1.1

Clinical evidence of late ISR and VLST

Table 1 and Fig. 1 summarize evidence of late ISR and VLST after DES. In particular, the rate of target lesion revascularization (TLR) after BMS at 5 years of follow-up ranges between 16.3% and 28.0% with 13.1%–23.7% of events occurring in the first year of follow-up, while the rate of TLR ranges from 10.3% to 15.9% after sirolimus-eluting stent and from 4.5% to 17.9% after paclitaxel-eluting stent with 0.0%–7.0% and 3.2%–10.4% of events occurring in the first year of follow-up, respectively . Accordingly, the rate of TLR after everolimus-eluting stent at 3–5 years of follow-up ranges between 5.4% and 8.3% with 1.8%–3.4% of events occurring during the first year . The rate of TLR after zotarolimus-eluting stent ranges between 3.1% and 8.1% with 2.0%–6.6% of events occurring in the first year of follow-up . Thus, taken together, these data suggest that second-generation DES have lowered the rate of late TLR without eliminating this phenomenon .

Proportion of target lesion revascularization (upper panel) and stent thrombosis (lower panel) occurring in the first year (black blocks) and after the first year (white blocks) following bare-metal stent and drug-eluting stent implantation. Data deriving from randomized controlled trials reported in Table 1 , with a follow-up ≥ 4 years. Percentages of events for each type of stent are calculated as ∑ [%TLR or ST in each trial × (trial enrolled patients/total enrolled patients for type of stent)]. BMS: 3000 patients; SES: 2119 patients; PES: 2310 patients; EES: 250 patients; ZES: 921 patients; BES: 857 patients.

BES = bioabsorbable drug-eluting stent; BMS = bare metal stents; EES = everolimus-eluting stents; PES = paclitaxel-eluting stents; SES = sirolimus-eluting stents; ZES = zotarolimus-eluting stents.

Along with late restenosis, first-generation DES have also been associated with VLST (i.e. occurring more than one year after the index procedure). The incidence was higher in real world registries than in randomized trials probably due to a frequent off-label use of DES. In particular the rate of VLST (definite or probable) with BMS after 5 years of follow-up ranges between 0.0% and 2.5% with 0.0%–1.7% of events occurring during the first year of follow-up, while it ranges from 0.9% to 4.6% with sirolimus-eluting stent and from 0.9% to 4.1% with paclitaxel-eluting stent with 0.0%–2.4% and 0.0%–2.6% of events occurring during the first year of follow-up, respectively . The rate of VLST with everolimus-eluting stent after 3–5 years ranges between 0.0% and 1.3% with 0.0%–1.1% of events occurring during the first year , while the rate of VLST with zotarolimus-eluting stent ranges between 0.7% and 1.1% with 0.1%–1.0% of events occurring during the first year of follow-up . Of importance, the Patient Related Outcomes with Endeavor versus Cypher stenting Trial (PROTECT), a randomized superiority trial designed with definite/probable stent thrombosis as primary end-point, failed to demonstrated a difference in the rate of definite/probable stent thrombosis at 3 years between patients undergoing zotarolimus-eluting stent and sirolimus-eluting stent. However, the occurrence of VLST (between 1 and 3 years) was significantly higher in the sirolimus-eluting stent group .

Thus, similarly to that observed for TLR, second-generation DES seem to have reduced by about half the rate of VLST. In spite of this low event rate, it is worth mentioning that VLST can be a devastating event with a high mortality . Therefore, every effort should be made to avoid VLST. Of note, a recent network meta-analysis proclaimed a paradigm shift as everolimus-eluting stent was associated with a lower rate of late ST compared to BMS . This study however, does not provide data about VLST and is mainly based on the results of the Basel Stent Kosten-Effectivitäts Trial-Prospective Validation Examination (BASKET PROVE), the only study included in the meta-analysis comparing everolimus-eluting stent with BMS with a 2 year follow-up .

Of note, it is worth noted that late events are not a specific feature of DES, as they may occur also in BMS patients , however, taken together, these data suggest that the burden of late ISR and VLST after implantation of first-generation DES outweighs that of BMS-related late events. Second-generation DES reduced, even if they did not eliminate, the incidence of late events as compared with first-generation DES, while further studies are needed to evaluate long-term results in comparison with BMS.

2.1

Mechanisms of late ISR

Three mechanisms may play a role in late ISR: persistent inflammation , poor response to drugs due to genetic polymorphisms , or neoatherosclerosis inside the neointima .

Persistent inflammation around stent struts has been proven by pathologists both in animal models and in humans . This phenomenon is exacerbated at the site of overlapping stents while it seems to be limited to the first twelve months for everolimus-eluting stent . Eosinophils appear to be more involved in DES than in BMS restenosis . Although DES can promote eosinophil recruitment through different mechanisms, available pathologic evidence supports the notion that hypersensitivity to the polymer is the most likely mechanism . Of interest, a recent study by Byrne et al. showed late lumen loss beyond six to eight months, which was less pronounced for polymer-free DES compared with permanent-polymer DES, thus suggesting a central role of polymer-induced inflammation in determining late DES restenosis . Interestingly, a polymer free biolimus-eluting stent showed improved healing and reduced inflammation at 180 days as compared with sirolimus-eluting stent in a porcine model . Accordingly, biolimus-eluting stent with biodegradable polymer has shown early better strut coverage as compared with sirolimus-eluting stent in man at 9-month follow up . It is worth noting that, despite the interesting findings previously mentioned and those that emerged from large scale clinical trials, such as NOBORI CORE trial and LEADERS trial, suggesting significant clinical advantages for polymer free biolimus-eluting stent as compared with first generation DES, at the present time there is no proof that this technology offers neither better nor similar clinical results as compared with second generation DES, even in terms of prevention of late adverse events following stent implantation .

Inflammatory biomarkers serum levels may be useful in order to assess both susceptibility and ongoing inflammatory phenomena. Of note, baseline high-sensitivity C-reactive protein levels failed to show an association with TLR in two large studies by Park et al. , although they predicted an aggressive pattern of ISR in a small study in DES treated patients . Interestingly, we showed that eosinophil cationic protein serum levels predicted MACEs rate after DES implantation with late TLR being the predominant component of the primary end-point .

Chronic inflammation may also cause endothelial dysfunction that has been associated with ISR in previous studies in patients treated by BMS . Dysfunctional endothelium might also be thrombogenic and, interestingly, ISR of DES has been suggested to be more thrombogenic than that of BMS in a study by Oikawa et al. .

Along with persistent inflammation, lack of efficacy of eluted drugs due to genetic polymorphisms of the gene involved in the metabolism of sirolimus and analogues or of paclitaxel may play a role in late TLR according to phenotype penetration of the genetic defects .

Interestingly, a recent angioscopic study by Higo et al. and a pathological study by Nakazawa et al. suggested that neoatherosclerosis inside the stented segment is frequent with DES and usually occurs earlier than with BMS. These findings have been confirmed by an optical coherence tomography study by Kang et al. that showed in-stent neoatherosclerosis as a common cause of stent failure, especially late after stent implantation .

These mechanisms may variably interact with procedural factors that have been associated with early restenosis . Indeed, in the j-Cypher registry most ISR predictors were common for both early and late TLR . Of note, in the study by Kuriyama et al., minimal lumen diameter at 8 months was the strongest predictor of late TLR suggesting that the process starts early (due to procedural or implantation factors), but it is sustained over time persisting after the classical window of BMS restenosis, because of chronic inflammation sustained by the polymer .

Finally, local mechanisms including shear stress or stent fracture could play a role in late restenosis although their role is still controversial .

2.2

Mechanisms of VLST

Occurrence of VLST after DES implantation is a complex and incompletely understood multifactorial process. Recently published meta-analysis of randomized controlled trials comparing DES and BMS in patients undergoing primary PCI clearly showed that the early benefit of first-generation DES with a reduction in TLR was offset in subsequent years especially by an increased risk of VLST . A common substrate with ISR may be represented by delayed healing associated with persistent inflammation and hypersensitivity leading to late incomplete stent apposition and/or aneurysm formation which along with poor strut coverage may be a substrate for ST . Incomplete healing following DES has consistently been shown for first-generation DES and is also associated with persistent inflammatory reaction . Hypersensitivity may lead to eosinophil coronary inflammation characterized by tissue necrosis and erosion around the stent strut. These represent the main cause of vessel remodeling and aneurysmal dilatation allowing for fibrin and platelet deposition that, in conjunction with altered hemodynamics, could promote local thrombosis . Moreover, in a recent study by Cook et al., eosinophils revealed to be more common in thrombi collected from patients presenting with VLST than in thrombi collected from patients presenting with other types of myocardial infarction . Finally, the Research on Adverse Drug Events and Reports (RADAR) study provided additional data on hypersensitivity reactions after DES implantation, supporting the hypothesis that both systemic and local hypersensitivity reactions against DES may be involved, at least in a subset of patients, in late ST and death .

The association between late incomplete stent apposition and VLST has been questioned by some intravascular ultrasound studies and by a recent optical coherence tomography (OCT) study . Of note, the incidence of late incomplete stent apposition seems to be reduced by second-generation DES . However, the rate of late incomplete stent apposition seems also to depend by clinical presentation, with patients with acute coronary syndrome showing a higher rate of incomplete stent apposition as compared with stable patients possibly due to both lysis of thrombus trapped underneath the stent and positive remodeling . Strut coverage as assessed by OCT seems to be lower in patients presenting with an acute coronary syndrome , and seems to be dependent on the type of DES implanted, with second-generation DES usually showing a more complete strut coverage at follow-up . Interestingly, uncovered struts have also been associated with the presence of thrombus detected by OCT and paradoxical constriction to acetylcholine . Yet, ST may occur also in the presence of neointima . Despite that, it is worth noting that data deriving from OCT studies are still debatable and that, although interesting, OCT studies failed until now to find significant OCT predictors of VLST. Guagliumi et al. demonstrated that patients presenting with late ST of DES as compared with controls showed higher prevalence of uncovered and malapposed struts . At the same time, a recent study by Im et al. failed to show a significant correlation between VLST and late stent malapposition .

Of note, the recently published PROTECT trial , showing a lower rate of VLST in patients undergoing zotarolimus-eluting stent implantation as compared with those undergoing sirolimus-eluting stent implantation, further suggested that different antiproliferative potency and vascular healing responses may occur between first-generation and second-generation DES, with zotarolimus-eluting stent being more similar to BMS . Moreover, the PROTECT trial clearly demonstrated that large study populations are required to detect significant differences in definite/probable stent thrombosis rate, thus potentially explaining the reason why previous meta-analysis comparing DES and BMS patients failed to demonstrated a significant difference among these two stent types . Furthermore, the PROTECT trial clearly demonstrated the strong implication of stent implantation technique in the pathogenesis of VLST.

Interestingly, neoatherosclerosis may contribute to VLST as thin-cap fibroatheroma and ruptured plaque have been described by optical coherence tomography in DES failure associated with intracoronary thrombi . Similar results have been shown by angioscopy suggesting that at least part of the thrombotic events may be due to rupture of lipid-laden plaque inside the neointima. Pathological changes following second-generation DES implantation seem to be different from those ones typically following first-generation DES implantation. Indeed, in a recent human autopsy study by Otsuka et al., everolimus-eluting stent demonstrated greater strut coverage with less inflammation, less fibrin deposition, and late and very late ST as compared with sirolimus-eluting stent and paclitaxel-eluting stent . However, the frequency of neoatherosclerosis lesions and their histopathological characteristics was comparable among these two groups, thus suggesting that a careful long-term follow up remains important even after implantation of second-generation DES.

Finally, VLST might be triggered by specific factors. In a recent study, Zwart et al. identified specific triggers of VLST including extreme physical stress, a very strong emotion and acute infection . An inflammatory and prothrombotic systemic activation has also been described following non-cardiac surgery and in the presence of cancer . Accordingly, the risk of perioperative ischemia and thrombotic complication especially late after surgery is an important issue in patients with DES and they are not always prevented by ongoing dual antiplatelet therapy .

In a large cohort of patients treated by DES, Park et al. showed that baseline C-reactive protein levels were associated with late ST . Accordingly, patients with renal failure have been shown to have a high risk of thrombotic events associated with C-reactive protein levels . We have recently suggested that while C-reactive protein is associated with ISR following BMS implantation, it is mainly associated with ST following DES implantation but not with ISR, probably because of the local anti-inflammatory effect of the eluted drug .

2.1

Mechanisms of late ISR

Three mechanisms may play a role in late ISR: persistent inflammation , poor response to drugs due to genetic polymorphisms , or neoatherosclerosis inside the neointima .

Persistent inflammation around stent struts has been proven by pathologists both in animal models and in humans . This phenomenon is exacerbated at the site of overlapping stents while it seems to be limited to the first twelve months for everolimus-eluting stent . Eosinophils appear to be more involved in DES than in BMS restenosis . Although DES can promote eosinophil recruitment through different mechanisms, available pathologic evidence supports the notion that hypersensitivity to the polymer is the most likely mechanism . Of interest, a recent study by Byrne et al. showed late lumen loss beyond six to eight months, which was less pronounced for polymer-free DES compared with permanent-polymer DES, thus suggesting a central role of polymer-induced inflammation in determining late DES restenosis . Interestingly, a polymer free biolimus-eluting stent showed improved healing and reduced inflammation at 180 days as compared with sirolimus-eluting stent in a porcine model . Accordingly, biolimus-eluting stent with biodegradable polymer has shown early better strut coverage as compared with sirolimus-eluting stent in man at 9-month follow up . It is worth noting that, despite the interesting findings previously mentioned and those that emerged from large scale clinical trials, such as NOBORI CORE trial and LEADERS trial, suggesting significant clinical advantages for polymer free biolimus-eluting stent as compared with first generation DES, at the present time there is no proof that this technology offers neither better nor similar clinical results as compared with second generation DES, even in terms of prevention of late adverse events following stent implantation .

Inflammatory biomarkers serum levels may be useful in order to assess both susceptibility and ongoing inflammatory phenomena. Of note, baseline high-sensitivity C-reactive protein levels failed to show an association with TLR in two large studies by Park et al. , although they predicted an aggressive pattern of ISR in a small study in DES treated patients . Interestingly, we showed that eosinophil cationic protein serum levels predicted MACEs rate after DES implantation with late TLR being the predominant component of the primary end-point .

Chronic inflammation may also cause endothelial dysfunction that has been associated with ISR in previous studies in patients treated by BMS . Dysfunctional endothelium might also be thrombogenic and, interestingly, ISR of DES has been suggested to be more thrombogenic than that of BMS in a study by Oikawa et al. .

Along with persistent inflammation, lack of efficacy of eluted drugs due to genetic polymorphisms of the gene involved in the metabolism of sirolimus and analogues or of paclitaxel may play a role in late TLR according to phenotype penetration of the genetic defects .

Interestingly, a recent angioscopic study by Higo et al. and a pathological study by Nakazawa et al. suggested that neoatherosclerosis inside the stented segment is frequent with DES and usually occurs earlier than with BMS. These findings have been confirmed by an optical coherence tomography study by Kang et al. that showed in-stent neoatherosclerosis as a common cause of stent failure, especially late after stent implantation .

These mechanisms may variably interact with procedural factors that have been associated with early restenosis . Indeed, in the j-Cypher registry most ISR predictors were common for both early and late TLR . Of note, in the study by Kuriyama et al., minimal lumen diameter at 8 months was the strongest predictor of late TLR suggesting that the process starts early (due to procedural or implantation factors), but it is sustained over time persisting after the classical window of BMS restenosis, because of chronic inflammation sustained by the polymer .

Finally, local mechanisms including shear stress or stent fracture could play a role in late restenosis although their role is still controversial .

2.2

Mechanisms of VLST

Occurrence of VLST after DES implantation is a complex and incompletely understood multifactorial process. Recently published meta-analysis of randomized controlled trials comparing DES and BMS in patients undergoing primary PCI clearly showed that the early benefit of first-generation DES with a reduction in TLR was offset in subsequent years especially by an increased risk of VLST . A common substrate with ISR may be represented by delayed healing associated with persistent inflammation and hypersensitivity leading to late incomplete stent apposition and/or aneurysm formation which along with poor strut coverage may be a substrate for ST . Incomplete healing following DES has consistently been shown for first-generation DES and is also associated with persistent inflammatory reaction . Hypersensitivity may lead to eosinophil coronary inflammation characterized by tissue necrosis and erosion around the stent strut. These represent the main cause of vessel remodeling and aneurysmal dilatation allowing for fibrin and platelet deposition that, in conjunction with altered hemodynamics, could promote local thrombosis . Moreover, in a recent study by Cook et al., eosinophils revealed to be more common in thrombi collected from patients presenting with VLST than in thrombi collected from patients presenting with other types of myocardial infarction . Finally, the Research on Adverse Drug Events and Reports (RADAR) study provided additional data on hypersensitivity reactions after DES implantation, supporting the hypothesis that both systemic and local hypersensitivity reactions against DES may be involved, at least in a subset of patients, in late ST and death .

The association between late incomplete stent apposition and VLST has been questioned by some intravascular ultrasound studies and by a recent optical coherence tomography (OCT) study . Of note, the incidence of late incomplete stent apposition seems to be reduced by second-generation DES . However, the rate of late incomplete stent apposition seems also to depend by clinical presentation, with patients with acute coronary syndrome showing a higher rate of incomplete stent apposition as compared with stable patients possibly due to both lysis of thrombus trapped underneath the stent and positive remodeling . Strut coverage as assessed by OCT seems to be lower in patients presenting with an acute coronary syndrome , and seems to be dependent on the type of DES implanted, with second-generation DES usually showing a more complete strut coverage at follow-up . Interestingly, uncovered struts have also been associated with the presence of thrombus detected by OCT and paradoxical constriction to acetylcholine . Yet, ST may occur also in the presence of neointima . Despite that, it is worth noting that data deriving from OCT studies are still debatable and that, although interesting, OCT studies failed until now to find significant OCT predictors of VLST. Guagliumi et al. demonstrated that patients presenting with late ST of DES as compared with controls showed higher prevalence of uncovered and malapposed struts . At the same time, a recent study by Im et al. failed to show a significant correlation between VLST and late stent malapposition .

Of note, the recently published PROTECT trial , showing a lower rate of VLST in patients undergoing zotarolimus-eluting stent implantation as compared with those undergoing sirolimus-eluting stent implantation, further suggested that different antiproliferative potency and vascular healing responses may occur between first-generation and second-generation DES, with zotarolimus-eluting stent being more similar to BMS . Moreover, the PROTECT trial clearly demonstrated that large study populations are required to detect significant differences in definite/probable stent thrombosis rate, thus potentially explaining the reason why previous meta-analysis comparing DES and BMS patients failed to demonstrated a significant difference among these two stent types . Furthermore, the PROTECT trial clearly demonstrated the strong implication of stent implantation technique in the pathogenesis of VLST.

Interestingly, neoatherosclerosis may contribute to VLST as thin-cap fibroatheroma and ruptured plaque have been described by optical coherence tomography in DES failure associated with intracoronary thrombi . Similar results have been shown by angioscopy suggesting that at least part of the thrombotic events may be due to rupture of lipid-laden plaque inside the neointima. Pathological changes following second-generation DES implantation seem to be different from those ones typically following first-generation DES implantation. Indeed, in a recent human autopsy study by Otsuka et al., everolimus-eluting stent demonstrated greater strut coverage with less inflammation, less fibrin deposition, and late and very late ST as compared with sirolimus-eluting stent and paclitaxel-eluting stent . However, the frequency of neoatherosclerosis lesions and their histopathological characteristics was comparable among these two groups, thus suggesting that a careful long-term follow up remains important even after implantation of second-generation DES.

Finally, VLST might be triggered by specific factors. In a recent study, Zwart et al. identified specific triggers of VLST including extreme physical stress, a very strong emotion and acute infection . An inflammatory and prothrombotic systemic activation has also been described following non-cardiac surgery and in the presence of cancer . Accordingly, the risk of perioperative ischemia and thrombotic complication especially late after surgery is an important issue in patients with DES and they are not always prevented by ongoing dual antiplatelet therapy .

In a large cohort of patients treated by DES, Park et al. showed that baseline C-reactive protein levels were associated with late ST . Accordingly, patients with renal failure have been shown to have a high risk of thrombotic events associated with C-reactive protein levels . We have recently suggested that while C-reactive protein is associated with ISR following BMS implantation, it is mainly associated with ST following DES implantation but not with ISR, probably because of the local anti-inflammatory effect of the eluted drug .