How To Repair Stent Thrombosis
Introduction
Coronary artery disease has had a tremendous impact on global wellness. Jacques Puel of Toulouse, France, implanted the get-go human coronary stent, a self-expanding stainless steel Wallstent, in 1986.1 Notwithstanding, the utilise of coronary endoprostheses did non become routine in the US until the 1990s, after the Palmaz-Schatz stent was canonical in 1994, heralding a new era in the treatment of coronary avenue disease.
The bare metallic stent (BMS) decreased restenosis and astute occlusion rates when compared with balloon angioplasty. With the subsequent increase in employ of stents during percutaneous coronary intervention (PCI), the focus of treatment evolved from procedural success to prevention of in-stent restenosis. The drug-eluting stent (DES) was added to the armamentarium in clinical practice to reduce BMS restenosis rates. Nevertheless, the initial enthusiasm was tempered by concerns regarding an increased gamble of late stent thrombosis (LST) and very late stent thrombosis (VLST).
Stent thrombosis is a serious outcome resulting from occlusion of the endoprosthetic lumen by thrombus and is an entity with a wide chronological spectrum that can occur anywhere from intraprocedurally to years after implantation. Large volumes of literature have been devoted to stent thrombosis, with research that spans the entire spectrum of epidemiologic exploration. Many of the larger trials accept resulted in bear witness that we at present accept for granted in our daily practice, while others have provided the impetus to create newer and improved stents.
With the wealth of literature available, deconstructing the basic tenets of stent thrombosis can be somewhat daunting. This review summarizes the salient features of this status, with a focus on the pertinent literature that has sculpted our current insights and understanding regarding stent thrombosis.
Classification of stent thrombosis
The Academic Inquiry Consortium2 (ARC) is an informal collaboration between academic inquiry organizations in the U.s. and Europe. In 2006, the ARC held two meetings with the master goal of creating consensus cease point definitions for DES evaluations. Their aim was to establish consistent definitions across which trials of DES could be compared.
The ARC therefore proposed two distinct classifications2 of stent thrombosis incorporating both levels of bear witness also equally timing of events, further stratified to define varying degrees of certainty and to imply different pathophysiological mechanisms, respectively. These classifications are summarized in Tables i and 2.
  | Tabular array 1 Academic Research Consortium classification of stent thrombosis based on timing of events |
 | Tabular array 2 "Trilevel of Certainty" classification of stent thrombosis proposed by the Academic Research Consortium |
Four years later, a written report performed by Cutlip et al3 was published. This written report recognized that although the ARC criteria for nomenclature of stent thrombosis were widely accustomed, there was no validation of their sensitivity and specificity confronting autopsy data. Hence an dissection registry of 139 subjects with prior coronary stenting was subjected to detailed histopathological analysis to assess for stent thrombosis.
The results of the written report by Cutlip et al showed that specificity was high for definite (99%) and definite plus probable (83%) criteria, just the sensitivity was poor at 18% and 51%, respectively. This grouping concluded that restricting ARC definitions to definite or definite plus probable stent thrombosis had resulted in substantial underreporting of truthful positive cases that were confirmed in their selected dissection sample.
Rates of stent thrombosis
Stent thrombosis is i of the most serious complications of PCI, so its incidence and prevalence has been followed very closely. The rates of stent thrombosis have also paralleled the development of improved stents and antiplatelet agents. Although there is much debate about whether randomized controlled trials accurately reverberate "real-globe" information applicative in clinical practice, there is abundant registry data and large observational studies to supplement the more traditional clinical trials.
The bulk of stent thrombosis occurs within the first 30 days after PCI. In general clinical do, the expected rate of early on stent thrombosis is ~1%, and beyond 30 days is 0.2%–0.half dozen% per year.four For first-generation DES, LST occurs steadily at an almanac rate of 0.iv%–0.6% for upwards to iv years.v The incidence of LST and VLST in patients with BMS has been poorly characterized. A retrospective analysis of 4,503 patients treated with at least one BMS indicated the cumulative incidence of stent thrombosis at 10 years to be 2%.6 Tabular array 3 depicts the rates of stent thrombosis by stent blazon as well as clinical presentation of coronary avenue disease.
 | Tabular array 3 Risk of early stent thrombosis according to clinical presentation |
The incidence of definite or probable stent thrombosis also differs by the type of stent. In a meta-analysis of randomized controlled trials of DES,8 the incidence was 0.1% versus 1.0% in the sirolimus-eluting stent (SES) group and 0.4% versus 0.3% in the paclitaxel-eluting stent (PES) group, respectively, equally compared with the respective BMS group. Most alarmingly however, remains the fact that acute stent thrombosis has been associated with mortality rates of 20%–45%nine and myocardial infarction rates of 50%–lxx%.nine Furthermore, approximately 20% of patients who accept stent thrombosis volition have a recurrent episode within 2 years.10
Pathophysiology of stent thrombosis
As with whatever course of vascular injury, the endothelium plays a pivotal role in the pathogenesis of stent thrombosis. Exposure of the vessel wall to an offending agent results in a stereotypical response of neointimal germination resulting in intimal thickening.xi This occurs primarily by smooth muscle proliferation and a multitude of histochemical reactions. Jeong et al studied the furnishings of crush injury with and without coronary stenting in porcine models. The thrombi formed in both groups were highly platelet-rich; even so, stent placement at injury sites enhanced platelet degradation over beat out injury alone.12
Whether animal models of intervention-related arterial thromboses can be extrapolated to humans has been a matter of some fence. Grewe et althirteen analyzed stented vessel segments in 21 autopsy cases with coronary stents implanted from 25 hours to 340 days earlier death. They noted that in the initial phase, stents were covered by a thin multilayered thrombus, where smooth muscle cells were found as the main cellular component of the neointimal tissue. In vi weeks, polish musculus cells formed on the vessel surface, and complete re-endothelialization was first noted 12 weeks after stenting. More recently, Finn et alxiv performed an autopsy registry written report, aiming to identify predictors of LST after DES placement. They showed that the external rubberband lamina, plaque area, and stent area were significantly greater in lesions with mural thrombus; however, neointimal growth was less when compared with patent DES lesions.
VLST, defined as stent thrombosis occurring one year later on stent implantation, is a distinct entity associated with DES. VLST is proposed to have a multifactorial etiology and in a majority of cases is likely associated with an abnormal vascular response, such as hypersensitivity reaction, excessive fibrin deposit, or neoatherosclerosis.15 Nishihira et al reported the development of organized thrombus in patients with VLST. The similar composition of tardily DES thrombi and de novo coronary thrombi suggests like mechanisms of symptomatic thrombus formation in patients with DES implantation and de novo acute myocardial infarction.16
VLST is also associated with histopathological signs of inflammation and bear witness of vessel remodeling on intravascular ultrasound. Cook et al17 performed an intravascular ultrasound-histopathological correlation, noting that the amount of eosinophils were three times higher in thrombus aspirates from patients with VLST compared with those having other causes of myocardial infarction.
Neoatherosclerosis, or atherosclerosis within the neointima, has been described as peristrut foamy macrophage clusters with or without calcification, thin-cap fibroatheromas, and plaque ruptures without communication with the underlying native atherosclerotic plaque.15 Nakazawa et al reviewed registry data from 299 postal service-PCI autopsies and found that the incidence of neoatherosclerosis was significantly (P<0.001) greater in DES lesions (31%) than in BMS lesions (xvi%).18 Furthermore, there are data to support the assertion that neoatherosclerosis with neointimal rupture is some other of import cause of delayed DES thrombosis.19
Factors implicated in stent thrombosis
Stent characteristics
Ane of the almost commonly incriminated factors predisposing to stent thrombosis is the type of coronary stent implanted. The standard teaching that DES are more prone to stent thrombosis while BMS take higher in-stent restenosis rates, although largely truthful, is overly simplistic when recognizing that at that place is a great degree of crossover in the pathological mechanisms responsible for both entities. Delayed arterial healing following DES implantation20 is characterized by a lack of complete re-endothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at dissection.21
DES are impregnated with cytotoxic drugs which act locally to inhibit neointimal hyperplasia and subsequently reduce in-stent restenosis. The stents are coated with polymers that are either biodegradable or durable, to dull down release of the active drug. Polymer-free stents coated with sirolimus resulted in less robust neointimal suppression but markedly improved arterial healing compared with the Cypher® DES in the rabbit model.22
Overall, the rates of stent thrombosis are highest in first-generation DES,23 such as the SES (Cipher®) and Human foot (Taxus®). Stent thrombosis with BMS normally occurs within the first 30 days of implantation, when these stents are prone to thrombus germination. Conversely, with first-generation DES, the greatest concerns are LST and VLST.
Second-generation DES, such as the zotarolimus-eluting stent (Endeavor®) and everolimus-eluting stents (Xience V®), take demonstrated a decreased take a chance of LST and VLST. In contempo work published past Tada et al from unselected patients in a large German language cohort,23 the cumulative incidence of definite stent thrombosis at 3 years was i.5% with the BMS, 2.2% with the kickoff-generation DES, and ane.0% with the second-generation DES. On multivariate analysis, the first-generation DES showed a significantly higher risk of stent thrombosis than the BMS, while 2nd-generation DES were associated with a similar take chances of stent thrombosis when compared with the BMS.
Stone et al24 performed a pooled analysis of information from ix double-blind trials in which patients were randomly assigned to receive a BMS or a first-generation DES. Although the four-yr rates of stent thrombosis were higher in the DES groups as compared with the BMS groups, the results were non statistically significant. However, later on one yr, these higher rates of stent thrombosis in the kickoff-generation DES groups did achieve statistical significance, once more alluding to the fact that the post implantation timing of stent thrombosis is disquisitional to understanding the part of device-related risk factors for this entity.
Ane of the factors that appears to be concerning with respect to the higher rates of stent thrombosis seen in DES is a localized hypersensitivity reaction to the polymer coatings. In porcine models, a high prevalence of diffuse granulomatous inflammation was noted with the SES as compared with the BMS, persisting at 180 days and associated with extensive remodeling of the avenue. The Human foot displayed persistent parastrut fibrin deposition within the neointima and medial smooth muscle cell death at a higher rate than was noted with the SES.25
Stent geometry, material, and coatings tin affect thrombogenicity. Kolandaivelu et al used ex vivo studies to demonstrate that thick-strutted (162 μm) stents were 1.5-fold more than thrombogenic than otherwise identical thin-strutted (81 μm) devices (P<0.001), commensurate with a 1.6-fold greater thrombus coverage 3 days afterwards implantation in porcine coronary arteries (P=0.004).26 Tada et al27 used optical coherence tomography in patients to determine that thin-strut DES were associated with improved rates of stent strut coverage as compared with thick-strut DES at 6–viii months follow-up. Table four shows sure fabric characteristics of DES and their propensity toward stent thrombosis when compared with BMS.
Biodegradable polymer-coated stents have been proposed as a promising strategy to enhance biocompatibility and meliorate the delayed healing in the vessel.28 These stents use bioabsorbable polymers that dissolve within a specified time catamenia, with the residual metal scaffolding seemingly gaining a safety profile similar to a BMS thereafter. A meta-analysis past Bangalore et al found that biodegradable polymer DES were superior to the PES but inferior to cobalt chromium everolimus-eluting stents with regard to long-term safety, defined in terms of definite stent thrombosis.29 Yin et al reported that biodegradable polymer DES were as condom as standard BMS with regard to death, stent thrombosis, and myocardial infarction.28
 | Table 4 Select material characteristics of drug-eluting stents |
Finally, in an attempt to minimize the long-term risks associated with coronary stent implantation including LST, a bioabsorbable everolimus-eluting scaffold known as the Blot stent has been studied through several years of follow-upwardly. Serruys et al31 used multiple imaging modalities to report that, 2 years after implantation, the stent was bioabsorbed, with vasomotion restored to the arterial segment. Farther, the Absorb stent was clinically safe, suggesting freedom from late thrombosis, a finding that remained consistent in the 4-twelvemonth follow-up results of the Absorb trial.32
Selection of antiplatelet agents and optimal duration of dual antiplatelet therapy
Post-PCI drug therapy is a delicate remainder of preventing thrombotic events while minimizing the hemorrhagic adventure that these drugs pose. Some of the earliest information came from Leon et al in 1998,33 who randomized patients into three treatment groups after successful stent implantation. The main finding was that a combination of aspirin and ticlopidine was superior to either a combination of warfarin and aspirin or aspirin lone in the prevention of stent thrombosis in these patients.
In 2001, Mehta et al published the results of the PCI-CURE trial,34 which demonstrated that long-term administration of clopidogrel in addition to aspirin afterwards PCI was associated with a lower rate of cardiovascular decease, myocardial infarction, or whatever revascularization, with an overall reduction in cardiovascular death or myocardial infarction of 31%. Notably, at follow-up, they showed no significant difference in major bleeding between the groups.
The landmark clinical trial that propelled prasugrel, a novel thienopyridine, to the forefront of interventional cardiology was TRITON-TIMI 38,35 in which 13,608 patients undergoing PCI were given either prasugrel or clopidogrel (including loading doses). The prasugrel grouping had lower rates of myocardial infarction, urgent target vessel revascularization, and stent thrombosis (two.4% versus 1.1%; P<0.001). However, major bleeding, including life-threatening haemorrhage, was observed in 2.4% of patients receiving prasugrel and in ane.viii% of patients receiving clopidogrel. Subsequently in 2009, the results of the multicenter randomized PLATO trial were published, exploring the use of ticagrelor, an oral, reversible, directly-acting inhibitor of the adenosine diphosphate receptor, P2Y12.36 In total, 18,624 patients with acute coronary syndrome were given loading and maintenance doses of either ticagrelor or clopidogrel. After ane yr, the principal end point, a composite of expiry from vascular causes, myocardial infarction, or stroke, had occurred in 9.8% of patients receiving ticagrelor every bit compared with 11.7% of those receiving clopidogrel, a finding of statistical significance. While no significant difference in overall rates of major bleeding were noted, ticagrelor was associated with a higher charge per unit of major haemorrhage not related to coronary artery bypass grafting, including more instances of fatal intracranial bleeding. Further, dyspnea was reported in 13.8% of the ticagrelor grouping versus seven.8% of the clopidogrel grouping, a pregnant finding that has become well known in the adverse effect profile of ticagrelor today. Amidst patients who received a stent during the study, the rate of definite stent thrombosis was lower in the ticagrelor group than in the clopidogrel group (1.3% versus 1.9%; P=0.009), thus clearly showing a do good of using ticagrelor in appropriately selected patients with astute coronary syndromes.
Resistance to antiplatelet agents has e'er been a very serious issue, but gained prominence with the initiation of DES utilise. In a prospective study by Matetzky et al,37 60 patients with ST segment myocardial infarction (STEMI) mail PCI were given clopidogrel and the pct reduction of adenosine diphosphate-induced platelet aggregation was used to split up them into four subgroups. 40 percentage of patients in the group with the highest clopidogrel resistance had a recurrent cardiovascular event during 6 months of follow-up. In registry data, patients with astute myocardial infarction who were receiving clopidogrel and carrying cytochrome P450 2C19 loss-of-role alleles had a higher rate of subsequent cardiovascular events, including stent thrombosis.38,39 This outcome was particularly marked among patients undergoing PCI.
In addition to assessing the all-time antiplatelet regimen, a great deal of effort has been spent on ascertaining the optimal duration of dual antiplatelet therapy after PCI. Steinhubl et altwoscore showed that long-term (one-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events in patients who underwent PCI, albeit with a nonsignificant trend of increased haemorrhage.
A prospective observational accomplice study by Iakovou et al41 looked at rates of stent thrombosis after first-generation DES implantation. Aspirin was connected indefinitely and clopidogrel or ticlopidine for at to the lowest degree three months afterwards implantation of a SES and for at least 6 months after implantation of a Foot. In the patients who discontinued antiplatelet therapy prematurely, a statistically significant 29% adult stent thrombosis. Another DES cohort study by Daemen et al showed that dual antiplatelet therapy was being taken by 87% of patients with early on stent thrombosis and 23% of patients with LST.42 Kuchulakanti et al showed that the incidence of discontinuation of clopidogrel therapy was significantly higher in patients with stent thrombosis compared with those without stent thrombosis (36.8% versus ten.7%; P<0.001).43
Amidst the long-standing debate regarding the benefit of longer versus shorter dual antiplatelet regimens, came the recently published results of the Dual Antiplatelet Therapy (DAPT) written report,44 a multicenter, randomized, placebo-controlled trial. The trial assessed 9961 patients who had undergone DES placement and were on aspirin. These patients were treated with 12 months of a thienopyridine drug (clopidogrel or prasugrel), and were so randomly assigned to continue receiving the thienopyridine or to receive a placebo for another 18 months.
Continued handling with thienopyridines, as compared with placebo, reduced the rates of ST (0.iv% vs i.iv%; P<0.001), and major agin cardiovascular and cerebrovascular events (four.3% vs. 5.9%; P<0.001). Even so, the rate of moderate or severe bleeding was increased with connected thienopyridine treatment (2.v% vs 1.6%, P=0.001). An interesting observation made past the investigators for both groups, was that an elevated chance of ST and MI existed during the first 3 months later discontinuing the thienopyridine handling.
Angioplasty-related factors
At that place are expansive data on the procedural factors that increase the risk for stent thrombosis. These studies take been performed in multiple different means, including the use of intravascular ultrasound and optical coherence tomography as well equally apply of autopsies and histopathologic data. A number of clear and specific angiographic findings have been associated with higher rates of stent thrombosis. Probably the best known of these is incomplete stent strut coverage, which has been constitute to be a directly correlate of poor endothelialization of the implanted stent.14 Effigy 1 is a representation of incomplete stent strut coverage every bit a consequence of inadequate endothelial coverage.
 | Figure ane Incomplete stent strut coverage. |
Deployment-associated factors, like underexpansion and malaposition17 of the stent have likewise been implicated, particularly since they can exist easily discovered with sophisticated intracoronary imaging techniques. Fujii et al45 used intravascular ultrasound to report that minimum stent cross-sectional expanse and stent expansion were significantly smaller in their stent thrombosis group than in matched control patients, in their study using SES. A pocket-size observational study by Alfonso et al,46 also using intravascular ultrasound, showed evidence of severe stent underexpansion in most patients, and no patient in that study fulfilled the standard criteria for optimal stent implantation.
Although performed several years ago, a meta-assay by Cutlip et al47 showed that the most significant predictors of stent thrombosis included persistent dissection after stenting, longer stent length, and concluding minimal luminal diameter within the stent. In an attempt to written report the etiology of VLST, Cook et al48 too showed that, compared with DES controls, patients with VLST had longer lesions and stents, more stents per lesion, and stent overlap. This was once again demonstrated by the Dutch Stent Thrombosis Registry where, in addition to stent length, multiple stents were shown to be associated with higher rates of stent thrombosis.49
Finally, in that location are data to suggest that a singled-out intimal histopathologic response occurs afterward DES placement in astute coronary syndromes that may predispose to stent thrombosis. This is especially apparent in patients with STEMI,50 who were shown to have a higher incidence of incomplete stent apposition and uncovered struts after primary PCI. Oyabu et al51 used angioscopy to analyze the underlying vessel characteristics after DES and BMS implantation and noted that the thrombogenic potential in DES-implanted lesions may be sustained by inhibition of neointima formation over thrombogenic plaques. Holmes et al9 reiterated that DES struts embedded in the necrotic lipid cadre demonstrate incomplete healing and reduced neointimal coverage compared with struts imbedded in next stable fibrocalcific plaque.
In summary, the procedural factors that predispose to ST were largely influenced by the advent of DES and subsequent evolution of a practice that aimed to treat the unabridged coronary lesion. This dictum led to the use of longer stents52 and resulted in technical difficulties associated with their deployment, such every bit incomplete stent apposition47 and resultant shear stress.45
Lesion-related factors
It remains fairly consistent beyond much of the published literature, that over and above the lesion characteristics themselves, it is the extent and vigil of pre-existing coronary disease that direct correlates with the risk of stent thrombosis. Patients with acute coronary syndrome are at higher hazard of early stent thrombosis and LST with either BMS or DES.53 A potential reason for this has been ascribed to the presence of ruptured plaques and necrotic lipid cores, which are seen particularly in patients with STEMI.15,54
In that location are also certain specific lesion characteristics, mayhap as well as the location of the lesion itself, which are associated with a predilection for stent thrombosis. Known factors associated with stent thrombosis are lesion length, location, and diameter. Complex lesions, including chronic total occlusions and bifurcation lesions, likewise equally lesions that occur in vein grafts from previous bypass surgeries, are associated with an increased risk of stent thrombosis.55
Cohort studies and big volume registry data have shown that patients with angiographically confirmed stent thrombosis accept a college incidence of lesions in the left inductive descending artery.43,50,56 Registry information obtained from 20 centers in Espana also demonstrated that the occurrence of stent thrombosis in longer lesions was statistically significant.56 Iakovu et al showed that for subacute thrombosis, stent length was a predictor; for each i mm increase in length, there was a ane.03 times greater hazard of thrombosis.41 Ong et al57 showed that bifurcation stenting in the setting of acute myocardial infarction was an independent risk factor for angiographic stent thrombosis in their entire study population.
Medical comorbidities
While much has been said nigh devices and medications, the underlying medical weather condition that patients suffer with can play a huge role in the occurrence of stent thrombosis. The heralding presentation of the events that warrant PCI clearly influences the rates of stent thrombosis, with STEMI patients posing a college risk than patients with stable coronary artery disease.54,56
There are also various underlying disease processes associated with an increased incidence of stent thrombosis that have emerged from subgroup analysis data. Stop-stage renal disease41,43 and diabetes mellitusfive,42 have been identified equally major culprits for the occurrence of stent thrombosis. Diabetics were found to have double the rates of stent thrombosis when compared with nondiabetics, with insulin dependence existence an associated take a chance factor.58
Registry data has been very useful in delineating the medical weather condition that are related to stent thrombosis. The Dutch Stent Thrombosis Registry49 cited present malignancy, ejection fraction <30%, and younger age as risks for stent thrombosis. Similarly, the RESTART trial from Japan59 differentiated the predictors for VLST from those for LST, including hemodialysis, heart failure, insulin-dependent diabetes mellitus, and low body mass index in the sometime category. A very large multicenter registry from Espana56 reported that independent predictors for subacute stent thrombosis, analyzed in a subgroup of 14,120 cases, were diabetes, renal failure, acute coronary syndrome, and STEMI. Older age and ejection fraction <45% were contained predictors for mortality as well.
Finally, some fairly robust data comes from the HORIZONS-AMI trial,60 which enrolled 3,602 STEMI patients undergoing principal PCI. Patients with stent thrombosis at any fourth dimension bespeak within the 2-year follow-upwardly period were analyzed and compared with patients without stent thrombosis. Patients with stent thrombosis were noted to exist younger and to accept higher rates of insulin-treated diabetes mellitus, current smoking, prior myocardial infarction, prior PCI, and a higher baseline platelet count.
Patient-related factors
While much has been written near the office of dual antiplatelet therapy in the prevention of stent thrombosis, there are certain ancillary issues associated with the employ of these medications that are non routinely addressed in the literature. Probably the most important of these is the office of patient compliance. Given that most patients are on a regimen of multiple medications, it is crucial that they recognize the importance of continuing dual antiplatelet therapy for the prescribed period of fourth dimension. In-hospital teaching, with accent on the life-threatening consequences of prematurely stopping these drugs is imperative prior to discharge, every bit is a clear agreement of dosing regimens.
Similarly, the ease of procuring medications is paramount. Lack of acceptable refills, access to pharmacies, and availability of physicians to replenish supplies are some of the triggers for poor compliance in post-PCI patients. This has assumed a new level of significance equally we run into newer antiplatelet agents routinely prescribed. Information technology is ideal to ensure, prior to discharge, that the patient's pharmacy carries the intended medication and that the patient can afford the toll of therapy or has admission to subsidized medications, especially when the duration of dual antiplatelet therapy is a year or longer.
Lastly, with longer dual antiplatelet therapy regimens, awareness about any planned and necessary procedures in the near future should be factored into the original pick of stent. Educating and specifically informing the patient and family virtually the necessity to discuss these types of decisions with their cardiologist tin assist to circumvent such issues and forestall catastrophic outcomes. Table v summarizes the risk factors that accept been associated with increased rates of stent thrombosis.
 | Table v Take a chance factors associated with higher rates of stent thrombosis |
Stent thrombosis: the literature at a glance
While there are vast expanses of literature devoted to coronary stents and their complications, randomized controlled trials looking primarily at stent thrombosis are fewer in number. Much of the information has been extrapolated from larger clinical trials of DES and supplemented by large observational studies and registry data. Some other important stardom in the trials related to stent thrombosis are the patient populations that were included in the studies. While many trials used low-chance patients with stable coronary avenue illness, there are significantly fewer trials that looked at patients with acute coronary syndromes, in particular patients with STEMI, who we at present know are at higher risk for stent thrombosis. Below we detail the findings from some of the larger clinical trials, categorized by type of trial and patient population. Tabular array 6 summarizes pertinent information from the major registries and randomized controlled trials that accept evaluated the use of DES in varying presentations of coronary artery disease.
 | Table six Major clinical trials from which data for stent thrombosis have been derived |
Randomized controlled trials
In 2002, Morice et al61 performed a randomized double-blind trial in 238 patients to compare the SES with standard BMS for revascularization of single primary lesions in native coronary arteries. At 6 months, the degree of neointimal proliferation, manifested equally mean tardily luminal loss, was significantly lower in the SES group than in the standard stent grouping (P<0.001). There were no episodes of stent thrombosis seen during 1 year of follow-up.
The original SIRIUS trial looked at SES compared with BMS in patients with de novo native coronary artery lesions and initially followed them for ane year.62 At one year, in that location was no meaning difference in rates of stent thrombosis between the two groups. Further, at five-year follow-upward, no significant differences were observed in the cumulative incidence of stent thrombosis for sirolimus versus control patients with either protocol-derived (ane.0% versus 0.eight%, respectively) or ARC definitions (3.9% versus 4.two%).63
Everolimus is a semisynthetic immunosuppressant that is an analog of rapamycin. It acts by blocking the stimulatory effects of growth factors and cytokines released after vascular injury and thereby inhibits smooth muscle cell proliferation.64 The Futurity-I study65 was the first human evaluation of the everolimus-eluting stent for the treatment of noncomplex coronary lesions. This study demonstrated significantly lower in-stent late lumen loss and in-segment diameter stenoses when compared with the BMS. The first-in-man randomized controlled trial assessing the safety and efficacy of the everolimus-eluting stent was SPIRIT Kickoff,66 which also institute significant suppression of neointimal growth at half-dozen months when compared with the BMS. Subsequently, the SPIRIT Four67 and COMPARE68 trials compared the everolimus-eluting stent with the Pes in patients with stable coronary avenue disease, and both showed a statistically pregnant lowering in the rate of stent thrombosis with second-generation DES.
Large-scale registry information
The Dutch Stent Thrombosis Registry49 was aimed at comprehensively identifying predictors of stent thrombosis. Of 21,009 registry patients treated with a BMS or a DES, 2.1% presented with definite stent thrombosis. A total of 140 stent thromboses were astute, 180 were subacute, 58 were late, and 59 were very late.
Another large-scale, multicenter Spanish registry56 enrolled 23,500 patients treated with DES, in whom definite stent thrombosis developed in 301 patients, with 24 being acute, 125 being subacute, and 152 being late. The cumulative incidence of stent thrombosis after DES implantation was 2% at three years, but no differences were institute betwixt types of stent.
Clinical trials looking at patients with STEMI/astute coronary syndrome
Stone et al76 randomly assigned iii,006 patients (in a 3:i ratio) with STEMI to receive a Foot or a BMS. The two master end points of the written report were the 12-calendar month rates of target vessel revascularization for ischemia and a composite rubber outcome mensurate of death, reinfarction, stroke, or stent thrombosis (powered for noninferiority). Patients who received the PES had significantly lower 12-calendar month rates of ischemia-driven target vessel revascularization and noninferior rates for the composite safety end points. Nonetheless, both groups had similar 12-month rates of expiry (iii.5% and 3.5%, respectively; P=0.98) and stent thrombosis (3.2% and three.4%, respectively; P=0.77).
Mauri et al77 conducted an observational study in an unselected cohort of vii,217 patients with astute myocardial infarction undergoing PCI. Propensity score matching was used to remainder the 2 groups of patients who received a DES versus a BMS. While there was a meaning decrease in mortality in the group receiving DES, the difference in ii-twelvemonth reinfarction rates was not statistically significant between the 2 groups other than in patients with not-STEMI. Although stent thrombosis was not specifically looked at equally an outcome in this written report, the lack of significant reinfarction at follow-up in the STEMI groups provides some useful information.
The prospective randomized ACUITY trial75 performed coronary angiographic analyses on 3,405 patients with moderate-risk and loftier-risk acute coronary syndrome in whom stents were implanted. Inside 30 days, definite or likely stent thrombosis occurred in 48 patients (ane.4%). Stent thrombosis rates were not significantly different in patients treated with BMS compared with DES (1.4% versus 1.4%; P=1.00).
Very recently, Sarno et al published results concerning 34,147 patients enrolled in the SCAAR study.78 Each of these patients presented with STEMI and was treated by PCI with either a new-generation DES (Endeavor Resolute, Xience V or Xience Prime, Promus or Promus Chemical element), an older-generation DES (Nix, Cypher Select, Taxus Express, Taxus Liberté, and Endeavor), or a BMS. The written report reported a significantly lower chance of stent thrombosis during the first twelvemonth later PCI with both the new-generation and older-generation DES as compared with the BMS, just a higher take a chance of VLST, occurring upwardly to three years afterwards in the older-generation DES group as compared with the BMS group. At that place was a like risk of VLST in the new-generation DES and BMS groups. The investigators surmised that STEMI patients could have an increased take a chance of stent thrombosis due to increased platelet activeness and delayed healing at the culprit site.78
Intraprocedural stent thrombosis
Thrombus germination during stent implantation, defined as intraprocedural stent thrombosis (IPST), was a rare event in the BMS era.79 Some of the earliest published information looking at IPST during beginning-generation DES implantation comes from Chieffo et al,79 who studied 670 patients with i,362 lesions treated with the Zippo DES. 5 of these patients had IPST, defined every bit an angiographically confirmed intraluminal filling defect within the stent resulting in TIMI grade 0 or 1 anterograde flow. Notably, all of these patients had been pretreated with thienopyridines. Notwithstanding, none of them received elective glycoprotein IIb/IIIa inhibitors, a do that was relatively routine at that time. Further, of all the variables studied, only the full stent length per vessel had a statistically pregnant association with the occurrence of IPST. Similar findings were published after analysis of the RECIPE study past Biondi-Zoccai et al, seeking to validate the predictors of IPST after DES implantation.80 Their research showed that IPST occurred in 0.5% of their i,320 study subjects and was predicted by number and total length of implanted stents, baseline minimal lumen diameter, and use of glycoprotein IIb/IIIa inhibitors.
Xu et al performed a retrospective study of i,901 patients with astute coronary syndrome who underwent primary PCI.81 Patients with IPST demonstrated involvement of significantly more bifurcation lesions and had more thrombus brunt at baseline. The IPST group as well had more major adverse cardiac events at their 30-day and one-year follow-ups. A very similarly designed but much larger written report conducted by Brener et al examined angiograms from 6,591 patients enrolled in ii large-scale clinical trials, and 0.7% of them were noted to have IPST.82 The occurrence of IPST in their data was associated with STEMI at presentation, a high white blood jail cell count, handling of thrombotic and bifurcation lesions, bivalirudin monotherapy, bail-out use of IIb/IIIa inhibitors, and BMS implantation. The number of major adverse ischemic events was markedly higher in patients with IPST versus those without IPST, including bloodshed at 30 days and one year.
Généreux et al performed a frame-by-frame angiographic analysis in 10,939 patients enrolled in the CHAMPION PHOENIX trial that sought to compare clopidogrel with cangrelor, a potent, reversible, intravenous, straight-acting platelet adenosine diphosphate P2Y12 inhibitor.83 IPST developed in 0.viii% of the total sample size, although the rate was significantly lower in the group treated with cangrelor. IPST was associated with a marked increase in composite ischemia or new-onset out-of-laboratory stent thrombosis at 48 hours and at thirty days.
Future directions and strategies for prevention
Stent thrombosis is a status that has evolved considerably forth with the evolution of PCI, with tremendous volumes of published literature available. As newer and more advanced stents accept arrived at catheterization laboratories, the incidence and presentation of this entity has transformed dramatically over many years, although much withal remains to exist discovered. Amalgamating the evidence garnered from structured clinical trials, real-world information, and anecdotal testify, the impetus lies in moving frontwards to design a structured multilevel solution to this ubiquitous problem.
Just as the etiological factors predisposing to stent thrombosis take been categorized under many subheadings, information technology may be prudent to practice the same when evaluating potentially preventive strategies as well. At that place is accelerated industry-driven momentum to invent newer and meliorate stents, with respect to both design and drug elution. To this end, the 4-yr follow-up results of the Absorb trial32 looking at ischemia-driven major adverse cardiac events after implantation of a bioresorbable everolimus-eluting scaffold in patients with de novo coronary artery disease were promising, with no stent thrombosis reported in these patients.
Simultaneously, pharmaceutical companies are striving to refine and redevelop novel antiplatelet agents to improve upon the adverse result profiles of currently prescribed medications. Given that some duration of dual antiplatelet therapy is essential after whatsoever stent implantation, the search is underway for a safety still strong antiplatelet agent with a lower bleeding risk or some degree of clinically relevant reversibility. While ticagrelor has been establish to be partly reversible in vitro by administration of uninhibited platelets,84 the clinical applicability of this finding in patients with major haemorrhage remains uncertain.
Two novel and reversible antiplatelet agents, cangrelor and elinogrel, are available in intravenous course (elinogrel is also available in an oral form). Contempo trials have tested these agents against clopidogrel regarding efficacy and safety outcomes. While resulting in fewer bleeding events during middle surgery, these reversible antiplatelet agents, similar ticagrelor, carry the risk of potential autoimmune reactions manifesting as dyspnea, which is a potential barrier to their widespread clinical use.85,86 Animal studies have also yielded promising results, with preliminary information showing that P2Y1 receptor antagonists (equally well as SAR216471, a new P2Y12 inhibitor) have antithrombotic furnishings with a relatively low bleeding risk.87,88
Every bit each new generation of stents is studied, a better understanding of lesion-associated factors and procedural pitfalls will as well enable interventional cardiologists and fellows to refine their techniques, with the assist of imaging such every bit intravascular ultrasound and optical coherence tomography in cases deemed to be at higher take a chance for stent thrombosis. Development of standardized guidelines regarding which subsets of patients and lesions should be routinely imaged, may decrease some of the arbitrariness with which post-PCI imaging is used and ensure the best possible outcome in all cases.
Even so, it is clearly evident that above and beyond whatever kind of device or procedural risk factor for stent thrombosis, the near unpredictable variable is the patient. Baseline medical weather condition, planned surgeries, bleeding issues, resistance to antiplatelet agents, and social factors that influence compliance with medication are merely some of the stumbling blocks that facilitate occurrence of stent thrombosis. Ensuring advisable screening of patients prior to PCI, admittedly challenging in the STEMI population, which poses one of the highest thrombotic risks, may mitigate these issues to some extent. Effigy 2 highlights various strategies that may be used to diminish the gamble of stent thrombosis.
 | Figure two Strategies to prevent stent thrombosis. |
Dangas et al looked at the validity of a adventure score to predict stent thrombosis using data from 2 large randomized controlled trials with a total of 6,139 patients undergoing PCI for acute coronary syndrome.89 The study population was divided into two cohorts, one for hazard score development and the other for validation. The score incorporated clinical, angiographic, and procedural variables, and studied rates of stent thrombosis in low-risk, intermediate-risk, and high-gamble categories. While the scoring arrangement may still prove to be a useful gamble stratification tool, a subsequent editorial comment past Waksman and Barbash90 highlighted that the study primarily looked at kickoff-generation DES and did non study the effects of well-known predictors of stent thrombosis, such as early cessation of antiplatelet therapy or factors related to stent deployment, thus questioning the applicability of such a risk score in routine clinical practice.
Conclusion
Stent thrombosis is a truly perplexing clinical entity and lowering its incidence is crucial, both for clinical safety as well as peace of mind for patients and physicians akin. Given that STEMI patients are 1 of the highest risk groups for developing stent thrombosis subsequently main PCI, this may exist an ideal arena to focus research efforts, particularly randomized controlled trials, going forward. Advisable patient selection, based on rigorous screening protocols when circumstances permit, will help physicians choose the appropriate stent in each case and minimize complications related to underlying medical atmospheric condition, socioeconomic factors, and pharmaceutical nonadherence. Overall in a clinical context however, using the current information to derive a diverse and multifaceted approach to coronary revascularization, focusing on both patient-related and procedure-related factors, volition probable yield the highest long-term benefits in the challenging world of stent thrombosis.
Disclosure
The authors report no conflicts of interest in this piece of work.
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