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Marta Francesca Brancati, 1 Francesco Burzotta, 2 Carlo Trani, 2 Ornella Leonzi, 1 Claudio Cuccia, 1 Filippo Crea2 1 Department of Cardiology, Poliambulanza Foundation Hospital, Brescia, 2 Department of Cardiology, Catholic University of the Sacred Heart of Rome, Italy Abstract: Drug-Eluting Stents ( DES) minimizes the limitations of bare metal stents (BMS) after percutaneous coronary intervention.However, although the introduction of second-generation DES appears to have moderated this phenomenon compared to first-generation DES, serious concerns remain about possible late complications of stent implantation, such as stent thrombosis (ST) and stent resection. Stenosis (ISR).ST is a potentially catastrophic event that has been significantly reduced through optimized stenting, novel stent designs, and dual antiplatelet therapy.The exact mechanism explaining its occurrence is under investigation, and indeed, multiple factors are responsible.The ISR in BMS was previously considered to be a steady state with an early peak of intimal hyperplasia (at 6 months) followed by a regression period of over 1 year.In contrast, both clinical and histological studies of DESs demonstrated evidence of persistent neointimal growth during long-term follow-up, a phenomenon known as the “late catch-up” phenomenon.The perception that ISR is a relatively benign clinical condition has recently been challenged by evidence that patients with ISR may develop acute coronary syndromes.Intracoronary imaging is an invasive technique that can identify stented atherosclerotic plaques and features of post-stent vessel healing; it is often used to complete diagnostic coronary angiography and drive interventional procedures.Intracoronary optical coherence tomography is currently considered the most advanced imaging technique.Compared to intravascular ultrasound, it provides better resolution (at least >10 times), allowing detailed characterization of the surface structure of the vessel wall.”In vivo” imaging studies consistent with histological findings suggest that chronic inflammation and/or endothelial dysfunction may induce late-stage neo-atherosclerosis within BMS and DES.Therefore, neo-atherosclerosis has become the primary suspect in the pathogenesis of late stent failure.Keywords: coronary stent, stent thrombosis, restenosis, neoatherosclerosis
Percutaneous coronary intervention (PCI) with stent implantation is the most widely used procedure for the treatment of symptomatic coronary artery disease, and the technique continues to evolve.1 Although drug-eluting stents (DES) minimize the limitations of bare-metal stents (BMSs), late complications such as stent thrombosis (ST) and in-stent restenosis (ISR) may occur with stent implantation. , serious concerns remain.2-5
If ST is a potentially catastrophic event, the recognition that ISR is a relatively benign disease has recently been challenged by evidence of acute coronary syndrome (ACS) in ISR patients.4
Today, intracoronary optical coherence tomography (OCT)6-9 is considered the current state-of-the-art imaging technique, offering better resolution than intravascular ultrasound (IVUS).”In vivo” imaging studies,10-12 consistent with histological findings, show a “new” mechanism of vascular response after stent implantation, with de novo “neoatherosclerosis” within BMS and DES.
In 1964, Charles Theodore Dotter and Melvin P Judkins described the first angioplasty.In 1978, Andreas Gruntzig performed the first balloon angioplasty (plain old balloon angioplasty); it was a revolutionary treatment but had the drawbacks of acute vessel closure and restenosis.13 This drove the discovery of coronary stents: Puel and Sigwart deployed the first coronary stent in 1986, providing a stent to prevent acute vessel closure and late systolic retraction.14 Although these initial stents prevented abrupt closure of the vessel, they caused severe endothelial damage and inflammation.Later, two landmark trials, the Belgian-Dutch Stent Trial 15 and the Stent Restenosis Study 16, advocated the safety of stenting with dual antiplatelet therapy (DAPT) and/or appropriate deployment techniques.17,18 After these trials, there was a significant increase in the number of PCIs performed.
However, the problem of iatrogenic in-stent neointimal hyperplasia following BMS placement was quickly identified, resulting in ISR in 20%–30% of treated lesions.In 2001, DES was introduced19 to minimize the need for restenosis and reintervention.DESs have increased the confidence of cardiologists, allowing an increasing number of complex lesions to be treated that were earlier thought to be resolved by coronary artery bypass grafting.In 2005, 80%–90% of all PCIs were accompanied by DES.
Everything has its drawbacks, and since 2005, concerns about the safety of “first-generation” DES have risen, and new-generation stents such as 20,21 have been developed and introduced.22 Since then, efforts to improve stent performance have grown rapidly, and new, surprising technologies have continued to be discovered and brought to market rapidly.
BMS is a mesh thin wire tube.After first experience with the “Wall” mount, Gianturco-Roubin mount and Palmaz-Schatz mount, many different BMSs are now available.
Three different designs are possible: coil, tubular mesh and slotted tube.Coil designs feature metal wires or strips formed into a circular coil shape; tubular mesh designs feature wires wrapped together in a mesh to form a tube; slotted tube designs consist of metal tubes that are laser cut made.These devices vary in composition (stainless steel, nichrome, cobalt chrome), structural design (different strut patterns and widths, diameters and lengths, radial strength, radiopacity) and delivery systems (self-expanding or balloon-expandable) .
Generally, the new BMS consists of a cobalt-chromium alloy, which results in thinner struts with improved navigability, maintaining mechanical strength.
They consist of a metal stent platform (usually stainless steel) and coated with a polymer that elutes anti-proliferative and/or anti-inflammatory therapeutics.
Sirolimus (also known as rapamycin) was originally designed as an antifungal agent.Its mechanism of action stems from blocking cell cycle progression by blocking the transition from G1 phase to S phase and inhibiting neointima formation.In 2001, the “first-in-human” experience with SES showed promising results, leading to the development of the Cypher stent.23 Large trials demonstrated its efficacy in preventing ISR.twenty four
Paclitaxel was originally approved for ovarian cancer, but its potent cytostatic properties — the drug stabilizes microtubules during mitosis, leads to cell cycle arrest and inhibits neointimal formation — make it the compound for Taxus Express PES.The TAXUS V and VI trials demonstrated the long-term efficacy of PES in high-risk, complex coronary artery disease.25,26 The subsequent TAXUS Liberté featured a stainless steel platform for easier delivery.
Conclusive evidence from two systematic reviews and meta-analyses suggests that SES has an advantage over PES due to lower rates of ISR and target vessel revascularization (TVR), as well as a trend toward increased acute myocardial infarction (AMI) in the PES cohort. 27,28
Second-generation devices have reduced strut thickness, improved flexibility/deliverability, enhanced polymer biocompatibility/drug elution profiles, and excellent re-endothelialization kinetics.In contemporary practice, they are the most advanced DES designs and major coronary stents implanted globally.
Taxus Elements is a further advancement with a unique polymer designed to maximize early release and a new platinum-chromium strut system that provides thinner struts and enhanced radiopacity.The PERSEUS trial 29 noted similar results between Element and Taxus Express for up to 12 months.However, trials comparing yew elements with other second-generation DES are lacking.
The zotarolimus-eluting stent (ZES) Endeavor is based on a stronger cobalt-chromium stent platform with higher flexibility and smaller stent strut size.Zotarolimus is a sirolimus analog with similar immunosuppressive effects but enhanced lipophilicity to enhance vessel wall localization.ZES uses a novel phosphorylcholine polymer coating designed to maximize biocompatibility and minimize inflammation.Most drugs are eluted during the initial injury phase, followed by arterial repair.After the first ENDEAVOR trial, the subsequent ENDEAVOR III trial compared ZES with SES, which showed greater late lumen loss and ISR but fewer major adverse cardiovascular events (MACE) than SES .30 The ENDEAVOR IV trial, which compared ZES with PES, again found a higher incidence of ISR, but a lower incidence of AMI, ostensibly from very advanced ST in the ZES group.31 However, the PROTECT trial failed to demonstrate a difference in ST rates between the Endeavor and Cypher stents.32
Endeavor Resolute is an improved version of the Endeavor stent with a new three-layer polymer.The newer Resolute Integrity (sometimes referred to as the third-generation DES) is based on a new platform with higher delivery capabilities (the Integrity BMS platform), and a novel, more biocompatible three-layer polymer , can suppress the initial inflammatory response and elute most of the drug over the next 60 days.A trial comparing Resolute with Xience V (everolimus-eluting stent [EES]) demonstrated noninferiority of the Resolute system in terms of death and target lesion failure.33,34
Everolimus, a derivative of sirolimus, is also a cell cycle inhibitor used in the development of Xience (Multi-link Vision BMS platform)/Promus (Platinum Chromium platform) EES.The SPIRIT trial 35-37 demonstrated improved performance and reduced MACE with Xience V compared to PES, while the EXCELLENT trial demonstrated that EES was noninferior to SES in suppressing late loss at 9 months and clinical events at 12 months.38 Finally, the Xience stent demonstrated advantages over BMS in the setting of ST-segment elevation myocardial infarction (MI).39
EPCs are a subset of circulating cells involved in vascular homeostasis and endothelial repair.Enhancement of EPCs at the site of vascular injury will promote early re-endothelialization, potentially reducing the risk of ST.EPC biology’s first attempt in the field of stent design is the CD34 antibody-coated Genous stent, capable of binding circulating EPCs through its hematopoietic markers to enhance re-endothelialization.Although the initial studies were encouraging, recent evidence points to high rates of TVR.40
Considering the potentially detrimental effects of polymer-induced delayed healing, which is associated with the risk of ST, bioabsorbable polymers offer the benefits of DES, avoiding long-standing concerns about polymer persistence.To date, different bioabsorbable systems have been approved (eg Nobori and Biomatrix, biolimus eluting stent, Synergy, EES, Ultimaster, SES), but the literature supporting their long-term results is limited.41
Bioabsorbable materials have the theoretical advantage of initially providing mechanical support when elastic recoil is considered and reducing the long-term risks associated with existing metal struts.New technologies have led to the development of lactic acid-based polymers (poly-l-lactic acid [PLLA]), but many stent systems are in development, although determining the ideal balance between drug elution and degradation kinetics remains a challenge.The ABSORB trial demonstrated the safety and efficacy of everolimus-eluting PLLA stents.43 The second-generation Absorb stent revision was an improvement over the previous one with a good 2-year follow-up.44 The ongoing ABSORB II trial, the first randomized trial comparing the Absorb stent to the Xience Prime stent, should provide further data, and the first available results are promising.45 However, the ideal setting, optimal implantation technique, and safety profile for coronary lesions need to be better clarified.
Thrombosis in both BMS and DES has poor clinical outcomes.In a registry of patients receiving DES implantation,47 24% of ST cases resulted in death, 60% from non-fatal MI, and 7% from unstable angina.PCI in emergency ST is usually suboptimal, with recurrence in 12% of cases.48
Advanced ST has potentially adverse clinical outcomes.In the BASKET-LATE study, 6 to 18 months after stent placement, the rates of cardiac mortality and non-fatal MI were higher in the DES group than in the BMS group (4.9% and 1.3%, respectively).20 A meta-analysis of nine trials, in which 5,261 patients were randomized to SES, PES, or BMS, reported that at 4 years of follow-up, SES (0.6% vs 0%, p=0.025) and PES (0.7%) ) increased the incidence of very late ST compared with BMS by 0.2%, p=0.028).49 In contrast, in a meta-analysis including 5,108 patients, 21 a 60% relative increase in death or MI was reported with SES compared with BMS (p=0.03), whereas PES was associated with a 15% non-significant increase (Follow-up 9 months to 3 years).
Numerous registries, randomized trials, and meta-analyses have investigated the relative risk of ST after BMS and DES implantation and have reported conflicting results.In a registry of 6,906 patients receiving BMS or DES, there were no differences in clinical outcomes or ST rates during 1-year follow-up.48 In another registry of 8,146 patients, the risk of persistent excess ST was found to be 0.6%/year compared with BMS.49 A meta-analysis of trials comparing SES or PES with BMS showed an increased risk of mortality and MI with first-generation DES compared with BMS, 21 and another meta-analysis of 4,545 patients randomized to SES or There was no difference in the incidence of ST between PES and BMS at 4 years of follow-up.50 Other real-world studies have demonstrated an increased risk of advanced ST and MI in patients receiving first-generation DES after discontinuation of DAPT.51
Given the conflicting evidence, several pooled analyses and meta-analyses together determined that first-generation DES and BMS did not differ significantly in the risk of death or MI, but SES and PES had an increased risk of very advanced ST compared with BMS. To review Evidence available, the US Food and Drug Administration (FDA) appointed an expert panel53 which issued a statement acknowledging that first-generation DES were effective for the on-label indications and that the risk of very advanced ST was small but small. A significant increase.As a result, the FDA and the association recommend extending the DAPT period to 1 year, although there is little data to support this claim.
As mentioned earlier, second-generation DES with advanced design features have been developed.CoCr-EESs have undergone the most extensive clinical studies.In a meta-analysis by Baber et al,54 including 17,101 patients, CoCr-EES significantly reduced definite/probable ST and MI compared with PES, SES, and ZES after 21 months.Finally, Palmerini et al showed in a meta-analysis of 16,775 patients that CoCr-EES had significantly lower early, late, 1- and 2-year definite ST compared with other pooled DES.55 Real-world studies have demonstrated a reduction in ST risk with CoCr-EES compared to first-generation DES.56
Re-ZES was compared with CoCr-EES in RESOLUTE-AC and TWENTE trials.33,57 There was no significant difference in the incidence of mortality, myocardial infarction, or definite ST between the two stents.
In a network meta-analysis of 50,844 patients including 49 RCTs,58CoCr-EES was associated with a significantly lower incidence of definite ST than BMS, a result not observed in other DES; the reduction was not only in Significant early and at 30 days (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.11-0.42) and also at 1 year (OR 0.27, 95% CI 0.08-0.74) and 2 years (OR 0.35 , 95% CI 0.17–0.69).Compared with PES, SES, and ZES, CoCr-EES was associated with a lower incidence of ST at 1 year.
Early ST is related to different factors.Underlying plaque morphology and thrombus burden appear to influence outcomes after PCI; 59 Deeper strut penetration due to necrotic core (NC) prolapse, medial tears in stent lengths, secondary dissection with residual margins, or significant margin narrowing Optimal stenting, incomplete apposition, and incomplete expansion60 Treatment regimen with antiplatelet drugs does not significantly affect the incidence of early ST: the incidence of acute and subacute ST during DAPT in a randomized trial comparing BMS with DES Rates were similar (<1%).61 Thus, early ST appears to be primarily related to underlying therapeutic lesions and surgical factors.
Today, a particular focus is on late/very late ST.If procedural and technical factors appear to play a major role in the development of acute and subacute ST, the mechanism of delayed thrombotic events appears to be more complex.It has been suggested that certain patient characteristics may be risk factors for advanced and very advanced ST: diabetes mellitus, ACS during initial surgery, renal failure, advanced age, reduced ejection fraction, major adverse cardiac events within 30 days of initial surgery.For BMS and DES, procedural variables, such as small vessel size, bifurcations, polyvascular disease, calcification, total occlusion, long stents, appear to be associated with the risk of advanced ST.62,63 Insufficient response to antiplatelet therapy is a major risk factor for advanced DES thrombosis 51 .This response may be due to patient nonadherence, underdosing, drug interactions, comorbidities affecting drug response, genetic polymorphisms at the receptor level (especially clopidogrel resistance), and upregulation of other platelet activation pathways.In-stent neoatherosclerosis is considered an important mechanism of late stent failure, including late ST64 (section “In-stent neoatherosclerosis”).The intact endothelium separates the thrombosed vessel wall and stent struts from the blood flow and secretes antithrombotic and vasodilatory substances.DES exposes the vessel wall to antiproliferative drugs and a drug-eluting platform with differential effects on endothelial healing and function, with a risk of late thrombosis.65 Pathological studies suggest that the durable polymers of first-generation DES may contribute to chronic inflammation, chronic fibrin deposition, poor endothelial healing, and a consequent increased risk of thrombosis.3 Late hypersensitivity to DES appears to be another mechanism leading to ST.Virmani et al66 reported post-mortem post-ST findings showing aneurysm expansion at the stent segment with local hypersensitivity reactions composed of T lymphocytes and eosinophils; these findings may reflect the influence of nonerodible polymers.67 Stent malapposition may be due to suboptimal stent expansion or occur months after PCI.Although procedural malapposition is a risk factor for acute and subacute ST, the clinical significance of acquired stent malapposition may depend on aggressive arterial remodeling or drug-induced delayed healing, but its clinical significance is controversial.68
The protective effects of second-generation DES may include more rapid and intact endothelialization, as well as differences in stent alloy and structure, strut thickness, polymer properties, and antiproliferative drug type, dose, and kinetics.
Relative to CoCr-EES, thin (81 µm) cobalt-chromium stent struts, antithrombotic fluoropolymers, low polymer, and drug loading may contribute to a lower incidence of ST.Experimental studies have shown that the thrombosis and platelet deposition of fluoropolymer-coated stents are significantly lower than those of bare-metal stents.69 Whether other second-generation DES have similar properties deserves further study.
Coronary stents improve the surgical success rate of coronary interventions compared with traditional percutaneous transluminal coronary angioplasty (PTCA), which has mechanical complications (vascular occlusion, dissection, etc.) and high restenosis rates (up to 40%–50% of cases). By the late 1990s, nearly 70% of PCIs were performed with BMS implantation.70
However, despite advances in technology, techniques, and medical treatments, the risk of restenosis after BMS implantation is approximately 20%, with >40% in specific subgroups.71 Overall, clinical studies have shown that restenosis after BMS implantation, similar to that observed with conventional PTCA, peaks at 3-6 months and resolves after 1 year.72
DES further reduces the incidence of ISR,73 although this reduction depends on the angiography and clinical setting.The polymer coating on the DES releases anti-inflammatory and anti-proliferative agents, inhibits neointima formation, and delays the vascular repair process for months to years.74 Persistent neointimal growth during long-term follow-up after DES implantation, a phenomenon known as “late catch-up”, was observed in clinical and histological studies. 75
Vascular injury during PCI produces a complex process of inflammation and repair in a relatively short period of time (weeks to months), leading to endothelialization and neointimal coverage.According to histopathological observations, the neointimal hyperplasia (BMS and DES) after stent implantation was mainly composed of proliferative smooth muscle cells in a proteoglycan-rich extracellular matrix.70
Thus, neointimal hyperplasia represents a repair process involving coagulation and inflammatory factors as well as cells that induce smooth muscle cell proliferation and extracellular matrix formation.Immediately after PCI, platelets and fibrin deposit on the vessel wall and recruit leukocytes through a series of cell adhesion molecules.Rolling leukocytes attach to adherent platelets through the interaction between leukocyte integrin Mac-1 (CD11b/CD18) and platelet glycoprotein Ibα 53 or fibrinogen bound to platelet glycoprotein IIb/IIIa.76,77
According to emerging data, bone marrow-derived progenitor cells are involved in vascular responses and repair processes.Mobilization of EPCs from bone marrow into peripheral blood promotes endothelial regeneration and postnatal neovascularization.It appears that bone marrow smooth muscle progenitor cells (SMPC) migrate to the site of vascular injury, leading to neointimal proliferation.78 Previously, CD34-positive cells were considered to be a fixed population of EPCs; further studies have shown that CD34 surface antigen actually recognizes undifferentiated bone marrow stem cells with the ability to differentiate into EPCs and SMPCs.Transdifferentiation of CD34-positive cells to the EPC or SMPC lineage depends on the local environment; ischemic conditions induce differentiation towards the EPC phenotype to promote re-endothelialization, while inflammatory conditions induce differentiation towards the SMPC phenotype to promote neointimal proliferation.79
Diabetes increases the risk of ISR by 30%–50% after BMS implantation,80 and the higher incidence of restenosis in diabetic patients compared with nondiabetic patients also persisted in the DES era.The mechanisms underlying this observation are likely multifactorial, involving systemic (eg, variability in inflammatory response) and anatomical (eg, smaller diameter vessels, longer lesions, diffuse disease, etc.) factors that increase independently Risk of ISR.70
Vessel diameter and lesion length independently affected the incidence of ISR, with smaller diameter/longer lesions significantly increasing restenosis rates compared with larger diameter/shorter lesions.71
The first-generation stent platforms showed thicker stent struts and higher ISR rates compared to second-generation stent platforms with thinner struts.
In addition, the incidence of restenosis was related to stent length, with stent lengths >35 mm almost twice as long as those <20 mm.The final stent minimum lumen diameter also played an important role: a smaller final minimum lumen diameter predicted a significantly increased risk of restenosis.81,82
Traditionally, intimal hyperplasia following BMS implantation is considered stable, with an early peak between 6 months and 1 year, followed by a late quiescent period.An early peak of intimal growth was previously reported, followed by intimal regression with lumen enlargement several years after stent implantation;71 smooth muscle cell maturation and alterations in the extracellular matrix have been suggested as possible mechanisms for late neointimal regression .83 However, studies with longer long-term follow-up have shown a triphasic response after BMS placement, with early restenosis, intermediate regression, and late lumen restenosis.84
In the DES era, late neointimal growth was initially demonstrated following SES or PES implantation in animal models.85 Several IVUS studies have shown an early attenuation of intimal growth followed by a late catch-up over time after SES or PES implantation, possibly due to an ongoing inflammatory process.86
Despite the “stability” traditionally attributed to ISR, about one third of BMS ISR patients develop ACS.4
There is increasing evidence that chronic inflammation and/or endothelial insufficiency induces advanced neoatherosclerosis within BMS and DES (mainly first-generation DES), which may be an important mechanism for advanced ISR or advanced ST.Inoue et al. 87 reported histological findings from autopsy samples following implantation of Palmaz-Schatz coronary stents, suggesting that peri-stent inflammation may accelerate new indolent atherosclerotic changes within the stent.Other studies10 have shown that restenotic tissue within the BMS, over 5 years, consists of newly emerging atherosclerosis, with or without peri-stent inflammation; samples from ACS cases show typical vulnerable plaques in native coronary arteries Histological morphology of the block with foamy macrophages and cholesterol crystals.In addition, when comparing BMS and DES, a significant difference in the time to development of new atherosclerosis was noted.11,12 The earliest atherosclerotic changes in foamy macrophage infiltration began 4 months after SES implantation, whereas the same changes in BMS lesions occurred 2 years later and remained a rare finding until 4 years.Furthermore, DES stenting for unstable lesions such as thin-cap fibroatherosclerosis (TCFA) or intimal rupture has a shorter time to development compared to BMS.Thus, neoatherosclerosis appears to be more common and occurs earlier in first-generation DES than in BMS, possibly due to a different pathogenesis.
The impact of second-generation DES or DES in development remains to be studied; although some existing observations of second-generation DESs88 suggest less inflammation, the incidence of neoatherosclerosis is similar to that of first-generation, but Further research is still needed.