架中段扩张不充分不除外贴壁不良的因素.结论:支架内血栓是金属裸支架和药物涂层支架置入术后很少发生但非常严重的并发症.急性的支架内血栓可能与贴壁不良有关.晚期支架内血栓在病因学上是多因素的,主要与双联抗血小板药物治疗依从性相关.     

Stent thrombosis following drug-eluting stent implantation. A single-center experience

BACKGROUND: The risk of stent thrombosis (ST) following drug-eluting stent (DES) implantation may extend beyond the initial period after successful implantation. METHODS: We evaluated the incidence, timing, and clinical outcomes of patients who presented with DES-related early (30 days) angiographic ST. Between 1/2004 and 9/2006, a total of 1339 patients underwent DES implantation (90% using Cypher stents) at our institution. Dual antiplatelet therapy was recommended for 3 to 12 months. Clinical follow-up was obtained and adjudicated at 1 and 6 months following any ST event. RESULTS: We identified eight patients (0.6% of the total patients treated with DES) with definite ST. Their mean age was 67+/-13 years. Six patients (75%) were male and 37.5% (3/8) had diabetes. Acute myocardial infarction (AMI) was the clinical presentation in 87.5% of patients. Time to ST was 4 days in two (25%) of eight patients. The other six patients (75%) had late ST (>30 days). The median time to late ST was 480 days (range: 90-1080 days). Two patients had recurrent events of late ST. All cases of late ST, except one, occurred after clopidogrel treatment was discontinued. Median time from clopidogrel withdrawal to late ST was 18 months (range: 0.5-35 months). At 6 months' follow-up from the time of ST, the subsequent major adverse cardiac event (MACE) rate (including death, re-infarction, recurrent ST or need for emergent CABG) was 62.5% and overall and/or cardiac mortality rate was 12.5%. CONCLUSION: We found that ST occurred infrequently (0.6%) and the majority (75%) of patients developed ST late (>30 days) and beyond the period recommended for dual anti-platelet pharmacotherapy. Major adverse cardiac events following ST are substantial at 6 months and thus deserve careful clinical attention.     

Simultaneous late stent thrombosis in two coronary arteries following drug-eluting stent implantation

Late stent thrombosis has emerged as an infrequent but serious complication of drug-eluting stent (DES) implantation. Premature cessation of dual antiplatelet therapy is the most common risk factor for its occurrence. In the era of multivessel stenting with DES, there is a potential for multivessel late stent thrombosis following cessation of dual antiplatelet therapy. We present a rare case of a patient who sustained simultaneous late stent thromboses in DESs implanted in two coronary arteries as a result of premature cessation of dual antiplatelet therapy.     

Comparison of factors affecting platelet reactivity in various platelet function tests

Previous studies have reported that various factors affect ADP-induced platelet reactivity during clopidogrel therapy. The aim of this study was to determine whether clinical and laboratory variables for platelet reactivity during dual antiplatelet therapy (DAPT) are dependent on the assay used. We enrolled 904 patients receiving DAPT following coronary intervention. Platelet reactivity was measured using three methods: the VerifyNow P2Y12 assay, multiple electrode aggregometry (MEA) ADP assay, and the light transmittance aggregometry (LTA) ADP assay at 24–48 h following coronary intervention. The VerifyNow results demonstrated a significant inverse correlation with hematocrit value (r = –0.268, p < 0.0001); however, MEA results had no such correlation with hematocrit (r = 0.044, p = 0.188). There was a positive correlation between the MEA results and platelet count (r = 0.255, p < 0.0001). LTA was weakly influenced by hematocrit (r = –0.064, p = 0.057) and platelet count (r = 0.069, p = 0.040). Gender (odds ratio 1.53, 95% CI 1.10–2.14, p = 0.013) and hematocrit (odds ratio 0.91,95% CI 0.88–0.94, p < 0.0001) were the independent variables for HPR by VerifyNow. Smoking (odds ratio 0.38, 95% CI 0.16–0.94, p = 0.036) and platelet count (odds ratio 1.01, 95% CI 1.00–1.01, p < 0.0001) were independent factors for HPR when using the MEA assay, whereas platelet count (odds ratio 1.00, 95% CI 1.00–1.01, p = 0.006) was identified as the only independent variable for HPR when using LTA. The incidence of HPR and the influencing variables involved are dependent on the platelet function test used.     

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.     

Impact of immature platelet fraction on platelet reactivity during prasugrel maintenance treatment

Residual high on-treatment platelet reactivity (HTPR) despite dual antiplatelet therapy (DAPT) has emerged as a predictor of major ischemic events in patients undergoing percutaneous coronary interventions (PCIs), especially after an acute cardiovascular event. However, its determinants are still poorly defined. Therefore, the aim of the present study was to evaluate the role of the percentage of reticulated platelets on HTPR in patients on DAPT with ASA (100–160 mg) and prasugrel (10 mg).

Platelet reactivity and the reticulated platelets fraction (immature platelets fraction [IPF]) were assessed at 30–90 days after an acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HTPR was defined as ADP test > 417 AU × min.

Our population is represented by 180 ACS patients undergoing stent implantation, divided according to median values of IPF (< or ≥ 2.8%). Higher IPF values were associated to lower platelet count (p < 0.001) and a higher rate of active smokers (p = 0.02). No difference was observed in terms of mean platelet reactivity, with different activating stimuli. The prevalence of HTPR on prasugrel did not significantly differ in patients with IPF < or ≥ 2.8% (8%vs. 11.8%, p = 0.46; adjusted OR [95% CI] = 1.89 [0.66–5.4], p = 0.24).

Our study showed that in patients treated with prasugrel after PCI for ACS, the immature platelet fraction influences neither platelet reactivity nor the rate of HTPR.     

下肢深静脉血栓形成患者血小板活化状态的变化及意义

为探讨下肢深静脉血栓形成(DVT)思考血小板活化状态的变化及其临床意义，用流式细跑术(PCM)，以单克隆抗体为探针，对35例下肢DVT患者(DVT组)及3l例健康人(对照组)血小板活化标记物溶酶体颗粒糖蛋白(CD63)、血小板表面选择素(CD62p)及凝血酶敏感蛋白(TSD)进行了检测。结果显示，DVT组3种血小板活化标志物阳性表达率均高于对照组(P均＜0．001)，溶栓治疗后3种血小板活化标志物的阳性表达率均呈降低趋势。提示DVT患者体内血小板活化亢进；FCM可作为活化血小板的良好检测手段。     

左心房血栓形成中血小板活化作用的研究

目的:检测风湿性二尖瓣狭窄合并心房颤动的患者血浆P-选择素浓度变化,研究P-选择素蛋白及其在左心耳组织中的基因表达情况,探讨血小板活化在左心房血栓形成中的作用。方法:风湿性二尖瓣狭窄合并心房颤动患者80例(血栓组40例,无血栓组40例),健康人对照组15例(心脏移植供体10例取左心耳)。采用酶联免疫吸附剂测定法检测左心房及外周血浆P-选择素浓度。左心耳组织切片免疫组化染色,光镜下观察。实时荧光定量PCR对左心耳组织P-选择素基因表达进行定量研究。结果:与无血栓组相比,血栓组心房颤动时间更长、二尖瓣口面积更小、左心房内径更大,两组左心房内径均大于对照组。左心房与外周血P-选择素浓度差异均无显著性,血栓组外周血P-选择素浓度高于无血栓组,两组均高于对照组,免疫组化染色显示血管性血友病因子(vWF)和p-选择素蛋白在心内膜和心肌细胞中均有表达。左心耳组织P-选择素基因相对于正常左心耳组织的表达量,各组间差异无统计学意义性。结论:风湿性二尖瓣狭窄合并心房颤动患者血浆P-选择素浓度水平升高,外周血P-选择素浓度可代表左心房血中的浓度水平,血浆P-选择素浓度升高与P-选择素基因表达水平改变无关。     

Stent thrombosis with an aneurysm 7 years after a drug eluting stent implantation

We report a case of very late stent thrombosis 7 years post sirolimus eluting stent implantation presenting as ST elevation MI while on dual antiplatelet therapy. Angiography revealed an aneurysm at the proximal end of the stent. The patient was managed successfully by primary percutaneous coronary intervention (PCI) with adjunct thrombus aspiration and intracoronary abciximab administration followed by deploying a mesh-covered stent MGuard. This very late complication is a rare presentation after a drug illuting stent (DES).     

Clopidogrel resistance: The way forward

Clopidogrel, a second generation thienopyridine has been the mainstay of ACS (Acute Coronary Syndrome) treatment for more than a decade. Clopidogrel Resistance has been associated with increased mortality in ACS patients with an increase in number of Stent Thrombosis. This review article tries to find out the causes of Clopidogrel Resistance, the main factors involving it, Laboratory evaluation of Clopidogrel Resistance. The overall incidence of Clopidogrel Resistance across the Globe & India has also been considered. The article also discusses the clinical significance of Clopidogrel Resistance & its relationship with adverse cardiovascular events. This review ends with the probable solutions to Clopidogrel Resistance & the new generation of antiplatelets which can be used for the same.     

血小板聚集功能监测现状

抗血小板药物存在很大的个体差异性,一部分患者接受抗血小板药物治疗后,仍然存在血小板高反应性(HPR),而HPR跟不良临床结果相关。因此,学者们提出,运用血小板聚集功能监测来指导抗血小板治疗,并开展了许多关于这方面的研究,但却得出两个相悖的结论。为此,未来还需要设计更完善的研究来验证血小板功能检测的临床意义。     

Very Late Stent Thrombosis after Discontinuation of Antiplatelet Agents during Anticoagulation Therapy in a Patient with Peri-stent Contrast Staining after Implantation of a Second-generation Drug-eluting Stent

A 54-year-old man was admitted to our hospital due to intermittent chest pain. He had a history of acute myocardial infarction, and peri-stent contrast staining had been observed at the stent implantation site. The patient previously underwent anticoagulation therapy for left ventricular thrombus and antiplatelet therapy to prevent stent thrombosis. More than one year after implantation of a drug-eluting stent, antiplatelet drugs were discontinued, and anticoagulant alone was prescribed according to the guidelines, which resulted in very late stent thrombosis. The risks of both bleeding and thrombosis must be fully considered when deciding whether or not to discontinue antiplatelet therapy during anticoagulation therapy.     

Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients

Clopidogrel is a prodrug that needs to be converted in vivo by several cytochrome (CYP) P450 iso-enzymes to become active. Both clopidogrel and the oral hypoglycemic drug class sulfonylureas are metabolized by the iso-enzyme CYP2C9. The objective of the study was to evaluate the relationship of sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients undergoing elective coronary stent implantation. In this prospective, observational study, on-clopidogrel platelet reactivity was quantified using adenosine diphosphate (ADP)-induced light transmittance aggregometry in 139 type 2 diabetes mellitus patients undergoing elective coronary stent implantation treated with clopidogrel and aspirin. High on-clopidogrel platelet reactivity was defined as >70.7% platelet reactivity to 20?µmol/L ADP. A total of 53 patients (38.1%) were on concomitant treatment with sulfonylureas. The remaining 86 patients were on other hypoglycemic drugs. On-clopidogrel platelet reactivity was significantly higher in patients with concomitant sulfonylurea treatment as compared to patients without concomitant sulfonylurea treatment (for 5?µmol/L ADP: 46.0%?±?11.8 vs. 40.6%?±?16.0; p?=?0.035, adjusted p?=?0.032 and for 20?µmol/L ADP: 64.6%?±?10.8 vs. 58.7%?±?15.5; p?=?0.019, adjusted p?=?0.017). The concomitant use of sulfonylureas was associated with a 2.2-fold increased risk of high on-clopidogrel platelet reactivity (OR 2.2, 95% CI 1.1–4.7, p?=?0.039 and after adjustment for confounders: OR_adj 2.0, 95% CI 1.0–5.7, p?=?0.048). Concomitant treatment with sulfonylureas might be associated with decreased platelet inhibition by clopidogrel in type 2 diabetes mellitus patients on dual antiplatelet therapy undergoing elective coronary stent implantation.     

High risk of stent thrombosis in the first 6 months after coronary stenting

Objectives

To estimate the incidence of stent thrombosis (ST) after early discontinuation of clopidogrel.

Background

Premature discontinuation of clopidogrel is the strongest risk factor for ST. In contrast, recent studies suggest that shorter dual antiplatelet therapy (DAPT) can be discontinued as soon as 3 months after stenting. However, these studies included very few ACS patients and were not powered for ST. Hence, little is known about the occurrence of ST in high‐risk populations when DAPT is discontinued early.

Methods

This is a subanalysis of The Dutch ST Registry 437 ST cases (mainly first‐generation DES and BMS). Acute coronary syndrome was the indication for index‐PCI in 74% of the patients. Clopidogrel discontinuation rates in ST patients and matched controls were used to calculate the absolute incidence of ST after early clopidogrel discontinuation.

Results

The overall rate of ST after cessation of clopidogrel was 4.6% (95%CI: 3.9‐5.4%), as compared to 1.7% (95%CI: 1.5‐1.9%) in patients who did not discontinue clopidogrel. The incidence of ST was 35.4% when clopidogrel was discontinued in the first 30 days after index‐PCI declining to 11.7% when clopidogrel was discontinued in the first 180 days.

Conclusions

This dedicated ST registry shows that ST rates were very high when clopidogrel was discontinued before 6 months after index‐PCI and therefore suggests that clopidogrel discontinuation in the first 6 months after ACS should be avoided.