Nikolaos Kafkas MD PhD, firstname.lastname@example.org, Director, Department of Cardiology, General Hospital of Attica ‘’KAT’’, Athens, Greece
Stylianos Dragasis MD MSc, email@example.com, Cardiology Resident, Department of Cardiology, General Hospital of Attica ‘’KAT’’, Athens, Greece
Keywords: stent, thrombosis, coronary
Very late stent thrombosis (VLST) represents a rare, but potentially lethal complication, in the era of percutaneous coronary intervention. Its aetiology, pathogenesis and predictive factors have not yet been established due to its relatively low prevalence and multifactorial nature. In this review article, after presenting the current definitions on stent thrombosis, we focus on the contemporary data on VLST, for both bare-metal stents and drug-eluting stents. Possible pathophysiological mechanisms and predictive factors are also illustrated, with data drawn from several multicentre studies. Factors such as younger patients, smokers at the time of initial DES implantation, STEMI or the presence of thrombus at the time of initial DES implantation, overlapping stents, seem to represent independent predictors of VLST. Finally, there is a special reference on cases of VLST, studied with optical coherence tomography (OCT). OCT managed to identify the cause of VLST in over 97% of the cases in these studies, while some of the most common mechanisms of VLST in these patients were stent malapposition, neoatherosclerosis rupture, uncovered struts and stent underexpansion.
Percutaneous coronary intervention (PCI) with stent implantation has emerged as a revolutionary treatment of choice in coronary artery disease, since the early 1990s. The metallic nature of the coronary stents, along with other factors however, may act as a trigger for platelet aggregation and stent thrombosis. While the incidence of bare metal stent (BMS) thrombosis ranged from 10 to 15% in the early 1990s[1,2], today its estimated rate has fallen to approximately 1%, mainly due to technical improvements during PCI and the adoption of dual antiplatelet therapy with aspirin plus a thienopyridine as a standard combination therapy for the first few months after PCI[4,5]. The promising emergence of first-generation drug eluting stents (DES) raised some considerations regarding their long-term safety, due to reports of a relatively small, but not negligible number of late and very late stent thrombosis events[6-8]. In this review article, we will focus on the current knowledge on very late stent thrombosis (VLST), a potentially hazardous although not well understood complication, mainly due to its low prevalence and lack of randomized, large-scale clinical trials.
Definition of stent thrombosis
On 2007, the Academic Research Consortium (ARC) published an article regarding the definition of stent thrombosis, based on a) the timing of stent thrombosis and b) the evidence of stent thrombosis.
Based on the timing of stent thrombosis, it is characterized as “acute“, when it occurs during the first 24 hours after its initial implantation. Beyond the first 24 hours and until the first 30 days after implantation, it is characterized as “subacute“, between 30 days to 1 year it is characterized as “late” and after the first year as “very late” (Image 1).
Based on the evidence of stent thrombosis, it can be characterized as “definite“, “probable” or “possible“. Definite stent thrombosis requires the presence of an angiographic confirmation of stent thrombosis (the presence of a thrombus that originates in the stent or in the segment 5mm proximal or distal to the stent). It is associated with the presence of at least one of the following criteria within a 48-hour window: i) acute onset of ischaemic symptoms at rest, ii) new ischaemic electrocardiographic changes that suggest acute ischaemia or iii) typical rise and fall in cardiac biomarkers, iv) the presence of a pathological confirmation of stent thrombosis (evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy). The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion).
Probable stent thrombosis is defined as the presence of any unexplained death within the first 30 days after stent implantation, or in the presence of any MI related to documented acute ischaemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause, irrespective of the time after the index procedure.
Possible stent thrombosis is defined as any unexplained death from 30 days after intracoronary stenting until the end of follow-up. Table 1 summarizes the aforementioned definitions.
Data on very late stent thrombosis
Although no difference has been found between BMS and DES in terms of acute and subacute stent thrombosis incidents, there have been several reports about an increased number of very late stent thrombosis events with DES (especially first-generation DES), when compared with BMS[5,10]. Using the ARC definition, Spaulding et al. performed a pooled analysis of four randomized trials comparing sirolimus-eluting stents with BMS, during a 4-year follow-up period. In their analysis, stent thrombosis seemed to be more frequent in the bare-metal stent group during the first year (14, vs. 6 in the sirolimus-stent group). On the contrary, VLST incidents were more frequent in the sirolimus-stent group (23 vs. 14 in the bare-metal stent group). Furthermore, the authors mention that the survival rate for the subgroup of patients with diabetes was significantly lower in the sirolimus-stent group (87.8%, vs. 95.6% in the bare-metal–stent group; hazard ratio for death, 2.90; 95% CI, 1.38 to 6.10; P=0.008).
The presence of diabetes has been outlined as a key predictor of stent thrombosis, along with premature antiplatelet therapy discontinuation, renal failure, bifurcation lesions and low ejection fraction. However, Spaulding et al. did not identify diabetes as an independent factor of mortality, due to the large heterogeneity among the causes of death in the diabetes group. Furthermore, among patients with diabetes, there was a small excess of VLST as defined by the ARC in the sirolimus-stent group (11 patients, vs. 3 in the bare-metal–stent group). Owing to the small number of events, the authors concluded that these results should be interpreted with caution, as their analysis was extremely underpowered on the number of subjects needed to extrapolate a statistically significant conclusion and found no significant difference between the rates of death, myocardial infarction or stent thrombosis between DES and BMS during their 4-years follow-up.
Lagerqvist et al. evaluated 6033 with first generation DES and 13.738 patients with BMS in 2003 and 2004, using data from the Swedish Coronary Angiography and Angioplasty Registry. The outcome analysis covered a period of 3 years. During that period, the authors concluded that DES were associated with an increased rate of death, as compared with BMS, a trend that appeared only after the first six months post-implantation, pointing out the need for large, randomized trials to evaluate the long-term safety of DES. Two other studies in the same year (2007) by Mauri et al. and Stettler et al. exhibited similar risks of mortality and rate of stent thrombosis between DES and BMS, during a 4-year follow up. Mauri et al. used the ARC classification on several randomized trials, involving 878 patients treated with sirolimus-eluting stents, 1400 treated with paclitaxel-eluting stents, and 2267 treated with bare-metal stents. The incidence of definite or probable events occurring 1 to 4 years after implantation was 0.9% in the sirolimus-stent group versus 0.4% in the bare-metal-stent group and 0.9% in the paclitaxel-stent group versus 0.6% in the bare-metal-stent group. The authors conclude that there was no statistically significant difference between DES and BMS thrombosis, although there were recognizable limitations in the power to detect small differences in rates. Stettler et al. included 38 trials with 18.023 patients. The risk of late definite stent thrombosis (>30 days) was increased with paclitaxel-eluting stents (HR 2.11, 95% credibility interval 1.19-4.23, p=0.017 vs bare-metal stents; 1.85, 1.02-3.85, p=0.041 vs sirolimus-eluting stents). The reduction in target lesion revascularisation seen with drug-eluting stents compared with bare-metal stents was more pronounced with sirolimus-eluting stents than with paclitaxel-eluting stents (0.70, 0.56-0.84; p=0.0021). The authors concluded that sirolimus-eluting stents seem to be clinically better than bare-metal and paclitaxel-eluting stents, but the risk of mortality associated with BMS and DES were similar.
In the more recent prospective, multicenter randomized PAINT study, drug-eluting stents (either with paclitaxel or sirolimus) coated with biodegradable polymers did not exhibit an increase in stent thrombosis rates, when compared with the same bare-metal platform, during a 5-year follow-up. More recent studies on the use of second generation DES in primary PCI in patients suffering ST-elevation myocardial infarction (STEMI), when compared with BMS and first generation DES, further support their safety, due to the observed lower incidence of major cardiac events, myocardial infarction and target vessel revascularization, after 3 years (12 trials, 9.673 patients) and the reduction in mortality after 2 years of observation(11.181 consecutive patients with STEMI, use of DES vs BMS during 2008-2014). This benefit in long-term survival beyond 1 year was largely attributed to second-generation DES.
Predictive factors and possible mechanisms of very late stent thrombosis
The aetiology and predictive factors of VLST have not yet been established, due to its multifactorial nature and also due to its low prevalence even among large cohort studies[17,18,19]. Factors associated with stent thrombosis in general are diabetes mellitus[11,18,19], acute coronary syndrome (ACS)[18,19], low ventricular ejection fraction[11,18,19], renal failure[11,18,19], antiplatelet discontinuation or resistance[11,18,19], long or type C or bifurcation lesions[11,18,19], stent underexpansion or malapposition[18,19], residual dissection and others[11,18,19]. Do these factors play a role in the occurrence of VLST?
The DESERT (International Drug-Eluting Stent Event Registry of Thrombosis) study, the largest multicenter, observational, case-control study of late/very late thrombosis of DES, tried to give answers to that question. Patients included were 18 years of age and older who presented with late/very late definite ST (according to the ARC definition) confirmed by angiography or autopsy. 492 cases of late/very late definite DES thrombosis from 21 international sites (USA, Canada, Italy and Switzerland) were enrolled, matched and compared in a 1:1 fashion with controls without stent thrombosis (ST). The most important univariable clinical correlates for VLST included African Americans, younger patients, smoking at the time of initial DES implantation, multivessel disease, those treated with overlapping stents, longer total stented length or patients with SVG lesions. Moreover, the most important angiographic univariable correlates included LAD location, the presence of thrombus, final in-stent diameter stenosis and SVG lesion location. When the aforementioned factors were combined into 1 model, the independent correlates for development of late/very late ST were younger patients, smokers at the time of initial DES implantation, STEMI or the presence of thrombus by QCA (Quantitative Coronary Angiography) at the time of initial DES implantation, the number of diseased vessels, type C lesions, longer total stented length, and overlapping stents.
It is very interesting that the DESERT study did not identify ACS as an independent correlate of late/VLST, a finding indicative of a completely different pathogenesis of late/VLST, when compared with the pathogenesis of acute and subacute ST (for which ACS is one of the most predictive risk factors). It is also very interesting that the DESERT study results do not support the idea that a longer duration of dual antiplatelet therapy beyond 1 year will further reduce VLST events on its own (nearly 1/4 of VLST patients were receiving DAPT at the time of the event) and that alternative independent correlates should also be taken into consideration. There was also an important decrease in mortality in VLST patients, when compared with acute/subacute ST patients, although its prognostic impact may be underestimated, due to the fact that patients who did not survive to coronary angiography were not included. This decrease in mortality may be attributed to the extended time interval between the first DES implantation and the VLST event, or even to the gradual deterioration of the stenotic area, possibly leading to ischemic preconditioning and development of collaterals. Finally, it should be mentioned that 90% of the patients in the DESERT study had first-generation DES and the remaining 10% had second generation DES. As a result, the correlates presented in the study may not be the same for both categories.
Optical Coherence Tomography (OCT) use in patients who present with late/VLST may have a meaningful clinical impact as a tool, especially in STEMI patients. In the Mechanism Of Stent Thrombosis (MOST) study, VLST was strongly associated with the percentage of uncovered and malapposed stent struts and also with the malapposition distance between the vessel wall and the centre of the reflection via OCT. In another study, OCT was performed in 10 BMS-treated patients and the presence of neoatherosclerosis after stent implantation was identified as the causative factor of VLST in most of these lesions. Moreover, the causes of VLST in DES were more various and complicated.
The PESTO (Morphological Parameters Explaining Stent Thrombosis assessed by OCT) registry, represents the largest attempt until now, to study and explain the aetiology of ST via OCT. It is a prospective, multicenter, observational study which included patients from 29 French catheterization facilities from January 2013 to October 2014. 120 patients were included in the final analysis, 75% of whom suffered VLST. One of the key findings of this registry was that with the use of OCT the authors were able to identify a morphological abnormality associated with ST in 97% of the cases. Main causes of VLST were malapposition (late-acquired, due to vessel remodeling) and neoatherosclerosis rupture (more frequent in BMS-treated lesions), while malapposition (acute, due to inadequate stent expansion) and underexpansion were more prominent in acute/subacute ST. Stent malapposition (34,5%), neoatherosclerosis (27,6%), uncovered struts (12,1%) and stent underexpansion (6,9%) in descending order were also the leading associated findings of VLST patients in another study, irrespective of the type of DES (either early or newer-generation stents) used. Interestingly enough, a combination of these mechanisms within the same lesion was observed more frequently (55% of the cases) than the presence of a single cause (43% of the cases). OCT was once again able to identify the underlying cause in>98% of these cases. Moreover, the longitudinal extension of malapposed and uncovered struts was directly related to VLST and thrombus formation.
Compared with first generation DES, second generation cobalt-chromium everolimus-eluting stent, seem to demonstrate greater strut coverage, less inflammation and fibrin deposition and less late and VLST, in human autopsy analysis. On the other hand, neoatherosclerosis and fracture-related adverse events of these newer stents were comparable with the first generation DES.
VLST still remains a relatively rare, but potentially hazardous complication, with incompletely understood mechanisms and risk factors. Some of the potentially predictive factors include smokers at the time of stent implantation, presence of thrombus, multivessel disease, longitudinal extension of malapposed stents and uncovered struts, along with neoatherosclerosis. Mortality rates in patients suffering VLST seem to be lower than those in acute/subacute ST, probably due to ischemic preconditioning mechanisms and the longer time interval between first stent implantation and VLST. OCT represents a valuable tool in order to assess VLST mechanism and clinical correlates, while second generation cobalt-chromium everolimus-eluting stent seems to demonstrate less VLST events compared with first generation DES and BMS.
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