Stent thrombosis with drug-eluting stents: a re-examination of the evidence.

The excitement of drug-eluting stents and their promise for reduced restenosis rates have been tempered by recent reports of stent thrombosis. The mechanism of stent thrombosis is multifactorial but appears to be related to delayed endothelialization and healing, late stent malapposition, and antiplatelet resistance. The most important risk factor appears to be the discontinuation of dual antiplatelet therapy. The data from clinical trials suggest that drug-eluting stents are associated with increased incidence of death or myocardial infarction compared with bare metal stents at long-term follow-up, suggesting that the window of thrombotic risk with drug-eluting stents may extend far beyond that for bare metal stents. Measures to possibly decrease the incidence of stent thrombosis include improvements in antiplatelet regimens and newer generation of drug-eluting stents which have biodegradable polymers or are polymer-free. In addition, percutaneous coronary intervention with bare metal stents in patients may be helpful in those known to be intolerant or noncompliant to antiplatelet therapy, have planned procedures or surgeries, or have overwhelming risks which may require discontinuation of dual antiplatelet therapy.     

Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials

Purpose

Drug-eluting stents are commonly used for percutaneous coronary intervention. Despite excellent clinical efficacy, the association between drug-eluting stents and the risk for late thrombosis remains imprecisely defined.

Methods

We performed a meta-analysis on 14 contemporary clinical trials that randomized 6675 patients to drug-eluting stents (paclitaxel or sirolimus) compared with bare metal stents. Eight of these trials have reported more than a year of clinical follow-up.

Results

The incidence of very late thrombosis (>1 year after the index procedure) was 5.0 events per 1000 drug-eluting stent patients, with no events in bare metal stent patients (risk ratio [RR] = 5.02, 95% confidence interval [CI], 1.29 to 19.52, P = .02). Among sirolimus trials, the incidence of very late thrombosis was 3.6 events per 1000 sirolimus stent patients, with no events in bare metal stent patients (RR = 3.99, 95% CI, .45 to 35.62, P = .22). The median time of late sirolimus stent thrombosis was 15.5 months, whereas with bare metal stents it was 4 months. Among paclitaxel trials, the incidence of very late thrombosis was 5.9 events per 1000 paclitaxel stent patients, with no events in bare metal stent patients (RR = 5.72, 95% CI, 1.08 to 32.45, P = .049). The median time of late paclitaxel stent thrombosis was 18 months, whereas it was 3.5 months in bare metal stent patients.

Conclusions

Although the incidence of very late stent thrombosis more than 1 year after coronary revascularization is low, drug-eluting stents appear to increase the risk for late thrombosis. Although more of this risk was seen with paclitaxel stents, it remains possible that sirolimus stents similarly increase the risk for late thrombosis compared with bare metal stents.     

Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up

Despite concerns regarding the long-term safety of drug-eluting stent (DES) implantation because of late-onset stent thrombosis, the actual incidence of stent thrombosis after 1 year is unknown. We investigated the incidence, risk factors, and association of antiplatelet therapy interruption for the development of stent thrombosis after DES implantation during long-term follow-up. A total of 1,911 consecutive patients with DES implantation were enrolled (sirolimus-eluting stents in 1,545 patients, 2,045 lesions; paclitaxel-eluting stents in 366 patients, 563 lesions). During long-term follow-up (median 19.4 months, interquartile range 15.3 to 24.3), 15 patients (0.8%, 95% confidence interval 0.5% to 1.3%) developed stent thrombosis within 6 hours to 20.4 months. Eleven patients (0.6%, 95% confidence interval 0.3% to 1.0%) had late thrombosis (median 6.1 months). The incidence of stent thrombosis was 3.3% (4 of 121 patients) in patients with complete interruption of antiplatelet therapy (vs 0.6% in those without, p = 0.004) and 7.8% (5 of 64 patients) with premature interruption of aspirin or clopidogrel, or both (vs 0.5% in those without, p < 0.001). Independent predictors of stent thrombosis were premature antiplatelet therapy interruption, primary stenting in acute myocardial infarction, and total stent length. Stent thrombosis also developed while patients were on dual antiplatelet therapy (all patients with acute/subacute stent thrombosis and 36% of those with late stent thrombosis; 47% of total with stent thrombosis). In conclusion, stent thrombosis occurred in 0.8% after DES implantation during long-term follow-up. The incidence of late stent thrombosis was 0.6%, similar to that for bare metal stents. The predictors of stent thrombosis were premature antiplatelet therapy interruption, primary stenting in acute myocardial infarction, and total stent length.     

中国多中心药物洗脱支架急性或亚急性血栓的调查

目的调查国内药物洗脱支架的急性或亚急性血栓发生率,与金属裸支架相比,评价其安全性。方法收集国内84个心脏介入中心近两年的经皮冠状动脉介入治疗资料和血栓病例,并汇总分析。结果支架术总例数为31412例,其中药物洗脱支架置入术占32.7%,金属裸支架置入术占67.3%。二者的血栓发生率分别为0.77%和0.75%。结论药物洗脱支架的安全性与金属裸支架相似。     

Effects of stent length and lesion length on coronary restenosis

The choice of drug-eluting versus bare metal stents is based on costs and expectations of restenosis and thrombosis risk. Approaches to stent placement vary from covering just the zone of maximal obstruction to stenting well beyond the lesion boundaries (normal-to-normal vessel). The independent effects of stented lesion length, nonstented lesion length, and excess stent length, on coronary restenosis have not been evaluated for bare metal or drug-eluting stents. We analyzed the angiographic follow-up cohort (1,181 patients) from 6 recent bare metal stent trials of de novo lesions in native coronary arteries. Stent length exceeded lesion length in 87% of lesions (mean lesion length 12.4 +/- 6.3 mm, mean stent length 20.0 +/- 7.9 mm, mean difference 7.6 +/- 7.9 mm). At 6- to 9-month follow-up, the mean percent diameter stenosis was 39.1 +/- 20.1%. In an adjusted multivariable model of percent diameter stenosis, each 10 mm of stented lesion length was associated with an absolute increase in percent diameter stenosis of 7.7% (p <0.0001), whereas each 10 mm of excess stent length independently increased percent diameter stenosis by 4.0% (p <0.0001) and increased target lesion revascularization at 9 months (odds ratio 1.12, 95% confidence interval 1.02 to 1.24). Significant nonstented lesion length was uncommon (12.5% of cases). In summary, stent length exceeded lesion length in most stented lesions, and the amount of excess stent length increased the risk of restenosis independent of the stented lesion length. This analysis supports a conservative approach of matching stent length to lesion length to reduce the risk of restenosis with bare metal stents.     

Very late thrombosis in a bare metal stent: an under-recognized problem

Recent publications have emphasized the concept that restenosis of a bare metal stent is not as clinically benign as previously believed. A case of very late (seven years) thrombosis after implantation of a bare metal stent is described. While doubts on the long-term safety of drug-eluting stents are debated, registry data and clinical reports suggest that the long-term safety of coronary bare metal stent implantation should also be reconsidered.     

Late coronary stent thrombosis and clopidogrel

The existence of late coronary stent thrombosis is a topical issue in cardiology today. The synoptic article discusses current definition of the above phenomenon, its delimitation in time and actual incidence. Based on data from available observation and randomised studies, long-term safety of conventional bare metal and drug-eluting stents is evaluated, as well as the safety profile following implantation. The length of thienopyridin treatment after percutaneous coronary intervention (PCI) varies according to the type of stent used. While a conventional bare metal stent (BMS) implant provides long-term safety with one month treatment, the implantation of a drug-eluting stent (DES) should be complemented with a 12-month period of clopidogrel administration. This approach may be in the future influenced by further progress in drug-eluting stents development and by prospectively acquired information on long-term administration of clopidogrel to such patients.     

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.     

Recurrent very late drug-eluting stent thrombosis

In-stent thrombosis is a severe and potentially fatal event. The incidence of this pathological process does not differ significantly after implantation of either bare metal or drug-eluting stents (DESs) in the first month after intervention, but stent thrombosis (ST) continues to occur over a long period of time after implantation of DESs, a phenomenon known as late and very late ST. Multiple predictors of late ST have been identified, and among others, patient's adherence to medical therapy as well as an optimal interventional technique of stent implantation emerge as crucial variables. Scarce data is available about the occurrence of recurrent very late ST. We report three cases of recurrent very late thrombosis of first generation DESs in middle-aged patients with different degrees of coronary artery disease, presenting with acute myocardial infarction.     

In-stent restenosis and thrombosis 41 months after drug-eluting stent implantation

Evidence indicates that very late stent thrombosis (> 1 year) occurs more frequently in drug-eluting stents than in bare metal stents after discontinuation of clopidogrel. We present a case of an 83 year old man with an LAD in-stent thrombosis 41 months after stenting with a sirolimus-eluting stent in whom clopidogrel was discontinued after 6 months based on these days' guidelines. In-stent thrombus was aspirated and intracoronary ultrasound (ICUS) showed significant in-stent restenosis which had narrowed the minimal lumen diameter by 1 mm. The lesion was stented with a bare metal stent. The patient was discharged after recovery and had no recurrence of stent thrombosis in one month follow-up. We recommended indefinite dual antiplatelet therapy with aspirin and clopidogrel.     

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.     

Very late stent thrombosis associated with multiple stent fractures and peri-stent aneurysm formation after sirolimus-eluting stent implantation.

Previous randomized trials have shown that drug-eluting stents (DES) are superior to bare-metal stents in reducing the need for target lesion revascularization, but safety issues with DES have recently been raised. We report a rare case of very late stent thrombosis 35 months after sirolimus-eluting stent implantation associated with delayed 5-segment stent fractures and peri-stent aneurysm formation.     

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.     

Simultaneous multivessel acute drug-eluting stent thrombosis

Stent thrombosis (ST) in the era of bare metal stents (BMS) using high-pressure stent deployment and combined anti-platelet therapy is an uncommon but feared complication. There is concern for an elevated risk of stent thrombosis (ST) with drug-eluting stents (DES). We describe a case of simultaneous multivessel drug-eluting stent thrombosis 8 h after deployment of paclitaxel-eluting stents in the right coronary (RCA) and left anterior descending (LAD) arteries.     

Late angiographic stent thrombosis after sirolimus-eluting stent implantation.

BACKGROUND: Although drug-eluting stents dramatically reduce revascularization after percutaneous coronary intervention (PCI), it is still unclear whether they increase the risk of stent thrombosis. Late stent thrombosis (>30 days) was a very rare complication after bare metal stent implantation. Four cases of confirmed late angiographic stent thrombosis (LAST) after sirolimus-eluting stent (SES) implantation are presented and the incidence, promoting factors and outcomes of such cases in Japan, where clopidogrel has not been approved, are described. METHODS AND RESULTS: Between September 2004 and March 2006, 725 patients underwent PCI with SES implantation and 679 patients (94%) were clinically followed up (median 271 days). There were 4 cases (0.6%) of LAST (at 60, 180, 215, and 508 days, respectively) after elective SES implantation resulting in myocardial infarction. Three cases occurred soon after antiplatelet therapy discontinuation 3 patients died after LAST events. The incidence of LAST was 0.6%. CONCLUSIONS: LAST is a rare complication, even after SES implantation, at least in patients with appropriate antiplatelet therapy. However, as it can lead to fatal complications, it must be taken into account, especially when antiplatelet therapy is discontinued.     

Sirolimus-eluting stent displaced fracture: case report and review of the literature

Drug-eluting stents have greatly reduced the risk of in-stent restenosis compared to bare metal stents by inhibiting neointimal growth. However, they may carry some long-term risks, especially the risk of late stent thrombosis. Recently, several cases of drug-eluting stent fracture have been also reported. The mechanisms, the diagnosis, the clinical implications and the management of this new complication are not well-known. We report the observation of a new case of displaced, sirolimus drug-eluting stent fracture. To our knowledge, this is the first reported case in France.     

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.     

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。     

The current status of stent placement in small coronary arteries < 3.0 mm in diameter

Data accrued to date indicate that stent placement in small vessels (< 3.0 mm reference diameter) suffers from the same disadvantage as other non-stent interventional devices in that the restenosis rate is significantly higher than observed following intervention involving large vessels. Randomized trials comparing systematic bare metal stenting versus conventional balloon angioplasty in the setting of small coronary arteries, however, show that the former therapeutic modality is probably superior to the latter treatment in its acute and mid-term angiographic and clinical results. Balloon angioplasty, even if performed optimally with resultant stent-like luminal outcome, yields a restenosis rate that is at best equivalent to that observed with stent placement. Stent performance is influenced profoundly by stent design and configuration. Tubular and corrugated stents are better than coil or meshwire stent design. Stents with thin struts appear to yield a lower restenosis rate compared with thick-strut stents. Coating the surface of stents with gold, phosphorylcholine or heparin does not appear to confer any additional long-term benefit compared with bare stainless-steel stents. On the other hand, impregnation of stents with anti-proliferative drugs, with or without a carrier polymer, has produced a significantly lower risk of restenosis, without an increase in stent thrombosis rate, compared with uncoated metal stents in multiple randomized trials. However, whether the clinico-anatomic benefits of drug-eluting stents can be sustained for several years and whether there are any long-term deleterious effects from the antiproliferative drug or carrier polymer remains unclear at this stage.