Overview of Stent Thrombosis: Mechanisms and Clinical Implications

Definition of stent thrombosis

In 2006, a group of experts known as the Academic Research Consortium proposed a standardized definition of ST. The diagnostic criteria of ST is defined by the degree of evidence of ST (as definite, probable and possible). ST is also classified by its diagnostic timeline based from the initial stent implantation date (as acute, subacute, late and very late) (Table 1) [8]. The pathophysiology and risk for ST is different according to the timeline after stent implantation. Generally, ST could be categorized into two groups because of its different risk factors and underlying pathophysiology; early ST (occurring within the first 30 days of stent implantation) and late ST (occurring beyond the first 30 days of stent implantation) [9,10].

Table 1.

Standard definition of stent thrombosis by the Academic Research Consortium

Incidence and outcomes

The overall rate of ST was up to 20% before the introduction of dual antiplatelet therapy (DAPT) in the early bare metal stent (BMS) era [3,11]. With contemporary DAPT and modern generation DES, the incidence of ST was reduced to less than 1% [12]. Systematic review of randomized trials with DES showed a median incidence of definite ST of 0.61% at 9-12 months [13]. Crucial point was that very late ST was strikingly higher compared to BMS in early generation DES after PCI. The rate of very late ST was up to 2% in the first 1st generation DES. After the progression and evolution of stent devices, the incidence of very late ST reduced to 0.2-0.4% in the modern generation DES era [14-16]. Recent large-scale registry data revealed that the cumulative event of ST in 3 years clinical follow up period was up to 1.5% in BMS, 2.2% in 1st generation DES, 1.0% in 2nd generation DES [17]. Although its incidence had markedly decreased, the mortality rate of ST is still high ranging from 10-40%. Clinical outcomes among ST lesions are poor compared with native coronary lesions which is associated with large thrombus burden and higher risk of distal embolization [18-20].

Risk factors for stent thrombosis

Various mechanisms could lead to ST. Principal risk factors for ST could be classified into i) patient and lesion factors, ii) stent and device factors, iii) procedural factors. As previously mentioned, these risk factors and pathophysiology of ST are also categorized according to the implanted time of the stent (early vs. late and very late ST) (Table 2) [21-24].

Table 2.

Principal risk factors for stent thrombosis

Neoatherosclerosis

Neoatherosclerosis (NA) is characterized by the accumulation of atherosclerotic plaque in the implanted intra-coronary stent [53,54]. Histologic definition of NA was the infiltration of lipid-laden foamy macrophages within the neo-intima or peri-strut with or without combined necrotic core formation, calcification and plaque rupture [55,56]. Although it shares similar pathophysiology, temporal time required for the development of NA is short compared with the atherosclerotic changes in the native coronary vessels [57,58]. Regenerated endothelium which sought to be functionally impaired and immature within the stented segment would likely be the responsible mechanism [59-61]. Between the stent devices, human autopsy studies and clinical imaging studies have demonstrated that temporal time for the development of NA is much shorter in the in DES compared with BMS (420 days vs. 2,260 days, P< 0.001) and the incidence of NA is also known to be higher in DES implantations compared to BMS (31% vs. 16%, P < 0.001) [62-64]. Another important finding was that the high-risk plaque characteristics in were common in NA after DES implantation than BMS implantation [65]. Pathology study by Otsuka et al. demonstrated that the development of NA was similar within the early generation and modern generation DES [45]. Above these findings could be explained by chronic inflammatory reaction to the regenerated endothelium by stent strut itself and drug coated polymer. Thoroughly, NA is known as the late final common pathway and the major remaining contributing factor in the DES era for the development of late stent failure including very late ST and late ISR [21,56].

Bioresorbable vascular scaffolds

In the recent decade, bioresorbable vascular scaffolds (BVS) had been one of the main hot issue. The theoretical background for the development of BVS was that remained polymer and metallic scaffold in the coronary vessel wound be the permanent trigger for chronic inflammation which causes very late ST [66-69]. Once the polymer and metallic scaffold have been fully degraded, restoration of normal vasomotor tone and positive vascular remodeling could be achieved [70,71]. Absorb BVS (Abbott, Lake Country, IL, USA) is the most widely used and the representative of early generation BVS. Absorb BVS consists of poly-L-lactide stent backbone (strut thickness: 157 μm), poly-D,L-lactide drug delivering polymer and anti-proliferative drug everolimus [72]. Results of the randomized clinical trials and meta-analysis showed that short term clinical outcomes of Absorb BVS were comparable with EES [69,73]. However, mid-term and long-term outcomes of Absorb BVS revealed higher risk of target lesion failure and significant increase of scaffold thrombosis compared with EES [74-77]. Due to it’s the major concern, all BVS devices are currently withdrawn from the stent device market. However, unceasing effort needs to be made for the development of new generation BVS with adequate degradation profile with thinner strut thickness [78-80].

Role of Intra-vascular imaging

Intra-vascular imaging including intravascular ultrasonography (IVUS) and optical coherence tomography (OCT) plays an important role in identifying specific pathophysiology of ST. Simultaneously intra-vascular imaging gives adequate treatment plan for the management ST. Also, it contributes on prevention of ST by providing precise guidance for stent optimization during PCI and reduce the procedure related risk factors of ST [81-85].

Stent under-expansion results from restricted stent expansion by the disease plaque character itself, implantation of a relatively undersized stent compared with the native vessel size or inadequate deployment during stent inflation [86,87]. IVUS definition of stent underexpansion is as followed: Minimal stent area (MSA) less than 90% of the average reference lumen area for reference vessel minimal lumen area (MLA) of < 9 mm² or MSA less than 80% of the average reference lumen area for reference vessel MLA of > 9 mm² [88]. OCT definition of stent-under-expansion is as followed: MSA less than 80% of the average reference lumen area if both references were available or less than 90% if only the distal reference was available or less than 70% if only the proximal reference was available [89]. According to previous studies, 20% to as many as 50% of patients were unable to achieve true intra-vascular imaging defined optimal stent expansion under coronary angiography guided only PCI despite high pressure post-dilatation with noncompliant balloon [90,91]. Stent underexpansion is a well-recognized as an independent risk factor for early ST in patients treated with both BMS and DES [92-94]. In the registry data from France, stent under-expansion was the underlying mechanism in 11% of patients and was more prevalent in acute and subacute ST [95].

Stent mal-apposition in other words, incomplete stent apposition is defined as the lack contact between abluminal surface of the stent strut (at least one) and the coronary intimal surface in a segment without an overlying side branch [96-97]. Stent mal-apposition is divided into acute (immediately detected at the time of stent implantation) and late (detected during follow up period) mal-apposition. The late stent mal-apposition could be further classified in to late persistent (remaining since the initial implantation time) and late acquired (detected during follow up period despite appropriate apposition during initial implantation period) [98]. Accurate detection of stent mal-apposition is capable by intra-vascular imaging [81,85,99]. Meta-analysis results revealed that especially late acquired stent mal-apposition is associated with increased risk of late and very late stent thrombosis [100]. The risk of late acquired mal-apposition was significantly higher after DES implantation (mainly early generation, DES) compared with BMS (HR, 4.36; 95% CI, 1.74-10.94; P = 0.002) due to positive remodeling of the vessel wall by inflammatory and hypersensitivity reactions by the anti-proliferative drugs, polymer and metallic strut [96,101-104]. Incidence of late mal-apposition was lower in 2nd generation DES than with early generation DES. In an autopsy study of stents implanted > 30 days, ≤ 3 years previously, the frequency of late mal-apposition was lower in 2nd generation EES compared to SES and PES (4% vs. 16% and 18%) [45].

Stent edge dissection is defined as disruptions of the luminal surface within in 5 mm segments proximal and distal to the stent. Edge dissection leads to exposure of the endothelial cell contents to the blood stream and increase the risk of early ST [105-106]. IVUS based data showed that the prevalence of edge dissection was 10-20% after BMS implantation and 8% after DES implantation [107]. In the OCT based study by Chamie et al. [108] demonstrated that overall incidence of OCT defined stent edge dissection was up to 37.8% but were mostly not apparent on conventional coronary angiography (84%). Majority of the edge dissection were non-flow-limiting, short, and superficial which were left untreated and completely healed on follow up OCT. However, flow limiting dissection, long and deep dissection should be treated by additional stenting [109,110].

Although coronary angiography is still the standard imaging modality, 2‐dimensional projection of coronary anatomical characteristics possess a major limitation in stent optimization. Various randomized clinical trials and meta-analysis proved that intravascular imaging guided stent optimization could reduce the risk of ST and other adverse cardiac events by preventing those potential risk factors [111-114]. In the ILUMIEN IV trial, OCT-guided PCI resulted in a statistically improvement in acute minimal stent area compared with angiography-guided PCI (5.72 mm² vs. 5.36 mm², P < 0.001). Despite there was no reduction in the 2-year primary clinical endpoint (target vessel failure), OCT-guided PCI was associated with a reduction in definite or probable ST compared to angiography-guided PCI (0.5% vs. 1.4%; HR, 0.36; 95% CI, 0.14-0.91; P = 0.02) [115]. Based on these studies, current 2024 European guideline strongly recommend intracoronary imaging guidance by IVUS or OCT when performing PCI on anatomically complex lesions, in particular left main stem, true bifurcations, and long lesions (Class I, Level of evidence A) [116].

Treatment approach in stent thrombosis

Thrombus aspiration, balloon angioplasty and pharmacologic treatment with intra-coronary antiplatelet agents are the mainstay for the treatment of ST [117]. Following diagnostic angiography, occlusive lesions can be treated initially with balloon angioplasty alone, sometimes with adjunctive thrombus aspiration when the clot burden is large. Glycoprotein IIb/IIIa antagonists should be considered to improve microvascular reperfusion because of distal embolization [118]. Once the patient is stabilized and coronary flow has been reestablished, the etiology of the ST should be assessed with intra-coronary imaging modalities to determine the adequacy of stent expansion, apposition, neoatherosclerosis formation and edge dissections. The 2021 American College of Cardiology revascularization guideline recommends IVUS or OCT to determine the mechanism of stent failure (Class IIA, Level of evidence C) [119]. However, OCT appears to be superior to IVUS as a main imaging modality in ST because it allows accurate assessment of lumen pathology and enables more detailed visualization of stent architecture and strut apposition and reliable description of neo-intima characteristics [120]. After the proper mechanism of ST has been documented, proper treatment including high-pressure non-compliant balloon expansion should be performed especially for underlying stent under-expansion and mal-apposition. Additional stent implantation should ordinarily be limited to significant residual dissections [121].